HETEROCYLCOALKENYL DERIVATIVES USEFUL AS AGONISTS OF THE GPR120 AND / OR GPR40
20210024483 ยท 2021-01-28
Inventors
Cpc classification
C07D405/04
CHEMISTRY; METALLURGY
C07D333/06
CHEMISTRY; METALLURGY
C07D405/12
CHEMISTRY; METALLURGY
C07D307/28
CHEMISTRY; METALLURGY
International classification
Abstract
The present invention is directed to heterocycloalkenyl derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the GPR120 and/or GPR40 receptors. More particularly, the compounds of the present invention are agonists of GPR120 and/or GPR40, useful in the treatment of, for example, obesity, Type II Diabetes Mellitus, dyslipidemia, etc.
Claims
1. A compound of formula (I) ##STR00138## wherein a is an integer from 1 to 2; b is an integer from 1 to 2; Z is selected from the group consisting of O, S and SO.sub.2; provided that when a is 1 and b is 2, or when a is 2 and b is 1 or when a is 2 and b is 2, then Z is O; c is an integer from 0 to 2; each R.sup.0 is independently selected from the group consisting of halogen, oxo, hydroxy, cyano, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-4alkoxy and fluorinated C.sub.1-2alkoxy; R.sup.1 is selected from the group consisting of C.sub.1-6alkyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, (C.sub.1-2alkyl)-C.sub.3-6cycloalkyl, C.sub.5-6cycloalkenyl, bicyclo[3.1.0]hexy-2-yl, (1S,4S)-2-methyl-bicyclo[2.2.1]hept-2-yl, (1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl, 2,2-difluoro-benzo[d][1,3]dioxol-4-yl, phenyl, (C.sub.1-2alkyl)-phenyl, C(CH)-phenyl, C(O)-phenyl, tetrahydropyranyl, furanyl, pyrimidinyl, pyridyl, thienyl, thiazolyl, (C.sub.1-2alkyl)-thiazolyl, 3,6-dihydro-pyran-4-yl and 1-methyl-imidazol-4-yl; wherein the C.sub.3-6cycloalkyl or C.sub.5-6cycloalkenyl, whether alone or as part of a substituent group is optionally substituted with one or more (preferably one to two) substituents independently selected from the group consisting of halogen, C.sub.1-4alkyl and fluorinated C.sub.1-2alkyl; and wherein the phenyl, furanyl, pyrimidinyl, pyridyl, thienyl, thiazolyl, or 3,6-dihydro-pyran-4-yl, whether alone or as part of a substituent group is optionally substituted with one or more (preferably one to three) substituents independently selected from the group consisting of halogen, hydroxy, cyano, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy, S(C.sub.1-2alkyl), SO(C.sub.1-2alkyl), SO.sub.2(C.sub.1-2alkyl), nitro, NR.sup.AR.sup.B, NHC(O)(C.sub.1-4alkyl) and phenyl; wherein R.sup.A and R.sup.B are each independently selected from the group consisting of hydrogen and C.sub.1-4alkyl; R.sup.2 is selected from the group consisting of hydrogen, halogen, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, (C.sub.1-4alkyl)-S(C.sub.1-2alkyl), (C.sub.1-4alkyl)-SO(C.sub.1-2alkyl) and (C.sub.1-4alkyl)-SO.sub.2(C.sub.1-2alkyl); R.sup.3 is selected from the group consisting of hydrogen, halogen, C.sub.1-4alkyl and fluorinated C.sub.1-2alkyl; R.sup.4 is selected from the group consisting of hydrogen, halogen, C.sub.1-4alkyl and fluorinated C.sub.1-2alkyl; R.sup.5 is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, vinyl, halogen substituted vinyl, ethynyl, hydroxy substituted C.sub.1-2alkyl, C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy and cyclopropyl-methyl-; alternatively, R.sup.2 and R.sup.5 or R.sup.3 and R.sup.4 are taken together with the carbon atoms to which they are bound to form cyclopenten-1-yl; or a pharmaceutically acceptable salt thereof.
2. A compound as in claim 1, wherein a is an integer from 1 to 2; b is an integer from 1 to 2; Z is selected from the group consisting of O, S, SO and SO.sub.2; provided that when a is 1 and b is 2, or when a is 2 and b is 1 or when a is 2 and b is 2, then Z is O; c is an integer from 0 to 2; each R.sup.0 is independently selected from the group consisting of halogen, oxo, hydroxy, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-2alkoxy and fluorinated C.sub.1-2alkoxy; R.sup.1 is selected from the group consisting of C.sub.1-6alkyl, C.sub.3-6cycloalkyl, (C.sub.1-2alkyl)-C.sub.3-6cycloalkyl, C.sub.5-6cycloalkenyl, 2,2-difluoro-benzo[d][1,3]dioxol-4-yl, phenyl, (C.sub.1-2alkyl)-phenyl, C(CH)-phenyl, C(O)-phenyl, pyrimidinyl, pyridyl, thienyl, and 1-methyl-imidazol-4-yl; wherein the C.sub.3-6cycloalkyl or C.sub.5-6cycloalkenyl, whether alone or as part of a substituent group is optionally substituted with one to two substituents independently selected from the group consisting of halogen, C.sub.1-2alkyl and fluorinated C.sub.1-2alkyl; and wherein the phenyl, pyrimidinyl or pyridyl, whether alone or as part of a substituent group is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy, and phenyl; R.sup.2 is selected from the group consisting of hydrogen, halogen, C.sub.1-4alkyl and fluorinated C.sub.1-2alkyl; R.sup.3 is selected from the group consisting of hydrogen, halogen, C.sub.1-2alkyl and fluorinated C.sub.1-2alkyl; R.sup.4 is selected from the group consisting of hydrogen, halogen, C.sub.1-4alkyl and fluorinated C.sub.1-2alkyl; R.sup.5 is selected from the group consisting of hydrogen, halogen, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, hydroxy substituted C.sub.1-2alkyl, C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy and cyclopropyl-methyl-; alternatively, R.sup.2 and R.sup.5 or R.sup.3 and R.sup.4 are taken together with the carbon atoms to which they are bound to form cyclopenten-1-yl; or a pharmaceutically acceptable salt thereof.
3. A compound as in claim 2, wherein a is an integer from 1 to 2; b is an integer from 1 to 2; Z is selected from the group consisting of O, S, SO and SO.sub.2; provided that when a is 1 and b is 2, or when a is 2 and b is 1 or when a is 2 and b is 2, then Z is O; c is an integer from 0 to 2; each R.sup.0 is independently selected from the group consisting of C.sub.1-4alkyl; R.sup.1 is selected from the group consisting of C.sub.1-6alkyl, C(CH)-phenyl, C.sub.3-6cycloalkyl, C.sub.5-6cycloalkenyl, (C.sub.1-2alkyl)-C.sub.5-6cycloalkyl, phenyl, (C.sub.1-2alkyl)-phenyl, pyrid-3-yl, and 2,2-difluoro-benzo[d][1,3]dioxol-4-yl; wherein the C.sub.5-6cycloalkylenyl, is optionally substituted with one to two C.sub.1-2alkyl; wherein the phenyl, whether alone or as part of a substituent group, is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy and phenyl; R.sup.2 is selected from the group consisting of hydrogen, halogen and C.sub.1-4alkyl; R.sup.3 is selected from the group consisting of hydrogen and halogen; R.sup.4 is selected from the group consisting of hydrogen, C.sub.1-4alkyl and fluorinated C.sub.1-2alkyl; R.sup.5 is selected from the group consisting of hydrogen, halogen, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl and cyclopropyl-methyl-; or a pharmaceutically acceptable salt thereof.
4. A compound as in claim 3, wherein a is an integer from 1 to 2; b is an integer from 1 to 2; Z is selected from the group consisting of O, S, SO and SO.sub.2; provided that when a is 1 and b is 2, or when a is 2 and b is 1 or when a is 2 and b is 2, then Z is O; c is an integer from 0 to 2; each R.sup.0 is methyl; R.sup.1 is selected from the group consisting of ethyl, isopropyl, n-butyl, 1-methyl-n-propyl, isobutyl, isopentyl, n-hexyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopent-2-en-1-yl, 5,5-dimethyl-cyclopenten-1-yl, cyclohexyl-methyl-, phenyl, 2-fluorophenyl, 4-fluorophennyl, 4-chlorophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-isopropyloxyphenyl, 2-trifluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 2-fluoro-4-chloro-phenyl, 2-fluoro-4-methyl-phenyl, 3-fluoro-4-chloro-phenyl, 3-fluoro-4-methyl-phenyl, 2-methyl-4-chloro-phenyl, 3-methyl-4-fluoro-phenyl, 3-methyl-4-chloro-phenyl, 2-isopropyl-4-methyl-phenyl, 3-isopropyl-4-methyl-phenyl, 2-methoxy-4-chloro-phenyl, 3-methoxy-4-chloro-phenyl, 2,4-dimethyl-phenyl, 2,6-dimethyl-phenyl, 3,4-dimethyl-phenyl, 2,4,5-trimethyl-phenyl, 2-phenyl-4-methyl-phenyl, 3-phenyl-4-methyl-phenyl, benzyl, 4-chloro-benzyl, 4-methyl-benzyl, 4-methoxy-benzyl, 1-phenyl-ethyl-, 1-phenyl-vinyl-, 1-(4-fluorophenyl)-vinyl-, 1-(2-chloro-phenyl)-vinyl-, 1-(4-trifluoromethyl-phenyl)-vinyl-, pyrid-3-yl, and 2,2-difluoro-benzo[d][1,3]dioxol-4-yl; R.sup.2 is selected from the group consisting of hydrogen, fluoro and methyl; R.sup.3 is selected from the group consisting of hydrogen and fluoro; R.sup.4 is selected from the group consisting of hydrogen, methyl and trifluoromethyl; R.sup.5 is selected from the group consisting of hydrogen, fluoro, chloro, methyl, difluoromethyl, trifluoromethyl and cyclopropyl-methyl-; or a pharmaceutically acceptable salt thereof.
5. A compound as in claim 4, wherein a is 1; b is 1; Z is selected from the group consisting of O, S, SO and SO.sub.2; c is 0; R.sup.1 is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl and cyclopentyl; R.sup.2 is selected from the group consisting of hydrogen, fluoro and methyl; R.sup.3 is selected from the group consisting of hydrogen and fluoro; R.sup.4 is hydrogen; R.sup.5 is selected from the group consisting of hydrogen, fluoro, methyl and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
6. A compound as in claim 4, wherein a is 1; b is 2; Z is O; c is an integer from 0 to 2; each R.sup.0 is 6-methyl; R.sup.1 is selected from the group consisting of ethyl, isopropyl, n-butyl, 1-methyl-n-propyl, isobutyl, isopentyl, n-hexyl, 2-fluorophenyl, 4-fluorophennyl, 4-chlorophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-isopropyloxyphenyl, 2-trifluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,4-dichlforophenyl, 2-fluoro-4-chloro-phenyl, 2-fluoro-4-methyl-phenyl, 3-fluoro-4-chloro-phenyl, 3-fluoro-4-methyl-phenyl, 2-methyl-4-chloro-phenyl, 3-methyl-4-fluoro-phenyl, 3-methyl-4-chloro-phenyl, 2-methoxy-4-chloro-phenyl, 3-methoxy-4-chloro-phenyl, 2,6-dimethyl-phenyl, 3,4-dimethyl-phenyl, 2,4,5-trimethyl-phenyl, benzyl, 4-chloro-benzyl, 4-methyl-benzyl, 4-methoxy-benzyl, 1-phenyl-ethyl-, 1-phenyl-vinyl-, 1-(4-fluorophenyl)-vinyl-, 1-(2-chloro-phenyl)-vinyl-, 1-(4-trifluoromethyl-phenyl)-vinyl-, cyclobutyl, cyclopentyl, cyclohexyl, cyclopent-2-en-1-yl, 5,5-dimethyl-cyclopenten-1-yl, cyclohexyl-methyl-, pyrid-3-yl, and 2,2-difluoro-benzo[d][1,3]dioxol-4-yl; R.sup.2 is selected from the group consisting of hydrogen, fluoro and methyl; R.sup.3 is selected from the group consisting of hydrogen and fluoro; R.sup.4 is selected from the group consisting of hydrogen and trifluoromethyl; R.sup.5 is selected from the group consisting of hydrogen, chloro, methyl, difluoromethyl, and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
7. A compound as in claim 4, wherein a is 2; b is 1; Z is O; c is 0; R.sup.1 is selected from the group consisting of phenyl, 4-chlorophenyl, 4-methylphenyl, 2-fluoro-4-methyl-phenyl, 3-fluoro-4-methyl-phenyl, 2,4-dimethyl-phenyl, 2-isopropyl-4-methyl-phenyl, 3-isopropyl-4-methyl-phenyl, 2-phenyl-4-methyl-phenyl, 3-phenyl-4-methyl-phenyl, and cyclopentyl; R.sup.2 is selected from the group consisting of hydrogen, fluoro and methyl; R.sup.3 is selected from the group consisting of hydrogen and fluoro; R.sup.4 is hydrogen; R.sup.5 is selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and cyclopropyl-methyl-; or a pharmaceutically acceptable salt thereof.
8. A compound as in claim 4, wherein a is 2; b is 2; Z is O; c is 0; R.sup.1 is selected from the group consisting of 4-chlorophenyl, 4-methylphenyl, 3-fluoro-4-methyl-phenyl, and cyclopentyl; R.sup.2 is selected from the group consisting of hydrogen, fluoro and methyl; R.sup.3 is selected from the group consisting of hydrogen and fluoro; R.sup.4 is selected from the group consisting of hydrogen and methyl; R.sup.5 is selected from the group consisting of hydrogen, fluoro, chloro, methyl and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
9. A compound as in claim 4, wherein a is an integer from 1 to 2; b is an integer from 1 to 2; Z is O; c is 0; R.sup.1 is selected from the group consisting of ethyl, isopropyl, 1-methyl-n-propyl, n-butyl, isobutyl, isopentyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopent-2-en-1-yl, 4-trifluoromethoxy-phenyl, 3-fluoro-4-methyl-phenyl, benzyl, 4-chloro-benzyl, 4-methyl-benzyl, 4-methoxy-benzyl, 1-phenyl-vinyl, 1-(2-chloro-phenyl)-vinyl, 1-(4-fluoro-phenyl)-vinyl and 1-(4-trifluoromethyl-phenyl)-vinyl; R.sup.2 is hydrogen; R.sup.3 is hydrogen; R.sup.4 is hydrogen; R.sup.5 is selected from the group consisting of chloro and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
10. A compound as in claim 4, wherein a is an integer from 1 to 2; b is an integer from 1 to 2; Z is O; c is 0; R.sup.1 is selected from the group consisting of isopropyl, n-butyl, isobutyl, cyclopentyl, cyclopent-2-en-1-yl, 4-chloro-benzyl, 4-methyl-benzyl, 4-methoxy-benzyl, 1-phenyl-vinyl, 1-(2-chloro-phenyl)-vinyl, 1-(4-fluoro-phenyl)-vinyl and 1-(4-trifluoromethyl-phenyl)-vinyl; R.sup.2 is hydrogen; R.sup.3 is hydrogen; R.sup.4 is hydrogen; R.sup.5 is selected from the group consisting of chloro and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
11. A compound as in claim 4, wherein a is an integer from 1 to 2 and b is 2; alternatively a is 2 and b is an integer from 1 to 2; Z is O; c is 0; R.sup.1 is selected from the group consisting of isobutyl, cyclopentyl, cyclopent-2-en-1-yl, 4-chloro-benzyl, 1-phenyl-vinyl, 1-(2-chloro-phenyl)-vinyl, 1-(4-fluoro-phenyl)-vinyl and 1-(4-trifluoromethyl-phenyl)-vinyl; R.sup.2 is hydrogen; R.sup.3 is hydrogen; R.sup.4 is hydrogen; R.sup.5 is trifluoromethyl; or a pharmaceutically acceptable salt thereof.
12. A compound as in claim 4, wherein a is 1 and b is 2; alternatively a is 2 and b is 1; Z is O; c is 0; R.sup.1 is selected from the group consisting of cyclopentyl, 1-phenyl-vinyl, 1-(2-chloro-phenyl)-vinyl, 1-(4-fluoro-phenyl)-vinyl and 1-(4-trifluoromethyl-phenyl)-vinyl; R.sup.2 is hydrogen; R.sup.3 is hydrogen; R.sup.4 is hydrogen; R.sup.5 is trifluoromethyl; or a pharmaceutically acceptable salt thereof.
13. A compound as in claim 4, wherein a is an integer from 1 to 2; b is an integer from 1 to 2; Z is selected from the group consisting of O and S; provided that when a is 1 and b is 2, or when a is 2 and b is 1 or when a is 2 and b is 2, then Z is O; c is 0; R.sup.1 is selected from the group consisting of cyclobutyl, cyclopentyl, phenyl, 4-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 4-methylphenyl, 2,4-difluorophenyl, 2-fluoro-4-chloro-phenyl, 3,4-difluorophenyl, 3-fluoro-4-chloro-phenyl and 3-fluoro-4-methyl-phenyl; R.sup.2 is selected from the group consisting of hydrogen, fluoro and methyl; R.sup.3 is selected from the group consisting of hydrogen and fluoro; R.sup.4 is hydrogen; R.sup.5 is selected from the group consisting of hydrogen, fluoro, methyl and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
14. A compound as in claim 4, wherein a is an integer from 1 to 2; b is an integer from 1 to 2; Z is selected from the group consisting of O and S; provided that when a is 1 and b is 2, or when a is 2 and b is 1 or when a is 2 and b is 2, then Z is O; c is 0; R.sup.1 is selected from the group consisting of phenyl, 4-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 4-methylphenyl, 2,4-difluorophenyl, 2-fluoro-4-chloro-phenyl, 3,4-difluorophenyl, 3-fluoro-4-chloro-phenyl and 3-fluoro-4-methyl-phenyl; R.sup.2 is selected from the group consisting of fluoro and methyl; R.sup.3 is selected from the group consisting of hydrogen and fluoro; R.sup.4 is hydrogen; R.sup.5 is selected from the group consisting of hydrogen, fluoro and methyl; or a pharmaceutically acceptable salt thereof.
15. A compound as in claim 4, wherein a is 1 and b is 1; alternatively, a is 2 and b is 1; alternatively, a is 2 and b is 2; Z is O; c is 0; R.sup.1 is selected from the group consisting of 4-chlorophenyl, 4-methylphenyl and 3-fluoro-4-methyl-phenyl; R.sup.2 is methyl; R.sup.3 is hydrogen; R.sup.4 is hydrogen; R.sup.5 is methyl; or a pharmaceutically acceptable salt thereof.
16. A compound as in claim 4, selected from the group consisting of 3-[4-[[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid; 3-[4-[[5-(p-tolyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; 3-[4-[(5-cyclopentyl-2,3,6,7-tetrahydrooxepin-4-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; 3-[4-[[5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid; 3-[4-[[5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; 3-[4-[[5-(p-tolyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; 3-[4-[(5-phenyl-3,6-dihydro-2H-pyran-4-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; 3-[4-[(5-cyclopentyl-3,6-dihydro-2H-pyran-4-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; 3-[4-[[5-(3-fluoro-4-methyl-phenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid; 3-[4-[[4-(4-chlorophenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid; 3-[4-[[4-(4-chlorophenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; 3-[4-[(4-ethyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; 3-[2-chloro-4-[(4-cyclopentyl-3,6-dihydro-2H-pyran-5-yl)methoxy]phenyl]propanoic acid; 3-[4-[(4-cyclopentyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; and pharmaceutically acceptable salts thereof.
17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1.
18-19. (canceled)
20. A method of treating a disorder which (a) is modulated by the GPR120 receptor, (b) is modulated by the GPR40 receptor, or (c) responds to dual agonism of the GPR120 and GPR40 receptors comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1.
21. The method of claim 20, wherein the disorder is selected from the group consisting of obesity, obesity induced inflammation, impaired glucose tolerance, elevated fasting glucose, insulin resistance, hyperglycemia, hyperinsulinemia, Type II Diabetes Mellitus, metabolic syndrome (also known as Syndrome X), gestational diabetes, diabetic retinopathy, kidney disease, ketoacidosis, diabetic nephropathy, dyslipidemia, elevated LDL, hyperipidemia, hyperlipoproteinemia, hypertriglyceridemia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis and cardiovascular disorders.
22. The method of claim 20, wherein the disorder is selected from the group consisting of obesity, impaired glucose tolerance, elevated fasting glucose, insulin resistance, hyperglycemia, hyperinsulinemia, Type II Diabetes Mellitus, metabolic syndrome (also known as Syndrome X), diabetic retinopathy, diabetic nephropathy, dyslipidemia, elevated LDL, hyperipidemia, hypertriglyceridemia, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).
23. The method of claim 20, wherein the disorder is selected from the group consisting of obesity, Type II diabetes, metabolic syndrome (also known as Syndrome X), dyslipidemia. hypertriglyceridemia (i.e. elevated triglycerides), non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).
24. The method of claim 20, wherein the disorder is selected from the group consisting of obesity, Type II diabetes, metabolic syndrome (also known as Syndrome X), dyslipidemia and hypertriglyceridemia.
25. A method of treating a disorder selected from the group consisting of obesity, obesity induced inflammation, impaired glucose tolerance, elevated fasting glucose, insulin resistance, hyperglycemia, hyperinsulinemia, Type II Diabetes Mellitus, metabolic syndrome (also known as Syndrome X), gestational diabetes, diabetic retinopathy, kidney disease, ketoacidosis, diabetic nephropathy, dyslipidemia, elevated LDL, hyperipidemia, hyperlipoproteinemia, hypertriglyceridemia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis and cardiovascular disorders comprising administering to a subject in need thereof a therapeutically effective amount of a compounds as in claim 1.
26-39. (canceled)
Description
DETAILED DESCRIPTION OF THE INVENTION
[0051] The present invention is directed to compounds of formula (I)
##STR00002##
[0052] wherein a, b, Z, c, R.sup.0, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as herein defined. The compounds of the present invention are agonists of the GPR120 and/or GPR40 receptors, useful in the treatment of disorders and diseases which are modulated by said receptors, including for example, obesity, obesity induced inflammation, impaired glucose tolerance, elevated fasting glucose, insulin resistance, hyperglycemia, hyperinsulinemia, Type II Diabetes Mellitus, metabolic syndrome (also known as Syndrome X), gestational diabetes, diabetic retinopathy, kidney disease, ketoacidosis, diabetic nephropathy, dyslipidemia, elevated LDL, hyperipidemia, hyperipoproteinemia, hypertriglyceridemia (i.e. elevated triglycerides), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis and cardiovascular disorders (including but not limited to hypertension, atherosclerosis, thrombotic disorders, and cardiac fibrosis). Preferably, the disorder or disease is selected from the group consisting of obesity, impaired glucose tolerance, elevated fasting glucose, insulin resistance, hyperglycemia, hyperinsulinemia, Type II Diabetes Mellitus, metabolic syndrome (also known as Syndrome X), diabetic retinopathy, diabetic nephropathy, dyslipidemia, elevated LDL, hyperlipidemia, hypertriglyceridemia (i.e. elevated triglycerides), non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD). More preferably, the disorder or disease is selected from the group consisting of obesity, Type II diabetes, metabolic syndrome (also known as Syndrome X), dyslipidemia. hypertriglyceridemia (i.e. elevated triglycerides), non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD). More preferably, the disorder or disease is selected from the group consisting of obesity, Type II diabetes, metabolic syndrome (also known as Syndrome X), dyslipidemia and hypertriglyceridemia.
[0053] In an embodiment, the present invention is directed to compounds of formula (A)
##STR00003##
[0054] (compounds of formula (I) wherein a is 1 and b is 1 and wherein Z is selected from the group consisting of O, S and SO.sub.2), and pharmaceutically acceptable salts thereof.
[0055] In another embodiment, the present invention is directed to compounds of formula (B)
##STR00004##
[0056] (compounds of formula (I) wherein a is 1 and b is 2), and pharmaceutically acceptable salts thereof.
[0057] In another embodiment, the present invention is directed to compounds of formula (C)
##STR00005##
[0058] (compounds of formula (I) wherein a is 2 and b is 1), and pharmaceutically acceptable salts thereof.
[0059] In another embodiment, the present invention is directed to compounds of formula (D)
##STR00006##
[0060] (compounds of formula (I) wherein a is 2 and b is 2), and pharmaceutically acceptable salts thereof.
[0061] In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 1 and b is 1. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 2 and b is 1. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 1 and b is 2. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 2 and b is 2.
[0062] In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is an integer from 1 to 2; and b is an integer from 1 to 2. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is an integer from 1 to 2 and b is 2; or wherein a is 2 and b is an integer from 1 to 2. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 1 and b is 2; or wherein a is 2 and b is 1. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 1 and b is 1; or a is 2 and b is 1; or a is 2 and b is 2.
[0063] In certain embodiments, the present invention is directed to compounds of formula (I) wherein Z is selected from the group consisting of O, S, SO and SO.sub.2; provided that when a is 1 and b is 2, or when a is 2 and b is 1 or when a is 2 and b is 2, then Z is O. In certain embodiments, the present invention is directed to compounds of formula (I) wherein Z is selected from the group consisting of O and S. In certain embodiments, the present invention is directed to compounds of formula (I) wherein Z is O.
[0064] In certain embodiments, the present invention is directed to compounds of formula (I) wherein c is an integer from 0 to 2. In certain embodiments, the present invention is directed to compounds of formula (I) wherein c is an integer from 0 to 1. In certain embodiments, the present invention is directed to compounds of formula (I) wherein c is 0. In certain embodiments, the present invention is directed to compounds of formula (I) wherein c is 2. In certain embodiments, the present invention is directed to compounds of formula (I) wherein c is 2.
[0065] In certain embodiments, the present invention is directed to compounds of formula (I) wherein each R.sup.0 is independently selected from the group consisting of halogen, oxo, hydroxy, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-2alkoxy and fluorinated C.sub.1-2alkoxy. In certain embodiments, the present invention is directed to compounds of formula (I) wherein each R.sup.0 is independently selected from the group consisting of C.sub.1-4alkyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein each R.sup.0 is methyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein each R.sup.0 is 6-methyl.
[0066] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of C.sub.1-6alkyl, C.sub.3-6cycloalkyl, (C.sub.1-2alkyl)-C.sub.3-6cycloalkyl, C.sub.5-6cycloalkenyl, 2,2-difluoro-benzo[d][1,3]dioxol-4-yl, phenyl, (C.sub.1-2alkyl)-phenyl, C(CH)-phenyl, C(O)-phenyl, pyrimidinyl, pyridyl, thienyl, and 1-methyl-imidazol-4-yl; wherein the C.sub.3-6cycloalkyl or C.sub.5-6cycloalkenyl, whether alone or as part of a substituent group is optionally substituted with one to two substituents independently selected from the group consisting of halogen, C.sub.1-2alkyl and fluorinated C.sub.1-2alkyl; and wherein the phenyl, pyrimidinyl or pyridyl, whether alone or as part of a substituent group is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, C.sub.1-4 alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy, and phenyl;
[0067] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of C.sub.1-6alkyl, C(CH)-phenyl, C.sub.3-6cycloalkyl, C.sub.5-6cycloalkenyl, (C.sub.1-2alkyl)-C.sub.5-6cycloalkyl, phenyl, (C.sub.1-2alkyl)-phenyl, pyrid-3-yl, and 2,2-difluoro-benzo[d][1,3]dioxol-4-yl; wherein the C.sub.5-6cycloalkylenyl, is optionally substituted with one to two C.sub.1-2alkyl; wherein the phenyl, whether alone or as part of a substituent group, is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy and phenyl.
[0068] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of ethyl, isopropyl, n-butyl, 1-methyl-n-propyl, isobutyl, isopentyl, n-hexyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopent-2-en-1-yl, 5,5-dimethyl-cyclopenten-1-yl, cyclohexyl-methyl-, phenyl, 2-fluorophenyl, 4-fluorophennyl, 4-chlorophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-isopropyloxyphenyl, 2-trifluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 2-fluoro-4-chloro-phenyl, 2-fluoro-4-methyl-phenyl, 3-fluoro-4-chloro-phenyl, 3-fluoro-4-methyl-phenyl, 2-methyl-4-chloro-phenyl, 3-methyl-4-fluoro-phenyl, 3-methyl-4-chloro-phenyl, 2-isopropyl-4-methyl-phenyl, 3-isopropyl-4-methyl-phenyl, 2-methoxy-4-chloro-phenyl, 3-methoxy-4-chloro-phenyl, 2,4-dimethyl-phenyl, 2,6-dimethyl-phenyl, 3,4-dimethyl-phenyl, 2,4,5-trimethyl-phenyl, 2-phenyl-4-methyl-phenyl, 3-phenyl-4-methyl-phenyl, benzyl, 4-chloro-benzyl, 4-methyl-benzyl, 4-methoxy-benzyl, 1-phenyl-ethyl-, 1-phenyl-vinyl-, 1-(4-fluorophenyl)-vinyl-, 1-(2-chloro-phenyl)-vinyl-, 1-(4-trifluoromethyl-phenyl)-vinyl-, pyrid-3-yl, and 2,2-difluoro-benzo[d][1,3]dioxol-4-yl.
[0069] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl and cyclopentyl.
[0070] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of ethyl, isopropyl, n-butyl, 1-methyl-n-propyl, isobutyl, isopentyl, n-hexyl, 2-fluorophenyl, 4-fluorophennyl, 4-chlorophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-isopropyloxyphenyl, 2-trifluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,4-dichlforophenyl, 2-fluoro-4-chloro-phenyl, 2-fluoro-4-methyl-phenyl, 3-fluoro-4-chloro-phenyl, 3-fluoro-4-methyl-phenyl, 2-methyl-4-chloro-phenyl, 3-methyl-4-fluoro-phenyl, 3-methyl-4-chloro-phenyl, 2-methoxy-4-chloro-phenyl, 3-methoxy-4-chloro-phenyl, 2,6-dimethyl-phenyl, 3,4-dimethyl-phenyl, 2,4,5-trimethyl-phenyl, benzyl, 4-chloro-benzyl, 4-methyl-benzyl, 4-methoxy-benzyl, 1-phenyl-ethyl-, 1-phenyl-vinyl-, 1-(4-fluorophenyl)-vinyl-, 1-(2-chloro-phenyl)-vinyl-, 1-(4-trifluoromethyl-phenyl)-vinyl-, cyclobutyl, cyclopentyl, cyclohexyl, cyclopent-2-en-1-yl, 5,5-dimethyl-cyclopenten-1-yl, cyclohexyl-methyl-, pyrid-3-yl, and 2,2-difluoro-benzo[d][1,3]dioxol-4-yl.
[0071] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of phenyl, 4-chlorophenyl, 4-methylphenyl, 2-fluoro-4-methyl-phenyl, 3-fluoro-4-methyl-phenyl, 2,4-dimethyl-phenyl, 2-isopropyl-4-methyl-phenyl, 3-isopropyl-4-methyl-phenyl, 2-phenyl-4-methyl-phenyl, 3-phenyl-4-methyl-phenyl, and cyclopentyl.
[0072] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of 4-chlorophenyl, 4-methylphenyl, 3-fluoro-4-methyl-phenyl, and cyclopentyl.
[0073] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of ethyl, isopropyl, 1-methyl-n-propyl, n-butyl, isobutyl, isopentyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopent-2-en-1-yl, 4-trifluoromethoxy-phenyl, 3-fluoro-4-methyl-phenyl, benzyl, 4-chloro-benzyl, 4-methyl-benzyl, 4-methoxy-benzyl, 1-phenyl-vinyl, 1-(2-chloro-phenyl)-vinyl, 1-(4-fluoro-phenyl)-vinyl and 1-(4-trifluoromethyl-phenyl)-vinyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of isopropyl, n-butyl, isobutyl, cyclopentyl, cyclopent-2-en-1-yl, 4-chloro-benzyl, 4-methyl-benzyl, 4-methoxy-benzyl, 1-phenyl-vinyl, 1-(2-chloro-phenyl)-vinyl, 1-(4-fluoro-phenyl)-vinyl and 1-(4-trifluoromethyl-phenyl)-vinyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of isobutyl, cyclopentyl, cyclopent-2-en-1-yl, 4-chloro-benzyl, 1-phenyl-vinyl, 1-(2-chloro-phenyl)-vinyl, 1-(4-fluoro-phenyl)-vinyl and 1-(4-trifluoromethyl-phenyl)-vinyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of cyclopentyl, 1-phenyl-vinyl, 1-(2-chloro-phenyl)-vinyl, 1-(4-fluoro-phenyl)-vinyl and 1-(4-trifluoromethyl-phenyl)-vinyl.
[0074] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of cyclobutyl, cyclopentyl, phenyl, 4-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 4-methylphenyl, 2,4-difluorophenyl, 2-fluoro-4-chloro-phenyl, 3,4-difluorophenyl, 3-fluoro-4-chloro-phenyl and 3-fluoro-4-methyl-phenyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of phenyl, 4-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 4-methylphenyl, 2,4-difluorophenyl, 2-fluoro-4-chloro-phenyl, 3,4-difluorophenyl, 3-fluoro-4-chloro-phenyl and 3-fluoro-4-methyl-phenyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of 4-chlorophenyl, 4-methylphenyl and 3-fluoro-4-methyl-phenyl.
[0075] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.2 is selected from the group consisting of hydrogen, halogen, C.sub.1-4alkyl and fluorinated C.sub.1-2alkyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.2 is selected from the group consisting of hydrogen, halogen and C.sub.1-4alkyl.
[0076] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.2 is selected from the group consisting of hydrogen, fluoro and methyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.2 is selected from the group consisting of fluoro and methyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.2 is hydrogen. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.2 is methyl.
[0077] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.3 is selected from the group consisting of hydrogen, halogen, C.sub.1-2alkyl and fluorinated C.sub.1-2alkyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.3 is selected from the group consisting of hydrogen and halogen. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.3 is selected from the group consisting of hydrogen and fluoro. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.3 is hydrogen.
[0078] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.4 is selected from the group consisting of hydrogen, halogen, C.sub.1-4alkyl and fluorinated C.sub.1-2alkyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.4 is selected from the group consisting of hydrogen, C.sub.1-4alkyl and fluorinated C.sub.1-2alkyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.4 is selected from the group consisting of hydrogen, methyl and trifluoromethyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.4 is selected from the group consisting of hydrogen and trifluoromethyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.4 is selected from the group consisting of hydrogen and methyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.4 is hydrogen.
[0079] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.5 is selected from the group consisting of hydrogen, halogen, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, hydroxy substituted C.sub.1-2alkyl, C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy and cyclopropyl-methyl-. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.5 is selected from the group consisting of hydrogen, halogen, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl and cyclopropyl-methyl-.
[0080] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.5 is selected from the group consisting of hydrogen, fluoro, chloro, methyl, difluoromethyl, trifluoromethyl and cyclopropyl-methyl-. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.5 is selected from the group consisting of hydrogen, chloro, methyl, difluoromethyl, and trifluoromethyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.5 is selected from the group consisting of hydrogen, fluoro, methyl and trifluoromethyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.5 is selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and cyclopropyl-methyl-. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.5 is selected from the group consisting of hydrogen, fluoro, chloro, methyl and trifluoromethyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.5 is selected from the group consisting of hydrogen, fluoro and methyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.5 is selected from the group consisting of chloro and trifluoromethyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.5 is trifluoromethyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.5 is methyl.
[0081] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.2 and R.sup.5 or R.sup.3 and R.sup.4 are taken together with the carbon atoms to which they are bound to form cyclopenten-1-yl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.2 and R.sup.5 are taken together with the carbon atoms to which they are bound to form cyclopenten-1-yl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.3 and R.sup.4 are taken together with the carbon atoms to which they are bound to form cyclopenten-1-y.
[0082] In certain embodiments, the present invention is directed to any one or more compounds of formula (I) selected from the group consisting of [0083] 3-[4-[[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid; [0084] 3-[4-[[5-(p-tolyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; [0085] 3-[4-[(5-cyclopentyl-2,3,6,7-tetrahydrooxepin-4-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; [0086] 3-[4-[[5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid; [0087] 3-[4-[[5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; [0088] 3-[4-[[5-(p-tolyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; [0089] 3-[4-[(5-phenyl-3,6-dihydro-2H-pyran-4-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; [0090] 3-[4-[(5-cylopentyl-3,6-dihydro-2H-pyran-4-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; [0091] 3-[4-[[5-(3-fluoro-4-methyl-phenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid; [0092] 3-[4-[[4-(4-chlorophenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid; [0093] 3-[4-[[4-(4-chlorophenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; [0094] 3-[4-[(4-ethyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid; [0095] 3-[2-chloro-4-[(4-cylopentyl-3,6-dihydro-2H-pyran-5-yl)methoxy]phenyl]propanoic acid; [0096] 3-[4-[(4-cyclopentyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid;
[0097] and pharmaceutically acceptable salts thereof.
[0098] In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 2, b is 1 and at least one of R.sup.2, R.sup.3, R.sup.4 or R.sup.5 is other than hydrogen.
[0099] In certain embodiment, the present invention is directed to compounds of formula (I) wherein a is 2, b is 1 and wherein R.sup.1 is selected from the group consisting of C.sub.1-6alkyl, C.sub.2-6-alkynyl, C.sub.1-6cycloalkyl, (C.sub.1-2alkyl)-C.sub.3-6cycloalkyl, C.sub.5-6cycloalkenyl, 5,5-dimethyl-cyclopenten-1-yl, bicyclo[3.1.0]hexy-2-yl, (1S,4S)-2-methyl-bicyclo[2.2.1]hept-2-yl, (1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl, 2,2-difluoro-benzo[d][1,3]dioxol-4-yl, (C.sub.1-2alkyl)-phenyl, C(CH.sub.2)-phenyl, C(O)-phenyl, biphenyl, tetrahydropyranyl, furanyl, thiazolyl, (C.sub.1-2alkyl)-thiazolyl, 3,6-dihydro-pyran-4-yl and 1-methyl-imidazol-4-yl; wherein the C.sub.3-6cycloalkyl or C.sub.5-6cycloalkenyl, whether alone or as part of a substituent group is optionally substituted with one or more (preferably one to two) substituents independently selected from the group consisting of halogen, C.sub.1-4alkyl and fluorinated C.sub.1-2alkyl; and wherein the furanyl, thiazolyl, or 3,6-dihydro-pyran-4-yl, whether alone or as part of a substituent group is optionally substituted with one or more (preferably one to three) substituents independently selected from the group consisting of halogen, hydroxy, cyano, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy, S(C.sub.1-2alkyl), SO(C.sub.1-2alkyl), SO.sub.2(C.sub.1-2alkyl), nitro, NR.sup.AR.sup.B and NHC(O)(C.sub.1-4alkyl); wherein R.sup.A and R.sup.B are each independently selected from the group consisting of hydrogen and C.sub.1-4alkyl.
[0100] In certain embodiment, the present invention is directed to compounds of formula (I) wherein a is 2, b is 1 and wherein R.sup.1 is selected from the group consisting of C.sub.1-6alkyl, C.sub.2-6-alkynyl, C.sub.3-6cycloalkyl, (C.sub.1-2alkyl)-C.sub.3-6cycloalkyl, C.sub.5-6cycloalkenyl, 5,5-dimethyl-cyclopenten-1-yl, bicyclo[3.1.0]hexy-2-yl, (1S,4S)-2-methyl-bicyclo[2.2.1]hept-2-yl, (1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl, 2,2-difluoro-benzo[d][1,3]dioxol-4-yl, (C.sub.1-2alkyl)-phenyl, C(CH.sub.2)-phenyl, C(O)-phenyl and tetrahydropyranyl; wherein the C.sub.3-6cycloalkyl or C.sub.5-6cycloalkenyl, whether alone or as part of a substituent group is optionally substituted with one or more (preferably one to two) substituents independently selected from the group consisting of halogen, C.sub.1-4alkyl and fluorinated C.sub.1-2alkyl.
[0101] In certain embodiment, the present invention is directed to compounds of formula (I) wherein a is 2, b is 1 and wherein R.sup.1 is selected from the group consisting of C.sub.1-6alkyl, C.sub.2-6alkynyl, (C.sub.1-2alkyl)-C.sub.3-6cycloalkyl, C.sub.5-6cycloalkenyl, 5,5-dimethyl-cyclopenten-1-yl, bicyclo[3.1.0]hexy-2-yl, (1S,4S)-2-methyl-bicyclo[2.2.1]hept-2-yl, (1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl, 2,2-difluoro-benzo[d][1,3]dioxol-4-yl, (C.sub.1-2alkyl)-phenyl, C(CH.sub.2)-phenyl, C(O)-phenyl and tetrahydropyranyl; wherein the C.sub.3-6cycloalkyl or C.sub.5-6cycloalkenyl, whether alone or as part of a substituent group is optionally substituted with one or more (preferably one to two) substituents independently selected from the group consisting of halogen, C.sub.1-4alkyl and fluorinated C.sub.1-2alkyl.
[0102] In certain embodiment, the present invention is directed to compounds of formula (I) wherein a is 1 and b is 1; or a is 1 and b is 2; or a is 2 and b is 2; provided that when a is 1 and b is 2, or when a is 2 and b is 2, then Z is O.
[0103] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.1 is selected from the group consisting of C.sub.1-6alkyl and C.sub.2-6-alkynyl.
[0104] In certain embodiments, the present invention is directed to compounds of formula (I) wherein at least one of R.sup.2, R.sup.3, R.sup.4 or R.sup.5 is fluorinated C.sub.1-2alkyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.2 is fluorinated C.sub.1-2alkyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.3 is fluorinated C.sub.1-2alkyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.4 is fluorinated C.sub.1-2alkyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.5 is fluorinated C.sub.1-2alkyl.
[0105] In certain embodiments, the present invention is directed to compounds of formula (I) wherein at least one of R.sup.2 is selected from the group consisting of fluorinated C.sub.1-2alkyl, (C.sub.1-4alkyl)-S(C.sub.1-2alkyl), (C.sub.1-4alkyl)-SO(C.sub.1-2alkyl) and (C.sub.1-4alkyl)-SO.sub.2(C.sub.1-2alkyl). In certain embodiments, the present invention is directed to compounds of formula (I) wherein R.sup.5 is selected from the group consisting of fluorinated C.sub.1-2alkyl, vinyl, halogen substituted vinyl, ethynyl, hydroxy substituted C.sub.1-2alkyl, C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy and cyclopropyl-methyl-.
[0106] Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (i.e. a, b, Z, c, R.sup.0, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, etc.) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.
[0107] In another embodiment of the present invention is any single compound or subset of compounds selected from the representative compounds listed in Tables 1-4, below.
[0108] Representative compounds of the present invention are as listed in Tables 1-4, below. Unless otherwise noted, wherein a stereogenic center is present in the listed compound, the compound was prepared as a mixture of stereo-isomers.
TABLE-US-00001 TABLE 1 Representative Compounds of Formula (I)
TABLE-US-00002 TABLE 2 Representative Compounds of Formula (I)
TABLE-US-00003 TABLE 3 Representative Compounds of Formula (I)
TABLE-US-00004 TABLE 4 Representative Compounds of Formula (I)
[0109] In an embodiment, the present invention is directed to a compound of formula (I); wherein the compound of formula exhibits an EC.sub.50 against GPR120, measured as described in the Biological Examples, which follow herein, of less than about 1.0 NM, preferably less than about 0.500 M, more preferably less than about 0.250 M, more preferably less than about 0.100 M, more preferably less than about 0.050 M, more preferably less than about 0.025 M.
[0110] In an embodiment, the present invention is directed to a compound of formula (I); wherein the compound of formula exhibits an EC.sub.50 against GPR40, measured as described in the Biological Examples, which follows herein, of less than about 1.0 M, preferably less than about 0.500 M, more preferably less than about 0.250 M, more preferably less than about 0.100 M, more preferably less than about 0.050 M.
Definitions
[0111] As used herein, unless otherwise noted, the term halogen shall mean chlorine, bromine, fluorine and iodine.
[0112] As used herein, unless otherwise noted, the term oxo shall mean an oxygen atom bound through a double bond (i.e O).
[0113] As used herein, unless otherwise noted, the term alkyl whether used alone or as part of a substituent group, include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. The term C.sub.X-Yalkyl wherein X and Y are integers, whether used alone or as part of a substituent group, include straight and branched chains of between X and Y carbon atoms. For example, the term C.sub.1-4alkyl includes straight and branched chains of between 1 and 4 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
[0114] One skilled in the art will recognize that the term (C.sub.X-Yalkyl)- shall denote any C.sub.1-4alkyl carbon chain as herein defined, wherein said C.sub.X-Yalkyl chain is divalent and is further bound through two points of attachment, preferably through two terminal carbon atoms.
[0115] As used herein, unless otherwise noted, the term fluorinated C.sub.X-Yalkyl shall mean any C.sub.X-Yalkyl group as defined above substituted with at least one fluoro atom. For example, the term fluorinated C.sub.1-4alkyl shall mean any C.sub.1-4alkyl group as defined above substituted with at least one, preferably one to five, more preferably one to three fluoro atoms. Suitable examples of fluorinated C.sub.X-Yalkyl groups include, but are not limited to CF.sub.3, CH.sub.2CF.sub.3, CF.sub.2CF.sub.3, CF.sub.2CF.sub.2CF.sub.2CF.sub.3, and the like.
[0116] As used herein, unless otherwise noted, the term hydroxy substituted C.sub.X-Yalkyl shall mean a C.sub.X-Yalkyl group as defined above substituted with at least one hydroxy group. Preferably, the C.sub.X-Yalkyl group is substituted with one hydroxy group. Preferably, the C.sub.X-Yalkyl group is substituted with a hydroxy group at the terminal carbon. Suitable examples include, but are not limited to, CH.sub.2(OH), CH.sub.2CH.sub.2(OH), CH.sub.2CH(OH)CH.sub.2, and the like.
[0117] As used herein, unless otherwise noted, the term halogen substituted vinyl shall mean a vinyl (i.e CHCH.sub.2) group substituted with one or more, preferably one to two, more preferably one independently selected halogen atoms as defined above. Preferably, the halogen substituted vinyl is substituted with one fluoro, chloro, bromo or iodo group. More preferably the halogen substituted vinyl is a bromo substituted vinyl.
[0118] As used herein, unless otherwise noted, the term C.sub.X-Yalkynyl shall mean a straight or branched chain of between X and Y carbon atoms, wherein the straight or branched chain contains as least one, preferably one, unsaturated triple bond. For example, the term C.sub.2-6alkynyl includes straight and branched chains of between 2 and 6 carbon atoms containing at least one, preferably one, unsaturated triple bond such as ethynyl, n-propyn-1-yl, n-pentyn-1-yl, pentyn-2-yl, and the like.
[0119] As used herein, unless otherwise noted, alkoxy shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like. The term C.sub.X-Yalkoxy wherein X and Y are integers, whether used alone or as part of a substituent group, shall denote an oxygen ether radical of the above described straight or branched chain of between X and Y carbon atoms. For example, the term C.sub.1-4alkoxy includes oxygen ether radicals of straight and branched chains of between 1 and 4 carbon atoms, including methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.
[0120] As used herein, unless otherwise noted, the term fluorinated C.sub.X-Yalkoxy shall mean any C.sub.X-Yalkoxy group as defined above substituted with at least one fluoro atom. For example, the term fluorinated C.sub.1-4alkoxy shall mean any C.sub.1-4alkoxy group as defined above substituted with at least one, preferably one to five, more preferably one to three fluoro atoms. Suitable examples of fluorinated C.sub.X-Yalkoxy groups include, but are not limited to OCF.sub.3, OCH.sub.2CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.2CF.sub.2CF.sub.2CF.sub.3, and the like.
[0121] As used herein, unless otherwise noted, the term C.sub.3-6cycloalkyl shall mean any stable 3-8 membered monocyclic, saturated ring system, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Similarly, the term C.sub.5-6cycloalkyl shall mean any stable 5-6 membered monocyclic, saturated ring system, more particularly cyclopentyl and cyclohexyl.
[0122] As used herein, unless otherwise noted, the term C.sub.5-6cycloalkenyl shall mean any stable 5-6 membered monocyclic, partially unsaturated ring system, wherein the partially unsaturated ring system contains one to two, preferably one unsaturated double bond. Suitably examples include, but are not limited to cyclopentenyl and cyclohexenyl.
[0123] When a particular group is substituted (e.g., alkyl, cycloalkyl, phenyl, pyridyl, etc.), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.
[0124] With reference to substituents, the term independently means that when more than one of such substituents is possible, such substituents may be the same or different from each other.
[0125] As used herein, the notation * shall denote the presence of a stereogenic center.
[0126] Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Preferably, wherein the compound is present as an enantiomer, the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%. Similarly, wherein the compound is present as a diastereomer, the diastereomer is present at an diastereomeric excess of greater than or equal to about 80%, more preferably, at an diastereomeric excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%.
[0127] Furthermore, some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
[0128] As used herein, unless otherwise noted, the term isotopologues shall mean molecules that differ only in their isotopic composition. More particularly, an isotopologue of a molecule differs from the parent molecule in that it contains at least one atom which is an isotope (i.e. has a different number of neutrons from its parent atom).
[0129] For example, isotopologues of water include, but are not limited to, light water (HOH or H.sub.2O), semi-heavy water with the deuterium isotope in equal proportion to protium (HDO or .sup.1H.sup.2HO), heavy water with two deuterium isotopes of hydrogen per molecule (D.sub.2O or .sup.2H.sub.2O), super-heavy water or tritiated water (T.sub.2O or .sup.3H.sub.2O), where the hydrogen atoms are replaced with tritium (.sup.3H) isotopes, two heavy-oxygen water isotopologues (H.sub.2.sup.18O and H.sub.2.sup.17O) and isotopologues where the hydrogen and oxygen atoms may each independently be replaced by isotopes, for example the doubly labeled water isotopologue D.sub.2.sup.18O.
[0130] It is intended that within the scope of the present invention, any one or more element(s), in particular when mentioned in relation to a compound of formula (I), shall comprise all isotopes and isotopic mixtures of said element(s), either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope .sup.1H, .sup.2H (D), and .sup.3H (T). Similarly, references to carbon and oxygen include within their scope respectively .sup.12C, .sup.13C and .sup.14C and .sup.16O and .sup.18O. The isotopes may be radioactive or non-radioactive. Radiolabelled compounds of formula (I) may comprise one or more radioactive isotope(s) selected from the group of .sup.3H, .sup.11C, .sup.18F, .sup.122I, .sup.123I, .sup.125I, .sup.131I, .sup.75Br, .sup.76Br, .sup.77Br and .sup.82Br. Preferably, the radioactive isotope is selected from the group of .sup.3H, .sup.11C and .sup.18F.
[0131] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a phenylC.sub.1-C.sub.6alkylaminocarbonylC.sub.1-C.sub.6alkyl substituent refers to a group of the formula
##STR00011##
[0132] Throughout the specification, wherein the
##STR00012##
(heterocycloalkenyl) group is named or listed as a separate substituent groupas a substituent group named independent of the groups bound to the carbon atoms of the heterocycloalkenyl double bond, (e.g. in the listing of the heterocycloalkenyl group in the tables of compounds, embodiments, etc.)said heterocycloalkenyl group shall be named using standard IUPAC heterocycle nomenclature. For example, wherein the heterocycloalkenyl group is listed or named as 3,6-dihydro-2H-pyranyl, the ring carbon positions shall be numbered as indicated below:
##STR00013##
[0133] wherein the 1-position is defined as the position of the heteroatom and the numbering proceeds in a direction such that the carbon atom bound to the CH.sub.2O portion of the compound of formula (I) has priority in numbering over the carbon bound to the R.sup.1 group.
[0134] One skilled in the art will recognize that when the complete compound of formula (I) containing said heterocycloalkenyl group is named according to standard naming convention, the numbering (defined position of the heteroatom or any R.sup.0 group(s)) may be different from the numbering used in naming the heterocycloalkenyl group independently, as a result of the presence and chemical structure of the R.sup.1 substituent group, which may change the numbering priority.
[0135] Abbreviations used in the specification, particularly the Schemes and Examples, are as follows:
TABLE-US-00005 ADDP = 1,1-(Azodicarbonyl)dipiperidine aq. = Aqueous BF.sub.3 EtO.sub.2 = Boron Trifluoride Diethyl Etherate BSA = Bovine Serum Albumin Bu.sub.3P or n-Bu.sub.3P = Tri(n-butyl)phosphine DCM = Dichloromethane DEAD = Diethylazodicarboxylate DIAD = Diisopropylazodicarboxylate DIBAL or DIBAL-H = Diisobutylaluminum hydride DIO = Diet-induced obese/obesity DIPEA or DIEA = Diisopropylethylamine DME = Dimethoxyethane DMEM = Dulbecco's Modified Eagle Medium DMF = N,N-Dimethylformamide DMSO = Dimethylsulfoxide dppf = 1,1-Ferrocenediyl-bis(diphenylphosphine) EA = Ethyl Acetate ESI = Electrospray ionization EtOAc = Ethyl acetate FBS = Fetal Bovine Serum FLIPR = Fluorometric imaging Plate Reader HBSS = Hank's Balanced Salt Solution HDL = High Density Lipoproetin HEPES = 4-(2-Hydroxyethyl)-1-Piperizine Ethane Sulfonic Acid .sup.1H NMR = .sup.1Hydrogen Nuclear Magnetic Resonance HPLC = High Pressure Liquid Chromatography i.p. = Intra-peritoneal IPGTT = Intra-peritoneal Glucose Tolerance Test LAH = Lithium Aluminum Hydride LDL = Low Density Lipoprotein MeOH = Methanol Mesyl = Methylsulfonyl MS = Mass Spectroscopy MTBE = Methyl t-Butyl Ether NASH = Non-alcoholic Steatohepatitis NAFLD = Non-alcoholic Fatty Liver Disease OGTT = Oral Glucose Tolerance Test OTf = Triflate (i.e CF.sub.3SO.sub.3-) Pd.sub.2(OAc).sub.2 = Palladium(II)acetate Pd.sub.2(dba).sub.3 = Tris(dibenzylidene acetone)dipalladium(0) Pd(dppf)Cl.sub.2 = [1,1-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) Pd(PPh.sub.3).sub.4 = Tetrakistriphenylphosphine palladium (0) Pd(PPh.sub.3).sub.2Cl.sub.2 = Bis(triphenylphosphine)palladium (II) chloride PPh.sub.3 or TPP = Triphenyl Phosphine Rochelle's salt = Potassium sodium tartrate tetrahydrate RuPhos = 2-Dicyclohexylphosphino-2,6- diisopropoxybiphenyl sat. = saturated SPhos = 2-Dicyclohexylphosphino-2,6- dimethoxybiphenyl t-BOC or Boc = Tert-Butoxycarbonyl TEA = Triethylamine THP = Tetrahydropyranyl TFA = Trifluoroacetic Acid TfO.sub.2 = Triflic Anhydride THF = Tetrahydrofuran TLC = Thin Layer Chromatography TMS = Trismethylsilyl Tosyl = p-Toluenesulfonyl
[0136] As used herein, unless otherwise noted, the term isolated form shall mean that the compound is present in a form which is separate from any solid mixture with another compound(s), solvent system or biological environment. In an embodiment of the present invention, the compound of formula (I) is present in an isolated form.
[0137] As used herein, unless otherwise noted, the term substantially pure form shall mean that the mole percent of impurities in the isolated compound is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably, less than about 0.1 mole percent. In an embodiment of the present invention, the compound of formula (I) is present as a substantially pure form.
[0138] As used herein, unless otherwise noted, the term substantially free of a corresponding salt form(s) when used to described the compound of formula (I) shall mean that mole percent of the corresponding salt form(s) in the isolated base of formula (I) is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent. In an embodiment of the present invention, the compound of formula (I) is present in a form which is substantially free of corresponding salt form(s).
[0139] As used herein unless otherwise noted, the term cardiovascular disorders shall mean any cardiovascular disease, disorder or condition in which obesity and/or diabetes (preferably, Type II Diabetes Mellitus) has a role in the initiation or exacerbation of said disorder or condition. Suitable examples include, but are not limited to, hypertension, atherosclerosis, and cardiac fibrosis.
[0140] For purposes of the present invention, the term modulated by the GPR120 receptor is used to refer to the condition of being affected by the modulation of the GPR120 receptor, including but not limited to, the state of being mediated by activation or agonism of the GPR120 receptor.
[0141] For purposes of the present invention, the term modulated by the GPR40 receptor is used to refer to the condition of being affected by the modulation of the GPR40 receptor, including but not limited to, the state of being mediated by activation or agonism of the GPR40 receptor.
[0142] As used herein, unless otherwise noted, the term disorder modulated by the GPR120 receptor shall mean any disease, disorder or condition characterized in that at least one of its characteristic symptoms is alleviated or eliminated upon treatment with a GPR120 receptor agonist. Suitably examples include, but are not limited to obesity, obesity induced inflammation, impaired glucose tolerance, elevated fasting glucose, insulin resistance, hyperglycemia, hyperinsulinemia, Type II Diabetes Mellitus, metabolic syndrome (also known as Syndrome X), gestational diabetes, diabetic retinopathy, kidney disease, ketoacidosis, diabetic nephropathy, dyslipidemia, elevated LDL, hyperipidemia, hyperlipoproteinemia, hypertriglyceridemia (i.e. elevated triglycerides), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and liver fibrosis.
[0143] Preferably, the disorder modulated by the GPR120 receptor is selected from the group consisting of obesity, impaired glucose tolerance, elevated fasting glucose, insulin resistance, hyperglycemia, hyperinsulinemia, Type II Diabetes Mellitus, metabolic syndrome (also known as Syndrome X), diabetic retinopathy, diabetic nephropathy, dyslipidemia, elevated LDL, hyperipidemia, hypertriglyceridemia (i.e. elevated triglycerides), non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD). More preferably, the disorder modulated by the GPR120 receptor is selected from the group consisting of obesity, Type II diabetes, metabolic syndrome (also known as Syndrome X), dyslipidemia. hypertriglyceridemia (i.e. elevated triglycerides), non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD). More preferably, the disorder modulated by the GPR120 receptor is selected from the group consisting of obesity, Type II diabetes, metabolic syndrome (also known as Syndrome X), dyslipidemia and hypertriglyceridemia.
[0144] As used herein, unless otherwise noted, the term disorder modulated by the GPR40 receptor shall mean any disease, disorder or condition characterized in that at least one of its characteristic symptoms is alleviated or eliminated upon treatment with a GPR40 receptor agonist. Suitably examples include, but are not limited to obesity, obesity induced inflammation, impaired glucose tolerance, elevated fasting glucose, insulin resistance, hyperglycemia, hyperinsulinemia, Type II Diabetes Mellitus, metabolic syndrome (also known as Syndrome X), gestational diabetes, diabetic retinopathy, kidney disease, ketoacidosis, diabetic nephropathy, dyslipidemia, elevated LDL, hyperipidemia, hyperlipoproteinemia, hypertriglyceridemia (i.e. elevated triglycerides), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis and cardiovascular disorders (including but not limited to hypertension, atherosclerosis, thrombotic disorders, and cardiac fibrosis).
[0145] Preferably, the disorder modulated by the GPR40 receptor is selected from the group consisting of obesity, impaired glucose tolerance, elevated fasting glucose, insulin resistance, hyperglycemia, hyperinsulinemia, Type II Diabetes Mellitus, metabolic syndrome (also known as Syndrome X), diabetic retinopathy, diabetic nephropathy, dyslipidemia, elevated LDL, hyperipidemia, hypertriglyceridemia (i.e. elevated triglycerides), non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD). More preferably, the disorder modulated by the GPR40 receptor is selected from the group consisting of obesity, Type II diabetes, metabolic syndrome (also known as Syndrome X), dyslipidemia. hypertriglyceridemia (i.e. elevated triglycerides), non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD). More preferably, the disorder modulated by the GPR40 receptor is selected from the group consisting of obesity, Type II diabetes, metabolic syndrome (also known as Syndrome X), dyslipidemia and hypertriglyceridemia
[0146] For purposes of the present invention, the terms modulated by the GPR120 and GPR40 receptor, responds to dual agonism of the GPR120 and GPR40 receptors and responds to agonism of both the GPR120 and GPR40 receptors are used to refer to the condition of being affected by the modulation of both the GPR120 and the GPR40 receptor, including but not limited to, the state of being mediated by the activation or agonism of both the GPR120 and the GPR40 receptor.
[0147] As used herein, unless otherwise noted, the terms modulated by the GPR120 and GPR40 receptor, responds to dual agonism of the GPR120 and GPR40 receptors and responds to agonism of both the GPR120 and GPR40 receptors shall mean any disease, disorder or condition characterized in that at least one of its characteristic symptoms is alleviated or eliminated upon treatment with a dual GPR120 and GPR40 receptor agonist. Suitably examples include, but are not limited to obesity, obesity induced inflammation, impaired glucose tolerance, elevated fasting glucose, insulin resistance, hyperglycemia, hyperinsulinemia, Type II Diabetes Mellitus, metabolic syndrome (also known as Syndrome X), gestational diabetes, diabetic retinopathy, kidney disease, ketoacidosis, diabetic nephropathy, dyslipidemia, elevated LDL, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia (i.e. elevated triglycerides), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis and cardiovascular disorders (including but not limited to hypertension, atherosclerosis, thrombotic disorders, and cardiac fibrosis).
[0148] Preferably, the disorder modulated by dual agonism of the GPR120 and GPR40 receptors is selected from the group consisting of obesity, impaired glucose tolerance, elevated fasting glucose, insulin resistance, hyperglycemia, hyperinsulinemia, Type II Diabetes Mellitus, metabolic syndrome (also known as Syndrome X), diabetic retinopathy, diabetic nephropathy, dyslipidemia, elevated LDL, hyperlipidemia, hypertriglyceridemia (i.e. elevated triglycerides), non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD). More preferably, the disorder modulated by dual agonism of the GPR120 and GPR40 receptors is selected from the group consisting of obesity, Type II diabetes, metabolic syndrome (also known as Syndrome X), dyslipidemia. hypertriglyceridemia (i.e. elevated triglycerides), non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD). More preferably, the disorder modulated by dual agonism of the GPR120 and GPR40 receptors is selected from the group consisting of obesity, Type II diabetes, metabolic syndrome (also known as Syndrome X), dyslipidemia and hypertriglyceridemia
[0149] In certain embodiments of the present invention, the disorder modulated by a dual GPR120 and GPR40 agonist is selected from the group consisting of obesity, hyperglycemia, impaired glucose tolerance, elevated fasting glucose, insulin resistance, hyperinsulinemia, Type II Diabetes Mellitus, metabolic syndrome (also known as Syndrome X), dyslipidemia, hyperlipoproteinemia, hyperlipidemia, elevated LDL, hypertriglyceridemia (i.e. elevated triglycerides), kidney disease, ketoacidosis, diabetic neuropathy and diabetic retinopathy.
[0150] In certain embodiments of the present invention, the disorder modulated by a dual GPR120 and GPR40 agonist is selected from the group consisting of obesity, hyperglycemia, impaired glucose tolerance, elevated fasting glucose, insulin resistance, hyperinsulinemia, Type II Diabetes Mellitus, metabolic syndrome (also known as Syndrome X), kidney disease, ketoacidosis, diabetic neuropathy and diabetic retinopathy. Preferably, the disorder modulated by a dual GPR120 and GPR40 agonist is selected from the group consisting of hyperglycemia, impaired glucose tolerance, elevated fasting glucose, insulin resistance, hyperinsulinemia and Type II Diabetes Mellitus.
[0151] As used herein, unless otherwise noted, the terms treating, treatment and the like, shall include the management and care of a subject or patient (preferably mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviate the symptoms or complications (including, to reduce the frequency or severity of one or more symptoms), or eliminate the disease, condition, or disorder.
[0152] As used herein, unless otherwise noted, the term prevention shall include (a) the delay or avoidance of the development of additional symptoms; and/or (b) delay or avoidance of the development of the disorder or condition along a known development pathway.
[0153] One skilled in the art will recognize that wherein the present invention is directed to methods of prevention, a subject in need of thereof (i.e. a subject in need of prevention) shall include any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented. A subject in need thereof may additionally be a subject (preferably a mammal, more preferably a human) who has not exhibited any symptoms of the disorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical profession to be at risk of developing said disorder, disease or condition. For example, the subject may be deemed at risk of developing a disorder, disease or condition (and therefore in need of prevention or preventive treatment) as a consequence of the subject's medical history, including, but not limited to, family history, pre-disposition, co-existing (comorbid) disorders or conditions, genetic testing, and the like.
[0154] The term subject as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
[0155] The term therapeutically effective amount as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
[0156] As used herein, the term composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
[0157] As more extensively provided in this written description, terms such as reacting and reacted are used herein in reference to a chemical entity that is any one of: (a) the actually recited form of such chemical entity, and (b) any of the forms of such chemical entity in the medium in which the compound is being considered when named.
[0158] One skilled in the art will recognize that, where not otherwise specified, the reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product. One skilled in the art will further recognize that, in the specification and claims as presented herein, wherein a reagent or reagent class/type (e.g. base, solvent, etc.) is recited in more than one step of a process, the individual reagents are independently selected for each reaction step and may be the same of different from each other. For example wherein two steps of a process recite an organic or inorganic base as a reagent, the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step. Further, one skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
[0159] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term about. It is understood that whether the term about is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.
[0160] To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that wherein a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any amount or range therein.
[0161] Examples of suitable solvents, bases, reaction temperatures, and other reaction parameters and components are provided in the detailed descriptions which follow herein. One skilled in the art will recognize that the listing of said examples is not intended, and should not be construed, as limiting in any way the invention set forth in the claims which follow thereafter.
[0162] As used herein, unless otherwise noted, the term aprotic solvent shall mean any solvent that does not yield a proton. Suitable examples include, but are not limited to DMF, 1,4-dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, acetone, and the like.
[0163] As used herein, unless otherwise noted, the term leaving group shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.
[0164] During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
[0165] As used herein, unless otherwise noted, the term nitrogen protecting group shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction. Suitable nitrogen protecting groups include, but are not limited to carbamatesgroups of the formula C(O)OR wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH.sub.2CHCH.sub.2, and the like; amidesgroups of the formula C(O)R wherein R is for example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivativesgroups of the formula SO.sub.2R wherein R is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogen protecting groups may be found in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991.
[0166] As used herein, unless otherwise noted, the term oxygen protecting group shall mean a group which may be attached to a oxygen atom to protect said oxygen atom from participating in a reaction and which may be readily removed following the reaction. Suitable oxygen protecting groups include, but are not limited to, acetyl, benzoyl, t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like. Other suitable oxygen protecting groups may be found in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
[0167] One skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
[0168] Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as ()-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
[0169] Additionally, chiral HPLC against a standard may be used to determine percent enantiomeric excess (% ee). The enantiomeric excess may be calculated as follows
[(RmolesSmoles)/(Rmoles+Smoles)]100%
[0170] where Rmoles and Smoles are the R and S mole fractions in the mixture such that Rmoles+Smoles=1. The enantiomeric excess may alternatively be calculated from the specific rotations of the desired enantiomer and the prepared mixture as follows:
ee=([obs]/[max])100.
[0171] The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term administering shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
[0172] For use in medicine, the salts of the compounds of this invention refer to non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
[0173] Representative acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cycamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, -oxo-glutaric acid, glycolic acid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, ()-DL-lactic acid, lactobionic acid, maleic acid, ()-L-malic acid, malonic acid, (t)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinc acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid.
[0174] Representative bases which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
General Synthesis Schemes
[0175] Compounds of formula (I) wherein a is an integer from 1 to 2 and wherein b is an integer from 1 to 2 may be prepared according to the process outlined in Scheme 1.
##STR00014##
[0176] Accordingly, a suitably substituted compound of formula (V), wherein A.sup.1 is selected from the group consisting of C.sub.1-4alkyl, preferably methyl or ethyl, a known compound or compound prepared by known methods, is reacted with a suitably selected triflating agent such as triflic anhydride, nonaflate (i.e. SO.sub.2C.sub.4F.sub.9), and the like, a known compound; in the presence of a suitably selected base such as NaH, TEA, DIPEA and the like; in a suitably selected solvent (other than THF) such as diethyl ether, MTBE, di-t-butyl ether, DCM, and the like; to yield the corresponding compound of formula (VI), wherein LG.sup.1 is OTf. Alternatively, the compound of formula (V) is reacted with N-phenyl-bis(trifluoromethanesulfonimide), a known compound; in the presence of a suitably selected base such as NaH, DIPEA, TEA, and the like; in a suitably selected solvent (other than THF) such as DMF, MTBE, diethyl ether, di(t-butyl)ether, and the like; to yield the corresponding compound of formula (VI), wherein LG.sup.1 is OTf.
[0177] The compound of formula (VI) is reacted with a suitably substituted boronic acid, a compound of formula (VII), a known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as Pd(OAc).sub.2, Pd(PPh.sub.3).sub.4, Pd.sub.2(dba).sub.3.CH.sub.2Cl.sub.2, and the like; in the presence of a suitably selected ligand such as SPhos, PPh.sub.3, dppf, and the like; in the presence of a suitably selected base such as Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (IX).
[0178] Alternatively, the compound of formula (VI) is reacted with a suitably substituted zinc bromide, a compound of formula (VIII); in the presence of a suitably selected coupling catalyst such as Pd(PPh.sub.3).sub.4, Pd.sub.2(dba).sub.3, Pd(OAc).sub.2; in a suitably selected organic solvent such as THF, 1,4-dioxane, toluene, and the like; to yield the corresponding compound of formula (IX).
[0179] The compound of formula (IX), is reacted with a suitably selected reducing agent such as LAH, DIBAL-H, and the like; in a suitably selected solvent such as THF, DCM, toluene, and the like; to yield the corresponding compound of formula (X).
[0180] The compound of formula (X), is reacted with a suitably substituted phenol, a compound of formula (XI), wherein A.sup.2 is selected from the group consisting of C.sub.1-4alkyl, preferably methyl or ethyl, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as DEAD, ADDP, DIAD, and the like; in the presence of a suitably selected ligand such as triphenylphosphine (TPP), Bu.sub.3P, and the like; in a suitably selected solvent such as DCM, THF, and the like; to yield the corresponding compound of formula (XII).
[0181] The compound of formula (XII) is reacted with a suitably selected base such as KOH, NaOH, LiOH, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of THF:methanol:water, methanol, ethanol, and the like; to yield the corresponding compound of formula (I).
[0182] One skilled in the art will recognize that the compounds of formula (V) are known compounds or compounds prepared by known methods, for example as disclosed in KOLCHIN, et al., Zhumal Obshchei Khimii, 1956, pp 3731-3734, Vol. 32; and GIANTURCO, M. A., et al., Tetrahedron, 1964, pp 1763-1772, Vol. 20.
[0183] Compounds of formula (I), wherein a is 2 and b is 1 or wherein b is 2 and a is 1 (such as for example compounds of formula (I) comprising a 4-(R.sup.1 substituted)-3,4-dihydropyranyl substituent group) may alternatively be prepared as described in Scheme 2, below.
##STR00015##
[0184] Accordingly, a suitably substituted compound of formula (XIV), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (XI), wherein A.sup.2 is selected from the group consisting of C.sub.1-4alkyl, preferably methyl or ethyl, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as DEAD, ADDP, DIAD, and the like; in the presence of a suitably selected ligand such as triphenylphosphine, Bu.sub.3P, and the like; in a suitably selected solvent such as DCM, THF, and the like; to yield the corresponding compound of formula (XV).
[0185] The compound of formula (XV) is reacted with a suitably substituted compound of formula (VI), a known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as Pd(OAc).sub.2, Pd(PPh.sub.3).sub.4, Pd.sub.2(dba).sub.3.CH.sub.2Cl.sub.2, and the like; in the presence of a suitably selected ligand such as SPhos, PPh.sub.3, dppf, and the like; in the presence of a suitably selected base such as Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (XVI).
[0186] Alternatively, the compound of formula (XV) is reacted with a suitably substituted zinc bromide, a compound of formula (VIII); in the presence of a suitably selected coupling catalyst such as Pd(PPh.sub.3).sub.4, Pd.sub.2(dba).sub.3, Pd(OAc).sub.2; in a suitably selected organic solvent such as THF, 1,4-dioxane, toluene, and the like; to yield the corresponding compound of formula (XVI).
[0187] The compound of formula (XVI) is reacted with a suitably selected base such as KOH, NaOH, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of THF:methanol:water, methanol, ethanol, and the like; to yield the corresponding compound of formula (I).
[0188] Alternatively, the compound of formula (XIV) is reacted with a suitably substituted compound of formula (VII), a known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as Pd(OAc).sub.2, Pd(PPh.sub.3).sub.4, Pd.sub.2(dba).sub.3.CH.sub.2Cl.sub.2, and the like; in the presence of a suitably selected ligand such as SPhos, PPh.sub.3, dppf, and the like; in the presence of a suitably selected base such as Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (XVII).
[0189] Alternatively, the compound of formula (XIV) is reacted with a suitably substituted zinc bromide, a compound of formula (VIII); in the presence of a suitably selected coupling catalyst such as Pd(PPh.sub.3).sub.4, Pd.sub.2(dba).sub.3, Pd(OAc).sub.2; in a suitably selected organic solvent such as THF, 1,4-dioxane, toluene, and the like; to yield the corresponding compound of formula (XVII).
[0190] The compound of formula (XVII) is reacted with a suitably substituted compound of formula (XI) wherein A.sup.2 is selected from the group consisting of C.sub.1-4alkyl, preferably methyl or ethyl, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as DEAD, ADDP, DIAD, and the like; in the presence of a suitably selected ligand such as triphenyl phosphine, Bu.sub.3P, and the like; in a suitably selected solvent such as DCM, THF, and the like; to yield the corresponding compound of formula (XVI).
[0191] The compound of formula (XVI) is reacted with a suitably selected base such as KOH, NaOH, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of THF:methanol:water, methanol, ethanol, and the like; to yield the corresponding compound of formula (I).
[0192] Compounds of formula (XIV), wherein a is 2 and b is 1 or wherein a is 1 and b is 2 may be prepared as described in Scheme 3, below.
##STR00016##
[0193] Accordingly, a suitably substituted compound of formula (XVII), a known compound or compound prepared by known methods, is reacted with a suitably selected brominating agent such as PBr.sub.3, and the like; in the presence of DMF, neat (using DMF as the solvent); to yield the corresponding compound of formula (XVIII).
[0194] The compound of formula (XVIII) is reacted with a suitably selected reducing agent such as NaBH.sub.4, in a solvent such as methanol, ethanol, and the like or DIBAL in a solvent such as DCM, toluene, THF, and the like; to yield the corresponding compound of formula (XIV).
[0195] Compounds of formula (I) wherein a is 1 and b is 2 (i.e. compounds of formula (I) comprising a 5-(R substituted)-3,4-dihydropyranyl substituent group) and wherein c is 0, may alternatively be prepared as described in Scheme 4, below.
##STR00017##
[0196] Accordingly, the compound of formula (XXIII), a known compound, is reacted with a suitably selected triflating agent such as triflic anhydride, bis(trifluoromethanesulfonimide), and the like, a known compound; in the presence of a suitably selected base such as NaH, DIPEA, TEA, and the like; in a suitably selected solvent such as THF, DCM, and the like; to yield the corresponding compound of formula (XXIV), wherein LG.sup.2 is OTf.
[0197] The compound of formula (XXIV) is reacted with a suitably substituted compound of formula (VI), a known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as Pd(dppf)Cl.sub.2, Pd(OAc).sub.2, Pd(PPh.sub.3).sub.4, Pd.sub.2(dba).sub.3.CH.sub.2Cl.sub.2, and the like; in the presence of a suitably selected ligand such as SPhos, PPh.sub.3, dppf, and the like; in the presence of a suitably selected base such as Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, K.sub.3PO.sub.4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (XXV).
[0198] The compound of formula (XXV) is reacted with a suitably selected reducing agent such as DIBAL, LiAlH.sub.4, and the like; in a suitably selected organic solvent such as DCM, toluene, THF, and the like; at a reduced temperature of about 78 C.; to yield the corresponding compound of formula (Xa).
[0199] The compound of formula (Xa) is then substituted for the compound of formula (X), in Scheme 1, and reacted as described in Scheme 1 to yield the desired, corresponding compound of formula (Ia).
[0200] One skilled in the art will recognize that additional compounds of formula (I) wherein the
##STR00018##
portion of the compound of formula (I) is other then
##STR00019##
may be similarly prepared as described in Scheme 4 above, by selecting and substituting a suitably substituted compound of formula (XXI)
##STR00020##
[0201] for the compound of formula (XXIII) and reacting as described in detail in Scheme 4.
[0202] One skilled in the art will recognize that compounds of formula (I) wherein X is SO.sub.2 may be prepared by reacting the corresponding compound of formula (I) wherein X is S with for example, oxone, in a suitably selected solvent or mixture of solvent such as a mixture of ethyl acetate and water.
Pharmaceutical Compositions
[0203] The present invention further comprises pharmaceutical compositions containing one or more compounds of formula (I) with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
[0204] To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.01 mg to about 1000 mg or any amount or range therein, and may be given at a dosage of from about 0.01 mg/kg/day to about 300 mg/kg/day, or any amount or range therein, preferably from about 0.1 mg/kg/day to about 100 mg/kg/day, or any amount or range therein, preferably from about 0.5 mg/kg/day to about 50 mg/kg/day, preferably from about 1.0 mg/kg/day to about 25 mg/kg/day, or any amount or range therein. The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
[0205] Preferably these compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.01 mg to about 1,000 mg, or any amount or range therein, of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
[0206] The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
[0207] The method(s) of treating disorders as described herein may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.01 mg and about 1000 mg of the compound, or any amount or range therein; preferably from about 1.0 mg to about 500 mg of the compound, or any amount or range therein, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
[0208] Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
[0209] For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
[0210] The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methylcellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
[0211] To prepare a pharmaceutical composition of the present invention, a compound of formula (I) as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
[0212] Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets. Second Edition. Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.
[0213] Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders, as described herein, is required.
[0214] The daily dosage of the products may be varied over a wide range from about 0.01 mg to about 1,000 mg per adult human per day, or any amount or range therein. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 300 mg/kg of body weight per day, or any amount or range therein. Preferably, the range is from about 0.1 to about 100.0 mg/kg of body weight per day, or any amount or range therein. More preferably, from about 0.5 to about 50.0 mg/kg of body weight per day, or any amount or range therein. More preferably, from about 1.0 to about 25.0 mg/kg of body weight per day, or any amount or range therein. The compounds may be administered on a regimen of 1 to 4 times per day.
[0215] Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
[0216] One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and/or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.
[0217] One skilled in the art will further recognize that human clinical trials including first-in-human, dose ranging and efficacy trials, in healthy patients and/or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts.
SYNTHESIS EXAMPLES
[0218] The Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.
[0219] In the Examples which follow, some synthesis products are listed as having been isolated as a residue. It will be understood by one of ordinary skill in the art that the term residue does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.
Example 1
3-[4-[[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0220] ##STR00021##
Step 1. Ethyl 5-oxooxepane-4-carboxylate
[0221] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of oxan-4-one (500 mg, 4.99 mmol, 1.00 equiv) in dichloromethane (30 mL), ethyl diazoethanoate (1.00 mL, 1.50 equiv). This was followed by the addition of BF.sub.3.Et.sub.2O (625 mg, 4.40 mmol, 0.88 equiv) dropwise with stirring at 78 C. The resulting solution was stirred for 30 min at 78 C. in a dry ice bath. The reaction was then quenched by the addition of aqueous sodium carbonate (50 mL). The resulting solution was extracted with DCM (350 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15) to yield ethyl 5-oxooxepane-4-carboxylate as light yellow oil.
Step 2. Ethyl 5-[(trifluoromethane)sulfonyloxy]-2,3,6,7-tetrahydrooxepine-4-carboxylate
[0222] Into a 100-mL round-bottom flask, was placed a solution of ethyl 5-oxooxepane-4-carboxylate (700 mg, 3.76 mmol, 1.00 equiv) in diethyl ether (30 mL). Sodium hydride (181 mg, 7.54 mmol, 2.01 equiv) was added at 0 C. The resulting solution was stirred for 2 h at 20 C. This was followed by the addition of Tf.sub.2O (1.60 g, 5.67 mmol, 1.51 equiv) at 0 C. The resulting solution was stirred for 2 h at 20 C. The reaction was then quenched by the addition of ice water (50 mL). The resulting solution was extracted with ethyl acetate (350 mL) and the organic layers combined. The resulting mixture was washed with aqueous sodium chloride (350 mL) and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum to yield ethyl 5-[(trifluoromethane)sulfonyloxy]-2,3,6,7-tetrahydrooxepine-4-carboxylate as a yellow oil.
Step 3. Ethyl 5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepine-4-carboxylate
[0223] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl 5-[(trifluoromethane)sulfonyloxy]-2,3,6,7-tetrahydrooxepine-4-carboxylate (500 mg, 1.57 mmol, 1.00 equiv) in 1,4-dioxane (30 mL), (4-chlorophenyl)boronic acid (245 mg, 1.57 mmol, 1.00 equiv), Pd(PPh.sub.3).sub.4 (91 mg, 0.080 mmol, 0.05 equiv), K.sub.3PO.sub.4 (667 mg, 3.14 mmol, 2.00 equiv). The resulting solution was stirred for 16 h at 80 C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to yield ethyl 5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepine-4-carboxylate as yellow oil.
Step 4. [5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methanol
[0224] Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added a solution of ethyl 5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepine-4-carboxylate (300 mg, 1.07 mmol, 1.00 equiv) in dichloromethane (20 mL). This was followed by the addition of DIBAL (2.1 mL) dropwise with stirring at 78 C. The resulting solution was stirred for 2 h at 78 C. in a dry ice bath. The reaction was then quenched by the addition of aqueous NH.sub.4Cl (30 mL). The resulting solution was extracted with DCM (3100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to yield [5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methanol as light yellow oil.
Step 5. Ethyl 3-(4-[[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2,3-dimethylphenyl) propanoate
[0225] Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added a solution of [5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methanol (100 mg, 0.42 mmol, 1.00 equiv) in dichloromethane (20 mL), ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate (93 mg, 0.42 mmol, 1.00 equiv), PPh.sub.3 (220 mg, 0.840 mmol, 2.00 equiv). The resulting solution was stirred for 10 min at 0 C. DIAD (170 mg, 0.84 mmol, 2.01 equiv) was then added. The resulting solution was stirred for 16 h at 25 C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield ethyl 3-(4-[[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2,3-dimethylphenyl)propanoate as light yellow oil.
Step 6. 3-(4-[[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2,3-dimethylphenyl)propanoic acid
[0226] Into a 50-mL round-bottom flask, was added a solution of ethyl 3-(4-[[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2,3-dimethylphenyl)propanoate (120 mg, 0.27 mmol, 1.0 equiv) in tetrahydrofuran (10 mL), LiOH (120 mg, 5.01 mmol, 18.5 equiv), water (5 mL). The resulting solution was stirred for 16 h at 25 C. The pH value of the solution was adjusted to 2 with hydrogen chloride (2N). The resulting solution was extracted with ethyl acetate (350 mL) and the organic layers combined. The resulting mixture was washed with aqueous sodium chloride (350 mL). The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was washed by CH.sub.3CN and dried by vacuum to yield 3-(4-[[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2,3-dimethylphenyl)propanoic acid as a white solid.
[0227] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.27 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 1H), 6.38 (d, J=8.4 Hz, 1H), 4.26 (s, 2H), 3.76-3.80 (m, 4H), 2.88-2.93 (m, 2H), 2.66-2.75 (m, 4H), 2.53-2.59 (m, 2H), 2.21 (s, 3H), 2.16 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.27ClO.sub.4, 413.2 [MH], Measured 413.1.
[0228] The following compound was similarly prepared according to the procedure as described in Example 1 above, selecting and substituting suitably substituted reactants, as would be readily recognized by those skilled in the art.
Example 2
3-[4-[[5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0229] ##STR00022##
[0230] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.28-7.39 (m, 3H), 7.13-7.17 (m, 2H), 6.97 (s, 1H), 6.86-6.91 (m, 1H), 4.41 (s, 2H), 3.76 (t, J=4.8 Hz, 2H), 3.69 (t, J=4.8 Hz, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.74 (t, J=4.8 Hz, 2H), 2.65 (t, J=4.8 Hz, 2H), 2.58 (t, J=7.2 Hz, 2H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 61.26. Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.22ClF.sub.3O.sub.4, 453.1 [MH], Measured 453.1.
Example 3
3-[4-[[5-(p-tolyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0231] ##STR00023##
Step 1. Ethyl 5-(4-methylphenyl)-2,3,6,7-tetrahydrooxepine-4-carboxylate
[0232] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added a solution of ethyl 5-[(trifluoromethane)sulfonyloxy]-2,3,6,7-tetrahydrooxepine-4-carboxylate (500 mg, 1.570 mmol, 1.00 equiv) in 1,4-dioxane (30 ml), (4-methylphenyl)boronic acid (257 mg, 1.890 mmol, 1.20 equiv), Pd(PPh.sub.3).sub.4 (91 mg, 0.080 mmol, 0.05 equiv), and K.sub.3PO.sub.4 (667 mg, 3.140 mmol, 2.00 equiv). The resulting solution was stirred for 16 h at 90 C. in an oil bath. The resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to yield ethyl 5-(4-methylphenyl)-2,3,6,7-tetrahydrooxepine-4-carboxylate as colorless oil.
Step 2. [5-(4-methylphenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methanol
[0233] Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of ethyl 5-(4-methylphenyl)-2,3,6,7-tetrahydrooxepine-4-carboxylate (320 mg, 1.230 mmol, 1.00 equiv) in dichloromethane (15 mL). The resulting solution was stirred at 78 C. and DIBAL (2.5 mL) was then added dropwise at this temperature. The mixture was warmed to 20 C. gradually and stirred for 2 h. The resulting mixture was quenched by methanol and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) to yield [5-(4-methylphenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methanol as colorless oil.
Step 3. Ethyl 3-(4-[[5-(4-methylphenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2-(trifluoromethyl) phenyl) propanoate
[0234] Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of [5-(4-methylphenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methanol (80 mg, 0.370 mmol, 1.00 equiv) in dichloromethane (10 mL), ethyl 3-[4-hydroxy-2-(trifluoromethyl)phenyl]propanoate (98 mg, 0.370 mmol, 1.02 equiv), and PPh.sub.3 (192 mg, 0.730 mmol, 2.00 equiv). The mixture was cooled to 0 C. and stirred for 10 min. DIAD (146 mg, 0.720 mmol, 1.97 equiv) was then added dropwise. The resulting solution was stirred for 16 h at 20 C. The resulting mixture was quenched with aqueous NH.sub.4Cl (20 mL). The resulting solution was extracted with ethyl acetate (350 mL) and the organic layers combined. The resulting mixture was washed with aqueous sodium chloride (350 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6) to yield ethyl 3-(4-[[5-(4-methylphenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2-(trifluoromethyl)phenyl)propanoate as colorless oil.
Step 4. 3-(4-[[5-(4-methylphenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2-(trifluoromethyl)phenyl) propanoic acid
[0235] Into a 50-mL round-bottom flask was added a solution of ethyl 3-(4-[[5-(4-methylphenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2-(trifluoromethyl)phenyl)propanoate (80 mg, 0.170 mmol, 1.00 equiv) in tetrahydrofuran/H.sub.2O (5 ml, 3:2), and lithium hydroxide (80 mg, 3.340 mmol, 19.31 equiv). The resulting solution was stirred for 16 h at 20 C. The pH value of the solution was adjusted to 3 with hydrogen chloride (2N). The resulting solution was extracted with ethyl acetate (350 mL) and the organic layers combined. The resulting mixture was washed with aqueous sodium chloride (350 mL) and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum and the residue was purified by reversed-phase HPLC on a SunFire C18 column (19 mm150 mm, 5 M) with a linear gradient of 50-90% acetonitrile in water (0.05% TFA) in 10 mins to yield 3-(4-[[5-(4-methylphenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2-(trifluoromethyl)phenyl)propanoic acid as an off-white solid.
[0236] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.30 (d, J=8.4 Hz, 1H), 7.16 (d, J=8.1 Hz, 2H), 7.04 (d, J=8.1 Hz, 2H), 6.92 (s, 1H), 6.83-6.87 (m, 1H), 4.42 (s, 2H), 3.75 (t, J=4.8 Hz, 2H), 3.67 (t, J=4.8 Hz, 2H), 2.98 (t, J=7.5 Hz, 2H), 2.74 (t, J=4.8 Hz, 2H), 2.64 (t, J=4.8 Hz, 2H), 2.41 (t, J=7.8 Hz, 2H), 2.33 (s, 3H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 61.17. Mass spectrum (ESI, m/z): Calculated. for C.sub.24H.sub.25F.sub.3O.sub.4, 433.2 [MH], Measured 433.1.
[0237] The following compounds were similarly prepared according to the procedure as described in Example 3 above, selecting and substituting suitably substituted reactants, as would be readily recognized by those skilled in the art.
Example 4
3-[4-[(5-cyclopentyl-2,3,6,7-tetrahydrooxepin-4-yl)methoxy]phenyl]propanoic acid
[0238] ##STR00024##
[0239] .sup.1H NMR (CHLOROFORM-d) : 7.12 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.51 (s, 2H), 3.61 (td, J=4.7, 1.3 Hz, 4H), 2.97-3.10 (m, 1H), 2.85-2.95 (m, 2H), 2.61-2.69 (m, 2H), 2.48-2.54 (m, 2H), 2.29-2.40 (m, 2H), 1.55-1.72 (m, 6H), 1.27-1.39 (m, 2H). Mass spectrum (ESI, m/z): Calculated. for C.sub.21H.sub.28O.sub.4, 367.1, [M+Na], Measured 367.3.
Example 5
3-[4-[(5-cyclopentyl-2,3,6,7-tetrahydrooxepin-4-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0240] ##STR00025##
[0241] .sup.1H NMR (CHLOROFORM-d) : 7.23-7.29 (m, 1H), 7.17 (d, J=2.5 Hz, 1H), 7.01 (dd, J=8.6, 2.5 Hz, 1H), 4.55 (s, 2H), 3.57-3.67 (m, 4H), 2.94-3.14 (m, 3H), 2.60-2.70 (m, 2H), 2.46-2.54 (m, 2H), 2.30-2.40 (m, 2H), 1.55-1.71 (m, 6H), 1.28-1.41 (m, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.27F.sub.3O.sub.4, 435.1, [M+Na], Measured 435.3.
Example 6
3-[4-[[5-(3-fluoro-4-methyl-phenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]phenyl]propanoic acid
[0242] ##STR00026##
[0243] .sup.1H NMR (CHLOROFORM-d) : 7.08-7.17 (m, 1H), 7.06 (d, J=8.6 Hz, 2H), 6.75-6.84 (m, 2H), 6.63-6.73 (m, 2H), 4.32 (s, 2H), 3.68-3.82 (m, 4H), 2.82-2.94 (m, 2H), 2.70-2.77 (m, 2H), 2.55-2.69 (m, 4H), 2.25 (d, J=1.5 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.25FO.sub.4, 407.1, [M+Na], Measured 407.3.
Example 7
3-[2-chloro-4-[(5-cyclopentyl-2,3,6,7-tetrahydrooxepin-4-yl)methoxy]phenyl]propanoic acid
[0244] ##STR00027##
[0245] .sup.1H NMR (CHLOROFORM-d) : 7.15 (d, J=8.6 Hz, 1H), 6.93 (d, J=2.5 Hz, 1H), 6.76 (dd, J=8.1, 2.5 Hz, 1H), 4.51 (s, 2H), 3.52-3.66 (m, 4H), 3.00 (br t, J=7.8 Hz, 3H), 2.66 (t, J=7.8 Hz, 2H), 2.44-2.53 (m, 2H), 2.31-2.39 (m, 2H), 1.50-1.76 (m, 6H), 1.21-1.40 (m, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.21H.sub.27ClO.sub.4, 401.1, [M+Na], Measured 401.3.
Example 8
3-[3,5-difluoro-4-[[5-(3-fluoro-4-methyl-phenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]phenyl]propanoic acid
[0246] ##STR00028##
[0247] .sup.1H NMR (CHLOROFORM-d) : 7.09 (t, J=7.8 Hz, 1H), 6.64-6.83 (m, 4H), 4.37 (s, 2H), 3.79-3.84 (m, 2H), 3.74-3.79 (m, 2H), 2.83-2.91 (m, 2H), 2.74-2.79 (m, 2H), 2.68-2.73 (m, 2H), 2.61-2.68 (m, 2H), 2.25 (d, J=2.0 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.23F.sub.3O.sub.4, 443.1, [M+Na], Measured 443.3.
Example 9
3-[4-[[5-(3-fluoro-4-methyl-phenyl-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0248] ##STR00029##
[0249] .sup.1H NMR (CHLOROFORM-d) : 7.10 (t, J=7.8 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.72-6.84 (m, 2H), 6.40 (d, J=8.1 Hz, 1H), 4.30 (s, 2H), 3.66-3.84 (m, 4H), 2.84-2.95 (m, 2H), 2.70-2.77 (m, 2H), 2.64-2.70 (m, 2H), 2.49-2.61 (m, 2H), 2.25 (d, J=1.5 Hz, 3H), 2.21 (s, 3H), 2.16 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.25H.sub.29FO.sub.4, 435.1, [MH], Measured 435.3.
Example 10
3-[5-fluoro-4-[[5-(3-fluoro-4-methyl-phenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2-methyl-phenyl]propanoic acid
[0250] ##STR00030##
[0251] 10 .sup.1H NMR (CHLOROFORM-d) : 7.13 (t, J=7.8 Hz, 1H), 6.74-6.87 (m, 3H), 6.46 (d, J=8.1 Hz, 1H), 4.40 (s, 2H), 3.67-3.84 (m, 4H), 2.79-2.88 (m, 2H), 2.70 (dt, J=16.4, 4.7 Hz, 4H), 2.54-2.63 (m, 2H), 2.27 (d, J=1.5 Hz, 3H), 2.18 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.26F.sub.2O.sub.4, 439.1, [M+Na], Measured 439.3.
Example 11
3-[2,3-difluoro-4-[[5-(3-fluoro-4-methyl-phenyl-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]phenyl]propanoic acid
[0252] ##STR00031##
[0253] .sup.1H NMR (CHLOROFORM-d) : 7.13 (t, J=7.8 Hz, 1H), 6.72-6.83 (m, 3H), 6.35-6.45 (m, 1H), 4.40 (s, 2H), 3.75 (dt, J=9.6, 4.8 Hz, 4H), 2.87-2.98 (m, 2H), 2.70-2.76 (m, 2H), 2.60-2.70 (m, 5H), 2.26 (d, J=1.5 Hz, 3H).). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.23F.sub.3O.sub.4, 443.1, [M+Na], Measured 443.3.
Example 12
3-[4-[[5-(3-fluoro-4-methyl-phenyl)-2,3,6,7-tetrahydrooxepin-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0254] ##STR00032##
[0255] .sup.1H NMR (CHLOROFORM-d) : 7.20 (d, J=8.6 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 7.00 (d, J=2.5 Hz, 1H), 6.85 (dd, J=8.6, 2.5 Hz, 1H), 6.75-6.82 (m, 2H), 4.37 (s, 2H), 3.69-3.81 (m, 4H), 3.04 (t, J=7.8 Hz, 2H), 2.71-2.77 (m, 2H), 2.58-2.67 (m, 4H), 2.26 (d, J=2.0 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.24F.sub.4O.sub.4, 475.1, [M+Na], Measured 475.3.
Example 13
3-[4-[[5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0256] ##STR00033##
Step A: ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H-pyran-4-carboxylate
[0257] To a solution of ethyl 3-oxotetrahydro-2H-pyran-4-carboxylate (4.40 g, 25.50 mmol) and DIEA (13.21 ml, 76.66 mmol) in 120 ml of DCM at 0 C. was added triflic anhydride (4.62 ml, 28.11 mmol) and the mixture was allowed to stir overnight at room temperature. DCM was removed under vacuum and the residue dissolved in EtOAc and washed with 1N HCl and then brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluting with 20% EtOAc/heptane to yield ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H-pyran-4-carboxylate as a light brown oil. Mass spectrum (ESI, m/z): Calculated for C.sub.9H.sub.11F.sub.3O.sub.6S, 305.2 (M+H), Measured 305.0.
Step B: ethyl 5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-carboxylate
[0258] To a solution of ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H-pyran-4-carboxylate (4.97 g, 16.34 mmol) in 109 ml of 25% water/1,4-dioxane was added 4-chlorophenylboronic acid (3.83 g, 24.50 mmol), Pd(dppf)Cl.sub.2 (668 mg, 0.82 mmol), and potassium phosphate (13.87 g, 65.34 mmol) and the mixture was heated at 80 C. for 40 mins. The mixture was diluted with EtOAc and washed with water and brine, then dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluting with 20% EtOAc/heptane to yield ethyl 5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-carboxylate as a colorless oil. Mass spectrum (ESI, m/z): Calculated for C.sub.14H.sub.15ClO.sub.3, 267.7 (M+H), Measured 267.0.
Step C: (5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl)methanol
[0259] To a solution of ethyl 5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-carboxylate (4.00 g, 15.00 mmol) in 25 mL of toluene at 40 C. was added diisobutylaluminum hydride (1M in toluene, 37.49 ml, 37.49 mmol) and the mixture was allowed to stir for 1 hr at 40 C. The reaction was quenched with sodium sulfate decahydrate and stirred for 1 hr at room temperature. To the mixture was then added diethyl ether (25 ml) and the mixture was filtered and concentrated. The residue was purified on a silica gel column eluting with 7-70% EtOAc/heptane step gradient to yield (5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl)methanol as a colorless oil. Mass spectrum (ESI, m/z): Calculated for C.sub.12H.sub.13ClO.sub.2, 249.7 (M+Na), Measured 249.0.
Step D: ethyl 3-(4-((5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl)methoxy)-2,3-dimethylphenyl)propanoate
[0260] To a solution of (5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl)methanol (2.80 g, 12.46 mmol), ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate (2.77 g, 12.46 mmol) and 1,1-(azodicarbonyl)dipiperidine (4.86 g, 18.69 mmol) in 62 ml of THF at room temperature was added tri-n-butylphosphine (4.76 mL, 18.69 mmol) and the mixture heated to 60 C. for 90 mins. The mixture was concentrated and then added 1:1 DCM/heptane to the residue (approx. 10 ml) and filtered the resulting precipitate. The filtrate was loaded on to a silica gel column and eluted with 20% EtOAc/hep to yield ethyl 3-(4-((5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl)methoxy)-2,3-dimethylphenyl)propanoate as a colorless oil. Mass spectrum (ESI, m/z): Calculated for C.sub.25H.sub.29ClO.sub.4, 451.9 (M+Na), Measured 451.3.
STEP E: 3-(4-((5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl)methoxy)-2,3-dimethylphenyl)propanoic acid
[0261] To a solution of ethyl 3-(4-((5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl)methoxy)-2,3-dimethylphenyl)propanoate (4.48 g, 10.44 mmol) in 26 ml of 10% MeOH/THF was added 3M NaOH (6.96 mL, 20.89 mmol) and the mixture stirred for 8 hrs at room temperature. The mixture was then diluted with water (20 ml) and acidified to pH 2 with 3N HCl and concentrated to remove organics. A precipitate formed that was collected by filtration and washed with water and dried to yield 3-(4-((5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl)methoxy)-2,3-dimethylphenyl)propanoic acid as a white solid.
[0262] .sup.1H NMR (400 MHz, CHLOROFORM-d) : 7.30 (d, J=8.59 Hz, 2H), 7.13 (d, J=8.59 Hz, 2H), 6.89 (d, J=8.59 Hz, 1H), 6.44 (d, J=8.59 Hz, 1H), 4.31 (s, 2H), 4.28 (s, 2H), 3.95 (t, J=5.56 Hz, 2H), 2.85-2.97 (m, 2H), 2.53-2.62 (m, 2H), 2.43 (dt, J=5.31, 2.91 Hz, 2H), 2.22 (s, 3H), 2.17 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.25ClO.sub.4, 422.9 (M+Na), Measured 423.0.
[0263] The following compounds were similarly prepared according to the procedure as described in Example 13 above, selecting and substituting suitably substituted reactants, as would be readily recognized by those skilled in the art.
Example 14
3-[4-[[5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-3,5-difluoro-phenyl]propanoic acid
[0264] ##STR00034##
[0265] .sup.1H NMR (400 MHz, CD.sub.3OD) : 7.30 (d, J=8.0 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 6.82 (d, J=8.6 Hz, 2H), 4.41 (s, 2H), 4.21 (s, 2H), 3.92 (t, J=7.8 Hz, 2H), 2.88 (t, J=7.8 Hz, 2H), 2.52 (t, J=7.8 Hz, 2H), 1.45 (s, 2H). .sup.19F NMR (400 MHz, CD.sub.3OD) : 129.81. Mass spectrum (ESI, m/z): Calculated for C.sub.21H.sub.19ClF.sub.2O.sub.4, 407.1 [MH], Measured 407.0.
Example 15
3-[4-[[5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-3-methyl-phenyl]propanoic acid
[0266] ##STR00035##
[0267] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.31 (d, J=8.1 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 6.94 (s, 1H), 6.84-6.87 (m, 1H), 6.47 (d, J=8.4 Hz, 1H), 4.32 (s, 2H), 4.24 (s, 2H), 3.88 (t, J=5.7 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H), 2.50 (t, J=7.5 Hz, 2H), 2.36-2.39 (m, 2H), 2.14 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.23ClO.sub.4, 385.1 [MH], Measured 385.1.
Example 16
3-[4-[[5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0268] ##STR00036##
[0269] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.26-7.40 (m, 3H), 7.15-7.23 (m, 2H), 7.00 (s, 1H), 6.89-6.93 (m, 1H), 4.41 (s, 2H), 4.24 (s, 2H), 3.87 (t, J=5.4 Hz, 2H), 2.96-3.01 (m, 2H), 2.50-2.57 (m, 2H), 2.32-2.36 (m, 2H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 61.21, 77.59. Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.20ClF.sub.3O.sub.4, 439.1 [MH], Measured 439.0.
Example 17
3-[4-[[5-(4-chlorophenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2-(cyclopropylmethyl)phenyl]propanoic acid
[0270] ##STR00037##
[0271] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.36 (d, J=6.6 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.1 Hz, 1H), 6.72 (s, 1H), 6.53-6.57 (m, 1H), 4.37 (s, 2H), 4.27 (s, 2H), 3.90 (t, J=5.7 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.47-2.51 (m, 4H), 2.37-2.41 (m, 2H), 0.88-0.94 (m, 1H), 0.47-0.53 (m, 2H), 0.13-0.18 (m, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.25H.sub.27ClO.sub.4, 425.2 [MH], Measured 425.1.
Example 18
3-[4-[[5-(D-tolyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0272] ##STR00038##
[0273] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.30 (d, J=8.7 Hz, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 7.00 (s, 1H), 6.93 (d, J=8.7 Hz, 1H), 4.47 (s, 2H), 4.27 (s, 2H), 3.90 (t, J=5.4 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.54 (t, J=8.4 Hz, 2H), 2.34-2.37 (m, 5H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 61.32. Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.23F.sub.3O.sub.4, 419.2 [MH], Measured 419.1.
Example 19
3-[4-[[5-(4-methyl-2-phenyl)-phenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0274] ##STR00039##
[0275] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.29-7.42 (m, 6H), 7.12-7.22 (m, 3H), 6.95 (s, 1H), 6.88 (d, J=8.4 Hz, 1H), 4.28-4.32 (m, 1H), 4.15-4.20 (m, 1H), 3.85-3.99 (m, 2H), 3.70-3.83 (m, 2H), 3.01 (t, J=7.8 Hz, 2H), 2.55 (t, J=7.8 Hz, 2H), 2.41 (s, 3H), 2.20-2.25 (m, 1H), 2.06-2.14 (m, 1H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 61.31, 77.04. Mass spectrum (ESI, m/z): Calculated For C.sub.30H.sub.27F.sub.4O, 495.2 [M-1], Measured 495.1.
Example 20
3-[4-[[5-(4-methyl-3-phenyl-phenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0276] ##STR00040##
[0277] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.29-7.37 (m, 5H), 7.12-7.21 (m, 3H), 7.05-7.07 (m, 2H), 6.96-7.00 (m, 1H), 4.52 (5, 2H), 4.35 (5, 2H), 3.93 (t, J=5.4 Hz, 2H), 3.00-3.06 (m, 2H), 2.57 (t, J=8.4 Hz, 2H), 2.39-2.42 (m, 2H), 2.25 (5, 3H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 61.28, 76.96. Mass spectrum (ESI, m/z): Calculated for C.sub.29H.sub.27F.sub.4O.sub.4, 495.2 [MH], Measured 495.1.
Example 21
3-[4-[[5-(2-fluoro-4-methyl-phenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0278] ##STR00041##
[0279] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.31 (d, J=8.1 Hz, 1H), 6.92-7.11 (m, 5H), 4.43 (s, 2H), 4.23 (s, 2H), 3.92 (t, J=5.7 Hz, 2H), 3.01 (t, J=7.8 Hz, 2H), 2.55 (t, J=8.4 Hz, 2H), 2.37-2.39 (m, 5H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 62.89, 79.12, 119.38. Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.22F.sub.4O.sub.4, 437.1 [MH], Measured 436.9.
Example 22
3-[4-[[5-(2,4-dimethylphenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0280] ##STR00042##
[0281] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.31 (d, J=8.7 Hz, 1H), 6.81-7.05 (m, 5H), 4.22-4.31 (m, 2H), 4.13 (s, 2H), 3.92 (t, J=7.8 Hz, 2H), 2.99 (t, J=7.8 Hz, 2H), 2.27-2.44 (m, 7H), 2.19 (s, 3H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 61.26. Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.25F.sub.3O.sub.4, 433.2 [MH], Measured 433.1.
Example 23
3-[4-[[5-(3-isopropyl-4-methyl-phenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0282] ##STR00043##
[0283] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.30 (d, J=8.4 Hz, 1H), 7.04-7.14 (m, 3H), 6.90-6.97 (m, 2H), 4.43 (s, 2H), 4.30 (s, 2H), 3.91 (t, J=5.4 Hz, 2H), 3.07-3.16 (m, 1H), 3.09 (t, J=6.9 Hz, 2H), 2.53 (t, J=7.8 Hz, 2H), 2.38-2.40 (m, 2H), 2.31 (s, 3H), 1.09 (d, J=6.9 Hz, 6H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 61.33. Mass spectrum (ESI, m/z): Calculated for C.sub.26H.sub.29F.sub.3O.sub.4, 461.2 [MH], Measured 461.0.
Example 24
3-[4-[[5-(2-isopropyl-4-methyl-phenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0284] ##STR00044##
[0285] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.31 (d, J=8.7 Hz, 1H), 7.16 (s, 1H), 3.88-7.00 (m, 4H), 4.26 (s, 2H), 4.02-4.26 (m, 2H), 3.89-3.99 (m, 2H), 2.96-3.10 (m, 3H), 2.45-2.55 (m, 3H), 2.33-2.36 (m, 4H), 1.21-1.30 (m, 6H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 61.28. Mass spectrum (ESI, m/z): Calculated for C.sub.26H.sub.29F.sub.3O.sub.4, 461.2 [MH], Measured 461.1.
Example 25
3-[4-[(5-phenyl-3,6-dihydro-2H-pyran-4-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0286] ##STR00045##
[0287] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.30-7.40 (m, 4H), 7.20-7.26 (m, 2H), 7.01 (s, 1H), 6.93 (d, J=8.4 Hz, 1H), 4.46 (s, 2H), 4.29 (s, 2H), 3.91 (t, J=5.4 Hz, 2H), 2.99 (t, J=7.8 Hz, 2H), 2.53 (t, J=7.8 Hz, 2H), 2.35-2.39 (m, 2H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 61.32, 77.48. Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.21F.sub.3O.sub.4, 405.1 [MH], Measured 405.1.
Example 26
3-[4-[(5-cyclopentyl-3,6-dihydro-2H-pyran-4-yl)methoxy]phenyl]propanoic acid
[0288] ##STR00046##
[0289] .sup.1H NMR (CHLOROFORM-d) : 7.13 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 4.49 (s, 2H), 4.13 (s, 2H), 3.82 (t, J=5.8 Hz, 2H), 2.91 (t, J=7.8 Hz, 3H), 2.55-2.73 (m, 2H), 2.27 (dt, J=5.3, 2.9 Hz, 2H), 1.45-1.81 (m, 6H), 1.28-1.45 (m, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.20H.sub.26O.sub.4, 353.1 [M+Na], Measured 353.2.
Example 27
3-[4-[(5-cyclopentyl-3,6-dihydro-2H-pyran-4-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0290] ##STR00047##
[0291] .sup.1H NMR (CHLOROFORM-d) : 7.26-7.30 (m, 2H), 7.19 (d, J=2.5 Hz, 1H), 7.03 (dd, J=8.1, 2.5 Hz, 1H), 4.54 (s, 2H), 4.14 (s, 2H), 3.81 (t, J=5.8 Hz, 2H), 3.08 (br t, J=7.8 Hz, 2H), 2.87-3.00 (m, 1H), 2.65 (t, J=7.8 Hz, 2H), 2.25 (dt, J=5.3, 2.9 Hz, 2H), 1.52-1.79 (m, 6H), 1.33-1.46 (m, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.21H.sub.25F.sub.3O.sub.4, 421.1 [M+Na], Measured 421.2.
Example 28
3-[4-[[5-(3-fluoro-4-methyl-phenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0292] ##STR00048##
[0293] .sup.1H NMR (CHLOROFORM-d) : 7.13 (s, 1H), 6.81-6.91 (m, 3H), 6.46 (d, J=8.6 Hz, 1H), 4.31-4.39 (m, 2H), 4.27 (s, 2H), 3.94 (t, J=5.6 Hz, 2H), 2.87-2.97 (m, 2H), 2.53-2.62 (m, 2H), 2.42 (dt, J=5.2, 2.7 Hz, 2H), 2.26 (d, J=1.5 Hz, 3H), 2.21 (s, 3H), 2.18 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.27FO.sub.4, 421.1 (M+Na), Measured 421.3.
Example 29
3-[3,5-difluoro-4-[[5-(3-fluoro-4-methyl-phenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]phenyl]propanoic acid
[0294] ##STR00049##
[0295] .sup.1H NMR (CHLOROFORM-d) : 7.10 (t, J=7.8 Hz, 1H), 6.68-6.82 (m, 3H), 6.63 (dd, J=10.6, 1.5 Hz, 1H), 4.40 (s, 2H), 4.23 (s, 2H), 3.94 (t, J=5.6 Hz, 2H), 2.82-2.95 (m, 2H), 2.61-2.72 (m, 2H), 2.46-2.58 (m, 2H), 2.18-2.33 (m, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.21F.sub.3O.sub.4, 429.4 (M+Na), Measured 429.0.
Example 30
3-[2,3-difluoro-4-[[5-(3-fluoro-4-methyl-phenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]phenyl]propanoic acid
[0296] ##STR00050##
[0297] .sup.1H NMR (CHLOROFORM-d) : 7.15 (t, J=8.1 Hz, 1H), 6.71-6.91 (m, 3H), 6.38-6.51 (m, 1H), 4.43 (s, 2H), 4.26 (s, 2H), 3.93 (t, J=5.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.60-2.73 (m, 2H), 2.41 (dt, J=5.3, 2.9 Hz, 2H), 2.27 (d, J=1.5 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.21F.sub.3O.sub.4, 429.4 (M+Na), Measured 429.0.
Example 31
3-[4-[[5-(3-fluoro-4-methyl-phenyl-3,6-dihydro-2H-pyran-4-yl]methoxy]phenyl]propanoic acid
[0298] ##STR00051##
[0299] .sup.1H NMR (CHLOROFORM-d) : 7.14 (t, J=7.8 Hz, 1H), 7.08 (d, J=8.6 Hz, 2H), 6.82-6.89 (m, 2H), 6.73 (d, J=8.6 Hz, 2H), 4.33-4.40 (m, 2H), 4.22-4.30 (m, 2H), 3.93 (t, J=5.6 Hz, 1H), 2.85-2.93 (m, 2H), 2.60-2.68 (m, 2H), 2.39 (dt, J=5.3, 2.9 Hz, 2H), 2.26 (d, J=1.5 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.23FO.sub.4, 393.1 [M+Na], Measured 393.3.
Example 32
3-[6-[[5-(3-fluoro-4-methyl-phenyl)-3,6-dihydro-2H-pyran-4-yl]methoxy]-2-methyl-3-pyridyl]propanoic acid
[0300] ##STR00052##
[0301] .sup.1H NMR (CHLOROFORM-d) : 7.95 (d, J=8.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 6.78-6.88 (m, 2H), 6.66 (d, J=9.1 Hz, 1H), 4.67 (s, 2H), 4.28 (s, 2H), 3.92 (t, J=5.6 Hz, 2H), 2.94 (t, J=6.8 Hz, 2H), 2.59-2.73 (m, 5H), 2.35 (br s, 2H), 2.27 (d, J=1.5 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.24FNO.sub.4, 386.1 [M+H], Measured 386.3.
Example 33
3-[4-[[4-(4-chlorophenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0302] ##STR00053##
Step 1: Methyl 4-oxooxane-3-carboxylate
[0303] To a solution of dimethyl carbonate (22.50 g, 249.78 mmol, 5.00 equiv) in tetrahydrofuran (70 mL) at 0 C. was added sodium hydride (6.00 g, 150.00 mmol, 3.00 equiv, 60%). The mixture was stirred at 15 C. for 1 h and then the mixture was cooled to 0 C. and oxan-4-one (5.00 g, 49.940 mmol, 1.00 equiv) was added dropwise. The resulting solution was stirred for 2 h at 60 C. in an oil bath. The reaction was then quenched by the addition of water and the pH adjusted to 6 with hydrogen chloride (2N). The resulting solution was extracted with ethyl acetate (320 mL) and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (10/90). The collected fractions were combined and concentrated under vacuum to yield methyl 4-oxooxane-3-carboxylate as yellow oil.
Step 2. Methyl 4-[(trifluoromethane)sulfonyloxy]-5,6-dihydro-2H-pyran-3-carboxylate
[0304] To a solution of methyl 4-oxooxane-3-carboxylate (550 mg, 3.480 mmol, 1.00 equiv) in diethyl ether (20 mL) at 0 C. was added sodium hydride (208 mg, 5.200 mmol, 1.50 equiv, 60%) and the mixture was stirred at 15 C. for 1 h. Triflic anhydride (1.50 g, 5.320 mmol, 1.53 equiv) was then added and resulting mixture was stirred overnight at 15 C. The reaction was quenched by the addition of water and the resulting solution was extracted with ethyl acetate (310 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to yield methyl 4-[(trifluoromethane)sulfonyloxy]-5,6-dihydro-2H-pyran-3-carboxylate as yellow oil.
Step 3. Methyl 4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-carboxylate
[0305] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added methyl 4-[(trifluoromethane)sulfonyloxy]-5,6-dihydro-2H-pyran-3-carboxylate (1.33 g, 4.580 mmol, 1.00 equiv), (4-chlorophenyl)boronic acid (2.86 g, 18.290 mmol, 3.99 equiv), Pd(PPh.sub.3).sub.4 (530 mg, 0.460 mmol, 0.10 equiv), K.sub.3PO.sub.4 (3.80 g, 17.900 mmol, 3.91 equiv) and 1,4-dioxane (20 mL). The resulting solution was stirred overnight at 90 C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (20/80). The collected fractions were combined and concentrated under vacuum to yield methyl 4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-carboxylate as a white solid.
Step 4. [4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl]methanol
[0306] To a solution of methyl 4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-carboxylate (150 mg, 0.590 mmol, 1.00 equiv) in toluene (10 mL) at 70 C. was added DIBAL (1N, 1.78 mL) dropwise with stirring. The resulting solution was stirred for 2 h at 15 C. and then quenched by the addition of NH.sub.4Cl/H.sub.2O. The pH was adjusted to 6 with hydrogen chloride (2N) and the mixture was extracted with ethyl acetate (310 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (57/43) to yield [4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl]methanol as colorless oil.
Step 5. Ethyl 3-(4-[[4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl]methoxy]-2,3-dimethylphenyl) propanoate
[0307] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added [4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl]methanol (110 mg, 0.490 mmol, 1.00 equiv), ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate (130 mg, 0.580 mmol, 1.19 equiv), ADDP (312 mg, 1.250 mmol, 2.55 equiv), Bu.sub.3P (151 mg, 0.750 mmol, 1.53 equiv) and toluene (4 mL). The resulting mixture was stirred overnight at 60 C. and then concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/3). The collected fractions were combined and concentrated under vacuum to yield ethyl 3-(4-[[4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl]methoxy]-2,3-dimethylphenyl)propanoate as colorless oil.
Step 6. [[4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl]methoxy]-2,3-dimethylphenyl)propanoic acid
[0308] Into a 50-mL round-bottom flask was added ethyl 3-(4-[[4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl]methoxy]-2,3-dimethylphenyl)propanoate (95 mg, 0.220 mmol, 1.00 equiv), LiOH (95 mg, 3.970 mmol, 17.91 equiv), tetrahydrofuran (2 mL) and water (2 mL). The resulting solution was stirred overnight at 15 C. The pH was adjusted to 5 with hydrogen chloride (2N) and the resulting mixture was extracted with ethyl acetate (32 mL) and the organic layers combined and concentrated under vacuum. The residue was purified by reversed-phase HPLC to yield 3-(4-[[4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl]methoxy]-2,3-dimethylphenyl)propanoic acid as a white solid.
[0309] .sup.1H NMR (300 MHz, CDCl.sub.3) : 7.30 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.1 Hz, 1H), 6.43 (d, J=8.1 Hz, 1H), 4.39 (s, 2H), 4.31 (s, 2H), 3.94 (t, J=5.4 Hz, 2H), 2.91 (t, J=7.5 Hz, 2H), 2.57 (t, J=8.4 Hz, 2H), 2.40-2.45 (m, 2H), 2.21 (s, 3H), 2.01 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.25ClO.sub.4, 418.1 [M+NH.sub.3], Measured 418.1.
[0310] The following compounds were similarly prepared according to the procedure as described in Example 33 above, selecting and substituting suitably substituted reactants, as would be readily recognized by those skilled in the art.
Example 34
3-[4-[[4-(4-chlorophenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-3,5-difluoro-phenyl]propanoic acid
[0311] ##STR00054##
[0312] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.31 (d, J=8.4 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 6.83 (d, J=9.6 Hz, 2H), 4.39-4.44 (m, 4H), 3.89 (t, J=5.4 Hz, 2H), 2.84 (t, J=8.1 Hz, 2H), 2.61 (t, J=8.1 Hz, 2H), 2.38-2.42 (m, 2H). .sup.19F NMR (300 MHz, CD3OD) : 129.8. Mass spectrum (ESI, m/z): Calculated for C.sub.21H.sub.19ClF.sub.2O.sub.4, 407.1 [MH], Measured 406.9.
Example 35
3-[4-[[4-(4-chlorophenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-3-methyl-phenyl]propanoic acid
[0313] ##STR00055##
[0314] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.36 (d, J=8.1 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 6.78 (s, 1H), 6.88-6.91 (m, 1H), 6.54 (d, J=8.1 Hz, 1H), 4.26 (s, 4H), 3.91 (t, J=5.7 Hz, 2H), 2.79 (t, J=7.5 Hz, 2H), 2.46-2.56 (m, 4H), 2.17 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.23ClO.sub.4, 385.1 [MH], Measured 385.1.
Example 36
3-[4-[[4-(4-chlorophenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0315] ##STR00056##
[0316] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.35-7.38 (m, 3H), 7.23 (d, J=6.3 Hz, 2H), 7.03 (s, 1H), 6.89-6.99 (m, 1H), 4.44 (s, 2H), 4.32 (s, 2H), 3.91 (t, J=5.7 Hz, 2H), 2.98-3.00 (m, 2H), 2.46-2.55 (m, 4H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.20ClF.sub.3O.sub.4, 439.1 [MH], Measured 439.0.
Example 37
3-[4-[[4-(4-methoxyphenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0317] ##STR00057##
[0318] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.16 (d, J=8.7 Hz, 2H), 6.91-6.85 (m, 3H), 6.43 (d, J=8.4 Hz, 1H), 4.35-4.37 (m, 4H), 3.93 (t, J=7.6 Hz, 2H), 3.79 (s, 3H), 2.87 (t, J=7.6 Hz, 2H), 2.51-2.46 (m, 4H), 2.22 (s, 3H), 2.16 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.28O.sub.5, 395.2 [MH], Measured 395.1.
Example 38
3-[4-[[4-(4-fluorophenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0319] ##STR00058##
[0320] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.22-7.28 (m, 2H), 7.03-7.11 (m, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.43 (d, J=8.4 Hz, 1H), 4.36 (s, 2H), 4.34 (s, 2H), 3.92 (t, J=7.6 Hz, 2H), 2.87 (t, J=7.6 Hz, 2H), 2.44-2.50 (m, 4H), 2.21 (s, 3H), 2.14 (s, 3H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 116.97. Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.25FO.sub.4, 383.2 [MH], Measured 383.1.
Example 39
3-[4-[[4-(2-fluorophenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0321] ##STR00059##
[0322] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.30-7.37 (m, 1H), 7.09-7.29 (m, 3H), 6.83 (d, J=8.7 Hz, 1H), 6.40 (d, J=8.7 Hz, 1H), 4.39 (s, 2H), 4.30 (s, 2H), 3.91 (t, J=5.4 Hz, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.42-2.48 (m, 4H), 2.19 (s, 3H), 2.11 (s, 3H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 117.48. Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.25FO.sub.4, 383.2 [MH], Measured 383.1.
Example 40
3-[2,3-dimethyl-4-[[4-(3-pyridyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]phenyl]propanoic acid
[0323] ##STR00060##
[0324] .sup.1H NMR (300 MHz, CD.sub.3OD) : 8.72 (s, 2H), 8.37 (d, J=9.6 Hz, 1H), 7.94-7.99 (m, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.50 (d, J=8.7 Hz, 1H), 4.41 (s, 2H), 4.36 (s, 2H), 3.97 (t, J=7.6 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H), 2.44-2.54 (m, 4H), 2.23 (s, 3H), 2.01 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.25NO.sub.4, 368.2 [M+H], Measured 368.1.
Example 41
3-[2,3-dimethyl-4-[[4-(p-tolyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]phenyl]propanoic acid
[0325] ##STR00061##
[0326] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.09-7.12 (m, 4H), 6.82 (d, J=8.4 Hz, 1H), 6.40 (d, J=8.4 Hz, 1H), 4.35 (s, 4H), 3.90 (t, J=7.6 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H), 2.45-2.49 (m, 4H), 2.33 (s, 3H), 2.20 (s, 3H), 2.14 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.28O.sub.4, 379.2 [MH], Measured 379.1.
Example 42
3-[4-[[4-(3-methoxyphenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0327] ##STR00062##
[0328] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.23-7.28 (m, 1H), 6.79-6.87 (m, 4H), 6.44 (d, J=8.4 Hz, 1H), 4.37 (s, 4H), 3.94 (t, J=7.6 Hz, 2H), 3.67 (s, 3H), 2.87 (t, J=7.6 Hz, 2H), 2.45-2.50 (m, 4H), 2.21 (s, 3H), 2.16 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.28O.sub.5, 395.2 [MH], Measured 395.1.
Example 43
3-[4-[[4-(3,4-difluorophenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0329] ##STR00063##
[0330] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.17-7.25 (m, 1H), 6.83-7.01 (m, 3H), 6.41 (d, J=8.4 Hz, 1H), 4.38 (s, 2H), 4.28 (s, 2H), 3.90 (t, J=5.4 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.31-2.45 (m, 4H), 2.19 (s, 3H), 2.10 (s, 3H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 112.75, 112.90. Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.24F.sub.2O.sub.4, 401.2 [MH], Measured 401.2.
Example 44
3-[4-[[4-(3-fluoro-4-methyl-phenyl-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0331] ##STR00064##
[0332] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.19 (t, J=8.1 Hz, 1H), 6.85-6.96 (m, 3H), 6.45 (d, J=8.4 Hz, 1H), 4.35 (s, 4H), 3.90 (t, J=5.4 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.46-2.51 (m, 4H), 2.25 (s, 3H), 2.21 (s, 3H), 2.14 (s, 3H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 77.04, 119.56. Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.27FO.sub.4, 397.2 [M-0.1CF.sub.3COOH-H], Measured 397.2.
Example 45
3-[4-[[4-(2,4-difluorophenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0333] ##STR00065##
[0334] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.12-7.27 (m, 2H), 7.02-7.07 (m, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.47 (d, J=8.4 Hz, 1H), 4.36 (s, 2H), 4.33 (s, 2H), 3.91 (t, J=5.4 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.45-2.50 (m, 4H), 2.21 (s, 3H), 2.14 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.23.4H.sub.24.2F.sub.2.6O.sub.4.4, 401.2 [M-0.2CF.sub.3COOH-H], Measured 401.2.
Example 46
3-[4-[[4-(4-fluoro-3-methyl-phenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0335] ##STR00066##
[0336] .sup.1H NMR (300 MHz, CD.sub.3OD) : 6.96-7.02 (m, 3H), 6.86 (d, J=8.4 Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 4.36 (s, 2H), 4.34 (s, 2H), 3.91 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.6 Hz, 2H), 2.42-2.50 (m, 4H), 2.21 (s, 6H), 2.11 (s, 3H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 121.47. Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.27F.sub.1O.sub.4, 397.2 [MH], Measured 397.1.
Example 47
3-[4-[[4-(4-chloro-2-methoxy-phenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0337] ##STR00067##
[0338] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.02 (d, J=8.1 Hz, 1H), 6.93 (s, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.14 (d, J=8.4 Hz, 1H), 4.25-4.35 (m, 2H), 4.25 (s, 2H), 3.89 (t, J=5.10 Hz, 2H), 3.78 (s, 3H), 2.85 (t, J=7.6 Hz, 2H), 2.40-2.49 (m, 4H), 2.19 (s, 3H), 2.13 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.27ClO.sub.5, 429.2 [MH], Measured 428.9.
Example 48
3-[4-[[4-(4-chloro-3-fluoro-phenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0339] ##STR00068##
[0340] .sup.1H NMR (300 MHz, D.sub.3OD) : 7.43 (t, J=8.0 Hz, 1H), 7.03-7.15 (m, 2H), 6.87 (d, J=8.4 Hz, 1H), 6.45 (d, J=8.4 Hz, 1H), 4.36 (s, 2H), 4.33 (s, 2H), 3.91 (t, J=5.7 Hz, 2H), 2.87 (t, J=7.6 Hz, 2H), 2.45-2.50 (m, 4H), 2.21 (s, 3H), 2.14 (s, 3H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 117.16. Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.24ClFO.sub.4, 417.1 [MH], Measured 417.0.
Example 49
3-[4-[[4-(4-chloro-3-methoxy-phenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0341] ##STR00069##
[0342] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.02 (d, J=9.6 Hz, 1H), 6.94 (s, 1H), 6.91 (d, J=2.1 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.14 (d, J=11.1 Hz, 1H), 4.38 (s, 2H), 4.29 (s, 2H), 3.91 (t, J=5.10 Hz, 2H), 3.80 (s, 3H), 2.86 (t, J=7.6 Hz, 2H), 2.40-2.49 (m, 4H), 2.19 (s, 3H), 2.14 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.27ClO.sub.5, 429.2 [MH], Measured 429.1.
Example 50
3-[2-(difluoromethyl)-4-[[4-(p-tolyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]phenyl]propanoic acid
[0343] ##STR00070##
[0344] .sup.1H NMR (CHLOROFORM-d) : 7.06-7.22 (m, 5H), 6.92 (d, J=2.5 Hz, 1H), 6.83 (dd, J=8.6, 2.5 Hz, 1H), 6.73 (t, J=55.3 Hz, 1H), 4.42 (s, 2H), 4.37 (s, 2H), 3.96 (t, J=5.6 Hz, 2H), 2.98 (t, J=7.8 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 2.48 (m, 2H), 2.35 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.24F.sub.2O.sub.4, 425.4 [M+Na], Measured 425.0.
Example 51
3-[4-[[4-(D-tolyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,6-bis(trifluoromethyl)phenyl]propanoic acid
[0345] ##STR00071##
[0346] .sup.1H NMR (CHLOROFORM-d) : 7.24 (s, 2H), 7.16-7.20 (m, 2H), 7.07-7.11 (m, 2H), 4.49 (s, 2H), 4.33 (s, 2H), 3.94 (t, J=5.6 Hz, 2H), 3.15-3.27 (m, 2H), 2.58-2.68 (m, 2H), 2.49 (br s, 2H), 2.36 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.22F.sub.6O.sub.4, 511.1 [M+Na], Measured 511.0.
Example 52
3-[4-[[4-(4-chloro-2-fluoro-phenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0347] ##STR00072##
[0348] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.15-7.25 (m, 3H), 6.85 (d, J=8.4 Hz, 1H), 6.42 (d, J=8.4 Hz, 1H), 4.35 (s, 2H), 4.25 (s, 2H), 3.89 (t, J=5.10 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H), 2.40-2.49 (m, 4H), 2.19 (s, 3H), 2.13 (s, 3H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 114.41. Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.24ClFO.sub.4, 417.1 [MH], Measured 417.1.
Example 53
3-[4-[[4-(D-tolyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0349] ##STR00073##
[0350] .sup.1H NMR (MeOH) : 7.29 (d, J=8.6 Hz, 1H), 7.07-7.20 (m, 4H), 7.00 (d, J=2.5 Hz, 1H), 6.92 (dd, J=8.1, 2.5 Hz, 1H), 4.45 (s, 2H), 4.30 (br d, J=2.0 Hz, 2H), 3.88 (t, J=5.6 Hz, 2H), 2.93-3.04 (m, 2H), 2.48-2.58 (m, 2H), 2.44 (br s, 2H), 2.32 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.23F.sub.3O.sub.4, 443.1 [M+Na], Measured 443.0.
Example 54
3-[2-chloro-4-[[4-(2,6-dimethylphenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]phenyl]propanoic acid
[0351] ##STR00074##
[0352] .sup.1H NMR (CHLOROFORM-d) : 7.00-7.15 (m, 4H), 6.73 (d, J=2.5 Hz, 1H), 6.59 (dd, J=8.6, 2.5 Hz, 1H), 4.44 (br s, 2H), 4.11 (s, 2H), 3.99 (br t, J=5.1 Hz, 2H), 2.95 (t, J=7.6 Hz, 2H), 2.64 (t, J=7.6 Hz, 2H), 2.28 (br s, 2H), 2.20 (s, 6H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.25ClO.sub.4, 423.1 [M+Na], Measured 423.0.
Example 55
3-[4-[[4-(5,5-dimethylcyclopenten-1-yl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0353] ##STR00075##
[0354] .sup.1H NMR (MeOH) : 7.35 (d, J=8.6 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 7.06 (dd, J=8.3, 2.3 Hz, 1H), 5.37-5.43 (m, 1H), 4.49 (s, 2H), 4.27 (br d, J=2.0 Hz, 2H), 3.76-3.83 (m, 2H), 2.94-3.06 (m, 2H), 2.50-2.61 (m, 2H), 2.21-2.36 (m, 4H), 1.76 (t, J=7.1 Hz, 2H), 1.09 (s, 6H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.27F.sub.3O.sub.4, 447.1 [M+Na], Measured 447.0.
Example 56
3-[4-[[4-(2,6-dimethylphenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0355] ##STR00076##
[0356] .sup.1H NMR (CHLOROFORM-d) : 7.17 (d, J=8.6 Hz, 1H), 6.98-7.14 (m, 4H), 6.82 (dd, J=8.6, 2.5 Hz, 1H), 4.47 (br s, 2H), 4.15 (s, 2H), 4.02 (br t, J=5.1 Hz, 2H), 3.03 (br t, J=7.6 Hz, 2H), 2.62 (br t, J=7.8 Hz, 2H), 2.30 (br s, 2H), 2.20 (s, 6H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.25F.sub.3O.sub.4, 457.1 [M+Na], Measured 457.3.
Example 57
3-[4-[[4-(2,2-difluoro-1,3-benzodioxol-4-yl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0357] ##STR00077##
[0358] .sup.1H NMR (CHLOROFORM-d) : 7.21 (d, J=8.1 Hz, 1H), 6.99-7.12 (m, 3H), 6.93 (dd, J=7.8, 1.3 Hz, 1H), 6.86 (dd, J=8.6, 2.5 Hz, 1H), 4.42 (s, 2H), 4.39 (s, 2H), 3.95 (t, J=5.6 Hz, 2H), 3.05 (br t, J=7.8 Hz, 2H), 2.63 (t, J=7.8 Hz, 2H), 2.50 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.19F.sub.5O.sub.6, 509.1 [M+Na], Measured 509.0.
Example 58
3-[4-[[4-[2-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0359] ##STR00078##
[0360] .sup.1H NMR (CHLOROFORM-d) : 7.16-7.40 (m, 5H), 6.99 (d, J=2.5 Hz, 1H), 6.85 (dd, J=8.6, 2.5 Hz, 1H), 4.32-4.45 (m, 2H), 4.28 (s, 2H), 3.82-4.05 (m, 2H), 3.03 (t, J=7.8 Hz, 2H), 2.57-2.69 (m, 2H), 2.41 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.20F.sub.6O.sub.5, 513.1 [M+Na], Measured 513.0.
Example 59
3-[4-[[4-(2-methoxyphenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0361] ##STR00079##
[0362] .sup.1H NMR (CHLOROFORM-d) : 7.29 (td, J=7.8, 1.5 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.07 (dd, J=7.3, 1.8 Hz, 1H), 7.01 (d, J=2.5 Hz, 1H), 6.90-6.97 (m, 2H), 6.86 (dd, J=8.6, 2.5 Hz, 1H), 4.31-4.46 (m, 4H), 3.90-4.02 (m, 2H), 3.81 (s, 3H), 3.03 (br t, J=7.8 Hz, 2H), 2.63 (t, J=7.8 Hz, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.23F.sub.3O.sub.5, 459.1 [M+Na], Measured 459.0.
Example 60
3-[4-[[4-(2-isobutoxyphenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0363] ##STR00080##
[0364] .sup.1H NMR (CHLOROFORM-d) : 7.22-7.31 (m, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.07 (dd, J=7.6, 1.5 Hz, 1H), 7.00 (d, J=2.5 Hz, 1H), 6.86-6.95 (m, 2H), 6.84 (dd, J=8.6, 2.5 Hz, 1H), 4.25-4.49 (m, 4H), 3.81-4.09 (m, 2H), 3.72 (br s, 2H), 3.03 (br t, J=7.6 Hz, 2H), 2.62 (br t, J=7.8 Hz, 2H), 2.27-2.57 (m, 2H), 2.05 (dquin, J=13.1, 6.6 Hz, 1H), 1.00 (d, J=7.1 Hz, 6H). Mass spectrum (ESI, m/z): Calculated for C.sub.2H.sub.29F.sub.3O.sub.5, 501.1 [M+Na], Measured 501.3.
Example 61
3-[4-[(4-benzyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0365] ##STR00081##
[0366] .sup.1H NMR (CHLOROFORM-d) : 7.13-7.35 (m, 7H), 7.02 (dd, J=8.6, 2.5 Hz, 1H), 4.59 (s, 2H), 4.29 (s, 2H), 3.78 (t, J=5.6 Hz, 2H), 3.52 (s, 2H), 3.07 (br t, J=7.8 Hz, 2H), 2.64 (t, J=7.8 Hz, 2H), 2.08 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.23F.sub.3O.sub.4, 443.1 [M+Na], Measured 443.0.
Example 62
3-[4-[[4-(4-chloro-3-methyl-phenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0367] ##STR00082##
[0368] .sup.1H NMR (CHLOROFORM-d) : 7.31 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 7.03 (d, J=2.5 Hz, 1H), 6.97 (dd, J=8.1, 2.0 Hz, 1H), 6.88 (dd, J=8.6, 2.5 Hz, 1H), 4.38 (s, 2H), 4.33 (s, 2H), 3.92 (t, J=5.6 Hz, 2H), 3.05 (t, J=7.8 Hz, 2H), 2.57-2.68 (m, 2H), 2.45 (br s, 2H), 2.34 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.22ClF.sub.3O.sub.4, 477.1 [M+Na], Measured 477.0.
Example 63
3-[4-[[4-(3,4-dichlorophenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-trifluoromethyl)phenyl]propanoic acid
[0369] ##STR00083##
[0370] .sup.1H NMR (CHLOROFORM-d) : 7.42 (d, J=8.1 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 7.01-7.09 (m, 2H), 6.89 (dd, J=8.6, 2.5 Hz, 1H), 4.36 (s, 4H), 3.95 (t, J=5.6 Hz, 2H), 3.06 (t, J=7.8 Hz, 2H), 2.59-2.69 (m, 2H), 2.45 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.19Cl.sub.2F.sub.3O.sub.4, 497.1 [M+Na], Measured 497.0.
Example 64
3-[2-(trifluoromethyl)-4-[[4-(2,4,5-trimethylphenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]phenyl]propanoic acid
[0371] ##STR00084##
[0372] .sup.1H NMR (CHLOROFORM-d) : 7.18 (d, J=8.1 Hz, 1H), 7.00 (d, J=2.5 Hz, 1H), 6.97 (s, 1H), 6.84 (dd, J=8.3, 2.8 Hz, 1H), 6.81 (s, 1H), 4.31-4.47 (m, 2H), 4.27 (s, 2H), 3.95 (t, J=5.6 Hz, 2H), 3.03 (t, J=7.8 Hz, 2H), 2.56-2.68 (m, 2H), 2.34 (br s, 2H), 2.22 (s, 3H), 2.20 (s, 3H), 2.14 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.25H.sub.27F.sub.3O.sub.4, 471.1 [M+Na], Measured 471.0.
Example 65
3-[4-[[4-(4-chloro-2-methyl-phenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0373] ##STR00085##
[0374] .sup.1H NMR (CHLOROFORM-d) : 7.12-7.23 (m, 3H), 6.97-7.03 (m, 2H), 6.96 (s, 1H), 6.83 (dd, J=8.6, 2.5 Hz, 1H), 4.31-4.49 (m, 2H), 4.21 (s, 2H), 3.96 (t, J=5.6 Hz, 2H), 3.04 (t, J=7.8 Hz, 2H), 2.55-2.69 (m, 2H), 2.32 (br d, J=1.5 Hz, 2H), 2.21 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.22ClF.sub.3O.sub.4, 477.1 [M+Na], Measured 477.0.
Example 66
3-[4-[[4-(3,4-dimethylphenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0375] ##STR00086##
[0376] .sup.1H NMR (CHLOROFORM-d) : 7.20 (d, J=8.6 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H), 7.03 (d, J=2.5 Hz, 1H), 6.98 (s, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.88 (dd, J=8.6, 2.5 Hz, 1H), 4.43 (s, 2H), 4.35 (s, 2H), 3.93 (t, J=5.6 Hz, 2H), 3.04 (br t, J=8.1 Hz, 2H), 2.58-2.68 (m, 2H), 2.47 (br s, 2H), 2.26 (s, 3H), 2.23 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.25F.sub.3O.sub.4, 457.1 [M+Na], Measured 457.0.
Example 67
3-[4-[[4-(2-fluoro-4-methyl-phenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0377] ##STR00087##
[0378] .sup.1H NMR (CHLOROFORM-d) : 7.20 (d, J=8.6 Hz, 1H), 6.99-7.08 (m, 2H), 6.89-6.97 (m, 2H), 6.86 (dd, J=8.6, 2.5 Hz, 1H), 4.35-4.43 (m, 4H), 3.96 (br t, J=5.1 Hz, 2H), 3.04 (br t, J=7.6 Hz, 2H), 2.64 (br t, J=7.6 Hz, 2H), 2.45 (br s, 2H), 2.35 (s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.22F.sub.4O.sub.4, 461.1 [M+Na], Measured 461.0.
Example 68
3-[4-[[4-(3-fluoro-4-methyl-phenyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0379] ##STR00088##
[0380] .sup.1H NMR (CHLOROFORM-d) : 7.21 (d, J=8.6 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 7.03 (d, J=2.5 Hz, 1H), 6.83-6.91 (m, 3H), 4.41 (s, 2H), 4.35 (s, 2H), 3.94 (t, J=5.6 Hz, 2H), 3.05 (t, J=7.8 Hz, 2H), 2.60-2.68 (m, 2H), 2.46 (br s, 2H), 2.27 (d, J=1.5 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.22F.sub.4O.sub.4, 461.1 [M+Na], Measured 461.0.
Example 69
3-[4-[[4-[[4-(trifluoromethoxy)phenyl]methyl]-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0381] ##STR00089##
[0382] .sup.1H NMR (CHLOROFORM-d) : 7.24-7.30 (m, 1H), 7.11-7.22 (m, 5H), 7.01 (dd, J=8.3, 2.3 Hz, 1H), 4.56 (s, 2H), 4.30 (br s, 2H), 3.80 (t, J=5.6 Hz, 2H), 3.51 (s, 2H), 3.07 (br t, J=7.6 Hz, 2H), 2.65 (br t, J=7.8 Hz, 2H), 2.07 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.22FO.sub.5, 527.1 [M+Na], Measured 527.0.
Example 70
3-[4-[[4-(1-phenylvinyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0383] ##STR00090##
[0384] .sup.1H NMR (CHLOROFORM-d) : 7.28-7.42 (m, 5H), 7.20 (d, J=8.6 Hz, 1H), 7.09 (d, J=2.5 Hz, 1H), 6.92 (dd, J=8.3, 2.3 Hz, 1H), 5.59 (s, 1H), 5.14 (s, 1H), 4.53 (s, 2H), 4.40 (s, 2H), 3.87 (t, J=5.3 Hz, 2H), 3.04 (br t, J=7.8 Hz, 2H), 2.63 (t, J=7.8 Hz, 2H), 2.23 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.23F.sub.3O.sub.4, 455.1 [M+Na], Measured 455.0.
Example 71
3-[4-[(4-benzyl-3,6-dihydro-2H-pyran-5-yl)methoxy]phenyl]propanoic acid
[0385] ##STR00091##
[0386] .sup.1H NMR (CHLOROFORM-d) : 7.27-7.33 (m, 2H), 7.15-7.24 (m, 3H), 7.13 (d, J=8.1 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 4.56 (s, 2H), 4.30 (s, 2H), 3.77 (t, J=5.6 Hz, 2H), 3.51 (s, 2H), 2.86-2.95 (m, 2H), 2.61-2.69 (m, 2H), 2.03-2.10 (m, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.24O.sub.4, 375.1 [M+Na], Measured 375.0.
Example 72
3-[4-[[4-(D-tolylmethyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]phenyl]propanoic acid
[0387] ##STR00092##
[0388] .sup.1H NMR (CHLOROFORM-d) : 7.02-7.17 (m, 6H), 6.86 (d, J=8.6 Hz, 2H), 4.55 (s, 2H), 4.28 (s, 2H), 3.76 (t, J=5.6 Hz, 2H), 3.46 (s, 2H), 2.83-2.96 (m, 2H), 2.60-2.70 (m, 2H), 2.32 (s, 3H), 2.05 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.26O.sub.4, 389.1 [M+Na], Measured 389.0.
Example 73
3-[4-[[4-(p-tolylmethyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0389] ##STR00093##
[0390] .sup.1H NMR (CHLOROFORM-d) : 7.23-7.29 (m, 1H), 7.17 (d, J=2.5 Hz, 1H), 7.03-7.13 (m, 4H), 7.02 (dd, J=8.6, 2.5 Hz, 1H), 4.58 (s, 2H), 4.28 (s, 2H), 3.77 (t, J=5.6 Hz, 2H), 3.47 (s, 2H), 3.07 (t, J=7.8 Hz, 2H), 2.60-2.69 (m, 2H), 2.32 (s, 3H), 2.07 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.25F.sub.3O.sub.4, 457.1 [M+Na], Measured 457.0.
Example 74
3-[4-[[4-[(4-chlorophenyl)methyl]-3,6-dihydro-2H-pyran-5-yl]methoxy]phenyl]propanoic acid
[0391] ##STR00094##
[0392] .sup.1H NMR (CHLOROFORM-d) : 7.26 (m, 2H), 7.12 (t, J=8.6 Hz, 4H), 6.85 (d, J=8.6 Hz, 2H), 4.52 (s, 2H), 4.28 (s, 2H), 3.76 (t, J=5.6 Hz, 2H), 3.47 (s, 2H), 2.83-2.97 (m, 2H), 2.59-2.72 (m, 2H), 2.03 (br s, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.23ClO.sub.4, 409.1 [M+Na], Measured 409.0.
Example 75
3-[4-[[4-[(4-chlorophenyl)methyl]-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0393] ##STR00095##
[0394] .sup.1H NMR (CHLOROFORM-d) : 7.21-7.31 (m, 3H), 7.17 (d, J=2.5 Hz, 1H), 7.10 (d, J=8.1 Hz, 2H), 7.01 (dd, J=8.6, 2.5 Hz, 1H), 4.56 (s, 2H), 4.31 (br s, 2H), 3.81 (t, J=5.6 Hz, 2H), 3.48 (s, 2H), 3.08 (br t, J=7.8 Hz, 2H), 2.66 (t, J=7.8 Hz, 2H), 2.06 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.22ClF.sub.3O.sub.4, 477.1 [M+Na], Measured 477.0.
Example 76
3-[4-[[4-[(4-methoxyphenyl)methyl]-3,6-dihydro-2H-pyran-5-yl]methoxy]phenyl]propanoic acid
[0395] ##STR00096##
[0396] .sup.1H NMR (CHLOROFORM-d) : 7.10 (dd, J=16.7, 8.6 Hz, 4H), 6.84 (dd, J=12.9, 8.3 Hz, 4H), 4.55 (s, 2H), 4.28 (br s, 2H), 3.69-3.89 (m, 5H), 3.44 (s, 2H), 2.80-3.02 (m, 2H), 2.53-2.73 (m, 2H), 2.05 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.2O.sub.5, 405.1 [M+Na], Measured 405.0.
Example 77
3-[4-[[4-[(4-methoxyphenyl)methyl]-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0397] ##STR00097##
[0398] .sup.1H NMR (CHLOROFORM-d) : 7.24-7.31 (m, 1H), 7.18 (d, J=2.0 Hz, 1H), 7.08 (d, J=8.6 Hz, 2H), 7.02 (br d, J=8.6 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 4.59 (s, 2H), 4.31 (br s, 2H), 3.74-3.83 (m, 5H), 3.45 (s, 2H), 3.07 (br t, J=7.6 Hz, 2H), 2.66 (t, J=7.8 Hz, 2H), 2.08 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.25F.sub.3O.sub.5, 473.1 [M+Na], Measured 473.0.
Example 78
3-[4-[[4-(1-phenylvinyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]phenyl]propanoic acid
[0399] ##STR00098##
[0400] .sup.1H NMR (CHLOROFORM-d) : 7.35 (br d, J=11.1 Hz, 5H), 7.06 (br d, J=8.1 Hz, 2H), 6.77 (br d, J=8.1 Hz, 2H), 5.57 (s, 1H), 5.14 (s, 1H), 4.51 (s, 2H), 4.42 (br s, 2H), 3.86 (br s, 2H), 2.84-2.92 (m, 2H), 2.63 (br t, J=7.6 Hz, 2H), 2.21 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.25F.sub.3O.sub.5, 387.1 [M+Na], Measured 387.0.
Example 79
3-[4-[[4-(1-phenylethyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0401] ##STR00099##
[0402] .sup.1H NMR (CHLOROFORM-d) : 7.14-7.35 (m, 7H), 7.03 (dd, J=8.3, 2.8 Hz, 1H), 4.60 (s, 2H), 4.30 (s, 2H), 4.17 (q, J=7.1 Hz, 1H), 3.84 (dt, J=11.0, 5.4 Hz, 1H), 3.69 (ddd, J=11.2, 6.9, 4.5 Hz, 1H), 3.08 (br t, J=7.8 Hz, 2H), 2.61-2.70 (m, 2H), 2.17 (br d, J=17.2 Hz, 1H), 1.77 (br d, J=17.2 Hz, 1H), 1.44 (d, J=7.1 Hz, 3H).). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.25F.sub.3O.sub.4, 457.1 [M+Na], Measured 457.0.
Example 80
3-[4-[[4-[1-(4-fluorophenyl)vinyl]-3,6-dihydro-2H-pyran-5-yl]methoxy]phenyl]propanoic acid
[0403] ##STR00100##
[0404] .sup.1H NMR (CHLOROFORM-d) : 7.30-7.39 (m, 2H), 7.07 (d, J=8.6 Hz, 2H), 6.95-7.05 (m, 2H), 6.76 (d, J=8.6 Hz, 2H), 5.50 (d, J=1.0 Hz, 1H), 5.11 (s, 1H), 4.49 (s, 2H), 4.40 (s, 2H), 3.84 (t, J=5.6 Hz, 2H), 2.80-2.93 (m, 2H), 2.52-2.68 (m, 2H), 2.18 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.23FO.sub.4, 405.1 [M+Na], Measured 405.0.
Example 81
3-[4-[[4-[1-(3-fluorophenyl)vinyl]-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0405] ##STR00101##
[0406] .sup.1H NMR (CHLOROFORM-d) : 7.27-7.34 (m, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.09 (d, J=3.0 Hz, 1H), 7.05 (dt, J=10.2, 2.0 Hz, 1H), 6.99 (td, J=8.3, 2.0 Hz, 1H), 6.92 (dd, J=8.6, 2.5 Hz, 1H), 5.61 (s, 1H), 5.19 (s, 1H), 4.50 (s, 2H), 4.41 (s, 2H), 3.89 (t, J=5.6 Hz, 2H), 3.05 (br t, J=7.8 Hz, 2H), 2.64 (t, J=7.8 Hz, 2H), 2.23 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.22F.sub.4O.sub.4, 473.1 [M+Na], Measured 473.1.
Example 82
3-[2-(trifluoromethyl)-4-[[4-[1-[4-(trifluoromethyl)phenyl]vinyl]-3,6-dihydro-2H-pyran-5-yl]methoxy]phenyl]propanoic acid
[0407] ##STR00102##
[0408] .sup.1H NMR (CHLOROFORM-d) : 7.58 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.21 (d, J=8.6 Hz, 1H), 7.07 (d, J=2.5 Hz, 1H), 6.91 (dd, J=8.3, 2.8 Hz, 1H), 5.67 (d, J=1.0 Hz, 1H), 5.26 (d, J=1.0 Hz, 1H), 4.49 (s, 2H), 4.36-4.43 (m, 2H), 3.87 (t, J=5.6 Hz, 2H), 3.04 (t, J=7.8 Hz, 2H), 2.57-2.66 (m, 2H), 2.21 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.25H.sub.22F.sub.6O.sub.4, 523.1 [M+Na], Measured 523.1.
Example 83
3-[4-[[4-[1-(2-chlorophenyl)vinyl]-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0409] ##STR00103##
[0410] .sup.1H NMR (CHLOROFORM-d) : 7.30-7.38 (m, 1H), 7.17-7.25 (m, 4H), 7.10 (d, J=2.5 Hz, 1H), 6.96 (dd, J=8.6, 2.5 Hz, 1H), 5.42 (d, J=1.5 Hz, 1H), 5.36 (d, J=1.5 Hz, 1H), 4.56 (s, 2H), 4.35 (s, 2H), 3.81 (t, J=5.6 Hz, 2H), 3.07 (br t, J=7.8 Hz, 2H), 2.59-2.69 (m, 2H), 2.14 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.24H.sub.22ClF.sub.3O.sub.4, 489.1 [M+Na], Measured 489.0.
Example 84
3-[4-[(4-butyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0411] ##STR00104##
[0412] .sup.1H NMR (CHLOROFORM-d) : 7.21-7.30 (m, 1H), 7.17 (d, J=2.5 Hz, 1H), 7.01 (dd, J=8.1, 2.5 Hz, 1H), 4.47 (s, 2H), 4.19 (br s, 2H), 3.71-3.87 (m, 2H), 2.99-3.16 (m, 2H), 2.65 (t, J=7.8 Hz, 2H), 2.15 (br d, J=5.6 Hz, 4H), 1.17-1.47 (m, 4H), 0.90 (t, J=7.3 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.20H.sub.25F.sub.3O.sub.4, 409.1 [M+Na], Measured 409.0.
Example 85
3-[2-chloro-4-[[4-[(4-chlorophenyl)methyl]-3,6-dihydro-2H-pyran-5-yl]methoxy]phenyl]propanoic acid
[0413] ##STR00105##
[0414] .sup.1H NMR (400 MHz, CD.sub.3OD) : 7.19-7.30 (m, 5H), 7.01 (s, 1H), 6.86 (d, J=8.4 Hz, 1H), 4.63 (s, 2H), 4.25 (s, 2H), 3.74 (t, J=5.6 Hz, 2H), 3.53 (s, 2H), 2.99 (t, J=7.2 Hz, 2H), 2.98 (t, J=7.2 Hz, 2H), 2.04 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.22C.sub.12O.sub.4, 419.1 [MH], Measured 419.0.
Example 86
3-[4-[(4-benzyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-chloro-phenyl]propanoic acid
[0415] ##STR00106##
[0416] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.15-7.29 (m, 6H), 6.84 (d, J=8.7 Hz, 1H), 4.90 (s, 2H), 4.23 (s, 2H), 3.72 (t, J=5.7 Hz, 2H), 3.52 (s, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.57 (t, J=7.5 Hz, 2H), 2.03 (br s, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.23ClO.sub.4, 385.1 [MH], Measured 385.1.
Example 87
3-[4-[(4-benzyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-3,5-difluoro-phenyl]propanoic acid
[0417] ##STR00107##
[0418] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.22-7.40 (m, 3H), 7.08-7.19 (m, 2H), 6.86-6.94 (m, 2H), 4.71 (s, 2H), 4.33 (s, 2H), 3.71 (t, J=5.7 Hz, 2H), 3.54 (s, 2H), 2.88 (t, J=7.8 Hz, 2H), 2.61 (t, J=7.8 Hz, 2H), 1.97-2.04 (m, 2H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 76.99, 129.93. Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.23F.sub.2O.sub.4, 387.1 [MH], Measured 387.1.
Example 88
3-[4-[(4-ethyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0419] ##STR00108##
[0420] .sup.1H NMR (CHLOROFORM-d) : 7.26 (m, 1H), 7.17 (d, J=2.5 Hz, 1H), 6.98-7.05 (m, 1H), 4.48 (s, 2H), 4.19 (s, 2H), 3.82 (t, J=5.6 Hz, 2H), 3.08 (t, J=7.8 Hz, 2H), 2.60-2.71 (m, 2H), 2.11-2.23 (m, 4H), 1.03 (t, J=7.6 Hz, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.18H.sub.21F.sub.3O.sub.4, 381.1 [M+Na], Measured 381.1.
Example 89
3-[4-[(4-isobutyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0421] ##STR00109##
[0422] .sup.1H NMR (CHLOROFORM-d) : 7.26 (m, 1H), 7.16 (d, J=2.5 Hz, 1H), 7.00 (dd, J=8.6, 2.5 Hz, 1H), 4.47 (s, 2H), 4.22 (br s, 2H), 3.81 (t, J=5.6 Hz, 2H), 3.07 (br t, J=7.8 Hz, 2H), 2.65 (t, J=7.8 Hz, 2H), 2.14 (br s, 2H), 2.04 (d, J=7.1 Hz, 2H), 1.80 (dquin, J=13.6, 6.7 Hz, 1H), 0.90 (d, J=6.6 Hz, 6H). Mass spectrum (ESI, m/z): Calculated for C.sub.20H.sub.25F.sub.3O.sub.4, 409.1 [M+Na], Measured 409.1.
Example 90
3-[4-[[4-(cyclohexylmethyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0423] ##STR00110##
[0424] .sup.1H NMR (CHLOROFORM-d) : 7.26-7.30 (m, 1H), 7.16 (d, J=2.5 Hz, 1H), 7.00 (dd, J=8.6, 2.5 Hz, 1H), 4.47 (s, 2H), 4.23 (br s, 2H), 3.83 (t, J=5.6 Hz, 2H), 3.08 (br t, J=7.6 Hz, 2H), 2.66 (t, J=7.8 Hz, 2H), 2.15 (br s, 2H), 2.04 (br d, J=7.1 Hz, 2H), 1.68 (br d, J=9.6 Hz, 5H), 1.43 (ddd, J=10.7, 7.5, 3.5 Hz, 1H), 1.04-1.29 (m, 3H), 0.77-0.95 (m, 2H).). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.29F.sub.3O.sub.4, 449.1 [M+Na], Measured 449.3.
Example 91
3-[4-[(4-hexyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0425] ##STR00111##
[0426] .sup.1H NMR (CHLOROFORM-d) : 7.24-7.29 (m, 1H), 7.16 (d, J=2.5 Hz, 1H), 7.01 (dd, J=8.6, 2.5 Hz, 1H), 4.47 (s, 2H), 4.20 (s, 2H), 3.81 (t, J=5.6 Hz, 2H), 3.07 (t, J=7.8 Hz, 2H), 2.57-2.71 (m, 2H), 2.15 (br d, J=7.6 Hz, 4H), 1.40 (br d, J=8.1 Hz, 2H), 1.27 (br s, 6H), 0.80-0.91 (m, 3H). Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.29F.sub.3O.sub.4, 437.1 [M+Na], Measured 437.3.
Example 92
3-(2-chloro-4-[[4-(1-phenylethenyl)-5,6-dihydro-2H-pyran-3-yl]methoxy]phenyl)propanoic acid
[0427] ##STR00112##
Step 1. 4,4,5,5-tetramethyl-2-(1-phenylethenyl)-1,3,2-dioxaborolane
[0428] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added (1-bromoethenyl)benzene (800 mg, 4.370 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.23 g, 4.840 mmol, 1.11 equiv), potassium phenolate (870 mg, 6.580 mmol, 1.51 equiv), Pd(PPh.sub.3).sub.2Cl.sub.2 (92 mg, 0.080 mmol, 0.02 equiv), PPh.sub.3 (69 mg, 0.260 mmol, 0.06 equiv) and toluene (15 mL). The resulting mixture was stirred for 5 h at 50 C. in an oil bath and then concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with water (10 mL) and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (5:95) to yield 4,4,5,5-tetramethyl-2-(1-phenylethenyl)-1,3,2-dioxaborolane as brown oil.
Step 2. Ethyl 3-(2-chloro-4-[[4-(1-phenylethenyl)-5,6-dihydro-2H-pyran-3-yl]methoxy]phenyl)propanoate
[0429] Into a 50-mL round-bottom flask was added ethyl 3-[4-[(4-bromo-5,6-dihydro-2H-pyran-3-yl)methoxy]-2-chlorophenyl]propanoate (100 mg, 0.250 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(1-phenylethenyl)-1,3,2-dioxaborolane (68.7 mg, 0.300 mmol, 1.21 equiv), Pd(dppf)Cl.sub.2 (18.2 mg, 0.020 mmol, 0.10 equiv), K.sub.3PO.sub.4 (105.4 mg, 0.500 mmol, 2.00 equiv), 1,4-dioxane (4 mL) and water (2 mL). The resulting mixture was stirred overnight at 80 C., then diluted with water (5 mL) and extracted with ethyl acetate (35 mL). The organic layers were combined and washed with brine (35 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to yield ethyl 3-(2-chloro-4-[[4-(1-phenylethenyl)-5,6-dihydro-2H-pyran-3-yl]methoxy]phenyl)propanoate as colorless oil.
Step 3. 3-(2-chloro-4-[[4-(1-phenylethenyl)-5,6-dihydro-2H-pyran-3-yl]methoxy]phenyl)propanoic acid
[0430] Into a 50-mL round-bottom flask was added ethyl 3-(2-chloro-4-[[4-(1-phenylethenyl)-5,6-dihydro-2H-pyran-3-yl]methoxy]phenyl)propanoate (45 mg, 0.110 mmol, 1.00 equiv), tetrahydrofuran (1 mL), LiOH (45 mg, 1.880 mmol, 17.83 equiv) and water (1 mL) and the reaction was stirred overnight at 20 C. The resulting mixture was diluted with ethyl acetate (5 mL) and the pH adjusted to 5-6 with 2N hydrochloric acid. The resulting solution was extracted with ethyl acetate (35 mL) and the organic layers combined and washed with brine (35 mL). The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase HPLC on a SunFire C18 column (19 mm100 mm, 5 M) with a linear gradient of 30-78% acetonitrile in water (0.05% TFA) in 10 mins to yield 3-(2-chloro-4-[[4-(1-phenylethenyl)-5,6-dihydro-2H-pyran-3-yl]methoxy] phenyl)propanoic acid as colorless oil.
[0431] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.25-7.41 (m, 5H), 7.15 (d, J=8.4 Hz, 1H), 6.86 (s, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.62 (s, 1H), 5.13 (s, 1H), 4.52 (s, 2H), 4.35 (s, 2H), 3.83 (t, J=8.4 Hz, 2H), 2.91 (t, J=7.8 Hz, 2H), 2.56 (t, J=7.8 Hz, 2H), 2.17-2.22 (m, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.23H.sub.23ClO.sub.4, 397.1 [MH], Measured 397.1.
[0432] The following compounds were similarly prepared according to the procedure as described in Example 92 above, selecting and substituting suitably substituted reactants, as would be readily recognized by those skilled in the art.
Example 93
3-[4-[[4-[(4-chlorophenyl)methyl]-3,6-dihydro-2H-pyran-5-yl]methoxy]-3,5-difluoro-phenyl]propanoic acid
[0433] ##STR00113##
[0434] .sup.1H NMR (300 MHz, CD.sub.3OD) :7.24 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.86-6.94 (m, 2H), 4.68 (s, 2H), 4.33 (s, 2H), 3.72 (t, J=8.4 Hz, 2H), 3.44 (s, 2H), 2.88 (t, J=7.8 Hz, 2H), 2.61 (t, J=7.8 Hz, 2H), 1.95-1.99 (m, 2H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 129.94. Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.21ClF.sub.2O.sub.4, 421.1 [MH], Measured 421.0.
Example 94
3-[4-[(4-isopentyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0435] ##STR00114##
[0436] .sup.1H NMR (CHLOROFORM-d) : 7.26-7.30 (m, 1H), 7.17 (d, J=3.0 Hz, 1H), 7.01 (dd, J=8.6, 2.5 Hz, 1H), 4.48 (s, 2H), 4.20 (s, 2H), 3.82 (t, J=5.6 Hz, 2H), 3.07 (br t, J=7.8 Hz, 2H), 2.66 (t, J=8.1 Hz, 2H), 2.06-2.21 (m, 3H), 1.54 (dquin, J=13.5, 6.6 Hz, 1H), 1.24-1.35 (m, 2H), 0.89 (d, J=6.6 Hz, 5H). Mass spectrum (ESI, m/z): Calculated for C.sub.21H.sub.27F.sub.3O.sub.4, 423.1 [M+Na], Measured 423.3.
Example 95
3-[3,5-difluoro-4-[[4-(1-phenylvinyl)-3,6-dihydro-2H-pyran-5-yl]methoxy]phenyl]propanoic acid
[0437] ##STR00115##
[0438] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.72-7.28 (s, 5H), 6.82 (d, J=9.0 Hz, 2H), 5.51 (s, 1H), 4.90 (s, 1H), 4.61 (s, 2H), 4.45 (s, 2H), 3.8 (t, J=5.6 Hz, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.58 (t, J=7.6 Hz, 2H), 2.14 (brs, 2H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 129.84. Mass spectrum (ESI, m/z): Calculated for C.sub.23.H.sub.22F.sub.2O.sub.4, 399.1 [MH], Measured 399.1.
Example 96
3-[4-[(4-cyclobutyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2,3-dimethyl-phenyl]propanoic acid
[0439] ##STR00116##
[0440] .sup.1H NMR (CHLOROFORM-d) : 6.97 (d, J=8.1 Hz, 1H), 6.66 (d, J=8.1 Hz, 1H), 4.40 (s, 2H), 4.22 (br s, 2H), 3.83 (t, J=5.6 Hz, 2H), 3.45 (quin, J=8.8 Hz, 1H), 2.86-2.98 (m, 2H), 2.53-2.66 (m, 2H), 2.22 (s, 5H), 2.15 (s, 3H), 1.94-2.11 (m, 4H), 1.81-1.94 (m, 1H), 1.66-1.78 (m, 1H). Mass spectrum (ESI, m/z): Calculated for C.sub.21H.sub.28O.sub.4, 367.1 [M+Na], Measured 367.3.
Example 97
3-[2-chloro-4-[(4-cyclobutyl-3,6-dihydro-2H-pyran-5-yl)methoxy]phenyl]propanoic acid
[0441] ##STR00117##
[0442] .sup.1H NMR (CHLOROFORM-d) : 7.15 (d, J=8.1 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 6.75 (dd, J=8.3, 2.3 Hz, 1H), 4.39 (s, 2H), 4.18 (br s, 2H), 3.83 (br t, J=5.3 Hz, 2H), 3.44 (quin, J=8.8 Hz, 1H), 3.00 (br t, J=7.6 Hz, 2H), 2.68 (br t, J=7.3 Hz, 2H), 2.24 (br s, 2H), 1.96-2.15 (m, 4H), 1.81-1.96 (m, 1H), 1.66-1.80 (m, 1H). Mass spectrum (ESI, m/z): Calculated for C.sub.19H.sub.23ClO.sub.4, 373.1 [M+Na], Measured 373.0.
Example 98
3-[2-chloro-4-[(4-cyclopentyl-3,6-dihydro-2H-pyran-5-yl)methoxy]phenyl]propanoic acid
[0443] ##STR00118##
[0444] .sup.1H NMR (CHLOROFORM-d) : 7.16 (d, J=8.6 Hz, 1H), 6.93 (d, J=2.5 Hz, 1H), 6.76 (dd, J=8.6, 2.5 Hz, 1H), 4.44 (s, 3H), 4.20 (s, 2H), 3.81 (t, J=5.3 Hz, 2H), 2.87-3.05 (m, 3H), 2.67 (t, J=7.6 Hz, 2H), 2.13 (br s, 2H), 1.50-1.76 (m, 6H), 1.43 (td, J=11.2, 4.3 Hz, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.20H.sub.25ClO.sub.4, 387.1 [M+Na], Measured 387.0.
Example 99
3-[4-[(4-cyclohexyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0445] ##STR00119##
Step 1. Methyl 4-cyclohexyl-5,6-dihydro-2H-pyran-3-carboxylate
[0446] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added methyl 4-[(trifluoromethane)sulfonyloxy]-5,6-dihydro-2H-pyran-3-carboxylate (200 mg, 0.69-mmol, 1.00 equiv), Pd(PPh.sub.3).sub.4 (398 mg, 0.340 mmol, 0.50 equiv), tetrahydrofuran (5 mL). This was followed by the addition of (cyclohexyl)zinc bromide solution (0.5 M in THF, 2.7 mL, 2.00 equiv) dropwise with stirring at 0 C. The resulting solution was stirred overnight at 50 C. in an oil bath and then quenched by the addition of water (20 mL). The resulting mixture was extracted with ethyl acetate (330 mL) and the organic layers combined and washed with brine (130 mL). The resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to yield methyl 4-cyclohexyl-5,6-dihydro-2H-pyran-3-carboxylate as light yellow oil. Mass spectrum (EI, m/z): Calculated for C.sub.13H.sub.20O.sub.3, 224.1 [M], Measured 224.1.
Step 2. (4-cyclohexyl-5,6-dihydro-2H-pyran-3-yl)methanol
[0447] To a solution of methyl 4-cyclohexyl-5,6-dihydro-2H-pyran-3-carboxylate (100 mg, 0.450 mmol, 1.00 equiv) in dichloromethane (4 mL) at 78 C. was added DIBAL (1M in toluene, 0.9 mL, 2.00 equiv) dropwise with stirring. The resulting solution was stirred for 2 h at 78 C. and then quenched by the addition of methanol (10 mL). The resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to yield (4-cyclohexyl-5,6-dihydro-2H-pyran-3-yl)methanol as colorless oil. Mass spectrum (EI, m/z): Calculated for C.sub.12H.sub.20O.sub.2, 178.1 [M-18], Measured 178.1.
Step 3. Ethyl 3-[4-[(4-cyclohexyl-5,6-dihydro-2H-pyran-3-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoate
[0448] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added (4-cyclohexyl-5,6-dihydro-2H-pyran-3-yl)methanol (40 mg, 0.200 mmol, 1.00 equiv), ethyl 3-[4-hydroxy-2-(trifluoromethyl)phenyl]propanoate (64 mg, 0.240 mmol, 1.20 equiv), ADDP (127 mg, 0.510 mmol, 2.50 equiv), n-Bu.sub.3P (62 mg, 0.310 mmol, 1.50 equiv), and toluene (5 mL). The resulting solution was stirred overnight at 60 C. in an oil bath and then concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to yield ethyl 3-[4-[(4-cyclohexyl-5,6-dihydro-2H-pyran-3-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoate as light yellow oil.
Step 4. ethyl 3-[4-[(4-cyclohexyl-5,6-dihydro-2H-pyran-3-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoate
[0449] Into a 50-mL round-bottom flask was added ethyl 3-[4-[(4-cyclohexyl-5,6-dihydro-2H-pyran-3-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoate (40 mg, 0.090 mmol, 1.00 equiv), tetrahydrofuran (2 mL), LiOH (11 mg, 0.460 mmol, 5.00 equiv) and water (1 mL) and the reaction was stirred for 2 h at 25 C. The pH was adjusted to 6 with 2N hydrochloric acid and the resulting solution was extracted with ethyl acetate (350 mL) and the organic layers combined and washed with brine (150 mL) and concentrated. The residue was purified by reversed-phase HPLC on a SunFire C18 column (19 mm100 mm, 5 M) with a linear gradient of 60-90% acetonitrile in water (0.05% TFA) in 10 mins to yield ethyl 3-[4-[(4-cyclohexyl-5,6-dihydro-2H-pyran-3-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoate as light yellow oil.
[0450] .sup.1H NMR (400 MHz, CD.sub.3OD) : 7.39 (d, J=8.8 Hz, 1H), 7.20 (s, 1H), 7.14 (dd, J.sub.1=2.4 Hz, J.sub.2=8.4 Hz, 1H), 4.57 (s, 2H), 4.17 (s, 2H), 3.77 (t, J=5.6 Hz, 2H), 3.04 (t, J=7.6 Hz, 2H), 2.57-2.63 (m, 3H), 2.10-2.15 (m, 2H), 1.68-1.80 (m, 3H), 1.44-1.54 (m, 2H), 1.33-1.40 (m, 5H). .sup.19F NMR (400 MHz, CD.sub.3OD) : 61.35. Mass spectrum (ESI, m/z): Calculated for C.sub.22H.sub.27F.sub.3O.sub.4, 411.2 [MH], Measured 411.1.
[0451] The following compounds were similarly prepared according to the procedure as described in Example 99 above, selecting and substituting suitably substituted reactants, as would be readily recognized by those skilled in the art.
Example 100
3-[4-[(4-cyclopentyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0452] ##STR00120##
[0453] .sup.1H NMR (300 MHz, CD.sub.3OD) :7.34 (d, J=8.4 Hz, 1H), 7.07-7.15 (m, 2H), 4.54 (s, 2H), 4.14 (s, 2H), 3.74 (t, J=5.4 Hz, 2H), 2.96-3.08 (m, 3H), 2.52 (t, J=8.1 Hz, 2H), 2.05-2.10 (m, 2H), 1.55-1.68 (m, 6H), 1.43-1.51 (m, 2H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 61.34. Mass spectrum (ESI, m/z): Calculated for C.sub.21H.sub.25F.sub.3O.sub.4, 397.2 [MH], Measured 397.2.
Example 101
3-[2-chloro-4-[(4-isobutyl-3,6-dihydro-2H-pyran-5-yl)methoxy]phenyl]propanoic acid
[0454] ##STR00121##
[0455] .sup.1H NMR (400 MHz, CD.sub.3OD) : 7.24 (d, J=8.4 Hz, 1H), 6.97 (s, 1H), 6.83 (dd, J.sub.1=2.4 Hz, J.sub.2=8.4 Hz, 1H), 4.51 (s, 2H), 4.20 (s, 2H), 3.79 (t, J=5.6 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H), 2.15-2.20 (m, 2H), 2.09 (d, J=7.6 Hz, 2H), 1.80-1.87 (m, 1H), 0.92 (d, J=6.4 Hz, 6H). Mass spectrum (ESI, m/z): Calculated for C.sub.19H.sub.25ClO.sub.4, 351.1 [MH], Measured 351.1.
Example 102
3-[3,5-difluoro-4-[(4-isobutyl-3,6-dihydro-2H-pyran-5-yl)methoxy]phenyl]propanoic acid
[0456] ##STR00122##
[0457] .sup.1H NMR (300 MHz, CD.sub.3OD) : 6.81-6.89 (m, 2H), 4.52 (s, 2H), 4.25 (s, 2H), 3.73 (t, J=5.4 Hz, 2H), 2.83 (t, J=7.6 Hz, 2H), 2.55 (t, J=7.4 Hz, 2H), 2.07-2.09 (m, 2H), 1.94 (d, J=7.5 Hz, 2H), 1.68-1.77 (m, 1H), 0.81 (d, J=6.6 Hz, 6H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 130.07. Mass spectrum (ESI, m/z): Calculated for C.sub.19H.sub.24F.sub.2O.sub.4, 353.2 [MH], Measured 353.2.
Example 103
3-[4-[(4-sec-butyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0458] ##STR00123##
Step 1. Methyl 4-(butan-2-yl)-5,6-dihydro-2H-pyran-3-carboxylate
[0459] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added methyl 4-[(trifluoromethane)sulfonyloxy]-5,6-dihydro-2H-pyran-3-carboxylate (300 mg, 1.030 mmol, 1.00 equiv), Pd(OAc).sub.2 (25.4 mg, 0.110 mmol, 0.10 equiv), RuPhos (97.1 mg 0.208 mmol, 0.20 equiv), and tetrahydrofuran (5 mL). This was followed by the addition of (butan-2-yl)zinc bromide solution (0.624 mL, 1.250 mmol, 1.20 equiv) dropwise with stirring at 0 C. The resulting solution was stirred overnight at 20 C. and then quenched by the addition of water (5 mL). The resulting solution was extracted with ethyl acetate (210 mL) and the organic layers combined and washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (8:92) to yield methyl 4-(butan-2-yl)-5,6-dihydro-2H-pyran-3-carboxylate as colorless oil and recovered methyl 4-[(trifluoromethane)sulfonyloxy]-5,6-dihydro-2H-pyran-3-carboxylate as colorless oil. .sup.1H NMR (300 MHz, CDCl.sub.3) : 4.27-4.38 (m, 2H), 3.76-3.78 (m, 2H), 3.75 (s, 3H), 3.51-3.53 (m, 1H), 2.52-3.56 (m, 1H), 2.17-2.30 (m, 2H), 1.33-1.48 (m, 3H), 1.03 (d, J=6.8 Hz, 3H), 0.87 (t, J=7.6 Hz, 3H).
Step 2. [4-(butan-2-yl)-5,6-dihydro-2H-pyran-3-yl]methanol
[0460] To a solution of methyl 4-(butan-2-yl)-5,6-dihydro-2H-pyran-3-carboxylate (80 mg, 0.400 mmol, 1.00 equiv) in tetrahydrofuran (3 mL) at 0 C. was added LiAlH.sub.4 (30.7 mg, 0.810 mmol, 2.00 equiv). The resulting mixture was stirred for 30 min at 0 C. in a water/ice bath. The reaction was then quenched by the addition of sodium sulfate.10H.sub.2O. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (25:75) to yield [4-(butan-2-yl)-5,6-dihydro-2H-pyran-3-yl]methanol as colorless oil.
Step 3. 3-(4-((4-sec-butyl-5,6-dihydro-2H-pyran-3-yl)methoxy)-2-(trifluoromethyl)phenyl)propanoic acid
[0461] Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added [4-(butan-2-yl)-5,6-dihydro-2H-pyran-3-yl]methanol (50 mg, 0.290 mmol, 1.00 equiv), ethyl 3-[4-hydroxy-2-(trifluoromethyl)phenyl]propanoate (92.5 mg, 0.350 mmol, 1.20 equiv), ADDP (185.3 mg, 0.740 mmol, 2.52 equiv), n-Bu.sub.3P (89.1 mg, 0.441 mmol, 1.50 equiv), and toluene (3 mL). The resulting solution was stirred overnight at 70 C. in an oil bath and the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to yield ethyl 3-(4-[[4-(butan-2-yl)-5,6-dihydro-2H-pyran-3-yl]methoxy]-2-(trifluoromethyl)phenyl)propanoate as colorless oil.
Step 4. 3-(4-[[4-(butan-2-yl)-5,6-dihydro-2H-pyran-3-yl]methoxy]-2-(trifluoromethyl)phenyl)propanoic acid
[0462] Into a 25-mL round-bottom flask, was placed ethyl 3-(4-[[4-(butan-2-yl)-5,6-dihydro-2H-pyran-3-yl]methoxy]-2-(trifluoromethyl)phenyl)propanoate (60 mg, 0.140 mmol, 1.00 equiv), tetrahydrofuran (1.5 mL), LiOH (60 mg, 2.510 mmol, 17.31 equiv) and water (1.5 mL). The resulting solution was stirred overnight at 20 C. and then the pH of the solution was adjusted to 4 with 2M hydrochloric acid and the resulting solution was extracted with ethyl acetate (35 mL). The organic layers were combined and washed with brine solution (25 mL) and concentrated under vacuum. The residue was purified by reversed-phase HPLC on a SunFire C18 column (19 mm100 mm, 5 M) with a linear gradient of 65-95% acetonitrile in water (0.05% TFA) in 9 mins to yield 3-(4-[[4-(butan-2-yl)-5,6-dihydro-2H-pyran-3-yl]methoxy]-2-(trifluoromethyl)phenyl)propanoic acid as light yellow oil.
[0463] .sup.1H NMR (400 MHz, CD.sub.3OD) : 7.27 (d, J=8.8 Hz, 1H), 6.97-7.14 (m, 2H), 4.41-4.50 (m, 2H), 4.01-4.09 (m, 2H), 3.63-3.72 (m, 2H), 2.92 (t, J=8.0 Hz, 2H), 2.57-2.65 (m, 1H), 2.46 (t, J=8.0 Hz, 2H), 1.97-2.04 (m, 2H), 1.26-1.33 (m, 2H), 0.91 (d, J=6.8 Hz, 3H), 0.74 (t, J=7.4 Hz, 3H). .sup.19F NMR (400 MHz, CD.sub.3OD) : 61.35. Mass spectrum (ESI, m/z): Calculated for C.sub.20H.sub.25F.sub.3O.sub.4, 385.2 [MH], Measured 385.1.
[0464] The following compounds were similarly prepared according to the procedure as described in Example 103 above, selecting and substituting suitably substituted reactants, as would be readily recognized by those skilled in the art.
Example 104
3-[4-[(4-isopropyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0465] ##STR00124##
[0466] .sup.1H NMR (300 MHz, CD.sub.3OD) : 7.36 (d, J=8.4 Hz, 1H), 7.02-7.15 (m, 2H), 4.51 (s, 2H), 4.13 (s, 2H), 3.74 (t, J=5.5 Hz, 2H), 2.89-3.05 (m, 3H), 2.32-2.46 (m, 2H), 2.04-2.11 (m, 2H), 0.99 (d, J=6.9 Hz, 6H). .sup.19F NMR (300 MHz, CD.sub.3OD) : 61.24. Mass spectrum (ESI, m/z): Calculated for C.sub.19H.sub.23F.sub.3O.sub.4, 371.2 [MH], Measured 371.1.
Example 105
3-[4-[(4-cyclopentyl-3,6-dihydro-2H-pyran-5-yl)methoxy]-3,5-difluoro-phenyl]propanoic acid
[0467] ##STR00125##
[0468] .sup.1H NMR (CHLOROFORM-d) : 6.68-6.84 (m, 2H), 4.55 (s, 2H), 4.30 (t, J=2.0 Hz, 2H), 3.79 (t, J=5.6 Hz, 2H), 2.91-3.02 (m, 1H), 2.83-2.91 (m, 2H), 2.59-2.70 (m, 2H), 2.01-2.13 (m, 2H), 1.40-1.70 (m, 6H), 1.20-1.39 (m, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.20H.sub.24F.sub.2O.sub.4, 389.1 [M+Na], Measured 389.3.
Example 106
3-[2-chloro-4-[(4-cyclopent-2-en-1-yl-3,6-dihydro-2H-pyran-5-yl)methoxy]phenyl]propanoic acid
[0469] ##STR00126##
[0470] .sup.1H NMR (CHLOROFORM-d) : 7.16 (d, J=8.1 Hz, 1H), 6.94 (d, J=2.5 Hz, 1H), 6.76 (dd, J=8.6, 2.5 Hz, 1H), 5.83-5.89 (m, 1H), 5.52 (dd, J=5.6, 2.5 Hz, 1H), 4.42-4.55 (m, 2H), 4.20 (d, J=1.5 Hz, 2H), 3.86-3.95 (m, 1H), 3.70-3.84 (m, 2H), 3.00 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.8 Hz, 2H), 2.28-2.46 (m, 2H), 2.00-2.14 (m, 3H), 1.64 (ddt, J=13.3, 9.1, 6.8 Hz, 1H). Mass spectrum (ESI, m/z): Calculated for C.sub.20H.sub.23ClO.sub.4, 385.1 [M+Na], Measured 385.3.
Example 107
3-[4-[(4-cyclopentyl-3,6-dihydro-2H-pyran-5-yl)methoxy]phenyl]propanoic acid
[0471] ##STR00127##
[0472] .sup.1H NMR (CHLOROFORM-d) : 7.13 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 4.45 (s, 2H), 4.22 (s, 2H), 3.80 (t, J=5.6 Hz, 2H), 2.93-3.06 (m, 1H), 2.87-2.93 (m, 2H), 2.60-2.69 (m, 2H), 2.13 (br s, 2H), 1.49-1.74 (m, 6H), 1.43 (td, J=11.4, 4.0 Hz, 2H). Mass spectrum (ESI, m/z): Calculated for C.sub.20H.sub.26O.sub.4, 353.1 [M+Na], Measured 353.2.
Example 108
3-[4-[(4-cyclopent-2-en-1-yl-3,6-dihydro-2H-pyran-5-yl)methoxy]-2-(trifluoromethyl)phenyl]propanoic acid
[0473] ##STR00128##
[0474] .sup.1H NMR (CHLOROFORM-d) : 7.25-7.30 (m, 1H), 7.17 (d, J=2.5 Hz, 1H), 7.02 (dd, J=8.6, 2.5 Hz, 1H), 5.85-5.91 (m, 1H), 5.51 (dq, J=5.9, 2.1 Hz, 1H), 4.45-4.61 (m, 2H), 4.23 (br d, J=1.5 Hz, 2H), 3.91 (br d, J=2.5 Hz, 1H), 3.74-3.86 (m, 2H), 3.07 (t, J=8.1 Hz, 2H), 2.60-2.69 (m, 2H), 2.22-2.54 (m, 2H), 2.03-2.18 (m, 3H), 1.64 (ddt, J=13.4, 9.3, 6.6 Hz, 1H). Mass spectrum (ESI, m/z): Calculated for C.sub.21H.sub.23F.sub.3O.sub.4, 419.1 [M+Na], Measured 419.3.
Example 109
3-[4-[(4-cyclopent-2-en-1-yl-3,6-dihydro-2H-pyran-5-yl)methoxy]phenyl]propanoic acid
[0475] ##STR00129##
[0476] .sup.1H NMR (CHLOROFORM-d) : 7.12 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 5.80-5.91 (m, 1H), 5.51 (dd, J=5.6, 2.0 Hz, 1H), 4.41-4.57 (m, 2H), 4.22 (br d, J=2.0 Hz, 2H), 3.92 (br dd, J=4.5, 2.0 Hz, 1H), 3.70-3.86 (m, 2H), 2.84-2.97 (m, 2H), 2.60-2.71 (m, 2H), 2.20-2.53 (m, 2H), 1.99-2.16 (m, 3H), 1.63 (ddt, J=13.4, 9.3, 6.6 Hz, 1H).). Mass spectrum (ESI, m/z): Calculated for C.sub.20H.sub.24O.sub.4, 351.1 [M+Na], Measured 351.3.
Example 110
3-(4-((4-(4-chlorophenyl)-2,5-dihydrofuran-3-yl)methoxy)-2,3-dimethylphenyl)propanoic acid
[0477] ##STR00130##
Step 1: methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate
[0478] To a solution of DIEA (860 L, 4.99 mmol) in dry DCM (20 mL) cooled to 78 C. under Argon was added a solution of methyl 4-oxotetrahydrofuran-3-carboxylate (628 mg, 4.63 mmol in 20 mL DCM) dropwise. The reaction mixture was stirred @ 78 C. for 30 minutes post addition and then treated dropwise with neat trifluoromethanesulfonic anhydride (820 L, 4.98 mmol). After stirring the reaction mixture for 2 h @ 0 C., the reaction mixture was quenched by the cautious addition of cold water (11 mL). The reaction mixture was warmed to ambient temperature and diluted with water and diethyl ether. The aqueous layer was extracted with diethyl ether and the combined organic layers washed with sat. NaHCO.sub.3 and brine, then dried over MgSO.sub.4. The resulting residue was concentrated in vacuo followed by flash chromatography (SiO.sub.2, 0-50% DCM/heptane) to yield a pale yellow oil.
Step 2: methyl 4-(4-chlorophenyl)-2,5-dihydrofuran-3-carboxylate
[0479] A suspension of anhydrous potassium phosphate (1.07 g, 5.04 mmol), tetrakis(triphenylphosphine) palladium (143 mg, 0.124 mmol), 4-chlorophenylboronic acid (268 mg, 1.714 mmol) and methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate (390 mg, 1.412 mmol) in 1,4-dioxane (20 mL) was sparged with a stream of argon for 20 minutes. The reaction was then placed under an Argon atmosphere and heated to 90 C. for 16 hours, before cooling to ambient temperature. The mixture was diluted with ether and filtered through a plug of CELITE. The filtrate was concentrated in vacuo and purified by flash chromatography (SiO.sub.2, 0-100% DCM/heptane) to yield a residue.
Step 3: (4-(4-chlorophenyl)-2,5-dihydrofuran-3-yl)methanol
[0480] A solution of methyl 4-(4-chlorophenyl)-2,5-dihydrofuran-3-carboxylate (268 mg, 1.123 mmol) in dry toluene (15 mL) was cooled to 78 C. under an Argon atmosphere. The reaction mixture was treated dropwise with DiBA-H (2.5 mL, 2.5 mmol in toluene) and stirred, allowing the reaction mixture to reach ambient temperature over 2 hours. After stirred one additional hour, the mixture was cooled to 10 C. and quenched by the dropwise addition of sat. Rochelle's salt (12 mL). The aqueous layer was extracted with diethyl ether and the combined organic layers washed with sat. NaHCO.sub.3 and brine, then dried over MgSO.sub.4. The resulting residue was concentrated in vacuo followed by flash chromatography (SiO.sub.2, diethyl ether) to yield a colorless crystalline solid.
Step 4: ethyl 3-(4-((4-(4-chlorophenyl)-2,5-dihydrofuran-3-yl)methoxy)-2,3-dimethylphenyl)propanoate
[0481] A solution of (4-(4-chlorophenyl)-2,5-dihydrofuran-3-yl)methanol (105 mg, 0.498 mmol), DEAD (110 L, 0.701 mmol) and methyl 3-(4-hydroxy-3-methylphenyl)propanoate (121 mg, 0.548 mmol) in toluene (7 mL) was placed under an argon atmosphere, cooled to 0 C. and treated with triphenylphosphine (183 mg, 0.698 mmol). The reaction was stirred warming gradually to ambient temperature at for 18 hours and then concentrated in vacuo. The residue was triturated with diethyl ether, the resulting white precipitate was filtered off and the filtrated concentrated and purified by flash chromatography (SiO.sub.2, 6:7 DCM:heptane) to yield a residue.
Step 5: 3-(4-((4-(4-chlorophenyl)-2,5-dihydrofuran-3-yl)methoxy)-2,3-dimethylphenyl)propanoic acid
[0482] A solution of ethyl 3-(4-((4-(4-chlorophenyl)-2,5-dihydrofuran-3-yl)methoxy)-2,3-dimethylphenyl)propanoate (123 mg, 0.296 mmol) was dissolved in THF (7 mL), water (3 mL) and methanol (3 mL) before being treated with a solution of KOH (0.600 mL, 3 mmol, SM). After stirring at ambient temperature overnight, the reaction mixture was adjusted to pH 4 with 1N HCl, then extracted with ethyl acetate. The organic extracts were dried (MgSO.sub.4) and concentrated in vacuo to yield the title compound.
[0483] .sup.1H NMR (CHLOROFORM-d) : 7.32-7.39 (m, 2H), 7.18 (d, J=8.6 Hz, 2H), 6.90-6.97 (m, 1H), 6.52-6.63 (m, 1H), 4.95-5.07 (m, 4H), 4.71 (s, 2H), 2.87-2.98 (m, 2H), 2.53-2.64 (m, 2H), 2.22 (s, 3H), 2.15 (s, 3H)
Example 111
3-(2,3-dimethyl-4-((4-phenyl-2,5-dihydrofuran-3-yl)methoxy)phenyl)propanoic acid
[0484] ##STR00131##
[0485] The title compound was prepared as describe in General Synthesis Scheme 1, selecting and substituting suitable starting materials and reagents as would be readily recognized by those skilled in the art.
[0486] .sup.1H NMR (CHLOROFORM-d) : 7.30-7.41 (m, 3H), 7.21-7.27 (m, 2H), 6.89-6.96 (m, 1H), 6.54-6.62 (m, 1H), 4.97-5.12 (m, 4H), 4.76 (s, 2H), 2.87-2.96 (m, 2H), 2.54-2.62 (m, 2H), 2.22 (s, 3H), 2.12-2.19 (m, 3H).
Example 112
3-(3-methyl-4-((4-phenyl-2,5-dihydrofuran-3-yl)methoxy)phenyl)propanoic acid
[0487] ##STR00132##
[0488] The title compound was prepared as describe in General Synthesis Scheme 1, selecting and substituting suitable starting materials and reagents as would be readily recognized by those skilled in the art.
[0489] .sup.1H NMR (CHLOROFORM-d) : 7.29-7.44 (m, 3H), 7.26 (s, 2H), 6.86-7.04 (m, 2H), 6.60-6.68 (m, 1H), 4.97-5.12 (m, 4H), 4.77 (s, 2H), 2.81-2.91 (m, 2H), 2.56-2.69 (m, 2H), 2.19 (s, 3H).
Example 113
3-(4-((4-(4-fluorophenyl)-2,5-dihydrothiophen-3-yl)methoxy)-3-methylphenyl)propanoic acid
[0490] ##STR00133##
[0491] The title compound was prepared as describe in General Synthesis Scheme 1, selecting and substituting suitable starting materials and reagents as would be readily recognized by those skilled in the art.
[0492] .sup.1H NMR (CHLOROFORM-d) : 7.15-7.24 (m, 2H), 7.03-7.11 (m, 2H), 6.96-7.01 (m, 1H), 6.85-6.94 (m, 1H), 6.47-6.59 (m, 1H), 4.51 (s, 2H), 4.12 (br s, 4H), 2.77-2.90 (m, 3H), 2.57-2.69 (m, 3H), 2.20 (s, 3H).
Example 114
3-(3,5-difluoro-4-((4-(4-fluorophenyl)-2,5-dihydrothiophen-3-yl)methoxy)phenyl)propanoic acid
[0493] ##STR00134##
[0494] The title compound was prepared as describe in General Synthesis Scheme 2, selecting and substituting suitable starting materials and reagents as would be readily recognized by those skilled in the art.
[0495] .sup.1H NMR (CHLOROFORM-d) : 7.14-7.22 (m, 2H), 6.98-7.08 (m, 2H), 6.61-6.81 (m, 2H), 4.56 (s, 2H), 4.01-4.26 (m, 4H), 2.88 (s, 3H), 2.65 (s, 3H).
Example 115
3-(4-((4-(4-fluorophenyl)-1-oxido-2,5-dihydrothiophen-3-yl)methoxy)-3-methylphenyl)propanoic acid
[0496] ##STR00135##
[0497] The title compound was prepared as describe in General Synthesis Scheme 2, selecting and substituting suitable starting materials and reagents as would be readily recognized by those skilled in the art.
[0498] .sup.1H NMR (CHLOROFORM-d) : 7.26 (s, 2H), 7.09 (s, 2H), 6.95-7.02 (m, 1H), 6.86-6.95 (m, 1H), 6.48-6.58 (m, 1H), 4.56-4.73 (m, 2H), 4.19-4.36 (m, 2H), 3.87-4.01 (m, 2H), 2.84 (s, 2H), 2.60 (s, 2H), 2.19 (s, 3H).
Example #116
3-(4-((4-(4-fluorophenyl)-1,1-dioxido-2,5-dihydrothiophen-3-yl)methoxy)-3-methylphenyl)propanoic acid
[0499] ##STR00136##
[0500] The title compound was prepared as describe in General Synthesis Scheme 1, selecting and substituting suitable starting materials and reagents as would be readily recognized by those skilled in the art.
[0501] .sup.1H NMR (CHLOROFORM-d) : 7.18-7.25 (m, 2H), 7.08-7.17 (m, 2H), 6.97-7.03 (m, 1H), 6.87-6.95 (m, 1H), 6.47-6.57 (m, 1H), 4.62 (s, 2H), 4.18 (d, J=8.1 Hz, 4H), 2.77-2.93 (m, 2H), 2.56-2.68 (m, 2H), 2.19 (s, 3H).
Example #117
3-(3,5-difluoro-4-((4-(4-fluorophenyl)-1,1-dioxido-2,5-dihydrothiophen-3-yl)methoxy)phenyl)propanoic acid
[0502] ##STR00137##
[0503] The title compound was prepared as describe in General Synthesis Scheme 1, selecting and substituting suitable starting materials and reagents as would be readily recognized by those skilled in the art.
[0504] .sup.1H NMR (CHLOROFORM-d) : 7.13-7.23 (m, 2H), 7.10 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 4.66 (s, 2H), 4.24 (s, 2H), 4.16 (s, 2H), 2.80-2.99 (m, 2H), 2.66 (s, 2H).
Biological Example 1: In Vitro Assay
Human GPR120 DiscoveRx PathHunter Beta-Arrestin Assay
Assay Principle:
[0505] The binding of an agonist (medium/long chain fatty acids or small molecule agonists) to the G-protein-coupled receptor GPR120 activates phospholipase C, leading to release of intracellular Ca.sup.+2 through the generation of inositol 1,4,5-trisphosphate (InsP3 or IP3). GPR120 activation can also trigger intracellular signaling via recruitment of Beta-Arrestin. In the present method, agonist-induced activation of the human GPR120 receptor is monitored through the use of PathHunter CHO-K1 GPR120 Beta-Arrestin Cell Line engineered by DiscoveRx, as detailed below. The cell lines were designed to co-express both the ProLink/Enzyme Donor (PK)-tagged GPCR and the Enzyme Activator (EA)-tagged Beta-Arrestin fusion proteins. Upon GPR120 receptor stimulation/activation, the EA-tagged Beta-Arrestin portion is translocated to the tagged receptor, where the two enzyme fragments are brought within close proximity. Under these conditions, these fragments can interact and form an active Beta-gal enzyme complex through Enzyme Fragment Complementation (EFC). This active Beta-gal complex can enzymatically hydrolyse the substrate to produce a detectable light signal; therefore, activation as a function of agonist concentration can be expressed as an EC.sub.50 value to determine relative compound activities. This in vitro assay therefore serves to assess compound agonist activity of the GPR120.
Procedure -Arrestin A:
[0506] In Procedure -arrestin A, the cell used were PathHunter CHO-K1 GPR120 -Arrestin Cell Line, expressing the long form of human GPR120 (Genbank accession number NM_181745), with 3000 cells per well.
Procedure -Arrestin B:
[0507] In Procedure -arrestin B the cells used were PathHunter CHO-K1 GPR120S -Arrestin Cell Line, expressing the short form of the GPR120 receptor (Accession #NM_181745), with 5000 cells/well.
Assay Procedure:
[0508] The selected CHO-K1 GPR120 -Arrestin cells were cultured in Ham's F12 media supplemented with 10% fetal bovine serum (FBS), 1% Glutamine, 1 p/s, 800 g/mL G418 and 300 g/mL Hygromycin B (for selection). Cell stocks were maintained and grown in a sub-confluent state using standard cell culture procedures. The day before the experiment, the cells were harvested with non-enzymatic cell dissociation buffer and re-suspended in complete growth media at the desired concentration. A Corning 384-plate was then seeded with the proper number of cells in a volume of 25 L, per well. The seeded plates were incubated overnight at 37 C.
[0509] On the day of the experiment, the Assay Buffer containing (a) HBSS with Ca.sup.++ and Mg.sup.++, (b) 20 mM HEPES, and (c) 0.1% BSA stabilizer (pH 7.4) was prepared. The growth medium was gently removed from the cell plates and 20 L of Assay Buffer added to each well. The plate was then incubated at 37 C. for 60 min. Test compounds were serially diluted in Assay Buffer to desired concentrations (more particularly to one or more of the following M concentrations: 25, 12.5, 6.25, 3.12, 1.56, 0.78, 0.39, 0.19, 0.10, 0.05, 0.02, 0.01). Five L of compound dilution was then added to each well and the plate incubated at 37 C. for 90 min. The detection reagents were prepared according to the manufacture's instruction. Twelve L of the detection reagents were added to each well and the plate incubated at room temperature for 60 min.
[0510] The plates were read on an EnVision instrument, using Protocol name: Luminescence, Plate type: 384 Costar, Measurement height: 3 mm, Measurement time: 1 s, Aperture: 384 Plate aperture. The % Activity relative to the positive control was calculated using the following equation:
[0511] The % Activity values were plotted versus the concentration of test compound and fitted to a sigmoidal dose-response curve with a Hill slope=1 (fixed value) using nonlinear regression with GraphPad Prism 5.0 to calculate the EC.sub.50 values. The Fitting Equation was: Y=Bottom+(TopBottom)/(1+10{circumflex over ()}((Log EC.sub.50X)*HillSlope)), where X is the log of the concentration and Y is the response.
Biological Example 2: In Vitro Assay
In Vitro Assay: Human GPR120 in Calcium Flux Assay
Assay Principle
[0512] This in vitro assay serves to assess test compound agonist activity against the short splice variant (SVS with Accession number NM_001195755.1 confirmed by sequencing data) of the GPR120 receptor. The Human Short splice variant #2 (NM_001195755.1) is missing an in-frame coding exon compared to variant 1 (the Human Long splice variant NM_181745.3), resulting in a shorter isoform (GPR120-S) lacking a 16 aa protein segment compared to isoform GPR120-L. The assay platform utilizes HEK-293 cells stably transfected to express the Human GPR120 short form. These cells are first loaded with the Ca.sup.+2 sensitive dye, Fluo-4 NW. Upon stimulation, intracellular released Ca.sup.+2 can bind to the dye and alter its fluorescence intensity. This increase in fluorescence signal, and thus the flux in intracellular [Ca.sup.2+], is detected and quantitated by fluorescence imaging using a FLIPR reader. The effect of the agonist is measured as a function of concentration and used to calculate an EC.sub.50 based upon a response curve.
Procedure Calcium A:
[0513] In this procedure 2500 cells/well were employed.
Procedure Calcium B:
[0514] In this procedure 4200 cells/well were employed.
Assay Procedure:
[0515] A Human GPR120 clone (Genbank accession number NM_001195755.1) was placed into the pcDNA3.1 mammalian expression vector carrying the neomycin resistance gene. A stable mammalian cell was generated by placing the above clone into a HEK293 background. Clonal cells responding to long chain fatty acids had expression levels of GPR120 confirmed by RT-qPCR. Human HEK-GPR120 cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM)/F12 medium supplemented with 10% fetal bovine serum (FBS), 1% L-Glutamine and 1% penicillin/streptomycin and 0.5 mg/ml G-418. Cells were split 2 times a week to keep the cells in the log-phase growth.
[0516] In preparation for the assay, HEK cells stably transfected with Human GPR120 (2.5K cells per well in 25 uL growth medium) were seeded into 384-well plates and then incubated overnight (37 C., 5% CO.sub.2). The next day, the media was changed to 20 L assay buffer and the cell starved for 1 h at 37 C. The dye loading solution (2 dye) was prepared using 10 mL assay buffer, 100 L of 250 mM probenecid, 1 bottle of Component A, and 20 l of dye in DMSO. Twenty L of the 2 dye loading buffer was then added to each well. The plates were incubated at 37 C. for 30 min, then at room temperature for an additional 15 minutes, before performing the assay on FLIPR.
[0517] Test compounds were prepared in assay buffer (2 L of compound+198 L assay buffer, final DMSO in assay plate is 0.2%) at the desired concentration, more particularly at 100, 50, 25, 12.5, 6.25, 3.125, 1.562, 0.781, 0.391, 0.195, 0.098, 0.049, 0.024 and 0.012 M.
[0518] The assay was performed on a FLIPR plate reader using the following parameters. Baseline was read for 10 seconds at 1 sec intervals. The program was set to transfer 10 L of ligand from compound plate to cell plate after baseline reading. Aspiration was executed at: 10 L/sec speed, 4.6 L height; Dispensing was executed at: 30 L/sec speed, 45 L height. After compound addition, each well was read for 300 sec, with measurements collected at 1 sec intervals.
[0519] The kinetic data from the FLIPR was based upon a 5 minute window for data collection. The fluorescence of each sample well was used for individual calculations of a normalized RFU value, which was defined as maximum response minus the minimum response. The normalized fluorescence reading (RFU) was calculated as follows:
RFU=F maxF min
[0520] The data were fitted to a sigmoidal dose-response curve with a variable Hill slope (<2) using nonlinear regression with GraphPad Prism 5.0 to calculate the EC.sub.50 values. The Fitting Equation was: Y=Bottom+(TopBottom)/(1+10{circumflex over ()}((Log EC.sub.50X)*HillSlope)), where X is the log of the concentration and Y is the response.
Biological Example 3: In Vitro Assay
GPR40 Calcium Flux Assay
[0521] Compounds were tested in a calcium flux assay using transfected HEK293 cells stably expressing either human GPR40 or rat GPR40. Human GPR40 expressing cells were cultured in DMEM-High Glucose media supplemented with 10% fetal bovine serum, 1L-Glutamine, 1 Penicillin/Streptomycin and 500 g/mL G418. Rat GPR40 expressing cells were cultured in DMEM-High Glucose media supplemented with 10% fetal bovine serum and 1 g/mL puromycin. Cells were plated into poly-D-lysine coated 384-well plates and cultured overnight in a 37 C. humidified tissue culture incubator under 5% CO.sub.2/90% O.sub.2 atmosphere.
[0522] On the day of the experiment, the culture media was replaced with assay buffer (HBSS, 20 mM HEPES, 0.1% BSA) and the cells incubated at 37 C. for 1 h. Calcium-sensitive fluorescent dye (Fluo 8 No-Wash Calcium Dye, ABD Bioquest) was then added and the cells incubated for another 30 min at 37 C. followed by 15 min at room temperature while protected from the light. The cell plate and a plate of diluted compounds of Formula (I) were loaded into a fluorescent plate reader that added compounds onto the cells while measuring the fluorescence intensity of each well. The plate reader recorded fluorescence intensity at 1 second intervals for 8 min and provided the data for analysis in an Excel format. EC.sub.50 values were calculated using Prism (GraphPad) software.
[0523] Representative compounds of the present invention were tested according to the procedure as described in Biological Examples 1, 2 and 3, with results as listed in Table 5, below.
TABLE-US-00006 TABLE 5 Biological Assays: GPR40 and GPR120 GPR40 Human GPR120 Human GPR120 Calcium Calcium Flux Assay Beta-Arrestin Assay Flux Procedure Procedure Procedure Procedure Assay A B A B ID No. EC.sub.50 (M) EC.sub.50 (M) EC.sub.50 (M) EC.sub.50 (M) EC.sub.50 (M) 620 1.042 0.226 0.446 621 0.387 0.092 0.101 625 0.124 0.11 626 0.309 0.317 627 >5 628 >5 629 3.984 630 0.229 631 0.364 1.447 632 2.584 0.422 633 1.127 0.709 634 1.235 0.503 640 0.538 0.729 641 0.172 0.204 642 0.176 0.623 645 0.269 0.275 646 0.628 3.648 647 >5 0.74 650 0.316 0.658 651 0.202 654 >5 655 0.094 656 0.868 658 0.142 0.169 659 >10 0.066 660 0.149 661 0.527 662 2.196 663 0.17 664 >5 665 0.832 666 2.746 667 0.115 668 0.498 669 >5 670 >5 671 >5 673 >5 674 >5 676 >5 677 >5 678 >5 679 1.916 680 2.629 681 >5 682 >5 683 1.058 684 2.702 0.786 685 0.829 0.97 686 0.74 >5 687 0.054 >5 688 3.247 2.936 691 3.624 2.4 692 0.324 >5 695 3.187 >5 696 0.218 >5 697 ~18.90 >5 698 0.335 >5 699 1.739 >5 701 0.145 >5 702 1.562 >5 703 0.068 >5 705 0.073 >5 706 0.038 >5 707 0.326 0.829 709 2.297 >5 713 0.703 >5 714 >10 1.926 716 0.571 1.836 717 0.133 1.304 718 1.426 >5 719 1.018 >5 720 0.339 >5 721 >10 2.416 722 0.973 1.191 723 >10 >5 724 >10 0.275 725 0.588 2.336 727 0.386 1.598 729 0.847 2.683 731 0.093 0.818 732 1.064 >5 733 >10 1.807 734 0.744 10.13 735 0.492 2.187 736 >10 0.615 737 0.272 0.515 738 2.68 0.927 739 0.15 1.02 740 2.078 1.139 745 >10 0.11 0.243 752 0.193 0.159 753 0.178 0.296 754 0.599 0.894 755 0.778 756 0.429 757 >5 758 >5 759 1.121 760 >5 761 2.897 762 >5 763 0.546 764 1.435 0.455 765 0.07 0.478 766 >10 0.155 767 4.324 0.131 768 >10 0.16 769 >10 1.093 775 >10 0.094 776 0.684 777 0.621 778 3.666 0.379 779 2.032 0.948 780 2.659 1.31 781 4.143 0.67 783 7.881 1.357 784 0.187 0.452 785 2.594 0.274
Biological Examide 4: In Vivo Assay
GPR120 DIO Mice OGTT Screening
Assay Procedure
[0524] 18-22 week old, C57Bl6 mice on a high fat diet (60% HFD) for 12-16 weeks (average body weight 37-41 g) were fasted for 6 hr, with removal of food occurring at 7 am on the morning of the study. The animals were sorted into treatment groups the day before the study by body weight. Animals outside the bounds of 30-50 g were left out of the study. The animals had been handled and shammed a total of 5-8 days (1-3 days immediately prior to the study). Glucose (in 1 mL syringes) was drawn up the morning of the study. Test compounds were kept spinning and were only drawn into 1 ml syringes prior to study commencement. Animals were bled via tail snip to determine basal glucose levels prior to dosing of treatments. An Ascensia BREEZE Blood Glucose Monitoring System by Bayer was used for determining glucose levels.
[0525] Animals were moved into the testing room at 9-11 am, to yield them time to acclimate. The bleeds and dosing started at approximately 1 pm in 30-second intervals per animal. All groups were dosed 30 minutes prior to glucose administration at a dose volume of 10 ml/kg (the dose volume was calculated separately for each individual animal). Test compounds were administered at one or more of the following dosages: 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg.
[0526] Thirty minutes after the first dose (with test compound) animals were bled again for a second baseline, or T=0, and immediately dosed with glucose (20% solution; TEKNOVA, 250 ml sterile bottle w/catalogue number G0525) via a PO injection. The exact dose volume for glucose was also calculated separately for each individual animal.
[0527] Blood glucose was measured at 15, 30, 45, 60, and 90 minutes post-glucose administration via the snipped tail. If an animal reached a value of HI, the upper limit of the glucometer (600 mg/dl) was substituted as the blood glucose value and the study was analyzed as normal with no exclusions. If 50% or more of any treatment group reaches a HI, value at least once, the study was considered invalid and repeated. Glucose values were typed into an EXCEL spreadsheet where they were used to calculate glucose AUC and delta AUC post-compound and post-glucose. The glucose excursion curves and the different versions of the AUC's were graphed in GraphPad Prism 5.
Statistical Methods:
[0528] Note: All statistics completed in this study were completed using the statistical software package GraphPad Prism 5. Standard procedures for analyzing data sets from screening GPR120 compounds in DIO mouse OGTT's were as listed here below. In addition to the statistics that were run using GraphPad Prism 5, Microsoft Excel was used to calculate the percent changes in AUC from vehicle groups as detailed below.
[0529] Change from 30 to 0 Baseline Glucose, Raw Glucose AUC 30 to 90 min, Delta Glucose AUC 30 to 90 min, Raw Glucose AUC 0 to 90 min, Delta Glucose AUC 0 to 90 min were analyzed using Column Statistics Analysis, with mean values used to calculate % change from the vehicle mean group, as well as mean, SEM and/or % change from vehicle, where appropriate; and using One-Way ANOVA w/ a Tukey Post-Test (Comparing All Pairs of Columns) with each treatment group examined to see if it was statistically significant compared to vehicle (*=P<0.05, *=P<0.01, **=P<0.001).
[0530] Compound #745 was tested according to the procedure as described above, at a dosage of 3 mg/kg. DIO lowering (30 to 90) was calculated at 63%.
Biological Example 5: In Vivo Assay (Prophetic Example)
A: GPR120 C57bl6 Mouse IPGTT
[0531] Male, C57bl6J Mice are ordered in at 8 weeks of age from Jackson Labs. Individual mice weigh anywhere in the range of 25-30 grams on study day. The mice are fasted, with removal of food occurring at 7 am on the morning of the study. Animals are moved into the room at 10:00 am, to give them time to acclimate. Glucose (insulin syringes) is drawn up either the night before or the morning of the study. Glucose is dosed (IP) at 1.5 g/kg at 7.5 ml/kg (20% glucose straight TEKNOVA, 250 ml sterile bottle w/catalogue number G0525). Test compounds are kept spinning and are only drawn into the syringes prior to study commencement. Animals are bled via tail snip to determine basal glucose levels prior to dosing of treatments. An Ascensia BREEZE Blood Glucose Monitoring System by Bayer (using unique 10-test disks) is used for determining glucose levels. The bleeds start at approximately 12:45 pm and dosing starts, at 1-minute intervals, immediately after. All groups are dosed 30 minutes prior to glucose administration at a dose volume of 10 ml/kg (the dose volume was calculated separately for each individual animal). Thirty minutes after the first dose animals are bled again for a second baseline, or T=0, and immediately dosed with glucose via an i.p. injection. The exact dose volume for glucose is also calculated separately for each individual animal. Glucose measurements are taken at 30 min prior to compound dose, at t=0 (immediately prior to glucose dose), and at 15, 30, 45, 60, 90 min post glucose dose.
[0532] Glucose values are entered into an Excel sheet and graphed in GraphPad Prism. The following can be calculated from GraphPad Prism: Change from 30 to 0 Baseline Glucose, Raw Glucose AUC 30 to 90 min, Delta Glucose AUC 30 to 90 min, Raw Glucose AUC 0 to 90 min, Delta Glucose AUC 0 to 90 min.
Formulation Example 1 (Prophetic Example)
Solid, Oral Dosage Form
[0533] As a specific embodiment of an oral composition, 100 mg of the Compound #745, prepared as described in Example 13 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
[0534] While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.
[0535] Throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.