Diphenethylamine derivatives which are inter alia useful as analgesics and method for their production
10377698 ยท 2019-08-13
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Inventors
Cpc classification
C07C215/52
CHEMISTRY; METALLURGY
C07C255/58
CHEMISTRY; METALLURGY
C07C217/74
CHEMISTRY; METALLURGY
C07C211/52
CHEMISTRY; METALLURGY
C07C217/60
CHEMISTRY; METALLURGY
C07C237/30
CHEMISTRY; METALLURGY
C07C211/29
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C07C215/64
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A61P15/00
HUMAN NECESSITIES
C07C211/27
CHEMISTRY; METALLURGY
International classification
C07C211/27
CHEMISTRY; METALLURGY
C07C237/30
CHEMISTRY; METALLURGY
C07C215/52
CHEMISTRY; METALLURGY
C07C215/64
CHEMISTRY; METALLURGY
C07C211/52
CHEMISTRY; METALLURGY
C07C255/58
CHEMISTRY; METALLURGY
C07C211/29
CHEMISTRY; METALLURGY
C07C217/60
CHEMISTRY; METALLURGY
Abstract
Diphenethylamine derivatives for use as highly active analgesics, diuretics, anxiolytics, for the treatment of neurodegenerative, psychiatric and neuropsychiatric disorders, and also as anti-itch, anti-addiction, anti-inflammatory, anti-obesity, anti-epileptic, anti-convulsant, anti-seizure, anti-stress, anti-psychotic and anti-depressant medications and their pharmaceutically acceptable salts and easily accessible derivatives thereof (e.g. esters, ethers, amides), processes for their preparation and their application in the manufacture of pharmaceutical products.
Claims
1. A compound of formula (I), ##STR00066## in which R.sub.1 is selected from C.sub.2-C.sub.30-alkynyl; C.sub.1-C.sub.30-monohydroxyalkyl; C.sub.2-C.sub.30-dihydroxyalkyl; C.sub.3-C.sub.30-trihydroxyalkyl; C.sub.3-C.sub.12-cycloalkyl; C.sub.4-C.sub.30-cycloalkylalkyl; C.sub.5-C.sub.30-cycloalkylalkenyl; C.sub.5-C.sub.30-cycloalkylalkynyl; C.sub.7-C.sub.30-arylalkyl; C.sub.8-C.sub.30-arylalkenyl; C.sub.8-C.sub.30-arylalkynyl; R.sub.2 is hydrogen; F; Cl; I; NO.sub.2; CN; SH; CO.sub.2H; CONH.sub.2; SO.sub.3H; SO.sub.2NH.sub.2; CONHSO.sub.3H; NHCONHSO.sub.2H; PO.sub.3H; PO.sub.2H; CF.sub.3; R.sub.3 is hydroxy; OCOA, wherein A is selected from C.sub.1-C.sub.6-alkyl, C.sub.6-C.sub.14-aryl, C.sub.7-C.sub.16-aryalkyl; F; Cl; Br; I; NO.sub.2; CN; SH; CO.sub.2H; CONH.sub.2; SO.sub.3H; SO.sub.2NH.sub.2; CONHSO.sub.3H; NHCONHSO.sub.2H; PO.sub.3H; PO.sub.2H; CF.sub.3; R.sub.4 is hydrogen; F; Cl; I; NO.sub.2; CN; SH; CO.sub.2H; CONH.sub.2; SO.sub.3H; SO.sub.2NH.sub.2; CONHSO.sub.3H; NHCONHSO.sub.2H; PO.sub.3H; PO.sub.2H; CF.sub.3; R.sub.5 is hydrogen; hydroxy; R.sub.6 is hydrogen; hydroxy; with the proviso that R.sub.1 cannot be cyclobutylmethyl (CBM) or cyclopropylmethyl (CPM) if R.sub.3 is hydroxy and R.sub.2, R.sub.4, R.sub.5 and R.sub.6 is hydrogen; and pharmaceutically acceptable acid addition salts and base addition salts.
2. A compound according to claim 1, wherein R.sub.1 is selected from C.sub.2-C.sub.12-alkynyl; C.sub.1-C.sub.12-monohydroxyalkyl; C.sub.2-C.sub.12-dihydroxyalkyl; C.sub.3-C.sub.12-trihydroxyalkyl; C.sub.3-C.sub.6-cycloalkyl; C.sub.4-C.sub.16-cycloalkylalkyl; C.sub.5-C.sub.16-cycloalkylalkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl; C.sub.7-C.sub.16-arylalkyl; C.sub.8-C.sub.16-arylalkenyl; C.sub.8-C.sub.16-arylalkynyl; R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are as defined above.
3. A compound of claim 1, wherein R.sub.1 is selected from C.sub.2-C.sub.6-alkynyl; C.sub.1-C.sub.6-monohydroxyalkyl; C.sub.2-C.sub.6-dihydroxyalkyl; C.sub.3-C.sub.6-trihydroxyalkyl; C.sub.3-C.sub.6-cycloalkyl; C.sub.4-C.sub.12-cycloalkylalkyl, where cycloalkyl is C.sub.3-C.sub.6-cycloalkyl and alkyl is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.12-cycloalkylalkenyl, where cycloalkyl is C.sub.3-C.sub.6-cycloalkyl and alkenyl is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.12-cycloalkylalkynyl, where cycloalkyl is C.sub.3-C.sub.6-cycloalkyl and alkynyl is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.12-arylalkyl where aryl is C.sub.6-aryl and alkyl is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.12-arylalkenyl where aryl is C.sub.6-aryl and alkenyl is C.sub.2-C.sub.6-alkyl; C.sub.8-C.sub.12-arylalkynyl where aryl is C.sub.6-aryl and alkynyl is C.sub.2-C.sub.6-alkyl; R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are as defined above.
4. A compound of claim 1, wherein R.sub.5 is hydroxy.
5. A compound selected from: 3-[2-[Allyl(phenethyl)amino]ethyl]phenol 3-[2-[(Cyclopentylmethyl)(phenethyl)amino]ethyl]phenol 3-[2-[(Cyclohexylmethyl)(phenethyl)amino]ethyl]phenol 3-[2-[Benzyl(phenethyl)amino]ethyl]phenol 3-[2-[Propargyl(phenethyl)amino]ethyl]phenol 3-[2-[Isopropyl(phenethyl)amino]ethyl]phenol 3-[2-[Isoamyl(phenethyl)amino]ethyl]phenol 3-[2-[(Cyclobutyl)(phenethyl)amino]ethyl]phenol N-(Cyclobutylmethyl)-N-(3-methoxyphenethyl)-2-(3-methoxyphenyl)ethanamine N-(Cyclopropylmethyl)-N-(3-methoxyphenethyl)-2-(3-methoxyphenyl)ethanamine N-Allyl-N-(3-methoxyphenethyl)-2-(3-methoxyphenyl)ethanamine 3,3-[2,2-(Cyclobutylmethylazanediyl)bis(ethane-2,1-diyl)]diphenol 3,3-[2,2-(Cyclopropylmethylazanediyl)bis(ethane-2,1-diyl)]diphenol 3,3-[2,2-(Allylazanediyl)bis(ethane-2,1-diyl)]diphenol 3-[2-(3-Methoxyphenethylamino)ethyl]phenol 4-[2-(3-Methoxyphenethylamino)ethyl]phenol 3-[2-[(Cyclohexylmethyl)(3-methoxyphenethyl)amino]ethyl]phenol 3-[2-[(Isoamyl)(3-methoxyphenethyl)amino]ethyl]phenol 3-[2-[(n-Butyl)(3-methoxyphenethyl)amino]ethyl]phenol 3-[2-[(n-Pentyl)(3-methoxyphenethyl)amino]ethyl]phenol 3-[2-[(n-Hexyl)(3-methoxyphenethyl)amino]ethyl]phenol 4-[2-[(Cyclobutylmethyl)(3-methoxyphenethyl)amino]ethyl]phenol 4-[2-[(Cyclohexylmethyl)(3-methoxyphenethyl)amino]ethyl]phenol 4-[2-[Allyl(3-methoxyphenethyl)amino]ethyl]phenol 4-[2-[n-Butyl(3-methoxyphenethyl)amino]ethyl]phenol 4-[2-[(Cyclopropylmethyl)(3-methoxyphenethyl)amino]ethyl]phenol 4-[2-[(Cyclopentylmethyl)(3-methoxyphenethyl)amino]ethyl]phenol 3-[2-[(Cyclopentylmethyl)(3-methoxyphenethyl)amino]ethyl]phenol 3,3-[2,2-(Cyclohexylmethylazanediyl)bis(ethane-2,1-diyl)]diphenol 3,3-[2,2-(Isoamylazanediyl)bis(ethane-2,1-diyl)]diphenol 3,3-[2,2-(n-Pentylazanediyl)bis(ethane-2,1-diyl)]diphenol 3,3-[2,2-(n-Hexylazanediyl)bis(ethane-2,1-diyl)]diphenol 3,3-[2,2-(Cyclopentylmethylazanediyl)bis(ethane-2,1-diyl)]diphenol 3-[2-[(Cyclobutylmethyl)(4-hydroxyphenethyl)amino]ethyl]phenol 3-[2-[(Cyclopropylmethyl)(4-hydroxyphenethyl)amino]ethyl]phenol 3-[2-[(Cyclohexylmethyl)(4-hydroxyphenethyl)amino]ethyl]phenol 3-[2-[Allyl(4-hydroxyphenethyl)amino]ethyl]phenol 3-[2-[n-Butyl(4-hydroxyphenethyl)amino]ethyl]phenol 1-(2-Fluoro-3-methoxyphenethyl)-2-phenethylamine N-(2-Fluoro-3-methoxyphenethyl)-2-(3-methoxyphenyl)ethanamine N-(Cyclopropylmethyl)-N-(2-fluoro-3-methoxyphenethyl)-2-phenylethanamine N-(Cyclobutylmethyl)-N-(2-fluoro-3-methoxyphenethyl)-2-phenylethanamine 4-[2-(2-Fluoro-3-methoxyphenethylamino)ethyl]phenol N-(Cyclohexylmethyl)-N-(2-fluoro-3-methoxyphenethyl)-2-phenylethanamine N-Benzyl-N-(2-fluoro-3-methoxyphenethyl)-2-phenylethanamine N-(Cyclobutylmethyl)-N-(2-fluoro-3-methoxyphenethyl)-2-(3-methoxyphenyl)ethanamine 4-[2-[(Cyclobutylmethyl)(2-fluoro-3-methoxyphenethyl)amino]ethyl]phenol 3-[2-[(Cyclobutylmethyl)(phenethyl)amino]ethyl]-2-fluorophenol 3-[2-[(Cyclopropylmethyl)(phenethyl)amino]ethyl]-2-fluorophenol 3-[2-[(Cyclohexylmethyl)(phenethyl)amino]ethyl]-2-fluorophenol 3-[2-[(Benzyl)(phenethyl)amino]ethyl]-2-fluorophenol 3-[2-[(Cyclobutylmethyl)(3-hydroxyphenethyl)amino]ethyl]-2-fluorophenol 3-[2-[(Cyclobutylmethyl)(4-hydroxyphenethyl)amino]ethyl]-2-fluorophenol 3-[2-[(Cyclobutylmethyl)(phenethyl)amino]ethyl]benzonitrile 3-[2-[(Cyclobutylmethyl)(phenethyl)amino]ethyl]benzamide N-(Cyclobutylmethyl)-N-phenethyl-2-phenylethanamine N-(Cyclobutylmethyl)-N-(3-nitrophenethyl)-2-phenylethanamine 3-[2-[(Cyclobutylmethyl)(phenethyl)amino]ethyl]aniline 4-[2-[(Cyclopentylmethyl)(phenethyl)amino]ethyl]phenol 4-[2-[(Cyclobutylmethyl)(phenethyl)amino]ethyl]phenol and pharmaceutically acceptable acid addition salts and base addition salts, esters.
6. A composition comprising a compound of claim 1 together with a pharmaceutically acceptable carrier and/or excipient.
7. A composition comprising a compound of claim 5 together with a pharmaceutically acceptable carrier and/or excipient.
8. A method for the treatment of pain in humans and animals, said method comprising administering a pain treating effective amount of a compound of claim 1 to a human or animal in need thereof.
9. A method for the treatment of pain in humans and animals, said method comprising administering a pain treating effective amount of a compound of claim 5 to a human or animal in need thereof.
10. A method for the treatment of depression in humans and animals, said method comprising administering a depression treating effective amount of a compound of claim 1 to a human or animal in need thereof.
11. A method for the treatment of depression in humans and animals, said method comprising administering a depression treating effective amount of a compound of claim 5 to a human or animal in need thereof.
12. A method for the treatment of water retention, oliguria, dysuria, edemas, pruritus or itching in humans and animals, said method comprising administering an water retention, oliguria, dysuria, edemas, pruritus or itching treating effective amount of a compound of claim 1 to a human or animal in need thereof.
13. A method for the treatment of water retention, oliguria, dysuria, edemas, pruritus or itching in humans and animals, said method comprising administering an water retention, oliguria, dysuria, edemas, pruritus or itching treating effective amount of a compound of claim 5 to a human or animal in need thereof.
Description
EXAMPLES
General Procedure for the Synthesis of Compounds 1-8
(1) A mixture of 3-[2-(phenylethylamino)ethyl]phenol (Journal of Medicinal Chemistry 2012, 55, pp. 10302-10306; 300 mg, 1.24 mmol.sup.1), the corresponding alkyl or allyl bromide or cyclobutyl tosylate (in case of compound 8) (1.71 mmol.sup.1), and NaHCO.sub.3 (229 mg, 2.73 mmol.sup.2) is refluxed for 48 h.sup.3 with a catalytic amount of KI in CH.sub.3CN.sup.4 (8 mL). The end of the reaction is monitored by TLC. The mixture is cooled and filtered, the filtrate is evaporated to dryness, and the crude product is purified by column chromatography.sup.5 to give the desired products (compounds 1-9 as oils or solids). The resulting oils or solids were used as such or converted into the hydrochloride salts. The hydrochloride salts were obtained by using the following procedure: a part of the obtained oil or solid was dissolved in Et.sub.2O and treated with HCl/Et.sub.2O. The precipitate was isolated.sup.6 and recrystallized from acetone/Et.sub.2O to afford the hydrochloride salt.sup.7.
(2) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 1000 mol. 2) The amount can vary from 0.01 mmol to 10000 mol. 3) The reaction time can vary from 0 to 500 hours. 4) CH.sub.3CN can be replaced by other solvents, preferably by acetone, ethanol, methanol, isopropanol, N,N-dimethylformamide, but also by other appropriate solvents. 5) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof. 6) Other appropriate procedures are possible to obtain the hydrochloride salt from the bases. The product can also be isolated by evaporating the reaction mixture. Or the residue can be dissolved in water and freeze dried to obtain a lyophylisate. 7) Recrystallization of the product can be performed by using many different kinds of protic solvents such as alcohols (e.g. methanol, ethanol, isopropanol etc.) and also with different kinds of aprotic solvents such as ethers (diethyl ether, diisopropyl ether etc.), or mixtures of two or more solvents, but also by other appropriate solvents.
Example 1
3-[2-[Allyl(phenethyl)amino]ethyl]phenol (Compound 1)
(3) ##STR00002##
(4) 32% yield (oil); IR (ATR) 3193 cm.sup.1 (OH); .sup.1H NMR (CDCl.sub.3): 7.26-7.03 (m, 6 arom. H), 6.67-6.58 (m, 3 arom. H), 5.90-5.74 (m, 1H olefin), 5.20-5.08 (m, 2H olefin), 3.20 (d, J=7.8 Hz, CH.sub.2-olefin), (2.90-2.87 (m, 8H), MS (ESI) m/z 282.25 [M+1].sup.+.
Example 2
3-[2-[(Cyclopentylmethyl)(phenethyl)amino]ethyl]phenol (Compound 2)
(5) ##STR00003##
(6) 40% yield (transparent oil); .sup.1H NMR (CDCl.sub.3): 7.24-7.02 (m, 6 arom. H), 6.67-6.54 (m, 3 arom. H), 2.67-2.63 (m, 8H), 2.25 (d, J=7 Hz, CH.sub.2-cyclopentyl), 1.69-0.73 (m, 9H).
(7) Compound 2.HCl: white solid; Mp: 154-156 C.; IR (ATR) 3080 cm.sup.1 (OH); MS (ESI) m/z 323.31 [M+1].sup.+.
Example 3
3-[2-[(Cyclohexylmethyl)(phenethyl)amino]ethyl]phenol (Compound 3)
(8) ##STR00004##
(9) 17% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.33-7.09 (m, 6 arom. H), 6.74-6.62 (m, 3 arom. H), 2.81-2.63 (m, 8H), 2.34 (d, J=7 Hz, CH.sub.2-cyclohexyl), 1.77-0.81 (m, 11H).
(10) Compound 3.HCl: beige solid; Mp: 150-151 C.; IR (ATR) 3062 cm.sup.1 (OH); MS (ESI) m/z 338.32 [M+1].sup.+.
Example 4
3-[2-[Benzyl(phenethyl)amino]ethyl]phenol (Compound 4)
(11) ##STR00005##
(12) 22% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.32-7.07 (m, 11 arom. H), 6.70-6.51 (m, 3 arom. H), 3.72 (s, 2H, CH.sub.2-benzyl), 2.79-2.74 (m, 8H).
(13) Compound 4.HCl: beige solid. Mp: 177-178 C.; IR (ATR) 3072 cm.sup.1 (OH); MS (ESI) m/z 332.26 [M+1].sup.+.
Example 5
3-[2-[Propargyl(phenethyl)amino]ethyl]phenol (Compound 5)
(14) ##STR00006##
(15) 23% yield (yellow oil); IR (ATR) 3290 cm.sup.1 (CH), 2935 cm.sup.1 (OH); .sup.1H NMR (CDCl.sub.3): 7.26-7.04 (m, 6 arom. H), 6.71-6.57 (m, 3 arom. H), 3.50 (d, J=2.2 Hz, CH.sub.2-propargyl), 2.74-2.70 (m, 8H), 2.16 (t, J=2.2 Hz, CH-propargyl); MS (ESI) m/z 280.41 [M+1].sup.+.
Example 6
3-[2-[Isopropyl(phenethyl)amino]ethyl]phenol (Compound 6)
(16) ##STR00007##
(17) 23% yield (beige oil); .sup.1H NMR (CDCl.sub.3): 7.39-7.09 (m, 6 arom. H), 6.74-6.66 (m, 3 arom. H), 3.16-3.03 (m, 1H, CH-isopropyl), 2.79-2.75 (m, 8H), 1.04 (d, J=6.6 Hz, (CH.sub.3).sub.2-isopropyl).
(18) Compound 6.HCI: IR (ATR) 3176 cm.sup.1 (OH); MS (ESI) m/z 284.14 [M+1].sup.+.
Example 7
3-[2-[Isoamyl(phenethyl)amino]ethyl]phenol (Compound 7)
(19) ##STR00008##
(20) 36% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.28-7.11 (m, 6 arom. H), 6.73-6.68 (m, 3 arom. H), 2.87-2.72 (m, 8H), 2.69-2.64 (m, 2H, CH.sub.2-isoamyl), 1.51-1.41 (m, 3H, CH+CH.sub.2-isoamyl), 0.90 (d, J=6.6 Hz, (CH.sub.3).sub.2-isoamyl).
(21) Compound 7.HCl: yellow solid; Mp: 149-150 C.; IR (ATR) 3095 cm.sup.1 (OH); MS (ESI) m/z 312.26 [M+1].sup.+.
Example 8
3-[2-[Cyclobutyl(phenethyl)amino]ethyl]phenol (Compound 8)
(22) ##STR00009##
(23) 32% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.21-7.07 (m, 6 arom. H), 6.65-6.60 (m, 3 arom. H), 2.90-2.71 (m, 8H), 2.51 (d, J=6.6 Hz, CH-cyclobutyl), 0.88-0.78 (m, 2H), 0.49-0.43 (m, 2H), 0.12-0.07 (m, 2H).
(24) Compound 8.HCl: light brown solid; Mp: 100-101 C.; IR (ATR) 3161 cm.sup.1 (OH); MS (ESI) m/z 296.16 [M+1].sup.+.
General Procedure for the Synthesis of Compounds 9-11
(25) ##STR00010##
(26) A mixture of N-(3-methoxyphenethyl)-2-(3-methoxyphenyl)ethanamine (A) (European Journal of Medicinal ChemistryChimica Therapeutica 1978, 13, pp. 553-563) (500 mg, 1.75 mmol.sup.1), the corresponding alkyl or allyl bromide (1.2 mmol.sup.1), and K.sub.2CO.sub.3 (484 mg, 3.5 mmol.sup.2) in anhydrous DMF.sup.3 (9 mL) is stirred under N.sub.2 at 80 C..sup.4 for 14 h.sup.5. 15 mL of H.sub.2O are added and the aqueous phase is extracted with CH.sub.2Cl.sub.2 (320 mL), washed with brine (15 mL), dried over Na.sub.2SO.sub.4 and evaporated. The resulting brown oil is purified by column chromatography.sup.6 to give the desired products.
(27) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 1000 mol. 2) The amount can vary from 0.01 mmol to 10000 mol. 3) DMF (N,N-dimethylformamide) can be replaced by other solvents, preferably by acetone, ethanol, methanol, isopropanol, acetonitrile but also by other appropriate solvents. 4) The reaction temperature can vary from 0 C. to 160 C. 5) The reaction time can vary from 0 to 500 hours. 6) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof.
Example 9
N-(Cyclobutylmethyl)-N-(3-methoxyphenethyl)-2-(3-methoxyphenyl)ethanamine (Compound 9)
(28) ##STR00011##
(29) 40% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 23-7.15 (m, 2 arom. H), 6.79-6.75 (m, 6 arom. H), 3.79 (s, 2CH.sub.3O), 2.95-2.71 (m, 8H), 2.62-2.53 (m, 2H), 2.04-1.69 (m, 7H).
Example 10
N-(Cyclopropylmethyl)-N-(3-methoxyphenethyl)-2-(3-methoxyphenyl)ethanamine (Compound 10)
(30) ##STR00012##
(31) 43% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.47-7.43 (m, 2 arom. H), 7.07-7.00 (m, 6 arom. H), 4.06 (s, 2CH.sub.3O), 2.95-2.71 (m, 10H), 1.18-1.15 (m, cycloprop), 0.82-0.76 (m, cycloprop), 0.47-0.42 (m, cycloprop.).
Example 11
N-Allyl-N-(3-methoxyphenethyl)-2-(3-methoxyphenyl)ethanamine (Compound 11)
(32) ##STR00013##
(33) 38% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.24-7.15 (m, 2 arom. H), 6.79-6.60 (m, 6 arom. H), 5.94-5.82 (m, 1H olefin), 5.33-5.12 (m, 2H olefin), 4.06 (s, 2CH.sub.3O), 3.26-3.17 (m, CH.sub.2-olefin), 2.95-2.71 (m, 8H).
General Procedure for the Synthesis of Compounds 12-14
(34) A mixture of compound 9, 10 or 11 (0.7 mmol.sup.1) and sodium ethanethiolate.sup.2 (942 mg, 11.2 mmol.sup.1) in anhydrous DMF.sup.3 (4 mL) is stirred under N.sub.2 at 130 C..sup.4 for 20 h.sup.5. After cooling, the mixture is poured on saturated NH.sub.4Cl solution. The resulting mixture is slightly acidified with 2N HCl and then alkalinized with diluted NH.sub.4OH.sub.conc. solution and extracted with CH.sub.2Cl.sub.2 (315 mL). The organic phase is washed with H.sub.2O (515 mL), brine (15 mL), dried over Na.sub.2SO.sub.4 and evaporated. The resulting oils are purified by column chromatography.sup.6 to give the desired products (compounds 13-15 as oils). The resulting oils are converted into the hydrochloride salts. The hydrochloride salts are obtained by using the following procedure: A part of the obtained oil or solid is dissolved in Et.sub.2O and treated with HCl/Et.sub.2O.sup.7. The precipitate is isolated and recrystallized from acetone/Et.sub.2O.sup.8 to afford the hydrochloride salt.
(35) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 1000 mol. 2) Other reagents and procedures can be used for the ether cleavage step. For instance BBr.sub.3 in dichlomethane at different temperatures, aqueous hydrohalic acids or potassium hydroxide at elevated temperatures, but also other appropriate reagents and procedures. 3) DMF can be replaced by other appropriate solvents. 4) The reaction temperature can vary from 80 C. to 160 C. 5) The reaction time can vary from 0 to 500 hours. 6) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof. 7) Other appropriate procedures are possible to obtain the hydrochloride salt from the bases. The product can also be isolated by evaporating the reaction mixture. Or the residue can be dissolved in water and freeze dried to obtain a lyophylisate. 8) Recrystallization of the product can be performed by using many different kinds of protic solvents such as alcohols (e.g. methanol, ethanol, isopropanol etc.) and also with different kinds of aprotic solvents such as ethers (diethyl ether, diisopropyl ether etc.), or mixtures of two or more solvents, but also by other appropriate solvents.
Example 12
3,3-[2,2-(Cyclobutylmethylazanediyl)bis(ethane-2,1-diyl)]diphenol (Compound 12)
(36) ##STR00014##
(37) 44% yield (transparent oil); .sup.1H NMR (CDCl.sub.3): 7.14 (t, J=8 Hz, 2 arom. H), 6.71-6.64 (m, 6 arom. H), 2.74-2.64 (m, 10H), 2.06-1.69 (m, 7H).
(38) Compound 12.HCl: beige solid; Mp: 100-101 C.; IR (ATR) 3202 cm.sup.1 (OH); MS (ESI) m/z 326.27 [M+1].sup.+.
Example 13
3,3-[2,2-(Cyclopropylmethylazanediyl)bis(ethane-2,1-diyl)]diphenol (Compound 13)
(39) ##STR00015##
(40) 44% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.12 (t, J=8 Hz, 2 arom. H), 6.70-6.66 (m, 6 arom. H), 2.96-2.89 (m, 4H), 2.80-2.71 (m, 4H), 2.56 (d, J=6.6 Hz, CH.sub.2-cycloprop), 0.92-0.90 (m, cycloprop), 0.57-0.48 (m, cycloprop), 0.19-0.12 (m, cycloprop.).
(41) Compound 13.HCl: beige solid; Mp: 106-107 C.; IR (ATR) 3190 cm.sup.1 (OH); MS (ESI) m/z 312.23 [M+1].sup.+.
Example 14
3,3-[2,2-(Allylazanediyl)bis(ethane-2,1-diyl)]diphenol (Compound 14)
(42) ##STR00016##
(43) 38% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.12 (t, J=8 Hz, 2 arom. H), 6.69-6.63 (m, 6 arom. H), 6.01-5.81 (m, 1H olefin), 5.27-5.16 (m, 2H olefin), 3.28 (d, J=6.6 Hz, CH.sub.2-olefin), 2.78-2.76 (m, 8H).
(44) Compound 14.HCl: beige solid. Mp: 104-106 C.; IR (ATR) 3197 cm.sup.1 (OH); MS (ESI) m/z 298.17 [M+1].sup.+.
General Procedure for the Synthesis of Compounds 15 and 16
(45) ##STR00017##
(46) To the stirred solution of 3-hydroxyphenylacetic acid (C) or 4-hydroxyphenylacetic acid (D) (5 g, 32.85 mmol.sup.1), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCl).sup.2 (8.2 g, 42.7 mmol.sup.2) and 1-hydroxy-1H-benzotriazole (HOAt).sup.3 (6 mL, 42.7 mmol.sup.2) in anhydrous CH.sub.2Cl.sub.2.sup.4 (200 mL), 3-methoxyphenethylamine (B) (5.8 mL, 39.5 mmol.sup.2) is added under N.sub.2 at room temperature.sup.5. The mixture is stirred overnight.sup.6 and then diluted to 350 mL with CH.sub.2Cl.sub.2. The organic layer is washed with NaHCO.sub.3 sat. (2100 mL), HCl 0.1 N (2100 mL), dried over Na.sub.2SO.sub.4 and evaporated. The resulting oils are purified by column chromatography.sup.6 to give the intermediates 2-(3-hydroxyphenyl)-N-(3-methoxyphenethyl)acetamide (E): .sup.1H NMR (CDCl.sub.3) 7.29-6.95 (m, 2 arom. H), 6.84-6.63 (m, 6 arom. H), 6.01 (br, s, .sup.+NH), 3.73 (s, CH.sub.3O), 3.47-3.37 (m, 2H), 2.92 (s, 1H), 2.85 (s, 1H), 2.72 (t, J=6.6 Hz, 2H), and 2-(4-hydroxyphenyl)-N-(3-methoxyphenethyl)acetamide (F): .sup.1H NMR (CDCl.sub.3) 7.16 (t, J=8.2 Hz, 2 arom. H), 7.03 (d, J=8. Hz, 2 arom. H), 6.80-6.72 (m, 2 arom. H), 6.63-6.61 (m, 2 arom. H), 5.48 (br, s, .sup.+NH), 3.77 (s, CH.sub.3O), 3.42-3.47 (m, 2H), 2.97 (s, 1H), 2.89 (s, 1H), 2.70 (t, J=6.6 Hz, 2H) as transparent oils.
(47) To a solution of 2-(3-hydroxyphenyl)-N-(3-methoxyphenethyl)acetamide (E) or 2-(4-hydroxyphenyl)-N-(3-methoxyphenethyl)acetamide (F) (5 g, 17.5 mmol.sup.1) in anhydrous THF (150 mL) is added BH.sub.3.THF 1M (87.5 mL, 87.5 mmol.sup.1) under N.sub.2 at 0 C..sup.5. The reaction mixture is refluxed overnight.sup.6 and then, after cooling, MeOH is added to destroy the excess of BH.sub.3. The solvent is evaporated, H.sub.2O (200 mL) and NaOH 0.1 N (50 mL) are added. The aqueous phase is extracted with CH.sub.2Cl.sub.2 (320 mL), washed with H.sub.2O (3100 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4 and evaporated. The resulting oils are purified by column chromatography.sup.7 to give the desired products (compounds 15 and 16) as transparent oils.
(48) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 1000 mol. 2) Instead of EDCl also other carbodiimides such as N,N-dicyclohexylcarbodiimide (DCC), N,N-diisopropylcarbodiimide or other coupling reagents can be used. 3) 1-Hydroxy-7-azabenzotriazol (HOAt) is a coupling reagent which can be substituted by hydroxybenzotriazol (HOBT), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate) (HATU), O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate (TBTU), 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), N-hydroxysuccinimide or ethyl-2-cyano-2-(hydroxyimino)acetat and others. 4) Other solvents such as tetrahydrofurane, acetonitrile N,N-dimethylformamide or others can be used. 5) The reaction temperature can vary from 80 C. to 160 C. 6) The reaction time can vary from 0 to 500 hours. 7) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof.
Example 15
3-[2-(3-Methoxyphenethylamino)ethyl]phenol (Compound 15)
(49) ##STR00018##
(50) 64% yield (transparent oil); .sup.1H NMR (CDCl.sub.3): 7.17-7.06 (m, 2 arom. H), 6.79-6.49 (m, 6 arom. H), 3.79 (s, CH.sub.3O), 3.06-2.74 (m, 8H).
Example 16
4-[2-(3-Methoxyphenethylamino)ethyl]phenol (Compound 16)
(51) ##STR00019##
(52) 70% yield (transparent oil); .sup.1H NMR (CDCl.sub.3): 7.16 (t, J=8 Hz, 2 arom. H), 7.01-6.88 (m, 2 arom. H), 6.78-6.62 (m, 4 arom. H), 3.77 (s, CH.sub.3O), 3.04-2.78 (m, 8H).
General Procedure for the Synthesis of Compounds 17-28
(53) A mixture of compound 15 or 16 (500 mg, 1.8 mmol.sup.1), the corresponding alkyl or allyl bromide (2.6 mmol.sup.1), and NaHCO.sub.3 (322 mg, 3.96 mmol.sup.2) is refluxed for 48 h.sup.3 with a catalytic amount of KI in CH.sub.3CN.sup.4 (5 mL). The mixture is cooled and filtered, the filtrate is evaporated to dryness, and the crude product is purified by column chromatography.sup.5 to give the desired products as oils (compounds 17-27).
(54) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 1000 mol. 2) The amount can vary from 0.01 mmol to 10000 mol. 3) The reaction time can vary from 0 to 500 hours. 4) CH.sub.3CN can be replaced by other solvents, preferably by acetone, ethanol, methanol, isopropanol, N,N-dimethylformamide, but also by other appropriate solvents. 5) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof.
Example 17
3-[2-[(Cyclohexylmethyl)(3-methoxyphenethyl)amino]ethyl]phenol (Compound 17)
(55) ##STR00020##
(56) 43% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.20-7.04 (m, 2 arom. H), 6.72-6.56 (m, 6 arom. H), 3.77 (s, CH.sub.3O), 2.95-2.63 (m, 8H), 2.1 (d, J=7 Hz, CH.sub.2-cyclohexyl), 1.88-0.96 (m, 11H).
Example 18
3-[2-[Isoamyl(3-methoxyphenethyl)amino]ethyl]phenol (Compound 18)
(57) ##STR00021##
(58) 61% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.16-7.10 (m, 2 arom. H), 6.82-6.67 (m, 6 arom. H), 3.79 (s, CH.sub.3O), 2.94-2.77 (m, 8H), 2.65-2.58 (m, 2H, CH.sub.2-isoamyl), 1.39-1.34 (m, 3H, CH+CH.sub.2-isoamyl), 0.90 (d, J=6.2 Hz, (CH.sub.3).sub.2-isoamyl).
Example 19
3-[2-[n-Butyl(3-methoxyphenethyl)amino]ethyl]phenol (Compound 19)
(59) ##STR00022##
(60) 31% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.25-7.10 (m, 2 arom. H), 6.88-6.70 (m, 6 arom. H), 3.80 (s, CH.sub.3O), 3.75-3.58 (m, 2H, CH.sub.2N), 3.18-3.00 (m, 8H), 1.50-1.25 (m, 4H, 2CH.sub.2-butyl), 1.03-0.88 (m, 3H, CH.sub.3-butyl).
Example 20
3-[2-[n-Pentyl(3-methoxyphenethyl)amino]ethyl]phenol (Compound 20)
(61) ##STR00023##
(62) 27% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.25-7.08 (m, 2 arom. H), 6.83-6.66 (m, 6 arom. H), 3.79 (s, CH.sub.3O), 3.19-2.96 (m, 10H, CH.sub.2N+8H), 1.28 (br, s, 6H, 3CH.sub.2-pentyl), 0.88-0.85 (m, 3H, CH.sub.3-pentyl).
Example 21
3-[2-[n-Hexyl(3-methoxyphenethyl)amino]ethyl]phenol (Compound 21)
(63) ##STR00024##
(64) 33% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.25-7.09 (m, 2 arom. H), 6.90-6.69 (m, 6 arom. H), 3.80 (s, CH.sub.3O), 3.63-3.46 (m, 2H, CH.sub.2N), 3.20-3.00 (m, 8H), 1.32-1.25 (m, 8H, 4CH.sub.2-hexyl), 0.90-0.88 (m, 3H, CH.sub.3-hexyl).
Example 22
4-[2-[(Cyclobutylmethyl)(3-methoxyphenethyl)amino]ethyl]phenol (Compound 22)
(65) ##STR00025##
(66) 57% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.19 (t, J=7.8 Hz, 2 arom. H), 7.04-7.00 (m, 2 arom. H), 6.77-6.73 (m, 4 arom. H), 3.79 (s, CH.sub.3O), 2.75-2.59 (m, 10H), 2.08-1.7 (m, 7H).
Example 23
4-[2-[(Cyclohexylmethyl)(3-methoxyphenethyl)amino]ethyl]phenol (Compound 23)
(67) ##STR00026##
(68) 45% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.19 (t, J=7.4 Hz, 2 arom. H), 7.03 (d, J=8.4 Hz 2 arom. H), 6.79-6.72 (m, 4 arom. H), 3.8 (s, CH.sub.3O), 2.71-2.76 (m, 10H), 2.3 (d, J=7 Hz, CH.sub.2-cyclohexyl), 1.43-0.85 (m, 11H).
Example 24
4-[2-[Allyl(3-methoxyphenethyl)amino]ethyl]phenol (Compound 24)
(69) ##STR00027##
(70) 33% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.22-7.16 (m, 2 arom. H), 7.03 (d, J=8.4 Hz 2 arom. H), 6.78-6.74 (m, 4 arom. H), 5.98-5.79 (m, 1H olefin), 5.30-5.28 (m, 2H olefin), 3.80 (s, CH.sub.3O), 3.28 (d, J=6.4 Hz, CH.sub.2-olefin), 2.80-2.75 (m, 8H).
Example 25
4-[2-[n-Butyl(3-methoxyphenethyl)amino]ethyl]phenol (Compound 25)
(71) ##STR00028##
(72) 30% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.26-7.17 (m, 2 arom. H), 7.01-6.96 (m, 2 arom. H), 6.85-6.76 (m, 4 arom. H), 3.79 (s, CH.sub.3O), 3.12-2.88 (m, 10H), 1.69-1.61 (m, 2H, CH.sub.2-butyl), 1.40-1.25 (m, 2H, CH.sub.2-butyl), 0.97-0.90 (m, 3H, CH.sub.3-butyl).
Example 26
4-[2-[(Cyclopropylmethyl)(3-methoxyphenethyl)amino]ethyl]phenol (Compound 26)
(73) ##STR00029##
(74) 39% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.22 (t, J=8.8 Hz, 2 arom. H), 7.04-7.01 (m, 2 arom. H), 6.80-6.75 (m, 4 arom. H), 3.80 (s, CH.sub.3O), 3.11-2.80 (m, 8H), 2.71 (d, J=6.2 Hz, CH.sub.2-cyclopropyl), 1.03-0.58 (m, 4H), 0.31-0.24 (m, 1H).
Example 27
(75) 4-[2-[(Cyclopentylmethyl)(3-methoxyphenethyl)amino]ethyl]phenol (Compound 27)
(76) ##STR00030##
(77) 60 mg, 23% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.24-7.16 (m, 1 arom. H), 7.06-7.02 (m, 2 arom. H), 6.79-6.73 (m, 5 arom. H), 3.80 (s, CH.sub.3O), 2.79-2.74 (m, 8H), 2.54-2.51 (m, 2H, CH.sub.2-cyclopentylmethyl), 2.12-2.05 (m, 1H), 1.73-1.19 (m, 8H).
(78) A part of the obtained oil of compound 27 was dissolved in Et.sub.2O and treated with HCl/Et.sub.2O. The precipitate was isolated and recrystallized from acetone/Et.sub.2O to afford 27.HCl as beige solid; Mp: 74-77 C.; IR (ATR) 3139 cm.sup.1 (OH); MS (ESI) m/z 354.5 [M+1].sup.+.
Example 28
3-[2-[(Cyclopentylmethyl)(3-methoxyphenethyl)amino]ethyl]phenol (Compound 28)
(79) ##STR00031##
(80) 65 mg, 25% yield (yellow oil); .sup.1H NMR (CDCl.sub.3): 7.24-7.10 (m, 3 arom. H), 6.81-6.68 (m, 5 arom. H), 3.81 (s, CH.sub.3O), 2.88 (br, s, 8H), 2.66-2.62 (m, CH.sub.2-cyclopentyl), 2.18-2.09 (m, 1H), 1.60-1.25 (m, 8H).
General Procedure for the Synthesis of Compounds 29-38
(81) A mixture of starting material (compound 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27) (1.03 mmol.sup.1) and sodium ethanethiolate.sup.2 (550 mg, 6.53 mmol.sup.1) in anhydrous DMF.sup.3 (5 mL) was stirred under N.sub.2 at 130 C..sup.4 (bath temperature) for 20 h.sup.5. After cooling, the mixture was poured on saturated NH.sub.4Cl solution. The resulting mixture was slightly acidified with 2N HCl and then alkalinized with diluted NH.sub.4OH.sub.conc. solution and extracted with CH.sub.2Cl.sub.2 (315 mL). The organic phase was washed with H.sub.2O (515 mL), brine (15 mL), dried over Na.sub.2SO.sub.4 and evaporated. The resulting oils were purified by column chromatography.sup.6 to give the desired compounds as transparent oils (compounds 13-15). The resulting oils are converted into the hydrochloride salts. The hydrochloride salts are obtained by using the following procedure: A part of the obtained oil or solid is dissolved in Et.sub.2O and treated with HCl/Et.sub.2O.sup.7. The precipitate is isolated and recrystallized from acetone/Et.sub.2O.sup.8 to afford the hydrochloride salt.
(82) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 1000 mol. 2) Other reagents and procedures can be used for the ether cleavage step. For instance BBr.sub.3 in dichlomethane at different temperatures, aqueous hydrohalic acids or potassium hydroxide at elevated temperatures, but also other appropriate reagents and procedures. 3) DMF can be replaced by other appropriate solvents. 4) The reaction temperature can vary from 80 C. to 160 C. 5) The reaction time can vary from 0 to 500 hours. 6) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof. 7) Other appropriate procedures are possible to obtain the hydrochloride salt from the bases. The product can also be isolated by evaporating the reaction mixture. Or the residue can be dissolved in water and freeze dried to obtain a lyophilisate. 8) Recrystallization of the product can be performed by using many different kinds of protic solvents such as alcohols (e.g. methanol, ethanol, isopropanol etc.) and also with different kinds of aprotic solvents such as ethers (diethyl ether, diisopropyl ether etc.), or mixtures of two or more solvents, but also by other appropriate solvents.
Example 29
3,3-[2,2-(Cyclohexylmethylazanediyl)bis(ethane-2,1-diyl)]diphenol (Compound 29)
(83) ##STR00032##
(84) 20% yield; .sup.1H NMR (CDCl.sub.3): 7.03-6.96 (m, 2 arom. H), 6.60-6.48 (m, 6 arom. H), 2.54 (br, s, 8H), 2.16 (d, J=6.6 Hz, CH.sub.2-cyclohexyl), 1.59-0.65 (m, 11H).
(85) Compound 29.HCl: white solid; Mp: 157-158 C.; IR (ATR) 2921 cm.sup.1 (OH); MS (ESI) m/z 354.4 [M+1].sup.+.
Example 30
3,3-[2,2-(Isoamylazanediyl)bis(ethane-2,1-diyl)]diphenol (Compound 30)
(86) ##STR00033##
(87) 25% yield; .sup.1H NMR (CDCl.sub.3): 7.15-7.07 (m, 2 arom. H), 6.69-6.63 (m, 6 arom. H), 2.76-2.60 (m, 10H),), 1.44-1.24 (m, 3H, CH+CH.sub.2-isoamyl), 0.86 (d, J=6.2 Hz, (CH.sub.3).sub.2-isoamyl).
(88) Compound 30.HCl: yellow solid; Mp: 71-72 C.; IR (ATR) 3191 cm.sup.1 (OH); MS (ESI) m/z 328.4 [M+1].sup.+.
Example 31
3,3-[2,2-(n-Butylazanediyl)bis(ethane-2,1-diyl)]diphenol (Compound 31)
(89) ##STR00034##
(90) 22% yield; .sup.1H NMR (CDCl.sub.3): 7.33-6.90 (m, 4 arom. H), 6.73-6.65 (m, 4 arom. H), 3.44-3.35 (m, 8H), 3.01-2.93 (m, 2H, CH.sub.2N), 1.66-1.31 (m, 4H, 2CH.sub.2-butyl), 0.99-0.89 (m, 3H, CH.sub.3-butyl).
(91) Compound 31.HCl: slightly brown solid; Mp: 62-64 C.; IR (ATR) 3156 cm.sup.1 (OH); MS (ESI) m/z 314.3 [M+1].sup.+.
Example 32
3,3-[2,2-(n-Pentylazanediyl)bis(ethane-2,1-diyl)]diphenol (Compound 32)
(92) ##STR00035##
(93) 25% yield; .sup.1H NMR (CDCl.sub.3): 7.19-6.94 (m, 4 arom. H), 6.72 (br, s, 4 arom. H), 3.50-3.45 (m, 8H), 3.01-2.93 (m, 2H, CH.sub.2N), 1.66-1.24 (m, 6H, 3CH.sub.2-pentyl), 0.91 (t, J=5.4 Hz, 3H, CH.sub.3-pentyl).
(94) Compound 32.HCl: yellowish solid; Mp: 70-72 C.; IR (ATR) 3191 cm.sup.1 (OH); MS (ESI) m/z 328.4 [M+1].sup.+.
Example 33
3,3-[2,2-(n-Hexylazanediyl)bis(ethane-2,1-diyl)]diphenol (Compound 33)
(95) ##STR00036##
(96) 21% yield; .sup.1H NMR (CDCl.sub.3): 7.15-6.85 (m, 4 arom. H), 6.71-6-64 (m, 4 arom. H), 3.37-3.15 (m, 8H), 2.94 (br, s, 2H, CH.sub.2N), 1.60-1.28 (m, 8H, 4CH.sub.2-hexyl), 0.98-0.89 (m, 3H, CH.sub.3-hexyl).
(97) Compound 33.HCl: slightly brown solid; Mp: 75-76 C.; IR (ATR) 3171 cm.sup.1 (OH); MS (ESI) m/z 342.4 [M+1].sup.+.
Example 34
3-[2-[(Cyclobutylmethyl)(4-hydroxyphenethyl)amino]ethyl]phenol (Compound 34)
(98) ##STR00037##
(99) 36% yield; .sup.1H NMR (CDCl.sub.3): 7.15 (t, J=7.8 Hz, 2 arom. H), 7.06-7.03 (m, 2 arom. H), 6.78-6.62 (m, 4 arom. H), 2.71-2.62 (m, 10H), 2.09-1.27 (m, 7H).
(100) Compound 34.HCl: white solid. Mp: 102-103 C.; IR (ATR) 3332 cm.sup.1 (OH); MS (ESI) m/z 326.4 [M+1].sup.+.
Example 35
3-[2-[(Cyclohexylmethyl)(4-hydroxyphenethyl)amino]ethyl]phenol (Compound 35)
(101) ##STR00038##
(102) 31% yield; .sup.1H NMR (CDCl.sub.3): 7.13 (t, J=7.6 Hz, 2 arom. H), 7.04 (d, J=8.4 Hz, 2 arom. H), 6.77-6.58 (m, 4 arom. H), 2.66 (br, s, 8H), 2.29 (d, J=6.8 Hz, CH.sub.2-cyclohexyl), 1.75-0.79 (m, 11H).
(103) Compound 35.HCl: white solid; Mp: 155-157 C.; IR (ATR) 2924 cm.sup.1 (OH); MS (ESI) m/z 354.4 [M+1].sup.+.
Example 36
3-[2-[Allyl(4-hydroxyphenethyl)amino]ethyl]phenol (Compound 36)
(104) ##STR00039##
(105) 23% yield; .sup.1H NMR (CDCl.sub.3): 7.14 (t, J=7.6 Hz, 2 arom. H), 7.03 (d, J=8 Hz 2 arom. H), 6.77-6.61 (m, 4 arom. H), 5.97-5.83 (m, 1H olefin), 5.30-5.14 (m, 2H olefin), 3.25 (d, J=6.2 Hz, CH.sub.2-olefin), 2.73 (br, s, 8H).
(106) Compound 36.HCl: white solid. Mp: 103-105 C.; IR (ATR) 3195 cm.sup.1 (OH); MS (ESI) m/z 298.2 [M+1].sup.+.
General Procedure for the Synthesis of Derivatives 37-39
(107) To a solution of compounds 25, 26 or 28 (0.31 mmol.sup.1) in 5 mL of CH.sub.2Cl.sub.2.sup.2 under N.sub.2 atmosphere is added BBr.sub.3 1M solution in CH.sub.2Cl.sub.2 (1.84 mmol) at 15 C..sup.3. After 30 min.sup.4 ice and concentrated NH.sub.4OH is added and the mixture is stirred at 0 C. for further 30 min. The organic phase is separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (320 mL). The combined organic layers are dried over Na.sub.2SO.sub.4 and evaporated. The resulting oils are purified by column chromatography.sup.5 to give the desired products (compounds 37-39) as transparent oils. The resulting oils are converted into the hydrochloride salts. The hydrochloride salts are obtained by using the following procedure: A part of the obtained oil is dissolved in Et.sub.2O and treated with HCl/Et.sub.2O.sup.7. The precipitate is isolated and recrystallized from acetone/Et.sub.2O.sup.8 to afford the hydrochloride salt.
(108) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 1000 mol. 2) CH.sub.2Cl.sub.2 can be replaced by other appropriate solvents. 3) The reaction temperature can vary from 80 C. to 60 C. 4) The reaction time can vary from 0 to 100 hours. 5) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof. 6) Other appropriate procedures are possible to obtain the hydrochloride salt from the bases. The product can also be isolated by evaporating the reaction mixture. Or the residue can be dissolved in water and freeze dried to obtain a lyophilisate. 7) Recrystallization of the product can be performed by using many different kinds of protic solvents such as alcohols (e.g. methanol, ethanol, isopropanol etc.) and also with different kinds of aprotic solvents such as ethers (diethyl ether, diisopropyl ether etc.), or mixtures of two or more solvents, but also by other appropriate solvents.
Example 37
3-[2-[n-Butyl(4-hydroxyphenethyl)amino]ethyl]phenol (Compound 37)
(109) ##STR00040##
(110) 60% yield; .sup.1H NMR (DMSO-d.sub.6): 7.15-7.07 (m, 3 arom. H), 6.76-6.67 (m, 5 arom. H), 3.24-2.98 (m, 10H), 1.69 (br, s, CH.sub.2-butyl), 1.38-1.27 (m, 2H, CH.sub.2-butyl), 0.95-0.88 (m, 3H, CH.sub.3-butyl).
(111) Compound 37.HCl: beige solid; Mp: 65-68 C.; IR (ATR) 2927 cm.sup.1 (OH); MS (ESI) m/z 314.4 [M+1].sup.+.
Example 38
3-[2-[(Cyclopropylmethyl)(4-hydroxyphenethyl)amino]ethyl]phenol (Compound 38)
(112) ##STR00041##
(113) 52% yield; .sup.1H NMR (CDCl.sub.3): 7.28-7.03 (m, 4 arom. H), 6.78-6.65 (m, 4 arom. H), 2.85-2.74 (m, 8H), 2.52 (d, J=6.2 Hz, CH.sub.2-cyclopropyl), 0.87 (br, s, 2H), 0.53-0.52 (m, 2H), 0.17-0.14 (m, 1H).
(114) Compound 38.HCl: beige solid. Mp: 104-105 C.; IR (ATR) 3017 cm.sup.1 (OH); MS (ESI) m/z 312.4 [M+1].sup.+.
Example 39
3,3-[2,2-(Cyclopentylmethylazanediyl)bis(ethane-2,1-diyl)]diphenol (Compound 39)
(115) ##STR00042##
(116) 69% yield (transparent oil); .sup.1H NMR (CDCl.sub.3): 7.19-7.10 (m, 3 arom. H), 6.76-6.65 (m, 5 arom. H), 2.75-2.71 (m, 8H), 2.45 (d, J=7.4 Hz, CH.sub.2-cyclopentyl), 1.62-1.25 (m, 9H).
(117) Compound 39.HCl as beige solid; Mp: 113 C.; IR (ATR) 2952 cm.sup.1 (OH); MS (ESI) m/z 339.4 [M].sup.+.
General Procedure for the Synthesis of Derivatives 40-42
(118) ##STR00043##
(119) To the stirred solution of starting material (B, G, or H) (1 g, 5.4 mmol.sup.1), EDCl.sup.2 (985 mg, 7 mmol.sup.1) and HOAt.sup.3 (0.98 mL, 7 mmol.sup.1) in anhydrous CH.sub.2Cl.sub.2.sup.4 (50 mL) under N.sub.2, compound I (6.5 mmol.sup.1) was added at room temperature.sup.5. The mixture was stirred overnight.sup.6 at room temperature.sup.5, then diluted to 100 mL with CH.sub.2Cl.sub.2. The organic layer was washed with NaHCO.sub.3 sat. (230 mL), HCl 0.1 N (230 mL), dried over Na.sub.2SO.sub.4 and evaporated. The resulting oils were purified by column chromatography.sup.7 to give the desired products (compounds J, K and L) as transparent oils. J: .sup.1H NMR (CDCl.sub.3): 7.28-7.21 (m, 3 arom. H), 7.14-6.99 (m, 3 arom. H), 6.93-6. (m, 3 arom. H), 5.51 (br, s, NH), 3.89 (s, CH.sub.3O), 3.55-3.52 (m, 2H), 3.48-3.42 (m, 2H), 2.74 (t, J=7.2 Hz, 2H). K: .sup.1H NMR (CDCl.sub.3): 7.28-6.65 (m, 7 arom. H), 5.68 (br, s, NH), 3.88 (s, CH.sub.3O), 3.77 (s, CH.sub.3O), 3.54 (s, 2H), 3.46 (q, J=6.6 Hz, 2H), 2.73 (t, J=7 Hz, 2H). L: .sup.1H NMR (CDCl.sub.3): 7.28-6.65 (m, 7 arom. H), 5.68 (br, s, NH), 3.88 (s, CH.sub.3O), 3.77 (s, CH.sub.3O), 3.54 (s, 2H), 3.46 (q, J=6.6 Hz, 2H), 2.73 (t, J=7 Hz, 2H).
(120) To a solution of J, K or L (7.4 mmol.sup.1) in anhydrous THF (150 mL) is added BH.sub.3.THF 1M (37 mL, 37 mmol.sup.1) under N.sub.2 at 0 C..sup.5. The reaction mixture is refluxed overnight.sup.6 and then, after cooling, MeOH is added to destroy the excess of BH.sub.3. The solvent is evaporated, H.sub.2O (100 mL) and NaOH 0.1 N (30 mL) are added. The aqueous phase is extracted with CH.sub.2Cl.sub.2 (320 mL), washed with H.sub.2O (350 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4 and evaporated. The resulting oils are purified by column chromatography.sup.7 to give the desired products (compounds 40-42) as transparent oils.
(121) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 1000 mol. 2) Instead of EDCI also other carbodiimides such as N,N-dicyclohexylcarbodiimide (DCC), N,N-diisopropylcarbodiimide or other coupling reagents can be used. 3) 1-Hydroxy-7-azabenzotriazol (HOAt) is a coupling reagent which can be substituted by hydroxybenzotriazol (HOBT), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate) (HATU), O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate (TBTU), 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), N-hydroxysuccinimide or ethyl-2-cyano-2-(hydroxyimino)acetat and others. 4) Other solvents such as tetrahydrofurane, acetonitrile N,N-dimethylformamide or others can be used. 5) The reaction temperature can vary from 80 C. to 160 C. 6) The reaction time can vary from 0 to 500 hours. 7) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof.
Example 40
1-(2-Fluoro-3-methoxyphenethyl)-2-phenethylamine (Compound 40)
(122) ##STR00044##
(123) 75% yield; .sup.1H NMR (CDCl.sub.3): 7.26-7.13 (m, 5 arom. H), 6.97-6.77 (m, 2 arom. H), 6.68-6.60 (m, 1 arom. H), 3.87 (s, CH.sub.3O), 3.14-2.75 (m, 8H).
Example 41
N-(2-Fluoro-3-methoxyphenethyl)-2-(3-methoxyphenyl)ethanamine (Compound 41)
(124) ##STR00045##
(125) 67% yield; .sup.1H NMR (CDCl.sub.3): 7.16-7.12 (m, 1 arom. H), 6.93-6.60 (m, 5 arom. H), 3.87 (s, CH.sub.3O), 3.78 (s, CH.sub.3O), 3.01-2.87 (m, 8H).
Example 42
4-[2-(2-Fluoro-3-methoxyphenethylamino)ethyl]phenol (Compound 42)
(126) ##STR00046##
(127) 63% yield; .sup.1H NMR (CDCl.sub.3): 6.98-6.84 (m, 4 arom. H), 6.71-6.64 (m, 2 arom. H), 3.89 (s, CH.sub.3O), 2.98-2.79 (m, 8H).
General Procedure for the Synthesis of Derivatives 43-48
(128) A mixture of compound 40, 41 or 42 (2.56 mmol.sup.1), the corresponding alkyl bromide (3.58 mmol.sup.1), and NaHCO.sub.3 (473 mg, 5.6 mmol.sup.2) was allowed to reflux for 48 h.sup.3 with a catalytic amount of KI in CH.sub.3CN.sup.4 (10 mL). The mixture was cooled and filtered, the filtrate was evaporated to dryness, and the crude product was purified by column chromatography.sup.5 to give the desired products (compounds 43-48) as transparent oils.
(129) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 1000 mol. 2) The amount can vary from 0.01 mmol to 5000 mol. 3) The reaction time can vary from 0 to 500 hours. 4) CH.sub.3CN can be replaced by other solvents, preferably by acetone, ethanol, methanol, isopropanol, N,N-dimethylformamide, but also by other appropriate solvents. 5) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof.
Example 43
N-(Cyclobutylmethyl)-N-(2-fluoro-3-methoxyphenethyl)-2-phenylethanamine (Compound 43)
(130) ##STR00047##
(131) 23% yield; .sup.1H NMR (CDCl.sub.3): 7.31-7.18 (m, 5 arom. H), 7.02-6.94 (m, 1 arom. H), 6.86-6.71 (m, 2 arom. H), 3.88 (s, CH.sub.3O), 2.77-2.65 (m, 8H), 2.64-2.61 (m, 2H), 2.10-1.64 (m, 7H).
Example 44
N-(Cyclopropylmethyl)-N-(2-fluoro-3-methoxyphenethyl)-2-phenylethanamine (Compound 44)
(132) ##STR00048##
(133) 25% yield; .sup.1H NMR (CDCl.sub.3): 7.31-7.21 (m, 4 arom. H), 7.06-6.80 (m, 4 arom. H), 3.87 (s, CH.sub.3O), 3.19-3.02 (m, 8H), 2.87 (d, J=6.6 Hz, CH.sub.2-cyclopropyl), 0.87-0.63 (m, 4H), 0.40-0.35 (m, 1H).
Example 45
N-(Cyclohexylmethyl)-N-(2-fluoro-3-methoxyphenethyl)-2-phenylethanamine (Compound 45)
(134) ##STR00049##
(135) 21% yield; .sup.1H NMR (CDCl.sub.3): 7.31-7.10 (m, 5 arom. H), 7.01-6.70 (m, 3 arom. H), 3.88 (s, CH.sub.3O), 2.74-2.72 (m, 8H), 2.30 (d, J=8 Hz, CH.sub.2-cyclohehyl), 1.89-0.74 (m, 11H).
Example 46
N-Benzyl-N-(2-fluoro-3-methoxyphenethyl)-2-phenylethanamine (Compound 46)
(136) ##STR00050##
(137) 16% yield; .sup.1H NMR (CDCl.sub.3): 7.36-7.12 (m, 9 arom. H), 7.11-6.64 (m, 3 arom. H), 3.89 (s, CH.sub.3O), 3.73 (s, CH.sub.2-benzyl), 3.67-2.68 (m, 8H).
Example 47
N-(Cyclobutylmethyl)-N-(2-fluoro-3-methoxyphenethyl)-2-(3-methoxyphenyl)ethanamine (Compound 47)
(138) ##STR00051##
(139) 21% yield; .sup.1H NMR (CDCl.sub.3): 7.24-7.15 (m, 1 arom. H), 7.01-6.93 (m, 1 arom. H), 6.84-6.71 (m, 5 arom. H), 3.87 (s, CH.sub.3O), 3.79 (s, CH.sub.3O), 2.77-2.74 (m, 8H), 2.63-2.49 (m, 2H), 2.09-1.64 (m, 7H).
Example 48
4-[2-[(Cyclobutylmethyl)(2-fluoro-3-methoxyphenethyl)amino]ethyl]phenol (Compound 48)
(140) ##STR00052##
(141) 18% yield; .sup.1H NMR (CDCl.sub.3): 7.05-6.94 (m, 3 arom. H), 6.85-6.72 (m, 4 arom. H), 3.87 (s, CH.sub.3O), 2.80-2.73 (m, 8H), 2.64-2.53 (m, 2H), 2.07-1.66 (m, 7H).
General Procedure for the Synthesis of Derivatives 49-54
(142) To a solution of compounds 43, 44, 45, 46, 47 or 48 (0.54 mmol.sup.1) in CH.sub.2Cl.sub.2.sup.2 (5 mL) under N.sub.2 atmosphere is added BBr.sub.3 1M solution in CH.sub.2Cl.sub.2 (3.23 mmol) at 15 C..sup.3. After 30 min.sup.4 ice and concentrated NH.sub.4OH is added and the mixture is stirred at 0 C. for further 30 min. The organic phase is separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (320 mL). The combined organic layers is dried over Na.sub.2SO.sub.4 and evaporated. The resulting oils are purified by column chromatography.sup.5 to give the desired products (compounds 49-54) as transparent oils. The resulting oils are converted into the hydrochloride salts. The hydrochloride salts are obtained by using the following procedure: A part of the obtained oil is dissolved in Et.sub.2O and treated with HCl/Et.sub.2O.sup.7. The precipitate is isolated and recrystallized from acetone/Et.sub.2O.sup.8 to afford the hydrochloride salt.
(143) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 8) The amount can vary from 0.01 mmol to 1000 mol. 9) CH.sub.2Cl.sub.2 can be replaced by other appropriate solvents. 10) The reaction temperature can vary from 80 C. to 60 C. 11) The reaction time can vary from 0 to 100 hours. 12) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof. 13) Other appropriate procedures are possible to obtain the hydrochloride salt from the bases. The product can also be isolated by evaporating the reaction mixture. Or the residue can be dissolved in water and freeze dried to obtain a lyophilisate. 14) Recrystallization of the product can be performed by using many different kinds of protic solvents such as alcohols (e.g. methanol, ethanol, isopropanol etc.) and also with different kinds of aprotic solvents such as ethers (diethyl ether, diisopropyl ether etc.), or mixtures of two or more solvents, but also by other appropriate solvents.
Example 49
3-[2-[(Cyclobutylmethyl)(phenethyl)amino]ethyl]-2-fluorophenol (Compound 49)
(144) ##STR00053##
(145) 70% yield; .sup.1H NMR (CDCl.sub.3): 7.34-7.18 (m, 5 arom. H), 6.99-6.92 (m, 2 arom. H), 6.77-6.70 (m, 1 arom. H), 2.98 (br, s, 8H), 2.90-2.87 (m, 2H), 2.15-1.26 (m, 7H).
(146) 49.HCl: beige solid. Mp 122-124 C.; IR (ATR) 2978 cm.sup.1 (OH); MS (ESI) m/z 328.3 [M+1].sup.+.
Example 50
3-[2-[(Cyclopropylmethyl)(phenethyl)amino]ethyl]-2-fluorophenol (Compound 50)
(147) ##STR00054##
(148) 70% yield; .sup.1H NMR (CDCl.sub.3): 7.27-7.20 (m, 7 arom. H), 6.89-6.86 (m, 1 arom. H), 2.92-2.78 (m, 8H), 2.55 (d, =6.2 Hz, CH.sub.2-cyclopropyl), 0.95-0.49 (m, 2H), 0.18-0.13 (m, 1H).
(149) 50.HCl: beige solid; Mp 120-122 C.; IR (ATR) 2978 cm.sup.1 (OH); MS (ESI) m/z 328.3 [M+1].sup.+.
Example 51
3-[2-[(Cyclohexylmethyl)(phenethyl)amino]ethyl]-2-fluorophenol (Compound 51)
(150) ##STR00055##
(151) 62% yield; .sup.1H NMR (CDCl.sub.3): 7.32-7.16 (m, 5 arom. H), 6.96-6.78 (m, 2 arom. H), 6.71-6.63 (m, 1 arom. H), 2.74 (br, s, 8H), 2.33 (d, J=6.6 Hz, 2H), 1.74-0.80 (m, 11H).
(152) 51.HCl: beige solid. Mp: 129-130 C.; IR (ATR) 2924 cm.sup.1 (OH); MS (ESI) m/z 356.4 [M+1].sup.+.
Example 52
3-[2-[Benzyl(phenethyl)amino]ethyl]-2-fluorophenol (Compound 52)
(153) ##STR00056##
(154) 61% yield; .sup.1H NMR (CDCl.sub.3): 7.26-7.11 (m, 9 arom. H), 6.91-6.83 (m, 2 arom. H), 6.65-6.62 (m, 1 arom. H), 3.74 (s, CH.sub.2-benzyl), 2.79 (br, s, 8H).
(155) 52.HCl: beige solid. Mp: 126-128 C.; IR (ATR) 2962 cm.sup.1 (OH); MS (ESI) m/z 350.3 [M+1].sup.+.
Example 53
3-[2-[(Cyclobutylmethyl)(3-hydroxyphenethyl)amino]ethyl]-2-fluorophenol (Compound 53)
(156) ##STR00057##
(157) 54% yield; .sup.1H NMR (DMSO): 7.23-7.10 (m, 1 arom. H), 6.92-6.79 (m, 2 arom. H), 6.71-6.59 (m, 3 arom. H), 2.48 (br, s, 4H), 3.08-2.97 (m, 4H), 2.64 (br, s, 2H), 2.10-1.60 (m, 7H).
(158) 53.HCl: beige solid. Mp: 130-133 C.; IR (ATR) 2932 cm.sup.1 (OH); MS (ESI) m/z 344.3 [M+1].sup.+.
Example 54
3-[2-[(Cyclobutylmethyl)(4-hydroxyphenethyl)amino]ethyl]-2-fluorophenol (Compound 54)
(159) ##STR00058##
(160) 48% yield; .sup.1H NMR (DMSO): 7.14-7.07 (m, 2 arom. H), 6.96-6.88 (m, 1 arom. H), 6.80-6.71 (m, 3 arom. H), 3.28-3.08 (m, 8H), 2.89 (br, s, 2H), 2.09-1.86 (m, 7H).
(161) 54.HCl: beige solid. Mp: 135-136 C.; IR (ATR) 3153 cm.sup.1 (OH); MS (ESI) m/z 344.3 [M+1].sup.+.
Example 55
3-[2-[(Cyclobutylmethyl)(phenethyl)amino]ethyl]benzonitrile (Compound 55)
(162) ##STR00059##
(163) To a mixture of HS665 (Journal of Medicinal Chemistry 2012, 55, pp. 10302-10306) (2 g, 6.46 mmol), pyridine (2.1 mL, 25.84 mmol) and CH.sub.2Cl.sub.2 (43 mL) was added triflic anhydride (2.17 mL, 12.92 mmol) at 0 C. The mixture was stirred at 0 C. for 2 h, diluted with CH.sub.2Cl.sub.2 (40 mL), washed with brine (50 mL) and dried over Na.sub.2SO.sub.4. After removal of the solvent in vacuo, 3-[2-[(cyclobutylmethyl)(phenethyl)amino]ethyl]phenyl trifluoromethanesulfonate (M) (2.65 g, 93%) was obtained as transparent oil: .sup.1H NMR (CDCl.sub.3): 7.26-7.06 (m, 9 arom. H), 3.30-2.97 (m, 10H), 2.81-2.67 (m, 1H), 2.12-1.74 (m, 6H).
(164) A mixture of M (1 g, 2.26 mmol), zinc cyanide (345 mg, 2.94 mmol) and tetrakis(triphenylphosphine)palladium(0) (261 mg, 0.226 mmol), in anhydrous DMF (41 mL) was stirred at 100 C. for 3 h under argon. After cooling to room temperature the reaction mixture was diluted with EtOAc (60 mL) and filtered. The filtrate was washed with NaHCO.sub.3 sat (50 mL), H.sub.2O (230 mL) and brine (50 mL). The organic layer was dried over Na.sub.2SO.sub.4 and evaporated in vacuo. After column chromatography (silica gel, hexane/EtOAc/NH.sub.4OH, 89:10:1) 300 mg (30%) of compound 55 were isolated as yellow oil: IR (ATR) 2228 cm.sup.1 (CN); .sup.1H NMR (CDCl.sub.3): 7.40-6.99 (m, 9 arom. H), 2.65-2.63 (m, 8H), 2.54-2.47 (m, 2H), 2.41-2.17 (m, 1H) 1.92-1.49 (m, 6H).
Example 56
3-[2-[(Cyclobutylmethyl)(phenethyl)amino]ethyl]benzamide (Compound 56)
(165) ##STR00060##
(166) To a solution of compound 55 (280 mg, 0.88 mmol) in t-BuOH (2.8 mL), KOH (148 mg, 2.64 mmol) was added. After the mixture was refluxed for 2 h, the solvent was evaporated and the residue was purified by column chromatography (silica gel, CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH, 98.5:0.5:1) to afford 30 mg (30%) of compound 56 as yellow oil: IR (ATR) 3351 cm.sup.1, 3187 cm.sup.1 (NH.sub.2), 1662 cm.sup.1 (CO); .sup.1H NMR (CDCl.sub.3): 7.65-7.59 (m, 2 arom. H), 7.35-7.16 (m, 7 arom. H), 6.03-5.82 (br s, NH.sub.2), 2.76-2.74 (m, 8H), 2.61-2.46 (m, 3H), 2.04-1.66 (m, 6H); MS (ESI) m/z 337.28 [M+1].sup.+.
Example 57
N-(Cyclobutylmethyl)-N-phenethyl-2-phenylethanamine (Compound 57)
(167) ##STR00061##
(168) Compound N was synthesized starting from phenylacetic acid and 2-phenylethylamine. To a stirred solution of phenylacetic acid (500 mg, 3.67 mmol.sup.1), EDCl.sup.2 (915 mg, 4.77 mmol.sup.1) and HOAt.sup.3 (0.67 mL, 4.77 mmol.sup.1) in anhydrous CH.sub.2Cl.sub.2.sup.4 (60 mL), 2-phenylethylamine (0.55 mL, 4.4 mmol.sup.1) was added under N.sub.2 at room temperature.sup.5. The mixture was stirred overnight.sup.6 and then diluted to 120 mL with CH.sub.2Cl.sub.2. The organic layer was washed with NaHCO.sub.3 sat. (225 mL), HCl 0.1 N (225 mL), dried over Na.sub.2SO.sub.4 and evaporated. The resulting oil was purified by column chromatography.sup.7 (silica gel, CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH, 97:2:1) to give 800 mg (91%) of 2-phenyl-N-phenethylacetamide (compound N) as transparent oil: .sup.1H NMR (CDCl.sub.3): 7.35-7.17 (m, 8 arom. H), 7.15-7.00 (m, 2 arom. H), 5.35 (br, s, .sup.+NH), 3.53 (s, 2H), 3.46 (q, J=7 Hz, 2H), 2.72 (t, J=7 Hz, 2H).
(169) BH.sub.3.THF 1M (16.7 mL, 16.7 mmol.sup.1) was added to a solution of compound N (800 mg, 3.34 mmol.sup.1) in anhydrous THF (60 mL) under N.sub.2 at 0 C..sup.5. The reaction mixture was refluxed overnight.sup.6 and then, after cooling, MeOH was added to destroy the excess of BH.sub.3. The solvent was evaporated, H.sub.2O (70 mL) and NaOH 0.1 N (14 mL) were added. The aqueous phase was extracted with CH.sub.2Cl.sub.2 (380 mL), washed with H.sub.2O (330 mL), brine (30 mL), dried over Na.sub.2SO.sub.4 and evaporated. The resulting oil was purified by column chromatography.sup.7 (silica gel, CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH, 98:1:1) to give 500 mg (67%) of diphenethylamine (compound O; Journal of Organic Chemistry 1981, 46, pp. 5344-5348: the synthesis described herein for compound O was a hydrogenation procedure of phenylacetonitrile resulting in low yields of compound O) as transparent oil: .sup.1H NMR (CDCl.sub.3): 7.32-7.15 (m, 8 arom. H), 7.08-7.03 (m, 2 arom. H), 3.12-2.74 (m, 8H). This is a new procedure for the synthesis of diphenethylamine.
(170) A mixture of diphenethylamine (O) (700 mg, 3.1 mmol.sup.1), cyclobutylmethyl bromide (0.49 mL, 4.35 mmol.sup.1), and NaHCO.sub.3 (573 mg, 6.82 mmol.sup.1) was allowed to reflux for 48 h with a catalytic amount of KI in CH.sub.3CN (20 mL). The mixture was cooled and filtered, the filtrate was evaporated to dryness, and the crude product was purified by column chromatography.sup.7 (silica gel, CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH, 98:1:1) to give 300 mg (31%) of compound 57 as slightly orange solid: Mp: 96-98 C.; IR (ATR) 2933 cm.sup.1 (CH); .sup.1H NMR (CDCl.sub.3): 7.33-7.15 (m, 10 arom. H), 2.83-2.75 (m, 8H), 2.74-2.65 (m, 2H, CH.sub.2-cyclobutyl), 2.11-1.81 (m, 7H); MS (ESI) m/z 294.21 [M+1].sup.+.
(171) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 1000 mol. 2) Instead of EDCl also other carbodiimides such as N,N-dicyclohexylcarbodiimide (DCC), N,N-diisopropylcarbodiimide or other coupling reagents can be used. 3) 1-Hydroxy-7-azabenzotriazol (HOAt) is a coupling reagent which can be substituted by hydroxybenzotriazol (HOBT), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate) (HATU), O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate (TBTU), 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), N-hydroxysuccinimide or ethyl-2-cyano-2-(hydroxyimino)acetat and others. 4) Other solvents such as tetrahydrofurane, acetonitrile N,N-dimethylformamide or others can be used. 5) The reaction temperature can vary from 80 C. to 160 C. 6) The reaction time can vary from 0 to 500 hours. 7) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof.
Example 58
N-(Cyclobutylmethyl)-N-(3-nitrophenethyl)-2-phenylethanamine (Compound 58)
(172) ##STR00062##
(173) Compound P was synthesized starting from 2-(3-nitrophenyl)acetic acid and 2-phenylethanamine. To a stirred solution of 2-(3-nitrophenyl)acetic acid (3 g, 16.56 mmol.sup.1), EDCl.sup.2 (4.13 g, 21.53 mmol.sup.1) and HOAt.sup.3 (3 mL, 21.53 mmol.sup.1) in anhydrous CH.sub.2Cl.sub.2.sup.4 (150 mL), 2-phenylethanamine (2.5 mL, 19.87 mmol.sup.1) was added under N.sub.2 at room temperature.sup.5. The mixture was stirred overnight.sup.6 then diluted to 250 mL with CH.sub.2Cl.sub.2. The organic layer was washed with NaHCO.sub.3 sat. (250 mL), HCl 0.1 N (250 mL), dried over Na.sub.2SO.sub.4 and evaporated. The resulting oil was purified by column chromatography.sup.7 (silica gel, CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH, 98:1:1) to give 3.5 g (74%) of 2-(3-nitrophenyl)-N-phenethylacetamide (P) as a transparent oil: .sup.1H NMR (CDCl.sub.3): 8.13-8.00 (m, 2 arom. H), 7.60-7.43 (m, 2 arom. H), 7.29-7.14 (m, 3 arom. H), 7.10-7.04 (m, 2 arom. H), 5.90 (br, s, .sup.+NH), 3.57-3.43 (m, 4H), 2.98-2.86 (m, 1H), 2.84-2.73 (m, 3H). The synthesis of P was described earlier in the U.S. Pat. No. 6,030,985 using the same starting materials but a different procedure.
(174) To a solution of P (3.5 g, 12.31 mmol.sup.1) in anhydrous THF (100 mL) under N.sub.2 was added BH.sub.3.THF 1M (61.55 mL, 61.55 mmol.sup.1) at 0 C.3. The reaction mixture was refluxed overnight.sup.6 and then, after cooling, MeOH was added to destroy the excess of BH.sub.3. The solvent was evaporated, H.sub.2O (150 mL) and NaOH 0.1 N (30 mL) were added. The aqueous phase was extracted with CH.sub.2Cl.sub.2 (3150 mL), washed with H.sub.2O (360 mL), brine (60 mL), dried over Na.sub.2SO.sub.4 and evaporated. The resulting oil was purified by column chromatography.sup.7 to give 930 mg (30%) of compound Q as transparent oil: .sup.1H NMR (CDCl.sub.3): 8.06-8.02 (m, 2 arom. H), 7.50-7.37 (m, 2 arom. H), 7.30-7.14 (m, 5 arom. H), 2.92-2.79 (m, 8H). Compound Q has been prepared from P earlier (U.S. Pat. No. 6,030,985) using a procedure similar to the one described here.
(175) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 1000 mol. 2) Instead of EDCl also other carbodiimides such as N,N-dicyclohexylcarbodiimide (DCC), N,N-diisopropylcarbodiimide or other coupling reagents can be used. 3) 1-Hydroxy-7-azabenzotriazol (HOAt) is a coupling reagent which can be substituted by hydroxybenzotriazol (HOBT), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate) (HATU), O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate (TBTU), 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), N-hydroxysuccinimide or ethyl-2-cyano-2-(hydroxyimino)acetat and others. 4) Other solvents such as tetrahydrofurane, acetonitrile N,N-dimethylformamide or others can be used. 5) The reaction temperature can vary from 80 C. to 160 C. 6) The reaction time can vary from 0 to 500 hours. 7) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof.
(176) A mixture of compound Q (930 mg, 3.44 mmol.sup.1), cyclobutylmethyl bromide (0.54 mL, 4.82 mmol.sup.1), and NaHCO.sub.3 (636 mg, 7.57 mmol.sup.2) was allowed to reflux for 48 h.sup.3 with a catalytic amount of KI in CH.sub.3CN.sup.4 (23 mL). The mixture was cooled and filtered, the filtrate was evaporated to dryness, and the crude product was purified by column chromatography.sup.5 to give 690 mg (59%) of compound 58 as yellow oil.
(177) IR (ATR) 1528 cm.sup.1, 1351 cm.sup.1 (NO); .sup.1H NMR (CDCl.sub.3): 8.05-8.01 (m, 2 arom. H), 7.48-7.16 (m, 7 arom. H), 2.86-2.79 (m, 8H), 2.66-2.39 (m, 3H), 2.06-1.60 (m, 6H); MS (ESI) m/z 339.30 [M+1].sup.+.
(178) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 1000 mol. 2) The amount can vary from 0.01 mmol to 5000 mol. 3) The reaction time can vary from 0 to 500 hours. 4) CH.sub.3CN can be replaced by other solvents, preferably by acetone, ethanol, methanol, isopropanol, N,N-dimethylformamide, but also by other appropriate solvents. 5) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof.
Example 59
3-[2-[(Cyclobutylmethyl)(phenethyl)amino]ethyl]aniline (Compound 59)
(179) ##STR00063##
(180) To a solution of compound 58 (50 mg, 0.15 mmol.sup.1) in EtOH.sup.2 (1 mL), FeSO.sub.4.7H.sub.2O (122 mg, 0.44 mmol.sup.3), H.sub.2O (0.15 mL) and NH.sub.4Cl (64 mg, 1.2 mmol.sup.3) were added subsequently, and then zinc powder (29 mg, 0.44 mmol.sup.3) was added to the mixture. The reaction was carried out for 3 h.sup.4 with an internal temperature of 50 C..sup.5. It was then cooled to room temperature and filtered over a pad of Celite. The filter cake was washed with EtOH (5 mL) and the filtrate was concentrated under reduced pressure. To the residue, EtOAc (10 mL) and 25%.sub.acq. NH.sub.4Cl (5 mL) were added. The biphasic mixture was stirred at room temperature for 5 min and the organic layer was separated. The organic layer was washed with H.sub.2O (10 mL), NaHCO.sub.3 sat (10 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. After column chromatography.sup.6 25 mg (54%) of compound 59 were obtained as yellow oil: .sup.1H NMR (CDCl.sub.3): 8.05-8.01 (m, 2 arom. H), 7.25-7.10 (m, 5 arom. H), 7.04-6.92 (m, 1 arom. H), 6.54-6.44 (m, 3 arom. H), 2.69-2.65 (m, 8H), 2.58-2.54 (m, 3H), 1.98-1.63 (m, 6H);
(181) A part of the obtained oil of compound 59 was converted into its hydrochloride salt 59.HCl.sup.7,8: yellowish solid; Mp: 68-70 C.; IR (ATR) 2937 cm.sup.1, 2860 cm.sup.1 (NH); MS (ESI) m/z 309.27 [M+1].sup.+.
(182) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 10000 mol. 2) Ethanol can be replaced by other protic solvent such as methanol, isopropanol and also other solvents. 3) The amount can vary from 0.01 mmol to 30000 mol. 4) The reaction time can vary from 0 to 500 hours. 5) The reaction temperature can vary from 0 C. to 160 C. 6) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof. 7) Other appropriate procedures are possible to obtain the hydrochloride salt from the bases. The product can also be isolated by evaporating the reaction mixture. Or the residue can be dissolved in water and freeze dried to obtain a lyophylisate. 8) Recrystallization of the product can be performed by using many different kinds of protic solvents such as alcohols (e.g. methanol, ethanol, isopropanol etc.) and also with different kinds of aprotic solvents such as ethers (diethyl ether, diisopropyl ether etc.), or mixtures of two or more solvents, but also by other appropriate solvents.
Example 60
4-[2-[(Cyclobutylmethyl)(phenethyl)amino]ethyl]phenol (Compound 60)
(183) ##STR00064##
(184) To the stirred solution of 4-hydroxyphenylacetic acid (500 mg, 3.29 mmol.sup.1), EDCl.sup.2 (818 mg, 4.27 mmol1) and HOAt.sup.3 (7.12 mL, 4.27 mmol.sup.1) in anhydrous CH.sub.2Cl.sub.2.sup.4 (66 mL) under N.sub.2, 2-phenylethylamine (0.5 mL, 3.95 mmol.sup.1) was added at room temperature.sup.5. The mixture was stirred overnight.sup.6 then diluted to 120 mL with CH.sub.2Cl.sub.2. The organic layer was washed with NaHCO.sub.3 sat. (225 mL), HCl 0.1 N (225 mL), dried over Na.sub.2SO.sub.4 and evaporated. The resulting oil was purified by column chromatography.sup.7 (silica gel, CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH, 95:4:1) to give 750 mg (89%) of 2-(4-hydroxyphenyl)-N-phenethylacetamide (compound R) as transparent oil: .sup.1H NMR (CDCI.sub.3) 8.36 (br s, .sup.+NH), 7.60-7.46 (m, 5 arom. H), 7.34 (d, J=8.8 Hz, 2 arom. H), 7.17 (d, J=8.4 Hz, 2 arom. H), 5.90 (br s, OH), 3.81 (s, CH.sub.2CO), 3:32-3:14 (m, NHCH.sub.2CH.sub.2), 3.10-3.04 (m, NHCH.sub.2 CH.sub.2).
(185) To a solution of R (700 mg, 2.73 mmol.sup.1) in anhydrous THF (90 mL) under N.sub.2 was added BH.sub.3.THF 1M (13.65 mL, 13.65 mmol.sup.1) at 0 C. The reaction mixture was refluxed overnight then, after cooling, MeOH was added to destroy the excess of BH.sub.3. The solvent was evaporated, H.sub.2O (70 mL) and NaOH 0.1 N (14 mL) were added. The aqueous phase was extracted with CH.sub.2Cl.sub.2 (380 mL), washed with H.sub.2O (330 mL), brine (30 mL), dried over Na.sub.2SO.sub.4 and evaporated. The resulting oil was purified by column chromatography (silica gel, CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH, 97:2:1) to give 470 mg (71%) of compound S: .sup.1H NMR (CDCl.sub.3) 7.26-7.22 (m, 3 arom. H), 7.07-7.04; (m, 2 arom. H); 6.90 (d, J=8.4 Hz, 2 arom. H), 6.68 (d, J=8.2 Hz, 2 arom. H), 3.04-2.80 (m, 8H). Compound S has been prepared earlier by another procedure using different starting materials: H. Pfanz and H. Mller, Patent (1956) DD 11918.
(186) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 1000 mol. 2) Instead of EDCl also other carbodiimides such as N,N-dicyclohexylcarbodiimide (DCC), N,N-diisopropylcarbodiimide or other coupling reagents can be used. 3) 1-Hydroxy-7-azabenzotriazol (HOAt) is a coupling reagent which can be substituted by hydroxybenzotriazol (HOBT), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate) (HATU), O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate (TBTU), 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), N-hydroxysuccinimide or ethyl-2-cyano-2-(hydroxyimino)acetat and others. 4) Other solvents such as tetrahydrofurane, acetonitrile N,N-dimethylformamide or others can be used. 5) The reaction temperature can vary from 80 C. to 160 C. 6) The reaction time can vary from 0 to 500 hours. 7) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof.
(187) A mixture of compound S (500 mg, 2.07 mmol.sup.1), cyclobutylmethyl bromide (0.33 mL, 2.9 mmol.sup.1), and NaHCO.sub.3 (383 mg, 4.55 mmol.sup.1) was allowed to reflux for 48 h.sup.2 in CH.sub.3CN.sup.3 (8 mL). The mixture was cooled and filtered, the filtrate was evaporated to dryness, and the crude product was purified by column chromatography.sup.4 (silica gel, CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH, 97.5:1.5:1) to give 176 mg (27%) of compound 60 as yellow oil. A part of the obtained oil of 60 was dissolved in Et.sub.2O and treated with HCl/Et.sub.2O.sup.5. The precipitate was isolated and recrystallized from acetone/Et.sub.2O.sup.6 to afford 62.HCl: Mp. 157-158 C.; .sup.1H NMR (DMSO-d.sub.6) 7.26-7.22 (m, 5 arom. H), 7.00 (d, J=8.4 Hz, 2 arom. H), 6.64 (d, J=8.4 Hz, 2 arom. H), 3.20-2.83 (m, 11H), 2.01-1.79 (m, 6H); IR (ATR) 3108 (OH); MS (ESI) m/z 309 [M+1].sup.+.
(188) Different modifications of this typical procedure are possible, and are commonly known to the skilled artisan, e.g.: 1) The amount can vary from 0.01 mmol to 1000 mol. 2) The reaction time can vary from 0 to 500 hours. 3) CH.sub.3CN can be replaced by other solvents, preferably by acetone, ethanol, methanol, isopropanol, N,N-dimethylformamide, but also by other appropriate solvents. 4) The liquid phase for column chromatography can consist of various mixtures of dichloromethane/methanol; or dichloromethane/methanol/ammonia solution; or dichloromethane/methanol/triethylamine; or other appropriate solvents and mixtures thereof. 5) Other appropriate procedures are possible to obtain the hydrochloride salt from the bases. The product can also be isolated by evaporating the reaction mixture. Or the residue can be dissolved in water and freeze dried to obtain a lyophylisate. 6) Recrystallization of the product can be performed by using many different kinds of protic solvents such as alcohols (e.g. methanol, ethanol, isopropanol etc.) and also with different kinds of aprotic solvents such as ethers (diethyl ether, diisopropyl ether etc.), or mixtures of two or more solvents, but also by other appropriate solvents.
Example 61
4-[2-[(Cyclopentylmethyl)(phenethyl)amino]ethyl]phenol (Compound 61)
(189) ##STR00065##
(190) A mixture of compound S (200 mg, 0.83 mmol), cyclopentylmethyl bromide (189 mg, 1.16 mmol), and NaHCO.sub.3 (153 mg, 1.83 mmol) was allowed to reflux for 48 h with a catalytic amount of KI in CH.sub.3CN (4 mL). The mixture was cooled and filtered, the filtrate was evaporated to dryness, and the crude product was purified by column chromatography (silica gel, CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH, 97:2:1) to give the desired product (compound 61) as yellow oil (60 mg, 22% yield); .sup.1H NMR (CDCl.sub.3) 7.14-7.04 (m, 5 arom. H), 6.92-6.86.00 (m, 2 arom. H), 6.63-6.58 (m, 2 arom. H), 2.71-2.64 (m, 8H), 2.46-2.42 (m, 2H, CH.sub.2-cyclopentylmethyl), 2.00-1.93 (m, 1H), 1.61-1.11 (m, 8H).
(191) A part of the obtained oil of compound 61 was dissolved in Et.sub.2O and treated with HCl/Et.sub.2O. The precipitate was isolated and recrystallized from acetone/Et.sub.2O to afford 61.HCl as white solid; Mp: 150-153 C.; IR (ATR) 3126 cm.sup.1 (OH); MS (ESI) m/z 324.4 [M+1].sup.+.
(192) Different modifications of this typical procedure are possible (s. example 60).
Example 62
(193) Opioid Receptor Binding, Functional Studies (KOR-Mediated G Protein Activation and KOR-mediated -Arrestin2 Recruitment) and Analgesic Activity
(194) Description of Procedures
(195) Opioid Receptor Binding Affinities: Opioid receptor binding studies were performed to determine the binding affinities at human opioid receptors (KOR, MOR and DOR) using membranes from Chinese hamster ovary (CHO) cells expressing one of the human opioid receptors, according to the published procedure (Journal of Medicinal Chemistry 2012, 55, pp. 10302-10306). The KOR, MOR and DOR binding affinities expressed as inhibition constants (K) are presented in Table 1. Inhibition constant (K) values were calculated from competition binding curves using GraphPad Prism program (San Diego, Calif., USA). Binding affinities of compounds of the invention were compared to the affinity of the reference KOR compounds HS665, U50,488 and U69,593 (Table 1).
(196) KOR-mediated G Protein Activation: G protein activation studies using [.sup.35S]GTPS binding assays were performed to determine the in vitro pharmacological activities at the KOR with membranes from CHO cells expressing human KOR, according to the published procedure (Journal of Medicinal Chemistry 2012, 55, pp. 10302-10306). Concentration-response curves were constructed, and potency (EC.sub.50, nM) and efficacy (E.sub.max, as % of maximum stimulation with respect to the reference KOR agonist U69,593) were calculated using curve fitting analysis with the GraphPad Prism Software. The effect on [.sup.35S]GTPyS binding produced by compounds of the invention was compared to that of the reference KOR compounds HS665, U50,488 and U69,593 (Table 1). Compounds producing a stimulation of 85% are considered to be full agonists, while compounds with stimulation between 20 and 84.9% are partial agonists, and compounds with stimulation below 20% are antagonists.
(197) KOR-mediated -Arrestin2 Recruitment: To investigate whether the compounds of the present invention are biased against -arrestin2 recruitment, they were evaluated for their ability to stimulate arrestin2 recruitment, based on the current knowledge that negative side effects (i.e. sedation, dysphoria, anhedonia, motor incoordination, reduced motivation) result from -arrestin2-mediated signaling events (Trends in Pharmacological Sciences, 2014, 35, pp 308.316; European Journal of Pharmacology, 2015, 763, pp 184-190). The effect to induce -arrestin2 recruitment upon KOR activation was investigated using the DiscoveRx PathHunter eXpress -arrestin assay (DiscoveRx, Fremont, Calif.), a commonly used assay to assess -Arrestin2 translocation for 7TM-GPCRs [www.discoverx.com]. The assay was performed using U2OS-hMOR--arrestin2 cells according to the manufacturer's protocol [www.discoverx.com]. Concentration-response curves were constructed, and potency (EC.sub.50, nM) and efficacy (E.sub.max, as % of maximum stimulation with respect to the reference KOR agonist U69,593) were calculated using curve fitting analysis with the GraphPad Prism Software.
(198) The potency and efficacy for recruiting -arrestin2 upon binding and activation of the KOR of compounds of the invention were compared to that of the reference KOR compounds HS665, HS666, U50,488 and U69,593 (Table 1). To determine the bias toward KOR-induced G protein signaling over -arrestin2 recruitment, bias factors were calculated using a similar procedure used to quantify the biased agonism of TRV130, a G protein MOR biased ligand, currently under development for moderate to severe acute pain (Journal of Pharmacology and Experimental Therapeutics 2013, 344, pp 708-717).
(199) Analgesic Activity: Analgesic activity was established in mice after subcutaneous (s.c.) administration using the acetic acid-induced writhing test, according to the described procedure (Journal of Medicinal Chemistry 2012, 55, pp. 10302-10306). The antinociceptive doses (ED.sub.50) at 30 min after s.c. administration to mice were calculated for compounds of the invention and compared to that of reference KOR compounds HS665,HS666 and U50,488 (Table 2).
(200) TABLE-US-00001 TABLE 1 Binding affinities, [.sup.35S]GTPS stimulation and -arrestin2 recruitment of compounds of the invention and reference compounds HS665, HS666, U50,488 and U69,593 Opioid receptor G protein assay binding assay [.sup.35S]GTPS binding -arrestin2 recruitment Cpd. Affinity K.sub.i (nM).sup.a KOR.sup.b assay.sup.c Bias No. KOR MOR DOR EC.sub.50 (nM) E.sub.max (%) EC.sub.50 (nM) E.sub.max (%) factor.sup.d 2 0.017 274 5206 4.19 72.9 1342 83.0 162 3 0.088 436 2139 0.23 61.9 1359 72.2 2909 4 0.71 463 1862 4.65 79.5 4454 37.3 1172 12 0.34 230 4184 5.51 71.4 n.t. n.t. n.t. 27 0.17 158 6238 22.8 73.6 n.t. n.t. n.t. 29 0.18 219 n.t. 10.6 92.2 n.t. n.t. n.t. 39 0.38 702 n.t. 14.2 83.6 n.t. n.t. n.t. 49 0.022 414 >10000 6.90 66.1 859 57.5 82 51 0.046 543 >10000 2.77 84.6 4179 48.4 1514 53 0.12 548 4748 1.49 53.1 529 41.2 263 HS665 0.49 542 >10000 3.62 90.0 563 54.2 148 HS666.sup.e 5.90 826 >10000 35.0 53.4 502 25.0 18 U50,488 0.95 n.t. n.t. 9.31 93.0 n.t. n.t. n.t. U69,593 1.47 n.t. n.t. 37.1 100 64.6 100 1 .sup.aDetermined in competition binding experiments using membranes from CHO cells stably expressing either human KOR, MOR, or DOR. .sup.bDetermined in [.sup.35S]GTPS binding experiments using CHO-hKOR cell membranes. .sup.cDetermined in DiscoveRx PathHunter assay using U2OS-hMOR cells. Efficacy (E.sub.max, %) is shown as relative to maximum stimulation of the reference KOR agonist U69,593. .sup.dBias factor was calculated as ratio of the intrinsic relative activity: RAi(-arrestin2)/RAi(G protein), where RAi = (E.sub.maxref EC.sub.50cpd)/(E.sub.maxcpd EC.sub.50ref), as described in Journal of Pharmacology and Experimental Therapeutics 2013, 344, pp 708-717. n.t.: not tested . . . cpd.: compound tested. ref.: reference ligand (i.e. U69,593). .sup.eHS666: 3-[2-[(Cyclopropylmethyl)(phenethyl)amino]ethyl]phenol Hydrochloride (compound 3 in Journal of Medicinal Chemistry 2012, 55, pp. 10302-10306).
(201) TABLE-US-00002 TABLE 2 Antinociceptive potency in the writhing test in mice of compounds of the invention and reference KOR compounds HS665, HS666 and U50,488 after s.c. administration Relative Relative analgesic analgesic ED.sub.50 potency potency Relative analgesic Cpd. No. (mg/kg, s.c.) to HS665 to HS666 potency to U50,488 2 0.54 3.5 6.0 2.9 3 0.97 2.0 3.3 1.6 4 1.21 1.6 2.7 1.3 12 1.59 1.2 2.0 1.0 51 1.20 1.6 2.7 1.3 HS665 1.91 1.0 1.7 0.8 HS666 3.23 0.6 1.0 0.5 U50,488 1.54 1.2 2.1 1.0
(202) The compounds according to the present invention display a high affinity to the KOR that is comparable or higher than the KOR affinity of the reference compounds HS665,HS666, U50,488 or U69,593. Generally, the compounds according to the present invention are either partial or full agonists, with comparable or higher agonist potency at the KOR compared to the above reference compounds. Remarkably, the compounds according to the present invention display comparable or higher antinociceptive potency than the known full KOR agonists HS665 and U50,488 or the partial KOR agonist HS666. At the same time, -arrestin2 recruitment by the compounds of the present invention is much lower, while exhibiting a much higher bias factor than the reference compounds HS665,HS666, or U50,488. These characteristics make them particularly suited for the treatment of human disorders where the KOR plays a central role with low propensity for unwanted side effects such as sedation, dysphoria, anhedonia, motor incoordination, reduced motivation, constipation or addictive potential.