Urea derivatives and their use as fatty-acid binding protein (FABP) inhibitors
09708340 ยท 2017-07-18
Assignee
Inventors
- Bernd Buettelmann (Schopfheim, DE)
- Simona M. Ceccarelli (Basel, CH)
- Aurelia Conte (Basel, CH)
- Holger KUEHNE (Loerrach, DE)
- Bernd KUHN (Reinach, CH)
- Werner Neidhart (Hagenthal-le-Bas, FR)
- Ulrike Obst Sander (Reinach, CH)
- Hans Richter (Grenzach-Wyhlen, DE)
Cpc classification
C07D409/12
CHEMISTRY; METALLURGY
C07D277/06
CHEMISTRY; METALLURGY
C07D209/52
CHEMISTRY; METALLURGY
A61P9/10
HUMAN NECESSITIES
A61P43/00
HUMAN NECESSITIES
C07D401/12
CHEMISTRY; METALLURGY
C07D207/16
CHEMISTRY; METALLURGY
C07D205/04
CHEMISTRY; METALLURGY
A61P1/16
HUMAN NECESSITIES
C07D211/60
CHEMISTRY; METALLURGY
International classification
C07D211/00
CHEMISTRY; METALLURGY
C07D295/00
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07D409/12
CHEMISTRY; METALLURGY
C07D205/04
CHEMISTRY; METALLURGY
C07D207/16
CHEMISTRY; METALLURGY
C07D277/06
CHEMISTRY; METALLURGY
C07D209/52
CHEMISTRY; METALLURGY
Abstract
The invention provides novel compounds having the general formula (I) ##STR00001##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, W, A and B are as described herein, compositions including the compounds and methods of using the compounds.
Claims
1. The compound selected from the group consisting of: 1-(Biphenyl-2-ylcarbamoyl)-piperidine-2-carboxylic acid; (R)-1-(5-chlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(2-phenoxyphenylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(2-benzylphenylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(5-chloro-2-phenoxyphenylcarbamoyl)pyrrolidine-2-carboxylic acid; 1-(Biphenyl-2-ylcarbamoyl)-2-phenyl-pyrrolidine-2-carboxylic acid; 3-(Biphenyl-2-ylcarbamoyl)-thiazolidine-2-carboxylic acid; (S)-3-(Biphenyl-2-ylcarbamoyl)-thiazolidine-4-carboxylic acid; (1SR,2SR,5RS)-3-(Biphenyl-2-ylcarbamoyl)-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid; (R)-1-(4-chlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(3-fluorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-chlorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid; (R)-1-(4-(trifluoromethyl)biphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4,6-difluorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; 1-(biphenyl-2-ylcarbamoyl)-2-methylpyrrolidine-2-carboxylic acid; (R)-1-(4-fluorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-(trifluoromethoxy)biphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4,6-dichlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(5-Chloro-[1,1;2,1]terphenyl-3-ylcarbamoyl)-pyrrolidine-2-carboxylic acid; (R)-1-(4-cyanobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(2-phenylbenzo[b]thiophen-3-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(2-phenylthieno[2,3-b]pyridin-3-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(6-allyl-4-chlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(2-phenylthiophen-3-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-chloro-6-cyanobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-[4-chloro-6-(cyclohexen-1-yl)-biphenyl-2-ylcarbamoyl]pyrrolidine-2-carboxylic acid; (S)-1-(4-chlorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid; (R)-1-(biphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid; (R)-1-(4-chloro-4-fluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid; (R)-1-(4-chloro-5-fluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid; (R)-1-(4-chloro-5-methylbiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid; (R)-1-(4-chloro-2,3-difluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid; (R)-1-(4-chloro-2-fluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid; (R)-1-(4-chloro-3-fluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid; (R)-1-(4-chloro-3,5-difluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid; (R)-1-(5-chloro-2-(thiophen-3-yl)phenylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(2-(benzo[b]thiophen-3-yl)-5-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-chloro-4-fluorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(3,4-dichlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(3-carbamoyl-4-chlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-[5-chloro-2-(cyclohexen-1-yl)phenylcarbamoyl]pyrrolidine-2-carboxylic acid; (R)-1-(5-chloro-2-(pyridin-4-yl)phenylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4,4-dichlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-chloro-4-methoxybiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-chloro-2-methylbiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-ethylbiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-chloro-2,4-difluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid; (R)-1-(4-chloro-4-fluoro-6-methoxybiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid; and pharmaceutically acceptable salts thereof.
2. The compound according to claim 1, selected from the group consisting of: (R)-1-(4-chlorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid; (R)-1-(4-chloro-4-fluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid; and pharmaceutically acceptable salts thereof.
3. A pharmaceutical composition comprising a compound according to claim 1 and a therapeutically diluent, carrier or excipient.
Description
EXAMPLES
(1) All examples and intermediates were prepared under argon atmosphere if not specified otherwise.
(2) General Method A: Synthesis of an Isocyanate from an Aniline
(3) To a solution of the aniline (5.21 mmol, 1.00 equivalent) in toluene (19.0 ml), triphosgene (0.35 equivalents) is added slowly and the reaction mixture is heated to reflux for 1 h. The reaction mixture is concentrated to dryness and the product is either purified by bulb-to-bulb distillation or used in the next step without further purification.
(4) General Method B: Synthesis of a Urea from an Isocyanate
(5) To a suspension of the aminoacid (1.48 mmol, 1 equivalent) in DCM (4 ml) are added triethylamine (1 equivalent) and the isocyanate (1 equivalent). The reaction mixture is stirred at r.t. for 5 to 36 h. Half-concentrated aqueous sodium carbonate solution is added. The layers are separated and the aqueous layer is washed with DCM. The organic layer is extracted with diluted sodium carbonate solution. The combined aqueous layers are acidified with concentrated hydochloric acid. If the product precipitates, it can be collected by filtration and dried. In case the product does not precipitate it can be obtained by extraction with DCM. The organic layers are dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness. If desired, the product can be further purified by chromatography.
(6) General Method C: Synthesis of a Urea from an Aniline Via Carbamate-Intermediate
(7) A solution of the aniline (2.09 mmol, 1.00 equivalent) in THF (4.0 ml) is cooled in an ice bath. A solution of phenyl chloroformate (1.04 equivalents) in THF (3.01 ml) is added. The reaction mixture is heated to reflux for 1 to 4 h. After cooling to r.t., the amino acid (1.1 equivalents), potassium carbonate (3 equivalents) and water (5.26 ml) are added. The reaction mixture is stirred at r.t. for 18 to 36 h. The mixture is diluted with water and washed with n-heptane. The aqueous layer is partially evaporated to remove organic solvents. At r.t., the aqueous layer is slowly acidified using 25% HCl. The precipitated product can be collected by filtration, washed with little water and dried. In case the product does not precipitate it can be obtained by extraction with DCM. The organic layers are dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness. If desired, the product can be further purified by chromatography.
(8) General Method D: Suzuki Coupling
(9) An aromatic bromide, iodide, triflate or mesylate (0.29 mmol, 1 equivalent), a boronic acid or boronic acid ester (1.5 equivalents) and a 2 M aqueous solution of sodium carbonate (3 equivalents) are combined under argon with dioxane (3.5 ml) and water (1.4 ml). [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.05 equivalents) is added and the reaction mixture is stirred at 80 C. for 3 to 10 h. After cooling to r.t., the mixture is filtered. Diluted aqueous HCl is added and the mixture is extracted with EtOAc. The combined organic layers are dried over MgSO.sub.4, filtered and concentrated in vacuo. The product can be purified by chromatography.
(10) TABLE-US-00002 Example Name / Structure / MS Method Reagents 1
Synthesis of Intermediates
Intermediate I14
4,6-Difluorobiphenyl-2-amine
(11) ##STR00057##
(12) Step 1:
(13) A solution of 2,4-difluoro-6-nitroaniline (CAS#364-30-7; 2.00 g) in DCM (97 ml) was cooled to 0 C. At this temperature boron trifluoride ethyletherate (1.61 g) was added, followed by tert-butyl nitrite (1.63 g). The resulting reaction mixture was allowed to warm to r.t. and stirred for 1 h. The liquid was poured out of the flask and the oily residue was washed with DCM, then the residue was dried under high vacuum and used without further purification for the next step.
(14) Step 2:
(15) The product of step 1 (2.18 g) and phenylboronic acid (1.0 g) were combined with 1,4-dioxane (20 ml), then palladium (II) acetate (55.2 mg) was added to give a foaming dark brown solution. The reaction mixture was stirred at r.t. overnight and then concentrated in vacuo. The product was purified by flash chromatography (silica gel, 0% to 50% EtOAc in heptane) to give 2,4-difluoro-6-nitrobiphenyl (688 mg) as a brown oil.
(16) Step 3:
(17) 2,4-Difluoro-6-nitrobiphenyl (684 mg) and sodium sulfite nonahydrate (2.08 g) were combined with ethanol (3.56 ml) and water (3.56 ml) to give a brown solution. The reaction mixture was stirred for 4.5 h at 100 C. and overnight at r.t. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc. The organic layer was washed with water, the aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuo. The product was purified by flash chromatography (silica gel, 0% to 50% EtOAc in heptane) to give the title compound (469 mg) as a light yellow liquid.
Intermediate I17
4-(Trifluoromethoxy)biphenyl-2-amine
(18) ##STR00058##
(19) 2-Bromo-5-(trifluoromethoxy)aniline (CAS#887267-47-2; 200 mg), phenylboronic acid (143 mg) and a 2 M aqueous solution of sodium carbonate (1.17 ml) were combined at r.t. under argon with dioxane (9.4 ml) and water (3.75 ml). [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (31.9 mg) was added to give yellow suspension. The reaction mixture was heated to 80 C. and stirred overnight at 80 C. The reaction mixture was cooled down and filtered through glass fiber paper, washed with 30 mL water and 30 mL EtOAc, the layers were separated, the aqueous layer was back-extracted with EtOAc. The organic layers were combined, dried over MgSO.sub.4 and concentrated in vacuo. The product was purified by flash chromatography (silical gel, 0% to 70% EtOAc in n-heptane) to give the title compound (198 mg) as a yellow oil.
Intermediate I19
5-Chloro-[1,1;2,1] terphenyl-3-ylamine
(20) ##STR00059##
(21) Step 1:
(22) To a solution of 2,4-dichloro-6-nitrophenol (CAS#609-89-2; 2.4 g) in DCM (150 ml) was added triethylamine (2.69 g). The reaction mixture was cooled to 20 C., trifluoromethanesulfonic anhydride (3.91 g) was added slowly at this temperature and stirred for 20 min. The cooling-bath was removed and the reaction mixture was stirred for 1 h at r.t. The reaction mixture was washed with a saturated aqueous NH.sub.4Cl solution and brine, the aqueous layers were extracted with DCM. The combined organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuo. The product was purified by flash chromatography (silica gel, 50 g, 0% to 40% EtOAc in heptane) to give 2,4-dichloro-6-nitrophenyl trifluoromethanesulfonate (3.9 g) as a light yellow solid.
(23) Step 2:
(24) 2,4-Dichloro-6-nitrophenyl trifluoromethanesulfonate (3.94 g), phenylboronic acid (2.12 g) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride, dichloromethane complex (474 mg) were combined with dioxane (34.1 ml), a 2 M aqueous sodium carbonate solution (17.4 ml) and water (24.7 ml) to give an orange suspension. The reaction mixture was stirred at 80 C. for 3.5 h. The reaction mixture was cooled down, then filtered through glass fiber paper and washed with EtOAc and KHSO.sub.4-solution. The filtrate was extracted with EtOAc, the organic layers were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The product was purified by flash chromatography (silica gel, 70 g, 0% to 50% EtOAc in n-hexane) followed by preparative HPLC to give 5-chloro-3-nitro-[1,1;2,1]terphenyl (455 mg) as an off-white solid.
(25) Step 3:
(26) 5-Chloro-3-nitro-[1,1;2,1]terphenyl (437 mg), iron powder (473 mg) and ammonium chloride (75.5 mg) were combined with ethanol (7.15 ml) and water (0.64 ml) to give a white suspension. The reaction mixture was heated to 85 C. (reflux) and stirred for 6.5 h, then at r.t. over night. Iron powder (145 mg) and ammonium chloride (25 mg) were added and the reaction was heated again to 85 C. for 2.5 h, then again over night at r.t. The reaction mixture was filtered through glass filter paper and concentrated in vacuo. The raw product was extracted with EtOAc, the organic phases were washed with NaHCO.sub.3 solution and brine. The organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuo. The product was purified by flash chromatography (silica gel, 0% to 20% EtOAc in heptane) to give the title compound (356 mg) as an off-white solid.
Intermediate I23
6-Allyl-4-chlorobiphenyl-2-amine
(27) ##STR00060##
(28) Step 1:
(29) In analogy to the synthesis of Intermediate I19, step 1, 2-allyl-4-chloro-6-nitrophenol (CAS#569688-58-0) was converted to 2-allyl-4-chloro-6-nitrophenyl trifluoromethanesulfonate.
(30) Step 2:
(31) In analogy to the synthesis of Intermediate I19, step 2, 2-allyl-4-chloro-6-nitrophenyl trifluoromethanesulfonate was reacted with phenylboronic acid to give 2-allyl-4-chloro-6-nitrobiphenyl.
(32) Step 3:
(33) In analogy to the synthesis of Intermediate I19, step 3, 2-allyl-4-chloro-6-nitrobiphenyl was reduced with iron to give the title compound as a light yellow liquid.
Intermediate I25
6-Amino-4-chlorobiphenyl-2-carbonitrile
(34) ##STR00061##
(35) Step 1:
(36) In analogy to the synthesis of Intermediate I19, step 1, 5-chloro-2-hydroxy-3-nitrobenzonitrile (CAS#88310-62-7) was converted to 4-chloro-2-cyano-6-nitrophenyl trifluoromethanesulfonate.
(37) Step 2:
(38) In analogy to the synthesis of Intermediate I19, step 2, 4-chloro-2-cyano-6-nitrophenyl trifluoromethanesulfonate was reacted with phenylboronic acid to give 4-chloro-6-nitrobiphenyl-2-carbonitrile.
(39) Step 3:
(40) In analogy to the synthesis of Intermediate I19, step 3, 4-chloro-6-nitrobiphenyl-2-carbonitrile was reduced with iron to give the title compound as a light yellow solid.
Intermediate I26
4-Chloro-6-(cyclohexen-1-yl)-biphenyl-2-amine
(41) ##STR00062##
(42) Step 1:
(43) In analogy to the synthesis of Intermediate I19, step 2, 2-bromo-4-chloro-6-nitrophenol (CAS#15969-10-5) was reacted with cyclohexenylboronic acid to give 4-chloro-2-cyclohexenyl-6-nitrophenol.
(44) Step 2:
(45) In analogy to the synthesis of Intermediate I19, step 1, 4-chloro-2-cyclohexenyl-6-nitrophenol was converted to 4-chloro-2-cyclohexenyl-6-nitrophenyl trifluoromethanesulfonate.
(46) Step 3:
(47) In analogy to the synthesis of Intermediate I19, step 2, 4-chloro-2-cyclohexenyl-6-nitrophenyl trifluoromethanesulfonate was reacted with phenylboronic acid to give 4-chloro-2-cyclohexenyl-6-nitrobiphenyl.
(48) Step 4:
(49) In analogy to the synthesis of Intermediate I19, step 3, 4-chloro-2-cyclohexenyl-6-nitrobiphenyl was reduced with iron to give the title compound as brown oil.
Intermediate I29
4-Chloro-4-fluorobiphenyl-2-amine
(50) ##STR00063##
(51) 2-Bromo-5-chloroaniline (CAS#823-57-4; 5 g), 4-fluorophenylboronic acid (3.56 g) and cesium carbonate (31.6 g) were combined in THF (70 ml) and water (35 ml). The mixture was degassed by bubbling argon through the solution. After addition of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (886 mg) the reaction mixture was stirred 1 h at 80 C. in a sealed tube. The reaction mixture was diluted with EtOAc, washed with water, dried over Na.sub.2SO.sub.4, evaporated and purified by chromatography (silica gel, 0% to 30% EtOAc in heptane). The product was finally bulb-to-bulb distilled at 0.3 mbar and 120-130 C. oven temperature to give the title compound (5.07 g) as a light yellow liquid.
(52) In analogy to the synthesis of Intermediate I29, the following intermediates were prepared:
(53) TABLE-US-00003 Intermediate Name Structure Reagents I30 4-chloro-5- fluorobiphenyl-2- amine
Intermediate I52
(R)-1-(2-bromo-5-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid
(54) ##STR00070##
(55) R-Proline (CAS#344-25-2) was reacted with 1-bromo-4-chloro-2-isocyanatobenzene (CAS#1261815-71-7) according to General Method B to give the title compound as an off-white solid.
Intermediate I62
(R)-1-(2-bromo-5-ethylphenylcarbamoyl)pyrrolidine-2-carboxylic acid
(56) ##STR00071##
(57) R-Proline (CAS#344-25-2) was reacted with 2-bromo-5-ethylaniline (CAS#80948-73-8) according to General Methods A and B to give the title compound as an off-white solid.
Intermediate I64
4-Chloro-4-fluoro-6-methoxybiphenyl-2-amine
(58) ##STR00072##
(59) Step 1:
(60) To a solution of 4-chloro-2-methoxy-6-nitrophenol (CAS#118724-89-3; 3.78 g) in DCM (200 ml) under argon was added triethylamine (4.32 g). The reaction mixture was cooled to 20 C., then trifluoromethanesulfonic anhydride (6.41 g) was added dropwise. The mixture was stirred for 20 min, then the cooling bath was removed and the reaction mixture was stirred at r.t. for 2.5 h. The crude reaction mixture was washed with sat. aqueous NH.sub.4Cl solution and with brine. The aqueos layers were extracted with DCM. The combined organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 100% EtOAc in n-heptane) to give 4-chloro-2-methoxy-6-nitrophenyl trifluoromethanesulfonate (6.23 g) as a yellow solid.
(61) Step 2:
(62) In analogy to the synthesis of Intermediate I19, step 2, 4-chloro-2-methoxy-6-nitrophenyl trifluoromethanesulfonate was reacted with 4-fluorophenylboronic acid to give 4-chloro-4-fluoro-2-methoxy-6-nitrobiphenyl as a yellow solid.
(63) Step 3:
(64) In analogy to the synthesis of Intermediate I19, step 3, 4-chloro-4-fluoro-2-methoxy-6-nitrobiphenyl was reduced with iron to give the title compound as a yellow oil which was used as a crude product for the next step.
Example A
(65) A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
(66) TABLE-US-00004 Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg
Example B
(67) A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:
(68) TABLE-US-00005 Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg