Sulfonamides as GPR40- and GPR120-agonists

Patent metadata

Field	Value
Publication number	US-10508090-B2
Application number	US-201716324243-A
Country	US
Kind code	B2
Filing date	Aug 7, 2017
Priority date	Aug 9, 2016
Publication date	Dec 17, 2019
Grant date	Dec 17, 2019

Abstract

The invention relates to compounds acting as agonists of G-protein coupled receptor 120 (GPR120) and/or 40 (GPR40), and having formula (I):

Said compounds are useful in the treatment of diseases or disorders modulated by GPR120 and/or GPR40 such as diabetes (particularly type 2 diabetes), impaired oral glucose tolerance, insulin resistance, obesity, obesity related disorders, metabolic syndrome, dyslipidemia, elevated LDL, elevated triglycerides, obesity induced inflammation, osteoporosis and obesity related cardiovascular disorders.

First claim

The invention claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
A is a mono or di-carbocyclic residue, optionally partially or totally unsaturated, comprising carbon atoms and optionally one or more heteroatoms selected from N, S and O;
R 1 , R 2 , and R 3 are independently selected from the group consisting of —H, -halogen, —CF 3 , —CN, —CH 2 CN, —OMe, —OCF 3 , —OH, phenyl, —OPh, —OCH 2 Ph, —OCH 2 OMe, —OCH 2 CN—NO 2 , —NR′R″, linear or branched C 1 -C 6 alkyl, —O(CH 2 ) p —S(O) 2 Me and a five-membered ring heterocycle;
wherein R′ and R″ are independently —H or C 1 -C 4 alkyl;
wherein phenyl and the five-membered ring heterocycle are independently unsubstituted or substituted with a group selected from the group consisting of linear or branched C 1 -C 4 alkyl, halogen, —OMe and —OH;
p is 1 to 4;
X is —CH 2 or —C(O);
n is 0, 1 or 2;
R 4 is —Y—C(O)OH, wherein Y is a straight chain C 4 -C 18 hydrocarbon, saturated or unsaturated; and
R 4 is in position meta or para on the aromatic ring;
wherein when A is phenyl, n is 0, and Y is a C 4 hydrocarbon, at least one of said R 1 , R 2 , R 3 is not hydrogen;
wherein when A is phenyl, n is 0, Y is a C 4 hydrocarbon, and R 1 and R 2 are hydrogen, R 3 is not Cl in position para on the aromatic ring.

2. The compound according to claim 1 , wherein A is phenyl, naphthyl, biphenyl or a saturated or unsaturated five-membered ring heterocycle having 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.

3. The compound according to claim 1 , wherein the five-membered ring heterocycle is selected from the group consisting of thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, and benzimidazole, which rings may optionally be partially saturated.

4. The compound according to claim 1 , wherein R 1 , R 2 , and R 3 are independently selected from the group consisting of —H, -halogen, —CF 3 , —OMe, —OH, phenyl, —OPh, —OCH 2 Ph, —OCH 2 OMe, —OCH 2 CN—NO 2 , —NH 2 , —NMe 2 , linear or branched C 1 -C 6 alkyl and —O(CH 2 ) p —S(O) 2 Me.

5. The compound according to claim 1 , wherein n is 0 or 1.

6. The compound according to claim 1 , wherein R 4 is in position meta on the aromatic ring.

7. The compound according to claim 1 , wherein Y is a straight chain C 6 -C 10 hydrocarbon which may be saturated or unsaturated.

8. The compound according to claim 1 , which is selected from the group consisting of:
7-(3-(N-(4-fluoro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(2,4,6-trimethylbenzyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(4-isopropyl-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(4-chloro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(4-(dimethylamino)-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(2,6-dimethyl-4-(trifluoromethyl)phenyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(4-bromo-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(4-methoxy-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(6-fluoro-4-methyl-[1,1′-biphenyl]-3-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(5-fluoro-3-methyl-[1,1′-biphenyl]-2-yl)sulfamoyl)phenyl)heptanoic acid;
6-{3-[(2,4,6-trimethylphenyl)sulfamoyl]phenyl}hexanoic acid;
7-(3-(N-(3,5-dimethyl-1H-pyrazol-4-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(2,4-dimethylthiazol-5-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(4,5-dimethylthiazol-2-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(4,5-dimethyloxazol-2-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(5-phenyl-1,2,4-thiadiazol-3-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(3-methyl-1,2,4-thiadiazol-5-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(5-methyl-1,3,4-thiadiazol-2-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(3,5-dimethylisoxazol-4-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(5-methyl-4H-1,2,4-triazol-3-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(3-phenylisothiazol-5-yl)sulfamoyl)phenyl)heptanoic acid;
7-{3-[(5-hydroxynaphthalen-1-yl)sulfamoyl]phenyl}heptanoic acid;
7-{3-[(4-fluoro-2,6-dimethylbenzoyl)sulfamoyl]phenyl}heptanoic acid;
7-{4-[(4-fluoro-2,6-dimethylphenyl)sulfamoyl]phenyl}heptanoic acid;
7-(3-(N-(2-ethyl-2H-1,2,3-triazol-4-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(2-methyl-2H-tetrazol-5-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(4-methyl-4,5-dihydrooxazol-2-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-2yl)sulfamoyl)phenyl) heptanoic acid;
7-(3-(N-(3-phenylisothiazol-4-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(4-hydroxy-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(3,5-dimethyl-[1,1′-biphenyl]-4-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(2,6-dimethyl-4-phenoxyphenyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(4-(benzyloxy)-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid; and
7-(3-(N-(2,6-dimethyl-4-(3(methylsulfonyl)propoxy)phenyl)sulfamoyl)phenyl)heptanoic acid.

9. The compound according to claim 8 , which is selected from the group consisting of:
7-(3-(N-(4-fluoro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(2,4,6-trimethylbenzyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(4-isopropyl-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(4-chloro-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(2,6-dimethyl-4-(trifluoromethyl)phenyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(4-bromo-2,6-dimethylphenyl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(6-fluoro-4-methyl-[1,1′-biphenyl]-3-yl)sulfamoyl)phenyl)heptanoic acid;
7-(3-(N-(5-fluoro-3-methyl-[1,1′-biphenyl]-2-yl)sulfamoyl)phenyl)heptanoic acid;
6-{3-[(2,4,6-trimethylphenyl)sulfamoyl]phenyl}hexanoic acid; and
7-(3-(N-(2,6-dimethyl-4-phenoxyphenyl)sulfamoyl)phenyl)heptanoic acid (33).

10. A method for the treatment of a disease or disorder modulated by GPR120 and/or GPR40 in a subject in need thereof, comprising administration of an effective amount of the compound according to claim 1 , alone or in combination with one or more pharmaceutically acceptable excipients.

11. The method according to claim 10 , wherein the disease or disorder is selected from the group consisting of diabetes, type 2 diabetes, impaired oral glucose tolerance, insulin resistance, obesity, obesity related disorders, metabolic syndrome, dyslipidemia, elevated LDL, elevated triglycerides, obesity induced inflammation, osteoporosis and obesity related cardiovascular disorders.

12. A pharmaceutical composition comprising as the active ingredient at least one compound according to claim 1 , in combination with physiologically acceptable excipients.

13. The pharmaceutical composition according to claim 12 , suitable to be administered by intravenous, intraperitoneal, inhalation, topical or oral route.

14. The pharmaceutical composition according to claim 12 , in the form of a liquid or a solid.

15. The pharmaceutical composition according to claim 14 , in the form of a capsule, tablet, coated tablet, syrup, powder, granules, cream, lotion, spray or ointment.

Assignees

• Dompe Farm Spa

Inventors

• De Pizzol Maria
• Sirico Anna
• Zippoli Mara
• Bianchini Gianluca
• Beccari Andrea
• Aramini Andrea
• Liberati Chiara Rossana Maria

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P19/08

  for bone diseases, e.g. rachitism, Paget's disease · CPC title