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Last Updated: November 29, 2021

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Claims for Patent: 8,853,412

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Summary for Patent: 8,853,412
Title:Pyrrolidinone derivatives as GPR119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
Abstract: The present invention relates to pyrrolidinone derivatives. The pyrrolidinone derivatives are GPR119 modulators and useful for the prevention and/or treatment of diabetes, obesity, dyslipidemia and related disorders. The invention furthermore relates to the use of pyrrolidinone derivatives as active ingredients in pharmaceuticals, and pharmaceutical compositions comprising them.
Inventor(s): Schwink; Lothar (Frankfurt am Main, DE), Bossart; Martin (Frankfurt am Main, DE), Glombik; Heiner (Frankfurt am Main, DE), Gossel; Matthias (Frankfurt am Main, DE), Kadereit; Dieter (Frankfurt am Main, DE), Klabunde; Thomas (Frankfurt am Main, DE), Maier; Thomas (Frankfurt am Main, DE), Stengelin; Siegfried (Frankfurt am Main, DE)
Assignee: Sanofi (Paris, FR)
Application Number:14/048,425
Patent Claims:1. A compound of the formula I ##STR00165## in which X is selected from the group consisting of CH.sub.2 and CH.sub.2-CH.sub.2; R.sup.1a is selected from the group consisting of H, F, Cl, Br, (C.sub.1-C.sub.6)-alkyl and CN; R.sup.1b is selected from the group consisting of H, F, Cl and (C.sub.1-C.sub.6)-alkyl; R.sup.1c is selected from the group consisting of H, F, Cl and (C.sub.1-C.sub.6)-alkyl; R.sup.2a is selected from the group consisting of H, F, Cl, Br, (C.sub.1-C.sub.6)-alkyl, CN, CO.sub.2R.sup.5 and CONR.sup.5R.sup.5'; R.sup.2b is selected from the group consisting of H, F, Cl and (C.sub.1-C.sub.6)-alkyl; R.sup.2c is selected from the group consisting of H, F, Cl and (C.sub.1-C.sub.6)-alkyl; R.sup.5, R.sup.5' are independently of each other selected from the group consisting of H and (C.sub.1-C.sub.4)-alkyl; one of the groups Y.sup.1 and Y.sup.2 is N, N-oxide or CR.sup.2d, the other is C--Z--R.sup.3--R.sup.4; R.sup.2d is selected from the group consisting of H, F, Cl and (C.sub.1-C.sub.4)-alkyl; Z is selected from the group consisting of a bond, O, CO, COO, S, SO and SO.sub.2; R.sup.3 is selected from the group consisting of a bond and (CR6R6').sub.n; R.sup.6, R.sup.6' are independently of each other selected from the group consisting of H and (C.sub.1-C.sub.6)-alkyl, which is unsubstituted or monofluorinated and the overall number of carbon atoms in a (CR.sup.6R.sup.6').sub.n group is below or equal to eight (8); n is selected from the group consisting of 1, 2, 3, 4 and 5; R.sup.4 is selected from the group consisting of (C.sub.1-C.sub.6)-alkyl, mono-, di- or trifluorinated (C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl, CO.sub.2R.sup.5, OR.sup.7, NR.sup.8R.sup.8', SR.sup.9, (C.sub.3-C.sub.8) -cycloalkyl, a 4- to 6-membered heterocycle, which comprises one or two identical or different ring heteroatoms selected from the group consisting of N and O, phenyl, a 5- to 6-membered heteroaryl, which comprises one, two or three identical or different ring heteroatoms selected from the group consisting of N, O and S, wherein all cyclic groups within R.sup.4 are unsubstituted or substituted by one to three identical or different substituents selected from the group consisting of (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkanoyl, hydroxy-(C.sub.0-C.sub.4)-alkyl, (C.sub.1-C.sub.3)-alkoxy-(C.sub.0-C.sub.4)-alkyl, oxo (.dbd.O), F and Cl; R.sup.7 is selected from the group consisting of H, (C.sub.1-C.sub.6)-alkyl, hydroxy-(C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.3)-alkoxy-(C .sub.1-C.sub.4)-alkyl; R.sup.8, R.sup.8' are independently of each other selected from the group consisting of H and (C.sub.1-C.sub.6)-alkyl and R.sup.9 is (C .sub.1-C.sub.6)-alkyl; in any of its stereoisomeric forms, or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them.

2. The compound of claim 1, wherein the 3-position of the pyrrolidinone ring has (R)-configuration.

3. The compound of claim 1, wherein X is CH.sub.2.

4. The compound of claim 1, wherein R.sup.1a is selected from the group consisting of H, F, Cl, methyl and CN; R.sup.1b is H and R.sup.1c is selected from the group consisting of H, F and methyl.

5. The compound of claim 1, wherein R.sup.2a is selected from the group consisting of H, F, Cl, methyl and CN; R.sup.2b is H and R.sup.2c is H.

6. The compound of claim 1, which is a compound of the formula Ia ##STR00166## wherein R.sup.1a is selected from the group consisting of H, F, Cl, (C.sub.1-C.sub.4)-alkyl and CN; R.sup.1c is selected from the group consisting of H, F and (C.sub.1-C.sub.4)-alkyl; R.sup.2a is selected from the group consisting of H, F, Cl, (C.sub.1-C.sub.4)-alkyl and CN; R.sup.3 is selected from the group consisting of a bond and (CR.sup.6R.sup.6').sub.n; n is selected from the group consisting of 1, 2 and 3; R.sup.6, R.sup.6' are independently of each other H or (C.sub.1-C.sub.2)-alkyl, and the overall number of carbon atoms in a (CR.sup.6R.sup.6').sub.n group is below or equal to eight (8) and R.sup.4 is selected from the group consisting of (C.sub.1-C.sub.6)-alkyl, mono-, di- or trifluorinated (C.sub.1-C.sub.6)-alkyl, O(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, a 4- to 6-membered heterocycle, which comprises one or two ring oxygen atoms, wherein all cyclic groups within R.sup.4 are unsubstituted or substituted by (C.sub.1-C.sub.4)-alkyl.

7. The compound of claim 1, wherein X is selected from the group consisting of CH.sub.2 and CH.sub.2-CH.sub.2; R.sup.1a is selected from the group consisting of H, F, Cl, Br, (C.sub.1-C.sub.4)- alkyl and CN; R.sup.1b is H; R.sup.1c is selected from the group consisting of H, F and methyl; R.sup.2a is selected from the group consisting of H, F and (C.sub.1-C.sub.4)-alkyl; R.sup.2b is H; R.sup.2c is H; one of the groups Y.sup.1 and Y.sup.2 is N, N-oxide or CR.sup.2d, the other is C--Z--R.sup.3--R.sup.4; R.sup.2d is H; Z is selected from the group consisting of a bond, O, CO, COO, S and SO; R.sup.3 is selected from the group consisting of a bond and (CR.sup.6R.sup.6').sub.n n is selected from the group consisting of 1, 2, 3, 4 and 5; R.sup.6, R.sup.6' are independently of each other selected from the group consisting of H, methyl, ethyl and 2-fluoro-ethyl, and the overall number of carbon atoms in a (CR.sup.6R.sup.6').sub.n group is below or equal to eight (8); R.sup.4 is selected from the group consisting of (C.sub.1-C.sub.6)-alkyl, mono-, di- or trifluorinated (C.sub.1-C.sub.6)-alkyl, (C.sub.4-C.sub.6)-alkenyl, CO.sub.2R.sup.5, OR.sup.7, NR.sup.8R.sup.8', SR.sup.9, (C.sub.3-C.sub.6)-cycloalkyl, a 4- to 6-membered heterocycle, which comprises one or two oxygen atoms or one nitrogen atom, phenyl, a 5- to 6-membered heteroaryl, which comprises one or two nitrogen atoms, one nitrogen and one oxygen atom, one nitrogen and one sulfur atom or two nitrogen atoms and one oxygen atom, wherein all cyclic groups within R.sup.4 are unsubstituted or mono -substituted by substituents selected from the group consisting of F, (C.sub.1-C.sub.4)-alkyl, hydroxymethyl, acetyl, hydroxyl and oxo (.dbd.O); R.sup.5 is (C.sub.1-C.sub.4)-alkyl; R.sup.7 is selected from the group consisting of H, methyl, ethyl and hydroxy-ethyl; R.sup.8, R.sup.8' are independently of each other (C.sub.1-C.sub.4)-alkyl and R.sup.9 is methyl.

8. The compound of claim 6 , wherein R.sup.1a is selected from the group consisting of H, F, Cl, Br, (C.sub.1-C.sub.4)-alkyl and CN; R.sup.1c is selected from the group consisting of H, F and methyl; R.sup.2a is selected from the group consisting of H, F and (C.sub.1-C.sub.4)-alkyl; R.sup.3 is selected from the group consisting of a bond and (CR.sup.6R.sup.6').sub.n; n is selected from the group consisting of 1, 2, 3, 4 and 5; R.sup.6, R.sup.6' are independently of each other selected from the group consisting of H, methyl, ethyl and 2-fluoro-ethyl, and the overall number of carbon atoms in a (CR.sup.6R.sup.6').sub.n group is below or equal to eight (8); R.sup.4 is selected from the group consisting of (C.sub.1-C.sub.6)-alkyl, mono-, di- or trifluorinated (C.sub.1-C.sub.6)-alkyl, (C.sub.4-C.sub.6)-alkenyl, CO.sub.2R.sup.5, OR.sup.7, NR.sup.8R.sup.8', SR.sup.9, (C.sub.3-C.sub.6)-cycloalkyl, a 4- to 6-membered heterocycle, which comprises one or two oxygen atoms or one nitrogen atom, phenyl, a 5- to 6-membered heteroaryl, which comprises one or two nitrogen atoms, one nitrogen and one oxygen atom, one nitrogen and one sulfur atom or two nitrogen atoms and one oxygen atom, wherein all cyclic groups within R.sup.4 are unsubstituted or mono -substituted by substituents selected from the group consisting of F, (C.sub.1-C.sub.4)-alkyl, hydroxymethyl, acetyl, hydroxyl and oxo (.dbd.O); R.sup.5 is (C.sub.1-C.sub.4)-alkyl; R.sup.7 is selected from the group consisting of H, methyl, ethyl and hydroxy-ethyl; R.sup.8, R.sup.8' are independently of each other (C.sub.1-C.sub.4)-alkyl and R.sup.9 is methyl.

9. A compound selected from the group consiting of (R)-3-[4-(2-Cyclopropyl-ethoxy)-phenoxy]-1-(7-fluoro-3-oxo-indan-5-yl)-py- rrolidin-2-one, (R)-3-(6-Cyclopropylmethoxy-pyridin-3-yloxy)-1-(7-fluoro-3-oxo-indan-5-yl- )-pyrrolidin-2-one, (R)-1-(7-Fluoro-3-oxo-indan-5-yl)-3-[6-(tetrahydro-pyran-4-yloxy)-pyridin- -3-yloxy]-pyrrolidin -2-one, (R)-3-(6-Ethoxy-pyridin-3-yloxy)-1-(7-fluoro-3-oxo-indan-5-yl)-pyrrolidin- -2-one, (R)-1-(7-Fluoro-3-oxo-indan-5-yl)-3-(6-isopropoxy-pyridin-3-yloxy)- -pyrrolidin-2-one and (R)-3-(6-Cyclopropoxy-pyridin-3-yloxy)-1-(7-fluoro-3-oxo-indan-5-yl)-pyrr- olidin-2-one; or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising at least one compound as claimed in claim 1 or a physiologically acceptable salt thereof.

11. The pharmaceutical composition as claimed in claim 10, comprising additionally one or more active ingredients selected from the group of: Insulin and insulin derivatives, GLP-1, GLP-1 analogues and GLP-1 receptor agonists, polymer bound GLP-1 and GLP-1 analogues, dual GLP-1/GIP agonists, dual GLP-1/glucagon receptor agonists, PYY3-36 or analogues thereof, pancreatic polypeptide or analogues thereof, glucagon receptor agonists or antagonists, GIP receptor agonists or antagonists, ghrelin antagonists or inverse agonists, xenin and analogues thereof, DDP-IV inhibitors, SGLT-2 inhibitors, dual SGLT-2/SGLT-1 inhibitors, biguanides, thiazolidinediones, PPAR agonists, PPAR modulators, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, amylin and amylin analogues, GPR119 agonists, GPR40 agonists, GPR120 agonists, GPR142 agonists, TGR5 agonists, AMPK stimulants, AMPK activators, inhibitors of 11-beta-HSD, activators of glucokinase, inhibitors of DGAT, inhibitors of protein tyrosine phosphatase 1, inhibitors of glucose-6-phosphatase, inhibitors of fructose-1,6-bisphosphatase, inhibitors of glycogen phosphorylase, inhibitors of phosphoenol pyruvate carboxykinase, inhibitors of glycogen synthase kinase, inhibitors of pyruvate dehydrogenase kinase, alpha2 adrenergic receptor antagonists, CCR-2 antagonists, modulators of glucose transporter-4, somatostatin receptor 3 agonists, HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and derivatives thereof, nicotinic acid receptor 1 agonists, ACAT inhibitors, cholesterol absorption inhibitors, bile acid-binding substances, IBAT inhibitors, MTP inhibitors, modulators of PCSK9, LDL receptor up-regulators (liver selective thyroid hormone receptor beta agonists), HDL-raising compounds, lipid metabolism modulators, PLA2 inhibitors, ApoA-I enhancers, cholesterol synthesis inhibitors, omega-3 fatty acids and derivatives thereof, active substances for the treatment of obesity, CB1 receptor antagonists, MCH-1 antagonists, MC4 receptor agonists and partial agonists, NPY5 or NPY2 antagonists, NPY4 agonists, beta-3 adrenergic receptor agonists, leptin or leptin mimetics, 5HT2c receptor agonists, lipase inhibitors, angiogenesis inhibitors, H3 antagonists, AgRP inhibitors, triple monoamine uptake inhibitors, MetAP2 inhibitors, antisense oligonucleotides against production of fibroblast growth factor receptor 4 or prohibitin targeting peptide-1, drugs for influencing high blood pressure, chronic heart failure or atherosclerosis, angiotensin II receptor antagonists, ACE inhibitors, ECE inhibitors, diuretics, beta-blockers, calcium antagonists, centrally acting antihypertensives, antagonists of the alpha-2 adrenergic receptor, inhibitors of neutral endopeptidase and thrombocyte aggregation inhibitors, drugs for influencing high blood pressure, chronic heart failure or atherosclerosis, nitric oxide donors, angiotensin II receptor antagonists, dual ARB agonists, ACE inhibitors, ACE-2 activators, AT1 antagonists, AT2 receptor agonists, renin inhibitors, prorenin inhibitors, ECE inhibitors, endothelin receptor blockers, endothelin antagonists, diuretics, aldosterone antagonists, aldosterone synthase inhibitors, alpha-blockers, antagonists of the alpha-2 adrenergic receptor, beta-blockers, mixed alpha-/beta-blockers, calcium antagonists/calcium channel blockers, nasal formulations of calcium channel blockers, dual mineralocorticoid/CCBs, centrally acting antihypertensives, antagonists of the alpha-2 adrenergic receptor, inhibitors of neutral endopeptidase, aminopeptidase-A inhibitors, vasopeptide inhibitors, dual vasopeptide inhibitors, neprilysin-ACE inhibitors, neprilysin-ECE inhibitors, dual-acting AT receptor-neprilysin inhibitors, dual AT1/ETA antagonists, advanced glycation end-product breakers, recombinant renalase, blood pressure vaccines, anti-RAAS vaccines, AT1- or AT2-vaccines, modulators of genetic polymorphisms with antihypertensive response and thrombocyte aggregation inhibitors.

12. The pharmaceutical composition as claimed in claim 10, comprising additionally one or more active ingredients selected from the group of: Insulin and insulin derivatives, GLP-1, GLP-1 analogues and GLP-1 receptor agonists, polymer bound GLP-1 and GLP-1 analogues, dual GLP-1/GIP agonists, dual GLP-1/ glucagon receptor agonists, PYY3-36 or analogues thereof, pancreatic polypeptide or analogues thereof, glucagon receptor agonists or antagonists, GIP receptor agonists or antagonists, ghrelin antagonists or inverse agonists, xenin and analogues thereof, DDP-IV inhibitors, SGLT-2 inhibitors, dual SGLT-2/SGLT-1 inhibitors, biguanides, thiazolidinediones, dual PPAR agonists, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, amylin and amylin analogues, GPR119 agonists, GPR40 agonists, GPR120 agonists, GPR142 agonists, systemic or low-absorbable TGR5 agonists, Cycloset, inhibitors of 11-beta-HSD, activators of glucokinase, inhibitors of DGAT, inhibitors of protein tyrosinephosphatase 1, inhibitors of glucose-6-phosphatase, inhibitors of fructose-1,6-bisphosphatase, inhibitors of glycogen phosphorylase, inhibitors of phosphoenol pyruvate carboxykinase, inhibitors of glycogen synthase kinase, inhibitors of pyruvate dehydrogenase kinase, alpha2 adrenergic receptor antagonists, CCR-2 antagonists, modulators of glucose transporter-4, somatostatin receptor 3 agonists, HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and derivatives thereof, nicotinic acid receptor 1 agonists, PPAR (-alpha, -gamma or -alpha/gamma) agonists or modulators, PPAR-delta agonists, ACAT inhibitors, cholesterol absorption inhibitors, bile acid-binding substances, IBAT inhibitors, MTP inhibitors, modulators of PCSK9, LDL receptor up-regulators (liver selective thyroid hormone receptor beta agonists), HDL-raising compounds, lipid metabolism modulators, PLA2 inhibitors, ApoA-I enhancers, cholesterol synthesis inhibitors, omega-3 fatty acids and derivatives thereof, active substances for the treatment of obesity, such as sibutramine, tesofensine, orlistat, CB1 receptor antagonists, MCH-1 antagonists, MC4 receptor agonists and partial agonists, NPY5 or NPY2 antagonists, NPY4 agonists, beta-3 adrenergic receptor agonists, leptin or leptin mimetics, 5HT2c receptor agonists, or the combinations of bupropione/naltrexone (Contrave), bupropione/zonisamide (Empatic), bupropione/phentermine or pramlintide/metreleptin, phentermine/topiramate (Qsymia), lipase inhibitors, angiogenesis inhibitors, H3 antagonists, AgRP inhibitors, triple monoamine uptake inhibitors, MetAP2 inhibitors, nasal formulations of the calcium channel blocker diltiazem, antisense oligonucleotides against production of fibroblast growth factor receptor 4 or prohibitin targeting peptide-1, drugs for influencing high blood pressure, chronic heart failure or atherosclerosis, such as angiotensin II receptor antagonists, ACE inhibitors, ECE inhibitors, diuretics, beta-blockers, calcium antagonists, centrally acting antihypertensives, antagonists of the alpha-2 adrenergic receptor, inhibitors of neutral endopeptidase and thrombocyte aggregation inhibitors.

13. The pharmaceutical composition as claimed in claim 10, comprising additionally metformin.

14. The pharmaceutical composition as claimed in claim 10, comprising additionally at least one DPP-IV inhibitor.

15. The pharmaceutical composition as claimed in claim 14, wherein the DPP-IV inhibitor is selected from the group consisting of alogliptin, linagliptin, saxagliptin, sitagliptin, anagliptin, teneligliptin, trelagliptin, vildagliptin, gemigliptin, omarigliptin, evogliptin and dutogliptin.

16. The pharmaceutical composition as claimed in claim 10, comprising additionally at least one SGLT-2 inhibitor.

17. The pharmaceutical composition as claimed in claim 16, wherein the SGLT-2 inhibitor is selected from the group consisting of canagliflozin, dapagliflozin, remogliflozin, remogliflozin etabonate, sergliflozin, empagliflozin, ipragliflozin, tofogliflozin, luseogliflozin and ertugliflozin.

18. The pharmaceutical composition as claimed in claim 10, comprising additionally at least one GPR40 agonist.

19. The pharmaceutical composition as claimed in claim 18, wherein the GPR40 agonist is selected from the group consisting of fasiglifam (TAK-875), TUG-424, P-1736, P-11187, JTT-851, GW9508, CNX-011-67, AM-1638 and AM-5262.

20. The pharmaceutical composition as claimed in claim 10, comprising additionally ezetimibe.

21. The pharmaceutical composition as claimed in claim 10, comprising additionally at least one HMG-CoA reductase inhibitor.

22. The pharmaceutical composition as claimed in claim 21, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of simvastatin, atorvastatin, rosuvastatin, pravastatin, fluvastatin, pitavastatin, lovastatin, mevastatin, rivastatin and cerivastatin.

23. The pharmaceutical composition as claimed in claim 10, comprising additionally at least one PPAR agonist or PPAR modulator.

24. The pharmaceutical composition as claimed in claim 23, in wherein the PPAR agonist or PPAR modulator is selected from the group consisting of aleglitazar, muraglitazar, tesaglitazar and saroglitazar.

25. The pharmaceutical composition as claimed in claim 23, in wherein the PPAR agonist or PPAR modulator is selected from the group consisting of pioglitazone, rivoglitazone, rosiglitazone, troglitazone and lobeglitazone.

26. The pharmaceutical composition as claimed in claim 10, comprising additionally acarbose.

27. A method for treating type 2 diabetes, obesity or dyslipidemia in a patient in need thereof comprising adminstering to said patient a therapeutically effective amount of the compound claim 1.

28. A method for treating type 2 diabetes, obesity or dyslipidemia in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 10.

29. A method for treating type 2 diabetes, obesity or dyslipidemia in a patient, the method comprising administering to the patient an effective amount of at least one compound of claim 1 and an effective amount of at least one other compound useful for treating type 2 diabetes, obesity or dyslipidemia.

30. The method as claimed in claim 29 wherein the effective amount of said compounds are adminstered to the patient simultaneously.

31. The method as claimed in claim 29 wherein the effective amount of said compounds are adminstered to the patient sequentially.

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