Dpp-IV Inhibitors

• US 20070265261A1
• Filed: 06/08/2005
• Published: 11/15/2007
• Est. Priority Date: 06/08/2004
• Status: Abandoned Application

• Current Assignee: Santhera Pharmaceuticals (Schweiz) AG
• Original Assignee: Santhera Pharmaceuticals (Schweiz) AG
• Inventors: Edwards, Paul, Hill, Oliver, Thiemann, Meinolf, Feurer, Achim, Rummey, Christian, Rosenbaum, Claudia, Cerezo-Galvez, Silvia, Matassa, Victor, Nordhoff, Sonja, Hoffmann, Barbara
• Application Number:
  US11/569,552
• Publication Number:
  US 20070265261A1
• Time in Patent Office: Days
• US Class Current: 514/235.500
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/10 of the posterior pituitary hormones, e.g. oxytocin, ADH
• CPC Class Codes: A61P 5/28 Antiandrogens
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 211/26 : with hydrocarbon radicals, substituted by nitrogen atoms

Abstract

The invention relates to compounds of formula (1)
wherein Z, R^1-3 and A have the meaning as cited in the description and the claims. Said compounds are useful as DPP-IV inhibitors. The invention also relates to the preparation of such compounds as well as the production and use thereof as medicament.

Claims

1. A compound of the formula (I)

or a pharmaceutically acceptable salt thereof, wherein

Z is selected from the group consisting of phenyl;

naphthyl;

indenyl;

C_3-7 cycloalkyl;

indanyl;

tetralinyl;

decalinyl;

heterocycle; and

heterobicycle, wherein Z is optionally substituted with one or more R⁴, wherein R⁴ is independently selected from the group consisting of halogen;

CN;

OH;

NH₂;

oxo (═

O), where the ring is at least partially saturated;

R⁵; and

R⁶;

R⁵ is selected from the group consisting of C_1-6 alkyl;

O—

C_1-6 alkyl; and

S—

C_1-6 alkyl, wherein R⁵ is optionally interrupted by oxygen and wherein R⁵ is optionally substituted with one or more halogen independently selected from the group consisting of F; and

Cl;

R⁶ is selected from the group consisting of phenyl;

heterocycle; and

C_3-7 cycloalkyl, wherein R⁶ is optionally substituted with one or more R⁷, wherein R⁷ is independently selected from the group consisting of halogen;

CN;

OH;

NH₂;

oxo (═

O), where the ring is at least partially saturated;

C_1-8 alkyl;

O—

C_1-6 alkyl; and

S—

C_1-6 alkyl;

R¹ is selected from the group consisting of H;

F;

OH; and

R⁸;

R² is selected from the group consisting of H;

F; and

R⁹;

R⁸ is independently selected from the group consisting of C_1-6 alkyl;

O—

C_1-6 alkyl;

N(R^8a)—

C_1-6 alkyl;

S—

C_1-6 alkyl;

C_3-7 cycloalkyl;

O—

C_3-7 cycloalkyl;

N(R^8a—

C_3-7 cycloalkyl;

S—

C_3-7 cycloalkyl;

—

C_1-6 alkyl-C_3-7 cycloalkyl;

O—

C_1-6 alkyl-C_3-7 cycloalkyl;

N(R^8a)—

C_1-6 alkyl-C_3-7 cycloalkyl;

S—

C_1-6 alkyl-C_3-7 cycloalkyl;

heterocycle;

O-heterocycle;

N(R^8a)-heterocycle;

S-heterocycle;

C_1-6 alkyl-heterocycle;

O—

C_1-6 alkyl-heterocycle;

N(R^8a)—

C_1-6 alkyl-heterocycle;

S—

C_1-6 alkyl-heterocycle;

wherein R⁸ is optionally substituted with one or more halogen independently selected from the group consisting of F; and

Cl;

R^8a is selected from the group consisting of H; and

C_1-6 alkyl;

R⁹ is independently selected from the group consisting of C_1-6 alkyl;

C_3-7 cycloalkyl; and

—

C_3-7 alkyl-C_3-7 cycloalkyl, wherein R⁹ is optionally substituted with one or more R^9a, wherein R^9a is independently selected from the group consisting of F;

Cl; and

OH;

R³ is selected from the group consisting of H; and

C_1-6 alkyl;

Optionally one or more pairs of R¹, R², R³ independently selected from the group consisting of R¹/R²; and

R²/R³;

form a C_3-7 cycloalkyl ring, which is optionally substituted with one or more of R^9b, wherein R^9b is independently selected from the group consisting of F;

Cl; and

OH;

A is selected from the group consisting of A⁰; and

A¹;

A⁰ is selected from the group consisting of C_3-7 cycloalkyl; and

a saturated heterocycle with at least one nitrogen as ring atom;

wherein A⁰ is substituted with one or more R^10a, wherein R^10a is independently selected from the group consisting of NR¹⁰R¹⁰B;

NR¹⁰S(O)₂R^10b;

NR¹⁰S(O)R^10b;

S(O)₂NR¹⁰R^10b;

C(O)NR¹⁰R^10b;

R¹⁰, provided that R¹⁰ is bound to a nitrogen, which is a ring atom of the saturated heterocycle; and

C_1-3 alkyl, which is optionally substituted with one or more R^10c, wherein R^10c is independently selected from the group consisting of F;

C_1-3 alkyl; and

C_3-4 cycloalkyl, wherein C_1-3 alkyl and C_3-4 cycloalkyl are optionally substituted with one or more F;

Optionally R^10a is independently selected from group consisting of F;

Cl, and oxo (═

O);

A¹ is selected from the group consisting of

X;

Y are independently selected from the group consisting of —

CH₂;

—

NR^10b—

;

—

O—

; and

—

S—

;

W is selected from the group consisting of

R¹⁰, R^10b are independently selected from the group consisting of T¹-T²; and

T²;

T¹ is selected from the group consisting of —

C_1-6 alkyl-;

—

C_1-6 alkyl-O—

;

—

C_1-6 alkyl-S—

;

—

C_1-6 alkyl-N(R¹¹);

—

C(O)—

;

—

C(O)—

C_1-6 alkyl-;

—

C(O)—

C_1-6 alkyl-O—

;

—

C(O)—

C_1-6 alkyl-S—

;

—

C(O)C_1-6 alkyl-N(R¹¹)—

;

—

C(O)O—

;

—

C(O)O—

C_1-6 alkyl-;

—

C(O)O—

C_1-6 alkyl-O—

;

—

C(O)O—

C_1-6 alkyl;

—

C(O)C—

C_1-6 alkyl-N(R¹¹)—

;

—

C(O)N(R¹¹)—

;

—

C(O)N(R¹¹)—

C_1-6 alkyl-;

—

C(O)N(R¹¹)C_1-6 alkyl-O—

;

—

C(O)N(R¹¹)—

C_1-6 alkyl-S—

;

—

C(O)N(R¹¹)—

C_1-6 alkyl-N(R^11a)—

;

—

S(O)₂—

;

—

S(O)₂—

C_1-6 alkyl-;

—

S(O)₂—

C_1-6 alkyl-O—

;

—

S(O)₂—

C_1-6 alkyl-S—

;

—

S(O)₂—

C_1-6 alkyl-N(R¹¹)—

;

—

S(O)—

;

—

S(O)—

C_1-6 alkyl-;

—

S(O)—

C_1-6 alkyl-O—

;

—

S(O)—

C_1-6 alkyl-S—

; and

—

S(O)—

C_1-6 alkyl-N(R¹¹)—

;

wherein each C_1-6 alkyl is optionally substituted with one or more halogen selected from the group consisting of F; and

Cl;

R¹¹, R^11a are independently selected from the group consisting of H;

C_1-6 alkyl;

C_3-7 cycloalkyl; and

—

C_1-6 alkyl-C_3-7 cycloalkyl;

T² is selected from the group consisting of H;

T³; and

T⁴;

T³ is selected from the group consisting of phenyl;

naphthyl; and

indenyl;

wherein T³ is optionally substituted with one or more R¹²;

wherein R¹² is independently selected from the group consisting of halogen;

CN;

COOR¹³;

OC(O)R¹³;

OR¹³;

—

C_1-6alkyl-OR¹³;

SR¹³;

S(O)R¹³;

S(O)₂R¹³;

C(O)N(R¹³R¹⁴);

S(O)₂N(R¹³R¹⁴);

S(O)N(R¹³R¹⁴);

C_1-6 alkyl;

N(R¹³)S(O)₂R¹⁴; and

N(R¹³)S(O)R¹⁴;

wherein each C_1-6 alkyl is optionally substituted with one or more halogen selected from the group consisting of F; and

Cl;

T⁴ is selected from the group consisting of C_3-7 cycloalkyl;

indanyl;

tetralinyl;

decalinyl;

heterocycle; and

heterobicycle;

wherein T⁴ is optionally substituted with one or more R¹⁵, wherein R¹⁵ is independently selected from the group consisting of halogen;

CN;

OR¹³;

—

C_1-6alkyl-OR¹³SR¹³;

oxo (═

O), where the ring is at least partially saturated;

N(R¹³R¹⁴);

COOR¹³;

OC(O)R¹³;

C(O)N(R¹³R¹⁴);

S(O)₂N(R¹³R¹⁴);

S(O)N(R¹³R¹⁴);

C_1-6 alkyl;

N(R¹³)C(O)R¹⁴;

S(O)₂R¹³;

S(O)R¹³;

N(R¹³)S(O)₂R¹⁴; and

N(R¹³)S(O)R¹⁴;

wherein each C_1-6 alkyl is optionally substituted with one or more halogen selected from the group consisting of F; and

Cl;

Optionally R¹⁵ is C(O)R¹³, provided that C(O)R¹³ is bound to a nitrogen, which is a ring atom of a heterocycle or heterobicycle;

R¹³, R¹⁴ are independently selected from the group consisting of H;

C_1-6 alkyl;

C_3-7 cycloalkyl; and

—

C_1-6 alkyl-C_3-7 cycloalkyl;

wherein each C_1-4 alkyl is optionally substituted with one more halogen selected from the group consisting of F; and

Cl.

2. A compound according to claim 1, wherein Z is selected from the group consisting of phenyl;

and heterocycle; and

wherein Z is optionally substituted with up to 2 R⁴, which are the same or different.

3. A compound according to claim 1, wherein R⁴ is selected from the group consisting of F;

Cl;

CN; and

C_1-6 alkyl.

4. A compound according to claim 1, wherein R¹, R² are independently selected from the group consisting of H;

F; and

C_1-6 alkyl, optionally substituted with one or more F.

5. A compound according to claim 1, wherein R³ is H.

6. A compound according to claim 1, wherein A is A⁰.

7. A compound according to claim 1, wherein A⁰ is a saturated heterocycle with at least one nitrogen as ring atom.

8. A compound according to claim 1, wherein A⁰ is piperidine.

9. A compound according to claim 8, wherein A⁰ is selected from the group consisting of

10. A compound according to claim 1, wherein R¹⁰ is selected from the group consisting of H;

and —

C(O)O—

C_1-6 alkyl.

11. A compound according to claim 1 selected from the group consisting of

12. A prodrug compound of a compound according to claim 1.

13. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 1 together with a pharmaceutically acceptable carrier.

14. A pharmaceutical composition according to claim 13, comprising one or more additional compounds or pharmaceutically acceptable salts thereof selected from the group consisting of another of said compound or said pharmaceutically acceptable salt thereof or a prodrug thereof;

another DPP-IV inhibitor;

insulin sensitizers;

PPAR agonists;

biguanides;

protein tyrosinephosphatase-IB (PTP-1B) inhibitors;

insulin and insulin mimetics;

sulfonylureas and other insulin secretagogues;

a-glucosidase inhibitors;

glucagon receptor antagonists;

GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;

GIP, GIP mimetics, and GIP receptor agonists;

PACAP, PACAP mimetics, and PACAP receptor 3 agonists;

cholesterol lowering agents;

HMG-CoA reductase inhibitors;

sequestrants;

nicotinyl alcohol;

nicotinic acid or a salt thereof;

PPARa agonists;

PPARoly dual agonists;

inhibitors of cholesterol absorption;

acyl CoA;

cholesterol acyltransferase inhibitors;

antioxidants;

PPARo agonists;

antiobesity compounds;

an ileal bile acid transporter inhibitor; and

anti-inflammatory agents.

15. A compound or a pharmaceutically acceptable salt thereof or a prodrug thereof of claim 1 for use as a medicament.

16. A method for the treatment or prophylaxis of non-insulin dependent (Type II) diabetes mellitus;

hyperglycemia;

obesity;

insulin resistance;

lipid disorders;

dyslipidemia;

hyperlipidemia;

hypertriglyceridemia;

hypercholestrerolemia;

low HDL;

high LDL;

atherosclerosis;

growth hormone deficiency;

diseases related to the immune response;

HIV infection;

neutropenia;

neuronal disorders;

tumor metastasis;

benign prostatic hypertrophy;

gingivitis;

hypertension;

osteoporosis;

diseases related to sperm motility;

low glucose tolerance;

insulin resistance;

ist sequelae;

vascular restenosis;

irritable bowel syndrome;

inflammatory bowel disease;

including Crohn'"'"'s disease and ulcerative colitis;

other inflammatory conditions;

pancreatitis;

abdominal obesity;

neurodegenerative disease;

retinopathy;

nephropathy;

neuropathy;

Syndrome X;

ovarian hyperandrogenism (polycystic ovarian syndrome;

Type n diabetes;

or growth hormone deficiency, comprising administering to a subject in need of said treatment said compound or said pharmaceutically acceptable salt thereof or a prodrug thereof of claim 1.

17. A method to inhibit DPP-IV peptidase activity comprising administering said compound or said pharmaceutically acceptable salt thereof or a prodrug thereof of claim 1 to a subject in an amount sufficient to inhibit DPP-IV peptidase activity.