Compounds as CRTH2 antagonist and uses thereof

• US 9,951,010 B2
• Filed: 09/11/2015
• Issued: 04/24/2018
• Est. Priority Date: 09/13/2014
• Status: Active Grant

• Current Assignee: Sunshine Lake Pharma Co Ltd (Shenzhen Dongyangguang Industry Co., Ltd.)
• Original Assignee: Sunshine Lake Pharma Co Ltd (Shenzhen Dongyangguang Industry Co., Ltd.)
• Inventors: Zhang, Yingjun, Yu, Tianzhu, Liu, Bing, Zhang, Xiangyu, Zhang, Shiguo, Cheng, Changchung, Zhang, Jiancun
• Primary Examiner(s): Ward, Paul V
• Application Number:
  US15/504,018
• Publication Number:
  US 20170267634A1
• Time in Patent Office: 956 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The compounds of Formula (I) which can be used as CRTH2 receptor antagonists are provided. The compounds of Formula (I) can be used in the treatment and prevention of asthma, allergic rhinitis and atopic dermatitis, as well as other diseases mediated by prostaglandin D2 (PGD2) at the CRTH2 receptor.

Claims

1. A compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof,

2. The compound of claim 1, wherein

A is 6- to 9-membered heterocyclylene, 4-membered heterocyclylene, C_5-12 spiro heterobicyclylene, C_5-12 fused heterobicyclylene, C_5-12 bridged heterobicyclylene, C_5-12 spiro bicyclylene, C_5-12 fused bicyclylene, C_5-12 bridged bicyclylene, C_3-12 cycloalkylene, C_1-9 heteroarylene or C_6-12 arylene;

and

each of 6- to 9-membered heterocyclylene, 4-membered heterocyclylene, C_5-12 spiro bicyclylene, C_5-12 fused bicyclylene, C_5-12 bridged bicyclylene, C_5-12 spiro heterobicyclylene, C_5-12 fused heterobicyclylene, C_5-12 bridged heterobicyclylene, C_3-12 cycloalkylene, C_1-9 heteroarylene and C_6-12 arylene is optionally and independently substituted with 1, 2, 3 or 4 independent R²;

or

A is one of the following sub-structures;

3. The compound of claim 1, wherein

A is

4. The compound of claim 1, wherein

E is C_1-9 heterocyclyl, C_5-12spiro heterobicyclyl, C_5-12fused heterobicyclyl, C_5-12bridged heterobicyclyl, C_3-12cycloalkyl, C_6-12 aryl or C_1-12 heteroaryl;

and

each of C_1-9 heterocyclyl, C_5-12spiro heterobicyclyl, C_5-12fused heterobicyclyl, C_5-12bridged heterobicyclyl, C_3-12cycloalkyl, C_6-12 aryl and C_1-12 heteroaryl is optionally and independently substituted with 1, 2, 3 or 4 independent R^2c;

or

E is one of the following monovalent groups;

5. The compound of claim 1 having Formula (II) or a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof,

6. The compound of claim 1 having Formula (IIa) or a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof,

7. The compound of claim 1, wherein

E is one of the following C_6-12 aryl and C_1-9 heteroaryl groups:

8. The compound of claim 1, wherein

each R^2c and R² is independently H, methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, trifluoromethyl, hydroxy, nitro, amino, cyano, F, Cl, Br, carboxy, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, methylacyl, aminomethyl, hydroxymethyl, sulfo, R^2b-L-, aminosulfonyl or aminoacyl;

and

each R^2b is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, trifluoromethyl, cyclopentyl, cyclohexyl, cyclobutyl, morpholinyl, piperidyl, pyrrolyl, hydroxymethyl or amino.

9. The compound of claim 1, wherein the pharmaceutically acceptable salt is an inorganic acid salt, organic acid salt, inorganic base salt, alkali metal salt or organic base salt.

10. The compound of claim 9, wherein the pharmaceutically acceptable salt is hydrochloride, hydrobromide, hydriodate, nitrate, sulfate, disulfate, phosphate, acetate, propionate, butyrate, lactate, mesylate, tosilate, maleate, benzoate, succinate, tartrate, citrate, oxalate, fumarate, taurinate, sodium salt, potassium salt or ammonium salt.

11. The compound of claim 1 having one of the following structures or a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof:

13. A pharmaceutical composition comprising the compound of claim 1;

and at least one of pharmaceutically acceptable carriers, excipients, diluents, adjuvants and vehicles.

14. The pharmaceutical composition of claim 13 further comprising one or more other active agents, wherein the other active agent is salmeterol, fluticasone, loratadine, montelukast, omalizumab, fusidic acid, clotrimazole, tacrolimus, pimecrolimus, DP antagonist, cilomilast, TNF-α

converting enzyme (TACE) inhibitor, blocking monoclonal antibody or soluble receptor of IL-4 and IL-5 or zileuton.

15. A method of treating a disease mediated by PGD₂ at the CRTH2 receptor in a patient comprising administering the compound of claim 1 to the patient, wherein the disease mediated by PGD₂ at the CRTH2 receptor is asthma, COPD, allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis, Crohn'"'"'s disease, and mastocytosis.

16. A method of treating a disease mediated by PGD₂ at the CRTH2 receptor in a patient comprising administering the pharmaceutical composition of claim 13 to the patient, wherein the disease mediated by PGD₂ at the CRTH2 receptor is asthma, COPD, allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis, Crohn'"'"'s disease, and mastocytosis.

12. A crystalline form of 2-(5-fluoro-3-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methyl-1H-indol-1-yl)acetic acid (Formula VI), wherein the crystalline form is crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V or crystalline form VI: