Carboxylic acid derivatives and pharmaceutical agent comprising the same as active ingredient

• US 7,786,161 B2
• Filed: 10/27/2008
• Issued: 08/31/2010
• Est. Priority Date: 08/09/2001
• Status: Expired due to Fees

• Current Assignee: ONO Pharmaceutical Company Limited
• Original Assignee: ONO Pharmaceutical Company Limited
• Inventors: Narita, Masami, Asada, Masaki, Ogawa, Mikio, Kobayashi, Kaoru, Tani, Kousuke
• Primary Examiner(s): Aulakh; Charanjit S
• Application Number:
  US12/259,012
• Publication Number:
  US 20090318703A1
• Time in Patent Office: 673 Days
• Field of Search: 514/406, 514/383, 514/367, 514/546, 514/557, 548/375.1, 548/267.2, 548/152, 560/155, 562/400
• US Class Current: 514/406
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 1/10 Laxatives
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 : Anxiolytics
• 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 29/02 : without antiinflammatory effect
• CPC Class Codes: A61P 3/14 : for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/24 : of the sex hormones
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• 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: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07C 229/34 : the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 309/66 : Methanesulfonates
• CPC Class Codes: C07C 309/67 : of an unsaturated carbon skeleton
• CPC Class Codes: C07C 309/73 : to carbon atoms of non-condensed six-membered aromatic rings
• CPC Class Codes: C07C 311/06 : to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 311/08 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/19 : to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 311/29 : having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/51 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 317/18 : with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
• CPC Class Codes: C07C 317/22 : with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 317/40 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 317/50 : at least one of the nitrogen atoms being part of any of the groups , X being a hetero atom, Y being any atom
• CPC Class Codes: C07C 323/19 : with singly-bound oxygen atoms bound to acyclic carbon atoms of the carbon skeleton
• CPC Class Codes: C07C 323/42 : Y being a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 323/59 : with acylated amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 323/60 : with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• CPC Class Codes: C07C 59/68 : the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 69/734 : Ethers
• CPC Class Codes: C07C 69/736 : the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 69/738 : Esters of keto-carboxylic acids or aldehydo-carboxylic acids
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Abstract

A carboxylic acid derivative of formula (I):

wherein R¹ is —COOH, —COOR⁶, etc.; A is a single bond, alkylene, etc.; R² is alkyl, alkoxy, etc.; B is a carbocyclic ring or a heterocyclic ring; Q is alkylnene-Cyc2, etc.; D is a linking chain; and R³ is alkyl, a carbocyclic ring or a heterocyclic ring, or a non-toxic salt thereof. The compound of formula (I) binds to PGE₂ receptor, especially subtypes EP₃ and/or EP₄ and show the antagonizing activity, are useful for the prevention and/or treatment of diseases induced pain, itch, urticaria, allergy, urinary frequency, urinary disturbance, Alzheimer'"'"'s disease, cancer, dysmenorrhea, endometriosis, etc.

Claims

1. A carboxylic acid derivative of formula (I):

2. The compound according to the claim 1, which is selected from

(1) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-ethoxyphenoxymethyl)phenyl)butanoic acid,

(2) (2E)-3-(2-((2-(naphthalen-2-yl)acetyl)amino)-4-(pyrazol-1-ylmethyl)phenyl)-2-propenoic acid,

(3) 2-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-(pyrazol-1-ylmethyl)benzyl)benzoic acid,

(4) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid,

(5) 4-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-phenoxymethylphenyl)butanoic acid,

(6) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-oxopyridin-1-ylmethyl)phenyl)butanoic acid,

(7) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(pyridin-3-yloxymethyl)phenyl)butanoic acid,

(8) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenylthiomethylphenyl)butanoic acid,

(9) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenylaminomethylphenyl)butanoic acid,

(10) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenylsulfinylmethylphenyl)butanoic acid,

(11) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenylsulfonylmethylphenyl)butanoic acid,

(12) 3-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-phenoxymethylphenyl)propanoic acid,

(13) 4-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-(pyrazol-1-ylmethyl)phenyl)butanoic acid,

(14) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-benzoylaminomethylphenyl)butanoic acid,

(15) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(pyridin-4-yloxymethyl)phenyl)butanoic acid,

(16) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-phenoxyethyl)phenyl)butanoic acid,

(17) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(pyridin-2-yloxymethyl)phenyl)butanoic acid,

(18) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(N-methyl-N-phenylaminomethyl)phenyl)butanoic acid,

(19) 4-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid,

(20) 4-(2-((2-phenylpropanoyl)amino)-4-phenoxymethylphenyl)butanoic acid,

(21) 3-(2-((4-methyl-2-phenylpentanoyl)amino)-4-phenoxymethylphenyl)propanoic acid,

(22) 3-(2-((2-phenylpentanoyl)amino)-4-phenoxymethylphenyl)propanoic acid,

(23) 3-(2-((2-phenylpropanoyl)amino)-4-phenoxymethylphenyl)propanoic acid,

(24) 3-(2-((2-phenylbutanoyl)amino)-4-phenoxymethylphenyl)propanoic acid,

(25) 4-(2-((2-phenylpropanoyl)amino)-4-phenylaminomethylphenyl)butanoic acid,

(26) 4-(2-((2-phenylpropanoyl)amino)-4-benzoylaminomethylphenyl)butanoic acid,

(27) 4-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-benzoylaminomethylphenyl)butanoic acid,

(28) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenylsulfonylaminomethylphenyl)butanoic acid,

(29) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-benzylaminomethylphenyl)butanoic acid,

(30) 4-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-phenylaminomethylphenyl)butanoic acid,

(31) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-cyanophenoxymethyl)phenyl)butanoic acid, phenylaminomethylphenyl)butanoic acid,

(32) 2-(2-((2-phenylpropanoyl)amino)-4-phenoxymethylbenzyl)benzoic acid,

(33) 2-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-phenoxymethylbenzyl)benzoic acid,

(34) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(furan-2-ylcarbonylaminomethyl)phenyl)butanoic acid,

(35) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-fluorobenzoylaminomethyl)phenyl)butanoic acid,

(36) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-methoxybenzoylaminomethyl)phenyl)butanoic acid,

(37) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-cyclopropylcarbonylaminomethylphenyl)butanoic acid,

(38) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(thiophen-2-ylcarbonylaminomethyl)phenyl)butanoic acid,

(39) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-methylbenzoylaminomethyl)phenyl)butanoic acid,

(40) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-chlorobenzoylaminomethyl)phenyl)butanoic acid,

(41) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-cyanobenzoylaminomethyl)phenyl)butanoic acid,

(42) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-fluorobenzoylaminomethyl)phenyl)butanoic acid,

(43) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-fluorobenzoylaminomethyl)phenyl)butanoic acid,

(44) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-chloro-4-fluorobenzoylaminomethyl)phenyl)butanoic acid,

(45) 4-(2-((2-(2-chlorophenyl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid,

(46) 4-(2-((2-(3-chlorophenyl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid,

(47) 4-(2-((2-(4-chlorophenyl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid,

(48) 4-(2-((2-(4-fluorophenyl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid,

(49) 4-(2-((2-(4-methoxyphenyl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid,

(50) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-ethoxybenzoylaminomethyl)phenyl)butanoic acid,

(51) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3,5-difluorobenzoylaminomethyl)phenyl)butanoic acid,

(52) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-fluorophenoxymethyl)phenyl)butanoic acid,

(53) 4-(2-((2-(4-methylphenyl)propanoyl)amino)-4-phenoxymethylphenyl)butanoic acid,

(54) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-cyano-2-methoxyphenoxymethyl)phenyl)butanoic acid,

(55) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-acetylphenoxymethyl)phenyl)butanoic acid,

(56) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-isopropyl-5-methylphenoxymethyl)phenyl)butanoic acid,

(57) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2,4,6-trifluorophenoxymethyl)phenyl)butanoic acid,

(58) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-trifluoromethylthiophenoxymethyl)phenyl)butanoic acid,

(59) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-bromophenoxymethyl)phenyl)butanoic acid,

(60) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-methoxyphenoxymethyl)phenyl)butanoic acid,

(61) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-methoxyphenoxymethyl)phenyl)butanoic acid,

(62) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-methylbenzothiazol-5-yloxymethyl)phenyl)butanoic acid,

(63) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-(1,2,4-triazol-1-yl)phenoxymethyl)phenyl)butanoic acid,

(64) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-ethoxyphenoxymethyl)phenyl)butanoic acid,

(65) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-methoxy-5-methylphenoxymethyl)phenyl)butanoic acid,

(66) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3,5-dimethoxyphenoxymethyl)phenyl)butanoic acid,

(67) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-fluoro-6-methoxyphenoxymethyl)phenyl)butanoic acid,

(68) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-isopropyloxyphenoxymethyl)phenyl)butanoic acid,

(69) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-acetyl-5-methoxyphenoxymethyl)phenyl)butanoic acid,

(70) 2-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-phenoxymethylbenzyl)benzoic acid,

(71) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-chloro-4,5-dimethylphenoxymethyl)phenyl)butanoic acid,

(72) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(1-oxo-1,2,3,4-tetrahydronaphthalen-6-yloxymethyl)phenyl)butanoic acid,

(73) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-cyanophenoxymethyl)phenyl)butanoic acid,

(74) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-chloro-5-methoxyphenoxymethyl)phenyl)butanoic acid,

(75) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-ethyl-2-methoxyphenoxymethyl)phenyl)butanoic acid,

(76) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-acetylamino-2-chlorophenoxymethyl)phenyl)butanoic acid,

(77) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-methylthiophenoxymethyl)phenyl)butanoic acid,

(78) 4-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(4-butanoylphenoxymethyl)phenyl)butanoic acid,

(79) (2E)-3-(2-((4-methyl-2-phenylpentanoyl)amino)-4-phenoxymethylphenyl)-2-propenoic acid,

(80) 4-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-(pyrazol-1-ylmethyl)phenyl)butanoic acid,

(81) 3-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-phenoxymethylphenyl)propanoic acid,

(82) 3-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-phenylaminomethylphenyl)propanoic acid,

(83) 3-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-(pyrazol-1-ylmethyl)phenyl)propanoic acid,

(84) 2-(2-((2-(4-fluoronaphthalen-1-yl)acetyl)amino)-4-phenoxymethylbenzyl)benzoic acid,

(85) 2-(2-((2-(4-fluoronaphthalen-1-yl)propanoyl)amino)-4-phenoxymethylbenzyl)benzoic acid,

(86) 2-(2-((4-methyl-2-phenylpentanoyl)amino)-4-phenoxymethylbenzyl)benzoic acid,

(87) 2-(2-((4-methyl-2-(3,5-dimethylphenyl)pentanoyl)amino)-4-phenoxymethylbenzyl)benzoic acid,

(88) 2-(2-((2-(naphthalen-1-yl)acetyl)amino)-4-phenoxymethylbenzyl)benzoic acid,

(89) 3-(2-((4-methyl-2-(4-fluoro-3-methylphenyl)pentanoyl)amino)-4-phenoxymethylphenyl)propanoic acid,

(90) 3-(2-((4-methyl-2-(3,5-dimethylphenyl)pentanoyl)amino)-4-phenoxymethylphenyl)propanoic acid,

(91) 2-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-methylphenoxymethyl)benzyl)benzoic acid,

(92) 2-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(2-chloro-5-methylphenoxymethyl)benzyl)benzoic acid,

(93) 2-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(3-cyanophenoxymethyl)benzyl)benzoic acid,

(94) 2-(2-((2-(naphthalen-1-yl)propanoyl)amino)-4-(pyridin-3-yloxymethyl)benzyl)benzoic acid,

methyl ester thereof, ethyl ester therof or non-toxic salts thereof.

3. A pharmaceutical composition, which comprises the compound of formula (I) according to claim 1, or a non-toxic salt thereof.

4. The compound according to claim 1, which is

2-(2-((4-methyl-2-(naphthalen-1-yl)pentanoyl)amino)-4-(pyrazol-1-ylmethyl) benzyl)benzoic acid.