Benzoic acid derivatives, processes for producing the same and drugs containing the same as the active ingredient

• US 6,710,205 B2
• Filed: 08/16/2002
• Issued: 03/23/2004
• Est. Priority Date: 02/22/2000
• Status: Expired due to Fees

• Current Assignee: ONO Pharmaceutical Company Limited
• Original Assignee: ONO Pharmaceutical Company Limited
• Inventors: Maruyama, Takayuki, Kobayashi, Kaoru, Tani, Kousuke
• Primary Examiner(s): Seaman, D. Margaret
• Application Number:
  US10/204,049
• Publication Number:
  US 20030114435A1
• Time in Patent Office: 585 Days
• Field of Search: 562/400, 562/405, 562/433, 562/441, 562/452, 562/455, 562/457, 562/458
• US Class Current: 562/455
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 233/55 having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
• CPC Class Codes: C07C 235/38 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/84 with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 255/60 at least one of the singly-bound nitrogen atoms being acylated
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07C 323/62 having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07D 213/30 Oxygen atoms
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/80 in position 3
• CPC Class Codes: C07D 215/06 having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
• CPC Class Codes: C07D 215/12 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 215/14 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 263/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

An agent comprising the benzoic acid of formula (I)

wherein A, B, R⁶, R⁷ are carbocyclic ring, heterocyclic ring, etc.; R¹ is hydroxy etc.; R², R³, R⁴ are alkyl etc.; R⁵, D, E are alkylene, etc.; G is oxygen etc., as active ingredient.

The compound of formula (I) is considered to be useful for the treatment and/or prophylaxis of bone diseases, cancer, systemic granuloma, immunological diseases, allergy, atopy, asthma, gumboil, gingivitis, periodontitis, neurocyte death, Alzheimer'"'"'s diseases, lungs injury, pulmopathy, acute hepatitis, nephritis, myocardial ischemia, Kawasaki disease, ambustion, ulcerative colitis, Crohn'"'"'s disease, multiple organ failure, sleeping disorder, platelet aggregation, etc.

Claims

1. A benzoic acid derivative of formula (I)

wherein

are each independently, phenyl,

D is C1-4 alkylene,

G is oxygen or sulfur,

E is a bond, oxygen, sulfur, C1-4 alkylene, C1-4 alkyloxy or C1-4 oxyalkyl,

R¹ is hydroxy, —

OR⁹ or —

NR¹⁰R¹¹, wherein R⁹ is C1-6 alkyl, and R¹⁰ and R¹¹ are each independently, hydrogen atom or C1-6 alkyl,

R² and R³ are each independently, C1-4 alkyl, C1-4 alkoxy, halogen atom, trihalomethyl, cyano or nitro,

R⁴ is hydrogen or C1-6 alkyl,

R⁵ is a bond, C1-6 alkylene, C1-6 alkylene substituted with C1-4 alkoxy, or C3-5 cycloalkylene,

R⁶ is phenyl or naphthyl,

R⁷ is hydrogen, C1-8 alkyl, C5˜

7 carbocyclic ring or 5-15 membered heterocyclic ring containing nitrogen, sulfur and/or oxygen,

m and n are each independently, 0, 1, 2 or 3,

the rings represented by R⁶ and R⁷ may be substituted with C1-4 alkyl, C1-4 alkoxy, halogen, trihalomethyl, nitro, cyano or oxo,

with the proviso that 2-[2-(benzoylamino)phenylmethyl]benzoic acid is excluded, or a non-toxic salt thereof.

2. The benzoic acid derivative according to claim 1, wherein D is methylene, or a non-toxic salt thereof.

3. The benzoic acid derivative according to claim 1, wherein R⁵ is a bond, or a non-toxic salt thereof.

4. The benzoic acid derivative according to claim 1, wherein R⁵ is branched C1˜

6 alkylene, or a non-toxic salt thereof.

5. The benzoic acid derivative according to claim 1, wherein R⁵ is C3˜

5 cycloalkylene, or a non-toxic salt thereof.

6. The benzoic acid derivative according to claim 1, which is selected from

(1) 2-[5-chloro-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid,

(2) 2-[2-[2-(1-naphthyl)propanoylamino]phenylmethyl]benzoic acid,

(3) 2-[2-[2-(2-naphthyl)propanoylamino]phenylmethyl]benzoic acid,

(4) 2-[2-[2-(4-biphenyl)propanoylamino]phenylmethyl]benzoic acid,

(5) 2-[3-chloro-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid,

(6) 2-[5-methoxy-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid,

(7) 2-[2-[2-(1-naphthyl)acetylamino]phenylmethyl]benzoic acid,

(8) 2-[2-[2-(1-naphthyl)carbonylamino]phenylmethyl]benzoic acid,

(9) 2-[3-methoxy-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid,

(10) 2-[4-methoxy-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid,

(11) 2-[4-chloro-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid,

(12) 2-[6-chloro-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid,

(13) 2-[6-methoxy-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid,

(14) 2-[4-fluoro-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid,

(15) 2-[4-trifluoromethyl-2-[2-(1-naphthyl)propanoyl amino]phenylmethyl]benzoic acid,

(16) 2-[4-methyl-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid,

(17) 2-[2-[2-(4-benzyloxyphenyl)acetylamino]phenylmethyl]benzoic acid,

(18) 2-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid,

or a methyl ester thereof or a non-toxic salt thereof.

7. The benzoic acid according to claim 1, which is selected from

(1) 2-[4-cyano-2-[4-methyl-2-(1-naphthyl)pentanoylamino]phenylmethyl]benzoic acid,

(2) 2-[2-[2-(4-benzyloxyphenyl)propanoylamino]phenyl methyl]benzoic acid,

(3) 2-[2-[2-(3-benzyloxyphenyl)propanoylamino]phenyl methyl]benzoic acid,

(4) 2-[2-[2-(1-naphthyl)butanoylamino]phenylmethyl]benzoic acid,

(5) 2-[2-[2-(1-naphthyl)pentanoylamino]phenylmethyl]benzoic acid,

(6) 2-[2-[3-methyl-2-(1-naphthyl)butanoylamino]phenyl methyl]benzoic acid,

(7) 2-[2-[2-(1,1′

-biphenyl-2-yl)propanoylamino]phenyl methyl]benzoic acid,

(8) 2-[2-[2-(1,1′

-biphenyl-3-yl)propanoylamino]phenyl methyl]benzoic acid,

(9) 2-[2-[2-(4-phenoxyphenyl)propanoylamino]phenyl methyl]benzoic acid,

(10) 2-[2-[2-[4-(2-phenylethoxy)phenyl]propanoylamino]phenylmethyl]benzoic acid,

(11) 2-[2-[2-[4-(3-phenylpropoxy)phenyl]propanoylamino]phenylmethyl]benzoic acid,

(12) 2-[2-[2-methoxy-2-(1-naphthyl)acetylamino]phenyl methyl]benzoic acid,

(13) 2-[2-[2-(4-isobutylphenyl)propanoylamino]phenyl methyl]benzoic acid,

(14) 2-[2-[4-methyl-2-(1-naphthyl)pentanoylamino]phenyl methyl]benzoic acid,

(15) 2-[2-[2-(1-naphthyl)hexanoylamino]phenylmethyl]benzoic acid,

(16) 2-[2-[2-[4-(4-phenylbutoxy)phenyl]propanoylamino]phenylmethyl]benzoic acid,

(17) 2-[2-[2(R)-(1-naphthyl)propanoylamino]phenylmethyl]benzoic acid,

(18) 2-[2-[2(S)-(1-naphthyl)propanoylamino]phenylmethyl]benzoic acid,

(19) 2-[4-cyano-2-[4-methyl-2-(1-naphthyl)pentanoylamino]phenylmethyl]benzoic acid,

(20) 2-[2-[2-ethoxy-2-(1-naphthyl)acetylamino]phenylmethyl]benzoic acid,

(21) 2-[2-[2-(1-naphthyl)heptanoylamino]phenylmethyl]benzoic acid,

(22) 2-[2-[4,4-dimethyl-2-(1-naphthyl)pentanoylamino]phenylmethyl]benzoic acid,

(23) 2-[2-[2-[4-(3-phenylpropyl)phenyl]propanoylamino]phenylmethyl]benzoic acid,

(24) 2-[2-[2-[4-[2-(3-pyridyl)ethoxy]phenyl]propanoyl amino]phenylmethyl]benzoic acid,

(25) 2-[2-[2-[4-(2-phenoxyethyl)phenyl]propanoylamino]phenylmethyl]benzoic acid,

(26) 2-[2-[4-methoxy-2-(1-naphthyl)butanoylamino]phenyl methyl]benzoic acid,

(27) 2-[2-[5-methyl-2-(1-naphthyl)hexanoylamino]phenyl methyl]benzoic acid,

(28) 2-[2-[2-[4-(2-phenylethylthio)phenyl]propanoyl amino]phenylmethyl]benzoic acid,

(29) 2-[2-[3-methoxy-2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid,

(30) 2-[4-ethoxy-2-[4-methyl-2-(1-naphthyl)pentanoyl amino]phenylmethyl]benzoic acid,

(31) 2-[4-isopropyloxy-2-[4-methyl-2-(1-naphthyl) pentanoylamino]phenylmethyl]benzoic acid,

(32) 2-[4-methoxy-2-[4-methyl-2-(1-naphthyl)pentanoyl amino]phenylmethyl]benzoic acid,

(33) 2-[2-[2-[4-[2-(pyridin-2-yl)ethoxy]phenyl]propanoyl amino]phenylmethyl]benzoic acid,

(34) 2-[2-[2-[4-[2-(pyridin-4-yl)ethoxy]phenyl]propanoyl amino]phenylmethyl]benzoic acid,

(35) 2-[4-cyano-2-(4-methyl-2-phenylpentanoylamino)phenyl methyl]benzoic acid,

(36) 2-[2-[2-(4-pentylphenyl)propanoylamino]phenylmethyl]benzoic acid,

or a methyl ester thereof or a non-toxic salt thereof.

8. A process for the preparation of a benzoic acid derivative of formula (Ia)

wherein all symbols have the same meaning as above, characterized by subjecting to hydrolysis under alkaline conditions the compound of formula (Ib)

wherein R²⁰ is C1-6 alkyl and the other symbols have the same meanings as defined in claim 1.

9. A process for the preparation of a benzoic acid derivative of formula (Ic)

wherein all symbols have the same meaning as defined in claim 1, characterized by subjecting to amidation reaction the compound of formula (Ia)

wherein all symbols have the same meaning as defined in claim 1, and the compound of formula

10. A process for the preparation of the benzoic acid of formula (Ib)

wherein R²⁰ is C1-6 alkyl and the other symbols have the same meaning as defined in claim 1, characterized by subjecting to a reaction the compound of formula (III)

wherein all symbols have the same meaning as defined in claim 1, and the compound of formula (IV)

wherein all symbols have the same meaning as defined in claim 1.

11. A pharmaceutical composition comprising the benzoic acid derivative of formula (I) described in claim 1 or a non-toxic salt thereof as active ingredient.

12. A method for antagonizing EP₄ receptor which comprises administering to a mammal an effective amount of the benzoic acid derivative of formula (I) as claimed in claim 1 or a non-toxic salt thereof as active ingredient.

13. A method for the treatment and/or prophylaxis of bone diseases, cancer, systemic granuloma, immunological diseases, allergy, atopy, asthma, gumboil, gingivitis, periodontitis, neurocyte death, Alzheimer'"'"'s diseases, pulmonary injury, hepatopathy, acute hepatitis, nephritis, myocardial ischemia, Kawasaki disease, ambustion, ulcerative colitis, Crohn'"'"'s disease, multiple organ failure, sleeping disorder, platelet aggregation, etc., comprising the benzoic acid derivative of formula (I) described in claim 1 or a non-toxic salt thereof as active ingredient.