Benzoic acid derivatives, processes for producing the same...

Details Benzoic acid derivatives, processes for producing the same... Benzoic acid derivatives, processes for producing the same...

2002-08-16

2004-03-23

Seaman, D. Margaret (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C562S400000, C562S405000, C562S433000, C562S441000, C562S452000, C562S457000, C562S458000

Reexamination Certificate

active

06710205

ABSTRACT:

Benzoic acid derivatives, processes for the preparation thereof and pharmaceutical agents comprising the same as active ingredient.
TECHNICAL FIELD
The present invention relates to benzoic acid derivatives.
More specifically, the present invention relates to a benzoic acid derivative of formula (I)
, wherein all symbols have the same meanings as hereafter described, a process for the preparation thereof and a pharmaceutical agent comprising the same as active ingredient.
BACKGROUND
Prostaglandin E
2
(abbreviated as PGE
2
) has been known as a metabolite in the arachidonic acid cascade. It has been known that PGE
2
possesses cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awaking effect, a suppressive effect on gastric acid secretion, hypotensive activity, and diuretic activity.
In the recent study, it was found hat PGE
2
receptor was divided into some subtypes which possesses different physical roles from each other. At present, four receptor subtypes are known and they are called EP
1
, EP
2
, EP
3
and EP
4
(Negishi M. et al, J. Lipid Mediators Cell Signaling 12, 379-391 (1995)) respectively.
Among these subtypes, EP
4
receptor was believed to be involved in suppression of TNF-&agr; production and induction of IL-10 production. So the compounds which can bind to EP
4
receptor strongly and show the antagonizing activity, are useful for the prevention and/or treatment of diseases including bone diseases (such as osteoporosis, rheumatoid arthritis, osteoarthritis, abnormal bone formation etc.) and cancer (formation, proliferation, metastasis to organs, and to bones, hypercalcemia etc. and systemic granuloma, immunological diseases such as ALS, multiple sclerosis, Sjoegren's syndrome, systemic lupus erythematosus, AIDS etc. and allergy (conjunctivitis, rhinitis, contact dermatitis, psoriasis), atopic dermatitis, asthma, pyorrhea, gingivitis, periodontitis, neuronal cell death, Alzheimer's disease, pulmonary injury, hepatopathy, acute hepatopathy, nephritis, renal failure, myocardiac ischemia, Kawasaki disease, scald, ulcerative colitis, Crohn's disease, multiple organ failure etc. Moreover, EP4 is thought to be involved in sleeping disorders and platelet aggregation, so the compounds are considered to be useful.
On the other hand, in the specification of JP-A-51-115456, as a compound analogous to the compound of the present invention, 2-[2-(benzoylamino)phenylmethyl]benzoic acid is disclosed as a synthetic example. This application is only to disclose the process for the synthesis and nothing is described about pharmacological effect etc.
DISCLOSURE OF THE INVENTION
The present inventors have energetically studied to find the compound which bind to EP4 receptor specifically and show an inhibitory activity against it, to find out that the benzoic acid derivatives of formula (I) achieve the purpose and completed the present invention.
The present invention relates to
(1) a benzoic acid derivative of formula (I)
, wherein
are each independently, C3~7 carbocyclic ring or 5~7 membered heterocyclic ring containing nitrogen, sulfur and/or oxygen atom,
D is C1-4 alkylene, oxygen or sulfur atom,
G is oxygen or sulfur,
E is a bond, oxygen, sulfur, C1-4 alkylene, C1-4 alkyloxy or C1-4 oxyalkyl,
R
1
is hydroxy, —OR
9
or —NR
10
R
11
, wherein R
9
is C1-6 alkyl, and
R
10
and R
11
are each independently, hydrogen atom or C1-6 alkyl,
R
2
and R
3
are each independently, C1-4 alkyl, C1-4 alkoxy, halogen atom, trihalomethyl, cyano or nitro,
R
4
is hydrogen or C1-6 alkyl,
R
5
is a bond, C1-6 alkylene, C1-6 alkylene substituted with C1-4 alkoxy, or C3-5 cycloalkylene,
R
6
is C5~15 carbocyclic ring or 5~15 membered heterocyclic ring containing nitrogen, sulfur and/or oxygen,
R
7
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 R
6
and R
7
may be substituted with C1-4 alkyl, C1-4 alkoxy, halogen, trihalomethyl, nitro, cyano or oxo,
with proviso that 2-[2-(benzoylamino)phenylmethyl]benzoic acid is excluded,
or a non-toxic salt thereof,
(2) a process for the preparation thereof and
(3) a pharmaceutical agent comprising the same as active ingredient.
DETAILED DESCRIPTION OF THE INVENTION
In the formula (I), C1-6 alkyl which R
8
, R
9
, R
4
, R
10
, R
11
represent includes, methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof.
In the formula (I), alkyl in C1-4 alkoxy and alkyl which R
2
, R
3
, R
5
, E, R
6
, R
7
represent includes, methyl, ethyl, propyl, butyl and isomers thereof.
In the formula (I), C1-8 alkyl which R
7
represents includes, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.
In the formula (I), C1-4 alkylene which D and E represent include, methylene, ethylene, trimethylene, tetramethylene and isomers thereof.
In the formula (I), C1-6 alkylene which R
5
represents include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and isomers thereof.
In the formula (I), halogen atom which R
2
, R
3
, R
6
, R
7
represent include fluorine, chlorine, bromine and iodine.
In the formula (I), C3~5 cycloalkylene which R
5
represents include cyclopropylene, cyclobutylene, cyclopentylene.
In the formula (I), C3~7 carbocyclic ring which A and B represent may be unsaturated or saturated, and for example the ones shown by the following formulae are included.
In the formula (I), 5-7 membered heterocyclic ring containing nitrogen, sulfur and/or oxygen atom which A and B represent may be saturated or unsaturated, and for example the following ones shown by the following formulae are included.
In the formula (I), C5~15 carbocyclic ring which R
6
and R
7
represent may be saturated or unsaturated and for example, the ones shown by the following formulae are included.
In the formula (I), 5~15 membered heterocyclic ring containing nitrogen, sulfur and/or oxygen atom which R6 and R7 represent may be saturated or unsaturated, and for example, the ones shown by the following formulae are included.
Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkenyl and alkynyl groups include straight-chain and also branched-chain ones. In addition, isomers in double bond, ring, fused ring (E-, Z-, cis-, trans-isomer), isomers generated from asymmetric carbon atom(s) (R-, S-, &agr;-, &bgr;-isomer, enantiomer, diastereomer), optically active isomers having optical rotation (D-, L-, d-, l -isomer), polar compounds separated by chromatography (more polar compound, less polar compound), equilibrium compounds, mixtures thereof at arbitrary ratios and racemic mixtures are included in branched-chain alkyl are included in the present invention.
In the compounds of the present invention of formula (I), the compounds described in examples and the compounds shown in the following tables 1~3 and corresponding esters and amides thereof are preferable.
TABLE 1
(1)



TABLE 2
(2)




TABLE 3
(3)






[Salt]
The compound of the present invention of formula (I) may be converted into a corresponding salt by known methods. Non-toxic and water-soluble salts are preferable. Appropriate salts are, salts of alkali metals (potassium, sodium, etc.), salts of alkaline-earth metals, ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine, etc.). The compound of the present invention of formula (I) and a salt thereof may also be converted into hydrates by known methods.
[Processes for the Preparation of the Compound of the Present Invention]
(a) Among the compound of formula (I), the compound wherein R
1
is hydroxy, i.e. the compound of formula (Ia)
wherein all symbols have the same mea

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