Carboxylic acid derivatives, processes for the preparation...

Details Carboxylic acid derivatives, processes for the preparation... Carboxylic acid derivatives, processes for the preparation...

2003-02-20

2004-12-28

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C562S433000

Reexamination Certificate

active

06835752

ABSTRACT:

TECHNICAL FIELD
The present invention relates to carboxylic acid derivatives. More specifically, the present invention relates to a carboxylic acid derivative of formula (I)
wherein all symbols are as hereinafter defined, a process for the preparation thereof and a pharmaceutical agent comprising the same as active ingredient.
BACKGROUND
Prostaglandin E
2
(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 that 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
respectively (J. Lipid Mediators Cell Signaling 12, 379-391 (1995)).
Among these subtypes, EP
a
receptor was believed to be involved in signal transduction of peripheral nerve, control of exothermal reaction in central nerve, formation of memory by expressing in cerebral neuron, vascularization, reabsorption of urine by expressing in renal tubular, uterine contraction, production of ACTH, platelet aggregation. Besides, it was expressed in vascular smooth muscle, heart and gastrointestinal tract also. EP
4
recptor 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
3
receptor and/or EP
4
receptor strongly and show the antagonizing activity, are useful for the prevention and/or treatment of diseases induced by excess activation of EP
3
receptor and/or EP
4
receptor, for example, pain such as cancerous pain, fractural pain, pain following surgical and dental procedures; allodynia, hyperalgesia, pruritus, urticaria, atopic dermatitis, contact dermatitis, allergic conjunctivitis, various symptoms by treating with dialysis, asthma, rhinitis, sneeze, urinary frequency, neurogenic bladder, urinary disturbance, ejaculatory failure, defervescence, systemic inflammatory response syndrome, learning disturbance, Alzheimer's disease, cancer such as formulation of cancer, growth of cancer and metastasis of cancer; retinopathy, patch of red, scald, burn, burn by steroid, renal failure, nephropathy, acute nephritis, chronic nephritis, abnormal blood levels of electrolytes, threatened premature delivery, abortion threatened, hypermenorrhea, dysmenorrhea, uterine fibroids, premenstrual syndrome, reproductive disorder, stress, anxiety disorders, depression, psychosomatic disorder, mental disorder, thrombosis, embolism, transient ischemia attack, cerebral infarction, atheroma, organ transplant, myocardial infarction, cardiac failure, hypertension, arteriosclerosis, circulatory failure and circulatory failure induced ulcer, neuropathies, vascular dementia, edema, various arthritis, rheumatism, diarrhea, constipation, disorder of bilious excretion, ulcerative colitis, Crohn's disease and/or bone diseases such as osteoporosis, rheumatoid arthritis, osteoarthritis, abnormal bone formation; cancer such as formation of cancer, proliferation of cancer, metastasis of cancer to organs and to bones and hypercalcemia induced metastasis to bones of cancer; systemic granuloma, immunological diseases such as ALS, multiple sclerosis, Sjoegren's syndrome, systemic lupus erythematosus, AIDS; allergy such as conjunctivitis, rhinitis, contact dermatitis, psoriasis; atopic dermatitis, asthma, pyorrhea, gingivitis, periodontitis, neuronal cell death, Alzheimer's disease's disease, pulmonary injury, hepatopathy, acute hepatopathy, nephritis, renal failure, myocardial ischemia, Kawasaki disease, scald, ulcerative colitis, Crohn's disease, multiple organ failure etc. Moreover, EP
4
is thought to be involved in sleeping disorder and platelet aggregation, so the compounds are considered to be useful.
DISCLOSURE OF THE INVENTION
The present inventors have energetically studied to find the compound which bind to PGE
2
receptor, EP
3
and/or EP
4
receptor specifically and show an inhibitory activity against it, to find out that the carboxylic acid derivatives of formula (I) achieve the purpose and completed the present invention.
This invention was relates to
(1) a carboxylic acid derivative of formula (I)
wherein R
1
is COOH, COOR
6
, CH
2
OH, CONHSO
2
R
7
or CONR
8
R
9
,
R
6
is C1-6 alkyl, (C1-4 alkylene)—R
16
,
R
7
is (1) C1-4 alkyl, or (2) substituted by 1-2 of substitutes selected form C1-4 alkyl, C1-4 alkoxy and halogen atom or unsubstituted (2-1) C6-12 mono- or bi-carbocyclic ring or (2-2) 5-15 membered mono- or bi-heterocyclic ring containing at least one of hetero atom selected from nitrogen, oxygen and sulfur, or (3) C1-4 alkyl substituted by the above substituents or unsubstituted carbocyclic ring or heterocyclic ring,
R
8
and R
0
each independently, is hydrogen or C1-4 alkyl,
R
16
is hydroxy, C1-4 alkoxy, COOH, C1-4 alkoxycarbonyl, CONR
8
R
9
,
A is C1-6 alkylene or —(C1-3 alkylene)
w
—G—(C1-3 alkylene)—,
w is 0 or 1,
G is oxygen, sulfur or NR
10
,
R
10
is hydrogen or C1-4 alkyl,
R
2
is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogen atom, CF
3
, cyano, nitro, hydroxy, NR
11
R
12
, CONR
11
R
12
, SO
2
NR
11
R
12
, or —S(O)
x
—(C1-6)alkyl,
m is 0, 1 or 2, when m is 2, then two R
2
may be same or difference,
R
11
and R
12
each independently, hydrogen or C1-4 alkyl,
x is 0, 1 or 2,
B ring is C5-7 mono-carbocyclic ring or 5-7 membered mono-heterocyclic ring containing at least one of nitrogen, oxygen and sulfur,
R
3
is hydrogen or C1-4 alkyl,
R
4
is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) C3-6 cycloalkyl, (5) hydroxy, (6) C1-4 alkoxy, (7) C1-4 alkoxy(C1-4)alkoxy, or (8) C1-8 alkyl substituted by 1-2 of substitutes selected from halogen atom, hydroxy, C1-6 alkoxy, C1-4 alkoxy(C1-4)alkoxy, phenyl and C3-6 cycloalkyl,
R
5
is substituted by 1-2 of R
13
or unsubstituted C5-10 mono- or bi-carbocyclic ring or 5-10 membered mono- or bi-heterocyclic ring containing at least one of nitrogen, oxygen and sulfur,
R
18
is C1-6 alkyl, C1-6 alkoxy, halogen atom, CF
3
, cyano, C1-4 alkoxy(C1-4)alkyl, phenyl, phenyl(C1-6)alkyl, —(C1-4 alkylene)
y
-J—(C1-8 alkylene)
x
—R
14
, benzoyl or thiophenecarbonyl and two R
13
may be same or difference,
y is 0 or 1,
z is 0 or 1,
R
14
is phenyl or pyridyl,
J is oxygen, S(O)
t
or NR
15
,
t is 0, 1 or 2,
R
16
is hydrogen, C1-4 alkyl or acetyl;
or non-toxic salts,
(2) a process of the preparation thereof, and
(3) a pharmaceutical agent comprising the same as active ingredient.


REFERENCES:
patent: 2164481 (1973-08-01), None
patent: 62-44738 (1987-02-01), None
patent: 2000-86657 (2000-03-01), None
International Search Report for PCT/JP01/07104 dated Dec. 11, 2001.

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