Lpa receptor antagonist   

Abstract: (wherein the symbols are as defined in the description), or a non-toxic salt thereof. This compound engages in LPA receptor bonding and antagonism and hence is useful in the prevention and/or treatment of urinary system disease (symptom with prostatic hypertrophy or neurogenic bladder dysfunction disease, symptom to be caused by spinal cord neoplasm, nucleous hernia, spinal canal stenosis or diabetes, occlusion disease of lower urinary tract, inflammatory disease of lower urinary tract, polyuria), carcinoma-associated disease (solid tumor, solid tumor metastasis, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leucemia and carcinomatous infiltration transition), proliferative disease (disorder with aberrant angiogenesis, artery obstruction and pulmonary fibrosis), inflammation/immune system disease (psoriasis, nephropathy, hepatitis and pneumonitis symptom), disease caused by secretory dysfunction (Sjogren syndrome), brain-related disease (brain infarction, cerebral apoplexy and brain or peripheral neuropathy) or chronic disease (chronic asthma, glomerulonephritis, obesity, prostate hyperplasia, diseases caused by arteriosclerosis process, rheumatism or atopic dermatitis). A compound of the general formula (I):

TECHNICAL FIELD

The present invention relates to a carboxylic acid derivative having antagonisitic activity against lysophosphatidic acid receptor (especially EDG-2 receptor) which is useful as medicament, a process for producing the same and the use thereof.

BACKGROUND ART

It is known that various lipid mediators such as eicosanoid and platelet activating factor (PAF) are produced by the activity of phospholipase from cell membranes.

Lysophosphatidic acid (hereinafter abbreviated as LPA) of formula (A)

(wherein RA is acyl, alkenyl or alkyl)

is a lipid which is produced from cell membranes or phospholipid which is present in the blood, acts as a mediator for signal transduction and delivers various signals into cells. LPA that exists naturally is L-α-LPA.

Recently, the existence of three subtypes of LPA receptor has been disclosed and it is gradually proved that their physiological activities are via LPA receptor. Three subtypes of LPA receptor are called EDG (Endothelial differentiation gene)-2, 4 and 7, respectively, and form part of EDG receptor family as well as EDG-1, 3, 5, 6 and 8 that are sphingosine-1-phosphate receptor. EDG-2 is also called LPA1 or VZG (Ventricular zone gene)-1 (Mol. Pharmacol., 2000 December; 58(6): 1188-96). LPA receptor to which LPA binds delivers signals into cells via G-protein coupled to the receptor. Gs, Gi, Gq, etc. are known as G-proteins that can bind to LPA receptor, and the receptors are said to relate to the response to the action of increase or, adversely, decrease of cell growth. Furthermore, since MAP-kinase systems operate in the downstreams of G-proteins, it has been known that LPA receptors deliver various signals.

Since localization of LPA receptors is different between their subtypes although they exist widely in living body, it is considered that the role of each receptor is different by the organ.

The increase of blood pressure in rats, and the contraction of colon in rats and ileum in guinea pigs have been known as the pharmacological activity induced by LPA (J. Pharm. Pharmacol. 1991, 43, 774, J. Pharm. Pharmacol. 1982, 34, 514). In addition, the effect of LPA on urethral contraction is set forth in WO02/062389 specification and the suppressive effect of LPA on secretion of pancreatic juice is set forth in WO03/007991 specification. Furthermore, the effect of LPA on chronic disease is set forth in the specification of Japan Patent Application (Tokugan 2002-185542).

In addition, concerning to the relationship between LPA and carcinoma, until now it is known that LPA enhances the proliferation of the epithelial cancer cells originated from prostate gland (J Cellular Physiol. 1998 174, 261) and ovarian cancer cells (J. Urol. 2000, 163, 1027).

In addition, it is known that LPA is related to the function of growth of various cells such as airway smooth muscle cells (Am. J. Physiol. Lung Cell Mol. Physiol., 2002, 282(1): L91), fibroblast (Mol. Cell. Biol., 1998, 18(12): 7119), mesangial cells (Clin. Science 1999, 96, 431), hepatocyte, liver stellate cells (Biochem. Biophys. Res. Commun., 1998, 248, 436), vasucular smooth muscle cells (Am. J. Physiol., 1994, 267 (Cell Physiol. 36): C204), vascular endothelial cells (Am. J. Physiol. Cell Physiol., 2000, 278(3): C612), glia cells/Schwann cells (Proc. Natl. Acad. Sci. USA, 1999, 96, 5233), adipocytes (J. Clin. Invest., 1998, 101, 1431) as well as cancer cells. In addition, it is known that LPA is related to the function of chemotaxis of inflammatory cells as well as cancer cells besides cell growth (Biochem Biophys Res Commun., 1993, 15; 193(2), 497). Moreover proliferation and cytokine-secreting activity in response to LPA of immune cells (J. Imuunol. 1999, 162, 2049), platelet aggregation activity to LPA (Biochem. Biophys. Res. Commun., 1981, 99, 391) are known. Besides, from analysis of knockout mouse of EDG-2 which is one of the LPA receptor, EDG-2 is concerned to be related to the brain function (Proc. Natl. Acad. Sci. USA, 2000, 97, 13384).

From these evidences, it is thought that a drug antagonizing to LPA receptor is useful for prevention and/or treatment of diseases such as various kinds of disease namely urinary system disease, carcinoma-associated disease, proliferative disease, inflammation/immune system disease, disease by secretory dysfunction, brain-related disease or chronic disease.

For example, for urinary system disease, prostatic hypertrophy or neurogenic bladder dysfunction disease, and dysuria (micturation initiation delay, extension between on urination, urinary stream very small, intermission micturation, two steps of micturation, etc.), pollakiuria, night urination, urodynia, etc. are known as symptoms with a urinary system disease. Similar urologic symptoms are symptoms caused by cerebrovascular disorder, Parkinson disease, cerebral oncosis, a multiple sclerosis, Shy-Drager symptom, spinal cord neoplasm, nucleous hernia, spinal canal stenosis, diabetes, etc. (such as dysuria (micturation initiation delay, extension between on urination, urinary stream very small, intermission micturation, two steps of miction), pollakiuria, night urination, urodynia). For other example, for urinary system disease, lower urinary tract symptom (for example, occlusion disease of lower urinary tract), inflammatory disease of lower urinary tract (such as infection), and polyuria are thought about. And these diseases are considered to be controlled by LPA receptor antagonists.

For example, for carcinoma-associated disease, solid tumor, solid tumor metastasis, angiofibroma, myeloma, multiple myeloma, Kaposi\'s sarcoma, leucemia are given. In solid tumor, mammary cancer, lung cancer, gastric cancer, carcinoma oesophagi, colon rectal cancer, liver cancer, ovarian cancer, theca cell tumor, androblastoma, cervix cancer, endometrial carcinoma, prostate cancer, kidney cancer, carcinoma cutaneum, osteosarcoma, pancreas cancer, urinary tract carcinoma, thyroid cancer, or cerebral oncosis, etc. are given. In addition, it is thought that carcinomatous infiltration transition is suppressed by LPA receptor antagonist.

For example, for proliferative disease, the disease with aberrant angiogenesis are given (for example, re-arctation, diabetic retinopathy, angiogenesis-related glaucoma, crystalline lens fiber multiplication symptom, thyroid gland hyperplasia (including Basedow\'s disease), lung inflammation, nephrotic syndrome or osteoporosis), and also artery obstruction, or pulmonary fibrosis, etc. are given.

For example, for inflammation/immune system disease, psoriasis, nephropathy (for example, IgA nephropathy, etc.), nephritis by other inflammation/immunopathy, hepatitis, or pneumonitis symptom, etc. are given.

For example, for secretory dysfunction, secretory dysfunction by autonomic nervous system dysfunction is given, for example, for secretory dysfunction by autonomic nervous system dysfunction, Sjogren syndrome, etc. is given.

For example, for brain-related disease, brain infarction, cerebral apoplexy, brain or peripheral neuropathy, etc. are given.

For example, for chronic disease, chronic asthma, glomerulonephritis, obesity, prostate hyperplasia, diseases caused by arteriosclerosis process, rheumatism or atopic dermatitis, etc. are given.

The compound of formula (B)

[wherein R1B represents optionally substituted alkyl, aryl, heterocyclic radical, alkyloxy, aryloxy, alkylthio, arylthio or halogen atom, R2B represents optionally substituted alkyl, aryl, heterocyclic radical, alkyloxy, aryloxy or halogen atom, R3B represents hydrogen atom, lower alkyl or alkyl substituted with halogen atom, R4B represents a radical selected from (a) optionally substituted phenyl, aryl or heterocyclic radical, (b) substituted or non-substituted alkyl or (c) substituted or non-substituted alkenyl, XB represents oxygen atom or sulfur atom. With the proviso that R3B and R4B may form a five- to ten-membered cyclic structure together with a carbon atom to which they bind, and when R3B is a hydrogen atom, R4B represents a group other than methyl.]

or a salt thereof is known as a compound having the LPA receptor antagonistic activity (WO01/60819).

The compound of formula (C)

or a salt thereof is known as a compound having the angiotensin II antagonistic activity (EP443983).

DISCLOSURE OF THE INVENTION

An agent of prevention and/or treatment of urinary system disease, carcinoma-associated disease, proliferative disease, inflammation/immune system disease, disease caused by secretory dysfunction, brain-related disease and chronic disease, etc. is useful for drug. It is eagerly desired to development of an LPA receptor (EDG-2, especially) antagonist which is excel at oral absorption, and safety.

The inventors of the present invention have carried out intensive studies for finding compounds which specifically binds to LPA receptors (EDG-2 receptor, especially) and exerts antagonistic activity, and as a result, they have found that a carboxylic acid derivative of formula (I) achieves the problem to accomplish the present invention.

The present invention can provide the novel compound which becomes various kinds of treatment of disease medicine by showing antagonistic activity to LPA receptor. For example, it may be an agent of prevention and/or treatment such as the urinary system disease that does not influence blood pressure is provided.

The carboxylic acid derivative of formula (I) of the present invention is the novel compound which is not known till now.

The present invention relates to the followings and the like:

(1) A compound of formula (I)

wherein R represents an aliphatic hydrocarbon group which may be substituted, or a cyclic group which may have a substituent(s);

G represents a bond or a spacer having from 1 to 8 atoms in its principle chain;

T represents —CH2—, or a spacer having one atom in its principle chain, the principle chain containing a hydrogen bond acceptable group which may have a substituent(s);

J represents a nitrogen atom or a carbon atom;

B represents an aliphatic hydrocarbon group which may be substituted, or a cyclic group which may have a substituent(s);

K represents (1) a bond, or (2) a spacer having from 1 to 8 atoms in its principle chain which may form a ring together with a substituent of the cyclic group in R, the ring D or a substituent on the ring D;

Q represents (1) a bond, or (2) a spacer having from 1 to 8 atoms in its principle chain which may form a ring together with the cyclic group in R, a substituent of the cyclic group in R or K;

ring D represents a cyclic group which may have an additional substituent(s);

L represents a bond, or a spacer having from 1 to 3 atoms in its principle chain;

ring E represents a cyclic group which may have an additional substituent(s);

M represents a bond, or a spacer having from 1 to 8 atoms in its principle chain;

A represents an acidic group; and

t represents 0 or 1, or

a salt thereof.

(2) A prodrug of the compound according to (1). (3) The compound according to (1), wherein R is an aliphatic hydrocarbon group which may be substituted. (4) The compound according to (1), wherein R is a cyclic group which may have a substituent(s). (5) The compound according to (4), wherein the cyclic group is a C3-15 mono-, bi- or tricyclic carbocyclic group, a bicyclic carbocyclic group having a spiro bond or a bicyclic bridged carbocyclic group. (6) The compound according to (5), wherein the cyclic group is a C3-15 mono-, bi- or tricyclic aromatic carbocyclic group. (7) The compound according to (5), wherein the cyclic group is a cyclopentane, cyclopentene, cyclohexane, benzene or naphthalene ring. (8) The compound according to (6), wherein the cyclic group is a benzene ring. (9) The compound according to (4), wherein the cyclic group is a three- to fifteen-membered monocyclic, bicyclic or tricyclic heterocyclic group, a bicyclic heterocyclic group having a spiro bond or a bicyclic bridged heterocyclic group containing from 1 to 5 hetero atoms selected from an oxygen atom(s), a nitrogen atom(s) and a sulfur atom(s). (10) The compound according to (9), wherein the cyclic group is a three- to fifteen-membered monocyclic, bicyclic or tricyclic aromatic heterocyclic group containing from 1 to 5 hetero atoms selected from an oxygen atom(s), a nitrogen atom(s) and a sulfur atom(s). (11) The compound according to (9), wherein the cyclic group is a furan, isoxazole, thiophene, 1,2,3-thiadiazole, pyrrole, pyrazole, benzothiophene, indole, 1,3-dioxaindan, pyridine or cinnoline ring. (12) The compound according to (10), wherein the cyclic group is a pyridine ring. (13) The compound according to (1), wherein G is a bond. (14) The compound according to (1), wherein T is —CHOH—, or —CO—. (15) The compound according to (1), wherein J is a nitrogen atom. (16) The compound according to (1), wherein J is a carbon atom. (17) The compound according to (1), wherein K is a spacer having from 1 to 4 atoms in its principle chain. (18) The compound according to (17), wherein K is C1-4 alkylene which may be substituted. (19) The compound according to (18), wherein K is trimethylene, or trimethylene substituted with two halogen atoms. (20) The compound according to (1), wherein B is a C3-15 mono-, bi- or tricyclic carbocyclic group, a bicyclic carbocyclic group having a spiro bond or a bicyclic bridged carbocyclic group. (21) The compound according to (20), wherein B is a C3-15 mono-, bi- or tricyclic aromatic carbocyclic group. (22) The compound according to (20), wherein B is a cyclohexane, benzene, indan, tetrahydronaphthalene or naphthalene ring. (23) The compound according to (21), wherein B is a benzene ring. (24) The compound according to (1), wherein B is a three- to fifteen-membered monocyclic, bicyclic or tricyclic heterocyclic group, a bicyclic heterocyclic group having a spiro bond or a bicyclic bridged heterocyclic group containing from 1 to 5 hetero atoms selected from an oxygen atom(s), a nitrogen atom(s) and a sulfur atom(s). (25) The compound according to (24), wherein B is a three- to fifteen-membered monocyclic, bicyclic or tricyclic aromatic heterocyclic group containing from 1 to 5 hetero atoms selected from an oxygen atom(s), a nitrogen atom(s) and a sulfur atom(s). (26) The compound according to (24), wherein B is a pyrrolidine, piperidine, piperazine, morpholine, pyridine, thiazole, imidazole, pyrrole, pyrazole, indol or thiophene ring. (27) The compound according to (25), wherein B is a thiophene ring. (28) The compound according to (1), wherein Q is a spacer having from 1 to 4 atoms in its principle chain. (29) The compound according to (28), wherein Q is C1-4 alkylene which may be substituted. (30) The compound according to (29), wherein Q is methylene. (31) The compound according to (1), wherein ring D is a C3-15 mono-, bi- or tricyclic carbocyclic group, bicyclic carbocyclic group having a spiro bond or a bicyclic bridged carbocyclic group. (32) The compound according to (31), wherein ring D is a C3-15 mono-, bi- or tricyclic aromatic carbocyclic group. (33) The compound according to (31), wherein ring D is a cyclohexane or benzene ring. (34) The compound according to (32), wherein ring D is a benzene ring. (35) The compound according to (1), wherein ring D is a three- to fifteen-membered monocyclic, bicyclic or tricyclic heterocyclic group, a bicyclic heterocyclic group having spiro bond or a bicyclic bridged heterocyclic group containing from 1 to 5 hetero atoms selected from an oxygen atom(s), a nitrogen atom(s) and a sulfur atom(s). (36) The compound according to (35), wherein ring D is a three- to fifteen-membered monocyclic, bicyclic or tricyclic aromatic heterocyclic group containing from 1 to 5 hetero atoms selected from an oxygen atom(s), a nitrogen atom(s) and a sulfur atom(s). (37) The compound according to (35), wherein ring D is a piperidine, pyrrole, pyrazole, pyridine, 1,3,4-oxadiazole, thiazole, dihydrobenzoxazine or indol ring. (38) The compound according to (36), wherein ring D is a pyrrole or indol ring. (39) The compound according to (1), wherein L is a bond. (40) The compound according to (1), wherein L is a spacer having from 1 to 3 atoms in its principle chain. (41) The compound according to (40), wherein L is —CH2—, —O—, —S—, —SO—, —SO2—, or —NH—. (42) The compound according to (40), wherein L is —O— or —S—. (43) The compound according to (1), wherein ring E is a C3-15 mono-, bi- or tricyclic carbocyclic group, bicyclic carbocyclic group having a spiro bond or a bicyclic bridged carbocyclic group. (44) The compound according to (43), wherein ring E is a C3-15 mono-, bi- or tricyclic aromatic carbocyclic group. (45) The compound according to (44), wherein ring E is a benzene ring. (46) The compound according to (1), wherein ring E is a three- to fifteen-membered monocyclic, bicyclic or tricyclic heterocyclic group, a bicyclic heterocyclic group having spiro bond or a bicyclic bridged heterocyclic group containing from 1 to 5 hetero atoms selected from an oxygen atom(s), a nitrogen atom(s) and a sulfur atom(s). (47) The compound according to (46), wherein ring E is a three- to fifteen-membered monocyclic, bicyclic or tricyclic aromatic heterocyclic group containing from 1 to 5 hetero atoms selected from an oxygen atom(s), a nitrogen atom(s) and a sulfur atom(s). (48) The compound according to (46), wherein ring E is a piperidine, isoxazole, pyrazole, pyridine, thiazole, imidazole, thiophene, pyrrole or pyrrolidine ring. (49) The compound according to (1), wherein M is a bond. (50) The compound according to (1), wherein M is a spacer having from 1 to 4 atoms in its principle chain. (51) The compound according to (50), wherein M is C1-4 alkylene which may be substituted. (52) The compound according to (51), wherein M is methylene. (53) The compound according to (1), wherein Z is —COORS, in which R5 represents a hydrogen atom, an aliphatic hydrocarbon group which may be substituted, or a cyclic group which may have a substituent(s). (54) The compound according to (53), wherein R5 is a hydrogen atom, or C1-4 alkyl. (55) The compound according to (1), wherein Z is tetrazole. (56) The compound according to (1), which is a compound of formula (I-J) in which K forms a ring together with a substituent of the cyclic group in R:

wherein ring A represents a cyclic group which may have a substituent(s) in R;

R1 represents a substituent of the cyclic group R; and

other symbols have the same meanings as described in (1).

(57) The compound according to (56), which is represented by formula (I-J-1):

wherein ring A1 has the same meaning as the ring A described in (56), with the proviso that it represents a benzene ring which may have a substituent(s); and

other symbols have the same meanings as described in (1).

(58) The compound according to (57), which is represented by formula (I-J-1-1):

K1 has the same meaning as K described in (1), with the proviso that it represents a spacer having from 1 to 7 atoms in its principle chain; and

other symbols have the same meanings as described in (1) or (57).

(59) The compound according to (1), which is a compound of either formula (I-K) or formula (I-N) in which K forms a ring together with the ring D or a substituent on the ring D:

wherein all symbols have the same meanings as described in (1).

(60) The compound according to (59), which is a compound of either following formula (I-K-1) or formula (I-N-1):

wherein ring D1 has the same meaning as the ring D described in (1), with the proviso that it represents a benzene ring which may have a substituent(s);

R3 represents a substituent on the ring D; and

other symbols have the same meanings as described in (1) or (58).

(61) The compound according to (60), which is a compound of either following formula (I-K-1-1), formula (I-K-1-2) or formula (I-N-1-1):

wherein all symbols have the same meanings as described in (1), (58) or (60).

(62) The compound according to (1), which is a compound of either formula (I-L) or formula (I-O) in which Q forms a ring together with a cyclic group of R or a substituent of the cyclic group in R:

wherein all symbols have the same meanings as described in (1) or (56).

(63) The compound according to (62), which is a compound of either following formula (I-L-1) or formula (I-O-1):

wherein all symbols have the same meanings as described in (1), (56) or (57).

(64) The compound according to (63), which is a compound of either following formula (I-L-1-1), formula (I-O-1-1), formula (I-O-1-2), formula (I-O-1-3), formula (I-O-1-4) or formula (I-O-1-5):

wherein R1-1 represents-CH2—, —O—, —S— or —NH—; and

other symbols have the same meanings as described in (1) or (57).

(65) The compound according to (1), which is a compound of formula (I-M) in which Q forms a ring together with K:

wherein all symbols have the same meanings as described in (1).

(66) The compound according to (65), which is represented by formula (I-M-1):

wherein Q1 has the same meaning as Q described in (1), with the proviso that it represents a spacer having from 1 to 7 atoms in its principle chain; and

other symbols have the same meanings as described in (1) or (58).

(67) The compound according to (66), which is a compound of either following formula (I-M-1-1), formula (I-M-1-2) or formula (I-M-1-3):

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