Lpa receptor antagonist

Abstract

A compound of the general formula (I): (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).

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 —CH 2 —, 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  claim 1 . 
     
     
         3 . The compound according to  claim 1 , wherein R is an aliphatic hydrocarbon group which may be substituted. 
     
     
         4 . The compound according to  claim 1 , wherein R is a cyclic group which may have a substituent(s). 
     
     
         5 . The compound according to  claim 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  claim 5 , wherein the cyclic group is a C3-15 mono-, bi- or tricyclic aromatic carbocyclic group. 
     
     
         7 . The compound according to  claim 5 , wherein the cyclic group is a cyclopentane, cyclopentene, cyclohexane, benzene or naphthalene ring. 
     
     
         8 . The compound according to  claim 6 , wherein the cyclic group is a benzene ring. 
     
     
         9 . The compound according to  claim 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  claim 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  claim 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  claim 10 , wherein the cyclic group is a pyridine ring. 
     
     
         13 . The compound according to  claim 1 , wherein G is a bond. 
     
     
         14 . The compound according to  claim 1 , wherein T is —CHOH—, or —CO—. 
     
     
         15 . The compound according to  claim 1 , wherein J is a nitrogen atom. 
     
     
         16 . The compound according to  claim 1 , wherein J is a carbon atom. 
     
     
         17 . The compound according to  claim 1 , wherein K is a spacer having from 1 to 4 atoms in its principle chain. 
     
     
         18 . The compound according to  claim 17 , wherein K is C1-4 alkylene which may be substituted. 
     
     
         19 . The compound according to  claim 18 , wherein K is trimethylene, or trimethylene substituted with two halogen atoms. 
     
     
         20 . The compound according to  claim 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  claim 20 , wherein B is a C3-15 mono-, bi- or tricyclic aromatic carbocyclic group. 
     
     
         22 . The compound according to  claim 20 , wherein B is a cyclohexane, benzene, indan, tetrahydronaphthalene or naphthalene ring. 
     
     
         23 . The compound according to  claim 21 , wherein B is a benzene ring. 
     
     
         24 . The compound according to  claim 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  claim 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  claim 24 , wherein B is a pyrrolidine, piperidine, piperazine, morpholine, pyridine, thiazole, imidazole, pyrrole, pyrazole, indol or thiophene ring. 
     
     
         27 . The compound according to  claim 25 , wherein B is a thiophene ring. 
     
     
         28 . The compound according to  claim 1 , wherein Q is a spacer having from 1 to 4 atoms in its principle chain. 
     
     
         29 . The compound according to  claim 28 , wherein Q is C1-4 alkylene which may be substituted. 
     
     
         30 . The compound according to  claim 29 , wherein Q is methylene. 
     
     
         31 . The compound according to  claim 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  claim 31 , wherein ring D is a C3-15 mono-, bi- or tricyclic aromatic carbocyclic group. 
     
     
         33 . The compound according to  claim 31 , wherein ring D is a cyclohexane or benzene ring. 
     
     
         34 . The compound according to  claim 32 , wherein ring D is a benzene ring. 
     
     
         35 . The compound according to  claim 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  claim 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  claim 35 , wherein ring D is a piperidine, pyrrole, pyrazole, pyridine, 1,3,4-oxadiazole, thiazole, dihydrobenzoxazine or indol ring. 
     
     
         38 . The compound according to  claim 36 , wherein ring D is a pyrrole or indol ring. 
     
     
         39 . The compound according to  claim 1 , wherein L is a bond. 
     
     
         40 . The compound according to  claim 1 , wherein L is a spacer having from 1 to 3 atoms in its principle chain. 
     
     
         41 . The compound according to  claim 40 , wherein L is —CH 2 —, —O—, —S—, —SO—, —SO 2 —, or —NH—. 
     
     
         42 . The compound according to  claim 40 , wherein L is —O— or —S— 
     
     
         43 . The compound according to  claim 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  claim 43 , wherein ring E is a C3-15 mono-, bi- or tricyclic aromatic carbocyclic group. 
     
     
         45 . The compound according to  claim 44 , wherein ring E is a benzene ring. 
     
     
         46 . The compound according to  claim 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  claim 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  claim 46 , wherein ring E is a piperidine, isoxazole, pyrazole, pyridine, thiazole, imidazole, thiophene, pyrrole or pyrrolidine ring. 
     
     
         49 . The compound according to  claim 1 , wherein M is a bond. 
     
     
         50 . The compound according to  claim 1 , wherein M is a spacer having from 1 to 4 atoms in its principle chain. 
     
     
         51 . The compound according to  claim 50 , wherein M is C1-4 alkylene which may be substituted. 
     
     
         52 . The compound according to  claim 51 , wherein M is methylene. 
     
     
         53 . The compound according to  claim 1 , wherein Z is —COOR 5 , in which R 5  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  claim 53 , wherein R 5  is a hydrogen atom, or C1-4 alkyl. 
     
     
         55 . The compound according to  claim 1 , wherein Z is tetrazole. 
     
     
         56 . The compound according to  claim 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; 
         R 1  represents a substituent of the cyclic group in R; and 
         other symbols have the same meanings as described in  claim 1 . 
       
     
     
         57 . The compound according to  claim 56 , which is represented by formula (I-J-1): 
       
         
           
           
               
               
           
         
         wherein ring A 1  has the same meaning as the ring A described in  claim 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  claim 1 . 
       
     
     
         58 . The compound according to  claim 57 , which is represented by formula (I-J-1-1): 
       
         
           
           
               
               
           
         
         K 1  has the same meaning as K described in  claim 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  claim 1  or  claim 57 . 
       
     
     
         59 . The compound according to  claim 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  claim 1 . 
       
     
     
         60 . The compound according to  claim 59 , which is a compound of either following formula (I-K-1) or formula (I-N-1): 
       
         
           
           
               
               
           
         
         wherein ring D 1  has the same meaning as the ring D described in  claim 1 , with the proviso that it represents a benzene ring which may have a substituent(s); 
         R 3  represents a substituent on the ring D; and 
         other symbols have the same meanings as described in  claim 1  or  claim 58 . 
       
     
     
         61 . The compound according to  claim 60 , which is a compound of either following formula (I-K-1-1), or formula (I-N-1-1): 
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as described in  claim 1 ,  claim 58  or  claim 60 . 
       
     
     
         62 . The compound according to  claim 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  claim 1  or  claim 56 . 
       
     
     
         63 . The compound according to  claim 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  claim 1 ,  claim 56  or  claim 57 . 
       
     
     
         64 . The compound according to  claim 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 R 1-1  represents —CH 2 —, —O—, —S— or —NH—; and 
         other symbols have the same meanings as described in  claim 1  or  claim 57 . 
       
     
     
         65 . The compound according to  claim 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  claim 1 . 
       
     
     
         66 . The compound according to  claim 65 , which is represented by formula (I-M-1): 
       
         
           
           
               
               
           
         
         wherein Q 1  has the same meaning as Q described in  claim 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  claim 1  or  claim 58 . 
       
     
     
         67 . The compound according to  claim 66 , which is a compound of either following formula (I-M-1-1), formula (I-M-1-2) or formula (I-M-1-3): 
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as described in  claim 1  or  claim 58 . 
       
     
     
         68 . The compound according to  claim 1 , which is a compound of either following formula (I-A), formula (I-C), formula (I-D) or formula (I-E): 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3  and R 4  each independently represents (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) a halogen atom, (5) trihalomethyl, (6) nitro, (7) cyano, (8) Cycl, (9) —OR 6 , (10) —SR 7 , (11) —NR 8 R 9 , (12) —CONR 10 R 11 , (13) —NR 12 COR 13 , (14) —SO 2 NR 14 R 15 , (15) —NR 16 SO 2 R 17 , (16) —SO 2 R 18 , (17) —COR 19 , (18) —COOR 20 , or (19) C1-8 alkyl substituted with —OR 6 , —SR 7 , —NR 8 R 9  or Cycl; 
         R 6  represents (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cycl, (6) methyl substituted with 1 to 3 halogen, or (7) C1-8 alkyl substituted with Cycl; 
         R 7  to R 16  and R 20  each independently represents (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, or (5) Cycl; 
         R 17 , R 18  and R 19  each independently represents (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, or (4) Cycl; 
         Cycl represents a C3-10 monocyclic or bicyclic carbocyclic group or a three- to ten-membered monocyclic or bicyclic heterocyclic group which contains 1 to 5 hetero atoms selected from an oxygen atom(s), a nitrogen atom(s) and a sulfur atom(s); 
         G, K and M each independently represents (1) a bond, (2) C1-8 alkylene, (3) C2-8 alkenylene, or (4) C2-8 alkynylene; 
         J represents a nitrogen atom or a carbon atom; 
         L represents a bond, an oxygen atom or a sulfur atom; 
         Ring A, ring B and ring D each independently represents a C3-10 monocyclic or bicyclic carbocyclic group or a three- to ten-membered monocyclic or bicyclic heterocyclic group which contains 1 to 5 hetero atoms selected from an oxygen atom(s), a nitrogen atom(s) and a sulfur atom(s); 
         Ring E represents a C3-7 monocyclic carbocyclic group or a three- to seven-membered monocyclic heterocyclic group which contains 1 to 5 hetero atoms selected from an oxygen atom(s), a nitrogen atom(s) and a sulfur atom(s); 
         p, q, r and s each independently represents 0 or an integer of from 1 to 5, 
         in which R 1 s are the same or different when p represents 2 or more; R 2 s are the same or different when q represents 2 or more; R 3 s are the same or different when r represents 2 or more; and R 4 s are the same or different when s represents 2 or more, respectively; 
         t represents 0 or 1; and 
         R 5  represents (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, or (4) C2-8 alkynyl, or 
         a salt thereof. 
       
     
     
         69 . A pharmaceutical composition comprising the compound according to  claim 1  or the prodrug according to  claim 2 . 
     
     
         70 . The pharmaceutical composition according to  claim 69 , which is an LPA receptor antagonist. 
     
     
         71 . The pharmaceutical composition according to  claim 70 , wherein the LPA receptor is EDG-2 receptor. 
     
     
         72 . The pharmaceutical composition according to  claim 71 , which is an agent for prevention and/or treatment for urinary system disease. 
     
     
         73 . The pharmaceutical composition according to  claim 71 , which is an agent for prevention and/or treatment for carcinoma-associated disease, proliferative disease, inflammation/immune system disease, disease caused by secretory dysfunction or brain-related disease. 
     
     
         74 . A method for prevention and/or treatment of diseases referred from EDG-2, which comprises administering an effective amount of the compound according to  claim 1  or a salt thereof to a mammal. 
     
     
         75 . The method for prevention and/or treatment according to  claim 74 , wherein the disease referred from EDG-2 is urinary system disease. 
     
     
         76 . The method for prevention and/or treatment according to  claim 74 , wherein the disease referred from EDG-2 is carcinoma-associated disease, proliferative disease, inflammation/immune system disease, disease caused by secretory dysfunction or brain-related disease. 
     
     
         77 . Use of the compound according to  claim 1  or a salt thereof for manufacture of a pharmaceutical for prevention and/or treatment of diseases referred from EDG-2. 
     
     
         78 . The use according to  claim 77 , wherein the disease referred from EDG-2 is urinary system disease. 
     
     
         79 . The use according to  claim 77 , wherein the disease referred from EDG-2 is carcinoma-associated disease, proliferative disease, inflammation/immune system disease, disease caused by secretory dysfunction or brain-related disease. 
     
     
         80 . A pharmaceutical composition for prevention and/or treatment of urinary system disease comprising a combination of an LPA receptor antagonist containing the compound according to  claim 1  or a prodrug thereof as an active ingredient and one or two more agent(s) selected from other LPA receptor antagonist, α1 blocking agent, anticholinergic agent, 5α-reductase inhibitor and/or anti-androgenic agent.