Naphthyloxy acetic acid derivatives and a pharmaceutical composition comprising them as an active ingredient

Abstract

The naphthyloxyacetic acid derivatives of the formula (I) wherein A is H, -(alkylene)COOR 1 , -(alkylene)CONR 2 R 3 , -(alkylene)OH, -(alkylene)tetrazole, -(alkylene)CN; E is single bond or alkylene; G is —S—, —SO—, —SO 2 —, —O— or —NR 4 —; L is alkylene, —(CH 2 ) m —CH═CH—(CH 2 ) n — or —(CH 2 ) x —CH(OH)—(CH 2 ) y —; M is phenyl, phenyl(thio, oxy, amino), diphenylmethyl, diphenylmethyl(thio, oxy, amino), and pharmaceutical composition comprising them as an active ingradient. The compounds of the formula (I) can combine PGE 2 receptor and exhibit the activity to antagonize or agonize for PGE 2 receptor. Therefore, they are useful as anti-hyperlipemia, for the prevention of abortion, for analgesics, as antidiarrheals, sleep inducer, diuretic, anti-diabetes, abortient, cathartics, antiulcer, anti-gastritis or antihypertensive etc.

What we claim is:  
     
         1 ) A naphthyloxyacetic acid derivative of the general formula. (I)  
       
         
           
           
               
               
           
         
       
       wherein A is 
 (i) hydrogen,  
 (ii) —(C1-4 alkylene)—COOR 1  in which R 1  is hydrogen or C1-4 alkyl,  
 (iii) —(C1-4 alkylene)—CONR 2 R 3  in which R 2  and R 3  each, independently, is hydrogen or C1-4 alkyl,  
 (iv) —(C1-4 alkylene)—OH,  
 (v) —(C1-4 alkylene)-tetrazolyl or  
 (vi) —(C1-4 alkylene)—CN;  
 E is (i) single bond or  
 (ii) C1-6 alkylene;  
 G is —S—, —SO—, —SO 2 —, —O— or —NR 4 — in which, R 4  is hydrogen or C1-4 alkyl;  
 L is (i) C1-6 alkylene,  
 (ii) R-(CH 2 ) m —CH═CH—(CH 2 ) n — in which m is 0 or an integer of 1-3, n is 0 or an integer of 1-3 or  
 (iii) —(CH 2 ) x —CH(OH)—(CH 2 ) y — in which x is an integer of 1-3, y is 0 or an integer of 1-3;  
 M is  
                     
 in which each phenyl group may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or trifluoromethyl;  
 in the formula  
                     
                     
 is single bond or double bond;  
 with the proviso that,  
 (1) when G is —SO— or —SO 2 —, M is neither  
                     
 in which each phenyl group may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or trifluoromethyl,  
 (2) when m in L is 0, G is —SO— or —SO 2 —,  
 (3) when n in L is 0, M is  
                     
 in which each phenyl group may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or trifluoromethyl,  
 (4) when y in L is 0, M is  
                     
 in which each phenyl group may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or trifluoromethyl,  
 (5) when A is hydrogen, L is —(CH 2 ) m —CH═CH—(CH 2 ) n — or —(CH 2 ) x —CH(OH)—(CH 2 ) y — in which m, n, x and y are the same meaning as defined in  claim 1 , and  
 (6) tetrazolyl in A is  
                     
 or non-toxic salt thereof, non-toxic acid addition salt thereof or their hydrate.  
 
     
     
         2 ) A compound according to  claim 1 , wherein A is —(C1-4 alkylene)—COOR 1 .  
     
     
         3 ) A compound according to  claim 1 , wherein A is —(C1-4 alkylene)—CONR 2  R 3 , —C1-4 alkylene)—OH, —(C1-4 alkylene)-tetrazolyl or —(C1-4 alkylene)—CN.  
     
     
         4 ) A compound according to  claim 1 , wherein A is hydrogen.  
     
     
         5 ) A compound according to claim  1 - 5 , wherein L is —(CH 2 ) m —CH═CH—(CH 2 ) n —or —(CH 2 ) x —CH(OH)—(CH 2 ) y —.  
     
     
         6 ) A compound according to  claim 5 , wherein G is —S—, —SO— or —SO 2 —.  
     
     
         7 ) A compound according to  claim 5 , wherein G is —O—.  
     
     
         8 ) A compound according to  claim 5 , wherein G is —NR 4 —.  
     
     
         9 ) A compound according to  claim 6 , which is 
 (1) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2RS-propanol,    (2) 1-[2-(5-hydroxy-1-naphthyl)ethylsulfinyl]-3-phenoxy-2RS-propanol,    (3) 1-[2-(5-hydroxy-1-naphthyl)ethylsulfonyl]-3-phenoxy-2RS-propanol,    (4) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2R-propanol,    (5) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2S-propanol,    (6) 1-(5-hydroxy-1-naphthyl)methylthio-3-phenoxy-2RS-propanol,    (7) 1-(5-hydroxy-1-naphthyl)methylsulfinyl-3-phenoxy-2RS-propanol,    (8) 1-(5-hydroxy-1-naphthyl)methylsulfonyl-3-phenoxy-2RS-propanol,    (9) 2-[3-(5-hydroxy-1-naphthyl)propylthio]-1-phenyl-1 RS-ethanol,    (10) 2-[3-(5-hydroxy-1-naphthyl)propylsulfinyl]-1-phenyl-1 RS-ethanol,    (11) 2-[3-(5-hydroxy-1-naphthyl)propylsulfonyl]-1-phenyl-1 RS-ethanol,    (12) 1-(5-hydroxy-1-naphthyl)thio-3-phenoxy-2RS-propanol,    (13) 1-(5-hydroxy-1-naphthyl)sulfinyl-3-phenoxy-2RS-propanol,    (14) 1-(5-hydroxy-1-naphthyl)sulfonyl-3-phenoxy-2RS-propanol,    (15) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-chlorophenoxy)-2RS-propanol,    (16) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-methylphenoxy)-2RS-propanol,    (17) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-methoxyphenoxy)-2RS-propanol,    (18) 1-[2-(5-hydroxy-1-naphthyl)ethylthiol-3-diphenylmethoxy-2RS-propanol,    (19) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-[1-phenyl-1-(4-chlorophenyl)-methoxy]-2RS-propanol,    (20) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenylthio-2RS-propanol,    (21) 1-(5-hydroxy-1-naphthyl)methylthio-3-diphenylmethoxy-2RS-propanol,    (22) 1-(5-hydroxy-1-naphthyl)methylthio-3-[1-phenyl-1-(4-chlorophenyl)-methoxy]-2RS-propanol,    (23) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}-acetic acid methyl ester,    (24) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyloxy}acetic acid methyl ester,    (25)2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl]-1-naphthyloxy}-acetic acid methyl ester,    (26) 2-{5-(2-(2R-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,    (27) 2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,    (28) 2-[5-(2RS-hydroxy-3-phenoxypropylthio)methyl-1-naphthyloxy]acetic acid methyl ester,    (29) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)methyl-1-naphthyloxy]acetic acid methyl ester,    (30) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]acetic acid methyl ester,    (31) 2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}acetic acid methyl ester,    (32) 2-{5-[3-(2RS-hydroxy-2-phenylethylsulfinyl)propyl]-1-naphthyloxy}acetic acid methyl ester,    (33) 2-{5-[3-(2RS-hydroxy-2-phenylethylsulfonyl)propyl]-1-naphthyloxy}acetic acid methyl ester,    (34) 2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]acetic acid methyl ester,    (35) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]acetic acid methyl ester,    (36) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy]acetic acid methyl ester,    (37) 2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic acid methyl ester,    (38) 2-[5-(3-styrylsulfinylpropyl)-1-naphthyloxy]acetic acid methyl ester,    (39) 2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,    (40) 2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,    (41) 2-{5-[2-(2RS-hydroxy-3-(4-methoxyphenoxy)propylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,    (42) 2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-1-naphthyloxy}-acetic acid methyl ester,    (43) 2-{5-[2-(2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio)-ethyl]-1-naphthyloxy}acetic acid methyl ester,    (44) 2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,    (45) 2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio)methyl-1-naphthyloxy]-acetic acid methyl ester,    (46) 2-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio]-methyl-1-naphthyloxy}acetic acid methyl ester,    (47) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}-acetic acid,    (48) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyloxy}acetic acid,    (49) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl]-1-naphthyloxy}-acetic acid,    (50) 2-{5-[2-(2R-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}-acetic acid,    (51) 2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}-acetic acid,    (52) 2-[5-(2RS-hydroxy-3-phenoxypropylthio)methyl-1-naphthyloxy]-acetic acid,    (53) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)methyl-1-naphthyloxy]acetic acid,    (54) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]acetic acid,    (55) 2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}acetic acid,    (56) 2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]acetic acid,    (57) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]acetic acid,    (58) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy] acetic acid,    (59) 2-[5-(3-styrylsulfinylpropyl)-1-naphthyloxy]acetic acid,    (60) 2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic acid,    (61) 2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-naphthyloxy}acetic acid,    (62) 2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-1-naphthyloxy}acetic acid,    (63) 2-{5-[2-(2RS-hydroxy-3-(4-methyoxyphenoxy)propylthio)ethyl]-1-naphthyloxy}acetic acid,    (64) 2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-1-naphthyloxy}-acetic acid,    (65) 2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-1-naphthyloxy}acetic acid,    (66) 2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio) methyl-1-naphthyloxy]acetic acid,    (67) 1-cyanlomethoxy-5-[2-(2RS-hydroxy-3-phenoxypropylthio)-ethyl]naphthalene,    (68) 1-cyano methoxy-5-{2-[2RS-hydroxy-3-(4-chlorophenoxy)propylthio]ethyl}-naphthalene,    (69) 1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-methylphenoxy)propylthio]ethyl} naphthalene,    (70) 1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-methoxyphenoxy)-propylthio]ethyl}naphthalene,    (71) 1-cyanomethoxy-5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)-ethyl]naphthalene,    (72) 1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenylthiopropylthio)-ethyl]naphthalene,    (73) 1-cyanomethoxy-5-[(2RS-hydroxy-3-diphenylmethoxy)propylthiomethyl]-naphthalene,    (74) 2-{5-[2-(2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio)-ethyl]-1-naphthyloxy}ethanol,    (75) 2-{5-[2-(2RS-hydroxy-3-phenylaminopropylthio)ethyl]-1-naphthyloxy}ethanol,    (76) 1-(tetrazol-5-ylmethoxy)-5-{2-{2RS-hydroxy-3-(4-methyoxyphenoxy)-propylthio]ethyl}naphthalene,    (77) N-methyl-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)-propylthio]methyl-1-naphthyloxy}acetic acid amide,    (78) 1-{2-[5-hydroxy-1-(1,2,3,4-tetrahydronaphthyl)]ethylthio}-3-phenoxy-2RS-propanol,    (79) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tetrahydro-naphthyloxy)}acetic acid methyl ester,    (80) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tetrahydro-naphthyloxy)}acetic acid or    (81) 1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-5,6,7,8-tetrahydronaphthalene.    
     
     
         10 ) A compound according to  claim 7 , which is 
 (1)1-[2-(5-hydroxy-1-naphthyl)ethoxy]-3-phenoxy-2RS-propanol,    (2) 2-{5-[2-(2RS-hydroxy-3-phenoxypropoxy)ethyl]-1-naphthyloxy}acetic acid methyl ester or    (3) 2-{5-[2-(2RS-hydroxy-3-phenoxypropoxy)ethyl]-1-naphthyloxy}acetic acid.    
     
     
         11 ) A compound according to  claim 8 , which is 
 (1) 1-[2-(5-hydroxy-1-naphthyl)ethylamino]-3-phenoxy-2RS-propanol or    (2) 2-{5-[2-(2RS-hydroxy-3-pheoxypropylamino)ethyl]-1-naphthyloxy}acetic acid.    
     
     
         12 ) A pharmaceutical composition which comprises a naphthyloxyacetic acid derivative of the formula (I) depicted in  claim 1 , non-toxic salt thereof, non-toxic acid addition salt thereof or their hydrate.  
     
     
         13 ) A prostaglandin E2 antagonist or agonist which comprises a naphthyloxyacetic acid derivative of the formula (I) depicted in  claim 1 , non-toxic salt thereof, non-toxic acid addition salt thereof or their hydrate.