Cyclopropane compounds and pharmaceutical use thereof

Abstract

The present invention provides a compound having aggrecanase inhibitory activity and MMP-13 inhibitory activity, and useful as a therapeutic agent for osteoarthritis, rheumatoid arthritis and the like, more specifically, a cyclopropane compound of formula (1): wherein R 1 is —(CH 2 ) m —X—(CH 2 ) n -A 1 etc., wherein m and n are the same or different and each is 0 to 6, X is a single bond, etc. and A 1 is a substituted C 3-14 hydrocarbon ring group, etc.; R 2 and R 3 are the same or different and each is a hydrogen atom, —(CH 2 ) p —X 1 —(CH 2 ) q -A 2 , etc., wherein p and q are the same or different and each is 0 to 6, X 1 is a single bond, etc. and A 2 is an optionally substituted C 3-14 hydrocarbon ring group, etc.; R 4 is —CO 2 R 9 , etc., wherein R 9 is a hydrogen atom, etc.; and R 20 and R 21 are the same or different and each is a hydrogen atom, —(CH 2 ) m12 —X 12 —(CH 2 ) m12 —R 30 etc., wherein m12 and m12 are the same or different and each is 0 to 6, X 12 is a single bond, etc. and R 30 is a hydrogen atom, etc.; or a prodrug thereof or a pharmaceutically acceptable salt thereof.

1 . A cyclopropane compound of formula (1): 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is selected from 
 (1) a substituted C 1-6  alkyl group 
 and 
 (2) —(CH 2 ) m —X—(CH 2 ) n -A 1 , 
 wherein
 m and n are the same or different and each is selected from 0 and an integer ranging from 1 to 6, 
 X is a linker selected from the following group A, 
 
 group A: 
 (a) a single bond, 
 (b) a C 1-6  alkylene group, 
 (c) a C 2-6  alkenylene group, 
 (d) a C 2-6  alkynylene group, 
 (e) —O—, 
 (f) —N(R 5 )—, 
 (g) —S(O) m1 —, 
 (h) —CO—, 
 (i) —COO—, 
 (j) —OCO—, 
 (k) —CON(R 5 )—, 
 (l) —N(R 5 )CO—, 
 (m) —SO 2 N(R 5 )—, 
 (n) —N(R 5 )SO 2 —, 
 (o) —N(R 5 )CON(R 6 )—, 
 (p) —N(R 5 )SO 2 N(R 6 )—, 
 (q) —OCON(R 5 )—, 
 (r) —N(R 5 )COO—, 
 and 
 (s) —S(O) m1 —(CH 2 ) n1 —CO—;
 wherein
 R 5  and R 6  are the same or different and each is selected from a hydrogen atom, a C 1-6  alkyl group optionally substituted by halogen atoms or hydroxyl groups, a C 3-14  hydrocarbon ring group and a heterocyclic group, 
 m1 is selected from 0 and an integer ranging from 1 to 2 and 
 n1 is selected from an integer ranging from 1 to 2, and 
 
 A 1  is selected from a substituted C 3-14  hydrocarbon ring group and a substituted heterocyclic group; 
 
 R 2  and R 3  are the same or different and each is selected from 
 (1) —(CH 2 ) p —X 1 —(CH 2 ) q -A 2 , 
 wherein
 p and q are the same or different and each is selected from 0 and an integer ranging from 1 to 6, 
 X 1  is a linker selected from the above-mentioned group A and 
 A 2  is selected from an optionally substituted C 3-14  hydrocarbon ring group and an optionally substituted heterocyclic group, 
 
 and 
 (2) —(CH 2 ) m8 —X 8 —(CH 2 ) n8 —R 27 , 
 wherein
 m8 and n8 are the same or different and each is selected from 0 and an integer ranging from 1 to 6, 
 X 8  is a linker selected from the above-mentioned group A and 
 R 27  is a substituent selected from the following group B, 
 
 group B: 
 (a) a hydrogen atom, 
 (b) a halogen atom, 
 (c) a hydroxyl group, 
 (d) a nitro group, 
 (e) a cyano group, 
 (f) a carboxyl group, 
 (g) an amino group, 
 (h) an amido group, 
 (i) a C 2-6  acyl group, 
 (j) a halogenated C 1-6  alkyl group, 
 (k) a C 1-6  alkyl group optionally substituted by hydroxyl groups, 
 (l) a C 2-6  alkenyl group optionally substituted by halogen atoms, 
 (m) a C 2-6  alkynyl group, 
 (n) a C 1-6  alkoxy group optionally substituted by hydroxyl groups, 
 (o) a C 1-6  alkoxy-C 1-6  alkyl group, 
 (p) a C 1-6  alkoxy-carbonyl group, 
 (q) a C 1-6  alkyl-aminocarbonyl group optionally substituted by halogen atoms, 
 (r) a mono(C 1-6  alkyl)amino group, 
 (s) a di(C 1-6  alkyl)amino group, 
 (t) a C 1-6  alkyl-carbonylamino group optionally substituted by halogen atoms, 
 (u) a C 1-6  alkylsulfonyl group, 
 and 
 (v) a C 1-6  alkylsulfonylamino group; 
 or A 2  and R 27  may be taken together to form an optionally substituted fused ring group, 
 or R 2  and R 3  may be taken together with a carbon atom bonded thereto to form the following ring 
 
     
       
         
         
             
             
         
       
       wherein m13 is selected from an integer ranging from 1 to 6, 
       provided that R 2  and R 3  are not hydrogen atoms at the same time; 
       R 4  is selected from 
       (1) —CO 2 R 9 , 
       (2) —C(O)NHOR 9 , 
       (3) —C(O)NH—SO 2 —R 9 , 
       (4) —C(O)NHR 9 , 
       (5) —SH, 
       (6) —CH 2 CO 2 R 9 , 
       (7) —C(O)R 9 , 
       (8) —N(OH)COR 9 , 
       (9) —SN 2 H 2 R 9 , 
       (10) —SONHR 9 , 
       (11) —CH 2 CO 2 H, 
       (12) —PO(OH) 2 , 
       (13) —PO(OH)NHR 9 , 
       (14) —CH 2 SH, 
       (15) —CH 2 OH, 
       (16) —(CH 2 ) r1 —PO(OH)—(CH 2 ) r2 —R 9 , 
       (17) —NHR 9 , 
       (18) —NH—NHR 9 , 
       and 
       (19) —(CH 2 ) r1 —R 50 ; 
       wherein
 r1 and r2 are the same or different and each is selected from 0 and an integer ranging from 1 to 6, 
 R 9  is selected from 
 (1) a hydrogen atom, 
 (2) an optionally substituted C 1-10  alkyl group, 
 (3) an optionally substituted C 6-14  aryl-C 1-6  alkyl groups 
 and 
 (4) —(CH 2 ) m9 —X 9 —(CH 2 ) n9 —R 28 ; 
 wherein
 m9 and n9 are the same or different and each is selected from 0 and an integer ranging from 1 to 6, 
 X 9  is a linker selected from the above-mentioned group A and 
 R 28  is a substituent selected from the following group C, 
 
 
       group C: 
       (a) a hydrogen atom, 
       (b) a halogen atom, 
       (c) a hydroxyl group, 
       (d) a nitro group, 
       (e) a cyano group, 
       (f) a carboxyl group, 
       (g) an amino group, 
       (h) an amido group, 
       (i) a C 2-6  acyl group, 
       (j) a halogenated C 1-6  alkyl group, 
       (k) a C 1-6  alkyl group optionally substituted by hydroxyl groups, 
       (l) a C 2-6  alkenyl group optionally substituted by halogen atoms, 
       (m) a C 2-6  alkynyl group, 
       (n) a C 1-6  alkoxy group optionally substituted by hydroxyl groups, 
       (o) a C 1-6  alkoxy-C 1-6  alkyl group, 
       (p) a C 1-6  alkoxy-carbonyl group, 
       (q) a C 1-6  alkyl-aminocarbonyl group optionally substituted by halogen atoms, 
       (r) a mono(C 1-6  alkyl)amino group, 
       (s) a di(C 1-6  alkyl)amino group, 
       (t) a C 1-6  alkyl-carbonylamino group optionally substituted by halogen atoms, 
       (u) a C 1-6  alkylsulfonyl group, 
       (v) a C 1-6  alkylsulfonylamino group, 
       (w) a C 3-14  hydrocarbon ring group optionally substituted by 1 to 5 substituent(s) selected from the above-mentioned group B, and 
       (x) a heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above-mentioned group B, 
       and
 R 50  is selected from an optionally substituted C 3-14  hydrocarbon ring group and an optionally substituted heterocyclic group; 
 
       or R 9  of —C(O)NHR 9 , A 2  and the cyclopropane ring may be taken together to form an optionally further substituted fused ring; 
       R 20  and R 21  are the same or different and each is selected from 
       (1) —(CH 2 ) m10 —X 10 —(CH 2 ) n10 -A 3 , 
       wherein
 m10 and n10 are the same or different and each is selected from 0 and an integer ranging from 1 to 6, 
 X 10  is a linker selected from the above-mentioned group A 
 and 
 A 3  is selected from an optionally substituted C 3-14  hydrocarbon ring group and an optionally substituted heterocyclic group, 
 
       and 
       (2) —(CH 2 ) m12 —X 12 —(CH 2 ) n12 —R 30 , 
       wherein
 m12 and n12 are the same or different and each is selected from 0 and an integer ranging from 1 to 6, 
 X 12  is a linker selected from the above-mentioned group A 
 and 
 R 30  is a substituent selected from the above-mentioned group B; 
 
       or A 2 , R 30  and the cyclopropane ring may be taken together to form a optionally further substituted fused ring, 
       or R 9  of —CO 2 R 9 , R 20  and the cyclopropane ring may be taken together to form an optionally further substituted fused ring, 
       or R 20  and R 21  may be taken together with a carbon atom bonded thereto to form the following ring 
     
     
       
         
         
             
             
         
       
       wherein m14 is selected from an integer ranging from 1 to 6; 
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       2 - 34 . (canceled)