US 2008/0242656 A1 · N-Substituted-N-Sulfonylaminocyclopropane 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 N-substituted-N-sulfonylaminocyclopropane compound of formula (1) wherein R1 is —W-A1-W1-A2, W is —(CH2)m—X—(CH2)n—, wherein W1 is —(CH2)m1—X1—(CH2)n1—, m, m1, n and n1 are the same or different and each is 0 to 6, X and X1 are the same or different and each is a single bond, etc., A1 is an optionally substituted C3-14 hydrocarbon ring group, etc. and A2 is a substituted C3-14 hydrocarbon ring group etc.; R2 is —(CH2)r—CO—R8, etc., wherein r is 0 to 6 and R8 is a C1-6 alkoxy group, etc.; R3 and R4 are the same or different and each is a hydrogen atom, a C1-6 alkyl group, etc.; and R5 is —CO2R21, etc.; R30 and R31 are the same or different and each is a hydrogen atom, etc.; or a prodrug thereof or a pharmaceutically acceptable salt thereof.

An N-substituted-N-sulfonylaminocyclopropane compound represented by the formula (1)

wherein
R1 is
—W-A1-W1-A2
wherein
W is —(CH2)m—X—(CH2)n—,
W1 is —(CH2)m1—X1—(CH2)n1—,
wherein
m, n, m1 and n1 are the same or different and each is selected from 0 and an integer ranging from 1 to 6,
X and X1 are the same or different and each is a linker selected from the following group A,
group A:
(a) a single bond,
(b) a C1-6 alkylene group,
(c) a C2-6 alkenylene group,
(d) a C2-6 alkynylene group,
(e) —O—,
(f) —N(R6)—,
(g) —S(O)m3—,
(h) —CO—,
(i) —COO—,
(j) —OCO—,
(k) —CON(R6)—,
(l) —N(R6)CO—,
(m) —SO2N(R6)—,
(n) —N(R6)SO2—,
(o) —N(R6)CON(R7)—,
(p) —N(R6)SO2N(R7)—,
(q) —OCON(R6)—,
(r) —N(R6)COO—,
and
(s) —S(O)m3—(CH2)n3—CO—,
(wherein R6 and R7 are the same or different and each is selected from a hydrogen atom, a C1-6 alkyl group optionally substituted by halogen atoms or hydroxyl groups, a C3-14 hydrocarbon ring group and a heterocyclic group, m3 is selected from 0 and an integer ranging from 1 to 2, and n3 is an integer ranging from 1 to 2),
A1 is selected from an optionally substituted C3-14 hydrocarbon ring group and an optionally substituted heterocyclic group,
and
A2 is selected from a substituted C3-14 hydrocarbon ring group and a substituted heterocyclic group,
or A1 and A2 may be taken together with a substituent thereof to form an optionally substituted fused C6-14 hydrocarbon ring group;
R2 is selected from
(1) —(CH2)m5—X5—(CH2)n5-A5
and
(2) —(CH2)m5—X5—(CH2)n5—R32
(wherein m5 and n5 are the same or different and each is selected from 0 and an integer ranging from 1 to 6,
X5 are the same or different and each is a linker selected from the above-mentioned group A,
A5 is selected from an optionally substituted C3-14 hydrocarbon ring group and an optionally substituted heterocyclic group,
and
R32 is a substituent selected from the following group B, provided that when m5 and n5 are 0 and X5 is a single bond, then R32 is not a hydrogen atom);
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 amide group,
(i) a C2-6 acyl group,
(j) a halogenated C1-6alkyl group,
(k) a C1-6 alkyl group optionally substituted by hydroxyl groups,
(l) a C2-6 alkenyl group optionally substituted by halogen atoms,
(m) a C2-6 alkynyl group,
(n) a C1-6alkoxy group optionally substituted by hydroxyl groups
(o) a C1-6 alkoxy-C1-6 alkyl group,
(p) a C1-6 alkoxy-carbonyl group,
(q) a C1-6 alkyl-aminocarbonyl group optionally substituted by halogen atoms,
(r) a mono(C1-6 alkyl)amino group,
(s) a di(C1-6 alkyl)amino group,
(t) a C1-6 alkyl-carbonylamino group optionally substituted by halogen atoms,
(u) a C1-6alkylsulfonyl group,
and
(v) a C1-6 alkylsulfonylamino group,
or R2 and R3 and the cyclopropane ring may be taken together to form an optionally further substituted fused ring);
R3 and R4 are the same or different and each is selected from
(1) —(CH2)m2—X2—(CH2)n2-A4
(wherein m2 and n2 are the same or different and each is selected from 0 and an integer ranging from 1 to 6, X2 is a linker selected from the above-mentioned group A, and A4 is selected from an optionally substituted C3-14 hydrocarbon ring group and an optionally substituted heterocyclic group)
and
(2) —(CH2)m6—X6—(CH2)n6—R33
(wherein m6 and n6 are the same or different and each is selected from 0 and an integer ranging from 1 to 6, X6 is a linker selected from the above-mentioned group A, and R33 is a substituent selected from the above-mentioned group B);
or A4 and R33 may be taken together to form an optionally substituted fused ring group, and R3 and R4 may be taken together with a carbon atom bonded thereto to form the following ring
(wherein m10 is an integer ranging from 1 to 6),
provided that R3 and R4 are not hydrogen atoms at the same time;
R5 is selected from
(1) —CO2R21,
(2) —C(O)NHOR21,
(3) —C(O)NH—SO2—R21,
(4) —C(O)NHR21,
(5) —SH,
(6) —CH2CO2R21,
(7) —C(O)R21,
(8) —N(OH)COR21,
(9) —SN2H2R21,
(10) —SONHR21,
(11) —CH2CO2H,
(12) —PO(OH)2,
(13) —PO(OH)NHR21,
(14) —CH2SH,
(15) —CH2OH,
(16) —(CH2)r1—PO(OH)—(CH2)r2—R21,
(17) —NHR21,
(18) —NH—NHR21,
and
(19) —(CH2)r1—R50
(wherein r1 and r2 are the same or different and each is selected from 0 and an integer ranging from 1 to 6,
R21 is selected from
(1) a hydrogen atom,
(2) an optionally substituted C1-10 alkyl group,
(3) an optionally substituted C6-14 aryl-C1-6 alkyl group
and
(4) —(CH2)m7—X7—(CH2)n7—R34
(wherein m7 and n7 are the same or different and each is selected from 0 and an integer ranging from 1 to 6, X7 is a linker selected from the above-mentioned group A,
R34 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 amide group,
(i) a C2-6 acyl group,
(j) a halogenated C1-6 alkyl group,
(k) a C1-6 alkyl group optionally substituted by hydroxyl groups,
(l) a C2-6 alkenyl group optionally substituted by halogen atoms,
(m) a C2-6alkynyl group,
(n) a C2-6 alkoxy group optionally substituted by hydroxyl groups,
(o) a C1-6 alkoxy-C1-6 alkyl group,
(p) a C1-6 alkoxy-carbonyl group,
(q) a C1-6 alkyl-aminocarbonyl group optionally substituted by halogen atoms,
(r) a mono(C1-6 alkyl)amino group,
(s) a di(C1-6 alkyl)amino group,
(t) a C1-6 alkyl-carbonylamino group optionally substituted by halogen atoms,
(u) a C1-6 alkylsulfonyl group,
(v) a C1-6 alkylsulfonylamino group,
(w) a C3-14 hydrocarbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group B,
and
(x) a heterocyclic group optionally substituted by 1 to 5 substituents selected from the above-mentioned group B),
and
R50 is selected from an optionally substituted C3-14 hydrocarbon ring group and an optionally substituted heterocyclic group;
or R21 of —C(O)NHR21, A4 and the cyclopropane ring may be taken together to form an optionally further substituted fused ring;
R30 and R31 are the same or different and each is selected from
(1) —(CH2)m8—X8—(CH2)n8-A6
(wherein m8 and n8 are the same or different and each is 0 or an integer ranging from 1 to 6, X8 is a linker selected from the above-mentioned group A, and A6 is selected from an optionally substituted C3-14 hydrocarbon ring group and an optionally substituted heterocyclic group),
and
(2) —(CH2)m9—X9—(CH2)n9—R36
(wherein m9 and n9 are the same or different and each is selected from 0 and an integer ranging from 1 to 6, X9 is a linker selected from the above-mentioned group A, and R36 is a substituent selected from the above-mentioned group B);
or A4, R36 and the cyclopropane ring may be taken together to form an optionally further substituted fused ring,
or R21 of —CO2R21, R30 and the cyclopropane ring may be taken together to form an optionally further substituted fused ring,
or further, R30 and R31 may be taken together with a carbon atom bonded thereto to form the following ring
(wherein m11 is an integer ranging from 1 to 6);
or a pharmaceutically acceptable salt thereof.

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N-Substituted-N-Sulfonylaminocyclopropane Compounds and Pharmaceutical Use Thereof

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N-Substituted-N-Sulfonylaminocyclopropane Compounds and Pharmaceutical Use Thereof

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Abstract

Claims27