US 7,351,825 B2 · 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 R1 is —(CH2)m—X—(CH2)n-A1 etc., wherein m and n are the same or different and each is 0 to 6, X is a single bond, etc. and A1 is a substituted C3-14 hydrocarbon ring group, etc.; R2 and R3 are the same or different and each is a hydrogen atom, —(CH2)p—X1—(CH2)q-A2, etc., wherein p and q are the same or different and each is 0 to 6, X1 is a single bond, etc. and A2 is an optionally substituted C3-14 hydrocarbon ring group, etc.; R4 is —CO2R9, etc., wherein R9 is a hydrogen atom, etc.; and R20 and R21 are the same or different and each is a hydrogen atom, —(CH2)m12—X12—(CH2)m12—R30, etc., wherein m12 and m12 are the same or different and each is 0 to 6, X12 is a single bond, etc. and R30 is a hydrogen atom, etc.; or a prodrug thereof or a pharmaceutically acceptable salt thereof.

A cyclopropane compound of formula (1):

wherein
R1 is
—(CH2)m—X—(CH2)n-A1,
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 C1-6 alkylene group,
(c) a C2-6 alkenylene group,
(d) a C2-6 alkynylene group,
(e) —O—,
(f) —N(R5)—,
(g) —S(O)m1—,
(j) —OCO—,
(l) —N(R5)CO—,
(m) —SO2N(R5)—,
(n) —N(R5)SO2—,
(o) —N(R5)CON(R6)—,
(p) —N(R5)SO2N(R6)—,
(q) —OCON(R5)—,
(r) —N(R5)COO—,
and
(s) —S(O)m1—(CH2)n1—CO—;
wherein
R5 and R6 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,
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
A1 is selected from a substituted C3-14 hydrocarbon ring group and a substituted heterocyclic group;
R2 and R3 are the same or different and each is selected from
(1) —(CH2)p—X1—(CH2)q-A2,
wherein
p and q are the same or different and each is selected from 0 and an integer ranging from 1 to 6,
X1 is a linker selected from the above-mentioned group A and
A2 is selected from an optionally substituted C3-14 hydrocarbon ring group and an optionally substituted heterocyclic group, and
(2) —(CH2)m8—X8—(CH2)n8—R27,
wherein
m8 and n8 are the same or different and each is selected from 0 and an integer ranging from 1 to 6,
X8 is a linker selected from the above-mentioned group A and
R27 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,
(g) an amino 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 C2-6 alkynyl group,
(n) a C1-6 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, and
(v) a C1-6 alkylsulfonylamino group;
or A2 and R27 may be taken together to form an optionally substituted fused ring group,
or R2 and R3 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 R2 and R3 are not hydrogen atoms at the same time;
R4 is selected from
(1) —CO2R9,
(2) —C(O)NHOR9,
(3) —C(O)NH—SO2—R9,
(4) —C(O)NHR9,
(5) —SH,
(6) —CH2CO2R9,
(7) —C(O)R9,
(8) —N(OH)COR9,
(9) —SN2H2R9,
(10) —SONHR9,
(11) —CH2CO2H,
(12) —PO(OH)2,
(13) —PO(OH)NHR9,
(14) —CH2SH,
(15) —CH2OH,
(16) —(CH2)r1—PO(OH)—(CH2)r2—R9,
(17) —NHR9,
(18) —NH—NHR9,
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,
R9 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)m9—X9—(CH2)n9—R28;
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
R28 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 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 C2-6 alkynyl group,
(n) a C1-6 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 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
R50 is selected from an optionally substituted C3-14 hydrocarbon ring group and an optionally substituted heterocyclic group;
or R9 of —C(O)NHR9, A2 and the cyclopropane ring may be taken together to form an optionally further substituted fused ring;
R20 and R21 are the same or different and each is selected from
(1) —(CH2)m10—X10—(CH2)n10-A3,
wherein
m10 and n10 are the same or different and each is selected from 0 and an integer ranging from 1 to 6,
X10 is a linker selected from the above-mentioned group A and
A3 is selected from an optionally substituted C3-14 hydrocarbon ring group and an optionally substituted heterocyclic group, and
—(CH2)m12—X12—(CH2)n12—R30,
wherein
m12 and n12 are the same or different and each is selected from 0 and an integer ranging from 1 to 6,
X12 is a linker selected from the above-mentioned group A and
R30 is a substituent selected from the above-mentioned group B;
or A2, R30 and the cyclopropane ring may be taken together to form a optionally further substituted fused ring,
or R9 of —CO2R9, R20 and the cyclopropane ring may be taken together to form an optionally further substituted fused ring,
or R20 and R21 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.

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Cyclopropane compounds and pharmaceutical use thereof

Life of this patent

Cyclopropane compounds and pharmaceutical use thereof

Life of this patent

Abstract

Claims33