US 2003/0144292 A1Published application

Carbocyclic side chain containing, N-substituted metalloprotease inhibitors

OwnerMichael George Natchus, Stanislaw Pikul +3inventors

InventorsMichael George Natchus, Stanislaw Pikul, Neil Gregory Almstead, Matthew John Laufersweiler, Biswanath De

Life of this patent

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Abstract

The compounds have a structure according to the following Formula (I): 1 are effective in treating conditions characterized by excess activity of metalloprotease enzymes.

Claims30

Dependent claims

A compound having a structure according to the following Formula (I):

68
wherein:
(A) R1 is selected from —OH and —NHOH;
(B) R2 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
or R2 and A form a ring as described in (D);
(C) R3 is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxyl, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
(D) A is a substituted or unsubstituted, monocyclic cycloalkyl having from 3 to 8 ring atoms;
or A is bonded to R2 where, together, they form a substituted or unsubstituted, monocyclic cycloalkyl having from 3 to 8 ring atoms;
(E) E and E′ are bonded to the same or different ring carbon atoms of A and are independently selected from a covalent bond, C1-C4 alkyl, aryl, heteroaryl, heteroalkyl, —O—, —S—, —N(R4)—, ═N, C═O, —C(═O)O—, —C(═O)N(R4)—, —SO2— and —C(═S)N(R4)—, where R4 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
or R4 and L join to form a ring as described in (F)(2);
(F) (1) L and L′ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, —C(═O)R5, —C(═O)OR5, —C(═O)NR5R5′ and —SO2R5, where R5 and R5′ each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
or
(2) L and R4 join to form an optionally substituted heterocyclic ring containing from 3 to 8 ring atoms of which from 1 to 3 are heteroatoms;
or
(3) L and L′ join to form an optionally substituted cycloalkyl containing from 3 to 8 ring atoms or an optionally substituted hetercycloalkyl containing from 3 to 8 ring atoms of which from 1 to 3 are heteroatoms;
(G) G is selected from —S—, —O—, —N(R6)—, —C(R6)═C(R6′)—, —N═C(R6)— and —N═N—, where R6 and R6′ each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;
and
(H) Z is selected from:
(1) cycloalkyl and heterocycloalkyl;
(2) -J-(CR7R7′)aR8 where:
(a) a is from 0 to about 4;
(b) J is selected from —C≡C—, —CH═CH—, —N═N—, —O—, —S— and —SO2—;
(c) each R7 and R7′ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy and alkoxy;
and
(d) R8 is selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl;
and, if J is —C≡C— or —CH═CH—, then R8 may also be selected from —CONR9R9′ where (i) R9 and R9′ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, or (ii) R9 and R9′, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
(3) —NR10R10′ where:
(a) R10 and R10′ each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl and —C(═O)-Q-(CR11R11′)bR12 where:
(i) b is from 0 to about 4;
(ii) Q is selected from a covalent bond and —N(R13)—;
and
(iii) each R11 and R11′ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy and alkoxy;
either (A) R12 and R13 each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, or (B) R12 and R13, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
or R10 and R13, together with the nitrogen atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 2 to 3 are heteroatoms;
or
(b) R10 and R10′, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
and
(4)
69
where:
(a) A′ and J′ are independently selected from —CH— and —N—;
(b) G′ is selected from —S—, —O—, —N(R15)—, —C(R15)═C(R15′)—, —N═C(R15)— and —N═N—, where R15 and R15′ each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;
(c) c is from 0 to about 4;
(d) each R14 and R14′ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy and alkoxy;
(e) D is selected from a covalent bond, —O—, —SOd—, —C(═O)—, —C(═O)N(R16)—, —N(R16)—, and —N(R16)C(═O)—;
where d is from 0 to 2 and R16 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkyl;
and
(f) T is —(CR17R17′)e—R18 where e is from 0 to about 4;
each R17 and R17′ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy;
and R18 is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;
or R17 and R18, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms;
or R16 and R18, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms;
or an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof.

50 more elements

A compound having a structure according to the following Formula (I):

71
wherein:
(A) R1 is selected from —OH and —NHOH;
(B) R2 is selected from hydrogen and alkyl;
or R2 and A form a ring as described in (D);
(C) R3 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
(D) A is a substituted or unsubstituted, monocyclic cycloalkyl having 5 or 6 ring atoms;
or A is bonded to R2 where, together, they form a substituted or unsubstituted, monocyclic cycloalkyl having 5 or 6 ring atoms;
(E) E and E′ are bonded to the same or different ring carbon atoms of A;
E is selected from —O—, —S—, NR4 and —SO2—, where R4 is selected from hydrogen, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
and E′ is a covalent bond;
(F) (1) L is selected from hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, —C(═O)R5, —C(═O)OR5, —C(═O)NR5R5′ and —SO2R5, where R5 is selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
and L′ is hydrogen;
or
(2) L and R4 join to form an optionally substituted heterocyclic ring containing from 3 to 8 ring atoms of which from 1 to 3 are heteroatoms;
or
(3) L and L′ join to form an optionally substituted cycloalkyl containing from 3 to 8 ring atoms or an optionally substituted hetercycloalkyl containing from 3 to 8 ring atoms of which from 1 to 3 are heteroatoms;
(F) G is selected from —S— and —C(R6)═C(R6′)—, where R6 and R6′ each is independently selected from hydrogen and alkyl;
(H) Z is selected from:
(1) —NR10R10′ where:
(a) R10 is hydrogen and R10′ is —C(═O)-Q-(CR11R11′)bR12 where:
(i) b is 0;
(ii) Q is selected from a covalent bond and —N(R13)—;
and
(iii) (A) R12 and R13 each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or (B) R12 and R13, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
or
(b) R10 and R10′, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing 5 or 6 ring atoms of which from 1 or 2 are heteroatoms;
and
(2)
72
where:
(a) A′ and J′ both are —CH—;
(b) G′ is selected from —C(R15)═C(R15′)— and —N═C(R15)—, where R15 and R15′ each is independently selected from hydrogen and lower alkyl;
(c) c is from 0;
(d) D is selected from is a covalent bond or —O—;
and
(e) T is —(CR17R17′)e—R18 where e is 0;
and R18 is selected from lower alkyl, lower heteroalkyl, halogen and aryl;
or an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof.

36 more elements

15 The compound of claim 1, selected from the group consisting of:

N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methyl-amino}-(4-hydroxycyclohexan-1-yl)-acetic acid;
(R)-N-{[4′-methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-methylamino-(1,5-dioxa-spiro[5.5]undec-9-yl)-acetic acid;
(R)—N-{[4′-bromo-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-methylamino-(1,5-dioxa-spiro[5.5]undec-9-yl)-acetic acid;
(1,4-Dioxa-spiro[4.5] dec-8-yl)-N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-methylamino-acetic acid;
(1,4-Dioxa-spiro[4.5]dec-8-yl)-N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-(pyridin-4-yl-methyl)-amino-acetic acid;
(1,4-Dioxa-spiro[4.5]dec-8-yl)-N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-(2-methoxyethyl)-amino-acetic acid;
(1,4-Dioxa-spiro[4.5]dec-8-yl)-N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-(N-morpholinoethyl)-amino-acetic acid;
2-(1,4-Dioxa-spiro[4.5]dec-8-yl)-2N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-methylamino-propionic acid;
[Spiro-(1,3-benzodioxole-2,1′-cyclohex-4′-yl]-N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-methylamino-acetic acid;
(7-methylthio-1,4-Dioxaspiro[4.5]dec-7-yl)-N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-methylamino-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[4-(N-benzylamino)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[4-(N-benzyl-N-acetyamino)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[4-(N-benzyl-N-methanesulfonylamino)-cyclohex-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-(4-N-methoxymethylacetylamino-cyclohexan-1-yl)-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-(4-N-methoxymethylacetyl-N-methylamino-cyclohexan-1-yl)-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfony-N-methyl-lamino}-(4-N-acetyl-N-methylamino-cyclohexan-1-yl)-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methyl-amino}-(4-N-dimethylacetyl-N-methyl-aminocyclohexan-1-yl)-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[4-(morpholin-4N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[4-(2-oxopyrrolidin-1N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-(2-methoxyethyl)-amino}-[4-(2-oxopyrrolidin-1N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[4-(oxazolidin-2-one-3N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[4-([1,3]-oxazinan-2-one-3N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[4-(2-oxomorpholin-1N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[4-(3N-methyl-hydantoin-1N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[4-(□-sultam-1N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-methyl-amino-(3-hydroxycyclohexan-1-yl)-acetic acid;
N-{[4′-methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-methylamino-(1,5-dioxa-spiro[5.5]undec-7-yl)-acetic acid;
N-{[4′-bromo-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-methyl-amino-(1,5-dioxa-spiro[5.5]undec-7-yl)-acetic acid;
N-{[4′-methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-benzylamino-(1,5-dioxa-spiro[5.5]undec-7-yl)-acetic acid;
N-{[4′-methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-methylamino-(7-methyl-1,5-dioxa-spiro[5.5]undec-7-yl)-acetic acid;
N-{[4′-methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-benzylamino-(7-methyl-1,5-dioxa-spiro[5.5]undec-7-yl)-acetic acid;
N-{[4′-methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-methyl-amino-(3-benzyloxycyclohexan-1-yl)-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[3-(N-benzylamino)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[3-(N-benzyl-N-acetyamino)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-(3-N-(2-methoxyethoxycarbonyl)-amino-cyclohexan-1-yl)-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-(3-N-methyl-N-(2-methoxyethoxycarbonyl)-amino-cyclohexan-1-yl)-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[3-(morpholin-4N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[3-(2-oxopyrrolidin-1N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[3-(2-oxomorpholin-1N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[3-(3N-methyl-hydantoin-1N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[3-(□-sultam-1N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[3-(□-sultam-1N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[3-(oxazolidin-2-one-3N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl-N-methylamino}-[1-methyl 3-(oxazolidin-2-one-3N-yl)-cyclohexan-1-yl]-acetic acid;
N-{[4′-methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-methylamino-(7-methyl-1,5-dioxa-spiro[5.4]dec-7-yl)-acetic acid;
and
N-{[4′-methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-methylamino-(7-methyl-1,4-dioxa-spiro[4.4]non-7-yl)-acetic acid.

44 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/246,224Filed 18 Sep 2002
Priority: 21 Mar 2000
Published: 31 Jul 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07D 207/27
With only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms: with substituted…
A61P 19/02
Drugs for skeletal disorders: for joint disorders, e.g. arthritis, arthrosis
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
A61P 35/00
Antineoplastic agents

Family

Application60/190,993Us provisional application · filed 21 Mar 2000
Application10/246,224Continuation in part · filed 18 Sep 2002
US 2003/0144292 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

The compounds have a structure according to the following Formula (I): 1 are effective in treating conditions characterized by excess activity of metalloprotease enzymes.

A compound having a structure according to the following Formula (I):

68
wherein:
(A) R1 is selected from —OH and —NHOH;
(B) R2 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
or R2 and A form a ring as described in (D);
(C) R3 is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxyl, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
(D) A is a substituted or unsubstituted, monocyclic cycloalkyl having from 3 to 8 ring atoms;
or A is bonded to R2 where, together, they form a substituted or unsubstituted, monocyclic cycloalkyl having from 3 to 8 ring atoms;
(E) E and E′ are bonded to the same or different ring carbon atoms of A and are independently selected from a covalent bond, C1-C4 alkyl, aryl, heteroaryl, heteroalkyl, —O—, —S—, —N(R4)—, ═N, C═O, —C(═O)O—, —C(═O)N(R4)—, —SO2— and —C(═S)N(R4)—, where R4 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
or R4 and L join to form a ring as described in (F)(2);
(F) (1) L and L′ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, —C(═O)R5, —C(═O)OR5, —C(═O)NR5R5′ and —SO2R5, where R5 and R5′ each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
or
(2) L and R4 join to form an optionally substituted heterocyclic ring containing from 3 to 8 ring atoms of which from 1 to 3 are heteroatoms;
or
(3) L and L′ join to form an optionally substituted cycloalkyl containing from 3 to 8 ring atoms or an optionally substituted hetercycloalkyl containing from 3 to 8 ring atoms of which from 1 to 3 are heteroatoms;
(G) G is selected from —S—, —O—, —N(R6)—, —C(R6)═C(R6′)—, —N═C(R6)— and —N═N—, where R6 and R6′ each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;
and
(H) Z is selected from:
(1) cycloalkyl and heterocycloalkyl;
(2) -J-(CR7R7′)aR8 where:
(a) a is from 0 to about 4;
(b) J is selected from —C≡C—, —CH═CH—, —N═N—, —O—, —S— and —SO2—;
(c) each R7 and R7′ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy and alkoxy;
and
(d) R8 is selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl;
and, if J is —C≡C— or —CH═CH—, then R8 may also be selected from —CONR9R9′ where (i) R9 and R9′ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, or (ii) R9 and R9′, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
(3) —NR10R10′ where:
(a) R10 and R10′ each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl and —C(═O)-Q-(CR11R11′)bR12 where:
(i) b is from 0 to about 4;
(ii) Q is selected from a covalent bond and —N(R13)—;
and
(iii) each R11 and R11′ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy and alkoxy;
either (A) R12 and R13 each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, or (B) R12 and R13, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
or R10 and R13, together with the nitrogen atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 2 to 3 are heteroatoms;
or
(b) R10 and R10′, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
and
(4)
69
where:
(a) A′ and J′ are independently selected from —CH— and —N—;
(b) G′ is selected from —S—, —O—, —N(R15)—, —C(R15)═C(R15′)—, —N═C(R15)— and —N═N—, where R15 and R15′ each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;
(c) c is from 0 to about 4;
(d) each R14 and R14′ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy and alkoxy;
(e) D is selected from a covalent bond, —O—, —SOd—, —C(═O)—, —C(═O)N(R16)—, —N(R16)—, and —N(R16)C(═O)—;
where d is from 0 to 2 and R16 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkyl;
and
(f) T is —(CR17R17′)e—R18 where e is from 0 to about 4;
each R17 and R17′ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy;
and R18 is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;
or R17 and R18, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms;
or R16 and R18, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms;
or an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof.

50 more elements

Facts

Application

10/246,224Filed 18 Sep 2002

Priority

21 Mar 2000

Published

31 Jul 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07D 207/27
With only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms: with substituted…
A61P 19/02
Drugs for skeletal disorders: for joint disorders, e.g. arthritis, arthrosis
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
A61P 35/00
Antineoplastic agents