Thiazole compounds and their pharmaceutical use

Details Thiazole compounds and their pharmaceutical use Thiazole compounds and their pharmaceutical use

2002-04-22

2003-08-19

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S318000, C514S342000, C544S315000, C544S331000, C544S332000, C546S194000, C546S270400

Reexamination Certificate

active

06608072

ABSTRACT:

This is a 371 of International Application PCT/EP00/10528, filed Oct. 25, 2000 and published in English, the contents of which are incorporated herein by reference.
This invention relates to heterocyclic compounds, in particular to thiazoles and imidazopyridines and to their use for treating TNF&agr; and IL-1 mediated diseases such as rheumatoid arthritis and diseases of bone metabolism, e.g. osteoporosis.
Accordingly the present invention provides a compound of formula I
wherein Nu is a heterocyclic nucleus selected from a thiazole in which the R
1
, R
2
and R
3
substituents are disposed as indicated below
and an imidazo[4,5-b]pyridine in which the R
1
, R
2
and R
3
substituents are disposed as indicated below
wherein
R
1
is pyrimidyl or pyridyl;
X is —NR
6
—Y—, —O— or —S—,
where R
6
is H, C
1
-C
4
alkyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkylC
1
-C
3
alkyl, C
6
-C
18
aryl, C
3
-C
18
heteroaryl, C
7
-C
19
aralkyl or C
4
-C
19
heteroaralkyl, and —Y— is C
1
-C
4
alkylene or a direct bond;
R
2
is phenyl, optionally substituted by one or more substituents, each of which is independently selected from
halo,
CF
3
,
cyano,
amido or thioamido which is optionally mono- or di-N-substituted by C
1
-C
4
alkyl or the N atom of which forms a 5-7 membered heterocyclic ring optionally containing an additional hetero atom selected from O, S or N which N is optionally C
1
-C
4
alkyl C
1
-C
4
alkylcarbonyl or C
1
-C
4
alkylthiocarbonyl substitued,
carboxylate or thiocarboxylate optionally in the form of an optionally halo-substituted C
1
-C
10
alkoxy, C
2
-C
10
alkenoxy, C
2
-C
10
alkynoxy, C
3
-C
7
cyclalkoxy, C
5
-C
7
cycloalkenoxy, aryloxy, arylalkoxy, heteroaryloxy or heteroarylalkoxy ester,
optionally mono- or di-C
1
-C
4
alkyl-substituted-C
0
-C
1
alkyl optionally C
1
-C
4
alkyl- or C
3
-C
5
cycloalkyl-substituted-carbonyl or -thiocarbonyl,
optionally halo-substituted-C
1
-C
4
alkoxy, C
2
-C
4
alkenoxy, C
2
-C
4
alkynoxy, C
3
-C
5
cycloalkoxy or C
3
-C
5
cyclothioalkoxy,
optionally halo substituted C
1
-C
4
alkyl,
oxycarbonyl or optionally N—C
1
-C
4
alkyl-substituted aminocarbonyl both of which are optionally C
1
-C
4
alkyl or C
3
-C
5
cycloalkyl substituted (including thiocarbonyl analogues thereof),
optionally mono- or di-C
1
-C
4
alkyl-substituted-C
0
-C
1
alkylamine which is optionally mono- or di-N—C
1
-C
4
alkyl substituted,
optionally mono- or di-C
1
-C
4
acyl-substituted-C
0
-C
1
alkyl optionally N—C
1
-C
4
alkyl-substituted amino-carbonyl or -thiocarbonyl,
optionally N—C
1
-C
4
alkyl-substituted amino-sulphinyl or -sulphonyl optionally substituted by
optionally mono- or di-N—C
1
-C
4
alkyl-substituted amino,
a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C
1
-C
4
alkyl C
1
-C
4
alkylcarbonyl or C
1
-C
4
alkylthiocarbonyl substitued, or
sulphinyl or sulphonyl optionally substituted by
optionally halo-substituted-C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl,
optionally mono- or di-C
1
-C
4
alkyl-substituted amino,
a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C
1
-C
4
alkyl C
1
-C
4
alkylcarbonyl or C
1
-C
4
alkylthiocarbonyl substitued;
R
3
is H, amino, C
1
-C
10
alkyl, C
3
-C
10
cycloalkyl, C
3
-C
18
heterocycloalkyl, C
6
-C
18
aryl, or C
3
-C
18
heteroaryl each of which is optionally substituted by up to 4 substituents separately selected from C
1
-C
4
alkyl, halogen, halo-substitued-C
1
-C
4
alkyl, hydroxy, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, C
6
-C
18
aryl, C
3
-C
18
heteroaryl, C
6
-C
18
arylC
1
-C
4
alkyl, C
3
-C
18
heteroarylC
1
-C
4
alkyl, C
3
-C
18
heterocycloalkyl or optionally mono- or di-C
1
-C
4
alkyl substituted amino or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally a further hetero atom selected from O, S or N, all of which are further optionally substituted halo, hydroxy, C
1
-C
4
alkyl, C
1
-C
4
alkoxy or C
1
-C
4
alkoxycarbonyl;
R
4
is C
1
-C
10
alkyl, C
6
-C
18
aryl, C
3
-C
18
heteroaryl, or C
3
-C
12
cycloalkyl optionally substituted by up to 3 substituents separately selected from C
1
-C
4
alkyl, halogen, halo-substitued-C
1
-C
4
alkyl, hydroxy, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, optionally mono- or di-C
1
-C
4
alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N,
and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
Above and elsewhere in the present description the terms halo or halogen denote I, Br, Cl or F.
Above and elsewhere in the present description the terms such as “C
3
-C
18
heteroaryl, C
4
-C
19
heteroaralkyl and C
3
-C
18
heterocycloalkyl” denote heteroaryl, heteroaralkyl or heterocycloalkyl substituents comprising at least 3 ring atoms, at least one of which is a hetero atom, e.g. N, O or S, and which in the case of C
4
-C
19
heteroaralkyl groups are attached via an alkylene moiety comprising at least 1 carbon atom.
In particular embodiments the invention provides a compound of formula II
wherein
Z is N or CH;
X is —NR
6
—Y—, —O— or —S—,
where R
6
is H, C
1
-C
4
alkyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkylC
1
-C
3
alkyl, C
6
-C
18
aryl, C
3
-C
18
heteroaryl, C
7
-C
19
aralkyl or C
4
-C
19
heteroaralkyl, and —Y— is C
1
-C
4
alkylene or a direct bond;
R
2
′ is phenyl, optionally substituted by one or more substituents, each of which is independently selected from halo, CF
3
, cyano, amido or thioamido, carboxylate or thiocarboxylate, C
1
-C
4
alkoxy, C
1
-C
4
alkyl, or NH
2
which is optionally mono- or di-C
1
-C
4
alkyl substituted;
R
3
′ is H, C
1
-C
10
alkyl, C
3
-C
10
cycloalkyl, C
3
-C
18
heterocycloalkyl, C
6
-C
18
aryl, or C
3
-C
18
heteroaryl each of which is optionally substituted by up to 4 substituents separately selected from C
1
-C
4
alkyl, halogen, halo-substitued-C
1
-C
4
alkyl, hydroxy, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, or optionally mono- or di-C
1
-C
4
alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N;
R
4
′ is C
6
-C
18
aryl, C
3
-C
18
heteroaryl, or C
3
-C
12
cycloalkyl each of which is optionally substituted by up to 4 substituents separately selected from C
1-4
alkyl, halogen, halo-substitued-C
1-4
alkyl, hydroxy, C
1-4
alkoxy, C
1-4
alkylthio, or optionally mono- or di-C
1
-C
4
alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N,
and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
When R
3
′ is aryl, it is preferably heteroaryl, e.g. pyridyl (e.g. 4-pyridyl) or pyrazyl, each optionally substituted, e.g. by 2 substituents, separately selected from C
1
-C
4
alkyl, halogen, hydroxy, C
1
-C
4
alkoxy, or optionally mono- or di-C
1
-C
4
alkyl substituted amino.
When R
3
′ is cycloalkyl it is preferably C
3
-C
8
, especially C
5
-C
6
cycloalkyl (e.g. cyclohexyl), optionally substituted, e.g. by 1 or 2 substituents, separately selected from C
1
-C
4
alkyl, halogen, hydroxy, C
1
-C
4
alkoxy, or optionally mono- or di-C
1
-C
4
alkyl substituted amino.
When R
3
′ is heterocycloalkyl it is preferably N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom, e.g. N or O, and is optionally substituted, e.g. by 1 or 2 substituents, separately selected from C
1
-C
4
alkyl, halogen, hydroxy, C
1
-C
4
alkoxy, or optionally mono- or di-C
1
-C
4
alkyl substituted amino.
When R
4
′ is aryl it is preferably phenyl. When R′
4
is cycloalkyl, it is preferably C
3
-C
7
cycloalkyl, e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl. R′
4
may be unsubstituted or substituted, conveniently mono-substituted, e.g. phenyl conveniently meta or para substituted, by halogen, C
1
-C
4
alkyl, ha

Affiliated with

Also associated with

Rating

Thiazole compounds and their pharmaceutical use does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Thiazole compounds and their pharmaceutical use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Thiazole compounds and their pharmaceutical use will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3094990