Substituted azoles

Details Substituted azoles Substituted azoles

2001-10-12

2003-06-17

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252190, C514S269000, C514S275000, C514S318000, C544S122000, C544S296000, C544S315000, C544S316000, C544S324000, C544S330000, C544S331000, C546S194000

Reexamination Certificate

active

06579874

ABSTRACT:

This invention relates to substituted azoles 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
a is N or C;
b is CH when a is N, or O when a is C;
═ denotes a single or a double bond dependent upon whether the azole ring is an imidazole or an oxazole ring;
Z is N or CH;
W 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
1-3
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-N-C
1
-C
4
alkyl substituted;
R
3
is H, halogen, C
1
-C
10
alkyl, C
1
-C
4
alkenyl, C
3
-C
10
cycloalkyl, C
3
-C
18
heterocycloalkyl, C
6
-C
18
aryl, C
3
-C
18
heteroaryl, or methyleneaminoguanidinyl (i.e. —CH═N—NH—C(NH).NH
2
), each of which is optionally substituted by up to 4 substituents separately selected from C
1
-C
4
alkyl optionally substituted by hydroxy, halogen, halo-substituted-C
1
-C
4
alkyl, hydroxy, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, carboxy, optionally C
1
-C
6
alkyl or C
1
-C
6
alkoxy substituted carbonyl, optionally mono- or di-N-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;
R
5
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
-C
4
alkyl halogen, halo-substitued-C
1
-C
4
alkyl, hydroxy, C
1
-C
4
alkoxy, C
1
-C
4
alkythio, or optionally mono- or di-N-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,
and 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.
In a particular embodiment the invention provides a 4-phenyl-5-[(2-substituted)-4-pyrimidyl or -pyridyl]-oxazole of formula I, or a pharmaceutically-acceptable and -cleavable ester thereof or acid addition salt thereof (wherein the numbering of the atoms of the oxazole ring is shown below in formula II.)
Thus in a particular embodiment the invention provides a compound of formula II
wherein
Z is N or CH;
W 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
12
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-N-C
1
-C
4
alkyl substituted;
R
13
is H, halogen, C
1
-C
10
alkyl, C
1
-C
4
alkenyl, C
3
-C
10
cycloalkyl, C
3
-C
18
heterocycloalkyl, C
6
-C
18
aryl, C
3
-C
18
heteroaryl, or methyleneaminoguanidinyl (i.e. —CH═N—NH—C(NH).NH
2
), each of which is optionally substituted by up to 4 substituents separately selected from C
1
-C
4
alkyl optionally substituted by hydroxy, halogen, halo-substitued-C
1
-C
4
alkyl, hydroxy, C
1-4
alkoxy, C
1-4
alkylthio, carboxy, optionally C
1
-C
6
alkyl or C
1
-C
6
alkoxy substituted carbonyl, optionally mono- or di-N-C
1-4
alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom;
R
15
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
-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-N-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,
and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
When R
13
is heteroaryl it is preferably pyridyl (e.g. 4-pyridyl) or pyrimidyl, each optionally substituted, e.g. by up to 2 substituents, separately selected from C
1
-C
4
alkyl optionally substituted by hydroxy, halogen, hydroxy, C
1
-C
4
alkoxy, carboxy, optionally C
1
-C
6
-alkyl or C
1
-C
6
alkoxy substituted carbonyl, or optionally mono- or di-N-C
1
-C
4
alkyl substituted amino.
When R
13
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-N-C
1
-C
4
alkyl substituted amino.
When R
13
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 optionally substituted by hydroxy, halogen, hydroxy, C
1
-C
4
alkoxy, carboxy, optionally C
1
-C
6
alkyl or C
1
-C
6
alkoxy substituted carbonyl, or optionally mono- or di-N-C
1-4
substituted amino.
When R
15
is aryl it is preferably phenyl. When R
15
is cycloalkyl, it is preferably C
3
-C
7
cycloalkyl, e.g. cylopropyl, cyclopentyl, cyclohexyl or cycloheptyl. R
15
may be unsubstituted or substituted, conveniently mono-substituted, e.g. phenyl conveniently meta or para substituted, by halogen, C
1
-C
10
alkyl, halo-substitued C
1
-C
10
alkyl, C
1
-C
10
alkoxy, hydroxy, or —NR
7
R
8
, where R
7
and R
8
are idependently H, C
1
-C
6
alkyl, C
6
-C
10
aryl, C
6
-C
10
heteroaryl, C
7
-C
11
aralkyl or C
7
-C
11
heteroaralkyl.
When Y is C
1
-C
4
alkylene, it is preferably C
1
-C
2
alkylene, and is optionally substituted, e.g. by C
1
-C
4
alkyl (e.g. methyl), halogen, hydroxy, C
1
-C
4
alkoxy, or amino.
More preferably R
12
is phenyl substituted, preferably mono- or di-substituted, by halogen or a halogen-containing group, e.g. 4-fluorophen-1-yl, or 3-CF
3
, 3-Cl, or 3,4-difluoro substituted.
More preferably R
13
is H, C
1-6
alkyl, C
1
-C
4
alkenyl, phenyl, pyridyl, morpholinyl, piperidinyl, piperazinyl, or N-mono- or di-C
1-4
alkylamino, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C
1
-C
4
alkyl optionally substituted by hydroxy, halogen, hydroxy, C
1
-C
4
alkoxy, carboxy, optionally C
1
-C
6
alkyl or C
1
-C
6
alkoxy substituted carbonyl, or optionally mono- or di-N-C
1
-C
4
alkyl substituted amino.
Preferably W is —NH—Y′—, —O— or —S—, where Y′ is —CH
2
—, —CH
2
—CH
2
—, —CH(CH
3
)— or a direct bond
Thus in preferred embodiments the invention provides a compound of formula II′
wherein
R
15
′ is phenyl or C
3
-C
7
cycloalky each of which is optionally mono-substituted by halogen, C
1
-C
10
alkyl, C
1
-C
10
alkoxy, hydroxy, trihalomethyl or —NR
7
R
8
, where R
7
and R
8
are independently H, C
1
-C
6
alkyl, C
6
-C
10
aryl, C
6
-C
10
heteroaryl C
7
-C
11
aralkyl or C
7
-C
11
heteroaralkyl;
R
10
is halogen, CF
3
, cyano, amido, thioamido, amino C
1-6
alkyl;
R
13
′ is H, C
1
-C
6
alkyl, C
1
-C
4
alkenyl, phenyl, pyridyl, morpholinlyl, piperidinyl, piperazinyl, or N-mono- or di-C
1
-C
4
alkylamino, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C
1
-C
4
alkyl optionally substituted by hydroxy, halogen, hydroxy, C
1
-C
4
alkoxy, carboxy, optionally C
1
-C
6
alkyl or C
1
-C
6
alkoxy substituted carbonyl or optionally mono- or di-N-C
1
-C
4
alkyl substituted amino;
Z is N or CH and
W′ is —NH—Y′—, —O— or —S—, where Y′ is —CH
2
—, —CH
2
—CH
2
—, —CH(CH
3
)— or a direct bond,
and pharmaceutically-acceptable and -cleavable esters the

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