Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Utility Patent
1999-06-08
2001-01-02
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S116000, C544S322000, C514S302000
Utility Patent
active
06169090
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel heterocyclic compounds and to their formulation and use as pharmaceuticals.
BACKGROUND OF THE INVENTION
EP-A-0637586 describes benzofuran derivatives of acetylcholine esterase inhibitors. U.S. Pat. No. 4,910,193 discloses benzofuran amides for the treatment of serotonin-induced gastrointestinal disturbances. WO-A-9408962 discloses benzofuran derivatives as fibrinogen receptor antagonists.
WO-A-9412461 discloses catechol diethers as selective phosphodiesterase (PDE) IV inhibitors. The modes of action of phosphodiesterases and also tumour necrosis factors (TNF), and the therapeutic utilities of inhibitors thereof, are described in WO-A-9636638 and U.S. patent application Ser. No. 07/650,231, the contents of which are incorporated herein by reference. WO-A-9744337 discloses benzofuran carboxamides as PDE IV inhibitors.
SUMMARY OF THE INVENTION
This invention provides novel compounds having therapeutic utility, in particular for the treatment of disease states associated with proteins which mediate cellular activity, for example by inhibiting TNF and/or PDE IV. According to the invention, the compounds are of formula (i):
wherein X and Y are independently CH, N or N-oxide, provided that X and Y do not both represent CH;
Z is CO or CS;
R
1
is alkyl, optionally substituted with one or more halogens;
R
2
is CF
3
, H, CN, C(═NOR
9
)R
9
, alkyl-C(═NOR
9
)R
O
, S(O)
P
R
6
, SO
2
NR
12
R
12
, CONR
12
R
13
, OR
9
, NR
6
R
15
; alkyl, cycloalkyl or cycloalkylalkyl optionally substituted with one or more R
8
; aryl, heteroaryl, arylalkyl or heterocycloalkyl, the aryl/heteroaryl portions of which may be otionally substituted by one or more R
2
or alkyl-R
10
and the alkyl portions of which may be optionally substituted by one or more R
8
; or heterocyclo or heterocycloalkyl, the heterocyclo portion of which may be optionally substituted by one or more R
11
or alkyl-R
10
and the alkyl portion of which may be optionally substituted by one or more R
3
,
R
3
is H, alkyl or halogen;
R
4
is H or alkyl;
R
5
is aryl or heteroaryl, optionally substituted at any position with (one or more) substituents alkyl-R
10
or R
7
;
R
6
is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclo or heterocycloalkyl, the cycloalkyl/alkyl portions of which may be optionally substituted with one or more R
8
, the aryl/heteroaryl portions of which may be optionally substituted with one or more R
7
or alkyl-R
10
and the heterocyclo portions of which may be optionally substituted with one or more R
11
or alkyl-R
10
;
R
7
is alkyl or R
17
;
R
8
is carbonyl oxygen (═O) or R
10
;
R
9
is H or R
6
;
R
10
is CO
2
R
16
, CONR
12
R
13
, SO
2
NR
12
R
13
, OH, OR
12
, CN, CF
3
, NR
12
R
15
, COR
12
, S(O)
7
R
12
, NHSO
2
CF
3
, NO
2
, aryl optionally substituted with one or more R
18
, heteroaryl optionally substituted with one or more R
18
, or heterocyclo optionally substituted with one or more R
19
;
R
11
is carbonyl oxygen, alkyl or R
10
;
R
12
and R
13
are the same or different and are H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl or NR
12
R
13
represents a heterocyclic ring, the aryl/heteroaryl portions of which may be optionally substituted with one or more R
18
and the heterocyclo portions of which may be optionally substituted with one or more R
19
;
R
15
is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclocarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, the aryl/heteroaryl portions of which may be optionally substituted with one or more R
18
and the heterocyclo portions of which may be optionally substituted with one or more R
19
,
R
16
is H, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclo or heterocycloalkyl;
R
17
is halogen or R
10
,
R
18
is alkyl, alkoxy, CF
3
, halogen, CN or CO
2
R
16
,
R
19
is alkyl, alkoxy, CF
3
, arylalkyl, carbonyl oxygen, CN or COR
2
R
16
; and
p is 0-2;
and N-oxides and pharmaceutically acceptable salts thereof.
This invention provides also a method for mediating or inhibiting the enzymatic activity or catalytic actvity of PDE IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mamnmal an effective amount of a compound of Formula (i) or a pharmaceutically-acceptable salt thereof.
DESCRIPTION OF THE INVENTION
Certain compounds of this invention are preferred. For example, it is preferred that any one or more of the following apply:
R
1
is methyl or difluoromethyl;
R
2
is alkyl or cycloalkyl optionally substituted with (one or more) R
8
, aryl or heteroaryl optionally substituted with (one or more) R
7
or alkyl-R
10
, or heterocyclo optionally substituted with one or more R
11
or alkyl-R
10
;
R
3
is H;
R
4
is H;
R
5
is phenyl, pyridinyl, pyridinyl-N-oxide, pyrimidinyl pyrazolyl, imidazolyl, isoxazolyl, any of which may be substituted at any position with (one or more) substituents R
7
(in which R
7
is alkyl, CF
3
, halogen or CN);
X is N and Y is CH or X is CH and Y is N; and
Z is CO.
The compounds of the Examples are particularly preferred.
Suitable pharmaceutically-acceptable salts are pharmaceutically-acceptable base salts and pharmaceutically-acceptable acid addition salts. Certain of the compounds of formula (i) which contain an acidic group form base salts. Suitable pharmaceutically-acceptable base salts include metal salts, such as alkali metal salts for example sodium salts, or organic amine salts such as that provided with ethylenediamine.
Certain of the compounds of formula (i) which contain an amino group form acid addition salts. Suitable acid addition salts include pharmaceutically-acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide, and pharmaceutically-acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphate, &agr;-ketoglutarate, &agr;-glycerophosphate and glucose-1-phosphate. The pharmaceutically-acceptable salts of the compounds of formula (i) are prepared using conventional procedures.
It will be appreciated by those skilled in the art that some of the compounds of formula (i) may exist in more than one tautomeric or geometric form. This invention extends to all tautomeric and geometric forms.
It will be appreciated that the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centers in a compound of formula (i) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers, and diastereoisomers and mixtures including racemic mixtures thereof.
When used herein the term alkyl whether used alone or when used as a part of another group includes straight and branched chain alkyl groups containing up to 6 atoms. Alkoxy means an alkyl-O-group in which the alkyl group is as previously described, and thioalkyl means an alkyl-S-group. Cycloalkyl includes a non-aromatic cyclic or multicyclic ring system of 3 to 10 carbon atoms. Cycloalkylalkyl means a cycloalkyl-alkyl-group wherein the cycloalkyl and alkyl groups are as previously defined. The cyclic alkyl may optionally be partially unsaturated. Aryl indicates a mono- or multicyclic aromatic radical containing 6 to 10 carbon atoms. Arylalkyl means an aryl-alkyl-group wherein the aryl and alkyl are as described herein. Heteroaryl means a 5 to 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from nitrogen (and N-oxides), oxygen and sulphur. Heterocyclo means a 4 to 10 membered saturated or partially saturated monocyclic
Buckley George
Dyke Hazel Joan
Haughan Alan Findlay
Lowe Christopher
Montana John
Darwin Discovery Ltd.
Liu Hong
Saliwanchik Lloyd & Saliwanchik
Shah Mukund J.
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