Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-21
2002-03-05
Raymond, Richard L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S249000, C514S321000, C514S324000, C514S375000, C514S394000, C544S353000, C544S354000, C544S355000, C546S197000, C546S200000, C546S202000, C548S559000, C548S152000, C548S217000, C548S304700, C548S357500
Reexamination Certificate
active
06353010
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel heterocyclic compounds and pharmaceutically-acceptable salts thereof, processes for their production and formulation and use as pharmaceuticals.
BACKGROUND OF THE INVENTION
2-Thienylbenzoxazoles with anti-aggregating activity are described in
Eur. J. Med. Chem
. (1994) 29:75.
EP-A-0116938 and
J. Med. Chem
. (1987) 30 62 describe heteroaryloxycarboxamides as lipolysis inhibitors useful in the treatment of ischemic heart disease and hypertriglyceridemia.
WO-A-9406783 and WO-A-9406782 describe heteroarylsulphonamides having insecticidal, nematicidal, acaricidal and fungicidal activity.
WO-A-9604251 describes aryloxy derivatives of heteroaryl compounds as bradykinin inhibitors.
Heteroaryl compounds are described as fibrinogen antagonists in WO-A-9408962.
EP-A-0498722 describes amide derivatives of heteroaryl compounds.
Quinoxalines are disclosed as performance enhancers for animals in EP-A-0456067.
Benzimidazoles are described as dopamine antagonists in WO-A-9422839.
DE-A-4237617 discloses imidazoles as antiparasitic agents.
Phosphodiesterases (PDE) and Tumour Necrosis Factor (TNF), their modes of action and the therapeutic utilities of inhibitors thereof, are described in WO-A-9720833 and PCT/GB97/01361, the contents of which are incorporated herein by reference. The same documents disclose carboxamides having utility as PDE and TNF inhibitors.
SUMMARY OF THE INVENTION
This invention is directed to the pharmaceutical use of a compound of formula (i) below to treat disease states, for example disease states associated with proteins which mediate cellular activity, for example by inhibiting tumour necrosis factor and/or by inhibiting phosphodiesterase IV. According to the invention, novel compounds are of formula (i):
wherein (1) X is N and (a) Z is ═CR
1
—CR
2
═ and Y is N, (b) Z is ═CR
1
— and Y is O, S or NR
4
, or (c) Z is ═CR
1
—N═ and Y is CR
2
, or (2) X is NR
4
, Z is —CR
1
═ and Y is N;
Q is O or S;
R
1
and R
2
are the same or different and are each COR
6
, C(═NOR
6
)R
13
, alkyl-C(═NOR
6
)R
13
, NR
8
R
9
, CON(R
6
)
2
, halogen, CF
3
, CN, CO
2
H, CO
2
R
10
, R
6
, CO-het where het is a heterocyclic ring (such as morpholine or piperidine) attached via a N atom in the ring and optionally substituted with one or more R
14
, or
R
3
is OH, thioalkyl, or C
1-4
alkoxy or cycloalkoxy each optionally substituted with one or more halogens,
R
4
is H or alkyl;
R
5
is aryl or heteroaryl, either of which may be optionally substituted with one or more substitutents chosen from halogen, optionally halogen-substituted alkyl, hydroxy, optionally halogen-substituted alkoxy, CO
2
H, CO
2
R
10
, CONR
11
R
12
, COR
10
, SO
2
R
10
, SO
2
NR
11
R
12
, NR
8
R
9
and CN;
each R
6
is independently H or a group selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkl, heteroarylalkyl and heterocycloalkyl, any of which groups is optionally substituted at any position with R
7
;
R
7
is alkyl, hydroxy, OR
10
, NR
8
R
9
, CN, CO
2
H, CO
2
R
10
, CONR
11
R
12
or COR
10
,
R
8
is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkly, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclocarbonyl, alkylsulphonyl, arylsulphonyl, heteroarylsulphonyl or heterocyclosulphonyl, R, is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroarylalkyl or heterocycloalkyl; or NR
8
R
9
is a heterocyclic ring (such as morpholine or piperidine) optionally substituted with R
14
;
R
10
is alkyl cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl or heterocycloalkyl;
R
13
and R
12
are the same or different and are each H or R
10
;
R
13
is R
10
optionally substituted with one or more R
7
;
R
14
is alkyl, arylalkyl or heteroarylalkyl; and
R
15
is alkyl, V is O or S, and n is 2-4; and pharmaceutically-acceptable salts thereof.
Compounds of the invention have a bicyclic aryl nucleus. Depending on the definitions of X, Y, and Z, they are (1a) quinoxalines, (1b) benzoxazole; benzthiazoles or benzimidazoles, (1c) quinazolines or (2) benzimidazoles (differently substituted from those under 1b). Preferred compounds are defined in the subclaims.
DESCRIPTION OF THE INVENTION
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 from 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, methane-sulphate, &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 form. This invention extends to all tautomeric 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. Cycloalkyl includes a non-aromatic cyclic or multicyclic ring system of about 3 to 10 carbon atoms. The cyclic alkyl may optionally be partially unsaturated. Cycloalkoxy means a cycloalkyl-I-group in which cycloalkyl is as defined above. Aryl indicates an aromatic monocyclic or multicyclic carbocyclic group containing about 6 to 10 carbon atoms. Arylalkyl means an aryl-alkyl-group wherein the aryl and alkyl are as described herein. Heteroarylalkyl means a heteroaryl-alkyl group and heterocycloalkyl means a heterocyclo-alkyl group. Alkylcarbonyl means an alkyl-CO-group in which the alkyl group is as previously described. Arylcarbonyl means an aryl-CO-group in which the aryl group is as previously described. Heteroarylcarbonyl means a heteroaryl-CO-group and heterocyclocarbonyl means a heterocyclo-CO-group. Arylsulphonyl means an aryl-SO
2
-group in which the aryl group is as previously described. Heteroarylsulphonyl means a heteroaryl-SO
2
-group and heterocyclosulphonyl means a heterocyclo-SO
2
-group. Alkoxycarbonyl means an alkyloxy-CO-group in which the alkoxy group is as previously described. Alkylsulphonyl means an alkyl-SO
2
-group in which the alkyl group is as previously described. Heterocyclic ring means about a 5 to about a 10 membered monocyclic or multicyclic ring system (which may saturated or partially unsaturated) wherein one or more of the atoms in the ring system is an element other than carbon chosen from amongst nitrogen, oxygen or sulphur atoms. Heteroaryl means about a 5 to about a 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 amongst nitrogen, oxygen or sulphur, if desired, a N atom may be in the form of an N-oxide. Heterocyclo means about a 5 to about a 10 membered saturated or partially saturated monocyclic or multicyclic hydrocarbon ring system
Dyke Hazel Joan
Montana John Gary
Darwin Discovery Ltd.
Raymond Richard L.
Saliwanchik Lloyd & Saliwanchik
Truong Tamthom
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