Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-02
2003-11-04
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252130, C514S253010, C514S253020, C514S253040, C514S255020, C540S492000, C544S359000, C544S360000, C544S361000, C544S362000, C544S363000, C544S385000
Reexamination Certificate
active
06642225
ABSTRACT:
BACKGROUND OF THE INVENTION
Lymphocyte function associated antigen 1 (LFA-1) mediates lymphocyte adhesion and plays a key role in inflammation and the immune response.
LFA-1 binds to intracellular adhesion molecules, e.g., ICAM-1, ICAM-2 or ICAM-3. The LFA-1/ICAM-1, ICAM-2 or ICAM-3 mediated interactions have been implicated in various disorders including transplant rejection, chronic inflammation, psoriasis, eczema/dermatitis, asthma and arthritis. LFA-1 antagonists are thus useful for the treatment and/or prevention of disorders which are responsive to LFA-1 inhibition, e.g., those cited herein, such as rheumatoid arthritis.
SUMMARY OF THE INVENTION
The present invention relates to diazacycloalkanedione derivatives, e.g., diazepanedione (hexahydrodiazepinedione) and diketopiperazine derivatives of formula I described herein which are particularly useful as LFA-1 antagonists, pharmaceutical compositions thereof, their methods of preparation and methods of treating conditions in mammals which are responsive to LFA-1 antagonism using said compounds or pharmaceutical compositions thereof.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates particularly to compounds of formula I
wherein R is carboxy, esterified carboxy or amidated carboxy;
R
1
and R
3
are independently lower alkyl, (hydroxy, lower alkoxy, amino, acylamino, mono- or di-lower alkylamino or mercapto)-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, cycloalkyl, aryl, biaryl, (cycloalkyl, aryl or biaryl)-lower alkyl, or (carboxy, esterified carboxy or amidated carboxy)-lower alkyl;
R
2
is hydrogen, lower alkyl, cycloalkyl, aryl, biaryl, arylaminocarbonyl, or aryl-(oxy, thio or amino); n is 1 or 2;
Y is lower-alkylene or lower alkenylene;
and pharmaceutically acceptable salts thereof.
A particular embodiment of the invention relates to the compounds of formula I wherein R is carboxy derivatized in form of a pharmaceutically acceptable amide; R
1
is aryl-lower alkyl; R
2
is aryl; R
3
is lower alkyl, aryl, or cycloalkyl-lower alkyl; and Y is C
1
-C
4
-alkylene or C
2-4
-alkenylene; and pharmaceutically acceptable salts thereof.
A more particular embodiment of the invention relates to the compounds of formula II
wherein R
1
′ is bicyclic aryl-lower alkyl; R
2
′ is bicyclic aryl; R
3
′ is monocyclic aryl or lower alkyl; R
4
is hydrogen or lower alkyl; n is 1 or 2; Y is C
1-4
-alkylene; and pharmaceutically acceptable salts thereof.
Particular embodiments of the invention relate to compounds of formula I and II wherein n is 1 and wherein n is 2.
Further preferred are said compound of formula II wherein R
1
′ is naphthyl-lower alkyl or quinolinyl-lower alkyl; R
2
′ is quinolinyl; R
3
′ is isobutyl; Y is methylene, and n is 2; and pharmaceutically acceptable salts thereof.
Compounds of the invention may possess one or more asymmetric centers and can exist as diastereomers, racemates and the enantiomers thereof, all of which are within the purview of the invention.
Preferred are the diastereomers of the formula Ia or IIa
wherein n, Y, R, R
1
, R
2
and R
3
in formula Ia, and n, Y, R
1
′, R
2
′, R
3
′ and R
4
in formula IIa have meaning as defined above.
Unless otherwise indicated, the general definitions used herein have the following meaning within the scope of the present invention.
Aryl represents carbocyclic or heterocyclic aryl, either monocyclic or bicyclic.
Monocyclic carbocyclic aryl represents optionally substituted phenyl, being preferably phenyl or phenyl substituted by one to three substituents, such being advantageously lower alkyl, hydroxy, lower alkoxy, acyloxy, halogen, cyano, trifluoromethyl, carbocyclic aryloxy or carbocyclic aryl-lower alkoxy; or phenyl substituted on adjacent carbon atoms by lower alkylene or by lower alkylene interrupted by O, or S or by N optionally substituted by lower alkyl.
Bicyclic carbocyclic aryl represents 1- or 2-naphthyl or 1- or 2-naphthyl substituted by, e.g., lower alkyl, lower alkoxy or halogen, advantageously 2-naphthyl. Naphthyl may also be named naphthalenyl.
Monocyclic heterocyclic aryl represents, e.g., optionally substituted thiazolyl, thienyl, furanyl or pyridyl.
Optionally substituted furanyl represents 2- or 3-furanyl preferably substituted by lower alkyl.
Optionally substituted pyridyl represents 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl preferably substituted by lower alkyl, halogen or cyano.
Optionally substituted thienyl represents 2- or 3-thienyl or 2- or 3-thienyl preferably substituted by lower alkyl.
Optionally substituted thiazolyl represents, e.g., 2- or 4-thiazolyl, or 2- or 4-thiazolyl preferably substituted by lower alkyl.
Bicyclic heterocyclic aryl represents, e.g., quinolinyl, isoquinolinyl, indolyl or benzothiazolyl optionally substituted by hydroxy, lower alkyl, lower alkoxy or halogen. Indolyl may also bear a substituent attached to the ring nitrogen, e.g., lower alkyl or aryl-lower alkyl.
Aryl-lower alkyl is advantageously arylmethyl optionally substituted on phenyl by one or two of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen, cyano or trifluoromethyl.
Biaryl represents phenyl substituted by carbocyclic aryl or heterocyclic aryl as defined herein, ortho, meta or para to the point of attachment of the phenyl ring, advantageously para, such as biphenyl, particularly 4-biphenyl, or pyridylphenyl, particularly 4-pyridylphenyl.
The term “lower” referred to herein in connection with organic radicals or compounds respectively defines such with up to and including 7, preferably up and including 4 and advantageously one or two carbon atoms. Such may be straight chain or branched.
A lower alkyl group preferably contains 1-4 carbon atoms and represents for example methyl, ethyl, propyl or butyl.
A lower alkylene group preferably contains 1-4 carbon atoms, and represents, for example, methylene, ethylene, propylene and the like.
A lower alkenylene group preferably contains 2-4 carbon atoms, and represents, for example, propenylene.
Cycloalkyl represents preferably cyclopentyl, cyclohexyl or cycloheptyl.
A lower alkoxy group preferably contains 1-4 carbon atoms and represents for example, methoxy, propoxy, isoproproxy or advantageously ethoxy.
Halogen (halo) preferably represents fluoro or chloro, but may also be bromo or iodo.
Acyl is derived from a carboxylic acid or carbonic acid and represents preferably optionally substituted lower alkanoyl, aroyl, lower alkoxycarbonyl or aryl-lower alkoxycarbonyl, advantageously aroyl.
Lower alkanoyl is preferably acetyl, propionyl, butyryl, or pivaloyl.
Optionally substituted lower alkanoyl for example represents lower alkanoyl or lower alkanoyl substituted, e.g., by lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoylthio, lower alkoxy, or by lower alkylthio.
Aroyl is preferably monocyclic carbocyclic or monocyclic heterocyclic aroyl.
Monocyclic carbocyclic aroyl is preferably benzoyl or benzoyl substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl.
Monocyclic heterocyclic aroyl is preferably pyridylcarbonyl or thienylcarbonyl.
Acyloxy is preferably optionally substituted lower alkanoyloxy, lower alkoxycarbonyloxy, monocyclic carbocyclic aroyloxy or monocyclic heterocyclic aroyloxy.
Esterified carboxy represents carboxy derivatized in form of a pharmaceutically acceptable ester, preferably lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono or disubstituted lower alkyl esters, e.g., the &ohgr;-(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the &agr;-(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxy-methyl ester, and the like conventionally used in the art.
Amidated carboxy represents carboxy derivatized in form of a pharmaceutically acceptable amide, e.g., primary, secondary and tertiary amides, e.g., the unsubstituted the N-mono-lower alkyl or N,N-di-lower alkylamides, or the amides of cyclic amines, e.g., of piperidine, pyrrolidine, morpholine or optiona
Albert Rainer
Dawson Janet
Ehrhardt Claus
Wattanasin Sompong
Weitz-Schmidt Gabriele
Gruenfeld Norbert
Kifle Bruck
Novartis AG
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