Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-05-28
2001-01-16
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S280000
Reexamination Certificate
active
06174888
ABSTRACT:
BACKGROUND AND SUMMARY OF THE INVENTION
The invention relates to the 9-deazaguanine derivatives, namely 2-amino-7-(1-substituted-2-hydroxyethyl)-3,5-dihydro-pyrrolo[3,2-d] pyrimidin-4-ones as defined herein which are particularly potent purine nucleoside phosphorylase (PNP) inhibitors, methods for preparation thereof, pharmaceutical compositions comprising said compounds, and a method of inhibiting purine nucleoside phosphorylase and of treating conditions in mammals which are responsive to purine nucleoside phosphorylase inhibition using said compounds or pharmaceutical compositions comprising said compounds of the invention.
7-(1-Substituted-hydroxyalkyl)-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-ones, including specific 7-(1-aryl-3-hydroxypropyl)-substituted compounds, are, inter alia, disclosed in U.S. Pat. No. 5,189,139 and International Application WO 93/21187. However, there is no suggestion to prepare the novel 7-(1-substituted-2-hydroxyethyl)-substituted compounds of the present invention to obtain unexpectedly potent PNP inhibitors.
The compounds of the invention are particularly useful in mammals as purine nucleoside phosphorylase (PNP) inihibitors, as selective inhibitors of T-cell formation and thus function as immunosuppressants suppressing cellular immunity. They can be used for the prevention and treatment of transplant rejection and for treatment of autoimmune diseases such as rheumatoid arthritis, psoriasis and dermatitis, Crohn's disease, uveitis, asthma, and diabetes in mammals. They can also be used to potentiate the antiviral and antitumor effect of antiviral or antitumor purine nucleosides, in particular 2′,3′-dideoxypurine nucleosides for the treatment of retrovirus infections such as AIDS (acquired immunodeficiency syndrome); and also for the treatment of gout.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to the compounds of formula I
and tautomers thereof, wherein Ar represents biaryl, carbocyclic or heterocyclic aryl; pharmaceutically acceptable prodrug ester derivatives; and pharmaceutically acceptable salts thereof.
The compounds of the invention possess an asymmetric carbon atom and therefore exist as racemates and the (R) and (S) enantiomers thereof. The present invention is intended to include these forms, also diastereoisomers and mixtures thereof if two or more asymmetric centers are present.
Preferred are the enantiomers of formula Ia
and tautomers thereof, wherein Ar represents biaryl, carbocyclic aryl or heterocyclic aryl; pharmaceutically acceptable prodrug ester derivatives thereof; and pharmaceutically acceptable salts thereof.
Embodiments of the invention are said compounds of formula I and Ia wherein Ar represents monocyclic carbocylic aryl or monocyclic heterocyclic aryl. A particular embodiment of the invention relates to the compounds of Formula I or Ia wherein Ar is phenyl or phenyl substituted by one to five substituents, preferably by one or two substituents. Preferred are the compounds of formula II and the corresponding enantiomers of formula IIa
and tautomers thereof, wherein R
1
and R
2
represent independently hydrogen, halo, lower alkyl, hydroxy, lower alkoxy, aryl-lower alkoxy, acyloxy, aryloxy, trifluoromethyl, cyano, (hydroxy, lower alkoxy or acyloxy)-lower alkyl, or (lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl)-lower alkyl; or R
1
and R
2
together on adjacent carbon atoms represent lower alkylenedioxy; prodrug pharmaceutically acceptable ester derivatives thereof; and pharmaceutically acceptable salts thereof.
A further embodiment of the invention relates to the compounds of formula I and Ia wherein Ar is monocyclic heterocyclic aryl comprising thienyl, furanyl, pyridyl, pyrrolyl, thiazolyl, pyrazinyl, pyridazinyl or pyrazolyl.
Preferred are the compounds of formulae I and Ia and tautomers thereof, wherein Ar is phenyl, pyridyl or halophenyl such as chloro- or fluorophenyl; pharmaceutically acceptable carboxylic acid derived prodrug ester derivatives thereof; and pharmaceutically acceptable salts thereof.
Particularly preferred are the enantiomers of formula III
and tautomers thereof, wherein R represents hydrogen, chloro, or fluoro;
pharmaceutically acceptable prodrug esters thereof; and pharmaceutically acceptable salts thereof.
Preferred in turn are the compounds of formula III wherein R is hydrogen or fluoro at the ortho position.
Further preferred embodiments of the invention relate to the specific compounds disclosed in the examples.
The compounds of the invention represent 9-substituted-9-deazaguanines which are named herein as 7-substituted 2-amino-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-ones. Such can exist in several tautomeric forms, e.g., as represented by structure IV.
and other structures involving allowable rearrangement of positions of double bonds. All tautomeric forms are within the scope of the invention.
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.
Bicyclic carbocyclic aryl represents 1- or 2-naphthyl or 1- or 2-naphthyl substituted by, e.g., lower alkyl, lower alkoxy or halogen.
Monocyclic heterocyclic aryl represents optionally substituted thienyl, furanyl, pyridyl, pyrrolyl, thiazolyl, pyrazinyl, pyridazinyl or pyrazolyl, preferably 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., 4-thiazolyl, or 4-thiazolyl substituted by lower alkyl.
Bicyclic heterocyclic aryl represents preferably indolyl or benzothiazolyl optionally substituted by hydroxy, lower alkyl, lower alkoxy or halogen, advantageously 3-indolyl or 2-benzothiazolyl.
Aryl as in aryl-lower alkyl is preferably phenyl or phenyl substituted by one or two of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen, trifluoromethyl or cyano; also, optionally substituted naphthyl.
Aryl-lower alkyl is advantageously benzyl or 1- or 2-phenethyl 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 4-biphenyl.
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, ethyl, propyl, butyl or advantageously methyl.
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 and represents preferably optionally substituted lower alkanoyl, carbocyclic aryl-lower alkanoyl, aroyl, lower alkoxycarbonyl or aryl-lower alkoxycarbonyl, advantageously optionally substituted lower alkanoyl, or aroyl.
Lower alkanoyl is preferably acetyl, propionyl, butyryl, or pivaloyl.
Optionally substituted lower alkanoyl for example represents lower alkanoyl or lower alkanoyl substituted
McQuire Leslie W.
Mugrage Benjamin B.
Van Duzer John H.
Ford John M.
Gruenfeld Norbert
Novartis AG
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