Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2000-01-17
2001-07-24
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S305000
Reexamination Certificate
active
06265578
ABSTRACT:
BRIEF SUMMARY OF THE INVENTION
The invention relates to compounds of formula I
wherein
R
1
is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyl, substituted alkynyl, alkoxy, substituted alkoxy, aryloxy or alkylalkoxy, and
R
2
is aryloxy, or a pharmaceutically acceptable salt of an acidic compound of formula I, or a prodrug thereof.
The compounds of the invention are matrix metalloprotease inhibitors useful for treating or controlling cancer associated with overexpression of gelatinase-A and/or gelatinase-B, particularly skin cancer, breast cancer, prostate cancer, colon cancer, lung cancer, and gastric cancer. The compounds of the invention are also useful for other diseases associated with unregulated degradation of extracellular matrix, including rheumatoid arthritis, osteoarthritis, multiple sclerosis, corneal ulceration, periodontal disease and the like.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to compounds of formula I
wherein
R
1
is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryloxy or alkylalkoxy, and
R
2
is aryloxy, or a pharmaceutically acceptable salt of an acidic compound of formula I, or a prodrug thereof.
A prodrug is a compound that may be converted under physiological conditions to a compound of formula I or a pharmaceutically acceptable salt thereof. Preferably, a prodrug is an acyl or alkylmethyl ether derivative of a compound of formula I or a pharmaceutically acceptable salt thereof.
As used herein, the term “alkyl” means a straight or branched-chain alkyl group containing a maximum of 13, preferably a maximum of 7, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, and pentyl, hexyl and the like.
The term “substituted alkyl” means alkyl which is substituted by one or more substituents, examples of which are hydroxy, halogen, and aryl.
The term “alkenyl” means a straight or branched chain hydrocarbon group containing a maximum of 13, preferably a maximum of 7, and at least 2, carbon atoms, and at least one double bond, such as ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.
The term “substituted alkenyl” means alkenyl which is substituted by one or more substituents, examples of which are hydroxy, halogen, and aryl.
The term “alkynyl” means a straight or branched chain hydrocarbon group containing a maximum of 13, preferably a maximum of 7, and at least 2, carbon atoms, and at least one triple bond.
The term “substituted alkynyl” means alkynyl which is substituted by one or more substituents, examples of which are hydroxy, halogen, and aryl.
The term “alkoxy” means a straight straight or branched-chain alkoxy group containing a maximum of 11, preferably a maximum of 5, carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like.
The term “substituted alkoxy” means alkoxy which is substituted by one or more substituents, examples of which are hydroxy, halogen and aryl.
The term alkylalkoxy means a combination of an alkyl or substituted alkyl group and an alkoxy or substituted alkoxy group.
The term “aryl”, alone or in combination, means an aromatic carbocyclic ring or a heterocyclic ring, which is unsubstituted or substituted by one or more, preferably one to three, substituents, examples of which are alkyl, hydroxy, alkoxy, and halogen. Examples of aromatic carbocyclic rings are phenyl and naphthyl. Examples of aromatic heterocyclic rings are pyridino, pyrrolo, thienyl, pyrazolo, imidazolo, thiazolo, oxazolo, triazolo, tetrazolo, oxadiazolo, thiadiazolo, benzofuryl, benzothienyl, benzimidazolo, benzotriazolo, quinolinyl, isoquinolinyl, and indolyl. Most preferably, aryl is an unsubstituted phenyl group or phenyl group having one or more, preferably one to three, substituents, examples of which are halogen, alkyl, hydroxy, alkoxy, and halogen.
The term “halogen” means fluorine, chlorine, bromine, or iodine.
The term “acyl” means a group derived from an alkanoic acid, for example, acetyl, propionyl or butyryl, or from an aromatic carboxylic acid for example, benzoyl. Examples of substituents on alkanoic acid includes one or more of the following: hydroxy, alkoxy, amino, halogen, thioalkyl, carboxy, carboxylic acid derivative or alkyl sulphinyl and the like. Examples of substituents on aromatic carboxylic acid include one or more of the following: halogen, alkyl, hydroxy, benzyloxy, alkoxy, haloalkyl, nitro, amino, cyano and the like.
Preferably, R
1
is hydrogen, alkyl, substituted alkyl, or substituted alkoxy. More preferably, R
1
is hydrogen, alkyl containing a maximum of 7 carbon atoms, substituted alkyl containing a maximum of 7 carbon atoms (preferably hydroxymethyl) or substituted alkoxy containing a maximum of 5 carbon atoms (preferably benzyloxy).
Preferably, R
2
is in the para position. More preferably, R
2
is phenoxy.
Preferably, the compound of formula I is 5-methyl-5-(4-phenoxyphenyl) pyrimidine-2,4,6-trione, 5-hexyl-5-(4-phenoxyphenyl)pyrimidine-2,4,6-trione, 5-benzyloxymethyl-5-(4-phenoxyphenyl)pyrimidine-2,4,6-trione, or 5-(2-hydroxyethyl)-5-(4-phenoxyphenyl)pyrimidine-2,4,6-trione.
The compounds of formula I may be prepared by the following Schemes I-II.
The compounds of formula I are prepared by the following Scheme I.
Compounds of formula III are prepared by treatment of compounds of formula II with a strong base, such as sodium hydride, lithium diisopropylamide, or lithium bis(trimethylsilyl)amide, in an aprotic solvent such as tetrahydrofuran (THF). The resultant anion is then reacted with with dimethylcarbonate or methyl chloroformate at temperatures ranging from room temperature to reflux to form a compound of formula III.
The compounds of formula IV are prepared by reacting a compound of formula III with urea in a basic solution, such as sodium methoxide in methanol, at reflux.
The compounds of formula I are prepared by reacting a compound of formula IV with a strong base, such as sodium hydride, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, in an aprotic solvent, such as THF, to form an anion. The anion is then treated with alkyl halide, such as methyl iodide, hexyl bromide, allyl bromide, or benzyl chloromethyl ether, at temperatures varying from room temperature to reflux. N-substituted-2,4,6-triones are then removed by chromatography to provide the desired compound of formula I.
The compounds of formula II are known or can prepared by known methods.
The compounds of formula I can also be prepared as described in Scheme II.
Compounds of formula V are prepared by reacting a compound formula III with a strong base such as sodium hydride, lithium diisopropylamide, lithium bis(trimethyl-silyl)amide, in an aprotic solvent such as THF. The resulting anion is then treated with an alkyl halide, such as methyl iodide, hexyl bromide, allyl bromide, or benzyl chloromethyl ether, at temperatures varying from room temperature to reflux.
In the case of a compound of formula V wherein R
1
is hydroxymethyl, compounds of formula V are also prepared by reacting a compound formula III with a strong base such as sodium hydride, lithium diisopropylamide, lithium bis(trimethyl-silyl)amide, in an aprotic solvent such as THF. The resulting anion is then treated with ethylene oxide. Alternatively, in the case of a compound of formula V wherein R
1
is hydroxymethyl, compounds of formula V are also prepared by carrying out oxidative cleavage of the compound of formula III, dimethyl 2-(2-propenyl)-2-(4-phenoxy-phenyl)malonate, with ozone and reducing the resultant ozonide with a phosphine or a thiol to give the aldehyde which is then reduced to the alcohol, using a reducing agent such as sodium borohydride.
Compounds of formula I are prepared by heating compounds of formula V with urea in the presence of Mg(OCH
3
)
2
as a paste at 80-100° C. for a period of time necessary to complete the reaction.
If desired, an acidic compound of formula I can be converted into a pharmaceutically acceptable salt with a base in a known manner. Suitable salts
Foley Louise Helen
Palermo Robert Edward
Wang Ping
Ford John M.
Hoffmann-La Roche Inc.
Johnston George W.
Rocha-Tramaloni Patricia S.
Silverman Robert A.
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