Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-01
2003-02-25
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S274000, C544S123000, C544S310000, C544S311000, C544S312000, C544S314000
Reexamination Certificate
active
06525050
ABSTRACT:
FIELD AND INDUSTRIAL APPLICABILITY OF THE INVENTION
The present invention relates to compounds that inhibit the enzyme aminoimidazole carboxamide ribonucleotide formyl transferase (AICARFT), to pharmaceutical compositions containing these compounds, and to their use to inhibit AICARFT. The-invention also relates to the preparation of these compounds, and to intermediates for preparing these compounds.
BACKGROUND OF THE INVENTION
The large class of antiproliferative agents includes antimetabolite compounds. A particular subclass of antimetabolites known as antifolates or antifoles are antagonists of the vitamin folic acid.
Aminoimidazole carboxamide ribonucleotide formyl transferase (AICARFT) is a folate-dependent enzyme in the de novo purine biosynthesis pathway. This pathway is critical to cell division and proliferation. Shutting down this pathway is known to have an antiproliferative, in particular, an antitumor effect.
There is a need for compounds that inhibit the enzyme AICARFT, having antitumor, antiinflammatory, antipsoriatic, and/or immunosuppressive activity.
SUMMARY OF THE INVENTION
An object of the invention is to provide small-molecule compounds that inhibit AICARFT. Another object of the invention is to provide antitumor, antiinflammatory, antipsoriatic, or immunosuppressive agents useful in pharmaceutical treatments.
Surprisingly, such objects have been achieved by the compounds of formula I:
wherein:
R
1
is H or CN;
R
2
is phenyl or thienyl, each of which may be optionally substituted with phenyl, phenoxy, thienyl, tetrazolyl, or 4-morpholinyl; and
R
3
is phenyl substituted with —SO
2
NR
5
R
6
or —NR
5
SO
2
R
6
and optionally further substituted by one or more of the suitable substituents defined below; wherein R
5
is H or lower alkyl, R
6
is lower alkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein the aryl and heteroaryl moieties may be substituted by one or more of the suitable substituents defined below; or
wherein n is an integer of from 1 to 4, R
4
is OH, lower alkoxy, or a glutamic-acid or glutamate-ester moiety linked through the amine functional group.
The invention also relates to pharmaceutically acceptable salts, solvates, prodrugs, and active metabolites of compounds of the formula I.
In preferred embodiments, R
2
is selected from
and/or
R
3
may be phenyl substituted with —SO
2
NR
5
R
6
or —NR
5
SO
2
R
6
and optionally further substituted by lower alkyl, lower alkoxy, or halogen. For example, R
3
may be:
each of which may be optionally substituted with one additional substituent selected from methyl, methoxy and chloro.
Perferred compounds of the invention are:
and pharmaceutically acceptable salts, solvates, prodrugs, and active metabolites of such compounds.
The invention further relates to use of the compounds of formula I, and especially the above-described preferred compounds, as inhibitors of the enzyme AICARFT.
The invention also relates to methods of synthesizing the compounds of the invention, comprising carrying out the following general alkylation reaction:
where R
1
, R
2
, and R
3
are as defined above.
Other features, objects, and advantages of the invention will become apparent from the detailed description of the invention provided below.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
In accordance with a convention used in the art,
is used in structural formulae herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
Where chiral carbons are included in chemical structures, unless a particular orientation is depicted, both stereoisomeric forms are intended to be encompassed. Further, the inventive compounds may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the broad scope of the present invention. Preferably, however, the inventive compounds are used in optically pure form.
As generally understood by those skilled in the art, an optically pure compound is one that is essentially enantiomerically pure. Preferably, an optically pure compound of the invention contains at least 90% of a single isomer (80% enantiomeric excess), more preferably at least 95% (90% e.e.), even more preferably at least 97.5% (95% e.e.), and most preferably at least 99% (98% e.e.).
The compounds illustrated by the chemical formulae referred to herein may exhibit the phenomenon of tautomerism. Although the structural formulae depict one of the possible tautomeric forms, it should be understood that the invention nonetheless encompasses all tautomeric forms.
As used herein, the term “alkyl group” is intended to mean a straight- or branched-chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl, and the like, which may be unsubstituted (i.e., containing only carbon and hydrogen) or substituted by one or more suitable substituents as defined below (e.g., one or more halogens, such as F, Cl, Br, or I, with F and Cl being preferred). A “lower alkyl group” is intended to mean an alkyl group having from 1 to 4 carbon atoms in its chain.
An “alkoxy group” is intended to mean the radical —OR
a
, where R
a
is an alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, and propoxy. “Lower alkoxy” refers to alkoxy groups wherein the alkyl portion has 1 to 4 carbon atoms.
An “aryl” group is intended to mean a cyclic aromatic hydrocarbon group, such as phenyl or naphthyl, which may be unsubstituted or substituted by one or more of the suitable substituents defined below (e.g., with one or more halogen, lower alkyl, and/or lower alkoxy group). Preferably, aryl is a substituted or unsubstituted phenyl group.
A “heteroaryl” group is intended to mean a cyclic aromatic group containing at least one heteroatom selected from oxygen, sulfur and nitrogen, wherein any position of the heteroaryl group may be unsubstituted or substituted by a suitable substituent, as defined below (e.g., with a halogen, lower alkyl, or lower alkoxy group). Preferably the heteroaryl group is a nitrogen-containing cyclic aromatic group. Exemplary nitrogen-containing heteroaryl groups include quinolyl, isoquinolyl, indolyl, pyridyl, pyrrolyl, pyrazinyl, and thiazolyl. A “heteroarylalkyl” group comprises an alkylenyl moiety bonded to a substituted or unsubstituted heteroaryl group, e.g., —(CH
2
)
x
-indolyl, wherein x may be an integer of from 1 to 4 and any position of the heteroaryl group may be unsubstituted or substituted by a suitable substituent, as defined below. Preferable heteroaryl groups include substituted or unsubstituted isoquinolyl or indolyl groups.
The term “substituent” or “suitable substituent” is intended to mean any suitable substituent that may be recognized or selected, such as through routine testing, by those skilled in the art. Illustrative examples of suitable substituents include hydroxy groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxy groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups, and the like.
The term “optionally substituted” is intended to expressly indicate that the specified group is unsubstituted or substituted with one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituents. As defined above, various groups may be unsubstituted or substituted (i.e., they are optionally substituted) unless indicated otherwise herein (e.g., by indicating that the specif
Bleckman Ted M.
Palmer Cynthia L.
Romines, III William H.
Varney Michael D.
Agouron Pharmaceuticals , Inc.
McKenzie Thomas C
Neidart Karl
Richardson Peter
Shah Mukund J.
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