Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-01
2003-02-04
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S184000, C548S185000
Reexamination Certificate
active
06515004
ABSTRACT:
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to compounds of formula I
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof wherein
R is alkyl;
R
1
is hydrogen or alkyl;
X is NR
2
or CHNR
2
R
3
;
R
2
and R
3
are each independently hydrogen, alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl; and
n is 0, 1, 2 or 3.
The compounds of formula I are particularly useful as potent, protein kinase inhibitors and are useful in the treatment of proliferative diseases, for example, cancer, inflammation and arthritis. They may also be useful in the treatment of Alzheimer's disease, chemotherapy-induced alopecia, and cardiovascular disease.
DESCRIPTION OF THE INVENTION
The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds, and for methods of using such compounds.
Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
The term “alkyl” or “alk” refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 12, preferably 1 to 6, and more preferably 1 to 4, carbon atoms unless otherwise defined. An alkyl group is an optionally substituted straight, branched or cyclic saturated hydrocarbon group. When substituted, alkyl groups may be substituted with up to four substituent groups, R
4
as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with “branched alkyl group”. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo (such as F, Cl, Br or I), haloalkyl (such as CCl
3
or CF
3
), alkoxy, alkylthio, hydroxy, carboxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, amino, carbamoyl, urea, amidinyl, or thiol.
Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings. Exemplary unsubstituted such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Exemplary substituents include one or more of the following groups: halogen, alkyl, alkoxy, alkyl hydroxy, amino, nitro, cyano, thiol and/or alkylthio.
The terms “alkoxy” or “alkylthio”, as used herein, denote an alkyl group as described above bonded through an oxygen linkage (—O—) or a sulfur linkage (—S—), respectively.
The term “alkyloxycarbonyl”, as used herein, denotes an alkoxy group bonded through a carbonyl group. An alkoxycarbonyl radical is represented by the formula: —C(O)OR
5
, where the R
5
group is a straight or branched C
1-6
alkyl group.
The term “alkylcarbonyl” refers to an alkyl group bonded through a carbonyl group.
The term “alkylcarbonyloxy”, as used herein, denotes an alkylcarbonyl group which is bonded through an oxygen linkage.
Pharmaceutically acceptable salts of compounds of formula I which are suitable for use in the methods and compositions of the present invention include, but are not limited to, salts formed with a variety of organic and inorganic acids such as hydrogen chloride, hydroxymethane sulfonic acid, hydrogen bromide, hydrogen iodide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid and various others, e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates, and the like. These salts include racemic forms as well as enantiomers, and diastereomers (such as, for example, D-tartrate and L-tartrate salts). In addition, pharmaceutically acceptable salts of compounds of formula I may be formed with alkali metals such as sodium, potassium and lithium; alkaline earth metals such as calcium and magnesium; organic bases such as dicyclohexylamine, tributylamine, and pyridines, and the like; and amino acids such as arginine, lysine and the like.
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The definition of the compounds according to the invention embraces all possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
All configurational isomers of compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds of the present invention very particularly embraces both cis and trans isomers of cycloalkyl rings.
In the context of the present invention, the definition of compounds of the present invention includes the free base, enantiomers, diastereomers as well as pharmaceutically acceptable salts. Examples of such pharmaceutically acceptable salts include, but are not limited to, hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts. Also included are salts formed with other organic and inorganic acids such as hydroxymethane sulfonic acid, acetic acid, benzenesulfonic acid, toluenesulfonic acid and various others, e.g., nitrates, phosphates, borates, benzoates, ascorbates, salicylates, and the like. These salts include racemic forms as well as enantiomers and diastereomers (such as, for example, D-tartrate and L-tartrate salts). In addition, pharmaceutically acceptable salts of the formula I compounds may be formed with alkali metals such as sodium, potassium and lithium; alkaline earth metals such as calcium and magnesium; organic bases such as dicyclohexylamine, tributylamine, and pyridines, and the like; and amino acids such as arginine, lysine and the like.
It should be understood that solvates (e.g. hydrates) of the compounds of formula I are also within the scope of the present invention. Methods of solvation are generally known in the art. Accordingly, the compounds of the instant invention may be in the free or hydrate form, and may be obtained by methods exemplified by the following schemes.
Compounds of formula I may generally be prepared, as shown in Scheme 1, by reacting an amine of formula II with a carboxylic acid of formula III in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a base.
Formula I compounds wherein X is NR
2
and R
2
is hydrogen may be prepared, as shown in Scheme 2, by reacting an amine of formula II with a carboxylic acid of formula IV in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a base to form an N-protected compound of formula V, and deprotecting the formula V compound with acid.
Compounds of formula I wherein X is NR
2
and R
2
is 2,3-dihydroxypropyl may be prepared, as shown in Scheme 3, by reacting a compound of formula I wherein X is NR2 and R
2
is hydrogen with glyceraldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride and an alcohol such as methanol.
Formula I compounds wherein X is NR
2
and R
2
is 2-hydroxyethyl may be prepared, as shown in Scheme 4, by reacting a compound of formula I wherein X is NR
2
and R
2
is hydrogen with a 2-(bromoethoxy)trialkylsilane of formu
Misra Raj N.
Xiao Hai-Yun
Bristol--Myers Squibb Company
Gerstl Robert
Patel Rena
LandOfFree
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