Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-26
2001-04-10
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...
C514S342000, C546S280700, C548S185000
Reexamination Certificate
active
06214852
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
and R
2
are each independently hydrogen or alkyl;
R
3
is hydrogen or alkyl, and R
4
is hydrogen or alkyl substituted with one or two hydroxy groups or one NR
5
R
6
group, or R
3
and R
4
are taken together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocyclic ring wherein R
3
R
4
is represented by —(CH
2
)
n
— where n is an integer of 3, 4, 5 or 6;
R
5
and R
6
are each independently hydrogen, alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl, or R
5
and R
6
are taken together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocyclic ring wherein R
5
R
6
is represented by —(CH
2
)
m
— where m is an integer of 3, 4, 5 or 6; and
X is CH or N.
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
7
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
8
, where the R
8
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 the formula I compounds 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, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others, e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates, and the like. 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.
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.
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 a coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or 1,3-dicyclohexylcarbodiimide optionally in the presence of a base.
Formula I compounds may also 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 a coupling reagent such as 1,3-dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to form an intermediate compound of formula V, and reacting the intermediate compound with an amine of formula VI.
Compounds of formula I wherein R
2
is hydrogen may be prepared, as shown in Scheme 3, by reacting a carboxylic acid of formula VII with oxalyl chloride to form an acid chloride intermediate, reacting the acid chloride intermediate with an amine of formula II to form an aldehyde intermediate of formula VIII, and reacting the aldehyde intermediate with an amine of formula VI in the presence of a reducing agent such as sodium triacetoxyborohydride.
Formula I compounds wherein R
2
is alkyl may be prepared, as shown in Scheme 4, by reacting an aldehyde of formula VIII with an alkylmagnesium bromide of formula IX to form an alcohol of formula X, reacting the formula X alcohol with thionyl chloride to form a chloride of formula XI, and reacting the chloride compound with an amine of formula VI.
Furthermore, the examples provided herein describe additional methods for the preparation of the formula I compounds of the present invention.
Starting amines of formula II may be prepared as shown in Scheme 5. An alpha-bromoketone of formula XII may be reacted with sodium azide in a solvent such as dimethylformamide to provide the azido ketone derivative XIII, which is reduced by a reducing agent such as hydrogen in the presence of palla
Kim Kyoung S.
Kimball S. David
Babcock Timothy J.
Bristol--Myers Squibb Company
Gerstl Robert
Patel Rena
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