Process for preparing arylacetylaminothiazoles

Details Process for preparing arylacetylaminothiazoles Process for preparing arylacetylaminothiazoles

2000-12-22

2002-05-21

Gerstl, Robert (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06392053

ABSTRACT:

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable
REFERENCE TO A “Microfiche Appendix”
Not Applicable
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns new processes for the preparation of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.
2. Description of the Related Art
The 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazole compounds of formula I
or a pharmaceutically acceptable salt thereof, wherein:
R
1
, R
2
, R
4
, R
5
, R
6
, R
8
, R
9
, R
12
and R
13
are each independently hydrogen, alkyl, aryl or heteroaryl;
R
3
, R
7
, R
10
and R
11
are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy; and
X is CH or N,
are novel, potent inhibitors of cyclin dependent kinases (cdks). They are useful in the therapy of proliferative diseases, for example, cancer, inflammation, autoimmune diseases such as arthritis, viral diseases, fungal diseases, chemotherapy-induced alopecia, neurodegenerative disorders such as Alzheimer's disease and cardiovascular disease. More specifically, the compounds of formula I are useful in the treatment of a variety of cancers such as bladder, breast, colon, kidney, liver and lung cancers.
The preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles, key intermediates in the synthesis of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles of formula I, has been described (K. S. Kim et al., WO 9924416, May 20, 1999 and corresponding U.S. Pat. No. 6,040,321).
4-Formylphenylacetic acid has been previously prepared from ethyl phenylacetate in four steps which provided <15% overall yield (J. W. Baker et al.,
J. Chem. Soc
. 1956, 404).
The reaction of 4-bromophenylacetic acid or ester with alkyl acrylates using palladium catalysts to give 4-(2-alkoxycarbonylvinyl)phenylacetic acid or ester has been previously reported in the literature (J. W. Tilley et al.,
J. Med. Chem
. 1991, 34, 1125; A. Cerri et al.,
J. Heterocycl Chem
. 1993, 30, 1581). The oxidation of &bgr;-arylacrylates to give aryl aldehydes has also been reported (G. Cainelli et al.,
Synthesis
, 1989, 47; D. G. Lee et al.,
Can. J. Chem
. 1972, 50; D. G. Lee et al.,
Liebigs Ann. Chem
. 1993, 503; S. Antus et al.,
Liebigs Ann. Chem
. 1993, 105).
BRIEF SUMMARY OF THE INVENTION
This invention concerns new efficient processes for the preparation of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs. The processes involve new strategy for the preparation of formylarylacetic acids, key intermediates in the synthesis of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.
BRIEF DESCRIPTION OF THE DRAWINGS
Not Applicable
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to new, more efficient processes for the preparation of formylarylacetic acids with application to the synthesis of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs, inhibitors of cyclin dependent kinases. The processes involve reaction of haloarylacetic acids or esters II with olefins III to give vinylarylacetic acids or esters IV. Oxidation of IV with an oxidizing reagent gives formylarylacetic acids or esters V. Compared to the previous process which takes four steps and has yields less than 15%, the process of the invention can obtain the formylacetic acids or esters in only two steps and at substantially higher yields.
Subsequent coupling of formylarylacetic acids or esters V with 5-(2-oxazolylalkylthio)-2-aminothiazoles VI produces amides VII. Reductive amination of the amide VII with amines affords 5-(2-oxazolylalkylthio)-2-(aminoalkyl)arylacetylaminothiazoles I, inhibitors of cyclin dependent kinases.
Alternatively, compounds of formula I can be prepared by coupling of haloalkylarylacetic acids VIII with 5-(2-oxazolylalkylthio)-2-aminothiazoles VI followed by aminolysis of the resulting amides IX with amines.
The above-described reactions are illustrated in the below Scheme 1.
In formulas I-IX of Scheme 1, the following terms apply:
R, R
1
, R
2
, R
4
, R
5
, R
6
, R
8
, R
9
, R
12
and R
13
are each independently hydrogen, alkyl, aryl or heteroaryl;
R
3
, R
7
, R
10
and R
11
are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;
W is halogen or sulfonate (RSO
2
O—, CF
3
SO
2
O—, etc.);
X is CH or N;
Y is CHO, C(O)R, COOR, CONRR
1
, CN, NO
2
, SO
2
OR or SO
2
NRR
1
; and
Z is hydrogen, CHO, C(O)R, COOR, CONRR
1
, CN, NO
2
, SO
2
OR or SO
2
NRR
1
.
Listed below are definitions of various terms used to describe the compounds involved in the processes of the present invention. These definitions apply to the terms as they are used throughout the specification (unless specifically indicated otherwise) either individually or as part of a larger group. It should be noted that any heteroatom with unsatisfied valences is assumed to have the hydrogen atom to satisfy the valences.
The term “alkyl” or “alk” (i.e., derivative forms of alkyl) refers to optionally substituted straight chain, branched or cyclic monovalent alkane (saturated hydrocarbon) derived radicals containing from 1 to 12 carbon atoms. When substituted, alkyl groups may be substituted with up to four substituent groups at any available point of attachment. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The alkyl can be optionally substituted with one or more halogens or alkyl groups such as, for example, trifluoromethyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, etc.
The term “aryl” or derivative forms thereof refers to monocyclic or bicyclic aromatic rings, e.g., phenyl, substituted phenyl and the like, as well as groups which are fused, e.g., napthyl, phenanthrenyl and the like, containing from 6 to 30 carbon atoms. An aryl group can thus contain at least one ring having 6 atoms, with up to five such rings being present, containing up to 22 or 30 atoms therein, depending upon optionally alternating (resonating) double bonds between carbon atoms or suitable heteroatoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, biphenyl and the like.
The term “halogen” or “halo” refers to chlorine, bromine, fluorine or iodine, with bromine being the preferred halogen. The term “heteroaryl” refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Exemplary heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrrolidinyl, piperidinyl, thiazolyl, oxazolyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinal triazinylazepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, benzofurazanyl, etc. The heteroaryl groups can be optionally substituted by one or more groups which include, but are not limited to, halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, trifluoromethyl, cycloalkyl, nitro, cyano, amino, alkylS(O)
m
(where m=0, 1 or 2), thiol and the like.
The term “pharmaceutically acceptable salt” refers to those salts of the biologically active compounds which do not significantly or adversely affect the pharmaceutical properties of the compounds, such as, for example, toxicity, efficacy, etc. and include those salts which are conventionally employed in the pharmaceutical industry. Suitable examples of salts include, but are not limited to, those formed with inorganic or organic acids such as

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