Process for preparing azacycloalkanoylaminothiazoles

Details Process for preparing azacycloalkanoylaminothiazoles Process for preparing azacycloalkanoylaminothiazoles

2000-12-22

2002-07-02

Gerstl, Robert (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S185000

Reexamination Certificate

active

06414156

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-azacycloalkanoylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.
2. Description of the Related Art
The 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazole compounds of formula I
or a pharmaceutically acceptable salt thereof, wherein:
R is alkyl, aryl or heteroaryl;
R
1
, R
2
, R
3
, R
4
and R
5
are each independently hydrogen, alkyl, aryl or heteroaryl;
R
6
and R
7
are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;
R
8
is hydrogen, alkyl, aryl, heteroaryl, CONR
9
R
10
, COR
11
or COOR
12
;
R
9
, R
10
, R
11
and R
12
are each independently hydrogen, alkyl or aryl;
m equals 0 to 5; and
n equals 0 to 5,
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.
WO 9924416 and corresponding U.S. Pat. No. 6,040,321 describe the preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles, key intermediates in the synthesis of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles of formula I, by reacting 5-acetylthio-2-acetylaminothiazole with a base followed by trapping the thiolate with a 2-oxazolylalkyl halide. Hydrolysis of the resulting 5-(2-oxazolylalkylthio)-2-acetylaminothiazole compounds afforded the 5-(2-oxazolylalkylthio)-2-aminothiazole key intermediates. The requisite 2-oxazolylalkyl halides were prepared by (i) reaction of &bgr;-hydroxy amines with &agr;-chloroacyl chlorides followed by oxidation of the resulting &bgr;-hydroxy-&agr;-chloroamides and subsequent oxazole ring formation (K. S. Kim et al., WO 9924416, May 20, 1999) or (ii) reaction of &agr;-diazo ketones with &agr;-chloronitriles (K. S. Kim et al, WO 9924416, May 20, 1999; T. Ibata et al.,
Bull. Chem. Soc. Japan
1979, 52, 3597). Although a variety of 5-(2-oxazolylalkylthio)-2-aminothiazoles can be prepared by this method, this process is not amenable to large scale synthesis due to the commercial availability of the starting 5-acetylthio-2-acetylaminothiazole, the use of hazardous &agr;-diazo ketones and expensive chromatographic separation of products.
Reaction of &agr;-halo ketones with azide to give &agr;-azido ketones has been previously reported in the literature (A. Hassner et al.,
Angew Chem. Int. Ed. Engl.
1986, 25, 478; M. G. Nair et al.,
J. Med. Chem.
1980, 23, 899; H.-J. Ha et al.,
Synth. Commun.
1994, 24, 2557). Reaction of &agr;-sulfonyloxy ketones with azide to give &agr;-azido ketones has also been previously reported (T. Patonay et al.,
J. Org. Chem.
1994, 59, 2902; G. A. Revelli et al,
Synth. Commun.
1993, 23, 1111).
Reduction of &agr;-azido ketones to &agr;-amino ketones has been described in the literature (H.-J. Ha et al.,
Synth. Commun.
1994, 24, 2557; J. P. Sanchez et al.,
J. Heterocycl. Chem.
1988, 25, 469; S. K. Boyer et al.,
J. Org. Chem.
1985, 50, 3408). Reaction of &agr;-amino ketones with &agr;-halo acyl halides to give the corresponding amides has further been described (G. T. Newbold et al.,
J. Chem. Soc.
1948, 1855; G. T. Newbold et al.,
J. Chem. Soc.
1950, 909).
Reaction of alkylthiouronium salts with alkyl halides to give sulfides has been previously reported (H. Chen et al.,
Synth. Commun.
1990, 20, 3313). Reaction of alkylthiols with 5-bromo-2-aminothiazole to give 5-alkylthio-2-aminothiazoles has been reported (J. B. Dickey et al.,
J. Org. Chem.
1959, 24, 187).
BRIEF SUMMARY OF THE INVENTION
This invention concerns new efficient processes for the preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles. The processes involve new strategies for the preparation of 2-oxazolylalkyl halides and 5-(2-oxazolylalkylthio)-2-aminothiazoles which include the method of making new key intermediate quaternary ammonium salts and 2-oxazolylalkyl sulfide derivatives. This invention further relates to processes for the preparation of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.
BRIEF DESCRIPTION OF THE DRAWINGS
Not Applicable


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