Process for preparing azacycloalkanoylaminothiazoles

Details Process for preparing azacycloalkanoylaminothiazoles Process for preparing azacycloalkanoylaminothiazoles

2002-03-18

2003-10-28

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

06639074

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
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to new, more efficient processes for the preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles with application to the synthesis of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs, inhibitors of cyclin dependent kinases. The process generally involves reaction of &agr;-halo ketones II with an azide to give &agr;-azido ketones III. Reduction of III with a reducing reagent gives &agr;-amino ketones IV. From a practical standpoint, safety concerns make this reaction through the azide economically unfeasible.
Alternatively and more advantageously, the &agr;-amino ketones IV are prepared by reaction of &agr;-halo ketones II with a cyclic alkylenetetramine such as hexamethylenetetramine and the like, followed by hydrolysis of the resulting, new quaternary ammonium salt III′. This reaction provides excellent yields of the desired intermediate compound IV, above 90%, yet in a safer manner.
Thereafter, reacting the &agr;-amino ketones IV with an &agr;-halo acyl halide V in the presence of a base or, alternatively, coupling the &agr;-amino ketones IV with an &agr;-halo acid, produces the corresponding amides VI. Then, ring closure of VI with a dehydrating reagent affords 2-oxazolylalkyl halides VII. When a conventional dehydrating reagent such as trihalophosphorus oxide like POCl
3
is used, product isolation is difficult due to the formation of large amounts of hydrochloric and phosphoric acids. Thus, the process of the present invention preferably utilizes the Burgess' reagent which produces excellent yields and permits easy, safe product isolation from water.
Subsequent treatment of 2-oxazolylalkyl halides VII with sulfur-containing reagent VIII or VIII′ affords new key intermediate compounds, 2-oxazolylalkyl sulfides IX. Coupling of IX with 5-halo-2-aminothiazole X gives 5-(2-oxazolylalkylthio)-2-aminothiazoles XI. Coupling of XI with an azacycloalkanoic acid derivative XII affords thiazolyl amides XIII, which may be deprotected (in the case where P is a protecting group, e.g., Boc) to give 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles I, where R
7
is hydrogen, inhibitors of cyclin dependent kinases.
The above-described reactions are illustrated in the below Scheme 1.
In formulas I-XIII of Scheme 1, the following terms apply:
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;
L is halogen or sulfonate (RSO
2
O—, CF
3
SO
2
O—, etc.);
M is hydrogen, Li, Na, K, Cs or quaternary ammonium (R
4
N);
X is hydroxy, halogen or acyloxy (RCOO—, ROCOO—, etc.);
Y is O, S, NH, N-alkyl, N-aryl or N-acyl;
Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH
2
, N-alkyl, N-aryl or N-acyl;
P is a nitrogen-protecting group (Boc, Cbz, R
3
Si, etc.);
m equals 0 to 5; and
n equals 0 to 5.
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

Affiliated with

Also associated with

Rating

Process for preparing azacycloalkanoylaminothiazoles does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for preparing azacycloalkanoylaminothiazoles, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing azacycloalkanoylaminothiazoles will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3139138