AU2001259369B2 - Process for preparing azacycloalkanoylaminothiazoles - Google Patents

Description

PROCESS FOR PREPARING AZACYCLOALKANOYLAMINOTHIAZOLES The present application is a divisional application from Australian patent application number 27264/01, the entire disclosure of which is incorporated herein by reference.

The present invention concerns new processes for the preparation of 5-(2oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.

The 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazole compounds of formula I

R

Rj> N

RS

I n or a pharmaceutically acceptable salt thereof, wherein: R is alkyl, aryl or heteroaryl;

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

i COR" or COOR' 2

R

9

R

1 0 and R 1 2 are each independently hydrogen, alkyl or aryl; m equals 0 to 5; and n equals 0 to are novel, potent inhibitors of cyclin dependent kinases (cdks). They are useful in the therapy of proliferative diseases, for example, cancer, inflammation, autoimmune YA\Louise\BMSSpedes\684975_specL.doc WO 02/10163 PCT/US01/14155 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. Patent 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)-2acetylaminothiazole compounds afforded the 5-(2-oxazolylalkylthio)-2-aminothiazole key intermediates. The requisite 2-oxazolylalkyl halides were prepared by reaction of P-hydroxy amines with a-chloroacyl chlorides followed by oxidation of the resulting 3hydroxy-a-chloroamides and subsequent oxazole ring formation S. Kim et al., WO 9924416, May 20, 1999) or (ii) reaction of a-diazo ketones with a-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 a-diazo ketones and expensive chromatographic separation of products.

Reaction of a-halo ketones with azide to give a-azido ketones has been previously reported in the literature Hassner et al., Angew Chem. Int. Ed. Engl. 1986, 478; M. G. Nair et al., J. Med. Chem. 1980, 23, 899; Ha et al., Synth. Commun.

1994, 24, 2557). Reaction of a-sulfonyloxy ketones with azide to give a-azido ketones has also been previously reported Patonay et al., J. Org. Chem. 1994, 59, 2902; G. A.

Revelli et al., Synth. Commun. 1993, 23, 1111).

Reduction of a-azido ketones to a-amino ketones has been described in the literature 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 a-amino ketones with a-halo acyl halides to give the corresponding amides has further been described 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 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 B. Dickey et al., J. Org. Chem. 1959, 24, 187).

The above discussion of background art is included to explain the context of the invention. It is not to be taken as an admission or suggestion that any of the material referred to was published, known or part of the common general knowledge in Australia at the priority date of any of the claims of this specification.

Throughout the description and claims of this specification the word "comprise" and variations of that word, such as "comprises" and "comprising", are not intended to exclude other additives,components, integers or steps.

This invention concerns new efficient processes for the preparation of 5-(2oxazolylalkylthio)-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.

In accordance with one aspect, the present invention provides a process for the preparation of a compound having the formula I

R

NN

R N R6 O .N I R or a pharmaceutically acceptable salt thereof, wherein: R is alkyl, aryl or heteroaryl;

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" or COOR' 2

R

9

R'

1

R"

1 and R 1 2 are each independently hydrogen, alkyl or aryl; m equals 0 to 5; and n equals 0 to which comprises the steps of: reacting an a-substituted ketone having the formula II 0 R L

R

1

II

wherein: R and R' are as described hereinabove; and L is halogen or sulfonate; Y:\Louise\BMS\Speaes\684975_speci.doc with a cyclic alkylenetetramine in a suitable solvent or solvent mixture to form a quaternary ammonium salt; reacting the quaternary ammonium salt with an acid in a suitable solvent or solvent mixture to form an a-amino ketone; reacting the a-amino ketone with an a-substituted acyl derivative having the formula V 0

R

2

R

3

V

wherein:

R

2

R

3 and L are as described hereinabove; and X is hydroxy, halogen or acyloxy; in the presence of a base in a suitable solvent or solvent mixture to form an amide; or, alternatively, reacting the a-amino ketone with an a-substituted acid in the presence of a coupling reagent to form the corresponding amide; reacting the amide with a dehydrating reagent in a suitable solvent or solvent mixture to give a 2-oxazolylalkyl derivative; reacting the 2-oxazolylalkyl derivative with a sulfur-containing reagent in a suitable solvent or solvent mixture to give a 2-oxazolylalkyl sulfide compound; reacting the 2-oxazolylalkyl sulfide with a 5-halo-2-aminothiazole compound in the presence of a base in a suitable solvent or solvent mixture to give a 5-(2oxazolylmethylthio)-2-aminothiazole compound; reacting the 5-(2-oxazolylmethylthio)-2-aminothiazole with an azacycloalkanoic acid derivative having the formula XII 0 R 6

-R

7

XII

wherein:

R

6

R

7 and X are as described hereinabove; P is a nitrogen-protecting group; m equals 0 to 5; and n equals 0 to V\Lou se\BMS\Speoes684975_ specdoc in the presence of a coupling reagent in a suitable solvent or solvent mixture to form a thiazolyl amide; and reacting the thiazolyl amide with a deprotecting reagent in a suitable solvent or solvent mixture to form the compound of formula I.

In another aspect, the present invention provides a process for the preparation of a compound having the formula III'

N

I N

N

i- R

R'

III'

or a salt thereof, wherein: R is alkyl; R' is hydrogen, alkyl, aryl or heteroaryl; and L is halogen or a sulfonate; with the proviso that when R is CH 3 R' can not be H; which comprises reacting an a-substituted ketone having the formula II 0

R

1

II

wherein: R, R' and L are as described hereinabove; with a cyclic alkylenetetramine in a suitable solvent or solvent mixture to form the compound of formula III'.

In a further aspect, the present invention provides a process for the preparation of a compound having the formula IX

Y

R1N S oR3

IX

or a salt thereof, wherein: R is alkyl, aryl or heteroaryl;

R

2 and R 3 are each independently hydrogen, alkyl, aryl or heteroaryl; Y.\Loise\BMSSpeaes\684075_ specdoc Y is O, S, NH, N-alkyl, N-aryl or N-acyl; and Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH2, N-alkyl, N-aryl or Nacyl; which comprises reacting a 2-oxazolylalkyl derivative having the formula VII a 1 R1 N L R R 2

VII

wherein: R, R' R 2 and R 3 are as described hereinabove; and L is halogen or sulfonate; with a sulfur-containing reagent in a suitable solvent or a solvent mixture to form the compound of formula IX.

In yet a further aspect, the present invention provides a compound having the formula III'

N

R N-

R'

III

or a salt thereof, wherein: R is alkyl; R' is hydrogen, alkyl, aryl or heteroaryl; and L is halogen or a sulfonate, with the proviso that when R is CH 3 then R' can not be H.

In still a further aspect, the present invention provides a compound having the formula IX

Y

R N 64

IX

or a salt thereof, wherein: R is alkyl, aryl or heteroaryl;

R

2 and R 3 are each independently hydrogen, alkyl, aryl or heteroaryl; Y is O, S, NH, N-alkyl, N-aryl or N-acyl; and Y:\Louise\BMS\Spees\684975_spec doc 3d Z is hydrogen, alkyl, aryl, 0-alkyl, 0-aryl, S-alkyl, S-aryl, NI- 2 N-alkyl, N-aryl or Nacyl.

The present invention relates to new, more efficient processes for the preparation 5-(2-oxazolylalkylthio)-2-aminothiazoles with application to the synthesis of 5-(2- YA:ouise\BMSSeaes\68A975_spec cloc WO 02/10163 PCT/US01/14155 oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs, inhibitors of cyclin dependent kinases. The process generally involves reaction of a-halo ketones II with an azide to give a-azido ketones III. Reduction of III with a reducing reagent gives aamino ketones IV. From a practical standpoint, safety concerns make this reaction through the azide economically unfeasible.

Alternatively and more advantageously, the a-amino ketones IV are prepared by reaction of a-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 a-amino ketones IV with an a-halo acyl halide V in the presence of a base or, alternatively, coupling the a-amino ketones IV with an ca-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 POC 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)-2aminothiazoles 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 WO 02/10163 WO 0210163PCT/US01/14155 group, Boc) to give 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles 1, where R 7 is hydrogen, inhibitors of cyclin dependent kinases.

The above-described reactions are illustrated in the below Scheme 1.

Scheme I 0

L

R M +N 3 0 R_'J

N

3

III

0 0 x LR V

IV

0 HR 2

R

3 Ri L

VI

R'N

L

R3 R 0

R

2 ViI

SM

or MY Z Vill,

NY

R 0

R

Ix

N

'~NHR

4 L)1

R

xl

NHR

4 WO 02/10163 PCT/US01/14155 In formulas I-XIII of Scheme 1, the following terms apply: R is alkyl, aryl or heteroaryl;

R

2

R

3

R

4 and R s 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'

0

COR

11 or COOR' 2

R

9 Ro 1 R" and R 1 are each independently hydrogen, alkyl or aryl; L is halogen or sulfonate (RSO20-, CF 3 SO20-, 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 Nacyl; P is a nitrogen-protecting group (Boc, Cbz, R 3 Si, etc.); m equals 0 to 5; and n equals 0 to 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" derivative forms of alkyl) refers to optionally substituted straight chain, branched or cyclic monovalent alkane (saturated hydrocarbon) WO 02/10163 PCT/US01/14155 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, phenyl, substituted phenyl and the like, as well as groups which are fused, 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 "acyl" refers to the radical RCO-, taken alone or in combination, for example, with oxygen, nitrogen, sulfur, etc. 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, 0, 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 WO 02/10163 PCT/US01/14155 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 thiol and the like.

When a functional group is termed "protected," this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds involved in the present processes will be recognized from the specification taking into account the level of skill in the art, and with reference to standard textbooks such as T. W. Greene et al., Protective Groups in Organic Synthesis, Wiley, N.Y. (1991).

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 hydrochloride, hydrobromide, sulfate, phosphate, etc.

Also included, particularly for the intermediate compounds of the invention, are salts WO 02/10163 PCT/US01/14155 which are unsuitable for pharmaceutical utility but which can be employed otherwise, for example, for isolation or purification of free active compounds or their pharmaceutically acceptable salts.

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 employed in the processes of the invention embraces all possible stereoisomers and their mixtures. The definition further 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.

It should be understood that solvates hydrates) of the compounds of formula I and the intermediate compounds are also within the scope of the present invention.

Methods of solvation are generally known in the art. Therefore, the compounds useful in the processes of this invention may be in the free or hydrate form.

As set forth in Scheme 1, the processes for the preparation of 5-(2oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs involve the following transformations: reacting an a-substituted ketone II such as, for example, an a-halo ketone, with an azide in a suitable solvent or solvent mixtures to give an a-azido ketone III; or, more desirably, reacting an a-substituted ketone II like the a-halo ketone with a WO 02/10163 PCT/US01/14155 cyclic alkylenetetramine such as, for example, hexamethylenetetramine in a suitable solvent or solvent mixtures to give a new quaternary ammonium salt III'.

The a-halo ketone includes a-halo aliphatic and c-halo aromatic ketones. The preferred a-halo ketones are a-halo pinacolones with a-bromo pinacolone most preferred. A sulfonate, for example, RSO20- (where R is alkyl, aryl or heteroaryl),

CF

3 SO20- and the like, may be substituted for the halogen in the a-position. The azides include both metal azides and quaternary ammonium azides. The metal azides are preferred with sodium azide most preferred. Suitable solvent(s) include solvents such as hydrocarbons, ethers, amides, for example, dimethylformamide, ketones, etc., or mixtures thereof, with ketones such as acetone preferred for both reactions and reacting the a-azido ketone III obtained in step with a reducing reagent in a suitable solvent or solvent mixtures to give an a-amino ketone IV, or, more desirably, reacting the quaternary ammonium salt III' obtained in step with an acid in a suitable solvent or solvent mixtures to give an a-amino ketone IV.

The reducing reagent in reaction includes hydrogen in the presence of a transition metal catalyst such as palladium, trialkyl or triarylphosphines like triphenylphosphinc. Hydrogen in the presence of a transition metal catalyst is preferred with hydrogen and palladium over activated carbon most preferred. Suitable solvent(s) in reaction include solvents such as hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohol such as methanol preferred. Alternatively, the reduction reaction can be carried out in the presence of an acidic medium such as, for example, hydrochloric acid in ethanol to give a-amino ketone acid salt which can be isolated as the acid salt or free amine forms.

WO 02/10163 PCT/US01/14155 The acid in reaction includes, but is not limited to, protic acids such as HC1, HBr, HI, H 2 S0 4

H

3

PO

4 etc., with HCI preferred. Suitable solvent(s) in reaction include solvents such as hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohol such as ethanol preferred. The a-amino ketone product may be isolated as the salt or free base forms.

reacting (acylating) the a-amino ketone IV or its acid salt obtained in step (b) or with an a-substituted acyl derivative V such as, for example, an a-halo acyl halide, in the presence of a base and in a suitable solvent or solvent mixtures to give an amide VI.

The a-halo acyl halide V includes a-alkyl or aryl substituted or unsubstituted ahalo acyl halide with the latter preferred. The most preferred a-halo acyl halide is achloroacetyl chloride. The base used in the reaction includes, but is not limited to, aromatic and aliphatic organic amines with the latter preferred. The most preferred base is triethylamine. Suitable solvent(s) include aprotic solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred. Alternatively, the reaction can be carried out using an a-substituted acid instead of the a-substituted acyl derivative and then employing a coupling reagent such as a water-soluble diimide like carbodiimide, haloformate, thionyl halide, etc. In either reaction, a sulfonate, for example, RSO20- (where R is an alkyl, aryl or heteroaryl), CF 3 SO20- and the like, may be substituted for the halogen in the a-position of the a-halo acyl halide or the a-halo acid reactants which are illustrated.

WO 02/10163 PCT/US01/14155 reacting the amide VI obtained in step with a dehydrating reagent in a suitable solvent or solvent mixtures to give the cyclized 2-oxazolylalkyl derivative VII such as, for example, the 2-oxazolylalkyl halide.

Advantageously, the reaction is carried out using (methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess' reagent) as the dehydrating reagent. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers and the like, or mixtures thereof. Most preferred is the use of the Burgess' reagent in tetrahydrofuran.

Suitable dehydrating reagents also include, but are not limited to, other bases, acids, acid anhydrides and the like, such as, concentrated sulfuric acid, polyphosphoric acid, etc. Although less conveniently, the dehydrating reagent, for instance, can be trihalophosphorus oxide such as tribromophosphorus oxide or trichlorophosphorus oxide, alone or with a solvent like toluene.

reacting the 2-oxazolylalkyl derivative VII obtained in step with a sulfurcontaining reagent VIII or VIII' in a suitable solvent or solvent mixtures to give 2oxazolylalkyl sulfide IX, a new key intermediate compound.

The sulfur-containing reagent includes N-substituted or unsubstituted thioureas, thio acids or salts such as thioacetic acid or its salt, xanthic acids or salts such as ethylxanthic acid potassium salt. Unsubstituted thiourea is preferred. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with alcohol such as methanol or ethanol preferred.

reacting the 2-oxazolylalkyl sulfide IX obtained in step with a 5-halo-2aminothiazole X in the presence of a base and in a suitable solvent or solvent mixtures to give 5-(2-oxazolylalkylthio)-2-aminothiazole XI.

WO 02/10163 PCT/US01/14155 The 5-halo-2-aminothiazole includes 4,N-substituted or unsubstituted 5-halo-2aminothiazoles with 5-bromo-2-aminothiazole preferred. A suitable base includes, but is not limited to, metal hydroxide, metal alkoxides, metal carbonates and aqueous amines such as ammonium hydroxide. Sodium hydroxide is preferred. Suitable solvent(s) include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.

reacting the 5-(2-oxazolylalkylthio)-2-aminothiazole XI obtained in step (f) with an azacycloalkanoic acid derivative XII in the presence of a coupling reagent in a suitable solvent or solvent mixtures to give thiazolyl amide XIII.

The azacycloalkanoic acid derivative includes N-protected derivatives, for example, N-protected isonipecotic acid or N-protected nipecotic acid. The preferred nitrogen-protecting groups are Boc, Cbz, silicon derivatives and the like with Boc being the most preferred. The coupling reagent includes, but is not limited to, water-soluble carbodiimides, haloformates and the like, with carbodiimides such as alkylcarbodiimides being preferred. Suitable solvent(s) include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, etc., or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.

reacting the thiazolyl amide XIII obtained in step with a deprotecting reagent in a suitable solvent or solvent mixtures to give a desired 5-(2-oxazolylalkylthio)- 2-azacycloalkanoylaminothiazole I (where R 7 is hydrogen).

The choice of the deprotecting reagent is based on the nature of the protecting group For the Boc protecting group, the preferred deprotecting reagent is an acid WO 02/10163 PCT/US01/14155 such as hydrochloric acid or trifluoroacetic acid and suitable solvent(s) for such deprotecting reaction include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane preferred.

The starting compounds of Scheme 1 are commercially available or may be prepared by methods known to one of ordinary skill in the art.

To further illustrate Scheme 1, a process to make 5-(5-t-butyl-2oxazolylmethylthio)-2-azacycloalkanoylaminothiazoles and analogs thereof, for example, starts with reaction of a-bromo pinacolone II (R Bu-t, R 1 H, L Br) with sodium azide to give an a-azido pinacolone III (R Bu-t, R 1 Reduction of a-azido pinacolone III (R Bu-t, R' H) with a reducing reagent gives a-amino pinacolone IV (R Bu-t, R' Alternatively and more desirably, the a-amino pinacolone IV (R Bu-t, R' H) is prepared by reaction of a-bromo pinacolone II (R Bu-t, R' H, L Br) with hexamethylenetetramine followed by hydrolysis of the resulting quaternary ammonium salt III' (R Bu-t, R' H, L Br). Coupling of a-amino pinacolone IV (R Bu-t, R' H) with an c-chloroacetyl chloride V (R 2

R

3 H, L X Cl) produces amide VI (R Bu-t, R' R 2

=R

3 H, L Cl). Ring closure of VI with a dehydrating reagent affords 5-t-butyl-2-oxazolylmethyl chloride VII (R Bu-t, R' R 2

=R

3 H, L Cl). Treatment of VII with sulfur-containing reagent VIII or VIII' such as thiourea affords 5-t-butyl-2-oxazolylalkyl sulfide IX (R Bu-t, R' R 2

=R

3 H, Y NH, Z

NH

2 Coupling of IX with 5-bromo-2-aminothiazole X (R 4

=R

5 L=Br) gives butyl-2-oxazolylmethylthio)-2-aminothiazole XI (R Bu-t, R' R 2

=R

3

R

4

R

S

H).

Coupling of XI with N-Boc azacycloalkanoic acid XII (X OH, R 6

R

7 H, m 0, n WO 02/10163 PCT/US01/14155 2, P Boc), affords thiazolyl amide XIII (R Bu-t, R' R 2

=R

3 R R 5

R

6

R

7 H, m 0, n 2, P Boc), which after deprotection, gives rise to the desired 2-oxazolylmethylthio)-2-azacycloalkanoylaminothiazole I (R Bu-t, R 1

R

2

=R

3 R

R

5

R

6

R

7

R

8 H, m 0, n or an analog thereof.

The present invention further includes two novel key intermediate compounds of formulae III' and IX which have been produced from the new processes to synthesize (2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles of formula I.

The following examples demonstrate certain aspects of the present invention.

However, it is to be understood that these examples are for illustration only and do not purport to be wholly definitive as to conditions and scope of this invention. It should be appreciated that when typical reaction conditions temperature, reaction times, etc.) have been given, the conditions both above and below the specified ranges can also be used, though generally less conveniently. The examples are conducted at room temperature (about 23°C to about 280C) and at atmospheric pressure. All parts and percents referred to herein are on a weight basis and all temperatures are expressed in degrees centigrade unless otherwise specified.

A further understanding of the invention may be obtained from the non-limiting examples which follow below.

WO 02/10163 PCT/US01/14155 EXAMPLE 1 A. Preparation of c-Azido-pinacolone 0 ac-Bromo-pinacolone (199.07 g, 1.1115 mol, 1 eq) was combined in 1.785 L of acetone with sodium azide (93.9 g, 1.4444 mol, 1.3 eq). The reaction was stirred at room temperature for 27.5 hours. The resulting slurry was filtered and washed with acetone (3 x 150 mL). The filtrate was concentrated in vacuo to provide 154.3 g of the title compound. HPLC 83.85% at 2.57 minutes (Phenomenex Inc., Torrance, CA, 5 pjm C18 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

EXAMPLE 2 A' Preparation of a-Hexamethylenetetramino-pinacolone Bromide 0 r(

N

SNtlN Bra-Bromo-pinacolone (179 g, 1 mol, 1 eq) was combined in 2 L of acetone with hexamethylenetetramine (154.21 g, 1.1 mol, 1.1 eq) and the reaction stirred under N 2 at room temperature for 26 hours. The resulting slurry was filtered, the filter cake was washed with ether (3 x 50 mL) and dried in vacuo at 50 0 C overnight to provide 330 g (100%) of the title compound containing 7% hexamethylenetetramine. HPLC R.T.=0.17 min (Phenomenex Inc., 5 tm C18 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

EXAMPLE 3 B. Preparation of a-Amino-pinacolone Hydrochloride 2

NH

2

HCI

WO 02/10163 PCT/US01/14155 o-Azido-pinacolone (128.5 g, 0.911 mol) was combined in 4.2 L of methanol with 77.1 mL of concentrated HC1 and 15.42 g of 10% Pd/C. The reaction mixture was stirred under hydrogen for 1.5 hours. The catalyst was removed by filtration. The solvent was distilled to give a wet solid. The residual water was azeotropically removed with isopropanol (2 x 500 mL). Tert-butyl methyl ether (300 mL) was added and the resulting slurry was stirred, filtered, washed with t-butyl methyl ether (3 x 100 mL) and dried to give 131.0 g of the title compound.

EXAMPLE 4 B' Preparation of ca-Amino-pinacolone Hydrochloride 0

SNH

2

HCI

a-Hexamethylenetetramino-pinacolone bromide (400 g, 1.254 mol, 1 eq) was combined in 2 L of ethanol with 12 N aqueous HCI (439 mL, 5.26 mol, 4.2 eq). The reaction was stirred at 75 0 C for 1 hour and then allowed to cool to room temperature, the resulting slurry filtered, the filtrate concentrated in vacuo and isopropyl alcohol was added. The solution was filtered again. Addition of 1.2 L of ether caused the desired material to precipitate from solution. The material was filtered, washed with ether (2 x 300 mL), and dried in vacuo at 50 0 C overnight to provide 184.1 g of the title compound.

EXAMPLE C. Preparation of a-N-(2-Chloroacetylamino)-pinacolone 0o Ho C1 The title compound of Example 4 (130.96 g, 0.8637 mol, 1 eq) was dissolved in 3.025 L of CH 2 C12 under N 2 at -5 0 C. Triethylamine (301 mL, 2.16 mol, 2.5 eq) was added, followed by chloroacetyl chloride (75.7 mL, 0.450 mol, 1.1 eq) in 175 mL of

CH

2 C1 2 The resulting slurry was stirred at -5 to -10 0 C for 2 hours. Water (1.575 L) was WO 02/10163 PCT/US01/14155 added, followed by 175 mL of concentrated HC1. The organic phase was washed a second time with 1.75 L of 10% aqueous HC1, and then with 500 mL of water. The organic phase was dried over Na 2

SO

4 and concentrated in vacuo to provide 155.26 g of the title compound. HPLC R.T.=2.27 min (Phenomenex Inc., 5 im C18 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

EXAMPLE 6 D. Preparation of 5-(t-Butyl)-2-oxazolylmethyl Chloride

N

0 Ci The title compound of Example 5 (180.13 g, 0.9398 mol, 1 eq) was combined with phosphorus oxychloride (262 mL, 2.8109 mol, 3 eq) under N 2 The reaction was heated at 105°C for 1 hour, the mixture was cooled to room temperature, and quenched with 1.3 kg of ice. The aqueous phase was extracted with ethyl acetate (1 L, then 2 x 500 mL). The organic extracts were washed with saturated aqueous NaHCO 3 (4 x 1 L) which was back-extracted several times with ethyl acetate. The organic phases were combined, washed with saturated aqueous NaHCO 3 (500 mL) followed by saturated aqueous NaCl (300 mL), dried over MgSO 4 and concentrated in vacuo to give a brown oil. The crude material was distilled under high vacuum at 100DC to provide 155.92 g of the title compound. HPLC R.T.=3.62 min (Phenomenex Inc., 5 pm C18 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

Alternatively, the title compound of Example 5 (10.0 g, 52.17 mmol, 1 eq.) in mL of tetrahydrofuran (THF) was combined with (methoxycarbonylsulfamyl)triethylammonium hydroxide (Burgess' reagent, 105.70 mmol, 2.03 eq., generated in situ from 9.2 mL of chlorosulfonyl isocyanate, 4.4 mL of methanol and 14.8 mL of triethylamine in 100 mL THF). The reaction was heated to 45°C for 1.5 hours. After cooling to room temperature, the reaction was quenched with water (50 mL). The organic layer was separated and washed with saturated NaHCO 3 (2 x 50 mL) and water (50 mL), WO 02/10163 PCT/US01/14155 dried over MgSO 4 and passed through a small silica gel plug. The solvent was removed to give an oil which was taken up in a mixture of 15 mL heptane and 90 mL of t-butyl methyl ether, and then washed with 0.2 N HCI (2 x 25 mL), saturated brine (25 mL) and dried (MgSO 4 Filtration and removal of solvent gave 10.9 g of the title compound.

EXAMPLE 7 E. Preparation of 5-(t-Butyl)-2-oxazolylmethyl Thiouronium Hydrochloride

NH

N S HCI NH2 The title compound of Example 6 (1.77 g, 10.2 mmol, 1.02 eq) was combined with thiourea (0.76 g, 9.98 mmol, 1 eq) under N 2 in 10 mL of absolute ethanol. The reaction was heated at reflux for 1.5 hours. The mixture was cooled to room temperature and concentrated in vacuo. Trituration of the resulting crude material with t-butyl methyl ether provided 2.32 g of the title compound. HPLC R.T.=2.05 min (Phenomenex Inc., 5 upm C18 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm); iH NMR (d- DMSO): 5 9.48 3H), 6.85 1H), 4.73 2H), 1.24 9H).

EXAMPLE 8 F. Preparation of 5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-aminothiazole 7-N N%

H

2 0 The title compound of Example 7 (1.25 g, 5 mmol, 1 eq) was added to a mixture of NaOH (3.0 g, 75 mmol, 15 eq), water (10 mL), toluene (10 mL) and tetrabutylammonium sulfate (50 mg, 0.086 mmol, 0.017 eq). 5-Bromo-2-aminothiazole hydrobromide (1.70 g, 5 mmol, 1 eq) was added and the reaction was stirred at room temperature for 14.5 hours. The mixture was diluted with water and extracted twice with ethyl acetate, the organic extracts washed with water (4 x 10 mL), dried over MgSO 4 and WO 02/10163 PCT/US01/14155 concentrated in vacuo to provide 1.1 g of the title compound. HPLC 86.3% at 2.75 min (Phenomenex Inc., 5 utm C18 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm); 1H NMR (CDC13): 6 6.97 1H), 6.59 1H), 5.40 (br s, 2H), 3.89 2H), 1.27 9H).

EXAMPLE 9 G. Preparation of 5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-[(N-t-butoxycarbonyl)azacycloalkanoyl]aminothiazole 0 H

N

s N o 0 The title compound of Example 8 (9.6 g, 35.6 mmol) was dissolved in N,Ndimethylformamide (36 mL) and CH 2 C12 (100 mL), to which was added 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.8 g, 72 mmol, 2 eq), N-tbutoxycarbonyl-azacycloalkanoic acid (12.6 g, 55 mmol, 1.5 eq), and 4-.

(dimethylamino)pyridine (2 g, 16 mmol, 0.45 eq). The clear reaction mixture became cloudy as it was stirred at room temperature for 3.5 hours. Water (300 mL) and ethyl acetate (200 mL) were added and the resulting precipitate was removed by filtration. The filtrate was extracted with ethyl acetate, the organic extracts dried over MgSO 4 and concentrated in vacuo to provide a yellow solid which was combined with the precipitate obtained by filtration. The solid was boiled in a mixture of ethanol, acetone and water for 20 minutes, filtered, washed with an ethanol/water mixture and dried to give 16.6 g of the title compound.

WO 02/10163 PCT/US01/14155 EXAMPLE H. Preparation of 5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-(azacycloalkanoyl)aminothiazole hydrochloride N s N O -S NH HCI The title compound of Example 9 (16.6 g) was dissolved in 150 mL of CH 2

CI

2 trifluoroacetic acid (30 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo, diluted with water (300 mL), cooled in ice, made basic with sodium hydroxide, and the resulting solid filtered and recrystallized from ethanol, water and methanol to provide 11.2 g of the title compound as a yellow solid. The white solid hydrochloride could be obtained by addition of 18 mL of IN aqueous HCI to 7 g of this material in methanol. MS: 381

[M+H]

4 HPLC: 100% at 3.12 min (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

In the foregoing, there has been provided a detailed description of particular embodiments of the present invention for the purpose of illustration and not limitation. It is to be understood that all other modifications, ramifications and equivalents obvious to those having skill in the art based on this disclosure are intended to be included within the scope of the invention as claimed.

Claims (52)

1. A process for the preparation of a compound having the formula I R NR S o RN R6 0 N or a pharmaceutically acceptable salt thereof, wherein: R is alkyl, aryl or heteroaryl; R 2 R 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'R'O, COR'' or COOR 2 R 9 R i o, R! and R 1 2 are each independently hydrogen, alkyl or aryl; m equals 0 to 5; and n equals 0 to which comprises the steps of: reacting an a-substituted ketone having the formula II 0 R' II wherein: R and R' are as described hereinabove; and L is halogen or sulfonate; Y:LowiseBMSXpeaes\684975_spec doc WO 02/10163 PCT/US01/14155 with a cyclic alkylenetetramine in a suitable solvent or solvent mixture to form a quaternary ammonium salt; reacting the quaternary ammonium salt with an acid in a suitable solvent or solvent mixture to form an a-amino ketone; reacting the a-amino ketone with an a-substituted acyl derivative having the formula V 0 X K-L R 2 R 3 V wherein: R 2 R 3 and L are as described hereinabove; and X is hydroxy, halogen or acyloxy; in the presence of a base in a suitable solvent or solvent mixture to form an amide; or, alternatively, reacting the a-amino ketone with an a-substituted acid in the presence of a coupling reagent to form the corresponding amide; reacting the amide with a dehydrating reagent in a suitable solvent or solvent mixture to give a 2-oxazolylalkyl derivative; reacting the 2-oxazolylalkyl derivative with a sulfur-containing reagent in a suitable solvent or solvent mixture to give a 2-oxazolylalkyl sulfide compound; reacting the 2-oxazolylalkyl sulfide with a 5-halo-2-aminothiazole compound in the presence of a base in a suitable solvent or solvent mixture to give a 5-(2- oxazolylmethylthio)-2-aminothiazole compound; WO 02/10163 PCT/US01/14155 reacting the 5-(2-oxazolylmethylthio)-2-aminothiazole with an azacycloalkanoic acid derivative having the formula XII O R 6 S 7 n P XII wherein: R 6 R 7 and X are as described hereinabove; P is a nitrogen-protecting group; m equals 0 to 5; and n equals 0 to in the presence of a coupling reagent in a suitable solvent or solvent mixture to form a thiazolyl amide; and reacting the thiazolyl amide with a deprotecting reagent in a suitable solvent or solvent mixture to form the compound of formula I.

2. The process as recited in Claim 1, wherein the a-substituted ketone in step (a) is an a-halo ketone.

3. The process as recited in Claim 2, wherein the a-halo ketone is an a-halo aliphatic ketone or an a-halo aromatic ketone.

4. The process as recited in Claim 3, wherein the a-halo ketone is an a-halo pinacolone. The process as recited in Claim 4, wherein the a-halo pinacolone is a-bromo pinacolone.

6. The process as recited in any one of Claims 1 to 5, wherein the solvent in step is a hydrocarbon, an ether, an amide, a ketone or a mixture thereof.

7. The process as recited in Claim 6, wherein the solvent is the ketone and the ketone is acetone.

8. The process as recited in any one of Claims 1 to 7, wherein the cyclic alkylenetetramine in step is hexamethylenetetramine.

9. The process as recited in any one of Claims 1 to 8, wherein the acid in step is HC1 HBr, HI, H 2 SO 4 or H 3 PO4. The process as recited in Claim 9, wherein the acids is HC1

11. The process as recited in any one of Claims 1 to 10, wherein the solvent in step is a hydrocarbon, an ether, an alcohol or a mixture thereof.

12. The process as recited in Claim 11, wherein the solvent is the alcohol and the alcohol is ethanol.

13. The process as recited in any one of Claims 1 to 12, further comprising isolating the a-amino ketone product as the salt or free base form before performing step

14. The process as recited in any one of Claims 1 to 13, wherein the a- substituted acyl derivative in step is an c-halo acyl halide. The process as recited in Claim 14, wherein the a-halo acyl halide is a- chloroacetyl chloride.

16. The process as recited in any one of Claims 1 to 15, wherein the base in step is an aromatic organic amine or an aliphatic organic amine.

17. The process as recited in Claim 16, wherein the base is the aliphatic organic amine and the aliphatic organic amine is triethylamine.

18. The process as recited in any one of Claims 1 to 17, wherein the a- substituted acid in step is an a-halo acid halide and the coupling reagent is water- soluble.

19. The process as recited in Claim 18, wherein the coupling reagent is a carbodiimide, a haloformate or a thionyl halide.

20. The process as recited in any one of Claims 1 to 19, wherein the dehydrating reagent in step is an acid, an acid anhydride or a base.

21. The process as recited in any one of Claims 1 to 20, wherein the dehydrating reagent in step is concentrated sulfuric acid, polyphosphoric acid, trichlorophosphorous oxide, tribromophosphorus oxide or (methoxycarbonylsulfamoyl)triethylammonium hydroxide.

22. The process as recited in Claim 21, wherein the dehydrating reagent is (methoxycarbonylsulfamoyl)triethylammonium hydroxide. Document

23. The process as recited in any one of Claims 1 to 22, wherein the solvent in step is tetrahydrofuran.

24. The process as recited in any one of Claims 1 to 21, wherein the dehydrating reagent in step is (methoxycarbonylsulfamoyl)triethylammonium hydroxide and the solvent is tetrahydrofuran. The process as recited in any one of Claims 1 to 24, wherein the sulfur- containing reagent in step is an N-substituted thiourea, an unsubstituted thiourea, a thio acid or a salt thereof, or a xanthic acid or a salt thereof.

26. The process as recited in Claim 25, wherein the sulfur-containing reagent is thiourea, thioacetic acid or the salt thereof, or ethylxanthic acid potassium salt.

27. The process as recited in any one of Claims 1 to 26, wherein the 2-aminothiazole compound in step is 5-bromo-2-aminothiazole.

28. The process as recited in any one of Claims 1 to 27, wherein the base in step is a metal hydroxide, a metal alkoxide, a metal carbonate or an aqueous amine.

29. The process as recited in Claim 28, wherein the base is the metal hydroxide and the metal hydroxide is sodium hydroxide. The process as recited in any one of Claims 1 to 29, wherein the solvent in step is a hydrocarbon, a halogenated hydrocarbon, an ether, an ester, an amide, an alcohol or a mixture thereof.

31. The process as recited in Claim 30, wherein the solvent is the halogenated hydrocarbon and the halogenated hydrocarbon is dichloromethane.

32. The process as recited in any one of Claims 1 to 31, wherein the nitrogen-protecting group in step is Boc or Cbz.

33. The process as recited in any one of Claims 1 to 32, wherein the coupling reagent in step is a carbodiimide, a haloformate or a thionyl halide.

34. The process as recited in Claim 33, wherein the coupling reagent is the carbodiimide and the carbodiimide is an alkylcarbodiimide. A process as recited in Claim 1 for the preparation of a compound having the formula I R R 0 R 2 -R 0 N In R Y \Loise'BMSlSpees\684975_speci doc or a pharmaceutically acceptable salt thereof, wherein: R is alkyl, aryl or heteroaryl; R 2 R 3 R 4 and R 5 are each independently hydrogen; R 6 is hydrogen; R 7 is hydrogen or alkyl; R 8 is hydrogen; m equals 1; and n equals 0, 1, 2 or 3; which comprises the steps of: reacting an a-substituted ketone having the formula II 0 R L II wherein: R is as described hereinabove; R' is hydrogen; and L is bromo; with hexamethylenetetramine in acetone to form a quaternary ammonium salt of formula III'; N R L" R 1 III reacting the quaternary ammonium salt with HCI in ethanol to form an a- amino ketone of formula IV; 0 R NH 2 R 1 IV reacting the a-amino ketone with an a-substituted acyl derivative having the formula V Y:\Louise\BMS\pe684es 975_spci d$C 0 )O R 2 R 3 V wherein: R 2 and R 3 are as described hereinabove; L is chloro; and X is chloro; in the presence of a base in a suitable solvent or solvent mixture to form an amide of formula VI; or, alternatively, reacting the a-amino ketone with an a-substituted acid in the presence of a coupling reagent to form the corresponding amide; 0 HR 2 R 3 R L R 0 VI reacting the amide with phosphorous oxychloride in toluene to give a 2- oxazolylalkyl derivative of formula VII; R1 N L R O R 2 VII reacting the 2-oxazolylalkyl derivative with thiourea in ethanol to give a 2- oxazolylalkyl sulfide compound of formula IX; R' N S- IX wherein: Y is NH; and ZisNH 2 Y:\Louise\BMS\Speoesl684975_spec.doc reacting the 2-oxazolylalkyl sulfide with 5-bromo-2-aminothiazole in the presence of potassium hydroxide in alcohol to give a 5-(2-oxazolylmethylthio)-2- aminothiazole compound of formula XI; R R m R3 NHR 4 R 0 R 2 XI wherein: R 4 and R 5 are hydrogen reacting the 5-(2-oxazolylmethylthio)-2-aminothiazole with an azacycloalkanoic acid derivative having the formula XII 0 RG R 7 x XII wherein: R 6 and R 7 are as described hereinabove; X is hydroxy; P is a Boc-protecting group; m equals 1; and n equals 0, 1, 2 or 3; in the presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide and a base in a suitable solvent or solvent mixture to form a thiazolyl amide of formula XIII; R R N S R4 IL R3 S N R6 R R RR ON, XIII and reacting the thiazolyl amide with acid in a suitable solvent or solvent mixture to form the compound of formula I.

36. A process for the preparation of a compound having the formula III' Y:\LouiseBMSISpecies\684975 sped doc N 0 R L" R 1 or a salt thereof, wherein: R is alkyl; R' is hydrogen, alkyl, aryl or heteroaryl; and L is halogen or a sulfonate; with the proviso that when R is CH 3 R' can not be H; which comprises reacting an a-substituted ketone having the formula II 0 R 1 II wherein: R, R' and L are as described hereinabove; with a cyclic alkylenetetramine in a suitable solvent or solvent mixture to form the compound of formula III'.

37. The process as recited in Claim 36, wherein R is t-butyl.

38. The process as recited in Claim 36 or Claim 37, wherein the cyclic alkylenetetramine is hexamethylenetetramine.

39. A process as recited in Claim 36 for the preparation of a compound having the formula I1I' N R y/-N III' or a salt thereof, wherein: R is alkyl; R' is hydrogen; and L is bromo; with the proviso that R is not CH 3 which comprises reacting an a-substituted ketone having the formula II Y:\Louise\BMS'Spees\684975 specidoc 0 RIL R 1 II wherein: R, R' and L are as described hereinabove; with hexamethylenetetramine in acetone to form the compound of formula III'.

40. A process for the preparation of a compound having the formula IX Y R' N S X) 1R 3 2 Z R 0 R IX or a salt thereof, wherein: R is alkyl, aryl or heteroaryl; R 2 and R 3 are each independently hydrogen, alkyl, aryl or heteroaryl; Y is O, S, NH, N-alkyl, N-aryl or N-acyl; and Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH 2 N-alkyl, N-aryl or N- acyl; which comprises reacting a 2-oxazolylalkyl derivative having the formula VII RI N L R 0 R 2 VII wherein: R, R' R 2 and R 3 are as described hereinabove; and L is halogen or sulfonate; with a sulfur-containing reagent in a suitable solvent or a solvent mixture to form the compound of formula IX.

41. The process as recited in Claim 40, wherein the sulfur-containing reagent is an N-substituted thiourea, an unsubstituted thiourea, a thio acid or a salt thereof, or a xanthic acid or a salt thereof.

42. The process as recited in Claim 41, wherein the sulfur-containing reagent is thiourea, thioacetic acid or the salt thereof, or ethylxanthic acid potassium salt. Y:\Louio \BMS\Spees\684975_ spei doc

43. The process as recited in any one of Claims 40 to 42, wherein the solvent is a hydrocarbon, a halogenated hydrocarbon, an ether, an ester, an amide, an alcohol or a mixture thereof.

44. The process as recited in Claim 43, wherein the solvent is the alcohol and the alcohol is methanol or ethanol. A process as recited in Claim 40 for the preparation of a compound having the formula IX a1 Y R' N S R 01R2 IX or a salt thereof, wherein: R is alkyl; R 2 and R 3 are each independently hydrogen; Y is NH; and Z is NH2; which comprises reacting a 2-oxazolylalkyl derivative having the formula VII R N L RR3 R 0 R 2 VII wherein: R, R' R 2 and R 3 are as described hereinabove; and L is chloro; with thiourea in ethanol to form the compound of formula IX.

46. A compound having the formula III' N N LU R L R Ill' or a salt thereof, wherein: R is alkyl; R' is hydrogen, alkyl, aryl or heteroaryl; and Y:\Louise\BMS\Speoes\684975 speddoc L is halogen or a sulfonate, with the proviso that when R is CH 3 then R' can not be H.

47. The compound as recited in Claim 46, wherein R is t-butyl.

48. The compound as recited in Claim 47, wherein R' is hydrogen.

49. The compound as recited in Claim 48, wherein L is halogen. The compound as recited in Claim 49, a-hexamethylenetetramino- pinacolone bromide.

51. A compound as recited in Claim 46 having the formula III' N R N--N L- R 1 III' or a salt thereof, wherein: R is alkyl; R' is hydrogen; and L is bromo, with the proviso that R is not CH 3

52. A compound having the formula IX Y R1 N S X N R 3 Z RAO R 2 Ix or a salt thereof, wherein: R is alkyl, aryl or heteroaryl; R 2 and R 3 are each independently hydrogen, alkyl, aryl or heteroaryl; Y is O, S, NH, N-alkyl, N-aryl or N-acyl; and Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH 2 N-alkyl, N-aryl or N- acyl.

53. The compound as recited in Claim 52, wherein R is t-butyl; Y is NH, N- alkyl, N-aryl or N-acyl and Z is NH 2 N-alkyl, N-aryl or N-acyl.

54. The compound as recited in Claim 53, wherein the salt is hydrochloride. The compound as recited in Claim 54, 5-(t-butyl)-2-oxazolylmethyl thiouronium hydrochloride.

56. A compound as recited in Claim 52 having the formula IX Y:\LouiseBMSSpees\884975_spec doc 33 Y R'N $4 R' 0 R 2 IX or a salt thereof, wherein: R is alkyl; R 2 and R 3 are each independently hydrogen; Y is NH; and Z is NH 2

57. A compound prepared by the process of any one of Claims 1 to

58. A compound prepared by the process of any one of Claims 36 to 39.

59. A compound prepared by the process of any one of Claims 40 to

60. A process according to any one of Claims 1, 36 or 40 substantially as hereinbefore described.

61. A compound according to Claim 46 or Claim 52 substantially as hereinbefore described. Y:\Louise\BMS\Speces684975_speo doc