CA1261847A - Process for preparing intermediates for preparing 4- (isozaxolyl)-thiazole-2-oxamic acids and derivatives thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

This invention relates to compounds of the general formula (III) (III) wherein Z is a group of the formula selected from

Description

~ nls appllcaelon lS a d1v1slonal appllcatlon of Canadlan patent appllcatlon s~rlal number 487,853 flled on July 31, 1985.
Tnls lnventlon eelates to compounds of the general formula (III):
R4 r~

Z N NH2 (III) wherein Z lS a group of the formula:

R ~ R~
N\o or \O

wherein R and Rl which may be the same or dif~erent are a hydrogen or a halogen atom, a hydroxy group, a Cl_3 alkoxycarbonyl group, a Cl_3 alkyl group optionally substltuted by hydroxy, C1~3 alkoxy or alkoxy Cl_3 oxalyloxy, a Cl_3 alkoxy group optionally subse~tuted ~0 by phenyl, or a phenyl group optionally substituted by ~alog~n, and R4 i~ ~ hydrogen atom or ~ Cl_3 alkyl group. These compounds are useful inter~edia~e compounds for psepar~ng new derivation of 4-(lsoxazolyl)-thi~zole~2-oxamic acid wbieh demostrate improved ant~-allerglc and anei-anaphyl~ctic action.

`~4~

.

- 2 -It is known that the disodium cromoglycate (Merck Index, IX ed., page 337) inhi~its the release of medlators of allergic reactions provoked by antibody-antigen interactions~
Because of this property the disodium cromoglycate may be used in therapy as an antiallergic agent especially in asthmatic forms.
However ~ said compound is not absorbed orally and thls drawback largely limits its field of applications.
To seek to overcome this drawback numerous other compounds were prepared which progressively modified the structure of the disodium cromoglycate until compounds structurally and chemically different from the parent compound were obtained.
Among these compounds may be mentioned the derivatives of phenyloxamic acid (J. Med. Chem., 21(9), 930, 1978) and 4-aryl-2-thiazole oxamic acid (UK Patent Application No. 2,023,580 - and European Patent Application No. 44442).
It has been now found that a valuable action is attained when the 4-posltion of a thiazole-2-oxamic acid is substituted by a 3 or a 5-isoxalyl group.

~,~ 6~

Therefor the parent application Serial No. 487,853 relates to the preparation of compounds of formula:
R4 r~
N NHcocoR2 (I) wherein Z lS a group of formula R ~ Rl ~ 1 in which R and Rl which may be the same or diffeeene are a hydeogen or a halogen atom, a hydroxy group, a Cl_3 alkoxycarbonyl group, a Cl_3 alkyl group optionally substituted by hydroxy, Cl_3 alkoxy or alkoxy(l-3C)oxalyloxy, a Cl_3 alkoxy group optionally su~stituted by phenyl, or a phenyl group optionally substituted by halogen; and R2 is a hydroxy group or OR3 where R3 iS a C3_6 cycloalkyl group or a Cl_3 alkyl group optionally substi~uted by phenyl or Cl 3 alkoxyt and R4 is a hydrogen atom or a Cl_3 alkyl ~roup;
and when R2 is a hydroxy group, their pharmaceut~o~lly acceptable salts with organic or inorganlc base~.

,, Typlcal examples of R and Rl include fluorine~
chlorlnel bromlne, lodine, propoxyca~bonyl, ethoxycarbonyl, methoxycarbonyl, meth~l, ethyl, propyl, lsopropyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, propyloxypropyl, propyloxymethyl, methyloxyethyl, metho~m~thyl, ethoxymethyl, ethoxalyloxyp~opyl (-C3H6 OCOCOOC2H5), propoxalyloxymethyl (-C~20COCOOC3H7), ethoxalyloxymethyl ~-CH20COCOOC2H5), 2-bromophenyl, 2-lodophenyl, 2-chlorophenyl, 2,6-dlchlorophenyl, 2-: 10 chloro-6-fluorophenyl, methoxy, ethoxy, propoxy, phenylethoxy and benzyloxy.
Preferred meanings of R and Rl are hydrogen, bromine, chlorine, hydroxy, methyl, hydroxymethyl, methoxymethyl, ethoxalyloxymethyl, ethoxycarbonyl, lS phenyl, 2-chloro-6-fluorophenyl7 benzyloxy and methoxy.
Typlcal examples of R3 include cyclopropyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, phenylmethyl, phenylethyl, phenylpropyl, methoxymethyl, pcopoxymethyl, e~hoxyet~yl, met~oxyethyl and met~oxypropyl.
Prefeered meanlngs of R2 are bydroxy and OR3 wherein ~3 is ethosyethyl, ethyl, cyclo~exyl and phenylmethyl.

I
.

- 5 ~ L8~

Ty~lcal examples of organlc bases useful for preparing the salts accordlng to thls 1nvention ate the primary and secondary allphatlc amlnes optlonally substituted by hydroxy and carboxy grou~s.
S Speciflc examples of sald organic ~ases are metnylamine, isopropylamine, hexylamlne, diethylamine, ethanolamlne, 2-hydroxymethyl-2-amino-l~3-propanedi glycine, alanine, vallne, leucine, isoleucine, serine, threonine, aspartic acld, glutamic acid, arginine, lysine, cystine, cysteine, methionine, phenylalanine, tyrosine, tryptophan, histidine.
Depending on the meaning of the substituents, some of the compounds o~ formula ~ can exist in ~he form of isomers.
The preparation sf ~he isomer mixtures and of the slngle isomers obtained by separation of the mixtures or by stereospecific synthesis are a further object of this inveneion.
Therefore, this: invention provides intermediate compounds useful in the preparation of the compounds of the general formula I. More particularly the Present invention relates to compounds of the general formula III.

: R4 ~ I (III) N ~ NH2 .
' ` ,;

- 6 ~

whereln 2 lS a yroup of ~ne formula selected from R ~ Rl r~ R

~0 or \0 wherein R and R which may be the same or dlfferent are a hydrogen or a halogen atom, a hydroxy group, a Cl_3 alkoxycarbonyl group, a Cl_3 alkyl group optionally substituted by hydroxy, Cl_3 alkoxy or alkoxy Cl_3 oxalyloxy, a C1~3 alkoxy group optionally substitu~ed by phenyl, or a phenyl group optlonally substituted by nalogen, and R4 is a hydrogen atom or a Cl_3 alkyl group.
The prepara~ion of a compound of formula (I) comprises the reaction shown in the following Scheme 1 20~ i N~2~YCOCOOR3~ NHCOCOOR3 (tll) (1) ~5 , - 7 - ~ 3~7 wherein Y is a halogen atom, and R4, Z and R3 have the above mentioned meanings, and, when desired, the hydrolization of the compound (I) and, optionally, the preparation of a pharmaceutically accept-able salt thereof with an inorganic or organic base.

In turn, the 2-amino-4-isoxazolyl-thiazole compound of formu-la (Ill) can be prepared by reacting a bromoacetyl-isoxazole compound of formula R ~ R1 R4-CHBrCO R

N ; CO-CHBrR , or ~ R1 (Il) with thiourea.
This reaction is performed by heating the reaction mixture in a protic or aprotic polar solvent at a temperature preferably between 50C and 100C.
The compound of formula (Ill) can be then reacted with a monoester oxalyl chloride to give the compounds of formula (I) wherein R2 is an OR3 group.
This reaction is performed preferably in pyridine or in an inert solvent in the presence of an acid-acceptor.
From the compound~ of formula (I) wherein R2=OR3 are prepared by basic hydrolysis the free acids (I, R2=OH).

- 8 - ~l2Ç~L~3~ 7 The artisan will appreciate that the compounds of this invention may be prepared by alternative procedures with respect to those set forth above.
For example, the esters of formula ~I) (R2=OR3) may also be prepared by transesterification of other esters of formula (I) or by reacting an acyl halide of an acid of formula (I) (R2=OH) with a suitable alcohol of formula R3-OH.
The compounds of formula (Il) are in part compounds known as such or at the precursor level.
In any case, they are prepared by known techniques.
An example of synthesis is given in Scheme 2 R1 Rl R ~ ~ COCl -~ R ~ COCH2R4 (IV) ~ (V) Rl R ~ ~ COCHBrR4 (11 ) Reaction 1 of scheme 2 is performed by reacting the acyl chloride (IV) with diethylmalonate or a diethyl-2-alkylmalonate and carbon tetrachloride in the presence of magnesium, according to known techniques.

Reaction 2 of scheme 2 is performed by brominating the intermediate (V) with pyridine perbrornide hydrobromide or other suitable brominating agents in a solvent such as carbon tetrachloride, chloroform, methyl chloride, etcetera.
Among the knonw compounds of formulas (V) and (II) may be mentioned

3-bromo-5-acetyl-isoxazole (European Patent No. 16,255), 3-methoxy-5-acetyl-isoxazole (Acta Chem. Scand., B, 28, ~39, 1~74).
3-bromo-5-bromoacetyl-isoxazole (European Patent No. 16,255), 3-methyl-5-acetylisoxazole (Gazz. Chim. It., 72, 242, 1942) 3-chloro-5-acetyl-isoxazole (Gazz. Chim. It., 91, 47, 1961) 5-hydroxymethyl-3-acetyl-isoxazole (ll Farmaco, ed. Sci~ 39, 487, 1984) 3-bromoacetyl-S-phenyl-isoxazol (J. Med. Chem., 10, 411, 1967).
The compounds of formula (lll) are new and their preparation is a further object of this invention.
The pharmacological evaluation showed that the compounds of this invention interfere with the appearance of the allergic pathology induced experimentally in the experimental animal.
This interference proved to be marked and highly selective.
In the experimental animal, following treatment with the compounds of this invention with even large dosages, no important variations were recorded in the principal regulatory functions studied, such as for exampl~e the cardiocirculatory and the respiratory functions.
In addition, the coordination functions peculiar to the central nervous system activity were not influenced and no phenomena o~ a st~muIating or sedatiYe type appeared , - 1o - ~L~ L~3~ 7 Neither in vitro nor in vivo was any direct antagonistic pharmacological action noted toward humoral or tissutal known mediators of the allergic pathology such as histamine, seroto-nin, bradykinin and SRS-A.
The pharmacological action of the compounds of this invention has been shown by a dual series of independent experiments in which was induced in the experimental animals a) a passive cutaneous anaphylaxis experimental model; b) an experimental model of systemic sensibilization approppriate for the appearan-ce of bronchoconstriction by inhalation of the specific antigen.
The first test was performed in the rat in accordance with Goose J. and Blair A.M.J.N. (Immunology, 16, 749, (1969)) and Binaghi R.A. and Benacerraf ~. (J. Immunol., 92, 920, (1964));
the production of hemocytotropic serum necessary for accomplish-ment of the test was obtained according to the method set forth by Mota 1. (l~munology, 7, 681, (1964)).
The second test was accomplished on the guinea-pig, senzitiz-ed for 4-5 weeks by parenteral administration of ovalbumin as the allergen and adjuvant. The trigger reaction was induced 2û following aerosol inhalation of the allergen until appearance of the characteristic signs of bronchoconstriction.
In these two tests the specific inhibitory activity of the campounds of this invention proved to be dose-dependent and clearly reproducible by the three selected administration ways:
oral, peritoneal (ip) and venous (iv).
The Passive Cutaneous Anaphylaxis test in rat has given the following results:
2-ethoxyethyl 4-(3-methyl-S-isoxazolyl)-thiazole-2-oxamate, E~50 = 0.83 mg/kg/os;
2-amin~ethanol 4-(3-hydroxymethyl-5-isoxazolyl)-thiazole_2-oxa-~z~

mate, ED50 = 0.6 mg/kg/os; 0.010 mg/kg/ip, 0.008 mg/kg/iv;
2-aminomethanol 4-(5-hydroxymethyl-3-isoxazolyl)-thiazole-2-oxa-mate, ED50 = 0.8 mg/kg/iv;
2-ethoxyethyl 4-(5-hydroxymethyl-3-isoxazolyl)-thiazole-2-oxa-mate, ED50 = 1.8 mg/kg/ip;
2-ethoxyethyl 4-(3-methoxymethyl-5-isoxazolyl)-thiazole-2-oxa-mate, ED50 = 0.98 mg/kg/os;
2-ethoxyethyl 4-(3-carbethoxy-5-isoxazolyl)-thiazole-2-oxamate, ED50 = 0.08 mg/kg/ip;
2-aminoethanol 4-(3-phenyl-5-isoxazolyl)-thiazole-2-oxamate, ED50 = 1 mg/kg/os, 0.1 mg/kg/ip, 0.06 mg/kg/iv;
2-ethoxyethyl 4-(3-phenyl-5-isoxazolyl)-thiazole-2-oxamate, ED50 = 0.8 mg/kg/iv;
2-aminoethanol 4-(5-phenyl-3-isoxazolyl)-thiazole-2-oxamate ED50, 2.3 mg/kg/os, 0.23 mg/kg/ip, 0.1 mg/kg/iv, L-lysine 4-(5-phenyl-3-isoxazolyl)-thiazole-2-oxamate ED50 = 0 9 mg/kg/os, 0.03 mg/kg/iv;
2-ethoxyethyl 4-(5-phenyl-3-isoxazolyl)-thiazole-2-oxamate, ED50 = 0-2? mg/kg/ip, 0.15 mg/kg/iv;
2-aminoethanol 4- L3-(2-chloro-6-fluorophenyl)-S-isoxazolyl~
-thiazole-2-oxamate, ED50 = 0.015 mg/kg/iv;
2-aminoethanol 4-(3-methoxy-5-isoxazolyl)-thiazole-2-oxamate, ED50 = 1.2 mg/kg/ip; 0.5 mg/kg/iv;
2-ethoxyethyl 4-(3-hydroxy-5~isoxazolyl)-thiazole-2-oxamate, ED50 = 0 5 mg/kg/ip-In the same experiments, known reference compounds gave the following results:

4-phenyl-thiazole oxamic acid, ED50=2.8 mg/kg/os; 3.5 mg/kg/ip,more than 1 mg/kg/iv;
4-(4-methoxyphenyl)-thiazole oxamic acid, ~6~8~7 ED50=2.9 mg/kg/os;
2.6 mg/kg/ip; more than 1 mg/kg/iv;
4-(2~furyl)-thiazole oxamic acid, ED50=3.1 mg/kg/os;
S 3.2 mg/kg/ip; more than 1 mg/kg/iv.
In addition to their high activity by oral route, a peculiar feature of the compounds of this invention is their very high activity by venous route. Those skilled in the pharmacological field will recognize that this means that the compounds of this invention possesS a very high intrinsic activity, the lower activity by oral route being due to absorption problems. When a compound is Pndowed with a very high intrinsic activity a large opportunity to improve its oral activity is offered by routine selection of the most suitable derivatives thereof which overcome the absorption problem.
Both local and systemic tolerability appeared very favourable for all the compounds tested. No toxic phenomena were observed for doses greater than 0.5 g/kg via parenteral administration and 1.5 g/kg via oral route.
For all the compounds the ratio of pharmacological dose to tolerated dose proved to be quite favourable. The therapeutic dosage ranges from 5 to 500 mg/day.
The compounds of this invention are useful for treating the various pathological syndromes having a recognized allergic base, with localization elther in the upper air tracts such as hay fever, bronchlal asthma, or in the cutaneous tissues and superficial mucous membranes: hives, eczematose dermatitis, itching, allergic conjunctivitis.
Another object of the present invention are the pharmaceuti-cal 60mpositions containing as active ingredient the compounds of formula (I) or their pharmaceutically acceptable salts with organic or inorganic bases.
These compositions can contain the active ingredient together with pharmaceutically acceptable organic or inorganic solid or liquid excipients and can be suitable for topical, oral, parenteral, rectal or inhalatory administration.
The finished pharmaceutical forms can be solid, such as for example tablets, pills, capsules, powders, granules, supposito-ries~ or liquid such as for example solutions, suspensions, emulsions, or semiliquids such as creams and ointments. They can even be prepared in such a manner that the release of the drug is prolonged after administration.
In additioh to the e~cipients they can contain preservative, stabilizing, wetting and emulsifying agents, salts to regulate osmotic pressure, buffers, colourings, flavourings, etc.
They can be prepared according to known methods and can also contain other therapeutic ingredients.
In order to better illustrate the present invention the following examples are now given.

-14~ 6~.B47 Example A
1- L-(2-chloro-6-fluorophenyl)-5-isoxazolyl] -ethanol 27.bO 9 (273 mmol) of triethylamine were added dropwise to a solution of 28.4 g (136.5 mmol) of alpha, 2-dichloro-6-fluo-robenzaldoxime and 19.14 9 (273 mmol) of 3-butin-2-ole in 250 ml of benzene kept under stirring at 8-10C.
When the addition was over the mixture was heated to 60C;
after 1 hour the mixture was cooled and extracted with 10%
hydrochloric acid and then with water.
Evaporation of the organic phase gave 31.1 of an oil which was purified by distillation and the fraction boiling at 140-150C (0.3 mmHg) was collected.
lHNMR (CDC13): delta 7.6 - 7 (m, 3H3; 6.4 (s, lH); 5.1 (q, 1H);
1.6 (t, 3H)~
Example B
1) 3-(2-chloro-6-fluorophenyl)-5-acetylisoxazole To a solution of 30 9 (124 mmol) of 1-[3-(2-chloro-6-fluo-rophenyl)-5-isoxazolyl3 -ethanol in 187 ml of acetic acid maintained under stirring at 5C were added dropwise 9.07 (90.7 mmol~ of CrO3 in 9.34 of water and 132 ml of acetic acid.
The mixture was kept overnight under stirring at roorn temperature; the solv0nt was then removed by evaporation and the residue was taken up with wa~er, made neutral with sodium bicarbonate and extracted with ethyl ether.
The ethereal extracts were combined and washed with water, dried and evaporated to dryness; 27.8 9 of an orange oily product were obtained. The oil was distilled under reduced pr~ssur~ and the fraction boiling at 120-122C (0.4 m~Hg3 was Go~lace~c yield, 23.7 ~.

The oil was allowed to crystallize by standing and then recrystallized from isopropyl ether; m.p. 46-47C.
lHNMR (DMS0): delta 7.9-7.3 (m, 4H); 2.8 (s,3H).
In a similar manner were obtained:
3-carbethoxy-5-acetylisoxazole Yield, 82%; m.p. 67-68C (isopropyl ether) lHNMR (CDC13): delta 7.3 (s, lH); 4.5 (q, 2H); 2.7 (s, 3H); 1.5 (t, 3H).
The starting compound, i.e. 1-(3-carbethoxy-5-isoxazolyl)-ethanol, was prepared according to European Patent 28,355.
3-methoxymethyl-S-acetylisoxazole Yield, 58.5%; colourless oil, b.p. 72-74C (0.4 mmHg) lHNMR (CDC13): delta 7.0 (s, 1H); 4.6 (s, 2H); 3.4 (s, 3H); 2.6 (s, 3H) The starting compound, i.e. 1-(3-methoxymethyl-5-isoxazol-yl)-ethanol, was prepared according to German Patent 2,754,832.
2) 3-benzyloxy-5-acetylisoxazole 2.2 9 (90.5 mmol) of magnesium turnings were added under stirring to a solution of 14 9 (87 mmol) of diethyl malonate in 78 ml of ethyl ether containing 63 9 of anhydrous ethyl alcohol and 0.90 ml of carbon tetrachloride.
The mixture was refluxed for 2 hours and then was added dropwise a solution of 18.8 g (79 mmol) of 3-benzyloxy-5-iso-xazolylcarbonyl chloride (Belgian Patent 665,249) in 65 ml of ethyl ether.
The mixture was refluxed~ for 2 hours, cooIed to room temperature and 159 ml of 2M sulfuric acid were added.
After vigorous stirring, the organic layer was separated, washed with water and evapo-ated to dryness.

8~7 - 16 _ The thus obtained oily residue (29.9 g) was added to a solution of 4.8 9 of concentrate sulfuric acid in 36.3 ml of acetic acid and 25 ml of water; the mixture was refluxed for 8 hours.
The mixture was cooled to 20C and made neutral (pH 6.5) with 10 M potassium hydroxide at constant temperature.
The mixture was extracted with chloroform; the combined organic extracts were evaporated to give an oily residue which was taken up with 150 ml of hexane. The crystalline precipitate was collected by filtration (6.7 q; Yield, 39%) and recrystallized from isopropyl ether. m.p. 77-78C.
lHNMR (CDC13): delta 7.5 (m, 5H); 7.2 (s, lH); 5.4 (s, 2H);
2.5 (s, 3H).
Example C
1) 3-chloro-5-bromoacetylisoxazole 28.65 9 ~179 mmol) of bromine in 20 ml of chloroform were added dropwise in 10 minutes to a solution of 25 g (172 mmol) of 3-chloro-5-acetylisoxazole containing 4.9 ml of glacial acetic acid while the reaction mixture was maintained under stirring at 48-50C.
After 5 minutes the mixture was poured into 330 9 of water and crushed ice.
The organic layer was separated, washed with water, dried and evaporated to residual.
Yield, 37 9 (96~) of an oily compound which can be purified by distillation; b.p. 97-99C (2 mmHg).
lHNMR (CDC13): delta 7.00 (s, lH), 4.37 (s, 2H).
In a similar manner were prepared the following compounds:
3-methoxy-5-bromoacetylisoxazole (from 3-metho~y-5acatyl-isoxa~ol~, Acta Chem. Scand. 28 B, 639, 17 ~ 3~

1947); Yield, 91%; deliquescent crystalline compound;
lHNMR (CDC13): delta 6.63 (s lH~; 4.33 (s, 2H); 4.00 (s, 3H) 3-benzyloxy-5-bromoacetylisoxazole Yield, 83%; white crystalline compound, m.p. 80-81C (isopropyl ether);
lHNMR (DMS0-d6): delta 7.37 (s, 5H), 7,29 (s, lH), 5.28 (s, 2H), 4.71 (s, 2H).

5-hydroxymethyl-3-bromoacetylisoxazole (from 5 -hydroxylethyl-3-acetylisoxazole, 11 Farmaco, Ed. sci, 39, 487, 1984); Yield 94%; oily compound, b.p. 160C/0.3 mmHg, lHNMR (CDC13~: delta 6.72 ~St lH), 4.85 (s, 2H), 4.60 (s, 2H).
3-methyl-5-bromoacetylisoxazole (from 3-methyl-5-acetylisoxazole, Gazz. Chim. Ital. 72, 242, 1942); Yield, 87%; white crystalline compound, m.p. 44-46C
(isopropyl ether) lHNMR (CDC13): delta 7.00 (s, 1H), 4.42 (s, 2H), 2.43 (s, 3H) 3-(2-chloro-6-fluorophenyl)-5-bromoacetylisoxazole Yield, 85%; oily compound, b.p. 145~150C/0.3 mmHg lHNMR (CDC13): delta 7.8-7 (m, 4H), 4.60 (s, 2H) 3-carbethoxy-5-bromoacetylisoxazole Yield, 83%; white crystalline compound, m.p. 74-75C (isopropyl ether) lHNMR (CDC13~: delta 7.5 (s, 1H), 4.52 (q, 2H), 4.50 (s, 2H), 1.5 (t, 3H) 3-methoxymethyl-5-bromoace~ylisoxazole (from 3-methoxy-5-acetylisoxazole, Acta Chem. Scand. 28 B, 639, 1947); yield, 91%; oily;compound.
lHNMR (CDC13): delta 7.1 (s, lH), 4.4 (s, 2H), 3.4 (s, 3H).
1-(3-bromo-S-isossalolyl)-2-bromo-1-butanone Yiel~ 9~; whlte crystalline compound, m.p. 53-54C (hexane).

~2~

1HNMR (CDCl3): delta 7.2 (5, 1H), 5.0 (t, 1H), 2.2 (m, 4~), 1.1 (t, 3H).
Example D
1) 2-amino-4-(3-bromo-5-isoxazolyl)-thiazole A mixture of 32.~ g (120.4 mol) of 5-bromoacetyl-3-bromo-isoxazole and 18.4 9 (240 mmol) of thiourea in 400 ml of anhydrous ethanol was refluxed for 90 minutes.
The solvent was removed by distillation and the residue was taken up while stirring with 750 ml of ethyl ether and 160 ml of 10% aqueous potassium hydroxide. The ethereal extract was separated and washed with 50 ml of ethyl ether.
The extracts and the ethereal washings were combined and washed with water till neutral, dried over sodium sulfate and then evaporated to dryness.
The crystalline residue (28.7 g; 97%) was purified by recrystallization from methanol, m.p. 160-162 C;
lHNMR (DMS0-d6): delta 7.47 (s, 1H); 6.97 (s, lH).
2) 2-amino-4-(3-methoxy-5-isoxazolyl)-thiazole A mixture of 9.2 g (41.8 mmol) of 3-methoxy-5-bromoacetyl-isoxazole and 6.36 g (83.6 mmol) of thiourea in 140 ml of methyl alcohol was refluxed for 90 minutes and then cooled for 1 hour with an ice bath.
The precipitate was collected by filtration and added to 120 ml of an 1% solution of sodium hydroxide while stirring 2S vigorously.
The solution was allowed to stand for 30 minutes at room temperature, the precipiate was collected by filtration and washed with water till neutral.
Yield, 6.9 9 (83.7%); after recrystallization from methyl alcohol the compound melts at 215-217C.

lHNMR (DMS0-d6): delta 7.37 (s, lH), 6.43 (57 lH), 4.03 (s, 3H).
In a similar manner was prepared the 2-amino-4-(5-hydroxylmethyl-3-isoxazolyl)-thiazole, Yield, 62.5%; m.pO 185-187C (methyl alcohol) lHNMR (DMS0-d6): delta 7.3 (s, lH), 6.7 (s, lH), 5.7 (t, lH) 4.6 (d, 2H).
3) 2-amino-4-t3-chloro-5-isoxazolyl)-thiazole A mixture of 11.2 g (50 mmol) of 3-chloro-5-bromoacetyl-isoxazole and 7.6 9 (100 mmol) of thiourea in 164 ml of ethyl alcohol was refluxed for 90 minutes and then cooled for 1 hour with an ice bath.
The precipiate was collected by filtration and added to a mixture of 25 ml of a 10% aqueous solution of sodium hydroxide and 100 ml of ethyl acetate under vigorous stir-ring.
The organic layer was separated, washed, dried and evapo-rated to dryness. Yield, 7.7 9 (77%); after recrystallization from acetonitrile the compound meIts at 169-170C.
lHN~R (DMS0-d6): delta 7.4 (s, lHj, 6.9 (s, lH).
ln a slmilar manner the following compounds were prepared:
2-amino-4-(3-benzyloxy-5-isoxazoIyl)-thiazole, Yield, 76.5%; m.p. 129-131C (acetonitrile) lHNMR (CDCl3): delta 7.3 (s, 1H), 6.5 (s, lH), 5.4 (s, 2H).
2-amino-4-~5-phenyl-3-isoxazolyl)-thiazole, (from 5-phenyl-3-bromoacetylisoxazole, J. Med. Chem. 10, 411, 1967~. Yield, 74.5%; m.p.~215-216C (methyl alcohol).
Anal: S = 12.98~o (Calcd. 13~.18%) 2-amino-4-(3-phenyl-5-isoxazolyl)-thiazole, ~0 (from 3-phenyl-5-bt~mo~Ce~ylisoXaZole, J. Med. Chem. 10, 411, .

B~7 _ 20 -1967). Yield, 65.5%; m.p. 192-193C (acetonitrile).
Anal.: S = 13.39% (Calcd. 13.18%) 2-amino-4- 3-(2-chloro-6-fluorophenyl)-5-isoxazolyl -thiazole Yield, 56.6%; m.p. 168-169C (acetonitrile) Anal: S = 11.03% (Calcd. 10.84%) 2-amino-4-~3-methyl-5-isoxazolyl)-thiazole Yield, 57%; m.p. 208-210C (acetonitrile) lHNMR (DMS0-d6): delta 7.03 (s, lH), 6.5 (s, 1H), 2.3 (s, 3H).
2-amino-4-(3-methoxymethyl-S-isoxazolyl)-thiazole Yield, 49%; m.p. 137-138C (acetonitrile) lHNMR (DMS0-d6): delta 7.3 (s, lH), 6.6 (s, lH), 4.5 (s, 2H), 3.~ (s, 3H).
2-amino-4-(3-bromo-5-isoxazolyl)-5-ethylthiazole Yield, 70%; m.p. 151-152C (acetonitrile) lHNMR (DMS0-d6): delta 6.8 (s, lH), 3.0 (q, 2H), 1.2 (t, 3H).
4) 2-amino-4-(3-hydroxymethyl-5-isoxazolyl)-thiazole 4.4 9 (116.2 mmol) of sodium boron hydride were added portionwise to a solution of 13.9 (58.1 mmol) of 2-amino-4-(3-carbethoxy-5-isoxazolyl)-thiazole in 40 ml of dimethyl formamide and 80 ml of methyl alcohol under stirring at about When the addition was over~ the reattion mixture was stirred at room temperature for 90 minutes and then was made acid by adding carefully 60 ml of 10% hydrochloric acid.
The reaction~mixture was evaporated under reduced pressu-re, the ~residue was taken up with water and made alkaline with potassium carbonate.
The precipiate was collected by filtration and washed with 3~ water. Yield, 11.1 (97%); m.p. 184-185C (acetonitrile)l.

, .

- 21~

1HNMR (DMS0-d6): delta 7.4 (s, 1H), 6.6 (s, lH), 4.6 (d, 2H).
5) 2-amino-4-(3-carbethoxy-5~isoxazolyl)-thiazole A solution of 54.8 (209 mmol) of 3-carbethoxy-5-bromo-acetylisoxazole and 31.û 9 (418 mmol) of thiourea in 685 ml of ethanol was refluxed for 90 minutes and then cooled for 1 hour with an ice bath.
The precipitate was collected by filtration and added to an aqueous solution of potassium bicarbonate under vigorous stirring.
The reaction mixture was shaken with ethyl acetate. The combined organic extracts were washed with water, dried and evaporated. Yield, 43.4 9 (86.7%); m.p. 156-157C (aceto-nitrile).
1HNMR (DMS0-d6): delta 7.4 (s, 1H), 7.0 (s, 1H), 4.4 (d, 2H), 1.4 (t, 3H).

6) 2-amino-4-(3-hydroxy-5-isoxazolyl)-thiazole hydrobromide A mixture of 13.5 9 (68~5 mmol) of 2-amino-4-(3-methoxy-5-isoxazolyl)-2-thiazol and 135 ml of 48% hydrobromic acid was heated while stirring with an outer bath at 100C for one hour.
After cooling with a water/ice bath the precipitate was collected by filtration under r~duced pressure and dried.
13.3 9 (73.6%) of a white crystalline compound were obtained which were purified by crystallization from 1% hydrobromic acid.
lHNMR (DMS0-d6): delta 7.5 (s, 1H); 6.6 ;(s, 1H).
Example~E
13 Ethyl 4-~3-bromo-5-isoxazolyl)-thiazole-2-oxamate To a mixture of 7.38 9 (30 mmol) of 4-(3-bromo-5-isoxa-zolyl)-2-thiazolamine and 3.50 9 (34~6 mmol) of trlethylamine in 6Q ml of py~idine, 5tirr~d at a temp¢rature not above 10C
~0 were added dt~pl~ 4.71 g (34.5 mmol) of ethoxalyl chloride.

., _ 22 -At the end of the addition ~he solution was stirred overnight and then diluted with 120 ml of water.
Th~ precipitate was collected by filtration and washed on the filter with abundant water.
After vacuum drying at 50C the compound was recrystalli~-ed two times from 110 ml and 130 ml of acetonitrile respectively to give 6.90 g of a crystalline compound analitically pure; m.p. 196.5-197C.
lHNMR (DMS0-d6): delta 8.20 (s, lH); 7.20 (s, lH); 4.42 (q, 2H,); 1.40 (t, 3H).
ln a similar manner was prepared the following compound:
Ethyl-4-(3-phenyl-5-methyl-4-isoxazolyl)-thiazole-2-axamate, Yield, 78%; m.p. 157-159C (acetonitrile) lHNMR (DMS0-d6): delta 7.o (m, SH), 7.3 (s, lH), 3.2 (q, 2H), lS 2.6 (s, 3H), 1.3 (s, 3H).
2) Ethyl 4-(3-~ethoxy-5-isoxazolyl)-thiazole-2-oxamate To a mixture of 6.60 g (33.5 mmol) of 2-amino-4-(3-met-oxy-S-isoxazolyl)-thiazole in 67 ml of pyridine while stirrin~ at C-10C were added dropwise 5.25 9 (38.5 mmol) of ethoxal~l chloride.
The reaction mixture was maintained under stirring over-night, then poured into 120 9 of crushed ice and made acid with concentrate hydrochloric acid.
The mixture was extracted with 75Q ml of l,2-dichloro-ethane, the organic layer was separated and washed with water.
The organic extracts were evaporated; Yield, 9 40 g (94.5%);~ ~.p. ~04-205C
lHNMR (DMSO-d6): d~lta~ 10 ~s, lH), 6.6 (s, lH), 4.4 (q, 2H), 4.0 ~, ~), 1.4 (t, 3H).

23 ~ 8 ~7 In a similar manner were prepared the following compounds:
Ethyl 4-(5-phenyl-3-isoxazolyl)-thiazole-2-oxamate, Yield, 47%; m.p. 169-170C ~ethyl alcohol) lHNMR ~DMS0-d6): delta 8.2-7.4 (m, 5H), 8.1 (s, lH), 7.5 (s, lH), 4.4 (q, 2H), 1.4 (t, 3H).
Ethyl 4-(3-ethoxalyloxymethyl-5-isoxazolyl)-thiazole-2-oxa-mate, Yield, 68%; m.p. 150-151C (ethyl alcohol);
lHNMR (DMS0-d6): delta 8.1 (s, lH), 7.0 (s, 1H), 5.5 ~s, 2H), 4.4 (q, 4H), 1.4 (t, 6H).
Benzyl 4- 3-(2-chloro-6-fluorophenyl-5-isoxazolyl -thiazole-2-oxamate, Yieldj 67%; m.p. 199-200C (acetonitrile);
lHNMR (DMS0-d6): delta 8.3 (s, lH), 7.5 (m, 8H), 7.2 (s, lH), lS 5.5 (s, 2H).
Cyclohexyl 4- 3-(2-chloro-6-fluorophenyl-S-isoxazolyl -thia-zole-2-oxamate, Yield, 74%; m.p. 77-78C (~thyl alcohol);
lHNMR (OMS0-d6): delta 8.2 (;s, lH), 7.6 (m, 3H), 7.1 (s, lH), 4.9 (m, lH), 2.2-1.1 (m, 10 H) 3) 2-ethoxyethyl 4-(3-benzyloxy-5-isoxazolyl)-thiazole-2-oxa-mate. `
To a mixture of 5.6 9 (20.5 mmol) of 2-amino-4-(3-~enzyl-oxy-5-isoxazolyl)-thiazole in 37.4 ml of pyridine malntained under stirring at 5C were added dropwise 4.25 9 (23.6 mmol) of 2-ethoxyethyloxalyl chloride.
The reaction mixture was maintained under stirring over-night, then poured into 100 9 of crushed ice, made acid with concentrat~ hy~rochloric acid and extracted with chloroform.
: Tho chlo~o~o-m extracts weré washed with water, drled and , evaporated to dryness. The residue (8.30 g) was recrys-tallized from 65 ml of acetonitrile; m.p. 142-144C.
lHNMR (DMS0-d6): delta 8.2 (s, 1H), 7.6 (m, 5H), 6.7 (s, lH), 4.5 (m, 2H), 3.8 (m, 2H), 3.6 (q, 2H), 1.2 (t, 3H).
In a similar manner were obtained the following compounds:
2-ethoxyethyl 4-(5-phenyl-3-isoxazolyl)-thiazole-2-oxamate, Yield, 82%; m.p. 146-147C (acetonitrile) 1HNMR (DMS0-d6): delta 8.1 (s, 1H), 8.1-7.5 (m, 5H)7 7.5 (s, lH), 4.5 (m, 2H), 3 (m, 2H), 3.6 (q, 2H), 1.2 (t, 3H).
2-ethoxyethyl 4-(3-phenyl-5-isoxazolyl)-thiazole-2-oxamate, Yield, 84%; m.p. 146-147C (acetonitrile) lHNMR (DMS0-d6): delta 8.2 (s, lH), 8.2-7.4 (m, 5H), 7.4 (s, lH), 4.5 (m, 2H), 3.8 (m, 2H), 3.6 (q, 2H), 1.2 (t, 3H).
2-ethoxyethyl 4- 3-(2-chloro-6-fluorophenyl)-5-isoxazolyl -thiazole-2-oxamate.
Yield, 87%; m.p. 140-141C (acetonitrile) lHNMR (DMS0-d6): delta 8.2 (s, lH)7 7.7 (m, 3H), 7.2 (s, lH), 4.5 (m, 2H), 3.8 (m, 2H), 3.b (q, 2H), 1.2 (t, 3H).
2-ethoxyethyl 4-(3-methyl-5-isoxazolyl)-thiazole-2-oxamate, Yield, 91%; m.p. 155-156C (acetonitrile);
lHNMR (DMS0-d6): deita 8.0 (s, lH), 6.7 (5, 1H), 4.5 ~m, 2H), 3.8 (m, 2H), 3.6 (q, 2H), 2.3 (s, 3H), 1.1 (t, 3H).
2-ethoxyethyl 4-(3-carbethoxy-5-isoxazolyl)-thiazole-2-oxa-mate, Yield, 75%; m.p. 145-146C (acetonitrile);
lHNMR (CDCl3): delta 7.7 (sl 1H), 7.0 (s, 1H), 4.5 (q, 2H), 4.5 (m, 2H), 3.8 (m, 2H), 3.6 (q, 2H), 1.4 (t, 3H), 1.2 (t, 3H).
2-ethoxyethyl 4-(3-methoxymethyl-5-isoxazoly~)-thiazole-2-oxamate, Yield, 86%; m.p. 136-137C (ethyl alcohol) lHNMR (DMS0-d6): delta 8.1 (s, 1H), 6.8 (s, 1H), 4.6 (s, 2H), 4.4 (m, 2H), 3.7 (m, 2H), 3.6 (q, 2H), 3.4 (s, 3H), 1.2 (t, 3H).
S 2-ethoxyethyl 4-(5-hydroxymethyl-3-isoxazolyl)-thiazole-2-oxamate, Yield, 58%; m.p. 159-161C (acetonitrile);
lHNMR (DMS0-d6): delta 8.0 (s, lH), 6.9 (s, lH), 4.7 (s, 2H), 4.5 (m, 2H), 3.~ ~m, 2H), 3.~ (q, 2H), 1.2 (t, 3H).
2-ethoxyethyl 4-(3-hydroxy-5-isoxazolyl)-thiazole-2-oxamate, m.p. 217-219C ~acetonitrile);
lHNMR (DMS0-d6); delta 8.00 (s, lH), 6.37 (s, 1H), 4.43 (m, 2H), 3.73 (m, 2H), 3.53 (q, 2H), 1.13 (t, 3H).
2-ethoxyethyl 4-(3-bromo-5-isoxazolyl)-5-ethyl-thiazole-2-oxamate, Yield, 92%; m.p. 128-129C (acetonitrile);
lHNMR (DMS0-d6): delta 7.0 (s, lH), 4.4 (m, 2H), 3.7 (m, 2H), 3.5 (q, 2H), 3.1 (q, 2H), 1.3 (t, 3H), 1.1 (t, 3H).
ethoxyethyl 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate Yield, 70%; m.p. 162-164C (acetonitrile);
1HNMR (DMS0-d6): delta 8.2 (s, 1H), 7.1 (s, 1H), 4.5 (m, 2H), 3.8 (m, 2H), 3.6 (q, 2H), 1.18 (t, 3H).
2-ethoxyethyl ~-~3-chloro-5-isoxazolyl) thiazole-2-oxamate Yield, 81%; m.p. 154-156C (acetonitrile);
1HNMR (DMS0-d6): delta 8.2 (s, lH), 7.1 (s, lH), 4.5 (m, 2H), 3.8 (m, 2H), 3.6 (q, 2H), 1.2 (t, 3H).
2-ethoxyethyl 4-(3-methoxy-5-isoxazolyl)-thiazole-2-oxamate Yield, 78%; m.p. 142-143C (acetonitrile);
lHNMR (DMS0-d6): delta 8.10 (s, lH), 6.58 (s, lH), 4.5 (m, 2H), 4.02 ( s , 3H), 3.8 tm, 2H), 3.60 (q, 2H), 1.18 (t, 3H).

~ 6 ~3~7 4) 2-methoxyethyl 4 (3-bromo-5-isoxazolyl)-thiazole-2-oxamate, Ts a mixture of 2.50 (10 mmol) of 2-amino-4-(bromo-5-iso-xazolyl)-2-thiazole and 1.16 9 (11.5 mmol) of triethylamine in 20 ml of pyridine stirred continously at a temperature of 5C were added dropwise 1.91 9 (11.5 mmole) of 2-methoxy-eth-yl-oxalyl chloride (prepared by adding 2-methoxy-ethanol to an excess of oxalyl chloride and collecting by distillation of the fraction with b.p. 124-128C/90 mmHg). At the end of the addition the solution was stirred for one night and then 1Q diluted with 50 ml of water.
The precipitate was collected by filtration under reduced pressure, washed abundantly on the filter with water, and dried under reduced pressure at 50C. 3.10 9 of raw material were obtained which were-recrystallized twice from acetoni-trile to give 2.30 (bl%) of an analytically pure crystalline compound, m.p. 175.5-177C;
1HNMR (DM50-d6): delta 8.17 (s, 1H); 7.13 (s, 1H); 4.50 (m, 2H,); 3.50 (m, 2H); 3.35 (s, 3H).
Example F
~0 1) 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamic acid A suspension of 12.60 9 (36.4 mmol) of ethyl 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate in 500 ml of N/10 sodium hydroxi-de was stirred at 40C for 45 minutes.
The reaction mixture was cooled to room teMperature, extracted twice with 150 ml of ethyl ether, treated with active charcoal, and filt~red.
The filtra~ waS acidified with 60 ml of lN hydrochloric acid and the~ preGlpl~ta was collected by filtration and washed on the filter abu~ntly with water.
Yield 9.80 g (~4.5%); m.p. 217-218.5C ~dec.).

, '~;2 6~
_ 27 _ 1HNMR (DMS0-d6): delta 8.13 (s, lH); 7.16 (s, lH).
2) 2-aminoethanol 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate salt, A suspension of 2.85 g (8.95 mmol) of 4-(3-bromo-5-isoxa-zolyl)-thiazole-2-oxamic acid in 25 ml of ethanol was heated on a steam-bath while stirring. To this mixture were added 0.59 9 (9.66 mmol) of ethanolamine in 10 ml-of ethyl alcohol and 20 ml of water.
The solution was cooled to room temperature and then allowed to stand at 4C for one night.
The precipitate was collected by filtration, dried and recrystallized from 65 ml of a 2:1 ethyl alcohol/water mixture.
Yield, 2 9 (59%); m.p. 190-193C (dec.).
lHNMR (DMSO-d6): delta 8.0 (s, lH), 7 (s, lH), 3.7 (m, 2H), 3.0 (m, 2H).
3) tromethamine 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate salt, To a solution of 3.20 9 (26.4 mmol) of tromethamine in 75 ml of methanol, kept under stirring with slight refluxing, were added all at once 8.4 9 (26.3 mmole) of 4-(3-bromo-5-isoxazolyl-2-thiazolyl oxamic acid.
The reaction mixture was cooled to room temperature and after approximately 15 minutes the precipitate was collected by filtration, washed on the filter with cold methanol, and dried.
The crude compound (7.10 9; 61.5%) was recrystallized from methanol; m.p. 1~3C (dec.);
lHNMR (DMS0-d6 + D2û): delta 8.07 (s, lH); 7.17 (s, lH); 3.65 (s, 6H).
4) L-lysine 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate salt, o 2.6 (~.2 mmol) of 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxa-~6~

mic acid were added to a solution of 1.25 (8.6 mmol) of L-lysine in 140 ml of 75% aqueous ethyl alcohol while re-fluxing and stirring.
After cooling to 0C the mixture was maintained under S stirring for 3 hours. The precipitate was collected by fil-tration; yield, 2.7 (71%); m.p. 196-197C (dec.) lHNMR (D20): delta 7.5 ~s, 1H), 6.5 (s, lH), 3.9 (t, 3H),`3.1 (m, 2H), 2.2-1.3 (m, 6H).
In a similar manner were prepared the following campounds:
4-(3-methoxy-5-isoxazolyl)-thiazole-2-oxamic acid Yield, 82%; m.p. 224-225DC (dec.);
lHNMR (DMS0-d6): delta 8.0 (s, lH), 6.5 (s, lH), 4.0 (s, 3H).
2-aminoethanol 4-(3-methoxy-5-isoxazolyl)-thiazole-Z-oxamate salt, Yield, 83.7%; m.p. 214-215C dec. (75% ethyl alcohol);
lHNMR (DMSC-d6): delta 7.1 (s, lH), 6.5 (s, lH), 4.0 (s, 3H), 3.7 (m, 2H), 3.0 (m, 2~).
2-aminoethanol 4-(3-chloro-5-isoxazolyl)-thiazole-2-oxamate salt, Yield, 71%; m.p. 211C dec. (70% ethyl alcohol);
lHNMR (TFAA): delta 8.1 (s, lH), 7.1 (s, 1H), 3.7 (m, 2H), 3.0 (m, 2H).
2-aminoethanol 4-(5-phenyl-3-isoxazolyl)-thiazole-2-oxamate salt, Yield, 68.5%; m.p. Z10-211C dec. (75% methyl alcohol);
1HNMR ~DMS0 d6): delta 8.2-7.1 (m, 5H), 8.2 (s, lH), 7.4 (s, lH), 3.8 (m, 2H), 3~0 (m~ ZH).
2-aminoethanol 4-~3-phenyl-5-isoxazolyl)-thiazole-2-oxamate salt, Yield, 73%~ m,p.~ 207~20~C dec. (85% ethyl alcohol);

lHNMR (DMS0 d6): delta 9-7.3 (m, 6H), 7 4 (s, lH), 3.8 (m, 2H), 3.1 (m, 2H).
L-lysine ~-(5-phenyl-3-isoxazolyl)-thiazole-2-oxamate salt, Yield, 64.5%; m.p. 240-241C dec. (20% methyl alcohol);
lHNMR (TFAA): delta 8.1-7.3 (m, 5H), 8.0 (s, lH), 7.3 (s, 1H), 4.0 (t, lH), 2.9 (m, 2H), 2.2-1.3 (m, oH).
2-aminoethanol 4- 3-(2-chloro-b-fluorophenyl)-5-isoxazolyl -thiazole-2-oxamate salt, Yield, 56%; m.p. 230-231C, dec. (70% ethyl alcohol) lHNMR (DMS0-d6): delta a.2-7.0 (m, 3H), 8.1 (s, 1H), 7.1 (s, lH), 3.7 (m, 2H), 3.0 (m, 2H).
2-aminoethanol 4-(5-hydroxymethyl-3-isoxazolyl)-thiazole-2-oxamate, Yield, 61%; m.p. 1-35~187C, dec. (methyl alcohol);
lHNMR (DMSû-d6): delta 7.9 (s, lH), 6.8 (s, lH), 4.6 (s, 2H), 3.7 (m, 2H), 3.0 (m, 2H).
2-aminoethanol 4-(3-hydroxymethyl-5-isoxazolyl)-thiazole -2-oxamate, Yield, 69%; m.p. 196-197C, dec. (75% methyl alcohol) lHNMR (DMS0-d6): delta 7.9 (s, 1H), 6.8 (s, lH), 4.6 (s, 2H)?
3.7 (m, 2H), 3.0 (m, 2H).
5) Sodium 4-(3-methoxy-5-isoxazolyl)-thiazole-2-oxamate, A suspension of 11.9 (35 mmol) of ethoxyethyl 4-(3-met-oxy-5-isoxazolyl)-thiazole-2-oxamate in S00 ml of N/10 sodium hydroxyde was stirred at 40C for 30 minutes.
After cooling to 0C, the precipitate was collected by filtration and dried.
Yield, 2.4 (23.5%); m.p. 320, dec.
lHNMR (TFM): d~lta 8.1 (s, lH), 6.3 (s, 1H), ~1.2 (S7 3U).
`~ Example~ G

_ 30 _ 1) Granules containing 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxa-mic acid ~L)-lysine salt A mixture of 1ûO g of active ingredient, 155 9 of lactose, 140 q of corn starch and 80 g of crystalline cellulose was stirred and the mixture was kneaded and granulated with a solution of 20 9 of hydroxypropylcellulose in 400 ml of water and dried at 50C for 1 hour; then was passed through a 12 mesh screen to obtain granules which were dried at 50C for lû hours.
2) Suppository containing 4-(3-phenyl-5-isoxazolyl)thiazol-2-(2-ethoxyethyl) oxamate A mixture of 5-15g of active ingredient and 180 g of Witepsol(R) ~-35 was heated and molten at 60C and the melt was cast into models so that the weight of each suppository was 1,5 9 or 3 9. The cast melt was cooled and solidified to obtain suppositories.
3) Tablets containing 4-(3-phenyl-S-isoxazolyl)-thiazole-2-oxa-mic ethanolamine salt.
A mixture of 100 g of active ingredient, 80 g of lactose, 70 9 of corn starch and 40 9 of crystalline cellulose was granulated in the conventional way.
The granulates was mixed with 4 9 of magnesium stearate and formed into tablet each having a weight of 200 mg by a tabletting machine.
4) Capsules containing 4-(3-methyl-5-isoxazolyl)-thiazole-2-(2-ethoxyethyl)oxamat~.
A mixture of 10C y of active ingredient, 100 g of lactose, 60 9 of èor~ st~rch 40 g of crystalline cellulose and 6 g of magnesium 5t~aFat~ was mixed and filled into hard capsules in an amount 0~ 200 mg for capsule by using an encapsulating - 31 ~ 7 machine.
5) Ampoules (iniection solution) containing 4-(5-phenyl-3-iso~a-zolyl)thiazole-2-oxamic acid (L)-lysine salt.
The active ingredient (100 parts by weight)l 2 parts by weight of sodium pyrosulfite, 1 part by weight of disodium salt of ethylendiamine-tetraacetic acid, 17 parts by weight of sodium chloride are dissolved in a sufficient quantity of water and brought to 2000 parts by weight with the double distilled water. The solution was filtered and filled into 1 ml ampoules, finally the ampoules were sealed and sterilized.
Each ampoule contains 50 mg of active ingredient.
6) lnhalation Aereosol Preparation containing 4-(3-methyl-5-iso-xazolyl)-thiazole-2-(2-ethoxyethyl) oxamate The active ingredient (1 to 20 parts), soya lecithin (0.20 to 4 parts) and mixture of propellant gases (Freon 11, 12 and 14) up to 100 parts was filled into aerosol containers with metering valve. The single dose can be adjusted in such a way that it provides 1 to 20 mg of active substance.

Claims (5)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A compound of the general formula (III) (III) wherein Z is a group of the formula selected from or wherein R and R1 which may be the same or different are a hydrogen or a halogen atom, a hydroxy group, a C1-3 alkoxycarbonyl group, a C1-3 alkyl group optionally substituted by hydroxy, C1-3 alkoxy or alkoxy C1-3 oxalyloxy, a C1-3 alkoxy group optionally substituted by phenyl, or a phenyl group optionally substituted by halogen; and R4 is a hydrogen atom or a C1-3 alkyl group.

2. A compound as claimed in claim 1, wherein R4 is hydrogen and Z is a group, wherein R is hydrogen; and R1 is phenyl.

3. A compound as claimed in claim 1, wherein R4 is hydrogen, and Z is a group, wherein R1 is hydrogen; and R is methyl, hydroxymethyl, methoxymethyl or phenyl.

4. A process for preparing a compound of the general formula (III) as defined in claim 1 which comprises reacting the corresponding alpha, bromo-acylisoxazole with thiourea.

5. A process as claimed in claim 4, wherein the reaction is carried out in a protic or aprotic polar solvent at a temperature between 50°C and 100°C.