Note: Descriptions are shown in the official language in which they were submitted.
~ 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
- 12 -
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
- 13 -
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.
- 19 -
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
35C
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
,
- 24 -
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,
- 25 -
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
- 26 -
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~
- 28 -
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);
- 29 --
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.
