The invention relates to compounds of the formula: ##STR1## wherein R is hydrogen or lower alkyl, R.sub.1, R.sub.2, R.sub.3 and R.sub.4, independently, are hydrogen, lower alkyl, lower alkenyl, cycloalkyl or phenyl unsubstituted or substituted by up to 3 substituents independently selected from lower alkyl, lower alkoxy or halogen, or R.sub.1 and R.sub.2 taken together with the carbon atom are alkylene of 2 to 5 carbon atoms unsubstituted or substituted by lower alkyl, and n is an integer of from 0 to 3, PA1 and, when R.sub.1 is different from R.sub.2 and/or when R.sub.3 is different from R.sub.4, enantiomers, diastereomers and racemates thereof and, when R is hydrogen, salts thereof with pharmaceutically acceptable bases. The compounds of formula I and, when R is hydrogen, pharmaceutically exceptable salts thereof are useful as bronchopulmonary agents, for example, in the relief of asthma and allergic reactions.

BRIEF SUMMARY OF THE INVENTION 
The invention relates to compounds of the formula 
##STR2## 
wherein R is hydrogen or lower alkyl, R.sub.1, R.sub.2, R.sub.3 and 
R.sub.4, independently, are hydrogen, lower alkyl, lower alkenyl, 
cycloalkyl or phenyl unsubstituted or substituted by up to 3 substituents 
independently selected from lower alkyl, lower alkoxy, or halogen, or 
R.sub.1 and R.sub.2 taken together with the carbon atom are alkylene of 2 
to 5 carbon atoms unsubstituted or substituted by lower alkyl, and n is an 
integer of from 0 to 3, and, when R.sub.1 is different from R.sub.2, 
and/or when R.sub.3 is different from R.sub.4, enantiomers, diastereomers 
and racemates thereof, and, when R is hydrogen, salts thereof with 
pharmaceutically acceptable bases. 
The compounds of formula I and pharmaceutically acceptable salts thereof 
are useful as bronchopulmonary agents, for example, in the relief of 
asthma and allergic reactions. 
In another aspect, the invention relates to pharmaceutical compositions, 
methods of using the compound of formula I and intermediates. 
DETAILED DESCRIPTIONOF THE INVENTION 
The invention relates to compounds of the formula 
##STR3## 
wherein R is hydrogen or lower alkyl, R.sub.1, R.sub.2, R.sub.3 and 
R.sub.4, independently, are hydrogen, lower alkyl, lower alkenyl, 
cycloalkyl or phenyl unsubstituted or substituted by up to 3 substituents 
independently selected from lower alkyl, lower alkoxy, or halogen, or 
R.sub.1 and R.sub.2 taken together with the carbon atom are alkylene of 2 
to 5 carbon atoms unsubstituted or substituted by lower alkyl, and n is an 
integer of from 0 to 3, and, when R.sub.1 is different from R.sub.2, 
and/or R.sub.3 is different from R.sub.4, enantiomers diastereomers and/or 
racemates thereof and, when R is hydrogen, salts thereof with 
pharmaceutically acceptable bases. 
As used herein, the term "lower alkyl" preferably denotes a straight or 
branched chain saturated hydrocarbon containing 1 to 7 carbon atoms, for 
example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, 
pentyl, heptyl and the like. The term "lower alkenyl" denotes a straight 
or branched chain saturated hydrocarbon containing 3 to 7 carbon atoms, 
for example, propenyl, butenyl, pentenyl, hexenyl and the like. Exemplary 
of "alkylene of 2 to 5 carbon atoms" are ethylene, propylene, butylene and 
pentylene. The term "cycloalkyl" denotes a cyclic alkyl group of 3 to 6 
carbon atoms, for example cyclopropyl, cyclopentyl, cyclohexyl and the 
like. The term "halogen" denotes chlorine, bromine, iodine and fluorine. 
The compounds of formula I and their salts exist as the (E) or trans 
geometric isomers. As used herein, the term "the compounds of formula I" 
shall include enantiomers, diastereomers and racemic mixtures thereof, 
when R.sub.1 is different from R.sub.2, and/or R.sub.3 is different from 
R.sub.4. 
A preferred group of the compounds of formula I are those wherein R is 
hydrogen, R.sub.1 and R.sub.2, independently, are lower alkyl R.sub.3 and 
R.sub.4 are hydrogen and n is 0 to 3. 
A more preferred group of compounds of formula I are those wherein R is 
hydrogen R.sub.1 and R.sub.2,independently, are lower alkyl, R.sub.3 and 
R.sub.4 are hydrogen, and n is 1. 
Preferred compounds of formula I of the invention are: 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-diethyl-4- 
oxobutanoic acid; and 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-diethyl-4 
-oxobutanoic acid. 
Exemplary of the compounds of formula I of the invention are: 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-dipropyl- 
4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-dihexyl-4 
-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-2-methyl-2-pr 
opyl-4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-2-ethyl-2-pro 
pyl-4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-2-butyl-4-oxo 
butanoic acid; 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-2-(2-butyl)-4 
-oxobutanoic acid; 
(E)-2-butyl-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2-ethy 
l-4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2-ethyl-2-meth 
yl-4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2-(1,1-dimethy 
lethyl)-4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclohexyl-2-thiazolyl)ethenyl]phenyl]amino]-2-hexyl-2-meth 
yl-4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2-(2-propenyl) 
-4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2-cyclopentyl- 
4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-3,3-dipropyl- 
4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-3,3-diethyl-4 
-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-dipropyl- 
4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-dihexyl-4 
-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-2-methyl-2-pr 
opyl-4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-2-ethyl-2-pro 
pyl-4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-2-butyl-4-oxo 
butanoic acid; 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-2-(2-butyl)-4 
-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2-ethyl-4-oxob 
utanoic acid; 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2-ethyl-2-meth 
yl-4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2-(1,1-dimethy 
lethyl)-4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclohexyl-2-thiazolyl)ethenyl]phenyl]amino]-2-hexyl-2-meth 
yl-4-oxobutanoic acid ethyl ester; 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2-(2-propenyl) 
-4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2-cyclopentyl- 
4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-3,3-dipropyl- 
4-oxobutanoic acid; 
(E)-4-[[3-[2-(4-Cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-3,3-diethyl-4 
-oxobutanoic acid methyl ester; and the like. 
The compounds of formula I can be prepared as hereinafter described in 
Reaction Schemes I, II, III and IV. 
##STR4## 
wherein n is as previously described and HAL is halogen. 
In Reaction Scheme I, a compound of formula II, which are known compounds 
or can be prepared according to known procedures, is halogenated to the 
corresponding compound of formula III in the presence of an alkanol, for 
example, methanol, and a halogenating agent, for example, bromine, at a 
temperature in the range of from about 10.degree. C. to about room 
temperature. The resulting compound of formula III can be recovered 
utilizing known procedures, for example, distillation, chromatography and 
the like. Alternatively, the compound of formula III can be utilized in 
situ in the next reaction step. 
The compound of formula IV, which is a known compound, is converted to the 
compound of formula V by treatment with a thiolating agent, for example, 
phosphorus pentasulfide or Lawesson's reagent in the presence of an inert 
solvent, for example, a hydrocarbon, such as, toluene or the like, at the 
reflux temperature of the reaction mixture. The resulting compound of 
formula V can be recovered utilizing known procedures, for example, 
crystallizarion, chromatography and the like. 
Thereafter, a compound of formula III is reacted with the compound of 
formula V conveniently in the presence of an inert solvent, for example, 
an alkanol, such as, ethanol, or the like, at a temperature in the range 
of from about 0.degree. C. to about 100.degree. C. A resulting compound of 
formula VI can be recovered utilizing known procedures, for example, 
crystallization, chromatography and the like. 
##STR5## 
when n is as previously described and HAL is halogen. 
In Reaction Scheme II, a compound of formula III, is reacted with the 
compound of formula VII, which is a known compound, to give the 
corresponding compound of formula VIII. The reaction is conveniently 
carried out in the presence for an inert solvent, for example, an alkanol, 
such as, ethanol, at a temperature in the range of from about 0.degree. C. 
to about 100.degree. C. The resulting compound of formula VIII can be 
recovered utilizing known procedures, for example, distillation, 
chromatography and the like. 
A compound of formula VIII is reacted with the compound of formula IX, 
which is a known compound, in the presence of a dehydrating agent, for 
example, acetic anhydride and the like, at a temperature in the range of 
from about 0.degree. C. to about 150.degree. C., to yield the 
corresponding compound of formula VI. The resulting compound of formula VI 
can be recovered utilizing known procedures, for example, distillation, 
chromatography and the like. 
##STR6## 
wherein R' is hydrogen, and R.sub.1, R.sub.2, R.sub.3, R.sub.4 and n are 
as previously described. 
In Reaction Scheme III, a compound of formula VI is reduced to the 
corresponding compound of formula X by utilizing a reducing agent, for 
example, stannous chloride, Raney Nickel with hydrogen and the like in the 
presence of an inert solvent, for example, an alkanol, such as, ethanol, 
at a temperature is in the range of from about 0.degree. C. to about 
100.degree. C. The resulting compound of formula X can be recovered 
utilizing known procedures, for example, extraction, chromatography and 
the like. 
A compound of formula X is reacted with a compound of formula XI, which are 
known compounds or can be prepared by known procedures, in an inert 
solvent, for example, a halogenated hydrocarbon, such as, methylene 
chloride, an ether, such as, 1,2-dimethoxyethane and the like, optionally 
in the presence of a base, for example, sodium acetate, at a temperature 
in the range of from about -10.degree. C. to about 100.degree. C. to yield 
the corresponding compound of formula Ia. The resulting compound of 
formula Ia can be recovered by known procedures, for example, 
crystallization, chromatography and the like. 
##STR7## 
wherein R" is lower alkyl, Y is a leaving group, such as, halogen, 
hydroxyl or the like, and R.sub.1, R.sub.2, R.sub.3, R.sub.4 and n are as 
previously described. 
In Reaction Scheme IV, a compound of formula X is acylated with a compound 
of formula XII, wherein Y is halogen, which are known compounds or can be 
prepared by known procedures, in an inert solvent, for example, a 
halogenated hydrocarbon, such as, methylene chloride and the like, at a 
temperature in the range of from about -10.degree. C. to about 50.degree. 
C. 
Alternatively, a compound of formula X is acylated with a compound of 
formula XII, wherein Y is hydroxyl, which are known compounds or can be 
prepared by known procedures, in an inert solvent, for example, a 
halogenated hydrocarbon, such as, methylene chloride and the like, at a 
temperature in the range of from about -10.degree. C. to about 50.degree. 
C., and in the presence of an activating agent, for example, 
dicyclohexylcarbodiimide and the like. The resulting compound of formula 
Ib can be recovered by known procedures, for example, crystallization, 
chromatography and the like. 
##STR8## 
wherein R', R.sub.1, R.sub.2 and n are as previously described, except 
that at least one of R.sub.1 and R.sub.2 must be other than hydrogen. 
In Reaction Scheme V, a compound of formula Ic can be transaminated to the 
corresponding compound of formula Id by first cyclizing a compound of 
formula Ic with a dehydrating agent, for example, an acid chloride such as 
acetyl chloride or the like, with or without a solvent, such as toluene or 
methylene chloride, at reflux. 
The resulting product of formula XIII can be used without purification or 
it can be isolated by standard procedures, such as crystallization or the 
like and then cleaved with a base, such as with an alkali metal or 
alkaline earth metal hydroxide such as lithium hydroxide or the like, in 
the presence of an aqueous/organic solvent such as water/methanol or the 
like and at a temperature in the range of from about 25.degree. to about 
100.degree. C. 
Thereafter, the resulting compound of formula Id, after acidification with 
an acid such as hydrochloric acid or the like, can be isolated by standard 
procedures, such as crystallization or the like. 
The invention also relates to the salts of the compounds of formula I, 
their enantiomers, diastereomers and racemates thereof wherein R is 
hydrogen, which salts can be prepared by the reaction of the said 
compounds with a base having a non-toxic, pharmaceutically acceptable 
cation. In general, any base which will form a salt with a carboxylic acid 
and whose pharmacological properties will not cause an adverse 
physiological effect when ingested is considered as being within the scope 
of this invention. Suitable bases thus include, for example, the alkali 
metal and alkaline earth metal hydroxides and carbonates, ammonia, 
primary, secondary and tertiary amines, such as, monoalkylamines, 
dialkylamines, trialkylamines, nitrogen containing heterocyclic amines, 
for example, piperidine and the like. 
The compounds of formula I and, when R is hydrogen, their pharmaceutically 
acceptable salts are active as inhibitors of bronchoconstriction and are 
therefor useful as bronchopulmonary agents, for example, in the relief of 
asthma and allergic reactions. The useful activity of the compounds of 
formula I of the invention can be demonstrated as hereinafter set forth. 
LEUKOTRIENE D.sub.4 RECEPTOR BINDING ASSAY (GUINEA PIG LUNG HOMOGENATE) 
(1) Methods 
(a) Preparation of membrane Homogenate 
Male albino guinea pigs (Hartley strain, 400-500 g body weight) were 
sacrificed by decapitation. The lungs were removed, frozen in liquid 
nitrogen and stored at -70.degree. until use. The frozen tissue (5 g) was 
thawed, minced into small pieces and rinsed in phosphate-buffered saline. 
The tissue was placed in 40 ml homogenization buffer containing 0.25 M 
sucrose, 10 mM Tris-HCl, (pH 7.5), and the following protease inhibitors: 
soybean trypsin inhibitor (5 .mu.g/ml) bacitracin (100 .mu.g/ml), 
benzamidine (10.sup.-3 M) and phenylmethylsulfonyl fluoride (10.sup.4 M). 
The protease inhibitors were included to inhibit proteolysis during the 
processes of homogenization and centrifugation. The tissue was then 
homogenized at 0.degree.-4.degree. C. with a Brinkman PT-20 polytron for a 
total of 1 minute (10 second pulses at a setting of 6). The homogenate was 
centrifuged (1000.times.g for 10 minutes) to remove tissue clumps, 
unbroken cells and nuclei. The supernatant was recentrifuged at 
30,000.times.g for 30 minutes to yield pellets which were referred to as 
crude membrane fractions. This fraction was then resuspended in the 
incubation buffer (10 mM pipes buffer, pH 7.5, 50 mM NaCl), homogenized in 
a Teflon homogenizer and recentrifuged at 30,000.times.g for 30minutes. 
The pellets were finally resuspended in the incubation buffer with a 
Teflon homogenizer at a concentration of 10 to 20 mg/ml of protein in the 
suspension. The concentrations of proteins were determined using the 
Biorad reaction kit. 
(b) Receptor-Ligand Binding Assay 
Optimum assay conditions were determined with an assay mixture containing: 
Tyrode solution; 0.1% bovine serum albumin (BSA); 1 mM glycine; 1 mM 
cysteine; 3.5 nM .sup.3 H-LTD.sub.4 and the membrane preparation (100-200 
.mu.g protein) in a final volume of 250 .mu.l. The incubation was carried 
out at 20.degree. C. for 30 minutes. At 20.degree. C., binding increased 
linearly with protein concentration, reached equilibrium in 20 minutes, 
was saturable, and reversible upon additions of unlabelled LTD.sub.4. 
Separation of bound from free .sup.3 H-LTD.sub.4 was performed by rapid 
filtration on GF/C glass fiber filters and washing with two 4 ml aliquots 
of Tyrode solutions containing 0.1% BSA. Radioactivity remaining on the 
filters was measured in 10 ml of Aquasol. Specific binding was defined as 
that displaced by 10.sup.-6 M unlabelled LTD.sub.4 and was 95% of total 
binding. 
LEUKOTRIENE-INDUCED BRONCHOCONSTRICTION IN GUINEA PIGS--IN VIVO LEUKOTRIENE 
D.sub.4 (LTD) ANTAGONIST TEST 
Intravenous and Oral Testing 
Male guinea pigs (Hartley strain Charles River) weighing 300-500 g were 
anesthetized with urethane (.about.2 g/kg) intraperitoneally and a 
polyethylene cannula was inserted into the jugular vein for intravenous 
drug administration. Tracheal pressure (cm of H.sub.2 O) was recorded from 
a Statham pressure transducer (P 32 AA). Propranolol was administered 5 
minutes prior to challenge with LTD. Two minutes later spontaneous 
breathing was arrested with succinylcholine chloride (1.2 mg/kg) 
administered intravenously, and the animals were ventilated with a Harvard 
(Model #680) small animal respirator set a 40 breaths/min and 4.0 cc 
stroke volume. Control vehicle or test drug was administered through the 
cannula into the jugular vein 1 minute before the animals were challenged 
intravenously with a maximum constrictory dose of LTD (25 .mu.g/kg) given 
intravenously. The change in tracheal pressure was averaged for control 
and drug-treated animals and percent inhibition was calculated. For 
determination of oral activity, animals were dosed with test compound or 
vehicle two hours prior to challenge with LTD (25 .mu.g/kg, i.v.). 
The relative potency (ID.sub.50 values) of test compounds administered by 
the intravenous and oral route was determined by administering increasing 
doses of test compound. For determination of the time course of inhibition 
for various compounds, the time between administration of compound and 
challenge with LTD was varied. The time course of activity was calculated 
as the time when inhibition decreased to 40%. 
TABLE I 
__________________________________________________________________________ 
LTD.sub.4 -Induced 
% Inhibition at 
Bronchoconstriction 
Duration 
LTD.sub.4 Binding 
1 mg/kg i.v. 
% Inhibition at 
10 mg/kg p.o. 
Compound IC.sub.50 (.mu.M) 
(ID.sub.50) 
10 mg/kg p.o. (ID.sub.50) 
4 hr. 
8 hr. 
18 hr. 
__________________________________________________________________________ 
(E)-4-[[3-[2-(4-cyclopropyl- 
0.020 94 .+-. 2 (0.18) 
98 .+-. 1 (1.1) 
99 .+-. 1 
95 .+-. 1 
61 .+-. 6 
2-thiazolyl)ethenyl]phenyl] 
amino]-2,2-diethyl-4-oxobu- 
tanoic acid 
(E)-4-[[3-[2-(4-cyclopropyl- 
4.0 15 .+-. 4 
-- -- -- -- 
2-thiazolyl)ethenyl]phenyl] 
amino]-4-oxobutanoic acid 
(E)-4-[[3-[2-(4-cyclopentyl- 
0.200 -- 27 .+-. 3 -- -- -- 
2-thiazolyl)ethenyl]phenyl]amino]- 
2-methylene-4-oxobutanoic acid 
(E)-4-[[3-[2-(4-cyclopentyl-2- 
0.060 99 .+-. 1 (0.08) 
97 .+-. 1 (0.34) 
99 .+-. 1 
98 .+-. 1 
70 .+-. 7 
thiazolyl)ethenyl]phenyl]amino]- 
2,2-diethyl-4-oxobutanoic acid 
(E)-4-[[3-[2-(4-cyclohexyl-2- 
0.080 96 .+-. 2 (0.31) 
87 .+-. 6 (0.66) 
69 .+-. 12 
81 .+-. 9 
38 .+-. 4 
thiazolyl)ethenyl]phenyl]amino]- 
2,2-diethyl-4-oxobutanoic acid 
(E)-4-[[3-[2-(4-cyclobutyl-2- 
0.015 98 .+-. 0 (0.13) 
99 .+-. 1 (0.12) 
100 .+-. 0 
98 .+-. 1 
-- 
thiazolyl)ethenyl]phenyl]amino]- 
2,2-diethyl-4-oxobutanoic acid 
(E)-4-[[3-(2-(4-cyclobutyl-2- 
0.110 (0.61) -- -- -- -- 
thiazolyl)ethenyl]phenyl]amino]- 
2-methyl-4-oxobutanoic acid 
__________________________________________________________________________ 
A compound of formula I, an enantiomer, a diastereomer or racemate thereof 
or a salt thereof or a composition containing a therapeutically effective 
amount of a compound of formula I, an enantiomer, a diastereomer or 
racemate thereof or a salt thereof can be administered by methods well 
known in the art. Thus, a compound of formula I, an enantiomer, a 
diastereomer or racemate thereof or a salt thereof can be administered 
either singly or with other pharmaceutical agents, for example, 
antihistamines, mediator release inhibitors, methyl xanthines, beta 
agonists or antiasthmatic steroids such as prednisone and prednisoline, 
orally, parenterally, rectally, or by inhalation, for example, in the form 
of an aerosol, micropulverized powder or nebulized solution. For oral 
administration they can be administered in the form of tablets, capsules, 
for example, in admixture with talc, starch, milk sugar or other inert 
ingredients, that is, pharmaceutically acceptable carriers, or in the form 
of aqueous solutions, suspensions, elixirs or aqueous alcoholic solutions, 
for example, in admixture with sugar or other sweetening agents, flavoring 
agents, colorants, thickeners and other conventional pharmaceutical 
excipients. For parenteral administration, they can be administered in 
solutions or suspension, for example, as an aqueous or peanut oil solution 
or suspension using excipients and carriers conventional for this mode of 
administration. For administration as aerosols, they can be dissolved in a 
suitable pharmaceutically acceptable solvent, for example, ethyl alcohol 
or combinations of miscible solvents, and mixed with a pharmaceutically 
acceptable propellant. Such aerosol compositions are packaged for use in a 
pressurized container fitted with an aerosol valve suitable for release of 
the pressurized compositons. Preferably, the aerosol valve is a metered 
valve, that is one which on activation releases a predetermined effective 
dose of the aerosol composition. 
In the practice of the invention, the dose of a compound of formula I or a 
salt thereof to be administered and the frequency of administration will 
be dependent on the potency and duration of activity of the particular 
compound of formula I or salt to be administered and on the route of 
administration, as well as the severity of the condition, age of the 
mammal to be treated and the like. Oral doses of a compound of formula I 
or a salt thereof contemplated for use in practicing the invention are in 
the range of from about 5 to about 1000 mg per day, preferably about 5 to 
about 250 mg either as a single dose or in divided doses. 
The compounds of formula I of the invention, when R.sub.1 and R.sub.2 
and/or R.sub.3 and R.sub.4 are different, possess one or two asymmetric 
carbon atom, they can thus be obtained as enantiomers, diastereomeric or 
as racemic mixtures. The diastereomeric mixtures can be separated by 
conventional methods. The resolution of racemates into the optically 
active isomers can be carried out by known procedures. Some racemic 
mixtures can be precipitated as eutectics and can thereafter be separated. 
Chemical resolution is, however, preferred. By this method, diastereomeric 
salts are formed from the racemic mixture of a compound of formula I, with 
an optically active resolving agent, for example, an optically active 
base, such as D-(+)-.alpha.-methylbenzylamine, which can be reacted with a 
carboxyl group. The formed diastereomers are separated by selective 
crystallization and converted to the corresponding optical isomer. Thus, 
the invention covers the racemates of the compounds of formula I as well 
as their optically active isomers (enantiomers). 
The examples which follow further illustrate the invention. All 
temperatures are in degrees celsius unless otherwise stated.

EXAMPLE 1 
Preparation of 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-diethyl- 
4-oxobutanoic acid 
To a solution of 25 g (92 mmol) of the compound of Example 9 in 100 ml of 
ethanol was added a solution of 75 g (0.33 mol) of stannous chloride 
dihydrate in 100 ml of ethanol. This mixture was stirred and heated under 
reflux for 1.5 hr. It was cooled to room temperature, made strongly 
alkaline (pH 13) by the addition of 3 N sodium hydroxide, and extracted 
with methylene chloride in three portions. The organic extracts were dried 
over magnesium sulfate and concentrated in vacuo. The residue was 
chromatographed on alumina using ethyl acetate as eluant to yield 12.6 g 
(53%) of the (E)-3-[2-[4-cyclopropyl)-2-thiazolyl]ethenyl]benzene amine as 
an oil. 
A mixture of 3.5 g (20 mmol) of 2,2-diethylsuccinic acid and 10 ml of 
acetyl chloride was heated under reflux for 2 hr, cooled, and concentrated 
in vacuo. The residue was reconcentrated three times with toluene and then 
dissolved in 50 ml of 1,2-dimethoxyethane. This solution was added to a 
mixture of 2.5 g (10 mmol) of the crude amine in 50 ml of 
1,2-dimethoxyethane and 4.1 g (50 mmol) of anhydrous sodium acetate. This 
mixture was heated on the steam bath for 2 hr and then filtered hot. The 
filtrate was concentrated in vacuo. The residue was digested with 500 ml 
of water on the steam bath for 0.25 hr. The solid was collected and 
recrystallized from 50 ml of aq. ethanol to give 2.5 g of 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)-ethenyl]phenyl]amino]-2,2-diethyl 
-4-oxobutanoic acid as off-white needles. Two more recrystallizations from 
aqueous ethanol gave 0.25 g, mp 153.degree.-157.degree. d. 
Anal. Calcd for C.sub.22 H.sub.26 N.sub.2 O.sub.3 S: C, 66.31; H, 6.58; N, 
7.03. Found: C, 66.47;H, 6.60; N, 7.00. 
EXAMPLE 2 
Preparation of 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)-ethenyl]phenyl]amino]-4-oxobutano 
ic acid 
A mixture of 2.5 g (10 mmol) of 
(E)-3-[2-[4-(cyclopropyl)-2-thiazolyl]ethenyl]benzeneamine prepared as in 
example 1 as above, 1.5 g (15 mol) of succinic anhydride, 1.64 g (20 mmol) 
of anhydrous sodium acetate and 200 ml of 1,2-dimethoxyethane was stirred 
and heated under reflux for 2 hr. The reaction mixture was cooled and 
concentrated in vacuo. The residue was heated on the steam bath with 200 
ml of water for 0.5 hr. The solid was collected and recrystallized from 
ethanol to give 1.4 g of 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)-ethenyl]phenyl]amino]-4-oxobutano 
ic acid, mp 177.degree.-179.degree. dec, as off-white needles. 
Anal. Calcd for C.sub.18 H.sub.18 N.sub.2 O.sub.3 S: C, 63.14; H, 5.30; N, 
8.18. Found: C, 63.10; H, 5.01; N, 8.23. 
EXAMPLE 3 
Preparation of 
(E)-4-[[3-[2-(4-cyclopentyl-2-thiazolyl)-ethenyl]phenyl]amino]-2,2-diethyl 
-4-oxobutanoic acid 
A mixture of 5.23 g (30 mmol) of 2,2-diethylsuccinic acid and 15 ml of 
acetyl chloride was heated under reflux for 3 hr, cooled, and concentrated 
in vacuo. The residue was reconcentrated twice with toluene and then 
dissolved in 75 ml of 1,2-dimethoxyethane. This solution was added to a 
mixture of 4.06 g (15 mmol) of 
(E)-3-[2-[4-cyclopentyl)-2-thiazolyl]ethenyl]benzene amine in 75 ml of 
1,2-dimethoxyethane and 6.0 g (73 mmol) of anhydrous sodium acetate. This 
mixture was heated on the steam bath for 2 hr and then filtered hot. The 
filtrate was concentrated in vacuo. The residue was digested with 100 ml 
of water on the steam bath for 1/4 hr. The solid was collected and rinsed 
with water to give 9.6 g of damp solid. This solid was recrystallized from 
700 ml of acetonitrile to give 3.42 g (53%) of 
(E)-4-[[3-[2-(4-cyclopentyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-diethyl- 
4-oxobutanoic acid, mp 172.degree.-174.degree.. 
Anal. Calcd for C.sub.21 H.sub.30 N.sub.2 O.sub.3 S: C, 67.58; H, 7.09; N, 
6.57. Found: C, 67.27; H, 7.20; N, 6.70. 
EXAMPLE 4 
Preparation of 
(E)-4-[[3-[2-(4-cyclohexyl-2-thiazolyl)-ethenyl]phenyl]amino]-2,2-diethyl- 
4-oxobutanoic acid 
A mixture of 9.26 g (53 mmol) of 2,2-diethylsuccinic acid and 30 ml of 
acetyl chloride was heated under reflux for 1.5 hr, cooled, and 
concentrated in vacuo. The residue was reconcentrated twice with toluene 
and then dissolved in 150 ml of 1,2-dimethoxyethane. To this solution was 
added 7.56 g (26.4 mmol) of the 
(E)-3-[2-[4-(cyclohexyl)-2-thiazolyl]-ethenyl]benzeneamine and 10.9 g of 
sodium acetate dissolved in 150 ml of 1,2-dimethoxyethane. This reaction 
mixture was heated on the steam bath for 3.5 hr and then concentrated in 
vacuo. The residue was digested with 600 ml of water on the steam bath for 
20 min. The solid was collected to give 10 g of crude product. 
Recrystallization from ethanol gave 3.5 g of product, mp 
180.degree.-185.degree.. Further recrystallization from methanol gave 
(E)-4-[[3-[2-(4-cyclohexyl-2-thiazolyl)-ethenyl]phenyl]amino]-2-methylene- 
4-oxobutanoic acid as off-white needles, mp 187.degree.-189.degree.. 
Anal. Calcd for C.sub.25 H.sub.32 N.sub.2 O.sub.3 S: C, 68.15; H, 7.32; N, 
6.36. Found: C, 67.87; H, 7.15; N, 6.36. 
EXAMPLE 5 
Preparation of 
(E)-4-[[3-[2-(4-Cyclobutyl-2-thiazolyl)-ethenyl]phenyl]amino]-2,2-diethyl- 
4-oxobutanoic acid 
A mixture of 8.4 g (48 mmol) of 2,2-diethylsuccinic acid and 30 ml of 
acetyl chloride was heated under reflux for 2 hr, cooled, and concentrated 
in vacuo. The residue was reconcentrated twice with toluene and then 
dissolved in 125 ml of 1,2-dimethoxyethane. The solution was added to a 
mixture of 6.1 g (24 mmol) of 
(E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 9.72 g (118 
mmol) of sodium acetate and 125 ml of 1,2-dimethoxyethane, and the mixture 
was stirred and heated under reflux for 2 hr. It was filtered hot. The 
filtrate was concentrated in vacuo to leave 15.47 g of oil. This oil was 
triturated with 350 ml of hot water, and the solid collected. 
Recrystallization from methanol gave 1.4 g of 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)-ethenyl]phenyl]amino]-2,2-diethyl- 
4-oxobutanoic acid as off-white prisms, mp 170.degree.-172.degree.. 
Anal. Calcd for C.sub.23 H.sub.28 N.sub.2 O.sub.3 S: C, 66.96; H, 6.84; N, 
6.79. Found: C, 66.72; H, 6.79; N, 6.67. 
EXAMPLE 6 
Preparation of 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)-ethenyl]phenyl]amino]-2-methyl-4-o 
xobutanoic acid 
A mixture of 6.34 g (48 mmol) of methylsuccinic acid and 30 ml of acetyl 
chloride was heated under reflux for 2 hr, cooled, and concentrated in 
vacuo. The residue was reconcentrated twice with toluene and then 
dissolved in 125 ml of 1,2-dimethoxyethane. The solution was added to a 
mixture of 6.1 g (24 mmol) of 
(E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 9.72 g (118 
mmol) of sodium acetate and 125 ml of 1,2-dimethoxyethane, and the mixture 
was stirred and heated under reflux for 2 hr. It was filtered hot. The 
filtrate was concentrated in vacuo to leave 14.2 g of oil. This oil was 
triturated with 400 ml of hot water for 20 minutes and then allowed to 
stand over the weekend. The solid was collected. Recrystallization from 
acetonitrile gave 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)-ethenyl]phenyl]amino]-2-methyl-4-o 
xobutanoic acid as off-white prisms, mp 165.degree.- 167.degree.. 
Anal. Calcd for C.sub.20 H.sub.22 N.sub.2 O.sub.3 S: C, 64.84; H, 5.99; N, 
7.56. Found: C, 64.79; H, 5.92; N, 7.61. 
EXAMPLE 7 
Preparation of 4-Cyclopropyl-2-methylthiazole 
A mixture of 80 g (0.49 mol) of bromomethylcyclopropylketone, 40.5 g (0.54 
mol) of thioacetamide and 600 ml of ethanol was stirred and heated under 
reflux for 4 hr. and then allowed to stand overnight at room temperature. 
It was concentrated to dryness in vacuo and then reconcentrated after the 
addition of toluene. The residue was slurried with ether. The ether was 
decanted. Ether was added to the residue and then carefully treated with 
saturated sodium bicarbonate solution. The aqueous phase was separated and 
reextracted with ether. The organic phases were combined, washed with 
brine, dried over magnesium sulfate and concentrated in vacuo to leave 60 
g of an amber oil. A solution of this oil in methylene chloride was 
filtered through a plug of Florisil using more methylene chloride to wash 
the plug. The eluates were concentrated in vacuo to give 44.1 g (65%) of 
4-cyclopropyl-2-methylthiazole as a yellow oil. 
EXAMPLE 8 
Preparation of (E)-4-cyclopropyl-2-[2-(3-nitrophenyl)-ethenyl]thiazole 
(a) From 4-Cyclopropyl-2-methylthiazole and m-nitrobenzaldehyde 
A mixture of 41.7 g (0.3 mole) of 4-cyclopropyl-2methylthiazole, 45.3 g 
(0.3 mol) of m-nitrobenzaldehyde and 15 ml of acetic anhydride was stirred 
and heated at 145.degree.-165.degree. under nitrogen for 17 hr. This 
reaction mixture was cooled and concentrated in vacuo. The residue was 
partitioned between water and methylene chloride. The organic layer was 
separated. dried over sodium sulfate and concentrated in vacuo to leave a 
black oil. This oil was dissolved in ethyl acetate, and the solution 
applied to 1 kg of Florisil which was eluted with ethyl acetate. The 
eluates were concentrated in vacuo to give 30 g (37 %) of crude product, 
mp 90.degree.-95.degree.. Recrystallization from ethyl acetate gave yellow 
needles, mp 92.degree.-94.degree.. 
Anal. Calcd for C.sub.14 H.sub.12 N.sub.2 O.sub.2 S: C, 61.75; H, 4.44; N, 
10.29. Found: C, 61.71; H, 4.49: N, 10.19. 
(b) From m-nitrothiocinnamide and bromoacetylcyclopropane 
A mixture of 16 g (0.098 mol) of bromoacetylcyclopropane, 100 ml of ethanol 
and 11.2 (0.054 mol) of m-nitrothiocinnamide was heated to reflux for 20 
min. at which time TLC (25% ethyl acetate/hexane on silica plates) showed 
no thioamide left. The reaction mixture was stirred for 0.5 hr and then 
concentrated in vacuo. The residual solid was collected with ether. The 
solid was partitioned between water, ammonia and ether. The aqueous phase 
was extracted with 100 ml of ether. The combined organic extracts were 
washed with water and with brine, dried over sodium sulfate and 
concentrated in vacuo. The residual was crystallized from hexane to give 
10.55 g (71%) of (E)-4-cyclopropyl-2-[2-(3-nitrophenyl)-ethenyl]thiazole 
as crude product. 
EXAMPLE 9 
Preparation of (E)-4-Cyclobutyl-2-[2-(3-nitrophenyl)-ethenyl]thiazole 
A mixture of 11 g (62 mmol) of bromoacetylcyclobutane, 12.9 g (62 mmol) of 
m-nitrothiocinnamide and 110 ml of ethanol was stirred and heated under 
reflux for 0.5 hr. The reaction mixture was collected and concentrated in 
vacuo. The residue was slurried with ether and the solid collected. This 
solid was shaken with water and ether. The aqueous phase was made alkaline 
by the addition of concentrated ammonium hydroxide. The organic phase was 
separated and the aqueous phase extracted with ether. The combined organic 
phases were washed with water and with brine, dried over sodium sulfate 
and concentrated in vacuo to give 14.67 g (82%) of crude product. 
Recrystallization of a small sample from acetonitrile gave 
(E)-4-cyclobutyl-2-[2-(3-nitrophenyl)ethenyl]thiazole as pale yellow 
needles, mp 78.degree.-80.degree.. 
Anal. Calcd for C.sub.15 H.sub.14 N.sub.2 O.sub.2 S: C, 62.92; H, 4.93; N, 
9.78. Found: C, 62.74; H, 4.88; N, 9.71. 
EXAMPLE 10 
Preparation of (E)-4-cyclopentyl-2-[2-(3-nitrophenyl)-ethenyl]thiazole 
A mixture of 11 g (57 mmol) of crude bromoacetylcyclopentane, 10 g (48 
mmol) of m-nitrothiocinnamide and 75 ml of ethanol was heated on the steam 
bath for about 5 min at which time the thiocinnamide was largely in 
solution. After a solid had precipitated the reaction mixture was allowed 
to stand at room temperature for 2 days. The solid was collected and 
rinsed with ethanol to give 14 g of crude damp hydrobromide. This salt was 
distributed between 100 ml of methylene chloride and 50 ml of saturated 
sodium bicarbonate solution to which a few ml of concentrated ammonium 
hydroxide were added. The organic layer was separated, dried over sodium 
sulfate and concentrated in vacuo. The residue was crystallized from 
hexane to give 10.6 g (73 %) of crude product, mp 65.degree.-70.degree.. 
Recrystallization from acetonitrile gave 
(E)-4-cyclopentyl-2-[2-(3-nitrophenyl)-ethenyl]thiazole as yellow spars, 
mp 68.degree.-70.degree.. 
Anal. Calcd for C.sub.16 H.sub.16 N.sub.2 O.sub.2 S: C, 63.98; H, 5.37; N, 
9.33. Found: C, 63.94; H, 5.25; N, 9.28. 
EXAMPLE 11 
Preparation of (E)-4-cyclohexyl-2-[2-(3-nitrophenyl)-ethenyl]thiazole 
A mixture of 5.02 g (24.5 mmol) of m-nitrothiocinnamide, 5.6 g (27 mmol) of 
crude bromomethylcyclohexylketone, and 40 ml of ethanol was stirred and 
heated under reflux for 5.3 hr. TLC (25% ethyl acetate/hexane on silica 
gel) showed thioamide still present. A further 5 ml of crude bromoketone 
was added to the reaction mixture for 0.5 hr when TLC showed no thioamide 
left. The reaction mixture was cooled, concentrated in vacuo and 
reconcentrated after addition of toluene to the residue. The resultant 
yellow solid was slurried with ether and collected. It was then 
partitioned between ether and water made alkaline by the addition of 
concentrated ammonium hydroxide. The organic layer was separated, dried 
over sodium sulfate and concentrated in vacuo. The residue was collected 
with hexane to give 5.6 g (73%) of product as a yellow solid. 
Recrystallization from hexane gave 
(E)-4-cyclohexyl-2-[2-(3-nitrophenyl)-ethenyl]thiazole as yellow needles, 
mp 102.degree.-104.degree.. 
Anal. Calcd for C.sub.17 H.sub.18 N.sub.2 O.sub.2 S: C, 64.94; H, 5.77; N, 
8.91. Found: C, 65.01; H, 5.68; N, 8.81. 
EXAMPLE 12 
Preparation of m-Nitrocinnamide 
A mixture of 19.3 g (0.1 mol) of m-nitrocinnamic acid, 80 ml of thionyl 
chloride and 0.5 ml of dimethyl formamide was heated under reflux for 5 hr 
and then allowed to stand overnight at room temperature. The reaction 
mixture was concentrated to dryness in vacuo and reconcentrated after the 
addition of toluene. The solid residue was slurried with ether and 
collected to give 20.4 g of crude acid chloride. This solid was slowly 
added with stirring to 200 ml of concentrated ammonium hydroxide. After 
the mixture had stirred for 0.5 hr the solid was collected and air dried 
to give 18.13 g (94%) of m-nitrocinnamide, mp 189-191. 
EXAMPLE 13 
Preparation of m-Nitrothiocinnamide 
(a) A mixture of 40.38 g (0.21 mol) of m-nitrocinnamide, 42.5 g (0.105 mol) 
of Lawesson's reagent 
(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide), and 
500 ml of 1,2-dimethoxyethane was stirred and heated under reflux for 2 
hr, cooled to room temperature and concentrated to dryness in vacuo. The 
residue was slurried with 300 ml of methylene chloride and collected to 
give 24.61 g (56%) of product, mp 196.degree.-197.degree.. 
Recrystallization from acetonitrile gave an analytical sample as orange 
needles, mp 200.degree.-202.degree.. 
Anal. Calcd. for C.sub.9 H.sub.8 N.sub.2 O.sub.2 S: C, 51.91; H, 3.87; N, 
13.45. Found: C, 51.85; H, 3.82; N, 13.52. 
(b) A mixture of 3.4 g (17.7 mmol) of m-nitrocinnamide, 1.96 g (8.8 mmol) 
of phosphorus pentasulfide, 1.5 g (17.7 mmol) of sodium bicarbonate and 
100 ml of acetonitrile (5 drops of pyridine) was stirred and heated under 
reflux for 3 hr and poured on to ice water. After 1 hr of stirring the 
solid was collected to give 2.75 (75%) of m-nitrothiocinnamide as crude 
product, mp 187.degree.-189.degree.. 
EXAMPLE 14 
Preparation of 2,2-diethylsuccinic anhydride 
A mixture of 3.5 g (20 mol) of 2,2-diethylsuccinic acid and 10 ml of acetyl 
chloride was heated under reflux for 2 hr, cooled, concentrated in vacuo, 
and reconcentrated three times after the addition of toluene. The residue 
was used without further purification. 
EXAMPLE 15 
Preparation of 2,2-diethylsuccinic acid 
To a stirred mixture of 186 g (1 mol) of ethyl 2-cyano-3,3-diethylacrylate 
and 800 ml of 50 % aqueous ethanol was added 98 g (2 mol) of sodium 
cyanide. The sodium cyanide slowly dissolved (exotherm). After stirring at 
room temperature for 0.5 hr the solution was heated on the steam bath for 
5 min., cooled, diluted with 2 l of water and made acid by the addition of 
concentrated hydrochloric acid. This mixture was extracted with 3.times.1 
l of methylene chloride. The organic extracts were combined, dried over 
sodium sulfate and concentrated in vacuo to leave 200 g of oil. This oil 
was heated overnight under reflux with 800 ml of concentrated hydrochloric 
acid. The reaction mixture was cooled and extracted three times with a 
one-third volume of ether. The ethereal extracts were combined, dried over 
magnesium sulfate, and concentrated in vacuo. The residue was crystallized 
from ether/hexane to give 86 g (49%) of crude product. This material was 
slurried with 500 ml of hexane to leave 76 g (44%) of 2,2-diethylsuccinic 
acid, mp 106.degree.-109.degree.. 
EXAMPLE 16 
Preparation of ethyl 2-cyano-3,3-diethylacrylate 
A mixture of 473 g (5.5 mol) of 3-pentanone, 565 g (5 mol) of ethyl 
cyanoacetate, 60 g (1 mol) of acetic acid, 38.5 g (0.5 mol) of ammonium 
acetate and 500 ml of toluene was stirred and heated under a Dean-Stark 
trap for 7 hr. and then allowed to stand for 2 days at room temperature. 
The reaction mixture was washed three times with 1 l of water and 
concentrated on the rotary evaporator at a low temperature. The residue 
was distilled in vacuum to give 460 g of ethyl 
2-cyano-3,3-diethylacrylate, bp 118.degree.-120.degree./8 mm. 
EXAMPLE 17 
Preparation of acetylcyclopentane 
To a solution of 35 g (0.35 mol) of chromium trioxide in 50 ml of water 
cooled in an ice bath was added 30.5 ml of concentrated sulfuric acid 
slowly with stirring. The precipitate was dissolved by the addition of 100 
ml of water to give approximately 200 ml of solution which was cooled to 
5.degree. in an ice bath. Into a 500 ml r. b. flask fitted with mechanical 
stirrer, thermometer and dropping funnel was placed 25 g (0.22 mol) of 
1-cyclopentylethanol and 120 ml of acetone. The reaction mixture was 
cooled to 5.degree. and then treated with 90 ml of the chromic acid 
solution added at such a rate that the temperature did not exceed 
20.degree. which took approximately 10 min. The reaction mixture was 
stirred at 20.degree.-25.degree. for 1 hr and then treated with sodium 
bisulfite to neutralize the excess chromic acid. The top layer of the 
reaction mixture was separated. the bottom layer was extracted with 50 ml 
of pentane. This extracted was added to the original top layer. The bottom 
layer that formed was added to the original bottom layer, and this phase 
was extracted with 150 ml of pentane in three portions. The combined 
organic (top) layers were washed with 100 ml of brine in two portions, 100 
ml of sodium bicarbonate in two portions and again with 100 ml of brine in 
two portions. This solution was dried over sodium sulfate and the pentane 
distilled off through a Vigreux column at atmospheric pressure. The 
residue was distilled at the water pump to give 16.1 g of 
acetylcyclopentane, bp 90.degree.-93.degree./7.5 cm (nominal) 
EXAMPLE 18 
Preparation of Bromomethylcyclopropylketone 
To a solution of 42 g (0.5 mol) of cyclopropylmethylketone in 625 ml of 
methanol cooled to 0.degree.-5.degree. in an ice bath was slowly added 29 
ml (0.6 mol) of bromine. After the addition was complete, the cooling bath 
was removed, and the color disappeared accompanied by a gradual rise in 
temperature to 40.degree.. The solution was diluted with 3 volumes of 
water, layered with ether and neutralized by the addition of saturated 
sodium bicarbonate solution. The aqueous phases was separated and 
extracted with ether in two portions. The organic phases were combined, 
washed with brine, dried over sodium sulfate and concentrated in vacuo to 
leave 80 g of crude bromomethylcyclopropylketone as an oil. 
EXAMPLE 19 
Preparation of Bromoacetylcyclopentane 
To a solution of 16.1 g (0.143 mol) of acetylcyclopentane in 175 ml of 
methanol cooled in an ice bath was added 7.7 ml (0.15 mol) of bromine 
during 5 min. The reaction mixture was then allowed to warm to 
10.degree.-15.degree. and held there by occasional application of the ice 
bath for 45 min until the reaction mixture became colorless. Then 100 ml 
of water was added and it was allowed to stir at room temperature for 0.5 
hr. It was partially neutralized by the cautious addition of 10 g (72 
mmol) of solid potassium carbonate, diluted with 200 ml of water and 
extracted with 4.times.150 ml of ether. The combined organic extracts were 
washed with 2.times.100 ml of saturated sodium bicarbonate solution and 
with 3.times.100 ml of water, dried over magnesium sulfate and 
concentrated in vacuo at room temperature to leave 30 g (110%) of 
bromoacetylcyclopentane as an oil whose nmr spectrum indicated that it was 
mainly the desired product. 
EXAMPLE 20 
Preparation of Bromoacetylcyclohexane 
To a solution of 63.1 g (0.5 mol) of acetylcyclohexane in 625 ml of 
methanol cooled to 5.degree. in an ice bath was added 29 ml (0.6 mol) of 
bromine during about 5 min. The cooling bath was removed and the 
temperature rose to 37.degree.. The reaction mixture slowly formed a clear 
solution. This solution was poured in 1 l of water, made alkaline by the 
addition of saturated sodium bicarbonate solution and extracted with 500 
ml of ether in two portions. The organic phases were combined, washed with 
200 ml of water and with 200 ml of brine, dried over sodium sulfate and 
concentrated in vacuo to leave 108.4 of a pale oil whose nmr spectrum 
indicated it to contain somewhat more than 50% product. 
EXAMPLE 21 
Preparation of (E)-3-[2-[4-(cyclopentyl)-2-thiazolyl]ethenyl]benzeneamine 
To a hot solution of 8.6 g (28.6 mmol) of 
(E)-4-cyclopentyl-2-[2-(3-nitrophenyl)ethenylthiazole in 50 ml of ethanol 
was added a hot solution of 21 g (93.1 mmol) of stannous chloride 
dihydrate in 50 ml of ethanol. An exothermic reaction ensued. The reaction 
was then heated on the steam bath for 45 min. After it had cooled 
slightly, to it was added 150 ml of 3 N sodium hydroxide, 50 ml of water 
and 100 ml of methylene chloride. A brown gum formed. The aqueous phase 
was separated and extracted with 200 ml of methylene chloride in two 
portions. The organic phases were combined, washed with 200 ml of water in 
two portions, dried over potassium carbonate and concentrated in vacuo. 
The residue was crystallized from hexane to give 7.3 g (94%) of 
(E)-3-[2-[4-(cyclopentyl)-2-thiazolyl]ethenyl]benzeneamine, mp 
59.degree.-61.degree.. 
Utilizing the above procedure the following compounds were prepared: 
(a) from (E)-4-cyclobutyl-2-[2-(3-nitrophenyl)ethylthiazole, 
(E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]-benzeneamine; and 
(b) from (E)-4-cyclohexyl-2-[2-(3-nitrophenyl)-ethenylthiazole, 
(E)-3-[2-[4-(cyclohexyl)-2-thiazolyl]ethenyl]-benzeneamine. 
EXAMPLE 22 
Preparation of 
(E)-[N-[[3-[2-(4-Cyclobutyl-2-thiazolyl)-ethenyl]phenyl]amino]-2-oxoethyl] 
-1-cyclopentane-1-carboxylic acid 
A mixture of 0.756 g of 1-carboxy-1-cyclopentaneacetic acid and 5 ml of 
acetyl chloride was heated to reflux for two hours. The mixture was then 
condensed by rotary evaporation followed by toluene flushes (2.times.) 
after which the residual materials were taken up in 25 ml of toluene. This 
solution was combined with a solution of 1.0 g of 
(E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzenamine in 25 ml of 
toluene and the resulting solution was warmed on a steam bath for 30 min. 
Upon cooling a crystal crop was obtained which was isolated by filtration 
and ether wash to give 1.1 g of 
(E)-[N-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]-phenyl]amino]-2-oxoethyl] 
-1-cyclopentane-1-carboxylic acid. Recrystallization from ethanol gave 
material of m.p. 188.degree.-190.degree. C. 
EXAMPLE 23 
Preparation of 
(E)-3-[[[3-[2-(4-Cyclobutyl-2-thiazolyl)-ethenyl]phenyl]amino]carbonyl]-3- 
ethylpentanoic acid 
A mixture of 5.0 g of 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-diethyl-4 
-oxobutanoic acid and 100 ml of acetyl chloride was heated to gentle reflux 
for 1.5 hr. The reaction mixture was then condensed by rotary evaporation 
and the residual materials were taken up in methylene chloride. This 
solution was washed with 5% sodium bicarbonate solution until neutral and 
then with sat. brine, dried (sodium sulfate) and condensed by rotary 
evaporation to yield 4.3 g of residual materials. 2.0 g of this material 
was solubilized along with 0.357 g of lithium hydroxide mono hydrate in 50 
ml of 1:4 (V/V) water/methanol. This solution was heated to reflux for 1 
hr. and then condensed to dryness by rotary evaporation. The residual 
materials were mixed with 50 ml of water, filtered, and the filtrate was 
acidified with dilute hydrochloric acid to yield 1.7 of 
(E)-3-[[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]carbonyl]- 
3-ethylpentanoic acid; m.p. 129.degree.-13 .degree. C. after 
recrystallization from acetonitrile. 
EXAMPLE 24 
Preparation of 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)-ethenyl]phenyl]amino]-4-oxobutanoi 
c acid ethyl ester 
Ethyl succinyl chloride (0.56 ml) was added to an ice-bath cooled solution 
composed of 1.0 g of 
(E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzenamine, 0.6 ml of 
triethylamine, and 10 ml of methylene chloride. After 1 hr, the reaction 
mixture was diluted with methylene chloride and washed with dilute 
hydrochloric acid, followed with water and sat. brine. The organic phase 
was separated and dried (Na.sub.2 SO.sub.4). Condensation by rotary 
evaporation gave 1.5 g 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-4-oxobutanoic 
acid ethyl ester; m.p. 98.degree.-100.degree. C. after recrystallization 
from ethyl acetate. 
EXAMPLE 25 
Preparation of 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)-ethenyl]phenyl]amino]-2,2-diethyl- 
4-oxobutanoic acid trihydroxymethylaminomethane salt 
Tri-hydroxymethylaminomethane (121.4 mg) and 412.5 mg of 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)-ethenyl]phenyl]amino]-2,2-diethyl- 
4-oxobutanoic acid were dissolved in 10 ml of ethanol. This solution was 
then condensed by rotary evaporation to yield 
(E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-diethyl-4 
-oxobutanoic acid tri-hydroxymethylaminomethane salt as a free flowing 
solid after trituration with cold acetonitrile, m.p. 80.degree.-87.degree. 
C. 
EXAMPLE 26 
(E)-4-[[3-[2-(4-Cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2-cyclohexyl-4 
-oxobutanoic acid 
A mixture of 1.0 g of 2-cyclohexylsuccinic acid and 10 ml of acetyl 
chloride was warmed to reflux for two hours. The reaction mixture was then 
condensed by rotary evaporation with toluene chase (2.times.). The 
residual materials and 1.28 g of 
(E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine were solubilized 
in 50 ml of toluene and the resulting solution was warmed on the steam 
bath for 0.5 hour. Upon cooling to room temperature a solid product 
formed. This material was isolated by filtration and recrystallized from 
acetonitrile to give 1.65 g of 
(E)-4-[[3-[2-(cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2-cyclohexyl-4- 
oxobutanoic acid; mp 205.degree.-207.degree. C. 
EXAMPLE 27 
(E)-4-[[3-[2-(Cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2-phenyl-4-oxobu 
tanoic acid 
A mixture of 1.0 g of 2-phenylsuccinic acid and 10 ml of acetyl chloride 
was warmed to reflux for two hours. The reaction mixture was then 
condensed by rotary evaporation with toluene chase (2.times.). The 
residual materials and 1.4 g of 
(E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine were solubilized 
in 50 ml of toluene and the resulting solution was warmed on the steam 
bath for 0.5 hour. Upon cooling to room temperature, the solids that 
formed were isolated by filtration. Recrystallization from acetonitrile 
gave 1.65 g of 
(E)-4-[[3-[2-(cyclobutyl-2-thiazolyl)-ethenyl]phenyl]amino]-2-phenyl-4-oxo 
butanoic acid; mp 202.degree.-203.degree. C. 
EXAMPLE 28 
Tablet Formulation (Wet Granulation) 
______________________________________ 
mg/tablet 
Item Ingredient 100 mg 500 mg 
______________________________________ 
1. (E)-4-[[3-[2-(4-cyclopropyl- 
100 500 
2-thiazolyl)ethenyl]phenyl]- 
amino]-2,2-diethyl-4-oxobutan- 
oic acid. 
2. Lactose 30 150 
3. Pregelatinized Starch 
6 30 
4. Microcrystalline Cellulose 
30 150 
5. Magnesium Stearate 1 6 
Total 167 836 
______________________________________ 
Preparation of Tablets 
(1) Mix Items 1, 2, 3 and 4 and granulate with water. 
(2) Dry the granulation at 50.degree. C. 
(3) Pass the granulation through suitable milling equipment. 
(4) Add Item 5 and mix for three minutes; compress on a suitable press. 
EXAMPLE 29 
Capsule Formulation 
______________________________________ 
mg/tablet 
Item Ingredient 100 mg 500 mg 
______________________________________ 
1. (E)-4-[[3-[2-(4-cyclopropyl- 
100 500 
2-thiazolyl)ethenyl]phenyl]- 
amino]-2,2-diethyl-4-oxobutan- 
oic acid. 
2. Corn Starch (Pregelatinized) 
8 40 
3. Modified Starch 4 20 
4. Talc 4 20 
5. Magnesium Stearate 1 2 
Total 117 582 
______________________________________ 
Preparation of Capsules 
(1) Mix Items 1, 2 and 3 and wet granulate with water. Dry at 45.degree. C. 
overnight. 
(2) Mill through suitable screen using appropriate milling equipment. 
(3) Add Items 4 and 5 and mix for five minutes. 
EXAMPLE 30 
Capsule Formulation 
______________________________________ 
Ingredients mg/capsule 
______________________________________ 
1. (E)-4-[[3-[2-(4-cyclo- 
0.01 0.5 5.0 25.0 
propyl-2-thiazolyl)- 
ethenyl] phenyl]- 
amino]-2,2-diethyl-4- 
oxobutanoic acid. 
2 Lactose Hydrous 168.99 168.5 159.0 123.0 
3. Corn Starch 20.0 20.0 25.0 35.0 
4. Talc 10.0 10.0 10.0 15.0 
5. Magnesium Stearate 
1.0 1.0 1.0 1.0 
Total 200.0 200.0 200.0 200.0 
______________________________________ 
Preparation of Capsules 
(1) Mix Items 1, 2 and 3 in a suitable mixer for 30 minutes. 
(2) Add Items 4 and 5 and mix for 3 minutes. 
(3) Fill into suitable capsule. 
EXAMPLE 31 
Wet Granulation Formulation 
______________________________________ 
Ingredients mg/capsule 
______________________________________ 
1. (E)-4-[[3-[2-(4-cyclo- 
0.01 0.5 5.0 25.0 
propyl-2-thiazolyl)- 
ethenyl]phenyl]- 
amino]-2,2-diethyl-4- 
oxobutanoic acid. 
2. Lactose Anhydrous DTG 
106.99 106.5 102.0 118.0 
3. Avicel PH 102 15.0 15.0 15.0 25.0 
4. Modified Starch 7.0 7.0 7.0 10.0 
5. Magnesium Stearate 
1.0 1.0 1.0 2.0 
Total 130.0 130.0 130.0 130.0 
______________________________________ 
Preparation of Capsules 
(1) Dissolve Item 1 in a suitable solvent such as alcohol. 
(2) Spread the solution in Step 1 over Item 2, dry. 
(3) Add Items 3 and 4 and mix for 10 minutes. 
(4) Add magnesium stearate and mix for 3 minutes and compress. 
EXAMPLE 32 
Cream 0.5% 
______________________________________ 
Reasonable 
Ingredients g/kg Variations 
______________________________________ 
(E)-4-[[3-[2-(4-cyclopropyl- 
5.150* -- 
2-thiazolyl)ethenyl]phenyl]- 
amino]-2,2-diethyl-4-oxobu- 
tanoic acid. 
Glyceryl Monostearate S.E..sup.1 
100.00 80-120 
Polysorbate 60.sup.2 
20.00 15-25 
Cetyl Alcohol 50.00 40-60 
Petrolatum 70.00 50-90 
Methylparaben 1.50 1.25-1.75 
Propylparaben 0.50 0.4-0.06 
Propylene Glycol 200.00 150-250 
Purified Water 568.05 475-575 
TOTAL 1,015.20 
______________________________________ 
*3% excess 
.sup.1 Arlacel 165 
.sup.2 Tween 60 
Preparation of Cream 
(1) Dissolve 
(E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)-ethenyl]phenyl]amino]-2,2-diethyl 
-4-oxobutanoic acid in propylene glycol, add methyl paraben, propyl paraben 
and water and heat to 70.degree. C. 
(2) Melt petrolatum, glyceryl monstearate S.E., and cetyl alcohol. Heat to 
70.degree. C. Add polysorbate 80 and mix. 
(3) Add solution in Step 2 to solution in Step 1 at 70.degree. C. cool to 
room temperature while stirring. 
EXAMPLE 33 
Inhalation Aerosol Formulation (Solution) 
______________________________________ 
Item Ingredients % w/w 
______________________________________ 
1. (E)-4-[[3-[2-(4-cyclopropyl- 
1.0 
2-thiazolyl)ethenyl]phenyl]- 
amino]-2.2-diethyl-4-oxobu- 
tanoic acid. 
2. Ethyl Alcohol 30.0 
3. Ascorbic Acid 0.5 
4. Freon 12 54.8 
5. Freon 114 13.7 
Total 100% 
______________________________________ 
Preparation of Aerosol 
(1) Dissolve Items 1 and 3 in Item 2. 
(2) Fill solution from Step 1 into a suitable glass bottle, insert valve 
and crimp to seal container. 
(3) Pressure-fill a 80:20 mixture of Items 4 and 5 into the container. 
NOTE: A suitable valve may be used to deliver 25 to 100 microliters in 
volume. 
EXAMPLE 34 
Inhalation Aerosol Formulation (Suspension) 
______________________________________ 
Item Ingredients % w/w 
______________________________________ 
1. (E)-4-[[3-[2-(4-cyclopropyl- 
1.0 
2-thiazolyl)ethenyl]phenyl]- 
amino]-2,2-diethyl-4-oxobu- 
tanoic acid. (micronized) 
2. Sorbitan Trioleate 
0.5 
3. Freon 12 64.0 
4. Freon 11 18.5 
5. Freon 114 16.0 
Total 100% 
______________________________________ 
Preparation of Aerosol 
(1) Mix Items 1 and 2 into 4 and homogenize. 
(2) Fill the concentrate suspension from Step 1 into a suitable can and 
place in valve and crimp to seal container. 
(3) Pressure-fill a 80:20 mixture of Items 3 and 5. 
NOTE: A suitable valve may be used to deliver 25 to 100 microliters in 
volume.