CA1103667A - 4,5-bis-phenyl-thiazole-2-yl derivatives - Google Patents
4,5-bis-phenyl-thiazole-2-yl derivativesInfo
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- CA1103667A CA1103667A CA309,785A CA309785A CA1103667A CA 1103667 A CA1103667 A CA 1103667A CA 309785 A CA309785 A CA 309785A CA 1103667 A CA1103667 A CA 1103667A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
- C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
Abstract
ABSTRACT OF THE DISCLOSURE
Novel compounds of Formula I:
Formula I
whereln R2 and R3 are the same or different, and are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, alkoxy of from one to four carbon atoms, inclusive, thioalkoxy of from one to four carbon atoms, inclusive, and alkyl of from one to four carbsn atoms, inclusive; R2. and R3. are the same or different and are chosen from the group consisting of hydrogen and alkoxy from one to four carbon atoms, inclu-sive, with the proviso that when R2' 1s alkoxy, then R2 = R2' and when R3' is alkoxy then R3 = R3'; R1 is selected from the group consisting of hydrogen; trifluoro-methyl; , where R4 is hydrogen, alkyl of one to four carbon atoms, inclus1ve, or , where R5 is alkyl of one to six carbon atoms, inclus1ve, R6 and R7 are the same or different and are chosen from the group consisting of hydrogen and alkyl of one to three carbon atoms;
where R8 and R9 are the same or different and are chosen from the group consisting of alkyl from one to three carbon atoms, inclusive, R14 is alkoxy of from one to three carbon atoms, incluslve, where R11, and R12 are the same or different and are chosen from the group consisting of hydrogen. alkyl of from one to six carbon atoms, inclusive, hydroxyalkyl of from one to six carbon atoms, inclusive, cycloalkyl of from five to seven carbon atoms, inclusive, or taken together with the nitrogen atom to which they are attached, , , , .
Novel therapeutic compositions are composed of an active ingredient described by Formula II:
Formula II
whelein R? and R3 are the same or different, and are selected-from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, alkoxy of from one to four carbon atoms, inclusive, thioalkoxy of from one to four carbon atoms, inclusive, and alkyl of from one to four carbon atoms. inclusive; R2' and R3' are the same or different and are chosen from the group consisting of hydrogen and alkoxy from one to four carbon atoms, inclu-sive, with the proviso that when R2, is alkoxy, then R2 = R2' and when R3' is alkoxy then R3 = R3'; R2 is selected from the group consisting of hydrogen; alkyl of from one to four carbon atoms, inclusive, trifluoromethyl;
, where R4 is hydrogen, alkyl of one to four carbon atoms, inclusive, or , where R5 is alkyl of one to six carbon atoms, inclusive, R6 and R7 are the same or differ-ent, and are chosen from the group consisting of hydrogen and alkyl of one to three carbon atoms; where R8 and R9 are the same or different and are chosen from the group consisting of hydrogen and alkyl from one to three carbon atoms, inclusive, R10 is alkoxy of from one to three carbon atoms, inclusive, -OM where M is a pharma-ceutically acceptable cation; where R11 and R12 are the same or different and are chosen from the group consisting of hydrogen, alkyl of from one to six carbon atoms, inclusive, hydroxyalkyl of from one to six carbon atoms, inclusive, cycloalkyl of from five to seven carbon atoms, inclusive, or taken together with the nitrogen atom to which they are attached, , , , in association with a pharmaceutical carrier. The compo-sitions are useful in vitro and in vivo for reduction of platelet adhesiveness and inhibition of platelet aggrega-tion and preventing or treating disease conditions result-ing from increased platelet adhesiveness or platelet aggregation.
-1c-
Novel compounds of Formula I:
Formula I
whereln R2 and R3 are the same or different, and are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, alkoxy of from one to four carbon atoms, inclusive, thioalkoxy of from one to four carbon atoms, inclusive, and alkyl of from one to four carbsn atoms, inclusive; R2. and R3. are the same or different and are chosen from the group consisting of hydrogen and alkoxy from one to four carbon atoms, inclu-sive, with the proviso that when R2' 1s alkoxy, then R2 = R2' and when R3' is alkoxy then R3 = R3'; R1 is selected from the group consisting of hydrogen; trifluoro-methyl; , where R4 is hydrogen, alkyl of one to four carbon atoms, inclus1ve, or , where R5 is alkyl of one to six carbon atoms, inclus1ve, R6 and R7 are the same or different and are chosen from the group consisting of hydrogen and alkyl of one to three carbon atoms;
where R8 and R9 are the same or different and are chosen from the group consisting of alkyl from one to three carbon atoms, inclusive, R14 is alkoxy of from one to three carbon atoms, incluslve, where R11, and R12 are the same or different and are chosen from the group consisting of hydrogen. alkyl of from one to six carbon atoms, inclusive, hydroxyalkyl of from one to six carbon atoms, inclusive, cycloalkyl of from five to seven carbon atoms, inclusive, or taken together with the nitrogen atom to which they are attached, , , , .
Novel therapeutic compositions are composed of an active ingredient described by Formula II:
Formula II
whelein R? and R3 are the same or different, and are selected-from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, alkoxy of from one to four carbon atoms, inclusive, thioalkoxy of from one to four carbon atoms, inclusive, and alkyl of from one to four carbon atoms. inclusive; R2' and R3' are the same or different and are chosen from the group consisting of hydrogen and alkoxy from one to four carbon atoms, inclu-sive, with the proviso that when R2, is alkoxy, then R2 = R2' and when R3' is alkoxy then R3 = R3'; R2 is selected from the group consisting of hydrogen; alkyl of from one to four carbon atoms, inclusive, trifluoromethyl;
, where R4 is hydrogen, alkyl of one to four carbon atoms, inclusive, or , where R5 is alkyl of one to six carbon atoms, inclusive, R6 and R7 are the same or differ-ent, and are chosen from the group consisting of hydrogen and alkyl of one to three carbon atoms; where R8 and R9 are the same or different and are chosen from the group consisting of hydrogen and alkyl from one to three carbon atoms, inclusive, R10 is alkoxy of from one to three carbon atoms, inclusive, -OM where M is a pharma-ceutically acceptable cation; where R11 and R12 are the same or different and are chosen from the group consisting of hydrogen, alkyl of from one to six carbon atoms, inclusive, hydroxyalkyl of from one to six carbon atoms, inclusive, cycloalkyl of from five to seven carbon atoms, inclusive, or taken together with the nitrogen atom to which they are attached, , , , in association with a pharmaceutical carrier. The compo-sitions are useful in vitro and in vivo for reduction of platelet adhesiveness and inhibition of platelet aggrega-tion and preventing or treating disease conditions result-ing from increased platelet adhesiveness or platelet aggregation.
-1c-
Description
` ` 3442 11~)3667 The following prior art was considered in preparing the patent application: U.S. Patent 3,707,475; U.S.
Patent 3,560,514; U.S. Patent 3,558,644; J. G. Lombardino and E. H. Wiseman, J. Med. Chem. 17:1182 (1974) and E. H.
Wiseman, H. M. McIllhenny and J. W. Bettes, J. Pharm.
Sci. 64:1469 (1975).
BRIEF DESCRIPTION OF THE INVENTION
This invention relates to novel compounds of the 10 Formula I and to a broader group of compounds, Formula II, which are useful in association with a pharmaceutical carrier for the in vitro and in vivo inhibition of plate-let adhesiveness and platelet aggregation and prevention or treatment of diseases arising from platelet adhesive-15 ness and platelet aggregation.
DETAILED DESCRIPTION OF THE INVENTION
Novel compounds of the formula:
R, ~ R, R3 ~\y R3, For~nula wherein R~ and R3 are the same or di fferent, and are sel~cted from the group consisting of hydrogen, fluorine, chl~rine, hromine, trifluoromethyl, alkoxy of from one to 30 follr carbon atoms, inclusive, thioa~koxy of froM one to ~ 66'7 3442 four carbon atoms, inclusive, and alkyl of from one to four carbon atoms, inclusive; R2~ and R3~ are the same or different and are chosen from the group consisting of hydrogen and alkoxy from one to four carbon atoms, inclu-sive, with the proviso that when R2~ is alkoxy, then R2 = R2~ and when R3~ is alkoxy then R3 = R3~i Rl is selected from the group consisting of hydrogen; trifluoro-,R6 methyl; -CCH20R4, where R4 is hydrogen, alkyl of one to four carbon atoms, inclusive, or CRs, where Rs is alkyl of one to six carbon atoms, inclusive, R6 and R7 are the same or different and are chosen from the group consisting oRfOhydrogen and alkyl of one to three carbon atoms;
Cj-C-Rlo where R8 and Rg are the same or different and are chosen from the group consisting of alkyl from one to three carbon atoms, inclusive, Rlo is alkoxy of from one to three /Rll carbon atoms, inclusive, N ~ where Rll and Rl2 are the same or different and are chosen from the group consist-ing of hydrogen, alkyl of from one to six carbon atoms, inclusive, hydroxyalkyl of from one to six carbon atoms, inclusive, cycloalkyl of from five to seven carbon atoms, inclusive, or taken together with the nitrogen atom to which they are attached, r~ / -I ~
-N ~ , -N ~ , -N ~ 0 -N Nl-l ~
~3667 3442 The compounds of this invention are prepared from readily available starting materials using chemical reac-tions that are well known in the art. For example, the requisite ~-bromoketones, e.g., 4 in Scheme I, may be prepared as outlined by Wagner et al., "Synthetic Organic Chemistry," J. Wiley & Sons, Inc., New York, N.Y., 1958, page 100. The ketones, e.g., 3 in Scheme I are prepared by the methods outlined by Gore in "Friedel Crafts and Related Reactions," G. Olah, ed., Vo1. III, Interscience Publishers, New York, N. Y. 1964, Chapter 31. As indicated in Scheme I, an appropriately substituted phenylacetic acid (1) is converted to the corresponding acid chloride
Patent 3,560,514; U.S. Patent 3,558,644; J. G. Lombardino and E. H. Wiseman, J. Med. Chem. 17:1182 (1974) and E. H.
Wiseman, H. M. McIllhenny and J. W. Bettes, J. Pharm.
Sci. 64:1469 (1975).
BRIEF DESCRIPTION OF THE INVENTION
This invention relates to novel compounds of the 10 Formula I and to a broader group of compounds, Formula II, which are useful in association with a pharmaceutical carrier for the in vitro and in vivo inhibition of plate-let adhesiveness and platelet aggregation and prevention or treatment of diseases arising from platelet adhesive-15 ness and platelet aggregation.
DETAILED DESCRIPTION OF THE INVENTION
Novel compounds of the formula:
R, ~ R, R3 ~\y R3, For~nula wherein R~ and R3 are the same or di fferent, and are sel~cted from the group consisting of hydrogen, fluorine, chl~rine, hromine, trifluoromethyl, alkoxy of from one to 30 follr carbon atoms, inclusive, thioa~koxy of froM one to ~ 66'7 3442 four carbon atoms, inclusive, and alkyl of from one to four carbon atoms, inclusive; R2~ and R3~ are the same or different and are chosen from the group consisting of hydrogen and alkoxy from one to four carbon atoms, inclu-sive, with the proviso that when R2~ is alkoxy, then R2 = R2~ and when R3~ is alkoxy then R3 = R3~i Rl is selected from the group consisting of hydrogen; trifluoro-,R6 methyl; -CCH20R4, where R4 is hydrogen, alkyl of one to four carbon atoms, inclusive, or CRs, where Rs is alkyl of one to six carbon atoms, inclusive, R6 and R7 are the same or different and are chosen from the group consisting oRfOhydrogen and alkyl of one to three carbon atoms;
Cj-C-Rlo where R8 and Rg are the same or different and are chosen from the group consisting of alkyl from one to three carbon atoms, inclusive, Rlo is alkoxy of from one to three /Rll carbon atoms, inclusive, N ~ where Rll and Rl2 are the same or different and are chosen from the group consist-ing of hydrogen, alkyl of from one to six carbon atoms, inclusive, hydroxyalkyl of from one to six carbon atoms, inclusive, cycloalkyl of from five to seven carbon atoms, inclusive, or taken together with the nitrogen atom to which they are attached, r~ / -I ~
-N ~ , -N ~ , -N ~ 0 -N Nl-l ~
~3667 3442 The compounds of this invention are prepared from readily available starting materials using chemical reac-tions that are well known in the art. For example, the requisite ~-bromoketones, e.g., 4 in Scheme I, may be prepared as outlined by Wagner et al., "Synthetic Organic Chemistry," J. Wiley & Sons, Inc., New York, N.Y., 1958, page 100. The ketones, e.g., 3 in Scheme I are prepared by the methods outlined by Gore in "Friedel Crafts and Related Reactions," G. Olah, ed., Vo1. III, Interscience Publishers, New York, N. Y. 1964, Chapter 31. As indicated in Scheme I, an appropriately substituted phenylacetic acid (1) is converted to the corresponding acid chloride
(2) by reacting the acid with an excess of thionyl chlo-ride for 1 to 5 hours at reflux.
1~03667 3442 SCHEME I
ArCH2C02H SOCl 2 ~ ArCH2CCl Ar'HAr'C-CH2Ar Br~ Ar'-CCHAr AlCl 3 OBr S Ar' N
Ar'CCHAr3 H~ CF
11~ rC H 3 C 1. H, \~ ~ C U 3 Ar' N
r ~ ,N
~5 7 ~ ~ CH CO ~Li ~ Rl ~ ~ CH2CO2R
Ar S Ar S
~ 3667 3442 Residual thionyl chloride is removed by distillation and the crude product (2) is used directly in the next step. The Friedel-Crafts acylation is run either neat, allowing the aromatic substrate to serve also as solvent, or in an inert solvent such as chloroform, methylene chlo-ride, carbon tetrachloride, carbon disulfide, benzene and the like. The reaction temperature varies from ambient to the reflux temperature of the solvent and the duration of the reaction may be from about one hour to several days. The reaction is run in the presence of a Lewis acid ' such as AlCl3, SnCl4 and the like. After work-up, the crude subst1tuted 2-aryl acetophenone, 3, is purified by t ~ distillation, crystallization, or chromatography.
.f~'- .
The ketone 3 is brominated by reaction with reagent grade molecular bromine in an inert solvent such as chloro-~; form, carbon tetrachloride, mixtures of chloroform-ether, ,.~. -carbon tetrachloride-ether, and the like. The reaction is run for periods ranging from O.S to 5 hours at temper-, ~
atures ranging from 10 to the reflux temperature of the solvent. Product 4 mdy be purified by standard techniques.
Thiazoles 5 and 6 are obtained by reacting the appro-i:~: ' ' priate bromoketone 4 with the appropriate thioamide. The ~ two reactants are heated in an inert organic solvent such k~ as methanol, ethanol, propanol, acetonitrile and the like.
t';~ ` ~ .2~5 More specifically, the reactants are used in molar ratios ~ of 4 to thioamide ranging from l:l to l:S, and the reaction, .. .~ .
when carried out at reflux temperature needs for completion between l and 24 hours. It is possible to carry out the i. ~
re~action at lower temperatures within longer reaction ~periods. In a preferred variation for the preparation of ~ ~ .
~ ~ -6-::
;
~1~3~67 5, trifluorothioacetamide is prepared in situ by refluxing trifluoroacetamide with pulverized phosphorus pentasulfide in benzene, toluene or the like for about 4 days followed by direct addition of bromoketone 4. The mixture is then refluxed for an additional 1 to 24 hours. The desired product is recovered in a conventional manner which in-cludes saponification of residual thioamide and removal of the solvent by distillation or precipitating the product by diluting the solvent with water or with another solvent in which the desired product is insoluble. The product can be purified by crystallization or chromatography.
In the event a 4,5-diaryl-2-thiazoleacetic acid derivative such as 7 or 8 is desired, a 2-alkyl-4,5-diaryl-thiazole such dS 6 is reacted with n-butyllithium at low temperatures in an inert organic solvent. Generally the thiazole reactant is in solution, e.g., in tetrahydrofuran, ether, dibutyl ether, or the like. whereas the n-butyl-lithium is in a hydrocarbon solvent which does not solidify at the temperature of the reaction (-25 to -80 C.), e.g., petroleum ether, n-pentane, n-hexane or the like. To the carbanion thus formed is added powdered carbon dioxide over a period of several minutes in order to form the carbonated product. The reaction mixture may then be warmed, concentrated, and the crude lithium salt may be isolated by filtration after slurring with ether. It may be purified by recrystallization from a solvent of appro-priate polarity such as acetone.
Salt 7 may be reacted with an appropriate alkylating agent, e.g., methyl iodide, to give the corresponding esters (8). The reaction is conveniently run at tempera-1~36~7 tures between ambient and the reflux temperature of thereaction mixture in a suitable solvent such as dimethyl-formamide for from several hours to 2 days. When reaction is complete, the reaction mixture is made aqueous and the product is extracted with a suitable organic solvent such as ether, chloroform, methylene chloride, and the like.
The product may be purified by conventional means such as chromatography or crystallization.
With reference to Scheme II, esters, e.g., 8, may be saponified with an appropriate alkali such as sodium hydroxide, potassium hydroxide, and the like to give the corresponding salt 9. The ester is reacted with an equi-molar amount of the above alkali metal hydroxides in aqueous-methanolic medium. Reaction conditions are not critical. The reaction is conveniently run at ambient temperature for from several hours to several days and the product is purified by removal of solvent and liberated alcohol in vacuo.
Esters 8 may be converted to amides 10 using standard reaction conditions by reacting an excess of a primary or secondary amine with the ester in solvents such as methanol, dimethylsulfoxide, dimethylformamide, and the like at temperatures ranging from -30 to ambient temperature or greater for periods of several minutes to several days.
The product may be purified by standard methods such as chromatography and the like.
SCHEME I I
A X ~ CH2CNR2 \ /
1 0'~OH
/ I L i A 1 ~) ¦ >--C H 2 C H 2 0 H
Ar' ~
ZO I ~R
Ar A r ~ C C O: R "
Ar 1 3 ~7 3442 Esters 8 may also be converted to the corresponding alcoho1s 11 by reaction with an excess of lithium aluminum hydride in an inert solvent such as ether, tetrahydrofuran and the like. Temperatures are generally held at room temperature or below. The product is purified by standard means.
Esters 8 may be alkylated at the ~-carbon using stan-dard techniques. The ester is first reacted with a slight molar excess of strong base such as lithium diisopropyl amide or the like in an inert solvent such as tetrahydro-furan or the like. The reaction is run by slow addition of the ester to the base maintaining the reaction temper-ature at -80 to -60, followed by stirring for one to two hours. The alkylating agent, e.g., alkyl iodide, bromide, or the like, is then added to the reaction mixture, and the mixture is stirred for up to one hour, allowed to warm to ambient temperature and worked up in a standard manner.
The product may be purified by chromatography, crystalliza-tion and the like. In the alkylation procedure control of the desired product, 12 or 13 is determined by the amount of alkylating agent used, 12 predominating when up to one equivalent is used and 13 predominating when more than two equivalents are used.
In the manner described above, esters 12 and 13 may be hydrolyzed to the corresponding salts with alkali, reacted with amines to give the corresponding amides, or reduced with metal hydrides to give the corresponding alcohols.
Example 1 2-Trifluoromethyl-4,5-bis(p-methoxyphenyl)-thiazole ~1~366~
Part A - Trifluoroacetamidine Using a modification of the procedure of Reilly ~
Brown, W. L. Reilly and H. C. Brown, J. Am. Chem. Soc., 78, 6032 (1956), trifluoroacetonitrile (ca. 30 ml.) was condensed into a 250 ml. 3-necked round bottom flask which was cooled in a dry ice-isopropanol bath and fitted with a dry ice condenser. Ammonia (ca. 60 ml.) was then con-densed into the flask. The dry ice-isopropanol bath was then removed, and the mixture was allowed to reflux for 1 hour. During the last 15 minutes of reflux time, a bath of cold water was placed around the flask in order to increase the rate of reflux. The dry ice condenser was removed and replaced with a drying tube filled with glass wool. A warm water bath (ca. 55) was used to enhance the evaporation of excess ammonia. When no ~as bubbles were visibie in the flask, heating was terminated. The remain-ing 1;quid was distilled through a 20 cm. Vigreux column to afford 27.55 9. of trifluoroacetamidine; b.p. 34-8 C./ll mm. [W. L. Reilly and H. C. Brown, J. Am. Chem.
Soc. 78, 6032 (1956), b.p. 35-36 C./llmm].
Part B - Trifluorothioacetamide Following the general procedure of Reilly and Brown, W. L. Reilly and H. C. Brown, J. Am. Chem. Soc., 78, 6032 (1956), trifluoroacetamidine (25.51 9.; 0.2278 mole) was dissolved in diethyl ether (80 ml.). Hydrogen sulfide was bubbled into this solution via a sintered glass frit for 15 minutes. The mixture was allowed to stand at ambient temperature for one hour and was then concentrated by rotary evaporation. The residual oil was distilled using a 20 cm. Vigreux column, the ma~jor fraction, 15.9 9., 1~3667 being collected at 29" C./1.5-2 mm [W. L. Reilly and H. C.
Brown, J. Am. Chem. Soc., 78, 6032 (1956), b.p. 40/2 mm~.
Part C
A solution of p-methoxy-2-bromo-2(p-methoxyphenyl)-acetophenone, U.S. Patent No. 3,560,514, (10.95 9.;
0.0848 mole) trifluorothioacetamide (28.4 9.; 0.0840 mole) and acetonitrile (400 ml.) was heated at reflux for 6 hours. The mixture was cooled and concentrated by rotary evaporation. The residue was partitioned with diethyl ether and sodium bicarbonate. The organic layer was washed with water and brine, dried (sodium sul fate) and concen-trated by rotary evaporation. This material was chromato-graphed with 10% ethyl acetate in hexane using a size C
pre-packed Merck silica column.
Consolidated fractions were prompted to crystallize in the freezer with scratching. Recrystallization from pentane afforded 8.64 9. (28% yield) of 2-trifluoromethyl-4,5-bis(p-methoxyphenyl)thiazole, m.p. 51-54.
Analysis:
Calc'd. for Cl8H,4F3N02S:
C, 59.18; H, 3.84; F, 15.62; N, 3.84; S, 8.77.
Found: C, 59.34; H, 3.90; F, 15.38; N, 3.84; S, 8.83.
Example 2 2-Trifluoromethyl-4,5-bis(p-chlorophenyl~-thiazole 25 Step I - p-Chloro-2-(p-chlorophenyl)acetophenone The requisite p-chlorophenylacetyl chloride was pre-pared in the following manner. p-Chlorophenylacetic acid (15 9.; O.û88 mole) and thionyl chloride (31.5 9.; 0.0264 mole) were heated at reflux for 2 hours. Excess thionyl 30 chloride was removed in vacuo to afford the acid chloride ~1~3~67 which was used without further purification.
Aluminum trichloride (11.75 g.; 0.088 mole) was added portionwise to a stirred mixture of the p-chlorophenyl-acetyl chloride and chlorobenzene (30 ml.). Following addition, the mixture was allowed to stand for 24 hours.
The resulting dark brown paste was scooped out and stirred into a slurry of ice and conc. hydrochloric acid which was then extracted with methylene chloride. The organic extracts were washed with 1 N hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride; dried over sodium sulfate and concentrated in vacuo. Recrystalliza-tion from methanol afforded 16.47 9. (71% yield), m.p.
.5-114 C.
Analysis:
Calc'd. for C14HloCl2:
C, 63.40; H, 3.77; Cl, 26.79.
Found: C, 63.52; H, 3.80; Cl, 26.76.
Step II - p-Chloro-2-bromo-2-(p-chlorophenyl)acetophenone Bromine (2 ml.) was added dropwise to a solution of p-chloro-2-(p-chlorophenyl)acetophenone (10 9.; 0.038 mole), chloroform (50 ml.) and diethyl ether (25 ml.).
The mixture was heated at reflux for 0.5 hour and cooled (ca. 20). Following a thorough washing with saturated sodium bicarbonate, the organic solution was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed at low pressure through silica gel 60 mesh (230-400) with 5% ethyl acetate in hexane. Re-crystalli2ation from hexane afforded 2.69 9.; m.p.
~1 5_~3 Analysis:
Calc'd. for C,4HgBrCl 2 C, 48.84; H, 2.62; Br, 23.25; Cl, 20.64.
Found: C, 48.75; H, 2.60; Br, 22.33; Cl, 21.10.
Step III - 2-rrifluoromethyl-4,5-bis(p-chlorophenyl)-thiazole p-Chloro-2-bromo-2-(p-chlorophenyl)acetophenone (2.69 9.; 0.0078 mole), tri fluoromethylthioamide (1.2 9.;
0.00936 mole) (prepared as in the previous example) and acetonitrile (40 ml.) were combined and heated at reflux for 20 hours. The reaction mixture was cooled and then concentrated in vacuo. The residue was partitioned with diethyl ether and saturated sodium bicarbonate, water, and brine; dried (sodium sulfate) and concentrated in vacuo.
The residue was triturated with hexane and the hexane solution was decanted and concentrated in vacuo. The residue was chromatographed at low pressure through silica gel 60 (mesh 230-400) with 5% ethanol in hexane. Recrys-tallization from pentane afforded 0.38 9., m.p. 101-2 C.
Analysis:
Calc'd. for Cl6H 8Cl 2 F3NS:
C, 51.34, H, 2.14; Cl, 18.98; F, 15.24;
N, 3.74; S, 8.56.
Found: C, 51.33; H, 2.19; Cl, 19.13; F, 15.43;
N, 3.61; S, 8.38.
25 Example 3 2-Trifluoromethyl-4,5-bis(phenyl)thiazole Following the procedure of Example 2 but substituting phenylacetic acid for p-chlorophenylacetic acid and benzene for chlorobenzene in Step I, 2-trifluoromethyl-4,5-bis-~phenyl)thiazole was prepared, m.p. 94-7 C.
Analxsis:
~14-lPg336~7 Calc'd. for ClôHlOF 3 NS:
C, 62.95; H, 3.28; N, 4.59i S, 10.49; F, 18.69.
Found: C, 62.84; H, 3.47; N, 4.52; S, 10.45; F, 1~.34.
Example 4 2-Trifluoromethyl-4,5-bis(p-fluorophenyl)-thiazole Following the procedure of Example 2 but substituting p-fluorophenylacetic acid for p-chlorophenylacetic acid and fluorobenzene for chlorobenzene in Step I, 2-trifluoro-methyl-4,5-bis(p-fluorophenyl)thiazole can be obtained.
0 Example 5 2-Trifluoromethyl-4~5-bis(p-bromophenyl) thiazole Following the procedure of Example 2 but substituting p-bromophenylacetic acid for p-chlorophenylacetic acid and bromobenzene for chlorobenzene in Step I, 2-trifluoro-methyl-4,5-bis(p-bromophenyl)thiazole can be obtained.
Example 6 2-Trifluoromethyl-4,5-bis(p-isopropoxyphenyl)-thiazole Following the procedure of Example 2 but substituting p-isopropoxyphenylacetic acid for p-chlorophenylacetic acid and isopropoxybenzene for chlorobenzene in Step I, 2-trifluoromethyl-4,5-bis(p-isopropoxyphenyl)thiazole can be obtained.
Example 7 2-Trifluoromethyl-4,5-bis(p-methoxyphenyl~-thiazole. Alternate Procedure for Preparation of 2-trifluoromethyl-4,5-bis(p-methoxyphenyl)-thiazole Trifluorothioacetamide was prepared in situ by heating a mixture of trifluoroacetamide (5.0 9.; 0.044 mole), pul-verized phosphorus pentasulfide (1.95 9.; 0.0088 mole), and benzene ~10 ml.) at reflux for 96 hours. p-Methoxy-~ 3667 3442 2-bromo-2-(p-methoxyphenyl)acetophenone (7.0 g.; 0.021 mole) was added portionwise over 15 minutes. After the nlixture was heated at reflux for an additional 1 hour, a solution composed of water (1 ml.) and conc. hydrochloric acid (0.2 ml.) was added. Following an additional hour at reflux, the mixture was cooled and the solvent was removed in vacuo and the residue was made strongly basic with 5C~% sodium hydroxide. This mixture was heated at 75 for 1 hour, cooled, and then extracted with methylene chloride. The organic extracts were washed with water, saturated sodium chloride, dried over sodium sulfate, and concentrated in vacuo. The resulting crude product was chromatographed at low pressure through silica gel 60 (mesh 230-400) with 10% ethanol in Skelly B hexanes as elutant to yield 2.57 9. of 2-trifluoromethyl-4,5-bis(p-methoxyphenyl)thiazole.
Using this procedure, and replacing p-methoxy-2-bromo-2-(p-methoxyphenyl)acetophenone with (1) 2-bromo-2-phenyl-acetophenone affords 2-trifluoromethyl-4,5-bis(phenyl)-thiazole; (2) p-chloro-2-bromo-2-(p-chlorophenyl)aceto-phenone affords 2-trifluoromethyl-4,5-bis(p-chlorophenyl)-thiazole; (3) p-fluoro-2-bromo-2-(p-fluorophenyl)aceto-phenone affords 2-trifluoromethyl-4,5-bis(p-fluorophenyl)-thiazole; (4) p-isopropoxy-2-bromo-2-(p-isopropoxyphenyl)-acetophenone affords 2-trifluoromethyl-4,5-bis)p-isopro-poxyphenyl)thiazolei (5) m,p-dimethoxy-2-bromo-2-(m,p-dimethoxyphenyl)acetophenone affords 2-trifluoromethyl-4,5-bis(m,p-dimethoxyphenyl)thiazole.
The above acetophenones are prepared as in Steps I and II of Example 2. 1) Substituting phenylacetic acid 1~3667 3442 for p-chlorophenylacetic acid and benzene for chlorobenzene affords 2-bromo-2-phenylacetophenone. 2) The preparation of p-chloro-2-bromo-2-(p-chlorophenyl)acetophenone is described in Steps I and II of Example 2. 3) Substituting 5 p-fluorophenylacetic acid for p-chlorophenylacetic acid and fluorobenzene for chlorobenzene affords p-fluoro-2-bromo-2-(p-fluorophenyl)acetophenone. 4) Substituting p-iso-propoxyphenylacetic acid for p-chlorophenylacetic acid and isopropoxybenzene for chlorobenzene affords p-iso-10 propoxy-2-bromo-2-(p-isopropoxyphenyl~acetophenone. 5) Substituting m,p-dimethoxyphenylacetic acid for p-chloro-phenylacetic acid and m,p-dimethoxybenzene for chloro-benzene affords m,p-dimethoxy-2-bromc-2-(m,p-dimethoxy-phenyl)acetophenone.
15 Example 8 4,5-Bis(p-methoxyphenyl~thiazole Part A - Thioformamide .
Following the work of Cerecedo and Tolpin [L. R.
Cerecedo and J. G. Tolpin, J. Amer. Chem. Soc., 59, 1660 (1937)], formamide (20 9.; 0.444 mole) was covered with 20 diethyl ether (200 ml.) and freshly powdered phosphorus pentasulfide ~12 g.; 0.054 mole) was added in several portions with ice water both cooling. The flask was re-frigerated at 5-10 for 72 hours and then allowed to warm to ambient temperature. After being shaken on a shaker 25 apparatus at ambient temperature for 16 hours the ethereal solution of thioformamide was decanted and used in the next step.
Part B - 4,5-Bis(p-methoxyphenyl)thiazole An ethereal solution of thioformamide (0.153 mole) 30 was concentrated in vacuo at less than 25. The residue was slurried with acetonitrile (10 ml.) and cooled in an ice water bath. p-Methoxy-2-bromo-2-(p-methoxyphenyl)-acetophenone (4.27 g.; 0.0128 mole) was dissolved in acetonitrile (50 ml.) and added via syringe to the above slurry. After stirring for 15 minutes in ice, the flask was refrigerated at 5-10 for 16 hours. The solution was then stirred at ambient temperature for 70 hours before work up. The solvent was removed in vacuo and the residue was partitioned with ether and saturated sodium bicar-bonate solution. The ether layer was washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, dried ~sodium sulfate), and concentrated in vacuo. The residue was chromatographed on silica gel 60 at low pressure with 5% ethyl acetate in benzene.
Recrystallization from hexane:benzene (11:1) afforded 2.25 9. (59~ yield) of 4,5-bis(p-methoxyphenyl)thiazole.
Analysis:
Calc'd. for C,7H1sNO2S:
C, 68.69; H, 5.05; N, 4.71; S, 10.77.
Found: C, 68.34; H, 5.07; N, 4.58; S, 10.67.
Example 9 4,5-Bis(p-methoxyphenyl)-2-thiazoleacetic acid, Lithium Salt 1.6 M n-Butyl lithium in hexane (26.6 ml.) was added by syringe over 10 minutes to a solution of 2-methyl-4,5-bis(p-methoxyphenyl3thiazole (described in U.S. Patent No. 3,560,5143 (11.0 g.; Q.0354 mole) and THF (275 ml.) cooled in a bath of dry ice and isopropyl alcohol. After stirring for 10 minutes the reaction mixture was poured slowly with stirring into a slush of powdered carbon diox-icll~ (5()() ml.) and THF (150 ml.). Once the mixture reached -lB-11~3667 ambient temperature it was concentrated by rotary evapor-ation. The resulting residue was slurried in diethyl ether and dried (vacuum oven) to afford 12.32 9. (96%
yield) of the crude salt. Two 9. of this crude material were dissolved in hot acetone. The resulting solution was filtered through a fine sintered glass funnel to remove the haze and allowed to crystallize to afford 1.2 9.
of 4,5-bis(p-methoxyphenyl)-2-thiazoleacetic acid, lithium salt.
Analysis:
Calc'd. for C,gHl6N04SLi:
C, 63.16; H, 4.43; I~, 3.88; S, 8.86; Li, 1.94.
Found: C, 62.61; H, 4.56; N, 3.90; S, 8.74; Li, 1.97.
Example 10 4,5-Bis(p-methoxyphenyl)-~,~-dimethyl-2-thia-lS zoleacetic Acid, Sodium salt A mixture of 4,5-bis(p-methoxyphenyl)-a,~-dimethyl-2-thiazoleacetic acid methyl ester (Example 4) (1.00 9.;
2.52 mm), sodium hydroxide (0.100 9.; 2.52 mm), methanol (50 ml.), and water (5 ml.) was stirred at ambient temper-ature for 48 hours. rhe solvents were removed in vacuo to afford 4,5-bis(p-methoxyphenyl)-~,~-dimethyl-2-thiazole-acetic acid, sodium salt.
Example 11 4,5-Bis(p-methoxyphenyl)-~,~-dimethyl-2-thia-zoleacetic acid, Potassium Salt A mixture of 4,5-bis(p-methoxyphenyl)-~,~-dimethyl-2-thiazoleacetic acid methyl ester (1.00 9.; 2.52 mm), potassium hydroxide (.141 9.; 2.52 mm), methanol (S0 ml.), and water (5 ml.) was stirred at ambient temperature for 48 hours. The solvents were removed in vacuo to afford 4,5-bis(p-methoxyphenyl)-~,~-dimethyl-2-thiazoleacetic 36~7 acid, potassium salt.
Example 12 4,5-Bis(p-methoxyphenyl)-2-thiazoieacetic acid, Methyl Ester A solution of 4,5-bis(p-methoxyphenyl)-2-thiazole-S acetic acid, lithium salt (8.82 9.; 0.024 mole), methyl iodide (17.4 9.; 0.122 mole) and DMF (100 ml.) was stirred at ambient temperature for 16 hours. The mixture was poured into water (l.S !.) and extracted with methylene chloride (500 ml.). The organic layer was washed with water (3 x 1.5 1.), saturated sodium bicarbonate (1.0 1.), water (1.5 1.), dried (sodium sulfate), and concentrated in vacuo. The oily residue was dissolved in acetone and applied directly to a Florisil-packed (340 ml.) gravity column (Florisil previously equilibrated with solvent mixture; 500 ml. packing:100 ml. solvent). The sample was eluted with 5% acetone in hexane. The recovered product was recrystallized from diethyl ether-pentane to afford
1~03667 3442 SCHEME I
ArCH2C02H SOCl 2 ~ ArCH2CCl Ar'HAr'C-CH2Ar Br~ Ar'-CCHAr AlCl 3 OBr S Ar' N
Ar'CCHAr3 H~ CF
11~ rC H 3 C 1. H, \~ ~ C U 3 Ar' N
r ~ ,N
~5 7 ~ ~ CH CO ~Li ~ Rl ~ ~ CH2CO2R
Ar S Ar S
~ 3667 3442 Residual thionyl chloride is removed by distillation and the crude product (2) is used directly in the next step. The Friedel-Crafts acylation is run either neat, allowing the aromatic substrate to serve also as solvent, or in an inert solvent such as chloroform, methylene chlo-ride, carbon tetrachloride, carbon disulfide, benzene and the like. The reaction temperature varies from ambient to the reflux temperature of the solvent and the duration of the reaction may be from about one hour to several days. The reaction is run in the presence of a Lewis acid ' such as AlCl3, SnCl4 and the like. After work-up, the crude subst1tuted 2-aryl acetophenone, 3, is purified by t ~ distillation, crystallization, or chromatography.
.f~'- .
The ketone 3 is brominated by reaction with reagent grade molecular bromine in an inert solvent such as chloro-~; form, carbon tetrachloride, mixtures of chloroform-ether, ,.~. -carbon tetrachloride-ether, and the like. The reaction is run for periods ranging from O.S to 5 hours at temper-, ~
atures ranging from 10 to the reflux temperature of the solvent. Product 4 mdy be purified by standard techniques.
Thiazoles 5 and 6 are obtained by reacting the appro-i:~: ' ' priate bromoketone 4 with the appropriate thioamide. The ~ two reactants are heated in an inert organic solvent such k~ as methanol, ethanol, propanol, acetonitrile and the like.
t';~ ` ~ .2~5 More specifically, the reactants are used in molar ratios ~ of 4 to thioamide ranging from l:l to l:S, and the reaction, .. .~ .
when carried out at reflux temperature needs for completion between l and 24 hours. It is possible to carry out the i. ~
re~action at lower temperatures within longer reaction ~periods. In a preferred variation for the preparation of ~ ~ .
~ ~ -6-::
;
~1~3~67 5, trifluorothioacetamide is prepared in situ by refluxing trifluoroacetamide with pulverized phosphorus pentasulfide in benzene, toluene or the like for about 4 days followed by direct addition of bromoketone 4. The mixture is then refluxed for an additional 1 to 24 hours. The desired product is recovered in a conventional manner which in-cludes saponification of residual thioamide and removal of the solvent by distillation or precipitating the product by diluting the solvent with water or with another solvent in which the desired product is insoluble. The product can be purified by crystallization or chromatography.
In the event a 4,5-diaryl-2-thiazoleacetic acid derivative such as 7 or 8 is desired, a 2-alkyl-4,5-diaryl-thiazole such dS 6 is reacted with n-butyllithium at low temperatures in an inert organic solvent. Generally the thiazole reactant is in solution, e.g., in tetrahydrofuran, ether, dibutyl ether, or the like. whereas the n-butyl-lithium is in a hydrocarbon solvent which does not solidify at the temperature of the reaction (-25 to -80 C.), e.g., petroleum ether, n-pentane, n-hexane or the like. To the carbanion thus formed is added powdered carbon dioxide over a period of several minutes in order to form the carbonated product. The reaction mixture may then be warmed, concentrated, and the crude lithium salt may be isolated by filtration after slurring with ether. It may be purified by recrystallization from a solvent of appro-priate polarity such as acetone.
Salt 7 may be reacted with an appropriate alkylating agent, e.g., methyl iodide, to give the corresponding esters (8). The reaction is conveniently run at tempera-1~36~7 tures between ambient and the reflux temperature of thereaction mixture in a suitable solvent such as dimethyl-formamide for from several hours to 2 days. When reaction is complete, the reaction mixture is made aqueous and the product is extracted with a suitable organic solvent such as ether, chloroform, methylene chloride, and the like.
The product may be purified by conventional means such as chromatography or crystallization.
With reference to Scheme II, esters, e.g., 8, may be saponified with an appropriate alkali such as sodium hydroxide, potassium hydroxide, and the like to give the corresponding salt 9. The ester is reacted with an equi-molar amount of the above alkali metal hydroxides in aqueous-methanolic medium. Reaction conditions are not critical. The reaction is conveniently run at ambient temperature for from several hours to several days and the product is purified by removal of solvent and liberated alcohol in vacuo.
Esters 8 may be converted to amides 10 using standard reaction conditions by reacting an excess of a primary or secondary amine with the ester in solvents such as methanol, dimethylsulfoxide, dimethylformamide, and the like at temperatures ranging from -30 to ambient temperature or greater for periods of several minutes to several days.
The product may be purified by standard methods such as chromatography and the like.
SCHEME I I
A X ~ CH2CNR2 \ /
1 0'~OH
/ I L i A 1 ~) ¦ >--C H 2 C H 2 0 H
Ar' ~
ZO I ~R
Ar A r ~ C C O: R "
Ar 1 3 ~7 3442 Esters 8 may also be converted to the corresponding alcoho1s 11 by reaction with an excess of lithium aluminum hydride in an inert solvent such as ether, tetrahydrofuran and the like. Temperatures are generally held at room temperature or below. The product is purified by standard means.
Esters 8 may be alkylated at the ~-carbon using stan-dard techniques. The ester is first reacted with a slight molar excess of strong base such as lithium diisopropyl amide or the like in an inert solvent such as tetrahydro-furan or the like. The reaction is run by slow addition of the ester to the base maintaining the reaction temper-ature at -80 to -60, followed by stirring for one to two hours. The alkylating agent, e.g., alkyl iodide, bromide, or the like, is then added to the reaction mixture, and the mixture is stirred for up to one hour, allowed to warm to ambient temperature and worked up in a standard manner.
The product may be purified by chromatography, crystalliza-tion and the like. In the alkylation procedure control of the desired product, 12 or 13 is determined by the amount of alkylating agent used, 12 predominating when up to one equivalent is used and 13 predominating when more than two equivalents are used.
In the manner described above, esters 12 and 13 may be hydrolyzed to the corresponding salts with alkali, reacted with amines to give the corresponding amides, or reduced with metal hydrides to give the corresponding alcohols.
Example 1 2-Trifluoromethyl-4,5-bis(p-methoxyphenyl)-thiazole ~1~366~
Part A - Trifluoroacetamidine Using a modification of the procedure of Reilly ~
Brown, W. L. Reilly and H. C. Brown, J. Am. Chem. Soc., 78, 6032 (1956), trifluoroacetonitrile (ca. 30 ml.) was condensed into a 250 ml. 3-necked round bottom flask which was cooled in a dry ice-isopropanol bath and fitted with a dry ice condenser. Ammonia (ca. 60 ml.) was then con-densed into the flask. The dry ice-isopropanol bath was then removed, and the mixture was allowed to reflux for 1 hour. During the last 15 minutes of reflux time, a bath of cold water was placed around the flask in order to increase the rate of reflux. The dry ice condenser was removed and replaced with a drying tube filled with glass wool. A warm water bath (ca. 55) was used to enhance the evaporation of excess ammonia. When no ~as bubbles were visibie in the flask, heating was terminated. The remain-ing 1;quid was distilled through a 20 cm. Vigreux column to afford 27.55 9. of trifluoroacetamidine; b.p. 34-8 C./ll mm. [W. L. Reilly and H. C. Brown, J. Am. Chem.
Soc. 78, 6032 (1956), b.p. 35-36 C./llmm].
Part B - Trifluorothioacetamide Following the general procedure of Reilly and Brown, W. L. Reilly and H. C. Brown, J. Am. Chem. Soc., 78, 6032 (1956), trifluoroacetamidine (25.51 9.; 0.2278 mole) was dissolved in diethyl ether (80 ml.). Hydrogen sulfide was bubbled into this solution via a sintered glass frit for 15 minutes. The mixture was allowed to stand at ambient temperature for one hour and was then concentrated by rotary evaporation. The residual oil was distilled using a 20 cm. Vigreux column, the ma~jor fraction, 15.9 9., 1~3667 being collected at 29" C./1.5-2 mm [W. L. Reilly and H. C.
Brown, J. Am. Chem. Soc., 78, 6032 (1956), b.p. 40/2 mm~.
Part C
A solution of p-methoxy-2-bromo-2(p-methoxyphenyl)-acetophenone, U.S. Patent No. 3,560,514, (10.95 9.;
0.0848 mole) trifluorothioacetamide (28.4 9.; 0.0840 mole) and acetonitrile (400 ml.) was heated at reflux for 6 hours. The mixture was cooled and concentrated by rotary evaporation. The residue was partitioned with diethyl ether and sodium bicarbonate. The organic layer was washed with water and brine, dried (sodium sul fate) and concen-trated by rotary evaporation. This material was chromato-graphed with 10% ethyl acetate in hexane using a size C
pre-packed Merck silica column.
Consolidated fractions were prompted to crystallize in the freezer with scratching. Recrystallization from pentane afforded 8.64 9. (28% yield) of 2-trifluoromethyl-4,5-bis(p-methoxyphenyl)thiazole, m.p. 51-54.
Analysis:
Calc'd. for Cl8H,4F3N02S:
C, 59.18; H, 3.84; F, 15.62; N, 3.84; S, 8.77.
Found: C, 59.34; H, 3.90; F, 15.38; N, 3.84; S, 8.83.
Example 2 2-Trifluoromethyl-4,5-bis(p-chlorophenyl~-thiazole 25 Step I - p-Chloro-2-(p-chlorophenyl)acetophenone The requisite p-chlorophenylacetyl chloride was pre-pared in the following manner. p-Chlorophenylacetic acid (15 9.; O.û88 mole) and thionyl chloride (31.5 9.; 0.0264 mole) were heated at reflux for 2 hours. Excess thionyl 30 chloride was removed in vacuo to afford the acid chloride ~1~3~67 which was used without further purification.
Aluminum trichloride (11.75 g.; 0.088 mole) was added portionwise to a stirred mixture of the p-chlorophenyl-acetyl chloride and chlorobenzene (30 ml.). Following addition, the mixture was allowed to stand for 24 hours.
The resulting dark brown paste was scooped out and stirred into a slurry of ice and conc. hydrochloric acid which was then extracted with methylene chloride. The organic extracts were washed with 1 N hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride; dried over sodium sulfate and concentrated in vacuo. Recrystalliza-tion from methanol afforded 16.47 9. (71% yield), m.p.
.5-114 C.
Analysis:
Calc'd. for C14HloCl2:
C, 63.40; H, 3.77; Cl, 26.79.
Found: C, 63.52; H, 3.80; Cl, 26.76.
Step II - p-Chloro-2-bromo-2-(p-chlorophenyl)acetophenone Bromine (2 ml.) was added dropwise to a solution of p-chloro-2-(p-chlorophenyl)acetophenone (10 9.; 0.038 mole), chloroform (50 ml.) and diethyl ether (25 ml.).
The mixture was heated at reflux for 0.5 hour and cooled (ca. 20). Following a thorough washing with saturated sodium bicarbonate, the organic solution was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed at low pressure through silica gel 60 mesh (230-400) with 5% ethyl acetate in hexane. Re-crystalli2ation from hexane afforded 2.69 9.; m.p.
~1 5_~3 Analysis:
Calc'd. for C,4HgBrCl 2 C, 48.84; H, 2.62; Br, 23.25; Cl, 20.64.
Found: C, 48.75; H, 2.60; Br, 22.33; Cl, 21.10.
Step III - 2-rrifluoromethyl-4,5-bis(p-chlorophenyl)-thiazole p-Chloro-2-bromo-2-(p-chlorophenyl)acetophenone (2.69 9.; 0.0078 mole), tri fluoromethylthioamide (1.2 9.;
0.00936 mole) (prepared as in the previous example) and acetonitrile (40 ml.) were combined and heated at reflux for 20 hours. The reaction mixture was cooled and then concentrated in vacuo. The residue was partitioned with diethyl ether and saturated sodium bicarbonate, water, and brine; dried (sodium sulfate) and concentrated in vacuo.
The residue was triturated with hexane and the hexane solution was decanted and concentrated in vacuo. The residue was chromatographed at low pressure through silica gel 60 (mesh 230-400) with 5% ethanol in hexane. Recrys-tallization from pentane afforded 0.38 9., m.p. 101-2 C.
Analysis:
Calc'd. for Cl6H 8Cl 2 F3NS:
C, 51.34, H, 2.14; Cl, 18.98; F, 15.24;
N, 3.74; S, 8.56.
Found: C, 51.33; H, 2.19; Cl, 19.13; F, 15.43;
N, 3.61; S, 8.38.
25 Example 3 2-Trifluoromethyl-4,5-bis(phenyl)thiazole Following the procedure of Example 2 but substituting phenylacetic acid for p-chlorophenylacetic acid and benzene for chlorobenzene in Step I, 2-trifluoromethyl-4,5-bis-~phenyl)thiazole was prepared, m.p. 94-7 C.
Analxsis:
~14-lPg336~7 Calc'd. for ClôHlOF 3 NS:
C, 62.95; H, 3.28; N, 4.59i S, 10.49; F, 18.69.
Found: C, 62.84; H, 3.47; N, 4.52; S, 10.45; F, 1~.34.
Example 4 2-Trifluoromethyl-4,5-bis(p-fluorophenyl)-thiazole Following the procedure of Example 2 but substituting p-fluorophenylacetic acid for p-chlorophenylacetic acid and fluorobenzene for chlorobenzene in Step I, 2-trifluoro-methyl-4,5-bis(p-fluorophenyl)thiazole can be obtained.
0 Example 5 2-Trifluoromethyl-4~5-bis(p-bromophenyl) thiazole Following the procedure of Example 2 but substituting p-bromophenylacetic acid for p-chlorophenylacetic acid and bromobenzene for chlorobenzene in Step I, 2-trifluoro-methyl-4,5-bis(p-bromophenyl)thiazole can be obtained.
Example 6 2-Trifluoromethyl-4,5-bis(p-isopropoxyphenyl)-thiazole Following the procedure of Example 2 but substituting p-isopropoxyphenylacetic acid for p-chlorophenylacetic acid and isopropoxybenzene for chlorobenzene in Step I, 2-trifluoromethyl-4,5-bis(p-isopropoxyphenyl)thiazole can be obtained.
Example 7 2-Trifluoromethyl-4,5-bis(p-methoxyphenyl~-thiazole. Alternate Procedure for Preparation of 2-trifluoromethyl-4,5-bis(p-methoxyphenyl)-thiazole Trifluorothioacetamide was prepared in situ by heating a mixture of trifluoroacetamide (5.0 9.; 0.044 mole), pul-verized phosphorus pentasulfide (1.95 9.; 0.0088 mole), and benzene ~10 ml.) at reflux for 96 hours. p-Methoxy-~ 3667 3442 2-bromo-2-(p-methoxyphenyl)acetophenone (7.0 g.; 0.021 mole) was added portionwise over 15 minutes. After the nlixture was heated at reflux for an additional 1 hour, a solution composed of water (1 ml.) and conc. hydrochloric acid (0.2 ml.) was added. Following an additional hour at reflux, the mixture was cooled and the solvent was removed in vacuo and the residue was made strongly basic with 5C~% sodium hydroxide. This mixture was heated at 75 for 1 hour, cooled, and then extracted with methylene chloride. The organic extracts were washed with water, saturated sodium chloride, dried over sodium sulfate, and concentrated in vacuo. The resulting crude product was chromatographed at low pressure through silica gel 60 (mesh 230-400) with 10% ethanol in Skelly B hexanes as elutant to yield 2.57 9. of 2-trifluoromethyl-4,5-bis(p-methoxyphenyl)thiazole.
Using this procedure, and replacing p-methoxy-2-bromo-2-(p-methoxyphenyl)acetophenone with (1) 2-bromo-2-phenyl-acetophenone affords 2-trifluoromethyl-4,5-bis(phenyl)-thiazole; (2) p-chloro-2-bromo-2-(p-chlorophenyl)aceto-phenone affords 2-trifluoromethyl-4,5-bis(p-chlorophenyl)-thiazole; (3) p-fluoro-2-bromo-2-(p-fluorophenyl)aceto-phenone affords 2-trifluoromethyl-4,5-bis(p-fluorophenyl)-thiazole; (4) p-isopropoxy-2-bromo-2-(p-isopropoxyphenyl)-acetophenone affords 2-trifluoromethyl-4,5-bis)p-isopro-poxyphenyl)thiazolei (5) m,p-dimethoxy-2-bromo-2-(m,p-dimethoxyphenyl)acetophenone affords 2-trifluoromethyl-4,5-bis(m,p-dimethoxyphenyl)thiazole.
The above acetophenones are prepared as in Steps I and II of Example 2. 1) Substituting phenylacetic acid 1~3667 3442 for p-chlorophenylacetic acid and benzene for chlorobenzene affords 2-bromo-2-phenylacetophenone. 2) The preparation of p-chloro-2-bromo-2-(p-chlorophenyl)acetophenone is described in Steps I and II of Example 2. 3) Substituting 5 p-fluorophenylacetic acid for p-chlorophenylacetic acid and fluorobenzene for chlorobenzene affords p-fluoro-2-bromo-2-(p-fluorophenyl)acetophenone. 4) Substituting p-iso-propoxyphenylacetic acid for p-chlorophenylacetic acid and isopropoxybenzene for chlorobenzene affords p-iso-10 propoxy-2-bromo-2-(p-isopropoxyphenyl~acetophenone. 5) Substituting m,p-dimethoxyphenylacetic acid for p-chloro-phenylacetic acid and m,p-dimethoxybenzene for chloro-benzene affords m,p-dimethoxy-2-bromc-2-(m,p-dimethoxy-phenyl)acetophenone.
15 Example 8 4,5-Bis(p-methoxyphenyl~thiazole Part A - Thioformamide .
Following the work of Cerecedo and Tolpin [L. R.
Cerecedo and J. G. Tolpin, J. Amer. Chem. Soc., 59, 1660 (1937)], formamide (20 9.; 0.444 mole) was covered with 20 diethyl ether (200 ml.) and freshly powdered phosphorus pentasulfide ~12 g.; 0.054 mole) was added in several portions with ice water both cooling. The flask was re-frigerated at 5-10 for 72 hours and then allowed to warm to ambient temperature. After being shaken on a shaker 25 apparatus at ambient temperature for 16 hours the ethereal solution of thioformamide was decanted and used in the next step.
Part B - 4,5-Bis(p-methoxyphenyl)thiazole An ethereal solution of thioformamide (0.153 mole) 30 was concentrated in vacuo at less than 25. The residue was slurried with acetonitrile (10 ml.) and cooled in an ice water bath. p-Methoxy-2-bromo-2-(p-methoxyphenyl)-acetophenone (4.27 g.; 0.0128 mole) was dissolved in acetonitrile (50 ml.) and added via syringe to the above slurry. After stirring for 15 minutes in ice, the flask was refrigerated at 5-10 for 16 hours. The solution was then stirred at ambient temperature for 70 hours before work up. The solvent was removed in vacuo and the residue was partitioned with ether and saturated sodium bicar-bonate solution. The ether layer was washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, dried ~sodium sulfate), and concentrated in vacuo. The residue was chromatographed on silica gel 60 at low pressure with 5% ethyl acetate in benzene.
Recrystallization from hexane:benzene (11:1) afforded 2.25 9. (59~ yield) of 4,5-bis(p-methoxyphenyl)thiazole.
Analysis:
Calc'd. for C,7H1sNO2S:
C, 68.69; H, 5.05; N, 4.71; S, 10.77.
Found: C, 68.34; H, 5.07; N, 4.58; S, 10.67.
Example 9 4,5-Bis(p-methoxyphenyl)-2-thiazoleacetic acid, Lithium Salt 1.6 M n-Butyl lithium in hexane (26.6 ml.) was added by syringe over 10 minutes to a solution of 2-methyl-4,5-bis(p-methoxyphenyl3thiazole (described in U.S. Patent No. 3,560,5143 (11.0 g.; Q.0354 mole) and THF (275 ml.) cooled in a bath of dry ice and isopropyl alcohol. After stirring for 10 minutes the reaction mixture was poured slowly with stirring into a slush of powdered carbon diox-icll~ (5()() ml.) and THF (150 ml.). Once the mixture reached -lB-11~3667 ambient temperature it was concentrated by rotary evapor-ation. The resulting residue was slurried in diethyl ether and dried (vacuum oven) to afford 12.32 9. (96%
yield) of the crude salt. Two 9. of this crude material were dissolved in hot acetone. The resulting solution was filtered through a fine sintered glass funnel to remove the haze and allowed to crystallize to afford 1.2 9.
of 4,5-bis(p-methoxyphenyl)-2-thiazoleacetic acid, lithium salt.
Analysis:
Calc'd. for C,gHl6N04SLi:
C, 63.16; H, 4.43; I~, 3.88; S, 8.86; Li, 1.94.
Found: C, 62.61; H, 4.56; N, 3.90; S, 8.74; Li, 1.97.
Example 10 4,5-Bis(p-methoxyphenyl)-~,~-dimethyl-2-thia-lS zoleacetic Acid, Sodium salt A mixture of 4,5-bis(p-methoxyphenyl)-a,~-dimethyl-2-thiazoleacetic acid methyl ester (Example 4) (1.00 9.;
2.52 mm), sodium hydroxide (0.100 9.; 2.52 mm), methanol (50 ml.), and water (5 ml.) was stirred at ambient temper-ature for 48 hours. rhe solvents were removed in vacuo to afford 4,5-bis(p-methoxyphenyl)-~,~-dimethyl-2-thiazole-acetic acid, sodium salt.
Example 11 4,5-Bis(p-methoxyphenyl)-~,~-dimethyl-2-thia-zoleacetic acid, Potassium Salt A mixture of 4,5-bis(p-methoxyphenyl)-~,~-dimethyl-2-thiazoleacetic acid methyl ester (1.00 9.; 2.52 mm), potassium hydroxide (.141 9.; 2.52 mm), methanol (S0 ml.), and water (5 ml.) was stirred at ambient temperature for 48 hours. The solvents were removed in vacuo to afford 4,5-bis(p-methoxyphenyl)-~,~-dimethyl-2-thiazoleacetic 36~7 acid, potassium salt.
Example 12 4,5-Bis(p-methoxyphenyl)-2-thiazoieacetic acid, Methyl Ester A solution of 4,5-bis(p-methoxyphenyl)-2-thiazole-S acetic acid, lithium salt (8.82 9.; 0.024 mole), methyl iodide (17.4 9.; 0.122 mole) and DMF (100 ml.) was stirred at ambient temperature for 16 hours. The mixture was poured into water (l.S !.) and extracted with methylene chloride (500 ml.). The organic layer was washed with water (3 x 1.5 1.), saturated sodium bicarbonate (1.0 1.), water (1.5 1.), dried (sodium sulfate), and concentrated in vacuo. The oily residue was dissolved in acetone and applied directly to a Florisil-packed (340 ml.) gravity column (Florisil previously equilibrated with solvent mixture; 500 ml. packing:100 ml. solvent). The sample was eluted with 5% acetone in hexane. The recovered product was recrystallized from diethyl ether-pentane to afford
3.32 9. (37% yield) of 4,5-bis(p-methoxyphenyl)-2-thiazole-acetic acid, methyl ester; m.p. 79-81.5.
Analysis:
Calc'd. for C~ oH I gNO4S:
C, 65.04; H, 5.15; N, 3.79; S, 8.67.
- Found: C, 64.00; H, 5.39; N, 3.58; S, 8.68.
Example 13 4,5-Bis(p-methoxyphenyl)-2-thiazole Ethanol A solution of 4,S-bis(p-methoxyphenyl~-2-thiazole-acetic acid, methyl ester (2.5 9.; 0.0068 mole) and THF
~10 ~1.) was added dropwise by syringe to an ice cooled slurry of lithium aluminum hydride (0.55 9.; 0.0145 mole) and THF i20 ml.). Stirrtns was continued for an additional 1.25 hours at ambient temperature. The reaction was * Trademark ~,.
1~;)36~7 3442 quenched by the dropwise addition of water (2 ml. via syringe) and then concentrated by rotary evaporation.
The residue was slurried with water, taken to pH 4 with 6N sul furic acid, and extracted with methylene chloride.
S The extracts were washed with water, dried (sodium sulfate), and concentrated by rotary evaporation. The crude mix-ture was chromatographed (HPLC) with 50% ethyl acetate in benzene through silica gel and then recrystallized from ether-pentane to afford 0.82 g. (35% yield) 4,5-bis(4-methoxyphenyl)-2-thiazole ethanol; m.p. 101-104 C.
Analysis:
Calc'd. for ClgHlgN03S:
C, 66.86; H, 5.57; N, 4.11; S, 9.38.
Found: C, 65.94; H, 5.50; N, 4.07; S, 9.75.
Example 14 4,5-Bis(p-methoxyphenyl)-c~ -dimethyl-2-thia-zoleacetic acid, Methyl Ester 1.6 M n-Butyl lithium in hexane (10.6 ml.; 0.017 mole) was added dropwise by syringe over 30 minutes to a solution of diisopropylamine (1.48 9.; 0.017 mole) and THF (15 ml.) 20 which was cooled in an ice water bath. Stirring was con-tinued for 15 minutes following addition. The temperature of the solution was lowered by substituting a bath of isopropyl alcohol and dry ice. 4,5-Bis(p-methoxyphenyl)-2-thiazoleacetic acid, methyl ester (S 9.; 0.0136 mole) 25 in THF (15 ml.) was added by syringe over one hour while the temperature of the reaction mixture was maintained below -60~. After stirring for 45 minutes (dry ice bath) methyl iodide (3.~3 9.; 0.027 mole) was added by syringe over 5 minutes. Stirring was continued for 15 minutes at 30 which time the solution was allowed to warm to ambient 34q2 ~03667 temperature (ca. 20 min.~. The reaction mixture was poured into water (500 ml.) and extracted with methylene chloride (2 x 250 ml.). The organic phase was washed with water (2 x 500 ml.), lN hydrochloric acid (2 x 250 ml.) and water (1 x 500 ml.); dried (sodium sulfate) and concentra-ted by rotary evaporation to afford a crude yield of 4.74 9. This material was taken up in absolute ethanol, treated with DARC0 , filtered and concentrated by rotary evapora-tion. The residue was chromatographed through two Merck silica gel columns (Size C) with 10% ethyl acetate in benzene. Consolidated fractions afforded 2.69 9. (50%
yield) of 4,5-bis(p-methoxyphenyl)-~ dimethyl-2-thiazole-acetic acid, methyl ester as an oil.
Analysis:
Calc'd. for C2~H23N04S:
C, 66.50; H, 5.79; N, 3.53; S, 8.06.
Found: C, 66.81; H, 5.93; N, 4.35; S, 8.16.
xample 15 4,5-Bis(p-methoxyphenyl~-2-thiazole-~
dimethylethanol
Analysis:
Calc'd. for C~ oH I gNO4S:
C, 65.04; H, 5.15; N, 3.79; S, 8.67.
- Found: C, 64.00; H, 5.39; N, 3.58; S, 8.68.
Example 13 4,5-Bis(p-methoxyphenyl)-2-thiazole Ethanol A solution of 4,S-bis(p-methoxyphenyl~-2-thiazole-acetic acid, methyl ester (2.5 9.; 0.0068 mole) and THF
~10 ~1.) was added dropwise by syringe to an ice cooled slurry of lithium aluminum hydride (0.55 9.; 0.0145 mole) and THF i20 ml.). Stirrtns was continued for an additional 1.25 hours at ambient temperature. The reaction was * Trademark ~,.
1~;)36~7 3442 quenched by the dropwise addition of water (2 ml. via syringe) and then concentrated by rotary evaporation.
The residue was slurried with water, taken to pH 4 with 6N sul furic acid, and extracted with methylene chloride.
S The extracts were washed with water, dried (sodium sulfate), and concentrated by rotary evaporation. The crude mix-ture was chromatographed (HPLC) with 50% ethyl acetate in benzene through silica gel and then recrystallized from ether-pentane to afford 0.82 g. (35% yield) 4,5-bis(4-methoxyphenyl)-2-thiazole ethanol; m.p. 101-104 C.
Analysis:
Calc'd. for ClgHlgN03S:
C, 66.86; H, 5.57; N, 4.11; S, 9.38.
Found: C, 65.94; H, 5.50; N, 4.07; S, 9.75.
Example 14 4,5-Bis(p-methoxyphenyl)-c~ -dimethyl-2-thia-zoleacetic acid, Methyl Ester 1.6 M n-Butyl lithium in hexane (10.6 ml.; 0.017 mole) was added dropwise by syringe over 30 minutes to a solution of diisopropylamine (1.48 9.; 0.017 mole) and THF (15 ml.) 20 which was cooled in an ice water bath. Stirring was con-tinued for 15 minutes following addition. The temperature of the solution was lowered by substituting a bath of isopropyl alcohol and dry ice. 4,5-Bis(p-methoxyphenyl)-2-thiazoleacetic acid, methyl ester (S 9.; 0.0136 mole) 25 in THF (15 ml.) was added by syringe over one hour while the temperature of the reaction mixture was maintained below -60~. After stirring for 45 minutes (dry ice bath) methyl iodide (3.~3 9.; 0.027 mole) was added by syringe over 5 minutes. Stirring was continued for 15 minutes at 30 which time the solution was allowed to warm to ambient 34q2 ~03667 temperature (ca. 20 min.~. The reaction mixture was poured into water (500 ml.) and extracted with methylene chloride (2 x 250 ml.). The organic phase was washed with water (2 x 500 ml.), lN hydrochloric acid (2 x 250 ml.) and water (1 x 500 ml.); dried (sodium sulfate) and concentra-ted by rotary evaporation to afford a crude yield of 4.74 9. This material was taken up in absolute ethanol, treated with DARC0 , filtered and concentrated by rotary evapora-tion. The residue was chromatographed through two Merck silica gel columns (Size C) with 10% ethyl acetate in benzene. Consolidated fractions afforded 2.69 9. (50%
yield) of 4,5-bis(p-methoxyphenyl)-~ dimethyl-2-thiazole-acetic acid, methyl ester as an oil.
Analysis:
Calc'd. for C2~H23N04S:
C, 66.50; H, 5.79; N, 3.53; S, 8.06.
Found: C, 66.81; H, 5.93; N, 4.35; S, 8.16.
xample 15 4,5-Bis(p-methoxyphenyl~-2-thiazole-~
dimethylethanol
4,5-Bis(p-methoxyphenyl)-~,~-dimethyl-2-thiazoleacetic acid, methyl ester (0.81 9.; 0.0020 mole) in THF (5 ml.) was added dropwise by syringe to an ice cooled slurry of - lithium aluminum hydride ~0.16 g.; 0.0042 mole) and THF
(10 ml.). Tne mixture was stirred for 1 hour at ambient temperature and was then cooled (5-10) prior to the dropwise addition of water (0.5 ml.) which quenched the reduction. Solvent was removed by rotary evaporation.
The residue was slurried with water (30 ml.), acidified to pH 3 with 6 N sulfuric acid and then extracted with methylene chloride. The extracts were washed with water~
~44~
dried (sodium sul fate~ and concentrated by rotary evapor-ation to afford a crude oil. This material was triturated with pentane to induce crystallization and then recrystal-lized from diethyl ether-pentane. The 0.45 g. of product
(10 ml.). Tne mixture was stirred for 1 hour at ambient temperature and was then cooled (5-10) prior to the dropwise addition of water (0.5 ml.) which quenched the reduction. Solvent was removed by rotary evaporation.
The residue was slurried with water (30 ml.), acidified to pH 3 with 6 N sulfuric acid and then extracted with methylene chloride. The extracts were washed with water~
~44~
dried (sodium sul fate~ and concentrated by rotary evapor-ation to afford a crude oil. This material was triturated with pentane to induce crystallization and then recrystal-lized from diethyl ether-pentane. The 0.45 g. of product
5 resulting from this procedure had a very broad melting point. The material was dissolved in methylene chloride and washed again with water to remove any inorganic impur-ities and recrystallized from diethyl ether-pentane to afford 0.19 9. (26% yield) of 4,5-bis(p-methoxyphenyl)-2-thiazole-c~ dimethylethano1; m.p. 101-105 C.
Analysis:
Calc'd. for C2IH23NO35:
C, 68.29; H, 6.23; N, 3.79; S, 8.67.
Found: C, 67.68; H, 6.41; N, 3.83; S, 8.48.
Example 16 2-Isopropyl-4,5-bis(p-methoxyphenyl)thiazole A solution of 4,5-bis(p-methoxyphenyl)-a,o~-dimethyl-2-thiazoleacetic acid, methyl ester (0.70 9.; 0.0018 mole), 6N sodium hydroxide (1.6 ml.) and methanol (15 ml.) was stirred at ambient temperature for 16 hours.
Methanol was removed by rotary evaporation; the residue was slurried in water (30 ml.) and then adjusted to pH 2 with conc. hydrochloric acid. Decarboxylation occurred while the mixture stirred at ambient temperature for 1.75 hours. The mixture was extracted with methylene chloride. The extracts were dried (sodium sul fate) and concentrated by rotary evaporation to afford O.S9 g. of oily product. The material crystallized slowly at -10 over a period of several days. Recrystallization from pentane affordQd 0.19 g. (32% yield) of 2-isopropyl-4,5-bis(p-methoxyphenyl)thiazolei m.p. 61-65 ~.
i~V~667 3442 Analysis:
Calc'd. for C? oH2lNO~S:
C, 70.80; H, 6.19; N, 4.13; S, 9.44.
Found: C, 70.44; H, 6.16; N, 4.16; S, 9.37.
Example 17 4,5-Bis(p-methoxyphenyl)-2-thiazoleacetamide A three neck flask containing a solution of 4,5-bis-(p-methoxyphenyl)-2-thiazoleacetic acid, methyl ester (0.5 9.; 0.00135 mole) and methanol (50 ml.), and fitted with a gas frit and dry ice condenser was cooled in an ice water bath. Ammonia was bubbled into the solution for 15 minutes. After 2 hours of maintaining the ice bath and condenser the entire apparatus (including bath) was wrapped in towels and foil and allowed to stand overnight.
The resulting orange solution was concentrated in vacuo.
lS The residue was dissolved in methanol, treated with DARC0 and then concentrated in vacuo. This material was chromatographed through silica gel 60 (mesh 230-400~ with 5% isopropyl alcohol in methylene chloride. Recrystal-lization from diethyl ether-pentane afforded 0.06 9. (13%
yield~ of product, m.p. 124-127 C.
Analysis:
Calc'd. for ClgHI8N20~S:
C, 64.41; H, 5.08; N, 7.91; S, 9.04.
Found: C, 64.51i H, 5.51; N, 7.56; S, 9.22.
Example 18 Following ~he procedure of Example 2, but substituting for p-chlorophenylacetic acid the compounds in entry A, and for chlorobenzene, the compounds in entry B, there are obtainecl in Step III, the products listed in entry C, respectively.
i~Q3667 A. m,p-dimethoxyphenylacetic acid B. chlorobenzene C. 2-trifluoromethyl-4-(p-chlorophenyl)-5-(m,p-dimethoxyphenyl)thiazole;
s A. p-chlorophenylacetic acid B. o,m-dimethoxYbenzene C. 2-trifluoromethyl-4-(m,p-dimethoxyphenyl)-5-(p-chlorophenyl)thiazole;
A. m,p-dimethoxyphenylacetic acid B. benzene C. 2-trifluoromethyl-4-phenyl_5_(m,p-dimethoxy-phenyl)thiazole;
A p-methylphenylacetic acid B. P-t-butoxybenzene C. 2-trifluoromethyl-4-(p-t-butoxyphenyl)-5-(p-methylphenyl)thiazole;
A. phenylacetic acid B. ethylbenzene C. 2-trifluoromethyl-4-(p-ethylphenyl)-5-phenyl-thiazole.
Example 19 Following the procedure of Example 41 of U.S. Patent 3,560,514, but substituting for p-methoxy-2-bromo-2-~p-methoxyphenyl)acetophenone the ~-bromoketones afforded as intermediates in Example 18~ above, t~ere are prepared the corresponding 2-methyl-4,S-diarylthiazoles.
i~3667 Example 20 Following the sequence established by Examples 9, 12, and 14, but starting with the 2-methyl compounds prepared as in the previous example, there are obtained the corres-ponding 4,5-diaryl-~,~-dimethyl-2-thiazoleacetic acid, methyl esters.
Example 21 Following the procedure of Example 17, but substitut-ing for ammonia the following amines:
bis(2-hydroxyethyl)amine, ethylamine, pyrrolidine, piperidine, morpholine, piperazine, and N-2-hydroxyethyl-N-ethylamine, there are obtained N,N-bis(2-hydroxyethyl)-4,5-bis(p-methoxyphenyl)-2-thiazoleacetamide, N-ethyl-4,5-bis(p-methoxyphenyl)-2-thiazoleacetamide, 1-[[4,5-bis(p-methoxyphenyl)-2-thiazolyl]acetylJ-pyrrolidine, l-[t4,5-bis(p-methoxyphenyl)-2-thiazolylJacetyl]-piperidine, 4-[c4~5-bis(p-methoxyphenyl)-2-thiazolylJacetyl]
morpholine, lt~4,5-bis(p-methoxyphenyl)-2-thiazolyl]acetylJ-piperazine, and N-2-hydroxyethyl~N-ethyl-4,5-bis(4'-nlethoxyphenyl)-2-thiazoleacetamide, respectively.
The compounds of the formula II:
~ ~313667 ~,~ R 2 ' ~// " 1\1 '~ ~\\ " ' ~ `
\\.,. ./~\
R~ Formula 11 wherein R~ and R3 are the same or different, and are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, alkoxy of from one to four carbon atoms, inclusive, thioalkoxy of from one to four carbon atoms, inclusive, and alkyl of from one to four carbon atoms, inclusive; R2~ and R3~ are the same or different and are chosen from the group consisting of hydrogen and alkoxy from one to four carbon atoms, inclu-sive, with the proviso that when R2~ is alkoxy, then R2 = R2~ and when R3~ is alkoxy then R3 = R3~; Rl is selected from the group consisting of hydrogen; alkyl of fRom one to four carbon atoms, inclusive, trifluoromethyl;
-CjCH20R4, where R4 isOhydrogen, alkyl of one to four carbon at3ms, inclusive, or CRs, where Rs is alkyl of one to six carbon atoms, inclusive, R6 and R7 are the same or differ-ent, and are chosen from the group consisting of hydrogenand alkyl of one to three carbon atoms; C-C-RIo where R8 and R~ are the same or different and are chnsen from the group ccnsisting of hydrogen and alkyl from one to three carbon atoms, inclusive, Rlo is alkoxy of from one to three carhon atoms, inclusives -OM where M is a pharma-i~3667 ceutically acceptable cation; N \ where R,l and Rl2 Rl 2are the same or different and are chosen from the group consisting of hydrogen, alkyl of from one to six carbon atolns, inclusive, hydroxyalkyl of from one to six carbon S atoms, inclusive, cycloalkyl of from five to seven carbon atoms, inclusive, or taken together with the nitrogen atom to which they are attached, -N , -N ~ , -N 0 -N NH
in association with a pharmaceutical carrier. The compo-sitions are useful in vitro and in vivo for reduction of platelet adhesiveness and inhibition of platelet aggrega-tion and preventing or treating disease conditions result-ing from increased platelet adhesiveness or plateletaggregation, are prepared in unit dosage form in associa-tion with conventional pharmaceutical carrier and admin-istered systemically to humans or animals. The compounds of the formula are also usefully added to in vitro platelet systems. In vitro systems include whole Slood and blood kept in blood banks, whole blood as used in heart~lung machines and platelet-rich concentrates. Administration of the compounds to humans or animals provides a method for reducing platelet adhesiveness and inhibiting platelet aggregation.
-2~-For in vivo applications the compositions of the present invention are presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspen-sions, and oil-in-water and water-in-oil emulsions con-taining suitable quantities of the compound of Formula II.
For oral administration either solid or fluid unit dosage forms can be prepared. For preparing solid compo-sitions such as tablets, the compound of Formula II ismixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers. Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appro-priate size. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an accept-able vegetable oil, light liquid petrolatum or otherinert oil.
Fluid unit dosage forms for oral administration such as syrups, elixirs, and suspensions can be prepared. The water-soluble forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preser-vatives to form a syrup. An elixir is prepared by using a hydroalcoholic (ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent.
Suspensions can be prepared with a syrup vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compounds, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solu-tions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampul and sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advan-tageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
For in vitro applications, aqueous solutions are prepared by dissolving a compound of the Formula II in water and adding salt to provide an isotonic solution and buffering to a pH compatible with blood.
Advantageously the composition prepared for parenteral administration can be used when prepared omitting the local anesthetic.
The dosage for humans and animals depends on the blood volume and condltion of the subject. A dosage 5 schedule of from about 5 to about 500 mg. per dose, pre-ferably from lO to 250 mg. administered l to 4 times daily is effective for reducing platelet aggregation in the subject. Expressed in terms of weight, the dose can be from 0.3 to 30 mg./kg./day, and preferably from 0.6 to -lS mg./kg./day.
For in vitro, dosage is from O.OOlO to O.lO micro-gramstml. of whole blood. -The addition of compounds of the Formula II to whole blood provide in vitro appl;cations of ~he invention such as in the storage of whole blood in blood banks, and whole blood to be used in heart-lung machines. Addition-ally, whole blood containing a compound of the Formula II
can be circulated through organs, e.g. ? heart and kidneys, which have been removed from a cadaver~ and prior to trans-plant.
~- The compounds of the Formula II can also be used for the preparation of stable platelet-rich plasma concentrates in the same manner as the prostaglandins as disclosed in U.S. Patent 3,62g,07l and Science, Vol. 175, pp. 536-542 (February 4, 1972).
In vivo applications are the administration to humans and a~nimals to prevent thrombus formation in situations such~as following surgery to prevent post-operative throm-bosis; to prevent transient cerebral ischemic attacks; and 30~ long-term prophylaxis following myocardial infarcts and strokes.
In general a compound of the Formula II is usefully administered prophylactically to humans having a platelet adhesiveness value in excess of 25% [Bygdeman et al., J.
Atheroscler. Res., 10, 33-39 (1969)~.
In addition to the administration of a compound of the Formula II as the principal active ingredient of compositions for the treatment of the conditions described herein, the said compound can be included with other types of compounds to obtain advantageous combinations of pro-perties. Such combinations include a compound of the Formula II with aspirin, prostaglandins and anti-coagulants such as heparin and dicumerol.
Example ?~?
A lot of 10,000 tablets each containing 50 mg. of 2-trifluoromethyl-4,5-bis(p-methoxyphenyl)thiazole is prepared from the following types and amounts of ingredients:
2-trifluoromethyl-4,5-bis-(p-methoxyphenyl)thiazole500 gm.
Dicalcium phosphate 1,500 gm.
Methylcellulose, U.S.P.
~15 cps.) 60 gm.
Talc 150 gm.
Corn starch 200 gm.
Calcium stearate 12 gm.
The dicalcium phosphate and active ingredient are mixed well, granulated with 7.5 percent solution of methyl-cellulose in water, passed through a No. 8 screen and dried carefully. The dried granules are passed through a No. 12 screen, mixed thoroughly with the talc, starch and ~3~7 3442 magnesium stearate, and compressed into tablets.
These tablets are useful in preventing thrombus formation at a dose of 1 tablet every four hours following surgery.
Example 23 One thousand two-piece hard gelatin capsules, each containing 100 mg. of 2-trifluoromethyl-4,5-bis(p-methoxy-phenyl)thiazole are prepared from the following types and amounts of ingredients:
2-trifluoromethyl-4,5-bis-(p-methoxyphenyl)thiazole100 gm.
Talc 100 gm.
Magnesium stearate 10 gm.
The ingredients are mixed well and filled into cap-sules of the proper size.
Capsules so prepared are useful in preventing further coronary infarcts at a dose of 1 to 4 capsules daily to a patient recovering from a coronary infarct.
Example 24 One thousand tablets, each containing 400 mg. of 2-trifluoromethyl-4,5-bis(p-methoxyphenyl)thiazole are made from the following types and amounts of ingredients:
2-trifluoromethyl-4,5-bis-(p-methoxyphenyl)thiazole400 gm.
Microcrystalline cellulose NF120 gm.
Starch 16 gm.
Magnesium stearate powder 4 gm.
The ingredients are screened and blended together and pressed into 540 mg. tablets.
The tablets are useful to protect against elevated 1~36~
platelet adhesiveness at a dose of 1 tablet daily.
Example 25 A sterile preparation suitable for intramuscular injection and containing 50 mg. of 2-trifluoromethyl-4,5-bis(p-methoxyphenyl)thiazole in each milliliter is prepared from the following ingredients:
2-tri fl uoromethyl-4,5-bis-(p-methoxyphenyl)thiazole50 gm.
Benzyl benzoate 200 ml.
Methylparaben 1.5 gm.
Propylparaben 0.5 gm.
Cottonseed oil q.s.1,000 ml.
One milliliter of this sterile preparation is injected for prophylactic treatment prior to surgery.
Example 26 Aqueous solution Six hundred ml. of an aqueous solution containing .001 mg. of the 2-tri fl uoromethyl-4,5-bis(p-methoxyphenyl)-thiazole per ml. is prepared as follows:
2-tri f l uoromethyl-4,5-bis-(p-methoxyphenyl)thiazole0.6 mg.
Sodium chloride 5,400 mg.
Water for injection q.s.600 ml.
The active compound and sodium chloride are dissolved in sufficient water to make 600 ml. and sterile filtered.
The solution is added to whole blood 16 ml./liter for use in a heart-lung machine.
Example 27 Following the procedure of the preceding Examples 22 through 26, ,nclusive, compositions are similarly prepared substituting an equimolar amount each of the compounds of i~3667 3442 the Formula II prepared in Examples 1 thru 21, inclusive, for the 2-trifluoromethyl-4,5-bis(p-methoxyphenyl)-thiazole.
Analysis:
Calc'd. for C2IH23NO35:
C, 68.29; H, 6.23; N, 3.79; S, 8.67.
Found: C, 67.68; H, 6.41; N, 3.83; S, 8.48.
Example 16 2-Isopropyl-4,5-bis(p-methoxyphenyl)thiazole A solution of 4,5-bis(p-methoxyphenyl)-a,o~-dimethyl-2-thiazoleacetic acid, methyl ester (0.70 9.; 0.0018 mole), 6N sodium hydroxide (1.6 ml.) and methanol (15 ml.) was stirred at ambient temperature for 16 hours.
Methanol was removed by rotary evaporation; the residue was slurried in water (30 ml.) and then adjusted to pH 2 with conc. hydrochloric acid. Decarboxylation occurred while the mixture stirred at ambient temperature for 1.75 hours. The mixture was extracted with methylene chloride. The extracts were dried (sodium sul fate) and concentrated by rotary evaporation to afford O.S9 g. of oily product. The material crystallized slowly at -10 over a period of several days. Recrystallization from pentane affordQd 0.19 g. (32% yield) of 2-isopropyl-4,5-bis(p-methoxyphenyl)thiazolei m.p. 61-65 ~.
i~V~667 3442 Analysis:
Calc'd. for C? oH2lNO~S:
C, 70.80; H, 6.19; N, 4.13; S, 9.44.
Found: C, 70.44; H, 6.16; N, 4.16; S, 9.37.
Example 17 4,5-Bis(p-methoxyphenyl)-2-thiazoleacetamide A three neck flask containing a solution of 4,5-bis-(p-methoxyphenyl)-2-thiazoleacetic acid, methyl ester (0.5 9.; 0.00135 mole) and methanol (50 ml.), and fitted with a gas frit and dry ice condenser was cooled in an ice water bath. Ammonia was bubbled into the solution for 15 minutes. After 2 hours of maintaining the ice bath and condenser the entire apparatus (including bath) was wrapped in towels and foil and allowed to stand overnight.
The resulting orange solution was concentrated in vacuo.
lS The residue was dissolved in methanol, treated with DARC0 and then concentrated in vacuo. This material was chromatographed through silica gel 60 (mesh 230-400~ with 5% isopropyl alcohol in methylene chloride. Recrystal-lization from diethyl ether-pentane afforded 0.06 9. (13%
yield~ of product, m.p. 124-127 C.
Analysis:
Calc'd. for ClgHI8N20~S:
C, 64.41; H, 5.08; N, 7.91; S, 9.04.
Found: C, 64.51i H, 5.51; N, 7.56; S, 9.22.
Example 18 Following ~he procedure of Example 2, but substituting for p-chlorophenylacetic acid the compounds in entry A, and for chlorobenzene, the compounds in entry B, there are obtainecl in Step III, the products listed in entry C, respectively.
i~Q3667 A. m,p-dimethoxyphenylacetic acid B. chlorobenzene C. 2-trifluoromethyl-4-(p-chlorophenyl)-5-(m,p-dimethoxyphenyl)thiazole;
s A. p-chlorophenylacetic acid B. o,m-dimethoxYbenzene C. 2-trifluoromethyl-4-(m,p-dimethoxyphenyl)-5-(p-chlorophenyl)thiazole;
A. m,p-dimethoxyphenylacetic acid B. benzene C. 2-trifluoromethyl-4-phenyl_5_(m,p-dimethoxy-phenyl)thiazole;
A p-methylphenylacetic acid B. P-t-butoxybenzene C. 2-trifluoromethyl-4-(p-t-butoxyphenyl)-5-(p-methylphenyl)thiazole;
A. phenylacetic acid B. ethylbenzene C. 2-trifluoromethyl-4-(p-ethylphenyl)-5-phenyl-thiazole.
Example 19 Following the procedure of Example 41 of U.S. Patent 3,560,514, but substituting for p-methoxy-2-bromo-2-~p-methoxyphenyl)acetophenone the ~-bromoketones afforded as intermediates in Example 18~ above, t~ere are prepared the corresponding 2-methyl-4,S-diarylthiazoles.
i~3667 Example 20 Following the sequence established by Examples 9, 12, and 14, but starting with the 2-methyl compounds prepared as in the previous example, there are obtained the corres-ponding 4,5-diaryl-~,~-dimethyl-2-thiazoleacetic acid, methyl esters.
Example 21 Following the procedure of Example 17, but substitut-ing for ammonia the following amines:
bis(2-hydroxyethyl)amine, ethylamine, pyrrolidine, piperidine, morpholine, piperazine, and N-2-hydroxyethyl-N-ethylamine, there are obtained N,N-bis(2-hydroxyethyl)-4,5-bis(p-methoxyphenyl)-2-thiazoleacetamide, N-ethyl-4,5-bis(p-methoxyphenyl)-2-thiazoleacetamide, 1-[[4,5-bis(p-methoxyphenyl)-2-thiazolyl]acetylJ-pyrrolidine, l-[t4,5-bis(p-methoxyphenyl)-2-thiazolylJacetyl]-piperidine, 4-[c4~5-bis(p-methoxyphenyl)-2-thiazolylJacetyl]
morpholine, lt~4,5-bis(p-methoxyphenyl)-2-thiazolyl]acetylJ-piperazine, and N-2-hydroxyethyl~N-ethyl-4,5-bis(4'-nlethoxyphenyl)-2-thiazoleacetamide, respectively.
The compounds of the formula II:
~ ~313667 ~,~ R 2 ' ~// " 1\1 '~ ~\\ " ' ~ `
\\.,. ./~\
R~ Formula 11 wherein R~ and R3 are the same or different, and are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, alkoxy of from one to four carbon atoms, inclusive, thioalkoxy of from one to four carbon atoms, inclusive, and alkyl of from one to four carbon atoms, inclusive; R2~ and R3~ are the same or different and are chosen from the group consisting of hydrogen and alkoxy from one to four carbon atoms, inclu-sive, with the proviso that when R2~ is alkoxy, then R2 = R2~ and when R3~ is alkoxy then R3 = R3~; Rl is selected from the group consisting of hydrogen; alkyl of fRom one to four carbon atoms, inclusive, trifluoromethyl;
-CjCH20R4, where R4 isOhydrogen, alkyl of one to four carbon at3ms, inclusive, or CRs, where Rs is alkyl of one to six carbon atoms, inclusive, R6 and R7 are the same or differ-ent, and are chosen from the group consisting of hydrogenand alkyl of one to three carbon atoms; C-C-RIo where R8 and R~ are the same or different and are chnsen from the group ccnsisting of hydrogen and alkyl from one to three carbon atoms, inclusive, Rlo is alkoxy of from one to three carhon atoms, inclusives -OM where M is a pharma-i~3667 ceutically acceptable cation; N \ where R,l and Rl2 Rl 2are the same or different and are chosen from the group consisting of hydrogen, alkyl of from one to six carbon atolns, inclusive, hydroxyalkyl of from one to six carbon S atoms, inclusive, cycloalkyl of from five to seven carbon atoms, inclusive, or taken together with the nitrogen atom to which they are attached, -N , -N ~ , -N 0 -N NH
in association with a pharmaceutical carrier. The compo-sitions are useful in vitro and in vivo for reduction of platelet adhesiveness and inhibition of platelet aggrega-tion and preventing or treating disease conditions result-ing from increased platelet adhesiveness or plateletaggregation, are prepared in unit dosage form in associa-tion with conventional pharmaceutical carrier and admin-istered systemically to humans or animals. The compounds of the formula are also usefully added to in vitro platelet systems. In vitro systems include whole Slood and blood kept in blood banks, whole blood as used in heart~lung machines and platelet-rich concentrates. Administration of the compounds to humans or animals provides a method for reducing platelet adhesiveness and inhibiting platelet aggregation.
-2~-For in vivo applications the compositions of the present invention are presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspen-sions, and oil-in-water and water-in-oil emulsions con-taining suitable quantities of the compound of Formula II.
For oral administration either solid or fluid unit dosage forms can be prepared. For preparing solid compo-sitions such as tablets, the compound of Formula II ismixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers. Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appro-priate size. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an accept-able vegetable oil, light liquid petrolatum or otherinert oil.
Fluid unit dosage forms for oral administration such as syrups, elixirs, and suspensions can be prepared. The water-soluble forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preser-vatives to form a syrup. An elixir is prepared by using a hydroalcoholic (ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent.
Suspensions can be prepared with a syrup vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compounds, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solu-tions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampul and sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advan-tageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
For in vitro applications, aqueous solutions are prepared by dissolving a compound of the Formula II in water and adding salt to provide an isotonic solution and buffering to a pH compatible with blood.
Advantageously the composition prepared for parenteral administration can be used when prepared omitting the local anesthetic.
The dosage for humans and animals depends on the blood volume and condltion of the subject. A dosage 5 schedule of from about 5 to about 500 mg. per dose, pre-ferably from lO to 250 mg. administered l to 4 times daily is effective for reducing platelet aggregation in the subject. Expressed in terms of weight, the dose can be from 0.3 to 30 mg./kg./day, and preferably from 0.6 to -lS mg./kg./day.
For in vitro, dosage is from O.OOlO to O.lO micro-gramstml. of whole blood. -The addition of compounds of the Formula II to whole blood provide in vitro appl;cations of ~he invention such as in the storage of whole blood in blood banks, and whole blood to be used in heart-lung machines. Addition-ally, whole blood containing a compound of the Formula II
can be circulated through organs, e.g. ? heart and kidneys, which have been removed from a cadaver~ and prior to trans-plant.
~- The compounds of the Formula II can also be used for the preparation of stable platelet-rich plasma concentrates in the same manner as the prostaglandins as disclosed in U.S. Patent 3,62g,07l and Science, Vol. 175, pp. 536-542 (February 4, 1972).
In vivo applications are the administration to humans and a~nimals to prevent thrombus formation in situations such~as following surgery to prevent post-operative throm-bosis; to prevent transient cerebral ischemic attacks; and 30~ long-term prophylaxis following myocardial infarcts and strokes.
In general a compound of the Formula II is usefully administered prophylactically to humans having a platelet adhesiveness value in excess of 25% [Bygdeman et al., J.
Atheroscler. Res., 10, 33-39 (1969)~.
In addition to the administration of a compound of the Formula II as the principal active ingredient of compositions for the treatment of the conditions described herein, the said compound can be included with other types of compounds to obtain advantageous combinations of pro-perties. Such combinations include a compound of the Formula II with aspirin, prostaglandins and anti-coagulants such as heparin and dicumerol.
Example ?~?
A lot of 10,000 tablets each containing 50 mg. of 2-trifluoromethyl-4,5-bis(p-methoxyphenyl)thiazole is prepared from the following types and amounts of ingredients:
2-trifluoromethyl-4,5-bis-(p-methoxyphenyl)thiazole500 gm.
Dicalcium phosphate 1,500 gm.
Methylcellulose, U.S.P.
~15 cps.) 60 gm.
Talc 150 gm.
Corn starch 200 gm.
Calcium stearate 12 gm.
The dicalcium phosphate and active ingredient are mixed well, granulated with 7.5 percent solution of methyl-cellulose in water, passed through a No. 8 screen and dried carefully. The dried granules are passed through a No. 12 screen, mixed thoroughly with the talc, starch and ~3~7 3442 magnesium stearate, and compressed into tablets.
These tablets are useful in preventing thrombus formation at a dose of 1 tablet every four hours following surgery.
Example 23 One thousand two-piece hard gelatin capsules, each containing 100 mg. of 2-trifluoromethyl-4,5-bis(p-methoxy-phenyl)thiazole are prepared from the following types and amounts of ingredients:
2-trifluoromethyl-4,5-bis-(p-methoxyphenyl)thiazole100 gm.
Talc 100 gm.
Magnesium stearate 10 gm.
The ingredients are mixed well and filled into cap-sules of the proper size.
Capsules so prepared are useful in preventing further coronary infarcts at a dose of 1 to 4 capsules daily to a patient recovering from a coronary infarct.
Example 24 One thousand tablets, each containing 400 mg. of 2-trifluoromethyl-4,5-bis(p-methoxyphenyl)thiazole are made from the following types and amounts of ingredients:
2-trifluoromethyl-4,5-bis-(p-methoxyphenyl)thiazole400 gm.
Microcrystalline cellulose NF120 gm.
Starch 16 gm.
Magnesium stearate powder 4 gm.
The ingredients are screened and blended together and pressed into 540 mg. tablets.
The tablets are useful to protect against elevated 1~36~
platelet adhesiveness at a dose of 1 tablet daily.
Example 25 A sterile preparation suitable for intramuscular injection and containing 50 mg. of 2-trifluoromethyl-4,5-bis(p-methoxyphenyl)thiazole in each milliliter is prepared from the following ingredients:
2-tri fl uoromethyl-4,5-bis-(p-methoxyphenyl)thiazole50 gm.
Benzyl benzoate 200 ml.
Methylparaben 1.5 gm.
Propylparaben 0.5 gm.
Cottonseed oil q.s.1,000 ml.
One milliliter of this sterile preparation is injected for prophylactic treatment prior to surgery.
Example 26 Aqueous solution Six hundred ml. of an aqueous solution containing .001 mg. of the 2-tri fl uoromethyl-4,5-bis(p-methoxyphenyl)-thiazole per ml. is prepared as follows:
2-tri f l uoromethyl-4,5-bis-(p-methoxyphenyl)thiazole0.6 mg.
Sodium chloride 5,400 mg.
Water for injection q.s.600 ml.
The active compound and sodium chloride are dissolved in sufficient water to make 600 ml. and sterile filtered.
The solution is added to whole blood 16 ml./liter for use in a heart-lung machine.
Example 27 Following the procedure of the preceding Examples 22 through 26, ,nclusive, compositions are similarly prepared substituting an equimolar amount each of the compounds of i~3667 3442 the Formula II prepared in Examples 1 thru 21, inclusive, for the 2-trifluoromethyl-4,5-bis(p-methoxyphenyl)-thiazole.
Claims (16)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of Formula 1 Formula I
wherein R2 and R3 are the same or different, and are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, alkoxy of from one to four carbon atoms, inclusive, thioalkoxy of from one to four carbon atoms, inclusive, and alkyl of from one to four carbon atoms, inclusive;
R2' and R3' are the same or different and are chosen from the group consisting of hydrogen and alkoxy from one to four carbon atoms, inclusive, with the proviso that when R2' is alkoxy, then R2 = R2' and when R3' is alkoxy then R3 = R3';
R1 is selected from the group consisting of hydrogen; tri-fluoromethyl; -?CH2OR4, where R4 is hydrogen, alkyl of one to four carbon atoms, inclusive, or ?R5, where R5 is alkyl of one to six carbon atoms, inclusive, R6 and R7 are the same or different and are chosen from the group consisting of hydrogen and alkyl of one to three carbon atoms; R10 where R8 and R9 are the same or different and are chosen from the group consisting of alkyl from one to three carbon atoms, inclusive, R10 is alkoxy of from one to three carbon atoms, inclusive, where R11 and R12 are the same or different and are chosen from the group consisting of hydrogen, alkyl of from one to six carbon atoms, inclusive, hydroxyalkyl of from one to six carbon atoms, inclusive, cycloalkyl of from five to seven carbon atoms, inclusive, or taken together with the nitrogen atom to which they are attached, are piperidinyl, pyrrolidinyl, mor-philinyl or piperizinyl; and wherein R6, R11 and R12 are as defined above; which comprises a process selected from the following:
(a) reacting a compound of Formula 2 Formula 2 wherein R2, R3, R2' and R3' are as defined above, with thio-formamide (H CSNH2) to provide a compound of Formula I wherein R1 is hydrogen;
(b) reacting a compound of Formula 2 defined above with tri-fluoroacetamide (CF3CSNH2) to provide a compound of Formula I
wherein R1 is CF3;
(c) reacting a compound of Formula 2 defined above with thio-acetamide (CH3CSNH2) to provide a compound of Formula I wherein methyl is in the R1-position, reacting said Formula I compound with n-butyl lithium and carbon dioxide to provide a corres-ponding compound in which the methyl group is replaced by -CH2CO2Li, and reacting this latter compound with an R- halide where R is alkyl of 1 to 4 carbon atoms to provide a compound of Formula 8 Formula 8 wherein R, R2, R3, R2' and R3' are as defined above, and (1) reacting said Formula 8 compound with an alkylating agent to provide a compound of the Formula 13 Formula 13 wherein R, R2, R3, R2' and R3' are as defined above and R6' and R7' may be the same or different alkyl radicals of 1 to 3 carbon atoms and one of R6' and R7' may be hydrogen; or (2) reacting said Formula 8 compound or Formula 13 compound with a primary or a secondary amine to provide an amide of the Formula 10 Formula 10 wherein R2, R3, R2', R3', R6, R7, R11 and R12 are as defined above; or (3) reacting said Formula 8 compound or Formula 13 compound with an excess of lithium aluminum hydride in an inert solvent to provide an alcohol of the formula II
Formula II
wherein R2, R3, R2', R3', R6 and R7 are as defined above; or (4) reacting said alcohol of Formula II with an acid chloride of the formula R5COC?, wherein R5 is defined above, to provide a compound of Formula I wherein R1 is -?-CH2-?-R5; or (5) reacting a compound of Formula 13 wherein R6'=R8 and R7'-R9 with hydroxide to provide a salt which is then reacted with an R10-halide, wherein R10 is defined above, to provide a compound of Formula I in which R1 is -?-?-R10.
wherein R2 and R3 are the same or different, and are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, alkoxy of from one to four carbon atoms, inclusive, thioalkoxy of from one to four carbon atoms, inclusive, and alkyl of from one to four carbon atoms, inclusive;
R2' and R3' are the same or different and are chosen from the group consisting of hydrogen and alkoxy from one to four carbon atoms, inclusive, with the proviso that when R2' is alkoxy, then R2 = R2' and when R3' is alkoxy then R3 = R3';
R1 is selected from the group consisting of hydrogen; tri-fluoromethyl; -?CH2OR4, where R4 is hydrogen, alkyl of one to four carbon atoms, inclusive, or ?R5, where R5 is alkyl of one to six carbon atoms, inclusive, R6 and R7 are the same or different and are chosen from the group consisting of hydrogen and alkyl of one to three carbon atoms; R10 where R8 and R9 are the same or different and are chosen from the group consisting of alkyl from one to three carbon atoms, inclusive, R10 is alkoxy of from one to three carbon atoms, inclusive, where R11 and R12 are the same or different and are chosen from the group consisting of hydrogen, alkyl of from one to six carbon atoms, inclusive, hydroxyalkyl of from one to six carbon atoms, inclusive, cycloalkyl of from five to seven carbon atoms, inclusive, or taken together with the nitrogen atom to which they are attached, are piperidinyl, pyrrolidinyl, mor-philinyl or piperizinyl; and wherein R6, R11 and R12 are as defined above; which comprises a process selected from the following:
(a) reacting a compound of Formula 2 Formula 2 wherein R2, R3, R2' and R3' are as defined above, with thio-formamide (H CSNH2) to provide a compound of Formula I wherein R1 is hydrogen;
(b) reacting a compound of Formula 2 defined above with tri-fluoroacetamide (CF3CSNH2) to provide a compound of Formula I
wherein R1 is CF3;
(c) reacting a compound of Formula 2 defined above with thio-acetamide (CH3CSNH2) to provide a compound of Formula I wherein methyl is in the R1-position, reacting said Formula I compound with n-butyl lithium and carbon dioxide to provide a corres-ponding compound in which the methyl group is replaced by -CH2CO2Li, and reacting this latter compound with an R- halide where R is alkyl of 1 to 4 carbon atoms to provide a compound of Formula 8 Formula 8 wherein R, R2, R3, R2' and R3' are as defined above, and (1) reacting said Formula 8 compound with an alkylating agent to provide a compound of the Formula 13 Formula 13 wherein R, R2, R3, R2' and R3' are as defined above and R6' and R7' may be the same or different alkyl radicals of 1 to 3 carbon atoms and one of R6' and R7' may be hydrogen; or (2) reacting said Formula 8 compound or Formula 13 compound with a primary or a secondary amine to provide an amide of the Formula 10 Formula 10 wherein R2, R3, R2', R3', R6, R7, R11 and R12 are as defined above; or (3) reacting said Formula 8 compound or Formula 13 compound with an excess of lithium aluminum hydride in an inert solvent to provide an alcohol of the formula II
Formula II
wherein R2, R3, R2', R3', R6 and R7 are as defined above; or (4) reacting said alcohol of Formula II with an acid chloride of the formula R5COC?, wherein R5 is defined above, to provide a compound of Formula I wherein R1 is -?-CH2-?-R5; or (5) reacting a compound of Formula 13 wherein R6'=R8 and R7'-R9 with hydroxide to provide a salt which is then reacted with an R10-halide, wherein R10 is defined above, to provide a compound of Formula I in which R1 is -?-?-R10.
2. A process of claim 1 which comprises reacting a compound of Formula 2 as defined in claim 1 with thioformamide to provide a compound of Formula I wherein R1 is hydrogen.
3. A process of claim 1 which comprises reacting a compound of Formula 2 as defined in claim 1 with trifluoroace-tamide to provide a compound of Formula I wherein R1 is CF3.
4. A process for preparing 2-trifluoromethyl-4,5-bis (p-methoxyphenyl) thiazole which comprises reacting p-methoxy-2-bromo-2(p-methoxyphenyl)acetophenone with trifluorothio-acetamide.
5. A process for preparing 2-trifluoromethyl-4,5-bis (p-chlorophenyl) thiazole which comprises reacting p-chloro-2-bromo-2-(p-chlorophenyl)acetophenone with trifluoromethyl-thioamide.
6. A process for preparing 2-trifluoromethyl-4,5-bis (phenyl) thiazole which comprises reacting 2-bromo-2-phenyl-acetophenone with trifluoromethylthioamide.
7. A process for preparing 4,5-bis-(4-methoxyphenyl)-2-thiazole ethanol which comprises the steps of (1) reacting thioacetamide with p-methoxy-2-bromo-2-(p-methoxyphenyl) acetophenone to provide 2-methyl-4,5-bis(p-methoxyphenyl) thiazole; (2) reacting the product of step (1) with n-butyl lithium and carbon dioxide to provide 4,5-bis(p-methoxyphenyl)-2-thiazoleacetic acid, lithium salt; (3) reacting the product of step (2) with methyl iodide to provide 4,5-bis(p-methoxy-phenyl)-2-thiazoleacetic acid, methyl ester; and (4) reacting said methyl ester with lithium aluminum hydride to provide the desired alcohol.
8. A process for preparing 4,5-bis(p-methoxyphenyl)-.alpha.,.alpha.-dimethyl-2-thiazoleacetic acid, methyl ester which comprises the steps of (1) reacting thioacetamide with p-methoxy-2-bromo-2-(p-methoxyphenyl) acetophenone to provide 2-methyl-4,5-bis(p-methoxyphenyl )thiazole; (2) reacting the product of step (1) with n-butyl lithium and carbon dioxide to provide 4,5-bis (p-methoxyphenyl)-2-thiazoleacetic acid, lithium salt; (3) reacting the product of step (2) with methyl iodide to provide 4,5-bis(p-methoxyphenyl)-2-thiazoleacetic acid, methyl ester;
and (4) reacting said methyl ester with a methylating agent to provide the desired compound.
and (4) reacting said methyl ester with a methylating agent to provide the desired compound.
9. A process for preparing 4,5-bis(p-methoxyphenyl)-2-thiazoleacetamide which comprises the steps of (1) reacting thioacetamide with p-methoxy-2-bromo-2-(p-methoxyphenyl)-acetophenone to provide 2-methyl-4,5-bis(p-methoxyphenyl)thiazole;
(2) reacting the product of step (1) with n-butyl lithium and carbon dioxide to provide 4,5-bis(p-methoxyphenyl)-2-thiazole-acetic acid, lithium salt; (3) reacting the product of step (2) with methyl iodide to provide 4,5-bis(p-methoxyphenyl)-2-thiazole-acetic acid, methyl ester; and (4) reacting said methyl ester with ammonia to provide the desired amide.
(2) reacting the product of step (1) with n-butyl lithium and carbon dioxide to provide 4,5-bis(p-methoxyphenyl)-2-thiazole-acetic acid, lithium salt; (3) reacting the product of step (2) with methyl iodide to provide 4,5-bis(p-methoxyphenyl)-2-thiazole-acetic acid, methyl ester; and (4) reacting said methyl ester with ammonia to provide the desired amide.
10. A compound of Formula I
wherein R1, R2, R3, R2' and R3' are as defined in claim 1, whenever prepared or produced by the process defined in claim 1 or by the obvious chemical equivalent.
wherein R1, R2, R3, R2' and R3' are as defined in claim 1, whenever prepared or produced by the process defined in claim 1 or by the obvious chemical equivalent.
11. 2-Trifluoromethyl-4,5-bis(p-methoxyphenyl)thiazole, whenever prepared or produced by the process defined in claim 4 or by the obvious chemical equivalent.
12. 2-Trifluoromethyl-4,5-bis(p-chlorophenyl)thiazole, whenever prepared or produced by the process defined in claim 5 or by the obvious chemical equivalent.
13. 2-Trifluoromethyl-4,5-bis(phenyl)thiazole, whenever prepared or produced by the process defined in claim 6 or by the ??
obvious chemical equivalent.
obvious chemical equivalent.
14. 4,5-Bis-(4-methoxyPhenyl)-2-thiazole ethanol, whenever prepared or produced by the process defined in claim 7 or by the obvious chemical equivalent.
15. 4,5-Bis(p-methoxyphenyl)-.alpha.,.alpha.-dimethyl-2-thiazole-acetic acid, methyl ester, whenever prepared or produced by the process defined in claim 8 or by the obvious chemical equivalent.
16. 4,5-Bis(p-methoxyphenyl)-2-thiazoleacetamide, whenever prepared or produced by the process defined in claim 9 or by the obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/837,083 US4168315A (en) | 1977-09-28 | 1977-09-28 | Dianisyl thiazole compound, compositions and method of antithrombotic treatment |
| US837,083 | 1977-09-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1103667A true CA1103667A (en) | 1981-06-23 |
Family
ID=25273474
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA309,785A Expired CA1103667A (en) | 1977-09-28 | 1978-08-22 | 4,5-bis-phenyl-thiazole-2-yl derivatives |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4168315A (en) |
| JP (1) | JPS5455566A (en) |
| AU (1) | AU527219B2 (en) |
| BE (1) | BE870851A (en) |
| CA (1) | CA1103667A (en) |
| CH (1) | CH642955A5 (en) |
| DE (1) | DE2836742A1 (en) |
| FR (1) | FR2404634A1 (en) |
| GB (2) | GB2032776B (en) |
| IL (1) | IL55550A (en) |
| IT (1) | IT1107235B (en) |
| NL (1) | NL7809404A (en) |
| ZA (1) | ZA785032B (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4322428A (en) * | 1980-04-02 | 1982-03-30 | Eli Lilly And Company | 2(4-Fluorophenyl)-4,5,-bis(4-methoxyphenyl)thiazole and method of use |
| US4477463A (en) * | 1982-05-10 | 1984-10-16 | E. I. Du Pont De Nemours And Company | Antiinflammatory and/or analgesic 1-alkyl-4,5-diaryl-2-fluoroalkyl-1H-pyrroles |
| US4495202A (en) * | 1983-06-22 | 1985-01-22 | Eli Lilly And Company | Terphenyl derivatives and pharmaceutical uses thereof |
| US4500533A (en) * | 1983-06-22 | 1985-02-19 | Eli Lilly And Company | 2,4,5-Triaryl pyrimidines and a method of treating pain, fever, thrombosis, inflammation and arthritis |
| US4533666A (en) * | 1983-06-22 | 1985-08-06 | Eli Lilly And Company | 6-Phenyl-2,3-bis-(4-methoxyphenyl)-pyridine derivatives having anti-inflammatory activity |
| US4659726A (en) * | 1984-04-19 | 1987-04-21 | Kanebo, Ltd. | Novel 4,5-Bis (4-methoxyphenyl)-2-(pyrrol-2-yl) thiazoles and pharmaceutical composition containing the same |
| US5098918A (en) * | 1985-05-17 | 1992-03-24 | The Upjohn Company | 1,2,3-thiadiazole compounds, compositions and method of anti-thrombotic treatment |
| JPH0753666B2 (en) * | 1987-09-14 | 1995-06-07 | 久光製薬株式会社 | Anti-inflammatory agent consisting of substituted diphenylthiazole derivative |
| US5229386A (en) * | 1989-01-05 | 1993-07-20 | Fujisawa Pharmaceutical Co., Ltd. | Thiazole compounds, processes for the preparation thereof and pharmaceutical composition comprising the same |
| US5217971A (en) * | 1989-01-05 | 1993-06-08 | Fujisawa Pharmaceutical Co., Ltd. | Thiazole compounds and pharmaceutical composition comprising the same |
| US5145860A (en) * | 1989-01-05 | 1992-09-08 | Fujisawa Pharmaceutical Co., Ltd. | Thiazole compounds and pharmaceutical composition comprising the same |
| US5077305A (en) * | 1990-02-13 | 1991-12-31 | Bristol-Myers Squibb Co. | Thiazole carboxylic acids and esters |
| EP0442448A3 (en) | 1990-02-13 | 1992-08-12 | Bristol-Myers Squibb Company | Heterocyclic carboxylic acids and esters |
| AU654125B2 (en) * | 1991-03-07 | 1994-10-27 | Hisamitsu Pharmaceutical Co., Inc. | Novel diphenylthyazole derivative |
| PT626968E (en) * | 1992-02-13 | 2002-03-28 | Merrell Pharma Inc | TIACICLIC PIPERIDINYL DERIVATIVES |
| JPH05229943A (en) * | 1992-02-25 | 1993-09-07 | Kanebo Ltd | Cerebral protecting agent |
| AU3417501A (en) * | 2000-02-29 | 2001-09-12 | Mitsubishi Tokyo Pharm Inc | Novel cyclic amide derivatives |
| JP2022051443A (en) | 2020-09-18 | 2022-03-31 | 富士フイルムビジネスイノベーション株式会社 | Inspection device, image forming apparatus, and inspection program |
| JP2022051444A (en) | 2020-09-18 | 2022-03-31 | 富士フイルムビジネスイノベーション株式会社 | Inspection device, image forming apparatus, and inspection program |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3458526A (en) * | 1966-09-26 | 1969-07-29 | Upjohn Co | Certain 2-amino-4,5-bis(p-methoxyphenyl)thiazoles |
| US3558644A (en) * | 1966-09-26 | 1971-01-26 | Upjohn Co | 2-substituted-4,5-dianisylthiazoles |
| IL28803A (en) * | 1966-11-18 | 1974-05-16 | Wyeth John & Brother Ltd | Oxazole and thiazole compounds,their preparation and pharmaceutical compositions containing them |
| IE32084B1 (en) * | 1967-06-07 | 1973-04-04 | Wyeth John & Brother Ltd | Thiazole derivatives |
| GB1380265A (en) * | 1971-05-18 | 1975-01-08 | Wyeth John & Brother Ltd | Thiazole derivatives |
| US3792170A (en) * | 1972-03-14 | 1974-02-12 | Merck & Co Inc | Novel alkylsulfinyl derivatives for pain,fever and inflammation |
| CH587836A5 (en) * | 1974-01-31 | 1977-05-13 | Serono Lab |
-
1977
- 1977-09-28 US US05/837,083 patent/US4168315A/en not_active Expired - Lifetime
-
1978
- 1978-08-22 CA CA309,785A patent/CA1103667A/en not_active Expired
- 1978-08-22 DE DE19782836742 patent/DE2836742A1/en active Granted
- 1978-09-05 ZA ZA00785032A patent/ZA785032B/en unknown
- 1978-09-06 AU AU39586/78A patent/AU527219B2/en not_active Expired
- 1978-09-11 IL IL55550A patent/IL55550A/en unknown
- 1978-09-15 NL NL7809404A patent/NL7809404A/en not_active Application Discontinuation
- 1978-09-25 GB GB7926680A patent/GB2032776B/en not_active Expired
- 1978-09-25 GB GB7837956A patent/GB2007643B/en not_active Expired
- 1978-09-27 FR FR7827627A patent/FR2404634A1/en active Granted
- 1978-09-27 IT IT51279/78A patent/IT1107235B/en active
- 1978-09-28 JP JP11988178A patent/JPS5455566A/en active Granted
- 1978-09-28 BE BE190783A patent/BE870851A/en not_active IP Right Cessation
- 1978-09-28 CH CH1012278A patent/CH642955A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IT1107235B (en) | 1985-11-25 |
| ZA785032B (en) | 1979-08-29 |
| AU527219B2 (en) | 1983-02-24 |
| DE2836742C2 (en) | 1989-06-01 |
| JPS6323190B2 (en) | 1988-05-16 |
| GB2007643B (en) | 1982-03-03 |
| NL7809404A (en) | 1979-03-30 |
| CH642955A5 (en) | 1984-05-15 |
| FR2404634A1 (en) | 1979-04-27 |
| IL55550A0 (en) | 1978-12-17 |
| BE870851A (en) | 1979-03-28 |
| US4168315A (en) | 1979-09-18 |
| GB2032776B (en) | 1982-06-23 |
| GB2007643A (en) | 1979-05-23 |
| FR2404634B1 (en) | 1982-12-10 |
| IT7851279A0 (en) | 1978-09-27 |
| JPS5455566A (en) | 1979-05-02 |
| AU3958678A (en) | 1980-03-13 |
| DE2836742A1 (en) | 1979-04-05 |
| US4168315B1 (en) | 1985-05-28 |
| GB2032776A (en) | 1980-05-14 |
| IL55550A (en) | 1983-12-30 |
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| MKEX | Expiry |