CA1036600A

CA1036600A - 2-substituted 4,5-diphenylthiazoles and synthesis thereof

Info

Publication number: CA1036600A
Application number: CA218,709A
Authority: CA
Inventors: Enzo Marchetti
Original assignee: Serono Laboratories Inc
Current assignee: Serono Laboratories Inc
Priority date: 1974-01-31
Filing date: 1975-01-27
Publication date: 1978-08-15
Also published as: ZA75494B; AU7747875A; BE825097A; IL46476A0; IL46476A; NO750278L; FR2259603B1; SE7501010L; FR2259603A1; AT339898B; JPS50121269A; CH587836A5; ATA55975A; NL7501086A; GB1490771A; DE2503436A1; ES434151A1; DK33175A

Abstract

Abstract of the Disclosure A new class of substituted thiazole compounds is described of the formula;

Description

1~)366QO :

This invention relates to a series of 4,5-diphenyl-thiazole compounds substituted in the 2-position of the thiaæole ring.
More particularly, this invention relates to -~

2-(substituted)-amino- and -aminoalkyl-4,5-diphenylthiazoles having chemotherapeutic activity.
French Patent No. 1,526,370 discloses 2-(arylamino)-thiazoles which are stated to be useful as photoconductors ¦-for electrophotographic layers.
Substituted thiazol-2-(and 4-)-yl-carboxylic acids and esters are reported to be therapeutically useful as antiinflammatories in South African Patent No. 67 06,327.
British Patent specification Nos. 1,152,627 and 1,284,379 describe antiinflammatory and analgesic 2-(substituted)-amino- and -aminoalkyl-4,5-diphenyloxazoles, respectively.
The new class of substituted thiazole compounds :; .
according to this invention is characterized by the formula: i C6 H5 - C--N Rl 5 \SJ \ 2 (I) wherein Rl and R2 when considered separately are each hydrogen, Cl-C4 alkyl, Cl-C4 hydroxyalkyl, Cl-C4 acyl or acyloxyalkyl having 1 to 4 carbon atoms in the alkyl chain, and R and R when taken together with the nitrogen atom to which they are attached form a heterocyclic amino radical selected from the group consisting of morpholino, piperidino and pyrrolidino; and A represents an alkylene group having 1 to 4 carbon atoms or a single bond.
This invention also provides a process for preparing a 2-substituted-4,5-diphenylthiazole of the formula:

-- 1 -- , ~ , q~ ', ,.
,~. -, ~':
' ~

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~(13660~

6 5~ N ~- :
~c~ ,e~ / R (I) ~ :
6 5 \ R2 wherein: Rl and R2 when considered separately are each hydrogen, Cl-C4 alkyl, Cl-C4 hydroxyalkyl, Cl-C4 acyl or acyloxyalkyl having 1 to 4 carbon atoms in the alkyl chain, and Rl and R2 when taken together with the nitrogen atom to which they are attached form a heterocyclic amino radical selected from the group consisting of morpholino, piperidino, and pyrrolidino; and A represents an alkylene ; .
group having 1 to 4 carbon atoms or a single bond; which method comprises either: ~ .

(a) cYCliZing with P2S5 an x-phenyl-acetophenone derivative of the formula: ::

6 5 Cl - NH - CO - A' - X

wherein A' represents an alkylene group having 1 to 4 carbon atoms; and X represents the group -N~ 2 as defined above or a halogen atom; and, when X represents ;:
a halogen atom, reacting the resulting cyclized product with an amine of the formula: Rl :

HN (III) wherein Rl and R2 are as defined above; or (b) reacting a 2-halo-4,5-diphenylthiazole with an amine of the formula: Rl HN ~ (III) , ~0366~)0 wherein Rl and R are as defined above; and when a pharma- ;
ceutically acceptable salt is required, reacting the resulting compound with a corresponding acid.
The cyclization process is monostep and uses readily available starting materials. In addition, the -~
cyclization with P2S5 is straightforward and directly leads to a high yield of the desired product. The cyclization reaction is carried out by heating the intimately mixed reagents, decomposing the excess P2S5 with water or alcohol, extracting with a water of alcohol immiscible solvent and evaporating the solvent. A slight molar excess of P2S5 ~
is preferably used. The cyclization reaction using P2S
initiates spontaneously and is exothermic. In order to avoid low yields and pitch formation, the reaction mixture is preferably quenched as soon as the reaction starts. Further operational particulars will become apparent from the description below.
The compounds of formula (I) above exhibit pharma-cological activity as shown by tests on laboratory animals.
In particular, the compounds of this invention are characterized by a strong inhibitory action on platelet aggregation, ~ '. . '. . .
often associated with a significant hypocholesterolemic ;
activity.
Antiinflammatory and analgesic activities are either low or completely absent.
Illustrative examples of the alkylene groups represented by A in the above formula (I) are: methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene and so on.
Illustrative examples of the alkyl or hydroxyalkyl radicals represented by Rl and R when considered separately are: methyl, ethyl, propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl and the like.
The reaction method (b) indicated above can be carried out in the presence or absence of an inert solvent. Reaction times and temperatures are not critical.
The reaction products are recovered by diluting the reaction mixture with water to precipitate the product, extracting with a water immiscible solvent and removing the solvent, preferably under reduced pressure.
The compounds of formula (II) above which are used in the process of this invention as starting materials for the synthesis of compounds (I) through cyclization with P2S5 are conventionally prepared by reacting desylamine with an acyl halide of the formula:
Hal - C0 - A' - X (IV) wherein A' and X are as previously defined and Hal re-presents a halogen atom.
As noted above, the compounds of formula (I) where-in A represents a single bond can be prepared by reacting an amine of form~la (III) with a 2-halo-4,5-diphenyl-thiazole, for example, 2-chloro-4,5-diphenylthiazole, 2-bromo-4,5-diphenylthiazole, and so on.
This reaction i8 conventional in organic chemistry and consists in heating the reagents for several hours, at atmospheric pressure or under pressure in a sealed tube, in the presence or in the absence of an organic solvent. An organic base, for example a tertiary amine, may be present as an acceptor of the hydrogen chloride which forms in the reaction.
Esters, diesters and ester-amides of the com-pounds of formula (I) can be obtained by means of con-ventional procedures. In general, acylation of compounds ~,~,,~
- : .

~ - `
1()36600 of formula (I) is carried out using the appropriate acid halide or anhydride. Acylated derivatives of compounds of formula (I) are to be considered within the scope of the present invention.
Addition salts of the compounds of this invention are also comprised in the scope thereof. Of course, pharmaceutically acceptable salts are preferred for therapeutical purposes.
The following Examples are provided for the pur-pose of illustration only and are not to be construedas limitations of this invention.
The compound 2-chloro-4,5-diphenylthiazole which is used as the starting material in several Examples herein has been prepared in accordance with Acta Chem.
Scand. 7 (2)~, 374-6 (1953) by first reacting desyl -chloride with potassium sulfocyanate to obtain desyl sulfocyanate which is then cyclized to 2-hydroxy-4,5- -~
diphenylthiazole by means of H2S04 in glacial acetic acid. The obtained thiazole is treated with POC13 to give pure 2-chloro-4,5-diphenylthiazole after crystal-lization from 50% acetone.

.~ .. . . . .

~036600 .

EXAMPI,E 1 .... .
5.4 g. 2-chloro-4,5-diphenylthiazole and 17.4 g. morpholine were refluxed for 8 hours, whereupon the reaction mixture was cooled and diluted with water to precipitate 2-morpholino-4,5-diphenyl-thiazole.
The precipitate was recovered and purified by crystallization from ethanol. Yield = 4.95 g. (~7%). Melting point = 116-118C.
Analysis. Calc. for C19H180N2S : C = 70.78%; H = 5.62%
Found : C = 70.46~; H = 5.53/0 2.71 g. 2-chloro-4,5-diphenylthiazolej 10.5 g. diethanolamine and 0. 5 g. powdered copper were heated to 16~1 70C for 8 hours on an oil bath.
After cooling, the reaction product was precipitated with water and extracted with ether. The ethereal layer was dried over Na2S04 and evaporated to dryness. The oily residue was converted to a crystalline mass through addition of petroleum ether, and then recrystallized 20 from an ethanol-ether-petroleum ether mixture.
2.5 g. 2-bis (2-hydroxyethyl)amino-4,5-diphenylthiazole (73.5,~) melting at 112-113C were thus obtained.
Analysis . Calc. for C19H2002N2S : C = 67.03,~; H = 5. 92%
Found : C = 67.11%; H = 5.69%

10.8 g. 2-chloro-4,5-diphenylthiazole were added to a solution of _ 6 _ - . . ~ ~ - . .~;, 1036t;00 25 g, methylamine ~n 200 ml~ benzene and heated to 120-130C for 8 hours in a sealed vessel.
~After cooling, the reaction mixture was washed with water in a separatory funnel, the benzene layer was recovered, decolorized wlth charcoal, dried over Na2SO4 and evaporated to dryness to give a residue which was crystallized by means of the addition of petroleum ether.
The thus obtained 2-methylamino-4,5-diph~nylthiazole was recrystallized from an ethanol-ether-petroleum ether mixture to give 4.1 g. (38,7%) pure product me~ting at 177-178C.
Analysis- Calc- for C16H14N2S : C = 72.14~; H = 5.29~
Found : C - 72.38%; H = 5.09% ~ -10-.8 g. 2-chloro-4,5-diphenylthiazole, 24 g. ethanol-amine and 1 g. powdered copper were heated to 120-130C on an oil bath and kept at this temperature for 5 hours. ~ -After cooling, the raction product was precipitated with water and extracted with ether. The ethereal layer was `"t~, dried over Na2SO4 and evaporated to dryness. The residue was crystallized from an ethanol-ether-petroleum ether mixture to giVe 2-(2-hydroxyethyl)amlno-4,5-diphenylthiazole. Yield = 45%.
Melting point = 113-115C.
Analysis. Calc. for C17H16ON2S : C = 68.89%; H = 5.44%
Found : C = 68.60%; H = 5.16%

2.9 g. 2-(2-hydroxyethyl)amino-4,5-diphenylthiazole and 10 ml. acetic anhydride were refluxed for 6 hours. The excess reagents were distilled off and the oily residue was suspended in petroleum ether to give a crystalline mass which was recrystallized from an ethanol-.

'; ,., ~ .

. ~, . .. . .. ..... .

-~ther-petroleum ether mixture. Yield = 2 gr. (52.6%). Melting ~ ~
point = 106-108C. ;
The analysis confirmed that the di-acetylated derivative of the starting compound had been obtained, that is, 2- tN-acetyl-N-(2--aceto.Yy)ethyl] amino-4,5-diphenylthiazole.
Analysis. Calc. ~or C21H2003N2S : C = 66. 29%; H = 5.3~/0 Found : C = 66.07%; H = 5. 28%
` EXAMPLE 6 The procedure described in Example 5 above was repeated to prepare 2-(N-methyl-N-acetyl)amlno-4,5-diphenylthiazole starting with 2--methylamino-4,5-diphenylthiazole and acetic anhydride.
The obtained monoacetylated derivative melted at 148-i50C.
Analysis. Calc. ~or C18H160N2S : C = 70.1 ~/0; H = 5. 23%
Found : C = 69 ~ 88%; H = 5.52/u 8.13 g. 2-chloro-4,5-diphenylthiazole ~ere added to a solution of 22 g. diethylamine in 100 ml. benzene and heated to 120C for 6 hours in a sealed vessel.
A~ter cooling, the reaction mixture was washed with water in a se-paratory ~unnel, the benzene layer was recovered, dried over Na2S04 and evaporated to dryness to give a residue which was dissolved in 100 ml. petroleum ether.
The solution was decolorized with charcoal and cooled to give 6 g.
(65%) crystalline 2-diethylamino-4,5-diphenylthiazole melting at 115-116C after recrystallization from an ethanol-ether-petroleum e~her mixture.
Analysis. Calc. for C19H20N2S : C = 73.98%; H = 6.53%
Found : C = 73.74~ H = 6.22%

. .. . ~ ~.
.

EYAMPI,~ 8 The procedure described in Example 7 a~ove was repeated to pre-pare 2-isopropylamino- 4,5-diphenylthiazole starting with 2-chloro-4,5-diphenylthiazole and isopropylamine, except that the reagents were kept in a sealed vessel for 10 hours at 1 00C.
The obtained product melted at 116-11 8C after recrystalli7,ation from aqueous ethanol.

Analysis. Calc. for C18H18N2S.H20 : C = 69.65~; H = 6.49~
Found : C = 69.90/~; H = 5.17%
EYAMPI,E 9 5.4 g. 2-chloro-4,5-diphenylthiazole and 14.2 g. pyrrolidine were refluxed for 8 hours, whereupon the reaction mixture was cooled and diluted with water to precipitate 2-pyrrolidino-4,5-diphenyl-thiazole.
The precipitate was recovered and purified by crystallization from aqueous ethanol. Yield = 4.9 g. (8a/O). Melting point = 116-117C.
Analysis. Calc. for C19H18N2S : C = 74.47/~; H = 5.92%

20Found : C = 74.21%; H = 5.70~/0 EXAMPI,E 1 0 a) o~-phenyl-~ -chloroacetamido-acetoPhenone 9.9 g. desylamine hydrochloride and 3.7 ml. chloroacetylchloride in 100 ml. anhydrous benzene were reflu~ced for 4 hours in a 250 -~
ml. flask.
After filtering, the filtrate was evaporated to dryness to give 10.5 g. (88.4~ -phenyl-o~-chloroacetamido-acetophenone melting at 117-119C after recrystallization from aqueous ethanol.
30 Analysis: Calc. for C1 6H1402N Cl : C - 66.78%; H = 4~90O/o Found : C = 66.32%; ~ = 4.79%
b) d~-phenyl-~-morpholinoacetamido-ace~ophenone.

_ - , ~ : . . .

` ~036600 ,~.4 g. ~ -phenyl-~ -chloroacetamido-acetophenone and 21. 7 g. morpho-line were reflu~ed for 4 hours, whereupon the reaction mi~ture was cooled and diluted with water to obtain a precipitate which was extract-ted with ether.
The ethereal layer was evaporated to dryness and the residue was re-dissolved in 70~ ethanol. After cooling to about 0C and maintaining at this temperature for about 48 hours, cr~stalline ~-phenyl~-morpho-linoacetamido-acetophenone was obtained. Yield = 13.2 g. (78~ 2~) Lo Melting point = 116-118C after recrystallization ~rom aqueous ethanol.
Analysis: Calc. for C20~H2203N2 : C = 70~98%; H = 6.55%
Found : C - 7 0~ 81 %; H = 6.65%
c) 2-morpholinomethyl-4,5-diphenylthiazole hydrochloride.
10 g. ~ -phenyl- ~-morpholinoacetamido-acetophenone were intimately mixed with 6.66 g.P2S5 , the mixture was gradually heated to 150-170C
on an oii bath and maintained at this temperature for 1 hour. After cooling, the residue was triturated in the presence of water to comple-tely decompose non-reacted phosphorous pentasulfide. The mixture was ,, then made alkaline with 2~/o NaOH and extracted with ether. The ethereal layer was dried over Na2S04, decolorized with charcoal, filtered and evaporated until dry. The residue was dissolved in ethanol and conver-ted to the hydrochloride by means of addition of ethanolic HCl. Preci-pitation of 2-morpholinomethyl-4,5-diphenylthiazole hydrochloride was ' brought to completion by adding anhydrous ether and cooling 4.5 g. (40.4%) product ~ere recovered melting at 238-242C (dec.)after recrystallizatinn from anhydrous ethanol.
30 Analysis. Calc. ~or C20H210N2ClS : C = 64.41%; H = 5.67~
Found : C - 64.29%; H = 5.77%
:. . .

: . , .

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~0366~)0 The procedure described in Example lO (b) above was repeated to prepare the following compounds starting with O<-phenyl-~-chloro-acetamido-acetophenone and the appropriate amine:
phenyl- ~-pyrrolidinoacetamido-acetophenone, m.p. 142-143C
2) ~ -phenyl-~'-piperidinoacetamido-acetop'nenone, m.p. 107-109C

3) G~-phenyl-~ -dimethylaminoacetamido-acetophenone, m.p. 119-1 20C

4) ~-phenyl-C~-isopropylaminoacetamido-acetophenone, m.p, 111-113C
When compounds 3 and 4 were prepared, the reaction was carried out lo at room temperature using benzene as the reaction medium.
,.
, ' ' ~he procedure described in Example 10 (c) above was repeated to pre- ~-;
pare the Pollowing compounds starting ~rom the appropriate ~ -phenyl-- ~-aminoacetamido-acetophenone. ;
1) 2-pyrrolidinomethyl-4,5-diphenylthiazole hydrochloride, m;p. 242-243C. ~
2) 2-piperidinomethyl-4,5-diphenylthiazole hydrochloride, m.p.230-235C ~ -3) 2-isopropylaminomethyl-4,5-diphenylthiazole hydrochloride, m.p.
210-212C.
4) ~-methylaminomethyl-4,5-diphenylthiazole hydrochloride, m.p. 122 124C.
Acute toxicity was determined in rats both by oral and i.p. admini-stration aEter a fasting period o~ 16 hours~ All o~ the test compounds were ~ound to be non-toYic up to the doses o~ 300 mg/kg p.o~ and 100 mg/kg i.p., respectively.
--. 11 -- .

EX~MPLE 13 - a) 2-chloromethyl-4,5-diphenylth;azole 14.4 g a-phenyl-~-chloroacetamido-acetophenone were intimately mixed with 11 g. P2S5, the mixture was heated to 150-170C on an oil bath and maintained at this temperature ~or 1 hour. A~ter cooling, the solid residue was triturated in the presence of a mixture 1:1 (w/w) of water and ethanol in order to completely decompose the non-reacted phosphor~us pentasulfide. The mixture was further diluted with water, then made alkaline with 20% NaOH
and extracted with ether.
The ethereal layer was dried over Na2S04, decolorized with charcoal, filtered and evaporated until dry under vacuum to give 6 g. (42% yield) of crude 2-chloromethyl-4,5-diphenylthiazole.
Melting point = 46-48C, after recrystallization from an ether-petroleum ether mixture.
b) 2-morpholinomethyl-4,5-diphenylthiazole , 6 g 2-chloromethyl-4,5-diphenylthiazole and 9.14 g morpholine were refluxed for 4 hours, whereupon the reaction mixture was cooled and diluted with water.
The oil which separated was extracted with ether and the ethereal layer was dried over Na2S04 and evaporated to dryness under high vacuum, The oily residue was redissolved in the minimum amount of abso-lute ethanol, made acid by means of 3~/0 ethanolic HCl and cry-stallized through addition of anhydrous ether.
6.65 g crystalline 2-morpholinomethyl-4,5-diphenylthiazole ~ .
: ' ' .

,. . . - . . ~ .

~ 036600 hydrochloride (a5% yield) were recovered by iltration.
Melting point and analysis were strictly in accord~nce with those indicated in example 10(c).
ExampleslO and 13 above show that identical products of formula (I') can be prepared through two alternative routes, that is, (a)cyclization o~ a compound o~ ~ormula (II) wherein X represents the radical to directly give a compound of formula (I'), and (b) cyclization of a compound o~ formula (II) whe-ein X represents a halogen atom and subsequent reaction of the obtained compound of formula (I") with an amine of ~ormula (III). -~
',' ' ' . ' ' ' Inhibitory activity on platelet aggregation was determined in vitro : on platelet-rich rabbit plasma prepared by collecting the blood ,;; :
in a plastic centrifuge tube containing enough 3,8% sodium citrate to give a concentration of 0.38 g/100 ml. when mixed with the blood, and then centrifuging at 100 ~ for 20 minutes.
1 ml. aliquots of the thus prepared plasma were placed in a Platelet ~ Aggregation Meter connected to a potentiometric recorder and tested -~ according to Born, Nature (London),194,927 (1962).Plasma-test compound mixtures were incubated for 10 min. at 37C before adding ~ ' .. ' ". ' ' .

the aggregating agents (ADP~ collagen), C~rves were read following the method described by O'Brien et al,, Thromb, Diath, ~aemorrhag. 16, 751 (1966). Slope and ~aximum transmission were recorded and expressed as % change with respect to controls, In the case of collagen induced platelet aggregation, the delay time ("reaction time") in seconds from the addition of the aggregating agent to the inflection of the curve was also measured and expressed as ~ change as above.
For comparison purposes, such known anti-aggregating 10 agents as acetylsalicylic acid and adenosine were also tested in the same conditions as the test compounds.
The results are shown in the following Tables. Negative - figures in slope and maximum transmission % changes indicate anti-aggregating activity; positive figures in delay time %
changes indicate that the compound is effective in prolonging the "reaction time" in the collagen induced platelet aggregation test.

ADP (5 ~g/ml) INDUCED PLATELET AGGREGATION

- 20 Compound Concentration Max.transmission Slope, ~of Example ~g/ml. ~ change % change . . ~
2 100 - 11.7 - 1.95 2 200 - 40.3 ~40.5 10 (c) 100 - 8,71 - 4.55 10 (c) 200 - 12.8 -10,0 1 100 - 12.5 -11.8 1 200 - 33.2 -31.8 ; Adenosine 100 - 72.3 -52.5 - - _ .
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lQ366(~0 TABLE 2 -~
, . . . .
COLL~GEN (40 ~g/ml,) INDUCED PLATELET ~GGREGATION

Concentra- Delay time Compound tion Max.transmis- Slope, ~'ireaction of Example ~g/ml sion, % change ~change time") - - - ' - - - - % change 2 5 - 82.4 - 92.2 +136.6 2 2.5 - 76.3 - 89.3 +108.2 2 1.25 - 84~3 - 97.7 +119.5 -10 (c) 5 - 84.7 - 93.8 + 29.8 10 (c) 2,5 - 63.0 - 80.4 - 7.14 10 (c) 1.25 - 24.9 - 23.6 + 51.6 ; -~
1 5 - 62.2 - 77.7 +118.5 1 2.5 - 60.8 - 74.9 + 85.0 ' 1 1.25 - 24.1 - 38.8 + 16.2 AceitylsalicYlic 5 - 61.6 - 74.2 - 49.0 " 2.5 - 41.9 - 52.0 + 15.5 " 1.25 + 6.70 + 10.6 + 7.3 Hypocholesterolemic activity was tested on hyperchol-esterolemic rats that had received the indicated daily doses of the test compounds for two days. Cholesterol was then assayed in ^
the blood and compared to controls. The compound of Bxample 10 (c) administered p.os at the dose of 200 mg/kg caused 17% decrease of the cholesterol amount with respect to controls. At the same dose p.os as above, the compound of Example 2 caused 22% decrease.
Antiinflammatory activity was tested plethysmometrically by measuring the rat-paw edema volume induced by brewer's yeast in rats to which the test compounds had been administered p.os 1 hour before the injection of the edema inducing agent. No sig-nificant reduction o~ edema volume was found in treated animals (100 mg/kg~ p.os) when compared with controls. ~
~ .., - 15 - ~ `

. . : .

-` ~036600 Analgesic activity was testecl by the hot-plate method.
An analgesic e~ect was not ~emonstrated hy any o~ the test com-pounds when administered p. os at the dose of 100-200 mg/kg.
The preferred way o~ administration o~ the compounds o~ this in-vention is per os. The following Example shows a typical prepa-ration of capsules.
EX~PLE 14 A blend is prepared containing the ~ollowing proportions o~ exci-pients expressed in parts by weight:

glycocoll 2.5 lactose 5 talc 2.5 magnesium stearate The above blend is mixed with suf~icient amounts o~ the compounds of Examples 1,2 and 10 (c) to give capsules containing 25,100 and 200 mg. of each o~ the active ingredients and ~illed into gelatin capsules for oral administration.

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Claims

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

1. A process for preparing a 2-substituted-4,5-diphenylthiazole of the formula:
(I) wherein: R1 and R2 when considered separately are each hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 acyl or acyloxyalkyl having 1 to 4 carbon atoms in the alkyl chain, and R1 and R2 when taken together with the nitrogen atom to which they are attached form a hetero-cyclic amino radical selected from the group consisting of morpholino, piperidino, and pyrrolidino; and A re-presents an alkylene group having 1 to 4 carbon atoms or a single bond; which method comprises either:
(a) cyclizing with P2S5 an x-phenyl-acetophenone derivative of the formula:
(II) wherein A' represents an alkylene group having 1 to 4 carbon atoms; and X represents the group as defined above or a halogen atom; and, when X represents a halogen atom, reacting the resulting cyclized product with an amine of the formula:
(III) wherein R1 and R2 are as defined above; or (b) reacting a 2-halo-4,5-diphenylthiazole with an amine of the formula:
(III) wherein R1 and R2 are as defined above; and when a pharmaceutically acceptable salt is required, reacting the resulting compound with a corresponding acid.

2. The process of claim 1(b) wherein the amine of formula (III) is reacted with 2-chloro-4,5-diphenyl-thiazole.

3. A process according to claim 1(a) in which, when at least one of R1 and R2 is hydrogen or hydroxyalkyl, the obtained product is further reacted with an acylating agent to give a compound of formula (I) in which at least one of R1 and R2 is acyl or acyloxyalkyl, respectively.

4. A process according to claim 1(b) for producing 2-morpholino-4,5-diphenylthiazole which comprises reacting 2-chloro-4,5-diphenylthiazole with morpholine.

5. A process according to claim 1(b) for producing 2-bis(2-hydroxyethyl)amino-4,5-diphenylthiazole which comprises reacting 2-chloro-4,5-diphenylthiazole with diethanolamine.

6. A process according to claim 1(b) for producing 2-methylamino-4,5-diphenylthiazole which comprises reacting 2-chloro-4,5-diphenylthiazole with methylamine.

7. A process according to claim 1(b) for producing 2-(2-hydroxyethyl)amino-4,5-diphenylthiazole which comprises reacting 2-chloro-4,5-diphenylthiazole with ethanolamine.

8. A process according to claim 3 for producing 2-[N-acetyl-N-(2-acetoxy)ethyl]amino-4,5-diphenylthiazole which comprises reacting 2-(2-hydroxyethyl)amino-4,5-diphenylthiazole produced according to claim 7 with acetic anhydride.

9. A process according to claim 3 for producing 2-(N-methyl-N-acetyl)amino-4,5-diphenylthiazole which comprises reacting 2-methylamino-4,5-diphenylthiazole produced according to claim 6 with acetic anhydride.

10. A process according to claim 1(b) for producing 2-diethylamino-4,5-diphenylthiazole which comprises reacting 2-chloro-4,5-diphenylthiazole with diethylamine.

11. A process according to claim 1(b) for producing 2-isopropylamino-4,5-diphenylthiazole which comprises reacting 2-chloro-4,5-diphenylthiazole with isopropylamine.

12. A process according to claim 1(b) for producing 2-pyrrolidino-4,5-diphenylthiazole which comprises reacting 2-chloro-4,5-diphenylthiazole with pyrrolidine.

13. A process according to claim 1(a) for producing 2-morpholinomethyl-4,5-diphenylthiazole or the hydro-chloride thereof, which comprises cyclizing alpha-phenyl-alpha-morpholinoacetamidoacetophenone with P2S5 and, when the hydrochloride is required, reacting the free base with hydrochloric acid.

14. A process according to claim 1(a) for producing 2-pyrrolidinomethyl-4,5-diphenylthiazole or the hydro-chloride thereof, which comprises cyclizing alpha-phenyl-alpha-pyrrolidinoacetamidoacetophenone with P2S5 and, when the hydrochloride is required, reacting the free base with hydrochloric acid.

15. A process according to claim 1(a) for producing 2-piperidinomethyl-4,5-diphenylthiazole or the hydro-chloride thereof, which comprises cyclizing alpha-phenyl-alpha-piperidinoacetamidoacetophenone with P2S5 and, when the hydrochloride is required, reacting the free base with hydrochloric acid.

16. A process according to claim 1(a) for producing 2-isopropylaminomethyl-4,5-diphenylthiazole or the hydrochloride thereof, which comprises cyclizing alpha-phenyl-alpha-isopropylaminoacetamidoacetophenone with P2S5 and, when the hydrochloride is required, reacting the free base with hydrochloric acid.

17. A process according to claim 1(a) for producing 2-methylaminomethyl-4,5-diphenylthiazole or the hydro-chloride thereof, which comprises cyclizing alpha-phenyl-alpha-methylaminoacetamidoacetophenone with P2S5 and, when the hydrochloride is required, reacting the free base with hydrochloric acid.

18. 2-Substituted-4,5-diphenylthiazole compounds of the formula:

(I) wherein: R1 and R3 when considered separately are each hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 acyl or acyloxyalkyl having 1 to 4 carbon atoms in the alkyl chain, and R1 and R2 when taken together with the nitrogen atom to which they are attached form a heterocyclic amino radical selected from the group consisting of morpholino, piperidino, and pyrrolidino; and A represents an alkylene group having 1 to 4 carbon atoms or a single bond; or the pharmaceutically acceptable salts thereof, whenever prepared by a process of claim 1 or by an obvious chemical equivalent.

19. 2-Morpholino-4,5-diphenylthiazole when produced by the process of claim 4 or an obvious chemical equivalent thereof.

20. 2-Bis(2-hydroxyethyl)amino-4,5-diphenylthiazole when produced by the process of claim 5 or an obvious chemical equivalent thereof.

21. 2-Methylamino-4,5-diphenylthiazole when produced by the process of claim 6 or an obvious chemical equi-valent thereof.

22. 2-(2-Hydroxyethyl)amino-4,5-diphenylthiazole when produced by the process of claim 7 or an obvious chemical equivalent thereof.

23. 2-[N-acetyl-N-(2-acetoxy)ethyl]amino-4,5-di-phenylthiazole when produced by the process of claim 8 or an obvious chemical equivalent thereof.

24. 2-(N-methyl-N-acetyl)amino-4,5-diphenylthiazole when produced by the process of claim 9 or an obvious chemical equivalent thereof.

25. 2-Diethylamino-4,5-diphenylthiazole when produced by the process of claim 10 or an obvious chemical equivalent thereof.

26. 2-Isopropylamino-4,5-diphenylthiazole when produced by the process of claim 11 or an obvious chemical equivalent thereof.

27. 2-Pyrrolidino-4,5-diphenylthiazole when produced by the process of claim 12 or an obvious chemical equivalent thereof.

28. 2-Morpholinomethyl-4,5-diphenylthiazole, or the hydrochloride thereof,when produced by the process of claim 13 or an obvious chemical equivalent thereof.

29. 2-Pyrrolidinomethyl-4,5-diphenylthiazole, or the hydrochloride thereof when produced by the process of claim 14 or an obvious chemical equivalent thereof.

30. 2-Piperidinomethyl-4,5-diphenylthiazole, or the hydrochloride thereof, when produced by the process of claim 15 or an obvious chemical equivalent thereof.

31. 2-Isopropylaminomethyl-4,5-diphenylthiazole, or the hydrochloride thereof, when produced by the process of claim 16 or an obvious chemical equivalent thereof.

32. 2-Methylaminomethyl-4,5-diphenylthiazole, or the hydrochloride thereof, when produced by the process of claim 17 or an obvious chemical equivalent thereof.