NO750278L - - Google Patents

Description

The present invention relates to a method for the production of 4,5-diphenylthiazole compounds which are substituted in the 2-position of the thiazole ring.

More particularly, the invention concerns the production of 2-(substituted)-amino- and -aminoalkyl-4,5-diphenylthiazoles with chemotherapeutic activity, as well as starting materials for this.

French Patent No. 1,526,370 relates to 2-(arylamino)-thiazoles which are stated to be useful as photoconductors for electrophotographic layers. '

Substituted thiazol-2-(and 4-)-yl carboxylic acids and esters thereof are indicated to be therapeutically useful as anti-inflammatory agents in South African Patent No. 67 06,327. British Patent Nos. 1,152,627 and 1,284,379 describe respectively anti-inflammatory and analgesic 2-(substituted)-amino- and -aminoalkyl-4,5-diphenyloxazoles.

The new group of substituted thiazole compounds produced according to the invention is characterized by the formula: where X is halogen or the group:

where R and R taken separately are hydrogen, C-3 - C4-alkyl, C-3-

C4-hydroxyalkyl, C^-C^-acyl or acyloxyalkyl with 1-4 carbon atoms in the alkyl chain, and R"1" and R<2> together with the nitrogen atom can

to which they are attached, form a heterocyclic amino group with 5 to 6 ring members; and A is an alkylene group or a single bond, but A cannot be a single bond when X is halogen. This invention also relates to a new process which is characterized by the fact that an a-phenylacetophenone derivative with the formula:

where A and X are as stated above, ring is closed with ?2^3nwhere a compound with the formula (I) is obtained. The procedure is one-step and uses readily available starting materials. Moreover, the cyclization with P2S5 is straightforward and leads directly to a high yield of the desired product. The cyclization reaction is carried out by heating the intimately mixed reagents, cleaving the excess of P2^5 with water or alcohol, extracting with a solvent immiscible with water or alcohol and evaporating the solvent. A small molar excess of ^ 2^ 5 anVen(3es preferably.

The cyclization reaction using ?2S5ke9 occurs spontaneously and is hexothermic. To avoid low yields and pitch formation, the reaction mixture is preferably quenched as soon as the reaction begins. Further details of the method will appear from the examples given below.

From a functional point of view, the new compounds of formula (I) can be divided into two broad groups represented by the following general formulas:

In the formulas (I<1>) and (I"), A, R 1 and R 2 are as indicated above, and Hal denotes halogen. The compounds of formula (I<1>) exhibit pharmacological activity as shown by experiments on laboratory animals In particular, the compounds produced according to the invention are characterized by a strong inhibitory effect on platelet aggregation, often associated with a considerable hypocholesterolemic activity.

Anti-inflammatory and analogetic activity is either

low or completely absent.

It is therefore an aim of the present invention to provide a method for the production of a new group of therapeutically useful thiazolamines characterized by formula (I<1>).

Illustrative examples of the alkylene groups represented by A in the above formula (I<1>) are: methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, etc.

Illustrative examples of the alkyl or hydroxyalkyl groups represented by R and R taken separately are: methyl, ethyl, :propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl and the like. Illustrative examples of the heterocyclic amino groups 12-

represented by R and R together with the nitrogen atom to which they are attached are: morpholino, pyrrolidino, piperidino, piperazino and the like.

The compounds of the general formula (I") are useful, for example, as starting materials with an alternative synthesis of the compounds of the general formula (I') which is carried out by reacting a compound of the formula (I") with an amine of the formula:

where R 1 and R 2 are as indicated above.

The reaction can be carried out without a solvent or in 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), which are used in the present process as starting materials for the preparation of compounds of formula (I) by ring closure with P2S5', are conveniently prepared by reacting decylamine with an acyl halide of the formula:

Hal - CO - A - X (IV)

where A and X are as above, and Hal is halogen.

The compounds of formula (I) where A is a single bond can also be prepared by reacting an amine of formula (III) with a 2-halo-4,5-diphenylthiazole, e.g. 2-chloro-4,5-diphenylthiazole, 2-bromo-4,5-diphenylthiazole, etc.

This reaction is conventional in organic chemistry and consists in heating the reagents for several hours at atmospheric pressure or negative pressure in a sealed tube, in the presence or absence of an organic solvent. An organic base, e.g. a tertiary amine may be present as an acceptor for the hydrogen chloride formed in the reaction.

Esters, diesters and ester-amides of the compounds of formula (I<1>) can be obtained by conventional methods. In general, the acylation of compounds of formula (I') is carried out using the appropriate acid halide or acid anhydride. Acylated derivatives of compounds of formula (I<1>) come within the scope of the invention.

Addition salts of the compounds produced according to the invention are also included. Of course, pharmaceutically acceptable salts are preferred for therapeutic applications.

The following examples are given to further illustrate the invention.

The compound 2-chloro-4,5-diphenylthiazole, which is used as the starting material in several examples, has been prepared according to Acta Chem. Scand. 7(2), 374-6 (1953) by first reacting decyl chloride with potassium sulphocyanate to obtain decyl sulphocyanate which is then ring-closed to 2-hydroxy-4,5-diphenylthiazole using sulfuric acid in glacial acetic acid. The thiazole obtained is treated with phosphorus oxychloride to obtain pure 2-chloro-4,5-diphenylthiazole after crystallization from 50% acetone.

Example 1

5.4 g of 2-chloro-4,5-diphenylthiazole and 17.4 g of morpholine were refluxed for 8 hours, after which the reaction mixture was cooled and diluted with water to precipitate 2-morpholino-4,5-diphenylthiazole.

The precipitate was recovered and purified by crystallization from ethanol. The yield was 4.95 g (77%). The melting point was 116 - 118° C.

Analysis calculated, for C-^I^gOi^S: C = 70.28%; H = 5.62%

Found: C = 70.46%; H = 5.53%

Example 2

2.71 g of 2-chloro-4,5-diphenylthiazole, 10.5 g of diethanolamine and 0.5 g of powdered copper were heated to 160-170° C. for 8 hours in an oil bath.

After cooling, the reaction product was precipitated with water and extracted with ether. The ether layer was dried over sodium sulfate and evaporated to dryness. The oily residue was converted into a crystalline mass by the addition of petroleum ether, and was then recrystallized from an ethanol-ether-petroleum ether mixture.

"You got 2.5 g of 2-bis-(2-hydroxyethyl)-amino-4,5-diphenylthiazole (73.5%) which melted at 112 - 113°C.

Analysis: Calculated for<C>19<H>20<O>2N2S: C = 67.03%} H = 5.92%

Found: C = 67.11%; H 5.69%

Example 3

10.8 g of 2-chloro-4,5-diphenylthiazole was added to a solution of 25 g of methylamine in 200 ml of benzene and heated to 120-130° C. for 8 hours in a closed vessel.

After cooling, the reaction mixture was washed with water in a separatory funnel, the benzene layer was isolated, decolorized with charcoal, dried over sodium sulfate and evaporated to dryness giving a residue which was crystallized by adding petroleum ether.

The thus obtained 2-methylamino-4,5-diphenylthiazole was recrystallized from an ethanol-ether-petroleum ether mixture whereby 4.1 g (38.7%) of pure product was obtained which melted at 177 - 178°C.

analysis: Calculated for Cl6H14N2S: C = 72.14%; H = 5.29%

Found: C = 72.38%; H = 5.09%

Example 4

10.8 g of 2-chloro-4,5-diphenylthiazole, 24 g of ethanolamine and 1 g of powdered copper were heated to 120 - 130° C in an oil bath and held at this temperature for 5 hours.

After cooling, the reaction product was precipitated with water and extracted with ether. The ether layer was dried over sodium sulfate and evaporated to dryness. The residue was crystallized from an ethanol-ether-petroleum ether mixture whereby 2-(2-hydroxyethyl)-amino-4,5-diphenylthiazole was obtained. Yield = 45% with melting point 113 - 115° C.

Analysis: Calculated for C^H^O^S: C = 68.89%; H = 5.44%

Found: C = 68.60%j H = 5.16%

Example 5

2.9 g of 2-(2-hydroxyethyl)-amino-4,5-diphenylthiazole and 10 ml of acetic anhydride were refluxed for 6 hours. Excess reagents were distilled off and the oily residue was suspended in petroleum ether, whereby a crystalline mass was obtained which was recrystallized from an ethanol-ether-petroleum ether mixture. The yield was 2 g (52.6 %), and the melting point was 106 - 108°C.

The analysis confirmed that the diacylated derivative of the starting material had been obtained, i.e. 2-(N-acetyl-N-(2-acetoxy)-ethyl)-amino~4,5-diphenylthiazole.

Analysis: Calculated for C21<H2>0°3N2S: C = 66.29%; H 5.30%

Found: C 66.07 H 5.28%

Example 6

The procedure described in example 5 was repeated to prepare 2-(N-methyl-N-acetyl)-amino-4,5-diphenylthiazole by starting from 2-methylamino-4,5-diphenylthiazole and acetic anhydride.

The obtained monoacetylated derivative melted at 148 - 150° C.

Analysis: Calculated for ci8Hi6ON2S: C = 70'10%'H = 5'23%

Found: C = 69.88%} H = 5.52%

Example 7

8.13 g of 2-chloro-4,5-diphenylthiazole was added to a solution of 22 g of diethylamine in 100 ml of benzene and heated to

120° C for 6 hours in a closed vessel.

After cooling, the reaction mixture was washed with water in a separatory funnel, the benzene layer was isolated, dried over sodium sulfate and evaporated to dryness, which gave a residue which was dissolved in 100 ml of petroleum ether.

The solution was decolored with charcoal and cooled, whereby 6 g (65%) of crystalline 2-diethylamino-4,5-diphenylthiazole was obtained which melted at 115 - 116° C after recrystallization from an ethanol-ether-petroleum ether mixture.

Analysis: Calculated for cigH2o<N>2<S:>C<=>73.98%; H = 6.53%

Found: C = 73.74%H = 6.22%

Example 8

The procedure in Example 7 was repeated to prepare 2-isopropylamino-4,5-diphenylthiazole starting from 2-chloro-4,5-diphenylthiazole and isopropylamine, except that the reagents were kept in a closed vessel for 10 hours at 100° C.

The product obtained melted at 116 - 118° C after recrystallization from aqueous ethanol.

analysis: Calculated for C^gH^r^S .H20: C = 69.65%f- H = 6.49%

Found : C = 69.90%} H = 6.17%

Example 9<*>•"

5.4 g of 2-chloro-4,5-diphenylthiazole and 14.2 g of pyrrolidine were refluxed for 8 hours, after which the reaction mixture was cooled and diluted with water to precipitate 2-pyrrolidino-4,5-diphenylthiazole.

The precipitate was recovered and purified by crystallization from aqueous ethanol. The yield was 4.9 g (80%) and the melting point was 116 - 117° C.

Analysis: Calculated for <C>19H18N2S: C = 74.47%; H =5.92%

Found: C = 74.21% H 5.7 0% '

Example 10

a) g-phenyl-g-chloroacetamido-acetophenone

9.9 g of decylamine hydrochloride and 3.7 ml of chloroacetyl chloride i

100 ml of anhydrous benzene was refluxed for 4 hours in a 250 ml flask.

After filtration, the filtrate was evaporated to dryness whereby 10.5 g (88.4%) of α-phenyl-α-chloroacetamido-acetophenone was obtained which melted at 117 - 119° C after recrystallization from aqueous ethanol.

Analysis: Calculated for C16G1402NC1: C = 66.78%; H = 4.90%

Found: C = 66.32%j H = 4.79%

b) a -£eny1-a-mor f olinoac etamido-ac e to £ enone

4.4 g of α-phenyl-α-morpholinoacetamido-acetophenone and 21.7 g

morpholine was refluxed for 4 hours after which the reaction mixture was cooled and diluted with water to give a precipitate which was extracted with ether.

The ether layer was evaporated to dryness and the residue was dissolved in 70% ethanol. After cooling to approx. 0° C and maintaining this temperature! about. After 48 hours, crystalline α-phenyl-α-morpholinoacetamido-acetophenone was obtained in a yield of 13.2 g (78.2%). Melting point was 116 - 118° C after recrystallization from aqueous ethanol.

Analysis: Calculated for c2o<H>2<2>°3<N>2<:>C<=>70'98% > H = 6.55%

Found: C = 70.81%- r H = 6.65%

c) 2- morpholinonre thy1- 4, 5- dipheny1th i a z o1- hy drochloride

10 g of α-phenyl-α-morpholinoacetamido-acetophenone was intimated

mixed with 6.66 g ^ 2S5t the mixture was gradually heated to 150 - 170° C in an oil bath and held at this temperature for 1 hour. After cooling, the residue was triturated in the presence of water to completely decompose unreacted phosphorus pentasulfide. The mixture was then made alkaline with 20% caustic soda and extracted with ether. The ether layer was dried over sodium sulfate, decolorized with charcoal, filtered and evaporated to dryness. The residue was dissolved in ethanol and transferred to the hydrochloride by addition of ethanolic hydrogen chloride. The precipitation of 2-morpholinomethyl-4,5-diphenylthiazole hydrochloride was brought to completion by addition of anhydrous ether and cooling. 4.5 g (40.4%) of product was obtained which melted

at 238 - 242° C (decomposition) after recrystallization from anhydrous ethanol.

Analysis: Calculated for C20H21ON2CiS: C - 64.41%•' H = 5.67%

Found: C = 64.29%j H = 5.77%

Example 11

The procedure in example 10(b) was repeated to prepare the following compounds starting from α-phenyl-α-chloroacetamido-acetophenone and the appropriate amine: 1). a-phenyl-a-pyrrolidinoacetamido-acetophenone, m.p. 142 - 143° C 2), α-phenyl-α-piperidinoacetamido-acetophenone, m.p. 107 - 109° C 3) α-phenyl-α-dimethylaminoacetamido-acetophenone, m.p. 119 - 120° C 4) α-phenyl~α-isopropylaminoacetamido-acetophenone, m.p. 111 - 113°C

When compounds 3 and 4 were prepared, the reaction was carried out at room temperature using benzene as the reaction medium.

Example 12

The procedure of Example 10(c) was repeated to prepare the following compounds starting from the appropriate α-phenyl-α-aminoacetamido-acetophenone.

1) 2-pyrrolidinomethyl-4,5-diphenylthiazole hydrochloride, m.p.

242 - 243° C

2) 2-piperidinomethyl-4,5-diphenylthiazole hydrochloride, m.p. 230 - 235° C 3) 2-isopropylaminomethyl-4,5-diphenylthiazole hydrochloride, m.p. .210 -'212° C 4) 2-methylaminomethyl-4,5-diphenylthiazole hydrochloride, m.p. 122 - 124° C

Acute toxicity was determined in rats both by oral and intraperitoneal administration after a fasting period of 16 hours. All test compounds were found to be non-toxic up to the doses of 300 mg/kg p.o. and 100 mg/kg i.p.

r- Of f i

Example 13

a) 2-chloromethyl-4,5-diphenylthiazole

14.4 g of α-phenyl-α-chloroacetamido-acetophenone was intimated

mixed with 11 g $ 2^ 5' the mixture was heated to 150 - 170°C on an oil bath and held at this temperature for 1 hour. After cooling, the solid residue was triturated in the presence of a mixture of water and ethanol (1:1 by weight) to completely decompose the unreacted phosphorus pentasulfide. The mixture was further diluted with water, then made alkaline with 20% caustic soda and extracted with ether.

The ether layer was dried over sodium sulfate, decolorized with charcoal, filtered and evaporated to dryness in vacuo to give 6 g (42% yield) of crude 2-chloromethyl-4,5-diphenylthiazole. The melting point was 46 - 48° C after recrystallization from an ether-petroleum ether mixture.

b) 2- mor fo linoma thy1- 4, 5- di feny11h i a z o1

6 g of 2-chloromethyl-4,5-diphenylthiazole and 9.14 g of morpholine

was refluxed for 4 hours after which the reaction mixture was cooled and diluted with water.

The oil that separated was extracted with ether and the ether layer was dried over sodium sulfate and evaporated to dryness under high vacuum.

The oily residue was dissolved in the minimal amount of absolute ethanol, acidified with 30% ethanolic hydrogen chloride and crystallized by adding anhydrous ether.

6.65 g of crystalline 2-morpholinomethyl-4,5-diphenylthiazole hydrochloride (85% yield) were obtained by filtration.

The melting point and analysis were in complete agreement with that reported in Example 10(c).

Examples 10 and 13 above show that identical products of formula (I1)- can be prepared by two alternative routes, i.e. (a) cyclization of a compound of formula (II) where X is the group:

pl

-N

XR2

whereby one directly obtains a compound of formula (I<1>), and (b) cyclization of a compound of formula (II) where X is halogen, and subsequent reaction of the obtained compound of formula (I") with an amine with formula (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 sufficient 3.8% sodium citrate to give a concentration of 0.38 g/100 ml after mixing

.with blood, and then centrifuge at 100 G for 20 minutes.

1 ml samples of the thus prepared plasma were placed

in a plate aggregation meter connected to a potentiometric recording apparatus and tested according to Born, Nature (London), 194, 927 (1962). The plasma-sample compound mixtures were incubated for 10 minutes at 37°C before addition of the aggregating agents (ADP, collagen)....

The curves were read following the procedure described by O'Brien et al., Thromb, Diath, Haemorrhag, 16, 751 (1966). Slope and maximum transmission were recorded and expressed as % change with respect to the control samples. In the case of collagen-induced plaque aggregation, the delay time ("reaction time") in seconds for addition of the aggregating agent to the change in slope of the curve was also measured and expressed as % change as above.

For comparison, known anti-aggregation agents such as acetylsalicylic acid and adenosine were also tested under the same conditions as the test compounds.

The results are shown in the following tables. Negative numbers for percent changes in slope and maximum transmission indicate anti-aggregation activity; positive figures in % changes in delay time indicate that the compound is effective in prolonging the "reaction time" in the collagen-induced plaque aggregation assay.

Hypocholesterolemic activity was tested on hypercholesterolemic rats given the indicated daily doses of the test compounds for 2 days. Cholesterol was then determined in the blood and compared with control samples. The compound from example 10 (c) administered per os at a dose of 200 mg/kg caused a 17% reduction in the amount of cholesterol compared to the controls. At the same dose per os as above, the compound from Example 2 caused 22% reduction.

Anti-inflammatory activity was tested plethysmometrically by measuring rat graft edema volume induced by brewer's yeast. in rats to which the test compounds had been administered per os 1 hour before the injection of the oedema-causing agent. No significant reduction in edema volume was found in the treated animals (100 mg/kg per os) compared to controls.

Analgesic activity was tested by the hot plate method.

An analgesic effect was not demonstrated with any of the test compounds when administered orally in doses of 100 - 200 mg/kg. The preferred administration method for the compounds produced according to the invention is, per us. The following example shows a typical preparation of capsules.

Example 14

A mixture was prepared containing the following amounts of excipients expressed in parts by weight:

glycocol 2.5

lactose 5

talc 2.5

magnesium stearate 1

The above mixture was mixed with sufficient amounts of the compounds of Examples 1, 2 and 10 (c) to obtain capsules containing 25, 100 and 200 mg of each of the active ingredients, and filled into gelatin capsules for oral administration.

Claims (19)

1- Procedure for the preparation of a 2-substituted 4,5-diphenylthiazole with the formula: where X is halogen or the group: where R" 1 and R 2 individually are hydrogen, alkyl with 1-4 carbon atoms, hydroxyalkyl with 1-4 carbon atoms, acyl with 1-4 carbon atoms or acyloxyalkyl with 1-4 carbon atoms in the alkyl chain, or R" 1 and R 2 can together with the nitrogen atom to which they are bound form a heterocyclic amino group with 5 to 6 members in the ring f and A is an alkylene group or a single bond, but A cannot be a single bond when X is halogen, characterized in that an a- phenyl-acetophenone derivative with the formula: where A and X are as stated above, closed with P2 S5* 2. Process according to claim 1, characterized in that when X in formula (I) is halogen, the obtained product of formula (I") is reacted with an amine of the formula: 12 where R and R are as above, to obtain a thiazole of the formula: 12 *1 • where A, R and R are as stated above. <*.> 3. Procedure for the preparation of a thiazole with the formula: where A is. a single bond, and R i and R o are as stated above, characterized in that an amine with the formula: 12 <f;> ' where R and R are as indicated above, is reacted with a 2-halo-4,5-diphenylthiazole. 4. Process according to claim 3, characterized in that the amine of formula (III) is reacted with 2-chloro-4,5-diphenylthiazole. 5. Method according to claims 1-4, characterized in that when X in formula (I) is the group: and at least one of R 1 and R 2 is hydrogen or hydroxyalkyl, the product obtained is reacted with an acylating agent to obtain a compound of formula (I <1> ) where at least one of R 1 and R 2 is acyl or acyloxyalkyl. 6. Process according to claim 3 for the production of 2-morpholino-4,5-diphenylthiazole, characterized in that 2-chloro-4,5-diphenylthiazole is reacted with morpholine. 7. Method according to claim 3 in the preparation of 2-bis-(2-h <y>drox <y>eth <y>l )-amino-4,5-diphen <y>lthiazole, grade d. - cert by reacting 2-chloro-4,5-diphenylthiazole with diethanol-am i-n • - yJ 8. Process according to claim 3 for the production of 2-methylamino~4,5-diphenylthiazole, characterized in that 2-chloro-4,5-diphenylthiazole is reacted with methylamine. 9- Process according to claim 3 for the production of 2-(2-hydroxyethyl)-amino-4,5-diphenylthiazole, characterized in that 2-chloro-4,5-diphenylthiazole is reacted with ethanolamine. 10. Process according to claim 5 in the preparation of 2-(n-acetyl-N-(2-acetoxy)-ethyl)-amino-4,5-diphenylthiazole, characterized in that 2-(2-hydroxyethyl)-amino-4, 5-diphenylthiazole prepared according to claim 9, is reacted with acetic anhydride. 11. Process according to claim 5 for the preparation of 2-(N-methyl-N-acetyl)-amino-4,5-diphenylthiazole, characterized in that 2-methylamino-4,5-diphenylthiazole prepared according to claim 8 is reacted with acetic anhydride. 12. Method according to claim 3 for the production of 2-diethyl-amino-4,5-diphenylthiazole, characterized in that 2-chloro-4,5-diphenylthiazole is reacted with diethylamine. 13. Process according to claim 3 for the production of 2-isopropylamino-4,5-diphenylthiazole, characterized in that 2-chloro-4,5-diphenylthiazole is reacted with isopropylamine. 14. Process according to claim 3 for the production of 2-pyrrolidino-4,5-diphenylthiazole, characterized in that 2-chloro-4,5-diphenylthiazole is reacted with pyrrolidine. 15. Method according to claim 1 for the production of 2-morpho-linomethyl-4,5-diphenylthiazole or its hydrochloride, characterized in that alpha-phenyl-alpha-morpholinoacetamido-acetophenone is ring-closed with P2 S5'°9 when the hydrochloride is desired, it is reacted free base with hydrochloric acid. 16. Method according to claim 1 for the production of 2-pyrrolidinomethyl-4,5-diphenylthiazole or its hydrochloride, characterized in that alpha-phenyl-alpha-pyrrolidinoacetamico-acetophenone is ring-closed with P2 S5'°9 when the hydrochloride is desired , the free base is reacted with hydrochloric acid. 17. Process according to claim 1 for the production of 2-piperidinomethyl-4,5-diphenylthiazole or its hydrochloride, characterized in that alpha-phenyl-alpha-piperidinoacetamido-acetophenone is ring-closed with ?2 S^ , and when the hydrochloride is desired, it is reacted free base with hydrochloric acid. 18. Method, according to claim..1 for the production of 2-iso-propylaminomethyl-4,5~ diphenylthiazole or its hydrochloride, characterized in that alpha-phenyl-alpha-isopropylamino-acetamido-acetophenone is ring-closed with <p>2 S5' and when the hydrochloride is desired, it is reacted. free base with hydrochloric acid. 19. Process according to claim 1 for the production of 2-methyl-aminomethyl-4,5-diphenylthiazole or its hydrochloride, characterized in that alpha-phenyl-alpha-methylamino-acetamido-acetophenone is ring-closed with P2 S5'°9 when the hydrochloride is desired , the free base is reacted with hydrochloric acid.