NO132760B - - Google Patents

Description

The present invention relates to a method for producing a group of new therapeutically active chemical compounds with the general formula I

where R, R^ and R^ are hydrogen or a lower alkyl group, with at least one of R, R^ and R^ preferably being other than hydrogen, while A is a phenyl group optionally substituted with one or more halogen atoms, one or more lower alkyl, lower alkoxy or

trifluoromethyl groups, or A is a thienyl, furyl, pyridyl, cycloalkyl group of up to 6 carbon atoms, a phenyl (lower alkyl), trifluoromethyl or lower alkyl group.

The invention includes the production of addition salts of

these compounds with pharmaceutically acceptable acids.

The new compounds are preferably 7- and/or 2- and/or 3- and/or 6-substituted thiazolino-pyrimidin-5-ones, and advantageously one of the 2-, 3- or 6-positions is substituted in addition

to the 7 position. It should be noted that when a substituent is present in the 2- and/or 3-position, the compounds (I) can exist in the form of stereoisomers, and the invention encompasses the production of both the racemic forms and the optically active forms .

In the preceding definition, they contain lower alkyl and

alkoxy groups advantageously from 1 to 4 carbon atoms.

The patentee has previously found that certain thiazole-pyrimidine derivatives, namely those obtained by the process according to his patent No. 126,022, have anti-inflammatory properties.

The surprising fact has now been found that the thiazolino-pyrimidin-5-ones obtained by the present method have analgesic activity and can be advantageously used as analgesics. Experimental results which show the compounds' analgesic activity in more detail are given at the end of this description.

The characteristic main feature of the method according to the invention is that a 2-imino-thiazolidine with the general formula

II

where R and R_ are as defined above, condensed with a p-carbonyl ester of the general formula III:

where R 1 and A have the meanings given above, while B is a lower alkyl residue, after which, if desired, the obtained compound of the general formula I is reacted with a pharmaceutically acceptable acid.

The imino-thiazolidine (II) can be used in free form, or in the form of a salt. In the latter case, the imine is liberated in s-<:>Us with an alkaline compound.

The condensation is advantageously carried out in an organic solvent such as toluene, xylene or dioxane. The reaction is activated by heating, e.g. to the solvent's temperature. The condensation can also be carried out by heating to 140 - 160°C in the absence of the solvent.

In order to further illustrate the invention, in the following some embodiments are described as examples.

Example 1 Synthesis of 7-phenyl-2,3-dihydrothiazol-(3,2.a)-pyrimidin-5-one

(Formula I: A = C6H5, R=R1=R2=H; code n°: 54 )

100 g of 2-iminothiazolidine (II, R = R2 = H) and 300 ml of xylene were added to a 1 liter round bottom flask equipped with a swirling device, skirts and heating device. The mixture was heated until dissolved, and 190 g of ethyl benzoyl acetate (III: A = C^ H5, R^ = H,

B = C2H5) was then added. After refluxing for 5 hours, the reaction mixture was allowed to stand overnight at room temperature. The resulting crystalline material was filtered, washed with ethanol and then recrystallized from ethyl ether, after which it was dried in vacuo. 50.7 g of a product with a melting point of 166 - 167°C were obtained.

Analysis: Total nitrogen

The resulting 7-phenyl-2,3-dihydrothiazolo(3.2.a)pyrimidin-5-one base can be converted to the hydrochloride as follows:

20 g of 7-phenyl-2,3-dihydrothiazolo(3.2.a)-pyrimidin-5-one were dissolved in 130 ml of chloroform at room temperature. 40 ml of 6N hydrochloric acid in ethanol solution was added with stirring. The mixture quickly turned into a mass. This was allowed to stand for 1 hour at room temperature, and then 1 hour in an ice bath. The mixture was then filtered, washed once with chloroform and then twice with absolute ethanol, after which it was dried in an oven at 40°C. 22 g of 7-phenyl-2,3-dihydrothiazolo)3.2.a)-pyrimidin-5-one hydrochloride with a melting point of 198°C were obtained.

Example 2 Alternative synthesis of 7-phenyl-2,3-dihydrothiazol-(3.2.a)-pyrimidin-5-one

(Formula I: A = CgH , R=R;L=R2=H; code n°: 540)

0.02 mol of iminothiazolidine was dissolved in 0.04 ml of ethyl benzoyl acetate under heating. The reaction mixture was then flame heated to incipient boiling which was maintained for a few minutes. The resulting orange solution is transferred to 50 g of ice-water tOanding. The mixture was then stirred for 15 minutes. A yellow reindeer product fell out. This was filtered and washed with water. The insoluble part was taken up in an ethanol-water mixture, filtered, washed with ether and dried in vacuo, whereby 1.7 kg of crystalline product, m.p. 166SC (no melting point depression until (Vcomes by mixing with the product obtained in example 1).

"in'

Analysis: Calculated Found

Basic nitrogen 6.08% 5.95%

Example 3 Preparation of 7-(m-trifluoromethylphenyl)-2,3-'dihydrothiazolo-(3;2.a)-pyrimidin-5-one

(Formula I: A = m-CF3-C6H4, R^R^H; code n°:672)

5 g of 2-iminothiazolidine and 12 g of ethyl 1-m-trifluoromethylbenzoyl acetate (III: A = m-CF 3 -C 6 H 4 , R 1 = H, B = C 2 H 5 ) were mixed with 20 ml of xylene. The reaction mixture was refluxed for 7 hours. After standing overnight at room temperature, an impure material was separated and then recrystallized from 20 ml of chloroform, whereby 3.2 g of the product with a melting point of 164°C were obtained.

Example 4 Preparation of 3-methyl-7-phenyl 1.-2, 3-dihydrothiazolo-(3.2.a)-pyrimidin-5-one

(Formula I: A = C^H,., R = R2 = H; code n°: 682)

0.2 mol of 2-imino-4-methylthiazolidine (UU: R = CH3, R2 = H, and 0.2 mol of ethylbenzoyl acetate (III: A = C6H5, R1 = H, B = C2H5, which was dissolved in toluene. The mixture was refluxed with stirring for 6 hours and then allowed to stand overnight at room temperature. The resulting material was washed three times with ethanol, filtered and then recrystallized from .'.?>0 ml of chloroform, whereby 16 g of a product with

.= ... Freezing point 117 - 119 °C.

Example 5 Preparation of 7-(3',4'-dichlorophenyl)-2,3-dihydrothiazolo-(3.2.a)-pyrimidin-5-one

(Formula I: A = 3 * 41-C10-C,H„; R = R,=R =H; code n°:

668) 13.5 g of 2-iminothiazolidine and 34.3 g of ethyl 3',4'-dichloro-benzoyl acetate (III: A = 3',4'-C12-C6H3; R± = H; B = C2H5) were mixed with 60 ml of xylene and then refluxed for 7 hours. After standing overnight at room temperature, the resulting crystals were filtered off, washed with xylene and with ethanol. By recrystallization from chloroform, 11.8 g of a product with a melting point of 183°C were obtained.

The structure and physical properties of compounds (I) obtained according to the previous examples and of other compounds (I) prepared in a similar manner are listed in the following table.

In this table, data are also given regarding the analgesic activity of the new compounds (I), determined by one of the usual, stated tests for this activity, the so-called "convulsion test"

("writhing test").

Mice are given a single intraperiionea1 injection of 0.2 ml

6 °/oo acetic acid. The compound I to be tested is administered orally at a dose of 10 - 60 mg/kg, 1/2 hour before the acetic acid is injected. The number of characteristic torques induced by the pain is counted during the 15 minutes following the acetic acid injection. Each compound's activity is expressed in from one to four +, where four + is maximum activity.

The analgesic activity of the new compounds I allows use in medicines, as the compounds can be administered orally, parenterally or rectally with a daily dose in the range of 300 and 900 mg.

For such administration, the compounds are formulated as therapeutic mixtures with carriers or excipients suitable for the various administration methods. The mixtures, formulated in unit doses such as tablets, suppositories and ampoules, preferably contain from 100 to 300 mg of the compound (I).

Claims (1)

Analogous method for the production of new, therapeutically active thiazolinc-pyrimidin-5-ones with the general formula: where R, R-1 and R2 are each hydrogen or a lower alkyl group, with at least one of R, R-1 and R2 preferably being other than hydrogen, while A ' is a phenyl group optionally substituted with one or more halogen atoms, one or more lower alkyl, lower alkoxy or trifluoromethyl groups, or A is a thienyl, furyl, pyridyl or cycloalkyl group with up to 6 carbon atoms, or a phenyl-(lower alkyl)-, trifluoromethyl- or lower alkyl group, and of their acid addition salts, characterized in that a 2-iminothiazolidine of the general formula: where R and R2 have the meanings given above, or preferably in the form of a salt which is released in situ with an acid, condensed, preferably in the presence of an organic solvent, or when no solvent is used by heating the reaction mixture to 140 - 160°C, with a 3-carbonyl ester of the general form where R 1 and A have the meanings indicated above, while B is a secondary alkyl residue, whereupon the compound obtained, if desired, is reacted with a pharmaceutically acceptable acid.