IL42097A - 1-acyl-homopyrimidazole-derivatives and salts thereof and their preparation - Google Patents

Description

ona ni |n n ai! ι·τRT*»»· *ato*ττ· *χκν| »?ι>%η lirAcyl^homopy lmidazole-derivatives and salts thereo and their preparation CHBT01H GYQGYSZEE ES VEGYESZETI TEHMEKEK GYAR&. ΒΓ. 0: 40282; ' ' . -2- 42097/3 This invention is directed to new pharmaceutically active l-acyl-homopyrimidazole-derivatives and Baits thereof, and process for their preparation.

It is known that homopyrimidazole-derivatives are pharmaceutically valuable compounds. (British Patent No. 1,209,946 corresponding to Israel Patent No. 28863). The known homopyrimidazole-derivatives contain hydrogen, alkyl-, aryl- or aralkyl-group in the position 1 of the homopyrimidazole ring.

According to a feature of the present invention there are provided new l-acyl-homopyrimidazoles and the salts thereof of the general formula I in which R is hydrogen or lower alkyl , R"^ .is a lower alkoxycarbonyl group, R is a lower alkanoyl, benzoyl or lower alkoxycarbonyl group .

The compounds of the general formula I and the salts thereof exhibit remarkable pharmaceutical activity, - 3 - 42097/2 particularly narcosis potentiating effect, similar to that of the compounds known from the above mentioned British Patent No; 1,209,946. The compounds of the present invention are distinguished, however, by having a eignifieantl lower toxicity than those known compounds. In other words, the novel compounds of the invention have a significantly wore favourable therapeutic index (LD50/ED50).

Th term "lower alk l" as used herein means preferably such groups containing 1-6 carbon atoms, particularly straight and branched chained hydrocarbon groups, containing 1-4 carbon atoms, such as methyl, ethyl, n-propyl , isobutyl group. KB suitable representatives of the alkoxy groups there may be mentioned straight or branched chained groups , containing 1-6 or particularly 1-4 carbon atoms, such as methoxy, ethoxy, isopropoxy, etc. g The lower alkanoyl group in the position of may contain 1-6 carbon atoms and may be, e.g. , acetyl , propionyl , or butiryl group. The lower alkoxycarbonyl 6 groups i the position of may preferably contain 2 to 7 carbon atoms (e.g. methoxycarbonyl or ethpxycarbonyl groups) .

Compounds of the general formula I may form salts. The salts may be formed with Inorganic acids as hydrochloric -4- 42097/3 acid, hydrogen bromide, sulphuric acid, phosphoric acid or with organic acids as tartaric acid, succinic acid, maleinic acid, lactic acid, nicotinic acid, malic acid, citric acid etc. x R in the general formula I stands preferably for a lower alkyl group, particularly for a methyl group.

R5. stands preferably for an ethoxycarbonyl group. R6 represents preferably an acetyl, propionyl , benzoyl or ethoxycarbonyl group.

Particularly useful compounds of the general formula I are the following derivatives: l-.acetyl-3-carbethoxy-4-pxo-6-methyl-l,6 ,7 ,8 ,9 ,10-hexa- hydro-homopyrimidazole , l-prop nyl-3-carbethoxy-4-oxo-6-methyl-l ,6 ,7 , 8 ,9 ,10-hexa- . hydro-homopyrimidazole , l-benzoyl~3-carbethoxy-4-oxo-6-methyl-l ,6 ,7 ,8 ,9. ,10-hexa- hydro-homopyrimidazole , l,3-dicarbethoxy-H-oxo-6-methyl-l ,6 ,7 , 8 ,9 ,10-hexahydro- -homopyrimidazole , ■ . ■ and the salts thereof. -5- 42097/3 According to a further feature of the present invention, there is provided a process for the preparation of the compounds of the general formula I , which comprises acylating a compound of the general formula II wherein R and R are as defined above, and if desired any of the groups R and/or R^ in the compound of the general formula I thus obtained is (are) converted into another R 5 and/or R substituent within the scope of the invention, and if desired the compound of the general formula I thus obtained is converted into a salt.

The acylation is carried out with the corresponding carboxylic acids, with active derivatives thereof or with alkyl haloformates . As. active acid derivatives acid halides, acid anhydrides or esters may be used.

When introducing a lower alkanoyl group into the 1-position of the homopyrimidazole ring (e.g. acetyl or pro-pionyl group) the reaction may be carried out preferably without any solvent, in an excess of the corresponding acid anhydride (e.g. acetanhydride or propionanhydride) . The reaction is conducted under heating, preferably under boiling the reaction mixture under reflux.

The introduction of a benzoyl group may be carried out preferably with benzoyl halides, e.g. with benzoyl chloride. The reaction is preferably carried out in apolar organic solvents, preferably in aromatic .hydrocarbons such as benzene, toluene. The hydrogen halide j !being set free is preferably bound with acid binding agents. j As acid binding agents tertiary amines (e.g. triethyl amine) or alkali metal hydrogen carbonates (sodium or potassium hydrogen carbonate) may be used. The reaction may be carried out at a higher temperature particularly while boiling the reaction mixture under reflux.

The acylation may be carried out with esters too.

According to a further feature of the present invention the compounds of the general formula II are acylated with the free carboxylic acids themselves. The reaction is carried out in the presence of a condensing agent (e.g. dic clohexyl-carbodiimi.de).

The alkox carbonyl groups may be introduced into the 1-position of the homopyrimidazole ring with alkyl haloformates . The reaction is carried out preferably in an inert solvent medium As reaction medium, ketones, -7- 42097/2 particularly acetone, are preferably used. An aqueous medium is desirable. The reaction is carried out preferably under heating at the boiling point of the reaction mixture.

In the compounds of the general formula I thus 5 obtained* the goups R and/or R may optionally be converted 5 into another R and/or R within the scope of the invention, by methods known per se. -8- 42097/2 The compounds of -the general formula I may be converted into acid addition salts. The formation of salts may be carried out by a method known per se, by reacting the compound of the general formula I in a solvent medium with the corresponding acid. The acid is usually used in an equivalent quantity. The starting materials, i.e. the com-pounds of the general formula II are known materials CBrit-ish Patent Specification No. 1 209 946) According to a further feature of the present invention there are provided pharmaceutical compositions containing as active ingredient at least one compound of the general formula I or a salt thereof in admixture with pharmaceutically acceptable inert, non-toxic organic or inorganic carriers or diluents .

As carriers water, gelatine, talcum, calcium carbonate, starch, polyalkylene glycol, magnesium stearate, etc. may be used. The products may be in form of tablets, capsules, suppositories, etc., in semisolid form, e.g. ointment or in liquid form, e.g. solution, suspension or emulsion. The products may be optionally sterilized, and may · contain auxiliary materials as stabilizers, wetting, emulga-ting, and suspending agents or salts or buffers causing the alteration of the osmotic pressure and further pharmaceutically acceptable excipients .: Further, details of the present .invention are illustrated in the examples without limiting the scope of -9- 42097/2 the invention to the examples.

Example 1 119.1 g. 0.5 molest of 3-carbethoxy-4-oxo-6;- -methyl-1,6 ,7 ,8 ,9 ,10-hexahydro-homopyrimidazole are boil- ed for 6 hours under reflux in 20" .0 g. (2.0 moles) of acetanhydride. The reaction mixture is cooled, poured on.' 300 g. of ice and neutralized with ice cold ammonium hydroxide The precipitated crystals are filtered, washed with water and dried. 120 g. of almost white l-acetyl-3-carbethoxy- -4-oxo-6-methyl-l ,6 ,7 ,8, ,9 ,10-hexahydro-homopyrimidazole are obtained. F. : 123 - 125 °C. Yield: 85.7 %.

After, recrystallization from water-free ethan-ol in a double amount a white product is obtained. F. : 125 - 126 °C.

Analysis: C% = 60.37 Ccalc. 60.10J H%. = 7.38 (calc. 7.20); N% = 10.23 Ccalc. 10.00J; acetyl = 15.25 (calc. 15.35).

Example. 2 U7i6 g. CO.2 moles) of 3-carbethoxy-U-oxo-6--methyl-1 ,6 ,7 ,8 ,9 ,10-hexahydro-homopyrimidazole are boiled for 8 hours under reflux with 150ml. of propionic anhydride. The reaction mixture is dried in vacuo, the rest is taken up in 200 ml. of water and is neutralized while cooling with a diluted ammonium hydroxide solution. The mixture is shaken out with 2 x 200 ml. of benzene and the benzen-ic solution is evaporated after drying. 56.6 g. of brown oily rest are obtained, which are dissolved while hot in AU 42097/2 200 ml. of ether and crystallized. 30.5 g. of 1-propion- yl-3-carbethoxy-4-oxo-6-methyl-l ,6,7,8,9, 10-hexahydro-homo- pyrimidazole are obtained in the form of beige needles.

F.: - us °ς. After recrys tallization from ether white needles are formed, which melt at 116 oc. Yield: 87.5 %.

Analysis : C% = 61.38 (calc, 61.15); H = 7.60 Ccalc. 7.54); N = . = 9.44 Ccalc 9.50).

Example 3 47.6 g. CO.2 moles D of 3-carbethoxy-4-oxo-6--methyl-1 ,6 ,7 ,8 ,9 ,10-hexahydro-homopyrimidazole and 24.2 g. (0.24 molest of triethylamine are dissolved in 200 ml. of water-free benzene. While stirring 33.6 g. (0.24 moles) of benzoylchloride are added to the mixture during 15 minutes. The temperature increases to 50 °C. The temperature of the reaction mixture is increased successively to boiling, whereafter the mixture is boiled for 2 hours under, reflux and cooled. The precipitated triethyl amine hydrochloride C32.3 g. is filtered, the benzenic filtrate is washed with a solution of sodium hydrogen carbonate, and water and the mixture is evaporated. The rest is 69.2 g. of yellow crystals. F . : 130-32 °C. The product i$ recryst-allized from a double amount of water-free ethanol and 56.0 g. of white l-benzoyl-3-carbethoxy-4-oxo-6-methyl-l,6,7,8,9,10--hexahydro-homopyrimidazole are obtained. F..: 138 - 139 °C.

Analysis : " C% = 66.70 Ccalc. 66.60 ; H% = 6.48 Ccalc. 6. 8;; N% = " = 8.04 Cc lc. 8.17J.

Example 4 47.6 g. CO.2 moles D of 3-carbethoxy-4-oxo-6- -methyl-1 ,6 ,7 ,8 , 9 ,10-hexahydro-homopyrimidazole , 33.2 g. CO,2 molest of potassium carbonate and 400 ml. of dry acetone form a suspension and 26.0 g. of freshly distilled ethyl chloroformiate are added. The reaction mixture is slowly heated to boiling, is boiled for 1.5 hours while the carbon dioxide is removed. After cooling 600 ml. of water are added to the reaction mixture, whereafter the •acetone is distilled. At the bottom of the aqueous rest a brown oily product is gathering, which is setting on. cooling and crystallizing. Aft r filtering, washing with water and drying 54.2 g. of the crude product are obtained. F. : 99-101 °C. After recrystallization from water free ethyl acetate in a double amount 32.0 g. of 1 ,3-dicarbethoxy- -4-oxo-6-methy1-1*6 ,7 ,8 ,9 ,10-hexahydro-homopyrimidazole are obtained in the form of white crystals. F.: 103-104°C.

Claims (1)

1. -12- 42097/3 CLAIMS ; \ · 1. . Compounds of the general formula I and the salts thereof, in which ■ R is hydrogen or lower alkyl, 5 R is a lower alkoxycarbonyl group, _ -. R is lower alkanoyl, benzoyl or lower alkoxycarbonyl group. 2. l-acetyl-3-carbethoxy-4-oxo-6-methyl-l,6,7,8,9,10- -hexahydro-homopyrimidazole . 3. l-propionyl-3-carbethoxy-U-oxo-6-methyl- -1,6 ,7 ,8 ,9 ,10-hexahydro-homopyrimidazole. . l-benzoyl-3^carbethoxy-4-oxo-6-methyl- -1,6 ,7,8 ,9 ,10-hexahydro-homopyrimidazole. 5. l,3-dicarbethoxy-H-oxo-6-methyl-l,6 ,7 ,8 ,9 ,10- ' -hexahydro-homopyrimidazole . . . .6. Process for the preparation of the compounds of the general . formula I in Claim 1.. -13- 42097/3 and salts thereof, which comprises acylating a compound of the general formula II R 0 in which R and R have the same meaning as in Claim 1, and, if desired, any of the groups R and/or R5 in the compound of the general formula I thus obtained is 5 (are) converted into another R and/or R substituent within the scope of the invention, and, if desired, the compound of the general formula I thus obtained is converted into a salt. 7. Process according to Claim 6, wherein a lower alkanoic acid, benzoic acid or reactive derivatives thereof or an alkyl haloformate, is used as the acylating agent. 8. Process according to Claim 7, wherein an acid-halide, acid anhydride or ah ester is used as the reactive acid derivative. 14- 42097/2 9. Process according to any of the claims 6-8, where the acyiation is carried with acetic anhydride or propionic anhydrid without using any solvent. 10. Process according to Claim 9, wherein the acyiation is carried out under heating, preferably by boiling the reaction mixture under reflux. 11. Process according to any of the claims 6-8, which comprises acylating with an acid chloride, particularly with benzoylchloride. 12. Process according to Claim 11, wherein the reaction is carried out in the presence of an acid binding agent, preferably a tertiary amine, particularly of triehy1amine. 13. Process according to any of the claims 6-7, wherein the reaction is carried out in an apolar organic solvent, preferably an aromatic hydrocarbon, particularly benzene. 14. Process according to Claim 6, wherein the acyiatio is carried out in the presence of dicyclocarbodi-imide with an alkanoic acid of 1-6 carbon atoms or with benzoic acid. 15. Process according to Claim 6, wherein an alkyl chloroformate, particularly ethyl chloroformate is used as acylating agent. 16. Process according to Claim 15, wherein the reaction is carried out in an inert organic solvent. 17. Process according to Claim 16, wherein -15- 42097/2 a ketone, particularly acetone, is used as an inert organic solvent. 18. Process according to any of the Claims 6-17, wherein 3-carbethoxy-4-oxo-6-methyl-l ,6,7-8,9 ^lO-hexahydro-homopyrimidazole is used as starting material. 19- Pharmaceutical compositions comprising as active ingredient at least one compound of th general formula I in Claim 1 or salts thereof, in admixture with suitable pharmaceutical carriers and/or excipients. 20. A pharmaceutical composition according to Claim 19 and comprising as active ingredient l-acetyl-3-carbethoxy-4-oxo-6-methyl-1,6,7,8,9 ,10-hexahydro-homopyrimidazole or salts thereof. 21. A pharmaceutical composition according to Claim 19 and comprising as active ingredient 1-propionyl-3^carbethoxy-4-oxo-6-methyl-l,6,7,8,9 ,10-hexahydro-homopyrimidazole or salts thereof. 22. A pharmaceutical composition according to Claim 19 and comprising as active ingredient 1-benzoy1-3-carbethoxy-4-oxo-6-raethyl-l,6,7,8,9,10-hexahydro-homopyrimidazole or salts thereof. 23. A pharmaceutical composition according to Claim 19 and comprising as active ingredient 1 , 3-dicarbethoxy 4-oxo-6-i3ethyl-i-l,6,7,8 ,9 ,10-hexahydro-homopyrimidazole or salts thereof. f! 24. A process for preparing a composition according to any one of Claims 19-23, which comprises admixing the active ingredient (s) of the general formula I in Claim 1, with suitable inert, organic or inorganic, solid or liquid carriers and/or excipients, and finishing the compositions in forms ready for medical use, preferably in the form of tablets, capsules, suppositories, solutions or injectable preparations.