DE2320377A1 - NEW 1-ACYL HOMOPYRIMIDAZOLE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Chinoin Gyogyszer es Vegyeszeti T <=> τ> πι * >> <?! - G- ^ r? RT, Bndp ^ ect IV, To utca 1-5, Hungary

NEW L-ACYL HOMOPYRIMIDAZOLE DERIVATIVES AND PROCESSES FOR THEIR PRODUCTION

It is known that homopyrimidazole derivatives have valuable pharmaceutical properties (Britir see patent specification No. 1,209.9UB) ¹ . The known homopyrimidazole derivatives contain hydrogen, alkyl, aryl or aralkyl groups in the 1 position of the ring.

It has been found that the new compounds of general formula I

A3 «f3-77 -1-

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and their salts where in the formula

R, R ¹ , R ² and R ³ hydrogen, halogen, alkyl, alkoxy, Ni -

"fcro dull amino group,
R is hydrogen, halogen, alkyl, alkoxy, phenoxy, aryl,

Aralkyl, hydroxyl or = 0 group,
R is hydrogen, halogen, alkyl, aryl, aralkyl, car.

ctoxyl group or a carboxylic acid derivative group,
R Acy! Group or alkoxycarbonyl group

and the dashed lines indicate possible double bonds, valuable compounds which are used in pharmacy WErd \ .. i can use it especially because of its narcosis-potentiating effect.

The alkyl group means a straight-chain or branched group containing 1-6, preferably 1-4 carbon atoms, advantageously methyl, ethyl, n-propyl,
i-butyl group. '.

The alkoxy group also means a straight-chain or branched group containing 1-6, preferably 1-4 carbon atoms, advantageously methoxy, ethoxy-j i- -propoxy group, etc. The term "halogen" can mean any halogen atom. such as fluorine, chlorine, bromine or iodine atom. The aryl group advantageously means phenyl group, and the
The aralkyl group can advantageously be a benzyl or a phenethyl group.

The carboxylic acid derivative group which is contained in the position R ⁵ can, for example, alkoxycarbonyl group (e.g.

Il ν

Methoxycarbonyl, athoxycarbony! Group / halocarbonyl,

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Aainocarbonyl, Alkylaminocarbonyl, Dialkylaminbcarbonyl, Mean hydroxycarbonyl group. The meaning of the carboxylic acid derivatives in position 3 of the homopyrimidazole ring can accordingly be ester, acid halide, acid amide, Be mono- or dialkylic acid or hydroxamic acid group.

The acyl group in position R ⁶ advantageously contains an alkanoyl group containing 1-6 carbon atoms (acetyl, propionyl or butyryl group) or aroyl group (benzoyl group). The alkoxycarbonyl group in the R position preferably contain 2-7 carbon atoms (methoxy carbonyl, ethoxycarbonyl group).

Salts of the compounds of the formula I can also be formed. Inorganic Acids ^ hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid ^ or organic acids {[tartaric acid, succinic acid, maleic acid, lactic acid, nicotinic acid, malic acid, Citric acid) can be used. The compounds of general formula I which have a carboxyl group in the R position can also form salts with bases {e.g. Alkali metal salts, preferably sodium or potassium salts).

The meaning of R in the formulas I can advantageously be an alkyl group, particularly advantageously a methyl group be.

R ¹ , R ² , R ³ and R ¹ * are advantageously water

r Il

staff, R alkoxycarbonyl group, particularly advantageous Ath-

fi II.

oxycarbonyl group, R acetyl, propionyl ", benzoyl-τ or ethoxycarbonyl group. The molecule advantageously contains one Double bond in the 2, 3 position and a single bond in the 6.7 and 8.9 positions.

Particularly effective representatives of the compounds of the general formula I are the following new compounds: l-A.cetyl-S-carbethoxy-U-oxo-e-methyl-l, 6,7, 9,9,10-hexa hydro-homopyrimidazole, l-Propionyl-S-carbäthoxy - ^ - oxo-S-methyl-l, 6,7, 8th, 9,10-hexa-

30984-8 / 1 138

hydro-homopyrimidazole,

l-Benzoyl-3-carbethoxy-4-oxo-6-methyl-l, 6,7,8,9,10-hexahydro-homopyrimidazole,

1, S-dicarbethoxy-t-oxo-e-methyl-l, 6,7,8,9,10-hexahydro- -homopyrimidazole

and their salts »

Infoigejier Keto-Enol-Taütomerie can make the connections of the general formula I also in the tautomer form of formula I-A

I-A

occurrence. According to the inventive method, the Compounds of the formula I and the compounds of the formula Ι-Ά are prepared.

The invention also relates to the preparation of compounds of the formula I and their salts, in which the substituents have the same meaning as indicated above, characterized in that compounds of general formula II

II

/ where R, R ¹ , R ² , R ³ , R ¹⁺ and R ⁵ are given above / acy-

3 09846/1138

If desired, in a compound of the formula I obtained in this way, one R, R ¹ , R ² , R ³ , R ⁴ and / or R ⁵ - group within the scope of protection of the preamble to another group R, R ¹ , R ² , R ³ , R ⁴ and / or R ⁵ is converted ^), optionally one or more bonds, which are drawn with dashed lines, are saturated and optionally a compound of the formula I thus obtained is converted into salt.

The acylation can be carried out with the corresponding carboxylic acid with their reactive derivatives or with alkyl haloformates be performed. Acid halides and acid anhydrides can be used as reactive acid derivatives and esters can be used.

When a lower alkanoyl group (^ cetyl- or Propionyl group) is to be introduced into position 1 of the homopyrimidazole ring, the reaction can be advantageous without solvent, in an excess of the corresponding acid anhydride (acetic anhydride, propionic anhydride) be performed. The reaction takes place during heating; the reaction under reflux is advantageous Cooking the mixture carried out.

Aroyl groups (CÖenzoylgruppe) can be advantageous introduced into the molecule by acid halide (benzoy! chloride) will. The reaction can preferably be carried out in an apolaric organic solvent, suitably in aromatic Hydrocarbons ^ benzene, toluene} are carried out. The acid halides released can be replaced by acid binders be included. Tertiary amines, triethylamine, alkali bicarbonates can advantageously be used as acid binders Oiatrium or potassium bicarbonate) can be used. The reaction can be carried out advantageously at a higher temperature carried out when the reaction mixture was boiled under reflux will.

The acylation can also be carried out with esters.

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According to a further embodiment of the invention In the process, the compounds of general formula II are acylated with the carboxylic acids themselves. the Reaction is carried out in the presence of a condensing agent ^ bicyclohexylcarbodiimide) carried out.

The alkoxycarbonyl group can be substituted by alkyl haloformates be introduced into position 1 of the homopyrimidazole ring. The reaction can be beneficial in one inert solvents are carried out. As a reaction medium, ketones ^ can be particularly advantageous Acetone ^ can be used. The reaction becomes convenient carried out when heated to the boiling point of the reaction mixture.

The compounds of formula I in this

Have been obtained in this way, further subsequent it ■ "12 3

Changes are subject to. The groups R »R, R, R ₉

4 5

R and / or R can, if desired, be within the scope of protection of the generic term can be transferred to other R, R, R, R, R and / or R The subsequent changes can be carried out using known methods. If the group R denotes hydroxyl group * so can by reaction with phosphorus oxychloride, thionyl chloride or another known chlorinating agents chlorine atom are introduced into the molecule, the chlorine atom can, if desired, be removed again by hydrogenation or one can also obtained by reaction with alcoholates or phenolates, alkoxy or phenoxy groups.

The halogen atoms in the compounds of the general Formula I can be removed by reduction, advantageously by hydrogenation, or by alcoholates with alkoxy groups or by phenates with phenyloxy groups be replaced.

The * halogen derivatives are made with ammonia or alkali metal amides reacted, whereby amino groups can be introduced into the molecule, which optionally diaauatiert and cooked in hydroxyl groups and by reducing

309848/1138

tion in hydrogenatoni and by Sandmeyer reaction in a halogen atom can be converted which differs from the halogen introduced at the outset. The unsubstituted Derivatives can be reacted with halogenating agents chlorine or bromine, whereby various Halogen atoms can be introduced into the molecule.

By saponifying the compounds of the general formula I which contain alkoxycarbonyl groups in the R position and the salt of the free acid or the free acid itself can be obtained by subsequent acidification. The esters form acid amides with ammonia, N-alkyl acid amides with alkylamines and Ν, Ν-dialkylamides with dialkylamines.

The compounds of the general formula I can, if appropriate, be converted into their acid addition salts. The salt formation can be carried out using a known method, characterized in that a compound of general formula I is reacted in a solvent with a suitable acid. The acid becomes appropriate used in an equivalent amount. The starting materials used to prepare the compounds of the formula I are known substances (British Patent No. I, 2o9,916).

The new compounds of formula I and their pharmaceutically acceptable salts can be "in the form of the Active ingredient and inert non-toxic, organic or inorganic Pharmaceutical preparations containing diluents or carriers can be used.

Water, gelatin, talc, calcium carbonate, starch, polyalkylene glycol, magnesium stearate can be used as carriers. The preparations are formulated in solid form ^ tablets, capsules, suppositories ^ in semi-solid form ^ SaI-ben ^ in liquid form ^ solution, emulsion, suspension ^. The preparations can optionally be sterilized and / or contain auxiliaries such as stabilizers, emulsifiers, suspending agents and salts or buffers which change the osmosis pressure _f

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and contain other pharmaceutically active substances.

Further details of the invention can be found in the examples, without the scope of protection being restricted to the examples to limit.

Example 1 .

119.1 g £ 0.5 Mole) S-carbethoxy - ^ - oxo-e-methyl-1,6, 1, 8,9,10-hexahydro-homopyrimidazo! are heated to the boil under reflux for 6 hours in 204.0 g £ 2 moles) of acetic anhydride. The reaction mixture is cooled, placed on 300 g of ice and neutralized with icy ammonium hydroxide, and the precipitated crystals are filtered, washed with water and dried. 120 g of almost white crystals of l-acetyl-S-carbethoxy - ^ - oxo -6-methyl-1,6,7,8,9,10-hexahydro-homopyrimidazole are obtained. F .: 123-125 C. Yield: 85.7% and recrystallized from double anhydrous ethanol, a white product is obtained. F .: 125-126 ° Ci

Analysis:

Found: C = 60.37 H = 7.38 N = 10.23 acetyl = 15.25 Calculated: C = 60.10 H = 7.20 N = 10.00 acetyl = 15.3 5%

Example 2

47.6 g (0.2 mol of S-carbethoxy-H-oxo-e-methyl- -1,6,7,8,9,10-hexahydro-homopyrimidazole are under reflux Boiled for 8 hours with 150 ml of propionic anhydride. The reaction mixture is concentrated to dryness in vacuo, the residue is taken up in 200 ml of water and, while cooling, neutralized with dilute ammonium hydroxide solution. The mixture is extracted by shaking with 2 × 200 ml of benzene and the benzene solution is evaporated after drying. There will be 5 6.6 red Obtained brown oily product, which is dissolved and crystallized while still warm in 200 ml of ether. It will be 30.5 g l-Propionyl-S-carbäthoxy-U-oxo-e-methyl-lje,?, 8,9,10- -hexahydro-homopyrimidazole obtained. F. 114-115 ° C. beige

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IT

Needle crystals. Whites are recrystallized from ether Needle received. F .: 116 ° C. Yield: 87.5%.

analysis , 38 H 7th , 60 N 9, 44 Found: C 61 , 15 H 7th , 54 N 9. 50 Calculated : C 61

Example 3

^ 7.6 g £ 0.2 MoIe ^ S-carbethoxy ^ -oxo-e-methyl- -1,6,7,8, 9,10-hexahydro-homopyrimidazole and 24.2 g £ 0.24 MoIe ^ triethylamine are dissolved in 200 ml of anhydrous benzene. 33.8 g (p, 24 mol} of benzoyl chloride are added within 15 minutes with stirring ^{. The temperature increases to 50 °} C. The temperature of the reaction mixture is gradually raised to boiling, the mixture is boiled under reflux for 2 hours and then cooled The precipitated triethylamine hydrochloride <[3 2.3 g) is filtered, the filtrate is washed with sodium bicarbonate and then with water and evaporated to dryness. 69.2 g of yellow crystals are obtained. M.p .: 130-132 ⁰ C. The product is recrystallized two times the anhydrous alcohol and 56 g of l-benzoyl-3-carbethoxy-4-oxo-6-methyl-l, 6, -7, 8, 9, lO -hexahydro-homopy / 'iniidazole obtained in the form of white crystals. F .: 138-139 ⁰ C.

Analysis:

Found: C 66.70 H 6.48 N 8.04% Calculated: C 66.60 H 6.48 N 8.17%.

Example k

For the suspension of 47.6 g of 0.2 mol of 3-carbethoxy-4-oxo-6-methyl-1 , 6,7,8,9,10-hexahydro-homopyrimidazole and 33.2 g £ 0.24 mol ^ potassium carbonate and 400 ml dry Acetone becomes 26 g £ 0.24 moles within 10 minutes given distilled ethyl chloroformate. The reaction mixture is slowly heated to a boil for 1 1/2 hours cooked, whereby the carbon dioxide is removed. After leaving

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cool, 600 ml of water are added to the reaction mixture, after which the acetone is distilled. It will be a brown one oily product obtained in the aqueous residue, which crystallizes on cooling. After filtering, washing with water and drying, 5 ^, 2 g of crude product are obtained

obtained- F .: 99-101 C. From 7, white anhydrous ethyl acetate 32 g of 1,3-dicarbethoxy-U-oxo- -6-methyl-1,6,7,8,9,1O-hexahydro-homopyrimidazole in the Preserved form of snow-white crystals. F .: 1O3-1O4 ° C.

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Claims (25)

PATENT CLAIMS 1. Compounds of the general formula I R, R ¹ , R ² , R ^{3 are} hydrogen, halogen, alkyl-; Alkoxy, nitro ü.
R is hydrogen, halogen, alkyl, alkoxy; Phenoxy-; Aryl ", R is hydrogen, halogen, alkyl-j aryl-; Aralkyl? Carbony 1- and their salts, in which R ¹ , R ² , R ³ water or amino group, hydrogen, HalOj aralkyl ^, hydroxyl or = 0 group, hydrogen, halogen, alkyl-j aryl group or carboxylic acid derivative group, R acyl group or alkoxycarbonyl group and the dashed Lines optionally denote double bonds. 2. l-Acetyl-a-carbMthoxy-it-oxo-e-methyl-l, 6.7 _t - 8.9-10-hexahydro-homopyrimidazoI. 3. 1-propionyl-S-carbethoxy - ^ - oxo-e-methyl- -1 * 6,7,8,9,10-hexahydro-homopyrimidazole. H. 1-Benzoyl-α-carbethoxy-i-oxo-e-methyl-1,6,7,8,9,10-hexahydro-homopyrimidazole. 5.!, S-dicarbethoxy-H-oxo-e-methyl-lje ^ ejSjlO -hexahydro-homopyrimidazole. 6. Process for the preparation of compounds of the formula I. , 3 "6 309846/1138 and their salts, in which the substituents have the same meaning as indicated above, characterized in that vi.:>; s compounds of the general formula II , (in which R, R, R ² , R ³ , R ⁴ and R ^ given above are sino ^? acylated, optionally an R, R ¹ , R, R, R and / or R group in a compound thus obtained of formula I is converted into another group R, R ¹ , R ² , R ³ , R ⁴ and / or R ⁵ within the scope of protection of the preamble ^), optionally one or more bonds which are drawn with dashed lines, are saturated and, if appropriate, a bond of the formula I obtained in this way is converted into salt. 7. The method according to claim 6, characterized characterized that ir; ^ n for acylation lower alkanecarboxylic acids, aromatic carboxylic acids or their ■ reactive derivatives od..ν UVylhaxog-informiate used . 8. The method according to claim 7, characterized marked that reactive acid derivatives, acid halides, pluric anhydrides or esters are used. 9. The method according to claims 6 to 8, d a through marked that acylation with acetic anhydride or P:? opionic acid ahydride without use a solvent is carried out. 10. The method according to claim S, d a d u r c "h marked that di «? Acylation at Er- 309846/1138 heating advantageous when boiling the reaction mixture Reflux is performed. 11. The method according to claims 6 to 8, characterized in that the acylation with acid chloride, preferably with benzoyl chloride. 12. The method according to claim 11, characterized characterized in that the reaction in the presence of an acid binder, advantageously tertiary Amines, is carried out particularly advantageously in the presence of triethylamine. 13. The method according to claims 6 to 7, d a through characterized in that the reaction in an apolaric organic solvent is advantageous is carried out in aromatic hydrocarbons, particularly advantageously in benzene. lh. The method according to claim S, characterized in that the acylation in the presence of. Dicyclohexylacarbodiimide is carried out with an alkanecarboxylic acid containing 1-6 carbon atoms or with an aromatic carboxylic acid, especially with benzoic acid. 15. The method according to claim 6, characterized in that the acylation is Alky Chloroformate, advantageously ethyl chloroformate used. 16. The method according to claim 15, characterized characterized in that the reaction is carried out in an inert organic solvent. 17. The method according to claim 16, characterized in that as an inert organic solvent Ketones »acetone can be used particularly advantageously. 18. The method according to claims 6 to 17, d adurch marked that as the starting point 309846/1130 l ~ is used a material ll ~ an alkoxy carbonyl lgruppe contained in the position compound of "general formula II, 19. The method according to claims 6 to 18, characterized in that a-carbethoxy-'l-oxo-G-methyl-ljB ,? , 8,9,10-hexahydro-homopyrimidazole is used. 20. Pharmaceutical Preparations »thereby indicated that they at least have a connection of the general formula I or their salts and suitable pharmaceutical carriers and / or auxiliaries. 21. Pharmaceutical preparations, thereby characterized as being an active ingredient 1- -Acetyl-S-carbethoxy - ^ - oxo-e-methyl-1, 6,1,8,9, 10-hexahydro-homopyrimidazole or contain their salts and suitable pharmaceutical carriers and / or auxiliaries. 22. Pharmaceutical preparations, thereby g e k e η η z, e i c Ii η e t that they are used as active ingredients 1- Propionyl-S-carbethoxy - ^ - oxo-e-methyl-ljS,?, 8,9,10-hexahydro-homopyrimidazole and their salts and suitable pharmaceutical carriers and / or auxiliaries. 23. Pharmaceutical preparations, thereby characterized as being an active ingredient 1- - Benzoyl-S-carbethoxy-f-oxo-e-methyl-l, 6,7,8,9,10-hexahydro-homopyrimidazole and their salts and suitable pharmaceutical carriers and / or auxiliaries. 2Ψ. Pharmaceutical preparations, characterized in that they are 1 _S 3- -Dicarbäthoxy-t-oxo-6-methyl-1, 6,7,8,9 »10-hexahydro-homopyrimidazole and their salts and suitable pharmaceutical carriers and / or aids included. 25. The method according to claims 20 to 24, d adurch marked that one has the active ingredient (jiie active ingredients / of the general formula I with 309846/1138 Suitable inert organic or inorganic solids or mixed liquid carriers and / or auxiliaries and the preparations advantageously in the form of tablets, capsules, Suppositories, formulated solutions. 309846/1138