DE2356005A1 - Analgesic 7-amino-imidazo (1,2-a) pyrimidines - pprepd. by condensation of substd. 2-amino imidazolin-(2) and substd. cyano fatty acid esters - Google Patents

Abstract

Novel 7-amino-imidazo 1,2-a pyrimidines of formula (I): (where R1 = opt. mono-, di or tri-F, Br, Cl, Alkyl, alkoxy or trifluoromethyl-substd. phenyl or -benzyl; R2 = H, lower alkyl (max 3C) or -(ch2)n -A; A = diaklkylamino(max 4C) pyrrolidin, morpholin or piperidin; n = 2 or 3) and their acid-addn salts have high analgesic activity, often comparable with morphine but without the undesirable side-effects. Dosage is 0.1-20 mg.

Description

235600

Case 1/501
Dr. Cr./sa

C. H. BOEKRIl JGER SOHN, Ingelheia am "Rhein

New 7-amino-imidazo [1,2-a] pyrimidines, medicaments containing them and processes for their Manufacture;

The invention "relates to new 7-amino-imidazo [1,2-a] pyrimidines of the general formula I.

in which R _{1 is} an unsubstituted or by fluorine, chlorine or bromine atoms, alkyl, alkoxy or trifluoromethyl groups one to three times substituted phenyl or benzyl radical and Rp is hydrogen, a lower alkyl radical with up to 3 carbon atoms or the radical - (CHp) - A denotes where A represents a dialkylamino radical with up to 4 carbon atoms in the alkyl groups or a pyrrolidine, morpholine or piperidine radical and η represents the number 2 or 3.

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The invention also relates to medicaments, the compounds of formula I or their acid addition salts contain as active ingredient.

The compounds of the formula I are prepared by reacting a substituted 2-aminoimidazoline (2) der general formula II

II

in the FL has the meaning given above, with a compound of the general formula III

^ C-pH-C _v
R ₂ ^X III

wherein R ₂ is defined as given above and X is a halogen atom, preferably a chlorine atom, or an alkoxy or alkylthio group with 1-4 carbon atoms in the alkyl part.

The condensation usually occurs in polar solvents, such as alcohols, or without the use of a solvent, by heating the two components Temperatures between 40 ° and 180 °, preferably 60 ° and 140 ° C., carried out. Basic catalysts such as Sodium ethylate, sodium methylate and the like prove in the implementation as advantageous or necessary. The intermediate stages that occur during condensation are usually not isolatable. They cyclize very easily to the compounds of the general formula I.

50 9 8 21/10 14 bad OR! Gf _NAL

The structures were assigned based on the NMR, IR and mass spectra.

Starting compounds of the formula II are, for example, in the UeIg. Patents 623 305,687 656, 687 657 and 705 9.44-described.

Starting compounds of the formula III in which Rp is a hydrogen atom means are commercially available products. The other compounds of the formula III in which Rp is not hydrogen, can by alkylation or aminoalkylation of the o: -C atom of cyanoacetic acid esters or other cyanoacetic acid derivatives be produced by known methods.

The 7-amino-imidazo [1,2-a] pyrimines according to the invention General formula I are basic compounds and can therefore be converted into acid addition salts in the usual way e.g. by dissolving the bases in alcohol and adding an ethereal acid solution. Acids suitable for salt formation are, for example, hydrochloric acid, hydrobromic acid, hydrogen iodide acid, hydrofluoric acid, sulfuric acid, phosphoric acid, Nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valeric acid, oxalic acid, malonic acid, succinic acid, Maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, Phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, ethanephosphonic acid, 8-chloro-theophylline and the same.

The compounds of the general formula I according to the invention as well as their acid addition salts are characterized by valuable therapeutic properties. They unfold in particular a strong analgesic effect. The potency comes close to that of morphine, if there are several representatives, without the undesirable side effects of morphine such as

/ 4 509821 / 1OU

Respiratory depression, addictive effects, and constipation can be observed. An antihypertensive effect is largely absent. The compounds of the general formula I and their acid addition salts can be used enterally or parenterally will. The dosage is 0.1-20 mg, preferably 2-10 mg.

The compounds of the formula I or their acid addition salts can also be used with other types of active ingredients. Suitable pharmaceutical dosage forms are for example tablets, capsules, suppositories, solutions, Emulsions or powders; in this case, the galenic auxiliary, carrier, Disintegrants or lubricants or substances to achieve a depot effect are used.

Corresponding tablets can, for example, by mixing the active ingredients with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate , or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, Lubricants such as magnesium stearate or talc and / or agents to achieve a depot effect such as carboxypolymethylene, Carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate are obtained.

The tablets can also consist of several layers. Correspondingly, coated tablets can be made by coating analog cores produced in the tablets with agents commonly used in tablet coatings, for example polyvinylpyrrolidone or Shellac, gum arabic, talc, titanium dioxide or sugar can be produced. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. The same can also be done the coated tablet can be made up of several layers to achieve a depot effect, the one above in the case of the tablets

509821/1014

mentioned additives can find application.

For the production of soft gelatin capsules or similar closed capsules, the active substance can be mixed with a vegetable oil can be mixed. Hard gelatin capsules can contain granules of the active substance in combination with solid powdery carrier materials such as lactose, sucrose, sorbitol, mannitol, starch, e.g. potato starch, Contain corn starch or amylopectin, cellulose derivatives or gelatin.

Juices of the active ingredients or combinations of active ingredients according to the invention you can also use a sweetener such as saccharin, cyclamate, glycerin or sugar, as well as a taste-improving agent, e.g. contain flavorings such as vanillin or orange extract. You can also use suspension aids or thickeners, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or contain protective substances such as p-hydroxybenzoates.

Injection solutions are used in the usual way, for example with the addition of preservatives such as p-hydroxybenzoates, or stabilizers, such as complexones, and filled sterile in injection bottles or ampoules. The solutions can also contain stabilizing agents and / or buffering agents.

Suitable suppositories can be created, for example, by mixing the active ingredients or active ingredient combinations provided for this purpose with conventional carriers such as neutral fats or polyethylene glycol or its derivatives. You can also use gelatine rectal capsules, which contain the active substance mixed with vegetable oil or paraffin oil, produce.

The following examples illustrate the invention without it to restrict.

£ 09821/1014

λ. nerstex examples

example 1

7-Amino-e- (2-chloro-o-methyl-phenyl) -2,3-dihydro-5-oxoimidazo- [1,2-a] pyrimidine.

To the mixture of 1.15 sodium and 5.65 g of ethyl cyanoacetate in 50 ml of absolute ethanol, 10.5 g of 2 - [(2-chloro-6-methylphenyl) -amino] -2-iraidazoline are added with stirring and the reaction mixture 5 Heated at reflux for hours. After cooling overnight, it is concentrated to dryness in vacuo. The remaining solid residue is mixed with water and the insoluble substance is filtered off with suction. This is washed with water and dried. (Yield 11.0g). For purification, the imidazo [1,2-a] pyrimidine derivative obtained in this way is stirred with about 50 ml of benzene. After filtering off with suction, washing with benzene and drying, a yield of 6.8 g is obtained, corresponding to 49.2 f of theory. 241 ⁰ C. The substance is pure according to thin layer chromatography. It is insoluble in water and benzene, soluble in methanol and dilute mineral acid.

Example 2

7-Amino-S- (2,6-dichlorophenyl) -2,5-dihydro-5-oxo-6- (3-piperidino-n-propyl) -imidazo [1,2-a] pyrimidine

To the solution of 0.57 g of sodium in 25 ml of absolute ethyl alcohol are added 5.95 g of 5-piperidino- {. ■ l) -2-cyano-valerian— ethyl acid ester was added and an additional 5.75 g of 2- (2,6-dichlorophenylamino) -2-imidazoline were added to the mixture. The mixture is then refluxed for 5 hours with thorough stirring. After cooling, the reaction mixture is in Concentrated in vacuo and the remaining residue mixed with water. The viscous mass that separates out in the process

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crystallizes after a while. It is suctioned off, washed with water, dried, stirred up with benzene, again suctioned off, washed with benzene and dried. Yield: 3.2 g corresponding to 30.4 $ of theory » Mp 232-235 ° C. .

The substance is pure according to thin-layer chromatography, it dissolves in methanol, chloroform and dilute mineral acid and is insoluble in water and benzene.

The following contains further examples analogous to Examples 1 and 2 Tabel:

/8th

09821/1014

Example no.

L °

? p.L ° c]

yield

[# of the theory]

7 8

10

11

12th

13th

Cl

, C

CH

OCH

CH θ

Cl

243

"H

202-203 127-128

157-158

225-226

140-141

211-214

228

191-194 156-159 149-152

16.2

20.3

79.0

37.2

24.2 43.5

9.3

35.8

13.5

33.7

46.1

S09821 / 10U

/ 9

example
No. R ₁ Cl Cl R ₂ [ ^fe c] [ mspoot
.% of theory] W-CHp- 229-232 it i "\
TT r ~ \ ^ ff \ - ^ _ γλ TT H 219-221 45.8. 15th 1 H 223-224 27.0 16 Cl H - 10.1 \ l 202-203 17th (° /
^ CH ₃ H 211-212 45.0 18th H 238-239 44.3 19th H 54.5 227-228 20th -CH ₂ -CH ₂ -I ^ J) 10.5 204-206 21 201-202 33.5 22 - -WHERE 11.2
-

& 03821 / 10U

/ 10

example

No.

R,

LSp-.

Yield £ of theory j

23 24

25th

26th

27

28

29

30th

J-J

N ι '

^C 2 ^H 5

CH ₀ -CH ₀ -R ^

-CH _o -CH _o -CH 2 2

-ir

CH

105-109

196-198

180-182

199-202

220-222

181-183

222-225

53.3

11.1

26.6

42.7

12.4

18.0

9.3

118-120

12.4

509821/1014

/ 11

B. Formulation Examples Example 31

Tablets'

7-amino-8- (2-chloro-6-methyl-phenyl) -

2,3-dihydro-5-oxo-imidazo- [1,2-a] 5.0 mg

pyrimidine

Milk sugar 23.5 mg

Corn starch ■ 20.0 mg

Gelatin 1.0 mg

Magnesium stearate 0.5 mg

50.0 mg

Manufacturing:

The mixture of the active ingredient with lactose and corn starch is mixed with a 10% aqueous gelatin solution Sieve with 1 mm mesh size, granulated, dried to 40 ° C and rubbed through a sieve again, this way obtained granules are with. Magnesium stearate mixed and compressed into tablets.

S09821 / 1 01A

Example 3? Coated tablets

7-amino- (2,6-dichlorophenyl) -2,3-dihydro-5-0X0-6- (3-piperidino-n-propyl) -imidazo 10.0 mg [1,2-a] pyrimidine

Corn starch 25.0 mg

Secondary calcium phosphate 100.0 mg

Magnesium stearate 15.0 mg

150.0 mg

Manufacture;

The mixture of the active substance with corn starch and secondary calcium phosphate is made into a paste and granulated in the usual way. The granules obtained are made with magnesium stearate mixed and pressed into tablet cores, which are coated in the usual way with a shell consisting of an aqueous Suspension consists of sugar, titanium dioxide, talc and gum arabic.

Example 33 Suppositories

7-amino- (2,6-dichlorophenyl) -2,3-dihydro-5-oxo-6- (3-piperidino-n-propyl) -imidazo 10.0 mg [1,2-a] pyrimidine

Milk sugar 190.0 mg

Suppository mass 1500.0 mg

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Manufacturing:

The finely powdered substance is made using an immersion homogenizer stirred into the melted suppository mass cooled to 40 °. The mass becomes light at 35 ° C pre-cooled suppository molds poured out.

509 821 / 1OU

Claims (1)

Claims . New 7-amino-imidazo [1,2-a] pyrimidines of the general formula 1 in which R, a phenyl or benzyl radical which is unsubstituted or substituted by fluorine, chlorine or bromine atoms, alkyl, alkoxy or trifluoromethyl groups, and R _{0 is} hydrogen, a lower alkyl radical with up to 3 carbon atoms or the radical - (CHp) -A denotes where A is a dialkylamino radical with up to 4 carbon atoms in the alkyl groups or a pyrrolidine, morpholine or piperidine radical and η stands for the number 2 or 3 and their acid addition salts. 2. Process for the preparation of compounds of general formula I and their acid addition salts according to Claim 1, characterized in that there is a substituted 2-aminoimidazoline of the general formula II II in the R-, which has the meaning given above, with a 5.0 9 821/1014 2356ÖQ5 Compound of the general formula III where R ₂ is defined as given above and X is a halogen atom, preferably a chlorine atom, or an alkoxy or alkylthio group having 1 to 4 carbon atoms in the alkyl moiety, and optionally converting the compound into an acid addition salt. 3 · The method of claim 2, characterized in that the reaction is performed in polar solvents or without use of a solvent by heating the two components at temperatures between 40 ° and 180 ⁰ C. 4. The method according to claim 2 and / or 3, characterized in that the reaction is carried out in the presence of a basic Catalyst makes. 5. Pharmaceutical preparations, characterized in that they contain a compound of the general formula I or their acid addition salt. 6. Process for the production of pharmaceutical preparations according to claim 5, characterized in that one uses a compound of the general formula I or its acid addition salts with the usual auxiliaries, carriers, disintegrants or lubricants or substances to achieve a depot effect '. to tablets, capsules, suppositories, solutions, emulsions or Powder processed. denotes, jlaJ3. ~ = msfi ^ e "a connection of the general night 509821/1014