DD205165A5 - PROCESS FOR PREPARING NEW IMIDAZO (1,2-A) PYRIMIDINES - Google Patents

Abstract

The invention relates to novel imidazo (1,2-a) pyrimidines of the general formula I, in which R denotes a phenyl radical which is monosubstituted or polysubstituted by a hydrogen, fluorine-chlorine or bromine atom or a methyl-o.-trifluoromethyl group, and also their acid addition salts. The novel compounds can be prepared by cyclization of compounds of formula II and are useful as analgesics, antihypertensives and cardiac and caronartherapeutics.

Description

Berlin, November 16, 1982 AP О 07 D / 241 056/6 (61 043/11)

Process for the preparation of imidazo Jjl _f 2-aJ pyrimidine

Field of application of the invention

The invention relates to a process for the preparation of new Imidazo £ i, 2-aj pyrimidines !! with valuable pharmacology, especially analgesic, blood pressure lowering and heart rate lowering properties.

The compounds according to the invention are used as medicaments, for example for the treatment of pain, hypertension and heart and coronary disorders.

Characteristic of the Known Technical Solutions The starting compounds for the preparation of the novel imidazo ti 12-a] pyrimidines are known.

Starting compounds of the general formula II

are described in DE-OS 2,523,103. Starting compounds of general formula III

17th HOV. 1982 * 048 243

16.11.1982

AP О 07 D / 241 056/6

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may be prepared by thermal cyclization of 2- [H- (Sutist, phenyl) -H-propargyl-be-aminqj2 iniidazolinen lemperaturen prepared at from 60 to 180 ⁰ O '

In the formulas, R represents a monosubstituted to trisubstituted phenyl radical.

Object of the invention

The aim of the invention is the provision of novel imidazo [i, 2-a] pyrimidines with valuable pharmacological, in particular analgesic, antihypertensive and heart rate lowering properties.

Explanation of the essence of the invention

The invention has for its object to find a process for the preparation of new Imidazo ε, 2-aJpyrimidinen with the desired properties of readily available starting compounds.

16.11.1982

IP O 07 D / 241 056/6

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According to the invention, novel, substituted imidazo [i, 2-a] pyrimidines of the general formula

⁴ - A

(I)

and their physiologically compatible SBureauditionasalze produced with valuable therapeutic properties. In the formula I, R is a monosubstituted to trisubstituted phenyl radical. They substituents which may be the same or different, a hydrogen), fluorine, chlorine or bromine atom or a methyl or Irifluormethylgruppe mean.

They produce the imidazo 1,2-a pyrimidines of the general formula I is carried out by

a) thermal cyclization of compounds of general formula II

HJI-

wherein the radical R is defined as indicated above, at temperatures between 60 and 180 ⁰ C; or

b) isomerization of imidazo [1,2-aj] pyrimidines of the general formula III

(III)

wherein the radical R is defined as indicated above, in the presence of a strong base, at temperatures of 40 to 60 ^° C.

The thermal cyclization according to process a is conveniently effected by heating the compounds of general formula II in the presence of a polar or non-polar organic solvent at temperatures of about 60 to 180 ⁰ C.

The specific temperatures depend on the reactivity of the particular compound of formula II.

In process a, in addition to the erfindüngsgemäflen compounds of the general formula I in addition also their isomeric compounds of the general formula IV.

^ ₂

I iv

(R is as defined above)

which must be disconnected.

Since the isomers of the general formulas I and IV differ significantly in their pk values (pk _I > pk _IV ), they can be easily separated from one another because of this difference. By fractional extraction of the aqueous solution of a mixture of compounds of formulas I and IV with increasing pH values, the weaker basic compounds of the general formula IV can be extracted first, while the more basic compounds of general formula I according to the invention still remain in the aqueous solution , The substances with

the largest pk value, ie the compounds of the general formula I _t according to the invention show in the thin-layer chromatography (silica gel) in the systems

A = toluene / dioxane / ethanol / conc. Ammonia (50: 40: 5: 5) В = ethyl acetate / isopropanol / conc. Ammonia (70: 50 ι 20) C = sec-butanol / formic acid (85 #) / H ₂ 0 (75: 15: 10) a lower R ^ value than the isomeric compounds of the general formula IV. The compounds of the invention Extract after further alkalization of the aqueous solution, for example with sodium hydroxide to a higher pH, also in pure form and thus isolate, the purity of the extracts can be checked by thin layer chromatography.

In the isomerization of the compounds of the general formula III (method b) is conveniently carried out in polar aprotic solvents in the presence of a strong base, for example potassium tert-butoxide as well as at elevated temperature, for example 40 to 6O ⁰ C.

The structures of the new imidazo [l, 2-a] pyrimidines of the general formula I are ensured by ^ J- or C-Кегпгезопапг and mass-pectroscopic investigations.

Starting compounds of general formula II are known and e.g. described in DE-OS 25 23 103.

Starting compounds of general formula III can be prepared by thermal cyclization of 2- [N- (naphth-phenyl) -N-propargyl-amino] -2-imidazolinen at temperatures of 60 to 18O ⁰ C.

The imidazo [l, 2-a] pyrimidines of the general formula I according to the invention can be converted into their physiological

gisch compatible acid addition salts überfuhrt be. Examples of suitable acids for salt formation are hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulfuric, phosphoric, nitric, acetic, propionic, butyric, caproic, valeric, oxalic, malonic, succinic, maleic, fumaric, lactic, tartaric, citric, malic, benzoic, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, 8-chlorothiophylline and the like.

The novel compounds of the general formula I and their acid addition salts have an analgesic action, lowering the blood pressure and lowering the heart rate. The analgesic effect was tested after the writhing test on the mouse. In addition, a blood pressure-lowering effect was observed in the blood of rabbit blood pressure. The influence of the heart rate was examined on spinal rats and intact anesthetized rats. Because of these effects, the compounds of general formula I are suitable as medicaments for the treatment of pain, hypertension and coronary diseases. The active substances can be administered enterally or parenterally. The dosage is 0.1 to 80 mg, preferably 1 to 30 mg.

The compounds of the formula I or their acid addition salts can also be used with other active compounds. Suitable pharmaceutical dosage forms are, for example, tablets, capsules, suppositories, solutions or powders; In this case, the usually used galenic auxiliaries, carriers, explosives or lubricants or substances for the production of a depot effect can be used for their preparation.

16.11.1982

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Auaf lihrungabe isplel

The following examples are intended to illustrate the invention and the preparation of the novel compounds without limiting them.

Herstellungabeiapiele

Example 1 fi- (2,6-Dichloro-pentynyl) -2- [i.5.8-tetrahydro-1-imo-azo-2-yl

5.4 g of 1-Progargyl-2- (2,6-dibhloropbenylimino) imidazolidine are refluxed in 40 cm of ethanol for 10 hours with stirring. The reaction mixture is then evaporated to dryness in vacuo. The residue is dissolved in 1 H hydrochloric acid and the resulting solution extracted at ascending pH values (alkalization with 2 Jf KaOH) fractionated with ether. The starting imidazolidine and an isomeric compound of formula IV can be separated by extraction at low pH (thin layer chromatogram control). Once the desired imidazo £ i, 2-aJ-pyrimidine is pure in the aqueous phase, basified with 2-H Hatronlauge and extracted ils new compound with ether (Dufnschichtohromatogramm-control of ether fractions). After removal of the ether in vacuo, efhält a yield of 1.1 g, corresponding to 20.5 % of theory

Melting point »156 to 166 ⁰ O

The Hjrdrobromid melts at 203 to 204 ⁰ O.

Example 2

8- (2-Вгеш-6-Диоімзпепу1) -2.5.5.8-tetrahydro-imidazoles. 2-a1i »Yrlmldl n

8.9 g of l-propargyl-2- (2-bromo-6-fluorophenylimino) -imidazolidine are heated in 60 ml of absolute ethanol for about 11 hours on RUoIc (IuS), then the solvent is removed in vacuo and the remaining residue is dissolved consisting of Ausgangsimldazolidin, l- (2-bromo-6-f luor-phenyl) -2,3 _f 5, 6-tetrahydrc-2-methylene-lH-imidazo [l, 2-a] imidazole and the desired imidazo [l, 2-a] -pyrimidine, in dilute IN hydrochloric acid.

With increasing pH values (alkalization with 2 N NaOH), the two first mentioned compounds are then removed by fractional extraction with ethyl acetate. As soon as the aqueous solution contains only the new imidazo [l, 2-a] pyrimidine (thin-layer chromatogram control), alkalinize again and the new compound is extracted with ethyl acetate.

Yield: (after concentration in vacuo): 0.9 g (10.1 % of theory) Melting point: 116 to 120 ° C.

Example 3

8- (2-chloro-6-methyl-phenyll) -2 3 5. 5-tetrahydro-imidazo- ri, 2-a-pentimidine

620 mg e- (2-chloro-6-methyl-phenyl) -2,3,7,8-tetrahydro-tmidazo [l, 2-a] pyrimidine are dissolved in 5 com dimethyl sulfoxide and this solution 280 mg of potassium tert. Butylate added with stirring. The mixture is then heated for 48 hours at 50 to 60 ⁰ O. After this time, part of the 2,3,7,8-tetrahydro-imidazo [1,2-a] pyrimidine used is 2,3,5,8-tetrahydro-imidazo [1,2-a] pyrimidine isomerized. A separation can be carried out after evaporation of the solvent and after dissolving the present isomer mixture in dilute IN HCl hydrochloric acid, as described in Examples Nos. 1 and 2, by fractional extraction at ascending pH values (DUnschiohtchroma togramm control).

Melting point: 107 to 113 ⁰ O.

Further examples of compounds of the general formula I can be found in the following table:

Example R Yield

No. (Si the (° 0)

Theory)

12.0 115-117

22.4

18.9 146-151

17.8 104-108

Yield mp.

(Ji the ( ⁰ C) theory)

19.6

91-94

16.0 113-117

26.0 134-138 21.9 120-123

Example no.

f ¹

H, C- (O

Formulation examples Example A: dragees

Active ingredient according to the invention lactose

corn starch

sec. Calcium phosphate soluble starch magnesium stearate colloidal silica

a total of 250 mg

production:

The active ingredient is mixed with a part of the excipients, thoroughly kneaded with an aqueous solution of the soluble starch and granulated in the usual way with the aid of a sieve. The granules are mixed with the remainder of the excipients and pressed into dragee cores of 250 mg in weight, which are then coated in the usual way with the aid of sugar, talc and gum arabic.

Example B: Ampoules

Active substance according to the invention 1.0 mg

Sodium chloride 18.0 mg

least. Water ad 2.0 ml

production:

Active substance and sodium chloride are dissolved in water and bottled under nitrogen in glass ampoules.

Example C: drops

Active ingredient according to the invention 0.02 g

p-hydroxybenzoic acid methyl ester 0.07 g

Propyl p-hydroxybenzoate 0.03 g

demineralised water ad 100 ml

Claims (3)

(61 048/11) Claim for damages 1. Process for the preparation of new imidazo [i, 2-a] pyrimidines !! the general formula wherein E is a mono- to trisubstituted by a hydrogen, fluorine, chlorine or bromine atom, a methyl or trifluoromethyl group-substituted phenyl radical, wherein the substituents are identical or different know. and their acid addition salts, characterized by a) a compound of the general formula шт. '- ^(π) · wherein R is as defined above, cyclisierti at temperatures of 60 to 180 ⁰ O or b) an imidazo [_ 1,2-aJpyrimidin the general formula CIII). wherein E is as defined above, in the presence of a strong base at temperatures of 40 to 60 ⁰ O iso- 16.11.1982 AP О 07 E / 241 056/6 (61 048/11) and, if appropriate, the resulting base is converted into an acid addition salt. 2. The method according to item 1 _f, characterized in that durchfuhrt the reaction in the presence of a polar or non-polar organic solvent. 3. A process for the preparation of medicaments, characterized in that one or more compounds according to item 1 with conventional galeniechen excipients, carriers, explosives or lubricants or substances to achieve a depot effect to tablets, capsules, suppositories, solutions or powder formulated.