DE2445335A1 - NEW ORGANIC COMPOUNDS AND PROCEDURES FOR THEIR PRODUCTION - Google Patents

Description

New organic compounds and processes for their

Manufacturing

The invention relates to new organic compounds of the formula I,

wherein R _{1 is} halogen, a nitro or amino group or an alkyl, alkoxy or an alkylthio group irate in each case 1-4 carbon atoms, η is 0, 1 or 2, where, if η is 2 , both R- are the same or are different, R _{2 is} hydrogen, an alkyl group with 1-4 carbon atoms

or a group of the formula

means in which

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R and R ₁ . are identical or different and are each hydrogen, an alkyl group with 1-3 carbon atoms, an alkoxy group with 1-3 carbon atoms, halogen or a hydroxyl, a nitro, an amino or an acetylamino group, or R and R together if they are at adjacent carbon atoms are a methylenedioxy group, and R is hydrogen, an alkyl group having 1-3 carbon atoms or an alkoxy group having 1-3 carbon atoms, and R is hydrogen or an alkyl group having 1-4 carbon atoms, so. ^T ie a process for their manufacture.

The compounds of the formula I can be converted into their acid addition salts transferred v / earth and vice versa.

The compounds of the formula I in which R and / or R _? has a meaning other than hydrogen, are obtained as racemates and can be separated into their optically active forms.

_{If the substituents R 1} , R ₄ and R ₅ in compounds of the formula I are halogen, halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, in particular chlorine. In the substituents R, to

R ₄ . Alkyl also stands for an even in the alkoxy group

chain or branched alkyl group, such as, for example, a methyl, ethyl or a straight-chain or branched propyl group or, with the exception of R, R and R, a straight-chain or branched butyl group. The substituents R., R- and R _ß can be at any point on the phenyl ring. ;.

According to the invention, compounds of the formula I are obtained by adding compounds of the formula II,

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II

where R, and η have the above meaning, with compounds the formula

* ... R ₂ -CH = C-COQR III

wherein R- and R _{3 have the} above meanings and R represents an alkyl group having 1-4 carbon atoms.

The implementation of compounds of the formula II with connec- fertilization of the formula III takes place either in an inert organic solvent, for example a lower one Alcohol, such as ethanol, by heating to temperatures between 80 and 110 ° C, preferably to the boiling point of the reaction mixture for approx. 120 to 140 hours, or in the absence of a solvent at temperatures between 130 and 150 ° C for approximately the same period of time or by heating in a chlorinated hydrocarbon, preferably in 1,2,4-trichlorobenzene to temperatures between 190-200 ° C for about 2 hours. In this reaction, it appears primarily a 1,4-addition product of the formula IV,

R ₀ R-12 1 3

- C - C - COOR

^HH iv

ε ο 'yes 1 ί, / 1 1 1, ο

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where R, R_, R and R and η have the above meaning,

JL £ » »J /

to arise, which cyclizes spontaneously under the condensation conditions with elimination of the -OR group.

According to the above procedure, a mixture of isomers is obtained, from which the compounds of formula I, for example by chromatography using aluminum oxide, silica gel, etc., and suitable eluents, for example the eluents mentioned in Example 1 or a mixture of toluene and Can isolate chloroform.

The compounds of the formulas II and III used as starting compounds in the above process are either known or can be prepared from known starting compounds in a manner known per se.

Compounds of the formula I in which R and / or R are different Have meaning as hydrogen, can be obtained as racemates or as optically active forms. The separation of the Racemates in their optically active forms are carried out in a manner known per se, for example by salt formation with dibenzoyltartaric acids and fractional crystallization of the salts obtained.

In animal experiments, the compounds of the formula I are distinguished by a pronounced analgesic effect and can therefore for the treatment of a wide variety of painful conditions Genesis can be used.

The analgesic effect of compounds of the formula I is shown in particular in the known test, in which the inhibition of the phenylbenzoquinone syndrome in the mouse is measured in doses of 2-50 mg / kg po ₇ and in the known tail-flick test in the mouse in Doses of approx. 3-50 mg / kg.

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In addition to the analgesic effect, the compounds of formula I also show an exudatherrir.ende effect and can therefore can also be used as anti-exudatives. The compounds of the formula I also have a diuretic effect and can therefore also be used as diuretics «

In the carrageenan edema test in rats, which is significant for the exudation-inhibiting effect, the edema being caused by subplantar injection of a carrageenan solution into the hind paw, the compounds of the formula I have an effect when administered in doses between 0.5 and 60 mg / kg po after 3 hours a reduction in swelling compared to a control group. The diuretic effect of compounds of the formula I is shown in tests on diuresis rats (method described by E. Flückiger et al. , Switzerland. Med. Wochenschrift 1963) when administered in doses of 0.1 to 50 mg / kg po

For the above application, the dose to be administered depends on the compound used and the mode of administration as well as the type of treatment. When using compounds of the formula I as analgesics, satisfactory results are obtained Results when the compounds are administered in a daily dose between 0.4 and 50 mg / kg p.o. In the When used as antiexudatives, satisfactory results are obtained with daily administration of the compounds between 0.5 and 60 mg / kg p.o. If compounds of the formula I are used as diuretics, satisfactory ones are obtained Results with daily administration of the

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Bonds of 0.05 and 50 mg / kg p.ο. With larger ones Mammals should be the daily dose when using compounds of the formula I as analgesics between 30 and 300 mg, as antiexudatives between 35 and 500 mg and as diuretics between 5 and 300 mg. These Amount can also be administered in correspondingly smaller doses 2-4 times a day or in sustained release form.

The preferred compounds of the formula I of the present invention are those in which R is halogen or an alkyl group, in particular chlorine or methyl, and η is 0 or 2, where, in the case η is 2, both R. ₁ are preferably in the positions 2,6.

The compounds of formula I and their acid addition salts, which have the same degree of activity as the free bases can be used orally, enterally or parenterally. In the manufacture of appropriate forms of administration can the compounds of formula I with appropriate carriers and auxiliaries, such as. Lactose, corn starch, Talc, magnesium stearate, etc., mixed together.

A preferred tablet composition consists of 50 mg of 8- (2,6-dichlorophenyl) -5- (4-chlorophenyl) -2,3,6,7-tetrahydroimidazo [1,2-a] pyrimidin-7 (8H) -one, 140 mg lactose, 5 mg corn starch, 5 mg talc and 0.1 mg magnesium stearate.

The compound used in this tablet composition is the preferred compound of the invention.

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Example 1; 8- (2,6-dichlorohenyl) -5-ohenvl-2,3,6,7-

"'te tr ahy dro- irr.i daz ο [1,2-a] py r iTri. din- 7 (8H) - on

33.5 g of 2- (2 _/ 6-dichloroanilino) inddazoline and 70 ml of ethyl cinnamate are mixed and the resulting mixture is heated to 150 ° C. for 166 hours. It is then cooled and the residue is dissolved in 500 ml of a mixture of chloroform and ether (1: 4). The solution is extracted 4 times with 80 ml of 2N hydrochloric acid each time and once with water. The combined aqueous extracts are concentrated with. Sodium hydroxide solution made alkaline (pH 13) and extracted 5 times with 400 ml of methylene chloride each time. The organic extract is washed twice with water, then dried over sodium sulfate and evaporated. The crude bases obtained are separated by chromography on aluminum oxide. _{8- (2/} 6-dichlorophenyl) -5> phenyl-2,3,6,7-tetrahydro-imidazo [1,2-a] pyrimidine is obtained from the fractions eluted with ether and ether-chloroform (9: 1) -7 (8H) -one obtained from m.p. 183-186 °.

Using the procedure described in Example 1 and corresponding starting compounds lead to the following compounds of the formula I:

Example ι · (R ₁ 'η- R _? Ί 2 2-Cl 6th -Cl CH 3 3 H H CH ^H 5 4th H H ^C 6

M.p. ('C)

2-Cl 6-ci

5a) (+) 2-Cl 6-Cl

H 160-165 °

H 79-81 °

H 213-216 ° (picrate)

H 222-224 '

H 212-219 °

[a]! Jn = + 19.7 °

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example

<Vn R ₃ m.p. ( ⁰ C)

5b) (-) 2-cl 6-Cl Cl

2-CH ₃ 6-Ch ₃ Cl-

lf \ H

= -19.7 '

H 214-216 '

2-CH ₃ 6-Cl Cl-r V-H 216-218 °

2-CH ₃ 6-Cl 2 -CH 6-CII

2-Cl. 6-Cl

^C 6 ^H 5 ^C 6 ^H 5

Cl

192-195 ° 186-188 °

H 145-150 ° (hydrochloride)

2-egg 6-; ci

Cl. Cl

2-CK ₃ 6-CH ₃

200-201 °

2-CII 6-CiI

Cl

2-Cl. 6-Cl Cl

Cl '

2-CH ₃ 6-CH ₃ Cl

Cl

H 187-191 °

ο ο π η η / 1 U η

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example

^R 2

R 3 m.p.

2-egg 6-Cl

172-175 '

17'- 2-CH ₃ O-CH ₃ H ₃ CO - // vs

18 2-Cl 6-Cl F

212-214 '

² ~ ^CK

213-216 °

20. 2- Cl 6-Cl Br-A

H. 213-217

21 '2-Cl 6-Cl • ^- CH

^not 3

'/ W

22 2-Cl 6-CH.

H 140-142 °

Cl

23 2-Cl 6-C1 Cl

H 189-190 °

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example

RJ Srop ,

25 2-Cl 6-Cl HC

19 4-19 7 '

26 2-Cl "" 6-Cl

27 2-ci 6-Cl H ₂ N- ^ ^ -

28 2-Cl 6-Cl

23 > 2- Cl 6-Cl

30 2-Cl 6-Cl

31 2- ei 6-ci

CH CO-NH

32 2-Cl 6-Cl

188-190 °

33 2-CH. 6-CH

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example

- 11 - ^(R l> n ^R 2

50 (2 ^ 335

M.p.

OCH

-34 2-egg 6-Cl

H ₃ CO

OCH.

H 100-106V 175-180 '

35

6-CH

H ₃ C

CH.

OCH.

36 2-Cl 6-Cl

Q-

37 2-Cl 6-Cl

38 2-Cl 6-Cl

OCH

39 2-Cl 6-Cl

2-Cl 6-Cl OCH. "CO _f ~ V"

^H 3 ^C °

OCH ₃

41 2-Cl 6, -Cl

^C 6 ^H 5

42 2-Cl 6-Cl HO-

43 2-Cl 6-CH ₃ F. // V

H 180-183 *

H 143-146 °

H 214-216 '

H 169-172 °

168-174 ^C

278-2 86 °

(Ilydrobromide)

The optically active forms of the racemate of Example 5 described in Examples 5a) and 5b) are obtained in a manner known per se by resolving it rait + or benzoylvic acid.

OIL 471 1 AO "'" · · "■ ·

Claims (5)

- 12 - 500-5357 Claims 1 «Process for the preparation of new organic compounds of the formula I ₁ where R ₁ denotes halogen, a nitro or amino group or an alkyl, alkoxy or an alkylthio group rr.with in each case 1-4 carbon atoms, η denotes 0, 1 or 2, where if η denotes 2, both R. or are different, hydrogen, an alkyl group having 1-4 carbon atoms // VV / 4 or a group of the formula - U "\) ·, in which V ^R 5 R. and R are identical or different and are each hydrogen, an alkyl group with 1-3 carbon atoms, a Alkoxy group with 1-3 carbon atoms, halogen or a hydroxyl, a nitro, an amino or an acetylamino group, or R and R together, if they are on adjacent carbon atoms, represent a methylenedioxy group and R ,. Denotes hydrogen, an alkyl group with 1-3 carbon atoms or an alkoxy group with 1-3 carbon atoms, and R denotes hydrogen or an alkyl group with 1-4 60981 4/1140 - 13 - · 500-5357 Carbon atoms, characterized in that compounds of the formula II, II wherein R ₁ and η have the above meaning, with compounds of the formula III, R-CH = C-COOR III where R ~ and R have the above meaning and R_ is a Alkyl group with 1-4 carbon atoms is implemented. 2. The method according to claim 1, characterized in that compounds of the formula I are converted into their salts. 3. The method according to claim 1, characterized in that compounds of the formula I, wherein R, and / or R has a meaning other than hydrogen, converted into their optically active forms. 6Q98U / 1U0 "14-500-5357 4. New organic compounds of the formula I, wherein R ₁ denotes halogen, a nitro or amino group or an alkyl, alkoxy or an alkylthio group lüit in each case 1-4 carbon atoms, η stands for 0, 1 or 2, where, if η stands for 2, both R's are identical or different are hydrogen, an alkyl group having 1-4 carbon atoms or a group of the formula (f "^ denotes in which ρ _R R. and R, - are identical or different and are each water-4 5 substance, an alkyl group with 1-3 carbon atoms, an alkoxy group with 1-3 carbon atoms, halogen or a hydroxyl, a nitro, an amino or an acetylamino group, or R and R ₁ . together, if they are on adjacent carbon atoms, represent a methylenedioxy group, and R represents hydrogen, an alkyl group with 1-3 carbon atoms or an alkoxy group with 1-3 carbon atoms, and R represents hydrogen or an alkyl group with 1-4 carbon atoms, optically active forms of compounds of the formula I in which R ₂ and / or R _{3 have} a meaning other than hydrogen, and acid addition salts of compounds of the formula 809814/1140 500-5357 5. Medicines, characterized by the content of compounds of formula I. © he patent attorney: 609814/1140