DE1026744B - Process for the preparation of substituted 1, 1, 2-triphenylaethylenes - Google Patents

Description

GERMAN

The invention relates to a process for the preparation of 1,1,2-triphenylethylenes in which a phenyl group is substituted by a carbamidine group, and their salts with acids. These connections are new.

The substituted 1,1., 2-triphenylethylenes of the present Invention can be expressed by the following formula

Rv

C = C

R '

represent, wherein one of the radicals R is a carbamidine group, which is either in the o- or m- or p-position on Is phenyl ring, and the other two are hydrogen or a low molecular weight alkyl or alkoxy group, which is either in the o- or m- or p-position on the phenyl ring, and Y is hydrogen or a cyano group means.

The alkoxycarbimino group contains the residue of a lower alcohol having 1 to 6 carbon atoms, usually an ethanol residue. The carbamidine group can be mono- or disubstituted, for example with lower ones Alkyl radicals, such as methyl, ethyl and propyl radicals, or the amido nitrogen of the carbamidine group can Part of a heterocyclic ring, e.g. B. a pyridine, piperidine, morpholine or pyrrolidine ring, be.

Many of these new compounds exist in the form of stereoisomers, and in some cases are both the cis and trans forms have been isolated. In the present description there is no difference made between the stereoisomers.

It is known that certain triphenylethylene derivatives, in particular certain triphenylhalogenoethylenes, are estrogens Possess properties. The compounds of the present invention are devoid of appreciable estrogens Properties, however, have a physiological effect on other parts of the endocrine system and point valuable physiological activity. For example, some decrease the peripheral level of eosinophils, some produce changes in adrenal ascorbic acid, some have anti-inflammatory effects, either due to local exposure or due to systematic hormonal activity or both, and some inhibit it Formation of granulomas. The new compounds have some or all of these effects to varying degrees Measures and are therefore used to combat non-endocrine inflammation and endocrine disorders in which Changes in hormonal effects are desired, such as with inflammatory lesions of the eye and valuable in so-called collagen diseases.

Process for the preparation of substituted 1,1,2-triphenylethylenes

Applicant:

The WM. S. Merrell Company, Cincinnati, Ohio (V. St. A.)

Representative: Dr. F. Zumstein, patent attorney, Munich 2, Bräuhausstr. 4th

Claimed priority: V. St. v. America August 18, 1953

Marcus George Van Campen Jr., Robert Edward Allen, Wyoming, Ohio, Frank Patrick Palopoli and Edward Lewis Schumann, Cincinnati, Ohio (V. St. A.),

have been named as inventors

In addition, some of the new compounds have a fungistatic effect, for example against histoplasmic, Trychophyton, Microsporum, Nocardia and Blastomyces organisms. In general, the new compounds exhibit these effects when administered parenterally and when applied locally. the new compounds are therefore effective when administered orally as well as when administered parenterally.

According to the invention, the new compounds are prepared by replacing one which is substituted by a cyano radical 1,1,2-triphenylethylene of the general formula

wherein one of the radicals R 'is a cyano group which is either in the o- or m- or p-position on the phenyl ring and the other two are hydrogen or a low molecular weight alkyl or alkoxy group either in

709 957/422

ο- or m- or p-position on the phenyl ring are and Y denotes hydrogen or a cyano group, in a manner known per se with

a) converts an alcohol in the presence of an acid to the corresponding alkoxycarbimino compound and this alkoxycarbimino compound with ammonia or a primary amine or a heterocyclic amine or a salt thereof or

b) with a secondary amine and a Grignard reagent to give the corresponding carbamidine compound implements.

From the German patent 839 350 it is known to produce 2-oxy-4,4'-diamidinostilbene by 2-Oxy-4,4'di-cyano-stilbene in solution or in suspension in an anhydrous alcohol with dry chlorine or Treated hydrogen bromide and the amido ether obtained with ammonia in the desired diamidine or its salt transferred.

From the German patent specification 850 297 it is known to use 4,4'-diamidino beets by a similar process to manufacture. These two compounds as well as the compounds made according to the present invention the following examples were examined for their anti-inflammatory effect. Two tests were used for this, the mustard test and the pill test.

The mustard test is a measure of effectiveness against acute inflammation, the pill test against chronic inflammation. A compound that is active in the latter test is considered to be antigranuloma active. the Tests themselves are briefly the following:

Mustard test: The test substances are administered subcutaneously three times a day for 3 days and once on the fourth Day. A standard dose of mustard suspension is injected subcutaneously into the sole of one hind foot of rats administered between the first and second dose on the third day. The volume of the limbs is just before the Mustard administration and determined 3 to 4 hours after the dose on the fourth day.

Pill test: sponge pellets of uniform size and weight are subcutaneously placed in rats implanted. The test compounds are administered subcutaneously once a day for 6 days with a daytime start administered to the implantation. The animals are sacrificed on the seventh day, the pills removed and weighed. The superiority of the compounds prepared according to the present invention over that according to the mentioned German patents 839 350 and 850 297 produced 2-oxy-4,4'-diamidinostilbene or 4,4'-Diamidinostilbene can be seen from the following table:

example

27

34

4,4'-diamidinostilbene.

2-oxy-4,4'-diamidinostilbene

Anti-inflammatory effect
lowest effective dose; mg / kg

Acute
Mustard test

10 subcutaneous
60 oral

4 subcutaneous

4 subcutaneous
15 oral

ineffective

Chronic
Pill test

4 subcutaneous 25 subcutaneous over 30

ineffective
at 50

Used as starting materials for the production of the

ao according to the invention compounds used cyano compounds can be prepared by adding the appropriate halogen substituted, usually the bromine substituted compounds with a heavy metal cyanide, usually cuprocyanide, in the presence a high-boiling tertiary amine, usually quinoline, with replacement of the halogen by the cyano group implements. The halogen compound, for its part, can be produced by condensation of the appropriately substituted benzophenone with the appropriately substituted benzyl magnesium halide and subsequent dehydration of the resulting triarylethanol can be obtained using an acidic catalyst. The production these compounds are not part of the present invention.

The alkoxycarbimines according to the invention are obtained by alcoholysis of the corresponding cyano-substituted 1,1,2-triphenylethylenes obtain. The carbamidines are made from the acoxycarbimines or their salts by treatment obtained with ammonia or ammonium salts. When N-monosubstituted carbamidine compounds are desired they are made from the salts of the alkoxycarbimino compounds by handling with limited amounts of a primary amine, while the N, N'-disubstituted carbamidines using a «; Over-shot on primary amine under somewhat more energetic conditions. The N, N-disubstituted Carbamidines are made from the cyano compounds according to the following formula by handling with an agent obtained from the particular secondary amine and a Grignard reagent.

R ^ NH + C ₂ H ₅ MgX

C = CH-

in ether

R ^ NMgX

in ether

^S CN

C = CH

N-MgX decomposition with 10% NaOH
Extraction with ether and chloroform

C = CH

NH

NRi ether-chloroform extract evaporated;
the residue with alk. Treated HCl;

then extracted with chloroform

When the compounds of the invention are used for therapeutic purposes, they will ordinarily used in the form of their salts, for example as hydrochlorides. It was found that for The oleates of the carbamidine compounds are particularly suitable for therapeutic purposes. They are made by mixing the free carbamidine base with an equimolar amount of oleic acid, if desired without Solvent, but advantageously using a solvent such as ether, followed by removal treated by evaporation of the solvent. The oleates are often rubbery masses, but they can can be obtained in crystalline form by recrystallization from solvents. A simple and convenient way of preparing the oleates in a form suitable for use is that the carbamidine free base is dissolved in an excess of oleic acid. For example, one solves about 1 to about 20 mg of the free base in 1 ecm oleic acid. In this form, the carbamidine compounds exhibit strong oral Effect on and are well tolerated when injected. Other forms that can be used are solutions of the Oleates, which are advantageously obtained in the manner described above, in oleaginous materials such as olive, Sesame, corn or peanut oil, in appropriate concentrations, such as in concentrations from 1 to 20 mg of free base in 1 ecm solution. Among the compounds in particular in the form of their oleates or hydrochlorides The compounds of Examples 2 and 4 are well suited for use.

The process according to the invention will be explained in more detail using examples.

example 1

a) 1,1-Di- (p-methoxyphenyl) -2- (p-ethoxycarbimino-phenyl) -ethylene

indicating the presence of stereoisomers. By using l, l-di- (m-methoxyphenyl) -2- (p-cyano-phenyl) -ethylene 1,1-di- (m - methoxy - phenyl) - 2 - (ρ - ethoxycarbimino - phenyl) ethylene hydrochloride.

b) 1,1-Di (methoxyphenyl) -2- (p-guanylphenyl) -ethylene

HXO

C = C

, NH,

- C

H ₃ CO

NH

H ₃ CO

C = C

HXO

OC ₂ H ₅

NH

A solution of 27.2 g of l, l-di (p-methoxyphenyl) -2- (p-cyanophenyl) -ethylene in 38 g of anhydrous ethanol and 500 ml of dry benzene is saturated with hydrogen chloride at 5 ° C and 3 days at room temperature ditched. The solvent is evaporated and the residue triturated with ether to crystallize bring about. The l, l-di- (p-methoxyphenyl) -2 - (p-ethoxycarbimino-phenyl) -ethylene hydrochloride obtained in this way is a yellow solid with a melting point of 131 ° C (decomposition).

If, instead of the l, l-di- (p-methoxyphenyl) -2- (p-cyano-phenyl) -ethylene of this example, l- (p-methoxyphenyl) -1 - (o-methoxyphenyl) - 2- (p-cyano-phenyl) -ethylene is used, 1 - (p-methoxy-phenyl) 1 - (ο - methoxy - phenyl) - 2 - (ρ - ethoxycarbimino - phenyl) ethylene hydrochloride is obtained as almost white solid substance with undefined melting and decomposition point, which is a suspension of 13.5 g of l-di- (p-methoxyphenyl) -2- (p-ethoxycarbimino-phenyl) -ethylene hydrochloride in 100 ml of chloroform gegössen over 160 g of crushed ice and neutralized with 30% sodium hydroxide to a p _H of about. 8 The chloroform layer is separated and kept at about 0 ° C while it is dried over sodium sulfate. The chloroform is then evaporated off under reduced pressure and the residue is dissolved in 65 ml of ethanol. The solution is heated to 60 ° C. and 2.5 g of ammonium chloride in 5 ml of water are added. The mixture is kept at 60 ° C. and stirred for 6 hours, then rapidly cooled, filtered and concentrated to a volume of about 25 ml.

A crystalline precipitate of 1,1-di- (p-methoxyphenyl) separates -2- (p-guanyl-phenyl) -ethylene hydrochloride, which is in a melting point tube at Decomposed at 252 to 256 ° C. This connection has pronounced acute, the peripheral level of eosinophils Leucocyte-depressing anti-inflammatory and anti-granuloma effects.

By reacting l, l-di- (m-methoxyphenyl) -2- (p-ethoxycarbimino-phenyl) -ethylene hydrochloride with alcoholic ammonia following the procedure of Example 4, 1,1-di- (m-methoxyphenyl) -2- (p-guanyl-phenyl) -ethylene hydrochloride is obtained as a white crystalline salt that decomposes without melting. l- (p-methoxyphenyl) -1 - (0 - methoxy - phenyl) - 2 - (ρ - guanyl - phenyl) ethylene hydrochloride is obtained if in the same way l- (p-methoxyphenyl) -l- (o-methoxyphenyl) -2- (päthoxy carbimino - phenyl) - ethylene - hydrochloride treated. Yield 96%.

Example 2

1,2-Di- (p-methoxyphenyl) -l- (m-ethoxycarbimino-phenyl) -ethylene

A mixture of 10 g of l, 2-di (p-methoxyphenyl) -l- (m-cyano-phenyl) -ethylene, 5 to 6 ml of absolute alcohol and 165 ml of dry benzene are mixed with dry at 5 ° C Saturated hydrogen chloride. After standing for 9 days at room temperature, the solvent is removed and the residue triturated with dry ether until crystallization occurs. The 1,2-di- (p-methoxy - phenyl) -1 - (m - ethoxycarbimino - phenyl) - ethylene-

7 8

hydrochloride shows a dissolution in the melting point tube with water. After drying the solution and

Settlement point of 119 to 120 ° C. Evaporation of the solvent crystallizes the back

,. ,. _. . . ,.,,. . was made of petroleum ether from bp 75 to 90 ° C. It has

b) 1,2-Di- (p-methoxyphenyl) -l- (m-guanyl- _{dnen R = m big 110} “ _{c The} hydrochloride is after

phenyl) -ethylene _{5 usual} process as a crystalline substance of F. = 221

A suspension of 4 g of the imido prepared in this way up to 222 ° C. is obtained. It has a fungistatic effect. Ausäther hydrochloride in 20 ml of absolute alcohol to yield 61 ° / _0th
- 50 ⁰ C or below cooled and in portions with 2 g

mixed with liquid ammonia. The mixture slowly becomes Example 5

heated and then carefully refluxed i ° for 6 hours

warmed up. Then it is filtered and the filtrate with dry ^a ) 1.2-Di- (p-methoxy-phenyl) -l- (p-ethoxy-

nem ether, with a white crystalline lower carbnmno-phenyl) -ethylene

shock arises. When recrystallizing from dry By following the procedure of Example 2, a) 1,2-di-

In alcohol, white prisms are obtained from 1,2-di- (p-meth- (p-methoxyphenyl) -l- (p-cyano-phenyl) -ethylene in 1,2-dioxy-phenyl) -1 - (m -guanyl-phenyl) -ethylene hydrochloride, * 5 (p - methoxy - phenyl) -1 - (ρ - ethoxycarbimino - phenyl) - which converts to ethylene hydrochloride in the melting point tube at 208 to 210 ° C. The thus obtained decomposed. This compound has acute, the peripheral yellow crystals have a decomposition point of 118 levels of the eosinophilic leucocytes lowering, anti-up to 120 ° C in the melting point tube.
phlogistic antigranuloma and fungistatic effects. ,, _A "_. ,,, _,. ,

Yield 53% ^ o b) 1,2-Di- (p-methoxyphenyl) 4- (p-guanyl-

phenyl) ethylene

Example 3 The imido ether hydrochloride is according to Example 2, b)

*., _Λ - ^. ,,, ν ο, ^m l, 2-di- (p-methoxy-phenyl) -l- (p-guanyl-phenyl) -ethy-

a) 1,1-di- (p-methoxyphenyl) -2- (m-ethoxylene hydrochloride converted. The yellow crystals are

carbimmo-phenyl) -ethylene _{25 after a} single ^ precipitation from its solution in ethanol

If in the process of Example 2, a) instead of using dry ether, pure and melt at 226 ° C (

there used 1,2-di- (p-methoxy-phenyl-l- (m-cyano- formation) in the melting point tube. You have acute,

phenyl) -ethylene l, l-di- (p-methoxyphenyl) -2- (m-cyano- the peripheral level of the eosinophilic leucocytes

phenyl) -ethylene is used, one obtains 1,1-di-lowering, anti-inflammatory and antigranuloma

(p-methoxyphenyl) -2- (m-ethoxycarbimino-phenyl) -3 ° kung. Yield 87%.
ethylene hydrochloride as a white crystalline substance

a decomposition point of 140 ° C. This compound Example 6

has a the peripheral level of eosinophils leuco-,. "_. ,,. ,,,. .

cyte-degrading effect. ^a ) U-Diphenyl-ym-athoxycarbmnno-

35 phenyl) ethylene

b) l, l-Di- (p-methoxyphenyl) -2- (m-guanyl- If l, 2-diphenyl-l- (m-cyano-phenyl) -ethylene according to

phenyl) ethylene the method of Example 2, a) with alcoholic

Treated with hydrogen chloride, the ethoxy

When using the procedure of Example 2, b) obtained in place of the carbimino derivative. That from the stereoisomer

there used 1,2-di- (p-methoxyphenyl) -1- (m-eth- 4 ° Cyanogen compound with a melting point of 135 to 137 ° C)

oxycarbimino-phenyl-ethylene-hydrochloride l, l-di- (p-imido ether hydrochloride has a decomposition point of

methoxy-phenyl) -2- (m-ethoxycarbimino-phenyl) -äthy- 142 ° C. From the stereoisomeric cyano compound from

len hydrochloride is used, then 1,1-di-F. = 168 to 169 ° C is obtained with an imido ether hydrochloride

(p-methoxyphenyl) -2- (m-guanyl-phenyl) -ethylene-hydro- obtained a decomposition point of 117 ° C,
chloride from F. = 232 to 233 ° C. This compound has 45 _{1 (JO} _.,. " _,,, " η,

the peripheral level of eosinophilic leukocytes ^b ) 1.2-D _ip henyl-l- (rn-guanyl-phenyl) -ethylene

Degrading, anti-inflammatory and antigranuloma we- When treating 1,2-diphenyl-l- (m-ethoxycarb-

kung. Yield 75%. imino-phenyl) -ethylene hydrochloride with alcoholic

Ammonia obtained by the method of Example 2, b)

Example 4 5 ° the guanylphenyl derivatives in the form of their hydro

. _Λ ._ ..,,, ,, ", ...-.,.,. ,, chloride. The lower-melting imidoether hydro-

II-di-ip-methoxy-phenyl -2- [o- (N, N-diethyl- _{cMorid ibt a gua} ° _{yl derivative with a} decomposition

guanyl-phenyl)] - ethylene _{point from 234 to 23r c The guanyl derivative from the}

From ethylmagnesium bromide and diethylamine higher-melting imidoether hydrochloride melts at 200 ml about 0.28 η diethylamino-magnesium bromide 55 237.5 to 238.5 ° C. It is fungistatic and anti-static. 13.6 g of 1,1-granuloma effect are slowly added to this solution. Yield 90%.
(p-methoxyphenyl) -2- (o-cyano-phenyl) -ethylene, in one

Mixture of 100 ml dry ether and 100 ml example 7
dissolved dry benzene, added. The mixture will.
Heated under reflux for 6 hours and then decomposed with 10% Oo ^a ) U-di-p-tolyl-2- (p-athoxycarbimmo-sodium hydroxide in excess. The ether-phenyl) -ethylene
layer is separated off and the aqueous layer is extracted with chloroform using the procedure of Example 1, a). The ether and chloroform turns of l, l-di-p-tolyl-2- (p-cyano-phenyl) -ethylene extract are combined and evaporated, whereby a 1,1-di-p-tolyl-2- (p-ethoxycarbimino-phenyl) -ethylene yellow rubbery substance is obtained. This is 65 hydrochloride with a temperature of 148 ° C (decomposition),
dissolved in a slight excess of alcoholic hydrogen chloride, diluted with water and repeatedly with ^b ) l, l-di-p-tolyl-2- (p-guanyl-phenyl) -ethylene

Chloroform extracted. The product is used in the If in the process of Example 2, b) instead

Chloroform layer extracted. The chloroform extracts of the 1,2-di- (p-methoxyphenyl) -l- (m werden with 10% sodium hydroxide and then 70 ethoxycarbimino-pheny ^ -ethylene hydrochloride 1,1-di-

9 10

p-tolyl-2- (ρ-ethoxycarbimino-phenyl) -ethylene-hydro- 2- (ρ-guanyl-phenyl) -ethylene hydrochloride from F. = chloride is used, 1,1-di-p-tolyl-314 ° C. is obtained. Yield 88%.

Example 8

l _J l-di (p-methoxyphenyl) -2- (p-piperidinocarbimino-phenyl) -ethylene

NH

C = C

A mixture of 10 g of l, l-di (p-methoxyphenyl) -2- (p-ethoxycarbimino-phenyl) -ethylene hydrochloride and 4 g of piperidine in 25 ml of absolute ethanol is left to stand for 2 days at room temperature. The solvent is removed, the residue is taken up with chloroform and washed several times with water. then the solvent is removed and the gummy substance is triturated with petroleum ether of b.p. 75 to 90 ° C, until it is free of excess piperidine. The hydrochloride. is formed by making the rubbery Dissolves the substance in ethanol, weakly acidifies the solution with alcoholic hydrogen chloride and with dry Ether diluted. After recrystallization from absolute ethanol and ether, the material has a mp = 150 ° C (Decomposition).

In place of piperidine, pyrrolidine or morpholine can be used in equimolar amounts, the analogous pyrrolidine and morpholine compounds being obtained, which are also gummy substances which can be converted into crystalline hydrochlorides. Yield 80 ° / ₀ .

Claims (2)

Patent claims: 1. Process for the preparation of substituted 1,1,2-triphenylethylenes the general formula C = C X. 45 wherein one of the radicals R is a carbamidine group, which is either in the 0- or m- or p-position on the phenyl ring, and the other two are hydrogen or CH ₉ - CH ₂ -CH / CH ₂ a low molecular weight alkyl or alkoxy group either in the o- or m- or p-position on the phenyl ring is, and Y is hydrogen or a cyano group, and their salts with acids, characterized in that that one is a cyano-substituted 1,1,2-triphenylethylene the general formula R ' , Y C = C JK. JK. wherein one of the radicals R 'is a cyano group either in the o- or m- or p-position on the phenyl ring is, and the other two are hydrogen or a low molecular weight alkyl or alkoxy group, either are in the o- or m- or p-position on the phenyl ring, and Y are hydrogen or a cyano group means in a manner known per se with a) converting an alcohol in the presence of an acid to the corresponding alkoxycarbimino compound and this alkoxycarbimino compound with ammonia or a primary amine or a heterocyclic one Amine or a salt thereof reacts or b) with a secondary amine and a Grignard reagent to give the corresponding carbamidine compound implements. 2. The method according to claim 1, characterized in that the free carbamidine compound with oleic acid to give the corresponding oleate. Considered publications:
German patent specifications No. 839 350, 850 297. © 709 957/422 3.58