NO135243B - - Google Patents

Description

This invention relates to an analogous process for the preparation of new therapeutically active |3-aryl-2-amino alkoxystyrenes of the general formula I

and their physiologically compatible acid addition salts with inorganic and organic acids.

In this formula means:

Ar is a phenyl residue, a 2-, 3- or 4-pyridyl residue, which may optionally be substituted with one or two lower alkyl groups, a 2-quinolyl or 2-pyrazinyl residue, which may optionally be substituted with a lower alkyl group, a pyrimidyl residue which may optionally may be substituted with a lower alkyl group, a 2-benzimidazolyl residue which may optionally be substituted with a 3t halogen atom and/or with a lower alkyl group and/or a trifluoromethyl group, a 2-furyl- or 2-thienyl residue, a 5-isoxazolyl residue which may optionally be substituted with a lower alkyl group or a phenyl group, or a 5-(1,2,4-oxadiazolyl) residue which may optionally be substituted with a lower alkyl group, and

Rl' R2°^ R4 which may be the same or different, hydrogen atoms or lower alkyl group,

R^ a hydrogen atom or a lower alkoxy group,

R b and R_/, which are the same or different, hydrogen atoms or lower alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl or aralkyl residues,

where the residues Rg and R^ together with the intermediate nitrogen atom can also form a piperidine, morpholine or methylpiperazine ring, and

n e~r 0 or 1.

The new compounds of formula I are produced according to the invention: 1) By separating water from the compounds with the general flour II

where the residues Ar, R^ to R^ and n have the meanings indicated above. The separation of water is carried out with suitable means, e.g. with phosphoric acid, polyphosphoric acids, phosphoric acid with phosphorous pentoxide or sulfuric acid; and it has proven particularly appropriate to use

85&ig phos foracid. The reaction takes place at elevated temperatures, preferably in the range between 70 and 130°C. 2) When reacting a phosphonic acid ester with the general formula III, where and Ar have the meanings given above, and Rg is a lower alkyl residue, with an aldehyde or ketone of the general formula IV

where the residues R2 to R? and n have the above meanings,

in the presence of^a base'under intermediate formation of the corresponding ■ carbanion of the compound of formula III.. Preferred bases are alkali ihy dr ider... r s; • The turnover is made in apple solvents^ Such as: dissolving ^; agents are particularly suitable high-boiling ethers, e.g. dioxane. The reaction can also be carried out in an aqueous solvent, e.g. in methanol/water in the presence of an inorganic base.

conventionally, the alkali hydride is first added to the phosphonic acid ester of the general formula III. After the hydrogen evolution has ceased, the aldehyde or ketone of formula IV is suitably added

without the formed carbanion being isolated in advance. The reaction is carried out at slightly elevated temperatures, preferably at temperatures between 30 and 60°C.

3) When reacting a phosphonic acid ester with the general formula V

O = P(OR ) .0°0£I po OT fliolløæ isbexocto i a.rinwu-j:x;\toX

,111 isnrio3. slls^ns^ rffeb böni :ta;*8sei ya«©5ao2 ne vs £.a.i irs s £:;;;,3 -■ ■.>/

where the residues R2 to R7 and n have the meanings indicated above^^ and Rn means a lower alkyl residue, with an aldehyde or ketone of the general formula VI ^~-->/' \ where Ar and S.^ are as indicated above ,^in the presence of a base during intermediate formation of a carbanion of the compound of formula V. Srøpfeas.ef^re^ek^es added .„ pQ ^ ^ ^ 3n9.t3_ .£ev,,. J^l igt ^np^^h^t^o^e^^ex^^om^f .^Xs^ dioks an . However, the reaction can also be carried out in an aqueous solution. ^aphøfetrr^M^j^ .rtje.4 formula VI without f otii^gåfi.n de, isjq^råag^^j^f^^^ap^fd Qx,.karban i on av r forbin de1s en mé&. fToæmej& Vvsm The turnover- rut4øre.S;_.yed slightly elevated temperatures, fCM<p>bcintoswi^ yedtBtjemneratures fm§llom ;.3.0 and..60.C. 4) Véd.\oms-.e.t»ing; styrene with the general formula VII where the radicals Ar, R^^ to R3 are as indicated above, and X means a hydrogen atom or an acetyl group, with an amine of the general formula VIII

where the residues R4 to R? has the meanings given above, and Y means a halogen atom, in the presence of a base.

The turnover is carried out in inert solvents such as e.g. benzene, 'chlorobenzene, toluene, xylene and at elevated temperatures, preferably at the boiling point of the solvent used. As bases, e.g. alkali hydroxides or carbonates are used, preferably, however, alkali alcoholates.

5) When converting a compound with the general formula IX

where the residues Ar, to R^ and n have the meanings given above, and Z means a residue that can be replaced by basic residues, such as e.g. a halogen atom or a tosyl group, with an amine of the general formula X

where the residues Rg and R7 are as indicated above.

The reaction is carried out in the presence of a solvent

of an acid-binding agent. Inorganic or organic bases or an excess of the amine of formula X can be used as acid-binding agent, and the latter can also serve as a solvent at the same time. The reaction is carried out at elevated temperatures, usually at temperatures between 60 and 120°C. If a highly volatile amine of formula X is used, the reaction is conveniently carried out in a closed vessel.

6) In the reaction of phosphorylides with the general formula XI

where Ar and are as indicated above, with basic ketones or aldehydes of formula IV

where the residues R 2 to R 1 and n have the meanings given above. Shortly before they are reacted, the phosphorylides of the general formula XI are liberated from the corresponding phosphonium halides by means of bases, e.g. by means of alkali alcoholates. The reaction is carried out in a solvent, e.g. in an alcohol such as ethanol. The reaction takes place at an elevated temperature between 40°C and the boiling point of the solvent used.

The compounds of formula I are generally formed as mixtures of their cis and trans isomers. If R^ and R ? are hydrogen atoms in method alternatives 1,2, 3 and 6, predominantly the trans compounds are formed. The cis and trans compounds, especially their salts, e.g. the hydrochlorides, can be separated from each other by fractional crystallization.

The compounds of formula I can be transferred in the usual way

to their acid addition salts using inorganic or organic acids. If Ar means an N-containing heterocyclic group, it is possible by stepwise neutralization to deposit a proton only on the nitrogen atom of the basic side chain. If you work with an excess of acid, you also get salt formation with the nitrogen atoms in the heterocyclic rings. Particularly suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, p-toluenesulfonic acid.

The compounds with the general formula II which are used as starting materials in process alternative 1) are prepared as follows:

A compound of the general formula XIII is condensed with an ester of the general formula XIV to a ketone of the general formula XV e.g. using sodium amide in toluene. The ketone of general formula XV is then reduced with complex hydrides, e.g. with sodium borohydride or with catalytically formed hydrogen, to the alcohol of the general formula II. In the formulas XIII to XV, the residues of R 1 and n have the meanings given above, and the residue R 2 means an alkyl residue. The phosphonic acid esters with the general formula III that are used in process alternative 2 can be prepared by reacting halomethyl compounds with the general formula XVI

where Ar and R1 are as indicated above, and Hal means a chlorine, bromine or iodine atom, with trialkyl phosphite by the method according to Arbusow - Michaelis (Houben-Weyl, Methoden der organischen Chemie, 4. oppi. Vol. XII, part 1, P. 433) or with dialkyl phosphite sodium by the method

according to Michaelis-Becker (Houben-Weyl, Methoden der organischen Chemie, 4. oppi. Vol. XII, part 1, p. 447).

The compounds of the general formula IV are prepared by basic alkylation of compounds of the general formula

by means of compounds of the general formula VIII by means of the method indicated in method alternative 4. The following compounds were thus prepared from the corresponding salicylaldehydes or 2-hydroxyacetophenones: 2-(2-dimethylaminoethoxy)-benzaldehyde, m.p._nc. = 110°C 2-(2-dimethylaminoethoxy)-acetophenone, b.p.Q ' Q^ = 103-105 oC 2-(3-dimethylaminopropoxy)-benzaldehyde b.p.Q Qg = 109-112°C 2-(3-dimethylaminopropoxy)-acetophenone, b.p.Q ^ = 130 C The phosphonic acid esters with the general formula V used in process alternative 3 can be prepared in the following way: By basic alkylation of compounds with the general formula XVII with compounds with the general formula VIII, ketones or aldehydes with the general formula IV are obtained . These are reacted with complex hydrides, preferably with sodium borohydride in methanol to the corresponding alcohols and these then with inorganic acid halides, e.g. with thionyl chloride, to the corresponding halogen compounds of the general formula XVIII

where the radicals R 2 to R 7 and n have the meanings given above, and Hal means a halogen atom, preferably a chlorine or bromine atom. The compounds of formula XVIII usually precipitate in a well-crystallized state, and are present as halogen hydrogen acids

salts. These salts are reacted in an inert solvent, such as e.g. in benzene, with the pr. mol calculated twice the amount of di-alkyl phosphite sodium by the method according to Michaelis-Becker (Houben-

Weyl, Methoden der organischen Chemie, 4. oppi., Vol. XII, part 1,

p. 447) to compounds of the general formula V.

The compounds of the general formula VII used in process alternative 4 can be prepared using known methods (cf. L. Horwitz, J. Org. Chem. 21, 1039-1041 [1956]). The compounds of the general formula VIII are known from the literature or they can be prepared by analogy with known methods.

The starting compounds with the general formula IX used in process alternative 5 can be prepared, e.g. by reacting the corresponding 2-(2-acetoxystyryl)-aryt compounds with benzenesulfonic acid 2-haloethyl esters in the presence of potassium methylate in toluene. Thus, e.g. the following starting compounds prepared: 2-[2-(2-chloroethoxy)styryl]-pyridine, m.p. 57-59°C,

2-[2-(2-chloroethoxy)styryl]-quinoline, m.p. of the hydrochloride 200-202°C.

The phosphonium halides which form the basis of the phosphorylides of formula XI used in process alternative 6 are produced by the action of triphenylphosphine on the halogenmethyl compound of the general formula

Thus, e.g. (3,5-dimethyl-isoxazolyl-4)-methyl-triphenylphosphonium chloride prepared from 3,5-dimethyl-4-chloromethylisoxazole and triphenyl-phosphine in a yield of 89% of the theoretical in the form of colorless crystals.

The compounds of the general formula I possess valuable pharmacological properties. They have a particularly analgesic effect without the side effects of morphine, and furthermore they have a good anesthetic and muscle relaxant effect. The compound which has been found to have the best analgesic and antiarrhythmic action, is 2-[o-(2-dimethylaminoethoxy)styryl]-pyridine and its salts.

For the physiological effect, the o-position of the basic side chain on the benzene nucleus is essential. Thus, e.g. the known, isomeric 4-aminoalkoxystyrenes (cf. Cavallini et al. Il Farmaco, Ed. Sei. 9, 405415 [1954] and P. Montegazza et al.,

Arch. internal, pharmacodyn. 103, 371-309) not a painkiller at all. According to the literature, these have an antinicotine

and antihistamine effect.

The compounds of the general formula I were investigated

with regard to its analgesic effect by the hot plate method according to Chen et. Beckmånn, Science 113, 1951, page 631. Groups of every 10 mice were then exposed to a heat pain by being placed on

a hot plate with a temperature of 56°C. The animals used in the experiment reacted normally within 20 seconds. The analgesic effect was judged by the percentage of experimental animals that did not react at a certain dose within 50 seconds. The value ED^q thus represents the dose which causes 50% of the mice not to react to the heat pain after administration. The active compounds were administered orally. The new compounds are only mildly toxic. The acute toxicity was determined in mice. Groups of 10 mice each were administered increasing doses of it

active compound orally. The LD^Q value, i.e. the dose that caused 50% of the mice to die within 14 days of administration,

was calculated on the basis of the values found by the method according to Litchfield and Wilcoxon.

The following compounds are particularly strong analgesics: 2-12-(2-dimethylaminoethoxy)styrylpyrazine monohydrochloride; 2-[2-(2-dimethylaminoethoxy)styrylJquinoline monohydrochloride, 2- 12-(2-dimethylaminoethoxy)styryl[-6-methyl-pyridine monohydrochloride, 2-t 2-(2-dimethylaminoethoxy)styrylpyridine monohydrochloride, 5- {[ 2-(2-dimethylamino)ethoxy]-styryl}-3-methyl-isoxazole hydrochloride, 5-[[2-(2-dimethylamino)ethoxy]-styryl}-3-phenyl-isoxazole hydrochloride, 2- [2-(2-Dimethylaminoethoxy)styryl]-1-methylbenzimidazole dihydrochloride, 2-(2-dimethylaminoethoxy)stilbene hydrochloride 2- 12-(2-dimethylaminoethoxy)styrylI-furan hydrochloride, 2-12-(2- dimethylaminoethoxy)styryl]thiophene hydrochloride, 1-(2-dimethylaminoethoxyphenyl)-2-(pyridyl-2-)-propene-1-monohydrochloride,

2-[2-(2-methylaminoethoxy)styryl]pyridine dihydrochloride and 2-[2-(2-morpholinoethoxy)styryl]pyridine dihydrochloride.

When administered orally, the compounds have an ED5Q between 10 and

60 mg/kg mouse. The compounds are only mildly toxic, and thus e.g. The LD50 values for the following compounds between 500

and 800 mg/kg mouse: 2-[2-(2-dimethylaminoethoxy)styryl]-1-methyl-benzimidazole dihydrochloride,

2-(2-Dimethylaminoethoxy)-stilbene hydrochloride

2-[2-(2-morpholinoethoxy)styryl]pyridine dihydrochloride and 2-[2-(2-dimethylaminoethoxy)styryl]6-methylpyridine hydrochloride.

Example 1

20.2 g of 1-pyrazinyl-2-(2-dimethylaminoethoxyphenyl)-ethanol-2 is stirred with 60 ml of 85% phosphoric acid, whereby the mixture is heated to 70°C. It is then heated for 1 hour at 110°C, the mixture is dissolved in 300 ml of water after cooling, neutralized and saturated with potassium carbonate. The reaction product formed is then extracted 3 times with 50 ml of ether each time, dried over anhydrous potassium carbonate and filtered with charcoal. The evaporation residue is distilled in vacuum. You get 13.25 g (corresponding to 70.2% of the theoretical) of a pale yellow oil with a boiling point c.p.Q 143-150°C. The oil is dissolved in 250 ml of acetone and carefully added enough of a solution of hydrogen chloride gas in acetone that a yellow coloration just begins. After cooling in an ice bath, white crystals are separated,

and this quantity is increased by stirring in 150 ml of ether. After suction and drying, 13.9 g (corresponding to 88.2% of the theoretical based on the hydrochloride formation) of 2-[2-(2-dimethylaminoethoxy)-styrylpyrazine monohydrochloride with m.p. 194-195°C.

It used as starting material 1-(pyrazinyl-2-)-2-(2-dimethylaminoethoxyphenyl)-ethanol-2, a non-distillable, yellow. oil, uniform in thin-layer chromatogram, is prepared from (pyrazinyl-2-)-(2-dimethylaminoethoxyphenyl)-ketone (non-distillable oil, forms a crystallized lithium enolate) by reduction with sodium borohydride. The necessary ketone is prepared from 2-methylpyrazine and 2-dimethylaminoethoxybenzoic acid methyl ester by condensation with sodium amide in toluene.

Analogous to the method described in example 1, the following compounds are prepared (examples 2-7).

Example 2

Of 1-(quinolyl-2)-2-(2-dimethylaminoethoxyphenyl)-ethanol-2,

a yellow, non-distillable oil, uniform in thin-layer chromatogram, 2-t2-(2-dimethylaminoethoxy)styryl]-quinoline monohydrochloride is prepared with m.p. 188°C in a yield of 87%.

Example 3

From 1-(6-methyl-pyridyl-2)-2-(o-dimethylaminoethoxyphenyl)-ethanol-2 (light yellow crystals, m.p. = 228°C) 2-[2-(2-dimethylaminoethoxy)styryl] is prepared -6-methylpyridine monohydrochloride with

melting point 200°C in a yield of 20%.

Example 4

2-[2-(2-dimethylaminoethoxy)styryl]-4 is prepared from 1(4,6-dimethylpyridyl-2)-2-(o-dimethylaminoethoxyphenyl)-ethanol-2 (light yellow, non-distillable oil, uniform in thin-layer chromatogram), 6-dimethylpyridine dihydrochloride with melting point 177°c in a yield of 81%.

Example 5

Of 1-(2-pyridyl)-2-(2-dimethylaminoethoxyphenyl)-ethanol-2,

a yellow, non-distillable, thin-layer chromatogram uniform oil, 2-[2-(2-dimethylaminoethoxy)styryl]pyridine monohydro-

chloride with melting point 183°C in a yield of 88%.

Example 6

From 1-(5-methylpyrazinyl-2)-2-(2-dimethylaminoethoxyphenyl)-ethanol-2, a colorless, non-distillable, thin-layer chromatogram uniform oil, 2-[2-(2-dimethylaminoethoxy)styryl]-5 -methylpyrazine-2-dihydrochloride, a resinous, white substance,

uniform in thin-layer chromatogram in a yield of 65%.

Example 7

From 1-(4-methylpyrimidyl-6)-2-(2-dimethylaminoethoxyphenyl)ethanol-2, a non-distillable, clear, yellow oil, uniform in thin-layer chromatogram; 6-[2-(2-dimethylaminoethoxy)-styryl]-4-methyl-pyrimidine with a melting point of 234°C is produced in a yield of

87%.

Example 8

12 g of a 50% suspension of sodium hydride in paraffin oil are freed from adhering paraffin oil by decanting twice with dioxane and suspended in 100 ml of absolute dioxane. This suspension is introduced, while stirring, in portions into a solution of 54 g of 3-methylisoxazolyl-5-methylphosphonic acid diethyl ester in 200 ml of anhydrous dioxane, heated to a temperature of 40°C. After completion of hydrogen evolution, stir for 1 hour at 50°C. After cooling to room temperature, 40 g of 2-(2-dimethylamino)-ethoxy-benzaldehyde are added dropwise, and then heated for 1 hour at 50°C. The reaction mixture is poured onto ice, acidified with 2N hydrochloric acid and extracted with ether. Ether extraction is discarded, the aqueous phase is made alkaline with dilute caustic soda and extracted with ether. The oily residue obtained after drying over sodium sulphate and evaporation of the ether is taken up in ethanol, treated with activated charcoal and ethereal hydrochloric acid is added. After two recrystallizations from ethanol/ether, 45 g (70.5% of the theoretical) of 5-[o-(2-dimethylamino)-ethoxy]styryl-3-methylisoxazole hydrochloride are obtained in the form of pale yellow crystals with a melting point of 150 -151°C.

The starting material 3-methylisoxazolyl-5-methylphosphonic acid diethyl ester is prepared in a yield of 84% of the theoretical from 3-methyl-5-chloromethylisoxazole and triethyl phosphite as a yellow oil with b.p. 76-80°C at 0.0015 mm Hg.

The compound 3-methyl-5-chloromethylisoxazole is known from the literature and can be prepared by the method according to G. Stagno. d'Alcontres and G. Gurrocres, Atti soc. Peloritana said. fart food. night 3, 179-86 (1956/57), [CA 52, 1994 c] from acetonitrile oxide and propargyl chloride.

2-(2-dimethylaminoethoxy)benzaldehyde (b.p.QQ5 = 110°C) is prepared from salicylaldehyde and dimethylaminoethyl chloride in chlorobenzene in the presence of potassium methylate.

Analogous to the method described in example 8, was

the following compounds (Example 9-23) prepared:

Example 9

5-[o-(2-dimethylamino)ethoxy]styryl-3-phenyl-isoxazole hydrochloride is prepared from (3-phenyl-isoxazolyl-5-)-methylphosphonic acid diethyl ester and 2-(2-dimethylamino)ethoxybenzaldehyde in a yield of 23.4% of the theoretical with a melting point of 189-190°C.

The phosphon ester used as starting material is prepared from 3-phenyl-5-bromomethylisoxazole (H. G. Sen, D. Seth und U. N. Joshi, J. med. chem. 9, p. 431-33 (1966)) and triethyl phosphite in the form

of a yellow, non-distillable oil. Yield: quantitative.

Example 10

5-[o-(2-dimethylamino)-ethoxy]styryl-3-methyl-oxadiazole-(1,2,4)-hydrochloride is prepared from (3-methyloxadiazolyl-(1,2,4)-5)-methylphosphonic acid diethyl ester and 2-(2-dimethylamino)ethoxybenzaldehyde in the form of colorless crystals with a melting point of 186-188 C. Yield: 55% of the theoretical.

The phosphon ester used as starting material is prepared from 3-methyl-5-chloromethyloxadiazole-(1,2,4) and triethyl phosphite as a yellow oil with b.p. 110-112°C at 0.2 mm Hg. Yield: 48.5% of the theoretical.

3-methyl-5-chloromethyloxadiazole-(1,2,4) is known from the literature (French patent 363,235, CA 62, p. 5282 b), and can

is produced from acetamidoxime and chloroacetyl chloride.

Example 11

From 1-methyl-benzimidazolyl-2-methanephosphonic acid diethyl ester (m.p. = 75.5 - 76.5°C) and 2-(2-dimethylaminoethoxy)benzaldehyde (b.p.Q Q5 = 110°C) 2- 12-(2 -dimethylaminoethoxy)styryl]-1-methylbenzimidazole dihydrochloride with m.p. 208°C with a yield of 45%.

Example 12

2-[2-( 2-dimethylamino-ethoxy)styryl]-1-phenyl-6-chloro-benzimidazole dihydrochloride (m.p. 256 C, Yield: 40%).

Example 13

From 1-methyl-6-chloro-benzimidazolyl-2-methanephosphonic acid diethyl ester (m.p. 103-106°C) and 2-(2-dimethylaminoethoxy)azetophenone (b.p. QQg = 103-105°C) is prepared 1-( 1-methyl-6-chloro-benzimidazolyl-(2))-2-(2-dimethylaminoethoxyphenyl)-propene dihydrochloride (m.p. 121°C, Yield: 55% of theory).

Example 14

2-[2-( 2-dimethylaminoethoxy)-styryl]-1-phenyl-5-trifluoromethyl-benzimidazole (m.p. 225°C;

Yield: 50% of the theoretical.

Example 15

From pyridyl-27:methanephosphonic acid diethyl ester (b.p.Q 02=H8oC) ~ and 2-(2-dimethylaminoethoxy)-acetophenone (b.p.Q Q5 = 103-105°C) 1-(2-pyridyl)-2-(2-dimethylaminoethoxyphenyl)- propene-1.

In the preparation of the dihydrochloride, the trans-isomer (m.p. 196-198°C) is obtained in crystalline form from acetone. In a thin-layer chromatogram; (acetone/ethyl acetate = 1:1 on basic aluminum oxide, spray reagent: Dragendorff's reagent) the compound has an Rf=0.85. The mother liquor from the preparation of the trans-isomer is evaporated, the residue is dissolved in water, caustic soda is added, 6g of the base is extracted with ether. After evaporation of the ether extract, it is fractionally distilled. The cis compound is obtained as a yellowish-colourless oil (b.p. 007= 122-135°C) as in thin-layer chromatogram

shows a lower Rf value (0.80) than the trans compound.

Example 16

Of pyridyl-2-methanephosphonic acid diethyl ester (b.p._ n,= 118°C)

0.03

and 2-(3-dimethylaminopropoxy)acetophenone (b.p.Q 4=130 C) is prepared 1-(2-pyridyl)-2- 12-(3-dimethylaminopropoxy)-phenylj-propene-1-dihydrochloride in trans form, analogously to trans - the compound in example 15 (m.p. = 196-197°C). From the mother liquor after the hydrochloride crystallization, the cis-compound is isolated as a colorless oil (b.p.0 16= 143°C). In a thin-layer chromatogram, both compounds separate see? clearly. Trans-compound: R^= 0, "cis-forTanaTélse: R,. = 0.65 (Eluent: ■ acetone/ethyl acetate = 1:1 on thin-layer plates of basic alumina, spray reagent: Dragendorff's reagent).

Example 17

From pyridyl-2-methanephosphonic acid diethyl ester (b.p.Q 03=118°C) and 2-(3-dimethylaminopropoxy)-benzaldehyde, 2-[2-(3-dimethylaminopropoxy)styryl]pyridine is prepared in the form of a glassy, brittle dihydrochloride in a yield of 36% of the theoretical.

Example 18

1-(l-Methyl-6 -chloro-benzimidazolyl-2)-2-(3-dimethylaminopropoxyphenyl)-propene-1-dihydrochloride. (m.p. 211 oC; Yield: 48% of the theoretical).

Example 19

From benzylphosphonic acid diethyl ester (b.p.^=148°C) and 2-(2-dimethylaminoethoxy)benzaldehyde (b.p.n ' _=11.0 C) 2-(2-dimethylaminoethoxy)-stilbene hydrochloride (m.p. 199 C) is prepared;

Yield: 58% of the theoretical).

Example 20

Of pyridyl-2-methanephosphonic acid diethyl ester (b.p.Q 02=118°C)

and 2-(2-diethylaminoethoxy)benzaldehyde (b.p.Q 05=110°C) 2-12-(2-diethylaminoethoxy)styryl]pyridine dihydrochloride is prepared (m.p. 198°C; Yield: 20% of the theoretical).

Example 21

From pyridyl-2-methanephosphonic acid diethyl ester (b.p.Q 03=118°C) and 2-(2-dimethylaminoethoxy)4-methoxy-benzaldehyde (b.p.Q 03=121-125 C) 2- 12-(2-dimethylaminoethoxy-4-methoxy) is prepared styryl]-pyridine-

dihydrochloride (m.p. 221°C; Yield: 31% of theory).

Example 22

2-[2-(2-dimethylaminoethoxy)styryl]-pyridine monohydrochloride (sm .p. 183°C; Yield: 43% of the theoretical). •

Example 23

Of 2-quinolylmethanephosphonic acid diethyl ester (b.p. =138-

O'035

145 C) and 2-(2-dimethylaminoethoxybenzaldehyde (b.p. = 110 C)

U z UD

2-[2-(2-dimethylaminoethoxy)styryl]-quinoline monohydrochloride is prepared (m.p. 188°C; Yield: 77% of theory).

Example 24

In 50 ml of absolute dioxane, suspend 2.0 g of sodium

hydride and add dropwise with good stirring during 15

minutes at 28°C a solution of 6.3 g of 2-(2-dimethylaminoethoxy)-benzylphosphonic acid diethyl ester, and moderate hydrogen evolution is observed. Stirring continues for 1 hour and then a solution of 2.14 g of pyridine-3-aldehyde in 20 ml of absolute dioxane is added dropwise over 15 minutes, whereby gas evolution can again be observed. After standing overnight, the mixture is split with ice and the reaction product is extracted with chloroform. After distilling off the solvent, a light brown oil remains. It is dissolved in ethanol and the hydrochloride is precipitated with ethereal hydrochloric acid,

and the hydrochloride is recrystallized from ethanol using bone charcoal. 3.0 g (corresponding to 44% of the theoretical) 3|-[ 2-(2-dimethylaminoethoxy) styrylpyridine dihydrochloride is obtained in the form of pale yellow crystals with a melting point of 238°C. The compound is uniform in thin-layer chromatogram (basic alumina (Merck); Eluent: ethyl acetate; Syringe reagent: Dragendorff's reagent)

(Rf = 0.75).

The 2-(2-dimethylaminoethoxy)-benzylphosphonic acid diethyl ester used as starting material is prepared as follows: 2-(2-dimethylaminoethoxy)benzaldehyde is reduced with sodium • borohydride in methanol in 77% yield to 2-(2-dimethylaminoethoxy)-benzyl alcohol (b.p. _ ,=125°C), and this is reacted with thionyl chloride to 2-(2-dimethylamino»ethoxy)benzyl chloride hydrochloride (m.p.=145-147 oC). This compound is reacted in benzene with an excess of sodium diethylphosphite to 2-(2-dimethylaminoethoxy)benzylphosphonic acid diethyl ester (<k>.<p.>o8 = 140-148°C).

Analogous to the method described in example 24, the following compounds are prepared (examples 25-30):

Example 25

From 2-(2-dimethylaminoethoxy)-benzylphosphonic acid diethyl ester (b.p.0 8=140-148°C) and furfurol, 2-[2-(2-dimethylaminoethoxy)styryl-1 furan hydrochloride (m.p. 156-158°) is prepared C) Dividend:

22% of the theoretical.

Example 26

From 2-(2-dimethylaminoethoxy)-benzylphosphonic acid diethyl ester (b.p.Q 8=140-148°C) and thiophene-2-aldehyde, 2-[2-(2-dimethylaminoethoxy)styryl]thiophene hydrochloride (m.p. 187- 188°C;

Yield: 60% of the theoretical).

Example 27

From 2-(2-dimethylaminoethoxy)^-benzylphosphonic acid diethyl ester (b.p.Q 8=140-148°C) and 2,7-naphthyridine-4-aldehyde [Ch. Jutz et al.

Pray. 99, 2479-2490 (1966)], 4-[2-(2-dimethylaminoethoxy)-styryl]-2,7Hyaphthyridine dihydrochloride (m.p. 197°C; Yield: 24% of theory) is prepared.

Example 28

From 2-(2-dimethylaminoethoxy)benzylphosphonic acid diethyl ester (b.p.Q 8=140-148°C) and pyridine-2-aldehyde is prepared 2-[2-(2-dimethylaminoethoxy)styryl]pyridine monohydrochloride (m.p.=183 C; Yield: 52% of the theoretical).

Example 29

2-12-(2-

°'° o dimethylaminoethoxy)styryl]quinoline monohydrochloride (m.p. 188 C; Yield: 48% of the theoretical).

Example 30

From 2-(2-dimethylaminoethoxy)benzylphosphonic acid diethyl ester (bp.q=140-148°C) and benzaldehyde, 2-(2-dimethylaminoethoxy)' stilbene hydrochloride (m.p. = 199 oC; Yield: 61% of the theoretical).

Example 31

A solution of 400 g of 2-(2-acetoxy-styryl)pyridine i

1250 ml of chlorobenzene is added to 235.5 g of potassium methylate and heated to 110°C with stirring, whereby a yellow suspension is formed. 483 g of dimethylaminoethyl chloride hydrochloride are shaken together in a shaking funnel

with 100 ml of ice-cold 30% caustic soda, and the released, oily base is separated and dripped into the suspension in 6 equal portions over the course of 15 minutes (the amount of dimethylaminoethyl chloride that is not used is stored at 0°C to prevent premature self-reaction). The mixture is stirred for a further 30 minutes at 110°C, then cooled

and add ice. After extraction with ether, drying with water-

free sodium sulfate and evaporation of the solvent leaves an oil which is distilled in vacuum; b.p.„ rt,=156-161°C.

O, Ob

You get 376 g of a honey-coloured oil (yield: 83.9% of the theoretical).

123 g of the oily reaction product are dissolved in a mixture of 750 ml of ethyl acetate and 330 ml of absolute ethanol. To this, with good stirring, gradually add 430 ml of a solution of 132 ml of ethanolic hydrochloric acid (12.72% weight/volume) in 638 ml of ethyl acetate,

and no yellowing should occur. 600 ml of ethyl acetate are then added and cooled to 0°C. The separated crystals of 2-12-(2-dimethylaminoethoxy)styryl]pyridine monohydrochloride are filtered off with suction, washed with ethyl acetate and dried in a desiccator over concentrated sulfuric acid and potassium hydroxide. Melting point: 186-187.5°C;

Yield by this salt formation: 93 g.

If an excess of ethanolic hydrochloric acid is used,

a total of 300 ml of the hydrochloric acid with the concentration indicated above, the solution is colored deep yellow, and the dihydrochloride of 2-[2-(2-dimethylaminoethoxy)styryl]pyridine with a melting point of 218-220°C is isolated. To prepare the p-toluenesulfonate, 2.68 g of it is dissolved

free base of 2-(2-(2-dimethylaminoethoxy)styryl]pyridine in 20 ml of absolute ethyl acetate and slowly add, with stirring, 19 ml of a solution of 1.72 g of p-toluenesulfonic acid in 20 ml of ethyl acetate. After cooling in ice, the mono-p-toluenesulfonate crystallizes out, which is washed with a little ethyl acetate and dried in a desiccator over sulfuric acid. Melting point: 128-130°C; Yield: 3.1 g.

To prepare the phosphoric acid salt, 2.68 g is dissolved

of the free base of 2-[2-(2-dimethylaminoethoxy)styrylpyridine in 40 ml of ethanol and slowly adding a solution of 0.346 g of 85% phosphoric acid dropwise while stirring. The colorless solution is evaporated to 25 ml, 25 ml of ethyl acetate is added and placed in a

ice bath. After 1 hour, a white precipitate of the phosphate crystallizes out

of the above base. According to the analysis, it comes on

1 mol base 1/3 mol phosphoric acid. Melting point: 133-134°C;

Yield: 1.1 g

The starting material 2-(2-acetoxy-styryl)-pyridine (b.p.Q(06=162-175°C)) was prepared from 2-picoline and salicylaldehyde in the presence of acetic anhydride at 170°C.

Analogous to the procedure described in example 31

the following compounds are also prepared (examples 32-34).

Example 32

From 1-(2-acetoxyphenyl)-2-(pyridyl-2)-propene-1 (b.p.Q 05=140°C) and dimethylaminoethyl chloride, 1-(2-dimethylaminoethoxyphenyl)-2-(pyridyl-2)-propene-1 is prepared -monohydrochloride. Sm.p. = 128-133°C;

yield: 85% of the theoretical.

Example 33

From 2-(2-acetoxystyryl)pyridine (b.p.Q 06=162-175°C) and 2-chloro-N,N-dimethylpropylamine, 2-[2-(3-dimethylaminoprop-2-oxy)-styryl]pyridine is prepared. (b.p. Q 025=158-159°C; yield: 86% of the theoretical).

Example 34

From 2-(2-hydroxystyryl)quinoline (m.p.=274-278°C) and dimethylaminoethyl chloride, 2-[2-(2-dimethylaminoethoxy)styryl-quinoline monohydrochloride (m.p.=188°C; yield) is prepared : 86% of the theoretical)

Example 35

16 g 2-12-(2-chloroethoxy)styryl]pyridine (m.p.=57-59°C)

dissolve in 50 ml of methanol and mix at -15°C with 120 ml of fresh, liquid methylamine from a bomb and heat in an autoclave for 4 hours at 80°C. After cooling and relaxation, the autoclave contents are evaporated, the residue is dissolved in dilute acetic acid and shaken twice with ether to remove the weakly basic products. The mixture is then made alkaline while cooling with 2N caustic soda, and the reaction product is extracted with ethyl acetate. After drying with sodium sulphate, an oily residue remains after distillation, which crystallizes on standing overnight (13.8 g,

corresponding to 88.2% of the theoretical). The compound is dissolved in 200 ml of acetone, filtered with activated carbon and 20 ml of ethanol is added.

To this mixture, carefully add a solution of 15.3 ml of ethanolic 12.72% hydrochloric acid (weight/volume) in 50 ml of acetone until it begins to turn yellow, and for this you need approx. 59 ml of the acidic trap solution. Ether is then added until it begins to cloud and stirred in an ice bath while cooling. Within 1 hour, a dull yellow substance crystallizes out, which is suctioned off and dried in a desiccator. 9.3 g (corresponding to 52% of the theoretical) of 2-12-(2-methylaminoethoxy)styryl]pyridine monohydrochloride with a melting point of 178-180°C are obtained.

The 2-12-(2-chloroethoxy)-styryl]pyridine (m.p. = 57-59°C) used as starting material is prepared from 2-(2-acetoxystyryl)-pyridine (see ex. 32) and benzenesulfonic acid-2- chloroethyl ester in the presence of potassium methylate in toluene.

Analogous to the method described in example 35, the following compounds are also prepared (examples 36-48):

Example 36

From 2-12-(2-chloroethoxy)styryl]pyridine (m.p.=57-59°C) and ammonia, 2-[2-(2-aminoethoxy)styryl]pyridine dihydrochloride (m.p. 269°C) is prepared; yield: 49% of the theoretical).

Example 37

From 2-t2-(2-chloroethoxy)styryl]quinoline hydrochloride (m.p. 214-220°C) and methylamine, 2-[2-(2-methylaminoethoxy)styryl]-quinoline monohydrochloride (m.p. 170°C; Yield: 12.0% of the theoretical.

Example 38

From 2-12-(2-chloroethoxy)styryl]pyridine (m.p. 57-58°C) and ethylamine, 2-12-(ethylaminoethoxy)styryl]pyridine dihydrochloride (m.p. 211°C) is prepared; yield: 48.3% of the theoretical).

Example 39

From 2-[2-(2-chloroethoxy)styryl]pyridine (m.p. 57-58°C) and piperidine, 2-12-(2-piperidinoethoxy)styryl]pyridine dihydrochloride (m.p. 176°C) is prepared ; yield: 31% of the theoretical).

Example 40

From 2-[2-(2-chloroethoxy)styryl]pyridine (m.p. 57-58°C) and morpholine, 2-[2-(2-morpholinoethoxy)styryl]pyridine dihydrochloride (m.p. 248°) is prepared C; yield: 53% of the theoretical).

Example 41

From 2-[2-(2-chloroethoxy)styryl]pyridine (m.p. 57-58°C) and N-methylpiperazine, 2-12-(2-methylpiperazineethoxy)styryl]-pyridine trihydrochloride (m.p. 268°C; yield: 45% of the theoretical).

Example 42

From 2-t2-(2-chloroethoxy)styryl]pyridine (m.p. 57-58°C) and allylamine, 2-12-(2-allylaminoethoxy)styryl]pyridine dihydrochloride (m.p. 201°C) is prepared; yield: 18% of the theoretical).

Example 43

From 2-t2-(2-chloroethoxy)styryl]pyridine (m.p. 57-58°C) and 2-phenylethylamine, 2-t2-(2-/3-phenylethylaminoethoxy)styryl]- pyridine dihydrochloride (m.p. 263°C; yield: 54% of theory).

Example 44

From 2-[2-(2-chloroethoxy)styryl]pyridine (m.p. 57-58°C) and 2-methoxyethylamine, 2-t 2-(2-/3-methoxyethylaminoethoxy)-styryl]-pyridine monohydrochloride is prepared (m.p. 147°C; yield: 45% of the theoretical).

Example 45

From 2-t2-(2-chloroethoxy)styryl]pyridine (m.p. 57-58°C) and di-(2-hydroxyethyl)amine, 2-t2-(2-dihydroxyethylaminoethoxy)styryl]pyridine dihydrochloride is prepared (m.p. 140°C; yield: 22%

of the theoretical).

Example 46

From 2-t2-(2-chloroethoxy)styryl]pyridine (m.p. 57-58°C) and methyl-2-hydroxyethylamine, 2-[2-(2-N-methyl-N-hydroxy-ethylaminoethoxy)styryl is prepared ]pyridine dihydrochloride (m.p. 190°C;

yield: 42% of the theoretical).

Example 47

From 2-t2-(2-chloroethoxy)styryl]pyridine (m.p. 57-59°C) and dimethylamine, 2-t 2-(2-dimethylaminoethoxy)styryl]pyridine monohydrochloride (m.p. 183°C) is prepared ; yield: 68% of the theoretical).

Example 48

From 2-t2-(2-chloroethoxy)styryl]quinoline (m.p. 214-220°C) and dimethylamine, 2-[2-(2-dimethylaminoethoxy)styryl]quinoline monohydrochloride (m.p. 188°C; yield) is prepared : 74% of the theoretical).

Example 49

24.5 g of (3,5-dimethylisoxazolyl-4)-methyl-triphenyl-phosphonium chloride in 150 ml of absolute ethanol is added to 1.4 g of sodium in 50 ml of absolute ethanol. 7.8 g of 2-(2-dimethylamino)-ethoxybenzaldehyde are added dropwise with stirring to the reaction mixture which has been heated to 40°C, and then heated for 15 minutes until boiling. After evaporation of the solvent, the reaction mixture is taken up

in dilute hydrochloric acid and extracted with benzene to remove the triphenylphosphine oxide formed. The aqueous phase is made alkaline with 2N caustic soda and extracted several times with ether. The oily residue obtained after drying with sodium sulphate and evaporation

of the ether, dissolve in acetone, and the hydrochloride precipitate with ethereal hydrochloric acid. After two recrystallizations from acetone, 6 g (70% of the theoretical) of 4-[2-(2-dimethylamino)-ethoxy-styryl]-3,4-dimethylisoxazole hydrochloride are obtained as colorless crystals with a melting point of 180-181°C .

The phosphonium chloride used as starting material is prepared from 3,5-dimethyl-4-chloromethylisoxazole and triphenylphosphite with a yield of 89% of the theoretical, in the form of colorless crystals.

3,5-dimethyl-4-chloromethylisoxazole can be prepared according to N.K. Kochetkov, E. D. Khomutova and M. V. Bazilevsky, J. Gen. Chem. (USSR) 28, 2736 (1958) by chloromethylation of 3,5-dimethylisoxazole.

Analogous to the method described in example 49, the following compounds are also prepared (examples 50-51):

Example 50

From benzyl chloride and triphenylphosphine, benzyl-triphenylphosphonium chloride is prepared [Wittig and Schlllkopf, Ber. 88, 1662

(1955)], and this is reacted with 2-(dimethylaminoethoxy)benzaldehyde (b.p.=110°C) to 2-(dimethylaminoethoxy)stilbene. The connection

0.05 o

is isolated as hydrochloride (m.p. 199 C; yield: 73% of the theoretical).

Example 51

From 2-chloro-methylpyridine (b.p.1=42-45°C) and triphenylphosphine, picolyl-2-triphenylphosphonium chloride is prepared and this is reacted

with 2-(dimethylaminoethoxy)benzaldehyde (b.p.Q 05=110°C) to 2-[2-(2-dimethylaminoethoxy)styryl]pyridine, and this is isolated as the mono-hydrochloride (m.p. 186-187°C; yield: 66% of the theoretical).

Claims (2)

1. Analogy method for the preparation of new, therapeutically active 8-aryl-2-amino alkoxystyrenes with the general formula where Ar means a phenyl residue, a 2-, 3- or 4-pyridyl residue, which may optionally be substituted with one or two lower alkyl groups, a 2-quinolyl or 2-pyrazinyl residue, which may optionally be substituted with a lower alkyl group, a pyrimidyl residue which may optionally be substituted with a lower alkyl group, a 2-benzimidazolyl residue which may optionally be substituted with a halogen atom and/or with a lower alkyl group and/or a trifluoromethyl group, a 2-furyl or 2-thienyl residue, a 5-isoxazolyl residue which may optionally may be substituted with a lower alkyl group or a phenyl group, or a 5-(1,2,4-oxadiazolyl) residue which may optionally be substituted with a lower alkyl group, Rl' R2°^ R4' sortl is ^^ ie eHer different from each other, means hydrogen atoms or lower alkyl groups, R- means a hydrogen atom or a lower alkoxy group, Rfi and R7, which are the same or different from each other, mean hydrogen atoms or lower alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl or aralkyl groups, the residues R^ and R^ also together with the intermediate nitrogen atom can form a piperidine- , morpholine or methylpiperazine ring, and n means 0 or 1, and their acid addition salts with inorganic or organic acids, characterized in that a) from a compound of the general formula where the residues Ar, R^ to R^, R&, R? and n has the meanings given above, water is split off using water-attracting agents at elevated temperature, or b) a phosphonic acid ester of the general formula where R1 and Ar have the meanings given above, and R means a lower alkyl group, is reacted in a solvent with an aldehyde or ketone of the general formula where the residues R^ to ^4» Rg< R7°9 n nar ^e meanings indicated above, in the presence of a base, with intermediate formation of a corresponding carbanion of the compound of the general formula III, or c) a phosphonic acid ester of the general formula ,. _,hyo55Tgestgn^aR2 ^fcriic*^» &Rg-/ sB-j^g^i/haas-^eiioQveaaiéar nangtUitee? bete<y>d-njnger/^ and«.Rg.^ethyr,.r.en3lrave]?;g a^yjigrtrøpjejsQmseifct^ Prepare a solvent with an aldehyde or ketone of the general formula Where Ar -og!:'-R£: -h.ar: dé! 'évé^o^åVig^rÉt^^e^y^diyi-hgér ^Såf^år a'v^<v>én base, under inttérmédiåir ^ QårfåéSsé-^ év^& t' .k^uSJÆiflS^dW^v ^^the compound with the general formula V, or d) a styrene of the general formula mel1-i where the radicals Ar and R^ to R^ have the meanings given above, and X is a hydrogen atom or an acetyl group, is reacted in the presence of a base and a solvent with an amine of the general formula where the radicals R^, R^ and R7 have the meanings given above, and Y means a halogen atom, or e) a compound with the general formula ,,..... ,. hyor the residues Ar; R, to R4 and n have the meanings given above, and Z means a radical which can be replaced by basic radicals, reacted at elevated temperatures with an amine of the general formula where the residues and have the meanings given above, or -'tim/rf-), a phospholide with the general formula where Ar and R^ have the meanings given above, are reacted in a solvent at elevated temperatures with a basic ketone or aldehyde of the general formula where the residues R^ to R^, R^ and R^ and n have the meanings indicated above, and optionally, a possibly formed mixture of the cis and trans isomers is then separated by fractional crystallization, and/or optionally, the compound of formula I obtained is transferred to its acid addition salt by means of an inorganic or organic acid. 2. Process as stated in claim 1 for the production of 2-[o-(2-dimethylaminoethoxy)styryl]-pyridine and salts thereof, characterized in that starting materials of the general formulas II - XI are used where R^ is each hydrogen, Rg and R7 are each methyl, Ar is 2-pyridyl, ..and n is 0.