NO132593B - - Google Patents

Description

The invention relates to an analogous method for the preparation of new compounds, namely basic dithienylpropene derivatives with the general formula

in which

R^ means hydrogen or a low molecular weight alkyl group, Rg means hydrogen or a low molecular weight alkyl group,

Rj means hydrogen or the hydroxy group, the residues R^ and R^, which are the same or different, mean hydrogen, halogen, hydroxy groups, low molecular weight alkyl groups, low molecular weight haloalkyl groups or low molecular weight alkoxy groups and the residues Rg and R^, mean , either both hydrogen or one means hydrogen and the other a low molecular weight alkyl group and the residues Rg, which may be the same or different, mean hydrogen or a low molecular weight alkyl group, as well as their optically active resp. diastereomeric forms and their salts.

The alkyl, haloalkyl and alkoxy groups are those with 1-6 carbon atoms. An example of the halogen-alkyl group is the trifluoromethyl group.

The compounds produced according to the invention are pharmacologically active, especially in heart and circulatory diseases. They cause an expansion of the coronary vessels and increase peripheral and cerebral blood flow. This effect is sometimes followed by a positive inotropic effect.

According to the invention, the new compounds can be prepared by reacting in a known manner an alcohol with the general formula in which the symbols have the above meaning, possibly their optically active resp. diastereomeric forms according to known methods with water-splitting agents to the corresponding unsaturated compounds, after which, if desired, the formed basic compounds are transferred in a known manner into their salts and/or cleave compounds that exist as "racemates in the optically active isomeric or diastereomeric forms.

The production of starting compounds with formula II can, for example, take place by the method according to Norwegian-laying_sskrift_ no. 131675.

The water separation is conveniently carried out at higher temperatures, for example in a temperature range from 20 to 150°C. Solvents are preferably used, such as e.g. glacial acetic acid, benzene, dioxane, etc.

As water-releasing agents, for example: Mineral acids, such as sulfuric acid or hydrohalic acids, organic acids, such as oxalic acid, formic acid, thionyl chloride, aluminum chloride, zinc chloride, stannous chloride, boron trifluoride, potassium hydrogen sulphate, aluminum oxide, phosphorus pentoxide, acid chlorides, red phosphorus + iodine in the presence of water;

The compounds which contain asymmetric carbon atoms and which can usually appear as racemates are split in a manner known per se, for example by means of an optically active acid into the optically active isomers. However, it is also possible to use originally optically active resp. also diastereomeric starting substances, as the end product is then a correspondingly pure optically active form resp. diastereomeric configuration.

The transfer in the salts takes place according to known methods, as anions for the salts are the known and therapeutically applicable acid residues.

From Norwegian patent no. 105,750, thienyl derivatives with valuable therapeutic properties are known, especially for the area of cardiac and circulatory therapy.

However, these thienyl derivatives have a different structure than the compounds produced according to the invention and

comparative experiments carried out with the compounds according to example

1 from Norwegian patent no. 105,750- with some compounds prepared according to the invention shows that the compounds according to the invention are surprisingly more effective in their pharmacological properties and are also less toxic. Furthermore, for the comparison compound from the Norwegian patent, no effect on cerebral perfusion was known at all, but only a cardiac effect such as on coronary perfusion and contraction amplitude. The effect on brain circulation of the compounds according to the invention is therefore surprising. The compounds produced according to the invention show a rather considerably better increase in cerebral perfusion than the known compounds.

The compounds produced according to the invention are surprisingly more effective in their pharmacological properties and, moreover, they are less toxic.

The compounds produced according to the invention are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or medicinal products contain as active substance one or more of the compounds available according to the invention, possibly in a mixture with other pharmacologically active substances. The preparation of the medicines can take place using the known and usual pharmaceutical carriers and additives. The drugs can be used enterally, parenterally, orally, perlingually or in the form of sprays.

The administration can take place in the form of tablets, capsules, pills, dragees, drops, liquids or aerosols. As liquida, it comes e.g. namely oily or aqueous solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions.

Example 1.

d ,Z-/~1, 1-dithieny 1-(2)-propene-(1)-y 1-(3i7-/~1-phenyl-propy 1-(2_)7-amine

In a slurry of 13 g (0.0275 mol) d,«-/_ 1,1-dithienyl-(2 )-1-hydroxy-propyl-(3y7-/~1-phenyl-propyl-(227-amine- maleate in 100 ml of glacial acetic acid is introduced until complete solution hydrogen chloride. The solvent is distilled off, the residue is treated with 25% ammonia and the base is taken up in ether. From the ethereal solution, the hydrochloride is precipitated with isopropanolic HC1 and recrystallized from acetic acid.

Yield 5 g. Melting point 127 - 128°C.

Example 2.

I-1,1-dithienyl-(2)-propen-(1)-yl-(327-/~1-phenyl-1-hydroxy-propyl-(2_)7-amine. 24 g (0.0586 mol) 1-Dithienyl-(2)-1-hydroxy-propyl-(J>)7-£~ 1-phenyl-1-hydroxy-propyl-(2_)_/-amine maleate is treated as in example 1 with hydrogen chloride in 100 ml of glacial acetic acid and work up The HCl salt is purified by recrystallization from isopropanol and 20 µg ethanol.

Yield 4 g. Melting point 189 - 190°C.

Example 3.

i-/~1-thienyl-(2)-1-thienyl-(3)-propen-(1)-yl-(327-/~1-phenyl-1-hydroxy-propyl-(227-amine

12.3 g (0.03 mol) £.-/~l-thienyl-(2 )-l-thienyl-(3 )-l-hydroxy-propyl-(3)7-1-phenyl-l- hydroxy-propyl-(2_)7-amine-HCl is treated in 100 ml of glacial acetic acid with HCl gas, as the substance first dissolves. After some time the HCl salt of the unsaturated compound precipitates,

which is recrystallized from 20 µg of ethanol.

Yield 6 g. Melting point 206 - 207°C

Example 4.

?-/~1-thienyl-(2)-1-thienyl-(3)-propen-(1)-yl-(327-/."1-phenyl-1-hydroxy-propyl-(227-methylamine

From 7.2 g (0.3 mol) of magnesium and 49 g (0.3 mol) of 2-bromothiophene in 100 ml of absolute ether, the Grignard compound is prepared.

To this solution are added 17 g (0.05 mol) -^-B-/_1-phenyl-1-hydroxy-propyl-(2)-methylamino-7-propiothienone-(3).HCl (melting point 145°C during sintering, prepared by boiling 3-acetylthiophene, paraformaldehyde and ^-ephedrine.HCl in isopropanol), suspended in 100 ml of absolute benzene and refluxed for 3 hours. After cleavage with ice and 50 g of ammonium chloride, the organic phase is separated, dried with potassium carbonate and the solvent is distilled off; The remaining base is dissolved in ether and acidified with isopropyl HCl. The syrupy formed HCl salt is dissolved in 50 ml of glacial acetic acid, treated for 15 minutes with HCl gas and the solvent is distilled off. The residue is treated with 25% ammonia, the base is dissolved in ether and neutralized with isopropanolic HC1. The HCl salt is recrystallized from isopropanol. Yield 3 g. Melting point 202 - 203°C.

Example 5-

^-/~l-thienyl-(2)-l-thienyl-(-3)-2-methyl-propen-(l)-yl-(327-

_/—1-phenyl-1-hydroxy-propyl-(227-amine).

The Grignard compound is prepared from 12.2 g (0.5 mol) magnesium and 81.5 g (0.5 mol) 2-bromothiophene in 100 ml absolute ether. To this solution is added a suspension of 33.9 g (0.1 mol) β-cx-methyl-3-β-1-phenyl-1-hydroxy-propyl-(2)-αMno7-propiothienone-(3).HCl (melting point 188 - 190°C, prepared by boiling 3-propionyl-thiophene, paraformaldehyde and -Æ-norephedrine.HCl in isopropanol) and boiled for 3 hours under reflux. After cleavage with ice and 70 g of ammonium chloride, the organic phase is separated, dried with potassium carbonate and the solvent is distilled off. The base is dissolved in ether and transferred with isopropanolic HCl into the HCl salt. The syrupy salt formed is crystallized with acetone and recrystallized from isopropanol. Yield 8 g. Melting point 200 - 201°C.

Example 6.

dyl-/"l-tieny 1-(2)-1-1 ieny 1-(3)-propene- (1)-y 1-(3J7-Z."1-pheny 1-1-hydroxy- propy 1-(2_)7-amine

4 g (0.01 mol) d,i-/~l-thienyl-(2)-l-thienyl-(3)-l-hydroxy-propyl-{' iVJ-C 1-phenyl-l-hydroxy-propyl -(2_)7-amine.HCl is treated in 50 ml of chloroform with HCl gas, as the substance dissolves. Up-. the solvent is distilled off, the residue is treated with 25 µg of ammonia and the base is taken up in ether. The hydrochloride is precipitated from the ethereal solution with isopropanolic HCl and recrystallized from water. Yield 2 g. Melting point 192 - 194°C. Example 7» 6-/~1,1-dithienyl-(3)-propene-(1)-y 1- (3 y7-/~1-pheny 1-1- hydroxy-propyl 1-(2j_7-amine 18 g (0.044 mol) Æ-/~1,1-dithienyl-(3)-1-hydroxy-propyl- (3) 7- £~l-phenyl-l-hydroxy-propyl-(227-amine.HCl is treated in 100 ml of chloroform with HCl gas until the combined substance has dissolved. The solvent is distilled off, the residue is treated with 10%- ig caustic soda, the base is taken up in ether and neutralized with isopropanolic HCl. The HCl salt is recrystallized from ethanol. Yield 8 g. Melting point 225°C.I

Example 8.

d,£-/~l,1-dithienyl-(3)-propen-(1 )-y 1-(3J,7- /~1-phenyl 1-1-hydroxy-propyl-(227-amine

50 g (0.13 mol) d,£-/~l,1-dithienyl-(3)-l-hydroxy-propyl-(3)7-£~ 1-phenyl-l-hydroxy-propyl-(227- amine is treated in 500 ml of chloroform with HCl gas until the combined substance has dissolved. The solvent is distilled off, the residue is treated with 10% caustic soda, the base is taken up in ether and neutralized with isopropanolic HCl. The HCl salt is recrystallized from ethanol. Yield' 31 g. Melting point. 215° C. Example 9• i-/_~l, 1-dithienyl-(3)-2-methyl-propen-(1)-yl-(327-_/~l- phenyl1-1-hydroxy-propyl-(227-amine

From 32 g (0.5 mol) of n-butyllithium in 333 ml of n-hexane and 81.5 g (0.5 mol) of 3-bromothiophene, the 3-thienyllithium solution is prepared at -70°C. 42 g (0.165 mol) of 1-phenyl-1-hydroxy-propyl-(2)-amino7-a-methyl-propionic acid methyl ester in 200 ml of absolute ether at -70°C are added dropwise to this solution. After warming up eventually

-10°C is split with 200 ml of water, the organic phase is separated, dried with potassium carbonate and the solvent is distilled off. The residue is dissolved in chloroform and treated for 30 minutes with HCl gas. The solvent is distilled off, the residue is treated with 10% caustic soda, the base is taken up in ether and neutralized with isopropanolic HCl. HC1-

the salt is recrystallized from isopropanol. Yield 7 g. Melting point 199°C.

The starting ester is obtained by reaction of /-norephedrine with methacrylic acid methyl ester and purification over a silica gel column (oil). Example 10.

d,l-ri,1-dithieny1-(3)-propene-(1)-y1-(3)7-(4-fluoro-phenyl)-1-hydroxy-propy1-(2j7-amine

A solution of 3-thienyllithium is prepared at -72°C from 37.8 g (0.59 mol) of n-butyllithium in 360 ml of n-hexane. and 8l.5 g

(0.5 mole) of 3-bromothiophene. To this solution 50 g (0.186 mol) of d,Æ-g-/~l-(4-fluoro-phenyl)-l-hydroxy-propyl-(2)-amirio7-propionic acid ethyl ester (melting point 70°C) slurry in 500 ml of absolute ether and stirred for 1 hour at -72°C. After the solution has warmed to -10°C, 200 ml of water is added, the organic phase is separated, dried with potassium carbonate and the solvent is distilled off. The residue is dissolved in 200 ml of chloroform, treated for 30 minutes with HCl gas, made alkaline after removal of the solvent with 10% caustic soda, the base is dissolved in ether and neutralized with isopropanolic HC1. The HCl salt is recrystallized from isopropanol. Yield 12 g. Melting point 206°C.

The aminopropionic acid esters used as starting materials in examples 10 to 13 are prepared by adding the corresponding amine to acrylic acid ethyl ester.

.. Example 11. d X- T1, 1-dithieny 1-(3)-propene-(1)-y 1-(327-/"1-(4-metoxy-phenyl)-1-hydroxy-propy1- (227^amine

A solution of 3-thienyllithium is prepared at -70°C from 13.6 g (0.21 mol) of n-butyllithium in 130 ml of n-hexane and 30.5 g (0.187 mol) of 3'-bromothiophene. To this solution, 20 g (71 m mol) of d,l-§-l~ l-(4-methoxy-phenyl)-1-hydroxy-propyl-(2)-amino7-propionic acid ethyl ester (melting point 77°C) suspended in 250 ml of absolute ether and stirred for 1 hour at -70°C. After the solution has warmed to -10°C, 100 ml of water is added, the organic phase is separated, dried with potassium carbonate and the solvent is distilled off. The residue is dissolved in 100 ml of chloroform, treated for 30 minutes with HCl gas, made alkaline after removal of the solvent with 10% caustic soda, the base is dissolved in ether and neutralized with isopropanolic HCl. The HCl salt is recrystallized from ethanol. Yield 4 g. Melting point 184°C.

Example 12.

d, l- Tl, 1-dithienyl-(3)-propene-(1)-y 1-( 3) 7-/_~ 1-(4-ethyl-phenyl)-1-hydroxy-propyl-(227- amine

A solution of 3-thienyllithium is prepared at -72 C

of 16.8 g (0.262 mol) of n-butyllithium in 160 ml of n-hexane and 39 g (0.24 mol) of 3-bromothiophene. 21 g (75.5 m mol) of d,l-l~l-(4-ethyl-phenyl)-1-hydroxy-propyl-(2)-aminoT-propionic acid ethyl ester (melting point 87°C) are added dropwise to this solution suspended in 250 ml of absolute ether and stirred for 1 hour at -72°C. After gradually heating to -10°C, 100 ml of water is added, the organic phase is separated, dried with potassium carbonate and the solvent is distilled off. The residue up-

dissolve in 100 ml of chloroform, treat for 30 minutes with HCl gas, make alkaline after removing the solvent with 10% caustic soda, dissolve the base in ether and neutralize with isopropanolic HCl. The HCl salt is recrystallized from isopropanol. Yield 8 g. Melting point 197°C.

Example 13-d,i-ri,1-dithienyl-(3)-propen-(1)-yl-(3)7-r2-(4-chloro-phenyl)-2-hydroxy-ethyl7-amine

Of 13.6 g (0.21 mol) of n-butyllithium in 130 ml of n-hexane

and 30.5 g (0.187 mol) of 3-bromothiophene is prepared at -72°C from the 3-thienyl-lithium solution. To this, 20 g (74 m mol) d,£-g-/~2-(4-chloro-phenyl)-2-hydroxy-ethyl-17-propionic acid ethyl ester (melting point 79°C) suspended in 250 ml of absolute ether at -72° C and stirred for 1 hour at

.this temperature. After gradually heating to -10°C, 100 ml of water is added, the organic phase is separated, dried with potassium carbonate and the solvent is distilled off. The residue is dissolved in 100 ml of chloroform, treated for 30 minutes with HCl gas, made alkaline with 10% caustic soda after removal of the solvent, the base is dissolved in ether and neutralized with isopropanolic HCl. The HCl salt is recrystallized from isopropanol. Yield 6 g. Melting point 180 - 182°C. Example 14. d, i- Tl, 1-dithienyl-(3)-propene-(1)-y 1-( 3) 7- Tl-(4-methyl- phenyl)-1-hydroxy-propyl-(227-amine).

A solution of 3-thienyllithium is prepared at -70°C from 23>5 g (0.367 mol) of n-butyllithium in 224 ml of n-hexane and 54.5 g (0.334 mol) of 3-bromothiophene. To this solution, 33.5 g (0.135 mol) d,£-&-/~ 1-(4-methyl-phenyl)-1-hydroxy-propyl-(2)-amino-7-propionic acid ethyl ester (melting point 66°C) slurry in 250 ml of absolute ether and stirred for 2 hours at -70°C. After this solution warms to -10°C, 100 ml of water is added, the organic phase is separated and the solvent is distilled off. The remaining crude d , 1-/~ 1,1-dithienyl-(3)-1-hydroxy-propyl-(3) 7- Tl-(4-methyl-phenyl)-1-hydroxy-propyl-(227-amine is dissolved in 100 ml of chloroform and for 30 minutes HCl gas is introduced. After removing the solvent, the residue is mixed with a 10% caustic soda solution, the base is dissolved in ether and neutralized with isopropanolic HCl. The hydrochloride is recrystallized from isopropanol. Melting point 183 - 184° C. Yield 6 g.

Example 15.

dyi- T\, 1-dithieny 1-(3)-propene-(1)-y 1-(3j.7-/~2-(3-tri-fluoromethylphenyl)-2-hydroxy-ethyl _l7-amine

A solution of 3-thienyllithium is prepared at -70°C from 10.5 g (0.165 mol) of n-butyllithium in 100 ml of n-hexane and 24.5 g (0.15 mol) of 3-bromothiophene. To this solution, 15 g (0.052 mol) of t-r~ 2-(3-trifluoromethyl-phenyl)-2-hydroxyethyl 7-propionic acid ethyl ester (melting point 45°C) suspended in 100 ml of absolute ether and stirred for 2 hours at -70°C. After the solution has warmed to -10°C, 50 ml of water is added, the organic phase is separated, the solvent is distilled off. The remaining crude d,.4-/<->1,1-dithienyl-(3)-1-hydroxy-propyl 1-(327-/_-2-(3-trifluoromethyl-phenyl)-2-hydroxy- ethyl7-amine is dissolved in 75 ml of chloroform and HCl gas is introduced for 30 minutes. After removal of the solvent, the residue is mixed with 1052 ig sodium hydroxide solution, the base is dissolved in ether and neutralized with isopropanolic HCl. The hydrochloride is recrystallized from isopropanol. Melting point 181°C .Yield 2.5 g.

Example 16.

I- Tl, 1-dithieny 1-(2 )-propen-(1)-y 1-( 3) 7- Tl-pheny 1-1-hydroxy-propy1-(227-amine

From 12.1 g (0.5 mol) of magnesium and 81.5 g (0.5 mol) of 2-bromothiophene in 150 ml of absolute ether, the Grignard compound is prepared. A slurry of 26 g (0.1 mol) of 1-phenyl-1-hydroxy-propyl-(2)-amino7-propionic acid chloride.HCl in 150 ml of absolute benzene is added to this solution and boiled under reflux for 2 hours. After cleavage with a 10% aqueous ammonium chloride solution, the organic phase is separated, dried with potassium carbonate and the solvent is distilled off. The remaining base, which next to the title compound contains 1-dithienyl-(2)-1-hydroxy-propyl-(3j7-/_~1-phenyl-1-hydroxy-propyl- ( 2_)7-amine, boil for complete

constant dehydration in 100 ml of ethanol and 10 ml of 7 N isopropa-

nolic HC1 for 15 minutes. After the solvent has been distilled off with ethyl acetate, the HCl salt is brought to crystallization and recrystallized from isopropanol. Yield h g. Melting

point 189 - 190°C.

^-g-/~phenyl-1-hydroxypropyl-(2)-amino7-propionic acid chloride.HCl is produced by reacting 1-phenyl-1-hydroxypropyl-(2)-amino7-propionic acid.HC1 at room temperature

rature in chloroform with a calculated amount of phosphorus pentachloride in the near-

be of a little dimethylformamide and used as a raw product (melting

point 152°C) in the above reaction.

Claims (1)

." • Analogy process for the production of new, pharmacologically active, basic dithienylpropene derivatives with the general formula wherein R^ means hydrogen or a low molecular weight alkyl group, R2 means hydrogen or a low molecular weight alkyl group, R^ means hydrogen or the hydroxy group, the residues R^ and R^, which are the same or different, mean hydrogen, halogen, hydroxy groups, low molecular weight alkyl groups, low molecular weight haloalkyl groups or low-molecular-weight alkoxy groups, the radicals Rg and R^ either both mean hydrogen or one of them hydrogen and the other a low-molecular-weight alkyl group, and the radicals Rg, which are the same or different, mean hydrogen or a low-molecular-weight alkyl group, as well as their optically active or diastereomers forms and their salts, characterized by reacting an alcohol with the general formula in which the symbols have the above-mentioned meanings, possibly its optically active resp. diastereomeric forms, according to known methods with water-releasing agents to the corresponding unsaturated compounds, after which, if desired, the formed basic compounds are transferred in a known manner into their salts and/or cleave compounds that exist as racemates in the optically active isomers resp. diastereomeric forms.