NO131675B - - Google Patents

Description

Analogy method for the production of new,

pharmacologically active basic dithienyl derivatives.

The invention relates to an analogous method for the production of new compounds with the general formula

where R2 means

hydrogen or a low molecular weight alkyl group, R^ means hydrogen or the hydroxy group and the residues R^ and R5 which are the same or different

means hydrogen, halogen, hydroxyl groups, low molecular weight alkyl groups, low molecular weight. haloalkyl groups or low molecular weight alkoxy groups, Rg and Ry mean hydrogen or lower alkyl groups, Rg are the same or different and mean hydrogen or a low molecular weight alkyl group, their optically active resp. diastereomeric forms and their salts.

At the alkyl, haloalkyl and alkoxy groups rotate

those with 1-6 carbon atoms. An example for the haloalkyl group is the trifluoromethyl group.

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

These thienyl derivatives, however, have a different structure to the compounds produced according to the invention, and comparison experiments carried out with the compound according to example 1 from Norwegian patent no. 105,750 with some compounds produced according to the invention show 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 brain flow was known at all, but only a cardiac effect such as on coronary flow and contraction amplitude. The effect on brain flow of the compounds according to the invention is therefore surprising.

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 the peripheral and cerebral blood flow. This effect is sometimes followed by a positive inotropic effect.

According to the invention, the compounds are produced by

one converts a connection with it in a manner known per se

where R2~Ry has the above meaning, Y is chlorine or bromine or an alkoxy group or a thienyl residue, optionally substituted with a low molecular weight alkyl residue, optionally its optically active resp. diastereomeric forms, with a thienyl metal compound (thienyllithium,

thienylgrignard compound), optionally substituted with a low molecular weight alkyl residue,

after which, if desired, the formed basic compounds are transferred according to known methods into the salts and/or compounds present as racemates are split according to known methods into the optically active isomers or diastereomeric forms.

The process for reacting a ketone of the general formula II with a thienyl metal compound is conveniently carried out in a temperature range between -100 and +100°C. Suitable solvents are, for example, dialkyl ethers, tetrahydrofuran, hydrocarbons, benzene, etc. If Y in formula II is a thienyl residue, then only one mole of thienyl metal compound is required for the actual reaction, while 2 moles of thienyl metal compound are at least necessary when Y means chlorine, bromine or an alkoxy group. As thienyl metal compounds, thienyllithium and thienylgrignard compounds are mentioned in particular.

However, a corresponding excess of organometallic compounds is always required when the compound II used contains active hydrogen (amlno-, hydroxy group, salt).

However, it generally pays off in many cases to use an excess of organometallic compounds, as better yields are thereby achieved.

The compounds contain asymmetric carbon atoms and usually appear as racemates, can be split into the optically active isomers in a manner known per se, for example with the aid of an optically active acid. However, it is also possible from the beginning to use optically active resp. also diastereomeric starting substances, as the end product is a correspondingly pure optically active form or diastereomeric form.

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

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 produced according to the invention, possibly in admixture with other pharmacologically active substances. The medicines can be manufactured using known and common 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. Liquids include, for example: oil or aqueous solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions.

Example 1.

d,Z-/_~1,1-dithienyl-(2)-l-hydroxy-propyl-(327-_/~l-phenyl 1-propyl-(2)7-amine

The Grignard compound is prepared from 4.8 g (0.2 mol) of magnesium and 32.6 g (0.2 mol) of 2-bromothiophene in 50 ml of absolute ether. For this solution, a slurry of 30.9 g (0.1 mol) d,-£-g-/~ 1-phenyl-propy1-(2)-amino7-propiothienone-(2).HC1 in 250 ml of absolute ether and kept for 2 hours when boiling. It is then decomposed with an aqueous ammonium chloride solution, the base is extracted with ether, the ether solution is dried with potassium carbonate, the solvent is distilled off and the base is purified by distillation. Boiling point 228-230°C/0.1 torr.

From the base, a maleate is produced in ethereal solution with maleic acid, which is recrystallized from isopropanol. Yield 24 g, melting point 134°C.

Example 2.

i-/_~1,1-dithienyl-(2 )-1-hydroxy-propyl-(327-/~1-phenyl-1-hydroxy-propyl-(2_)7-amine

The Grignard compound is prepared from 60.5 g (2.5 mol) of magnesium and 408 g (2.5 mol) of 2-bromothiophene in 500 ml of absolute ether. For this solution, 163 g (0.5 mol) -g-_/—1-phenyl-1-hydroxypropyl-(2)-amino7-propiothienone-(2).HCl, have been suspended in one liter of absolute benzene, and boiled in 3 hours under reflux. After cleavage with a 25% aqueous ammonium chloride solution, the organic phase is separated, dried with potassium carbonate and the solvent is distilled off. The remaining base dissolves in ether and is transferred with maleic acid into the maleate. The salt is extracted with acetic acid and then with water and recrystallized from benzene-acetone (1:1). Yield 67 g, melting point 137-138°C.

Example 3.

/-/~l-thienyl-(2)-l-thienyl-(3)-1-hydroxy-propyl-(3) J-l_ 1-phenyl-l-hydroxy-propyl 1-(2_)_7-amine

From 12.1 g (0.5 mol) magnesium and 8l.5 g (0.5 mol) 2-bromothiophene, prepare in 150 ml absolute ether the Grignard compound and react with 32.5 g (0.1 mol) j£ -g-/^_1-phenyl-1-hydroxy-propyl 1-(2)-amino7-propiothienone-(3).HC1 in 200 ml of absolute benzene as in example 2 and worked up. However, from the ethereal solution the base hydrochloride is precipitated with isopropanolic HCl and recrystallized from water and then from 10^-ig ethanol. Yield 12, g, melting point 199-200°C.

Example 4.

-£-_/_1,1-dithienyl-(2)-1-hydroxy-propyl-(327-^~1-phenyl-1-hydroxy-propyl 1-(2_)_7-amine

Of 7.2 g (0.3 mol) magnesium and 49 g (0.3 mol) 2-bromothiophene are prepared in 100 ml abs. ether Grignard compound. For this solution, 12.5 g (0.05 mol) of i-g-/<->l-phenyl-l-hydroxy-propyl-(2)-amino/-propionic acid ethyl ester (melting point 76-77°C, prepared by reaction of .£-norephedrine with acrylic acid ethyl ester in ethanol),' dissolved in 200 ml abs. benzene, and boil for 3 hours under reflux. 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 is dissolved in ether and transferred by maleic acid into the maleate. The salt is extracted with acetic acid ethyl ester and then with water and recrystallized from benzene-acetone (1:1). Yield 5 g, melting point 137-138°C.

Example 5.

^-{1-thienyl-(3)-1-/._2-methyl-thienyl-(527'-1-hydroxy-propyl-(3)}-/_"!-phenyl 1-1-hydroxy-propyl 1 - (2_)7-amine

From 12.2 g (0.5 mol) magnesium and 88.5 g (0.5 mol) 2-bromo-5-methyl-thiophene are prepared in 200 ml abs. ether Grignard compound. To this solution, a suspension of 32.5 g (0.1 mol) $-/~1-phenyl-1-hydroxy-propyl-(2)-amino7-propiothienone-(3).HCl (melting point 195-196° C, prepared by boiling 3-acety1-thiophene, paraformaldehyde and -£-norephedrine.HC1 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 neutralized with isopropanolic HCl. The precipitated HCl salt is recrystallized from water-ethanol (9:1). Yield 9 g, melting point 193-195°C

Example 6.

d,^-/_~l-thienyl-(2)-l-thienyl-(3)-1-hydroxy-propyl-(327-l~ 2-(4-tert.-butyl-phenyl)-2- hydroxy-ethyl]_7-amine

From 12.2 g (0.5 mol) magnesium and 8l.5 g (0.5 mol) 2-bromothiophene are prepared in 200 ml abs. ether Grignard compound. Add to this solution a suspension of 33.1 g (0.1 mol) d,/-3-/~2-(4-tert-butyl-phenyl)-2-hydroxy-ethylamino-7-propiothienone-(3) (melting point 133°C, prepared by reaction of 3-dimethylamino-propiothienone-(3) and 2-(4-tert,-butyl-phenyl)-2-hydroxyethylamine in water alcohol) and boiled for 3 hours under reflux. After cleavage with ice and 70 g of ammonium chloride, the organic phase is separated, dried with calcium carbonate and the solvent is distilled off. The remaining base is treated with ether and recrystallized from benzene. Yield 11 g, melting point 158°C.

Example 7-

d,.X-/__l-thienyl-(2 )-l-thienyl-(3)-1-hydroxy-propyl-(3_)7-l_ 1-phenyl-1-hydroxy-propyl i-(2_)_/ -amine

The Grignard compound is prepared from 6.8 g (0.28 mol) magnesium and 45.6 g (0.28 mol) 2-bromothiophene in 100 ml absolute otter. To this solution, a suspension of 22.8 g (0.07 mol) d,/-g-r~ 1-phen<y>1-1-hydroxy-<p>rop<y>1- (2)-amino/-propiothienone-(3).HCl in 200 ml of absolute .oenzene and boiled for 3 hours under reflux. 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 acetone and neutralized with isopropanolic HCl. The HCl salt is recrystallized from ethanol. Yield 7 g, melting point 177-178°C.

The starting ketone is produced by boiling 3-acetylthiophene EJ^eimDel^^^

^-/~1,1-dithienyl-(3)-1-hydroxy-propyl -(3).7-/"~1-phenyl-1-hydroxy-propyl-(2j)_/-amine

a) From 21 g (0.33 mol) of n-butyllithium dissolved in 200 ml of n-hexane and 48.9 g (0.3 mol) of 3-bromothiophene, the 3-thienyl-lithium solution is prepared at -70°C. For this solution, at -70°C, 28.9 g (0.1 mol) of 1-phenyl-1-hydroxy-propyl 1-(2)-amino/-propiothienone-(3) are added to 200 ral of absolute ether and kept in 30 minutes at -70°C. After heating each to -10°C, the mixture is decomposed with 100 ml of water, the organic phase is separated, dried with potassium carbonate and the solvent is distilled off. The remaining base is dissolved in ether and neutralized with isopropanolic HCl. The HCl salt is recrystallized from isopropanol. Yield 8.5 g, melting point 214°C.

The starting ketone is produced by boiling 3 acetylthiophene with paraformaldehyde and ^-norephedrine.HC1 in isopropanol and releasing the base NaOH (melting point 125°C). b) From 16 g (0.25 mol) of n-butyllithium in 167 ml of n-hexane and 40.7 g (0.25 mol) of 3-bromothiophene, the 3-thienyllithium solution is prepared at -70°C. For this solution, 25.1 g (0.1 mol) of ^-g-/_—1-phenyl-1-hydroxy-propyl-(2)-amino/-propionic acid ethyl ester are added to 100 ml of absolute ether and kept for 30 minutes at - 70°C. After heating gradually to -10°C, the mixture is decomposed with 100 ml of water, the organic phase is separated, dried with potassium carbonate, filtered and neutralized with isopropanolic HCl. The HCl salt is recrystallized from isopropanol. Yield 10 g, melting point 214°C.

The starting ester is obtained by reacting >£-norephedrine with acrylic acid ethyl ester in ethanol (melting point 75-77°C).

Example 9•

d,/-/<_>l,l-dithienyl-(3)-1-hydroxy-propyl-(3!7-/~l-phenyl-1-hydroxy-propyl-(2_)_7-amine

From 21 g (0.33 mol) of n-butyllithium in 200 ml of n-hexane and 48.9 g (0.3 mol) of 3-bromothiophene, the 3-thienyllithium solution is prepared at -70°C. 28.9 g (0.1

mol) d,/<-£-/_ 1-phenyl-1-hydroxy-propyl-(2 )-amino/-propiothienone - (3)

in 200 ml of absolute ether and kept for 30 minutes at -70°C. After heating gradually to -10°C, the mixture is decomposed with 100 ml of water, the organic phase is separated, dried with potassium carbonate and the solvent is distilled off. The remaining base is crystallized with ether and recrystallized from ethanol. Yield 19 g with melting point 151°C. The HCl salt melts at 205°C.

The starting ketone is obtained by boiling 3-acetylthiophene with paraformaldehyde and d,i-norephedrine.HCl in isopropanol and releasing the base with NaOH. (Melting point 133°C).

In the following, a number of substances produced according to the invention have been compared with 2(N(3'-phenyl-3<1->thieny1-3'-hydroxy-propyl-(1')))-amino-3-phenyl-propane .HC1 prepared according to example 1 in Norwegian patent no. 105,750 with regard to brain flow and acute toxicity.

The cerebral perfusion was measured in anesthetized dogs after intravenous application. For this purpose, the flow through the Arteria vertebralis (the brain) was determined with an electromagnetic flowmeter.

The DQ value indicates the average percentage increase in cerebral perfusion over the duration of 1 hour referred to the baseline value. It was determined graphically by the surface integral of the action curve over 1 hour.

The acute toxicity was determined according to Miller and Tainter (Proe. Soc. Exper. Biol. and Med. 57 (1944) 261).

The results appear in the following table:

As can be seen from the table, the compounds produced according to the invention cause a rather considerably better increase in brain flow than the known compound.

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

Furthermore, it should be pointed out that for the comparison compound no effect on brain flow was known at all, but only a cardiac effect such as on coronary flow and contraction amplitude. The effect on brain flow is therefore already surprising as such.

Claims (1)

Analogy method for the preparation of pharmacologically active compounds with the general formula where R2 means hydrogen or a low molecular weight alkyl group, R means hydrogen or the hydroxy group, and the radicals 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, Rg and Rr-, means hydrogen or lower alkyl groups, Rg are the same or different and means hydrogen or a low molecular weight alkyl group, their optically active resp. diastereomeric forms and their salts, characterized by reacting in a manner known per se a compound with the general formula where R2~Ry has the above meaning, Y is chlorine or bromine or an alkoxy group or a thienyl residue, optionally substituted with a low molecular weight alkyl residue, optionally its optically active resp. diastereomeric forms, with a thienyl metal compound (thienyllithium, thienylgrignard compound), possibly substituted with a low molecular weight alkyl residue, after which, if desired, the formed basic compounds are transferred according to known methods into the salts and/or compounds which exist as racemates are resolved according to known methods in the optical active isomers resp. diastereomeric forms.