NO128611B - - Google Patents

Description

Analogy process for the preparation of therapeutically active, basic 8-thienyl derivatives.

In Austrian Patent Nos. 235,832 and 240,850 it is

■ discussed compounds with the following general formulas as well as methods for their production:

In these formulas, Alk<1> is a linear or branched saturated alkylene group with 2-4 carbon atoms, with at least 2 carbon atoms forming the chain between the groups -C-OH and the group >NR. Alk is a linear or branched, saturated lower alkylene group with at least 2 carbon atoms as a chain between the groups >NR and the phenyl residue. R and R are the same or different and mean hydrogen, halogen, a hydroxyl group or an alkoxy group, R 4 resp. - R 1 is hydrogen or_a lower alkyl group.

These compounds have central stimulating and coronary dilating properties.

It has now been found that compounds which have a similar structure to those mentioned above, with the thienyl residue being bound above the three position, are also pharmacologically active and in particular increase peripheral and cerebral blood flow.

The invention relates to analogue methods for the production of therapeutically active compounds with a general formula

where the bridge link..- B - has either the structure >C(OH) - CCR1)!! - or the structure >C ='C(R1) - and R1, R2, R<3> and R^ mean hydrogen or low molecular weight alkyl groups, R5 J means hydrogen or a hydr. oxy 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: R 8 and R Q which are the same or different mean hydrogen or low molecular weight alkyl groups, R means hydrogen or a low molecular weight alkyl group, their optically active resp. diastereomeric forms and their salts, the method being characterized in that, in a manner known per se, a) reacts a compound with the general formula

where R 1 - R 7 have the meaning given above and X is an optional

with one or two low-molecular alkyl groups substituted thienyl-(3)-residue, optionally its optically active resp. stereoisomeric forms, with one of the compound

where R 8 and R 9 have the meaning indicated above, derived metal compound, or b) reacts with a compound of the general formula II, X being the group

8 9

where R and R have the meaning given above, with a thienyl-(3)-metal compound optionally substituted with one or two low molecular weight alkyl groups, and optionally transfer the formed compounds with water-splitting agents into the corresponding unsaturated compounds ( ^A-B- = >C= CR<1->), and/or transfer the formed basic compounds according to known methods into the acid addition salts, and/or split compounds that exist as racemates according to known methods into the optically active isomers or stereoisomeric forms.

The process for reacting a ketone of the general formula II with an organometallic compound, preferably thienyllithium or thienylgrignard compound or phenyllithium or phenylgrignard compound, is conveniently carried out in a temperature range between -40 and +100°C. Suitable solvents are, for example, dialkyl ether, tetrahydrofuran, hydrocarbons, benzene, etc.

For the actual reaction, only one mole of organometallic compound is required, however, a corresponding excess is always required when the compound II used contains active hydrogen (amino, hydroxy group, salt). However, in many cases it generally pays to use an excess of organometallic compound at all, as better yields are thereby achieved.

The water splitting of compounds where A - B - = C(OH) - CHCR<1>) - is suitably carried out at higher temperatures, for example in a temperature range from 20 - 150°C. Solvents such as glacial acetic acid, benzene, dioxane, etc. are preferably used.

As water-splitting agents, for example, mineral acids such as sulfuric acid or halogenated hydrogen acids, organic acids such as oxalic acid, formic acid, zinc chloride, stannous chloride, boron trifluoride, potassium hydrogen sulphate, aluminum chloride, phosphorus pentoxide, aluminum oxide, acid chloride, red phosphorus + iodine in the presence of water come into consideration.

When the water is removed, alkoxy groups present can optionally be split into hydroxy groups. In detail, this depends on the water-releasing agent as well as the other conditions for this dehydration reaction.

The compounds which contain asymmetric carbon atoms and which 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 then a correspondingly pure optically active form, resp. diastereomer configuration.

The transfer in the salts takes place according to known methods,

known and therapeutically applicable acid residues are used as anions for the salts.

The compounds produced according to the invention are pharmacologically active and above all increase the peripheral and cerebral perfusion. They are therefore suitable for increasing brain and muscle blood flow.

The compounds are therefore 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 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. Medicines can be used enterally, parenterally, orally, perlingually or in the form of sprays.

The dose for humans is usually between 1 and 100 mg of active substance one or more times per day. day.

The administration can take place in the form of tablets, capsules, pills, dragées, drops, liquids or aerosols. Liquids include, for example, oil or aqueous solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions.

Example 1.

The Grignard compound is prepared from 12.1 g (0.5 mol) of magnesium shavings and 78.5 g (0.5 mol) of bromobenzene in 150 ml of absolute ether. For this solution, a slurry of 32.5 g (0.1 mol) L-g-/-1-phenyl-1-hydroxy-propyl-(2)-amino/-propiothienone-(3)•HCl in §00 ml of absolute benzene and kept for 2 hours while boiling. It is then decomposed with a solution of 25 mg of ammonium chloride in 250 ml of 10% ammonia, the organic phase is separated, dried with potassium carbonate and dissolved. the agent is distilled off. The remaining base is dissolved in 200 ml of ether and neutralized with 10% isopropanolic HCl, the HCl salt being precipitated and recrystallized from water.

Yield: 17 g.

Melting point: 2l4-215°C. L-fJ-V 1-phenyl-1-hydroxy-propyl-(2)-amino7-propiothienone-(3)-hydrochloride is prepared as follows: 31.5 g (0>25 mol) 3-acetylthiophene, 7.5 g of paraformaldehyde and 47 g (0.25 mol) of L-norephedrine.HC1 are boiled in 100 ml of isopropanol for 3 hours under reflux, with a further 3.8 g of paraformaldehyde being added after 1 hour. The HCl salt precipitates on cooling and is recrystallized from ethanol. Yield 52 g, melting point 195-196°C.

Example 2.

L-{1-[2,5-dimethyl-thienyl-(3)7-1-phenyl-1-hydroxypropyl-(3)}-/. 1-phenyl-1-hydroxy-propyl-(2_)/-amine

From 12.1 g (0.5 mol) magnesium shavings and 78.5 g (0.5 mol) bromobenzene, the Grignard compound is prepared in 150 ml of absolute ether, which, as in example 1, is reacted with 35.4 g (0.1 mol) L -3-/~1-phenyl-1-hydroxypropyl-(2)-amino7-2,5-dimethyl-propiothienone-(3).HCl in 200 ml of absolute benzene and worked up. The HCl salt is recrystallized from 20% ethanol and then from methyl ethyl ketone.

Yield: 12 g.

Melting point:. 192-193°C. L-3-/. 1-phenyl-1-hydroxy-propyl-(2)-amino/-2,5-dimethyl-propiothienone-(3)-hydrochloride is prepared as follows: 115.5 g (0.75 mol) 3-acetyl-2 ,5-dimethylthiophene, 22.5 g of paraformaldehyde and 140.7 g (0.75 mol) of L-norephedrine.HC1 is boiled in 500 ml of isopropanol for 3 hours under reflux, with a further 11.3 g of paraformaldehyde being added after 1 hour .

The HCl salt precipitates on cooling and is recrystallized from ethanol. Yield 161 g, melting point 207-208°C.

Example 3-

L-/~1-1 ieny1-(3)-phenyl-propene-(1)-y1-(3V7-/~1-pheny1-1-hydroxy-propyl-(22/-amine

In a slurry of 16 g (0.04 mol) L-/~ 1-thienyl-O)-1-phenyl-l-hydroxy-propyl- (~ b)_ l - l_ 1-phenyl-l-hydroxy-propyl - (2) 7-amine.HCl in 150 ml of glacial acetic acid, HCl gas is introduced, as the starting material first dissolves and the HCl salt of the reaction product falls out after approx. 20 minutes. The HCl salt is recrystallized from 20% ethanol.

Yield: 10 g, melting point: 228-230°C.

Example 4.

L-/~1-thienyl-(3)-l-ferriyl-l-hydroxy-2-methyl-propyl- (3_)_/ — l<_> l-phen<y>l-l-hydroxy-<p >rop<y>l-(2<2>/-amine).

From 12.1 g (0.5 mol) magnesium and 78.5 g (0.5 mol) bromobenzene, 150 ml of the absolute ether Grignard compound is prepared, which is reacted with 33.9 g (0.1 mol) L-α-methyl-3-/ ~l-phenyl-l-hydroxypropyl-(2)-amino/- propiothienone-(3).HC1 (melting point l88-190°C, prepared by reaction of 3-propionylthiophene with paraformaldehyde and L-norephedrine.HC1 in isopropanol at boiling temperature ) as in example 1 and processed. The base becomes solid on treatment with ether (m.p. 62-68°C). It is dissolved in 100 ml of acetone and neutralized with isopropanolic HCl (7-n). The HCl salt is recrystallized from acetone, m.p. 184-185°C.

Yield: 8 g.

Example 5»

L-/_ 1-thienyl-( 3 )-1-p-isopropylphenyl-1-hydroxy-propyl-(3_)/-/. 1-phenyl-1-hydroxy-propyl-(2_)/-amine

From 12.1 g (0.5 mol) magnesium and 99.5 g (0.5 mol) 4-bromocumol, the Grignard compound is prepared in 150 ml of absolute ether and reacted with 32.5 g (0.1 mol) L-g-/< ->l-phenyl-l-hydroxypropyl-(2)-amino7-propiothio-enone-(3).HCl (m.p. 195-196°C, prepared by reaction of 3-acetylthiophene with paraformaldehyde and L-norephedrine.HC1 in isopropanol at boiling temperature) in 200 ml of absolute benzene as in example 1 and worked up. The HCl salt is recrystallized from isopropanol.

Melting point- 220-221°C, yield: 10 g.

Example 6.

L-[1-thienyl-(3)-1-m,p-dimethylphenyl-1-hydroxy-propyl-

(32/-/. 1~f,enyl-1-hydroxy-propyl-(22/-amine

From 12.1 g (0.5 mol) magnesium and 92.5 g (0.5 mol) 4-bromo-o-xylene, prepare in 150 ml absolute ether the Grignard compound and react as in example 1 with 32.5 g (0 .1 mol) L-3-/~1-phenyl-1-hydroxypropyl-(2)-amino/-propiothienone-(3).HC1 in 200 ml of absolute benzene and worked up. The HCl salt is recrystallized from water, m.p. 185-188°C.

Yield: 9 g.

Example 7-

D,L-/_~1-thienyl-(3)-1-phenyl-1-hydroxy-propyl-(3l7-/_~2-(4-fluorophenyl)-2-hydroxy-ethyl]17amine

From 9.8 g (0.4 mol) magnesium and 62.8 g (0.4 mol) bromobenzene, the Grignard compound is prepared in 120 ml of absolute ether and reacted with 29.3 g (0.1 mol) D,L-e-/~ 2-(4-Fluorophenyl)-2-hydroxy-ethyl-amino-7-propiothienone-(3) (m.p. 152°C, prepared by reacting 3-dimethyl-amino-propiothienone-(3)•HC1 with 2- (4-fluorophenyl)-2-hydroxyethylamine in ethanol/water at room temperature) in 180 ml of benzene as in example 1 and worked up. The HCl salt is recrystallized from isopropanol.

Temp. 180°C. Yield: 8 g.

Example 8.

D,L-/~l-thienyl-(3)-1-phenyl-1-hydroxy-propyl-(3l7-/~2-(4-tert-butyl-phenyl)-2-hydroxy-ethyl-7-amine

From 9.8 g (0.4 mol) of magnesium and 62.8 g (0.4 mol) of bromobenzene, the Grignard compound is prepared in 120 ml of absolute ether and reacted with 26.5 g (0.08 mol) of D,L-$- /~2-(4-tert.-butyl-phenyl)-2-hydroxyethyl-amino-7-propiothienone-(3) (m.p. 133°C, prepared by reaction of $-dimethylamino-propio.thienone.HCl with 2-( 4-tert.-butyl-phenyl 1)-2-hydroxy-ethylamine in ethanol/water at room temperature) in 180 ml of absolute benzene as in example 1 and worked up. The HCl salt is recrystallized from isopropane phtl/ether. Melting point: l63°C. Yield: 3 g.

Example 9 -

D,L-/_~1-thienyl-(3)-1-phenyl-1-hydroxy-propyl-(3l7-/_~2-(4-chlorophenyl)-2-hydroxy-ethyl/-amine

From 7.3 g (0.3 mol) magnesium and 47.1 g (0.3 mol) bromobenzene, the Grignard compound is prepared in 100 ml of absolute ether and reacted with 20.8 g (0.06 mol) D,L-6- /_— 2-( 4-Chlorophenyl 1)-2-hydroxy-ethyl-amino7-propiothienone-(3).HCl (m.p. 160°C, prepared by reacting B-dimethylamino-propiothienone-(3). HCl and 2-(4-chlorophenyl)-2-hydroxyethylamine in ethanol/water at room temperature) in 150 ml of absolute benzene as in example 1 and worked up. The HCl salt is recrystallized from isopropanol/ether. Temp. 196°C. Yield: 4 g.

Example 10.

L-/^~l-thien<y>l-(3)-l-phen<y>l-2-met<y>l-<p>ro<p>ene-(l)-<y>l -(327-^<->1-phenyl-1-hydroxy-propyl-(2_)7-amine

4.1 g (0.01 mol) L-/~l-thienyl-(3)-l-phenyl-l-hydroxy-2-methyl-propyl-(317-/- 1-phenyl-l-hydroxy-propyl -(2_)7-amine.HCl is suspended in JO ml of glacial acetic acid and treated to complete dissolution with HCl gas. The solvent is distilled off, the residue is alkalized with ammonia and the base is dissolved in ether. Upon neutralization of the ethereal solution

with isopropanol HC1, the HCl salt is prepared, which is recrystallized from isopropanol. Temp. 215-216°C. Yield: 3 g.

Example 11.

L-/~1-thienyl-(3)-1-(4-isopropylphenyl)-propen-(1)-yl- (~ b) J-1_ 1-phenyl-1-hydroxy-propyl-(2_) /-amine

S (0.01 mol) L-/_ 1-thienyl-(3)-1-p-isopropylphenyl-1-hydroxypropyl-(32/-/. 1-phenyl-1-hydroxy-propyl-(2_)_/ -amine.HC1 is suspended in 30 ml of glacial acetic acid and for 30 min. HCl gas is introduced. The solvent is distilled off and the residue is treated with ammonia. The base is dissolved in ether and transferred with isopropanolic HC1 into the HCl salt which is recrystallized from ethanol. Mp.. 236- 237° C. Yield: 2 g.

Example 12.

L-/"l-thienyl-(3)-1-phenyl-propen-(1)-yl-(3) 7- Tl-phenyl-1-hydroxy-propyl-(2_)_/-methylamine

The Grignard compound is prepared from 7.2 g (0.3 mol) of magnesium and 47.2 g (0.3 mol) of bromobenzene in 100 ml of absolute ether. A suspension of 17 g (0.05 mol) L-3-/ is added to this solution. 1-phenyl-l-hydroxy-propyl-(2)-methylamino/-propiothienone-(3).HC1 (m.p. 145°C, prepared by reacting 3-acetylthiophene with paraformaldehyde and L-ephedrine.HC1 in isopropanol at room temperature ) in 100 ml of absolute benzene and kept for 3 hours by boiling. It is then decomposed with a solution of 25 g of ammonium chloride in 250 ml of ice water, the organic phase is separated, dried with potassium carbonate and the solvent is distilled off. The remaining base is dissolved in ether, transferred with isopropanolic HCl into the HCl salt which is recrystallized from ethanol. Temp. 202-203°C. Yield: 6 g.

Example 13.

L-/<->l-thienyl-(3)-1-(3,4-dimethylphenyl)-propen-(1)-yl-(3_)7-/-l-phenyl-1-hydroxy-propyl-(2_ )7-amine

21.6 g (0.05 mol) L-[1-thienyl-(3)-1-m,p-dimethylphenyl-1-hydroxypropyl-(30.7-C 1-phenyl-1-hydroxy-propyl-( 2_)7-amine. HC1 is suspended in 100 ml of glacial acetic acid and treated with HCl gas until complete dissolution. The solvent is distilled off, the residue is treated with ammonia and the base is dissolved in ether. It is transferred with isopropanolic HC1 into the HCl salt and recrystallized from. 5055- ig ethanol, mp 215-217° C. Yield: 7 g.

The g-dimethylaminopropiothione hydrochloride used in examples 8 and 9 is obtained from 3-acetylthiophene, paraformaldehyde and dimethylamine hydrochloride in an analogous manner to the starting compound in example 1. Example 14.

L-/ 1-thienyl-(3)-l-phenyl-l-hydroxy-propyl-(3Y7-f~ l-phenyl-l-hydroxy-propyl-(2_)7amine

A solution of 3-thienyllithium is prepared at -70°C 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. This solution is mixed at -70°C with a suspension of 28.3 g (0.1 mol) !•-$-/_ 1-phenyl-1-hydroxy-propyl-(2)-amino7-propiophenone in 200 ml absolute ether and kept for 3 hours at -70°C.

After uniform heating 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 solution is dissolved in 200 ml of ether and neutralized with 10% isopropanolic HCl, the HCl salt falling out, which is recrystallized from water. Yield: 11 g. Melting point 2l4-215°C.

The main effect of the compounds produced according to the invention is that they increase cerebral blood flow. This effect is coupled with very good compatibility.

Brain perfusion was measured in anesthetized dogs after intravenous application at a dose of 0.3 mg/kg. For this purpose, the flow in the Arteria vertebralis (brain) was determined with an electromagnetic flowmeter.

The D^ values give the average percentage increase in cerebral perfusion over the duration of 1 hour, referred to the baseline value. They were determined by the area 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) 26l).

In the compounds according to NP 105750, the thienyl residue is attached over the 2-position. The table shows that the compounds produced according to the invention cause a considerably greater increase in cerebral blood flow. Hereby, it is also necessary to take into account that the compounds produced according to the invention have a significantly lower toxicity and are thus considerably better tolerated. Only the compound from example 1 has approximately the same toxicity as the comparison substance.

Furthermore, it must be taken into account that for the compounds known from Norwegian patent no. 105,750, only a coronary dilating effect and a centrally stimulating effect are known. The fact that these known compounds also cause a certain perfusion of the cerebral blood vessels was previously unknown and has only been shown in the comparison experiments carried out in connection with the present invention. A coronary dilating effect or a central stimulating effect is, however, something completely different from a cerebral effect, as the compounds produced according to the invention show.

It is therefore surprising that the compounds produced according to the invention show a cerebral effect at all and that this cerebral effect is considerably better than with the compounds produced according to the Norwegian patent no. 105,750.

Claims (1)

Analogy method for the preparation of therapeutically active compounds of the general formula where the bridge link >A - B - has either the structure >C(0H) - CCR<1>)!! - or the structure >C = C(R ) - and R 1, R 2 , R 3 and R <4> means hydrogen or low molecular weight alkyl groups, R 5 means hydrogen or a hydroxy group, the residues R 6 and R 7 which are the same or different , means hydrogen,' halogen, hydroxy groups, low molecular weight alkyl groups, low molecular weight haloalkyl groups or low molecular weight alkoxy groups, and the residues R and R which are the same or different, mean hydrogen or low molecular weight alkyl groups, R 1^ means hydrogen or a low molecular weight alkyl group, their optically active resp. diastereomeric forms and their salts, characterized in that one reacts in a manner known per se a) a compound of the general formula 1 7 where R -R has the meaning given above, and X is a optionally substituted with one or two low molecular weight alkyl groups thienyl-(3)-r^st, optionally its optically active resp. stereoisomeric forms, with one of the compound