HU182581B - Process for producing alkyl-thio-phenoxy-propanol-amine derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of novel alkylthiophenoxypropanolamine derivatives and pharmaceutical compositions containing these compounds. Compounds of formula I wherein A, B and R are independently hydrogen or C 1-4 alkyl; R 1 is C 1-5 alkyl and R 2 is C 6 -C 12 alkyl, or cycloalkylalkyl having 5 to 8 carbon atoms and 2 to 6 carbon atoms in the alkylene chain, such that an alkylthiophenol is an epihalogen. the product is then condensed with an amine and optionally converted to the acid addition salt of the compound of formula (I) obtained as the free base. The compounds of the present invention have vasodilatation and spasmolytic activity, inhibit platelet aggregation, but have virtually no β-adrenergic blocking activity. Particularly preferred therapeutic effects are 1- [4- (1-methyl-ethylthio) -phenoxy] -3- (octylamino) -2-propanol. OH A λ / r-OCH ^CH-C-NH-R, -S -1-

Description

The present invention relates to a process for the preparation of biologically active carbon compounds as medicaments. More particularly, the present invention relates to the preparation of novel alkylthio-phenoxypropanolamines for use in pharmaceutical compositions and therapeutic methods. The alkylthio-phenoxypropanolamines of the present invention increase peripheral circulation, relax vascular smooth muscle, inhibit platelet aggregation, and are particularly useful in the treatment of peripheral vascular disorders such as interrupted claudication and cerebral arteriosclerosis. .

Various alkylthiophenoxypropanolamine derivatives have been prepared and tested for adrenergic activity, in particular to find more potent and more selective β-adrenergic blockers without undesirable pharmacological effects. These compounds are generally used for the treatment of certain forms of hypertension, angina pectoris, cigiarrhythmia and pheochromocytoma. As a result of these studies, the following compounds, as well as patents and publications, have been obtained:

Villa et al. Farmaco. Sci., Ed., 24, 349-357 (1969)] discloses the structure-activity relationship of alkylthiophenoxypropanolamine of formula XI:

Keizer et al., U.S. Patent No. 3,542,874, issued November 24, 1970, disclose 2- (alkylthio) phenoxypropanolamines of Formula XII wherein R ^{1 is C} 1-4 alkyl and wherein R ²

C 1 -C 12 alkyl or C 3 -C 12 cycloalkyl. According to this patent, compounds of the given type are highly potent β-adrenergic blocking compounds. Specific compounds described by Keizer et include those compounds of formula XII wherein in formula R ¹ is methyl or ethyl and R ² is isopropyl; or wherein R ^{1 is} methyl, ethyl or propyl and R ^{2 is} tert-butyl; and wherein R ^{1 is} methyl and R ^{2 is} cyclopropyl, cyclopentyl or cyclohexyl; and those wherein R ^{1 is} tert-butyl and R ^{2 is} cyclopentyl.

Crowther et al., U.S. Patent No. 350,179, March 17, 1970, disclose, inter alia, a series of compounds of Formula XIII wherein R ^{1 is} alkyl having up to 10 carbon atoms; R ^{2 is} alkyl of up to 20 carbon atoms, cycloalkyl of up to 10 carbon atoms, etc .; R ^{3 is} hydrogen or alkyl having up to 10 carbon atoms. However, Crowther et al. Do not disclose alkylthio derivatives in any of the examples.

Koppe et al., U.S. Patent No. 3,872,147, March 18, 1975, disclose a series of alkylthiophenoxypropanolamines having the structure XIV wherein R 1 is C 4 -C 4 alkyl; R ^{1 is C} 1 -C 5 alkyl, and wherein R ^{2 is C} 5 -C 8 alkyl, which compounds contain at least one quaternary carbon atom bonded directly to the nitrogen atom through a C 1 -C 4 alkylene chain. However, no alkylthio-phenoxypropanolamine is exemplified in the compounds discussed in detail by Koppe et al.

German Patent No. 2551141 (May 18, 1977) discloses alkylthio-phenoxypropanolamine as defined in Formula XV.

As can be seen from the literature described above, in general, numerous alkylthiophenoxypropanolamine are disclosed, but relatively few alkylthiophenoxypropanolamine are described in detail. Compared to the β-adrenergic blocking compounds in the literature, the alkylthiophenoxypropanolamines of this patent are unique in that they reduce vascular resistance while minimizing the β-adrenergic blocking effect.

The present invention relates to a process for the preparation of alkylthiophenoxypropanolamines of formula I wherein:

A, B and R are each independently hydrogen,

C 1-4 lower alkyl;

R _{3 is C} 1-8 alkyl;

R _{2 is C} 6-12 alkyl or in the ring

A cycloalkylalkyl group containing from 5 to 8 carbon atoms, which is attached to the nitrogen atom of the amino group via a C2-C6 alkylene chain; The invention further relates to a process for the preparation of pharmaceutically acceptable acid addition salts thereof.

The invention further relates to a process for the preparation of a pharmaceutical composition containing the above alkylthiophenoxypropanolamines.

The process of the present invention thus provides compounds of formula I wherein

A, B and R are each independently hydrogen or lower alkyl of 1 to 4 carbon atoms;

R 1 is C 1 -C 18 alkyl;

R _{2 is C} 6-12 alkyl or in the ring

A cycloalkylalkyl group containing from 5 to 8 carbon atoms having from 2 to 6 carbon atoms in the alkylene chain.

The invention also relates to the preparation of pharmaceutically acceptable acid addition salts thereof.

In the foregoing, below a lower alkyl group

C 1-4 straight-cut branched-chain groups are meant. Examples of such groups include methyl, ethyl, propyl, isopropyl, 1-bi-ethyl, 1-ethyl-propyl, 2-methyl-propyl or tert-butyl.

By alkyl is meant straight or branched carbon atoms having a number of carbon atoms (e.g., 1-4, 1-8 carbon atoms).

6-12) if appropriate.

Cycloalkylalkyl refers to groups having a cycloalkyl moiety of 5 to 8 carbon atoms.

-2182581 glazes such as cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; this cycloalkyl moiety is attached to the nitrogen atom of the amino group by a C 2 -C 6 alkylene chain. It will be appreciated by those skilled in the art that the alkylene chain linking the cycloalkyl to the nitrogen atom of the amino group may be straight or branched.

Non-toxic pharmaceutically acceptable acid addition salts are those salts of the compounds of formula I which are prepared with various inorganic or organic acids and whose anion is relatively non-toxic. Such acid addition salts are pharmacologically equivalent to the bases represented by formula (I). The salts are prepared for example, Acetic acid, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfonic such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic, and related acids. According to the invention, acid addition salts are prepared by known methods, for example by reacting a solution or suspension of the free base in a non-reactive solvent with the appropriate acid, concentrating or crystallizing the salt solution under reduced pressure. Acid addition salts which are relatively toxic and therefore do not meet the requirements for pharmaceutical use described above may in some cases be used as intermediates in the isolation and purification of the bases of formula I and may also be used for other chemical purposes such as the isolation of optical isomers. The preparation of these salts is also within the scope of the present invention.

It will be apparent to those skilled in the art that the compounds of formula I have one or more asymmetric carbon atoms, so that optically active isomers, racemates and diastereoisomers, all fall within the scope of the present invention. Diastereoisomeric mixtures may be separated into diastereomerically pure racemates by physico-chemical differences in the ingredients by known techniques such as chromatography and / or fractional crystallization. The separation of the racemates of the optically active isomers of formula I is carried out by known separation methods. For example, the base of formula I is reacted with an optically active acid to form salts from which the enantiomers can be separated by fractional crystallization. Acids useful for separating the optically active isomers of the compounds of formula T include, for example, optically active forms of tartaric acid, di-ortho-tolyltartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, and the like. optically active acids known in the literature. Preferably, the biologically active optically active stereoisomer is prepared in the process of the invention.

According to the present invention, a process for the preparation of a compound of formula I wherein A and B are hydrogen atoms is carried out by reacting an alkylthiophenol derivative of formula II wherein R and R, as defined above, reacting epihalohydrin cyanohydrin of formula where: X is halogen, preferably chlorine or bromine and the product obtained after epihalohydrin reaction is condensed with an amine of formula H ₂ N-R _2, wherein in the general formula as characterized by R ₂ having the meaning given above; followed by reacting the free base of formula I with an acid, optionally to form its acid addition salt.

For the preparation of alkylthiophenols of formula II, a diazotized aminophenol is reacted with an alkyl mercaptan and the resulting diazosulfide is cleaved to give the corresponding alkylthiophenol. This method is preferred and is based on the method of Wagner and Zook, Synthetic Organic Chemistry, page 789, 1953, Wiley; see also Miller et al., J. Am. Chem. Soc. 55, 1224, 1933, and Asaka et al., Chem. Abstrs., 61, 13343a],

In the process according to the invention, the alkylthiophenols represented by the following general formula II are preferably used: 4-methylthiophenol, 4-ethylthiophenol, 4-n-propylthiophenol, 4-n-butyl thio-phenol, 4-n-pentyl-thiophenol, 4-n-hexyl-thiophenol, 4-n-heptyl-thiophenol, 4-n-octylthiophenol, 4-isopropylthio -phenol, 4- (3-methyl-butylthio) -phenol,

2-n-butylthiophenol, 3-n-butylthiophenol, 2-ethylthiophenol,

2-n-propylthiophenol, 2-isopropylthiophenol, 3-ethylthiophenol, 3-n-propylthiophenol, 3-isopropylthiophenol, 2-methyl- 4- (methylthio) phenol, 3-methyl-4- (methylthio) phenol.

Preferred amines of the formula H ₂ N-R ₂ are, for example, n-hexylamine, n-heptylamine, n-octylamine, nnonylamine, n-decylamine, n-undecylamine, n-dodecylamine, n-isoacetylamine, 2,2-dimethylhexyl -amine, 1,1-dimethylheptylamine is used.

When two reactive sites are present in the epihalohydrin molecule of formula III, the product obtained after reaction with the alkylthiophenol (compound of formula II) may comprise a mixture of compounds of formula IV and V, wherein R, R, and X are have the meaning given above.

However, in the remainder of the reaction, compounds IV and V react with the amine H ₂ N-R _{2 to} give the same alkylthiophenoxypropanolamine product. Thus, it is not necessary to separate mixtures of intermediates of formulas IV and V resulting from the reaction of phenols II with epihalohydrin III. Under the reaction conditions provided by the process of the present invention, the epoxides of formula IV are predominantly obtained.

Optionally, the epihalohydrine reaction product is dissolved in a non-reactive organic solvent such as chloroform, and an excess of concentrated salt 3182581 is added to the reaction mixture to convert the epoxides of formula V to the corresponding alkylthiophenoxy halohydrins of formula IV. In contrast, the halohydrin of Formula IV can be converted to the compound of Formula V by any conventional method, for example by reaction with a base (Stephenson, J. Chem. Soc., 1574, 1954).

The reaction of the phenols II and the epihalohydrins III is carried out in the presence of a sufficient amount of a dilute aqueous alkali metal hydroxide such as sodium hydroxide at 0 ° C to 100 ° C, preferably 25 ° C to 35 ° C, to neutralize the acidic phenolic group. et al., J. Pharm. Pharmacol., 10, 47-59, 1958].

In another preferred embodiment of the process according to the invention, the phenols of formula II are reacted with the epihalohydrins of formula III in the presence of catalysts such as N-benzylisopropylamine hydrochloride, pyrrolidine, pyridine, piperidine, piperidine acetate, piperidine hydrochloride and the like. in the presence of epihalohydrine.

The condensation of the epihalohydrine reaction product of formula IV or V is preferably carried out in a reaction mixture with an amine of formula H ₂ N-R _{2 in} an inert organic solvent. Preferred solvents are methanol, ethanol, butanol, hexanol, toluene, dioxane, tetrahydrofuran, dibutyl ether, dimethoxyethane, ethylene glycol. The condensation reaction can also be carried out with equimolar amounts of reagents in the absence of solvent.

In another preferred embodiment of the process according to the invention, a phenol of formula II is reacted with a compound of formula VI in an alkaline reaction mixture to produce a compound of formula 1 wherein A and B are hydrogen atoms in a basic reaction mixture to give a compound of formula VII. wherein R, R 1 and R ₂ are as defined above and wherein R _{3 is a} hydrogenolysable cleavage group such as benzyl or benzhydryl. After completion of the reaction, the product of formula VIII is converted to an alkylthiophenoxypropanolamine of formula I. Deprotection by hydrogenolysis can be accomplished by catalytic hydrogenation, for example hydrogenation in the presence of palladium on charcoal, when the reaction mixture is prepared with a non-reactive solvent such as ethanol or aqueous ethanol.

The compounds of formula VI are prepared according to known methods. For example, according to Villa et al. (Farmaco, Ed. Sci., 24, 349-357, 1969), N-benzyl-n-octylamine and epichlorohydrin are reacted in an alkaline reaction mixture such as aqueous potassium hydroxide solution, followed by l - [(N- benzyl) -n-octylamino] -2,3-epoxypropane is obtained.

The invention according to a preferred embodiment of the compounds of formula I, wherein in formula A, B and R independently represent hydrogen or C1-4 rővid8 alkyl, R 1-8 alkyl and R ₂ C6-12 linear or branched alkyl group having a carbon atom attached to the amino nitrogen atom through a methylene group, or wherein C5-8 cycloalkyl group linked to R @ ₂ C2-6 alkylene chain, wherein the alkylene chain is attached via a methylene group to the amino nitrogen atom of the preparation is carried out by a formula VIII reducing a compound wherein A, B, R and R _{t have} the meanings given above to give compounds of formula IX wherein A, B, R and R j have the meanings given above; followed by reductive alkylation of a compound of Formula IX with an aldehyde of the general formula X wherein Ϋ is a straight or branched alkyl group having from 5 to 11 carbon atoms or a cycloalkylalkyl group having from 5 to 8 carbon atoms wherein the alkylene chain is 1-5. carbon atoms.

The corresponding nitroalkanes and aldehydes may be subjected to an aldol-type condensation in the presence of a base, or the sodium salt of the nitroalkane may be condensed with the sodium hydrogensulfite addition product of the aldehyde in the presence of a trace amount of alkali or weak acid. To prepare the alkylthiophenoxy aldehyde starting materials, the corresponding alkylthiophenol is reacted with diethyl acetal of bromoacetaldehyde, followed by acid catalyzed hydrolysis to cleave the acetal group.

As stated above, the alkylthiophenoxypropanolamines of the present invention increase peripheral blood flow, relax vascular smooth muscle, and inhibit platelet aggregation. The compounds have virtually no β-adrenergic blocking effect, which reduces the peripheral vasodilatory activity of β-adrenergic stimulating endogenous amines. Standard in vivo and in vitro pharmacological studies are performed to demonstrate the activity of the compounds of formula I. Among the studies to be considered are the dorsal vasodilation effect study with a fixed dorsal limb, the rat aortic strip treated with spasmogen used to test antispasmodic activity, and the anti-platelet adenosine doplasmate and collagen determination. To measure β-adrenergic blocking activity, a guinea pig trachea experiment, known as the standard method, is performed after the animals are treated with isoproterenol.

In addition, the compounds of the formula I according to the invention have vasodilatory and antispasmodic effects and inhibit platelet aggregation, inhibit lipolysis and cholesterol biosynthesis. Inhibition of lipolysis was demonstrated in a rat lipolysis model.

An effective amount of vasodilation is the dose that is vasodilatory in the mammal to be treated

-4182581 and at the same time does not cause unwanted side effects.

Systemic administration refers to oral and parenteral administration. Parenteral administration may be intramuscular, intravenous, intraperitoneal, rectal or subcutaneous. Ointments and suppositories may be used for rectal administration. Although the dosage administered will vary to a certain extent depending on the route of administration and the compound selected, it will generally be in the range of 0.5 mg to 25 mg per kilogram body weight. One of the compounds of the formula I, or pharmaceutically acceptable non-toxic salts thereof, may be used which is administered in one or more doses to produce the desired vasodilatory effect.

The composition further comprises, in addition to the active ingredient, a pharmaceutically acceptable carrier. The carrier may be a solid, semi-solid, or liquid material, and may be incorporated into a capsule.

Accordingly, it is a further object of the present invention to provide a pharmaceutical composition comprising the compounds of Formula I, or non-toxic pharmaceutically acceptable acid addition salts thereof, together with this pharmaceutically acceptable carrier.

For the preparation of a pharmaceutical composition for oral administration containing a unit dose of a compound of Formula I, the active compound is formulated with a solid carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose, a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol resins or the like, and finally tablets are prepared. The tablets may be used without a topcoat, but may be coated by known methods to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action. If coated tablets are desired, the active ingredient and excipient base formulation as prepared above is coated with a concentrated sugar solution containing, for example, gum arabic, gelatin, talc, titanium dioxide or the like. The tablets may also be coated with a lacquer layer dissolved in a volatile organic solvent or mixture of solvents. Paint may also be added to the topcoat.

In the preparation of soft gelatine capsules or other similar closed formulations, the active compound is dissolved in vegetable oil. Hard gelatine capsules may contain the active ingredient in granular form together with a solid powder carrier such as lactose, sucrose, sorbitol, starch such as potato starch, corn starch or amylopectin, as well as cellulose derivatives or gelatin.

Dosage unit forms for rectal administration may be prepared as a suppository containing the active compound of the formula I together with a neutral fat, but gelatin rectal capsules may be prepared which contain the active compound together with a vegetable oil or paraffin oil.

Liquid preparations for oral administration are prepared as elixirs, syrups or suspensions containing from 0.2 to 20% of the active ingredient. Such liquid preparations may also contain coloring agents, perfuming agents, sweetening agents and carboxymethylcellulose as a thickener.

Preferred solutions for parenteral administration by injection are prepared with water by dissolving the water-soluble pharmaceutically acceptable salt of the compounds of Formula I in water and adjusting the pH of the solution to a physiologically acceptable value. These solutions may also contain stabilizers.

Pharmaceutical tablets for oral use are prepared by known methods, for example, by mixing the therapeutically active compound of formula I and the required excipient.

Specific alkylthiophenoxypropanolamines prepared by the process of the present invention are described in the Examples. Particularly preferred compounds having no vasodilatory activity and 3-adrenergic blocking activity are:

- [4- (methylthio) phenoxy] -3- (octylamino) -2-propanol, 1- {4 - [(1-methylethyl) thio] phenoxy} -3- (octyl) amino) -2-propanol,

1- 3 - [(1-Methyl-ethyl) -thio] -phenoxy} -3- (octylamino) -2-propanol, 1- 4 - [(1-ethyl-ethyl) -thio] -phenoxy} -3- (dodecyl-amino) -2-propanol,

1- [4-Cyclohexyl-ethyl] -amino] -5-phenyl-methyl-ethyl-thiophenoxy] -propanol,

1 - [(4-Cyclohexyl-butyl) -amino] -3- {4 - [(1-methyl-ethyl) -thio] -phenoxy} -2-propanol, 1- [2-methyl-4- (methyl-thio) ) -phenoxy] -3-octylamino-2-propanol,

1- [2- (methylthio) phenoxy] -3- (octylamino) -2-propanol.

The invention is further illustrated by the following non-limiting examples.

Example 1

Preparation of 1- [4- (methylthio) phenoxy] -3-octylamino-2-propanol of formula XVI in 5.6 g (0.04 M) of 4- (methylthio) phenol and

Dissolve 2.4 g (0.06 M) of sodium hydroxide in the solution

7.4 g (0.08 M) of epichlorohydrin were added. After stirring for 24 hours at 30 to 35 ° C, the reaction mixture was extracted with chloroform. Wash the chloroform extract with water, remove the magnesium sulfate and distill under reduced pressure.

-5182581 remove volatile ingredients. The residue was distilled to give the epichlorohydrin derivative, 1- (4-methylthio) phenoxy-2,3-epoxypropane, which was dissolved in 30 ml of water. To the solution was added 7.5 g (0.06 M) of n-octylamine and the mixture was refluxed for 4 hours. By distillation under reduced pressure, the mixture is concentrated to about half volume when a white precipitate precipitates out of solution. This was collected and crystallized from ethanol. In this way, 1- [4- (methylthio) phenoxy] -3-octylamino-2-propanol is obtained which is analytically pure, m.p. 79.5 ° C to 80.5 ° C.

Analysis calculated for C ₁₈ H ₃₁ NO ₂ S: C, 66.42; H, 9.60; N, 4.30;

S, 9.85%;

Found: C, 66.30; H, 9.69; N4,13;

S, 9.58%.

Example 2

Preparation of 1- {4 - [(1-methylethyl) thio] phenoxy} -3-octylamino-2-propanol hydrochloride of formula XVII

a) Preparation of 4- (isopropylthio) phenol

A solution of sodium nitrite (113.8 g, 1.65 M) in water (210 mL) was added to a solution of para-aminophenol (163.7 g, 1.5 M) in 825 mL of 4N hydrochloric acid at -5 ° C with stirring. After stirring for two hours at -5 ° C, 270.6 g (6.77 M) sodium hydroxide and 126.4 g (1.66 M) 2-propanethiol are dissolved in 525 ml of water, and the mixture is stirred at -5 ° C. After cooling to ambient temperature, the solution of diazotized phenol prepared above is added under nitrogen over 45 minutes. After the addition was complete, the reaction mixture was allowed to warm to 27 ° C and maintained at this temperature for 16 hours. It is then cooled to 0 ° C and acidified with 570 ml of 12N hydrochloric acid. Nitrogen gas was passed through the mixture to remove excess 2-propanethiol, which was trapped in a permanganate trap. The bubbling was performed for two hours. The resulting solution was extracted several times with dichloromethane, and the extracts were combined, washed with water, dried over magnesium sulfate containing charcoal and filtered. The filtrate was concentrated under reduced pressure to give an oily product as a distillation residue. This was distilled to give 81 g of hot (1.2 mmHg) 4- (isopropylthio) phenol (32 g) at 114 ° C to 123 ° C.

(b) Dissolve 6.6 g (0.04 M) 4- (isopropylthio) phenol and 2.6 g (0.065 M) sodium hydroxide in 50 ml of water and add 7.4 g (0.08 M) of epichlorohydrin. We are added. After stirring for 24 hours at 30 to 35 ° C, the reaction mixture was extracted with chloroform. The chloroform extract is washed with water, dried over magnesium sulfate and distilled under reduced pressure to remove volatile constituents. The distillation residue yielded an epichlorohydrin intermediate, 1- (4-isopropylthiophenoxy) -2,3-epoxypropane.

The epichlorohydrin derivative was dissolved in ethanol (ml), n-octylamine (7.5 g, 0.06 M) was added and refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure, the distillation residue was dissolved in ethanol, and 6 ml of 12N hydrochloric acid were added. Concentrate the acidic solution under reduced pressure and crystallize the product from ethanol to give an analytical purity of 1 - {4 - [(l) at 171 ° C, 183 ° C and 186.5 ° C (double melting point) in 20% yield. methyl methylethylthio] phenoxy} -3- (octylamino) -2-propanol hydrochloride is obtained.

Elemental analysis for C ₂₀ H ₃₅ NO ₂ SX HCl

date: C, 61.59; H, 9.30; N, 3.59; 15 S, 8.22; Cl, 9.09%; because: C, 61.68; H, 9.29; N, 3.47; S, 8.15; Cl, 9.15%.

Example 3

Preparation of 1- {3 - [(1-methylethyl) thio] phenoxy} -3-octylamino-2-propanol hydrochloride of formula XVIII

By repeating the procedure of Example 2b), 3.85 g (0.029 M) of 3- (isopropylthio) phenol is reacted with epichlorohydrin and 4 g (0.031 M) n-octylamine, and the crude product is crystallized from ethanol-ether (13%). of analytical purity of 125 ° C and

127 DEG C. Yield: 1- {3 - [(1-methylethyl) thio] phenoxy} -3-octylamino-2-propanol hydrochloride.

Analysis calculated for C ₂₀ H ₃₅ NO ₂ Sx HCl: C, 61.59; Η 9.30; N, 3.59%;

Found: C, 61.22; H, 9.09; N, 3.53%.

Example 4

Preparation of 1- {4 - [(1-methylethyl) thio] phenoxy} -3-dodecylamino-2-propanol hydrochloride of formula XIX

By the procedure of Example 2b, 15.7 g (0.07 M)

4- (isopropylthio) -phenol is reacted with epichlorohydrin and 13.9 g (0.075 M) of n-dodecylamine and the crude product is crystallized from methanol in 13% yield at 153.5 ° C and 156.6 ° C. and 1- (4 - [(1-methylethyl) thio] phenoxy) -3- (dodecylamino) -250 propanol hydrochloride, m.p. 190 DEG C. (double melting point).

Analysis calculated for C ₂₄ H ₄₃ NO ₂ SX HCl: C, 64.61; H, 9.94; % N3,14;

Found: C, 64.38; H, 10.07; N, 2.97%.

Example 5

Preparation of 1 - [(2-cyclohexylethyl) amino] -3- (4 - [(1-methylethyl) thio] phenoxy (2-propanol-hydrogen) chloride of formula XX

-6182581

By repeating Example 2b, 5.0 g (0.022 M) of 4- (isopropylthio) -phenol is reacted with epichlorohydrin and 3.3 g (0.026 M) of cyclohexylethylamine. The crude product was crystallized from isopropyl alcohol with an analytical purity of 1 - [(2-cyclohexylethyl) amino] -3- {4 - [(1-methylethyl) thio] m.p. 180 ° C to 182 ° C. phenoxy} 2-propanol hydrochloride was obtained.

Analysis calculated for C ₂₀ H ₃₃ NO ₂ SxHCl to Calculated: C, 61.01; N, 8.83; % N3,61;

Found: C, 61.73; H8,71; N, 3.88%.

Preparation of 1 - [(4-cyclohexyl-butyl) -amino] -3- {4 - [(1-methylethyl) thio] -phenoxy} -2-propanol hydrochloride of formula XXI

Repeat Example 2b to give 4- (isopropylthio) phenol (9.0 g, 0.04 M), epichlorohydrin and 6.7 g (0.043 M) cyclohexyl butylamine. The crude product was crystallized from methanol in an analytical grade of 1 - [(4-cyclohexyl-butyl) -amino] -3- {4- [1-methyl-ethyl] melting at 179 ° C and previously softening at 118 ° C. ) -thio] phenoxy} -2-propanol hydrochloride is obtained.

Analysis calculated for C ₂₂ H ₃₇ NO ₂ SxHCl: C, 63.51; H, 9.20; N, 3.37%;

Found: C, 63.46; H, 9.35; N, 3.29%.

Example 7

Preparation of 1- [2-methyl-4- (methylthio) phenoxy] -3-octylamino-2-propanol of formula XXII

In the same manner as in Example 1, 3.14 g (0.015 M) of 2-methyl-4- (methylthio) phenol, epichlorohydrin and 1.93 g (0.015 M) of n-octylamine are reacted. The reaction mixture was concentrated and the distillation residue was crystallized from ethyl acetate / hexane to give analytically pure 1- [2-methyl-4- (methylthio) phenoxy] m.p. 59-60 ° C in 19% yield. 3- (octylamino) -2-propanol is obtained.

Analysis calculated for C _lfl to S H ₃₃ NO ₂ Theory: C, 67.21; H, 9.80; % N4,13;

Found: C, 66.80; H, 9.92; N, 3.81%.

Example 8

Preparation of 1- [2- (methylthio) phenoxy] -3- (octylamino) -2-propanol hydrochloride of formula XXIII

In the same manner as in Example 2b, 14 g (0.071 M) of 2-methylthio-phenol, epichlorohydrin and 9.04 g (0.07 M) of n-octylamine are reacted. The crude product was crystallized from a mixture of methanol and ether in 18% yield with an analytical purity of 1- [2- (methylthio) phenoxy] 3- (octylamino) melting at 105.5 ° C to 107.5 ° C. 2-Propanol hydrochloride is obtained.

Elemental Analysis calculated for C30H16NO2XHCl: C, 59.73; H8,91; % N3,87;

Found: C, 59.86; H, 9.07; N, 3.71%.

Example 9

Preparation of 1- {4 - [(L-methylethyl) thio] phenoxy} -3 - [(2,2-dimethyl-1-hexyl) amino] -2-propanol of formula XXIV

a) Preparation of 2,2-dimethylhex-1-ylamine In 25 ml of anhydrous toluene was dissolved 25 g (0.26 M) capronitrile and 75 g (0.53 M) methyl iodide, and the solution was heated to 80 ° C. 25.4 g (0.65 M) of sodium amide dissolved in 100 ml of toluene are added portionwise so that the solution remains boiling. After the addition was complete, stirring was continued for another two hours, and the reaction mixture was refluxed, cooled, and water (150 mL) was added. The organic solvent layer was separated, washed with water and dried over magnesium sulfate. The anhydrous solution was concentrated under reduced pressure and the distillation residue was distilled off in 81% yield.

2,2-Dimethyl capronitrile is obtained.

Dissolve 10.0 g (0.078 M) of 2,2-dimethylcapronitrile in 100 ml of ether, maintaining the reaction mixture at 0 ° C to 5 ° C, slowly with 6.0 g (0.158 M) of lithium in 200 ml of ether. is added to the anhydride. After stirring for two hours at 0.5 ° C, the product was hydrolyzed by adding 6.0 mL of water followed by 6.0 mL of 15% sodium hydroxide solution and finally 18 mL of water. After stirring for one hour, the hydrolyzed reaction mixture is filtered and the ethereal phase is separated off, which is distilled off under reduced pressure. After distillation of the distillation residue, 2,2-dimethylhex-1-ylamine is obtained.

b) Proceeding as in Example 2b)

The epichlorohydrin derivative of 4- (isopropylthio) phenol is reacted with 2,2-dinethylhex-1-ylamine and the product obtained as the free base is converted to its hydrochloride salt to give 1- (4 - [(1-methylethyl) ) -thio] -phenoxy} -3 - [(2,2-dimethyl-1-hexyl) amino] -2-propanol hydrochloride.

Example 10

Preparation of 1- {4 - [(1-methylethyl) thio] phenoxy (-3 [(2-methyl-2-octyl) amino] -2-propanol of formula XXV

a) Preparation of 2-methyl-2-octanol

Dissolve 14.5 g (0.1 M) of methyl heptanoate in 200 mL of ether and add the solution to 200 mL of a 3M solution of methyl magnesium bromide in ether (0.6 M) at such a rate that the reaction mixture remains boiling. After the addition is complete, reflux for one hour under reflux

-7182581 and then stirred at 26 ° C for 16 hours. The product was hydrolyzed by addition of dilute ammonium chloride solution, filtered and the filtrate was dissolved in 2N hydrochloric acid and extracted with ether. The ether extract was combined with the filtrate, washed with water, dilute sodium bicarbonate solution and brine, and then dried over magnesium sulfate. The anhydrous solution was concentrated by distillation of the concentrate under reduced pressure to give 13.1 g (yield 91%) of 2-methyl-2-octanol (130 mmHg) hot (100 mm Hg).

b) Preparation of N- (2-methyl-2-octyl) -acetamide To a glacial acetic acid was added 5.55 g (0.055 M) of sulfuric acid, 2.5 g (0.016 M) of acetonitrile and 8.0 g (0.055 M) of M) 2-Methyl-2-octanol was added. The resulting reaction mixture was stirred at 26 ° C for 17 hours. The reaction mixture was diluted with water (125 mL) and extracted with ether. Wash the ethereal extract with water and repeat the wash with dilute sodium bicarbonate solution and brine, then dry over magnesium sulfate. Concentration of the anhydrous solution gave 8.7 g (85%) of N- (2-methyl-2-octyl) -acetamide as a distillation residue which was used in the next step without further purification.

c) Preparation of 2-methyl-2-octylamine

Potassium hydroxide (10.0 g, 0.18 M) was dissolved in ethylene glycol (100 mL) and N- (2-methyl-2-octyl) acetamide (13.0 g, 0.07 M) was added. The reaction was heated at 200 ° C for 64 hours. Water (400 mL) was then added to the reaction mixture and extracted with ether. Wash the ether extract with water, repeat the wash with brine, and dry over sodium sulfate. The anhydrous solution was distilled under reduced pressure to give 10.4 g (62% yield) of 2-methyl-2-octylamine as a distillation residue. The product was used in the next step without further purification.

d) Preparation of 1- {4 - [(1-methylethyl) thio] phenoxy} 3 - [(2-methyl-2-octyl) amino] -2-propanol

7.8 g (0.035 M) of 4- (isopropylthio) phenol-epichlorohydrin derivative and 5.0 g (0.035 M) in 100 ml of ethanol

2-Methyl-2-octylamine was dissolved and the reaction mixture was refluxed for 17 hours. The mixture was concentrated under reduced pressure and the residue obtained by distillation was heated at 80 ° C in a pressure of 0.5 mm Hg to remove excess reagent. The crude free base thus obtained was treated with 6N hydrochloric acid, whereupon a hydrochloride salt was obtained which was crystallized from ether / hexane. Yield: 3.0 g (21%)

{4 - [(1-methylethyl) thio] phenoxy} -3 - [(2-methyl-2-octyl) amino] -2-propanol hydrochloride is obtained. M.p. 165 ° C.

Example 11

Preparation of 3-methyl-1- (4 - [(1-methylethyl) thio] feroxy) -3-octylamino-2-butanol of formula XXVI

a) Preparation of the diethyl acetal derivative of 4 - [(1-methylethyl) thio] phenoxyacetaldehyde

24.2 g (0.144 M) of 4 - [(1-methylctyl) thio] phenol are dissolved in 180 ml of 2-ethoxyethanol and 7.2 g of a 50% dispersion of sodium hydride in mineral oil are added and stirred until the reaction mixture until hydrogen evolution ceases. Bromoacetaldehyde diethyl acetal (30.0 g, 0.152 M) was added to the reaction mixture and the mixture was heated under reflux for 19 hours. It is then cooled, diluted with water and extracted with ether. The ethereal extracts were combined, washed with water, dried over magnesium sulfate and distilled under reduced pressure to an oily distillation residue. The oil obtained by distillation under reduced pressure gave 28.1 g (69% yield) of 4 - [(1-methylethyl) thio] phenoxyacetaldehyde diethyl acetate, which was 142 ° C and 146 ° C at 0.07 mm Hg. It boils at a temperature between C.

b) Preparation of 4 - [(1-methylethyl) thio] phenoxyacetaldehyde

Dissolve 10 g (0.035 M) 4 - [(1-methylethyl) thio] phenoxyacetaldehyde diethyl acetal in 100 ml of a 60:40 mixture of water and ethanol and add 5 ml of 6N hydrochloric acid. and reflux for 2 hours. Pour the cooled mixture into ether / water, separate the ether phase, wash with water, then brine, and dry over magnesium sulfate. The anhydrous ethereal solution was concentrated under reduced pressure and the distillation residue was distilled. This gives 4 - [(1-methylethyl) thio] phenoxyacetaldehyde.

c) Preparation of 3-methyl-1- {4 - [(1-methylethyl) thio] phenoxy} 3-nitro-2-butanol in water (1.8 g, 0.02 M) and 2-nitropropane Dissolve 1.0 g of sodium hydroxide. 4.2 g (0.02 M) 4 - [(1-methylethyl) thio] phenoxyacetaldehyde and 2.1 g (0.02 M) sodium hydrogen sulfate are suspended in 10 ml of water. Combine the above solution and suspension and heat the reaction mixture on a steam bath for 8 hours. It is cooled and then acidified with glacial acetic acid. The acidified mixture is extracted with ether, the ether extracts are combined, washed successively with water, dilute sodium bicarbonate solution and brine, and finally dried over magnesium sulfate. Distill the anhydrous ethereal solution under reduced pressure to give 3-methyl-1- {4 - [(1-methylethyl) thio] phenoxy} -3-nitro-2-butanol as a distillation residue.

d) Preparation of 3-amino-3-methyl-1- (4 - [(1-methylethyl) thio] phenoxy) 2-butanol

In 100 ml of ether was dissolved 2.5 g (0.008 M) of 3-methyl-1- (4 - [(1-methylcyl) thio] phenoxy] -3-nitro-2-butanol, 0.5 g (0.013 M) of lithium aluminum hydride was added. the mixture was stirred for 4 hours at 25 ° C, cooled and washed successively with 0.5 mL water, 0.5 mL of 15% aqueous sodium hydrogen for hydrolysis ¹ 9

-8182581 xid solution and finally 1.5 ml water. After stirring for one hour at room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. This gives 3-amino-3-methyl-1- {4 - [(1-methylethyl) thio] phenoxy} -2-butanol.

e) Preparation of 3-methyl-1- {4 - [(1-methylethyl) thio] phenoxy} 3- (octylamino) -2-butanol in mL of isopropyl alcohol 2.0 g (0.007 M) 3- Amino-3-methyl-1- (4 - [(1-methylethyl) thio] phenoxy) -2-butanol was dissolved in 1.0 g (0.008 M) n-octane and 1.0 g (0.017 M). sodium cyanoborohydride was added. After stirring at room temperature for 16 hours, the reaction mixture was poured into water and extracted with ether. The ether extract was washed with water and brine, then dried over magnesium sulfate. Concentrate the anhydrous ethereal solution and convert the resulting free base into its hydrochloride salt to give 3-methyl-1- (4 - [(1-methylethyl) thio] phenoxy) -3- (octylamino) -2-butanol hydrochloride.

Example 12

Preparation of 1- {4 - [(1-methylethyl) thio] phenoxy} -3- (octylamino) 2-butanol (XXVII)

a) Preparation of 3-amino-1- (4 - [(1-methylethyl) thio] phenoxy] -2-butanol

In the same manner as in Example lld, l- (4 - [(1-methylethyl) thio] phenoxy) -3-nitro-2-butanol is reduced with lithium aluminumunide hydride to give the amine. The starting material of 1- (4 - [(1-methylethyl) thio] phenoxy) -3-nitro-2-butanol is prepared as described in Example 11c except that the 2-nitro- an equivalent amount of nitroethane is used instead of propane.

b) Preparation of 1- {4 - [(1-methylethyl) thio] phenoxy} -3-octylamino-2-butanol

As in Example He), 3-amino-1- {4 - [(1-methylethyl) thio] phenoxy} -2-butanol is reacted with n-octanol and sodium cyanoborohydride to give 1- {4 - [(1-Methyl-ethyl) -thio] -phenoxy} -3-octylamino-2-butanol is obtained.

13-28. example

The compounds listed in Table 1 are prepared as in Example 1 by reaction of the epichlorohydrin derivative of the starting phenol with n-octylamine.

Table 1

Compounds of formula XXVIII

5 Example number Starting Thiophenol Product with R ₄ —S 13th 4-ethyl-thio-phenol 4-C ₂ H ₅ S 14th 4-n-propyl-thio-phenol 4 —- n — C ₃ H ₇ S 10 15th 4-n-butylthio-phenol 4 — n — C ₄ H _b S 16th 4-n-pentyl-thio-phenol 4 — n — C _s H _n S 17th 4-n-hexylthio-phenol 4 — n — C _e Ií ₁₃ S 18th 4-n-heptyl-thio-phenol 4 - n - C ₇ H ₁₅ S 19th 4-n-octyl-thio-phenol 4 — n — C ₈ H ₁₇ S 15 20th 4- (3-methyl-butylthio) - phenol 4- (CH ₃ ) ₂ CHCH ₂ ch ₂ s 21st 2-n-but il-t io-f enol 2 — n — C ₄ H ₈ S 22nd 3-n-butylthio-phenol 3 - n - C ₄ H ₉ S 23rd 2-ethyl-thio-phenol 2 — C ₂ H _s S 20 24th 2-n-propyl-thio-phenol 2 — n — C ₃ H ₇ S 25th 2-isopropylthiophenol 2-iso-C ₃ H ₇ S 26th 3-ethyl-thio-phenol 3-C ₂ H ₅ S 27th 3-n-propyl-thio-phenol 3 — n — C ₃ H ₇ S 25 28th 3-iso-propyl-thio-phenol 3-iso-C ₃ H ₇ S Example 29 Preparation of tablets

The following materials are blended using known pharmaceutical techniques to produce a tablet base:

Ingredient Lactose

corn starch

talc

Tragancanth 40 Magnesium stearate

Quantity (weight) 79 10

This tablet stock is blended in an amount of 1- {4 (1-methylethyl) thio] phenoxy} -3- (octylamino) -2-propanol hydrochloride) to provide 10,

20, 40, 80, 160 and 320 mg of active compound are obtained. The raw material is converted into tablets using a known tablet press.

Example 30

Preparation of dry filled capsules

By weight, known in the art Ingredient Lactose, U.S.P. Starch Magnesium stearate is mixed with the following materials

Quantity (weight)

-9182581

A quantity of 1- {4 - [(1-methylethyl) thio] phenoxy} -3- (octylanuno) -2-propanol hydrochloride is added to the feedstock such that 10, 20, 40, 80, 160 and 320 mg of active compound are obtained. It is filled into hard gelatin capsules of appropriate size.

Example 31

Comparison of _these peripheral vasodilator activity in anesthetized dogs

Female and male mongrel dogs weighing between 11 kg and 16 kg were anesthetized with 30 mg pentobarbital intravenously per kg body weight. A cannula was inserted into the left brachial vein and 5 mg pentobarbital per kg body weight per hour was administered continuously throughout the experiment. Tracheotomy is performed and dogs are mechanically ventilated with room air at a volume of 18 per minute and a volume of 20 ml / kg body weight. Bilaterally, the neck of the animals is incised in the central cervical section. After cannulation, the right brachial vein is injected, and the right artery is measured with Stapham pressure transducer. All measurements are recorded using a Beckman-Offner dinograph. The abdominal aorta is medially incised and loosely ligated to the left renal artery. Cannulas were inserted into the right (donor) and left (recipient) femoral arteries and then posterior limb perfusion. Heparin (5 mg / kg body weight) and gallamine triethiodide (2 mg) were administered intravenously per kg body weight and the right femoral artery was cannulated and the catheter was inserted into the abdominal aorta to the height of the renal arteries. We cannulate the left femoral artery and perfuse the hind limb using a Harvard Perfusion pump. The twine previously placed around the aorta is ligated to reduce collateral circulation. 2.5 mg of heparin and 1 mg of gallamine triethiodide per kg body weight per hour are administered intravenously. The perfusion pressure at the perfusion dosing device is adjusted to 150 mmHg by adjusting the pump speed. The volume of blood flowing into the limb is measured as the conclusion of the experiment. The test compound in an amount between 0.1 mg to 1.0 mg per minute infusion with ^k added over 6 minutes and measuring the decrease in blood pressure maximum. 1-3 animals were observed per test compound.

Table 2 below shows the results of experiments with the alkylthiophenoxypropanolamines of the present invention. Also reported are the results obtained with other alkylthiophenoxypropanolamine derivatives described in the literature, such as the 1-isopropylamino-3- [3- (methylthio) phenoxy] -2-propanol (triprenolol) and the 1- (iso-20-propylamino) - compound described by Villa et al., (Farmac. Sci., Ed., 24, 349-357, 1969). The results obtained with 3- [4- (methylthio) phenoxy] -2-propanol (indicated by A and B) and the reference standard, papaverine, were also obtained.

The literature described by A and B and a

The compound prepared in Example 2 was tested essentially as described above, with the exception that the three compounds were tested in the same dog, i.e., blood pressure was allowed to return to control value when the test compounds were administered. In this way, differences in animal differences were excluded, allowing direct comparison of vasodilatory activity. The results of this comparison study are also shown in Table 2.

Table 2

Perfusion dog vasodilation activity measured in hind limbs

Compounds of formula XXIX

^The compound was tested R Ltd. r ₂ Reduction in blood pressure * ¹ Dose (mg / min) ⁰ 0.3 1.0 First H 4-CH ₃ nC ₈ H ₁₇ —22 —59 Second H 4 i Pr nC ₈ H ₁₇ —44 —99 —63 ^d Third H 3-i-Pr nC ₈ H ₁₇ —20 —87 5th H 4-i-Pr cyclohexyl- ethyl —63 —87 6th H 4-i-Pr cyclohexyl- butyl —47 —74 7th 2 — CH _a 4-CH ₃ nC ₈ H ₁₇ —56 —80 8th H 2-CH ₃ nC ₈ H ₁₇ —15 —64 THE H 2-CH ₃ i-Pr -20 ^d -27 ^d B H 4-CH ₃ i-Pr —3 ^d -29 ⁴ Pope- - - —31 — 55

verin ^a numbers denote the number of examples in which a given compound was prepared.

^b mmHg '' infusion rate ^d of the same consecutive comparison animal compared to the known art and substantially with Compound B, of an alkylthio phenoxypropanol amines produced according to this invention 1-3 and 5-8 of the test compounds have a greater vasodilatory effect when infused at 1.0 mg / min. These compounds cause a reduction in blood pressure between 59 mmHg and 99 mmHg, whereas Compounds A and B, when administered at the same dose, induce a decrease in blood pressure between 27 mmHg and 29 mmHg.

-10182581, the test compounds of the invention are 0.8-3.2 times more active than A and 5-21 times more active than B known in the literature. All of the test compounds are valuable for their vasodilatory activity as they give a significantly greater or almost the same reduction in blood pressure as papaverine when administered at 1.0 mg / min. The compound prepared as in Example 2 and the alkylthiophenoxypropanolamines A and B, both known in the literature, exhibit different effects when administered at a concentration of 0.3 mg / min in a side-by-side comparative study; its action is 3.2-fold greater than that of Compound A and 2.1-fold greater than that of Compound B. This means that Compound 2 prepared and tested according to the invention is a much more potent vasodilator than the alkylthiophenoxypropanolamine A and B known in the literature.

Example 32

Inhibition of platelet aggregation (antithrombogenic activity)

Born's method (Naturre, 194, 927, 1962) and O'Brien's (J. Clinical Pathology, 15, 446, 1962) were used for this study. The method involves nephelometric measurement, i.e., measurement of the change in the density of a platelet-rich human plasma after platelet aggregation following administration of adenosine diphosphate (ADP) or collagen as a thrombogenic inducer. The amount of transmitted light3. spreadsheet

Inhibition of platelet aggregation in vitro

The examined ED _so b

compound* ADP First 69 42 Second 56 31 Third 53 24 5th 56 47 6th 53 29 7th 82 39 8th 65 32 The ^c 137 33 B ^c 107 28

means ^the compound prepared in the example given. ^b (ug) 0.5 ml of platelet-rich human plasma when 1 μg of adenosine-5'-diphosphate (ADP) or the smallest amount of collagen is induced to induce aggregation ^c The compounds of Example 31 increase when adding platelet-rich plasma to a thrombogenic agent as platelets clump together. The potency of the test compound is determined by its ability to prevent this collision and subsequent increase in light transmission. Compounds are tested at various concentrations and the concentration causing a 50% reduction in thrombogenic response is determined from the concentration-response curve.

Table 3 below shows the results obtained with the compounds of the present invention and the compounds known from the literature A and B described in Example 31.

The data in the table show that all of the compounds tested are significantly more active in inhibiting ADP-induced platelet aggregation than the alkylthiophenoxypropanolamines A and B known in the literature.

Example 33

Investigation of β-adrenergic blocking activity in isolated guinea pig trachea

We cut the trachea from adult guinea pigs weighing more than 400 grams, spirally dissect it, and

It is suspended in a modified Tyrode solution (20 ml) at 37.5 ° C and oxygen is continuously passed through the suspension. The lower end of the tracheal segment is attached to a stable glass rod, and the upper end is connected to an isometric pressure transducer. Spontaneous tonal changes in the smooth muscle of the trachea are captured through the transducer and continuously recorded with an electrical display instrument. Adrenergic β-re-receptor blocking activity is determined by monitoring the extent to which the test compound inhibits the response of isolated tissue to adrenergic β-stimulant isoproterenol administered at a concentration of 0.1 pg / ml. The tissue is treated with a solution of the test compound for 15 minutes prior to the addition of isoproterenol to the medium. The β-receptor blocking capacity of the test compound is calculated from the concentration-response curve, which is expressed as the percent inhibition of isoproterenol-induced tissue response. The IC50 value is the concentration at which the test compound inhibits the action of isoproterenol by 50%. The IC _{50 is} determined by interpolation. The test compound solution is added to the tissue culture medium in the same volume of 0.2 ml / ml and a single piece of tissue is tested at only one concentration. The activity of the test compound is compared with that of propranolol β-adrenergic blocking agent, which is used as reference substance. The comparison is made by comparing the ICj y values. Table 4 below shows the results of the experiments. Experiments with alkylthiophenoxypropanolamines of the invention and in the literature

-11182581 with known alkylthiophenoxypropanolamines (see Keizer et al., U.S. Patent No. 3,542,874; and Villa et al., I. Farmaco. Sci., 24, 349-357, 1969). See also Example 31 for compounds A and B.

Table 4 β-adrenergic blocking activity of isolated guinea pig tracheal compounds XXIX

Test compound ¹¹ R r ₄ r ₂ β-adrenergic blocking effect ^b First H 4-CH ₃ nC ₈ H ₁₇ <0.001 Second H 4-i-Pr n C ₈ H ₁₇ <0.001 Third H 3-i-Pr n; C ₈ U 7 <0.001 4th H 4-i-Pr n C ₁₂ H ₂₅ <0.001 5th H 4-i-Pr cyclohexyl- ethyl <0.0006 6th H 4-i-Pr cyclohexyl- butyl <0.002 7th 2 CH-, 4-CH ₃ n C ₈ H ₁₇ <0.0006 8th H 2-CH ₃ nC ₈ H ₁₇ <0.004 The ^e H 2-CH ₃ i-Pr 1.0 B ^c H 4-CH ₃ i-Pr 0.2

^{a is} the compound produced in the example given ^{b is} compared to the effect of propranolol considered as one by determining the concentration of compound that causes 50% inhibition of the isoproterenol-induced tissue response (propranolol EC ₅₀ : 0.028 pg / ml medium) ^c see Example 31.

From the data in Table 4, it can be clearly seen that the β-adrenergic blocking effect is shown in Figures 1-8. There is a significant difference between the compounds prepared in Example 1 and the alkylthiophenoxypropanolamines known in the literature. Obviously, in FIGS. Compounds prepared as described in Examples 1 to 4 have practically no β-adrenergic blocking activity, unlike the alkyl thiophenoxypropanolamines A and B which have significant activity in the literature. Therefore, the compounds of the present invention, when used for the purposes stated above, do not cause side effects associated with β-adrenergic blocking activity.

Example 34

Potassium chloride-mediated spasmolytic activity in isolated rat thoracic aorta

In vitro, spasmolytic activity is assayed by determining the effect of test compounds on the contraction of arterial smooth muscle. Adult male New Zealand white rabbits weighing between 2.5 and 4 kg were used for the experiments. Animals are sacrificed by intravenous air injection. The thorax is opened and the thoracic aorta is removed and placed in Krebs bicarbonate solution. The outer tissues are removed and the aorta is helically dissected along its entire length. Spiral segments of 2 cm in length are dissected from each thoracic aorta. A spiral segment is placed in a 10 mL tube, the lower end is secured to a glass rod tissue holder, and the upper portion of the segment is connected to a pressure transfer arm that exerts a constant pressure of 3 g on the tissue. The Krebs bicarbonate solution surrounding the aorta is maintained at a temperature of 37.5 ° C and passed through a mixture of 95% oxygen and 5% carbon dioxide. Using an electrical display, plot the activity of the aortic smooth muscle using the pressure transducer. After steady state (60 minutes), a cumulative dose-response curve was made with potassium chloride or rorepinephrine and the tissue was washed. 75 minutes later, a cumulative dose response curve is again drawn and the aortic segment is washed again. 60 minutes later, the test compound solution is added to the tissue medium and 15 minutes later the third and last dose response curves are recorded without washing. The dosages are 0.1 ml by volume. water solutions.

Table 5 below shows the experimental data. Potassium chloride is used as the muscle response inducer and is determined by the above assays for the alkylthiophenoxypropanolamines of Example 33 and compounds known in the literature (Keizer et al., U.S. Patent No. 3,542,874; see also Compound A; and Villa et al. , Farmaco II Sci., 24, 349-357 (1969; see also Compound B; see also Example 31) compared to papaverine. Papaverine is a direct acting antispasmodic agent and is used as a standard in the literature.

The antagonism of potassium chloride induced muscle spasms indicates a non-adrenergic direct antispasmodic effect. From the results shown in Table 5, it is clear that the compounds of the present invention exhibit significant anticonvulsant activity, while compounds known from A and B (see Example 31) are relatively weak. According to the data in the table, the compounds prepared in Examples 2, 3, 5, 7 and 8 are 15 to 65 times more active than potassium chloride-induced muscle spasms than non-adrenergic antispasmodic agents, as is known in the literature from A and B. thiophenoxy-propanol amines. Compounds prepared as described in Examples 4 and 6 exhibit approximately the same antispasmodic activity, and Compound A and B as compared to the compound prepared in Example 4, approximately 2-fold. The effect of the compound prepared in Example 6 is half that of known v.

-12182581

Table 5

Spasmolytic activity in rat aortic aorta

Test compound ⁴ Antispasmolytic activity ⁶

1st -

2. 0.6

3. 0.7

4. 0.08

5. 2.4

6. 0.02

7. 0.8

8. 2.6

A ^{c is} 0.04

B ^c 0.04 "refers to the compound prepared in this example ^b the relative activity relative to papaverine (taken as papaverine activity alone) obtained from the pA ₂ value. The pA ₂ -values obtained by KCl induced contraction is measured. The pA ₂ is the negative logarithm of the antagonist CPM molar concentration at which the concentration of the antagonist effect of the double dose of agonist reduces to the value that occurs when the single dose of agonist in the absence of antagonist.

^c see Example 31

Example 35

Spasmolytic activity against norepinephrine-induced muscle spasm in isolated rat thoracic aorta

We will further examine 1-8 of this patent. The compounds of Examples A and B (see Example 34), prepared according to the method of Examples 1 to 6, are known to have anti-α-adrenergic activity. Assays were performed as described in Example 34, however, using norepinephrine instead of potassium chloride as the α-adrenergic stimulant. Selective activity against norepinephrine-induced muscle spasms is indicative of α-adrenergic blocking (i.e., antispasmodic) activity. Experiments performed according to the above modification of the antispasmodic assay indicate that all alkylthiophenoxypropanolamine produced in this patent has virtually no anti-α-adrenergic activity (0.3% or less of the effect of phentolamine). except for the compound prepared in Example 8. Phentolamine is an α-adrenergic blocker and is used as a standard in the literature. Compound B, known in the literature, has no anti-α-adrenergic activity, but the compound described in Example 8 of this patent and Compound A, known in the literature (see Example 31), exhibit slightly higher activity than the compounds 1-7. the compounds prepared in the Examples; they account for 1-2% of the effect of phentolamine.

According to the results of this experiment, the compounds of the present invention do not have anti-α-adrenergic anti-spasmodic activity, they directly induce smooth muscle relaxation (see Example 34) and do not exhibit significant selective α-adrenergic blocking activity.

Example 36

Further bioassay of 1- {4 - [(1-methylethyl) thio] phenoxy} -3- (octylamino) 2-propanol

The vasoactivity of the above compound, prepared according to Example 2 of this patent, was further investigated by various pharmacological methods. The results are given below.

a) The rat survival time of rats with intra-arterial catheters is reduced due to blood aggregation. This resets the shorter survival time to the original value by adding the compound prepared in Example 2.

b) Administration of the compound prepared as in Example 2 increases the baseline pressure in the mesenteric arteries of dogs and rats. This effect is advantageous in the treatment of peripheral and central vascular diseases.

c) The above compound, prepared as described in Example 2, reduces the stiffness of red blood cells measured by the chromium ⁵¹ isotope technique and thus allows the cells to penetrate more closely the narrowed capillaries of the tissues affected by vascular disease.

Claims (11)

Patent claims: A process for the preparation of alkylthio-phenoxypropanolamines of the formula I and their acid addition salts, wherein: A, B and R are hydrogen or lower alkyl having 1 to 4 carbon atoms; R 1 is _C 1-5 alkyl; R _{2 is C} 6 -C 12 alkyl, or cycloalkylalkyl of 5 to 8 carbon atoms and C 2 -C 6 alkyl, wherein a) reducing a compound of Formula VIII, wherein R, R _p A and B are as defined above, and then reductively alkylating the resulting primary amino compound of Formula IX, wherein A, B, R, and R j are the above, with an aldehyde of Formula X, wherein Y is C 5 -C 11 alkyl or C 5 -C 8 cycloalkyl (C 1 -C 5) alkyl, or b) for the preparation of compounds of formula I wherein A and B are hydrogen and R and the above alkylthiophenyl derivative of formula II wherein R and Rj are reacted with an epihalohydrine of formula III above, wherein X a halogen atom, preferably a chlorine or bromine atom, and the resulting reaction product is condensed with an amine of the formula H ₂ N-R ₂ , wherein R ₂ is converted to the acid addition salt of the resulting compound of formula I if desired. -13182581 The process of claim 1 for the preparation of 1- [4- (methylthio) phenoxy] -3- (octylamino) -2-propanol or a non-toxic pharmaceutically acceptable acid addition salt thereof, characterized in that: reacting 4- (methylthio) phenol with epichlorohydrin followed by n-octylamine and, if desired, reacting the product with a pharmaceutically acceptable acid. 3. A process according to claim 1 for the preparation of 1- {4 - [(1-methylethyl) thio] phenoxy} -3- (octylamino) 2-propanol or a nontoxic pharmaceutically acceptable acid addition salt thereof. characterized in that 4- (isopropylthio) -phenol is reacted with epichlorohydrin and then n-octylamine and, if desired, the product is reacted with a pharmaceutically acceptable acid. The process of claim 1 for the preparation of 1- {4 - [(1-methylethyl) thio] phenoxy} -3- (octylamino) -2-propanol hydrochloride, characterized in that - (isopropylthio) phenol is reacted with epichlorohydrin followed by n-octylamine and treated with hydrochloric acid. 5. The process according to claim 1, wherein 1- {3 - [(1-methylethyl) thio] phenoxy} -3- (octylamino) -2-propanol or its non-toxic, pharmaceutically acceptable A process for preparing an acceptable acid addition salt thereof comprising reacting 3- (isopropylthio) phenol with epichlorohydrin and then n-octylamine and optionally reacting the product with a pharmaceutically acceptable acid. 6. A process according to claim 1 for the preparation of 1- {4 - [(1-methylethyl) thio] phenoxy} -3- (dodecylamino) -2-propanol or a nontoxic pharmaceutically acceptable acid addition salt thereof. characterized in that the 4- (isopropylthio) phenol is reacted with epichlorohydrin followed by dodecylamine and, if desired, the product is reacted with a pharmaceutically acceptable acid. 7. The process of claim 1, which is 1 - {[2-cyclohexylethyl) amino] -3- {4 -] (1-methylethylthio] phenoxy} -2-propanol or nontoxic, a pharmaceutically acceptable acid addition salt, comprising reacting 4- (isopropylthio) phenol with epichlorohydrin followed by cyclohexylethyl ethyl, and optionally reacting the product with a pharmaceutically acceptable acid. 8. The process according to claim 1, wherein the process is 1 - [(4-cyclohexyl-butyl) -amino] -3 - {- 4 - [(1-methylethyl) -thio] -phenoxy} -2-propanol or a pharmaceutically acceptable acid addition salt thereof, comprising reacting 4- (isopropylthio) phenol with epichlorohydrin followed by cyclohexylbutylamine and, if desired, reacting the product with a pharmaceutically acceptable acid. 9. A process according to claim 1 for the preparation of 1- [2-methyl-4- (methylthio) phenoxy] -3-octylamino-2-propanol or a nontoxic pharmaceutically acceptable acid addition salt thereof. characterized in that 2-methyl-4- (methylthio) phenol is reacted with epichlorohydrin followed by n-octylamine and, if desired, the product is reacted with a pharmaceutically acceptable acid. 10. A process according to claim 1 for the preparation of 1- [2- (methylthio) phenoxy] octylamino) -2-propanol or a non-toxic pharmaceutically acceptable acid addition salt thereof, characterized in that: reacting 2- (methylthio) phenol with epichlorohydrin followed by n-octylamine and In the case 0, the product is reacted with a pharmaceutically acceptable acid. 11. A method of enhancing peripheral blood flow, vascular smooth muscle relaxant, and antiplatelet agent free of ftadrenergic effects. 5, characterized in that one of claims 1-10. A pharmaceutically acceptable salt of a compound of formula I as claimed in any one of claims 1 to 5 in admixture with pharmaceutically acceptable excipients, preferably fillers, tackifiers, lubricants, diluents, flavoring agents, solubilizers, diluents, emulsifiers, into conventional dosage forms.