KR820001235B1 - Process for the preparation of alkylthiophenoxypropanolamines - Google Patents

Abstract

Twenty-eight title compds. (I; R = H, Me; R2 = C6-12 straight chain alkyl) useful as therapeutic agent of treating vascular disease, were prepd. by reaction of alkylthiophenol (II) and spihalohydrine(III; X = halogen, optionally Cl, Br) followed by condn. with amine(III). Thus, 5.6 g II(R = Me) and 2.4 g NaOH in 50 ml H2O were treated with 7.4 g III(X=Cl) to give 1-(4-methoxythio)phenoxy-2,3-epoxypropane followed by refluxing with IV(R2 = n-C8H17) to give I(yield, 21%; m.p., 79.5-80.5≰C).

Description

Method for preparing alkylthiophenoxypropanolamine

The present invention relates to a carbon compound having a medicinal and biological effect. In particular it relates to new and useful alkylthiophenoxypropanolamines and their use in pharmaceutical preparations and to methods of preparing alkylthiophenoxypropanolamines. Alkylthiophenoxypropanolamine of the present invention increases the blood flow in peripheral blood vessels, relaxes the lotus root of the vessels and inhibits platelet aggregation to prevent obstructive peripheral vascular diseases such as cerebrovascular insufficiency with hepatic celiac disease and atherosclerosis. It is considered to be particularly useful for treatment.

Variations of various alkylthiophenoxypropanolamines have been described and studied in the field of adrenergic agonists for the purpose of developing selective beta-adrenergic blockers that are stronger and free of side effects. Such compounds are generally considered useful for treating hypertension, angina pectoris, cardiac arrhythmias and pheochromocytosis. Representatives of this effort are the compounds described in the following patents and publications.

L. Villa, et al., II. Farmaco. Sci., Ed. 24, 349-357 (1969) disclose the following alkylthiophenoxypropanolamines, in particular as part of structure-activity-correlation studies.

Keizer, et al. In US Pat. No. 3,542,384, filed Nov. 24, 1970, discloses 2- (alkylthio) phenoxypropanolamines having the structure:

Wherein R ¹ is an alkyl (C ₁ -C ₄ ) group and R ² is an alkyl (C ₁ -C ₁₂ ) or cycloalkyl (C ₈ -C ₁₂ ) group. This patent has beta-adrenergic blocking properties in which compounds of this type are extremely effective. Specific compounds disclosed by Keiaer, et al include the following compounds. That is, R ¹ is methyl or ethyl and R ² is isopropyl: R 'is methyl, ethyl or propyl and R ² is tert-butyl; R 'is methyl and R ² is cyclopropyl, cyclopentyl, or cyclohexyl; R ¹ is tert-butyl and R ² is cyclopentyl.

Crowther, et al. In US Pat. No. 3,501,769, issued March 17, 1970, generally disclose compounds of the form

Wherein R ¹ is alkyl (up to 10C), R ² is alkyl (20C), cycloalkyl (up to 10C) and the like; R ³ is hydrogen or alkyl (up to 10C). Despite the scope of the general disclosure, Crowther, et al. Has not been described in any single implementation for particular "alkylthio" compounds.

Koppe, et al., US Pat. No. 3,872,147, issued March 18, 1975, generally discloses alkylthiophenoxypropanolamines, which are demonstrated by the following structure.

In the above formula, R is alkyl (1-4C); R ¹ is an alkyl (C ₁ -C ⁵ ) group and R ² is an alkyl (C ₅ -C) containing at least one quaternary carbon bonded directly to an aminonitrogen atom via an alkylene chain (C ¹ -C ₄ ) ₈ ). However, the specially disclosed compounds of Koppe, et al. Do not constitute examples for “alkylthiophenoxypropanolamine” at all.

Publication 2,551,141, issued May 18, 1977, describes in particular alkylthiophenoxypropanolamine.

While several alkylthiophenoxypropanolamines have been generally published as seen in the prior art, relatively few alkylthiophenoxypropanolamines are particularly described. Compared with the prior art compounds reported as beta-adrenergic blockers, the alkylthiophenoxypropanolamines of the present invention are unique in that they reduce the resistance of the vessels with minimal beta-adrenergic blocking effects.

As described broadly, the present invention relates to novel alkylthiophenoxypropanolamines having the structure:

A, B and R in the above structural formulas are hydrogen, lower alkyl containing 1-4 carbon atoms; R ₁ is alkyl containing 1-8 carbon atoms; R ₂ is cycloalkylalkyl which is 5-8 ring carbon atoms bonded to an amino nitrogen atom atom via an alkylene chain containing 6-12 carbon atoms or an alkylene chain containing 2-6 carbon atoms. Also pharmaceutically acceptable are their acid addition salts.

The present invention also relates to a pharmaceutical composition containing alkylthiophenoxypropanolamine, which further attempts to prepare and therapeutically use the aforementioned compounds and compositions.

More specifically, the alkylthiophenoxypropanolamine provided by the present invention is represented by the following structural formula (I).

A, B and R in the above formula (I) are independently selected from the group formed as hydrogen and are lower alkyl containing 1-4 carbon atoms; R ₁ is alkyl containing 1-8 carbon atoms; R ₂ is cycloalkyl having 2-6 carbon atoms and 5-8 ring carbon atoms in the alkyl or alkylene chain containing 6-12 carbon atoms. Also their pharmaceutically acceptable acid addition salts.

The term "lower alkyl" as used herein refers to a carbon chain composed of straight and branched carbon groups containing 1-4 carbon atoms. Examples of groups of these carbon chains are methyl, ethyl, propyl, isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl and tert-butyl.

As used herein, the term "alkyl" refers to a special alkyl group specifically designated or referred to by standard notation such as (C ₁ -C ₄ ), (C ₁ -C ₈ ) and (C ₆ -C ₁₂ ). References are made to linear or branched carbon groups as well as carbon atoms and numbers.

As used herein, the term "cycloalkylalkyl" refers to a cycloalkyl group containing 5-8 carbon atoms, for example cyclopentyl, cyclohexyl, cyclo, deficient in amino nitrogen atoms by alkylene chains having 2-6 carbons. Attempts to refer to heptyl and cyclooctyl).

As used herein, the term "non-toxic pharmaceutically acceptable acid addition salt" refers to salts of compounds of formula I formed of various kinds of inorganic and organic acids and their anions are relatively nontoxic. Such acid addition salts are considered to be pharmaceutically equivalent to the base characterized by formula (I). Examples of acids that form useful salts include acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascolic acid, benzoic acid, cinnamic acid, fumaric acid, reduced acid, phosphoric acid, hydrochloric acid, hydrochloric acid, hydroiodine acid And acids associated with sulfonic acids such as sulfamic acid, methanesulfonic acid, benzene sulfonic acid, and P-fluenesulfonic acid. Acid salts of the present invention are prepared and separated by conventional methods. For example, a solution or suspension of free base in a reaction inert solvent is treated with a desired acid and concentrated under reduced pressure or a salt is formed which is formed by crystallization operation or other standard chemical operation. Slightly toxic acid addition salts are sometimes useful as intermediates for the separation and purification of bases of formula I or for other chemical purposes, such as the separation of optical isomers, because they do not meet the pharmaceutically acceptable criteria described above. Such salts are also considered part of the present invention.

As will be apparent to those skilled in the art, the compounds characterized by the general formula I may exist as optically active isomers, racemates and diastereomas as they have one or more subtitle carbon atoms, all of which Considered part of the invention. Diastereomeric mixtures can be separated into pure racemates of diastereomeric by conventional methods such as chromatography and / or fractional crystallization, depending on the physicochemical differences of the components. The cleavage of the racemates of the present invention to obtain optically active isomers of the compounds of formula I can be carried out by conventional cleavage methods. For example, when the base of formula I is reacted with an optically active acid, they provide a salt from which the left and right phases can be separated by fractional crystallization. Suitable acids that dissolve the compounds of formula I include the optically active forms of tartaric acid, di-º-tolyltinic acid, diacetyltinic acid, dibenzoyltinic acid, dried acid, mandenlinic acid, camphorsulfonic acid, and other optically known compounds in the art. As active acid. Preferably, more biologically active and optically active stereoisomers are isolated.

According to a feature of the invention there is provided a process for preparing the alkylthiophenoxypropanolamine of formula (I). Here, A and B are limited to hydrogen, and the production chambers use the alkylthiophenol derivatives of

R and R ₁ in the above formula (II) have the same meaning as described above.

Reacted with epihalohydrin having the structure

X in the above formula (III) means halogen, preferably chlorine or cancellation.

The epihalohydrin reaction product is condensed with an amine having the following formula (IV)

In formula (IV), R2 has the same meaning as described above. If desired, there is provided a process for the process consisting of the reaction of a free base form I product with an acid to form an acid addition salt thereof.

The necessary structural formula II alkylthiophenols can be obtained by combining diazotized amino phenols with alkylmercaptans to form diazosulfides and then decomposing to give the corresponding alkylthiophenols.

This is the usual method, and the article adopting it is R.B. Wagner, and H.D. Zook Organic Synthetic Chemistry, page 789 (1985 Wiley); E. Miller, et al., J. Am. Chem. Soc., 55, 1224 (1933); S. Asaka, et al., Chem. Abrs. 61, 13243a, and the like.

Suitable alkylthiophenol reactants of formula II that may be employed in the current production process include the following.

Suitable amines of formula IV that may be employed in the present invention include the following.

As long as the epihalohydrin molecule of formula III has two reaction phases, the reaction with the alkylthiophenol of formula II can produce a mixture of the reaction products V and VI.

Wherein R, R ₁ and X are as defined above.

In the future, however, two possible intermediates of Formula V and Formula VI in the condensation reaction with the amine of Formula IV yield the same final alkylthiophenoxypropanolamine product. As a result, there is no need to separate any mixtures of Formula V and VI intermediates, which may be the result from the interaction of the phenol of Formula II with the epihalohydrin of Formula III. Under the reaction conditions employed in this process, the epoxides of formula VI are preferably formed.

If desired, the epihalohydrin reaction product can be taken up in an inert solvent such as chloroform and shaken with excess concentrated hydrochloric acid to convert the epoxide of formula VI to alkylthiophenoxy-halohydrin of formula V. Conversely, if desired, halohydrins of formula V can be used in conventional manners, for example O. Stephenson, J. Chem. Soc., 1574 (1954), can be translocated to a compound of formula VI by treating as a base.

The interaction of the phenols of formula II with the epihalohydrin of formula III is carried out in the presence of a sufficient amount of sparse water soluble alkali metal hydroxides such as sodium hydroxide and is in the temperature range of 0-100 ° and preferably 25-35 °. YM Beasley, et al., J. Pharm. Acidic phenol groups can be enriched according to the methods of Pharmacol., 10, 46-59 (1958).

On the other hand, the interaction of phenol of formula II with epihalohydrin of formula III is also known as N-benzylisopropylamihydrochloride, pyrrolidine, pyridine, piperidine, pyriridine acetate, piperidinehydro Effects can occur as catalysts such as those with chlorides and excess epihalohydrin.

Condensation of the epihalohydrin reaction product of formula V or VI with the amine of formula IV may be preferably carried out in an inert organic solvent under the present reaction conditions. Suitable solvents include methanol, ethanol, butanol, hexanol, toluene, dioxane, tetrahydrofuran, dibutyl ether, dimethoxyethane, ethylene glycol. This condensation reaction can also be effective in the absence of a reaction solvent as equimolar reactants.

Another feature of the invention includes an alternative method for preparing a compound of formula I. Wherein A and B are limited to hydrogen and the process is carried out by reacting Structural Formula II phenol in an alkali medium with a compound of formula

To obtain a compound of formula VIII

In the above formula, R, R ₁ and R ₂ have the same meaning as in formula (I). Also R ₃ means a hydrocrackable group such as benzyl or benzyldrill;

The compound of formula VIII obtained above is transposed to the alkylthiophenoxypropanolamine of formula I. Removal of hydrocrackable blocking groups is possible by hydrogenation with a catalyst, for example by hydrogenation in the presence of a palladium catalyst on carbon in an inert solvent such as ethanol or aqueous ethanol.

Compounds of formula VII can be obtained according to known methods. For example, 1-[(N-benzyl) -n-octylamino] -2,3-epoxypropane is described in L. Villa, et al., Farmaco., Ed. Obtained by reacting N-benzyl-n-octylamine with epichlorohydrin in an alkaline medium (eg aqueous potassium hydroxide) according to the method described by Sci., 24 (3), 349-357 (1969). have.

Another feature of the invention relates to a process for preparing a compound of formula I wherein A, B and R in formula I are independently selected from the group consisting of hydrogen and lower (C ₁ -C ₄ ) alkyl, R ₁ is (C ₁ -C ₈ ) alkyl and R ₂ is (C ₆ -C ₁₂ ) straight or branched chain alkyl with a carbon atom linked to an amino nitrogen atom via a divalent methylene (ie -CH _2- ) group; Or a (C ₅ -C ₈ ) cycloalkyl linked through an alkylene chain containing 2-6 carbon atoms wherein the alkylene chain described above is linked to an amino nitrogen atom through a divalent methylene (ie —CH ₂ —) group. This reduces the compound of formula

In the above structural formula, A, B, R and R ₁ are as defined above. Obtaining the primary amino compound of formula (X)

In the above structural formula, A, B, R and R ₁ are as defined above. And a continuous process of reductively alkylating a compound of formula X with an aldehyde of formula XI.

Wherein Y is straight or molecular chain alkyl containing 5-10 carbon atoms or cycloalkylalkyl having 5-8 ring carbon atoms and 1-5 carbon atoms in the alkylene chain.

Nitroalcohols of formula XI are obtained by aldol-like condensation of suitable nitroalkanes and aldehydes in the presence of a base or by condensation of the sodium salt of nitroalkane as a sodium sulphate addition product of aldehydes in the presence of trace alkalis or weak acids. Can be. Alkylthiophenoxyaldehyde starting materials can be obtained by reacting a particular alkylthio phenol as diethylacetal of bromoacetaldehyde treated by acid catalyzed hydrolysis of an acetal group.

As described above, the alkylthiophenoxypropanolamines of the present invention increase blood flow in peripheral blood vessels, relax the lotus root of the vessels and inhibit platelet aggregation. The compound is substantially devoid of beta-adrenergic blocking effects that inhibit peripheral vasodilator action of bio-amines in beta-adrenergic stimulation. Criteria in pharmacological test methods in animals and in vitro can be adopted in assessing the activity of the compounds characterized by formula (I). Such methods that are considered useful include test methods for the Fuji of perfused dogs (extension), test methods for anti-convulsive earthenware aortic bands (anticonvulsive action), and inhibition of adenosine diphosphate and collagen in human abundant platelet plasma. There are methods for producing the platelet aggregation (anti-thrombogen action) test. Guinea pig laboratory tests that resist isoproterenol are standard in the art and are suitable for measuring beta-adrenergic blocking action.

In addition to inhibiting vasodilation, antispasmodic and platelet aggregation, some of the compounds of formula I inhibit lipolysis (as can be seen in the lipolysis modality of epidimal fat pads in rats) and also in the production of cholesterol biosynthesis. Suppress Compounds of this type are valuable as hypocholesterolemia preparations.

Another aspect of the invention relates to a therapeutic method for treating a stray animal in need of vasodilatation, comprising the systemic administration of an effective amount for vasodilatation of a compound selected from the group characterized by Structural Formula I to a mammal. Pharmaceutically acceptable nontoxic upper salts.

As used herein, the term "effective amount for vasodilation" is interpreted to mean a dose that exerts an vasodilating effect in an effective mammal that does not cause side effects.

Systemic administration includes both oral and parenteral administration. Examples of parenteral administration include intramuscular injection, intravenous injection, intraperitoneal administration, anal injection and subcutaneous injection. Ointments and suppositories can be used by rectal administration. Dosages vary to some extent depending on the method of administration and the particular compound selected, and are generally characterized as Structural Formula I or a nontoxic pharmaceutically acceptable salt thereof administered in an effective single or multiple dose that provides the desired vasodilator effect. Approximately 0.5 mg-25 mg / kg body weight.

In carrying out the treatment of the present invention, the compound of formula I is generally in the form of a pharmaceutical formulation comprising a free base of formula I or a pharmaceutically acceptable non-toxic acid addition salt thereof as an active ingredient in combination with an acceptable carrier. It is administered for vasodilation purposes. The carrier may be a solid, semisolid, diluent or capsule. Thus another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula I in combination with a pharmaceutically acceptable carrier or a nontoxic pharmaceutically acceptable acid addition salt thereof.

To prepare a pharmaceutical composition containing a compound of formula I in a dosage form for oral administration, the compound may be prepared as a solid powder carrier (e.g. lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amyloxectin, polyethylene). Mixed with glycol wax) and compressed into tablets. Tablets are used as uncoated or coated tablets as conventional techniques to delay disintegration and absorption in the gastrointestinal tract, thereby maintaining long-lasting action. If a coated tablet is desired, the uncoated tablet prepared as described above may be coated with a concentrated sugar solution, which may contain, for example, a gum, arabic acid group, gelatin, talc, titanium dioxide, or the like. Moreover, tablets can be coated as lacquers dissolved in a mixture of easily or volatile organic solvents or solvents. If desired, pigments may be added to the coating.

In the preparation of soft gelatin capsules or the preparation of similar closed capsules, the active compound is mixed with the vegetable oil. Hard gelatin capsules may include the active ingredient of granules mixed with solid powder carriers such as lactose, sucrose, sorbitol, starch (eg potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage forms for rectal administration may be prepared in the form of suppositories containing the active substance of formula I in which neutral fatty bases are mixed. Or in the form of gelatin-rectal capsules containing the active substances mixed with vegetable or paraffin oils.

Solutions for oral administration may be administered in the form of elixirs, syrups or suspensions containing from about 0.2% -20% by weight of the active ingredient. Such liquids may contain carboxymethylcellulose as pigments, flavors, sweeteners and thickening agents.

Suitable solutions for parenteral administration by injection may be prepared as aqueous solutions of pharmaceutically acceptable salts that are water soluble of a compound of the formula adjusted to a physiologically acceptable pH. These solutions may also contain stabilizers.

Pharmaceutical tablets for oral administration may be prepared by conventional methods, including mixing the therapeutic compound of Formula I with the required solution.

Particular alkylthiophenoxypropanolamines of the present invention are the following as described in the following examples. Among these, the compounds which are particularly preferable for their vasodilating action and lack large beta-adrenergic blocking action are as follows.

1- [4- (methylthio) phenoxy] -3- (octylamino) -2-propanol,

1- [4-[(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol,

1- [3-[(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol,

1- [4-[(1-methylethyl) thio] phenoxy] -3- (dodecylamino) -2-propanol,

1-[(2-cyclohexylethyl) amino] -3- [4-[(1-methylethyl) thio] -phenoxy] -2-propanol,

1-[(4-cyclohexylethyl) amino] -3- [4-[(1-methylethyl) thio] -phenoxy] -2-propanol,

1- [2-methyl-4- (methylthio) phenoxy] -3- (octylamino) -2-propanol,

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

The following examples are illustrative and do not limit the scope of the invention. All temperatures shown here are in degrees Celsius.

Example 1

1- [4- (methylthio) phenoxy] -3- (octylamino) -2-propanol

A solution of 4- (methylthio) phenol (5.6 g, 0.04 mol) and sodium hydroxide (2.4 g, 0.06 mol) dissolved in 50 ml of water is treated with epichlorohydrin (7.4 g, 0.08 mol). The resulting mixture is first stirred at 30-35 ° for 24 hours and extracted with chloroform. The chloroform extract is washed with water, dried over magnesium sulfate and the distillable is removed under reduced pressure to give the epichlorohydrin derivative 1- (4-methylthio) phenoxy-2,3-epoxypropane. It is taken up in 30 ml of ethanol and treated with n-octylamine (7.5 g, 0.06 mol) and refluxed for 4 hours. The reaction mixture is concentrated to about 1/2 volume under reduced pressure to give a white solid. This was collected and crystallized as ethanol to yield 21% of analytical pure 1- [4- (methylthio) phenoxy] -3- (octylamino) -2-parophanol with a melting point of 79.5-80.5 ° C (Corr.).

Found C ₁₈ H ₃₁ NO ₂ S

Calculation: C, 66.42; H, 9. 60; N, 4.30; S, 9.85

Actual quantity: C, 66.30; H, 9.69; N, 4.13; S, 9.58

Example 2

1- [4-[(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol hydrochloride

(a) A solution of sodium nitrite (113.8 g, 1.65 moles) dissolved in 210 ml of 4- (isopropylthio) phenol-water was stirred at -5 ° in 825 ml of 4-N hydrochloric acid (163.7 g, 1.5 mole) of solution. After stirring for an additional 2 hours at -5 °, the diazotized phenol solution was dissolved in 525 ml of water (270.6 g, 6.77 moles) and 2-propanethiol (126.4 g) with the reaction maintained in the presence of nitrogen gas. , 1.66 mol) to a pre-prepared cold (-5 °) solution for at least 45 minutes. When the addition is complete, the mixture is warmed to 27 ° and held at that temperature for 16 hours. The mixture is then cooled to 0 ° and acidified with 570 ml of 12N hydrochloric acid. Excess 2-propane thiol is removed by a permanganate trip for 2 hours through a solution acidified by bubbling nitrogen gas. The solution thus formed is extracted several times with dichloromethane, washed with water with a combined extract, dried over magnesium sulfate containing charcoal and filtered. Concentration of the filtrate under reduced pressure yields an oily residue which is distilled to yield 81 g (yield 32%) of 4- (isopropylthio) phenol, boiling point 114-123 ° (1.2 mmHg).

(b) A solution of 4- (isopropylthio) phenol (6.6 g, 0.04 mol) and sodium hydroxide (2.6 g, 0.065 mol) dissolved in 50 ml of water was treated with epichlorohydrin (7.4 g, 0.08 mol). . The resulting mixture is first stirred at 30-35 ° for 24 hours and extracted with chloroform. The chloroform extract is washed with water and then dried over magnesium sulfate to remove distillable one under reduced pressure to give epichlorohydrin intermediate 1- (4-isopropylthiophenoxy) -2,3-ethoxypropane. Epichlorohydrin intermediate was taken up in 30 ml of ethanol and treated with n-octylamine (4.5 g, 0.06 mol) and refluxed for 4 hours. Concentration of the reaction mixture under reduced pressure afforded a residue, which was taken up in ethanol and treated with 6 ml of 12N hydrochloric acid. Concentrate the acidified solution under reduced pressure and crystallize the residue from ethanol to give analytical pure (20% yield) 1- [4-[(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-pro Panol hydrochloride, melting point 171173-186.5 ° (Corr.) (Double melting point) is obtained.

For C ₂₀ H ₃₅ NO ₂ S

Calculation: C, 61.59; H, 9. 30; N, 3.59; S, 8.22; Cl, 9.09

Actual amount: C, 61.68; H, 9. 29; N, 3.47; S, 8.15; Cl, 9.15

Example 3

1- [3-[(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol hydrochloride

The epichlorohydrin derivative of 3- (isopropylthio) phenol (4.85 g, 0.029 mol) was reacted with n-octylamine (4 g, 0.031 mol) according to the procedure of Example 2 (b) and the crude product was ethanol- Analytical pure 1- [3-[(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol hydrochloride with 13% yield when crystallized from ether, melting point 125-127 ° (Corr Get.)

Found C ₂₀ H _{35 for} NOS HCl

Calculation: C, 61.59; H, 9. 30; N, 3.59

Actual amount: C, 61.22; H, 9.09; N, 3.53

Example 4

1- [4-[(1-methylethyl) thio] phenoxy] -3- (dodecylamino) -2-propanol hydrochloride

The epichlorohydrin derivative of 4- (isopropylthio) phenol (15.7 g, 0.07 mole) was reacted with n-dodecylamine (13.9 g, 0.075 mole) according to the procedure of Example 2 (b) and crude from methanol Crystallization of the product yields 13% of analytical pure 1- [4-[(1-methylethyl) thio] phenoxy] -3- (dodecylamino) -2-propanol hydrochloride, melting point 153.5-156.6-190.5 (Corr.) (Double melting point) is obtained.

Found C ₂₄ H _{43 for} NOS HCl

Calculation: C, 64.61; H, 9.94; N, 3.14

Actual amount: C, 64.38; H, 10.07; N, 2.97

Example 5

1-[(2-cyclohexylethyl) amino] -3- [4-[(1-methylethyl) thio] -phenoxy] -2-propanol hydrochloride

The epichlorohydrin derivative of 4- (isopropylthio) phenol (5.0 g, 0.022 mol) was reacted with cyclohexylethylamine (3.3 g, 0.026 mol) according to the procedure of Example 2 (b), and then the crude product Crystallization from isopropyl alcohol yields 18% analytical pure 1-[(2-cyclohexylethyl) amino] -3- [4-[(1-methylethyl) thio] -phenoxy] -2-propanol hydro Chloride, melting point 180-182 ° (Corr.).

Anal for C ₂₀ H ₃₃ NO ₂ S HCl

Calculation: C, 61.91; H, 8.83; N, 3.61

Actual amount: C, 61.73; H, 8.71; N, 3.88

Example 6

1-[(4-cyclohexylethyl) amino] -3- [4- [4-[(1-methylethyl) thio] -phenoxy] -2-propanol hydrochloride

The epichlorohydrin derivative of 4- (isopropylthio) phenol (9.0 g, 0.04 mole) was reacted with cyclohexylethylamine (6.7 g, 0.043 mole) according to the procedure of Example 2 (b) and the following crude product Crystallization from ethanol yields 11.4% of analytical pure 1-[(4-cyclohexylbutyl) amino] -3- [4-[(1-methylethyl) thio] -phenoxy] -2-propanol hydrochloride ( Melting from 179 ° or 118 °).

Anal for C ₂₂ H ₃₇ NO ₂ S HCl

Calculation: C, 63.51; H, 9. 20; N, 3.37

Actual amount: C, 63.46; H, 9. 35; N, 3.29

Example 7

1- [2-methyl-4- (methylthio) phenoxy] -3- (octylamino) -2-propanol

The epichlorohydrin derivative of 2-methyl-4- (methylthio) -phenol (3.14 g, 0.015 mole) is reacted with n-octylamine (1.93 g, 0.015 mole) according to the procedure of Example 1. The reaction mixture was concentrated and the residue crystallized from ethyl acetate-hexane to yield 19% of analytical pure 1- [2-methyl-4- (methylthio) phenoxy] -3- (octylamino) -2-propanol. And melting point 59-60 ° (Corr.).

Found C ₁₉ H ₃₃ NO ₂ S

Calculation: C, 67.21; H, 9. 80; N, 4.13

Actual quantity: C, 66.80; H, 9.92; N, 3.81

Example 8

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

According to the process of Example 2 (b), the epichlorohydrin derivative of 2- (methylthio) phenol (14 g, 0.071 mol) is reacted with 9.04 g n-octylamine (0.07 mol) and the crude product is methanol Determination with ether gives 1- [2- (methylthio) phenoxy] -3- (octylamino) -2-propanol hydrochloride as a 105.5-107.5 ° melting point. Yield 18%

Analysis result C ₁₈ H ₃₁ NO ₂ SHCl

Calc .: C 59.73; H 8.91; N, 3.87

Anal: C 59.86; H 9.07; N 3.71

Example 9

1- [4-[(1-methylethyl) thio] phenoxy-3-[(2,2-dimethyl-1-hexyl) amino] -2-propanol

(a) A solution of 25 g (0.26 mol) of capronitrile and 75 g (0.53 mol) of methyl iodide dissolved in 80 ml of 2,2-dimethylhex-1-yl amine-dried toluene was heated to 80 ° and dissolved in 100 ml of toluene. A suspension of 25.4 g (0.65 mole) of amide is added and treated at a rate that will maintain normal reflux, and the mixture is stirred at reflux for another 2 hours. The mixture is cooled, treated with 150 ml of water, the organic layer is separated, washed with water and dried over magnesium sulfate. The dry solution is concentrated under reduced pressure and then the residual material is distilled to produce 81% yield of 2,2-dimethyl capronitrile.

A 10.0 g (0078 mole) solution of 2,2-dimethyl tapronitrile dissolved in 100 ml of ether was slowly added to a 6.0 g (0.158 mole) suspension of lithium aluminum hydride dissolved in 200 ml of ether, keeping the reaction temperature at 0-5 °. give.

The mixture is stirred for 2 more hours at 0-5 ° and then hydrolyzed the mixture by addition of 6.0 ml of water, 6.0 ml of 15% sodium hydroxide solution and 18 ml of water. The hydrolyzed mixture is stirred for 1 hour, filtered and the ether layer is concentrated under reduced pressure. The residual material is distilled off to give 2,2-dimethylhex-1-yl amine.

(b) reacting the epichlorohydrin fluid of 4- (isopropyl thio) phenol with 2,2-dimethyltex-1-yl amine according to the process of Example 2 (b) and converting the free base to hydrobromide Hydrochloride is produced by 1- [4-[(1-methylethyl) thio] phenoxy] -3-[(2,2-dimethyl-1-hexylamino] -2-propane.

Example 10

1- [4-[(1-methylethyl) thio] phenoxy] -3-[(2-methyl-2-octyl) amino] -2-propanol

(a) A solution of 14.5 g (10.1 mol) of methyl heptanoate dissolved in 200 ml of 2-methyl-2-octanol-ether is added to 200 ml of 3 M solution (0.6 mol) of methylmagnesium bromide dissolved in ether while maintaining the reflux rate. . The reaction mixture is refluxed for 1 hour and then stirred at 26 ° for 16 hours. The diluted ammonium chloride solution was added to the mixture, hydrolyzed and filtered, and the filter cake was dissolved in 2N hydrochloric acid and extracted with ether. The ethereal extract and the filtrate are combined, washed in order of water, dilute sodium bicarbonate solution and brine and then dried over magnesium sulfate. The dry solution was concentrated and the residual material was distilled off under reduced pressure to yield 13.1 g (91% yield) of 2-methyl-2-octanol at 130 ° boiling point (100 mmHg).

(b) A solution of 5.55 g (0.055 mol) of concentrated sulfuric acid dissolved in 32 ml of N- (2-methyl-2-octyl) acetamide-glacial acetic acid, 2.5 g (0.016 mol) of acetonitrile 8.0 g ( 0.055 mole) and then the mixture is stirred at 26 ° for 17 hours. After dilution with 125 ml of water, the mixture is extracted with ether and the ethereal extract is washed in order of water, dilute solution of sodium bicarbonate and brine and dried over magnesium equivalent. The dried solution is concentrated to yield 8.7 g (85% yield) of N- (2-methyl-2-octyl) -acetamide that can be used in the next step without going through a purification step.

(c) A solution of 10.0 g (0.18 mole) of potassium hydride dissolved in 100 ml of 2-methyl-2-octylamine-ethylene glycol was treated with 13.0 g (0.07 mole) of N- (2-methyl-2-octyl) acetamide. The mixture is then heated to 200 ° for 64 hours. The reaction is diluted with 400 ml of water and then extracted with ether. The ethereal extract is washed with water and brine and dried over sodium sulfate. The dried solution under reduced pressure is concentrated to yield 10.4 g (62% yield) of 2-methyl-2-octylamine that can be used without purification in the next step.

(d) Preparation of [1- [4-[(1-methylethyl) thio] phenoxy] -3- (2-methyl-2-octyl) amino] -2-propanol] 4- (iso) dissolved in 100 ml of ethanol Propylthio) phenol 7.8 g (0.035 moles) of epichlorohydrin derivative and a solution of 5.0 g (0.035 moles) of 2-methyl-2-octylamine are refluxed for 17 hours. The reaction mixture is concentrated under reduced pressure and the residual material is heated to 80 ° (0.5 mm Hg) to remove excess residual reaction material. The hydrochloric acid salt obtained by treating the crude free base with 6N hydrochloric acid was determined with ether-hexane to determine 1- [4-[(1-methylethyl) thio] phenoxy-3-[(2-methyl-) having a melting point of 165 DEG. 2-octyl) amino] -2-propanol hydrochloride to 3.0 g (21% yield).

Example 11

3-methyl-1- [4-[(1-methylethyl) thio] -phenoxy] -3- (octyl amino) -2-butanol

(a) A solution of 24.2 g (0.144 mol) of 4-[(1-methylethyl) thio] phenol dissolved in 180 ml of diethylacetyl-2-ethoxyethanol of 4-[(1-methylethyl) thio] phenoxyacetaldehyde Is treated with 7.2 g of sodium hydride 50% dispersion dissolved in mineral oil and then the mixture is stirred until no further hydrogen evolution occurs. 30.0 g (0.152 mol) of dienyl acetal of bromoacetaldehyde was added to the mixture, which was stirred for 19 hours, refluxed, cooled, diluted with water, and extracted with ether. The ether extracts are mixed, washed with water, dried over magnesium sulfate and concentrated to an oil under reduced pressure. The residual oil is distilled off under reduced pressure to yield 28.1 g (69% yield) of diethyl acetal of 4-[(1-methylethyl) thio] phenoxyacetaldehyde having a boiling point of 142-146 ° (0.07 mmHg).

(b) 10 g of diethylacetal solution of 4-[(1-methylethyl) thio] phenoxyacetaldehyde dissolved in 100 ml of 4-[(1-methylethyl) thio] phenoxyacetaldehyde-aqueous ethanol (60:40) (0.035 mol) is treated with 5 ml of 6N hydrochloric acid and the mixture is refluxed for 2 hours. The cooled mixture is partitioned into ether, water and the like and the ether layer is washed with fire and brine and dried over magnesium sulfate. The dry ethereal solution is concentrated under reduced pressure and the residue is then distilled to produce 4-[(1-methylethyl) thio] phenoxyacetaldehyde.

(c) 1.8 g (0.02 mol) of 2-nitropropane dissolved in 10 ml of 3-methyl-1- [4-[(1-methylethyl) thio] phenoxy] -3-nitro-2-butanol-fire and sodium hydroxide 1.0 g solution is added to 4.2 g of 4-[(1-methylethyl) thio] phenoxyacetaldehyde (0.02 mol) suspension suspended in a 2.1 g (0.02 mol) solution of sodium bisulfate dissolved in 10 ml of water. The mixture is cooled by heating in a steam bath for 8 hours and then acidified by addition of glacial acetic acid. The acidified mixture is extracted with ether and the ether extracts are mixed, washed with water, dilute sodium bicarbonate solution and brine in that order and dried over magnesium sulfate. The dried ethereal solution is concentrated under reduced pressure to yield 3-methyl-1- [4-[(1-methylethyl) thio] phenoxy] -3-nitro-2-butanol.

(d) 3-methyl-1- [4-[(1-) dissolved in 10 ml of 3-amino-3-methyl-1- [4-[(1-methylethyl) thio] phenoxy] -2-butanol-ether A solution of 2.5 g (0.008 mol) of methylethyl) thio] phenoxy] -3-nitro-2-butanol was treated with 0.5 g (0.013 mol) of lithium aluminum hydride. The mixture is cooled by stirring at 25 ° for 4 hours and then hydrolyzed by adding 0.5 ml of water, 15% sodium hydroxide solution and 1.5 ml of water in that order. After stirring for 1 hour to room temperature, the solution was filtered and concentrated under reduced pressure to yield 3-amino-3-methyl-1- [4-[(1-methylethyl) thio] phenoxy] -2-butanol.

(e) Preparation of 3-methyl-1- [4-[(5-methylethyl) thio] phenoxy] -3- (octylamino) -2-butanol- 3-amino-3- dissolved in 60 ml of isopropyl alcohol To a solution of methyl-1- [4-[(1-methylethyl) thio] phenoxy] -2-butanol 2.0 g (0.007 mol) in 1.0 g (0.008 mol) of n-octanal and sodium cyano-borohydride 1.0 Treated with g (0.017 mol). After stirring for 16 hours to room temperature, it is poured into water and extracted with ether. The ethereal extract is washed with water and brine and then dried over magnesium sulfate. Concentrate the dried etheric solution and then convert the remaining free base to hydrochloride to 3-methyl-1- [4-[(1-methylethyl) thio [phenoxy] -3- (octyl-amino) -2-butanol Hydrochloride is produced.

Example 12

1- [4-[(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-butanol

(a) 3-amino-1- [4-[(1-methylethyl) thio] phenoxy-2-butanol-wherein the amine field is 1- [4-[(1-methylethyl) thio] phenoxy] 3-nitro-2-butanol is produced by reduction with lithium aluminum hydride according to the process of Example 11 (d). Nitro starting material (1- [4-[(1-methylethyl) thio] phenoxy] -3-nitro-2-butanol) was used in an equal amount of nitroethanol instead of 2-nitropropane in Example 11 (c). To prepare.

(b) 3-amino-1-[(1-) according to the process of Example 11 (e) of 1- [4-[(1-methylethyl) thio] phenoxy] -3-octylamino-2-butanol Methylethyl) thiophene] -2-oxybutanol- octanal and sodium cyanoborohydride to produce 1-[(1-methylethyl) thio] phenoxy] -3-octylamino-2-butanol do.

Example 13-28

The following compounds in Table A are prepared by treating epichlorohydrin derivatives of the starting phenol with n-octylamine according to the process of Example 1.

Example 29

[refine]

The following ingredients are mixed in the weight ratios shown below according to known pharmaceutical techniques for preparing tablet bases.

The purification vessel was mixed with a sufficient amount of 1- [4-[(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propane with hydrochloride to give 10,20,40,18,160 and 320 ml of To prepare a static containing the active ingredient

Example 30

[Dry-Shaped Capsules]

The following components are mixed in the weight ratios shown below according to the co-worked method.

A sufficient amount of 1- [4-[(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propane was added to the mixture to form a gelatinous capsule of 10 sized hard gelatin with hydrochloride. Prepare capsules containing 20, 40, 80, 160 and 320 ml of active ingredient.

Example 31

Comparison of Peripheral Vasodilation Activity in Anesthetized Dogs

Experimental Methods—11 and 16 kg male and female monrol dogs, respectively, were anesthetized by intravenous injection of pentobarbital (30 mg / kg). Pipe the left brachial vein and continue injecting pentobarbital at the rate of 5 mg / kg / hr during the experiment. The trachea is dissected and the dog is operatively ventilated with indoor air at a rate of 18 strokes per minute and a volume volume of 20 ml per kg. Cut the left and right vagus nerve of the middle neck part of the neck. Pipe the right upper arm vein and artery, inject the medicine, and monitor blood pressure with a Statham pressure transducer. All values are recorded on a Beckman-Offner dynograph. The center of the abdominal aorta is incised to open and the loose ligation line is placed in the left renal artery near the distal aorta. The right and left femoral arteries are ventilated to allow for posterior perfusion to the pipes and connections. Heparin (5 mg / kg) and galamine triethiodide (2 mg / kg) are administered intravenously, then the right femoral artery is piped and the tip of the catheter entering the abdominal aorta is raised to the renal artery height. The left femoral artery is plumbed and perfused into the Fuji using a Harvard Perfusion Pump. Tie the pre-made ligation lines around the aorta to minimize the side segment. Heparin and galamine triethio-dide are injected intravenously at rates of 2.5 and / 1 mg / kg / hr, respectively. The perfusion pressure measured at the point of the perfusion pump is fixed to 120 mmHg by adjusting the pump speed. The volume of blood flow to the ground is measured at the time of determination of the experiment. The test substance is infused at a rate of 0.1 to 1.0 mg / min. For 6 minutes and then the maximum reduction is determined in pressure units. One to three animals are used for each test substance.

Results—Table I below shows the test results for amines of representative alkylthiopheneoxypropanes of the present invention. The data is presented in this chapter as 1- (isopropylamino) -3- [4- (methylthio) phenoxy] -2-propanol- (diphnolol) (Keizer et. al, VS 3,542,984) and alkyl of 1- (isopropylamino) -3- [4- (methylthio) phenoxy] (Villa et al, II. Farmaco. Sci., Ed. 24, 349-357 (1969) Thio-phenoxy propanol amine full-length compound and reference standard papaverine.

Comparison tests for the compounds of the full length compounds "A" and "B" and Example 2 (Test Substance 2) resulted in the three compounds being given to the same dog (blood pressure can be controlled between injections of the test substances). As a modified method for experimenting with the subject it is carried out as described above. The process record is only for the same animal, allowing a direct comparison of vasodilation activity. The results of this comparison are also listed in Table I below.

TABLE 1

Vasodilation Activity-Fuji in Dogs

a. Test substance number corresponding to example number.

b. mmHg

c. Injection speed

d. Direct comparison to the same animal.

In comparison to the opinion full-length compounds "A" and "B", the alkylthiophenoxypropanolamine compound tested was more remarkable than the case of "A" and "B" at an injection rate of 1.0 mg per minute. The pressure reduction of 59-99mmHg is shown in comparison with the case of "A" and "B" which show the vasodilation effect and the pressure reduction of 72-29mmHg. Compared to the "A" and "B" compounds injected at 0.3 mg per minute, the compounds tested showed 0.8-3.2 and 5-21 fold activity in this case, respectively. All compounds tested in this chapter were tested at doses of 1.0 mg / min and greater or nearly similar pressure drop than papaverin at test dose 2 and full-length compound alkyllithiophenoxy-propanolamine “A When comparing "and" B ", Test Substance 2 shows a vasodilation effect 3.2 and 21 times greater than that of Test Substances" A "and" B ", respectively. As a result, it was found that Tettete 2 is a vasodilator that is superior to the full-length compounds alkylthiophenoxypropanolamines "A" and "B".

Example 32

[Inhibition of Platelet Aggregation]

(Hamthrombogen activity)

Experimental Methods—This method is described in Bonn, Nature 194,15,927 (1962) and O'Brien, J. Clinical Path. 15,446 (1962). This test uses a turbidity method to measure the change in turbidity of human platelet-rich plasma because platelet aggregation occurs with the addition of thrombogen influent adenosine diphosphate (ADP) or collagen. The addition of to the platelet-rich plasma causes the aggregation of platelets to increase the transmitted light The efficacy of the test compound depends on the frequency of suppressing the increased coexistence of aggregation and transmittance. The concentration causing the 50% reduction in the trobogen response is determined in the concentration-response curve.

Results—Table 2 below is the results of each test for the full length compounds “A” and “B” of the present invention and Example 31.

TABLE 2

Inhibition of platelet aggregation in animal studies

a. Test substance identical to Example Number.

b. Microgram 10.5ml Human platelet-rich plasma when using 1 mcg of adenosine-5'-diphosphate (ADP) or minimal collagen to cause aggregation.

c. See Example 31

Opinion-The above data show that in inhibiting ADP-induced platelet aggregation, all compounds tested showed superior activities over full length alkylthiophenoxypropanolamines "A" and "B".

Example 33

Isolated Guinea Pick Organs (Betty-Adrenergic Inhibitory Activity)

Experimental Method—Spirally cut trachea cut from guinea pigs weighing more than 400 g in weight are suspended vertically in 20 ml of fertilized tie rod liquid solution maintained at 37.5 ° C. and continuously vented with oxygen. Any tension in tracheal smooth muscle is observed through the transducer and continues to be recorded on the electrograph. The adrenergic Betty-receptor inhibitory activity is determined by the effect of the test substance inhibiting the response of the isolated tissue to the adrenergic Betty-stimulant "isoproterenol" at a concentration of 0.1 mcg / ml liquid reflux. The operation is moistened with the test substance solution at 15 minute intervals before adding isoproterenol to the liquid reflux. The beta-receptor inhibitory efficacy of the test drug can confirm the concentration-response relationship in which the response is expressed as% inhibition of isoproterenol-induced tissue response. IC ₅₀ values, the test drug concentrations that inhibit the isoproterenol relaxation effect by 50%, are determined by interpolation. Each drug solution is added to a tissue liquid medium having a fixed volume of 0.2 ml per ml of liquid reflux and only one type of test drug concentrate is used for each tissue segment. The potency of the test substance against the beta-adrenergic inhibitor "propanolol", which is a standard reference substance, is compared with the IC ₅₀ value.

Results—Table 3 below shows the full length of the compound alkylthiophenoxypropanolamine (keizer et al. Supra and Villa et al), referred to as test substances “A” and “B”, respectively (see chemical names in Example 31). supra) representative alkylthiopheneoxy propane of the present invention, which is indicated by a test number (experimental number) to be compared, is an experimental result of amines.

TABLE 3

Of separate guinea pigs

Betty-adrenergic inhibitory activity

a. Test substance identical to Example Number.

b. Isoproterenol-induced tissue reactions have an effect on propanol (1 species) determined by determining a 50% inhibitory test drug concentration (propanol EC ₅₀ = 0.02-mcg / ml liquid reflux)

c. See Example 31

Opinion-Table 3 data clearly show that test substance 1-8 differs significantly from that of full-length alkylthiophenoxypropanolamine in beta-adrenergic inhibitory activity. The beta-adrenergic inhibitory activity is remarkably less than that of the full-length compound alkylthiophenoxypropanolamines "A" and "B" which exhibit substantial activity. Therefore, the compounds used for the purposes of this chapter have relatively small side effects related to beta-adrenergic inhibitory activity.

Example 34

Isolated thoracic aorta of rabbit

(Anti-Spasulin I Activity Potassium Chloride)

Experimental Methods—In animal experiments, anticonvulsant activity is determined by measuring the effect of a test substance on arterial smooth muscle contraction caused by the following method. New Zealand white rabbits (males) weighing 2.5-4 kg are used. Each rabbit is killed by air injection. Incision of the rib cage and spiral cutting of the descending thoracic aorta. Four helical segments of about 2 cm in length (not straight) are obtained from the angular thoracic aorta. The spiral segment is placed in a 10 ml volume chamber and the bottom is connected to a glass rod tissue holder and the top is connected to an input transducer with a constant key line pressure of 3 gm on the tissue. The liquid medium surrounding the aortic helix (Crep-bicarbonate solution) is kept at 37.5 ° C. and constantly aerated at 95% O ₂ : 5% CO ₂ . The activity of the aortic smooth muscle is recorded on an electrical polygraph connected to a pressure transducer. After a 60-minute equilibrium period, cumulative dosing-response curves for the cohort group (eg, potassium chloride or norepinephrine) are obtained and tissues are washed. After 75 minutes, a second cumulative dosing-response curve for the cohort is obtained and tissues are washed again. After 60 minutes, the test drug solution is added to the tissue liquid reflux, and after 15 minutes, the drug is exposed to the drug and the third final cohort-response curve is obtained without washing. The total amount of the aqueous solution added to the liquid reflux is 0.1 ml.

Results—Table 4 below shows the alkylthiophenoxypropanol amines and full length compounds of Example 33 (eizer et al., Supra. (A) and Villaet al., Supra (B) in the test using potassium chloride as the cohort group. )-Comparative table of efficacy for papaverine of (see chemical name of Example 31).

TABLE 4

Anticonvulsive activity

(Rabbit's thoracic aorta)

a. Same test substance number as the example number.

b. Comparative potency against papaverine units measured by pA ₂ values determined by contraction induced by potassium chloride. The pA ₂ value is the negative log value for the molar concentration of the antagonist group in which the antagonist group is reduced in effect with twice as much as in the absence of the antagonist.

c. See Example 31

Opinion-antagonist activity against twitch muscles induced by potassium chloride is indicative of a non-adrenergic anticonvulsive action that acts directly. The results shown in Table 4 thus reveal that all of the tested compounds show good anticonvulsant activity while the full length compounds "A" and "B" show significantly lower activity. The data also show that for conjugation induced by potassium chloride, test substances 2,3,5,7 and 8 are "A" and "B" activity as the corresponding full-length compound alkylthiophenoxypropanolamine as a non-adrenergic anticonvulsant. It is 15-65 times more effective. The anticonvulsant activity of Test Substances 4 and 6 is similar to that of the full-length compounds "A" and "B", with Test Substance 4 being twice as potent and Substance 6 being about 1/2 potent.

Example 35

Isolated thoracic aorta of rabbit

(Anticonvulsive activity large norepinephrine)

The anti-alpha-adrenergic according to the method of Example 34, in which test substance 1-8 full-length compounds "A" and "B" of Example 34 were used as norepinephrine, an alpha-adrenergic stimulant, in place of potassium chloride Experiment with activity. Selective activity on the seizure induced by norepinephrine is an indicator of alpha-adrenergic inhibitory (eg anticonvulsive) activity. The modification test of the anticonvulsant test shows that the alkylthiophenoxypropanolamine compound except Test Substance 8 is deficient in anti-alpha-adrenergic action having an activity of less than 0.3% which is represented by phentolamine. Become. Pentolamines are known in the art as alpha-adrenergic inhibitors. Full-length compound "B" is inactive as an anti-alpha-adrenergic substance, while test substance 8 and full-length compound "A" show higher activity than compounds 1-7 and exhibit a phentolamine potency of about 1-2%. Indicates. The experiment shows that the compound is a non-anti-alpha-adrenergic antipsychotic with a direct smooth muscle relaxation effect insensitive to a significant degree of selective alpha-adrenergic inhibitory effect (see Example 34).

Example 36

Secondary biotest of 1- [4-[(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol

Vascular activity of the compound of Example 2 is measured and evaluated according to various pharmacological tests. The order is as follows.

(a) Reduce platelet survival in mice with catheter in the artery. Shortened survival is leveled with Example 2 compound.

(b) Example 2 The compound increases the salt mobility of the mesenteric solution of dogs and rabbits.

This effect is effective in curing the disease of peripheral and cerebral vessels.

(c) Example The compound reduces the elongation rate of erythrocyte cells measured by a technique leveled to Croch 51 so that the cells can more easily pass through the narrowed capillaries of tissues that have been transformed into vascular disease.

Claims (1)

An alkylthiophenol derivative of formula (II) is reacted with epihalohydrin of formula (III) and the epihalohydrin reaction product is condensed with an amine of formula (IV), Process for preparing alkylthiophenoxypropanol amine of formula (I) to react the product of formula (I) with acid to make acid addition salt thereof

Wherein R is hydrogen or methyl, R is straight-chain alkyl having 6-12 carbon atoms and X is halogen, preferably chlorine or bromine.