SE446631B - 1-PHENYL-1-PROPANOL DERIVATIVES AND SETS TO PREPARE THIS - Google Patents

Description

Another preferred class of compounds according to the invention comprises derivatives of the formula I, in which: a) Ra is a straight or branched alkylsulfinyl (C1-C3) radical, b) R2 is an NH3 radical, in which R 3 is a straight or branched alkyl (c6-cm) radical, a straight alkyl radical substituted by a carboxy or carbomethoxy group in the U] position.

Examples of compounds of the invention are: 1- (4-isopropylsulfonylphenyl) -2-n-octylamino-1-propanol, 1-quisopropylthiophenyl) -2- [3- (methoxycarbonyl) propylamine] -1-propanol, 1- ( -isopropylthiophenyl-2-β- (carboxy) propylamino] -1- [1,1] [1- (4-methylthiophenyl) -2-la- (methoxycarbonyl) propylamine] -I- propanol, 1- (β-methylthiophenyl) -2-La- (carboxy) propylamino-1-propanol, 1- (α-isopropylsulfinylphenyl) -2- [3- (methoxycarbonyl) propylamino-1-propanol, 1- Α-isopropylsulfinylphenyl) -2- [3- (carboxy) propylamino] -β-propanol, 1- (α-isopropylsulfinylphenyl) -2- β- (2-oxopyrrolidinyl) -1-propanol, and 1- (4-mercaptophenyl) -2 -n-octylamino-1-propanol.

Derivatives of the formula I can be isolated as ointments, in particular hydrochlorides and sulphates.

Derivatives of formula I can be transferred in a known manner to salts with acids and when the derivatives are obtained directly as salts, they can also be transferred to their free bases or to salts with other acids.

According to the invention, these salts are particularly pharmaceutically acceptable, non-toxic acid addition salts, prepared with suitable inorganic acids, e.g. hydrochloric acid, 446 631 sulfuric acid or phosphoric acid, or with suitable organic acids, such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic acids and carboxylic or sulfonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutanoic acid, hydrochloric acid, hydrocyanic acid , phenylacetic acid, mandelic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, pantothenic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, ¿§-hydroxypropionic acid, ¿¶-hydroxybutyric acid, galalic acid, gallic acid.

These salts can also be obtained from natural or synthetic amino acids, such as lysine, glycine, arginine, ornithine, asparagine, glutamine, alanine, valine, threonine, serine, leucine, cysteine and the like.

Most products according to the invention have two asymmetric centers. Derivatives where R 1 is an alkylsulfinyl radical have three asymmetric centers.

With products according to the invention, which have two asymmetric centers, two racemates corresponding to erythro and threo configuration can be obtained. These two racemates can be prepared in a conventional manner, e.g. by forming diastereoisomeric salts by the action of optically active acids such as tartaric acid, diacetyltartaric acid, tartranilic acid, dibenzoyl and ditoluoyltartaric acid and separating the diastereomeric mixture by crystallization, distillation or chromatography, after which optically active salts are released from .

With products according to the invention, which have three asymmetric centers, eight optical isomers can be obtained.

The same preparation method can be used for the said mixtures.

The most active derivatives of the invention 44sl631 can be used in the form of mixtures containing several diastereoisomers with arbitrary relative proportions, or in the form of enantiomeric pairs in either equal proportions (racemic mixture) or not, or also in the form of optically pure compounds . However, derivatives of erythro configuration at the level of the two asymmetric carbon atoms in the propanol chain are preferred. The invention also relates to a process for preparing the above-mentioned 1-phenyl-1-propanol derivatives and corresponding salts and esters. The process is characterized in that a compound corresponding to formula I is converted into a compound of z. © - Q i (III) in which Z is one of the substituents R1 or a formula group YS, where Y is a hydrogen-exchangeable protecting group, and Q is one of the following groups: "-CO-CO-CH 3; -CO-HOH-CH 3; -CO- $ HX; -CH-CH-CH 3; -CO-? H-NHR 3; CH CH 3 3_ -CHOH-? HX; -CHOH-? H-R2, 'c CH3 H3 where R2 and R3 have the meaning given above and X is a halogen atom, such as Cl, Br, F.

Preferably, derivatives of formula I, when R is a hydroxy group, are obtained by reduction of the corresponding ketones of the general formulas: RVQ-co-co-CHB (III); R 1 -O- co-cHoH-CHB (IV), in which R 1 has the previously defined meaning.

This reduction can be done in the usual way, e.g. by the action of hydrides, such as NaBH 4, LiALHu, LiAL (oAlkyl) 3H, AlH3, (Alkyl) 2A11-1,, NaB (ocH3) 3H, LiBHBCN, 332116, (Aikynssnli, (Aiky ßsilieeiier Nan. 6 as solvent 44). , tetrahydrofuran, ethanol, methanol, diglyme, toluene or xylene, by the action of alkali metals, such as sodium or lithium, in solvents such as ammonia or ethanol, by the action of hydrogen in the presence of hydrogenation catalysts, such as platinum or palladium, in solvent, such as ethanol, or by the action of aluminum alkoxides, such as aluminum isopropoxide, in a solvent, such as isopropanol. If the reduction process of ketones of formulas III and IV is not stereoselective, erythro / threo mixtures are separated according to conventional procedures (t eg by distillation or plate or column chromatography).

Compounds of formula I, when R 9 is an oxo-2-pyridinidinyl-I ring, which is optionally substituted by a hydroxy group, are preferably obtained according to such general reaction formulas as the following: oo - \ ua) RIG- c% -cH- c113 ____._.> RIÖ- CHOHoII-xiñ CH, 3 O b) RIG- co- fl lzH-Br 'cH3 1. NH2 (cH2) 3coocH3 2. Reduction 3. Base (cyclization). o r u R á / L »cHoHoH-Nš w C113 f In these reaction formulas, R1 has the meaning previously given.

In the reaction a) an epoxide is condensed with 2-pyrrolidinone without difficulty either without solvent, or above without the use of excess 2-pyrrolidinone, or in the presence of solvent, e.g. methanol or ethanol. 446 631 This method makes it possible to obtain alcohols with Lrookon I 'in gura t i un. In reaction b) a O (bromooketone) is condensed with an ester of 4 H -aminobutyric acid in a solvent such as methanol, ethanol, chloroform, aretonitrile, benzene or a mixture thereof, preferably at room temperature.

The reduction can be done with alkali metal hydrides, especially with NaNH 4, in solvents such as methanol or ethanol, at room temperature.

The cyclization to pyrrolidinone can be done by the action of an organic or inorganic base, e.g. an alkoxide or sodium, alternatively potassium hydroxide, in an alcohol or hydroalcoholic solvent, such as methanol, ethanol or isopropanol, at a temperature between room temperature and the reflux temperature of the selected solvent, but preferably at room temperature.

K This method enables the obtaining of alcohols with erythro configuration.

Compounds of formula I, when R 2 is a radical of the type NHR 3, from a compound of the general formula: (V) or depending on the qualitative meaning of Q, optionally from a salt of a compound of this formula, in which R 1 has the previously mentioned meaning and Q is one of the following groups: O '/ \ -CH-CH-CH3 -COÉH-NHR3 -CHOHCH-X -CO? HX C. '¿H CH H3 s 3 i where R2 has the meaning mentioned above while X is a halogen atom.

The latter process can be carried out in two different ways, mainly depending on the starting product, ie. qualitative meaning of Q in formula V. 446 631 Method A According to a first process, an δ-amino ketone according to formula V is reduced, in which Q represents a group CO-CH-NHR 3, where R B has the previously defined H3 meaning.

This reaction can be done in the usual way, easiest e.g. by the action of alkali metal hydrides, such as sodium borohydride, in a solvent, such as methanol or ethanol, preferably at low temperature, or by the action of aluminum or lithium hydride in a solvent, such as diethyl ether or tetrahydrofuran, or by the action of an aluminum alkoxide, such as aluminum propoxide , in a solvent, such as isopropanol, and most conveniently at reflux. The reduction can also be done by hydrogenation in the presence of a catalyst, such as palladium on carbon, Raney nickel or platinum oxide, in a solvent such as methanol, ethanol or dioxane.

The most interesting products according to the invention can, as previously mentioned, have erythro and treo configurations. The choice of starting aminoketane and reduction conditions make it possible to obtain either of these two forms stereoselectively. Thus, reduction of an amino ketone, in which Q is CO 3? H-NHR 3 to a CH 3 amino alcohol of erythro configuration, leads to the general conditions described above.

To obtain a compound with threonconfiguration, an amino ketone is reduced in which Q is Co-oH-INHBRh, where R is CH 3 and Ru is a protecting group, such as a benzyl, trityl, acetyl, the previously mentioned meaning, 3 formyl or benzhydryl group. The reduction is preferably made m> non | effect of: 1.l.kal.i.nu,: tu1.lhydiiidc-: oy safisoxn 11a.l, | 'i_u ||| hur'- hydride or aluminum] hydride. 446 631 The starting aminoketones can be easily prepared, e.g. by the action of an amine, R 3 NH 2 or RBRENH, on a GC halogen ketone in solvents such as ether, benzene, chloroform, dioxane, methanol, isopropanol or acetonitrile.

Method B According to this preparation method, a compound of formula V, wherein Q is a group, -cHoH-cix fl- x, cn 3 is reacted with an amine RBNH2, in which R3 and X have the meaning previously given.

This reaction is carried out in a solvent such as alcohol, chloroform, dioxane, carbon tetrachloride and suitably in the presence of an agent which binds the halohydride formed, e.g. inorganic or organic bases, or in an excess of amine. It is well known that in these cases the -CHOH-? H-X- group first gives an oxirane group CH3-of-type -CH-CH-CH3, which reacts with amine compounds.

Thus, the present process also encompasses the preparation of amino alcohols from oxiranes.

The compounds of formula I in which R1 is a mercaptan radical can be obtained from compounds of the general formula * Ys -Q- cHoHoH-Rg (vi), CH3 in which R2 has the previously mentioned meaning and Y is a protecting group which can be replaced with hydrogen according to processes well known in the literature, e.g. an alkyl group, such as an isopropyl, benzyl or substituted benzyl group, which can be moved by the action of alkali metals, such as sodium or lithium, in a solvent, such as ammonia, or by the action of hydrogen in the presence of hydrogenation catalysts, or by the action of lead diacetate or hydrofluoric acid, a diphenylmethyl group which is substituted with or not mobile by the action of acids such as trifluoroacetic acid or hydrobromic acid, a triphenylmethyl group which is substituted or not mobile by the action of acids such as hydrochloric acid or hydrobromic acid or by agents as HgCl 2, AgNO 3 or Hg (OAc) 2, a benzylthiomethyl group which is mobile by the action of oxidizing agents, such as HgCl 2 or Hg (OAc) 2, e.g. mercury salts, a carboxymethyl group which is an acetamide methyl group which is mobile with liquid oxidizing agents in acid solution or a tetrahydropyranyl or tetrahydrofuranyl group which is mobile with such oxidizing agents as AgNO3, Ir, SO2Cl2, (SCN) 2-Zn or with acids.

The compounds of formula I in which R 1 is an alkylsulfinyl or alkylsulfonyl radical can be obtained from compounds of formula I in which R 1 is an alkylthor radical, by oxidation according to a well-known procedure in the literature. This oxidation can, during the preparation of the products according to the invention, be done at any synthesis step.

To obtain sulfoxides, oxidizing agents such as iodine or bromine in water, or in the presence of acetate ions or in complexes with pyridine, peracids such as peracetic acid, monoperacetic acid or m-chloroperbenzoic acid, N-halosuccinimides such as N-bromosuccin hypochlorites such as sodium, t-butyl or isopropyl hypochlorite, periodates such as sodium periodate, hydrogen peroxide in the presence of acetic anhydride or in the presence of vanadium hemipentoxide in t-butanol, nitrates such as acetyl nitrate or ammonium and cerium nitrate, oxides such as chromium (VI) oxide in pyridine or vanadium hemipentoxide in the presence of oxygen or nitrogen hemipentoxide, peroxides, ozone, oxygen, in the single or triple state, acids such as nitric acid, nromic acid or carboxylic acid or in other means, such as sulfuryl chloride, 1-chlorobenzotriazole, chloramine, N-chloronyline 66, iodobnuzone dichloride, Iodosobenzene, iodobenzene diacetate, N-chlorotriazole, 2,4, h, 6-tetrabromocyclohexadienone or hydrochloric acid (HAuClh).

These oxidation reactions must be carried out in solvents, such as water, acetic acid, chloroform, dichloromethane, carbon tetrachloride, methanol, t-butanol or acetone.

To obtain sulfones, oxidizing agents such as hydrogen peroxide should be used, preferably in the presence of zirconium salts, peracids, such as peracetic acid, monoperphthalic acid and m-chloroperbenzoic acid (for oxidation with peracids, catalysts based on the transition metals are preferably used). or basic solution, sodium or potassium bichromate, osmium tetroxide, selenium oxide, t-butyl hypochlorite, nitric acid, ozone, oxygen, preferably in the presence of iridium or rhodium salt, iodobenzene chloride, periodic acid or by electrochemical oxidation.

These reactions are carried out in solvents such as water, acetic acid, chloroform, dichloromethane, methanol, ethanol, isopropanol, At-butanol, dioxane or acetone.

Sometimes it may be advantageous to carry out the oxidation reactions described above with compounds of formula 1, in which R 1 is an alkylthio group and in which functions which are sensitive to the oxidizing agent used have been protected, e.g. ..by the formation of esters, when hydroxy groups are present, or of ketals, when ketone groups are present.

The following are detailed examples of the preparation of some 1-phenyl-1-propanol derivatives according to the invention. The purpose of the examples is mainly to more fully illustrate the particular features of the method according to the invention.

Example 1 1- (N-Isopropylsulfinylphenyl) -2-n-octylaminopropanol Table 1, No. 6! To m g of 1- (h-isopropylthiophenyl) -z-n-octyl-aminopropanol, which is dissolved in 250 ml of chloroform, is slowly added δ μm m-chloroperbenzoic acid. The mixture is stirred overnight at room temperature, washed with a saturated aqueous solution of NaHCO 3 and evaporated in vacuo.

The residue thus obtained is treated with 50 ml of ether and filtered.

The organic phase is dried over MgSO 2, filtered and evaporated. The oily residue is vacuum dried overnight, redissolved in anhydrides and hydrochloride is obtained by passing a dry HCl gas. After recrystallization from a mixture of methanol and ether, 8.4 g of product are obtained. Yield: 60%; SMP (mp): 167-16900.

Centesimal analysis CHN Calculated, 1/0 61, 59 9, 30 3, 59 Found,% 61, 28 9.05 ß, ü5 Example gel 2 1- (ü-Isopropylthiophenyl) -2- Ü- (2-oxopyrrolidinyl)] - 1- Broganol [Table I, No. 7! a) 2-Methyl-34 (N-isopropylthiophenyl) oxirane To a solution containing 28.5 g of 2-bromo-1- (h-isopropylthiophenyl) -1-propanone, 350 ml of ethanol and 125 ml of ethoxyethanol is slowly added at -2500 and with shaking 3.83 g NaBHh dissolved in 25 ml water. The mixture is then allowed to slowly return to room temperature again and stirring is allowed to continue for 1.30 hours. Then slowly add 3.8 g of KOH dissolved in 100 ml of water, followed by stirring for 30 minutes. The reaction mixture is diluted with water and extracted with chloroform. The chloroform solutions are collected, dried and filtered, after which the solvent is removed by vacuum distillation. 23.6 g of an oil thus obtained, which is again vacuum distilled. Weight: 19.2 g; Yield: 65%; KP (boiling point): 81-BÅOC (0.7 mm); NM spectrum is consistent with 2-methyl-3- (4-isopropylthiophenyl) -oxirane structure w 446 631 b) 1- (4-Isopropylthiophenyl) -2-β- (2-oxopyrrolidinyl] -1-proganol _ 10, hg of the preceding product, H, 25 g of 2-pyrrolldinone and 0.5 g of NaOU are heated in nitrogen at 12,000 for 17 hours After cooling, the oil thus obtained is solidified by the addition of petroleum ether. The solid is filtered off, washed with a minimum of of petroleum ether, dried and recrystallized from diethyl ether to give 4.68 g of product Yield: 25%, SMP (° C) = 115-116.

The conformity of the structure is checked by mass spectrometry and NMR (threon configuration).

Centesimal analysis CHN Calculated,% 65, h9 7.90 h, 77 _Found,% 65, Ä5 7.80 4.70 Example gel 3 1- (4-Isopropylsulfonylphenyl) -2- Ü- (2-oxopyrrolidinyl fl-1- Eroganol ' (Table I, No. 92 A solution containing 2.93 g of 1- (U-isopropylthiophenyl) -2-IE- (2-oxopyrrolidinyl)] - 1-propanol, 6.5 ml, acetic acid and 6.5 ml % HO is progressively heated to 2 2 85-9000 and kept at this temperature for 2 hours, after cooling slowly add a solution of 6 g Na 2 S 2 O 5 in 15 ml of water, then dilute with 50 ml of water, the residue is extracted from chloroform The organic phase is dried over MgSO 4, filtered and evaporated, the oily residue thus prepared is solderified by adding petroleum ether and recrystallized from a mixture of ether and methanol to give 1.95 g of product, mp (° C) = 170, 5.

Centesimal analysis j C B _ ”N Calculated,% 59.05 7.12 '- 4.30 Found,'% 58.95 7.15 Ä, 10 NM spectrum confirms the threon configuration. 446 631 '13 ExemEel_§ 1- (h- [sopropylthiophenyl) -2-'3- (carbomethoxy) propylamine] -1- Qroganol' ¶Table 1, No. 12! 17 g of 2-bromo-1- (fl-isopropylthiophenyl) -1-propanone, 200 ml of methanol, 17.3 ml of triethylamine and 10 g of methyl-ul-aminobutyrate (hyarochloride) are reboiled for 17 hours.

The solution is then cooled to a temperature of 500 and Ä.5 g of NaBHn is added slowly. The reaction mixture is then stirred overnight at room temperature. After vacuum evaporation of the solvent and dilution of the residue with water, the same is extracted from chloroform. The chloroform solutions are collected, dried and filtered, after which the solvent is removed by vacuum distillation. This gives 13 .mu.g of crude product, which after treatment with hydrochloride in a diethyl ether / methanol (50/50) mixture gives 12 .mu.g of sample. Inbyte: 58 96; sMP (° c) = 175.6.

The conformity of the structure has been checked by mass spectrometry.

Centesimal analysis C H N Calculated,% 56.41 7.79 3.87 Found% 56110 7:65 3975 NM spectrum confirms the erythro configuration.

Example 5 1- (4-1-isopropylthiophenyl) -2- [ε- (carboxy) propylamine] -1- Eroganol Table 1, No. 232 7 g 1- (h-isopropylthiophenyl) -2-Ib-methoxycarbonyl) propylamino] -1-propanol is dissolved in 70 ml of water to which 7 ml of concentrated hydrochloric acid are added. The solution is heated and kept at SOOC for 1 hour, after which it is allowed to cool and the solvent is evaporated off under vacuum. It is then crystallized from methanol / ether mixture. 446k631 1h weight: h, 5 g§ Yield: 68%; SMP (° C) = 197.5.

Centesimal Analysis C 'NH Calculated,% 55.24 7.53 4.03 Found,% 55.35 7.50 3.80 Example 6 1- (4-Isopropylthiophenyl) -2-β- (2-oxopyrrolidinyl) -1 pronanol §eg1tro) ¶Table L, no. 24! In a mixture of 100 ml of methanol and 50 ml of water is dissolved 6 g of 1- (4-isopropylthiophenyl) -2- {3- (carboxy) -propylamino] -1-propanol. Addition of 10 N sodium hydroxide solution raises the pH to 13. After stirring for 1 hour at room temperature, the methanol is evaporated. Extraction is done with chloroform. The organic phase is dried over MgSO 4 and the solvent is evaporated. The product is solidified with petroleum ether and recrystallized from ether to give 1.3 g of product in 27% yield. SMP (° c) E 80. Conformity in structure is determined by NMR spectrum and mass K spectrometry (erythroconfiguration).

Centesimal analysis CH 'N Calculated,% 65, h9 7.90' 4.77 Found,% 65.15 7.70 h, 75 Example gel 7- 1- (α-Jsopropylthiophenyl) -1,2-propanol 1Table I, no. 18! 170 g of 1- (h-isopropylthiophenyl) -2-hydroxy-1-propanone are dissolved in 1500 ml of methanol. After cooling to 0 DEG C., 57 g of sodium borohydride are slowly added, followed by stirring overnight at room temperature. The solvent is evaporated off and diluted with water, then chloroform is extracted and dried on MQSUM. After evaporation of the solvent, recrystallization is carried out in a benzene / hexane mixture. 446 631 weight: 66.8 g; Yield: 39%; SMP (° C) = 83-85.

NM spectrum confirms the erythro configuration of the obtained product.

Centesimal Analysis C H Calculated,% 63.68 8.01 Found,% 63.50 8.05 Example Gel 8 I- (β-Mercaptophenyl) -2-n-octylamino-1-propanol §Table1 I, No. 40! To a solution containing 5.25 g of lithium, 1000 ml of liquid ammonia and 500 ml of tetrahydrofuran is slowly added a solution containing 16 g of 1- (β-isopropylthiophenyl) -2-n-6-ethylamino-1-propanol dissolved in 500 ml tetrahydrofuran. After the addition is complete, stirring is continued for about 15 minutes, after which 16 g of NHuCl are added in small quantities at a time.

The ammonia is slowly evaporated in a water bath, after which the residue is diluted with water. The solid thus obtained is filtered and recrystallized from methanol. 12 g of 1- (h-labeltephenyl) -2-n-ectylemine_1-propanol were thereby obtained.

SMP (° o) = 110-112; Yield: 82.1%.

Centeeimal analysis C H N Calculated,% 69.10 9.90 4.74 Found,% 69, ho 10.10 h, 60 As already mentioned above, the derivatives according to the invention may be in the form of their salts or esters.

Specific esters are those having the formulas: 446 651? 16 “Ä ïHß cnåso- <::» CH-cH + NHnc H. Hcl ,, / ”3 17 cH3 0-fi-032- c (cH3) 3 O SMP (° c) = 112-114 cH cH 3 I 3 \\\\ cH-so / \ CH-c fl- N fl nc n. H01 cH3 I 0-c-CH n 3 o SMP (° c) = 1u8,5-150 Melting points of the derivatives in the examples given above as well as other derivatives prepared in accordance with the present invention are given in the following table; I 446 631 17 c ^ mv ^ nwpwe: wHonpmm | @ = @ uv ~. ~ OH mwwz z QH _.

Sv Aääšomš mät u .. Nom fi z fi uøm? m ¶. _.

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S. N30 ä Nâå fl uoww nmw .. 31: u. 2. m »Nä ß mw: ~ - - N 2: 2 c3ïö <.ëëšâ SN _; _ 3 __ 03 .. HN _ ANV APV Aoov aænsma fl msm mm az MH Hqwnae 5 -_- íš = u @ ~ «446 631 18 ^.« V ^ mv ^ »@ ~ w- = ° @ = v ~ @ ~ - = m ~ = °° U ~ ^ ~ = Uv == ~ Qw ~ = mu ° m «HN ^ <.. mv ^ fi @» u- = Q @ =. æ. ~ wH MIUOQUNANIQVIZ ~ ow ~ = mu ° m, ON ^ m. ~ «. ß fifi o Is om ~ = ~ U ° m * ím fi ^ @. ^ = - ~ = - @ = @ U. mw- ~ w ¶ IQ ¶m ~ = mQ ° ww .w fi ^ «. ^ ~,% fi @ ~ m- = o @ = v Hß fi v fl = u ° = u ~ = u == m ~ = mu ° m @ Nä ^ @ v ^ ~. ^ fi @ »uJ = ° @ =. m @ ~ - ~ @ ~ == ° Q ~ = u: = m ~ = mu ° wW w fi. @. ^ ~. ^ = ° “@u <- = ° ~ =. ~ m ~ - ° @ _ ~ == @ m ~ = ~ u ° m @ mä ^ «. ^ ~ v. = °« = v «@ _- w @ ~ @ = u ° @% - = Qv == w ~ = u ga. «. ^ ~ V ^ = ° @ =. w.m ~. m = Q °° um ^ ~ = U. = z w ~ = mQ ° m * mä _. Q Am. ^ n @ fi ~ - == ~ =. mm _- @ m ~ ~ @@ = ~ ° wm = ° N.

Q ^ mV ^ H @@ ws: @ H ° »» @@ - ~ _U = uv ~ .- ~ mm @ = mm = Q fifi i É SL šasæim å: _ å T fi neï Song. 446 631 I 19 vÃillnvšsxiunilkfnïill. ïïïêomf: 3-3 * yuoouåäz Qwrmuø! S 3: 2 f fi ßmåoæ:: TSH åä8m2 = uv = z Q fl znuor. 2 o ¶: L 783.462: 2-3 az wmš S Q 2 :. ïßmïä fl š ... Såå Ü: Nowmš ä C t: ïm fi: mïå fi Ü? omåmuß .. 5 g: L éëüåcs: m2 Û .. Ncmfmuønw 3 Q: L cšâš 2723 a .. = 2 ¶ w S; v33: ä z 1:52; _ ä. 212 ^. ,,. @ fi _-_ ës: mf: šcufåušz 1:33? 8 Awv ^ _v Aoov uxcnau fl msm Nm .m az Ama fi ouv H fl wnwe 446 631 _20 ß fi zw Åwuuowv fifl wnme 212.03: 273 "US; ä. 3. Mi .. ¶ _ 2: 2: Bäï STS. B fl uïššu 2 ofmuä; 02 QUBSMQIUZZ Små 2 3: 2 ï Szàï @ ¿~ ^ ~ = Qš = âfmu fl m * S SIS 373: gíwšvë omk fi ä! Å 2: 2 21-2; m ~ = ïu == z Qwåmuâ .. ... m? I2r $ ... =. 272 .; šøumt flfi ušz är? S; å. _ O S. Ašäuï ~ JS Û .. ärm ". 2. O S; ïw fi ïåwu. mi: Oz wwzä ä Amy AFV Åoov ßxøsma fl wsw mm .m wz 446 631 '21 .w fiflfiflfl ma fl owhæ \ ohuäm Am Co fi ß fi mhdm fl æ fl ou fl owàu Am Qo fi pmhdw fl m fl oxohuh vm n: n Ö: fl. AHÜÜHWP .QuAWmHMvÜHOÜP Uue mw fi wäämwmm al OHW> m w HSS> S00 z .m .O al wv al Mem f w hmm muhoww .HMS mhaßißhøv al Mew f m AN WÜnf-HÜHÜQ EOÉH ÜNWHxWOÜÛH, .HW .HÜÜQEWWHHMÜWÉ-Hw f NNV al ä al w.HHHNQW flfi vmmvnn Q _ NI w ~ = mu ° m. ~ <Así fi wumë fl m fi ohßm lhouuv æmußm.

AQVAMV ^ n @ ~ u- = ° ~ uV ~ @ ~ -m @ ~ m = ~ u °° u ~ ^ ~ = u. == ~ ° m ~ = mu ° m @ @ «o w flfi o: °» m »= ~ = W ~ = ~ u ° wm m«. «.. ~. ^ = o »uuH = ° = um ^ ~ = U. == = w ~ = ~ Q ° mw« «.« v. fl ._ == ~ =. - ~ -m ~. = ° = um ^ ~ = uv == m ~ = ~ uømf ~ <^ «. ^ ~ V ^ ~ wuu- = °« = v ow fi ~ = u °° Qm ^ ~ = Uv == ° m ~ = » u ° m «NQ ^«. ^ ~. ^ H @ »u- = °« =. . ° ~ - @ m ~ ~ = u ° QUm ^ ~ = uv == m ~ = ~ u ° mW av Awv ^ _v Aoov axnnau fi wsm Nm .m az ^ m »uo @ v fifl onae 446 631 22 The compounds of the invention have in generally, as they are somewhat toxic, effects on the cardiovascular system, in particular antispasmodic effects, antihypertensive effects, peripheral vasodilator effects, hypolipidemic effects, normolipoproteinemic effects, antithrombotic effects and an inhibitory effect on platelet aggregation. Thus, they may be useful in the treatment of cardiovascular disorders in particular, which may or may not be associated with arteriosclerosis. They may also prove useful as stimulants for cerebral metabolism or as sedatives.

The effect on behavior has been studied using a method based on S. lrwin's method (Gordon Res.

Conf. on Medicinal Chem., 133, 1959). The substances in suspension with 1% tragacanth mucus were administered orally by intragastric probe to 5 groups of male mice (CCD1 breed, Charles River, starved for 18 hours). If the available amount of substance allowed, the doses were set at 3000, 1000 and 300 mg / kg. When the substances had an effect, the drug's effect was tested at 100, 30, 10 and if possible 3 mg / kg. The behavior was studied 2, H, 6 and Zü hours after treatment. The observation continued when the symposium persisted after this time. Mortality was recorded during the 14-day period following treatment. The LD50 values were calculated according to the method of Hitchfield and Wilcoxon (J. Pharmacol Exp. Ther., 96, 99, 19 # 9) and expressed in mg / kg.

Results obtained, in terms of effect on behavior, show minimal active dee in mg / kg (MAD) and the observed symptomatology. The LD5O values are given with their reliability limits (p = 0.95). Under prevailing conditions, a significant level of activity was observed, especially with respect to compounds 6, 13 and 20. The antihypertensive effect was tested by oral administration to non-anesthetized, spontaneously hypertensive rats, on which the systolic blood pressure was measured at the 446 631 middle tail artery by plethysmic method. , G. Lambelin, AF De Schaepdryver, Arch. Int. Pharmacodyn., ÉQQ, 182, 1972). Blood pressure was measured every 30 minutes for two hours before and three hours after oral administration of 60 mg / kg of the substance to be tested or of a blank (1% tregantsiem).

Only rats with systolic blood pressure up to 180-220 mm Hg were used. Each substance was tested on two rats. The measurements were performed by staff without knowledge of the treatment. The antihypertensive effects were documented with a rating followed by an index. The grading was done in the following way: 0: decrease by 10 mm Hg +: decrease by 10 - 20 mm Hg ++: decrease by 20 - 30 mm Hg +++: decrease by 30 - 30 mm Hg ++++: decrease by :> 50 mm Hg Index was calculated by multiplying the difference in systolic pressure, which was measured every 30 minutes after the treatment, by a coefficient 1-6 corresponding to the time intervals of 30-180 minutes.

With current experimental conditions, <3¿- | nety1dopa was graded: +++ (47) at 100 mg / kg, reser-pain: +++ (53) at 3 mg / kg and guanetid1n = +++ (62) at 60 mg / kg, In these experiments, products 6 and 7 in particular showed an interesting antihypertensive effect.

The peripheral vasodilatory effect of the products was measured on an anesthetized dog in the circulatory system of the femoral artery. Secondary vessels from the femoral artery were kept cordoned off and constant blood flow was supplied from the aorta, whereby this flow pressure, measured at the femoral artery, varied as a function of the resistance in the flow-through area. The test products and corresponding solvents were injected directly into the system at doses of 30 pg / kg. The blood circulation was kept constant, so that a vasodilation could be measured by a 446 531 2 :; reduction of the flow pressure and was registered in relation to the effect of papaverine in a standard dose, injected once per group of four products.

The products were also tested in other doses under the same conditions, when deemed justified. The vasodilatory effect was graded as follows: O: no effect, decrease <: 10 mm Hg +: 1/3 of the effect of the papaverine ++: 2/3 of the effect of the papaverine +++: ~ the same effect as the papaverine +++ +: greater effect than papaverine Among the products according to the invention, in particular, compounds 5, 6 and 20 showed a peripheral vasodilato- risk effect equal to, or greater than that of papaverine.

The antispasmodic effect of the studied substances was investigated against small intestinal contraction in guinea pigs, which was produced with histamine and acetylcholine. Its trials involve revealing an antihistaminic, anticholinergic or muscularotropic antispasmodic effect. The reaction of the contraction-triggering agent (submaximal concentration) was determined every 5 minutes before and after injection of successively increasing doses of the tested substances (10_7 - 104 M).

The magnitude of the inhibitory effect expressed as a percentage of the tested products was calculated and the theoretical concentration giving 50% inhibition was determined graphically for each experiment. These values were expressed as -log IC 50 (M). In this experiment, compounds 5 and 6 in particular proved to be active. _ _ Platelet aggregation was examined according to G.v.R. as and NJ. cross' turbidimetric method in (J. Physiol., 168, 178-195, 1973), Bpapia-rich plasma was preincubated for 4 minutes before the introduction of the inductor (Thrombofax). The small variations were recorded over a period of l () Inínuter 'with an a¿ç; ç.r'c; 5r »|| 1otor" Upchurv.] 1 ". Down 446 631 inhibitory effect on the maximum aggregation amplitude was measured.

This experiment showed that compounds 5, 6, 13 and le in particular were active.

For the study of the anti-lipolysis effect, epididymal fat was taken from starving rats. Fragments of adipose tissue (É 150 mg) were incubated in Krebs-Ringer buffer containing 3% albumin from bovine serum and the substance to be examined. A sample at time 0 was taken after 30 minutes of incubation at 37 ° C. Norepinephrine was used to induce lipolysis. The amount of free amino acids was measured after 20 minutes of incubation. (Duncombe, W.G., Clin.Chim.

Acta. §, 122, I96ü). In this experiment, compounds 5, 6, 8 and 13 in particular were active.

The inhibitory effect on cholesterol cholesterol biosynthesis was investigated as follows.

Buffered homogeneous pieces of rat liver were enriched with appropriate additives. Equal amounts were incubated for 60 minutes with 1-140 acetate and the compound to be tested. After saponification of the medium, sterols were extracted from petroleum ether and the dry residue was precipitated with digitonin in an alcohol-acetone solution.

The IÄC content of the precipitate dissolved in pyridine was measured by sointillation counting according to a method described by N. ßucher (J. Biol.Chem., 233, 1-I5, 1956). Under the prevailing conditions, compounds 1, 13 and 15 in particular showed a remarkable activity.

Inhibitory effect on bioamine uptake of synaptosomes was investigated by isolating sunaptosomes from rat brains after partial subcellular fractionation in sucrose solution (Gray R.G. and Whittaker V.P., J.

Anat. gg, 79, 1962). The uptake of 5-HT (serotonin) was done as follows. After incubation for 5 minutes of the Lestpr product with synaptosomes, incubation of the preparation in the presence of TMC-SHT for 5 minutes at 3706 and filtration on a Millipore filter followed, after which the filters were washed with ice-cold buffer. The radioactivity of the filters was measured by scin- Lillation count. The uptake capacity is given by the difference in radioactivity measured at 3700 and 0OC, respectively. In this test, compounds 5, 6, 13 and 14 in particular were active.

The active compounds of the invention may be administered orally, parenterally or rectally in association with various pharmaceutical excipients.

For oral administration, pills, powders, lozenges, capsules are used; tablets and capsules with controllable release of active agent, as well as sublingual tablets, solutions, syrups and emulsions containing traditional additives or excipients in Galician pharmaoi. For parenteral administration, sterile water or an oil is used, e.g. peanut oil or ethyl oleate. Suppositories or rectal capsules are used for rectal administration.

The active compounds can be used alone or together with other active products which have similar or other effects.

The products according to the invention can be used in various forms. The following examples are not limiting and relate to galenic formulation. They contain as active product, designated "A" below, one of the following compounds: 1- (H-isopropylsulfinylphenyl) -2- (- (2-oxopyrrolidinyl) -1-propanol - I- 1- ((-isopropylsulfinylphenyl) -2-n-octylamino-1-propanol.

Intramuscular injection A _ V J 10 mg Isopropyl myristate ': Ü _ I 0.75 ml Peanut oil, q.s.ad. gu _j_ 'B ml _Intravenous injection A _ 10 mg 446 631 27 L-aspartic acid 6 mg Benzyl alcohol 50 mg Distilled water, qsad V 5 ml Solution for oral administration A 5 mg Ethyl alcohol 0.1 ml Propylene glycol 0.05 ml 10% - acetic acid 0.05 ml Simple syrup (65% sucrose) gsad 1 ml A '0 5 mä Ethyl alcohol 0.2 ml 100 / Pig acetic acid 0.011 m1 Simple syrup, qsad 1 ml Tablets A 50 mg Lactose 20 mg Aerosil 2' mg starch GLS STA-Rx 1500 (TM) l 18_ mg Calcium phosphate (canpon) 25 mg Microcrystalline cellulose 100 mg Sodium acetate 15 mg A 50 mg Maize starch 50 mg Sodium acetate 15 mg Magnesium stearate 2 mg Aerosil (TM) 3 mg starch STA-Rx 1500 (TM ) 80 mg Sublinggala_tablets VA 25 mg Lactose - 117.75 mg Soluble starch 10 mg Sodium saccharin, 0.25 mg Gelatin 3 mg 44sL6s1 28 A 25 mg Lactose 1 50 mg Sucrose '_. 25 mg Glycine 2.5 mg Stearic acid 0 - 5 mg KaE 'slar A _' 50 mg 'starch STA-Rx 1500 (TM) __ _ _1oo mg Magnesium stearate _ -_ I 1 mg Sodium lauryl sulphate' 10 mg Microcrystalline cellulose - 30 mg Aerosol (TM) _ - 1 mg M juka kaBs> A 220 mg Liquid paraffin '222 mg Soy lecithin - 3 mg Controllably released capsules A _' 50, mg Lactose 45 mg Polyvinylpyrrolidone I 15 mg _Mannitol 5 mg Euaragit E (TM) 1 mg Suggositorier A 150 mg 'Lidocaine - 20 mg 2_u_ Novata 299 grad. (TM). - 2000 mg A V 100 mg witepsol s 58 grad. (TM) 2 gooo mg The meaning of some terms used in the above galenic arrangement is given in the following.

- Aerosol (TM) § Trade name for atomized silica. _ starch STA-Rx 15oo (TM) = corn starch] - Lidocaine: Trade name for lignocaine. 446 631 29 - Novata 299 grad. (TM) = Mixing of saturated (C11-c1) fatty acid triglycerides with partial glycerides of acetylcrade foot acid- Novata B grade. (TM): Mixture of natural (C | 1-C17) - fatty acid triglycerides, di- and monoglyceride triglycerides.

Eudragit E (TM) (Röhm): Polymer of acrylic acid dimethylaminoethyl ester.

Depending on the disease, the desired effect and the type of compound used, 1-phenyl-1-propanol derivative according to the invention is administered in daily doses of 5-3000 mg.

For intravenous injection, the derivatives are administered in daily doses of 1-20 mg. witespol s 58 degrees. (TM): Mixture of natural (c12-c18) -

Claims (1)

Claims 1 to 1-phenyl-1-propanol derivatives and non-toxic and pharmaceutically acceptable salts and esters thereof, characterized by the general formula R 1 -O-cnoncfi-R 2 -, (I) CH 3 wherein a) gl consists of a straight or branched alkylthio (C1-C3) radical, a straight or branched alkylsulfinyl (C1-C3) radical, a straight or branched alkylsulfonyl (C1-C3) radical or a mercaptan radical, and b) R 2 is (b-2) a 2-oxo-pyrrolidin-1-yl radical, which may be substituted by a hydroxy group, or (b-3) an NHR 3 radical, in which R 3 is - a straight or branched alkyl (C 6 -C 16) radical or straight alkyl (C 2 -C 4) radical substituted with a phenyl or phenoxy group provided that R 1 is not an alkylthio radical, or - a straight or branched alkyl (C 1 -C 7) radical substituted with a lower carboxy- or carbalcoxy (C1-C3) group in the U) position. 2. A derivative according to claim 1, characterized in that R 3 is a straight or branched alkyl (C 10 -C 16) radical. _ _ _-3. Derivatives according to claim 1, characterized in that R 3 is a straight or branched alkyl (CC radical. 6 '10) 4. Derivatives according to claim 3, characterized in that R 3 is a straight or branched octyl radical. 446 631 31 5. A derivative according to any one of claims 1 to 4, characterized in that R 1 in formula I is a straight or branched alkylthio (C 1 -C 3) radical. Derivative according to any one of claims 1 to 4, characterized in that R 1 in formula I is a straight or branched alkylsulfinyl (C 1 -C 3) radical. A derivative according to any one of claims 1 to 6, characterized in that R 2 in formula I represents an NHR 3 radical, wherein R 3 is a straight or branched alkyl (C 1 -C 3) radical substituted by a carboxy- or carbonyl radical. methoxy group in the ul position. Derivative according to any one of claims 1 to 7, characterized in that it is selected from the following compounds: 1- (Ä-isopropylsulfinylphenyl) -2-n-octylamino-1-propano], 1- (β-isuprupylLLophenyl) -2- (3- (methoxycurbyl) propylamino) -1-propanol, 1- (H-isopropylthiophenyl) -2- (3- (carhoxy) propylamino) -1-propanol, 1- (H-methylthiophenyl) -2 - (3- (methoxycarbonyl) propylamino) -1-propanol, 1- (α-methylthiophenyl) -2- (3- (carboxy) propylamino) -1-propanol, 1- (H-isopropyl] sulfinylphenyl) -2- ( 3- (methoxycarbonyl) propylamino-1-propanol, 1- (4-isopropylsulfinylphenyl) -2- (3- (carboxy) propylamino) -1-propanol, 1- (h-isopropylsulfinylphenyl) -2- (1- ( 2-Oxopyrrolidinyl) -1-propanol, and 1- (N-mercaptophenyl) -2-n-octylamino-1-nropanol Derivatives according to any one of claims 1 to 8, characterized in that it is of erythrocon figuration at the level of the two asymmetric carbon atoms in the propanol chain 1446 sar 32 10. Methods for preparing 1-phenyl-1-propanol1 derivatives according to any one of claims 1 to 9, known as by converting into a derivative corresponding to formula I a compound of formula z- / \ -o (u) in which Z is one of the substituents R1 or a group YS, where Y is a hydrogen-exchangeable protecting group, and Q is one of the following groups: * -CO-C 6 -CH 3 -CO-CHOH-CH 3; -öO-QH-X; -CÉ: šH-CH3; -CO-? H-NHR3; CH3 CH3 -CHOH6H-X; -CHOH-ï fl- R2 CH3 CHB where R2 and R3 have the meaning mentioned above and X is a halogen atom. 11. A method according to claim 10, characterized in that derivatives with erythro- or threo-configuration are separated from derivatives with mixed erythro-threo-configuration, preferably by distillation or plate or column chromatography. 12. A process according to claim 10, characterized in that in the preparation of derivatives of formula I, when R 2 is an oxo-2-pyrrolidinyl-1-radical, which may be substituted by a hydroxy group, a compound is condensed according to formula II, in which Q is the group / 1 '-cH-cH-CHB, with 2-pyrrolidinone either without solvent, whereby an excess of 2-pyrrolidinone can be used, or in the presence of a solvent, e.g. methanol or ethanol. 446 631 33 13. A method according to claim 10, characterized in that in the preparation of derivatives of formula I, when R 2 is an oxo-2-pyrrolidinyl radical, which may be substituted by a hydroxy group, omgelnirnp; A compound of the formula, wherein R 1 has the meaning given above and R is an alkyl group, preferably a lower alkyl (R 2). C, -CB) radical, 1H. According to patent-pending IS, it is possible to carry out the hydrolysis with an organic or inorganic base, for example an alkoxide or sodium or potassium hydroxide. , in a solvent consisting of an alcohol or hydroalcohol, such as methanol, ethanol or isopropanol, at a temperature between room temperature and the reflux temperature of the selected solvent, preferably at room temperature 15. A method according to claim 10, characterized in by producing derivatives of formula I, when R 2 is an NHR 3 radical, wherein R 3 is an alkyl radical substituted with a carboxy or carbomethoxy group in the O 2 position, by condensation of a derivative of formula II, wherein Q is the group CO-CH-X, CH3 with a U) -aminoalkanoic acid or an ester of the acid, with the following reduction. 16. A process according to claim 15, characterized in that the condensation is carried out in a solvent such as methanol, ethanol, chloroform, acetonitrile, benzene or a mixture thereof, preferably at room temperature. 17. A method according to claim 15, characterized in that one reduces with alkali metal hydrides, preferably BaBHu, in a solvent such as methanol or ethanol at room temperature. ... M. 446 631 34 18. A method according to claim 10, characterized in that derivatives are prepared according to a pre-formula I, when R is a radical of the type NHR 2 3 = slightly of the general formula, m-Qya (v) or depending on the qualitative meaning of Q, optionally from a salt of a compound of this formula, in which R] has the previously mentioned meaning and Q is one of the following groups: O / \ -CH-CH-CH3 - CO 3 H-NHR 3 -CHOH? HX -CO? HX CH CH CH, 3 "3 3 where R 3 is as defined above while X is a halogen atom. 19. A method according to claim 18, characterized in: that in order to obtain 1-phenyl-1-propanol derivatives of the formula I with an erythro configuration, an amino-ketone of the formula V is reduced, in which Q then represents a group -CO-? H-NHR 3 and R 20. A method according to claim 19, characterized in that the reduction is carried out with an alkali metal hydride, for example sodium borohydride in solvents such as methanol or ethanol, preferably at low temperature, or with aluminum lithium hydride in solvents such as diethyl ether or tetrahydrofuran, or with an aluminum alkoxide such as aluminum propoxide, in a solvent such as isopropanol, preferably under reflux (reflpx), or by hydrogenation in the presence of catalyst, such as palladium on carbon, Raney nickel, platinum oxide in solvents, such as methanol, ethanol and dioxane. 446 631 21. A method according to claim 1, wherein - in order to obtain a derivative especially of threo-configuration, an amino ketone of formula V, in which Q is constituted by a group -CO-? H-, is reduced. NR 3 R 4, CH 3 preferably with alkali metal hydrides such as sodium borohydride or aluminum lithium hydride. A process according to claim 181, characterized in that a compound of formula V, in which Q is a group -CHOH-? HX, is reacted with CH 3 with an amine, R 3 NH 2, preferably in solvents such as alcohols, chloroform, dioxane and carbon tetrachloride and most easily in the presence of a substance which binds the halogen hydride formed thereon, such as inorganic or organic bases, alternatively with excess amine¿ 23. A method according to claim 18, characterized in that a the oxirane of formula V, wherein Q is a group -then-EH-CH 3, react with an amine, R 3 NH 2, preferably in solvents such as alcohols, chloroform, dioxane and carbon tetrachloride and preferably in the presence of a The halide hydride formed is adapted to 1 "er1i | 1¿; a ~ = | xu- alternatively with excess amine. 2h. A process according to claim 10, characterized in that in the preparation of compounds of formula I, wherein R1 is a mercaptan radical, by the action of alkali metals, ie n compound of formula II, in which Z corresponds to the group YS, the protecting group Y, in particular an alkyl group, such as a lower branched or straight chain alkyl radical, replaces with hydrogen. 446 631 36 25. A method according to claim JO, characterized in that for the preparation of derivatives of formula I, when R1 is a alkylsulfinyl or alkylsulfonyl radical, a compound of formula V is subordinated, wherein Z is an alkylthio radical , action of an oxidizing agent, whereby functions sensitive to the oxidizing agent used may be protected, e.g. by formation of esters, when the hydroxy group is present, or of ketals, when ketone groups are present.