LU79970A1 - PROCESS FOR THE PREPARATION OF 1-PHENYL-1-PROPANOL DERIVATIVES - Google Patents

Description

'' t ,. you MEMORY DESCRIPTION filed in support of a PATENT INVENTION request in the name of the public limited company known as: "Continental Pharma" for r "Process for the preparation of 1-phenyl-l-propanol derivatives".

Inventors: IAMBELIN Georges RONCUCCI Roméo ROBA Joseph GILLET Claude

The subject of the present invention is derivatives of 1-phenyl-1-propanol of general formula I: R -CHOHCH-R2 (I) • '~ ^ H3 in which: a) R ^ represents hydrogen, an alkylthio radical linear or branched (C ^ -C ^), a linear or branched alkylsulfinyl radical (C ^ -C ^), a linear alkylsulfonyl radical or /

ν- »¥ ή · ί -Pi λ (Π \ nn πνι n rra 1 mulV * ntanf-n / / J

B) R2 represents: b-1) a hydroxyl radical b-2) an oxo-2-pyrrolidinyl-1 ring which may be substituted by a hydroxyl group b-3) a radical of the NHR type in which represents. * ^ hydrogen, a linear or branched alkyl radical as far as does not represent an alkylthio radical, an alkyl radical (C - ^ - Cg) substituted by a carboxyl or carbalkoxy group in position ω or simultaneously by a carboxyl or carbalkoxy group in the OJ position and by a carbonyl or hydroxyl group in the CJ-2 position, their salts and esters, as well as, for the hydroxy acid-forming derivatives, the corresponding lactones.

In a particular way, the invention relates to the derivatives of formula I in which R ^ is an isopropylthio radical or an isopropylsulfinyl radical and those in which R2 is of the type: a) -NH (CEL) COOH (η = 1 to 7) 2 nb) -NH (CH2) nCOOR (η = 1 to 7; R = CH3) c) -NH (CHj CHOHCH COOH (n = 1, 3, 5) znzd) -NH (CH-) COCH COOH ( n = 1,3,5) or

Z Tl Z

e) -l (~ r 0

The compounds of general formula I having R2 substituents of the type a, c and d described above are therefore hydroxy acids which can exist in equilibrium with the corresponding lactones / - i · - 3 - I CH3 R, - ((- CHOHCH-NH (CEL) COOH ^ R '(CH) 1 \ = JI 2 n 1 \ = J \ / 2 n CH_ O ^ c'

3 II

o (II) (III)

Examples of compounds according to the invention are: 1- (4-mercaptophenyl) -2-n.octylamino-1-propanol! 1- (4-isopropylsulfinylphenyl) -2-n.octylamino-l-propanol i 1- (4-isopropylthiophenyl) -2- [4- (carboxy) propylamino] -l-propano] i • 1- (4-isopropvlsulfonylphenyl) -2 [1- (2-oxopyrrolidinyl)] - l-pro-! panol i! 1- (4-isopropylsulfinylphenyl) -2 [1- (2-oxopyrrolidinyl)] - l-pro- | panol 1- (4-isopropylthiophenyl) -2 [l- (2-oxopyrrolidinyl)] - l-propanol 1- (4-isopropylsulfinylphenyl) -2-amino-l-propanol

If the derivatives according to formula I are in the form of addition salts with acids, it can be transformed, according to usual methods, into their free base or into salts with other acids.

The most commonly used salts are acid addition salts, in particular non-toxic acid addition salts, pharmaceutically usable, formed with suitable inorganic acids, for example hydrochloric acid, sulfuric acid or phosphoric acid or with suitable organic acids, such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic carboxylic or sulfonic acids, for example - 4 -

»I

glycolic, gluconic, glucuronic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, hydroxÿbenzoic, salicylic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, tolhotenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic.

The most active products of the invention having two centers of asymmetry, one can obtain two race-mates corresponding respectively to. erythro and threo configurations; these two racemates can be resolved by conventional methods, for example by forming dia-stereoisomeric salts by the action of optically active acids, such as tartaric, diacetyltartaric, tartranilic, di-benzoyltartaric, ditoluoyltartaric acid and separation of the mixture of diastereoisomers by crystallization, distillation, chromatography, then release of the optically active bases from these salts.

The same methods can be used if the compounds of the invention contain more than two asymmetry centers.

The most active derivatives of the invention; can therefore be used either in the form of racemates of erythro or threo configuration, or in the form of a mixture of these two forms or else in the form of optically active compounds of each of these two forms. A preference __J -_____. 1 -, - 4- _______ .1 _, 1-, ____ 4-, · 1 »- 5 - The invention also relates to a process for the preparation of the abovementioned derivatives of 1-phenyl-1-propanol.

This process is characterized by the fact that it consists in transforming, into one of the corresponding derivatives of formula I, a compound of formula: z ^ -0 (I ') in which Z represents one of the substituents of defined above or corresponds to a group YS in which Y is a protective group replaceable by hydrogen and Q is one of the following groups: -CO-CO-CH ^; -CO-CH-X 7 -CH-CH-CH ^; CH3 -CO ~ CH-NHR_; -CHOH-CH-X; -CO-CH-X; -CHOH-CH-R „, in) 3 I I 1 2 CH3 CH3 ch3 ch3 which R„ and R_ have the meaning given above and X represents a halogen atom.

Advantageously, the derivatives of formula I in which R2 is a hydroxyl group are obtained by reduction of the corresponding diketones of general formula IV

V © —CO — CO — CH3 (iv) in which R ^ has the meaning given above.

This reduction can be carried out in the usual way, for example by the action of hydrides such as NaBH ^, LiAlH „, LiAl (OAlkyl) H, A1H, (Alkyl) _A1H, NaB (OCH„) H, LiBH_CN, B „H ^ , (Alkyl) nSnH, (Alkyl) -, SiH or Nali and this in

I I

- 6 - 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 solvents such as ethanol or by the action of aluminum alcoholates, such as aluminum isopropylate, in a solvent such as isopropanol.

The compounds of general formula I in which R2 is an oxo-2-pyrrolidinyl-1 ring optionally substituted by a hydroxyl group are advantageously obtained according to the general schemes described below: 1 £ * JJ QQ y

(a) R -COCH-Br ----> R - / "^ - CHOHCH-N

'Vrv j, 2. reduction' - '* ^ - CH3 CH3 (V) (VI) m

_ AT

b) R1-fj \ -CH-CH-CH3 —--> R ^ VCHOHCH-N

ce3 (VII) (VIII)

In the general formulas V to VIII R ^ has the meaning given above.

In reaction (a), the condensation of a halogenated ketone of type V with the O-alkylated derivative of a lactam can be carried out in a solvent such as dimethyl- "" - 7 - principles well known and easily for example by the action of a hydride, such as NaBH 4, and this in a solvent, such as methanol or ethanol.

In reaction (b), the condensation of a type VII compound with 2-pyrrolidinone is easily carried out either without solvent using optionally an excess of 2-pyrrolidinone or in the presence of solvents, such as for example methanol or 1 * ethanol.

The compounds of general formula I in which R2 is a radical of the NHR ^ type can be obtained from a compound of general formula IX l

Rl - ^) - Q (IX) or optionally, depending on the value of Q, from a salt of a compound corresponding to this formula, in which R ^ has the meaning given above and Q represents one of the following groups:

AT

-CH-CH-CH -COCH-NHR_ -CHOHCH-X -COCH-X

3 (3,, ch3 ch3 ch3 in these R3 groups has the meaning given above while X represents a halogen atom.

The above process can be carried out in two modes which are essentially determined by the starting material, that is to say by the value of Q in formula IX.

1 - 8 - 4! ‘

Mode A.

! In a first way, an α-aminoketone corresponding to formula IX is reduced in which Q represents a group CO-CH-NH-R ^ »R ^ aYant the cation given above.

This reduction can be carried out in the usual manner, most easily for example by the action of alkali metal hydrides such as sodium borohydride, in a solvent / such as methanol or ethano, preferably in

II

it low temperature, or aluminum hydride and lithium in j ί a solvent such as diethyl ether or tetrahydrofuran ^

It is either by the action of an aluminum alcoholate, such as aluminum isopropylate, and this in a solvent such as isopropanol, most advantageously at reflux thereof. The reduction ! can also be carried out by hydrogenation - in the presence of a catalyst, such as palladium on carbon, Raney nickel, platinum oxide in a solvent, such as methanol ethanol, dioxane.

As previously mentioned, the most interesting products of the invention can have two erythro and threo configurations. The choice of the starting aminoketone and the reduction conditions make it possible to obtain one or the other of these two forms in a stereoselective manner. Thus the reduction of an aminoketone where Q = CQ-CH-NHR0 leads,

! -3 CH

in the general conditions described above, to an amind- / // »*! - 9 - i i

To obtain a compound of threo conformation, the reduction is carried out on an aminoketone where Q = CO-CH-NR3R4 in which R3 has the value indicated preceded L3 ment and is a protective group which can be eliminated afterwards by hydrolysis or hydrogenolysis, such as the groups benzyl, trityl, acetyl, formyl, benzhydryl; this reduction is then preferably carried out by the action of alkali metal hydrides, such as sodium borohydride or aluminum and lithium hydride.

The starting aminoketones are easily accessible, for example, by the action of an amine R3 NH ^ or R ^ R ^ NH on an α-halogen ketone in solvents such as ethe benzene, chloroform, dioxane, methanol, isopropanol or acetonitrile.

Mode B.

According to this mode of preparation, a compound of the general formula IX is reacted, in which Q represents a group -CHOH-CH-X, with an amine R_NH 2, formulas in I 32 CH3 in which R3 and X have the meaning given above.

This reaction is carried out in a solvent such as alcohols, chloroform, dioxane, carbon tetrachloride, and most easily in the presence of a product fixing the halogenated hydracid formed, such as inorganic or tertiary organic bases / or even in the presence of excess of mine. It is well known that in these cases the group /? /

* AT

- 10 - 0 / \ -CHOH-CH-X first gives an oxirane of the type -CH-CH-CH \ 'CH3 which reacts with the amino compound.

The present process therefore also includes the preparation of amino alcohols from oxirannes.

The compounds of general formula I in which is a mercapto radical can be obtained from compounds of general formula X: YS "O -choiich-r 2 (x) CK3 in which R2 has the value indicated above and Y is a protective group replaceable with hydrogen according to methods well known in the literature, for example an alkyl group such as isopropyl, benzyl or substituted benzyl which can be removed 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 substituted or not eliminable by the action of acids such as trifluoroacetic acid or hydrobromic acid, a triphenylmethyl group substituted or not removable by the action of acids such as hydrochloric acid or hydrobromic acid or agents such as HgCl2, AgNO ^ or Hg (0Ac) 2 / a benzylthiomethyl group which can be removed by pa r the action of agents such as HgCl2 or Hg (0Ac) 2, an acetamidomethyl group which can be removed for example by mercury salts, a carboxymethyl groupa / * Λ - 11 - which can be removed by oxidizing agents in an acid medium or a group tetraliydropyrannyle or tetra-hydrofurannyle eliminable by agents like AgN03, I2> SO2Cl2, (SCN) 2-Zn or acids.

The compounds of general formula I in which R is an alkylsulfinyl or alkylsulfonyl radical can be obtained starting from the compounds of general formula I in which R ^ is an alkylthio radical and this by oxidation according to methods well documented in the literature. To obtain sulfoxides, it is thus possible to use agents such as iodine, peracids, such as peracetic, monoperphthalic or chloroperbenzoic acids, such as N-halosuccinimides, such as N-bromosuccinimide, for example, hypochlorites, sodium hypochlorite or t-butyl iodates ^ such as sodium periodate, hydrogen peroxide preferably in the presence of aceric anhydride, acyl nitrates, such as acetyl nitrate for example or agents such as sulfuryl chloride or 1-chlorobenzo-triazole. These oxidation reactions will be carried out in solvents such as, for example, water, acetic acid, chloroform, methylene chloride, carbon tetrachloride, methanol or acetone.

To obtain the sulfones, agents such as hydrogen peroxide, peracids such as peracetic, monoperphthalic and m-chloro-perbenzoic acids, or potassium permanganate are preferably used in solvents such as water, acetic acid, chloroform, chloride / de ^ - 12 - I i

In certain cases, it may be advantageous to carry out the oxidation reactions described above on compounds of general formula I where is an alkylthio group and in which the functions sensitive to the oxidizing agent used have been protected by example by formation of esters in the eas of hydroxyl groups or ketals in the case of ketone groups.

Below are given detailed examples of the preparation of a few 1-phenyl-1-propanol derivatives according to the invention. These examples are mainly intended to further illustrate the particular characteristics of the process according to the invention.

Example No. 1 1- (4-isopropylsulf inylphenyl) -2-n. octylaminopropanol (Tabl. I. n ° 8).

To 14 g of 1- (4-isopropylthiophenyl) -2-n.octylaminopropanol dissolved in 250 ml of chloroform, 6.4 g of m-chloroperbenzoic acid is gradually added. The mixture is stirred overnight at room temperature, washed with a saturated aqueous solution of NaHCO3 and evaporated in vacuo.

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

The organic phase is dried over MgSO 4, filtered and evaporated. The oily residue is dried under vacuum overnight, redissolved in anhydrous ether and the hydrochloride is obtained by passing a stream of dry HCl gas. After recrystallization from a mixture of methanol and ether, we obtain Q Λ rr r \ ca r ^ -v-rxr ^ n τ 4- P + · DP · Ί £ 7 - Ί innî nf rî Ä * Fn c Vt \ y 7 t - 13 -

Centesimal analysis C H N

% wedge. 61.59 9.30 3.59% tr. 61.28 9.05 3.45

Example No. 2 1- (4-isopropylsulfonvbhenyl) ~ 2- [l ~ (2-oxopyrrolidinyl)] -1-propanol (Table I, No. 10).

A solution containing 2.93 g of 1- (4-isopropylthiophenyl) -2- [1- (2-oxopyrrolidinyl) Jl-propanol, 6.5 ml of acetic acid and 6.5 ml of 0 to 30% H is gradually heated to C * c * 85-90 ° C and maintained for 2 hours at this temperature. After cooling, a solution of 6 g of Na ^ S ^ O ^ in 15 ml of water is gradually added, then diluted with 50 ml of water. The residue is extracted with chloroform, the organic phase is dried over MgSO 4, filtered and evaporated. The oily residue obtained is solidified by adding petroleum ether and recrystallized from a mixture of ether and methanol.

1.95 g of product are thus obtained. PP (° C): 170.5 Centesimal analysis C H N

% wedge. 59.05 7.12 4.30% tr. 58.95 7.15 4.10

Example 3.

1- (4-isopropylthiophenyl) -2- [l- (2-oxopyrrolidinvl) j-1-propanol (Tabl. I. n ° 7).

a) 2-methyl-3- (4-isopropylthiophenyl) oxirane.

To a solution containing 28.5 g of 2-bromo-l- (4-isopropylthio- __- i- i \ -I __________ -ir * / * \ „~ im -r · Ί _ J_ inr j I ____„ Λ - 14 - gradually added at -25 ° C and with stirring, 3.83 g of

NaBH, in 25 ml of water. After addition, the mixture 4 is allowed to gradually return to room temperature and the stirring is continued for 1.30 h. Then 3.8 g of KOH in 40 ml of water are added dropwise and the mixture is stirred for 30 minutes. The reaction medium is diluted with water and extracted with chloroform. The chloroform solutions are collected, dried and filtered, then the solvent is removed by vacuum distillation. 23.6 g of an oil are thus obtained which is rectified under vacuum.

Weight: 19.2 g; Rdt. : 65%; Bp: 81-84 ° C (0.7 mm); the NMR spectrum conforms to the structure of 2-methyl-3- (4-isopropylthiophenyl) oxirane.

b) 1- (4-isopropvlthiophenyl) -2 ~ [1- (2 "Oxopyrrolidinyl)] - l-propanol.

10.4 g of the above product, 4.25 g of 2-pyrrolidinone and 0.5 g of NaOH are heated under nitrogen for 17 h at 120 ° C. After cooling, the oil obtained is solidified by the addition of petroleum ether. The solid is filtered, washed with a minimum of petroleum ether, dried and recrystallized from diethyl ether. 4.68 g of product are thus obtained.

Yid: 45%; PF (° C): 115-116.

The conformity of the structure is checked by mass and NMR spectrometry.

Centesimal analysis C H N

% wedge. 65.49 7.90 4.77% rev. 65.45 7.80 4.70 y

J

- 15 -

Example No. 4 l- (4-isopropvlthioDhénvl) -2- [4- (carbomethoxy) propylaminol -2-propanol (Table I, No. 12).

17 g of 2-bromo-l ~ (4-isopropylthiophenyl) -2-propanone, 200 ml of methanol, 17.3 ml of triethylamine and 10 g of H C00C (CH) NH .HCl are brought to reflux during 17 h.

O MW U

The solution is then cooled to a temperature of 5 ° C. and 4.5 g of NaBH 4 is added little by little. The reaction medium is then stirred overnight at room temperature. After evaporation of the solvent under vacuum and dilution of the residue with water, extraction is carried out with chloroform. The chloroform solutions are collected, dried and filtered, then the solvent is removed by vacuum distillation. 13.4 g of crude product are thus obtained which, after preparation of the hydrochloride, in a 50/50 mixture of diethyl ether-methanol, 12.4 g of product.

YId: 58%; PF (° G): 161-162.

The conformity of the structure was checked by NMR spectrometry.

Elementary analysis C H N

% wedge. 56.41 7.79 3.87% rev. 56.10 7 d 65 3.75

Example 5.

l- [4- (isopropylsulfonyl) phenyl] - !, 2-prooanediol (Tabl.I, n ° 2). In a 250 ml flask fitted with a magnetic stirrer, an ascending cooler, an introduction bulb and a thermometer, a solution of 10.2 g of l- [4- (iso- : tj -16.-

Ihydrofuran. 2.3 g of NaBH 4 in 20 ml of water and 1 ml of 33% sodium hydroxide are added little by little to the solution cooled in an ice bath, taking care to keep the temperature of the reaction medium close to 5 °. vs. After addition, this temperature is maintained for 30 minutes. The temperature of the reaction medium is then brought to + 35 ° C. and 10 ml of methanol are added to dissolve the precipitate formed. The mixture is heated to 35 ° C with stirring for 90 minutes. After cooling in an ice bath to + 10 ° C, the I solution is acidified to pH 7 using dilute hydrochloric acid (IN) and filtered.

The filtrate is reduced in vacuo and the residue obtained is acidified to pH 4 with dilute hydrochloric acid and then basified to pH 10 with a 25% ammonia solution. The mass obtained is extracted using chloroform.

The organic phase is dried over MgSO 4, filtered and evaporated in vacuo.

7.2 g of an oily residue are obtained which is purified by chromatography on a dry column. 5 ^ 6 g of oily product are thus obtained, the mass spectrum and NMR spectrum of which conform to the structure.

YId: 54.9%

Elementary analysis C H

% wedge. 55.80 6.98% tr. 55.20 6.90

The above starting material, 1- [4-isopropyl-pm 1 f envb-nhen vl 1-1. 2-d ioxonronane. oeut oar exemole to be - / 1 *; · '·' · -17-.

obtained from 4-isopropylthiopropiophenone by oxidation then oximation with isoamyl nitrite followed by treatment with hydrochloric acid as illustrated by the reaction scheme below: ch3 ch3 / CHS ^ O) -C0CH2CH3 -5-5 "^ CHS02- <g) -C0CH2CH3 j ^ CH O" 'CH3 CH3 CH3 CH3 ^ chso2 ^ -coç-ch3 -5¾ ^ chso2 ^) - cococh3 CH3 n-oh CH3

Example 6.

1- (4-mercaptophenyl) -1,2-prooanediol (Table I, n ° 1).

In a three-necked 500 ml flask cooled to -75 ° C., 100 ml of ammonia are condensed and then 0.55 g of lithium is gradually added (blue coloring). . · ’

50 ml of tetrahydrofuran are then introduced dropwise while maintaining the temperature <70 ° C.

5.4 g of 1- (4-isopropylthiophenyl) -1,2-propanediol solubilized in 50 ml of tetrahydrofuran are added dropwise over 15 minutes to the stirred reaction medium maintained at a temperature of -70 ° C. Agitation is continued for an additional 15 minutes. Then, while maintaining the temperature at -70 ° C., 6 g of ammonium chloride are added in small portions over a period of 30 minutes.

The ammonia is evaporated slowly by gradual reheating of the reaction mixture. 'i i - 18 -

When the temperature reaches + 20 ° C / the medium is acidified to pH 7 using dilute hydrochloric acid.

The tetrahydrofuran is evaporated in vacuo and water is added until the precipitate is completely dissolved.

The aqueous solution is extracted with diethyl ether.

The organic phase is dried, filtered and concentrated in vacuo. The residue obtained is purified by chromatography on a column of silica gel. 2 g of a pale yellow oil are obtained, solidifying at rest, the NMR spectrum of which conforms to the structure of 1- (4-mercaptophenyl) -1.2 ~ propanediol.

YId: 37.0%

Elementary analysis C H

% wedge. 58 ^ 7 6T5% tr. 58 f 3 6.3

Example 7.

1- (4-mercaptophenyl) -2-n.octylamino-1-propanol (Table X, n ° 4).

A solution containing 5 g 25 g of lithium, 1000 ml of liquid ammonia and 500 ml of tetrahydrofuran is gradually added a solution containing 16 g of 1- (4-isopropylthiophenyl) -2-n.octyl-amino-l- propanol in 500 ml of tetrahydrofuran. After addition, the mixture is stirred again for approximately 15 minutes and then 16 g of NH 4 Cl are added in small portions.

The ammonia is evaporated slowly in a water bath and then the residue is diluted with water. The solid obtained is filtered and recrystallized from methanol.

12 g of 1- (4-mercaptophenyl) -2-n.octylamino-1- i j * I - 19 - I PF (° C): 110-112 are thus obtained; YId: 82.1%

I Centesimal analysis C H N

d% hold. 69.10 9.90 4? 74% tr. 69.40 10.10 4.60! Example 8.

i 2- (4-isopropylthiophenyl) -3-methyl-8 ~ oxo-perhvdro-! (1,4) -oxazocin.

j 18 g of 1- (4-isopropylthiophenyl) -2- [4- (carbomethoxy) propyl j amino] -1 propanol (hydrochloride), 450 ml of methanol and 6 g j of NaOH are brought to reflux for 2 h. After cooling i

Iet evaporation of the solvent, the residue is acidified with 2N HCl

and repeatedly extracted with chloroform. The organic extracts are dried over MgSO 4, filtered and the solvent is distilled under vacuum. The residue is dried under vacuum and the hydrochloride of the final product is obtained by passing dry HCl gas in a 50/50 acetone-ether mixture.

12.4 g are thus obtained; YId: 74%

Mp (° C): 114.4

NMR, IR and mass spectra confirm the structure of the product.

Centesimal analysis C H N

% wedge. 58.25 7.33 4.25% tr. 58f45 7.30 4.07

The melting points of the derivatives given in the examples as well as other derivatives prepared according to the invention are given in the following table: - 20.- »»

Tabjeau I

R1 - ^^ - CH0HCH-R2 k

Rj 1 ^ 2 PP (° C) ^ (melting point I HS- -OH oil; '2 isoC ^ H ^ SO ^ - -OH oil 3 HS- -NH2 oil 4 HS- -NHnC H 110-112 (ethanol -ether) 8 1 / (3) 5 isoC ^ H ^ SO ^ “NH2 228-229v 1 (methanol-ether) 6 isoC H SO - -NHnC H1 68-69 (acetone)

O

7 isoCgH ^ S- -N ^ | 115-116 (ether) 8 isoC.H S0- '-NHnC H, _ 167-169 ^ (methanol-ether) 3 7 8 J. / 0 V, 9 H -N 110.4 (benzene-ether of petro- V, 10 isoC H SO -N 170.5 (methanol-ether) J / M \ 0 V! II isoC ^ H ^ SO- -N 149-150 (acetone) 12 isoC H S- -NH (CH) COOCH 161-162 (methanol -ether)

j / & O O

0 y_ 13 CH ^ SO ^ - —_ | 158-159 (methanol-ether) 0 h 14 CH3S- -N 124.9 (chloroform-ether of '- petroleum) 0 15 C2H ^ S- -n ^ | 104.9 (benzene-ether) 0 16 C2H5SO- J] 121.2 (Acetone) 1) the recrystallization solvent is given in brackets / · - 21 -

I V

As already indicated above, the derivatives according to the invention can be in the form of their salts or esters.

- A specific ester is that corresponding to the formula:

CH

ch3 I

CH-S0 - <^ \ - CH-CH-NHnCoH1_. HCl CH w 1 8 17 OÇ-CH „~ C (CH) _ ij Λ at 0 PF (° C): 112-114 \

I V

7 22 ~ ..

The products of the invention have various pharmacological activities, mainly in the cardiovascular system.

Their hypertensive activity was tested by oral administration in spontaneously hypertensive non anesthetized rats, in which the systolic blood pressure is measured at the level of the median coccygeal artery by a plethysmographic method (J. Roba, G. Lambelin, A.F.

De Schaepdryver, Arch.int. Parmacodyn. 200, 182, 1972). Under these conditions, products no. 4 and 8 exhibit an interesting antihypertensive activity.

The peripheral vasodilator activity of the products of the invention was measured in the anesthetized dog, at the level of the femoral arterial circulation. For this purpose, the femoral artery, the collaterals of which have been ligated, is perfused at a constant rate by means of blood drawn from the aorta.

Among the products of the invention, compound No. 4 has a peripheral vasodilator activity greater than that of papaverine.

The antispasmodic activity of the products of the invention was tested against the contractions of the guinea pig ileum induced by histamine and acetylcholine and barium chloride. These tests make it possible to demonstrate antihistamine, anticholinergic or antispasmodic musculotropic activity.

All the products of the invention have a *? 23 -

t V

say without an antichlolinergic or antihistamine component but the most active are compounds no. 4, 6 and 8 which have an activity 10 times greater than that of papaverine.

Compounds Nos. 5, 8 and 11 show a marked antilipolytic activity demonstrated in vitro on rat epididymal fat.

Furthermore, also in vitro, compound No. 8 manifests a powerful anti-platelet aggregating effect on human blood.

The acute toxicity of the products of the invention was also determined after oral administration (gavage of a mucilage with 1% of tragacanth) to male mice (CD 1 strain, Charles River, fasting for 18 hours).

The products of the invention are generally not very toxic.

The behavioral changes observed consist mainly of tracking accompanied by sedation at higher doses.

From the above, it follows that the compounds according to the invention, while being not very toxic, are generally endowed with activities on the cardiovascular system, in particular antispasmodic, antihypertensive, peripheral vasodilator, protective against myocardial anoxia, hypolipidemic, normolipoproteinemic, antithrombotic, inhibitor of platelet aggregation; they can therefore be useful in particular for the treatment of cardiovascular conditions./ t * - 24 - linked or not to. atherosclerosis. In ultramarines could also prove useful as stimulating agents of the cerebral metabolism or as tranquilizers.

The active compounds of the invention can be administered in combination with various pharmaceutical excipients and this by oral, parenteral or rectal route.

For oral administration, dragees, granules, tablets, capsules, tablets and capsules with controlled release of the active ingredient, solutions, syrups, emulsions or suspensions containing conventional additives or excipients in galenic pharmacy will be used. For parenteral administration, sterile water or an oil, such as peanut oil or ethyl oleate, will be used. For rectal administration, suppositories or rectal capsules will be used.

These active compounds can be used alone or in combination with other active products having a similar or different activity.

The products of the invention can be used in various forms. The following examples are not. limiting and relate to the galenical formulations containing as active product, hereinafter designated by the reference "h"; one of the following compounds: 1- (4-isopropylsulfonylphenyl) -2 [1- (2-oxopyrrolidinyl)] - 1-propanol 1- (4-isopropylsulfinylphenyl) -2-n.octylamino-l-propano] ^^^ / ' "\ A 10 mg - 25 -

IV injection

Isopropyl myristate 0; 75 ml

Peanut oil qs ad 3 ml, A 10 mg

D-glucuronic acid 6 mg

Benzyl alcohol 50 mg

Dist. Water qs ad 5 ml To 10 mg

Ethyl alcohol 0.50 ml

Polyethylene glycol 400 0.25 ml

Propylene glycol 0.50 ml

Acetic acid 10% 0; 125 ml

Sorbitol 70% 0.75 ml

Dist. Water qs ad 3 ml to 10 mg

L-aspartic acid 6 mg

Benzyl alcohol 50 mg

Dist. Water qs.ad. 5 ml

Solution for oral administration A 5 mg

0.1 ml ethyl alcohol

Propylene glycol 0.05 ml

Acetic acid 10% 0.05 ml / A 5 mg t * ί - 26 -

0.2 ml ethyl alcohol

Acetic acid 10% 0.04 ml

Simple syrup qs ad 1 ml

Tablets A 50 mg

Lactose 20 mg Aerosil 2 mg

STA-RX 1500® starch, 18 mg

Calcium phosphate (CaHPO ^) 25 mg

Microcrystalline cellulose 100 mg

Sodium acetate 15 mg to 50 mg

Microcrystalline cellulose 100 mg

Starch STA-RX 1500® 99 mg Aerosil 1 mg To 50 mg

Corn starch 50 mg

Sodium acetate 15 mg

Magnesium stearate 2 mg Aerosil ® 3 mg

Starch STA-RX 1500 ® 80 ing ^^ / ^ - 27 -

50 mg capsules

Starch STA-RX 1500® 94 mg

Magnesium stearate 1 mg

Sodium lauryl sulfate 5 mg to 50 mg

Microcrystalline cellulose 70 mg

Corn starch 30 mg

Glycerin 0? 01 mg

Sodium lauryl sulfate ’5 mg to 50 mg

STA-RX 1500® 100 mg starch

Magnesium stearate 1 mg

Sodium lauryl sulfate 10 mg

Microcrystalline cellulose 30 mg

Aerosil 1 mg to 200 mg

Liquid paraffin 222 mg Soy lecithin 8 mg

Controlled release capsules A 50 mg

Lactose 45 mg

Polyvinylpyrrolidone 15 mg

Mannitol 5 mg *. > - 28 - '- At 100 mg

Suppositories

Lidocaine 20 mg (R)

Novata 299 grad. ^ 2000 mg to 100 mg

Lidocaine 20 mg d Cutina GMS ® 100 mg | Nova ta B grad. ® 2000 mg to 100 mg | Witepsol S 58 grad.® 2000 mg j The meanings of certain terms used j in the above galenical formulas are explained below: I! - Aérosil ®: trade name for silicon dioxide

Inely divided - Starch STA-RX 1500®: corn starch 4 - Lidocaine: trade name for lignocaine - Novata 299 grad.®: mixture of triglycerides of saturated fatty acids from to with partial glycerides of acetylated fatty acids - Novata B grad.®: mixture of tri-di- and monoglycerides of saturated fatty acids from to - Cutina GMS®: glycerine monostearate /} / ^>: -29-

R

- Witepsol S 58 grad. : mixture of natural triglycerides | s from C12 to C18 * j * - Eudragit E (Röhm): polymer of the dimethylamino ester ί: ethyl of acrylic acid: Depending on the case, the route of administration, the nature of the activity sought and of the specific compound used, the 1-phenyl-1-propanol derivatives according to the invention are administered in daily doses of 5 to 3000

Claims (20)

1.- 1-Phenyl-1-propanol derivatives of the general formula I: R1-fVH ° HOH-R2 (I) ch3 in which: a) R ^ represents hydrogen, a linear or branched alkylthio radical (C ^ -C ^), a linear or branched alkylsulfinyl radical (C ^ -C ^), a linear or branched alkylsulfonyl radical (C ^ -C ^) or a capto mer radical b) R2 represents: b-1) a hydroxyl radical b-2) an oxo-2-pyrrolidinyl-l ring which can be substituted by a hydroxyl group b-3) a radical of the NHR ^ type in which R3 represents hydrogen, a linear or branched alkyl radical (C ^ -Cg ) provided that R ^ does not represent an alkylthio radical, an alkyl radical (CC) substituted by a carboxyl group j _ or carbalkoxy in position or simultaneously by a carboxyl or carbalkoxy group in position W and by a carbonyl or hydroxyl group in position ^ -2 ,. their salts and esters as well as, for the derivatives closing hydroxy acids, the corresponding lactones. /? / - 31 - 2, - Derivatives according to claim 1, characterized in that, in formula I, is an isopropylthio or isopropylsulfinyl radical. 3, - Derivatives according to either of Claims 1 and 2, characterized in that, in formula X, R2 represents a radical: a) -NH (CHJ COOH (n = 1 to 7) 2 nb) -NH (CH2) COQR (n = 1 to 7; R = CH3) c) -NH (CH2) CHOHCH COOH (n - 1, 3, 5). d) -NH (CH2) nCOCH2COOH (n. = 1, 3, 5) or / - e) -N 4, - Derivatives according to either of Claims 1 and 2, characterized in that in the formula I, R2 represents an oxo-2-pyrrolidinyl-1 ring. 5. Derivative according to claim 3, characterized in that they comprise the lactones corresponding to the hydroxy acids of formula I in which R2 represents a radical -NH (CH) COOH, 2 n ~ NH (CH „) CHOHCH COOH or 2 n 2 -NH (CHj COOT COOH. 2 n 2 6. Derivatives according to any one of claims 1 to 5 / characterized in that they are in the form of addition salts with acids chosen from the group formed by hydrochloric, sulfuric, phosphoric, formic, acetic acids, propionic, succinic, glycolic, gluconic, glucuronic, / "" ·! - 32 - fumaric, pyruvic, aspartic, glutamic, benzoic, anthrailic, hydroxybenzoic, salicylic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, panthotenic, toluene su Ifonic, sulfanilic, cyclobexylaminosulfonic, stearic, alginic. 7. Derivatives according to any one of claims 1 to 5, characterized in that they are chosen from the group formed by the following compounds: 1- (4-mercaptophenyl) -2-n.octylamino-l-propanol 1- (4-isopropylsulfinylphenyl) -2-n.octylamino-1-propanol 1- (4-isopropylthiophenyl) -2- [4- (carboxy) propylamino] -l-propanol 1- (4-isopropylsulfonylphenyl) -2 [1- ( 2-oxopyrrôlidinyl)] - 1-propanol 1- (4-isopropylsulfinylphenyl) -2 [l- (2-oxopyrrolidinyl)] - 1-propanol 1- (4-isopropylthiophenyl) -2 [1- (2-oxopyrrolidinyl)] - 1-propanol 1- (4-isopropylsulfinylphenyl) -2-amino-l-propanoll 8. Derivatives according to any one of claims 1 to 7, characterized in that, for those having two centers of asymmetry, they are presented either in the form of racemates of erythro or threo configuration, or in the form of a mixture of these two forms, either in the form of optically active compounds of each of these two forms. v 9. Derivatives according to claim 8, characterized in that they have the erythro configuration. 10.- Process for the preparation of 1-phenyl-1-Ipropanol derivatives according to any one of Claims 1 to 9, characterized in that it consists in transforming / into a corresponding derivative of formula I, a compound of formula : / Ζ- ^ Λ-Ο (! ') / Β% «- 33 - in which Z represents one of the substituents of defined above or corresponds to a group YS in which Y is a protective group replaceable by hydrogen and Q is one of the following groups: -CO-CO-CH 7 -CO-CH-X? -CH-CH-CH; -CO-CH-NHR 7 CH3 CH3 "-CHOH-CH-X 7 -CO-CH-X; -CHOH-CH-R, in which R and R I I \ ^ é J CH3. ch3 ch3 have the meaning given above and X represents a halogen atom. 11, - Process according to claim 10, characterized in that, for the preparation of derivatives of formula I in which R £ is a hydroxyl radical, a corresponding diketone of formula 1 'is reduced in which Q is formed by the group - CO-CO-CH3. 12, - process according to claim 11, characterized in that the abovementioned reduction is carried out by the action of hydrides such as NaBH4, LiAlH ^, LiAl (OAlkyl) 3H, A1H3, (Alkyl ^ AlH, NaBtOCH ^ H, LiBH3CN , B2H6 # (Alkyl) 3SnH, (Alkyl) 3SiH or NaH and this in solvents like ether, tetrahydrofuran, ethanol, methanol, diglyim toluene or xylene, by the action of alkali metals like sodium or lithium in solvents like ammonia or etha->? nol, by the action of hydrogen in the presence of hydrogenation catalysts such as platinum or palladium in solvents such as ethanol or by the action of alcoholates aluminum such as aluminum isopropyl pylate in a solvent such as Isopropanol 13. - Process according to claim 10, characterized in that, for the preparation of derivatives of formula I in which R is an oxo-2 radical -pyrrolidinyl-l possibly subst: 34. l'v ': r formula 1' in which Q represents the group -CO-CH-X with. ···· '> ··: ··' ch3 a der v-O-alkylated lactam, preferably in a solvent such as dimethylformamide, and the carbonyl radical is reduced. 14. Method according to claim 10, characterized; in that, for the preparation of derivatives of formula I in which is an oxo-2-pyrrolidinyl-l radical optionally substituted by a hydroxyl group, condensation is carried out · :: · Λ; · '; of a compound corresponding to formula 1 'in which Q represents -.:.1-1- V-: A:' - · feels the group -CH-CH-CHL with 2-pyrrolidrnone, ie without J * solvent optionally using an excess of 2-pyrrolidinone either in the presence of a solvent, such as for example methanol or ethanol. 15. Method according to claim 10, characterized in that, for the preparation of derivatives of formula I in which R2 is an NHRR radical, a compound corresponding to the formal 1 ′ is transformed into such a derivative or optionally, according to the value of Q, a salt of a compound corresponding to this formula, in which Q represents one of the following groups: '. · · .Y :: 0 ·: *:> -CH-CH-CH. ; -COCH-NHR; -CHOHCH-X; -COCH-X; -CO-CH-NR.R.,: ' 3 I 3 i II 3 4 CH3 CH3 CH3 CH3 in which R3 and X have the meaning given above and is a protective group which can be removed by hydrolysis or hydrogenolysis, such as benzyl, trityl, acetyl, formyl, j I. benzhydryl. 16. Method according to claim 15, characterized y.:y.ôv:n in that, in particular to obtain a compound of erythro configuration, an α-amino ketone corresponding to the formula y ... 'is reduced in which Q represents a group -CO-CH-NH-R. y /! CH, // Γ ·· ^ "U - 35 - 17. The method of claim 16, characterized in that this reduction is carried out by the action of alkali metal hydrides such as sodium borohydride in a solvent. such as methanol or ethanol preferably at low temperature or aluminum hydride and lithium in a solvent such as diethyl ether or tetrahydrofuran or by the action of an aluminum alcoholate, such as isopropylate aluminum and this in a solvent such as isopropanol, most advantageously at reflux thereof or by hydrogenation in the presence of a catalyst, such as palladium on carbon, Raney nickel, oxide of platinum in a solvent such as methanol, ethanol, dioxane. 18. Method according to claim 15, characterized in that, in particular to obtain a derivative of threo configuration, an amino ketone of formula 1 ′ is reduced in which Q represents a group -CO- <pH ~ NR3R4, preferably by l action of CH3 hydrides of alkali metals such as sodium borohydride or aluminum and lithium hydride. 19. Method according to claim 15, characterized in that a compound of formula 1 ′ is reacted in which Q represents a group -CHOH-CH-X with an amine preferably ch3 in a solvent such as alcohols, chloroform, dioxane , carbon tetrachloride, and most easily in the presence of a product fixing the halogenated hydracid formed, such as inorganic or tertiary organic bases, is still in the presence of an excess of amine. V · "- 36 - 20, - Process according to claim 15, characterized in that an oxirane of formula 1 'is reacted in which Q represents a group -CH-CH-CH ^ with an amine R ^ NE ^, Pre ~ * ference in a solvent such as alcohols, chloroform, dioxane, carbon tetrachloride and most easily in the presence of a "product fixing the halogenated hydracid formed, such as mineral or tertiary organic bases, or even in the presence of 'an excess of amine 21, - Process according to Claim 10, characterized' · in that, for the preparation of compounds of formula I in which is a mercapto radical, it is replaced by hydrogen, in a compound of formula 1 ′ in which Z corresponds to the group YS, the protective group Y, (a) if the latter is formed from an alhy-le, benzyl or substituted benzyl group, 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, (b) if the latter is formed from a diphenylmethyl group substituted or not, by the action of acids, such as trifluoroacetic acid or hydrobromic acid, (c) if this is formed from a triphenylmethyl group substituted or not, by the action of acids, such as hydrochloric acid or hydrobromic acid, or agents such as HgCl2, AgNO ^ or Hg (0Ac) 2, (d) if the latter is formed from a benzylthiomethyl group, by the action of agents such as HgCl2 or Hg (0Ac) 2, (e) if the latter is formed d '' an acetamidomethyl group, by the action of mercury salts, (f) if the latter is formed from a hydrofuranyl or hydropyrannyl group, by the action of agents such as AgN03, I2, S02C12, (SCN) 2Zn or acids, (g) if this one - »S *, -I 1 n« -1 · n _ _i_ J _. _ ^ 2 ’Y 2. (- * Λ. S 4 - 37 - 22. Process according to claim 10, characterized in that, for the preparation of derivatives corresponding to formula I in which R ^ represents an alkylsulfinyl or alkylsulfonyl radical, a compound of formula 1 ′ in which Z represents an alkylthio radical and in which the functions sensitive to the oxidizing agent used have optionally been protected, for example, by formation of esters in the case of hydroxy groups or of ketals in the case of ketone gpupes. 23. Process for the preparation of 1-phenyl-1-propanol derivatives as described above. 24. 1-Phenyl-1-propanol derivatives as described above. 25. Pharmaceutical composition comprising, as active product, at least one of the derivatives according to any one of claims 1 to 9 and 24, combined with at least one suitable excipient and / or optionally with at least one other therapeutic agent. 26. Pharmaceutical composition exhibiting antihypertensive, peripheral vasodilator, antispasmodic, protective against myocardial anoxia, lipid-lowering, poproteinemic normoli, antithrombotic and / or inhibitor of platelet aggregation, characterized in that it comprises, as active product, at least one of the derivatives according to any one of claims 1 to 9 and 24 combined with at least one suitable excipient and / or optionally with at least one other therapeutic agent. / - 38 - 27.- Method of using the derivatives according to any one of Claims 1 to 9 and 24 and of the composition according to either of Claims 25 and 26 / characterized in that the derivatives of 1 are administered -phenyl-1-propanol in daily doses of 5 to 3000 mg. 3sins: —plates · I3 / _ pages including ----------------- cover page ..... Âl ... description pages ........ .B ...- claims pages _________________ short description jxembourg, le Jà- ΟΊ-- 7 / Charles München