CH644355A5 - 1-PHENYL-1-PROPANOL DERIVATIVES. - Google Patents

Description

The subject of the present invention is 1-phenyl-1-propanol derivatives of general formula I:

r

1_ ^ 3-chûhç.h-r2

(I)

ch.

in which:

a) Rj represents hydrogen, a linear or branched alkylthio radical (Cj-C,), a linear or branched alkylsulfinyl radical

(C, -C3), a linear or branched alkylsulfonyl radical (C] -C3) or a mercapto radical;

b) R2 represents:

b-1) a hydroxyl radical:

50 b-2) an oxo-2-pyrrolidinyl-1 radical which may be substituted by a hydroxyl group;

b-3) an NHR3 radical in which R3 represents:

- hydrogen;

- as far as R! does not represent an alkyl-55 thiò radical, a linear or branched alkyl radical (C6-C16) or a linear alkyl radical (C2-C4) substituted by a phenyl or phenoxy group;

- a linear or branched radical (Cj-C7) substituted by a carboxyl or lower carbalkoxy group (C, -C3) in posi-

60 tion co,

as well as the non-toxic and pharmaceutically usable salts and esters of these derivatives.

A preferred class of compounds according to the invention relates to the derivatives of formula I in which:

A) Ri represents a linear or branched alkylthio radical (C1-C3); b) R2 represents a NHR3 radical in which R3 represents a linear or branched alkyl radical (C, -C3) substituted by a carboxyl or carbomethoxy group in position co.

644,355

4

30

Another preferred class of compounds according to the invention is that in which:

a) Rj represents a linear or branched alkylsulfinyl radical (C, -

c3);

b) R2 represents a NHR3 radical in which R3 represents a linear or branched alkyl radical (C6-C14), a linear alkyl radical (CrC3) substituted by a carboxyl or carbo-methoxy group in position co.

Examples of compounds according to the invention are: 1- (4-isopropylsulfinylphenyl) -2-n-octylamino-1-propanol 10

] - (4-isopropylthiophenyl) -2- [3- (methoxycarbonyl) propylamino] -1-propanol l- (4-isopropylthiophenyl) -2- [3- (carboxy) propylamino] -l-propanol l- (4-methylthiophenyl ) -2- [3- (methoxycarbonyl) propylamino] -l-

propanol 15

1 - (4-methylthiophenyl) -2- [3- (carboxy) propylamino] -1 -propanol l- (4-isopropylsulfinylphenyl) -2- [3- (methoxycarbonyl) propylamino] -1-propanol l- (4-isopropylsulfinylphenyl) ) -2- [3- (carboxy) propylamino] -l-

propanol 20

1 - (4-isopropy] sulfinylphenyl) -2- [1 - (2-oxopyrrolidinyl)] - l -propanol l- (4-mercaptophenyl) -2-n-octylamino-l-propanol

The derivatives according to formula I can be isolated in the form of organic salts, in particular hydrochlorides or sulphates.

The derivatives of formula I can be transformed, according to usual methods, into salts with acids and, if the derivatives are obtained directly in the form of salts, they can also be transformed into their free base or into salts with other acids.

According to the invention, they are more particularly 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, cy-cloaliphatic, aromatic, araliphatic or heterocyclic, carboxylic or sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic acids,

malic, tartaric, citric, ascorbic, glucuronic, maleic, fu-maric, pyruvic, aspartic, glutamic, benzoic, anthranilic, hydroxybenzoic, salicylic, phenylacetic, mandelic, 4o embonic, methanesulfonic, ethanesulfonic, panthotenic, toluenesulfonic, toluenesulfonic, toluenesulfonic , stearic, alginic, ß-hydroxypropionic, ß-hydroxybutyric, oxalic, malonic, galactaric, galacturonic. These salts can also be derived from natural or unnatural amino acids, such as lysine, glycine, arginine, ornithine, asparagine, glutamine, alanine, valine, threonine, serine, leucine, cysteine, etc.

Most of the products of the invention have two centers of asymmetry. Derivatives where R! represents an alkylsulfinyl radical contain three centers of asymmetry. 50

For the products of the invention having two centers of asymmetry, two racemates can be obtained corresponding respectively to the erythro and threo configurations; these two racemates can be resolved by conventional methods, for example by formation of diastereomeric salts by the action of optically active acids, such as tartaric, diacetyltartaric, tartranilic, diben-zoyltartric, ditoluoyltartaric acids and separation of the mixture of diastereoisomers by crystallization, distillation, chromatography, then release of the optically active bases from these salts.

For the products of the invention having three asymmetry centers, 60 one can obtain eight optical isomers. The same methods can be applied for the resolution of these mixtures.

The most active derivatives of the invention can therefore be used either in the form of mixtures containing several diastereoisomers whatever their relative proportions, or in the form of 65 pairs of enantiomers in equal proportions (racemic mixture) or not , or again in the form of optically pure compounds. Preference is however given to configuration derivatives

erythro at the two asymmetric carbons of the propanol chain.

The invention also relates to processes for the preparation of the above-mentioned derivatives of 1-phenyl-1-propanol and the corresponding salts and esters, as described in claims 10, 13, 15, 17, 20, 22, 24 and 26.

The compounds of formula II:

O "

(ii)

in which Z represents one of the substituents of R, 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 — ch3; —Co —choh — ch3; -co-ch-x;

ch3

-choh — ch — x; I

ch3

/ ° \

—CH —CH — CH3;

—Co — ch — nhr3; I

ch3

-choh-ch-r2,

I

ch.

in which R2 and R3 have the meaning given above and X represents a halogen atom, such as Cl, Br, F, are typical starting compounds.

Advantageously, the derivatives of formula I in which R2 is a hydroxyl group are obtained by reduction of the corresponding ketones of general formulas III and IV:

c0-c0-ch.

r

"L-O-

i-o c0-ch0h-ch.

(ili)

(iv)

in which Rj has the meaning given above.

This reduction can be carried out in the usual way, for example by the action of hydrides such as NaBH4, LiAlH4, LiAl (OAlkyl) 3H, A1H3, (Alkyl) 2AlH, NaB (OCH3) 3H, LiBH3CN, B2H6, (Al-kyl) 3SnH, (Alkyl) 3SiH or NaH, and this in solvents like ether, tetrahydrofuran, ethanol, methanol, diglyme, toluene or sylene, by the action of alkali metals, like sodium or lithium, in solvents like 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.

If the reduction process for ketones of general formulas III and IV is not stereoselective, the erythro / threo mixtures will be separated according to conventional methods (for example by distillation or plate or column chromatography).

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:

at)

Rl "£ 3" CH "NcH" CH3

chqhch ch

U

■ to

„0

b)

o

CO-CH-Br i

CH,

1. nh2 (ch2) 3cooch3

2. Reduction

3. Base (cyclization)

- Rio

CHOHCH-K CH -,

In these diagrams, Rj has the meaning given above.

In reaction a, the condensation of an epoxide 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 ethanol.

This method makes it possible to obtain threo configuration alcohols.

In reaction b, the condensation of a cc-bromoketone with an ester of co-aminobutyric acid will take place in a solvent such as methanol, ethanol, chloroform, acetonitrile, benzene or in a mixture thereof. most advantageously at room temperature.

The reduction can be carried out with alkali metal hydrides and more particularly with NaBH 4, and this in a solvent such as methanol or ethanol at room temperature.

Cyclization to pyrrolidinone can be carried out by the action of an organic or inorganic base, for example an alcoholate or sodium hydroxide or potassium hydroxide, and this in an alcoholic or hydroalcoholic solvent such as methanol, ethanol or isopropanol at a temperature. between room temperature and the reflux temperature of the chosen solvent, but most advantageously at room temperature.

This method makes it possible to obtain alcohols of erythro configuration. 35

The compounds of general formula I in which R2 is a radical of the NHR3 type can be obtained from a compound of general formula V:

R

.O

(Y) 40

or optionally, depending on the value of Q, from a salt of a compound corresponding to this formula, in which Rj has the meaning given above and Q represents one of the following groups:

/ 0 \

-CH-CH-

CH,

-CHOHCH — X

I

CH,

-COCH-nhr3

I

CH,

-COCH-X I

CH,

In these groups, R3 has the meaning given above, while X represents a halogen atom.

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

Mode A.

In a first way, an α-aminoketone corresponding to formula V is reduced in which Q represents a ch group,

having the meaning given previously.

644,355

This reduction can be carried out in the usual way, most easily for example by the action of alkali metal hydrides such as sodium borohydride, in a solvent, such as methanol or ethanol, preferably at low temperature, or d aluminum or lithium hydride in a solvent such as diethyl ether or tetrahydrofuran, or by the action of an aluminum alcoholate, such as aluminum isopropylate, and this in a solvent such as isopropanol , most advantageously at the 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 configurations: erythro and threo. The choice of the starting aminoketone and the reduction conditions makes it possible to obtain one or the other of these two forms in a stereo-selective manner. So reducing an aminoketone where

Q = CO-CH-NHR3 I

ch3

leads, in the general conditions described above, to a friend-noalcool of erythro configuration.

To obtain a compound of threo conformation, the reduction is carried out on an aminoketone where

Q = CO-CH-NR3R4

I

ch3

wherein R3 has the value indicated above and R4 is a protective group which can be eliminated by hydrolysis or hydrogenolysis, such as the benzyl, trityl, acetyl, formyl, benzhydryl groups; 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 R3NH2 or R3R4NH on an α-halogen ketone in solvents such as ether, benzene, chloroform, dioxane, methanol, isopropanol or acetonitrile.

Mode B.

According to this mode of preparation, a compound of the general formula V is reacted, in which Q represents a group

—CHOH — CH — X,

I

ch3

with an amine R3NH2, formulas in which R3 and X have the si-50 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 else in 55 presence of an excess of amine. It is well known that in these cases the group

- CHOH — CH — X I

CH3

60 s first gives an oxirane of type a

-CH3,

45

/ \

-CH-CH-C

which reacts with the amino compound.

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

644,355

6

The compounds of general formula I in which Rt is a mercapto radical can be obtained from compounds of general formula VI:

in which R2 has the value indicated above and Y is a protective group replaceable by hydrogen according to methods well known in the literature, for example an alkyl group such as isopropyl, benzyl or substituted benzyl, eliminable 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 substituted diphenylmethyl group or not, eliminable by the action of acids, such as trifluoroacetic acid or hydrobromic acid, a substituted or unsubstituted triphenylmethyl group, eliminable by the action of acids like hydrochloric acid or hydrobromic acid or agents such as HgCl2, AgN03 or Hg (OAc) 2, a benzylthiomethyl group removable by the action of oxidizing agents such as HgCl2 or Hg (OAc) 2, an acetamidomethyl group removable for example by salts of mercury, a eliminated carboxymethyl group able by oxidizing agents in an acid medium or a tetrahydropyrannyl or tetrahydrofuranyl group which can be eliminated by oxidizing agents such as AgN03.12, SO2C12, (SCN) 2-Zn or acids.

The compounds of general formula I, in which Rx is an alkylsulfinyl or alkylsulfonyl radical, can be obtained starting from the compounds of general formula I in which Rj is an alkylthio radical, and this by oxidation according to methods well documented in the literature. This oxidation can be carried out at any stage of the synthesis of the products of the invention.

To obtain sulfoxides, it is thus possible to use oxidizing agents such as iodine, bromine in water or in the presence of acetate ions or in complex with pyridine, peracids such as peracetic or monoperphthalic acids. or m-chlolroper-benzoic, N-halosuccinimides such as N-bromosuccinimide, hypochlorites such as sodium, t-butyl or i-propyl hypochlorite, periodates such as sodium periodate, hydrogen peroxide in the presence of acetic anhydride or in the presence of vanadium hemipen-oxides in t-butanol, nitrates, such as acetyl nitrate or ammonium and cerium nitrate, oxides such as chromium oxide ( VI) in pyridine or vanadium hemipentoxide in the presence of oxygen or nitrogen emipentoxide, peroxides, ozone, oxygen, in singlet or triplet state, acids such as nitric acid, chromic acid or Caro acid, or other agents such as sulfuryl chloride, 1-chlorobenzotriazo , chloramine, N-chloronylon 66, iodobenzene dichloride, iodosobenzene, iodobenzene diacetate, N-chlorotriazole, 2,4,4,6-tetrabromocyclohexadienone or chloroauric acid ( HAuCl4). These oxidation reactions will be carried out in solvents, for example water, acetic acid, chloroform, dichloromethane, carbon tetrachloride, methanol, t-butanol or acetone.

To obtain sulfones, agents such as hydrogen peroxide are preferably used, preferably in the presence of zirconium salts, peracids such as peracetic, monoperphthalic and m-chloroperbenzoic acids (in the case of peracid oxidation , advantageously use catalysts based on transition metals), potassium permanganate in acid or basic medium, sodium or potassium dichromate, osmium tetroxide, selenium oxide, hypochlorite of t-butyl, nitric acid, ozone, oxygen, advantageously in the presence of iridium or rhodium salts, iodobenzene dichloride, periodic acid or by electrochemical oxidation. These reactions will be carried out in solvents such as water, acetic acid, chloroform, dichloromethane, methanol, ethanol, isopropanol, t-butanol, dioxane or acetone.

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

Below are given detailed examples of the preparation of some 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 1:

1- (4-isopropylsulfinylphenyl) -2-n-octylaminopropanol.

(Table, No. 6)

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 MgSO4, 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, 8.4 g of product are obtained.

Yid: 60%; Mp (° C): 167-169 (melting point).

Centesimal analysis:

Calculated: C 61.59 H 9.30 N3.59%

Found: C 61.28 H 9.05 N 3.45%

Example 2:

1- (4-Isopropylthiophenyl) -2- [1- (2-oxopyrrolidinyl)] -1-propanol. (Table, N ° 7)

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

To a solution containing 28.5 g of 2-bromo-1- (4-isopropylthio-phenyl) -l-propanone, 350 ml of ethanol and 125 ml of ethoxyethanol, is added little by little, at -25 ° C. and with stirring, 3.83 g of NaBH4 in 25 ml of water. After addition, the mixture is allowed to gradually return to room temperature and the stirring is continued for 1 hour. Then 3.8 g of KOH in 40 ml of water are added dropwise and the mixture is stirred for 30 min. 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; Yid: 65%; Bp: 81-84 ° C (0.7 mm); the NMR spectrum conforms to the structure of 2-methyl-3- (4-isopropylthio-phenyl) oxirane.

b) 1- (4-Isopropylthiophenyl) -2- [1- (2-oxopyrrolidinyl) J-1- 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 adding ether of oil. The solid is filtered, washed with a minimum of petroleum, 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 (threo configuration).

Centesimal analysis:

Calculated: C 65.49 H 7.90 N 4.77%

Found: C 65.45 H 7.80 N 4.70%

5

10

15

20

25

30

35

40

45

50

55

60

65

7

644,355

Example 3:

l- (4-Isopropylsulfonylphenyl) -2- [l- (2-oxopyrrolidinylj] -l-propanol. (Table, No. 9)

A solution containing 2.93 g of 1- (4-isopropylthiophenyl) -2- [1- (2-oxopyrrolidinyl)] - 1-propanol, 6.5 ml of acetic acid and 6.5 ml of H2O2 at 30 % is gradually heated to 85-90 ° C and maintained for 2 hours at this temperature. After cooling, a solution of 6 g of Na2S2Os 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 MgSO4, 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. PF ("C): 170.5.

Centesimal analysis:

Calculated: C 59.05 H 7.12 N 4.30%

Found: C 58.95 H 7.15 N 4.10%

The NMR spectrum confirms the threo configuration.

Example 4:

l- (4-Isopropylthiophenyl) -2- [3- (carbomethoxy jpropylamino J-I-

propanol.

(Table, N ° 13)

17 g of 2-bromo-1- (4-isopropylthiophenyl) -l-propanone, 200 ml of methanol, 17.3 ml of triethylamine and 10 g of methyl co-aminobutyrate (hydrochloride) are brought to reflux for 17 h .

The solution is then cooled to a temperature of 5 ° C. and 4.5 g of NaBH4 is added little by little. The reaction medium is then stirred overnight at room temperature. After eva-poration 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 provides, after preparation of the hydrochloride in a diethyl ether / meth-anol 50/50 mixture, 12.4 g of product.

YId: 58%; Mp (° C): 175.6.

The conformity of the structure was checked by mass spectrometry.

Centesimal analysis:

Calculated: C 56.41 H 7.79 N 3.87%

Found: C 56.10 H 7.65 N 3.75%

The NMR spectrum confirms the erythro configuration.

Example 5:

1- (4-Isopropylthiophenyl) -2- [3- (carboxy) propylamino] -1-propanol. (Table, No 23)

Dissolve in 70 ml of water 7 g of 1- (4-isopropylthiophenyl) -2- [3- (methoxycarbonyl) propylamino] -l-propanol and add 7 ml of concentrated hydrochloric acid. Heat at 80 ° C for 1 h. Leave to cool, remove the solvent under vacuum, then crystallize from a methanol / ether mixture.

Weight: 4.5 g; YId: 68%; Mp (° C): 197.5.

Centesimal analysis:

Calculated: C 55.24 H 7.53 N 4.03%

Found: C 55.35 H 7.50 N 3.80%

Example 6:

J- (4-Isopropylthiophenyl) -2- [l- (2-oxopyrrolidinyl)] -l-propanol

(erythro).

(Table, No. 24)

Dissolve 6 g of 1- (4-isopropylthiophenyl) -2- [3- (carboxy) -propylamino] -l-propanol in a mixture containing 100 ml of methanol and 50 ml of water. Bring the pH to 13 by adding a 10N solution of sodium hydroxide. Shake for 1 hour at room temperature,

evaporate the methanol, extract with chloroform, dry the organic phase over MgSO4 and evaporate the solvent. The product solidifies in petroleum ether, it is recrystallized from ether. 1.3 g of product are collected, ie a yield of 27%. PF (° C): 80.

5 The conformity of the structure is established by NMR and by mass spectrometry (erythro configuration).

Centesimal analysis: Calculated: C 65.49 io Found: C 65.15

H 7.90 N 4.77% H 7.70 N 4.75%

Example 7:

1- (4-Isopropylthiophenyl) -1,2-propanediol.

(Table, No. 18)

Dissolve 170 g of 1- (4-isopropylthiophenyl) -2-hydroxy-1-propanone in 1500 ml of methanol. Cool to 0 ° C, gradually add 57.4 g of sodium borohydride and stir overnight at room temperature. Evaporate the solvent, dilute with water, extract with chloroform and dry over MgS04. After evaporation of the solvent, re-crystallize from a benzene / hexane mixture.

Weight: 66.8 g; Yid: 39%; PF (° C): 83-85.

The NMR spectrum confirms the erythro configuration of the product obtained.

25 Centesimal analysis:

Calculated: C 63.68 H 8.01%

Found: C 63.50 H 8.05%

Example 8:

1- (4-Mercaptophenyl) -2-n-octylamino-1-propanol.

(Table, N ° 40)

A solution containing 5.25 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-octylamino. -1-propanol in 500 ml of tetrahydrofuran. After addition, the mixture is still stirred for approximately 15 min, then 16 g of NH4Cl 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 the

40 r methanol.

12 g of 1- (4-mercaptophenyl) -2-n-octylamino-1-propanol are thus obtained.

YId: 82.1%; Mp (° C): 110-112.

45 Centesimal analysis:

Calculated: C 69.10 H 9.90 N 4.74%

Found: C 69.40 H 10.10 N4.60%

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

Specific esters are those corresponding to the formulas:

CH3 ÇH3

^ CH-S0- ^ y-C H - C H - N H n C n H. "cHo '

'8 17

. HCl

0C-CH? -C (CH,) o

It ^ o i

0

PF (° C): 112-114

60CH3 CH3

^ C H - S 0 -V y- CH-CH-NHnCQH.

CH. W!

65 0-C-CH,

to J

0

PF (° C): 148.5-150

'8 17

.HCl

644 355 8

The melting points of the derivatives given in the examples as well as other derivatives prepared according to the invention are listed in the table.

Board

R1- ^ r \ _ CH0HCH-R2 W CH3

No.

ri r2

PF (° C) 12 (melting point)

1

2

3

4

5

6

iso-C3H7S02 HS

iso-C3H7S02 HS

iso-C3H7S02 iso-C3H7SO

nh2 OH OH NH2 NHnC8H17 NHnC8H17

251-252 (MeOH / acetone) 3 4

75-78 (C6H6) 4

oil6

209-211 (MeOH / ether) 3 4 68-69 (petroleum ether) 4 167-169 (MeOH / ether) 3 4

7

iso-C3H7S

9

115-116 (ether) 5

8

iso-C3H7SO

0

0

146-148 (acetone) 5

9

iso-C3H7S02

NP

0

170.5 (MeOH / ether) 5

10

H

NP

0

107.2 (CsHfi / petroleum ether) 5

11

ch3s

O

0

121.2 (CHCl3 / petroleum ether) 5

12

ch3so2

NP

158-159 (MeOH / ether) 5

13

14

15

16

17

18

19

20

21

22

23

iso-C3H7S

ch3s iso-C3H7SO iso-C3H7S iso-C3H7S iso-C3H7S iso-C3H7SO iso-C3H7S02 iso-C3H7S02 CH3S iso-C3H7S

0

NH (CH2) 3COOCH3 NH (CH2) 3COOCH3

nh2 nhch2cooh nhch2cooch3 oh

OH

NH (CH2) 2COOCH3 NH (CH2) 2COOH NH (CH2) 2COOH NH (CH2) 3COOH

Np

0

175.6 (MeOH) 3 4 168-169 (MeOH) 3 4 190-191 (MeOH / acetone) 34 161-163 (MeOH / ether) 3 4 171 (MeOH / ether) 34 83-85 (C6H6 / hexane) 4 oil 4 5

182.8 (MeOH / ether) 3 4 190-192 (MeOH / ether) 3 4 190.5-191 (MeOH) 34 197.5 (MeOH / ether) 3 4

24

iso-C3H7S

80 (ether) 4

25

H

0

121-122 (hexane) 4

26

iso-C3H7S02

NP

0

175 (MeOH / ether) 4

9,644,355

Table (continued)

n °

ri r2

PF (° C) 12 (melting point)

27

iso-C3H7SO

NP

0

114-115 (ether) 4

28

ch3so2

0

0

159-160 (MeOH / ether) 4

29

ch3s

NP

0

90-92 (MeOH / ether) 4

30

31

iso-C3H, SO iso-C3H7SO

NH (CH2) 3COOCH3

nhch2cooch3

152-154 (MeOH / ether) 3 4 85-86 (MeOH) 3 4

32

c2h5s

NP

0

104.9 (C6H6 / ether) 5

33

C2HsSO

Np

0

121.2 (acetone) 5

34

35

iso-C3H7SO iso-C3H7SO

NH (CH2) 3COOH NHnC14H29

197-198 (MeOH) 34 143-146 34

36

iso-C3H7SO

nh (ch2) 4 ^)

167-168 34

37

iso-C3H7SO

nh (ck2) 20- @

143-144 3 4

38

CH3SO

NH (CH2) 3COOCH3

169-170 (acetone) 3 4

39

iso-C3H7SO

NHCH —nC6HI3 1

ch3

139-141 (acetone) 34

40

41

42

43

44

HS iso-C3H7S iso-C3H7SO iso-C3H7S iso-C3H7SO

NHnC8H17 NH (CH2) 5COOCH3 NH (CH2) 5COOCH3 NH (CH2) 5COOH NH (CH2) sCOOH

110-112 (MeOH) 4 199-201 (MeOH / ether) 34 160 (MeOH / ether) 3 4 175-177 (MeOH) 3 4 175 (MeOH / acetone) 34

45

iso-C3H7S02

^ oh?

NH (CH2) 2COOC2H5

nh2

oil

46

47

iso-C3H7S02 iso-C3H7S

165-167 (EtOH / ether) 34 97-98 (ether / petroleum ether) 4

1 The recrystallization solvent is given in parentheses.

2 The elementary analyzes were carried out for the elements C, H, N and conform to the theoretical values.

3 Melting point of the hydrochloride.

4 Erythro configuration.

5 Threo configuration.

6 Erythro / threo mixture.

The compounds according to the invention, while being not very toxic, in particular antispasmodic, antihypertensive, vaso-

are generally endowed with activities on the cardiovascular system, peripheral dilator, protective against myocardial anoxia,

644,355

10

lipid-lowering, normolipoproteinemiant, antithrombic, inhibiting platelet aggregation; they can therefore be useful in particular for the treatment of cardiovascular conditions, linked or not to atherosclerosis. In addition, they could prove useful also as stimulating agents of the cerebral metabolism or as tranquilizers.

The effect on behavior is studied using a method derived from that of S. Irwin ("Görden Res. Conf. On Médicinal Chem.", 133, 1959). The substances, suspended in a mucilage containing 1% of tragacanth, are administered orally by means of an intragastric probe to groups of 5 male mice (strain CD1, Charles River, fasting for 18 h). If the quantity of substance available allows, the doses are 3000, 1000 and 300 mg / kg. In the case where the latter is active, the effect of the drug is examined at 100, 30.10 and possibly 3 mg / kg. Behavior is studied 2, 4, 6 and 24 hours after treatment. Observation is extended if symptoms persist at this time. Mortalities are recorded during the 14 days following treatment. The DLS0 are calculated according to the method of Litchfield and Wilcoxon ("J. Pharmacol. Exp. Ther.", 96, 99.1949) and expressed in milligrams per kilo.

The results presented with regard to the effects on behavior indicate the minimum active dose (AMD), in milligrams per kilo, and the symptomatology observed.

The DLS0 are given with their confidence limits (P = 0.95).

Under these conditions, an appreciable level of activity was observed, in particular with regard to compounds 6, 13 and 20.

Antihypertensive 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 medial coccygeal artery by a plethysmographic method (J. Roba, G. Lambelin, AF de Schaepdryver, "Arch. int. Pharmacodyn.", 200,182,1972). The blood pressure is measured every 30 min, from 2 h before to 3 h after the oral administration of the products tested at 60 mg / kg or of a placebo (mucilage with 1% of gum tragacanth).

Only rats with a systolic pressure of 180 to 220 mmHg are used. Two rats are used per product. The treatments are administered without the knowledge of the person taking the measurements. Antihypertensive effects are noted by a score followed by an index. The scoring system is as follows:

0: reduction of <10 mmHg

+: reduction from 10 to 20 mmHg

+ +: reduction from 20 to 30 mmHg

+ + +: reduction from 30 to 50 mmHg

+ + + 4-: reduction of> 50 mmHg

The index is calculated by multiplying the difference in systolic pressure (cmHg) measured every 30 min after treatment, by a coefficient of 1 to 6 corresponding to the times of 30 to 180 min.

Under the conditions of the test, a-methyldopa is scored +++ (47) at 100 mg / kg, reserpine +++ (53) at 3 mg / kg and guanethidine +++ (62) at 60 mg / kg.

In these tests, an interesting antihypertensive activity is presented in particular by products 6 and 7.

The peripheral vasodilator activity of the products 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. The perfusion pressure, measured at the level of the femoral artery, therefore varies according to the resistance of the perfused territory. The tested products and the corresponding solvents are injected directly into the circuit, at a dose of 30 ng / kg. The blood flow being kept constant, a vasodilation is therefore measured by a decrease in the perfusion pressure. This is scored in relation to the action of papaverine, considered as a reference and injected once per group of four products. In case of interest, the products are tested at other doses under the same conditions. The vasodilator activity is assessed as follows:

0: inactive <10 mmHg reduction

+:] / 3 of papaverine activity

+ +: y3de activity of papaverine

+ + 4-: activity equal to that of papaverine + + + +: activity greater than that of papaverine

Among the products of the invention, a peripheral vasodilator activity greater than or equal to that of papaverine is observed in particular for compounds 5, 6 and 20.

The antispasmodic activity of the substances studied was examined against the contractions of the guinea pig ileum induced by histamine and acetylcholine. These experiments make it possible to demonstrate an antihistamine, anticholinergic or muscu-lotropic activity. The response to the contracting agent (submaximal concentration) is obtained every 5 min before and after injection of the increasing concentrations of the products tested (10 ~ 7 to 10_4M). The percentage of inhibition is calculated under the influence of the products tested and the theoretical concentration producing 50% inhibition is determined graphically for each experiment.

These values are expressed in - logCIS0 (M).

In this test, in particular compounds 5 and 6 were found to be active.

The inhibition of platelet aggregation was studied by the turbidimetric method described by G.V.R. Born and M.J. Cross ("J. Physiol.", 168,178-195, 1973).

The platelet-rich plasma is preincubated for 4 min before the introduction of the inducer (Thrombofax). Slight variations are recorded over a period of 10 min with an Upchurch aggregometer. The inhibition of the amplitudes of the maximum aggregation is measured. This test showed that in particular the compounds 5, 6, 13 and 14 were found to be active.

For the examination of the inhibition of lipolysis, epididymary fat is removed from fasted rats.

Fragments of adipose tissue (+150 mg) are incubated in the Krebs-Ringer buffer containing 3% of bovine serum albumin and the substance to be studied. A sample at time zero is taken after an incubation of 30 min at 37 ° C. Norepinephrine is used to induce lipolysis. The level of free amino acids is measured after 20 min of incubation (Duncombe, W.G., "Clin. Chim. Acta", 8,122,1964).

In this test, in particular compounds 5, 6, 8 and 13 were found to be active.

The inhibition of cholesterol biosynthesis has been studied as follows:

Buffered rat liver homogenates are enriched with appropriate co-factors. Aliquots are incubated for 60 min with l-14C-acetate and the compound to be studied.

After saponification of the medium, the sterols are extracted with petroleum ether and the dry residue is precipitated with digitonin in an alcohol / acetone solution. The 14C content of the precipitate dissolved in pyridine is measured by liquid scintillation counting according to the method described by N. Bucher ("J. Biol. Chem.", 222, 1-15,1956).

Under these conditions, an appreciable level of activity has been shown in particular in compounds 1, 13 and 15.

The inhibition of bioamines uptake by synaptosomes is studied by isolating synaptosomes from rat brains after partial subcellular fractionation in a sucrose gradient (Gray R.G. and Whittaker V.P., "J. Anat.", 92,79,1962). The capture of 5-HT (serotonin) is done as follows:

After incubation for 5 min of the drug tested with synaptosomes, the preparation is incubated for 5 min at 37 ° C. in the presence of 14C-5HT, filtered on a Millipore filter and the filters are washed with ice-cold buffer. The radioactivity of the filters is measured by counting by liquid scintillation. The uptake is the difference between the radioactivity measured at 37 ° C and that measured at 0 ° C. In this test, in particular compounds 5, 6, 13 and 14 were found to be active.

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

5

10

15

20

25

30

35

40

45

50

55

60

65

11

644,355

For oral administration, dragees, granules, tablets, capsules, tablets and capsules with controlled release of the active ingredient, sublingual tablets, solutions, syrups, emulsions 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 examples which follow are not limiting and relate to galenical formulations containing as active product, hereinafter designated by the reference A, one of the following compounds: l- (4-isopropylsulfinylphenyl) -2- [l- (2-oxopyrrolidinyl) ] -l-propanol l- (4-isopropylsulfinylphenyl) -2-n-octylamino-l-propanol

Intramuscular injection

Isopropyl myristate Peanut oil qs.ad

Intravenous injection A

L-aspartic acid Benzyl alcohol Distilled water qs.ad Solution for oral administration A

Ethyl alcohol

Propylene glycol

Acetic acid 10%

Simple syrup (65% sucrose) qs.ad

AT

Ethyl alcohol Acetic acid 10%

Simple syrup qs.ad Tablets

10 mg 0.75 ml 3 ml

10 mg 6 mg 50 mg 5 ml

5 mg 0.1 ml 0.05 ml 0.05 ml 1 ml

5 mg 0.2 ml 0.04 ml lml

AT

50 mg

Lactose

20 mg

Aerosil

2 mg

STA-RX 1500® starch

18 mg

Calcium phosphate (CaHP04)

25 mg

Microcrystalline cellulose

100 mg

Sodium acetate

15 mg

AT

50 mg

Corn starch

50 mg

Sodium acetate

15 mg

Magnesium stearate

2 mg

Aerosil *

3 mg

STA-RX 1500® starch

80 mg

Soluble starch Sodium saccharin Gelatin A

Lactose Sucrose Glycine

Stearic acid

Capsules A

Starch STA-RX 1500 "Magnesium stearate Sodium lauryl sulfate 15 Microcrystalline cellulose Aerosil *

Soft capsules A

20 Liquid paraffin Soy lecithin

Controlled release capsules A

2S Lactose

Polyvinylpyrrolidone Mannitol Eudragit E®

Suppositories A

Lidocaine Novata 299 grad.®

AT

35 Witepsol S 58 grad. ®

10 mg 0.25 mg 3 mg

25 mg 150 mg 25 mg 2.5 mg 0.5 mg

50 mg 100 mg 1 mg 10 mg 30 mg 1 mg

220 mg 222 mg 8 mg

50 mg 45 mg 15 mg 5 mg 1 mg

100 mg 20 mg 2000 mg

100 mg 2000 mg

Sublingual tablets A

Lactose

25 mg 117.75 mg

The meanings of certain terms used in the above galenical formulas are explained below:

- Aérosil®: trade name for finely divided silicon dioxide.

- STA-RX 1500® starch: corn starch.

- Lidocaine: trade name for lignocaine.

- Novata 299 grad. *: Mixture of triglycerides of saturated fatty acids from Cn to C17 with partial glycerides of acetylated fatty acids.

- Novata B grad.®: mixture of tri-, di- and monoglycerides of saturated fatty acids from Cn to C17.

- Witepsol S 58 grad.®: mixture of natural triglycerides from C12 to Cl8-

- Eudragit E® (Röhm): polymer of the dimethylaminoethyl ester of acrylic acid.

Depending on the case, the route of administration, the nature of the activity sought and that of the specific compound used, the 1-phen-yl-1-propanol derivatives according to the invention are administered at daily doses of 5 to 3000 mg and, by intravenous injection, the 1-phenyl-1-propanol derivatives according to the invention are administered in daily doses of 1 to 20 mg.

R

Claims (30)

644,355 CLAIMS 1 - (4-methylthiophenyl) -2- [3- (carboxy) propylamino] -1 -propanol l- (4-isopropylsulfinylphenyl) -2- [3- (methoxycarbonyl) propylamino] -1-propanol l- (4-isopropylsulfinylphenyl) ) -2- [3- (carboxy) propylamino] -l-propanol l- (4-isopropylsulfinylphenyl) -2- [l- (2-oxopyrrolidinyl)] - l-propanol l- (4-mercaptophenyl) -2-n -octylamino-l-propanol 1. 1-Phenyl-1-propanol derivative of general formula (I): ri- <q-chohçh-r2 (i) chj in which: a) Rj represents hydrogen, a linear or branched alkylthio radical (C, -C3), a linear or branched alkylsulfinyl radical (Q-C-,), a linear or branched alkylsulfonyl radical (Ci-C3) or a mercapto radical; b) R2 represents: b-1) a hydroxyl radical; b-2) an oxo-2-pyrrolidinyl-1 radical or an oxo-2-pyrroli- radical 1-dinyl substituted with a hydroxyl group; b-3) an NHR3 radical in which R3 represents: - hydrogen; - a linear or branched alkyl radical (C6-C16) or a linear alkyl radical (C2-C4) substituted by a phenyl or phenoxy group, as far as R, does not represent an alkylthio radical; - a linear or branched radical (Cl-C-I) substituted by a carboxyl or lower carbalkoxy group (Cj-Cy in position Cû, as well as the non-toxic and pharmaceutically usable salts and esters of this derivative. 2 2. Derivative according to claim 1, characterized in that R3 represents a linear or branched alkyl radical (C10-C16). 3 644,355 characterized in that a condensation is carried out on a derivative corresponding to formula (II) in which Z has the meaning given in claim 13 and Q represents the group co-ch-x I ch3 wherein X represents a halogen atom on a co-aminoalkanoic acid or on an ester thereof, followed by reduction. 3. Derivative according to claim 1, characterized in that R3 represents a linear or branched alkyl radical (C6-C10). 4. Derivative according to claim 3, characterized in that R3 represents a linear or branched octyl radical. 5 5. Derivative according to one of claims 1 to 4, characterized in that, in formula (I), Rt represents a linear or branched alkylthio radical (Q-Q). 6. Derivative according to one of claims 1 to 5, characterized in that, in the general formula (I), Rj represents a linear or branched alkylsulfinyl radical (Cj-C3). 7. Derivative according to one of claims 1 to 6, characterized in that, in formula (I), R2 represents an NHR3 radical in which R3 is a linear or branched alkyl radical (Cj-Q) substituted by a carboxyl group or carbomethyl in position <d. 8. Derivatives according to one of claims 1 to 6, characterized in that they are chosen from the group formed by the following compounds: l- (4-isopropylsulfinylphenyl) -2-n-octylamino-l-propanol l- (4-isopropylthiophenyl) -2- [3- (methoxycarbonyl) propylamino] -1-propanol l- (4-isopropylthiophenyl) -2- [ 3- (carboxy) propylamino] -1-propanol 1- (4-methylthiophenyl) -2- [3- (methoxycarbonyl) propylamino] -1-propanol 9. Derivative according to one of claims 1 to 8, characterized in that it has the erythro configuration at the two asymmetric carbons of the propanol chain. 10/0 R1- ^ ~ ^ -CH-CH-CH3 10 10. Process for the preparation of derivatives of formula (I) in which Ra has the meaning given in claim 1 and R2 is a hydroxyl radical, characterized in that these corresponding ketones of general formulas (III) and (IV) are reduced ): in which Rj has the meaning given above with the meaning - SH, this group being protected intermediately. 11. Method according to claim 10, characterized in that the abovementioned reduction is carried out by the action of metal hydrides or by the action of complex metal hydrides, and this in aromatic solvents or ethers or alcohols, 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 like ethanol, or by the action of aluminum alcoholates like aluminum isopropylate in a solvent like isopro-panol. 12. Method according to one of claims 10 or 11, characterized in that the derivatives of erythro or threo configuration are separated, in particular by distillation or plate or column chromatography, from erythro-threo mixtures of these derivatives. 13. Process for the preparation of derivatives of formula (I) in which Rj has the meaning given in claim 1 and R2 is an oxo-2-pyrrolidinyl-l radical optionally substituted by a hydroxyl group, characterized in that one carries out the condensation of a compound corresponding to formula (II): in which Z represents one of the substituents of Ri defined above or corresponds to a group YS in which Y is a protective group replaceable by hydrogen, and Q represents the group -ch-ch-ch3 with 2-pyrrolidone and, in the case where Z has the meaning YS, the protective group is removed. 14. The method of claim 11, characterized in that a solvent is used, for example methanol or ethanol, optionally using an excess of 2-pyrrolidinone. 15 with an amine R3NH2, wherein R3 has the meaning given in claim 1. 15 15. Process for the preparation of derivatives of formula (I) in which R2 is an oxo-2-pyrrolidinyl-1 radical optionally substituted by a hydroxyl group, characterized in that the hydrolysis is carried out in basic medium of a compound of formula: ^ - ^ "^ - CHOH-CH-NHtCHj) jCOORJ ch3 wherein Rt has the meaning given in claim 1 and R5 represents an alkyl group, in particular a lower alkyl (Cr C3). 16. The method of claim 15, characterized in that the hydrolysis is carried out by the action of an organic or inorganic base, for example an alcoholate or soda or potash and that in an alcoholic or hydroalcoholic solvent such as methanol , ethanol or isopropanol, at a temperature between room temperature and the reflux temperature of the chosen solvent, but most advantageously at room temperature. 17. A process for the preparation of derivatives of general formula (I) in which R 1 has the meaning given in claim 1 and R 2 represents an NHR 3 radical where R 3 represents an alkyl radical substituted by a carboxyl or carbomethoxy group in the c position, 18. The method of claim 17, characterized in that the condensation is carried out in a solvent such as methanol, ethanol, chloroform, acetonitrile, benzene or in a mixture of these, and this most advantageously at room temperature. 19. The method of claim 17, characterized in that the reduction is carried out with alkali metal hydrides and more particularly with NaBH4, and this in a solvent such as methanol or ethanol at room temperature. 20 in the presence of an excess of amine. 20. Process for the preparation of a 1-phenyl-1-propanol derivative of general formula (I), in which Rj has the meaning given in claim 1 and R2 represents an NHR3 radical, as defined in claim 1, of erythro configuration, characterized in that an α-aminoketone corresponding to the formula is reduced: nhr. ch. wherein R: and R3 have the meanings given in claim 1. 20 21. Method according to claim 20, 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 aluminum isopropylate, and this in a solvent such as l isopropanol, most advantageously at reflux thereof or 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. 22. Process for the preparation of a derivative of formula (I) threo configuration, in which Rj has the meaning given in claim 1 and R2 signifies NHR3, characterized in that an aminoketone of formula is reduced: R1- ^ y-CO-ÇH-MR3R4 in3 wherein Rt and R3 have the meanings given in claim 1 and R4 is a group which can be removed by hydrolysis or hydrogenolysis. 23. The method of claim 22, characterized in that the reduction is carried out by the action of hydrides of alkali metals, such as sodium borohydride, or aluminum hydride and lithium. 24. Process for the preparation of a derivative of formula (I) in which Rj has the meaning given in claim 1 and R2 signifies NHR3, characterized in that a compound of formula is reacted: Rj ^ - ^ y-CHOH-ÇH-X cb3 in which R! has the meaning given in claim 1 and X represents a halogen atom with an amine R3NH2, in which R3 has the meaning given in claim 1. 25 alkylthio and in which the functions sensitive to the oxidizing agent used may have been protected intermediate. 25. The method of claim 24, characterized in that the 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, like s mineral or organic bases, or still in the presence of an excess of amine. 25 30 35 40 45 50 55 60 65 26. Process for the preparation of a derivative of formula (I) in which R [and R2 have the meanings given in claim 24, characterized in that an oxirane of formula is reacted: 27. The method of claim 26, characterized in that the reaction is carried out in a solvent such as alcohols, chloroform, dioxane, carbon tetrachloride, and most easily 28. Process for the preparation of derivatives corresponding to formula (I) in which Rj represents an alkylsulfinyl or alkylsulfon-yl radical, characterized in that a compound of the formula is subjected to the action of an oxidizing agent I) in which Rj represents a radical 29. Pharmaceutical composition comprising, as active product, at least one of the derivatives according to one of claims 1 to 9 combined with at least one excipient. 30. The pharmaceutical composition of claim 29, comprising at least one other therapeutic agent.