CA1127164A - Derivatives of 1-phenyl-1-propanol - Google Patents
Derivatives of 1-phenyl-1-propanolInfo
- Publication number
- CA1127164A CA1127164A CA331,500A CA331500A CA1127164A CA 1127164 A CA1127164 A CA 1127164A CA 331500 A CA331500 A CA 331500A CA 1127164 A CA1127164 A CA 1127164A
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- Prior art keywords
- radical
- group
- propanol
- ramified
- linear
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/19—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/34—Compounds containing oxirane rings with hydrocarbon radicals, substituted by sulphur, selenium or tellurium atoms
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- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT
A derivative of 1-phenyl-1-propanol of the general formula I :
(I) wherein :
(a) R1 represents hydrogen, an linear or ramified alkylthio (c1-C3), linear or ramified alkylsulfinyl (C1-C3), li-near or ramified alkylsulfonyl (C1-C3) or mercapto ra-dical ;
(b) R2 represents :
b-1 a hydroxy radical ;
b-2 an oxo-2-pyrrolidinyl-1 radical which may bc subs-tituted by a hydroxy group ;
b-3 a NHR3 radical wherein R3 represents :
- hydrogen - a linear or ramified alkyl (C6-C16) radical or a linear alkyl (C2-C4) radical substituted by a phe-nyl or phenoxy group, with the proviso that R1 is not an alkylthio radical - a linear or ramified alkyl (C1-C7) radical substi-tuted by a lower carboxy or carbalkoxy (C1-C3) group in the position ;
as well as non toxic and pharmaceutically acceptable salts and esters of these derivatives.
A derivative of 1-phenyl-1-propanol of the general formula I :
(I) wherein :
(a) R1 represents hydrogen, an linear or ramified alkylthio (c1-C3), linear or ramified alkylsulfinyl (C1-C3), li-near or ramified alkylsulfonyl (C1-C3) or mercapto ra-dical ;
(b) R2 represents :
b-1 a hydroxy radical ;
b-2 an oxo-2-pyrrolidinyl-1 radical which may bc subs-tituted by a hydroxy group ;
b-3 a NHR3 radical wherein R3 represents :
- hydrogen - a linear or ramified alkyl (C6-C16) radical or a linear alkyl (C2-C4) radical substituted by a phe-nyl or phenoxy group, with the proviso that R1 is not an alkylthio radical - a linear or ramified alkyl (C1-C7) radical substi-tuted by a lower carboxy or carbalkoxy (C1-C3) group in the position ;
as well as non toxic and pharmaceutically acceptable salts and esters of these derivatives.
Description
llZ7:164 This invention relates to derivatives of l-phenyl-l-propanol of the general formula I
R 1 ~ C H O I I C ~1 - R 2 - ( I ) wherein :
(a) Rl represents hydrogen, a linear or ramified alkylthio (Cl-C3), linear or ramified alkylsulfinyl (Cl-C3), li-near or ramified alkylsulfonyl (Cl-C3) or mercapto radi-cal ;
(b) R2 represents :
b-l a hydroxy radical ;
b-2 an oxo-2-pyrrolidinyl-1 radical which may be subs- tituted by a hydroxy group ;
b-3 a NHR3 radical wherein R3 represents :
- hydrogen - a linear or ramified alkyl (C6-C16) radical or a linear alkyl (C2-C4) radical substituted by a phe-~: nyl or phenoxy group, with the proviso that Rl is not an alkylthio radical - a linear or ramified alkyl (Cl-C7) radical substi-tuted by a lower carboxy or carbalkoxy (Cl-C
. group in the position ~ ;
as well as non toxic apd pharmaceutically acceptable salts and esters of these derivatives.
A preferred class of compounds according to the invention comprises derivatives of formule I wherein :
(a) Rl represents a linear or ramified alkylthio (Cl-C3) ra-, .:
, ~ . . .
, -, llZ7~64 dical (b) R2 representts a NHR3 radical in which R3 is a linear or ramified alkyl (C1-C3) radical substituted by a carboxy or carbomethoxy group in the position~.
Another preferred class of compounds accor-ding to the invention comprises derivatives of formula I
wherein :
(a) Rl represents a linear or ramified alkylsulfinyl (C1-C3) radical (b) R2 represents a NHR3 radical in which R3 is a linear or ramified alkyl (C6-C14) radical, a linear alkyl ~Cl-C3) radical substituted by a carboxy or carbomethoxy group in the position~ .
Examples of compounds according to the inven-tion are :
1-(4-isopropylsulfinylphenyl)-2-n.octylamino-1-propanol.
1-(4-isopropylthiophenyl)-2-~3-(methoxycarbonyl)propylami-; no~-1-propanol.
1-(4-isopropylthiophenyl)-2-~3-(carboxy)propylaminoJ-l-pro-panol.
1-(4-methylthiphenyl)-2-~3-(methoxycarbonyl) propylamino~
-l-propanol.
1-(4-methylthiophenyl~-2-C3-(carboxy)propylamin ~-1-pro-panol.
1-(4-isopropylsulfinylphenyl)-2-~3-(methoxycarbonyl)propy-lamino~-l-propanol.
1-(4-isopropylsulfinylphenyl)-2-~3-(carboxy)propylamino?
-l-propanol.
1-(4-isopropylsulfinylphenyl)-2-~i-(2-oxopyrrolidinyl)~7-1-- 30 propanol.
- .
~1~7164 1-(4-mercaptophenyl)-2-n.octylamino-1-propanol.
Derivatives of formula I may be isolated as salts, in particular hydrochlorides and sulfates.
Derivatives of formula I may be transformed according to usual processes into salts with acids and, when the derivatives are directly obtained as salts, they may al-so be transformed into their free base or into salts with other acids.
According to the invention, these are more particularly pharmaceutically acceptable non toxic acid addition salts, formed with suitable inorganic acids, for example hydrochloric, sulfuric or phosphoric acid or with suitable organic acids, such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic, carboxylic or sulfo-nic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascor-bic, glucuronic, maleic, fumaric, pyruvic, aspartic, gluta-mic, benzoic, anthranilic, hydroxybenzoic, salicylic, phe-nylacetic, mandelic, embonic, methanesulfonic, ethanesulfo-;:
nic, panthatenic, toluenesulfonic, sulfanilic, cyclohexyl-aminosulfonic, stearic, alginic~ ~ -hydroxypropionic, ~ -hy-droxybutyric, oxalic, malonic, galactaric, galacturonic acids. These salts can also derive from amino-acids, which are natural or not, such as lysine, glycine, arginine, orni-thine, asparagine, glutamine, alanine, valine, threonine, serine, leucine, cysteine, and the like.
Most of the products according to the inven-tion have two asymmetry centres. Derivatives where Rl repre-sents an alkylsulfinyl radical have three asymmetry centres.
:, ;.
- , .
llZ7164 With products of the invention having two asymmetry centres, two racemates corresponding to erythro and threo configurations respectively may be obtained ; the-se two racemats may be resolved by conventional processes, for e~ample by formation of diastereoisomer salts by action of optically active acids, such as tartaric, diacetyltarta-ric, tartranilic, dibenzoyltar~aric, ditoluoyltartaric acids and separation of the diastereoisomer mixture by crystalli-zation, distillation, chromatography, then liberation of op-tically active bases from said salts.
With products of the invention having three asymmetry centres, eight optical isomers may be obtained.
The same processes may be used for resolving said mixtures.
The most active derivatives of the invention may thus be used as mixtures comprising several diastereoi-somers whatever the relative proportions may be, or as enan-tiomer pairs in equal proportions (racemic mixture) or not, or also as optically pure compounds. However, derivatives of the erythro configuration at the level of the two asymmetri-cal carbon atoms of the propanol chain are preferred.
This invention also relates to a process for preparing above-mentioned derivatives of l-phenyl-l-propanol and corresponding salts and esters.
This process is characterized in that it con-sists of transforming into one of the corresponding deriva-tives of formula I, a compound having the formule II :
` 'Z ~ Q (~I) .: , , :
` 1127164 wherein Z represents one of the substituents Rl such as he-reinabove defined or corresponds to a group YS in which Y is a protecting group replaceable by hydrogen and Q is one of the following groups :
-CO-CO-CH3 ;
/ \
-CO-HOH-CH3 ; -CO-fH-X ; -CH-CH-CH3 ;-CO-CH-NHR3 ;
-CHOH-CH-~ ; -CHO~1-CH-R2, where R2 and R3 have the above-mentioned meaning and X is a halogen atom, such as Cl, Br, F.
Advantageously, derivatives of formula I whe-rein R2 is a hydroxy group are obtained by reduction of cor-responding ketones of general formulae III and IV :
`~1 ~ C0-C0-C~13 (IJI) Rl- ~ C0-~H~ CH3 (IV) wherein Rl has the previously defined meaning.
This reduction may be made in the usual man-ner, for example by action of hydrides such as NaBH~, LiAlH4, LiAl(OAlkyl)3H, AlH3, (Alkyl)2AlH, NaB(OCH3)3H, LiBH3CN, B2H6, (Alkyl)3SnH, (Alkyl)3SiH or NaH in solvents such as ether, tetrahydrofuran, ethanol, methanol, diglyme, toluene or xylene, by action of alkaline metals, such as so-dium or lithium, in solvents such as ammoniac or ethanol, by action of hydrogen in the presence of hydrogenation cata-~ lysts, such as platinum or palladium, in solvents such as : ethanol or by action of alwminium alkoxides, such as alumi-~ - ~
11271~4 niunlisopropoxide, in a solvent such as isopropanol.
If the process of reduction of ketones of ge-neral formulae III and IV is not stereoselective, erythro/
threo mixtures are separated according to conventional pro-cesses (for example by distillation or plate or column chro-matography).
The compounds of general formula I wherein R2 is an oxo-2-pyrrolidinyl-1 ring, optionally substituted by a hydroxy group are advantageously obtained according to gene-ral schemas such as hereinafter described :
a) R1~3 Cll-CII-C~ Rl~> CIIOII(`H-N~
(!
b) Rl ~> CO-CIl-Br ~ R ~ CH(~Hc~
Cll 1 N~(C112)3C~OCH3 1 ~ C1~3 3 2 . Reduc t i on 3. Ease (ring-clo~ure), In these schemes, Rl has the previously given meaning.
In reaction (a), condensation of an epoxide with 2-pyrrolidinone is easily made either without solvent while optionally using excess of 2-pyrrolidinone, or in the presence of solvents, for example methanol or ethanol.
This method allows alcohols of threo configu-ration to be obtained.
In reaction (b), condensation of a ~-bromoke-tone with an ester of ~-aminobutyric acid will be made in a solvent such as methanol, ethanol, chloroform, acetonitrile, : .
llZ7~6~
benzene or a mixture thereof, most advantageously at room temperature.
The reduction may be made with hydrides of alkaline metals, more particularly with ~aNH4, in a solvent such as methanol or ethanol at room temperature.
The ring-closure into pyrrolidinone may be made by action of an organic or inorganic base, for example an alkoxide or sodium or potassium hydroxyde in an alcoholic ; or hydro-alcoholic solvent such as methanol, ethanol or iso-propanol at a temperature between room temperature and the reflux temperature of the selected solvent but most advanta-geously at room temperature.
This method allows alcohols of erythreo con-figuration to be obtained.
The compounds of general formula I wherein R2 is a radical of the kind NHR3 may be obtained from a com-pound of the general formule V :
Rl~ Q ( Y) or optionally, according to the value of Q, from a salt of a ; ~0 compound having this formula, wherein R2 has the previously given meaning and Q represents one of the following groups :
O
/ ~
~ In these formulae, R3 has the previously gi-`~ ven meaning while X represents a halogen atom.
. ..
~ Said process may be carried out according to .
~-.
,:
, 1~2716~
two embodiments which are essentially determined by the starting product, namely by the value of Q in formula V.
Embodiment A.
According to a first way of proceeding, a ~-aminoketone of formula V wherein Q represents a group :
CO-CH-NHR3, R3 having the previously defined meaning are re-duced.
This reaction may be made in the usual way, most easily for example by action of alkaline metal hydri-des, such as sodium borohydride, in a solvent such as metha-nol or ethanol, preferably at low temperature, or by action of aluminiu~ or lithium hydride in a solvent such as diethyl ether or tetrahydrofuran, or by action of an aluminium alko-xide, such as aluminium propoxide in a solvent such as iso-propanol, most advantageously at the reflux thereof. The re-duction may also be made by hydrogenation in the presence of a catalyst, such as palladium on carbon, Raney nickel, pla-tinum oxide in a solvent, such as methanol, ethanol, dioxa-ne.
As previously mentioned, the most interesting products according to the invention may have two erythro and threo configurations. The selection of the starting aminoke-tone and of the reduction conditions allows either of these two forms to be obtained stereoselectively. Thus the reduc-tion of an aminoketone wherein Q represents : CO-CH-NHR3 leads to an amino-alcohol of erythro configuration under ~: the general hereinabove described conditions.
112~16~
In order to obtain a compound of the threo configuration, reduction is made on an aminoketone wherein Q represents : CO-CH-NH3R4 in which R3 has the previously mentioned meaning and R4 is a protecting group which is la-ter removable by hydrolysis or hydrogenolysis, such as ben-zyl, trityl, acetyl, formyl, benzhydryl groups ; this reduc-tion is then preferably made by action of alkaline metal hy-drides, such as sodium borohydride or aluminium lithium hy-dride.
The starting aminoketones are easily accessi-; ble, for example by action of an amine R3NH2 or R3R4NH on a ~-halogenoketone in solvents such as ether, benzene, chlo-roform, dioxan, methanol, isopropanol or acetonitrile.
Embodiment B.
According to this preparation method, a com-pound of the general formula V, in which Q represents a group :
-CHOH-CH-X, is reacted with an amine R3NH2, in which formulae R3 and have the previously given meaning.
This reaction is made in a solvent such as alcohols, chloroform, dioxan, carbon tetrachloride, most ea-sily in the presence of a scavenger for the formed halogen hydride, such as inorganic or organic bases, or in the pre-- sence of excess of amine. It is well known that in these cases, the -CHOH-fH-X group first gives an oxirane group '' - ` :.: `L :
" -~ ~ ' `
~127164 f the type -CH-CH-CH3 which reacts with the amine compound.
Thus the present process also comprises pre-paration of amino-alcohols from oxiranes.
The compounds of general formula I wherein Rl is a mercapto radical may be obtained from compounds of the general formula VI :
Y S ~ OH C ll - R 2 ( ~11 ) wherein R2 has the previously indicated value and Y is a protecting group which is replaceable by hydrogen according to processes well known in the literature, for example an alkyl group such as isopropyl, benzyl or substituted benzyl group which is removable by action of alkaline metals, such as sodium or lithium, in a solvent such as ammoniac, or by action of hydrogen in the presence of hydrogenation cata-lysts or by action of lead diacetate or hydrofluoric acid, a diphenylmethyl group which is substituted or non removable by action of aci~s such as trifluoroacetic acid or hydro-bromic acid, a triphenylmethyl group which is substituted or non removable by action of acids swch as hydrochloric or hy-drobromic acid or of agents such as HgCl2, AgNO3 or Hg (OAc)2, a benzylthiomethyl group which is removable by action of oxidation agents such as HgCl2 or Hg(OAc)2, an acetamidomethyl group which is removable for example with mercury salts~ a carboxymethyl group which is removable with oxidation agents in acid medium or a tetrahydropyranyl o;
tetrahydrofuranyl group which is removable with oxidation 1127~6 agents such as AgNO3, Ir, SO2C12, (SCN)2-Zn or with acids.
The compounds of general formula I, wherein Rl is an alkylsulfinyl or alkylsulfonyl radical may be ob-tained from compounds of general formula I wherein Rl is an alkylthio radical, by oxidation according to processes well known in the literature. This oxidation may be made at any stage of the synthesis of the products according to the in-vention.
In order to obtain sulfoxides, one may use lQ oxidation agents, such as iodine, bromine in water or in the presence of acetate ions or in a complex with pyridine, pe-racids such as peracetic, monoperphthalic or m-chloroperben-zoic acids, N-halosuccinimides, such as N-bromosuccinimide, hypochlorites such as sodium, t-butyl or isopropyl hypochlo-rites, periodates such as sodium periodate, hydrogen peroxi-de in the presence of acetic anhydride or in the presence of vanadium hemipentoxide in t-butanol, nitrates, such as ace-tyl nitrate or ammonium and cerium nitrate, oxides such as chromium (VI) oxide in pyridine or vanadium hemipentoxide in ; 20 the presence of oxygen or nitrogen hemipentoxide, peroxides, ozone, oxygen, in the singlet or triplet state, acids such as nitric acid, chromic acid or Caro acid or still ln other agents, such as sulfuryl chloride, l-chlorobenzotriazole, chloramine, N-chloro-nylon 66, iodobenzene dichloride, iodo-~ sobenzene, iodobenzene diacetate, N-chlorotriazole,
R 1 ~ C H O I I C ~1 - R 2 - ( I ) wherein :
(a) Rl represents hydrogen, a linear or ramified alkylthio (Cl-C3), linear or ramified alkylsulfinyl (Cl-C3), li-near or ramified alkylsulfonyl (Cl-C3) or mercapto radi-cal ;
(b) R2 represents :
b-l a hydroxy radical ;
b-2 an oxo-2-pyrrolidinyl-1 radical which may be subs- tituted by a hydroxy group ;
b-3 a NHR3 radical wherein R3 represents :
- hydrogen - a linear or ramified alkyl (C6-C16) radical or a linear alkyl (C2-C4) radical substituted by a phe-~: nyl or phenoxy group, with the proviso that Rl is not an alkylthio radical - a linear or ramified alkyl (Cl-C7) radical substi-tuted by a lower carboxy or carbalkoxy (Cl-C
. group in the position ~ ;
as well as non toxic apd pharmaceutically acceptable salts and esters of these derivatives.
A preferred class of compounds according to the invention comprises derivatives of formule I wherein :
(a) Rl represents a linear or ramified alkylthio (Cl-C3) ra-, .:
, ~ . . .
, -, llZ7~64 dical (b) R2 representts a NHR3 radical in which R3 is a linear or ramified alkyl (C1-C3) radical substituted by a carboxy or carbomethoxy group in the position~.
Another preferred class of compounds accor-ding to the invention comprises derivatives of formula I
wherein :
(a) Rl represents a linear or ramified alkylsulfinyl (C1-C3) radical (b) R2 represents a NHR3 radical in which R3 is a linear or ramified alkyl (C6-C14) radical, a linear alkyl ~Cl-C3) radical substituted by a carboxy or carbomethoxy group in the position~ .
Examples of compounds according to the inven-tion are :
1-(4-isopropylsulfinylphenyl)-2-n.octylamino-1-propanol.
1-(4-isopropylthiophenyl)-2-~3-(methoxycarbonyl)propylami-; no~-1-propanol.
1-(4-isopropylthiophenyl)-2-~3-(carboxy)propylaminoJ-l-pro-panol.
1-(4-methylthiphenyl)-2-~3-(methoxycarbonyl) propylamino~
-l-propanol.
1-(4-methylthiophenyl~-2-C3-(carboxy)propylamin ~-1-pro-panol.
1-(4-isopropylsulfinylphenyl)-2-~3-(methoxycarbonyl)propy-lamino~-l-propanol.
1-(4-isopropylsulfinylphenyl)-2-~3-(carboxy)propylamino?
-l-propanol.
1-(4-isopropylsulfinylphenyl)-2-~i-(2-oxopyrrolidinyl)~7-1-- 30 propanol.
- .
~1~7164 1-(4-mercaptophenyl)-2-n.octylamino-1-propanol.
Derivatives of formula I may be isolated as salts, in particular hydrochlorides and sulfates.
Derivatives of formula I may be transformed according to usual processes into salts with acids and, when the derivatives are directly obtained as salts, they may al-so be transformed into their free base or into salts with other acids.
According to the invention, these are more particularly pharmaceutically acceptable non toxic acid addition salts, formed with suitable inorganic acids, for example hydrochloric, sulfuric or phosphoric acid or with suitable organic acids, such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic, carboxylic or sulfo-nic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascor-bic, glucuronic, maleic, fumaric, pyruvic, aspartic, gluta-mic, benzoic, anthranilic, hydroxybenzoic, salicylic, phe-nylacetic, mandelic, embonic, methanesulfonic, ethanesulfo-;:
nic, panthatenic, toluenesulfonic, sulfanilic, cyclohexyl-aminosulfonic, stearic, alginic~ ~ -hydroxypropionic, ~ -hy-droxybutyric, oxalic, malonic, galactaric, galacturonic acids. These salts can also derive from amino-acids, which are natural or not, such as lysine, glycine, arginine, orni-thine, asparagine, glutamine, alanine, valine, threonine, serine, leucine, cysteine, and the like.
Most of the products according to the inven-tion have two asymmetry centres. Derivatives where Rl repre-sents an alkylsulfinyl radical have three asymmetry centres.
:, ;.
- , .
llZ7164 With products of the invention having two asymmetry centres, two racemates corresponding to erythro and threo configurations respectively may be obtained ; the-se two racemats may be resolved by conventional processes, for e~ample by formation of diastereoisomer salts by action of optically active acids, such as tartaric, diacetyltarta-ric, tartranilic, dibenzoyltar~aric, ditoluoyltartaric acids and separation of the diastereoisomer mixture by crystalli-zation, distillation, chromatography, then liberation of op-tically active bases from said salts.
With products of the invention having three asymmetry centres, eight optical isomers may be obtained.
The same processes may be used for resolving said mixtures.
The most active derivatives of the invention may thus be used as mixtures comprising several diastereoi-somers whatever the relative proportions may be, or as enan-tiomer pairs in equal proportions (racemic mixture) or not, or also as optically pure compounds. However, derivatives of the erythro configuration at the level of the two asymmetri-cal carbon atoms of the propanol chain are preferred.
This invention also relates to a process for preparing above-mentioned derivatives of l-phenyl-l-propanol and corresponding salts and esters.
This process is characterized in that it con-sists of transforming into one of the corresponding deriva-tives of formula I, a compound having the formule II :
` 'Z ~ Q (~I) .: , , :
` 1127164 wherein Z represents one of the substituents Rl such as he-reinabove defined or corresponds to a group YS in which Y is a protecting group replaceable by hydrogen and Q is one of the following groups :
-CO-CO-CH3 ;
/ \
-CO-HOH-CH3 ; -CO-fH-X ; -CH-CH-CH3 ;-CO-CH-NHR3 ;
-CHOH-CH-~ ; -CHO~1-CH-R2, where R2 and R3 have the above-mentioned meaning and X is a halogen atom, such as Cl, Br, F.
Advantageously, derivatives of formula I whe-rein R2 is a hydroxy group are obtained by reduction of cor-responding ketones of general formulae III and IV :
`~1 ~ C0-C0-C~13 (IJI) Rl- ~ C0-~H~ CH3 (IV) wherein Rl has the previously defined meaning.
This reduction may be made in the usual man-ner, for example by action of hydrides such as NaBH~, LiAlH4, LiAl(OAlkyl)3H, AlH3, (Alkyl)2AlH, NaB(OCH3)3H, LiBH3CN, B2H6, (Alkyl)3SnH, (Alkyl)3SiH or NaH in solvents such as ether, tetrahydrofuran, ethanol, methanol, diglyme, toluene or xylene, by action of alkaline metals, such as so-dium or lithium, in solvents such as ammoniac or ethanol, by action of hydrogen in the presence of hydrogenation cata-~ lysts, such as platinum or palladium, in solvents such as : ethanol or by action of alwminium alkoxides, such as alumi-~ - ~
11271~4 niunlisopropoxide, in a solvent such as isopropanol.
If the process of reduction of ketones of ge-neral formulae III and IV is not stereoselective, erythro/
threo mixtures are separated according to conventional pro-cesses (for example by distillation or plate or column chro-matography).
The compounds of general formula I wherein R2 is an oxo-2-pyrrolidinyl-1 ring, optionally substituted by a hydroxy group are advantageously obtained according to gene-ral schemas such as hereinafter described :
a) R1~3 Cll-CII-C~ Rl~> CIIOII(`H-N~
(!
b) Rl ~> CO-CIl-Br ~ R ~ CH(~Hc~
Cll 1 N~(C112)3C~OCH3 1 ~ C1~3 3 2 . Reduc t i on 3. Ease (ring-clo~ure), In these schemes, Rl has the previously given meaning.
In reaction (a), condensation of an epoxide with 2-pyrrolidinone is easily made either without solvent while optionally using excess of 2-pyrrolidinone, or in the presence of solvents, for example methanol or ethanol.
This method allows alcohols of threo configu-ration to be obtained.
In reaction (b), condensation of a ~-bromoke-tone with an ester of ~-aminobutyric acid will be made in a solvent such as methanol, ethanol, chloroform, acetonitrile, : .
llZ7~6~
benzene or a mixture thereof, most advantageously at room temperature.
The reduction may be made with hydrides of alkaline metals, more particularly with ~aNH4, in a solvent such as methanol or ethanol at room temperature.
The ring-closure into pyrrolidinone may be made by action of an organic or inorganic base, for example an alkoxide or sodium or potassium hydroxyde in an alcoholic ; or hydro-alcoholic solvent such as methanol, ethanol or iso-propanol at a temperature between room temperature and the reflux temperature of the selected solvent but most advanta-geously at room temperature.
This method allows alcohols of erythreo con-figuration to be obtained.
The compounds of general formula I wherein R2 is a radical of the kind NHR3 may be obtained from a com-pound of the general formule V :
Rl~ Q ( Y) or optionally, according to the value of Q, from a salt of a ; ~0 compound having this formula, wherein R2 has the previously given meaning and Q represents one of the following groups :
O
/ ~
~ In these formulae, R3 has the previously gi-`~ ven meaning while X represents a halogen atom.
. ..
~ Said process may be carried out according to .
~-.
,:
, 1~2716~
two embodiments which are essentially determined by the starting product, namely by the value of Q in formula V.
Embodiment A.
According to a first way of proceeding, a ~-aminoketone of formula V wherein Q represents a group :
CO-CH-NHR3, R3 having the previously defined meaning are re-duced.
This reaction may be made in the usual way, most easily for example by action of alkaline metal hydri-des, such as sodium borohydride, in a solvent such as metha-nol or ethanol, preferably at low temperature, or by action of aluminiu~ or lithium hydride in a solvent such as diethyl ether or tetrahydrofuran, or by action of an aluminium alko-xide, such as aluminium propoxide in a solvent such as iso-propanol, most advantageously at the reflux thereof. The re-duction may also be made by hydrogenation in the presence of a catalyst, such as palladium on carbon, Raney nickel, pla-tinum oxide in a solvent, such as methanol, ethanol, dioxa-ne.
As previously mentioned, the most interesting products according to the invention may have two erythro and threo configurations. The selection of the starting aminoke-tone and of the reduction conditions allows either of these two forms to be obtained stereoselectively. Thus the reduc-tion of an aminoketone wherein Q represents : CO-CH-NHR3 leads to an amino-alcohol of erythro configuration under ~: the general hereinabove described conditions.
112~16~
In order to obtain a compound of the threo configuration, reduction is made on an aminoketone wherein Q represents : CO-CH-NH3R4 in which R3 has the previously mentioned meaning and R4 is a protecting group which is la-ter removable by hydrolysis or hydrogenolysis, such as ben-zyl, trityl, acetyl, formyl, benzhydryl groups ; this reduc-tion is then preferably made by action of alkaline metal hy-drides, such as sodium borohydride or aluminium lithium hy-dride.
The starting aminoketones are easily accessi-; ble, for example by action of an amine R3NH2 or R3R4NH on a ~-halogenoketone in solvents such as ether, benzene, chlo-roform, dioxan, methanol, isopropanol or acetonitrile.
Embodiment B.
According to this preparation method, a com-pound of the general formula V, in which Q represents a group :
-CHOH-CH-X, is reacted with an amine R3NH2, in which formulae R3 and have the previously given meaning.
This reaction is made in a solvent such as alcohols, chloroform, dioxan, carbon tetrachloride, most ea-sily in the presence of a scavenger for the formed halogen hydride, such as inorganic or organic bases, or in the pre-- sence of excess of amine. It is well known that in these cases, the -CHOH-fH-X group first gives an oxirane group '' - ` :.: `L :
" -~ ~ ' `
~127164 f the type -CH-CH-CH3 which reacts with the amine compound.
Thus the present process also comprises pre-paration of amino-alcohols from oxiranes.
The compounds of general formula I wherein Rl is a mercapto radical may be obtained from compounds of the general formula VI :
Y S ~ OH C ll - R 2 ( ~11 ) wherein R2 has the previously indicated value and Y is a protecting group which is replaceable by hydrogen according to processes well known in the literature, for example an alkyl group such as isopropyl, benzyl or substituted benzyl group which is removable by action of alkaline metals, such as sodium or lithium, in a solvent such as ammoniac, or by action of hydrogen in the presence of hydrogenation cata-lysts or by action of lead diacetate or hydrofluoric acid, a diphenylmethyl group which is substituted or non removable by action of aci~s such as trifluoroacetic acid or hydro-bromic acid, a triphenylmethyl group which is substituted or non removable by action of acids swch as hydrochloric or hy-drobromic acid or of agents such as HgCl2, AgNO3 or Hg (OAc)2, a benzylthiomethyl group which is removable by action of oxidation agents such as HgCl2 or Hg(OAc)2, an acetamidomethyl group which is removable for example with mercury salts~ a carboxymethyl group which is removable with oxidation agents in acid medium or a tetrahydropyranyl o;
tetrahydrofuranyl group which is removable with oxidation 1127~6 agents such as AgNO3, Ir, SO2C12, (SCN)2-Zn or with acids.
The compounds of general formula I, wherein Rl is an alkylsulfinyl or alkylsulfonyl radical may be ob-tained from compounds of general formula I wherein Rl is an alkylthio radical, by oxidation according to processes well known in the literature. This oxidation may be made at any stage of the synthesis of the products according to the in-vention.
In order to obtain sulfoxides, one may use lQ oxidation agents, such as iodine, bromine in water or in the presence of acetate ions or in a complex with pyridine, pe-racids such as peracetic, monoperphthalic or m-chloroperben-zoic acids, N-halosuccinimides, such as N-bromosuccinimide, hypochlorites such as sodium, t-butyl or isopropyl hypochlo-rites, periodates such as sodium periodate, hydrogen peroxi-de in the presence of acetic anhydride or in the presence of vanadium hemipentoxide in t-butanol, nitrates, such as ace-tyl nitrate or ammonium and cerium nitrate, oxides such as chromium (VI) oxide in pyridine or vanadium hemipentoxide in ; 20 the presence of oxygen or nitrogen hemipentoxide, peroxides, ozone, oxygen, in the singlet or triplet state, acids such as nitric acid, chromic acid or Caro acid or still ln other agents, such as sulfuryl chloride, l-chlorobenzotriazole, chloramine, N-chloro-nylon 66, iodobenzene dichloride, iodo-~ sobenzene, iodobenzene diacetate, N-chlorotriazole,
2,4,4,6-tetrabromocyclohexadienone or auric acid (HAuC14~.
.~
These oxidation reactions will be carried out in solvents such as for example water, acetic acid, chloroform, dichlo- j romethane, carbon tetrachloride, methanol, t-butanol or ace-, .. ~
:
-.
- :
11~7164 tone.
For obtaining sulfones, oxidation agents such as hydrogen peroxide will be used, preferably in the presen-ce of zirconium salts, peracids such as peracetic, monoper-phthalic and m-chloroperbenzoic acids (in the case of oxida-tion with peracids, catalysts based on transition metals will be advantageously used), potassium permanganate in acid or basic medium, sodium or potassium bichromate, osmium te-troxide, selenium oxide) t-butyl hypochlorite, nitric aci~, ozone, oxygen, advantageously in the presence of iridium or rhodium salts, iodobenzene dichloride, periodic acid or by electrochemical oxidation. These reactions will be made in solvents, such as water, acetic acid, chloroform, dichloro-methane, methanol, ethanol, isopropanol, t-butanol, dioxan or acetone.
In some cases, it may be advantageous to car-ry out the hereinabove described oxidation reactions on com-pounds of general formula I wherein R1 is an alkylthio group =~ and wherein the functions which are sensible to the oxida-tion agent used will have been protected for example by for-mation of esters in the case of hydroxy groups or of ketals in the case of ketonic groups.
Hereinafter detailed examples of preparation of some derivatives of l-phenyl-1-propanol according to the ` invention are given. These examples have mainly for their object to more completely illustrate the particular features of the process according to the invention.
Example 1 1-(4-Isopropylsulfinylphenyl)-2-n-octylaminopropanol.
. , , ~
~lZ~1~4 (Table I, n 6).
To 14 gr of 1-(~-isopropylthiophenyl)-2-n-octylaminopropanol dissolved in 250 ml of chloroform, 6,4 gr of m-chloroperbenzoic acid are slowly added. The mixture is stirred overnight at room temperature, washed with an aque-ous satured solution of NaHCO3 and evaporated under vacuum.
The so obtained residue is treated with 50 ml of ether and filtered.
The organic phase is dried on MgS04, filtered and evaporated. The oily residue is vacuum dried overnight, redissolved in anhydrous ether and hydrochloride is obtained by passing of a dry gaseous HCl stream through this residue.
After recrystallization with a mixture of methanol and ether, 8,4 gr of product are obtained. Yield : 60% ; MP
(C): 167-169 (melting point).
Centesimal analysls C H N
Calculated, % 61.59 9.30 3.59 Found, % 61.28 9.05 3.45 ~20 Example 2.
1-(4-Isopropylthiophenyl)-2-~l-(2-oxopyrrolidiny~ -pr panol.
(Table I, n7).
` a) 2-methyl-3-(4-isopropylthiophenyl)oxirane.
,~ To a solution containing 28.5 gr of 2-bromo-, 1-(4-isopropylthiophenyl)-1-propanone, 350 ml of ethanol and } 125 ml of ethoxyethanol, 3.83 gr of NaBH4 in 25 ml of water are slowly added at -25QC while agitating. After the addi-. . .
tion is complete, the mixture is allowed slowly to come ,' ' .
, :,, .
112~164 again to room temperature and stirring is carried on for 1.30 hour. 3.8 gr of KOH in 40 ml of water are then slowly added and then stirring is followed for 30 minutes. The re-action mixture is diluted with water and extracted from chloroform. The chloroform solutions are collected, dried and filtered, then the solvent is removed by vacuum distil-lation. 23.6 gr of an oil are thus obtained, this oil being vacuum redistilled. Weight : 19,2 gr ; yield 65% ; BP :
81-84C (0~7 mm) ; the NMR spectrum is in agreement with the structure of 2-methyl-3-(4-isopropylthiophenyl)oxirane.
b) 1-(4-Isopropylthiophenyl)-2-/~-(2-oxopyrrolidinyl)~-1-propanol.
10.4 gr of the preceding product, 4.25 gr of 2-pyrrolidinone and 0.5 gr of NaOH are heated under nitrogen for 17 hours at 120C. After cooling, the oil so obtained is solidified by addition of petroleum ether. The solid is fil-tered, washed with a minimum of petroleum ether, dried and recrystallized in diethyl ether. 4.68 gr of product are thus obtained. Yield : 45% ; MP (C) : 115-116.
The structure conformity is checked by mass spectrometry and NMR (threo configuration).
Centesimal analysis C H N
Calculated, % 65.4~7.90 4.77 Found, % ~5.~57.80 4.70 Example 3.
1-4-Isopropylsulfonylphen~1)-2-~1-(2-oxopyrrolidinyl)~-1-propanol.
(Table I, n9).
` ` -- ~ ~
716~
1~
A solution containing 2.93 gr of 1-(4-isopro-pylthiophényl)-2~ (2-oxopyrrolidinyl)~-1-propanol, 6.5 ml of acetic acid and 6.5 ml of 30 % H2O2 is progressively hea-ted to 85-90C and maintained at this temperature for 2 hours. After cooling, a solution of 6 gr of Na2S2O5 in 15 ml of water are slowly added, then it is diluted with 50 ml of water. The residue is extracted from chloroform, the organic phase is dried on MgSO4, filtered and evaporated. The oily residue so obtained is solidified by addition of petroleum ether and recrystallized with a mixture of ether and metha-nol.
1.95 gr of product are so obtained.
MP(C) : 170.5.
;i Centesimal analysis ~!
C H N
Calculated, % 59.5 7.12 4.30 :. .
Found, % 58.95 7.15 4,10 The NMR spectrum confirms the threo configu-.
ration.
~:
~; 20 Example 4.
1-(4-Isopropylthiophenyl)-2-~3-(carbomethoxy~propylamino~-`~: 1-propanol.
(Table I, n 13).
17 gr of 2-bromo-1-(4-isopropylthiophenyl~-1-propanone, 200 ml of methanol, 17.3 ml of triethylamine and 10 gr of methyl ~-aminobutyrate (hydrochloride) are refluxed - for 17 hours.
The solution is then cooled to a temperature of 5C and 4.5 gr of NaBH4 are slowly added. The reaction i~
.~
-, :...... - ' . ' ' . - ' .
: ~: - ~
il2716 mixture is then stirred overni~ht at room temperature. ~fter vacuum evaporation of the solvent and dilution of the resi-due with water, it is extracted from chloroform. The chloro-fornl solutions are collected, dried and filtered, then the solvent is eliminated by vacuum distillation. Thus 13.4 gr of crude product are obtained ; this crude product, after having prepared hydrochloride in a diethyl ether-methanol (50/50) mixture, gives 12.4 gr of product. Yield : 58% ; MP
(C) : 175.6.
The conformity of the structure has been che-cked by mass spectrometry.
Centesimal analysis.
C H N
Calculated, % 56.41 7.79 3.87 Found, % 56.10 7.65 3.75 ; The NMR spectrum confirms the erythro confi-guration.
; Example 5.
1-(4-Isopropylthiophenyl)-2-~3-(carboxy)propylamino~-1-pro-panol.
(Table I, n23).
7 gr of 1-(4-isopropylthiophenyl)-2-~3-me-thoxycarbonyl)propylamino~-l-propanol are dissolved in 70 ml of water and 7 ml of concentrated hydrochloric acid are ad-ded thereto. The solution is heated at 80C for 1 hour, allowed to cool, ~he solvent is driven out under vacuum, then one crystallizes in a methanol-ether mixture.
Weight : 4.5 gr ; Yield : 68% ; MP (C) : 197.5 l~Z~64 ~8 Centesimal analysis :
C ll N
Calculated, % 55.24 7.53 4.03 Found, % 55.35 7.50 3.80 Example 6.
1-(4-Isopropylthiophenyl)-2-~ 2-oxopyrrolidinyl)~-1-pro-panol(erythro).
(Table I, n24.
6 gr of 1-(4-isopropylthiophenyl-2-~3-(carbo-xy)propylamino~ propanol are dissolved in a mixture con-taining 100 ml of methanol and 50 ml of water. The pH is brought to 13 by addition of a lON sodium hydroxide solu-tion. After stirring for 1 hour at room temperature, metha-nol is evaporated, extraction is made with chloroform, the organic phase is dried on MgSO4 and the solvent is evapora-ted. The product solidifies in petroleum ether and is then recrystallized with ether. 1.3 gr of product are collected, namely a yield of 27%. MP (C) : 80. The conformity of the structure is established by NMR and mass spectrometry (ery-thro configuration).
, Centesimal analysis.
I C H N
; Calculated, % 65.49 7.90 4.77 Found, % 65.15 7.70 4.75 Example 7.
1-(4-Isopropy~thiophenyl)-1,2-propanediol.
(Table I, n 18).
; 170 gr of 1-(4-isopropylthiophenyl)-2-hydro-~ xy-1-propanone are dissolved in 1500 ml of methanol, then ' : - .
~12716 cooled to 0C, 57.4 gr of sodium borohydride are slowly ad-ded ~ith stirring overnight at room temperature. The solvent is evaporated, one dilutes with water, then e~tracts from chloroform and dries on MgS04. After solvent evaporation, recrystallization is made in a benzene-hexane mixture.
; Weight : 66.8 gr ; yield : 39 % ; MP (C) 83-85.
The NMR spectrum confirms the erythro confi-guration of the product so obtained.
Centesimal analysis :
C H
Calculated, % 63.68 8.01 Found, % 63.50 8.05 Example 8.
1-(4-Mercaptophenyl)-2-n-octylamino-1-propanol.
(Table I, n40).
To a solution containing 5.25 gr of lithium, 1000 rnl of liquid ammoniac and 500ml of tetrahydrofuran, a ~, solution comprising 16 gr of 1-(4-isopropylthiophenyl)-2-n-octylamino-l-propanol in 500 ml of tetrahydrofuran is slowly added. After the addition is complete, stirring is still continued for about 15 minutes, then 16 ~r of NH4Cl are ad-ded in small portions.
The ammoniac is slowly evaporated in a wa-ter-bath, then the residue is diluted with water. The solid so obtained is filtered and recrystallized with methanol.
12 gr of 1-(4-mercaptophenyl)-2-n-octylami-no-l-propanol are thus obtained.
MP (C) : 110-112 ; Yield : 82,1%.
- ~ :, :
~1~716 Centesimal analysis C H N
Calculated, % 69.10 9.90 4.74 Found, % 69.40 10.10 4.60 As already hereinabove mentioned, the deri-vatives according to the invention may be as their salts or esters.
` Specific esters are those having the formw-lae Cl~3 cH-cll-N~ c8ll]7 . I~Cl 0,C,-c~2-C(C1~)3 l MP ( C) : 112-114 i! ' C 1/- S 0 ~3 C H - CH - NH nC8H 17 . HC 1 . O-C-Ct~3 O
MP (C) : 14~,5 _ 150 The melting points of the derivatives mentio-ned in the examples, as well as of other derivatives prepa-red according to the invention are given in the following table.
~, ~
~127164 `" 21 ~ _ " _ ~
_ . ~ ~ C Z
~-- Z L~ O T
., ~ I~ O C~ O
~ D ¦ ~ T C 1 C T ~o ~` ~ ~
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~ 1127164 _ ~
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r~
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r~ ~ I I ~ ~ ~ I C:>
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C~ r~ ~ r :!
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.
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t~J ~ ~r ~uL. J ~ ~ U
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o ~n L~ I I I O~ I CO
~_ ~ ~ r--l Lf~cr 01 I ~J
r~ C~ O ~n m 1~CJ~ O r-~r~lr~~r--1 0~ ~'~ ~
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c) r~ O
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a~ Q O vl v~ I r ~r v~
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' ~ ~ ' . : ~ -'.': , 112~164 .
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:
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, . I
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r.~l ~ r~
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1 . . .
(1) the recrystallization solvent is given between brackets.
(2) the elementary analyses were made for C, H, N elements and are in agreement with theoretical values.
.~
These oxidation reactions will be carried out in solvents such as for example water, acetic acid, chloroform, dichlo- j romethane, carbon tetrachloride, methanol, t-butanol or ace-, .. ~
:
-.
- :
11~7164 tone.
For obtaining sulfones, oxidation agents such as hydrogen peroxide will be used, preferably in the presen-ce of zirconium salts, peracids such as peracetic, monoper-phthalic and m-chloroperbenzoic acids (in the case of oxida-tion with peracids, catalysts based on transition metals will be advantageously used), potassium permanganate in acid or basic medium, sodium or potassium bichromate, osmium te-troxide, selenium oxide) t-butyl hypochlorite, nitric aci~, ozone, oxygen, advantageously in the presence of iridium or rhodium salts, iodobenzene dichloride, periodic acid or by electrochemical oxidation. These reactions will be made in solvents, such as water, acetic acid, chloroform, dichloro-methane, methanol, ethanol, isopropanol, t-butanol, dioxan or acetone.
In some cases, it may be advantageous to car-ry out the hereinabove described oxidation reactions on com-pounds of general formula I wherein R1 is an alkylthio group =~ and wherein the functions which are sensible to the oxida-tion agent used will have been protected for example by for-mation of esters in the case of hydroxy groups or of ketals in the case of ketonic groups.
Hereinafter detailed examples of preparation of some derivatives of l-phenyl-1-propanol according to the ` invention are given. These examples have mainly for their object to more completely illustrate the particular features of the process according to the invention.
Example 1 1-(4-Isopropylsulfinylphenyl)-2-n-octylaminopropanol.
. , , ~
~lZ~1~4 (Table I, n 6).
To 14 gr of 1-(~-isopropylthiophenyl)-2-n-octylaminopropanol dissolved in 250 ml of chloroform, 6,4 gr of m-chloroperbenzoic acid are slowly added. The mixture is stirred overnight at room temperature, washed with an aque-ous satured solution of NaHCO3 and evaporated under vacuum.
The so obtained residue is treated with 50 ml of ether and filtered.
The organic phase is dried on MgS04, filtered and evaporated. The oily residue is vacuum dried overnight, redissolved in anhydrous ether and hydrochloride is obtained by passing of a dry gaseous HCl stream through this residue.
After recrystallization with a mixture of methanol and ether, 8,4 gr of product are obtained. Yield : 60% ; MP
(C): 167-169 (melting point).
Centesimal analysls C H N
Calculated, % 61.59 9.30 3.59 Found, % 61.28 9.05 3.45 ~20 Example 2.
1-(4-Isopropylthiophenyl)-2-~l-(2-oxopyrrolidiny~ -pr panol.
(Table I, n7).
` a) 2-methyl-3-(4-isopropylthiophenyl)oxirane.
,~ To a solution containing 28.5 gr of 2-bromo-, 1-(4-isopropylthiophenyl)-1-propanone, 350 ml of ethanol and } 125 ml of ethoxyethanol, 3.83 gr of NaBH4 in 25 ml of water are slowly added at -25QC while agitating. After the addi-. . .
tion is complete, the mixture is allowed slowly to come ,' ' .
, :,, .
112~164 again to room temperature and stirring is carried on for 1.30 hour. 3.8 gr of KOH in 40 ml of water are then slowly added and then stirring is followed for 30 minutes. The re-action mixture is diluted with water and extracted from chloroform. The chloroform solutions are collected, dried and filtered, then the solvent is removed by vacuum distil-lation. 23.6 gr of an oil are thus obtained, this oil being vacuum redistilled. Weight : 19,2 gr ; yield 65% ; BP :
81-84C (0~7 mm) ; the NMR spectrum is in agreement with the structure of 2-methyl-3-(4-isopropylthiophenyl)oxirane.
b) 1-(4-Isopropylthiophenyl)-2-/~-(2-oxopyrrolidinyl)~-1-propanol.
10.4 gr of the preceding product, 4.25 gr of 2-pyrrolidinone and 0.5 gr of NaOH are heated under nitrogen for 17 hours at 120C. After cooling, the oil so obtained is solidified by addition of petroleum ether. The solid is fil-tered, washed with a minimum of petroleum ether, dried and recrystallized in diethyl ether. 4.68 gr of product are thus obtained. Yield : 45% ; MP (C) : 115-116.
The structure conformity is checked by mass spectrometry and NMR (threo configuration).
Centesimal analysis C H N
Calculated, % 65.4~7.90 4.77 Found, % ~5.~57.80 4.70 Example 3.
1-4-Isopropylsulfonylphen~1)-2-~1-(2-oxopyrrolidinyl)~-1-propanol.
(Table I, n9).
` ` -- ~ ~
716~
1~
A solution containing 2.93 gr of 1-(4-isopro-pylthiophényl)-2~ (2-oxopyrrolidinyl)~-1-propanol, 6.5 ml of acetic acid and 6.5 ml of 30 % H2O2 is progressively hea-ted to 85-90C and maintained at this temperature for 2 hours. After cooling, a solution of 6 gr of Na2S2O5 in 15 ml of water are slowly added, then it is diluted with 50 ml of water. The residue is extracted from chloroform, the organic phase is dried on MgSO4, filtered and evaporated. The oily residue so obtained is solidified by addition of petroleum ether and recrystallized with a mixture of ether and metha-nol.
1.95 gr of product are so obtained.
MP(C) : 170.5.
;i Centesimal analysis ~!
C H N
Calculated, % 59.5 7.12 4.30 :. .
Found, % 58.95 7.15 4,10 The NMR spectrum confirms the threo configu-.
ration.
~:
~; 20 Example 4.
1-(4-Isopropylthiophenyl)-2-~3-(carbomethoxy~propylamino~-`~: 1-propanol.
(Table I, n 13).
17 gr of 2-bromo-1-(4-isopropylthiophenyl~-1-propanone, 200 ml of methanol, 17.3 ml of triethylamine and 10 gr of methyl ~-aminobutyrate (hydrochloride) are refluxed - for 17 hours.
The solution is then cooled to a temperature of 5C and 4.5 gr of NaBH4 are slowly added. The reaction i~
.~
-, :...... - ' . ' ' . - ' .
: ~: - ~
il2716 mixture is then stirred overni~ht at room temperature. ~fter vacuum evaporation of the solvent and dilution of the resi-due with water, it is extracted from chloroform. The chloro-fornl solutions are collected, dried and filtered, then the solvent is eliminated by vacuum distillation. Thus 13.4 gr of crude product are obtained ; this crude product, after having prepared hydrochloride in a diethyl ether-methanol (50/50) mixture, gives 12.4 gr of product. Yield : 58% ; MP
(C) : 175.6.
The conformity of the structure has been che-cked by mass spectrometry.
Centesimal analysis.
C H N
Calculated, % 56.41 7.79 3.87 Found, % 56.10 7.65 3.75 ; The NMR spectrum confirms the erythro confi-guration.
; Example 5.
1-(4-Isopropylthiophenyl)-2-~3-(carboxy)propylamino~-1-pro-panol.
(Table I, n23).
7 gr of 1-(4-isopropylthiophenyl)-2-~3-me-thoxycarbonyl)propylamino~-l-propanol are dissolved in 70 ml of water and 7 ml of concentrated hydrochloric acid are ad-ded thereto. The solution is heated at 80C for 1 hour, allowed to cool, ~he solvent is driven out under vacuum, then one crystallizes in a methanol-ether mixture.
Weight : 4.5 gr ; Yield : 68% ; MP (C) : 197.5 l~Z~64 ~8 Centesimal analysis :
C ll N
Calculated, % 55.24 7.53 4.03 Found, % 55.35 7.50 3.80 Example 6.
1-(4-Isopropylthiophenyl)-2-~ 2-oxopyrrolidinyl)~-1-pro-panol(erythro).
(Table I, n24.
6 gr of 1-(4-isopropylthiophenyl-2-~3-(carbo-xy)propylamino~ propanol are dissolved in a mixture con-taining 100 ml of methanol and 50 ml of water. The pH is brought to 13 by addition of a lON sodium hydroxide solu-tion. After stirring for 1 hour at room temperature, metha-nol is evaporated, extraction is made with chloroform, the organic phase is dried on MgSO4 and the solvent is evapora-ted. The product solidifies in petroleum ether and is then recrystallized with ether. 1.3 gr of product are collected, namely a yield of 27%. MP (C) : 80. The conformity of the structure is established by NMR and mass spectrometry (ery-thro configuration).
, Centesimal analysis.
I C H N
; Calculated, % 65.49 7.90 4.77 Found, % 65.15 7.70 4.75 Example 7.
1-(4-Isopropy~thiophenyl)-1,2-propanediol.
(Table I, n 18).
; 170 gr of 1-(4-isopropylthiophenyl)-2-hydro-~ xy-1-propanone are dissolved in 1500 ml of methanol, then ' : - .
~12716 cooled to 0C, 57.4 gr of sodium borohydride are slowly ad-ded ~ith stirring overnight at room temperature. The solvent is evaporated, one dilutes with water, then e~tracts from chloroform and dries on MgS04. After solvent evaporation, recrystallization is made in a benzene-hexane mixture.
; Weight : 66.8 gr ; yield : 39 % ; MP (C) 83-85.
The NMR spectrum confirms the erythro confi-guration of the product so obtained.
Centesimal analysis :
C H
Calculated, % 63.68 8.01 Found, % 63.50 8.05 Example 8.
1-(4-Mercaptophenyl)-2-n-octylamino-1-propanol.
(Table I, n40).
To a solution containing 5.25 gr of lithium, 1000 rnl of liquid ammoniac and 500ml of tetrahydrofuran, a ~, solution comprising 16 gr of 1-(4-isopropylthiophenyl)-2-n-octylamino-l-propanol in 500 ml of tetrahydrofuran is slowly added. After the addition is complete, stirring is still continued for about 15 minutes, then 16 ~r of NH4Cl are ad-ded in small portions.
The ammoniac is slowly evaporated in a wa-ter-bath, then the residue is diluted with water. The solid so obtained is filtered and recrystallized with methanol.
12 gr of 1-(4-mercaptophenyl)-2-n-octylami-no-l-propanol are thus obtained.
MP (C) : 110-112 ; Yield : 82,1%.
- ~ :, :
~1~716 Centesimal analysis C H N
Calculated, % 69.10 9.90 4.74 Found, % 69.40 10.10 4.60 As already hereinabove mentioned, the deri-vatives according to the invention may be as their salts or esters.
` Specific esters are those having the formw-lae Cl~3 cH-cll-N~ c8ll]7 . I~Cl 0,C,-c~2-C(C1~)3 l MP ( C) : 112-114 i! ' C 1/- S 0 ~3 C H - CH - NH nC8H 17 . HC 1 . O-C-Ct~3 O
MP (C) : 14~,5 _ 150 The melting points of the derivatives mentio-ned in the examples, as well as of other derivatives prepa-red according to the invention are given in the following table.
~, ~
~127164 `" 21 ~ _ " _ ~
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1 . . .
(1) the recrystallization solvent is given between brackets.
(2) the elementary analyses were made for C, H, N elements and are in agreement with theoretical values.
(3) melting point of hydrochloride.
(4) erythro configuration.
(5) threo configuration.
(6) erythro/threo mixture.
The compounds according to the invention, while being sparingly to~ic, are generally endowed with ac-tivities on the cardiovascular systems, in particular anti-spasmodic, antihypertensive, peripheral vasodilator acti-vies, hypolipidemient, normolipoproteinemic, antithrombic activities, an inhibing activity against platelet aggrega-tion. Thus they can in particular be useful in the treatment of cardiovascular affections which are bound or not to athe-rosclerosis. Furthermore, they could also reveal as useful as agents stimulating cerebral metabolism or as tranquilli-zers.
The effect on the behaviour has been studied while using a method deriving from that of S.lrwin (Gordon Res. Conf. on Medicinal Chem., 133, 1959). The substances in suspension in a 1% tragacanth gum mucilage were administered orally by means of an intragastric probe to 5 groups of male mice (CCD1 strain, Charles River, fasted from 18 hours). If the available amount of substance allowed it, the doses were 3000, 1000 and 300 mgr/kg. When the substance was active, the effect of the drug was checked at 100, 30, 10 and possi-bly 3 mg/kg. The behaviour was studied 2, 4, 6 and 24 hours after treatment. The observation was continued when symptons . .
llZ7164 were persistent at that time. The mortalities were registe-red during the 14 day period following the treatment. The LD50 values were calculated according to the Hitchfield and Wilcoxon method (J.Pharmacol Exp. Ther., 96, 99, 1949) and expressed as mgr/kg.
The results given as relating to the effects on the behaviour show the minimal active dose in mgr/kg (MAD) and the observed symptomatology. The LD50 values are given with their confidence limits (p = 0.95). Under these conditions, an appreciable activity level was observed, in particular concerning compounds 6, 13 and 20.
The antihypertensive activity was tested by oral administration to spontaneously hypertensed unanaesthe-tized rats, of which the systolic arterial pressure was mea-sured at the level of the median coccidial artery by means ; of a plethysmographic method (J.Roba, G.Lambelin, A.F. De Schaepdryver, Arch.int.Pharmacodyn. 200, 182, 1972).
The arterial pressure was measured every 30 minutes, from two hours before to three hours after oral administration of the products tested at 60 mgr/kg or of a placebo (1% traca-ganth gum mucilage).
Only rats with a systolic pressure of 180 to 220 mm Hg were used. Two rats were used for each product.
The treatments were administered without the knowledge of the persan making the measures. The antihypertensive effects ` were noted by a score followed by an index. The scoring sys-tem was as follows.
0 : reduction < lO mm Hg + : reduction of 10 to 20 mm Hg , 11~,716~a 2~
++ : reduction of 20 to 30 ~m H~
+++ : reduction of 30 to 50 mm Hg ++++ : reduction > 50 mm Hg.
The index was calculated by multiplying the systolic pressure difference (cm Hg) measured every 30 minu-tes after the treatment, by a coefficient of 1 to 6 corres-ponding to the time periods of 30 to 180 mintes.
Vnder the test conditions,~ -methyldopa has been scored ~++ (47) at 100 mg/kg ; reserpine +++ (53) at 3 mgr/kg ; and guanethidine : +++ (62) at 60 mgr/kg.
In these tests, an interesting antihyperten-slve activity was presented in particular by products 6 and
The compounds according to the invention, while being sparingly to~ic, are generally endowed with ac-tivities on the cardiovascular systems, in particular anti-spasmodic, antihypertensive, peripheral vasodilator acti-vies, hypolipidemient, normolipoproteinemic, antithrombic activities, an inhibing activity against platelet aggrega-tion. Thus they can in particular be useful in the treatment of cardiovascular affections which are bound or not to athe-rosclerosis. Furthermore, they could also reveal as useful as agents stimulating cerebral metabolism or as tranquilli-zers.
The effect on the behaviour has been studied while using a method deriving from that of S.lrwin (Gordon Res. Conf. on Medicinal Chem., 133, 1959). The substances in suspension in a 1% tragacanth gum mucilage were administered orally by means of an intragastric probe to 5 groups of male mice (CCD1 strain, Charles River, fasted from 18 hours). If the available amount of substance allowed it, the doses were 3000, 1000 and 300 mgr/kg. When the substance was active, the effect of the drug was checked at 100, 30, 10 and possi-bly 3 mg/kg. The behaviour was studied 2, 4, 6 and 24 hours after treatment. The observation was continued when symptons . .
llZ7164 were persistent at that time. The mortalities were registe-red during the 14 day period following the treatment. The LD50 values were calculated according to the Hitchfield and Wilcoxon method (J.Pharmacol Exp. Ther., 96, 99, 1949) and expressed as mgr/kg.
The results given as relating to the effects on the behaviour show the minimal active dose in mgr/kg (MAD) and the observed symptomatology. The LD50 values are given with their confidence limits (p = 0.95). Under these conditions, an appreciable activity level was observed, in particular concerning compounds 6, 13 and 20.
The antihypertensive activity was tested by oral administration to spontaneously hypertensed unanaesthe-tized rats, of which the systolic arterial pressure was mea-sured at the level of the median coccidial artery by means ; of a plethysmographic method (J.Roba, G.Lambelin, A.F. De Schaepdryver, Arch.int.Pharmacodyn. 200, 182, 1972).
The arterial pressure was measured every 30 minutes, from two hours before to three hours after oral administration of the products tested at 60 mgr/kg or of a placebo (1% traca-ganth gum mucilage).
Only rats with a systolic pressure of 180 to 220 mm Hg were used. Two rats were used for each product.
The treatments were administered without the knowledge of the persan making the measures. The antihypertensive effects ` were noted by a score followed by an index. The scoring sys-tem was as follows.
0 : reduction < lO mm Hg + : reduction of 10 to 20 mm Hg , 11~,716~a 2~
++ : reduction of 20 to 30 ~m H~
+++ : reduction of 30 to 50 mm Hg ++++ : reduction > 50 mm Hg.
The index was calculated by multiplying the systolic pressure difference (cm Hg) measured every 30 minu-tes after the treatment, by a coefficient of 1 to 6 corres-ponding to the time periods of 30 to 180 mintes.
Vnder the test conditions,~ -methyldopa has been scored ~++ (47) at 100 mg/kg ; reserpine +++ (53) at 3 mgr/kg ; and guanethidine : +++ (62) at 60 mgr/kg.
In these tests, an interesting antihyperten-slve activity was presented in particular by products 6 and
7.
The peripheral vasodilator activity of the products was measured on anaesthetized dog at the level of the femoral arterial circulation. To this end, the femoral artery whose the collaterals have been ligatured was perfu-sed with a steady flow rate of blood taken from aorta. The ' :
perfusion pressure, measured at the level of the femoral ar-~,~ 20 tery, thus varied as a function of the resistance of the perfused area. The tested products and the corresponding solvents were directly injected into the stream at a dose of 30 mg/kg. The blood circulation being maintained constant, a vasodilation was thus measured by a decrease of the perfu-.;
sion pressure. The latter was scored with respect to the ac-tion of papaverine, considered as standard and injected once per group of four products.
When being interesting, the products were tested at other doses under the same conditions. The vasodi-- . . . . -: , ,.: - -lator activity was appreciated as follows :
0 : inactive, reduction < 10 mm HG
+ : 1/3 of the papaverine activity ++ : 2/3 of the papaverine activity +++ : activity equal to that of papaverine ++++ : activity higher than that of papaverine.
Amongst the products according to the inven-tion, a peripheral vasodilator activity equal or higher than that of papaverine was observed in particular with compounds 5, 6 and 20.
The antispasmodic activity of the studied substances was examined against contractions of guinea pig ileum such as induced by histamine and acetylcholine. These tests allow to reveal an antihistaminic, anticholinergic or musculotropic activity. The response to the contracting agent (sub-maximum concentration) was obtained every 5 minu-tes before and after injection of increasing doses of the ; tested products (10 7 M to 10 4 M). The inhibition percen-tage under the influence of the tested products was calcu-lated and the theoretical concentration giving 50% inhibi-tion was graphically determined for each experience. Theses values are expressed as -log IC50 (M). In this test, com-pounds 5 and 6 in particular revelated as active.
The blood platelet aggregation was studied according to the turbidimetric method of G.V.R. Born and N.J. Cross (J.Physiol., 168, 178-195, 1973). The plasma rich in platelets was preincubated for 4 minutes before introduc-tion of the inductor (Thrombofax). The slight variations we-re registered for a period of 10 minutes with a aggregometer - . : ~ . . .
'' ' ' 11;2~164 "Upchurch". The inhibition of the amplitudes of the maximum aggregation was measured. This test has shown that in parti-cular compounds 5, 6, 13 and 14 were active.
For the e~amination of the lipolysis inhibi-tion, epididymal fat was taken from fasted rats. Fragments of adipose tissue (+ 150 mgr) were incubated in the Krebs-Ringer buffer containing 3% albumin of bovine serum and thesubstance to be studied. A sample at the time 0 was taken after an incubation of 30 minutes at 37C. Norepinephrine was used for inducing lipolysis. The rate of free amino-acids was measured after 20 minutes of incubation (Duncombe, W.G., Clin.Chim.Acta. 8, 122, 1964). In this test, compounds 5, 6, 8 and 13 were in particular active.
The inhibition of the cholesterol biosynthe-sis was studied as follows.
Buffered homogenates of rat liver were enri-ched with suitable cofactors. Aliquots were incubated for 60 minutes with 1-14C acetate and the compound to be studied.
After saponification of the medium, sterols were extracted from petroleum ether and the dry residue was precipitated by digitonine in a alcohol-acetone solution. The content in 14C
of the precipitate dissolved in pyridine was measured by li-qwid scintillation counting according to the method descri-bed by N.Bucher (~.Biol.Chem., 222, 1-15, 1956~. Under these conditions, an appreciable activity level was shown by com-pounds 1, 13 and 15 in particular.
The inhibition of bioamine uptake by synapto-somes was studied by isolating synaptosomes of rat brains after partial subcellular fractionation in sucrose gradient :
112'71~4 (Gray R. G. and Whittaker V.P., J.Anat. 92, 79, 1962). The uptake of 5-HT (serotonine) was made as follows.
After incubation for 5 mintes of the tested product with synaptosomes, the preparation was incubated for 5 minutes at 37C in the presence of 14C-5HT, filtered on a "Millipore" filters and filters were washed with iced buffer. The radioactivity of the filters was measured by li-quid scintillation counting. The uptake is the difference between the radioactivity measured at 37~C and that measured at 0C. In this test, compounds 5, 6, 13 and 14 were active in particular.
The active compounds according to the inven-tion may be administered in association with various phar-maceutical exceptients orally, parenterally or rectally.
For oral administration, pills, granules, lo-zenges, capsules, and tablets and capsules with controlled release of the active agent will be used, and also sublin-gual tablets, solutions, syrups, emulsions containing tra-ditional additives or excipients in galenic pharmacy. For parenteral administration, sterile water or an oil, such as peanut oil or ethyl oleate will be used. For rectal adminis-tration, suppositories or rectal capsules will be used.
These active compounds may be used alone or in association with other active products ha-ving a similar or different activity.
The products of the invention may be used as different forms. The following examples are not limitative and relate to galenic formulations containing as active pro-., duct, designated by "A" hereinafter, one of the following ~ ;
11;~3~64 compounds :
1-(4-isopropylsulfinylphenyl)-2-~1-(2-oxopyrrolidinyl)~-1-propanol 1-(4-isopropylsulfinylphenyl)-2-n-octylamino-1-propanol.
Intramuscular injection A 10 mgr Isopropyl myristate 0,75 ml Peanut oil, q.s.ad 3 ml Intravenous injection A 10 mgr L-aspartic acid 6 mgr Benzyl alcohol 50 mgr Distilled water, q.s.ad 5 ml Solution for oral administration A 5 mgr Ethyl alcohol 0,1 ml Propylene glycol 0,05 ml 10% Acetic acid 0,05 ml Simple syrup (65% saccharose) q.s.ad 1 ml A 5 mgr Ethyl alcohol 0,2 ml 10% Acetic acid 0~04 ml Simple syrup 3 q . S . ad 1 ml Tablets A 50 mgr 716~ , Lactose 20 mgr Aerosil 2 mgr Starch STA-RX 1500 (Trademark) 18 mgr Calcium phosphate (CaHPO4)25 mgr Microcrystalline cellulose100 mgr Sodium acetate 15 mgr A 50 mgr Corn starch 50 mgr Sodium acetate 15 mgr 10 Magnesium stearate 2 mgr Aerosil (Trademark) 3 mgr Starch STA- RX 1500 (Trademark) 80 mgr Sublingual tablets A 25 mgr Lactose 117,75 mgr Soluble starch 10 mgr ; Sodium saccharine 0,25 mgr i Gelatine 3 mgr A 25 mgr 20 Lactose 150 mgr Saccharose 25 mgr glycine 2.5 mgr Stearic acid 0.5 mgr Capsules A 50 mgr ~1 .
11271¢4 Starch STA-RX 1500 (Trademark)100 mgr Magnesium stearate 1 mgr Sodium laurylsulfate 10 mgr Microcrystalline cellulose 30 mgr Aerosol (Trademark) 1 mgr Soft capsules A 220 mgr Liquid paraffin 222 mgr Soja lecithin 8 mgr Controlled release capsules A 50 mgr Lactose 45 mgr Polyvinyl pyrrolidone 15 mgr Mannitol 5 mgr Eudragit E (Trademark) 1 mgr Suppositories A 150 mgr Lidocaine 20 mgr Novata 299 grad. (Trademark~2000 mgr 20 A 100 mgr Witepsol S 58 grad. (Trademark) 2000 mgr The meaning of some terms used in the above galenic formulations is given hereinafter -- Aerosol (Trademark): finely divided silicium dioxide ~' 6~
- Starch STA-RX 1500 (Trademark): cornstarch - ~idocaine : trade name for lignocaine - Novata 299 grad. (Trademark) : mixture of saturated Cll-C17 fatty acid triglycerides with partial glycerides of acetyla-ted fatty acid - Novata B grad. (Trademark) : mixture of saturated Cll-C17 fatty acid tri-, di- and mono-glycerides - Witepsol S 58 grad. (Trademark): mixture of C12-C18 natural triglycerides - Eudragit E (Trademark) (Rohm) : polymer of acrylic acid di-methylaminoethyl ester According to the case, the administration way, the kind of researched activity and the kind of specific compound used, l-phenyl-l-propanol derivatives according to the invention are administered at daily doses of 5 to 3000 mgr and as intra-venous injection the l-phenyl-l-propanol derivatives according to the invention are administered at daily doses of 1 to 20 mgr;
~,.
-.' ' , :
The peripheral vasodilator activity of the products was measured on anaesthetized dog at the level of the femoral arterial circulation. To this end, the femoral artery whose the collaterals have been ligatured was perfu-sed with a steady flow rate of blood taken from aorta. The ' :
perfusion pressure, measured at the level of the femoral ar-~,~ 20 tery, thus varied as a function of the resistance of the perfused area. The tested products and the corresponding solvents were directly injected into the stream at a dose of 30 mg/kg. The blood circulation being maintained constant, a vasodilation was thus measured by a decrease of the perfu-.;
sion pressure. The latter was scored with respect to the ac-tion of papaverine, considered as standard and injected once per group of four products.
When being interesting, the products were tested at other doses under the same conditions. The vasodi-- . . . . -: , ,.: - -lator activity was appreciated as follows :
0 : inactive, reduction < 10 mm HG
+ : 1/3 of the papaverine activity ++ : 2/3 of the papaverine activity +++ : activity equal to that of papaverine ++++ : activity higher than that of papaverine.
Amongst the products according to the inven-tion, a peripheral vasodilator activity equal or higher than that of papaverine was observed in particular with compounds 5, 6 and 20.
The antispasmodic activity of the studied substances was examined against contractions of guinea pig ileum such as induced by histamine and acetylcholine. These tests allow to reveal an antihistaminic, anticholinergic or musculotropic activity. The response to the contracting agent (sub-maximum concentration) was obtained every 5 minu-tes before and after injection of increasing doses of the ; tested products (10 7 M to 10 4 M). The inhibition percen-tage under the influence of the tested products was calcu-lated and the theoretical concentration giving 50% inhibi-tion was graphically determined for each experience. Theses values are expressed as -log IC50 (M). In this test, com-pounds 5 and 6 in particular revelated as active.
The blood platelet aggregation was studied according to the turbidimetric method of G.V.R. Born and N.J. Cross (J.Physiol., 168, 178-195, 1973). The plasma rich in platelets was preincubated for 4 minutes before introduc-tion of the inductor (Thrombofax). The slight variations we-re registered for a period of 10 minutes with a aggregometer - . : ~ . . .
'' ' ' 11;2~164 "Upchurch". The inhibition of the amplitudes of the maximum aggregation was measured. This test has shown that in parti-cular compounds 5, 6, 13 and 14 were active.
For the e~amination of the lipolysis inhibi-tion, epididymal fat was taken from fasted rats. Fragments of adipose tissue (+ 150 mgr) were incubated in the Krebs-Ringer buffer containing 3% albumin of bovine serum and thesubstance to be studied. A sample at the time 0 was taken after an incubation of 30 minutes at 37C. Norepinephrine was used for inducing lipolysis. The rate of free amino-acids was measured after 20 minutes of incubation (Duncombe, W.G., Clin.Chim.Acta. 8, 122, 1964). In this test, compounds 5, 6, 8 and 13 were in particular active.
The inhibition of the cholesterol biosynthe-sis was studied as follows.
Buffered homogenates of rat liver were enri-ched with suitable cofactors. Aliquots were incubated for 60 minutes with 1-14C acetate and the compound to be studied.
After saponification of the medium, sterols were extracted from petroleum ether and the dry residue was precipitated by digitonine in a alcohol-acetone solution. The content in 14C
of the precipitate dissolved in pyridine was measured by li-qwid scintillation counting according to the method descri-bed by N.Bucher (~.Biol.Chem., 222, 1-15, 1956~. Under these conditions, an appreciable activity level was shown by com-pounds 1, 13 and 15 in particular.
The inhibition of bioamine uptake by synapto-somes was studied by isolating synaptosomes of rat brains after partial subcellular fractionation in sucrose gradient :
112'71~4 (Gray R. G. and Whittaker V.P., J.Anat. 92, 79, 1962). The uptake of 5-HT (serotonine) was made as follows.
After incubation for 5 mintes of the tested product with synaptosomes, the preparation was incubated for 5 minutes at 37C in the presence of 14C-5HT, filtered on a "Millipore" filters and filters were washed with iced buffer. The radioactivity of the filters was measured by li-quid scintillation counting. The uptake is the difference between the radioactivity measured at 37~C and that measured at 0C. In this test, compounds 5, 6, 13 and 14 were active in particular.
The active compounds according to the inven-tion may be administered in association with various phar-maceutical exceptients orally, parenterally or rectally.
For oral administration, pills, granules, lo-zenges, capsules, and tablets and capsules with controlled release of the active agent will be used, and also sublin-gual tablets, solutions, syrups, emulsions containing tra-ditional additives or excipients in galenic pharmacy. For parenteral administration, sterile water or an oil, such as peanut oil or ethyl oleate will be used. For rectal adminis-tration, suppositories or rectal capsules will be used.
These active compounds may be used alone or in association with other active products ha-ving a similar or different activity.
The products of the invention may be used as different forms. The following examples are not limitative and relate to galenic formulations containing as active pro-., duct, designated by "A" hereinafter, one of the following ~ ;
11;~3~64 compounds :
1-(4-isopropylsulfinylphenyl)-2-~1-(2-oxopyrrolidinyl)~-1-propanol 1-(4-isopropylsulfinylphenyl)-2-n-octylamino-1-propanol.
Intramuscular injection A 10 mgr Isopropyl myristate 0,75 ml Peanut oil, q.s.ad 3 ml Intravenous injection A 10 mgr L-aspartic acid 6 mgr Benzyl alcohol 50 mgr Distilled water, q.s.ad 5 ml Solution for oral administration A 5 mgr Ethyl alcohol 0,1 ml Propylene glycol 0,05 ml 10% Acetic acid 0,05 ml Simple syrup (65% saccharose) q.s.ad 1 ml A 5 mgr Ethyl alcohol 0,2 ml 10% Acetic acid 0~04 ml Simple syrup 3 q . S . ad 1 ml Tablets A 50 mgr 716~ , Lactose 20 mgr Aerosil 2 mgr Starch STA-RX 1500 (Trademark) 18 mgr Calcium phosphate (CaHPO4)25 mgr Microcrystalline cellulose100 mgr Sodium acetate 15 mgr A 50 mgr Corn starch 50 mgr Sodium acetate 15 mgr 10 Magnesium stearate 2 mgr Aerosil (Trademark) 3 mgr Starch STA- RX 1500 (Trademark) 80 mgr Sublingual tablets A 25 mgr Lactose 117,75 mgr Soluble starch 10 mgr ; Sodium saccharine 0,25 mgr i Gelatine 3 mgr A 25 mgr 20 Lactose 150 mgr Saccharose 25 mgr glycine 2.5 mgr Stearic acid 0.5 mgr Capsules A 50 mgr ~1 .
11271¢4 Starch STA-RX 1500 (Trademark)100 mgr Magnesium stearate 1 mgr Sodium laurylsulfate 10 mgr Microcrystalline cellulose 30 mgr Aerosol (Trademark) 1 mgr Soft capsules A 220 mgr Liquid paraffin 222 mgr Soja lecithin 8 mgr Controlled release capsules A 50 mgr Lactose 45 mgr Polyvinyl pyrrolidone 15 mgr Mannitol 5 mgr Eudragit E (Trademark) 1 mgr Suppositories A 150 mgr Lidocaine 20 mgr Novata 299 grad. (Trademark~2000 mgr 20 A 100 mgr Witepsol S 58 grad. (Trademark) 2000 mgr The meaning of some terms used in the above galenic formulations is given hereinafter -- Aerosol (Trademark): finely divided silicium dioxide ~' 6~
- Starch STA-RX 1500 (Trademark): cornstarch - ~idocaine : trade name for lignocaine - Novata 299 grad. (Trademark) : mixture of saturated Cll-C17 fatty acid triglycerides with partial glycerides of acetyla-ted fatty acid - Novata B grad. (Trademark) : mixture of saturated Cll-C17 fatty acid tri-, di- and mono-glycerides - Witepsol S 58 grad. (Trademark): mixture of C12-C18 natural triglycerides - Eudragit E (Trademark) (Rohm) : polymer of acrylic acid di-methylaminoethyl ester According to the case, the administration way, the kind of researched activity and the kind of specific compound used, l-phenyl-l-propanol derivatives according to the invention are administered at daily doses of 5 to 3000 mgr and as intra-venous injection the l-phenyl-l-propanol derivatives according to the invention are administered at daily doses of 1 to 20 mgr;
~,.
-.' ' , :
Claims (14)
1. A process for preparing a derivative of 1-phenyl-1-propanol of the general formula I:
(I) wherein:
(a) R1 represents hydrogen, a linear or ramified alkylthio (C1-C3), linear or ramified alkylsulfinyl (C1-C3), linear or ramified alkylsulfonyl (C1-C3) or mercapto radical;
(b) R2 represents:
b-1 a hydroxy radical when R1 is not hydrogen;
b-2 an oxo-2-pyrrolidinyl-1 radical which may be substituted by a hydroxy group;
b-3 a NHR3 radical wherein R3 represents:
- hydrogen when R1 is not hydrogen - a linear or ramified alkyl (C6-C16) radical or a linear alkyl (C2-C4) radical subctituted by a phenyl or phenoxy group, with the proviso that R1 is not an alkylthio radical - a linear or ramified alkyl (C1-C7) radical substituted by a lower carboxy or carbalkoxy (C1-C3) group in the position .omega.;
as well as non toxic and pharmaceutically acceptable salts and esters of these derivatives, said process comprising transforming, into a corresponding derivative of formula I, a compound of formula II:
(II) wherein Z represents one of the substituents R1 such as herein-above defined or corresponds to a group YS in which Y is a protecting group replaceable by hydrogen and Q is one of the following groups:
-CO-HOH-CH3 ; ; ; ;
; , where R2 and R3 have the above-mentioned meaning and X is a halogen atom, said transforming being carried out by:-(i) when R2 is a hydroxy radical, reducing corresponding ketones of general formulae III and IV
(III) (IV) (ii) separating derivatives with erythro and threo configuration, in particular by distillation or plate or column chromatography from erythro-threo mixtures of said derivatives, (iii) when R2 is an oxo-2-pyrrolidinyl-1 radical, possibly sub-stituted by a hydroxy group, condensing a compound of formula II
wherein Q represents the group with 2-pyrrolidinone, either without solvent with possible use of excess of 2-pyrrolidinone or in the presence of a solvent, for example methanol or ethanol, (iv) when R2 is an oxo-2-pyrrolidinyl-1-radical, possibly sub-stituted by a hydroxy group, hydrolyzing a compound of formula:
wherein Z1 has the above-mentioned meaning and R5 represents an alkyl group, more particularly a lower alkyl (C1-C3) radical, in basic medium, or (v) when R2 represents a NHR3 radical in which R3 represents an alkyl radical substituted by a carboxy or carbomethoxy group in the position .omega., condensing a derivative of formula II wherein Q
represents the group with a .omega.-aminoalkanoic acid or with an ester thereof, followed by a reduction, (vi) when R1 is a mercapto radical, replacing by hydrogen, in a compound of formula II wherein Z corresponds to the group YS, the protecting group Y, in particular an alkyl group, such as a lower alkyl radical, ramified or not, by action of alkaline metals, or (vii) when R1 represents an alkylsulfinyl or alkylsulfonyl radical, oxidizing a compound of formula V wherein Z represents an alkyl-thio radical and optionally protecting the functions sensible to the used oxidation agent for example by formation of esters in the case of hydroxy groups or of ketals in the case of ketonic groups, or when R2 is a radical of NHR3 type, transforming into a corresponding derivative of formula I a compound of the general formula V:
(V) or optionally, according to the value of Q, from a salt of a compound having this formula, wherein R1 has the above-mentioned meaning and Q represents one of the following groups:
wherein R3 has the above-mentioned meaning while X represents a halogen atom, said transforming being carried out by:-(viii) for obtaining a derivative of 1-phenyl-1-propanol of general formula I with erythro configuration, reducing a .omega.-aminoketone of formula V, wherein Q represents a group and R1 has the above-mentioned meaning, (ix) for obtaining a derivative with threo configuration, reducing an aminoketone of formula V wherein Q represents a group , preferably by action of alkaline metal hydrides, such as sodium borohydride or aluminium lithium hydride, (x) reacting a compound of formula V wherein Q represents a group with an amine R3NH2, preferably in a solvent such as alcohols, chloroform, dioxan, carbon tetrachloride, most easily in the presence of a scavenger for the formed halogen hydride, such as inorganic or organic bases, or still in the presence of excess of amine, or (xi) reacting an oxirane of formula V wherein Q represents a group with an amine R3NH3, preferably in a solvent such as alcohols, chloroform, dioxan, carbon tetrachloride and most easily in the presence of a scavenger for the formed halogen hydride, such as inorganic or organic bases, or still in the presence of excess of amine.
(I) wherein:
(a) R1 represents hydrogen, a linear or ramified alkylthio (C1-C3), linear or ramified alkylsulfinyl (C1-C3), linear or ramified alkylsulfonyl (C1-C3) or mercapto radical;
(b) R2 represents:
b-1 a hydroxy radical when R1 is not hydrogen;
b-2 an oxo-2-pyrrolidinyl-1 radical which may be substituted by a hydroxy group;
b-3 a NHR3 radical wherein R3 represents:
- hydrogen when R1 is not hydrogen - a linear or ramified alkyl (C6-C16) radical or a linear alkyl (C2-C4) radical subctituted by a phenyl or phenoxy group, with the proviso that R1 is not an alkylthio radical - a linear or ramified alkyl (C1-C7) radical substituted by a lower carboxy or carbalkoxy (C1-C3) group in the position .omega.;
as well as non toxic and pharmaceutically acceptable salts and esters of these derivatives, said process comprising transforming, into a corresponding derivative of formula I, a compound of formula II:
(II) wherein Z represents one of the substituents R1 such as herein-above defined or corresponds to a group YS in which Y is a protecting group replaceable by hydrogen and Q is one of the following groups:
-CO-HOH-CH3 ; ; ; ;
; , where R2 and R3 have the above-mentioned meaning and X is a halogen atom, said transforming being carried out by:-(i) when R2 is a hydroxy radical, reducing corresponding ketones of general formulae III and IV
(III) (IV) (ii) separating derivatives with erythro and threo configuration, in particular by distillation or plate or column chromatography from erythro-threo mixtures of said derivatives, (iii) when R2 is an oxo-2-pyrrolidinyl-1 radical, possibly sub-stituted by a hydroxy group, condensing a compound of formula II
wherein Q represents the group with 2-pyrrolidinone, either without solvent with possible use of excess of 2-pyrrolidinone or in the presence of a solvent, for example methanol or ethanol, (iv) when R2 is an oxo-2-pyrrolidinyl-1-radical, possibly sub-stituted by a hydroxy group, hydrolyzing a compound of formula:
wherein Z1 has the above-mentioned meaning and R5 represents an alkyl group, more particularly a lower alkyl (C1-C3) radical, in basic medium, or (v) when R2 represents a NHR3 radical in which R3 represents an alkyl radical substituted by a carboxy or carbomethoxy group in the position .omega., condensing a derivative of formula II wherein Q
represents the group with a .omega.-aminoalkanoic acid or with an ester thereof, followed by a reduction, (vi) when R1 is a mercapto radical, replacing by hydrogen, in a compound of formula II wherein Z corresponds to the group YS, the protecting group Y, in particular an alkyl group, such as a lower alkyl radical, ramified or not, by action of alkaline metals, or (vii) when R1 represents an alkylsulfinyl or alkylsulfonyl radical, oxidizing a compound of formula V wherein Z represents an alkyl-thio radical and optionally protecting the functions sensible to the used oxidation agent for example by formation of esters in the case of hydroxy groups or of ketals in the case of ketonic groups, or when R2 is a radical of NHR3 type, transforming into a corresponding derivative of formula I a compound of the general formula V:
(V) or optionally, according to the value of Q, from a salt of a compound having this formula, wherein R1 has the above-mentioned meaning and Q represents one of the following groups:
wherein R3 has the above-mentioned meaning while X represents a halogen atom, said transforming being carried out by:-(viii) for obtaining a derivative of 1-phenyl-1-propanol of general formula I with erythro configuration, reducing a .omega.-aminoketone of formula V, wherein Q represents a group and R1 has the above-mentioned meaning, (ix) for obtaining a derivative with threo configuration, reducing an aminoketone of formula V wherein Q represents a group , preferably by action of alkaline metal hydrides, such as sodium borohydride or aluminium lithium hydride, (x) reacting a compound of formula V wherein Q represents a group with an amine R3NH2, preferably in a solvent such as alcohols, chloroform, dioxan, carbon tetrachloride, most easily in the presence of a scavenger for the formed halogen hydride, such as inorganic or organic bases, or still in the presence of excess of amine, or (xi) reacting an oxirane of formula V wherein Q represents a group with an amine R3NH3, preferably in a solvent such as alcohols, chloroform, dioxan, carbon tetrachloride and most easily in the presence of a scavenger for the formed halogen hydride, such as inorganic or organic bases, or still in the presence of excess of amine.
2. A process according to claim 1 wherein R3 represents a linear or ramified alkyl (C10-C16) radical.
3. A process according to claim 1 wherein R3 represents a linear or ramified alkyl (C6-C10) radical.
4. A process according to claim 3 wherein R3 represents a linear or ramified octyl radical.
5. A process according to claim 1 wherein R1 represents a linear or ramified alkylthio (C1-C3) radical.
6. A process according to claim 1 wherein R1 represents a linear or ramified alkylsulfinyl (C1-C3) radical.
7. A process according to claim 1 wherein R2 represents a NHR3 radical in which R3 is a linear or ramified alkyl (C1-C3) radical substituted by a carboxy or carbomethoxy group in the position .omega..
8. A process according to claim 1 wherein the derivative is selected from the following group of compounds:
1-(4-isopropylsulfinylphenyl)-2-n-octylamino-1-propanol 1-(4-isopropylthiophenyl)-2-[3-(methoxycarbonyl)propylamino]-1-propanol 1-(4-isopropylthiophenyl)-2-[3-(carboxy)propylamino]-1-propanol 1-(4-methylthiophenyl)-2-[3-(methoxycarbonyl)propylamino]-1-propanol 1-(4-methylthiophenyl)-2-[3-(carboxy)propylamino]-1-propanol 1-(4-isopropylsulfinylphenyl)-2-[3-(methoxycarbonyl)propyl-amino-1-propanol 1-(4-isopropylsulfinylphenyl)-2-[3-(carboxy)propylamino]-1-propanol 1-(4-isopropylsulfinylphenyl)-2-[1-(2-oxopyrrolidinyl]-1-propanol 1-(4-mercaptophenyl)-2-n-octylamino-1-propanol
1-(4-isopropylsulfinylphenyl)-2-n-octylamino-1-propanol 1-(4-isopropylthiophenyl)-2-[3-(methoxycarbonyl)propylamino]-1-propanol 1-(4-isopropylthiophenyl)-2-[3-(carboxy)propylamino]-1-propanol 1-(4-methylthiophenyl)-2-[3-(methoxycarbonyl)propylamino]-1-propanol 1-(4-methylthiophenyl)-2-[3-(carboxy)propylamino]-1-propanol 1-(4-isopropylsulfinylphenyl)-2-[3-(methoxycarbonyl)propyl-amino-1-propanol 1-(4-isopropylsulfinylphenyl)-2-[3-(carboxy)propylamino]-1-propanol 1-(4-isopropylsulfinylphenyl)-2-[1-(2-oxopyrrolidinyl]-1-propanol 1-(4-mercaptophenyl)-2-n-octylamino-1-propanol
9. A process according to claim 1 wherein the derivative is of the erythro configuration at the level of the two asymmetri-cal carbon atoms of the propanol chain.
10. A process according to claim 1 wherein the reduction of paragraph (i) is made by action of metal hydrides or by action of complex metal hydrides in aromatic solvents or in ethers or alcohols, by action of alkaline metals, such as sodium or lithium, in solvents such as ammoniac or ethanol, by action of hydrogen in the presence of hydrogenation catalysts, such as platinum or palladium, in solvents such as ethanol or by action of aluminium alkoxides, such as aluminium isopropoxide, in a solvent such as isopropanol.
11. A process according to claim 1 wherein the hydrolysis of paragraph (iv) is made by action of an organic or inorganic base, for example an alkoxide or sodium or potassium hydroxide in an alcoholic or hydro-alcoholic solvent such as methanol, ethanol or isopropanol at a temperature between room temperature and the reflux temperature of the selected solvent but most advantageously at room temperature.
12. A process according to claim 1 wherein the condensation of paragraph (v) is carried out in a solvent such a methanol, ethanol, chloroform, acetonitrile, benzene or a mixture thereof, most advantageously at room temperature.
13. A process according to claim 1 wherein the reduction of paragraph (v) is made by alkaline metal hydrides, more particularly BaBH4 in a solvent such as methanol or ethanol at room temperature.
14. A process according to claim 1 wherein the reduction of paragraph (viii) is made by action of alkaline metal hydrides, such as sodium borohydride, in a solvent such as methanol or ethanol, preferably at low temperature, or by action of aluminium lithium hydride in a solvent such as diethyl ether or tetra-hydrofuran, or by action of an aluminium alkoxide, such as aluminium propoxide in a solvent such as isopropanol, most advantageously at the 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LU79970A LU79970A1 (en) | 1978-07-13 | 1978-07-13 | PROCESS FOR THE PREPARATION OF 1-PHENYL-1-PROPANOL DERIVATIVES |
| LU79.970 | 1978-07-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1127164A true CA1127164A (en) | 1982-07-06 |
Family
ID=19728955
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA331,500A Expired CA1127164A (en) | 1978-07-13 | 1979-07-10 | Derivatives of 1-phenyl-1-propanol |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS5943943B2 (en) |
| AT (1) | AT368491B (en) |
| BE (1) | BE877694A (en) |
| CA (1) | CA1127164A (en) |
| CH (1) | CH644355A5 (en) |
| DE (1) | DE2927789A1 (en) |
| DK (1) | DK293779A (en) |
| ES (1) | ES482432A1 (en) |
| FI (1) | FI792123A (en) |
| FR (2) | FR2438649A1 (en) |
| GB (1) | GB2025417B (en) |
| IT (1) | IT1122180B (en) |
| LU (1) | LU79970A1 (en) |
| NL (1) | NL7905507A (en) |
| NO (1) | NO148452C (en) |
| PT (1) | PT69909A (en) |
| SE (1) | SE446631B (en) |
| ZA (1) | ZA793554B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8178077B2 (en) | 2004-10-19 | 2012-05-15 | Reverse Proteomics Research Institute Co., Ltd. | Drug development target protein and target gene, and method of screening |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3128117A1 (en) * | 1980-07-29 | 1982-03-11 | Yamanouchi Pharmaceutical Co., Ltd., Tokyo | NEW PHENYL-AETHYLAMINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF |
| LU83039A1 (en) * | 1980-12-24 | 1982-07-07 | Continental Pharma | METHODS OF SYNTHESIS OF 1- (4 ISOPROPYLTHIOPHENYL) -2-N OCTYLAMINOPROPANOL |
| EP0066919B1 (en) * | 1981-05-27 | 1985-03-20 | MAGGIONI FARMACEUTICI S.p.A. | 4-alkyl-thiophenyl-ethanolamines, having an activity on the cerebral circulation, the blood platelet-aggregation and the lipemia |
| FR2537132B1 (en) * | 1982-12-06 | 1987-01-09 | Lafon Labor | NOVEL SULFUR DERIVATIVES OF 2-AMINO-1-PHENYL-1-ETHANOL, USE IN THERAPEUTICS AND METHOD OF PREPARATION |
| US4582918A (en) * | 1984-09-19 | 1986-04-15 | Schering Corporation | Preparation of intermediates for (threo)-1-aryl-2-acylamido-3-fluoro-1-propanols |
| BE1014245A4 (en) * | 2001-04-03 | 2003-07-01 | Malak Jean | Chemical compounds octopamine derivatives and uses thereof as agonists beta 3-adrenergic. |
| IL187245A0 (en) * | 2007-11-08 | 2008-12-29 | Hadasit Med Res Service | Synthetic sphingolipid analogs |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1366096A (en) * | 1962-05-28 | 1964-07-10 | Castrol Ltd | Copolymers for use in lubricating oil compositions and their intermediates |
| FR1480780A (en) * | 1965-05-24 | 1967-05-12 | Shell Int Research | Pyrrolidone production |
-
1978
- 1978-07-13 LU LU79970A patent/LU79970A1/en unknown
-
1979
- 1979-07-05 FI FI792123A patent/FI792123A/en not_active Application Discontinuation
- 1979-07-10 DE DE19792927789 patent/DE2927789A1/en not_active Ceased
- 1979-07-10 SE SE7905992A patent/SE446631B/en not_active Application Discontinuation
- 1979-07-10 CA CA331,500A patent/CA1127164A/en not_active Expired
- 1979-07-11 AT AT0483579A patent/AT368491B/en not_active IP Right Cessation
- 1979-07-12 CH CH651479A patent/CH644355A5/en not_active IP Right Cessation
- 1979-07-12 DK DK293779A patent/DK293779A/en not_active Application Discontinuation
- 1979-07-12 NO NO792329A patent/NO148452C/en unknown
- 1979-07-12 GB GB7924292A patent/GB2025417B/en not_active Expired
- 1979-07-12 ES ES482432A patent/ES482432A1/en not_active Expired
- 1979-07-12 PT PT69909A patent/PT69909A/en unknown
- 1979-07-12 FR FR7918156A patent/FR2438649A1/en active Granted
- 1979-07-13 NL NL7905507A patent/NL7905507A/en not_active Application Discontinuation
- 1979-07-13 JP JP54088352A patent/JPS5943943B2/en not_active Expired
- 1979-07-13 BE BE0/196294A patent/BE877694A/en not_active IP Right Cessation
- 1979-07-13 ZA ZA00793554A patent/ZA793554B/en unknown
- 1979-07-13 IT IT24357/79A patent/IT1122180B/en active
-
1980
- 1980-02-13 FR FR8003187A patent/FR2443457A1/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8178077B2 (en) | 2004-10-19 | 2012-05-15 | Reverse Proteomics Research Institute Co., Ltd. | Drug development target protein and target gene, and method of screening |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2443457A1 (en) | 1980-07-04 |
| PT69909A (en) | 1979-08-01 |
| FI792123A (en) | 1980-01-14 |
| NO148452C (en) | 1983-10-12 |
| AT368491B (en) | 1982-10-11 |
| FR2438649A1 (en) | 1980-05-09 |
| NL7905507A (en) | 1980-01-15 |
| BE877694A (en) | 1979-11-05 |
| NO148452B (en) | 1983-07-04 |
| GB2025417B (en) | 1983-03-02 |
| DK293779A (en) | 1980-01-14 |
| IT7924357A0 (en) | 1979-07-13 |
| SE7905992L (en) | 1980-01-14 |
| JPS5943943B2 (en) | 1984-10-25 |
| GB2025417A (en) | 1980-01-23 |
| ATA483579A (en) | 1982-02-15 |
| IT1122180B (en) | 1986-04-23 |
| NO792329L (en) | 1980-01-15 |
| DE2927789A1 (en) | 1980-01-24 |
| SE446631B (en) | 1986-09-29 |
| FR2443457B1 (en) | 1983-09-23 |
| CH644355A5 (en) | 1984-07-31 |
| LU79970A1 (en) | 1980-02-14 |
| ZA793554B (en) | 1980-06-25 |
| ES482432A1 (en) | 1980-04-01 |
| FR2438649B1 (en) | 1983-03-25 |
| JPS5533467A (en) | 1980-03-08 |
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