CA1196919A - N-substituted 2,4-dialkoxy benzensulfonamides - Google Patents
N-substituted 2,4-dialkoxy benzensulfonamidesInfo
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- CA1196919A CA1196919A CA000401378A CA401378A CA1196919A CA 1196919 A CA1196919 A CA 1196919A CA 000401378 A CA000401378 A CA 000401378A CA 401378 A CA401378 A CA 401378A CA 1196919 A CA1196919 A CA 1196919A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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Abstract
ABSTRACT
N-substituted 2,4-dialkoxy benzenesulfonamides.
The invention relates to new N-substituted benzenesulfonamides, the process for their preparation and their use.
The compounds according to the invention correspond to the general forrnula (I) :
(I) in which :
n and m have values from O to 4 ;
R3 and R4 represent in particular a lower alkyl radical ;
R1 and R2 represent in particular hydrogen atoms, linear or branched alkyl groups having from 1 to 4 carbon atoms ;
R5 represents particularly a hydrogen atom, a halogen, the NO2, NH2, or CF3 group ;
R6 and R7 represent in particular a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms.
The invention is useful in the preparation of tranquilizing or anxiolytic medicines.
(no Figure).
N-substituted 2,4-dialkoxy benzenesulfonamides.
The invention relates to new N-substituted benzenesulfonamides, the process for their preparation and their use.
The compounds according to the invention correspond to the general forrnula (I) :
(I) in which :
n and m have values from O to 4 ;
R3 and R4 represent in particular a lower alkyl radical ;
R1 and R2 represent in particular hydrogen atoms, linear or branched alkyl groups having from 1 to 4 carbon atoms ;
R5 represents particularly a hydrogen atom, a halogen, the NO2, NH2, or CF3 group ;
R6 and R7 represent in particular a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms.
The invention is useful in the preparation of tranquilizing or anxiolytic medicines.
(no Figure).
Description
N-substituted 2,4-dialkoxy benzenesulfonamides.
The invention relates to new compounds of the N-substitu-ted benzenesulfonamide type as well as to their corresponding salts. The invention also relates to a process for preparing these compounds. The in-vention finally relates to new medicaments containing, as active principle, these new compounds of the N-substituted benzenesulfonamide type as well as their salts obtained with physiologically acceptable organic or inorganic acids. The new N-substituted benzene-sulfonamides according to the invention correspond to the general formula:
SO - N - (CH2)n - CH (CH2)m \ R (I) in which:
n and m independently from each other take values from 0 to 4;
R3 and R4 each represent, independently from each other, a lower alkyl radical having from 1 to 4 carbon atoms;
Rl and R2 represent~ independently from each other, hydrogen atoms, linear or branched alkyl groups having from 1 to 4 carbon atoms, or forming conjointly with the nitrogen atom a heterocyclic nitrogenous group with 5 or 6 links, particularly a pyrrolidino, morpholino, piperazinyl, pyrrole or piperidino group substituted or not by linear or branched alkyl radicals having from 1 to 4 carbon atoms;
R5 represents a hydrogen atom, a halogen, the NO2, NH2, CF3 group or an alkoxy radical having from 1 to 4 carbon atoms, or an alkylsulfonyl radical having from 1 to 4 carbon atoms;
6~
R6 and R7 representing, independently Erom each other, a hydrogen atom, an alkyl radical with 1 to 6 carbon atoms or a cycloalkyl radical with 3 to 6 carbon atoms.
The invention also rela-tes to the addition sal-ts of compounds of formula (I) obtained with physio-logically acceptable organic or inorganic acids.
The invention is also concerned, when R7 is different from the hydrogen atom, with all the optical isomers of the compounds of formula (I) as well as their salts obtained with physiologically acceptable organic or inorganic acids.
As physiologically acceptable organic or inor-ganic salts, may be mentioned, for example, the hydro-chloride, the hydrobromide, sulfates, phosphates, methane sulfonate, acetate, fumarate, succinate, lactate, pyru-vate, citrate, tartrate, maleate, malonate, benzoate, salicylate, 2,6-dichloro-benzoate, trimethoxy benzoate, diamino benzene sulfonate, chromoglycate, benzene sulfo-na e, dipropyl ace-tate and l-glucose phosphate.
In the rest of the description, the compounds of formula (I) accordin~ to the invention in which R5 represents a hydrogen atom, are denoted by disubstituted compounds and whose in which R5 has the aboveindicated meaning, with the exception of hydrogen, are denoted by trisubstituted compounds.
A preferred class of compounds according to the invention is constituted by the 2,~-dialkoxy benzene sulfonamides possibly substituted in the 5 position and corresponding to the following formula (II) :
The invention relates to new compounds of the N-substitu-ted benzenesulfonamide type as well as to their corresponding salts. The invention also relates to a process for preparing these compounds. The in-vention finally relates to new medicaments containing, as active principle, these new compounds of the N-substituted benzenesulfonamide type as well as their salts obtained with physiologically acceptable organic or inorganic acids. The new N-substituted benzene-sulfonamides according to the invention correspond to the general formula:
SO - N - (CH2)n - CH (CH2)m \ R (I) in which:
n and m independently from each other take values from 0 to 4;
R3 and R4 each represent, independently from each other, a lower alkyl radical having from 1 to 4 carbon atoms;
Rl and R2 represent~ independently from each other, hydrogen atoms, linear or branched alkyl groups having from 1 to 4 carbon atoms, or forming conjointly with the nitrogen atom a heterocyclic nitrogenous group with 5 or 6 links, particularly a pyrrolidino, morpholino, piperazinyl, pyrrole or piperidino group substituted or not by linear or branched alkyl radicals having from 1 to 4 carbon atoms;
R5 represents a hydrogen atom, a halogen, the NO2, NH2, CF3 group or an alkoxy radical having from 1 to 4 carbon atoms, or an alkylsulfonyl radical having from 1 to 4 carbon atoms;
6~
R6 and R7 representing, independently Erom each other, a hydrogen atom, an alkyl radical with 1 to 6 carbon atoms or a cycloalkyl radical with 3 to 6 carbon atoms.
The invention also rela-tes to the addition sal-ts of compounds of formula (I) obtained with physio-logically acceptable organic or inorganic acids.
The invention is also concerned, when R7 is different from the hydrogen atom, with all the optical isomers of the compounds of formula (I) as well as their salts obtained with physiologically acceptable organic or inorganic acids.
As physiologically acceptable organic or inor-ganic salts, may be mentioned, for example, the hydro-chloride, the hydrobromide, sulfates, phosphates, methane sulfonate, acetate, fumarate, succinate, lactate, pyru-vate, citrate, tartrate, maleate, malonate, benzoate, salicylate, 2,6-dichloro-benzoate, trimethoxy benzoate, diamino benzene sulfonate, chromoglycate, benzene sulfo-na e, dipropyl ace-tate and l-glucose phosphate.
In the rest of the description, the compounds of formula (I) accordin~ to the invention in which R5 represents a hydrogen atom, are denoted by disubstituted compounds and whose in which R5 has the aboveindicated meaning, with the exception of hydrogen, are denoted by trisubstituted compounds.
A preferred class of compounds according to the invention is constituted by the 2,~-dialkoxy benzene sulfonamides possibly substituted in the 5 position and corresponding to the following formula (II) :
2 - NH - (CH2)n - N / 1 k ~ ' 3 \ R2 5 1 (II) in which:
n takes -the values of 1 to 4, particularly 2 or 3;
R3 and R4 each represent, independen-tly from each other, a lower alkyl radical having from 1 to 4 carbon atoms, Rl and R2 represent independently from each other, hydrogen atoms, linear or branched alkyl groups having from 1 to 4 carbon atoms, or forming conjointly with the nitrogen atom a nitrogeneous heterocyclic group with 5 ox 6 links, particularly a pyrrolidino, morpholino, piperazinyl, pyrrole or piperidino group substituted or not by linear or branched radicals having from 1 to 4 carbon atoms, R5 represents a hydrogen atom, halogen, the group NO2, NH2, CF3, an alkoxy radical having from 1 to 4 carbon atoms, or an alkyl sulfonyl radical having from 1 to 4 carbon atoms.
A preferred class of compounds according to the invention is cons-tituted by the 2,4-dimethoxy benzenesulfonamides substituted in the 5 position and corresponding to the following general formula (III)o / Rl S2 - NH - (CH2)n - N \ (III) ~ OCH3 2 R5 ~
in which n, Rl, R2, R5 have the aboveindicated meanings.
An advantageous class of compounds according to the invention is constituted by the 2,4-dimethoxy benzenesulfonamides of formula (III) in which n, Rl, R2 have the aboveindicated meanings and R5 represen-ts hydrogen. These compounds are disubstituted.
Among the disubstituted compounds an advanta-geous class of compounds according to the invention is ~1 constituted by the compounds of formula (III) in which :
n is 2 or 3 ;
R5 represents a hydrogen atom ;
-N _ R1 represents one of the radicals selected frorn the group comprising dimethylamino, diethylamino, pyrro-lidino, piperidino, morpholino or piperidino radicals substituted by a methyl group at the 2 position.
An advantageous class of compounds according to the invention is constituted by the 2,4-dimethoxy ben-zenesulfonamides substituted at the 5 position, of for-m;ila (III) in which n, Rl and R2 have the aboveindicated meanings, R5 has also the aboveindicated meaning, with the exception of hydrogen. These compounds are trisubsti-tuted.
Among these trisubstituted compounds, an ad-vantageous class of compounds according to the invention is constituted by the compounds of formula (III), in which R5 represents Cl, Br, OCH3, S02C2H5, S02nC3H7, 20 S02iC3H7, Another advantageous class of trisubstituted compounds according to the invention is constituted by the compounds of formula (III) in which R5 represents Cl, Br, OCH3.
Another class of preferred trisubstituted compounds according to the invention is constituted by the compounds of formula (III) in which :
n is 2 or 3 ;
R5 represents the OCH3, Cl, Br, S02-CH3, S02C2H5, 30 so2nC3H7, S2iC3 7 -N - R1 represents one of the radicals selected from the group comprising dimethylamino, diethylamino, pyrro-lidino, piperidino, morpholino or piperidino radicals substituted by a methyl group particularly at the 2 position.
~9~
A preferred class of trisubstituted compounds according to the invention is constituted by the com-pounds of formula (III) in which :
n is 2 or 3 ;
5 R5 represents Cl, Br, S02CH3, S02C2H5 ;
and -N R1 represents the pyrrolidino, piperidino or \R2 morpholino radical.
A particularly advantageous class of trisub-stituted compounds is constituted by the compounds of formula (III) in which :
n is 2 or 3 ;
R5 represents Cl, Br, S02CH3 ;
and -N _ R1 represents the pyrrolidino, piperidino or morpholino radical.
Another advantageous class of trisubstituted compounds according to the invention is constituted by the compounds of formula (III) in which :
n is 3 ;
R5 represents Cl, Br, S02CH3, OCH3 ;
and -N _ R1 represents the morpholino radical.
Another advantageous class of trlsubstitu~ed compounds according to the invention is constituted by the compounds of ~ormula (III) in which :
n is 2 ;
R5 represents S02C2H5 ;
and -N _ R1 represents the diethylamino radical or n is 3 ;
R5 represents S02C2H5 ;
and -N _ Rl represents the dimethylamino or diethyla-mino radical~
The compounds of these various preferred ~6~
groups are advantageously in the Eorm of salts, particu-larly the hydrochloride.
To -form the compounds according to the inven-tion, it is possible to have recourse to the sulfohali-des, particularly to the sulfohalides of formula (IV) :
52- ~
, l~3 (IV) ~//
q in which X is a halogen group, particularly bromine or preferably chlorine, R3 and R4 each representing, inde-pendently from each other, a lower alkyl radical havingfrom 1 to 4 carbon atoms, A has any one of the above-indicated meanings for R5, with the exception of NH2 (that is to say represents hydrogen, a halogen, alkoxy radicals having from 1 to 4 carbon atoms, alkylsulfonyl groups having 1 to 4 carbon atoms, or the group N02, CF3).
To prepare the sulfohalides of formula (IV) indicated above, particularly the sulfochlorides of formula (V) :
~7C' , OK3 Il J (v) ''~--1//
q _ in which A, R3 and R4 have the aboveindicated meanings, recourse may be had to the arylamine of formula (VI) :
~
~7~3bi~
~ OR3 J I (VI) A
in which A, R3 and R4 have the aboveindicated meanings, and from which:
a) the diazonium salt is formed particularly the diazonium chloride of formula (VII). This diazonium salt is obtained particularly by reacting the arylamine in a solution of the corresponding halo acid, particu-larly hydrochloric acid, with a solution of a nitrite of alkali metal, and keepiny the reaction mixture at a temperature preferably lower than about 10C.
b) the diazonium salt obtained is then reacted in solution with sulfurous anhydride. The operation is preferably carried out in the presence of acetic acid as well as of a catalyst suitable for assisting in the con-version of the diazonium group into a sulfohalide group,particularly sulfochloride~ This catalyst is, for example, based on copper (modified Sandmeyer reaction).
The steps a) and b) of this reac~ion applied by way of example to the preparation of sulfochlorides of formula (V) may be represented as follows:
NH2 N-N, Cl ~ 3 NaNO2 ~ ~ OR3 A ~ J HCl ~ (VII) N_N, Cl SO2Cl (VII)~ - _ 2 ~ ~ OR3 A ~ copper salt A
~4 OR4 ~' By way of preferred arylamines for the prepa-ration oE the sulfochlorides of formula (V) may be men-tioned :
2,4-dimethoxy aniline 5-chloro 2,4-dimethoxy aniline, 5-bromo 2,4-dimethoxy aniline, 2,4,5-trimethoxy aniline, 2,4-dimethoxy 5-methylsulfonyl aniline, 2,4-dimethoxy S-ethylsulfonyl ani.line, 2,4-dimethoxy 5-propylsulfonyl aniline, 2,4-dimethoxy 5-isopropylsulfonyl aniline.
To prepare the sulfochlorides of formula (V) in which A has the aboveindicated meaning, it is also possible to proceed by sulfonation or halogenosulfona-tion, preferably chlorosulfonation of the compound offormula (VIII) in which A, R3 and R4 have the above-indicated meanings :
~ OR
I ~ 3 ~ I (VIII) ~ \//
4 _ In the case of sulfonation (by reaction of the compound (VIII) with sulfuric acid) in a first step the sulfonic acid of formula (IX) was obtained :
~o~
n takes -the values of 1 to 4, particularly 2 or 3;
R3 and R4 each represent, independen-tly from each other, a lower alkyl radical having from 1 to 4 carbon atoms, Rl and R2 represent independently from each other, hydrogen atoms, linear or branched alkyl groups having from 1 to 4 carbon atoms, or forming conjointly with the nitrogen atom a nitrogeneous heterocyclic group with 5 ox 6 links, particularly a pyrrolidino, morpholino, piperazinyl, pyrrole or piperidino group substituted or not by linear or branched radicals having from 1 to 4 carbon atoms, R5 represents a hydrogen atom, halogen, the group NO2, NH2, CF3, an alkoxy radical having from 1 to 4 carbon atoms, or an alkyl sulfonyl radical having from 1 to 4 carbon atoms.
A preferred class of compounds according to the invention is cons-tituted by the 2,4-dimethoxy benzenesulfonamides substituted in the 5 position and corresponding to the following general formula (III)o / Rl S2 - NH - (CH2)n - N \ (III) ~ OCH3 2 R5 ~
in which n, Rl, R2, R5 have the aboveindicated meanings.
An advantageous class of compounds according to the invention is constituted by the 2,4-dimethoxy benzenesulfonamides of formula (III) in which n, Rl, R2 have the aboveindicated meanings and R5 represen-ts hydrogen. These compounds are disubstituted.
Among the disubstituted compounds an advanta-geous class of compounds according to the invention is ~1 constituted by the compounds of formula (III) in which :
n is 2 or 3 ;
R5 represents a hydrogen atom ;
-N _ R1 represents one of the radicals selected frorn the group comprising dimethylamino, diethylamino, pyrro-lidino, piperidino, morpholino or piperidino radicals substituted by a methyl group at the 2 position.
An advantageous class of compounds according to the invention is constituted by the 2,4-dimethoxy ben-zenesulfonamides substituted at the 5 position, of for-m;ila (III) in which n, Rl and R2 have the aboveindicated meanings, R5 has also the aboveindicated meaning, with the exception of hydrogen. These compounds are trisubsti-tuted.
Among these trisubstituted compounds, an ad-vantageous class of compounds according to the invention is constituted by the compounds of formula (III), in which R5 represents Cl, Br, OCH3, S02C2H5, S02nC3H7, 20 S02iC3H7, Another advantageous class of trisubstituted compounds according to the invention is constituted by the compounds of formula (III) in which R5 represents Cl, Br, OCH3.
Another class of preferred trisubstituted compounds according to the invention is constituted by the compounds of formula (III) in which :
n is 2 or 3 ;
R5 represents the OCH3, Cl, Br, S02-CH3, S02C2H5, 30 so2nC3H7, S2iC3 7 -N - R1 represents one of the radicals selected from the group comprising dimethylamino, diethylamino, pyrro-lidino, piperidino, morpholino or piperidino radicals substituted by a methyl group particularly at the 2 position.
~9~
A preferred class of trisubstituted compounds according to the invention is constituted by the com-pounds of formula (III) in which :
n is 2 or 3 ;
5 R5 represents Cl, Br, S02CH3, S02C2H5 ;
and -N R1 represents the pyrrolidino, piperidino or \R2 morpholino radical.
A particularly advantageous class of trisub-stituted compounds is constituted by the compounds of formula (III) in which :
n is 2 or 3 ;
R5 represents Cl, Br, S02CH3 ;
and -N _ R1 represents the pyrrolidino, piperidino or morpholino radical.
Another advantageous class of trisubstituted compounds according to the invention is constituted by the compounds of formula (III) in which :
n is 3 ;
R5 represents Cl, Br, S02CH3, OCH3 ;
and -N _ R1 represents the morpholino radical.
Another advantageous class of trlsubstitu~ed compounds according to the invention is constituted by the compounds of ~ormula (III) in which :
n is 2 ;
R5 represents S02C2H5 ;
and -N _ R1 represents the diethylamino radical or n is 3 ;
R5 represents S02C2H5 ;
and -N _ Rl represents the dimethylamino or diethyla-mino radical~
The compounds of these various preferred ~6~
groups are advantageously in the Eorm of salts, particu-larly the hydrochloride.
To -form the compounds according to the inven-tion, it is possible to have recourse to the sulfohali-des, particularly to the sulfohalides of formula (IV) :
52- ~
, l~3 (IV) ~//
q in which X is a halogen group, particularly bromine or preferably chlorine, R3 and R4 each representing, inde-pendently from each other, a lower alkyl radical havingfrom 1 to 4 carbon atoms, A has any one of the above-indicated meanings for R5, with the exception of NH2 (that is to say represents hydrogen, a halogen, alkoxy radicals having from 1 to 4 carbon atoms, alkylsulfonyl groups having 1 to 4 carbon atoms, or the group N02, CF3).
To prepare the sulfohalides of formula (IV) indicated above, particularly the sulfochlorides of formula (V) :
~7C' , OK3 Il J (v) ''~--1//
q _ in which A, R3 and R4 have the aboveindicated meanings, recourse may be had to the arylamine of formula (VI) :
~
~7~3bi~
~ OR3 J I (VI) A
in which A, R3 and R4 have the aboveindicated meanings, and from which:
a) the diazonium salt is formed particularly the diazonium chloride of formula (VII). This diazonium salt is obtained particularly by reacting the arylamine in a solution of the corresponding halo acid, particu-larly hydrochloric acid, with a solution of a nitrite of alkali metal, and keepiny the reaction mixture at a temperature preferably lower than about 10C.
b) the diazonium salt obtained is then reacted in solution with sulfurous anhydride. The operation is preferably carried out in the presence of acetic acid as well as of a catalyst suitable for assisting in the con-version of the diazonium group into a sulfohalide group,particularly sulfochloride~ This catalyst is, for example, based on copper (modified Sandmeyer reaction).
The steps a) and b) of this reac~ion applied by way of example to the preparation of sulfochlorides of formula (V) may be represented as follows:
NH2 N-N, Cl ~ 3 NaNO2 ~ ~ OR3 A ~ J HCl ~ (VII) N_N, Cl SO2Cl (VII)~ - _ 2 ~ ~ OR3 A ~ copper salt A
~4 OR4 ~' By way of preferred arylamines for the prepa-ration oE the sulfochlorides of formula (V) may be men-tioned :
2,4-dimethoxy aniline 5-chloro 2,4-dimethoxy aniline, 5-bromo 2,4-dimethoxy aniline, 2,4,5-trimethoxy aniline, 2,4-dimethoxy 5-methylsulfonyl aniline, 2,4-dimethoxy S-ethylsulfonyl ani.line, 2,4-dimethoxy 5-propylsulfonyl aniline, 2,4-dimethoxy 5-isopropylsulfonyl aniline.
To prepare the sulfochlorides of formula (V) in which A has the aboveindicated meaning, it is also possible to proceed by sulfonation or halogenosulfona-tion, preferably chlorosulfonation of the compound offormula (VIII) in which A, R3 and R4 have the above-indicated meanings :
~ OR
I ~ 3 ~ I (VIII) ~ \//
4 _ In the case of sulfonation (by reaction of the compound (VIII) with sulfuric acid) in a first step the sulfonic acid of formula (IX) was obtained :
~o~
3 o ~ O R
ll ¦ ( IX) A ~//
()R ~,~
. .
The acid (IX) obtained can then be converted into a salt of an vrganic or inorganic base, by the ac~tion of the suitable base such as sodium hydroxide, po-tassium hydroxide or pyridine.
This salt is represented by the formula (X) 5 below :
S03 , ~
OR~ ( X) ~ .' lo A
in which B represents a metal, notably an alkali or al]caline-earth metal, and A has any one of the above-indicatèd meanings. The chloride of formula (V) is thenobtained by the action on the compound of formula (IX) - or on the corresponding organic or inorganic salt of formula (X) - of a chlorinating agent, such as thionyl chloride, ~hosphorus pentachloride, or phosphorus oxy-chloride.
By way of example, the reaction diagram forthe production of compounds (V) in which A has any one of the aboveindicated meanings from compounds of formula (VIII) can be represented as follows :
9~9 ( V I I I ) ~ -~ H 2 SO 4 - > ~ ( I X
ll ¦ ( IX) A ~//
()R ~,~
. .
The acid (IX) obtained can then be converted into a salt of an vrganic or inorganic base, by the ac~tion of the suitable base such as sodium hydroxide, po-tassium hydroxide or pyridine.
This salt is represented by the formula (X) 5 below :
S03 , ~
OR~ ( X) ~ .' lo A
in which B represents a metal, notably an alkali or al]caline-earth metal, and A has any one of the above-indicatèd meanings. The chloride of formula (V) is thenobtained by the action on the compound of formula (IX) - or on the corresponding organic or inorganic salt of formula (X) - of a chlorinating agent, such as thionyl chloride, ~hosphorus pentachloride, or phosphorus oxy-chloride.
By way of example, the reaction diagram forthe production of compounds (V) in which A has any one of the aboveindicated meanings from compounds of formula (VIII) can be represented as follows :
9~9 ( V I I I ) ~ -~ H 2 SO 4 - > ~ ( I X
4 / OR4 chlorinating /
agent k/ ~ /
chlorinating 2Cl ~ agent OR
In the case of chlorosulfonation, the chloro-sulfonic acid is reacted with the compound of formula (VIII) in which A, R3 and R4 have the aboveindicated meanings.
The reaction can be written:
S02Cl ~ OR3 ~OH ~ OR3 (VIII) ~ J Cl A~J (V) The hydrochloride of the compounds of formula (I) can be obtained by the reaction of an amine of formula (XI)o HN - (CH ) - CH - (CH ) - N~ 1 (XI ) !~
in which:
n and m independently from each other take values from 1 to 4, Rl, R2, R6 and R7 have the aboveindicated meanings, on a sulfochloride of formula (V):
S02Cl ll l (V) A
OR~
in which:
R3 and R4 have the aboveindicated meanings and A has any one of the aboveindicated meanings for R5 with the exception of the NH2 group (it being understood that another halogenate of the compounds of the formula (I), is obtained if another sulfohalide is utilized, for example, a sulfobromide, instead and in place of the abovesaid sulfochloride).
The production of compounds of formula (I) in which R5 represents NH2, is carried ou-t by reducing the compound of formula (I) in which R5 represents NO2 by catalytic hydrogenation or by chemical reduction.
The hydrochloride of the compounds of formula (I) obtained as has just been indicated has ~he formula:
~ H - (CH2)n - IH ~ (CH2)m \R
R (XII) The passage from the hydrochloride of formula (XII) indicated above to the unsalted compound of formu-la (I), that is to say in the form of base, can be done in solution, by the reaction with a strong base such as sodium hydroxide) or potassium hydroxide, or any other ~;s -base having an equivalent basic character.
Conversion of the hydrochloride of formula (XII) into a different salt can be effected by passing through the base of formula (I) and then by salifying the latter according to conventional processes.
A preferred group of amines used in the pre-paration of the compounds of formula (I), or of their corresponding salts, is constitu-ted by the following :
dimethylamino-ethylamine, diethylamino-ethylamine, pyrrolidino-ethylamine, piperidino-ethylamine, morpholino-ethylamine, dimethylamino-propylamine, diethylamino-propylamine, piperidino-propylamine, 3-(2-methyl piperidino)propylamine, morpholino-propylamine.
The following examples, relatir.g to the pre-paration of a certain number of sulfochlorides and new benzenesulfonamides serve to illustrate the invention, but are not limiting.
EXAMPLE 1.
Preparation of 2,4-dimethoxy benzenesulfonyl chloride.
This is carried out in two steps, following the technique of C.M. SUTER and H.L. HANSEN reported in J. of Am. Chem. Soc. 1933, 55, 2080.
ls-t~ e : Preparation of potassium 2,4-dime-thoxy benzenesulfonate.
85 g (0.615 mole) of 1,3-dimethoxy benzene are placed into a triple-necked flask of 250 cm3, pro-vided with a thermometer, with a dropping funnel and with a magnetic stirring system. After cooling to about 0C, 50 cm3 (0.9 mole) of sulfuric acid (d=1.83-1.8~) were added drop by drop. The mixture was then brought to room temperature and lef-t to stand 1.5 h. The reaction mixture set solid, was poured into 750 cm3 of a saturated solution of potassium carbonate (138 g/l), then le~t to stand overnight. The precipitate obtained was filtered then dried under phosphoric vacuum.
Yield 79 %.
2nd step : Conversion to 2,4-dimethoxy benzene-sulfonyl chloride.
Successively. 124 g (0.484 mole) of potassium 2,4-dimethoxy benzenesulfonate and 500 cm3 of dimethyl-formamide were introduced into a triple-necked flask of one liter, provided with a stirring system and a calcium chloride trap. To the suspenslon obtained were added drop by drop and at room temperature 69.5 g (0.583 mole) of thionyl chloride. After standing overnight, the mix-ture was poured onto crushed ice. The white precipitateobtained was drained, washed a~undantly with water then dried under phosphoric vacuum.
Yield 75 % mp 72C (litt. 70.5C).
EXAMPLE 2.
Pre~aration of 2,4,5-trimethoxy benzenesulfonyl chloride.
This may be carried out according to two methods :
1st method.
Into a triple-necked flask of 500 cm3, provid-ed with a thermometer, with a dropping funnel, with acalcium chloride trap and a magnetic stirring system, were placed 42 g (0.25 mole) of 1,2,4-trimethoxy ~enzene in solution in 200 cm3 of pure chloroform. The reaction medium, placed under a nitrogen atmosphere and cooled to -10C, were added drop by drop 80 cm3 of chlorosul-fonic acid. Successively a creamy white milky precipitate was formed, then a greenish solution with changes to brown. T~hen the addition was ended, the reaction medium was left to stand 1 h at ambient temperature, then poured over crushed ice. The precipitate obtained was extracted with chloroform ; the organic phase was then dried over 36~
sodium sulfate and then evaporated under reduced pressure.
The brown residue formed was washed with a minimurn of toluene until the obtaining of a beige solid which was then chromatographed on a silica column.
Elution with benzene, then with a benzene-chloroform mixture (50-50) gave the 2,4,5-trimethoxy benzenesulfonyl chloride.
Yield 26 % mp 147C.
NMR (CDCl3) at 80 MHz :
~ 7.29 ppm (s lH ArH) ; ~ 6.55 ppm (s lH ArH) ;
3.g3, 3.78 and 3.53 ppm (3s 9H OCH3) IR (K~r) v S02, as 1350 cm 1, s 1160 cm 1 2nd method~
It comprises 4 steps :
3,4-dimethoxy chlorobenzene :
Into a triple-necked flask of a li-ter, provided with a magnetic stirriny system, with a thermometer, with a calcium chloride trap and with a dropping funnel, were intro~uced in the cold at a~ou~ 0~ and successively 138 g (1 mole) of veratrol then drop by drop 135 g (1 mole) of sulfuryl chloride. When the addition was terminated, the reaction medium was brought to room temperature, then after standing one hour was distilled under reduced pressure.
Yield 83 % b.p. : 120C
under 1 999,83 Pa (15mm Hg) 4,5-dimethoxy 2-nitro chlorobenzene :
Into a triple-necked flask of one liter, pro-vided with a magnetic stirring system, with a thermometer and a dropping funnel, were introduced successively 143.9 g (0.83 mole) of 3,4-dimethoxy chlorobenzene, then drop by drop 166 cm3 of nitric acid (d=1.38), wlthout the temperature exceedinq 25C~ When the addition was ended, the reaction mixture was allowed to stand 1.5 h and then filtered.
Yield 95 % mp 105C
~g~
2,4,5-trimethoxy nitrobenzene :
Into a two liter flask, provided with a cool-iny device, were introduced successively a soLution of methanolic potash (100 g of KOH and 500 cm3 of methanol), then 100 g (0.46 mole) of 4,5-dimethoxy 2-nitro chloro-benzene and carborundum. The mixture was brought to boil-ing under reflux for 6 h. After cooling, the reaction medium was filtered ; the ~recipitate obtained was washed with methanol.
Yield 95 % mp 129C
2,4,5-trimethoxy aniline :
Into a 500 cm3 flask, provided with a cooling device, were added successively 21.3 g (0.1 mole) of 2,~,5-trimethoxy nitrobenzene, 80 g of chemically pure stannous chloride for mirror making, 100 cm3 of a hydro~
chloric acid solution (d=1.18) and carborundum. The mix-ture was brought to boiling under reflux for 1 h. After cooling, a caustic soda solution was added until the precipitate disolved. The solution obtained was extracted with methylene chloride. The organic extracts were dried over sodium sulfate then evaporated under reduced pres-sure. The residue obtained was crystallized in ethanol.
Yield 80 % mp 94C
2,4,5-trimethoxy benzenesulfonyl chloride :
Into a triple-necked flask of 250 cm3, provid-ed with a stirring system and a thermometer, were intro-duced 18.3 y (0.1 mole of 2,4,5-trimethoxy aniline then 50 cm3 of a hydrochloric acid solution (d=1.18). After standing for 4 hours, the amine was diazotized at -5C
by the addition of a sodium nitrite solution (10 g of NaN02 in 50 cm3 of water). The diazonium salt obtained was poured slowly into a triple-necked flask, heated to 400C and under a nitrogen atmos~here, containing 200 cm3 of acetic acid saturated with sulfur dio~ide and 7 y of cupric chloride. ~he mixture was brouyht for 2 h to 600C, then poured on to crushed ice.
Y3~
Yield 35 % mp 1~7C.
EXAMPLE 3.
Preparation_of 5-chloro 2,4-dimethoxy benzenesul-fonyl chloride.
It was carried out in 2 steps from 1,3-dime-thoxy benzene :
lst step : Pre~aration oE 2,4-dimethoxv chlorobenzene.
Procedure was according to the technique of G. CA5TELFRANCHI and G. BORRA reported in Annali di Chi-mica, 1953, 43, 293.
Into a -triple-necked flask of 500 cm3, provid-ed with a magnetic stirring sys-tem, with a thermome-ter, with a calcium chloride trap and a dropping funnel, and cooled to 10C, were introduced successively 97.5 (0.70 mole) of 1,3-dimethoxy benzene and then drop by drop 96.5 g (0.70 mole) of sulfuryl chloride. Once the addi-tion was ended, the solution was brought back to ambient temperature and allowed to stand 2 h and then distilled.
Yield 85 % b.p. 137C under 2 399,80 Pa (18 mm ~g).
2nd ste~ : Conversion to 5-chloro 2,4-dimetho-xY benzenesulfonyl chloride.
Into a triple-necked flask of 500 cm3, provid-ed with a magnetic stirring system, with a calcium chlo-ride trap, a thermome-ter and a dropping funnel, were introduced 35 g (0.2 mole) of 2,4 dime-thoxy chlorobenzene in solution in 250 cm of pure chloroform. ~he solution was cooled to 0C, -then supplemented drop by drop with 50 cm3 (0.75 mole) of chlorosulfonic acid. Once the addition was ended, the reaction medium was brought to ambient temperature, then left to stand 3 h ; it was then poured over crushed ice. The mixture obtained was ex-tracted with chloroform. The organic extracts were dried over sodium sulfate then concentra-ted to crystalli-zation. The solid obtained was recrystallized in an ethylether/benzene mixture.
~6~3~9 Yield 7~ % mp 175C
NMR (CDCl3) at 80 MHz :
7.87 p~m (S lH ArH) ; ~ 5.55 ppm (s lH ArH) ;
~ 4 and 3.96 ppm (2s 6H OCH3) IR (KBr) : v S02, as 1385 cm 1, s 1170 cm 1.
EXAMPLE 4.
Preparation of 5-bromo 2,4-dimethoxy benzenesulfonyl chloride.
This was carried out in 2 steps starting from 1,3-dimethoxy benzene :
1st step : Preparation of 2,4-dimethoxy bromobenzene.
This was done according to the procedure of S.T. FENG and K.Y. CHIU reported in Hsueh Pao, 1959, 25, 277.
Into a triple-necked flask of 250 cm3, pro-vided with a magnetic stirring system, with a thermome-ter, and cooled to 10C, were added successively 27.6 g (0.2 mole) of 1,3-dimethoxy benzene then in small por-tions 36 g (0.2 mole) of N-bromosuccinimide. Once the addition was ended, the reaction medium was brought to ambient temperature and left to stand 2 h. After washing with water and extraction with chloroform, the organic extracts were dried over sodium sulfate then concentrat-ed under reduced pressure. The residual liquid was dis-tilled.
Yield 82 % b.p. : 150C under 1 999,83 Pa (15 mm Hg~.
2nd step : Conversion to 5-bromo 2,4-dimetho-xy benzenesulfonyl chloride.
It was obtained according to the same proce-dure as that described in ~xample 3 to prepare 5-chloro 2,4-dimethoxy benzenesulfonyl chloride. By using 65.1 g (0.3 mole) of 2,4-dimethoxy bromobenzene and 100 cm3 of chlorosulfonic acid, the yield was 77 %.
35 mp 195C
NMR (CDCl3) at 60 ~Hz 7.85 p~m (s lH ArH) ; ~ 6.70 ppm (s lH ArH) ;
3.92 and 3.88 ppm (2s 6H OCH3) ;
IR (KBr) : v S02, as 1385 cm 1, s 1165 cm l.
EXAMPLE _.
agent k/ ~ /
chlorinating 2Cl ~ agent OR
In the case of chlorosulfonation, the chloro-sulfonic acid is reacted with the compound of formula (VIII) in which A, R3 and R4 have the aboveindicated meanings.
The reaction can be written:
S02Cl ~ OR3 ~OH ~ OR3 (VIII) ~ J Cl A~J (V) The hydrochloride of the compounds of formula (I) can be obtained by the reaction of an amine of formula (XI)o HN - (CH ) - CH - (CH ) - N~ 1 (XI ) !~
in which:
n and m independently from each other take values from 1 to 4, Rl, R2, R6 and R7 have the aboveindicated meanings, on a sulfochloride of formula (V):
S02Cl ll l (V) A
OR~
in which:
R3 and R4 have the aboveindicated meanings and A has any one of the aboveindicated meanings for R5 with the exception of the NH2 group (it being understood that another halogenate of the compounds of the formula (I), is obtained if another sulfohalide is utilized, for example, a sulfobromide, instead and in place of the abovesaid sulfochloride).
The production of compounds of formula (I) in which R5 represents NH2, is carried ou-t by reducing the compound of formula (I) in which R5 represents NO2 by catalytic hydrogenation or by chemical reduction.
The hydrochloride of the compounds of formula (I) obtained as has just been indicated has ~he formula:
~ H - (CH2)n - IH ~ (CH2)m \R
R (XII) The passage from the hydrochloride of formula (XII) indicated above to the unsalted compound of formu-la (I), that is to say in the form of base, can be done in solution, by the reaction with a strong base such as sodium hydroxide) or potassium hydroxide, or any other ~;s -base having an equivalent basic character.
Conversion of the hydrochloride of formula (XII) into a different salt can be effected by passing through the base of formula (I) and then by salifying the latter according to conventional processes.
A preferred group of amines used in the pre-paration of the compounds of formula (I), or of their corresponding salts, is constitu-ted by the following :
dimethylamino-ethylamine, diethylamino-ethylamine, pyrrolidino-ethylamine, piperidino-ethylamine, morpholino-ethylamine, dimethylamino-propylamine, diethylamino-propylamine, piperidino-propylamine, 3-(2-methyl piperidino)propylamine, morpholino-propylamine.
The following examples, relatir.g to the pre-paration of a certain number of sulfochlorides and new benzenesulfonamides serve to illustrate the invention, but are not limiting.
EXAMPLE 1.
Preparation of 2,4-dimethoxy benzenesulfonyl chloride.
This is carried out in two steps, following the technique of C.M. SUTER and H.L. HANSEN reported in J. of Am. Chem. Soc. 1933, 55, 2080.
ls-t~ e : Preparation of potassium 2,4-dime-thoxy benzenesulfonate.
85 g (0.615 mole) of 1,3-dimethoxy benzene are placed into a triple-necked flask of 250 cm3, pro-vided with a thermometer, with a dropping funnel and with a magnetic stirring system. After cooling to about 0C, 50 cm3 (0.9 mole) of sulfuric acid (d=1.83-1.8~) were added drop by drop. The mixture was then brought to room temperature and lef-t to stand 1.5 h. The reaction mixture set solid, was poured into 750 cm3 of a saturated solution of potassium carbonate (138 g/l), then le~t to stand overnight. The precipitate obtained was filtered then dried under phosphoric vacuum.
Yield 79 %.
2nd step : Conversion to 2,4-dimethoxy benzene-sulfonyl chloride.
Successively. 124 g (0.484 mole) of potassium 2,4-dimethoxy benzenesulfonate and 500 cm3 of dimethyl-formamide were introduced into a triple-necked flask of one liter, provided with a stirring system and a calcium chloride trap. To the suspenslon obtained were added drop by drop and at room temperature 69.5 g (0.583 mole) of thionyl chloride. After standing overnight, the mix-ture was poured onto crushed ice. The white precipitateobtained was drained, washed a~undantly with water then dried under phosphoric vacuum.
Yield 75 % mp 72C (litt. 70.5C).
EXAMPLE 2.
Pre~aration of 2,4,5-trimethoxy benzenesulfonyl chloride.
This may be carried out according to two methods :
1st method.
Into a triple-necked flask of 500 cm3, provid-ed with a thermometer, with a dropping funnel, with acalcium chloride trap and a magnetic stirring system, were placed 42 g (0.25 mole) of 1,2,4-trimethoxy ~enzene in solution in 200 cm3 of pure chloroform. The reaction medium, placed under a nitrogen atmosphere and cooled to -10C, were added drop by drop 80 cm3 of chlorosul-fonic acid. Successively a creamy white milky precipitate was formed, then a greenish solution with changes to brown. T~hen the addition was ended, the reaction medium was left to stand 1 h at ambient temperature, then poured over crushed ice. The precipitate obtained was extracted with chloroform ; the organic phase was then dried over 36~
sodium sulfate and then evaporated under reduced pressure.
The brown residue formed was washed with a minimurn of toluene until the obtaining of a beige solid which was then chromatographed on a silica column.
Elution with benzene, then with a benzene-chloroform mixture (50-50) gave the 2,4,5-trimethoxy benzenesulfonyl chloride.
Yield 26 % mp 147C.
NMR (CDCl3) at 80 MHz :
~ 7.29 ppm (s lH ArH) ; ~ 6.55 ppm (s lH ArH) ;
3.g3, 3.78 and 3.53 ppm (3s 9H OCH3) IR (K~r) v S02, as 1350 cm 1, s 1160 cm 1 2nd method~
It comprises 4 steps :
3,4-dimethoxy chlorobenzene :
Into a triple-necked flask of a li-ter, provided with a magnetic stirriny system, with a thermometer, with a calcium chloride trap and with a dropping funnel, were intro~uced in the cold at a~ou~ 0~ and successively 138 g (1 mole) of veratrol then drop by drop 135 g (1 mole) of sulfuryl chloride. When the addition was terminated, the reaction medium was brought to room temperature, then after standing one hour was distilled under reduced pressure.
Yield 83 % b.p. : 120C
under 1 999,83 Pa (15mm Hg) 4,5-dimethoxy 2-nitro chlorobenzene :
Into a triple-necked flask of one liter, pro-vided with a magnetic stirring system, with a thermometer and a dropping funnel, were introduced successively 143.9 g (0.83 mole) of 3,4-dimethoxy chlorobenzene, then drop by drop 166 cm3 of nitric acid (d=1.38), wlthout the temperature exceedinq 25C~ When the addition was ended, the reaction mixture was allowed to stand 1.5 h and then filtered.
Yield 95 % mp 105C
~g~
2,4,5-trimethoxy nitrobenzene :
Into a two liter flask, provided with a cool-iny device, were introduced successively a soLution of methanolic potash (100 g of KOH and 500 cm3 of methanol), then 100 g (0.46 mole) of 4,5-dimethoxy 2-nitro chloro-benzene and carborundum. The mixture was brought to boil-ing under reflux for 6 h. After cooling, the reaction medium was filtered ; the ~recipitate obtained was washed with methanol.
Yield 95 % mp 129C
2,4,5-trimethoxy aniline :
Into a 500 cm3 flask, provided with a cooling device, were added successively 21.3 g (0.1 mole) of 2,~,5-trimethoxy nitrobenzene, 80 g of chemically pure stannous chloride for mirror making, 100 cm3 of a hydro~
chloric acid solution (d=1.18) and carborundum. The mix-ture was brought to boiling under reflux for 1 h. After cooling, a caustic soda solution was added until the precipitate disolved. The solution obtained was extracted with methylene chloride. The organic extracts were dried over sodium sulfate then evaporated under reduced pres-sure. The residue obtained was crystallized in ethanol.
Yield 80 % mp 94C
2,4,5-trimethoxy benzenesulfonyl chloride :
Into a triple-necked flask of 250 cm3, provid-ed with a stirring system and a thermometer, were intro-duced 18.3 y (0.1 mole of 2,4,5-trimethoxy aniline then 50 cm3 of a hydrochloric acid solution (d=1.18). After standing for 4 hours, the amine was diazotized at -5C
by the addition of a sodium nitrite solution (10 g of NaN02 in 50 cm3 of water). The diazonium salt obtained was poured slowly into a triple-necked flask, heated to 400C and under a nitrogen atmos~here, containing 200 cm3 of acetic acid saturated with sulfur dio~ide and 7 y of cupric chloride. ~he mixture was brouyht for 2 h to 600C, then poured on to crushed ice.
Y3~
Yield 35 % mp 1~7C.
EXAMPLE 3.
Preparation_of 5-chloro 2,4-dimethoxy benzenesul-fonyl chloride.
It was carried out in 2 steps from 1,3-dime-thoxy benzene :
lst step : Pre~aration oE 2,4-dimethoxv chlorobenzene.
Procedure was according to the technique of G. CA5TELFRANCHI and G. BORRA reported in Annali di Chi-mica, 1953, 43, 293.
Into a -triple-necked flask of 500 cm3, provid-ed with a magnetic stirring sys-tem, with a thermome-ter, with a calcium chloride trap and a dropping funnel, and cooled to 10C, were introduced successively 97.5 (0.70 mole) of 1,3-dimethoxy benzene and then drop by drop 96.5 g (0.70 mole) of sulfuryl chloride. Once the addi-tion was ended, the solution was brought back to ambient temperature and allowed to stand 2 h and then distilled.
Yield 85 % b.p. 137C under 2 399,80 Pa (18 mm ~g).
2nd ste~ : Conversion to 5-chloro 2,4-dimetho-xY benzenesulfonyl chloride.
Into a triple-necked flask of 500 cm3, provid-ed with a magnetic stirring system, with a calcium chlo-ride trap, a thermome-ter and a dropping funnel, were introduced 35 g (0.2 mole) of 2,4 dime-thoxy chlorobenzene in solution in 250 cm of pure chloroform. ~he solution was cooled to 0C, -then supplemented drop by drop with 50 cm3 (0.75 mole) of chlorosulfonic acid. Once the addition was ended, the reaction medium was brought to ambient temperature, then left to stand 3 h ; it was then poured over crushed ice. The mixture obtained was ex-tracted with chloroform. The organic extracts were dried over sodium sulfate then concentra-ted to crystalli-zation. The solid obtained was recrystallized in an ethylether/benzene mixture.
~6~3~9 Yield 7~ % mp 175C
NMR (CDCl3) at 80 MHz :
7.87 p~m (S lH ArH) ; ~ 5.55 ppm (s lH ArH) ;
~ 4 and 3.96 ppm (2s 6H OCH3) IR (KBr) : v S02, as 1385 cm 1, s 1170 cm 1.
EXAMPLE 4.
Preparation of 5-bromo 2,4-dimethoxy benzenesulfonyl chloride.
This was carried out in 2 steps starting from 1,3-dimethoxy benzene :
1st step : Preparation of 2,4-dimethoxy bromobenzene.
This was done according to the procedure of S.T. FENG and K.Y. CHIU reported in Hsueh Pao, 1959, 25, 277.
Into a triple-necked flask of 250 cm3, pro-vided with a magnetic stirring system, with a thermome-ter, and cooled to 10C, were added successively 27.6 g (0.2 mole) of 1,3-dimethoxy benzene then in small por-tions 36 g (0.2 mole) of N-bromosuccinimide. Once the addition was ended, the reaction medium was brought to ambient temperature and left to stand 2 h. After washing with water and extraction with chloroform, the organic extracts were dried over sodium sulfate then concentrat-ed under reduced pressure. The residual liquid was dis-tilled.
Yield 82 % b.p. : 150C under 1 999,83 Pa (15 mm Hg~.
2nd step : Conversion to 5-bromo 2,4-dimetho-xy benzenesulfonyl chloride.
It was obtained according to the same proce-dure as that described in ~xample 3 to prepare 5-chloro 2,4-dimethoxy benzenesulfonyl chloride. By using 65.1 g (0.3 mole) of 2,4-dimethoxy bromobenzene and 100 cm3 of chlorosulfonic acid, the yield was 77 %.
35 mp 195C
NMR (CDCl3) at 60 ~Hz 7.85 p~m (s lH ArH) ; ~ 6.70 ppm (s lH ArH) ;
3.92 and 3.88 ppm (2s 6H OCH3) ;
IR (KBr) : v S02, as 1385 cm 1, s 1165 cm l.
EXAMPLE _.
5-alkylsulfonyl 2,4-dimethoxy benzen_sulfonyl chlorides.
They were obtained from the 2,4-dimethoxy benzenesulfonyl chlorides described in Example 1. The general diagram for their preparation is as follows :
10 ~ ~ 3 ~ Ma~cn ~ /~ ,laOH
2 l ~lO2S T ---~
oc~3 OC~13 2,4-dimethoxy benzenesulfonyl 2,4-dimethoxy benzenesul-chloride finic acid ~ 13 ~-X / ~ / OC~3 NaO2S I 2S ~
Sodium 2,4-dimethoxy benzene- (2,4-dime-thoxy phenyl) sulfinate alkylsulfone S02Cl ~ ~ 0~3 .
OCH
5-alkylsulfonyl 2,4-dime-thoxy benzenesulfonyl chloride 2,4 imethoxY benzenesulfinic acid :
To an aqueous solution containing 129 g (0.974 ~6~
mole) of sodium sulfite were added in small amounts and with stirrlng 115 g (0.487 mole) of 2,4-dimethoxy ben-zenesulfonyl chloride. During this operation, the pH was kept alkaline by the addition of caustic soda. After standing for 3 h, the reaction medium was filtered. The filtrate was acidified with 2N sulfuric acid until the precipitation of the sulfinic acid.
Yield 72 % mp 122C
Sodium 2! 4-dimethoxy benzenesulfinate :
This was obtained by the addition of the stoi-chiometric amount of sodium hydroxide in aqueous solu-tion. The sulfinate solution was evaporated to dryness.
(2,4-dimethoxy phenyl)alkvlsulfones :
General procedure :
Into a 500 cm3 flask, provided with a cooling system and a magnetic stirring system, were added succes-sively 0.1 mole of sodium 2,4-dimethoxy benzenesulfonate, 250 cm3 of isopropanol, and then 0.15 mole of alkyl hali-de, preferably an iodide. The mixture was brought to boiling under reflux 5 to 30 h according to the hzlide used. After cooling, the reaction medium was evaporated tu dryness. The residue was taken up again in water and then extracted with chloroform. The evaporation of the organic phase, after drying over sodium sulfate gave an oil which was crystallized in benzene.
. .
\
R-2S J~OCH3 MW Time of MP C Viuld CH3 216 5 h 109 65 C2H5 230 7 h 94 70 n 3 7 244 15 h 70 90 iC3H7 244 30 h 100 64 5-alkylsulfonyl 2,4-dimethoxy benzenesulfonyl chlorides:
General procedure:
Into a triple-necked flask of one liter, pro-vided with a magne-tic stirring system, with a calcium chloride trap, with a thermometer and a dropping funnel, was introduced a solution of (2,4-dimethoxy-phenyl) alkylsulfone (0.2 mole) in 200 cm3 of pure chloroform.
lQ After cooling to -10C, 100 cm3 of chlorosulfonic acid were added drop by drop. Once the acldition was ended, the mixture was left to stand 0.5 h at -10C, then brought back to room temperature and lef-t with stirring for 7 h; it was then poured over crushed iceO The mixture obtained was extracted with chloroform~ The organic phase was clried over sodium sulfate, filtered, then evaporated under reduced pressure. The residue was crystallized in benzene.
3~l~
S02 Cl ~ C~3 ~-25 ____________ _______________________________________ R MW ~P C Yield %
_~__________ ____ _______ ____________ _______. _____ CH3 314,5 204 52 C2~5 328,5 191 . 77 n 3 7 342,5 169 87 i ~ 7 342,5 218 ` 66 _ __ __ __ _____ _ .. _ _ __ ___. _ _ _ _ _ __ __ _ ____ 2,4-dimethox~ 5-methylsulfonvl benzenesulfonyl chloride.
NMR (DMSO) at 80 MHz :
8.2 ppm (s lH ArH) ; ~ 6.9 ppm (s lH ArH) , 4.1 ppm and 4.05 ppm (2s 6H OCH3) ; 3.2 ppm (s 3H CH3).
IR (KBr) :
v S02-Cl, as 1360 cm~l, s 1170 cm~l ;
v S02-CH3, as 1300 cm 1, s 1140 cm 1, 5-ethYlsulfonyl 2,4-dimethoxy benzenesulfonyl chloride.
NMR (DMSO) at 80 MHz :
~ 8.2 ppm (s lH ArH) ; ~ 6.93 ppm (s lH ArH) ;
~ 4.15 ppm and 4.1 ppm (2s 6H OCH3) ; ~ 3.25 ppm (q 2H
-CH2-) ; ~ 1.18 ppm (t 3H CH3-)-IR (KBr) :
v S02-Cl, as 1370 cm 1, s 1175 cm 1 ;
v S02-CH2-, as 1315 cm 1, s 1140 cm 1, 2~4-dimethoxy 5-~ropylsulfonyl benzenesulfonyl chloride.
NMR (DMSO) at 80 MHz :
8.05 ppm (s lH ArH) ; ~ 6.72 ppm ~s lH ArH) ;
3.92 and 3.87 ppm (2s 6H OCH3) ; ~ 3.2 ppm (t 2H-CH2-S02-~ ; ~ 1.45 ppm (m 2H-CH2-) ; ~ 0.85 ~pm (t 3H CH3).
IR (KBr) :
v S02Cl, as 1370 cm~l, s 1180 cm~l , v S02-CH2, as 1315 cm 1, s 1135 cm 1.
5-isopro~vlsulfonyl 2,4-dimethoxy benzenesulfonyl chlo-ride.
NMR (DMS0) at 80 MHz :
~ 8.02 ppm (s 1~ ArH) ; ~ 6.7 ppm (s lH ArH) , 3.92 and 3.85 ppm (2s 6H OCH3) , ~ 3.~ ppm (m lH -CH-);
1.11 and 1.03 ppm (2s 6H CH3).
IR ~KBr) :
v S02-Cl, as 1365 cm~l, s 1175 cm~l ;
v S02-CH, as 1300 cm , s 1130 cm 1 EXAMPLE 6.
Pre~aration of substituted 2,4-dimethoxy benzenesulfona-mides.
To 0.015 mole of benzenesulfonyl chloride in solution in a mixture of methylene chloride (40 cm3) and methanol (10 cm3), was added 0.015 mole of dialkylamino-alkylamine in solution in 10 cm3 of methylene chloride.
After standing 2 h, with stirring and at room temperature, the reaction medium was evaporated to dryness and then taken up again in 50 cm3 of water. The aqueous solution was washed with ethyl ether, then evaporated to dryness.
The residue was crystallized in an isopropanol/methanol mixture. Possible conversion to the base was carried out by treating the aqueous solution of the hydrochloride with N soda until precipitation. The preci~itate was extracted with methylene chloride. The organic solution was dried then evaporated under reduced pressure. The base obtained was crystallized in an ethyl ether/petro-leum ether mixture.
Other compounds were prepared similarly and are assembled in the following Table I (the melting point indicated for each compound is, except for indica-tion to the contrary, that of the hydrochloride).
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The new benzenesulfonamides according to the invention, as well as their physiologically acceptable organic or inorganic salts, have rernarkable pharmacolo-gical properties.
The compounds according to the invention exert a control action on the central nervous system and parti-cularly a psychomodulator reaction~ They can act parti-cularly, either as antidepressant agents, or as tranqui-lizing anxiolytic agents. The activity of these compounds is reinforced by the lipophile nature of the molecule, due to the presence of an alkoxy group on the aromatic nucleus at the 4 position.
The compounds according to the invention are also distinguished by the fact that they potentiate pen-tobarbital sleep, that they have little or no affinity for the dopaminergic sites usually recognized as associat-ed with certain undesirable effects (galactorrea, ame-norrhea, extrapyramidal syndromes), and that they are devoid of toxicity.
Their therapeutic index is compatible with their use as a medicament.
The compounds are advantageously introduced as the active principle in the treatment of deseases with depressive, anxiety components and causing in particular psychosomatlc disorders.
The compounds according to the invention are for this purpose packaged with excipients and traditional adjuvants, particularly those used for the preparation of tablets, powders, capsules, drinkable ampoules and injectable solutions.
The administration of medicaments containing the compounds according to the invention is carried out preferably orally, parenterally, rectally or topically and the doses of active compound administered are prefe-rably comprised between 10 and 700 mg and particularlybetween 50 and 500 mg/day.
9~
By way of examp]e, different tests for the estaglishing of the pharmacological properties of the compounds according to the invention are reported below.
TESTS RELATING TO STUDY OF THE INTERACTIONS OF THE
MEDICAMENTS ACCORDING TO THE INVENTION WITH PENTOBARBITAL.
The tests were warried out on EOPS SWISS mice of male sex, weighing from 20 to 24 g, cominq from the breeding center of LE GENEST.
The animals were acclimatized at least 8 days in the animal section of the laboratory before the tests.
The batches were of 10 mice per test and per product.
As reference products, to carry out control tests, the three following substances were used :
N~ ethyl 2-pyrrolidinyl)methy~7 2-methoxy 5-sulfamoyl benzamide known under the name sulpiride ;
N-~1-ethyl 2-pyrrolidinyl)methy~7 2-methoxy 5-ethylsul-fonyl benzamide known under the sultopride , N-(2-diethylamino ethyl) 2-methoxy 5-methylsulfonyl benzamide known under the tiapride.
The compounds according to the invention and the reference substances were administered in aqueous suspension in water with 3 % of gum arabic for the oral route (tests of interactions with barbiturates).
The pharmacological reagent namely the pento-barbital was administered in solution in an isotonic NaCl solution.
The volumes administered were 0.5 ml of a solution with 1.6 g/l for 20 g of body weight intraperi-toneally (40 mg/kg).
To carry out these tests, there were adminis-tered to these batches of 10 SWISS male mice, the com-pounds according to the invention or the reference products (namely sulpiride, sultopride or tiapride) orally at the dosage of 200 mg/kg. 60 minutes after ingestion of the compounds according to the invention g~
or of the reerence product, pentabarbital was adminis-tered to the animals in the sodium form such as that marketed under -the trademark NEMBUTAL. Measurement was then made of :
- the drowsiness time, - the sleeping time, and the percentage of variations over and under the sleeping time was measured. The results of these tests are shown in the following Table II.
~a6~3~9 .. .
1 r~ I3L I _ I l _ ' : Sleeping time : Variation Prod u ~ t n : I p e r- to ha r b i t a l ) : s rnn _ _ . _ _ _ _ _ _ _ _ . _ _ _ _ _ _ _ 880 ' ' ~ 55,6 881 , , ~ 30,8 882 : 176 + 21 : .t 144,4 883 176 + 12 , + 147,9 884 150 + 24 ' ~ 111,3 886 ' + 36,4 887 . + 2q,7 888 140 + 20 ; + 97,Z
889 156 + 15 + 119,7 B97 ; - 8,8 898 : : -15,4 899 +23,1 900 : : +14,3 901 +11,0 893 : : +3,3 894 . , +12,1 895 ; +67,1 924 : : ~16,5 925 ' ' +29,4 926 16fl _ 30 : + 133,3 927 169 26 ' + 134,7 928 165 _ 24 : + 129,2 930 ' ' + 52,8 931 : ~ 28,6 932 142 ~ 15 ' ~ 97,2 933 180 32 : ~ 150, n 955 ' ' + 11,7 956 : - 26,4 -Unable to recognize this page.
1~6~
The new trisubstitu-ted benzenesulfonamides according to the invention constitute a class of product and a class of medicaments which is particularly pre-ferred.
The disubstituted benzenesulfoamides have interesting properties, but takiny into account the results obtained, it results that when R5 is different from hydrogen, the biological properties of the trisub-stituted benzenesulfoamides are amplified with respect to those of the corresponding disubstituted benzene~
sulfonamides.
Consequently, the combination of the disubsti-tution at (2,4), by alkoxy groups and the substitution at the 5 position is particularly favorable with respect to the overall activity of the molecules.
Study of the results obtained shows that the compounds according to the invention are psychomodula-tors. Those for which the percentage variation of the sleep time is greater than + 50 % are very distinct potentiators of pentobarbital sleep and consequently can be used as tranquilizers or anxiolytic agents.
The compounds according to the invention for which the percentage variation in sleep time varies from about 0 % to about 50 % are potentiators of activity in the neighborhood of the reference compounds sultopride and tiapride, used.
The compounds according to the invention for which the percentage variation in sleep time is less than 0 % are antagonists and can be used as antidepres-san-t agents.
It is noted that the sulpiride used as refe-rence product shows itself to be either a potentiator, or an antagonist which shows its double profile of neuro-leptic and antidepressant agent.
They were obtained from the 2,4-dimethoxy benzenesulfonyl chlorides described in Example 1. The general diagram for their preparation is as follows :
10 ~ ~ 3 ~ Ma~cn ~ /~ ,laOH
2 l ~lO2S T ---~
oc~3 OC~13 2,4-dimethoxy benzenesulfonyl 2,4-dimethoxy benzenesul-chloride finic acid ~ 13 ~-X / ~ / OC~3 NaO2S I 2S ~
Sodium 2,4-dimethoxy benzene- (2,4-dime-thoxy phenyl) sulfinate alkylsulfone S02Cl ~ ~ 0~3 .
OCH
5-alkylsulfonyl 2,4-dime-thoxy benzenesulfonyl chloride 2,4 imethoxY benzenesulfinic acid :
To an aqueous solution containing 129 g (0.974 ~6~
mole) of sodium sulfite were added in small amounts and with stirrlng 115 g (0.487 mole) of 2,4-dimethoxy ben-zenesulfonyl chloride. During this operation, the pH was kept alkaline by the addition of caustic soda. After standing for 3 h, the reaction medium was filtered. The filtrate was acidified with 2N sulfuric acid until the precipitation of the sulfinic acid.
Yield 72 % mp 122C
Sodium 2! 4-dimethoxy benzenesulfinate :
This was obtained by the addition of the stoi-chiometric amount of sodium hydroxide in aqueous solu-tion. The sulfinate solution was evaporated to dryness.
(2,4-dimethoxy phenyl)alkvlsulfones :
General procedure :
Into a 500 cm3 flask, provided with a cooling system and a magnetic stirring system, were added succes-sively 0.1 mole of sodium 2,4-dimethoxy benzenesulfonate, 250 cm3 of isopropanol, and then 0.15 mole of alkyl hali-de, preferably an iodide. The mixture was brought to boiling under reflux 5 to 30 h according to the hzlide used. After cooling, the reaction medium was evaporated tu dryness. The residue was taken up again in water and then extracted with chloroform. The evaporation of the organic phase, after drying over sodium sulfate gave an oil which was crystallized in benzene.
. .
\
R-2S J~OCH3 MW Time of MP C Viuld CH3 216 5 h 109 65 C2H5 230 7 h 94 70 n 3 7 244 15 h 70 90 iC3H7 244 30 h 100 64 5-alkylsulfonyl 2,4-dimethoxy benzenesulfonyl chlorides:
General procedure:
Into a triple-necked flask of one liter, pro-vided with a magne-tic stirring system, with a calcium chloride trap, with a thermometer and a dropping funnel, was introduced a solution of (2,4-dimethoxy-phenyl) alkylsulfone (0.2 mole) in 200 cm3 of pure chloroform.
lQ After cooling to -10C, 100 cm3 of chlorosulfonic acid were added drop by drop. Once the acldition was ended, the mixture was left to stand 0.5 h at -10C, then brought back to room temperature and lef-t with stirring for 7 h; it was then poured over crushed iceO The mixture obtained was extracted with chloroform~ The organic phase was clried over sodium sulfate, filtered, then evaporated under reduced pressure. The residue was crystallized in benzene.
3~l~
S02 Cl ~ C~3 ~-25 ____________ _______________________________________ R MW ~P C Yield %
_~__________ ____ _______ ____________ _______. _____ CH3 314,5 204 52 C2~5 328,5 191 . 77 n 3 7 342,5 169 87 i ~ 7 342,5 218 ` 66 _ __ __ __ _____ _ .. _ _ __ ___. _ _ _ _ _ __ __ _ ____ 2,4-dimethox~ 5-methylsulfonvl benzenesulfonyl chloride.
NMR (DMSO) at 80 MHz :
8.2 ppm (s lH ArH) ; ~ 6.9 ppm (s lH ArH) , 4.1 ppm and 4.05 ppm (2s 6H OCH3) ; 3.2 ppm (s 3H CH3).
IR (KBr) :
v S02-Cl, as 1360 cm~l, s 1170 cm~l ;
v S02-CH3, as 1300 cm 1, s 1140 cm 1, 5-ethYlsulfonyl 2,4-dimethoxy benzenesulfonyl chloride.
NMR (DMSO) at 80 MHz :
~ 8.2 ppm (s lH ArH) ; ~ 6.93 ppm (s lH ArH) ;
~ 4.15 ppm and 4.1 ppm (2s 6H OCH3) ; ~ 3.25 ppm (q 2H
-CH2-) ; ~ 1.18 ppm (t 3H CH3-)-IR (KBr) :
v S02-Cl, as 1370 cm 1, s 1175 cm 1 ;
v S02-CH2-, as 1315 cm 1, s 1140 cm 1, 2~4-dimethoxy 5-~ropylsulfonyl benzenesulfonyl chloride.
NMR (DMSO) at 80 MHz :
8.05 ppm (s lH ArH) ; ~ 6.72 ppm ~s lH ArH) ;
3.92 and 3.87 ppm (2s 6H OCH3) ; ~ 3.2 ppm (t 2H-CH2-S02-~ ; ~ 1.45 ppm (m 2H-CH2-) ; ~ 0.85 ~pm (t 3H CH3).
IR (KBr) :
v S02Cl, as 1370 cm~l, s 1180 cm~l , v S02-CH2, as 1315 cm 1, s 1135 cm 1.
5-isopro~vlsulfonyl 2,4-dimethoxy benzenesulfonyl chlo-ride.
NMR (DMS0) at 80 MHz :
~ 8.02 ppm (s 1~ ArH) ; ~ 6.7 ppm (s lH ArH) , 3.92 and 3.85 ppm (2s 6H OCH3) , ~ 3.~ ppm (m lH -CH-);
1.11 and 1.03 ppm (2s 6H CH3).
IR ~KBr) :
v S02-Cl, as 1365 cm~l, s 1175 cm~l ;
v S02-CH, as 1300 cm , s 1130 cm 1 EXAMPLE 6.
Pre~aration of substituted 2,4-dimethoxy benzenesulfona-mides.
To 0.015 mole of benzenesulfonyl chloride in solution in a mixture of methylene chloride (40 cm3) and methanol (10 cm3), was added 0.015 mole of dialkylamino-alkylamine in solution in 10 cm3 of methylene chloride.
After standing 2 h, with stirring and at room temperature, the reaction medium was evaporated to dryness and then taken up again in 50 cm3 of water. The aqueous solution was washed with ethyl ether, then evaporated to dryness.
The residue was crystallized in an isopropanol/methanol mixture. Possible conversion to the base was carried out by treating the aqueous solution of the hydrochloride with N soda until precipitation. The preci~itate was extracted with methylene chloride. The organic solution was dried then evaporated under reduced pressure. The base obtained was crystallized in an ethyl ether/petro-leum ether mixture.
Other compounds were prepared similarly and are assembled in the following Table I (the melting point indicated for each compound is, except for indica-tion to the contrary, that of the hydrochloride).
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The new benzenesulfonamides according to the invention, as well as their physiologically acceptable organic or inorganic salts, have rernarkable pharmacolo-gical properties.
The compounds according to the invention exert a control action on the central nervous system and parti-cularly a psychomodulator reaction~ They can act parti-cularly, either as antidepressant agents, or as tranqui-lizing anxiolytic agents. The activity of these compounds is reinforced by the lipophile nature of the molecule, due to the presence of an alkoxy group on the aromatic nucleus at the 4 position.
The compounds according to the invention are also distinguished by the fact that they potentiate pen-tobarbital sleep, that they have little or no affinity for the dopaminergic sites usually recognized as associat-ed with certain undesirable effects (galactorrea, ame-norrhea, extrapyramidal syndromes), and that they are devoid of toxicity.
Their therapeutic index is compatible with their use as a medicament.
The compounds are advantageously introduced as the active principle in the treatment of deseases with depressive, anxiety components and causing in particular psychosomatlc disorders.
The compounds according to the invention are for this purpose packaged with excipients and traditional adjuvants, particularly those used for the preparation of tablets, powders, capsules, drinkable ampoules and injectable solutions.
The administration of medicaments containing the compounds according to the invention is carried out preferably orally, parenterally, rectally or topically and the doses of active compound administered are prefe-rably comprised between 10 and 700 mg and particularlybetween 50 and 500 mg/day.
9~
By way of examp]e, different tests for the estaglishing of the pharmacological properties of the compounds according to the invention are reported below.
TESTS RELATING TO STUDY OF THE INTERACTIONS OF THE
MEDICAMENTS ACCORDING TO THE INVENTION WITH PENTOBARBITAL.
The tests were warried out on EOPS SWISS mice of male sex, weighing from 20 to 24 g, cominq from the breeding center of LE GENEST.
The animals were acclimatized at least 8 days in the animal section of the laboratory before the tests.
The batches were of 10 mice per test and per product.
As reference products, to carry out control tests, the three following substances were used :
N~ ethyl 2-pyrrolidinyl)methy~7 2-methoxy 5-sulfamoyl benzamide known under the name sulpiride ;
N-~1-ethyl 2-pyrrolidinyl)methy~7 2-methoxy 5-ethylsul-fonyl benzamide known under the sultopride , N-(2-diethylamino ethyl) 2-methoxy 5-methylsulfonyl benzamide known under the tiapride.
The compounds according to the invention and the reference substances were administered in aqueous suspension in water with 3 % of gum arabic for the oral route (tests of interactions with barbiturates).
The pharmacological reagent namely the pento-barbital was administered in solution in an isotonic NaCl solution.
The volumes administered were 0.5 ml of a solution with 1.6 g/l for 20 g of body weight intraperi-toneally (40 mg/kg).
To carry out these tests, there were adminis-tered to these batches of 10 SWISS male mice, the com-pounds according to the invention or the reference products (namely sulpiride, sultopride or tiapride) orally at the dosage of 200 mg/kg. 60 minutes after ingestion of the compounds according to the invention g~
or of the reerence product, pentabarbital was adminis-tered to the animals in the sodium form such as that marketed under -the trademark NEMBUTAL. Measurement was then made of :
- the drowsiness time, - the sleeping time, and the percentage of variations over and under the sleeping time was measured. The results of these tests are shown in the following Table II.
~a6~3~9 .. .
1 r~ I3L I _ I l _ ' : Sleeping time : Variation Prod u ~ t n : I p e r- to ha r b i t a l ) : s rnn _ _ . _ _ _ _ _ _ _ _ . _ _ _ _ _ _ _ 880 ' ' ~ 55,6 881 , , ~ 30,8 882 : 176 + 21 : .t 144,4 883 176 + 12 , + 147,9 884 150 + 24 ' ~ 111,3 886 ' + 36,4 887 . + 2q,7 888 140 + 20 ; + 97,Z
889 156 + 15 + 119,7 B97 ; - 8,8 898 : : -15,4 899 +23,1 900 : : +14,3 901 +11,0 893 : : +3,3 894 . , +12,1 895 ; +67,1 924 : : ~16,5 925 ' ' +29,4 926 16fl _ 30 : + 133,3 927 169 26 ' + 134,7 928 165 _ 24 : + 129,2 930 ' ' + 52,8 931 : ~ 28,6 932 142 ~ 15 ' ~ 97,2 933 180 32 : ~ 150, n 955 ' ' + 11,7 956 : - 26,4 -Unable to recognize this page.
1~6~
The new trisubstitu-ted benzenesulfonamides according to the invention constitute a class of product and a class of medicaments which is particularly pre-ferred.
The disubstituted benzenesulfoamides have interesting properties, but takiny into account the results obtained, it results that when R5 is different from hydrogen, the biological properties of the trisub-stituted benzenesulfoamides are amplified with respect to those of the corresponding disubstituted benzene~
sulfonamides.
Consequently, the combination of the disubsti-tution at (2,4), by alkoxy groups and the substitution at the 5 position is particularly favorable with respect to the overall activity of the molecules.
Study of the results obtained shows that the compounds according to the invention are psychomodula-tors. Those for which the percentage variation of the sleep time is greater than + 50 % are very distinct potentiators of pentobarbital sleep and consequently can be used as tranquilizers or anxiolytic agents.
The compounds according to the invention for which the percentage variation in sleep time varies from about 0 % to about 50 % are potentiators of activity in the neighborhood of the reference compounds sultopride and tiapride, used.
The compounds according to the invention for which the percentage variation in sleep time is less than 0 % are antagonists and can be used as antidepres-san-t agents.
It is noted that the sulpiride used as refe-rence product shows itself to be either a potentiator, or an antagonist which shows its double profile of neuro-leptic and antidepressant agent.
Claims (13)
1. Process for the preparation of the hydrochlo-rides of the compounds of the general formula (I) :
(I) in which :
- n and m independently from each other have values from O to 4 :
- R3 and R4 each represent, independently from each other, a lower alkyl radical having from 1 to 4 carbon atoms ;
- R1 and R2 represent, independently from each other, hydrogen atoms, linear or branched alkyl groups having from 1 to 4 carbon atoms, or forming conjointly with the nitrogen atom a nitrogenous heterocyclic group with 5 or 6 links, selected from a pyrrolidino, morpholino, pipe-razinyl, pyrrole or piperidino group, substituted or not by linear or branched alkyl radicals having from 1 to 4 carbon atoms ;
- R5 represents a hydrogen atom, a halogen, the group NO2, NH2, CF3, an alkoxy radical having from 1 to 4 car-bon atoms, or an alkyl sulfonyl radical having from 1 to 4 carbon atoms ;
- R6 and R7 represent, independently from each other, a hydrogen atom, an alkyl radical with 1 to 6 carbon atoms or a cycloalkyl radical with 3 to 6 carbon atoms ;
as well as their salts obtained with physiologically ac-ceptable organic or inorganic acids, comprising reacting an amine of the formula (XI) :
(XI) in which :
- n and m, independently from each other, have values from 1 to 4 :
- R1 and R2 are hydrogen atoms, linear or branched alkyl groups having from 1 to 4 carbon atoms, or forming con-jointly with the nitrogen atom a nitrogenous heterocy-clic group with 5 or 6 links, selected from a pyrrolidi-no, morpholino, piperazinyl, pyrrole or piperidino group, substituted or not by linear or branched alkyl radicals having from 1 to 4 carbon atoms :
- R6 and R7 represent, independently from each other, a hydrogen atom, an alkyl radical having from 1 to 6 car-bon atoms or a cycloalkyl radical having from 3 to 6 carbon atoms ;
with a sulfochloride of formula :
(V) in which R3 and R4 each represent, indenpendently from each other, a lower alkyl radical having from 1 to 4 carbon atoms. A has the same meaning as R5, with the exception of NH2, followed if necessary by a reduction when A represents the NO2 group.
(I) in which :
- n and m independently from each other have values from O to 4 :
- R3 and R4 each represent, independently from each other, a lower alkyl radical having from 1 to 4 carbon atoms ;
- R1 and R2 represent, independently from each other, hydrogen atoms, linear or branched alkyl groups having from 1 to 4 carbon atoms, or forming conjointly with the nitrogen atom a nitrogenous heterocyclic group with 5 or 6 links, selected from a pyrrolidino, morpholino, pipe-razinyl, pyrrole or piperidino group, substituted or not by linear or branched alkyl radicals having from 1 to 4 carbon atoms ;
- R5 represents a hydrogen atom, a halogen, the group NO2, NH2, CF3, an alkoxy radical having from 1 to 4 car-bon atoms, or an alkyl sulfonyl radical having from 1 to 4 carbon atoms ;
- R6 and R7 represent, independently from each other, a hydrogen atom, an alkyl radical with 1 to 6 carbon atoms or a cycloalkyl radical with 3 to 6 carbon atoms ;
as well as their salts obtained with physiologically ac-ceptable organic or inorganic acids, comprising reacting an amine of the formula (XI) :
(XI) in which :
- n and m, independently from each other, have values from 1 to 4 :
- R1 and R2 are hydrogen atoms, linear or branched alkyl groups having from 1 to 4 carbon atoms, or forming con-jointly with the nitrogen atom a nitrogenous heterocy-clic group with 5 or 6 links, selected from a pyrrolidi-no, morpholino, piperazinyl, pyrrole or piperidino group, substituted or not by linear or branched alkyl radicals having from 1 to 4 carbon atoms :
- R6 and R7 represent, independently from each other, a hydrogen atom, an alkyl radical having from 1 to 6 car-bon atoms or a cycloalkyl radical having from 3 to 6 carbon atoms ;
with a sulfochloride of formula :
(V) in which R3 and R4 each represent, indenpendently from each other, a lower alkyl radical having from 1 to 4 carbon atoms. A has the same meaning as R5, with the exception of NH2, followed if necessary by a reduction when A represents the NO2 group.
2. Process according to claim 1, for preparing the hydrochlorides of the compounds of the general for-mula (II) :
(II) in which :
- n is 2 or 3 ;
- R3 and R4 each represent, independently from each other, a lower alkyl radical having from 1 to 4 carbon atoms :
- R1 and R2 represent, independently from each other, hydrogen atoms, linear or branched alkyl groups of 1 to 4 carbon atoms, or forming conjointly with the nitrogen atom a nitrogenous heterocyclic group with 5 or 6 links, selected from a pyrrolidino, morpholino, piperazinyl, pyrrole or piperidino group, substituted or not by li-near or branched alkyl radicals having from 1 to 4 car-bon atoms :
- R5 represents a hydrogen atom, halogen, the NO2, NH2, CF3 group, an alkoxy radical having from 1 to 4 carbon atoms, or an alkylsulfonyl radical having from 1 to 4 carbon atoms ;
as well as their salts obtained with physiologically ac-ceptable organic or inorganic acids,
(II) in which :
- n is 2 or 3 ;
- R3 and R4 each represent, independently from each other, a lower alkyl radical having from 1 to 4 carbon atoms :
- R1 and R2 represent, independently from each other, hydrogen atoms, linear or branched alkyl groups of 1 to 4 carbon atoms, or forming conjointly with the nitrogen atom a nitrogenous heterocyclic group with 5 or 6 links, selected from a pyrrolidino, morpholino, piperazinyl, pyrrole or piperidino group, substituted or not by li-near or branched alkyl radicals having from 1 to 4 car-bon atoms :
- R5 represents a hydrogen atom, halogen, the NO2, NH2, CF3 group, an alkoxy radical having from 1 to 4 carbon atoms, or an alkylsulfonyl radical having from 1 to 4 carbon atoms ;
as well as their salts obtained with physiologically ac-ceptable organic or inorganic acids,
3. Process according to claim 1, for preparing the hydrochlorides of the compounds of the following formula (III) :
(III) in which :
- n is 2 or 3 ;
- R5 represents the OCH3. C1, Br, SO2CH3, SO2C2H5, SO2nC3H7, SO2iC3H7 group :
represents one of the radicals selected from the group comprising dimethylamino, diethylamino, pyrro-lidino, morpholino, piperidino, piperidino group substi-tuted by a methyl radical :
as well as their physiologically acceptable organic or inorganic salts.
(III) in which :
- n is 2 or 3 ;
- R5 represents the OCH3. C1, Br, SO2CH3, SO2C2H5, SO2nC3H7, SO2iC3H7 group :
represents one of the radicals selected from the group comprising dimethylamino, diethylamino, pyrro-lidino, morpholino, piperidino, piperidino group substi-tuted by a methyl radical :
as well as their physiologically acceptable organic or inorganic salts.
4. Process according to claim 1, for preparing the hydrochlorides of the compounds of the following formula (III) :
(III) in which :
- n is 2 or 3 :
- R5 represents the OCH3, C1, Br, SO2CH3, SO2C2H5, SO2nC3H7, SO2iC3H7 group ;
represents one of the radicals selected from the group comprising dimethylamino, diethylamino, pyrro-lidino, morpholino, piperidino, piperidino group substi-tuted by a methyl radical at the 2 position ;
as well as their physiologically acceptable organic or inorganic salts.
(III) in which :
- n is 2 or 3 :
- R5 represents the OCH3, C1, Br, SO2CH3, SO2C2H5, SO2nC3H7, SO2iC3H7 group ;
represents one of the radicals selected from the group comprising dimethylamino, diethylamino, pyrro-lidino, morpholino, piperidino, piperidino group substi-tuted by a methyl radical at the 2 position ;
as well as their physiologically acceptable organic or inorganic salts.
5. Process according to claim 1, for preparing the hydrochlorides of the compounds according to claim 3 or 4, in which R5 represents hydrogen.
6. Process according to claim 1, for preparing the hydrochlorides of the compounds according to claim 3 or 4, in which :
- n is 2 or 3 :
- R5 represents a hydrogen atom :
represents one of the radicals selected from the group comprising the dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or piperidino radi-cals substituted by a methyl group.
- n is 2 or 3 :
- R5 represents a hydrogen atom :
represents one of the radicals selected from the group comprising the dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or piperidino radi-cals substituted by a methyl group.
7. Process according to claim 1, for preparing the hydrochlorides of the compounds according to claim 3 or 4, in which :
- n is 2 or 3 ;
- R5 represents a hydrogen atom ;
represents one of the radicals selected from the group comprising the dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or piperidino radi-cals substituted by a methyl group at the 2 position.
- n is 2 or 3 ;
- R5 represents a hydrogen atom ;
represents one of the radicals selected from the group comprising the dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or piperidino radi-cals substituted by a methyl group at the 2 position.
8. Process according to claim 1, for preparing the hydrochlorides of the compounds according to claim 3 or 4, in which :
- R5 represents a halogen, the NO2, NH2, CF3 group, an alkoxy radical having from 1 to 4 carbon atoms, or an alkylsulfonyl radical having from 1 to 4 carbon atoms.
- R5 represents a halogen, the NO2, NH2, CF3 group, an alkoxy radical having from 1 to 4 carbon atoms, or an alkylsulfonyl radical having from 1 to 4 carbon atoms.
9. Process according to claim 1, for preparing the hydrochlorides of the compounds according to claim 3 or 4, in which :
- n is 2 or 3 ;
- R5 represents the OCH3, C1, Br, SO2CH3, SO2C2H5, SO2nC3H7, SO2iC3H7 group :
represents one of the radicals selected from the group comprising the dimethylamino, diethylamino, pyrrolidino, morpholino, piperidino, piperidino radicals substituted by a methyl radical ;
as well as their physiologically acceptable organic or inorganic salts.
- n is 2 or 3 ;
- R5 represents the OCH3, C1, Br, SO2CH3, SO2C2H5, SO2nC3H7, SO2iC3H7 group :
represents one of the radicals selected from the group comprising the dimethylamino, diethylamino, pyrrolidino, morpholino, piperidino, piperidino radicals substituted by a methyl radical ;
as well as their physiologically acceptable organic or inorganic salts.
10. Process according to claim 1, for preparing the hydrochlorides of the compounds according to claim 3 or 4, in which :
- n is 2 or 3 ;
- R5 represents the OCH3, C1, Br, SO2CH3, SO2C2H5, SO2nC3H7, SO2iC3H7 group ;
represents one of the radicals selected from the group comprising the dimethylamino, diethylamino, pyrrolidino, morpholino, piperidino, piperidino radicals substituted by a methyl radical at the 2 position ;
as well as their physiologically acceptable organic or inorganic salts.
- n is 2 or 3 ;
- R5 represents the OCH3, C1, Br, SO2CH3, SO2C2H5, SO2nC3H7, SO2iC3H7 group ;
represents one of the radicals selected from the group comprising the dimethylamino, diethylamino, pyrrolidino, morpholino, piperidino, piperidino radicals substituted by a methyl radical at the 2 position ;
as well as their physiologically acceptable organic or inorganic salts.
11. Process for the preparation of the compounds or of their physiologically acceptable organic or inor-ganic salts, corresponding to the hydrochlorides of the compounds obtained according to claim 1, wherein said hydrochloride is converted into the corresponding base or converted into a different salt followed if necessary by reduction when A represents the NO2 group.
12. Process according to claim 1, wherein the amine is selected from among :
-dimethylamino-ethylamine, - diethylamino-ethylamine, - pyrrolidino-ethylamine, - piperidino-ethylamine, - morpholino-ethylamine, - dimethylamino-propylamine, - diethylamino-propylamine, - piperidino-propylamine, - 3-(2-methyl piperidino)propylamine, - morpholino-propylamine.
-dimethylamino-ethylamine, - diethylamino-ethylamine, - pyrrolidino-ethylamine, - piperidino-ethylamine, - morpholino-ethylamine, - dimethylamino-propylamine, - diethylamino-propylamine, - piperidino-propylamine, - 3-(2-methyl piperidino)propylamine, - morpholino-propylamine.
13. Process according to claim 1 wherein the sulfochloride of formula (V) is obtained from the following arylamines :
- 2,4-dimethoxy aniline, - 5-chloro 2,4-dimethoxy aniline, - 5-bromo 2,4-dimethoxy aniline, - 2,4,5-trimethoxy aniline, - 2,4-dimethoxy 5-methylsulfonyl aniline.
- 2,4-dimethoxy 5-ethylsulfonyl aniline, - 2,4-dimethoxy 5-propylsulfonyl aniline, - 2,4-dimethoxy 5-isopropylsulfonyl aniline.
- 2,4-dimethoxy aniline, - 5-chloro 2,4-dimethoxy aniline, - 5-bromo 2,4-dimethoxy aniline, - 2,4,5-trimethoxy aniline, - 2,4-dimethoxy 5-methylsulfonyl aniline.
- 2,4-dimethoxy 5-ethylsulfonyl aniline, - 2,4-dimethoxy 5-propylsulfonyl aniline, - 2,4-dimethoxy 5-isopropylsulfonyl aniline.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8108125A FR2504528A1 (en) | 1981-04-23 | 1981-04-23 | DIALCOXY (2,4) N-SUBSTITUTED BENZENESULFONAMIDES |
| FR8108125 | 1981-04-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1196919A true CA1196919A (en) | 1985-11-19 |
Family
ID=9257710
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000401378A Expired CA1196919A (en) | 1981-04-23 | 1982-04-21 | N-substituted 2,4-dialkoxy benzensulfonamides |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0064445B1 (en) |
| JP (1) | JPS57181053A (en) |
| AT (1) | ATE9996T1 (en) |
| CA (1) | CA1196919A (en) |
| DE (1) | DE3261038D1 (en) |
| DK (1) | DK178782A (en) |
| ES (1) | ES511609A0 (en) |
| FR (1) | FR2504528A1 (en) |
| IE (1) | IE52855B1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3363289D1 (en) * | 1982-09-28 | 1986-06-05 | Beecham Wuelfing Gmbh & Co Kg | SULFON AMIDES |
| JPS5976051A (en) * | 1982-10-21 | 1984-04-28 | Tanabe Seiyaku Co Ltd | Naphthalene derivative, its preparation and method for determining optical purity using said derivative |
| FR2553409B1 (en) * | 1983-10-18 | 1986-04-18 | Choay Sa | NOVEL BENZENESULFONYL-LACTAMES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS ACTIVE SUBSTANCE OF PHARMACEUTICAL COMPOSITIONS |
| FR2598412B1 (en) * | 1986-03-12 | 1988-10-21 | Sanofi Sa | NOVEL DIARYLCETON DERIVATIVES AND PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| CA2165662A1 (en) * | 1993-06-23 | 1995-01-05 | Nobuhiro Ohi | Benzene derivatives effective on ischemic diseases |
| EP0883613A1 (en) * | 1996-02-09 | 1998-12-16 | Smithkline Beecham Plc | Sulfonamide derivatives as 5ht7 receptor antagonists |
| WO1997049695A1 (en) * | 1996-06-25 | 1997-12-31 | Smithkline Beecham P.L.C. | Sulfonamide derivatives as 5ht7 receptor antagonists |
| ES2161594B1 (en) * | 1998-12-17 | 2003-04-01 | Servier Lab | NEW DERIVATIVES OF HYDRAZIDE, ITS PREPARATION PROCEDURE AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| SK542007A3 (en) * | 2007-04-20 | 2008-11-06 | Unimed Pharma, Spol. S R. O. | Substituted sulfonamides, process for preparing them, medicament containing them and their use |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB667772A (en) * | 1947-11-28 | 1952-03-05 | Gen Aniline & Film Corp | Monosulfonamide derivatives of resorcinol |
| DE2128011A1 (en) * | 1971-06-05 | 1972-12-14 | Cassella Farbwerke Mainkur AG, 6000 Frankfurt-Fechenheim | New sulfonyl compounds and processes for their production |
| FR2313918A1 (en) * | 1975-06-09 | 1977-01-07 | Choay Sa | 2-METHOXY BENZENESULFONAMIDES N-SUBSTITUTE, PROCESS FOR THE PREPARATION AND MEDICINAL PRODUCTS CONTAINING THEM |
-
1981
- 1981-04-23 FR FR8108125A patent/FR2504528A1/en active Granted
-
1982
- 1982-04-20 IE IE925/82A patent/IE52855B1/en unknown
- 1982-04-21 CA CA000401378A patent/CA1196919A/en not_active Expired
- 1982-04-21 AT AT82400717T patent/ATE9996T1/en active
- 1982-04-21 EP EP82400717A patent/EP0064445B1/en not_active Expired
- 1982-04-21 DE DE8282400717T patent/DE3261038D1/en not_active Expired
- 1982-04-22 ES ES511609A patent/ES511609A0/en active Granted
- 1982-04-22 DK DK178782A patent/DK178782A/en not_active Application Discontinuation
- 1982-04-23 JP JP57068566A patent/JPS57181053A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| ES8306107A1 (en) | 1983-06-01 |
| IE52855B1 (en) | 1988-03-30 |
| IE820925L (en) | 1982-10-23 |
| EP0064445A1 (en) | 1982-11-10 |
| ES511609A0 (en) | 1983-06-01 |
| EP0064445B1 (en) | 1984-10-24 |
| DK178782A (en) | 1982-10-24 |
| ATE9996T1 (en) | 1984-11-15 |
| DE3261038D1 (en) | 1984-11-29 |
| JPS57181053A (en) | 1982-11-08 |
| FR2504528A1 (en) | 1982-10-29 |
| FR2504528B1 (en) | 1984-05-11 |
| JPH0153669B2 (en) | 1989-11-15 |
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