CA1253157A - Derivatives of 2-amino-1,3,4,6,7,11b-hexahydro-2h- benzo¬a|quinolizine - Google Patents
Derivatives of 2-amino-1,3,4,6,7,11b-hexahydro-2h- benzo¬a|quinolizineInfo
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- CA1253157A CA1253157A CA000555802A CA555802A CA1253157A CA 1253157 A CA1253157 A CA 1253157A CA 000555802 A CA000555802 A CA 000555802A CA 555802 A CA555802 A CA 555802A CA 1253157 A CA1253157 A CA 1253157A
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- hexahydro
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Abstract
Abstract This reaction concerns benzoquinolizines of general formula (XIV) wherein R1 and R2 which may be the same or different each represent hydrogen, lower alkyl, lower alkoxy or halogen, A represents a lower alkylene group having 1 to 3 carbon atoms in the chain between the two N atoms and Z1 and Z2 are both hydrogen and R is hydrogen or lower alkyl or Z1 is hydrogen and Z2 is SO2R4 [where R4 is lower alkyl, halo(lower)alkyl, phenyl or phenyl substituted by one or more halogen, alkoxy, lower alkyl, alkylenedioxy, nitro, amino, acylamino, lower alkylamino, diloweralkylamino or trifluoromethyl substituents] or Z1 is SO2R3(where R3 is lower alkyl, halo(lower) alkyl, phenyl or phenyl substituted by one or more halogen, alkoxy, lower alkyl, alkylenedioxy, nitro, amino, acylamino, lower alkylamino, diloweralkylamino or trifluoromethyl substituents], Z2 is hydrogen and R is hydrogen.
The compounds are useful as intermediates. for pharmacologically active benzoquinolizines.
The compounds are useful as intermediates. for pharmacologically active benzoquinolizines.
Description
~ 5 7 ~I-336/34la-cA
The invention relates to benzoquinolizines, in particular to intermedials useful for preparlng other benzoquinolizines, having pharmaceutical activity.
Our copending Canadian Patent Application No. 449054, from which the presen-t application is divided, discloses novel benzoquinolizines of the general formula (I) R"~
S~ 5~Q4 and their pharmaceutically acceptable acid addition salts.
In formula (I), R represents hydrogen or lower alkyl, R and R which may be the same or different each represent hydrogen, lower alkyl, halo(lower)alkyl, phenyl or phenyl substitu-ted by one or more halogen, alkoxy, lower alkyl alkylenedioxy, ni-tro, amino, acylamino, lower alkylamino, diloweralkylamino or triflouromethyl aubstituents and A
representsalower alkylene group having 1 -to 3 carbon atoms in the chain betweent~e two N atoms.
The term "lower" as used herein means tha-t -the radical referred to contains 1 to 6 carbon atoms.
Preferably such radicals contain 1 to 4 carbon atoms.
For example, a lower alkyl group may be methyl, ethyl, propyl or butyl. When Rl and/or R represen-t lower alkoxy the group may be, for examp:Le, methoxy, e-thoxy, propoxy or butoxy. When Rl and/or R2 represents halogen the substi-tuen-t may be, for example, fluorine, chlorine or bromine.
Preferably both Rl and R2 are hydrogen.
The lower alkylene group A may be branched or straight chain provided that there are 1 -to 3 carbon atoms in the chain between the two N atoms.
For example, the lower alkylene group may be methylene, ethylene, trimethylene or a branched chain group such as ethylethylene or propylene[-CH(CH3).CH2-1.
Preferably A is ethylene.
.~.,~.~
v~
H-336/341a-CA
When R3 and R4 is a substituted phenyl group the substituents are chosen fron halogen (e.g. chlorine, fluorine or bromine), alkoxy (e.g. lower alkoxy such as methoxy or ethoxy), lower alkyl (e.g. methyl, ethyl, propyl or butyl), alkylenedioxy (e.g. me-thylenedioxy or ethylenedioxy), nitro, amino, acylamino (particularly lower acylamino), lower alkylamino, diloweralkylamino or trifluoromethyl.
When R3 or R is lower alkyl, the group can be, for example, methyl, ethyl, propyl or bu-tyl. When R3 or R4 is halo(lower)alkyl the halo subs-tituent may be fluorine, chlorine, bromine or iodine. More than one halo atom may be present in the halo(lower)alkyl group; if more than one halo atom is present the halo atoms may be on the same carbon atom of the (lower)alkyl radical or on different carbon a-toms (if the radical contains more than one carbon atom). Examples of halo(lower)alkyl groups include, for example, trifluoromethyl and chloromethyl.
Preferably R4 is lower alkyl, e.g. methyl, and R3 is lower alkyl (e.g. methyl or propyl) or phenyl.
Preferably R is hydrogen.
The present invention provides novel intermediates which may be used in preparing the compounds of formula (I) by the processes described in Canadian Patent Application No. 449054. The novel intermediates have the general formula (XIV) I V ) Z / ~ Z~
wherein R , R and A are as defined above and Z and Z are both hydrogen and R is hydrogen or lower alkyl or zl is hydrogen, Z is S02R (where R4 is as defined above) and R
is hydrogen or lower alkyl or zl is S02R3 (where R is as defined above), z2 is hydrogen and R is hydrogen.
H-336/3~1a-CA
5~
The present inven-tion particularly provides processes for preparing the compounds of formula (XIV). For example the compound in which zl and z2 are both hydrogen and R is hydrogen or lower alkyl i.e. the compounds of general formula (III) R~
H
may be prepared by reductive amination of a ketone of general formula R!
where R and R have the meanings given above. For example, the ketone may be reacted with a diamine of formula NH2-A-NHR (\/ ) (where A and R have the meanings given above) and with a hydride transfer agent, e.g. sodium cyanoborohydride.
When R in the diamine is a lower alkyl group it may be necessary to replace the hydrogen on -the amino carrying -the loweralkylsuhs-ti-tuent with a protecting group, such as benzyl and remove the protecting group after the reductive amination.
~ a~ 7 H-336/341a-CA
The compounds of formula (III) may be prepared by an alternative method comprising reductive amination (by reaction with a diamine of formula VII and e.g. a hydride tranfer reagent such as sodium borohydride) of a quaternary salt precursor of the ketone (VI), the quaternary salt having the formula:
~ cll~CH7~G.CH, A (~
(where R and R have the meanings given above and A is an anion, e.g. halide).
The compounds oE formula (XIV) in which Z is hydrogen, Z2is So2R4 and R is hydrogen or lower alky~ are of the general formula (IX) ~L~
so~-R4 (wherein A, R, R , R and R have the meanings given above) may be prepared by known methods.
For example, the benzoquinolizine of formula (III) may be selectively sulphonated with the reactive derivative of a sulphonic acid oE formula R5So20H (II) (where R5 has the meanings of R3 and R4 above) using the requisite amount of reactive derivative for forming the monosulphonamide (IX) rather than -the disulphonamide (I); it may be necessary to block one of the amine groups i-n-the diamine (III) with a protecting group such as benzyl and remove the protecting group ater -the sulphonation. The reactive derivative of the sulphonic acid can be, for example, the acid halide or anhydride. Preferably it is the acid halide, i.e. a compound .
H-336/341a-CA
of formula R S02X (V) (where R5 is as defined above and X is halogen, preferably chlorine). The benzoquinolizine (IX) alternatively may be prepared by reductive amination of the ke-tone (VI) with an amine NH2ANRSo2R4 (where A, R and R have the meanings given above) and a hydride -transEer agent such as sodium borohydride.
Compounds of formula (XIV) in which zl is So2R3 and Z and R are both hydrogen are benzoquinolizines of general formula ~\J ~X~
~ 2/ \A.~, (where A, Rl, R and R3 are as defined above) and may be prepared by methods knownper se. For example, a benzo-quinolizine of general formula R~ Xl ) R3So, ~ ~
(where Rl, R2 and R3 have the meanlngs given above) may be reacted with a phthalimido protected haloamine of form~la Y ~ ~ ~ r~\~3 (~\/) H-336/341a-CA
~3~
(where A has the meaning given above and Y is halogen, preferably bromine) in presence of a strong base such as sodium hydride or lithium diisopropylamide and the phthalimido protec-ting group removed.
If inthe processes described above the compound of the inventionis obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base, an acid addition salt, particularly a pharmaceu-tically acceptable acid addi-tion salt may be obtained by dissolving the free base in a sultable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from the base compound.
Examples of acid addition sales are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic and p-toluenesulphonic acids.
The compounds of the invention possesstwoasymmetric carbon atoms and hence can exist in various stereochemical forms. In addition they can exist as cis or trans isomers.
The following Examples illustrate the invention:
N-[2~11b~)-1,3,4,6,7,11b-hexahydro-2_-benzo[a]quinolizin-
The invention relates to benzoquinolizines, in particular to intermedials useful for preparlng other benzoquinolizines, having pharmaceutical activity.
Our copending Canadian Patent Application No. 449054, from which the presen-t application is divided, discloses novel benzoquinolizines of the general formula (I) R"~
S~ 5~Q4 and their pharmaceutically acceptable acid addition salts.
In formula (I), R represents hydrogen or lower alkyl, R and R which may be the same or different each represent hydrogen, lower alkyl, halo(lower)alkyl, phenyl or phenyl substitu-ted by one or more halogen, alkoxy, lower alkyl alkylenedioxy, ni-tro, amino, acylamino, lower alkylamino, diloweralkylamino or triflouromethyl aubstituents and A
representsalower alkylene group having 1 -to 3 carbon atoms in the chain betweent~e two N atoms.
The term "lower" as used herein means tha-t -the radical referred to contains 1 to 6 carbon atoms.
Preferably such radicals contain 1 to 4 carbon atoms.
For example, a lower alkyl group may be methyl, ethyl, propyl or butyl. When Rl and/or R represen-t lower alkoxy the group may be, for examp:Le, methoxy, e-thoxy, propoxy or butoxy. When Rl and/or R2 represents halogen the substi-tuen-t may be, for example, fluorine, chlorine or bromine.
Preferably both Rl and R2 are hydrogen.
The lower alkylene group A may be branched or straight chain provided that there are 1 -to 3 carbon atoms in the chain between the two N atoms.
For example, the lower alkylene group may be methylene, ethylene, trimethylene or a branched chain group such as ethylethylene or propylene[-CH(CH3).CH2-1.
Preferably A is ethylene.
.~.,~.~
v~
H-336/341a-CA
When R3 and R4 is a substituted phenyl group the substituents are chosen fron halogen (e.g. chlorine, fluorine or bromine), alkoxy (e.g. lower alkoxy such as methoxy or ethoxy), lower alkyl (e.g. methyl, ethyl, propyl or butyl), alkylenedioxy (e.g. me-thylenedioxy or ethylenedioxy), nitro, amino, acylamino (particularly lower acylamino), lower alkylamino, diloweralkylamino or trifluoromethyl.
When R3 or R is lower alkyl, the group can be, for example, methyl, ethyl, propyl or bu-tyl. When R3 or R4 is halo(lower)alkyl the halo subs-tituent may be fluorine, chlorine, bromine or iodine. More than one halo atom may be present in the halo(lower)alkyl group; if more than one halo atom is present the halo atoms may be on the same carbon atom of the (lower)alkyl radical or on different carbon a-toms (if the radical contains more than one carbon atom). Examples of halo(lower)alkyl groups include, for example, trifluoromethyl and chloromethyl.
Preferably R4 is lower alkyl, e.g. methyl, and R3 is lower alkyl (e.g. methyl or propyl) or phenyl.
Preferably R is hydrogen.
The present invention provides novel intermediates which may be used in preparing the compounds of formula (I) by the processes described in Canadian Patent Application No. 449054. The novel intermediates have the general formula (XIV) I V ) Z / ~ Z~
wherein R , R and A are as defined above and Z and Z are both hydrogen and R is hydrogen or lower alkyl or zl is hydrogen, Z is S02R (where R4 is as defined above) and R
is hydrogen or lower alkyl or zl is S02R3 (where R is as defined above), z2 is hydrogen and R is hydrogen.
H-336/3~1a-CA
5~
The present inven-tion particularly provides processes for preparing the compounds of formula (XIV). For example the compound in which zl and z2 are both hydrogen and R is hydrogen or lower alkyl i.e. the compounds of general formula (III) R~
H
may be prepared by reductive amination of a ketone of general formula R!
where R and R have the meanings given above. For example, the ketone may be reacted with a diamine of formula NH2-A-NHR (\/ ) (where A and R have the meanings given above) and with a hydride transfer agent, e.g. sodium cyanoborohydride.
When R in the diamine is a lower alkyl group it may be necessary to replace the hydrogen on -the amino carrying -the loweralkylsuhs-ti-tuent with a protecting group, such as benzyl and remove the protecting group after the reductive amination.
~ a~ 7 H-336/341a-CA
The compounds of formula (III) may be prepared by an alternative method comprising reductive amination (by reaction with a diamine of formula VII and e.g. a hydride tranfer reagent such as sodium borohydride) of a quaternary salt precursor of the ketone (VI), the quaternary salt having the formula:
~ cll~CH7~G.CH, A (~
(where R and R have the meanings given above and A is an anion, e.g. halide).
The compounds oE formula (XIV) in which Z is hydrogen, Z2is So2R4 and R is hydrogen or lower alky~ are of the general formula (IX) ~L~
so~-R4 (wherein A, R, R , R and R have the meanings given above) may be prepared by known methods.
For example, the benzoquinolizine of formula (III) may be selectively sulphonated with the reactive derivative of a sulphonic acid oE formula R5So20H (II) (where R5 has the meanings of R3 and R4 above) using the requisite amount of reactive derivative for forming the monosulphonamide (IX) rather than -the disulphonamide (I); it may be necessary to block one of the amine groups i-n-the diamine (III) with a protecting group such as benzyl and remove the protecting group ater -the sulphonation. The reactive derivative of the sulphonic acid can be, for example, the acid halide or anhydride. Preferably it is the acid halide, i.e. a compound .
H-336/341a-CA
of formula R S02X (V) (where R5 is as defined above and X is halogen, preferably chlorine). The benzoquinolizine (IX) alternatively may be prepared by reductive amination of the ke-tone (VI) with an amine NH2ANRSo2R4 (where A, R and R have the meanings given above) and a hydride -transEer agent such as sodium borohydride.
Compounds of formula (XIV) in which zl is So2R3 and Z and R are both hydrogen are benzoquinolizines of general formula ~\J ~X~
~ 2/ \A.~, (where A, Rl, R and R3 are as defined above) and may be prepared by methods knownper se. For example, a benzo-quinolizine of general formula R~ Xl ) R3So, ~ ~
(where Rl, R2 and R3 have the meanlngs given above) may be reacted with a phthalimido protected haloamine of form~la Y ~ ~ ~ r~\~3 (~\/) H-336/341a-CA
~3~
(where A has the meaning given above and Y is halogen, preferably bromine) in presence of a strong base such as sodium hydride or lithium diisopropylamide and the phthalimido protec-ting group removed.
If inthe processes described above the compound of the inventionis obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base, an acid addition salt, particularly a pharmaceu-tically acceptable acid addi-tion salt may be obtained by dissolving the free base in a sultable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from the base compound.
Examples of acid addition sales are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic and p-toluenesulphonic acids.
The compounds of the invention possesstwoasymmetric carbon atoms and hence can exist in various stereochemical forms. In addition they can exist as cis or trans isomers.
The following Examples illustrate the invention:
N-[2~11b~)-1,3,4,6,7,11b-hexahydro-2_-benzo[a]quinolizin-
2-yl]ethylenediamine A solu-tion of 2-oxo-1,3,4,6,7,11b~-hexahydro-2H-benzo Ia]quinolizine (4 g, 0.02 mol) in ethanol (40 cm3) was acidified with e-thanolic HCl Ethylenediamine (7.2 g, 0.12 mol) and 2-oxo-1,3,4,6,7,11b~-hexahydro-2H-benzo[a]
quinolizine (4g, 0.02 mol) were then added -to the above solu-tion and the mix-ture refluxed for 1.5 hour. The solu-tion was then cooled in ice and sodium borohydride (2 g) added wi-th stirring. The mixture was stirred for 4 hours at ambient temperature and then evaporated.
quinolizine (4g, 0.02 mol) were then added -to the above solu-tion and the mix-ture refluxed for 1.5 hour. The solu-tion was then cooled in ice and sodium borohydride (2 g) added wi-th stirring. The mixture was stirred for 4 hours at ambient temperature and then evaporated.
3~7 H-336/3~ 1 a-cA
The residue was diluted with water and extracted with chloroform. The extracts were dried and evaporated, the residue was dissolved in ethanol (60 cm3) and acidified with ethanolic HCl to precipi-tate the amine salt (~0.5g), m.p. 225-30C.
N-[(2~,11b~)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]
quinolizin-2-~1]-N'-methylethylenediamine _ A mixture of 4-(3,4-dihydroisoquinolinium)butane-2-one chloride (4.17 g), N-methylethylenediamine (2.6 g) and ethanol (15 cm3) was heated at ~lux for 1.5 hours. The solution was then cooled in ice and sodium borohydride (1 g) added. After stirring overnight the solvent was evaporated, the residue was diluted with water and extracted with chloroform. The extract was dried and evaporated, the residue was dissolved in ethanol and acidified with e~hanolic hydrogen chloride to precipitate the title compound as the crystalline trihydrochloride 4.4 g, m.p. 245-8C.
~ XAMPL~ 3 _-(2-[((2~,11b~)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl)amino]ethyl)propanesulphonamide Propanesulphonyl chloride (1.57g, 1.24cm3) was added dropwise -to a vigourously stirred mixture of N-[(2~,11b~)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinoli2in-2-yl]ethylenediamine trihydrochloride (3.55g),potassium carbonate (6.9g), CH2CH2 (40cm3) and water (20cm ).
After addition was completed the mix-ture was stirred for 0.5 hours then the organic phase was separated, dried and evaporated. The residue was dissolved in ethanol (30cm3) and acidified with concentra-ted aqueous hydrobromic acid (60~) to precipitate the title compound dihydrobromide (2.3g), m.p. 190-92C.
~ H-336/341a-CA
N-(2-[((2~,11b~)-1,3,4,6,7,11b-Hexahydro-2H-benzo[a]-. . . _ . . .
quinolizine-2-yl)amino]ethyl)benzenesulphonamide _ Benzenesulphonyl chloride (2.58cm ) was added dropwise to a stirred ice cooled mixture of N-((2~,11b~)-1,3,4,6,7, llb-hexahyclro-2H-benzo[a]quinolizine-2-yl)ethylenediamine trihydrochloride (7.08g), potassium carbona-te (11.04g), CH2C12 (80cm3) and water (40cm3). After 0.5 hours -the organic phase was separated, dried and evaporated. The residue was dissolved in methanol (40cm3) and acidified with aqueous hydrobromic acid (60~ w/v S.G. 1.7) to precipitate the title compound as the crystalline dihydrobromide (5.4g). A sample recrystallised from aqueous methanol gave m.p. 245-7C.
N-[(28,11b~)-1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-2H-. . . _ . _ benzo[a]quinolizin-2-yl]ethylenediamine . _ . . _ _ . _ .
2-Oxo-9,10-dimethoxybenzoquinolizine (7.8g) in ethanol (30cm ) was just neutralised by addition of ethanolic-HCl. Ethylenediamine (10cm ) was then added and the solution refluxed for 2 hours. The solution was then cooled in ice and sodium borohydride (1.5g) added carefully with stirring. The mixture was then allowed to stir at ambient tempera-ture over nigh-t. The solution was evaporated, diluted with water and ex-tracted into chloroform. The ex-tract was dried and evaporated and the residue dissolved in ethanol (50cm ) and acidified with e-thanolic-HCl -to precipita-te a gum which crystallised when the mixture was warmed brieEly. After cooling in ice the title compound was collec-ted as the crystalline trihydrochloride and washed with ethanol -to give 7.3g, m.p. 259-62C.
H-336/341a-CA, 3~S'~
N-(2-[((2~,11b~)-1,3,4,6,7,11b-Hexahydro-2H-benzo[a]--quinolizin-2-yl)amino]ethyl)methanesulphonamide _ Methanesulphonic anhydride (11.3g) was added por-tionwise over 2-3 min -to a vigorously stirred, ice cooled mixture of N-[(2~,11ba)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl]ethylenediamine trihydrochloride (17.7g), potassium carbonate (27.6g), CH2C12 (200cm3) and water (lOOcm ). After stirring for a further 0.5 hours the mixture was diluted with water, to dissolve MeSO3K, the organic phase was separated and the aqueous phase extracted with chloroform. The combined organic phases were dried and evaporated. The residue was dissolved in ethanol:methanol (1:1, 300 cm ) and acidified with aqueous hydrobromic acid (60~ w/v) to precipitate title compound as the dihydrobromide on ice cooling ~3.2g, m.p. 238-45C.
N-[2~,11b~)-1,3,4,6,7,11b-Hexahydro-2H-benzo[a]quinolizin-_ 2-yl]propane-1,3-diamine A mixture of 3,4-dihydro-2-(3-oxobutyl)isoquinolinium chloride (38.4g) and 1,3-propanediamine (67 cm3) was refluxed for 1.5 hours in ethanol (100 cm3). The reaction was then cooled in ice and sodium borohydride (8 g) added portionwise with stirring. Stirring was continued overnight at room temperature then -the mixture concentrated in vacuo.
The residue was carefully hydrolysed wi-th water and then extracted with dichlorome-thane. The combined organic phases were washed (brine), dried (Na2SO4), and evaporated to dryness. The residue was dissolved in ethanol and acidified with ethanolic hydrogen chloride to precipitate the trihydrochloride (44.5g).
The salt was converted to the free base and used in the prepara-tion of N-(3-[((2~,11b~)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl)amino3propyl)methanesulphonamide.
H-336/341a-CA
5'~
_-(3-[((2~,11b~)-1,3,4,6,7,11b-Hexahydro-2H-benzo[a]
_ quinolizin-2-yl)amino]propyl)methanesulphonamide _ _ , _ _ _ A solution of methanesulphonic anhydrlde (9.Og) in dichloromethane (100 cm ) was added dropwise over 2-3 mins. to a rapidly stirred, ice-cooled mixture of _-[(2~,11b~)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl]propane-1,3-diamine (lO.Sg), potassium carbonate (16.5g), dichloromethane (100 cm3) and water (100 cm3).
The reaction was stirred for a fur-ther 0.5 hours then -the organic phase was separated, washed (brine), dried (Na2S04), and concentrated in vacuo to leave a viscous dark brown syrup (13.6g).
The residue was dissolved in ethanol (125 cm3) and a solution of oxalic acid dihydrate (10.6g) in ethanol (75 cm3) was added. The solution was allowed to crystallise overnight then the white crystalline salt collected by filtration, washed well with ethanol and dried in vacuo to yield dioxalate (16.6g) which could be recrystallised from methanol/water (1:1).
The salt was converted to the free base and used in the preparation of _-[(2~,11b~)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl]-N-(3-methanesulphonamidopropyl)-methanesulphonamide as described in our copending Canadian Patent Application No. 449054.
The residue was diluted with water and extracted with chloroform. The extracts were dried and evaporated, the residue was dissolved in ethanol (60 cm3) and acidified with ethanolic HCl to precipi-tate the amine salt (~0.5g), m.p. 225-30C.
N-[(2~,11b~)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]
quinolizin-2-~1]-N'-methylethylenediamine _ A mixture of 4-(3,4-dihydroisoquinolinium)butane-2-one chloride (4.17 g), N-methylethylenediamine (2.6 g) and ethanol (15 cm3) was heated at ~lux for 1.5 hours. The solution was then cooled in ice and sodium borohydride (1 g) added. After stirring overnight the solvent was evaporated, the residue was diluted with water and extracted with chloroform. The extract was dried and evaporated, the residue was dissolved in ethanol and acidified with e~hanolic hydrogen chloride to precipitate the title compound as the crystalline trihydrochloride 4.4 g, m.p. 245-8C.
~ XAMPL~ 3 _-(2-[((2~,11b~)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl)amino]ethyl)propanesulphonamide Propanesulphonyl chloride (1.57g, 1.24cm3) was added dropwise -to a vigourously stirred mixture of N-[(2~,11b~)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinoli2in-2-yl]ethylenediamine trihydrochloride (3.55g),potassium carbonate (6.9g), CH2CH2 (40cm3) and water (20cm ).
After addition was completed the mix-ture was stirred for 0.5 hours then the organic phase was separated, dried and evaporated. The residue was dissolved in ethanol (30cm3) and acidified with concentra-ted aqueous hydrobromic acid (60~) to precipitate the title compound dihydrobromide (2.3g), m.p. 190-92C.
~ H-336/341a-CA
N-(2-[((2~,11b~)-1,3,4,6,7,11b-Hexahydro-2H-benzo[a]-. . . _ . . .
quinolizine-2-yl)amino]ethyl)benzenesulphonamide _ Benzenesulphonyl chloride (2.58cm ) was added dropwise to a stirred ice cooled mixture of N-((2~,11b~)-1,3,4,6,7, llb-hexahyclro-2H-benzo[a]quinolizine-2-yl)ethylenediamine trihydrochloride (7.08g), potassium carbona-te (11.04g), CH2C12 (80cm3) and water (40cm3). After 0.5 hours -the organic phase was separated, dried and evaporated. The residue was dissolved in methanol (40cm3) and acidified with aqueous hydrobromic acid (60~ w/v S.G. 1.7) to precipitate the title compound as the crystalline dihydrobromide (5.4g). A sample recrystallised from aqueous methanol gave m.p. 245-7C.
N-[(28,11b~)-1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-2H-. . . _ . _ benzo[a]quinolizin-2-yl]ethylenediamine . _ . . _ _ . _ .
2-Oxo-9,10-dimethoxybenzoquinolizine (7.8g) in ethanol (30cm ) was just neutralised by addition of ethanolic-HCl. Ethylenediamine (10cm ) was then added and the solution refluxed for 2 hours. The solution was then cooled in ice and sodium borohydride (1.5g) added carefully with stirring. The mixture was then allowed to stir at ambient tempera-ture over nigh-t. The solution was evaporated, diluted with water and ex-tracted into chloroform. The ex-tract was dried and evaporated and the residue dissolved in ethanol (50cm ) and acidified with e-thanolic-HCl -to precipita-te a gum which crystallised when the mixture was warmed brieEly. After cooling in ice the title compound was collec-ted as the crystalline trihydrochloride and washed with ethanol -to give 7.3g, m.p. 259-62C.
H-336/341a-CA, 3~S'~
N-(2-[((2~,11b~)-1,3,4,6,7,11b-Hexahydro-2H-benzo[a]--quinolizin-2-yl)amino]ethyl)methanesulphonamide _ Methanesulphonic anhydride (11.3g) was added por-tionwise over 2-3 min -to a vigorously stirred, ice cooled mixture of N-[(2~,11ba)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl]ethylenediamine trihydrochloride (17.7g), potassium carbonate (27.6g), CH2C12 (200cm3) and water (lOOcm ). After stirring for a further 0.5 hours the mixture was diluted with water, to dissolve MeSO3K, the organic phase was separated and the aqueous phase extracted with chloroform. The combined organic phases were dried and evaporated. The residue was dissolved in ethanol:methanol (1:1, 300 cm ) and acidified with aqueous hydrobromic acid (60~ w/v) to precipitate title compound as the dihydrobromide on ice cooling ~3.2g, m.p. 238-45C.
N-[2~,11b~)-1,3,4,6,7,11b-Hexahydro-2H-benzo[a]quinolizin-_ 2-yl]propane-1,3-diamine A mixture of 3,4-dihydro-2-(3-oxobutyl)isoquinolinium chloride (38.4g) and 1,3-propanediamine (67 cm3) was refluxed for 1.5 hours in ethanol (100 cm3). The reaction was then cooled in ice and sodium borohydride (8 g) added portionwise with stirring. Stirring was continued overnight at room temperature then -the mixture concentrated in vacuo.
The residue was carefully hydrolysed wi-th water and then extracted with dichlorome-thane. The combined organic phases were washed (brine), dried (Na2SO4), and evaporated to dryness. The residue was dissolved in ethanol and acidified with ethanolic hydrogen chloride to precipitate the trihydrochloride (44.5g).
The salt was converted to the free base and used in the prepara-tion of N-(3-[((2~,11b~)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl)amino3propyl)methanesulphonamide.
H-336/341a-CA
5'~
_-(3-[((2~,11b~)-1,3,4,6,7,11b-Hexahydro-2H-benzo[a]
_ quinolizin-2-yl)amino]propyl)methanesulphonamide _ _ , _ _ _ A solution of methanesulphonic anhydrlde (9.Og) in dichloromethane (100 cm ) was added dropwise over 2-3 mins. to a rapidly stirred, ice-cooled mixture of _-[(2~,11b~)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl]propane-1,3-diamine (lO.Sg), potassium carbonate (16.5g), dichloromethane (100 cm3) and water (100 cm3).
The reaction was stirred for a fur-ther 0.5 hours then -the organic phase was separated, washed (brine), dried (Na2S04), and concentrated in vacuo to leave a viscous dark brown syrup (13.6g).
The residue was dissolved in ethanol (125 cm3) and a solution of oxalic acid dihydrate (10.6g) in ethanol (75 cm3) was added. The solution was allowed to crystallise overnight then the white crystalline salt collected by filtration, washed well with ethanol and dried in vacuo to yield dioxalate (16.6g) which could be recrystallised from methanol/water (1:1).
The salt was converted to the free base and used in the preparation of _-[(2~,11b~)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl]-N-(3-methanesulphonamidopropyl)-methanesulphonamide as described in our copending Canadian Patent Application No. 449054.
Claims (37)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of general formula (XIV) wherein R1 and R2 which may be the same or different each represent hydrogen, lower alkyl, lower alkoxy or halogen, A represents a lower alkylene group having 1 to 3 carbon atoms in the chain between the two N atoms and Z1 and Z2 are both hydrogen and R is hydrogen or lower alkyl or Z1 is hydrogen and Z is SO2R4[where R4 is lower alkyl, halo(lower)alkyl, phenyl or phenylsubstituted by one or more halogen, alkoxy, lower alkyl, alkylenedioxy, nitro, amino, acylamino, lower alkylamino, diloweralkylamino or trifluoromethyl substituents] or Z1 is SO2R3 where R3 is lower alkyl, halo(lower)alkyl, phenyl or phenyl substituted by one or more halogen, alkoxy, lower alkyl, alkylenedioxy, nitro, amino, acylamino, lower alkylamino, diloweralkylamino or trifluoromethyl substituents], Z2 is hydrogen and R is hydrogen which comprises (a) reductively aminating a compound of formula (VI) (where R1 and R2 are defined as above) with a diamine of formula (VII) NH2ANRH (VII) (where A and R are as defined above) and a reducing agent or (b) reductively aminating a quaternary salt having the formula (VIII) (VIII) (where R1 and R2 are as defined above and A- is an anion) with a diamine of formula (VII) (as defined above) and a reducing agent or (c) selectively sulphonating a benzoquinolizine of formula (III) (II) (wherein R, R1, R2 and A are as defined above) with a reactive derivative of a sulphonic acid of formula (II) R5SO2OH (II) (where R5 has the meaning of R3 or R4 above) or (d) reductively aminating a benzoqulinolizine of general formula (VI) [as defined above] with an amine of formula (where A, R and R4 are as defined above) and a reducing agent or (e) reacting a benzoquinolizine of general formula (XI) (XI) (where R1, R2 and R3 are as defined above) with a phthalimido protected haloamine of formula (IV) (IV) (where A is as defined above and Y is halogen) in the presence of a strong base and removing the phthalimido protecting group.
2. A process as claimed in Claim 1 for preparing a compound of formula (XIV) in which Z1 and Z2 are both hydrogen and R is hydrogen or lower alkyl which comprises reacting a compound of formula (VI) as defined in Claim 1 and a hydride transfer agent.
3. A process as claimed in Claim 1 for preparing a compound of formula (XIV) in which Z1 and Z2 are both hydrogen and R is hydrogen or lower alkyl which comproses reacting a quaternary salt of formula (VIII) as defined in Claim 1 and a hydride transfer reagent.
4. A process as claimed in Claim 1 for preparing a compound of formula (XIV) in which Z1 is hydrogen, Z2 is SO2R4 (where R4 is as defined in Claim 1) and R is hydrogen or lower alkyl which comprises selectively sulphonating a benzoquinolizine of formula (III) as defined in Claim 1 with an acid halide or anhydride of the sulphonic acid of formula (II) as defined in Claim 1.
5. A process as claimed in Claim 1 for preparing a compound of formula (XIV) in which Z1 is hydrogen, Z2 is SO2R
(where R4 is as defined in Claim 1) and R is hydrogen or lower alkyl which comprises reductively aminating a benzoquinolizine of general formula (VI), as defined in Claim 1 with an amine of formula (where A, R and R4 are as defined immediately above) and a hydride transfer agent.
(where R4 is as defined in Claim 1) and R is hydrogen or lower alkyl which comprises reductively aminating a benzoquinolizine of general formula (VI), as defined in Claim 1 with an amine of formula (where A, R and R4 are as defined immediately above) and a hydride transfer agent.
6. A process as claimed in Claim 1 for preparing a compound of formula (XIV) in which Z1 is SO2R3 (where R3 is as defined in Claim 1), Z2 and R are both hydrogen which comprises reacting a benzoquinolizine of general formula (XI), as defined in Claim 1, with a phthalimido protected haloamine of formula (IV), as defined in Claim 1, in the presence of sodium hydride or lithium diisopropylamide and removing the phthalimido protecting group.
7. A process for preparing N-[2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl]ethylenediamine which comprises reacting 2-oxo-1,3,4,6,7,11b.alpha.-hexahydro-2H-benzo[a]quinolizine with ethylene diamine and sodium borohydride.
8. A process for preparing N-[(2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl]-N'-methylene diamine which comprises reacting 46(3,4-dihydro-isoquinolinium) butane -2-one chloride with N-methylene diamine and sodium borohydride.
9. A process for preparing N-(2-[((2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl)amino]ethyl) propanesulphonamide which comprises reacting propane-sulphonyl chloride with N-[(2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl)]ethylenediamine.
10. A process for preparing N-(2-[((2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizine-2-yl)amino]ethyl) benzenesulphonamide which comprises reacting benzene-sulphonyl chloride with N-((2.beta.,11b.alpha.-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl)ethylenediamine.
11. A process for preparing N-[(2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizin-2-yl]
ethylenediamine which comprises reacting 2-oxo-9,10-dimethoxybenzoquinolizine and sodium borohydride.
ethylenediamine which comprises reacting 2-oxo-9,10-dimethoxybenzoquinolizine and sodium borohydride.
12. A process for preparing N-(2-[((2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl)amino]ethyl) methanesulphonamide which comprises reacting methane-sulphonic anhydride wi-th N-[(2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl)]ethylenediamine.
13. A process for preparing N-[23,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl]propane-1,3-diamine which comprises reacting 3,4-dihydro-2-(3-oxobu-tyl)-isoquinolinium chloride with 1,3-propanediamine and sodium borohydride.
14. A process for preparing N-(3-[((2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin 2-yl)amino]propyl) methanesulphonamide which comprises reacting N-[(2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yllpropane-1,3-diamine with methanesulphonic anhydride.
15. A compound of generalformula(XIV) as defined in Claim 1 whenever prepared by the process as claimed in Claim 1 or its obvious chemical equivalent.
16. A compound of general formula (XIV) wherein Z1 and Z2 are both hydrogen and R is hydrogen or lower alkyl wherever prepared by the process as claimed in claim 2 or its obvious chemical equivalent.
17. A compound of general formula (XIV) wherein Z1 and Z2 are both hydrogen and R is hydrogen or lower alkyl wherever prepared by the process as claimed in Claim 3 or its obvious equivalent.
18. A compound of general formula (XIV) wherein Z1 is hydrogen, Z2 is SO2R4 and R is hydrogen or lower alkyl wherever prepared by the process as claimed in Claim 4 or its obvious equivalent.
19. A compound of general formula (XIV) wherein Z1 is hydrogen, Z2 is SO2R4 and R is hydrogen or lower alkyl wherever prepared by the process as claimed in Claim 5 or its obvious equivalent.
20. A compound of general formula (XIV) in which Z1 is SO2R3 and Z2 and R are both hydrogen wherever prepared by the process as claimed in Claim 6 or its obvious equivalent.
21. N-[2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2yl]ethylenediamine whenever prepared by the process as claimed in Claim 7 or its obvious chemical equivalent.
22. N-[(2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl]-N'-methylethylenediamine whenever prepared by the process as claimed in Claim 8 or its obvious chemical equivalent.
23. N-(2-[((2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl)amino]ethyl)propanesulphonamide whenever prepared by the process as claimed in Claim 9 or its obvious chemical equivalent.
24. N-(2-[((2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]
quinolizine-2-yl)amino]ethyl)benzenesulphonamide whenever prepared by the process as claimed in Claim 10 or its obvious chemical equivalent.
quinolizine-2-yl)amino]ethyl)benzenesulphonamide whenever prepared by the process as claimed in Claim 10 or its obvious chemical equivalent.
25. N-[(2.beta.,11b.alpha.)-1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizin-2-yl]ethylenediamine whenever prepared by the process as claimed in Claim 11 or its obvious chemical equivalent.
26. N-(2-[((2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl)amino]ethyl)methanesulphonamide whenever prepared by the process as claimed in Claim 12 or its obvious chemical equivalent.
27. N-[2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl]propane-1,3-diamine whenever prepared by the process as claimed in Claim 13 or its obvious chemical equivalent.
28. N-(3-[((2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl)amino]propyl)methanesulphonamide whenever prepared as claimed in Claim 14 or its obvious chemical equivalent.
29. A compound of general formula (XIV) wherein R1 and R2 which may be the same or different each represent hydrogen, lower alkyl, lower alkoxy or halogen, A represents a lower alkylene group having 1 to 3 carbon atoms in the chain between the two N atoms and Z1 and Z2 are both hydrogen and R is hydrogen or lower alkyl or Z1 is hydrogen and Z2 is SO2R4 [where R4 is lower alkyl, halo(lower)alkyl, phenyl or phenyl substituted by one or more halogen, alkoxy, lower alkyl, alkylenedioxy, nitro, amino, acylamino, lower alkylamino, diloweralkylamino or trifluoromethyl substituents] or Z1 is SO2R3 [where R3 is lower alkyl, halo(lower)alkyl, phenyl or phenyl substituted by one or more halogen, alkoxy, lower alkyl, alkylenedioxy, nitro, amino, acylamino, lower alkylamino, diloweralkylamino or trifluoromethyl substituents], Z2 is hydrogen and R is hydrogen.
30. N-[2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl]e-thylenediamine
31. N-[(2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[al-quinolizin-2-yl]-N'-methylethylenediamine
32. N-(2-[((2.beta.,11b.alpha.-1,3,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl)amino]ethyl)propanesulphonamide
33. N-(2-[((2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizine-2-yl)amino]ethyl)benzenesulphonamide
34. N-[(2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizin-2-yl]ethylenediamine
35. N-(2-[((2.beta.,11b.alpha.)-1,3,4,6,7,11b hexahydro-2H-benzo[a]-quinolizin-2-yl)amino]ethyl)methanesulphonamide
36. N-[2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl]propane-1,3-diamine
37. N-(3-[((2.beta.,11b.alpha.)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizin-2-yl)amino]propyl)methanesulphonamide
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000555802A CA1253157A (en) | 1983-03-25 | 1988-01-04 | Derivatives of 2-amino-1,3,4,6,7,11b-hexahydro-2h- benzo¬a|quinolizine |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8308321 | 1983-03-25 | ||
| GB838308321A GB8308321D0 (en) | 1983-03-25 | 1983-03-25 | Benzoquinolizines |
| GB8333232 | 1983-12-13 | ||
| GB838333232A GB8333232D0 (en) | 1983-12-13 | 1983-12-13 | Benzoquinolizines |
| CA000449054A CA1247622A (en) | 1983-03-25 | 1984-03-07 | Sulphonamide derivatives of 2-amino-1,3,4,6,7,116- hexahydro-2h-benzo ¬a|quinolizine |
| CA000555802A CA1253157A (en) | 1983-03-25 | 1988-01-04 | Derivatives of 2-amino-1,3,4,6,7,11b-hexahydro-2h- benzo¬a|quinolizine |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000449054A Division CA1247622A (en) | 1983-03-25 | 1984-03-07 | Sulphonamide derivatives of 2-amino-1,3,4,6,7,116- hexahydro-2h-benzo ¬a|quinolizine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1253157A true CA1253157A (en) | 1989-04-25 |
Family
ID=27167424
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000555802A Expired CA1253157A (en) | 1983-03-25 | 1988-01-04 | Derivatives of 2-amino-1,3,4,6,7,11b-hexahydro-2h- benzo¬a|quinolizine |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1253157A (en) |
-
1988
- 1988-01-04 CA CA000555802A patent/CA1253157A/en not_active Expired
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