CA1055944A - 2-methyl-6-phenyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-(c)-(1,6) naphthyridine compounds - Google Patents
2-methyl-6-phenyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-(c)-(1,6) naphthyridine compoundsInfo
- Publication number
- CA1055944A CA1055944A CA219,303A CA219303A CA1055944A CA 1055944 A CA1055944 A CA 1055944A CA 219303 A CA219303 A CA 219303A CA 1055944 A CA1055944 A CA 1055944A
- Authority
- CA
- Canada
- Prior art keywords
- hydroxy
- carbon atoms
- hydrogen
- alkoxy
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
2-METHYL-6-PHENYL-1,2,3,4,4a,5,6,10b-OCTAHYDROBENZO-[c]-[1,6] NAPHTHYRIDINE COMPOUNDS
Abstract of the Disclosure This invention provides new compounds of formula I, I
wherein the indicated radical in the 8 or 9 position cf the benzonaphthyridine structure (R1) is hydrogen, alkoxy of 1 to 4 carbon atoms or hydroxy, and R2, R3 and R4 are selected in certain combinations from hydrosen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy, halogen, nitro, amino, dimethylamino, or -NHCOR5 wherein R5 is hydrogen or alkyl of 1 to 4 carbon atoms, useful as bronchospasmolytics.
Abstract of the Disclosure This invention provides new compounds of formula I, I
wherein the indicated radical in the 8 or 9 position cf the benzonaphthyridine structure (R1) is hydrogen, alkoxy of 1 to 4 carbon atoms or hydroxy, and R2, R3 and R4 are selected in certain combinations from hydrosen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy, halogen, nitro, amino, dimethylamino, or -NHCOR5 wherein R5 is hydrogen or alkyl of 1 to 4 carbon atoms, useful as bronchospasmolytics.
Description
1055944 Case 100-4126
2-METHYL-6-PHENYL-1,2,3,4,4a,5,6,10b-OCTAHYDROBENZO-[c]-[1,6]NAPHTHYRIDINE COMPOUNDS
The present lnvention relates to new hetero-cyclic compounds.
In accordance with the lnvention there are provided new compounds of formula I, .. - fH3 Rl ~
4 ~ 2 wherein the indicated radical in the 8 or 9 position of the benzonaphthyridine structure (Rl) is hydrogen, alkoxy of 1 to 4 carbon atoms or hydroxy, and (i) R2 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy, halogen, nitro, amino, dimethylamino, or -NHCOR5 whereln R5 is hydrogen or alkyl of 1 to 4 carbon atoms, and R3 and R4 are hydrogen, - ` 1055944`
: or (ii) R2 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy, halogen or nitro, R3 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy or chlorine, and R4 is hydrogen, "
tiii) R2,R3 and R4 are, independently, alkoxy of 1 to 4 carbon atoms or henzyloxy, or (iv) R2,R3 and R4 are, independently, alkyl of 1 to 4 carbon atoms, or tv) R2,R3 and R4 are hydroxy, with the proviso that (i) when one of the radicals R2, R3 and R4 is benzyloxy, the indi-cated radical in the 8 or 9 position of the benzonaphthyridine structure (Rl) is hydrogen . or alkoxy of 1 to 4 carbon atoms, (ii) when the indicated radical in the 8 or 9 position of th~ benzonaphthyridine structure (Rl) is other than hydrogen or alkoxy and is in the 9 position, each of the radicals R2, R3 and R4 is other than alkoxy of 1 to 4 carbon atoms, and:(iii) when one of the radicals R2 and R3 :~-lQ55944
The present lnvention relates to new hetero-cyclic compounds.
In accordance with the lnvention there are provided new compounds of formula I, .. - fH3 Rl ~
4 ~ 2 wherein the indicated radical in the 8 or 9 position of the benzonaphthyridine structure (Rl) is hydrogen, alkoxy of 1 to 4 carbon atoms or hydroxy, and (i) R2 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy, halogen, nitro, amino, dimethylamino, or -NHCOR5 whereln R5 is hydrogen or alkyl of 1 to 4 carbon atoms, and R3 and R4 are hydrogen, - ` 1055944`
: or (ii) R2 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy, halogen or nitro, R3 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy or chlorine, and R4 is hydrogen, "
tiii) R2,R3 and R4 are, independently, alkoxy of 1 to 4 carbon atoms or henzyloxy, or (iv) R2,R3 and R4 are, independently, alkyl of 1 to 4 carbon atoms, or tv) R2,R3 and R4 are hydroxy, with the proviso that (i) when one of the radicals R2, R3 and R4 is benzyloxy, the indi-cated radical in the 8 or 9 position of the benzonaphthyridine structure (Rl) is hydrogen . or alkoxy of 1 to 4 carbon atoms, (ii) when the indicated radical in the 8 or 9 position of th~ benzonaphthyridine structure (Rl) is other than hydrogen or alkoxy and is in the 9 position, each of the radicals R2, R3 and R4 is other than alkoxy of 1 to 4 carbon atoms, and:(iii) when one of the radicals R2 and R3 :~-lQ55944
3 100-4126 ls benzyloxy or alkoxy of 1 to 4 carbon atoms, the remainlng radical R2 or R3 is other than hydroxy, or a pharmaceutically acceptable acid addition salt thereof.
Any alkyl or alkoxy substituents of the 6-phenyl radical especially contaln 1 or 2, preferably l carbon atom.
When Rl is alkoxy of 1 to 4 carbon atoms, thls especially contains 1 or 2, preferably 1 carbon atom.
When R5 is alkyl of 1 to 4 carbon atoms, this radical especlally denotes methyl, ethyl, or an -branched alkyl radlcal such as lsopropyl or tert.butyl.
When the radlcal R2 ls halogen, this signifies fluorine, chlorine or bromine, preferably fluDrine or chlorine.
As may be seen from the formulae, the hydrogen atoms in the 4a, 6 and lOb positions of the benzo-naphthyridine structure are ln the cls positlon.
Further, ln accordance wlth the lnventlon a compound of formula I may be obtained by a proaess comprlslng a) educing a compound of formula II, lO5S944
Any alkyl or alkoxy substituents of the 6-phenyl radical especially contaln 1 or 2, preferably l carbon atom.
When Rl is alkoxy of 1 to 4 carbon atoms, thls especially contains 1 or 2, preferably 1 carbon atom.
When R5 is alkyl of 1 to 4 carbon atoms, this radical especlally denotes methyl, ethyl, or an -branched alkyl radlcal such as lsopropyl or tert.butyl.
When the radlcal R2 ls halogen, this signifies fluorine, chlorine or bromine, preferably fluDrine or chlorine.
As may be seen from the formulae, the hydrogen atoms in the 4a, 6 and lOb positions of the benzo-naphthyridine structure are ln the cls positlon.
Further, ln accordance wlth the lnventlon a compound of formula I may be obtained by a proaess comprlslng a) educing a compound of formula II, lO5S944
- 4 - 100-4126 R ~ ~ ~
I II
4~R3 R2 wherein R6 ls in the 8 or 9 position of the benzo-naphthyridine structure and is hydrogen, alkoxy of 1 to 4 carbon atoms, hydroxy, or an ether radical capable of being split under the reaction conditions to form a hydroxy radical, and R2, R3 and R4 are as defined above with the proviso thereto, or b) treating a compound of formula III, ~H3 7 ~ III
4 ~ _ R2
I II
4~R3 R2 wherein R6 ls in the 8 or 9 position of the benzo-naphthyridine structure and is hydrogen, alkoxy of 1 to 4 carbon atoms, hydroxy, or an ether radical capable of being split under the reaction conditions to form a hydroxy radical, and R2, R3 and R4 are as defined above with the proviso thereto, or b) treating a compound of formula III, ~H3 7 ~ III
4 ~ _ R2
- 5 - 100-4126 ;
wherein R2, R3, R4 are as defined above with the provlso thereto, R7 is an ether radicyl capable of being split under the reactlon conditlons to form a S hydroxy radical, under the conditlons of an ether splitting, to produce a compound of formula Ia, Ia 4 ~ R2 wherein R2, R3 and R4 are as defined above with the proviso thereto and the further proviso that (iv) each of R2, R3 and R4 is other than benzyloxy, or an obvious chemical equlvalent thereof, and where ne-cessary converting the resulting product into a pharmaceu-tically acceptable acid addition salt thereof.
The octahydrobenzo[c][l,6~naphthyridine derivatives produced in accordance wlth the processes described above, may be isolated in the u~ual manner and purified in accordance with known methods.
wherein R2, R3, R4 are as defined above with the provlso thereto, R7 is an ether radicyl capable of being split under the reactlon conditlons to form a S hydroxy radical, under the conditlons of an ether splitting, to produce a compound of formula Ia, Ia 4 ~ R2 wherein R2, R3 and R4 are as defined above with the proviso thereto and the further proviso that (iv) each of R2, R3 and R4 is other than benzyloxy, or an obvious chemical equlvalent thereof, and where ne-cessary converting the resulting product into a pharmaceu-tically acceptable acid addition salt thereof.
The octahydrobenzo[c][l,6~naphthyridine derivatives produced in accordance wlth the processes described above, may be isolated in the u~ual manner and purified in accordance with known methods.
- 6 - 100-4126 Process varlant a) may be effected in conventional manner for the reduction of simllar double bonds, with or without ether spllttlng, in similar compounds.
When R6 is an ether group in the ~ or 9 position of the benzonaphthyrldine structure, capable of being split off under the reactlon condltlons, thls group pre-ferably slgnifies an ether group capable of being split off hydrogenolytically, especially ln the presence of a - metal catalyst such as platlnum or palladium. Examples of such R6 groups are the benzyloxy group, and benzyloxy groups substltuted on the phenyl ring or alkylated in posltlon.
The reactlon may be effected with a complex alkali metal hydrlde ln a sultable solvent, e.g. sodium boro-hydrlde ln methanol or ethanol, or llthium aluminiumhydride in ether, tetrahydrofuran, dioxane or dimethoxy-ethane. The reductlon ls preferably effected at an elevated temperature, e.g. between about 50 and 100 C.
When these reactlon condltlons are used, it ls convenlent to choose as startlng materlal compounds of formula II
whereln R6 is hydrogen, alkoxy of 1 to 4 carbon atoms or hydroxy. The reduction products are isolated and puri-fied in accordance wlth known met~ods, for example after decomposltion of the excess reducing agent and the re-sultlng complex by shaklng between an aqueous solutionand an organic solvent immiscible with this aqueous solution, such as chloroform or ethyl acetate.
When R6 is an ether group in the ~ or 9 position of the benzonaphthyrldine structure, capable of being split off under the reactlon condltlons, thls group pre-ferably slgnifies an ether group capable of being split off hydrogenolytically, especially ln the presence of a - metal catalyst such as platlnum or palladium. Examples of such R6 groups are the benzyloxy group, and benzyloxy groups substltuted on the phenyl ring or alkylated in posltlon.
The reactlon may be effected with a complex alkali metal hydrlde ln a sultable solvent, e.g. sodium boro-hydrlde ln methanol or ethanol, or llthium aluminiumhydride in ether, tetrahydrofuran, dioxane or dimethoxy-ethane. The reductlon ls preferably effected at an elevated temperature, e.g. between about 50 and 100 C.
When these reactlon condltlons are used, it ls convenlent to choose as startlng materlal compounds of formula II
whereln R6 is hydrogen, alkoxy of 1 to 4 carbon atoms or hydroxy. The reduction products are isolated and puri-fied in accordance wlth known met~ods, for example after decomposltion of the excess reducing agent and the re-sultlng complex by shaklng between an aqueous solutionand an organic solvent immiscible with this aqueous solution, such as chloroform or ethyl acetate.
- 7 - 100-4126 `
The reduction may also be effected by catalytic hydrogenation, e.g. over platinum or palladium or platinum oxide. There may be present an inert solvent, e.g. a lower alkanol such as ethanol or methanol. The reaction is preferably effected at room temerature and e.g. at normal pressure or an elevated pressure. The hexahydro-benzo-[c][1,6]naphthyridine derivatives to be reduced are preferably used in free base form.
Under the latter conditions, any benzyloxy groups and/or ether groups capable of being split off under these conditions, which may be present in the compounds of formula II, are converted into hydroxy groups; in this case the benzyloxy group is conveniently used as ether group capable of being split off, and palladium ls conveniently used as catalyst.
When platinum is used as catalyst and a benzy-loxy radical is present in the compound of formula II, the 5/6 double bond may be reduced selectively without splitting of the benzyloxy radical.
Further, under the conditions of a catalytic hydrogenation any nitro group is reduced to the amino group or, when formaldehyde is present in the reaction mixture, to the dimethylamino group. The production of compounds of formula I wherein R2 is the nitro group, is therefore conveniently effected with complex hydrides when process variant a) is used.
~055~44 .
The reduction may also be effected by catalytic hydrogenation, e.g. over platinum or palladium or platinum oxide. There may be present an inert solvent, e.g. a lower alkanol such as ethanol or methanol. The reaction is preferably effected at room temerature and e.g. at normal pressure or an elevated pressure. The hexahydro-benzo-[c][1,6]naphthyridine derivatives to be reduced are preferably used in free base form.
Under the latter conditions, any benzyloxy groups and/or ether groups capable of being split off under these conditions, which may be present in the compounds of formula II, are converted into hydroxy groups; in this case the benzyloxy group is conveniently used as ether group capable of being split off, and palladium ls conveniently used as catalyst.
When platinum is used as catalyst and a benzy-loxy radical is present in the compound of formula II, the 5/6 double bond may be reduced selectively without splitting of the benzyloxy radical.
Further, under the conditions of a catalytic hydrogenation any nitro group is reduced to the amino group or, when formaldehyde is present in the reaction mixture, to the dimethylamino group. The production of compounds of formula I wherein R2 is the nitro group, is therefore conveniently effected with complex hydrides when process variant a) is used.
~055~44 .
- 8 - 100-4126 ., , ` After the hydrogen take up is complete, the catalyst is filtered off, the filtrate is evaporated to dryness, and the crude octahydro compound obtainedas residue is purified in accordance with known methods.
The reduction of the 5/6 double bond takes place stereospecifically in any case; compounds of formula I wherein the hydrogen atoms in positions 4a, 6 and lOb are all in a cis position to one another, are obtained.
Process variant b) is an ether splitting. ~t may be effected in a manner analogous to known methods for the ether splitting of analogous compounds.
Thus, for example, the ether splitting may be - effected with a Lewis acid, e.g. boron tribromide or aluminium chloride. The reaction is preferably effected in an inert organic solvent, e.g. a halogenated hydrocarbon such as methylene chloride or carbon tetra-chloride, or an aromatic hydrocarbon such as toluene or benzene. The temperature may ke from about -80 to 70C.
The ether splitting may alternatively be effected with a strong mineral acid, e.g. hydrobromic or hydriodic acid. The reaction is preferably effected at an elevated temperature, e.g. between about 50 and 150C, for example at the boiling temperature of the reaction mixture. An inert solvent may optionally be used.
" 105~944
The reduction of the 5/6 double bond takes place stereospecifically in any case; compounds of formula I wherein the hydrogen atoms in positions 4a, 6 and lOb are all in a cis position to one another, are obtained.
Process variant b) is an ether splitting. ~t may be effected in a manner analogous to known methods for the ether splitting of analogous compounds.
Thus, for example, the ether splitting may be - effected with a Lewis acid, e.g. boron tribromide or aluminium chloride. The reaction is preferably effected in an inert organic solvent, e.g. a halogenated hydrocarbon such as methylene chloride or carbon tetra-chloride, or an aromatic hydrocarbon such as toluene or benzene. The temperature may ke from about -80 to 70C.
The ether splitting may alternatively be effected with a strong mineral acid, e.g. hydrobromic or hydriodic acid. The reaction is preferably effected at an elevated temperature, e.g. between about 50 and 150C, for example at the boiling temperature of the reaction mixture. An inert solvent may optionally be used.
" 105~944
- 9 - 100-4126 An ether group in the 8 position of the benzonaphthyridine structure may be split off selectively, without the splitting of any alkoxy groups on the non-condensed phenyl ring, by carrying out the splitting with a mineral acid under milder conditions, e.g. with a dilute mineral acid at an elevated temperature, e.g.
with dilute hydrobromic acid at about 80 to 150C.
When the groups to be split are ether groups capable of being split off hydrogenolytically, e.g. the benzyloxy group, these are conveniently converted into hydroxy groups by catalytic hydrogenation in the presence of a palladium catalyst. This is preferably effected in an inert organic solvent, e.g. in a lower alkanol such as methanol or ethanol, in ethyl acetate or in glacial lS acetic acid. The temperature may be from about 20 to 100C.
The reaction is effected at normal pressure or at an ele-vated pressure, preferably at normal pressure; any alkoxy group in the 8 or 9 position is generally not split off under these conditions; any nitro group is generally reduced to the amino group.
Process b) is the preferred process for the production of compounds having more than one hydroxy group.
The ether splitting of compounds of formula III
wherein R2II is -NHCOR5, is conveniently effected under catalytic conditions; in this case R7 preferably denotes benzyloxy.
` ` 105S~)44
with dilute hydrobromic acid at about 80 to 150C.
When the groups to be split are ether groups capable of being split off hydrogenolytically, e.g. the benzyloxy group, these are conveniently converted into hydroxy groups by catalytic hydrogenation in the presence of a palladium catalyst. This is preferably effected in an inert organic solvent, e.g. in a lower alkanol such as methanol or ethanol, in ethyl acetate or in glacial lS acetic acid. The temperature may be from about 20 to 100C.
The reaction is effected at normal pressure or at an ele-vated pressure, preferably at normal pressure; any alkoxy group in the 8 or 9 position is generally not split off under these conditions; any nitro group is generally reduced to the amino group.
Process b) is the preferred process for the production of compounds having more than one hydroxy group.
The ether splitting of compounds of formula III
wherein R2II is -NHCOR5, is conveniently effected under catalytic conditions; in this case R7 preferably denotes benzyloxy.
` ` 105S~)44
- 10 - 100-4126 It will be appreciated that insofar as similar reactions may be used for both precesses a) and b) for the splitting of ether groups, e.g. catalytic hydrogenation, then similar considerations apply to both processes.
The compounds of formula II are either known or may be produced in a manner analogous to known methods, e.g. for compounds of formula II wherein Rl is other than hydrogen.
The production of compounds of formula II
containing an amino group is preferably effected using the corresponding nitro compounds of formula II as starting materials, e.g. by selective reduction with nascent hydrogen, e.g. with iron shavings in an aqueous acid, optionally in an inert solvent, e.g. in a lower alkanol such as ethanol, preferably at an elevated temperature, e.g. at the boil.
The production of compounds of formula II
containing an acylamino group is preferably effected by treating a compound of formula II containing an amino group with an acylating agent, e.g. a carboxylic acid chloride or anhydride,in the presence of an acid-binding agent, e.g. pyridine, optionally in an inert solvent - and at an elevated temperature.
The compounds of formula II are either known or may be produced in a manner analogous to known methods, e.g. for compounds of formula II wherein Rl is other than hydrogen.
The production of compounds of formula II
containing an amino group is preferably effected using the corresponding nitro compounds of formula II as starting materials, e.g. by selective reduction with nascent hydrogen, e.g. with iron shavings in an aqueous acid, optionally in an inert solvent, e.g. in a lower alkanol such as ethanol, preferably at an elevated temperature, e.g. at the boil.
The production of compounds of formula II
containing an acylamino group is preferably effected by treating a compound of formula II containing an amino group with an acylating agent, e.g. a carboxylic acid chloride or anhydride,in the presence of an acid-binding agent, e.g. pyridine, optionally in an inert solvent - and at an elevated temperature.
- 11 - 100-4126 The production of compounds of formula II
contalnlng a dlmethylamlno group may, for example, be effected by reductive methylation of a compound of formula II containlng an amlno group with formaldehyde and formlc acld as reduclng agent (Leuckart-Wallach reaction).
The remaining compounds of formula II may, for example, be obtained by cyclizatlon of the correspond-ing cis-4-benzoylamlno-1-methyl-3-phenylpiperidlne in accordance with Bischler-Napleralski.
The compounds of formula III
may be produced in accordance wlth known methods, or uslng the methods descrlbed for the production of com-pounds of formulae I and II.
Insofar as the productlon of the requlred starting materlals is not descrlbed, these are known or may be produced in accordance wlth known processes, or in a manner analogous to the processes described herein or to known processes.
Free base forms of compounds of formula I may be converted into acid addltion ~salt forms in conventional manner and vice versa. Suitable acids for salt formation include maleic, hydrochloric and hydrobromic aclds.
lQ55g~4
contalnlng a dlmethylamlno group may, for example, be effected by reductive methylation of a compound of formula II containlng an amlno group with formaldehyde and formlc acld as reduclng agent (Leuckart-Wallach reaction).
The remaining compounds of formula II may, for example, be obtained by cyclizatlon of the correspond-ing cis-4-benzoylamlno-1-methyl-3-phenylpiperidlne in accordance with Bischler-Napleralski.
The compounds of formula III
may be produced in accordance wlth known methods, or uslng the methods descrlbed for the production of com-pounds of formulae I and II.
Insofar as the productlon of the requlred starting materlals is not descrlbed, these are known or may be produced in accordance wlth known processes, or in a manner analogous to the processes described herein or to known processes.
Free base forms of compounds of formula I may be converted into acid addltion ~salt forms in conventional manner and vice versa. Suitable acids for salt formation include maleic, hydrochloric and hydrobromic aclds.
lQ55g~4
- 12 - 100-4126 In the following non-limitatlve Examples all temperatures are indicated ln degrees Centigrade and are uncorrected.
EXAMPLE 1 Cis-8-hydroxy-2-methYl-6-phenYl-1,2,3,4~4a,5,6,10b-octahydrobenzo-[c][1~6]naPhthyridine [process varlant a)]
2 g of cls-8-hydroxy-2-methyl-6-phenyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyrldine (M.P. of the dihydro~romlde 268-271) are dlssolved ln 20 cc of methanol, and after the addltlon of 0.1 g of platinum oxlde hydrogenatlon ls effected at room temp-erature and normal pressure ln an atmosphere of hydrogen.
After the take up of hydrogen ls complete the catalyst ls flltered off and the flltrate ls evaporated to dryness ln a vacuum. The evaporatlon resldue ls dlssolved ln water, is made alkallne with potasslum carbonate, ls ex-tracted thrlce wlth methylene chlorlde, the organic phases are drled and evaporated to dryness, the resldue ls dls-solved ln alcohol, and a small excess of maleic acld is added, whereby the bishydrogen maleate of the title com-pound crystalllzes (M.P. 196-197).
EXAMPLE 2: Cis-8-hydrox~-2-methYl-6-Phenyl 1,2,3,4,4a,5,6,10b-actahYdrobenzo-[c][1,6]naphthyridlne [process variant a)]
1 g of cis-8-hydroxy-2-methyl-6-phenyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyrldlne (M.P. of the dlhydrobromide 268-271) ls dlssolved in 10 cc of ethanol, 0.1 g of sodlum borohydrlde ls added, and this reaction solutlon is boiled at reflux for 1055~44
EXAMPLE 1 Cis-8-hydroxy-2-methYl-6-phenYl-1,2,3,4~4a,5,6,10b-octahydrobenzo-[c][1~6]naPhthyridine [process varlant a)]
2 g of cls-8-hydroxy-2-methyl-6-phenyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyrldine (M.P. of the dihydro~romlde 268-271) are dlssolved ln 20 cc of methanol, and after the addltlon of 0.1 g of platinum oxlde hydrogenatlon ls effected at room temp-erature and normal pressure ln an atmosphere of hydrogen.
After the take up of hydrogen ls complete the catalyst ls flltered off and the flltrate ls evaporated to dryness ln a vacuum. The evaporatlon resldue ls dlssolved ln water, is made alkallne with potasslum carbonate, ls ex-tracted thrlce wlth methylene chlorlde, the organic phases are drled and evaporated to dryness, the resldue ls dls-solved ln alcohol, and a small excess of maleic acld is added, whereby the bishydrogen maleate of the title com-pound crystalllzes (M.P. 196-197).
EXAMPLE 2: Cis-8-hydrox~-2-methYl-6-Phenyl 1,2,3,4,4a,5,6,10b-actahYdrobenzo-[c][1,6]naphthyridlne [process variant a)]
1 g of cis-8-hydroxy-2-methyl-6-phenyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyrldlne (M.P. of the dlhydrobromide 268-271) ls dlssolved in 10 cc of ethanol, 0.1 g of sodlum borohydrlde ls added, and this reaction solutlon is boiled at reflux for 1055~44
- 13 - 100-4126 30 minutes. The excess sodium borohydride is decomposed by the addition of dilute hydrochloric acid, the solution is concentrated, is made strongly alkaline with dilute sodium hydroxide, and this alkaline aqueous solution is extracted with methylene chloride. After drying and evaporating the organic phase the residue is dissolved in ethanol and maleic acid is added, whereby the bishydrogen maleate of the title compound crystallizes (M.P. 196-197).
EX~MPLE 3: Cis-8-methoxy-2-methyl-6-phenyl-1,2,3,4,4~,5,6,10b-octahydrobenzo-[c][1,6]naphthyridine The process is effected in a manner analogous to that described in Example 1 or 2, and the title com-pound is obtained by reduction of cis-8-methoxy-2-methyl-6-phenyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine (M.P. of the bishydrogen maleate 146-147 from ethanol).
The title compound crystallizes from ethanol as bishydrogen maleate having an M.P. of 144-145.
Cis-8-methoxy-2-methyl-6-phenyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine is obtained by addition of 3-amino-2-~-methoxyphenyl-propionic acid ethyl ester to acrylic acid ethyl ester, reductive methylation of 2-~-methoxyphenyl-3,3'-imino-dipropionic acid diethyl ester (M.P. of the hydrogen oxalate 152) with formaldehyde to obtain 2~p-methoxy-methyl-N-methyl-3,3'-iminodipropionic acid diethyl ester, reaction of the latter compound to obtain 3-carbethoxy-5-(~-methoxyphenyl)-1-methyl-4-piperidone (M.P. of the :lOS5~44
EX~MPLE 3: Cis-8-methoxy-2-methyl-6-phenyl-1,2,3,4,4~,5,6,10b-octahydrobenzo-[c][1,6]naphthyridine The process is effected in a manner analogous to that described in Example 1 or 2, and the title com-pound is obtained by reduction of cis-8-methoxy-2-methyl-6-phenyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine (M.P. of the bishydrogen maleate 146-147 from ethanol).
The title compound crystallizes from ethanol as bishydrogen maleate having an M.P. of 144-145.
Cis-8-methoxy-2-methyl-6-phenyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine is obtained by addition of 3-amino-2-~-methoxyphenyl-propionic acid ethyl ester to acrylic acid ethyl ester, reductive methylation of 2-~-methoxyphenyl-3,3'-imino-dipropionic acid diethyl ester (M.P. of the hydrogen oxalate 152) with formaldehyde to obtain 2~p-methoxy-methyl-N-methyl-3,3'-iminodipropionic acid diethyl ester, reaction of the latter compound to obtain 3-carbethoxy-5-(~-methoxyphenyl)-1-methyl-4-piperidone (M.P. of the :lOS5~44
- 14 - 100-4126 hydrochloride 180-182), which is converted by hydrolysis and subsequent decarboxylation into 3-~-methoxyphenyl-l-methyl-4-piperidone (M.P. of the hydrogen oxalate 137-138). The resulting piperidone is reacted with hydroxylamine to obtain 3-~-methoxyphenyl-1-methyl-4-piperidone oxime (M.P. 121-122), the oxime is hydrogen-ated with Raney nickel to obtain 4-amino-3-~-methoxy-phenyl-l-methyl-piperidine (mixture of the two diastereo-lsomers), the amino compound is treated with benzoyl chloride, cis-4-benzoylamino-3-~-methoxyphenyl-1-methyl-piperidine (M.P. 164-165) is isolated from the reaction mixture, and the latter amide is cyclized with phosphorus oxychloride to obtain the desired benzonaphthyridine.
EXAMPLE 4: Cis-6-(4-aminophenyl)-9-methoxv-2-methyl-_ 1,2,3 ! 4,4a,5,6,10b-octahydrobenzo-[c][1,6]naphthyridine The process is effected in a manner analogous to that described in ~xample 1 or 2, and the title com-pound is obtained by reduction of cis-6-(4-aminophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridine (oil, crude). The title compound crystallizes from ethanol as trihydrochloride having an M.P. of 289-2gl .
The cis-6-(4-aminophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine, re-quired as starting material, is produced as follows:
2.7 g of iron shavings are added to a hot solution of 2 g of cis-9-methoxy 2-methyl-6-(4-nitro-phenyl)-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine lVS5944 - lS - 100-4126 (oil, crude, from ethyl acetate) in 40 cc of ethanol and 13 cc of water. A mixture of 13 cc of ethanol, 3 cc of water and 0.7 cc of 2 N hydrochloric acid is added dropwise thereto within 40 minutes while heating, and the reaction mixture is boiled at reflux for a further 3 hours. 1 cc of 2 N caustic soda solution is then added, filtration is effected, and the filtrate is con-centrated by evaporation in a vacuum. The residue is dissolved in chloroform, the solution is dried over sodium sulphate, filtered and concentrated by evaporation in a vacuum, and the resulting viscous oil is used for the next reaction without purification.
E PLE 5: Cis-6-(4-acetamidophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-[c][1,6]naphthvridine The process is effected in a manner analogous to that described in Example 1 or 2, and the title com-pound is obtained by reduction of cis-6-(4-acetamido-phenyl) 9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo-[c][1,6]naphthyridine. The dihydrochloride of the title compound has an M.P. of 294-296 from methanol.
The cis-6-(4-acetamidophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine, required as starting material, is obtained from cis-6-(4-aminophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine by allowing to stand over night at room temperature in the presence of acetic anhydride and pyridine. The resulting crude product (foam) is used as such for the next reaction.
EXAMPLE 6: Cis-6-(4-dimethylaminophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-[c][1,6]naphthyridine The process is effected in a manner analogous to that described in Example 1 or 2, and the title com-pound is obtained by reduction of cis-6-(4-dimethylamino-phenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo-[c][1,6]naphthyridine. The dihydrochloride of the title compound has an M.P. of 275-277 .
The cis-6-(4-dimethylaminophenyl)-9-methoxy-- 2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyricJine, required as starting material, is obtained in accordance with Leuckart-Wallach from cis-6-(4-aminophenyl)-9-methc-xy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridine by reductive dimethylation with formaldehyde and formic acid. The resulting crude product is used as such for the next reaction.
1055~
al O o o o o o o o o o o o o o o U~ n o ~
~ O a)_I 1` 1` ~ t~ O
O ~ ~ ~ ~ _~ ,1 ~ ~ ~ _I ~ _I
_l .
P~ ~I ~ o u~ a) ~ 0 o u~
. ~ O 1~~1 u~ n 1` 0 ~ ~ ~ t`J ~ ~ N ~ 1 0 .q h a~
O ~
_l O ~ O ~ O ~ O
~a ~
~ ~ ~ O '~ 0~ ~ O' ~
O O ~ O ~ O ~ O
~ ~ =
: HU~ C~ m ~ m '~ m a o o o o o o o o o ~o ~ ~
~o P;-l ' ' I ec m ~ 0 0 o o H ~o ~ ~
~r ~; tc m ~ . . . . . ......... ._ ..... _ ~ o o o o O O n~
o P;~ 3: :: m 5: $ ' . ' . . _ ~q o oo o o o a ~o . ~ X
~ ~ N
o ~ ~r;
~ X
o a~ ~n t),~ g X
b O
--I O
3 ~ fO ~ t`~ ~1 ~ N N N ~ `1 N N ~1 N N
O
_I O ~ ~1 --I P.
O U~
~1 ~ . .
1~1 X ~1 1` 0 ~ O _I N 0 'r U~ ~D1` 0 a~ O
S O ~1 2 ~ ~ N
. _..
* Us~ng as startlng materlal the corresponding compounds of formula II wlth each hydroxy group replaced by a benzyloxy group, and as catalyst palladium ln place of platinum.
~ . . _ . . _ . ..
O ~ O NO 11~ 0 a~
.: N N ~ N N 0 N N ~_I ~ N ~ ~ N _I N N N
P~ CD 1~ If~ 0 IJ~ NIn N O 1~ ~ 0 N 0 D Ul 0 ~ u~
. OD 1~ --I 0 a~ I ~ ~r 1~ N a~ ~0 1~ ~ 11~ I`
N N ~ N N 0 N N ~--I ~ N 0 N N ~I N N N
. _ , ,~
. ~ ~ .
a ~ ~ g ~ A~ 1 , . _ _1 ~ o o m s~ O ~ o ~; a~ ~: 0 P~ ~ 0 ao c~ 0 0 co' ~
-- o - '~- -~ -- . -. ~ m I ~ I x ~ ~ ~ m ~' m O ~ Om ~ ~ O
. ~ m ~ ~ m m m ~ ~ I m m I m m m m m m _ _ _ . ,~
. . o~ o m N ~ o o o o o Om - o ~ ~ m mN z ~ z O
N m I I I ' I I ' -m l l l ' ~-O x d ON ~'1 N N Nt~l N N N N
. ~~ ~ *
I ~I N~ I N
X ~,~ D r` 0 o~ o ~ r u) ~ r` 0 a~ ~a æ N N N N N N t~l N N 0 0 ~7 0 ~~ 0 ~) r~ 0 0 lO5S~44 EXAMPLE 40: Cis-8-hydroxy-6-phenyl-2-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-[c][1,6]naphthyridine [process variant b)]
2 g of cis-8-methoxy-6-phenyl-2-methyl-1,2,3,4,4a,5,6,10b-oc~ahydrobenzo[c][1,6]naphthyridine bishydrogen maleate (M.P. 144-145 from ethanol) are converted into the free base in the usual manner. This is then boiled at reflux with 20 cc of 60 % hydrobromic acid for 2 hours. The residue obtained after evaporating to dryness in a vacuum is recrystallized from alcohol.
The bishydrogen maleate of the title compound has a M.P. of 196-197.
EXAMPLE 41: Cis-6-(4-hydroxvphenyl)-9-methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-[c][1,6]naphthyridine [process variant b)]
5 g of cis-6-(4-benzyloxyphenyl)-9-methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[c][1,6]-naphthyridine are dissolved in 50 cc of ethanol, and after the addition of 5 g of palladium (10 % on aluminium - oxide) hydrogenation is effected at room temperature and normal pressure in an atmosphere of hydrogen until the take up of hydrogen is complete. The dihydrochloride of the resulting title compound has an M.P. of 312-315 from ethanol.
1055~
_ _ ..
OOO OOOOO OO~
F~ ~ ~) O N O L(~ O
N O ~O ~ I`
.,.~ ~ ~ N ~) ~ ~ N ~) ~ ~J r~) N ,-1 J-) X . t`l O 1` 0 co N ~ ~ u') U~ ~D
UJ O ~ ~ ~ '.D 'J' r- N ~ ~D ~1 1` ~`.
-1 N ~ ~1 ~ N ~1 N N ~ N ,~
U~
a N . t7 ~ Q
0 O ~ ~ O o ' O
~, ~1 - ~ C) $ R Q O Q O ~
~I X ~ h ~5 0 0 h ).1 a ~D O ~ h 1~ 'D
~ ~. U~
Ei E3 1~ Ei m ~n ~ _ .
g ~
o ~ o ~ ~
~ g ~, ~
O O ~ c~ ~ co ct) ~ co 03 oo ~ ~ a:
~ o _ ____ ~:5 H
Q~ H
O ~ H O
~ ~ ~ ~ ~ ~~ ~ ~ Lf- ~ :C ~ ~
~ 4~ ~
~1 lO
H ~
HH t~ O ~ ~ O
~ ~ ~; ~ $ ~ ~
O~ _ ~
O
O ~1 H ~ N
O H N O V ~ 4 0 Z O ~:
P~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~:
~ U~
o a ~ ~ _ .... ___ g O ~q -~ ~ O
3 ~ ~ O O O O O O O O O O ~ ~1 O ~ ~r ~ er ~r ~ ~r ~1 _ '¢
O ~,~
S~ ~ X S~ N ~ ~ 1~) ~ ~ ~ 0~ O _I N
~1 Z ~r ~ ~ ~ ~ ~ ~r ~r Is~ U) I~
_ 105~9~
The compounds of formula I exhlblt pharmacologlcal activlty. In particular the compounds exhiblt bronchospasmo-lytic actlvlty as lndlcated ln standard tests, for example in the Konzett-Rossler test, by an inhlbition of broncho-spasms induced by hlstamlne anesthetiæed cats and gulneapigs.
The compounds are therefore further indlcated for use as bronchospasmolytlc agents. For thls use an indicated dally dose ls from about 35 to about 700 mg, convenlently admlnlstered ln dlvided doses 2 to 4 tlmes a day in unit dosage form contalning from about 6 to about 350 mg, or ln sustalned release form.
The compounds of formula I may be admlnlstered ln pharmaceutically acceptable acid addltlon salt form.
Such acld addltion salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventlonal manner. The present invention also provldes a pharmaceutical composltion comprislng a compound of formula I, in free base form or ln pharmaceutically acceptable acld addition salt form, in associatlon with a pharmaceutical carrler or dlluent. Such compositlons may be formulated in conventional manner to be in the form of, for example, a solu-tion suitable for inhalation as a spray, or a tablet.
105S5~
Interestiny compounds are those wherein R
is hydroxy or alkoxy, preferably methoxy. Preferably R1 is hydroxy in the 8-position or alkoxy, e.g. methoxy in the 9-position. Especially preferred are the compounds cis-9-methoxy-2-methyl-6-phenyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo[c~[1,6]naphthyridine and more especially cis-8-hydroxy-2-methyl-6-phenyl-1,2,3,4,4a,5,6, l0b-octahydrobenzotc][1,6]naphthyridine.
EXAMPLE 4: Cis-6-(4-aminophenyl)-9-methoxv-2-methyl-_ 1,2,3 ! 4,4a,5,6,10b-octahydrobenzo-[c][1,6]naphthyridine The process is effected in a manner analogous to that described in ~xample 1 or 2, and the title com-pound is obtained by reduction of cis-6-(4-aminophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridine (oil, crude). The title compound crystallizes from ethanol as trihydrochloride having an M.P. of 289-2gl .
The cis-6-(4-aminophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine, re-quired as starting material, is produced as follows:
2.7 g of iron shavings are added to a hot solution of 2 g of cis-9-methoxy 2-methyl-6-(4-nitro-phenyl)-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine lVS5944 - lS - 100-4126 (oil, crude, from ethyl acetate) in 40 cc of ethanol and 13 cc of water. A mixture of 13 cc of ethanol, 3 cc of water and 0.7 cc of 2 N hydrochloric acid is added dropwise thereto within 40 minutes while heating, and the reaction mixture is boiled at reflux for a further 3 hours. 1 cc of 2 N caustic soda solution is then added, filtration is effected, and the filtrate is con-centrated by evaporation in a vacuum. The residue is dissolved in chloroform, the solution is dried over sodium sulphate, filtered and concentrated by evaporation in a vacuum, and the resulting viscous oil is used for the next reaction without purification.
E PLE 5: Cis-6-(4-acetamidophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-[c][1,6]naphthvridine The process is effected in a manner analogous to that described in Example 1 or 2, and the title com-pound is obtained by reduction of cis-6-(4-acetamido-phenyl) 9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo-[c][1,6]naphthyridine. The dihydrochloride of the title compound has an M.P. of 294-296 from methanol.
The cis-6-(4-acetamidophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine, required as starting material, is obtained from cis-6-(4-aminophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine by allowing to stand over night at room temperature in the presence of acetic anhydride and pyridine. The resulting crude product (foam) is used as such for the next reaction.
EXAMPLE 6: Cis-6-(4-dimethylaminophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-[c][1,6]naphthyridine The process is effected in a manner analogous to that described in Example 1 or 2, and the title com-pound is obtained by reduction of cis-6-(4-dimethylamino-phenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo-[c][1,6]naphthyridine. The dihydrochloride of the title compound has an M.P. of 275-277 .
The cis-6-(4-dimethylaminophenyl)-9-methoxy-- 2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyricJine, required as starting material, is obtained in accordance with Leuckart-Wallach from cis-6-(4-aminophenyl)-9-methc-xy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridine by reductive dimethylation with formaldehyde and formic acid. The resulting crude product is used as such for the next reaction.
1055~
al O o o o o o o o o o o o o o o U~ n o ~
~ O a)_I 1` 1` ~ t~ O
O ~ ~ ~ ~ _~ ,1 ~ ~ ~ _I ~ _I
_l .
P~ ~I ~ o u~ a) ~ 0 o u~
. ~ O 1~~1 u~ n 1` 0 ~ ~ ~ t`J ~ ~ N ~ 1 0 .q h a~
O ~
_l O ~ O ~ O ~ O
~a ~
~ ~ ~ O '~ 0~ ~ O' ~
O O ~ O ~ O ~ O
~ ~ =
: HU~ C~ m ~ m '~ m a o o o o o o o o o ~o ~ ~
~o P;-l ' ' I ec m ~ 0 0 o o H ~o ~ ~
~r ~; tc m ~ . . . . . ......... ._ ..... _ ~ o o o o O O n~
o P;~ 3: :: m 5: $ ' . ' . . _ ~q o oo o o o a ~o . ~ X
~ ~ N
o ~ ~r;
~ X
o a~ ~n t),~ g X
b O
--I O
3 ~ fO ~ t`~ ~1 ~ N N N ~ `1 N N ~1 N N
O
_I O ~ ~1 --I P.
O U~
~1 ~ . .
1~1 X ~1 1` 0 ~ O _I N 0 'r U~ ~D1` 0 a~ O
S O ~1 2 ~ ~ N
. _..
* Us~ng as startlng materlal the corresponding compounds of formula II wlth each hydroxy group replaced by a benzyloxy group, and as catalyst palladium ln place of platinum.
~ . . _ . . _ . ..
O ~ O NO 11~ 0 a~
.: N N ~ N N 0 N N ~_I ~ N ~ ~ N _I N N N
P~ CD 1~ If~ 0 IJ~ NIn N O 1~ ~ 0 N 0 D Ul 0 ~ u~
. OD 1~ --I 0 a~ I ~ ~r 1~ N a~ ~0 1~ ~ 11~ I`
N N ~ N N 0 N N ~--I ~ N 0 N N ~I N N N
. _ , ,~
. ~ ~ .
a ~ ~ g ~ A~ 1 , . _ _1 ~ o o m s~ O ~ o ~; a~ ~: 0 P~ ~ 0 ao c~ 0 0 co' ~
-- o - '~- -~ -- . -. ~ m I ~ I x ~ ~ ~ m ~' m O ~ Om ~ ~ O
. ~ m ~ ~ m m m ~ ~ I m m I m m m m m m _ _ _ . ,~
. . o~ o m N ~ o o o o o Om - o ~ ~ m mN z ~ z O
N m I I I ' I I ' -m l l l ' ~-O x d ON ~'1 N N Nt~l N N N N
. ~~ ~ *
I ~I N~ I N
X ~,~ D r` 0 o~ o ~ r u) ~ r` 0 a~ ~a æ N N N N N N t~l N N 0 0 ~7 0 ~~ 0 ~) r~ 0 0 lO5S~44 EXAMPLE 40: Cis-8-hydroxy-6-phenyl-2-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-[c][1,6]naphthyridine [process variant b)]
2 g of cis-8-methoxy-6-phenyl-2-methyl-1,2,3,4,4a,5,6,10b-oc~ahydrobenzo[c][1,6]naphthyridine bishydrogen maleate (M.P. 144-145 from ethanol) are converted into the free base in the usual manner. This is then boiled at reflux with 20 cc of 60 % hydrobromic acid for 2 hours. The residue obtained after evaporating to dryness in a vacuum is recrystallized from alcohol.
The bishydrogen maleate of the title compound has a M.P. of 196-197.
EXAMPLE 41: Cis-6-(4-hydroxvphenyl)-9-methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-[c][1,6]naphthyridine [process variant b)]
5 g of cis-6-(4-benzyloxyphenyl)-9-methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[c][1,6]-naphthyridine are dissolved in 50 cc of ethanol, and after the addition of 5 g of palladium (10 % on aluminium - oxide) hydrogenation is effected at room temperature and normal pressure in an atmosphere of hydrogen until the take up of hydrogen is complete. The dihydrochloride of the resulting title compound has an M.P. of 312-315 from ethanol.
1055~
_ _ ..
OOO OOOOO OO~
F~ ~ ~) O N O L(~ O
N O ~O ~ I`
.,.~ ~ ~ N ~) ~ ~ N ~) ~ ~J r~) N ,-1 J-) X . t`l O 1` 0 co N ~ ~ u') U~ ~D
UJ O ~ ~ ~ '.D 'J' r- N ~ ~D ~1 1` ~`.
-1 N ~ ~1 ~ N ~1 N N ~ N ,~
U~
a N . t7 ~ Q
0 O ~ ~ O o ' O
~, ~1 - ~ C) $ R Q O Q O ~
~I X ~ h ~5 0 0 h ).1 a ~D O ~ h 1~ 'D
~ ~. U~
Ei E3 1~ Ei m ~n ~ _ .
g ~
o ~ o ~ ~
~ g ~, ~
O O ~ c~ ~ co ct) ~ co 03 oo ~ ~ a:
~ o _ ____ ~:5 H
Q~ H
O ~ H O
~ ~ ~ ~ ~ ~~ ~ ~ Lf- ~ :C ~ ~
~ 4~ ~
~1 lO
H ~
HH t~ O ~ ~ O
~ ~ ~; ~ $ ~ ~
O~ _ ~
O
O ~1 H ~ N
O H N O V ~ 4 0 Z O ~:
P~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~:
~ U~
o a ~ ~ _ .... ___ g O ~q -~ ~ O
3 ~ ~ O O O O O O O O O O ~ ~1 O ~ ~r ~ er ~r ~ ~r ~1 _ '¢
O ~,~
S~ ~ X S~ N ~ ~ 1~) ~ ~ ~ 0~ O _I N
~1 Z ~r ~ ~ ~ ~ ~ ~r ~r Is~ U) I~
_ 105~9~
The compounds of formula I exhlblt pharmacologlcal activlty. In particular the compounds exhiblt bronchospasmo-lytic actlvlty as lndlcated ln standard tests, for example in the Konzett-Rossler test, by an inhlbition of broncho-spasms induced by hlstamlne anesthetiæed cats and gulneapigs.
The compounds are therefore further indlcated for use as bronchospasmolytlc agents. For thls use an indicated dally dose ls from about 35 to about 700 mg, convenlently admlnlstered ln dlvided doses 2 to 4 tlmes a day in unit dosage form contalning from about 6 to about 350 mg, or ln sustalned release form.
The compounds of formula I may be admlnlstered ln pharmaceutically acceptable acid addltlon salt form.
Such acld addltion salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventlonal manner. The present invention also provldes a pharmaceutical composltion comprislng a compound of formula I, in free base form or ln pharmaceutically acceptable acld addition salt form, in associatlon with a pharmaceutical carrler or dlluent. Such compositlons may be formulated in conventional manner to be in the form of, for example, a solu-tion suitable for inhalation as a spray, or a tablet.
105S5~
Interestiny compounds are those wherein R
is hydroxy or alkoxy, preferably methoxy. Preferably R1 is hydroxy in the 8-position or alkoxy, e.g. methoxy in the 9-position. Especially preferred are the compounds cis-9-methoxy-2-methyl-6-phenyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo[c~[1,6]naphthyridine and more especially cis-8-hydroxy-2-methyl-6-phenyl-1,2,3,4,4a,5,6, l0b-octahydrobenzotc][1,6]naphthyridine.
Claims (5)
1. A process for the production of a compound of formula I, I
wherein the indicated radical in the 8 or 9 position of the benzonaphthyridine structure (R1) is hydrogen, alkoxy of 1 to 4 carbon atoms or hydroxy, and (i) R2 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy, halogen, nitro, amino, dimethylamino, or -NHCOR5 wherein R5 is hydrogen or alkyl of 1 to 4 carbon atoms, and R3 and R4 are hydrogen, or (ii) R2 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy, halogen or nitro, R3 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy or chlorine, and R4 is hydrogen, (iii) R2, R3 and R4 are, independently, alkoxy of 1 to 4 carbon atoms or benzyloxy, or (iv) R2, R3 and R4 are, independently, alkyl of 1 to 4 carbon atoms, or (v) R2, R3 and R4 are hydroxy, with the proviso that (i) when one of the radicals R2, R3 and R4 is benzyloxy, the indicated radical in the 8 or 9 position of the benzonaphthyridine structure (R1) is hydrogen or alkoxy of 1 to 4 carbon atoms, (ii) when the indicated radical in the 8 or 9 position of the benzonaphthyridine structure (R1) is other than hydrogen or alkoxy and is in the 9 position, each of the radicals R2, R3 and R4 is other than alkoxy of 1 to 4 carbon atoms, and (iii) when one of the ra-2 and R3 is benzyloxy or alkoxy of 1 to 4 carbon atoms, the remaining radical R2 or R3 1 other than hydroxy, or a pharmaceutically acceptable acid addition salt thereof, which comprises a) reducing a compound of formula II
II
wherein R6 is in the 8 or 9 position of the benzo-naphthyridine structure and is hydrogen, alkoxy of 1 to 4 carbon atoms, hydroxy, or an ether radical capable of being split under the reaction conditions to form a hydroxy radical, and R2, R3 and R4 are as defined above with the proviso thereto, or b-) treating a compound of formula III, III
wherein R2, R3, R4 are as defined above with the proviso thereto, R7 is an ether radical capable of being split under the reaction conditions to form a hydroxy radical under the conditions of an ether splitting, to produce a compound of formula Ia, Ia wherein R2, R3 and R4 are as defined above with the proviso thereto and the further proviso that (iv) each of R2, R3 and R4 is other than benzyloxy or an obvious chemical equivalent thereof, and where necessary converting the resulting product into a pharmaceutically acceptable acid addition salt thereof.
wherein the indicated radical in the 8 or 9 position of the benzonaphthyridine structure (R1) is hydrogen, alkoxy of 1 to 4 carbon atoms or hydroxy, and (i) R2 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy, halogen, nitro, amino, dimethylamino, or -NHCOR5 wherein R5 is hydrogen or alkyl of 1 to 4 carbon atoms, and R3 and R4 are hydrogen, or (ii) R2 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy, halogen or nitro, R3 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy or chlorine, and R4 is hydrogen, (iii) R2, R3 and R4 are, independently, alkoxy of 1 to 4 carbon atoms or benzyloxy, or (iv) R2, R3 and R4 are, independently, alkyl of 1 to 4 carbon atoms, or (v) R2, R3 and R4 are hydroxy, with the proviso that (i) when one of the radicals R2, R3 and R4 is benzyloxy, the indicated radical in the 8 or 9 position of the benzonaphthyridine structure (R1) is hydrogen or alkoxy of 1 to 4 carbon atoms, (ii) when the indicated radical in the 8 or 9 position of the benzonaphthyridine structure (R1) is other than hydrogen or alkoxy and is in the 9 position, each of the radicals R2, R3 and R4 is other than alkoxy of 1 to 4 carbon atoms, and (iii) when one of the ra-2 and R3 is benzyloxy or alkoxy of 1 to 4 carbon atoms, the remaining radical R2 or R3 1 other than hydroxy, or a pharmaceutically acceptable acid addition salt thereof, which comprises a) reducing a compound of formula II
II
wherein R6 is in the 8 or 9 position of the benzo-naphthyridine structure and is hydrogen, alkoxy of 1 to 4 carbon atoms, hydroxy, or an ether radical capable of being split under the reaction conditions to form a hydroxy radical, and R2, R3 and R4 are as defined above with the proviso thereto, or b-) treating a compound of formula III, III
wherein R2, R3, R4 are as defined above with the proviso thereto, R7 is an ether radical capable of being split under the reaction conditions to form a hydroxy radical under the conditions of an ether splitting, to produce a compound of formula Ia, Ia wherein R2, R3 and R4 are as defined above with the proviso thereto and the further proviso that (iv) each of R2, R3 and R4 is other than benzyloxy or an obvious chemical equivalent thereof, and where necessary converting the resulting product into a pharmaceutically acceptable acid addition salt thereof.
2. A compound of formula I, as stated in claim 1, or a pharmaceutically acceptable acid addition salt thereof, whenever produced by a process according to claim 1, or an obvious chemical equivalent thereof.
3. A process according to claim 1 for the pro-duction of cis-8-hydroxy-2-methyl-6-phenyl-1,2,3,4,4a,5,6, 10b-octahydrobenzo[c][1,6]naphthyridine, or a pharma-ceutically acceptable acid addition salt thereof, which comprises a) reducing a compound of formula II, wherein R6 is in the 8 position of the benzonaphthyridine struc-ture and is hydroxy or an ether radical capable of being split under the reaction conditions to form a hydroxy radical, and R2, R3 and R4 are hydrogen, or b) treating a compound of formula III, wherein R2, R3 and R4 are hydrogen and R7 is in the 8 position of the benzonaphthyridine structure and is an ether radical capable of being split under the reaction conditions to form a hydroxy radical ,under the conditions of an ether splitting, or an obvious chemical equivalent thereof, and where necessary converting the resulting product into a pharmaceutically acceptable acid addition salt thereof.
4. A process according to claim 3 which comprises a) hydrogenating cis-8-hydroxy-2-methyl-6-phenyl-1,2,3, 4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine over platinum oxide in an atmosphere of hydrogen, or b) treating cis-8-methoxy-6-phenyl-2-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo[c][1,6]naphthyridine with aqueous hydrobromic acid or cis-8-benzyloxy-6-phenyl-2-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[c][1,6]
naphthyridine with hydrogen over palladium, or an obvious chemical equivalent thereof, and where necessary converting the resulting product into a pharmaceutically acceptable acid addition salt thereof.
naphthyridine with hydrogen over palladium, or an obvious chemical equivalent thereof, and where necessary converting the resulting product into a pharmaceutically acceptable acid addition salt thereof.
5. Cis-8-hydroxy-2-methyl-6-phenyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[c][1,6]naphthyridine, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of claim 3 or claim 4 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH155074 | 1974-02-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1055944A true CA1055944A (en) | 1979-06-05 |
Family
ID=4213026
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA219,303A Expired CA1055944A (en) | 1974-02-05 | 1975-02-04 | 2-methyl-6-phenyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-(c)-(1,6) naphthyridine compounds |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS50108297A (en) |
| AT (1) | AT351536B (en) |
| BE (1) | BE825124A (en) |
| CA (1) | CA1055944A (en) |
| DD (1) | DD117216A5 (en) |
| DE (1) | DE2503156A1 (en) |
| DK (1) | DK136189B (en) |
| ES (1) | ES434406A1 (en) |
| FI (1) | FI750205A (en) |
| FR (1) | FR2259611B1 (en) |
| GB (2) | GB1497723A (en) |
| HU (1) | HU169923B (en) |
| IL (1) | IL46553A (en) |
| NL (1) | NL7501159A (en) |
| NO (1) | NO750263L (en) |
| NZ (1) | NZ176550A (en) |
| PH (1) | PH11824A (en) |
| SE (1) | SE7500859L (en) |
| ZA (1) | ZA75743B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8800397D0 (en) * | 1988-01-08 | 1988-02-10 | Sandoz Ltd | Improvements in/relating to organic compounds |
| MY105344A (en) * | 1990-05-16 | 1994-09-30 | Byk Gulden Lomberg Chemische Fabrik | New sulphonyl compounds |
-
1975
- 1975-01-27 FI FI750205A patent/FI750205A/fi not_active Application Discontinuation
- 1975-01-27 DE DE19752503156 patent/DE2503156A1/en active Pending
- 1975-01-27 SE SE7500859A patent/SE7500859L/xx unknown
- 1975-01-27 DK DK24275AA patent/DK136189B/en unknown
- 1975-01-29 NO NO750263A patent/NO750263L/no unknown
- 1975-01-31 NL NL7501159A patent/NL7501159A/en not_active Application Discontinuation
- 1975-02-03 DD DD183969A patent/DD117216A5/xx unknown
- 1975-02-03 HU HUSA2741A patent/HU169923B/hu unknown
- 1975-02-03 BE BE153007A patent/BE825124A/en unknown
- 1975-02-03 IL IL46553A patent/IL46553A/en unknown
- 1975-02-03 GB GB30857/77A patent/GB1497723A/en not_active Expired
- 1975-02-03 PH PH16771A patent/PH11824A/en unknown
- 1975-02-03 NZ NZ176550A patent/NZ176550A/en unknown
- 1975-02-03 ES ES434406A patent/ES434406A1/en not_active Expired
- 1975-02-03 GB GB4516/75A patent/GB1497722A/en not_active Expired
- 1975-02-04 AT AT79975A patent/AT351536B/en not_active IP Right Cessation
- 1975-02-04 CA CA219,303A patent/CA1055944A/en not_active Expired
- 1975-02-04 JP JP50014021A patent/JPS50108297A/ja active Pending
- 1975-02-05 ZA ZA00750743A patent/ZA75743B/en unknown
- 1975-02-05 FR FR7503547A patent/FR2259611B1/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2259611B1 (en) | 1980-01-11 |
| DK24275A (en) | 1975-09-29 |
| NZ176550A (en) | 1978-09-25 |
| FR2259611A1 (en) | 1975-08-29 |
| DK136189B (en) | 1977-08-29 |
| GB1497723A (en) | 1978-01-12 |
| SE7500859L (en) | 1975-08-06 |
| ZA75743B (en) | 1976-09-29 |
| JPS50108297A (en) | 1975-08-26 |
| IL46553A (en) | 1977-12-30 |
| DE2503156A1 (en) | 1975-08-07 |
| ATA79975A (en) | 1979-01-15 |
| HU169923B (en) | 1977-02-28 |
| IL46553A0 (en) | 1975-04-25 |
| NL7501159A (en) | 1975-08-07 |
| GB1497722A (en) | 1978-01-12 |
| DK136189C (en) | 1978-01-30 |
| AU7784375A (en) | 1976-08-05 |
| DD117216A5 (en) | 1976-01-05 |
| NO750263L (en) | 1975-09-01 |
| PH11824A (en) | 1978-07-19 |
| ES434406A1 (en) | 1977-03-01 |
| BE825124A (en) | 1975-08-04 |
| AT351536B (en) | 1979-07-25 |
| FI750205A (en) | 1975-08-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0179383B1 (en) | 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds, a process for their preparation and their use as medicaments | |
| Gill et al. | β-Acylethylation with Ketonic Mannich Bases. The Synthesis of some diketones, ketonic sulfides, nitroketones and pyridines | |
| Popp et al. | Syntheses of papaverine, papaverinol and papaveraldine from Reissert compounds | |
| CA1332836C (en) | 3-oxadiazole and 3-carboxylic acid .beta.-carboline derivatives, their production and their use as drugs | |
| PL119501B1 (en) | Process for manufacturing novel,condensed pyrimidine derivatives pirimidina | |
| CA1162189A (en) | Dibenzoxazepine derivative, process for preparing the same, and pharmaceutical composition comprising the same | |
| CA1055944A (en) | 2-methyl-6-phenyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-(c)-(1,6) naphthyridine compounds | |
| CA1203801A (en) | Piperazine derivatives, their production and pharmaceutical compositions containing them | |
| IE42486B1 (en) | Tetralone and indanone derivatives and process for their preparation | |
| GB2035311A (en) | Dibenzothiepins | |
| Guchhait et al. | Pyridine C3-arylation of nicotinic acids accessible via a multicomponent reaction: an entry to all-substituted-3, 4-diarylated pyridines | |
| Molina et al. | Fused carbazoles by tandem Aza Wittig/electrocyclic ring closure. Preparation of 6H-pyrido [4, 3-b] carbazole, 11H-pyrido [4, 3-a] carbazole and 11H-pyrido [3, 4-a] carbazole derivatives | |
| CA1088541A (en) | 1,3,8-triazaspiro [4.5] decan-4-one derivatives | |
| US3462443A (en) | Indeno(1,2-c)pyridine derivatives | |
| US2470108A (en) | Heterocyclic amines | |
| CA1175428A (en) | Process for preparing imidazo /1,2-a/ quinoline derivatives | |
| US4251659A (en) | Polyfluorohydroxyisopropyl-heterocyclic compounds | |
| CA1152993A (en) | 3h-naphtho [1,2-d]imidazoles, the process for preparing them, their use as antiinflammatory agents and compositions containing them | |
| GB1601991A (en) | Pyrido (2,1-b) quinazoline derivatives | |
| US3332949A (en) | 1-phenyl-4-[2-(2-pyridyl)-ethyl] piperazines | |
| HU189215B (en) | Process for preparing 3,3,-dialkyl- and 3,3-alkylene-indoline derivatives | |
| JPS5855138B2 (en) | Houkozoku carbon sanamide | |
| Uff et al. | Formation of reissert analogs from benzimidazole and use of carboxylic acids in a retro‐reissert reaction Reissert Analogs from Benzimidazole | |
| US4677109A (en) | 1-(6-(2'-substiuted-5', 6', 7', 8'-tetrahydro-4',-oxo-quinazolino))-3-4-dihydro-6,7-disubstituted-isoquinoline derivatives and pharmaceutical compostions containing them | |
| US3154556A (en) | Nu-pyridylethyl-2:3-polymethyleneindoles |