Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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
R3
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`
- 2 - 100-4126
: 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
- 4 - 100-4126
CH3
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
R3
1055944
- 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,
CH3
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.
1055944
- 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.
1055944
- 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
.
- 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
- 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
- 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.
1055944
- 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
- 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
- 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
- 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.
1055944
- 16 - 100-4126
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~
- 17 - 100-4126
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1055944
- 18 - 100-4126
* 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.
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lO5S~44
- 19 - 100-4126
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~
- 20 - 100-4126
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105~9~
- 21 - 100-4126
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~
- 22 - 100-4126
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.
