IL46553A - Octahydrobenzo-(c) (1,6) naphthyridine derivatives their preparation and pharmaceutical compositions containing the - Google Patents

Abstract

1497722 2 - Methyl - 6 - phenyl - octahydrobenzo[c][1,6]naphthyridines SANDOZ Ltd 3 Feb 1975 [5 Feb 1974] 4516/75 Heading C2C Novel compounds I and salts thereof in which R 1 is H, OH or C 1-4 alkoxy and (a) R 2 is H, C 1-4 alkyl, C 1-4 alkoxy, OH, halogen, NO 2 NH 2 , NMe 2 or C 1-5 alkanoylamino and R 3 and R 4 are H (b) R 2 is C 1-4 alkyl, C 1-4 alkoxy, OH, halogen or NO 2 , R 3 is C 1-4 alkyl, C 1-4 alkoxy, OH or Cl and R 4 is H (c) R 2 , R 3 and R<SP>4</SP> are C 1-4 alkoxy (d) R 2 , R 3 nd R 4 are C 1-4 alkyl or (e) R 2 , R 3 and R 4 are OH with the provisos that (i) when R 1 is OH in the 9 position, each of R 2 , R 3 and R 4 is other than C 1-4 alkoxy (ii) when one of R 2 and R 3 is C 1-4 alkoxy, the other is not OH (iii) R 1 is other than H when R 2 , R 3 and R 4 represent as substituents 4-methyl, 3,4,5- trimethoxy, 3,4,5-trihydroxy, 3,4-dimethoxy or 3,4-dichloro and (iv) R 1 is other than 8-OH when R 2 , R 3 and R 4 represent as substituents 4-chloro or 4-acetylamino or represent no substituent; are prepared by reducing a compound II where R 6 is H, OH, C 1-4 alkoxy or benzyloxy and if desired converting the compound obtained into a salt. Compounds I (R 1 = OH) are also produced by ether splitting of the corresponding C 1-4 alkyl or benzyl ether. Compounds I (R 2 , R 3 and/or R 4 or OH) are also produced by hydrogenolysis of the corresponding benzyloxy compounds. Compounds II are obtained by cyclization of the corresponding cis 4-benzoylamino-1- methyl - 3 - phenyl piperidine according to Bischler-Napieralski and, for compounds where R 2 is NH 2 , NMe 2 or C 1-5 acylamino, reducing the corresponding compound where R 2 is NO 2 followed by acylation or reductive methylation. Compounds I (excluding those where R 1 is 9-OMe and R 2 , R 3 and R 4 represent as substituents 4-dimethylamino, 3,4-dimethoxy, 3,4- dichloro or 3,4-dihydroxy and where R 1 is 8-OMe and R 2 , R 3 and R 4 represent as substituents 3,4,5-trimethoxy, 4-fluoro or 4- methoxy) have bronchospasmolytic activity and form with a carrier or diluent a pharmaceutical composition which may be administered orally or by inhalation. [GB1497722A]

Description

46553/3 jniK D' Oan mnpn 'wani j-nx»» Octahydrobenzo-jV) (l, β) naphthyridine derivatives, their production and pharmaceutical compositions containing them SA DOZ A.G.

C. 444H The present invention relates to new heterocyclic compounds, to their preparation and to pharmaceutical preparations containing them. The compounds of the present invention exhibit bronchospasmolytic activity.

French Patent 2,100,649 discloses compounds of a structure similar to those of the present invention and having the formula wherein Rj^ is hydrogen, fluorine, bromine, chlorine, lower alkyl, lower alkoxy or lower alkylthio, nitro, trifluoromethyl , amino or acylated amino, R2 is hydrogen, chlorine, lower alkyl or lower alkoxy, and either R^ and R4 are identical and each are hydrogen or methoxy , or R3 and R^ together are methylenedioxy These compounds are indicated for use as inhibitors of blood platelet aggregation.

In accordance with the present invention there are provided new compounds of formula wherein the indicated radical in the 8 or 9 position of the benzonaphthyridine structure (R^) is hydrogen, alkoxy of 1 to 4 carbon atoms or hydroxy, and (i) 2 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 R^ is hydrogen or alkyl of 1 to 4 carbon atoms, and R, and R. are hydrogen, - 1b - - 2 - 100-4126 or (ii) 1*2 is alky! of 1 to 4 carbon atoms, alkoxy σ?^β"~~ 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 R^ 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 nYdroxY' with the proviso that (i) when one of the radicals R2, and R^ is benzyloxy, the indicated radical in the 8 or 9 position of the benzonaphthyridine structure (R^) 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 (R^) is other than hydrogen or alkoxy and is in the 9 position, each of the radicals R2» R^ and R^ is other than alkoxy of 1 to 4 carbon atoms, and (iii) when one of the radicals R„ and R_ - 3 - 100-4126 is benzyloxy or alkoxy of 1 to 4 carbon atoms, the remaining radical or is "**" " other than hydroxy.

Any alkyl or alkoxy substituents of the 6-phenyl radical especially contain 1 or 2, preferably 1 carbon atom .

When R^ is alkoxy of 1 to 4 carbon atoms, this especially contains 1 or 2, preferably 1 carbon atom.

When R,- is alkyl of 1 to 4 carbon atoms, this radical especially denotes methyl, ethyl, or an a-branched alkyl radical such as isopropyl or tert.butyl.

When the radical is halogen, this signifies fluorine, chlorine or bromine, preferably fluorine or chlorine.

As may be seen from the formulae, the hydrogen atoms in the 4a, 6 and 10b positions of the benzo-naphthyridine structure are in the cis position.

Further, in accordance with the invention a compound of formula I may be obtained by a process comprising a) reducing a compound of formula II, 4 100-4126 wherein Rg 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 R^r R3 and are as defined above with the proviso thereto, orb) treating a compound of formula III, III - 5 - 100-4126 wherein R , R_, R. are as defined above with the proviso thereto, 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 la, R 3 wherein R , R_ and R. are as defined above with the proviso thereto and the further proviso that (iv) each of R2, R3 and R4 is other than benzyloxy.

The octahydrobenzo [c] [1 , 6 ] naphthyridine derivatives produced in accordance with the processes described above, may be isolated in the usual manner and purified in accordance with known methods. - 6 - 100-4126 Process variant a) may be effected in conventional manner for the reduction of similar double bonds, wit?. or without ether splitting, in similar compounds.

When R, is an ether group in the 8 or 9 position o of the benzonaphthyridine structure, capable of being split off under the reaction conditions, this group preferably signifies an ether group capable of being split off hydrogenolytically , especially in the presence of a metal catalyst such as platinum or palladium. Examples of such Rg groups are the benzyloxy group, and benzyloxy groups substituted on the phenyl ring or alkylated in a position.

The reaction may be effected with a complex alkali metal hydride in a suitable solvent, e.g. sodium boro-hydride in methanol or ethanol, or lithium aluminium hydride in ether, tetrahydrofuran, dioxaneor dimethoxy-ethane. The reduction is preferably effected at an elevated temperature, e.g. between about 50 and 100°C. When these reaction conditions are used, it is convenient to chose as starting material compounds of formula II wherein R^ is hydrogen, alkoxy of 1 to 4 carbon atoms or hydroxy. The reduction products are isolated and purified in accordance with known methods, for example after decomposition of the excess reducing agent and the resulting complex by shaking between an aqueous solution and 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 piatinu 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] aphthyridine 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 is conveniently used as catalyst.

When platinum is used as catalyst and a benzyloxy 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 di ethylamino group. The production of compounds of formula I wherein is the nitro group, is therefore conveniently effected with complex hydrides when process variant a) is used. - 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 obtained as 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 10b are all in a cis position to one another, are obtained.

Process variant b) is an ether splitting. It 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 tetrachloride, or an aromatic hydrocarbon such as toluene or benzene. The temperature may be from about -80 to 70°C.

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 150°C, for example at the boiling temperature of the reaction mixture. An inert solvent may optionally be used. - 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 150°C.

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 acetic acid. The temperature may be from about 20 to 100°C.

The reaction is effected at normal pressure or at an elevated 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 III wherein R2 is -NHCOR^, is conveniently effected under catalytic conditions; in this case preferably denotes benzyloxy. - 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 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 t containing a di ethylamino group may, for example, be effected by reductive methylation of a compound of formula II containing an amino group with formaldehyde and formic acid as reducing agent (Leuckart-Wallach reaction) .

The remaining compounds of formula II may, for example, be obtained by cyclization of the corresponding cis-4-benzoylamino-l-methyl-3-phenylpiperidine in accordance with Bischler-Napieralski .

The compounds of formula III aose-e-t½Jaea--k*«WR or may be produced in accordance with known methods, or using the methods described for the production of compounds of formulae I and II.

Insofar as the production of the required starting materials is not described, these are known or may be produced in accordance with 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 addition salt forms in conventional manner and vice versa. Suitable acids for salt formation include maleic, hydrochloric and hydrobromic acids. - 12 - 100- 126 In the following non-limitative Examples all temperatures are indicated in degrees Centigradex and are uncorrected.

EXAMPLE It Cis-8-hydroxy-2-methyl-6-phenyl- 1,2 , 3 , 4 , 4a , 5 , 6 , lOb-octahydrobenzo- [c] [l,6]naphthyridine [process variant a) ] 2 g of cis-8-hydroxy-2-methyl-6-phenyl- 1,2,3,4,4a, lOb-hexahydrobenzo [c] [1 , 6] naphthyridine (M.P. of the dihydrobromide 268-271°) are dissolved in 20 cc of methanol, and after the addition of 0.1 g of platinum oxide hydrogenation is effected at room temperature and normal pressure in an atmosphere of hydrogen. After the take up of hydrogen is complete the catalyst is filtered off and the filtrate es evaporated to dryness in a vacuum. The evaporation residue is dissolved in water, is made alkaline with potassium carbonate, is extracted thrice with methylene chloride, the organic phases are dried and evaporated to dryness, the residue is dissolved in alcohol, and a small excess of maleic acid is added, whereby the bishydrogen maleate of the title compound crystallizes (M.P. 196-197°) .

EXAMPLE 2; Cis-8-hydroxy-2-methyl-6-phenyl- 1,2, 3, 4, 4a, 5, 6, Ob-octahydrobenzo- [c] [1 , 6 ] naphthyridine [process variant a) ] 1 g of cis-8-hydroxy-2-methyl-6-phenyl- 1,2,3,4,4a, lOb-hexahydrobenzo [c] [1,6] naphthyridine (M.P. of the dihydrobromide 268-271°) is dissolved in 10 cc of ethanol, 0.1 g of sodium borohydride is added, and this reaction solution is boiled at reflux for - 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°).

EXAMPLE 3; Cis-8-methoxy-2-methyl-6-phenyl- 1 , 2 , 3 , 4 , 4a , 5, 6 , IQb-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-l , 2,3,4,4a, lOb-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, lOb-hexahydrobenzo [c] [1,6] naphthyridine is obtained by addition of 3-amino-2-p_-methoxyphenyl-propionic acid ethyl ester to acrylic acid ethyl ester, reductive methylation of 2-p_-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) -l-methyl-4-piperidone (M.P. of the - 14 - 100-4126 hydrochloride 180-182°) , which is converted by hydrolysis and subsequent decarboxylation into 3-p_-methoxyphenyl-l-methyl-4-piperidone (M.P. of the hydrogen oxalate 137-138°). The resulting piperidone is reacted with hydroxylamine to obtain 3-p_-methoxyphenyl-l-methyl-4-piperidone oxime (M.P. 121-122°) , the oxime is hydrogen-ated with Raney nickel to obtain 4-amino-3-p_-methoxy-phenyl-l-methyl-piperidine (mixture of the two diastereo-isomers) , the amino compound is treated with benzoyl chloride, cis-4-benzoylamino-3-p_-methoxyphenyl-l-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-methoxy-2-methyl- 1,2,3,4, 4a ,5,6, lOb-octahydrobenzo- [c] [1 , 6 ] naphthyridine The process is effected in a manner analogous to that described in Example 1 or 2, and the title compound is obtained by reduction of cis-6- (4-aminophenyl) -9-methoxy-2-methyl-l , 2 , 3 , 4 , 4a, lOb-hexahydrobenzo [c] [1,6]-naphthyridine (oil, crude) . The title compound crystallizes from ethanol as trihydrochloride having an M.P. of 289-291°.

The cis-6- (4-aminophenyl) -9-methoxy-2-methyl-1, 2 , 3 , 4 , 4a, lOb-hexahydrobenzo [c] [1, 6 ] naphthyridine , required 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, lOb-hexahydrobenzo [c] [1,6] naphthyridine - 15 - 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'"¾e' 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 concentrated 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.

EXAMPLE 5; Cis-6- (4-acetamidophenyl) -9-methoxy-2-methyl- 1,2, 3, 4, a, 5,6, lOb-octahydrobenzo- [c] [1 , 6 ] naphthyridine The process is effected in a manner analogous to that described in Example 1 or 2, and the title compound is obtained by reduction of cis-6- (4-acetamidophenyl) -9-methoxy-2-methyl-l,2 , 3,4, 4a, lOb-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, lOb-hexahydrobenzo [c] [1,6] naphthyridine, required as starting material, is obtained from cis-6-(4-aminophenyl) -9-methoxy-2-methyl-l , 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. - 16 - 100-4126 EXAMPLE 6 ; Cls-6- (4-dimethylaminophenyl) -9-methoxy-2- methyl-1 ,2,3,4,4a, 5,6, lOb-octahydrobenzo^^- ~ [c] [1,63 naphthyridine The process is effected in a manner analogous to that described in Example 1 or 2 , and the title compound is obtained by reduction of cis-6- (4-dimethylamino-phenyl) -9-methoxy-2-methyl-l ,2,3,4,4a, lOb-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-l , 2,3,4,4a, lOb-hexahydrobenzo [c] [1,6 ]naphthyridine, required as starting material, is obtained in accordance with Leuckart-Wallach from cis-6- (4-aminophenyl) -9-methoxy-2-methyl-l , 2 ,3,4,4a, lOb-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.

The following compounds of formula I are obtained in of the corresponding hexahydro compounds of formula II Ex. Analogous R R R R Nr. to Ex. 2 3 4 1 7 1,2 4-F H 9-Me 8 1,2 4-Me H 9-Me 9 1,2 4-Cl H H 9-Me 10 1,2 4-Cl H H H 11 1,2 4-Me H H K 12 1,2 3-MeO 4-MeO H H 13 1,2 3-MeO 4-MeO 5-MeO H 14 1,2 3-Cl 4-Cl H H 15 1,2 H H H 9-Me 16 1,2 3-MeO 4-MeO 5-MeO 8-Me 17 1,2 4-F H H 8-Me 18 1,2 4-MeO H H 8-Me 19 1,2 3-MeO 4-MeO H 9-Me 20 1,2 3-Cl 4-Cl K 9-Me 21 1,2 3-MeO 4-MeO 5-MeO 9-Me * Using as starting material the corresponding compou group replaced by a benzyloxy group, and as catalys - 19 - 100-4126 EXAMPLE 40; Cis-8-hydroxy-6-phenyl-2-methyl- 1,2,3,4,43,5,6, lOb-octahydrobenzo- [c] [1 , 61 naphthyridine [process variant b) ] 2 g of cis-8-methoxy-6-phenyl-2-methyl-1 , 2 , 3 , 4 , 4a, 5 , 6 , lOb-octahydrobenzo [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-hydroxyphenyl) -9-methoxy-2-methyl- 1,2, 3, , a, 5, 6, lOb-octahydrobenzo- [c] [1 , 6 ] naphthyridine [process variant b) ] 5 g of cis-6- (4-benzyloxyphenyl) -9-methoxy- 2-methyl-l, 2 , 3 , 4 , 4a, 5 ,6 , lOb-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.

The following compounds of formula la are obtained i material the corresponding compounds of formula III Example 53: (-) -Cis-8-hydroxy-2-methyl-6-phenyl- 1 , 2 ,3 ,Ά', 4a ,5,6, lOb-octahydrobenzo [c1 t1 , 6 ]naphthyridlne [process variant b] 2.35 g of (+) -cis-8-methoxy-2-methyl-6-phenyl- 1,2,3/4, 8,5,6, lOb-octahydrobenzo [c] [1 , 6] naphthy-ridine in free base form, and 50 ml of cone. HC1 are heated in a sealed tube in an oil bath at 125°. The reaction solution is evaporated to dry-ness and the yellow residue is boiled with ethanol. (-)-Cis-8-hydroxy-2-methyl-6-phenyl-l,2 ,3,4 ,4a, 5, 6 , lOb-octahydrobenzo [c] [l,6]naphthyridine in dihydro-chloride form crystallizes out as white crystals: ta]5?8 -98° (c = 1.0? CHC13) (M. P.325-7°) .

The starting material is obtained as follows: (a) 5.0 g of racemic cis-4-benzoyl-amino-3-£-methoxy-phenyl-l-methylpiperidine and 2.31 g of L-tartaric acid are dissolved together in 90 ml of water using a slight amount of warming. The solution is evaporated to about half its original volume under a vacuum. The concentrated solution is allowed to stand overnight. The L-tartrate salt which crystallized out is converted into the corresponding crystalline free base' by treatment with 2N sodium hydroxide solution and methylene chloride. The base , (+) -cis-4-benzoylamino-3-p_-methoxyphenyl- 20b - 1-methylpiperidine, exhibits the following specific rotation: [al578 =+67,2° (c-1,0) CHC13) .

A sample of this base is converted as indicated above into the L-tartrate salt and this salt is again converted into the free base, which has substantially the same specific rotation as the previously obtained sample. (b) 5.0 g of (+) -cis-4-benzoylamino-3-£-methoxy-phenyl-1-methylpiperidine and 100 ml P0C13 (pre-viously activated by 3% v/v of water) are boiled under reflux for five hours. The reaction mixture Is worked up in conventional manner to yield the dihydrochloride of (-) -cis-8-methoxy-2-methy1-6-pheny1-1 ,2,3,4,4a, lOb-hexahydrobenzo [c] [1,6] naphthyridine (m.p. 245-8°). The corresponding free base is a bright yellow oil having a specific rotation ta3578 = -305° (c = 1.0? CHC13) · (c) 2,66 g of (-) -Cis-8-methoxy-2-methyl-6-phenyl- 1,2,3,4,4a, lOb-hexahydrobenzo [c] [1,6] naphthyridine dissolved in 100 ml of ethanol is reduced with 0,5 g NaBH^ over one hour at room temperature. After working up in conventional manner (+) -cis-8-methoxy-2-methyl-6-phenyl-l ,2 ,3, , a , 5 , 6 , lOb-octahydrobenzo [c] [1,6] naphthyridine in free base form as a yellow oil is obtained: [ot]578 = + 7,2° (c=l,0? CHC13) . - 20c - · Example 5 : (+) -Cis-8-hydroxy-2-methy1-6'-pheny1- 1,2,3 4, 4a ,'5,6', lOb-octahydrobenzo [c3 [l,6]naphthyridlne [process variant b] The title compound Is obtained In a manner analogous to that described in Example 53 using (-)-cis- 8-methoxy-2-methy1-6-phenyl- 1,2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [c] [l,6]naphthyridine as starting material ( .p. of the dihydrochloride of the title compound: 324-326°): [«]578 ■ + 100° (c = 1.0» CHC13) .

The starting material is obtained in a manner analogous to that described in Example 53,, steps a) to c) , starting from D-tartaric acid} the following intermediates are isolated: (a) (-)-Cis-4-benzoylamino-3-p_-methoxyphenyl-l- ethylpiperidine: ta_578 = - 67.2°; [c = 1.0? CHC133- (b) (+) -Cis-8-methoxy-2-methyl-6-phenyl-l , 2 , 3 , 4 , 4a , 10b-hexahydrobenzo [c] [l,6]naphthyridine: [a3578 = + 276° (c = 1.0; CHC13) . ic) (-) -Cis-8-methoxy-2-methyl-6-phenyl-l , 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [c] [1 ,6 ] naphthyridine : [a]57g = -9,5° (c = lrO; CHC1-) . 20a Example 53 ; X-V-CiB-6-hydroxy-2-methy-I-6-phenyl- 1,2 ,3 /4 ,4a, 5 ,6 ,10b-octahydrobenzo [cl [1 , 6]naphthyridine [process variant b] 2.35 g of (+) -cis-8-methoxy-2-methyl-6-phenyl- 1,2,3,4,48,5,6/ lOb-octahydrobenzo [c] [1,6] naphthy-ridine in free base form, and 50 ml of cone. HC1 are heated in a sealed tube in an oil bath at 125°. The reaction solution is evaporated to dry-ness and the yellow residue is boiled with ethanol. (-) -Cis-8-hydroxy-2-methyl-6-phenyl-l , 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [c] [l,6]naphthyridine in dihydro-chloride form crystallizes out as white crystals: [a]578 -98° (c =.1.0» CHC13) (M.P .325-7°) .

The starting material is obtained as follows: (a) 5.0 g of racemic cis-4-benzoy.¥-amino-3-£-methoxy-phenyl-l-methylpiperidine and 2.31 g of L-tartaric acid are dissolved together in 90 ml of water using a slight amount of warming. The solution is evaporated to about half its original volume under a vacuum. The concentrated solution is allowed to stand overnight. The L-tartrate salt which crystallized out is converted into the corresponding crystalline free base- by treatment with 2N sodium hydroxide solution and methylene chloride. The base , (+) -cis-4-benzoylamino-3-£-methoxyphenyl- 1-methylpiperidine , exhibits the following specific rotation: [a]578 =+67,2° (c=l,Oj CHC13) .

A sample of this base is converted as indicated above into the L-tartrate salt and this salt is again converted into the free base, which has substantially the same specific rotation as the previously obtained sample. (b) 5.0 g of (+) -cis-4-benzoylamino-3-£-methoxy-phenyl-l-methylpiperidine and 100 ml P0C13 (pre-viously activated by 3% v/v of water) are boiled under reflux for five hours. The reaction mixture is worked up in conventional manner to yield the dihydrochloride of (-)-cis-8-methoxy-2-methyl-6-phenyl-l ,2,3,4 , 4a, lOb-hexahydrobenzo [c] [1,6] naphthyridine (m.p. 245-8°). The corresponding free base is a bright yellow oil having a specific rotation [a] 578 = -305° (c = 1.0} CHC13) · (c) 2,66 g of (-)-Cis-8-methoxy-2-methyl-6-phenyl-l,2,3,4,4a,10b-hexahydrobenzo[c] [1,6] naphthyridine dissolved in 100 ml of ethanol is reduced with 0,5 g NaBH^ over one hour at room temperature. After working up in conventional manner (+) -cis-8-methoxy-2-methy1-6-pheny1-1 ,2,3, 4 , 4a , 5 , 6 , lOb-octahydrobenzo [c] [1,6] naphthyridine in free base form as a yellow oil is obtained: [a],.,. = + 7,2° (c=l,0f CHCl-J . - 20c - Example 54; (+) -Cis-8-hydroxy-2-methyl-6-phenyl- 1,2,3, 4 , 4a ,5,6, lOb-octahydrobenzo [c] [1 ,6 Inaphthyrldine [process variant b] The title compound Is obtained In a manner analogous to that described in Example 53 using (-)-cis-8-methoxy-2-methyl-6-phenyl-l , 2,3,4,43,5,6, 10b-octahydrobenzo [c] tl,6]naphthyridine as starting material (m.p. of the dihydrochloride of the title compound: 324-326°): [al578 = + 100° (c = 1.0» CHC13) .

The starting material is obtained in a manner analogous to that described in Example 53,, steps a) to c) , starting from D-tartaric acid; the following intermediates are isolated: (a) (- ) -Cis- -benzoy1amino- 3-p_-methoxyphenyl- 1-methylpiperidine : [a)^Q = - 67.2°; [c = 1.0» CHC133- (b) (+) -Cis-8-methoxy-2-methyl-6-phenyl-l , 2 , 3 , 4 , 4a , 10b-hexahydrobenzo [c] [l,6]naphthyridine: [«357Q - + 276° (c = 1.0» CHC13) . <(c) (-) -Cis-8-methoxy-2-methyl-6-phenyl-l , 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [c][l ,6]naphthyridine: [a],.^ » -9,5° (c = lr0» CHC13) . - 21 - 100-4126 The compounds of formula I exhibit pharmacological activity. In particular the compounds exhibit bronchospasmolytic activity as indicated in standard tests, for example in the Konzett-Rossler test, by an inhibition of bronchospasms induced by histamine anesthetized cats and guinea pigs. Ί The compounds are therefore further indicated for use as bronchospasmolytic agents. For this use an indicated daily dose is from about 35 to about 700 mg, conveniently administered in divided doses 2 to 4 time.s a day in unit dosage form containing from about 6 to about 350 mg, or in sustained release form.

The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.

Such compositions may be formulated in conventional manner to be in the form of, for example, a solution suitable for inhalation as a spra er a tablet. - 22 - . 100-4126 Interesting compounds are those wherein is hydroxy or alkoxy, preferably methoxy. Preferably 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-l ,2,3,4,4a, 5, 6, lOb-octahydrobenzo [c] [1,6] naphthyridine and more especially ci s-8-hydroxy-2-methyl-6-phenyl-l, 2 , 3 , 4 , 4a, 5 , lOb-octahydrobenzo [c] [1 , 6] naphthyridine .

Claims (55)

1. A process for the production of a compound formula I , wherein the indicated radical in the 8 or 9 position of the benzonaphthyridine structure (R^) is. hydrogen aikoxy of 1 to 4 carbon atoms or hydroxy, and (i) hydrogen, alkyl of 1 to 4 carbon atoms, aikoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy, halogen, nitro, amino, dimethylami o , or -NHCORc - 24 - 100-4126 wherein R^ is hydrogen or alkyl of 1 to 4 carbon atoms , and R3 and R4 are hydrogen, or ' (ϋ) 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 R^ is hydrogen, (iii) R2'R3 and R4 are» independently, alkoxy of 1 to 4 carbon atoms or benzyloxy, or (iv) R2'R3 nc^ 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 R^, ^ and R4 is benzyloxy, the indi- cated radical in the 8 or 9 position of the benzonaphthyridine structure (R^) 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 (R^) is other than hydrogen or alkoxy and is in the 9 position, each of the radicals R^, ^ and R^ is other than alkoxy of 1 to 4 carbon atoms, - 25 - 100-4126 is benzyloxy or alkoxy of 1 to 4 carbon atoms, the remaining radical R2 or R3 is other than hydroxy which comprises a) reducing a compound of formula II, wherein R is in the 8 or 9 position of the benzo- 6 naphthyridine structure and is hydrogen, alkoxy of 1 to 4 carbon atoms, hydroxy, or an ether radical capable of being spl under the reaction conditions to form a hydroxy radical, and R2 r ^ arid R^ are as defined above with the proviso thereto, b) treating a compound of formula III, - 26 - 100-4126 wherein R , R , R are as defined above with the proviso thereto, 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 la, - 27 - 100-4126 wherein R2, R3 and R4 are as defined above with ¾he proviso thereto and the further proviso that (iv) each of R_ , R_ and R. is other 2 3 4 than benzyloxy.

2. A process for the production of a compound of formula I, as stated in claim 1, substantially as hereinbefore described with reference to any one of the Example

3. A compound of formula I, whenever produced by a process according to claim 1 or 2.

4. A compound of formula I, as defined in claim 1

5. A compound of claim 4 wherein R2 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy, halogen, nitro, amino, dimethylamino or -NHC0R5 wherein ^ is hydrogen or alkyl of 1 to 4 carbon atoms, and 3 and R^ are hydrogen „

6. A compound of claim 4 wherein R'2 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy, halogen or nitro, - 28 - 100-4126 R3 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, benzyloxy, hydroxy or chlorine , and R^ is hydrogen,

7. A compound of claim 4 wherein R2, R3 and R^ are, independently, alkoxy of 1 to 4 carbon atoms or benzyloxy.

8. A compound of claim 4 wherein R2, R^ and R^ are, independently, alkyl of 1 to 4 carbon atoms.

9. A compound of claim 4 wherein R2, R^ and R^ are hydroxy.

10. The compound of claim 4 which is cis-8-hydroxy 2-methyl-6-phenyl-1, 2 , 3 , 4 , 4a, 5 , 6 , lOb-octahydrobenzo- [c] [1,6] naphthyridine .

11. The compound of claim 4 which is cis-8-methoxy 2-methyl-6-phenyl-l, 2 , 3 , 4 , 4a, 5 , 6 ,10b-octahydrobenzo- [c] [1, 6] naphthyridine .

12. The compound of claim 4 which is cis-6-(4-aminophenyl) -9-methoxy-2-methyl-l , 2-, 3, 4, 4 a, 5, 6 ,10b-octahydrobenzo- [ c] [1,6] naphthyridine .

13. The compound of claim 4 which is cis-6-(4-acetamidophenyl) -9-methoxy-2-methyl-l, 2 , 3, 4, 4a, 5 ,6 ,10b- - 29 - 100-4126 octahydrobenzo- tc] [1, 6 ] naphthyridine .

14. The compound of claim 4 which is cis-6- (4-dimethylaminophenyl) -9-methoxy-2-methyl-l, 2 , 3, 4, 4a, 5 ,6 ,10b-octahydrobenzo- tc] [1 , 6] naphthyridine .

15. The compound of claim 4 wherein R^, R.-., R4 and R^ are respectively 4-F, H, H, 9-MeO.

16. The compound of claim 4 wherein R2, ^/ R^ and R^ are respectively 4-Me, H, H, 9-MeO.

17. The compound of claim 4 wherein R^r R^, R4 and R^ are respectively 4-Cl, Hf H, 9-MeO.

18. The compound of claim 4 wherein R^, R^, R4 and R^ are respectively 4-Cl, H, H, H.

19. The compound of claim 4 wherein R^, Rg, R^ and R^ are respectively 4-Me, H, H, H.

20. The compound of claim 4 wherein R2, 3, R4 and R^ are respectively 3-MeO, 4-MeO, H, H.

21. The compound of claim 4 wherein R2, R^, R^ and R^ are respectively 3-MeO, 4-MeO, 5-MeO, H.

22. The compound of claim 4 wherein R^, R^r R4 an( are respectively 3-Cl, 4-Cl, H, H. - 30 - 100-4126

23. The compound of claim 4 wherein R2, R^, R4 and ^ are respectively H, H, H, 9-MeO.

24. The compound of claim 4 wherein R2, R^, R4 and R^ are respectively 3-MeO, 4-MeO, 5HYleO, 8-MeO.

25. The compound of claim 4 wherein R2, R^, R^ and R^ are respectively 4-F, H, H, 8-MeO.

26. The compound of claim 4 wherein R^, R^, R4 and R.^ are respectively 4-MeO, H, H, 8-MeO.

27. The compound of claim 4 wherein R^, ^, R4 and R1 are respectively 3-MeO, 4-MeO, H, 9-MeO.

28. The compound of claim 4 v/herein R2, R3, R4 and R^ are respectively 3-Cl, 4-CI, H, 9-MeO.

29. The compound of claim 4 wherein R2, R^, R4 and R^ are respectively 3-MeO, 4-MeO, 5-MeO, 9-MeO.

30. The compound of claim 4 wherein R2, R^, 4 and R1 are respectively 3-OH, 4-OH, H, H.

31. The compound of claim 4 wherein R2, R3, R4 and R^j^ are respectively 4-OH, H, H, 8-OH.

32. The compound of claim 4 wherein R2 , R^, R4 and R^ are respectively 3-OH, 4-OH, 5-OH, H. - 31 100-4126

33. The compound of claim 4 wherein R2, , R^ and 1 are respectively 3-OH, 4-OH, H, 9-MeO.

34. The compound of claim 4 wherein R2# R2, R4 and R1 are respectively 4-OH, H, H, 9-MeO.

35. The compound of claim 4 wherein R2, R^, R^ and Rj^ are respectively 2-OH, H, H, 9-MeO.

36. The compound of claim 4 wherein R2, ^ 4 and R1 are respectively H, E, E, 9-OH.

37. The compound of claim 4 wherein R2, R^, R^ and R1 are respectively 3-OH, 4-OH, H, 8-OH.

38. The compound of claim 4 wherein R2, R3, 4 and R1 are respectively 3-Cl, 4-Cl, H, 8-OH.

39. The compound of claim 4 wherein 2, R^, R^ and R^ are respectively 3-Me, 4-Me, H, 8-OH.

40. The compound of claim 4 wherein R2, R^, R^ and 1 are respectively 4-Cl, H, H, 8-OH.

41. The compound of claim 4 wherein R2, R^, R^ and R-j^ are respectively 4-F, H, H, 8-OH.

42. The compound of claim 4 wherein R2, R^, ^ and R1 are respectively 3-OH, 4-OH, 5-OH, 8-OH. - 32 - 100-4126

43. The compound of claim 4 wherein R2 , R^' R| and R^ are respectively 4-NH2, H, H, 8-OH.

44. The compound of claim 4 wherein R^r R3* R4 anc^ ^ are respectively H, H, H, H.

45. The compound of claim 4 wherein ^ , R^, and R^ are respectively 4-N02, H, H, 9-MeO.

46. The compound of claim 4 wherein ^ , R^r R^ anc^ R ^ are respectively 4-NH2, H, Hf 8-MeO.

47. The compound of claim 4 wherein R^, R^, R^ and R1 are respectively 4-NHCOCH3, H, H, 8-OH.

48. The compound of claim 4 wherein an<3 R ^ are respectively 4-0«CH2 •CgHg , H, H, H,

49. A compound of claim 4 wherein R^ is hydroxy.

50. A compound of claim 4 or 49 wherein R^ is in the 8-position.

51. A compound of claim 4 wherein R^ is alkoxy.

52. A compound of claim 4 or 51 wherein R^ is in the 8-position.

53. A compound according to any one of claims 3 to 52 in free base form. - 33 - 100-4126

54. A compound according to any one of claims 3 to 52 in acid addition salt form.

55. A pharmaceutical composition comprising a compound according to any one of claims 3 to 52 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent. 3700/RR/IL