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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/02—Preparation by ring-closure or hydrogenation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/56—Nitrogen atoms
  • C07D211/58—Nitrogen atoms attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D211/74—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

• each of the two symbols R signifies hydrogen, hydroxy or lower alkoxy, or the symbols R together signify methylenedioxy
• each of the two symbols X signifies hydrogen, or the symbols X together signify a second bond between the carbon and the nitrogen atom
• the new compounds have a benzo[c][1,6]naphthyridine structure, the numbering of which may be seen in Formula I.
• the symbols X in Formula I together signify a second bond between the carbon and the nitrogen atom, the compounds are 1,2,3,4,4a,lOb-hexahydrobenzo- [c] [1,6]naphthyridine derivatives which have asymmetric carbon atoms in the positions 4a and 10b. These compounds may therefore be obtained in two racemic forms.
• each of the two symbols X in Formula I signifies hydrogen
• the compounds are 1,2,3,4,4a,5,6,l0boctahydrobenzo[c][l,6]naphthyridine derivatives which aside from the 4a and 10b positions also have an asymmetric carbon atom in the 6 position. These compounds may therefore be obtained in four racemic forms.
• the compounds obtained by the ring closure are hereinafter named isomer A or isomer B"; they differ from each other in the stereochemistry of the ring linkage (positions 4a and 10b).
• R and X have the above significance, and R signifies hydroxy
• Any isomer mixtures which are obtained in the above processes may be separated into their individual racemates, and any individual racemates may be split into their optically active antipodes.
• reaction may be effected at the boil in an inert organic solvent, e.g. xylene, and the water which is formed may be continuously removed from the reaction mixture by azeotropic distillation.
• inert organic solvent e.g. chloroform
• tertiary organic base e.g. pyridine
• Acylation may, however, also be efiected with 3,3-diphenylpropionic acid itself, with its azide or with one of its lower alkyl esters.
• reaction may be effected at the boil in an inert organic solvent, e.g. xylene, and the water which is formed may be continuously removed from the reaction mixture by azeotropic distillation.
• the amides of Formula II have two asymmetric carbon atoms as do the piperidylamines of Formula III and may therefore be obtained in two racemic forms.
• a separation of the sterically uniform racemates of the A and B series is possible at the amide stage, as well as at the amine stage. Also, a separation of the racemates into their optically active antipodes is possible.
• the amides may be used as mixtures of isomers, as pure A or B racemates, or as optically uni form compounds.
• the amides of Formula II are preferably used as uniform racemates (isomer A or B).
• the ring closure step which may be effected in accordance with the known method of Bischler and Napieralski, does not alter the steric arrangement of the substituents on the piperidine ring, so that the stereochemistry of the two centres of asymmetry in positions 4a and 10b (ring linkage) of the resulting l,2,3,4,4a,IOb-hexahydrobenzo[c] [l,6]naphthyridine derivatives of Formula Ia agrees with that of the starting materials. Therefore, isomer mixtures, A or B racemates, or optically uniform compounds may be obtained, dependent on the composition of the starting materials.
• Cyclisation may be eflFected by boiling an amide of Formula II with phosphorus oxychloride and/or phosphorus pentoxide under reflux for a prolonged period of time, e.g. 1 to 10 hours.
• This reaction may be carried out in an organic solvent such as chloroform, benzene, toluene, xylene or tetraline.
• the ring closure is effected by boiling in an excess of phosphorus oxychloride. Amides which are not substituted in the benzene ring usually require stronger reaction conditions and are, for example, treated with phosphorus pentoxide in boiling phosphorus oxychloride.
• the organic phase is subsequently washed until neutral, such as with an aqueous sodium chloride solution. This is then dried and concentrated by evaporation.
• the crude compound of Formula Ia obtained as residue may be purified in manner known per se, such as by crystallization, distillation, adsorption chromatography, and salt formation.
• condensation agents which are suitable for the cyclisation in accordance with Bischler-Napieralski, are polyphosphoric acid, phosphorus pentachloride, aluminium chloride, and zinc chloride. These may be used as condensation agents in place of phosphorus oxychloride and/or phosphorus pentoxide.
• a third centre of asymmetry is formed in the 6 position of the ring structure, so that the corresponding 1,2,3,4,4a,5,6,lb-octahydrobenzo [c] [l,6]naphthyridine derivatives may exist in 4 racemic forms, namely 2 racemates of the A series and 2 racemates of the B series.
• the reduction of the double bond in the 5-6 position is, however, governed by stereometric factors, and for this reason only one of the two possible racemic forms, or an isomer mixture in which one of the two racemic predominates, is obtained.
• the reduction may be effected by catalytic hydrogenation, e.g. in the presence of platinum, palladium, or Raney nickel, in a lower alkanol, e.g. ethanol, at room temperature and at a normal or elevated pressure.
• catalytic hydrogenation e.g. in the presence of platinum, palladium, or Raney nickel
• a lower alkanol e.g. ethanol
• hydrogenation may be stopped after one mol of hydrogen has been taken up, i.e. after saturation of the double bond in the 5-6 position and before the benzyl radical has been affected.
• the octahydro compounds are obtained by filtering off the catalyst, evaporating the filtrate to dryness, and purifying the crude residue in manner known per se.
• a complex alkali metal hydride e.g. sodium borohydride in methanol or lithiumaluminium hydride in ether, tetrahydrofuran, dioxane or 1,2-dirnethoxy ethane may also be used as reducing agents.
• the reduction products are isolated by dividing between water and a water-immiscible organic solvent, e.g. benzene, and are subsequently purified in manner known per se.
• nascent hydrogen may also be used for the reduction.
• the hexahydrobenzo[c][l,6] naphthyridine derivatives may be treated with metallic zinc or tin in an aqueous acid, with metallic sodium in a lower alkanol, or with sodium amalgam in water.
• Compounds of Formula I which have a hydroxy radical in the 8 and 9 position, are produced by subjecting the corresponding 8,9-dialkoxyor 8,9-methylenedioxy derivatives of the 1,2,3,4,4a,10b-hexahydro or 1,2,3,4,4a,5,6,l0boctahydro series to an acid ether splitting, preferably by boiling for 1 to 5 hours with an approximately 50% aqueous hydrogen bromide solution. After the reaction has been completed, the mixture is allowed to cool, is then evaporated to dryness in a vacuum, and the 8,9- dihydroxy compounds obtained as residue are purified in manner known per se.
• the final products of Formula I are obtained as mixtures of two to four racemates. These racemates may optionally be separated in known manner, such as by chromatography or by fractional crystallization.
• the individual uniform racemates may subsequently be separated into their optically active antipodes.
• the racemates may be reacted with optically active acids, such as d-tartaric acid, l-malic acid, or dor l-mandelic acid.
• optically active acids such as d-tartaric acid, l-malic acid, or dor l-mandelic acid.
• the resulting diastereoisomeric salts may then be separated by fractional crystallization and, if desired, the resulting optically active bases may again be liberated from the corresponding salts with an alkali.
• the final products of Formula I in the form of mixtures of isomers, sterically uniform racemates, or pure optically active compounds, may be converted to the corresponding salts by reaction with inorganic or organic acids.
• salts for acid addition salt formation are hydrochloric, hydrobromic, sulphuric, maleic, fumaric, malic, tartaric, benzoic, methanesulphonic, p-toluenesulphonic or cyclohexylsulphamic acid.
• piperidylamines of Formula III which, except for the two isomeric l-methyl-3-phenyl-4-piperidylamines, have hitherto not been described in the literature may, for example, be produced as follows:
• YCH --CH COOR VIII in which Y signifies chlorine or bromine
• R signifies lower alkyl
• the resulting compounds of Formulae IX and IXa are cyclized by heating with a strong basic condensation agent, e.g. sodium hydride in toluene.
• a strong basic condensation agent e.g. sodium hydride in toluene.
• the resulting products are converted by hydrolysis and decorboxylation into the corresponding piperidones of Formula XI,
• R and the two R have the above significance, e.g. by heating in an aqueous mineral acid, such as concentrated hydrochloric acid.
• 3-(3,4-dimethoxyphenyl) 1 methyl-4-piperidonef 1- methyl-3-(3,4-methylenedioxyphenyl) -4 piperidone and 1-benzyl-3-(3,4-dimethoxyphenyl)-4-piperidone are especially useful; these hitherto unknown compounds may be widely used as intermediates for the synthesis of a variety of organic compounds, especially pharmaceuticals.
• the piperidones XI are catalytically hydro genated in the presence of ammonia, e.g. in a solution of ammonia in ethanol at 60 C. and 51 atmospheres in the presence of Raney nickel.
• the resulting imine intermediates are reduced in situ to the corresponding piperidylamines of Formula III.
• a benzyl radical is present, reduction conditions are used which do not affect this radical.
• a suitable average daily dose is 0.07 to 7 mg./kg. body weight of warm-blooded animal.
• the compounds of the invention or their water-soluble, physiologically tolerable acid addition salts may be used as pharmaceuticals on their own or in the form of appropriate medicinal preparations, e.g. tablets, drages, suppositories and injectable solutions, for administration, e.g. enterally or parenterally.
• appropriate medicinal preparations e.g. tablets, drages, suppositories and injectable solutions
• for administration e.g. enterally or parenterally.
• inorganic or organic adjuvants which are physiologically inert, e.g.
• the preparations may also contain suit-
• the reductions described above usually give mixtures of the two possible racemic forms of the piperidylamines III, the percentage compositions of which may vary depending on the reduction conditions. If desired, the resulting mixtures are separated, e.g. by fractional crystallization of their acid addition salts, into the individual racements, and these are then optionally separated into their optically active components in manner known er se.
• the naphthyridine derivatives of Formula I have hitherto not been described in the literature.
• the crystalline residue is recrystallized from methanol/ ethanol, whereby pure 8,9-dimethoxy-6-(2,2-diphenylethyl)-l,2,3,4,4a,10b hexahydro-Z-methylbenzo[c][1,6] naphthyridine (Isomer A as racemate), having a melting point of 189-191", is obtained.
• the dihydrochloride has a melting point of 241-243" (decomposition) after crystallization from ethanol.
• the starting material may be produced as follows:
• Cooling is subsequently effected to 45, 1230 ml. of 4 N sulphuric acid are sub sequently allowed to flow in during the course of 3 minutes at a temperature of -10 and 0.5 g. of hydroquinone are subsequently added.
• 400 g. of a Formalin solution (36% formaldehyde in water) are allowed to flow into the above reaction mixture while stirring and 1280 ml. of a saturated aqueous potassium carbonate solution are subsequently added dropwise during the course of 1 hour.
• the mixture is stirred at room temperature for 2 /2 hours and a further 200 g. of Formalin solution are subsequently added.
• the reaction mixture is stirred at room temperature overnight and subsequently diluted with 4000 ml. of water.
• the toluene layer is separated, washed once with water, dried over sodium sulphate and concentrated by evaporation in a vacuum after the addition of 0.5 g. of hydroquinone.
• the residue is distilled in a high vacuum, whereby decomposition initially sets in; the relatively unstable 2-(3,4-dimethoxyphenyl) acrylic acid ethyl ester distills over at 135-140/0.06 mm. of Hg as a yellow viscous oil and is further worked up without delay.
• Heating is eflected to 80 and after the reaction has commenced a further 1000 g. of the above reaction mixture are added dropwise during the course of 2 hours.
• the mixture is subsequently heated to the boil at reflux for 4 hours, is cooled to -l, 376 ml. of glacial acetic acid are carefully added and 340 ml. of water are allowed to flow in while stirring well; a crystalline precipitate gradually results which is separated by filtration.
• Most of the toluene is removed from the filtrate in a vacuum and a solution of hydrogen chloride in ethanol is added while stirring and cooling until an acid reaction to Congo red is obtained. 2500 ml. of ether are added, the mixture is allowed to stand in a refrigerator overnight and the resulting precipitate is filtered oif.
• the resulting -ethoxycarbonyl- 3-(3,4-dimethoxyphenyl)-1-methyl-4 piperidone hydrochloride as a melting point of 190192 (decomposition).
• Isomer A dihydrochloride: M.P. 321 (decomposition) after crystallization from ethanol.
• Free base B.P. /0.04 mm. of Hg; M.P. 7880 (from ethyl acetate/ petroleum ether).
• Isomer B dihydrochloride: M.P. 280 (decomposition) after crystallization from 90% ethanol. Free base: 546/ 0.09 mm. of Hg; M.P. of the solidified material Mixed M.P. of the isomers A and B 6674.
• Dihydrochloride M.P. 226-228 (decomposition) after crystallization from ethanol; contains about 1.5 Inols of water of crystallization.
• the starting material may be' produced as follows:
• the free base is obtained therefrom by adding potassium carbonate to the aqueous solution of the hydrochlo ride and extracting with chloroform.
• the base has a M.P. of l69170 (from ethyl acetate).
• EXAMPLE 4 8,9 dimethoxy 6 (2,2 diphenylethyl) 2 methyl-1,2, 3,4,4a,5,6,10b octahydrobenzo[c] [1,61naphthyridine (isomer B) -25 g. of 8,9-dimethoxy-6-(2,2-diphenylethyl)-l,2,3,4, 4a,10b-hexahydro-2 methylbenzo[c][1,6]naphthyridine (isomer B as racemate, production see Example 3) are hydrogenated in the presence of 1 g. of a platinum catalyst in 400 ml. of ethanol at normal pressure and room temperature.
• the fumarate has a M.P. of 249 (decomposition) after crystallization from methanol/water.
• the catalyst is filtered off, the filtrate is evaporated to dryness and the 6-(2,2-diphenylethyl)-2-methyl-1,2,3,4, 421,5,6,10b-octahydrobenzo[c] [l,6]naphthyridine (isomer A as racemate), obtained as residue, is converted into its dihydrochloride with 73 ml. of 1 N hydrochloric acid; M.P. 224 (decomposition), after crystallization from ethanol.
• octahydrobenzo[c] [l,6]naphthyridine (isomer B as racemate) 3.0 g. of 4-(3,3-diphenylpropionylamino)-1-methyl-3- phenylpiperidine (isomer B as racemate, M.P. 166168) are heated to the boil at reflux with 25 ml. of phosphorus oxychloride and 6 g. of phosphorus pentoxide while stirring for 1 hour. The excess phosphorus oxychloride is subsequently evaporated, the residue is dissolved in water while cooling, a concentrated sodium hydroxide solution is added until an alkaline reaction is obtained and the oil which separates is extracted With benzene.
• the separated benzene layer is dried over sodium sulphate and concentrated by evaporation.
• the base obtained as residue is taken up in ether and converted into its hydrobromide by passing gaseous hydrogen bromide through the solution; the hydrobromide precipitates and is filtered off.
• the resulting hydrobromide is taken up in water, the base is again liberated by the addition of a saturated aqueous potassium carbonate solution and extraction is effected with chloroform; the chloroform layer is separated, dried over sodium sulphate and concentrated by evaporation.
• the residue is taken up in 40 ml. of ethanol and hydrogenation is effected in the presence of 300 mg. of a platinum catalyst at normal pressure and room temperature.
• the catalyst is filtered off, the filtrate is concentrated by evaporation, the residue is dissolved in 4 ml. of 1 N hydrochloric acid While heating and the solution is allow to cool, wherebythe dihydrochloride of the compound indicated in the heading crystallizes. It persistently retains about 1.5 mols of water of crystallization upon drying (conditions of drying 16 hours); M.P. 225-275 (decomposition, sintering over 214).
• the monohydrochloride has a M.P. of 258-260.
• EXAMPLE 8 6 (2,2-diphenylethyl)-1,2,3,4,4a,10b-hexahydro-2-methyl 8,9 methylene-dioxybenzo[c][1,6]naphthyridine (isomer A) 5.8 g. of 4-(3,3-diphenylpropionylamino)-1-methyl-3- (3,4-methylene-dioxyphenyl)piperidine (isomer A as racemate) are dissolved in 50 ml. of benzene and 4.0 g. of phosphorus oxychloride are added. The mixture is heated to the boil at reflux for 4 hours, the benzene and excess phosphorus oxychloride are subsequently evaporated, 25 ml.
• the starting material may, for example, be produced as follows:
• the residue is distilled in a high vacuum, whereby decomposition initially occurs; the relatively unstable 2-(3,4-lrnethylene-dioxyphenyl) acrylic acid ethyl ester distills over at 114/ 0.02 mm. of Hg as a yellow, viscous oil and is furhter worked up without delay.
• the oxime is precipitated by the addition of a saturated aqueous potassium carbonate solution and extraction is eflected with chloroform.
• the chloroform layer is separated, dried over sodium sulphate and concentrated by evaporation; the compound indicated in the heading results as a viscous oil which crystallizes and which has a melting point of 153-155 after crystallization from ethyl acetate.
• the distillate which is a yellow, viscous oil and consists of a mixture of the isomers A and B (racemates) of the compound indicated in the heading, is chromatographed on 550 g. of neutral aluminium oxide.
• the isomer A is eluted with benzene/ether 1:1, the isomer B with ether/chloroform 1:1.
• Isomer A MP. of the dihydrochloride 292-297" (decomposition), after crystallization from methanol.
• Isomer B MP. of the dihydrochloride 307309 (decomposition), after crystallization from ethanol.
• EXAMPLE 9 6 (2,2 diphenylethyl) 2 methyl 8,9 methylenedioxy 1,2,3,4,4a,5,6,l0b-octahydrobenzo[c] [l,6]naphthyridine (isomer A) 2.3 g. of 6-(2,2-diphenylethyl)-1,2,3,4,4a,10b-hexahydro 2 methyl 8,9 methylene-dioxybenzo[c][1,6] naphthyridine (isomer A as racemate, production see Example 8) are dissolved in ml. of ethanol and hydrogenation is effected in the presence of 100 mg. of a platinum catalyst at normal pressure and room temperature.
• the catalyst is filtered ofi, the filtrate is concentrated by evaporation and the 6-(2,2-diphenylethyl)-2- methyl 8,9 methylene-dioxybenzoIc] [l,6]napl1thyridrobenzo[c][1,6]naphthyridine (isomer A as racemate) obtained as residue is converted into its dihydrochloride by the addition of a 3 N solution of hydrogen chloride in ethanol; the dihydrochloride has a M.P. of 262 with decomposition (slightly hygroscopic), after crystallization from methanol.
• EXAMPLE 10 6 (2,2 diphenylethyl) 1,2,3,4,4a,lb hexahydro 2- methyl -8,9 methylene-dioxybenzo[c][1,6]naphthyridine (isomer B) 3.0 g. of 4-(3,3-diphenylpropionylarnino)-1-methyl-3- (3,4-methylene-dioxyphenyl)piperidine (isomer B as racemate), which have been dissolved in 50 ml. of benzene, are heated to the boil at reflux with 3.0 g. of phosphorus oxychloride for 4 hours. The benzene and excess phosphorus oxychloride are subsequently evaporated, 25 ml.
• the starting material may, for example, be produced as follows:
• the free base is produced by dissolving the hydrochloride obtained above in water, adding a saturated aqueous potassium carbonate solution and extracting with chloroform. The organic phase is washed with a saturated aqueous sodium chloride solution, is dried over sodium sulphate and concentrated by evaporation; the crude base has a M.P. of 181 and is further worked up without purification.
• the dihydrochloride has a melting point of 250 with decomposition after crystallization from methanol.
• EXAMPLE 12 8,9-dihydroxy-6-(2,2-diphenylethyl) 1,2,3,4,4a,10b-hexahydro 2 methylbenzo[c] [l,6]naphthyridine (isomer A as racemate) 20.4 g. of 8,9-dimethoxy 6-(2,2-diphenylethyl)-l,2,3,4, 4a,l0b-hexahydro 2 methylbenzo [0] [1,6] naphthyridine (isomer A as" racemate, having a melting point of 189- l91, production see Example 1), are heated to the boil at reflux in 250 ml.
• EXAMPLE 14 2 benzyl 8,9 dimethoxy-6-(2,2-diphenylethyl)-1,2,3, 4,4a,10b hexahydrobenzo[c][1,6]naphthyridine (isomer A) 12.7 g. of 1-benzyl-3-(3,4-dimethoxyphenyl)-4-(3,3-diphenylpropionylamino)piperidine (isomer A as racemate) are dissolved in 60 ml. of benzene and heated to the boil at reflux with 6.8 g. of phosphorus oxychloride for 1 /2 hours, whereby after 15 minutes the solution becomes turbid and an oil starts to precipitate.
• the starting material may be produced as follows:
• the mixture is stirred at room temperaturefor 40 hours, the precipitate is filtered off, the filtrate is concentrated by evaporation and the evaporation residue is divided between benzene and water.
• the organic phase is separated, dried over sodium sulphate and concentrated by evaporation; the residue is dried in a high vacuum at 100 for 4 hours and is worked up as crude product.
• the resulting compound may be converted into its oxime, in a manner analogous to that described in Example 1 section ((1); after crystallization from ethanol the oxime has a melting point of 133-134"; the monohydrochloride of the oxime has a melting point of 223 with decomposition (after crystallization from ethanol/ ether) (b) 1-benzyl-3-(3,4-dimethoxyphenyl)-4-piperidylamine (isomer A) 2.5 l. of ethanol are mixed with 1.5 1. of liquid ammonia while cooling with chloroform/Dry Ice. 490 g.
• EXAMPLE 16 Galenical preparation tablets 1 Corresponds to 50 mg. of the free base.
• each of the twosymbols R are hydrogen, hydroxy or lower alkoxy, or the symbols R are together methylenedioxy, and each of the two symbols X is hydrogen, or the symbols X together are a second bond,

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