US3503981A - Hydro benzo(c)(1,6)naphthyridines - Google Patents
Hydro benzo(c)(1,6)naphthyridines Download PDFInfo
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- US3503981A US3503981A US672972A US3503981DA US3503981A US 3503981 A US3503981 A US 3503981A US 672972 A US672972 A US 672972A US 3503981D A US3503981D A US 3503981DA US 3503981 A US3503981 A US 3503981A
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
Definitions
- Patented Mar. 31, 1970 The present invention further provides processes for 3,503,981 the production of compounds I and their acid addition HYDRO BENZO[c][1,6]NAPHTI -IYRIDINES Salts, characterized in that Rudolf Siiess, Bettingen, and Adolf Llndenmann, Basel, (a) A com ound of Formula Ia Switzerland, assignors to Sandoz Ltd. (also known as P Sandoz A.G.), Basel, Switzerland 5 R: No Drawing. Filed on. s, 1967, Ser. No. 672,972 1 Claims priority, application Switzerland, Oct. 7, 1966,
- the invention provides a naphthyridine derivative of (Ia) formula: in which R R and the two symbols R have the above R1 significance, is produced by cyclizing a compound of Formula II, /I; R1 H 1 3 10a H R3 8 ⁇ 7 6a 5N ⁇ Rs ⁇ / ⁇ g/ ⁇ X H n N R NH 00 wherein R is lower alkyl of 1 to 3 carbon atoms, R is (H) hydrogen or methyl, each of the two symbols R is lower alkoxy of 1 to 4 carbon atoms, or together the two symin which R R and the two symbols R have the above bols R are methylenedioxy, and each of the two symbols significance, by treating with an acid water-
- the compounds and their pharmaceutically acceptable R1 salts are indicated for use in medicaments, especially in 1 the treatment of pains of various origins. 1
- the present invention relates to new heterocyclic com- R pounds and processes for their production.
- the present invention provides naphthyridine deriva- R; NH tives of Formula I,
- R2 Ib) I in which R R and the two symbols R have the above significance, is produced by reducing the double bond in the 5-6 position of the above compound of Formula Ia; or
- a compound of the above Formula Ib is produced R3 by reacting, under acid conditions, a piperidylamine of 9 6g Formula HI, g 3% R1 R2 X (I) in which:
- R signifies a lower alkyl radical of 1-3 carbon atoms
- R3 R signifies a hydrogen atom or a methyl radical
- each of the two symbols R signifies a lower alkoxy radical of l-4 carbon atoms
- (III) or together the two symbols R signifies methylenedioxy
- each of the two symbols 3 Whlch R1 the two symbols R3 have the above X signifies a hydrogen atom, or together the two symbols mficance Wlth an aldehyde of ula R CHO, or
- X signifies a second bond between the carbon and the niwith a reactive functional derivative thereof, in which R trogen atom, has the above significance; and where an acid addition salt is required, salification is efiected.
- amides of Formula II used as starting materials have hitherto not been described in the literature, and form part of the present invention. They may be obtained by formylation or acetylation of piperidylamines of Formula III.
- Formylation may be effected by heating the piperidylamines of Formula III with formamide, formic acid or a lower alkyl ester of formic acid, or by reacting at room temperature with a mixture of formic acid and acetic anhydride.
- cis-3-(3,4-di-methoxyphenyl)-1- methyl-4-piperidylamine is heated to 100130 C. for 4 hours in an atmosphere of nitrogen with an excess of formamide, the cooled reaction mixture is diluted with water and extraction is effected several times with a Water-immiscible organic solvent, e.g. chloroform; the combined organic phases are subsequently washed with a saturated aqueous sodium chloride solution, are dried, e.g. over sodium sulphate, and concentrated by evaporation, whereby crude cis-3-(3,4-dimethoxyphenyl) 4 formylamino-l-methylpiperidine is obtained as residue.
- the acetylation of the piperidylamines of Formula III is preferably effected by reacting with acetic anhydride or acetyl chloride.
- an acid-binding agent e.g. a tertiary organic base such as pyridine
- a small excess, e.g. 1.2 to 2 mols, of acetic anhydride is added, for example, to cis-3-(3,4-dimethoxyphenyl)-1-methyl-4piperidylamine in an organic solvent which is inert under the reaction conditions, e.g.
- the mixture is stirred for 1 to 3 hours at room temperature, is subsequently heated to the boil under reflux for a short time, e.g. half an hour, and the resulting cis-4-acetylamino-3- (3,4-dimethoxyphenyl)-1-methylpiperidine is isolated by the addition of water and an alkali, e.g. potassium carbonate, and subsequent extraction with a water-immiscible organic solvent, e.g. chloroform.
- an alkali e.g. potassium carbonate
- the amides of Formula II have cis substituents in the positions 3 and 4 of the piperidine ring, as do the piperidylamines of Formula III, and may be obtained as cis racemates or as optically uniform cis compounds. A splitting of the cis racemates into their optical antipodes is possible in the amide and in the amine stage.
- the piperidylamines of Formula III are preferably used as cis racemates, whereby the amides of Formula II are also obtained as cis racemates.
- the ring closure reaction which is 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 in the position 4a and b (ring linkage) of the resulting 1,2,3,4,4a,10b-hexahydrobenzo [c][l,6]naphthyridine derivatives of Formula Ia corresponds to that of the starting materials. Cis racemates or optically uniform cis compounds are thus obtained, depending on the composition of the starting materials.
- Cyclization is effected by heating the amides of Formula II to the boil under reflux with phosphorus oxychloride and/or phosphorus pentoxide in an organic solvent which is inert under the reaction conditions, e.g. chloroform, benzene, toluene, xylene or tetraline, for some time, e.g. 3 to 10 hours.
- an organic solvent which is inert under the reaction conditions, e.g. chloroform, benzene, toluene, xylene or tetraline
- the ring closure is effected in an excess of boiling phosphorus oxychloride or in a mixture of phosphorus pentoxide and boiling phosphorus oxychloride
- cis-3-(3,4-dimethoxyphenyl)-4-formylamino-l-methylpiperidine is heated to the boil under reflux with an excess of phosphorus oxychloride in chloroform for about 1 hour, the liquid is decanted from the resulting precipitate after cooling the reaction mixture, the residue is taken up in water, and the resulting solution is heated on a boiling water bath for some time, e.g.
- reagents which are suitable for the cyclization of the invention in accordance with Bischler-Napieralski preferably polyphosphoric acid, phosphorus pentachloride, aluminium chloride or zinc chloride, may likewise be used as condensation agents in place of phosphorus oxychloride and/or phosphorus pentoxide.
- the 1,2,3,4,4a,10b-hexahydrobenzo [0] [1,6] naphthyridine derivatives obtained as cyclization products in accordance with the process described above have the Formula Ia; if desired, they may be reduced to the corresponding 1,2,3,4,4a,5,6,10b octahydrobenzo [c][l,61 naphthyridine derivatives.
- This 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 normal pressure or at an elevated pressure.
- hexahydrobenzo[c] [1,6] naphthyridine derivatives to be reduced may be used as free bases or in the form of their salts, e.g. hydrochlorides.
- Working up is effected by filtering off the catalyst, evaporating the filtrate to dryness and purifying the crude octayhdro compounds obtained as residue in manner known per se.
- R in the 1,2,3,4,4a,10b-hexahydrobenzo [c] [1,6]naphthyridine derivatives of Formula Ia used signifies the methyl radical
- a center of asymmetry is formed in the 6-position of the ring structure upon reduction, so that the resulting 6-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[c][1,6]naphthyridine derivatives may be obtained in two racemates or in two (optically active) epimeric forms.
- the reduction of the double bond in the position 56 mostly occurs stereospecifically and therefore usually only yields one of the two possible racemates (or epimers), or a mixture, in which one of the two racemates (or epimers) predominates.
- 1,2,3,4,4a,5,6,10b octahydrobenzo[c][1,6]naphthyridine derivatives of Formula Ib may also be produced in accordance with the known method of Pictet and Spengler.
- a piperidylamine of Formula III is reacted with formaldehyde or acetaldehyde or with a reactive functional derivative of these aldehydes, e.g.
- the amine of Formula III is heated, for example, with an excess (10 to of acetaldehyde or formaldehyde, e.g. with an aqueous formaldehyde solution, to 100 C. for 15 to 60 minutes.
- An excess (about 1.1 mols) of hydrochloric acid, of an aqueous hydrogen bromide solution or dilute sulphuric acid, is added to the reaction mixture and heating to the boil under reflux is subsequently effected for minutes to 8 hours.
- the resulting octahydrobenzo[c] [l,6]naphthyridine derivatives of Formula Ib may be isolated in the form of their salts or may be liberated from the reaction solution with an alkali, e.g. by the addition of an aqueous potassium carbonate solution.
- the piperidylamine of Formula III as free base or in the form of a salt, e.g. the hydrochloride, is heated to about 100 with formaldehyde or acetaldehyde and an acid, e.g. dilute hydrochloric acid, for 1 to 3 hours.
- a salt e.g. the hydrochloride
- an acid e.g. dilute hydrochloric acid
- 1,2,3,4,4a,5,6,10boctahydrobenzo [c] [1,6] naphthyridine derivatives having a methyl radical in the 6 position may be obtained as mixtures of two racemates or of two (optically active) epimers, in accordance with process (a) and in accordance with process (b). These mixtures may optionally be separated in known manner, e.g. by chromatography or fractional crystallization.
- racemate which may result may optionally be separated into its optically active components.
- the racemate is treated with an optically active acid, e.g. d-tartaric acid, l-malic acid, dor l-mandelic acid, the resulting diastereoisomeric salts are separated by fractional crystallization and the bases are optionally liberated from the resulting optically uniform salts with an alkali.
- an optically active acid e.g. d-tartaric acid, l-malic acid, dor l-mandelic acid
- the resulting diastereoisomeric salts are separated by fractional crystallization and the bases are optionally liberated from the resulting optically uniform salts with an alkali.
- the final products of Formula I may subsequently be converted with inorganic or organic acids into the corresponding salts.
- acids for acid addition formation are hydrochloric, hydrobromic, sulphuric, maleic, fumaric, malic, tartaric, benzoic, methanesulphonic, ptoluenesulphonic and cyclohexylsulphamic acid.
- Piperidylamines of Formula III may, for example, be produced as follows:
- phenylacrylic acid ester of Formula VI is condensed with an amine of formula R NH in which R in which R the two R R and R have the above significance, is obtained.
- Compounds of Formula VIII may also be obtained by reacting a phenylacrylic acid ester of the above Formula VI with an amino acid ester of Formula IX,
- the compounds of Formula VIII are cyclized by heating with a strong basic condensation agent, e.g. sodium hydride in toluene; the resulting products are converted by hydrolysis and decarboxylation into the corresponding piperidones of Formula X,
- R and the two R have the above significance, e.g. by heating in an aqueous mineral acid, for example 3-6 N hydrochloric acid.
- the piperidones of Formula X are reacted with hydroxylamine hydrochloride and the resulting oximes are reduced to the corresponding piperidylamines, e.g. by hydrogenation over a metal catalyst, e.g. Raney nickel, by reaction with complex alkali metal hydrides, e.g. lithium aluminium hydride or sodium borohydride, or with metallic sodium in a lower alkanol.
- a metal catalyst e.g. Raney nickel
- complex alkali metal hydrides e.g. lithium aluminium hydride or sodium borohydride
- metallic sodium metallic sodium in a lower alkanol.
- the piperidones X are hydrogenated catalytically in the presence of ammonia, e.g.
- the aboveindicated reductions generally yield mixtures of the two possible racemates, the composition in percentages of which may vary depending on the reduction conditions.
- the cis-piperidylamines of Formula III are separated from these mixtures as racemates in manner known per se, e.g. by fractional crystallization of their acid addition salts or by adsorption chromatography; the resulting cis racemates are optionally separated into their optically active components in manner known per se.
- the compounds of Formula I and their acid addition salts have hitherto not been described in the literature. These compounds and their pharmaceutically acceptable salts exhibit therapeutically useful pharmacodynamic properties. Thus, for instance, in the well known hotplate test carried out with mice, the compounds are shown to exhibit pronounced analgesic effects. For example, the compound 8,9 dimethoxy-2-methyl-l,2,3,4,4a,5,6,l0boctahydrobenzo[c] [1,6]-naphthyridine, such as in the form of its bis-(hydrogen maleinate), administered p.o., is particularly eflective in this test. Compounds of Formula I and their pharmaceutically acceptable salts are therefore indicated for use in medicaments, especially in the treatment of pains of various origins. A suitable average daily dose amounts to from 1 to mg./ kg. body weight of warm-blooded animals, such as primates.
- the compounds of Formula I and their pharmaceutically acceptable acid addition salts are of a low toxicity.
- the compounds I and their pharmaceutically acceptable salts may thus be administered at the daily dosages indicated.
- the compounds of the invention or their water-soluble physiologically tolerated acid addition salts may be used as pharmaceuticals on their own or in the form of appropriate medicinal preparations, e.g. tablets, drages, suppositories, injectable solutions, for administration, e.g. ente'rally or parenterally.
- appropriate medicinal preparations e.g. tablets, drages, suppositories, injectable solutions, for administration, e.g. ente'rally or parenterally.
- pharmacologically inert adjuvants e.g. lactose, starch, talcum, stearic acid, water, alcohols, glycerin, natural or hardened oils or waxes
- these preparations may also contain suitable preserving, stabilizing or wetting agents, solubilizers, sweetening or colouring substances and fiavourings.
- the starting material may be produced as follows:
- Cooling is subsequently effected to -45, 1230 cc. of 4 N sulphuric acid are subsequently allowed to flow in. at a temperature of 10 during the course of 3 hours and 0.5 g. of hydroquinone are subsequently added.
- the residue is distilled in a high vacuum, whereby decomposition initially occurs; the relatively unstable 2-(3,4-dimethoxyphenyl)acrylic acid ethyl ester distills over at 140/0.06 mm. of Hg as a yellow viscous oil and is further worked up without delay.
- EXAMPLE 2 8,9-dimethoxy-2,6-dimethyl-1,2,3,4,4a,5,6,10boctahydrobenzo[c] 1,6]naphthyridine
- 20.0 g. of 8,9-dimethoxy-2,6-dimethyl-l,2,3,4,4a,10bhexahydrobenzo[c][1,6]naphthyridine (racemate, production see Example 1) are dissolved in 250 cc. of ethanol and shaken with hydrogen over 0.5 g. of a platinum catalyst at normal pressure and room temperature. After the calculated molar amount of hydrogen has been taken up, the catalyst is filtered off, the filtrate is concentrated by evaporation, 80 cc.
- 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-methylenedioxyphenyl)acrylic acid ethyl ester distils over at 114/0.02 mm. of Hg as a yellow, viscous oil and is further worked up without delay.
- the oxime is precipitated 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 compound indicated in the heading is obtained as a viscous oil which crystallizes and which has a M.P. of 153-155 after crystallization from ethyl acetate.
- the distillate which is a yellow, viscous oil and which consists of a mixture of cis and trans isomers (racemates) of the compound indicated in the heading, is chromatographed on 550 g. of neutral aluminium oxide.
- the cis isomer is eluted wtih benzene/ether (1:1); the dihydrochloride has a M.P. of 292297 (decomp.) after crystallization from methanol.
- the trans isomer is eluted with ether/chloroform (1:1); the dihydrochloride has a M.P. of 307-309 (decomp.) after crystallization from ethanol.
- Cis-4-acetylamino-1-methy1-3- 3,4-methylenedioxyphenyl) piperidine 2.8 g. of cis-1-methyl-3-(3,4-methylenedioxyphenyl)-4- piperidylamine (racemate) are dissolved in 10 cc. of chloroform and 1.9 g. of acetic anhydride are added while cooling with ice. The mixture is heated to the boil at reflux for 1 hour, is then cooled, diluted with chloroform and shaken out with 20 cc. of a saturated aqueous potassium carbonate solution. The chloroform layer is washed with a saturated aqueous sodium chloride solution, is dried over sodium sulphate .and concentrated by evaporation. The compound indicated in the heading is obtained as residue and is further worked up as crude product without previous purification.
- EXAMPLE 5 8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-2- methylbenzo [c] 1,6 naphthyridine 43.0 g. of phosphorus oxychloride are added to a solution of 31.0 g. of cis-3-(3,4-dimethoxyphenyl)-4-formylamino-l-methylpiperidine (racemate as crude product) in 500 cc. of chloroform, and heating to the boil at reflux is effected for 1 hour, whereby the solution already, becomes turbid and the formation of a crystalline precipitate commences. After cooling the reaction mixture the'liquid is decanted, the residue is taken up in 100 cc.
- the starting material may, for example, be produced as follows:
- the catalyst is filtered off, the filtrate is concentrated and the small amount of precipitate which results is filtered off; a solution of 15.0 g. of maleic acid in 30 cc. of methanol is subsequently added to the filtrate, the mixture is allowed to crystallize and the precipitate is isolated by filtration.
- octahydrobenzo[c] [1,6] naphthyridine 64.6 g. of cis-3-(3,4-dimethoxyphenyl)-1-methyl-4- piperidylamine dihydrochloride (racemate, production see Example 1) are dissolved in 200 cc. of water with heating, the solution is cooled and 20 cc. of 2 N hydrochloric acid and 35.0 g. of a 35% aqueous formaldehyde solution are added. The mixture is heated on a boiling water bath for 1 hour, whereby the formation of a colourless precipitate already commences after 5 minutes.
- Cooling is eflFected and the resulting 8,9-dimethoxy- 2 methyl 1,2,3,4,4a,5,6,10b octahydrobenzo[c] [1,6]- naphthyridine dihydrochloride is filtered ofli. M.P. 343 (decomp.), dark colouration and sintering above 320; upon recrystallization from water the melting point is no longer raise'd.
- octahydrobenzo[ c] [1,6] naphthyridine 6.0 g. of cis-1-methyl-3-(3,4-methylenedioxyphenyl)- 4-piperidylarnine (racemate, production see Example 3) are dissolved in 35 cc. of 2 N hydrochloric acid and 5.0 g. of a 35% aqueous formaldehyde solution are added. The mixture is allowed to stand at room temperature for half an hour, is heated to 100 for half an hour and is subsequently evaporated to dryness. The hydrochloride of the compound indicated in the heading (racemate) obtained as residue is recrystallized from methanol and has a M.P. of 304 (decomp.).
- octahydrobenzo c] [1,6] naphthyridine 15.0 g. of cis-3-(3,4-dimethoxyphenyl)-1-methyl-4- piperidylamine (racemate, production see Example 1) are heated to 100 with 7.5 g. of acetaldehyde for half an hour. 160 cc. of N hydrochloric acid are then added, the mixture is heated to 100 for a further 8 hours and the excess aldehyde and hydrochloric acid are subsequently evaporated in a vacuum.
- a saturated aqueous potassium carbonate solution is added to the residue and extraction is effected with chloroform; the chloroform layer is washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation.
- the residue is chromatographed on 450 g. of neutral aluminum oxide. Elution with petroleum ether/ether 1:1) or ether/chloroform (1:1) yields a yellowish, viscous oil, which is taken up in ethanol.
- a solution of hydrogen chloride in ethanol is added until an acid reaction to Congo red is obtained, ether is added and the mixture is allowed to crystallize in a refrigerator.
- the precipitate is filtered oil and crystallized several times from methanol/water, whereby the dihydrochloride of the compound indicated in the heading (racemate), having a M.P. of 328 (decomp.), is obtained.
- the free base has a M.P. of 122 after crystallization from ethyl acetate.
- octahydrobenzo [c] 1,6] naphthyridine dihydrochloride compound of Example 2 1 0.0260 Magnesium stearate 0.0010 Polyvinyl pyrrolidone 0.0040 Talcum 0.0080 Maize starch 0.010 Lactose 0.1075 Dimethyl silicone oil 0.0005 Polyethylene glycol 6000 0.0030
- R is lower alkyl of 1 to 3 carbon atoms, R is hydrogen or methyl,
- each of the two symbols R is lower alkoxy of 1 to 4 carbon atoms
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
United States Patent Office 3,503,981
Patented Mar. 31, 1970 The present invention further provides processes for 3,503,981 the production of compounds I and their acid addition HYDRO BENZO[c][1,6]NAPHTI -IYRIDINES Salts, characterized in that Rudolf Siiess, Bettingen, and Adolf Llndenmann, Basel, (a) A com ound of Formula Ia Switzerland, assignors to Sandoz Ltd. (also known as P Sandoz A.G.), Basel, Switzerland 5 R: No Drawing. Filed on. s, 1967, Ser. No. 672,972 1 Claims priority, application Switzerland, Oct. 7, 1966,
14,515/66; Dec. 28, 1966, 18,628/66; May 31, 1967, 7,704/ 67; July 19, 1967, 10,252/ 67 H Int. Cl. C0711 35/10 US. Cl. 260-288 8 Claims R3 rr ABSTRACT OF THE DISCLOSURE The invention provides a naphthyridine derivative of (Ia) formula: in which R R and the two symbols R have the above R1 significance, is produced by cyclizing a compound of Formula II, /I; R1 H 1 3 10a H R3 8\ 7 6a 5N\ Rs \/\g/\ X H n N R NH 00 wherein R is lower alkyl of 1 to 3 carbon atoms, R is (H) hydrogen or methyl, each of the two symbols R is lower alkoxy of 1 to 4 carbon atoms, or together the two symin which R R and the two symbols R have the above bols R are methylenedioxy, and each of the two symbols significance, by treating with an acid water-removing con- X is hydrogen, or together the two symbols X are a secdensation agent; or 0nd bond between the carbon and the nitrogen atom, and (b) A compound of Formula Ib, a pharmaceutically acceptable acid addition salt thereof.
The compounds and their pharmaceutically acceptable R1 salts are indicated for use in medicaments, especially in 1 the treatment of pains of various origins. 1
H 40 The present invention relates to new heterocyclic com- R pounds and processes for their production.
The present invention provides naphthyridine deriva- R; NH tives of Formula I,
R2 Ib) I in which R R and the two symbols R have the above significance, is produced by reducing the double bond in the 5-6 position of the above compound of Formula Ia; or
4&4 (c) A compound of the above Formula Ib is produced R3 by reacting, under acid conditions, a piperidylamine of 9 6g Formula HI, g 3% R1 R2 X (I) in which:
R signifies a lower alkyl radical of 1-3 carbon atoms, R3 R signifies a hydrogen atom or a methyl radical, each of the two symbols R signifies a lower alkoxy radical of l-4 carbon atoms, (III) or together the two symbols R signifies methylenedioxy, and each of the two symbols 3 Whlch R1 the two symbols R3 have the above X signifies a hydrogen atom, or together the two symbols mficance Wlth an aldehyde of ula R CHO, or
X signifies a second bond between the carbon and the niwith a reactive functional derivative thereof, in which R trogen atom, has the above significance; and where an acid addition salt is required, salification is efiected.
and their acid addition salts. Any mixtures of isomers which may result may sub- The new compounds have a benzo[c] [l,6 ]naphthyrisequently be separated into their individual racemates or dine structure, the numbering of which may be seen in epimeric for-ms, and any individual racemates which re- Formula I. There is a cis ring linkage in the positions sult may be separated into their optically active compo- 4a and 10b. nents.
The amides of Formula II used as starting materials have hitherto not been described in the literature, and form part of the present invention. They may be obtained by formylation or acetylation of piperidylamines of Formula III.
Formylation may be effected by heating the piperidylamines of Formula III with formamide, formic acid or a lower alkyl ester of formic acid, or by reacting at room temperature with a mixture of formic acid and acetic anhydride. For example, cis-3-(3,4-di-methoxyphenyl)-1- methyl-4-piperidylamine is heated to 100130 C. for 4 hours in an atmosphere of nitrogen with an excess of formamide, the cooled reaction mixture is diluted with water and extraction is effected several times with a Water-immiscible organic solvent, e.g. chloroform; the combined organic phases are subsequently washed with a saturated aqueous sodium chloride solution, are dried, e.g. over sodium sulphate, and concentrated by evaporation, whereby crude cis-3-(3,4-dimethoxyphenyl) 4 formylamino-l-methylpiperidine is obtained as residue.
The acetylation of the piperidylamines of Formula III is preferably effected by reacting with acetic anhydride or acetyl chloride. In this reaction, the presence of an acid-binding agent, e.g. a tertiary organic base such as pyridine, is advantageous but not essential. A small excess, e.g. 1.2 to 2 mols, of acetic anhydride is added, for example, to cis-3-(3,4-dimethoxyphenyl)-1-methyl-4piperidylamine in an organic solvent which is inert under the reaction conditions, e.g. chloroform, the mixture is stirred for 1 to 3 hours at room temperature, is subsequently heated to the boil under reflux for a short time, e.g. half an hour, and the resulting cis-4-acetylamino-3- (3,4-dimethoxyphenyl)-1-methylpiperidine is isolated by the addition of water and an alkali, e.g. potassium carbonate, and subsequent extraction with a water-immiscible organic solvent, e.g. chloroform.
The amides of Formula II have cis substituents in the positions 3 and 4 of the piperidine ring, as do the piperidylamines of Formula III, and may be obtained as cis racemates or as optically uniform cis compounds. A splitting of the cis racemates into their optical antipodes is possible in the amide and in the amine stage. The piperidylamines of Formula III are preferably used as cis racemates, whereby the amides of Formula II are also obtained as cis racemates. The ring closure reaction, which is 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 in the position 4a and b (ring linkage) of the resulting 1,2,3,4,4a,10b-hexahydrobenzo [c][l,6]naphthyridine derivatives of Formula Ia corresponds to that of the starting materials. Cis racemates or optically uniform cis compounds are thus obtained, depending on the composition of the starting materials.
Cyclization is effected by heating the amides of Formula II to the boil under reflux with phosphorus oxychloride and/or phosphorus pentoxide in an organic solvent which is inert under the reaction conditions, e.g. chloroform, benzene, toluene, xylene or tetraline, for some time, e.g. 3 to 10 hours. In accordance with another embodiment of the process, the ring closure is effected in an excess of boiling phosphorus oxychloride or in a mixture of phosphorus pentoxide and boiling phosphorus oxychloride For example, cis-3-(3,4-dimethoxyphenyl)-4-formylamino-l-methylpiperidine is heated to the boil under reflux with an excess of phosphorus oxychloride in chloroform for about 1 hour, the liquid is decanted from the resulting precipitate after cooling the reaction mixture, the residue is taken up in water, and the resulting solution is heated on a boiling water bath for some time, e.g. minutes; the resulting 8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-2- methylbenzo[c] [1,6Jnaphthyridin'e may be liberated from the solution with an alkali, e.g. by the addition of solid potassium carbonate.
Other reagents which are suitable for the cyclization of the invention in accordance with Bischler-Napieralski, preferably polyphosphoric acid, phosphorus pentachloride, aluminium chloride or zinc chloride, may likewise be used as condensation agents in place of phosphorus oxychloride and/or phosphorus pentoxide.
The 1,2,3,4,4a,10b-hexahydrobenzo [0] [1,6] naphthyridine derivatives obtained as cyclization products in accordance with the process described above have the Formula Ia; if desired, they may be reduced to the corresponding 1,2,3,4,4a,5,6,10b octahydrobenzo [c][l,61 naphthyridine derivatives. This 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 normal pressure or at an elevated pressure. The hexahydrobenzo[c] [1,6] naphthyridine derivatives to be reduced may be used as free bases or in the form of their salts, e.g. hydrochlorides. Working up is effected by filtering off the catalyst, evaporating the filtrate to dryness and purifying the crude octayhdro compounds obtained as residue in manner known per se.
In accordance with another embodiment of the process a complex alkali metal hydride, e.g. sodium borohydride in methanol or lithium aluminium hydride in ether, tetrahydrofuran, dioxane or dimethoxyethane, is used as reducing agent. In this case, after decomposing the excess reducing agent and the resulting complex by shaking out with water and a water-immiscible organic olvent, e.g. benzene, the reduction products are isolated and subsequently purified in manner known per se.
Nascent hydrogen may also be used for reduction, in which case the hexahydrobenzo[c][1,6]naphthyridine derivative is treated, for example, with metallic zinc or tin in an aqueous acid, with metallic sodium in a lower alkanol or with sodium amalgam in water.
When R in the 1,2,3,4,4a,10b-hexahydrobenzo [c] [1,6]naphthyridine derivatives of Formula Ia used signifies the methyl radical, a center of asymmetry is formed in the 6-position of the ring structure upon reduction, so that the resulting 6-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[c][1,6]naphthyridine derivatives may be obtained in two racemates or in two (optically active) epimeric forms. The reduction of the double bond in the position 56, however, mostly occurs stereospecifically and therefore usually only yields one of the two possible racemates (or epimers), or a mixture, in which one of the two racemates (or epimers) predominates.
1,2,3,4,4a,5,6,10b octahydrobenzo[c][1,6]naphthyridine derivatives of Formula Ib may also be produced in accordance with the known method of Pictet and Spengler. A piperidylamine of Formula III is reacted with formaldehyde or acetaldehyde or with a reactive functional derivative of these aldehydes, e.g. methylal, under acid conditions, where-by the steric arrangement of the substituents on the piperidine ring is not altered, as is the case in the ring closure in accordance with Bischler- Napieralski described in section (a), so that the stereochemistry in the position 4a and 10b (ring linkage) of the resulting octahydrobenzo [c] 1,6]naphthyridine derivatives of Formula Ib correspond to that of the starting materials III; the compounds III are preferably used as cis racemates. When the ring closure is effected with acetaldehyde, compounds of Formula Ib are obtained, in which R signifies methyl, and which have a center of asymmetry in the 6 position of the ring structure and therefore may be obtained in two racemates or two (optically active) epimers. A mixture of isomers is usually obtained, in which one of the two racemates (or epimers) predominates.
The amine of Formula III is heated, for example, with an excess (10 to of acetaldehyde or formaldehyde, e.g. with an aqueous formaldehyde solution, to 100 C. for 15 to 60 minutes. An excess (about 1.1 mols) of hydrochloric acid, of an aqueous hydrogen bromide solution or dilute sulphuric acid, is added to the reaction mixture and heating to the boil under reflux is subsequently effected for minutes to 8 hours. The resulting octahydrobenzo[c] [l,6]naphthyridine derivatives of Formula Ib may be isolated in the form of their salts or may be liberated from the reaction solution with an alkali, e.g. by the addition of an aqueous potassium carbonate solution.
In accordance with another embodiment of the process the piperidylamine of Formula III, as free base or in the form of a salt, e.g. the hydrochloride, is heated to about 100 with formaldehyde or acetaldehyde and an acid, e.g. dilute hydrochloric acid, for 1 to 3 hours. The isolation of the resulting 1,2,3,4,4a,5,6,lOb-octahydrobenzo[c] [l,6]naphthyridine derivatives of Formula Ib is effected as described above.
As has already been indicated above, 1,2,3,4,4a,5,6,10boctahydrobenzo [c] [1,6] naphthyridine derivatives having a methyl radical in the 6 position may be obtained as mixtures of two racemates or of two (optically active) epimers, in accordance with process (a) and in accordance with process (b). These mixtures may optionally be separated in known manner, e.g. by chromatography or fractional crystallization.
Any individual racemate which may result may optionally be separated into its optically active components. For this purpose the racemate is treated with an optically active acid, e.g. d-tartaric acid, l-malic acid, dor l-mandelic acid, the resulting diastereoisomeric salts are separated by fractional crystallization and the bases are optionally liberated from the resulting optically uniform salts with an alkali.
The final products of Formula I, as mixtures of racemates or epimers, as sterically uniform racemates or as pure optically active compounds, may subsequently be converted with inorganic or organic acids into the corresponding salts. Examples of acids for acid addition formation are hydrochloric, hydrobromic, sulphuric, maleic, fumaric, malic, tartaric, benzoic, methanesulphonic, ptoluenesulphonic and cyclohexylsulphamic acid.
Piperidylamines of Formula III may, for example, be produced as follows:
A phenylacetic acid of Formula IV,
in which the two R have the above significance, and each of R and R signifies lower alkyl, is treated with formaldehyde, e.g. with an aqueous formaline solution, in the presence of an alkali, e.g. potassium carbonate, and the reaction product is distilled, whereby a phenylacrylic acid ester of Formula VI,
(6H2 R C0 0 O-R4 in which the two R and R have the above significance, is obtained.
The phenylacrylic acid ester of Formula VI is condensed with an amine of formula R NH in which R in which R the two R R and R have the above significance, is obtained. Compounds of Formula VIII may also be obtained by reacting a phenylacrylic acid ester of the above Formula VI with an amino acid ester of Formula IX,
in which R and R have the above significance.
The compounds of Formula VIII are cyclized by heating with a strong basic condensation agent, e.g. sodium hydride in toluene; the resulting products are converted by hydrolysis and decarboxylation into the corresponding piperidones of Formula X,
in which R and the two R have the above significance, e.g. by heating in an aqueous mineral acid, for example 3-6 N hydrochloric acid.
The piperidones of Formula X are reacted with hydroxylamine hydrochloride and the resulting oximes are reduced to the corresponding piperidylamines, e.g. by hydrogenation over a metal catalyst, e.g. Raney nickel, by reaction with complex alkali metal hydrides, e.g. lithium aluminium hydride or sodium borohydride, or with metallic sodium in a lower alkanol. In accordance with another embodiment of the process the piperidones X are hydrogenated catalytically in the presence of ammonia, e.g. in an ethanolic ammonia solution in the presence of Raney nickel at an elevated temperature and under pressure, whereby the imines resulting as intermediates are reduced in situ to the corresponding piperidylamines. The aboveindicated reductions generally yield mixtures of the two possible racemates, the composition in percentages of which may vary depending on the reduction conditions. The cis-piperidylamines of Formula III are separated from these mixtures as racemates in manner known per se, e.g. by fractional crystallization of their acid addition salts or by adsorption chromatography; the resulting cis racemates are optionally separated into their optically active components in manner known per se.
The compounds of Formula I and their acid addition salts have hitherto not been described in the literature. These compounds and their pharmaceutically acceptable salts exhibit therapeutically useful pharmacodynamic properties. Thus, for instance, in the well known hotplate test carried out with mice, the compounds are shown to exhibit pronounced analgesic effects. For example, the compound 8,9 dimethoxy-2-methyl-l,2,3,4,4a,5,6,l0boctahydrobenzo[c] [1,6]-naphthyridine, such as in the form of its bis-(hydrogen maleinate), administered p.o., is particularly eflective in this test. Compounds of Formula I and their pharmaceutically acceptable salts are therefore indicated for use in medicaments, especially in the treatment of pains of various origins. A suitable average daily dose amounts to from 1 to mg./ kg. body weight of warm-blooded animals, such as primates.
The compounds of Formula I and their pharmaceutically acceptable acid addition salts are of a low toxicity. The compounds I and their pharmaceutically acceptable salts may thus be administered at the daily dosages indicated.
The compounds of the invention or their water-soluble physiologically tolerated acid addition salts may be used as pharmaceuticals on their own or in the form of appropriate medicinal preparations, e.g. tablets, drages, suppositories, injectable solutions, for administration, e.g. ente'rally or parenterally. Aside from the usual inorganic or organic, pharmacologically inert adjuvants, e.g. lactose, starch, talcum, stearic acid, water, alcohols, glycerin, natural or hardened oils or waxes, these preparations may also contain suitable preserving, stabilizing or wetting agents, solubilizers, sweetening or colouring substances and fiavourings.
The term in manner known per se as used herein designates methods in use or described in the literature on the subject.
In the following non-limitative examples all temperatures are indicated in degrees centigrade, without corrections.
EXAMPLE 1 8,9-dimethoxy-2,6-dimethyl-1,2,3,4,4a,10b-hexahydrobenzo [c] [1,6 naphthyridine 120 g. of phosphorus oxychloride are added to a solution of 153 g. of cis-4-acetylamino-3-(3,4-dimethoxyphenyl)-1-methylpiperidine (racemate) in 500 cc. of benzene during the course of 10 minutes while stirring and cooling with ice. The mixture is stirred at room temperature for half an hour and is subsequently heated to the boil at reflux for 2 /2 hours, whereby an oil precipitates, which gradually crystallizes. The excess phosphorus oxychloride and the benzene are subsequently removed by distillation at reduced pressure, 500 cc. of water are carefully added to the resulting residue and heating is effected on a boiling water bath for half an hour. 200 g. of solid potassium carbonate are added to the resulting brown solution, and the oil which precipitates is extracted with chloroform. The chloroform layer is washed with a saturated aqueous sodium chloride solution, is dried over sodium sulphate and concentrated by evaporation. The resulting residue is subsequently taken up in 200 cc. of ethanol, 520 cc. of a 2 N solution of hydrogen chloride in ethanol are added, 400 cc. of ether are added and the mixture is allowed to stand in a refrigerator for 16 hours, whereby the dihydrochloride of the compound indicated in the heading (racemate) precipitates in the form of slightly hygroscopic crystals; M.P. 218 (decon1p.) after drying in a high vacuum for 16 hours at 70"; contains 0.5 to 1 mol of water of crystallization. The base obtained from the dihydrochloride by liberating with potassium carbonate is recrystallized from ethyl acetate; M.P. 125.
The starting material may be produced as follows:
(a) 2-(3,4-dimethoxyphenyl)acrylic acid ethyl ester (3,4-dimethoxyatropic acid ethyl ester) 1435 g. of oxalic acid diethyl ester are added while stirring during the course of minutes to a suspension of sodium ethylate in 3000 cc. of toluene (produced from 113 g. of metallic sodium). 1000 g. of 2-(3,4-dimethoxyphenyl)acetic acid ethyl ester (homoveratric acid ethyl ester )are added to the resulting solution at a temperature of 3040 during the course of 25 minutes, and a resulting dark solution is heated to the boil at reflux while stirring for 2 hours. Cooling is subsequently effected to -45, 1230 cc. of 4 N sulphuric acid are subsequently allowed to flow in. at a temperature of 10 during the course of 3 hours and 0.5 g. of hydroquinone are subsequently added.
400 g. of a formaline solution (36 formaldehyde in water) are allowed to flow into the above reaction mixture, and cc. 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 hours and a. further 200 g. of formaline solution are subsequently added. The reaction mixture is stirred at room temperature over night and is subsequently diluted with 4000 cc. 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 occurs; the relatively unstable 2-(3,4-dimethoxyphenyl)acrylic acid ethyl ester distills over at 140/0.06 mm. of Hg as a yellow viscous oil and is further worked up without delay.
(b) 5-ethoxycarbionyl-3-( 3 ,4-dimethoxyphenyl -1- 'methyl-4-piperidone 412 g. of B-methylaminopropionic acid ethyl ester are added during the course of 30 minutes while stirring to 738 g. of above 2-(3,4-dimethoxyphenyl)acrylic acid ethyl ester, and the mixture is stirred at room temperature for 72 hours.
2500 cc. of toluene are subsequently added to 300 g. of a sodium hydride suspension (50% in paraffin oil), and g. of the above reaction mixture are allowed to flow in in an atmosphere of nitrogen. Heating is effected to 80, and after the reaction commences, the remaining 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 1 0, 376 cc. of glacial acetic acid are carefully added and 340 cc. 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 well until an acid reaction to Congo red is obtained. 2500 cc. of ether are added, the mixture is allowed to stand over night in a refrigerator, and the resulting precipitate is filtered off. The resulting 5-ethoxycarbonyl- 3-(3,4-dimethoxyphenyl)-l-methyl 4 piperidone hydrochloride has a M.P. of 192 (decomp.).
(c) 3 3 ,4-dimethoxypheny1) l -methyl-4-piperid one 1170 g. of 5-ethoxycarbonyl-3-(3,4-dimethoxyphenyl)- 1-methyl-4-piperidone hydrochloride are heated to the boil at reflux for 2 /2 to 3 hours in 5000 cc. of 4 N hydrochloric acid. The hydrochloric acid is evaporated in a vacuum, 755 cc. of water are added, 3-(3,4-dimethoxyphenyl)-1-methyl-4-piperidone is precipitated in the form of an oil by the addition of a large amount of potassium carbonate, and extraction is effected with 2500 cc. of chloroform. The chloroform solution is dried over sodium sulphate and concentrated by evaporation, whereby the compound indicated in the heading is obtained as residue; the picratehas an M.P. of 191192 (decomp.) after crystallization from ethanol.
(d) 3- (3,4-dimethoxyphenyl) -1-methyl-4-piperidoneoxime The crude 3-(3,4-dimethoxyphenyl)-1-methyl-4-piperidone obtained in section (c) is taken up in 800 cc. of ethanol and a suspension of 250 g. of hydroxylamine hydrochloride in 2300 .cc. of hot ethanol is added while stirring. The mixture is heated to the boil at reflux for 4 hours, the crystalline mash is subsequently stirred at room temperature for a further 12 hours and filtration 1s effected. The resulting crude 3-(3,4-dimethoxyphenyl)- 1-methyl-4-piperidone-oxime hydrochloride has a M.P. of 220221 (decomp.). The free base as an M.P. of 150 after crystallization from ethanol.
9 (e) 3-(3,4-dimethoxyphenyl)-1-methyl-4-piperidylamine 350 g. of 3-(3,4-dimethoxyphenyl)-1-methyl 4-piperidone-oxime are hydrogenated in 2500 cc. of ethanol over Raney nickel in an autoclave for 6 hours at 80 and 51 atmospheres. After cooling the catalyst is filtered oif, the filtrate is concentrated to a volume of 500 cc. and 760 cc. of a 3.53 N solution of hydrogen chloride in ethanol is added; the colourless precipitate is filtered off after cooling the solution to 35. Thisprecipitate is the practically pure dihydrochloride of the cis isomer (racemate) of the compound indicated in the heading; M.P. 321 (decomp.) after crystallization from 80% ethanol. Free base: B.P. 135/0.04 mm. of Hg, M.P. 7880 (from ethyl acetate/petroleum ether). The dihydrochloride of the corresponding trans isomer (racemate) remains in the filtrate and then also crystallizes; M.P. 280 (decomp.) after crystallization from 90% ethanol.
(f) cis-4-acetylamino-3- 3,4-dimethoxyphenyl -1- methylpiperidine 102 g. of acetic anhydride are added during the course of 45 minutes while stirring and cooling with ice to 125 g. of cis-3-(3,4-dimethoxyphenyl)-1-methyl-4-piperidylamine (racemate), dissolved in 250 cc. of chloroform. Stirring is effected at room temperature for 2 hours and the reaction solution is subsequently heated to the boil at reflux for half an hour. Cooling is effected, 250 cc. of a saturated aqueous potassium carbonate solution are added while cooling and solid potassium carbonate is added to the solution, whereby an oily product precipitates, which is extracted with chloroform. The chloroform layer is separated, washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The cis-4-acetylamino-3- (3,4-dimethoxyphenyl)-1-methylpiperidine (racemate) is obtained in the form of a hard, glassy residue, which is further worked up as crude product without purification.
EXAMPLE 2 8,9-dimethoxy-2,6-dimethyl-1,2,3,4,4a,5,6,10boctahydrobenzo[c] 1,6]naphthyridine 20.0 g. of 8,9-dimethoxy-2,6-dimethyl-l,2,3,4,4a,10bhexahydrobenzo[c][1,6]naphthyridine (racemate, production see Example 1) are dissolved in 250 cc. of ethanol and shaken with hydrogen over 0.5 g. of a platinum catalyst at normal pressure and room temperature. After the calculated molar amount of hydrogen has been taken up, the catalyst is filtered off, the filtrate is concentrated by evaporation, 80 cc. of a 2 N solution of hydrogen chloride in ethanol are added to the oil obtained as residue, 150 cc. of ether are subsequently added and the mixture is allowed to stand in a refrigerator for 16 hours. The dihydrochloride of the compound indicated in the heading (racemate) which crystallizes is filtered off and recrystallized from 98% methanol and a small amount of ether; M.P. 328 (decomp.). The base liberated therefrom with potassium carbonate has an M.P. of 122 (after crystallization from ether); mixed M.P. with 8,9-dimethoxy-2,6 dimethyl 1,2,3,4,4a,IOb-hexahydrobenzo- [c] [l,6]naphthyridine 95-110".
EXAMPLE 3 2,6-dimethyl-1,2,3,4,4a,10b-hexahydro-8,9-methylenedioxybenzo [c] [1,6]naphthydridine 2.6 g. of cis-4-acetylamino-1-methyl-3-(3,4-methylenedioxyphenyl)piperidine (racemate) are dissolved in 50 cc. of absolute benzene and 3.0 g. of phosphorus oxychloride are added. The mixture is heated to the boil reflux for 4 hours and the benzene and excess phosphorus oxychloride are subsequently evaporated. 25 cc. of water are added to the resulting residue, heating is effected on a boiling water bath for 40 minutes, solid potassium carbonate is added to the resulting clear, yellow solution while cooling with ice until an alkaline reaction is obtained, and extraction is effected thrice with chloroform. The combined chloroform layers are washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The 2,6-dirnethyl-1,2,3,4,4a,l0b hexahydro-8,9 -methylenedioxybenzo[c][1,6]naphthyridine (racemate) obtained as residue is converted into its dihydrochloride by the addition of 10 cc. of a 3 N solution of hydrogen chloride in ethanol; M.P. 299 (decomp.).
The starting material may, for example, be produced as follows:
(a) 2-(3,4-methylenedioxyphenyl)acetic acid ethyl ester A suspension of g. of 2-(3,4-mehtylenedioxyphenyl)acetic acid in 300 cc. of absolute ethanol is saturated with dry hydrogen chloride gas while stirring, whereby the material gradually dissolves. The solution is allowed to stand at room temperature for 36 hours, the excess ethanol is subsequently evaporated and the yellow, oily residue is taken up in ether. The resulting ether solution is shaken out with ice water, then with an aqueous sodium hydrogen carbonate solution and again with ice water, is dried over sodium sulphate and concentrated by evaporation. The residue is distilled in a high vacuum; the compound indicated in the heading has a B.P. of l00/0.01 mm. of Hg.
(b) 2-(3,4-methylenedioxyphenyl)acrylic acid ethyl ester 170 g. of oxalic acid diethyl ester are added while stirring during the course of 5 minutes to a suspension of sodium ethylate in 300 cc. of absolute toluene (produced from 13.4 g. of metallic sodium), whereby the material dissolves. g. of 2-(3,4-methylenedioxyphenyl)- acetic acid ethyl ester are then added at a temperature of 3040 and the resulting dark solution is heated to the boil at reflux while stirring for 2 hours. Cooling is subsequently effected to 45 and 146 cc. of 4 N aqueous sulphuric acid are allowed to flow in at a temperature of 10 during the course of 3 minutes; subsequently 0.1 g. of hydroquinone is added.
49 g. of a formaline solution (36% formaldehyde in water) are allowed to flow into the above reaction mixture while stirring, and cc. of a saturated aqueous potassium carbonate solution are subsequently added dropwise during the course of 15 minutes. The mixture is stirred at room temperature for 2 /2 hours and a further 30 g. of formaline solution are added. The reaction mixture is stirred at room temperature over night and is then diluted with 500 cc. of water. The toluene layer is separated, washed once with water, dried over sodium sulphate and concentrated in a vacuum after the addition of 0.5 g. of hydroquinone. The residue is distilled in a high vacuum, whereby decomposition initially occurs; the relatively unstable 2-(3,4-methylenedioxyphenyl)acrylic acid ethyl ester distils over at 114/0.02 mm. of Hg as a yellow, viscous oil and is further worked up without delay.
(c) 5 -ethoxycarbonyl-1 -methyl-3- (3 ,4-methylenedioxyphenyl) -4-piperidone 53 g. of 3-methylaminopropionic acid ethyl ester are added within the course of 10 minutes while stirring to 88 g. of the above 2-(3,4-methylenedioxyphenyl)acrylic acid ethyl ester and the mixture is stirred at room temperature for 72 hours.
400 cc. of absolute toluene are then added to 38.4 g. of a sodium hydride suspension (50% in paraffin oil) and 20 g. of the above reaction mixture are allowed to flow in in an atmosphere of nitrogen. Heating is eifected to 80 and after the reaction commences the remaining 121 g. of the above reaction mixture are added dropwise during the course of 1 hour. Heating to the boil at reflux is subsequently effected for 4 hours, cooling is efiected to 10 and 48 g. of glacial acetic acid and 44 cc. of water are carefully added; a crystalline precipitate gradually re- 11 sults, 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 added while stirring and cooling well until an acid reaction to Congo red is obtained, whereupon crystallization commences. 200 cc. of ether are added, the mixture is allowed to stand in a refrigerator over night and is filtered. The resulting S-ethoxycarbonyl 1 methyl 3 (3,4 methylenedioxyphenyl)-4-piperidone hydrochloride has a M.P. of 212 (decomp) (after crystallization from methanol/ether).
(d) 1-methyl-3- 3,4-methylenedioxyphenyl -4-piperidone 65 g. of 5 ethoxycarbonyl-l-methyl-3-(3,4-methylene- ,dioxyphenyl)-4-piperidone hydrochloride are heated to the boil at reflux for 2 /2 to 3 hours in 500 cc. of 4 N hydrochloric acid. The hydrochloric acid is evaporated in a vacuum, 100 cc. of water are added to the residue, 1-methyl-3-(3,4-methylenedioxyphenyl) 4 piperidone is precipitated in the form of an oil by the addition of a large amount of potassium carbonate and extraction is effected with 300 cc. of chloroform. The chloroform solution is. dried over sodium sulphate and concentrated by evaporation; the compound indicated in the heading is obtained as residue and is directly worked up as crude product.
(e) 1-methyl-3-(3,4-methylenedioxyphenyl) -4- piperidone-oxime The crude l-methyl-S-(3,4-rnethylenedioxyphenyl)-4- piperidone obtained above is taken up in 70 cc. of ethanol and a suspension of 12.5 g. of hydroxylamine hydrochloride in cc. of hot ethanol is added while stirring. The mixture is heated to the boil at reflux while stirring for 4 hours and the crystalline mash is subsequently stirred at room temperature for a further 12 hours. Evaporation to dryness is effected, the residue is taken up in 75 cc. of water, the oxime is precipitated 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 compound indicated in the heading is obtained as a viscous oil which crystallizes and which has a M.P. of 153-155 after crystallization from ethyl acetate.
(f) 1-Inethyl-3-( 3,4-methylenedioxyphenyl -4- piperidylamine 25 g. of 1-methyl-3-(3,4-methylenedioxyphenyl)-4-piperidone-oxime are hydrogenated in 300 cc. of ethanol over Raney nickel in an autoclave at 80 and 51 atmospheres for 6 hours. After cooling, the catalyst is filtered off, the ethanol is evaporated and the residue is distilled in a high vacuum; B.P. 131/0.07 mm. of Hg.
The distillate, which is a yellow, viscous oil and which consists of a mixture of cis and trans isomers (racemates) of the compound indicated in the heading, is chromatographed on 550 g. of neutral aluminium oxide. The cis isomer is eluted wtih benzene/ether (1:1); the dihydrochloride has a M.P. of 292297 (decomp.) after crystallization from methanol. The trans isomer is eluted with ether/chloroform (1:1); the dihydrochloride has a M.P. of 307-309 (decomp.) after crystallization from ethanol.
(g) Cis-4-acetylamino-1-methy1-3- 3,4-methylenedioxyphenyl) piperidine 2.8 g. of cis-1-methyl-3-(3,4-methylenedioxyphenyl)-4- piperidylamine (racemate) are dissolved in 10 cc. of chloroform and 1.9 g. of acetic anhydride are added while cooling with ice. The mixture is heated to the boil at reflux for 1 hour, is then cooled, diluted with chloroform and shaken out with 20 cc. of a saturated aqueous potassium carbonate solution. The chloroform layer is washed with a saturated aqueous sodium chloride solution, is dried over sodium sulphate .and concentrated by evaporation. The compound indicated in the heading is obtained as residue and is further worked up as crude product without previous purification.
EXAMPLE 4 2,6-dimethyl-8,9-methylenedioxy-1,2,3,4,4a,5,6,10boctahydrobenzo [c] 1,6] naphthyridine 1.6 g. of 2,6 dimethyl-1,2,3,4,4a,10b-hexahydro-8,9 methylenedioxybenzo [c] 1,6]naphthyridine dihydrochloride (racemate, production see Example 3) are dissolved in 500 cc. of 85% ethanol and hydrogenated in the presence of 100 mg. of a platinum catalyst at normal pressure and room temperature. After the theoretical amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is concentrated by evaporation. The 2,6- dimethyl 8,9 methylenedioxy 1,2,3,4,4a,5,6,10b octahydrobenzo[c][1,6]naphthyridine dihydrochloride (racemate) obtained as crystalline residue is recrystallized from 98% methanol; M.P. 294 (decomp.).
EXAMPLE 5 8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-2- methylbenzo [c] 1,6 naphthyridine 43.0 g. of phosphorus oxychloride are added to a solution of 31.0 g. of cis-3-(3,4-dimethoxyphenyl)-4-formylamino-l-methylpiperidine (racemate as crude product) in 500 cc. of chloroform, and heating to the boil at reflux is effected for 1 hour, whereby the solution already, becomes turbid and the formation of a crystalline precipitate commences. After cooling the reaction mixture the'liquid is decanted, the residue is taken up in 100 cc. of water and the resulting clear solution is heated on a boiling water bath for 15 minutes. Cooling is again effected, solid potassium carbonate is added until an alkaline reaction is obtained and the oil which precipitates is extracted thrice with chloroform. The organic phases are combined, washed with asaturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation, whereby the compound indicated in the heading (as racemate) is obtained in the form of an oil which crystallizes; M.P. 108110 after crystallization from ethyl acetate.
The starting material may, for example, be produced as follows:
27.0 g. of cis-3-(3,4-dimethoxwphenyl)-1-methyl-4- piperidylamine (racemate, production see Example 1) are heated to 130 together with 90 cc. of formamide in an atmosphere of nitrogen for 4 hours. The reaction EXAMPLE 6 8,9-dimethoxy-2-methyl-1,2,3,4,4a,5,6,10b-
octahydrobenzo[c] 1,6] naphthyridine 15.7 g. of 8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-2- methylbenzo[c][1,6]naphthyridine (racemate, production see Example 5) are dissolved in 300 cc. of ethanol and hydrogenated in the presence of 300 mg. of prehydrogenated platinum oxide at room temperature and normal pressure, whereby the taking up of hydrogen stops after 3 /2 hours (1480 cc. =98% of the theoretical amount of hydrogen are taken up). The catalyst is filtered off, the filtrate is concentrated and the small amount of precipitate which results is filtered off; a solution of 15.0 g. of maleic acid in 30 cc. of methanol is subsequently added to the filtrate, the mixture is allowed to crystallize and the precipitate is isolated by filtration.
EXAMPLE 7 8,9-dimethoxy-2-methyl-1,2,3,4,4a,5,6,10b-
octahydrobenzo[c] [1,6] naphthyridine 64.6 g. of cis-3-(3,4-dimethoxyphenyl)-1-methyl-4- piperidylamine dihydrochloride (racemate, production see Example 1) are dissolved in 200 cc. of water with heating, the solution is cooled and 20 cc. of 2 N hydrochloric acid and 35.0 g. of a 35% aqueous formaldehyde solution are added. The mixture is heated on a boiling water bath for 1 hour, whereby the formation of a colourless precipitate already commences after 5 minutes. Cooling is eflFected and the resulting 8,9-dimethoxy- 2 methyl 1,2,3,4,4a,5,6,10b octahydrobenzo[c] [1,6]- naphthyridine dihydrochloride is filtered ofli. M.P. 343 (decomp.), dark colouration and sintering above 320; upon recrystallization from water the melting point is no longer raise'd.
EXAMPLE 8 2-methyl-8,9-methylenedioxy-1,2,3,4,4a,5,6,10b-
octahydrobenzo[ c] [1,6] naphthyridine 6.0 g. of cis-1-methyl-3-(3,4-methylenedioxyphenyl)- 4-piperidylarnine (racemate, production see Example 3) are dissolved in 35 cc. of 2 N hydrochloric acid and 5.0 g. of a 35% aqueous formaldehyde solution are added. The mixture is allowed to stand at room temperature for half an hour, is heated to 100 for half an hour and is subsequently evaporated to dryness. The hydrochloride of the compound indicated in the heading (racemate) obtained as residue is recrystallized from methanol and has a M.P. of 304 (decomp.).
EXAMPLE 9 8,9-dimethoxy-2,6-dimethyl-1,2,3,4,4a,5,6,10b-
octahydrobenzo c] [1,6] naphthyridine 15.0 g. of cis-3-(3,4-dimethoxyphenyl)-1-methyl-4- piperidylamine (racemate, production see Example 1) are heated to 100 with 7.5 g. of acetaldehyde for half an hour. 160 cc. of N hydrochloric acid are then added, the mixture is heated to 100 for a further 8 hours and the excess aldehyde and hydrochloric acid are subsequently evaporated in a vacuum. A saturated aqueous potassium carbonate solution is added to the residue and extraction is effected with chloroform; the chloroform layer is washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The residue is chromatographed on 450 g. of neutral aluminum oxide. Elution with petroleum ether/ether 1:1) or ether/chloroform (1:1) yields a yellowish, viscous oil, which is taken up in ethanol. A solution of hydrogen chloride in ethanol is added until an acid reaction to Congo red is obtained, ether is added and the mixture is allowed to crystallize in a refrigerator. The precipitate is filtered oil and crystallized several times from methanol/water, whereby the dihydrochloride of the compound indicated in the heading (racemate), having a M.P. of 328 (decomp.), is obtained. The free base has a M.P. of 122 after crystallization from ethyl acetate.
14 EXAMPLE 10 Galenical Preparation.Tablets Grams 8,9 dimethoxy-2,6-dimethyl-1,2,3,4,4a,5,6,10b-
octahydrobenzo [c] 1,6] naphthyridine dihydrochloride (compound of Example 2) 1 0.0260 Magnesium stearate 0.0010 Polyvinyl pyrrolidone 0.0040 Talcum 0.0080 Maize starch 0.010 Lactose 0.1075 Dimethyl silicone oil 0.0005 Polyethylene glycol 6000 0.0030
For a tablet of 0.160
1 Corresponds to 20 mg. of the free base. What is claimed is: 1. A compound of formula:
in which:
R is lower alkyl of 1 to 3 carbon atoms, R is hydrogen or methyl,
each of the two symbols R is lower alkoxy of 1 to 4 carbon atoms,
or together the two symbols R are methylenedioxy, and
each of the two symbols X is hydrogen,
or together the two symbols are a second bond between the carbon and the nitrogen atom,
and a pharmaceutically acceptable acid addition salt thereof.
2. 8,9-dimethoxy 2,6 dimethyl 1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine, in accordance with claim 1.
3. 8,9 dimethoxy 2,6 dimethyl 1,2,3,4,4a,5,6,10boctahydrobenzo[c] [1,6]naphthyridine, in accordance with claim 1.
4. 2,6 dimethyl 1,2,3,4,4a,10b hexahydro-8,9-methylenedioxybenzo [c] [1,6]naphthyridine, in accordance with claim 1.
5. 2,6-dimethyl 8,9 methylenedioxy 1,2,3,4,4a,5,6, 10b-octahydrobenzo[c] [1,6]naphthyridine, in accordance with claim 1.
6. 8,9-dimethoxy 1,2,3,4,4a,10b hexahydro-Z-methylbenzo [c] [1,6]naphthyridine, in accordance with claim 1.
7. 8,9-dimethoxy 2 methyl 1,2,3,4,4a,5,6,10b-octahydrobenzo [c] [1,6]naphthyridine, in accordance with claim 1.
8. 2-methyl 8,9 methylenedioxy 1,2,3,4,4a,5,6,10boctahydrobenzo [c] [1,6]naphthyridine, in accordance with claim 1.
References Cited U.S. Cl. X.R.
zg g UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent m. 3 5 3,981 Dated March 31, 1970 Inventor-(s) Rudolf Suess et a1 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
In the printed patent, column 8, line 53 change:
755 cc. to 750 cc.
Column 14, claim 1, fourth line from bottom of claim 1:
After "symbols" insert X SIGN ED AND SEALED AUG 4 -1970 @EAL} Aces:
mm 1:. sum, JR- mwud member Gomissioner of Patent Meeting Officer
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH1451566A CH485755A (en) | 1966-10-07 | 1966-10-07 | Process for the preparation of new naphthyridine derivatives |
CH963569A CH485756A (en) | 1966-10-07 | 1966-10-07 | Process for the preparation of new naphthyridine derivatives |
CH1862866 | 1966-12-28 | ||
CH770467A CH511870A (en) | 1966-10-07 | 1967-05-31 | (A) Cmpds. (I) and (III):- R' = lower alkyl R2 = H or Me R3 = lower Oalkyl or together = -OCH2O-IA - X = H; IB X = double bond. (B) Sa |
CH1025267 | 1967-07-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
US3503981A true US3503981A (en) | 1970-03-31 |
Family
ID=27509311
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US672972A Expired - Lifetime US3503981A (en) | 1966-10-07 | 1967-10-05 | Hydro benzo(c)(1,6)naphthyridines |
Country Status (7)
Country | Link |
---|---|
US (1) | US3503981A (en) |
BE (1) | BE704748A (en) |
CH (3) | CH485756A (en) |
DE (1) | DE1695782A1 (en) |
FR (2) | FR1549379A (en) |
GB (1) | GB1193523A (en) |
NL (1) | NL6713346A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007537233A (en) * | 2004-05-12 | 2007-12-20 | ファイザー・プロダクツ・インク | Piperidine derivatives as NK1 and NK3 antagonists |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2467692A (en) * | 1949-04-19 | Naphthyridones and processes fob |
-
1966
- 1966-10-07 CH CH963569A patent/CH485756A/en not_active IP Right Cessation
- 1966-10-07 CH CH1451566A patent/CH485755A/en not_active IP Right Cessation
-
1967
- 1967-05-31 CH CH770467A patent/CH511870A/en not_active IP Right Cessation
- 1967-09-22 GB GB43302/67A patent/GB1193523A/en not_active Expired
- 1967-10-02 NL NL6713346A patent/NL6713346A/xx unknown
- 1967-10-04 DE DE19671695782 patent/DE1695782A1/en active Pending
- 1967-10-04 FR FR1549379D patent/FR1549379A/fr not_active Expired
- 1967-10-05 BE BE704748D patent/BE704748A/xx unknown
- 1967-10-05 US US672972A patent/US3503981A/en not_active Expired - Lifetime
-
1968
- 1968-01-02 FR FR134546A patent/FR7530M/fr not_active Expired
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2467692A (en) * | 1949-04-19 | Naphthyridones and processes fob |
Also Published As
Publication number | Publication date |
---|---|
CH485755A (en) | 1970-02-15 |
FR1549379A (en) | 1968-12-13 |
CH485756A (en) | 1970-02-15 |
FR7530M (en) | 1969-12-22 |
NL6713346A (en) | 1968-04-08 |
BE704748A (en) | 1968-02-15 |
GB1193523A (en) | 1970-06-03 |
CH511870A (en) | 1971-08-31 |
DE1695782A1 (en) | 1971-04-29 |
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