US3634410A - Amides of benzoic acids with amine substituted piperidines - Google Patents

Amides of benzoic acids with amine substituted piperidines Download PDF

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Publication number
US3634410A
US3634410A US19474A US3634410DA US3634410A US 3634410 A US3634410 A US 3634410A US 19474 A US19474 A US 19474A US 3634410D A US3634410D A US 3634410DA US 3634410 A US3634410 A US 3634410A
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piperidinoethyl
piperidine
compounds
acid
piperidine hydrochloride
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US19474A
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Ole Bent Tvaermose Nielsen
Hans-Hasso Frey
Peter Werner Feit
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Leo Pharma AS
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Leo Pharmaceutical Products Ltd AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/023—Preparation; Separation; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids

Definitions

  • Novel compounds are described and claimed, which are amides of benzoic acid with heterocyclic amines carrying a tertiary amino group, together with methods of producing the said compounds.
  • the novel compounds aretherapeutically active in the treatment of parkinsomsm.
  • This invention relates to a series of hitherto unknown compounds of the general formula:
  • R is a straight or branched C4 to C12 aliphatic hydrocarbon chain, unsubstituted or substituted with phenyl, phenoxy, or phenylthio, which R is directly attached to the benzene nucleus, or optionally may be attached to the benzene nucleus through a hetero atom selected from the group consisting of O and S;
  • R is alkyl;
  • R is a cycloalkyl radical with from 5 to 8 carbon atoms in the ring, or R together with (R can complete a heterocyclic ring which may be alkyl-substituted, n is an integer from 2 to 4, n is an integer from 1 to 5, and n is an integer from 1 to 3; to salts of the above compounds with pharmaceutically acceptable inorganic and organic acids; and to methods for the preparation of the compounds and their salts.
  • alkyl means lower-alkyl, including straight and branched aliphatic hydrocarbon chains with from 1 to 6 carbon atoms.
  • the compounds of the invention possess valuable pharmacological activities, e.g. displaying a favourable central anticholinergic action, and they are intended to be used in the treatment of patients suffering, for instance, from parkinsonism, including the post-encephalytic or arteriosclerotic parkinsonism and similar conditions.
  • post-encephalytic parkinsonism refers to the appearance, as a sequence to encephalitis, of muscle rigidity and tremor, frequently along with spasmodic phenomena
  • arteriosclerotic parkinsonism refers to the appearance, as a consequence of multiple cerebral vascular lesions, of difficulties of movements and fixity of posture and similar conditions occurring in the older age group, often combined with muscle rigidity while tremor is absent.
  • the said disorders are chronic and progressive, and consequently all treatment is symptomatic and must be continued for long periods of time.
  • the known medication may comprise treatment with belladonna alkaloids, e.g. atropine, with amphetamine alone or in combination with belladonna alkaloids, with certain antihistamines or apomorphine, and similar unspecific medications, which may offer some degree of Patented Jan. 11, 1972 "ice symptomatic relief on tremor or spasmotic conditions, but no fixed dosage can be recommended, and ordinarily small amounts of the drug in question are used initially while larger doses are ultimately required whereby it may be necessary to approach the limit of tolerance and several toxic symptoms appear.
  • belladonna alkaloids e.g. atropine
  • amphetamine alone or in combination with belladonna alkaloids with certain antihistamines or apomorphine
  • similar unspecific medications which may offer some degree of Patented Jan. 11, 1972 "ice symptomatic relief on tremor or spasmotic conditions, but no fixed dosage can be recommended, and ordinarily small amounts of the drug in question are used initially while larger doses are ultimately required whereby it may
  • trihexyphenidyl (3- l-piperidyl l-phenyll-cyclohexyll-propanol) Caramiphen (2 diethylaminoethyl-l-phenyl-cyclopentane-l-carboxylate hydrochloride), or diethazide (diethylaminoethyl-N-dibenzoparathiazine)
  • the action of trihexyphenidyl resembles that of atropine in particular as far as the antispasmotic properties are concerned, whereas some of the undesired effects of atropine are weaker, but still the peripheral parasympatholytic action of trihexyphenidyl must be considered an undesired effect in the treatment of parkinsonism where in particular the central action is important.
  • the compounds of the present invention are widely different from the drugs mentioned above, and it has surprisingly been found that the compounds of Formula I exert a favourable specific therapeutic action in the treatment of all forms of parkinsonism.
  • the preferred compounds for the treatment of parkinsonism are those of Formula I in which R is a C5 to C7 aliphatic hydrocarbon chain attached to the benzene nucleus through one of the hetero atoms 0 and S the integers in and n being within the limits from 2 to 3, and from 2 to 4 respectively, and in which R is a C1 to C2 aliphatic group, and R is a C4 to C7 cycloalkyl group, or in which R and R together with the N atom form a heterocyclic ring.
  • the preferred compounds are those in which R has the meaning defined above and is in the 4-position in the benzene nucleus, and in which R and R together form an unsubstituted or alkyl-substituted pyrrolidino, piperidino, or hexamethyleneimino group.
  • the compound l-(4-n-hexyloxybenzoyl)-4-(piperidinoethyl)-piperidine hydrochloride displayed a promising central anticholinergic activity, while its peripheral parasympatholytic effects were comparably weak.
  • Its antagonistic effects against the tremorgenic action of tremorine and oxotremorine which is considered to be the most predictive pharmacological model of parkinsonism, were two to five times stronger than those of trihexyphenidyl, being at present the drug of choice in the treatment of parkinsonism.
  • the central effects of oxotremorine (tremor) were inhibited with lower doses than the peripheral effects (salivation) which as mentioned above is highly desirable for antiparkinsonism drugs.
  • the acute oral toxicity of e.g. l-(4-n-hexyloxybenzoyl)- 4-(piperidinoethyl)-piperidine HCl expressed in LD (mice) is 470 mg./kg., which may be considered low when compared to the degree of activity in the antiparkinson test in which an effect could be observed with amounts of the order 0.5 to 2.0 rug/kg.
  • the chronical toxicity was studied in animal experiments in which the test animals were rats (Leo Wistar strain). The compounds were administered orally each day during a period of six months in various doses, in one animal section in a daily dose of 50 mg./ kg.
  • compositions containing a compound of the invention also constitute part of this invention.
  • the proportion of therapeutically ac tive material to carrier substances and auxiliary agents can vary between 0.04 and depending upon the form of pharmaceutical presentation.
  • compositions in question can be worked up to pharmaceutical forms of presentations, such as tablets, pills, dragees and suppositories, or the compositions can be filled in medical containers, such as capsules or ampoules or, as far as mixtures or elixirs are concerned, they may be filled into bottles and similar containers.
  • compositions suitable for enteral and parenteral administration can be used to make up the compositions, water, gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal oils and fats, benzyl alcohol, gums, polyalkylene glycol and similar other known carriers for medicaments being suitable as carriers, while stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers for securing an adequate pH-value of the compositions can be used as auxiliary agents.
  • the compounds of Formula I may be present as such or in the form of one of their salts with a pharmaceutically acceptable inorganic or organic acid, as for instance a hydrochloride, hydrobromide, hydroiodide, sulphonate, sulphate, phosphate, sulphamate, tartrate, maleate, citrate, acetate, succinate, or benzoate.
  • a pharmaceutically acceptable inorganic or organic acid as for instance a hydrochloride, hydrobromide, hydroiodide, sulphonate, sulphate, phosphate, sulphamate, tartrate, maleate, citrate, acetate, succinate, or benzoate.
  • An object of the invention also resides in the selection of a dose of the compounds of Formula I which can be administered so that the desired activity is achieved without simultaneous secondary eflects.
  • the compounds of the invention may conveniently be administered by injection, preferably once per day, and in amounts corresponding to a total daily dose of from 0.1 to mg.
  • the compounds may be given by the oral route in the form of tablets and the like, or in the form of a mixture or elixir, one to four times per day and in a total daily dose of from 0.2 to 50 mg, always with due regard to the condition of the patient and in accordance with the prescription of the medical practitioner.
  • the compounds of the invention may conveniently be administered in dosage units containing not less than 0.5 mg, and preferably from 1 to 25 mg. of the active compound.
  • dosage unit is meant a unitary, i.e. a single dose capable of being administered to the patients, and which may be readily handled and packed remaining as a physically stable unit dose comprising either the active material as such or as a mixture of it with a solid or liquid pharmaceutical diluent or carrier.
  • a sealed ampoule, a vial or a similar container may be provided, containing a parenterally acceptable aqueous or oily injectable solution or dispersion of the active material as a dosage unit as mentioned above.
  • the dosage unit may contain from 0.5 to 25 mg., and preferably contains from 1 to 10 mg. of the active compound which is readily absorbed when orally administered.
  • the dosage unit When in the form of injectable preparation, the dosage unit preferably contains from 0.1 to 25 mg. of the active compound.
  • this pharmaceutical preparation may preferably contain 0.5 to 10 mg. per cc.
  • the dosage units aforesaid also constitute part of the present invention.
  • a compound of the general formula C C-COY wherein R has the meaning hereinbefore defined is reacted with a compound of the general formula (III) wherein R R 12, n and 11 have the meanings hereinbefore defined, and the terms COY and XN in Formulae II and III shall mean radicals capable of reacting with each other to form a CON bridge, the resulting compound being recovered as such or as one of its salts with an acid.
  • alkylthiobenzoic acids used as starting substances in the method are hitherto unknown compounds which may be prepared in a Sandmeyer reaction in which the diazotized mor p-aminobenzoic acid is reacted with an alkalimetal xanthogenate to form the corresponding xanthate, which is hydrolyzed and alkylated in one step by reacting with an alkyl halide under alkaline conditions resulting in the desired alkylthiobenzoic acid.
  • the radical COY of the starting substances of Formula II stands for various reactive groups corresponding to starting substances as for instance an acid halide, such as an acid chloride or bromide, an anhydride, a mixed anhydride with an alkyl-carbonic acid, such as isobutyl-carbonic acid, a carboxylic acid, an inorganic acid or a sulphonic acid; or a radicalobtained by reacting the corresponding free acid with a carbodiimide or N',N- carbonyldiimidazole 'or a similar functioning compound.
  • an acid halide such as an acid chloride or bromide
  • an anhydride such as a mixed anhydride with an alkyl-carbonic acid, such as isobutyl-carbonic acid, a carboxylic acid, an inorganic acid or a sulphonic acid
  • a radicalobtained by reacting the corresponding free acid with a carbodiimide or N',N- carbonyldiimidazole
  • X may preferably be hydrogen.
  • the process of the invention is conveniently performed in the presence of an inert solvent and, if in the absence of water, at room temperature for a period of time necessary to accomplish the desired degree of conversion, commonly by standing overnight.
  • equimolar amounts or an excess of the compound of Formula II may appropriately be employed in order to form e.g. the hydrogen halide of compounds of Formula I directly in the reaction mixture.
  • the reaction is performed in the presence of an inert solvent, preferably immiscible with water, and at temperatures on or below 0 C. while any acid component formed during the reaction, e.g. a hydrogen halide, is continuously removed by adding an aqueous solution of a base, e.g. an alkali metal hydroxide.
  • a base e.g. an alkali metal hydroxide.
  • the desired compound is readily recovered from the organic phase, if necessary after removal of a possible excess of the starting substance of Formula II by extraction with an aqueous solution of an inorganic base, by evaporation of the organic solvent, and recrystallization of the residue, or the compound may be isolated as a salt with an acid by neutralizing the base, in a suitable solvent or mixture of solvents, with a view to the precipitation or crystallization of the salt.
  • EXAMPLE 1 4-n-hexylthiobenzoic acid To a solution of 4-aminobenzoic acid (32 g.), sodium nitrite (18.8 g.), and sodium hydroxide (11 g.) in water (150 ml.), concentrated hydrochloric acid (50- ml.) was slowly added while stirring vigorously at 50 C. After the addition was completed, the stirring was continued further for 1 hour at O5 C. The cooled diazonium-solution was filtered and slowly added to a solution of potassium xanthogenate (62.5 g.) and sodium carbonate (87.5 g.) in water (250 ml.) at 6570 C. while stirring vigorously. The mixture was stirred at 6570 C. further for 1 hour.
  • EXAMPLE 2 4- (4-phenylbutoxy) -b enzoic acid A solution of ethyl 4-hydroxy benzoate (11 g.), 4- phenylbutyl bromide (17 g.), and sodium (1.53 g.) in ethanol (50 ml.) was refluxed for 20 hours and was then evaporated in vacuo. 4 N sodium hydroxide ml.) was added to the residue, and the mixture was heated on a steam bath for 5 hours. After cooling, the resulting solution was acidified with concentrated hydrochloric acid (15 ml.). The precipitated material was collected by filtration and washed with water. After drying, 4-(4-phenylbutoxy)-benzoic acid with a melting point of 128131 C.
  • EXAMPLE 4 4- [2- (4-methylpiperidino -ethyl] -piperidine dihydrochloride A mixture of 4-vinylpyridine (25 g.) 4-methylpiperidine (35.4 g.) and acetic acid (3.5 ml.) was heated on a steam bath for 24 hours. 4 N sodium hydroxide (25 ml.)
  • EXAMPLE 6 By substituting equimolar amounts of respectivelv 4-n-propyloxybenzoyl chloride, 4-isopropyloxybenzoyl chloride, 4-n-butyloxybenzoyl chloride, 4-sec.-butyloxybenzoyl chloride, 4-isobutyloxybenzoyl chloride, 4-isoamyloxybenzoyl chloride, 4-n-heptyloxybenzoyl chloride, 4-n-octyloxybenzoyl chloride, 3-n-propyloxybenzoyl chloride,
  • EXAMPLE 8 By using the procedure described in the Example 5 above and substituting equimolar amounts of 4-n-aniyl oxybenzoyl chloride for the 4-n-hexyloxybenzoyl chloride and 48% hydrobromic acid for the ethanolic hydrochloric acid, 1-(4-n-amyloxybenzoyl)-4-(2-piperidinoethyl) piperidine hydrobromide (M.P. 192.5-l94 'C.) was obtained.
  • a piperidine compound of the formula References Cited UNITED STATES PATENTS 3,468,892 9/1969 Tomcufcik et al. 260,293

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US19474A 1969-03-19 1970-03-13 Amides of benzoic acids with amine substituted piperidines Expired - Lifetime US3634410A (en)

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US (1) US3634410A (enrdf_load_stackoverflow)
AT (1) AT296306B (enrdf_load_stackoverflow)
AU (1) AU1212770A (enrdf_load_stackoverflow)
BE (1) BE747627A (enrdf_load_stackoverflow)
DE (1) DE2013179A1 (enrdf_load_stackoverflow)
ES (1) ES377734A1 (enrdf_load_stackoverflow)
FR (1) FR2035063A1 (enrdf_load_stackoverflow)
GB (1) GB1250719A (enrdf_load_stackoverflow)
NL (1) NL7003855A (enrdf_load_stackoverflow)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4885302A (en) * 1987-08-07 1989-12-05 Pascal George 2-((4-Piperidyl)methyl)-1,2,3,4-tetrahydroisoquinoline derivatives, their preparation and their application in therapy
US4925850A (en) * 1988-07-12 1990-05-15 Synthelabo Derivatives of 2-((4-piperidinyl)methyl)-1,2,3,4-tetrahydroisoquinoline, their preparation and their application in therapeutics
FR2659323A1 (fr) * 1990-03-07 1991-09-13 Synthelabo Derives de 4-(aminomethyl) piperidine, leur preparation et leur application en therapeutique.
US5272157A (en) * 1990-03-07 1993-12-21 Synthelabo Derivatives of 4-(aminomethyl) piperidine, their preparation and their therapeutic application
US6152681A (en) * 1996-05-03 2000-11-28 Arrowhead Systems, Llc Container sweep for a palletizer and method

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1585165A (en) * 1976-06-29 1981-02-25 Leo Pharm Prod Ltd Derivatives of 6-amidino penicillanic acid
EP0052311A1 (en) * 1980-11-19 1982-05-26 Sterling Drug Inc. 1-((Benzoylphenyl) - lower-alkyl) piperidines and carbinol analogs and preparation thereof
DE3670080D1 (de) * 1985-12-23 1990-05-10 Zambeletti Spa L Azacyclische verbindungen, verfahren zur ihrer herstellung und ihre verwendung als pharmazeutika.
PT86427B (pt) * 1986-12-22 1990-11-20 Zambeletti Spa L Processo para a preparacao de derivados de piperidina
FR2630113B2 (fr) * 1987-08-07 1990-07-20 Synthelabo Derives de ((piperidinyl-4)methyl)-2 tetrahydro-1,2,3,4 isoquinoleine, leur preparation et leur application en therapeutique
FR2630114B2 (fr) * 1987-08-07 1990-07-20 Synthelabo Derives de (piperidinyl-4)methyl)-2 tetrahydro-1,2,3,4 isoquinoleine, leur preparation et leur application en therapeutique
FR2634205B2 (fr) * 1987-08-07 1990-09-07 Synthelabo Derives de me thyl-4 ((piperidinyl-4)methyl)-2 tetrahydro-1,2,3,4 isoquinoleine, leur preparation et leur application en therapeutique
FR2634204B2 (fr) * 1987-08-07 1990-09-07 Synthelabo Derives de ((piperidinyl-4)methyl)-2 tetrahydro-1,2,3,4 isoquinoleines, leur preparation et leur application en therapeutique
FR2625504B2 (fr) * 1987-08-07 1990-05-04 Synthelabo Derives de ((benzoyl-1 piperidinyl-4)methyl)-2 tetrahydro-1,2,3,4 isoquinoleine, leur preparation et leur application en therapeutique
EP1140834A1 (en) * 1998-12-18 2001-10-10 Du Pont Pharmaceuticals Company Heterocyclic piperidines as modulators of chemokine receptor activity
BR0210733A (pt) 2001-07-02 2004-07-20 Astrazeneca Ab Derivados de piperidina de utilidade úteis como moduladores da atividade do receptor de quimocina
GB0120461D0 (en) 2001-08-22 2001-10-17 Astrazeneca Ab Novel compounds
GB0122503D0 (en) 2001-09-18 2001-11-07 Astrazeneca Ab Chemical compounds
SE0200843D0 (sv) 2002-03-19 2002-03-19 Astrazeneca Ab Chemical compounds
SE0200844D0 (sv) 2002-03-19 2002-03-19 Astrazeneca Ab Chemical compounds
SE0300850D0 (sv) * 2003-03-25 2003-03-25 Astrazeneca Ab Chemical compounds
SE0300957D0 (sv) 2003-04-01 2003-04-01 Astrazeneca Ab Chemical compounds
CN100554236C (zh) * 2004-04-01 2009-10-28 住友化学株式会社 制备羧酸化合物的方法
KR20080037655A (ko) 2005-07-21 2008-04-30 아스트라제네카 아베 신규 피페리딘 유도체

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4885302A (en) * 1987-08-07 1989-12-05 Pascal George 2-((4-Piperidyl)methyl)-1,2,3,4-tetrahydroisoquinoline derivatives, their preparation and their application in therapy
US4945096A (en) * 1987-08-07 1990-07-31 Synthelabo Treatment of a depressive state with 2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline derivates
US4925850A (en) * 1988-07-12 1990-05-15 Synthelabo Derivatives of 2-((4-piperidinyl)methyl)-1,2,3,4-tetrahydroisoquinoline, their preparation and their application in therapeutics
FR2659323A1 (fr) * 1990-03-07 1991-09-13 Synthelabo Derives de 4-(aminomethyl) piperidine, leur preparation et leur application en therapeutique.
EP0447292A1 (fr) * 1990-03-07 1991-09-18 Synthelabo Dérivés de 4-(aminométhyl)pipéridine, leur préparation et leur application en thérapeutique
US5179108A (en) * 1990-03-07 1993-01-12 Synthelabo Derivatives of 4-(aminomethyl) piperidine, their preparation and their therapeutic application
US5272157A (en) * 1990-03-07 1993-12-21 Synthelabo Derivatives of 4-(aminomethyl) piperidine, their preparation and their therapeutic application
US6152681A (en) * 1996-05-03 2000-11-28 Arrowhead Systems, Llc Container sweep for a palletizer and method

Also Published As

Publication number Publication date
FR2035063A1 (enrdf_load_stackoverflow) 1970-12-18
GB1250719A (enrdf_load_stackoverflow) 1971-10-20
DE2013179A1 (de) 1970-10-01
ES377734A1 (es) 1972-05-16
NL7003855A (enrdf_load_stackoverflow) 1970-09-22
AT296306B (de) 1972-02-10
AU1212770A (en) 1971-09-09
BE747627A (fr) 1970-08-31

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