WO1991008200A1 - Nouveaux derives de tetrahydropyridine, leur procede de preparation et compositions pharmaceutiques contenant lesdits composes en tant qu'agents actifs - Google Patents

Nouveaux derives de tetrahydropyridine, leur procede de preparation et compositions pharmaceutiques contenant lesdits composes en tant qu'agents actifs Download PDF

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Publication number
WO1991008200A1
WO1991008200A1 PCT/HU1990/000076 HU9000076W WO9108200A1 WO 1991008200 A1 WO1991008200 A1 WO 1991008200A1 HU 9000076 W HU9000076 W HU 9000076W WO 9108200 A1 WO9108200 A1 WO 9108200A1
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WO
WIPO (PCT)
Prior art keywords
tetrahydropyridine
chlorophenyl
carbonylethyl
formula
hydrogen atom
Prior art date
Application number
PCT/HU1990/000076
Other languages
English (en)
Inventor
Károly NÁDOR
Pál SCHEIBER
Péter NEMES
Egon KÁRPÁTT
Béla Kiss
László Szporny
Éva PÁLOSI
Dóra Groó
Erzsébet Lapis
Zsolt Szombathelyi
Ádám SARKADI
Mihály Bodó
István Laszlovszky
Aniko Gere
Katalin Csomor
Judit Laszy
Zsolt Szentirmai
Original Assignee
Richter Gedeon Vegyészeti Gyár Rt.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Richter Gedeon Vegyészeti Gyár Rt. filed Critical Richter Gedeon Vegyészeti Gyár Rt.
Publication of WO1991008200A1 publication Critical patent/WO1991008200A1/fr

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Classifications

    • 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
    • C07D211/70—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • This invention relates to novel tetrahydropyridine derivatives, a process for their preparation and pharmaceutical compositions containing such compounds as active agents.
  • Ar1 means a phenyl group optionally mono- or polysubstituted
  • Ar means a phenyl group optionally substituted
  • R means a hydrogen atom or an alkyl group with 1-6 carbon atoms
  • R 1 can only mean a hydrogen atom and Ar2 is in any case substituted.
  • Ar 1 and Ar2 groups are either phenyl or substituted phenyl groups. Phenyl groups can be mono- or polysubstituted with halo, trifluoromethyl , hydroxy, alkyl with 1-6 carbon atoms and alkoxy with 1-6 carbon atoms.
  • Halo is generic to fluoro, chloro, bromo or iodo.
  • Alkyl groups as such or as a part of other groups are straight and branch chained saturated hydrocarbon groups such as methyl-, ethyl-, jv-pr ⁇ pyl-, isopropyl-, ji-butyl-, sec-butyl-, jn-pentyl-, isope ⁇ tyl, ⁇ i-hexyl, isohexyl and the like.
  • ⁇ c - or /_•- -aminoketones can be regarded as ⁇ c - or /_•- -aminoketones, depending on the value of n where the nitrogen atom is the heteroatom of the substituted tetrahydropyridine cycle.
  • ⁇ -amino ketones which are also called as Man ⁇ ich ketones, are well known. Their chemical characteristics are described, for example, in F. F. Singhe: Organic reactions, Vol. 1, p. 303-341, 3. Wiley, New York, London (1942); B. Reichert: Die Mannich-Recision, Springer Verlag, Berlin, Gotti ⁇ ge ⁇ -Heidelberg, (1959); H. Hellmann - G.
  • Tetrahydropyridine compounds which can be considered as o -amino ketones, are discussed by M. Rajsner, E. Adlerova and M. Protiva in Collection Czechoslov. Chem. Communs. 28. 1031-43 (1963), however, the analgetic effect mentioned in said article is not proven for compounds containing a tetra ⁇ hydropyridine cycle.
  • 865,314 and 870,700 describe a - ⁇ ami ⁇ o keto ⁇ e type compound which is a well known analgetic under the name methadon and its chemical name is 6-(dimethylami ⁇ o)- -4, -diphenyl-3-heptanone.
  • the compounds of the formula (I) are, however, nootropic agents, they are protecting cerebral activity from several harmful effects, like hypocrisy, having a damaging influence on the cognitive functions. This effect is shown by controlling amnesia, caused by hypocrisy.
  • mice Male, spontaneous hypertensive rats weighing between 190 and 220 grams (average blood pressure is about 180-220 mmHg) are trained in conditioning boxes, so-called shuttle boxes, consisting of two parts, to form two way active preventing reaction.
  • the animals performed 30 cycles per day which consist of 15 sec i ⁇ tersignal relaxation time, 15 sec light stimuli (conditioned stimulus: flashing light signal of 1 Hz frequency) and 10 sec electrical shock (unconditioned stimulus: 0.8 mA electrical shock through the foot grid). Shocking effect can be avoided if animals change their area under light stimulus, hence a conditioned protective reaction is shown. Animals were conditioned for 3 days.
  • 60 minutes after pretreatment either with a solvent or with a compound to be tested animals are put to a shuttle box, where nitrogen enriched compressed air is flown (200 litres per minute per box) and during 10 minutes, the oxygen content of inspired air is reduced to 6 per cent. After equilibru animals perform 30 cycles under hypoxic conditions.
  • the number of conditioned reactions is registered by a microprocessor controlled system automatically. From the number of conditioned reactions given by the animals the average of groups can be computed. Antihypoxic effect of compounds to be tested, expressed in percentage, can be computed by the formula shown below:
  • Normobaric hypoxia used in the described tests serves modelling such human conditions in which cognitive functions caused by disturbance in circula ⁇ tion and metabolic poblems, like supply troubles in old age, are getting worse.
  • the compounds according to the invention possess an acceptable therapy range when added orally.
  • Ar1 means a phenyl group optionally mono- or polysubstituted
  • Ar' means a phenyl group optionally substituted
  • R 1 can only mean a hydrogen atom and Ar2 is in any case substituted and their acid addition salts can be prepared e. g. as follows a) a keto ⁇ e of the formula (II)
  • Process a) according to the invention is performed suitabl by reacting a tetrahydropyridine derivative of the formula (III in basic form with a halo compound of the formula (II) in a polar solvent, like acetone, ethanol or acetonitrile or their mixtures, in the presence of an acid binding agent, which bonds the acid HX liberated during said reaction.
  • a polar solvent like acetone, ethanol or acetonitrile or their mixtures
  • an acid binding agent which bonds the acid HX liberated during said reaction.
  • acid binding agents tertiary amines of low number of carbon atoms, prefer- ably triethyl amine; 1-methylpiperidine, or salts of weaker acids than HX, suitably salts of organic acids, preferably sodium acetate, can be used.
  • Compounds of formula (I) obtained in basic form can be transformed to a salt, if required.
  • salts both in the case of the compounds of the formulae (I) and (III) most preferable materials are those mineral acids which can be used to medical purposes.
  • mineral acids Prefer ⁇ ably hydrogen chloride, hydrobromic acid, sulphuric acid and similar acids are used.
  • the raw products can be purified e. g. by recrystalliza- tio ⁇ .
  • Process b) according to the present invention can prefer- ably be realized so that an aromatic keto ⁇ e of the formula (IV), in which Ar 1 and R1 are as defined above, is reacted with paraformaldehyde and a salt of a tetrahydropyridine derivative of the formula (III), in a polar solvent under heating in a condensation reaction.
  • solvent preferably ethanol or 2-propanol is used.
  • Paraformaldehyde is preferably used in an excess of e. g. 2.5 moles, based on the ketone, and it is given in several portions to the reaction mixture.
  • the depolymerization of paraformaldehyde to formaldehyde can be catalized by an acid, preferably with the acid used for preparing a salt of the tetrahydropyridine of the formula (III)
  • Paraformaldehyde can be replaced by ormaldehyde, prefer ⁇ ably in aqueous solution.
  • the reaction is performed in the presence of a water soluble organic solvent, preferably ethanol or metha ⁇ ol.
  • Paraformaldehyde can be also replaced by those compounds which can be transformed during the reaction to formaldehyde and an another compound which does not affect the reaction required.
  • an alkali metal carbonate e. g. potassium carbonate
  • Raw compounds of the formula (I) are recrystallized in a usual manner. It is preferable to use methanol only, or a mixture of methanol and ethanol because by this method the raw product can be separated from the salt of a heterocyclic compound of the formula (III) which is a by-product.
  • Other polar solvents like acetone or acetonitrile, can be used, naturally.
  • the compounds according to the invention can be converted into pharmaceutical compositions. These compositions may be administered in oral, rectal and/or par- enteral route.
  • the composition may be formulated e. g. as a tablet, dragee or capsule.
  • lactose or starch may be used as carriers.
  • Gelatine, carboxymethylcellulose sodium, mRthylcellulose, polyvinylpyrrolido ⁇ e or starch gum are suit ⁇ able binding or granulating agents.
  • disintegrating agents mainly potato starch or microcrystalline cellulose may be added though ultraamylopectin or formaldehyde-casein and the like are also useful.
  • Talc colloidal silicic acid, stearin, calcium or magnesium stearate and the like are suitable anti-adhesive and sliding agents.
  • Tablets may be prepared e. g. by compression following the wet granulation.
  • the mixture of the active ingredient with the carriers and optionally with a part of the disintegrating additive is granulated with an aqueous, alcoholic or aqueous- -alcoholic solution of the binding agents in a suitable equip ⁇ ment, then the granulate is dried. Subsequently, after mixing the other disintegrating, sliding and anti-adhesive additives to the dried granulate, the mixture is compressed to tablets. If desired, the tablets may be provided with a groove in order to facilitate the administration. Tablets may also directly be prepared from a mixture containing the active ingredient and suitable additives. The tablets may optionally be converted to dragees by employing the commonly used pharmaceutical additives, e.
  • compositions are prepared by filling a mixture of the active ingredient with the additives into capsules.
  • the composition of the inven ⁇ tion is formulated as a suppository containing a carrier mass, the so-called “adeps pro suppositorio" in addition to the active ingredient.
  • a carrier mass vegetable fats such as hardened vegetable oils, or triglycerides of C-J T O fatty acids (prefer ⁇ ably the carriers bearing the trade name Witepsol) may be used.
  • the active ingredient is uniformly distributed in the molten carrier mass, then suppositories are prepared by moulding.
  • the composition of the invention is formulated as an injectable solution.
  • the active ingredients are dissolved in distilled water and/or various organic solvents, e. g.
  • glycol ethers if desired, in the presence of solubiliz- ing agents such as polyoxyethylene sorbita ⁇ monolaurate or monooleate or monostearate (Tween 20, Tween 60 or Twee ⁇ 80), respectively.
  • the injectable solution may further contain various additives (auxiliary agents), e. g. preservatives such as ethyle ⁇ ediamine tetraacetate as well as pH-modifying and buffering substances or, if desired, a local anaesthetic agent such as lidocai ⁇ e.
  • auxiliary agents e. g. preservatives such as ethyle ⁇ ediamine tetraacetate as well as pH-modifying and buffering substances or, if desired, a local anaesthetic agent such as lidocai ⁇ e.
  • Example 1 4-(4-Chlorophenyl)-l-((4-chlorophenyl)carbonylethyl)- -1,2,3,6-tetrahydropyridine hydrochloride
  • the precipitated crystals are filtered, the amount of the product is 2.9 g.
  • Melting point is 188-189 °C after double recrystalliza- tion from ethanol.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouveaux dérivés de tétrahydropyridine, leur procédé de préparation et compositions pharmaceutiques contenant lesdits composés utilisés comme agents actifs. Dans la formule (I), Ar1 représente un groupe phényle facultativement mono ou polysubstitué, Ar2 représente un groupe phényle facultativement substitué, R1 représente un atome d'hydrogène ou un groupe alkyle contenant 1 à 6 atomes de carbone, n peut représenter soit 0 soit 1, à condition que si n = 0 alors R1 représente uniquement un atome d'hydrogène et Ar2 est substitué dans tous les cas.
PCT/HU1990/000076 1989-12-01 1990-11-22 Nouveaux derives de tetrahydropyridine, leur procede de preparation et compositions pharmaceutiques contenant lesdits composes en tant qu'agents actifs WO1991008200A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU6335/89 1989-12-01
HU633589A HU208118B (en) 1989-12-01 1989-12-01 Process for producing tetrahydropyridine derivatives and pharmaceutical compositions comprising such compounds

Publications (1)

Publication Number Publication Date
WO1991008200A1 true WO1991008200A1 (fr) 1991-06-13

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PCT/HU1990/000076 WO1991008200A1 (fr) 1989-12-01 1990-11-22 Nouveaux derives de tetrahydropyridine, leur procede de preparation et compositions pharmaceutiques contenant lesdits composes en tant qu'agents actifs

Country Status (2)

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HU (1) HU208118B (fr)
WO (1) WO1991008200A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5589486A (en) * 1991-12-02 1996-12-31 Richter Gedeon Vegyeszeti Gyar Rt. N-hydroxyalkyl-substituted 1,2,3,6-tetrahydro-pyridine and piperidine derivatives
FR2757512A1 (fr) * 1996-12-24 1998-06-26 Sanofi Sa Utilisation de benzoylalkyl-1-1,2,3,6-tetrahydropyridines
EP1666464A1 (fr) * 2003-09-25 2006-06-07 Shionogi & Co., Ltd. Derive de piperidine presentant une activite antagoniste du recepteur ndma

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB948071A (en) * 1959-05-01 1964-01-29 May & Baker Ltd New heterocyclic compounds
GB1246656A (en) * 1967-12-13 1971-09-15 Robins Co Inc A H Aryl-tetrahydropyridinyl-alkanol and alkylamine derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB948071A (en) * 1959-05-01 1964-01-29 May & Baker Ltd New heterocyclic compounds
GB1246656A (en) * 1967-12-13 1971-09-15 Robins Co Inc A H Aryl-tetrahydropyridinyl-alkanol and alkylamine derivatives

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5589486A (en) * 1991-12-02 1996-12-31 Richter Gedeon Vegyeszeti Gyar Rt. N-hydroxyalkyl-substituted 1,2,3,6-tetrahydro-pyridine and piperidine derivatives
FR2757512A1 (fr) * 1996-12-24 1998-06-26 Sanofi Sa Utilisation de benzoylalkyl-1-1,2,3,6-tetrahydropyridines
WO1998028274A1 (fr) * 1996-12-24 1998-07-02 Sanofi Utilisation de benzoylalkyl-1,2,3,6-tetrahydropyridines
US6936621B2 (en) * 1996-12-24 2005-08-30 Sanofi-Aventis Use of benzoylalkyl-1,2,3,6-tetrahydropyridines
US7151107B2 (en) 1996-12-24 2006-12-19 Sanofi-Aventis Use of benzoylalkyl-1,2,3,6-tetrahydropyridines
US7297799B2 (en) 1996-12-24 2007-11-20 Sanofi-Aventis Preparation of benzoylalkyl-1,2,3,6-tetrahydropyridines and use thereof
EP1666464A1 (fr) * 2003-09-25 2006-06-07 Shionogi & Co., Ltd. Derive de piperidine presentant une activite antagoniste du recepteur ndma
JPWO2005030720A1 (ja) * 2003-09-25 2007-11-15 塩野義製薬株式会社 Ｎｍｄａ受容体拮抗作用を有するピペリジン誘導体
EP1666464A4 (fr) * 2003-09-25 2008-12-10 Shionogi & Co Derive de piperidine presentant une activite antagoniste du recepteur ndma
US7786140B2 (en) 2003-09-25 2010-08-31 Shionogi & Co., Ltd. Piperidine derivative having NMDA receptor antagonistic activity
JP4737418B2 (ja) * 2003-09-25 2011-08-03 塩野義製薬株式会社 Ｎｍｄａ受容体拮抗作用を有するピペリジン誘導体

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Publication number Publication date
HU896335D0 (en) 1990-02-28
HU208118B (en) 1993-08-30
HUT56065A (en) 1991-07-29

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