WO1992010495A1 - Nouveaux derives de 14-(aminomethyle n-substitue)eburbane, leur procede de preparation et compositions les contenant - Google Patents

Nouveaux derives de 14-(aminomethyle n-substitue)eburbane, leur procede de preparation et compositions les contenant Download PDF

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Publication number
WO1992010495A1
WO1992010495A1 PCT/HU1991/000051 HU9100051W WO9210495A1 WO 1992010495 A1 WO1992010495 A1 WO 1992010495A1 HU 9100051 W HU9100051 W HU 9100051W WO 9210495 A1 WO9210495 A1 WO 9210495A1
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WO
WIPO (PCT)
Prior art keywords
formula
galkyl
nitrogen atom
eburnane
group
Prior art date
Application number
PCT/HU1991/000051
Other languages
English (en)
Inventor
László Szporny
Béla Kiss
Egon Kárpáti
Éva PÁLOSI
Zsolt Szombathelyi
Ádám SARKADI
Anikó Gere
Mihály Bodó
Katalin Csomor
Judit Laszy
Zsolt Szentirmay
Erzsébet Lapis
Sándor Szabó
János Kreidl
György Visky
László Czibula
András NEMES
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 WO1992010495A1 publication Critical patent/WO1992010495A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine

Definitions

  • the invention relates to novel, optically active cis and trans 14-(N-substituted aminomethyl)eburnane derivatives and their pharmaceutically acceptable salts, the preparation thereof and pharmaceutical com ⁇ positions containing them.
  • novel compounds according to the invention are therapeutically useful, they possess mainly an antioxi ⁇ dative (lipid peroxidation-inhibiting) and cholinery (muscarine-1 agonist) effect.
  • the invention relates to pharmaceutical compositions containing these novel compounds as active ingredients, too.
  • antioxidative compounds Due to their lipid peroxidation-inhibiting effect, antioxidative compounds provide for a protective action against free radical-induced injuries under ischaemic hypoxic conditions; therefore, antioxidants as anti- ischaemic or antihypoxic substances are useful for the treatment of such clinical patterns.
  • M-l muscarinic-1
  • M-l receptors might be primary targets of therapeutical intervention aiming to restore of damaged cholinergic functions by compounds acting as selective agonists at M-l choli ⁇ nergic receptors.
  • the invention relates to novel, optically active cis and trans l4-(N-substituted aminomethyl)eburnane derivatives of the formula (I) ,
  • Rl stands for hydrogen, a C ⁇ galkyl or C 2 - 6 alkenyl group
  • R2 means a C ⁇ _galkyl, C2- 6 alkenyl or a hydroxy-Cx-galkyl group; or Rl and 2 represent together with the adjacent nitrogen atom - -
  • a 5 to 7-membered sat rated ring optionally containing one oxygen at and/or one optionally substituted nitrogen atom heteroatom; and n is 2 or 3, as well as their pharmaceutically acceptable salts and pha maceutical compositions containing these compounds.
  • the invention relates to a process for the preparati of these novel compounds.
  • Ri and R2 represent, together with the adjacen nitrogen atom to which they are attached, a nitrogen-con taining 5 to 7-membered saturated ring, said nitrogen ato may be substituted by a C _galkyl, C 2 - 6 alkenyl, phenyl-C -g alkyl, diphenylmethyl or p_-hydroxyphenyl group.
  • Wistar rats with about 200 to 250 g body-weight were decapitated and their whole brain was homogenized in 9 volu mes of a Krebs-Ringer buffer solution containing 15 mM HEPE
  • the inhibitory agents were given in a volume of 5 ⁇ l t 200 ⁇ l of the above homogenizate under cooling by ice, the the incubation mixture obtained was incubated at 37°C for 2 minutes.
  • the Fe 2+ -induced lipid peroxidation was elicited b adding 5 ⁇ l of a 8 mM Fe(NH4)2(SO4) _ solution.
  • the reaction was stopped by adding 1 ml o a stopping solution containing 0.8 M HC1 and 12.5% of tri- chloroacetic acid, then the samples were centrifuged with 2000 x g at 4°C in a Janetzky K-70 equipment for 10 minutes.
  • the receptor binding studies were carried out using plastic test tubes in a final volume of 1 ml of the same buffer containing 970 ⁇ l membrane suspension (about 1.2 mg membrane protein) , 10 ⁇ l of DMSO with the appropriate con ⁇ centrations of the test compounds and 20 ⁇ l of radioligand.
  • Nonspecific binding was defined in the presence of 1 ⁇ M of atropine.
  • the reaction was initiated by the addition of 1.0 nM of 3H-Cis-methyl-Dioxolane (specific activity: 2.1 TBq/mmol; New England Nuclear) and continued at 25°C for 60 min.
  • the incubation was terminated by rapidly filtering the mixture under vacuum through Whatman GF/B glass fiber filters presoaked in an aqueous polyethyleneimine solution (0.05%) for at least 30 min using a Brandel M 48R Cell Harvester. The filters were further washed with 20 ml of ice-cold washing buffer.
  • radioactivity re ⁇ tained on the filters was determined by liquid scintillation spectroscopy using an LKB Rackbeta liquid scintillation counter. IC 50 values were expressed in nM.
  • the receptor binding studies were carried out in a final volume of 1 ml of Krebs HEPES buffer containing 970 ⁇ l of membrane suspension (about 0.8 mg membrane protein), 10 ⁇ l of DMSO with the appropriate concentrations of the test compounds and 20 ⁇ l of radioligand.
  • Nonspecific binding was defined in the presence of 1 ⁇ M of atropine.
  • the reaction was initiated by the addition of 1.0 nM of 3H-Pirenzepine (specific activity: 3.2 TBq/mm ⁇ l; New England Nuclear) and continued at 30°C for 60 min. The incubation was terminated by rapidly filtering the mixture under vacuum through What ⁇ man BF/B glass fiber filters using a Brandel M 48R Cell Harvester. The filters were further washed with 20 ml of ice-cold washing buffer.
  • radioactivity re ⁇ tained on the filters was determined by liquid scintillation spectroscopy using an LKB Rackbeta liquid scintillation counter.
  • IC5 0 values were expressed in nM.
  • the receptor binding studies were carried out in a final volume of 1 ml of Krebs HEPES buffer containing 970 ⁇ l membrane suspension (about 0.8 mg membrane protein), 10 ⁇ l of DMSO with the appropriate concentrations of the test com ⁇ pounds and 20 ⁇ l of radioligand.
  • Nonspecific binding was defined in the presence of 1 ⁇ M of atropine.
  • the reaction was initiated by the addition of 1.0 nM of 3H-N-methyl- scopolamine (specific activity: 2.9 TBq/mmol; New England Nuclear) and continued at 30°C for 60 min.
  • the incubation was terminated by rapidly filtering the mixture under vacuum through Whatman BF/B glass fiber filters using a Brandel M 48R Cell Harvester. The filters were further washed with 20 ml of ice-cold washing buffer.
  • radioactivity re ⁇ tained on the filters was determined by liquid scintillation spectroscopy using an LKB Rackbeta liquid scintillation counter.
  • IC5 0 values were expressed in nM.
  • AD Alzheiner's disease
  • n is as defined above, with a primary or secondary amine of the formula (III) ,
  • Ri and R are as defined above, in an inert organic solvent in the presence of an acid binding agent and, if desired, converting the compound of the formula (I) obtained to its pharmaceutically acceptable salt.
  • novel trans compounds of formula (II) used as start ⁇ ing substances can be prepared by using the process described in Examples 1 and 2.
  • the novel cis compounds of formula (II) can similarly be prepared according to Examples 1 and 2, except that 14-hydroxymethyleburnane prepared according to Examples 6 and 7 of the Hungarian patent spec ⁇ ification No. 171,663 is used as starting substance.
  • the primary and secondary amines of the formula (III) are known, commercially available products.
  • Suitable primary amines are e.g. Cl-6alkylamines, C2-3 hydroxyalkylamines, benzylamine and phenethylamine.
  • Useful secondary amines are e.g. symmetric or asymmetric dialkylamines or dialkenyl- amines or 5 to 7-membered saturated cyclic amines containing optionally oxygen and/or optionally substituted nitrogen in their ring.
  • the starting 14-(chloroalkylammomethyl)eburnane deriva tive of the formula (II) is reacted with an amine of th formula (III) in an inert, high-boiling organic solvent at temperature of 100 to 160°C in the presence of an acid bind ing agent.
  • Any inorganic or organic base can be employed a an acid binding agent, which is inert under the reactio conditions.
  • Suitable inorganic acid binding agents are e.g. anhydrous potassium and sodium carbonate; useful organi acid binding agent is e.g. a dialkylaniline though even ⁇ tually, an excess of the a ine of formula (III) may prefer ⁇ ably be used as acid binding agent.
  • the compound of formula (I) formed can be separated in such a way that after termi ⁇ nation of the reaction, the mixture is diluted with water, the organic phase is dried, filtered, the solvent is removed and the residue is recrystallized from a suitable solvent or purified through salt formation in a known manner.
  • the compounds of formula (I) can be con ⁇ verted to their acid addition salts by reacting them with an inorganic or organic acid.
  • suitable inorganic acids for salt formation are hydrogen bromide; sulfuric acid; perhalogenic acids such as perchloric acid; useful organic acids are e.g. formic, acetic and propionic acid as well as alkanesulfonic acids, e.g. methanesulfonic and ethanesulfonic acid; and a ino acids such as aspartic or glutamic acid.
  • the active agents of formula (I) or their pharmaceuti ⁇ cally acceptable salts can be formulated to pharmaceutical compositions by mixing them with non-toxic inert, solid or liquid carriers and/or auxiliaries commonly used in the therapy for parenteral or enteral administration.
  • Suitable carriers are e.g. water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil and the like.
  • the active ingredient may be formulated in the form of usual pharmaceutical compo ⁇ sitions, particularly in a solid form, e.g. in the form of rounded or angled tablet, dragee, capsule such as gelatin capsule, pill, suppository and the like.
  • the amount of the solid carrier may be varied within a wide range; preferably, it is between about 25 mg and 1 g.
  • the pharmaceutical compositions may contain usual pharmaceutical additives, e.g. preservatives, stabili ⁇ zers, wetting or emulsifying agents and the like.
  • the compo ⁇ sitions can be prepared by using well known methods, e.g. in the case of solid compositions by sieving, mixing, granulat ⁇ ing and compressing the components.
  • the compositions may be subjected to other usual operation of the pharmaceutical technology, such as sterilization.
  • the invention also relates to a method of treating cognitive disorders and disorders connected with lipid per ⁇ oxidation.
  • This method comprises administering a therapeu- tically effective amount of an active agent of the formula (I) or a pharmaceutically acceptable salt thereof to the patient.
  • a daily dose of 0.1 to 50 mg/kg body weight is used generally for treating an adult human by administering this amount daily once or in divided doses.
  • Example 3 The process described in Example 3 was followed, except that 15 g of (+)-14 ⁇ -hydroxymethyl-3c_,16 ⁇ -eburnane were used as starting substance to give 17.5 g (98.7%) of an oily residue.
  • Example 13 The process described in Example 13 was followed, except that 4.8 g of ⁇ -phenethylamine were used instead of 8 ml of piperidine.
  • Example 17
  • Example 19
  • Example 20 Preparation of 14 ⁇ -[(diethylamino)ethylaminomethyl]- 3 ⁇ ,16 ⁇ -eburnane dihydrochloride

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Nouveaux dérivés cis et trans optiquement actifs de 14-(aminométhyle N-substitué)éburbane répondant à la formule (I), dans laquelle R1 représente hydrogène, ou un groupe alkyle C1-6 ou alcényle C2-6; R2 représente un groupe alkyle C1-6, alcényle C2-6 ou hydroxyalkyle C1-6; ou R1 et R2 représentent, conjointement avec l'atome d'azote voisin auquel ils sont liés, un cycle saturé penta- ou heptogonal renfermant éventuellement un atome d'oxygène et/ou un atome d'azote éventuellement substitué à titre d'hétéroatome; et n est 2 ou 3 ; ainsi que les sels pharmaceutiquement acceptables de ces composés. Lesdits composés présentent un effet antioxydant (inhibiteur de la peroxydation lipidique) et sont donc utiles au traitement des maladies associées à la peroxydation lipidique, par exemple les maladies intestinales ischémiques, l'ischémie myocardique, les troubles cérébro-vasculaires ischémiques ainsi que certaines maladies des tissus conjonctifs, par exemple la polyarthrite rhumatismale. Ces composés sont également utiles au traitement ou à la prophylaxie des troubles cognitifs.
PCT/HU1991/000051 1990-12-07 1991-12-06 Nouveaux derives de 14-(aminomethyle n-substitue)eburbane, leur procede de preparation et compositions les contenant WO1992010495A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
HU8107/90 1990-12-07
HU908107A HU207074B (en) 1990-12-07 1990-12-07 Process for producing optically active cis and trans 14-(n-substituted-aminomethyl)-eburnane derivatives and pharmaceutical compositions comprising same
CN91112610.4A CN1073945A (zh) 1990-12-07 1991-12-30 新的14-(n-取代的氨甲基)象牙烷衍生物，制备方法和组合物

Publications (1)

Publication Number Publication Date
WO1992010495A1 true WO1992010495A1 (fr) 1992-06-25

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PCT/HU1991/000051 WO1992010495A1 (fr) 1990-12-07 1991-12-06 Nouveaux derives de 14-(aminomethyle n-substitue)eburbane, leur procede de preparation et compositions les contenant

Country Status (4)

Country Link
CN (1) CN1073945A (fr)
AU (1) AU9050091A (fr)
HU (1) HU207074B (fr)
WO (1) WO1992010495A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7534800B2 (en) 2002-03-28 2009-05-19 Eisai R & D Development Co., Ltd. 7-azaindoles as inhibitors of c-Jun N-terminal kinases for the treatment of neurodegenerative disorders

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1392908A (en) * 1972-03-22 1975-05-07 Synthelabo Salts thereof
GB1461300A (en) * 1974-06-24 1977-01-13 Synthelabo Dihydroapovincaminic acid amides
GB1563396A (en) * 1975-09-01 1980-03-26 Richter Gedeon Vegyeszet 14-substituted vincane derivative and a process for the preparation thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1392908A (en) * 1972-03-22 1975-05-07 Synthelabo Salts thereof
GB1461300A (en) * 1974-06-24 1977-01-13 Synthelabo Dihydroapovincaminic acid amides
GB1563396A (en) * 1975-09-01 1980-03-26 Richter Gedeon Vegyeszet 14-substituted vincane derivative and a process for the preparation thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7534800B2 (en) 2002-03-28 2009-05-19 Eisai R & D Development Co., Ltd. 7-azaindoles as inhibitors of c-Jun N-terminal kinases for the treatment of neurodegenerative disorders

Also Published As

Publication number Publication date
AU9050091A (en) 1992-07-08
CN1073945A (zh) 1993-07-07
HU207074B (en) 1993-03-01
HU908107D0 (en) 1991-06-28

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