WO1995003291A1 - Nouveaux derives substitues de 1-propene, compositions pharmaceutiques les contenant et leur procede de preparation - Google Patents

Nouveaux derives substitues de 1-propene, compositions pharmaceutiques les contenant et leur procede de preparation Download PDF

Info

Publication number
WO1995003291A1
WO1995003291A1 PCT/HU1994/000030 HU9400030W WO9503291A1 WO 1995003291 A1 WO1995003291 A1 WO 1995003291A1 HU 9400030 W HU9400030 W HU 9400030W WO 9503291 A1 WO9503291 A1 WO 9503291A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid addition
propene
formula
phenyl
addition salts
Prior art date
Application number
PCT/HU1994/000030
Other languages
English (en)
Inventor
Tibor Gizur
Kálmán Harsányi
Attila Csehi
Szabó Anikó DEMETERNÉ
Éva VAJDA
László Szporny
Béla Kiss
Egon Kárpáti
Éva PÁLOSI
Ádám SARKADI
Kálmán Eszter THÚRÓCZYNÉ
Judit Laszy
Katalin Csomor
Erzsébet Lapis
Sándor Szabó
Anikó Gere
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.
Priority to AU74665/94A priority Critical patent/AU7466594A/en
Publication of WO1995003291A1 publication Critical patent/WO1995003291A1/fr

Links

Classifications

    • 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
    • C07D295/027—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 containing only one hetero ring
    • C07D295/03—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 containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon 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
    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • the invention relates to novel, therapeutically active 1-propene derivatives of the formula (I) ,
  • X and Y are independently from each other unsubstituted or halogen substituted phenyl or benzyl group, as well as their acid addition salts and pharmaceutical compositions containing these compounds.
  • the invention relates to a process for preparation of the above compounds and compositions.
  • the compounds of formula (I) according to the invention show a very significant antiischaemic and antihypoxic effect exceeding those of known compounds possessing a similar action. Thus, they can be used to protect the organism from the hypoxia-induced harmful sequels or to diminish these sequels.
  • the invention relates also to a method of treatment, which comprises administering a thera ⁇ Implantically effective amount of one or more compound(s) of formula (I) or a pharmaceutically acceptable acid addition salt thereof alone or in the form of a pharma ⁇ ceutical composition into the organism of a mammal (including human) to be treated, for achieving an anti ⁇ ischaemic and/or antihypoxic effect, i.e. for strengthen- ing the tolerance to hypoxic states.
  • the novel compounds of formula (I), wherein X and Y are as defined above, as well as their acid addition salts are prepared by treating an 1-propanol derivative of formula (II),
  • X and Y are as defined above, or an acid addition salt thereof with a dehydrating agent, then, if desired, converting a thus obtained base of formula (I) , wherein X and Y are as defined above, to an acid addition salt by treating the base with an acid; and/or, if desired, liberating a free base of formula (I), wherein X and Y are as defined above, from its acid addition salt by treating the salt with a base.
  • a mixture of concentrated hydrochloric acid solution and glacial acetic acid is used as dehydrating agent and the reaction is carried out under boiling.
  • isopropenyl acetate may also be employed as dehydrating agent in an acidic medium.
  • the reaction is accomplished in an inert solvent such as dioxane.
  • the reaction is carried out at the boiling point of the reaction mixture with reaction times of 30 to 120 minutes.
  • the progress of the reaction can be followed by thin layer chro atography (TLC) .
  • TLC thin layer chro atography
  • the compound of formula (I) formed in the reaction can be isolated e.g. by filtration or, after evaporating the reaction mixture, by adding water and then carrying out filtration or extraction. If desired, the compounds of formula (I) isolated may be purified by recrystallization from an organic solvent.
  • the compounds of formula (II) used as starting substances in the process according to the invention are similarly new 1-propanol derivatives and also possess a bio ⁇ logical activity. However, differently from that of the target compounds of the present invention, they show antipsychotic and/or anxiolytic effects.
  • Complex metal hydrides e.g. sodium borohydride
  • the reduction of the oxo derivatives of formula (III) by sodium borohydride is suitably carried out on the base form of the compound to be reduced, preferably in a lower alcohol or in a mixture of such an alcohol and acetonitrile at a temperature between 20 °C and 25 °C under stirring. The progress of the reaction may be followed by thin layer chromatography.
  • the oxo compounds of formula (III) which are also novel, can preferably be prepared in a manner known in se by reacting an oxo derivative of formula (IV) ,
  • mice After starvation for 16 hours the mice were treated with oral doses of the substances to be tested. One hour following this treatment the animals were placed in air- tight glass bottles of 100 ml volume each and the survival time of the animals was measured. In the case of groups consisting of 10 animals each treated with the compounds, animals were considered to be protected, if their survival time was at least by 30 % longer than that of the average survival time of the placebo-treated group. The effective dose of 50 % (ED50 value) was calculated from the percentage of surviving animals by using probit analysis.
  • each animal was treated with 5 mg intravenous (i.v.) dose of potassium cyanide.
  • the survival time was measured from the time of administering potassium cyanide until the last respiratory movement.
  • the protective effect was stated according to the evaluation described above for the anoxic asphyxia.
  • the rats were placed by pairs in desiccators of 6 1 volume each.
  • the pressure in the desiccator was decreased to 170 Hgmm (22.66 kPa) during 20 seconds and the survival time was measured from this point until the last respiratory movement. Animals were considered to be protected if their survival time was at least by 30 % longer than the average survival time of the control group.
  • the effective dose of 50 % (ED5 0 value) with the pertaining fiducial limits of 95 % were calculated from the percentage of protected animals by using porbit analysis.
  • Electroshock was induced on mice by introducing a current of 20 mA for 0.2 second through corneal electrodes.
  • the abolishment of tonic extensor convulsion under effect of treatment was considered to be protective effect.
  • the ED50 value was calculated from the percentage of protected animals by using probit analysis.
  • Nimodipine chemically i ⁇ opropyl 2-methoxyethyl-l,4- -dihydro-2,6-dimethyl-4-(m-nitrophenyl) - -3,5-pyridinedicarboxylate
  • Flunarizine chemically l-cinnamyl-4-[bis(4-fluoro- phenyl)methyl]piperazine
  • the antihypoxic and cerebroprotective effects of the compounds of formula (I) are 2 to 4 times stronger than those of any of both reference drugs used for comparison in all models used for investigating the tolerance of healthy animals against a severe hypoxic insult with a fatal end.
  • the antihypoxic effect is even more significant on spontaneously hypertensive (SH) animals [test No. 4)].
  • the anticonvulsive effect of compounds of formula (I) is also stronger than or about similar to such effect of the reference drugs.
  • the therapeutical utilization of compounds of formula (I) may be taken into consideration in all clinical pictures where the mental and cognitive functions are injuried as a consequence of chronic disturbances of the cerebral metabolism and/or circula- tion.
  • the daily dose of compounds of formula (I) is 0.1 to 10 mg/kg of body- weight given in a single dose or in several subdoses through oral or parenteral route.
  • the active compounds of formula (I) can be trans ⁇ formed to pharmaceutical compositions by mixing them with nontoxic inert solid or liquid carriers and/or additives commonly used in the therapy for enteral or parenteral administration.
  • Useful carriers are inter alia e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, talc or vegetable oils.
  • the active compounds may be formulated to the usual pharmaceutical compositions such as especially to solid forms, e.g. rounded or edged tablet, dragee, capsule (such as gelatine capsule) , pill, suppository and the like.
  • the amount of the solid active ingredient may be varied within broad limits, preferably it may be between 25 mg and 1 g in one tablet.
  • the compositions may contain the common pharmaceutical auxiliaries, e.g. preservatives. These compositions may be prepared by using common methods, e.g. sieving, mixing, granulating and optionally compressing the ingredients to obtain solid compositions.
  • the compositions may be subjected to further usual operations of the pharmaceutical techno- logy, e.g. sterilization to obtain injectable composi ⁇ tions.
  • the dry product was dissolved in 30 ml of chloroform and acidified to pH 2 by adding ethanolic hydrogen chloride solution. After evaporation of the solution the residue was recrystallized from isopropanol to give the title compound in a yield of 2.68 g (73 %) , m.p.: 199-200 °C.

Landscapes

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

Abstract

L'invention se rapporte à de nouveaux dérivés substitués de 1-propène de la formule (I), dans laquelle X et Y représentent indépendamment l'un de l'autre un groupe phényle ou benzyle non substitué ou substitué par halogène, ainsi que des sels d'addition acides de ceux-ci, ainsi qu'un procédé de préparation des composés et compositions décrits ci-dessus. Les composés de l'invention ont une activité anti-ischémique et/ou antihypoxique. L'invention se rapporte également à un procédé de traitement de l'ischémie ou de l'hypoxie dont souffrent les mammifères (y compris l'homme), procédé qui consiste à administrer une ou plusieurs dose(s) thérapeutiquement efficace(s) des composés de l'invention.
PCT/HU1994/000030 1993-07-26 1994-07-26 Nouveaux derives substitues de 1-propene, compositions pharmaceutiques les contenant et leur procede de preparation WO1995003291A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU74665/94A AU7466594A (en) 1993-07-26 1994-07-26 Novel substituted 1-propene derivatives, pharmaceutical compositions containing them and process for preparing same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP9302155 1993-07-26
HU9302155A HU9302155D0 (en) 1993-07-26 1993-07-26 New substituted 1-propene derivatives and method for producing them

Publications (1)

Publication Number Publication Date
WO1995003291A1 true WO1995003291A1 (fr) 1995-02-02

Family

ID=10983828

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU1994/000030 WO1995003291A1 (fr) 1993-07-26 1994-07-26 Nouveaux derives substitues de 1-propene, compositions pharmaceutiques les contenant et leur procede de preparation

Country Status (4)

Country Link
AU (1) AU7466594A (fr)
HU (1) HU9302155D0 (fr)
IS (1) IS4194A (fr)
WO (1) WO1995003291A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0755923A1 (fr) * 1995-01-23 1997-01-29 Suntory Limited Ameliorant ou remede contre des symptomes provoques par des maladies ischemiques et composes utiles a cet effet

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 106, No. 11, issued 1987, March 16, (Columbus, Ohio, USA), J. ROCAS-SOROLLA, "Process for Preparing N'-Substituted N-Cinnamyl - Piperazines", page 617, Abstract No. 84652g; & ES,A,549 465. *
CHEMICAL ABSTRACTS, Volume 108, No. 17, issued 1988, April 25, (Columbus, Ohio, USA), H. OHTAKA, "Benzylpiperazine Derivatives. I. Syntheses and Biological Activities of 1-(2,3,4-Trimethoxybenzyl)Piperazine Derivatives", page 742, Abstract No. 150421a; & CHEM. PHARM. BULL., 1987, 35(7) 2774-81. *
CHEMICAL ABSTRACTS, Volume 74, No. 5, issued 1971, February 01, (Columbus, Ohio, USA), T. IRIKURA, "1-Benzyl-4-Cinnamylpiperazine Derivatives", page 318, Abstract No. 22879y; & JP,B,45 029 508 (26-09-70). *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0755923A1 (fr) * 1995-01-23 1997-01-29 Suntory Limited Ameliorant ou remede contre des symptomes provoques par des maladies ischemiques et composes utiles a cet effet
EP0755923A4 (fr) * 1995-01-23 1997-04-09 Suntory Ltd Ameliorant ou remede contre des symptomes provoques par des maladies ischemiques et composes utiles a cet effet
US6048876A (en) * 1995-01-23 2000-04-11 Suntory Limited Medicament for the alleviation or treatment of symptom derived from ischemic disease and compound useful therefor
US6469010B1 (en) 1995-01-23 2002-10-22 Suntory Limited Medicament for the alleviation or treatment of symptom derived from the ischemic disease and compound useful thereof

Also Published As

Publication number Publication date
AU7466594A (en) 1995-02-20
HU9302155D0 (en) 1993-10-28
IS4194A (is) 1995-01-27

Similar Documents

Publication Publication Date Title
BG63992B1 (bg) Амидно съединение и приложение му като rho киназен инхибитор
CH644105A5 (fr) Acides et esters 4-amino-3-quinoleinecarboxyliques, utiles notamment comme agent antisecretoires et anti-ulcere.
CZ277698B6 (en) Racemic or optically active bis-aza-bicyclic compounds, process for preparing thereof, intermediates and use thereof
EP0198456B1 (fr) Dérivés de la 1,7-naphtyridine et préparations médicales les contenant
US4052508A (en) Heterocyclic dihydroanthracen imines
US4179563A (en) 3-Aryloxy-substituted-aminopyridines and methods for their production
EP0316279A2 (fr) Composés azacycliques ayant un groupe hydroxyle estérifié
GB2214181A (en) 1,2-ethylene diamine compounds
US5204343A (en) 5h-benzodiazepin derivative
DE2804519C2 (fr)
KR100352899B1 (ko) 새로운3-페닐설포닐-3,7-디아자바이사이클로[3,3,1]노난-화합물을함유하는약제
SU927111A3 (ru) Способ получени оксимэфиров или их солей
DE69215482T2 (de) 2,2'-Alkylendiindolderivate, Verfahren zu ihrer Herstellung, sie enthaltende Arzneimittel und deren Verwendung als Ulcustherapeutikum
KR870001681B1 (ko) 히단토인 유도체의 제조방법
WO1995003291A1 (fr) Nouveaux derives substitues de 1-propene, compositions pharmaceutiques les contenant et leur procede de preparation
EP0427526A1 (fr) Dérivés de la pyridine, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0725776B1 (fr) 3-aryl-4-alkyl et 4,5-dialkyl-4h-1,2,4-triazoles permettant d'ameliorer la memoire
US5114944A (en) 2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid derivatives exhibiting therapeutic effects
DE3432985C2 (fr)
DE3605676C2 (de) Ergolinderivate und deren Säureadditionssalze und deren Verwendung
EP0425282A2 (fr) Dérivés triazolo et leur procédé de préparation
EP0171912B1 (fr) Composés de pyrrolizidine, leurs méthodes de préparation et leur utilisation
CA1220200A (fr) Procede de preparation d'halomethylates de levallorphan et composes pharmaceutiques les contenant et ayant une action inhibitrice des opiaces
JP2001512731A (ja) ＡＭＰＡ／Ｋａｉｎａｔｅ受容体阻害剤としての１，３−ジオキソロ／４，５−Ｈ／２，３／ベンゾジアゼピン誘導体
US3760082A (en) Compositions containing 5-amino-3-ethyl-1-phenyl-4-pyrazolecarboxamides and methods of using the same

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA CN FI JP KR LK NO NZ US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA