[go: up one dir, main page]

WO1994014768A1 - Nouveaux derives de pyrroline, compositions pharmaceutiques les contenant et leur procede de preparation - Google Patents

Nouveaux derives de pyrroline, compositions pharmaceutiques les contenant et leur procede de preparation Download PDF

Info

Publication number
WO1994014768A1
WO1994014768A1 PCT/HU1993/000076 HU9300076W WO9414768A1 WO 1994014768 A1 WO1994014768 A1 WO 1994014768A1 HU 9300076 W HU9300076 W HU 9300076W WO 9414768 A1 WO9414768 A1 WO 9414768A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
represents hydrogen
group
pyrroline
hydrogen
Prior art date
Application number
PCT/HU1993/000076
Other languages
English (en)
Inventor
György HOFFMAN
János Fischer
Elemér Ezer
Judit MATÚZ
Katalin Sághy
László Szporny
György Hajós
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 AU58215/94A priority Critical patent/AU5821594A/en
Publication of WO1994014768A1 publication Critical patent/WO1994014768A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones

Definitions

  • the invention relates to novel, therapeutically active pyrroline derivatives of the formula
  • R represents hydrogen, halogen, a C ⁇ _4alkyl or nitro group
  • R 1 represents hydrogen or a C 1 _ 4 alkyl group
  • R 2 represents a C 1 _ 4 alkyl group
  • m is 1 or 2
  • n is 0 or 1, with the proviso that R 1 means hydrogen when n is 1, as well as pharmaceutical compositions containing these compounds.
  • alkyl as used herein, includes saturated, monovalent hydrocarbon radicals having straight or branched carbon chains wherein the number of carbon atoms varies within the limits defined above, such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl or tert-butyl groups.
  • the halogen substituents may be chlorine, bromine, fluorine or iodine, preferably chlorine.
  • the compounds of the formula (I) according to the invention possess valuable pharmacological effects. Namely, they exert gastrocytoprotective and antibacterial effects and are useful for the prevention and/or healing of various inflammatory and ulcerative diseases of the oesophagus, stomach and duodenum.
  • Compounds of the formula (I) are especially active, when the aetiology of the disease is an infection induced by the pathogenic bacterial strain Helicobacter pylorus.
  • the invention relates also to a method for the prevention and/or healing of various ulcerative diseases of oesophagus, stomach and duodenum in a mammal, including human, which comprises administer ⁇ ing to said mammal a therapeutically effective amount of a compound of the formula (I) .
  • the gastrocytoprotective effect was expressed by the percentage of the average total length of longitu- dinal bleedings in relation to the average total length measured in the control group.
  • the ED 50 value of the compound of Example 1 was found to be 3.3 mg/kg of body weight in the above test after oral (p.o.) administration.
  • the ED5 0 value of Sucralfate, a known drug was found to be 150 mg/kg of body weight in the above test used for measuring the gastrocytoprotective effect.
  • the compounds of the formula (I) according to the invention substantially exceed the activity of the reference drugs both in the test showing the gastro ⁇ cytoprotective effect as well as in their activity against Helicobacter pylori bacteria.
  • the therapeutic dose for adult human patients may vary between 50 mg and 200 mg per day.
  • the active agents of the formula (I) can be transformed to pharmaceutical compositions by mixing them with non-toxic, inert, solid or liquid carriers and/or other auxiliaries commonly used in pharma ⁇ ceutical formulations for parenteral or enteral administration.
  • Useful carriers are e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil and the like.
  • the active agent can be for ⁇ mulated to usual pharmaceutical compositions, par- ticularly solid compositions, e.g. rounded or edged tablets, dragees or capsules such as gelatine capsules, pills, suppositories and the like.
  • the amount of the solid active agent may be varied within broad limits, preferably it is between about 25 mg and 1 g per unit dose (i.e. tablet, capsule, one unit of solution, etc.).
  • these compositions may also contain other conventional pharmaceutical auxiliaries, e.g. stabilizers, preservatives, wetting agents, emul ⁇ sifying agents and the like.
  • the compositions can be prepared in a known manner, e.g. by sieving, mixing.
  • compositions may be subjected to other usual operations of the pharmaceutical tech ⁇ nology, e.g. sterilization.
  • the dose level to be used can be varied within broad limits depending on the body weight and the individual response of the patient or animal being treated, sever ⁇ ity of the condition to be influenced as well as the frequency and the particular route of administration.
  • the amount of the suitable dose can easily be determined by a physician skilled in the art.
  • the invention relates also to a method for the prevention and/or healing of various ulcerative diseases of oesophagus, stomach and duodenum.
  • This method comprises administering a therapeutically effect ⁇ ive amount of an active agent of the formula (I) to the patient.
  • novel pyrroline de ⁇ rivatives of general formula (I) are prepared by ir- radiating a 4-phenyl-4-oxo-2-butenoic acid amide derivative of the formula
  • This reaction is carried out in a photoreactor by irradiation with a high-pressure mercury vapour lamp in an inert organic solvent, preferably methanol. After a reaction lasting for 6 to 8 hours at room temperature the compounds of the formula (I) can be isolated in a yield of about 70 to 90%.
  • the compounds of the formula (II) can be ob ⁇ tained as described in Hungarian Patent No. 198,294. The preparation of novel derivatives thereof is des ⁇ cribed in Example 11.
  • R and m are as defined above, with the cor- responding amino acid by using the mixed anhydride method.
  • amino acid reactants are either commercially available products or they can be prepared according to the process described in: Houben-Weyl, 15/1. pages 316 to 340, Thieme-Verlag, Stuttgart (1974).
  • reaction mixture is success ⁇ ively extracted with 50 ml of water, 50 ml of a 10% sodium bicarbonate solution, 50 ml of a 5% hydrochloric acid solution and finally twice with 50 ml of water each.
  • the solid residue is suspended in diethyl ether and then filtered to obtain a yield of 50 to 80%.
  • Tablets weighing 150 or 300 mg, respectively each are compressed from the powder mixture with the composi ⁇ tion defined under a) or under b) , respectively in the usual manner by wet granulation and compression.
  • Each tablet contains 5 or 50 mg, respectively of active ingredient.

Landscapes

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

Abstract

Nouveaux dérivés de pyrroline répondant à la formule (I), dans laquelle R représente hydrogène, halogène, ou un groupe alkyle C1-4 ou nitro; R1 représente hydrogène ou un groupe alkyle C¿1-4; R?2 représente un groupe alkyle C¿1-4?; m est 1 ou 2; et n est 0 ou 1, à condition que R?1¿ représente hydrogène lorsque n est 1; et compositions pharmaceutiques contenant ces composés. On a également prévu un procédé de préparation des composés et compositions précités. Les composés de la formule (I) présentent une activité cytoprotectrice ainsi qu'une activité antibactérienne dirigée contre les souches de Helicobacter pylori. De ce fait, ils sont utilisables dans la prévention et/ou le traitement de diverses maladies inflammatoires et ulcératives du duodénum, de l'estomac et de l'÷sophage.
PCT/HU1993/000076 1992-12-23 1993-12-17 Nouveaux derives de pyrroline, compositions pharmaceutiques les contenant et leur procede de preparation WO1994014768A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58215/94A AU5821594A (en) 1992-12-23 1993-12-17 Novel pyrroline derivatives, pharmaceutical compositions containing them and process for preparing same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU9204118A HU213105B (en) 1992-12-23 1992-12-23 Process for producing pyrroline derivatives and pharmaceutical compositions containing them
HUP9204118 1992-12-23

Publications (1)

Publication Number Publication Date
WO1994014768A1 true WO1994014768A1 (fr) 1994-07-07

Family

ID=10982770

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU1993/000076 WO1994014768A1 (fr) 1992-12-23 1993-12-17 Nouveaux derives de pyrroline, compositions pharmaceutiques les contenant et leur procede de preparation

Country Status (4)

Country Link
CN (1) CN1095711A (fr)
AU (1) AU5821594A (fr)
HU (1) HU213105B (fr)
WO (1) WO1994014768A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014006629A1 (fr) * 2012-07-02 2014-01-09 Pnb Vesper Life Science Pvt Limited Nouveaux ligands d'un récepteur de la cholécystokinine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993008190A1 (fr) * 1991-10-25 1993-04-29 Byk Gulden Lomberg Chemische Fabrik Gmbh Pyrrolo-pyridazine a effets protecteurs du tube gastro-intestinal

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993008190A1 (fr) * 1991-10-25 1993-04-29 Byk Gulden Lomberg Chemische Fabrik Gmbh Pyrrolo-pyridazine a effets protecteurs du tube gastro-intestinal

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 96, No. 3, issued 18 January 1982, (Columbus, Ohio, USA), J. ROBERT et al., "Synthesis and Pharmacological Activity of Some Pyrrolidinonecarboxylic Acids and Several Derivatives", pages 432, column 2, abstract no. 19904 b; & ANN. PHARM. FR. 1981, 39(4), 337-46, (Fr.). *
CHEMICAL ABSTRACTS, Volume 96, No. 3, issued 18 January 1982, (Columbus, Ohio, USA), K. YAKUSHIJIN et al., "Ring Transformation of 2-Furylcarbamates to 5-Hydroxy-3-Pyrroline-2-Ones. Effects of Substitution in the Benzene Ring on the N-Carbobenzyloxy-5-Hydroxy-5-Phenyl-3-Pyrro line-2-One - Cis-Gamma-Ketoamide *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014006629A1 (fr) * 2012-07-02 2014-01-09 Pnb Vesper Life Science Pvt Limited Nouveaux ligands d'un récepteur de la cholécystokinine
EA027136B1 (ru) * 2012-07-02 2017-06-30 Пнб Веспер Лайф Сайенс Пвт Лимитед Новые лиганды холецистокининовых рецепторов

Also Published As

Publication number Publication date
AU5821594A (en) 1994-07-19
HU9204118D0 (en) 1993-04-28
HU213105B (en) 1997-05-28
CN1095711A (zh) 1994-11-30

Similar Documents

Publication Publication Date Title
EP0550006B1 (fr) Utilisation de dérivés N-acylés d'aminoalcools pour la fabrication d'un médicament pour le traitement de maladies mastocytaires
FR2530247A1 (fr) Nouveaux derives de la thieno (3, 2-c) pyridine, leur procede de preparation et leur application therapeutique
KR960005167B1 (ko) 3-l-피로글루타밀-l-티아졸리딘-4-카르복실산 및 그 제조 방법
WO1991016338A1 (fr) Derive de glutathion a substitution-s-(acide gras inferieur)
EP0089900B1 (fr) N-((2-oxo-1-pyrrolidinyl)acétyl)pipérazines, procédés pour leur préparation et leurs sels, ainsi que leur utilisation dans des préparations pharmaceutiques
HUT63610A (en) Process for producing immune modifying n-phenyl-2-cyano-3-hydroxycrotonic acid derivatives and pharmaceutical compositions comprising such compounds
HU203766B (en) Process for producing estramustine-esters and pharmaceutical compositions containing them as active components
EP0007441B1 (fr) N - (N-Acétyl-L-methionyl) - 3,4 -diethoxy-carbonyloxy-phénéthylamine, procédé pour sa préparation et compositions pharmaceutiques la contenant.
CS209857B2 (en) Method of making the new derivatives of the aminoacids
WO1994014768A1 (fr) Nouveaux derives de pyrroline, compositions pharmaceutiques les contenant et leur procede de preparation
CH646138A5 (fr) Amino-2-benzoyl-3-phenylacetamides et leurs homologues cycliques utiles comme medicaments et compositions pharmaceutiques les contenant.
CA2091459A1 (fr) Derives de l'acide amino 5 salicylique pour le traitement des maladies inflammatoires chroniques de l'intestin
US5116857A (en) Method of increasing gastrointestinal motility with substituted benzamides
EP0226753A2 (fr) Alpha-tocophérol (halo) uridine diester de l'acide phosphorique, leurs sels, leurs procédés de préparation
LU84429A1 (fr) A titre de medicaments,certains derives de l'acide 4-phenyl 4-oxo 2-butenoique et compositions les renfermant
CZ20021433A3 (cs) Proléčivo na bázi 6-methoxy-2-naftyloctové kyseliny
EP0166439B1 (fr) Dérivés de la 4H-pyrimido(2,1-a)isoquinoléine-4-one
EP0309261B1 (fr) Amides d'acide buténoique, leur sels, compositions pharmaceutiques les contenant et leur procédé de préparation
WO1993012079A1 (fr) Nouveaux derives d'ester de phenylsulfonylacrylate
JPS6354338A (ja) ４−フエニル−４−オキソ−２−ブテン酸の新誘導体、その製造法、薬剤としての使用及びそれを含有する組成物
EP0106251A1 (fr) Dérivés de pyrazolidinedione doués d'activités vasodilatatrices, antiagrégatives et hypocholestérolémiques
US4156009A (en) Diazepine derivatives
EP0022737B1 (fr) Imines dérivées de l'amino-5 benzodioxole-1,3 utiles comme médicaments et leur préparation
WO1994014788A1 (fr) Nouveaux derives de benzene a cycles pentagonaux condenses, compositions pharmaceutiques les contenant, et leur procede de preparation
US4443474A (en) Pharmaceutical N-phenyl carbamoyl glycinate compositions

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BY CA CZ FI JP KR KZ LK NO NZ PL RO RU SK UA 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