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WO1993013776A1 - Utilisation d'antagonistes du paf pour le traitement de la dysmenorrhee - Google Patents

Utilisation d'antagonistes du paf pour le traitement de la dysmenorrhee Download PDF

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Publication number
WO1993013776A1
WO1993013776A1 PCT/EP1993/000047 EP9300047W WO9313776A1 WO 1993013776 A1 WO1993013776 A1 WO 1993013776A1 EP 9300047 W EP9300047 W EP 9300047W WO 9313776 A1 WO9313776 A1 WO 9313776A1
Authority
WO
WIPO (PCT)
Prior art keywords
dysmenorrhea
paf
thieno
sri
triazolo
Prior art date
Application number
PCT/EP1993/000047
Other languages
German (de)
English (en)
Inventor
Eberhard Kutter
Original Assignee
Eberhard Kutter
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 Eberhard Kutter filed Critical Eberhard Kutter
Publication of WO1993013776A1 publication Critical patent/WO1993013776A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • the invention relates to the use of
  • PAF antagonists in particular PAF antagonists of hetrazepinoid structure for the treatment of
  • Dysmenorrhea especially the primary dysmenorrhea.
  • Sex hormones can also have a number of side effects, including:
  • Prostaglandin synthesis inhibitor or cyclooxygenase inhibitor proposed; the disadvantages of such active substances - in particular the occurrence of gastric and intestinal ulcers are well known. With all these preparations, the effect, especially with heavy forms, is
  • Another task was to provide a drug for treatment with fewer side effects. This task is accomplished by using
  • PAF antagonists in particular solved by PAF antagonists of hetrazepinoid structure.
  • This task is accomplished by using
  • PAF antagonists resolved in the treatment of dysmenorrhea, especially primary dysmenorrhea.
  • PAF platelet activating factor
  • Patent literature and the specialist literature known e.g. in Prostaglandins 35, 781 (1988) or also in Handbook of PAF and PAF-Antagonists, Pierre Braguest, 1991 by CRC Press, Inc.
  • PAF antagonists are, for example, L-668750, LG-30435, MK-287, UK 74.505, Y 20411, Y24180,
  • PAF antagonists are also of interest.
  • EP-A-0.254.245 EP-A-0.255.028, EP-A-0.268.242,
  • EP-A-0.279.681 EP-A-0.284.359, EP-A-0.291.594,
  • Hetrazepines of the general formula are of particular interest .
  • R 1 is hydrogen, a branched or unbranched
  • R 2 is a radical of the formula
  • A is branched or unbranched
  • n is one of the numbers 0, 1, 2, 3, 4, 5, 6, 7 or 8
  • R 6 and R 7 which can be the same or different
  • R 6 or R 7 is a saturated or unsaturated 5-, 6- or 7-membered heterocyclic ring optionally substituted one or more times by branched or unbranched alkyl having 1 to 4 carbon atoms, bonded via a carbon atom or nitrogen; or
  • Alkyl groups with 1 to 4 carbon atoms Alkyl groups with 1 to 4 carbon atoms
  • substituted 5-, 6- or 7-ring which may contain nitrogen, oxygen or sulfur as further heteroatoms, where each further nitrogen atom may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl; R 8 phenyl, substituted phenyl;
  • R 9 is hydrogen, C 1 to C 4 alkyl
  • R 3 is hydrogen, C 1 -C 4 alkyl
  • R 4 is phenyl, where the phenyl ring can be substituted one or more times, preferably halogen, nitro and / or trifluoromethyl;
  • R 5 is hydrogen, hydroxy, C 1 -C 4 -alkyl
  • R 2 and R 3 together form a fused-on five- or six-membered ring of the formula
  • Ra is a radical of the formula wherein A, R 6 , R 7 , R 8 and R 9 are the aforementioned
  • R 10 is C 1 -C 4 alkyl or cyclopropyl
  • R 4 is phenyl, where the phenyl ring can be substituted one or more times, preferably halogen, nitro and / or trifluoromethyl;
  • R 5 is hydrogen, hydroxy, C 1 -C 4 alkyl, preferably methyl, optionally substituted by hydroxy or halogen
  • X can be nitrogen or CH.
  • R 2 -CH 2 -CH 2 -CONR 6 R 7
  • R 2 -CH 2 -CH 2 -NR 6 R 7
  • R 2 -CH 2 -CH 2 iso-butyl
  • R 6 / R 7 C 3 H 7 is particularly preferred
  • R 5 hydrogen, or methyl
  • R 4 ortho chlorophenyl
  • alkyl groups also insofar as they are part of other radicals
  • alkyl groups are: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.
  • Alkenyl groups are, for example, the alkyl groups mentioned above, provided that they have at least one double bond, such as vinyl (if no unstable enamines are formed), propenyl, isopropenyl, butenyl, pentenyl, hexenyl.
  • Alkynyl groups are, for example, alkyl groups mentioned above, provided that they have at least one triple bond, such as, for example, propargyl, butynyl, pentynyl, hexynyl.
  • Cycloalkyl radicals having 3 to 6 carbon atoms are, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which can be substituted by branched or unbranched alkyl having 1 to 4 carbon atoms, hydroxy, and / or halogen.
  • Heterocycles can be substituted by alkyl with 1 to 4 carbon atoms - preferably methyl;
  • heterocyclic radicals which can be linked via a carbon atom are thiophene, 2-methylthiophene, furan, tetrahydrofuran,
  • Definition generally also stands for a 5- to 6-membered ring which may contain oxygen, sulfur and / or nitrogen as heteroatoms, such as, for example, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolyl,
  • the drug is expediently taken when the menstrual pain begins, as
  • PAF antagonists generally graded compared to this compound according to their relative PAF receptor binding affinities.
  • the compounds can be administered orally or parenterally
  • Suppositories are administered.
  • the compounds are active ingredients in the usual way
  • compositions consisting essentially of an inert pharmaceutical
  • Carrier and an effective dose of the active ingredient e.g. Tablets, coated tablets, capsules,
  • the dosage then having to be correspondingly lower than in the case of oral application.
  • the active ingredient corn starch, milk sugar and
  • Polyvinyl pyrrolidone are mixed and moistened with water.
  • the moist mixture is pressed through a sieve with a mesh size of 1.5 mm and dried at approx. 45 ° C.
  • the dry granulate is passed through a sieve with a 1.0 mm mesh size and with
  • Magnesium stearate mixed The finished mixture is pressed into tablets on a tablet press with stamps of 7 mm in diameter, which are provided with a partial notch.
  • the active ingredient corn starch, milk sugar and
  • Polyvinyl pyrrolidone are mixed well and moistened with water.
  • the moist mass is pressed through a sieve with a 1 mm mesh size, dried at approx. 45 ° C and then the granules are passed through the same sieve.
  • domed dragee cores with a diameter of 6 mm are pressed on a tablet machine.
  • the dragee cores thus produced are coated in a known manner with a layer consisting essentially of sugar and talc.
  • the finished coated tablets are polished with wax.
  • Corn starch is moistened evenly with an aqueous polyvinyl pyrrolidone solution.
  • the mass is passed through a sieve with a mesh size of 2 mm
  • the substance and corn starch are mixed and moistened with water.
  • the moist mass is sieved and
  • the dry granules are sieved and mixed with magnesium stearate.
  • the final mixture is filled into size 1 hard gelatin capsules.
  • the hard fat is melted.
  • the milled active substance is homogeneously dispersed at 40 ° C. It is cooled to 38 ° C and weakly pre-cooled
  • Distilled water is heated to 70 ° C. Hydroxyethyl cellulose is dissolved therein with stirring. After adding sorbitol solution and glycerin, the mixture is cooled to room temperature. Sorbic acid, aroma and substance are added at room temperature. To vent the suspension, evacuate with stirring.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'antagonistes du PAF (facteur d'activation plaquettaire) pour le traitement de la dysménorrhée.
PCT/EP1993/000047 1992-01-13 1993-01-12 Utilisation d'antagonistes du paf pour le traitement de la dysmenorrhee WO1993013776A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19924200610 DE4200610A1 (de) 1992-01-13 1992-01-13 Verwendung von paf-antagonisten zur behandlung der dysmenorrhea
DEP4200610.4 1992-01-13

Publications (1)

Publication Number Publication Date
WO1993013776A1 true WO1993013776A1 (fr) 1993-07-22

Family

ID=6449410

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1993/000047 WO1993013776A1 (fr) 1992-01-13 1993-01-12 Utilisation d'antagonistes du paf pour le traitement de la dysmenorrhee

Country Status (2)

Country Link
DE (1) DE4200610A1 (fr)
WO (1) WO1993013776A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7618975B2 (en) 2003-07-03 2009-11-17 Myriad Pharmaceuticals, Inc. 4-arylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US7989462B2 (en) 2003-07-03 2011-08-02 Myrexis, Inc. 4-arylamin-or-4-heteroarylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
US8796261B2 (en) 2010-12-02 2014-08-05 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9249161B2 (en) 2010-12-02 2016-02-02 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9328117B2 (en) 2011-06-17 2016-05-03 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9422292B2 (en) 2011-05-04 2016-08-23 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9493483B2 (en) 2012-06-06 2016-11-15 Constellation Pharmaceuticals, Inc. Benzo [C] isoxazoloazepine bromodomain inhibitors and uses thereof
US9624244B2 (en) 2012-06-06 2017-04-18 Constellation Pharmaceuticals, Inc. Benzo [B] isoxazoloazepine bromodomain inhibitors and uses thereof
US9969747B2 (en) 2014-06-20 2018-05-15 Constellation Pharmaceuticals, Inc. Crystalline forms of 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[C]isoxazolo[4,5-e]azepin-4-yl)acetamide

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7607872A (nl) * 1975-07-16 1977-01-18 Boehringer Sohn Ingelheim Werkwijze voor de bereiding van gesubstitueerde 6-aryl-h-s-triazolo-(3,4-c)-thieno-(2,3-e)-1,4- -diazepinen.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7607872A (nl) * 1975-07-16 1977-01-18 Boehringer Sohn Ingelheim Werkwijze voor de bereiding van gesubstitueerde 6-aryl-h-s-triazolo-(3,4-c)-thieno-(2,3-e)-1,4- -diazepinen.

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
EICOSANOIDS, VOL. 4, NO. 3, PAGE(S) 137-141, 1991, BERLIN, DE S NIGAM 'Increased concentrations of eicosanoids and platelet-activating fac tor in menstrual blood from women with primary dysmenorrhea.' *
J. REPROD. FERTIL., VOL. 88, NO. 1, PAGE(S) 241-248, 1990, DORSET,GB N.R. SPINKS ET AL. 'Antagonists of embryo-derived platelet-activating factor act by inhibiting the ability of the mouse embryo to implant' *
R.BERKOW ET AL (ED.) 'The Merck Manual of diagnosis and therapy, 15. Ausgabe' 1987 , MERCK & CO. , RAHWAY, US *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7618975B2 (en) 2003-07-03 2009-11-17 Myriad Pharmaceuticals, Inc. 4-arylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US7989462B2 (en) 2003-07-03 2011-08-02 Myrexis, Inc. 4-arylamin-or-4-heteroarylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
US9522920B2 (en) 2010-12-02 2016-12-20 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9249161B2 (en) 2010-12-02 2016-02-02 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US8796261B2 (en) 2010-12-02 2014-08-05 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9422292B2 (en) 2011-05-04 2016-08-23 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9328117B2 (en) 2011-06-17 2016-05-03 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9493483B2 (en) 2012-06-06 2016-11-15 Constellation Pharmaceuticals, Inc. Benzo [C] isoxazoloazepine bromodomain inhibitors and uses thereof
US9624244B2 (en) 2012-06-06 2017-04-18 Constellation Pharmaceuticals, Inc. Benzo [B] isoxazoloazepine bromodomain inhibitors and uses thereof
US9925197B2 (en) 2012-06-06 2018-03-27 Constellation Pharmaceuticals, Inc. Benzo [C] isoxazoloazepine bromodomain inhibitors and uses thereof
US9969747B2 (en) 2014-06-20 2018-05-15 Constellation Pharmaceuticals, Inc. Crystalline forms of 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[C]isoxazolo[4,5-e]azepin-4-yl)acetamide

Also Published As

Publication number Publication date
DE4200610A1 (de) 1993-07-15

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