EP0000152B1 - Oxamin-Säuren und Ester hiervon, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Gemische - Google Patents

Oxamin-Säuren und Ester hiervon, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Gemische Download PDF

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Publication number
EP0000152B1
EP0000152B1 EP78100167A EP78100167A EP0000152B1 EP 0000152 B1 EP0000152 B1 EP 0000152B1 EP 78100167 A EP78100167 A EP 78100167A EP 78100167 A EP78100167 A EP 78100167A EP 0000152 B1 EP0000152 B1 EP 0000152B1
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EP
European Patent Office
Prior art keywords
compound
carbon atoms
formula
alkoxy
compounds
Prior art date
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Expired
Application number
EP78100167A
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English (en)
French (fr)
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EP0000152A1 (de
Inventor
Trevor Glyn Dr. Payne
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Sandoz AG
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Sandoz AG
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Publication date
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to oxaminic acids and esters thereof, a process for the preparation of said compounds and pharmaceutical compositions containing these compounds.
  • R 1 is alkyl of 1 to 10 carbon atoms, this preferably contains 1 to 5 carbon atoms, especially 2 or 3 carbon atoms.
  • R 1 can also be hydrogen.
  • R 2 can be chlorine.
  • R 2 can also be alkoxy of 1 to 4 carbon atoms.
  • R 1 and R 2 together can also be ⁇ (CH 2 ) m wherein m is 3 or 4, preferably 3.
  • R 3 can be OH.
  • R 3 can also be alkoxy of 1 to 4 carbon atoms.
  • the invention also provides a process for the production of compounds of formula I comprising,
  • Process variant a) can be effected according to known methods.
  • the reaction may conveniently be effected in the presence of an inert solvent such as a hydrocarbon, chlorinated hydrocarbon, an ether or a tertiary amine, or in excess of the compound of formula III.
  • the reaction may suitably be effected at a temperature of from -5° to 200°C.
  • a basic catalyst such as a tertiary amine, for example pyridine or triethylamine may be employed.
  • R 4 is alkoxy of 1 to 4 carbon atoms, this preferably has the same significance as R 3 .
  • Process variant b) can be effected according to known methods.
  • the reaction is preferably effected in the presence of a base, for example in the presence of a dilute, alkali metal hydroxide or a tertiary amine.
  • the reaction may suitably be effected at a temperature of from 0°C to the boiling temperature of the reaction mixture, conveniently in the presence of an inert organic solvent which is miscible with water, such as a lower alcohol, dimethyl sulphoxide or dimethoxy ethane.
  • the resulting compounds of formula I may be isolated and purified using conventional techniques.
  • the compounds of formula I wherein R 3 is OH may be converted into salt forms in conventional manner and vice versa.
  • Suitable salt forms include those with alkali metals, for example sodium and potasium, alkaline earth metals, for example calcium and magnesium, and with organic bases such as amines.
  • the compounds of formula II can be prepared by nitrating a compound of formula IV, for example in a mixture of sulphuric and nitric acids, and reducing the resulting nitro derivative, according to known methods, to yield the compounds of formula II.
  • the reduction may conveniently be effected by catalytic hydrogenation or by using iron filings in an aqueous acid.
  • the 2,6,7,8,9,9a-hexahydro-2-oxo-1 H-benz[c,d]azulen-3yl-amine employed as starting material can be prepared as follows:
  • the compounds of formula I exhibit pharmacological activity.
  • the compounds exhibit disodium chromoglycate (DSCG)-like activity, in particular histamine release inhibiting activity, and are therefore indicated for use in the treatment and prophylaxis of allergic conditions, such as allergic asthma, exercise induced asthma and allergic gastrointestinal disorders, as indicated in the passive cutaneous anaphylaxis (PCA) test in the rat, based on the principles of Mota, J. Immunology, (1964), 7, 681.
  • DSCG disodium chromoglycate
  • PCA passive cutaneous anaphylaxis
  • the (DSCG)-like activity in particular histamine release inhibiting activity, can be confirmed by inhibition of histamine release in the rat peritoneal mast cell test, basically as described by Kusner et al., J. Pharmacol. Exp. Therap. (1973) 184, 41-46.
  • An indicated suitable daily dosage is from 1 to 100 mg, suitably administered in divided doses of from 0.25 to 50 mg, 2 to 4 times daily or in retard form.
  • the compounds of formula I wherein R 3 is OH may be administered in free form or in pharmaceutically acceptable salt form.
  • Such salt forms possess the same order of activity as the free forms and are readily prepared in conventional manner. Examples of suitable salt forms are those of sodium and potassium.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, and in the case of compounds wherein R 3 is OH, in free form or in pharmaceutically acceptable salt form, in association with a pharmaceutically acceptable diluent or carrier.
  • Such compositions may, for example be in the form of a solution or capsule.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Claims (10)

1. Eine Verbindung der Formel I
Figure imgb0014
worin
R1 für Wasserstoff oder Alkyl mit 1 bis 10 Kohlenstoffatomen
R2 für Chlor Alkoxy mit 1 bis 4 Kohlenstoffatomen oder
R1 and R2 zusammen ―(CH2)m

worin
m 3 oder 4 bedeutet, und
R3 für OH oder Alkoxy mit 1 bis 4 Kohlenstoffatomen stehen.
2. Eine Verbindung gemäss Anspruch 1, worin R1 und R2 zusammen Für ―(CH2)3― stehen.
3. Eine Verbindung gemäss Anspruch 1, worin R3 für OH steht.
4. Eine Verbindung gemäss Anspruch 1, worin R3 für Alkoxy mit 1 bis 4 C-Atomen steht.
5. Eine Verbindung gemäss Anspruch 3 in Salzform.
6. Eine Verbindung gemäss Anspruch 1, worin R1 und R2 zusammen für―(CH2)3― und R3 für OH stehen.
7. Eine pharmazeutische Zusammensetzung enthaltend eine Verbindung gemäss einem der Ansprüche 1 bis 6, welche, falls in der Verbindung R3 für OH steht, in freier Form oder in Form eines pharmazeutisch verträglichen Salzes vorliegt, in Kombination mit einem pharmazeutisch verträglichen Träger oder Verdünnungsmittel.
8. Ein Verfahren zur Herstellung einer Verbindung der Formel I gemäss Anspruch 1, dadurch ge-. kennzeichnet, dass man
a) zur Herstellung einer Verbindung der Formel la
Figure imgb0015
worin
R1 und R2 die oben angegebenen Bedeutungen haben und
R'3 für Alkoxy mit 1 bis 4 Kohlenstoffatomen steht, eine Verbindung der Formel II
Figure imgb0016
worin
R1 und R2 die oben angegebenen Bedeutungen haben, mit einer Verbindung der Formel III
Figure imgb0017
worin
R'3 die oben angegebene Bedeutung hat und
R4 für Chlor, Brom, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Phenoxy oder durch Chlor, Brom, Alkyl mit 1 bis 4 Kohlenstoffatomen oder Alkoxy mit 1 bis 4 Kolenstoffatomen monosubstituiertes Phenoxy steht,

umsetzt, oder
b) zur Herstellung einer Verbindung der Formel Ib
Figure imgb0018
eine Verbindung der Formel la, wie oben definiert, hydrolysiert.
9. Eine Verbindung gemäss einem der Ansprüche 1 bis 6 zur Verwendung bei der Behandlung oder Prophylaxe von allergischen Zuständen.
10. Eine Verbindung gemäss Anspruch 9 zur Verwendung bei der Behandlung oder Prophylaxe von allergischem Asthma, anstrengungsbedingtem Asthma oder allergischen gastro-intestinalen Störungen.
EP78100167A 1977-06-28 1978-06-15 Oxamin-Säuren und Ester hiervon, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Gemische Expired EP0000152B1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH791377 1977-06-28
CH7914/77 1977-06-28
CH791477 1977-06-28
CH7913/77 1977-06-28

Publications (2)

Publication Number Publication Date
EP0000152A1 EP0000152A1 (de) 1979-01-10
EP0000152B1 true EP0000152B1 (de) 1981-09-09

Family

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Country Status (14)

Country Link
US (1) US4148916A (de)
EP (1) EP0000152B1 (de)
JP (1) JPS5412360A (de)
AU (1) AU519473B2 (de)
CA (1) CA1130307A (de)
DE (1) DE2861051D1 (de)
DK (1) DK275378A (de)
FI (1) FI781946A (de)
IE (1) IE47627B1 (de)
IL (1) IL55006A (de)
IT (1) IT1097293B (de)
NZ (1) NZ187677A (de)
PH (1) PH14995A (de)
PT (1) PT68216A (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0013726B1 (de) * 1978-12-22 1982-09-29 Sandoz Ag Indanyloxaminsäure-Derivate, ihre Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
DE2926271A1 (de) * 1979-06-29 1981-01-08 Behringwerke Ag Mittel zum nachweis peroxidatisch wirksamer substanzen
US4290773A (en) * 1979-11-13 1981-09-22 Miles Laboratories, Inc. Stabilization of benzidine-type indicators with various enhancers
US4579869A (en) * 1985-08-02 1986-04-01 Merck & Co., Inc. Substituted [(2,3-dihydro-1-oxo-1H-inden-5-yl)amino]alkanoic acids, their derivatives and their salts

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2589934A (en) * 1950-08-24 1952-03-18 Abbott Lab 2-aminomethyl-tetrahydroacenapthones-1 and their preparation
CH485485A (de) * 1966-02-07 1970-02-15 Ciba Geigy Verwendung von Oxalsäure-esteramiden als Ultraviolettschutzmittel ausserhalb der Textilindustrie
US3993679A (en) * 1972-12-20 1976-11-23 The Upjohn Company Cyano phenylene dioxamic molecules
US3966965A (en) * 1973-03-23 1976-06-29 American Home Products Corporation Oxamic acid derivatives for the prevention of immediate type hypersensitivity reactions
US4069343A (en) * 1973-03-23 1978-01-17 American Home Products Corporation Oxamic acid derivatives for the prevention of immediate type hypersensitivity reactions
US4011337A (en) * 1975-07-07 1977-03-08 The Upjohn Company Oxamide-oxamic compounds, compositions and methods of use
US4017538A (en) * 1975-10-01 1977-04-12 The Upjohn Company Alkyl thio sulfinyl and sulfonyl oxamic compounds, compositions and methods of use
US4061791A (en) * 1975-12-29 1977-12-06 The Upjohn Company Anti-allergic oxanilate compounds

Also Published As

Publication number Publication date
IE47627B1 (en) 1984-05-16
IL55006A0 (en) 1978-08-31
AU519473B2 (en) 1981-12-03
PT68216A (fr) 1978-07-01
JPS5412360A (en) 1979-01-30
US4148916A (en) 1979-04-10
DE2861051D1 (en) 1981-11-26
FI781946A (fi) 1978-12-29
IT7825028A0 (it) 1978-06-27
PH14995A (en) 1982-03-22
IT1097293B (it) 1985-08-31
EP0000152A1 (de) 1979-01-10
NZ187677A (en) 1981-01-23
CA1130307A (en) 1982-08-24
IE781272L (en) 1978-12-28
AU3746978A (en) 1980-01-03
DK275378A (da) 1978-12-29
IL55006A (en) 1981-11-30

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