EP0000152B1 - Acides et esters oxaminiques, procédés pour leur préparation et compositions pharmaceutiques les contenant - Google Patents

Acides et esters oxaminiques, procédés pour leur préparation et compositions pharmaceutiques les contenant 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
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EP78100167A
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German (de)
English (en)
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EP0000152A1 (fr
Inventor
Trevor Glyn Dr. Payne
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz AG
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Sandoz AG
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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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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (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. Un composé de formule I,
Figure imgb0019
dans laquelle
R1 signifie l'hydrogène ou un groupe alkyle de 1 à 10 atomes de carbone,
R2 signifie le chlore ou un groupe alcoxy de 1 à 4 atomes de carbone, ou
R1 et R2 signifient ensemble un groupe ―(CH2)m où
m signifie 3 ou 4 et
R3 signifie OH ou un groupe alcoxy de 1 à 4 atomes de carbone.
2. Un composé selon la revendication 1, dans lequel R1 et R2 signifient ensemble un groupe ―(CH2)3―.
3. Un composé selon la revendication 1, dans lequel R3 signifie OH.
4. Un composé selon la revendication 1, dans lequel R3 signifie un groupe alcoxy de 1 à 4 atomes de carbone.
5. Un composé selon la revendication 3, sous la forme d'un sel.
6. Un composé selon la revendication 1, dans lequel Ri et R2 signifient ensemble un groupe -(CH2)3- et R3 signifie OH.
7. Une composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 6, et, dans le cas de composés où R3 signifie OH, sous forme libre ou sous forme d'un sel acceptable du point de vue pharmaceutique, en association avec un excipient ou diluant acceptables du point de vue pharmaceutique.
8. Un procédé de préparation d'un composé de formule I, tel que défini à la revendication 1, comprenant .
a) la préparation d'un composé de formule la,
Figure imgb0020
dans laquelle
Ri et R2 sont tels que définis précédemment et
R'3 signifie un groupe alcoxy de 1 à 4 atomes de carbone, par réaction d'un composé de formule II,
Figure imgb0021
dans laquelle
R1 et R2 sont tels que définis précédemment, avec un composé de formule III,
Figure imgb0022
dans laquelle
R'3 est tel que défini précédemment et
R4 signifie le chlore, le brome, un groupe alcoxy de 1 à 4 atomes de carbone, phénoxy, ou phénoxy monosubstitué par le chlore, le brome ou par un groupe alkyle de 1 à 4 atomes de carbone ou alcoxy de 1 à 4 atomes de carbone,

ou
b) la préparation d'un composé de formule Ib,
Figure imgb0023
par hydrolyse d'un composé de formule la, tel que défini ci-dessus.
9. Un composé selon l'une quelconque des revendications 1 à 6 pour l'utilisation dans le traitement ou la prophylaxie d'états allergiques.
10. Un composé selon la revendication 9 pour l'utilisation dans le traitement ou la prophylaxie de l'asthme d'origine allergique, de l'asthme consécutif à l'effort ou de troubles gastro-intestinaux allergiques.
EP78100167A 1977-06-28 1978-06-15 Acides et esters oxaminiques, procédés pour leur préparation et compositions pharmaceutiques les contenant Expired EP0000152B1 (fr)

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 (fr) 1979-01-10
EP0000152B1 true EP0000152B1 (fr) 1981-09-09

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EP78100167A Expired EP0000152B1 (fr) 1977-06-28 1978-06-15 Acides et esters oxaminiques, procédés pour leur préparation et compositions pharmaceutiques les contenant

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

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0013726B1 (fr) * 1978-12-22 1982-09-29 Sandoz Ag Dérivés d'acide indanyloxamique, leur préparation et préparations pharmaceutiques les contenant
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 (fr) 1979-01-10
NZ187677A (en) 1981-01-23
CA1130307A (fr) 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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