EP0000152B1

EP0000152B1 - Oxaminic acids and esters, process for their preparation and pharmaceutical compositions containing them

Info

Publication number: EP0000152B1
Application number: EP78100167A
Authority: EP
Inventors: Trevor Glyn Dr. Payne
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1977-06-28
Filing date: 1978-06-15
Publication date: 1981-09-09
Also published as: DE2861051D1; US4148916A; IL55006A0; EP0000152A1; PT68216A; DK275378A; IL55006A; FI781946A7; JPS5412360A; IT7825028A0; IE781272L; CA1130307A; PH14995A; NZ187677A; IE47627B1; AU3746978A; IT1097293B; AU519473B2

Description

This invention relates to oxaminic acids and esters thereof, a process for the preparation of said compounds and pharmaceutical compositions containing these compounds.
More particularly, the invention provides compounds of formula I,
wherein

R₁ is hydrogen or alkyl of 1 to 10 carbon atoms,
R₂ is chlorine or alkoxy of 1 to 4 carbon atoms, or
R₁ and R₂ together are ―(CH)-m

m is 3 or 4, and
R₃ is OH or alkoxy of 1 to 4 carbon atoms.

When R₁ is alkyl of 1 to 10 carbon atoms, this preferably contains 1 to 5 carbon atoms, especially 2 or 3 carbon atoms. R₁ can also be hydrogen.
R₂ can be chlorine. R₂ can also be alkoxy of 1 to 4 carbon atoms. R₁ and R₂together can also be ―(CH₂)_m wherein m is 3 or 4, preferably 3.
R₃ can be OH. R₃ 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,

a) producing a compound of formula la,
wherein
- R₁ and R₂ are as previously defined and
- R^' ₃ is alkoxy of 1 to 4 carbon atoms, by reacting a compound of formula II,
  wherein
- R₁ and R₂ are as previously defined, with a compound of formula III,
  wherein
- R^' ₃ is as previously defined and
- R₄ is chlorine, bromine, alkoxy of 1 to 4 carbon atoms, phenoxy, or phenoxy monosubstituted by chlorine, bromine, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms.
or
b) producing a compound of formula Ib,
by hydrolysing a compound of formula la as hereinbefore defined.

Process variant a) can be effected according to known methods. For example, 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. When R₄ is alkoxy of 1 to 4 carbon atoms, this preferably has the same significance as R₃.
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 R₃ 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.
Insofar as the production of the starting materials has not been described, these are either known or may be produced in conventional manner from available materials, or by methods analogous to those described herein.
In the following Examples, all temperatures are in degrees Celsius.

Example 1.

N-(2,6,7,8,9,9a-hexahydro-2-oxo-1 H-benz[c,d]azulen-3yl) oxaminic acid ethyl ester

A solution of 5.0 g of 2,6,7,8,9,9a-hexahydro-2-oxo-1H_-benz[c,d]azulen-3yl-amine in 26 ml of diethyl oxalate is refluxed for 2 hours and then cooled to room temperature. The reaction mixture is then distilled in a bulb tube at 90-100¹/11 mm to remove the excess of diethyl oxalate, and the residue is purified by chromatography on 300 g of silica gel. The title compound is recrystallised from ether, m.p. 115-117°.
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:

a) A solution of 20 g of potassium nitrate in 100 ml of conc. sulphuric acid is added dropwise, with stirring, to a solution of 36 g of 2,6,7,8,9,9a-hexahydro-2-oxo-1H-benz[c,djazuien-2-one in 200 ml of conc. sulphuric acid at 5° and then stirred for 1 hour at 0-5°. the reaction mixture is poured onto ice, extracted with chloroform, the extract washed with water, dried over sodium sulphate and concentrated. The raw product is dissolved in methylene chloride and filtered through 400 g of silica gel. After reducing the volume of the solvent, raw 2,6,7,8,9,9a-hexahydro-3-nitro-1 H-benz[c,d]azulen-2-one (containing 2,6,7,8,9,9a-hexahydro-4-nitro-1 H-benz[c,d]azulen-2-one) is crystallized from methanol, m.p. 107-110°.
b) 20g of 2,6,7,8,9,9a-hexahydro-3-nitro-1 H-benz[c,d]azulen-2-one are added to 135 ml of acetic acid and 6 g of iron filings and 18 ml of water added whilst stirring. Further charges of 6 g of iron filings and 18 ml of water are added over intervals of 15, 30, 45 and 60 minutes. The mixture is stirred for a further 30 minutes, diluted, with 900 ml of water and extracted with methylene chloride. After reducing the volume of the methylene chloride extract, the remaining 2,6,7,8,9,9a-hexahydro-2-oxo-1H-benz[c,d]azulen-3yl-amine is purified by chromatography on silica gel. M.p. 135-138°.

The following compounds can be prepared in manner analogous to that described in Example 1, using appropriate starting materials in approximately equivalent amounts.

Example 6

N-(2,6,7,8,9,9a-hexahydro-2-oxo-1 H-benz[c,d]azulen-3-yl) oxaminic acid

A solution of 0.95 of potassium hydroxide in 2 ml of water is added to a solution of 4 g of the title compound of Example 1 in 150 ml of methanol and the mixture refluxed for 1 hour. The solution is concentrated, diluted with water and the neutral side products extracted with CH₂CI₂. The aqueous phase is acidified with hydrochloric acid and the title compound filtered off. M.P. 191-192⁰.
The following compounds can be prepared in manner analogous to that described in Example 6, using appropriate starting materials in approximately equivalent amounts.
The compounds of formula I exhibit pharmacological activity. In particular, 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.
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 R₃ 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 comprising a compound of formula I, and in the case of compounds wherein R₃ 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.

Claims

1. A compound of formula I,

wherein

R₁ is hydrogen or alkyl of 1 to 10 carbon atoms,

R₂ is chlorine or alkoxy of 1 to 4 carbon atoms, or

R₁ and R₂ together are ―(CH₂)_m

wherein

m is 3 or 4 and

R₃ is OH or alkoxy of 1 to 4 carbon atoms.

2. A compound of Claim 1, wherein R₁ and R₂ together are -(CH₂)_3―.

3. A compound of Claim 1. wherein R₃ is OH.

4. A compound of Claim 1, wherein R₃ is alkoxy of 1 to 4 carbon atoms.

5. A compound of Claim 3, in salt form.

6. A compound of Claims 1, wherein R, and R₂ together are ―(CH₂)₃― and R₃ is OH.

7. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 6, and, in the case of compounds wherein R₃ is OH, in free form or in pharmaceutically acceptable salt form, in association with a pharmaceutically acceptable carrier or diluent.

8. A process for the production of a compound of formula I, as defined in Claim 1, comprising

a) producing a compound of formula la,

wherein

R₁ and R₂ are as previously defined and

R'₃ is alkoxy of 1 to 4 carbon atoms, by reacting a compound of formula II,

wherein

R₁ and R₂ are as previously defined, with a compound of formula II,

wherein

R'₃ is as previously defined and

R₄ is chlorine, bromine, alkoxy of 1 to 4 carbon atoms, phenoxy, or phenoxy monosubstituted by chlorine, bromine, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms,

or

b) producing a compound of formula Ib,

by hydrolysing a compound of formula la, as hereinbefore defined.

9. A compound according to any one of claims 1 to 6 for use in the treatment of prophylaxis of allergic conditions.

10. A compound according to claim 9 for use in the treatment of prophylaxis of allergic asthma, exercise induced asthma or allergic gastro-intestinal disorders.