The present invention relates to novel quinoline-3-carboxanilide derivatives, processes for their preparation, pharmaceutical composi¬ tions containing them and methods of treatment therewith.

The object of this invention is to provide novel compounds which can be used in therapy of diseases which respond to treatment with immuno- modulating agents.

Prior art

A group of heterocyclic carboxamides which increase the activity of the immune system is disclosed in US pat no 4,547,511. A compound which is included in said patent is roquinimex, also known by the code no LS 2616.

The im unomodulating activity of LS 2616 is described further in ref (2).

Disclosure of the invention

It has been found that compounds of the general formula I possess use¬ ful immunomodulating activity. These compounds, unlike those described in the above mentioned US patent, have no substituents on the nitrogen atom of the quinoline ring.

It is known (3) that N-methyl groups are converted by metabolic reac¬ tions to formaldehyde which is a toxic substance. The compounds of the general formula I thus have a lower potential to produce toxic metabo¬ lites, which is an advantage especially in individuals with impaired liver function.

SUBSTITUTESHEET

The compounds of the general formula I also show higher chemical sta¬ bility in free form compared with corresponding known compounds cited above. This makes them more useful in certain types of pharmaceutical compositions, e g those intended for transdermal application where it is essential that the active ingredient be in neutral form.

Summary of the invention

The invention comprises compounds having the general formula

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are selected from the group con¬ sisting of hydrogen, hydroxy and methoxy. At most one of R ¹ , R ² and R ³ and at most one of R ⁴ , R ⁵ , R ⁶ and R ⁷ is selected from the group con¬ sisting of hydroxy and methoxy.

M is selected from the group consisting of hydrogen and pharmaceuti¬ cally acceptable inorganic or organic cations.

As it is apparent to one skilled in the art the compounds of the gene¬ ral formula I may exist in different tautomeric forms.

Methods of preparation

The compounds of the general formula I are prepared by conventional methods.

Method I

Compounds of the general formula I are prepared by reacting a carboxy- lic acid II or a reactive derivative thereof

with an amine of the general formula III or a reactive derivative there

Having a reactive derivative of II the reaction may be carried out by mixing the reagents in an inert solvent medium at a temperature bet¬ ween 0° and 200°C depending on the reactivity of the reactive deriva¬ tive of the carboxylic acid used. As such reactive derivatives the following conventional types may be mentioned: acid chlorides, anhyd¬ rides, mixed anhydrides with aliphatic and aromatic sulphonic acids, and reactive derivatives obtained with carbodiimides and similar rea¬ gents.

The carboxylic acids II and the reactive derivatives thereof may be prepared by conventional methods as described in (4). The amines III are known compounds.

SUBSTITUTE SHEET

Method II

A compound of the general formula I wherein at least one of the groups R*-R ⁷ is a hydroxy group and none of R*-R ⁷ is a methoxy group may be prepared by deal kylation of a compound of the general formula having lower alkoxy (preferably methoxy) groups in positions where hydroxy groups are desired.

The dealkylation is preferably carried out with boron tribromide.

The starting materials of the general formula I having methoxy groups in desired positions may be prepared using the type of reaction des¬ cribed in Method I above and in references given there.

Example 1

N,N-dicyklohexylcarbodiimide (2.2 parts) is added to a mixture consis¬ ting of 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxylic acid (2.0 parts), N-metylaniline (1.1 parts) and dry toluene (25 parts) while stirring. The stirring is continued at 110°C for 4 hrs. The reaction mixture is cooled to room temperature and the precipitate formed is filtered off. The precipitate is dissolved at pH 8.2 in 2M sodium hyd¬ roxide solution and clarified by filtration to remove the N,N-dicyklohexylurea formed. The solution is acidified with hydrochlo¬ ric acid solution and the precipitate formed is filtered off. The pre¬ cipitate is washed with water and methanol and dried to give N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-ca rboxamide, m p >300°C (1:1).

In essentially the same manner the following compounds are obtained:

N-methyl-N-(4-methoxyphenyl)-l,2-dihydro-4-hydroxy-2-oxo- quinoline-3- carboxamide, m p >250°C (1:2)

N-methyl-4-phenyl-1,2-dihydro-4-hydroxy-6-methoxy-2-oxo-q uinoline-3- carboxamide, m p >250°C (1:3)

N-methyl-N-(4-methoxyphenyl)-l,2-dihydro-4-hydroxy-6-meth oxy-2-oxo- quinoline-3-carboxamide, p >250°C (1:4)

N-methyl-N-(3-methoxyphenyl)-l,2-dihydro-4-hydroxy-7-meth oxy-2-oxo- quinoline-3-carboxamide, p >250°C (1:5).

Example 2

N-methyl-N-(4-methoxyphenyl)-1,2-dihydro-4-hydroxy-2-oxo- quinoline-3- carboxamide (6.5 parts) is suspended in 100 parts of ethylene chlori¬ de and the mixture obtained is cooled to -60°C.

A solution of boron tribromide (20 parts) in methylene chloride (100 parts) is added dropwise while stirring. The mixture is allowed slowly to assume room temperature and is then poured into ice-water. The pre¬ cipitate obtained is filtered off, washed with water and dried to give N-methyl-N-(4-hydroχyphenyl)-l,2-dihydro-4-hydroxy-2-oxo-qu inoline-3- carboxamide, p 250°C (2:1).

In essentially the same manner the following compounds are obtained:

N-methyl-N-phenyl-1,2-dihydro-4,6-dihydroxy-2-oxo-quinoli ne-3- carboxamide (2:2)

N-methyl-N-phenyl-1,2-dihydro-4,7-dihydroxy-2-oxo-quinoli ne-3- carboxamide (2:3)

N-methyl -N-(4-hydroxy-phenyl )-l , 2-di hydro-4-hydroxy-2-oxo-qui nol i ne- 3-carboxamide (2:4)

N-methyl -N- (4-hydroxy-phenyl ) -1 ,2-di hydro-4 , 6-di hydroxy-2-oxo-qui no¬ l i ne-3-carboxamide (2:5)

Exampl e 3

This example illustrates the effect of the compounds of the general formula I in the oxazolone induced hypersensitivity test in mice. A modification of a method described in (5) was used.

Female mice BALB/c weighing 18-20 g were purchased from Bomholdtgaard Breeding and Research Centre, DH-8680 Ry, Denmark. The animals were randomized in groups of five animals.

Mice were sensitized day 0 by epicutaneous application of 150 μl of absolute ethanol-aceton (3:1) solution containing 3% oxazolone (4-ethoxymethyleπe-2-phenyloxazol-5-one) on the shaved thorax and ab¬ domen. Seven days after the sensiti zation (day 7) both ears of all mice were challenged on both sides by topical application of 20 μl of 1% oxazolone in peanut oil. Ear thickness was measured prior to 0 hrs and 24 hrs after challenge, using an Oditest spring caliper (Krδplin, Hessen, FRG). The test compounds were administered, suspended in aque¬ ous methocel solution in a volume of 10 g/kg, by gastric intubation once daily on days 0, 1, 2 and 3. The control animals received the same volume of aqueous methocel solution by gastric intubation.

The results are expressed in percent increase of the ear thickness of the animals treated with the test compounds as compared with the cont¬ rol animals treated with the vehicle.

SUBSTITUTE SHEET

Table 1

Preliminary results from the oxazolone induced hypersensitivity test in mice:

N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-l-methyl-2-oxo-qu inoline- 3-carboxamide.

The following compounds were also tested in the oxazolone induced hy¬ persensitivity test in mice as described above and produced an increa¬ se in ear thickness:

N-methyl-N-(4-methoxyphenyl)-l,2-dihydro-4-hydroxy-2-oxo- quinoline-3- carboxa ide (1:2)

N-methyl-4-phenyl-1,2-dihydro-4-hydroxy-6-methoxy-2-oxo-q uinoline-3- carboxa ide (1:3)

N-methyl-N-(4-methoxyphenyl)-l,2-dihydro-4-hydroxy-6-meth oxy-2-oxo- quinoline-3-carboxamide (1:4)

N-methyl-N-(3-methoxyphenyl)-l,2-dihydro-4-hydroxy-7-meth oxy-2-oxo- quinoline-3-carboxamide (1:5).

N-methyl -N-phen 1 -1, 2-di hydro-4,6-dihydroxy-2-oxo-qui nol ine-3-carbox amide (2:2)

N-methyl -N-phenyl -1 , 2-di hydro-4 ,7-dihydroxy-2-oxo-qui nol ine-3-carbox amide (2:3)

N-methyl -N-(4-hydroxy-phenyl )-l , 2-di hydro-4-hydroxy-2-oxo-qui nol i ne- 3-carboxamide (2:4)

N-methyl -N- (4-hydroxy-phenyl ) -1 ,2-di hydro-4 ,6-di hydroxy-2-oxo-qui no l ine-3-carboxamide (2:5)

References

(1) US pat no 4,547,511

(2) A. Tarkowski et al, Arthritis Rheum. 29 1405 (1986)

(3) Manfred E. Wolff (Ed.), Burger's Medicinal Chemistry, John Wiley & So New York 1980 vol. 1 p. 146 ff

(4) G. Jones (Ed.), Quinolinεs part 1, John Wiley & Sons (1977) p. 93-318

(5) U. Bicker et al , Journal of Immunopharmacology 6 (1-2) 57 (1984).