NO762922L - - Google Patents

Description

The present invention relates to a method for the production of new compounds of formula I

wherein means hydrogen, chlorine or bromine

1*2 means hydrogen or an alkyl group with 1-4 C atoms R-, means hydrogen, an alkyl group with 1-4 e atoms, an alkenyl or alkynyl group with 3-5 e atoms, where the unsaturated bond is not located adjacent to the N atom, an cycloalkyl group with 5 or 6 C atoms or a hydroxyalkyl group with 2 to 4 C atoms, whose hydroxy group is separated from the N atom by at least two C atoms,

R4 means an alkyl group with 1-4 C atoms, an alkenyl or alkynyl group with 3-5 C atoms, where the unsaturated bond is not located in a neighboring position to the N atom, an cycloalkyl group with 5 or 6 C atoms, a hydroxyalkyl group with 2-4 C atoms, whose hydroxy group is separated from the N atom by at least 2 C atoms, or if R^ means hydrogen or an alkyl group with 1-4 C atoms, also one optionally in the phenyl ring with fluorine, chlorine, bromine or an alkyl- alkoxy group with 1-4 e-atoms mono- or disubstituted phenyl- or phenylalkyl group, whose alkylene chain contains 1-4 C-atoms, or a pyridinyl-or optionally with 1 or 2 methyl groups substituted pyrimidinyl group, or

R-. and R., together with the N atom to which they are attached, means a

where X stands for -CH2~, -0- or a bond,

and the salts of the acids of formula I.

In the compounds of formula I, R. is preferably chlorine or hydrogen, especially chlorine. The substituent R^ preferably means hydrogen. If R2 stands for an alkyl group, this is preferably methyl or ethyl.

R^ and R^ stand as an alkyl group preferably for methyl or ethyl, as an alkenyl group for allyl, as an alkynyl group for propargyl and as a hydroxyalkyl group preferred for 2-hydroxyethyl.

R^ as an optionally substituted phenylalkyl group is preferably an optionally substituted benzyl or phenylethyl group as defined above.

R^ and R^ preferably stand for alkyl groups.

The peculiarity of the method according to the invention for the production of the new compounds of formula I and their salts is that

a) reactive acid derivatives of sulfonic acids with formula II

in which

R21 means alkyl with 1-4 C atoms,

is reacted with amines of formula III

and the obtained compounds of formula Ia are optionally hydrolysed to compounds of formula Ib b) to produce compounds of formula Ic

in which

' and R^' have the same meanings as R^ respectively. R^ with the exception of alkenyl or alkynyl groups with 3-5 C atoms, the halogen atom R^<1> is removed by catalytic hydrogenation from compounds of formula Id

in which

R^' stands for chlorine or bromine, and the obtained acids with formulas Ib or Ic are optionally transferred in their salts.

The reaction of reactive derivatives of the sulfonic acids of formula II with amines of formula III can be carried out according to the usual methods for the formation of sulfonamides. The acid chlorides are particularly suitable as reactive acid derivatives. E.g. can the reaction take place in an organic solvent that is inert under the reaction conditions, e.g. an aromatic hydrocarbon, at a temperature between G and 100°C, preferably between 10 and 25°C.

The hydrolysis of the compounds of formula Ia can take place according to methods known per se for ester hydrolysis, the reaction conditions being chosen so gently that cleavage of the amide group is avoided. The reaction is preferably carried out in the presence of dilute bases, e.g. about. 1-normal potassium or sodium hydroxide solution, or potassium carbonate at temperatures between ea. room temperature and the boiling temperature of the reaction mixture. Optionally, an organic solvent miscible with water, which is inert under the reaction conditions, can be added.

The catalytic hydrogenation of the compounds of formula Id can take place according to usual methods for the catalytic removal of chlorine or bromine atoms from chlorinated or brominated aromatic compounds. A noble metal catalyst, especially palladium on coal, is preferably used as a catalyst. The hydrogenation takes place in a solvent that is inert under the reaction conditions, e.g. water or a lower alcohol at temperatures between 20 and 100°C. The reaction can be carried out at from normal pressure to 100 ato H2~ pressure. In the course of this hydrogenation, any alkenyl and/or alkynyl groups present in the starting product are converted to alkyl groups, and depending on the reaction conditions and the structure of the starting compounds, the Cl or Br atoms present in the substituent R^ may be replaced with hydrogen atoms.

The acids of formula Ib which can be produced by the method according to the invention can be in the form of the free acids or their salts with bases. The free acids can be transferred in a manner known per se into their salts with bases and vice versa. Examples of salts with inorganic bases are i.a. alkali metal such as sodium

or the potassium salts or the alkaline earth metal salts such as calcium or magnesium. Organic bases suitable for salt formation are e.g. amines.

The reactive acid derivatives of acids of formula II used as starting compounds can be prepared by diaminobenzenesulfonic acids of formula IV

following in and of itself for the formation of aromatic oxamide acid esters usual methods are reacted with oxalic acid derivatives of formula V

in which

Y stands for an aminolytically cleavable residue, preferred

for chlorine or alkoxy,

and the obtained sulfonic acids of formula II are transferred in a manner known per se into their acid derivatives.

To the extent that the production of the starting compounds is not described, these are known or can be produced in per se known ways or analogously to the methods described here or analogously to methods known per se.

The compounds of formula I and their physiologically tolerable salts are distinguished by interesting pharmacological properties and can consequently be used as medicine.

In particular, the compounds show a disodium eromoglycate (DSCG)-like action, which is more advantageous than might be expected for compounds of this structural type. Due to their DSCG-like action, the compounds can be used for the prophylaxis and therapy of allergic and exercise-induced asthma as well as for the prophylaxis of allergic disorders.

As medicine, the compounds of formula I and their physiologically tolerable salts together with common pharmaceutical excipients can be used in galenic preparations, such as e.g. tablets, capsules or solutions. These galenic preparations can be prepared according to methods known per se.

In the following examples which will illustrate the invention in more detail, all temperature indications are in °C.

In the following table, 2-Cl means a chlorine atom, which is bound between the two oxamide groups and 4-C1 means a chlorine atom which is bound between a sulfamide and an oxamide group on the benzene ring.

C6H11betvr a GYkl°hexylres't'

Example 1; 2-Chloro-5-dimethylfulamoYl-li3-f

i23S2^iS^YE§^§£Yl§§ter)__XFremgan2småte_a)_.

7.8 g of 4-chloro-3,5-bis(methoxyalylamino)benzene sulphochloride is suspended in 120 ml of toluene and a solution of 2.5 g of dimethylamine in 30 ml of toluene is added at 15 - 20°C. The mixture is stirred for 3 hours at room temperature, the reaction product is filtered off, washed with methanol and dried in a vacuum. Temp. of the compound mentioned in the title is 210 - 212°C.

The starting material is obtained as follows:

a) 18.0 g of 3,5-diamino-4-chlorobenzenesulfonic acid and 31 ml of triethylamine are dissolved while stirring and cooling in 180 ml of dimethylformamide.

At -5 to 0°C, 18.3 g of oxalic acid monomethyl ester chloride are added dropwise and it is then stirred for 10 hours at room temperature. The crystallized triethylamino hydrochloride is then filtered off, the filtrate is evaporated and the residue is dissolved in a little methanol. The solution is now added to a solution of 6.0 g of potassium hydroxide in 100 ml of methanol, whereby the potassium salt of 4-chloro-3,5-bis(methoxyalylamino)-benzenesulfonic acid crystallizes out. Temp. 248 - 249°C.

b) The potassium salt of 4-chloro-3,5-bis(methoxyalylamino)-benzenesulfonic acid is reacted with phosphorus oxychloride and phosphorus pentachloride to

4-Chloro-3,5-bis-(methoxyallylamino)benzenesulfochloride.

Melting point: 167 - 170°C.

Example 2: 2-chloro-5-dimethylsulfamoyl-1^S-phenylene^bis^oxamic acid)_.

3.3 g of the methyl ester of the compound mentioned in the title obtained in example 1 is stirred for 40 minutes with 20 ml of 5% caustic soda. The solution is then acidified with 2N hydrochloric acid, the compound mentioned in the title is precipitated, filtered off, washed with water and dried. Temp. 185 - 187°C.

Analogous to example 1 or 2, the following compounds can also be obtained:

Claims (1)

Example 24: 5-d^methylsulfimgyl-1^S-fQSYiSQl^iSiQlSSSo^iDiYEil (Procedure b) 4.0 g of 2-chloro-5-dimethylsulfamoyl-1,3-phenylene-bis(oxamic acid) is dissolved in 100 ml of water and hydrogenated at 40°C and 4 ato I^ pressure with the addition of palladium charcoal for 8 hours. After filtration and evaporation, the product mentioned in the title crystallizes. Temp. 218 - 220°C. Analogous to this example, the compounds mentioned in Examples 3B and C can also be prepared. PATENT CLAIMS Procedure for the preparation of new compounds of formula IN wherein R-^ means hydrogen, chlorine or bromine R2 means hydrogen or an alkyl group with 1-4 C atoms R^ means hydrogen, an alkyl group with 1-4 C atoms, an alkenyl or alkynyl group with 3-5 C atoms, where the unsaturated bond is not in a neighboring position to the N atom, an cycloalkyl group with 5 or 6 C atoms or a hydroxyalkyl group with 2-4 C atoms, whose hydroxy group is separated from the N atom by at least 2 e atoms, R4 means an alkyl group with 1-4 C- atoms, an alkenyl or alkynyl group with 3-5 C atoms, where the unsaturated bond is not adjacent to the N atom, an cycloalkyl group with 5 or 6 C atoms, a hydroxyalkyl group with 2-4 C atoms, whose hydroxy group is separated from the N atom at least 2 C atoms, or if R^ means hydrogen or an alkyl group with 1-4 C atoms, also an optionally in the phenyl ring with fluorine, chlorine, bromine or an alkyl or alkoxy group with 1-4 C atoms, mono- or disubstituted phenyl or phenylalkyl group, whose alkylene chain contains 1-4 C atoms, or a pyridinyl or optionally with a or two methyl groups substituted pyrimidinyl group or R-, and R. together with the N-atom, to which they are bound one in which X stands for '-CH2 -, -0- or a bond, and the salts of the acids of formula I, characterized by ata) reactive acid derivatives of sulfonic acids of formula II in which R 2 ' means alkyl with 1-4 C atoms, reacts with amines of formula III and the obtained compounds of formula Ia are hydrolysed, possibly to compounds of formula Ib orb) for the preparation of compounds of formula Ic in which ' and R4<1> have the same meanings as R^ respectively. R4 with the exception of alkenyl or alkynyl group with 3-5 C atoms, the halogen atom R,' is removed in compounds of formula Id R-^' stands for chlorine or bromine. by catalytic hydrogenation, optionally during simultaneous reaction of the alkenyl or alkynyl groups present as R^ and/or R4~ substituents to the corresponding alkyl groups and/or simultaneous removal of the chlorine and bromine atoms present in the substituent R4, and the obtained acids with formulas Ib or Ic are optionally transferred in their salts.