SE460517B - USE OF A COMPOSITION FOR THE PREPARATION OF A MEDICINE FOR THE TREATMENT OF INFECTIONS CAUSED BY TRYPANOSOMA BRUCEI - Google Patents

Description

460,517 S-adenosylmethionine synthetase forms S-adenosylmethionine, which is then decarboxylated. The propylamine moiety in the activated methionine can then be converted to putrescine to form spermidine. Alternatively, the propylamine moiety can be transferred to spermidine to form spermine. Consequently, putrescine serves as a precursor to spermidine and spermine. Furthermore, putrescine has been shown to have a clear regulatory effect on the biosynthetic pathway to polyamine. An increased synthesis of putrescine has also been shown to be an early indication that a tissue is affected by a renewed growth process. Cadaverine, which is a decarboxylation product of lysine, has been shown to stimulate the activity of S-adenosylmethionine decarboxylase and is known to be essential in the growth processes of many microorganisms, for example H. parainfluenza.

The logical background for polyamine metabolism has been suggested by Cohen, Science 205, 964 (1979). The apparently unique role of polyamine metabolism in trysanosomes and the dependence of trysanosomes on ornithine decarboxylase as a putrescine source further supports our observations that certain specific ornithine decarboxylase inhibitors in polyamine synthesis are clearly effective in preventing the growth of protozoa.

It has now been found that certain compounds belonging to a type of irreversible inhibitors of ornithine decarboxylase are useful for inhibiting the growth of protozoa. Furthermore, this inhibition occurs against a large number of protozoa, such as members of the subcomyl Sarcomastigophora and Sporozoa. In particular, the compounds described below are useful in preventing the growth of species of the upper class Mastigophora, in particular Trypanosoma bnxnilnncei and organisms which cause coccidiosis in poultry.

The compounds which can be used for the above purposes of the present invention are Mrs-substituted amines or K-substituted diamino acids of the general formula I Y I Z-ç-R1 NH2 where R1 represents hydrogen or a carboxyl group PP7 where Y represents CH2F or CHF2; where Z represents H2N * (CH2 \ 3, H2N-ÉH- (CH2) 2 and CH3 HZN-CH2CH = CH; provided that when R1 represents hydrogen Z represents HZN- optical isomers CH3 thereof.

Administered in vivo to animals exposed to active protozoal infections, the compounds of formula (I) may be used to treat the animals by inhibiting further growth of the protozoal infections. Alternatively, the described compounds may be administered prophylactically to prevent such protozoal infections from occurring.

In the general formula (I) above, the symbol R 1 represents either hydrogen or a carboxyl group. When the symbol R1 denotes hydrogen, a type of avlX-substituted amines is included. When the symbol R1 represents a carboxyl group, unsubstituted amino acids are obtained.

The symbol Z represents either the 3-aminopropyl group, the 3-amino-3-methylpropyl group or the 3-amino-1-propylene group. The saturated groups, namely the 3-amino-propyl group and the 3-amino-3-methyl-propyl group represent the preferred side chains.

It is intended to exclude a particular type of diamine from the general definition of the compounds of the present invention.

Excluded from the invention by this delimitation are thus Vx-substituted diamines where the symbol Z represents the 3-aminopropyl group or the 3-amino-1-propylene group, i.e. such compounds having the general formulas YI 112m- (C112) 3-cH-NH2 (II) and Y1 HZN-cnzcnæn-cn-NHZ (III) where Y has been previously defined. 46Û 517 4 Within the group of compounds included are IÅ-substituted amino acids of the formula YI H2N- (CH2) 3-o-COOH (V) NH2 YIH N- - - - 2 çH (CH2) 2 ç COOH ( V1) CH3 NH2 and I 4 I HZN-CH2CH = CH-C-COOH (VII) In NH2 In formulas (V), (VI) and (VII) above, the symbol Y has been previously defined.

The fi-unsubstituted amines included within the scope of the present invention which can be advantageously used have the general formula Y 1 HZN-ç fl- (CH 2) 2 -CH-NH 2 (VIII) where the symbol Y represents CH 2 F or CHF 2.

Illustrative examples of salts of compounds of the present invention include non-toxic acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and organic acids such as methanesulfonic acid, salicylic acid, maleic acid, malonic acid, tartaric acid, citric acid, n -cyclohexyl- sulfamic acid and ascorbic acid.

A preferred group of compounds of the present invention are those compounds in which the symbol Y represents the difluoromethyl group. Another preferred group of compounds are those in which the symbol Z represents the 3-aminopropyl group or the 3-amino-3-methylpropyl group.

In addition to the salts indicated above, the term also includes internal salts or zwitterions of these compounds of formula (I) above, which are amphoteric in nature. Furthermore, while the optical configuration of the compounds described herein is not specifically stated, it should be remembered that the fl-carbon atom has an asymmetric center and that individual optical isomers of these compounds exist.

Accordingly, within the scope of the invention, both d- and 1-optical isomers and racemic mixtures of said compounds are included. Lactam formation can take place in the cases where the symbol R1 represents a carboxyl group and the symbol Z represents the 3-aminopropyl group or 3-amino-3- methylpropyl group and is represented by the following general formula (IX) of Ycc = o (Ix) r (cH2) 3 Now in the above general formula, the symbol Y has been previously defined. Where the symbol Z represents the 3-amino-3-methylpropyl group, the (CH 2) 3 group of formula (IX) may also be substituted by a 3-methyl group.

Illustrative examples of compounds of the present invention are: 2,5-diamino-2- (fluoromethyl) pentanoic acid 2,5-diamino-2- (difluoromethyl) pentanoic acid 2,5-diamino-2-fluoromethyl-5-methylpentanoic acid 2,5- diamino-2-difluoromethyl-5-methylpentanoic acid 2,5-diamino-2-fluoromethyl-3-pentenoic acid 2,5-diamino-2-difluoromethyl-3-pentenoic acid 1-fluoromethyl-4-methyl-1,4-butanediaryl and 2 -difluoromethyl-4-methyl-1,4-butanediamine.

The compounds of general formula (I) wherein Z represents HZN- (CH 2) 3; where Y represents CH 2 F or CHF 2 and where R 1 represents a carboxyl group is prepared by treating the corresponding ester derivatives of ornithine, the amino groups being suitably protected, with a strong base to form a carbonate intermediate. This is reacted with a suitable halomethyl-haloalkylating reagent in an aprotic solvent such as dimethylsulfoxide, dimethylformamide, dimethylacetamide, benzene, toluene, ethers such as tetrahydrofuran, diethyl ether or dioxane, and in the presence of hexamethylphosphorus triamide when Y , at a temperature of from about -120 to 120 ° C, preferably about 25 to 50 ° C for about Q hour to 48 hours, followed by acidic or basic hydrolysis. This can be done according to the following reaction scheme. Z1-Y COOR2: Z1-Y COOR2 ß N = ï-R3 strong base; | N = ç-R3 | I | - In Z2-C-COOR2 solution of Z1-C-COORZ NH acid / hydrazine | 2

Claims (3)

Claims 10 Use of a compound for the manufacture of a medicament for the treatment of infections caused by Trypanosoma brucei. characterized in that the compound has the formula wherein 81 represents hydrogen or a carboxyl group. Y represents CHZP. or CHF2: Z represents HZN- (CH H N- $ H- (CH2) 2- or 2 CH3 2) 3-0 -H2N-CH2-CH-CH- and that where RI represents hydrogen Z represents H N-CH (CH3) - (CH2) 2- or salts or individual 2. Optical isomers thereof in combination with a suitable carrier. Use according to claim 1, characterized in that the compound consists of 2,5-diamino-2-difluoromethylpentanoic acid. k ä n n e t e c k n a d of att Use according to claim 1. The compound is monofluoromethylornitine.