FR2484255A1 - NEW VETERINARY DRUGS FOR INHIBITING THE DEVELOPMENT OF PROTOZOA AND THERAPEUTIC COMPOSITIONS AND PHARMACEUTICAL FORMS CONTAINING THESE MEDICAMENTS - Google Patents

Abstract

THE INVENTION CONCERNS NEW VETERINARY MEDICINAL PRODUCTS TO INHIBIT THE DEVELOPMENT OF PROTOZOA AND THERAPEUTIC COMPOSITIONS AND PHARMACEUTICAL FORMS CONTAINING THESE MEDICINES; THE COMPOUNDS OF THE INVENTION ARE A-SUBSTITUTE AMINOACIDS OR A-SUBSTITUTE AMINES RESPONDING TO THE FORMULA: (CF DRAWING IN BOPI) OR R REPRESENTS A HYDROGEN ATOM, OR A RADICAL CARBOXY; Y REPRESENTS A RADICAL -CHF, -CHF, -CF OR -CCH; Z REPRESENTS A RADICAL HN- (CH)

Description

248425'5

  The present invention relates to novel veterinary drugs for inhibiting the development of protozoa and therapeutic compositions and dosage forms containing these drugs. In general, the invention relates to certain α-substituted amines and some α-substituted amino acids which are

  useful for inhibiting the development of protozoa in animals.

  and, in particular, in poultry.

  Polyamines have been involved in various aspects

  of cell division. It seems that the alterations of the bio-

  Polyamine synthesis by enzymatic inhibitors cause

  a decrease in cell proliferation in mammals.

  Although the physiological role of polyamines has not been clearly

  Some data suggest that they intervene in cell division and growth, H. G. Williams-Ashman et al. The Italian J. Biochem 25, 5-32 (1976), A. Raina and J. Janne, Med. Biol. 53, 121-147 (1975) and D.H. Russell, Life Sciences 13,

1635, 1647 (1973).

  It is also known that polyamines are essential growth factors for certain microorganisms such as, for example, E. coli, Enterobacter, Klebsiella, Staphylococcus aureus,

  C. cadaveris, Salmonella typhosa and Haemophilus parainfluenza.

  Some evidence suggests that polyamines are associated with mammals in normal and neoplastic cell development, and there is an increase in synthesis and accumulation of

  polyamines after a stimulus causing cell proliferation.

  We also know that there is a correlation between training

  polyamines and the activity of the decarboxylase enzymes of

  thine, S-adenosylmethionine, arginine and lysine.

  The term "polyamines" includes the diamine putrescine and the polyamines spermidine and spermine. Putrescine is the product of decarboxylation of ornithine, catalyzed by ornithine decarboxylase. The formation of putrescine can also be carried out by decarboxylation of arginine with formation of dagmatin which is hydrolyzed to putrescine and urea. Arginine is also involved in the formation of ornithine by the action of the enzyme arginase. Activation of methionine by the enzyme S-adenosylmethioninesynthetase forms S-adenosylmethionine which is decarboxylated. Propylamine fragment of activated methionine

  can then be transferred to putrescine to form spermidine.

  Alternatively, the propylamine moiety may be transferred to spermidine to form spermine. So, putrescine serves as a precursor to spermidine and spermine. In addition, putrescine was found

  have a net regulatory effect on the biosynthetic pathway of poly-

  amines. Also, an increase in putrescine synthesis has been shown to be an early indication that a tissue is experiencing a recrudescence of growth. Cadaverine, which is the product of the decarboxylation of lysine, has been shown to stimulate the activity of Sadenosylmethionine decarboxylase and is known to be essential for the growth processes of many microorganisms.

for example H. Parainfluenza.

  A reasoned discussion of polyamine metabolism has been suggested by Cohen, Science 205, 964 (1979). The remarkable remarkable role of polyamine metabolism in trypanosomes and the dependence of trypanosomes on ornithine decarboxylase producing putrescine support the Applicant's observations that certain specific ornithine decarboxylase inhibitors in the synthesis of polyamines are

  very effective in inhibiting the development of protozoa.

  The Applicant has discovered that certain compounds which

  belong to a category of irreversible inhibitors of

  Thine-decarboxylase are useful for inhibiting the development of protozoa. Moreover, this inhibition is observed in a large spectrum of protozoa belonging to the subphylaSarcomastigophora

  and Sporozoa. More particularly, these compounds are particularly

  useful for inhibiting the development of members of the super-

  Mastigophora, including Trypanosoma brucei brucei and members of the Telosporea class, including Eimeria tenella which is

  the organism causing coccidiosis of poultry.

  The compounds useful in the practice of the invention are asubstituted amines or α-substituted α-amino acids, having the general formula: Y

Z-C-R (I)

  fIN2 oh RY represents a carboxy radical; Y represents a -CH2F, -CHF2, -CF3 or -C-CH radical; Z represents a radical H N- (CH2) 3, H2N-CH- (CH2) 2 or H2N-CH2CH = CH-, under

2 2 3> 2 22Y 2 2

  CH3 reserves that, when R1 represents a hydrogen atom, Y can not represent -CF3 and Z must represent H2N-CH- (CH2) 2-; so

CH3

  the corresponding individual salts and optical isomers.

  When administered in vivo, animals pre-

  infected with active protozoa, the compounds of formula (I) may allow the treatment of these animals by

  inhibition of the further development of the provo-

  protozoa. Otherwise, these compounds can be administered prophylactically to prevent the onset of these infections.

caused by protozoa.

  The invention will now be described so

Detailed.

  In the general formula (I) above, the symbol R1 represents a hydrogen atom or a carboxy radical. When

  the symbol R1 represents a hydrogen atom, a category is obtained

  a class of α-substituted amines. When the symbol R1 represents a

  carboxy radical, a class of α-amino acids

  titués. The symbol Y represents either an acetylenic radical or a fluoro-substituted methyl radical. We can mention as

  examples of fluoro-substituted methyl radicals are mono-

  fluoromethyl, difluoromethyl or trifluoromethyl.

  The symbol Z represents a 3-aminopropyl radical,

  3-amino-3-methylpropyl or 3-amino-propylene-1. Lateral cat

  are saturated radicals, that is - & -

  say the 3-amino-propyl radical and the 3-amino-3-methyl radical

propyl.

  The above-mentioned limitation excludes certain categories of diamines from the composite compounds of the invention. This limitation excludes from the invention the α-substituted diamines in which the symbol Z represents the 3-amino-propyl radical or the 3-amino-propylene-1 radical, that is to say the compounds corresponding to the general formulas: Y

R2N- (CH2) 3-CH-NH2 (II)

and

Y

!

H2N-CH2CH = CH-CH-NH2 (

  o the symbol Y has the same definition as before.

  The compounds where the symbol Y represents the trifluoromethyl radical are in particular excluded from the α-substituted diamines

  remaining. Thus, the compound (IV), which is methyl-4 trifluoro-

  methyl-1 butanediamine-1,4 is excluded from the compounds that may be

usefully employed.

CF t3

H2N CH- (CH2) 2-CH- (IV)

CH3

  Among the compounds that can be used are the asubstituted amino acids corresponding to the formulas: Y H 2 N- (CH 2 3 -C-CoOH ()

NU2

Y

H2N-CH- (CH) -C-COOH (VI)

H2- -C2 2,

CH3 NU2

  and N-CZH-CEH-C-CooH (VII) 21 tNS R In formulas (V), (VI) and (VII) above, the symbol Y has the

  same definition as before.

  The α-substituted amines forming part of the compounds which can be usefully employed in the practice of the invention have the general formula

H2 N-CH (CH2) 2 CH-NH2 (VIII)

  CH3 o the symbol Y represents the radicals -CH 2F, -CHF2 and -CnCH,

  the -CF3 radical being excluded in the case of diamines.

  Examples of the salts of the compounds of the invention are the non-toxic acid addition salts formed with mineral acids, such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and organic acids such as

  methanesulfonic acid, salicylic acid, maleic acid, malonic acid,

  trique, citric, cyclamic and ascorbic.

  Another preferred class of compounds of the invention

  -tion is constituted by those where the symbol Y represents the difluoromethyl radical. Another category of compounds is constituted by those where the symbol Z represents the 3-amino-propyl radical or

  the 3-amino-3-methylpropyl radical.

  In addition to the aforementioned salts, the term salts includes the internal salts or zwitterions of the compounds of formulas (1) (above) which are amphoteric in nature. In addition, although the configuration

  of the compounds described here is not specified, it is obvious

  that the α-carbon atom has a center of asymmetry and that the individual optical isomers of these compounds exist. Therefore, the optical isomers d and 1 as well as the mixtures

  racemates are within the scope of the invention.

  The formation of a lactam can occur when

  the symbol R1 represents the carboxy radical and the symbol Z represents

  is the 3-amino-propyl radical or the 3-amino-3-methylpropyl radical, as represented by the following general formula: NH 2

Y- C- C = O

(C 3 H

(CHA> NU

(Ix)

  In the general formula above, the symbol Y has the same definition

  than previously. When the symbol Z represents the radical

  3-amino-3-methylpropyl, the (CH 2) 3 radical of formula (IX)

  above can be further substituted by a methyl-3 radical.

  Examples of useful compounds according to the invention are: diamino-2,5-acid, diamino-2,5-acid, 2,5-diamino-2,5-diamino-acid, and diamino-2,5-acid. 2.5 diamino-2,5 acid 2,5 diamino acid 2,5 diamino acid 2,5 diamino acid 2,5 diamino acid 2,5 diamino acid 2- (5-difluoromethyl) -pentanoic, -2-diamino-5 (fluoromethyl) pentanoic acid, 2- (pentafluoromethyl) pentanoic (2-ethynyl) pentanoic, 2-fluoromethyl-5-pentanoic, 2-difluoromethyl-5-methylpentanoic 2-Trifluoromethyl-5-methylpentanoic, 2-ethynyl-5-methylpentanoic, 2-fluoromethyl-3-pentene, 2-difluoromethyl-3-pentene, 2-trifluoromethyl-3-pentene, 2-ethynyl-3-pentenoic 1-fluoromethyl-4-butanediamine-1,4-methyl, 2-difluoromethyl-4-butanediamine-1,4-methyl, and

  ethynyl-1-methyl-4-butanediamine-1,4.

  The compounds of the general formula (I) are prepared: Z represents H2N- (CH2) 3-, Y represents -CH2F, -CHF2 or -CF3 and R represents the carboxy radical by treatment of an ester derivative of the ornithine, whose amino radicals are

  suitably protected, with a strong base to form the car-

  intermediate banion. This carbanion is reacted with a halomethylhalogenated alkylation agent in an aprotic solvent.

  such as dimethylsulfoxide, dimethylformamide, dimethyl

  acetamide, benzene, toluene, ethers such as tetra-

  hydrofuran, ethyl ether or dioxane, and in the presence of hexamethylphosphorotriamide when Y is other than F2CH-, at a temperature of about -120 C to 120 C, preferably about

  250.degree. C. at 50.degree. C. for about 0.5 to 48 hours, then

  acidic or basic lysis. This preparation can be represented by the following reaction sequence: ## STR2 ##

1 3 RC-R

R 1t3 -

R4 R

R4 Compounds 1 alkylating agent

Y Y

  S t Z -COOR Aqueous acid z2, diluted Coolt2 / hydrazine

NH2 '<N = C-R

2 1 3

R

  Compounds 3 Compounds 2 H20 (acid / base) Y

H N- (

HN- (CH) 3-C-COOH

  NH2 (Formula V) In the above reaction sequence, Y represents FCH2-, F2CH-, F3C-; R2 represents a lower alkyl radical, for example methyl, ethyl, isopropyl, propyl or butyl; R3 represents a hydrogen atom or a phenyl radical, straight or branched alkyl having 1 to 8 carbon atoms, methoxy or ethoxy; R4 represents a phenyl radical or a straight or branched alkyl radical having 1 to 8 carbon atoms, methoxy or ethoxy; R4 represents a phenyl radical or a straight or branched alkyl radical having 1 to 8 atoms of

  carbon; or R3 and R4 may together form a common alkylene radical

  carrying 1 to 7 carbon atoms, i.e. -CH2- (CH2) m -CH2-

  m is equal to 3, 4 or 5. Examples of straight or branched alkyl radicals having 1 to 8 carbon atoms which may be represented by R 3 and R 4 are methyl, ethyl and propyl radicals,

  isopropyl, butyl, tert-butyl, pentyl, neopentyl or triethyl

O

  methyl. The symbol Z1 represents R3-C = N (CH2) 3-, R5-CNH (CH2) 3- or

1 3, 2 3.

  R4 0o R6-OCNH (CH2) 3-; R3 and R4 are the same and have the previously indicated meanings; and each of R 5 and R 6 represents a benzyl phenyl radical or straight or branched lower alkyl

  having 1 to 4 carbon atoms, for example methyl, ethyl or iso-

O 0

nt he

  propyl; Z2 is H2N (CH23-, R5-GNH (CH2) 3- or R6-OCNH (CH2) 3-

  o R and R6 have the same meaning as before.

  The appropriate strong bases that can be used in the above reaction sequence to form the carbanion

  intermediate are those that remove a proton from the carbon atom

  in the α-position with respect to the carboxy radical, such as an alkyl lithium, for example butyl lithium or phenyl lithium, a lithium dialkylamide, for example diisopropylamide of

  lithium, lithium amide, potassium tert-butylate, amine

  sodium hydride, metal hydrides, for example sodium hydride or potassium hydride, tertiary amines such as

  triethylamine, lithium acetylide or dilithium acetylide.

  The most preferred bases are acetylurea

  lithium, dilithium acetylide, sodium hydride and diisocyanate

lithium propylamide.

  Examples of alkylating agent may be mentioned

  which can be used in the reaction sequence

  chlorofluoromethane, bromofluoromethane, fluoro-

  methane, chlorodifluoromethane, bromodifluoromethane,

  difluoroiodomethane, bromotrifluoromethane, chlorotrifluoro-

  methane, trifluoroiodomethane, bromochloromethane, dichloro-

  methane, chloroiodomethane, bromodichloromethane and dichloro-

  iodomethane. These alkylating agents are well known in the art.

  It is possible to carry out in a single step the elimination of the protective groups of the amine function and the carboxylic acid function by treatment of the compound 2 with an aqueous acid, for example hydrochloric acid or toluenesulphonic acid, at a temperature of about 0 to 100 C, for about 4 to 24 hours to obtain the compounds of general formula (V). It is preferred to first remove the amine functional groups or amine functions of the compounds 2 when these functions are protected as a Schiff base by treating the compounds 2 with a dilute aqueous acid, for example the acid. hydrochloric acid or with hydrazine or phenylhydrazine, in solvents such as lower alcohols, for example methanol or ethanol, ethers, chlorinated hydrocarbons, benzene and water. To eliminate

  protecting groups of the carboxylic acid function and

  When the amine functions are not protected in the form of a Schiff base, the compounds 3 are treated with concentrated aqueous acids, for example hydrobromic acid, at a temperature of about 0.degree. to 100.degree. aqueous base, by

for example, ammonium hydroxide.

  To prepare the protected amine ester derivatives, i.e. compounds 1, in which R 3 is

  other than a methoxy or ethoxy radical, an amino ester is treated

  suitable acid with a carbonyl compound to form a Schiff base in a generally known manner, in particular: (a) when R3 represents a hydrogen atom, the appropriate amino acid ester is treated with benzaldehyde or with an alkanal having 1 to Straight or branched carbon atoms, for example propanal-1, butanal-1, 2,2-dimethylpropanal-1 or 2,2-diethylbutanal-1; (b) when R3 represents a phenyl radical, the appropriate amino acid ester is treated with benzophenone or with a phenylalkylketone whose

  The alkyl moiety has 1 to 8 carbon atoms and is straight or branched.

  such as phenyl methyl ketone, phenyl ethyl ketone,

  phenylisopropylketone, phenylbutylketone or phenyl-tert-butyl-

  ketone; and (c) when R represents a straight alkyl radical or

  branched from 1 to 8 carbon atoms, the amino ester is treated

  suitable acid with a phenylalkylketone as previously described, or with a dialkylketone of which each alkyl moiety has 1

  to 8 carbon atoms and is straight or branched, for example the

  ethyl ketone, diethyl ketone, methyl isopropyl ketone, dibutyl

  ketone or methyl tert-butyl ketone. The carbonyl compounds are known in the art or can be prepared according to

well known in the art.

  When, in the compound 1, R3 represents a radical

  methoxy or ethoxy, an amino ester derivative is reacted

  suitable acid with a benzoyl halide or an alkanoic acid halide derived from an alkanoic acid having 1 to 9 carbon atoms and which may be straight or branched, such as acetyl chloride, propionyl chloride, chloride butyryl, tert-butyryl chloride, 2,2-diethylbutyric acid chloride or valeryl chloride. The reaction is carried out at 0 ° C. in an organic solvent such as ether, methylene chloride, dimethylformamide, dimethylacetamide or chlorobenzene, in the presence of an organic base, such as triethylamine or pyridine. After the reaction, the reaction mixture is allowed to warm to about 25 ° C for 1 hour. The type derivative is combined

  amide thus obtained with an alkylating agent, such as

  methyl sulphonate, dimethyl sulphate, methyl iodide,

  methyl p-toluenesulfonate or trishexafluorophosphate

  methyloxonium (when R3 represents a methoxy radical) or tetra-

  triethyloxonium fluoroborate (when R3 is ethoxy) at about 25 ° C in a chlorinated hydrocarbon solvent such as methylene chloride, chlorobenzene or chloroform. The reaction mixture is refluxed for about 12 to 20 hours, cooled to about 25 ° C., an organic base such as triethylamine or pyridine is added and the solution is then extracted.

  with salt water and isolate the product.

  When R 3 and R 4 together form an alkylene radical having 5 to 7 carbon atoms in the compounds 1, the corresponding amino acid ester derivatives are obtained by treatment of the amino acid ester with a cyclic alkanone, to form a base.

  Schiff according to procedures generally known in the art.

  Among the cyclic alkanones that can be used are the

  cyclopentanone, cyclohexanone and cycloheptanone.

  When, in compounds 1, the symbol Z1 represents

O O

  R5CNH (CH2) 3- or R60CNH (CH2) 3-, the protective groups are added

O O

the t.

  -C-R5 or COR to the corresponding free amino acid, that is to say ornithine, by treating this amino acid with an excess of a copper salt such as copper carbonate, in water boiling, for about 1 to 6 hours. After cooling to room temperature, the insoluble materials are filtered off and the filtrate is treated with an acid halide.

  (when Z1 represents R5CNH (CH2) n-) or with a halogeno

  Suitable alkyl or aryl formate (when Z1 is O R6OCNH (CH2) n-), in a solvent such as acetone, in the presence of a base such as sodium bicarbonate or sodium hydroxide. This treatment is followed by treatment with hydrogen sulfide. Examples of acid halides are

  that acetyl chloride, chloride of

  pionyl, benzoyl chloride or 2-phenyl acetyl chloride. Examples of useful halogenoformates include benzyl chloroformate, phenyl chloroformate, methyl chloroformate or ethyl chloroformate. The lactams of the compounds of general formula (I) are prepared. R 1 represents a carboxy radical, starting from the corresponding amino acid esters of formula: Y

H2N (CH) -C-CO (X)

2 2 3, i '

N'2

  o Y has the same definition as for formula (I) and R7 represents a straight or branched alkoxy radical containing 1 to 8 atoms of i2

  carbon such as methoxy, ethoxy, isopropoxy, butoxy or hexyloxy.

  To prepare the lactams, these amino acid esters are treated with a suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide , potassium methoxide, potassium tert-butylate, sodium amide or an organic amine such as trialkylamine, by

  For example, triethylamine in a solvent such as an alcohol

  such as methanol, ethanol, isopropanol, butadiene

  normal water, water, dimethylformamide, dimethylsulfoxide, hexamethylphosphorotriamide or a mixture thereof. The reaction is carried out for a period of 0.5 to 24 hours at a temperature of

  from about 0 C to 120 C, optionally under a nitrogen atmosphere.

  The compounds of the general formula (X) are obtained according to procedures well known in the art, for example by the use of the corresponding amino acid and treatment of this amino acid with a suitable alcohol such as methanol, ethanol, methanol and the like. isopropanol, normal butanol or normal heptanol saturated with gaseous hydrochloric acid. The compounds of general formula (I) are prepared. Z represents H N -CH (CH 2) 2-, Y represents -CH 2 F -CHF 2 or -CF and CH 3

  R 1 represents a carboxy radical, according to operating procedures

  to those just described.

  To prepare the compounds of general formula (I) where Z is H2NCH (GCH2) 2- or I2N- (CH2) 3-, Y is -C-CH and R1 CR3

  representing a carboxy radical, a propargyl derivative is treated.

  suitably protected amine, such as a silyl derivative, with a

  strong base, to form a protected propargylamine carbanion

  médiaire. This intermediate carbanion is reacted with an alkylating agent of the formula RX, where X represents a halogeno radical such as chloro or bromo and R8 represents PhHC = N (CH2) n- where n is equal to n to 3. the drift of propargylamine protected alkylated

  thus formed with a strong base to form a propargyl carbanion

  Preferred amine is alkylated. The second carbanion is reacted with a hydrogenation and then the protecting groups are removed by

  acid or basic hydrolysis, as indicated in the reaction scheme

next: (R9) 3-Si-C-C-CH2

N = C-R 1

R0O Strong Base Compound 4

(R 9

t1 t _ __) 3-S i-C-C

R8 I

N -R11

KING_

have- -

{% 3sicCC ('-)!

I 10

! I

I (R9O '! H

____ _

Rx r 10 Strong base (R9) 3-Si-CUC-CH

N = C-R 1

  R10 Acylating Agent (9-3-Si-CC-C-R12)

N = C -R

  1 1 Rlo Compounds 6 H2O 2 (acid / base) (based> z

HCSC-C-COOH

  In the above reaction scheme, R8 and X have the same meanings as above, Ph represents the phenyl radical, R10 represents a hydrogen atom or a methoxy radical.

  or ethoxy, R 11 represents a phenyl, tert-butyl or tri-

  ethylmethyl, R9 represents a straight or branched lower alkyl radical having 1 to 4 carbon atoms, R12 represents a carboxy anion, a carboxylic acid ester, a carboxamide, a nitrile or another group that can be hydrolyzed to an acidic function

  carboxylic acid and Z is H2N-C- (CH2) or H2N (CH2) 3.

CH3

  Compounds Suitable strong bases which can be used in the above reaction to form each carbanion are those which remove a proton from the carbon atom adjacent to the acetylene moiety, such as an alkyl lithium. Among the alkyl lithium that can be used include butyl lithium, phenyl lithium,

* lithium diisopropylamide, lithium amide, tert-

  potassium butylate and sodium amide.

  Alkylating agents, RX, used in the reaction

  The above are known in the art and can be prepared according to conventional methods known in the art. It is thus possible to prepare, for example, the reactive compound PhHC = N (CH 2) n - by reaction of 3-bromo-propylamine hydrochloride or 4-bromo-butylamine hydrochloride with benzaldehyde, in the presence of an organic amine such as triethylamine in a suitable solvent. Among the solvents that can be used are ethyl ether,

  tetrahydrofuran, dioxane, chloroform or dichloro-

methane.

  Suitable acylating agents which can be used are

  in the above reaction are haloformates such as methyl chloroformate or ethyl chloroformate, tert-butyl azidoformate, cyanogen bromide, carbon dioxide, diethyl carbonate, isocyanate phenyl, the

  triethoxymethyl tetrafluoroborate, N, N-dimethyl

  carbamoyl, 2-methylthio-1,3-dithiolinium iodide, ethylene carbonate or ethylene trithiocarbonate. When 2-methylthio-1,3-dithiolinium iodide is used, an additional alcoholysis stage using a lower alcohol such as ethanol or

  isopropanol is necessary before the hydrolysis of the protective groups

  tors. The alkylation reaction is easily carried out in the presence of an aprotic solvent such as benzene, toluene,

  ether, tetrahydrofuran, dimethylsulfoxide, dimethylfor-

  mamide, dimethylacetamide or hexamethylphosphorotriamide. The

  reaction temperature varies between -120 ° C. and about 25 ° C., the temperature

  preferred reaction rate being about -70 ° C., and the reaction time is between about 0.5 hours and 24 hours.

2484255

  To remove the protecting groups, as shown in the previous reaction scheme, in the step of converting the compounds 6 to the compounds of the formula (XI), the compounds 6 are treated with an aqueous acid such as hydrochloric acid or toluenesulfonic acid. Alternatively, an aqueous base such as sodium hydroxide or potassium hydroxide or

hydrazine or phenylhydrazine. The propargylamine derivatives of the compounds

  poses 4 o Rio represents a hydrogen atom, by addition of protective groups on the acetylene function and the nitrogen function

  propargylamine. To protect the nitrogen function of the propar-

  glylamine, a Schiff base is formed with a non-enolizable carbonyl compound, such as benzaldehyde, 2,2-dimethylpropanal or 2,2-diethylbutanal. In order to protect the acetylenic function, the Schiff base which has just been described is reacted with a trialkylsilyl chloride whose alkyl moiety contains 1 to 4 carbon atoms.

  carbon and is straight or branched. Among the trialkyl chlorides

  silyl that can be used include trimethyl chloride.

  silyl and triethylsilyl chloride.

  The propargylamine derivatives of the

  compounds 4, RO10 represents a methoxy or ethoxy radical, by reaction

  propargylamine, the acetylene function of which is protected

  by a trialkylsilyl radical with benzoyl chloride, chlorine

  Pivaloyl chloride or 2,2-diethyl 2,2-butyric acid chloride in a suitable solvent. Suitable solvents include ethyl ether, dioxane, tetrahydrofuran, chloroform, methylene chloride, dimethylformamide, dimethylacetamide and chlorobenzene. The reaction is carried out in the presence of an organic base such as triethylamine or pyridine, and then the reaction mixture is allowed to warm to about 25 ° C for 1 hour. The resulting amide derivative is combined with an alkylating agent such as methyl fluorosulfonate, dimethyl sulfate, methyl iodide, methyl p-toluenesulfonate or trimethyloxonium hexafluorophosphate, when RO 10 represents a radical. methoxy, or

  triethyloxonium tetrafluoroborate when Rio represents a radical

  ethoxy cal: at about 25 ° C. in a chlorinated hydrocarbon solvent such as

  methylene chloride, chlorobenzene or chloroform. The reaction mixture is refluxed for about 12 to 20 hours, cooled to about 25 ° C, and an organic base such as triethylamine or pyridine is added. The solution obtained is extracted with

  salt water and isolates the desired product.

  To obtain the propargyl-type starting material

  protected amine, a benzylimino-1-trialkylsilyl-3 propyne-2, that is to say a compound 4, RO10 represents a hydrogen atom and

  R 11 represents a phenyl radical, with hydrazine or phenylhydrogen

  Drazine at about 25 ° C. for about 0.5 hours, then the mixture is diluted, for example with petroleum ether, benzene or toluene, and the amine is isolated. Otherwise, the imine is hydrolyzed with a 0.5 N hydrochloric acid solution and the phase is evaporated.

  aqueous to obtain the amine in the form of the hydrochloride.

  To prepare the compounds of the formula -I, o Z represents

  H2N-CH (CH2) 2, Y is -CH2F or -CHF, and R is a moiety2 22 2 2 R1resin

CH3

  hydrogen atom, a ketone of formula ## STR2 ##

  Z 'represents a radical phthaloyl-NCH (CH2) 2-, benzoyl-NHCH (CH2) 2-

R13

  alkanoyl-NHCH (CH2) 2 -alkoxycarbonyl-NHCH (CH2) 2- or benzyloxy-

  carbonyl-NHCH (CH2) 2-, where the alkanoyl moiety has 2 to 5 carbon atoms and is straight or branched, the alkoxy moiety has 1 to

  4 carbon atoms and is straight or branched, Y represents -CH2F or-

  -CHF2 and R13 represents a methyl radical. The ketones are reduced to the corresponding alcohol which is treated with one equivalent of an imide, such as phthalimide, succinimide or maleimide, 1.1 equivalents.

  phosphine, for example triphenylphosphine or a trialkyl-

  phosphine such as tributylphosphine and 1.1 equivalents of azodi-

  diethyl carboxylate in a suitable solvent. Among the solvents

  ethers, such as ethyl ether, tetrachloride,

  hydrofuran or p-dioxane, benzene and dimethoxyethane. The reaction is carried out between about 0 ° C. and 100 ° C., preferably at

  about 25 ° C., for a period of about 0.5 h to 24 h, under an atmosphere of about

  inert gas such as a nitrogen or argon atmosphere. Hydrolysis

  then the imido derivative thus obtained in the free amine.

  To prepare the compounds of general formula (XII) where Y represents FCH2on a compound of formula II

Z'-C-CH2R14 (XIII)

  Z 'has the same definition as above and R14 represents a suitable leaving group, such as chloro, bromo or iodo, mesylate, tosylate, triflate or trifluoroacetate with a suitable fluorinating agent such as potassium fluoride, fluoride, silver, fluoride

  of cesium, thallium fluoride or tetrabutylammonium

  monium, in a suitable solvent. Among the appropriate solvents,

  solvents such as dimethoxyethane, dimethylsulphonate,

  foxide, dimethylformamide, ethylene glycol, acetonitrile, acetone, benzene or hydrofluoric acid. The reaction is carried out at a temperature of about 0 ° C to 2000 ° C for a period of about 2 hours to 48 hours. The leaving group R14 may also be a diazo group, in which case the fluorinating agent used is a mixture of hydrofluoric acid and pyridine. Suitable solvents

  for the reaction in which R14 is a diazo group are sol-

  Aprotic solvents such as ethyl ether, tetrahydrofuran and pentane. The reaction time varies between about 30 minutes and

  24 hours at a temperature between about -20 C and 65 C.

  For example, a compound of formula O is added

Z '-C-R14

  as previously defined, R 14 is a diazo group in a suitable aprotic solvent, a solution of hydrofluoric acid and pyridine and cooled to -10 ° C. The reaction mixture is vigorously stirred at 10 ° C. for 1 hour, heated to about 25 C for 2 hours then poured on ice. The organic phase is separated, washed with a base such as sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to give

  obtain the appropriate fluoromethyl ketone derivative of formula (XII).

  Derivatives of the diazoketone type, that is to say the

  compounds of formula (XIII) where R14 represents the radical diazo, may

  can be obtained through the acid halide cor-

  substituent represented by a compound of formula Z'-C-halo o the halo radical may be for example the chloro radical and

  Z 'has the definition given for formula (XII). The halo is added

  acid genius contained in an aprotic solvent, such as, for example, ethyl ether, tetrahydrofuran, pentane, hexane,

  benzene, dimethoxyethane or dioxane, to a solution of diazo-

  methane in ether cooled between about -40 C and 20 C, then

  Stir vigorously at about 25 ° C for about 1 to 24 hours.

  The diazoketone derivative thus obtained can be isolated according to

  standard techniques such as solvent evaporation with

  Subsequent application by recrystallization or chromatography. Alternatively, the reaction mixture can be treated with a fluorinating agent

  suitable as previously described without isolation.

  The diazoketone derivative can be used

  suitably substituted previously described to prepare

  poses of formula (XIII) o R14 represents for example a halogeno, mesylate, tosylate, triflate or trifluoroacetate according to procedures generally known in the art. To obtain the compounds of general formula (XIII) where R14 represents a radical

  halogen, such as chloro, bromo, or iodo, the compound cor-

  substituent of formula (XIII) wherein R 14 represents a diazo radical with aqueous hydrochloric acid, hydrobromic acid or hydroiodic acid in a suitable aprotic solvent. To obtain the compounds of formula (XIII), R 14 represents a mesylate radical,

  tosylate, triflate or trifluoroacetate, the corresponding derivative is dissolved

  diazoketone type, where R14 represents a diazo radical, in which

  a suitable aprotic solvent and treated with sulfuric acid.

  diluted to obtain the corresponding benzylmethanolketone compound. Finally, the benzylmethanolketone is esterified with a suitable acid chloride or acid anhydride using methanesulfonic acid, p-toluenesulfonic acid,

  trifluoromethylsulfonic acid or trifluoroacetic acid.

  The acid halides, that is, the compounds of the formula ZI-C-hlogno Z '-C-ha logeno as previously described, are known compounds which can be prepared from the corresponding acids. Thus, for example, treating the appropriate acid with thionyl chloride in an aprotic solvent, such as ethyl ether, tetrahydrofuran, benzene or dichloromethane at a temperature between about 0 ° C and the reflux temperature of the solvent during about

  1 to 24 hours form the corresponding acid halide. Otherwise the-

  treatment of the appropriate acid with oxalyl chloride in one of the aprotic solvents previously described at a temperature of about

  0 C at 40 C for about 1 to 24 hours also produces the halogen

corresponding acid genius.

  It is also possible to obtain the compounds of formula

  general mule (XII) where Y represents FCHG2- and Z 'is other than

R R

  benzoyl-NHC (CH2) 2- or alkanoyl-NHC (CH2) 2-, treat a compound of formula Z2-R15 (XIv)

  Z 2 represents a phthaloyl-N-CH (CH 2) 2 -, alkoxycarbonyl-

  RR f13,13 NHC (CH2) 2- benzyloxycarbonyl-NHC (CH2) 2-, p-methylthioethyl or

  P-benzylthioéthyle; R13 represents a methyl radical; and R15 represents

  a chloro, bromo or iodo radical, mesylate or tosylate. We

  thereby reacting a compound of formula (XIV) with triphenyl-

  phosphine or a tri (lower alkyl) phosphine, for example tributylphosphine in a solvent such as benzene, toluene, methanol, ethanol, acetonitrile, tetrahydrofuran, ether

  ethyl or dimetoxyethane. The reaction is carried out at a time

  between 25 ° C. and the reflux temperature of the solvent

  for a period of between about 10 minutes and 48 hours.

  By cooling, a precipitate is formed which is washed with a solvent and recrystallized to obtain the phosphonium salt.

  appropriate. The triphenylphosphonium or trialkyl salt is added

  phosphonium to an excess (up to 25%) of sodium or lithium metal-

  dissolved in liquid ammonium to which a catalytic amount of ferric nitrate is added. Stirring is continued for about 10 minutes to 3 hours and then the ammonia is evaporated in an inert atmosphere such as a nitrogen or argon atmosphere. A suitable solvent such as benzene, toluene, ethyl ether, tetrahydrofuran or dimethoxyethane is added and the resulting substituted methylidene phosphorane is recovered. The methylidene

  phosphorane with a lower alkyl ester of monofluoro-

  acetic acid in a solvent such as benzene, toluene, ethyl ether, tetrahydrofuran or dimethoxyethane. The reaction is carried out in an inert atmosphere such as a nitrogen atmosphere

  or argon at a temperature between about 0 C and the temperature

  solvent reflux for a period of about 30 minutes to 24 hours. The reaction mixture is concentrated by distillation to obtain an olefin. The olefin is treated with an aqueous mineral acid such as hydrochloric acid or hydrobromic acid or a

  organic acid such as trifluoroacetic acid or p-toluene acid;

  sulfonic acid in the presence of a cosolvent such as tetrahydrofuran,

  ethyl ether or benzene for a period of about 30 minutes.

  at 24 hours at a temperature between about 0 C and the reflux temperature of the solvent. The amount of acid used may vary between a catalytic amount and a concentrated acid solution. In the general formula (XIV), the term phthaloyl-N-CH (CH2) 2- denotes the radical O il R

C / N-CH (CH2> 2 "

R

  and the term alkoxycarbonyl-NHCH (CH2) 2- denotes the alkyl radical

O R, 13

  R 1 alkyl-OC-NHCH (CH 2) 2 - the term benzyloxycarbonyl-NHCH (CH 2) 2 is designated as OR 13 and leiradical (1C3-OCNHCU (CH) -o is the moiety> J2CH (H2-O R13 at meaning indicated for formula (XIV) and the alkyl radical is straight or

  branched and has 1 to 4 carbon atoms.

  To obtain the compounds of general formula (XII) where Y represents F 2 CHon treats [[(methyl) sulfinyl) methyl] thio] methane or [[(ethylsulfinyl) methyl] thiolethane with a suitable strong base and then alkylated with a derivative appropriate formula

Z '-R16 (XV)

  o Z 'has the same definition as for formula (XII) and R16 represents

  a chloro, bromo, iodo, mesylate or tosylate radical. The Z'-substituted sulfinyl derivative thus formed is treated with a strong base

  and then alkylated with a halomethylated alkylating agent.

  halogen selected from chlorodifluoromethane, bromodifluoro-

  methane, and fluoroiodomethane. The alkylation reaction is followed

  hydrolysis with an aqueous solution of acid.

  Suitable strong bases that can be used to prepare the difluoromethyl-substituted ketone derivatives described above are sodium hydride, dilithium acetylide, lithium diisopropylamide, butyl lithium, tert- potassium butylate, sodium tertbutylate, lithium tert-butylate, phenyl lithium, methyl lithium, sodium amide, amide

  lithium or potassium hydride.

  The alkylation reaction described is carried out in order to prepare the difluoromethyl ketone derivatives in a suitable solvent, for example tetrahydrofuran or ethyl ether.

  hexamethylphosphoric triamide, dimethylsulfoxide, or benzene.

  The reaction is carried out at a temperature of between about

  -78 C and 65 C for a period of about 30 minutes to 24 hours.

  Preferably, a temperature of about 40 ° C. is used for the difluoromethyl alkylation stage. The alkyl sulfinyl intermediates are isolated by stopping with a saline solution and then

  extracted with ethyl ether, dichloromethane or benzene.

  The alkylated sulfinyl intermediates are recovered in the

combined extracts.

  To hydrolyze the alkylated sulfinyl derivatives in the ketoneon uses an aqueous solution of a mineral acid such as hydrochloric, hydrobromic, perchloric or sulfuric acid in a solvent such as tetrahydrofuran, acetonitrile, ethyl ether or benzene. The hydrolysis is carried out at a temperature of between about -20 ° C. and 105 ° C., preferably at about 25 ° C., for a period of about 30 minutes to 24 hours, preferably

  about 2 hours. Generally, a solution of 0.3 equi

  are worth 1.5% mineral acid in water. The following examples illustrate the preparation of difluoromethyl ketone derivatives.

of formula (XII).

  The compounds corresponding to formulas (XIV) and (XV) where R 15 and R 16 represent a halo radical are known in the art

16

  or can be prepared from a suitable carboxylic acid derivative having the formula

Z 4-COOH (XVI)

  13.13 Z4 represents a phthaloyl-NCH radical (CHI2, benzoyl-NHCH (CH2) -, RR 13.13

  alkanoyl-NHCH (CH2) -, alkoxycarbonyl-NHCH (CH2) -, benzoyloxycarbonyl

  nyl-NHCH (CH 2) -, methylthiomethyl or benzylthiomethyl. These acids are known in the art or can be obtained according to known methods from the corresponding unprotected amino acids. It is possible, to prepare the compounds of formulas (XIV) and (XV) where R15 and R6

R15 16

  represent a mesylate or tosylate radical, treat the corresponding derivatives o R15 and R16 represent a halogeno radical with a metal salt of methanesulfonic acid or p-toluenesulphonic acid. For example, one can use sodium salt

  methanesulfonic acid or p-toluenesulfonic acid.

  The ketones of formula (XII) are chemically reduced to the corresponding alcohols by using 1 to 10 equivalents of a metal hydride such as lithium borohydride, sodium borohydride, sodium cyanoborohydride or lithium hydride. and aluminum. In addition, the ketones can be reduced by borane or dimethylthioborane or catalytic reduction can be carried out, for example, by Raney nickel, rhodium, palladium on carbon or platinum oxide. In general, the duration of

  reaction varies between about 10 minutes and 24 hours and the temperature

  The temperature at which the reduction is carried out may be from about -40 ° C to about 100 ° C depending on the particular reducing agent used. When reduced by hydride or borane, the reaction is carried out in a suitable solvent for a period of about minutes to 24 hours at temperatures between about -40 ° C and 65 ° C. Suitable solvents include to reduce the compounds of general formula (XII) can be used lower alcohols such as methanol or ethanol or ethers such as ether. ethyl or tetrahydrofuran. When carrying out a catalytic reduction, the reaction time varies between about 1 hour and 24 hours, the reaction temperature is between about 25 C and 100C and the hydrogen pressure can be

between 1 and 120 bar.

  To hydrolyze the amine and remove it

  For any protecting group of the distal amine function, a strong mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid is used, or an organic acid such as toluenesulfonic acid or trifluoroacetic acid. The hydrolysis is carried out in water or an aqueous solvent at the reflux temperature for a period of about 4 to 48 hours. Alternatively, 1 to 3 equivalents of hydrazine, methylhydrazine or methylamine can be used at a temperature between about 25 ° C and the reflux temperature of the solution for about 1 to 12 hours and then treated with a strong mineral acid or an organic acid such as

- previously described.

  To prepare the compounds of formula (I) where Z represents

  H2N-CH (CH2) 2, R1 represents a hydroxy radical and Y represents

  C.sub.3 -C.sub.3.sup.-, or as indicated below, an alkynyl radical, the previously described alkylated compounds are hydrolysed. The desired alkylating agents of the formula R 8 X used can be prepared according to methods known in the art. It is thus possible to prepare the agent PhHC = NCH2 CH2> 2

  by reaction of bromo-3-propylamine hydrochloride with benzal-

  dehyde and an organic trialkylamine such as triethylamine, in a solvent such as ethyl ether, tetrahydrofuran, dioxane, chloroform or dichloromethane. To prepare the agent CH 3 PhHC = NCH (CH 2) 2, 3-amino butylbromide hydrobromide is reacted with benzaldehyde and an organic amine such as triethylamine. 3-Amino-butylbromide hydrobromide is a known compound which can be prepared from the corresponding alkanol by treatment with concentrated hydrobromic acid at a temperature of 25 ° C to 110 ° C.

  for a period of 1 to 12 hours. To obtain the 7-amino derivative

  an appropriate 9-ketoalkanoic acid ester of formula

O O

CH 3 C-CH 2 C-OCH2CH3

  The β-ketoalkanoic acid ester is treated with hydroxylamine to form the corresponding oxime which is reduced with lithium aluminum hydride in ether or tetrahydrofuran at a temperature of from 25 ° C. to 50 ° C. for a period of between 1 and 12 hours. The subsequent hydrolysis of the fragment

ester produces γ-aminoalkanol.

  The alkylation reaction can be carried out in an aprotic solvent, for example benzene, toluene, ether,

  tetrahydrofuran, dimethylsulfoxide or hexamethylphosphoro-

  triamide. The reaction temperature is between about -100 ° C and 25 ° C, preferably about -70 ° C, and the reaction time varies.

  between about 0.5 hours and 24 hours.

  To eliminate the protective groups, as

  In the reaction scheme in the stage from compounds 5 to the desired amines, it is treated with an aqueous acid, for example hydrochloric acid, then with an aqueous base, for example

  sodium or potassium hydroxide, or is treated with phenyl

  hydrazine, hydroxylamine or hydrazine and then with an aqueous base.

  The individual optical isomers of the compounds of formula (I) are double-bonded. R 1 represents a carboxyl radical or a

  hydrogen atom with a salt of (+) or (-) - binaphthylphosphoric acid

  according to the procedure of R. Viterbo et al., Tetrahedron Letters 48, 4617 (1971). Other resolving agents such as (+) - camphorsulfonic acid-IO can also be used. Otherwise, when Z is H2N-CH- (CH2) 2- or H2N (CH2) n-, CH2 is performed by means of the lactam of said compounds. We

  can use the acids and amines thus resolved, as pre-

  previously described for racemic mixtures.

  The compounds described herein are useful for inhibiting the development of protozoa in animals. The term "animals" includes, inter alia, mammals, such as mice, rats, guinea pigs, rabbits, ferrets, dogs, cats, cows, horses and primates including humans. The term animal also includes fish and birds. The term "birds" refers to male or female birds of all types including parrots and canaries, but refers primarily to poultry raised for their eggs or meat. Therefore, the term "birds" refers especially to hens, roosters,

  turkeys, turkeys, ducks and ducks.

  The term "protozoan" includes members of the subphyla Sarcomastigophora and Sporozoa of the Protozoa species. In particular, "protozoa" is understood here to mean the genera of

  parasitic protozoa that are important to humans because they

  evoke human diseases or domestic animals. These genres belong for the most part to the Mastigophora superclass

  of the subphylum Sarcomastigophora and the Telosp o class of the sub-phylum

  Phylum Sporozoa according to Baker's classification (1969). Examples of such genera include Histomonas, Trypanosoma, Giardia, Trichomonas, Eimeria, Isora, Toxoplasma, and Plasmodium.

  The genus Leishmania, some species

  In man, tropical diseases called leishmaniasis are excluded from the Mastigophora superclass. Also the species o Trypanosoma cruzi which causes in humans Chagas disease and

  Trypanosoma lewisi species are specifically excluded from the Trypa genus

  nosoma. The compounds described here have proved not to be

  highly effective against these species.

  On the other hand, the compounds of formula (1) are particularly useful for inhibiting the development of Trypanosoma brucei which is the causative agent of Nagana, or tsetse disease of horses and ruminants in Central Africa. The compounds described are also remarkably effective in inhibiting the development of Eimeria tenella, which is a species of protozoa

  causing coccidiosis of birds.

  A preferred embodiment of the invention is the use of these compounds to inhibit the development of intestinal coccidia in industrial poultry. Intestinal coccidiosis is of great economic importance. Thus, in 1972, the losses

  estimates of industrial poultry farming in the United States of America

  as a result of coccidian infections, were approximately $ 47 million. As coccidia become rapidly drug-resistant and some of the drugs used to treat coccidiosis have relatively high toxicity, coccidiostats are sought which are non-toxic and to which intestinal coccidia do not become

quickly resistant.

  It is not clear how the compounds of

  the invention are capable of inhibiting the development of protozoa.

  Among others, the compounds described here are irreversible inhibitors.

  of ornithine decarboxylase and S-adenosylmethionine-

  decarboxylase. These compounds, as they are irreversible inhibitors,

  of these enzymes, inhibit the formation of polyamines which may be necessary for cell division of protozoa. In any case, the practice of the invention is in no way limited to a theory

  or a particular mode of action according to which the compounds of the invention

  vention are able to effectively inhibit the development of

protozoa.

  The effect of the compounds of the general formula (I) on the development of protozoa, and more particularly on the development of coccidia, can be demonstrated by the use of Eimeria tenella and male white leghorn chicks, two weeks 'study. Birds are raised in batteries and infected and uninfected birds are housed in rooms

  separated to protect birds without coccidiosis.

  Each experimentally infected bird receives 100,000 oocysts

  sporulated by gavage. The test compound is administered at

  particular logie chosen in the drinking water and is provided to

  will of the pie without medication. To evaluate the effect of

  active ingredient on E. tenella infections, chicks are sacrificed with carbon dioxide, and are usually autopsied

  at the 5th day of the study, and the caecal lesions are evaluated.

  In order to determine the inhibition of protozoan development, it is also possible to use Trypanosoma PbEcei brucei,

  which is the causative agent of bovine trypanosomiasis (nagana) in Africa.

  The related species Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense are the causative agents in Africa of the disease

of man's sleep.

  In general, the drug activity against established infections of a pleomorphic strain EATRO 110 of T. b. brucei in the mouse. The animals are infected with 5x105 parasites 24 hours before the test. Control animals thus infected usually die 5 days after inoculation. The test compound is administered to the treated animals in drinking water in varying doses. Healing animals remain free of parasites more than 30 days after the death of control animals as indicated by blood smear examination.

  The compounds described here are used in amounts

  effective in inhibiting the development of protozoa. These quantities

  These depend, of course, on various factors such as the type and nature of protozoan infection, the activity of the particular compound, the age, sex and species of the animal being treated, as well as the prophylaxis or therapeutic treatment. In general,

  the compounds described here can be administered orally or

  at a daily dose of between 5 mg / kg and 7 g / kg.

  Preferably in the case of Trypanosoma infections, the dosage is from about 600 mg / kg to about 2 g / kg. In the case of Eimeria infections, the dosage may be reduced to

  is between about 15 mg / kg and about 1 g / kg.

  Because of the low toxicity of the compounds described herein, they can be administered at will through the drinking water of treated animals during the treatment of coccidiosis of birds. In general, concentrations of active ingredient of between about 0.01% and about 27% are suitable depending primarily on the nature of the protozoan infection to be treated, the prophylactic or therapeutic nature

  treatment, the severity of the infection and the period of

  is lying. It is thus possible, for example, to effectively administer 2-difluoromethyl-2,5-diamino pentanoic acid to

  chicks for the treatment of coccidiosis a day before

  fection as a 2% solution. Otherwise, we can realize

  prophylaxis eight days before infection with

* reading 2-difluoromethyl-2,5-diamino pentanolic acid concentrations as low as 0.015% in chicks' drinking water. Preferably, a prophylactic concentration is preferred

from 0.06% to about 1.0%.

  The prophylactic treatment of protozoan development inhibition is one of the main advantages of the use of the decarboxylase inhibitors described herein. Thus in the case of coccidian infections of chicks, Eimeria tenella, for example, develops inside epithelial cells of the cecum in a trophozoic stage. Then these cells undergo

  a form of multiple mitosis producing a large number of merozoites.

  These merozoites are released by lysis of the host cell and cause significant infection of new cells. The result is that the wall of the cecum is severely damaged, causing significant loss of blood and fluid and eventually death. In addition, during the life cycle of E. tenella, resistant oocysts are formed which are evacuated in the feces of the chicks. Chicks are by nature coprophages so well

  that the disease spreads rapidly through contamination of the diet.

  Therefore, coccidial infections of industrial farms, when they occur, are treated as epidemics with massive doses of common chemotherapeutic agents which are essentially coccidiocidal in nature. Therefore, we use

  fluids with added drugs to the point that

  all the industrial farms are subjected to a close treatment.

  than constant to avoid the appearance of outbreaks of coccidiosis.

  The fact that the decarboxylase inhibitors described herein can be administered prophylactically enables the host to overcome a subsequent natural or artificial infection, according to an enzymatic mechanism of inhibition and not according to an action.

  coccidiocidal. Therefore, in the case of E. tenella infection,

  fection is shortened because the host uses the defense mechanisms of his own organism. This fight against infection

  produces antibodies that are more likely to immunize

  hosts the host against future E. tenella infections.

  Pharmaceutical compositions which are particularly suitable for the prophylaxis or treatment of infections caused by the protozoa of birds include α-substituted amines or α-substituted amino acids previously

  described in combination with a suitable vehicle in pharmacy.

  Advantageously, to prepare the antiprotozoal compositions,

  the active compound is mixed with an inert carrier. Among the vehicles

  Inert substances include talc, clay, pumice, silica, chalk, diatomaceous earth, nut shell meal and their equivalents. Alternatively, the active ingredient can be mixed with a food or premix containing vitamins and substances

  mineral trade particularly suitable for birds.

  In most cases, a concentrated aqueous solution of the active ingredient is used for the treatment of coccidiosis of birds. For the most part the compounds described are very soluble especially in the form of their salts. These solutions may advantageously contain preservatives such as

  parabens, benzyl alcohol, phenol or thimerosal.

  In addition, it is possible to use isotonicity agents,

  sugars, stabilizers or buffers.

  The compounds of formula (I) may be used in combination with other known medicaments commonly used for chemotherapy and chemoprophylaxis of diseases caused by parasitic protozoa. In general, this has the effect of reducing the amount of enzymatic inhibitors administered. These drugs include Antrycide, quinapyramine, Bérénil, Diminazene aceturate, Pentamidine isethionate,

  Primaquine, Tryparsamide, Amicarbalide, Amprolium, Ampho-

  terin B, quinine, Monensin, Minocycline, 6-dimethylamino-6-demethyl-6-deoxy tetracycline, Clindamycin, 7-deoxy-chloro-7-lincomycin, Buquinolate, Robenidine and

  Nicarbazin. In some cases, the compounds of formula (1)

  or potentiate the effects of these drugs.

  In this respect, 2,5-diaminodio-2-difluoromethylpentanoic acid is particularly interesting because it has been shown to have a synergistic action with the antiprotozoan agents Antrycide, quinapyramine, Pentamidine isethionate and

  the Amicarbalide. Thus, the concentration can be reduced by

  2-diamino-2,5-difluoromethylpentanoic acid when used in combination with sub-curative

1.0 mg / kg) of these drugs.

  In addition, the compounds of formula (I) can be used in combination with other cytotoxic agents known for chemotherapy and chemoprophylaxis of parasitic diseases, in particular trypanosomiases. These cytotoxic agents include the antineoplastic antibiotic Bleomycin and other well-known cytotoxic agents such as, for example, cyclophosphamide, methotrexate, prednisone, 6-mercapto purine, procarbozine, daunorubicin, vincristine, vindesine, vinblastine, chlorambucile, cytosine arabinoside, thio-6 guanine, thio-TEPA, 5-fluoro-uracil, 5-fluoro-2-deoxy-uridine, 5-aza-cytidine, nitrogen mustard, bis (2-chloroethyl) -1,3 nitroso-1 urea (BCNU), 2-chloroethyl) -l

  3-cyclohexyl-1-nitroso urea (UNFC), busulfan or adriamycin.

  The use of the enzyme inhibitor diamino-2,5-difluoromethyl-2-pentanoic acid in combination

  with the anti-tumor antibiotic Bleomycin is particularly

  particularly interesting for the treatment of trypanosomiasis in general, and more particularly the treatment of nagana of cattle. This particular enzyme inhibitor appears to have a synergistic action with Bleomycin. Thus mice infected with Trypanosoma brucei are cured after 3 days of daily intraperitoneal administration of Bleomycin d

  the dose of 7 mg / kg. Similarly, trypanosome infections

  Mouse nosomes are cured by the administration of a 1% solution of diamino-2,5-difluoromethyl-2 pentanoic acid in water

of drink for 3 days.

  The results of several combined experiments indicate that cures are regularly obtained with 0.5 mg / kg of Bleomycin in combination with 0.5% of 2,5-diamino-2-difluoromethylpentanoic acid by administration in water of drink. Also cures for Bleomycin concentrations of 0.25 mg / kg are obtained in combination with only 0.25% 2,5-diamino-2-difluoromethylpentanoic acid in drinking water. A combination of 0.1 mg / kg Bleomycin and 0.1%

  2,5-diamino-2-difluoromethyl pentanoic acid has no effect.

  Thus the dosage of Bleomycin can be reduced from 1/2 to 1/28 of the curative dose of the drug alone when used in combination with a sub-curative dose of 1/2 to 1/4 of the dose.

  curative dose of diamino-2,5-difluoromethyl-2-pentanoic acid.

  The following examples illustrate in a non-limitative

  tive preparation and use of the compounds of the invention.

Example i

  2-difluoromethyl-2,5-diamino pentanoic acid.

  Under a nitrogen atmosphere, a solution (500 ml) of 2 M butyl lithium in hexane, a stirred solution of 143.1 ml of diisopropylamine in 1.5 liter of tetrahydrofuran at -78 C and then

  261 g (0.81 mol) of ornithine-dibenzalum methyl ester are added

  dimine in 1.5 liters of tetrahydrofuran. When the addition is

  completed, the reaction temperature is raised to 40 C and

  holds between 40 C and 500C for 3 hours during which one makes

  bubbling gaseous chlorodifluoromethane into the mixture with stirring.

  The reaction mixture is then treated with saturated sodium chloride solution. The organic material is extracted with ether, the ether extract is washed several times with sodium chloride solution, dried over magnesium sulfate and evaporated to give a viscous oil. The oil is stirred with 1N hydrochloric acid (1.5 liters) for 3 hours, the mixture is extracted several times with chloroform and the aqueous solution is evaporated to dryness. The oily residue is refluxed with 12 N hydrochloric acid (1.5 liter) for 16 hours, the cooled solution is clarified.

  by chloroform extraction before concentrating

  discolouration (charcoal) and then a new concentration at about 750 ml. The pH of the solution is adjusted to 3.5 by addition of triethylamine, the solution is treated again with coal before

  concentrate to about 500 ml and dilute with 7-8 liter of acetone.

  The precipitated product is filtered off and washed with ethanol.

  nol. The crude product is recrystallized by dissolving in about 1 ml of hot water and treating the solution with ethanol

  hot (450 ml). By cooling 71 g (37%) of chlorine crystals

  2-difluoromethyl-2,5-diamino pentanotric acid hydrochloride monohydrate

separate; M.p. 183 C.

Example 2

  Α-ethynyl α, β-diaminovaleric acid.

  11.8 g (0.048 mol) of N-benzenecarboxymidate (3-trimethylsilylpropyn-2-yl) in 20 ml of tetrahydrofuran is added to lithium diisopropylamide prepared from 4.9 g (6.78 ml, 0.048 mol). of diisopropylamide in 60 ml of tetrahydrofuran and 23.6 ml of a 2.05 M solution of butyl lithium at -70 ° C. and then 9.5 g (0.042 mol) of N- (3-bromo-propyl) are added; benzylimine and the mixture is stirred at -70 ° C. for 5.5 hours. 23.6 ml of a 2.05 M solution of butyl lithium and then 4.5 g (3.67 ml, 0.048 mole) of methyl chloroformate are added to the reaction mixture. After 30 minutes at -78 C,

  the mixture is treated with salt water and the reaction product is isolated.

  by extraction with ether. The ether extract is evaporated, 300 ml of 3N hydrochloric acid is added to the residue obtained and the mixture is refluxed for 7 hours. The mixture is cooled, thoroughly washed with methylene chloride, basified and washed again. The aqueous solution is acidified and concentrated to dryness. We

  The residue is triturated with ethanol, filtered and the ethanol evaporated.

  The residue is dissolved in water, the pH is adjusted to 6 and the solution is applied to a column of Amberlite 120 H, eluting with 1M ammonium hydroxide to obtain after recrystallization from a mixture of ethanol and water; α-ethynyl α, β-diaminovaleric acid;

F = 168-169 ° C (decomposition).

  In the above operations, the N- (bromo-

  3-propyl) benzylimine from 3-bromo-propylamine and benzal-

  dehyde according to procedures generally known in the art.

Example 3

  1-Fluoromethyl-1,4-butanediamine dihydrochloride

  To a solution of 40 mmol of diazomfthane in 110 ml of ether, cooled to 0 ° C. and stirred magnetically, a solution of 20 ml of sodium chloride is added dropwise under nitrogen over one hour.

  4-phthalimido-butyryl in 75 ml of ether. We continue the agitation

  1 hour at 250 ° C. and then the reaction mixture is added to a solution.

  40 ml of a mixture of hydrofluoric acid and pyridine

  The resulting heterogeneous mixture is stirred at 250 ° C. for 1.5 hours and then poured into ice-cold water. The ethereal phase is separated, washed with a solution of bicarbonate, then with salt water and dried over magnesium sulfate. The solvent is concentrated under reduced pressure to obtain a solid which is recrystallized from

  a mixture of ethyl ether and pentane to obtain the fluoro-

  methyl (3-phthalimido propyl) ketone; Mp = 92C.

  To a solution of 550 mg (2.2 mmol) of fluoromethyl

  (3-phthalimido propyl) ketone in a mixture of 5 ml of tetrahydro-

  furan and 5 ml of methanol cooled to -20 C, a solution is added

  0.8 mmol of sodium borohydride in a mixture of 5 ml of tetrahydrofuran

  hydrofuran and 5 ml of methanol previously cooled to -20 C.

  The reaction mixture is stirred for 15 minutes at -20.degree.

  at pH 1 with 2M hydrochloric acid. The solids are evaporated.

  under reduced pressure and the residue is partitioned between water and chloroform. The organic phase is washed with salt water and then dried over magnesium sulfate and concentrated to give

  obtain a residue which is recrystallized from a mixture of tetrahydro-

  furan and ethyl ether to obtain fluoro-1-phthalimido-5-pentanol-2; Mp = 85 ° C. A mixture of 264 mg (1.05 mmol) of 1-fluoro-5-phthalimido-2-pentanol is stirred under nitrogen for 2 hours at 25 ° C.

  170 mg (1.05 mmol) of phthalimide, 302 mg (1.05 mmol) of triphenyl-

  phosphine and 201 mg (1.15 mmol) of diethyl azodicarboxylate in 8 ml of tetrahydrofuran. The solvent is evaporated under reduced pressure and the residue is taken up in benzene. The insoluble material is discarded and the residue obtained after concentration of the filtrate is recrystallized from a mixture of tetrahydrofuran and ethyl ether.

  obtain 1-fluoromethyl butanediyl-1,4 bis-phthalimide; F = 112 C.

  A suspension of 3.1 g of 1-fluoromethyl butanediyl-1,4-bis-phthalimide in 140 ml of concentrated hydrochloric acid is heated at reflux temperature for 3 days. The phthalic acid which precipitates is filtered off by cooling to 4 ° C. The filtrate is concentrated to approximately 20 ml and cooled to 4 ° C. The acid is filtered off.

  remaining phthalic acid which separates and the filtrate is concentrated under pressure.

  reduced. The residue is treated 3 times with 40 ml of isopropyl alcohol.

  boiling pyline and then recrystallized from absolute ethanol to give 1-fluoromethyl butanediamine-1,4-dihydrochloride

F = 154 C.

Example 4

  Fluoromethyl-1-methyl-4-butanediamine-1,4-dihydrochloride.

  To a solution of 40 mmol of diazomethane in 110 ml of 0.degree. C. cooled and magnetically stirred ether is added dropwise under nitrogen in 1 hour a solution of 20 ml of sodium chloride.

  4-phthalimido-4-methyl butyryl in 75 ml of ether. We continue

  1 hour at 25 ° C. and then the reaction mixture is added to a solution of 40 ml of a mixture of hydrofluoric acid and pyridine pre-cooled to 0 ° C. The heterogeneous mixture obtained is stirred at 25 ° C. for 1.5 hours. then poured on ice water.

  The ethereal phase is separated off, washed with a bicarbonate solution

  then salted with salt water and dried over magnesium sulfate.

  The solvent is concentrated under reduced pressure to obtain a solid which is recrystallized from a mixture of ethyl ether and pentane.

  to obtain fluoromethyl (3-phthalimido-3-methylpropyl) ketone.

  To a solution of 550 mg (2.2 mmol) of fluoromethyl

  (3-phthalimido-3-methyl-propyl) ketone in a mixture of 5 ml of tetra-

  hydrofuran and 5 ml of methanol cooled to -20 ° C, a solution of

  0.8 mmol of sodium borohydride in a mixture of 5 ml of

  tetrahydrofuran and 5 ml of methanol previously cooled to -20 C.

  The reaction mixture is stirred for 15 minutes at -20 ° C. and then acidified to pH 1 with 2M hydrochloric acid. The solvents are evaporated off under reduced pressure and the residue is partitioned between water and chloroform. The organic phase is washed with brine, dried over magnesium sulphate and concentrated to give

  obtain a residue which is recrystallized from a mixture of tetrahydro-

  furan and ethyl ether to obtain fluoro-1-phthalimido-5-methyl-2-pentanol. Stirred under nitrogen for 2 hours at 25 ° C.

  mixture of 264 mg (1.05 mmol) of 1-fluoro-5-phthalimido-5-methyl-

  tan, 170 mg (1.05 mmol) of phthalimide, 302 mg (1.05 mmol) of

  phenylphosphine and 201 mg (1.15 mmol) of diethyl azodicarboxylate in 8 ml of tetrahydrofuran, the solvent is evaporated under reduced pressure and the residue is taken up in benzene. The insoluble material is discarded and the residue obtained is recrystallized after concentration of the filtrate in a mixture of tetrahydrofuran and ethyl ether.

  to obtain fluoromethyl-1-methyl-4-butanediyl-1,4 bis-phthalimide.

  A suspension of 3.1 g of 1-fluoromethyl-4-methyl-1,4-butanediyl bis-phthalimide in 1 ml of concentrated hydrochloric acid is heated at reflux temperature for 3 days. The phthalic acid precipitated by cooling is filtered off. We concentrate

  filtrate to about 20 ml and cooled to 4 ° C.

  the remaining phthalic acid which separates and concentrate the

  trat under reduced pressure. The residue is treated 3 times with 40 ml of boiling isopropyl alcohol and then recrystallized from absolute ethanol to give 1-fluoromethyl-4-methyl-1,4-butanediamine dihydrochloride.

Example 5

  Ethynyl-1-methyl-4-butanediamine-1,4.

  To 10.8 g (0.05 mole) of 1-benzylimino-trimethylsilyl-propyn-2 in 500 ml of tetrahydrofuran under a nitrogen atmosphere is added butyl lithium (0.05 mole). After 10 minutes, the dark red carbanion is treated with 11.3 g (0.05 mol) of 4-bromo-2-iminobenzylbutane in 20 ml of tetrahydrofuran. After 3 hours at -78 ° C, 50 ml of water are added and the tetrahydrofuran is evaporated to leave a residue which is refluxed under a nitrogen atmosphere with

  100 ml of 6 N hydrochloric acid for 48 hours. After cooling

  The aqueous solution is washed with methylene chloride, basified with aqueous sodium hydroxide and extracted with methylene chloride. The methylene chloride extract is dried over magnesium sulfate, filtered, concentrated and

  distils to obtain 1-ethynyl-4-methylbutanediamine-1,4.

Example 6

  Suitable granules are prepared for the addition to drinking water of poultry having the following composition: Gram 2-difluoromethyl-2,5-diamino pentanotac acid 33.0 starch 18.5 lactose 48.2 zinc stearate , 0

  2-difluoromethyl-2,5-diamino-2,5-diamine

  TanoTque with about 6 to 9 g of lactose and treated with a jet mill or micronizer to obtain a particle size of 1 to 25 μm. 35 ml of water are added to about 2.0 g of the starch of maize.

  and mixed to prepare a starch of 5% starch. We mix

  the micronized powder of 2-difluoromethyl-2,5-diaminopentanoic acid and lactose, the remainder of lactose and the rest of the starch of mats. The starch paste is added and the mixture is mixed and passed through a sieve of 1.4 mm mesh size. The granules obtained are dried at 38 ° C. to a moisture content of about 3%, ground to obtain particles passing through a sieve of 1.4 mm mesh size and lubricated by mixing with

0.3 g of zinc stearate.

Example 7

  To prepare a 10% stock solution useful for the

  treatment of coccidiosis 37.5 grams of difluorinated acid are

  2-methyl-2,5-diaminopentanol in 3.75 liters of water at ordinary temperature. Part of this stock solution is diluted with 9 parts of water to prepare a solution of drinking water containing 1% of

  useful medicine for the prevention of coccidiosis of poultry.

Example 8

  To prepare an animal feed supplemented with

  suitable for poultry, the following ingredients are used:

  solvents. Food is fed at will to the birds.

  % by weight But yellow crushed 60.3 soybean meal alfalfa leaf meal dicalcium phosphate calcium carbonate iodized salt acid 2-difluoromethyl-2,5-diamino pentanothane Mixture of vitamins, elements

  acids and antibiotics for 45 kg of food.

  oxytetracycline penicillin (as procaine salt) manganese sulfate DL-methionine riboflavin DL-calcium pantothenate niacin pyridoxine vitamin B12 33.0 1.0 3.0 1.0 0.2 0.33

minerals, amino

  0.5 g 0.25 g 8 g 22.7 g mg 930 mg 1 400 mg mg 1 mg choline chloride 22.7 g vitamin A 300 000 units vitamin 3 25 000 units

Example 9

  This example illustrates the effect of 2-difluoromethyl-2,5-diamino pentanotacic acid on Trypanosoma brucei brucei infections.

of the mouse.

  Groups of five mice weighing 20 to 25 g were inoculated with T. b. brucei (strain EATRO 110, 5 x 105 organisms / mouse). The compound is administered via the drinking water supplied at will 24 hours after infection. The results are expressed as the average survival (in days) beyond the death of the control animals, based on the average survival of the control animals on the 5th day. We

  used as control trypanocide the Berenil (diminazene aceturate).

  The results are shown in Table I below.

T A B L E A U I

  Dose Average total survival Drug Treatment (mg) (days) none 0 O 2-difluoromethyl-2,5-diamino pentanotec 2% in drinking water, 6 days 600-> 30k at 2% in drinking water, 3 days 300-> 30 1% in drinking water, 6 days 3001f> 30 1% in drinking water, 3 days 150-> 30% in drinking water, 3 days 75- 28.6 to 0.11% in drinking water, 3 days 15- 2300 mg / kg po, per day 3 days 22.5 26.3 mg / kg po, per day 3 days 11.3 22, 8 75 mg / kg po, daily 3 days 5, 6 19.2 mg / kg po, daily 3 days 3.8 0 2-methyl-2,5-diamino pentanotec acid 2% in drinking water, 3 days 300- 0 diminazene aceturate 2.5 mg / kg ip, per day 3 days 0.2> 30 a for a daily consumption of 5 ml of water / 25 g of mouse / day, b dose considered curative; the animals survive more than one month after the witnesses; parasites are not observed in blood smears after one month; attempts to secondary inoculate brain suspensions with uninfected animals remain negative after more than 30 days.

Example 10

  This example illustrates the effect of a 2% solution

  of 2-difluoromethyl-2,5-diamino pentanotec acid in water of wood-

  chicks infected with Eimeria tenella oocysts.

  On day 1, 20 chicks were infected with 100,000 oocysts of E. tenella. 10 animals are supplied with drinking water containing in solution 2% of 2-difluoromethyl-2,5-diaminopentanotec acid. The remaining animals serve as witnesses. On day 3 all the control animals show clinical signs of the disease. On day 7 all the animals are sacrificed, a macroscopic examination of

  caecal lesions and the results are recorded as follows.

  0 = no detectable macroscopic lesions +1 = some petechiae disseminated in the caecal wall; no thickening of the wall and presence of normal caecal content +2 = the lesions are numerous with a notable decrease in the caecal content; the cecal wall is slightly thickened +3 = presence of abundant quantities of blood and tissue debris, that is, cecal swirls, the cecal wall is strongly thickened, there is little or no caecal content normal +4 = the cecal wall is strongly distended with presence of a lot of blood or cecal swirls. Caecal debris is absent or incorporated into the lumps; (the birds

deaths are also noted + 4).

T A B L E A U I I

  Notes of animal injuries Average score of individual lesions in group Control + 4 + 3 + 4 + 4 + 4 + 4 + 4 + 2 + 4 + 4 + 4 3,6

(N = 10)

  Treated with 2-difluoromethyl-2,5-diamino pentanotacic acid

  (N = 10) +1 +1 + 0 + 1 + 1 +3 +4 +4 +1 +1 1,7

Example 11

  Essentially, the procedure of the preceding example is followed to administer a 2% solution of 2-difluoromethyl-2,5-diamino pentanotecic acid (DFMO) in drinking water for a period of 3 days. On day 1 we infect this group of 6 chicks in addition to two groups of 10 chicks each,

  oral administration of 100,000 E. tenella oocysts per

  sin. One group of 10 chicks serves as a control group, the other group of 10 chicks receiving a standard dose of Amprolium in their drinking water for the next 5 days. Currently Amprolium is the coccidiostatic of choice. At day 5, all animals are sacrificed and the disease is evaluated according to the lesion rating index described.

  in the previous example. The following results are obtained.

T A B L E A U 1 I I

  Number of average treatment score chicks days of treatment lesions Control 10 --- 3.70 solution of 6 3

DFM0 at 2% 6

Amprolium solution 10 5 O, 3

at 0, 120%

Example 12

  This example illustrates the effect of various doses of 2-difluoromethyl-2,5-diamino pentanotec acid on Eimeria infections.

tenella chicks.

  The procedure of Example 10 is essentially repeated by modifying the dosage of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) as indicated in Table IV below. Treatment with DFMO begins at day -I. Chicks are infected orally at day 0 and treatment is continued for a further 5 days, for a total of 6 days. Animals are inactivated by day 5 and the disease is assessed according to the

lesions described in Example 10.

T A B L E A U I V

  Number of Mean Score of Treatment Chicks Treatment Days Injury Control 7 --- 3.29 2% DFMO 6 6 0 1.0% DFMO 6 6 0.5 0.5% DFMO 6 6 1.00

Example 13

  This example illustrates the effectiveness of a prophylactic dose

  weak lactic lesions on Eimeria tenella chicks.

  Essentially, the procedure described in Example 10 is repeated, but by varying the administered dose of acid.

  2-difluoromethyl-2,5-diamino pentanotec (DFMO) and the administration period

  tration. The following results are obtained.

TA B L E A U V

  Number of Mean Score of Treatment Chicks Days of Treatment lesions Control 9 --- 3.33 2% DFMO 9 -1 to +5 O 1% DFMO 9 -1 to +5 0 0, 5% DFMO 9 -1 a +5 o 0.25% DFMO 9 -8 to +5 0.44 0.125% DFMO 9 -8 to +5 0 0.0625% DFMO 9 -8 to +5 0.66

Example 14

  This example illustrates the acquisition of

  to Eimeria tenella infections in chicks.

  One week after the completion of the treatment, as indicated in Table VI below, birds previously treated with 2-difluoromethyl-2,5-diamino pentanotacic acid are tested at similar concentrations. low than 0.5% from day -8 to day +5 relative to infection. The results indicate that prophylactic and low dose

  appropriate development of parasites in the absence of pathological

  This allows the development of immunity from

  subsequent infections with E. tenella.

T A B L E A V I

  Number of Days of Mean Score Mean Score Treatment Chicks Final Initial Treatment of lesion lesions Control 9 --- 0 2.50 1, 0% DPMF 9 -8 to +5 0.33 0 0.5% DFMO 9 - Of course, various modifications may be made by those skilled in the art to devices or methods which

  have been described only as non-limitative examples

  without departing from the scope of the invention.

Claims (10)

CLAIMS ---- V ----- D-I-C-A-T-I-O ----   1. New medicaments useful in particular for inhibiting the development of protozoa in animals, characterized in that they consist of an α-substituted amino acid or an α-substituted amine corresponding to formula Y! ZCR NH 2 o R represents a hydrogen atom or a carboxy radical, Y represents a radical -CH 2 F, -CHF 2, -CF 3 or -CCH, Z represents a radical H2N- (CH 2) 3 H 2 N -CH- (CH 2) 2 and H N-CH CHCH- under 2 23 2 2 2 2 2 su CH3 reserves that when R1 represents a hydrogen atom, Y can not   represent -CF3 and Z must represent H2N-CH- (CH) 2- CH 0.3   and their individual salts and optical isomers.   Medicines according to claim 1, characterized   in that R1 represents a hydrogen atom.   Medicines according to claim 1, characterized   in that R1 represents a carboxy radical.   4. Medicaments according to claim 1, characterized   in that Z represents H2N-CH- (CH2) 2- or H2N- (CH2) 3-.   CH 5. Medicaments according to claim 1, characterized in that Y represents -CHF2.   Medicament according to claim 1, characterized   in that it consists of diamino-2,5-difluoromethyl-2-penta   nolque. 7. Therapeutic composition, characterized in that it contains as active ingredient a drug according to one of   any of the preceding claims in combination with a appropriate vehicle.   8. Therapeutic composition, characterized in that it is suitable for the treatment of birds, the vehicle is water and the active ingredient is diamino-2,5-difluoromethyl-2-acid   pentanotic present at the concentration of 0.01 to 2%.   9. Therapeutic composition according to claim 8,   characterized in that the active ingredient is combined with a   synergistic effect of an antiprotozoan agent selected from Antrycide,   Pentamidine, Amicarbalide and Bleomycin.   Pharmaceutical forms of oral or parenteral administration of a therapeutic composition according to claim 7, characterized in that they are packaged for   the administration of amounts corresponding to 5 to 7 g of the ingredient active.