CH642055A5 - ALPHA FLUORMETHYL DERIVATIVES FROM ALPHA AMINO ACIDS. - Google Patents

Description

The invention relates to new a-fluoromethyl derivatives of a-amino acids of the formula I.

Y

Z-C-CORi (j)

nhrb.

where Y is one of the radicals FCH2 or F2CH, Z is the y-guanidinopropyl radical, a radical of the formula RaHN (CH2) “-, in which n is the number 3, and the radicals Ra and Rb are each hydrogen, and R! is the hydroxyl group, or a straight-chain or branched alkoxy radical having 1 to 8 carbon atoms, with the proviso that if Z is the y-guanidinopropyl radical, Rj is the hydroxyl group and their lactams of the formula II

h_n

2I

y-c c = o (Ii)

I I

(CH2) i-NH

wherein Y and n are defined above, and their, preferably pharmaceutically acceptable, salts, and preferably individual optical isomers.

The lactams of formula II also fall within the scope of the invention. The invention further preferably comprises pharmaceutically acceptable salts and individual optical isomers of the compounds of the formula I.

In formula I, the symbol Z denotes, in addition to the RaHN (CH2) radical, “- the y-guanidinopropyl radical of the following

Formula: ....

HN

Jj y-guanidinopropyl.

h2n-c-nh (ch2) 3-

Examples of alkox3 radicals with 1 to 8 carbon atoms which are possible in formula I are the methoxy, ethoxy, propoxy, butoxy, pentoxy and octyloxy radical.

The lactams of compounds of the formula I in which Z is the radical RaHN (CH2) “- and Ra and Rb are hydrogen have the following formula II

nh2

y-c c = 0 i [

I I

(ch2) nh

In formula II, n denotes the number 3, Y denotes one of the radicals FCH2 ~ or F2CH-

Examples of pharmaceutically acceptable salts of the invention are non-toxic acid addition salts formed with inorganic acids such as e.g. with hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, or with organic acids such as methanesulfonic acid, salicylic acid, maleic acid, malonic acid,

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60

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Tartaric acid, citric acid, cyclamic acid and ascorbic acid, as well as the non-toxic salts which are formed with inorganic or organic bases such as e.g. with alkali metals such as sodium, potassium and lithium, alkaline earth metals such as calcium and magnesium, light metals of group IIIA, such as. As aluminum or with organic amines such as primary, secondary or tertiary amines, e.g. B. cyclohexylamine, ethylamine, pyridine, methylaminoethanol, ethanolamine and piperazine. The salts are formed in a conventional manner.

Preferred compounds according to the invention are those of the formula I in which Rx denotes the hydroxyl group. More preferred are compounds of the formula I in which Ra is the hydroxyl group, Z is the y-guanidinopropyl radical or a radical of the formula RaHN (CH2) "- and Ra and Rb are hydrogen, and the lactams of the compounds in which Z is RaHN (CH2)" - is.

Examples of compounds according to the invention are as follows:

2-amino-2-fluoromethyl-5-guanidinovaleric acid,

2-amino-2-difluoromethyl-5-guanidinovaleric acid,

2,5-diamino-2-fluoromethylvaleric acid,

2,5-diamino-2-difluoromethylvaleric acid,

Methyl 2-amino-2-fluoromethyl-5-guanidinovalerate,

Methyl 2,5-diamino-2-difluoromethylvalerate,

Isopropyl-2,5-diamino-2-fluoromethylvalerate.

The compounds of formula I have various uses.

The compounds of the formulas I and II are inhibitors of decarboxylase enzymes which intervene in the formation of polyamines, so that they can be used as pharmacological agents. Polyamines, especially putrescine, spermidine and spermine are present in plant and animal tissues and in some microorganisms. The exact physiological role of polyamines is not yet completely clear, but it is reasonable to assume that polyamines are involved in cell division and growth (see HG Williams-Ashman et al., The Italian J. Biochem. 25, 5-32 (1976 ), A. Raina and J. Janne, Med. Biol. 53, 121-147 (1975) and DH Russell, Life Sciences 13, 1635-1647 (1973)).

Polyamines are essential growth factors in the growth processes of certain microorganisms such as E. coli, Enterbacter, Klebsiella, Staphylococcus aureus, C. cadaveris, Salmonella typhosa and Haemophilus Parainfluenza. The polyamines are involved in both normal and neoplastic rapid growth, with increasing synthesis and accumulation of polyamines following a stimulus that causes cell division. The polyamine levels are also known to be high in embryonic systems, tests and in patients with rapidly growing tissues. It is known that there is a relationship between the activity of the decarboxylase enzymes for ornithine, S-adenosylmethionine, arginine and lysine and the formation of polyamines.

The biosynthesis of putrescine, spermidine and spermin are interrelated. Putrescin is the decarb oxylation product of ornithine, its formation is catalyzed by ornithine decarboxylase. Putrescine can also be formed by decarboxylation of arginine to form agmatine, which is then hydrolyzed to putrescine and urea. Arginine is also involved in the formation of ornite with the help of the enzyme Argina-se. Activation of methionine with S-adenosylmethionine synthetase produces S-adenosylmethionine, which is decarb-oxylated, whereupon the propylamine residue of the activated methionine can be transferred to putrescine to form spermidine or to spermidine to form spermine. The putrescin thus serves as a precursor for

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midin and spermin, it could also be shown that it has a significant regulatory effect on polyamine bio-synthesis, since an increased putrescine synthesis is the first indication that renewed growth processes take place in a tissue. Cadaverine, which is the decarb oxylation product of lysine, stimulates the action of S-adenosylmethionine decarboxylase and is known to be essential for the growth processes of numerous microorganisms, e.g. H. Parainfluenza.

The compounds of the formula I in which Z represents the radical RaHN (CH2) n - and their lactams are inhibitors of ornithine decarboxylase or lysine decarboxylase. The compounds of formula I with a y-guanidinopropyl radical Z are inhibitors of arginine decarboxylase. As inhibitors of the above decarboxylases, the compounds of the formulas I and II are active as agents against infections for combating microorganisms, e.g. Bacteria and viruses that depend on polyamines for their growth, such as B. E. coli, Enterbacter, Klebsiella, Staphylococcus aureus, C. cadaveris, viruses such as H. parainfluenza, picornaviruses, e.g. B. of encephalomyocarditis, herpes simplex, pox viruses and arboviruses, e.g. B. Semliki forest. The compounds of formulas I and II are also useful for controlling certain rapid growth processes. For example, the compounds are useful for inhibiting spermatogenesis and embryogenesis and therefore find use as male contraceptives and abortion agents. The compounds are also useful for inhibiting the immune response, therefore they are immunosuppressors, and are useful for controlling neoplastic growth, e.g. for solid tumors, leukemia and lymphomas.

The compounds are also useful as inhibitors of prostate hypertrophy, excessive scalp growth associated with dandruff and as inhibitors of abnormal skin cell growth such as in psoriatic conditions. The utility of the compounds of the formula I as irreversible inhibitors of ornithine or S-adenosylmethionine decarboxylases in vivo can be demonstrated as follows: an aqueous solution of the compound of the formula I in question is administered orally or parenterally to male mice or rats. 1 to 48 hours after administration, the animals are sacrificed and the abdominal flaps of the prostate are removed and homogenized, the activity of ornithine or S-adenosylmethionine decarboxylase according to the general instructions of E. A. Pegg and H.G. Williams-Ashman, Biochem. J. 108,533-539 (1968) and J. Janne and H.G. Williams-Ashman, Biochem. and biophys. Res. Comm. 42, 222-228 (1971) is measured.

The compounds of the formula I in which Rj denotes the hydroxyl group are useful as intermediates for the preparation of new cephalosporin derivatives which can be used as antibiotics and have the following formula:

Y

* ç

Z-C-Ç0NH — f—

L i -N CH2X hi

NH 0 Ò00M

In this formula, Z and Y have the meaning given for formula Ï. M means hydrogen or a negative charge and X means hydrogen or the acetoxy group.

The compounds of formula III and their pharmaceutically acceptable salts and optical isomers are new, are useful as antibiotics and can be administered in a manner similar to most known cephalosporin derivatives such as e.g. Cephalexin, or cephalothin

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Cephaloglycin. The compounds of formula III and their pharmaceutically acceptable salts and isomers can be administered alone or in the form of pharmaceutical preparations orally, parenterally and topically to warm-blooded animals, i.e. birds and mammals, e.g. Cats, dogs, cattle, sheep, horses and people. For oral administration, the compounds are given in the form of tablets, capsules or pills, or in the form of elixirs or suspensions. For parenteral administration, the compounds are best used in the form of sterile aqueous solutions which may contain other solutes, e.g. sufficient amounts of table salt or glucose to form isotonic solutions. For topical administration, the compounds of the formula III, their salts and isomers are incorporated into creams or ointments.

Examples of bacteria against which the compounds of formula III, their pharmaceutically acceptable salts and individual optical isomers are active are Staphylococcus aureus, Salmonella schotmuehleri, Klebsiella pneumoniae, Diplococcus pneumoniae and Streptococcus pyogenes.

Examples of pharmaceutically acceptable non-toxic inorganic acid addition salts of the compounds of formula III are addition salts with mineral acids, e.g. B. the hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, further addition salts with organic acids such as e.g. the maleate, acetate, citrate, oxalate, succinate, benzoate, tartrate, fumarate, malate and ascorbate. The salts are made in a conventional manner.

Examples of compounds of the formula III are the 7 - [[2,5-diamino-2-difluoromethylvaleryl] amino] -3-acetyloxy-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2 -en-2-car-bonic acid,

7 - [[2,6-diamino-2-fluoromethylcaproyl] 3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and

7 - [[2-Amino-2-trifluoromethyl-5-guanidinovaleryl] amino] 3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

The preparation of the compounds of formula III is described below.

The compounds of the formula I and II can be administered as pharmacological agents in various ways. The compounds can be given alone or in combination with one another. Furthermore, the compounds can be administered in the form of pharmaceutical preparations. Administration can be oral, parenteral, e.g. intravenously, intraperitoneally, or subcutaneously or topically. The amount to be administered varies within a wide range and is any effective amount. Depending on the condition to be treated, the disease and the mode of administration, the effective amount is between about 0.1 and 500 mg / body weight / dose unit, and preferably about 10 to about 100 mg / body weight / dose unit. A typical dose unit is a tablet with 10 to 300 mg of a compound of formula I or II, which is administered to the patient one to four times a day to achieve the desired effect.

The term "patient" means warm-blooded animals such as mammals, e.g. Cats, dogs, rats, mice, guinea pigs, horses, cattle, sheep and humans.

The fixed dose unit can be conventional. The solid form s. B. consist of a conventional gelatin capsule containing the new compound of the invention and a carrier, e.g. Contains lubricants or inert fillers such as lactose, cane sugar or corn starch. According to another embodiment, the new compounds are tablet-coated with conventional tablet bases such as lactose, cane sugar or corn starch in combination with binders such as gum acacia, corn starch or gelatin, disintegrants such as corn starch, potato starch or alginic acid and a lubricant such as stearic acid or magnesium stearate . Suitable for parenteral administration are injectable doses of a solution or suspension of the compound in a physiologically acceptable diluent, together with a pharmaceutical carrier, which can be a sterile liquid such as water or oil, optionally with the addition of a surface-active agent or other pharmaceutically acceptable excipients . Examples of oils which can be used in such preparations are those of petroleum, animal, vegetable or synthetic origin, e.g. B. peanut oil, soybean oil and mineral oil. In general, water, saline, aqueous dextrose and similar sugar solutions, ethanols and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, especially for injectable solutions.

The compounds can be administered in the form of a depot injection or an implant that is formulated in such a way that the active ingredient is delayed. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as a Depot-35 injection or implant. Inert substances such as biodegradable polymers or synthetic silicones can be used in implants, e.g. a silicone rubber of the trade name Silastic (manufacturer DOW-Corning Corporation).

40 The compounds of formula I, wherein Z den

RaHN (CH2) n radical, Rt is the hydroxyl group and Ra and Rb are hydrogen, are prepared by reacting an ester derivative of ornithine, the amino groups of which are suitably protected, with a strong base to form the carbanion intermediate, which is then reacted with a compound selected from the group consisting of chlorofluoromethane, bromofluoromethane, fluorodiodomethane, chlorodifluoromethane, bromodifluoromethane and difluorodiodomethane in an aprotic solvent, such as, for example Dimethylsulf-50 oxide, dimethylflormamide, dimethylacetamide, benzene, toluene, ether such as tetrahydrofuran, diethyl ether or di-oxane, and in the presence of hexamethylphosphoramide, if Y is different from F2CH-, at a temperature of about -120 to 120 ° C. , and preferably at about 25 to 55 50 ° C, about 14 to 48 hours, whereupon acidic or basic hydrolyzed.

The process is preferably carried out as indicated in the following reaction scheme:

Zi-CH-C00R's strong base

I.

Rs.

Connection 1

«-Zol-c

<-)

coors

1 1

n = c-rr 1

I 1

Ks _1

Alkylating agent

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4-

y I

Zg-C-COORs nh2

Connection 3

h2o

Y

I.

dilute aqueous acid / hydrazine

(Acid / base)

V

y I

z3-c-cooh I

nh2

Formula xv

In the formulas of the above scheme, R6 represents a lower alkyl group, e.g. the methyl, ethyl, isopropyl, n-propyl or n-butyl radical. R7 denotes hydrogen, the phenyl radical, a straight-chain or branched alkyl radical with 1 to 8 carbon atoms, the methoxy or ethoxy group. Rs represents the phenyl radical or a straight-chain or branched alkyl radical having 1 to 8 carbon atoms, or R7 and Rs together form an alkylene radical having 5 to 7 carbon atoms, that is to say a radical of the formula -CH2- (CH2) m-CH2-, in which m is a means integer from 3 to 5. Examples of straight-chain or branched alkyl radicals having 1 to 8 carbon atoms, which can be represented by R7 and Rg, are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl -, n-Pentyl, neopentyl or triethylmethyl. Zt means a radical of the formula Rio (CH2) n-, where n is the number 3 and R10 is a radical of the formula

-N »

■ C-Rj

R

8th

is in which R7 and Rg have the meaning given above, a radical of the formula

0 0

-NH-J-

II

■ R11 or -NH-COR

12

where R! j and R12 represent the phenyl or benzyl radical, or a straight-chain or branched lower alkyl radical having 1 to 4 carbon atoms, for example methyl, ethyl or isopropyl. Z2 denotes a radical of the formula R, 3 (CH2) “-,

wherein R13 represents -NH2, - NH - ^ - Rn or -NH-c8R12, where Rn and R12 have the meaning given above. Z3 means the H2N (CH2) n radical, in which n represents the number 3. Y has the meaning given for formula I. If compounds 1 Zx represents the radical R10 (CH2) n-, where R10 denotes -N = C-R7, then R7 and R8 are the same. Rs

Strong bases suitable for the preparation of the carbanion intermediate are those which withdraw a proton from the carbon atom located a to the carboxyl group, e.g. Alkyl lithium compounds such as butyllithium or phenyllithium, lithium dialkylamides such as e.g. Lithium-

zi-c-c00rs i n = c-r7

rs

Connection lengths 2

diisopropylamide, lithium amide, potassium tert-butoxide, sodium amide, metal hydrides, e.g. B. sodium hydride or i5 potassium hydride, tertiary amines such as triethylamine, lithium acetylide or dilithium acetylide. Particularly preferred bases are lithium acetylide, dilithium acetylide, sodium hydride and lithium diisopropylamide.

Alkylating agents which can be used in the above reaction sequence are chlorofluoromethane, bromofluoromethane, fluoroiodomethane, chlorodifluoromethane, bromodifluoromethane and di-fluoroiodomethane. The alkylating agents are known.

The deprotection of amine, mercapto and carboxylic acid functions can be done in one step 25 by treating compounds 2 with aqueous acid, e.g. with hydrochloric acid or toluenesulfonic acid at a temperature of about 0 to 160 ° C for about 4 to 24 hours. The compounds of formula IV are obtained. Preferably, the protecting groups of the amine function (s) of compounds 2 are first removed, if these functions are protected as a base, by treating compounds 2 with dilute aqueous acid, e.g. B. with hydrochloric acid, or with hydrazine or phenylhydrazine in solvents such as lower alcohols, for. B. methanol 35 or ethanol, ethers, chlorinated hydrocarbons, benzene and water. The removal of the protective groups from carboxylic acid functions, mercapto groups and amino group (s), if the latter are not protected as a base, is carried out by treating compounds 3 with concentrated -40 aqueous acid, e.g. with hydrobromic acid at a temperature of about 0 to 160 ° C, or in aqueous bases, e.g. Ammonium hydroxide. The Merkapto protecting groups are removed in the absence of oxygen, e.g. in a nitrogen atmosphere.

45 The ester derivatives with a protected amino group, that is to say compounds 1, in which Z denotes the R10 (CH2) radical, where n and R10 have the meaning given above, are obtained if R7 is different from the methoxy or ethoxy radical by treatment of the corresponding 50 amino acid ester with a carbonyl

group-containing compound, whereby a Schiff base is prepared in a known manner, in particular (a) if R7 is hydrogen, by treating the amino acid ester with benzaldehyde or a straight-chain or branched Al-55 channel with 1 to 9 carbon atoms, e.g. 1-propanal, 1-butanal, 2,2-dimethylpropane-l-al or 2,2-diethylbutane-l-al, (b) if R7 is the phenyl radical by treating the amino acid ester with benzophenone or a phenyl alkyl ketone with straight-chain or branched alkyl portion 60 having 1 to 8 carbon atoms, e.g. B. with phenylmethyl ketone, phenyl ethyl ketone, phenyl isopropyl ketone, phenyl-n-butyl ketone or phenyl tert-butyl ketone, and (c) if R7 is a straight-chain or branched alkyl radical having 1 to 8 carbon atoms by using the amino acid 65 ester with one of the above phenylalkyl ketones or with a dialkyl ketone in which each alkyl radical can be straight-chain or branched and has 1 to 8 carbon atoms, for example with dimethyl ketone, diethyl

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ketone, methyl isopropyl ketone, di-n-butyl ketone or methyl tert-butyl ketone. The compounds containing carbonyl groups are known or can be prepared by known methods.

If R7 is the methoxy or ethoxy radical, the corresponding amino acid ester derivative is treated with a benzyl halide, e.g. the chloride, or an alkane carboxylic acid halide, e.g. the chloride of an alkane carboxylic acid with 1 to 9 carbon atoms, which can be straight-chain or branched, for example with acetyl chloride, propionyl chloride, butyryl chloride, tert-butyryl chloride, 2,2-diethylbutyryl chloride or valeryl chloride at 0 ° C. in ethers, methylene chloride, dimethylformamide, Dimethylacetamide or chlorobenzene is reacted in the presence of an organic base such as triethylamine or pyridine, whereupon the reaction mixture is allowed to warm to about 25 ° C. for 1 hour. The resulting amide is treated with an alkylating agent such as e.g. Methyl fluorosulfonate, dimethyl sulfate, methyl iodide, methyl p-toluenesulfonate or trimethyloxonium hexafluorophosphate if R7 is the methoxy group or with triethyloxonium tetrafluoroborate if R7 is the ethoxy group at about 25 ° C in a chlorinated hydrocarbon solvent such as methylene chloride , Chlorobenzene or chloroform are added and the reaction mixture is heated under reflux for about 12 to 20 hours. The mixture is then cooled to about 25 ° C. and an organic base such as tri-ethylamine or pyridine is added, the solution is then extracted with sodium chloride solution and the product is isolated.

If compounds 1 R7 and R8 together form an alkylene group with 5 to 7 carbon atoms, the corresponding amino acid ester derivatives are obtained by reacting the amino acid ester with one of the cyclic alkanoic cyclopentanone, cyclohexanone or cycloheptanone in a known manner to give a Schiff base.

Zj is a radical of the formula R10 (CH2) n-, in which ^ &

R10 is -NH-CRj j or -NH-CORj 2, then the

9 <?

Protecting groups -CRj i and -COR, 2 to the free amino acid, i.e. ornithine, added by treating the amino acid with an excess of copper salt, e.g. Copper carbonate in boiling water for about 1 to 6 hours, cool to room temperature, filter off the insoluble material and treat the filtrate with an acid

halide if R10 is -NH-? Rn, or with an alkyl or aryl haloformate if R10

-NH-c5oR12 is, for example in acetone in the presence of a base such as sodium bicarbonate or sodium hydroxide, followed by treatment with hydrogen sulfide. Examples of usable acid halides are acetyl chloride, propionyl chloride, benzoyl chloride and 2-phenyl-acetyl chloride. Examples of halogen formic acid esters which can be used are the benzyl, phenyl, methyl and ethyl esters of chloroformic acid.

The amino acid esters are produced by known methods. For example, the amino acid is reacted with the corresponding alcohol, such as methanol, ethanol or n-buta-nol, which is saturated with hydrogen chloride gas.

The compounds of the formula I, in which Z represents the y-guanidinopropyl radical, are generally prepared from the corresponding, suitably protected derivatives, in which Z represents the radical RaHN (CH2) n-, where Ra is hydrogen and n is 3, and in which furthermore Y is one of the radicals FCH2- or F2CH-, that is to say from compounds of the formula

40

y »

h2n (ch2) 3-c-cooh nhr.

V

wherein Y 'is one of the radicals FCH2- or F2CH- and Rb has the meaning given for formula I by io this with an alkylisothiouronium salt, for. B. Ethyliso-thiouronium hydrobromide by known methods, see e.g. Organic Synthesis III, p. 440 (1955). The reaction takes place in the presence of a base, e.g. aqueous sodium hydroxide or potassium hydroxide solution at a pH of about 8 to 12 and at a temperature of about 0 to 100 ° C for 6 hours to 8 days. Then the reaction mixture is concentrated with concentrated mineral acid, e.g. neutralized with hydrochloric acid and the product isolated. If Rb is hydrogen, the a-amino group can be protected, 20 e.g. by a benzyloxycarbonyl radical.

The amino protecting group is later removed by acid hydrolysis, for example with hydrochloric acid.

The compounds of formula I, in which Rx is a straight-chain or branched alkoxy radical having 1 to 8 25 carbon atoms, are prepared, for example, by converting the corresponding compound, in which Rt is the hydroxyl group, into the acid halide, e.g. by treatment with thionyl chloride, then carrying out an Al-alcoholysis with an alcohol of the formula R17OH, in which R17 30 has a straight-chain or branched alkyl radical having 1 to 8 carbon atoms, in a manner known per se. The compounds of the formula I, in which Rx is a straight-chain or branched alkoxy radical having 1 to 8 carbon atoms, can also be prepared from the corresponding derivative with Rj = hydroxy by reacting this derivative for about 30 minutes to 12 hours at a temperature of about 25 ° C. to the boiling point with an alcohol of the formula R17OH saturated with hydrogen chloride gas.

The lactams of the compounds of the formula I in which Ra and Rb are hydrogen and Rj is the hydroxyl group are prepared, for example, from the corresponding amino acid ester of the formula

45

50

y h2n (ch2) -i-cor viii n

> 19th

nh;

wherein n and Y have the meaning given for formula I and R19 is a straight-chain or branched alkoxy radical having 1 to 8 carbon atoms, e.g. represents the methoxy, ethoxy, isopropoxy, butoxy or hexyloxy radical, or preferably, if Y is C1CH2-, from the a-hydroxymethyl-substituted amino acid ester of the formula ch2oh i

«H2n (ch25n-c-cgri9 ix nh2

where n and R19 have the meaning given for formula VIII 65, wherein this amino acid ester is mixed with a suitable base such as e.g. Sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium methylate, potassium methylate, potassium tert-butoxide,

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Sodium amide or an organic amine such as a tri-alkylamine, e.g. Triethylamine, in a solvent such as e.g. a lower alcohol such as methanol, ethanol, iso-propyl alcohol or n-butanol, in water, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide or mixtures of these solvents Vi for up to 24 hours at a temperature of about 0 to 120 ° C, optionally treated in a nitrogen atmosphere , wherein in the case of Y = C1CH2- the additional step of treatment with a chlorinating agent such as thionyl chloride, phosphorus oxychloride or phosphorus pentachloride in a solvent such as formamide, dimethylformamide or dimethylacetamide is connected for about 12 to 36 hours at a temperature of about 40 to 120 ° C. becomes.

The compounds of formula VIII are usually prepared in a known manner from the corresponding amino acid, e.g. by reacting the amino acid with a suitable alcohol saturated with hydrogen chloride gas, e.g. Reacts methanol, ethanol, isopropyl alcohol, n-butanol or n-heptanol.

The compounds of formula IX are usually prepared by the methods described in Synthesis 1973, e.g. by reacting 1 equivalent of ornithine or lysine with 2 equivalents of benzoyl chloride and then with 2 equivalents of a base such as sodium hydroxide to form the bis-amide, which is then reacted with an acid anhydride such as e.g. Acetic anhydride is reacted at about 90 ° C for about 1/2 hour. Treatment with aqueous formaldehyde and pyridine is then carried out at about 25 ° C. for about 8 to 24 hours. The mixture is then treated with water to give the oxodioxane, which is treated with a catalytic amount of sodium methylate in methanol, then neutralized and treated with acid. e.g. with hydrochloric acid at about 120 ° C for about 2 to 24 hours.

The individual optical isomers of the compounds of the formula I in which Z is the radical RaHN (CH2) n-, where Ra and Rb are hydrogen and Rx is the hydroxyl group, are usually obtained from the lactam of these compounds using a (+) or (-) -Binaphthylphos-phosphoric acid salt according to the method of R. Viterbo et al., Tetrahedron Letters 48.4617 (1971). Other means of separating the isomers such as (+) - camphor-10-sulphonic acid can also be used. The individual optical isomers of compounds of the formula I in which R is hydrogen and Rx is the hydroxyl group are also converted from the free amino acid using a (+) or (-) - binaphthylphosphoric acid salt or other agents such as (4-) camphor-10-sulfonic acid receive.

The individual optical isomers of compounds of the formula I in which Z denotes the y-guanidinopropyl radical are prepared as described for the racemate, but starting from the ornithine analogues which have already been broken down.

The compounds of formula III are generally obtained by using a 7-aminocephalosporanic acid or a derivative thereof of the formula

HsN— | - ^ 1

1 — NV ^ -CHaX -j-x COOM

wherein M is hydrogen or a negative charge and X is hydrogen or the acetoxy group, with an acid of the formula y z-c-cooh x

I.

nh2

or a functional derivative thereof, e.g. the acid chloride or an acid anhydride in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, using the free acid, where Z and Y have the meaning given for formula I, and provided that the amino group is replaced by a suitable protective group, e.g. the tert-butoxycarbonyl radical is protected. This is followed by acid hydrolysis to remove the amino protecting groups.

The coupling reaction is generally carried out in a solvent such as ethyl acetate, dioxane, chloroform or tetrahydrofuran in the presence of a base such as alkali bicarbonate. The reaction temperature can be at about -10 to 100 ° C and the reaction time between about Vi and 10 hours. The cephalosporin products are isolated in a conventional manner. The compounds of formula X are prepared by the methods described above, the compounds of formula IX are commercially available.

The following reference example 1 illustrates the use of a compound of the formula I, in which Rx is the hydroxyl group, as an intermediate for the preparation of a cephalosporin of the formula III:

Reference Example 1 7 - [[2,5-Diamino-2-difluoromethylvaleryl] amino] 3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-en-

2-carboxylic acid A mixture of 1 g of 3-acetyloxy-7-amino-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and 1 g of 2,5-di- amino-2-difluoromethylvaleric acid chloride, in which the free amino groups are protected by tert-butoxycarbonyl residues, in 50 ml of ethyl acetate is heated under reflux for 2 hours, then the solvent is removed and a residue is obtained, which is treated with mild acid and chromatographed on silica gel is made using benzene / acet as an eluent. The 7 - [[2,5-diamino-2-difluoromethylvaleryl] amino] -3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid receive.

Reference example 2 This example relates to a mixture for hard gelatin capsules, which consists of the following components:

(a) a, ö-diamino-a-difluoromethylvaleric acid 20 mg

(b) Talc 5 mg

(c) Lactose 90 mg

The formulation is prepared by passing the dry powders of (a) and (b) through a fine mesh sieve and mixing well. The powder is then filled into hard gelatin capsules in an amount of 115 mg / capsule.

Reference Example 3 A tablet formulation is as follows: (a) a-amino-a-fluoromethyl-S-guanidino-

valeric acid 20 mg

(b) Strength 43 mg

(c) Lactose 45 mg

(d) Magnesium stearate 2 mg

The mixture obtained by mixing the lactose with the compound (a) and part of the starch and granulating the granules obtained with starch paste is dried, sieved and mixed with

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mixed with the magnesium stearate. The mixture is pressed into tablets of 110 mg.

Reference example 4 A 1 ml ampoule filling for intramuscular injection is composed as follows:

% By weight

(a) a-Amino-a-difluoromethyl-y-methyl-thiobutyric acid 1.0

(b) Polyvinyl pyrrolidone 0.5

(c) Lacithin 0.25

(d) Water for injections 100.0

Components (a) to (d) are mixed, homogenized and filled into 1 ml ampoules, which are sealed and treated in an autoclave at 121 ° C. for 20 minutes. Each ampoule contains 10 mg / ml of the new compound (a).

example 1

3-Amino-3-difluoromethyl-2-piperidone 2 equivalents of sodium methylate in methanol are added to a solution of 2.7 g of methyl 2-difluoromethyl-2,5-diaminopentanoate dihydrochloride in 30 ml of dry methanol. 46 g sodium in 20 ml methanol) added. The reaction mixture is stirred for 3 hours at room temperature, then the solvent is evaporated off under reduced pressure. The residue is extracted with ether to give the crude 3-amino-3-difluoromethyl-2-piperidone, which is purified by crystallization from chloroform / pentane (F. 149 ° C) or by distillation (bp = 135 ° C / 0.05 mmHg).

(-) and (+) 3-amino-3-difluoromethyl-2-piperidone hydrochloride

A solution of 0.546 mg (+) 3-amino-3-difluoromethyl-2-piperidone in 5 ml of hot ethanol is added to a solution of 1.27 g of (-) binaphthylphosphoric acid (BNPA) in 50 ml of hot ethanol. Crystals separate out on cooling. The reaction mixture is then left to stand at 4 ° C. overnight. The resulting precipitate is filtered off, washed with ethanol and diethyl ether, 0.54 g of the (-) binaphthylphosphoric acid salt [a] D = 409 °, c = 0.3, MeOH, F. 300 ° C. are obtained. When the mother liquors are recrystallized, 0.15 g of (-) binaphthylphosphoric acid salt is obtained. When the filtrate is concentrated, 1.1 g of a sticky material are obtained, which is treated with 3 molar hydrochloric acid at room temperature for 3 hours. The (-) BNPA is filtered off and the filtrate is concentrated under reduced pressure. When the residue (320 mg) was recrystallized from ethanol, 160 mg (+) of 3-amino-3-difluoromethyl-2-piperidone monohydrochloride, (Md = + 18.6 °, c = 1, MeOH) of melting point 238 ° C. If the (-) BNPA salt (436 mg) is treated in the same way, 137 mg of (-) 3-amino-3-difluoromethyl-2-piperidone monohydrochloride are obtained, from which, when recrystallized from ethanol, 67 mg of product are obtained with ([ a] D = -19 °, c = 1.02, MeÒH) of mp 240 ° C (decomposition) can be obtained.

(-) and (+) 2-difluoromethyl-2,5-diamino-pentanoic acid monohydrochloride 60 mg (-) 3-difluoromethyl-3-amino-2-piperidone-hydro-.

chloride are refluxed in 4 ml of 6 molar hydrochloric acid for 12 hours. After concentration under reduced pressure, the residue is dissolved in water and the pH of the solution is adjusted to 4.5 with a triethylamine solution. The solution is concentrated under reduced pressure and the residue is extracted several times with chloroform and then recrystallized from water / ethanol. This gives 54 mg (+) 2-difluoromethyl-2,5-diamino-pentanoic acid monohydrochloride ([a] D = + 6 °, C = 0.48, MeOH, F.> 240 ° C. In an analogous manner from 96 mg (+) 3-difluoromethyl-3-amino-2-piperidone hydrochloride 56 mg (-) 2-difluoromethyl-2,5-diaminopentanoic acid monohydrochloride ([a] D = -10 ° C, C = 0 , 7, MeOH, F.> 244 ° C).

Example 2

2-difluoromethyl-2-amino-5-guanidinopentanoic acid. To a solution of 5 g (21.13 millimoles) of 2-difluoromethyl-2,5-diaminopentanoic acid monohydrate monohydrochloride in 8.5 ml of 2 molar sodium hydroxide solution 7.82 g (42.26 millimoles) of ethylthiouranium hydrobromide were added. The pH of the solution is adjusted to 10.5 with 2 molar sodium hydroxide solution and kept at this value for 4 days. The reaction mixture is then neutralized to pH = 7 with molar hydrochloric acid and concentrated under reduced pressure. The residue is passed through a column with Amberlite IR 120 H + form. Elution with 2 molar ammonia gives 2-difluoromethyl-2-amino-5-guanidino-pentanoic acid which, after recrystallization from water / ethanol, gives 2.3 g of product with a melting point of 257 ° C.

Example 3

2-Difluoromethyl-2,5-diaminopentanoic acid Under nitrogen, 500 ml of a 2 molar solution of butyllithium in hexane are added with stirring to a solution of 143.1 ml of diisopropylamine in 1.5 ml of tetrahydrofuran at -78 ° C. Then 261 g (0.81 mol) ornithine dibenzaldimine methyl ester in 1.51 tetrahydrofuran are added. When the addition is complete, the reaction temperature is raised to 40 ° C. and kept between 40 and 50 ° C. for 3 hours, chlorodifluoromethane being passed through the reaction mixture with stirring. Then the mixture is 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 concentrated to a viscous oil. This oil is stirred with 1.511N hydrochloric acid for 3 hours, then the mixture is extracted several times with chloroform and the aqueous solution is evaporated to dryness. The oily residue is refluxed with 1.5112N hydrochloric acid for 16 hours, the cooled solution is clarified by chloroform extraction and then concentrated, decolorized with charcoal and further concentrated to about 750 ml. The pH of the solution is adjusted to 3.5 with triethylamine, then the solution is treated again with charcoal, concentrated to about 500 ml and diluted with 7 to 81 acetone. The precipitated product is filtered off and washed with ethanol. The crude product is recrystallized by dissolving it in about 150 ml of hot water and adding 450 ml of hot ethanol to the solution. When cooling, crystals of 2-difluoromethyl-2,5-diaminopentanoic acid hydrochloride having a melting point of 183 ° C. are separated in an amount of 71 g (37%).

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Claims (10)

642 055 1. Compound of the formula Y I. zc-cori ISIHRb wherein Y is one of the radicals FCH2 or F2CH, Z is the y-guanidinopropyl radical or a radical of the formula RaHN (CH2) n, where n is the integer 3 and the radicals Ra and Rb are each hydrogen, and Rj represents the hydroxyl group, or a straight-chain or branched alkoxy radical having 1 to 8 carbon atoms, provided that when Z represents the y-guanidinopropyl radical, Rj is the hydroxyl group and their lactams of the formula II h0n I. Y-C C = 0 (II) I I (ch2) - nh where Y and n are defined above, and the salts of these compounds. 2. A compound according to claim 1, characterized in that Z is a radical of the formula RaHN (CH2) 3-. 2nd PATENT CLAIMS 3. A compound according to claim 1, characterized in that Z represents the y-guanidinopropyl radical. 4. Connection according to one of claims 1, 2 or 3, characterized in that Y means F2CH-. 5. A compound according to claim 1, characterized in that Y means FCH2-. 6.2-difluoromethyl-2,5-diaminovaleric acid or a salt thereof as a compound according to claim 1. 7.2-fluoromethyl-2,5-diaminovaleric acid or a salt thereof as a compound according to claim 1. 8.2-difluoromethyl-2-amino-5-guanidinopentanoic acid or a salt thereof as a compound according to claim 1. 9. A compound of formula II according to claim 1 y-c c = 0 (ii) I I (ch2) -nh where n is 3. 10. A process for the preparation of a compound of the formula IA according to claim 1, y h_n- (ch _) _— c cooh (i a) / Z J | nh2 wherein Y is FCH2- or F2CH-, characterized in that an ornithine ester whose amino groups are protected is treated with a strong base to form a carbanion intermediate, this with a compound selected from the group consisting of chlorofluoromethane , Bromofluoromethane, fluoro-iodomethane, chlorodifluoromethane, bromodifluoromethane and difluoroiodomethane in an aprotic solvent and in the presence of hexamethylphosphoric triamide if Y is not the remainder F2CH-, is reacted at a temperature of -120 to 120 ° C. for 48 to 48 hours and then hydrolysed acidic or basic, cleaves off protective groups present and, if a salt is desired, the compound thus obtained with an acid or base treated.