CH636846A5 - ALPHA-HALOGENMETHYL-AMINOSAEUREN AND ALPHA-HALOGENMETHYLAMINOSAEUR DERIVATIVES. - Google Patents

Description

The present invention relates to new, therapeutically active α-halomethylamino acids and their derivatives, which are inhibitors of aromatic amino acid decarboxy-40.

The amino acids tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine (DOPA), tyrosine and phenylalanine are metabolized into tryptamine, 5-hydroxy-43 tryptamine, 3,4-dihydroxyphenethylamine or dopamine by an aromatic amino acid decarboxylase. Tyr-amine or phenethylamine transferred. The aromatic amino acid decarboxylase enzyme is believed to be non-specific, particularly as far as peripheral catalysis is concerned. However, there are indications that decarboxylation enzymes specific for DOPA and 5-hydroxytryptophan exist in the brain.

The aromatic amines mentioned above are known to play a role in various pathophysiological processes. For example, it has been found that tryptamine, 55 the tryptophan decarboxylation product, is enzymatically methylated to monomethyltryptamine, which in turn is enzymatically methylated to dimethyltryptamine (DMT) in human red blood cells, plasma and platelets. The methylating enzyme is present in many mammalian species and has been shown to be produced in various types of brain tissue, including humans. DMT, which has strong hallucinogenic or psychomimetic properties, can play a role in the aetiology of schizophrenia and other mental illnesses. As a result, any agent that blocks the formation of DMT may be useful as an antipsychotic agent. Blocking the decarboxylation of tryptophan leads to reduced

3rd

636 846

Tryptamine levels with removal of the substrate for the formation of DMT. Therefore, an inhibitor of the aromatic amino acid decarboxylase, which blocks the conversion of tryptophan to tryptamine, may be useful as an antipsychotic agent.

Both 5-hydroxytryptamine (5-HT), the decarboxylation product of 5-hydroxytryptophan, and 3,4-di-hydroxyphenethylamine (dopamine), the decarboxylation product of DOPA, play a role in peripheral and central physiological processes, and Agents that are effective in regulating the levels of these amines have resulted in useful pharmacological agents. It has been shown that the central levels or brain levels of 5-HT and norepinephrine, which is formed in the metabolism by hydroxylation of dopamine, are greater in patients with manic disorders than in those without such disorders. It has also been demonstrated that agents that target the central levels of monoamines, e.g. 5-HT, and especially norepinephrine, have antimanic properties when administered to humans, while drugs that increase monoamine levels can cause mania in susceptible individuals. As a result, agents that block the formation of 5-HT and dopamine, e.g.

by inhibiting the aromatic amino acid decarboxylase enzyme which converts 5-hydroxytryptophan and DOPA to 5-HT and dopamine, respectively, may be useful as antipsychotic agents or major tranquilizers in the treatment of manic conditions.

It has also been demonstrated that agents useful for inhibiting the decarboxylation of DOPA to dopamine are also useful for the treatment of Parkinsonism when co-administered with exogenous DOPA or L-DOPA. Parkinsonism is believed to be due, at least in part, to decreased central levels of dopamine, as exogenous administration of DOPA or L-DOPA is known to be an effective means of treating Parkinsonism. However, since exogenously administered DOPA is easily converted enzymatically into dopamine peripherally, it is necessary to administer large amounts in order to have an increased absorption centrally. DOPA easily penetrates the blood-brain barrier, while dopamine does not. The administration of DOPA or L-DOPA together with a peripherally active inhibitor of the enzyme which converts DOPA into dopamine reduces the amount of L-DOPA that must be administered in order to have sufficient circulating levels for central absorption. Other advantages are also achieved by administering an aromatic amino acid decarboylase inhibitor together with L-DOPA. By preventing peripheral dopamine formation, side effects attributed to dopamine, e.g. Cardiac arrhythmia, dizziness and vomiting should be avoided.

Research shows that the levels of 5-hydroxytryptamine (5-HT) are lower in patients with depressive syndromes than in people without such syndromes. The administration of exogenous L-5-hydroxytryp-tophan (L-5-HTP) is also effective for the treatment of certain patients suffering from depression. However, just like in the case of DOPA, it is necessary to administer large amounts of L-5-HTP if one wants to achieve increased central levels of the amino acid, since L-5-HTP is easily metabolized peripherally to 5-HT. It has been demonstrated that by administering an aromatic amino acid decarboxylase enzyme inhibitor which catalyzes the formation of 5-HT from 5-HTP peripherally, the amount of exogenous 5-HTP required to achieve elevated central levels can be significantly reduced . In other words, inhibitors of aromatic amino acid decarboxylase, when used with exogenous 5-HTP, have been shown to be useful in the treatment of depression.

Agents that block peripheral conversion of 5-HTP to 5-HT may be useful in treating other conditions that are responsive to elevated central levels of 5-HTP as a result of exogenous administration of 5-HTP. Exogenous L-5-HTP has been shown to be useful in the treatment of muscle spasms. Research also showed that the administration of exogenous 5-HTP is useful for the treatment of insomnia. As a result, concomitant administration of 5-HTP and an aromatic amino acid decarboxylase inhibitor may be beneficial in treating these conditions.

Blocking the peripheral formation of 5-hydroxy-tryptamine can also lead to other advantageous effects, since 5-HT is known to play a role, for example, in the etiology of rheumatoid arthritis and carcinoid syndrome due to increasing collagen levels. 5-HT is also reported to be the primary autocoid which is responsible for anaphylactoid reactions in humans and bronchoconstriction in asthmatics, and agents which counteract or inhibit 5-HT formation are in the treatment of these Conditions usable. As is well known, 5-HT causes platelet aggregation and has been included as a causal factor in the syndrome of rapid gastric emptying after gastric resection and migraine headache. Methylsergide, an antagonist of 5-hydroxytryptamine, has been shown to be effective in treating such syndromes.

It has been suggested that phenethylamine, the decarboxylation product of phenylalanine, as an endogenous compound, contributes to schizophrenic symptoms and triggers migraine headaches. It was also believed that endogenous tyramine, the decarboxylation product of tyrosine, contributed to seizure disorders.

It is easy to see from this that agents useful for controlling the levels of aromatic amino acids and amines are used in many pharmacological conditions. The compounds according to the invention are inhibitors of aromatic amino acid decarboxylase, which convert tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine, tyrosine and phenylalanine into the corresponding amines; consequently, they are useful pharmacological agents.

The compounds according to the invention have the following general formula I.

CH

In this general formula I, Y is the group FCH2 or F2CH, Rj is a hydrogen atom, an alkylcarbonyl group in which the alkyl radical has 1 to 4 carbon atoms and is straight or branched chain or the group

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4th

—C — CH — R ,,

NH,

in R27 is a hydrogen atom, a straight or branched chain Cj to C4 alkyl group which is benzyl or p-hydroxy-benzyl group; R2 is the hydroxyl group, a straight-chain or branched-chain Ct to Cs alkoxy group, the Grappe -NR7R8, in which R7 and R8 are each a hydrogen atom or a straight-chain or branched-chain Cj to C4 alkyl group, or the group

—NHCH — COOH

Ro in Rg is a hydrogen atom, a straight or branched chain Cj to C4 alkyl group which is benzyl or p-hydroxy-benzyl group; while Rs, R4, R5, R'4 and R6 each have the meanings given in Table I below, where R10 is a hydrogen atom, the methyl radical or an alkylcarbonyl group in which the alkyl radical is straight or branched chain and comprises 1 to 6 carbon atoms, represents the benzoyl or a phenylalkylenecarbonyl group in which the alkylene radical is straight or branched chain and comprises 1 to 6 carbon atoms

TABLE I

The compounds of general formula I are useful pharmacological agents by inhibiting aromatic amino acid decarboxylase; they are also useful as intermediates for the manufacture of pharmacological agents.

In the above formula I, the term "alkylcarbonyl group" means the group

O

10th

Alkyl — i understood, in which the alkyl radical comprises 1 to 4 carbon atoms and is straight or branched chain.

15 The group is called "benzoyl group"

0

understood.

Rs

R4

Rs

R'4

Re h

H

ORjo h

h h

OR10

h h

h h

OR10

ORio h

H

OR10

H

Cl h

h h

OR10

Cl h

H

Cl o to o

h h

H

Cl o

3 °

O

Cl h

H

Cl, f h

ORJO

h h

OR10

h ch3

h ch3

h h

ORjo h

ch3

h h

ORio h

c2h5

ORi0

h ca h

c2h5

H

OR10

H

ORJO

h h

O

F

O

ORJO

O

F

o h

h h

och3

oh h

h h

oh och3

H

OR10

ORw h

h h

° Rio

H

H

H

H

H

H

ORjo

H

tert-C4H9

The invention further comprises the pharmaceutically acceptable salts of the compounds of the general formula I.

20th

The group is called "phenylalkylene carbonyl group"

0

25 / r = \

-Alkylene-C-

understood in which the alkylene radical comprises 1 to 6 carbon atoms 30 and is straight or branched, such as e.g. the methylene, ethylene, isopropylene and butylene group.

Examples of straight or branched chain alkoxy groups with 1 to 8 carbon atoms are as follows:

the methoxy, ethoxy, isopropoxy, n-butoxy, tert-35 outoxy, n-pentyloxy, tert-pentoxy, n-hexyloxy and n-oc-tyloxy grappe.

Examples of straight or branched chain Cj to C6 alkyl groups are the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and n-pentyl groups.

40 Examples of pharmaceutically acceptable salts of the compounds according to the invention are the non-toxic acid addition salts, which are combined with inorganic acids, e.g. Hydrochloric, hydrobromic, sulfuric and phosphoric acids and organic acids are formed, e.g. 45 methanesulfonic acid, salicylic acid, maleic acid, malonic acid, tartaric acid, citric acid and ascorbic acid, as well as the non-toxic salts which are formed with inorganic or organic bases, such as e.g. those of the alkali metals, for example sodium, potassium and lithium, 50 alkaline earth metals, for example calcium, and magnesium, light metals of Grappe IIIA, for example aluminum, and organic amines, e.g. primary, secondary or tertiary amines, for example cyclohexylamine, ethylamine, pyridine, methylaminoethanol, ethanolamine and piperazine. 55 The salts are produced using conventional methods.

Preferred compounds according to the invention are those of the general formula I in which Ri is a hydrogen atom or an alkylcarbonyl group in which the 60 alkyl radical comprises 1 to 4 carbon atoms and is straight-chain or branched-chain, compounds in which Rj is a hydrogen atom being particularly preferred are. Another preferred embodiment of the invention are the compounds of the general formula I in which R 2 is the 65 hydroxyl group or a straight or branched chain C 1 -C 4 -alkoxy group. Compounds in which R2 is the hydroxy group are particularly preferred. Compounds of the general formula I in which R3, R4, R'5, R5

5

636846

and Re each represents a hydrogen atom or the group OR10, where R10 is a hydrogen atom, represent another preferred embodiment of the invention.

Examples of compounds of the general formula I are as follows:

2-difluoromethyl-2-amino-3-phenylpropionic acid, 2-difluoromethyl-2-amino-3- (3-hydroxyphenyl) propionic acid, 2-difluoromethyl-2-amino-3- (3,4-dihydroxyphenyl) propion- acid,

2-difluoromethyl-2-amino-3- (4-hydroxyphenyl) propionic acid, 2-fluoromethyl-2-amino-3- (4-chloro-2-hydroxyphenyl) propionic acid,

2-fluoromethyl-2-amino-3- (2,4-dichloro-3-hydroxyphenyl) propionic acid,

2-difluoromethyl-2-amino-3- (2-chloro-4-hydroxyphenyl) propionic acid,

2-fluoromethyl-2-amino-3- (2,4-dichloro-6-methylphenyl) propionic acid,

2-fluoromethyl-2-amino-3- (4-hydroxy-6-methylphenyl) propionic acid,

2-difluoromethyl-2-amino-3- (4,6-diethyl-2-hydroxyphenyI) propionic acid,

2-fluoromethyl-2-amino-3- (4-chloro-6-tert-butylphenyl) propionic acid,

2-difluoromethyl-2-amino-3- (6-tert-butyl-4-hydroxyphenyl) propionic acid,

N, N-di-n-propyl-2-difluoromethyl-2-amino-3- (4-acetyloxy-

phenyl) propionic acid amide 2-fluoromethyl-2- [N- (2-amino-l'-oxoethyl) amino] -3- (3-hy-

droxyphenyl) propionic acid, 2-fluoromethyl-2-amino-3- (3,4-dihydroxy) phenyl-l-oxopro-

pylaminoacetic acid,

2- [(2-difluoromethyl-2-amino-l-oxo-3-phenyl) propylamino] -

dihydrocinnamic acid, 2-difluoromethyl-2- (l-oxoethylamino) -3- (4-hydroxy) -phenyl-

-l-oxopropylamino-2-propionic acid, N, N-dimethyl-2-difluoromethyl-2-amino-3- (3-hydroxyphenyl) -

-propionic acid amide, N-n-butyl-2-difluoromethyl-2-amino-3- (4-hydroxyphenyl) -

propionic acid amide, 2-fluoromethyl-2-amino-3- (4-hydroxyphenyl) propionic acid - tert-butyl ester,

Difluoromethyl-2-amino-3- (4-chloro-3-methoxyphenyl) propion-

acid ethyl ester and 2-fluoromethyl-2-amino-3- (4-hydroxyphenyl) propionic acid amide.

The compounds of general formula I are irreversible inhibitors of the enzyme, which converts tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine, tyrosine and phenylalanine into tryptamine, 5-hyroxytryptamine, 3,4-dihydroxyphenylethylamine, tyramine and Metabolically catalyzed phenethylamine. As already mentioned above, results of investigations show that the enzyme responsible for the conversion of the aforementioned amino acids into the corresponding amines in a peripheral way is a non-specific aromatic amino acid decarboxylase. Central conversion studies show that specific decarboxylases are responsible for the conversion of 5-hydroxy-tryptophan and 3,4-dihydroxyphenylalanine respectively, while the remaining amino acids mentioned above are enzymatically converted into the corresponding amines by a non-specific aromatic amino acid decarboxylase be transferred. The compounds according to the invention are both centrally and peripherally active for irreversibly inhibiting the activity of non-specific aromatic amino acid decarboxylase and the activity of 3,4-dihydroxyphenylamine decarboxylase (DOPA decarboxylase). The term “central” used here in connection with the usability of the compounds according to the invention relates to the central nervous system, primarily the brain, while “peripheral” refers to other body tissues in which the decarboxylase enzyme is present. The selectivity of the peripheral or central inhibition of the amino acid decarboxylases in the administration of the compounds I according to the invention depends on the dose.

As irreversible inhibitors of aromatic amino acid decarboxylase and DOPA decarboxylase, the compounds according to the invention have a wide variety of pharmaceutical uses. As peripheral, irreversible inhibitors of aromatic amino acid decarboxylase, the compounds of the formula I are useful for the treatment of Parkinsonism if they are used together with 3,4-dihydroxyphenylalanine (DOPA) or L-3,4-dihydroxyphenylala-2o nin (L-DOPA) be administered. DOPA and in particular the active isomer L-DOPA are known to be effective in the treatment of Parkinsonism when they are systemically administered usually in an amount of 0.5 to 1 g daily initially, after which the amount administered 25 gradually over a period of 3 to 7 Days to the maximum tolerated daily dose of about 8 g. Simultaneous administration of a compound of general formula I and L-DOPA represents an improved method of treatment for Parkinsonism in that compounds of formula I peripherally decarboxylate L-DOPA to L-3,4-dihydroxyphenethylamine (L-dopamine) block by inhibiting the activity of the aromatic amino acid decarboxylase enzyme and thus maintaining high levels of L-DOPA in the circulatory system for central absorption 35 and also preventing the peripheral formation of elevated dopamine levels which are known to cause certain undesirable side effects, such as e.g. Cardiac arrhythmia. By simultaneously administering a compound of general formula I and L-DOPA, the amount of L-DOPA administered can be reduced 2 to 10 times compared to the amounts required for usability when the L-DOPA is administered alone becomes. It is preferred to administer the compounds of the invention prior to the administration of L-DOPA 45. For example, a compound of Formula I can be administered 30 minutes to 4 hours prior to the administration of L-DOPA, depending on the route of administration and the condition of the patient to be treated.

so the compounds of general formula I are also useful for the treatment of depressive syndromes,

if taken with 5-hydroxytryptophan (5-HTP)

or in particular administered with the active levo isomer, which is known to be useful for treating 55 depressions when administered systemically. The compounds of general formula I block the conversion of 5-hydroxytryptophan to 5-hydroxytryptamine by peripheral inhibition of aromatic amino acid decarboxylase activity, thereby maintaining higher 60 levels of 5-HTP for central absorption in the circulation. When administered together with exogenous 5-HTP, the compounds of general formula I are also useful for the treatment of muscle spasms which are known to be effectively treated by increased central levels of 5-HTP.

Thanks to their peripheral inhibitory effect on aromatic amino acid decarboxylase, the compounds of the general formula I are also suitable for the treatment of

636846

6

rheumatoid arthritis, carcinoid syndrome and anaphylactoid reactions in humans as well as bronchoconstriction in asthmatics and also of other conditions which are known to be caused by high peripheral 5-hydroxytryptamine levels.

As indicated earlier, agents that reduce the elevated levels of 5-HT and norepinephrine, the hydroxylation product of dopamine, have been shown to be useful in treating patients with manic conditions. As a result, the compounds of general formula I are useful as central irreversible inhibitors of aromatic amino acid decarboxylase and DOPA decarboxylase for the treatment of manic conditions. Furthermore, thanks to their central inhibitory action on aromatic amino acid decarboxylase, the compounds of the general formula I can also be useful as antipsychotic agents, since the central tryptamine levels are reduced when they are administered; they can also be useful in the treatment of schizophrenia and seizure disorders, since the central phenethylamine and tyramine levels are reduced when they are administered.

The utility of the compounds of the general formula I as irreversible inhibitors of aromatic amino acid decarboxylase can be demonstrated as follows: A compound of the formula I is administered to rats or mice as an aqueous solution or suspension. At different times, 1 to 48 hours after administration of the compound to be tested, the animals are sacrificed and the aromatic amino acid decarboxy-lase activity is determined by the radiometric method according to Christenson et al., Arch. Biochem. Biophys., Vol. 141, p. 356 (1970) measured in homogenates of the kidney, heart and brain, which according to the Burkard method, among others,

Arch. Biochem. Biophys., Volume 107, p. 187 (1964).

In order to achieve the desired effect, the compounds according to the invention can be administered in various ways. They can be administered to the patient to be treated either orally or parenterally, for example subcutaneously, intravenously or intraperitoneally, alone or in the form of pharmaceutical preparations. The compounds can also be by intranasal blowing or by application to the mucous membranes, e.g. to those of the nose, throat and bronchus, for example in an aerosol spray containing small particles of the compound according to the invention in a spray solution or in the form of a dry powder.

The amount of the compound according to the invention to be administered fluctuates; it can be any effective amount. Depending on the patient, the condition to be treated and the mode of administration, the amount of the new compound can vary widely to provide an effective amount in a unit dosage form. When the compounds of the present invention are administered to effect peripheral irreversible inhibition of the aromatic amino acid decarboxylase, the effective amount of the compound to be administered usually varies from about 0.1 mg / kg to 100 mg / kg of the patient's body weight per dose, preferably from about 5 mg to 25 mg / kg. For example, the desired peripheral effect can be achieved by taking a unit dosage form, such as a tablet with a content of 10 to 250 mg of a compound according to the invention, which is to be taken 1 to 4 times a day. If the compounds according to the invention are administered in order to achieve a central irreversible inhibition of the aromatic amino acid decarboxylase or 3,4-dihydroxyphenylalanine decarboxylase, the effective amount of the compound to be administered usually varies from about 100 to 500 mg / kg of body weight of the patient per day, preferably from about 150 to 300 mg / kg. For example, the desired central effect can be achieved by taking a unit dosage form, e.g. a tablet with a content of about 350 to 500 mg of the compound according to the invention can be achieved, which is to be taken 1 to 4 times a day.

In the present, the term “patient” is understood to mean a warm-blooded being, such as Mammals such as cats, dogs, rats, mice, guinea pigs, sheep, horses, cattle, cows and humans.

The solid dosage unit forms can be of conventional type. Thus the solid form can be a capsule, which is of the type of ordinary gelatin capsules, containing the compound according to the invention and e.g. a carrier, lubricant and inert fillers such as e.g. Lactose, sucrose and cornstarch. In another embodiment, the new compounds are treated with conventional tablet bases, e.g. Lactose, sucrose and corn starch (in combination with binders such as gum arabic) corn starch or gelatin, disintegrants such as Corn starch, potato starch or alginic acid, and a lubricant such as e.g. Tableted stearic acid or magnesium stearate. For parenteral administration, the compounds can be administered as injectable dosages of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which is a sterile liquid, e.g. Water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable auxiliary agents. Examples of oils in these preparations are those of petroleum, those of animal, vegetable or synthetic origin, e.g. Peanut oil, soybean oil and mineral oil. In general, especially for injectable solutions, water, saline, aqueous dextrose and similar sugar solutions, ethanol and glycols such as e.g. Propylene glycol or polyethylene glycol, preferred as liquid carriers.

The compounds can be administered in the form of a depot injection or an implant, which are formulated in such a way that a delayed release of the active ingredient is made possible. The active ingredient can be pressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. In the case of implants, inert materials such as e.g. organisms degradable polymers or synthetic silicones, e.g. Use silicone rubber (for example, the commercial product Silastic from Dow-Corning Corporation).

For use as aerosols, the compounds according to the invention can be filled into an aerosol pressure container in solution or suspension, e.g. with dichlorodifluoromethane, dichlorodifluoromethane with dichlorodifluoroethane, carbon dioxide, nitrogen or propane and, if necessary or desired, with the usual auxiliaries, e.g. Co-solvents and wetting agents. The compounds can also be in a non-pressurized form, e.g. in a nebulizer or sprayer.

What has already been pointed out above, the compounds I according to the invention are used in particular together with exogenous L-DOPA, it being possible for individual formulations of a compound according to the invention and L-DOPA to be administered, or both active ingredients s

io

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can be formulated into a single combination pharmaceutical preparation. In both types of use, the amount of the compound according to formula I varies from about 1: 1 to 1:10 compared to the amount of L-DOPA that is administered. A combination preparation can comprise an inner part containing L-DOPA and an outer part containing the compound according to the invention, each active ingredient being formulated in a suitable manner. A particularly suitable combination preparation can be produced by compressing L-DOPA, optionally with suitable carriers, into a core and providing this core with a lamination coating which is resistant to gastric juice, and applying an outer layer over the coated core, which formulates a suitable Contains compound of formula I. When using such a combination preparation, the decarboxylase inhibitor, i.e. the compound of formula I is released before L-DOPA, preferably 30 to 60 minutes before. The lamination coating can be made using a non-aqueous solution of glycerides or a water-insoluble polymer, e.g. Ethyl cellulose or cellulose acetate phthalate. A formulation can also be used in which the L-DOPA has been provided with a coating which is soluble in the intestine, using Shellac mixtures and Shellac derivatives and cellulose acetate phthalates.

Suitable pharmaceutical formulations are described in more detail in the examples.

However, the compounds of the formula I according to the invention can be used not only as pharmacologically active substances, but also as intermediates for the preparation of valuable cephalosporin antibiotics. Compounds of the general formula I in which R 2 is the hydroxyl group can be used for the preparation of cephalosporin derivatives of the following formula II:

R4 R3 Y Rs ~~ \\ —CH2-C-C0NH i * "" 1

y-K I H ^ JLcHsX ««

NHRi y-

0 C00M

In this formula, Y, Rt, R3, R4, R5, R'4 and R6 have the meanings given in connection with the general formula I; M is a hydrogen atom or a negative charge, while X is a hydrogen atom or the acetoxy group.

The compounds of general formula II and the pharmaceutically acceptable salts and individual optical isomers thereof are new and useful as antibiotics; they can be administered in a manner which is the same for many known cephalosporin derivatives, e.g. Cephalexin, cephalothin or cephaloglycin. The compounds of general formula II and their pharmaceutically acceptable salts and isomers can be administered alone or in the form of pharmaceutical preparations either orally or parenterally and topically to warm-blooded animals, i.e. to birds and mammals, e.g. Cats, dogs, cattle, sheep, horses and humans. The compounds can be administered orally in the form of tablets, capsules or pills or else in the form of elixirs or suspensions. For parenteral administration, the compounds are best administered in the form of a sterile aqueous solution which contains other solutes such as e.g. May contain sufficient table salt or glucose to make the solution isotonic. For topical use, the compounds of the formula II, their salts and isomers can be incorporated into creams or ointments.

Examples of bacteria against which the compounds II, 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 usable non-toxic inorganic acid addition salts of the compound of the general formula II are mineral acid addition salts, such as e.g. the hydrogen chloride, the hydrogen bromide, sulfate, sulfamate and phosphate as well as addition salts of organic acids, e.g. the maleate, acetate, citrate, oxalate, succinate, benzoate, tartrate, fumarate, malate and ascorbate. The salts can be formed by conventional methods.

The compounds of general formula II in which Rj is a hydrogen atom are e.g. prepared by coupling 7-aminocephalosporanic acid or a derivative thereof of the general formula

C00M

wherein X and M have the meanings given in connection with the general formula II, with an acid of the general formula

R

or a functional derivative thereof, e.g. the acid chloride or an acid anhydride, if the free acid is used, preferably in the presence of a dehydrating agent such as e.g. Dicyclohexylcarbodiimide, where R3, R4, Rj, R'4 and R6 have the meanings given in connection with the general formula II and the amino group with a suitable protective group, e.g. the tert-butoxycarbonyl group, is protected, after which the amino protecting groups can be removed by hydrolysis with acid.

The coupling reaction is usually carried out in a solvent such as e.g. Ethyl acetate, dioxane, chloroform or tetrahydrofuran, in the presence of a base such as e.g. an alkali carbonate. The reaction temperature can vary from about -10 to 100 ° C and the reaction time from about 0.5 to 10 hours. The cephalosporin products can be separated by conventional methods. The compounds of the general formula IV can be prepared by processes described above, while the compounds of the formula III are commercially available or can be prepared by known processes.

The compounds of the general formula II in which Rj has a meaning other than hydrogen can be obtained from the corresponding derivatives in which Rj represents a hydrogen atom, according to those described below

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636846

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general processes for compounds of general formula I are prepared in which Rx has a meaning other than hydrogen.

The compounds of the general formula I in which Rj represents a hydrogen atom, R2 represents a hydroxyl group and R3 and R4 each represent the group OR10, in which R10 represents a hydrogen atom or R4 and R5 each represent OR10, in which R10 represents a hydrogen atom, or in which R3, R4, Rg, R'4 and R6 have the meaning given in Table I, with the exception that R10 denotes the methyl group, can be prepared by using an appropriately protected phenylpropionic acid ester of the general formula V

TABLE II

10th

15

R1

CHa-CH-COR.

NH = C-R, I 1 R /.

(V)

treated with a strong base to form a carbanion, which in turn is treated with a suitable halomethyl alkylating agent and then hydrolyzed with acid. In the above general formula V, Ra is a straight or branched chain Cr to C8 alkoxy group, Rb is a hydrogen atom, a phenyl group, a straight or branched chain Cr to C8 alkyl group, a methoxy or ethoxy group, Rc is a phenyl group or a straight line - or branched chain Cr to Cs-alkyl group or Rb and Rc together an alkylene group with 5 to 7 carbon atoms, ie the group

—CH2— (CH ^ —CH2—

where m is an integer from 3 to 5. Specific examples of straight-chain or branched-chain Cr to C8-alkyl groups which can represent Rt) and Rc are the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-hexyl -, n-Oc-tyl and the neopentyl group. The radicals Rjj, R12, R13, R'12 and R14 each have the meaning given in Table II below:

30th

35

Marg

Rl2

Rl3

R'ia

Rl4

h h

och3

h h

h och3

h h

h h

och3

och3

h h

och3

H

Cl h

h h

och3

Cl h

H

Cl och3

h h

H

Cl och3

Cl h

H

Cl, F

h och3

h h

och3

h ch3

h ch3

h h

och3

h ch3

h h

och3

h c2h5

och3

h c2h5

h c2h5

H

och3

H

och3

H

H

och3

och3

och3

H

H

H

och3

OCH2Ph

H

i H

H

OCH2Ph och3

H

och3

och3

H

H

H

och3

H

H

H

H

. H

H

och3

H

tert-C4H9

Suitable strong bases that can be used in the above reaction step to form the carbanion intermediate include those that can withdraw a proton from the carbon atom in a-position with respect to the carboxyl group, for example alkyl lithium such as butyllithium or phenyllithium, lithium dialkylamide, such as lithium diisopropylamide, or lithium 45thamide, tert-potassium butoxide, sodium amide, metal hydrides, such as sodium hydride or 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. Suitable halomethyl alkylating agents that can be used in the above reaction are, for example, chlorofluoromethane, bromofluoromethane, fluorodiodomethane, chlorodifluoromethane, bromodifluoromethane, di-fluorodiodomethane, bromochloromethane, dichloromethane, chlorine-55 diiodomethane, bromodichloromethane and dichlorodiodane. The halomethyl alkylating agents are known.

The alkylation reaction can be carried out in an aprotic solvent, for example benzene, toluene, Etilem, tetra-hydrofuran, dimethyl sulfoxide or hexamethylphosphoric acid retriamide. The reaction temperature can range from -120 to + 65 ° C; the preferred reaction temperature is about 40 ° C. The reaction time can range from 0.5 to 24 hours.

«5 The acid hydrolysis, which is preferably carried out to remove unreacted starting product and the protective groups, can be carried out in one step or step by step.

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In the one-step hydrolysis, the acid concentration used can change with the duration of the hydrolysis step and the temperature used. For example, the one-step hydrolysis can be carried out by treatment with concentrated hydrochloric acid at temperatures of about 25 to 120 ° C. over a period of 1 to 4 days. The gradual hydrolysis can be carried out by treatment with a dilute acid at a temperature of about 25 ° C. in a period of 0.5 to 6 hours to remove unreacted starting product. Repeated treatment with dilute acid is preferred to remove any amine protecting groups. This is usually followed by treatment with concentrated acid at temperatures of about 25 to 125 ° C. for a period of about 1 to 3 days in order to remove all ester or ether groups. Gradual hydrolysis is preferred.

The compounds of the general formula I in which R2 represents the hydrogen atom, R2 the hydroxyl group and the radicals R3, R4, R'4 or R5 each denote the group OR10, where R10 is the hydrogen atom, can be prepared by using the corresponding derivative , in which the radicals R3, R4, R'4 or R5 each denote the group OR10, where Rj0 is the methyl group, with hydrogen bromide in water or acetic acid at temperatures of about 25 to 125 ° C. in a period of about 4 to 24 hours treated.

The compounds of the general formula I in which R2 is a hydroxyl group, Rx is the hydrogen atom and R3, R4, R'4 or R5 each represent the group OR10, where R10 is an alkylcarbonyl group in which the alkyl radical has 1 to 6 carbon atoms and straight or is branched chain, means a benzoyl or phenylalkylenecarbonyl group in which the alkylene group is straight or branched chain and has 1-6 carbon atoms can be prepared by reacting the corresponding derivatives in which R10 is the hydrogen atom with an acid anhydride of the general formula

O

II

(R22 — c—

or an acid halide of the general formula

O

R22 — C — halo in the halo is a chlorine or bromine atom and R22 is a straight or branched chain CrC6 alkyl group, a phenyl or phenylalkylene group in which the alkylene group is straight or branched chain and has 1-6 carbon atoms in the presence of an organic Base, such as pyridine, quinoline or triethylamine, which also serve as a solvent, are treated in a period of about 1-24 hours at temperatures of about 25 to 100 ° C. This is usually done with the proviso that the a-amino group and optionally the carboxy group of the starting material substituted with a hydroxy group are protected with a suitable protective group, for example with the tert-butoxycarbonyl or benzyloxycarbonyl group or the benzyl group, before the reaction, which then removed with acid, for example trifluoroacetic acid, and hydrogenolysis. The acid anhydrides and the acid halides which are preferably used in this reaction are known or can easily be prepared from the corresponding acids by known processes.

The compounds of general formula I in which R2 represents a straight or branched chain Cr to Ca alkoxy group are preferably prepared by treating the corresponding derivatives in which R2 represents a hydroxyl group with thionyl chloride to form the acid chloride. The acid chloride obtained is e.g. with an alcohol of the general formula

Ras-OH

in which R23 represents a straight or branched chain QQ-alkyl group, for example the methyl, ethyl, n-propyl, isopropyl, n-butyl, hexyl or the octyl group, at about 25 ° C. in implemented over a period of about 4 to 12 hours.

The compounds of the general formula I in which R2 denotes the group —NR7R8, in which R and R8 each denote a hydrogen atom or a straight-chain or branched-chain QQ alkyl group, can be reacted by an acylation reaction of an acid halide, for example an acid chloride, of the corresponding Compound are prepared in which R2 represents the hydroxy group and Rt has the meaning according to formula I. However, this is usually done with the proviso that each free amino group with a suitable protective group, for example the carbobenzyloxy or tert-butoxycarbonyl group, and, if R3, R4, R5 or R'4, the group OR10 and R10 each represent the hydrogen atom mean, these groups, like the corresponding alkylcarbonyloxy group, are preferably protected with an excess of an amine, which is represented by the formula

HNR7R8

can be represented. The reaction is usually carried out in methylene chloride, chloroform, dimethylformamide, ethers such as tetrahydrofuran or dioxane, or benzene at about 25 ° C. in a period of about 1 to 4 hours. Examples of amines are ammonia or a compound which is a possible source of ammonia, for example hexamethylenetetramine, primary amines such as methylamine, ethylamine or n-propylamine, and secondary amines such as dimethylamine, diethylamine or di-n-butylamine. After the acylation reaction, the amino protecting group is removed by treatment with an acid, for example hydrogen bromide in dioxane, or by hydrogenolysis. The hydroxy protecting group can conveniently be removed by basic or acid hydrolysis.

The compounds of general formula I, in which R2 is the group

—'NH — CH — COOH

I.

R «

means can be prepared by the corresponding derivative in which R2 is a hydroxyl group or a functional derivative thereof, for example an acid anhydride, and Rt has the meaning given in formula I, with the proviso that each free amino group by a suitable protecting group, for example the benzyloxycarbonyl or tert-butoxycarbonyl group, is protected with a compound of the general formula

NH2-CH-COOR24

I.

R9

in which R9 has the meaning according to formula I and R24 is a lower alkyl group, for example the methyl or

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Ethyl group, in an ether, such as tetrahydrofuran or dioxane, at temperatures from 0 to about 50 ° C in a period of about 1-24 hours. This is usually followed by acid hydrolysis to remove the protective groups, with the proviso that if a free acid has been used, the reaction is carried out using a dehydrating agent, for example dicyclohexylcarbodiimide.

The compounds of the general formula I in which Rj represents an alkylcarbonyl group in which the alkyl radical is straight or branched chain and has 1 to 4 carbon atoms can be prepared by the corresponding derivatives in which Rj represents the hydrogen atom and R2 is the hydroxyl group, with an acid halide of the general formula

O

II

R25 — C —— halo in the halo represents a halogen atom, e.g. chlorine or bromine, and R25 represents a straight or branched chain Cj-Cj alkyl group in water in the presence of a base such as sodium hydroxide or sodium borate at temperatures from 0 to Treated 25 ° C in a period of 0.5 to 6 hours. These compounds can also be derived from the ester derivative, i.e. from the compounds of the general formula I in which Rj denotes a hydrogen atom and R2 denotes an alkoxy group having 1-8 carbon atoms, by treatment with an acid halide of the above general formula

0

II

Rgg-C-halo in water, methylene chloride, chloroform or dimethyl acetamide in the presence of a base such as sodium hydroxide, potassium hydroxide, or an excess of triethylamine at temperatures of about 0-25 ° C in a period of about 0.5 to 24 hours getting produced.

The compounds of general formula I, in which Rj the formula

O

II

—C — CH — R27

1

nh2

in the R27 the hydrogen atom, a straight or branched chain lower CrC4 alkyl group, the benzyl or p-hydroxybenzyl group, can be prepared by using the corresponding derivative in which the hydrogen atom and Rz is a straight or branched chain Cj-Cg alkoxy group represent with an acid of the general formula

HOOC-CH-R2V

I.

NHa or an anhydride thereof, in which the amino group is protected with a suitable protective group, for example the benzyloxycarbonyl or tert-butoxycarbonyl group, and R2, which has the above meaning, in an ether such as tetrahydrofuran or dioxane, methylene chloride or chloroform and in the presence of a dehydrating agent, if the free acid is used, at temperatures of about 0 to 35 ° C in a period of about

Treated for 1 to 12 hours. The acidic and basic hydrolysis to remove the protective groups is then usually carried out. If necessary, the basic hydrolysis can be omitted, the ester peptide derivative being obtained 5.

The individual optical isomers of the compounds of the general formula I, in which Rx represents the hydrogen atom and R2 represents the hydroxyl group, can be obtained using the (+) or (-) - binaphthylphosphoric acid salt according to the melodic method of R. Viterbo et al., Tetrahedron Letters, 48, p. 4617 (1971). Other release agents such as (+) - camphor-10-sulfonic acid can also be used. The individual optical isomers of the compounds of the general formula I in which R 1 and R 2 have a meaning other than the hydrogen atom or the hydroxyl group can, as described for the racemate, be obtained if the corresponding optically separated amino acid is used.

The starting compounds of the general formula V 20 can be prepared by one equivalent of a glycine ester of the formula VI

CH2-CORa

25 NH = C — Rb VI

I.

Rc in which Ra, Rb and Re have the meaning according to formula V be-30, with an equivalent of a strong base, for example alkyl lithium, such as butyllithium or phenyllithium, lithium dialkylamide, such as lithium diisopropylamide or lithium amide, tert-potassium butylate, sodium amide, metal hydrides, such as sodium hydride, tertiary amines, such as triethyl-35 amine, lithium acetylide or dilithium acetylide, treated and then with an alkylating agent of the general formula VII

R'ia Ri 4

in which Rn, R12, R13, R'12 and R14 have the meaning given in the formula V and Xa is a halogen atom, for example the chlorine or bromine atom. The alkylation reaction can also be carried out in an aprotic solvent, for example benzene, ether, tetrahydrofuran, dimethyl sulfoxide or hexamethylphosphoric triamide. The reaction time is about 0.5 to 24 hours, the temperature is about -120 to + 25 ° C. 55 The compounds of the general formula VI can be prepared by treating an appropriate alkyl glycinate with a compound having a carbonyl group to form a Schiff base in a conventional manner. In particular, 60 (a) if Rb denotes the hydrogen atom, the corresponding amino acid ester with benzaldehyde or a straight-chain or branched-chain QQ alkanal, for example 1-propanal, 1-butanal, 2,2-dimethylpropan-l-al or 2, 2-diethyl-butane-l-al,

65 (b) when Rb represents the phenyl group, the corresponding amino acid ester with benzophenone or a phenyl alkyl ketone in which the alkyl group has 1-8 carbon atoms and is straight or branched chain, for example

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the phenyl methyl ketone, phenylethyl ketone, phenyl isopropyl ketone, phenyl n-butyl ketone or phenyl tert-butyl ketone, and

(c) when Rb is a straight-chain or branched-chain CrCa-alkyl group, the corresponding amino acid ester with a phenylalkyl ketone, a dialkyl ketone described above, in which the alkyl group each has 1-8 carbon atoms and is straight-chain or branched-chain, for example dimethylisopropyl ketone, Di-n-butyl ketone or methyl tert-butyl ketone treated. Such compounds containing a car bonyl group are known or can be prepared by known processes.

If Rb in the compounds of the general formula VI denotes the methoxy or ethoxy group, a corresponding alkylglycinate can be substituted with a benzoyl halide, for example the chloride, or with an aliphatic carboxylic acid halide, for example the chloride in which the alkyl radical of the acid has 1-9 carbon atoms and is straight or branched chain, for example acetyl chloride, propionyl chloride, butyryl chloride, tert-butyryl chloride, 2,2-di-ethylbutyric acid chloride or valeryl chloride, at 0 ° C. in ethers, methylene chloride, dimethylformamide, dimethylacetamide or chlorobenzene in the presence of an organic base, such as triethylamine or pyridine. Subsequently, the reaction mixture is usually allowed to warm to about 25 ° C. in one hour. The amide derivative obtained can be used with an alkylating agent such as methyl fluorosulfonate, dimethyl sulfate, methyl iodide, methyl p-toluenesulfonate or trimethyloxonium hexafluorophosphate if Rb is methoxy or with triethyloxonium tetrafluoroborate if Rb is ethoxy at about 25 ° C in a chlorinated hydrocarbon as a solvent, for example methylene chloride, chlorobenzene or chloroform, are combined. This reaction mixture is generally refluxed for about 12-20 hours. The mixture is then expediently allowed to cool to about 25 ° C. and an organic base, for example triethylamine or pyridine, is added. The solution can then be extracted with a saline solution and the product separated.

If in the compounds of the general formula VI Rb and Rr together form an alkylene group having 5-7 carbon atoms, the corresponding amino acid ester derivatives can be obtained by reacting the amino acid ester with a cyclic alkanol, for example cyclopentanone, cyclohexanone and cycloheptanone, to form a Schiff 'treated base in a conventional manner.

The alkyl glycinates are preferably obtained by treating the glycine with an alcohol of the general formula RaH saturated with hydrogen chloride gas, in which Ra has the meaning according to formula VI, over a period of about 12-36 hours at about 25 ° C., or they can be obtained commercially.

The compounds of the general formula VII are known or can be prepared from the corresponding substituted benzoic acids or benzaldehyde derivatives, which are also known. For example, the benzyl halides of the general formula VII can be prepared from the corresponding benzaldehyde by reduction with sodium borohydride, lithium aluminum hydride or by catalytic reduction or from the corresponding benzoic acid ester by reduction with lithium aluminum hydride or borane or by reduction of the corresponding benzoic acid derivative with lithium hydride, the benzyl alcohol derivative obtained, for example, with Thionyl chloride, phosphorus oxychloride, phosphorus trichloride, Phosphortribro-mid or phosphorus pentachloride is treated.

Certain compounds of the general formula V can be obtained directly from the corresponding amino acid by converting the corresponding acids into the ester and then protecting the a-amino group according to the general methods described above for protecting the alkylglycinate amino group. For example, the ester derivative of tyrosine or phenylalanine protected in the amino group can be obtained in such a manner. However, this process cannot be used to prepare the compounds of the general formula V in which the aromatic ring has a hydroxyl group in the meta position.

The following application example 1 explains the use of a compound of the general formula I, in which R2 represents the hydroxyl group, as an intermediate for the preparation of a cephalosporin of the general formula II.

Application example 1

7 - [(2-difluoromethyl-2-amino-3-phenylpropionyl) amino] -3 - acetoxymethyl ~ 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-di-fluoromethyl-2- amino-3-phenylpropionoyl chloride, in which the free amino group is protected by the tert-butoxycarbonyl group, in 50 ml of ethyl acetate is heated under reflux for 2 hours. The solvent is then removed. The residue obtained is treated under mild acidic conditions and chromatographed on silica gel with benzene-acetone as the eluent. The title link will be obtained.

The following application examples 2 to 4 illustrate pharmaceutical formulations of the compounds according to the invention.

Application example 2

Contains a formulation for hard gelatin capsules

(a) 2-difluoromethyl-2-amino-3- (3-hydroxy-

phenyl) propionic 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 them well. The powder is then filled into hard gelatin capsules with a filling of 115 mg per capsule.

Application example 3

A formulation for tablets has the following compositions:

(a) 2-difluoromethyl-2-amino-3- (3,4-dihydroxy-

phenyl) propionic acid

20 mg

(b) starch

43 mg

(c) lactose

45 mg

(d) Magnesium stearate

2 mg

The granules which were obtained after the lactose had been mixed with the compound (a) and part of the starch and were granulated with the starch paste are dried

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sieves and mixed with the magnesium stearate. The mixture is then pressed into tablets each weighing 110 mg.

Application example 4

The following 1 ml ampoule for intramuscular injection is a formulation for an injectable suspension:

% By weight

(a)

2-difluoromethyl-2-amino-3- (4-hydroxy-

phenyD-propionic acid

1.0

(b)

Polyvinyl pyrrolidone

0.5

(c)

Lecithin

0.25

(d)

Water for injections

100.0

The substances a-d are mixed, homogenized and in

1 ml ampoules filled, which are then melted and treated in an autoclave at 121 ° C for 20 minutes. Each ampoule contains 10 mg / ml of the compound a.

The following examples illustrate the compounds of the general formula I.

example 1

2-A mino-2-difluoromethyl-3- (3,4-dihydroxyphenyl) propionic acid

25 g of glycine methyl ester hydrochloride are added to a solution of 112 g of potassium carbonate in 100 ml of water, which is cooled in an ice-salt freeze mixture, with stirring. The mixture is then extracted 5 times with ether. The combined ether extracts are dried over magnesium sulfate and evaporated at room temperature. The free glycine methyl ester is obtained. While stirring, a solution of 17.7 g of the free glycine methyl ester in 150 ml of methylene chloride, which is cooled in an ice bath, is added dropwise with 21.1 g (1 equivalent) of benzaldehyde. After the addition, the ice bath is removed. The mixture is stirred for a further 3 hours at room temperature. The methylene chloride phase is washed with brine and aqueous sodium bicarbonate, then dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is distilled at 0.3-0.5 mm Hg. The glycine methyl ester benzaldimine with a boiling point of 104 ° C. is obtained.

Preparation 1 3,4-dimethoxybenzyl bromide

With stirring, a solution of 50.3 g of 3,4-dimethoxybenzyl alcohol in 500 ml of anhydrous ether is slowly mixed with 27.1 g (9.5 ml) of phosphorus tribromide at 0 ° C.

After the addition, the mixture is stirred at room temperature for 1 hour, then poured into a solution of 56 g of potassium carbonate in 50 ml of water. The ethereal phase is separated off, dried over magnesium sulfate and evaporated.

The 3,4-dimethoxybenzyl bromide is obtained, which is recrystallized from petroleum ether (boiling range 35-60 ° C).

Example 2

2-amino-2-difluoromethyl-3- (3,4-dihydroxyphenyl) propionic acid

(A) Isopropylamine (53 ml, 1N solution in tetrahydrofuran) is mixed with 25 ml (2.05 m) of n-butyllithium with stirring and a nitrogen atmosphere at -78 ° C. After a few minutes, the mixture is treated with a solution of the benzaldimine of the glycine methyl ester (8.85 g, 50 mmol) in 50 ml of anhydrous tetrahydrofuran. After a further 5 minutes, a solution of 11.52 g (50 mmol) of 3,4-dimethoxybenzyl bromide in 80 ml of anhydrous tetrahydrofuran is added very slowly within one hour at -78 ° C. The cooling bath is then removed. The mixture is allowed to warm to room temperature from 2.5 hours with stirring. The mixture is then cooled again to -78 ° C. and with a solution of lithium isopropylamide which consists of diisopropylamine (62 ml, 1 m solution in tetrahydrofuran) and n-butyllithium (27.2 ml, 2.05 m ) was prepared, treated at -78 ° C 15. The cooling bath is then removed and replaced by a warm water bath at a temperature of 45-50 ° C. When the reaction mixture has reached this temperature, a rapid stream of chlorodifluoromethane is bubbled through the solution with stirring for 1 hour. The cooled mixture is diluted with ether, washed 3 times with brine, dried over magnesium sulfate and evaporated. The crude a-difluoromethyl-3,4-di-methoxyphenylalanine-N-benzaldimine methyl ester is obtained.

25 (B) 17.5 g of the a-difluoromethyl-3,4-dimethoxyphenylalanine-N-benzaldimine'-methyl ester obtained above with a mixture of 100 ml of ether and 250 ml of 1N hydrochloric acid were stirred at room temperature for 6 hours. The ether phase is then separated off. The aqueous phase is extracted 30 5 times with methylene chloride and then evaporated to dryness under reduced pressure. The residue is refluxed with concentrated hydrobromic acid (250 ml, 47%) overnight under nitrogen. The solution is then evaporated to dryness 35. The residue obtained is treated successively with water and twice isopropanol. The solutions flow heated. The solution is then evaporated to dryness. The nitrogen atmosphere is maintained during these and subsequent treatments to avoid any oxidation of the catechin. A solution of the residue in 250 ml of water is decolorized with acid, washed with charcoal, filtered off and concentrated to about 75 ml. The pH of the solution is adjusted to 4.5-4.8 using triethylamine. Then 45 ml of acetone are added. The precipitate obtained is filtered off, washed with choroform and recrystallized from water / ethanol (1: 5). The 2-amino-2-difluoromethyl-3- (3,4-dihydroxyphenyl) propionic acid of mp> 250 ° C. is obtained.

50

Preparation 2

Methyl 2-benzaldimine 3- (4-hydroxyphenyl) propionate

An ice-cooled suspension of 11.58 g (50 mmol) of 55 tyrosine methyl ester hydrochloride in 300 ml of methylene chloride is mixed with 5.3 g (50 mmol) of benzaldehyde and then dropwise with a solution of 5.05 g (50 mmol) of triethylamine in methylene chloride. The reaction mixture is stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained is extracted with ether. After the usual working up and crystallization from methylene chloride / pentane, the title compound is obtained with an mp. 109-111 ° C.

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Preparation 3

Methyl 2-chloromethyl-2-benzaldimine-3- (4-hydroxyphenyl) propionate

A solution of lithium diisopropylamide (8 mmol), prepared in situ from a solution of 1 M diisopropylamine in tetrahydrofuran and a solution of 2 M butyllithium in hexane, in tetrahydrofuran and hexamethylphosphotriamide (2.5 ml) is brought to -78 ° C cooled. A solution of 1.132 g (4 mmol) of methyl 2-benzaldimine-3- (4-hydroxyphenyl) propionate in 30 ml of tetrahydrofuran is slowly added to this solution with stirring in a nitrogen atmosphere. The cooled reaction mixture is stirred at -78 ° C for 0.5 hours. A solution of chlorobromopropane (1.05 g, 8 mmol) in tetrahydrofuran is then added. The temperature is allowed to rise slowly to room temperature and stirring is continued overnight. The reaction mixture is quenched with water and then extracted with ether. After the usual work-up and crystallization from ether / pentane, the title compound is obtained with an mp. <50 ° C.

Example 2

Ethyl 2-difluoromethyl-2-amino-3- (3,4-dihydroxyphenyl) propionate hydrochloride

A suspension of 2.47 f (10 mmol) of 2-difluoromethyl-2-amino-3- (3,4-dihydroxyphenyl) propionic acid in 30 ml of ethanol is saturated with anhydrous hydrogen chloride gas. The solution obtained is left to stand for 24 hours Stand at 25 ° C. After evaporation of the solvent, a residue is obtained which is recrystallized from ethanol / ether to give the title compound.

Example 3

2-difluoromethyl-2- (acetylamino) -3- (3,4-dihydroxyphenyl) propionic acid

A stirred solution of 6.8 g of borax in 10 ml of water is mixed with 2.47 g (10 mmol) of 2-difluoromethyl-2-amino-3 - (3,4-dihydroxyphenyl) propionic acid under argon. After 15 minutes, the pH is adjusted to 9 by adding a 2N sodium hydroxide solution. 780 mg of acetyl chloride are then added dropwise, the pH being kept between 9.0 and 9.5. The aqueous solution is washed with ether, adjusted to pH 1 using 6N sulfuric acid and extracted with methylene chloride. The organic phase is dried and evaporated to give the title compound. The corresponding methyl ester is obtained by treatment with ethanolic HCl.

Example 4

2- [2- (difluoromethyl-2-amino-3- (3,4-diacetyloxyphenyl) -1 - oxopropylamino] propionic acid

A solution of 4.66 g (10 mmol) of 2-difluoromethyl-2 - (carbobenzyloxyamino) -3- (3,4-diacetyloxyphenyl) propionic acid, which consists of 2-difluoromethyl-2-amino-3- (3rd , 4-diacetyloxy-phenyO-propionic acid and benzyl chloroformate was prepared, in 50 ml of ether is treated with 1 g (10 mmol) of triethylamine and then with 1.08 g (10 mmol) of eth> ichloroformate, and after one hour at 25 ° C. the precipitate is filtered off, dissolved in ether and then with a solution of alanine benzyl ester (10 mmol) in 30 ml

Ether displaced. The solution is treated at 25 ° C. overnight and then evaporated to dryness. The residue is treated with hydrogen bromide in dioxane (40% w / w; 20 ml) at 25 ° C for 30 minutes. Then ether is added. The precipitated hydrobromide is filtered off to give the title compound.

Example 5

2-difluoromethyl-2- (2-amino-l-oxopropylamino) -3- (3,4-dihydrophenyl) propionic acid hydrochloride

A suspension of 3.56 g (10 mmol) of benzyl-2-difluoromethyl-2-amino-3- (3,4-dihydroxyphenyl) propionate in 50 ml of methylene chloride is treated with 1 g (10 mmol) of triethylamine. Then 10 mmol of N-carbobenzyloxyalanine, in which the acid function was activated by an ethoxycarbonyl group, are added in 10 ml of methylene chloride. The mixture is stirred at 25 ° C. for about 16 hours and then washed with water. The organic layer is dried and evaporated. The residue is taken up in ether. The ether solution is cooled to 0 ° C. A strong stream of HCl gas is blown through this solution for 3 hours. The ether solution is then washed with water. The aqueous phase is separated off and evaporated to give the title compound as a gummy residue.

Example 6

2- (2-A mino-2-difluoromethyl-3-phenyl-l-oxopropylamino) propionic acid

A solution of 3.15 g of N-tert-butoxycarbonyl-a-di-fluoromethylphenylalanine in 30 ml of ether is mixed with 1.01 g of triethylamine and then with an ethanolic solution of freshly distilled ethyl chloroformate (1 g). The reaction mixture is stirred for 3 hours at room temperature. The precipitated triethylamine hydrochloride is filtered off. A solution of 1.45 g of alanine tert-butyl ester in ether is immediately added to the filtrate. The reaction mixture is then kept at room temperature overnight and then evaporated to dryness. The residue obtained is taken up in trifluoroacetic acid. The solution is concentrated. The residue obtained is purified on a resin by ion exchange chromatography to give the title compound.

Example 7

2- (2-amino-l-oxopropylamino) -2-difluoromethyl-3-phenylpropionic acid

A solution of 2.3 g of α-difluoromethylphenylalanine methyl ester in 30 ml of ether is cooled to 0 ° C. and a solution of 2.9 g of N-benzyloxycarbonyl-O-ethoxycarbonylalanine in ether is added under a nitrogen atmosphere. After the addition, the cooling bath is removed and stirring is continued overnight. The solution is evaporated. The syrupy residue is taken up in 5 ml of methanol and 10 ml of 2N ammonia in water.

The reaction mixture is stirred at room temperature overnight and then extracted several times with ether. The aqueous phase is neutralized and the title compound is separated by ion exchange chromatography on an Amberlite IR 120 H + resin.

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Example 8

Methyl 2-difluoromethyl-2-amino-3- (3,4-dimethoxyphenyl) propionate

A solution of 30 g of methyl 2-difluoromethyl-2-benzalimine-3- (3,4-dimethoxyphenyl) propionate in 200 ml of ether is mixed with a solution of HCl (0.5 m; 15 ml). The heterogeneous mixture is stirred at room temperature for 12 hours. The organic phase is separated off and then a solution of HCl (1 m; 200 ml) is added. The reaction mixture is further stirred for 1 hour at room temperature. The aqueous phase is then separated off and concentrated under reduced pressure, the hydrochloride of the title compound being obtained.

Example 9

2-difluoromethyl-2-amino-3- (3,4-dihydroxyphenyl) propionic acid s A solution of 20 g methyl-2-difluoromethyl-2-amino - 3- (3,4-dimethoxyphenyl) propionate hydrochloride in 200 ml of 47% aqueous HBr is refluxed for 12 hours under a nitrogen atmosphere. The solution is concentrated under reduced pressure and the residue obtained is dissolved in 30 ml of water. The pH of the solution is adjusted to 4.5 with a solution of NEt3. Acetone is added until precipitation begins. The dihydrate of the title compound is then filtered off with an mp.> 260 ° C.

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Claims (10)

636846 2nd PATENT CLAIMS 1. Therapeutically effective a-halomethyl amino acids and their derivatives of the general formula I CH2-C-C0R2 (I) NHRi wherein Y is the group FCH2 or F2CH, Rj is a hydrogen atom, an alkylcarbonyl group with a straight or branched chain Cr to C4 alkyl radical or the group O —C — CH — R2Y, NHa wherein R21 is a hydrogen atom, a straight or branched chain Cj to C4 alkyl group, the benzyl or p-hydroxy-benzyl group; R2 is the hydroxyl group, a straight or branched chain Cr to C3 alkoxy group, the group -NR7Re, where R7 and R8 each represent a hydrogen atom or a branched or straight chain Cr to C4 alkyl radical, or the group —NH — CH — COOH I. * 9 represent wherein R9 represents a hydrogen atom, a straight or branched chain Cx to C4 alkyl radical, the benzyl or p-hydroxybenzyl radical; where R ^ R4, R5, R'4 and R0 each have the following meanings: where R10 represents a hydrogen atom, the methyl radical or an alkylcarbonyl radical, in which the alkyl group is straight or branched chain and comprises 1 to 6 carbon atoms, the benzoyl or a phenylalkylene carbonyl radical, where-5 in the alkylene radical is straight or branched chain and 1 to Comprises 6 carbon atoms, and the pharmaceutically acceptable salts thereof. 2. Compounds according to claim 1, characterized in that Rj is a hydrogen atom or a straight or 10 means branched chain Cx to C4 alkylcarbonyl group. 3. Compounds according to claim 1, characterized in that R2 represents a hydroxyl group or a straight or branched chain Ci to C8 alkoxy group. 4. Compounds according to claim 1, characterized in that R10 denotes a hydrogen atom. 5. Compounds according to claim 4, characterized in that Rj is a hydrogen atom and R2 is the hydroxy group. 6. Compounds according to claim 1, characterized in that Y denotes the group FCH2-. 7. A compound according to claim 1, characterized in that Y represents the group F2CH. 8. Compounds according to claim 5, characterized in that Y represents the group F2CH. 25 9. 2-difluoromethyl-2-amino-3- (3,4-dihydroxyphenyl) propionic acid and its pharmaceutically acceptable salts as a compound according to claim 1. 10. 2-difluoromethyl-2-amino-3- (3-hydroxyphenyl) propionic acid and its pharmaceutically acceptable salts as 30 Connection according to claim 1. 11. 2-difluoromethyl-2-amino-3- (4-hydroxyphenyl) propionic acid and its pharmaceutically acceptable salts as a compound according to claim 1. Rs R4 Rs R'4 re H H ORJO H H H ORjj, H H H H ORJO O F e H H ORw H Cl H H H ORjo Cl H H Cl O S3 0 H H H Cl 0 F 0 Cl H h cl, F H ORJO H H OR10 H ch3 h ch3 H H ORJO H ch3 H H ORJO H c2h5 O O H c2h5 h c2h5 H O 0 H O 3 ° 0 H H ORJO 0 F 0 ORJO H H H och3 OH H H H OH och3 H O S3 0 ORJO H H H ORJO H H H H H H O 0 H tert-C4H9 35 1