CH646939A5 - ALPHA HALOGENMETHYL AMINO ACIDS. - Google Patents

Description

The present invention relates to new, pharmaceutically useful α-halomethylamino acids and their derivatives, which are inhibitors of aromatic amino acid decarboxylase.

The amino acids tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine (DOPA), tyrosine and phenyl-15 alanine are metabolized into tryptamine, 5-hydroxytryptamine, 3,4-dihydroxyphenethylamine or dopamine by an aromatic amino acid decarboxylase. Tyramine or phenetylamine 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 there are decarboxylation enzymes specific for DOPA and 5-hydroxytryptophan in the brain.

The aforementioned aromatic amines are known to play a role in various pathophysiological processes. For example, it has been found that tryptamine, the decarboxylation product of tryptophan, is enzymatically methylated to monomethyltryptamine, which in turn is methylated enzymatically to dimethyltryptamine (DMT) in red blood cells, plasma and platelets in humans. The methylating enzyme is found 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 etiology 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 tryptamine levels with removal of the substrate for the formation of DMT. Therefore, an aromatic amino acid decarboxylase inhibitor that blocks the conversion of tryptophan to tryptamine may be useful as an antipsychotic agent.

45 Both 5-hydroxytryptamine (5-HT), the decarboxylation product of 5-hydroxytryptophan, and 3,4-dihydroxyphenethylamine (dopamine), the decarboxylation product of DOPA, play a role in peripheral and central physiological processes and agents which are effective for regulating the levels of these amines have led to 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 55 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 anti-man 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 that converts 5-hydroxytryptophan and DOPA to 5-HT and 65 dopamine, respectively, may be useful as antipsychotic agents or major tranquilizers in the treatment of manic conditions.

It has also been shown that agents used for Hem

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Decarboxylation of DOPA to dopamine are useful for the treatment of Parkinsonism when administered simultaneously with exogenous DOPA or L-DOPA. Parkinsonism is believed to be due, at least in part, to decreased central dopamine levels, 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. Administration of DOPA or L-DOPA together with a peripheral inhibitor of the enzyme that converts DOPA to dopamine reduces the amount of L-DOPA that must be administered in order to have sufficient circulatory levels for central absorption. Other advantages are also achieved by administering an aromatic amino acid decarboxylase 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-hydroxy-tryptamine (5-HT) are lower in patients with depressive syndromes than in those without such syndromes. The administration of exogenous L-5-hydroxytryptophan (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 for treating 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 responsible for anaphylactoid reactions in humans and bronchoconstriction in asthmatics, and agents that counter or inhibit 5-HT formation are in the treatment of these conditions useful. It is known that 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; as a result, they are useful pharmacological agents.

The compounds according to the invention have the following general formula

Rs

In this general formula I, Y is the group FCH2, F2CH, CICH2 or CI2CH, Ri is a hydrogen atom, an alkylcarbonyl group in which the alkyl radical comprises 1 to 4 carbon atoms and is straight or branched chain, an alkoxycarbonyl group, in which the alkoxy radical comprises 1 to 4 carbon atoms and is straight or branched chain, or the group

O

II

-C-CH-R27 I

NH2

in R27 is a hydrogen atom, a straight or branched chain Cr to Gt alkyl group which is benzyl or p-hydroxybenzyl group; R2 is the hydroxyl group, a straight or branched chain Cr to Cs alkoxy group, the group -NR7R8, in which R7 and Rg are each a hydrogen atom or a straight or branched chain Cr to Gt alkyl group, or the group

-NHCH-COOH

I.

R9

in R9 is a hydrogen atom, a straight or branched chain Cr to Gt alkyl group which is benzyl or p-hydroxybenzyl group; while R3, R4, R5, R'4 and Rö each have the meanings given in Table I below:

Table I

r3

r4

r5

r'4

Re oh ch3

h h

h h

oh ch3

h h

oh h

ch3

h h

Oh

OCH3

h h

h oh h

oh h

h oh h

h h

ch3

oh h

OCH3

h h

oh h

h oh h

oh ch3

oh h

h oh h

h h

Oh

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The invention further comprises the pharmaceutically acceptable salts and individual optical isomers of the compounds of the general formula 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.

Compounds of formula X and their preparation are also described. These compounds are useful chemical intermediates in the preparation of compounds of Formula I wherein Y is FCH2-.

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

O

II

Alkyl-C-

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

The group is called "benzoyl group"

0

Roger that.

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

the methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, tert-pentoxy, n-hexyloxy and n-octyloxy group.

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

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. 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, e.g. sodium, potassium and lithium, alkaline earth metals, e.g. calcium, and magnesium, light metals of group IIIA, e.g. aluminum, and organic amines, e.g. primary, secondary or tertiary amines, for example cyclohexylamine, ethylamine, pyridine, methylaminoethanol, ethanolamine and piperazine. The salts are made by conventional methods.

Preferred compounds according to the invention are those of the general formula I in which R] is a hydrogen atom or an alkylcarbonyl group in which the alkyl radical comprises 1 to 4 carbon atoms and is straight or branched chain, compounds in which Ri is a hydrogen atom being particularly preferred are. Another preferred embodiment of the invention are the compounds of the general formula I in which R2 is the hydroxyl group or a straight-chain or branched-chain Cr to C8 alkoxy group. Compounds in which R2 is the hydroxy group are particularly preferred. Compounds of the general formula I in which R3, R4, R'4, R5 and Rö each represent a hydrogen atom represent another preferred embodiment of the invention. Compounds of the general formula I in which Y denotes the group FCH2- or F2CH- are also preferred.

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

2-difluoromethyl-2-amino-3-phenylpropionic acid, 2- [(2-difluoromethyl-2-amino-1-oxo-3-phenyl) propylamino] - dihydrocinnamic acid,

2-chloromethyl-2-amino-3-phenylpropionic acid amide, 2-fluoromethyl-2-amino-3- (3-hydroxy-4-methylphenyl) propionic acid, and 2-difluoromethyl-2-amino-3- (2-hydroxy -4-methylphenyl) propionic acid.

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-hydroxytryptamine, 3,4-dihydroxyphenylethylamine, tyramine and phenethylamine metabolically catalyzed. As already mentioned above, results of studies show that the enzyme responsible for the conversion of the abovementioned 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-hydroxytryptophan and 3,4-dihydroxyphenylalanine, respectively, while the remaining amino acids mentioned above are converted enzymatically into the corresponding amines by a non-specific aromatic amino acid decarboxylase . 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 refers 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 when administering 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 pharmacological uses. As peripheral, irreversible inhibitors of aromatic amino acid decarboxylase, the compounds of the formula I are useful for the treatment of Parkinsonism when they are administered together with 3,4-dihydroxyphenylalanine (DOPA) or L-3,4-dihydroxyphenylalanine (L-DOPA). DOPA and in particular the active isomer L-DOPA are known to be effective for the treatment of Parkinsonism,

if they are systemically administered usually in an amount of 0.5 to 1 g per day initially, after which the amount administered is gradually increased to the maximum tolerated daily dose of about 8 g within a period of 3 to 7 days. Simultaneous administration of a compound of general formula I and L-DOPA represents an improved method of treatment for Parkinsonism in that the compounds of formula I peripherally block the decarboxylation of L-DOPA to L-3,4-dihydroxyphenethylamine (L-dopamine), by inhibiting the activity of the aromatic amino acid decarboxy-lase enzyme and thus maintaining high levels of L-DOPA in the circulation for central absorption 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 if

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the L-DOPA is administered alone. It is preferred to administer the compounds of the invention prior to the administration of L-DOPA. For example, a compound of the formula can be administered 130 minutes to 4 hours before the administration of L-DOPA, depending on the route of administration and the condition of the patient to be treated.

The compounds of general formula I are also useful for the treatment of depressive syndromes when administered together with 5-hydroxytryptophan (5-HTP) or in particular with the active levo isomer, which is known to be useful for the treatment of depression when it is systemic is administered. 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 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 action on aromatic amino acid decarboxylase, the compounds of the general formula I are also suitable for the treatment of rheumatoid arthritis, carcinoid syndrome and anaphylacoid reactions in humans and bronchoconstriction in asthmatics and other conditions usable, which are known to be caused by high peripheral 5-hydroxy-tryptamine levels.

As indicated above, it has been shown that agents that reduce the elevated levels of 5-HT and norepinephrine, the hydroxylation product of dopamine, are useful for 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 general formula I as irreversible inhibitors of aromatic amino acid decarboxylase can be demonstrated as follows. A compound of formula I is administered as an aqueous solution or suspension to rats or mice. At different times, the animals are killed 1 to 48 hours after administration of the compound to be tested and the aromatic amino acid decarboxylase activity is determined by the radiometric method according to Christenson et al., Arch. Biochem. Biophys., Vol. 141, p. 356 (1970) in homogeneous kidney of the heart and brain measured according to the method of Burkard et al., 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 injected intranasally 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 will vary from about 0.1 mg / kg to 100 mg / kg of the patient's body weight per dose, preferably 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 varies from about 25 to 500 mg / kg body weight of the patient per day, preferably from about 50 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 10 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 e.g. Corn starch, potato starch or alginic acid, and a lubricant such as e.g. Stearic acid or magnesium stearate, tableted. 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 like 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. Sili5

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Use 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 further, if necessary or desired, with the usual auxiliaries, e.g. Colourants and wetting agents. The compounds can also be in a non-pressurized form, e.g. in a nebulizer or sprayer.

What has already been mentioned above, the compounds I according to the invention are used in particular together with exogenous L-DOPA, individual formulations of a compound according to the invention and L-DOPA being able to be administered, or both active compounds can be formulated into a single pharmaceutical combination preparation. In both types of use, the amount of the compound of the formula I varies in comparison with the amount of L-DOPA to be administered, from about 1: 1 to 1: 10. A combination preparation can have an inner part containing L-DOPA and an outer part Include 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 pressing 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 one contains suitably formulated 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 such as e.g. Ethyl cellulose or cellulose acetate phthalate. It is also possible to use a formulation 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 r 3 y

Rs-0> -CH2-Ç-C0NH i ^

J-n ^ -CH2X II

NHRi ^ no

0 C00M

In this formula, Y, R 1, R 3, R 4, R 5, R 4 and R 6 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, Ce-phalothin 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 formula II, their salts and isomers can be incorporated in 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.

Examples of cephalosporin derivatives of the general formula II are as follows:

7 - [(2-Acetylen-2-amino-3-phenylpropionyl) amino] -3-acetyloxy-methyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-en-2- carboxylic acid, 7 - [(2-acetylene-2-amino-3- <3-hydroxyphenyl> propionyl) - amino] -3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo [4.2.0] - oct-2-en-2-carboxylic acid,

7 - [(2-acetylen-2-amino-3- <3,4-dihydroxyphenyl) propionyl) -

-amino] -3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-

-2-en-2-carboxylic acid,

7 - [(2-acetylen-2-amino-3- <4-hydroxyphenyI> propionyl) -

-amino] -3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-

-2-en-2-carboxylic acid.

The compounds of the general formula II in which Rj is a hydrogen atom are prepared, for example, by coupling 7-aminocephosphosporanic acid or a derivative thereof of the general formula

COOK

wherein X and M have the meanings given in connection with the general formula II, with an acid of the general formula ch2-c-cooh or a functional derivative thereof, e.g. the acid chloride or an acid anhydride, when the free acid is used, in the presence of a dehydrating agent such as e.g. Dicyclohexylcarbodiimid, where R3ï R4, R5, R'4 and Re have the meanings given in connection with the general formula II and the amino group with

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a suitable protecting group, e.g. the tert-butoxycar- 'bonyl group, is protected, after which the amino protective groups are 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 bicar bonate. 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 are usually separated by conventional methods. The compounds of general formula IV are generally prepared by the processes described above, while the compounds of formula III are commercially available or can be prepared by known processes.

The compounds of the general formula II, in which Ri has a meaning other than hydrogen, are expediently prepared from the corresponding derivatives, in which Ri is a hydrogen atom, by the general processes described below for compounds of the general formula I in which Rj is another Meaning as hydrogen.

The compounds of the general formula I in which Ri represents a hydrogen atom, R2 represents a hydroxyl group and R3 and R4 each represent the group OR10, in which Rio represents a hydrogen atom or R4 and R5 each represent OR10, in which Rio represents a hydrogen atom, or R4 and R5 together the group -0-CH2-0- or in which R3, R4, R5, R'4 and R6 have the meaning given in Table I, with the exception that Rio is the methyl group, are prepared by protecting one appropriately Phenylpropionic acid esters of the general formula V

R12 Rh

CH2-CH-C0Ra (V)

/ \ NH = C-RU

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

-CH2- (CH2) m-CH2-

where m is an integer from 3 to 5. Specific examples of straight-chain or branched-chain C 1 -C 6 -alkyl groups which Rb and Rc can represent are the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.-butyl, n- Hexyl, n-octyl and the neopentyl group. The radicals Rn, Ri2, R13, R'i2 and R14 each have the meaning given in Table II below:

Table ii

Marg

Rl2

R13

R'l2

R14

OCH3

ch3

H

H

H

H

och3

ch3

H

H

OCH3

H

ch3

H

H

OCH2Ph och3

H

H

H

och3

H

OCH3

H

H

och3

H

H

H

ch3

OCH2Ph

H

OCH3

H

H

OCH3

H

H

OCH3

H

OCH3

ch3

och3

H

H

och3

H

H

H

OCH3

Suitable strong bases which can be used in the above reaction step to form the carbanion intermediate include those which can withdraw a proton from the carbon atom in the a-position with respect to the carboxyl group, for example alkyl lithium, such as butyllithium or phenyllithium, Lithium dialkyl amide, such as lithium diisopropylamide, or lithium amide, 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 halomethylating agents that can be used in the above reaction are, for example, chlorofluoromethane, bromofluoromethane, fluoroiodomethane, chlorodifluoromethane, bromodifluoromethane, difluoroiodomethane, bromochloromethane, dichloromethane, chloroiodomethane, bromodichloromethane and dichloroiodomethane. The halomethylating agents are known.

The halomethylation can be carried out in an aprotic solvent, for example benzene, toluene, ethers, tetrahydrofuran, dimethyl sulfoxide or hexamethylphosphoric acid triamide. 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.

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

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 is usually performed with dilute acid to remove any amine protecting groups. This is followed expediently by treatment with concentrated acid at temperatures of about 25 to 125 ° C. over a period of about 1 to 3 days in order to remove all ester or ether groups. Gradual hydrolysis is preferred.

The compounds of formula I, wherein Y is -CH2F, Ri is hydrogen, and each of the symbols R3, R4, R5, R'4 and Rö has the meanings as defined in Table I, are preferably also prepared according to the following reaction scheme :

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r t 2 r 1 1 R i 3 - ^ C H gX <

Mg i z rl 4

Ri2 Rii

-) Ri3 - ^ - CHgMcX, R112 R i 4

(VII)

NCCHsF

(VI! I)

Ria Rii

Rl3 ~ ^ ~ / ~ Ch r '1 2 r 1 4

R12 R11

-Ç-CHaF R: = ^>: a = -Ç-CHaF

/ - (NMgXa r '1 2 r 1 4

(X)

4 * 5

R'12 R14

r 4 r3

JTL

w r! 4 ra

(XI)

(IX)

CK a F CHa-C-COCH NH2

(XII)

In the above reaction sequence, Xa means chlorine or bromine. Rn, r12, r13, R'12 and rh have the meanings defined in Table II, R3, R4, Rs, R'4 and R6 as defined in Table I.

According to the preferred reaction sequence shown above, a benzyl halide is added very slowly to magnesium shavings in a suitable ethereal solvent such as tetrahydrofuran, diethyl ether or mixtures thereof and the mixture is left for 30 minutes to 24 hours at a temperature of about −20 ° C. to 70 ° C. preferably from about 25 ° C to the boiling point of the solvent. A trace of methyl iodide is added at the start of the reaction. In general, the reaction is carried out in tetrahydrofuran.

To the Grignard derivative thus formed, fluoroacetonitrile is added in a ratio of 0.5 to 3.0 in an aprotic solvent such as e.g. Tetrahydrofuran, diethyl ether, dioxane, benzene, dimethoxyethane, dimethoxymethane or mixtures thereof. The reaction temperature during the addition of fluoroacetonitrile can be from about -20 ° C to -70 ° C, preferably from about -20 ° C to -25 ° C, and the reaction time from about 10 minutes to 12 hours, preferably from 10 minutes to 1 Hour, vary. This gives ketimine salts of the formula IX, which are hydrolyzed with acid to the ketone. Acid hydrolysis can be accomplished by emptying the ketimine salt onto water and concentrated HCl and maintaining a strongly acidic environment. The ketone of formula X can be isolated in the usual ways, for example by extraction with petroleum ether, pentane or hexane and then with ethers such as diethyl ether.

Under the conditions of a Strecker synthesis, the ketone is converted into the amine nitrile of the formula XI by either using 1 to 10 equivalents of sodium cyanide and an ammonium salt, for example ammonium chloride, either in a basic medium using aqueous ammonium hydroxide (1 molar to concentrated) ) in a lower alcohol, such as Methanol or ethanol, or treated in a neutral medium using water and a lower alcohol.

The hydrolysis of the amine nitrile to the amino acid of the formula XII can be achieved in various ways.

For example, one can hydrolyze by treating with 40 hydrogen bromide at about 25 ° C to 100 ° C for about 1/2 to 24 hours.

It can also be hydrolyzed with sulfuric acid by well known methods.

Hydrolysis can also be achieved by treatment with a lower alcohol, such as methanol, which has been saturated with water-free hydrogen chloride for 1 to 24 hours, preferably 10 hours, at about 0 ° C to 50 ° C, preferably about 25 ° C , whereby the corresponding amino amide is obtained, which is hydrolyzed by treatment with aqueous hydrochloric acid or 50% aqueous sulfuric acid for about 2 to 6 50 hours at about 60 ° C to 100 ° C, preferably 95 ° C, followed by neutralized with barium hydroxide when using sulfuric acid.

The closest prior art regarding the preparation of the ketones of formula X is the known process 55 for the preparation of fluoromethyl-m-tolyl ketone [E. D. Bergmann et al., J. Chem. Soc. 3452 (1961)]. The process described in the above reaction sequence can, however, be easily distinguished from it and also offers certain advantages over the prior art. First, in this procedure described here, the Grignard reagents are benzylic. Second, the temperature of the reaction mixture must be kept at -20 ° C or below during the Grignard addition. Third, finally, the fluoroacetonitrile reagent used in the present process is much less toxic than the monofluoroacetic acid derivatives used in the prior art to make the fluoromethyl ketone.

The compounds of the general formula I in which R 1 is hydrogen, R 2 is the hydroxyl group and the radicals R 3, R 4, R 4

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or R5 each represent the group -OH, are generally prepared by reacting the corresponding derivative in which the radicals R3, R4, R'4 or R5 each represent the group -OCH3 with hydrogen bromide in water or acetic acid at temperatures of treated at about 25 to 125 ° C in a period of about 4 to 24 hours.

The compounds of the general formula I in which R2 represents a straight or branched chain C 1 -C 4 -alkoxy group are prepared by treating the corresponding derivatives in which R 2 is a hydroxyl group with thionyl chloride to form the acid chloride. The acid chloride obtained is mixed with an alcohol of the general formula

R23-OH

in which R23 represents a straight or branched chain Q-Cs-alkyl group, for example the methyl, ethyl, n-propyl, iso-propyl, 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 —NR7Rs, in which R7 and Rg each denote a hydrogen atom or a straight-chain or branched-chain Ci-C4-alkyl group, are obtained by an acylation reaction of an acid halide, for example an acid chloride, of the produced corresponding compound in which R2 represents the hydroxyl group and Rj has the meaning according to formula I. However, this is 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, Rs or R'4 each represent the group OR10 and Rio the hydrogen atom, these groups how to protect the corresponding alkylcarbonyloxy group with an excess of a suitable amine represented by the formula

HNR7RS

can be represented. The reaction is 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 hexamethylene tetramine, primary amines such as methylamine, ethylamine or n-propylamine, and secondary amines such as dimethylamine, di-ethylamine 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 hydrolysis. The hydroxy protecting group is suitably removed by basic or acid hydrolysis.

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

-NH-CH-COOH

I.

Rs are prepared by preparing the corresponding derivative in which R2 is a hydroxy group or a functional derivative thereof, for example an acid anhydride, and Ri has the meaning given in formula I, with the proviso that each free amino group is replaced by a suitable one Protecting group, for example the benzyloxycarbonyl or tert-butoxycarbonyl group, is protected with a compound of the general formula

NH2-CH-COOR24

!

R9

in which R9 has the meaning according to formula I and R24 is a lower alkyl group, for example the methyl or 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 implements. This is followed by acid hydrolysis to remove the protective groups with the proviso that if a free acid has been used as the amino protective group, the reaction is carried out with a dehydrating agent, for example dicyclohexylcarbodiimide.

The compounds of 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, are prepared by the corresponding derivatives in which R 1 is the hydrogen atom and R 2 is the hydroxyl group , with an acid halide of the general formula

O

II

R25-C-halo in the halo is a halogen atom, for example the chlorine or bromine atom, and R25 is a straight-chain or branched-chain C1-C4-alkyl group in water in the presence of a base such as sodium hydroxide or sodium borate at temperatures from 0 to 25 ° C treated 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 with 1-8 carbon atoms, by treatment with an acid halide of the above general formula

0

II

R25-C-halo in water, methylene chloride, chloroform or dimethylaceta-mid 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 the general formula I in which Ri represents an alkoxycarbonyl group, in which the alkoxy group is straight or branched chain and has 1-4 carbon atoms, are prepared by the corresponding derivative in which Ri denotes the hydrogen atom and R2 denotes the hydroxyl group, with an alkyl haloformate of the general formula

O

II

halo-C-OR26

in which a halogen atom, for example the chlorine or bromine atom, and R26 represent a straight-chain or branched-chain C1-C4-alkyl group, in water in the presence of a base, such as sodium hydroxide or sodium borate, at temperatures of about 0-25 ° C. in one Treated period of about 0.5 to 6 hours.

The compounds of general formula I, in the Ri the formula

O

II. :.

-C-CH-R27 '•'

1

NH2

in R27 the hydrogen atom, a straight-chain or branched-chain lower-Ci-Ct-alkyl group, the benzyl or p-hydroxy

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represents benzyl group, are prepared by the corresponding derivative in which Ri represents the hydrogen atom and R2 represents a straight or branched chain Ci-C8 alkoxy group with an acid of the general formula

HOOC-CH-R27

I.

NH2

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 R27 has the above meaning, in an ether such as tetrahydrofuran or dioxane, methylene chloride or chloroform and in Presence of a dehydrating agent, if the free acid is used, is treated at temperatures of about 0 to 35 ° C for a period of about 1 to 12 hours. The acidic and basic hydrolysis is then carried out to remove the protective groups. If necessary, the basic hydrolysis can be omitted, the ester peptide derivative being obtained.

The individual optical isomers of the compounds of the general formula I, in which Ri represents the hydrogen atom and R2 represents the hydroxyl group, can be obtained using the (+) or (-) - binaphthylphosphoric acid salt by the method of R. Viterbo et al., Tetrahedron Letters, Vol 48, S, 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 be obtained, as described for the racemate, if the corresponding optically separated amino acid is used.

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

CH2-CORa

I VI

NH = C-Rb

I.

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

R '1 2 Ri-4

in which Rn, Ri2, R13, R'12 and RM 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 be carried out in an aprotic solvent, for example benzene, ether, tetrahydrofuran, dimethyl sulfoxide or hexamethylphosphoric acid triamide. The reaction time is about 0.5 to 24 hours, the temperature is about -120 to + 25 ° C.

The compounds of general formula VI can be prepared by treating an appropriate alkyl glycinate with a compound having a carbonyl group to form a Schiff's base in a conventional manner. Special will

(a) if Rb represents the hydrogen atom, the corresponding amino acid ester with benzaldehyde or a straight-chain or branched-chain C1-C9 alkanal, for example 1-propanal, 1-butanal, 2,2-dimethylpropan-l-al or 2,2-diethylbutane -l-al,

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

(c) when Rb is a straight-chain or branched-chain Ci-C8-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, treated with dimethyl isopropyl ketone, di-n-butyl ketone or methyl tert-butyl ketone. Such compounds containing a carbonyl 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 with a benzoyl halide, for example the chloride, or 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-diethylbutyric 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, implemented. The reaction mixture is then allowed to warm to about 25 ° C. in one hour. The amide derivative obtained is reacted with an alkylating agent such as methyl fluorosulfonate, dimethyl sulfate, methyl iodide, methyl p-toluenesulfonate or trimethyloxonium hexafluorophosphate if Rb is the methoxy group or with triethyloxonium tetrafluoroborate if Rb is the ethoxy group at about 25 ° C combined in a chlorinated hydrocarbon as a solvent, for example methylene chloride, chlorobenzene or chloroform. This reaction mixture is refluxed for about 12-20 hours. The mixture is then allowed to cool to about 25 ° C. and an organic base, for example triethylamine or pyridine, is added. The solution is then extracted with a saline solution and the product is separated off.

If in the compounds of the general formula VI Rb and Rc together form an alkylene group with 5-7 carbon atoms, the corresponding amino acid ester derivatives are obtained by forming the amino acid ester with a cyclic alkanone, for example cyclopentanone, cyclohexanone and cycloheptanone a ship's base treated in a manner known per se.

The alkyl glycinates are 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 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 obtained from the corresponding benzaldehyde by reduction with sodium borohydride, lithium aluminum hy5

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drid 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 benzylalkchole derivative obtained being treated, for example, with thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride.

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 alkylglycinato 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 preparation 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.

Preparation 1

7 - [(2-Difluoromethyl-2-amino-3-phenylpropionyl) aminoJ - 3-acetyloxymethyl-8-oxa-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-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and 1 g of 2-difluoromethyl-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 Examples 1 to 3 illustrate pharmaceutical formulations of the compounds according to the invention.

Formulation 1

Contains a formulation for hard gelatin capsules

(a) Compound 20 mg according to the invention

(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.

Formulation 2

A formulation for tablets has the following compositions:

(a) Compound 20 mg according to the invention

(b) Strength 43 mg

(c) Lactose 45 mg

(d) Magnesium stearate 2 mg

The granules obtained after mixing the lactose with the compound (a) and part of the starch and granulated with the starch paste are dried, sieved and mixed with the magnesium stearate. The mixture is then pressed into tablets each weighing 110 mg.

Formulation 3

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

% By weight

(a) Compound 1.0 according to the invention

(b) Polyvinyl pyrrolidone 0.5

(c) Lecithin 0.25

(d) water for injections, to 100.0

The substances a-d are mixed, homogenized and filled into 1 ml ampoules, which are then melted off and treated in an autoclave at 121 ° C. for 20 minutes; Each ampoule contains 10 mg / ml of the compound a.

Production Example 1

2-Amino-2-fluoromethyl ~ 3- (3-hydroxy-4-methylphenyl) propionic acid a) Preparation of 2-amino-2-fluoromethyl-3- (3-methoxy-4-methylphenyl) propionitrile

A mixture of l-fluoro-3- (3-methoxy-4-methylphenyl) -2-propanone (4.81 g, 0.0245 mol), ammonium chloride (2.62 g, 0.049 mol) and 28% aqueous Ammonia (32.5 ml) was treated with sodium cyanide (2.40 g, 0.049 mol) and the mixture was stirred at room temperature for five days under a nitrogen atmosphere. The oil which had separated was extracted with ether, the ethereal extracts were washed with a saturated solution of sodium chloride in water and dried over magnesium sulfate. After evaporation of the ether, an oily residue remained (4.65 g), which mainly consisted of the target compound 2-amino-2-fluoromethyl-3- (3-methoxy-4-methylphenyl) propio-nitrile, as by means of NMR can be seen.

The corresponding hydrochloride was precipitated in ether by dropwise addition of a saturated solution of HCl in ether to an ethereal solution of 2-amino-2-fluoromethyl-3- (3-methoxy-4-methylphenyl) propio-nitrile.

b) Preparation of 2-amino-2-fluoromethyl-3- (3-methoxy - 4-methylphenyl) propionamide hydrochloride

A solution of 2-amino-2-fluoromethyl-3- (3-methoxy-4-methylphenyl) propionitrile hydrochloride (3.30 g, 0.0127 mol) in anhydrous methanol (50 ml) was washed with dry HCl with ice cooling saturated. After evaporation of the solvent, the amide hydrochloride was obtained as a yellow solid (3.35 g, 95%). It was recrystallized from ethanol / ether.

NMR (CD3OD): 1.78 ppm (s, 3H); 2.93 ppm (m, 2H); 3.43 ppm (s, 3H); 4.40 ppm (d, Jhf = 45 Hz, 2H); 4.52 ppm (s, broad, 4H); 6.30-6.82 ppm (m, 3H).

c) Preparation of 2-amino-2-fluoromethyl-3- (3-hydroxy - 4-methylphenyl) propionic acid

A solution of 2-amino-2-fluoromethyl-3- (3-methoxy-4-methylphenyl) propionamide hydrochloride (3.00 g, 0.0108 mol) in 47% aqueous hydrobromic acid (50 ml) was added under nitrogen heated at a temperature of 100 ° C for 20 hours. The solution was evaporated to dryness under reduced pressure, the residue was dissolved in isopropanol, the ammonium bromide was filtered off, and the iso-

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propanol was evaporated. Triethylamine was added to a solution of the residue in isopropanol until the pH reached 5. The precipitated solid was filtered off and recrystallized from water to give 2-amino-2-fluoromethyl-3- (3-hydroxy-4-methylphenyl) propionic acid (1.60 g, 65%). Melting point: 213 ° C.

Production Example 2 2-Amino-2-fluoromethyl-3- (2,4-dihydroxyphenyl) propionic acid a) Production of 2,4-dimethoxybenzyl triphenylphosphonium chloride

A mixture of 2,4-dimethoxybenzyl chloride (55.950 g, 0.30 mol), triphenylphosphine (78.600 g, 0.30 mol) and benzene (400 ml) was refluxed for 48 hours. The solid which was separated out was filtered off and recrystallized from a dichloromethane / benzene mixture to give hygroscopic crystals of 2,4-dimethoxybenzyl triphenylphosphonium chloride (42 g). These were used for the next stage.

b) Preparation of 2-ethoxy-l-fluoro-3- (2,4-dimethoxy-phenyl) prop-2-ene

To a suspension of finely divided 2,4-dimethoxybenzyl-triphenylphosphonium chloride (13.60 g, 0.030 mol) in anhydrous benzene (45 ml) was added a solution of sodium hexamethyldisilazane (0.030 mol) in anhydrous benzene (48 ml) and the mixture was heated under reflux for one hour under nitrogen. The cooled solution was filtered under nitrogen and treated with ethyl fluoroacetate (3.18 g, 0.030 mol). The stirred mixture was refluxed under nitrogen until the deep red color disappeared (6 days).

The benzene was evaporated under slightly reduced pressure and the residue was dissolved in anhydrous ether. The solid triphenylphosphine oxide was filtered off and the filtrate was concentrated under reduced pressure. Distillation of the residue gave 2-ethoxy-l-fluoro-3- (2,4-di-methoxyphenyl) prop-2-ene.

Boiling point 110 ° C / 0.05 mm Hg (2.650 g, 36%)

NMR (CDCI3): 1.35 ppm (t, Jhh = 7 Hz, 3H); 3.80 ppm (s, 6H); 4.01 ppm (q, Jhh = 7 Hz, 2H); 4.95 ppm (d, Jhf = 48 Hz, 2H); 6.05 ppm (d, J = 6 Hz, 1H); 6.33-8.00 ppm (m, 3H).

c) Preparation of l-fluoro-3- (2,4-dimethoxyphenyl) -2-propanone

2-Ethoxy-l-fluoro-3- (2,4-dimethoxyphenyl) prop-2-ene (1,900 g, 0.008 mol) was stirred with a saturated solution of hydrogen chloride in ether (40 ml) overnight. Water (30 ml) was added and stirring continued for an additional hour. The ether layer was separated, washed with water and dried over magnesium sulfate. After evaporation of the solvent, 1-fluoro-3- (2,4-dimethoxyphenyl) -2-propanone (1.450 g) was obtained.

Yield: 86%

NMR (CDCI3): 3.53-3.83 ppm (m, 8H); 4.82 ppm (d, Jhf = 48 Hz, 2H); 6.23-7.06 ppm (m, 3H).

d) Preparation of 2-amino-2-fiormethyl-3- (2,4-di-methoxyphenyl) propionitrile

A mixture of l-fluoro-3- (2,4-dimethoxyphenyl) -2-pro-panon (1.450 g, 0.0068 mol), ammonium chloride (0.728 g, 0.0136 mol) and 28% aqueous ammonia (9 ml) was treated with sodium cyanide (0.666 g, 0.0136 mol), and that

Mixture was stirred at room temperature for 3 days under nitrogen. The oil which had separated was extracted with ether, the ethereal extracts were washed with a saturated solution of sodium chloride in water and dried over magnesium sulfate. After evaporation of the ether, an oily residue (1.550 g) remained, which mainly consisted of the intended 2-amino-2-fiormethyl-3- (2,4-dimethoxyphenyl) propionitrile, as shown by NMR.

10 e) Preparation of 2-amino-2-fluoromethyl-3- (2,4-di-hydroxyphenyl) propionic acid

A solution of the crude 2-amino-2-fluoromethyl-3- (2,4-di-methoxyphenyl) propionitrile (1.520 g, 0.0063 mol) in 47% aqueous hydrobromic acid (50 ml) was left under nitrogen at a temperature heated from 100 ° C for 20 hours. The solution was evaporated to dryness under reduced pressure, the residue was dissolved in isopropanol, the ammonium bromide was filtered off and the isopropanol was evaporated. Triethylamine was added to a solution of the residual 20-des in isopropanol until the pH reached 5. The precipitated solid was filtered off and recrystallized from water to give 2-amino-2-fluoromethyl-3 - (2,4-dihydroxyphenyl) propionic acid (0.380 g, 26%).

Melting point: 248 ° C with decomposition. 25 NMR (DjO / DCl): 3.17 ppm (m, 2H); 4.95 ppm (2AB, JAB = 11 Hz, JHF = 45 Hz, 2H); 6.30-7.10 ppm (m, 3H).

Production Example 3

2-Amino-2-fluoromethyl-3- (2,5-dihydroxyphenyl) propion-30 acid dihydrate

40 0h a) Production of monofluoroacetonitrile fch2conh2 | ^ - »fch2cn 45 hmpa

A stirred mixture of phosphorus pentoxide (200 g), fluoroacetamide (150 g) and hexamethylphosphoramide (500 ml) in a 2 liter reaction vessel, which is equipped with a simple 50 distillation head, a distillation condenser and a collecting vessel, which contains a mixture of solid carbon dioxide and Acetone was cooled, was equipped, was slowly heated to a temperature of 50 ° C and a pressure of 90 mm Hg. A violent reaction started at this temperature and fluoroacetonitrile began to distill at a temperature of 38 ° C.

After the violent reaction stopped (approximately 3 minutes) the temperature of the oil bath was slowly raised to 140 ° C and the remaining fluoroacetonitrile was collected at 60 a temperature of 38-50 ° C. The fluoroacetonitrile (111 g; 96.5%) was obtained as a colorless liquid. NMR showed that it contained traces of hexamethylphosphoramide, which can be removed by redistillation, but its presence is not a problem in 65 Grignard reactions.

The residue in the reactor vessel can be emptied into waste containers and the reactor can be cleaned with ethanol in the usual way for reuse.

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b) Preparation of 2,5-dimethoxybenzyl chloride

OMe OMe

SOCI;

2,4,6-collidine

OMe

Thionyl chloride (108 g) was slowly added to a stirred mixture of 2,5-dimethoxybenzyl alcohol (150 g), 2,4,6-collidine (108 g) and methylene chloride (750 ml) at room temperature over an hour. The reaction was slightly exothermic. After stirring for an additional 30 minutes, the mixture was washed with hydrochloric acid (2N) and water before being dried (MgS04) and concentrated. The residue of 2,5-dimethoxybenzyl chloride crystallized (127 g). Found: C 57.93, H 5.94; CpHnCl requires: C 57.92, H 5.94%.

(NB: 2,6-lutidine can be used instead of 2,4,6-collidine).

c) Preparation of 2-amino-2-fluoromethyl-3- (2,5-dimeth-oxyphenyl) propionitrile hydrochloride

OMe

NMgCl

-i /

OMe

Oh

NaCN

NH.C1

UMe

Ethyl bromide (2 ml) was added to magnesium shavings (25 g; 1 mol), which were covered with anhydrous tetrahydrofuran, at room temperature and under nitrogen. After the reaction started, 2,5-dimethoxy-benzyl chloride (102.5 g; 0.55 mol) in anhydrous tetrahydrofuran (200 ml) was added slowly at such a rate that gentle reflux was effected. After stirring for an additional hour, the Grignard solution was decanted from excess magnesium (11.7 g), cooled to a temperature of -35 ° C, and with a solution of fluoroacetonitrile (33.6 g; 0.59 mol) anhydrous tetrahydrofuran (200 ml) treated dropwise while maintaining a nitrogen atmosphere throughout the process. The mixture was stirred for a further hour at a temperature of -35 ° C and then poured into a stirred solution of sodium cyanide (55 g) and ammonium chloride (88 g) in water (1 liter) at a temperature of 10 ° C.

After stirring for 30 minutes, the organic phase was separated, the aqueous phase was saturated with sodium chloride and extracted with ether (2 ×). The combined organic phases were charcoaled, dried over magnesium sulfate and concentrated to give an oil (112 g). A solution of the oil in anhydrous ether was treated with ethereal hydrogen chloride and the precipitated oil was crystallized by rubbing. The solid was filtered off and washed well with ether to give the crude 2-amino-2-fluoromethyl-3- (2,5-dimethoxyphenyl) propionitrile hydrochloride (80 g, 53%). NMR (D20) Figure 1.

d) Preparation of 2-amino-2-fluoromethyl-3- (2,5-di-methoxyphenyl) propionamide hydrochloride

• OMe

CONH.

MeOH

7 "

HCl

HCl

HCl

OMe

The nitrii (80 g) described above was dissolved in a minimal amount of methanol and treated with an equal volume of methanol saturated with hydrogen chloride at a temperature of 0 ° C. The mixture was left in a refrigerator overnight, then concentrated, and the residue was crystallized by rubbing under ether to give -amino-2-fluoromethyl-3- (2,5-dimethoxyphenyl) propionamide hydrochloride ( 68 g, 80%) was obtained. NMR [CDCI3 + (CDa ^ CO] Figure 2.

e) Preparation of 2-amino-2-fluoromethyl-3 ~ (2,5-di-hydroxyphenyl) propionic acid dihydrate

HBr

0H

CONH.

A mixture of the amide described above (68 g) in 47% hydrobromic acid (250 ml) was refluxed under nitrogen overnight, the hot solution was treated with activated carbon, filtered and evaporated to dryness. The added dioxane was evaporated, the residue was treated twice to remove the last traces of water. A solution of the residue in isopropanol was filtered to remove ammonium bromide and concentrated to an amount of about 250 ml. The pH of the solution was adjusted to a value of about 5 by adding triethylamide in isopropanol. The product started to crystallize at this point. Anhydrous ether (approximately 1 liter) was added, the mixture was filtered, and the solid was washed with chloroform to remove triethylamine hydrobromide.

The solid was dissolved in water (1 liter at a temperature of 100 ° C., the solution was treated with activated carbon, and the mixture was concentrated to an amount of about 500 ml, giving crystals of 2-amino-2-fluoromethyl-3- (2,5-di-hydroxyphenyl) propionic acid dihydrate (21 g) was obtained. A further 10 g were obtained by concentrating the mother liquors. Yield: 49%. NMR (D2O.DCI) Figure 3. Melting point: 121 °.

NB: The crystals were dried in vacuum at room temperature without phosphorus pentoxide to avoid loss of water from the dihydrate.

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646 939

Production Example 4

2-Amino-2-fluoromethyl-3- (2-hydroxy-3-methylphenyl) propionic acid semi-hydrate

A stirred mixture of 3-methyl-salicylic acid (104 g), potassium carbonate (188 g), methyl iodide (86 ml) and acetone was refluxed over a week, the solution was filtered and concentrated, and the oily mixture was treated with water and ether . After the ethereal solution which had been separated off and dried over MgSO4 was concentrated, the crude methyl 2-methoxy-3-methylbenzoate (128) was obtained.

b) Preparation of 2-methoxy-3-methylbenzyl alcohol

The crude methyl 2-methoxy-3-methylbenzoate (43 g) was slowly added to a stirred suspension of lithium aluminum hydride (9.1 g) in anhydrous ether (300 ml) at room temperature under nitrogen. After standing overnight, the mixture was refluxed for two hours and wet ether was added to the cooled solution until the violent reaction stopped. The mixture was then treated with water and enough dilute hydrochloric acid to acidify the mixture. The ether was separated, dried and concentrated to give a residue of 2-methoxy-3-methyl-benzyl alcohol (32 g). Distillation was not carried out because the residue polymerized in an earlier attempt.

c) Preparation of 2-methoxy-3-methylbenzyl chloride

Thionyl chloride (16.5 g) slowly became a stirred

Mixture of 2-methoxy-3-methylbenzyl alcohol (21 g), 2,6-lutidine and methylene chloride (250 ml) was added at room temperature. After stirring for an additional 30 minutes, the mixture was washed with dilute hydrochloric acid, the methylene chloride solution was dried over MgSO4 and distilled, and 2-methoxy-3-methylbenzyl chloride, boiling point 62 ° / 14 mn (20.5 G).

d) Preparation of 2-amino-2-fluoromethyl-3- (2-methoxy - 3-methyl) phenylpropionitrile hydrochloride

All operations were carried out in a nitrogen atmosphere.

A solution of ethylene dichloride (10.59 g; 0.107 mol) in anhydrous tetrahydrofuran (150 ml) was slowly added to a stirred mixture of magnesium shavings and anhydrous tetrahydrofuran (50 ml). The violent exothermic reaction was controlled by cooling with an ice water bath. The reaction was finally heated to a temperature of 30 ° C to dissolve all magnesium and the resulting solution became a freshly prepared solution of sodium (4.9 g; 0.214 mol) in a mixture of naphthalene (28.2 g ; 0.22 mol) and anhydrous tetrahydrofuran (200 ml) added. A fine black suspension of magnesium was immediately formed.

Magnesium shavings (2.5 g; 0.107 mol) were added to the suspension mentioned above to maintain an excess of magnesium and the stirred mixture was cooled to a temperature of -20 ° C. A solution of 2-methoxy-3-methylbenzyl chloride (18.3 g; 0.107 mol) was added over an hour and the black color of the mixture disappeared at the end of the addition. The solution was decanted from the excess magnesium and treated with a solution of fluoroacetonitrile (6.3 g; 0.107 mol) in anhydrous tetrahydrofuran (50 ml) at a temperature of -20 ° C by dropwise addition over 30 minutes. The mixture was stirred for a further hour at a temperature of -20 ° C and then in a stirred aqueous solution of a mixture of sodium cyanide (10.49 g; 0.214 mol) and ammonium chloride (17.2 g; 0.32 Mol) emptied.

After half an hour the organic layer was separated using ether, dried and concentrated to a third of the original volume. Ethereal hydrogen chloride was added and the mixture was left to crystallize. The crystals of 2-amino-2-fluoromethyl-3- (2-methoxy-3-methylphenyl) propionitrile-hydrochloride (mp. 128 ° C.) were filtered off and recrystallized from acetonitrile 15 (8 g).

e) Preparation of 2-amino-2-fluoromethyl-3- (2-methoxy - 3-methylphenyl) propionamide

A solution of 2-amino-2-fluoromethyl-3- (2-methoxy-3-methylphenyl) propionitrile hydrochloride (5.2 g) in methanol, 20 which was saturated with hydrogen chloride (100 ml), was added during 64 hours left in a refrigerator. The methanol was evaporated, the residue was dissolved in water and the solution was made basic by the addition of aqueous potassium carbonate. The organic material (4.8 g) was isolated by extraction with dichloromethane. The syrup was first purified by column chromatography using silica gel and a mixture of 93% chloroform and 7% acetone as the eluent and then by crystallization from benzene, 30 µm crystals of 2-amino-2-fluoromethyl-3- (2 to give -methoxy-3-methylphenyl) propionamide with a melting point of 118 ° C (3.5 g).

f) Preparation of 2-amino-2-fluoromethyl-3- (2-hydroxy - 3-methyphenyl) propionic acid

35 A solution of 2-amino-2-fluoromethyl-3- (2-methoxy-3-methyphenyl) propionamide (1.5 g) in 48% hydrobromic acid was refluxed overnight, the acid was evaporated and the residue became dissolved in isopropanol. After the ammonium bromide had been filtered off, the pH-40 value of the solution was adjusted to a value of 5 by adding triethylamine. The crystals that separated out were filtered off, washed well with chloroform and dissolved in water. The aqueous solution was concentrated and the residue was crystallized from ethanol to give 2-45-amino-2-fluoromethyl-3- (2-hydroxy-3-methylphenyl) propionic acid semi-hydrate with a melting point of 168 ° C to surrender.

Production Example 5 50 2-Amino-2-difluoromethyl-3- (2,5-dihydroxyphenyl) propionic acid

0H

a) 2,5-Dimethoxybenzyl bromide

2,5-Dimethoxybenzyl alcohol (50 g) and PBr3 (9.5 ml) er-65 gave 60 g of the bromide.

b) Tert. -butyl-methyl-2- (2,5-dimethoxybenzyl) malonate

Treatment of tert-butyl methyl malonate (24.5 g) with sodium hydride (4.35 g; 50%) and 2,5-dimethoxybenzyl bromide

646 939

16

(20.21) gave tert-butyl-methyl-2- (2,5-dimethoxybenzyl) malo-nate (22.76 g), boiling point 140 ° / 0.05 mm.

c) Tert.-butyl-methyl-2-difluoromethyl-2- (2,5-methoxybenzyl) malonate

The above malonate (22.76 g) was difluoromethylated to give tert-butyl-methyl-2-difluoromethyl-2- (2,5-dimethoxybenzyl) malonate (24.77 g).

d) 2-methoxycarbonyl-2-difluoromethyl-3- (2,5-dimethoxy-phenyl) propionyl chloride

The above malonate (24.77 g) was first treated with trifluoroacetic acid (50 ml) for one hour and then with thionyl chloride (50 ml) to give the acid chloride (23 g).

e) 2-methoxycarbonyl-2-difluoromethyl-3- (2,5-dimethoxyphenyl) propionyl azide

Treatment of the acid chloride (23 g) with sodium azide (9.2 g) gave the acid azide (20 g). 5 f) l-difluoromethyl-l-methoxycarbonyl-2- (2,5-dimethoxy-phenyl) ethylamine hydrochloride (via the isocyanate)

The above acid azide (20 g) was heated with benzene and then treated with 6 N HC 1 (150 ml) to give the amine hydrochloride (16 g). 10 g) 2-amino-2-difluoromethyl-3- (2,5-dihydroxyphenyl) propionic acid

Treatment of the amine hydrochloride (16 g) with hydrochloric acid (150 ml), 48% hydrobromic acid (100 ml) and finally treatment of the residue with propylene oxide (14 g) gave 2-amino-2-difluoromethyl-3- (2,5-di-hydroxyphenyl) propionic acid (8.5 g), which crystallized from a mixture of ethanol / methanol (150/100). Melting point 202 ° C.

v

3 sheets of drawings

Claims (3)

646 939 2nd PATENT CLAIMS 1. a-Halomethylamino acid derivatives of the general formula ch 5 r wherein Y is the group FCH2, F2CH, CICH2 or CI2CH, Ri is a hydrogen atom, an alkylcarbonyl group with a straight or branched chain C 1 to C 4 alkyl radical, an alkoxy carbonyl group with a straight or branched chain Cr to C4 Alkoxy radical or the group O II -c-ch-r27 I. nh2 wherein R27 is a hydrogen atom, a straight or branched chain C 1 to C 4 alkyl group, the benzyl or p-hydroxybenzyl group; R2 is the hydroxyl group, a straight-chain or branched-chain Cr to Cs-alkoxy group the group -nr7r8, in which R7 and R8 each represent a hydrogen atom or a branched or straight-chain Cr to Gi-alkyl radical, or the group -NH-CH-COOH I. R9 represent wherein Rg represents a hydrogen atom, a straight or branched chain Cr to Gt-alkyl radical, the benzyl or p-hydroxybenzyl radical; where r3, R4, rs, r'4 and rß each have the following meanings: r3 r4 r5 r'4 rô oh ch3 h h h h oh ch3 h h oh h ch3 h h Oh OCH3 h h h oh h oh h h oh h h h ch3 oh h OCH3 h h oh h h oh h oh ch3 oh h h oh h h h oh and their pharmaceutically acceptable salts and the individual optical isomers. 2. A process for the preparation of the compounds according to claim 1, characterized in that an appropriately protected phenylpropionic acid ester of the formula r12 r.i 1 is used to prepare those compounds in which R 1 is the hydrogen atom, R 2 is the hydroxyl group r13-rv ch2-ch-c0r, Vk / J j ° p) ^ vr nh = c-rh r 12 k14 jd in which Ra is a straight or branched chain Cr to Cg alkoxy group, Rb the hydrogen atom, the phenyl group, a straight or branched chain Cr to Cs alkyl group, the methoxy or ethoxy group , Re is the phenyl group, a straight-chain or branched-chain Cr to Cs-alkyl group or Rb and Rc together denote an alkylene group with 5 to 7 carbon atoms, the radicals Rn, r12, r13. R'i2 and R14 each have the following meanings: r11 ri2 Rl3 r'12 Rl4 OCH3 ch3 h h h h och3 ch3 h h OCH3 h ch3 H H OCH2Ph OCH3 H H H OCH3 H OCH3 H H OCH3 H H H ch3 OCH2Ph h OCH3 H H OCH3 H H OCH3 H OCH3 ch3 OCH3 H H OCH3 H H H OCH3 treated with a strong base and the carbanion intermediate obtained with a halogen methylating agent for half an hour to 24 hours at temperatures of -120 to 65 ° C in an aprotic solvent and then subjected to acid hydrolysis, and optionally to prepare the pharmaceutically acceptable salts obtained compounds are reacted with a pharmaceutically acceptable acid or base. 3. A process for the preparation of the compounds according to claim 1, characterized in that (a) for the preparation of those compounds in which R2 is a straight or branched chain Cr to Cs alkoxy group, the corresponding derivative in which R2 is a hydroxyl group with thionyl chloride and then with an alcohol of the general formula R23OH in which R23 denotes a straight-chain or branched-chain Cr to Cg-alkyl group, treated at 25 ° C. for 4 to 12 hours; (b) for the preparation of those compounds in which R2 denotes the group —NR7R8, in which R7 and R8 each have the meaning given in claim 1, an acid halide of the corresponding derivative in which R2 is a hydroxy group and Rj has the meaning given in claim 1 with the proviso that each free amino acid is protected with a suitable protective group and that if one of the substituents R3, R4, R5 or R'4 denotes the group OR10, in which Rio is a hydrogen atom, these groups are protected as corresponding alkylcarbonyloxy groups be, with an excess of a suitable amine of the general formula NHR7R8 in which R7 and Rs are as defined above, treated in a suitable solvent at 25 ° C. for 1 to 4 hours and then hydrolyzed with an acid or base or carry out hydrogenolysis; (c) for the preparation of those compounds in which R2 is the group -NH-CH-COOH I. r9 is in which R9 has the meaning given in claim 1 10th 15 20th 25th 30th 35 40 45 50 55 60 65 3rd 646 939 sits, the corresponding derivative in which R2 is the hydroxyl group or a functional derivative thereof and Ri has the meaning given in claim 1 with the proviso that all free amino groups are protected in a suitable manner, with a compound of the general formula nh2ch-coor24 I. R9 in which R9 has the meaning given in Claim 1 and R24 represents a lower alkyl group, treated in a suitable solvent at 50 ° C for 1 to 24 hours and then hydrolyzed acidic with the proviso that if the free acid with protected amino group is used, the Reaction is carried out in the presence of a dehydrating agent; (d) for the preparation of those compounds in which Ri represents an alkylcarbonyl group in which the alkyl group has 1 to 4 carbon atoms and is straight or branched chain, the corresponding derivative in which Ri represents the hydrogen atom and R2 is the hydroxyl group with an acid halide of the general formula 0 II R25-C-halo in the halo represents a halogen atom and R25 represents a straight-chain or branched-chain CrC4-alkyl group, treated in a suitable solvent in the presence of a base at temperatures from 0 to 25 ° C. for half an hour to 6 hours; (e) for the preparation of those compounds in which Ri represents an alkoxycarbonyl group in which the alkoxy group has 1 to 4 carbon atoms and is straight or branched chain, the corresponding derivative in which Rj represents a hydrogen atom and R2 represents the hydroxyl group, with a Haloalkyl formate of the general formula O II halo-C-OR26 in which halo represents a halogen atom and R26 denotes a straight or branched chain C 1 -C 4 -alkyl group, treated in water in the presence of a base at temperatures from 0 to 25 ° C. for half a to 6 hours; (f) for the preparation of those compounds in which Rj is the group O II -c-ch-r27 1 nh2 wherein R27 has the meaning given in claim 1, the corresponding derivative in which Ri is the hydrogen atom and R2 is a straight or branched chain Ci-Cg-alkoxy group, with an acid of the general formula HOOC-CH-R27 I. nh2 or an anhydride thereof, in which R27 is as defined above and the amino group is appropriately protected, treated in a suitable solvent and in the presence of a dehydrating agent, if the free acid is used, at temperatures from 0 to 35 ° C. for 1 to 12 hours and then acid and base hydrolyzed; and if necessary (g) for the preparation of the pharmaceutically acceptable salts, the compounds thus obtained are reacted with a pharmaceutically acceptable acid or base.