NL8002417A - ALFA-HALOGEN METHYLAMINO ACID DERIVATIVES. - Google Patents

Description

• k * α-Halomethylamino acid derivatives.

The invention relates to novel pharmaceutically valuable α-haloamino acid derivatives, which are inhibitors of aromatic amino acid decarboxylase.

The amino acids tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine (DOPA), tyrosine and phenylalanine are metabolically converted into tryptamine, 5-hydroxytryptamine, 3,4-dihydroxyphenethylamine or dopamine, tyramine and phenethylamine by an aromatic amino acid decarboxylase. The aromatic amino acid decarboxylase is believed to be a nonspecific enzyme, especially as far as peripheral catalase is concerned. However, there are facts that indicate that there are specific decarboxylation enzymes in the brain for DOPA and 5-hydroxytryptophan each.

It is known that the above-mentioned aromatic amines are involved in various pathophysiological processes. For example, it has been found that tryptamine, the decarboxylation product of tryptophan, is enzymatically methylated to monomethyl-tryptamine, which in turn is methylated enzymatically to dimethyltryptamine (DMT 2) in human red blood cells, plasma and platelets. Present in many mammalian species, it has been shown to be produced in brain tissues of various species, including humans DMT, which has strong hallucinogenic or psychomimitic properties, may play a role in the etiology of schizophrenia and other psychotic disorders Thus any DMT blocking agent can be a valuable antipsychotic Blocking the decarboxylation of tryptophan leads to lower tryptamine levels thereby removing the substrate for DMT formation Thus an inhibitor of aromatic amino acid decarboxylase which can convert tryptophan in tryptamine, a valuable antipsy be a chotic.

Both 5-hydroxytryptamine (5-HT), the decarboxylation product of 5-hydroxytryptophan, and 3,4-dihydroxyphenethylamine BAD ORIGtyl§L0 2 4 17 2 «(dopamine), the decarboxylation product of DOPA, are peripheral and central physiological processes involved, and agents that effectively control the levels of these amines have become pharmacologically valuable agents. It has been found that the central or brain level of 5-HT and norepinephrine, which is metabolically formed by hydroxylation of dopamine, is higher in patients with manic abnormalities than in persons without such abnormalities. It has also been shown that monoamine central mirror lowering agents, for example 5-HT and in particular norepinephrine, when administered to human subjects have anti-manic properties, while monoamine mirror enhancing drugs can induce mania in susceptible individuals. Thus, agents that block the formation of 5-HT and dopamine, for example by inhibiting the enzyme aromatic amino acid decarboxylase, which converts 5-hydroxytryptophan and DOPA into 5-HT and dopamine, respectively, may be of value as antipsychotics or main tranquilizers in the treatment of manic abnormalities.

It has also been shown that agents suitable for the inhibition of decarboxylation of DOPA to dopamine when co-administered with exogenous DOPA or L-DOPA are suitable for the treatment of Parkinson's disease. It is believed that Parkinson's disease can be attributed at least in part to decreased dopamine levels, since exogenous administration of DOPA or L-DOPA is a known agent for the treatment of Parkinson's disease. However, since exogenously administered DOPA is enzymatically converted peripherally to dopamine, larger amounts of administration are measured to increase central absorption. DOPA readily penetrates the brain-blood barrier while dopamine does not. Administration of DOPA or L-DOPA in combination with a peripherally active inhibitor of the enzyme, which converts DOPA to dopamine, reduces the amount of L-DOPA that must be administered to obtain sufficient blood level for central absorption. Other advantages are also achieved by co-administration of an aromatic amino acid decarboxylase inhibitor with L-DOPA. By preventing the peripheral formation of dopamine, side effects attributed to dopamine such as cardiac arrhythmia, nausea and vomiting can be prevented.

BATH 4 17. 3, ν

Studies indicate that 5-hydroxytryptamine (5-HT) levels are lower in patients with depressive syndromes than in those without such syndromes. Also, administration of exogenous L-5-hydroxytryptophan (L-5-HTP) for the treatment of certain depression-5ve patients is effective. However, since L-5-HTP, like DOPA peripheral, is readily metabolized to 5-HT, large amounts of L-5-HTP must be administered in order to achieve the increased central amino acid levels. It has been shown that by administering an aromatic amino acid decarboxylase inhibitor that catalyzes the peripheral formation of 5-HT from 5-HTP, the amount of exogenous 5-HTP required to form elevated center levels is significantly reduced. In other words, inhibitors of aromatic amino acid decarboxylase have proven valuable in the treatment of depression in combination with exogenous 5-HTP.

15 · Resources, which are peripheral conversion of 5-HTP to 5-HT

block, may be valuable in the treatment of other conditions that respond to elevated 5-HTP levels due to exogenous administration of 5-HTP. It has been found that one can use exogenous L-5-HTP for the treatment of myocidal activity. Studies have also revealed that administration of exogenous 5-HTP is suitable for the treatment of insomnia. Thus, co-administration of 5-HTP and an aromatic amino acid decarboxylase inhibitor for the treatment of these conditions may be beneficial.

Blocking the peripheral formation of 5-hydroxy-25 tryptamine can lead to other beneficial effects, since it is known that 5-HT is involved, for example, in the etiology of rheumatoid arthritis and carcinoid syndrome by increasing collagen levels. It is also reported that 5-HT is the primary autocoid responsible for anaphylactoid reactions in human subjects as well as bronchoconstriction in asthmatic patients and agents that antagonize or inhibit the formation of 5-HT are therefore for the treatment of these disorders of value. It is also known that 5-HT causes platelet aggregation and is involved as a causal factor in post-gastrectoric dumping syndrome and migraine headache. Methylsergide, a 5-hydroxytryptamine antagonist, has been shown to be effective in treating post-gastrectomy BAD omcgiptg 2 4 17 4 dumping syndrome. *

It has been suggested that phenethylamine, the decarboxylation product of phenylalanine, as an endogenous compound contributes to schizophrenia symptoms and triggers migraine headaches. It has also been suggested that endogenous tyramine, the decarboxylation product of tyrosine, contributes to seizures.

It is thus clear that agents which can be used to control the levels of aromatic amino acids and amines are used in many pharmacological situations. The compounds of the invention are inhibitors of aromatic amino acid decarboxylase, which converts tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine, tyrosine and phenylalanine to amines, respectively, and therefore have pharmacological value.

The compounds of the invention have the general formula 1, wherein Y represents Fcn2, F2CH, C1CH2, or C12CH2, hydrogen, alkylcarbonyl having a straight or branched chain alkyl radical of 1 to 4 carbon atoms, alkoxycarbonyl with a straight or branched chain alkyl radical of 1-4 carbon atoms or a group of the formula 1-3 wherein R22 is hydrogen, a straight or branched alkyl radical of 1-4 carbon atoms, benzyl or p-hydroxybenzyl, R2 represents hydroxyl, a straight or branched altoxy group of 1-8 carbon atoms -NR_R, wherein R_ and R are each hydrogen or a straight or branched alkyl group% / o / 8 with 1-4 carbon atoms, or a group of the formula: wherein R ^ is hydrogen, a straight or branched alkyl group having 1-4 carbon atoms, benzyl or * p -hydroxybenzyl, and each of the symbols R ^ »Rj» Rg »R'4 and Rg has the meaning defined in Table A below, wherein R hydrogen is a straight or branched chain alkyl group of 1-8 carbon atoms, alkyl carbonyl carbon black with a straight or branched chain alkyl radical 1-6 carbon atoms, benzoyl or phenylalkylene carbonyl with a straight or branched alkylene radical having 1-6 carbon atoms.

badori <8KM) 2 4 17 5 »

Table A

R3 R4 R5 R> 4 R6

H -0-CH2-0- 'Η H

Η Η Η Η H

5 Η H 0R10 Η H

H ORj 0 Η Η H

H 0R1q OR10 Η H

0R10 H Cl Η H

H 0R1q Cl Η H

10 Cl 0Rj0 Η Η H

Cl ORjq Cl Η H

Cl, F H 0R] 0 Η H

Cl Η Η H CH3

Cl H Cl H CH3 15 Η H Cl, F H CH3 OR] 0 H CH3 H CH3

Cl H CH3 H CH3 Η H 0R10 H CH3 Η H ORjq H C2H5 20 0R10 H C2H5 H C2H5

H ORjq H 0R, q H

H ORjq ORjq ORjq H

Η H 0CH3 OH H

OH H OH 0CH3 H

25 ORjq ORjq Η Η H

ORjq Η Η Η H

Η h Cl H C2H5 Η H Cl H t-C4H5 Η H ORjq H t_C4H5

30 OH CH3 Η Η H

H OH CHq Η H

OH H. GH3 Η H

OH 0CH3 Η Η H

OH H OH Η H

35 OH Η Η H CH3 bad ori (8 ^ 0 2 4 17 6 *

Continued from Table A.

R3 R4 R5 R> 4 R6

OH H OCH3 Η H

OH Η H OH H

5 OH CH3 OH Η H

OH Η Η H OH

Also included in the invention are pharmaceutically acceptable salts and individual optical isomers of the compounds of general formula 1.

The compounds of the general formula I have great pharmacological values, because these compounds are inhibitors of aromatic amino acid decarboxylase and can be used as intermediates in the preparation of valuable pharmacological agents.

The compounds of the general formula (10) described here and their preparation method are also part of the present invention. The compounds of formula 10 are valuable chemical intermediates for the preparation of compounds of formula 1, wherein Y represents.

In the definition of formula 1, alkylcarbonyl is understood to mean a group of formula 15 having a straight or branched chain alkyl radical containing 1-6 carbon atoms.

The term benzoyl used in the definition of formula 1 refers to a group of formula 16.

The term phenylalkylene carbonyl used in connection with the definition of general formula 1 refers to a group of formula 17 having a straight or branched chain alkylene radical of 1-6 carbon atoms, for example methylene, ethylene, isopropylene or butylene.

Good examples of straight or branched chain alkoxy groups of 1 to 8 carbon atoms are methoxy, ethoxy, isopropoxy, n-butoxy, t-butoxy, n-pentyloxy, t-pentoxy, n-hexyloxy and n-octyloxy.

Good examples of straight or branched chain alkyl groups of 1 to 6 carbon atoms are methyl, ethyl, n-propyl, iso-EJAD ORIOW 2 4 17 7 m propyl, n-butyl, t-butyl and n-pentyl.

Good examples of pharmaceutically acceptable salts of the compounds of the invention are non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric and organic acids such as methanesulfonic, salicylic, maleic, malonic, tartaric, and ascorbic acid and non-toxic salts formed with inorganic or organic bases, such as those derived from alkali metals, for example sodium, potassium and lithium, alkaline earth metals, for example calcium and magnesium, light metals of group UIA, for example aluminum, or from organic amines, as primary, secondary or tertiary amines, for example cyclohexylamine, ethylamine, pyridine, methylaminoethanol, ethanolamine and piperazine. The salts are prepared in the usual manner.

Preferred compounds of the invention are those having the general formula 1, wherein R 1 represents hydrogen or alkyl carbonyl having a straight or branched chain alkyl radical of 1 to 4 carbon atoms, most preferred are compounds wherein R 1 is hydrogen. Another preferred embodiment of the invention are the compounds of formula I wherein R2 is hydroxyl or a straight or branched chain alkoxy group with no. # 1-8 represents carbon atoms. Most preferred are compounds wherein R 1 is hydroxyl. Also preferred are the compounds of formula I, wherein R 1, R 1, R 1, R 1, R 1, and R 8 each represent hydrogen or OR 1, wherein R 1 is hydrogen. Also compounds in which R is OH and one of the symbols R ^, R ^, R '^ or Rg is OH, OCH ^ or CH ^ and compounds, in which R ^ is OH and one of the symbols R ^ or R' ^ OH OCH 1 or CH 2 are preferred embodiments of the present invention. Compounds of the formula 1, wherein Y is FCH 2 - or F 2 CH - are also preferred.

Good examples of compounds of the general formula 1 are: 2-difluoromethyl-2-amino-3-phenylpropionic acid, 2-difluoromethyl-2-amino-3- (3-hydroxyphenyl) propionic acid, 2-difluoromethyl-2-amino- 3- (3,4-dihydroxyphenyl) propionic acid, 2-difluoromethyl-2-amino-3- (4-hydroxyphenyl) propionic acid, 2-fluoromethyl-2-amino-3- (4-chloro-2-hydroxyphenyl) propionic acid 2-chloromethyl-2-amino-3- (4-chloro-3-methoxyphenyl) propionic acid, 2-dichloromethyl-2-amino-3- (2-chloro-3-benzoyloxyphenyl) propionic acid, BAD ORIGl 2 4 17 8 2-Fluoromethyl-2-amino-3- (2,4-dichloro-3-hydroxyphenyl) propionic acid, 2-Difluoromethyl-2-amino-3- (2-chloro-4-hydroxyphenyl) propionic acid, 2- chloromethyl-2-amino-3- (2-chloro-6-methylpheny1) propionic acid, 2-fluoromethyl-2-amino-3- (2,4-dichloro-6-methylphenyl) propionic acid, 5 2-dichloromethyl-2-amino -3- (4-chloro-6-methylphenyl) propionic acid, 2-dichloromethyl-2-amino-3- (2-hydroxy-4,6-dimethylphenyl) propionic acid, 2-chloromethyl-2-amino-3- (2- chloro-4,6-dimethylphenyl) propionic acid, 2-fluoromethyl-2-amino-3- (4-hydroxy-6 -methylphenyl) propionic acid, 2-dichloromethyl-2-amino-3- (5-ethyl-4-phenylpropionyloxyphenyl) -10 propionic acid, 2-difluoromethyl-2-amino-3- (4,6-diethyl-2-hydroxypheny1) propionic acid 2-chloromethyl-2-amino-3- (4-chloro-6-ethylphenyl) propionic acid, 2-fluoromethyl-2-amino-3- (4-chloro-6-t-butylphenyl) propionic acid, 2-difluoromethyl-2 -amino-3- (6-t-butyl-4-hydroxyphenyl) propionic acid, 2-dichloromethyl-2- (N-ethoxycarbonylamino) -3- (4-n-butoxyphenyl) -propionic acid, N, N-di-n -propyl-2-difluoromethyl-2-amino-3- (4-acetyloxyphenyl) -propionic acid, 2-fluoromethyl-2- / N- (2-amino-1-oxoethyl) amino / -3- (3-hydroxyphenyl) - 20-propionic acid, 2-fluoromethyl-2-amino-3- (3,4-dihydroxy) phenyl-1-oxo-propylamino-acetic acid, 2- / (2-difluoromethyl-2-amino-1-oxo-3-phenyl ) propylamino / dihydro-cinnamic acid, 2-difluoromethyl-2- (1-oxoethylamino) -3- (4-hydroxy) phenyl-1-oxopropylamino-2-propionic acid, methyl 2-fluoromethyl-2- (1-oxoethylamino 3-(4-hydroxy) -phenyl-1-oxopropylaminoacetate, 2-chloromethyl-2-amino-3-phenylpropionamide, 30 N, N-dimethyl-2-difluoromethyl-2 -amino-3- (3-hydroxyphenyl) propionamide, N, N-diethyl-2-dichloromethyl-2-amino-3- (3 '^' - dimethoxyphenyl) -propionamide, Nn-butyl-2-difluoromethyl-2-amino -3- (4-hydroxyphenyl) propionamide, methyl 2-chloromethyl-2-amino-3- (3-hydroxyphenyl) prop ionate, 35-isopropyl 2-dichloroethyl-2-amino-3- (3,4-dihydroxyphenyl) - propionate, bath or6iQXL 2 4 17 8a 0 t-butyl 2-fluoromethyl-2-amino-3- (4-hydroxyphenyl) propionate, ethyl-2-difluoromethyl-2-amino-3- (4-chloro-3-methoxyphenyl) propionate, 2-fluoromethyl-2-amino-3- (4-hydroxyphenyl) propionamide, ^ 2-fluoroethyl-2-amino-3- (3-hydroxy-4-methoxyphenyl) propionic acid, 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 the general formula] are irreversible inhibitors of the enzyme, which metabolically catalyzes the conversion of tryptophan, 5-hydroxytryptophan, 3,4-dihydrophenylalanine, tyrosine and phenylalanine into tryptamine, 5-hydroxytryptamine, 3,4-dihydroxyphenylethylamine, respectively. , tyramine and phenethylamine. As noted above, research results indicate that the enzyme responsible for the peripheral conversion of the above amino acids into amines, respectively, is a nonspecific aromatic amino acid decarboxylase. Central conversion studies indicate that specific decarboxylases are responsible for the conversion of 5-hydroxytryptophan and 3,4-dihydroxyphenylalanine each, while the remaining 20 above.

amino acids are enzymatically converted into respective amines by a nonspecific aromatic amino acid decarboxylase. The compounds of the invention irreversibly effectively inhibit both central and peripheral activity of nonspecific aromatic amino acid decarboxylase and the activity of 3,4-dihydroxyphenylalanine (DOPA decarboxylase). The expression used herein in connection with the use of the compounds of the invention refers centrally to the central nervous system, mainly the brain, while peripherally refers to other body tissues in which the decarboxylase is present. The central or peripheral selectivity of the inhibition of the 30 ..... .

amino acid decarboxylases when doses of compounds of the general formula 1 are administered.

BATH ORlgffKO 2 4 17 __ 9 -

[If irreversible inhibiting of aroma I

The amino acid decarboxylase and DOPA decarboxylase can be used in the compound; pharmacologically apply the things of the invention in various ways.

As peripheral irreversible inhibitors of aromatic amino acid decarboxy- . ί i lase one can use the compounds of the general formula 1 for I # ί; treating Parkinson's disease when administered in combination j! with 3,3-dihydroxyphenylalanine (DOPA) or L-3Λ-dihydroxyphenylalanine! : (L-DOPA). DOPA and in particular the active isomer L-DOPA2,! i! known, effective agents for treating Parkinson's disease when administered systemically, usually in an amount! from initially 0 to 5 to 1 g daily, after which the amount administered is slowly increased in 3 to 7 days to a maximum tolerated daily dose of 8 g. Co-administration of a compound> i • of the general formula 1 and L-DOPA provides a better method of treating Parkinson's disease, because the compounds containing i | formula 1 peripherally block the deearboxylation of L-DOPA to L-3, - dihydroxyphenethyl amine (L-dopamine) by inhibition of activity] *. .

| of the enzyme, aromatic amino acid decarboxylase, so that high | L-DOPA blood levels for central absorption are maintained and also by preventing the peripheral formation of elevated dopamine levels, which are known to lead to certain undesirable side effects such as cardiac! arrhythmia. By simultaneous administration of a compound with the! formulas 1 and L-DOPA, the amount of L-DOPA administered can be reduced by one-half or one-tenth part, compared to the amounts, 1.; | needed when administering L-DOPA alone. It is preferable to administer the compounds of the invention before being administered [| Administer L-DOPA. For example, one can use a compound of the formula 1; : Administer 30 minutes to b hours before the administration of L-DOPA, depending on the route of administration and depending on the condition of the patient; treat patient. The compounds of the formula I are also suitable for the treatment of depression syndromes when administered in combination with 5-hydroxytryptophan (5-HTP), or in particular the ij active levo isomer, which is known to be used in systemic administration. | can use to treat depression. The connections to the | block general formula 1 by peripheral inhibition of action of 8002417

BAD ORIGINAL

- 10 - - aromatic amino acid decarboxylase where the conversion of e5-hydroxytryptophan into 5-hydroxytryptamine is observed. higher 5-HTP blood levels for central absorption are maintained. The compounds of formula 1 are. with simultaneous administration of exogenous 5-HTP also suitable for the | Treatment of myoclonus activity, which is known to be effective.

ί. . i

. J den treated by increasing the 5-HTP central level. I

The compounds have the general formula 1 carbon black are also suitable for the treatment of rheumatoid arthritis because of their peripheral inhibitory effect on aromatic amino acid I decarboxylase, 10. carcinoid syndrome, anaphylactic reactions in humans, bronchoconstruction in asthmatics, as well as other conditions known to be caused by high peripheral 5-hydroxytryptamine levels. | As has already been shown, it has been shown that agents, which increase the 5-HT and norepinephrine, the hydroxylation product of dopamine, lowering suitable for treating patients carbon black I. manic abnormalities. Thus, the compounds of the general formula 1 as irreversible central inhibitors of aromatic amino acid I decarboxylase and DOPA decarboxylase are suitable for treating manic abnormalities. Furthermore, due to the centrally inhibiting; action of the compounds of the general formula 1 on aromatic

> V

. amino acid decarboxylase these compounds also as anti-psychotics. i.use, as tryptamine center levels are lowered and use}.

for the treatment of schizophrenia and sudden seizures, since phenethylamine and tyrarain center levels are lowered by administration of a compound of general formula 1.

^ | Using the connections with the,! general formula 1 as irreversible inhibitors of aromatic amino acid decarboxylase can be demonstrated as follows. A connection should be made I. .

30 Add water of general formula 1 as a solution or suspension to rats or mice. At various times from 1 to 12 hours after administration of the compound, the animals are sacrificed by decapitation i and the aromatic amino acid decarboxylase activity is measured radioraetrically as described by Christenson et al., Arch. Biochem. Biophys. 1¾1, | 35 | 356 (1970) in homogenates of kidney, heart and brain, prepared according to Burkard et al., Arch. Biochem. Biophys. 107, 187 (19 ^ * 0 · j

BAD ORIGINAL

- 11 ....

The compounds of the invention may be used; I. *! | administer in various ways to obtain the desired effect. The compounds can be used individually or in the form of pharmaceuticals Organic preparations either orally or parenterally, for example subcutaneous,! Inadvertently, intravenously or intraperitoneally to the patient to be treated! serve. The compounds can be administered by intranasal instillation! or by application to mucous membranes such as the nose, throat and bronchi, for example in an aerosol spray, containing small particles of the new compound of the invention in a spray solution or dry powder. ; contains, j j The amount of new compound administered , # 'thing varies and can be any effective amount. Depending on the patient, the condition to be treated and the method of administration, the amount of new compound administered as effective amount in dosage unit form may vary over a long range. When administering the compounds of the general formula 1 for peripheral irreversible inhibition of aromatic decarboxylase, the effective amount of compound administered ranges from Q, J to 100 mg / kg body weight; patient weight * per dose and preferably from 5 to 25 mg / kg. i

For example, one can obtain the desired peripheral effect by consuming a dosage unit such as a tablet containing 10 to 250 mg of the new compound of the invention and 1 to 1 time. taken daily ... When administering the compounds of the invention to obtain a centrally irreversible inhibition of aromatic decarboxylase or 3-dihydroxyphenylalanine decarboxylase, the target rates to be administered vary. the amount of from 25 to 500 mg / kg of body weight of the patient> per day and preferably from 50 to 300 mg / kg. For example, I ·! obtain the desired central effect by consuming a dosage unit as a tablet containing 350 to 500 mg of the new compound of the drug; invention and is taken 1 to 10 times daily. j. The expression patient used here has' | refers to warm-blooded animals such as mammals, for example cats,! dogs, rats, mice, guinea pigs, sheep, horses, cattle and people. * j j The solid dosage unit forms can be of the usual type. Thus, the solid form can be a capsule of

BAD ORIGINAL

- 12 ....

! the ordinary gelatin type, which is a new compound of the invention i. . Contains a carrier, for example lubricant and inert fillers such as lactose, sucrose and corn starch. In another embodiment, the new compounds can be tableted with the j5; conventional tablet bases such as lactose, sucrose or corn starch in combination! combination with binders such as acacia, corn starch or gelatin, disintegrating agents such as corn starch, potato starch or alginic acid and an i

f * · * 1 j lubricant such as stearic acid or magnesium stearate. I

1 For parenteral administration, the therapy can be! Λ m 9 e 10. ! process bonds into injectable doses of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier, which may be a sterile liquid such as; ,. > water and oils, with or without the addition of a surfactant dust and other pharmaceutically acceptable additives. Good examples of oils to be used in such preparations are those derived from petroleum or from animal, vegetable or synthetic origin, for example peanut oil, soybean oil and mineral oil. Generally used! liquid carriers, especially for injectable solutions, preferably water, saline, dextrose in water and related sugar solutions, ethanols and glycols * such as propylene glycol and polyethylene glycol. The compounds can be administered as depot injections or implants, which can be formulated to produce a steady release of active ingredient. The active ingredient may be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injection or implantation, implantations may contain inert substances such as i * I biodegradable polymers or synthetic silicone, such as jj Silastic, a silicone rubber from Dow- Corning Corporation. | -, - - I "3 j

For use as aerosols, the; fill new compounds in solution or suspension in a pressurized • aerosol container together with a gaseous or liquid propellant, • for example dichlorodifluoromethane, dichlorodifluoromethane and dichloro- | j difluoroethane together, carbon dioxide, nitrogen or propane with the use of j -c | additives as well as solvents and wetting agents such as i. . . . ! may be necessary or desired. One can also connect the joints with below.

Administer BAD Ol8 (i! LJ3u? ^ ^ 13 0 in a pressurized form, for example as a vaporiser or atomizer.

As already indicated above, the compounds of the general formula I can be used particularly well when administered together with exogenous L-DOPA, in which case one can administer separate preparations of a compound of the general formula 1 and of L-DOPA, or can process both active ingredients into a single combined pharmaceutical preparation. In either mode of administration, the amount of compound of general formula 1 compared to the amount of L-DOPA administered ranges from 1: 1 to 1:10. A combined preparation may consist of an inner portion containing L-DOPA and an outer portion containing a compound of the general formula 1, with each active ingredient suitably incorporated. A particularly suitable combined preparation can be prepared by pressing L-DOPA, optionally with suitable carriers, into a core, providing this core with a coating resistant to gastric juice and applying an outer layer over the coated core, which layer is applied on a suitable way processed compound of the general formula 1. Using such a combination, the decarboxylase inhibitor, i.e., a compound of the general formula 1, is wiped off preferably 30 to 60 minutes before the L-DOPA. The coating layer can be formed using a non-aqueous solution of glycerides or a water-insoluble polymer such as ethyl cellulose or cellulose acetate phthalate. It is also possible to use preparations in which the L-DOPA enterisC5s are coated using mixtures of shellac and shellac derivatives and cellulose acetate phthalates.

Good examples of suitable pharmaceutical preparations are described below.

The compounds of the general formula I are, in addition to valuable pharmacological agents, also intermediates for the preparation of cephalosporins with antibiotic activity. Thus, one can use the compounds of the general formula 1, wherein R 2 is hydroxyl, for the preparation of cephalosporin derivatives of the general formula 2. In this formula 2, Y, R 1, R 1, R 1, R 8, R 4 and Rg has the same meaning as in the general formula 1, M represents hydrogen or a negative charge and X represents hydrogen or acetoxy.

The compounds of the general formula II and their BAD cffedbOlAL 4 17 14 k - pharmaceutically acceptable salts and individual optical isomers are new compounds, which can be used as antibiotics and administered in the same way as many known cephalosporin derivatives, for example cephalexin, cephalothine and cepaloglycine . The compounds of the 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 or topically to warm-blooded animals, ie birds and mammals, e.g. cats, dogs, cattle, sheep, horses and humans. Orally, the compounds can be administered in the form of tablets, capsules or pills or in the form of elixirs or suspensions. Parenterally, the compounds are best used in the form of a sterile aqueous solution, which may contain other solutes, for example an amount of salt or glucose sufficient to obtain an isotonic solution. For topical administration, the compounds of the general formula II or their salts and isomers can be incorporated into creams and ointments.

Good examples of bacteria against which the compounds of the general formula II and their pharmaceutically acceptable salts and individual optical isomers are active are Staphylococcus aureus, Salmonella Schottmuehlero, Klebsiella pneumoniae, Diplococcus pneumoniae and Streptococcus pyogenes.

Good examples of pharmaceutically acceptable non-toxic inorganic acid addition salts of the compounds of general formula II are the hydrochloride, hydrobromide, sulfate, sulfamate, and phosphate, and organic acid addition salts are, for example, the maleate, acetate, citrate, oxalate, succinate, benzoate , tartrate, fumarate, malate and ascorbate. The salts can be formed in the usual ways.

Good examples of cephalosporin derivatives of the general formula II are 7 - / - f-2-difluoromethyl-2-araino-3-phenylpropionyl / / - amino __ / - 3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo / - 4.2.0 / octene-2-2-carboxylic acid, 7 - / ^ / - 2-difluoromethyl-2-amino-3- (3-hydroxyphenyl) propionyl / / - amino __ / - 3-acetyloxymethyl-8-oxo-5-thia -1-azabicyclo / 4.2.0 / octene-2-2-carboxylic acid, 7 - / 2-difluozmethyl-2-amino-3- (3,4-dihydroxyphenyl) propionyl / - 35 amino / 3-acetyloxymethyl -8-oxo-5-thia-1-azabicyclo4.2.0 / octene-2-2-bath oriA2 4 17 15 carbonzmir and 7- / [2-fluoromethyl-2-amino-3- (4-hydr © xyphenyl) propionyl / - amino 7-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclop 4.2.0 / octene-2-2-carboxylic acid.

The compounds of the general formula 2, wherein hydrogen is, can be prepared by coupling Vein 7-aminocephalosporanic acid or a derivative thereof of the formula 3, wherein X and M have the same meaning as in formula 2, with an acid of the formula 4 or a functional derivative thereof as the acid chloride or an anhydride and in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, if the free acid is used, in which formula R 4, R 4, R 3, R 1, and R 5 have the same meaning as in formula 2 and the amino group is protected with a suitable blocking group, for example t-butoxycarbonyl, followed by acid hydrolysis to remove the protecting group from the amino group.

The coupling reaction is generally carried out in a solvent, for example ethyl acetate, dioxane, chloroform or tetrahydrofuran, in the presence of a base, for example alkali bicarbonate. The reaction temperature can vary from -10 to 100 ° C and the reaction time lean from half an hour to 10 hours. The cephalosporin products are obtained in the usual ways. The compounds of the general formula IV are prepared in the ways described above, while the compounds of the formula 3 are commercially available or can be prepared in well known ways. The compounds of the general formula II, wherein R1 is not hydrogen, can be prepared from the corresponding derivatives, wherein R1 is hydrogen according to the general methods described below for compounds of the general formula I, wherein R1 is not hydrogen is.

One can use the compounds of the general formula 1, wherein R 1 is hydrogen, R 1 is hydroxyl, and R 1 and R 4 are both OR ^ 0, where R 1 is hydrogen, or R 1 and R 1. both are OR10, where Rj is hydrogen, or Rj and Rj. together are -O-CH ^ -O-, or wherein R ^, R ^, R ^ »R'4 and Rg each have the meanings defined in Table A, except that R ^ q is methyl, prepare by a suitably protected phenylpropionate of formula 5 with a strong base to form a carbion ion, BAD O0 | Q | Oa2 4 17 which is treated with a suitable halomethylalkylating agent, followed by acid hydrolysis. In the general formula S, R represents a straight or branched chain alkoxy group with 1 to 8 carbon atoms, R 1 hydrogen, phenyl, a straight or branched chain alkyl group with 1 to 8 carbon atoms, methoxy or ethoxy, R 1 phenyl or a straight or branched chain alkyl group carbon black 1-8 carbon atoms or R 4 and R 8 together form an alkylene group of 5-7 carbon atoms, i.e. -C 1 -C 1 -C 1 -C 2 -, wherein m is an integer of 3-5. Good examples of straight or branched chain alkyl groups of 1 to 8 carbon atoms which can be represented by R 1 and Rc are 10 methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-hexyl, n-octyl and neopentyl. Each of the symbols Rjj, R12 'R13' R'l2 and R14 ^ has the meanings defined in Table B below.

TABLE B

R11 R12 R13. R'12 R14 15 · -O-C-O- X \ H3C CH3 Η η h

H -O-C-O- Η H

κ \ h3c ch3

20 H -O-CH ^ -O— Η H

Η Η Η * Η H

Η H OCH, Η H

H 0CH3 Η Η H

H OCHj OCH3 Η H

25 iCH3 H Cl Η H

H OCH3 Cl Η H

Cl och3 H H H

Cl OCH3 Cl Η H

Cl, P H 0 CH 3 Η H

30 Cl Η Η H CH3

Cl H Cl H CH3 Η H Cl, F H CH3 och3 h ch3 h ch3 ci h ch3 h ch3 35 Η H OCH3 H CH3 BAD0RllftA.2 4 17 17 0

Table B continued R11 R12 R13 R * 12 R14 Η H 0CH3 H C2H5 och3 h c2h5 h c2h5

5 H OCH3 H OCH3 H

h och3 och3 och3 H

Η H OCH3 OCH2Ph H

Η H OCH2Ph OCH3 H

och3 och3 H H H

10 och3 H H H H

Η H Cl H C2H5 Η H Cl H t-C.H- 4 9 Η H OCH „H t-C.Hn j 4 9

och3 ch3 H H H

15 H OCH3 CH3 Η H

och3 h ch3 H H

OCH2Ph OCH3 Η Η H

och3 h och3 H H

OCH3 h h H CH3

20 OCH2Ph H OCH3 Η H

och3 η h och3 H

OCH3 CH3 0CH3 h h och3 h h H OCH3

Suitable strong bases which can be used in the reaction series above to form the intermediate carbaan ion are those which can withdraw a proton from the carbon atom in the α-position relative to the carboxyl group, for example an alkyl lithium such as butyl lithium or phenyl lithium, a lithium alkyl amide such as lithium diisopropylamide, or lithium amide, t-potassium butyl, sodium amide, metal hydrides, for example sodium hydride or potassium hydride, tertiary amines such as triethylamine, lithium acetylide or dilithium acetylide. Lithium acetylide, dilithium acetylide, sodium hydride and lithium diisopropylamide are preferably used as the base.

Suitable halogeenmethylalkyleermiddelen for the top-35 above reaction are for example chlorofluoromethane, bromofluoromethane, bath Orks & D 2 4 17 18 ê fluoro jew methane, chlorodifluoromethane, broomdifluormethaan, difluoro-jew chloride, bromochloromethane, methylene chloride, chloro jew methane, bromodichloromethane and methylene jew methane. The halomethyl alkylating agents are known in the art.

The alkylation reaction can be carried out in an aopic solvent, for example benzene, toluene, ether, tetrahydrofuran, dimethyl sulfoxide, or hexamethylphosphoric triamide. The reaction temperature can vary from -120 to 65 ° C, preferably using 40 ° C. The reaction time can vary from half to 24 hours.

Acid hydrolysis to remove any unreacted starting material and protecting groups can be done in one step or in steps. In one-stage hydrolysis, the acid concentration used naturally varies with the duration of the hydrolysis step and the temperature used. For example, one-stage hydrolysis can be carried out by treatment with concentrated hydrochloric acid at 25-120 ° C for 1-4 days. Stepwise hydrolysis can be performed with dilute acid at 25 ° C for half to 6 hours to remove unreacted starting material, repeated dilute acid treatment to remove any protecting groups from the amine group, followed by concentrated acid treatment at 25- 125 ° C for 1-3 days to remove any ester or ether groups. Stepwise hydrolysis is preferred.

The compounds of the general formula 1, wherein Y represents FCH 2 -, is hydroxyl, R 1 is hydrogen, R 2 and R 2 both represent OR 2, wherein R is hydrogen, or R 2 and R 1. both ORjq represent, where R is hydrogen, or R ^ and R ^ both represent -0-CH2-0-, or wherein each of the symbols R ^, R ^, R ^, R '^ and R ^ represents one of the other Table A has defined meanings, except that R 1 is methyl or hydrogen, all can be prepared according to the procedure shown in the accompanying reaction scheme.

In this reaction scheme Xa represents chlorine or bromine, Rj j, RJ2> Rj3 »R'i2 and R14 have this meaning as in table B and R ^, R ^, R ^, R '^ and R ^ have the same meaning as in Table A, except R iq is methyl or hydrogen.

According to the attached reaction scheme, a benzyl halide of the formula 7 is added very slowly to magnesium curls in BAD ORIGir & P 0 2 4 17 19 * a suitable ether as a solvent, for example tetrahydrofuran, diethyl ether or a mixture thereof, and the reaction is allowed to proceed for 30 minutes. continue for up to 24 hours at a temperature from -20 ° C to 70 ° C, preferably from 25 ° C to the boiling point of the solvent. A trace of methyl iodide is added at the start of the reaction. Also, if either rjj or Rjj is methoxy, the reaction is started in tetrahydrofuran.

To the Grignard reagent thus formed, i.e. a compound of the formula 8, fluoroacetic nitrile in a ratio which can vary from 0.5 to 3 is added in an aprotic solvent, for example tetrahydrofuran, diethyl ether, dioxane, benzene, dimethoxyethane or dimethoxymethane or a mixture thereof. The reaction temperature ranges from -20 ° C to -70 ° C, preferably from -20 ° C to -25 ° C and the reaction time from 10 minutes to 12 hours, preferably from 10 minutes to 1 hour. The ketimine salt thus formed, ie a compound of the formula 9, is hydrolyzed with acid to form the ketone.

Acid hydrolysis can be obtained by pouring the ketimine salt into water and concentrated hydrochloric acid while maintaining a strong acidic medium. The ketone of formula 10 is recovered in the usual ways, for example, by extraction with petroleum ether or pentane or hexane and then with an ether as diethyl ether.

The ketone is converted to the amino nitrile of the formula II under the conditions of a Strecker reaction by treatment with 1 to 10 equivalents of sodium cyanide and 1 to 10 equivalents of ammonium salt, for example ammonium chloride, in either a basic medium using ammonium hydroxide in water (1 molar to concentrated) in a lower alcohol, such as methanol or ethanol, or a neutral medium using water and a lower alcohol.

Hydrolysis of the amino nitrile to the amino acid of formula 12 can be carried out in various ways. For example, hydrolysis can be carried out by treatment with hydrogen bromide for half to 24 hours at 25 to 100 ° C. However, when using hydrogen bromide, Rjq in the formula 12 is hydrogen. Hydrolysis can also be carried out with sulfuric acid in a generally known manner. Hydrolysis can also be effected by treatment with a lower alcohol, for example methanol, saturated with anhydrous hydrogen chloride, for 1 to 24 hours, preferably 10 hours, at 0 to 50 ° C, preferably 25 ° C, under BAO origin aC Π 2 4 1 7 9 20 obtaining the corresponding amino amide, which is hydrolyzed by treatment with aqueous hydrochloric acid or 50% aqueous sulfuric acid for 2 to 6 hours at 60 to 100 ° C, preferably 95 ° C, followed by neutralization with barium hydroxide if sulfuric acid has been used.

The most related prior art in the preparation of the ketones of formula 10 is the known method of preparing fluoromethyl m-tolyl ketone, E.D. Bergmann et al., J. Chem. Soc. 1961. 3452. The method described in the accompanying reaction scheme clearly differs from the prior art and also offers certain advantages over the prior art. In the process described above, the Grignard compounds are firstly benzyl compounds, secondly, the temperature of the reaction mixture during the Grignard addition must be kept at or below -20 DEG C., while the fluoroacetic acid nitrile reagent used in the present process is much less toxic. is then the monofluoroacetic acid derivatives used in the prior art to prepare fluoromethyl benzyl ketone.

The compounds of the general formula I, wherein R 1 is hydrogen and R 2 is hydroxyl and represents R 1, R 1, R 1, R 1 or R 2 OR 1, where R 1 is hydrogen, can be prepared by the corresponding derivative, wherein R 1, R ^, R ^ or R ^ ORjq, where Rjq is methyl, to be treated with aqueous hydrobromic acid or acetic acid for 4-24 hours at 25-125 ° C.

Compounds of the general formula I in which R 1 is hydrogen and R 2 is hydroxyl and R 1, R 1, R 1, and / or R 1 OR 4 can be represented, wherein R 1 is straight or branched chain alkyl of 1-8 carbon atoms, by the corresponding compound, wherein R iq is hydrogen, prepare for 1-24 hours at 25-85 ° C in a lower alcohol, for example, methanol or ethanol, or a hydrocarbon such as benzene or toluene, in the presence of an organic base, as triethylamine or pyridine, or in an aprotic solvent, such as dimethylformamide, dimethylacetamide, or dimethyl sulfoxide, to alkylate in the presence of sodium hydride with an alkyl halide of the formula R2JY2 * where ^ n R21 is a straight branched alkyl group with 1-8 carbon atoms and Y2 halogen, e.g. bromine or iodine, -35, followed by hydrolysis with an aqueous base, it being understood that • the α-amino group and optionally the carboxyl group of the starting hydroxyl compound are suitable for the alkylation reaction. protected by, for example, t-butoxycarbonyl or benzyloxycarbonyl or benzyl, which protection is subsequently removed again by hydrogenolysis or by treatment with acid, for example with trifluoroacetic acid. The alkyl halides used in this process are well known or can be prepared in well known ways.

The compounds of the general formula I, wherein R 2 is hydroxyl, and R 1 is hydrogen and R 8, R 1, R 1, R and / or R 5 are OR 1, wherein R is alkylcarbonyl having a straight or branched chain alkyl radical of 1-6 carbon atoms, benzoyl or phenylalkylene carbonyl with a straight or branched alkylene radical having 1-6 carbon atoms, prepared by the corresponding derivative, wherein R iq is hydrogen, 1-24 hours at 25-100 ° C in the presence of an organic base such as pyridine, quinoline or triethyl amine, which serves as a solvent, to be treated with an acid anhydride of the formula 18 or an acid halide of the formula 19, wherein Hal 15 is chlorine or bromine and R 2 is a straight or branched chain alkyl group with 1-6 carbon atoms phenyl or phenylalkylene with a straight or branched chain alkyl radical containing 1-6 carbon atoms, provided that before the reaction the α-amino group and optionally the carboxyl group of the starting hydroxyl compound are suitably protected, for example with t- butoxy-20 approx rbonyl or benzyloxycarbonyl or benzyl, which is then removed by treatment with acid, for example with trifluoroacetic acid and hydrogenolysis. The acid anhydrides and acid halides used in this reaction are well known or can be prepared from the appropriate acids in well known ways.

The compounds of the general formula 1, wherein R 2 is a straight or branched chain alkoxy group having 1 to 8 carbon atoms, can be prepared by treating the corresponding derivative, wherein R 2 is hydroxyl, with thionyl chloride to form the acid chloride which reacts with an alcohol of formula R2gOH at 25 ° C for 4-12 hours, wherein R22 represents a straight or branched chain alkyl group with 1-8 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, hexyl or octyl.

The compounds of the general formula 1, wherein R 2 represents -NR 1 Rg, wherein R 1 and R 5 each are hydrogen or a straight or branched chain alkyl group having 1 to 4 carbon atoms, can be prepared by an acylation reaction of an acid halide, for example an acid chloride of the corresponding compound, wherein R 2 is hydroxyl and R 1 has the same meaning as in formula 1, with the proviso that an optional bad origin free amino group is suitably protected, for example, with carbobenzyloxy or t-butoxycarbonyl and when R 1, R 1, R 1, and / or R '1, OR 2 g, and r 1 is hydrogen, such a group is protected as the corresponding alkyl-carbonyloxy group, with an excess of appropriate amine, which may be represented as HNR ^ Rg. The reaction is carried out in methylene chloride, chloroform, dimethylformamide, ethers such as tetrahydrofuran or dioxane, or benzene for 1-4 hours at 25 ° C. Suitable amines are, for example, ammonia, or a compound which is a potential ammonia source, for example hexamethylene tetramine, primary amines, for example methylamine, ethylamine or n-propylamine or secondary amines such as dimethylamine, diethylamine or di-n-butylamine. After the acylation reaction, the protecting group of the amino group is removed by treatment with acid, for example hydrogen bromide in dioxane or hydrolysis, and the protection of the hydroxyl group, if applicable, is removed by basic or acid hydrolysis.

The compounds of the general formula 1, wherein R 1 represents a group of the formula 14, can be prepared by the corresponding derivative, wherein R 1 is hydroxyl or a functional derivative thereof, for example an acid anhydride and R 1 has the same meaning as in the formula 1, with the proviso that an optional free amino <20 group is suitably protected, for example as benzyloxycarbonyl or t-butoxy carbonyl, for 1-24 hours at 0-50 ° C in an ether, for example tetrahydrofuran or dioxane. reacting with a compound of formula 20 wherein .Rg has the same meaning as in formula 1 and R24 represents a lower alkyl group, for example methyl or ethyl, followed by acid hydrolysis to remove the protecting group, with the which, when using the free acid, of which the amino group is protected, performs the reaction using a derhydrating agent, for example, dicyclohexylcarbodiimide.

The compounds of general formula 1, wherein R 1 alkylcarbonyl having a straight or branched chain alkyl radical containing 1 to 4 carbon atoms, can be prepared by the corresponding derivative, wherein R 1 is hydrogen and R 1 hydroxyl, for half an hour to 6 hours at 0-25 ° C in water, in the presence of a base such as sodium hydroxide or sodium borate, to be treated with an acid halide of formula 21, wherein hal is a halogen atom, for example chlorine or bromine and R2g is a straight or branched BAD ORIGINAL 8 0 0 2 4 1 7 23 # represents alkyl group of 1-4 carbon atoms. These compounds can also be prepared from the ester derivative, i.e. from a compound of the general formula 1 wherein R 1 is hydrogen and an alkoxy group of 1-8 carbon atoms, by such a derivative at 0-25 ° C for half to 24 hours. in water, methylene chloride, chloroform or dimethylacetamide in the presence of a base such as sodium hydroxide, potassium hydroxide or excess triethylamine with the acid halide of formula 21 as described above.

The compounds of the general formula 1, wherein R 1 is alkoxycarbonyl with a straight or branched chain alkoxy radical having 1 to 4 carbon atoms, can be prepared by the corresponding derivative, wherein R 1 is hydrogen and R 1 hydroxyl, for half to 6 hours at 0-25 ° C in water in the presence of a base such as sodium hydroxide or sodium borate, to be treated with an alkyl haloformate of formula 22 wherein hal is a halogen atom such as chlorine or bromine and represents a straight or branched chain alkyl group of 1-4 carbon atoms.

The compounds of the general formula I, wherein R 1 represents a group of the formula 23, wherein R 1 is hydrogen, a straight or branched chain alkyl group containing 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl, can be prepared by the corresponding derivative wherein Rj is hydrogen and Rj represents a straight or branched chain alkoxy group having 1 to 8 carbon atoms, treating for 1-12 hours at 0-35 ° C with an acid of the formula 24 or an anhydride thereof, wherein the amino group is suitably is protected, for example, if benzoxycarbonyl or t-butoxycarbonyl group and Ry has the above meaning, in an ether, for example tetrahydrofuran or dioxane, methylene chloride or chloroform and in the presence of a dehydrating agent, when the free acid is used, followed by acidic and basic hydrolysis to remove the protecting groups. Optionally, the basic hydrolysis can be omitted, whereby the ester peptide derivative is obtained.

The individual optical isomers of compounds of the formula 1, wherein hydrogen and R 2 is hydroxyl, can be separated using a (+) or (-> binaphthylphosphoric acid salt according to the method of R. Viterbo et al., Tetrahedron Letters 48, 4617 (1971) Other splitting agents can also be used as (+) camphor-BAD ORIGI & 0 2 4 17 24 10-sulfonic acid The Individual optical isomers of the compounds of the formula wherein R 1 and R 2 are other than hydrogen or hydroxyl can be obtained as described for the racemic mixture, but starting from the cleaved amino acid.

The compounds of general formula 5 can be prepared by treating one equivalent of glycinate of formula 6, in which Rft, R 1 and Rc have the same meaning as in general formula 5, with one equivalent of a strong base such as an alkyl lithium, for example butyl lithium or phenyl lithium, lithium di-alkylamide, for example lithium-10-diisopropylamide, or lithium amide, t-potassium butylate, sodium amide, a metal hydride such as sodium hydride, a tertiary amine such as triethylamine, lithium acetylide or dilithium acetylide, followed by treatment with the alkylating agent wherein R 1, R 12, R 13, R 12 and R 14 have this meaning when in formula 5 and X is halogen, for example chlorine d 15 or bromine. The alkylation can be carried out in an aprotic solvent, for example benzene, ethers, tetrahydrofuran, diraethyl sulfoxide or hexamethylphosphoric triamide. The reaction time varies from half to 24 hours and the temperature from -120 to 25 ° C.

The compounds of the general formula 6 can be used. prepare by treating an appropriate alkyl glycinate with a carbonyl compound to form a base of Schiff, in a well known manner, typically (a) when R 1 is hydrogen, by treating the appropriate amino acid ester with benzaldehyde or a straight or branched alkanal having 1 to 9 carbon atoms, for example propanal-1, butanal-1, 2,2-dimethylpropanal-25, or 2,2-diethylbutanal-1,1 (b) as phenyl, by treatment of the appropriate amino acid ester with benzophenone or a phenyl or alkyl ketone with a straight or branched chain alkyl radical of 1 to 8 carbon atoms, for example phenyl methyl ketone, phenylethyl ketone, phenyl isopropyl ketone, phenyl n-butyl ketone or phenyl t-butyl ketone and (c) as R 1, straight or branched chain alkyl group with 1 Is 8 carbon atoms, treatment of the appropriate amino acid ester with a phenyl alkyl ketone as defined above, with a dialkyl ketone, wherein each alkyl radical is straight or branched and contains 1 to 8 carbon atoms, for example dimethyl isopropyl ketone, di-n-butyl ketone or meth yl-t-butyl ketone. The carbonyl compounds are well known or can be prepared in well known ways.

BAD ORIGINA & 0 0 2 4 1 7 25 *

When in the compounds of formula 6 there is methoxy or ethoxy, an appropriate alkyl glycinate is reacted with a benzoyl halide, for example the chloride or an alkanoic acid halide, for example the chloride, the alkanoic acid being straight or branched and containing 1 to 9 carbon atoms, for example acetyl chloride, propionyl chloride, butyryl chloride, t-butyryl chloride, 2,2-diethylbutyryl chloride or valeryl chloride, at 0 ° C in an ether, methylene chloride, dimethylformamide, dimethyl acetamide or chlorobenzene in the presence of an organic base such as triethylamine or pyridine, after which the allow the reaction mixture to warm to 25 ° C for 1 hour. The amide derivative obtained, at 25 ° C, is dissolved in a chlorohydrocarbon such as methylene chloride, chlorobenzene or chloroform, an alkylating agent such as methyl fluorosulfonate, dimethyl sulfate, methyl iodide, methyl p-toluenesulfonate or trimethyl oxonium hexafluorophosphate, methyl carbonate , or triethyloxonium tetrafluoroborate, as ethoxy, and heat the resulting reaction mixture at reflux for 12-20 hours. The reaction mixture is then cooled to 25 ° C, an organic base is added, for example triethylamine or pyridine, the solution is extracted with brine and the product is recovered.

When and Rc in the compounds of the formula VI together form an alkylene group of 5-7 carbon atoms, said amino acid ester derivatives can be obtained by treating the amino acid ester with a cyclic alkanone, namely cyclopentanone, cyclohexanone or cycloheptanone, under formation of a Schiff base in a well known manner.

The alkyl glycinates can be obtained by treating glycine at 25 ° C for 12-36 hours with an alcohol of the formula RH, wherein R has the same meaning as in the formula 6, which is saturated with aa HCl gas, or the compounds are obtained off the market,

The compounds of the general Formula 7 are well known or can be prepared from the corresponding appropriately substituted benzoic acid and benzaldehyde derivatives which are well known. For example, the benzyl halides of formula 7 can be prepared from the corresponding benzaldehyde by reduction with sodium borohydride, lithium aluminum hydride, or by catalytic reduction of the corresponding benzoic acid ester with lithium aluminum hydride or boran or BAD ORI (Sr (k0 2 4 17 9 26 reduction of the corresponding benzoic acid derivative with lithium hydride and treatment of the benzyl alcohol derivative thus formed with, for example, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride.

Certain compounds of the general formula V can be obtained directly from the appropriate amino acid by converting this acid into an appropriate ester, followed by protecting the α-amino group according to the above-described methods of protecting the amino group of the alkyl glycinate. For example, the ester derivative of tyrosine or phenylalanine with protected amino group can be obtained in such a manner. This method cannot be used to prepare compounds of the formula [II] whose aromatic ring contains a hydroxyl group in the meta position.

The following Example I employs the use of a compound of the general formula II wherein R1 is hydroxyl as a chemical intermediate in the preparation of a cephalosporin of the formula II.

Example I

7- / ~ / ~ 2-Difluoromethyl-2-amino-3-phenylpropionyl / anino / - 3-acetyloxyraethyl-20 8-oxo-5-thia-1-azabicyclo / _ 4.2.0 / octene-2-2- carboxylic acid.

A mixture of 1 g of 3-acetyloxy-7-araino-8-oxo-5-thia-1-azabicyclo / 4.2.0 / octene-2-2-carboxylic acid and 1 g of 2-i -difluoromethyl-2- is heated anino-3-phenylpropionic acid chloride, of which the free amino group is protected with t-butoxycarbonyl, in a reflux condenser in 50 ml of ethyl acetate for 2 hours, after which time the solvent is removed leaving a residue which is treated with weak acid and over silica gel chromatographs using benzene-acetone as an eluent to give 7- / 2-2-difluoromethyl-2-amino-3-phenyl-30-propionyl / amino-3-acetyloxy-methyl-8-oxo-5-thia-1 -azabicyclo [4.2.0] -Octene-2-2-carboxylic acid.

The following Examples II to IV relate to pharmaceutical preparations of the compounds of the invention. Example II

35. A good example of a filling for hard BAD ORIG0M§L () 2 4 17. 27.

Gelatin capsules are the following formulation: (a) 2-difluoromethyl-2-amino-3- (3-hydroxyphenyl) propionic acid 20 mg (b) talc 2 mg 5 (c) lactose 90 mg

The preparation is prepared by passing the dry powders of (a) and (b) through a sieve and mixing them well. The powder is then filled into hard gelatin capsules with a net filling of 115 mg per capsule.

Example III

A good example of a tablet composition is: (a) 2-difluoromethyl-2-amino-3- (3,4-dihydroxyphenyl) propionic acid 400 mg (b) starch 43 mg 15 (c) lactose 45 mg (d) magnesium tearate 2 mg

The granulated product, which is obtained after mixing the lactose with compound (a) and part of the starch and granulation with starch paste, is dried, sieved and mixed with the magnesium stearate. The mixture is pressed into tablets of 490 mg each. Fr; fr;

Example IV

A good example of an injectable suspension is the following 1 ml ampoule for intramuscular injection.

25 wt% (a) 2-difluoromethyl-2-amino-3- (4-hydroxy-phenyl) propionic acid 1.0 (b) polyvinylpyrrolidone, 0.5 (c) lecithin 0.25 (d) water for injection in addition to 100.0

The components (a) - (d) are mixed, homogenized and filled into 1 ml ampoules, which are sealed and autoclaved for 20 minutes at 121C. Each ampoule contains 10 mg of new compound (a) per ml. .....] The following examples serve to further illustrate the compounds of the general formula 1-8002417

BAD ORIGINAL

28 ê

Example V

1-fluoro-3- (3,4-dimethoxyphenyl) -2-propanone.

Under a nitrogen atmosphere, 12.20 g of 3,4-dimethoxybenzyl chloride in 80 ml of tetrahydrofuran (THF) are slowly added (within 5 hours) to 3.0 g of magnesium shavings in 50 ml of THF, the flask being

immersed in a room temperature water bath. Stirring is continued for 1 hour, after which the Grignard reagent is separated from the excess magnesium and transferred to a second flask (under nitrogen) and cooled to -20 ° C. 4.0 g of CH 2 FCN in 25 ml of THF are added from a dropping funnel at a rate such that the internal temperature is maintained between -25 and -20 ° C. After adding everything, stirring is continued for 1 hour at -20 ° C and then the solution is poured onto a mixture of 200 g of ice, 240 ml of water and 120 ml of concentrated hydrochloric acid and extracted with 2 x 100 ml of petroleum ether and 4 x 100 ml diethyl ether. After drying over sodium sulfate and evaporation of the ether extract, 4.53 g or 33% pure ketone, boiling point 100 ° C / 0.35 mm Hg, is obtained. Example VI

2-amino-2-fluoromethyl-1-3- (3,4-dimethoxyphenyl) propionic nitrile.

To a suspension of 31.5 g or 0.149 mol 1-fluoro-3-20 (3,4-dimethoxyphenyl) -2-propanone and 9.57 g or 0.179 mol ammonium chloride in 170 ml 28% ammonia in water is added 8.77 g or 0.179 mol of sodium cyanide. The reaction mixture is stirred at room temperature under nitrogen for 20 hours. The solid which separates is filtered off on sintered glass and then washed with 50 ml 28% aqueous ammonia.

The solid is dissolved in 1.3 liters of ether and the organic phase is washed with water and then dried with brine and over magnesium sulfate. At the concentration of the solvent, 21.8 g of 2-amino-2-fluoromethyl-1-3- (3,4-dimethoxyphenyl) propionic acid crystallize at mp 76 ° C.

Example VII

2-Fluoromethyl-2-amino-3- (3,4-dihydroxyphenyl) propionic acid.

A solution of 20.7 g or 0.086 mol of 2-amino-2-fluoromethyl-3- (3,4-dimethoxyphenyl) propionic acid in 300 ml of 47% hydrobromic acid in water was heated at 100 ° C for 32 hours under nitrogen. Concentration of the solvent under reduced pressure yields a residual bath solution, which is dissolved in 300 ml of isopropanol. The solution is allowed to mature at 4 ° C for 12 hours. The ammonium bromide which separates is filtered off and washed with 3 x 40 ml of isopropanol. The filtrate is neutralized with 16 g of triethylamine in isopropanol until the pH of the solution reaches 4.5-5. The precipitate that forms is collected and washed intensively with chloroform. The 19.4 g residue is dissolved in 500 ml of water and treated with activated charcoal. When concentrated, 13 g of α-fluoromethyl-DOPA crystallize out. A second batch of 1.2 g of 2-fluoromethyl-2-10 amino-3- (3,4-dihydroxyphenyl) propionic acid, m.p. 230 ° C, is obtained from the mother liquor.

Example VIII

2-amino-2-fluoromethyl-3- (p-methoxyphenyl) propionic nitrile.

Using the appropriate amount of p-methoxybenzyl bromide in place of 3,4-dimethoxybenzyl chloride in the method of Example V gives 1-fluoro-3- (p-methoxyphenyl) -2-propanone which, when the method of example VI in an appropriate amount used instead of 1-fluoro-3- (3,4-dimethoxyphenyl) -2-propanone, the compound 2-amino-2-fluoromethyl-3- (p-methoxyphenyl) -propionic nitrile yields.

Example IX

2-Fluoromethyl-amino-S-CB-methoxyphenylpropionic acid.

A solution of 1.0 g of 2-amino-2-fluoromethyl-3- (p-methoxyphenyl) propionic nitrile hydrochloride is saturated in 40 ml of anhydrous methanol under ice-cooling with dry HCl. The mixture is left overnight at room temperature. Evaporation of the solvent gives the corresponding amide hydrochloride in quantitative yield. Nmr (D2O) J ppm: 6.88 (4H, AB, = 9 Hz), 4.76 (2H, 2AB, J. = 11 Hz, J__ = 46 Hz), 3.64 (3H, s), 3 .08 (2H, AB, Jrir JAB * Uliz) · 30 600 mg of amide hydrochloride thus obtained, dissolved in 50 ml of 3N sodium hydroxide and extracted with 3 x 50 ml of diethyl ether, yield 420 mg of free amide, Nmr (CDC1_) J ppm: 6 94 (4H, AB, J = 9Hz); δ Ad 4.56 (2H, 2AB, = 9 Hz, JHF = 47 Hz); 3.80 (3H, s), 3.0 (2H, AB, = 14 Hz), 1.68 (2H, broad s).

920 g of free amide and 7 ml of 50% by volume of sulfuric acid BAD OR! Gir $ 10 0 2 4 17 30 # were heated in water for 2 hours at 95 ° C. The mixture is diluted with water to a volume of 50 ml and neutralized with a barium hydroxide solution (after which the total volume is 150 ml). An equal volume of 0.2N sulfuric acid is added and the barium sulfate is removed by filtration over celite.

The filtrate is passed over 50 ml of Amberlite resin in the H + form in a column, the resin is neutral washed with water and eluted with 150 ml of 3N ammonium hydroxide. Evaporation of the ammonia fraction gives 390 mg of 2-fluoromethyl-2-amino-3- (p-methoxyphenyl) propionic acid, Nmr (D20 / DC1) J ppm: 7.0 (4H, AB, = 9 Hz), 4, 80 (2H, 2AB, -11 Hz, 10 Yy, = 46 Hz), 3.80 (3H, s), 3.20 (2H, AB, = 14 Hz).

8002417

BAD ORIGINAL

Claims (29)

31 ë A compound of the formula 1, wherein Y represents FCHg, FgCH, CICHg or ClgCH-, R 1 hydrogen, alkylcarbonyl with a straight or branched alkyl radical of 1-4 carbon atoms, alkoxycarbonyl with a straight or branched alkyl radical of 1- 4 carbon atoms, or a group of the formula 13, wherein hydrogen is straight or branched chain alkyl of 1-4 carbon atoms, benzyl or p-hydroxybenzyl, R 9 represents hydroxyl, a straight or branched chain alkoxy group of 1 to 8 carbon atoms, -NHR ^ Rg, wherein Rg and Rg are each hydrogen or a straight or branched alkyl group of 1-4 carbon atoms, or a group of the formula wherein Rg is hydrogen, a straight or branched alkyl group of 1-4 carbon atoms, benzyl or p-hydroxybenzyl represents and has each of the symbols Rg, R ,, R ^, R '^ and the meaning defined in Table A' below, Table A ' 15 R3 R4 R5 R '4 R6 OH CHg Η Η H H OH CHg Η H OH H CHg Η H OH OCHg Η Η H 20 OH H OH Η H OH Η Η H CHg OH H OCHg Η H OH Η H OH H OH CHg OH Η H 25 OH Η Η H OH and its pharmaceutically acceptable salts and individual optical isomers. 2. 2-Fluoromethyl-2-amino-3- (3,4-dihydroxyphenyl) propionic acid, or a pharmaceutically acceptable salt thereof. 3. 2-Fluoromethyl-2-amino-3- (3-hydroxyphenyl) propionic acid, or a pharmaceutically acceptable salt thereof. 4. 2-Fluoromethyl-2-amino-3- (4-hydroxyphenyl) propionic acid, or a pharmaceutically acceptable salt thereof. Process for the preparation of a compound according to claim 1, characterized in that (a) when Rj is hydrogen and Rg is hydroxyl, a suitable BAD ORIGINgL0 2 4 17 9 32 protected phenylpropionate of formula 5 wherein R represents a straight or branched chain alkoxy group of 1 to 8 carbon atoms, R 1 hydrogen, phenyl, a straight or branched chain alkyl group of 1 to 8 carbon atoms, methoxy or ethoxy, R 1 phenyl, a straight or branched chain alkyl 5 represents 1 to 8 carbon atoms, or and Rc together represent an alkylene group of 5 to 7 carbon atoms and each of the symbols Rn, R12, Rj2> R 'j2 and Ri4 has the meaning defined in Table B' below, Table B * 10- R11 R12 R13 Rt12 R14 och3 ch3 H H H H OCH3 CH3 Η H och3 h ch3 H H OCH2Ph OCH3 Η Η H 15 OCH3 H OCI3 Η H OCH3 hh H CH3 OCH2Ph H 0CH3 Η H OCH3 hh OCH3 h OCH3 CH3 OCH3 hh 20 0CH3 hhh 0CH3 treated with a strong base and the intermediate carbaanion thus obtained for half to 24 hours at -120 to 65 ° C in an aprotic solvent treated with a suitable halomethylalkylating agent followed by acid hydrolysis, (b) when R2 is a straight or branched chain alkoxy group having 1 to 8 carbon atoms, the corresponding derivative wherein R2 is hydroxyl reacts with thionyl chloride, followed by treatment with an alcohol of the formula R ^ OH, wherein R23 is a straight or branched chain alkyl group of 1 to 8 carbon atoms, at 25 ° C, for 4 to 12 hours, (c) when R2 is -NR ^ Rg, where R ^ and Rg have the same meaning as in claim 1, an acid halide of the corresponding derivative, wherein R 2 is hydroxyl and R 1 has the same meaning as in claim 1, except that any free amino-35 group is suitably protected and as Rg, R ^, R ^ and / or R * ^ ORjq * s »where” at RJ0 is hydrogen, these groups are protected as the corresponding alkylcarbonyl BAD ORIG®0-0 2 4 17 33 oxy group, 1 to 4 hours at 25 C in an appropriate solvent treated with an excess of appropriate amine of the formula NHR ^ Rg, wherein R ^ and Rg have the above meaning, followed by acidic or basic hydrolysis or hydrogenolysis, 5 (d) when R2 represents a group of formula 14, where in Rg the same meaning as in claim 1, the corresponding derivative, wherein R 2 is hydroxyl or a functional derivative thereof and R 1 has the same meaning as in claim 1, with the proviso that an optional free amino group is suitably protected, 1 to 24 hours at 10 50 ° C is treated in a suitable solvent with a compound of the formula wherein Rg has the same meaning as in claims I and R24 represents a lower alkyl group, followed by acid hydrolysis, with the proviso that when the free acid is used, of which the am protected in reaction, the reaction is carried out in the presence of a dehydrating agent, (e) when R 1 is alkyl carbonyl with a straight or branched chain alkyl radical of 1 to 4 carbon atoms, the corresponding derivative, wherein R 1 is hydrogen and R 2 is hydroxyl up to 6 hours at 0 to 25 ° C in a suitable solvent, in the presence of a base, treats 20 with an acid halide of formula 21, wherein hal is a halogen atom and R22 is a straight or branched alkyl group having 1 to 4 carbon atoms, (f ) when R 1 is alkoxycarbonyl with a straight or branched chain alkoxy radical having 1 to 4 carbon atoms, the corresponding derivative, wherein R 1 is hydrogen and R 2 hydroxyl, is treated with a base for half to 6 hours at 0 to 25 ° C in water in the presence of a base. haloalkyl formate of formula 22, wherein hal is a halogen atom and R 2 ^ is a straight or branched chain alkyl group of 1 to 4 carbon atoms, (g) when R 1 represents a group of formula 23, where -30 in R 2 has the same meaning eft as in claim 1, the corresponding derivative, wherein R 1 is hydrogen and R 2 is a straight or branched chain alkoxy of 1 to 8 carbon atoms, is treated with an acid of formula 24, or an anhydride at 0-35 ° C for 1 to 12 hours. thereof, in which the above meaning and the amino group is suitably protected, in a suitable solvent and, if the free acid is used, in the presence of a dehydrating agent, followed by acid and basic hydrolysis BAD origjnjlo 2 4 17 34 ê and (h ) if one desires a pharmaceutically acceptable salt, the compound thus obtained reacts with a pharmaceutically acceptable acid or a pharmaceutically acceptable base. 6. Process for preparing a compound of formula 1, wherein Y represents FCH2 ~, Rj represents hydrogen, R2 represents hydroxyl and each of the symbols R3, R19, R5, R '^ and Rg has the meaning defined in Table A below Table A has 10 R3 R4 ^ 5 ® ·? 4 Rg H -0-CH2-0 Η H Η Η Η Η H Η H ORj0 Η H H 0R] 0 Η Η H 15. ORjq OR] 0 Η H ORj0 H Cl Η H H 0R] 0 Cl Η H Cl ORj0 Η Η H Cl ORj0 Cl Η H 20 Cl, F H 0R10 Η H Cl Η Η H CH3 Cl H Cl H CH3 Η H Cl, F H CH3 0RJ0 H CH3 H CH3 25 Cl H CH3 H CH3 Η H 0R] 0 H CH3 Η H 0RJ0 H C2H5 OR] 0 H C2H5 H C2H5 H ORjq H ORjq H 30. ORjq 0R, q ORjq H Η H 0CH3 OH H Η H OH 0CH3 H ORjq ORjq H H H ORjq Η Η Η H 35. H Cl H C2H5 Η H Cl H t-C.HQ 4 9 bath originaS 0 0 2 4 17 continued from table A 35 ê R3 R4 R5 R> 4 R6 Η H 0RiQ H t-C4Hg OH CH3 Η Η H 5. OH CH3 Η H OH H CH3 Η H OH OCH3 Η Η H OH H OH Η H OH Η Η H CH3 10 OH H 0CH3 Η H OH Η H OH H OH CH3 OH Η H OH Η Η H OH or a pharmaceutically acceptable salt or individual optical isomer thereof, wherein R3 and R ^ are both ORjq, where Rjq is hydrogen, or R ^ and R ^ are both ORjq, where R ^ q is hydrogen or R ^ and R ^ together represent -O-CH ^ -O-, or wherein each of the symbols R3, R ^, R ^, R'4 and R ^ is a has other meanings defined in table A, except Rjq is methyl or hydrogen, characterized in that a compound of the formula 7, wherein Xa is chlorine or bromine and each of the symbols Rj j, R ^ j Rl3 'R 'j2 and Rj4 have the meaning defined in table B below. Table B R11 R12 R13 R> 12 R14 -OCO- Η Η H 25 Λ H3C CH3 H -OCO Η HA H3C CH3 30 H -0-CH -ο- Η H Η Η Η Η H Η H 0CH3 Η HH 0CH3 Η Η HH 0CH3 0CH3 Η H 35 0CH3 H Cl Η H BAD ORIGINAL βΟ 0 2 4 IJ Continuation from table B 36 a R11 R12 R13 R> 12 R14 H OCH3 Cl Η H Cl och3 HH h 5 Cl, OCH3 Cl Η H C1, FH OCH3 Η H Cl Η Η H CH3 Cl H Cl H CH3 Η H C1, FH CH3 io och3 h ch3 h ch3 Cl H CH3 H CH3 Η H 0CH3 H CH3 Η H 0CH3 H C2H5 och3 h c2h5 h c2h5 15 H 0CH3 H 0CH3 H h och3 och3 och3 H Η H 0CH3 0CH2Ph H Η H OCH ^ Ph 0CH3 H 0CH3 0CH3 H --- Η H 20 0CH3 Η Η Η H Η H Cl H C2H5 Η H Cl H tC.HQ 4 9 Η H 0CH3 H t_C4H9 och3 ch3 HHH 25. OCH3 CH3 Η H och3 h ch3 HH 0CH2Ph 0CH3 Η Η H 0CH3 H OCH3 hh och3 hhh ch3 30 0CH2Ph H 0CH3 Η H 0CH3 h H 0CH3 h 0CH3 CH3 och3 hh very slowly in a solvent or a mixture of the like ethers at a temperature of -20 to 70 ° C very slowly add magnesium curls for half to 24 hours to the al-BADORW) m 17 37 »thus formed Grignard derivative fluoroacetic nitrile in a ratio of 0.5 to 3.0 in a suitable aprotic solvent at a temperature of -20 to -70 ° C for 10 minutes to 12 hours, add the ketimine salt thus formed with acid until the corresponding ketone hydrolyses, treating this ketone with from 1 to 10 equivalents of sodium cyanide and ammonium salt in a basic or neutral medium, followed by acid or basic hydrolysis of the amino nitrile thus formed to the corresponding amino acid. 7. Compound of formula 10, wherein each of the symbols 10 * 4 i »Rj2» Rj3 »R * | 2 and Ri4 ** e ί ·η Table B has defined meaning below Table B R11 R12 R13 R <12 R14 15 - 0-C-0- Η Η H / \ H3C ch3 H -0-C-0 Η H h3c VCH3 H -0-CH2_0 h H 20 Η Η Η Η H Η H 0CH3 Η HH 0CH3 Η Η HH 0CH3 0CH3 Η H och 3 H Cl HH 25 H 0CH3 Cl Η H Cl och3 H H H Cl 0CH3 Cl h h Cl, F H 0CH3 Η H Cl Η Η H CH3 30 Cl H Cl H CH3 Η H Cl, F H CH3 och3 h ch3 h ch3 Cl H CH3 H CH3 Η H 0CH3 H CH3 35. H 0CH3 H C2H5 och3 h c2h5 h c2h5 H 0CH3 H 0CH3 H badorigi8 & 0 2 4 17 Continued from table B 38 * R11 R12 R13 Rt 12 R14 h och3 och3 och3 H Η H OCH3 OCH2Ph H 5. H OCH2Ph OCH3 H och3 och3 H H H OCH3 h h h h Η H Cl H C2H5 Η H Cl H t-C, H. 4 9 10. H OCH3 H t_C4H9 och3 ch3 H H H H OCH3 CH3 Η H och3 h ch3 H H 0CH2Ph OCH3 Η Η H 15 och3 h och3 H H OCH3 h h h CH3 OCH2Ph H 0CH3 Η H OCH3 h h OCH3 h OCH3 CH3 OCH3 h h. Process for preparing a compound according to claim 7, characterized in that a compound of the formula 7 wherein Xa is chlorine or bromine and each of the symbols Rjj »Rj2» R13 »R'j2 and Rj ^ are the same meaning as in claim 7, in a suitable ether as a solvent or a mixture of such ethers at a temperature of -20 to -70 ° C, it adds very slowly from half an hour to 24 hours to magnesium shavings to the Grignard derivative fluoroacetic nitrile thus formed in a ratio of 0.5 to 3.0 in a suitable aprotic solvent at a temperature of -20 to -70 ° C for 10 minutes to 12 hours, followed by acid hydrolysis of the salt thus formed. Pharmaceutical preparation, characterized in that it contains a compound of the formula 1, 2 or 10 as defined above, or a pharmaceutically acceptable salt thereof. 8002417 BAD ORIGINAL «uwm * · * · 'Ι, ΓΊ' -« - ΐ 5. Improvement of errata in the specification associated with patent application No. 80.02417 Ned. proposed by applicant dated 30 June 1980 On page 31, after line 25, the following line is added to the table: H OH H OH H On page 35, after line 13, the following line is added to the table: H OH H OH H On page 36, after line 32, the following line is added to the table: och3 hhh och3 On page 38, after line 19, the following line is added to the table: OCH3 hhh och3 On page 38, read on line 25: "-20 to +70 ° C". Thü / TB 8002417 BAD ORIGINAL