CH641150A5 - ALPHA-ACETYLENIC AMINO ACIDS. - Google Patents

Description

The invention relates to new compounds of the general formula

CsCH

R

NHR

and their salts.

The compounds mentioned act as inhibitors of decarboxylase aromatic amino acids.

The amino acids tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine (DOPA), tyrosine and phenylalanine are metabolically converted into tryptamine, 5-hydroxy-tryptamine, 3,4-dihydroxyphenethylamine or dopamine, tyramine and phenethylamine by a decarboxylase for aromatic amino acids . The decarboxylase enzyme is believed to be non-specific, particularly as far as peripheral catalysis is concerned. However, there are indications that specific decarboxylase enzymes are present in the brain for each of the two amino acids DOPA and 5-hydroxytryptophan.

The aromatic amines mentioned above are known to participate 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 enzymatically methylated in human red blood cells, plasma and platelets to dimethyltryptamine (DMT). The methylation enzyme is present in numerous mammals and is produced by various types of brain tissue, including humans. DMT, which has strong hallucinogenic or psychomimetic properties, can play a role in the development of schizophrenia and other psychotic diseases. Any agent that blocks the formation of DMT may therefore be useful as an antipsychotic agent. Blocking the decarboxylation of tryptophan leads to reduced tryptamine levels, so that the substrate for DMT formation is eliminated. An aromatic amino acid decarboxylase inhibitor that blocks the conversion of tryptophan to tryptamine may therefore be useful as an antipsychotic agent.

Both 5-hydroxytryptamine (5-HT), the decarboxylation product of 5-hydroxytryptophan, and 3,4-dihydroxyphenethylamine (dopamine), the decarboxylation product of DOPA, are involved in peripheral and central physiological processes, and agents that control the amount of these amines effective control, proved to be useful pharmacological substances. It has been found that the amount of 5-HT and norepinephrine, which is metabolically produced by hydroxylation of dopamine, is higher in the central system or brain in patients with manic symptoms than in people without such a disease. It has also been found that agents which lower the central monoamine level, for example of 5-HT and in particular of norepinephrine, have anti-manic properties in humans, while the monoamine level is increased

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Means can cause mental illness in people who respond to it. Agents that block the formation of 5-HT and dopamine, for example, by inhibiting aromatic amino acid decarboxylase, which converts 5-hydroxy-tryptophan and DOPA to 5-HT and dopamine, can be used as an antipsychotic agent or major tranquilizer in the treatment of mental illness be useful.

It has also been found that substances that inhibit the decarboxylation of DOPA to dopamine are effective in the treatment of Parkinsonism when administered simultaneously with exogenous DOPA or L-DOPA. Parkinson's disease is believed to be at least partially due 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 peripheral enzymatically into dopamine, large amounts must be administered so that centrally increased absorption occurs. DOPA easily crosses the blood / brain barrier, unlike dopamine. 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 to achieve the amount of circulation required for central absorption. Other advantages are also achieved when the decarboxylase inhibitor for the aromatic amino acids is administered together with L-DOPA. By preventing peripheral dopamine formation, side effects attributed to dopamine such as cardiac arrhythmia, nausea and vomiting are avoided.

Research has shown that 5-hydroxy-tryptamine (5-HT) levels are lower in patients with depressive syndromes than in those without such syndromes. The administration of exogenous L-5-hydroxy-tryptophan (L-5-HTP) is therefore effective in the treatment of depressed patients in certain cases. As with DOPA, however, L-5-HTP, which metabolizes slightly to 5-HT peripherally, requires large amounts of L-5-HTP to be administered to achieve elevated central levels of this amino acid. It was found that when an aromatic amino acid decarboxylase inhibitor is administered which catalyzes the peripheral formation of 5-HT from 5-HPT, the amount of exogenous 5-HTP required to achieve elevated central levels is markedly reduced. Thus, inhibitors of aromatic amino acid decarboxylase in combination with exogenous 5-HTP have been shown to be useful in the treatment of depression.

Agents that block peripheral conversion of 5-HTP to 5-HT may be useful for treating other conditions that respond 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 for the treatment of myoclonus. In addition, the administration of exogenous 5-HTP has been found useful in the treatment of insomnia. Simultaneous administration of 5-HTP and a decarboxylase inhibitor for aromatic amino acids is therefore useful in the treatment of these diseases.

Blocking the peripheral formation of 5-hydroxy-tryptamine can lead to further advantageous effects, since it is known that 5-HT is involved, for example, in the etiology of rheumatoid arthrites and carcinoid syndrome due to increased collagen levels. It is also reported that 5-HT is the major autocoid responsible for anaphylactoid reactions in humans and bronchoconstriction in asthmatics, and agents

which antagonize or inhibit the formation of 5-HT are therefore useful in treating these conditions. As is well known, 5-HT causes platelet aggregation and therefore proves to be a causative factor in dumping syndrome after gastric surgery and in migraines. Methylsergide, an antagonist of 5-hydroxytryptamine, has been shown to be effective in the treatment of dumping syndrome.

Phenethylamine, the decar boxylation product of phenylalanine, is believed to contribute to schizophrenic symptoms and trigger migraines as an endogenous compound. Endogenous tyramine, the decarboxylation product of tyrosine, is also believed to be involved in seizure disorders.

It is therefore easy to see that agents which regulate the amounts of aromatic amino acids and amines can be used in numerous pharmacological situations. The compounds according to the invention are inhibitors of aromatic amino acid decarboxylase, which converts tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine, tyrosine and phenylalanine into the corresponding amines; they are therefore useful pharmacological agents.

The compounds according to the invention correspond to the following formula

CH

In formula I above, R means! Hydrogen, an alkylcarbonyl radical with a straight-chain or branched alkyl portion with 1 to 4 carbon atoms, an alkoxy-carbonyl radical with a straight-chain or branched alkoxy portion with 1 to 4 carbon atoms or a radical of the formula

O

—C — CH — R27

I.

NH,

wherein R27 represents hydrogen, a straight-chain or branched lower alkyl radical having 1 to 4 carbon atoms, the benzyl or p-hydroxybenzyl radical. R2 represents a hydroxyl group, a straight-chain or branched alkoxy radical having 1 to 8 carbon atoms, a radical of the formula -NR7R8, in which R7 and R8 represent hydrogen or straight-chain or branched alkyl radicals having 1 to 4 carbon atoms, or a radical of the formula

—NH — CH — COOH,

I.

r8

wherein R9 represents hydrogen, a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, the benzyl or p-hydroxybenzyl radical. Each of the radicals R3, R4, R5, R'4 and R6 has the meaning given in Table I below.

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TABLE I

r3

r4

r5

R'4

Re h

-o-ch2-o-

h h

h h

h h

h h

h o

"H

Pi O

h h

h orJO

h h

h h

orjo orio h

H

OR10

H

Cl h

h h

O

F

O

Cl h

H

Cl o F

o h

h h

Cl orio

Cl h

H

Cl, F

H

O

o h

H

Cl h

h h

ch3

Cl h

Cl h

ch3

h h

Cl, F

h ch3

ORio h

ch3

h ch3

Cl h

ch3

h ch3

h h

orIO

h ch3

h h

orIO

h c2h5

O

fS o h

c2h5

h c2h5

h orio h

O

Pi O

h h

o pT o orJO

orio h

h h

och3

oh h

h h

oh och3

H

O

V-t e

o pi O

h h

h orio h

h h

h h

H

Cl h

approx h

H

Cl h

tert-CAh9

h h

orio h

tert-CJÄ0

understood, wherein the alkyl portion has 1 to 6 carbon atoms and is straight-chain or branched. A benzoyl radical is understood to mean a radical of the formula. A phenylalkylenecarbonyl radical is an io radical of the formula

0

^ Alkylene - & -

15

In this table, R10 means hydrogen, a straight-chain or branched alkyl radical having 1 to 8 carbon atoms, an alkylcarbonyl radical with a straight-chain or branched alkyl radical with 1 to 6 carbon atoms, the benzoyl or a phenylalkylene carbonyl radical with a straight-chain or branched alkyl radical with 1 to 6 carbon atoms. The invention also relates to the salts, preferably the pharmaceutically acceptable salts, and the individual optical isomers of the compounds of the formula I.

The compounds of formula I are useful pharmacological agents. They are inhibitors of aromatic amino acid decarboxylase and are useful as intermediates in the preparation of useful pharmacological agents.

In the above formula I, an alkylcarbonyl radical is a radical of the formula

O

Alkyl — C—

understood, the alkylene portion has 1 to 6 carbon atoms and can be straight-chain or branched. Examples of the alkylene chains are the methylene, ethylene, iso-propylene and butylene radical.

2o Examples of straight-chain or branched alkoxy radicals having 1 to 8 carbon atoms are the methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, tert-pentoxy, n-hexyloxy and n-octyloxy group.

Examples of straight-chain or branched alkyl radicals with 25 1 to 6 carbon atoms are the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and n-pentyl radical.

Examples of pharmaceutically acceptable salts according to the invention are non-toxic acid addition salts which are formed with inorganic acids, for example with hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or with organic acids, for example methanesulfonic acid, salicylic acid, maleic acid, malonic acid , Tartaric acid, citric acid and ascorbic acid, furthermore non-toxic salts which are combined with inorganic or organic bases such as alkali metals, for example sodium, potassium and lithium, alkaline earth metals, for example calcium and magnesium, light metals of group IIIA, for example aluminum, or organic amines, for example primary, secondary and tertiary amines such as cyclohexylamine, 40 ethylamine, pyridine, methylaminoethanol, ethanolamine and piperazine. The salts are made in a conventional manner.

Preferred compounds according to the invention are those of the formula I in which R 1 denotes hydrogen or an alkylcarbonyl radical with a straight-chain and branched alkyl portion having 1 to 4 carbon atoms. Compounds where RL is hydrogen are more preferred. A further preferred embodiment of the invention are compounds of the general formula I in which the hydroxyl-50 grappe or a straight-chain or branched alkoxy radical having 1 to 8 carbon atoms. Compounds in which R2 is the hydroxyl group are more preferred. Compounds of the general formula I in which each of the radicals R3, R4, R5, R'4 and R6 is hydrogen or OR10, 55 where R10 is hydrogen, represent a further preferred embodiment of the invention.

The following are examples of compounds of the formula I according to the invention: 2-acetylene-2-amino-3-phenylpropionic acid, 6o 2-acetylene-2-amino-3- (3-hydroxyphenyl) propionic acid, 2-acetylene-2-amino-3- ( 3,4-dihydrophenyl) propionic acid, 2-acetylene-2-amino-3- (4-hydroxyphenyl) propionic acid, 2-acetylene-2-amino-3- (4-chloro-2-hydroxyphenyl) propionic acid,

65 2-acetylene-2-amino-3- (4-chloro-3-methoxyphenyl) propionic acid,

2-acetylene-2-amino-3- (2-chloro-3-benzoyloxyphenyl) propionic acid,

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

2-acetylene-2-amino-3- (2-chloro-4-hydroxyphenyl) propionic acid, 2-acetylene-2-amino-3- (2-chloro-6-methylphenyI) propionic acid, 2-acetylene-2-amino-3- (2,4-dichloro-6-methylphenyl) propionic acid,

2-acetylene-2-amino-3- (4-chloro-6-methylphenyl) propionic acid, 2-acetylene-2-amino-3- (2-hydroxy-4,6-dimethylphenyl) propionic acid,

2-acetylene-2-amino-3- (2-chloro-4,6-dimethylphenyl) propionic acid,

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

2-acetylene-2-amino-3- (5-ethyl-4-phenylpropionyloxyphenyl) propionic acid,

2-acetyl-2-amino-3- (4,6-diethyl-6-hydroxyphenyl) propionic acid,

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

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

2-acetylene-2- (N-ethoxycarbonylamino) -3- (4-n-butoxyphenyl) propionic acid,

N, N-di-n-propyl-2-acetylene-2-amino-3- (4-acetyloxyphenyl) propionamide,

2-acetylene-2- [N- (2-amino-l-oxoethyl) amino] -3- (3-hydroxy-

phenyl) propionic acid, 2-acetylene-2-amino-3- (3,4-dihydroxy) phenyl-l-oxopropyl-

-aminoacetic acid, 2 - [(2-acetylene-2-amino-1-oxo-3-phenyl) propylamino] dihydrocinnamic acid,

2-acetylene-2- (l-oxoethylamino) -3- (4-hydroxy) phenyl-1-oxo-

propylamino-2-propionic acid, methyl-2-acetylene-2- (l-oxoethylamino) -3- (4-hydroxy) phenyl-

-1-oxopropylaminoacetate, 2-acetylene-2-amino-3-phenylpropionamide, N, N-dimethyl-2-acetylene-2-amino-3- (3-hydroxyphenyl) propionamide,

N, N-diethyI-2-acetylene-2-amino-3- (3 ', 4'-dimethoxyphenyl) propionamide,

N-n-butyl-2-acetylene-2-amino-3- (4-hydroxyphenyl) propionamide,

Methyl 2-acetylene-2-amino-3- (3-hydroxyphenyl) propionate, isopropyl-2-acetylene-2-amino-3- (3,4-dihydroxyphenyl) propionate,

tert-butyl-2-acetylene-2-amino-3- (4-hydroxyphenyl) propionate, ethyl-2-acetylene-2-amino-3- (4-chloro-3-methoxyphenyl) propionate and

2-acetylene-2-amino-3- (4-hydroxyphenyl) propionamide.

The compounds of formula I are irreversible inhibitors of the enzyme which metabolically converts tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine, tyrosine and phenylalanine into tryptamine, 5-hydroxy-tryptamine, 3,4-dihydroxyphenylethylamine, tyramine and Phenethylamine, catalyzed. As already mentioned, studies indicate that the enzyme responsible for the conversion of the above amino acids into the amines in question is a non-specific decarboxylase for aromatic amino acids. In the central conversion, specific decarboxylases are apparently responsible for both the conversion of 5-hydroxytryptophan and 3,4-di-hydroxyphenylalanine, while the remaining amino acids listed above are converted enzymatically to the amines in question by a non-specific decarboxylase. The compounds according to the invention irreversibly inhibit the action of the non-specific aromatic decarboxylase centrally and peripherally

Amine acids and the effect of 3,4-dihydroxyphenyl-alanine (DOPA) decarboxylase. “Central” in relation to the effectiveness of the compound is understood to mean the action on the central nervous system, in particular the brain, while “peripheral” is understood to mean other body tissues in which the decarboxylase enzyme is present. The selectivity of the central or peripheral inhibition of the amino acid decarboxylases by administration of the compounds of the formula I is quantity-dependent.

As irreversible inhibitors of aromatic amino acid decarboxylase and DOPA decarboxylase, the compounds according to the invention have various pharmacological uses. As peripheral irreversible inhibitors of aromatic amino acid decarboxylase, the compounds of the formula I are useful for the treatment of Parkinson's disease when administered in conjunction with 3,4-dihydroxyphenylalanine (DOPA) or L-3,4-dihydroxyphenylalanine (L-DOPA) . DOPA, and in particular the more active isomer L-DOPA, are known agents for treating Parkinsonism when administered systemically, usually in amounts of 0.5 to 1 g / day initially, followed by the amount to be administered gradually over the course of 3 to 7 Days to a maximum tolerated daily dose of about 8 g. The simultaneous administration of a compound of formula I with L-DOPA represents an improved method for the treatment of Parkinson's disease, since the compounds of formula I are the peripheral decarboxylation of L-DOPA to L-3,4-dihydro-phenethylamine Block (L-dopamine) by inhibiting the activity of the decarboxylase enzyme, so that high circulating amounts of L-DOPA are maintained for central absorption and the peripheral formation of increased amounts of dopamine is avoided, which is known to have undesirable side effects Cardiac arrhythmia leads. By simultaneously administering a compound of formula I with L-DOPA, the amount of L-DOPA can be reduced by 2 to 10 times, based on the amounts required when L-DOPA is administered alone. The compounds according to the invention are preferably administered before the 40 L-DOPA. For example, a compound of Formula I can be given 30 minutes to 4 hours before L-DOPA administration, depending on the mode of administration and the condition of the patient being treated.

The compounds of formula I are also useful 45 for the treatment of depressive syndromes, given together with 5-hydroxytryptophan (5-HTP) or in particular the more active, left-turning isomer, which is known to be suitable for the treatment of depression when administered systemically. The compounds of For-50 mei I peripherally inhibit the effectiveness of the decarboxylase for aromatic amino acids and block the conversion of 5-hydroxytryptophan to 5-hydroxytryptamine while maintaining higher circulating amounts of 5-HTP for central absorption. The compounds of formula I, when administered simultaneously with exogenous 5-HTP, are also useful for the treatment of myoclonus which, as is known, can be successfully treated by increasing the central amount of 5-HTP.

The compounds of the formula I, owing to their peripheral inhibitory action on the decarboxylase of aromatic amino acids, are also useful for the treatment of rheumatoid arthritis, carcinoid syndrome, anaphy-lactoid reactions in humans, bronchoconstriction in asthmatics and other conditions which are caused by high 65 peripheral 5- Hydroxytryptamine levels are caused.

As already mentioned, it was found that agents which reduce increased amounts of 5-HT and norepinephrine, the hydroxylation product of dopamine, were used for the treatment

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suitable for patients with manic symptoms. The compounds of the formula I are therefore suitable as central irreversible inhibitors of the decarboxylase of aromatic amino acids and of the DOPA decarboxylase for the treatment of manic symptoms. Because of the central inhibitory effect of the compounds of the formula I on the decarboxylase of aromatic amino acids, these compounds are also suitable as antipsychotic agents, since the central amounts of tryptamine are reduced, and also for the treatment of schizophrenia and seizure disorders, since the central amounts of phenethylamine and tyramine are caused by Administration of a compound of formula I can be reduced.

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 to rats or mice in aqueous solution or suspension. At various times after administration of the compound between 1 and 48 hours, the animals are decapitated and the decraboxylase activity is measured radiometrically according to the method of Christenson et al., Arch. Biochem. Biophys. 141, 356 (1970) in homogenates from kidneys, heart and brain, which according to Burkard et al., Arch. Biochem. Biophys. 107,187 (1964).

The compounds according to the invention can be administered in various ways in order to achieve the desired effect. The compounds can be administered orally or parenterally, either alone or in the form of pharmaceutical preparations, for example subcutaneously, intravenously or intraperitoneally. The compounds can also be added by dripping into the nose or by application to mucous membranes of the nose, throat and bronchial tubes, for example in an aerosol spray which contains small particles of a compound according to the invention in a spray solution or in dry powder form.

The amount to be administered is any effective amount. Depending on the patient, the disease to be treated and the mode of administration, the amount can vary over a wide range, which is the effective amount in a unit dose. If the compounds of formula I e.g. administered to effect peripheral irreversible inhibition of the amino acid decarboxylase, the effective amount is about 0.1 to 100 mg / kg body weight / dose, and preferably about 5 to 25 mg / kg. For example, the desired peripheral effect can be achieved by taking a dose unit, for example a tablet with 10 to 250 mg of a new compound according to the invention 1 to 4 times a day. If the compounds of the formula I are administered to effect a central irreversible inhibition of the aromatic amino acid decarboxylase or 3,4-dihydroxyphenylalanine decarboxylase, the effective amount is preferably about 100 to 500 mg / kg of body weight / day, and in particular about 150 to 300 mg / kg body weight. For example, the desired central effect can be achieved by taking a dose unit, for example fine tablets with about 350 to 500 mg of a new compound according to the invention 1 to 4 times a day.

The patient is understood to mean warm-blooded animals such as mammals, for example cats, dogs, rats, mice, guinea pigs, sheep, horses, cattle, cows and humans.

A fixed dose unit can be conventional. For example, it can be a capsule, for example an ordinary gelatin capsule, which contains the new compound according to the invention and a carrier, for example lubricants and inert fillers such as lactose, cane sugar and corn starch. In a further embodiment, the compounds according to the invention can be tableted with conventional tablet bases such as lactose, cane sugar or corn starch and binders such as gum acacia, corn starch or gelatin, disintegrants such as corn starch, potato starch or alginic acid and lubricants such as stearic acid or magnesium stearate.

For parenteral administration, the compounds are usually administered as a solution or suspension in a physiologically acceptable diluent with a pharmaceutical carrier which may consist of a sterile liquid such as water or oils, optionally with the addition of surface-active and other pharmaceutically acceptable auxiliaries. Examples of oils which can be used in these preparations are oils of petroleum, animal or vegetable or synthetic origin, for example peanut oil, soybean oil and mineral oil. Preferred liquid carriers, in particular for injectable solutions, are generally water, saline, aqueous dextrose solution and similar sugar solutions, ethanols and glycols such as propylene glycol or polyethylene glycol.

The compounds according to the invention can be administered in the form of a depot injection or as an implant, so that there is delayed release of the active ingredient. The active ingredient can be pressed into pellets or small cylinders and given subcutaneously or intramuscularly as a depot injection or implant. In the case of implants, inert materials such as biodegradable polymers or synthetic silicones, for example Silastic (silicone rubber from DOW-Corning-Corporation) can also be used.

For use as aerosols, the new compounds are preferably packaged in solution or suspension in aerosol containers which are under pressure, with the use of a gaseous or liquefied propellant such as dichlorodifluoromethane, dichlorodifluoroethane and carbon dioxide, nitrogen or propane, the usual auxiliaries such as co-solvents and wetting agents can be added as needed or desired. The compounds can also be administered without pressure using nebulizers.

As already mentioned, the compounds of the formula I find particular use in the case of simultaneous administration with exogenous L-DOPA, individual formulations being administered with a compound of the formula I and L-DOPA or the two active compounds being combined to form a combined formulation. In any case, the amount of the compound of the formula I is preferably about 1: 1 to 1:10 compared to the L-DOPA. A combination preparation can contain an inner part with the L-DOPA and an outer part with the compound of the formula I, each active ingredient being suitably formulated. A particularly advantageous combination formulation can be produced by pressing L-DOPA, optionally with suitable carriers, into a core, providing this core with a laminate layer which is resistant to gastric juice, and applying an outer layer over the coated core, which connects the Formula I contains in a suitable formulation. When using such a combination formulation, the decarboxylase inhibitor, that is to say the compound of the formula I, is preferably given 30 to 60 minutes before the L-DOPA. The laminate coating can be formed using a non-aqueous solution of glycerides or a water-insoluble polymer such as ethyl cellulose or cellulose acetate phthalate. Formulations can also be used in which the L-DOPA has been given an enteric coating by using mixtures of Shellack and Shellack derivatives and cellulose acetate phthalates.

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Suitable pharmaceutical formulations are described in the following examples of use.

The compounds of formula I are not only useful pharmacological agents, but are also useful as intermediates for the preparation of useful cephalosporin antibiotics. Compounds of the formula I in which R2 represents the hydroxyl group are particularly useful in the preparation of cephalosporin derivatives of the following formula X:

Rs

R * 4 6

CsCH

I / S

CHa-C-CONH r-f

NHRi

0 COOM

H = N-rrsi_

o I

ch2x

XI

10th

coom where X and M have the meaning given for formula X, couples with an acid of the formula

, ^ 3

CH2x (S

15

CsCH • CHa-C-COOH

^ I

// -

XII

R "

NH;

In formula X, Rw R3, R4, R5, R'4 and R6 have the meaning given for formula I. M means hydrogen or a negative charge and X means hydrogen or the acetoxy radical.

The compounds of formula X and their pharmaceutically acceptable salts and the individual optical isomers are new compounds which are useful as antibiotics and can be administered similarly to the known cephalosporin derivatives such as cephalexin, cephalothin or cephaloglycin. The compounds of formula X, their pharmaceutically acceptable salts and isomers can be administered alone or as pharmaceutical preparations orally or parenterally and topically to warm-blooded animals, that is to say to birds and mammals, for example cats, dogs, cattle, cows, sheep, horses and People. For oral administration, the compounds are given as tablets, capsules or pills, or in the form of elixirs or suspensions. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other dissolved components, for example the amounts of table salt or glucose required to form an isotonic solution. For topical administration, the compounds of the formula X, their salts or isomers are preferably incorporated into creams or ointments.

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

Examples of pharmaceutically acceptable non-toxic inorganic acid addition salts of the compounds of the formula X are salts with mineral acids, for example chloride, bromide, sulfate, sulfamate, phosphate, furthermore salts with organic acids, for example the maleate, acetate, citrate, oxalate, succinate, Benzoate, tartrate, fumarate, malate and ascorbate. The salts are formed in a conventional manner.

Examples of cephalosporin derivatives of the formula X are the 7 - {[2-acetylene-2-amino-3-phenylpropionyl] amino} -3 - acetyloxymethyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct- 2-ene-2-carboxylic acid, 7 - {[2-acetylene-2-amino-3- (3-hydroxyphenyl) propionyl] amino [-3-acetoxymethyl-8-oxo-5-thia-l-azabicyclo- [4.2.0] oct-2-en-2-carboxylic acid, 7 - {[2-acetylene-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, and 7- {[2-acetylen-2-amino-3- (4-hydroxyphenyl) propionyl] amino} - 3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

The compounds of formula X wherein Rx is hydrogen can be prepared by using 7-amino-cephalosporanic acid or a derivative thereof of the formula or a functional derivative thereof such as the acid chloride or an acid anhydride, in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, if the free acid is used, where R3, R4, R5, R'4 and R6 have the meaning given for formula X and the amino group is protected by a suitable protective group such as, for example, the tert-butoxycarbonyl radical. Subsequently, acidic hydrolysis is usually carried out to remove the amino protective groups.

The coupling reaction is generally carried out in a solvent such as ethyl acetate, dioxane, chloroform or tetrahydrofuran in the presence of a base such as alkali bicarbonate. The reaction temperature can be about -10 to 100 ° C and the reaction time can be about Yi to 10 hours. The cephalosporin products are usually isolated using conventional methods. The compounds of the formula XII are preferably prepared by the processes described above. The compounds of the formula XI are commercially available or can be prepared by known processes.

The compounds of formula X, wherein R i is different from hydrogen, can be formed from the corresponding derivatives, in which R t is hydrogen, using the methods described below for compounds of formula I according to the invention, in which R x is not hydrogen .

New compounds of the formula

45

50

(IA)

55 and their salts are obtained according to the invention by using a protected propargylamine of the formula

60

(Rie) 3 ~ S Î-C = C ~ ÇH2

N = C-Ri7 (II) I

Ria

65 in which crack is CrQ-alkyl,

R17 is phenyl, tert-butyl, triethylmethyl, 1-adamantyl or 2-furyl and

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R18 is hydrogen, methoxy or ethoxy,

with the proviso that when R17 is 1-adamantyl or 2-furyl, R18 is not hydrogen, treated with a strong base to form a protected propargylamine carbanion of the formula groups are removed hydrolytically and any compounds obtained are converted into corresponding salts. The new compounds of the formula

(Ri®) 3-S ï-CsC-CH ^

I; at)

N —C * ■ R17

I.

Ria

10th

C-CH

1

Hs-C-COOH

(ID)

llH-

alkylated with a 2,3-isopropylidenedioxybenzyl halide, reacting the alkylated compound with a strong base to form an alkylated propargylamine carbanion, acylating this propargylamine carbanion accordingly, the alkylation and acylation reactions in a solvent at Y1 to 24 hours at -120 to 25 ° C are carried out and, finally, the protective groups present are removed hydrolytically and the compounds obtained are converted, if appropriate, into corresponding salts.

New compounds of the formula

H0 H c = CH

I.

-V> -CHa-C-C0OH (iB)

H H NH »

and their salts 15 in which the substituents Rs, R4, Rs, R'4 and Rg are defined in Table IA below are prepared according to the invention by preparing, as described above, a protected propargyl anion of the formula III, this with a Compound of formula

20th

TABLE IA

HO

and salts thereof are obtained according to the invention by first preparing, as described above, a protected propargylamine carbanion of the formula III, alkylating it with a 3,4-isopropylidenedioxybenzyl halide, reacting the alkylated compound with a strong base to form an alkylated propargylamine carbanion, this propargylamine carbanion correspondingly acylated, the alkylation and acylation reactions being carried out in a solvent for from Yi to 24 hours at −120 to 25 ° C. and finally the protective groups present being removed hydrolytically and any compounds obtained being converted into appropriate salts.

Other new compounds of the formula

H2C,

O.

H

1 - ^ K-r '= CH

0 \\ / -cha-c-cooh

(IC)

V f

H H

NH.

and their salts are prepared according to the invention by, as already described, preparing the compound of formula III and alkylating it with a 3,4-methylenedioxybenzylhalogenide, reacting the alkylated compound with a strong base to form an alkylated propargylamine carbanion, this Propargylamine carbanion correspondingly acylated, the alkylation and acylation reactions being carried out in a solvent for from Yl to 24 hours at −120 to 25 ° C. and finally any protective

Rs re

Rs

R'4

Rs

25th

H

H

H

H

H

H

H

OCH3

H

H

H

OCH3

H

H

H

30 h

OCH3

OCH3

H

H

_ OCH3

H

Cl

H

H

H

OCH3

Cl

H

H

35 cl

OCH3

H

H

H

Cl

OCH3

Cl

H

H

Cl, F

H

OCH3

H

H

40 cl

H

H

H

ch3

Cl h

Cl

H

ch3

H

H

Cl, F

H

ch3

45 OCH3

h ch3

h ch3

Cl

H

ch3

H

ch3

h h

och3

H

ch3

50 h

H

OCH3

H

ça

OCH3

H

c2h5

h cft

H

OCH3

H

OCH3

H

55 H.

OCH3

och3

OCH3

H

H

H

och3

Oh

H

h h

Oh

OCH3

H

60 ochj

OCH3

h h

H

OCH3

h h

h h

h h

Cl h

ça

65 h h

Cl h

tert-c4h9

h h

OCH3

h ferf-C4H9

11

641150

Ri 1

(V)

wherein Y represents a halogen atom and the radicals Rn, R12, Ri3, R'12 and R14 correspond to the radicals R3, R4, Rs, R'4 and R6, alkylated, the alkylated compound is reacted with a strong base to add an alkylated propargylamine carbanion form, this propargylamine carbanion accordingly

(Ri6) S ~ S i-C = C-CH2 (II)

N "s = C

l

Ria strong base acylated, wherein the alkylation and acylation reactions are carried out in a solvent for% to 24 hours at -120 to 25 ° C and finally existing protective groups are removed hydrolytically and 5 compounds obtained optionally converted into corresponding salts.

The processes according to the invention for the preparation of the new compounds of the formulas IA, IB, IC and ID can be summarized schematically as follows: io The alkylated propargylamine derivative is treated with a strong base to form an alkylated propargylamine carbanion, and this second carbanion intermediate is reacted with an acylating agent, after which the protective groups are removed, as can be seen from the following 15 shears:

! (Rie) s ~ S i-CHC-CH ^

i

»

(Iii)

.18

Connection 1

IRi sY

I - - -, (Rie) 3-S Î-ChC-CH

I Ris 1 |

I / r, \. m-ì strong N = C-Ri7

(Riq) 3-Si-ChC-Ç * ', base |

1 I <Ria l N = C-RI7.

I 1

i Ria I connection 2

Acylating agent

\ y

I.

19th

distance

(Ria) 3 ~ SÏ-C = C-C-R20 the protective

I group

N = C-R17

Ria

CHS

I.

HCHC-C-C00H I

NHo

VIII

In the above reaction scheme, R16 represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, for example the methyl, ethyl, n-propyl and tert-butyl radical. R17 denotes the phenyl, tert-butyl or 60 triethylmethyl, 1-adamantyl or 2-furyl radical. R18 represents hydrogen, the methoxy or ethoxy group, provided that when R17 is the 1-adamantyl or 2-fuyl radical, R18 means no hydrogen. R19Y means the alkylating agent of the formula V or the 2,3-isopropyli-65-dendioxybenzyl halide, 3,4-isopropylidendioxybenzyl halide or 3,4-methylenedioxybenzyl halide. Ph means the phenyl radical, R ^ means a carboxy anion, a carboxylic acid ester, a carboxamide, a nitrile group or

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another group that can be hydrolyzed to a carboxylic acid function that depends on the acylating agent used. The radicals R3a, R4a, R5a, R'4a, and R6a have the meaning R3, R4, R5, R'4 and Rs of Table I, but where R10 is methyl, or RSa and R4a are OR10 and R10 are hydrogen,

or R4a and R5a mean OR10 and R10 means hydrogen.

Strong bases suitable for carrying out the above reaction for the production of the carbanions are in particular bases which withdraw a proton at the carbon atom which is adjacent to the acetylene group, for example alkyl lithium compounds such as butyllithium or phenyllithium, lithium dilakylamides such as lithium diisopropylamine, lithium amide, potassium tert . -butylate or sodium amide.

The alkylating agents described in the above reaction scheme are known or can be prepared by known methods. For example, 2,3-iso-propylidenedioxybenzyl halide can be obtained from 2,3-dihydroxy-toluene with treatment with acetone in the presence of phosphorus pentoxide, followed by treatment with bromosuccinimide by the method of K. Ogura and G. Tsuchihashi, Tetrahedron Letters 1971, 3151 follows.

Acylating agents suitable for the reactions according to the invention are, above all, the halogenoformates such as methyl chloroformate or ethyl chloroformate, tert-butyl azidoformate, cyanogen bromide, carbon dioxide, diethyl carbonate, phenyl isocyanate, triethoxy methylium tetrafluoroborate, N, N-dimethyl carbamate , 3-dithiolinium iodide, ethylene carbonate or ethylene tri-thiocarbonate. When using 2-methylthio-1,3-dithiolinium iodide, the further step of alcoholysis with a lower alcohol such as ethanol or isopropanol is usually required before the protective groups are removed by hydrolysis.

The alkylation reaction and acylation reaction can be carried out in an aprotic solvent, for example benzene, toluene, ethers, tetrahydrofuran, dimethyl sulfoxide or hexamethylphosphoric triamide. The temperature of each reaction is between -120 to 25 ° C, with a preferred reaction temperature being about -70 ° C. The response times vary between about% and 24 hours.

The protecting groups are usually removed by treatment with an aqueous base, for example with sodium or potassium hydroxide solution or with hydrazine or phenylhydrazine, followed by acid hydrolysis, for example with hydrochloric acid, if the alkylating agent consists of 3,4-isopropylidenedioxybenzyl halide or 2,3 -Isopropylidendioxy-benzalhalide exists. If the alkylating agent contains a benzyloxy group, the basic hydrolysis is usually followed by treatment with lithium amide or sodium amide in ammonia, after which lithium or sodium metal is added until the blue color persists for about 15 minutes.

The propargylamine derivatives, in which R18 is hydrogen, can be prepared by adding the protective group to the acetylene function and the nitrogen function of the propargylamine. The nitrogen function of the propargylamine is usually protected by forming a Schiff base with one of the nonenolizable carbonyl compounds such as benzaldehyde, 2,2-dimethylpropanol or 2,2-diethylbutanal in a known manner. The protection of the acetylene function can be carried out by reacting the Schiff base with a triaalkyl silyl chloride whose alkyl radical has 1 to 4 carbon atoms and is straight-chain or branched, for example with trimethylsilyl chloride or triethylsilyl chloride.

The propargylamine derivatives, wherein R18 represents the methoxy or ethoxy group, are e.g. obtained by the propargylamine, the acetylene function of which is protected by a trialkylsilyl radical having 1 to 4 carbon atoms in the alkyl moiety, with benzoyl chloride, pivalic acid chloride, 2,2-diethylbutyric acid chloride, 2-furanoyl chloride or 1-adamantane carboxylic acid chloride at 0 ° C in diethyl ether, dioxane, tetrahydrofuran , Chloroform, methylene chloride, dimethylformamide, dimethylacetamide or chlorobenzene in the presence of an organic base such as trietylamine or pyridine, after which the reaction mixture is allowed to warm to about 25 ° C. for 1 hour. The resulting amide derivative can be mixed with an alkylating agent, for example methyl fluorosulfonate, dimethyl sulfate, methyl iodide, methyl p-toluenesulfonate or trimethyloxonium hexafluorophosphate if Rlg is the methoxy group, or triethyloxonium tetrafluoroborate if R18 is the ethoxy group at about 25 ° C in a chlorinated hydrocarbon solvent such as methylene chloride, chlorobenzene or chloroform. The reaction mixture is generally refluxed for about 12 to 20 hours. The mixture can then be cooled to about 25 ° C and an organic base such as triethylamine or pyridine can be added, after which the solution e.g. extracted with saline and the product is isolated.

The protected propargylamine used as the starting material can be obtained by reacting a 3-trialkyl-silylprop-2-ynyl-1-imino-benzyl derivative with hydrazine or phenylhydrazine at about 25 ° C. for about y% hour, after which the mixture is diluted to Example with petroleum ether, benzene or toluene. Then the protected propargylamine derivative is usually isolated. The hydrochloride is obtained by preferred treatment with 0.5 to 1N hydrochloric acid.

The compounds of formula V are known or can be prepared from suitably substituted benzoic acid or benzaldehyde derivatives. For example, the benzyl halides of the formula V can be obtained from the corresponding benzaldehyde by reduction with sodium borohydride, lithium aluminum hydride or by catalytic reduction or from the corresponding benzoic acid ester by reduction with lithium aluminum hydride or borane, or by reducing the corresponding benzoic acid derivative with lithium hydride and treating the resulting benzyl alcohol derivative, for example with thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride.

The compounds of the formula I in which Ri is hydrogen and R2 is the hydroxyl group and one of the radicals R3, R4, Rs or R'4 represents the radical OR10, in which R10 is hydrogen, can be obtained from the corresponding derivative in which one of the radicals R3, R4, R5 or R'4 denote the radical OR10 and R10 methyl, can be prepared by treating this derivative with a lower alcohol, for example with methanol saturated with anhydrous hydrogen chloride, for about 25 hours at about 25 ° C. This produces the lower alkyl ester, for example the methyl ester, which is preferably suspended in methylene chloride, dimethylformamide, dimethylacetamide, chlorobenzene or an ether such as diethyl ether, dioxane or tetrahydrofuran and then treated with benzoyl chloride. This is usually followed by treatment with an organic base such as triethylamine or pyridine, with stirring at about 25 ° C. for about 24 hours. This gives the alkyl ester derivative in which the amino group is protected by the phenylcarbonyl radical, which can subsequently be treated with a Lewis acid, for example with boron tribromide, boron tri-

5

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65

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641150

chloride or boron trifluoride and then with aqueous acid such as hydrochloric acid.

The compounds of the formula I in which Rj is hydrogen and R2 is the hydroxyl group and one of the radicals R3, R4, Rj or R'4 the radical OR10 and R10 is a straight-chain or branched alkyl radical having 1 to 8 carbon atoms can be obtained by alkylation of the corresponding compounds in which R10 is hydrogen, using an alkyl halide of the formula R21Y2, in which R21 is a straight-chain or branched alkyl radical having 1 to 8 carbon atoms and Y2 is a halogen, for example bromine or iodine, in a lower alcoholic solvent such as methanol or ethanol or in a hydrocarbon solvent such as benzene or toluene in the presence of an organic base such as triethylamine or pyridine or in an aprotic solvent such as dimethylformamide, dimethylacetamide or dimethyl sulfoxide in the presence of sodium hydride for about 1 to 24 hours at a temperature of about 25 to 85 ° C. The hydrolysis can then be carried out with an aqueous base, provided that before the alkylation reaction the a-amino group of the hydroxy-substituted starting material is protected by a suitable protective group such as, for example, the tert-butoxycarbonyl radical, which is later treated with Acid, for example trifluoroacetic acid, is removed. The alkyl halides used in the above reaction are known or can be prepared by known methods.

The compounds of the formula I in which R2 is the hydroxyl group or a straight-chain or branched alkoxy radical having 1 to 8 carbon atoms and Rx is hydrogen, and one of the radicals R3, R4, R5 or R'4 is the radical OR10 and Rio is an alkylcarbonyl radical with a straight-chain or Branched alkyl portion having 1 to 6 carbon atoms, the benzoyl residue, or a phenylalkylene carbonyl residue having a straight-chain or branched alkylene portion having 1 to 6 carbon atoms can be obtained by the corresponding derivatives, wherein R10 is hydrogen, with an acid anhydride of the formula

O

II

(Rffl C) 2®

or an acid halide of the formula

O

II

R22 — C — halogen, in which the halogen is chlorine or bromine, and R ^ is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, the phenyl radical or a phenylalkylene radical having a straight-chain or branched alkylene part having 1 to 6 carbon atoms, in Presence of an organic base such as pyridine, quinoline or triethylamine, the base serving as a solvent. The reaction is preferably carried out at about 25 to 100 ° C. for about 1 to 24 hours, provided that before the reaction the a-amino group of the hydroxy-substituted starting material is protected by a suitable protective group such as, for example, the tert-butoxycarbonyl radical which can then be removed with acid, for example with trifluoroacetic acid.

The acid anhydrides and acid halides used in the above reaction are known or can be prepared from the corresponding acids by known methods.

The compounds of formula I in which R2 is a straight-chain or branched alkoxy radical having 1 to 8 carbon atoms can be prepared by reacting the corresponding derivatives, in which R2 is the hydroxyl-5 grappe, with thionyl chloride to form the acid chloride which is associated with a Alcohol of the formula R23-OH is reacted, in which R23 is a straight-chain or branched alkyl radical having 1 to 8 carbon atoms, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, hexyl or io octyl radical. The reaction is preferably carried out at about 25 ° C for about 4 to 12 hours.

The compounds of formula I in which R2 represents the radical -NR7R8, in which R7 and R8 are hydrogen or straight-chain or branched lower alkyl radicals 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 , in which R2 represents the hydroxyl group and Rj has the meaning given for formula I, provided that 20 each free amino group is protected by a suitable protective group such as the carbobenzyloxy radical or the tert-butoxycarbonyl radical and that if one of the radicals R3, R4, R5 or R'4 represent the radical OR10 and R10 hydrogen, these groups are protected as corresponding alkylcar-25 bonyloxy groups, with an excess of an amine of the formula NHR7R8. The reaction is usually carried out in methylene chloride, chloroform, dimethylformamide, ethers such as tetrahydrofuran, or dioxane or benzene at about 25 ° C. for about 1 to 4 hours. Suitable amines 30 are, for example, ammonia or a potential source of ammonia, for example hexamethylenetetramine, primary amines such as methylamine, ethylamine or n-propylamine and secondary amines such as dimethylamine, diethylamine or di-n-butylamine. After the acylation reaction, the amino protecting group can be removed by treatment with acid or hydrogen bromide in dioxane, and the hydroxyl protecting groups are optionally removed by basic or acid hydrolysis.

The compounds of the formula I in which R2 is a radical 40 of the formula

—NH — CH — COOH

45 /

means can be prepared by the corresponding derivative, in which R2 represents the hydroxyl group or a functional derivative such as an acid anhydride and Ri has the meaning given for formula I, under 50, provided that all free amino groups are replaced by a suitable protective group such as the benzyloxycarbonyl radical or the tert-butoxycarbonyl radical are protected with a compound of the formula

55 NH2-CH-COOR24

in which R9 has the meaning given for formula I 60 and R24 represents a lower alkyl radical, for example the methyl or ethyl radical, in an ether such as tetrahydrofuran or dioxane at 0 to about 50 ° C. for about 1 to about 24 hours. This is usually followed by acidic hydrolysis to remove the protecting group, provided 65 that when using a free acid with a protected amino group, the reaction is carried out using a dehydrating agent such as dicyclohexylcarbodiimide.

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14

The compounds of the formula I in which Rt is an alkylcarbonyl radical having a straight-chain or branched alkyl moiety having 1 to 4 carbon atoms can be obtained by corresponding derivatives in which R 1 is hydrogen and R 2 is the hydroxyl group with an acid halide of the formula

O

II

R23-C-halogen, in which the halogen is, for example, chlorine or bromine, and in which R25 represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, in water in the presence of a base such as sodium hydroxide or sodium borate at a temperature of 0 to 25 ° C during% to 6 hours. These compounds can also be prepared from the esters, that is to say from compounds of the formula I in which R 1 is hydrogen and R 2 is an alkoxy radical having 1 to 8 carbon atoms, these esters being reacted with an acid halide of the formula

O

II

R25-C-halogen in water, methylene chloride, chloroform or dimethylacetamide in the presence of a base such as sodium hydroxide, potassium hydroxide or excess triethylamine at a temperature of about 0 to 25 ° C for about Yl to 24 hours.

The compounds of the formula I in which R 1 is an alkoxy-carbonyl radical having a straight-chain or branched alk-oxyan moiety having 1 to 4 carbon atoms can be obtained by reacting the corresponding derivative, in which R 1 is hydrogen and R 2 is the hydroxyl group, with an alkyl haloformate formula

0

II

Halogen — C — OR26

in which the halogen is, for example, chlorine or bromine and R26 is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, in water in the presence of a base such as sodium hydroxide or sodium borate at a temperature of about 0 to 25 ° C. for about Yi to 6 Hours.

The compounds of formula I, wherein Rj is a radical of the formula

O

—C — CH — R27

I.

nh2

in which R27 is hydrogen, a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, the benzyl or p-hydroxybenzyl radical can be obtained by using the corresponding derivative in which Ri is hydrogen and R2 is a straight-chain or branched alkoxy radical having 1 to 8 Carbon atoms mean with an acid of the formula

HOOC- CH-R27

1

Reacts NHa or its anhydride, the amino group being protected by a suitable protective group such as the benzyloxycarbonyl radical or the tert-butoxycarbonyl radical, and where R27 has the meaning given above, in an ether such as tetrahydrofuran or dioxane, in methylene chloride or chloroform and in the presence of a Dehydrating agent when using the free acid, at a temperature of about 0 to 35 ° C for about 1 to 12 hours. Acidic and basic hydrolysis are then generally carried out to remove the protective groups.

The individual optical isomers of the compounds of formula I, wherein Rj is hydrogen and R2 is the hydroxyl group, can be separated from one another using a (+) or (-) binaphthylphosphoric acid salt by the method of R. Viterbo et al., Tetrahedron Letters 48, 4671 (1971). Other reagents suitable for decomposition, such as (+) camphor-10-sulfonic acid, can also be used. The individual optical isomers of the compounds of the formula I, in which Rj and R2 are different from hydrogen or the hydroxyl group, can then be produced as described for the racemate, starting only from the amino acid formed during the decomposition.

The following use example 1 illustrates the use of a compound of the formula I, in which R2 denotes the hydroxyl group, as a chemical intermediate for the preparation of a cephalosporin of the formula X:

Example of use 1

7- \ l2-acetylen-2-amino-3-phenylpropionyl] amino} 3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-en-2-car-bonic acid

A mixture of 1 g of 3-acetyloxy-7-amino-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and 1 g of 2-acetylene-2- amino-3-phenylpropionoyl chloride, in which the free amino group is protected by the tert-butoxycarbonyl radical, in 50 ml of ethyl acetate, the mixture is heated under reflux for 2 hours,

then the solvent is removed, leaving a residue. This is treated with mild acid and chromatographed on silica gel with benzene / acetone as the eluent. This gives the 7 - {[2-acetylene-2-amino-3 - phenylpropionyl] amino} 3 -acetyloxymethyl-8-oxo-5-thia-1 - azabicyclo [4.2.0] oct-2-en- 2-carboxylic acid.

The following examples of use 2 to 4 illustrate pharmaceutical preparations from the compounds according to the invention:

Example of use 2 A mixture for hard gelatin capsules is composed as follows:

(a) 2-Acetylene-2-amino-3- (3-hydroxyphenyl) propionic acid 20 mg

(b) Talc 5 mg

(c) Lactose 90 mg

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

Example of use 3 tablets are produced from the following components:

(a) 2-acetylene-2-amino-3- (3,4-dihydroxyphenyl) -

propionic acid 20 mg

(b) Strength 43 mg

(c) Lactose 45 mg

(d) Magnesium stearate 2 mg

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641150

After the lactose and component (a) and part of the starch have been mixed and granulated with starch paste, the granules are dried, sieved and mixed with magnesium stearate. The mixture is compressed into tablets of 110 mg each.

Example of use 4 1 ml ampoules for intramuscular injection:

% By weight

(a) 2-Acetylene-2-amino-3- (4-hydroxyphenyl) propionic acid 1.0

(b) Polyvinyl pyrrolidone 0.5

(c) Lecithin 0.25

(d) Water for injections to 100.0

Components (a) to (d) are mixed, homogenized and filled into 1 ml ampoules, which are sealed and treated in an autoclave at 121 ° C. for 20 minutes.

Each ampoule contains 10 mg / ml of the new compound (a).

The following examples illustrate the preparation of compounds of the formula I:

example 1

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

(A) A solution of 32.4 g (0.15 mol) of 3-trimethylsilylprop-2-ynyl-1-iminobenzyl in 20 ml of tetrahydrofuran becomes lithium diisopropylamide, made from 21 ml (0.15 mol) of diisopropylamine and 73 , 2 ml of a 2.05 molar solution of n-butyllithium (0.15 mol) in 1 liter of tetrahydrofuran was added at -78 ° C. After 15 minutes, 32.7 g (1.35 mol) of 3,4-isopropylidenedioxybenzyl bromide in 20 ml of tetrahydrofuran are added and the mixture is kept at -78 ° C. for 2 hours, followed by the addition of 73.2 ml of a 2 05 molar solution (0.15 mol) of n-butyllithium and then 14.2 g (11.6 ml, 0.15 mol) of methyl chloroformate are added. After a further 30 min at -78 ° C the reaction mixture is treated with brine and extracted with ether. The ether extract is concentrated, the residue is dissolved in 300 ml of petroleum ether with a boiling point of 30 to 60 ° C. and 16.2 g (0.15 mol) of phenylhydrazine at 25 ° C.

Implemented 2 hours. The precipitate is filtered off and the petroleum ether is evaporated off, the residue is treated with 40 g of potassium hydroxide in 300 ml of ethanol and 300 ml of water at 25 ° C. for about 15 hours. The ethanol is evaporated and the aqueous solution is washed well with methylene chloride, then acidified and washed again with methylene chloride. The water is evaporated off and the remaining solid residue is triturated with ethanol and filtered off, the filtrate is concentrated and gives a residue which is dissolved in water. The pH of the aqueous solution is adjusted to 6 and the resulting solution is applied to a column of Amberlite resin 120 H + and eluted with 2 molar ammonium hydroxide solution. After recrystallization from water and ethanol, 2-acetylene-2-amino-3 ', 4'-isopropylidenedioxy-phenylpropionic acid is obtained.

(B) 3 g (0.13 mol) of 2-acetylene-2-amino-3,4-isopropylidene-dioxyphenylpropionic acid are mixed with 200 ml of 6N hydrochloric acid

Heated at reflux for 2 hours, then the solvent is evaporated off. The residue is taken up in water and the pH is adjusted to 6 by carefully adding hydrazine hydrate. When the solution is cooled to 0 ° C., a precipitate is formed which is collected and recrystallized from water (coal). This gives 2-acetylen-2-amino-3- (3,4-dihydroxyphenyI) propionic acid (melting point: 210 ° C; with decomposition).

According to the procedure of this example, 2-acetylene-2-amino-3- (3-hydroxyphenyl) propionic acid can be prepared from the corresponding starting materials.

Example 2

2-A cetylene-2-amino-3- (3-methoxyphenylpropionic acid

Using 25.8 g (0.12 mol) of 3-trimethylsilylprop-2-ynyl-1-iminobenzyl in the process of Example 1 (A) instead of 32.4 g (0.15 mol) and 20.1 g (0 , 1 mol) 1-bromomethyl-3-methoxybenzene instead of the 5-bromomethyl-1,3-benzo-dioxol, the 2-acetylene-2-amino-3- (3-methoxyphenyl) is obtained after recrystallization from water propionic acid.

Example 3

2-acetylene-2-amino-3- (3-hydroxyphenyl) propionic acid

A suspension of 2.0 g (9.1 millimoles) of 2 acetylene-2-amino-3- (3-methoxyphenyl) propionic acid in 20 ml of methanol saturated with anhydrous hydrogen chloride is stirred at 25 ° C. for about 15 hours, then that Solvent evaporated. The resulting methyl ester is suspended in 50 ml of methylene chloride and treated with 1.26 g of benzoyl chloride, then 3.6 g of triethylamine are added. The mixture is stirred for 24 hours, then washed with water, dried and concentrated. The resulting residue is recrystallized from methanol to give the methyl ester derivative, the amino group of which is protected by the phenylcarbonyl radical.

A solution of 1.2 g (3.5 millimoles) of the methyl ester with a protected amino group in 50 ml of methylene chloride at 25 ° C. is mixed with 0.9 g of boron tribromide. The mixture is stirred at 25 ° C. for about 15 hours, then 10 ml of methanol are added and the solvents are evaporated off. The residue is refluxed with 50 ml of 6N hydrochloric acid for 5 hours. The solution is then concentrated, the pH is adjusted to 6 and the resulting solution is applied to a column of Amberlite 120 H +. Elution with 1 molar ammonium hydroxide solution gives 2-acetylene-2-amino-3- (3-hydroxyphenyl) propionic acid, which is recrystallized from water / ethanol.

In the process of Example 1, the 3,4-isopropylidenedioxybenzyl bromide is replaced by the appropriate amount of benzyl chloride, 4-chloro-2-methoxybenzyl chloride, 2-chloro-6-methylbenzyl chloride, 2,4-dichloro-6-methylbenzyl chloride, 4- Methoxy-6-methylbenzyl chloride or 6-tert-butyl-4-chloro-benzyl chloride, the following products are obtained: 2-acetylene-2-amino-3-phenylpropionic acid, 2-acetylene-2-amino-3- (4- chloro-2-methoxyphenyl) propionic acid,

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

2-acetylene-2-amino-3- (4-methoxy-6-methylphenyl) propionic acid, and

2-acetylene-2-amino-3- (6-tert-butyl-4-chlorophenyl) propionic acid.

Example 4

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

A suspension of 2.2 g (10 millimoles) of 2-acetylene-2-amino-3 (3,4-dihydroxyphenyl) propionic acid in 30 ml of ethanol is saturated with anhydrous hydrogen chloride, then the resulting solution is kept at 25 ° C. for 24 hours ditched. After the solvent has evaporated, a residue remains5

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stood, which is recrystallized from ethanol / ether. The ethyl 2-acetylene-2-amino-3- (3,4-dihydroxyphenyl) propionate hydrochloride is obtained.

Example 5

2-acetylene-3- (3,4-diacetyloxyphenyl) -2- (tert-butoxycarbonylamino) propionic acid

2N aqueous sodium hydroxide solution and acetic anhydride (3.5 g) become simultaneously over the course of% hours a solution of 6 g of 2-acetylene-2- (tert-butoxycarbonylamino) -3 - (3,4-dihydroxyphenyl) propionic acid added, consisting of 2-acetylene-2-amino-3- (3,4-dihydroxyphenyl) propionic acid and tert-butylazidoformate in 30 ml of 1N sodium hydroxide solution in argon while maintaining a pH between 6.5 and 7.5 was manufactured. After 1 hour at 25 ° C., the pH is adjusted to 1 with 6N sulfuric acid, then the mixture is extracted with methylene chloride. The organic phase is dried and concentrated to give the 2-acetylene-3- (3,4-diacetyloxyphenyl) -2- (tert-butoxycarbonylamino) propionic acid.

Example 6

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

2.2 g (10 millimoles) of 2-acetylen-2-amino-3- (3,4-dihydroxyphenyl) propionic acid are added to a suspension of 6.8 g (10 millimoles) of borax in 10 ml of water with stirring under argon. After 15 minutes, the pH is adjusted to 9 with 2N sodium hydroxide, then 780 mg of acetyl chloride are added dropwise, the pH being kept between 9.0 and 9.5. The aqueous solution is washed with ether, adjusted to pH 1 with 6N sulfuric acid and extracted with methylene chloride. The organic phase is dried and concentrated to give the 2-acetylene-2- (acetylamino) -3- (3,4-dihydroxyphenyl) propionic acid, which can be reacted with ethanolic hydrochloric acid to give the ethyl ester.

Example 7

2- [2-acetylene-2-amino-3- (3,4-diacetyloxyphenyl) -1-oxo-propylamino] propionic acid

A solution of 4.4 g (10 millimoles) of 2-acetylene-2-carbo-benzyloxyamino) -3- (3,4-diacetyloxyphenyl) propionic acid made from 2-acetylene-2-amino-3- (3,4- diacetyloxyphenyl) propionic acid and benzyl chloroformate, in 50 ml ether is treated with 1.0 g (10 millimole) triethylamine and then with 1.08 g (10 millimole) ethyl chloroformate. After 1 hour at 25 ° C., the precipitate is filtered off and the solution of ether is mixed with a solution of 10 millimoles of alanine benzyloxyester in 30 ml of ether. Solution 5 is left overnight at 25 ° C. and then evaporated to dryness. The residue is treated with hydrogen bromide in dioxane (40% w / w, 20 milliliters) at 25 ° C. for 30 minutes. Then ether is added and the precipitated hydrobromide is filtered off. This gives 2- [2-acetylene-2-amino-3- (3,4-diacetyloxyphenyl) -1-oxopropylamino] propionic acid.

Example 8

2-acetylene-2- (2-amino-l-oxopropylamino) -3- (3,4-dihydroxy-15 phenyl) propionic acid hydrochloride

A suspension of 3.3 g (10 millimoles) of benzyl-2-acetylene-2-amino-3- (3,4-dihydroxyphenyl) propionate in 50 ml of methylene chloride is mixed with 1 g (10 millimoles) of triethylamine 20, then 10 millimoles of N-carbobenzyloxyalanine, the acid function of which is activated by the ethoxycarbonyl radical, are added in 20 ml of methylene chloride. The mixture is stirred at 25 ° C. for about 16 hours and then washed with water. The organic phase is dried and concentrated, the residue is taken up in ether and the ether solution is cooled to 0.degree. A vigorous stream of hydrogen chloride gas is then passed through the solution for 3 hours, after which the ether solution is washed with water. The aqueous phase is concentrated and gives the 30 2-acetylene-2- (2-amino-l-oxopropylamino) -3- (3,4-dihydroxy-phenyl) propionic acid hydrochloride in the form of a gum.

Example 9

35 2-acetylene-2-amino-3- (4-hydroxy-3-methoxyphenyl) propion-

acid

A solution of 3.25 g (10 millimoles) of 2-acetylen-2-ami-no-3- (4-benzyloxy-3-methoxyphenyl) propionic acid in 20 ml of 40 tetrahydrofuran is added to 100 ml of ammonia at -30 ° C Contains 0.5 g of lithium amide. After 1 hour, metallic lithium is added until the blue color persists for 20 minutes. Then ammonium chloride is added and the ammonia is allowed to evaporate. The residue is dissolved in 45 water, the pH is adjusted to 6 and the solution is applied to Amberlite 120 H + resin. Elution with 1 molar ammonium hydroxide solution gives 2-acetylene-2-amino-3- (4-hydroxy-3-methoxyphenyl) propionic acid, which is recrystallized from water.

Claims (12)

641150 2nd PATENT CLAIMS 1. Compound of the formula R Rs wherein Rx is hydrogen, an alkylcarbonyl radical having an alkyl moiety with 1 to 4 carbon atoms which can be straight-chain or branched, an alkoxycarbonyl radical with an alkoxy moiety having 1 to 4 carbon atoms which can be straight-chain or branched, or a radical of the formula O II —C — CH — R27 NH, wherein R27 is hydrogen, a straight-chain or branched lower alkyl radical having 1 to 4 carbon atoms, the benzyl or p-hydroxybenzyl radical, R2 is a hydroxyl group, a straight-chain or branched alkoxy radical having 1 to 8 carbon atoms, a radical of the formula -NR7R8, in which R, and R8 are each hydrogen or a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, or a radical of the formula —NH — CH — COOH, r9 wherein R9 is hydrogen, a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, which is benzyl or p-hydroxybenzyl radical, and R3, R4, R5, R'4 and Rg, which have the meaning given in Table I. TABLE I Ra R4 Rs R'4 re H -O-chä-O- H H H H H H H H H a pi O H H H ORio H H H H ORio ORio H H O F O H Cl H H H ORio Cl H H Cl o oi o H H H Cl ORio Cl h H Cl, F H ORio H H Cl H H h ch3 Cl H Cl H ch3 H H Cl, F H ch3 ORio H CHS H ch3 Cl H chs H ch3 H H ORio H ch3 H H ORio H c2h5 ORio H C2H5 H approx H ORio H ORio H H ORio ORio ORio H H H OCHg OH H H H OH OCH3 H s pi O O F O H H H ORio H H H H H H Cl H QÄ H H Cl H tert-CJig H H ORw H tert-C4Hg where R10 is hydrogen, a straight-chain or branched alkyl radical with 1 to 8 carbon atoms, an alkylcarbonyl radical with a straight-chain or branched alkyl radical with 1 to 6 carbon atoms, the benzoyl or a phenylalkylene carbonyl radical with an alkylene radical with 1 to 6 carbon atoms, the straight-chain or can be branched means and their salts. 2. A compound according to claim 1, characterized in that Rj is hydrogen or an alkylcarbonyl radical having a straight-chain or branched alkyl portion having 1 to 4 carbon atoms. 3. A compound according to claim 1, characterized in that R2 is the hydroxyl group or a straight-chain or branched alkoxy radical having 1 to 8 carbon atoms. 4. A compound according to claim 1, characterized in that Rc is hydrogen and each of R3, R4, R5 and R'4 is hydrogen or -OR10, wherein R10 is hydrogen or Cj-Cg-alkyl. 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 3rd 641150 5. A compound according to claim 4, characterized in that Rj0 is hydrogen. 6. A compound according to claim 1, characterized in that each of the radicals R4 and R5 is hydrogen or a radical OR10, wherein R10 is hydrogen. 7. A compound according to claim 6, characterized in that Rx is hydrogen and R2 is the hydroxyl group. 8. 2-acetylene-2-amino-3- (3,4-dihydroxyphenyl) propionic acid or a salt thereof as compounds according to claim 1. 9. 2-acetylene-2-amino-3- (3-hydroxyphenyl) propionic acid or a salt thereof as compounds according to claim 1. 10. Process for the preparation of new compounds of the formula ° H OB C = CH h ") -c-coqh (ia) H H NH0 and salts thereof, characterized in that a protected propargylamine of the formula (Ri6) a-Si-CaC-CH2 Nï = C-Ri7 R18 wherein Rjg is C ^ Q-alkyl, R17 phenyl, tert-butyl, triethylmethyl, 1-adamantyl or Means 2-furyl and R18 is hydrogen, methoxy or ethoxy, with the proviso that when R17 is 1-adamantyl or 2-furyl, R18 is not hydrogen, treated with a strong base to form a protected propargylamine carbanion of the formula (RisJs-S i-CsC-CH ^ N = C riv I. Ria (in) alkylated with a 2,3-isopropylidenedioxybenzyl halide, reacting the alkylated compound with a strong base to form an alkylated propargylamine carbanion, acylating this propargylamine carbanion accordingly, with the alkylation and acylation reactions in a solvent at -120 to 25 ° for% to 24 hours C are carried out and, finally, the protective groups present are removed hydrolytically and the compounds obtained are converted, if appropriate, into corresponding salts. 11. Process for the preparation of new compounds of the formula H0 H c = CH y = r (I ho-4> -ch2-c-cooh (IB) 10th H H NH, and salts thereof, characterized in that a protected propar-15 gylamine carbanion of the formula III is prepared by the process according to claim 10, alkylated with a 3,4-isopropylidenedioxybenzyl halide, the alkylated compound is reacted with a strong base in order to add an alkylated propargylamine carbanion form, this propargylamine carbanion accordingly acylated, the Al-20 alkylation and acylation reactions being carried out in a solvent for up to 24 hours at −120 to 25.degree. C. and finally protecting groups present being hydrolytically removed and any compounds obtained being converted into corresponding salts. 25 12. Process for the preparation of new compounds of the formula C = CH ^ / -CH2-C-COOH NH " (IC) and salts thereof, characterized in that a protected propargylamine carbanion of the formula III is prepared by the process according to claim 10, this is alkylated with a 3,4-methylenedioxybenzyl halide, the alkylated compound is reacted with a strong base to form an alkylated propargylamine carbanion, this propargylamine carbanion correspondingly acylated, the alkylation and acylation reactions being carried out in a solvent for 45 to 24 hours at −120 to 25 ° C. and finally protecting groups present being hydrolytically removed and any compounds obtained being converted into corresponding salts. 13. Process for the preparation of new compounds of formula 50 55 (ID) 60 and salts thereof, wherein the substituents R; following table LA are defined, 3, R4, Rs, R 4 and R6 in the 65 641150 TABELLA IA Ra R4 Rs R'4 Re h h h h h h h och3 h h h och3 h h h h och3 och3 h h och3 H Cl h h h och3 Cl h H Cl och3 h h H Cl och3 Cl h H Cl, F h och3 h h Cl h h h ch3 Cl h Cl h ch3 h h Cl, F h ch3 och3 h ch3 h ch3 Cl h ch3 h ch3 h h och3 h ch3 h h och3 h ca och3 h c2h5 h ca h och3 h och3 h h och3 och3 och3 h h h och3 oh h h h oh och3 h och3 och3 h h h och3 h h h h h h Cl h approx h H Cl h tert-CJig h h och3 h tert-ci hg, characterized in that a protected propargylamine carbanion of the formula III is prepared by the process according to claim 10, this with a compound of the formula Ri 12 1 4 wherein Y represents a halogen atom and the radicals Rn, R12, Rj3, R'j2 and R14 correspond to the radicals R3, R4, R5, R'4 and Rg, alkylated, the alkylated compound is reacted with a strong base to give an alkylated propargylamine carbanion form, this propargylamine carbanion accordingly acylated, the alkylation and acylation reactions in a solvent during Yl to 24 hours - 120 to 25 ° C are carried out and finally existing protective groups are removed hydrolytically and the resulting compounds are optionally converted into corresponding salts.