CA1157030A - .alpha.-VINYL AMINO ACIDS - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Novel compounds of the following general structure:

Description

FIELD OF_INVENTION
This invention relates to novel p~larmaceutically use-ful a-vinyl amino acid derivatives which are inhibitors of aromatic amino acid decarboxylase.
BACKGROUND OF i~VENTiON
The amino acids tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine ~DOPA), tyrosine and phenylalanine are metabolically converted to tryptamine, 5-hydroxy-tryptamine, 3~4-dihydroxyphenethylamlne or dopamine, tyra-mine and phenethylamine respectively by an aromatic amino acid decarboxylase. It is believed that the aromatic amino acid decarboxylase enzyme is non-specific, particu-larly, insofar as pertpheral catalysis is concerned.
Evidence does exist, however to indicate that in the brain specific decarboxylation enzymes exist for each of DOPA and 5-hydroxytryptophan.
The above-enumerated aromatic amines are known to be lnvolved in various pathophysiological processes. For example, it has been found that tryptamine, the decarb-oxylation product of tryptophan is enzymatically methylated to monomethyltryptamine which in turn is methylated enzy-matlcally to dlmethyltryptamine (DMT) in human red blood cells, plasma and platele~s. The methylating enzyme is present in many mammalian species and has been shown to be produced in brain tissues of several species including man.
DMT which has strong hallucinogenic or psychomimetic proper-ties may play a role in the etiology of schizophrenia and other psychotic disorders. Hence any agent which would block formation of DMT may be useful as an antipsychotic ~0 agent. Blocking the decarboxylatîon of tryptophan results -q~

l~L$7030 in decreased levels of tryptamine, removing the substrate for DMT formation. Hence an inhibitor of aromatic amino acid decarboxylase which would block conversion of tryptophan to tryptamine may be useful as an antipsychotic agent.
Both 5-hydroxytryptamine (5-HT), the decarboxylation product of 5-hydroxytryptophane, and 3,4-dihydroxyphenethyl-amine (dopamine) the decarboxylation product of DOPA are involved in peripheral and central physiological processes, and agents which are effective in the control of levels of these amines have resulted in useful pharmacological agents.
It has been shown that central or brain levels of 5-HT and norepinephrine, which is formed metabolically by hydroxyla-tion of dopamine, are higher in patients with manic dis-orders than in individuals without such disorders. It has also been shown that agents which decrease central levels of monoamines, for example, 5-HT and particularly norepi-nephrine have antimanic properties when given to human sub-jects, whereas drugs that increase monoamine levels could precipitate mania in susceptible individuals. Hence, agents ' which block formation of 5-HT and dopamine, such as, for example, by inhibiting the aromatic amino acid decarboxylase enzyme which converts 5-hydroxytryptophan and DOPA to 5-HT
and dopamine respectively may be useful as antipsychotic agents or major tranquilizers in treating manic disorders.
It has alSO been shown that agents useful in inhibit-ing the decarboxylation of DOPA to dopamine are useful in the treatment of Parkinsonism when administered concurrent-ly with exogenous DOPA or L-DOPA. It is believed that Parkinsonism is due, at least in part, to decreased ~ 1~c~7S330 central levels of dopamine since exogenous administration of DOPA or L-DOPA is known to be an effective means of treat-ing Parkinsonism. However, since exogenously administered DOPA is readily converted enzymaticallv to dopamine peri-pherally it is necessary to administer large amounts inorder to have increased absorption centrally. DOPA readily penetrates the blood-brain barrier whereas dopamine does not. Administration of DOPA or L-DOPA in conjunction with a peripherally active inhibitor of the enzyme which converts DOPA to dopamine reduces the amount of L-DOPA that must be administered in order to have adequate circulating levels for central absorption. Other advantages are also realized by administration of an aromatic amino acid decarboxylase inhibitor along with L-DOPA. By preventing formation of dopamine peripherally, side effects attributed to dopamine such as, cardiac arrhythmia, nausea and vomiting may be avoided.
Studies indicate that levels of 5-hydroxytryptamine (5-HT) are lower in patients with depressive syndromes than in individuals without such syndromes. Also, administra-tion of exogenous L-5-hydroxytryptophan (L-5-HTP) is effective in treating certain depressed patients. However, as with DOPA, since L-5-HTP is readily metabolized peri-pherally to 5-HT it i5 necessary to administer large amounts of L-5-HTP in order to achieve increased central levels of the amino acid. It has been shown that by administering an inhibitor of the aromatic amino acid decarboxylase enzyme that cataly7es the formation of 5-HT
from 5-HTP peripherally the amount of exogenous 5-HTP
required to give increased central levels is markedly ~` :

~57030 reduced. In other words inhibitors of aromatic amino acid decarboxylase when used in conjunction with exogenous 5-HTP have been shown to be useful in treating depression.
Agents which block peripheral conversion of 5-HTP to 5-HT may be useful in treating other conditions which respond to increased central levels of 5-HTP as a result of exogenous administration of 5-HTP. It has been shown that exogenous L-5-HTP iS useful in treating action myoclonus. Also, studies reveal that administration of exogenous 5-HTP iS useful in treating insomnia. Hence concurrent administration of 5-HTP and an aromatic amino acid decarboxylase inhibitor may be beneficial in treating these conditions.
Blocking peripheral formation of 5-hydroxytryptamine may result in other beneficial effects since it is known that 5-HT iS involved, for example, in the etiology of rheumatoid arthritis and the carcinoid syndrome by in-creasing collagen levels. Also, it is reported that 5-HT
is the primary autocoid responsible for anaphylactoid reactions in human subjects as well as bronchoconstriction in asthmatic human subjects, and agents which antagonize or inhibit formation of 5-HT are useful in treating these conditions. 5-HT is known to cause platelet aggregation and has been implicated as a causal factor in the post-gastrectomy dumping syndrome and migraine headache. Methyl-sergide, a 5-hydroxytryptamine antagonist, has proven effective in treating post-gastrectomy dumping syndrome.
It has been suggested that phenethylamine, the de-carboxylation product of phenylalanine, as an endogenous compound contributes to schizophrenic symptoms and triggers ~i -4-:~ .

':::; :

~57(~30 migraine headaches. Also, it has been suggested that endogenous tyramine, the decarboxylation product of tyro-sine, contributes to seizure disorders.
Hence, it is readily evident that agents which are useful in regulating the levels of aromatic amino acids and amines find use in many pharmacological situations.
The compounds of the present invention are inhibitors of the aromatic amino acid decarboxylase which converts tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine, tyrosine and phenylalanine to the respective amines and hence provide useful pharmacologic agents.
SUMMARY OF INVENTION
The compounds of the present invention are represented by the following general Formula:

~ CH=CH2 R5 ~ \ / ~ CH2cl-coR2 Formula l ~ HRl R'4 R6 In the above general Formula l R1 is selected from hydrogen, alkylcarbonyl wherein the alkyl moiety has from l to 4 carbon atoms and is straight or branched, alkoxycarbonyl wherein the alkoxy moiety has from l to 4 carbon atoms and o 0 is straight or branched and -C-fH-R17 wherein Rl7 is seIected from hydrogen, a straight or branched lower alkyl group of from l to 4 carbon atoms, benzyl and p-hydroxy-benzyl; R2 is selected from hydroxy, a straight or branched alkoxy group of from l to 8 carbon atoms, -NR7Rg wherein ~7~30 each of R7 and R8 is hydrogen or a straight or branched alkyl group of from 1 to 4 carbon atoms and -NHCH-COOH

Rg wherein Rg is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl andp -hydroxy-benzyl; each of R3, R4, R5, R'4 and R6 has the meaningdefined in the following Table 1 wherein Rlo is hydrogen, a straight or branched alkyl group of from 1 to 8 carbon atoms, alkylcarbonyl wherein the alkyl moiety is straight or branched and has from 1 to 6 carbon atoms, benzoyl or phenylalkylenecarbonyl wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms;

_ R4 R5 R~4 R6- - -H H H H H

H H ORlo H H

H ORlo H H H

H ORlo ORlo H H

ORlo H Cl H H

H ORlo Cl H H

Cl ORlo H H H

Cl ORlo Cl H H

Cl,F H ORlo H H

Cl H H H CH3 Cl H Cl H CH3 H H Cl,F H CH3 ORlo H CH3 H CH3 Cl H CH3 H CH3 H H ORlo H CH3 H H ORlo H C2H5 ~ 57 0 30 MI-916 OR1o H C~Hs H C2Hs H OR~o H ORlo H
H ORlo OR~o OR10 H

ORlo OR1o H H H
OR1o H H H H
H H Cl H C2H5 H H Cl H tert-C4H9 H H OR1o H tert-C4H~
Pharmaceutically acceptable salts and individual optical isomers of the compounds of general Formula I are also included within the scope of this invention.
The compounds of general Formula I are useful pharma-cological agents in that said compounds are inhibitors of aromatic amino acid decarboxylase and useful pharmacological agents.
DETAILED DESCRIPTION OF INVENTION
In the above general Formula I the term alkylcarbonyl is taken to mean the group alkyl-~- wherein the alkyl moiety has from 1 to 6 carbon atoms and is a straight or branched chain.
The term benzoyl as used in general Formula I means the group ~ - C-.
The term phenylalkylenecarbonyl as used in general Formula I is taken to mean the group ~ -alkylene~C-wherein the alky!ene moiety has from 1 to 6 carbon atoms and is a straight chain or a branched chain, illustra-- .

Ml-916 tively, methylene, ethylene~ isapropylene and butylene.
Illustrative examples of straight or branched alkoxy groups having from 1 to ~ carbon atoms as used herein are methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, tert-pentoxy, n-hexyloxy and n-octyloxy.
Illustratlve examples of straight or branched alkyl groups having from 1 to 6 carbon atoms are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and n--pentyl.~
Illustrative examples of pharmaceutically acceptable salts of the compounds of this invention include non-toxic acid addition salts formed with inorganic acids, such as, hydrochloric, hydrobromic, sulfuric and phos- -phoric acid, and organic acids, such as, methane sulfonic, salicyltc, maleic, malonic, tartaric, citric and ascorbic acids; and non-toxic salts formed with inorganic or or-ganic bases such as those of alkali metals, for example, sodium, potassium and lithium, alkaline earth metals~
for example, calcium and magnesium, light metals of Group lll A, for example, aluminum~ organic amines, such as, primary, secondary or tertiary amines, for example, cyclohexylamine, ethylamine, pyridine, methylamino-ethanol, ethanolamine and piperazine. The salts are prepared by conventional means.
Preferred compounds of this invention are those of general Formula I wherein R1 is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched with compounds wherein R~ is hydrogen being more preferred. Another preferred embodi-ment of this invention is the compounds of general Formula I
wherein R2 is hydroxy or a straight or branched alkoxy ' 7 ~ 30 ~ g~

group of ~rom 1 to 8 carbon atoms. Compounds wherein R4 is hydroxy are more preferred. Compounds of general ~ormula I wherein each of R3, R4, R5 and R~ is hydrogen or OR1o wherein R1o is hydrogen represent another pre-ferred embodiment of this invention.
Illustrative examples o~ compounds of general Formula I are the following:

2-amino-3-phenyl-2-vinylpropionic acid, 2-amino-3-(4-hydroxyphenyl)-2-vinylpropionic acid, 2-amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionic acid, 2-amino-3-(4-hydroxyphenyl)-2-vinylpropionic acid, 2-amino-3-(4-chloro-2-hydroxyphenyl)-2-vinylpropionic acid, 2-amino-3-(4-chloro-3-methoxyphenyl)-2-vinylpropionic acid, 2-amino-3-(2-chloro-3-benzoyloxyphenyl)-2-vinylpropionic acid, 2-amino-3-(2,4-dichloro-3-hydroxyphenyl)-2-vinylpropionic acid, ::
2-amino-3-(2-chloro-4-hydroxyphenyl)-2-vinylpropionic acid, 2-amino-3-(2-chloro-6-methylphenyl)-2-vinylpropionic acid, 2-amino-3-(2,4-dichloro-6-methylphenyl)-2-vinylpropionic acid, 2-amino-3-(4-chloro-6-methylphenyl)-2-vinylpropionic acid, 2-amino-~-(2-hydroxy-4,6-dimethylphenyl)-2-vinylpropionic acid, 2-amino-3-(2-chloro-4,6-dimethylphenyl)-2-vinylpropionic acid, 2-amino-~-(4-hydroxy-6-methylphenyl)-2-vinylpropionic acid, 2-amino-3-(5-ethyl-4-phenylpropionyloxyphenyl)-2-vinyl-propionic acid, g_ ~57030 2-amino-3-(4,6-diethyl-2-hydroxyphenyl)-2-vinylpropionic acid, 2-amino-3-(4-chloro-6-ethylphenyl)-2-vinylpropionic acid, 2-amino-3-(4-chloro-6-tert-butylphen~l)-2-vinylpropionic acid, 2-amino-3-(6-tert-butyl-4-hydroxyphenyl)-2-vinylpropionic acid, 2-(N-ethoxycarbonylamino)-3-(4-_-butoxyphenyl)-2-vinyl-propionic acid, N,N-di-_-propyl 2-amino-3-(4-acetyloxyphenyl)-2-vinyl-propionamide, 2 [N-(2-amino-1-oxoethyl)amino]-3-(3-hydroxyphenyl)-2-vinylpropionic acid, 2-amino-3-(3,4-dihydroxy)phenyl-1-oxo-2-vinylpropylamino-acetic acid, 2-[2-amino-1-oxo-3-phenyl -2-vinylpropylamino]dihydro-cinnamic acid, 2-(1-oxoethylamino)-3-(4-hydroxy)phenyl-1-oxo-2-vinyl-propylamino-2-propionic acid, 2-(1-oxoethylamino)-3-(4-hydroxy)phenyl-1-oxo-2-vinylpropylaminoacetic acid, 2-amino-3-phenyl-2-vinylpropionamide, N,N-dimethyl 2-amino-3-(3-hydroxyphenyl)-2-vinylpropion-amide, N,N-diethyl 2-amino-3-(3',4'-dimethoxyphenyl)-2-vinyl-propionamide, N,n-butyl 2-amino-3-(4-hydroxyphenyl)-2-vinylpropionamide, methyl 2-amino-3-(3-hydroxyphenyl)-2-vinylpropionate, isopropyl 2-amino-3-(3,4-dihydroxyphenyl)-2-vinylpro-pionate, t _ -butyl 2-amino-3-(4-hydroxyphenyl)-2-vinylpropionate, ~`~ -10-~7~ 3~
Ml-916 ethyl 2-amino-3-(~-chloro-~-methoxyphenyl)-2-vinylpro-pionate, and 2-amino-~-(4-hydroxyphenyl)-2-vinylpropionamide.
The compounds of general Formula i are irreversible inhibitors of the enzyme which metabolically catalyzes the conversion of tryptophan, 5-hydroxytryptophan~ 3,4-di-hydroxyphenylalanine, tyrosine and phenylalanine to trypta-mine, 5-hydroxytryptamineJ 3,4-dihydroxyphenylethylamine, tyramine and phenethylamine respectively~ As indicated hereinabove results of studies indicate that the enzyme responsible for the conversion of the above-enumerated amino acids to the respective amines peripherally is a non-specific aromatic amino acid decarboxylase. Fqr central conversion studies indicate that specific decarboxylases are responsible for the conversion of each of 5-hydroxy-tryptophan and 3,4-dihydroxyphenylalanine whereas the re-maining above-enumerated amino acids are enzymatically transformed to the respective amines by a non-specific aro-matic amino acid decarboxylase. The compounds of the pre-sent invention are effective in irreversibly inhibitingboth centrally and peripherally the activity of non-specific aromatic amino acid decarboxylase as well as the activity of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase. As used herein ~ith regard to the utility of the compounds of the present invention the term central refers to the central nervous system, primarily the brain, whereas peripheral refers to other body tissues wherein the decarboxylase enzyme is present. Selectivity of inhibition of the amino acid decarboxylases centrally or peripherally by adminis-~0 tering compounds of general Formula I is dose dependent.

~157030 MI-916 As irreversible inhibitors of aromatic amino acid decarboxylase, and DOPA decarboxylase the compounds of the present invention possess many pharmacologiGal utilities.
As peripheral irreversible inhibitors of aromatic amino acid decarboxylase the compounds of general Formula I are useful in the treatment of Parkinsonism when given in conjunction with ~,4-dihydroxyphenylalanine (DOPA) or L-3,4-dihydroxyphenylalanine (L-DOPA)~ DOPA and more particularly the active isomer L-DOPA are known to be effective in treating Parkinsonism when administered systemically, usually in an amount from 0.5 to 1 gram daily initially after which the amount administered is ~.
gradually increased over a 3 to 7 day period to.a maximally tolerated daily dose of about 8 grams. Concurrent admin-.
istration of a compound of general Formula I and L-DOPA
provides an improved method of treating Parktnsonism in that the compounds of Formula I will block th~ decarboxyla-tion of L-DOPA to L-3,4-dihydroxyphenethylamine (L-dop~mine?
peripherally by inh;biting the activity of aromatic amino acid decarboxylase enzyme, thus retaining high circulating levels of L-DOPA for central absorption and also preventing peripheral formation of increased levels of dopamine which is known to result in certain undesirable side effects such as cardiac arrhythmia. By concurrently administering a compound of general Formula I and L-DOPA the amount of L-DOPA administered may be reduced 2 to 10-fold as com-pared to amounts required for utility when L-DOPA is administered alone. It is preferred that the compounds of this invention be administered prior to administration of L-DOPA. For example, a compound of Formula I may be ~57(~30 Ml-916 administered from 30 minutes to 4 hours prior to administra-tion of L-DOPA depending on the route of administration and condition of the patient to be treated.
The compounds of general formula I are also useful in treating depressive syndromes in ;nd;viduals when given in conjunction with 5-hydroxytryptophan (5-HTP) or more particularly the active levo isomer which is known to be useful in the treatment of depression when adminis-tered systemically. The compounds of general Formula 1, by inhibiting peripherally the activity of aromatic amino acid decarboxylase will block the conversion of 5-hydroxy-tryptophan to 5-hydroxytryptamine thus retaining higher circulating levels of 5-HTP for central absorption. The compounds of general Formula I when administered con-currently with exogenous 5-HTP are also useful in treating action myoclonus which is known to be effectively treated by increasing central levels of 5-HTP.
The compounds of general Formula 1, by virtue of their inhibitory action on aromatic amino acid decarboxyl-ase peripherally are also useful in the treatment of rheumatoid arthritis, carcinoEd syndrome, anaphylactoid reactions in humans, bronchoconstriction in asthmatic humans as well as other conditions known to be caused by high peripheral levels of 5-hydroxytryptamine.
As indicated hereinabove it has been shown that agents which decrease the elevated levels of 5-HT and norepi-nephrine, the hydroxylation product of dopamineJ are use-ful in treating patients with manic disorders. Hence, as central irreversible inhibitors of aromatic amino acid ~0 decarboxylase, and DOPA decarboxylase the compounds of ~ 57 ~ 3~ Ml-916 general Formula I are useful in treating manic disorders.
Additionally, by virtue of the central inhibitory action of the compounds of general Formula I on aromatic amino acid decarboxylase said compounds may also be useful as antipsychotic agents, since central levels of tryptamine are decreased~ and use~ul in the treatment of schizophrenia and seizure disorders since central levels of phenethylamine and tyramine are decreased by administration of a compound of general Formula 1.
The utility of the compounds of general Formula I as irreversible inhibitors of aromatic amino acid decarboxylase may be demonstrated as follows. A compound of general Formula I is administered as an aqueous solution or sus-pension to rats or mice. At different time intervals after administration of the compound from 1 to 48 hours the animals are sacrificed by decapitation and aromatic amino acid decarboxylase activity is measured by a radiometric assay as described by Christenson et al., Arch. Biochem.
Biophys. 141, ~56 (1970) in homogenates of kidney, heart and brain prepared according to Burkard et al., Arch.
Biochem. Biophys. 107, 187 (1964).
The compounds of this invention can be administered in various manners to achieve the desired effect. The compounds can be administered alone or in the form of pharmaceutical preparations to the patient being treated either orally or parenterally, for example, subcutaneously~
intravenously or intraperitoneally. The compounds can be administered by intranasal instillation or by application to mucous membranes such as that of the nose, throat and bronchial tubes, for example, in an aerosol spray con-~57~30 taining small particles of a novel compound of this inven-tion in a spray solution or dry powder form.
The amount of novel compound administered will vary and can be any effective amount. Depending on the patient, the condition being treated and the mode of administration, the quantity of novel compound administered may vary over a wide range to provide an effective amount in a unit dosage form. When the compounds of general Formula 1 are administered to affect a peripheral irreversible inhibition of aromatic amino acid decarboxylase the effective amount of compound administered will vary from about 0.1 mg/kg (milli-grams per kilogram) to 100 mg/kg of body weight of the patient per dose and preferably from about 5 mg/kg to 25 mg/kg. For example, the desired peripheral effect can be obtained by consumption of a unit dosage form, such as, for example, a tablet containing from 10 to 250 mg of a novel compound of this invention taken 1 to 4 times daily. When the compounds of general Formula 1 are administered to achieve a central irreversible inhibition of aromatic amino acid decarboxylase :

Ml-916 or 3,~-dihydroxyphenylalanine decarboxylase the effective amount of compound administered will vary from about 100 mg/kg to 500 mg/kg of body weiyht of the patient per day and preferably from about 150 mg/kg to ~0~ mg/kg. For example, the desired central effect can be achieved by consumptlon of a unit dosage form, such as, for example, a tablet containing from about ~50 mg to 500 mg of a novel compound of this invention taken from 1 to 4 times daily.
As used herein the term patient i5 taken to mean warm blooded animals such as mammals, for example, cats, dogs, rats, mice, guinea pigs, sheep, horses, bovine cows, and humans.
The solid unit dosage forms can be of the conventional type. Thus, the solid form can be a capsule which can be of the ordinary gelatin type containing a novel compound of this invention and a carrier, for example, lubricant and inert fillers such as lactose, sucrose and corn starch.
In another embodiment, the novel compounds are tableted with conventional tablet bases such as lactose, sucrose or corn starch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents such as corn starch, potato starch, or alginic acid, and a lubricant such as stearic ac7d, or magnesium stearate.
For parenteral administration the compounds may be administered as injectable dosages of a solution or sus- ;
pension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils with or without the addition of a surfactant and other pharmaceutically ~0 acceptable adjuvants. Illustrative of oils which can be -~ 5~ ~3~ MI-916 employed in these preparations are ~hose of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, and mineral oil. In general water, saline, aqueous dextrose, and related sugar solutions, ethanols and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
The compounds can be administered in the form of a depot injection or implant preparation wh;ch may be formu-lated in such a manner as to permit a sustained releaseof the active ingredient. The active ingredlent can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber manufactured by the Dow-Corning Corporation.
For use as aerosols the novel compounds in solution or suspension may be packaged in a pressurized aerosol container together with a gaseous or liquified propellant, for example, dichlorodifluoromethane, dichlorodifluoro-methane with dichlorodifluoroethane, carbon dioxide, nitrogen or propane, wlth the usual adjuvants such as cosolvents, and wettlng agents, as may be necessary or desirable. The compounds may also be adminis~ered in a non-pressurized form such as in a nebulizer or atomizer.
As indicated hereinabove the compounds of general Formula I find particular utility when administered together with exogenous L-DOPA in which case individual formulations of a compound of general Formula I and L-DOPA may be ad-* Trade Mark -17-,....................................................... .

~ 57 ~ 30 ministered, or both active ingredients may be formulated into a single combination pharmaceutical formulation. In either mode of administration the amount of compound of general Formula I as compared to the amount of L-DOPA
administered will vary from about 1:1 to 1:10. A combi-nation formulation may contain an internal portion con-taining L DOPA and an outer portion containing a compound of general Formula I~ each active ingredient being suit-ably formulated. A particularly suitable combination formulation may be prepared by compressing L-DOPAg optionally with suitable carriers, to a core, providing said core with a laminated coating that is resistant to gastric juice, and applying over the coated core an external layer that contains a compound of general Formula I suitably formulated~ Using such a combination formula-tion the decarboxylase inhibitor, that is, a compound of general Formula I is released, preferably ~0 to 60 minutes prior to the L-DOPA. The laminated coating may be formed by use of a nonaqueous solution of glycerides or a water-insoluble polymer such as ethyl cellulose or cellulose acetate phthalate. Formulation wherein the L-DO~A is enteric coated by use of mixtures of shellacs and shellac derivatives and cellulose acetate phthalates may also be employed.
In the specific examples included hereinbelow illustrative examples of suitable pharmaceutical formula-tions are described.
In addition to being useful pharmacological agents compounds of general Formula I are also useful as inter-mediates for the preparatlon of useful cephalosporin anti-ii7(330 biotics. Compounds of general Formu]a 1 wherein R2 is hydroxy are useful in the preparation of cephalosporin derivatives of the following general Formula 11:

R4 R3 Formula 11 ~ CH=CH2 R5 ~ CH2-f-CONH
~ NHRl ~I~CH2X
R'4 R6 COO~
In the above general Formula 11, Rl, R3, R4, Rs and R6 have the meanings defined in general Formula l; M is hydrogen or a negative charge; and X is hydrogen or acetoxy.
The com~ounds of general Formula 11 and the pharma-ceutically acceptable salts and individual optical isomers thereof are novel compounds useful as antibiotics and can be administered in a manner similar to that of many well known cepllalosporin derivatives, for example, cephalexin, cephalothin, or cephaloglycine. The compounds of general Formula 11 and pharmaceutically acceptable salts and isomers thereof can be administered alone or in the form of pharmaceutical preparations either orally or parenter-ally and topically to warm blooded animals, that is, birds and mammals, for example, cats, dogs, bovine cows, sheep, horses and humans. For oral administration the compounds can be administered in the form of tablets, capsules or pills or in the form of elixirs or suspensions.
For parenteral administration, the compounds may best be used in the form of a sterile aqueous solution which may contain other solutes, for example, enough saline or glucose to make the solution isotonic. For topical .

~7 ~ 3~
Ml-916 administration the compounds of general Formula ll, salts and isomers thereof may be incorporat~d into creams or o i ntments .
Illustrative examples of bacteria against which the compounds of general Formula ll and the pharmaceutically acceptable salts and individual optical isomers thereof are active are Staphylococcus aureus, Salmonella schot-m~ehleri, Klebsiella pneumoniae, ~iplococcus pneumoniae and Streptococcus pyogenes.
Illustrative pharmaceutically acceptable non-toxic inorganic acid additions salts of the compounds o~ general Formula ll are mineral acid addition salts, for example, hydrogen chloride, hydrogen bromide, su-lfates, sulfamates, phosphate, and organic acid addition salts are, for ex-ample, maleate, acetate, citrate, oxalate, succinate, benzoate, tartrate, fumarate, malate and ascorbate. The salts can be formed by conventional means.
Illustrative examples of cephalosporin derivatives as represented by general Formula ll are 7-[~2-amino-3-phenyl-2-vinylpropionyl]amino]-~-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-~C2-amino-3-t3-hydroxyphenyl)-2-vinylpropionyl]amino]-

3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-~[2-amino-3-~3,4-dihydroxy-phenyl)-2-vinylpropionyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid, and 7-~2-amino-3-(4-hydroxyphenyl)-2-vinylpropionyl]-amino]-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic a~id.

~57(~30 ~ I - 916 The compounds of general Formula ll wherein R~ is hydrogen are prepared by coupling 7-aminocephalosporanic acid or a derivative thereof having the formula H2N F~ S~
CH2X Formula lll COOM
wherein X and M have the meanings defined in general Formula ll with an acid of the formula ~ ÇH=CH2 Rs ~ H2-C-COOH Formula IV
R' 4 R8 NH2 or a functional derivative thereof such as the acid chloride or an acid anhydride and in the presence of a dehydrating 3gent such as dTcyclohexylcarbodiimide when the free acid is employed, wherein R1 and R2 have the meanings defined in general Formula ll and the amino group is protected with a suitable blocking group such as tert-butoxycarbonyl followed by acid hydrolysis to remove the amino protecting groups.
The coupling reaction is generally carried out in a solvent, such as, ethyl acetate, dioxane, chloroform or tetrahydrofuran in the presence of a base, such as, alka-line bicarbonate. The temperature of the reaction may vary from about -10C to 100C and the reaction time may vary from about 1/2 hour to 10 hours. The cephalosporin products are isolated-by conventional procedures. The compounds of general Formula IV are prepared by procedures described hereinabove and the compounds of Formula lll are commercially available or are made by procedures well known in the art.

57 ~ ~
Ml-~16 The compounds of general Formula ll wherein Rl is other than hydrogen are prepared from the corresponding derivatives wherein Rl is hydrogen by the general proce-dures set forth hereinbelow for compounds of general Formula I wherein Rl is other than hydrogen.
The compounds of general Formula I wherein R2 is hydroxy or a straight or branched alkoxy group of from 1 to 8 carbon atoms and R~ is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and :
is straight or branched are prepared by catalytic or chemical semi-hydrogenation of the corresponding acetylene derivatives having the structure R4 R3 CaCH
Rs ~ CH2-C-COORl1 Formula V
R'4 R6 NHR12 wherein R3 to R6 and R'~ have the meanings defined in general Formula 1, R11 is a straight or branched alkyl group of from 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentylJ neopentyl and n-hexyl, and Rlz is hydrogen or an alkylcarbonyl group whereln the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.
Catalytic hydro~enation of a compound of general Formula V is carried out in a solvent such as lower alco-hols, for example, methanol, ethanol or isopropyl alcohol, hydrocarbon solvents such as ben~ene or toluene or chloro-form optionally in the presence of an organic amine such as pyridine or triethylamine, which may serve as the ~L~57~30 solvent, using inorganic catalysts as described by E.N.
Marvell and T. Li, Synthesis, No. 8, August, 1973, pp. 457-468, for example, palladium-on-barium sulfate or the Lindlar catalysts, that is, lead poisoned palladium-on-calcium carbonate. The hydrogenation process is carriedout at temperatures of about 0 to 25C and is continued until there is a reduction in the uptake of hydrogen and followed by hydrolysis with aqueous acid, for example, hydrogen bromide or hydrochloric acid when R2 is hydroxy and Rl is hydrogen, Chemical semi-hydrogenation of an acetylene compound of general Formula V is achieved by reacting equimolar amounts of the acetylene derivative and catecholborane under a nitrogen atmosphere at about 60C for about 2 hours by the general procedures described by H.C. Brown and S.K. Gupta, J. Am. Chem. Soc. 94, 4370-71 (1972);
H.C. Brown, et al., J. Am. Chem. Soc. 95, 5786-8 and 6456-7 (1973), followed by hydrolysis with aqueous acid, for example, acetic acid when R2 is hydroxy and Rl is hydrogen.
Alternatively the compounds of general Formula 1 wherein Rl is hydrogen, R2 is hydroxy and the substituents on the aromatic ring are other than chlorine or bromina may be prepared by treating the corresponding ~-acetylene derivatives with sodium, potassium or lithium in liquid ammonia and ammonium sulfate at about -70 to 25C until the blue color persists for about 15 minutes. When in the above reaction the aromatic substituent(s) is methoxy and the corresponding hydroxy derivative is desired either the methoxy substituted acetylene derivative may be treated Ml-916 with concentrated hydrobromic acid prior to reduction to the vinyl derivative or the methoxy substituted vinyl derivative may be treated with concentrated hydrobromic acid. Hydrolysis with hydrobromic acid is carried out at about 120C for about 1 to 8 hours.
Compounds of general Formula I wherein R2 is a straight or branched alkoxy group of from 1 to 8 carbon atoms may also be prepared by reacting the corresponding derivative wherein R2 is hydroxy with thionyl chloride to form the acid chloride which is reacted with an alcohol of the formula R13-OH, wherein R1~ is a straight or branched alkyl group of from 1 to 8 carbon atoms, such as, methyl, ethyl, n-propylJ isopropyl, n-butyl, tert-butyl~ n-pentyl, neopentyl, hexyl, or octyl, at about 25C for about 4 to 12 hours.
The compounds of general Formula I wherein R2 is -NR7R8 wherein each of R7 and R8 is hydrogen or a straight or branched lower alkyl of 1 to 4 carbon atoms are pre-pared by an acylation reaction of an acid halide, for example, an acid chloride, of the corresponding compound wherein R2 7s hydroxy and R1 has the meaning defined in Formula I with the proviso that any free amino group ts protected with a suitable protecting group, for example, carbobenzyloxy or tert-butoxycarbonyl and when any of R3, R4, Rs or R' 4 i5 OR1o and Rlo is hydrogen sa;d groups are protected as the corresponding alkylcarbonyloxy group, with an excess of an appropriate amine which may be repre-sented as HNR7R8. The reaction is carried out in methylene chloride, chloroform, dtmethylformamide, ethers such as ~0 tetrahydrofuran or dioxane or benzene at about 25C for -2l~-57 ~ 3~
Ml-916 about 1 to 4 hours. Suitable amines are3 for example, ammonia, or a compound which is a potential source of ammonia, for example, hexamethylenetetramine; primary amines~ for example, methylamine, ethylamine or n-propyl-amine; and secondary amines such as dimethylamine, diethyl-amine or di-n-butylamine. Foilowing the acylation reaction the amino protecting group is removed by treatment with acid or hydrogen bromide in dioxane, and the hydroxy protecting group when appropriate is removed by base hydrolysis.
The compounds of general Formula I wherein R~ is -NH-CH-COOH are prepared by reacting the corresponding R~
derivative wherein R2 is hydroxy or a functional derivative thereof such as an acid anhydride and R1 has the meaning defined in Formula î with the proviso that any free amino group is protected with a suitable blocking group, such as benzyloxycarbonyl or tert-butoxycarbonyl with a compound of the formula NH2~fH~COOR1g wherein R9 has the meaning Rg defined in general Formula I and R14 is a lower alkyl group, for example, methyl or ethyl in an ether, such asJ tetra-hydrofuran or dioxane at 0 to about 50C for about 1 to 24 hours followed by acid hydrolysis to remove the pro-tecting group, with the proviso that when the amine pro-tected free acid is employed the reaction is carried out using a dehydrating agent such as dicyclohexylcarbodiimide.
The compounds of general Formula I wherein R~ Ts alkylcarbonyl wherein the alkyl moiety is straight or branched and has from 1 to 4 carbon atoms may also be 57~ 30 Ml-916 prepared by treating the corresponding derivatives wherein R1 is hydrogen and R2 is hydroxy with an acid halide of O
the formula R1s-~-halo wherein halo is a halogen atom, for example, chlorine or bromine and R1s is a straight or branched alkyl group having from 1 to 4 carbon atoms in water in the presence of a base such as sodium hydroxide or sodium borate at a temperature of from 0C to 25C for from 1/2 hour to 6 hours.
The compounds of general Formula I wherein R1 is alkoxycarbonyl wherein the alkoxy moiety is straight or branched and has from 1 to 4 carbon atoms are prepared by treating the corresponding derivative wherein Rl is hydro-gen and R2 is hydroxy with an alkyl haloformate of the o formula halo-~-OR1~ wherein halo is a halogen atom such 1~ as chlorine or bromine and R13 is a straight or branched alkyl group having from 1 to 4 carbon atoms in water in the presence of a base such as sodium hydroxide or sodium borate at a temperature of from about 0C to 25C for from about 1/2 hour to 6 hours.
The compounds of general Formula I wherein R1 is o -C-fH-R17 wherein R17 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl are prepared by treating ~he corresponding derivative wherein R1 is hydrogen and R2 is a straight or branched alkoxy group of from 1 to 8 carbon atoms with an acid of the formula HOOC-FH-R17 or an anhydride thereof -26~

Ml-916 wherein the amino group is protected with a suitable blocking group such as benzyloxycarbonyl or tert-butoxy-carbonyl and R17 has the meaning defined hereinabove in an ether, such as, tetrahydrofuran or dloxane, methylene chloride or chloroform and in the presence of a dehydrating agent, such as, dicyclohexylcarbodiimide when the free acid is employed, at a temperature of from about 0C to 75C for about 1 to 12 hours followed by acid and base hydrolysis to remove the protecting groups.
The individual optical isomers of the compounds of general Formula I wherein R1 is H and R2 is OH may be separated by using a (+) or (-) binaphthylphosphoric acid salt by the method of R. Viterbo et al., Tetrahedron Letters, 48, 4617 (1971)o Other resolving agents such as (+) camphor-10-sulfonic acid may also be employed. The individual optical isomers of compounds wherein Rl and R2 `
are other than H and OH may be ob~ained as described herein for the racemate only starting with the resolved amino acid.
The compounds of general Formula V wherein both R3 and R4 are ORlo wherein Rlo is hydrogen, both R4 and Rs are are OR1o wherein Rlo is hydrogen, both R4 and R5 are -O-CH2-O- or wherein each of R3, R4, R5, R' 4 and R~ have the meanings deflned in general Formula I except Rlo is methyl are prepared by treating a suitably protected pro-pargylamine derivative with a strong base to form a `
protected propargylamine carbanion intermediate which is alkylated respectively when R3 and R4 are both Rlo and R1o is hydrogen with 2,3-isopropylidenedioxybenzylhalide and when R4 and R5 are both OR1o and Rlo is hydrogen, with 3J4-Ml-916 isopropylidenedioxybenzyl halide, and when R4 and R5 together are -O-CH2-O- with 3,4-methylenedioxybenzylhalide wherein hal;de is, for example, chloride or bromide, and :~
when R3 ~o R~ and R' 4 are as otherwise described above, with a compound of the formula Rl g Rl8 R20 ~ CH2Y Formula Vl R ' 1 9 R2l wherein Y is a halogen atom, for example, chlorine or bromine and each of R18, Rl9, R20, R' 19 and R21 have the meanings defined in the following Table ll wherein R22 is methyl:
TAB~E ll Rl~ Rl9 ~Q R' ~ 9 ~ZL
H H H H H

H R22 OR2z H H
OR22 H C l H H
H R22 C l H H
C l OR22 H H H
C l R22 C l H H
Cl,F H OR22 H H
Cl H H H CH3 Cl H Cl H CH3 H H Cl,F H CH3 OR22 H 'CH3 H CH3 Cl H CH3 H CH3 ~ `

.
~1 57~ 30 Ml-916 H H OR22 H C2Hs OR22 H C2Hs H CzHs H H OCHg OCH2Ph H
H H OCH2Ph OCH9 H

H H Cl H C2Hs H H Cl H tert-C4H9 H H OR22 H tert-C4H9 The thus formed alkylated propargylamine derivative is treated with a strong base to form an alkylated propargyl-15 amine carbanion, said second carbanion intermediate is treated with an acylating reagent with subsequent removal of the protecting groups as represented by the following reaction sequence:
r~
(R2g)3-S i-CaC-CH2 strong l(R23)3 S i-CaC-fH( =f-R24 base ~ I NslC-R
R2s I__ . R2s _ compounds 1 1R2~Y

I 28 1 ~2el (R2~ )3-S i -C3C-f ( ) I strong (R23)3-S i -C-C-fH
N-lC-R24 ~ N=l -R24 !_ R2s I R2s ¦acylating compounds 2 ~reagent -29- .

,. : ~ ~. . -57 ~ 30 Ml-916 R2~
Rsa (R23 )3-S i -C~C-~ -R~7 R-4a ~ 4a I deprotec~ion I tl N=C-R24 R`8a ~ R3a R2s CH2 Hcac -F -COOH

Formula Vll In the above reaction scheme R23 represents a straight or branched lower alkyl group having from 1 to 4 carbon .~ : :
atoms, such as, methy.l, ethyl, n-propyl and tert-butyl;
R24 is phenyl, tert-butyl or triethylmethyl, 1-adamantanyl or 2-furyl; R25 is hydrogen, methoxy or ethoxy with the proviso that when R24 is 1-adamantanyl or 2-furyl, R2s is not hydrogen; R2~Y represents the alkylating reagents 2,3-isopropylidenedioxybenzylhalide, 3,4-isopropylidenedioxy-benzylhalide, ~,4-methylenedioxybenzylhalide or the com-pounds of Formula Vl; Ph represents phenyl; R27 is a carboxy anion, a carboxylic acid ester~ a carboxamide, a nitrile or other group capable of being hydrolv~ed to a carboxylic acid function which varies with the acylating reagent employed; and each of R3a, R4a, Rsa~ R'4a and R~a respectively has the meaning defined for R9, R4, R5, R' 4 and R3 in Table I except R~o is methyl, or both R3a and R4a represent ORIo wherein R~o is hydrogen, both R4a and R5a represent ORIo and R1o ls hydrogen.
The compounds of Formula Vll are then converted to the ester amide derivative by treatment with thionyl chloride to form the acid chloride which is treated with an alcohol of the formula Rll-OH, wherein Rll has the meaning defined -3~

- ~ , .

Ml-916 in Formula V at about 25C for about 4 to 12 hours followed o by treatment with an acid halide of the formula R12-C-halo wherein R12 has the meaning defined in Formula V and halo is a halogen atom, such as, chlorine or bromine, in the presence of a base such as sodium hydroxide, potassium hydroxide or an excess of triethylamine for about 1/2 hour to 24 hours at about 0C to 25C.
Suitable strong bases which may be employed in the above reaction sequence to form each carbanion are those which will abstract a proton from the carbon atom adjacent to the acetylene moiety, such as, alkyl lithium, for example, butyl lithium or phenyl lithium, lithium di-alkylamide, for example, lithium diisopropylamide, lithium amide, terttary potassium butylate or sodium amide.
The alkylating reagents employed in the above reaction sequence are known in the art. For example, 2,3-isopropyli-denedioxybenzylhalide may be obtained from 2,3-dihydroxy-toluene by treatment with acetone in the presence of phosphorus pentoxide followed by treatment with bromo-succinimide by the general procedure of K. Ogura and G. Tsuchihashi, Tetrahderon Letters 1971, 3151, Suitable acylating reagents which may be employed in the above reaction are halo-formates, such as chloromethyl formate or chloro ethylformate, azido tert-butylformate, cyanogen bromide, carbon dioxide, diethylcarbonate~ phenyl-isocyanate, triethoxymethylium tetrafluorobora~e, N,N- -dimethylcarbamoyl chloride, 2-methylthio-1,3-dithiolinium iodide, ethylene carbonate or ethylene trithiocarbonate.

571330 `
~ I - 916 When 2-methylthio-1,3-dithiolinium iodide is employed the additional step of alcoholysis with a lower alcohol, for example ethanol or isopropyl alcohol i5 required prior to deprotection by hydrolysis.
The alkylating reaction and the acylating reaction may be carried out in an aprotic solvent, for exa~?le, benzene, toluene, ethers, tetrahydrofuran, dimethylsul-foxide, hexamethyl phosphortriamide. For each reaction the temperature varies from -120C to about 25C, a pre-ferred reaction temperature being about -70C, and the reaction time varies from about 1/2 hour to 24 hours.
Removal of the protecting groups is achieved by treatment with aqueous base, for example, sodium or potassium hydroxide or use of hydrazine or phenylhydrazine followed by acid hydrolysis with, for example, hydrochloric acid when the alkylating reagent is 3,4-lsopropylidene-dioxybenzyl halide or 2,3-isopropylidenedioxybenzyl halide, and when the alkylating reagent contains a benzyloxy group base hydrolysis is followed by treatment with lithium amide or sodium amide in ammonia followed by the addition of lithium or sodium metal until the blue color persists for about 15 minutes.
The propargylamine derivatives wherein R2s is hydrogen are prepared by the addition of protecting groups on the acetylene function and the nitrogen function of propargyl-amine. Protection of the nitrogen function of the propar-gylamine is accomplished ~y forming in a known manner a Schiff's base with a nonenolizable carbonyl bearing com-pound selected from benzaldehyde, 2,2-dimethylpropanal and 2,2-diethylbutanal. Protection of the acetylenic function ~ 57 ~30 Ml-916 is accomplished by reacting the above-described Schiff's base with a trialkylsilylchloride wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, for example, trimethylsilylchloride or triethylsilylchloride forming in a known manner the corresponding trialkylsilyl derivative.
The propargylamine derivatives wherein R2s is methoxy or ethoxy are prepared by reacting propargylamine wherein the acetylene function is protected by a trialkylsilyl group, wherein the alkyl moiety has from 1 to 4 carbon atoms, with benzoyl chloride, pivalic acid chloride, 2,2-diethylbutyric acid chloride, 2-furoic acid chloride or 1-adamantane carboxylic acid chloride at 0C in diethyl ether, dioxane, tetrahydrofuran, chloroform, methylene-chloride, dimethylformamide, dimethylacetamide, or chloro-benzene in the presence of an organic base such as tri-ethylamine or pyridine after which the reaction mixture is allowed to warm to about 25C for one hour. The resulting amide derivative is combined with an alkylating reagent, such as, methylfluorosulfonate, dimethylsulfate, methyliodide, methyl p-toluenesulfonate or trimethyl-oxon7um hexafluorophosphate when R25 is methoxy and tri-ethyloxonium tetrafluoroborate when R~5 is ethoxy.at about 25C in a chlorinated hydrocarbon solvent such as methylene 25 chloride, chlorobenzene or chloroformJ and the reaction mix-ture is then cooled to about 25C and an organic base such as triethylamine or pyridine is added, after which the solution is extracted with brine and the product isolated.
The protected propargylamine starting material is obtained by treating a 3-trialkylsilylprop-2-ynyl-1-imino--~3-~ 57~30 Ml-916 benzyl derivative with hydrazine or phenylhydrazine at about 25C for about 1/2 hour after which the mixture is diluted with, for example, petroleum ether, benzene or toluene and the protected propargylamine derivative iso-lated. Alternatively treatment with 0.5 to 1 N HCl gives the hydrochloride.
The compounds of general Formula Vl are known in the art or may be prepared from the cor~esponding appropriately substituted benzoic acid or benzaldehyde derivative which are known in the art. For example, the benzylhalides of Formula Vl may be prepared from the corresponding benz-aldehyde 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 reduction of the correspond-ing benzoic acid derivative with lithium hydride and treating the thus formed benzyl alcohol derivatTve with, for exampleJ thionyl chloride or phosphorus oxychloride.
The compounds of general Formula V wherein either of R9, R4, R5 or R'4 is OR1o wherein R1o is hydrogen are prepared from the corresponding ester amide derivative whereTn either of R9, R4, R5 or R' 4 is OR1o and R1o iS
methyl by treatment of said derivative with a Lewis acid such as, boron tribromide, boron trichloride or boron tri-fluoride.
Compounds of general Formula V wherein any of R9, R4 R5 or R' 4 Ts OR~o and R1o is a straight or branched alkyl group of from 1 to 8 carbon atoms may be prepared by alkyl-ating the corresponding ester amide derivative wherein R1o ~0 is hydrogen with an alkyl halide of the formula R28Y2 ~4-~157~30 Ml-916 wherein R28 is a straight or branched alkyl group of from 1 to 8 carbon atoms and Y2 is halogen, for example, bromine or iodine in a lower alcoholic solvent such as methanol or ethanol or hydrocarbon solvents such as benzene or toluene in the presence of an organic base such as triethylamine or pyridine or in an apro~ic solvent such as dimethylform- ::
amide, dimethylacetamide or dimethylsulfoxide in the presence of sodium hydride for about 1 to 24 hours at a temperature of about 25C to 85C ~ollowed by hydrolysis with aqueous base with the proviso that prior to the alkylation reaction the ~-amino group of the hydroxy sub-stituted starting material is protected with a suitable protecting group such as tert-butoxycarbonyl which is subsequently removed by treatment with acidJ such as, trifluoroacetic acidO The alkyl halides employed in the above reaction are known in the art or can be prepared by procedures well known in the art.
The compounds of general Formula I wherein any of R9, R4, R5 or R' 4 is OR1o and Rlo is alkylcarbonyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched, benzoyl, or phenylalkylenecarbonyl wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms are prepared by treating the corres-ponding ester amide derivative wherein R1o is hydrogen with an acid anhydride of the formula (R29-C-)20 or an acid halide of the formula R29-~-halo wherein halo is chlorine or bromine and R29 is a straight or branched alkyl group of from 1 to 6 carbon atoms, phenyl or phenylalkylene wherein the alkylene moiety is straight or branched and has ~57(330 from l to 6 carbon atoms in the presence of an organic base such as pyridine, quinoline or triethylamine, which base serves as the solvent, for about 1 to 24 hours at a temperature of about 25C to 100C with the proviso that prior to the reaction the ~-amino group of the hydroxy substituted starting material is protected with a suitable blocking group, such as tert-butoxycarbonyl which is subsequently removed by treatment with acid, for example, trifluoroacetic acid.
The acid anhydride and acid halide reactants employed in the above reaction are known in the art or can be pre-pared from the appropriate acids by procedures well known in the art.
The following Example 1 illustrates the use of a compound of general Formula 1 wherein R2 is hydroxy as a chemical intermediate in the preparation of a cephalosporin of Formula 11.
EXAMP:LE 1 7-[[2-amino-3-phenyl-2-vinylpropionyllamino]-3-acetyl-oXymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxvl'ic ac'id A mixture of 1 g of 3-acetyloxy-7-amino-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1 g of 2-amino-3-phenyl-l-vinylpropionic acid chloride wherein the free amino group is protected with t _ -butoxycarbonyl in 50 ml of ethyl acetate is refluxed for 2 hours after which the solvent is removed leaving a residue which is treated with mild acid and chromatographed on silica gel using benzene-acetone or the eluant to give 7-[[2-amino-3-phenyl-2-vinylpropionyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

: : .

57 ~30 Ml-916 The following Examples 2 to 4 are illustrative of pharmaceutical preparations of the compounds of this invention.

An illustrative composition for hard gelatin capsules ts as follows:
(a) 2-amino-~-(3-hydroxyphenyl)- 20 mg 2-vinylpropionic acid (b) talc 5 mg (c) lactose 90 mg The formulation is prepared by passing the dry powders of (a) and (b) through a fine mesh screen and mixing them :
well. The powder is then filled into hard gelatin C3p-sules a~ a net fill of 115 mg per capsule.

An illustrative composition for tablets is as follows:
(a) 2-amino-3-(~,4-dihydroxyphenyl)- 20 mg 2-vinylpropionic acid (b) starch 4~ mg (c) lactose 45 mg (d) magnesium stearate 2 mg The granulation obtained upon mixing the lactose with the compound (a) and part of the starch and granulated : wlth starch paste is dried, screened, and mixed with the magnesium stearate. The mixture is compressed into tablets weighing 110 mg each.

An illustrative composition for an injectable suspen-sion is the following 1 ml ampul for an intramuscular injectionO

-~7-57 ~ 30 Ml-916 Weight per cent (a) 2-amino-3-(4-hydroxyphenyl)- 1.0 2-vinylpropionic acid (b) polyvinylpyrrolidone 0.5 (c) lecithin 0.25 (d) water for injection to make 100.0 The materials (a) - (d) are mixed~ homogenized~ and filled into 1 ml ampuls which are sealed and autoclaved 20 minutes at 121C. Each ampul contains 10 mg per ml of novel compouns (a).
The following Examples further illustrate the com-pounds of general Formula 1.

2-Amino-3-(3-chloro-4-hydroxyphenyl)-2-vinylpropionic acid (A) A solution of 2.53 (10 mM) of 2-acetylene-2-amino-3-(3-chloro-4-methoxyphenyl)propionic acid in 100 ml of methanol saturated with dry hydrogen chloride is stirred for about 16 hours at 25C- after which the solvent is evaporated leaving a residue which is suspended in 30 ml of methylene chloride. To the suspension is added 2.5 9 (?5 mM) of triethylamine followed by 780 mg (10 mM) of acetyl chloride. After 2 hours at 25C the mixture is washed with 2 N HCl, dried and evaporated. The resulttng residue is recrystallized from methanol to give methyl 2-acetylamino-2-acetylene-3-(3-chloro-4-methoxyphenyl)-propionate.
(~) A solution of ~ g (5 mM) of methyl 2-acetyl-amino-2-acetylene-3-(3-chloro-4-methoxyphenyl)propionate in 40 ml of methanol containing Lindlar's catalyst is stirred under an atmosphere of hydrogen at 25C until .

~15~30 Ml-916 absorption ceases at 120 ml. The suspension is filtered, l -the filtrate evaporated. The resulting residue is recrystal-lized from ethyl acetate-petroleum ether then suspended !~n 48% hydrogen bromide and heated at reflux for 3 hours. The solvent is evaporated leaving a residue which is dissolved in the minimum quantity of water and hydrazine is added until a pH of 5 is reached. On cooling a precipitate forms which is collected to give 2-amino-3-(3-chloro-4-hydroxy-phenyl)-2-vinylpropionic acid.
10When in the procedure of Example 5(A) an appropriate amount of 2-acetylene-2-amino-3-(3,4-dihydroxyphenyl)-propionic acid, 2-acetylene-2-amino-3-(3-methoxyphenyl)-propionic acid, 2-acetylene-2-amino-3-(3-hydroxyphenyl)-propionic acid, 2-acetylene-2-amino-3-phenylpropionlc acid, 152-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 or 2~acetylene-2-amino-3-(6-~ert-butyl-4-chlorophenyl)propionic acid is substituted for 2~acetylene-2-amino-3-(3-chloro-~-methoxy-phenyl)propionic acid the following respective ester amide derivatives are obtained:
methyl 2-acetylamino-2-acetylene-3-(3,4-dihydroxyphenyl)-propionate,methyl 2-acetylamino-2-acetylene-3-(3-methoxyphenyl)-propionate, methyl 2-acetylamino-2-acetylene-3-(~-hydroxyphenyl)-propionate, ~9 ~ 571)30 Ml-916 methyl 2-acetylamino-2-acetylene-3-phenylpropionate, methyl 2-acetylamino-2-acetylene-~-(4-chloro-2-methoxy-phenyl)propionate, methyl 2-acetylamino-2-acetylene-3-(2-chloro-6-methylphenyl)-propionate,methyl 2-acetylamino-2-acetylene-~-(2,4-dichloro-6-methyl-phenyl)propionate, methyl 2-acetylamino-2-acetylene-3-(4-methoxy-6-methyl-phenyl)propionate, and methyl 2-acetylamino-2-acetylene-3-(6-tert-butyl-4-chloro-phenyl)propionate.
When in the procedure of Example 5(B) an appropriate amount of the above enumerated methyl ester derivatives is substituted ~or methyl 2-acetylamino-2-acetylene-~-(3-chloro-4-methoxyphenyl)propionate the following respective compounds are obtained:
2-amino-3-(~,4-dihydroxyphenyl)-2-vinylpropionic acid, 2-amino-3-(~-hydroxyphenyl)-2-vinylpropionic acid, 2-amino-3-phenyl-2-vinylpropionic acid, 2-amino-3-(4-chloro-2-hydroxyphenyl)-2-vinylpropionic acidJ
2-amino-3-(2-chloro-6-methylphenyl)-2-vinylpropionic acid, 2-amino-3-~2,4-dichloro-6-methylphenyl)-2-vinylpropionic acid, 2-amino-~-(4-hydroxy-6-methylphenyl)-2-vinylpropionic acid, and 2-amino-3-(6-tert-butyl-4-chlorophenyl)-2-vinylpropionic acid.

~5'7~)30 Ml-916 Ethyl 2-amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionate F~roc ori e A suspension of 2.2 9 (10 mM) of 2-amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionic acid in 30 ml of ethanol is saturated with anhydrous HCl, and the resulting solu-tion allowed to stand at 25C for 24 hours. The solvent is evaporated leaving a residue which is recrystallized from ethanol-ether to give ethyl 2-amino-3-(3,4-dihydroxy-phenyl)-2-vinylpropionate hydrochloride.

3-(~J4-Diacetyloxyphenyl)-2-(benzyloxycarbonylamino)-2-v i ny prop l on Ic ac l 2 N aqueous sodium hydroxide and acetic anhydride (3.5 9) are added simultaneously during 1/2 hour to a solution of 2-(benzyloxycarbonylamino)-3-(3,4-dihydroxy-phenyl)-2-vlnylpropionic acid (6 9) prepared from 2-amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionic acid and benzyl chloroformate in 30 ml of 1 N sodium hydroxide under argon so that the pH is maintained between 6.5 and 7.5. After 1 hour at 25C the pH is adjusted to 1 using 6 N sulfuric acid then extracted with methylene chloride. The organic phase is dried and concentrated to give 3-(3,4-diacetyl-oxyphenyl)-2-(benzyloxycarbonylamino)-2-vinylpropionic acid.

2-~Acetylamino)-3- ~ droxyphenyl)-2-vinylpropionic acl To a stirred suspension of 6.8 g (10 mM) of borax in 10 ml of water is added 2.2 9 (10 mM) of 2-amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionic acid under argon.

1 5~ ~ 30 Ml-916 After 15 minutes the pH is adjusted to 9 by the addition of 2 N sodium hydroxide then treated dropwise wlth 780 mg of acetyl chloride, maintaining the pH between 9.0 and 9.5. The aqueous solution is washed with ether, adjusted to a pH of 1 using 6 N sulfuric acid and extracted with methylene chloride. The organic phase is dried and con-centrated to afford 2-(acetylamino~-3-(3,4-dihydroxyphenyl)-2-vinylpropionic acid, which may be treated with ethanol7c HCl to afford the ethyl ester.

2-~2-Amino-3-~3,4-diacetyloxyphenyl)-2-oxo-2-vinylpropyl-amlno~propionlc aci y robromi e A solution of 4.4 9 (10 mM) of 2-(carbobenzyloxy-amino)-3-(3,4-diacetyloxyphenyl)-2-vinylpropionic acid prepared from 2-amino-3-(3,4-diacetyloxyphenyl)-2-vinyl-propionic acid and benzyl chloroformate, in 50 ml of ether is treated with 1.0 9 (10 mM) of triethylamine followed by 1.08 g (10 mM) of ethyl chloroformate. After 1 hour at 25C the precipitate is filtered off and to the ether solution is added a solution of alanine benzyloxy ester (10 mM) in 30 ml of ether. The solution is maintained at 25C overnight then evaporated to dryness. The residue is treated with 20 ml of hydrobromic acid in dioxane (40~ w/w) at 25C for 30 minutes after which ether is added and the pre~ipitate filtered off to give 2-~2-amino-3-(3~4-diacetyloxyphenyl)-2-oxo-2-vinylpropylamino]-propionic acid hydrobromide.

2-(2-Amino-1-oxopropylamino~-3-(3,4-dihydroxyphenyl)-2-vlny propionic acl hydroc ori e A suspension of 3.3 g (10 mM) of benzyl 2-amino-3-

-4~-~57~30 Ml-916 (3,4-dihydroxyphenyl)-2-vinylpropionate in 50 ml of methylene ehlc\ride is treated with 1 9 (10 mM) of triethylamine after which 10 mM of N-carbobenzyloxyalanine wherein the acid func:tion is activated by ethoxycarbonyl in 20 ml of methyl-ene chloride is added. The mixture is stirred at 25C forabout 16 hours then washed with water. The organic layer is dried and evaporated. The residue is taken up in ether and the ether solution cooled to 0C. A vigorous stream of HCl gas is bubbled through the solution for 3 hours after ~ -which the ether solution is washed with water. The aqueous phase is evaporated to afford 2-(2-amino-1-oxopropylamino)-3-(3,4-dihydroxyphenyl)-2-vinylpropionic acid hydrochloride as a gum.

2-Acetylene-2-amino-3-(3,4-dihydroxyphenyl)propionic acid (A) A solution of 32.4 9 (0.15 M) of 3-trimethyl-silylprop-2-ynyl-1-iminobenzyl in 20 ml of tetrahydrofuran is added to llthium diisopropylamide, prepared fro~ 21 ml (0,15 M) of diisopropylamide and 73.2 ml of a 2.05 M
solution of n-butyllithium (0.15 M), in 1 liter of tetra-hydrofuran at -78C. After 15 minutes 32.7 g (1.35 M) of 3,4-isopropylidenedioxybenzyl bromide in 2Q ml of tetra-hydrofuran is added, and the mixture is maintained at -78C
for 2 hours after which 73.2 ml of a 2.05 M solution (0.15 M) of n-butyllithium is added followed by the addition of 14.2 9 11.6 ml (0.15 M) of methyl chloroformate. After an addi-tional 30 minutes at -78C the reaction mixture is treated with brine and extracted with ether. The ether extract is evaporated leaving a resldue which is dissolved in 300 ml of petroleum ether, b.p. ~o-60CJ and treated with 16.2 9 Ml-916 ~ 5'~ 3~

(0.15 M) of phenylhydrazine at 25C for 2 hours. The precipitate is filtered off and the petroleum ether evapo-rated leaving a residue which is treated with 40 9 of potassium hydroxide in 300 ml of ethanol and ~00 ml of water at 25C for about 15 hours. The ethanol is evapo-rated, and the aqueous solution is washed well with methyl-ene chloride, then acidified and rewashed with methylene chloride. The water is evaporated, and the remaining solid residue is triturated with ethanol, filtered and the fil-trate evaporated leaving a residue which is dissolved in water. The pH of the water solution is adjusted to 6 and applied to a column of Amberlite resin 120 H+ and eluting with 2 M ammonium hydroxide solution affords 2-acetylene-2-amino-3,4-isopropylidenedioxyphenylpropionic acid after recrystallization from water-ethanol.
(B) 3 9 (0.13 M) of 2-acetylene-2-amino~3,4-isopropyl-idenedioxyphenylpropionic acid is heated at reflux with 200 ml of 6 N hydrochloric acid for 2 hours after which the solvent is evaporated. The resulting residue is taken up in water and the pH is adjusted to 6 by careful addition of hydrazine hydrate. On cooling the solutton to 0C a precipitate forms which is collected and recrystallized (charcoal) from watar to afford 2-acetylène-2-amlno-3-(3,4-dihydroxyphenyl~proplonlc acid.

2-Acetylene-2-amino-3-(3-m thoxyphenyl)propionlc acld When in the procedure of Example 5 (A) 25.8 9 (0.12 M) of 3-trlmethylsllylprop-2-ynyl-1-iminobenzyl ;s used instead of 32.4 9 (0.15 M) and 20.1 9 (0.1 M) of 1-bromo-methyl-3-methoxybenzene is used in place of 5~bromomethyl-* Trade Mark ~ 57 ~ 30 M I - 916 1,3-benzodioxole, upon recrystallization from water, 2-acetylene-2-a~ino-3-(3-methoxyphenyl)propionic acid is o~tained.
EXAMPLE 1~
2-Acetylene-2-amino-~ -hydroxy~henyl)propionic acid A suspension of 2.0 9 (9.1 mM) of 2-acetylene-2-amino-3-(3-methoxyphenyl)propionic acid in 20 ml of methanol saturated wTth anhydrous HCl is stirred for about 15 hours at 25C after which the solvent is evaporated. The resulting methyl ester derivative is suspended in 50 ml of methylene chloride and treated with 1.26 9 of benzoyl chloride followed by treatment with 3~6 9 of triethylamine.
The mixture is stirred for 24 hours then washed with water, dried and evaporated. The resulting res7due Ts recrystal-lized from methanol to give the methyl ester derivative wherein the amino group is protected with phenylcarbonyl.
A solution of 1.2 9 (~.5 mM) of the amine protected methyl ester in 50 ml of methylene chlortde at 25C is treated with 0.9 9 of boron trTbromide. The mixture is stirred for about 15 hours at 25C after whtch 10 ml of methanol is added and the solvents evaporated. The resulting residue i5 heated to reflux wlth 50 ml of 6 N
hydrochlorlc acid for 5 hours~ The solution ls concen-trated, the pH adjusted to 6 and applied to a column of *Amberlite 120 H+. Eluting with 1 M ammontum hydroxide affords 2-acetylene-2-amino-3-(7-hydroxyphenyl)propionlc ac7d after recrystallizat70n from water-ethanol.
When in the procedure of Exampla 5 an appropriate amount of benzylchloride, 4-chloro-2-methoxybenzyl-chloride, 2-chloro-6-methylbenzylchloride, 2,4-dichloro-* Trade Mark ~ S7 ~3 0 Ml-916 6-methylbenzylchloride, 4-methoxy-6-methylbenzylchloride, or 6-tert-butyl-4-chlorobenzylchloride Is substituted for 3,l~ isopropylidenedioxybenzyl bromide the following products are obtained: , 2-ace~ylene-2-amino-~-phenylpropionic acid, 2-acetylene-2-amino-~-(4-chloro-2-~ydroxyPhenyl)propionic acid, 2-acetylene-2-amino-3-(2-chloro-6-methylphenyl)prapionic acid, 2-acetylene-2-amino-3-(2,4-dichloro-6-methylphenyl)pro-pionic acid, 2-acetylene-2-amino-~-(4-hydroxy-6-methylphenyl)propionic acid, and 2-acetylene-2-amino-~-(6-tert-butyl-4-chlorophenyl)pro-pionic acid.

2-Amino-~ -hydroxyphenyl)-2-vinylpropionic acid A solution of 2.1 9 ~10 mM) of 2-acetylene-2-amino-~-(3^methoxyphenyl)propionic acid in 10 ml of hydrobromio acld Is heated to reflux for 4 hours then evaporated to dryness. The residue is dissolved in the minimum amount of water and the pH adjusted to 4.5 by careful addiélon of hydrazlne hydrate. On cooling to room temperature a precipltate formed which was collected and recrystallized from water. The precipitate is added to 100 ml of llquid ammonia at reflux and sodium is added until the blue color persists for 15 minutes after which 2 9 of ammonlum chlor-ide is added and the ammonia allowed to evaporate. The resulting residue is dissolved Tn water, the pH ad~usted to 6 and applied to a column of Amberlite 120 H+. Elution ~ * Trade Mark :

O ~ ~ 5~ ~ 30 ~I-916 wlth 1 M ammonium hydroxide gives 2-amino-3-(~-hydroxy-phenyl)-2-vinylpropionlc acid which is recrystallized from water-acetone.
EXAMPLE ~5 2-AmTno-3-(~,4-dThydroxyphenyl)-2-vinylpropionic acid When in the procedure of Example 11 an appropriate amount of 3,4-dimethoxybenzylbromTde is substituted for 3,4-isopropylldenedioxybenzylbromide 2-acetylene-2-amTno-3-(3,4-dimethoxyphenyl)propionTc acTd is obtainedJ
M.P. 225C.
600 ml of ammonia is condensed into a flask contaln-ing 10.24 9 of 2-amino-3-(~,4-dThydroxyphenyl~-2-vinyl-propionic acid and 10 9 of ammoniur sulfate. Maintaining the temperature of the reaction mixture at -78C, small pieces of sodium are added to the mTxture until the blue color persists for 30 minutes after which ammonTum chloride ls added untll the blue color Ts disslpated and the ammonla Ts ailowed to evaporater Water Ts carefully added to the mixture, and the solution evaporated to dryness.
The residue is taken up in water and applied to an Amberlite resin. Elution with 2 M ammonium hydroxida af~ords 2-amino-~ ,4-dTmethoxyphenyl)-2-vlnylproplonlc acld whlch is recrystalllzed ~rom ethanol/water, M.P. 250C.
7.9 9 of 2-amlno-3-(3,4-dlmethoxyphenyl)-2-vtnyl-proplonlc acid ls heated under reflux for 2-1/2 hours with 47% HBr under a nltrogen atmosphere after whTch the solvent Ts evaporated. The residue is taken up In water and the pH
adjusted to ~.5 by-the careful add;tTon of hydrazine hy-drate. On cooling to 0C a precipitate forms which is . .
.'' ~ * Trade Mark .

1~ 5'~V30 - ~
M!~916 :', collected and recrystallized (charco~l) from watèr to glve 2-amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionic;acid, M.P. 260C.
,. : . .

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, ~ , : . ;.

Claims (10)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for preparing a compound of the formula wherein R1 is hydrogen, alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, or alkoxycarbonyl wherein the alkoxy moiety has from 1 to 4 carbon atoms and is straight or branched; R2 is hydroxy or a straight or branched alkoxy group of from 1 to 8 carbon atoms; each of R3, R4, R5, R'4 and R6 has the meaning defined in Table I wherein R10 is hydrogen, a straight or branched alkyl group of from 1 to 8 carbon atoms, or alkylcarbonyl wherein the alkyl moiety is straight or branched and has from 1 to 6 carbon atoms, TABLE I

or a pharmaceutically acceptable salt or an individual opti-cal isomer thereof; which comprises either (a) when R2 is hydroxy or a straight or branched al-koxy group of from 1 to 8 carbon atoms and R1 is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, reducing an acety-lene derivative of the formula wherein each of R3, R4, R5, R'4 and R6 has the meaning de-fined in claim 1, R11 is a straight or branched alkyl group of from 1 to 8 carbon atoms; and R12 is hydrogen or alkyl-carbonyl wherein the alkyl moiety is a straight or branched lower alkyl group of from 1 to 4 carbon atoms, by catalytic hydrogenation in an appropriate solvent, optionally in the presence of an organic amine using an appropriate inorganic catalyst at about 0° to 25°C. until there is a reduction in the uptake of hydrogen or by chemical semi-hydrogenation by reacting equimolar amounts of the acetylene derivative and catecholborane under a nitrogen atmosphere at about 60°C.
for about 2 hours, followed by hydrolysis with aqueous acid when R2 is hydroxy and R1 is hydrogen; or (b) when R1 is hydrogen, R2 is hydroxy and the sub-stituents on the aromatic ring are other than chlorine or bromine treating the corresponding .alpha.-acetylene derivative with sodium, potassium or lithium in liquid ammonia and ammonium sulfate at about -70°C. to 25°C. until the blue color persists for about 15 minutes; or (c) when R1 is alkoxycarbonyl wherein the alkoxy moiety has 1 to 4 carbon atoms and is straight or branched, treating the corresponding derivative wherein R1 is hydro-gen and R2 is hydroxy with a halo alkylformate of the for-mula wherein halo is a halogen atom and R16 is a straight or branched alkyl group having from 1 to 4 car-bon atoms in water in the presence of a base at a tempera-ture of from about 0°C. to 25°C. for from about 1/2 hour to 6 hours; or (d) when a pharmaceutically acceptable salt is desired, reacting the thus obtained compound with a pharmaceutically acceptable acid or base.

2. A compound of the formula wherein R1, R2, R3, R4, R5, R'4 and R6 have the meanings de-fined in claim 1 when prepared by the process of claim 1.

3. The process of claim 1 wherein R2 is hydroxy or a straight or branched alkoxy group of from 1 to 8 carbon atoms which comprises either (a) when R1 is hydrogen or alkyl carbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, reducing an acetylene derivative of the for-mula wherein each of R3, R4, R5, R'4 and R6 has the meaning de-fined in claim 1, R11 is a straight or branched alkyl group of from 1 to 8 carbon atoms; and R12 is hydrogen or alkyl-carbonyl wherein the alkyl moiety is a straight or branched lower alkyl group of from 1 to 4 carbon atoms, by catalytic hydrogenation in an appropriate solvent, optionally in the presence of an organic amine using an appropriate inorganic catalyst at about 0° to 25°C. until there is a reduction in the uptake of hydrogen or by chemical semi-hydrogenation by reacting equimolar amounts of the acetylene derivative and catecholborane under a nitrogen atmosphere at about 60°C.
for about 2 hours, followed by hydrolysis with aqueous acid when R2 is hydroxy and R1 is hydrogen; or (b) when R1 is hydrogen, R2 is hydroxy and the sub-stituents on the aromatic ring are other than chlorine or bromine treating the corresponding .alpha.-acetylene derivative with sodium, potassium or lithium in liquid ammonia and am-monium sulfate at about -70°C. to 25°C. until the blue color persists for about 15 minutes; or (c) when R1 is alkoxycarbonyl wherein the alkoxy moiety has 1 to 4 carbon atoms and is straight or branched, treating the corresponding derivative wherein R1 is hydro-gen and R2 is hydroxy with a halo alkylformate of the for-mula wherein halo is a halogen atom and R16 is a straight or branched alkyl group having from 1 to 4 car-bon atoms in water in the presence of a base at a tempera-ture of from about 0°C. to 25°C. for from about 1/2 hour to 6 hours; or (d) when a pharmaceutically acceptable salt is desired, reacting the thus obtained compound with a pharmaceutically acceptable acid or base.

4. A compound of the formula wherein R1, R3, R4, R5, R'4 and R6 have the meanings defined in claim 1 and R2 is hydroxy or a straight or branched alkoxy group of from 1 to 8 carbon atoms or a pharmaceutically acceptable salt thereof when prepared by the process of claim 3.

5. The process of claim 1 wherein R1 is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 car-bon atoms and is straight or branched which comprises either (a) when R2 is hydroxy or a straight or branched alkoxy group of from 1 to 8 carbon atoms, (a) reducing an acetylene derivative of the formula wherein each of R3, R4, R5, R'4 and R6 has the meaning de-fined in claim 1, R11 is a straight or branched alkyl group of from 1 to 8 carbon atoms; and R12 is hydrogen or alkyl-carbonyl wherein the alkyl moiety is a straight or branched lower alkyl group of from 1 to 4 carbon atoms, by catalytic hydrogenation in an appropriate solvent, optionally in the presence of an organic amine using an appropriate inorganic catalyst at about 0° to 25°C. until there is a reduction in the uptake of hydrogen or by chemical semi-hydrogenation by reacting equimolar amounts of the acetylene derivative and catecholborane under a nitrogen atmosphere at about 60°C.
for about 2 hours, followed by hydrolysis with aqueous acid when R2 is hydroxy and R1 is hydrogen, or (b) when R1 is hydrogen, R2 is hydroxy and the sub-stituents on the aromatic ring are other than chlorine or bromine treating the corresponding .alpha.-acetylene derivative with sodium, potassium or lithium in liquid ammonia and am-monium sulfate at about -70°C. to 25°C. until the blue color persists for about 15 minutes; or (c) when a pharmaceutically acceptable salt is desired, reacting the thus obtained compound with a pharmaceutically acceptable acid or base.

6. A compound of the formula wherein R1 is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched and R2, R3, R4, R5, R'4 and R6 have the meanings defined in claim 1 or a pharmaceutically acceptable salt thereof when prepared by the process of claim 5.

7. The process of claim 1 wherein R1 is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 car-bon atoms and is straight or branched and R2 is hydroxy or a straight or branched alkoxy group of from 1 to 8 carbon atoms which comprises either (a) reducing an acetylene derivative of the formula wherein each of R3, R4, R5, R'4 and R6 has the meaning de-fined in claim 1, R11 is a straight or branched alkyl group of from 1 to 8 carbon atoms; and R12 is hydrogen or alkyl-carbonyl wherein the alkyl moiety is a straight or branched lower alkyl group of from 1 to 4 carbon atoms, by catalytic hydrogenation in an appropriate solvent, optionally in the presence of an organic amine using an appropriate inorganic catalyst at about 0° to 25°C. until there is a reduction in the uptake of hydrogen or by chemical semi-hydrogenation by reacting equimolar amounts of the acetylene derivative and catecholborane under a nitrogen atmosphere at about 60°C.
for about 2 hours, followed by hydrolysis with aqueous acid when R2 is hydroxy and R1 is hydrogen; or (b) when R1 is hydrogen, R2 is hydroxy and the sub-stituents on the aromatic ring are other than chlorine or bromine treating the corresponding .alpha.-acetylene derivative with sodium, potassium or lithium in liquid ammonia and am-monium sulfate at about -70°C. to 25°C. until the blue color persists for about 15 minutes; or (c) when a pharmaceutically acceptable salt is desired, reacting the thus obtained compound with a pharmaceuticallv acceptable acid or base.

8. A compound of the formula wherein R1 is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched and R2 is hydroxy or a straight or branched alkoxy group of from 1 to 8 carbon atoms, and R3, R4, R5, R'4 and R6 have the meanings defined in claim 7 or a pharmaceutical-ly acceptable salt thereof when prepared by the process of claim 7.

9. A process for preparing 2-amino-3-(3,4-dihydroxy-phenyl)-2-vinylpropionic acid or a pharmaceutically accept-able salt thereof which comprises reducing an acetylene de-rivative of the formula wherein R4 and R5 are hydroxy, R3, R'4, R6 and R12 are hy-drogen and R11 is a straight or branched alkyl group of from 1 to 8 carbon atoms by catalytic hydrogenation in an appro-priate solvent, optionally in the presence of an organic amine using an appropriate inorganic catalyst at about 0°
to 25°C. until there is a reduction in the uptake of hydrogen or by chemical semi-hydrogenation by reacting equimolar amounts of the acetylene derivative and catecholborane under a nitrogen atmosphere at about 60°C. for about 2 hours, followed by hydrolysis with aqueous acid when R11 is hydroxy and R12 is hydrogen; or when a pharmaceutically acceptable salt is desired reacting the thus obtained compound with a pharmaceutically acceptable acid or base.

10. The compound 2-amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionic acid or a pharmaceutically acceptable salt thereof when prepared by the process of claim 9.