JPS6338345B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel pharmaceutically useful α-vinyl amino acid derivatives that are inhibitors of aromatic amino acid decarboxylase. The amino acids tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine (DOPA), tyrosine, and phenylalanine are metabolically converted to tryptamine, 5-hydroxytryptamine, and 3,4-dihydroxytryptamine, respectively, by aromatic amino acid decarboxylase. Converted to dihydroxyphenethylamine, ie dopamine, tyramine and phenethylamine. Aromatic amino acid decarboxylases are believed to be non-specific, especially as far as peripheral catalysis is concerned. However, there is evidence that specific decarboxylating enzymes exist for each of DOPA and 5-hydroxytryptophan in the brain. It is known that the above-mentioned aromatic amines are involved in various pathophysiological methods. For example, in Iruma's red blood cells, plasma, and platelets, the decarboxylation product of tryptophan, tryptamine, is enzymatically methylated to monomethyltryptamine, which is then enzymatically methylated to dimethyltryptamine (DMT).
Methylating enzymes are present in many mammalian species, and it has been shown to be produced in the brain tissue of some species, including humans. DMT, which has strong hallucinogenic or psychomimetic properties, may play a role in the pathogenesis of schizophrenia and other psychoses. Therefore, reagents that would interfere with the production of DMT could be used as antipsychotics. Preventing tryptophan decarboxylation reduces tryptamine levels and removes the substrate for DMT production. Therefore, inhibitors of aromatic amino acid decarboxylase that would prevent the conversion of tryptophan to tryptamine can be used as antipsychotics. Both 5-hydroxytryptamine (5-HT), the decarboxylation product of 5-hydroxytryptophan, and 3,4-dihydroxyphenethylamine (dopamine), the decarboxylation product of DOPA, are Reagents that are relevant to physiological methods and effective in regulating the levels of these amines would provide useful pharmacological reagents. Central or brain levels of norepinephrine, which is produced metabolically by hydroxylation of 5-HT and dopamine, have been shown to be higher in patients with manic symptoms than in those without such symptoms. Monoamines, e.g. 5-HT
Agents that reduce central levels of norepinephrine and norepinephrine in particular have antimanic properties when given to human subjects, whereas drugs that increase monoamine levels have also been shown to induce mania in sensitive individuals.
Therefore, agents that block the production of 5-HT and dopamine, for example by inhibiting the aromatic amino acid decarboxylase enzyme that converts 5-hydroxytryptophan and DOPA to 5HT and dopamine, respectively, may be used as antipsychotics in the treatment of manic symptoms. It can be used as a tranquilizer for severe cases. Reagents useful in inhibiting the decarboxylation of DOPA to dopamine include exogenous POPA or L
- Useful in the treatment of Parkinson's syndrome when administered simultaneously with DOPA. Because exogenous administration of DOPA or L-DOPA is known to be an effective means of treating parkinsonism, it is likely that parkinsonism is due, at least in part, to reduced central levels of dopamine. It is believed. However, since exogenously administered DOPA is easily converted peripherally to dopamine by enzymes, large doses must be administered to increase central absorption. DOPA readily penetrates the blood-cerebrospinal fluid barrier, while dopamine does not. Administering DOPA or L-DOPA with a peripherally active inhibitor of the enzyme that converts DOPA to dopamine reduces the amount of L-DOPA that must be administered to obtain circulating levels suitable for central absorption. reduce Other benefits are also realized by administering aromatic amino acid decarboxylase inhibitors with L-DOPA. By peripherally preventing dopamine production, dopamine-induced side effects such as cardiac arrhythmia, nausea and vomiting are avoided. Studies have shown that levels of 5-hydroxytryptamine (5-HT) are lower in patients with depressive syndromes than in people without such syndromes. The administration of exogenous L-5-hydroxytryptophan (L-5-HTP) is also effective in treating certain depressed patients. however
As when using DOPA, L-5-HTP is easily metabolized to 5-HT in the periphery.
Large amounts of L-5-HTP need to be administered to obtain increased central levels of amino acids. 5-HTP
By administering an inhibitor of aromatic amino acid decarboxylase, which catalyzes the peripheral production of 5-HT from do. In other words, aromatic amino acid decarboxylase has been shown to have utility in the treatment of depression when used in conjunction with exogenous 5-HTP. Agents that prevent the peripheral conversion of 5-HTP to 5-HT can also be used in the treatment of other conditions that respond to increased central levels of 5-HTP as a result of exogenous administration of 5-HTP. Exogenous L-5-HTP
has also been shown to be used in the treatment of active clonic muscle spasms. The administration of exogenous 5-HTP is also being investigated for use in the treatment of insomnia. Therefore, co-administration of 5-HTP and aromatic amino acid decarboxylase inhibitors is advantageous in the treatment of these conditions. Preventing the peripheral production of 5-hydroxytryptamine has other beneficial effects, since by increasing collagen levels 5-HT has been implicated in the pathogenesis of e.g. rheumatoid arthritis, carcinoid syndrome. This is because it is known. It has also been reported that 5-HT is the main autacoid that responds to anaphylaxis-like reactions in human subjects and bronchial constriction in human subjects with asthma, and reagents that antagonize or inhibit the production of 5-HT have been reported. are used in the treatment of these conditions. 5-HT is known to cause platelet aggregation and has been thought to be a causative factor in postgastrectomy rapid migration syndrome and migraine. Methylsergide, a 5-hydroxytryptamine antagonist, has proven effective in the treatment of postgastrectomy rapid migration syndrome. As an exogenous compound, phenethylamine, a carboxyl breakdown product of phenylalanine, has been shown to contribute to schizophrenic symptoms and cause migraine headaches. It has also been shown that exogenous tyrosine carboxyl breakdown product tyramine contributes to epileptic seizures. It is therefore easy to see that reagents used in regulating the levels of aromatic amino acids and amines will find use in many pharmacological situations. The compounds of the present invention are inhibitors of aromatic amino acid decarboxylase, which converts tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine, tyrosine and phenylalanine to their respective amines, and are therefore useful. provide pharmacological agents. The present invention is based on the general formula Represented by Pharmaceutically acceptable salts and individual optical isomers of compounds of general formula 1 are _also included within the scope of this invention. Compounds of general formula 1 are useful pharmacological agents in that they are inhibitors of aromatic amino acid decarboxylase and are useful pharmacological agents. Examples of pharmaceutically acceptable salts of the compounds of this invention are with inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric acids, and with methanesulfonic, salicylic, maleic, malonic, tartaric, and citric acids. ,
and non-toxic acid addition salts formed with organic acids such as ascorbic acid and alkali metals such as sodium, potassium and lithium, alkaline earth metals such as calcium and magnesium, Group A light metals such as aluminum, cyclohexylamine, ethylamine. , pyridine, methylaminoethanol,
Included are non-toxic salts formed with inorganic or organic bases, such as with organic amines such as primary, secondary, and tertiary amines such as ethanolamine and piperazine. These salts are prepared by conventional methods. Examples of compounds of the general formula are as follows. 2-Amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionic acid, compounds of the general formula are tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine, tyrosine and phenylalanine It is an irreversible inhibitor of the enzyme that metabolically catalyzes the conversion of tryptamine, 5-hydroxytryptamine, 3,4-dihydroxyphenylethylamine, tyramine, and phenethylamine, respectively. As indicated above, the results of the study indicate that the enzyme responsible for converting the above-mentioned amino acids to their respective amines in the periphery is a non-specific aromatic amino acid decarboxylase.
In the central conversion, specific decarboxylases convert 5-hydroxytryptophan and 3,4-
Studies have shown that the remaining above-mentioned amino acids are enzymatically converted by non-specific aromatic amino acid decarboxylase to their respective amines, whereas dihydroxyphenylalanine is responsible for the conversion of each. It is shown. The compounds of the present invention can be used both centrally and peripherally.
It is effective in irreversibly inhibiting non-specific aromatic amino acid decarboxylase activity and 3,4-dihydroxyphenylalanine (DOPA) decarboxylase activity. The term "central" as used in connection with the use of the compounds of the invention refers to the central nervous system, primarily the brain, whereas the term "peripheral" refers to other body tissues where decarboxylases are present. . The selectivity of centrally or peripherally inhibiting amino acid decarboxylase by administering a compound of the general formula will depend on the dose. The compounds of the invention have many pharmacological uses as irreversible inhibitors of aromatic amino acid decarboxylase and DOPA decarboxylase.
Compounds of the general formula are useful as peripheral irreversible inhibitors of aromatic amino acid decarboxylase.
- Useful in the treatment of Parkinson's syndrome when administered with dihydroxyphenylalanine (DOPA) or L-3,4-dihydroxyphenylalanine (L-DOPA).
DOPA and more particularly its active isomer L
-DOPA is administered systemically, usually at 0.5 per day at first.
It is known to be effective in the treatment of Parkinson's syndrome when administered in amounts of ˜1 g, with the dose gradually increased over 3 to 7 days to a maximum tolerated dose of about 8 g per day. When a compound of the general formula and L-DOPA are administered simultaneously, the compound of the formula suppresses the activity of aromatic amino acid decarboxylase, resulting in the central absorption of L-DOPA.
L-
An improved method of treating Parkinson's syndrome is provided in that it prevents the decarboxylation of DOPA to L-3,4-dihydroxyphenethylamine (L-dopamine). By simultaneously administering a compound of general formula and L-DOPA, L-
The dosage of DOPA can be reduced by a factor of 2 to 10 compared to that required when only L-DOPA is administered. Preferably, the compounds of the invention are administered before administration of L-DOPA. For example, depending on the route of administration and the condition of the patient being treated, a compound of formula
It can be administered 30 minutes to 4 hours before administration of L-DOPA. Compounds of general formula 1 are known to have utility in the treatment of depression when administered systemically.
-Hydroxytryptophan (5-HTP), or more particularly when given with its active levoisomer, is also useful in the treatment of depressive syndromes in individuals. The compound of general formula 1 inhibits 5-hydroxytryptophan by peripherally inhibiting the activity of aromatic amino acid decarboxylase.
Prevents conversion to hydroxytryptamine, thus retaining higher circulating levels of 5-HTP for central absorption. Compounds of general formula 1 contain exogenous 5-
When administered concurrently with HTP, it is also useful in the treatment of behavioral clonic muscle spasms, which are known to be effectively treated by increasing central levels of 5-HTP. Compounds of general formula 1, due to their peripheral inhibitory effect on aromatic amino acid decarboxylase, are associated with rheumatoid arthritis, carcinoid syndromes, anaphylaxis-like reactions in humans, bronchial stenosis in asthmatic humans as well as high peripheral levels of 5-hydroxytiptamine. It is also useful in the treatment of other conditions known to be caused by. As mentioned above, reagents that reduce elevated levels of 5-HT and norpinephrine, a hydroxylation product of dopamine, have been shown to be useful in treating patients with manic symptoms. Therefore, as central irreversible inhibitors of aromatic amino acid decarboxylase and DOPA decarboxylase, compounds of the general formula are useful in the treatment of manic symptoms. Moreover, because of the central depressant action of compounds of general formula 1 on aromatic amino acid decarboxylase, the compounds can also be used as antipsychotic agents since the central levels of tryptamine are reduced, and the administration of compounds of general formula 1 It is useful in the treatment of schizophrenia and epileptic seizure symptoms because central levels of phenethylamine and tyramine are reduced. The use of compounds of general formula 1 as irreversible inhibitors of aromatic amino acid decarboxylase has been demonstrated as follows. The compound of general formula 1 is administered to mice or mice in the form of an aqueous solution or suspension. Animals were killed by decapitation at different time intervals 1 to 48 hours after administration of the compound and as described in Christenson et al., Arch.Biochem.Biophys.141.356 (1970). Radiometric analysis as described in Burkard et al., Archives of Biochemistry and Biophysics 107.187
Aromatic amino acid decarboxylase activity was measured in kidney, heart and brain homogenates prepared according to (1964). The compounds of the present invention can be administered in a variety of ways to achieve the desired effect. The compounds, alone or in pharmaceutical dosage form, can be administered to the patient to be treated 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 the nose, throat and bronchi, for example in the form of an aerosol spray containing small particles of the novel compounds of the invention in a spray solution or in the form of a dry powder. Can be administered. The dosage of the novel compounds can vary and can be any effective amount. Depending on the patient, the condition being treated, and the mode of administration, the dosage of the novel compounds can vary over a wide range to provide an effective amount in unit dosage form. When administering a compound of general formula 1 to affect peripheral irreversible inhibition of aromatic amino acid decarboxylase, the effective dosage of the compound is about 0.1 to 100 mg per kg of patient body weight per dose, and Suitably it can vary from about 5 to 25 mg per kg of patient's body weight. The desired peripheral effect is obtained by ingestion of a unit dosage form, such as a tablet containing 10 to 250 mg of the novel compound of the invention, administered 1 to 4 times per day. When a compound of general formula 1 is administered to obtain central irreversible inhibition of aromatic amino acid decarboxylase or 3,4-dihydroxyphenylalanine decarboxylase, the effective dosage of the compound is about 100-500 mg/( Kg of patient's body weight) and preferably varies between about 150 and 300 mg/Kg. For example, about
Ingestion of a unit dosage form such as a tablet containing 350 mg to 500 mg of the novel compound of the invention provides the desired central effect. As used herein, the term "patient" refers to warm-blooded animals such as mammals such as cats, dogs, rats, rats, guinea pigs, sheep, horses, cows, and humans. Solid unit dosage forms can be of conventional type. Thus, the solid form may be a capsule, which is of the common gelatin type, containing a compound of the invention and a carrier, such as a lubricant and an inert filler, such as lactose, sucrose and cornstarch. Can be done. In another embodiment, the novel compounds are combined with common tablet substrates such as lactose, sucrose or cornstarch and binders such as acacia, cornstarch or gelatin, disintegrants such as cornstarch, potato starch or alkynic acids and lubricants such as stearic acid. Alternatively, it can be tabletted in combination with magnesium stearate. For parenteral administration, the compounds may be administered in sterile liquids, such as oils and water, with or without the addition of surfactants and other pharmaceutically acceptable agents. The dose is administered as an injectable solution or suspension of the compound in a physiologically acceptable diluent with a suitable pharmaceutical carrier. Typical examples of oils that can be used in these preparations are oils of petroleum, animal, vegetable or synthetic origin, such as bed bean oil, soybean oil, and mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, ethanol and glycols such as propylene glycol or polyethylene glycol are suitable liquid carriers, particularly for injectable solutions. The compounds can be administered in the form of depot injections or implantable preparations that can be formulated in such a way as to allow sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or into the muscle as a depot injection or implant. The implant can be an inert material, such as a biodegradable polymer or a synthetic silicone, such as "Silastick", a silicone rubber manufactured by Dow Corning Corporation. For use as an aerosol, the novel compound in solution or suspension is brought under pressure together with a gaseous or liquefied propellant, such as dichlorodifluoromethane, dichlorodifluoromethane and dichlorodifluoroethane, carbon dioxide, nitrogen or propane. It can be packaged in a sprayed aerosol container, where conventional agents such as co-solvents and wetting agents are used if necessary or desired. The compounds can also be administered in a pressureless form, eg, in an atomizer or nebulizer. As mentioned above, the compound of general formula 1 may contain exogenous L-
It finds particular use when administered together with DOPA, in which case compounds of general formula 1 and L-
Separate preparations of DOPA can be administered or both active ingredients can be formulated into a single combined pharmaceutical composition. In either mode of administration,
The amount of compound of general formula 1 to the dosage of L-DOPA can vary between about 1:1 and 1:10. The combination preparation comprises an inner part containing L-DOPA and an outer part containing the compound of general formula 1, each active ingredient being formulated appropriately. A particularly suitable combination preparation consists of compressing L-DOPA, optionally with a suitable carrier, into a core, applying a laminate coating to the core that is resistant to gastric juices, and applying a suitable combination to the coated core. by applying an outer layer containing a compound of general formula 1 formulated as follows. Using such a combination formulation, the decarboxylase inhibitor, i.e. the compound of general formula 1, is
It is preferably released 30 to 60 minutes earlier than DOPA.
Laminate coatings can be formed by the use of non-aqueous solutions of glycerides or water-insoluble polymers such as ethyl cellulose or cellulose acetate phthalate. Formulations can also be used in which L-DOPA is enteric coated with a mixture of Sieraac and Sieraac derivatives and cellulose acetate phthalate. Representative examples of suitable pharmaceutical formulations are provided in the specific examples below. In addition to being useful pharmacological reagents, compounds of the general formula are also useful as intermediates for the production of useful cephalosporin antibiotics. Compounds with the general formula where R ₂ is hydroxy are the following general formula: can be used in the production of cephalosporin derivatives. In the above general formula, R ₁ , R ₃ , R′ ₄ , R ₆
is hydrogen, and R ₄ and R ₅ are OH or lower alkoxy. M is hydrogen or a negative charge and X is hydrogen or acetoxy. The compounds of the general formula and their pharmaceutically acceptable salts and their individual optical isomers are novel compounds useful as antibiotics and the administration of many known cephalosporin derivatives, such as cephalexin, cephalosine or cephaloglycine. It can be administered in a similar manner to the Compounds of the general formula and pharmaceutically acceptable salts and isomers thereof, alone or in the form of pharmaceutical preparations, can be used orally or parenterally and topically in warm-blooded animals, i.e. birds and mammals. It can be administered to animals such as cats, dogs, 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 are best employed in the form of a sterile aqueous solution which may also contain sufficient other solutes, such as saline or glucose, to render the solution isotonic. For topical administration, compounds of the general formula,
Salts and their isomers can also be included in creams or ointments. Representative examples of bacteria against which the compounds of the general formula and their pharmaceutically acceptable salts and individual optical isomers are active are Staphylococcus aureus, S. paratyphi B, Klebsiella pneumoniae, Diplococcus pneumoniae and S. pyogenes. It is coccus. Representative pharmaceutically acceptable non-toxic inorganic acid addition salts of compounds of the general formula include mineral acid addition salts such as hydrogen chloride, hydrogen bromide, sulfates, sulfamates,
phosphates, and organic acid addition salts such as malate, acetate, citrate, oxalate, succinate, benzoate, tartrate, fumarate,
maleate and ascorbate. Salts can be produced by conventional methods. A typical example of a cephalosporin derivative represented by the general formula is 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, 7-[[2-amino-3-(3-
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-dihydroxyphenyl)-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 acid. Compounds of the general formula where R ₁ is hydrogen are of the formula [wherein X and M have the meanings defined in the general formula] 7-aminocephalosporanic acid or a derivative thereof having the formula [wherein R ₁ and R ₂ have the meanings defined in the general formula and the amino group is protected with a suitable capping group such as tert-butoxycarbonyl] or a functional derivative thereof, e.g. It is produced by coupling an acid chloride or acid anhydride with a free acid, when used, in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, followed by acid hydrolysis to remove the amino protecting group. 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 an alkali bicarbonate. Reaction temperature is approximately -10℃
Can be varied between ~100℃, and the reaction time is about 1/2
It can vary between hours and 10 hours. Cephalosporin products are isolated by standard methods. Compounds of the general formula are made by the methods described above, and compounds of the formula are commercially available or can be made by methods well known in the art. Compounds of the general formula in which R ₁ is other than hydrogen are prepared from the corresponding derivatives in which R ₁ is hydrogen by the general methods described above for compounds of the general formula in which R ₁ is other than hydrogen. . R ₂ is hydroxy or a straight chain or branched alkoxy group having 1 to 8 carbon atoms, and R ₁
is hydrogen or a linear or branched alkylcarbonyl having 1 to 4 carbon atoms in the alkyl moiety, the compound has the structure [In the formula, R ₃ to _{R 6} and R′ ₄ have the meanings defined in the general formula, and R ₁₁ is a straight chain or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl , n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, neopentyl and n-hexyl, and R ₁₂ is hydrogen or a straight chain or branched chain having 1 to 4 carbon atoms in the alkyl moiety. alkylcarbonyl groups such as methyl, ethyl, n-propyl, isopropyl, n
-butyl and tert-butylcarbonyl] by contacting or chemical hemihydrogenation of the corresponding acetylene derivatives. Catalytic hydrogenation of compounds of the general formula is carried out in a solvent, for example a lower alcohol such as methanol, ethanol or isopropyl alcohol, a hydrocarbon solvent such as benzene or toluene, or chloroform, optionally an organic amine which can also act as a solvent. For example, in the presence of pyridine or triethylamine,
Inorganic catalysts, such as palladium on barium sulfate or Lindlar's catalyst, i.e. calcium carbonate, as described in Synthesis, No. 8, August 1973, pages 457-468 by M. Marvell and T.Ri. Performed using lead-poisoned palladium. The hydrogenation process is carried out at a temperature of approximately 0° to 25°C;
and continued until hydrogen absorption decreases, after which
When R ₂ is hydroxy and R ₁ is hydrogen, it is hydrolyzed with aqueous acids such as hydrogen bromide or hydrochloric acid. Chemical hemihydrogenation of acetylene compounds of the general formula is carried out using H.C. Brown (HC
Brown) and SKGupta.
Journal of the American Chemical Society (J.Am.Chem.Soc.) 94 , 4370–71
(1972) H.C. Brown et al. Journal of the American Chemical Society
95, 5786-8 and 6456-7 (1973), followed by hydrolysis using an aqueous acid, e.g. acetic acid, when R ₂ is hydroxy and R ₁ is hydrogen. This is done by Alternatively, compounds of the general formula in which R ₁ is hydrogen, R ₂ is hydroxy, and the substituents on the aromatic ring are other than chlorine or bromine, may have the corresponding α
- When an acetylene derivative is prepared with sodium, potassium or lithium in liquid ammonia and ammonium sulfate at a temperature of about -70° to 25°C, a blue color of about 15
It can be manufactured by processing until connection for minutes. When the aromatic substituent in the above reaction is methoxy and the corresponding hydroxy derivative is desired, the methoxy-substituted acetylene derivative can also be treated with concentrated hydrobromic acid before reduction to the vinyl derivative, or Methoxy-substituted vinyl derivatives can also be treated with concentrated hydrobromic acid. Hydrolysis with hydrobromic acid is carried out at about 120°C for about 1 to 8 hours. Compounds of the general formula in which R ₂ is a straight chain or branched alkoxy group having 1 to 8 carbon atoms are:
The corresponding derivative in which R ₂ is hydroxy is reacted with thionyl chloride to produce the acid chloride, which can be expressed as
R ₁₃ -OH [wherein R ₁₃ is a straight chain or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n- pentyl, neopentyl, hexyl, or octyl) at about 25° C. for 4 to 12 hours. Compounds of the general formula where R ₂ is -NR ₇ R ₈ , where R ₇ and R ₈ are each hydrogen or straight chain or branched lower alkyl having 1 _to 4 carbon atoms, hydroxy and R ₁ has the meaning defined in the formula, with the proviso that any free amino group is protected, for example with carbobenzyloxy or tert-butoxycarbonyl, and R ₃ , R ₄ , Acid halides of the corresponding compounds, such that any of R ₅ or R′ ₄ is OR ₁₀ and when R ₁₀ is hydrogen, the group is protected as the corresponding alkylcarbonyloxy group;
For example, it is produced by acylating an acid chloride with an excess of the appropriate amine represented by HNR ₇ R ₈ . The reaction is carried out in methylene chloride, chloroform, dimethylformamide, ethers such as tetrahydrofuran or dioxane or benzene at about 25 DEG C. for about 1 to 4 hours. Suitable amines are, for example, ammonia or compounds that are potential sources of ammonia, such as hexamethylenetetramine; primary amines, such as methylamine, ethylamine or n-propylamine; and secondary amines, such as dimethylamine, diethylamine. Or G-n-
Butylamine. After the acylation reaction, the amino protecting groups are removed by treatment with acid or hydrogen bromide in dioxane and, if appropriate, the hydroxy protecting groups are removed by basic hydrolysis. Compounds of _the general formula in _which R ₂ is The corresponding derivative, in which any amino group is protected with a suitable capping agent, such as benzyloxycarbonyl or tert-butoxycarbonyl, is dissolved in an ether, such as tetrahydrofuran or dioxane, at a temperature of from 0° to about 50°C for about 1 reacting with a compound of the formula in which R ₉ has the meaning as defined in the general formula and R ₁₄ is a lower alkyl group, such as methyl or ethyl, for ~24 hours; Thereafter, the protecting groups are removed by acid hydrolysis, provided that when an amine-protected free acid is used, the reaction is carried out using a dehydrating agent such as dicyclohexylcarbodiimide. Compounds of the general formula in which R ₁ is straight-chain or branched alkylcarbonyl having 1 to 4 carbon atoms in the alkyl moiety can be prepared by preparing the corresponding derivatives in which R ₁ is hydrogen and R ₂ is hydroxy in water. For example, in the presence of a base such as sodium hydroxide or sodium borate, at a temperature of 0° to 25°C for 1/2 hour to 6 hours, a compound of the formula [Formula] [where halo is a halogen atom, such as chlorine or bromine] and R ₁₅ is a straight chain or branched alkyl group having 1 to 4 carbon atoms]. A compound of the general formula in which R ₁ is a linear or branched alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety, R ₁ is hydrogen and R ₂
is hydroxy in water in the presence of a base such as sodium hydroxide or sodium borate for a period of about 1/2 hour to 6 hours at a temperature of about 0° C. obtained by treatment with an alkyl haloformate in which halo is a halogen atom, such as chlorine or bromine, and R ₁₆ is a straight-chain or branched alkyl group having 1 to 4 carbon atoms. It will be done. Compounds of the general formula where R ₁ is [Formula] and R ₁₇ is hydrogen, a linear or branched lower alkyl group having 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl are R ₁ is hydrogen and R ₂ has 1 to 8 carbon atoms
The corresponding derivative, which is a straight-chain or branched alkoxy group of ~1 ~ at a temperature of ~35°C
Over a period of 12 hours, the amino group is protected with a suitable blocking group such as benzyloxycarbonyl or tert-butoxycarbonyl and R ₁₇ has the meaning defined above. It is produced by treating with an acid or anhydride thereof, followed by acid or base hydrolysis to remove the protecting group. The individual optical isomers of compounds of the general formula in which R ₁ is H and R ₂ is OH are (+) or (-)
It can be resolved by the method of R. Veterbo et al., Tetrahedron Letters 48 , 4617 (1971) using binaphthyl phosphate. Other decomposing agents such as (+) camphor-10-sulfonic acid can also be used. R ₁ and R ₂ are H
The individual optical isomers of the compounds, other than OH and OH, are obtained as described above for the racemates simply by starting with the resolved amino acids. Either R ₃ and R ₄ are both OR ₁₀ and R ₁₀ is hydrogen, or both R ₄ and R ₅ are OR ₁₀ and R ₁₀ is hydrogen, or both R ₄ and R ₅ are -O- _CH2-
O- or in which each of R ₃ , R ₄ , R ₅ , R′ ₄ and R ₆ has the meaning as defined in the general formula but R ₁₀ is methyl, as appropriate. Treatment of the protected propargylamine derivative with a strong base produces a protected propargylamine carbanion intermediate, in which both R ₃ and R ₄ are
2 when OR ₁₀ and R ₁₀ is hydrogen;
using 3-isopropylidene dioxybenzyl halide, and when both R ₄ and R ₅ are OR ₁₀ and R ₁₀ is hydrogen, using 3,4-isopropylidene dioxybenzyl halide and R ₄ and R ₅ together -O-CH ₂ -O-
When 3,4-methylenedioxybenzyl halide is used where the halide is, for example, chloride or bromide, and when R ₃ to R ₆ and R′ ₄ are other than the above, the formula [wherein Y is a halogen atom, such as chlorine or bromine, and each of R ₁₈ , R ₁₉ , R ₂₀ , R′ ₁₉ and R ₂₁ has the meaning defined in the table below, ₂₂ is methyl] respectively. [Table] [Table] The alkylated propargylamine derivative thus produced was treated with a strong base to produce an alkylated propargylamine carbanion as shown in the reaction sequence below. , this second carbanion intermediate is treated with an acylating agent, followed by removal of the protecting group. In the above reaction formula, R ₂₃ has 1 to 4 carbon atoms.
represents a straight-chain or branched lower alkyl group, such as methyl, ethyl, n-propyl and tert-butyl; R ₂₄ is phenyl, tert-butyl or triethylmethyl, 1-adamantanyl or 2-furyl; represents; R ₂₅ is hydrogen, methoxy or ethoxy, provided that R ₂₄ is 1
- When it is adamantanyl or 2-furyl, R ₂₅ is not hydrogen and R ₂₆ Y is the alkylating agent 2,3-isopropylidene dioxybenzyl halide, 3,4-isopropylidene dioxybenzyl halide, 3,4 - methylenedioxybenzyl halide or a compound of the formula; Ph represents phenyl; R ₂₇ is a carboxy anion, a carboxylic acid ester, a carboxamide, a nitrile or other hydrolysable to different carboxylic acid functional groups depending on the acylating reagent used; is the basis of; and
R ₃ a, R ₄ a, R ₅ a, R′ ₄ a and R ₆ a are the same as R ₃ , R ₄ , R ₅ , R′ ₄ and R ₆ in the table except when R ₁₀ is methyl. Each has a defined meaning, or
or both R ₃ a and R ₄ a represent OR ₁₀ , where
R ₁₀ is hydrogen, R ₄ a and R ₅ a both represent OR ₁₀ and R ₁₀ is hydrogen. The compound of formula is then converted to the esteramide derivative by treatment with thionyl chloride, which is then treated with an alcohol of formula R ₁₁ -OH, in which R ₁₁ has the meaning as defined in the formula, at 25°C. in 4
~12 hours and then using an acid halide of the formula [Formula] in which R ₁₂ has the meaning as defined in the formula and halo is a halogen atom, such as chlorine or bromine, e.g. Treat in the presence of a base such as sodium hydroxide, potassium hydroxide or excess triethylamine at about 0°C to 25°C for about 1/2 hour to 24 hours. Suitable strong bases that can be used in the above reaction sequence to produce each carbanion are those that extract protons from the carbon atom adjacent to the acetylene moiety, such as alkyllithiums such as butyllithium or phenyllithium, lithium Dialkylamides such as lithium diisopropylamide, lithium amide, tert-potassium butyrate or sodium amide. The alkylating agents used in the above reaction schemes are known in the art. For example, 2,3-isopropylidene dioxybenzyl halide is prepared by converting 2,3-dihydroxytoluene into phosphorus pentoxide by the general method of K. Ogura and G. Tsuchihashi, Tetrahedron Letters 1971 , 3151. by treatment with acetone in the presence of bromosuccinimide, followed by treatment with bromosuccinimide. Suitable acylating reagents that can be used in the above reactions include halo-formates such as chloromethylformate or chloroethylformate, azido-tert-butylformate, cyanogen bromide, carbon dioxide, diethyl carbonate, phenyl isocyanate, Ethoxymethylium tetrafluoroborate, N,N-dimethylcarbamoyl chloride, 2-methylthio-1,3-dithiolinium iodide, ethylene carbonate or ethylene trithiocarbonate. 2-methylthio-1,3-
When using dithiolinium iodide, a separate step of alcoholysis using a lower alcohol such as ethanol or isopropyl alcohol is necessary prior to hydrolytic deprotection. Alkylation reaction and acylation reaction are carried out using a neutral solvent,
For example, it can be carried out in benzene, toluene, ethers, tetrahydrofuran, dimethylsulfoxide, hexamethylphosphorotriamide. The temperature for each reaction varied between -120°C and about 25°C;
The preferred reaction temperature is about -70°C and the reaction time varies between about 1/2 hour and 24 hours. Removal of the protecting group can be carried out if the alkylating agent is 3,4-isopropylidene dioxybenzyl halide or 2,
When it is 3-isopropylidene dioxybenzyl halide, treatment with an aqueous base such as sodium or potassium hydroxide or with hydrazine or phenylhydrazine followed by acid hydrolysis using, for example, hydrochloric acid, and the alkyl When the oxidation reagent contains benzyloxy groups, base hydrolysis is followed by treatment with lithium or sodium amide in ammonia and then addition of lithium or sodium metal until the blue color persists for about 15 minutes. It will be done. Propargylamine derivatives in which R ₂₅ is hydrogen are prepared by adding protecting groups to the acetylene and nitrogen functions of propargylamine. Protection of the nitrogen functional group of propargylamine can be achieved by forming a Schiff base using a non-enolizable carbonyl-containing compound selected from benzaldehyde, 2,2-dimethylpropanal and 2,2-diethylbutanal in a known manner. This is done by The acetylene functional group can be protected by converting the above Schiff base into a linear or branched trialkylsilyl chloride with an alkyl moiety having 1 to 4 carbon atoms,
For example, this is carried out by reacting with trimethylsilyl chloride or triethylsilyl chloride to produce the corresponding trialkylsilyl derivative by a known method. Propargylamine derivatives in which R ₂₅ is methoxy or ethoxy are propargylamine derivatives in which the acetylene functional group is protected by trialkylsilyl having 1 to 4 carbon atoms in the alkyl moiety. , benzoyl chloride, pivalic acid chloride, 2,2-diethylbutyric acid chloride, 2-furancarboxylic acid chloride or - produced by reacting with adamantane carboxylic acid chloride and then warming the reaction mixture to about 25°C for 1 hour. The resulting amide derivative is treated with an alkylating reagent such as methylfluorosulfonate, dimethyl sulfate, methyl iodide, methyl p-toluenesulfonate or trimethyloxonium hexafluorophosphate when R ₂₅ is methoxy, and when R ₂₅ is ethoxy. Sometimes the triethyloxonium tetrafluoroborate is combined in a chlorinated hydrocarbon solvent such as methylene chloride, chlorobenzene or chloroform at about 25°C, and then the reaction mixture is cooled to about 25°C and, for example, An organic base such as triethylamine or pyridine is added, then the solution is extracted with brine and the product is isolated. The protected propargylamine starting material is 3
-trialkylsilylprop-2-ynyl-1-
The imino-benzyl derivative is treated with hydrazine or phenylhydrazine at about 25° C. for about 1/2 hour, the mixture is then diluted with e.g. petroleum ether benzene or toluene, and the protected propargylamine derivative is isolated. It can be obtained by Alternatively, treatment with 0.5-1NHCl gives the hydrochloride salt. Compounds of the general formula are known in the art or can be prepared from corresponding appropriately substituted benzoic acid or benzaldehyde derivatives known in the art. For example, a benzyl halide of the formula can be prepared by reducing the corresponding benzaldehyde with sodium borohydride, lithium aluminum hydride or by catalytic reduction, or by reducing the corresponding benzoic acid ester with lithium aluminum hydride or borane, Alternatively, it can be prepared by reducing the corresponding benzoic acid derivative with lithium hydride and then treating the benzyl alcohol derivative thus produced with, for example, thionyl chloride or phosphorous oxychloride. Compounds of the general formula in which either R ₃ , R ₄ , R ₅ or R′ ₄ is OR ₁₀ and R ₁₀ is hydrogen:
From the corresponding ester amide derivatives in which either R ₃ , R ₄ R ₅ or R' ₄ is OR ₁₀ and R ₁₀ is methyl, the derivatives can be prepared, for example, from boron tribromide, boron trichloride or trifluoride. It is produced by treatment with a Lewis acid such as boron. Compounds of the general formula in which any of R ₃ , R ₄ , R ₅ or R′ ₄ are OR ₁₀ and R ₁₀ is a straight chain or branched alkyl group having 1 to 8 carbon atoms,
The corresponding esteramide derivatives in which R ₁₀ is hydrogen in a lower alcoholic solvent, such as methanol or ethanol, or a hydrocarbon solvent, such as benzene or toluene, and in the presence of an organic base, such as triethylamine or pyridine, or in a neutral solvent, For example in dimethylformamide, dimethylacetamide or dimethylsulfoxide and in the presence of sodium hydride, R ₂₈ is a straight-chain or branched alkyl group having 1 to 8 carbon atoms and Y ₂ is a halogen, e.g. bromine or With an alkyl halide of formula R ₂₈ Y ₂ which is iodine about 25
It can be prepared by alkylation for about 1 to 24 hours at a temperature between 1 and 85 degrees Celsius, followed by hydrolysis with an aqueous base, provided that the hydroxy-substituted starting material α- The amino group is protected with a suitable protecting group, such as tert-butoxycarbonyl, which is then removed by treatment with an acid, such as trifluoroacetic acid. The alkyl halides used in the above reactions are known in the art or can be prepared by methods known in the art. Any of R ₃ , R ₄ , R ₅ or R′ ₄ is OR ₁₀ and R ₁₀ is a linear or branched alkylcarbonyl, benzoyl or alkylene moiety having 1 to 6 carbon atoms in the alkyl moiety; The compound of general formula 1 which is a linear or branched phenylalkylenecarbonyl having 1 to 6 carbon atoms can be prepared by converting the corresponding esteramide derivative in which R ₁₀ is hydrogen into an acid anhydride of the formula [formula] or a formula [ Acid halide of the formula [where halo is chlorine or bromine and R ₂₉ is a straight chain or branched alkyl having 1 to 6 carbon atoms, phenyl or a straight chain having 1 to 6 carbon atoms in the alkylene moiety] or branched phenylalkylene] at about 25°C to 100°C for about 1 to 24 hours in the presence of an organic base, such as pyridine, quinoline, or triethylamine, acting as a solvent. with the proviso that, prior to the reaction, the α-amino group of the hydroxy-substituted starting material is protected with a suitable capping agent such as tert-butoxycarbonyl, which is then protected with an acid such as trifluoroacetic acid. Process and remove. The acid anhydrides and acid halides used in the above reactions are known in the art or can be prepared from the appropriate acids by methods known in the art. Reference Example 1 below illustrates the use of a compound of the general formula in which R ₂ is hydroxy as a compounding intermediate in the preparation of a cephalosporin of the formula. Example 1 7-[[2-Amino-3-phenyl-2-vinylpropionyl]amino]-3-acetyl-oxymethyl-8-oxo-5-thia-1-azabicyclo[4,2,0]oct- 2-en-2-
Carboxylic acid 1g of 3-acetyloxy-7-amino-8-
Oxo-5-thia-1-azabicyclo[4,2,
0] Oct-2-ene-2-carboxylic acid and 1g
A mixture of 2-amino-3-phenyl-1-vinylpropionic acid chloride, the free amino group of which is protected with tert-butoxycarbonyl, is refluxed in 50 ml of ethyl acetate for 2 hours, after which the solvent is removed, leaving a residue. The rest is treated with mild acid,
and chromatographed on silica gel with benzene-acetone eluent.
-amino-3-phenyl-2-vinylpropionyl]amino]-3-acetyloxymethyl-8-
Oxo-5-thia-1-azabicyclo[4,2,
0] Oct-2-ene-2-carboxylic acid is obtained. Reference Examples 2 to 4 below are examples of pharmaceutical formulations of the compounds of the present invention. Reference Example 2 A typical composition for hard gelatin capsules is as follows: (a) 2-amino-3-(3-hydroxyphenyl)
-2-Vinylpropionic acid 20 mg (b) Talc 5 mg (c) Lactose 90 mg The formulation is prepared by passing the dry powders of (a) and (b) through a fine mesh screen and mixing them well. Next, add this powder to 115 capsules per capsule.
Fill into hard gelatin capsules with a net fill of mg. Reference Example 3 A typical composition for tablets is as follows: (a) 2-amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionic acid 20 mg (b) Starch 43 mg (c) Lactose 45mg (d) Magnesium stearate 2mg Lactose is mixed with compound (a) and a part of starch,
The granulated granules with starch paste are then dried, sieved and mixed with magnesium stearate. 110mg each of the mixture
compressed into tablets of weight. Reference Example 4 A typical composition for an injection suspension is the following 1 ml ampoule for intramuscular injection. Weight% (a) 2-amino-3-(4-hydroxyphenyl)
-2-Vinylpropionic acid 1.0 (b) Polyvinylpyrrolidone 0.5 (c) Lecithin 0.25 (d) Make up the injection solution to 100.0% by weight with water. Substances (a) to (d) are mixed, homogenized and filled into 1 ml ampoules, the ampoules are sealed and
Autoclave at 121°C for 20 minutes.
Each ampoule contains 10 mg of new compound (a) per ml. The following reference examples further illustrate the compound of general formula 1. Reference Example 5 2-Amino-3-(3-chloro-4-hydroxyphenyl)-2-vinylpropionic acid (A) 2.53 g (10 mmol) of 2 in 100 ml of methanol saturated with dry hydrogen chloride. -A solution containing acetylene-2-amino-3-(3-chloro-4-methoxyphenyl)propionic acid was stirred at 25°C for about 16 hours, after which the solvent was evaporated leaving a residue, which was collected in 30 ml. of methylene chloride. 2.5g in this suspension
(25 mmol) of triethylamine followed by 780 mg (10 mmol) of acetyl chloride. After 2 hours at 25°C, the mixture is washed with 2NHCl, dried and evaporated. When the resulting residue is recrystallized from methanol, methyl 2-acetylamino-2-acetylene-3-
(3-chloro-4-methoxyphenyl)-propionate is obtained. (B) 2.0 g (5 mmol) of methyl 2-acetylamino-2-acetylene-3-(3-chloro-4-methoxyphenyl)propionate in 40 ml of methanol containing Lindlar's catalyst. The solution is stirred at 25° C. under a hydrogen atmosphere until absorption ceases at 120 ml.
Filter the suspension and evaporate the liquid. The resulting residue is recrystallized from ethyl acetate-petroleum ether, then suspended in 48% hydrogen bromide and heated under reflux for 3 hours. Evaporation of the solvent leaves a residue which is dissolved in a minimum amount of water and hydrazine is added until the pH reaches 5. Upon cooling, a precipitate forms, which is collected to yield 2-amino-3-(3-chloro-4-hydroxyphenyl)-2-vinylpropionic acid. In the method of Reference Example 5(A), 2-acetylene-
Instead of 2-amino-3-(3-chloro-4-methoxyphenyl)propionic acid, 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-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 or 2-acetylene-2-amino-3-(6-tert-butyl-4-
When using chlorophenyl)propionic acid, the following esteramide 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-(3-hydroxyphenyl)-propionate, methyl 2-acetylamino-2-acetylene-
3-phenylpropionate, methyl 2-acetylamino-2-acetylene-
3-(4-chloro-2-methoxyphenyl)propionate, methyl 2-acetylamino-2-acetylene-
3-(2-chloro-6-methylphenyl)propionate, methyl 2-acetylamino-2-acetylene-
3-(2,4-dichloro-6-methylphenyl)
Propionate, methyl 2-acetylamino-2-acetylene-
3-(4-methoxy-6-methylphenyl)propionate and methyl 2-acetylamino-2-acetylene-
3-(6-tert-butyl-4-chlorophenyl)
Propionate. In the method of Reference Example 5(B), methyl 2-acetylamino-2-acetylene-3-(3-chloro-
When a suitable amount of the abovementioned methyl ester derivative is used instead of 4-methoxyphenyl)propionate, the following compounds are obtained in each case: 2-amino-3-(3,4-dihydroxyphenyl)-2-vinyl Propionic acid, 2-amino-3-(3-hydroxyphenyl)-
2-vinylpropionic acid, 2-amino-3-phenyl-2-vinylpropionic acid, 2-amino-3-(4-chloro-2-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-hydroxy -6-methylphenyl)-2-vinylpropionic acid, and 2-amino-3-(6-tert-butyl-4-chlorophenyl)-2-vinylpropionic acid. Reference example 6 Ethyl 2-amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionate hydrochloride 2.2 g (10 mmol) of 2-amino-3-(3,4) in 30 ml of ethanol -dihydroxyphenyl)-2-vinylpropionic acid suspension in anhydrous
The HCl is saturated and the resulting solution is left at 25° C. for 24 hours. Evaporation of the solvent leaves a residue which is recrystallized from ethanol-ether to give ethyl 2-amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionate hydrochloride. Reference example 7 3-(3,4-diacetyloxyphenyl)-2
-(Benzyloxycarbonylamino)-2-vinylpropionic acid Prepared from 2-amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionic acid and benzyl chloroformate in 30 ml of 1N sodium hydroxide. 2-(benzyloxycarbonylamino)-3-(3,4-dihydroxyphenyl)
- In a solution of 2-vinylpropionic acid (6 g),
2N aqueous sodium hydroxide and acetic anhydride (3.5g)
are added simultaneously under argon to keep the PH between 6.5 and 7.5. After 1 hour at 25°C, the pH is adjusted to 1 using 6N sulfuric acid and then extracted with methylene chloride. Drying and concentrating the organic phase yields 3-
(3,4-Diacetyloxyphenyl)-2-(benzyloxycarbonylamino)-2-vinylpropionic acid is obtained. Reference Example 8 2-(acetylamino)-3-(3,4-dihydroxyphenyl)-2-vinylpropionic acid To a stirred suspension of 6.8 g (10 mmol) of borax in 10 ml of water, 2.2 g (10 mmol) of 2-amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionic acid are added under argon. After 15 minutes the PH is adjusted to 9 by addition of 2N sodium hydroxide and then treated dropwise with 780 mg acetyl chloride to keep the PH between 9.0 and 9.5. The aqueous solution is washed with ether, the pH is adjusted to 1 using 6N sulfuric acid, and extracted with methylene chloride. Drying and concentrating the organic phase gives 2-(acetylamino)-3-(3,4-dihydroxyphenyl)-2-vinylpropionic acid, which on treatment with ethanolic HCl gives the ethyl ester. Reference Example 9 2-[2-Amino-3-(3,4-diacetyloxyphenyl)-1-oxo-2-vinylpropylamino]propionic acid hydrobromide In 50 ml of ether, 2-amino- 3-(3,
4.4 g (10 mmol) of 2-(carbobenzyloxyamino)-3-(3,4-diacetyloxyphenyl) prepared from 4-diacetyloxyphenyl)-2-vinylpropionic acid and benzyl chloroformate. The solution containing -2-vinylpropionic acid is treated with 1.0 g (10 mmol) of triethylamine and then with 1.08 g (10 mmol) of ethyl chloroformate. After 1 hour at 25°C, the precipitate was separated and the ether solution was
Add a solution containing alanine benzyloxy ester (10 mmol) in 30 ml of ether.
The solution is kept at 25°C overnight and then evaporated to dryness. The residue was treated with 20 ml of hydrobromic acid in dioxane (40% w/w) at 25° C. for 30 minutes, then ether was added and the precipitate was separated to give 2-
[2-Amino-3-(3,4-diacetyloxyphenyl)-2-oxo-2-vinylpropylamino]-propionic acid hydrobromide is obtained. Reference example 10 2-(2-amino-1-oxopropylamino)
-3-(3,4-dihydroxyphenyl)-2-
Vinylpropionic acid hydrochloride 3.3 g (10 mmol) in 50 ml methylene chloride
of benzyl 2-amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionate was treated with 1 g (10 mmol) of triethylamine and then dissolved in 20 ml of methylene chloride. , 10 mmol of N-carbobenzyloxyalanine, the acid function of which has been activated by ethoxycarbonyl, is added. The mixture is stirred at 25° C. for about 16 hours and then washed with water. The organic layer is dried and evaporated. The residue is extracted in ether and the ether solution is cooled to 0°C. A torrent of HCl gas is bubbled into the solution for 3 hours, after which the ether solution is washed with water. Evaporating the aqueous phase results in 2-(2
-amino-1-oxopropylamino)-3-
(3,4-dihydroxyphenyl)-2-vinylpropionic acid hydrochloride is obtained in the form of a rubber. Reference example 11 2-acetylene-2-amino-3-(3,4-
Dihydroxyphenyl)propionic acid (A) 32.4 g in 20 ml of tetrahydrofuran
(0.15M) of 3-trimethyl-silylpropylene
A solution containing 2-ynyl-1-iminobenzyl was prepared at -78°C in 1 part of tetrahydrofuran.
of 21 ml (0.15 mol) of diisopropylamide and 73.2 ml of n-butyllithium.
Add to lithium diisopropylamide made from a 2.05M solution (0.15M). After 15 minutes, 20
32.7g (1.35M) in ml of tetrahydrofuran
of 3,4-isopropylidenedioxybenzyl bromide was added and the mixture was heated to -78°C for 2 hours.
73.2ml of a 2.05M solution (0.15M) of n-butyllithium was added, then 14.2g
Add 11.6 ml (0.15 M) of methyl chloroformate. After an additional 30 minutes at -78°C, the reaction mixture is treated with brine and extracted with ether. Evaporation of the ether extract leaves a residue which is dissolved in 300 ml of petroleum ether boiling point 30-60°C and treated with 16.2 g (0.15M) phenylhydrazine at 25°C for 2 hours. Separating the precipitate and evaporating the petroleum ether leaves a residue which is treated with potassium hydroxide in 300 ml ethanol and 300 ml water at 25° C. for about 15 hours. Evaporate the ethanol
The aqueous solution is washed well with methylene chloride, then acidified and washed again with methylene chloride. The water is evaporated, the remaining solid residue is triturated with ethanol, filtered and the filtrate is evaporated leaving a residue which is dissolved in water. aqueous solution
Adjust the pH to 6 and add it to Amberlite resin.
When applied to a column of 120H ⁺ and eluted with a 2M ammonium hydroxide solution, the 2-acetylene-2
-Amino-3,4-isopropylidenedioxyphenylpropionic acid was obtained. (B) 3 g (0.13 mol) of 2-acetylene-2-amino-3,4-isopropylidenedioxyphenylpropionic acid are heated under reflux with 200 ml of 6N hydrochloric acid for 2 hours, then the solvent is evaporated.
The resulting residue is taken into water and the pH is brought to 6 by careful addition of hydrazine hydrate.
Adjust to When the solution is cooled to 0°C, a precipitate forms, which is collected and recrystallized from water (charcoal) to give 2-acetylene-2-amino-3-
(3,4-dihydroxyphenyl)propionic acid is obtained. Reference Example 12 2-acetylene-2-amino-3-(3-methoxyphenyl)propionic acid Using the method of Reference Example 5(A), 25.8 g (0.12 M) of 3- instead of 32.4 g (0.15 M) was used. Using trimethylsilylprop-2-ynyl-1-iminobenzyl,
And when 20.1 g (0.1 M) of 1-bromomethyl-3-methoxybenzene is used instead of 5-bromomethyl-1,3-benzodioxole, recrystallization from water results in 2-acetylene-2
-Amino-3-(3-methoxyphenyl)propionic acid was obtained. Reference example 13 2-acetylene-2-amino-3-(3-hydroxyphenyl)propionic acid In 20 ml of methanol saturated with anhydrous HCl
A suspension containing 2.0 g (9.1 mM) of 2-acetylene-2-amino-3-(3-methoxyphenyl)propionic acid is stirred at 25° C. for about 15 hours, after which the solvent is evaporated. The methyl ester derivative formed is suspended in 50 ml of methylene chloride and treated with 1.26 g of benzoyl chloride followed by 3.6 g of triethylamine. The mixture is stirred for 24 hours, then washed with water, dried and evaporated. Recrystallization of the resulting residue from methanol yields a methyl ester derivative in which the amino group is protected with phenylcarbonyl. 1.2 g (3.5 mM) of amine-protected methyl ester in 50 ml of methylene chloride at 25°C.
solution is treated 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 solvent is evaporated. The resulting residue is heated under reflux for 5 hours with 50 ml of 6N hydrochloric acid. Concentrate the solution and adjust the pH to 6,
Then apply it to a column of Amberlite 120H ⁺ .
Elution with 1M ammonium hydroxide yields water-
2-acetylene- after recrystallization from ethanol
2-amino-3-(3-hydroxyphenyl)propionic acid is obtained. In Reference Example 11, instead of 3,4-isopropylidenedioxybenzyl bromide, appropriate amounts 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
-When using chlorobenzyl chloride, the following products are obtained: 2-acetylene-2-amino-3-phenylpropionic acid 2-acetylene-2-amino-3-(4-chloro-2-hydroxyphenylpropionic acid) enyl)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-hydroxy-6-methylphenyl)propionic acid and 2-acetylene-2-amino-3-(6-tert-butyl-4- Chlorophenyl) propionic acid. Reference example 14 2-amino-3-(3-hydroxyphenyl)-
2-vinylpropionic acid 2.1 g (10 mM) of 2-vinylpropionic acid in 10 ml of hydrobromic acid
The solution containing acetylene-2-amino-3-(3-methoxyphenyl)propionic acid is heated to reflux for 4 hours and then evaporated to dryness. Dissolve the residue in a minimum amount of water and adjust the PH to 4.5 by carefully adding hydrazine hydrate. Upon cooling to room temperature, a precipitate forms, which is collected and recrystallized from water. Sinden,
Add to 100 ml of liquid ammonia at reflux and add sodium until the blue color persists for 15 minutes, then add 2 g of ammonium chloride and evaporate the ammonia. The resulting residue is dissolved in water, the pH is adjusted to 6, and it is applied to a column of Amberlite 120H ⁺ . Elution with 1M ammonium hydroxide yields 2-amino-3-(3
-hydroxyphenyl)-2-vinylpropionic acid is obtained, which is recrystallized from water-acetone. Example 1 2-Amino-3-(3,4-dihydroxyphenyl)-2-vinylpropionic acid In the method of Reference Example 11, instead of 3,4-isopropylidenedioxybenzyl bromide, an appropriate amount of 3,4- When dimethoxybenzyl bromide is used, 2-acetylene-2-amino-3
-(3,4-dimethoxyphenyl)propionic acid,
A melting point of 225°C is obtained. 600 ml of ammonia are condensed into a flask containing 10.24 g of 2-acetylene-2-amino-3-(3,4-dimethoxyphenyl)propionic acid and 10 g of ammonium sulfate. While maintaining the temperature of the reaction mixture at -78°C, sodium is added to the mixture in small portions until the blue color persists for 30 minutes, then ammonium chloride is added until the blue color disappears and the ammonia is evaporated. Water is carefully added to the mixture and the solution is evaporated to dryness. The residue is taken into water and applied to Amberlite resin. Elution with 2M ammonium hydroxide gave 2-amino-3-(3,4-dimethoxyphenyl)-2-vinylpropionic acid,
It is recrystallized from ethanol/water. melting point
250℃. Example 2 7.9 g of 2-amino-3-(3,4-dimethoxyphenyl)-2-vinylpropionic acid in 47% HBr
Heat under reflux for 2 1/2 hours under a nitrogen atmosphere, then evaporate the solvent. Take up the residue in water and adjust the pH to 4.5 by carefully adding hydrazine hydrate. 0℃
On cooling to
-(3,4-dihydroxyphenyl)-2-vinylpropionic acid is obtained. Melting point 260℃.

Claims (1)

[Claims] 1 formula wherein R ₁₀ is hydrogen or lower alkyl and pharmaceutically acceptable salts. 2 formulas α of [wherein R ₁₀ is hydrogen or lower alkyl]
- acetylene derivatives in liquid ammonia and ammonia sulfate at -70°C to 25°C with sodium,
treatment with potassium or lithium until the blue color persists for 15 minutes, heating it under reflux with HBr if necessary and adding hydrazine hydrate to convert the alkoxy ring substituent to hydroxy. A process for producing a compound and pharmaceutically acceptable salts of the formula: wherein R ₁₀ is hydrogen or lower alkyl.