JPS6334145B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel pharmaceutically useful alpha-acetylenic amino acid derivatives that are inhibitors of aromatic amino acid carboxyl group degrading enzymes. The amino acids tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine (DOPA), tyrosine, and phenylalanine are converted to tryptophan, 5-hydroxytryptamine, 3,4-dihydroxytryptophan, and 3,4-dihydroxytryptophan, respectively, by organic amino acid carboxyl group-degrading enzymes. - Metabolically converted to dihydroxyphenethylamine or dopamine, tyramine and phenylethylamine. Aromatic amino acid carboxylases are believed to be non-specific, especially as far as peripheral catalysis is concerned. however
There is evidence that there are brain-specific decarboxylating enzymes for each of DOPA and 5-hydroxytryptophan. It is known that the aromatic amines mentioned above have been implicated in various pathophysiological processes. For example, the decarboxylation product of tryptophan, tryptamine, is enzymatically methylated to monomethyltryptamine, which is then enzymatically methylated in human red blood cell plasma and plasma plates to dimethyl Becomes tryptamine (DMT). Enzymes that perform methylation have been shown to exist in many mammalian species and to be produced in the brain tissue of some species, including humans. DMT, which has strong hallucinogenic or psychotomimetic properties, plays a role in the pathogenesis of schizophrenia and other psychotic illnesses.
Any drug that blocks the production of DMT may therefore be useful as an antipsychotic. Blocking tryptophan decarboxylation results in a decrease in tryptamine levels, eliminating the substrate for DMT production. Therefore, inhibitors of aromatic amino acid carboxyl group degrading enzymes that block the conversion of tryptophan to tryptamine may be useful as antipsychotics. Both 5-hydroxytryptamine (5-HT), the decarboxylation product of 5-hydroxytryptophan, and 3,4-dihydroxyphenethylamine (dopamine), the decarboxylation product of DOPA, are and central physiological processes, and agents effective in regulating the levels of these amines have yielded useful pharmacological agents. 5-HT
Central or brain levels of norepinephrine, which is produced metabolically by hydroxylation of dopamine, have been shown to be higher in patients with manic disorders than in individuals without such disorders. Ta. Whereas drugs that reduce central levels of monoamines, such as 5-HT and especially norepinephrine, have antimanic properties when given to human subjects;
Drugs that increase monoamine levels could cause susceptible individuals to become manic. Therefore 5-HT
and drugs that block the production of topamine, such as antipsychotics or manic disorders, such as by inhibiting aromatic amino acid carboxyl-degrading enzymes that convert 5-hydroxytryptophan and DOPA to 5-HT and dopamine, respectively. may be useful as a primary tranquilizer in the treatment of Agents useful for preventing the decarboxylation of DOPA to dopamine are useful in the treatment of Parkinson's syndrome when administered concurrently with exogenous DOPA or L-DOPA. DOPA or L-
Since exogenous administration of DOPA is known to be an effective means of treating parkinsonism, it is believed that parkinsonism is at least partially due to decreased central levels of dopamine. However, since exogenously administered DOPA is readily enzymatically converted to dopamine peripherally, it is necessary to administer large amounts to have increased absorption centrally. DOPA readily penetrates the blood-cerebrospinal fluid barrier, whereas dopamine does not. Administering DOPA or L-DOPA simultaneously with a peripherally active inhibitor of the enzyme that converts DOPA to dopamine reduces the amount of L-DOPA that must be administered to have adequate circulating levels for central absorption. let Other benefits are also realized by administering an aromatic amino acid carboxylase inhibitor along with L-DOPA. By preventing dopamine production peripherally, the side effects attributed to dopamine, such as cardiac arrhythmias, nausea, and vomiting, are avoided. Studies have shown that 5-hydroxytryptamine (5-HT) levels are lower in patients with depressive syndromes than in individuals without such syndromes. Administration of exogenous L-5-hydroxytryptophan (L-5-HTP) has also been effective in treating certain depressed patients. However, as with DOPA, L-5-HTP is readily metabolized peripherally, so it is necessary to administer large amounts of L-5-HTR to achieve increased central levels of the amino acid. Exogenous 5-HTP required to provide increased central levels by administering an inhibitor of aromatic amino acid carboxylase, which peripherally catalyzes the production of 5-HT from 5-HTP. It was shown that the amount of In other words, the exogenous 5-
Inhibitors of aromatic amino acid carboxyl group degrading enzymes have been shown to be useful in treating depression when used concomitantly with HTP. Agents that block the peripheral conversion of 5-HTP to 5-HT can be used as a result of exogenous administration of 5-HTP.
- May be useful in treating other conditions that respond to increased central levels of HTP. Exogenous L-5-
HTP is active clonic muscle spasm (disappears during sleep)
It is useful for treating. Also, exogenous 5-
Studies have shown that administration of HTR is useful in treating insomnia. Therefore, co-administration of 5-HTP and an aromatic amino acid carboxyl group degrading enzyme inhibitor is beneficial in treating these conditions. Blocking the peripheral production of 5-hydroxytryptamine is known to be associated with increased collagen levels in the pathogenesis of 5-HT, e.g. rheumatoid arthritis and carcinoid syndrome. This may have other beneficial effects. Also 5
-HT is the main autocoid responsible for anaphylaxis-like reactions in human subjects as well as bronchial narrowing in asthmatic human subjects, and is responsible for the production of 5-HT. Counteracting and preventive agents are useful in treating these conditions. 5-HT is known to cause plasma plate aggregation and rapid movement after gastrectomy (after gastrectomy or gastrointestinal anastomosis, rapid movement of food from the stomach to the jejunum occurs upon ingestion, resulting in weakness). It has been implicated as a causative factor in migraine and migraine. Methylsurgite, a 5-hydroxytryptamine antagonist, has proven effective in treating rapid migration syndrome after gastrectomy. As an endogenous compound, phenethylamine, a decarboxylation product of phenylalanine, contributes to the symptoms of schizophrenia and causes migraines. It has also been suggested that endogenous tyramine, a decarboxylation product of tyrosine, contributes to epileptic seizure disease. It is therefore readily apparent that agents useful for regulating the levels of aromatic amino acids and amines will find use in many pharmacological situations. The compounds of the present invention are useful as inhibitors of aromatic amino acid carboxyl group-degrading enzymes that convert tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine, tyrosine and phenylalanine to their respective amines. to provide effective pharmacological agents. The compound of the present invention is represented by the following general formula. formula In the above general formula, ₄ is a hydrogen atom, hydroxy, or lower alkoxy, and R ₅ is a hydrogen atom or hydroxy. Pharmaceutically acceptable salts and individual optical isomers of compounds of general formula are also included within the scope of this invention. Compounds of the general formula are useful pharmacological agents in that they are inhibitors of aromatic amino acid carboxyl group degrading enzymes and are useful as intermediates in the preparation of useful pharmacological agents. Illustrative pharmaceutically acceptable salts of compounds of the invention include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, methanesulfonic acid, salicylic acid, malic acid, malonic acid, tartaric acid, citric acid,
organic acids such as ascorbic acid, alkali metals such as sodium, potassium and lithium, alkaline earth metals such as calcium or magnesium,
With inorganic or organic bases such as light metals of group A, such as aluminum, primary, secondary or tertiary amines, such as salts of organic amines such as cyclohexylamine, ethylamine, pyridine, methylamino-ethanol, ethanolamine, and piperazine. Contains non-toxic salts produced. Salt is made by conventional means. Illustrative compounds of the general formula are as follows. 2-acetylene-2-amino-3-phenylpropionic acid 2-acetylene-2-amino-3-(3-hydroxyphenyl)propionic acid 2-acetylene-2-amino-3-(3,4-
dihydroxyphenyl)propionic acid 2-acetylene-2-amino-3-(4-hydroxyphenyl)propionic acid 2-acetylene-2-amino-3-(4-chloro-3-methoxyphenyl)propionic acid General formula The compounds are tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine, tryptamine of tyrosine and phenylalanine, 5-hydroxytryptamine, 3,4-dihydroxyphenylethylamine, tyramine and phenylethylamine. It is an irreversible inhibitor of the enzyme that metabolically catalyzes the conversion of As indicated earlier herein, the results of the study indicate that the enzymes responsible for peripherally converting the amino acids listed above to their respective amines are non-specific aromatic amino acid carboxyl groups. Indicates that it is a degrading enzyme. For central conversion, research shows that special carboxyl-degrading enzymes are responsible for the conversion of 5-hydroxytryptophan and 3,4-dihydroxyphenylalanine, respectively, while the remaining amino acids listed above are enzymatically converted to each other. amines by nonspecific aromatic amino acid carboxyl group degrading enzymes. The compounds of the present invention irreversibly prevent the activity of non-specific aromatic amino acid carboxyl-degrading enzymes as well as the activity of 3,4-dihydroxyphenylalanine (DOPA) carboxyl-degrading enzymes, both centrally and peripherally. It is effective for As used herein with respect to uses of the compounds of the present invention, the term central refers to the central nervous system, primarily the brain, while peripheral refers to other body tissues where carboxyl-degrading enzymes are present.
The selectivity of centrally or peripherally inhibiting amino acid carboxyl group degrading enzymes by administering compounds of the general formula is dose dependent. Aromatic amino acid carboxyl group degrading enzyme
As irreversible inhibitors of DOPA carboxylase, the compounds of the present invention have many pharmacological uses. As a peripheral irreversible inhibitor of aromatic amino acid carboxyl group-degrading enzymes, the compound of the general formula can be used simultaneously with 3,4-dihydroxyphenylalanine (DOPA) or L-3,4-dihydroxyphenylalanine (L-DOPAP). When given it is useful in the treatment of Parkinson's syndrome.
In detail, DOPA is an active isomer L-
DOPA is commonly administered systemically in doses of 0.5 to 1 gram daily initially, with the dose then gradually increased over a period of 3 to 7 days to a maximum tolerated daily dose of about 8 grams. It is known to be effective in treating Parkinson's syndrome when administered. Simultaneous administration of a compound of the general formula and L-DOPA means that the compound of the formula is L-3 of L-DOPA,
Peripheral decarboxylation to 4-dihydroxyphenethylamine (L-dopamine) is blocked by inhibiting the activity of aromatic amino acid carboxyl-degrading enzymes, thus increasing L-DOPA's potential for central absorption. It maintains circulating levels and prevents peripheral production of increased levels of topamine, which is known to cause certain undesirable side effects such as cardiac arrhythmias. Compounds of general formula and L-
By co-administering DOPA, the dose of L-DOPA is reduced by a factor of 2 to 10 compared to the amount required for the application when L-DOPA is administered alone. Preferably, the compound of the invention is administered prior to the administration of L-DOPA. For example, a compound of formula L-
It can be administered 30 minutes to 4 hours before administration of DOPA. Compounds of the general formula also include 5-hydroxytryptophan (5-HTP) or its active levorotatory isomer, which is known to be useful in the treatment of depressive disorders, particularly when administered systemically. It is useful in treating depressive syndromes in individuals when given simultaneously.
By peripherally inhibiting the activity of aromatic amino acid carboxyl group degrading enzymes, compounds of the general formula block the conversion of 5-hydroxytryptophan to 5-hydroxytryptamine, thus resulting in higher levels of central absorption. It will maintain circulating levels of 5-HTP. Compounds of the general formula contain exogenous 5-
When administered concurrently with HTP, it is also useful in treating active clonic muscle spasms, which are known to be effectively treated by increasing central levels of 5-HTP. Compounds of the general formula have a peripherally protective effect on aromatic amino acid carboxyl group-degrading enzymes, and therefore cause rheumatoid arthritis, carcinoid syndrome, and anaphylaxis-like reactions in humans, resulting in bronchial stenosis in humans with asthma. It is also useful in treating other conditions known to be caused by high peripheral levels of 5-hydroxytryptamine. As indicated herein above, agents that reduce elevated levels of 5-HT and norepinephrine, hydroxylated products of dopamine, are useful in treating patients with manic disorders. Therefore, aromatic amino acid carboxyl group degrading enzyme
As central irreversible inhibitors of DOPA carboxylase, compounds of the general formula are useful in treating manic disorders. In addition, because of the central inhibitory action of compounds of the general formula on aromatic amino acid carboxyl group degrading enzymes, said compounds are also useful as antipsychotics because central levels of tryptamine are reduced, and central levels of phenethylamine and tyramine are reduced. may be useful in the treatment of schizophrenia and epileptic seizure disorders as the The usefulness of the compound of the general formula as an irreversible inhibitor of aromatic amino acid carboxyl group degrading enzymes is demonstrated as follows. Compounds of the general formula are administered to mice or mice as an aqueous solution or suspension. At different time intervals after administration of the compound for 1 to 48 hours, the animals were sacrificed by decapitation;
Kidney, heart, by Burkard et al. in Arch.Biochem.Biophys. 107 , 187 (1964);
Arch.Biochem.Biophys. 141 , 356 in the homoplasm of the brain
Aromatic amino acid carboxyl group degrading enzyme activity is measured by radiometric evaluation analysis as described by Christenson et al. (1970). The compounds of this invention may be administered in a variety of ways to achieve the desired effect. The compounds may be administered alone or in the form of a pharmaceutical preparation to the patient being treated orally or parenterally, such as subcutaneously, intravenously, or intraperitoneally. The compounds can be administered by intranasal instillation or application to mucous areas such as the nose, throat and bronchi, for example in aerosol solutions or aerosols containing small particles of the novel compounds of the invention in dry powder form. The dosage of the novel compounds will vary and can be any effective amount. Depending on the condition being treated by the patient and the mode of administration, the amount of the novel compound administered can be varied over a wide range to provide an effective amount in unit dosage form. When a compound of the general formula is administered to effect peripheral irreversible inhibition of aromatic carboxyl-degrading enzymes, the effective amount of the compound administered is about 0.1 mg per kg of patient body weight per appropriate dose.
It may vary from about 5 mg/Kg to 25 mg/Kg, preferably from about 5 mg/Kg to 100 mg (milligrams per kilogram). For example, the desired peripheral effect may be achieved in unit dosage form, e.g., from 1 to 250 mg of the novel compounds of this invention taken 1 to 4 times daily.
can be obtained by consumption such as tablets containing mg. When a compound of the general formula is administered to achieve central irreversible inhibition of aromatic carboxyl-degrading enzyme or 3,4-dihydroxyphenylalanine carboxyl-degrading enzyme, the effective amount of the compound administered is per day. Approximately 100 per kg of patient's weight
It will vary from mg to 500 mg and preferably from about 150 mg to 300 mg per Kg. For example, the desired central effect is achieved by consumption of a unit dosage form, such as a tablet containing about 350 mg to 500 mg of the novel compound of the invention taken one to four times daily. As used herein, the term patient refers to mammals such as cats, dogs, mice, chicks, guinea pigs,
taken to mean warm-blooded animals such as sheep, horses, cows, cows, and humans. The solid unit dosage form may be of the conventional type. The solid form may thus be a capsule which may be of the conventional gelatin type containing the novel compound of the invention and a carrier such as a lubricant and inert fillers such as lactose, sucrose and corn starch.
In another embodiment, the novel compound is combined with a binder such as gum arabic, corn starch or gelatin, a disintegrant such as corn starch, potato starch or alginic acid, a lubricant such as stearic acid or magnesium stearate. It is tabletted with conventional tablet bases such as lactose, sucrose, and corn starch. For parenteral administration, the compounds are combined with a pharmaceutically acceptable carrier, which can be a sterile liquid such as water or oil, with or without the addition of surfactants and other pharmaceutically acceptable excipients. It is administered as a suitable injectable amount of a solution or suspension of the compound in a physiologically acceptable diluent. Examples of oils that can be used in these pharmaceutical preparations are oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil.
In general, water, saline, aqueous dextrose and related sugar solutions, ethanol, glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions. The compounds may be administered in the form of depot injections, implant preparations, which may be formulated in such a manner as to permit sustained release of the active ingredient. The active ingredient is compressed into small pellets or small cylinders and inserted subcutaneously or intramuscularly as a depot injection or implant. Implants are made of biodegradable polymers or synthetic silicones, such as those manufactured by Dow-Corning Corporation.
An inert material may be used, such as silicone rubber silastic made by the United States Corporation. The novel compounds in solution or suspension for use as fumes include, for example, dichlorodifluoromethane,
Dichlorodifluoromethane with dichlorodifluoroethane, together with gaseous or liquefied propellants such as carbon dioxide, nitrogen or propane, in a pressurized atomized container with the usual excipients such as co-solvents, wetting agents as required. It can be packaged as desired. The compound may also be administered in an unpressurized form, such as in a nebulizer or atomizer. As indicated hereinabove, compounds of the general formula find particular utility when administered with exogenous L-DOPA, in which case the compounds of the general formula Separate formulations of DOPA can be administered or both active ingredients can be formulated into a single combined pharmaceutical formulation. L- administered in any mode of administration
The amount of compound of general formula compared to the amount of DOPA will vary from about 1:1 to 1:10. The combination formulation may include an inner portion containing L-DOPA and an outer portion containing a compound of the general formula, each active ingredient being formulated as appropriate. A particularly suitable combination formulation compresses L-DOPA with a suitable carrier and optionally into a core, provides this core with a layered coating that is resistant to gastric juices, and is suitably formulated onto the coated core. It is created by applying an outer layer containing a compound of the general formula. Using such combination formulations, the carboxyl-degrading enzyme inhibitor, i.e., a compound of the general formula
Released in 60 minutes. Laminated coatings may be produced by the use of non-aqueous solutions of glycerides or water-insoluble polymers such as ethyl cellulose or cellulose acetate phthalate. Formulations in which L-DOPA is enteric coated by the use of a mixture of shellac and shellac derivatives and cellulose acetate may also be used. Illustrative examples of suitable pharmaceutical formulations are described in the specific examples included herein below. In addition to being useful pharmacological agents, compounds of the general formula are also useful as intermediates for the production of useful cephalosporin antibiotics. Compounds of the general formula in which R ₂ is hydroxy are useful in the preparation of cefrosporin derivatives of the following general formula: In the above general formula, R ₁ , R ₄ and R ₆ are hydrogen atoms, R ₃ , R ₄ and R ₅ have the meanings defined in the general formula; M is hydrogen or a negative loading; is hydrogen or acetoxy. The compounds of the general formula and their pharmaceutically acceptable salts and individual optical isomers are novel compounds useful as antibiotics, similar to the practice of many well-known cephalosporin derivatives such as cephalexin, cephalosin or cephaloglycine. It can be administered in a similar manner. Compounds of the general formula and pharmaceutically acceptable salts and isomers thereof can be administered orally, parenterally and topically, alone or in the form of pharmaceutical preparations, to warm-blooded animals such as birds and mammals such as cats, dogs, and cattle. , sheep, horses and humans. For oral administration, the compounds may be administered in the form of tablets, capsules or pills or elixirs or suspensions. For parenteral administration, the compounds are best employed in the form of a sterile aqueous solution which may contain other solutes, such as sufficient saline or glucose to make the solution isotropic. For topical administration, compounds of the general formula
Salts and their isomers can be incorporated into creams or salves. Exemplary of the bacteria against which the compound of the general formula, its pharmaceutically acceptable salts and individual optical isomers are active and resistant are Staphylococcus aureus, Salmonella
schotmuehleri), Klebsiella pneumoniae, Diplococcus pneumoniae and Streptococcus pneumoniae.
pyogenes). Examples of pharmaceutically acceptable non-toxic inorganic acid addition salts of compounds of general formula are mineral acid addition salts such as hydrogen chloride, hydrogen bromide, sulfates, sulfamates, phosphates; organic acid addition salts include For example, maleate,
The acetate, citrate, oxalate, succinate, benzoate, tartrate, fumarate, maleate, alcoholate salts can be produced by conventional means. An exemplary cephalosporin derivative represented by the general formula is 7-[[2-acetylene-2-
Amino-3-phenylpropionyl]amino]-
3-Acetyloxymethyl-8-oxo-5-thia-1-azebicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[2-acetylene-2
-amino-3-(3-hydroxyphenyl)propionyl]-amino]-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carvone acid,
7-[[2-acetylene-2-amino-3-(3,
4-dihydroxyphenyl)propionyl]amino]-3-acetyloxymethyl-8-oxo-
5-thia-1-ozabicyclo [4.2.0] octo-
2-ene-2-carboxylic acid and 7-[[2-acetylene-2-amino-3-(4-hydroxyphenyl)-propionyl]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 include 7-aminocephalosporanic acid or its derivatives having the following formula: An acid of the following formula (wherein X and M have the meanings defined for the general formula) or by combining derivatives of that functional group, such as acid chlorides, acid anhydrides, and when the free acid is used, in the presence of a dehydrating agent such as dicyclohexylcarbodiimide. In the formula, R ₃ , R ₄ , R ₅ , R ₄ ′ and
R ₆ has the meaning defined for the general formula and the amino group is protected with a suitable blocking group such as tert-butoxycarbonyl, followed by removal of the amino protecting group by acid hydrolysis. do. 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. The reaction temperature can vary from about -10°C to 100°C;
Reaction times can vary from about 1/2 hour to 10 hours. Cephalosporin products are isolated by conventional procedures. Compounds of the general formula are made by the procedures described hereinabove, and compounds of the formula are commercially available or made by procedures well known in the art. Compounds of the general formula where R ₁ is other than hydrogen can be obtained from the corresponding derivatives when R ₁ is hydrogen by the general procedure given herein for compounds of the general formula where R ₁ is other than hydrogen. It is made by hand. Compounds of the general formula can be prepared by treating a suitably protected propargylamine derivative with a strong base to form a protected propargylamine carbanion intermediate, in which both R ₄ and R ₅ are OR ₁₀ and R ₁₀ is hydrogen. 3,4-isopropylidenedioxybenzyl halide (wherein the halide is, for example, chloride or bromide) and a compound of the following formula other than the above:

[Formula] or

[Formula] [In the formula, Y is a halogen atom]] is produced by alkylation, respectively. The alkylated propargylamine derivative thus produced is treated with a strong base to produce the alkylated propargylamine carbanion, and said second carbanion intermediate is treated with an acylating reagent to form the alkylated propargylamine carbanion. It involves subsequent removal of the protecting group as indicated by the reaction sequence. In the above reaction system, R ₁₆ is methyl, ethyl,
represents a straight-chain or branched lower alkyl group having 1 to 4 carbon atoms, such as n-propyl and tert-butyl; R ₁₇ is phenyl, tert-butyl,
or triethylmethyl, 1-adamantanyl or 2-furyl; R ₁₈ is hydrogen methoxy or ethoxy, provided that when R ₁₇ is 1-adamantanyl or 2-furyl, R ₁₈ is not hydrogen; R ₁₉ Y is an alkylating reagent of the formula or 2,3-
isopropylidene dioxybenzyl halide,
3,4-isopropylidenedioxybenzyl halide or 3,4-methylenedioxybenzyl halide; Ph represents phenyl; _R20 represents a carboxy anion, a carboxylic acid ester, a carboxamide, a nitrile or the acylating reagent used. R _3a , R _4a , R 5a , R _{′ 4a and R 6a each represent R 3 , R 4 , R 5 , R} ′ in the table. ₄ and R ₆ except that R ₁₀ is methyl, or both R _3a and R _4a are OR ₁₀ and R ₁₀ is hydrogen, or both R _4a and R _5a are OR ₁₀ and R ₁₀ is hydrogen. Suitable strong bases used in the above reactions to produce each carbanion remove protons from the carbon atom adjacent to the acetylene moiety, such as lithium alkyls, e.g. lithium butyl, lithium phenyl, lithium di-alkylamides, e.g. lithium diisopropylamide. , lithium amide, tertiary potassium butyrate or sodium amide. The alkylating reagents used in the above reaction sequences are known in the art or can be made by procedures known in the art.
For example, 2,3-isopropylidene dioxybenzyl halide can be prepared by treatment of 2,3-dihydroxytoluene with acetone in the presence of phosphorus pentoxide, followed by Tetrahedron Letters 1971 , 3151/K.
Obtained by treatment with bromosuccinimide according to the general procedure of Ogura and G. Tsuchihashi. Suitable acylating reagents that can be used in the above reaction are haloformates such as chloromethylformide or chloroethylformate, azide tert-butylformate, cyanogen bromide, carbon dioxide, diethyl carbonate, phenyl isocyanate. ate, triethoxymethylium tetrafluoroborate, N,N-dimethylcarbamoyl chloride, 2-methylthio-1,3-dithiolinium iodite, ethylene carbonate or ethylene trithiocarbonate. When 2-methylthio-1,3-dithiolinium iodide is used, an additional step of alcoholysis with a lower alcohol such as ethanol or isopropyl alcohol is necessary before deprotecting the group by hydrolysis. Alkylation reactions and acylation reactions include benzene, toluene, ether, tetrahydrofuran,
It can be carried out in a neutral solvent such as dimethylsulfoxide, hexamethylphosphortriamide.
For each reaction, the temperature varied from -120°C to approximately 25°C;
The preferred reaction temperature is about -70℃ and the reaction time is about 1/2.
Changes from hour to 24 hours. Removal of the protecting group is accomplished by treatment with an aqueous base such as sodium hydroxide, or potassium or hydrazine or phenylhydrazine, followed by treatment with an alkylating agent such as 3,4-isopropylidenedioxybenzyl halide or 2,3-isopropylidenedioxybenzyl. When the halide is hydrochloric acid, when the alkylating reagent contains a benzyloxy group, base hydrolysis is followed by treatment with lithium or sodium amide in ammonia, followed by addition of lithium or sodium metal until the blue color connects for about 15 minutes. This is achieved by continuing. Propargylamine derivatives when R ₁₈ is hydrogen are made by adding protecting groups on the acetylene and nitrogen functional groups of propargylamine. The nitrogen group of the propalkylamine is protected by forming a Schiff base in a known manner with a compound having a non-enolized carbonyl selected from benzaldehyde, 2,2-dimethylpropanal and 2,2-diethylbutanol. carried out. Protection of the acetylene group can be achieved in a known manner by reacting the Schiff base described above with a straight-chain or branched trialkylsilyl chloride in which the alkyl moiety has 1 to 4 carbon atoms, such as trimethylsilyl chloride or triethylsilyl chloride derivatives. This is accomplished by generating the corresponding triarykylsilyl derivative. Propargylamine derivatives when R ₁₈ is methoxy or ethoxy include benzoyl chloride, vivalin, etc. Acid chloride, 2,2-diethylbutyric acid chloride, 2-Freuzk acid chloride or 1
- Reaction with adamantane carboxylic acid chloride in diethyl ether, dioxane, tetrahydrofuran, chloroform, methylene chloride, dimethyl formamide, dimethyl acetamide, chlorobenzene at 0°C in the presence of an organic base such as triethylamine or pyridine, followed by reaction. It is made by leaving the mixture to warm to about 25°C for 1 hour. The resulting amide derivatives are methyl fluorosulfoneate, dimethyl sulfate, methyl iodide, methyl P-toluenesulfonate or trimethyloxonium hexafluorophosphate when R ₁₈ is methoxy, triethyloxonium when R ₁₈ is ethoxy. with an alkylating reagent such as tetrafluoroborate and at approximately 25°C.
in a chlorinated hydrocarbon solvent such as methylene chloride, chlorobenzene or chloroform, and the reaction mixture is refluxed for about 12 to 20 hours. The mixture is then cooled to about 25°C, an organic base such as triethylamine or pyridine is added, and the solution is then extracted with brine to isolate the product. The protected propalkylamine starting material is 3
-trialkylsilylprop-2-ynyl-1-
The imino-benzyl derivative is treated with hydrazine or phenylhydrazine at about 25 DEG C. for about 11/2 hours, after which the mixture is diluted with, for example, petroleum ether, benzene or toluene, and the protected propargylamine derivative is liberated. instead
Treatment with 0.5-1NHCl gives the hydrochloride salt. Compounds of the general formula can be made from suitably substituted benzoic acids known in the art or benzaldehyde derivatives known in the art. For example, a benzyl halide of the formula can be reduced from the corresponding benzaldehyde with sodium borohydride, lithium aluminum hydride or catalytic reduction or from the corresponding benzoic acid ester with lithium aluminum hydride or borane, or from the corresponding benzoate. It is prepared by reduction of the acid derivative with lithium hydride and by treating the thus formed benzyl alcohol derivative with, for example, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride. When R ₁ is H and R ₂ is OH, the individual optical isomers of the compound of the general formula are described in Tetrahydron Letters.
R. Viterbo et al. (R. 48.4617 (1971)).
(+) or (-) by the method of Viterbo et al.
It can be separated using binaphthyl phosphoric acid salt. Other resolving agents such as (+) camphor 10-sulfonic acid may also be used. R ₁ and R ₂ are H
and OH, the individual optical isomers of the compounds of the formula are obtained simply starting with the amino acids resolved as described herein for the racemates. The following reference examples illustrate the use of compounds of the general formula when R ₂ is hydroxy as chemical intermediates in the preparation of cephalosporins of the formula. Note: In this specification, octo is a translation of (Oct),
Prop is the translation of (Prop). Reference example 1 7-[[2-acetylene-2-amino-3-phenylpropionyl]amino]-3-acetyl-
Oxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
Carboxylic acid 1g of 3-acetyloxy-7-amino-8-
Oxo-5-thia-1-azabicyclo [4.2.0]
2-acetylene-2-amino-3 with oct-2-ene-2-carboxylic acid and 1 g of free amino group protected with tert-butoxycarbonyl
- a mixture of phenylpropionic acid chlorides,
It was refluxed in 50 ml of ethyl acetate for 2 hours, after which the solvent was removed leaving a residue that was treated with mild acid and chromatographed on silica gel using benzene-acetone as eluent. 2-acetylene-2-amino-3-phenylpropionyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid give. The following Reference Examples 2 to 4 are illustrative of pharmaceutical formulations of the compounds of this invention. Reference Example 2 An exemplary composition for hard gelatin capsules is as follows. (a) 2-acetylene-2-amino-3-(3-hydroxyphenyl)propionic acid 20 mg (b) Talc 5 mg (c) Lactose 90 g It is made by passing it through a net of mesh and mixing it well. The powder is then filled into hard gelatin capsules with a net fill of 115 mg per capsule. Reference Example 3 An exemplary composition for tablets is as follows. (a) 2-acetylene-2-amino-3-(3,4
-dihydroxyphenyl)propionic acid 20 mg (b) Starch 43 mg (c) Lactose 45 mg (d) Magnesium stearate 2 mg Obtained by mixing lactose with compound (a) and a portion of starch and granulated with starch paste. The granules are dried, sieved and mixed with magnesium stearate. The mixture is compressed into tablets and each
It weighs 110mg. Reference Example 4 An exemplary composition for an injectable suspension is the following 1 ml ampoule for intramuscular injection. Weight percent (a) 2-acetylene-2-amino-3-(4-hydroxyphenyl)propionic acid 1.0 (b) Polyvinylpyrrolidone 0.5 (c) Lecithin 0.25 (d) Water for injection 100.0 Materials (a) -(d) is mixed, homogenized and filled into 1 ml ampoules, which are sealed and heated to 121°C.
processed in an autoclave for 20 minutes. Each ampoule contains 10 mg per ml of novel compound (a). The following examples further illustrate compounds of the general formula. Example 1 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
21ml of 2-ynyl-1-iminobenzyl
Lithium diisopropylamide was prepared from a 2.05M solution of diisopropylamide (0.15M) and 73.2ml of n-butyllithium (0.15M) in a standing atmosphere of tetrahydrofuran at -78°C. After 15 minutes, 32.7 g (1.35 M) of 3,4-isopropylidenedioxybenzyl bromide in 20 ml of tetrahydrofuran was added and the mixture was kept at -78°C for 2 hours before adding a 2.05 M solution of n-butyllithium ( 73.2ml of (0.15M) was added followed by 14.2g 11.6ml (0.15M)
of methyl chloroformate is added. After a further 30 minutes at -78°C the reaction mixture is treated with brine and extracted with ether. The ether extract is evaporated to leave a residue, which has a boiling point of 30° to 60°.
16.2g dissolved in 300ml petroleum ether at °C
(0.15M) phenylhydrazine for 2 hours at 25°C. The precipitate is separated and the petroleum ether is evaporated leaving a residue, which is 300 ml.
of ethanol and 40 g of potassium hydroxide in 300 ml of water at 25° C. for about 15 hours. The ethanol is evaporated and the aqueous solution is washed thoroughly with methylene chloride, then acidified and washed again with methylene chloride. The water is evaporated and the solid residue remaining is triturated with ethanol, filtered and the liquid is evaporated leaving a residue which is dissolved in the water. The pH of the aqueous solution was adjusted to 6 and applied to a column of Amberlite resin 120H ⁺ 2-acetylene-2-amino-3',4 after recrystallization from water-ethanol and eluting with 2M ammonium hydroxide solution. '-isopropylidenedioxyphenylpropionic acid. (B) 3 g (0.13 M) of 2-acetylene-2-amino-3,4-isopropylidenedioxyphenylpropionic acid are heated under reflux with 200 ml of 6N hydrochloric acid for 2 hours, after which the solvent is evaporated. . The resulting residue is taken up in the water and the pH
6 by careful addition of hydrazine hydrate.
adjusted to. When the solution is cooled to 0°C, a precipitate forms, which is collected and recrystallized from water (charcoal).
2-acetylene-2-amino-3
-(3,4-dihydroxyphenyl)propionic acid. The melting point was 210°C (decomposition). Example 2 2-Acetylene-2-amino-3-(3-methoxyphenyl)propionic acid 25.8 g (0.12 M) of 3-trimethylsilylprop-2-ynyl-1 in the procedure of Example 1(A) −
Iminobenzyl was used instead of 32.4 g (0.15 M) and 20.1 g (0.1 M) of 1-bromomethyl-3-
Methoxybenzene is 5-bromomethyl-1,3-
It is used in place of benzodioxole and when recrystallized from water it forms 2-acetylene-2-amino-3-(3
-methoxyphenyl)propionic acid is obtained.
The melting point was 243°C. Example 3 An appropriate amount of benzyl chloride is substituted for 3',4'-isopropylidenedioxybenzyl bromide in the procedure of Example 1 to yield the following product. 2-acetylene-2-amino-3-phenylpropionic acid, melting point was 180°C (decomposed).

Claims (1)

[Claims] 1 formula [wherein R ₄ is a hydrogen atom, hydroxy, or lower alkoxy, and R ₅ is a hydrogen atom or hydroxy] and pharmaceutically acceptable salts. 2 2-acetylene-2-amino-3-(3,4
-dihydroxyphenyl)propionic acid or a pharmaceutically acceptable salt thereof. 3 Treat the protected propargylamine derivative with a strong base to form the propargylamine carbanion intermediate, which can be converted to 3,4-isopropylidenedioxy when R ₄ and R ₅ in the formula below are both OH. benzyl halide, otherwise with a compound of the formula [Formula] or [Formula] in which Y is a halogen atom, and the alkylated propargylamine derivative thus produced is treated with a suitable strong base. to form an alkylated propargylamine carbanion, and the second carbanion intermediate is reacted with a suitable acylating agent, followed by hydrolysis, and the alkylation and acylation reactions are carried out in a suitable solvent. at about -120°C to 25°C for about 1/2 hour to 24 hours, and if necessary, reacting with a pharmaceutically acceptable acid or salt. [wherein R ₄ is a hydrogen atom, hydroxy, or lower alkoxy, and R ₅ is a hydrogen atom or hydroxy] and a method for producing a pharmaceutically acceptable salt.