JPS6326101B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to pharmaceutically useful α-halomethyl amino acid derivatives that are aromatic amino acid decarboxylase inhibitors. 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. , 4-dihydroxyphenylethylamine or dopamine, tyramine and phenethylamine. Aromatic amino acid decarboxylase enzymes are believed to be nonspecific, especially as far as peripheral catalysis is concerned. However, there is evidence that specific decarboxylases exist in the brain for each of DOPA and 5-hydroxytryptophan. The aromatic amines listed above are known to be involved in various pathophysiological processes. For example, tryptamine, the decarboxylation product of tryptophan, is methylated to monomethyltryptamine by the action of enzymes in human red blood cells, plasma, and platelets, and then further methylated by the action of enzymes to dimethyltryptamine (DMT). It was discovered that Methytransferases are present in many mammalian species and have been shown to be produced in the brain tissue of several species, including humans. DMT is a powerful hallucinogen or psychotic and is responsible for schizophrenia and other mental illnesses. Therefore any drug that stops the production of DMT may be useful as an antipsychotic. Stopping tryptophan decarboxylation results in decreasing tryptamine levels and removing the substrate for DMT formation. Aromatic amino acid decarboxylase inhibitors that stop the conversion of tryptophan to tryptamine may therefore be useful as antipsychotics. 5-hydroxytryptamine (5-hydroxytryptamine) is a decarboxylation reaction product of 5-hydroxytryptophan.
HT) and DOPA decarboxylation reaction product 3,
4-dihydrotoxyphenethylamine (dopamine)
Both are related to peripheral and central physiological processes;
Agents effective in controlling the levels of these amines have resulted in useful pharmacological agents.
Central or brain levels of norepinephrine, which is produced metabolically by hydroxyphenylation of 5-HT and dopamine, have been shown to be higher in patients with manic disorders than in individuals without such disorders.
Also, drugs that reduce central levels of monoamines, such as 5-HT and norepnephrine in particular, have antimanic properties when administered to human subjects;
On the other hand, it has also been shown that drugs that increase monoamine levels can promote mania in susceptible individuals.
Therefore, agents that stop the production of 5-HT and dopamine include, for example, 5-hydroxytophane and DOPA
It may be useful as an antipsychotic or medial tranquilizer in the treatment of manic disorders by inhibiting aromatic amino acid decarboxylase that adds to 5-HT and dopamine, respectively. Agents useful for inhibiting the decarboxylation of DOPA to dopamine have also been shown to be useful in treating parkinsonism when administered concurrently with exogenous DOPA or L-DOPA. DOPA or L-
Because exogenous administration of DOPA is known to be useful in treating parkinsonism, it is believed that parkinsonism is due, at least in part, to decreased central levels of dopamine. There is. However, since exogenously administered KOPA is easily enzymatically converted to dopamine in the periphery, large doses are required to increase central absorption. DOPA easily penetrates the blood-cerebrospinal fluid barrier, but dopamine does not.
Administration of DOPA or L-DOPA in combination 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 adequate circulating levels for central absorption. Decrease the amount. Other benefits may also be obtained by administering aromatic amino acid decarboxylase inhibitors with L-DOPA. Prevention of dopamine production in the periphery can prevent dopamine-induced cardiac arrhythmia,
Side effects such as nausea and vomiting can be prevented. Studies have shown that levels of 5-hydroxytryptamine (5-HT) are lower in patients with depressive syndromes than in individuals without such conditions. Administration of exogenous L-5-hydroxytryptophan (L-5-HTP) is effective in treating certain depressive patients. However, as in the case of DOPA,
Because L-5-HTP is readily metabolized to 5-HT in the periphery, it is necessary to administer large amounts of L-5-HTP to increase central levels of the amino acid. 5-HTP to 5- in the periphery
The amount of exogenous 5-5-mg required to provide increased central levels by administration of an inhibitor of the aromatic amino acid decarboxylase enzyme that catalyzes the production of HT.
It was shown that the amount of HTP was significantly reduced. In other words, inhibitors of aromatic amino acid decarboxylase have been shown to be useful in treating depression when used in conjunction with exogenous 5-HTP. Agents that stop the conversion of 5-HTP to 5-HT in the periphery may also be useful in treating other conditions that respond to increased central levels of 5-HTP as a result of exogenous administration of 5-HTP. sell. Exogenous L-5
-HTP has been shown to be useful in the treatment of clonic muscle spasms. Studies have also shown that administration of exogenous 5-HTP is useful in the treatment of insomnia; therefore, co-administration of 5-HTP and aromatic amino acid decarboxylase inhibitors may be advantageous in treating these conditions. It can be. Stopping the production of 5-hydroxytryptamine in the periphery, as 5-HT is known to be involved in the pathogenesis of, for example, rheumatoid arthritis and carcinomatoid syndromes due to increased collagen levels. may result in other beneficial effects. Also 5-
HT is the main autocoid responsible for anaphylaxis-like reactions in human subjects and bronchial obstruction in human subjects with asthma, and 5-HT
Drugs that antagonize 5-HT or inhibit the production of 5-HT are said to be useful in treating this condition. 5-
HT is known to cause platelet aggregation and has been implicated as a causative factor in rapid migration syndrome and migraine after gastrectomy. Methylsurgaide, a 5-hydroxytryptamine antagonist, has been demonstrated to be effective in the treatment of rapid migration syndrome after gastrectomy. Phenethylamine, a decarboxylation product of phenylalanine, has been suggested as an endogenous compound to contribute to the symptoms of schizophrenia and to cause migraines. Endogenous tyramine, a product of tyrosine decarboxylation, has also been shown to contribute to epileptic seizure disorders. It is therefore clear that agents useful for controlling the levels of aromatic amino acids and amines will find use in many pharmacological situations. The compounds of the present invention are useful inhibitors of aromatic amino acid decarboxylase, which converts tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine, tyrosine, and phenylalanine into their respective amines. to provide effective pharmacological agents. The compound of the present invention is represented by the following general formula (). formula [In the formula, Y is _F2CH- or _ClCH2- , _R2 is a hydroxy group or lower alkoxy group, Y,
R ₃ , R ₄ , R ₅ , R ₄ ' and R ₆ have the meanings defined in Table 1. ]

Also included within the scope of this invention are pharmaceutically acceptable salts of compounds of general formula () (R ₁₀ is alkyl of 1 to 8 carbon atoms). The compounds of general formula () are useful pharmacological agents in that they are inhibitors of aromatic amino acid decarboxylase and are useful as intermediates in the production of useful pharmacological agents. Examples of lower alkoxy groups are methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy. Examples of straight-chain or branched alkyl groups having 1 to 8 carbon atoms are methyl, ethyl, n
-propyl, isopropyl, n-butyl, tert-butyl and n-pentyl. Examples of pharmaceutically acceptable salts of the compounds of the invention are inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric acids, and organic acids such as methanesulfonic acid,
Non-toxic acid addition salts formed with salicylic, maleic, malonic, tartaric, citric, and ascorbic acids, and inorganic or organic bases, such as alkali metals such as sodium, potassium, and lithium, alkalis such as calcium, magnesium, etc. non-containing compounds formed with earth groups, light metals of group A such as aluminium, primary, secondary or tertiary amines, bases such as cyclohexylamine, ethylamine, pyridine, methylaminomethanolethanolamine and piperidine; Includes toxic salts.
Salt is made by conventional means. The compound of the present invention is more preferably a compound in which R ₂ in the general formula () is a hydroxy group. The compound of general formula () is tryptophan, 5-
Metabolically catalyzes the conversion of hydroxytryptophan, 3,4-dihydroxyphenylalanine, tyrosine, and phenylalanine to tryptamine, 5-hydroxytryptamine, 3,4-dihydroxyphenylethylamine, tyramine, and phenethylamine, respectively. It is an irreversible inhibitor of the acting enzyme. As already mentioned, studies have shown that the enzymes that peripherally convert the amino acids listed above to their respective amines are nonspecific aromatic amino acid decarboxylases. For central conversion, research shows that specific decarboxylase
- converting each of hydroxytryptophan and 3,4-dihydroxyphenylalanine,
The remaining amino acids listed above are converted to their respective amines by a nonspecific aromatic amino acid decarboxylase. The compounds of the invention are effective in irreversibly inhibiting the activity of nonspecific aromatic amino acid decarboxylase and the activity of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase both centrally and peripherally. It is. As used herein with respect to the usefulness of the compounds of the present invention, the term central refers to the central nervous system, primarily the brain, whereas the term peripheral refers to other body tissues where carboxylase enzymes are present. . The selectivity with which amino acid decarboxylase is centrally or peripherally inhibited by administration of the compound of general formula () depends on the dose. aromatic amino acid decarboxylase and
As irreversible inhibitors of DOPA decarboxylase, the compounds of this invention have many pharmacological utilities. Compounds of general formula () as peripheral irreversible inhibitors of aromatic amino acid decarboxylase include 3,4-dihydroxyphenylalanine (DOPA) or L-3,4-dihydroxyphenylalanine (L- When administered with DOPA), it is useful in the treatment of Parkinsonism. DOPA and its more particularly active isomer, L-DOPA, usually contain 0.5 to 1
It is known to be effective in the treatment of Parkinson's disease patients when administered systemically in doses up to 8 grams per day, with the dose then gradually increased over 3 to 7 days to a maximum tolerated daily dose of 8 grams. ing.
If the activity of the general formula () and L-DOPA are administered simultaneously, the activity of the general formula () will be reduced in the periphery by inhibiting the activity of aromatic amino acid decarboxylase enzyme. Provides an improved treatment for Parkinson's syndromes in that it blocks the decarboxylation reaction to dihydroxyphenethylamine (L-dopamine), thus preserving high circulating levels of L-DOPA for central absorption. ,
It also prevents peripheral production of increased levels of dopamine, which is known to cause certain undesirable side effects such as cardiac arrhythmias. General formula ()
If the compound and L-DOPA are administered simultaneously,
The dosage of L-DOPA can be reduced by a factor of 2 to 10 compared to the amount required for the application when administered alone. Preferably, the compounds of the invention are administered prior to administration of L-DOPA. For example, compounds of formula () may be
- Can be administered 30 minutes to 4 hours before administering DOPA. Compounds of general formula () may also be referred to as 5-hydroxytryptopamine (5-HTP) or, more specifically, an active levorotatory compound known to be useful in the treatment of depressive disorders when administered systemically. It is also useful in the treatment of depressive disorders when given together with the isomer. The compound of general formula () inhibits the activity of aromatic amino acid decarboxylase in the periphery, thereby stopping the conversion of 5-hydroxytryptophan to 5-hydroxytroptamine, and inhibiting the central absorption of 5-hydroxytryptophan. - Will maintain higher circulating levels of HTP. When a compound of general formula () is administered with exogenous 5-HTP,
- Useful in the treatment of clonic muscle spasms, known to be effective by increasing central levels of HTP. Because the compound of general formula () has an inhibitory effect on aromatic amino acid decarboxylase in the periphery, it is associated with rheumatoid arthritis, arthritis, carcinomatosis, anaphylactic reactions in humans, bronchial stenosis in people with asthma, and 5 - Useful in the treatment of other conditions known to be caused by high peripheral levels of hydroxytryptamine. As previously shown herein, agents that reduce elevated levels of 5-HT and norepinephrine, a hydroxylation product of dopamine, are useful in treating patients with manic disorders. Therefore, as central irreversible inhibitors of aromatic amino acid decarboxylase and DOPA decarboxylase, compounds of general formula () are useful in the treatment of manic disorders. Furthermore, the central inhibitory effect of the compound of general formula () on aromatic amino acid decarboxylase reduces central levels of tryptamine, making this compound potentially useful as an antipsychotic. Administration of compounds of general formula () reduces central levels of phenethylamine and tyramine, making them useful in the treatment of schizophrenia and epileptic seizure disorders. The usefulness of the compound of general formula () as an irreversible inhibitor of aromatic amino acid decarboxylase is demonstrated as follows. A compound of general formula () is administered to rats or mice as an aqueous solution or suspension. From 1 to 48 hours after administration, animals were killed by decapitation at different time intervals and the activity of aromatic amino acid decarboxylase was determined by Burkard.
Kidney, heart, and brain prepared by Kard) and other Archives of Biochemistry and Biophysics [(Arch. Biochem Bio Phys.) Vol. 107, p. 187 (1964)] according to the method described by Christenson et al. in the Archives of Biochemistry and Biophysics [(Arch. Biochem Bio Phys.) vol. 141, p. 356 (1970). Measured by radiometric methods. The compounds of the invention may be administered in a variety of ways to achieve the desired effect. The compounds are administered to the patient to be treated, either parenterally or parenterally, either alone or in the form of a pharmaceutical preparation, eg, subcutaneously, intravenously or intraperitoneally. The compounds can also be applied to mucous membranes, such as those of the nasal cavity, throat, bronchi, etc., by intranasal instillation or as an atomized or dry powder containing small particles of the novel compounds of the invention in a spray solution. It can be administered by The dosage of the novel compounds can vary and be any effective amount. The amount administered of the novel compounds may vary over a wide range depending on the patient, the condition being treated, and the mode of administration to provide an effective amount in unit dosage form. When a compound of general formula (1) is administered to affect irreversible inhibition of aromatic decarboxylase in the periphery, the effective amount of the compound administered is about 0.1 mg/Kg of patient body weight per administration.
It varies from 100mg/Kg to about 5mg/Kg to 25mg/Kg.
Preferably up to Kg. For example, the desired peripheral effect may be achieved by administering the novel compounds of the invention for example from 10 to 250
1 to 4 doses per day, such as tablets containing mg/Kg.
It can be obtained by taking multiple doses and consuming it. When a compound of general formula (1) is administered to obtain central irreversible inhibition of aromatic decarboxylase or 3,4-dihydroxyphenylalanine decarboxylase, the effective dosage of the compound per day is 25mg/Kg to 500mg/kg of body weight
up to Kg, preferably about 150 mg/Kg to 300 mg/Kg. For example, the desired central effects can be obtained by consuming the novel compounds of the invention in unit dosages, such as tablets, containing from about 300 mg to 500 mg, taken one to four times per day. As used herein, the term patient refers to mammals such as cats, dogs, rats, mice, guinea pigs, sheep,
It is used to refer to warm-blooded animals such as horses, cows, and humans. Unit dosages of solids may be conventional. Therefore, the solid form is suitable for the novel compounds of the present invention and the carrier;
Capsules may be of the usual gelatin type, for example containing a lubricant and inert fillers such as lactose, sucrose and corn starch. In another embodiment, the novel compounds can be prepared using conventional tablet bases such as lactose, sucrose or corn starch, with binders such as gum arabic, corn starch or gelatin, and with binders such as corn starch, potato starch or alginic acid. A disintegrant and a lubricant such as stearic acid or magnesium stearate may be combined to form a tablet. For parenteral administration, the compounds may be administered with or without pharmaceutical carriers, which can be sterile liquids such as water and oils, with or without the addition of surfactants and other pharmaceutically acceptable excipients. may be administered as a suitable injectable solution or suspension of the compound in a physiologically acceptable diluent. Illustrative oils that can be used in these formulations are petroleum, animal and vegetable oils, synthetic sources such as peanut oil, soybean oil and mineral oil. In general, water, saline, aqueous dextrose, related sugar solutions, ethanol, and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions. The compounds may also be administered in the form of depot injections or implants that may be formulated in such a manner as to permit sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as a depot injection or implant.
The implant may be an inert material such as biodegradable polymers or synthetic silicones, such as Silastic, silicone rubber manufactured by Dow Corning. For use as aerosols, the novel compounds in solution or suspension can be used as gaseous or liquefied propellants such as dichlorodifluoromethane, mixtures of dichlorodifluoromethane and dichlorodifluoroethane, carbon dioxide, nitrogen or propane and as necessary or desired. It is filled into a pressurized atomized container along with the usual adjuvants such as co-solvents, wetting agents, etc. The compounds may also be administered in non-pressurized form in a nebulizer, atomizer, and the like. As shown previously, the compound of general formula (1)
- Has particular utility when administered with DOPA. In this case, the compound of general formula (1) and L-
Each individual formulation of DOPA can be administered or both active ingredients can be formulated into a single combined pharmaceutical formulation. In either mode of administration, the general formula
The amount of compound (1) will vary from about 1:1 to 1:10 compared to the amount of L-DOPA. The combination formulation may contain an inner layer containing L-DOPA and an outer layer containing a compound of general formula (1), each active ingredient being formulated appropriately. Particularly suitable combination formulations are
L-DOPA is compressed into a core material, optionally with a suitable carrier, and this core material is provided with a gastric juice-resistant laminated coating, containing a suitably formulated compound of general formula (1) on the coated core material. manufactured by applying an outer layer of Using such a combination formulation, the decarboxylase inhibitor, ie the compound of general formula (1), is
It is preferably released 30 to 60 minutes before DOPA is released. Laminated coatings may be formed by the use of non-aqueous solutions of glycerides or water-insoluble polymers such as ethyl cellulose or cellulose acetate phthalate. Enteric coated formulations of L-DOPA with a mixture of shellac, shellac derivatives and cellulose acetate phthalate are also used. Illustrative examples of suitable pharmaceutical formulations are described in the specific examples included below. In addition to being useful pharmacological agents, compounds of general formula (1) are also useful as intermediates for the production of useful cephalosporin antibiotics. A compound of general formula (1) in which R ₂ is a hydroxy group is useful for producing a cephalosporin derivative of general formula () below. In the above general formula (), R ₁ is hydrogen, Y,
R ₃ , R ₄ , R ₅ , R' ₄ and R ₆ have the meanings defined in the general formula (); M is hydrogen or negatively charged;
is hydrogen or acetoxy. The compounds of general formula () and their pharmaceutically acceptable salts and individual optical isomers are novel compounds useful as antibiotics, and include many well-known cephalosporin derivatives, such as cephalexin, cephalothin or cephaloglycine. etc. is used in a similar manner. Compounds of general formula () and their pharmaceutically acceptable salts and isomers can be administered either orally or parenterally and topically to warm-blooded animals, namely birds and mammals, alone or in the form of mixed preparations.
For example, it can be administered to cats, dogs, cattle, sheep, horses and humans. For oral administration, the compounds may be administered in the form of tablets, capsules or pills or elixirs, suspensions, and the like. For parenteral administration, the compounds may best be used in the form of sterile aqueous solutions that may contain other solutes, such as sufficient salts or glucose to make the solution isotonic. For local administration,
Compounds of general formula () and their salts and isomers may be incorporated into creams or ointments. Exemplary bacteria against which the compound of general formula () and its pharmaceutically acceptable salts and individual optical isomers exhibit activity include Sthphylococcus aureus, Salmonella shoots Salmonella schotmuelleri), Klebuella pneumoniae
pneumoniae), Diplococcus pneumoniae and Streptococcus pyogenes
pyogenes). Exemplary pharmaceutically acceptable non-toxic inorganic acid addition salts of compounds of general formula () include, for example, the hydrochloride,
Hydrobromide, sulfate, sulfamate, phosphate; organic acid addition salts such as maleate, acetate, citrate, oxalate, succinate, benzoate, tartrate, fumarate. acid salts, malate and ascorbate. Salts are produced by conventional methods. Compounds of the general formula () where R ₁ is hydrogen are of the formula () (X and M have the meanings defined in the general formula ()) or a functional derivative thereof, such as an acid chloride or acid anhydride, and when the free acid is used, in the presence of a dehydrating agent such as dicyclohexylcarbodiimide. R ₃ , R ₄ , R ₅ of the compound of general formula (),
R′ ₄ and R ₆ have the meanings defined in the general formula (), the amino group is protected by a suitable blocking group such as tert-butoxycarbonyl,
Removed by acid hydrolysis. The coupling reaction is generally carried out in the presence of a base such as an alkali bicarbonate in a solvent of ethyl acetate, dioxane, chloroform or tetrahydrofuran. The reaction temperature can vary from -10°C to 100°C. Reaction times can vary from about 1/2 to 10 hours. The cephalosporin product is isolated in a conventional manner. Compounds of general formula () are prepared by the methods described herein above, and compounds of general formula () are commercially available or prepared by methods well known in the art. Compounds of general formula (1) as defined in Table 1 are represented by the appropriately protected formula () phenylproonic acid ester is treated with a strong base to produce a carbanion, which is then treated with a suitable halomethyl alkylating agent and then acid hydrolyzed. In the above general formula (), R _a is a linear or branched alkoxy group having 1 to 8 carbon atoms, R _b is hydrogen,
phenyl, straight-chain or branched alkyl group of 1 to 8 carbon atoms, methoxy or ethoxy;
R _c is phenyl or a linear or branched alkyl group of 1 to 8 carbon atoms; or R _b and R _c taken together are an alkylene group of 5 to 7 carbon atoms, i.e. -CH ₂ −(CH ₂ ) _n −CH ₂ −(m is 3
to 5). Illustrative straight-chain or branched alkyl groups of 1 to 8 carbon atoms represented by R _b and R _c include methyl, ethyl,
n-propyl, isopropyl, n-butyl, tert-butyl, n-hexyl, n-octyl, and netipentyl. R ₁₁ , R ₁₂ , R ₁₃ , R′ ₁₂ and R ₁₄
correspond to R ₃ , R ₄ , R ₅ , R′ ₄ , and R ₆ , respectively. Suitable strong bases that can be used in the above reaction sequence to form the carbanion intermediate are those that abstract a proton from the carbon atom α to the carboxyl group, and include alkyllithiums such as butyllithium or phenyllithium, lithium dialkylamides, such as lithium diisopropylamide, or lithium amide, tertiary potassium butyrate,
Sodium amides, metal hydrides such as sodium hydride or potassium hydride, tertiary amines such as triethylamine, lithium acetylide or dilithium acetylide. Lithium acetylide, dilithium acetylide, sodium hydride and lithium diisopropylamide are particularly preferred bases. A suitable halomethyl alkylating agent for use in the above reaction is chlorofluoromethane and the like.
Halomethyl alkylating agents are known. The alkylation reaction is carried out in a neutral solvent such as benzene, toluene, ethers, tetrahydrofuran, dimethylsulfoxide, or hexamethylphosphortriamide. The reaction temperature is from about -120°C to about 65°C, with a preferred reaction temperature of about 40°C. Reaction time is approximately 1/2 hour to 24 hours
Even time will change. Acid hydrolysis to remove unreacted starting materials and protecting groups is carried out in one step or in stages. 1
The concentration of acid used in staged hydrolysis obviously varies depending on the duration and temperature of the hydrolysis step. For example, one-step hydrolysis uses concentrated hydrochloric acid to
This is achieved by processing from 25°C to 120°C for 1 to 4 days. Stepwise hydrolysis is about 1/2 with dilute acid
Treat at about 25°C for up to 6 hours to remove unreacted starting materials, repeat treatment with dilute hydrochloric acid to remove amine protecting groups, and then treat with concentrated acid at about 25°C to 125°C for about 1 to 3 days. to exclude ester and ether groups. Stepwise hydrolysis is preferred. R ₂ is a hydroxy group, R ₃ , R ₄ , R′ ₄ or R ₅ is OR ₁₀
The compound of general formula (1) in which R ₁₀ is hydrogen is R ₃ , R ₄ ,
From the corresponding derivative in which either R′ ₄ and R ₅ is OR _{10 and} R ₁₀ is a methyl group, it is treated with hydrobromic acid in water or acetic acid at about 25° C. to 125° C. for about 4 hours to 24 hours. obtained by doing. General where R ₂ is a hydroxy group, any of R ₃ , R ₄ , R′ ₄ or R ₅ is OR ₁₀ and R ₁₀ is a straight or branched alkyl group of 1 to 8 carbon atoms; Compounds of formula (1) are prepared by combining the corresponding derivatives in which R ₁₀ is hydrogen, R ₂₁ is a straight-chain or branched alkyl group of 1 to 8 carbon atoms, and Y ₂ is halogen, for example bromine or iodine. An alkyl halide of formula R ₂₁ Y ₂ in the presence of an organic base such as triethylamine or pyridine, in a lower alcoholic solvent such as methanol or ethanol, or in a hydrocarbon solvent such as benzene or toluene, or in the presence of sodium hydride, It is prepared by alkylation in a neutral solvent such as dimethylformamide or dimethyl sulfoxide at about 25°C to 85°C for about 1 to 24 hours, followed by hydrolysis with aqueous base. In this case, before the alkylation reaction, the α-amino group and optionally the carboxyl group of the hydroxy-substituted starting material are each protected by a suitable protecting group, such as tert-butoxycarbonyl or benzyloxycarbonyl and benzyl group, These protecting groups are later removed by hydrogenolysis or treatment with an acid such as trifluoroacetic acid. The alkyl halides used in this procedure are known or can be made by procedures known in the art. The compound of general formula (1) in which R ₂ is a lower alkoxy group is obtained by treating the corresponding derivative in which R ₂ is hydroxy with thionyl chloride to form an acid chloride;
R ₂₃ is an alcohol with lower alkyl formula R ₂₃ OH and about 25
It is prepared by reacting at ℃ for about 4 to 12 hours. The individual optical isomers of the compound of general formula (1) where R ₁ is hydrogen and R ₂ is OH are defined by the tetrahedron letters.
R. described in Volume 48, Page 4617 (1971). Separated using (+) or (-) binaphthyl phosphate by the method of R. Viterbo et al. Other resolving agents such as (+)camphor-10-sulfonic acid may also be used. The individual optical isomers of compounds of general formula (1) in which R ₁ and R ₂ are other than H and OH, respectively, start with the amino acids simply resolved as described herein for the racemate. can be obtained. Compounds of general formula () have the formula () in which R _a , R _b and R _c have the meanings defined in general formula () of glycinate, an alkyllithium such as butyllithium or phenyllithium, a lithium dialkylamide such as lithium diisopropylamide, or a metal hydride such as lithium amide, tertiary potassium butyrate, sodium amide, sodium hydride, After treatment with a tertiary amine such as triethylamine, one equivalent of a strong base such as lithium acetylide or dilithium acetylide, R ₁₁ , R ₁₂ , R ₁₃ , R′ ₁₂ and R ₁₄ in formula () Formula () having the defined meaning and in which Xa is a halogen atom, such as chlorine or bromine is produced by treatment with an alkylating agent. The alkylation reaction is carried out in a neutral solvent such as benzene, ethers, tetrahydrofuran, dimethyl sulfoxide or hexamethylphosphortriamide. Reaction time starts from about 1/2 hour
The reaction temperature changes from about -120°C to 25°C in up to 24 hours. Compounds of general formula () are prepared by treating suitable alkylglycinates to form Schiff's bases in a manner generally known for carbonyl-containing compounds, in particular (a) R _b is hydrogen, a suitable amino acid ester is substituted with benzaldehyde or a linear or branched alkanal having 1 to 9 carbon atoms, such as 1-propanal, 1-butanal, 2,2-dimethylpropan-1-al. or 2,2-diethylbutane-
(b) When R _b is phenyl, a suitable amino acid ester is added to a benzophenone or a straight or branched phenyl alkyl ketone in which the alkyl moiety has from 1 to 8 carbon atoms. ,
For example, phenyl methyl ketone, phenylethyl ketone, phenyl isopropyl ketone, phenyl-
n-butyl ketone or phenyl-tert-butyl ketone, and (c) when R _b is a straight-chain or branched alkyl group having from 1 to 8 carbon atoms, the appropriate amino acid ester is Similarly, phenyl alkyl ketones can be treated with straight-chain or branched dialkyl ketones in which each alkyl moiety has from 1 to 8 carbon atoms, such as dimethyl isopropyl ketone, di-n-butyl ketone or methyl tert-butyl ketone. built. Carbonyl-containing compounds are known in the art or prepared by known procedures. In the compound of formula (), when R _b is methoxy or ethoxy, the appropriate alkylglycinate is substituted with a benzoyl halide, such as chloride, an alkanoic acid halide, such as acetyl chloride, propiolyl chloride, butyl chloride, tert-butyl chloride, Alkanoic acid chlorides and ethers, such as 2,2-diethylbutyric acid chloride or valeryl chloride, where the alkanoic acid has from 1 to 9 carbon atoms and can be linear or branched, methylene chloride, dimethylformamide, dimethyl After reacting in acetamide or chlorobenzene in the presence of an organic base such as triethylamine or pyridine at 0°C, the reaction mixture is allowed to warm to about 25°C for 1 hour. The resulting amide derivative can be treated with an alkylating agent such as methylfluorosulfonate, dimethylsulfate, methyl iodide, methyl p-toluenesulfonate or trimethyloxonium hexafluorophosphate when R _b is methoxy, or when R _b is ethoxy. The triethyloxonium tetrafluoroborate is then mixed at about 25° C. in a basic 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 and an organic base such as triethylamine or pyridine is added followed by brine extraction to isolate the product. In the compound of formula (), when R _b and R _c are taken together to form an alkylene group of 5 to 7 carbon atoms, this amino acid ester derivative can be used to convert the amino acid ester into cyclopentanone, cyclohexanone, and A cycloalkanone selected from cycloheptanone, obtained by treatment to form a Schiff base by procedures generally known in the art. Alkylglycinate is prepared by treating glycine with an alcohol of formula R _a H saturated with HCl gas at about 25°C for about 12 to 36 hours, where R _a has the meaning defined by the formula Alternatively, the compound may be obtained from commercial sources. Compounds of general formula () are known in the art or prepared from the corresponding appropriately substituted benzoic acid or benzaldehyde derivatives known in the art. For example, the benzyl halide of formula () is reduced by reducing the corresponding benzaldehyde with sodium borohydride, lithium aluminum hydride, etc., or by catalytic reduction, or by reducing the corresponding benzoic acid ester with lithium aluminum hydride or borane. , by reducing the corresponding benzoic acid derivative with lithium hydride and treating the benzyl alcohol derivative thus produced with e.g. thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride. made by. Certain compounds of general formula () can be directly converted from a suitable amino acid to a suitable ester, and then the α-amino group can be converted to an alkylglycinate amino group as previously described herein to protect the amino group. It can be obtained by protection according to the general procedure. for example,
Amino-protected derivatives of tyrosine or phenylalanine are obtained in such a manner. This procedure, however, cannot be used to prepare compounds of formula () in which the aromatic ring has a hydroxyl group in the meta position. The following Example 1 illustrates the use of a compound of general formula () in which R ₂ is a hydroxy group as a chemical intermediate in the preparation of cephalosporins of formula (). Reference example 1 7-[[2-difluoromethyl-2-amino-3
-phenylpropionyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1
-Azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid 1 g of 3-acetyloxy-7-amino-8-
Oxo-5-thia-1-azabicyclo[4.2.0]
A mixture of oct-2-ene-2-carboxylic acid and 2-difluoromethyl-2-amino-3-phenylpropionic acid chloride in which 1 g of the free amino acid is protected with tert-butoxycarbonyl is added in 50 ml of ethyl acetate. for 2 hours at reflux, the solvent was then evaporated leaving a residue which was treated with a weak acid and chromatographed on silica gel using benzene-acetone as eluent to give 7-[[2-difluoromethyl-2 -amino-3-phenylpropionyl]
Amino]-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is obtained. The following Formulation Examples 1-3 are illustrative of pharmaceutical formulations of the compounds of the present invention. Formulation Example 1 An exemplary composition for hard gelatin capsules is as follows. (a) 2-difluoromethyl-2-amino-3-
(3-Hydroxyphenyl)propionic acid 20 mg (b) Talc 5 mg (c) Lactose 90 mg The formulation is made by thoroughly mixing the dry powders of (a) and (b) through a fine mesh screen. The powder is filled into hard gelatin capsules with a net fill of 115 mg per capsule. Formulation Example 2 An exemplary composition for an injectable suspension is the following 1 ml ampoule for intramuscular injection. Weight% (a) 2-difluoromethyl-2-amino-3-
(4-Hydroxyphenyl)propionic acid 1.0 (b) Polyvinylpyrrolidone 0.5 (c) Lecithin 0.25 (d) Water for injection 100 Mix the substances (a) to (d), homogenize and fill into 1 ml ampoules, This is sealed and autoclaved at 121°C for 20 minutes. Each ampoule contains a novel compound (a)
Contains 10mg per ml. Reference example 2 Glycine methyl ester benzaldimine in 100 ml of water cooled with ice and salt as a cryogen.
25 to a stirred solution of 112g potassium carbonate
g of glycine methyl ester hydrochloride are added dropwise, after which the mixture is immediately extracted five times with ether.
The combined ether extracts were dried over magnesium sulfate and the ether was evaporated at ambient temperature.
The free base of glycine methyl ester is obtained.
21.1 g (1 equivalent) of benzaldehyde is added to a stirred solution of 17.7 g of glycine methyl ester in 150 ml of methylene chloride cooled in an ice bath. After the addition, the ice bath is removed and the mixture is stirred at room temperature for 3 hours. The methylene chloride phase is washed with saline and aqueous sodium bicarbonate solution,
Dry over magnesium sulphate and evaporate under reduced pressure. The resulting residue is evaporated at 0.3-0.5 mmHg b.
Glycine methyl ester benzaldimine at p.104°C is obtained. Reference Example 3 3,4-dimethoxybenzyl bromide To a stirred solution of 50.3 g of 3,4-dimethoxybenzyl alcohol in 500 ml of anhydrous ether at 0° C. 27.1 g (9.5 ml) of phosphorus tribromide was added slowly. It will be done. After the addition is complete, the mixture is stirred for 1 hour at room temperature and then poured into a solution of 56 g of potassium carbonate in 50 ml of water. The ether phase is separated, dried over magnesium sulfate and evaporated to give 3,4-dimethoxybenzyl bromide recrystallized from petroleum ether at bp 35-60°C. Reference example 4 2-amino-2-difluoromethyl-3-(3,
4-Dihydroxyphenyl)propionic acid (A) 25 ml (2.05 M) n- in diisopropylamine (53 ml, 1N solution in tetrahydrofuran)
Butyllithium is added at −78° C. with stirring under nitrogen. After a few minutes, the mixture is treated with a solution of benzaldimine glycine methyl ester (8.85 g, 50 mmol) in 50 ml of anhydrous tetrahydrofuran. After a few more minutes, a solution of 11.52 g (50 mmol) of 3,4-dimethoxybenzyl bromide dissolved in 80 ml of anhydrous tetrahydrofuran is added very slowly within an hour at a temperature maintained at -78 DEG. The cooling bath is then removed and the stirred mixture is allowed to return to room temperature for two and a half hours. Then the mixture is again −78
diisopropylamine (62 ml,
1 molar solution in tetrahydrofuran) and n-butyllithium (27.2 ml, 2.05 mol). The cooling bath is then removed to 45°C to 50°C.
It can be replaced with a warm water bath. The temperature of the reaction mixture is 45
When ~50°C is reached, a rapid stream of chlorodifluoromethane is bubbled through the stirred solution for 1 hour while stirring. The cooled mixture was diluted with ether and washed three times with brine,
Dry over magnesium sulfate and evaporate to obtain crude α-difluoromethyl-3,4-dimethoxyphenylalanine-N-benzaldimine methyl ester. (B) Crude α-difluoromethyl-3 obtained above,
100 4-dimethoxyphenylalanine-N-benzaldimine methyl ester (17.5 g)
6 ml of ether and 250 ml of 1N hydrochloric acid at room temperature.
Stir for an hour. The ether phase is separated off. The aqueous phase is washed five times with methylene chloride and evaporated to dryness under reduced pressure. The residue was refluxed with concentrated hydrobromic acid (250 ml, 47%) under nitrogen overnight.
The solution is then evaporated to dryness and the residue is treated twice successively with water and isopropanol, each solution being evaporated to dryness after each treatment. A nitrogen atmosphere is maintained during this and subsequent steps to prevent oxidation of the catechol. The residue in 250ml of water is decolorized with acid-washed activated carbon and filtered to about 75ml.
concentrated in The pH of the solution is adjusted to 4.5-4.8 using triethylamine, then 300 ml of acetone is added. The formed precipitate was collected, washed with chloroform, and recrystallized from water/ethanol (1:5) to give 2-amino-2-
Difluoromethyl-3-(3,4-dihydroxyphenyl)propionic acid mp>250°C or higher is obtained. Reference Example 5 Methyl 2-benzaldoimine-3-(4-hydroxyphenyl)propionate 5.3 g of a cooled suspension of 11.58 g (50 mmol) of tyrosine methyl ester hydrochloride in 300 ml of methylene chloride (50 mmol) of benzaldehyde was added to 5.05 methylene chloride.
A solution of g (50 mmol) of triethylamine is added dropwise. The reaction mixture is stirred at room temperature overnight and concentrated under reduced pressure to give a residue which is extracted with ether. Crystallization from a methylene chloride/pentane mixture is carried out in a conventional manner to obtain methyl 2-benzaldoimine-3-(4-hydroxyphenyl)propionate, mp 109-111°C. Reference example 6 2-chloromethyl-2-benzaldoimine-
Methyl 3-(4-hydroxyphenyl)propionate Lithium diisopropylamide (8 mmol) prepared in situ from a solution of 1 molar diisopropylamine in tetrahydrofuran and 2 molar butyllithium in hexane in tetrahydrofuran and hexamethylphosphorol Stirred solution (cooled to -78°C) in amide (2.5ml)
A solution of 1.132 g (4 mmol) of methyl 2-benzaldoimine-3-(4-hydroxyphenyl)propionate in 30 ml of tetrahydrofuran is added slowly under a nitrogen atmosphere. The cooled reaction mixture is stirred at −78° C. for 1/2 hour before a solution of chlorobromopropane (1.05 g, 8 mmol) in tetrahydrofuran is added. The temperature is gradually increased to room temperature and stirring is continued overnight. The reaction mixture is cooled with water and extracted with ether. Recrystallization from an ether/pentane mixed solution is carried out in a conventional manner to obtain methyl 2-chloromethyl-2-benzaldimine-3-(4-hydroxyphenyl)propionate, mp 50°C or less. Example 1 2-Amino-2-chloromethyl-3-(4-hydroxyphenyl)propionic acid (A) 645 mg of 2-chloromethyl-2-benzaldoimine-3-(4-hydroxy) in 10 ml of ether. Methyl phenyl propionate solution is 10
Stir vigorously with ml of 1N hydrochloric acid at room temperature for 2 1/2 hours and then extract with ether. The aqueous phase was concentrated under reduced pressure to form an oily residue of 2-amino-
Methyl 2-chloromethyl-3-(4-hydroxyphenyl)propionate is obtained. (B) 450 ml (1.6 mmol) of 2 in 10 ml of concentrated hydrochloric acid
The methyl-amino-2-chloromethyl-3-(4-hydroxyphenyl)propionate hydrochloride solution is refluxed for 15 hours. The brown solid obtained by concentration under reduced pressure is taken up in dilute hydrochloric acid and decolorized with activated carbon, after which the solvent is evaporated and the residue is dried in vacuo to give a white solid powder. This is water 2
washed twice and 2-amino-2-chloromethyl-3
-(4-hydroxyphenyl)propionic acid m.
p.Produces 256℃. Reference example 7 2-difluoromethyl-3-(3,4-dihydroxyphenyl)-2-(benzyloxycarbonylamino)propionic acid 2-difluoromethyl-2-amino-3-(3,
30 ml of 2-difluoromethyl-2-(benzyloxycarbonylamino)-3-(3,4-dihydroxyphenyl)propionic acid (6 g) prepared from 4-dihydroxyphenyl)propionic acid and benzyl chloroformate ester 2N aqueous sodium hydroxide and acetic anhydride (3.5 g) were added simultaneously under argon for 30 min to maintain the PH between 6.5 and 7.5 in 1 M aqueous sodium hydroxide. After 1 hour at 25°C, the pH is adjusted to 1 using 6N sulfuric acid and extracted with methylene chloride. The organic phase was dried and concentrated to give 2-difluoromethyl-3
-(3,4-dihydroxyphenyl)-2-(benzyloxycarbonylamino)propionic acid is obtained. Reference example 8 2-difluoromethyl-2-(acetylamino)
-3-(3,4-dihydroxyphenyl)propionic acid 2.47 g (10 mmol) of 2-(3,4-dihydroxyphenyl)propionic acid in a stirred solution of 6.8 g of borax in 10 ml of water under argon.
difluoromethyl-2-amino-3-(3,4-
dihydroxyphenyl)propionic acid is added. After 15 minutes, the PH is adjusted to 9 by adding 2N sodium hydroxide and 780 mg of acetyl chloride is added dropwise while the PH is maintained between 9.0 and 9.5.
The aqueous solution is washed with ether, adjusted to a pH of 1 using 6N sulfuric acid, and extracted with methylene chloride. The organic phase was dried and concentrated to give 2-difluoromethyl-2-(acetylamino)-3-(3,4
-dihydroxyphenyl)propionic acid is obtained. This is treated with methanolic hydrochloride to give the corresponding methyl ester. Reference example 9 2-[2-difluoromethyl-2-amino-3
-(3,4-diacetyloxyphenyl)-1-oxopropylamino]propionic acid 2-difluoromethyl-2-amino-3-(3,
2 prepared from 4-diacetyloxyphenyl)propionic acid and chloroformic acid benzyl ester
50 ml of 4.66 g (10 mmol) of -difluoromethyl-2-(carbobenzyloxyamino)-3-(3,4-diacetyloxyphenyl)propionic acid
A solution of in ether is treated with 1.0 g (10 mmol) of triethylamine followed by 1.08 g (10 mmol) of ethyl chloroformate. After 1 hour at 25° C., the precipitate is filtered off and a solution of alanine benzyl ester (10 mmol) in 30 ml of ether is added to the ether solution. The solution is kept at 25°C overnight and then evaporated to dryness. The residue is treated with HBr in dioxane (40% W/W, 20 ml) at 25° C. for 30 minutes. Ether was added and the precipitated hydrobromide salt was filtered off to give 2-[2-difluoromethyl-2-amino-3-(3,4-diacetyloxyphenyl)-1-oxopropylamino].
Propionic acid is obtained. Reference example 10 2-difluoromethyl-2-(2-amino-1
3.56 g (10 mmol) of 2-difluoromethyl-2-amino-3 in 50 ml of methylene dichloride
- A suspension of (3,4-dihydroxyphenyl)propionic acid benzyl ester is treated with 1 g (10 mmol) of triethylamine and then 10 mmol of N-carbobenzyl whose acid function is activated with an ethoxycarbonyl group. of oxyalanine,
A solution in 10 ml of methylene chloride is added.
The mixture is stirred at 25° C. for about 16 hours and then washed with water. The organic phase is dried and evaporated. The residue is taken up in ether and the ether solution is cooled to 0°C. A vigorous stream of hydrogen chloride gas is bubbled through the solution for 3 hours, after which the ether solution is washed with water. The aqueous phase is evaporated to give 2-difluoromethyl-2-(2-amino-1-oxopropylamino)-3-(3,4-dihydroxyphenyl)propionic hydrochloride as a gum. Reference example 11 2-difluoromethyl-2-carbobenzoxyamino-3-(3,4-dihydroxyphenyl)
Propionic acid 8.2 g 2-difluoromethyl-2-amino-
A solution of 3-(3,4-dihydroxyphenyl)propionic acid and 12.7 g of borax in 80 ml of water cooled to 0°C and kept under nitrogen for 1 hour.
7.5 g of chloroformic acid benzyl ester was added dropwise;
At this time, the pH of the solution is maintained at 9 by adding a 2N aqueous sodium hydroxide solution. After the dropwise addition is completed, stirring is continued for 1 hour, and insoluble matter is filtered off. The filtrate is extracted several times with ether. The organic layer is discarded and the pH of the aqueous phase is reduced to 1 by addition of concentrated sulfuric acid while cooling.
is adjusted to Extract with ether to obtain crude 2-difluoromethyl-2-carbobenzoxyamino-3-
Produces (3,4-dihydroxyphenyl)propionic acid. 2-difluoromethyl-2-acetylamino-3-(3,
4-dihydroxyphenyl)propionic acid and 2-
Difluoromethyl-2-benzoylamino-3-
(3,4-dihydroxyphenyl)propionic acid is obtained. Reference example 12 2-(2-amino-2-difluoromethyl-3
-Phenyl-1-oxopropanamino)propionic acid To a solution of 3.15 g N-tert-butoxycarbonyl-α-difluoromethylphenylalanine in 30 ml ether was added 1.01 g triethylamine and freshly distilled A solution of chloroformic acid ethyl ester (1 g) in ethanol is added. The reaction mixture is stirred at room temperature for 3 hours and the precipitated triethylamine hydrochloride is filtered off. To the filtrate is immediately added 1.45 g of a solution of alanine tert-butyl ester in ether. The reaction mixture is kept at room temperature overnight and then evaporated to dryness. The residue is taken up in trifluoroacetic acid. The solution is concentrated and the residue is purified by ion exchange chromatography on resin to yield 2-(2-amino-2-difluoromethyl-3-phenyl-1-oxopropanamine)propionic acid. Reference example 13 2-(2-amino-1-oxopropylamino)
-2-Difluoromethyl-3-phenylpropionic acid To a solution cooled to 0°C of 2.3 g of α-difluoromethylphenylalanine in 30 ml of ether is added 2.9 g of N-benzyloxycarbonyl-O-ethoxycarbonylalanine. ) in ether is added under nitrogen atmosphere. After the addition is complete, the cooling bath is removed and stirring is continued overnight. The solution is evaporated and the syrupy residue is taken up in 5 ml of methanol and 10 ml of 2N aqueous ammonia.
The reaction mixture is stirred overnight at room temperature and then extracted several times with ether. The aqueous phase is neutralized and 2-(2-amino-1-oxopropylamino)-2-difluoromethyl-3-phenylpropionic acid is isolated by ion exchange chromatography on Amberlite 1R12OH ⁺ resin. . Example 2 2-difluoromethyl-2-amino-3-(3,
Methyl 4-dimethoxyphenyl)propionate 2-difluoromethyl- in 200 ml of ether
To a solution of methyl 2-benzaldoimine-3-(3,4-dimethoxyphenyl)propionate (30 g) is added a solution of 15 ml of 0.5M hydrochloric acid. This heterophasic mixture is stirred at room temperature for 12 hours. The organic phase is separated and then 1M hydrochloric acid (200ml) is added. After stirring the reaction mixture for 1 hour at room temperature, the aqueous phase was separated and concentrated under reduced pressure to yield methyl 2-difluoromethyl-2-amino-2-(3,4-dimethoxyphenyl)propionate hydrochloride. It will be done. Reference example 14 2-difluoromethyl-2-amino-3-(3,
4-Dihydroxyphenyl)propionic acid Methyl 2-difluoromethyl-2-amino-3-(3,4-dimethoxyphenyl)propionic acid hydrochloride (20
g) The solution is heated to reflux under nitrogen for 12 hours. The residue obtained after concentration under reduced pressure is dissolved in 30 ml of water, the pH of the liquid is adjusted to 4.5 with a solution of trimethylamine and acetone is added until precipitation begins. and 2-difluoromethyl-2-amino-3-
(3,4-dihydroxyphenyl)propionic acid dihydrate mp 260°C or higher is collected by filtration. Examples 3 to 13 In the formula (), Y, R ₂ ,
Example 3 in which R ₃ , R ₄ , R ₅ , R ₄ ′, and R ₆ are each as follows,
Compounds 4, 5, 1, 6, 7, 8, 9, 10, 11, 12 and 13 are obtained.

【table】

Claims (1)

[Claims] 1 formula [In the formula, Y is _F2CH- or _ClCH2- , _R2 is a hydroxy group or lower alkoxy group, Y,
R ₃ , R ₄ , R ₅ , R ₄ ' and R ₆ have the meanings defined in Table 1. [Table] [Table] Compounds of (R ₁₀ is alkyl of 1 to 8 carbon atoms) and pharmaceutically acceptable salts thereof. 2 2-difluoromethyl-2-amino-3-
Claim 1: (4-hydroxyphenyl)propionic acid or a pharmaceutically acceptable salt thereof
Compounds described in Section.