CN85106982A - Bicyclic compound and its preparation method - Google Patents

Abstract

The compound of general formula (I) wherein R ¹ is hydrogen, alkanoyl or aroyl; R ² is hydrogen or alkyl; R ³ is hydrogen or aryl; R ⁴ and R ⁵ are each hydrogen or R ⁴ and R ⁵ together are oxy; and Y is -CH ₂ -, -CH ₂ CH ₂ - or -N(R ⁶ )-, wherein R ⁶ is hydrogen, alkyl or aralkyl, and when R ² is hydrogen When Y is -N(R ⁶ )-, the salt formed by the compound of formula I and an acid can be used as a drug, which has antihypertensive effect and can Pharmaceutical form as a drug. The finished medicine can be prepared by known methods.

Description

The present invention relates to a bicyclic compound, a preparation method thereof, and a medicine containing the compound.

In particular, the present invention relates to bicyclic compounds having the following general formula.

Wherein R ¹ represents hydrogen, alkanoyl or aroyl; R ² represents hydrogen or alkyl; R ³ represents hydrogen or aryl; R ⁴ and R ⁵ represent hydrogen or R ⁴ and R ⁵ together represent oxy; Y represents -CH ₂ -, -CH ₂ CH ₂ - or -N(R ⁶ )- where R ⁶ represents hydrogen, alkyl or aralkyl. And when R ² represents hydrogen, the compound of general formula I and the base form a pharmaceutically acceptable salt. When Y represents -N(R ⁶ )-, the compound of formula I and the acid form a pharmaceutically acceptable salt.

The compounds of general formula I contain at least one asymmetric carbon atom. The present invention includes not only these optically identical compounds, but also racemates of various diastereoisomers and mixtures of different diastereoisomer racemates. In the compounds of general formula I, the most preferred configuration for the asymmetric carbon atom having substituents R ¹ -SC ₄ H ₂ - and R ² COO- is the (S) form.

The term "alkyl" used in this specification means a straight chain or branched chain alkyl; its carbon number is 1-8, preferably 1-4 (such as methyl, ethyl, propyl, isopropyl , butyl, tert-butyl, jonyl, hexyl, etc.). The term "aryl" means phenyl, or phenyl with one or more substituents selected from halogen, alkyl, alkoxy, trifluoromethyl, and the like. Examples of aryl are phenyl, 4-chlorophenyl, p-tolyl, 4-methoxyphenyl and the like. The term "aralkyl" means an alkyl group in which one hydrogen atom has been replaced by an aryl group. Examples of aralkyl groups are benzyl, 2-phenylethyl, 3-phenylpropyl, 4-chlorobenzyl, 4- -Methoxybenzyl and the like. The term "alkanoyl" means an alkanoyl group derived from an alkanecarboxylic acid; and the alkanecarboxylic acid contains 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, such as acetic acid, propionic acid , butyric acid, valeric acid, pivalic acid and so on. The term "aroyl" means an aroyl group derived from benzoic acid, or benzoic acid bearing one or more substituents selected from halogen, alkyl, alkoxy, trifluoromethyl, and the like. Benzoic acid such as 4-chlorobenzoic acid, p-benzoic acid, 4-methoxybenzoic acid and the like. The term "alkoxy" means an alkyl group attached to an oxygen atom, examples of alkoxy are methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, Pentyloxy, hexyloxy, etc. The term "halogen" means fluorine, chlorine, bromine, iodine.

When ^R2 represents hydrogen, the compounds of general formula I form pharmaceutically acceptable salts with bases. Examples of such salts are alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, ammonium salts and salts with organic bases such as dicyclohexylamine and the like. When Y represents -N(R ⁶ )-, the compounds of general formula I form pharmaceutically acceptable salts with acids; and examples of acids are inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) and organic acids. Acids (such as acetic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, toluenesulfonic acid, etc.).

The most preferred class of compounds provided by the present invention are those wherein R ¹ represents hydrogen, R ² preferably represents hydrogen, R ³ preferably represents hydrogen, and Y preferably represents -CH ₂ -.

From the above it is evident that particularly preferred compounds of the general formula I are those wherein R ¹ , R ² and R ³ each represent hydrogen and Y represents -CH ₂ -.

The preferred compounds of the above-mentioned general formula I are mainly:

-1-羧酸和Octahydro-9-ylmethyl-6,10-dioxo-6H-pyridazino[1,2-α]-[1,2]-diazepine

-1-carboxylic acid and

-1-羧酸Octahydro-9-ylmethyl-10-oxyl-6H-pyridazino[1,2-α]-[1,2]-diazepine

-1-carboxylic acid

Other interesting examples of compounds of general formula I are:

-1-羧酸，9-acetylthiomethyl-octahydro-6,10-dioxy-6H-pyridazino-[1,2-α][1,2]diazepine

-1-carboxylic acid,

-1-羧酸。9-acetylthiomethyl-octahydro-10-oxyl-6H-pyridazino-[1,2-α][1,2]diazepine

-1-carboxylic acid.

-1-羧酸叔丁酯和9-acetylthiomethyl-octahydro-6,10-dioxy-6H-pyridazino[1,2-α][1,2]diazepine

-1-tert-butyl carboxylate and

-1-羧酸叔丁酯。9-acetylthiomethyl-octahydro-10-oxyl-6H-pyridazino-[1,2-α][1,2]diazepine

- tert-Butyl 1-carboxylate.

In addition, some interesting examples of compounds of general formula I are:

Decahydro-10-methyl-6,11-dioxy-6H-pyridazino[1,2-α][1,2]diazaocine-1-carboxylic acid.

tert-butyl 10-acetylthiomethyl-decahydro-6,11-dioxy-6H-pyridazino[1,2-α][1,2]diazaocine-1-carboxylate.

-1-羧酸。9-acetylthiomethyl-8-benzyl-octahydro-6,10-dioxy-6H-pyridazino[1,2-α][1,2,5]triazepine

-1-carboxylic acid.

-1-羧酸。8-Benzyl-octahydro-9-ylmethyl-6,10-6H-pyridazino-[1,2-α][1,2,5]triazepine

-1-carboxylic acid.

-1-羧酸。9-acetylthiomethyl-8-methyl-octahydro-6,10-dioxy-6H-pyridazino[1,2-α][1,2,5]triazepine

-1-carboxylic acid.

-1-羧酸。Octahydro-9-ylmethyl-8-methyl-6,10-dioxy-6H-pyridazino[1,2-α][1,2,5]triazepine

-1-carboxylic acid.

-1-羧酸叔丁酯。9-acetylthiomethyl-8-benzyl-octahydro-6,10-dioxy-6H-pyridazino[1,2-α][1,2,5]triazepine

- tert-Butyl 1-carboxylate.

-1-羧酸叔丁酯和9-acetylthiomethyl-8-methyl-octahydro-6,10-dioxy-6H-pyridazino[1,2-α][1,2,5]triazepine

-1-tert-butyl carboxylate and

9-acetylthiomethyl-octahydro-6,10-dioxy-6H-pyridazino[1,2-α][1,2]diazepine - Methyl 1-carboxylate.

According to the preparation method provided by the present invention, the compounds of general formula I and their pharmaceutical salts can be prepared as follows,

a) To prepare the compound of general formula I; wherein R ⁴ and R ⁵ together represent an oxygen group, the following compound of general formula II can be reacted with the compound of general formula III; wherein R ² , R ³ , Y in general formula II has the meaning given above. R ¹ in formula III has the meaning given above.

R¹-SH Ⅲ

R ¹ -SHⅢ

or

b) for the preparation of compounds with general formula I; wherein R ¹ represents alkanoyl or aroyl, R ² represents alkyl, and Y represents -CH ₂ -, -CH ₂ CH ₂ -, or -N(R ⁶ ) -; wherein R ⁶ represents an alkyl group or an aralkyl group, which can be reacted with an alkali metal salt of a compound of general formula IV and a compound of general formula V;

In general formula IV, R ³ , R ⁴ and R ⁵ have the meanings given above, R ²⁰ represents an alkyl group, Y ¹ represents -CH ₂ -, -CH ₂ CH ₂ - or -N(R ⁶⁰ )-; wherein R ⁶⁰ represents an alkyl or aralkyl group, and Z represents the remaining group.

R ¹⁰ -SH V

In the general formula V, R ¹⁰ represents alkanoyl or aroyl.

or

C) For the preparation of compounds with general formula I; wherein R ¹ represents alkanoyl or aroyl, R ² represents alkyl, R ⁴ and R ⁵ together represent oxy, and Y represents -CH ₂ - or -CH ₂ CH ₂ -, can cyclize compounds with general formula VI;

wherein R ³ , R ⁴ and R ²⁰ have the meanings given above, and Y ² represents —CH ₂ — or —CH ₂ CH ₂ —.

or

d) For the preparation of compounds having general formula I; wherein R ¹ represents alkanoyl or aroyl, R ² represents alkyl, R ⁴ and R ⁵ together represent oxy, and Y represents -CH ₂ - or -CH ₂ CH ₂ -, can cyclize the compound of general formula VII;

wherein R ³ , R ¹⁰ , R ²⁰ and Y ² have the meanings given above.

or

e) To prepare compounds with general formula I; wherein R ¹ represents alkanoyl or aroyl, R ² represents an alkyl group, R ⁴ and R ⁵ together represent an oxygen group, and Y represents -NH-, which can be cyclized Compounds with general formula VIII;

wherein R ³ , R ¹⁰ and R ²⁰ have the meanings given above. Hal stands for halogen.

or

f) For the preparation of compounds of general formula I; wherein R ¹ represents alkanoyl or aroyl, R ² represents alkyl, and R ⁴ and R ⁵ each represent hydrogen, the compound of general formula I can be reduced; wherein R ¹ represents Alkanoyl or aroyl, R ² represents an alkyl group, and R ⁴ and R ⁵ together represent an oxy group.

or

g) For the preparation of compounds of general formula I; wherein R ¹ represents alkanoyl or aroyl, and Y represents -N(R ⁶ )-; wherein R ⁶ represents alkyl or aralkyl, the formula I can be Compound; wherein R ¹ represents alkanoyl or aroyl, and Y represents -NH-, reacts with a compound of general formula IX;

R ⁶⁰ -Z Ⅸ

wherein R ⁶⁰ and Z have the meanings given above.

or

h) For the preparation of compounds of general formula I; wherein R ¹ represents hydrogen, compounds of general formula I wherein R ¹ represents alkanoyl or aroyl can be treated with a base.

or

i) For the preparation of compounds of general formula I; wherein ^R2 represents hydrogen, compounds of formula I; wherein ^R2 represents alkyl, may be treated with acid or base.

or

j) For the preparation of compounds of general formula I; wherein R ¹ represents alkanoyl or aroyl, and Y represents -CH ₂ -, -CH ₂ CH ₂ - or -N(R ⁶ )-; wherein R ⁶ represents alkyl or aralkyl, suitably alkanoylation or aroylation of the corresponding compound of general formula I wherein R ¹ represents hydrogen.

or

k) separation, if desired, of the obtained diastereomeric racemate mixture; into diastereomeric racemates or optically active diastereoisomers.

and / or

l) If necessary, resolve the resulting racemates into their optical antipodes.

as well as

m) If necessary, use a base to convert the obtained compound of general formula I into a salt that can be used as a drug; and ^R2 in formula I represents hydrogen, and use a salt to convert the obtained compound of general formula I It can be used as a pharmaceutical salt; and Y in formula I represents -N(R ⁶ )-.

According to embodiment a), the reaction of the compound of the general formula II with the compound of the general formula III can be carried out by known methods. The reaction can be carried out with or without the presence of an inert organic solvent. When inert organic solvents are used, they can be: aliphatic or aromatic hydrocarbons (such as n-ethane, benzene, toluene, etc.), halogenated hydrocarbons (such as methylene chloride, chloroform, 1,1,1-trichloro ethane, etc.), aliphatic ethers (such as diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), amides (such as dimethyl formamide), aliphatic ketones (such as acetone, methyl ethyl ketone wait wait wait. Preferred solvents are halogenated hydrocarbons, especially dichloromethane. The reaction temperature is not critical and may be between about room temperature and the reflux temperature of the reaction mixture. Preference is given to carrying out the reaction at room temperature.

In the implementation of method b), the remaining group is represented by Z, and a compound of general formula IV can be used as a starting material, for example, wherein Z can be a halogen atom such as a chlorine atom or a bromine atom, an alkylsulfonic acid group such as methanesulfonic acid Acid group or arylsulfonic acid group such as p-toluenesulfonic acid group.

According to embodiment b), the reaction of the compound of general formula IV with the alkali metal salt of the compound of general formula V is conveniently carried out in an inert organic solvent. Such alkali metal salts may be sodium or preferably potassium salts. In the presence of a catalytic amount of alkali metal iodide (such as sodium iodide, potassium iodide, etc.), the reaction can be facilitated. Suitable inert organic solvents are aliphatic ketones (such as acetone, methyl ethyl ketone, etc.), halogenated hydrocarbons (such as methylene chloride, chloroform, 1,1,1-trichloroethane, etc.), aliphatic esters (such as ethyl acetate esters, butyl acetate, etc.), amides (such as dimethylformamide, etc.) and so on.

The reaction temperature is not critical, for example, the reaction can be carried out at a reaction temperature between about 10°C and the reflux temperature of the reaction mixture. It is best to carry out the reaction at the reflux temperature of the reaction mixture.

According to embodiment c), the cyclization of the compounds of general formula VI can be carried out by known methods. In the preferred scheme, according to the known method, it is treated with suitable halogenating agent such as phosphorus pentahalide (such as phosphorus pentachloride, etc.) or thionyl halide (such as thionyl chloride, etc.), so that the Conversion of the compound to the corresponding acid halide (e.g. acid chloride) followed by spontaneous cyclization affords the desired compound of general formula I.

According to embodiment d), the cyclization of the compounds of general formula VII can be carried out by known methods. In a preferred embodiment, treatment with a suitable halogenating agent such as phosphorus pentahalide (such as phosphorus pentachloride, etc.) or thionyl halide (such as thionyl chloride, etc.) according to known methods, has the general formula Conversion of compounds of VII to the corresponding acid halides (e.g. acid chlorides) followed by spontaneous cyclization affords the desired compounds of general formula I.

According to embodiment e), the cyclization of compounds of general formula VIII is readily carried out under the following conditions. For example, in the presence of bases such as alkali metal carbonates or bicarbonates (such as aqueous sodium bicarbonate), and the presence of inert organic solvents such as aliphatic or aromatic hydrocarbons (such as n-hexane, benzene, toluene, etc. ), halogenated hydrocarbons (such as dichloromethane, chloroform, 1,1,1-trichloroethane, etc.), aliphatic ethers or cyclic ethers (such as diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, di Oxane, etc.), amides (such as dimethyl formamide), aliphatic ketones (such as acetone, methyl ethyl ketone, etc.) and so on. Although the cyclization reaction is preferably carried out at about room temperature, it can be carried out at elevated temperatures, for example up to the reflux temperature of the reaction mixture, if desired.

According to implementation method f), the compound with general formula I is reduced with borane; wherein R ¹ represents alkanoyl or aroyl, R ² represents an alkyl group, and R ⁴ and R ⁵ together represent an oxygen group, the reduction reaction Conveniently, suitable borane complexes are borane/tetrahydrofuran, borane/dimethylsulfide, borane/N,N-diethylaniline and the like. The reduction reaction with borane is suitably carried out at low temperature and in an inert organic solvent. For example, the reduction is carried out using a borane/tetrahydrofuran complex in an inert organic solvent of tetrahydrofuran at a temperature between about 0°C and 20°C.

According to embodiment g), compounds of the general formula I; wherein R ¹ represents alkanoyl or aroyl, and Y represents -NH-, can be reacted with compounds of the general formula IX by known methods. The reaction is suitably carried out in the presence of an inert organic solvent. Such as halogenated hydrocarbons (such as dichloromethane, chloroform, etc.), amides (such as dimethylformamide, etc.), nitriles (such as acetonitrile, etc.) and other solvents.

The reaction can be carried out in the presence of an organic base, if desired. For example, trialkylamines (such as triethylamine, triethylisopropylamine, etc.). Pyridine, N, N-dimethylaniline, etc., the reaction temperature is room temperature or high temperature, for example, the reaction is carried out at the reflux temperature of the reaction mixture.

According to embodiment h), a compound of general formula I wherein ^R1 represents alkanoyl or aroyl is converted into a compound of general formula I wherein ^R1 represents hydrogen by treatment with a base. This treatment can be carried out by known methods. Suitable bases are alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and ammonium hydroxide. The temperature at which the treatment is carried out may be about room temperature or the boiling temperature of the reaction mixture. Room temperature is preferred.

According to embodiment i), the compound of general formula I; wherein R ² represents an alkyl group is converted into a compound of general formula I; wherein R ² represents hydrogen, by treatment with a base, which can be treated with known method to proceed. When the alkyl group is tert-butyl, it is treated with acid. Suitable bases are alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and ammonium hydroxide. The treatment temperature can be between about room temperature and the boiling temperature of the reaction mixture, preferably at room temperature. When treating with an acid, a particularly suitable acid is anhydrous trifluoroacetic acid, in which case the treatment is conveniently carried out at room temperature.

According to embodiment j), the alkanoylation or aroylation of compounds of the general formula I in which ^R¹ represents hydrogen can be carried out by known methods. For example, alkanoylation is effected by reacting a compound of general formula I with a suitable acid reactive derivative such as an acid chloride in the presence of a base and an inert organic solvent. Suitable bases are: organic bases such as trialkylamines (such as triethylamine), pyridine, N, N-dimethylaniline, etc., and suitable inert organic solvents are halogenated hydrocarbons (such as dichloromethane, chloroform, etc. ), amides (such as dimethylformamide, etc.) and so on. The reaction temperature is not critical and may be between room temperature and the reflux temperature of the reaction mixture.

According to embodiment k), the separation of diastereomeric mixtures into diastereomeric racemates or optically pure diastereomers can be carried out by known methods. For example, perform chromatography (eg on silica gel) using an appropriate solvent system (eg ethyl acetate/n-hexane).

According to implementation method 1), the racemate is resolved into the optical antipodes, which can be carried out according to known methods. In this case, for example, it is necessary to treat with a suitable optically active base or acid and to separate the resulting optically active salts (for example by fractional crystallization), and to separate them from these salts by customary methods. Compounds with consistent optical activity.

According to embodiment m), the compound of general formula I; wherein R ² represents hydrogen is converted into a pharmaceutically desired salt with a base, and the compound of general formula I; wherein Y represents -N(R ⁶ )- The compound can be converted into a pharmaceutically desired salt by treating it with a suitable acid or base in a customary manner.

In the implementation method a), the compound having the general formula II as the raw material is also a novel substance prepared by the present invention.

Compounds of general formula II can be prepared, for example, compounds of general formula X

wherein ^R3 and ^R20 have the meanings given above and Bz represents benzyl, from which the benzyloxycarbonyl group is cleaved to form a compound of general formula XI.

wherein ^R3 and ^R20 have the meanings given above, with this compound (XI) reacted with an anhydride of general formula XII

where Y has the meaning given above.

The cyclization reaction takes place to form a compound of the general formula XIII

wherein R ³ , R ²⁰ and Y have the meanings given.

And, if desired, the resulting compound of formula II; wherein ^R2 represents alkyl can be treated with an acid or base to give the corresponding compound of general formula II; wherein ^R2 represents hydrogen. This compound can also be esterified, if desired, to give the corresponding compound of formula II; wherein ^R2 represents alkyl.

Cleavage of the oxycarbonyl group from the compound of general formula X can be carried out according to known methods. For example, the cleavage reaction is carried out with hydrogen in the presence of a catalyst such as a noble metal catalyst such as palladium adsorbed on carbon, and in an inert solvent such as an alkanol such as methanol, etc.

The resulting compound of formula XI is then reacted with an anhydride of formula XII to form a compound of formula XIII. This reaction is suitably carried out in an inert organic solvent, such as a halogenated hydrocarbon or preferably an aliphatic or cyclic ether (such as dioxane), at a temperature between room temperature and the reflux temperature of the reaction mixture, preferably room temperature .

The cyclization reaction of compounds of general formula XIII can be carried out by known methods. Under optimal reaction conditions, according to known methods, with a suitable halogenating agent such as phosphorus pentahalide (such as phosphorus pentachloride, etc.) or thionyl halide (such as thionyl chloride, etc.), the Compounds, which are transformed into the corresponding acid halides (e.g. acid chlorides), which undergo spontaneous cyclization to form compounds of the general formula II; wherein R ² represents an alkyl group.

If desired, the compound of general formula II; wherein R ² represents an alkyl group obtained by the above method can be converted into a compound of general formula II; wherein R ² represents hydrogen, by treating it with an acid or base. This treatment can be carried out by known methods. Suitable bases are alkali metal hydroxides such as sodium hydroxide and potassium hydroxide and ammonium hydroxide. The treatment temperature may be between about room temperature and the boiling temperature of the reaction mixture, with room temperature being advantageous.

The esterification of compounds of general formula II wherein ^R2 represents hydrogen can be carried out by known methods. For example, treatment with a suitable diazoalkane such as diazomethane.

Preparation of the above compound with the general formula XIII; wherein R ²⁰ represents tert-butyl, and Y represents -CH ₂ - or -CH ₂ CH ₂ -, another alternative method is to use the compound of the above general formula XI; wherein R ²⁰ represents the compound of tert-butyl and 2-methylene-glutaric acid hydrogen ester or-adipate hydrogen ester to react; And the ester group wherein is the alkyl group that carbon atom number is 1～3, and uses Alkaline treatment of the reaction product.

With known method, with general formula XI; Wherein R ²⁰ represents the compound of tert-butyl and α-methylene-hydrogen glutarate or -hydroadipate react, and wherein ester group is C _{1 to 3} alkyl, the aforementioned half esters are converted into reactive derivatives, such as activated esters, which then react with compounds of general formula XI, and this reaction is suitable for inert organic solvents (i.e. etc.), and at a temperature between about 0°C and room temperature.

Treat the reaction product with a base to generate a compound of general formula XIII; wherein R ²⁰ represents a tert-butyl group, and Y represents -CH ₂ - or -CH ₂ CH ₂ -, and the similar method described above can be used, That is, by treatment with a base, a compound of general formula II wherein ^R2 represents an alkyl group is converted into a compound of general formula II wherein ^R2 represents hydrogen. This treatment is carried out.

In the implementation of method b), the compound of general formula IV used as starting material is also a novel substance prepared by the present invention.

Compounds of the general formula IV; wherein Y represents -CH ₂ - or -CH ₂ CH ₂ - can be prepared. For example, react with a compound of the above-mentioned general formula X and a compound of the general formula XIV, and Y ² , Z and Bz in the XIV formula have the given meanings, and then generate a compound of the general formula XV; wherein R ^3. In compounds where R ²⁰ , Y ² , Z and Bz have the given meanings, benzyl and benzyloxycarbonyl are removed and the resulting acid of general formula XVI is cyclized; and wherein R ³ , R ²⁰ , Y ² and Z have the meanings given.

And if necessary, the resulting compound of general formula IV is reduced; wherein R ⁴ and R ⁵ together represent an oxygen group, and Y ¹ represents -CH ₂ - or -CH ₂ CH ₂ -, to generate the corresponding , with general formula IV; wherein R ⁴ and R ⁵ each represent a compound of hydrogen.

The reaction of a compound of general formula X with a compound of general formula XIV can be carried out in a conventional manner, for example, in an inert organic solvent (such as a halogenated hydrocarbon such as methylene chloride) and in a base (such as an alkali metal The reaction is carried out in the presence of a carbonate such as sodium carbonate or an alkali metal bicarbonate such as sodium bicarbonate, and the reaction temperature is suitably room temperature.

From the compound of general formula XV, the removal of benzyl and benzyloxycarbonyl can be carried out according to generally known methods. For example, with hydrogen in the presence of a catalyst such as a noble metal catalyst (i.e. palladium adsorbed on carbon), or with hydrogen bromide in glacial acetic acid when ^R2 does not represent tert-butyl.

The cyclization of acids of general formula XVI can be carried out by known methods. In a preferred embodiment, treatment with a suitable halogenating agent such as phosphorus pentahalide (such as phosphorus pentachloride, etc.) or thionyl halide (such as thionyl chloride, etc.) Compounds of formula XVI are converted to the corresponding acid halides (for example acid chlorides) followed by spontaneous cyclization to generate compounds of general formula IV; wherein R ^{and R} taken together represent oxy, and ^Y represents - _CH2- or _{-CH2CH2- .}

For compounds with general formula IV; wherein R ⁴ and R ⁵ together represent an oxygen group, and Y ¹ represents -CH ₂ - or -CH ₂ CH ₂ -, the reduction reaction can be conveniently carried out with borane, and a suitable form Complexes of borane such as borane/tetrahydrofuran, borane/dimethylsulfide, borane/N,N-diethylaniline or similar complexes, in an inert organic solvent, at low temperature, Borane is suitable for carrying out this reduction. For example in tetrahydrofuran, with borane/tetrahydrofuran, the reaction temperature is between about 0°C and 20°C.

Compounds of the general formula IV in which ^Y1 represents -N( ^R6 )- can be prepared. For example, reacting the above-mentioned compound of general formula XI with a haloacetyl halide produces a compound of general formula XVII;

wherein R ³ , R ²⁰ and Hal have the given meanings, reacting this compound with a compound of general formula XVIII;

wherein Z has the given meanings and X represents an amino protecting group, in the resulting compound of formula XIX; wherein R ³ , R ²⁰ , X, Z and Hal have the given meanings, cleavage An amino protecting group represented by X.

The resulting compound of formula XX is then cyclized;

wherein R ³ , R ²⁰ , Z and Hal have the meanings given. The resulting compound of formula XXI;

wherein R ³ , R ²⁰ and Z have the given meanings, react with a compound of general formula IX and, if desired, react the resulting compound of general formula IV; wherein R ⁴ and R ⁵ together represent Oxygen, and Y ¹ represents -N(R ⁶⁰ ), is reduced to the corresponding compound of formula IV; wherein R ⁴ and R ⁵ each represent hydrogen.

The reaction of the compound of general formula XI with a haloacetyl halide, such as chloroacetyl chloride, bromoacetyl bromide, bromoacetyl chloride, etc., can be carried out according to known methods. For example, in an inert organic solvent, such as a halogenated hydrocarbon (such as methylene chloride, etc.), and in a base such as an alkali metal carbonate or bicarbonate (such as sodium bicarbonate, etc.), the reaction is carried out at a suitable temperature It is carried out at about 0°C to room temperature.

In the compound of general formula XVIII, the amino-protecting group represented by X may be any conventional amino-protecting group. Preferably, the amino protecting group represented by X is removed by treatment with a base such as trifluoroacetyl.

The reaction of the compound of general formula XVII with the compound of general formula XVIII can be carried out by known methods. For example, the reaction is carried out in an inert organic solvent such as a halogenated hydrocarbon (e.g. dichloromethane, etc.), and in a base, such as an alkali metal carbonate or bicarbonate (e.g. sodium bicarbonate, etc.). When the temperature is about 0°C to room temperature, it is convenient for the reaction to proceed.

Cleavage of the amino protecting group represented by X in compounds of general formula XIX, using known methods depending on the nature of the protecting group, gives compounds of general formula XX.

Under the following conditions, the cyclization reaction of the compound of general formula XX can be carried out easily, for example in a base, such as in aqueous alkali metal carbonate or bicarbonate (such as sodium bicarbonate, etc.), and in Inert organic solvents, such as aliphatic or aromatic hydrocarbons (such as n-hexane, benzene, toluene, etc.), halogenated hydrocarbons (such as methylene chloride, chloroform, 1,1,1-trichloroethane, etc.) , aliphatic ether or cyclic ether (such as diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), amides (such as dimethyl formamide, etc.), aliphatic ketones (such as acetone, methyl ethyl ketone, etc. ) or similar compounds for cyclization. Although this cyclization reaction is preferably at room temperature, it can be carried out if desired at elevated temperatures, for example at elevated temperatures up to the reflux temperature of the reaction mixture.

The removal of the above-mentioned amino protecting group represented by X, and the cyclization reaction, if desired, can also be carried out in reverse order. For example, with an alkali metal hydride such as sodium hydride, in an inert organic solvent such as an amide (such as dimethylformamide, etc.), at room temperature, the compound of the general formula XIX is cyclized, and then by known methods, the A protecting group represented by X is opened.

The reaction of the compound of the general formula XXI with the compound of the general formula IX can be carried out by known methods. The reaction is suitably carried out in an inert organic solvent. Examples include halogenated hydrocarbons (such as dichloromethane, chloroform, etc.), amides (such as dimethylformamide, etc.), nitriles (such as acetonitrile, etc.), or similar compounds. If desired, the reaction can be carried out in an organic base such as trialkylamine (e.g. triethylamine, diethylisopropylamine, etc.). Pyridine, N, N-diethylaniline, etc. The reaction can be carried out at about room temperature or elevated temperature, for example at the reflux temperature of the reaction mixture.

For compounds of the general formula IV; wherein R ⁴ and R ⁵ taken together represent oxy, and Y ¹ represents -N(R ⁶⁰ )-, the reduction can conveniently be carried out with borane. Suitable borane complexes such as borane/tetrahydrofuran, borane/dimethylsulfide, borane/N,N-diethylaniline or other similar complexes. The reduction reaction with borane is suitably carried out in an inert organic solvent at low temperature, for example, in tetrahydrofuran at about 0°C to 20°C with borane/tetrahydrofuran reduction reaction.

According to a method different from that described above, i.e. different from the preparation of compounds of general formula IV; wherein Y ¹ represents -N(R ⁶⁰ )-, instead of a compound of general formula XVIII, it may be a The corresponding compound; wherein Z represents a hydroxy protecting group (such as phenoxy). In the later steps of the process, the hydroxy protecting group is retained until the cyclization reaction is complete. Then, it is converted into a hydroxyl group by known methods. For example, when the hydroxy protecting group is phenoxy, the protecting group can be converted to hydroxy by catalytic hydrogenation in the presence of a noble metal catalyst such as palladium. The resulting compound corresponds to the general formula XXI; but with Z representing the hydroxyl group, this compound is then reacted with a compound of the general formula IX, as described above, and the reaction product is converted into a compound of the general formula IV by known methods. Compounds wherein R ⁴ and R ⁵ taken together represent oxy and Y ¹ represents -N(R ⁶⁰ )-; for example, reaction with an alkanesulfonyl halide such as methanesulfonyl chloride. Finally, if desired, the resulting compound of formula IV can be reduced, as described above, to give the corresponding compound wherein ^R4 and ^R5 each represent hydrogen.

In the embodiment c), the compound of general formula VI used as starting material is also a novel substance produced in the present invention.

Can prepare the compound with general formula VI, for example, with above-mentioned general formula XIII; Wherein Y represents -CH ₂ - or -CH ₂ CH ₂ - compound reacts with the compound of above-mentioned general formula V, just prepares the compound of formula VI compound.

The reaction of a compound of general formula XIII; wherein Y represents -CH ₂ - or -CH ₂ CH ₂ - with a compound of general formula V can be carried out by known methods. The reaction can be carried out with or without an inert organic solvent. When using inert organic solvents, they are: aliphatic or aromatic hydrocarbons (such as n-hexane, benzene, toluene, etc.), halogenated hydrocarbons (such as methylene chloride, chloroform, 1,1,1-trichloroethane, etc. ), aliphatic ethers or cyclic ethers (such as diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), amides (such as dimethylformamide), aliphatic ketones (such as acetone, methyl Ethyl ketone, etc.) or other similar compounds. Preferred solvents are halogenated hydrocarbons, especially dichloromethane. The reaction temperature is not critical and may be between about room temperature and the reflux temperature of the reaction mixture, with the preferred embodiment being to carry out the reaction at about room temperature.

In the embodiment d), the compound of general formula VII used as starting material is also a novel substance produced according to the invention.

A compound of general formula VII can be prepared, for example, a compound of formula XXIII can be prepared by reacting a compound of general formula X above with a compound of general formula XXII;

In formula XXII, R ²⁰ , Y ² and Bz have the meanings given above, and from the resulting compound of general formula XXIII, benzyl and benzyloxycarbonyl are removed

In formula XXIII, R ³ , R ¹⁰ , R ²⁰ , Y ² and Bz have the meanings given.

The reaction of a compound of general formula X with a compound of general formula XXII can be carried out in a conventional manner; for example, in an inert organic solvent (such as a halogenated hydrocarbon such as dichloromethane) and adding a base (such as an alkali metal carbonate Such as sodium carbonate or an alkali metal bicarbonate such as sodium bicarbonate), the reaction is suitably carried out at room temperature.

From the compound of general formula XXIII, benzyl and benzyloxycarbonyl can be removed according to generally known methods; for example, in the presence of a catalyst such as a noble metal catalyst (such as palladium adsorbed on carbon), with hydrogen, or when When ^R20 does not represent tert-butyl, the reaction is carried out with hydrogen bromide in glacial acetic acid.

In the implementation method e), the compound having the general formula VIII as the raw material is also a novel substance produced by the present invention.

Compounds of general formula VIII can be prepared, for example, by reacting a compound of general formula XVII above with a compound of general formula XXIV,

wherein ^R and X have the given meanings,

Then, in the resulting compound of formula XXV, the protecting group represented by X is cleaved,

wherein R ³ , R ¹⁰ , R ²⁰ , X and Hal have the meanings given.

The reaction of the compound of general formula XVII with the compound of general formula XXIV can be carried out by known methods. For example, in an inert organic solvent, such as a halogenated hydrocarbon (such as dichloromethane, etc.), and adding a base, such as an alkali metal carbonate or bicarbonate (such as sodium bicarbonate, etc.), the reaction temperature is suitably from about 0 ° C to room temperature.

In compounds of general formula XXV, the protecting group represented by X is cleaved by known methods depending on the nature of the protecting group.

In the practice of processes a), b) and g), the compounds of the general formulas III, V and IX used as starting materials are known compounds.

As mentioned above, in the preparation of raw materials, the compounds with the general formulas X, XII, XIV, XVIII, XXII and XXIV used are known compounds, or are similar to known compounds, and such similar compounds It can be prepared by methods analogous to the preparation of known compounds.

The compounds of general formula I and their pharmaceutically acceptable salts mentioned above are useful as antihypertensive agents. Because they can inhibit angiotensin-converting enzyme (ACE); and this ACE can promote the conversion of angiotensin Ⅰ to angiotensin Ⅱ, so the above-mentioned compounds and their pharmaceutically acceptable salts are effective in reducing or alleviating the effects of angiotensin. Hypertension is useful.

In glass test tubes, the above compounds inhibit the activity of angiotensin converting enzyme as determined by the following assay.

The assay used was based on the method of Cushman and Cheung (Biochem pharmacol 20, 1637-1648) with a modification proposed by Hayakari et al. (Anal Biochem., 84, 361-369). In the presence or absence of different concentrations of the test substance, the substrate (hippuryl (base)-histidyl (base)-leucine, 2mM) was mixed with angiotensin-converting enzyme (ACE) at 37°C. ) were incubated together for 24 minutes in potassium phosphate buffer (pH = 8.3; 100 mM) containing sodium chloride (300 mM) in a total volume of 500 µl. (If the test substance is an ester, it should be cleaved with pig liver esterase before the above test). Then, at a temperature of 0°C, 3 ml of potassium phosphate buffer (pH 8.3; 200 mM) was added to the above solution, and the reaction was terminated, and then 2,4,6-tris, which had been dissolved in 1.5 ml of dioxane, was added. Chloro-S-triazine (3%), and the solution mixture was stirred until the yellow chromophore was completely developed. The sample is then centrifuged to remove any precipitate that has formed. The yellow chromophore formed by the reaction of 2,4,6-trichloro-S-triazine and free hippuric acid can be measured by spectrophotometry at a wavelength of 382 nm. The IC ₅₀ value is defined as: under the above conditions, the concentration of the test substance that can reduce the cleavage of hippuryl (yl)-histidyl (yl)-leucine by angiotensin converting enzyme by 50%.

In above-mentioned test, when using representative compound in general formula I as test substance, its obtained result tabulation is as follows:

surface

Compound IC ₅₀ (nM)

A 4.0

B 2.6

C 19

D 50

-1（S）-羧酸。Compound A = octahydro-9(S)-mercaptomethyl-6,10-dioxo-6H-pyridazino[1,2-α][1,2]diazepine

-1(S)-carboxylic acid.

Compound B = octahydro-9(S)-mercaptomethyl-10-oxyl-6H-pyridazino-[1,2-α][1,2]diazepine -1(S)-carboxylic acid.

Compound C = Decahydro-10(R,S)-mercaptomethyl-6,11-dioxyl-6H-pyridazino[1,2-α][1,2]diazapine-1(S )-carboxylic acid.

-1（S）-羧酸（非对映异构体1）。Compound D = octahydro-9-mercaptomethyl-8-methyl-6,10-dioxy-6H-pyridazino[1,2-α][1,2,5]triazepine

-1(S)-carboxylic acid (diastereomer 1).

The compound of formula I and the above-mentioned pharmaceutically acceptable salts thereof can be used as medicines in the form of pharmaceuticals, and they are combined with co-existing pharmaceutical carrier materials. This carrier material can be suitable for enteral use (oral), or parenteral The organic carrier material or inorganic carrier material used in the road. Examples of such carrier materials are water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, rapeseed oil, poly(alkylene) glycols, petrolatum, and the like. Pharmaceutical preparations may be in solid form (eg, as a tablet, dragee, suppository, or capsule), or in liquid form (eg, as a solution, suspension, or emulsion).

Pharmaceuticals must adopt standard pharmaceutical operations, such as disinfection and sterilization, and/or some auxiliary agents can be added, such as preservatives, stabilizers, wetting agents or emulsifiers, and salts for changing osmotic pressure when making finished drugs Or buffering agent, the finished medicine may also contain other therapeutically useful substances.

For adults, the compound of formula I and the above-mentioned pharmaceutically acceptable salts can be used in a daily dose of about 0.1 mg to 100 mg, preferably about 1 mg to 50 mg per kg body weight. The daily dose may be administered in one dose or in divided doses. It should be understood that the above ranges are given as examples only and that ranges may vary depending on factors such as the particular The particular compound or salt, requirements for administration, severity, and condition of the patient are all at the discretion of the attending physician.

Some examples illustrating the invention are as follows:

Example 1

-1（S）-羧酸叔丁酯，其熔点为95～96℃（来自乙醚/正己烷），是白色固体，最后得到1.16克（46%）9（R）-乙酰硫甲基-八氢-6，10-二氧-6H-哒嗪并〔1，2-α〕〔1，2〕二氮杂 -1（S）-羧酸叔丁酯，其为白色非结晶形固体。In 20ml of dichloromethane, add 2.0g (6.8mmol) octahydro-9-methylene-6,10-dioxo-6H-pyridazino[1,2-α][1,2]diazepine - 1(S)-tert-butylcarboxylate and 1.0 ml (14 mmol) thiolacetic acid, and stirred at room temperature for 20 hours, after evaporation, chromatographed on a silica gel column using ethyl acetate/n-hexane Used as eluent to separate residual oil. First, 1.3 g (52%) of 9(S)-acetylthiomethyl-octahydro-6,10-dioxo-6H-pyridazino[1,2-α][1,2]diazepine was obtained

-1(S)-Tert-butyl carboxylate, the melting point of which is 95-96°C (from ether/n-hexane), is a white solid, and finally 1.16 g (46%) of 9(R)-acetylthiomethyl-octyl Hydrogen-6,10-dioxo-6H-pyridazino[1,2-α][1,2]diazepine - tert-butyl 1(S)-carboxylate as a white non-crystalline solid.

-1（S）-羧酸叔丁酯的制备方法如下：Octahydro-9-methylene-6,10-dioxo-6H-pyridazino[1,2-α][1,2]diazepine used as starting material

-1 (S)-The preparation method of tert-butyl carboxylate is as follows:

嗪酸叔丁酯溶于100毫升甲醇中，在室温下，和常压下，用5%钯/碳作催化剂，进行氢化反应。然后用过滤方法除去催化剂，并把滤液蒸发至干。将得到的

嗪酸叔丁酯粗产品溶于100毫升二恶烷中，使溶液冷却到0℃，加入3.94克（0.0313mol）α-亚甲基-戊二酸酐（溶于100毫升二恶烷中）。在20℃温度下，搅拌上述混合物18小时，蒸发以除去溶剂。将残渣分配在甲基叔丁醚和饱和的碳酸氢钠溶液二相之间，用盐酸酸化水相，并用二氯甲烷提取，就得到8.34克（85%）3（S）-叔丁氧基羰基-六氢-α-亚甲基-S-氧-1-哒嗪戊酸。其熔点为96℃-99℃，是白色结晶。将5.0克（16mmol）上述酸溶于350毫升四氢呋喃中，使溶液冷却到0℃，加入3.75克（18mmol）五氯化磷，在0℃温度下，搅拌该混合物1小时，然后在20℃温度下，搅拌18小时。蒸发以除掉溶剂，然后残渣分配在乙酸乙酯和饱和的碳酸氢钠溶液之间，蒸发有机相，用色谱分离法，在硅胶柱上，用乙酸乙酯/正己烷作洗脱剂，分离残渣。得到3.7克（79%）八氢-9-亚甲基-6，10-二氧-6H-哒嗪并〔1，2-α〕〔1，2〕二氮杂

-1（S）-羧酸叔丁酯，其熔点105°-106℃（己烷），是白色固体。10 grams (0.0313mol) of 1-benzyloxycarbonyl-S-

Tert-butyl oxinate was dissolved in 100 ml of methanol, and hydrogenation was carried out at room temperature and under normal pressure with 5% palladium/carbon as a catalyst. The catalyst was then removed by filtration and the filtrate was evaporated to dryness. will get

The crude t-butyl oxinate was dissolved in 100 ml of dioxane, the solution was cooled to 0°C, and 3.94 g (0.0313 mol) of α-methylene-glutaric anhydride (dissolved in 100 ml of dioxane) was added. The above mixture was stirred at 20°C for 18 hours and evaporated to remove the solvent. The residue was partitioned between methyl tert-butyl ether and saturated sodium bicarbonate solution, the aqueous phase was acidified with hydrochloric acid and extracted with dichloromethane to give 8.34 g (85%) of 3(S)-tert-butoxy Carbonyl-hexahydro-α-methylene-S-oxo-1-pyridazine valeric acid. Its melting point is 96°C-99°C, and it is a white crystal. 5.0 g (16 mmol) of the above acid was dissolved in 350 ml of tetrahydrofuran, the solution was cooled to 0°C, 3.75 g (18 mmol) of phosphorus pentachloride was added, and the mixture was stirred for 1 hour at 0°C, then at 20°C Next, stir for 18 hours. Evaporate to remove the solvent, then partition the residue between ethyl acetate and saturated sodium bicarbonate solution, evaporate the organic phase, and chromatograph on a silica gel column using ethyl acetate/n-hexane as eluent to separate residue. Obtained 3.7 g (79%) of octahydro-9-methylene-6,10-dioxo-6H-pyridazino[1,2-α][1,2]diazepine

tert-Butyl 1(S)-carboxylate, m.p. 105°-106°C (hexane), is a white solid.

Example 2

-1（S）-羧酸叔丁酯溶于5毫升四氢呋喃中，在0℃温度下，用2毫升0.5M甲硼烷/四氢呋喃处理上述溶液。在0℃温度下，搅拌该混合物1小时，再在20℃温度下，继续搅拌3小时，然后用二氯甲烷稀释。细心地加入15毫升稀盐酸，并在0℃温度下，搅拌上述混合物0.5小时。用碳酸钠调节混合物的PH为8，然后进行相分离，蒸发有机相，用色谱分离法，在硅胶柱上，以乙酸乙酯/正己烷作洗脱液，分离残余物。就得到150毫克（42%）9（S）-乙酰硫甲基-八氢-10-氧-6H-哒嗪并〔1，2-α〕〔1，2〕二氮杂

-1（S）-羧酸叔丁酯，是无色油状物。370 mg (1 mmol) of 9(S)-acetylthiomethyl-octahydro-6,10-dioxo-6H-pyridazino[1,2-α][1,2]diazepine

- tert-butyl 1(S)-carboxylate was dissolved in 5 ml of tetrahydrofuran, and the above solution was treated with 2 ml of 0.5M borane/tetrahydrofuran at 0°C. The mixture was stirred for 1 hour at 0°C and for a further 3 hours at 20°C, then diluted with dichloromethane. 15 ml of dilute hydrochloric acid was carefully added, and the above mixture was stirred at 0°C for 0.5 hours. The pH of the mixture is adjusted to 8 with sodium carbonate, the phases are separated, the organic phase is evaporated and the residue is separated by chromatography on a silica gel column with ethyl acetate/n-hexane as eluent. 150 mg (42%) of 9(S)-acetylthiomethyl-octahydro-10-oxo-6H-pyridazino[1,2-α][1,2]diazepine were obtained

- tert-Butyl 1(S)-carboxylate, a colorless oil.

Example 3

-1（S）-羧酸叔丁酯中，制得200毫克（56%）9（R）-乙酰硫甲基-八氢-10-氧-6H-哒嗪并〔1，2-α〕〔1，2〕二氮杂 -1（S）-羧酸叔丁酯，是无色油状物。Using a method similar to that described in Example 2, 370 mg (1 mmol) of 9(R)-acetylthiomethyl-octahydro-6,10-dioxo-6H-pyridazino[1,2-α] [1,2] diazepine

- 200 mg (56%) of 9(R)-acetylthiomethyl-octahydro-10-oxo-6H-pyridazino[1,2-α] from tert-butyl 1(S)-carboxylate [1,2] diazepine - tert-Butyl 1(S)-carboxylate, a colorless oil.

Example 4

-1（S）-羧酸叔丁酯于3毫升三氟代乙酸中，在20℃温度下，将溶液放置1.5小时。蒸发以后，可得到230毫克（90%）9（S）-乙酰硫甲基-八氢-6，10-二氧-6H-哒嗪并-〔1，2-α〕〔1，2〕二氮杂

-1（S）-羧酸，其熔点为133°-135℃（乙酸乙酯/正己烷），是白色固体。Dissolve 300 mg (0.81 mmol) of 9(S)-acetylthiomethyl-octahydro-6,10-dioxo-6H-pyridazino[1,2-α][1,2]-diazepine

- tert-butyl 1(S)-carboxylate in 3 ml of trifluoroacetic acid was allowed to stand at 20°C for 1.5 hours. After evaporation, 230 mg (90%) of 9(S)-acetylthiomethyl-octahydro-6,10-dioxo-6H-pyridazino-[1,2-α][1,2]di Aza

-1(S)-Carboxylic acid, melting point 133°-135°C (ethyl acetate/n-hexane), is a white solid.

Example 5

-1（S）-羧酸，是白色的非结晶形固体。Using a method similar to that described in Example 4, 300 mg (0.81 mmol) of 9(R)-acetylthiomethyl-octahydro-6,10-dioxo-6H-pyridazino[1,2-α ][1,2]-diazepine - 235 mg of 9(R)-acetylthiomethyl-octahydro-6,10-dioxo-6H-pyridazino-[1,2-α] from tert-butyl 1(S)-carboxylate [1,2] diazepine

-1(S)-carboxylic acid is a white non-crystalline solid.

Example 6

-1（S）-羧酸叔丁酯中，制得105毫克9（S）-乙酰硫甲基-八氢-10-氧-6H-哒嗪并-〔1，2-α〕〔1，2〕二氮杂

-1（S）-羧酸，是白色的泡沫胶。Using a method similar to that described in Example 4, 130 mg of 9(S)-acetylthiomethyl-octahydro-10-oxo-6H-pyridazino[1,2-α][1,2]di Aza

-105 mg of 9(S)-acetylthiomethyl-octahydro-10-oxo-6H-pyridazino-[1,2-α][1, 2) diazepine

-1(S)-Carboxylic acid, white foam gum.

Example 7

-1（S）-羧酸，是无色胶。Using a method similar to that described in Example 4, 180 mg of 9(R)-acetylthiomethyl-octahydro-10-oxo-6H-pyridazino[1,2-α][1,2]di Aza -150 mg of 9(R)-acetylthiomethyl-octahydro-10-oxo-6H-pyridazino[1,2-α][1,2 ] diazepine

-1(S)-carboxylic acid, a colorless gum.

Example 8

-1（S）-羧酸溶解在1.6毫升水中，而该水中含有1.6毫升浓氢氧化铵，将该混合物在20℃温度下放置1小时。然后用盐酸调节混合物的PH为1，并用二氯甲烷进行萃取。蒸发二氯甲烷萃取液，再用正己烷研制残渣，可得到116毫克八氢-9（S）-巯甲基-6，10-二氧-6H-哒嗪并〔1，2-α〕〔1，2〕二氮杂

-1（S）-羧酸，是非晶形固体。160 mg (0.51 mmol) of 9(S)-acetylthiomethyl-octahydro-6,10-dioxo-6H-pyridazino[1,2-α][1,2]diazepine

-1(S)-carboxylic acid was dissolved in 1.6 ml of water containing 1.6 ml of concentrated ammonium hydroxide, and the mixture was left at 20°C for 1 hour. The pH of the mixture was then adjusted to 1 with hydrochloric acid and extracted with dichloromethane. The dichloromethane extract was evaporated, and the residue was triturated with n-hexane to obtain 116 mg of octahydro-9(S)-mercaptomethyl-6,10-dioxo-6H-pyridazino[1,2-α][ 1,2) diazepine

-1(S)-carboxylic acid, which is an amorphous solid.

Example 9

-1（S）-羧酸中，可制得75毫克的八氢-9（R）-巯甲基-6，10-二氧-6H-哒嗪并〔1，2-α〕〔1，2〕二氮杂

-1（S）-羧酸，是非晶形固体。Using a method similar to that described in Example 8, from 210 mg of 9(R)-acetylthiomethyl-octahydro-6,10-dioxo-6H-pyridazino[1,2-α][1,2 ] diazepine

-1(S)-carboxylic acid, 75 mg of octahydro-9(R)-mercaptomethyl-6,10-dioxo-6H-pyridazino[1,2-α][1, 2) diazepine

-1(S)-carboxylic acid, which is an amorphous solid.

Example 10

-1（S）-羧酸中，可制得75毫克八氢-9（S）-巯甲基-10-氧-哒嗪并〔1，2-α〕〔1，2〕二氮杂

-1（S）-羧酸，其为非晶形固体。Using a method similar to that described in Example 8, from 110 mg of 9-(S)-acetylthiomethyl-octahydro-10-oxo-6H-pyridazino[1,2-α][1,2]di Aza

-1(S)-carboxylic acid, 75 mg of octahydro-9(S)-mercaptomethyl-10-oxo-pyridazino[1,2-α][1,2]diazepine can be obtained

- 1(S)-carboxylic acid which is an amorphous solid.

Example 11

-1（S）-羧酸中，可制得100毫克的八氢-9（R）-巯甲基-10-氧-6H-哒嗪并〔1，2-α〕〔1，2〕二氮杂 -1（S）-羧酸，其为非晶形固体。Using a method similar to that described in Example 8, from 165 mg of 9(R)-acetylthiomethyl-octahydro-10-oxo-6H-pyridazino[1,2-α][1,2]diazepine miscellaneous

-1(S)-carboxylic acid, 100 mg of octahydro-9(R)-mercaptomethyl-10-oxo-6H-pyridazino[1,2-α][1,2]di Aza - 1(S)-carboxylic acid which is an amorphous solid.

Example 12

Using a method similar to that described in Example 1, from 0.36 g of decahydro-10-methylene-6,11-dioxo-6H-pyridazino[1,2-α][1,2]-diazepine In aryl octane (S)-tert-butyl carboxylate, 0.21 g of 10(R,S)-acetylthiomethyl-decahydro-6,11-dioxo-6H-pyridazino-[1, 2-α][1,2]-Diazocine-1(S)-carboxylate tert-butyl ester as a white solid, melting at 105°-108°C (methyl tert-butyl ether).

Decahydro-10-methylene-6,11-dioxo-6H-pyridazino[1,2-α][1,2]diazaocine-1(S)-carboxylic acid tertiary The preparation method of butyl ester is as follows:

嗪酸叔丁酯的溶液（该化合物溶于25毫升无水四氢呋喃中）。在-10℃温度下，搅拌混合物30分钟，然后在室温下继续搅拌16小时。蒸发除掉溶剂，残余物分配在乙酸乙酯和1N盐酸水溶液之间，用饱和的氯化钠水溶液洗涤有机相，和用饱和的碳酸氢钠水溶液洗涤有机相，然后蒸发掉有机相，可得到1.99克1-〔5-（乙氧羰基）-5-己烯酰〕-六氢-3（S）-哒嗪羧酸叔丁酯，其熔点为63°-65℃（乙酸乙酯/正己烷），是白色固体。Dissolve 1.86 g of 1-ethyl hydrogen 2-methylene-hexanedioate (1-ethyl hydrogen 2-methylene-hexanedioate) in 25 ml of anhydrous tetrahydrofuran, and cool the solution to -10°C. Add 1.01 g of triethylamine and 1.37 g of isobutyl chloroformate. At a temperature of -10°C, the above mixture was stirred for 15 minutes, and then 1.86 g of

A solution of tert-butyl oxinate (this compound was dissolved in 25 ml of anhydrous tetrahydrofuran). The mixture was stirred at -10°C for 30 minutes and then at room temperature for a further 16 hours. The solvent was removed by evaporation, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid, the organic phase was washed with saturated aqueous sodium chloride, and the organic phase was washed with saturated aqueous sodium bicarbonate, and the organic phase was evaporated to give 1.99 g of tert-butyl 1-[5-(ethoxycarbonyl)-5-hexenoyl]-hexahydro-3(S)-pyridazinecarboxylate, melting point 63°-65°C (ethyl acetate/n-hexyl alkane), a white solid.

Dissolve 8.2 g of tert-butyl 1-[5-(ethoxycarbonyl)-5-hexenoyl]-hexahydro-3-(S)-pyridazinecarboxylate in 25 ml of ethanol, and add 23.7 ml of 1N hydrogen Aqueous sodium oxide solution was carried out for 16 hours. The above solution was diluted with 30 ml of water, then evaporated to reduce the volume of the solution to 80 ml. The solution was washed with ether, and the pH of the aqueous solution was adjusted to 3 with 2N hydrochloric acid (aqueous) solution. The above aqueous solution was extracted with dichloromethane, the organic phase was evaporated and the residue was separated by chromatography on a silica gel column with dichloromethane/methanol (9:1) as eluent. 3.62 g of tert-butyl 1-[5-(carboxy)-5-hexenoyl]-hexahydro-3(S)-pyridazinecarboxylate can be obtained, with a melting point of 86°-88°C (n-hexane), It is a white solid.

Dissolve 0.56 g of tert-butyl 1-[5-(carboxy)-5-hexenoyl]-hexahydro-3-(S)-pyridazinecarboxylate in 12 ml of dichloromethane and add 0.31 g of thionyl chloride , the above solution was stirred at room temperature under a slow flow of nitrogen for 20 hours, the solution was washed with saturated aqueous sodium bicarbonate solution, and then the solution was evaporated. Then use chromatography to separate the residue on a silica gel column with ether as the eluent to obtain 0.21 g of decahydro-10-methylene-6,11-dioxo-6H-pyridazino[ 1,2-α][1,2]Diazocine-1(S)-carboxylic acid tert-butyl ester, melting point 108°-110°C (diethyl ether).

Example 13

At room temperature, 0.19 g of 10(R,S)-acetylthiomethyl-decahydro-6,11-dioxo-6H-pyridazino[1,2-α][1, 2) tert-butyl diazocine-1(S)-carboxylate for 2 hours. The mixture was evaporated and the residue was dissolved in toluene and evaporated. Repeat this operation two more times. Under nitrogen, the residue was dissolved in 1.5 ml of concentrated ammonia and 1.5 ml of water at room temperature and stirred for 1.5 hours. The solution was cooled to 0°C and the pH was adjusted to 1 with concentrated hydrochloric acid. The solution was then saturated with sodium chloride, and the solution was extracted with dichloromethane. Evaporation of the organic phase yielded 75 mg of decahydro-10(R,S)-mercaptomethyl-6,11-dioxo-6H-pyridazino[1,2-α][1,2]diazapine -1(S)-carboxylic acid as a white amorphous solid.

Example 14

-1（S）-羧酸叔丁酯（非对映异构体1），其熔点为156°-158℃（乙酸乙酯/正己烷），是黄色结晶。Dissolve 720 mg (1.5 mmol) of 8-benzyl-octahydro-9-methanesulfonyloxymethyl-6,10-dioxo-6H-pyridazino[1,2-α][1,2,5] - Triazine - tert-butyl 1(S)-carboxylate (diastereoisomer 1) in 20 ml of butanone, and added 340 mg (2 mmol) of potassium thiolate. The above mixture was heated at reflux for 8 hours, then evaporated to dryness. The residue was partitioned between ethyl acetate and water. Wash the organic phase successively with aqueous sodium bicarbonate solution and saturated sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, then evaporate the organic phase, and use chromatographic separation on a silica gel column to wash with ethyl acetate/n-hexane The liquid was removed and the residue was separated. 400 mg of 9-acetylthiomethyl-8-benzyl-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2,5]triazepine can be obtained

tert-Butyl-1(S)-carboxylate (diastereomer 1), melting at 156°-158°C (ethyl acetate/n-hexane), as yellow crystals.

-1（S）-羧酸叔丁酯（非对映异构体1）的制备方法如下：8-Benzyl-octahydro-9-methanesulfonyloxymethyl-6,10-dioxo-6H-pyridazino[1,2-a][1,2,5]triazepine used as starting material

- tert-Butyl 1(S)-carboxylate (diastereomer 1) was prepared as follows:

嗪酸叔丁酯于400毫升乙醇中，在常压下，用2克5%钯/碳作催化剂，对上述溶液进行氢化5小时。过滤除去催化剂，并蒸发滤液。残渣溶解于50毫升氯甲烷和75毫升碳酸氢钠水溶液的混合物中，并进行搅拌，在0℃温度下，用15分钟时间，加入5.16毫升溴乙酰氯（溶于150毫升二氯甲烷中）溶液。再搅拌混合物45分钟，然后进行分层。有机相用无水硫酸钠进行干燥，并蒸发之。用色谱分离法，在硅胶柱上，以乙酸乙酯/正己烷作洗脱液，分离残余物。可制得9.9克1-溴乙酰-六氢-3（S）-哒嗪羧酸叔丁酯，其熔点为99°-101℃（乙酸乙酯/正己烷），是白色固体。Dissolve 20 g (0.062 mol) of 1-benzyloxycarbonyl-S-

In 400 ml of ethanol, tert-butyl oxinate was hydrogenated for 5 hours under normal pressure using 2 g of 5% palladium/carbon as a catalyst. The catalyst was removed by filtration, and the filtrate was evaporated. The residue was dissolved in a mixture of 50 ml of methyl chloride and 75 ml of aqueous sodium bicarbonate solution, and stirred, and a solution of 5.16 ml of bromoacetyl chloride (dissolved in 150 ml of dichloromethane) was added at 0°C for 15 minutes. . The mixture was stirred for an additional 45 minutes, then the layers were separated. The organic phase was dried over anhydrous sodium sulfate and evaporated. The residue was separated by chromatography on a silica gel column with ethyl acetate/n-hexane as eluent. 9.9 g of tert-butyl 1-bromoacetyl-hexahydro-3(S)-pyridazinecarboxylate, melting at 99°-101°C (ethyl acetate/n-hexane), were obtained as a white solid.

Dissolve 13.9 g (0.048 mol) of N-trifluoroacetyl-O-benzyl-D,LL-serine in 150 ml of dichloromethane and allow the solution to cool to -20°C. At this temperature, 9.96 g (0.048 mol) of phosphorus pentachloride was added to the above solution, the temperature was returned to room temperature, and then the solution was stirred at room temperature for 30 minutes. After evaporation, an oily residue is obtained which is dissolved in 150 ml of dichloromethane. This solution was added over 1 hour at 0°C under constant stirring to a mixture comprising 9.8 g of 1-bromoacetyl-hexahydro-3(S)-pyridazinecarboxylate Acetyl tert-butyl ester, 100 ml of dichloromethane and 100 ml of aqueous sodium bicarbonate. The above mixed solution was stirred at room temperature for 17 hours, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and evaporated. The residue was separated by chromatography on a silica gel column with ethyl acetate/n-hexane as eluent. 12.5 g of 1-bromoacetyl-2-/[3-benzyloxy-2(R,S)-trifluoroacetylamino]propionyl/-pyridazine-3(S)-carboxylic acid tert-butyl ester as a yellow oil.

The above oil was dissolved in 650 ml of anhydrous dimethylformamide, and 980 mg of sodium hydride was added to the solution. After 2 hours, the above solution was poured into 1.6 liters of ice water at a temperature of 20°C, then the solution was extracted with dichloromethane, the organic extract was evaporated, and chromatographic separation was performed on a silica gel column with ethyl acetate/n-hexane Alkane was used as eluent, and the residue was separated. Two diastereomers of 9-benzyloxymethyl-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2,5]triazine can be obtained miscellaneous - tert-butyl 1(S)-carboxylate, wherein the yield of diastereomer 1 was 3.1 g, and that of diastereomer 2 was 1.05 g, both as pale yellow gums.

500 mg of the above diastereoisomer 1 was dissolved in 10 ml of methanol containing a few drops of acetic acid, and the solution was hydrogenated for 17 hours under normal pressure using 50 mg of 5% palladium on carbon as a catalyst. The catalyst was removed by filtration, and the filtrate was evaporated to give 440 mg of octahydro-9-hydroxymethyl-6,10-dioxo-6H-pyridazino[1,2-a][1,2,5]triazepine - tert-butyl 1(S)-carboxylate (diastereoisomer 1) as a colorless gum.

-1（S）-羧酸叔丁酯（非对映异构体1），其熔点133°-135℃（乙酸乙酯/正己烷），为白色固体。0.41 ml of benzyl bromide was dissolved in 20 ml of acetonitrile containing 1 ml of diethylisopropylamine, and the colorless gum prepared above was reacted with the solution at 20°C for 24 hours. After evaporation, the residue was chromatographed on a silica gel column using ethyl acetate/n-hexane as eluent to give 400 mg of 8-benzyl-octahydro-9-hydroxymethyl-6,10 -Dioxo-6H-pyridazino[1,2-a][1,2,5]triazepine

- tert-butyl 1(S)-carboxylate (diastereomer 1), mp 133°-135°C (ethyl acetate/n-hexane), as a white solid.

-1（S）-羧酸叔丁酯（非对映异构体1）于10毫升二氯甲烷中，并在20℃温度下，该溶液与0.2毫升三乙胺发生反应，然后再与0.09毫升甲基磺酰氯反应。在室温下，搅拌混合物2小时，然后用水洗涤混合物，并用无水硫酸钠进行干燥，蒸发混合物，就得到230毫克8-苄基-八氢-9-甲基磺酰氧甲基-6，10-二氧-6H-哒嗪并〔1，2-a〕〔1，2，5〕三氮杂

-1（S）-羧酸叔丁酯（非对映异构体1），其熔点55°-57℃（乙醚/正己烷），为白色固体。Dissolving 8-benzyl-octahydro-9-hydroxymethyl-6,10-dioxo-6H-pyridazino[1,2-a][1,2,5]triazepine

- tert-butyl 1(S)-carboxylate (diastereoisomer 1) in 10 ml of dichloromethane, and at 20°C, this solution was reacted with 0.2 ml of triethylamine and then with 0.09 mL of methanesulfonyl chloride was reacted. At room temperature, the mixture was stirred for 2 hours, then the mixture was washed with water and dried over anhydrous sodium sulfate, and the mixture was evaporated to obtain 230 mg of 8-benzyl-octahydro-9-methylsulfonyloxymethyl-6,10 -Dioxo-6H-pyridazino[1,2-a][1,2,5]triazepine

- tert-Butyl 1(S)-carboxylate (diastereoisomer 1), melting at 55°-57°C (ether/n-hexane), as a white solid.

Example 15

-1（S）-羧酸叔丁酯（非对映异构体1），与0.5毫升溶于乙酸中的45%溴化氢溶液发生反应30分钟。然后在上述溶液中加入无水乙醚，并过滤掉沉淀物。就可得到60毫克非晶形的9-乙酰硫甲基-8-苄基八氢-6，10-二氧-6H-哒嗪并〔1，2-a〕〔1，2，5〕三氮杂

-1（S）-羧酸（非对映异构体）。At a temperature of 20°C, 110 mg of 9-acetylthiomethyl-8-benzyl-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2,5] Triazine

- tert-butyl 1(S)-carboxylate (diastereomer 1) was reacted with 0.5 ml of 45% hydrogen bromide solution in acetic acid for 30 minutes. Anhydrous diethyl ether was then added to the above solution, and the precipitate was filtered off. 60 mg of amorphous 9-acetylthiomethyl-8-benzyl octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2,5]triazine can be obtained miscellaneous

-1(S)-Carboxylic acid (diastereoisomer).

Example 16

氢溴化物作原料，反应生成物经色谱分离后;色谱分离在硅胶柱上进行，用2%的醋酸/乙醚溶液作洗脱剂，这样就可得到20毫克8-苄基-八氢-9-甲基-6，10-二氧-6H-哒嗪并〔1，2-a〕〔1，2，5〕三氮杂-1（S）-羧酸（非对映异构体1），其熔点85℃（分解了;用二乙基醚/正己烷），为白色固体。Using a method similar to that described in Example 8, 60 mg of 9-acetylthiomethyl-8-benzyl-octahydro-6,10-pyridazino[1,2-a][1,2,5] Triazine

Hydrobromide is used as a raw material, and the reaction product is separated by chromatography; the chromatography is carried out on a silica gel column, and 2% acetic acid/ether solution is used as an eluent, so that 20 mg of 8-benzyl-octahydro-9 can be obtained -Methyl-6,10-dioxo-6H-pyridazino[1,2-a][1,2,5]triaza-1(S)-carboxylic acid (diastereomer 1) , with a melting point of 85°C (decomposed; with diethyl ether/n-hexane), as a white solid.

Example 17

-1（S）-羧酸叔丁酯作原料，可得到二种非对映异构体（即非对映异构体1，和非对映异构体2）的9-乙酰硫甲基-8-甲基-八氢-6，10-二氧-6H-哒嗪并〔1，2-α〕〔1，2，5〕三氮杂

-1（S）-羧酸叔丁酯，其为胶状物。Using a method similar to that described in Example 14, 8-methyl-octahydro-9-methanesulfonyloxymethyl-6,10-dioxo-6H-pyridazino[1,2-α][1 , 2,5] triaza

- 1 (S) - tert-butyl carboxylate as raw material, two diastereoisomers (i.e., diastereomer 1, and diastereomer 2) of 9-acetylthiomethyl can be obtained -8-Methyl-octahydro-6,10-dioxo-6H-pyridazino[1,2-α][1,2,5]triazepine

- tert-butyl 1(S)-carboxylate in the form of a gum.

-1（S）-羧酸叔丁酯胶状物的制备方法，可采用在例14中所描述的其中有关原料制备的类似方法。8-Methyl-octahydro-9-methanesulfonyloxymethyl-6,10-dioxo-6H-pyridazino[1,2-α][1,2,5]triazepam used as raw material miscellaneous

-1(S)-t-Butyl carboxylate jelly can be prepared in a manner similar to that described in Example 14 for the preparation of the raw materials therein.

Example 18

-1（S）-羧酸叔丁酯（非对映异构体1）为原料，可得到100毫克9-乙酰硫甲基-8-甲基-八氢-6，10-二氧-6H-哒嗪并〔1，2-α〕〔1，2，5〕三氮杂

-1（S）-羧酸（非对映异构体1），其为非晶形固体。Using a method similar to that described in Example 15, 110 mg of 9-acetylthiomethyl-8-methyl-octahydro-6,10-dioxo-6H-pyridazino-[1,2-α][ 1,2,5] triaza

- Starting from tert-butyl 1(S)-carboxylate (diastereomer 1), 100 mg of 9-acetylthiomethyl-8-methyl-octahydro-6,10-dioxo-6H -Pyridazino[1,2-α][1,2,5]triazepine

- 1(S)-carboxylic acid (diastereoisomer 1) as an amorphous solid.

Example 19

-1（S）-羧酸叔丁酯（非对映异构体2）作原料，可制得50毫克9-乙酰硫甲基-8-甲基-八氢-6，10-二氧-6H-哒嗪并〔1，2-α〕〔1，2，5〕-三氮杂

-1（S）-羧酸（非对映异构体2），其为非晶形固体。Using a method similar to that described in Example 15, 80 mg of 9-acetylthiomethyl-8-methyl-octahydro-6,10-dioxo-6H-pyridazino-[1,2-α][ 1,2,5] triaza

-1(S)-tert-butyl carboxylate (diastereomer 2) as starting material, 50 mg of 9-acetylthiomethyl-8-methyl-octahydro-6,10-dioxo- 6H-pyridazino[1,2-α][1,2,5]-triazepine

- 1(S)-Carboxylic acid (diastereomer 2) as an amorphous solid.

Example 20

-1（S）-羧酸（非对映异构体1）作原料，可制得10毫克八氢-9-甲基-8-甲基-6，10-二氧-6H-哒嗪并〔1，2-α〕〔1，2，5〕三氮杂

-1（S）-羧酸（非对映异构体1），其为白色冻干物。Using a method similar to that described in Example 8, 50 mg of 9-acetylthiomethyl-8-methyl-octahydro-6,10-dioxo-6H-pyridazino-[1,2-α][ 1,2,5] triaza

-1(S)-carboxylic acid (diastereoisomer 1) as starting material, 10 mg of octahydro-9-methyl-8-methyl-6,10-dioxo-6H-pyridazino [1,2-α][1,2,5]triazepine

- 1(S)-carboxylic acid (diastereomer 1), which is a white lyophilizate.

Example 21

-1（S）-羧酸（非对映异构体2）作原料，可制得10毫克八氢-9-甲基-8-甲基-6，10-二氧-6H-哒嗪并〔1，2-a〕〔1，2，5〕三氮杂

-1（S）-羧酸（非对映异构体2），其为白色冻干物。Using a method similar to that described in Example 8, 50 mg of 9-acetylthiomethyl-8-methyl-octahydro-6,10-dioxo-6H-pyridazino-[1,2-a][ 1,2,5] triaza

-1(S)-carboxylic acid (diastereoisomer 2) as starting material, 10 mg of octahydro-9-methyl-8-methyl-6,10-dioxo-6H-pyridazino [1,2-a][1,2,5]triazepine

- 1(S)-carboxylic acid (diastereomer 2), which is a white lyophilizate.

Example 22

-1（S）-羧酸甲酯，其熔点127°-129℃（乙醚/正己烷），为白色结晶，以及制得1.2克9（R）-乙酰硫甲基-八氢-6，10-二氧-6H-哒嗪并〔1，2-α〕〔1，2〕二氮杂

-1（S）-羧酸甲酯，其为无色胶状物。Using a method similar to that described in Example 1, 2.02 g of octahydro-9-methylene-6,10-dioxo-6H-pyridazino[1,2-α][1,2]diazepine -1(S)-Methyl carboxylate was used as raw material to obtain 1.17 g of 9(S)-acetylthiomethyl octahydro-6,10-dioxo-6H-pyridazino[1,2-α] [1,2]-diazepine

- 1(S)-methyl carboxylate, melting point 127°-129°C (ether/n-hexane), as white crystals, and 1.2 g of 9(R)-acetylthiomethyl-octahydro-6,10 -Dioxo-6H-pyridazino[1,2-α][1,2]diazepine

- 1(S)-methyl carboxylate as a colorless gum.

-1（S）-羧酸甲酯的制备方法如下：Octahydro-9-methylene-6,10-dioxo-6H-pyridazino[1,2-α][1,2]diazepine used as starting material

The preparation method of -1(S)-methyl carboxylate is as follows:

-1（S）-羧酸叔丁酯，与40毫升三氟乙酸一起搅拌3小时，蒸发上述混合物，将得到的油状物用乙醚进行处理就制得7.6克八氢-9-亚甲基-6，10-二氧-6H-哒嗪并〔1，2-α〕〔1，2〕-二氮杂 -（S）-羧酸，其熔点169°-172℃，为白色固体。At a temperature of 20°C, 10 g of octahydro-9-methylene-6,10-dioxo-6H-pyridazino-[1,2-α][ 1,2) diazepine

- tert-butyl 1(S)-carboxylate was stirred with 40 ml of trifluoroacetic acid for 3 hours, the mixture was evaporated and the resulting oil was treated with ether to give 7.6 g of octahydro-9-methylene- 6,10-Dioxo-6H-pyridazino[1,2-α][1,2]-diazepine -(S)-Carboxylic acid, melting point 169°-172°C, white solid.

-1（S）-羧酸悬浮在200毫升乙酸乙酯中，在0℃温度下，在不断地搅拌的情况下，在悬浮液中加入100毫升重氮甲烷-醚溶液。30分钟以后，逐滴加入醋酸，以便破坏掉悬浮液中过量的重氮甲烷。该混合物用碳酸氢钠水溶液进行洗涤，并用硫酸钠干燥之，蒸发混合物，就可得到5.17克八氢-9-亚甲基-6，10-二氧-6H-哒嗪并〔1，2-α〕〔1，2〕二氮杂 -1（S）-羧酸甲酯，其熔点73°-75℃（正己烷），为白色固体。7.6 grams of octahydro-9-methylene-6,10-dioxo-6H-pyridazino-[1,2-α][1,2]diazepine

- 1(S)-carboxylic acid was suspended in 200 ml of ethyl acetate, and 100 ml of diazomethane-ether solution was added to the suspension at 0°C with constant stirring. After 30 minutes, acetic acid was added dropwise to destroy excess diazomethane in the suspension. The mixture was washed with aqueous sodium bicarbonate and dried over sodium sulfate. The mixture was evaporated to give 5.17 g of octahydro-9-methylene-6,10-dioxo-6H-pyridazino[1,2- α][1,2]diazepine -1(S)-Methyl carboxylate, melting point 73°-75°C (n-hexane), white solid.

The preparation method of the medicament containing the compound provided by the present invention is illustrated as follows:

Example A

Tablets containing the following ingredients can be produced by the usual method:

Ingredients content in each tablet

Compound of chemical formula Ⅰ 10.0 mg

Lactose 125.0 mg

Corn starch 75.0 mg

Talc powder 4.0 mg

Magnesium Stearate 1.0 mg

Total weight 215.0 mg

Example B

Capsule pills containing the following ingredients can be produced using a general method:

Ingredients content in each capsule

Compound of chemical formula Ⅰ 25.0 mg

Lactose 150.0 mg

Corn starch 20.0 mg

Talc powder 5.0 mg

Total weight of capsules and pills 200.0 mg

Claims (29)

1, a kind of preparation method with the compound shown in the following general formula I is characterized in that:

R wherein ¹Represent hydrogen, alkanoyl or aroyl; R ²Represent hydrogen or alkyl; R ³Represent hydrogen or aryl; R ⁴And R ⁵Each represents hydrogen or R ⁴And R ⁵Lump together for epoxy group; Y representative-CH ₂-,-CH ₂CH ₂-or-NCR ⁶-; R here ⁶Expression hydrogen, alkyl or aralkyl, and at R ²When representing hydrogen, above-claimed cpd and alkali generate and can be used as the salt of medicine and at Y representative-N (R ⁶) for the moment, above-claimed cpd and acid generate the preparation method of the salt that can be used as medicine, and this preparation method comprises following content:

A) be to prepare general formula I, wherein R ⁴And R ⁵For the compound of epoxy group, the compound of following general formula II compound and general formula III is reacted together; R in its formula of II ²R ³, Y has the above-mentioned implication that has provided, R in the general formula III ¹Have the implication that the front has provided,

Or

B) for preparing compound with general formula I; R wherein ¹Represent alkanoyl or aroyl, R ²Represent alkyl, and Y representative-CH ₂-,-CH ₂CH ₂-or-N (R ⁶)-, be R wherein ⁶Represent alkyl or aralkyl, can react the compound of general formula IV and an alkali metal salt with general formula V compound,

R in the general formula IV ³, R ⁴And R ⁵Has the implication that has provided, R ²⁰Represent alkyl, Y ¹Representative-CH ₂-,-CH ₂CH ₂-or-N (R ⁶⁰)-; R wherein ⁶⁰Represent alkyl or aralkyl, and Z representative residue group,

R among the general formula V ¹⁰Represent alkanoyl or aroyl,

Or

C) for preparing compound with general formula I; R wherein ¹Represent alkanoyl or aroyl, R ²Represent alkyl, R ⁴And R ⁵Together for epoxy group, and Y representative-CH ₂-or-CH ₂CH ₂-, but cyclisation has the compound of general formula VI,

R wherein ³, R ¹⁰And R ²⁰Have the implication that has provided, and Y ²Representative-CH ₂-or-CH ₂CH ₂-,

Or

D) for preparing compound with general formula I; R wherein ¹Represent alkanoyl or aroyl, R ²Represent alkyl, R ⁴And R ⁵Together for epoxy group, and Y representative-CH ₂-or-CH ₂CH ₂-, but cyclisation has the compound of general formula VII;

R wherein ³, R ¹⁰And R ²⁰And Y ²Have the implication that has provided,

Or

C) for preparing compound with general formula I; R wherein ¹Represent alkanoyl or aroyl, R ²Represent alkyl, R ⁴And R ⁵Together for epoxy group, and Y representative-NH-, but cyclisation has the compound of general formula VIII,

R wherein ³, R ¹⁰And R ²⁰Have the implication that has provided, Hal represents halogen,

Or

F) for preparing compound with general formula I; R wherein ¹Represent alkyloyl or aroyl, R ²Represent alkyl, and R ⁴And R ⁵Each represents hydrogen, reducible compound of Formula I; R wherein ¹Represent alkanoyl or aroyl, R ²Represent alkyl, and R ⁴And R ⁵Together for epoxy group,

Or

G) for preparing the compound with general formula I, wherein R ¹Represent zinc alkyloyl or aroyl, and

Y representative-N-(R ⁶)-; R wherein ⁶Represent alkyl or aroyl, available general formula I

Compound and compound reaction with general formula I X; Its in formula I, R ¹Represent alkanoyl or

Aroyl, and Y representative-NH-,

In the IX formula, R ⁶⁰Have the implication that has provided with Z,

Or

H) for preparing compound with general formula I; R wherein ¹Represent hydrogen, available bases is handled has general formula I; R wherein ¹Represent the compound of alkanoyl or aroyl,

Or

I) for the compound of preparation formula I, R wherein ²Represent hydrogen, usable acid or alkaline purification formula I's;

And R wherein ²Represent the compound of alkyl,

Or

J) for preparing compound with general formula I; R wherein ¹Represent alkanoyl or aroyl, and Y representative-CH ₂-,-CH ₂CH ₂-or-N (R ⁶)-; R wherein ⁶Represent alkyl or aralkyl, appropriately to having general formula I; R wherein ¹Represent the corresponding compounds of hydrogen, carry out alkanoylization or aroylation,

Or

K) if necessary, the mixture that separates the racemoid of the diastereomer that obtains; Make it to become the racemoid or the optically pure diastereo-isomerism spare of diastereomer,

And/or

L) if desired, split the racemoid that obtains, make it to be optically active enantiomorph,

With

M) if desired, with alkali the general formula I that has that is obtained; R wherein ²Represent the compound of hydrogen, change the salt that can be used as medicine into, and with acid the general formula I that has that is obtained; Y wherein

Representative-N (R ⁶)-compound, change the salt that can be used as medicine into.

2, according to the method for claim 1, it is characterized by R ¹Represent hydrogen.

3, according to the method for claim 1 or claim 2, it is characterized by R ²Represent hydrogen.

4, according to the method for arbitrary claim in the claim 1 to 3, it is characterized by R ³Represent hydrogen.

5, according to the method for arbitrary claim in the claim 1 to 4, it is characterized by Y representative-CH ₂-.

6, according to the method for arbitrary claim in the claim 1 to 5, it is characterized by R ¹, R ²And R ³Each represents hydrogen, and Y representative-CH ₂-.

7, according to the method for claim 1, it is characterized by and can prepare octahydro-9-mercapto methyl-6,10-dioxy base-6H-pyridazine is (1,2-α) (1,2) diaza also

-1-carboxylic acid.

8, according to the method for claim 1, it is characterized by and can prepare also (1,2-α) (1,2) diaza of octahydro-9-mercapto methyl-10-oxygen base-6H-pyridazine

-1-carboxylic acid.

9, according to the method for claim 1, it is characterized by and can prepare decahydro-10-mercapto methyl-6,11-dioxy base-6H-pyridazine is (1,2-α) (1,2) diazocine-1-carboxylic acid also.

10, according to arbitrary claim method in the claim 1 to 9, it is characterized by has R on unsymmetrical carbon ¹-S-CH ₂And R ²-OOC-substituting group, its configuration are (S) types.

11, a kind of preparation method as antihypertensive drug is characterized in that this method has comprised the compound of the formula I that will state or worked as R in claim 1 ²When representing hydrogen, I formula compound and alkali are formed the salt that can be used as medicine or represents N(R as Y ⁶)-time, I formula compound and acid are generated the salt that can be used as medicine be prepared into the galenical medicine.

12, a kind of medicine and the treatment on be inert excipients, it is characterized in that this medicine contains the compound of the formula I described in the claim 1, or contain following pharmaceutical salts; Promptly work as R ²When representing hydrogen, the pharmaceutical salts that I formula compound and alkali generate, or work as Y and represent N(R ⁶)-time, I formula compound and the sour pharmaceutical salts that generates.

13, a kind of antihypertensive medicine; It contains the compound of the formula I of being stated in claim 1; Or contain and work as R ²When representing hydrogen, I formula compound and alkali form pharmaceutical salts; Or contain as Y and represent N(R ⁶) time; I formula compound and acid form pharmaceutical salts and a kind of in treatment inert excipients.

14, the compound of formula I

R wherein ¹Represent hydrogen, alkanoyl or aroyl; R ²Represent hydrogen or alkyl; R ³Represent hydrogen or aryl; R ⁴And R ⁵Each represents hydrogen or R ⁴And R ⁵Lump together for epoxy group; And Y representative-CH ₂-,-CH ₂CH ₂-or-N(R ⁶)-; R wherein ⁶Represent hydrogen, alkyl or aralkyl, and work as R ²When representing hydrogen, I formula compound and alkali form pharmaceutical salts and work as Y representative-N(R ⁶)-time, I formula compound forms pharmaceutical salts with acid, when above-mentioned I formula compound of preparation and medicinal salts thereof, and should be according to method described in the claim 1 or according to its tangible chemical equivalent relation preparation.

15, according to claim 14 described compounds, it is characterized by R ¹Represent hydrogen, when preparation, should be according to the method for claim 2 requirements or according to the preparation of tangible chemical equivalent relation.

16, according to claim 14 or 15 described compounds, it is characterized by R ²Represent hydrogen, when preparation, should be according to the method for claim 3 requirements or according to its tangible chemical equivalent relation preparation.

17, according to the described compound of arbitrary claim in the claim 14 to 16, it is characterized by R ³Represent hydrogen, when preparation, should be according to the method for claim 4 requirements or according to its tangible chemical equivalent relation preparation.

18, according to the described compound of arbitrary claim in the claim 14 to 17, it is characterized by Y representative-CH ₂-, when preparation, should be according to the method for claim 5 requirements or according to its tangible chemical equivalent relation preparation.

19, according to the described compound of arbitrary claim in the claim 14 to 18, it is characterized by R ¹, R ²And R ³Each represents hydrogen, and Y representative-CH ₂-, when preparation, according to the method for claim 6 requirements or according to its tangible chemical equivalent relation preparation.

20, octahydro-9-mercapto methyl-6,10-dioxy base-6H-pyridazine be (1,2) diaza also-(1,2-α)

-1-carboxylic acid is whenever when preparation, according to desired method in the claim 8 or rely on its tangible chemical equivalent relation preparation.

21, octahydro-9-mercapto methyl-10-oxygen base-6H-pyridazine (1,2-α) (1,2) diaza also

-1-carboxylic acid is when preparation, according to the method for claim 8 requirements or according to its tangible chemical equivalent relation preparation.

22, decahydro-10-mercapto methyl-6,11-dioxy base-6H-pyridazine be (1,2) diazocine-1-carboxylic acid also-(1,2-α), when preparation, according to the method that requires in the claim 9 or according to its tangible chemical equivalent relation preparation.

23, according to the described compound of arbitrary claim in the claim 14 to 22, it is characterized by has R on unsymmetrical carbon ¹-S-CH ₂-and R ²-OOC-is substituent, and configuration is (S) type, when preparation, according to the method that requires in the claim 10 or according to its tangible chemical equivalent relation preparation.

24, the present invention mentioned above.

25, general formula is the compound of II; It is characterized in that:

R wherein ²Represent hydrogen or alkyl; R ³Represent hydrogen or aryl; And Y representative-CH ₂-,-CH ₂CH ₂-or-N(R ⁶)-; R wherein ⁶Represent hydrogen, alkyl or aralkyl.

26, general formula is the compound of IV; It is characterized in that:

R wherein ³Represent hydrogen or aryl; R ⁴And R ⁵Each represents hydrogen, or R ⁴And R ⁵Lump together for epoxy group; R ²⁰Represent alkyl; Y ¹Representative-CH ₂-,-CH ₂CH ₂-or-N(R ⁶⁰)-; R wherein ⁶⁰Represent alkyl or aralkyl; Z representative residue group.

27, general formula is that the compound of VI is characterized in that,

R wherein ³Represent hydrogen or aryl; R ¹⁰Represent alkanoyl or aroyl, R ²⁰Represent alkyl; And Y ²Representative-CH ₂-or-CH ₂CH ₂-.

28, general formula is the compound of VII;

R wherein ³Represent hydrogen or aryl; R ¹⁰Represent alkanoyl or aroyl; R ²⁰Represent alkyl; And Y ²Representative-CH ₂-or-CH ₂CH ₂-.

29, general formula is that the compound of VIII is characterized in that

R wherein ³Represent hydrogen or aryl; R ¹⁰Represent alkanoyl or aroyl; R ²⁰Represent alkyl; And Hal represents halogen.