JPS5939423B2 - Method for producing N↓2-naphthalenesulfonylargininamides or acid addition salts thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing N2-naphthalenesulfonylargininamides or acid addition salts thereof, which have a strong inhibitory effect on thrombin, which is one of the important proteolytic enzymes involved in the blood coagulation system. .

N2-naphthalenesulfonylargininamide or its acid addition salt exhibits a strong antithrombin effect as a thrombin inhibitor, is a unique physiologically active substance that inhibits blood coagulation, and is characterized by a sustained antithrombin effect. has.

The purpose of the present invention is to provide a method for producing N2-naphthalenesulfonylarginine amides that are useful as described above. Formula (1)-N/R”\R.

(In the formula, R1 and R2 represent a hydrogen atom, an alkyl group, a cycloalkylalkyl group, or an alkyl group substituted with an alkoxy group or an alkoxycarbonyl group.

) or the general formula (2) -NZ (in the formula, Z is a methylene group -CH2- and a monosubstituted methylene group -C-(R3
represents an alkyl group, an acyl group, an alkoxy group or an alkoxycarbonyl group.

) and an oxy group -0-,
Thio group -5-, cycloalkylene group, alkyl-substituted imino group 1 (R6 represents an alkyl group 0=C=R7.

), acyl-substituted imino group 1 (R7 represents an alkyl group.

) and a phenylene group o, representing a divalent group in which zero or one or more groups selected from o are bonded in any order.

). ) or its acid addition salt represented by the following general formula (■) R'-SO2X (■
) (In the above general formula (■), R' is a 1-naphthyl group; 2-naphthyl group; 1-naphthyl substituted with a halogen atom, a nitro group, an alkoxycarbonyloxy group, a dialkylamino group, a cyano group, or an alkyl group) group or 2-naphthyl group, and X represents a halogen atom.

However, 5-(dimethylamino)-1-naphthyl group is excluded. ) or a substituted naphthalenesulfonyl halide represented by the following general formula (■) (in the above general formula (1), R is the general formula (
1 N/i: C'1\R9 (wherein R1 and R2 represent a hydrogen atom, an alkyl group, a cycloalkylalkyl group, or an alkyl group substituted with an alkoxy group or an alkoxycarbonyl group.

) or the general formula (2)-] poly (in the formula, Z is a methylene group -
two or more groups selected from CH2- and a monosubstituted methylene group -C- (R3 represents an alkyl group, acyl group, alkoxy group or alkoxycarbonyl group), an oxy group -0-, a thio group -S-, Cycloalkylene group, alkyl-substituted imino group (R6 represents an alkyl group).

), an acyl-substituted imino group (R7 represents an alkyl group).

) and phenylene group] [? ] - represents a divalent group in which O selected from - or one or more groups are bonded in any order.
). ) to arginine amide or its acid addition salt represented by the following general formula () (in the above general formula (), R5 is a 1-naphthyl group; a 2-naphthyl group; an atom atom, a nitro group, an alkoxycarbonyloxy group, It represents a 1-naphthyl group or a 2-naphthyl group substituted with a dialkylamino group, a cyano group, or an alkyl group, and X represents a halogen atom.

However, 5-(dimethylamino)-1-naphthyl group is excluded. ) or a substituted naphthalenesulfonyl halide represented by the following general formula () (in the above general formula (), R is the above general formula ()).
It has the same meaning as in 1), and R' is the above general formula ()
has the same meaning as in .

) is achieved by obtaining N2-naphthalenesulfonylarginine amides. To explain the present invention in detail, the argininamide used as a raw material in the present invention is represented by the above general formula (), and examples of R in the above general formula are as follows.

R and R2 are substituted with a hydrogen atom, an alkyl group usually having 10 or less carbon atoms, a cycloalkylalkyl group usually having 15 or less carbon atoms, an alkoxy group usually having 10 or less carbon atoms, or an alkoxycarbonyl group usually having 10 or less carbon atoms. It usually represents an alkyl group having 10 or less carbon atoms.

More specifically, methyl group, ethyl group, n-propyl group,
Alkyl groups such as isopropyl group, n-butyl group, isobutyl group, n-pentyl group, n-hexyl group, n-heptyl group, cycloalkylalkyl group such as cyclohexylmethyl group, 3-cyclohexylpropyl group, or methoxyethyl group , a methoxypropyl group, an ethoxyethyl group, an ethoxycarbonylmethyl group, a 2-ethoxycarbonylethyl group, a 3-ethoxycarbonylpropyl group, or an alkyl group substituted with an alkoxy group or an alkoxycarbonyl group.

z represents a methylene group -CH2- or a monosubstituted methylene group C- (R3 usually represents an alkyl group, acyl group, alkoxy group or alkoxycarbonyl group having 10 or less carbon atoms);

), and an oxy group -0-
, thio group -S-, cycloalkylene group usually having 10 or less carbon atoms, alkyl-substituted imino group ((R6 usually represents an alkyl group having 10 or less carbon atoms).

), acyl-substituted imino group (R7 is usually carbon Represents an alkyl group with a prime number of 10 or less.

) and phenylene group {:] represents a divalent group in which O or one or more groups are bonded in any order, and the number of bonded groups is usually 20 or less. More specifically, the above R is a 1-aziridinyl group, a 1-azetidinyl group, a 3-methoxy-1 azetidinyl group, a 3-ethoxy-
1-azetidinyl group, 1-pyrrolidinyl group, 1-piperidino group, 4-methyl-1-piperidino group, 4-ethyl-
1-piperidino group, 4-(n-propyl)-1-piperidino group, 4-isopropyl-1-piperidino group, 2-methyl-1-piperidino group, 3-methyl-1-piperidino group, 2-ethoxycarbonyl-1 -pyrrolidinyl group, 4-
1-Polymethyleneiminyl groups such as methoxy-1-piperidino group, 4-acetyl-1-piperidino group, 4-methoxycarbonyl-1-piperidino group, 1-hexamethyleneiminyl group, and 1-octamethyleneiminyl group or derivatives thereof, oxazole and thiazole groups such as 3-oxazolidinyl group and 3-thiazolidinyl group, isoxazole and isothiazole groups such as 2-isoxazolidinyl group and 2-isothiazolidinyl group, 4 -morpholino group, 2,6-dimethyl4-morpholino group, 3-
Oxazine groups such as (tetrahydro-1,3-oxazinyl) group, thiazine groups such as 4-(tetrahydro-1,4-thiazyl) group, 4-methyl-1-piperazinyl group, 4-acetyl-1-piperazinyl group. group, 2-isoindolinyl group, 1-indolinyl group, 1, 2, 3, 4
-tetrahydro 2-isoquinolyl group, 3-azapine guro [3.2.2] non-3-yl group, 1.2.3.4
-tetrahydro-1-quinolyl group, etc. The N2-naphthalenesulfonylarginine amide obtained by the method of the present invention is represented by the above general formula ().

Examples of acid addition salts of argininamide or N2-naphthalenesulfonylargininamides include inorganic acid salts and organic acid salts such as hydrochloride, hydrobromide, P-toluenesulfonate, formate, and acetate. .

N2-argininamide or its acid addition salt used as a raw material in the present invention is a guanidino group and an α-amino group of arginine that are nitrated, acetylated, formylated, putarolated, trifluoroacetylated, and P-methoxybenzyloxycarbonyl. oxidation, benzoylation, benzyloxycarbonylation, tritylation, etc., and then combine it with an amine represented by RH corresponding to R in the above general formula (1) and an acid chloride method, an acid azide method, or a mixed acid method. It can be obtained by condensation according to a conventional method such as an anhydride method, active esterification method, carbodiimide method, etc. and then removing the protective group.

Naphthalenesulfonyl halide or substituted naphthalenesulfonyl halide, which is another raw material for N2-naphthalenesulfonylargininamides or acid addition salts thereof, is represented by the above general formula (), and in the general formula (), R
' is 1-naphthyl group; 2-naphthyl group; halogen atom,
1 substituted with a nitro group, alkoxycarbonyloxy group, dialkylamino group, cyano group or alkyl group
-Represents a naphthyl group or a 2-naphthyl group.

Specifically, the substituents on the naphthalene ring are Cl, . Halogen atoms such as Br; nitro groups; lower alkoxycarbonyloxy groups, usually having 5 or less carbon atoms, such as methoxycarbonyloxy and ethoxycarbonyloxy groups; dialkylamino groups, usually having 10 or less carbon atoms, such as dimethylamino and diethylamino groups; Cyano group; an alkyl group usually having 10 or less carbon atoms, preferably 5 or less carbon atoms, such as a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, or t-butyl group. Note that 5(dimethylamino)-1-naphthyl group is excluded. Also, X is Cl. Br
etc., but as the naphthalenesulfonyl halide or substituted naphthalenesulfonyl halide, naphthalenesulfonyl chloride or substituted naphthalenesulfonyl chloride is usually used. The reaction between argininamide or its acid addition salt and naphthalenesulfonyl halide or substituted naphthalenesulfonyl halide is usually carried out in the presence of a base.

The base captures the hydrogen halide produced in the reaction and accelerates the reaction. Examples of the base include organic bases such as triethylamine and pyridine, and common inorganic bases such as sodium hydroxide, potassium hydroxide, and potassium carbonate.

Inorganic bases are usually used as aqueous solutions. The base is usually used in an amount equivalent to or more than the amount of argininamide.

When using an acid addition salt of argininamide as a raw material, it is preferable to use an excess amount of base sufficient to convert the acid addition salt of argininamide into argininamide.
The naphthalenesulfonyl halide or substituted naphthalenesulfonyl halide is usually reacted with equimolar amounts of arginine amide or its acid addition salt.

The reaction between argininamide or its acid addition salt and naphthalenesulfonyl halide or substituted naphthalenesulfonyl halide is generally carried out in a solvent. Water as a solvent: Chlorinated solvents such as methylene chloride, chloroform, and carbon tetrachloride; Aromatic hydrocarbons such as benzene, toluene, and xylene; Ether solvents such as ether, tetrahydrofuran, dioxane, and tetrahydropyran, acetone, methyl ethyl ketone, and cyclohexanone. A basic solvent such as ketone solvents such as dimethylacetamide, dimethylformamide, tetramethylurea, N-methylpyrrolidone, pyridine, or quinoline, or a mixture of two or more of these solvents are used. When basic solvents are used, there is no need to add a base since these solvents act as acid acceptors.

The reaction temperature varies depending on the arginine amide and base used, but is generally selected from a temperature range of 0° C. to the boiling point of the solvent. The reaction time varies depending on the arginine amide used, but is usually selected from a range of 10 minutes to 15 hours.

After the reaction is completed, the salts produced are removed by washing with water, and the solvent is distilled off. When the product is washed with water and/or solvent, N2-
Naphthalenesulfonylarginine amides are obtained.

Also, the N2 naphthalenesulfonylarginine amide obtained in this way is combined with an ether and an acid (e.g. hydrochloric acid, P-
Toluenesulfonic acid, etc.) can also be added, and the generated acid addition salt of N2-naphthalenesulfonylargininamide can be isolated. Next, the pharmacological effects of N2-naphthalenesulfonylargininamides obtained by the method of the present invention will be explained.

As mentioned above, N2-naphthalenesulfonylarginine amides have antithrombin effects, but TAME (N2-(P-tolylsulfonyl)-
The antithrombin effects of L-arginine, methylesterno(c), and N2-naphthalenesulfonylargininamides were compared by measuring fibrinogen clotting time.

Test 1 was conducted as follows. Bovine fibrinogen (
COllnFractiOn
l), manufactured by Armour) 150 40
m1 borate Sarainbatuja A (BOrateSa
0.8 ml of the solution dissolved in llneBuffer (PH7.4) and 0.1 ml of borate saline buffer (control sample) or sample solution were mixed under ice cooling, and then 5 units/ml of thrombin (manufactured by Mochida Pharmaceutical Co., Ltd.) was mixed. Add 0.1 ml of reagent under ice-cooling, mix well, and immediately transfer to a constant temperature bath at 25°C.

A stopwatch was started the moment the sample was placed in the thermostatic chamber, and the time until filipin formation was observed was measured. The coagulation time when no sample was added (control experiment) was 5055 seconds. The experimental results are shown in Table-1.

In Table 1, the concentration that doubles the clotting time refers to the concentration required to prolong the clotting time from 50-55 seconds in the control experiment to 100-110 seconds. For TAME, the concentration that doubles its clotting time is 1100 μM.
It was hot.

In Table 1 below, N2-naphthalenesulfonylarginine amides are indicated by specifying RsR' and adducts in the table.

Next, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples unless the gist thereof is exceeded.
Example 1 4-methyl-1-(L-arginyl)piperidine 1.0
7 (0.0039 mol) to potassium carbonate 0.65y (0
．． 0047 mol) and H2OlOml and cooled to 0°C.

While vigorously stirring, 1.17 (0.0047 mol) of 1-naphthalenesulfonyl chloride was added to this suspension at 100%.
ml of a solution in dioxane is added dropwise over 30 minutes. After stirring at room temperature for 5 hours, the precipitate was removed and the solvent was distilled off under reduced pressure. Add 10% acetic acid-containing chloroform, remove insoluble matter, and then distill off the solvent to obtain powdered 4-methyl-1-
(N2-(1 naphthalenesulfonyl)-L-arginyl)piperidine acetate is obtained.

It is purified by reprecipitation from methanol-ether. Yield 6
1% elemental analysis; C22H3,O3N5S-CH3COO
Example 2 1.0y (0.0041 mol) of 4-(L-arginyl)morpholine and 100ml of chloroform as H
1 and 0.52 f (0.0052 mol) of triethylamine are added.

Claims (1)

[Claims] 1 The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the above general formula (I), R is the general formula (1)▲The mathematical formulas, chemical formulas, tables, etc. ▼(In the formula, R_1 and R_2 are hydrogen atoms,
It represents an alkyl group, a cycloalkylalkyl group, or an alkyl group substituted with an alkoxy group or an alkoxycarbonyl group. ) or general formula (2) -NZ (in the formula, Z is a methylene group -
CH_2- and mono-substituted methylene group ▲ mathematical formula, chemical formula,
There are tables, etc. ▼ (R_3 represents an alkyl group, acyl group, alkoxy group, or alkoxycarbonyl group.)
Two or more groups selected from oxy group -O-, thio group -S-, cycloalkylene group, alkyl-substituted imino group ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (R_6 represents an alkyl group), acyl Substituted imino group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R_7 represents an alkyl group) and phenylene group ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ Zero or more groups selected from the following in any order Represents a bonded divalent group. ). ) or its acid addition salt represented by the following general formula (
II) R'-SO_2X(II) (In the above general formula (II), R' is a 1-naphthyl group; a 2-naphthyl group; a halogen atom, a nitro group, an alkoxycarbonyloxy group, a dialkylamino group, a cyano group, or an alkyl group) represents a 1-naphthyl group or 2-naphthyl group substituted with a group, and X represents a halogen atom. However, R' excludes a 5-(dimethylamino)-1-naphthyl group. or the following general formula (III) characterized by reacting substituted naphthalenesulfonyl halide ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (III) (In the above general formula (III), R is the above general formula (I) has the same meaning as in R
' has the same meaning as in the above general formula (II). ) or an acid addition salt thereof.