JPS5857431B2 - Method for producing cerebral vasodilator 2,3-substituted-4-heterocyclic aminosulfonylbenzenesulfonamide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to cyclic N-substituted derivatives of 4-benzenedisulfonamide that have cerebral vasodilatory properties and are therefore useful for treating conditions that cause inhibition of blood flow to the brain. useful for.

Such conditions include atherosclerosis, occlusion of cerebral blood vessels, stroke attacks, and other cerebral blood diseases.

Compounds which are particularly useful with respect to the invention of this application in the treatment of the above-mentioned conditions have selective effects on cerebral blood vessels, and have relatively little effect on blood vessels of other tissues, such as peripheral tissues and kidneys; Therefore, it is a compound that does not significantly lower blood pressure or promote diuresis.

The above derivatives include compounds of general formula (1): and salts of compounds of the above formula with pharmaceutically acceptable cations.

In the above formula, R1 is a 3-trifluoromethyl group, a chlorine atom,
It is a bromine atom or a fluorine atom; (R'')y is one or two C1-4 alkyl groups bonded to the heterocycle in the formula.

Among the compounds of the present invention having a cerebral vasodilator effect, preferred compounds are those of formula I in which (R2)y is two C1-4 alkyl groups.

In view of cerebral vasodilatory action, it has one or more of the preferable structural characteristics described above, and R1 in the formula is 2-chlor, 2-
Also particularly preferred are compounds of this invention that are 7" rom, or 3-trifluoromethyl.

The compounds of this invention can be prepared from 4-sulfamoylbenzenesulfonyl chloride of general formula (1) by reacting a cyclic amine of general formula (1) in a suitable solvent such as acetone or dichloromethane.

Preferably, the reaction is carried out in the presence of an excess amount of the amine reactant, or an equivalent amount of an organic tertiary amine, to remove the hydrochloric acid formed during the reaction.

The reaction is complete in 1 to 24 hours when carried out at 20°C, but can also be carried out at elevated temperatures, ie 30 to 100°C, for 1 to 8 hours.

The product can be isolated by simply adding the reaction mixture to a conventional aqueous hydrochloric acid solution, filtering, washing and recrystallizing from an appropriate solution.

Salts of the compounds of this invention include salts obtained based on all pharmaceutically acceptable cations.

Preferred pharmaceutically acceptable cations are alkali metal cations, especially sodium and potassium cations.

These salts can be easily obtained by conventional methods.

For example, the compound of general formula (1) may be dissolved in an aqueous or alcoholic solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, and the resulting solution may be simply concentrated.

The treatment methods of this invention allow the compounds described herein to be administered to a patient either orally or parenterally.

Generally, for cats, dogs, and cracks, dosing three times a day;
For intravenous administration, a single dose of 2.5 to 25 η/kg;
In the case of oral administration, a single dose of 10 to 50 kg/kg has a remarkable effect on increasing cerebral blood flow, and this effect is gradually enhanced.

Although the exact dosage for human patients is determined by the physician, it is generally 0.5 to 100 for intravenous administration.
g/kg, 2 to 200 η/ky for oral administration,
Dosage forms containing these dosages are administered four times a day.

While the compounds of this invention can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier selected with regard to the method of administration and standard pharmaceutical practice.

For oral administration in the form of tablets or capsules, the compounds of this invention may be finely ground (e.g. to a size of 30 microns or less) and mixed with a high molecular weight solid polyethylene glycol, e.g. Carbowax 6000.
It has been discovered that it is advantageous to dissolve or dissolve in a matrix of polyethylene glycol having an average molecular weight of 6000-7500, such as.

Nonionic wetting agents as dispersants, such as Myr
j) Polyoxyethylene monostearate having an average molecular weight of about 1000, such as 52, is also preferably included.

To obtain formulations of this type, the compounds of the invention can be dissolved in molten polyethylene glycol together with a dispersant and then cooled, or mixed as an aqueous dispersion with molten polyethylene glycol to form a paste, dried,
It can then, if desired, be granulated or directly encapsulated with other excipients by methods well known in the art prior to compression into tablets.

Tablets can also be made in which the excipients are predominately substances that, when compressed, provide a slower dissolution rate than normally obtained by standard tabletting.

These substances include sugar and edible amino acids such as glycine.

Preferably, the compound of this invention (finely ground) is first mixed with the above materials and then granulated with relatively small amounts of high molecular weight polyethylene glycol and dispersants before being shaped into tablets in a conventional manner.

For parenteral administration, as the compounds of this invention are acidic substances, they are best used as alkali metal (e.g., sodium) salts in the form of sterile aqueous solutions, and such solutions may also be supplemented with other solutes (e.g., sodium chloride). can increase the stability of a solution containing a compound of the invention when administered intravenously, intramuscularly, or subcutaneously, and can increase the compatibility of the solution with body fluids, such as blood.

The above alkali metal salt solution is prepared by dissolving the compound of this invention (and all other necessary solutes) in sterile water and adjusting its pH to a value of 10.5 to 12.0 with a suitable alkali metal hydroxide. It can be made more conveniently.

The following Reference Examples and Examples illustrate the production of the cerebral vasodilator of the invention of this application.

Example 1 3-chloro-4-sulfamoyl-benzenesulfonyl chloride (8,7tγ) in 2-chloro-4-(4-methoxypiperidinosulfonyl)benzenesulfonamide acetone (1001rLl)
)) Triethylamine (4.2m
1) and 4-methoxypiperidi:/(3,15P) were added.

The resulting mixture was stirred at room temperature for 1 hour and then poured into 50 ml of IN hydrochloric acid.

The obtained product was collected by filtration, washed with water, and recrystallized from Impropatool to obtain the target compound.

Yield: 8.4. ! ? Melting point: 165-167℃ Analytical accuracy (C1□H1□ClN205S2) = C13
9,06; R14,64; N, 7.59 actual value =
C, 39,16; R14,91; N, 7.53 Example
1-6 The compounds shown in Table 1 were prepared by the method of Reference Example 1 using a suitable cyclic amine and substituted 4-sulfonylbenzenesulfonyl chloride as starting materials.

The starting material R1-monosubstituted 4-sulfamoyl-benzenesulfonyl chloride is described in U.S. Pat. No. 3,165,550.
or easily prepared from the corresponding R1 monosubstituted 4-amine benzenesulfonamides by methods described therein.

The compounds in Table 1 have the formula: It is represented by

The activity of the compounds of this invention as cerebral vasodilators was measured by the method described below.

Cats were induced with halosan, nitrous oxide/oxygen (3:1 by volume) and then treated with chlorolose (80T
Anesthetized with n9/kg, intravenous injection).

They were allowed to breathe normal room air and the rate and depth of breathing, heart rate, and femoral artery pressure were recorded.

The probe of the electromagnetic blood flow meter was placed near the ipsilateral vertebral artery.

To zero-correct the probe, the artery was momentarily closed to establish a zero flow rate.

Test compound (dissolved in −iN sodium hydroxide in isotonic saline, warmed, stirred, then adjusted to pH 1 with dilute hydrochloric acid)
(back titrated to 0) from the femoral vein at 10 or 25 ~/k
g and readings were taken every 2 hours.

Control observations were also made after administration of excipient alone in saline.

Preferred compound selection criteria are as shown in Table 2, 10-
The test was based on whether the increase in blood flow in the ipsilateral vertebral artery was maintained for 30 minutes or longer when the drug was administered.

The quality of blood flow was evaluated by measuring the maximum (during contraction) blood flow and average blood flow.

It was found that when the product of Example 1.6 was fed at a rate of 10~/kg, the peak and mean blood flow increased significantly.

The product of Example 1 shows a remarkable effect.

Table 2 and the following tables summarize the effects and other effects of the typical cerebral vasodilator of the invention of this application obtained by the method described above.

(1) The average particle size (determined from surface area/1) shall be less than 16 microns.

(2) Polyoxyethylene glycol with an average molecular weight of 6,000.

(3) Polyoxyethylene stearate, a surfactant for preserving food quality.

The main component and glycine are PEG6000. The mixture was granulated with an aqueous solution containing Milzi 52 and gelatin, then added to magnesium stearate, and tableted by a conventional method.

Formulation example 2 Capsule formulation The main ingredient is ball milled in water to reduce the particle size and PEG6
000 and Milzi 52 to form a paste, and then dried at 40° C. to form a powder, which was packed into capsules by a conventional method.

Formulation example 3 Formula for parenteral administration The main ingredients and sodium chloride are dissolved in sterile water free of pyrogens and carbon dioxide under nitrogen, and the pH is adjusted to 11.75 with a 10% aqueous sodium hydroxide solution. Sterilized water was added to make a constant volume.

The resulting solution was then filtered into 5 or 10 ml ampoules and autoclaved for 30 minutes at 115°C.

Claims (1)

[Claims] 1 General formula: (In the formula, R1 is a fluorine atom, a chlorine atom, or a bromine atom; (R2) y is one or two 01-4 lower atoms bonded to the heterocycle in the formula. 4-sulfamoylbenzenesulfonyl chloride of the formula: (wherein R1 is as defined above) is converted to 4-sulfamoylbenzenesulfonyl chloride of the formula: (wherein (R2) y is as defined above). ) with a cyclic amine, and the target compound is recovered as a product.