JPH08109177A - Cycloalkylalkylamine derivative and its use - Google Patents

Abstract

PURPOSE: To obtain the subject new derivative having excellent tracheal smooth muscle relaxing action and IgE production-inhibitory action, thus useful as a preventive/therapeutic agent for asthma, bronchodilator, or preventive/ therapeutic agent for allergic diseases, etc., induced due to the abnormal level of IgE antibody. CONSTITUTION: This compound is expressed by formula I [A is a (1-4C alkyl- substituted) 2-6C alkylene; B is a (1-4C alkyl-substituted) 1-6C alkylene or single bond; R1 is H or a 1-4C alkyl; R2 and R3 are each H or a 1-6C alkyl, or mutually combined into a (1-4C alkylsubstituted) 1-4C alkylene; R4 is a (1-4C alkyl- substituted) 3-7C cycloalkyl] or an acid-added salt thereof, e.g. N-(7- benzothiazolesulfonyl)-N'-cyclohexylmethyl-ethylenediamine. The compound of formula I is obtained, for example, by reaction of a compound of formula II (X is a halogen) with an amine of formula III in an inert solvent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel benzothiazole sulfonamide derivative containing a cycloalkyl (alkyl) amino group and its pharmaceutical use.

[0002]

2. Description of the Related Art WO 92-14712 (International Publication No. 5-1037) discloses a benzothiazolesulfonylaminoethyl derivative having a bronchial smooth muscle relaxing action based on an antihistamine action, specifically a compound. (20) as 1- (6-benzothiazolesulfonylaminoethyl) -4- [3- (phenoxy) propyl]
Piperazine, namely 1- [2- (6-benzothiazolesulfonylamino) ethyl] -4- (3-phenoxypropyl) piperazine, has been disclosed, but its action is still unsatisfactory.

[0003]

Bronchodilators such as xanthine drugs and β-receptor stimulants are widely used as clinical remedies for respiratory diseases such as asthma. These drugs are intracellular cyclic adenosine 3 ', 5'-monophosphate (cyclic adenosine).
It is believed to increase the 3 ', 5'-monophosphate concentration. Aminophylline can be mentioned as a representative compound of the xanthine drug, and isopretenol can be mentioned as a β receptor stimulant.

However, xanthine drugs, β-receptor stimulants and the like do not always satisfy the desires of clinicians due to side effects on the heart and the appearance of resistant asthma that does not ameliorate with these drugs. In addition, immunoglobulin E
As diseases caused by increased production of (IgE), allergic diseases such as atopic asthma, atopic dermatitis and nasal allergy are known. Conventionally, the treatment of allergic diseases is a method of suppressing degranulation of mast cells or basophils and release of chemical mediators, and / or a method of suppressing allergic reaction caused by the released chemical mediators by its antagonistic action. The symptomatic treatment such as was only performed. Since these symptomatic treatments do not suppress the excessive production of IgE antibody, which is the basis of allergic reaction, their effects are limited.

In recent years, IgE antibody production inhibitory substances have been developed and reported, but it is well known that there is a limit to the administration of such an antiallergic agent alone in the treatment of asthma. Under such circumstances, it would be preferable to provide a novel compound having both a superior tracheal smooth muscle relaxing action and an IgE antibody production inhibitory action.

[0006]

[Means for Solving the Problems] In order to solve the above problems, as a result of intensive studies by the present inventors, a cycloalkylalkylamine derivative represented by the following general formula, which is a novel compound, has an excellent tracheal smooth muscle relaxing action. The present invention has been completed by discovering that it has an IgE production inhibitory action.

That is, the present invention is based on the general formula (1)

[0008]

Embedded image

(In the formula, A represents an alkylene group having 2 to 6 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms, and B is substituted with an alkyl group having 1 to 4 carbon atoms. Represents an optionally substituted alkylene group having 1 to 6 carbon atoms or represents a single bond, and R ₁ represents a hydrogen atom or 1 to 4 carbon atoms.
Or R ₂ and R ₃ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
Alternatively, R ₂ and R ₃ together represent an alkylene group having 1 to 4 carbon atoms which may be substituted with an alkyl group having 1 to ₄ carbon atoms, and R ₄ is an alkyl group having 1 to ₄ carbon atoms. A compound represented by a cycloalkyl group having 3 to 7 carbon atoms which may be substituted with (hereinafter, may be simply referred to as "target compound (1)") or an acid addition salt thereof. That is the purpose.

Another object of the present invention is to provide a medicament characterized by comprising a compound represented by the above general formula (1) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. It is a thing. Group A in the general formula (1)
Is defined as an alkylene group having 2 to 6 carbon atoms, which may be substituted with 1 to 4 alkyl groups. Carbon number 2
Examples of the ~ 6 alkylene groups include ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene groups, with ethylene and trimethylene groups being particularly preferred. This alkylene group has a linear or branched alkyl group having 1 to 4 carbon atoms at any substitution position, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-methylpropyl, t-
It may be substituted with a butyl group or the like, and a methyl group is mentioned as a preferable example. For example, in the case of an ethylene group, 1- (7-benzothiazolesulfonyl) -4-cyclohexylmethyl-containing a methyl group at the 3-position. 3-methyl-
1,4-diazabutane and the like are preferable.

The group B represents an alkylene group having 1 to 6 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms, or is defined as a single bond. Examples of the alkylene group having 1 to 6 carbon atoms include methylene, ethylene,
Examples include trimethylene, tetramethylene, pentamethylene and hexamethylene groups, with methylene and ethylene groups being particularly preferred. This alkylene group is a linear or branched alkyl group having 1 to 4 carbon atoms at any of the substitution positions as described above, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1
A methyl group which may be substituted with a methylpropyl group, a t-butyl group or the like is preferred. Also group B
As the above, a single bond is also preferable.

The alkyl group having 1 to 4 carbon atoms defined in the group R ₁ may have a branched chain, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-methylpropyl , T-butyl group and the like, and a methyl group is a preferred example. A hydrogen atom is also very preferable as the group R ₁ . The alkyl group having 1 to 6 carbon atoms defined in the groups R ₂ and R ₃ may have a branched chain, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-methylpropyl , T-butyl, pentyl, hexyl groups and the like, but methyl, ethyl and propyl groups are preferred. Further, as the groups R ₂ and R ₃ , independent hydrogen atoms are also very preferable.

The groups R ₂ and R ₃ together have 1 carbon atom.
It may also be up to 4 alkylene groups. Examples of the alkylene group include methylene, ethylene, trimethylene and tetramethylene groups, with ethylene and trimethylene groups being preferred. This alkylene group has a linear or branched alkyl group having 1 to 4 carbon atoms at any substitution position, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-methylpropyl, t
-A butyl group or the like may be substituted, and a methyl group and an ethyl group are preferred examples.

Furthermore, the radical R ₄ is defined as a cycloalkyl radical having 3 to 7 carbon atoms which may be substituted by an alkyl radical having 1 to ₄ carbon atoms. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups, with cyclobutyl, cyclopentyl and cyclohexyl groups being particularly preferred. This cycloalkyl group has a linear or branched alkyl group having 1 to 4 carbon atoms at any substitution position, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-methylpropyl, t-
It may be substituted with a butyl group or the like, and a methyl group is a preferred example.

In the general formula (1), the benzene in the formula
Group at 4-position, 5-position, 6-position or 7-position of the zothiazole ring;-
SO₂-N (R₂) -AN (R₃) -BR_FourIs joined
Then, it is defined that it can bind to the 6- or 7-position.
Preferred is 7th position. Preferred for the present invention
The range is that in the general formula (1), A is substituted with a methyl group.
Represents an optionally substituted ethylene group or trimethylene group, B
Represents a methylene group, an ethylene group, or a single bond
Then R₁Represents a hydrogen atom or a methyl group, and R₂And R₃
Each independently represent a hydrogen atom, R_FourHas 3 to 7 carbon atoms
A cycloalkyl group, and a benzothiazole ring in the formula
Based on the 6- or 7-position of;₂-N (R ₂) -AN
(R₃) -BR_FourThe compound according to claim 1, wherein
Compound or an acid addition salt thereof, or a general formula
In (1), A is ethyl which may be substituted with a methyl group.
Represents a len group or trimethylene group, and B represents a methylene group or ethyl group.
A len group or a single bond, R₁Is a hydrogen atom
Indicates R₂And R₃Together with ethylene group or trimmer
Shows a thylene group, R_FourIs a cycloalkyl having 3 to 7 carbon atoms
6-position of the benzothiazole ring in the formula or
Based on the 7-position; -SO₂-N (R₂) -AN (R₃) -B
-R_FourOr a compound according to claim 1, wherein
Is an acid addition salt of. Specific examples of the object compound (1) of the present invention
As the above, the following compounds can be mentioned. (1) N- (7-benzothiazolesulfonyl) -N '
-Cyclohexylmethyl-ethylenediamine (2) N- (7-benzothiazolesulfonyl) -N '
-Cyclopentylmethyl-ethylenediamine (3) N- (7-benzothiazolesulfonyl) -N '
-Cyclopropylmethyl-ethylenediamine (4) N- (7-benzothiazolesulfonyl) -N '
-Cycloheptylmethyl-ethylenediamine (5) N- (7-benzothiazolesulfonyl) -N '
-Cyclohexylmethyl-trimethylene diamine (6) 1- (7-benzothiazolesulfonyl) -4-
Cyclohexylmethyl-3-methyl-1,4-diazab
Tan (7) N- (7-benzothiazolesulfonyl) -N '
-Cyclohexyl-ethylenediamine (8) N- (7-benzothiazolesulfonyl) -N '
-(2-Cyclohexylethyl) -ethylenediamine (9) 1- (7-benzothiazolesulfonyl) -4-
Cyclohexylmethylhomopiperazine (10) N- (6-benzothiazolesulfonyl)-
N'-cyclohexylmethyl-ethylenediamine (11) N- (7-benzothiazolesulfonyl)-
N'-cyclopentyl-ethylenediamine (12) 1- (7-benzothiazolesulfonyl) -4
-Cyclopropylmethyl-3-methyl-1,4-diaza
Butane (13) N- (7-benzothiazolesulfonyl)-
N'-Cyclobutylmethyl-ethylenediamine (14) N- (2-methyl-7-benzothiazolesul
Honyl) -N'-cyclohexylmethyl-ethylenedia
Min As the acid addition salt of the target compound (1), it is pharmaceutically acceptable.
Are preferred salts, such as hydrochloric acid, hydrobromic acid, phosphoric acid,
Acid addition salts with inorganic acids such as sulfuric acid, acetic acid, citric acid, tartar
Acid, lactic acid, succinic acid, fumaric acid, maleic acid, methane
Organic acids such as rufonic acid, glutamic acid, and aspartic acid
Acid addition salts thereof can be mentioned. Attachment with other known acids
It goes without saying that salting is also included.

The object compound (1) of the present invention can be produced by various methods. For example, the compound (1) has the general formula (2)

[0017]

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A compound represented by the following formula (wherein X represents a halogen atom and R ₁ has the same meaning as described above) [hereinafter simply referred to as "compound (2)"] in an inert solvent and represented by the general formula (3)

[0019]

[Chemical 4]

Reaction of an amine (3) represented by the formula (wherein R ₂ , R ₃ , R ₄ , A and B have the same meanings as described above) [hereinafter simply referred to as "amine (3)"] Can be obtained. Amine (3) is a method known per se,
For example, Experimental Chemistry Course, 4th Edition, Volume 20, 284 (Maruzen Co., Ltd., 1992), Synthesis (197).
5) 135-146 and Tetrahedron Let
ters, 29 (1988) 50, 6651-6654.
And J. Org. Chem. 58 (1993) 14,
It can be synthesized according to the method described in 3736-3741.

The compound (2) is represented by the general formula (4)

[0022]

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(Wherein R ₁ has the same meaning as described above)
The sulfonic acid (4) represented by Medic
al Chemistry 32 , 42-46 (198).
It can be obtained by converting to a sulfonyl halogenide by a known method described in 9) and the like. For example, a method of chlorination with thionyl chloride is a suitable example. The sulfonic acid (4) can be prepared by a method known per se, for example, Bull. So
c. Chim. Belges. 80 , 43-58 (19
71) and the like.

Examples of the inert solvent used in the reaction of the compound (2) with the amine (3) include halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran, dioxane and diethyl ether, and dimethyl sulfoxide. , N, N-dimethylformamide, acetonitrile and the like. These alone,
Alternatively, it can be used as a mixed solvent. The amount of the inert solvent used is 1-10 in weight ratio to the compound (2).
0 times, preferably 5 to 50 times is exemplified.

The reaction between the compound (2) and the amine (3) is
It is preferably carried out in the presence of an acid acceptor. As the acid acceptor used, for example, sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, alkali metal compounds such as sodium methylate,
Examples include organic tertiary amines such as pyridine, trimethylamine, and triethylamine. The amount of the acid acceptor to be used is generally 0.3-10 times mol, preferably 1-3 times mol, of the compound (2).

The amount of amine (3) used in the above reaction is 1 to 20 times mol, preferably 1 to 10 times mol, of the compound (2). 2.5 in the absence of acid acceptor
It is particularly preferably -5 to 5 times the molar amount, and particularly preferably 1 to 3 times the molar amount in the presence of the acid acceptor. The reaction temperature is generally -30 to 120 ° C, preferably -20 to 50 ° C. The reaction time is generally 0.5 to
48 hours, preferably 0.5-6 hours,
Since the progress of the reaction can be traced by thin layer chromatography (TLC), high performance liquid chromatography (HPLC), etc., the reaction may be appropriately terminated after the disappearance of compound (2).

To collect the target compound (1) in the free base state from the reaction solution thus obtained, when the reaction solvent is a hydrophilic solvent, the solvent is distilled off and the residue is removed. It is carried out by dissolving in a non-hydrophilic solvent, washing with a weak alkaline aqueous solution, water or the like, and distilling off the solvent. When the reaction solvent is a non-hydrophilic solvent, the reaction is carried out by washing the solution with a weak alkaline aqueous solution, water, etc., and then distilling off the solvent.

The object compound (1) of the present invention can form an acid addition salt by a known method. For example, the target compound (1) is dissolved in alcohols such as methanol and ethanol, and an equivalent or several times amount of acid is added to obtain an acid addition salt thereof. Examples of the acid used include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, fumaric acid, maleic acid, methanesulfonic acid, glutamic acid and aspartic acid. Mention may be made of organic acids. Of course,
It goes without saying that other known acids can also be used.

By using the compound (1) of the present invention as an acid addition salt, storage stability is improved; oral solubility is facilitated due to increased water solubility; purification and crystallization are facilitated, and quality and specifications are improved. However, if desired, for example, from the above-mentioned acid addition salts, for example, Experimental Chemistry Lecture, 4th Edition, Vol. 20, page 284 (Maruzen Co., Ltd., 199).
It is also possible to obtain the target compound (1) in the free base state again by subjecting it to alkali treatment by a known method described in, for example, 2 years). The acid addition salt is preferably a pharmacologically acceptable acid addition salt. When the obtained target compound (1) or an acid addition salt thereof is further purified,
It can be carried out by a known method, for example, recrystallization or column chromatography using a known carrier such as silica gel.

The object compound (1) of the present invention and a pharmaceutically acceptable acid addition salt thereof (hereinafter sometimes simply referred to as "the compound of the present invention") exhibit a strong tracheal smooth muscle relaxing action, and also IgE. Since it has an inhibitory effect on antibody production, and no death was observed even after oral administration to rats at 300 mg / kg, it is a safe compound to be used as a drug and a useful substance as an active ingredient of a drug. . Therefore, according to another aspect of the present invention, there is provided a pharmaceutical composition containing an effective amount of the compound of the present invention and a pharmacologically administrable carrier. This pharmaceutical composition is a prophylactic / therapeutic agent for asthma,
Prevention of diseases caused by bronchodilators or abnormally elevated IgE antibody levels (hereinafter sometimes referred to as abnormalities)
It can be used as a therapeutic agent. Diseases caused by abnormal IgE antibody levels are diseases caused by abnormal IgE production, and examples thereof include allergic diseases such as atopic asthma, atopic dermatitis, and nasal allergy.

Examples of dosage forms for formulating the above-mentioned pharmaceutical composition include tablets, powders, granules, syrups, suppositories, suspensions, capsules, injections and inhalants. For production, various carriers depending on these preparations are used. For example, as an oral carrier, excipients such as lactose, sucrose, glucose, starch, crystalline cellulose and the like;
Hydroxypropyl cellulose, carboxymethyl cellulose, starch, gum arabic, gelatin, glucose, sucrose, tragacanth, sodium alginate and other binders; carboxymethyl cellulose, starch, calcium carbonate and other disintegrants; stearic acid, purified talc, sucrose fatty acid ester, hydrogen Lubricants such as added vegetable oil, magnesium stearate, calcium stearate; surfactants such as sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80; lecithin, soybean oil,
Examples thereof include additives such as glycerin, fluidity promoters, and colorants.

When the compound of the present invention is used as a parenteral preparation such as an injection, a diluent as a carrier, for example, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol, etc. Can be used. Furthermore, if necessary, a bactericide, an antiseptic, a stabilizer, an isotonicity agent, a soothing agent, etc. may be added. Further, when preparing an inhalant, polychloromonofluoromethane or the like can be used as a solvent.

When the compound of the present invention is administered to humans, it can be orally administered in the form of tablets, powders, granules, suppositories, suspensions and capsules. Can be administered parenterally in the form of a cream or spray. The dose varies depending on the indication, the administration form, the age, body weight of the patient, and the degree of symptoms, but generally 3 to 300 mg per day for an adult is administered in 1 to 3 divided doses. The administration period is generally several days to 2 months, and is generally daily. However, both the daily dose and the administration period can be increased or decreased depending on the symptoms of the patient.

[0034]

The pharmacological action of the compound of the present invention will be described below. A. Tracheal smooth muscle relaxant action on KCl contraction in trachea specimens isolated from guinea pigs (1) Inhibition test method on KCl contraction Method using isolated trachea specimens from guinea pigs (Takagi, Ozawa; Pharmacological experiment, 1
00-102, 1960, Nanzandou, Fujiwara, Shibata; Basic Pharmacology Experimental Method, 131-134, 1982, Kyorin Publishing Co., Ltd.).

[0039] 350 to 500 g of a male guinea pig (Heartrate type, Kuroda pure type animal) isolated trachea specimen was isometrically (initial load: 1 ml) in a Magnus device (volume: 20 ml) filled with Krebs-Hensleit nutrient solution (containing 3 μM of indomethacin). 0.5 g), and an aqueous KCl solution (final concentration 20 mM) was applied into the Magnus tube while keeping the liquid temperature at 37 ° C. under aeration of 95% oxygen and 5% carbon dioxide gas to contract the trachea specimen.

After the contraction was stabilized, the compound of the present invention described in the below-mentioned Examples dissolved in distilled water or physiological saline was cumulatively added to the Magnus tube, and its relaxing action was observed to obtain a dose-response curve. . After the measurement, 100 μM of papaverine was added to determine the maximum relaxation, and the relaxation rate at that time was set to 100%. The number of samples was all 3. WO92-as a control
1- [2- (6-
Benzothiazolesulfonylamino) ethyl] -4-
(3-phenoxypropyl) piperazine dihydrochloride was used. (2) Measurement result The measurement result is as shown in Table 1.

[0037]

[Table 1]

As is clear from the results shown in Table 1, the compounds of the present invention have a tracheal smooth muscle relaxing action on KCl contraction in the isolated trachea of guinea pigs, while WO92-1
It was found that the control product described in WO 4712 had almost no tracheal smooth muscle relaxing action under the test conditions. Therefore, since the objective compound (1) of the present invention or a pharmacologically acceptable acid addition salt thereof has a tracheal smooth muscle relaxing action on KCl contraction in a guinea pig isolated trachea specimen, it serves as a bronchodilator and thus for the prevention and treatment of asthma. It is useful as an agent. B. IgE antibody production inhibitory effect on mouse spleen cells (1) Measuring method Cellular Immunology, 145 , 2
99-310 (1992) or Immunology
According to the method described in Letters, 34 , 99-104 (1992), the IgE antibody production inhibitory action of the compound of the present invention was evaluated. Ie, 6-8 week old female AKR
10 μg of dinitrophenylated conalbumin (dinitrophenylconalbumi) adsorbed to 4 mg aluminum hydroxide gel (PIERCE) intraperitoneally in a mouse (Charles River).
n, DNP-conalbumin) (Seiji Wako; Immune Experiment Operation Method B, page 1129, prepared according to the Japan Immunological Society). After 4 weeks, remove the spleen,
A suspension was prepared using spleen cells obtained by grinding and Click's MEM medium (manufactured by Irvine Scientific).

1 × 10 ^{4 of} these spleen cells and mouse Th
2 clone cells (D10.G4.1) (manufactured by ATCC)
2 × 10 ⁵ cells containing 200 μl of 10% fetal bovine serum c
1 ng / ml DNP in lick's MEM medium
After culturing with conalbumin for 7 days, the supernatant was collected. International Archi
ves of Allergy and Applie
d Immunology, 85 , 47-54, (19
88), the amount of IgE antibody produced by the compound of the present invention was measured. That is, the IgE antibody in the supernatant was the optimal concentration of rat anti-mouse IgE monoclonal antibody (2 μg / ml) and biotin-labeled rat anti-mouse IgE.
Antibodies Quantification was performed by enzyme immunoassay using monoclonal antibody (2 μg / ml) and avidin peroxidase (2.5 μg / ml) (Funakoshi). Two types of rat anti-mouse IgE monoclonal antibodies are Inte
national Archives of Alle
rgy and Applied Immunolog
y, 85 47-54 (1988), and one of them was labeled with biotin using a biotin labeling kit (American Qualex, USA). The compound of the present invention was added to the medium at a concentration of 1 μg / ml over the entire culture period. As a control product (1), 1-described in the international publication specification of WO92-14712
[2- (6-Benzothiazolesulfonylamino) ethyl] -4- (3-phenoxypropyl) piperazine dihydrochloride, as reference products (2) and (3) WO94-1933
The following compounds described in International Publication No. 6 were used. Control product (1) 1- [2- (6-benzothiazolesulfonylamino) ethyl] -4- (3-phenoxypropyl) piperazine dihydrochloride Control product (2) N- [2- (3,4-methylenedi) Oxybenzylamino) ethyl] -7-benzothiazolesulfonamide monohydrochloride Control product (3) N- [2- (3-fluorobenzylamino) ethyl] -7-benzothiazolesulfonamide monohydrochloride (2) Measurement results The measurement results are as shown in Table 2.

[0040]

[Table 2]

As is clear from the results in Table 2 above, under the present test conditions, the compound of the present invention is a control product described in WO92-14712 International Publication, WO94-19336.
Significantly stronger than the control product described in the international publication
It was confirmed to have a gE antibody production inhibitory action. Therefore, since the objective compound (1) of the present invention or a pharmacologically acceptable acid addition salt thereof has an IgE antibody production inhibitory action, it is an IgE antibody production inhibitor or a prophylactic / therapeutic treatment of diseases caused by abnormal IgE antibody levels It is useful as an agent. It is also useful as a therapeutic / preventive agent for asthma.

As described above, the compound of the present invention is a compound of the conventionally known W.
Compared with the compound disclosed in O92-14712, it shows a markedly stronger tracheal smooth muscle relaxing action, and exhibits a stronger IgE antibody production inhibitory action not present in a benzothiazole sulfonamide derivative having no cycloalkylalkylamide group at the terminal. Therefore, it was confirmed that the substance has a novel and inventive step.

[0043]

EXAMPLES Next, production examples of the compound of the present invention will be described in more detail with reference to Examples. The nuclear magnetic resonance spectrum (NMR) and mass spectrum (FabMS) of the hydrochloride of the target compound (1) obtained in the following examples.
Are described in Tables 3 and 4 below. Example 1 N- (7-benzothiazolesulfonyl) -N'-cyclohexylmethyl-ethylenediamine (Compound 1) and its hydrochloride salt To 12 g of 7-benzothiazolesulfonic acid, 120 ml of thionyl chloride and 1.2 ml of dimethylformamide were added.
Heated to reflux for hours. After the reaction, thionyl chloride was distilled off under reduced pressure. The residue was dissolved in 100 ml of ice water, adjusted to pH 6 with saturated aqueous sodium carbonate solution, and diluted with 100 ml of dichloromethane.
Extracted with ml. This dichloromethane layer was cooled with ice to give N-
A solution of 26.1 g of cyclohexylmethyl-ethylenediamine in 100 ml of dichloromethane was added dropwise over 30 minutes, and the mixture was stirred at 0-5 ° C for 1 hour.

After completion of the reaction, the reaction mixture was washed with 200 ml of water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is silica gel (Wako Gel C-20
0, manufactured by Wako Pure Chemical Industries, Ltd., Japan, 600 g) and charged by a column and purified by column chromatography using a mixed solvent of methanol-chloroform (5 to 10% methanol) as an elution solvent to obtain the title compound 1. Yield 1
0.8 g (yield 55%).

The obtained compound 1 (10.8 g) was dissolved in 100 ml of methanol, an equivalent amount of aqueous hydrochloric acid was added, and the mixture was stirred for 10 minutes. The solvent was distilled off under reduced pressure to obtain the hydrochloride salt of compound 1. Yield 11.2 g (94% yield). Example 2 1- (7-Benzothiazolesulfonyl) -4-cyclohexylmethyl-3-methyl-1,4-diazabutane (Compound 6) and its hydrochloride salt In Example 1, 26.1 g of N-cyclohexylmethyl-ethylenediamine The title compound 6 was obtained in substantially the same manner as in Example 1 except that 28.2 g of 1-cyclohexylmethyl-2-methyl-1,4-diazabutane was used instead. Yield 10.2 g (yield 50%)
The hydrochloride salt of compound 6 was obtained in the same manner as in Example 1. Yield 1
0.1 g (yield 90%) Example 3 N- (7-benzothiazolesulfonyl) -N '-(2
-Cyclohexylethyl) -ethylenediamine (Compound 8) and its hydrochloride salt In Example 1, except that 28.2 g of N-2-cyclohexylethyl-ethylenediamine was used instead of 26.1 g of N-cyclohexylmethyl-ethylenediamine. The title compound 8 was obtained in a substantially similar manner. Yield 9.4 g (yield 46%) Further, the hydrochloride of compound 8 was obtained in the same manner as in Example 1. Yield 8.5 g (Yield 8
2%) Example 4 N- (6-benzothiazolesulfonyl) -N'-cyclohexylmethyl-ethylenediamine (Compound 10) and its hydrochloride salt In Example 1, 7-benzothiazolesulfonic acid 1
12 g of 6-benzothiazole sulfonic acid instead of 2 g
The title compound 10 was obtained in substantially the same manner as in Example 1 except that was used. Yield 9.6 g (yield 49%) Further, the hydrochloride of compound 10 was obtained in the same manner as in Example 1.
Yield 10.1 g (yield 93%) Example 5 N- (7-benzothiazolesulfonyl) -N'-cyclopentylmethyl-ethylenediamine (Compound 2) and its hydrochloride salt In Example 1, N-cyclohexylmethyl-ethylenediamine 26 The title compound 2 was obtained in substantially the same manner as in Example 1 except that 23.8 g of N-cyclopentylmethyl-ethylenediamine was used instead of .1 g.
Yield 9.4 g (yield 49%) The hydrochloride of compound 2 was obtained in the same manner as in Example 1. Yield 10.0 g (Yield 96
%) Example 6 N- (7-benzothiazolesulfonyl) -N'-cyclopropylmethyl-ethylenediamine (Compound 3) and its hydrochloride salt In Example 1, N-cyclohexylmethyl-ethylenediamine was replaced with 26.1 g of N- The title compound 3 was obtained in substantially the same manner as in Example 1 except that 19.1 g of cyclopropylmethyl-ethylenediamine was used.
Yield 8.8 g (51% yield) Also, the hydrochloride of compound 3 was obtained in the same manner as in Example 1. Yield 8.6g (Yield 87
%) Example 7 N- (7-benzothiazolesulfonyl) -N'-cycloheptylmethyl-ethylenediamine (Compound 4) and its hydrochloride salt In Example 1, N-cyclohexylmethyl-ethylenediamine was replaced with 26.1 g of N- The title compound 4 was obtained in substantially the same manner as in Example 1 except that 28.4 g of cycloheptylmethyl-ethylenediamine was used.
Yield 11.4 g (yield 56%) The hydrochloride of compound 4 was obtained in the same manner as in Example 1. Yield 11.2g (Yield 8
9%) Example 8 N- (7-benzothiazolesulfonyl) -N'-cycloheptylmethyl-trimethylene diamine (Compound 5)
And its hydrochloride salt In the same manner as in Example 1 except that 28.4 g of N-cyclohexylmethyl-ethylenediamine was used instead of 26.1 g of N-cyclohexylmethyl-ethylenediamine, the title compound was obtained. Compound 5 was obtained. Yield 9.7 g (yield 47%) Further, the hydrochloride of compound 5 was obtained in the same manner as in Example 1. Yield 10.2 g (yield 96%) Example 9 N- (7-benzothiazolesulfonyl) -N'-cyclohexyl-ethylenediamine (Compound 7) and its hydrochloride salt In Example 1, N-cyclohexylmethyl-ethylenediamine 26. N-cyclohexyl instead of 1 g
The title compound 7 was obtained in substantially the same manner as in Example 1 except that 23.8 g of ethylenediamine was used. Yield 9.9 g (yield 52%) Further, the hydrochloride of compound 7 was obtained in the same manner as in Example 1. Yield 9.7 g (88% yield) Example 10 1- (7-Benzothiazolesulfonyl) -4-cyclohexylmethylhomopiperazine (Compound 9) and its hydrochloride In Example 1, N-cyclohexylmethyl-ethylenediamine 26. Example 1 except that 32.8 g of 4-cyclohexylmethylhomopiperazine was used instead of 1 g.
The title compound 9 was obtained in a manner substantially similar to. Yield 12.9 g (yield 59%) Further, the hydrochloride of compound 9 was obtained in the same manner as in Example 1. Yield 12.7 g (yield 90
%) Example 11 N- (7-benzothiazolesulfonyl) -N'-cyclopentyl-ethylenediamine (Compound 11) and its hydrochloride salt In Example 1, N-cyclopentylmethyl-ethylenediamine was replaced with 26.1 g of N-cyclopentyl-
By substantially the same method as in Example 1 except that 21.4 g of ethylenediamine was used, the title compound 11 was obtained. Yield 10.2 g (yield 56%) Further, the hydrochloride of compound 11 was obtained in the same manner as in Example 1. Yield 9.7 g (yield 85
%) Example 12 1- (7-Benzothiazolesulfonyl) -4-cyclopropylmethyl-3-methyl-1,4-diazabutane (Compound 12) and its hydrochloride salt In Example 1, N-cyclohexylmethyl-ethylenediamine 26 The title compound 12 was obtained in substantially the same manner as in Example 1 except that 21.4 g of 1-cyclopropylmethyl-2-methyl-1,4-diazabutane was used instead of 1 g. Yield 9.9 g (yield 54%)
The hydrochloride salt of compound 12 was obtained in the same manner as in Example 1. Yield 9.3 g (84% yield) Example 13 N- (7-benzothiazolesulfonyl) -N'-cyclobutylmethyl-ethylenediamine (Compound 13) and its hydrochloride salt In Example 1, N-cyclohexylmethyl-ethylenediamine The title compound 13 was obtained in substantially the same manner as in Example 1 except that 21.4 g of N-cyclobutylmethyl-ethylenediamine was used instead of 26.1 g.
Yield 10.5 g (yield 58%) Also, the hydrochloride of compound 13 was obtained in the same manner as in Example 1. Yield 9.9g (Yield 8
5%) Example 14 N- (2-methyl-7-benzothiazolesulfonyl)
-N'-cyclohexylmethyl-ethylenediamine (compound 14) and its hydrochloride salt In Example 1, 7-benzothiazolesulfonic acid 1
The title compound 14 was obtained in substantially the same manner as in Example 1 except that 12.8 g of 2-methyl-7-benzothiazolesulfonic acid was used instead of 2 g. Yield 11 g (yield 54%) Further, the hydrochloride of compound 14 was obtained in the same manner as in Example 1. Yield 9.9 g (yield 82%)

[0046]

[Table 3]

[0047]

[Table 4]

Claims (8)

[Claims] 1. A compound represented by the general formula (1): (In the formula, A represents an alkylene group having 2 to 6 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms, and B is substituted with an alkyl group having 1 to 4 carbon atoms. Also represents an alkylene group having 1 to 6 carbon atoms or represents a single bond, R ₁ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ₂ and R ₃ each independently represent a hydrogen atom. Or, it represents an alkyl group having 1 to 6 carbon atoms, or R ₂ and R ₃ together represent an alkylene group having 1 to 4 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms. R ₄ represents a cycloalkyl group having 3 to 7 carbon atoms which may be substituted with an alkyl group having 1 to ₄ carbon atoms) or an acid addition salt thereof. 2. In the general formula (1), A represents an ethylene group which may be substituted with a methyl group or a trimethylene group, B represents a methylene group or an ethylene group, or a single bond, and R ₁ Represents a hydrogen atom or a methyl group, R ₂ and R ₃ each independently represent a hydrogen atom, and R ₄ has 3 to 3 carbon atoms.
7 cycloalkyl groups are shown, and a group at the 6-position or 7-position of the benzothiazole ring in the formula; —SO ₂ —N (R ₂ ) —
The compound or acid addition salt thereof according to claim 1, wherein A-N (R ₃ ) -B-R ₄ is bonded. 3. In the general formula (1), A represents an ethylene group or a trimethylene group which may be substituted with a methyl group,
B represents a methylene group, an ethylene group, or a single bond, R ₁ represents a hydrogen atom, R ₂ and R ₃ together represent an ethylene group or a trimethylene group, and R ₄ has 3 carbon atoms.
To seven of a cycloalkyl group, 6 or 7 position based on the benzothiazole ring in the formula; -SO ₂ -N (R ₂₎
The compound or acid addition salt thereof according to claim 1, wherein -AN (R ₃ ) -B-R ₄ is bonded. 4. The compound represented by the general formula (1) is N-
(7-benzothiazolesulfonyl) -N'-cyclohexylmethyl-ethylenediamine; N- (7-benzothiazolesulfonyl) -N'-cyclopentylmethyl-
Ethylenediamine; N- (7-benzothiazolesulfonyl) -N'-cyclopropylmethyl-ethylenediamine; N- (7-benzothiazolesulfonyl) -N'-
Cycloheptylmethyl-ethylenediamine; N- (7-
Benzothiazolesulfonyl) -N'-cyclohexylmethyl-trimethylenediamine; 1- (7-benzothiazolesulfonyl) -4-cyclohexylmethyl-3-
Methyl-1,4-diazabutane; N- (7-benzothiazolesulfonyl) -N'-cyclohexyl-ethylenediamine; N- (7-benzothiazolesulfonyl)-
N '-(2-cyclohexylethyl) -ethylenediamine; and N- (6-benzothiazolesulfonyl)
The compound or acid addition salt according to claim 1 or 2, which is a compound selected from the group consisting of -N'-cyclohexylmethyl-ethylenediamine. 5. The compound represented by the general formula (1) is N—
(7-benzothiazolesulfonyl) -N'-cyclopentyl-ethylenediamine; 1- (7-benzothiazolesulfonyl) -4-cyclopropylmethyl-3-methyl-1,4-diazabutane; and N- (7-benzothiazole Sulfonyl) -N'-cyclobutylmethyl-
The compound or acid addition salt according to claim 1 or 2, which is a compound selected from the group consisting of ethylenediamine. 6. The compound according to claim 1 or 2 or 4, which is N- (7-benzothiazolesulfonyl) -N′-cyclohexylmethyl-ethylenediamine or an acid addition salt thereof, or an acid addition salt thereof. 7. A medicine comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. 8. A prophylactic / therapeutic agent for asthma, a bronchodilator or IgE, which comprises the compound according to any one of claims 1 to 6 or a pharmacologically acceptable acid addition salt thereof as an active ingredient. A prophylactic / therapeutic agent for diseases caused by abnormal antibody levels.