WO1996006088A1

WO1996006088A1 - Benzothiazolesulfonamide derivative having terminal cycloalkyl group and medicinal use thereof

Info

Publication number: WO1996006088A1
Application number: PCT/JP1995/001637
Authority: WO
Inventors: Takeshi Tonegawa; Yoshihide Nozaki
Original assignee: Asahi Kasei Kogyo Kabushiki Kaisha
Priority date: 1994-08-18
Filing date: 1995-08-18
Publication date: 1996-02-29

Abstract

A benzothiazolesulfonamide derivative having a terminal cycloalkyl group, represented by general formula (I), or a pharmaceutically acceptable acid-addition salt thereof, (wherein A represents a C2-C6 alkylene group which is unsubstituted or substituted by a C1-C4 alkyl group; B represents either a C1-C6 alkylene group which is unsubstituted or substituted by a C1-C4 alkyl group, or a single bond; R1 represents hydrogen or a C¿1?-C4 alkyl group; R?2 and R3¿ represent each independently hydrogen or a C¿1?-C6 alkyl group, or R?2 and R3¿ are combined together to form a C¿1?-C4 alkyl group which is unsubstituted or substituted by a C1-C4 alkyl group; and R?4¿ represents a C¿3?-C7 cycloalkyl group which is unsubstituted or substituted by a C1-C4 alkyl group). These compounds are useful as the active ingredient of a remedy or preventive for asthma, a bronchodilator, or a medicinal composition for treating or preventing diseases caused by an abnormal IgE antibody level.

Description

Title of invention

Benzothiazol sulfonamide derivatives having an alkyl group at the terminal end and pharmaceutical uses thereof

Background of the Invention

Technical field

The present invention relates to a novel benzothiazolsulfonamide derivative and a pharmaceutical use thereof. More specifically, the present invention relates to a novel benzothiazole having a terminal cycloalkyl group having an N-substituted sulfonamide group, wherein the substituent group has a cycloalkyl group at its terminal. The present invention relates to a sulfonamide derivative and a medicinal use thereof.

The benzothiazo-norresulfonamide derivative having a terminal alkyl group of the present invention and a pharmaceutically acceptable acid addition salt thereof have a strong tracheal smooth muscle relaxing action, and are therefore used as bronchodilators or asthma preventive / therapeutic agents. It is useful as an active ingredient of a pharmaceutical composition which is Furthermore, since the benzothiazole sulfonamide derivative having a terminal cycloalkyl group and the pharmaceutically acceptable acid addition salt thereof of the present invention have an activity of suppressing IgE antibody production, the IgE antibody As an active ingredient of a pharmaceutical composition which is an agent for treating and / or preventing diseases caused by abnormally elevated levels (hereinafter, often simply referred to as “abnormalities”), particularly allergic diseases including bronchial asthma. Useful.

Conventional technology Generally, bronchodilators such as xanthine drugs and / 3 receptor stimulants are used as clinical treatments for respiratory diseases such as asthma. These drugs are thought to increase the concentration of cyclic adenosine 3,5'-monophosphate (cAMP) in cells. Have been. Aminofilin is a typical example of a xanthine drug, and isoprenetenol is a typical example of a receptor stimulant.

However, xanthine drugs and / or /? Receptor stimulants have various side effects on the heart, etc., as well as the emergence of resistant asthma, which does not relieve with these drugs. It did not satisfy the medical needs.

WO92-147172 (corresponding to EP Publication No. 0 525 203) discloses that benzothiazolesulfonyl having tracheal smooth muscle relaxing action based on antihistamine action Aminoethyl derivative, specifically, compound (20) as 1- (6-benzothiazolesnolephonylaminoethyl) 141- [3- (phenoxy) propyl] pi Perazine, that is, 1- [2- (6-benzothiazolsnorrehonylamino) ethyl] 1-41- (3-phenoxypropyl) piperazine, is disclosed, but its action is Not enough yet.

On the other hand, diseases caused by excessive production of IgE antibodies include atopic asthma, atopic dermatitis, and nasal allele. Allergic diseases such as giants are known. Traditionally, the treatment of allergic monogenic disease involves methods of inhibiting mast cell or basophil degranulation and release of chemical mediators, and antagonizing the allergic response triggered by Z or released chemical mediators. Only symptomatic treatment, such as a method of suppressing it by reaction, was performed. These palliative treatments did not suppress the excessive production of IgE antibody, which is the basis of the allergic reaction, and their effects were limited.

In recent years, inhibitors of IgE antibody production have been developed and reported.However, it is well known that administration of such an anti-allergic agent alone is still not sufficient in the treatment of atopic asthma. It is a fact of.

Accordingly, it is desirable to provide a novel compound that has not only a strong tracheal smooth muscle relaxing action but also a strong IgE antibody production inhibitory action, particularly from the viewpoint of treatment of atopic asthma. It is also desirable from the viewpoint of the treatment of bronchoconstriction other than atopic asthma and diseases caused by abnormal IgE antibody levels.

Summary of the Invention

Under such circumstances, the present inventors have synthesized various compounds and have conducted intensive studies on their pharmacological actions. As a result, it is surprisingly surprising that the novel benzothiazolsulfonamide derivative having a terminal alkyl group represented by the formula (I), which is a new compound, has a conventional terminal alkyl group. No benzo In addition to having a tracheal smooth muscle relaxing action equal to or greater than that of the thiazolesulfonamide derivative, the conventional benzothiazole snolefonamide derivative without a terminal alkyl group did not have I The present inventors have also found that they have a gE antibody production inhibitory action, and completed the present invention.

Accordingly, one object of the present invention is to provide a novel compound having a strong tracheal smooth muscle relaxing action and an IgE antibody production inhibitory action.

Another object of the present invention is to provide a medicament containing the above compound, which is useful as a therapeutic / prophylactic agent for asthma, a bronchodilator or a therapeutic / prophylactic agent for diseases caused by abnormal levels of IgE antibodies. In providing the composition.

Still another object of the present invention is to provide a method for treating asthma, which comprises administering the above pharmaceutical composition to an asthmatic patient.

Yet another object of the present invention is to provide a method for treating bronchoconstriction, which comprises administering the above pharmaceutical composition to a patient having bronchoconstriction.

Yet another object of the present invention is to provide a method for treating an abnormal IgE antibody level, comprising administering the above pharmaceutical composition to a patient suffering from an abnormal IgE antibody level. It is intended to provide a method for treating the diseases that occur.

The above and other objects, features and benefits of the present invention. Will be apparent from the following detailed description and the appended claims.

According to one aspect of the invention, formula (I)

(In the formula, A represents an unsubstituted or alkylene group having 2 to 6 carbon atoms, which is substituted with an alkyl group having 4 carbon atoms; B represents an unsubstituted or 1 alkylene group;

Number of carbon atoms substituted with 4 alkyl groups

Represents 6 alkylene groups or a single bond; R ¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R ² and R ³ each independently represent a hydrogen atom or a carbon atom; or shows a 6 alkyl group, or, R ² and R ³ taken together, form an unsubstituted or C 4 alkylene group having a carbon substituted with number 4 alkyl group having a carbon; R ⁴ Is unsubstituted or substituted by an alkyl group having 14 carbon atoms.

Represents two alkyl groups) And a benzothiazo-nolesulfonamide derivative having a terminal alkyl group at the terminal [hereinafter often referred to as “compound (I)”] or an acid addition salt thereof.

As can be seen from the above formula (I), the benzothiazole sulfonamide derivative having a terminal cycloalkyl group of the present invention has an N_-substituted sulfonamide group, and the substituent has It is characterized by containing a cycloalkyl group at the terminal.

In the above formula (I), A represents an alkylene group having 2 to 6 carbon atoms which is unsubstituted or substituted by an alkyl group having 1 to 4 carbon atoms. Examples of the alkylene group having 2 to 6 carbon atoms include an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group. Limethylene groups are particularly preferred. This alkylene group is an alkyl group having 1 to 4 carbon atoms at any of its substitution positions, for example, methyl, ethyl, propyl, isopropynole, butylisobutyl, 1-methylpropyl, t-butyl. It may be substituted with a group or the like. As a substituent, a methyl group is particularly preferred. For example, when the above alkylene group is an ethylene group, a 3- (7-benzothiazolesulfoninole) -14-cyclohexynolemethinole——3-methylinyl group substituted at the 3-position with a methyl group —— 1,4-Diazabutane is preferred.

In the formula (I), B is an alkylene group having 1 to 6 carbon atoms which is unsubstituted or substituted by an alkyl group having 1 to 4 carbon atoms. Or-or a single bond. Examples of the alkylene group having 1 to 6 carbon atoms include a methylene group, an ethylene group, a trimethylene tetramethylene group, a pentamethylene group, and a hexamethylene group. Groups and ethylene groups are particularly preferred. The alkylene group is an alkyl group having 1 to 4 carbon atoms at any of its substitution positions, for example, methyl, ethyl, propyl isopropyl, butyl, isobutynole, 1-methyl propylene, t It may be substituted with a monobutyl group or the like. As a substituent, a methyl group is particularly preferred. It is also preferred that B is a single bond.

In the formula (I), R ¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. Examples of the alkyl group having 1 to 4 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutynole, 1-methylopenyl pill, and t-butyl group. And a methyl group is particularly preferred. It is also particularly preferred that R ¹ is a hydrogen atom.

In the formula (I), R ² and R ³ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or R ² and R ³ together form unsubstituted or 1 to 4 carbon atoms. It forms an alkylene group having 1 to 4 carbon atoms, which is substituted with a plurality of alkyl groups. R ² and R ³ each independently represent an alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl isopropyl, butyl, isobutyl, 1-methyl propylene, Examples thereof include t-butyl, pentyl, and hexyl groups, and methyl, ethyl and propyl groups are particularly preferred. It is particularly preferable that R ² and R ³ are each a hydrogen atom.

Examples of the alkylene group having 1 to 4 carbon atoms formed by R ² and R ³ together include a methylene, ethylene, trimethylene, and tetramethylene group. , Ethylene, and trimethylene groups are particularly preferred. The alkylene group is an alkyl group having 1 to 4 carbon atoms at any of the substitution positions, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-methylpropyl, It may be substituted with a t-butyl group or the like. As a substituent, a methyl group or an ethyl group is particularly preferred.

In the formula (I), R ⁴ represents an unsubstituted group or a cycloalkyl group having 3 to 7 carbon atoms which is substituted with an alkyl group having 1 to 4 carbon atoms. Examples of the cycloalkyl group include cyclopropynole, cycloprop "tinole, cyclopentinole, cyclohexinole, and cyclohexyl, and cyclobutyl, cyclopentyl, and cyclohexyl groups. A cycloalkyl group is an alkyl group having 1 to 4 carbon atoms at any of its substitution positions, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and 1-methylpropyl. It may be substituted by pill, t-butyl group, etc. As a substituent, a methyl group is particularly preferred. In the formula (I), an alkyl group represented by R ¹ , R ² and R ³ and an alkyl group as a substituent in A, B, R ² , R ³ and R ⁴ are respectively It may be linear or branched.

In the formula (I), N-substituted Suruhon'a Mi de group - S 〇 ₂ N- A- N- B- R ⁴ Gabe Nzochiazoru 4 position of the ring,

I I

R ² R ³

5-position, but that it binds to the 6-position or 7-position, 6-position or 7-position and this for binding is rather preferred for the compounds of this and are preferred correct _c present invention that bind to particular 7-position (I) In the above, A represents an unsubstituted or substituted methylene or trimethylene group; B represents a methylene or ethylene group, or represents a single bond. R ¹ represents a hydrogen atom or a methyl group; R ² and R ³ each represent a hydrogen atom; R ⁴ represents a cycloalkyl group having 3 to 7 carbon atoms; and,

In the formula (I), the group S 0 ₂ N— A— N— B— R ⁴

R ² R ³ It is preferably bonded to the 6- or 7-position of the benzothiazole ring.

In the compound (I) of the present invention, A represents an ethylene group or a trimethylene group which is unsubstituted or substituted with a methyl group; B represents a methylene group or an ethylene group. R ¹ represents a hydrogen atom; R ² and R ³ represent R 4 represents a cycloalkyl group having 3 to 7 carbon atoms, and R 4 represents a cycloalkyl group having 3 to 7 carbon atoms, and in the formula (I), ₂ N— A— N— B— R ⁴

I I

It is also preferred that R ² R ³ is bonded to position 6 or 7 of the benzothiazole ring.

Specific examples of the compound (I) of the present invention include the following compounds.

(1) N-(7-benzothia zole snorehoninole)-N '-cyclohexinolemethinoleethylene diamine;

(2) N- (7-benzothiazolsulfonyl) -N'-cyclopentinolemethinoleethylenediamine:

(3) N-(7-benzothiazolesulfonyl)-N '-cyclopropinolemethylethylenediamine;

(4) N- (7-benzothiazolylsulfonyl) -1-N'-cycloheptylmethylethylenediamine;

(5) N-(7-benzothia sol snolefonyl)-N '-cyclohexylmethyl-trimethylenediamine;

(6) 1-(7-benzothiazolesnolefonyl) 1-4-cyclohexylmethyl-3-methyl-1,4-diazabutane;

(7) N-(7-benzothiazol sulfonyl)-N '-cyclohexynoleethylenediamine;

(8) N— (7-benzothiazolesnorefonyl) -N'- (2-cyclohexynoletin) 1 ethylenediamine;

(9) 1-(7-benzothiazolsulfonyl) 1-4-cyclohexylmethyl homo homopyrazine;

(10) N— (6-benzothiazole snorephonyl) 1 N'—cyclohexylmethyl-ethylenediamine;

(11) N- (7-benzothiazolsulfonyl) -N'-cyclopentinoleethylene diamine;

(1 2) 1-(7-Benzothiazol snorrehoninole) 1-4-cyclopropirme chinole 3-Mechinole 1, 4-diazabutane;

(13) N- (7-benzothiazolsulfonyl) -N'-cyclobutylmethylenethylenediamine; and

(14) N- (2-methyl-7-benzothiazolsulfonyl) -N'-cyclohexylmethyl-ethylenediamine.

Compound (I) of the present invention can be produced by various methods. For example, compound (I) has the formula (Π)

(In the formula, X represents a halogen atom, and R ¹ has the same meaning as described above.)

A compound represented by the formula (m) in an inert solvent:

HN-1 A-1 N- B-1 R

(m)

FT R-

(Wherein, R ² , R ³ , R ⁴ , A and B have the same meanings as described above)

(Hereinafter often referred to as “amine (ΠΙ)”). Amin (ΙΠ) is a method known per se, for example, Experimental Chemistry Lecture, 4th edition, Vol. 20, page 28 (issued by Nihon Kuni Maruzen Co., Ltd., 1992); Synthes is (1975) 135-146 Tet rahedron Letters, 29 (50), 6651-6654 (1988) and Journal of Organic Chemist, 58 (14), 3736.

The compound can be synthesized according to the method described in -3741 (1993). Three

The compound (Π) has the formula (IV)

(Wherein, R ¹ has the same meaning as described above)

(Hereinafter often referred to as “sulfonic acid (IV)”) is described, for example, in Journal of Medicine, Chem.

42-46 (1989), etc., and can be obtained by conversion to lysulfonyl halide. For example, a method of chlorinating with chloromethane is a suitable example. Sulfonic acid (IV) can be prepared by a method known per se, for example, Bull. Soc. Chim.

80, 43-58 (1971).

Examples of the inert solvent used in the reaction between the compound (III) and the amide (III) include halogenated hydrocarbons such as dichloromethane and cross-linked form, and tetrahydrofuran. Ethers such as lahydrofuran, dioxane, and diethyl ether; dimethyl sulfoxide; N

, N-dimethylformamide, acetonitrile and the like. These can be used alone or as a mixed solvent. The amount of the inert solvent to be used is 100 times, preferably 5 to 50 times, the weight ratio of the compound (Π).

The reaction between the compound (π) and the amine (m) depends on the presence of the acid acceptor. It is preferable to do it below. Acid acceptors include, for example, sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium methylate, and the like. Organic tertiary amines such as metal compounds, pyridine, trimethylamine, and triethylamine. The amount of the acid acceptor to be used is 0.3 to 10 moles, preferably 1 to 3 moles, relative to compound (III).

The amount of the amine (m) to be reacted with the compound (π) is 1 to 20 times, and preferably 1 to 10 times, the mole of the compound (Π). It is particularly preferred that the molar ratio is 2.5 to 5 times in the absence of an acid receptor, and it is particularly preferable that the amount is 1 to 3 times in the presence of an acid acceptor. The reaction temperature is generally from 130 to 120 ° C, preferably from 120 to 50 ° C. The reaction time is generally 0.5 to 48 hours, preferably 0.5 to 6 hours, but thin-layer chromatography (TLC), high-speed liquid chromatography. The progress of the reaction may be monitored by chromatography (HPLC) or the like to confirm the disappearance of the compound (II), and the reaction may be terminated as appropriate.

From the reaction mixture thus obtained, compound (I) can be obtained in a free base state as follows. When the reaction solvent is a hydrophilic solvent, the solvent is distilled off from the reaction mixture, the resulting residue is dissolved in a non-hydrophilic solvent, and the residue is washed with a weak aqueous solution of alkali, water, and the like. To remove the non-hydrophilic solvent As a result, compound (I) is obtained. When the reaction solvent is a non-hydrophilic solvent, the reaction mixture is directly washed with a weak aqueous alkali solution, water, or the like, and the non-hydrophilic solvent is distilled off to remove the compound ( I) can be obtained.

The compound (I) of the present invention is preferably in the form of an acid addition salt by a known method. For example, compound (I) is dissolved in alcohols such as methanol and ethanol, and an acid is added in an equivalent to several times the amount to obtain an acid addition salt thereof. Can be done.

As the acid addition salt of compound (I), a pharmaceutically acceptable acid addition salt is preferable. 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, sulfuric acid, conodic acid, fumanoleic acid, maleic acid, and metaphoric acid. Organic acids such as acetic acid, guesoleamic acid and aspartic acid can be mentioned as typical examples, but other known acids can also be used.

By converting the compound (I) of the present invention into an acid addition salt, storage stability is improved; oral solubility is increased by increasing water solubility; purification and crystallization are facilitated. However, if desired, the above-mentioned acid addition salt can be used, for example, in Experimental Chemistry Course, 4th Edition, Vol. 20, pp. 284 (Maruzen, Japan) (Published by Co., Ltd., 1992)) to recycle compound (I) by realizing the compound by a known method. It can also be obtained in the state of a released base.

When the obtained compound (I) or an acid addition salt thereof is to be further purified, a known method, for example, column chromatography using a known carrier such as recrystallization or silica gel is used. You can do it all at once.

The compound (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof (hereinafter, often referred to as “the compound of the present invention”) not only exhibits a strong tracheal smooth muscle relaxing action, but also a strong IgE. Has production for antibody production suppression. In addition, no death was observed when the compound of the present invention was orally administered to rats at 300 mg / kg. Therefore, the compound of the present invention is useful, active, and safe as an active ingredient of a pharmaceutical composition.

That is, according to another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, and at least one pharmaceutically acceptable carrier.

Typical uses of the pharmaceutical composition of the present invention include asthma preventive / therapeutic agents, bronchodilators, and preventive / therapeutic agents for diseases caused by abnormal IgE antibody levels.

Examples of the dosage form for preparing the pharmaceutical composition of the present invention include tablet powders, granules, syrups, suppositories, suspensions, capsules, injections, inhalants, and the like. For the production, various pharmaceutically acceptable carriers are used according to these preparations.For example, tablets, powders, granules, syrups, suppositories, suspensions Carriers for oral preparations such as capsules include excipients such as lactose, sucrose, glucose, starch, and crystalline cellulose; hydroxypropinoresenolose, dexamethasyl cellulose, and starch. Binders such as gum arabic, gelatin, gelatin, glucose, sucrose, tragacanth, sodium anoregate; disintegrators such as carboxymethylcellulose, starch, calcium carbonate; stearic acid, Lubricants such as refined talc, sucrose fatty acid ester, hydrogenated vegetable oil, magnesium stearate, calcium stearate; sodium lauryl sulfate, soy lecithin, sucrose fatty acid ester, Surfactants such as polysorbate 80; additives such as lecithin and soybean oil glycerin; fluidity enhancers; and coloring agents. Can Ru.

When the compound of the present invention is used as a parenteral preparation such as an injection, diluents such as distilled water for injection, physiological saline, aqueous solution of glucose, vegetable oil for injection, propylene glycol, and polyethylene glycol are generally used. Can be used. If desired, bactericides, preservatives, stabilizers, tonicity agents, soothing agents and the like may be added. <Also, in the preparation of inhalants, polychloromonofluoromethan Etc. can be used as a solvent.

According to still another aspect of the present invention, there is provided a method for treating asthma, comprising administering to a patient with asthma a therapeutically effective amount of the compound of the present invention.

According to another aspect of the present invention, there is provided a therapeutically effective amount of the present invention. There is provided a method for treating bronchoconstriction, comprising administering a light compound to a patient having bronchoconstriction.

According to yet another aspect of the present invention, an abnormal IgE antibody level comprises administering a therapeutically effective amount of a compound of the present invention to a patient suffering from an abnormal IgE antibody level. Provides a method for treating the diseases caused by the above.

When the compound of the present invention is administered to humans, it can be orally administered in the form of tablets, powders, granules, syrups, suppositories, suspensions, and capsules as described above. It can be administered parenterally, by injection, including infusion, or in the form of a cream or spray. The dosage varies depending on the indication, dosage form, patient age, body weight, and the degree of symptoms. In general, 3 to 300 mg per day for an adult is administered in 1 to 3 divided doses. The daily administration period is generally several B to 2 months, but the daily dose and administration period can be reduced depending on the patient's symptoms.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to examples and application examples, but the present invention is not limited to these examples.

The nuclear magnetic resonance spectrum (NMR) and the mass spectrometry spectrum of the hydrochloride of the compound (I) obtained in the following Examples

(FabMS) is described in Table 1 below.

Example 1

N- (7-benzothiazolesnolefonyl) -N'-cyclohexylmethyl-ethylenediamine (Compound 1) and its hydrochloride

To 12 g of 7-benzothiazolesulfonic acid was added 120 ml of thionyl chloride and 1.2 ml of dimethylformamide, and the mixture was heated under reflux for 3 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 a saturated aqueous solution of sodium carbonate, and extracted with 100 ml of dichloromethane. After cooling the ice layer in the mouth, the solution was added to a 100 ml solution of dichloromethane containing 26.1 g of N-hexylhexylmethyl-ethylenediamine for 30 minutes. Then, the mixture was stirred at 0 to 5 ° C for 1 hour. After completion of the reaction, the reaction mixture was washed with 200 ml of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is charged into a silica gel (Wako Gel C-200, manufactured by Wako Pure Chemical Industries, Japan, 600 g) column, and methanol is used as the elution solvent. — Purification by column chromatography using a chloroform mixed solvent (5-10% methanol) gave the title compound 1. The yield was 10.8 g (55% yield).

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 a hydrochloride of Compound 1. Yield 11.2 g (94% yield).

Example 2

1- (7- Benzothia zonoreth norefoni) 1 4-cyclohexylmethyl 3-methyl 4-, 4-diazabutane (compound 6) and its hydrochloride

In Example 1, 28.2 g of 1-cyclohexylmethyl-1,2-methyl-1,4-diazabutane 28.2 g was used instead of N-cyclohexylmethyl-ethylenediamine 26.1 g. The title compound 6 was obtained in substantially the same manner as in Example 1 except for using it ₍ yield: 10.2 g (yield: 50%)

The obtained hydrochloride salt of compound 6 was obtained in the same manner as in Example 1 (yield: 100.1 g (yield: 90%)

Example 3

N- (7-benzothiazole sodium) —— N '— (2-cyclohexylethyl) monoethylenediamine (compound 8) and its hydrochloride

In Example 1, N-cyclohexylmethyl-ethylene was used. The title compound was prepared in substantially the same manner as in Example 1 except that N—2—cyclohexylethyl-ethylenediamine 28.2 g was used instead of diamine 26.1 g. I got 8. Yield 9.4 g (Yield 46%)

The resulting hydrochloride salt of compound 8, _c yield 8 obtained in the same manner as in Example 1. 5 g (8 2% yield)

Example 4

N- (6-benzothia zo-noles-norefoninole)--N '-cyx hexylmethyl-ethylethylenediamine (Compound 10) and its hydrochloride

The title compound was prepared in substantially the same manner as in Example 1 except that 12 g of 6-benzothiazolesulfonic acid was used instead of 12 g of 7-benzothiazolesulfonic acid. 1

Got 0. Yield 9.6 g (Yield 49%)

The obtained hydrochloride of compound 10 was obtained in the same manner as in Example 1. Yield 10.1 g (93% yield)

Example 5

N— (7——Benzothiazonolesnorehininor) 1 N ′ —— Six-pentyl pentylmethyl-ethylenediamine (Compound 2) and its hydrochloride

Example 1 is the same as Example 1 except that 23.8 g of N-cyclopentylmethylethylethylenediamine was used instead of 26.1 g of N-cyclohexylmethylethylethylenediamine. And real / 06

twenty two

In a similar manner, the title compound 2 was obtained. Yield 9.4 g (Yield 49%)

The obtained hydrochloride of compound 2 was obtained in the same manner as in Example 1, yield 10.0 g (yield 96%)

Example 6

N- (7-benzothiazonolesnorefonyl) -N'-cyclopropyl propylmethylethylenediamine (Compound 3) and its hydrochloride

Example 1 was repeated except that 19.1 g of N-cyclopropylmethylethylethylenediamine was used in place of 26.1 g of N-cyclohexylmethylethylethylenediamine in Example 1. In substantially the same manner, the title compound 3 was obtained. Yield 8.8 g (Yield 51%)

The obtained hydrochloride of compound 3 was obtained in the same manner as in Example 1, yield 8.6 g (yield 87%)

Example 7

N- (7-benzothiazolesulfonyl) -N'-cyclyl heptylmethyl-ethylenediamine (Compound 4) and its hydrochloride

Example 1 is the same as Example 1 except that N-cyclohexylmethyl-ethylenediamine 26.1 g was replaced with N-cycloheptylmethyl-ethylenediamine 28.4 g. In substantially the same manner as described above, the title compound 4 was obtained. Yield 11.4 g (Yield 56%)

The obtained hydrochloride of compound 4 was obtained in the same manner as in Example 1. Yield 11.2 g (89% yield)

Example 8

N- (7-benzothiazolsulfonyl) -N'-cyclohexylmethyl-trimethylenediamine (compound 5) and its hydrochloride

Example 1 was repeated except that 26.1 g of N-cyclohexylmethyl-ethylenediamine was used in place of 26.1 g of N-cyclohexylmethyl-ethylenediamine. In substantially the same manner as in Example 1, the title compound 5 was obtained. Yield 9.7 g (Yield 47%)

The obtained hydrochloride of compound 5 was obtained in the same manner as in Example 1. Yield 10.2 g (Yield 96%)

Example 9

N- (7-benzothiazolsulfonyl) -N'-cyclohexylethylenediamine (Compound 7) and its hydrochloric acid ¾a

Example 1 is the same as Example 1 except that 23.8 g of N-cyclohexylmethylethylenediamine was used in place of 26.1 g of N-cyclohexylmethylethylethylenediamine. In substantially the same manner, the title compound 7 was obtained. Yield 9.9 g (52% yield) The obtained hydrochloride of compound 7 was obtained in the same manner as in Example 1. Yield 9.7 g (Yield 8.8%)

Example 10

1- (7-Benzothiazole sulfoninole) 4-cyclohexylmethyl homopidazine (compound 9) and its oxalate

Example 1 is substantially the same as Example 1 except that 32.8 g of 4-cyclohexylmethyl ylhomopiperazine is used in place of 26.1 g of N-cyclohexylmethylethylethylenediamine in Example 1. In a similar manner, the title compound 9 was obtained. Yield 12.9 g (yield 59%)

The obtained hydrochloride of compound 9 was obtained in the same manner as in Example 1. Yield 12.7 g (90% yield)

Example 1 1

N- (7-benzothiazole sulfoninole) 1 N'-cyclopentyl-ethylenediamine (Compound 11) and its hydrochloride

Example 1 was repeated except that 21.4 g of N-cyclopentynoleethylenediamine was used in place of 26.1 g of N-cyclohexylmethylethylethylenediamine. In substantially the same manner, the title compound 11 was obtained. Yield 10.2 g (Yield 56%)

The resulting hydrochloride salt of Compound 1 1 was a obtained in the same manner as in Example 1 ₍ 6/0

twenty five

Yield 9.7 g (Yield 85%)

Example 1 2

1— (7—Benzothiazolone sulfoninole) 1-4—Cyclopropylmethyl-3—methyl1,4,1-diazabutane (compound 12) and its hydrochloride

In Example 1, N-cyclohexylmethylethylenediamine (26.1 g) was replaced with 1-cyclopropylmethyl-2-1-2-methyl-1,4-diazabutane (21.4 g). The title compound 12 was obtained in substantially the same manner as in Example 1 except that was used. Yield 9.9 g (54% yield)

The obtained hydrochloride of compound 12 was obtained in the same manner as in Example 1, yield 9.3 g (yield 84%)

Example 13

N— (7—Venzothiazonoresolenoyl) —— N ′ —— Cyclobutylmethylethylenediamine (Compound 13) and its hydrochloride

Example 1 is the same as Example 1 except that 21.4 g of N-cyclobutylmethylethylethylenediamine was used in place of 26.1 g of N-cyclohexylmethylethylethylenediamine. In substantially the same manner as 1, the title compound 13 was obtained. Yield 10.5 g (Yield 58%)

The obtained hydrochloride of compound 13 was obtained in the same manner as in Example 1, yield 9.9 g (yield 85%) Example 14

N- (2-Methyl-7-benzothiazolesnolephonyl) -N'-cyclohexylmethyl-ethylenediamine (Compound 14) and its hydrochloride

Substantially the same method as in Example 1 except that 12.8 g of 2-methyl-7-benzothiazolesulfonate was used instead of 12 g of 7-benzothiazolesulfonate in Example 1. Afforded the title compound 14. Yield 11 g (54% yield)

The obtained hydrochloride of compound 14 was obtained in the same manner as in Example 1 and yield 9.9 g (yield 82%)

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L £ 9I0 / S6dT / XD <I 88090/96 OM. Application Example 1 (Relaxation of tracheal smooth muscle on KC1 contraction in tracheal specimens isolated from guinea pig)

(1) Inhibition test method for K C 1 contraction

A method using isolated guinea pig trachea specimens (Takagi, Ozawa "Pharmacological Experiments", 100-102, 1960, published by Nankoku Sando, Japan; Fujiwara, Shibata "Basic Pharmacological Experiments" The method of the present invention was used to measure the relaxing effect of the compound of the present invention on tracheal smooth muscle in accordance with the method described in "P.

350 to 500 g of male guinea pigs (heart rate, pure Kuroda) were excised from a tracheal specimen of Creps-Henslite nutrient solution (containing 3M of indomethacin). Hang it isometrically (1.5 g initial load) on a filled Magnus apparatus (capacity: 20 ml), maintain the liquid temperature at 37 ° C under 95% oxygen and 5% carbon dioxide gas ventilation. However, an aqueous KC 1 solution (final concentration 20 mM) was applied to the Magnus tubes to shrink the tracheal specimen.

After the contraction was stabilized, the compound of the present invention described in the following example was dissolved in distilled water or physiological saline, and the compound of the present invention was added to the Magnus tube in a cumulative manner. The relaxation effect was observed, and a dose-response curve was obtained. . After the measurement was completed, the maximum relaxation of papaverine 10 OjuM was determined, and the relaxation rate at that time was 100%. The number of samples was all three. As a control, 1- [2-(6) in WO92-147712 (corresponding to EP Publication No. 0 525 2023 A1) Nzothiazolsulfonylamino) ethyl] 1 4— (3 —Phenoxypropyl) Piperazine dihydrochloride was used. (2) Measurement results

The measurement results are as shown in Table 2.

Table 2

From the results in Table 2 above, it is clear that the compound of the present invention has a tracheal smooth muscle relaxation action on KC1 contraction in guinea pig isolated trachea, whereas WO092-1470712 discloses the compound. It was found that the control product described in the specification had almost no tracheal smooth muscle relaxing activity under the test conditions.

Therefore, the compound (I) of the present invention or a pharmacologically acceptable acid addition salt thereof has a tracheal smooth muscle relaxing action on KC 1 contraction in a guinea pig isolated tracheal specimen. It is especially useful as a treatment and prevention agent for asthma.

Application Example 2 (IgE antibody production inhibitory effect on mouse spleen cells) (1) Measurement method

Cellular Immunology, 145, 299—310 (1992) or

According to the method described in Immunology Letters, 3, 99-104 (1992), the inhibitory effect of the compound of the present invention on IgE antibody production was evaluated. That is, 10 g of dinitroff was adsorbed intraperitoneally to 6- to 8-week-old female AKR mice (Charles River, Japan) on 4 mg aluminum hydroxide gel (PIERCE, USA). Administered dini trophenyl cona 1 bumi n (DNP-cona 1 bumin) (Seiji Wako; "Immunological Experiment Procedure B", p. 1129, prepared according to the Japanese Society of Immunology, Japan) did. After a lapse of 4 weeks, the spleen was excised, and the spleen cells obtained by crushing and a suspension were prepared in Cick's MEM medium (Irvine scie- mentific, USA). The spleen cells 1 X 1 0 ⁴ pieces and mouse T h 2 clone cells

(D 1 0. G 4. 1) of the (U.S. ATCC Corp.) 2 X 1 0 ⁵ pieces at the click 's MEM medium containing 1 0% fetal calf serum 2 0 0 μ 1 I ng Zm l DNP — After culturing with cona 1 bumin for 7 days, the supernatant was recovered.

Internationa l Archives of Allergy and Applied

The IgE antibody production of the compound of the present invention was measured according to the method described in Immunology, 15, 47-54, (1988). That is, the IgE antibody in the supernatant was added to the optimal concentration of rat anti-mouse IgE monoclonal antibody (2 μg / ml), biotin-labeled rat anti-mouse Ig E antibody was quantified by an enzyme immunoassay using a monoclonal antibody (2 μg / m 1) and avidin peroxidase (2.5 ug / ml) (Funakoshi, Japan). Two types of rat anti-mouse IgE monoclonal antibodies

Allergy and Applied Immunology, 8_5, 47-54, (1988), one of which was prepared using a biotin-labeling kit (Amer ican Qua 1ex, USA). Labeled. The compound of the present invention was added to the medium at a concentration of 1 μg / m 1 throughout the culture. W O 9 2— as a control (1)

1- [2- (6-Benzothiazolsulfonylamino) ethyl] -41- (3-phenoxypropyl) pidazine dihydrochloride described in International Patent Publication No. 1 4 7 12 WO 94-193 336 international specification (EP Publication No. The following compounds described as Compounds (7) and (10), respectively, (corresponding to No. 0 636 564) were used. Control product (1) 1 [2-(6-Benzothiazolsulfoninorea mino) ethyl]-4-(3-phenoxypropyl) piperazine dihydrochloride Control product (2) N — [2— (3, 4—Methylene benzyloxyamino) ethyl] — 7—Venzothia azole sulfonamide

^ fffl

Control product (3) N- [2- (3-Fluorobenzylamino) ethyl] -17-benzothiazolsulfonamido hydrochloride

(2) Measurement results

The measurement results are as shown in Table 3.

Table 3 Test Drug IgE Production Inhibition Rate (%) Compound 1 (hydrochloride) 5 1

Compound 2 (hydrochloride) 7 5

Compound 3 (hydrochloride) 30

Compound 4 (hydrochloride) 8 5

Compound 5 (hydrochloride) 5 2

Compound 6 (hydrochloride) 7 8

Compound 7 (hydrochloride) 50

Compound 8 (hydrochloride) δ 2

Compound 9 (hydrochloride) 7 2

Compound 10 (hydrochloride) 24

Compound 1 1 (hydrochloride) 4 3

Compound 1 2 (hydrochloride) 2 3

Compound 1 3 (hydrochloride) 3 9

Control (1) ≤ 10

Control (2) ≤ 10

Control (3) ≤ 10 As is clear from the results in Table 3 above, under the test conditions, the compound of the present invention, which is a benzothiazolsulfonamide derivative having a terminal cycloalkyl group, is a benzothiazolsulfolamide having no terminal cycloalkyl group. A control product described in WO92-147271, which is a amide derivative (1) and a control product described in WO94193336

Compared with (2) and (3), it was confirmed that the compound had a markedly stronger action of suppressing IgE antibody production.

As described above, since the compound (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof has an inhibitory action on IgE antibody production, it prevents and treats diseases caused by abnormal IgE levels. It is useful as an active ingredient of an agent, particularly an agent for treating and preventing atby asthma.

Industrial applicability

The benzothiazolsulfonamide derivative having a terminal cycloalkyl group of the present invention represented by the formula (I) and the acid addition salt thereof are the conventional benzothiazolsulfonamides having no terminal cycloalkyl group. Not only has a tracheal smooth muscle relaxing activity equal to or greater than that of benzothiazole sulfonamide derivatives, but also becomes a conventional benzothiazole sulfonamide derivative without a terminal cycloalkyl group, and IgE antibody production It also has an inhibitory effect. Therefore, the benzothiazolsulfonamide derivative having a cycloalkyl group of the present invention and the pharmaceutically acceptable acid addition salt thereof can be used as a therapeutic / prophylactic agent for asthma, a bronchodilator or an IgE antibody. It is useful as an active ingredient of a pharmaceutical composition that is an agent for treating and preventing diseases caused by abnormal levels.

Claims

The scope of the claims

1. Formula (I)

(Wherein, A represents an unsubstituted or substituted alkylene group having 1 to 4 carbon atoms; an alkylene group having 2 to 6 carbon atoms; B represents an unsubstituted or substituted alkylene group;

Number of carbon atoms substituted with 4 alkyl groups

R ¹ represents a hydrogen atom or an alkyl group having 4 carbon atoms; R ² represents an alkyl group having 4 carbon atoms; R ² and R ³ each independently represent a hydrogen atom or 1 to 6 carbon atoms Or R ² and R ³ together form an alkylene group having 1 to 4 carbon atoms which is unsubstituted or substituted by an alkyl group having 1 to 4 carbon atoms; R ⁴ represents a cycloanolealkyl group having 3 to 7 carbon atoms which is unsubstituted or substituted with an alkyl group having 1 to 4 carbon atoms)

A benzothiazole sulfonamide derivative having a terminal alkyl group or an acid addition salt thereof.

2. In the formula (I), A represents an ethylene group or a trimethylene group which is unsubstituted or substituted by a methyl group; and B represents a methylene group or an ethylene group. Or a single bond;

R ¹ represents a hydrogen atom or a methyl group; R ² and R ³ each represent a hydrogen atom; R ⁴ represents a cycloalkyl group having 3 to 7 carbon atoms;

In the formula (I), based on one S 〇 ₂ N- A- N- B- R ⁴

I I

The benzothiazole sulfonamide derivative having a terminal alkyl group or the acid addition thereof according to claim 1, which is bonded to the 6-position or 7-position of the R ² R ³ benzothiazole ring. salt.

3. In the formula (I), A represents an unsubstituted or substituted with an methyl group or a trimethylene group; B represents a methylene group or an ethylene group; Shows mosquito or a single bond;

R ¹ represents a hydrogen atom; R ² and R ³ together form an ethylene group or a trimethylene group; R ⁴ represents a cycloalkyl group having 3 to 7 carbon atoms. Li and

In the formula (I), a group S 0 ₂ N—A—N—B—R ⁴ force;

I I

The terminal cycloalkyl group according to claim 1, which is bonded to the 6-position or the 7-position of the R ² R ³ benzothiazole ring. A benzothiazole sulfonamide derivative or an acid addition salt thereof.

4 (1) N-(7-benzothiazoles / lefonyl) N-cyclohexinolemethinoleethylenediamine;

(2) N- (7-benzothiazole)

(3) N-(7-benzothiazole snoreleonyl)-N '-cyclopropylmethyluethylenediamine;

(4) N- (7-benzothiazolsulnorethonyl) N cycloheptylmethylethylenediamine;

(5) N— (7-benzothiazolylsulfonyl) -1-N'-cyclohexylmethyl trimethylenediamine

(6) 1 7 —Venzothiazole (north) —— 4—Mouth hexinoleme chinore 1—3-Methinole——1,4-Diazabutane;

(7) N-(7-benzothiazole sodium phenol)-N '-cyclohexylethylene diamine;

(8) N- (7-benzothiazolsulfonyl) -N '-(2-cyclohexylethyl) -ethylenediamine; and

(9) (7-Benzothiazol-l-snorrehoninole) 4-six-methyl hexylmethinole homopidazine;

(10) N-(6 zothiazolone snorrehoninole) 1 N hex mouth hexinolemethinoleethylene diamine; (11) N- (7-benzothiazolylsulfonyl) -1-N'-cyclopentyl-ethylene diamine;

(1 2) 1-(7-benzothiazole snorehoninole) 1-4-mouth Propyrmethyl 3-methyl 1, 4-diazabutane; or

(13) N- (7-benzothiazoles) -N'-cyclobutylmethyl-ethylenediamine,

Alternatively, the benzothiazole sulfonamide derivative having a terminal cycloalkyl group or the acid addition salt thereof according to claim 1, which is an acid addition salt thereof.

5. N- (7-Benzothiazolylsulfonyl) -N'-cyclohexylmethyl-ethylenediamine or an acid addition salt thereof according to claim 4, wherein the benzothiazo-one having a cycloalkyl group at the end thereof. A sulfonamide derivative or an acid addition salt thereof.

6. A therapeutically effective amount of the formula (I)

(In the formula, A represents an unsubstituted or substituted alkyl group having 4 to 6 carbon atoms. R represents hydrogen or a single bond representing an alkylene group having 1 to 6 carbon atoms which is unsubstituted or substituted by an alkyl group having 1 to 4 carbon atoms; R ′ represents hydrogen; the atom or an alkyl group having 1 to 4 carbon shows; R ² and either R ³ each show ~ 1 hydrogen atom or carbon atoms to the independent 6 alkyl group, or, R ² and R ³ are jointly To form an alkylene group having 1 to 4 carbon atoms which is unsubstituted or substituted with an alkyl group having 1 to 4 carbon atoms; R ⁴ is an unsubstituted or alkyl group having 1 to 4 carbon atoms Indicates a substituted cycloalkynol group having 3 to 7 carbon atoms)

A pharmaceutical composition comprising a benzothiazole sulfonamide derivative having a terminal alkyl group or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, which is a prophylactic / therapeutic agent for asthma, a bronchodilator, or a prophylactic / therapeutic agent for a disease caused by an abnormal level of IgE antibody.

8. A therapeutically effective amount of the formula (I)

(Wherein, A represents an unsubstituted or substituted alkyl group having 4 to 6 carbon atoms; and B represents an unsubstituted or alkyl group having 1 to 4 carbon atoms.) R ¹ represents a hydrogen atom or an alkyl group having 4 carbon atoms; R ¹ represents a hydrogen atom or an alkyl group having 4 carbon atoms; R ² and R ³ each represent an alkylene group having 1 to 6 carbon atoms; Represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or R ² and R ³ together represent 1 carbon atom which is unsubstituted or substituted by an alkyl group having 1 to 4 carbon atoms. R ⁴ represents an alkyl group having 3 to 7 carbon atoms which is unsubstituted or substituted with an alkyl group having 4 carbon atoms.

A method for treating asthma, comprising administering to a patient with asthma a benzothiazolyl sulfonamide derivative having a terminal alkyl group represented by the formula (I) or a pharmaceutically acceptable acid addition salt thereof. Law

9. A therapeutically effective amount of the formula (I)

(Wherein, A represents an alkyl group having 2 to 6 carbon atoms which is unsubstituted or substituted by an alkyl group having 4 carbon atoms; B represents an unsubstituted or alkyl group having 1 to 4 carbon atoms) R ¹ represents a hydrogen atom or an alkyl group having 4 carbon atoms; R ² represents a hydrogen atom or an alkyl group having 4 carbon atoms; and R ² and R ³ each represent an independent bond. Represents a hydrogen atom or an anoalkyl group having 6 carbon atoms, or R ² and R ³ together represent an alkyl group having 4 carbon atoms which is unsubstituted or substituted by an alkyl group having 4 carbon atoms. R ⁴ represents a cycloalkyl group having 3 to 7 carbon atoms which is unsubstituted or substituted with an alkyl group having 1 to 4 carbon atoms)

A benzothiazo compound having an alkyl group at a terminal end represented by A method for treating bronchoconstriction, which comprises administering a rusulfonamide derivative or a pharmaceutically acceptable acid addition salt thereof to a patient having bronchoconstriction.

10. A therapeutically effective amount of the formula (I)

(In the formula, A represents an unsubstituted or substituted alkyl group having 4 to 6 carbon atoms; an alkyl group having 2 to 6 carbon atoms; B represents an unsubstituted or alkyl group having 1 to 4 carbon atoms. each R ² and R ^3; in either a substituted has been has 1 to 6 carbon atoms alkylene group, or a single bond; R ¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms Independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or R ² and R ³ together represent 4 carbon atoms which are unsubstituted or substituted by a alkynole group having 4 carbon atoms R ⁴ is unsubstituted or substituted by an alkyl group having 4 carbon atoms and has 3 to 7 carbon atoms. Represents two alkyl groups)

The administration of a benzothiazole sulfonamide derivative having a terminal cycloalkyl group or a pharmaceutically acceptable acid addition salt thereof to a patient suffering from abnormal IgE antibody levels. To treat diseases caused by abnormal levels of IgE antibodies.