JP2003104975A - New benzothiazole compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new compound useful for allergic rhinitis, urticaria, inflammatory diseases, etc. SOLUTION: This new benzothiazole compound represented by the general formula (I) [wherein R represents a substituted or unsubstituted phenyl group and Y represents C(=O), O or CH2 and Z represents COOH, CN, CONR<1> R<2> or NR<3> CO-R<4> ] or a pharmaceutically permissible salt thereof has an activity inhibiting a bond of a physiologically active amine to a receptor of the physiologically active amine and is useful as a medicine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel benzothiazole compound or a pharmaceutically acceptable salt thereof, and a medicament containing the benzothiazole compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0002]

2. Description of the Related Art Physiologically active amines such as histamine and serotonin are involved in signal transduction in various parts of the body. The physiologically active amine is involved in various central functions as a neurotransmitter in central tissues. Peripheral tissues also have various physiological effects due to the interaction with specific receptors. For example, histamine
It is a type of physiologically active amine present in mast cells, basophilic leukocytes in blood and the like, and has an action of contracting smooth muscle in the bronchus and the like via the H 1 -receptor, for example. That is, when the action of histamine becomes excessive, the contraction of the bronchi blocks the inflow of air into and out of the lung, causing asthma symptoms. Also, histamine
It increases leakage of blood components into the interstitial spaces due to increased capillary permeability, and edema is formed due to increased lymph and protein components. Histamine is the other central nervous system,
It plays a wide variety of physiological activities in the digestive and circulatory organs. Therefore, drugs that control the interaction between physiologically active amines and their receptors, such as antihistamines, can be effective drugs for various diseases. Examples of the disease include allergic rhinitis, allergic dermatitis, urticaria and other allergic diseases, inflammatory diseases, central nervous system diseases, digestive system diseases, cardiovascular system diseases and the like.

On the other hand, various compounds represented by diphenhydramine, chlorcyclidine, terphenazine, cimetidine, chloropheniramine, and memiramine have been reported as active ingredients of physiologically active amine receptor antagonists represented by antihistamines. , Is used in clinical practice as an antiallergic agent, etc., but their pharmacological profiles usually differ depending on their structures. In addition, various side effects such as sedation, drowsiness, and arrhythmia have been reported in medicines used clinically as physiologically active amine receptor antagonists, and an active ingredient with few side effects is required.

[0004]

The problem to be solved by the present invention is to find a novel low molecular weight compound useful as an active ingredient of a medicine.

[0005]

As a result of intensive studies, the present inventors have found that a novel benzothiazole compound or a pharmaceutically acceptable salt thereof binds to a physiologically active amine and the physiologically active amine receptor. It was found that the compound has an activity of inhibiting the above-mentioned effects and is useful as an active ingredient of a medicine, and thus completed the present invention.

That is, the present invention is [1] General formula (1):

[Chemical 14] [In the formula, R represents a substituted or unsubstituted phenyl group.
Y is -C (= O)-, -O-, or -CH._Two−
Represents, Z is -COOH, -CN, -CONR
¹R^Two, Or -NR^ThreeCO-R^Four {In the above, R
¹And R^ThreeRepresents a hydrogen atom or a lower alkyl group.
And R^TwoAnd R^FourIs a hydrogen atom, a lower alkyl group, a formula
(2):

[Chemical 15] (In the formula, X ² represents a lower alkyl, a halogen atom, a cyano group, a nitro group, a lower haloalkyl group, a lower alkoxy group, a lower haloalkoxy group, or a methylenedioxy group, and p represents an integer of 0 to 3. ), Formula (3):

[Chemical 16] (In the formula, n represents an integer of 0 to 3, R ⁵ represents a hydrogen atom or a lower alkyl group, R ⁶ represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, a 4 to 7-membered cycloalkyl group. A group, a substituted or unsubstituted phenyl group, or
Represents a 5- to 7-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from 0 to 2 nitrogen atoms, 0 or 1 oxygen atom, and 0 or 1 sulfur atom; When the cycloalkyl group contains a nitrogen atom,
The nitrogen atom may be substituted with a substituted or unsubstituted lower alkyl group. R ⁵ and R ⁶ are combined,
Even if it forms a 5 to 7 membered heterocycloalkane containing 1 to 2 heteroatoms selected from 1 to 2 nitrogen atoms, 0 or 1 oxygen atom, 0 or 1 sulfur atom, Good. A carbon atom on the heterocycloalkane may be substituted with a lower alkyl group, and when the heterocycloalkane contains a nitrogen atom, the nitrogen atom may be substituted with a substituted or unsubstituted lower alkyl group. Good. ), Equation (4):

[Chemical 17] (In the formula, m represents an integer of 2 to 5, R ⁷ represents a hydrogen atom or a lower alkyl group, and R ⁸ represents a hydrogen atom, a lower alkyl group, or a 4- to 7-membered cycloalkyl group. Or alternatively, R ⁷ and R ⁸ are combined to form 0-1
5 to 7-membered heterocycloalkane containing 1 oxygen atom, 0 to 1 sulfur atom, or 1 to 2 nitrogen atoms may be formed. When the heterocycloalkane contains a nitrogen atom, the nitrogen atom may be substituted with a substituted or unsubstituted lower alkyl group. ) Or equation (5):

[Chemical 18] (In the formula, q represents an integer of 0 to 5, and the ring A is 1 to 2
Nitrogen atom, 0 or 1 oxygen atom, 0 or 1
1 to 2 heteroatoms selected from the sulfur atom of
Represents a 5- to 7-membered heterocycloalkyl group, R¹⁵Is
Hydrogen atom or substituted or unsubstituted lower alkyl
Represents a group. ) Or R¹And R^TwoIs joined
Then, 1 to 2 nitrogen atoms, 0 or 1 oxygen source
Child, 1 or 2 selected from 0 or 1 sulfur atom
5- to 7-membered heterocycloalkanes containing heteroatoms
And the heterocycloalkane is a nitrogen atom.
When containing an atom, each of the nitrogen atoms is substituted or
Is an unsubstituted lower alkyl group, cycloalkyl group, phenyl group
It may be substituted with a phenyl group or a pyridyl group. }
Or R represents a hydrogen atom or a substituent.
, Y represents a bond, and Z is -CONR.⁹R¹⁰,
Or-NR¹¹CO-R¹² {In the above, R⁹And
And R¹¹Represents a hydrogen atom or a lower alkyl group,
R¹⁰And R¹²Is a hydrogen atom, a lower alkyl group, or
Or equation (3):

[Chemical 19] (In the formula, n, R ⁵ , and R ⁶ have the same meanings as described above.). } Is represented. ] The benzothiazole compound represented by these, or its pharmaceutically acceptable salt. [2] The benzothiazole compound according to [1], wherein Y is represented by-(CO)-, or a pharmaceutically acceptable salt thereof. [3] The bonding position of Y in the formula (1) is any of 5-position, 6-position, or 7-position of the benzothiazole ring,
The benzothiazole compound according to [1] or [2], or a pharmaceutically acceptable salt thereof. [4] General formula (6):

[Chemical 20] [Wherein, X ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group, a haloalkyl group, a cyano group, a nitro group, a lower alkoxy group, or a lower haloalkoxy group, and Y 1
¹ represents -C (= O)-or -O-, and Z is
It has the same meaning as Z in formula (1). ],
A benzothiazole compound, or a pharmaceutically acceptable salt thereof. [5] General formula (7):

[Chemical 21] [Wherein, X ¹ and Y ¹ are each represented by the general formula (6):
Is the same as X ¹ and Y ¹ in, and Z is the same as Z in the general formula (1). ] The benzothiazole compound represented by these, or its pharmaceutically acceptable salt. [6] General formula (8):

[Chemical formula 22] [Wherein, X ¹ and Y ¹ are each represented by the general formula (6):
Has the same meaning as ^{X 1} and ^{Y 1} in, n, ^{R 5,} and ^{R 6} is an n in each formula (3), ^{R 5,} and the ^{R 6 synonymous, Z} 1 is -CONH-, or - N
Represents HCO-. ] The benzothiazole compound represented by these, or its pharmaceutically acceptable salt. [7] General formula (9):

[Chemical formula 23] [Wherein X ¹ , Y ¹ , n, R ⁵ , R ⁶ , and Z ¹ are
It is synonymous with general formula (8). ] The benzothiazole compound represented by these, or its pharmaceutically acceptable salt. [8] General formula (10):

[Chemical formula 24] Wherein, n, ^{R 5,} and ^{R 6,} n in each formula (3), ^{R 5,} and have the same meaning as ^{R 6, Z 1} has the same meaning as ^{Z 1} in the general formula (8), r represents an integer of 0 to 3, X ³ represents a halogen atom, a lower alkyl group,
It represents a haloalkyl group, a cyano group, a nitro group, a lower alkoxy group, or a lower haloalkoxy group. ] The benzothiazole compound represented by these, or its pharmaceutically acceptable salt. [9] General formula (11):

[Chemical 25] [X ¹ and Y ¹ have the same meanings as X ¹ and Y ¹ in formula (6), respectively, R ¹³ represents a hydrogen atom or a lower alkyl group, and R ¹⁴ represents a hydrogen atom, a substituted or unsubstituted group. A substituted lower alkyl group, a 4- to 7-membered cycloalkyl group, a substituted or unsubstituted phenyl group, or
Represents a 5- to 7-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from 0 to 2 nitrogen atoms, 0 or 1 oxygen atom, and 0 or 1 sulfur atom; When the cycloalkyl group contains a nitrogen atom,
The nitrogen atom may be substituted with a substituted or unsubstituted lower alkyl group. Or R ¹³ and R
¹⁴ is bonded to one or two nitrogen atoms, 0 or 1
5 to 7-membered heterocycloalkane containing 1 to 2 heteroatoms selected from 0 oxygen atom and 0 or 1 sulfur atom may be formed. When the heterocycloalkane contains a nitrogen atom, the nitrogen atom may be substituted with a substituted or unsubstituted lower alkyl group, cycloalkyl group, phenyl group, or pyridyl group, respectively. ] The benzothiazole compound represented by these, or its pharmaceutically acceptable salt. [10] General formula (12):

[Chemical formula 26] [X¹And Y¹Are respectively in general formula (6)
X¹And Y¹Is synonymous with R^ThirteenAnd R¹⁴Is
R in the general formula (11) respectively^ThirteenAnd R ¹⁴When
Are synonymous. ], A benzothiazole compound represented by
Or a pharmaceutically acceptable salt thereof. [11] Y¹Is represented by-(C = O)-, [4]
To the benzothiazole compound according to any one of [10],
Or a pharmaceutically acceptable salt thereof. [12] Y¹Is represented by -O-,
Nzothiazole compound, or pharmaceutically acceptable thereof
salt. [13] The benzo according to any one of [1] to [12]
A thiazole compound, or a pharmaceutically acceptable salt thereof,
A drug contained as an active ingredient. [14] Benzo according to any one of [1] to [12]
A thiazole compound, or a pharmaceutically acceptable salt thereof,
An antihistamine contained as an active ingredient.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The halogen atom in the present invention includes a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom or a chlorine atom. Examples of the lower alkyl group in the present invention include a linear or branched lower alkyl group having 1 to 6 carbon atoms, and preferably a linear or branched lower alkyl group having 1 to 4 carbon atoms. Specifically, methyl group, ethyl group, propyl group, 2-propyl group, butyl group, 2-butyl group, 2-methyl-2-propyl group, 2-
Examples thereof include a methyl-1-propyl group, a pentyl group, a hexyl group and the like. Examples of the lower alkoxy group in the present invention include a linear or branched lower alkoxy group having 1 to 6 carbon atoms, and preferably a linear or branched lower alkoxy group having 1 to 4 carbon atoms. Specifically, a methoxy group, an ethoxy group, a propoxy group, a 2-propoxy group, a butoxy group, a 2-butoxy group, a 2-methyl-2-propoxy group, a 2-methyl-1-propoxy group,
Examples thereof include a pentoxy group and a hexyloxy group. The lower haloalkyl group is the same or different from 1 to
A lower haloalkyl group having 1 to 6 carbon atoms, which contains 5 halogen atoms, is mentioned, and preferably the same or different 1 to
A lower haloalkyl group having 1 to 4 carbon atoms containing 3 halogen atoms can be mentioned. Specific examples include a trifluoromethyl group and a 2,2,2-trifluoroethyl group. The lower haloalkoxy group may be the same or different 1
A lower haloalkyl group having 1 to 6 carbon atoms and containing 1 to 5 halogen atoms, preferably the same or different 1
Examples include lower haloalkyl groups having 1 to 4 carbon atoms and containing 3 to 3 halogen atoms. Specific examples include a trifluoromethoxy group and a 2,2,2-trifluoroethoxy group.

Examples of the 4- to 7-membered cycloalkyl group in the present invention include a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group, preferably a 5- to 6-membered cycloalkyl group. The 5- to 7-membered heterocycloalkyl group in the present invention includes 0 to 2 nitrogen atoms, 0 or 1 oxygen atom,
Examples thereof include a 5- to 7-membered heterocycloalkyl group containing 0 or 1 sulfur atom, and specific examples thereof include tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl and the like. As the 5- to 7-membered heterocycloalkane in the present invention, 1 or 2 nitrogen atoms,
Examples thereof include 5- to 7-membered heterocycloalkanes containing 0 or 1 oxygen atom and 0 or 1 sulfur atom, and specifically, tetrahydrofuran, tetrahydropyran, pyrrolidine, morpholine, thiomorpholine, piperazine, piperidine. Etc.

In the present specification, when the heterocycloalkyl group or the heterocycloalkane contains a nitrogen atom, the nitrogen atom may be a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted It may be substituted with a substituted phenyl group or pyridyl group. In the present specification, when the lower alkyl group is substituted, examples of the substituent include a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, a substituted or unsubstituted phenyl group and a pyridyl group. In the present specification, when the cycloalkyl group is substituted, the substituent includes a hydroxyl group, a lower alkyl group or a lower haloalkyl group. In the present specification, when the phenyl group is substituted, it may be substituted with 1 to 3 substituents which are the same or different, and examples of the substituent include a halogen atom, a cyano group, a nitro group and a lower alkyl. Group, lower alkoxy group, lower haloalkyl group, lower haloalkoxy group, cycloalkyl group, cycloalkoxy group, methylenedioxy group and the like.

In the general formula (1), Y is preferably
Represents-(C = O)-or -O-, more preferably
Represents-(C = O)-. In the general formula (1), Z
Is preferably -CONR¹R^Two, Or -NR ^ThreeCO
-R^FourAnd more preferably -CONR¹R^TwoThe table
You In the general formula (1), the phenyl group in R is
When it is substituted, the substituent is a halogen atom,
Cyano group, nitro group, lower alkyl group, lower haloalkyl
Group, lower alkoxy group, lower haloalkoxy group, cyclo
Low alkyl group, cycloalkoxy group, and methylenedi
An oxy group is mentioned, and a plurality of the same or different ones are substituted.
You may have. In Formula (2), p represents 1 to 3.
If X^TwoThe bonding position of is X^TwoOn the benzene ring where
Is any carbon atom of, and p is 2 or 3,
X^TwoMay be the same or different. Preferred
Specifically, p represents 0 or 1. Also, preferred X^TwoWhen
As a result, halogen atoms (fluorine atom, chlorine atom, etc.), low
Class alkyl group (methyl group, ethyl group, 2-propyl group
Etc.), lower alkoxy group (methoxy group, ethoxy group
Etc.), lower haloalkyl group (trifluoromethyl etc.),
Lower haloalkoxy (trifluoromethoxy etc.), nit
And a cyano group and the like. In equation (2), p
Preferably represents 0 or 1.

In the formula (3), n is preferably 0-2.
And more preferably 0 or 1. Also, R ⁶
Examples of the cycloalkyl group in include a cyclopentyl group or a cyclohexyl group. Also, R ⁶
The heterocycloalkyl group in, a tetrahydrofuryl group, a tetrahydropyranyl group, a piperidyl group,
Examples thereof include a pyrrolidinyl group and a morpholinyl group. Examples of the heterocycloalkane formed by combining R ⁵ and R ⁶ include piperazine, pyrrolidine, piperidine, morpholine and thiomorpholine. In the formula (3), R ⁵ preferably represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, more preferably a formula (3) representing a hydrogen atom, a methyl group, an ethyl group or a propyl group. In the formula, R ⁶ is preferably a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a 5- or 6-membered cycloalkyl group, or a 5- or 6-membered heterocycloalkyl group, and the heterocycloalkyl group is a nitrogen atom. When containing an atom, the nitrogen atom may be substituted with a substituted or unsubstituted lower alkyl group, a cycloalkyl group, a substituted or unsubstituted phenyl group, or a pyridyl group.

When the lower alkyl group is substituted, the substituent is a substituted or unsubstituted phenyl group (the substituent is a lower alkoxy group, a halogen atom,
Examples thereof include a nitro group, a cyano group, a hydroxyl group and a lower alkoxy group. ), A hydroxyl group, a lower alkoxy group and the like. More preferably, it is a phenyl group. M in Formula (4) preferably represents 2 to 4. Also,
R ⁷ and R ⁸ are preferably the same or different,
Represents a hydrogen atom, a methyl group, an ethyl group, or a propyl group, or R ⁷ and R ⁸ are preferably bonded to each other and optionally substituted with a lower alkyl group,
It forms heterocycloalkanes such as morpholine, thiomorpholine, pyrrolidine, piperidine and piperazine. The heterocycloalkane in ring A in formula (5) is preferably pyrrolidine, piperazine,
Examples thereof include piperidine. Further, R ¹⁵ includes a substituted or unsubstituted lower alkyl group, and when the lower alkyl group is substituted, the substituent is a substituted or unsubstituted phenyl group (the substituent is a lower alkyl group). And alkoxy groups, halogen atoms, nitro groups, cyano groups, hydroxyl groups, lower alkoxy groups, etc.),
Examples thereof include a hydroxyl group and a lower alkoxy group. More preferable R ¹⁵ includes a methyl group, an ethyl group, a benzyl group and the like.

In the general formula (1), R ¹ and R ² are bonded to each other to form a heterocycloalkyl group, or in the general formula (11) or general formula (12), R ¹³ and R ¹⁴ are bonded to each other. Examples of the heterocycloalkyl group formed include pyrrolidine, piperazine, morpholine, piperidine and the like, and the nitrogen atom of the piperazine is preferably a cycloalkyl group (cyclohexyl,
Cyclopentyl, etc.), a substituted or unsubstituted phenyl group (the substituent of the phenyl group includes a halogen atom, a lower alkoxy group, a nitro group, a cyano group, a hydroxyl group, a lower alkoxy group, etc.), a pyridyl group, or A substituted or unsubstituted lower alkyl group is mentioned. When the lower alkyl group is substituted, the substituent is a substituted or unsubstituted phenyl group (the substituent includes a lower alkoxy group, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a lower alkoxy group and the like. , Hydroxyl group,
A lower alkoxy group and the like can be mentioned. In the general formula (1), when R represents a hydrogen atom or a substituent, the substituent is a halogen atom, a cyano group, a lower alkyl group,
Examples thereof include a lower haloalkyl group, a lower alkoxy group, a lower haloalkoxy group, a cycloalkyl group, a cycloalkoxy group, and a methylenedioxy group, and the same or different ones may be substituted. Preferably R represents a hydrogen atom.

The benzothiazole compound of the present invention can be produced, for example, by the following production method. [1] Production method 1: Synthesis of 5- or 6-position-substituted benzothiazole

[Chemical 27] (In the formula, R and Y have the same meanings as described above.) The mixture was stirred at room temperature in chloroform in the presence of pyridine, and from compound (11-1) and 4,5-dichloro-1,2,3-dithiazolium chloride, 1,2,3-Dithiazolimine (11-2) can be obtained. Then, the compound (1
The cyano compound (11-3) can be obtained by heating 1-2) with stirring in pyridine in the presence of 4-dimethylaminopyridinium perbromide. Compound (1
Carboxylic acid (11-4) can be obtained by hydrolyzing 1-3) with an aqueous sodium hydroxide solution.

[2] Production Method 2: Synthesis of 2-aminobenzothiazole skeleton

[Chemical 28] (In the formula, R, Y, and R ³ are as defined above. E
Represents a chlorine atom or a bromine atom. ) Compound (11-1) and potassium thiocyanate are dissolved in a solvent such as acetic acid and reacted at 50 to 200 ° C, and then the reaction solution is cooled so that the reaction temperature does not exceed 10 ° C. Is dripped little by little. After completion of the dropwise addition, the reaction solution is stirred at 0 ° C to 100 ° C for about 1 hour to 10 hours, water is added, and ammonium chloride or the like is further added to adjust the reaction solution to about pH.
Set to 10. The reaction solution is stirred for 12 hours, and the produced precipitate is collected by filtration to obtain the compound (12-1).
Compound (12-2) can be obtained by reacting this with a halide such as R ³ —Br in the presence of a base such as triethylamine, sodium carbonate, sodium hydride and the like.

[3] Production method 3: Z is --CONR ¹ R ² ,
Or when represented by -NR ³ COR ⁴

[Chemical 29] (In the formula, R, Y, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above. E represents a chlorine atom or a bromine atom.) The compound (11-4) and the amine component are added to DMF. Compound (13-1) can be obtained by dissolving in a suitable solvent such as methylene chloride or the like and condensing with a suitable condensing agent. As the condensation method, a water-soluble carbodiimide may be used, if necessary.
Method used in the coexistence of hydroxybenztriazole,
A mixed acid anhydride method, a method via acid halogenation and the like can be mentioned, and the reaction can be carried out at 0 ° C. to 100 ° C. for 1 hour to 20 hours. The compound (13-2) can also be synthesized by condensing the compound (12-2) and the carboxylic acid component in the same manner as described above.

The method for producing the benzothiazole compound of the present invention will be described in more detail below. [4] Production method 4: When R is represented by a substituted or unsubstituted phenyl group

[Chemical 30] (In the formula, Y is as defined above, X is a halogen atom,
Alternatively, it represents a lower alkyl group. ) Compound (14-1) is a commercially available product and is easily available. Many compounds (14-2) can be easily obtained as commercially available products. Alternatively, it can be produced from the compound (14-1). That is, when X is represented by a chlorine atom, Zanka, A, Kubota, A, Sy
nlett, 1999, (12), 1984-1986.
Page or Hirano, M, Monobe, H, Ya
kabe, S, Morimoto, T, J .; Chem.
Res. Synop, 1998, (10), 662-6.
It can be produced by the method described on page 63. When X is represented by a bromine atom, Ardeshir, K, Ab
bas, S, Synth. Commun, 1999, 2
9 (23), 4079-4085, or Korn.
Berg, B.A. E, Nikam, S .; S, Raffer
ty, M. F. J. Heterocycl. Chem,
It can be produced by the method described in 1999, 36 (5), 1271-1277. When X is represented by an iodine atom, Lulinski, P, Skuls
ki, L, Bull. Chem. Soc. Jpn, 20
00, 73 (4), pp. 951-956, or Kry
ska, A, Skulski, L, J .; Chem. Re
s. Synop, 1999, (10), 690-591.
It can be produced by the method described on the page. Also, X
Is a lower alkyl group, Yamamoto,
G, Mochida, H, Chem. Lett. , 20
00, (5), pp. 454-455, Park, M, Bu.
ch, J. R, Rizzo, C.I. J, Tetrahed
ron, 1998, 54 (42), 12707-127.
Page 14, or Li, C, Angelici, R .;
J, Tertahedron Lett, 1998, 3
9 (24), 4235-4238, can be used for the production. The compound of the present invention can be produced by using the compound represented by the above formula (14-2) and the methods described in Production Methods 1 to 3.

[5] Production Method 5: Production Method of 7-Substituted Benzothiazole (when Y is a carbonyl group)

[Chemical 31] (In the formula, X has the same meaning as described above.) The compound represented by the formula (15-7) can be produced by the above production method. That is, by using a method such as reacting 2-bromo-3-nitrobenzoic acid (15-1) with thionyl chloride for about 1 to 20 hours, the acid chloride (15
-2) can be obtained. Aluminum chloride is suspended in chloroform, and a chloroform solution of the compound (15-2) obtained above is added with stirring at 0 ° C. After stirring for about 30 minutes to 3 hours, a solution of the benzene derivative in a suitable solvent is added at 0 to 50 ° C. After stirring at 0 ° C to 200 ° C for about 30 minutes to 3 hours, excess reagent is inactivated by adding water or the like. Concentrated hydrochloric acid is added to the reaction solution to make the solution acidic, and the desired compound (15-3) can be obtained through post-treatment steps such as extraction and washing. The compound (15-3) obtained above is treated at 0 ° C. for 30 minutes to 20 hours using a solution of sodium dithionite in water containing diethylene glycol monomethyl ether.
Heat to reflux at ~ 200 ° C. Then, the reaction solution is treated with an acid such as by adding concentrated hydrochloric acid and heating under reflux, so that the compound (15-4) can be produced. Compound (15-5) can be obtained in the same manner as above. The compound (15-5) obtained here is dissolved in pyridine, copper (I) iodide is added, and the mixture is reacted at 0 ° C to 100 ° C for 0 to 20 hours to synthesize the compound (15-6). be able to. The above compound (15-6) in a suitable solvent at 0 ° C. to 20 ° C. in the presence of a strong alkaline aqueous solution such as 10% sodium hydroxide aqueous solution.
Compound (15-7) can be synthesized by reacting at 0 ° C. for about 1 to 20 hours.

[6] Production Method 6: Production Method of 7-Substituted Benzothiazole (When Y is Ether or Methylene)

[Chemical 32] (In the formula, X and Y have the same meanings as described above.) Using a commercially available compound (16-1) that is easily available, Sec
o, S, Miyake, K, Kawamura, N,
J. Chem. Soc. Perkin Trans.
1, 1999, (11), pp. 1437-1444, or Makosza, M, Bialecki, M, J .; O
rg. Chem, 1998, 63 (15), 4878-.
Compound (16-2) can be produced by performing an amination reaction by the method described on page 4888. Compound (16-3) of the present invention can be derived from compound (16-2) by the method described in production method 5.

[7] Production method 7: Z is represented by —CONHR ² , R ² is represented by the formula (3), and n is represented by 1 in the formula (3).

[Chemical 33] (In the formula, R, Y, R ⁵ , and R ⁶ have the same meanings as described above.) In the same manner as in Production method 3, compound (17-1) is reacted with aniline derivative to give compound (17- 2) can be synthesized. The compound (17-3) can be synthesized by dissolving the compound (17-2) and the starting amine compound in a suitable solvent such as DMF and reacting at 0 ° C to 200 ° C.

[8] Production method 8: Z is represented by —NHCO—R ⁴ , R ⁴ is represented by the formula (3), and n in the formula (3) is represented by 1.

[Chemical 34] (In the formula, R, Y, R ⁵ , and R ⁶ have the same meanings as described above.) From the compound (18-1) to the compound (18-3) in the same manner as above.
Can be synthesized.

[9] Production method 9: Z is represented by —CONHR ² , R ² is represented by the formula (3), and n is represented by 0 in the formula (3).

[Chemical 35] (In the formula, X, Y, R ⁵ and R ⁶ have the same meanings as described above.) From compound (19-1) to compound
(19-2) can be synthesized.

[10] Production method 10: Z is -NHCO-R
^And R ⁴ is represented by formula (3), and n in formula (3) is represented by 0.

[Chemical 36] (In the formula, X, Y, R ⁵ , and R ⁶ have the same meanings as described above.) From compound (20-1) to a compound in the same manner as above.
(20-2) can be synthesized.

The present invention also includes a pharmaceutically acceptable salt of the benzothiazole compound represented by the general formula (1).
Examples of the salt include a salt of a benzothiazole compound represented by the general formula (1) and an acid, or a salt of a benzothiazole compound represented by the general formula (1) and a metal. Examples of such acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, inorganic acids such as carbonic acid, citric acid, malic acid,
Organic acids such as tartaric acid, fumaric acid and methanesulfonic acid can be mentioned. Examples of such metals include alkali metals such as sodium and potassium, and alkaline earth metals such as calcium and magnesium.

When the compound of the present invention has an asymmetric carbon atom, its steric configuration is not particularly limited, and both S-configuration and R-configuration are included in the present invention. Further, the present invention is a concept including isomers such as optical isomers and geometric isomers. Since the compound of the present invention has a physiologically active amine receptor antagonistic activity such as histamine, it can be used as a therapeutic / preventive drug for a disease in which a physiologically active amine is involved. Examples of the disease include allergic disease, inflammatory disease, digestive system disease, circulatory system disease, central nervous system disease, and the like, and specifically, allergic rhinitis, atopic dermatitis, renal disease. Measles, anaphylactic shock, conjunctivitis, asthma, gastrointestinal ulcer, mast cell type, basophilic leukemia, reflux esophagitis,
Arteriosclerosis, vascular restenosis after intimal injury, aortic aneurysm,
Chronic rheumatoid arthritis, osteoarthritis, ulcerative colitis,
Examples include multiple sclerosis, pulmonary fibrosis, glomerulonephritis, pulmonary fibrosis, psoriasis and the like.

The present invention is prepared by formulating a therapeutically effective amount of a benzothiazole compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier and / or diluent. It can be a medicine. That is, the benzothiazole compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof may be administered orally or parenterally such as intravenously, subcutaneously, intramuscularly, transdermally, or rectally. it can. Examples of the dosage form for oral administration include tablets, pills, granules, powders, solutions, suspensions and capsules.

In the form of tablets, for example, excipients such as lactose, starch and crystalline cellulose; binders such as carboxymethylcellulose, methylcellulose and polyvinylpyrrolidone; disintegrants such as sodium alginate, sodium hydrogen carbonate and sodium lauryl sulfate. And the like can be used for molding by an ordinary method. Pills, powders,
Similarly, the granules can be molded by the usual method using the above-mentioned excipients and the like. Liquids and suspensions are formed by a usual method using, for example, glycerin esters such as tricaprylin and triacetin, alcohols such as ethanol and the like. Capsules are formed by filling granules, powders or liquids into capsules such as gelatin.

The subcutaneous, intramuscular, and intravenous administration forms include injections in the form of aqueous or non-aqueous solutions. As the aqueous solution, for example, physiological saline is used. As the non-aqueous solution, for example, propylene glycol, polyethylene glycol, olive oil, ethyl oleate, etc. are used, and if necessary, a preservative, a stabilizer and the like are added. The injection is sterilized by appropriately performing treatments such as filtration through a bacteria-retaining filter and addition of a germicide.

The dosage form for transdermal administration is, for example, an ointment,
Creams and the like can be mentioned. Ointments are oils and fats such as castor oil and olive oil; vaseline and the like are used, creams are fatty oils, and emulsifiers such as diethylene glycol and sorbitan monofatty acid ester are used, and they are molded by a usual method. It For rectal administration, usual suppositories such as gelatin soft capsules are used. The dose of the benzothiazole compound of the present invention or a pharmaceutically acceptable salt thereof varies depending on the type of disease, administration route, age of patient, sex, degree of disease, etc., but is usually 1 to 5 per adult.
It is 00 mg / day.

[0030]

EXAMPLES The present invention will be specifically described below with reference to examples. First, production examples of typical compounds of the present invention are shown.
The purity and structure of the compound were identified by LC-MS and / or NMR measurement. The LC-MS conditions are:
It is as follows. HPLC: LC-8A (made by Shimazu) Mass spectrometry: API 150EX (made by PE SCIEX) Ionization method: ESI
(Posi) HPLC conditions: Column: Mightysil RP-18 50 * 4.6 (manufactured by Kanto Kagaku) A solution: 0.05% TFA / H2O B solution: 0.035% TFA / CH3CN Flow rate: 3.5 ml / min B solution concentration gradient: 1% (0min) → 1% (0.5min) → 99%
(4.2min) → 99% (4.4min) → 1% (4.8min)
→ 1% (6.3min) UV detection wavelength: 220nm

Example 1: 4,5-Dichloro-1,2,3
-Dithiazolium chloride

[Chemical 37] Chloroacetonitrile (6.04 g, 8
To a methylene chloride solution (50 ml) of 0 mmol), a methylene chloride solution (30 ml) of disulfur dichloride (54.0 g, 0.4 mol) was added dropwise at room temperature. The mixture was stirred overnight at room temperature, and the obtained dark green crystals were collected by filtration. This was washed with methylene chloride to obtain the desired product in a quantitative yield. Melting point 172 [deg.] C. M ⁺ : 207.

Example 2: N- (4-chloro-5H-dithiazole-5-ylidene) aniline

[Chemical 38] Aniline (0.93 g, 10 mmol) under nitrogen atmosphere
Chloroform solution (40 ml) under stirring with 4,5-
Dichloro-1,2,3-dithiazolium chloride (2.
5 g, 12 mmol) and pyridine (1.19 g, 1
5 mmol) was added. After stirring at room temperature for 3 hours, the reaction solution was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to obtain the desired product as a vermillion crystal in a quantitative yield. Melting point 65-67 ° C. M + 1: 229.

Example 3: 2-Cyano-1,3-benzothiazole

[Chemical Formula 39] Under a nitrogen atmosphere, N- (4-chloro-5H-dithiazole-5-ylidene) aniline (2.28 g, 10 mmo)
l) and 4-dimethylaminopyridinium perbromide (4.35 g, 12 mmol) in pyridine (50 m
1) and heated under reflux for 2 hours and 30 minutes. After cooling to room temperature, pyridine was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) and recrystallized from ethanol to obtain the desired product as yellow crystals in a quantitative yield. Melting point 77-78 [deg.] C. M + 1: 161.

Example 4: 2-Carboxyl-1,3-benzothiazole

[Chemical 40] 2-cyano-1,3-benzothiazole (320 mg,
2 mmol) was suspended in a 10% aqueous sodium hydroxide-dioxane mixture (1: 1), and the mixture was heated with stirring at 50 ° C. for 10 hours. The reaction solution was poured into ice and acidified to pH 1 with 1N hydrochloric acid. The precipitated yellow crystals were collected by filtration and recrystallized from water to obtain the desired product as yellow crystals (160 mg, 45%). ^{1 H-NMR (300MHz, (} CD 3) 2 SO): 7.59 (2H, m), 8.17 (2H, m).

Example 5: 2-Bromo-3-nitrobenzophenone

[Chemical 41] A chloroform suspension (10 ml) of aluminum chloride (4.0 g, 30 mmol) was stirred at 0 ° C. and 2-bromo-3-nitrobenzoyl chloride (5.29 g, 20 m).
Chloroform solution (10 ml) was added. 0
After stirring at ℃ for 30 minutes, benzene (1.56g, 20mmo
A chloroform solution (10 ml) of 1) was added. After stirring at 0 ° C for 30 minutes, the mixture was stirred at room temperature overnight. The reaction solution was cooled in an ice bath, and water was added slowly so that the reaction solution did not exceed 20 ° C. Concentrated hydrochloric acid was added to acidify the reaction solution. The organic layer was separated, the aqueous layer was extracted with chloroform, and this chloroform layer was added to the organic layer. The chloroform layer was washed with water, a 2% aqueous sodium hydroxide solution and water in this order, and the organic layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) and recrystallized from ethanol to obtain the desired product as colorless crystals (5.67 g, 92%). M +: 306.

Example 6: 2-Bromo-3-aminobenzophenone

[Chemical 42] Sodium dithionite (6.96 g, 40 mmol)
2-Bromo-3-nitrobenzophenone (3.06 g, 10 mmol) was added to the diethylene glycol monomethyl ether-water mixed solution (40 ml) of, and the mixture was heated under reflux for 3 hours and 30 minutes. Concentrated hydrochloric acid was added, and the mixture was heated under reflux for 10 minutes. The reaction solution was cooled to room temperature, and sodium carbonate was added to make the reaction solution alkaline. It was extracted with ethyl acetate and washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) and further purified by ethyl acetate-
Recrystallization from a mixed solvent of hexane gave the desired product as yellow crystals (1.81 g, 66%). M +: 276.

Example 7: 2-Bromo-3-benzoyl-
N- (4-chloro-5H-dithiazole-5-ylidene) aniline

[Chemical 43] The compound of Example 6 was used as a starting material and synthesized in the same manner as in Example 2. M +: 411.

Example 8: 7-Benzoyl-2-cyano-
1,3-benzothiazole

[Chemical 44] 2-Bromo-3-benzoyl-N- (4-chloro-5H
-Dithiazole-5-ylidene) aniline (1.75)
g, 4.25 mmol), copper (I) iodide (1.21)
g, 6.38 mmol) was suspended in pyridine (20 ml), and the mixture was heated under reflux for 2 hours. The reaction mixture was extracted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was washed with ether to obtain the desired product as yellow crystals (980 m
g, 87%). M +: 264.

Example 9: 7-Benzoyl-2-carboxyl-1,3-benzothiazole

[Chemical formula 45] Using the compound of Example 8 as a starting material, a target product was obtained in the same manner as in Example 4. M +: 283.

Example 10: 4-benzoyl-N- (4-
Chloro-5H-dithiazole-5-ylidene) aniline

[Chemical formula 46] Using 4-aminobenzophenone as a starting material, an intended product was obtained in the same manner as in Example 2. M +: 332.

Example 11: 3-Benzoyl-N- (4-
Chloro-5H-dithiazole-5-ylidene) aniline

[Chemical 47] Using 3-aminobenzophenone as a starting material, an intended product was obtained in the same manner as in Example 2. M +: 332.

Example 12: 6-Benzoyl-2-cyano-1,3-benzothiazole

[Chemical 48] Using the compound of Example 10 as a starting material, a target product was obtained in the same manner as in Example 3. M +: 264.

Example 13: 5-benzoyl-2-cyano-1,3-benzothiazole

[Chemical 49] Using the compound of Example 11 as a starting material, a target product was obtained in the same manner as in Example 3. M +: 264.

Example 14: 6-Benzoyl-2-carboxyl-1,3-benzothiazole

[Chemical 50] Using the compound of Example 12 as a starting material, a target product was obtained in the same manner as in Example 4. M +: 283.

Example 15: 5-Benzoyl-2-carboxyl-1,3-benzothiazole

[Chemical 51] Using the compound of Example 13 as a starting material, an intended product was obtained in the same manner as in Example 4. M +: 283.

Example 16: N-phenyl-1,3-benzothiazole-2-carboxamide

[Chemical 52] 2-Carboxyl-1,3-benzothiazole (72 mg, 0.4 mmol) and aniline (37 mg, 0.4 mmol) obtained in Example 4 were dissolved in a mixed solution (5 ml) of DMF: methylene chloride (1: 1). Under room temperature,
Water-soluble carbodiimide (80 mg, 0.42 mmol)
And 1-hydroxybenzotriazole (57 mg,
0.42 mmol) was added. Stir at room temperature for 5 hours. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to obtain the desired product as colorless crystals (6
0 mg, 60%). M + 1: 255.

Example 17: 2-Amino-6-benzoyl-1,3-benzothiazole

[Chemical 53] 4-aminobenzophenone (0.985g, 5mmo
l) and potassium thiocyanate (0.97 g, 10 mmo
l) was dissolved in acetic acid (10 ml) and cooled to 10 ° C.
Under stirring, a solution of bromine (0.958 g, 6 mmol) in acetic acid (10 ml) was slowly added dropwise, and during the addition, the reaction temperature was cooled so as not to exceed 10 ° C. After stirring for 12 hours at room temperature, the reaction solution was poured into water (300 ml). A saturated aqueous ammonium chloride solution was added little by little to adjust the pH to 10.
The mixture was stirred at room temperature for 12 hours, and the obtained precipitate was collected by filtration to give the desired product (860 mg, 68%). ¹ H-NMR (300MHz, (CD ₃ ) ₂ SO): 7.40 (1H, d, J = 8.4Hz), 7.54 (2
H, m), 7.61-7.78 (4H, m), 7.94 (2H, m), 8.12 (1H, m).

Example 18: N- (6-benzoyl-1,
3-benzothiazol-2-yl) -4- (dimethylamino) benzamide

[Chemical 54] 4-Diethylaminobenzoic acid (290m
g, 1.5 mmol) and the 2-obtained in Example 17
Amino-6-benzoyl-1,3-benzothiazole (254 mg, 1 mmol) was dissolved in a mixed solution (5 ml) of DMF: methylene chloride (1: 1), and water-soluble carbodiimide (287 mg, 1.5 mmol) was stirred at room temperature. And 1-hydroxybenzotriazole (202 mg,
1.5 mmol) was added. Stir at room temperature for 5 hours. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from DMF-ethanol to obtain the desired product as colorless crystals (321 mg, 75%). M +: 429.

Example 19: N- (6-benzoyl-1,
3-benzothiazol-2-yl) -4- (bromomethyl) benzamide

[Chemical 55] Using the compound of Example 17 and 4-bromomethylbenzoic acid as raw materials, the target product could be synthesized by the method of Example 18. M +: 451.

Example 20: N- (6-benzoyl-1,
3-benzothiazol-2-yl) -4-[(diethylamino) methyl] benzamide

[Chemical 56] N- (6-benzoyl-1,3-obtained in Example 19
Benzothiazol-2-yl) -4- (bromomethyl)
Benzamide (225 mg, 0.5 mmol) and diethylamine (3 ml) were dissolved in DMF and stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine, dried and evaporated under reduced pressure. The obtained residue was recrystallized from DMF-ethanol to give the desired product as colorless crystals (177 mg, 80%). ¹ H-NMR (300MHz, CDCl ₃ ): 1.02 (6H, t, J = 7.1Hz), 2.51 (4H, q,
J = 7.1Hz), 3.62 (2H, s), 7.47-7.52 (4H, m), 7.59 (1H, m), 7.6
5 (1H, d, J = 8.6Hz), 7.79 (2H, m), 7.87 (1H, dd, J = 1.7,8.6H
z), 7.93 (2H, m), 8.32 (1H, d, J = 1.7Hz).

The following compounds could be synthesized according to the methods described in the above examples. N- (6-benzoyl-1,3-benzothiazol-2-yl) -4-
(1H-Pyrrol-1-yl) benzamide

[Chemical 57] ^{1 H-NMR (300MHz, (} CD 3) 2 SO): 7.56-7.61 (4H, m), 7.68 (1H,
m), 7.76-7.88 (6H, m), 8.25 (2H, d, J = 8.8Hz), 8.48 (1H, m) .N- (6-benzoyl-1,3-benzothiazol-2-yl)- 2- [4-
(Dimethylamino) phenyl] acetamide

[Chemical 58] ¹ H-NMR (300MHz, CDCl ₃ ): 2.97 (6H, s), 3.78 (2H, s), 6.74 (2
H, d, J = 8.6Hz), 7.16 (2H, d, J = 8.6Hz), 7.48 (2H, t, J = 7.2H
z), 7.57 (1H, m), 7.73 (1H, d, J = 8.6Hz), 7.78 (2H, m), 7.88 (1
H, dd, J = 1.6,8.5Hz), 8.28 (1H, d, J = 1.6Hz) .N- (6-benzoyl-1,3-benzothiazol-2-yl) -4- (bromomethyl) benzamide

[Chemical 59] ^{1 H-NMR (300MHz, (} CD 3) 2 SO): 4.86 (2H, s), 7.56-7.69 (5H,
m), 7.78 (2H, m), 7.84-7.90 (2H, m), 8.15 (2H, d, J = 8.6Hz),
8.50 (1H, m). N-[(3S) -1Benzylpyrrolidin-3-yl] -1,3-benzothiazole-2-carboxamide hydrochloride

[Chemical 60] ^{1 H-NMR (300MHz, (} CD 3) 2 SO): 3.24-3.55 (6H, m), 4.40 (2H,
s), 4.69 (1H, m), 7.44-7.46 (3H, m), 7.56-7.64 (4H, m), 8.14
(1H, d, J = 7.7Hz), 8.22 (1H, d, J = 7.7Hz) .N- (6-benzoyl-1,3-benzothiazol-2-yl) -4-[(4
-Methylpiperazin-1-yl) methyl] benzamide

[Chemical formula 61] ¹ H-NMR (300MHz, CDCl ₃ ): 2.28 (3H, s), 2.48 (8H, m), 3.58 (2
H, s), 7.45-7.52 (4H, m), 7.60 (1H, m), 7.75-7.83 (3H, m), 7.
89-7.95 (3H, m), 8.33 (1H, m) .N- (6-benzoyl-1,3-benzothiazol-2-yl) -4- (piperidin-1-ylmethyl) benzamide

[Chemical formula 62] ¹ H-NMR (300MHz, CDCl ₃ ): 1.57 (6H, m), 2.35 (4H, m), 3.53 (2
H, s), 7.45-7.52 (4H, m), 7.59 (1H, m), 7.76-7.82 (3H, m), 7.
90-7.95 (3H, m), 8.33 (1H, m). N- (6-benzoyl-1,3-benzothiazol-2-yl) -4-
{[(2-hydroxyethyl) (methyl) amino] methyl} benzamide

[Chemical formula 63] ^{1 H-NMR (300MHz, (} CD 3) 2 SO): 2.17 (3H, s), 2.46 (2H, m), 3.52
(2H, t, J = 6.3Hz), 3.59 (2H, s), 7.50 (2H, d, J = 8.3Hz), 7.58
(2H, t, J = 7.3Hz), 7.67 (1H, m), 7.75-7.78 (2H, m), 7.84-7.8
8 (2H, m), 8.12 (2H, d, J = 8.3Hz), 8.45 (1H, m) .N- (6-benzoyl-1,3-benzothiazol-2-yl) -4- (morpholine- 4-ylmethyl) benzamide

[Chemical 64] ¹ H-NMR (300MHz, CDCl ₃ ): 2.45 (4H, t, J = 4.7Hz), 3.57 (2H,
s), 3.71 (4H, t, J = 4.7Hz), 7.45-7.52 (4H, m), 7.60 (1H, m),
7.74 (1H, d, J = 8.4Hz), 7.81 (2H, m), 7.89-7.96 (3H, m), 8.33
(1H, m).

The following compounds were synthesized in the same manner as in Example 16 below.

[Chemical 65]

[0053]

[Chemical formula 66]

[0054]

[Chemical formula 67]

Next, the compound of the present invention is combined with a physiologically active amine
Has the activity of inhibiting the binding to physiologically active amine receptors
This will be shown in a test example. Test Example: Receptor Binding Assay, Hil
1 et al. (Hill et al., J. Neurochem.
1,997-1004 (1978))
be able to.Membrane receptor preparation Whole guinea pig (Hartley system, weight 400-600g)
5 times the volume of 50 mM Na-K phosphate buffer (pH
7.5), homogenize and centrifuge (6000 g, 2
(0 minutes) Operate. The resulting pellet is added to 8 ml of 50
suspended in mM Na-K phosphate buffer (pH 7.5),
Further, it is subjected to a centrifugation (8700 g, 1 minute) operation. Got
The pellet was washed with 8 ml of 50 mM Na-K phosphate buffer.
Suspend in a buffer solution (pH 7.5) and use immediately for the test.
You canBinding assay Prepare the suspension (50 μl, about 0.5 mg protein)
1.95 ml of 50 mM Na-K phosphate buffer (p
H7.5). In addition to this, various concentrations of 3H-mepi
Lamin (20 Ci / mmol, 5-position label on pyridine ring)
Body) and various concentrations of test compound,
Was incubated at 30 ° C for 1 hour, and a part of the test solution
Centrifuge (0.4ml) (8700g for 1 minute)
Attached to. The obtained pellet is mixed with 0.1 ml of phosphate buffer solution.
Wash twice with and irradiate with liquid scintillation counter
The activity can be measured. Instead of the test compound,
Pyramine was added to a final concentration of 1.2 nM, and
Radioactivity when subjected to the operation of
The radioactivity without addition of the compound of the present invention is 100%.
% For binding of 3H-mepyramine to the prepared membrane
The inhibitory potency (inhibition constant: Ki value) of the test compound can be calculated.
You can

[0056]

The benzothiazole compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof of the present invention has a physiologically active amine receptor antagonistic action and is an active ingredient of a medicine, especially an antiallergic agent. Is useful as

[0057]

Front page continuation (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 1/00 A61P 1/00 1/04 1/04 3/04 3/04 9/00 9/00 9/08 9 / 08 9/10 9/10 11/00 11/00 11/02 11/02 11/06 11/06 13/02 13/02 17/00 17/00 17/06 17/06 19/02 19/02 25/00 25/00 27/02 27/02 29/00 29/00 101 101 35/02 35/02 37/08 37/08 43/00 113 43/00 113 C07D 277/82 C07D 277/82 417 / 12 417/12 417/14 417/14 F term (reference) 4C033 AE04 AE14 AE16 AE17 AE20 4C063 BB09 CC62 DD03 DD04 DD10 DD34 DD54 EE01 4C086 AA01 BC84 GA07 GA09 GA10 MA01 MA04 NA14 ZA02 ZA33 ZA34 ZA45 ZA36 ZA36 ZA36 ZA36 ZA36 ZA36 ZA36 ZA36 ZA39 ZA39 ZA36 ZA36 ZA36 ZA36 ZA39 ZA39 ZA89 ZA96 ZB11 ZB13 ZB27 ZC13

Claims (14)

[Claims] 1. General formula (1): [Chemical 1] [In the formula, R represents a substituted or unsubstituted phenyl group.
Y is -C (= O)-, -O-, or -CH._Two−
Represents, Z is -COOH, -CN, -CONR
¹R^Two, Or -NR^ThreeCO-R^Four {In the above, R
¹And R^ThreeRepresents a hydrogen atom or a lower alkyl group.
And R^TwoAnd R^FourIs a hydrogen atom, a lower alkyl group, a formula
(2): [Chemical 2] (In the formula, X^TwoIs lower alkyl, halogen atom, cyano
Group, nitro group, lower haloalkyl group, lower alkoxy
Group, lower haloalkoxy group, or methylenedioxy group
And p represents an integer of 0 to 3. ), Equation (3): [Chemical 3] (In the formula, n represents an integer of 0 to 3, and R⁵Is also a hydrogen atom
Or lower alkyl group, R⁶Is a hydrogen atom, substitution
Or an unsubstituted lower alkyl group, a 4- to 7-membered cycloalkyl group
An alkyl group, a substituted or unsubstituted phenyl group, or
0 to 2 nitrogen atoms, 0 or 1 oxygen atom, and 0
1 to 2 hetero atoms selected from 1 sulfur atom
Represents a 5 to 7 membered heterocycloalkyl group, including child
And when the heterocycloalkyl group contains a nitrogen atom,
The nitrogen atom is a substituted or unsubstituted lower alkyl group.
It may be substituted. R⁵And R⁶Joins
1 to 2 nitrogen atoms, 0 or 1 oxygen atom, and 0
1 to 2 hetero atoms selected from 1 sulfur atom
Forming a 5- to 7-membered heterocycloalkane, including the child
You may stay. The carbon atom on the heterocycloalkane is low
Optionally substituted with a primary alkyl group, said heterocyclo
When the alkane contains a nitrogen atom, the nitrogen atom is also substituted.
Or may be substituted with an unsubstituted lower alkyl group
Yes. ), Equation (4): [Chemical 4] (In the formula, m represents an integer of 2 to 5, and R⁷Is also a hydrogen atom
Or lower alkyl group, R⁸Is a hydrogen atom, lower
Represents an alkyl group or a 4- to 7-membered cycloalkyl group
Or R⁷And R⁸Is bound to 0-1
Oxygen atoms, 0 to 1 sulfur atoms, or 1 to 2
Form a 5- to 7-membered heterocycloalkane containing nitrogen atoms of
May be made. The heterocycloalkane is a nitrogen atom
, The nitrogen atom is a substituted or unsubstituted lower
It may be substituted with an alkyl group. ) Or expression
(5): [Chemical 5] (In the formula, q represents an integer of 0 to 5, and the ring A is 1 to 2
Nitrogen atom, 0 or 1 oxygen atom, 0 or 1
1 to 2 heteroatoms selected from the sulfur atom of
Represents a 5- to 7-membered heterocycloalkyl group, R¹⁵Is
Hydrogen atom or substituted or unsubstituted lower alkyl
Represents a group. ) Or R¹And R^TwoIs joined
Then, 1 to 2 nitrogen atoms, 0 or 1 oxygen source
Child, 1 or 2 selected from 0 or 1 sulfur atom
5- to 7-membered heterocycloalkanes containing heteroatoms
And the heterocycloalkane is a nitrogen atom.
When containing an atom, each of the nitrogen atoms is substituted or
Is an unsubstituted lower alkyl group, cycloalkyl group, phenyl group
It may be substituted with a phenyl group or a pyridyl group. }
Or R represents a hydrogen atom or a substituent.
, Y represents a bond, and Z is -CONR.⁹R¹⁰,
Or-NR¹¹CO-R¹² {In the above, R⁹And
And R¹¹Represents a hydrogen atom or a lower alkyl group,
R¹⁰And R¹²Is a hydrogen atom, a lower alkyl group, or
Or equation (3): [Chemical 6] (In the formula, n, R⁵, And R⁶Is as defined above
It ), Represents. } Is represented. ], Benzothia
A sol compound or a pharmaceutically acceptable salt thereof. 2. The benzothiazole compound according to claim 1, wherein Y is represented by — (C═O) —, or a pharmaceutically acceptable salt thereof. 3. The benzothiazole compound according to claim 1, wherein the bonding position of Y in the formula (1) is at the 5-position, 6-position or 7-position of the benzothiazole ring, or a pharmaceutically acceptable compound thereof. Acceptable salt. 4. General formula (6): [Wherein, X ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower haloalkyl group, a cyano group, a nitro group, a lower alkoxy group, or a lower haloalkoxy group, and Y
¹ represents -C (= O)-or -O-, and Z is
It has the same meaning as Z in formula (1). ],
A benzothiazole compound, or a pharmaceutically acceptable salt thereof. 5. General formula (7): embedded image [Wherein, X ¹ and Y ¹ are each represented by the general formula (6):
Is the same as X ¹ and Y ¹ in, and Z is the same as Z in the general formula (1). ] The benzothiazole compound represented by these, or its pharmaceutically acceptable salt. 6. General formula (8): [Wherein, X ¹ and Y ¹ are each represented by the general formula (6):
Has the same meaning as ^{X 1} and ^{Y 1} in, n, ^{R 5,} and ^{R 6} is an n in each formula (3), ^{R 5,} and the ^{R 6 synonymous, Z} 1 is -CONH-, or - N
Represents HCO-. ] The benzothiazole compound represented by these, or its pharmaceutically acceptable salt. 7. General formula (9): [Wherein X ¹ , Y ¹ , n, R ⁵ , R ⁶ , and Z ¹ are
It is synonymous with general formula (8). ] The benzothiazole compound represented by these, or its pharmaceutically acceptable salt. 8. A compound represented by the general formula (10): Wherein, n, ^{R 5,} and ^{R 6,} n in each formula (3), ^{R 5,} and have the same meaning as ^{R 6, Z 1} has the same meaning as ^{Z 1} in the general formula (8), r represents an integer of 0 to 3, X ³ represents a halogen atom, a lower alkyl group,
It represents a haloalkyl group, a cyano group, a nitro group, a lower alkoxy group, or a lower haloalkoxy group. ] The benzothiazole compound represented by these, or its pharmaceutically acceptable salt. 9. A compound represented by the general formula (11): [X ¹ and Y ¹ have the same meanings as X ¹ and Y ¹ in formula (6), respectively, R ¹³ represents a hydrogen atom or a lower alkyl group, and R ¹⁴ represents a hydrogen atom, a substituted or unsubstituted group. A substituted lower alkyl group, a 4- to 7-membered cycloalkyl group, a substituted or unsubstituted phenyl group, or
Represents a 5- to 7-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from 0 to 2 nitrogen atoms, 0 or 1 oxygen atom, and 0 or 1 sulfur atom; When the cycloalkyl group contains a nitrogen atom,
The nitrogen atom may be substituted with a substituted or unsubstituted lower alkyl group. Or R ¹³ and R
¹⁴ is bonded to one or two nitrogen atoms, 0 or 1
5 to 7-membered heterocycloalkane containing 1 to 2 heteroatoms selected from 0 oxygen atom and 0 or 1 sulfur atom may be formed. When the heterocycloalkane contains a nitrogen atom, the nitrogen atom may be substituted with a substituted or unsubstituted lower alkyl group, cycloalkyl group, phenyl group, or pyridyl group, respectively. ] The benzothiazole compound represented by these, or its pharmaceutically acceptable salt. 10. The general formula (12): [Chemical 13] [X¹And Y¹Are respectively in general formula (6)
X¹And Y¹Is synonymous with R^ThirteenAnd R¹⁴Is
R in the general formula (11) respectively^ThirteenAnd R ¹⁴When
Are synonymous. ], A benzothiazole compound represented by
Or a pharmaceutically acceptable salt thereof. 11. Y ¹ is represented by — (C═O) —,
The benzothiazole compound according to any one of claims 4 to 11, or a pharmaceutically acceptable salt thereof. 12. The method according to claim 7, wherein Y ¹ is represented by —O—.
The benzothiazole compound described above, or a pharmaceutically acceptable salt thereof. 13. A medicament containing the benzothiazole compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient. 14. An antihistamine containing the benzothiazole compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient.