JPH0138791B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel 2 compound represented by the following general formula ().
-Phenylimidazo[2,1-b]benzothiazole derivatives and salts thereof. (The symbols in the formula have the following meanings. R ¹ ; Hydrogen atom, halogen atom, lower alkyl group,
Hydroxy lower alkyl group, hydroxyl group, lower alkoxy group, phenyl lower alkoxy group, carboxy lower alkoxy group, lower alkoxycarbonyl lower alkoxy group, acyloxy group, amino group, mono- or di-lower alkylamino group,
Or an acylamino group. R ² and R ³ ; Same or different, hydrogen atom, halogen atom, lower alkyl group, hydroxy lower alkyl group, hydroxyl group, lower alkoxy group, phenyl lower alkoxy group, carboxy lower alkoxy group, lower alkoxycarbonyl lower alkoxy group, acyloxy group, lower alkylthio group,
A lower alkylsulfinyl group, a lower alkylsulfonyl group, a sulfamoyl group, a carboxy group, a lower alkoxycarbonyl group, a nitrile group, a carbamoyl group, a nitro group, an amino group, a mono- or di-lower alkylamino group, or an acylamino group. R ⁴ and R ⁵ ; Same or different, hydrogen atom, lower alkyl group, hydroxy lower alkyl group, hydroxyl group, lower alkoxy group, carboxy lower alkoxy group, lower alkoxycarbonyl lower alkoxy group, acyloxy group, lower alkylthio group, lower alkyl A sulfinyl group, a lower alkylsulfonyl group, a thiocyanate group, an amino group, a mono- or di-lower alkylamino group, or an acylamino group. R ⁶ ; hydrogen atom, halogen atom, lower alkyl group,
A hydroxy lower alkyl group, a nitroso group, a nitro group, an amino group, a mono- or di-lower alkylamino group, an acylamino group, or a group represented by the formula [Formula]. Note that any two adjacent groups of R ¹ , R ² and R ³ may be combined to form a benzene ring or a lower alkylenedioxy group. However, the combination of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ satisfies at least one of the following conditions. (1) R ¹ is an acyloxy group other than a phenyl lower alkoxy group, a lower alkanoyloxy group, or a lower alkoxycarbonylamino group. (2) At least one of R ² and R ³ is an acyloxy group other than a hydroxy lower alkyl group, a phenyl lower alkoxy group, a lower alkanoyloxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, Be a sulfamoyl group, nitrile group, carbamoyl group, or lower alkylsulfonylamino group. (3) Any two adjacent R ¹ , R ² and R ³ form a lower alkylenedioxy group. (4) Both R ⁴ and R ⁵ are substituents other than hydrogen atoms. (5) When one of R ⁴ and R ⁵ is a hydrogen atom, the other is at least a hydroxy lower alkyl group, hydroxyl group, carboxy lower alkoxy group, lower alkoxycarbonyl lower alkoxy group, acyloxy group, amino group, mono- or di-lower alkylamino or acylamino group. (6) R ⁶ is a hydroxy lower alkyl group, a lower alkylthio group, a lower alkylsulfinyl group, or a lower alkylsulfonyl group. ) In the definition of the general formula of the present invention, the term "lower" means a straight or branched carbon chain having 1 to 5 carbon atoms. Therefore, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶
Specifically, the lower alkyl groups shown in the lower alkyl group, hydroxy lower alkyl group, mono- or di-lower alkylamino group, lower alkylthio group, lower alkylsulfinyl group, and lower alkylsulfonyl group include methyl group, ethyl group, propyl group,
Isopropyl group, butyl group, sec-butyl group,
A tert-butyl group is a lower alkoxy group, a phenyl lower alkoxy group, a carbonyl lower alkoxy group, a lower alkoxycarbonyl lower alkoxy group, a lower alkoxy group of a lower alkoxycarbonyl group is a methoxy group, an ethoxy group, a propoxy group, a butoxy group. etc. Examples of the acylamino group and acyloxy group include lower alkanoyl groups such as formyl group, acetyl group, propionyl group, and butyryl group, aromatic acyl groups such as benzoyl group and 4-methylbenzoyl group, ethoxycarbonyl group, and methoxyoxy group. Zaryl group, ethoxyoxalyl group, oxalo group,
Examples include a carbamoyl group, a tetrazol-5-ylcarbonyl group, a methanesulfonyl group, and an ethanesulfonyl group. Furthermore, halogen atoms include fluorine atoms,
Examples include chlorine atom, iodine atom, and bromine atom. Further, examples of the lower alkylenedioxy group formed by combining any two adjacent R ¹ , R ² , and R ³ include a methylenedioxy group and an ethylenedioxy group. The compound of the above general formula () provided by the present invention forms an acid addition salt or, depending on the type of substituent, a salt with a base. The present invention also includes pharmacologically acceptable salts of the compound of general formula (), such as mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid, and methanesulfonic acid. , addition salts with organic acids such as para-toluenesulfonic acid, salts formed depending on the type of substituents in general formula () include alkali metals such as sodium and potassium, alkaline earth metals such as calcium, etc. salts, ammonium salts, and salts with organic bases such as methylamine, ethylamine, diethylamine, trimethylamine, triethylamine, pyridine, picoline, arginine, and lysine. Conventionally, the following compounds are known as 2-phenylimidazo[2,1-b]benzothiazole derivatives. 2-Phenylimidazo[2,1-b]benzothiazole [Chem.Abstr.,
34, 5082 (1940)], 2-(4-bromophenyl, 4
-chlorophenyl or 4-fluorophenyl)imidazo[2,1-b]benzothiazole, 2-
(4-chlorophenyl or phenyl)-7-ethoxy, methoxy or methyl)imidazo[2,1-
b] Benzothiazole [Chem.Abstr., 65 ,
7164a (1966)], 2-(4-nitrophenyl)imidazo[2,1-b]benzothiazole, 2-(4-nitrophenyl)imidazo[2,1-b]benzothiazole,
-nitrophenyl)-3-nitroimidazo[2,
1-b] Benzothiazole, 2-phenyl-3-
Nitroimidazo[2,1-b]benzothiazole [Chem.Abstr., 68 , 95754q (1968)], 2-(4-
nitrophenyl or phenyl)-3-(nitro or nitroso)-5,6,7 or 8-(methoxy or methyl)imidazo[2,1-b]benzothiazole, 2-(4-nitrophenyl or phenyl)-
5,6,7 or 8-(methoxy or methyl)imidazo[2,1-b]benzothiazole [Chem.
Abstr., 71 , 124309t (1969)], 2-(4-methoxyphenyl)imidazo[2,1-b]benzothiazole [Chem.Abstr., 72 , 100606g (1970)], 2
-(4-bromophenyl, 4-chlorophenyl or phenyl)-3-(bromo or thiocyanate)
Imidazo[2,1-b]benzothiazole [Chem.Abstr., 77 , 114304x (1972)], 2-(4-
biphenyl or 4-methylphenyl)imidazo[2,1-b]benzothiazole, 2-(4-biphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-nitrophenyl or phenyl)-7-
(bromo, ethoxy, methoxy, methyl or nitro)imidazo[2,1-b]benzothiazole [Chem.Abstr., 77 , 164598s (1972)]. These documents do not disclose any use of these compounds as medicines. However, J.Indian Chem.Soc., 51 (12)1031 (1974)
[Chem.Abstr., 83 164112c (1975)] 2-phenylimidazo[2,1-b] represented by
It is disclosed that benzothiazole derivatives were found to have bactericidal action, but no antihistamine action. That is, conventionally, 2-phenylimidazo[2,1-
b] As mentioned above, various compounds have been known as benzothiazole derivatives, but it was not known that this type of compound acts on the immune system and has a strong immunomodulatory effect. The compound of the present invention has an immunomodulatory effect and is useful as an antiallergic agent, an antiasthma agent, an antirheumatic agent, an anticancer agent, a therapeutic agent for autoimmune diseases, and a rejection inhibitor during organ transplantation or skin transplantation. . The compounds of the present invention have an immunomodulating effect, and some have an immunosuppressing effect and others have an immunoenhancing effect. Compounds of the present invention that have immunosuppressive effects, such as those that suppress cellular immunity, such as delayed allergic reactions that are representative of cellular immunity to protein antigens, are antiallergic agents, antirheumatic agents, and therapeutic agents for autoimmune diseases. It is also useful as an anti-rejection agent during organ transplantation and skin transplantation. It is particularly useful as a delayed allergy suppressant and an antirheumatic agent. That is, so far, only steroid drugs have been known as antiallergic agents, especially delayed allergy suppressants. The same applies to anti-rheumatic drugs. However, when steroids are used continuously for a long period of time, serious side effects occur, resulting in so-called steroid dependence, so there is a desire for the development of non-steroidal anti-allergic and anti-rheumatic agents with fewer side effects. The compound of the present invention, which has a strong delayed allergy-suppressing effect, can be used as a substitute for these steroids, and when used in combination with steroids, the amount of steroids used can be reduced. Compounds of the present invention that have immunosuppressive effects, such as suppressing humoral antibody production, such as suppressing IgE antibody production, are useful as antiallergic agents because they suppress the production of IgE antibodies, which are the main cause of immediate allergies. The compound of the present invention has an immune-enhancing effect, such as enhancing cellular immunity, e.g., enhancing delayed allergic reactions, and immature lymphocytes, and has an effect of enhancing humoral antibody production, e.g., blood antibody formation. Compounds that have the effect of increasing
It is also useful as a treatment for chronic hepatitis. Furthermore, the compounds of the invention show inhibition in the passive cutaneous anaphylaxis (PCA) test. That is, it has an antiallergic effect and is useful as an antiallergic agent and an antiasthma agent. Since the compound of the present invention has extremely low toxicity, it can be used as a medicine for the various purposes mentioned above. The experimental results showing the excellent pharmacological action of the compound of the present invention are shown below. Effect on delayed-type allergy in Γ mice: 0.1 ml of a 7% Picrylchloride (PC) ethanol solution was administered to 7-week-old male ICR-SLC mice (Shizuoka Experimental Animals).
Sensitization was achieved by applying this to the shaved abdomen. To prevent this PC from depositing, it was used with humidification. Seven days later, induction was induced by applying 0.02 ml of 1% PC in olive oil to the inside of both earlobes. Ear thickness before induction and 24 hours after induction by 2
Measured twice. Data were expressed as the difference in ear thickness before and after induction and compared with the control group. The drug was orally administered for 3 days from the day of immunization. The results are shown in Table 1. [Table] A drug containing the compound of the present invention as a main component can be prepared by any conventional method using any conventional pharmaceutical carrier or excipient. Administration may be in the form of oral administration such as tablets, pills, capsules, or granules, or parenteral administration such as injections such as intravenous or intramuscular injection, or aerosols or suppositories. The dosage is determined on a case-by-case basis, taking into consideration the symptoms, the age and gender of the recipient, but it is usually 50 to 500 mg per adult for oral administration and 20 to 300 mg for parenteral administration. Yes, this is administered in 2 to 3 divided doses a day. The compound of the present invention can be produced by any of the following methods. [A] Cyclization (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the above meanings). This reaction is usually carried out in a solvent, and examples of the solvent include methanol, ethanol, isopropanol, methoxyethanol, methyl cellosolve, ethyl cellosolve, diglyme, ethyl acetate, acetonitrile, chloroform, carbon tetrachloride, and the like. This reaction is carried out under heating, preferably under heating to reflux. When a raw material compound () in which any one of R ¹ to ^{R 5} is an acyloxy group is used, it is hydrolyzed during this reaction, and the corresponding present invention in which any one of R ¹ to ^{R 5} is a hydroxyl group is used. It can be a compound (). Note that this raw material compound () can be produced according to the following reaction formula, and can also be used as a raw material without being isolated. (In the above reaction formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the above-mentioned meanings, and Y means a halogen atom, such as an iodine atom, a bromine atom, a chlorine atom, etc.) [B] Hydrolysis In the compound () of the present invention, a compound having a hydroxyl group, a carboxy group, or an amino group can be obtained by hydrolyzing a compound having an acyloxy group, a lower alkoxycarbonyl group, or an acylamino group by a conventional method. It can be manufactured by That is, in the compound () of the present invention, R ¹ -
A compound in which at least one group among R ⁵ is a hydroxyl group can be obtained by hydrolyzing a compound in which a corresponding group among R ¹ to ^{R 5} is an acyloxy group under alkaline conditions by a conventional method. ²
- A compound in which at least one group among ^{R 3} is a carboxy group, or at least one group among R ¹ to R ³ is a carboxy lower alkoxy group is a compound in which at least one group among R ² to R ³ or R ¹ to ^{R 3} is a carboxy group. By hydrolyzing a compound in which the corresponding group is a lower alkoxycarbonyl group or a lower alkoxycarbonyl lower alkoxy group under alkaline conditions by a conventional method, at least one group among R ⁴ to ^{R 5} is converted to carboxy lower alkoxy. The compound which is a group can be produced by hydrolyzing a compound in which the corresponding group among R ⁴ to ^{R 5} is a lower alkoxycarbonyl lower alkoxy group under alkaline conditions by a conventional method. In addition, a compound in which at least one group among R ¹ to ^{R 6} is an acylamino group containing a carboxyl group, such as an oxalamide group (-NHCOCOOH), is a compound containing a lower alkoxycarbonyl group, such as an ethoxyoxalylamide group (-
It can be produced by hydrolyzing a compound (NHCOCOOC ₂ H ₅ ) under alkaline conditions using a conventional method. Furthermore, a compound in which at least one group among R ¹ to R ⁶ is an amino group can be obtained by hydrolyzing a compound in which the corresponding group among R ¹ to ^{R 6} is an acylamino group under acidic conditions by a conventional method. It can be manufactured by [C] Alkylation In the compound of the present invention (), a lower alkoxy group, a phenyl lower alkoxy group, a lower alkoxycarbonyl lower alkoxy group, a lower alkylenedioxy group, a lower alkoxy group, a carbonyl group, or a mono- or di-lower alkylamino group. A compound having a hydroxyl group, a carboxy group, or an amino group can be produced by alkylating a compound having a hydroxyl group, a carboxy group, or an amino group by reacting it with a corresponding alkylating agent in a conventional manner. That is, in the compound () of the present invention, a compound in which at least one group of R ¹ to R ⁵ is a lower alkoxy group or a lower alkoxycarbonyl lower alkoxy group is obtained by converting a compound in which the corresponding group is a hydroxyl group by a conventional method. alkylating agents, such as lower alkyl halides,
R ¹ by alkylation by reaction with a lower alkoxycarbonyl alkyl halide.
A compound in which at least one group in ~R ³ is a phenyl lower alkoxy group can be alkylated by reacting a compound in which the corresponding group is a hydroxyl group with a corresponding alkylating agent, such as a phenyl lower alkyl halide, by a conventional method. According to
Compounds in which any two adjacent R ¹ to R ³ are combined to form a lower alkylenedioxy group can be obtained by converting a compound in which two of the corresponding R ¹ to ^{R 3} are adjacent hydroxyl groups by a conventional method. It can be produced by alkylation by reaction with an alkylating agent such as a lower alkylene dihalide. Furthermore, in the compound of the present invention (),
Compounds in which ^at least one group among R ¹ to ^{R 5 is} a lower alkoxycarbonyl lower alkyl group are prepared by adding a corresponding alkylating agent such as a lower It can be produced by reacting with an alkyl halide and alkylating it. Furthermore, in the compound () of the present invention, a compound in which at least one group among R ¹ to ^{R 6} is a mono- or di-lower alkylamino group can be prepared by converting a compound in which the corresponding group is an amino group by a conventional method. It can be produced by reacting with an alkylating agent such as a lower alkyl halide to cause alkylation. [D] Acylation In the compound of the present invention (), at least one group among R ¹ to ^{R 6} is an acyloxy group or
A compound in which at least one group among R ¹ to ^{R 5} is an acylamino group is R ¹ to R ⁶ or R ¹ to ^{R 5}
It can be produced by reacting a compound in which the corresponding group is a hydroxyl group or an amino group with a corresponding acylating agent such as an acyl halide or an acid anhydride to acylate it by a conventional method. [E] Amidation In the compound () of the present invention, a compound having a carbamoyl group can be produced by amidating a compound having a carboxy group or a lower alkoxycarbonyl group by a conventional method. That is, in the compound of the present invention (), R ² ~
A compound in which at least one group in R ³ is a carbamoyl group can be obtained by amidating a compound in which the corresponding R ² to R ³ are a carboxy group or a lower alkoxycarbonyl group by reacting with ammonia in a conventional manner. Therefore, at least one group among R ¹ to ^{R 6} is an acylamino group containing a carbamoyl group, such as an oxamide group (-
NHCOCONH ₂ ), the corresponding R ¹
~ R ⁶ is an acylamino group containing a carboxy group or a lower alkoxycarbonyl group, such as an ethoxyoxalylamide group (-NHCOCOOC ₂ H ₅ )
It can be produced by reacting with ammonia and amidation using a conventional method. [F] Halogenation In the compound of the present invention (), the compound in which R ⁶ is a halogen atom is prepared by adding a halogenating agent such as bromine to the compound in which R ⁶ is a hydrogen atom by a conventional method.
It can be produced by halogenation by reaction with chlorine, iodine, sulfuryl chloride, or N-bromosuccinimide. [G] Nitration In the compound of the present invention (), the compound in which R ⁶ is a nitro atom can be nitrated by reacting the compound in which R ⁶ is a hydrogen atom with a nitrating agent such as nitric acid by a conventional method. It can be manufactured by. [H] Nitrosation In the compound of the present invention (), the compound in which R ⁶ is a nitroso group can be nitrosated by reacting the compound in which R ⁶ is a hydrogen atom with a nitrosating agent such as nitrous acid by a conventional method. It can be manufactured by. [I] Reduction In the compound of the present invention (), a compound having an amino group or a hydroxy lower alkyl group can be produced by reducing a compound having a nitro group, a lower alkanoyl group, or a lower alkoxycarbonyl group by a conventional method. can do. That is, in the compound () of the present invention, R ¹ -
A compound in which at least one group in R ⁶ is an amino group can be obtained by reducing a compound in which R ¹ to ^{R 6} are a nitro group by a conventional method.
In addition, compounds in which at least one group among R ¹ to ^{R 6} is a hydroxy lower alkyl group can be obtained by reducing a compound in which the corresponding R ¹ to ^{R 6} have a lower alkanoyl group or a lower alkoxycarbonyl group by a conventional method. Therefore, it can be manufactured. [J] Lower alkylthiolation In the compound () of the present invention, the compound in which R ⁶ is a ^lower alkylthio group is treated with a lower alkylthiolating agent such as a lower alkylsulfinyl halide by a conventional method. It can be produced by reacting with and converting into lower alkylthiolation. [K] Oxidation In the compound () of the present invention, a compound in which at least one group among R ² to R ⁵ is a lower alkylsulfinyl group or a lower alkylsulfonyl group, the corresponding R ² to ^{R 5} is a lower alkylsulfinyl group or a lower alkylsulfonyl group. It can be produced by oxidizing a compound having a lower alkylthio group by a conventional method. The target compound (2) thus produced is isolated and purified by any chemical operation commonly used in the art, such as recrystallization, extraction, and various chromatography techniques. Example 1 3 g of 2-amino-6-hydroxybenzothiazole and 4.2 g of p-methoxyphenacyl bromide
was added to 60 ml of methyl ethyl ketone and heated under reflux for 3 hours. After the reaction was completed, the reaction solution was cooled, and the precipitated crystals were collected by filtration and washed with methyl ethyl ketone.
When dried, 6-hydroxy-2-imino-3-
(3.25 g of p-methoxybenzizoylmethyl-2,3-dihydrobenzothiazole hydrobromide is obtained. Next, 3.25 g of crystals of this hydrobromide are added to 60 ml of methyl cellosolve at 130-140°C. Stir for 2 hours. After the reaction is complete, the reaction solution is cooled to about 60°C, then 5% aqueous ammonia is added to make it alkaline, cooled on ice, and the formed crystals are collected by filtration to give 7-hydroxy-2-( p-methoxyphenyl)imidazo[2,
1-b] Obtain 2.3 g of benzothiazole. Melting point 287-289℃ Elemental analysis value (as C ₁₆ H ₁₂ N ₂ O ₂ S) C (%) H (%) N (%) S (%) Theoretical value 64.85 4.08 9.45 10.82 Experimental value 64.83 4.01 9.41 10.69 Example 2-16 The following compounds were produced in the same manner as in Example 1. Example 2 2-(3,5-dichloro-4-ethoxycarbonylamidophenyl)imidazo[2,1-b]benzothiazole Melting point 256-258℃ Elemental analysis C(%) H(%) N(%) S(% ) Theoretical value 53.21 3.22 10.34 7.89 Experimental value 53.05 3.12 10.34 7.79 Cl(%) Theoretical value 17.45 Experimental value 17.28 Example 3 7-acetamido-2-phenylimidazo[2,1-b]benzothiazole monohydrate Melting point 267-269℃ Elemental analysis value (as C ₁₇ H ₁₅ N ₃ O ₂ S) C (%) H (%) N (%) S(%) Theoretical value 62.75 4.65 12.91 9.85 Experimental value 62.71 4.62 12.97 10.13 Example 4 2-(p-chlorophenyl)-7-hydroxyimidazo[2,1-b]benzothiazole Melting point 300℃ or higher Elemental analysis value (as C ₁₅ H ₉ N ₂ OSCl) C(%) H(%) N(%) S(%) Theoretical value 59.90 3.02 9.31 10.66 Experimental value 59.80 2.92 9.25 10.52 Cl(%) Theoretical value 11.79 Experimental value 12.00 Example 5 7-hydroxy-2-(p-hydroxyphenyl)imidazo[2,1-b]benzothiazole.
Hemihydrate melting point 300℃ or above Elemental analysis value (as C ₁₅ H ₁₀ N ₂ O ₂ S・1/2H ₂ O) S (%) Theoretical value 11.00 Experimental value 11.27 Example 6 7-hydroxy-2-phenylimidazo [2,
1-b] Benzothiazole melting point 234-236℃ Elemental analysis value (as C ₁₅ H ₁₀ N ₂ OS) C (%) H (%) N (%) S (%) Theoretical value 67.65 3.78 10.52 12.04 Experimental value 67.76 3.73 10.66 11.96 Example 7 2-(3,4-methylenedioxyphenyl)imidazo[2,1-b]benzothiazole Melting point 210-212℃ Elemental analysis value (as C ₁₆ H ₁₀ N ₂ O ₂ S) C(%) H(% ) N(%) S(%) Theoretical value 65.29 3.42 9.52 10.89 Experimental value 65.34 3.35 9.55 10.74 Example 8 2-(m-methylsulfonylamidophenyl)
Imidazo[2,1-b]benzothiazole Melting point 194℃ Elemental analysis value (as C ₁₆ H ₁₃ N ₃ O ₂ S ₂ ) C (%) H (%) N (%) S (%) Theoretical value 55.96 3.82 12.24 18.68 Experimental value 55.67 3.90 12.39 18.94 Example 9 2-(3-methoxysulfinyl-4-methylphenyl)imidazo[2,1-b]benzothiazole Melting point 262-264℃ Elemental analysis value (as C ₁₇ H ₁₄ N ₂ O ₂ S ₂ ) C(%) H (%) N(%) S(%) Theoretical value 59.63 4.12 8.18 18.73 Experimental value 59.46 3.98 8.31 18.43 Example 10 2-(m-cyanophenyl)imidazo[2,1
-b] Benzothiazole melting point 234℃ Elemental analysis value (as C ₁₆ H ₉ N ₃ S) C (%) H (%) N (%) S (%) Theoretical value 69.80 3.29 15.26 11.64 Experimental value 69.78 3.27 15.18 11.63 Implementation Example 11 2-(m-sulfamoylphenyl)imidazo[2,1-b]benzothiazole Melting point 306℃ Elemental analysis value (as C ₁₅ H ₁₁ N ₃ O ₂ S ₂ ) C(%) H(%) N( %) S(%) Theoretical value 54.70 3.37 12.76 19.47 Experimental value 54.54 3.51 12.44 19.32 Example 12 2-(4-methyl-3-methylthiophenyl)
Imidazo[2,1-b]benzothiazole Melting point 130-132℃ Elemental analysis value (as C ₁₇ H ₁₄ N ₂ S ₂ ) C (%) H (%) N (%) S (%) Theoretical value 65.78 4.55 9.02 20.66 Experimental value 65.85 4.55 9.03 20.84 Example 13 2-(4-Methyl-3-methylsulfinylphenyl)imidazo[2,1-b]benzothiazole Melting point 220-222℃ Elemental analysis value (as C ₁₇ H ₁₄ N ₂ OS ₂ ) C(%) H (%) N(%) S(%) Theoretical value 62.55 4.32 8.58 19.64 Experimental value 62.37 4.27 8.35 19.49 Example 14 2-(4-Methyl-3-methylsulfonylphenyl)imidazo[2,1-b]benzothiazole Melting point 261-263℃ Elemental analysis value (as C ₁₇ H ₁₄ N ₂ O ₂ S ₂ ) C(%) H (%) N(%) S(%) Theoretical value 59.63 4.12 8.18 18.73 Experimental value 59.56 4.05 8.02 18.55 Example 15 7-Hydroxy-2-(m-methoxycarbonylphenyl)imidazo[2,1-b]benzothiazole 1/2 hydrate Melting point 210-212℃ Elemental analysis value (C ₁₇ H ₁₂ N ₂ O ₃ S (as 1/2H ₂ O) C(%) H(%) N(%) S(%) Theoretical value 61.25 3.93 8.40 9.62 Experimental value 61.50 3.70 8.40 9.91 Example 16 7-hydroxy-2-(m-hydroxyphenyl)imidazo[2,1-b]benzothiazole.
2/3 hydrate melting point 178-180℃ Elemental analysis value (as C ₁₅ H ₁₀ N ₂ O ₂ S・2/3H ₂ O) C(%) H(%) N(%) S(%) Theoretical value 61.21 3.88 9.52 10.89 Experimental value 61.36 3.81 9.35 10.61 Example 17 2-aminobenzothiazole 4.5g, 3,5-
Dibenzyloxyphenacyl bromide 12.3g,
A mixture of a large excess of anhydrous potassium carbonate, 0.1 g of tetra-n-butylammonium bromide, and 100 ml of methyl ethyl ketone was heated under reflux for 8 hours. After cooling,
Excess potassium carbonate was filtered off, and the filtrate was concentrated under reduced pressure. Toluene was added to the residue, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crystalline residue was recrystallized twice from toluene and then from a toluene-n-hexane mixture to obtain 3.75 g of 2-(3,5-dibenzyloxyphenyl)imidazo[2,1-b]benzothiazole. Ta. Melting point 160-161℃ Elemental analysis value (as C ₂₉ H ₂₂ N ₂ O ₂ S) C (%) H (%) N (%) S (%) Theoretical value 75.30 4.79 6.06 6.93 Experimental value 75.41 4.73 5.87 7.08 Example 18 6-Methoxy-2-phenyl-7-thiocyanatoimidazo[2,1-b]benzothiazole Melting point 217-220℃ Elemental analysis value (as C ₁₇ H ₁₁ N ₃ S ₂ O) C(%) H(% ) N(%) Theoretical value 60.52 3.29 12.45 Experimental value 60.38 3.22 12.26 Example 19 7-hydroxy-2-phenylimidazo [2,
1-b] 1.7 g of benzothiazole, 1 g of monochloroacetic acid ethyl ester, 1.3 g of anhydrous potassium carbonate,
Potassium iodide 0.1g, methyl ethyl ketone 50ml
The mixture was heated under reflux for 12 hours. After cooling, excess potassium carbonate was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with dilute aqueous sodium hydroxide solution, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 7-ethoxycarbonylmethyloxy-
1.7 g of 2-phenylimidazo[2,1-b]benzothiazole (melting point 114-116°C) was obtained. 1 g of this product was added to a mixture of 50 ml of methanol and 6 ml of 1N aqueous sodium hydroxide solution, and the mixture was stirred at 60° C. for 6 hours. After concentrating the reaction solution and washing the residue with water and isopropanol, 500 ml of water and 2 g of sodium hydrogen carbonate were added and stirred. Insoluble matters were removed by filtration, and acetic acid was added to the filtrate to make the liquid acidic. The resulting crystals were collected by filtration and recrystallized from isopropyl alcohol to give 7-carboxymethyloxy-2-phenylimidazo[2,1-b]benzothiazole 1/
0.2 g of dihydrate was obtained. Melting point 240-243℃ Elemental analysis value (as C ₁₇ H ₁₂ N ₂ O ₃ S・1/2H ₂ O) C (%) H (%) N (%) S (%) Theoretical value 61.25 3.93 8.40 9.63 Experimental value 61.42 3.96 8.15 9.36 Example 20 7-acetamido-2-phenylimidazo[2,1-b]benzothiazole monohydrate 8.5g
Add to a mixture of 100 ml of concentrated hydrochloric acid and 300 ml of methyl cellosolve, and stir at 100-110°C for 4 hours. After cooling the reaction solution, the crystals are collected by filtration. These crystals are suspended in 200 ml of methyl cellosolve, made alkaline by adding concentrated ammonia water, and then 80 ml of water is added and cooled to precipitate crystals. The precipitated crystals were collected by filtration and dried to give 7-amino-2-phenylimidazo[2,1-
b] Obtain 5.76 g of benzothiazole. Melting point 161-163℃ Elemental analysis value (as C ₁₅ H ₁₁ N ₃ S) C (%) H (%) N (%) S (%) Theoretical value 67.90 4.18 15.84 12.08 Experimental value 67.99 4.11 15.80 12.12 Example 21 7-hydroxy-2-phenylimidazo [2,
1-b] 1.7 g of benzothiazole, 1 g of ethyl monochloroacetate, 1.3 g of potassium carbonate, and 0.1 g of potassium iodide are stirred in 50 ml of methyl ethyl ketone and heated under reflux overnight. After the reaction is completed, the reaction solution is cooled, insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue is extracted with 100 ml of ethyl acetate. After washing the extract once with dilute sodium hydroxide solution,
Washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was recrystallized from benzene-n-hexane.
-1.7 g of phenylimidazo[2,1-b]benzothiazole are obtained. Melting point 114-116℃ Elemental analysis value (as C ₁₉ H ₁₆ N ₂ O ₃ S) C (%) H (%) N (%) S (%) Theoretical value 64.76 4.58 7.95 9.10 Experimental value 64.61 4.56 7.89 9.15 Example twenty two 7-amino-2-phenylimidazo[2,1-
b] Dissolve 2 g of benzothiazole in a mixture of 4 ml of pyridine, 2 ml of triethylamine, and 100 ml of methylene chloride, and dissolve 1.2 g of ethyloxalyl chloride.
g dissolved in 10 ml of methylene chloride.
Drop at below ℃. After returning to room temperature and stirring for 3 hours, add 200 ml of water to precipitate an oily substance. This stuff will crystallize if left alone. The crystals were collected by filtration and recrystallized from methyl cellosolve-water to give 7-ethoxyoxalylamide-2-phenylimidazo[2,1
-b] Obtain 2 g of benzothiazole. Melting point 238-241℃ Elemental analysis value (as C ₁₉ H ₁₅ N ₃ O ₃ S) C (%) H (%) N (%) S (%) Theoretical value 62.45 4.14 11.50 8.77 Experimental value 62.20 4.07 11.43 9.07 Example twenty three 2-(m-hydroxyphenyl)imidazo[2,
1-b] In a solution of 1.5 g of benzothiazole, 100 ml of tetrahydrofuran, and 2 ml of triethylamine,
Add a solution of 0.96 g of p-toluoyl chloride and 10 ml of tetrahydrofuran at below 10°C, and stir overnight at room temperature. 100 ml of toluene was added to the reaction solution, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was recrystallized from toluene-n-hexane to give 2-[3-(p-toluoyloxy)phenyl]imidazo. [2,1-b]benzothiazole 2
get g. Melting point: 173-175°C Elemental analysis value (as C ₂₃ H ₁₆ N ₂ O ₂ S) S (%) Theoretical value 8.34 Experimental value 8.36 Example 24 The following compound was obtained by processing in the same manner as in Example 23. 7-acetoxy-2-(p-methoxyphenyl)
Imidazo[2,1-b]benzothiazole Melting point 215℃ Elemental analysis value (as C ₁₈ H ₁₄ N ₂ O ₃ S) C(%) H(%) N(%) S(%) Theoretical value 63.89 4.17 8.28 9.47 Experimental value 63.95 4.03 8.23 9.52 Example 25 Add 3.2 g of 2-(m-methoxycarbonylphenyl)imidazo[2,1-b]benzothiazole to 50 ml of a methanol solution containing 9 g of ammonia,
Stir overnight at 100-110℃ in a sealed tube. After cooling, the precipitated crystals were collected by filtration, washed with chloroform, and dried to obtain 2 g of white crystals of 2-(m-carbamoylphenyl)imidazo[2,1-b]benzothiazole.
get. Melting point 261℃ Elemental analysis value (as C ₁₆ H ₁₁ N ₃ OS) C (%) H (%) N (%) S (%) Theoretical value 65.51 3.78 14.32 10.93 Experimental value 65.26 3.65 14.18 10.97 Example 26 Add 1 g of sodium borohydride to a suspension of 2 g of 2-(p-chlorophenyl)-3-formylimidazo[2,1-b]benzothiazole, 100 ml of chloroform, and 200 ml of ethanol, and stir overnight at room temperature. The reaction solution was concentrated under reduced pressure, 900 ml of chloroform was added to the residue, insoluble matter was removed, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was recrystallized from isopropyl alcohol to give 2-( p-chlorophenyl)-3-hydroxymethylimidazo[2,1-b]benzothiazole
Obtain 1.2g. Melting point 218-220℃ Elemental analysis value (as C ₁₆ H ₁₁ N ₂ OSCl) C(%) H(%) N(%) S(%) Theoretical value 61.05 3.52 8.90 10.18 Experimental value 60.90 3.42 8.97 10.24 Cl(%) Theoretical value 11.26 Experimental value 11.24 Example 27 2-(p-chlorophenyl)imidazo[2,1
-b] A solution of 1,1,2,2-tetrachloroethane of methylsulfuryl chloride obtained from 4g of dimethylsulfide and 5.2g of sulfur chloride is added dropwise to a solution of 10g of benzothiazole and 70ml of methylene chloride under ice cooling. . After the addition is complete, stir at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was extracted with 200 ml of chloroform. 5 extracts
% aqueous sodium bicarbonate solution, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was recrystallized with methyl cellosolve to give 2-
10.9 g of (p-chlorophenyl)-3-methylthioimidazo[2,1-b]benzothiazole was obtained. Melting point 190-192℃ Elemental analysis value (as C ₁₆ H ₁₁ N ₂ S ₂ Cl) C(%) H(%) N(%) S(%) Theoretical value 58.09 3.35 8.87 19.38 Experimental value 57.80 3.16 8.62 19.12 Cl( %) Theoretical value 10.72 Experimental value 11.01 Example 28 Add m-chloroperbenzoic acid to a solution of 1.5 g of 2-(p-chlorophenyl)-3-methylthioimidazo[2,1-b]benzothiazole and 50 ml of chloroform.
Add 1.7g and stir overnight at room temperature. The reaction solution was washed with a 5% aqueous sodium hydrogen carbonate solution, washed with water,
Dry over anhydrous magnesium sulfate and concentrate under reduced pressure.
The residue was recrystallized with methyl cellosolve to give 2-(p
1.25 g of -chlorophenyl)-3-methylsulfinyl imidazo[2,1-b]benzothiazole are obtained. Melting point 185-187℃ (decomposition) Elemental analysis value (as C ₁₆ H ₁₁ N ₂ S ₂ OCl) C (%) H (%) N (%) S (%) Theoretical value 55.41 3.20 8.08 18.49 Experimental value 55.28 3.25 7.92 18.32 Cl(%) Theoretical value 10.22 Experimental value 10.31 Example 29 Add 0.2g of lithium aluminum hydride to 20ml of tetrahydrofuran cooled to 0.5℃
After gradually dropping a solution of 1.2 g of (m-methoxycarbonylphenyl)imidazo[2,1-b]benzothiazole dissolved in 10 ml of tetrahydrofuran,
Stir for another 10 minutes at 0-5°C. 10 to the reaction solution
After gradually adding 5 ml of % acetic acid, 50 ml of ethyl acetate is added for extraction. The extract was dried over anhydrous magnesium sulfate and concentrated to obtain 1.0 g of solid. Recrystallization from isopropanol yields 0.8 g of 2-(m-hydroxymethylphenyl)imidazo[2,1-b]benzothiazole. Melting point 159℃ Elemental analysis value (as C ₁₆ H ₁₂ N ₂ OS) C (%) H (%) N (%) S (%) Theoretical value 68.55 4.31 9.99 11.44 Experimental value 68.36 4.30 10.07 11.56 Similarly, the following compounds was manufactured. Example 30 7-(1-Hydroxyethyl)-2-phenylimidazo[2,1-b]benzothiazole Melting point 132℃ Elemental analysis value (as C ₁₇ H ₁₄ N ₂ OS) C(%) H(%) N(%) S (%) Theoretical value 69.36 4.79 9.52 10.89 Experimental value 69.20 5.01 9.49 10.75 Example 31 7-amino-2-phenylimidazo[2,1-
b] Benzothiazole 500mg, methyl iodide 265
While stirring vigorously, a mixture of 260 mg of anhydrous potassium carbonate and 50 ml of ethanol was heated under reflux for 2 days. After cooling the reaction solution, it was concentrated under reduced pressure and the residue was extracted with 50 ml of ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (elution solvent: toluene: ethyl acetate = 4:
1) and recrystallized from toluene to obtain 50 mg of 7-methylamino-2-phenylimidazo[2,1-b]benzothiazole. Melting point 175-176℃ Elemental analysis value (as C ₁₆ H ₁₃ N ₃ S) C (%) H (%) N (%) S (%) Theoretical value 68.79 4.69 15.04 11.48 Experimental value 68.85 4.57 14.93 11.59

Claims (1)

[Claims] 1. General formula (The symbols in the formula have the following meanings. R ¹ ; Hydrogen atom, halogen atom, lower alkyl group,
Hydroxy lower alkyl group, hydroxyl group, lower alkoxy group, phenyl lower alkoxy group, carboxy lower alkoxy group, lower alkoxycarbonyl lower alkoxy group, acyloxy group, amino group, mono- or di-lower alkylamino group,
Or an acylamino group. R ² and R ³ ; Same or different, hydrogen atom, halogen atom, lower alkyl group, hydroxy lower alkyl group, hydroxyl group, lower alkoxy group, phenyl lower alkoxy group, carboxy lower alkoxy group, lower alkoxycarbonyl lower alkoxy group, acyloxy group, lower alkylthio group,
A lower alkylsulfinyl group, a lower alkylsulfonyl group, a sulfamoyl group, a carboxy group, a lower alkoxycarbonyl group, a nitrile group, a carbamoyl group, a nitro group, an amino group, a mono- or di-lower alkylamino group, or an acylamino group. R ⁴ and R ⁵ ; Same or different, hydrogen atom, lower alkyl group, hydroxy lower alkyl group, hydroxyl group, lower alkoxy group, carboxy lower alkoxy group, lower alkoxycarbonyl lower alkoxy group, acyloxy group, lower alkylthio group, lower alkyl A sulfinyl group, a lower alkylsulfonyl group, a thiocyanate group, an amino group, a mono- or di-lower alkylamino group, or an acylamino group. R ⁶ ; hydrogen atom, halogen atom, lower alkyl group,
A hydroxy lower alkyl group, a nitroso group, a nitro group, an amino group, a mono- or di-lower alkylamino group, an acylamino group, or a group represented by the formula [Formula]. Note that any two adjacent groups of R ¹ , R ² and R ³ may be combined to form a benzene ring or a lower alkylenedioxy group. However, the combination of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ satisfies at least one of the following conditions. (1) R ¹ is an acyloxy group other than a phenyl lower alkoxy group, a lower alkanoyloxy group, or a lower alkoxycarbonylamino group. (2) At least one of R ² and R ³ is an acyloxy group other than a hydroxy lower alkyl group, a phenyl lower alkoxy group, a lower alkanoyloxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, Be a sulfamoyl group, nitrile group, carbamoyl group, or lower alkylsulfonylamino group. (3) Any two adjacent R ¹ , R ² and R ³ form a lower alkylenedioxy group. (4) Both R ⁴ and R ⁵ are substituents other than hydrogen atoms. (5) When one of R ⁴ and R ⁵ is a hydrogen atom, the other is a hydroxy lower alkyl group, hydroxyl group, carboxy lower alkoxy group, lower alkoxycarbonyl lower alkoxy group, acyloxy group, amino group, mono- or di-lower alkyl group. Must be an amino group or an acylamino group. (6) R ⁶ is a hydroxy lower alkyl group, a lower alkylthio group, a lower alkylsulfinyl group, or a lower alkylsulfonyl group. ) Novel 2-phenylimidazo [2,1
-b] Benzothiazole derivative or salt thereof.