JPH07179471A - Thienotriazolodiazepine compound - Google Patents

Abstract

PURPOSE:To obtain a new thienotriazolodiazepine compound useful for treating inflammatory diseases, allergic diseases, rheumatoid arthritis, autoimmune diseases, etc., having inhibitory action on leukocyte adhesion. CONSTITUTION:This compound of formula I [Ar is phenyl, pyridyl, thienyl, etc.; R<1> and R<2> each is H, a halogen, a 1-6C alkyl, etc.; R<3> is 1, a halogen or 1-6C alkyl; R<4> and R<5> each is H or (CH2)nYH ((n) is 0-6; Y is O or S), etc.] such as N-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] (1,4]diazepin-6-yl)-N'-(2-hydorxyethyl)urea. The compound of formula I is obtained by reacting a compound of formula II with 1,1'-carbonyldiimidazole to give a carbamoylimidazole derivative and reacting the derivative with an amine of formula III.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel thienotriazolodiazepine compound having a leukocyte adhesion inhibitory action.

[0002]

BACKGROUND ART From WO93 / 12117, a thienotriazolodiazepine compound having a cell adhesion inhibitory action is known. In addition, JP-A-2-2818
No. 1 and JP-A-3-223290 disclose thienodiazepine compounds having an antagonistic effect on cholecystokinin (CCK) and gastrin. Further, International Publication WO93 / 07129 discloses a thienotriazolodiazepine compound used for treating osteoporosis.

In various inflammatory and allergic diseases, infiltration of so-called inflammatory cells (white blood cells in a broad sense) such as polymorphonuclear leukocytes, macrophages and lymphocytes is deeply involved in the pathological condition. It has long been thought that it is important for leukocytes to adhere to vascular endothelial cells as the first step of leukocyte infiltration, but the mechanism has not been clarified. Due to recent advances in molecular biology, molecules involved in adhesion have been identified one after another, and their functional significance, that is, a specific adhesion molecule expressed on vascular endothelial cells and leukocytes that specifically bind to it It has been clarified that leukocyte adhesion occurs via the adhesion molecule of erythrocyte, followed by leukocyte infiltration into inflamed tissue. The following combinations are considered to be particularly important as molecules involved in leukocyte adhesion to vascular endothelial cells, but the degree of involvement of each adhesion molecule in various inflammatory and allergic diseases is not always clear. is not.

[0004]

[Table 1]

Among these adhesion molecules, especially ICAM-
1 and LFA-1 have been shown to be deeply involved not only in cell invasion but also in adhesion between lymphocytes and their activation (for example, IC on macrophages).
Binding of AM-1 to LFA-1 on T lymphocytes activates T lymphocytes). Therefore, IC
A substance that inhibits the binding between AM-1 and LFA-1 can also be expected to have a broadly defined immunosuppressive action.

In relation to diseases, in inflammatory dermatitis (contact hypersensitivity, photosensitivity, etc.) and rheumatoid arthritis, ICAM-1 and E-select at the site of inflammation are involved.
In addition to increased expression of in, IC has been reported in asthma.
Involvement of AM-1, Mac-1 and the like has been suggested. It has also been reported that cell adhesion via ICAM-1 and the like plays an important role in rejection reaction after organ transplantation. Furthermore, it has been shown that adhesion molecules are involved in cancer metastasis.

Also in experimental animals, the expression of adhesion molecules is enhanced in various inflammation models (delayed hypersensitivity, autoimmune nephritis models, etc.), and anti-ICAM-1
It has been reported that antibodies and anti-LFA-1 antibodies suppress inflammatory reactions (adjuvant arthritis, collagen arthritis, etc.). The role of adhesion molecules in eosinophil activation in a monkey asthma model has also been clarified. Furthermore, the effectiveness of anti-LFA-1 and anti-ICAM-1 antibodies was also reported in a mouse ectopic heart transplant model, suggesting the importance of adhesion molecules in transplant rejection, as in humans. There is.

[0008]

As therapeutic agents for various inflammatory diseases and allergic diseases, various steroid agents, non-steroidal anti-inflammatory agents and inflammatory / allergy-related mediator release inhibitors have been used. . Of these drugs, steroid drugs often cause serious side effects, and other drugs have not been able to achieve a sufficient therapeutic effect.

On the other hand, in recent years, it has become clear that various cell adhesion molecules are deeply involved in the onset and progression of some inflammatory diseases and allergic diseases, and the cell adhesion inhibitory action. It is expected that the compounds having the above can be excellent anti-inflammatory agents or anti-allergic agents. For example, Proceedings of National Academy of Sciences USA
(Proc. Natl. Acad. Sci. USA), Volume 88 (199)
Pp. 355-359, N- (fluorenyl-9).
-Methoxycarbonyl) amino acids inhibit leukocyte adhesion and thus suppress reactions in various animal inflammation models.
Four Clinical Research Annual Meeting (American Federation for Clinical Research An
nual Meeting, May 6, 1991), it is described that leukocyte adhesion to vascular endothelial cells is inhibited by the inhibition of the expression of adhesion molecules (CD18 etc.) on leukocytes by syngeneic compounds. .

However, the compounds described in various known literatures including the above literatures cannot yet obtain a sufficient cell adhesion inhibitory action, and further development of more potent inhibitors is desired.

[0011]

Means for Solving the Problems The present inventors have investigated human umbilical vein-derived vascular endothelial cells (human umbilical vein veins) for the purpose of searching for a compound that strongly inhibits leukocyte adhesion to vascular endothelial cells.
bilical vein-derived endothelial cells (HUVEC) and human leukemia cell line
Upon intensive research to solve the above problems, it was found that the thienotriazolodiazepine compound represented by the general formula (I) has a strong inhibitory effect on leukocyte adhesion,
The present invention has been completed.

That is, the present invention is as follows. (1) General formula

[0013]

[Chemical 3]

[Wherein Ar is phenyl, pyridyl, thienyl, 1 to 3 selected from halogen as a substituent, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, cyano, amino and trihalomethyl. Or phenyl having 1 to 3 or pyridyl or thienyl having 1 to 3 selected from halogen, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons as a substituent.

R ¹ and R ² are the same or different and each is hydrogen, halogen, alkyl having 1 to 6 carbon atoms or the formula-(CH ₂ ) m-CON (R ⁶ ) (R ⁷ ), where m is 1 .R ^6, R ⁷ indicating a 6 integers are the same or different, and represent hydrogen, alkyl of 1 to 6 carbon atoms, a 2-7 alkanoyl or cycloalkyl carbon atoms, or R ^6, R ^7, Is bonded to form a cyclic amine together with the adjacent nitrogen atom), or R ¹ and R ² are bonded to each other to form a ring having 5 to 7 carbon atoms or a ring. It shows a group forming a 5- to 7-membered ring having N (R ⁸ ) therein (R ⁸ represents an alkanoyl or cycloalkylcarbonyl having 2 to 7 carbon atoms).

R ³ is hydrogen, halogen or 1 to 6 carbon atoms
Represents alkyl. One of R ⁴ and R ⁵ represents hydrogen,
On the other hand or sometimes both

[0017]

[Chemical 4]

(In the formula, n represents 0 or an integer of 1 to 6. Y represents an oxygen atom or a sulfur atom. R ⁹ represents alkyl having 1 to 6 carbon atoms. R ¹⁰ and R ¹¹ are the same. Or differently, selected from hydrogen, alkyl having 1 to 6 carbons, phenyl, heteroaryl, halogen as a substituent, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, cyano, amino and trihalomethyl. Phenyl having 1 to 3 or halogen as a substituent, carbon number of 1 to 6
Represents a heteroaryl having 1 to 3 selected from alkyl and alkoxy having 1 to 6 carbons. R ¹² represents hydrogen or alkyl having 1 to 6 carbons. X represents halogen. R ¹³ is hydrogen, alkyl having 1 to 6 carbons,
Aralkyl or halogen as a substituent, carbon number 1 to 6
Alkyl, C 1-6 alkoxy, cyano,
Shows an aralkyl having 1 to 3 selected from amino and trihalomethyl. ) Represents a group represented by
Alternatively, R ⁴ and R ⁵ are bonded to each other and a hetero atom in the ring is an oxygen atom, a sulfur atom or N (R ¹⁴ ) (R ¹⁴ is hydrogen, alkyl having 1 to 6 carbons, or C 1 to 6 Hydroxyalkyl, phenyl or a phenyl having 1 to 3 carbon atoms selected from halogen, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, alkoxy, cyano, amino and trihalomethyl as a substituent. 1 to 4 may be further selected as a substituent from halogen, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, hydroxyl group, carboxyl, alkoxycarbonyl, cyano, amino or mono- or di-substituted amino. A group forming a nitrogen-containing ring which may have 3 is shown. ] The thienotriazolo diazepine compound represented by these, or its pharmaceutically acceptable salt.

In the present specification, pyridyl means 2-pyridyl, 3-pyridyl and 4-pyridyl. Thienyl means 2-thienyl and 3-thienyl. Halogen means chlorine, bromine, fluorine and iodine. C1-C6 alkyl means methyl, ethyl, propyl, isopropyl,
It shows butyl, isobutyl, tertiary butyl, pentyl, tertiary pentyl, 1-methylbutyl, hexyl, 1-methylpentyl, etc., and alkyl having 1 to 4 carbon atoms is preferable, and methyl is particularly preferable. Alkoxy having 1 to 6 carbon atoms represents methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, tertiary pentyloxy, hexyloxy, etc., and has 1 to 4 carbon atoms. Alkoxy is preferred and methoxy is especially preferred. Trihalomethyl refers to trifluoromethyl, trichloromethyl, tribromomethyl and the like, with trifluoromethyl being preferred. Alkanoyl having 2 to 7 carbon atoms is acetyl, propionyl, butyryl,
Isobutyryl, valeryl, isovaleryl, pivaloyl,
Hexanoyl, heptanoyl, etc. are shown, having 2 to 5 carbon atoms
Alkanoyl is preferable, and acetyl and propionyl are particularly preferable. Cycloalkyl is cyclopropyl,
It represents cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, with cyclopropyl and cyclohexyl being preferred. Cycloalkylcarbonyl means cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl and the like, with cyclopropylcarbonyl being preferred. Heteroaryl is pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), thienyl (2
-Thienyl, 3-thienyl), furyl (2-furyl, 3
-Ruffle) etc. Aralkyl is benzyl, 1-
It represents phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl and the like, with benzyl being preferred. The hydroxyalkyl having 1 to 6 carbon atoms means hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, etc., and has 1 carbon atom. 4 to 4 hydroxyalkyls are preferable, and hydroxymethyl and 2-hydroxyethyl are particularly preferable. Alkoxycarbonyl means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, etc., and methoxycarbonyl,
Ethoxycarbonyl is preferred. Mono- or di-substituted amino is methylamino, dimethylamino, ethylamino,
Diethylamino, propylamino, dipropylamino,
Butylamino, dibutylamino and the like are shown, and methylamino and dimethylamino are preferable.

The cyclic amine formed by combining R ⁶ and R ⁷ together with the adjacent nitrogen atom is 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino or 1-piperazinyl, and piperidino and morpholino are preferred. R
^1, carbon atoms R ² is formed by bonding with 5-7 ring or in the ring N (R ⁸⁾ cyclopentene ring with 5 to 7-membered ring (R ⁸ are the as defined above) having a pyrroline ring , Pyrazoline ring, cyclopentadiene ring, cyclohexene ring, tetrahydropyridine ring, cyclohexadiene ring, benzene ring, cycloheptene ring, cycloheptadiene ring, cycloheptatriene ring and the like, and cyclohexene ring and tetrahydropyridine ring are preferable. The nitrogen-containing ring which may contain an oxygen atom, a sulfur atom or N (R ¹⁴ ) (R ¹⁴ is the same as defined above) as a hetero atom in the ring formed by R ⁴ and R ⁵ being bonded to each other is 1- Pyrrolidinyl, piperidino, morpholino, thiomorpholino, 4-R ¹⁴ -1-piperazinyl, 1-pyrazolyl and the like, which are halogen as a substituent, alkyl having 1 to 6 carbons (as described above), 1 to 1 carbons It may have 1 to 3 selected from 6 alkoxy (as described above), hydroxyl group, carboxyl, alkoxycarbonyl (as described above), cyano, amino or mono- or di-substituted amino (as described above). .

The form of Ar is phenyl, 2-chlorophenyl, 4-chlorophenyl, 4-methylphenyl,
2-pyridyl, 3-pyridyl, 2-thienyl, etc. are mentioned, and phenyl, 4-chlorophenyl, and 2-chlorophenyl are preferable.

In an embodiment of R ¹ , hydrogen and methyl are R ²
As an embodiment of, halogen, methyl, ethyl, hexyl,
2- (N-acetylcarbamoyl) ethyl, 2- (N-
Tert-butylcarbamoyl) ethyl, 2- (N-cyclopropylcarbamoyl) ethyl, 2-morpholinocarbonyl, 2-piperidinocarbonylethyl, R
¹ is preferably hydrogen or methyl, R ² is preferably methyl or 2-morpholinocarbonylethyl. Also, R ¹ and R
^The ring formed by combining ² is preferably a cyclohexyl ring or a tetrahydropyridine ring in which cyclopropylcarbonyl is substituted at the N position.

Examples of R ³ include methyl, butyl, hexyl and the like, with methyl being preferred.

As an embodiment of R ⁴ and R ⁵ , R ⁴ represents hydrogen and R ⁵ is the group of the above (1) to (6), or R ⁴ and R 5 are
Preferred are those in which ⁵ is both the above (1), R ⁴ represents hydrogen, R ⁵ represents the above (1), n is 2 and Y is an oxygen atom. Or, as an embodiment of a ring formed by combining R ⁴ and R ⁵ , morpholino, piperidino, 4-hydroxypiperidino, 4-dimethylaminopiperidino, 4- (2-hydroxyethyl) -1-piperazinyl , 4- (2-methoxyphenyl) -1-piperazinyl, 2-carboxy-1-pyrrolidinyl, 2-ethoxycarbonyl-1-pyrrolidinyl, etc. are preferred, and monophorino, piperidino, and 4-hydroxypiperidino are preferred.

The pharmaceutically acceptable salt of the compound of formula (I) includes an acid addition salt with an inorganic acid or an organic acid, and a salt with an inorganic base, an organic base or an amino acid,
For the purposes of the present invention, those salts are preferably substantially non-toxic. In addition, hydrates (hemihydrate, monohydrate, 3/2 hydrate, etc.) and other solvates are also included. Furthermore, since the compound of the general formula (I) has at least one chiral carbon atom, all racemates, optically active isomers, diastereomers and the like based thereon are included in the present invention. .

The compound of the general formula (I) can be produced, for example, by the method shown in the following chemical formula 5.

[0027]

[Chemical 5]

The reaction of Method 1 is carried out in a suitable solvent (tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, which does not inhibit the reaction of the compound of the general formula (II) and 1,1'-carbonyldiimidazole (CDI).
(Dichloromethane, chloroform, dichloroethane, ethyl acetate, benzene, toluene, xylene, dimethylformamide, dimethylacetamide, etc.) at −20 ° C. to the boiling point of the solvent, preferably at room temperature for 2 to 5 hours to give a carbamoylimidazole derivative, and then It proceeds by reacting the amine of the general formula (III) from -20 ° C to the boiling point of the solvent, preferably room temperature.

The reaction of Method 2 is carried out by reacting the compound of the general formula (II) with triphosgene in the presence of a suitable solvent (triethylamine, pyridine, N-methylmorpholine, 4-dimethylaminopyridine, etc.), which does not inhibit the reaction. Reaction in a solvent (tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, dichloromethane, chloroform, dichloroethane, ethyl acetate, benzene, toluene, xylene, dimethylformamide, dimethylacetamide, etc.) at -20 ° C to the boiling point of the solvent for 1 to 24 hours To give an isocyanate derivative, and then the amine of the general formula (III) is reacted at −20 ° C. to the boiling point of the solvent for 1 to 24 hours to proceed.

The reaction of Method 3 is carried out by reacting the compound of the general formula (II) with 4-nitrophenyl chloroformate in the presence of a suitable base (triethylamine, pyridine, N-methylmorpholine, 4-dimethylaminopyridine, etc.). A suitable solvent that does not inhibit the reaction (tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane,
Dichloromethane, chloroform, dichloroethane, ethyl acetate, benzene, toluene, xylene, dimethylformamide, dimethylacetamide, etc.) is reacted at −20 ° C. to the boiling point of the solvent for 1 to 24 hours to obtain an active carbamate compound, and then the compound of the general formula (III ) Amine
The reaction proceeds from 20 ° C. to the boiling point of the solvent for 1 to 24 hours.

The compound of formula (I) thus obtained can be separated and purified from the reaction mixture by a method known per se such as recrystallization and column chromatography. The compound of the general formula (I) is an inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), an organic acid (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid) by a conventional method , Citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, ascorbic acid, etc.), inorganic bases (sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, ammonium hydroxide, etc.) ), An organic base (methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, trishydroxymethylaminomethane, quinine, guanidine, cinchonine, etc.) or an amino acid (lysine, ornithine, arginine, alanine, etc.). Is pharmaceutically acceptable by It can be.

When the compound of the present invention has a chiral carbon atom, it is usually obtained as a racemate. The racemate can be resolved into optical isomers by a conventional method. Such optical isomers can also be prepared by using optically active starting materials. Individual diastereomers can be purified by fractional crystallization or chromatography.

The compounds included in the general formula (I) of the present invention are exemplified in the following table. In the table, Cl is chlorine, Et is ethyl, Me is methyl, MeO is methoxy, and Ph is phenyl.

[0034]

[Table 2]

[0035]

[Table 3]

[0036]

[Table 4]

[0037]

[Table 5]

[0038]

[Action]

Experimental Example 1: CD1 of human histiocytic leukemia cell line U937
Effect on 1b expression M, which is one of adhesion molecules expressed on the surface of leukocyte cells
The effect on the expression of the CD11b antigen that constitutes the α chain of ac-1 was examined. U937 cells, 20 fetal bovine serum
% Of phorbol-12,13-dibutyrate (PDB, 10 ng /
ml) and test compounds in 96-well filtration plates (30000 cells / well). 37 ° C,
After culturing for 3 days in the presence of 5% carbon dioxide, RPMI1
After washing once with 640 medium, rat anti-human CD11b monoclonal antibody (2 μg / ml) was added. After leaving it for 1 hour under ice cooling, it was washed twice and peroxidase-labeled anti-rat immunoglobulin antibody (1 μg / ml) was added. After leaving it under ice-cooling for 1 hour, it was washed 3 times, and a color-developing substrate for peroxidase (ortho-phenylenediamine)
Was added. After leaving it for 15 minutes at room temperature, the absorbance at 490 nm was measured using an absorptiometer for 96-well plate and used as an index of CD11b antigen expression.

50% inhibitory concentration (IC) calculated with the expression level with PDB added as 100% and the expression level without PDB added as 0%.
₅₀ values, μM) are shown in Table 6 below.

Table 6 ──────────────────────────────────── Test compound IC ₅₀ values for CD11b expression ( μM) ──────────────────────────────────── A 0.04 B 0.38 C 0.40 ────────────────────────────────────

As shown in Table 6 above, compounds A, B and C strongly suppressed the expression of CD11b in U937 cells.
Compound A is the compound of Example 1, compound B is the compound of Example 5, and compound C is the compound of Example 13.

Experimental Example 2: Effect on oxazolone-induced mouse ear edema After sensitization by applying 50 μl of an oxazolone solution (50 mg / ml in acetone) to the abdomen of a mouse from which hair had been removed, on the 7th day the front and back of the mouse right ear 5 μl of oxazolone was applied to each. After 24 hours, the left and right ears have a diameter of 6
It was hollowed out using a mm puncher and its weight was measured by a direct balance. The value obtained by subtracting the weight of the untreated ear (left ear) from the weight of the treated ear (right ear) was used as an index of edema. Test compound A was suspended in 0.5% methylcellulose solution,
Oral administration was performed 0 to 8 days after sensitization (0.1 ml / body weight 1
0 g). The results are shown in Table 7.

Table 7 ──────────────────────────────────── Treatment Compound A Ear weight increase ( mg / kg / day) (mg, mean ± SD) ──────────────────────────────────── Sensitization 0 5.8 ± 0.8 Sensitization 0 17.7 ± 0.5 Sensitization 1 14.8 ± 0.8 ** Sensitization 3 13.0 ± 0.6 ** Sensitization 10 11.2. ± 0.8 ** ──────────────────────────────────── **: P <0.01 (Comparison with oxazolone-sensitized group by one-way analysis of variance n = 6)

As shown in Table 7 above, it was suggested that Compound A suppresses mouse ear edema in a dose-dependent manner and also suppresses leukocyte infiltration into inflammatory sites by inhibiting cell adhesion in vivo. .

The pharmaceutical composition of the present invention inhibits various inflammatory diseases, allergic diseases, autoimmune diseases, rheumatoid arthritis, and rejection reactions during organ transplantation in which the leukocyte adhesion reaction to vascular endothelial cells is involved in the onset and progression thereof. It is used to prevent or treat, and also to prevent metastasis of tumor cells.

In the preparation of the medicament of the present invention, the compound of general formula (I) is preferably contained in a therapeutically effective amount, usually about 0.1 to 50 mg. The drug is mixed with pharmaceutically acceptable carriers, excipients, diluents, solubilizers, disintegrating agents, binders and the like in addition to these active ingredients, and tablets, powders, capsules, injections, suppositories. It can be safely orally or parenterally administered to a patient by using a drip infusion. The dose is usually 5 to 100 mg by oral administration and 1 by intravenous administration to an adult per day.
It is about 50 mg.

[0047]

[Examples] The present invention will be specifically described below with reference to raw material preparation examples, examples, and formulation examples, but the present invention is not limited thereto.

Raw Material Preparation Example 1 4- (4-chlorophenyl) in 150 ml of diethyl carbonate
-2,3,9-Trimethyl-6H-thieno [3,2-
f] [1,2,4] triazolo [4,3-a] [1,
4] 12 g of diazepine and 2.4 g of sodium hydride
Add and heat. At around 100 ° C., hydrogen gas starts to foam, and the reaction solution gradually becomes purple. After refluxing for 1 hour, the mixture is cooled to 20 ° C., 8 g of O- (2,4-dinitrophenyl) hydroxylamine is added, and the mixture is stirred for 2 hours.
After the reaction, the mixture is poured into ice water, the diethyl carbonate layer is separated, washed twice with water, and then dried over anhydrous magnesium sulfate. Diethyl carbonate was distilled off under reduced pressure, diisopropyl ether was added to the resulting residue, and the precipitated crystals were collected by filtration and washed with ethyl (6-
Amino-4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2-f] [1,2,4]
Triazolo [4,3-a] [1,4] diazepine-6-
Ill) carboxylate 11 g was obtained.

Ethyl (6-amino-4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,3] was added to a mixed solution of 250 ml of ethanol and 80 ml of water.
2-f] [1,2,4] triazolo [4,3-a]
[1,4] diazepin-6-yl) carboxylate 1
Dissolve 1 g, add 8.4 g of barium hydroxide octahydrate, and stir at room temperature for 24 hours. The solvent is distilled off under reduced pressure, 100 ml of water is added, the pH is adjusted to 2 with 1N hydrochloric acid, the mixture is stirred for 20 minutes, neutralized with an aqueous sodium hydrogen carbonate solution, and extracted twice with chloroform. After the organic layer is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure and subjected to silica gel column chromatography. After distilling off the solvent, the obtained residue was crystallized from diisopropyl ether and collected by filtration, and 6-amino-4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,3] was obtained.
2-f] [1,2,4] triazolo [4,3-a]
7 g of [1,4] diazepine was obtained.

Raw Material Preparation Example 2 In the same manner as in Raw Material Preparation Example 1, 2,3,9-trimethyl-
4-phenyl-6H-thieno [3,2-f] [1,2,
4] Triazolo [4,3-a] [1,4] diazepine to 6-amino-2,3,9-trimethyl-4-phenyl-6H-thieno [3,2-f] [1,2,4] Triazolo [4,3-a] [1,4] diazepine was obtained.

Raw Material Preparation Example 3 In the same manner as in Raw Material Preparation Example 1, 4- (2-chlorophenyl) -9-methyl-2- (2-morpholinocarbonylethyl) -6H-thieno [3,2-f] [1 , 2,4] triazolo [4,3-a] [1,4] diazepine to 6-
Amino-4- (2-chlorophenyl) -9-methyl-2
-(2-morpholinocarbonylethyl) -6H-thieno [3,2-f] [1,2,4] triazolo [4,3-]
a] [1,4] diazepine was obtained.

Raw Material Preparation Example 4 In the same manner as in Raw Material Preparation Example 1, 6- (2-chlorophenyl) -3-cyclopropylcarbonyl-11-methyl-
2,3,4,5-tetrahydro-8H-pyrido [4 ',
3 ': 4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine to 8-
Amino-5- (2-chlorophenyl) -3-cyclopropylcarbonyl-11-methyl-2,3,4,5-tetrahydro-8H-pyrido [4 ', 3': 4,5] thieno [3,2- f] [1,2,4] triazolo [4,3-
a] [1,4] diazepine was obtained.

Example 1 40 ml of chloroform was added to 6-amino-4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4. 3-
a] [1,4] diazepine (6 g) was dissolved, 1,1'-carbonyldiimidazole (4.1 g) was added, and the mixture was stirred at room temperature for 2 hours, and then ethanolamine (1.3 ml) was added under ice cooling, and the mixture was stirred at room temperature for 6 hours. . The reaction solution was washed with 0.3N hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue to form crystals, and the crystals were recrystallized from methanol-water to give N- (4- (4-chlorophenyl) having a melting point of 240 to 242 ° C (decomposition). -2,3,9-Trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-
a] [1,4] diazepin-6-yl) -N '-(2-
3.5 g of hydroxyethyl) urea was obtained.

Example 2 6-Amino-2,3,9-trimethyl-4-phenyl-6H-thieno [3,2-f] was prepared in the same manner as in Example 1.
[1,2,4] triazolo [4,3-a] [1,4] diazepine and ethanolamine from melting point 227-228 ° C
N- (2-hydroxyethyl) -N '-(2,3,9
-Trimethyl-4-phenyl-6H-thieno [3,2-
f] [1,2,4] triazolo [4,3-a] [1,
4] Diazepin-6-yl) urea was obtained.

Example 3 In the same manner as in Example 1, 6-amino-4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2-f] [1,2,4 ] Triazolo [4,3-
a] [1,4] diazepine and 4-amino-1-butanol, N- (4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2-, having a melting point of 223 to 226 ° C. f] [1,2,4] triazolo [4,3-
a] [1,4] diazepin-6-yl) -N '-(4-
Hydroxybutyl) urea was obtained.

EXAMPLE 4 In the same manner as in Example 1, 6-amino-4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2-f] [1,2,4 ] Triazolo [4,3-
a] [1,4] diazepine and 6-amino-1-hexanol, N- (4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2-, having a melting point of 237 to 238 ° C. f] [1,2,4] triazolo [4,3-
a] [1,4] diazepin-6-yl) -N '-(6-
Hydroxyhexyl) urea was obtained.

The following compounds are obtained in the same manner as in Example 1. (5) N- (4- (4-chlorophenyl) -2,3,
9-trimethyl-6H-thieno [3,2-f] [1,
2,4] Triazolo [4,3-a] [1,4] diazepin-6-yl) morpholine-4-carboxamide, melting point 167-170 ° C.

(6) N- (2,3,9-trimethyl-
4-phenyl-6H-thieno [3,2-f] [1,2,
4] Triazolo [4,3-a] [1,4] diazepine-
6-yl) morpholine-4-carboxamide, melting point 24
7 ~ 248 ℃

(7) Ethyl N- (3- (4- (4-
Chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3]
-A] [1,4] diazepin-6-yl) ureido) acetate, melting point 233-235 ° C

(8) N- (4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2]
-F] [1,2,4] triazolo [4,3-a] [1,
4] diazepin-6-yl) piperidine-1-carboxamide, melting point 232-236 ° C.

(9) N- (2-chloroethyl) -N '
-(4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine- 6-yl) urea, melting point 247-251 ° C (decomposition)

(10) N- (4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2]
-F] [1,2,4] triazolo [4,3-a] [1,
4] diazepin-6-yl) -N ', N'-(bis (2
-Hydroxyethyl)) urea, melting point 172-175 ° C

(11) N- (4- (2-chlorophenyl) -9-methyl-2- (2-morpholinylcarbonylethyl) -6H-thieno [3,2-f] [1,2,4]
Triazolo [4,3-a] [1,4] diazepine-6-
Yl) -N '-(2-hydroxyethyl) urea,

(12) N- (6- (2-chlorophenyl) -3-cyclopropylcarbonyl-11-methyl-
2,3,4,5-tetrahydro-8H-pyrido [4 ',
3 ': 4,5-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-8-yl) -N'-(2-hydroxyethyl) ) Urea,

(13) N- (4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2]
-F] [1,2,4] triazolo [4,3-a] [1,
4] diazepin-6-yl) -N ′-(2-dimethylaminoethyl) urea, melting point 272-274 ° C.

(14) N- (4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2]
-F] [1,2,4] triazolo [4,3-a] [1,
4] diazepin-6-yl) -4-hydroxypiperidine-1-carboxamide, melting point 202-207 ° C.

(15) N- (1-benzyl-4-piperidyl) -N '-(4- (4-chlorophenyl) -2,
3,9-Trimethyl-6H-thieno [3,2-f]
[1,2,4] Triazolo [4,3-a] [1,4] diazepin-6-yl) urea, melting point 247 to 250 ° C. Compounds shown in Tables 2 to 5 in the same manner as in Example 1 Is obtained.

Pharmaceutical Formulation Example 1 0.5 part of the compound of Example 1, 25 parts of lactose, 35 parts of crystalline cellulose and 3 parts of corn starch were mixed well and then kneaded well with the binder prepared from 2 parts of corn starch. The mixture is sieved through 16 mesh and placed in an oven for 5
After drying at 0 ° C, it was sieved with 24 mesh. The kneaded powder thus obtained was mixed well with 8 parts of cornstarch, 11 parts of crystalline cellulose and 9 parts of talc, and the mixture was compressed and compressed to give 1
A tablet is obtained containing 0.5 mg of active ingredient per tablet.

Formulation Example 2 1.0 mg of the compound of Example 1 and 9.0 m of sodium chloride
g in water for injection and filtered to remove pyrogens,
The filtrate is aseptically transferred to an ampoule, sterilized, and melt-sealed to give an injection containing 1.0 mg of the active ingredient.

[0070]

As is clear from the above description, particularly the experimental examples, the thienotriazolodiazepine compound of the present invention is
It has an action of inhibiting leukocyte adhesion to vascular endothelial cells by suppressing CD11b expression on leukocytes,
It also suppresses leukocyte infiltration in vivo. Due to this action, the present compound is expected to be useful as a therapeutic or prophylactic drug for various inflammatory diseases, allergic diseases, rheumatoid arthritis and the like in which cell adhesion is involved in the onset and progression thereof. It can also be used to prevent or treat autoimmune diseases as well as rejection during organ transplantation, and also to prevent metastasis of tumor cells.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/55 ADU C07D 495/22 // (C07D 495/14 243: 08 249: 08 333: 10 (72) Inventor Hirotsugu Komatsu 3-7-25 Oyata, Iruma City, Saitama Prefecture Yoshitomi Pharmaceutical Co., Ltd. Drug Discovery Research Center (72) Inventor Mariko Nagasawa 3-7-25 Oyada, Iruma City, Saitama Prefecture Yoshitomi Pharmaceutical Co., Ltd. Company Drug Discovery Research Institute

Claims (1)

[Claims] 1. A general formula: [In the formula, Ar is phenyl, pyridyl, thienyl, halogen as a substituent, alkyl having 1 to 6 carbons, and 1 carbon.
To phenyl having 1 to 3 selected from alkoxy, cyano, amino and trihalomethyl, or 1 selected from halogen, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons as a substituent. Represents pyridyl or thienyl having ˜3. R ¹ and R ² are the same or different and each is hydrogen, halogen, alkyl having 1 to 6 carbons or a formula — (CH ₂ ) m-CON (R ⁶ ) (R ⁷ ) (where m is 1 to 6). R ⁶ and R ⁷ are the same or different and represent hydrogen, alkyl having 1 to 6 carbons, alkanoyl or cycloalkyl having 2 to 7 carbons, or R ⁶ and R ⁷ are bonded to each other. Form a cyclic amine together with the adjacent nitrogen atom), or R ¹ and R ² are bonded to each other to form a ring having 5 to 7 carbon atoms or N in the ring. (R ⁸ ) (R ⁸ represents an alkanoyl or cycloalkylcarbonyl having 2 to 7 carbon atoms) and forms a group having 5 to 7 members. R ³ represents hydrogen, halogen or alkyl having 1 to 6 carbon atoms. One of R ⁴ and R ⁵ represents hydrogen, and the other or, depending on the case, both have the formula: (In the formula, n represents 0 or an integer of 1 to 6. Y represents an oxygen atom or a sulfur atom. R ⁹ represents alkyl having 1 to 6 carbon atoms. R ¹⁰ and R ¹¹ are the same or different. Hydrogen, alkyl having 1 to 6 carbons, phenyl, heteroaryl,
Phenyl having 1 to 3 selected from halogen, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, cyano, amino and trihalomethyl as a substituent, or halogen as a substituent, 1 to 6 carbons Represents a heteroaryl having 1 to 3 selected from alkyl and alkoxy having 1 to 6 carbons. R ¹² represents hydrogen or alkyl having 1 to 6 carbons. X represents halogen. R
¹³ is hydrogen, alkyl having 1 to 6 carbons, aralkyl or halogen as a substituent, alkyl having 1 to 6 carbons,
It represents an aralkyl having 1 to 3 carbon atoms having 1 to 3 carbon atoms selected from alkoxy, cyano, amino and trihalomethyl. ) Or a group represented by R ⁴ or R ⁴ ,
⁵ are bonded to each other, an oxygen atom as a hetero atom in the ring,
Sulfur atom or N (R ¹⁴ ) (R ¹⁴ is hydrogen, carbon number 1 to 6)
Alkyl, hydroxyalkyl having 1 to 6 carbon atoms,
Phenyl or phenyl having 1 to 3 selected from halogen, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, cyano, amino and trihalomethyl as a substituent is shown. ) May be included, and is further selected from halogen, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, hydroxyl group, carboxyl, alkoxycarbonyl, cyano, amino, or mono- or di-substituted amino. 1 to 3 represents a group forming a nitrogen-containing ring which may have 1 to 3. ] The thienotriazolo diazepine compound represented by these, or its pharmaceutically acceptable salt.