JP2821674B2 - Benzimidazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel benzimidazole derivative.

[0002]

DISCLOSURE OF THE INVENTION The benzimidazole derivatives of the present invention are:
A novel compound not described in the literature, which is represented by the following general formula (1).

[0003]

Embedded image

[In the formula, R ¹ represents a hydrogen atom or a halogen atom. R ² represents a phenyl lower alkyl group. R ³ is an indolyl group, an indolinyl group, a 1H-indazolyl group,
2 (1H) -quinolinonyl group, 3,4-dihydro-2
(1H) -quinolinonyl group and 3,4-dihydro-1,
And a heterocyclic group selected from the group consisting of 4 (2H) -benzooxazinyl groups. On the heterocycle, a group -B-
R ⁴ (B is a lower alkylene group, R ⁴ is a 5- to 11-membered saturated or unsaturated monocyclic or dicyclic ring having 1 to 4 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom (May have 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and an oxo group as a substituent on the heterocyclic ring) or a group -NR ⁵ R ⁶ (R ⁵ and R ⁶ are the same or different and each is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a pyridylcarbonyl group, or isoxazolylcarbonyl which may have 1 to 3 lower alkyl groups as a substituent. R ⁵ represents an amino-substituted lower alkyl group which may have a lower alkyl group as a group, a pyrrolylcarbonyl group or a substituent.
And R ⁶ may be bonded to each other via a nitrogen atom or an oxygen atom together with or without a nitrogen atom to which they are bonded to form a 5- to 6-membered saturated heterocyclic ring. The heterocyclic ring may have 1 to 3 groups selected from the group consisting of a hydroxyl group and a phenyl group as a substituent. ). A lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on the phenyl ring; a group selected from the group consisting of a halogen-substituted lower alkyl group and a lower alkoxycarbonyl-substituted lower alkyl group. May be provided for 1 to 3. A represents a lower alkylene group. n represents 0 or 1. Proliferation of vascular smooth muscle cells causes intimal thickening of blood vessels, causing arteriosclerotic diseases such as myocardial infarction and cerebral infarction in the long term, and percutaneous coronary angioplasty (P
TCA), stents, cause reocclusion after atherectomy procedures. Under these circumstances, conventional drugs are indirect therapeutics aimed at treating intimal hypertrophy such as hyperlipidemia and hypertension, and their effects are limited. There is a demand for the development of effective drugs.

In view of the current state of such drug treatment, the present inventors act directly on vascular smooth muscle cells as an essential therapeutic drug for arteriosclerotic diseases different from conventional drugs, and suppress their proliferation. A drug study was conducted.

[0006] It is known that cGMP is involved in smooth muscle proliferation. Nitro preparations, which are coronary vasodilators, are known to activate guanylate cyclase, enhance cGMP production, and suppress cell growth, but the action time is extremely short, and repeated administration is required. And is hardly used for arteriosclerotic diseases requiring long-term administration. On the other hand, c
Several drugs have recently been reported that increase the cGMP concentration by inhibiting the enzyme that degrades GMP (cGMP PDE), but most of these drugs have not been suggested to have a cytostatic effect. Conference (IBC's International Conference on RESTE)
NOSIS, 1994, USA), it is only known that guanine derivatives have both cGMP PDE inhibitory activity and cytostatic activity.

Under these circumstances, the present inventors have determined that cG
The present inventors have found that among the benzimidazole derivatives having an MP PDE inhibitory action, there is a compound having a cell growth inhibitory action, and completed the present invention.

The compound of the present invention has a weak inhibitory effect on cAMP PDE and a selective strong inhibitory effect on cGMP PDE.

The compound of the present invention has a cell growth inhibitory action. In particular, it has a strong growth inhibitory effect on mesenchymal cells. The growth inhibitory effect on smooth muscle cells
The growth inhibitory effect (in vitro) on 10 cells was measured, and the effect was confirmed. Rat A10 cells are an established cell line derived from rat fetal thoracic aortic smooth muscle.
Exptl. Cell Ress., 98, (1976) pp. 349-365 (BWKimes an
d BLBrandt). The growth inhibitory effect on fibroblasts and mesangial cells was similarly measured using human fibroblasts or rat mesangial cells instead of rat A10 cells, and a strong inhibitory effect was observed. Current Prot
ocol in Immunology (ed.Coligan et al., (1991) Ch.3, p.12, [Will
y Interscience]), and the effect was confirmed. As described above, the compound of the present invention also has an immunosuppressive action based on the T cell proliferation suppressive action.

The compound of the present invention has a collagen synthesis and secretion inhibitory action. In other words, J. Clin. Invest., 83
Volume, (1989) pages 1160-1167 (K. Mackay et al.) By culturing human fibroblasts, Calcif.
t., 35, (1983) pages 542-548 (M. Kumegawa et al.), the effect of which was recognized by applying the assay method.

Further, the compound of the present invention has an anti-inflammatory effect. The anti-inflammatory effect when the compound of the present invention is used as an external preparation is described in Agents Actions, vol. 26, (1989) p. 319 (Carlson et al.
al.) (the experimental animals and the method of drug administration were partially modified. For details, see pharmacological test (6) for the description of the inhibitory effect of TPA-induced edema).

The fact that smooth muscle proliferation is a major cause of arteriosclerosis is described in Nature, Vol. 362, (1993), pp. 801-809 (Russell
Ross), and it has been reported that fibroblast proliferation and collagen synthesis and secretion are responsible for arteriosclerosis in Am. J. Pathol., 125, (1986) 191-207 (AMGow
n et al.). Eu.J. Clin., Invest., Volume 23, shows that smooth muscle tends to grow abnormally during diabetes.
(1993) pages 84-90 (M. Kawano et al.). Am. Rev. Respir. Dis., Vol. 138, (1988) 7 that fibroblast proliferation and collagen synthesis and secretion cause pulmonary fibrosis.
03-708 (G. Raghu et al.) And Therapeutics, 28, (1994) 62-6
It is described on page 6 (Toshihiko Sakai et al.). cGMP PDE
Tren inhibits platelet aggregation and is also effective in preventing or treating allergies, asthma, psoriasis, and thrombus
ds Phamacol.Sci., 12, (1991) 19-27 (CDNicholson
et al.), and that increasing cGMP reduces blood pressure is described in Circ. Res., 74, (1994) pp. 416-421 (A. Kol.
ler et al.), Molecular Medicine of Arteriosclerosis (ed. Kita Toru (1994) Yodosha), pp. 27-28 and 147-164.

From the above pharmacological actions of the compounds of the present invention, the compounds of the present invention can be used for the treatment of diseases involving cGMP, diseases involving proliferation of smooth muscle cells and fibroblasts, and diseases involving collagen synthesis and secretion. The present invention can be applied to the treatment and prevention of skin diseases involving immunity or inflammation. Examples of such diseases are restenosis after PTCA, after angioplasty and bypass surgery, arteriosclerotic diseases (eg angina, myocardial infarction, cerebral infarction, cerebrovascular dementia, TIA, peripheral circulatory insufficiency, diabetes Complications, atherosclerosis, arteriosclerosis, fibrous thickening of arteries, etc., and cell proliferative diseases other than arteriosclerotic diseases (eg, kidney disease, asthma, bronchitis, proliferative dermatitis, keloids,
Hypertrophic scars, limbus, etc.), pulmonary fibrosis, collagen disease, psoriasis, allergic diseases (especially atopic dermatitis, chronic contact dermatitis), other dermatitis, hypertension, organ damage due to high blood pressure, heart failure And cardiac hypertrophy.

The compound of the present invention can be administered orally or parenterally by administering an appropriate preparation as a pharmaceutical.
In the case of application to skin diseases, a method in which a preparation formulated for external use is directly applied to the affected area is also possible. When the compound of the present invention is applied as a topical drug to skin diseases,
J. Dermatol.Sci., Vol. 8, (1994), p. 54 (kitagaki et al.) And Agents Actions, Vol. 26, (1989) 3
Perform the experiment described on page 19 (Carlson et al.) (Partially modified with respect to experimental animals and drug administration method. For details, refer to pharmacological test (6) Description of inhibitory effect on TPA-induced edema described below). Confirmed by That the latter experimental system is a model of psoriasis is described in Models in Dermatology, 1, 50-5
It is described on page 8 (edited by HIMaibach, NJ Lowe [krager, Basel] 1985).

The compound of the present invention was tested using a rat carotid artery scraping model [Am. J. Pathol., 141, (1992) pp. 685-690 (U. Ze
ymer et al.), etc.] is effective not only in vitro but also in vivo.

The compound of the present invention can obtain a sufficient blood concentration necessary for the onset of the drug effect even when administered orally, and the blood concentration and the duration of action are extremely long. Can be reduced.

The compound of the present invention has a very weak effect on a rapid blood pressure lowering effect, a cardiac contractility-enhancing effect, a heart rate-increasing effect, etc. at a dose exhibiting a cGMP PDE inhibitory effect or a dose exhibiting a cell growth inhibitory effect. Has features.

The compounds of the present invention do not show strong toxicity even when used continuously for short or long periods.

The benzimidazole derivatives of the general formula (1) of the present invention include the compounds of the following various embodiments.

(1) R ¹ represents a hydrogen atom, R ² is the same as defined in the above formula (1), n represents 0,
A benzimidazole derivative represented by the general formula (1) or a salt thereof, wherein R ³ is an indolyl group (substituents of the indolyl group are the same as defined in the general formula (1)).

(2) R ¹ represents a hydrogen atom, R ² is the same as defined in the above formula (1), n represents 0,
R ³ is an indolinyl group (the substituent of the indolinyl group is
Same as the definition in the general formula (1). A) a benzimidazole derivative represented by the general formula (1) or a salt thereof.

(3) R ¹ is a hydrogen atom, R ² is the same as defined in the above formula (1), n is 0,
R ³ is a 1H-indazolyl group (substituents of the 1H-indazolyl group are the same as defined in the general formula (1))
A benzimidazole derivative represented by the above general formula (1) or a salt thereof.

(4) R ¹ represents a hydrogen atom, R ² has the same definition as in the above formula (1), n represents 0,
A benzimidazole derivative represented by the general formula (1) wherein R ³ is a 2 (1H) -quinolinonyl group (substituents of the 2 (1H) -quinolinonyl group are the same as defined in the general formula (1)) Or a salt thereof.

(5) R ¹ represents a hydrogen atom, R ² has the same definition as in the above formula (1), n represents 0,
R ³ is a 3,4-dihydro-2 (1H) -quinolinonyl group (substituents of the 3,4-dihydro-2 (1H) -quinolinonyl group are the same as defined in the general formula (1)). A benzimidazole derivative represented by the general formula (1) or a salt thereof.

(6) R ¹ represents a hydrogen atom, R ² is the same as defined in the above formula (1), n represents 0,
R ³ is a 3,4-dihydro-1,4 (2H) -benzoxazinyl group (the substituent of the 3,4-dihydro-1,4 (2H) -benzoxazinyl group is represented by the general formula ( A benzimidazole derivative represented by the general formula (1) or a salt thereof, which is the same as defined in 1).

(7) R ¹ is a halogen atom, R ² is the same as defined in the above formula (1), n is 0, R ³ is an indolyl group (the substituent of the indolyl group is
Same as the definition in the general formula (1). A) a benzimidazole derivative represented by the general formula (1) or a salt thereof.

(8) R ¹ is a halogen atom, R ² is the same as defined in the above formula (1), n is 0, R ³ is an indolinyl group (the substituent of the indolinyl group is A benzimidazole derivative represented by the general formula (1) or a salt thereof represented by the general formula (1).

(9) R ¹ is a halogen atom, R ² is the same as defined in the above formula (1), n is 0, and R ³ is 1H-indazolyl group (1H-indazolyl group) The substituent is the same as defined in the general formula (1).) A benzimidazole derivative represented by the general formula (1) or a salt thereof.

(10) R ¹ is a halogen atom, R ² is the same as defined in the above formula (1), n is 0, and R ³ is a 2 (1H) -quinolinonyl group (the 2 ( 1
The substituent of the H) -quinolinonyl group is the same as the definition in the general formula (1). A) a benzimidazole derivative represented by the general formula (1) or a salt thereof.

(11) R ¹ is a halogen atom, R ² is the same as defined in the above formula (1), n is 0, and R ³ is 3,4-dihydro-2 (1H)- A benzimidazole derivative represented by the general formula (1), which is a quinolinonyl group (substituents of the 3,4-dihydro-2 (1H) -quinolinonyl group are the same as defined in the general formula (1)), or a benzimidazole derivative thereof; salt.

(12) R ¹ is a halogen atom, R ² is the same as defined in the above formula (1), n is 0, and R ³ is 3,4-dihydro-1,4 (2H ) -Benzoxazinyl group (the 3,4-dihydro-1,4 (2
The substituents of the (H) -benzoxazinyl group are the same as defined in the general formula (1). The general formula (1)
Or a benzimidazole derivative represented by the formula:

(13) R ¹ is a hydrogen atom, R ² is the same as defined in the above formula (1), n is 1, R ³ is an indolyl group (the substituent of the indolyl group is
Same as the definition in the general formula (1). A) a benzimidazole derivative represented by the general formula (1) or a salt thereof.

(14) R ¹ is a hydrogen atom, R ² is the same as defined in the above formula (1), n is 1 and R ³ is an indolinyl group (the substituent of the indolinyl group is A benzimidazole derivative represented by the general formula (1), which is the same as the definition in the general formula (1), or a salt thereof.

(15) R ¹ is a hydrogen atom, R ² is the same as defined in the above formula (1), n is 1 and R ³ is a 1H-indazolyl group (for the 1H-indazolyl group) The substituent is the same as defined in the general formula (1).) A benzimidazole derivative represented by the general formula (1) or a salt thereof.

(16) R ¹ is a hydrogen atom, R ² is the same as defined in the above formula (1), n is 1 and R ³ is a 2 (1H) -quinolinonyl group (the 2 ( 1H)
The substituent of the -quinolinonyl group is the same as the definition in the general formula (1). A) a benzimidazole derivative represented by the general formula (1) or a salt thereof.

(17) R ¹ is a hydrogen atom, R ² is the same as defined in the above formula (1), n is 1 and R ³ is 3,4-dihydro-2 (1H)- A quinolinonyl group (substituents of the 3,4-dihydro-2 (1H) -quinolinonyl group are the same as defined in the general formula (1))
A benzimidazole derivative represented by the above general formula (1) or a salt thereof.

(18) R ¹ is a hydrogen atom, R ² is the same as defined in the above formula (1), n is 1 and R ³ is 3,4-dihydro-1,4 (2H ) -Benzoxazinyl group (the 3,4-dihydro-1,4 (2H)
The substituent of the -benzoxazinyl group is represented by the general formula (1)
Same as the definition in A) a benzimidazole derivative represented by the general formula (1) or a salt thereof.

(19) R ¹ is a halogen atom, R ² is the same as defined in the above formula (1), n is 1, R ³ is an indolyl group (the substituent of the indolyl group is A benzimidazole derivative represented by the general formula (1), which is the same as the definition in the general formula (1), or a salt thereof.

(20) R ¹ is a halogen atom, R ² is the same as defined in the above formula (1), n is 1, R ³ is an indolinyl group (the substituent of the indolinyl group is A benzimidazole derivative represented by the general formula (1) or a salt thereof represented by the general formula (1).

(21) R ¹ is a halogen atom, R ² is the same as defined in the above formula (1), n is 1 and R ³ is a 1H-indazolyl group (for the 1H-indazolyl group) The substituent is the same as defined in the general formula (1).) A benzimidazole derivative represented by the general formula (1) or a salt thereof.

(22) R ¹ is a halogen atom, R ² is the same as defined in the above formula (1), n is 1 and R ³ is 2 (1H) -quinolinonyl group (2 (1H) 1
The substituent of the H) -quinolinonyl group is the same as the definition in the general formula (1). A) a benzimidazole derivative represented by the general formula (1) or a salt thereof.

(23) R ¹ is a halogen atom, R ² is the same as defined in the above formula (1), n is 1 and R ³ is 3,4-dihydro-2 (1H)- A benzimidazole derivative represented by the general formula (1), which is a quinolinonyl group (substituents of the 3,4-dihydro-2 (1H) -quinolinonyl group are the same as defined in the general formula (1)), or a benzimidazole derivative thereof; salt.

(24) R ¹ is a halogen atom, R ² is the same as defined in the above formula (1), n is 1 and R ³ is 3,4-dihydro-1,4 (2H ) -Benzoxazinyl group (the 3,4-dihydro-1,4 (2
The substituents of the (H) -benzoxazinyl group are the same as defined in the general formula (1). The general formula (1)
Or a benzimidazole derivative represented by the formula:

(25) R ¹ , R ² , A and n are the same as defined in the above formula (1), and R ³ is an indolyl group [a group represented by -BR ⁴ ( B is a lower alkylene group; R ⁴ is a group having 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms;
To a 11-membered saturated or unsaturated monocyclic or dicyclic heterocyclic group (a group selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and an oxo group as a substituent on the heterocyclic ring) which may have 1 to 3) or a group -NR ⁵
R ⁶ (R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a lower alkyl group, a cycloalkyl group, a pyridylcarbonyl group, an isoxazolylcarbonyl group which may have 1 to 3 lower alkyl groups as substituents; And R ⁵ and R ⁶ represent a pyrrolylcarbonyl group or an amino-substituted lower alkyl group which may have a lower alkyl group as a substituent, and R ⁵ and R ⁶ together with a nitrogen atom to which they are bonded are linked via a nitrogen atom or an oxygen atom. Combined with each other without
A 6-membered saturated heterocyclic ring may be formed. The heterocyclic ring may have 1 to 3 groups selected from the group consisting of a hydroxyl group and a phenyl group as a substituent. ). A lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on the phenyl ring; a group selected from the group consisting of a halogen-substituted lower alkyl group and a lower alkoxycarbonyl-substituted lower alkyl group. May be provided for 1 to 3. ] And a benzimidazole derivative represented by the above general formula (1) or a salt thereof.

(26) R ¹ , R ² , A and n are the same as defined in the above formula (1), and R ³ is an indolinyl group [on the indolinyl group, a group -BR is substituted as a substituent.
⁴ (B is a lower alkylene group, R ⁴ is a 5- to 11-membered saturated or unsaturated mono- or dicyclic ring having 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms. A heterocyclic group (a halogen atom as a substituent on the heterocyclic ring,
May have from 1 to 3 groups selected from the group consisting of lower alkyl groups, lower alkoxy groups and oxo groups) or groups-
NR ⁵ R ⁶ (R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom,
It may have a lower alkyl group, a cycloalkyl group, a pyridylcarbonyl group, an isoxazolylcarbonyl group which may have 1 to 3 lower alkyl groups as a substituent, a pyrrolylcarbonyl group or a lower alkyl group as a substituent. Indicates an amino-substituted lower alkyl group. Also R ⁵ and R ⁶
Is defined as being bonded to each other with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded.
A 6- to 6-membered saturated heterocyclic ring may be formed. The heterocyclic ring may have 1 to 3 groups selected from the group consisting of a hydroxyl group and a phenyl group as a substituent. ). A lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on the phenyl ring; a group selected from the group consisting of a halogen-substituted lower alkyl group and a lower alkoxycarbonyl-substituted lower alkyl group. May be provided for 1 to 3. ] And a benzimidazole derivative represented by the above general formula (1) or a salt thereof.

(27) R ¹ , R ² , A and n are the same as defined in the above formula (1), and R ³ is a 1H-indazolyl group [1H-indazolyl group is represented by a group -B -R ⁴ (B is a lower alkylene group, R ⁴ is a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom;
A 5- to 11-membered, saturated or unsaturated, monocyclic or binomial heterocyclic group having 4 to 4 members (a group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and an oxo group as a substituent on the heterocyclic ring; May have 1 to 3 groups selected from)
Or a group -NR ⁵ R ⁶ (R ⁵ and R ⁶ are the same or different and each may have a hydrogen atom, a lower alkyl group, a cycloalkyl group, a pyridylcarbonyl group, or an iso group having 1 to 3 lower alkyl groups as a substituent. R ⁵ and R ⁶ represent an oxazolylcarbonyl group, a pyrrolylcarbonyl group or an amino-substituted lower alkyl group which may have a lower alkyl group as a substituent, and R ⁵ and R ⁶ represent a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded. A 5- to 6-membered saturated heterocyclic ring may be formed by bonding to each other with or without an atom, and a group selected from the group consisting of a hydroxyl group and a phenyl group as a substituent on the heterocyclic ring. May be provided.). A lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on the phenyl ring; a group selected from the group consisting of a halogen-substituted lower alkyl group and a lower alkoxycarbonyl-substituted lower alkyl group. May be provided for 1 to 3. ] And a benzimidazole derivative represented by the above general formula (1) or a salt thereof.

(28) R ¹ , R ² , A and n are the same as defined in the above formula (1), and R ³ is 2 (1H)-
A quinolinonyl group or 3,4-dihydro-2 (1H) -quinolinonyl group [2 (1H) -quinolinonyl group and 3,4
- dihydro -2 (IH) - Kinorinoniru group -B-R ⁴ as a substituent on the group (B is a lower alkylene group, R ⁴ is 1 hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom the group consisting of A 5- or 11-membered, saturated or unsaturated, monocyclic or dicyclic heterocyclic group having 4 (including a halogen atom, a lower alkyl group, a lower alkoxy group and an oxo group as a substituent on the heterocyclic ring) selected to the 1-3 has may be) or a group -NR ⁵ R ⁶ (R ⁵ and R ⁶ groups represent a hydrogen atom, a lower alkyl group, a cycloalkyl group,
A pyridylcarbonyl group, an isoxazolylcarbonyl group which may have 1 to 3 lower alkyl groups as a substituent, a pyrrolylcarbonyl group or an amino-substituted lower alkyl group which may have a lower alkyl group as a substituent. R ⁵ and R ⁶ may be combined with each other via a nitrogen atom or an oxygen atom together with or without a nitrogen atom to which they are bonded to form a 5- to 6-membered saturated heterocyclic ring. The heterocyclic ring may have 1 to 3 groups selected from the group consisting of a hydroxyl group and a phenyl group as a substituent. )
Is shown. A lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on the phenyl ring; a group selected from the group consisting of a halogen-substituted lower alkyl group and a lower alkoxycarbonyl-substituted lower alkyl group. May be provided for 1 to 3. ] And a benzimidazole derivative represented by the above general formula (1) or a salt thereof.

(29) R ¹ , R ² , A and n are the same as defined in the above formula (1), and R ³ is a 3,4-dihydro-1,4 (2H) -benzooxazinyl group [3,4
On the -dihydro-1,4 (2H) -benzoxazinyl group, as a substituent, a group -BR ⁴ (B is a lower alkylene group, and R ⁴ is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom A 5- to 11-membered saturated or unsaturated monocyclic or dicyclic heterocyclic group having 1 to 4 heteroatoms (a halogen atom, a lower alkyl group, a lower alkoxy group, A group selected from the group consisting of
3 may have) or a group -NR ⁵ R ⁶ (R ⁵ and R ⁶
Are the same or different and are a hydrogen atom, a lower alkyl group, a cycloalkyl group, a pyridylcarbonyl group, an isoxazolylcarbonyl group, a pyrrolylcarbonyl group or a substituent group which may have 1 to 3 lower alkyl groups as a substituent. Represents an amino-substituted lower alkyl group which may have a lower alkyl group. R ⁵ and R ⁶ may be combined with each other via a nitrogen atom or an oxygen atom together with or without a nitrogen atom to which they are bonded to form a 5- to 6-membered saturated heterocyclic ring. The heterocyclic ring may have 1 to 3 groups selected from the group consisting of a hydroxyl group and a phenyl group as a substituent. ). A lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on the phenyl ring;
A group selected from the group consisting of a halogen-substituted lower alkyl group and a lower alkoxycarbonyl-substituted lower alkyl group,
You may have one. ] And a benzimidazole derivative represented by the above general formula (1) or a salt thereof.

(30) The benzimidazole derivative or a salt thereof according to the above (25), wherein R ¹ is a hydrogen atom and n is 0.

(31) The benzimidazole derivative or a salt thereof according to the above (25), wherein R ¹ is a hydrogen atom and n is 1.

(32) The benzimidazole derivative or a salt thereof according to the above (25), wherein R ¹ is a halogen atom and n is 0.

(33) The benzimidazole derivative or a salt thereof according to the above (25), wherein R ¹ is a halogen atom and n is 1.

(34) The benzimidazole derivative or a salt thereof according to the above (26), wherein R ¹ is a hydrogen atom and n is 0.

(35) The benzimidazole derivative or a salt thereof according to the above (26), wherein R ¹ is a hydrogen atom and n is 1.

(36) The benzimidazole derivative or a salt thereof according to the above (26), wherein R ¹ is a halogen atom and n is 0.

(37) The benzimidazole derivative or a salt thereof according to the above (26), wherein R ¹ is a halogen atom and n is 1.

(38) The benzimidazole derivative or a salt thereof according to the above (27), wherein R ¹ is a hydrogen atom and n is 0.

(39) The benzimidazole derivative or a salt thereof according to the above (27), wherein R ¹ is a hydrogen atom and n is 1.

(40) The benzimidazole derivative or a salt thereof according to the above (27), wherein R ¹ is a halogen atom and n is 0.

(41) The benzimidazole derivative or a salt thereof according to the above (27), wherein R ¹ is a halogen atom and n is 1.

(42) The benzimidazole derivative or a salt thereof according to the above (28), wherein R ¹ is a hydrogen atom and n is 0.

(43) The benzimidazole derivative or a salt thereof according to the above (28), wherein R ¹ is a hydrogen atom and n is 1.

(44) The benzimidazole derivative or a salt thereof according to the above (28), wherein R ¹ is a halogen atom and n is 0.

(45) The benzimidazole derivative or a salt thereof according to the above (28), wherein R ¹ is a halogen atom and n is 1.

(46) The benzimidazole derivative or a salt thereof according to the above (29), wherein R ¹ is a hydrogen atom and n is 0.

(47) The benzimidazole derivative or a salt thereof according to the above (29), wherein R ¹ is a hydrogen atom and n is 1.

(48) The benzimidazole derivative or a salt thereof according to the above (29), wherein R ¹ is a halogen atom and n is 0.

(49) The benzimidazole derivative or a salt thereof according to the above (29), wherein R ¹ is a halogen atom and n is 1.

(50) When the 5- to 11-membered saturated or unsaturated monocyclic or dicyclic heterocyclic group represented by R ⁴ is pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, pyridyl, homopiperazinyl, , 2,
5,6-tetrahydropyridyl, thienyl, quinolyl,
1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl, pyridazyl, pyrrolyl, carbostyril, 3,4-dihydrocarbostyril, 1,2,3,4
-Tetrahydroquinolyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, benzoxazolyl, imidazolidinyl, isoquinolyl, quinazolidinyl, 1,2-dihydroisoquinolyl, 1,2,3,4
-Tetrahydroisoquinolyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,2,3,4-tetrazolyl, 1,2,4-triazolyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl, imidazolyl, pyrazolidinyl, imidazo [1,2-a] Pyridyl, benzofuryl, 2,3-dihydrobenzo [b] furyl, benzothienyl, 1-azacycloheptyl, 4H-
Chromenil, 1H-indazolyl, 2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, pyranyl, pyrazolidinyl, 2-pyrazolinyl,
Quinuclidinyl, 1,4-benzoxazinyl, 3,4
-Dihydro-2H-1,4-benzoxazinyl, 3,
4-dihydro-2H-1,4-benzothiazinyl, 1,
4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dithia-2,4-dihydronaphthalenyl, tetrahydro-1,3-oxazinyl, tetrahydrooxazolyl or 1,4 -The benzimidazole derivative or a salt thereof according to any one of the above (30) to (49), which is a dithianaphthalenyl group.

(51) The benzimidazole derivative or a salt thereof according to the above (30) to (49), wherein the heterocyclic group represented by R ⁴ is an imidazolyl, pyrazolyl or 1,2,4-triazolyl group.

(52) When the group represented by R ⁴ is a group NR ⁵ R ⁶
Benzimidazole derivative or a salt thereof according to the (30) ~ (49) (R ⁵ and R ⁶ are the same. As defined in the general formula (1)) is.

(53) 1-benzyl-6-chloro-2-
{1- [3- (Imidazol-1-yl) propyl] indol-5-ylaminocarbonyl} benzimidazole.

(54) 1-benzyl-6-chloro-2-
{1- [3- (N-Cyclohexyl-N-methylamino) propyl] indol-5-ylaminocarbonyl} benzimidazole.

(55) 1-benzyl-6-chloro-2-
{1- [3- (Pyrazol-1-yl) propyl] indol-5-ylaminocarbonyl} benzimidazole.

(56) 1-benzyl-6-chloro-2-
{1- [3- (1,2,4-triazol-1-yl)
Propyl] indol-5-ylaminocarbonyl {benzimidazole.

(57) 1-benzyl-6-chloro-2-
{1- [3- (3,5-dimethylisoxazole-4)
-Ylcarbonylamino) propyl] indole-5-
Ilaminocarbonyl @ benzimidazole.

(58) 1-benzyl-6-chloro-2-
{1- [3- (4-Phenyl-4-hydroxy-1-piperidin-1-yl) propyl] indol-5-ylaminocarbonyl} benzimidazole.

(59) 1-benzyl-6-chloro-2-
{4-} 3- (pyridin-2-ylcarbonylamino)
Propyl] -3,4-dihydro-1,4 (2H) -benzoxazin-7-ylaminocarbonyl {benzimidazole.

Each group represented by the above general formula (1) is more specifically as follows.

Examples of the halogen atom include a fluorine atom,
Examples include a chlorine atom, a bromine atom and an iodine atom.

Examples of the phenyl lower alkyl group include benzyl, 2-phenylethyl, 1-phenylethyl,
3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1,1-dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl, diphenylmethyl, 2,2-diphenylethyl group Is a linear or branched alkyl group having 1 to 6 carbon atoms, and an alkyl group having 1 to 2 phenyl groups.

Examples of the lower alkylene group include methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene C1 of group etc.
To 6 linear or branched alkylene groups.

A nitrogen atom, an oxygen atom or a sulfur atom
Examples of the saturated or unsaturated 5- to 11-membered monocyclic or dimeric heterocyclic group having 5 to 11 members include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino,
Pyridyl, homopiperazinyl, 1,2,5,6-tetrahydropyridyl, thienyl, quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl, pyridazyl, pyrrolyl, carbostyryl, 3,4-
Dihydrocarbostyril, 1,2,3,4-tetrahydroquinolyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, benzoxazolyl, imidazolidinyl, isoquinolyl, quinazolidinyl, 1,2-
Dihydroisoquinolyl, 1,2,3,4-tetrahydroisoquinolyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,2,3,4-tetrazolyl, 1,2,4-
Triazolyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl, imidazolyl, pyrazolidinyl, imidazo [1,2-a] pyridyl, benzofuryl,
2,3-dihydrobenzo [b] furyl, benzothienyl, 1-azacycloheptyl, 4H-chromenyl, 1H
-Indazolyl, 2-imidazolinyl, 2-pyrolinyl, furyl, oxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, pyranyl,
Pyrazolidinyl, 2-pyrazolinyl, quinuclidinyl,
1,4-benzoxazinyl, 3,4-dihydro-2H
-1,4-benzoxazinyl, 3,4-dihydro-2
H-1,4-benzothiazinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl,
Examples thereof include 1,3-dithia-2,4-dihydronaphthalenyl, tetrahydro-1,3-oxazinyl, tetrahydrooxazolyl, and 1,4-dithianaphthalenyl groups.

The heterocyclic ring having 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom and an oxo group includes, for example, 1-oxo-1,
2,3,4-tetrahydroisoquinolyl, 2-oxopiperidinyl, 2-oxo-1-azacycloheptyl, 2
-Oxopyrrolidinyl, 1,3-dioxoisoindolinyl, 2,4-dioxoimidazolidinyl, 2-oxooxazolidinyl, 1-methylimidazolyl, 1-propylimidazolyl, 4-methylimidazolyl, 5 , 6-
Dimethylbenzimidazolyl, 1,4-dimethylpyrrolyl, 2-isopropylimidazolyl, 4-methylpiperazinyl, 4-phenylpiperidinyl, 4-methylthiazolyl, 2-oxothiazolyl, 5-ethylthiazolyl,
4-phenylthiazolyl, 4-propylthiazolyl, 5
-Butylthiazolyl, 4-pentylthiazolyl, 2-hexylthiazolyl, 3,5-dimethylisoxazolyl, 4,5-dimethylthiazolyl, 5-methoxy-4-
Methylthiazolyl, 1-ethylimidazolyl, 4-propylimidazolyl, 5-butylimidazolyl, 1-pentylimidazolyl, 1-hexylimidazolyl, 1,4
-Dimethylimidazolyl, 1,4,5-trimethylimidazolyl, 1-methoxyimidazolyl, 2-ethoxyimidazolyl, 5-propoxyimidazolyl, 1-methyl-4-chloroimidazolyl, 4,5-dichloroimidazolyl, 3-methyl-1, 2,4-triazolyl, 5-ethyl-1,2,4-triazolyl, 3-methyl-1,
2,4-triazolyl, 2-oxo-1-methylimidazolyl, 2-oxoimidazolyl, 2-ethylpyrrolyl, 3-propylpyrrolyl, 5-butylpyrrolyl, 4-
Pentylpyrrolyl, 2-hexylpyrrolyl, 2,4,5
-Trimethylpyrrolyl, 2-bromopyrrolyl, 2,5-
Dibromopyrrolyl, 2-methyl-5-methoxypyrrolyl, 2-oxopyrrolyl, 1-methyl-1,2,3,4
-Tetrazolyl, 1-isopropyl-1,2,3,4-
Tetrazolyl, 1-ethyl-1,2,3,4-tetrazolyl, 1-propyl-1,2,3,4-tetrazolyl,
1-butyl-1,2,3,4-tetrazolyl, 1-pentyl-1,2,3,4-tetrazolyl, 1-hexyl-
1,2,3,4-tetrazolyl, 5-methoxyindolyl, 2-methylpyridyl, 3-ethylpyridyl, 4-propylpyridyl, 2-butylpyridyl, 3-pentylpyridyl, 4-hexylpyridyl, 2-methoxypyridyl , 3-phenylpyridyl, 4-phenylpyridyl,
2,4-dimethylpyridyl, 2,4,6-trimethylpyridyl, 2-methyl-4-chloropyridyl, 2,4-difluoropyridyl, 2,4,6-trichloropyridyl,
2-oxopyridyl, 4-oxopyridyl, 4-methyl-2-oxopyridyl, 2-chloro-4-oxopyridyl, 3-methylimidazo [1,2-a] pyridyl, 4-
Ethyl imidazo [1,2-a] pyridyl, 3-methoxyimidazo [1,2-a] pyridyl, 5-chloroimidazo [1,2-a] pyridyl, 3-methyl-1H-indazolyl, 3-iodo-1H -Indazolyl, 1-methyl-
1,2,3,4-tetrahydroisoquinolyl, 5-ethyl-1,2,3,4-tetrahydroisoquinolyl, 6-
Bromo-1,2,3,4-tetrahydroisoquinolyl,
1-oxo-6-methyl-1,2,3,4-tetrahydroisoquinolyl, 1-oxo-7-methoxy-1,2,2,
3,4-tetrahydroisoquinolyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 1-methylpyrrolidinyl, 3,4,5-
Trimethylpiperidinyl, 4-butylpiperidinyl, 3
-Pentylmorpholino, 4-hexylpiperazinyl, 3
-Methylthiomorpholino, 3-chloropyrrolidinyl, 2
-Oxo-4-methylpiperidinyl, 2-oxo-3-
Methylpyrrolidinyl, 2-oxo-4-fluoropiperidinyl, 4-methyl-1-azacycloheptyl, 5-methoxy-1-azacycloheptyl, 6-methyl-2-oxo-1-azacycloheptyl, 1-methyl-2-oxoimidazolidinyl, 1-isobutyl-2-oxoimidazolidinyl, 1-methyl-2-oxoimidazolidinyl, 2-oxotetrahydro-1,3-oxazinyl,
3-bromo-2-oxo-1-azacycloheptyl, 2
-Oxotetrahydrooxazolyl, 3-chloropyridyl, 4-methylpiperazinyl, 4-isobutylpiperazinyl, 4-methylhomopiperazinyl, 3-chloropiperazinyl, 4-methoxypiperazinyl, 4- Selected from the group consisting of linear or branched alkyl groups having 1 to 6 carbon atoms such as ethyl homopiperazinyl group, linear or branched alkoxy groups having 1 to 6 carbon atoms, halogen atoms and oxo groups. The heterocyclic group having 1 to 3 groups described above can be exemplified.

Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups. it can.

As the lower alkyl group, for example, methyl,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms, such as ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups.

Examples of the cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.

As the isoxazolylcarbonyl group which may have 1 to 3 lower alkyl groups as the substituent, for example, isoxazolylcarbonyl, 3,5-dimethylisoxazolylcarbonyl, 3-methylisoxaylcarbonyl Zolylcarbonyl, 4-ethylisoxazolylcarbonyl, 5-propylisoxazolylcarbonyl, 3
Straight chain having 1 to 6 carbon atoms such as -butylisoxazolylcarbonyl, 4-pentylisoxazolylcarbonyl, 5-hexylisoxazolylcarbonyl, 3,4,5-trimethylisoxazolylcarbonyl group or Examples include isoxazolylcarbonyl groups which may have 1 to 3 branched alkyl groups.

The amino-substituted lower alkyl group which may have a lower alkyl group as a substituent includes, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl,
-Aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2 -Propylaminoethyl, 3-isopropylaminopropyl, 4-
Butylaminobutyl, 5-pentylaminopentyl, 6
Hexylaminohexyl, dimethylaminomethyl, 2
-Diethylaminoethyl, 2-dimethylaminoethyl,
(N-ethyl-N-propylamino) methyl, 2- (N
-Methyl-N-hexylamino) ethyl group as a substituent such as a straight-chain or branched alkyl group having 1 to 6 carbon atoms.
Examples thereof include a linear or branched alkyl group having 1 to 6 carbon atoms and having two amino groups.

Examples of the 5- or 6-membered saturated heterocyclic group formed by bonding together with or without a nitrogen atom or an oxygen atom together with a nitrogen atom to which R ⁵ and R ⁶ are bonded include pyrrolidinyl, piperidinyl, Examples include piperazinyl and morpholino groups.

Examples of the above heterocyclic group in which 1 to 3 groups selected from the group consisting of a hydroxyl group and a phenyl group are substituted include, for example,
4-phenyl-4-hydroxypiperidinyl, 4-phenylpiperazinyl, 3-phenylpiperazinyl, 3-hydroxypyrrolidinyl, 4-hydroxypiperazinyl,
3-phenylmorpholino, 2,4-diphenylpiperazinyl, 3-phenylpyrrolidinyl, 2,3,4-triphenylpiperazinyl, 3-hydroxymorpholino, 2-hydroxymorpholino
Phenyl-2-hydroxymorpholino, 3-phenyl-
Examples of the above-mentioned heterocyclic group in which 1 to 3 groups selected from the group consisting of a hydroxyl group such as a 3-hydroxypiperazinyl group and a phenyl group are substituted.

Examples of the lower alkenyl group include straight-chain or branched alkenyl having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl and 2-hexenyl. Groups.

Examples of the lower alkoxycarbonyl group include linear groups having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl. Or a branched alkoxycarbonyl group.

Examples of the phenoxy lower alkyl group which may have a cyano group as a substituent on the phenyl ring include phenoxymethyl, 2-phenoxyethyl, 1-phenoxyethyl, 4-phenoxybutyl, 5-phenoxypentyl, -Phenoxyhexyl, 1,1-dimethyl-2-phenoxyethyl, 2-methyl-3-phenoxypropyl, (2-cyanophenoxy) methyl, 2- (2
-Cyanophenoxy) ethyl, 3-phenoxypropyl, 4- (3-cyanophenoxy) butyl, 5- (2-
(Cyanophenoxy) pentyl, 6- (3-cyanophenoxy) hexyl, (4-cyanophenoxy) methyl, 3
-(2-cyanophenoxy) propyl, 3- (3-cyanophenoxy) propyl, 1- (3-cyanophenoxy) ethyl, 3- (3,4-dicyanophenoxy) propyl, 2- (3,4,5- A cyano group as a substituent on a phenyl ring such as tricyanophenoxy) ethyl group;
Examples thereof include a phenoxy group-substituted linear or branched alkyl group having 1 to 6 carbon atoms.

Examples of the halogen-substituted lower alkyl group include trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2
-Trichloroethyl, 3-bromopropyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5 Examples of the substituent such as -bromohexyl, 5,6-dichlorohexyl and the like include a straight-chain or branched-chain alkyl group having 1 to 3 halogen atoms and 1 to 6 carbon atoms.

The lower alkyl group substituted with a lower alkoxycarbonyl group includes, for example, methoxycarbonylmethyl, 3
-Methoxycarbonylpropyl, ethoxycarbonylmethyl, 3-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 5-isopropoxycarbonylpentyl, 6-propoxycarbonylhexyl, 1,1-dimethyl-2-butoxycarbonylethyl, 2-methyl-
An alkoxycarbonyl moiety such as 3-tert-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl, hexyloxycarbonylmethyl group has 1 to 1 carbon atoms.
A straight-chain or branched-chain alkoxycarbonylalkyl group having 1 to 6 carbon atoms, which is a straight-chain or branched-chain alkoxycarbonyl group of 6 can be exemplified.

The compound of the present invention can be produced by various methods.

[0098]

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Wherein R ¹ , R ² , R ³ , A and n are as defined above. The method represented by the reaction formula-1 is a method in which a benzimidazole compound (carboxylic acid) of the general formula (2) and an amine of the general formula (3) are reacted by a usual amide bond formation reaction. Known conditions for the amide bond formation reaction can be easily applied to the acid amide bond formation reaction. For example, (a) a mixed acid anhydride method, that is, a method in which an alkylhalocarbonate is reacted with a carboxylic acid (2) to form a mixed acid anhydride, and this is reacted with an amine (3); The acid (2) is converted to p-nitrophenyl ester, N-
A method in which an active ester such as hydroxysuccinimide ester or 1-hydroxybenzotriazole ester is used and reacted with the amine (3); (c) a carbodiimide method, that is, the amine (3) is converted from the carboxylic acid (2) to dicyclohexylcarbodiimide; A method of performing a condensation reaction in the presence of an activator such as carbonyldiimidazole, and (d) other methods, for example, converting carboxylic acid (2) into a carboxylic anhydride with a dehydrating agent such as acetic anhydride, and adding amine (3) A method of reacting an amine (3) with an ester of a carboxylic acid (2) and a lower alcohol at an elevated temperature,
Examples thereof include a method of reacting an acid halide of a carboxylic acid (2), that is, a carboxylic acid halide with an amine (3).

The mixed acid anhydride used in the above mixed acid anhydride method (a) is obtained by a reaction similar to the usual Schotten-Baumann reaction, and this is usually reacted with the amine (3) without isolation. Thereby, the compound of the present invention of the general formula (1) is produced. The Schotten-Baumann reaction is performed in the presence of a basic compound. Examples of the basic compound used include compounds commonly used in the Schotten-Baumann reaction, such as triethylamine, trimethylamine, pyridine, dimethylaniline, 1-methyl-2-pyrrolidinone (NMP), N-methylmorpholine, 1,5
-Diazabicyclo [4.3.0] nonene-5 (DB
N), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), 1,4-diazabicyclo [2.2.
2] Organic bases such as octane (DABCO), and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. The reaction is usually
The reaction is carried out at about 20 to 100 ° C, preferably about 0 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and the amine (3) is usually performed at about -20 to 150 ° C, preferably about 10 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably 5 minutes to 5 hours. It is about 5 hours. The mixed anhydride method is generally performed in a solvent. As the solvent used, any of the solvents commonly used in the mixed acid anhydride method can be used, and specifically, chloroform, dichloromethane, halogenated hydrocarbons such as dichloroethane, and the like,
Aromatic hydrocarbons such as benzene, p-chlorobenzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dimethoxyethane; esters such as methyl acetate and ethyl acetate; N, N-dimethylformamide, dimethyl Examples include aprotic polar solvents such as sulfoxide, acetonitrile, and hexamethylphosphoric triamide, and mixed solvents thereof. Examples of the alkyl halocarbonate used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate. The ratio of the carboxylic acid (2), the alkyl halocarbonate and the amine (3) to be used in the method is usually preferably equimolar, but the alkyl halocarbonate and the carboxylic acid (2) are used with respect to the amine (3). Each can be used in the range of about 1 to 1.5 times the molar amount.

When the method of reacting a carboxylic acid halide with an amine (3) is employed among the other methods (d), the reaction is carried out in a suitable solvent in the presence of a basic compound. As the basic compound to be used, known compounds can be widely used.For example, in addition to the basic compound used for the above-mentioned Schotten-Baumann reaction, for example, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like can be used. Can be illustrated. Examples of the solvent used include, in addition to the solvent used in the mixed acid anhydride method, alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve; pyridine; Acetone, water and the like can be exemplified. The ratio of the amine (3) and the carboxylic acid halide to be used is not particularly limited and can be appropriately selected within a wide range. Usually, the latter is at least about equimolar, preferably about equimolar to about 5 times the molar amount of the former. Good to use. The reaction is carried out usually at about -20 to 180 ° C, preferably at about 0 to 150 ° C, generally for 5 minutes to
The reaction is completed in about 30 hours.

Further, in the amide bond forming reaction shown in the above reaction formula-1, the carboxylic acid (2) and the amine (3) are reacted with phenylphosphine-2,2'-dithiodipyridine, diphenylphosphinyl chloride, phenyl- N-phenylphosphoramide chloridate, diethyl chlorophosphate,
It can also be carried out by a method in which the reaction is carried out in the presence of a condensing agent for a phosphorus compound such as diethyl cyanophosphate, azide diphenylphosphate, bis (2-oxo-3-oxazolidinyl) phosphinic chloride.

The reaction is usually carried out at about -20 to 150 ° C., preferably about 0 to 100 ° C., in the presence of a solvent and a basic compound used in the method for reacting the carboxylic acid halide with the amine (3). And generally takes 5 minutes to
The reaction is completed in about 30 hours. The amount of the condensing agent and the amount of the carboxylic acid (2) to be used are at least about an equimolar amount, and preferably about an equimolar to about 2 times the molar amount of the amine (3).

The reaction of carboxylic acid (2) with an ester of a lower alcohol and an amine (3) in the presence or absence of a basic compound in the absence or presence of a solvent can also be carried out in the above-mentioned reaction formula-1. The indicated reaction is performed. This reaction is carried out usually at room temperature to 200 ° C., preferably at room temperature to 12 ° C.
The reaction is generally completed at about 0 ° C. in about 30 minutes to 5 hours. The amount of the amine (3) used is at least 0.5 times, preferably 0.5 to 3 times the molar amount of the ester of the carboxylic acid (2) and the lower alcohol. As the solvent in this reaction, any of the solvents used in the method of reacting the amine (3) with the carboxylic acid halide can be used. As the basic compound, any of the basic compounds used in the method of reacting the carboxylic acid halide with the amine (3) can be used, and further, sodium methylate, sodium ethylate, potassium methylate, potassium Alkali metal alcoholates such as ethylate can also be used.

After reacting a condensing agent such as an aluminum compound such as lithium aluminum hydride and trimethylaluminum with an amine (3) in a suitable solvent, the carboxylic acid (2) is reacted with an ester of a lower alcohol. By doing so, the reaction represented by the above reaction formula-1 is performed. As the solvent used here, for example, dioxane, diethyl ether, diglyme, ethers such as tetrahydrofuran, benzene, toluene, aromatic hydrocarbons such as xylene, cyclohexane, heptane, aliphatic hydrocarbons such as hexane and the like, These mixed solvents can be exemplified. The amount of the amine (3) to be used is at least equimolar, preferably equimolar to 5 times the molar amount of the ester of the carboxylic acid (2) and the lower alcohol. The amount of the condensing agent used is at least equimolar to the ester of the carboxylic acid (2) and the lower alcohol, preferably from equimolar to 1.5 times the molar amount. In the reaction between the condensing agent and the amine (3), the reaction is usually carried out at -8.
The reaction proceeds around 0 to 100 ° C., and generally takes 30 minutes to 20 minutes.
The reaction is completed in about an hour. In the subsequent reaction of the ester of the carboxylic acid (2) with a lower alcohol, the reaction is usually carried out at room temperature to 200 ° C., preferably at room temperature to 1
The reaction proceeds at about 50 ° C., and the reaction is generally completed in about 1 to 10 hours.

[0106]

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[Wherein R ¹ , R ² , A and n are the same as above. R ^3a is a group —BR ⁴ (B and R ⁴ are as defined above) as a substituent; a lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on a phenyl ring. A heterocyclic group represented by R ³ having 1 to 2 groups selected from the group consisting of a halogen-substituted lower alkyl group and a lower alkoxycarbonyl-substituted lower alkyl group, and having a heterocyclic group —NH—. . R ^3b represents a group —BR ⁴ (B and R ⁴
The same as above); lower alkenyl group; lower alkoxycarbonyl group; phenoxy lower alkyl group which may have a cyano group as a substituent on the phenyl ring; halogen-substituted lower alkyl group and lower alkoxycarbonyl-substituted lower alkyl group It may have one or two selected groups, and the group -N (R ⁷ )-(R ⁷
-R ⁴ (B and R ⁴ have the same meanings as defined above); a lower alkenyl group;
A lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on the phenyl ring; a halogen-substituted lower alkyl group or a lower alkoxycarbonyl-substituted lower alkyl group. Is a heterocyclic group of R ³ having the above formula (1). X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group. Here, specific examples of the lower alkanesulfonyloxy group include methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, isopropanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy, and hexanesulfonyloxy. And the like. As the arylsulfonyloxy group, specifically, phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-
Examples thereof include a substituted or unsubstituted arylsulfonyloxy group such as methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-naphthylsulfonyloxy group. As the aralkylsulfonyloxy group, specifically, benzylsulfonyloxy, 2-phenylethylsulfonyloxy,
4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, α-naphthylmethylsulfonyloxy group, etc. Or an unsubstituted aralkylsulfonyloxy group.

The reaction between compound (1a) and compound (4)
In general, the reaction is performed in a suitable inert solvent in the presence or absence of a basic compound. Examples of the inert solvent used include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethylene glycol dimethyl ether; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; methanol and ethanol. , Isopropanol,
Examples thereof include lower alcohols such as butanol and tert-butanol, acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, and a mixed solvent thereof. Examples of the basic compound include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, carbonates such as potassium hydrogen carbonate, sodium hydroxide, metal hydroxides such as potassium hydroxide, sodium hydride, potassium, sodium, sodium amide, and the like. Sodium methylate, metal alcoholates such as sodium ethylate, pyridine, N-ethyldiisopropylamine,
Dimethylaminopyridine, triethylamine, 1,5-
Diazabicyclo [4.3.0] nonene-5 (DBN),
1,8-diazabicyclo [5.4.0] undecene-7
(DBU) and organic bases such as 1,4-diazabicyclo [2.2.2] octane (DABCO). The ratio of the compound (1a) to the compound (4) is not particularly limited and may be appropriately selected in a wide range. The amount of the latter is at least about equimolar, preferably about 10 to 10 times the amount of the former. It is better to use about the amount. The reaction is usually carried out at about 0 to 200 ° C., preferably about 0 to 170 ° C., and is completed generally in about 30 minutes to 75 hours. An alkali metal halide such as sodium iodide and potassium iodide, copper powder and the like may be added to the reaction system.

[0109]

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Wherein R ¹ , R ² , A and n are as defined above. R ^3c represents a group —BR ⁴ (B and R ⁴ are as defined above) as a substituent; a lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on a phenyl ring. May have one or two groups selected from the group consisting of a halogen-substituted lower alkyl group and a lower alkoxycarbonyl-substituted lower alkyl group, and a heterocyclic group -N (R ⁹ )-(R ⁹ is a halogen-substituted lower group; R ^{3 represents} a heterocyclic group having an alkyl group). R ^3d is a group —BR ⁴ (B and R ⁴ are the same as above) as a substituent; a lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on a phenyl ring. ; it may have one to two halogen-substituted lower alkyl group and a lower alkoxycarbonyl-substituted lower alkyl group comprising a group selected from the group, and heterocyclic in group ^{-N (R 10) - (R} 10 is a group -B −
R ⁴ (B and R ⁴ are as defined above) or a phenoxy lower alkyl group which may have a cyano group as a substituent on the phenyl ring. Is a heterocyclic group of R ³ having the above formula (1). R ⁸ is a group -R ^4a (R ^4a is the R ⁴ heterocyclic group or a group defined by -NR ⁵ R ⁶ (R ⁵ and R ⁶ having at least one group -N <in the heterocyclic ring in the The same)) or a phenoxy group which may have a cyano group as a substituent on the phenyl ring. The reaction between the compound (1c) and the compound (5) is carried out under the same reaction conditions as the reaction between the compound (1a) and the compound (4) in the above Reaction Scheme-2.

[0111]

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[Wherein R ¹ , R ² , A and n are the same as above. R ^3e is a group —BR ⁴ (B and R ⁴ are the same as above) as a substituent; a lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on a phenyl ring. May have one or two groups selected from the group consisting of a halogen-substituted lower alkyl group and a lower alkoxycarbonyl-substituted lower alkyl group, and a heterocyclic group -N (R ¹⁵ )-(R ¹⁵ is a phthalimido-substituted lower group; R ^{3 represents} a heterocyclic group having an alkyl group). R ^3f is a group —BR ⁴ (B and R ⁴ are as defined above) as a substituent; a lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on a phenyl ring. A halogen-substituted lower alkyl group or a lower alkoxycarbonyl-substituted lower alkyl group may have 1 to 2 groups, and a heterocyclic group -N (R ¹⁶ )-(R ¹⁶ is an amino-substituted lower group; R ³ having an alkyl group.)
Represents a heterocyclic group. R ^3g represents a group -BR as a substituent
⁴ (B and R ⁴ are the same as above); lower alkenyl group; lower alkoxycarbonyl group; phenoxy lower alkyl group which may have a cyano group as a substituent on a phenyl ring; halogen-substituted lower alkyl group and lower alkoxycarbonyl substitution A group selected from the group consisting of lower alkyl groups
To 2 and a heterocyclic group -N (B-N
R ^5a R ¹¹ )-(B is the same as above. R ^5a is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a pyridylcarbonyl group, or isoxazolyl which may have 1 to 3 lower alkyl groups as substituents. R ¹¹ represents an amino-substituted lower alkyl group which may have a lower alkyl group as a carbonyl group, a pyrrolylcarbonyl group or a substituent, and R ¹¹ is a lower alkyl group, a cycloalkyl group or an amino group which may have a lower alkyl group as a substituent. R ³ represents a substituted lower alkyl group.). R ^3h is a group —BR ⁴ (B and R ⁴ are the same as above) as a substituent; a lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on a phenyl ring. ; may have one to two halogen-substituted lower alkyl group and a lower alkoxycarbonyl-substituted lower alkyl group comprising a group selected from the group, and heterocyclic in group ^{-N (B-NR 5a R 14} ) - (B and R ^5a same .R to above ¹⁴ pyridylcarbonyl group, benzisoxazolyl carbonyl or which may have 1 to 3 lower alkyl groups as a substituent of the R ³ having a.) showing a pyrrolyl group Shows a heterocyclic group. R ¹² and R ¹³ each represent a hydrogen atom or a lower alkyl group. The reaction for converting the compound (1e) into the compound (1f) can be carried out by reacting the compound (1e) with hydrazine or hydrolyzing the compound (1e) in a suitable solvent. As a solvent used in the reaction of hydrazine, the same solvent as used in the reaction between compound (1a) and compound (4) in the above-mentioned reaction formula-2 can be used in addition to water. The reaction is carried out usually at room temperature to about 120 ° C., preferably at 0 to 100 ° C.
C., and is generally completed in about 0.5 to 15 hours. The amount of hydrazine to be used is at least about an equimolar amount, preferably about equimolar to about 5-fold molar amount, relative to compound (1e).

The hydrolysis reaction can be carried out in a suitable solvent or without a solvent in the presence of an acid or a basic compound. As the solvent used, for example, water, methanol, ethanol, lower alcohols such as isopropanol, acetone, ketones such as methyl ethyl ketone,
Examples thereof include ethers such as dioxane, tetrahydrofuran, and ethylene glycol dimethyl ether; fatty acids such as acetic acid and formic acid; and mixed solvents thereof. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as formic acid, acetic acid, and aromatic sulfonic acids such as p-toluenesulfonic acid.The basic compounds include Examples thereof include metal carbonates such as sodium carbonate and potassium carbonate, and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide. The reaction proceeds normally at room temperature to about 200 ° C., preferably at room temperature to about 150 ° C.
It ends in about 25 minutes to 25 hours.

The reaction between the compound (1f) and the compound (8) is carried out under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above Reaction Scheme-1.

The reaction of compound (1f) with compound (6) is generally carried out in a suitable inert solvent in the presence or absence of a basic compound. Examples of the inert solvent used include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethylene glycol dimethyl ether; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; methanol and ethanol. And lower alcohols such as isopropanol, butanol and tert-butanol, acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, and a mixed solvent thereof. Examples of the basic compound include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, carbonates such as potassium hydrogen carbonate, sodium hydroxide, metal hydroxides such as potassium hydroxide, sodium hydride, potassium, sodium, sodium amide, and the like. Metal alcoholates such as sodium methylate and sodium ethylate, pyridine, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, 1,
5-diazabicyclo [4.3.0] nonene-5 (DB
N), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), 1,4-diazabicyclo [2.2.
2] Organic bases such as octane (DABCO) and the like can be mentioned. The ratio of the compound (1f) to the compound (6) is not particularly limited and may be appropriately selected in a wide range.
Preferably, it is used in an equimolar to about 10-fold molar amount.
The reaction is usually carried out at about 0 to 200 ° C, preferably at 0 to 170 ° C.
C., and is generally completed in about 30 minutes to 75 hours. An alkali metal halide such as sodium iodide and potassium iodide, copper powder and the like may be added to the reaction system.

The reaction between compound (1f) and compound (7) is carried out without a solvent or in a suitable solvent in the presence of a reducing agent. Examples of the solvent used herein include water, alcohols such as methanol, ethanol, and isopropanol; acetonitrile, formic acid, acetic acid, dioxane, diethyl ether, diglyme, and ethers such as tetrahydrofuran; and aromatic hydrocarbons such as benzene, toluene, and xylene. Examples thereof include hydrogens and a mixed solvent thereof. As the reducing agent, for example, formic acid, ammonium formate, alkali metal salts of fatty acids such as sodium formate, hydride reducing agents such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, palladium-black, palladium-carbon, oxidized Examples thereof include a catalytic reducing agent such as platinum, platinum black, and Raney nickel.

When formic acid is used as a reducing agent, the reaction temperature is usually from room temperature to about 200 ° C., preferably from 50 to 150 ° C.
C. is appropriate, and the reaction is completed in about 1 to 10 hours. The amount of formic acid used is preferably a large excess with respect to compound (1f).

When a hydride reducing agent is used, the reaction temperature is usually about -30 to 100 ° C, preferably 0 to 70 ° C.
The reaction is properly performed, and the reaction is completed in about 30 minutes to 12 hours. The amount of the reducing agent to be used is generally about equimolar to about 20-fold molar quantity, preferably about 1- to 6-fold molar quantity, relative to compound (1f). In particular, when lithium aluminum hydride is used as the reducing agent, it is preferable to use ethers such as diethyl ether, dioxane, tetrahydrofuran, and diglyme as solvents, and aromatic hydrocarbons such as benzene, toluene, and xylene.

Further, when a catalytic reducing agent is used, it is usually in a hydrogen atmosphere at normal pressure to about 20 atm, preferably normal pressure to about 10 atm, or a hydrogen donor such as formic acid, ammonium formate, cyclohexene or hydrazine hydrate. The reaction is usually carried out at a temperature of about -30 to 100 ° C., preferably about 0 to 60 ° C., and the reaction is usually completed in about 1 to 12 hours. The amount of the catalytic reducing agent used may be the compound (1
f) usually from 0.1 to 40% by weight, preferably from 1 to 40% by weight.
The content is preferably about 20% by weight. The amount of the hydrogen donor to be used is generally preferably a large excess with respect to the compound (1f).

The amount of compound (7) to be used is generally at least equimolar, preferably equimolar to large excess, relative to compound (1f).

The reaction between compound (1f) and compound (9) is carried out without a solvent or in a suitable solvent in the presence or absence, preferably in the presence of a basic compound. Examples of suitable solvents include the above-mentioned aromatic hydrocarbons, methanol, ethanol, lower alcohols such as propanol, dimethylformamide, dimethyl sulfoxide, and the like, chloroform, halogenated hydrocarbons such as methylene chloride, acetone, and the like. Pyridine and the like can be used. Examples of the basic compound include organic bases such as triethylamine and pyridine, sodium hydroxide, potassium hydroxide, and sodium hydride. The above reaction can also be carried out in a solvent such as acetic acid in the presence of a mineral acid such as sulfuric acid. The use ratio of the compound (9) may be an equimolar amount to a large excess amount relative to the starting material, and the reaction is usually performed at about 0 to 200 ° C, preferably about 0 to 150 ° C, for 0.5 to 20 hours. Complete in about a degree.

Compounds (2) and (3) used as starting materials are easily produced, for example, according to the following method.

[0123]

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[Wherein R ¹ and R ² are as defined above. R ¹⁷ represents a lower alkoxy group. R ¹⁸ represents a lower alkoxy group. R ¹⁹ represents a lower alkyl group. X ¹ , X ² and X ³ each represent a halogen atom. The reaction between compound (9a) and compound (10) can be carried out in a suitable solvent in the presence of an acid. As the solvent used herein, for example, water, methanol, ethanol, lower alcohols such as isopropanol, acetone, ketones such as methyl ethyl ketone, dioxane, tetrahydrofuran, ethers such as ethylene glycol dimethyl ether, acetic acid, fatty acids such as formic acid, These mixed solvents are exemplified. Examples of the acid used include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, formic acid, acetic acid, p
Organic acids such as aromatic sulfonic acids such as toluenesulfonic acid; The amount of compound (10) to be used is generally at least equimolar, preferably equimolar to 2-fold molar amount, relative to compound (9a). The reaction is usually carried out at room temperature to
The process suitably proceeds at about 200 ° C., preferably about room temperature to about 150 ° C., and generally ends in about 0.5 to 5 hours.

The reaction between the compound (11) and the compound (12) is carried out under the same reaction conditions as the reaction between the compound (1a) and the compound (4) in the above Reaction Scheme-2. In this case, the compound (12) is preferably used in a large excess as a solvent.

In the reaction for converting the compound (13) into the compound (2a) and the reaction for converting the compound (2a) into the compound (2), the compound (1e) in the above Reaction Formula-4 is converted into the compound (1f).
Under the same reaction conditions as the hydrolysis reaction among the reactions leading to

The reaction between the compound (9a) and the compound (10a) is carried out under the same reaction conditions as the reaction between the compound (9a) and the compound (10).

Compound (9a) and compound (10a)
The reaction is carried out in a suitable solvent in the presence or absence of an acid and in the presence of an oxidizing agent. As the solvent used,
For example, water, methanol, ethanol, lower alcohols such as isopropanol, dioxane, tetrahydrofuran, ethers such as ethylene glycol dimethyl ether, acetic acid, fatty acids such as formic acid, n-hexane, benzene,
Examples thereof include aromatic hydrocarbons such as toluene, and a mixed solvent thereof. As the acid, any acid used in the reaction between the compound (9a) and the compound (10) can be used. Examples of the oxidizing agent include nitro compounds such as iodine and nitrobenzene, and dehydrogenation catalysts such as palladium carbon. Compound (10
The amount of a) to be used is usually at least equimolar, preferably equimolar to 3 times the molar amount of compound (9a). The amount of the oxidizing agent to be used is generally at least 0.1 mol, preferably 0.1 to 2 mol, per mol of compound (9a). The reaction usually proceeds suitably at room temperature to about 200 ° C, preferably at room temperature to about 150 ° C,
Generally, it is completed in about 10 minutes to 5 hours. The presence of the oxidizing agent in the reaction system allows the compound (2
a) can be produced in high yield and high purity.

[0129]

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[Wherein R ^3a , R ^3b , A, n, R ⁷ and X are as defined above. R ²⁰ represents an amino group or a group convertible to an amino group. Here, the group which can be converted to an amino group represented by R ²⁰ means a group which can be converted to an amino group by ordinary conversion means such as reduction or hydrolysis of a nitro group, a cyano group, an azide group, a phthalimide group, and the like. I do.

The reaction between the compound (3a) and the compound (4) is carried out under the same reaction conditions as the reaction between the compound (1a) and the compound (4) in the above Reaction Scheme-2.

[0132]

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[Wherein R ^3c , R ^3d , A, n, R ²⁰ and R ⁸
Is the same as above. The reaction between the compound (3c) and the compound (5) is carried out under the same reaction conditions as the reaction between the compound (1c) and the compound (5) in the aforementioned Reaction Formula-3.

[0134]

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[Wherein R ^3e , A, n, R ²⁰ , R ^3f , R ^3g ,
R ^3h , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and X are the same as described above. The reaction for converting the compound (3e) into the compound (3f) is carried out under the same reaction conditions as the reaction for converting the compound (1e) into the compound (1f) in the aforementioned Reaction Formula-4.

The reaction of the compound (3f) with the compound (6) or the compound (7) is carried out by reacting the compound (1)
The reaction is performed under the same reaction conditions as in the reaction of f) with the compound (6) or the compound (7).

The reaction of the compound (3f) with the compound (8) or the compound (9) is carried out by reacting the compound (1)
The reaction is performed under the same reaction conditions as in the reaction of f) with the compound (8) or the compound (9).

Compound (3a), compound (3b), compound (3c), compound (3d), compound (3e), compound (3f), compound (3g) and compound (3h) in which R ²⁰ represents a nitro group By reducing these, the compound (3a) wherein the corresponding R ²⁰ is an amino group, the compound (3
b), compound (3c), compound (3d), compound (3
e), compound (3f), compound (3g) and compound (3
h). This reduction reaction is carried out, for example, by (1) reduction using a catalytic reduction catalyst in a suitable solvent or (2) a metal or metal salt and an acid or a metal or metal salt and an alkali metal hydroxide in a suitable inert solvent. , A sulfide, a mixture with an ammonium salt, or a hydride reducing agent such as lithium aluminum hydride as a reducing agent.

When the reduction catalyst of (1) is used, examples of the solvent to be used include water, alcohols such as acetic acid, methanol, ethanol and isopropanol, hydrocarbons such as hexane and cyclohexane, dioxane, tetrahydrofuran, diethyl ether, and the like. Examples include ethers such as diethylene glycol dimethyl ether, esters such as ethyl acetate and methyl acetate, aprotic polar solvents such as N, N-dimethylformamide and the like, or a mixed solvent thereof. Palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like can be mentioned. In general, the catalyst is preferably used in an amount of about 0.02 to 1 times the amount of the starting material. The reaction temperature is usually about −20 to 150 ° C., preferably about 0 to 100 ° C., and the hydrogen pressure is usually 1 to 10 atm. The reaction is generally completed in about 0.5 to 10 hours. Further, an acid such as hydrochloric acid may be added to the reaction.

When the method (2) is used, iron, zinc,
Tin or stannous chloride and hydrochloric acid, mineral acids such as sulfuric acid, or iron,
Mixtures of ferrous sulfate, zinc or tin and alkali metal hydroxides such as sodium hydroxide, sulfides such as ammonium sulfide, ammonia water, ammonium salts such as ammonium chloride, or hydride reduction such as lithium aluminum hydride An agent is used as a reducing agent. Examples of the inert solvent used include water, acetic acid, methanol, ethanol, dioxane and the like. When lithium aluminum hydride is used as the reducing agent, it is preferable to use ethers such as diethyl ether, dioxane, tetrahydrofuran, and diglyme as the solvent. Conditions for the above reduction reaction may be appropriately selected depending on the reducing agent used. For example, when stannous chloride and hydrochloric acid are used as the reducing agent, the temperature is preferably around 0 to 80 ° C, 0.5 to 10 ° C.
The reaction is preferably performed for about an hour. The reducing agent is used at least in an equimolar amount, usually in an equimolar to 5-fold molar amount, relative to the raw material compound.

Compound (3a) wherein R ²⁰ represents a nitrile group,
Compound (3b), compound (3c), compound (3d), compound (3e), compound (3f), compound (3g) and compound (3h) are reduced to reduce the corresponding R ²⁰ to an amino group. Compound (3a), Compound (3
b), compound (3c), compound (3d), compound (3
e), compound (3f), compound (3g) and compound (3
h). For this reduction reaction, a reduction method using a hydride reducing agent is suitably used. Examples of the hydride reducing agent to be used include lithium aluminum hydride, lithium borohydride, sodium borohydride, diborane, and the like, and the amount of the hydride reducing agent is at least equimolar, preferably equimolar to 15 to the raw material compound. The range is twice as high. This reduction reaction is usually carried out using an appropriate solvent, for example, water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether and diglyme, and a mixed solvent thereof. The reaction is carried out at a temperature of 150 ° C., preferably -30 to 100 ° C. for about 10 minutes to 15 hours. When lithium aluminum hydride or diborane is used as the reducing agent, an anhydrous solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, or diglyme is preferably used. When sodium borohydride is used as the hydride reducing agent, the reaction proceeds advantageously when a metal halide such as cobalt chloride is added to the reaction system.

Compound (3) wherein R ²⁰ represents a phthalimide group
a), compound (3b), compound (3c), compound (3
d), compound (3e), compound (3f), compound (3
g) and compound (3h) are treated under the same reaction conditions as in the reaction for converting compound (1e) into compound (1f) in the above-mentioned reaction formula-4, so that corresponding R ²⁰ is an amino group. It can be derived into compound (3a), compound (3b), compound (3c), compound (3d), compound (3e), compound (3f), compound (3g) and compound (3h).

Compound (3a), compound (3b), compound (3c), compound (3d), compound (3e), compound (3f), compound (3g) and compound (3h) in which R ²⁰ represents an azide group These compounds are reduced under the same conditions as the reduction using a catalytic reduction catalyst or the nitrile group in the reduction of the nitro group, whereby the corresponding compound (3a) or compound (3b) wherein R ²⁰ is an amino group. ), Compound (3
c), compound (3d), compound (3e), compound (3
f), compound (3g) and compound (3h).

[0144]

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[Wherein R ¹ , R ² and X are as defined above. R ²¹
Represents a hydrogen atom or a lower alkyl group. The reaction between the compound (14) and the compound (15) is carried out under the same reaction conditions as the reaction between the compound (1a) and the compound (4) in the aforementioned Reaction Formula-2.

In the compound of the general formula (1), the compound in which R ³ represents a substituted or unsubstituted 2 (1H) -quinolinonyl group is reduced to obtain a compound in which R ³ is substituted or unsubstituted. , 4-dihydro-2 (1H) -quinolinonyl group.

In the compound of the general formula (1), the compound in which R ³ represents a substituted or unsubstituted 3,4-dihydro-2 (1H) -quinolinonyl group is subjected to a dehydrogenation reaction to give the corresponding R ³ can be derived to a compound showing a substituted or unsubstituted 2 (1H) -quinolinonyl group.

For the above reduction reaction, ordinary catalytic reduction conditions can be applied. Examples of the catalyst used include metals such as palladium, palladium-carbon, platinum and Raney nickel, and such metals are used in a usual catalytic amount. Examples of the solvent used include alcohols such as methanol, ethanol and isopropanol; ethers such as dioxane and tetrahydrofuran; aliphatic hydrocarbons such as hexane and cyclohexane; esters such as ethyl acetate; and fatty acids such as acetic acid. be able to. The reduction reaction can be carried out at normal pressure or under pressure, but is usually carried out at normal pressure to about ²⁰ kg / cm ² , preferably at normal pressure to 10 kg / cm ² . The reaction temperature is usually about 0 to 150 ° C, preferably about room temperature to about 100 ° C.

The above dehydrogenation reaction is carried out in an appropriate solvent using an oxidizing agent. As the oxidizing agent used,
For example, benzoquinones such as 2,3-dichloro-5,6-dicyanobenzoquinone and chloranyl (2,3,5,6-tetrachlorobenzoquinone), halogenation such as N-bromosuccinimide, N-chlorosuccinimide, and bromine Agent, selenium dioxide, palladium-carbon, palladium-
Dehydrogenation catalysts such as black, palladium oxide, Raney nickel and the like can be mentioned. The amount of the halogenating agent to be used is not particularly limited and may be appropriately selected from a wide range. The amount is usually about 1 to 5 moles, preferably about 1 to 2 moles per mole of the raw material compound. Is good. When a dehydrogenation catalyst is used, it is preferable to use a normal catalyst amount.
Examples of the solvent include ethers such as dioxane, tetrahydrofuran, methoxyethanol and dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, xylene and cumene; and halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride. Alcohols such as butanol, amyl alcohol, and hexanol; polar protons such as acetic acid; and polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The reaction is carried out usually at room temperature to about 300 ° C., preferably at room temperature to 20 ° C.
The reaction is performed at about 0 ° C. and is generally completed in 1 to 40 hours.

Among the compounds (1) of the present invention, the compound having an acidic group can form a salt with a pharmacologically acceptable basic compound. Such basic compounds include, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide, alkali metal carbonates or bicarbonates such as sodium carbonate and sodium hydrogen carbonate, sodium methylate And alkali metal alcoholates such as potassium ethylate. In addition, among the compounds (1) of the present invention, a compound having basicity can easily form a salt with a usual pharmacologically acceptable acid. Such acids include, for example, inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid,
Organic acids such as succinic acid and benzoic acid can be exemplified. These salts can also be used as the active ingredient compound in the present invention, like the compound (1) in a free form. The compound (1) includes stereoisomers and optical isomers, and these can also be used as the active ingredient compound.

The target compound obtained by the method shown in each of the above reaction schemes can be separated from the reaction system by usual separation means and can be further purified. Such separation and purification means include, for example, distillation, recrystallization, column chromatography, ion exchange chromatography,
Gel chromatography, affinity chromatography, preparative thin-layer chromatography, solvent extraction and the like can be employed.

When the compound of the present invention is used as a medicine, it is usually used in the form of a general pharmaceutical preparation. The preparation is prepared using a diluent or excipient such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant and a lubricant, which are usually used. Various forms can be selected as the pharmaceutical preparation depending on the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.). In molding into tablets, various carriers well-known in the art can be widely used as carriers. Examples thereof include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, Gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrating agents such as sodium, stearic acid monoglyceride, starch, lactose; disintegrating inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium bases; absorption promoting agents such as sodium lauryl sulfate; Phosphorus, moisturizing agents such as starch, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, purified talc, stearates, boric acid powder, a lubricant such as polyethylene glycol can be used. Further, the tablet can be made into a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet or a multilayer tablet. In molding into the form of pills, a wide variety of carriers conventionally known in this field can be used. Examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oils, kaolin, talc, binders such as gum arabic, tragacanth, gelatin, ethanol, disintegrants such as laminaran, agar, etc. Can be used. In the case of molding into a suppository form, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. Capsules are prepared according to a conventional method, usually by mixing an active ingredient compound with the various carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like. When prepared as an injection, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and are commonly used as diluents in the art when formed into these forms. And water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent, etc. may be added. You may. Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals can be contained in the pharmaceutical preparation.

The amount of the active ingredient compound to be contained in the pharmaceutical preparation of the present invention is not particularly limited and may be appropriately selected from a wide range, but is usually about 1 to 70% by weight, preferably about 1 to 70% by weight in the pharmaceutical composition. The content is preferably 5 to 50% by weight.

The administration method of the pharmaceutical preparation of the present invention is not particularly limited, and may be various preparation forms, patient age, sex, other conditions,
The drug is administered according to the degree of the disease. For example, tablets,
In the case of pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally. In the case of an injection, it is administered intravenously, alone or as a mixture with a normal replenisher such as glucose or amino acid, and, if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally.

The dose of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the age of the patient, gender and other conditions, the degree of the disease, etc. Usually, the amount of the active compound is about 0 to 1 kg / body weight per day. It is preferable to be about 0.6 to 50 mg.
In addition, the active ingredient compound is contained in a dosage unit form preparation in an amount of about 10%.
Desirably, it is contained in the range of １０００1000 mg.

The amount of the active ingredient compound to be incorporated in the external preparation of the present invention is not particularly limited and can be appropriately selected from a wide range, but is usually 0.01 to 20% by weight in the external preparation.
, Preferably 0.1 to 5% by weight.

As the base used in the present invention, oil-based bases and water-soluble bases conventionally known in this field can be widely used as long as they have no medicinal effect. As the oily base, specifically, peanut oil, rubber oil, soybean oil,
Corn oil, rapeseed oil, menz oil, castor oil, camellia oil, coconut oil, olive oil, cacao oil, lanolin fat,
Fats and oils such as beef tallow, squalane, and wool fat; those obtained by modifying these fats and oils by a chemical change such as hydrogenation; mineral oils such as petrolatum, paraffin, and silicone oil; isopropyl myristate, n-butyl myristate , Isopropyl linoleate, cetyl ricinolate, stearyl ricinolate, diethyl sebacate, diisopropyl adipate, cetyl alcohol, stearyl alcohol, salami beeswax, gay wax, higher wax esters such as wood wax,
Higher fatty acid alcohols and waxes; stearic acid,
Higher aliphatic acids such as oleic acid and palmitic acid; having 1 carbon atom
Mixtures of mono-, di-, and triglycerides of 2 to 18 natural saturated fatty acids can be exemplified. Among these, the above-mentioned various vegetable oils and mixtures of the above-mentioned mono-, di- and triglycerides are particularly preferred. Specific examples of the water-soluble base include polyethylene glycol, propylene glycol, glycerin, glycerogelatin, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypinyl polymer, and polyvinyl alcohol. it can. In the present invention, these bases may be used alone or in combination of two or more.

The external preparation of the present invention includes conventional additives such as water, surfactants, gelling agents, preservatives, antioxidants, buffers, pH adjusters, wetting agents, preservatives, coloring agents, A fragrance or the like can be appropriately added as needed.

The form of the external preparation of the present invention is not particularly limited, but is preferably in the form of an ointment, cream, lotion, emulsion or gel, and these forms can be prepared according to a conventional method.

[0160]

EXAMPLES The present invention will be further clarified with reference to Formulation Examples, Reference Examples, Examples and Pharmacological Test Examples.

Formulation Example 1 1-benzyl-6-chloro-2- {1- [3- (pyrazol-1-yl) propyl] indol-5-ylaminocarbonyl} benzimidazole 150 g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g corn starch 30 g magnesium stearate 2 g hydroxypropyl methylcellulose 10 g polyethylene glycol-6000 3 g castor oil 40 g ethanol 40 g After mixing and polishing the active ingredient compound of the present invention, Avicel, corn starch and magnesium stearate, sugar coating R10 m
Tablet with m-kine. The obtained tablets were treated with hydroxypropyl methylcellulose, polyethylene glycol-600.
0, coating with a film coating agent consisting of castor oil and ethanol to produce film-coated tablets.

Formulation Example 2 1-benzyl-6-chloro-2- [1- (1-isopropyltetrazol-5-ylmethyl) -3,4-dihydro-2 (1H) -quinolinone-6-ylaminocarbonyl ] Benzimidazole 150 g Citric acid 1.0 g Lactose 33.5 g Dicalcium phosphate 70.0 g Pluronic F-68 30.0 g Sodium lauryl sulfate 15.0 g Polyvinylpyrrolidone 15.0 g Polyethylene glycol (Carbowax 1500) 4.5 g Polyethylene glycol (Carbowax 6000) 45.0 g Corn starch 30.0 g Dry sodium stearate 3.0 g Dry magnesium stearate 3.0 g Ethanol Appropriate amount Active compound of the present invention, citric acid, lactose, dicalcium phosphate, pull Mixing the nick F-68 and sodium lauryl sulfate.

The above mixture was designated as No. The mixture is sieved with a 60 screen and wet granulated with an alcohol solution containing polyvinylpyrrolidone, carbowax 1500 and 6000. If necessary, alcohol is added to make the powder into a pasty mass. Add corn starch and continue mixing until uniform particles are formed. The mixture was no. Pass through 10 screens, place in trays and dry at 100 ° C open for 12-14 hours. The dried particles were no. Sieve through 16 screens, add dry sodium lauryl sulfate and dry magnesium stearate, mix and compress to desired shape on tablet press.

The above-mentioned core is treated with varnish, and talc is sprayed to prevent moisture absorption. An undercoat layer is coated around the core. Apply varnish a sufficient number of times for internal use. A further subbing layer and a smooth coating are applied to make the tablet completely round and smooth. Color coating is carried out until the desired hue is obtained. After drying, the coated tablets are polished into tablets of uniform gloss.

Formulation Example 3 1-benzyl-6-chloro-2- {1- [3- (imidazol-1-yl) propyl] indol-5-ylaminocarbonyl} benzimidazole 5 g polyethylene glycol (molecular weight: 4000) 0.3 g sodium chloride 0.9 g polyoxyethylene-sorbitan monooleate 0.4 g sodium metabisulfite 0.1 g methyl-paraben 0.18 g propyl-paraben 0.02 g distilled water for injection 10.0 ml The sodium bisulfite and sodium chloride are dissolved in about half of the above distilled water at 80 ° C. with stirring. The obtained solution is cooled to 40 ° C., and the active ingredient compound of the present invention, and then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the above solution. Next, distilled water for injection is added to the solution to make the final volume, and the solution is sterilized by sterile filtration using an appropriate filter paper to prepare an injection.

Reference Example 1 15 ml of O-methyl-trichloroacetimidate was added dropwise at 20 to 25 ° C. to a solution of 20 g of 2-benzylamino-4-chloroaniline in 100 ml of acetic acid, and the mixture was stirred at room temperature for 3 hours, and water was added. , And the precipitated crystals were collected by filtration.
29.6 g of -benzyl-6-chloro-2-trichloromethylbenzimidazole were obtained.

¹ H-NMR (250 MHz, DMSO-
d ₆ ) δ ppm; 5.94 (2H, s), 7.04 (2
H, d, J = 6.5 Hz), 7.25-7.5 (5H,
m), 7.88 (1H, d, J = 9.0 Hz).

Reference Example 2 A suspension of 5 g of 1-benzyl-6-chloro-2-trichloromethylbenzimidazole and 7.7 g of potassium carbonate in 50 ml of methanol was heated under reflux for 24 hours. After filtration,
The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, and the insoluble material was removed by filtration. The solvent was distilled off to obtain 1-benzyl-6 as a brown oil.
4.7 g of -chloro-2-trimethoxymethylbenzimidazole were obtained. This was dissolved in 50 ml of acetone, and p
-Add 1 g of toluenesulfonic acid, heat to reflux for 2 hours,
The solvent was distilled off under reduced pressure. Dissolve the residue in chloroform,
After washing with water and saturated aqueous sodium hydrogen carbonate and drying over magnesium sulfate, the solvent was distilled off. The residue was crystallized from diisopropyl ether-ethyl acetate to give a light brown powder of methyl 1-benzyl-6-chlorobenzimidazole-2.
2.84 g of carboxylate were obtained.

Melting point: 184-186 ° C.

Reference Example 3 200 g of dimethylformamide was added to 4.4 g of 5-nitro-1- (3-phthalimidopropyl) indole, and 0.15 g of 10% palladium-carbon was further added. And catalytic reduction at 4 kg / cm ² for 7 hours. After completion of the reaction, the reaction mixture was filtered, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent; 3% methanol / dichloromethane) to obtain brown amino acid 5-amino-1- ( 3.4 g of 3-phthalimidopropyl) indole were obtained.

¹ H-NMR (250 MHz, CDCl ₃ )
δ ppm; 2.16-2.28 (2H, m), 3.73
(2H, t, J = 7 Hz), 4.12 (2H, t, J =
7 Hz), 6.28 (1H, d, J = 3 Hz), 6.6
4-6.69 (1H, m), 6.9 (1H, d, J = 2
Hz), 7.11-7.14 (2H, m), 7.7-
7.73 (2H, m), 7.82-7.86 (2H,
m).

Using the appropriate starting materials, the compounds of Reference Examples 15 to 22, 26 to 33, 47 and 49 were obtained in the same manner as in Reference Example 3.

Reference Example 4 To 2.3 g of lithium aluminum hydride was added 100 ml of tetrahydrofuran, and the mixture was stirred to obtain 5-cyano-1- [3
-(2-Isopropylimidazol-1-yl) propyl] indole 6 g was gradually added. Thereafter, the mixture was heated under reflux for 4 hours, and after confirming the completion of the reaction, cooled to 0 ° C. and cooled under a water supply of 2.3 m.
1, 2.3 ml of 10% aqueous potassium hydroxide and 7 ml of water were gradually added dropwise. This was diluted with ethyl acetate, filtered through celite, and the solvent was distilled off.
5.3 g of 1- [3- (2-Isopropylimidazol-1-yl) propyl] indole was obtained.

¹ H-NMR (250 MHz, CDCl ₃ )
δ ppm; 1.22 (6H, d, J = 7 Hz), 2.3
-2.4 (2H, m), 2.7-2.8 (2H, m),
3.81 (2H, t, J = 7.5 Hz), 3.95 (2
H, s), 4.16 (2H, t, J = 7 Hz), 6.5.
1 (1H, d, J = 3 Hz), 6.77 (1H, d, J
= 1.5 Hz), 6.98-7.04 (2H, m),
7.19 (2H, s), 7.57 (1H, s).

Using the appropriate starting materials, compounds shown in Table 1 below were obtained in the same manner as in Reference Example 4.

[0176]

[Table 1]

Reference Example 6 1.5 g of 5-nitroindole was dissolved in 70 ml of dimethylformamide, and sodium hydride (oil-based) 3
70 mg was added and the mixture was stirred at 60 ° C. for 1 hour under a nitrogen stream.
Thereafter, 1.63 g of 5-chloromethyl-1-isopropyl-1,2,3,4-tetrazole was added under cooling at 0 ° C., and the mixture was stirred at room temperature for 4.5 hours. It was collected by filtration and washed with water. The crystals were dissolved in dichloromethane, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; dichloromethane → 3% methanol / dichloromethane) to give a yellow powder 1- (1-isopropyl-
1,2,3,4-tetrazol-5-ylmethyl) -5
2.3 g of nitroindole were obtained.

¹ H-NMR (250 MHz, CDCl ₃ )
δ ppm; 1.35 (6H, d, J = 6.5 Hz),
4.37-4.47 (1H, m), 5.70 (2H,
s), 6.79-6.81 (1H, m), 7.27-
7.30 (1H, m), 7.48 (1H, d, J = 9H)
z), 8.12-8.17 (1H, m), 8.59 (1
H, d, J = 2 Hz).

Using the appropriate starting materials, the compounds shown in Tables 2 to 8 were obtained in the same manner as in Reference Example 6.

[0180]

[Table 2]

[0181]

[Table 3]

[0182]

[Table 4]

[0183]

[Table 5]

[0184]

[Table 6]

[0185]

[Table 7]

[0186]

[Table 8]

The NMR spectra of the compounds of Reference Examples obtained above are as follows.

Compound ¹ of Reference Example 5 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.60 (2H, brs), 4.07 (2H, d, J =
1 Hz), 7.10-7.26 (3H, m), 7.36
-7.39 (1H, m), 7.65-7.68 (1H,
m), 8.12 (1H, brs).

Compound ¹ of Reference Example 7 ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m: 2.2-2.4 (2H, m), 4.20 (2H,
t, J = 7.5 Hz), 4.29 (2H, t, J = 7.
5 Hz), 6.44 (1 H, d, J = 3 Hz), 6.7
7 (1H, d, J = 3 Hz), 7.0-7.2 (2H,
m) 7.35-7.45 (2H, m), 7.5-7.7
5 (3H, m), 7.97-8.02 (1H, m),
8.58 (1H, d, J = 2 Hz).

Compound ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm of Reference Example 8:
2.4-2.5 (2H, m), 3.86 (3H, s),
4.07-4.13 (4H, m), 6.47 (1H,
t, J = 2.5 Hz), 6.69 (1H, d, J = 3.
5Hz), 6.83-6.88 (1H, m), 7.01
(1H, d, J = 3 Hz), 7.07-7.18 (4
H, m), 8.06 (1H, dd, J = 2.5 Hz, 9
Hz), 8.59 (1H, d, J = 2.5 Hz).

Compound ¹ of Reference Example 9 ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m: 2.2-2.3 (2H, m), 3.97 (2H,
t, J = 6 Hz), 4.46 (2H, t, J = 7H)
z), 6.77 (1H, d, J = 3 Hz), 7.23-
7.27 (1H, m), 7.37-7.51 (3H,
m), 7.67-7.72 (2H, m), 7.98 (1
H, dd, J = 2 Hz, 9 Hz), 8.57 (1H,
d, J = 2 Hz). Compound ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp of Reference Example 10
m: 2.25-2.35 (2H, m), 4.07 (2
H, t, J = 6 Hz), 4.48 (2H, t, J = 7H)
z), 6.78 (1H, d, J = 3 Hz), 7.07-
7.19 (2H, m), 7.61-7.78 (4H,
m), 8.0 (1H, dd, J = 2 Hz, 9 Hz),
8.58 (1H, d, J = 2 Hz).

Compound ¹ of Reference Example ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.57 (6H, d, J = 6.5 Hz), 2.2-2.
3 (2H, m), 2.89 (2H, t, J = 7 Hz),
3.08 (2H, t, J = 9 Hz), 3.44 (2H,
t, J = 7 Hz), 3.67 (2H, t, J = 9H)
z), 4.4-4.6 (1H, m), 6.24 (1H,
d, J = 9 Hz), 7.85-7.9 (1H, m),
7.99-8.03 (1H, m).

Compound ¹ of Reference Example ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m: 1.9-2.0 (2H, m), 3.01 (2H,
t, J = 8.5 Hz), 3.37 (2H, t, J = 9H)
z), 3.66 (4H, m), 6.51 (1H, d, J
= 9 Hz), 7.78-7.96 (6H, m).

Compound of Reference Example 13 ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m: 2.0-2.1 (2H, m), 3.02 (2H,
t, J = 8.5 Hz), 3.25 (2H, t, J = 7.
5Hz), 3.62 (2H, t, J = 8.5Hz),
3.74 (3H, s), 4.21 (2H, t, J = 7H)
z), 6.30-6.35 (2H, m), 6.73-
6.78 (1H, m), 7.05 (1H, d, J = 2.
5Hz), 7.32 (1H, d, J = 3Hz), 7.3
8 (1H, d, J = 9 Hz), 7.80 (1H, s),
7.90-7.95 (1H, m).

Compound of Reference Example 14 ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m: 2.0-2.1 (2H, m), 3.02 (2H,
t, J = 8.5 Hz), 3.27 (2H, t, J = 7.
5Hz), 3.62 (2H, t, J = 9Hz), 4.2
6 (2H, t, J = 7 Hz), 6.34 (1H, d, J
= 9 Hz), 6.44-6.45 (1H, m), 6.9
8-7.15 (2H, m), 7.38 (1H, d, J =
3 Hz), 7.48-7.56 (2H, m), 7.80
(1H, d, J = 2.5 Hz), 7.93 (1H, d
d, J = 2.5 Hz, 9 Hz).

Compound ¹ of Reference Example 15 H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.35-2.45 (2H, m), 4.00-4.11
(4H, m), 6.33-6.34 (1H, m), 6.
52 (1H, d, J = 3 Hz), 6.64-6.68
(1H, m), 6.94-7.22 (7H, m), 7.
64 (1H, d, J = 7.5 Hz).

Compound ¹ of Reference Example ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.35-2.45 (2H, m), 3.85 (3H,
s), 3.99-4.07 (4H, m), 6.33 (1
H, d, J = 3 Hz), 6.43 (1H, d, J = 3H)
z), 6.64-6.68 (1H, m), 6.83-
6.88 (1H, m), 6.94-6.97 (2H,
m), 7.01-7.04 (2H, m), 7.10-
7.13 (2H, m).

Compound ¹ of Reference Example 17 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.25-2.35 (2H, m), 3.4-3.6 (2
H, br), 3.85 (2H, t, J = 6 Hz), 4.
30 (2H, t, J = 6.5 Hz), 6.28-6.3
0 (1H, m), 6.62-6.66 (1H, m),
6.92-6.97 (2H, m), 7.07-7.15
(3H, m), 7.23-7.26 (1H, m), 7.
33-7.39 (1H, m).

Compound ¹ of Reference Example ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.3-2.4 (2H, m), 3.3-3.7 (2H,
br), 3.89 (2H, t, J = 8 Hz), 4.38
(2H, t, J = 8 Hz), 6.26 (1H, d, J =
3 Hz), 6.6-6.7 (1H, m), 6.75-
6.81 (1H, m), 6.91 (1H, s), 7.0
−7.1 (2H, m), 7.17-7.20 (1H,
m), 7.4-7.5 (1H, m), 7.58 (1H,
d, J = 8 Hz).

Compound ¹ of Reference Example 19 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.55 (6H, d, J = 6.5 Hz), 2.1-2.
25 (2H, m), 2.8-3.4 (8H, m), 4.
51-4.62 (1H, m), 6.2-6.6 (3H,
m).

Compound ¹ of Reference Example 20 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.92-2.04 (2H, m), 2.6-3.5 (8
H, brm), 3.83 (2H, t, J = 7 Hz),
6.3-6.6 (3H, m), 7.67-7.86 (4
H, m).

Compound ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm of Reference Example 21:
2.0-2.2 (2H, m), 2.8-3.0 (4H,
m), 3.19 (2H, t, J = 8 Hz), 3.86
(3H, s), 4.25 (2H, t, J = 6.5H
z), 6.2-6.3 (1H, m), 6.4-6.5
(2H, m), 6.57 (1H, s), 6.84-6.
88 (1H, m), 7.08-7.11 (2H, m),
7.26 (1H, t, J = 5 Hz).

Compound ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm of Reference Example 22:
2.1-2.2 (2H, m), 2.8-3.0 (4H,
m), 3.20 (2H, t, J = 8 Hz), 4.29
(2H, t, J = 7 Hz), 6.2-6.3 (1H,
m), 6.4-6.6 (3H, m), 7.1-7.3.
(3H, m), 7.38 (1H, d, J = 8 Hz),
7.64 (1H, d, J = 7.5 Hz).

Compound ¹ of Reference Example 23 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.22 (6H, d, J = 7 Hz), 2.3-2.4
(2H, m), 2.7-2.8 (2H, m), 3.81
(2H, t, J = 7.5 Hz), 3.95 (2H, s
), 4.16 (2H, t, J = 7 Hz), 6.51.
(1H, d, J = 3 Hz), 6.77 (1H, d, J =
1.5 Hz), 6.98-7.04 (2H, m), 7.
19 (2H, s), 7.57 (1H, s).

Compound ¹ of Reference Example 24 1H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.23-2.33 (2H, m), 3.45 (2H,
t, J = 6 Hz), 4.38 (2H, t, J = 6.5H)
z), 6.60 (1H, d, J = 3.5 Hz), 7.2
(1H, s), 7.44 (2H, d, J = 1 Hz),
7.98 (1H, t, J = 1 Hz).

Compound ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm of Reference Example 25:
2.6-2.7 (2H, m), 2.8-2.9 (2H,
m), 3.55 (2H, brs), 4.4-4.6 (2
H, m), 5.1-5.3 (2H, m), 5.8-6.
0 (1H, m), 6.5-6.6 (2H, m), 6.8
-6.9 (1H, m).

Compound ¹ of Reference Example 26 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.36-2.46 (2H, m), 3.3-3.7 (2
H, br), 4.0-4.1 (4H, m), 6.2-
6.4 (2H, m), 6.6-6.7 (1H, m),
6.93 (1H, d, J = 2 Hz), 7.0-7.1
(2H, m), 7.30 (1H, d, J = 2 Hz),
7.56 (1H, d, J = 1.5 Hz).

Compound ¹ of Reference Example 27 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.4-2.6 (2H, m), 3.1-3.8 (2H,
br), 4.1-4.3 (4H, m), 6.33 (1
H, d, J = 3 Hz), 6.68 (1H, dd, J =
8.5 Hz, 2 Hz), 6.9-7.1 (3H, m),
7.97 (2H, d, J = 12 Hz).

Compound ¹ of Reference Example 28 1H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.0-2.1 (2H, m), 2.85-2.9 (4
H, m), 3.19 (2H, t, J = 9 Hz), 4.1
1 (2H, t, J = 7 Hz), 6.25 (1H, d, J
= 8 Hz), 6.45-6.5 (1H, m), 6.5-
6.6 (1H, m), 6.93 (1H, s), 7.08
(1H, s), 7.49 (1H, s).

Compound ¹ of Reference Example 29 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.7-2.0 (4H, m), 2.2-2.4 (2H,
m), 2.5-2.7 (4H, m), 2.9-3.0
(4H, m), 3.01 (2H, t, J = 7 Hz),
3.24 (2H, t, J = 8 Hz), 6.37 (1H,
d, J = 8 Hz), 6.4-6.5 (1H, m), 6.
56 (1H, s), 7.3-7.4 (3H, m), 7.
52 (2H, d, J = 7 Hz).

Compound ¹ of Reference Example 30 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.43 (6H, d, J = 6.5 Hz), 2.4-2.
5 (2H, m), 2.59 (2H, t, J = 8 Hz),
4.1-4.2 (1H, m), 4.29 (2H, t, J
= 6.5 Hz), 6.3 (1H, d, J = 2.5H)
z), 6.62-6.66 (1H, m), 6.92-
7.03 (3H, m).

Compound ¹ of Reference Example 31 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.25 (6H, d, J = 6.5 Hz), 4.2-4.
3 (1H, m), 5.57 (2H, s), 6.4 (1
H, d, J = 3 Hz), 6.64-6.69 (1H,
m), 6.9 (1H, d, J = 2 Hz), 6.99 (1
H, d, J = 3 Hz), 7.1 (1H, d, J = 8.5)
Hz).

Compound ¹ of Reference Example 32 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.16-2.28 (2H, m), 3.73 (2H,
t, J = 7 Hz), 4.12 (2H, t, J = 7H)
z), 6.28 (1H, d, J = 3 Hz), 6.64−
6.69 (1H, m), 6.9 (1H, d, J = 2H
z), 7.11-7.14 (2H, m), 7.7-7.
73 (2H, m), 7.82-7.86 (2H, m).

Compound ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm of Reference Example 33:
2.35-2.5 (8H, m), 4.0-4.1 (4
H, m), 6.35 (1H, d, J = 2.5 Hz),
6.67-6.70 (1H, m), 6.96-7.06
(4H, m), 7.57 (1H, s), 7.70 (1
H, s).

Compound ¹ of Reference Example ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.5-1.7 (1H, br), 1.76-1.87
(4H, m), 2.1-2.2 (2H, m), 2.43
−2.5 (4H, m), 2.7-2.8 (2H, m),
3.08 (2H, t, J = 8.5 Hz), 3.33 (2
H, t, J = 7 Hz), 3.68 (2H, t, J = 8.
5 Hz), 6.32 (1H, d, J = 9 Hz), 7.2
−7.4 (3H, m), 7.52 (2H, d, J = 7H)
z), 7.88 (1H, s), 8.02-8.06 (1
H, m).

Compound ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm of Reference Example 35:
2.1-2.18 (2H, m), 3.09 (2H, t,
J = 8.5 Hz), 3.20 (2H, t, J = 7H)
z), 3.59 (2H, t, J = 8.5 Hz), 4.0
7 (2H, t, J = 7 Hz), 6.17 (1H, d, J
= 9 Hz), 6.92 (1 H, t, J = 1.5 Hz),
7.12 (1H, s), 7.48 (1H, s), 7.9
1 (1H, s), 8.02-8.06 (1H, m).

Compound ¹ of Reference Example 36 ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m: 2.1-2.2 (2H, m), 3.61 (2H,
t, J = 7 Hz), 4.36 (2H, t, J = 7H)
z), 6.75 (1H, d, J = 2.5 Hz), 7.7
1-7.76 (2H, m), 7.8-7.9 (4H,
m), 7.99-8.04 (1H, m), 8.55 (1
H, d, J = 2 Hz).

Compound ¹ of Reference Example 37 ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m: 2.18-2.29 (2H, m), 3.57 (2
H, t, J = 6.5 Hz), 4.40 (2H, t, J =
7 Hz), 6.78 (1H, d, J = 3 Hz), 7.6
2-7.73 (2H, m), 8.02-8.06 (1
H, m), 8.57 (1H, d, J = 2 Hz).

Compound ¹ of Reference Example 38 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.40-2.51 (2H, m), 4.11 (2H,
t, J = 6.5 Hz), 4.19 (2H, t, J = 7H)
z), 6.31 (1H, t, J = 2 Hz), 6.69-
6.71 (1H, m), 7.24-7.34 (3H,
m), 7.59 (1H, d, J = 1.5 Hz), 8.0
8-8.13 (1H, m), 8.59 (1H, d, J =
2 Hz).

Compound ¹ of Reference Example 39 ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m: 2.2-2.4 (2H, m), 4.19 (2H,
t, J = 7 Hz), 4.32 (2H, t, J = 7H)
z), 6.77 (1H, d, J = 3 Hz), 7.65 −
7.68 (2H, m), 7.99-8.06 (2H,
m), 8.50 (1H, s), 8.58 (1H, d, J
= 2 Hz).

Compound ¹ of Reference Example 40 1H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.0-2.1 (2H, m), 3.09 (2H, t, J
= 8 Hz), 3.4-3.5 (2H, m), 3.6-
3.7 (4H, m), 6.33-6.38 (1H,
m), 7.89 (1H, s), 8.03-8.08 (1
H, m).

Compound ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm of Reference Example 41:
1.5 (6H, d, J = 6.5 Hz), 2.4-2.6
(2H, m), 2.68 (2H, t, J = 6.5H
z), 4.3-4.4 (1H, m), 4.47 (2H,
t, J = 6.5 Hz), 6.71 (1H, d, J = 3H)
z), 7.2-7.3 (2H, m), 8.0-8.1
(1H, m), 8.59 (1H, d, J = 2 Hz).

Compound ¹ of Reference Example 42 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.35 (6H, d, J = 6.5 Hz), 4.37−
4.47 (1H, m), 5.70 (2H, s), 6.7
9-6.81 (1H, m), 7.27-7.30 (1
H, m), 7.48 (1H, d, J = 9 Hz), 8.1.
2-8.17 (1H, m), 8.59 (1H, d, J =
2 Hz).

Compound ¹ of Reference Example 43 1H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.33 (3H, s), 2.37 (3H, s), 2.4
5-2.56 (2H, m), 4.09-4.20 (4
H, m), 6.74 (1H, d, J = 3 Hz), 6.9
4 (1H, s), 7.15-7.21 (2H, m),
7.58 (1H, s), 7.72 (1H, s), 8.0
5-8.09 (1H, m), 8.60 (1H, d, J =
2 Hz).

Compound ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm of Reference Example 44:
1.22 (6H, d, J = 7 Hz), 2.3-2.4
(2H, m), 2.6-2.8 (1H, m), 3.84
(2H, t, J = 7 Hz), 4.19 (2H, t, J =
7 Hz), 6.63 (1H, d, J = 3 Hz), 6.7
8 (1H, d, J = 1.5 Hz), 7.01 (1H,
d, J = 1.5 Hz), 7.16 (1H, d, J = 3.
5 Hz), 7.2-7.3 (1H, m), 7.4-7.
5 (1H, m), 8.0 (1H, s).

Compound ¹ H-NMR of Reference Example 45 (250 MHz, CDCl ₃ ) δ ppm:
2.1-2.2 (2H, m), 3.5-3.7 (6H,
m), 4.2-4.3 (2H, m), 6.63 (1H,
d, J = 9 Hz), 7.67 (1 H, d, J = 2.5 H)
z), 7.78-7.87 (1H, m).

Compound ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm of Reference Example 46:
2.1-2.2 (2H, m), 3.3-3.4 (4H,
m), 4.06 (2H, t, J = 6.5 Hz), 4.2
3 (2H, t, J = 4.5 Hz), 6.42 (1H,
d, J = 9 Hz), 6.95 (1H, s), 7.13
(1H, s), 7.50 (1H, s), 7.67 (1
H, d, J = 2.5 Hz), 7.78 (1H, dd, J)
= 2.5 Hz, 9 Hz).

Compound ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm of Reference Example 47:
2.0-2.1 (2H, m), 3.1-3.2 (4H,
m), 4.04 (2H, t, J = 7 Hz), 4.22
(2H, t, J = 4.5 Hz), 6.2-6.3 (2
H, m), 6.35-6.45 (1H, m), 6.93
(1H, s), 7.09 (1H, s), 7.49 (1
H, s).

Compound ¹ of Reference Example 48 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.0-2.1 (2H, m), 3.4-3.5 (4H,
m), 3.78 (2H, t, J = 7 Hz), 4.25
(2H, t, J = 4.5 Hz), 6.56 (1H, d,
J = 9 Hz), 7.64 (1H, d, J = 2.5H)
z), 7.73-7.88 (5H, m).

Compound ¹ of Reference Example 49 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.95-2.04 (2H, m), 3.17-3.23
(4H, m), 3.77 (2H, t, J = 7 Hz),
4.22 (2H, t, J = 4.5 Hz), 6.2-6.
24 (2H, m), 6.5-6.55 (1H, m),
7.7-7.74 (2H, m), 7.83-8.02
(2H, m).

Reference Example 50 30 ml of dimethylformamide and 230 mg of sodium hydride (oil-based) were added to 926 mg of 5-methoxyindole.
Was added and stirred at 60 ° C. for 1 hour under a nitrogen stream. Then 0
At 1 ° C., 1.5 g of 1- (3-chloropropyl) -5-nitroindole was added, and the mixture was stirred at room temperature overnight. 60 ° C
After stirring for 5.5 hours, water was added, and the precipitated crystals were collected by filtration and washed with water. The residue was subjected to silica gel column chromatography (eluent; dichloromethane) to give 1- [3-
(5-methoxyindol-1-yl) propyl] -5
1.8 g of nitroindole were obtained.

¹ H-NMR (250 MHz, CDCl ₃ )
δ ppm; 2.4-2.5 (2H, m), 3.86 (3
H, s), 4.07-4.13 (4H, m), 6.47.
(1H, t, J = 2.5 Hz), 6.69 (1H, d,
J = 3.5 Hz), 6.83-6.88 (1H, m),
7.01 (1H, d, J = 3 Hz), 7.07-7.1
8 (4H, m), 8.06 (1H, dd, J = 2.5H
z, J = 9 Hz), 8.59 (1H, d, J = 2.5H)
z).

Using appropriate starting materials, in the same manner as in Reference Example 50, the above Reference Examples 7, 9, 10, 12 to 18, 20 to 20
23, 26-29, 32-36, 38, 39, 43, 4
Compounds 4 and 46-49 were obtained.

Reference Example 51 To a solution of 26 g of 2-benzylamino-4-chloroaniline in 500 ml of ethanol was added 45.7 g of glyoxylic acid ethyl ester, polymer form (45-50% toluene solution, manufactured by Tokyo Chemical Industry Co., Ltd.), followed by iodine. 28.4 g was added and the mixture was stirred at room temperature for 20 minutes. A 27.8 g aqueous solution of sodium thiosulfate was added thereto, and the precipitated crystals were collected by filtration.
After washing with water and ethanol and drying, a light brown powder of ethyl 1-benzyl-6-chlorobenzimidazole-
26.1 g of 2-carboxylate were obtained.

¹ H-NMR (250 MHz, CDCl ₃ )
δ ppm; 1.45 (3H, t, J = 7 Hz), 4.4
9 (2H, q, J = 7 Hz), 5.85 (2H, s),
7.1-7.5 (7H, m), 7.85 (1H, d, J
= 8.5 Hz).

The compound of Reference Example 2 was obtained in the same manner as in Reference Example 51 using appropriate starting materials.

Example 1A 2.2 g of methyl 1-benzyl-6-chlorobenzimidazole-2-carboxylate and 1- [3- (2-
Isopropyl imidazol-1-yl) propyl] -5
A mixture of 5.3 g of -aminomethylindole was heated and stirred at 80 ° C for 1.5 hours. After confirming disappearance of the raw materials, the mixture was dissolved in chloroform and washed with water and saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; 3% methanol / dichloromethane), fumaric acid was added, and the residue was recrystallized from diisopropyl ether-ethanol to give 1-benzyl-6-chloro-2 as a pale yellow powder. -｛1- [3- (2-
4 g of isopropyl-1-imidazol-1-yl) propyl] indol-5-ylmethylaminocarbonyl @ benzimidazole fumarate was obtained.

¹ H-NMR (250 MHz, DMSO-
d ₆ ) δ ppm; 1.10 (6H, d, J = 7 Hz),
2.1-2.3 (2H, m), 2.8-2.95 (1
H, m), 3.88 (2H, t, J = 7.5 Hz),
4.20 (2H, t, J = 7 Hz), 4.55 (2H,
d, J = 6.5 Hz), 5.98 (2H, s), 6.4
3 (1H, d, J = 3 Hz), 6.62 (2H, s),
6.66 (1H, d, J = 1.5 Hz), 7.10 (1
H, d, J = 1.5 Hz), 7.15-7.38 (10
H, m), 7.53 (1H, s), 7.77 (1H,
d, J = 8.5 Hz), 7.84 (1H, d, J = 1.
5 Hz), 9.57 (1 H, t, J = 4 Hz).

Example 1B 130 mg of lithium aluminum hydride was suspended in 70 ml of tetrahydrofuran, and 6-amino-3,4-
2.2 g of dihydro-2 (1H) -quinolinone was gradually added, and the mixture was stirred at room temperature overnight. After further stirring under reflux for 2 hours, 1 g of methyl 1-benzyl-6-chlorobenzimidazole-2-carboxylate was added. After refluxing for 3 hours to complete the reaction, water and 10% aqueous potassium hydroxide were added, diluted with ethyl acetate, filtered through celite, washed with chloroform, and evaporated under reduced pressure. Ethanol was added to the residue, and after heating, the insolubles were collected by filtration and recrystallized from dimethylformamide to give 1-benzyl-6-chloro-2- (3,4-dihydro-2 (1H 0.11 g))-quinolinone-6-ylaminocarbonyl) benzimidazole was obtained.

Melting point: 290 ° C. or higher ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m; 2.44 (2H, t, J = 7 Hz), 2.87 (2
H, t, J = 7 Hz), 5.99 (2H, s), 6.8
3 (1H, d, J = 9 Hz), 7.21-7.40 (6
H, m), 7.57-7.6 (1H, m), 7.72.
(1H, s), 7.86-7.88 (2H, m), 1
0.08 (1H, s).

Example 1C To 2.2 g of 5-amino-1- [3- (1-isopropyl-5-tetrazolyl) propyl] indole was added toluene 4%.
0 ml was added, and the mixture was stirred in a methanol-ice bath under a nitrogen atmosphere. After 4 ml of 2M trimethylaluminum n-hexane was added dropwise to this with a syringe, the mixture was stirred for 20 minutes, and further stirred at room temperature for 1 hour. Then methyl 1-benzyl-6
1. chlorobenzimidazole-2-carboxylate
18 g was added, and the mixture was stirred under reflux for 5 to 6 hours. Then 10
% Hydrochloric acid was added, and the crystals were collected by filtration. Water-chloroform was added thereto, and the mixture was made alkaline with 10% aqueous potassium hydroxide, filtered through celite, and the chloroform layer was washed with water and saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; 3% methanol / dichloromethane).
The crystals were recrystallized from ethyl acetate-n-hexane to give 1-benzyl-6-chloro-2- {1- [3- (1-isopropyltetrazol-5-yl) propyl] indol-5-ylamino as yellow needles. 2.27 g of carbonyl @ benzimidazole were obtained.

Melting point: 190-191 ° C.

Examples 1A to 1C using appropriate starting materials
In the same manner as in the above, compounds shown in the following Tables 9 to 33 were obtained.

[0244]

[Table 9]

[0245]

[Table 10]

[0246]

[Table 11]

[0247]

[Table 12]

[0248]

[Table 13]

[0249]

[Table 14]

[0250]

[Table 15]

[0251]

[Table 16]

[0252]

[Table 17]

[0253]

[Table 18]

[0254]

[Table 19]

[0255]

[Table 20]

[0256]

[Table 21]

[0257]

[Table 22]

[0258]

[Table 23]

[0259]

[Table 24]

[0260]

[Table 25]

[0261]

[Table 26]

[0262]

[Table 27]

[0263]

[Table 28]

[0264]

[Table 29]

[0265]

[Table 30]

[0266]

[Table 31]

[0267]

[Table 32]

[0268]

[Table 33]

The NMR spectra of the compounds of the examples obtained as described above are as follows.

Compound ^{1 of} Example 18 H-NMR (250 MHz, DMSO-d ₆ ) δpp
m: 1.10 (6H, d, J = 7 Hz), 2.1-2.
3 (2H, m), 2.8-2.95 (1H, m), 3.
88 (2H, t, J = 7.5 Hz), 4.20 (2H,
t, J = 7 Hz), 4.55 (2H, d, J = 6.5H)
z), 5.98 (2H, s), 6.43 (1H, d, J
= 3 Hz), 6.62 (2H, s), 6.66 (1H,
d, J = 1.5 Hz), 7.10 (1H, d, J = 1.
5Hz), 7.15-7.38 (10H, m), 7.5
3 (1H, s), 7.77 (1H, d, J = 8.5H)
z), 7.84 (1H, d, J = 1.5 Hz), 9.5
7 (1H, d, J = 4 Hz).

Compound ^{1 of} Example 28 H-NMR (250 MHz, DMSO-d ₆ ) δpp
m: 1.7-1.9 (2H, m), 2.89 (2H,
t, J = 8 Hz), 3.07 (2H, t, J = 7.5 H)
z), 3.2-3.4 (4H, m), 5.99 (2H,
s), 6.0-6.1 (1H, m), 6.47 (1H,
d, J = 8.5 Hz), 6.7-6.8 (1H, m),
6.8-6.9 (1H, m), 7.2-7.5 (7H,
m), 7.57 (1H, s), 7.8-7.9 (2H,
m), 8.0-8.1 (1H, m).

Compound ^{1 of} Example 31 ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m: 2.25-2.4 (2H, m), 2.9-3.1
(2H, m), 3.5-3.65 (2H, m), 4.1
-4.3 (4H, m), 5.97 (2H, s), 7.0
2 (1H, t, J = 7.5 Hz), 7.11-7.43
(9H, m), 7.60-7.64 (2H, m), 7.
71-7.75 (2H, m), 7.81 (1H, d, J
= 1.5 Hz), 9.09 (1H, s), 9.25 (1
H, t, J = 8 Hz).

Compound ^{1 of} Example 35 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.2-2.35 (2H, m), 3.4-3.5 (2
H, m), 4.3-4.4 (2H, m), 6.05 (2
H, s), 6.5-6.6 (1H, m), 7.1-7.
2 (1H, m), 7.2-7.5 (9H, m), 7.7
−7.8 (1H, m), 8.1-8.2 (1H, m),
9.62 (1H, s).

Compound ^{1 of} Example 36 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.26 (2H, m), 3.75 (2H, t, J = 7H
z), 4.2 (2H, t, J = 7 Hz), 6.06 (2
H, s), 6.48 (1H, d, J = 3 Hz), 7.2
4-7.5 (10H, m), 7.7-7.86 (5H,
m), 8.07 (1H, s), 9.60 (1H, s).

Compound ^{1 of} Example 37 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.26 (3H, t, J = 7 Hz), 4.15-4.3
(2H, m), 4.84 (2H, s), 6.06 (2
H, s), 6.56 (1H, d, J = 3 Hz), 7.1
2 (1H, d, J = 3 Hz), 7.23-7.47 (7
H, m), 7.75 (1H, d, J = 8.5 Hz),
8.12 (1H, s), 9.62 (1H, s).

Compound ^{1 of} Example 38 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.95-2.1 (2H, m), 2.92 (2H, t,
J = 8.5 Hz), 3.13 (2H, t, J = 7H)
z), 3.36 (2H, t, J = 8 Hz), 3.83
(2H, t, J = 7.5 Hz), 6.02 (2H,
s), 6.44 (1H, d, J = 8.5 Hz), 7.2
5-7.33 (7H, m), 7.39 (1H, d, J =
1.5Hz), 7.52 (1H, s), 7.69-7.
73 (3H, m), 7.82-7.85 (2H, m),
9.40 (1H, s).

Compound ^{1 of} Example 39 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
2.2-2.3 (2H, m), 3.10 (2H, t, J
= 7 Hz), 3.44 (2H, t, J = 6 Hz), 3.
75-3.85 (2H, m), 4.30 (2H, t, J
= 6 Hz), 5.97 (2H, s), 7.03 (1H,
s), 7.12-7.37 (10H, m), 7.61-
7.66 (2H, m), 7.8-7.9 (1H, m).

Compound ^{1 of} Example 40 ¹ H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.31 (2H, brs), 1.70-1.81 (2
H, m), 2.83 (2H, t, J = 7 Hz), 2.9
7 (2H, t, J = 8 Hz), 3.12 (2H, t, J
= 7.5 Hz), 3.36 (2H, t, J = 8 Hz),
6.02 (2H, s), 6.45 (1H, d, J = 8.
5Hz), 7.23-7.32 (7H, m), 7.38
(1H, d, J = 2 Hz), 7.53 (1H, s),
7.71 (1H, d, J = 9 Hz), 9.43 (1H,
s).

Compound ^{1 of} Example 41 H-NMR (250 MHz, DMSO-d ₆ ) δpp
m: 2.44 (2H, t, J = 7 Hz), 2.87 (2
H, t, J = 7 Hz), 5.99 (2H, s), 6.8
3 (1H, d, J = 9 Hz), 7.21-7.40 (6
H, m), 7.57-7.6 (1H, m), 7.72.
(1H, s), 7.86-7.88 (2H, m), 1
0.08 (1H, s).

Compound ^{1 of} Example 46 ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m: 6.01 (2H, s), 6.50 (1H, d, J =
9.5 Hz), 7.22-7.41 (7H, m), 7.
84-7.93 (4H, m), 8.25 (1H, s).

Compound ^{1 of} Example 49 ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m: 1.9-2.1 (2H, m), 2.5-2.6 (2
H, m), 2.8-3.0 (2H, m), 3.6-3.
8 (2H, m), 3.9-4.1 (2H, m), 5.9
9 (2H, s), 7.1-7.5 (7H, m), 7.6
-8.0 (4H, m).

Compound ^{1 of} Example 50 H-NMR (250 MHz, CDCl ₃ ) δ ppm:
1.9-2.1 (2H, m), 3.28-3.34 (4
H, m), 3.77 (2H, t, J = 7 Hz), 4.2
6 (2H, t, J = 4 Hz), 6.01 (2H, s),
6.63 (1H, d, J = 9 Hz), 7.11-7.4
0 (9H, m), 7.70-7.74 (3H, m),
7.81-7.87 (2H, m), 9.34 (1H,
s).

Example 51 To 0.66 g of 1-benzyl-6-chloro-2- (indol-5-ylaminocarbonyl) benzimidazole was added 50 ml of dimethylformamide, and 170 mg of oily sodium hydride was added. 1 in ° C
Stirred for hours. Allyl bromide was added to the mixture under cooling at 0 ° C.
After adding 14 ml and stirring at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate and washed with water and saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; 10% n-hexane /
After recrystallization from ethyl acetate-ethanol, 0.35 g of colorless needle crystals of 1-benzyl-6-chloro-2- (1-allylindol-5-ylaminocarbonyl) benzimidazole was obtained. Was.

Melting point: 154-155 ° C.

Using suitable starting materials, the same procedures as in Example 51 were repeated except that Examples 3, 4, 6 to 8, 10 to 20, and 22
Compounds 29, 31, 33-40, 42-45 and 47-50 were obtained.

Example 52 1-Benzyl-6-chloro-2- [1- (3-chloropropyl) indol-5-ylaminocarbonyl] benzimidazole was added to 3.8 g of dimethylformamide.
ml, further 1H-1,2,3,4-tetrazole 1.4
g, potassium carbonate 2.2 g, and sodium iodide 7.2 g, and the mixture was heated and stirred at 100 ° C. for 2 days. Water was added, extracted with ethyl acetate, and washed with water and saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; ethyl acetate / n-
Hexane = 1/1) to separate the isomers, and then recrystallized from ethyl acetate-n-hexane to give colorless needle crystals of 1-.
Benzyl-6-chloro-2- {1- [3- (1,2,
3,4-tetrazol-1-yl) propyl] indol-5-ylaminocarbonyl @ benzimidazole (A) (1.1 g) was recrystallized from dichloromethane-n-hexane to give 1-benzyl as pale yellow needles. 0.9 g of -6-chloro-2- {1- [3- (1,2,3,4-tetrazol-2-yl) propyl] indol-5-ylaminocarbonyl} benzimidazole (B) was obtained.

Melting point of (A): 178-179 ° C. Melting point of (B): 146-147 ° C.

Using suitable starting materials, the same procedures as in Example 52 were carried out except that Examples 3 to 4
20, 23-29, 31, 33, 34, 36, 38, 4
Compounds 0, 43, 44, 47, 48 and 50 were obtained.

Example 53 To 5 g of 1-benzyl-6-chloro-2- [1- (3-phthalimidopropyl) indol-5-ylaminocarbonyl] benzimidazole was added 100 ml of ethanol, the mixture was stirred, and hydrazine / water was added. 0.5 ml of the hydrate was added, and the mixture was refluxed overnight. After returning to room temperature, the white crystals were filtered off, water was added, and the mixture was made alkaline with 10% aqueous potassium hydroxide. This was extracted with dichloromethane and washed with water and saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure.
The residue was crystallized from ethyl acetate-n-hexane to give yellow granular crystals of 1-benzyl-6-chloro-2- [1- (3-
[Aminopropyl) indol-5-ylaminocarbonyl] benzimidazole (3.2 g) was obtained.

Melting point: 106-108 ° C.

Using the appropriate starting materials, the compound of Example 40 was obtained in the same manner as in Example 53.

Example 54 50 ml of dimethylformamide was added to 0.29 g of nicotinic acid.
And 1-benzyl-6-chloro-2- [1-
(3-Aminopropyl) indol-5-ylaminocarbonyl] benzimidazole (1.2 g) and triethylamine (0.7 ml) were added, and the mixture was stirred while cooling to 0 ° C. Then, after dissolving 0.49 g of diethyl cyanophosphonate in 20 ml of dimethylformamide, the mixture was stirred at room temperature for 1 day. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate.
Washed with water and saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; 2% methanol / dichloromethane), and recrystallized from chloroform to give yellow needles of 1-benzyl-6-chloro-2- {1- [3- ( 1 g of [pyridin-3-ylcarbonylamino) propyl] indol-5-ylaminocarbonyl @ benzimidazole was obtained.

Melting point: 206-207 ° C.

Using the appropriate starting materials, the same procedures as in Examples 9, 12, 28, 33, 34 and 47 were carried out in the same manner as in Example 54.
Was obtained.

Example 55 1-benzyl-6-chloro-2- (3,4-dihydro-
2 (1H) -quinolinone-6-ylaminocarbonyl)
To 0.35 g of benzimidazole, 30 ml of dioxane and 2,3-dichloro-5,6-dicyanobenzoquinone 2
80 mg was added and the mixture was heated under reflux. While confirming by thin layer chromatography, 2,3-dichloro-5,6-dicyanobenzoquinone was further added little by little, and the mixture was heated under reflux for one day. The precipitated crystals were collected by filtration and recrystallized from chloroform-isopropyl alcohol to give 1-benzyl-
6-Chloro-2- (2 (1H) -quinolinone-6-ylaminocarbonyl) benzimidazole was obtained.

Melting point: 290 ° C. or higher ¹ H-NMR (250 MHz, DMSO-d ₆ ) δpp
m; 6.01 (2H, s), 6.50 (1H, d, J =
9.5 Hz), 7.22-7.41 (7H, m), 7.
84-7.93 (4H, m), 8.25 (1H, s).

Example 56 27.9 g of ethyl 1-benzyl-6-chlorobenzimidazole-2-carboxylate, 17.8 g of 1- [3- (imidazol-1-yl) propyl] -5-aminoindole, sodium methyl A mixture of 8 g of the latet and 600 ml of toluene was stirred at 100 ° C. for 1.5 hours. After cooling to room temperature, the precipitated crystals were collected by filtration and washed with toluene. The obtained crystals are chloroform 500m.
1 and further added with 100 ml of water and filtered through celite. The chloroform layer was separated, washed with water, dried over magnesium sulfate, and then the solvent was distilled off to obtain a brown oil.
This was dissolved in methanol, n-hexane was further added,
The precipitated crystals were collected by filtration and recrystallized with methanol.
Dried and pale yellow needle-like 1-benzyl-6-chloro-2
-{1- [3- (imidazol-1-yl) propyl]
31.8 g of indole-5-ylaminocarbonyl @ benzimidazole were obtained.

Melting point: 187-188 ° C.

Using the appropriate starting materials, the compounds of Examples 2, 4 to 50 were obtained in the same manner as in Example 56.

Pharmacological Test (1) Measurement of cGMP PDE Inhibitory Activity The separation and purification of PDE from human platelets and the measurement of PDE inhibitory activity were performed by the method of Hidaka et al. (Biochimica et Biophysica Acta,
429 (1976) pp. 485-497). That is, platelets obtained from healthy adults were washed, suspended in Tris-buffer, centrifuged, the supernatant was applied to DEAE-cellulose, and fractionated into FI-FIII fractions with a concentration gradient of sodium acetate. FI was used as cGMP-PDE. PD
The E inhibitory activity was measured using 0.4 μM [ ³ H] cGMP. The results are shown in Table 34.

[0301]

[Table 34]

(2) Measurement of rat A10 cell proliferation inhibitory action N. Morisaki (Atherosclerosis, 71, (1988) 165-171)
The method was modified. That is, rat A10 cells (purchased from Dainippon Pharmaceutical) were placed on a 24-well immunoplate at 10,000 cells.
After culturing in 10% FBS (fetal bovine serum) for 2 days, the cells were further cultured in a serum-free culture medium for 2 days for introduction into the cessation phase. Thereafter, the test compound and [ ³ H] -thymidine 0.5 μC at the same time as growth stimulation with 1% FBS.
i / well was added, and the amount of [ ³ H] -thymidine incorporation 24 hours later was measured and used as an index of the amount of DNA synthesis. The results are shown in Table 35.

[0303]

[Table 35]

[0304] (3) using human fibroblast determined rat A10 cytostatic as well as human fibroblasts cytostatic (purchased from Dainippon Pharmaceutical Co., Ltd.) ^[3 H] - to measure thymidine uptake . Examples 3, 16 and 3 as test compounds
As a result of using the compounds obtained in 1, 33, 45 and 47, the IC ₅₀ values were 0.04 μM and 0.049 μM, respectively.
M, 0.18 μM, 0.042 μM, 0.041 μM and 0.021 μM.

(4) Measurement of T Cell Proliferation Inhibition Effect The method for measuring T cell proliferation was Current Protocol in Immunology.
(Edited by Coligan et al., (1991) Ch. 3, p. 12 [Willy Interscience]). Balb / c male mice were sacrificed and their spleens were removed and spleen cell suspensions were prepared in RPMI-1640 medium. After filtration through a nylon mesh, centrifugation (12
00 rpm, 5 minutes) and add 0.15 M ammonium chloride, 10 mM potassium bicarbonate and 0.1 mM
The cells were suspended by adding 5 ml of EDTA disodium salt (pH 7.2) per spleen, and incubated at 37 ° C. for 5 minutes. Add an appropriate amount of RPMI-1640 medium,
The cells were washed by centrifugation (1200 rpm, 5 minutes), and the washing operation was repeated twice. After that, the cells were suspended in an RPMI-1640 medium (RPMI-10) containing 10% FBS. After counting the number of cells using a hemocytometer,
The cell density was adjusted to 10 ⁶ / ml by dilution with RPMI-10. The test compound was dissolved in dimethyl sulfoxide to prepare a 2 × 10 ^-2 M solution, and a six-stage 10-fold dilution series was prepared using RPMI-10 as a diluent. After adding each dilution series to a 96-well tissue culture plate at 10 μl / well, the previously prepared cell suspension was added at 190 μl / well (final concentration of test compound: 10 ⁻⁹ to 10 ⁻⁴ M). 4
10 μl / well of 0 μg / ml concanavalin A was added, and cultured at 37 ° C. for 2 days in a 5% carbon dioxide gas phase.
20 μCi / ml [methyl- ³ H] thymidine was added to 10 μl
After adding 1 / well and further culturing overnight, the cells were collected on a filter using a cell harvester. The filter was cut out and placed in a vial, 5 ml of scintillation cocktail (ACS-II) was added, and measurement was performed using a liquid scintillation counter. As a result of using the compound obtained in Example 3 as a test compound, the IC ₅₀ value was 2 μM.

(5) Inhibitory effect on chronic contact dermatitis Action on chronic contact dermatitis similar to atopic dermatitis reported by Kitagaki et al. (J. Dermatol. Sci., Vol. 8, (1994) p. 54). Was examined using the following method. To the right auricle of a male Balb / c mouse, 20 μl of 1% trinitrochlorobenzene (TNCB) dissolved in acetone was applied to sensitize the antigen. Seven days later, 20 μl of 1% TNCB was applied to the right auricle to induce the antigen, and the induction was repeated every two days to induce chronic contact dermatitis. In this test, chronic contact dermatitis leads to an increase in pinna thickness. The test compound was dissolved in acetone-methanol (4: 1 v / v), and administered once a day from the 24th day of the antigen induction to the right auricle for 2 weeks. The vehicle was similarly administered as a control.
Antigen induction during the administration period of the test compound was performed 30 minutes before administration. The pinna thickness after 14 days was measured using a dial thickness gauge. The results are shown in Table 36.

[0307]

[Table 36]

(6) Inhibitory effect on TPA-induced edema Method of Carlson et al. (Agents Actions, 26, (1989) p. 319)
Was modified. That is, 20 μl of 200 μg / ml tetraphorbol ester (TPA) dissolved in acetone was applied to the auricle of an ICR female mouse to induce inflammation. The pinna thickness was measured 4 hours after TPA application, and the difference from the previous value was calculated as pinna edema. The test compound was dissolved in acetone-methanol (4: 1 v / v) so as to be 1%, and TPA was dissolved.
Twenty μl was administered 30 minutes before application. As a result of using the compound obtained in Example 3 as a test compound, edema was 66%.
Could be suppressed.

(7) Inhibitory effect on rat mesangial cell proliferation The method of F. Jaffer et al. (Am. J. Pathol., 135 (1989) 261-269)
Mesangial cells were collected according to the procedure described in (p. The rat was aseptically removed from the kidney under anesthesia, the pertinent part was cut out, and the cortical part was pressed on a stainless steel sieve (120 mesh). The passed fraction was placed on a 200-mesh sieve, and PBS
And it was confirmed that the fraction remaining on the sieve was a glomerulus. This fraction was separated from RPMI 1640 medium (15
% Calf serum (FCS) containing 5 μg / ml insulin) for 4 weeks. Two more subcultures were performed, and the remaining cells were regarded as mesangial cells from this morphology and used for experiments.

The growth inhibitory effect was measured by the method of MBGanz et al.
(Am. J. Physiol., Vol. 259, (1990) F269-F278).
That is, 2 × 10 ⁴ / ml of mesangial cells were dispensed into a culture plate (48 wells, 0.5 ml / well), and RP
The cells were cultured in MI medium (containing 15% FCS) for 3 days. The medium was replaced with RPMI medium with the FCS concentration reduced to 0.5%, and the cells were further cultured for 3 days. Then, the test compound was exchanged with RPMI medium containing the same FCS, and the test compound dissolved in dimethyl sulfoxide (final concentration of dimethyl sulfoxide was within 0.1%) and PDGF-BB 5 ng / ml.
(Final concentration) was added. After 24 hours, [ ³ H] -thymidine was added at 1 μCi / well, and the cells were further cultured for 24 hours.
The culture supernatant was taken, and thymidine incorporated into the cells was measured with a scintillation counter. As a result of using the compound obtained in Example 3 as a test compound, the IC ₅₀ value was 0.79 μM.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/445 ABN A61K 31/445 ABN 31/47 ABC 31/47 ABC 31/535 ABE 31/535 ABE C07D 401/12 235 C07D 401/12 235 401/14 209 401/14 209 233 233 235 235 403/14 207 403/14 207 413/14 209 413/14 209 213 213 233 233 (72) Inventor Mikiyasu Saito Tateiwa, Fuyo-cho, Naruto City, Tokushima Prefecture 144 characters at five characters (72) Inventor Shinji Yoshinaga 1810 Pana Heights 23, 1090 Kagasuno, Kawauchi-machi, Tokushima City, Tokushima Prefecture (58) Fields investigated (Int.Cl. ⁶ , DB name) C07D 403/12 209 C07D 403 / 12 231 C07D 401/12 235 C07D 401/14 209 C07D 401/14 233 C07D 401/14 235 C07D 403/14 207 C07D 413/14 209 C07D 413/14 213 C07D 413/14 233 CA (ST ) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A compound of the general formula [In the formula, R ¹ represents a hydrogen atom or a halogen atom. R ² represents a phenyl lower alkyl group. R ³ is an indolyl group,
Indolinyl group, 1H-indazolyl group, 2 (1H)-
And a heterocyclic group selected from the group consisting of a quinolinonyl group, a 3,4-dihydro-2 (1H) -quinolinonyl group, and a 3,4-dihydro-1,4 (2H) -benzooxazinyl group. Heterocyclic onto a -B-R ⁴ as a substituent on (B is a lower alkylene group, R ⁴ is 5 to chromatic 1-4 heteroatoms selected from nitrogen atom, oxygen atom and a sulfur atom the group consisting of
An 11-membered saturated or unsaturated monocyclic or binomial heterocyclic group (a group selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and an oxo group as a substituent on the heterocyclic ring; 1-3 has may be) or a group -NR ⁵ R ⁶
(R ⁵ and R ⁶ may be the same or different and are each a hydrogen atom, a lower alkyl group, a cycloalkyl group, a pyridylcarbonyl group, an isoxazolylcarbonyl group which may have 1 to 3 lower alkyl groups as a substituent, R ⁵ and R ⁶ represent, together with or without a nitrogen atom or an oxygen atom, a nitrogen atom or an oxygen atom to which they are bonded, which represents an amino-substituted lower alkyl group which may have a lower alkyl group as a substituent. A 5- to 6-membered saturated heterocyclic ring may be formed by bonding to each other, wherein a group selected from the group consisting of a hydroxyl group and a phenyl group is substituted on the heterocyclic ring by 1
You may have up to three. ). A lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on the phenyl ring; a group selected from the group consisting of a halogen-substituted lower alkyl group and a lower alkoxycarbonyl-substituted lower alkyl group. May be provided for 1 to 3. A represents a lower alkylene group. n represents 0 or 1. A benzimidazole derivative or a salt thereof. 2. R ¹ is a halogen atom and R ³ is an indolyl group [a group represented by -BR ⁴
(B is a lower alkylene group, R ⁴ is a 5- to 11-membered saturated or unsaturated monocyclic or dicyclic heterocyclic having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. A ring group (a halogen atom as a substituent on the heterocyclic ring,
May have from 1 to 3 groups selected from the group consisting of lower alkyl groups, lower alkoxy groups and oxo groups) or groups-
NR ⁵ R ⁶ (R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom,
It may have a lower alkyl group, a cycloalkyl group, a pyridylcarbonyl group, an isoxazolylcarbonyl group which may have 1 to 3 lower alkyl groups as a substituent, a pyrrolylcarbonyl group or a lower alkyl group as a substituent. Indicates an amino-substituted lower alkyl group. Also R ⁵ and R ⁶
Is defined as being bonded to each other with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded.
A 6- to 6-membered saturated heterocyclic ring may be formed. The heterocyclic ring may have 1 to 3 groups selected from the group consisting of a hydroxyl group and a phenyl group as a substituent. ). A lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy lower alkyl group which may have a cyano group as a substituent on the phenyl ring; a group selected from the group consisting of a halogen-substituted lower alkyl group and a lower alkoxycarbonyl-substituted lower alkyl group. May be provided for 1 to 3. ]
2. The benzimidazole derivative or a salt thereof according to claim 1, wherein n is 0. 3. 1-benzyl-6-chloro-2- {1-
[3- (imidazol-1-yl) propyl] indol-5-ylaminocarbonyl @ benzimidazole,
1-benzyl-6-chloro-2- {1- [3- (N-cyclohexyl-N-methylamino) propyl] indol-5-ylaminocarbonyl} benzimidazole;
1-benzyl-6-chloro-2- {1- [3- (pyrazol-1-yl) propyl] indol-5-ylaminocarbonyl} benzimidazole, 1-benzyl-6
-Chloro-2- {1- [3- (1,2,4-triazol-1-yl) propyl] indol-5-ylaminocarbonyl} benzimidazole, 1-benzyl-6
Chloro-2- {1- [3- (3,5-dimethylisoxazol-4-ylcarbonylamino) propyl] indol-5-ylaminocarbonyl} benzimidazole, 1-benzyl-6-chloro-2- {1 − [3- (4
-Phenyl-4-hydroxy-1-piperidin-1-yl) propyl] indol-5-ylaminocarbonyl {benzimidazole and 1-benzyl-6-chloro-2- {4-} 3- (pyridin-2-yl) Carbonylamino) propyl] -3,4-dihydro-1,4 (2H)
At least one compound selected from the group consisting of -benzoxazin-7-ylaminocarbonyl @ benzimidazole. 4. 1-benzyl-6-chloro-2- {1-
[3- (Imidazol-1-yl) propyl] indole
Ru-5-ylaminocarbonyl @ benzimidazole.