JP7032724B2 - New benzimidazole derivatives and their uses - Google Patents

Description

The present invention relates to novel benzimidazole derivatives and their uses. More specifically, the present invention relates to a novel benzimidazole derivative having Prostate Cancer Antigen-1 (PCA-1) inhibitory activity, a PCA-1 inhibitor containing the compound, a pharmaceutical agent, and the like.

Prostate cancer, which has the highest morbidity and mortality rate in Europe and the United States, has been found to have a rapid increase in morbidity rate in Japan due to the westernization of dietary habits. This early stage cancer of prostate cancer can be completely cured by surgical therapy, etc., but hormone therapy is performed for prostate cancer and advanced cancer in elderly people who have difficulty in surgical therapy. However, during this treatment, the emergence of hormone therapy-resistant prostate cancer has been observed, and therefore no effective treatment for prostate cancer has been established at present.

On the other hand, pancreatic cancer is currently regarded as one of the most difficult cancers to treat. Even if tumor resection surgery is performed for pancreatic cancer, about 90% will relapse and die. Gemcitabine hydrochloride and 5-FU are being used for locally advanced unresectable pancreatic cancer, and multidrug therapy centered on gemcitabine hydrochloride is being promoted when distant metastasis is observed, but the prognosis is still median. It is 4 to 6 months.

Lung cancer also accounts for the top number of cancer deaths in Japan. Among them, non-small cell lung cancer has the largest number of patients among lung cancers. Although taxane-based chemotherapeutic agents are used as therapeutic agents, it is said that only about 30% of regression is observed. In addition, gefitinib as a molecular target drug is indicated for patients with mutations in EGFR.

Therefore, the development of effective therapeutic agents for these cancers is eagerly desired, and it is necessary to establish a drug discovery base at an early stage.

A novel gene (Prostate Cancer Antigen-1: PCA-1) that is highly expressed in prostate cancer and is not highly expressed in normal prostate epithelial cells and benign prostatic hyperplasia has been reported (Non-Patent Document 1, Non-Patent Document 1, Non-Patent Document 1). Patent Document 2). A method using the expression status of PCA-1 for the diagnosis of prostate cancer (Patent Document 1), an apoptosis-promoting agent containing a compound that suppresses the expression or function of PCA-1 as an active ingredient, a cell proliferation inhibitor, and cancer prevention. -Therapeutic agents and the like (Patent Document 2) have been reported. PCA-1 is also highly expressed in pancreatic cancer (Patent Document 3) and non-small cell lung cancer (Non-Patent Document 3). As a result of suppressing PCA-1 expression in these cancer cells using siRNA, a remarkable growth inhibitory effect on prostate cancer cells (Patent Document 2), pancreatic cancer cells (Patent Document 3), and non-small cell lung cancer was obtained. It was recognized (Non-Patent Document 3). In addition, the tumor formed by transplanting cancer cells into mice showed regression by administration of siRNA to PCA-1. These results suggest that PCA-1 is a new molecular target for cancer treatment such as prostate cancer and pancreatic cancer.

In addition, since tRNA demethylated from PCA-1 increases protein translation efficiency, PCA-1 is also useful for diseases in which abnormal proteins can cause the onset (eg, neurodegenerative diseases, arteriosclerosis). Is.

On the other hand, benzimidazole derivatives having the following structures have been reported (Patent Documents 4 and 5), but none of them is known to have an effect on the enzymatic activity of PCA-1.

In addition, the present inventors have reported that a benzimidazole derivative having the following structure has excellent PCA-1 inhibitory activity (Patent Document 6).

International Publication No. 2006/098464 Pamphlet International Publication No. 2007/015587 Pamphlet Japanese Unexamined Patent Publication No. 2011-1286 U.S. Pat. No. 2,895,955 UK Pat. No. 815866 Japanese Patent No. 5854390 Gazette

Abstracts of the 123rd Annual Meeting of the Pharmaceutical Society of Japan 4, p. 15,2003 Konishi N et al., Clin Cancer Res. 2005 Jul 15; 11 (14): 5090-7. Tasaki M et al., Br J Cancer. 2011 104 (4): 700-6.

The present invention provides a compound effective for cancers, particularly prostate cancer, pancreatic cancer, non-small cell lung cancer, etc. for which an effective treatment method has not been established and / or a cancer having a poor prognosis. It is an object of the present invention to provide an anticancer agent or the like containing a compound as an active ingredient. Furthermore, it is an object of the present invention to provide a compound capable of inhibiting PCA-1 which can be a target of a novel therapeutic method for various diseases, and to provide a pharmaceutical use of the compound.

In view of the above problems, the present inventors have conducted diligent studies. Specifically, in addition to measuring the enzyme activity of PCA-1 using a screening system for measuring the enzyme activity of demethylating the methylated cytosine, measurement of the inhibitory effect on the growth of prostate cancer cells, We have succeeded in producing a series of useful compounds by measuring the time course of tumor volume using the Xenograft model and investigating both in vitro and in vivo activities such as oral absorbability, and have completed the present invention.

That is, the present invention provides the following.
[1] Equation (I):

[During the ceremony,
R ₁ is a hydrogen atom, -SO ₂ NR'R'' (in the formula, R'and R'' indicate the same or different hydrogen atoms or substituents, which may be combined to form a ring) or. Indicates a substituent;
R ₂ indicates a substituent;
R ₃ indicates a hydrogen atom or substituent;
R ₂ and R ₃ may be combined to form a ring;
However, when R ₂ and R ₃ do not form a ring, R ₁ indicates a compound represented by -SO ₂ NR'R'' or a pharmaceutically acceptable salt thereof.
[2] Equation (Ia):

[During the ceremony,
Ra'and Ra'' indicate the same or different hydrogen atoms or substituents;
R _2a indicates a C _1-6 alkyl group;
R _3a represents a C _7-12 aralkyl group].
The compound according to the above [1] or a pharmaceutically acceptable salt thereof.
[3] Ra'and Ra'' are the same or different hydrogen atoms, optionally substituted C _7-12 aralkyl groups or optionally substituted C _1-6 alkyl groups.
The compound according to the above [2] or a pharmaceutically acceptable salt thereof.
[4] The following formula:

The compound according to the above [1] or a pharmaceutically acceptable salt thereof.
[5] Equation (Ib):

[During the ceremony,
R _1b is a hydrogen atom, -SO ₂ NRb'Rb'' (in the formula, Rb'and Rb'' indicate the same or different hydrogen atoms or substituents, which may be combined to form a ring) or. Indicates a substituent;
X indicates -N (R)-, C _1-6 alkylene group, -O-, -S- or -S (O) _2- ;
R indicates a substituent], which is the compound according to the above [1] or a pharmaceutically acceptable salt thereof.
[6] The compound according to the above [5] or a pharmaceutically acceptable salt thereof, wherein R _1b is a hydrogen atom.
[7] R _1b is -SO ₂ NRb'Rb'', and Rb'and Rb'' are the same or different hydrogen atom, C _1-6 alkyl group, or C _3-6 cycloalkyl group, C ₁ The compound according to the above [5] or a pharmaceutically acceptable salt thereof, which is a _C7-12 aralkyl group which may be substituted with a _-6 alkoxy group.
[8] The compound according to the above [5] or pharmaceutically acceptable thereof, wherein R _1b is a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group optionally substituted with a halogen atom, or a nitro group. Salt that can be.
[9] R is C _1-6 alkyl group, C _3-6 cycloalkyl group, C _7-12 aralkyl group, formyl group, C _1-6 alkyl-carbonyl group, C _3-6 cycloalkyl-carbonyl group, C _{A 6-10} aryl-carbonyl group, a C _1-6 alkoxy-carbonyl group, a C _1-6 alkylsulfonyl group optionally substituted with a halogen atom, or a C ₆ optionally substituted with a C _1-6 alkyl group. The compound according to any one of the above [5] to [8], which is a _-10 arylsulfonyl group, or a pharmaceutically acceptable salt thereof.
[10] The following formula:

The compound according to the above [1] or a pharmaceutically acceptable salt thereof.
[11] Equation (I):

[During the ceremony,
R ₁ is a hydrogen atom, -SO ₂ NR'R'' (in the formula, R'and R'' indicate the same or different hydrogen atoms or substituents, which may be combined to form a ring) or. Indicates a substituent;
R ₂ indicates a substituent;
R ₃ indicates a hydrogen atom or substituent;
R ₂ and R ₃ may be combined to form a ring;
However, if R ₂ and R ₃ do not form a ring, R ₁ represents a -SO ₂ NR'R''] PCA-1 inhibitor comprising the compound represented by] or a pharmaceutically acceptable salt thereof. ..

[12] The compound represented by the formula (I) is the formula (Ia) :.

[During the ceremony,
Ra'and Ra'' indicate the same or different hydrogen atoms or substituents;
R _2a indicates a C _1-6 alkyl group;
R _3a is a compound represented by _C7-12 aralkyl group], which is the PCA-1 inhibitor according to the above [11].
[13] Ra'and Ra'' are the same or different hydrogen atoms, optionally substituted C _7-12 aralkyl groups or optionally substituted C _1-6 alkyl groups.
The PCA-1 inhibitor according to the above [12].
[14] The compound represented by the formula (I) has the following formula:

The PCA-1 inhibitor according to the above [11], which is a compound represented by.
[15] The compound represented by the formula (I) is the formula (Ib) :.

[During the ceremony,
R _1b is a hydrogen atom, -SO ₂ NRb'Rb'' (in the formula, Rb'and Rb'' indicate the same or different hydrogen atoms or substituents, which may be combined to form a ring) or. Indicates a substituent;
X indicates -N (R)-, C _1-6 alkylene group, -O-, -S- or -S (O) _2- ;
R represents a substituent], which is the PCA-1 inhibitor according to the above [11].
[16] The PCA-1 inhibitor according to the above [15], wherein R _1b is a hydrogen atom.
[17] R _1b is -SO ₂ NRb'Rb'', and Rb'and Rb'' are the same or different hydrogen atom, C _1-6 alkyl group, or C _3-6 cycloalkyl group, C _{1 -6} The PCA-1 inhibitor according to [15] above, which is a C _7-12 aralkyl group optionally substituted with an alkoxy group.
[18] The PCA-1 inhibitor according to the above [15], wherein R _1b is a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group optionally substituted with a halogen atom, or a nitro group.
[19] R is C _1-6 alkyl group, C _3-6 cycloalkyl group, C _7-12 aralkyl group, formyl group, C _1-6 alkyl-carbonyl group, C _3-6 cycloalkyl-carbonyl group, C _{A 6-10} aryl-carbonyl group, a C _1-6 alkoxy-carbonyl group, a C _1-6 alkylsulfonyl group optionally substituted with a halogen atom, or a C ₆ optionally substituted with a C _1-6 alkyl group. The PCA-1 inhibitor according to any one of the above [15] to [18], which is a _-10 arylsulfonyl group.
[20] The compound represented by the formula (I) is the following formula:

The PCA-1 inhibitor according to the above [11], which is a compound represented by.
[21] Equation (I):

[During the ceremony,
R ₁ is a hydrogen atom, -SO ₂ NR'R'' (in the formula, R'and R'' indicate the same or different hydrogen atoms or substituents, which may be combined to form a ring) or. Indicates a substituent;
R ₂ indicates a substituent;
R ₃ indicates a hydrogen atom or substituent;
R ₂ and R ₃ may be combined to form a ring;
However, if R ₂ and R ₃ do not form a ring, R ₁ comprises the compound represented by -SO ₂ NR'R'' or a pharmaceutically acceptable salt thereof.
A prophylactic and / or therapeutic agent for a disease involving PCA-1.
[22] The compound represented by the formula (I) is the formula (Ia) :.

[During the ceremony,
Ra'and Ra'' indicate the same or different hydrogen atoms or substituents;
R _2a indicates a C _1-6 alkyl group;
_{R3a represents a C7-12 aralkyl} group].
The prophylactic and / or therapeutic agent according to the above [21].
[23] Ra'and Ra'' are the same or different hydrogen atoms, optionally substituted C _7-12 aralkyl groups or optionally substituted C _1-6 alkyl groups.
The prophylactic and / or therapeutic agent according to the above [22].
[24] The compound represented by the formula (I) is the following formula:

The prophylactic and / or therapeutic agent according to the above [21], which is a compound represented by.
[25] The compound represented by the formula (I) is the formula (Ib) :.

[During the ceremony,
R _1b is a hydrogen atom, -SO ₂ NRb'Rb'' (in the formula, Rb'and Rb'' indicate the same or different hydrogen atoms or substituents, which may be combined to form a ring) or. Indicates a substituent;
X indicates -N (R)-, C _1-6 alkylene group, -O-, -S- or -S (O) _2- ;
R indicates a substituent], which is the prophylactic and / or therapeutic agent according to the above [21].
[26] The prophylactic and / or therapeutic agent according to the above [25], wherein R _1b is a hydrogen atom.
[27] R _1b is -SO ₂ NRb'Rb'', and Rb'and Rb'' are the same or different hydrogen atom, C _1-6 alkyl group, or C _3-6 cycloalkyl group, C _{1 -6} The prophylactic and / or therapeutic agent according to [25] above, which is a _C7-12 aralkyl group optionally substituted with an alkoxy group.
[28] The prophylactic and / or therapeutic agent according to [25] above, wherein R _1b is a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group optionally substituted with a halogen atom, or a nitro group. ..
[29] R is C _1-6 alkyl group, C _3-6 cycloalkyl group, C _7-12 aralkyl group, formyl group, C _1-6 alkyl-carbonyl group, C _3-6 cycloalkyl-carbonyl group, C _{A 6-10} aryl-carbonyl group, a C _1-6 alkoxy-carbonyl group, a C _1-6 alkylsulfonyl group optionally substituted with a halogen atom, or a C ₆ optionally substituted with a C _1-6 alkyl group. The prophylactic and / or therapeutic agent according to any one of the above [25] to [28], which is a _-10 arylsulfonyl group.
[30] The compound represented by the formula (I) has the following formula:

The prophylactic and / or therapeutic agent according to the above [21], which is a compound represented by.
[31] The prevention and / or treatment according to any one of the above [21] to [30], wherein the disease in which PCA-1 is involved is selected from the group consisting of cancer, cranial nerve degenerative disease, and arteriosclerosis. medicine.
[32] The above-mentioned [31], wherein the cancer is at least one selected from the group consisting of prostate cancer, pancreatic cancer and non-small cell lung cancer, and has an anticancer effect against the above-mentioned cancers. The prophylactic and / or therapeutic agents described.
[33] An anticancer concomitant agent comprising the compound according to any one of the above [1] to [10] or a pharmaceutically acceptable salt thereof and at least one anticancer agent.
Hereinafter, the compound represented by the formula (I) (also referred to as compound (I)) and a pharmaceutically acceptable salt thereof may be collectively referred to as the compound of the present invention.

The compound of the present invention has an excellent inhibitory effect on the enzyme activity of PCA-1, and is useful for the prevention and / or treatment of diseases in which PCA-1 is involved. Furthermore, the compound of the present invention is useful as an anticancer agent because it can suppress the growth of prostate cancer cells in vitro and suppress the increase in tumor volume in the Xenograft model.

The result of Test Example 3 is shown. It is a graph which shows the antitumor action of the compound of this invention (Example 1 and Example 2) in a DU145 cell xenograft model.

Hereinafter, the present invention will be described. The terms used herein have meanings commonly used in the art unless otherwise noted.
The terms used herein are defined below.

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

The "C _1-6 alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, and specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and the like. Examples thereof include sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl and the like.

The "C _3-6 cycloalkyl group" means a cyclic alkyl group having 3 to 6 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The "C _6-10 aryl group" means an aryl group having 6 to 10 carbon atoms, and specific examples thereof include phenyl and naphthyl.

The "C _7-12 aralkyl group" means an arylalkyl group having 7 to 12 carbon atoms (an alkyl group substituted with an aryl group), and specifically, a benzyl group, a phenylethyl group, or a phenylpropyl group. , Naftylmethyl group and the like.

The "C _1-6 alkoxy group" means a linear or branched alkoxy group having 1 to 6 carbon atoms, and specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy. , Sc-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, neopentyloxy, 2-pentyloxy, 3-pentyloxy, n-hexyloxy, 2-hexyloxy and the like. ..

"C _1-6 alkyl-carbonyl group" means a carbonyl group substituted with a C _1-6 alkyl group (above), specifically methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butyl. Examples thereof include carbonyl, isobutylcarbonyl, tert-butylcarbonyl and the like.

"C _3-6 cycloalkyl-carbonyl group" means a carbonyl group substituted with a C _3-6 cycloalkyl group (described above), specifically cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, Examples thereof include cyclohexylcarbonyl.

The "C _6-10 aryl-carbonyl group" means a carbonyl group substituted with a C _6-10 aryl group (described above), and specific examples thereof include phenylcarbonyl and naphthylcarbonyl.

The “C _1-6 alkoxy-carbonyl group” means a carbonyl group substituted with a C _1-6 alkoxy group (described above), and specifically, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, Examples thereof include butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and the like.

The "C _1-6 alkyl sulfonyl group" means a sulfonyl group substituted with a C _1-6 alkyl group (described above), and specifically, methyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl. , Isobutylsulfonyl, tert-butylsulfonyl and the like.

The "C _6-10 aryl sulfonyl group" means a sulfonyl group substituted with a C _6-10 aryl group (described above), and specific examples thereof include phenyl sulfonyl and naphthyl sulfonyl.

The "C _1-6 alkylene group" is, for example, a linear or branched chain of methylene, ethylene, trimethylene, tetramethylene, ethylethylene, isopropylene, isobutylene, s-butylene, t-butylene, isopentylene and neopentylene. Examples thereof include alkylene having 1 to 6 carbon atoms.

Substituents that the "C _1-6 alkyl group", "C _6-10 aryl group", and "C _7-12 aralkyl group" may have include
(1) Halogen atoms (eg, fluorine, chlorine, bromine, iodine; preferably fluorine),
(2) C _1-6 alkyl groups such as lower alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl) which may be substituted with halogen atoms. Such),
(3) Cycloalkyl group (for example, C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
(4) Lower alkynyl group (eg, C _2-6 alkynyl group such as ethynyl, 1-propynyl, propargyl, etc.),
(5) Lower alkenyl groups (eg, C _2-6 alkenyl groups such as vinyl, allyl, isopropenyl, butenyl, isobutenyl, etc.),
(6) An aralkyl group that may be substituted with a C _1-6 alkoxy group (eg, methoxy) (eg, a C _7-12 aralkyl group such as benzyl, α-methylbenzyl, phenethyl, etc.),.
(7) Aryl groups (eg, _C6-10 aryl groups such as phenyl and naphthyl, preferably phenyl groups),
(8) Lower alkoxy groups (eg, C _1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., trifluoro, which may be substituted with halogen atoms. (Methoxy, etc.),
(9) Aryloxy groups (eg, _C6-10 aryloxy groups such as phenoxy),
(10) C _1-6 alkyl-carbonyl group such as acetyl, propionyl, butyryl, isobutyryl, C _3-6 cyclo such as cycloalkylcarbonyl, which may be substituted with a halogen atom, a formyl group or a lower alkanoyl group. Alkyl-carbonyl group, etc.),
(11) Arylcarbonyl group (eg, _C6-10 aryl-carbonyl group such as benzoyl, naphthoyl, etc.),
(12) Formyloxy group or lower alkanoyloxy group (eg, C _1-6 alkyl-carbonyloxy group such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.),.
(13) Arylcarbonyloxy groups (eg, _C6-10 aryl-carbonyloxy groups such as benzoyloxy and naphthoyloxy),
(14) Carboxyl group,
(15) Lower alkoxycarbonyl groups (eg, C _1-6 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl),
(16) Aralkyloxycarbonyl group (eg, _C7-12 aralkyloxy-carbonyl group such as benzyloxycarbonyl),
(17) Carbamic acid group,
(18) Mono-, di- or tri-halogeno-lower alkyl groups (eg, mono-, di- or tri-halogeno such as chloromethyl, dichloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl). C _1-6 alkyl group, etc.),
(19) Oxo group,
(20) Amidino group,

(21) Imino group,
(22) Amino group,
(23) Mono-lower alkylamino group (eg, mono-C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.),
(24) Di-lower alkylamino group (eg, di-C _1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, N-ethyl-N-methylamino, etc.),.
(25) It may contain 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom and one nitrogen atom which may have a substituent 3 to 3. 8-membered nitrogen-containing heterocyclic group (eg, halogen atom, nitro group, cyano group, hydroxy group, C _1-6 alkyl group which may be halogenated, C _1-6 alkoxy group which may be halogenated. , Amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, carboxyl group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, carbamoyl group, mono- C _1-6 alkyl-carbamoyl group, di-C _1-6 alkyl-carbamoyl group, C _6-10 aryl-carbamoyl group, C _6-10 aryl group, C _6-10 aryloxy group, and halogenated. It may have 1 to 5 substituents selected from a C _1-6 alkyl-carbonylamino group, an oxo group, etc., in addition to a carbon atom and one nitrogen atom, a nitrogen atom, an oxygen atom and A 3- to 8-membered nitrogen-containing heterocyclic group which may contain 1 to 3 heteroatoms selected from sulfur atoms; for example, aziridinyl, azetidinyl, pyrrolidinyl, pyridyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidyl. , Oxaziazolyl, isooxazolyl, morpholinyl, dihydropyridyl, tetrahydropyridyl, piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, etc.),
(26) alkylenedioxy group (for example, C _1-3 alkylenedioxy group such as methylenedioxy and ethylenedioxy),
(27) Hydroxy group,
(28) Nitro group,
(29) Cyano group,
(30) Mercapto group,
(31) Sulfonic group,
(32) Sulfino group,
(33) Phosphono group,
(34) Sulfamoyl group,
(35) Mono-lower alkyl sulfamoyl groups (eg, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.) Mono-C _1-6 alkyl sulfamoyl group, etc.),
(36) Di-lower alkyl sulfamoyl groups (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, etc. Di-C _1-6 alkyl sulfamoyl group, etc.),
(37) Lower alkylthio groups (eg, C _1-6 alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.),.
(38) Arylthio groups (eg, _C6-10 arylthio groups such as phenylthio, naphthylthio, etc.),
(39) Lower alkylsulfinyl groups (eg, C _1-6 alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.),.
(40) Arylsulfinyl groups (eg, _C6-10 arylsulfinyl groups such as phenylsulfinyl, naphthylsulfinyl, etc.),.

(41) A lower alkylsulfonyl group which may have a substituent (eg, a halogen atom) (eg, a C _1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl), etc.
(42) Arylsulfonyl groups that may have substituents (eg, C _1-6 alkyl groups) (eg, C _6-10 arylsulfonyl groups such as phenylsulfonyl, naphthylsulfonyl, etc.),
(43) Lower alkylcarbonylamino group (eg, C _1-6 alkylcarbonylamino group such as methylcarbonylamino),
(44) Aralkylamino group (eg, _C7-12 aralkylamino group such as benzylamino),
(45) An alkylsulfonylamino group which may have a substituent (eg, a C _1-6 alkyl group which may have a halogen atom) (eg, C _6- such as phenylsulfonylamino and naphthylsulfonylamino). ₁₀ arylsulfonylamino groups, etc.),
Substituents selected from the group consisting of the above (referred to as Substituent Group A in the present specification) are used.

Hereinafter, the compound represented by the formula (I) will be described. Unless otherwise specified, the definition of each group has the same meaning as described above.

In formula (I), R ₁ represents a hydrogen atom, -SO ₂ NR'R'' (in the formula, R'and R'' represent the same or different hydrogen atom or substituent, and together form a ring. May) or indicate a substituent; R ₂ indicates a substituent; R ₃ indicates a hydrogen atom or a substituent; R ₂ and R ₃ may together form a ring;
However, when R ₂ and R ₃ do not form a ring, R ₁ indicates −SO ₂ NR'R''.
Here, examples of the "substituent" include those exemplified as the above-mentioned substituent group A.
When R ₂ and R ₃ do not form a ring, a preferred embodiment of the compound represented by the formula (I) can be represented by the following formula (Ia).

[During the ceremony,
Ra'and Ra'' indicate the same or different hydrogen atoms or substituents;
R _2a indicates a C _1-6 alkyl group;
R _3a represents a C _7-12 aralkyl group].
Examples of the "substituent" in Ra'and Ra'' include those exemplified as the above-mentioned substituent group A, but preferably substituted _C7-12 aralkyl groups (eg, benzyl, methoxybenzyl). ), Or a optionally substituted C _1-6 alkyl group (eg, tert-butyl).
R _2a is preferably methyl.
R _3a is preferably benzyl.

Preferred examples of the compound represented by the formula (Ia) include the following compounds.

When R ₂ and R ₃ form a ring, a preferred embodiment of the compound represented by the formula (I) can be represented by the following formula (I-b).

[During the ceremony,
R _1b is a hydrogen atom, -SO ₂ NRb'Rb'' (in the formula, Rb'and Rb'' indicate the same or different hydrogen atoms or substituents, which may be combined to form a ring) or. Indicates a substituent;
X indicates -N (R)-, C _1-6 alkylene group, -O-, -S- or -S (O) _2- ;
R indicates a substituent]
Examples of the "substituent" in Rb'and Rb' include those exemplified as the above-mentioned substituent group A, preferably a C _1-6 alkyl group (eg, methyl, ethyl, propyl, butyl, pentyl). , C _3-6 cycloalkyl group (eg, cyclohexyl), C _7-12 aralkyl group (eg, benzyl) which may be substituted with C _1-6 alkoxy group (eg, methoxy).
Examples of the ring formed by Rb'and Rb'' together include a piperidine ring.
Examples of the "substituent" in R _1b include those exemplified as the above-mentioned substituent group A, preferably a halogen atom (eg, fluorine atom, chlorine atom), C _1-6 alkyl group (eg, methyl). , C _1-6 alkoxy groups (eg, methoxy) and nitro groups which may be substituted with halogen atoms (eg, fluorine atoms).
Preferred examples of the "C _1-6 alkylene group" in X include methylene, ethylene and isopropylene.
Examples of the "substituent" in R include those exemplified as the above-mentioned substituent group A, preferably a C _1-6 alkyl group (eg, isopropyl) and a C _3-6 cycloalkyl group (eg, cyclo). Propyl), C _7-12 aralkyl group (eg, benzyl), formyl group, C _1-6 alkyl-carbonyl group (eg, acetyl, tert-butylcarbonyl), C _3-6 cycloalkyl-carbonyl group (eg, cyclohexyl). Substituent with C _6-10 aryl-carbonyl group (eg phenylcarbonyl), C _1-6 alkoxy-carbonyl group (eg tert-butoxycarbonyl), halogen atom (eg chlorine atom, fluorine atom) Examples include the C _6-10 aryl sulfonyl group (eg, phenylsulfonyl) which may be substituted with a C _1-6 alkyl sulfonyl group (eg, methyl sulfonyl) or a C _1-6 alkyl group (eg, methyl) which may be substituted. Be done.

Preferred examples of the compound represented by the formula (Ib) include the following compounds.

A compound represented by the formula (I) including a compound represented by the formula (Ia) and a compound represented by the formula (Ib) may be referred to as a compound (I).

Examples of the salt of the compound (I) include pharmaceutically acceptable salts, such as trifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleic acid, tartrate acid, citric acid, gluconic acid, ascorbic acid, and benzoic acid. Acid addition salts with acids such as methanesulfonic acid, p-toluenesulfonic acid, silicic acid, fumaric acid, phosphonic acid, hydrochloric acid, nitrate, hydrobromic acid, hydroiodic acid, sulfamic acid, sulfuric acid; for example, sodium , Metal salts such as potassium, magnesium, calcium; for example, salts with organic bases such as trimethylamine, triethylamine, pyridine, picolin, N-methylpyrrolidin, N-methylpiperidine, N-methylmorpholin and the like.

When compound (I) has isomers such as optical isomers, stereo isomers, positional isomers, and rotational isomers, either one isomer or a mixture of isomers is included in compound (I). Will be done. For example, when the optical isomer is present in the compound (I), the optical isomer separated from the racemate is also included in the compound (I). Each of these isomers can be obtained as a single product by a synthesis method and a separation method (concentration, solvent extraction, column chromatography, recrystallization, etc.) known per se. Further, the compound (I) contains structural isomers such as tautomers and geometric isomers, and such isomers are also within the scope of the present invention.

Examples of the tautomer include the following structures.

(Definition of each symbol in the formula is synonymous with the above)

Compound (I) may be crystalline or amorphous. When compound (I) is crystalline, it is included in compound (I) whether it has a single crystalline form or a crystalline mixture. Crystals can be produced by crystallization by applying a crystallization method known per se.

The compound (I) may be a solvate (for example, a hydrate or the like) or a non-solvate, and both are included in the compound (I).

Compound (I) may be labeled with an isotope (eg, ^3H , ^14C , ^35S , ^125I , etc.) or the like.

The compound of the present invention has Prostate Cancer Antigen-1 (PCA-1) binding activity and has an action of inhibiting the enzymatic activity of PCA-1. PCA-1 is highly expressed specifically in prostate cancer, and since the PCA-1 gene has high homology with the E. coli protein AlkB, which is a DNA and RNA alkylation damage repair enzyme, human AlkB homolog 3 (human AlkB homolog). 3: Also called hALKBH3), it has been confirmed that it catalyzes DNA and RNA demethylation like AlkB. Inhibiting the enzymatic activity of PCA-1 directly and / or indirectly inhibits the DNA and RNA demethylation reaction of PCA-1, for example, by specifically binding to PCA-1. , Inhibits enzyme activity. The enzyme activity can be measured according to a method usually practiced in the art or by modifying the method as necessary. For example, it can be evaluated by measuring the degree of demethylation using methylated substrate DNA.

Furthermore, the compound of the present invention has a growth inhibitory activity on cells (particularly cancer cells). Examples of cancer cells in which the compound of the present invention exhibits an inhibitory effect include, but are not limited to, prostate cancer cells, pancreatic cancer cells, non-small cell lung cancer cells, renal cancer cells, bladder cancer cells and the like. Preferred are DU145 (prostate cancer cells), PC-3 (prostate cancer cells), Panc-1 (pancreatic cancer cells), Mia-Paca-2 (pancreatic cancer cells), A549 (non-small cell lung cancer cells). , H520 (non-small cell lung cancer cells) and the like.

Due to the excellent PCA-1 inhibitory activity and / or cancer cell growth inhibitory activity of the compound of the present invention, the compound of the present invention can be used in mammals (eg, humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs). , Dogs, rabbits, etc.), PCA-1 is useful as a prophylactic or therapeutic agent for diseases involved in the onset or progression (diseases in which the onset or progression is promoted).
Examples of such diseases include cancer (eg, prostate cancer, pancreatic cancer, non-small cell lung cancer), cerebral neurodegenerative diseases (eg, Alzheimer, Parkinson), arteriosclerosis and the like.

The content of the compound of the present invention in a drug containing the compound of the present invention as an active ingredient (for example, an anticancer agent, etc.) is usually about 0.01 to about 99.9% by weight, preferably about 0, based on the entire preparation. .1 to about 50% by weight.

The dose of the compound of the present invention depends on the age, body weight, general health condition, gender, diet, administration time, administration method, excretion rate, drug combination, and degree of medical condition of the patient being treated at that time. It is decided in consideration of those or other factors.
The dose varies depending on the target disease, symptom, administration target, administration method, etc., but for example, the daily dose of the compound (I) of the present invention is about 0.1 to 100 mg / kg (body weight), preferably about 0.1 to 100 mg / kg (body weight). It is preferable to administer about 1 to 10 mg / kg (body weight), more preferably about 1 to 3 mg / kg (body weight) in one dose or in two to three divided doses.

The compound of the present invention can be used in combination with other drugs depending on the target disease. These concomitant agents may be small molecule compounds, high molecular weight proteins, polypeptides, antibodies, vaccines and the like. In this case, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be combined at the time of administration. For example, it can be used in combination with other anticancer agents that exhibit anticancer activity by a mechanism of action different from that of the compound of the present invention, such as cisplatin, gemcitabine, carboplatin, taxol, taxotere, methotrexate, vinblastine, and adriamycin.

The compound of the present invention may be blended with a pharmaceutically acceptable carrier to form a solid preparation such as a tablet, a capsule, a granule or a powder; a liquid preparation such as a syrup or an injection; a patch, an ointment, a plaster or the like. It can be appropriately formulated as a transdermal absorbent; an inhalant; a suppository.
The pharmaceutical substance containing the compound of the present invention may be orally or parenterally administered, and the above-mentioned compounds may be used alone or in combination of two or more.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical material can be used. Specifically, it contains excipients, lubricants, binders, disintegrants, solvents, lysis aids, suspending agents, tonicity agents, buffers, pain-relieving agents, etc. in solid formulations. can do. Further, if necessary, pharmaceutical additives such as preservatives, antioxidants, colorants, and sweeteners can be used.

Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, citrus powder, mannitol, sodium hydrogencarbonate, calcium phosphate, calcium sulfate and the like.

Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, purified talc, colloidal silica and the like.

Examples of the binder include crystalline cellulose, sucrose, mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like.

Examples of the disintegrant include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium croscarmellose, sodium carboxymethyl starch and the like.

Preferable examples of the solvent include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.

Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

Examples of suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate; polyvinyl alcohol, polyvinylpyrrolidone, etc. Examples thereof include sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like.

Preferable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like.

Preferable examples of the buffer include, for example, buffers such as phosphates, acetates, carbonates and citrates.
Preferable examples of the soothing agent include benzyl alcohol and the like.

Suitable examples of preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Preferable examples of the antioxidant include sulfites, ascorbic acid and the like.
Preferable examples of the colorant include tar pigments, caramel, iron sesquioxide, titanium oxide, riboflavins and the like.
Suitable examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.

Production Method The compounds represented by the formula (I) of the present invention, their isomers, solvates and pharmaceutically acceptable salts thereof utilize various characteristics based on the basic skeleton or the type of substituent. It can be produced by applying a known synthetic method. For example, it can be produced according to the following synthetic method, but the present invention is not limited to these, and it can be appropriately modified as desired. Such modifications include alkylation, acylation, amination, iminization, halogenation, reduction, oxidation and the like, and reactions or methods usually used in the art are used. At that time, depending on the type of the functional group, it is effective in terms of manufacturing technology to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at the stage of the raw material or the intermediate. There is. The chemistry of protecting groups, the method of introduction thereof, and their removal are detailed, for example, in T. Greene and P. Wuts “Protective Groups in Organic Synthesis” (3rd ^ed .), John Wiley & Sons NY (1999). ing.

Unless otherwise specified, the starting compound can be easily obtained on the market, or can be produced according to a method known per se or a method similar thereto.

Further, in each reaction and each reaction of the synthesis of the raw material compound, a solvent generally known may be used during the reaction.
Commonly known solvents include, for example, ethers such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyetane and 1,4-dioxane, esters such as ethyl acetate and butyl acetate, and aromatic carbonization such as benzene and toluene. Aromatic heterocyclic compounds such as hydrogen, pyridine and lutidine, amides such as N, N-dimethylformamide and N-methylpyrrolidone, halides such as chloroform and methylene chloride, methanol, ethanol, 2-propanol, 2,2 -Alcohols such as dimethylethanol, hydrocarbon compounds such as hexane, heptane and petroleum ether, carboxylic acids such as formic acid and acetic acid, water and the like can be mentioned.
Further, the solvent used in the reaction may be a single solvent or a mixture of 2 to 6 kinds of solvents.
Further, in the reaction, for example, amines such as triethylamine, N, N-diisopropylamine, pyridine and N-methylmorpholine and bases such as sodium hydroxide and potassium carbonate may coexist.
Further, in the reaction, for example, an acid such as hydrochloric acid, sulfuric acid or acetic acid may coexist.

The synthesis scheme of the compound of the present invention is shown below (detailed reaction is according to Examples). Although it may be described by a specific group or compound in the scheme, it is clear to those skilled in the art that an alternative group or compound can be used.
Production method 1: When the compound represented by the formula (I) is a compound represented by the formula (Ia)

In the formula, Et means ethyl, and the definitions of the other symbols are as described above.
Step 1 is a step of introducing a sulfonyl group. The step can be carried out by allowing a reagent such as halogenated sulfonic acid (eg, chlorosulfuric acid) to act.
Step 2 is a step of introducing a substituted amino group through a reaction with the sulfonyl group obtained in step 1. The step can be carried out by allowing the desired substituted amine to act in the presence of the base.
Steps 3 and 4 are steps of introducing a hydrazino group into the benzimidazole skeleton. The reaction can be carried out by chlorinating with a chlorinating agent such as phosphoryl chloride and then allowing hydrazine to act.
Step 5 is a step of forming a ring further than the reaction between the hydrazine derivative and the ketone.
Both are carried out by methods usually carried out in the art and by appropriately combining them.
Production method 2: When the compound represented by the formula (I) is a compound represented by the formula (Ib)

In the formula, Et means ethyl, and the definitions of the other symbols are as described above.
Step 1 is a step of forming a benzimidazolone skeleton through a cyclization reaction. The cyclization reaction can be carried out by allowing a reagent such as carbonyldiimidazole (CDI) to act.
Steps 2 and 3 are steps of introducing a hydrazino group into the benzimidazole skeleton. The reaction can be carried out by chlorinating with a chlorinating agent such as phosphoryl chloride and then allowing hydrazine to act.
Step 4 is a step of forming a ring further than the reaction between the hydrazine derivative and the ketone.
Both are carried out by methods usually carried out in the art and by appropriately combining them.

The present invention will be described in detail with reference to the following examples, but the present invention is not limited to the following examples. In addition, the reagents and materials used are commercially available unless otherwise specified. The data of physicochemical properties were measured by the following methods and devices.
^{1 1} H-NMR spectrum uses deuterated chloroform (CDCl ₃ ), dimethyl sulfoxide-d ₆ (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) or acet on-d ₆ as a solvent, and is a JEOL JNM-ECX400 spectrum meter ( Recorded on a 400 MHz) or Agilent NMR system PS 600 system (600 MHz).
The chemical shift is indicated by a δ value (ppm) with tetramethylsilane (δ = 0.00) as an internal standard, and the coupling constant (J) is indicated by Hz.
The abbreviations for signal multiplicity used herein have the following meanings.
s: singlet
d: Doublet
t: triplet
q: quartet
m: Multiplet
br: broad
dd: double doublet
The IR spectrum was recorded with a JEOL FT-IR 4100 spectrum meter.
The ESI-MS spectrum was measured with a Bruker micrOTO F-Q mass spectrometer.
All reactions were monitored by thin layer chromatography. Thin-layer chromatography was performed on 0.25 mm thick silica gel plates (E. Merck silica gel plates 60 F254), and a 5% ethanol phosphomolybite solution under UV light irradiation, iodine treatment or heating conditions as a coloring reagent was performed. Processing was used.
The purity of the synthesized compound was measured by the TOSOH LC-8020 system carried out under the following conditions: YMC-Pack Pro C18 reverse phase column, 150 mm x 4.6 mm (5 μm); solvent: methanol / 0.1% aqueous TFA solution. (Appropriate gradient conditions), flow velocity: 1 mL / min; column temperature: 25 ° C; UV detector: 254 nm

Example 1
(1) 5-Methyl-1,3-dihydrobenzimidazol-2-one

A solution of 1,1'-carbonyldiimidazole (23.4 g, 0.225 mol) in dichloromethane (160 mL) was added dropwise to a solution of 4-methyl-1,2-phenyldiamine (16 g, 0.205 mol) in tetrahydrofuran (160 mL). Added. After stirring at ambient temperature for 8 hours, diisopropyl ether (300 mL) was added to the reaction mixture. The resulting precipitate was collected by filtration. The precipitate was washed with diisopropyl ether and dried in vacuo to give the title compound (17.3 g, 89%).
ESI-HRMS calcd. For C ₈ H ₈ N ₂ ONa ([M + Na] ⁺ ) 171.0529; found: 171.0529.
¹ H-NMR (DMSO-d ₆ ) δ 2.27 (3H, s), 6.70-6.81 (3H, m), 10.46 (2H, br. S).
(2) 2-Chloro-5-methyl-1H-benzo [d] imidazole

A mixture of 5-methyl-1,3-dihydrobenzimidazole-2-one (17.3 g, 116 mmol) and phosphorus oxychloride (108 mL, 1.16 mol) was stirred at 90 ° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was carefully added to chloroform (100 mL) and the resulting precipitate was collected by filtration. Saturate the precipitate NaHCO ₃ aq. It was added to a mixture of (50 mL) and ethyl acetate (50 mL). The separated organic phase was washed with water and brine and dried over י ₄ . After filtration, the filtrate was distilled under reduced pressure. The resulting precipitate was collected by filtration and successfully washed with isopropyl ether to give the title compound (12.4 g, 64%).
ESI-HRMS calcd. For C ₈ H ₈ ClN ₂ ([M + H] ⁺ ) 167.0371; found 167.0390.
¹ H-NMR (DMSO-d ₆ ) δ: 2.40 (3H, s), 7.00-7.06 (1H, m), 7.29 (1H, s), 7.39 (1H, d, J = 8.2 Hz).
(3) 2-Hydradinyl-5-methyl-1H-benzo [d] imidazole

A mixture of 2-chloro-5-methyl-1H-benzo [d] imidazole (12.4 g, 74.3 mmol) and hydrazine monohydrate (37 mL, 743 mmol) was stirred at 100 ° C. for 6 hours. After cooling to ambient temperature, water (40 mL) was added to the reaction mixture. After stirring under ice-cooling, the resulting precipitate was collected by filtration. The precipitate was washed 5 times with water and then dried in vacuo to give 2-hydrazinyl-5-methyl-1H-benzo [d] imidazole (10.3 g, 85%).
ESI-HRMS calcd. For C ₈ H ₁₁ N ₄ ([M + H] ⁺ ) 163.0978; found m / z 163.0985.
¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (3H, s), 4.39 (2H, br. S), 6.63-6.70 (1H, m), 6.91-6.94 (1H, m), 6.97-7.01 ( 1H, m), 7.69 (1H, br. S), 10.87 (1H, br. S).
(4) 5-Benzyl-2- (5-methyl-1H-benzo [d] imidazol-2-yl) -4,5,6,7-tetrahydro-2H-pyrazolo [4,3-c] pyridine-3 -All

2-Hydradinyl-5-methyl-1H-benzo [d] imidazole (1.37 g, 8.40 mmol) and 1-benzyl-4-oxopiperidine-3-carboxylate ethyl hydrochloride (2.50 g, 8.40 mmol) acetic acid (10) The mixture in mL) was stirred at ambient temperature for 12 hours. The reaction mixture was poured into water (30 mL) and stirred at ambient temperature. The resulting precipitate was collected by filtration and washed with water. The precipitate was washed with a mixed solution of ethanol / water (1/1) to give the title compound (1.12 g, 37%).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ 2.47 (3H, s), 3.03 (2H, t, J = 6.4 Hz), 4.03 (2H, br. S), 4.48 (2H, s), 7.24 ( 1H, d, J = 8.4 Hz), 7.42 (1H, s), 7.48 (1H, d, J = 8.4 Hz), 7.50-7.59 (5H, m);
IR (KBr): 3389, 3208, 1654, 1617, 1562, 1515, 1489, 1456, 1139, 1005 cm ^-1 ;
ESI-HRMS (negative ion): calcd for C ₂₁ H ₂₀ N ₅ O ([MH] ^- ) 358.1668; found 358.1672;
Melting point: 145-148 ℃.

Example 2
(1) 2-oxo-2,3-dihydro-1H-benzo [d] imidazole-5-sulfonyl chloride

2-Hydroxybenzimidazole (8.00 g, 41.2 mmol) was added to a solution of chlorosulfonic acid (13 mL) in 10 portions over 1 hour under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture was added to water under ice-cooling. The reaction mixture was filtered, washed with water and dried under reduced pressure to give the title compound (10.8 g, 77%).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ 6.84 (1H, d, J = 8.3 Hz), 7.17 (1H, d, J = 1.4 Hz), 7.23 (1H, dd, J = 8.3 and 1.4 Hz) , 10.64 (1H, s), 10.68 (1H, s).
(2) N-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazole-5-sulfonamide

Triethylamine (6.00 mL, 43.0 mmol) and cyclohexylamine (4.90) in a DMF (50 mL) solution of 2-oxo-2,3-dihydro-1H-benzo [d] imidazole-5-sulfonyl chloride (5.00 g, 21.5 mmol) mL, 43.0 mmol) was added under ice cooling. After stirring at room temperature for 2 hours, the reaction mixture was added to 1N HCl (100 mL) under ice cooling, and the resulting precipitate was recovered by filtration. The precipitate was washed with water and then dried in vacuo to give the title compound (4.63 g, 73%).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ 0.85-1.15 (5H, m), 1.34-1.43 (1H, m), 1.44-1.60 (4H, m), 2.75-2.90 (1H, m), 7.04 (1H, d, J = 8.4 Hz), 7.32 (1H, d, J = 1.4 Hz), 7.42 (1H, dd, J = 8.4 and 1.4 Hz), 7.44 (1H, d, J = 7.6 Hz), 10.96 (1H, s), 11.04 (1H, s).
(3) 2-Chloro-N-cyclohexyl-1H-benzo [d] imidazole-5-sulfonamide

Of N-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazole-5-sulfonamide (2.63 g, 11.3 mmol), phosphoryl chloride (10 mL, 113 mmol) and DMF (0.5 mL) The mixture was stirred at 110 ° C. for 24 hours. After cooling to the ambient temperature, a 1N NaOH aqueous solution was added to the mixture to bring the pH to 8. The aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined, washed with water and brine, then dried over anhydrous ו ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/2) to give the title compound (1.15 g, 32%) as a pale yellow solid.
¹ H-NMR (400MHz, DMSO-d ₆ ) δ 0.85-1.15 (5H, m), 1.34-1.43 (1H, m), 1.44-1.60 (4H, m), 2.80-3.00 (1H, m), 7.50 -7.56 (1H, br.), 7.60-7.67 (2H, br.), 7.88-7.92 (1H, br.).
(4) N-cyclohexyl-2-hydrazinyl-1H-benzo [d] imidazole-5-sulfonamide

2-Chloro-N-cyclohexyl-1H-benzo [d] imidazole-5-sulfonamide (1.15 g, 3.66 mmol) and hydrazine monohydrate (3.52 mL, 73.3 mmol) were stirred at 120 ° C. for 12 hours. After cooling to ambient temperature, water was added to the reaction mixture. NaCl was added to the mixture and the mixture was stirred at ambient temperature. The resulting precipitate was collected by filtration. The precipitate was washed with water and then dried in vacuo to give the title compound (960 mg, 85%) as a white solid.
¹ H-NMR (400MHz, DMSO-d ₆ ) δ 0.90-1.10 (5H, m), 1.34-1.42 (1H, m), 1.46-1.59 (4H, m), 2.74-2.86 (1H, m), 4.42 -4.65 (2H, br.), 7.05-7.45 (4H, br.), 8.00-8.25 (2H, br.).
(5) N-cyclohexyl-2- (3-hydroxy-4,5,6,7-tetrahydro-2-H-indazole-2-yl) -1H-benzo [d] imidazole-5-sulfonamide

N-cyclohexyl-2-hydrazinyl-1H-benzo [d] imidazole-5-sulfonamide (960 mg, 3.06 mmol) and ethyl 2-oxocyclohexanecarboxylate (524 mg, 3.06 mmol) in acetic acid (7 mL). The mixture was stirred at ambient temperature for 12 hours. The reaction mixture was poured into water (30 mL) and stirred at ambient temperature. The resulting precipitate was collected by filtration and washed with water. The precipitate was washed with a mixture of ethanol / water (1/1) to give the title compound (1.08 g, 85%).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ 0.92-1.18 (5H, m), 1.35-1.45 (1H, m), 1.46-1.60 (4H, m), 1.63-1.78 (4H, m), 2.22 (2H, t, J = 6.0 Hz), .2.51 (2H, t, J = 6.0 Hz), 2.90 (br. S), 7.51 (1H, d, J = 6.8 Hz), 7.61 (1H, dd, J) = 8.4 and 1.6 Hz), 7.65 (1H, d, J = 8.4 Hz), 7.96 (1H, br. S);
IR (KBr): 3275, 3166, 2936, 2852, 1659, 1623, 1553, 1428, 1322, 1159, 1150 1104, 984 cm ^-1 ;
ESI-MS (negative ion, sodium formate): calcd for C ₂₀ H ₂₄ N ₅ O ₃ S ([MH] ^- ) 414.1600; found 414.1549;
Melting point: 175-177 ℃.

The compounds of Examples 3 to 44 were synthesized in the same manner as in Example 1 or Example 2 using the corresponding raw material compounds. Table 1 below summarizes the structures of Examples 1-44 and their physicochemical properties.

Test Example 1: Evaluation method of PCA-1 inhibitory activity An enzyme reaction solution containing 80 fmol of 3-methylcitosine-containing oligo DNA as a substrate (50 mM Tris-hydrochloric acid buffer (pH 8.0), 2 mM ascorbic acid, 100 μM oxoglutaric acid, 40 μM iron sulfate). ), The test compound (10 μM, 1 μM) and 4 ng of the silkworm recombinant PCA-1 were added, and the mixture was incubated at 37 ° C. for 1 hour. After completion of the reaction, the enzyme reaction solution was diluted 20-fold with water to terminate the reaction, and 2 μL of the enzyme reaction solution was used to perform real-time PCR (Bio-Rad iQ SYBR Green Supermix) in a 20 μL reaction system. The calibration curve was prepared using a dilution series of unmethylated oligo DNA. The primers used were forward primer 24base and reverse primer 22base, and the reaction conditions were: 95 ° C. 10 seconds → 95 ° C. 5 seconds, 61 ° C. 30 seconds, 72 ° C. 15 seconds for 40 cycles → 95 ° C. 1 minute → 55 ° C. 1 minute → The temperature was increased by 0.5 ° C. from 55 ° C. for 10 seconds and stored at 95 ° C. for 10 seconds → 25 ° C.
The inhibitory activity was evaluated by comparing the degree of demethylation in the presence and absence of a predetermined concentration of the test compound.
The PCA-1 inhibitory activity (%) of the compound of the present invention is shown in Table 4.

Test Example 2: Evaluation of cancer cell growth inhibitory effect Cell line used: DU145 (Prostate cancer cell: Medical Cell Resource Center, Institute of Aging Medicine, Tohoku University)
Cells were seeded at 5x10 ³ cells / hole / 90 μL on a 96-well plate and cultured overnight. After adding the test compound (10 μM) and culturing for 48 hours, 1-methoxy-5-methylphenazinium methylsulfate (PMS) aqueous solution and 2- (4-iodophenyl) -3- (4-nitrophenyl) -5- (2) , 4-disulfophenyl) -2H-tetrazolium, monosodium salt (WST-1) / 20 mM 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES) solution (DOJIN) 1: 9 mixture, or Cell Counting Kit -8 (Dojin Kagaku Kenkyusho) was added in an amount of 10 μL, and the absorbance at 450 nm was measured 2 hours later. 630 nm was used as the control wavelength.
Table 5 shows the cancer cell growth inhibitory activity (%) of the compound of the present invention at a predetermined concentration.

Test Example 3: Evaluation of antitumor effect using a prostate cancer xenograft model The preparation of a prostate cancer xenograft model was as follows.
8 × 10 ⁶ DU145 cells were mixed with BD Matrigel Basememt Membrane Matrix High Concentration (Becton, Dickinson and Company) and transplanted subcutaneously into the back of BALB / c nu / nu mice. After transplantation, when the tumor volume reaches about 200 mm ³ , it is removed, shredded to about 10 mm ³ , and transplanted subcutaneously to the back of another BALB / c nu / nu mouse to form a model mouse for compound evaluation. did.
The test compound was suspended in 0.5 w / v% sterile carboxycellulose (Wako Pure Chemical Industries, Ltd.) and orally administered at 10 mg / 10 mL / kg twice daily for 18 days. Docetaxel (DTX) was subcutaneously administered at 2.5 mg / 5 mL / kg once a week for a total of 3 times using the same solvent. The tumor volume was calculated using the formula (major axis) × (minor axis) ² × 0.5. The results of evaluating the changes in tumor volume over time are shown in FIG.
The same xenograft model was used to measure body weight and liver, kidney, and spleen weights on the final day of measurement of tumor volume changes, as well as changes in blood parameters such as GOT, GPT, creatinine, and BUN. Since no effect of administration of the compound of the present invention was confirmed in any of these, it was found that the compound of the present invention had no side effects.

Test Example 4: For oral absorbability evaluation, the test compound was made into a Na salt in a 0.5% methylcellulose (MC) suspension, and the test compound was orally administered to rats at 10 mg / kg overnight under fasting, and then 30 minutes and 60 minutes later. Blood was collected and the compound concentration was measured by HPLC. Good oral absorbability was confirmed for the compound of the present invention.

Since the compound of the present invention has an excellent action of inhibiting the enzymatic activity of PCA-1, it is useful for the prevention and / or treatment of diseases in which PCA-1 is involved. In particular, the compound of the present invention is useful as an anticancer agent against prostate cancer, pancreatic cancer, non-small cell lung cancer and the like.

Claims (10)

The following formula:

A compound represented by the above or a pharmaceutically acceptable salt thereof. Equation (Ia):

[During the ceremony,
Ra'and Ra'' indicate the same or different hydrogen atoms , optionally substituted C _7-12 aralkyl groups or optionally substituted C _1-6 alkyl groups ;
R _2a indicates a C _1-6 alkyl group;
R _3a represents a _C7-12 aralkyl group], which is a PCA-1 inhibitor comprising the compound represented by the above or a pharmaceutically acceptable salt thereof . The compound represented by the formula (Ia) is the following formula:

The PCA-1 inhibitor according to claim 2 , which is a compound represented by. The following formula:

A PCA-1 inhibitor comprising a compound represented by the above or a pharmaceutically acceptable salt thereof . Equation (Ia):

[During the ceremony,
Ra'and Ra'' indicate the same or different hydrogen atoms , optionally substituted C _7-12 aralkyl groups or optionally substituted C _1-6 alkyl groups ;
R _2a indicates a C _1-6 alkyl group;
R _3a represents a C _7-12 aralkyl group], which comprises a compound represented by C 7-12 aralkyl group or a pharmaceutically acceptable salt thereof .
A prophylactic and / or therapeutic agent for a disease involving PCA-1 . The compound represented by the formula (Ia) is the following formula:

The prophylactic and / or therapeutic agent according to claim 5 , which is a compound represented by. The following formula:

A prophylactic and / or therapeutic agent for a disease associated with PCA-1, which comprises a compound represented by the above or a pharmaceutically acceptable salt thereof . The prophylactic and / or therapeutic agent according to any one of claims 5 to 7 , wherein the disease in which PCA-1 is involved is selected from the group consisting of cancer, cranial nerve degenerative disease, and arteriosclerosis. The prevention and prevention according to claim 8 , wherein the cancer has an anticancer effect against the above-mentioned cancer, which is at least one selected from the group consisting of prostate cancer, pancreatic cancer and non-small cell lung cancer. / Or a remedy. An anticancer concomitant agent comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and at least one anticancer agent.

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