JP2007119417A - NEW THIENO[2,3-d]PYRIMIDIN-4-OL DERIVATIVE AND APPLICATION THEREOF - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new anticancer agent having no cross-resistance with an existing anticancer agent. <P>SOLUTION: The thieno[2,3-d]pyrimidin-4-ol derivative represented by general formula (1) (wherein, X and Y are each independently a hydrogen atom, a lower alkyl group or a cycloalkyl group, or a 3-5C alkylene group, alkenylene group or alkynylene group for forming a cyclic structure by bonding to each other; n is an integer of 1-3; A is an aryl group, a heteroaryl group or the like which may have one or more substituents selected from the group consisting of a halogen atom and the like; and m is an integer of 0-3), a hydrate, a solvate or a pharmacologically acceptable salt thereof is used as a medicine. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  As anticancer agents, as shown in Non-Patent Documents 1 and 2, many drugs having different action mechanisms have been developed. Adriamycin, cisplatin, taxol, vincristine, gemcitabine and the like are widely used in clinical practice. Among these, anthracycline compounds such as adriamycin are widely used clinically as typical anticancer agents, but they cannot be adequately treated due to side effects such as cardiotoxicity and bone marrow suppression and the emergence of drug-resistant cancer cells. Has increased and has become a therapeutic problem.

  In addition, as shown in Non-Patent Document 3, acquisition of resistance of cancer cells to anticancer agents is a major obstacle in cancer treatment. Mechanisms for acquiring resistance include a mechanism for excretion of drugs outside the cell, a mechanism for detoxification inside the cell, a mechanism for repair when DNA is damaged, and the development of inhibitors against these. There is a craving for anticancer drugs that do not have cross-resistance.

On the other hand, similar compounds of the thieno [2,3-d] pyrimidin-4-ol derivative of the present invention inhibit mycobacterial protein kinase G and purine receptor antagonistic inhibition as shown in Patent Documents 1, 2, and 3. Physiological activities such as cyclic GMP-specific phosphodiesterase inhibition have been reported. Although Non-Patent Document 4 describes the cell growth inhibitory activity of thieno [2,3-d] pyrimidin-4-one derivatives, thieno [2,3-d] having piperidine, pyrrolidine, and azepan as substituents. d] There is no disclosure about pyrimidin-4-ol derivatives, and no reports have been made on cross-resistance to drug-resistant cancer.
Cancer and Chemotherapy 26 Supplement 1, p. 23-31 (1999) Chemotherapy Areas 19 Supplement 1, p. 9-15 (2003) Nagahiro Saijo Cancer Chemotherapy 56: Supplement p. 525-535 (2001) Bioorganic & Medicinal Chemistry Letters 15, p. 3763-3766 (2005) International Publication No. 05/23818 International Publication No. 02/55524 JP-A-8-143571

  The object of the present invention is to provide a novel anticancer agent that is effective even against cancer that exhibits resistance to existing anticancer agents.

  As a result of various searches for synthetic compounds in order to solve the above-mentioned problems, the present inventors have found that a novel thieno [2,3-d] pyrimidin-4-ol derivative has a cell growth inhibitory action and is resistant to anticancer drug resistant cells. However, the present inventors have found that it has an equivalent cell growth inhibitory effect and completed the present invention.

  That is, the present invention

(1) The following general formula (1)

Wherein X and Y each independently represent a hydrogen atom, a lower alkyl group or a cycloalkyl group, or X and Y are an alkylene group having 3 to 5 carbon atoms for bonding to form a cyclic structure, alkenylene. N represents an integer of 1 to 3. A represents an optionally substituted lower alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, or heteroaryl group. And the substituent represents one or more selected from the group consisting of a halogen atom, a hydroxyl group, a carbonyl group, a lower alkyl group, and a lower alkoxy group, and m represents an integer of 0 to 3. [2,3-d] pyrimidin-4-ol derivatives, hydrates, solvates, or pharmaceutically acceptable salts thereof,
(2) In the general formula (1), X and Y are both methyl groups, or X and Y are bonded to form a cyclic structure to form a cyclic structure. Thieno [2,3-d] pyrimidin-4-ol derivative, hydrate, solvate, or pharmacologically acceptable salt thereof,
(3) The thieno [2,3-d] pyrimidin-4-ol derivative according to (2), a hydrate, a solvate thereof, or the general formula (1), wherein n is 2. A pharmacologically acceptable salt,
(4) In the general formula (1), A is an alkyl group having 1 to 6 carbon atoms and carbon substituted with one or more selected from the group consisting of a halogen atom, a hydroxyl group, a carbonyl group, and a lower alkoxy group A cycloalkyl group having a number of 3 to 7, a phenyl group, a naphthyl group, a furyl group, a thienyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a tetrahydrobenzothieno group, a quinoxalyl group, a tetrahydrofuryl group, a pyrrolidinyl group, a furazanyl group, a thiadiazolyl group , A pyrazyl group, or a pyrazolopyrimidyl group, the thieno [2,3-d] pyrimidin-4-ol derivative according to any one of (1) or (3), a hydrate thereof, Solvates, or pharmacologically acceptable salts,
(5) The following general formula (2)

(In the formula, A ₁ represents an optionally substituted lower alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, or heteroaryl group, and the substituent includes a halogen atom, a hydroxyl group, and a carbonyl group. 1 or more selected from the group consisting of lower alkyl group and lower alkoxy group, and m ₁ represents an integer of 0 to 3.) The thieno [2,3- d] Pyrimidin-4-ol derivative, hydrate, solvate, or pharmacologically acceptable salt thereof,

(6) In the general formula (2), m ₁ is 0, and A ₁ may be substituted with one or more selected from the group consisting of a halogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxy group. The thieno [2,3-d] pyrimidin-4-ol derivative according to (5) above, which is a lower alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, a hydrate thereof, Solvates, or pharmacologically acceptable salts,
(7) In the general formula (2), m ₁ is 1 or 2, and A ₁ is substituted with one or more selected from the group consisting of a hydroxyl group, a carbonyl group, a lower alkyl group, and a lower alkoxy group. The thieno [2,3-d] pyrimidin-4-ol derivative according to (5) above, which is a heterocycloalkyl group, an aryl group, or a heteroaryl group, a hydrate, a solvate, or a drug thereof A physically acceptable salt,
(8) The thieno [2,3-d] pyrimidine-4- described in (6) above, wherein A ₁ is an isopropyl group, a tert-butyl group, a cyclopentyl group, a tetrahydrofuryl group, a phenyl group, a quinoxalyl group, or a thiadiazolyl group. All derivatives, hydrates, solvates, or pharmaceutically acceptable salts thereof,
(9) The thieno [2,3-d] pyrimidine according to the above (7), wherein A ₁ is a pyrrolidinyl group, an oxopyrrolidinyl group, a phenyl group, a thienyl group, a tetrazolyl group, a dioxoimidazolidyl group or a flazanyl group. -4-ol derivatives, hydrates, solvates, or pharmaceutically acceptable salts thereof,
(10) The following general formula (3)

(In the formula, A ₂ represents an optionally substituted lower alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, or heteroaryl group, and the substituent includes a halogen atom, a hydroxyl group, and a carbonyl group. 1 or more selected from the group consisting of lower alkyl groups and lower alkoxy groups, and m ₂ represents an integer of 0 to _3. ) 3-d] pyrimidin-4-ol derivative, hydrate, solvate, or pharmacologically acceptable salt thereof,

(11) In the general formula (3), m ₂ is 0, and A ₂ is a lower alkyl group, cycloalkyl group, aryl group or heteroaryl group which may be substituted with one or more halogen atoms, 10) the thieno [2,3-d] pyrimidin-4-ol derivative, its hydrate, its solvate, or pharmacologically acceptable salt,
(12) The general formula (3), wherein m ₂ is 1, and A ₂ is a heterocycloalkyl group or an aryl group which may be substituted with one or more lower alkoxy groups. Thieno [2,3-d] pyrimidin-4-ol derivative, hydrate, solvate, or pharmacologically acceptable salt thereof,
(13) The thieno [2,3-d] pyrimidin-4-ol derivative according to (11), wherein A ₂ is a tert-butyl group, a cyclopentyl group, a phenyl group, a pyrazyl group or a pyrazolopyrimidyl group, Its hydrate, its solvate, or pharmacologically acceptable salt,
(14) The thieno [2,3-d] pyrimidin-4-ol derivative, its hydrate, its solvate, or pharmacologically according to the above (12), wherein A ₂ is a pyrrolidinyl group or a phenyl group. Acceptable salts,
(15) The following general formula (4)

(In the formula, A ₃ represents an optionally substituted lower alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, or heteroaryl group, and the substituent includes a halogen atom, a hydroxyl group, and a carbonyl group. 1 or more selected from the group consisting of lower alkyl groups and lower alkoxy groups, m ₃ represents an integer of 0 to _3. ) 3-d] pyrimidin-4-ol derivative, hydrate, solvate, or pharmacologically acceptable salt thereof,

(16) In the general formula (4), m ₃ is 0, and A ₃ is a lower alkyl group, a cycloalkyl group or a heteroaryl group, which may be substituted with one or more lower alkyl groups, ) Thieno [2,3-d] pyrimidin-4-ol derivative, hydrate, solvate, or pharmacologically acceptable salt thereof,
(17) In the general formula (4), m ₃ is 1, and A ₃ is an aryl group which may be substituted with one or more selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group, The thieno [2,3-d] pyrimidin-4-ol derivative according to (15), a hydrate, a solvate thereof, or a pharmaceutically acceptable salt thereof, which is a heteroaryl group,
(18) The thieno [2,3-d] pyrimidin-4-ol derivative or hydrate thereof according to (16), wherein A ₃ is an isopropyl group, a tert-butyl group, a cyclopentyl group, a furyl group, or a thienyl group. , Solvates, or pharmaceutically acceptable salts thereof,
(19) The thieno [2,3-d] pyrimidin-4-ol derivative according to (17), wherein A ₃ is a phenyl group or a thienyl group, a hydrate, a solvate thereof, or a pharmacologically Acceptable salts,
(20) A mammalian pharmaceutical agent comprising the compound according to any one of (1) to (19) or a hydrate, solvate, or pharmacologically acceptable salt thereof as an active ingredient, or Preventive or therapeutic agent for diseases,
(21) A cell growth inhibitor comprising as an active ingredient the compound according to any one of (1) to (19) or a hydrate, solvate, or pharmacologically acceptable salt thereof,
(22) An anticancer agent comprising as an active ingredient the compound according to any one of (1) to (19) or a hydrate, solvate, or pharmacologically acceptable salt thereof,
(23) The anticancer agent according to (22), wherein the cancer is a drug resistant cancer,
About.

  According to the present invention, a novel thieno [2,3-d] pyrimidin-4-ol derivative having a cell growth inhibitory action is provided. Furthermore, it was shown that the thieno [2,3-d] pyrimidin-4-ol derivative of the present invention has growth inhibitory activity against multidrug resistant cells.

  In the present invention, the lower alkyl group represents a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, ethyl group, n-propyl group, isopropyl group, dimethylpropyl group, isobutyl group, n- Examples thereof include a butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, and an n-hexyl group. Among these, preferred groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an isobutyl group. More preferably, a methyl group is mentioned.

  In the present invention, the aryl group represents an aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a biphenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. Among these, a preferred group is a phenyl group.

  In the present invention, a heteroaryl group refers to a heteroaromatic group containing 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms as heteroatoms as the same or different heteroatoms, such as a furyl group, a thienyl group, an imidazolyl group, or a triazolyl group. , Tetrazolyl group, oxazolyl group, thiazolyl group, pyridyl group, indolyl group, thiadiazolyl group, furazanyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, quinoxalyl group, thiadiazolyl group, pyrazolopyrimidinyl group and the like. Of these, preferred groups include a furazanyl group, a thienyl group, and a quinoxalyl group. More preferred is a quinoxalyl group.

  In the present invention, the lower alkoxy group represents a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, Examples thereof include a tert-butoxy group. Among these, preferred groups include a methoxy group, an ethoxy group, and a tert-butoxy group. More preferably, a methoxy group is mentioned.

  In the present invention, the cycloalkyl group represents a saturated cyclic hydrocarbon group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Among these, a cyclopentyl group can be mentioned as a preferable group.

  In the present invention, the heterocycloalkyl group refers to a cycloalkyl group containing 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms as the same or different heteroatoms as heteroatoms, such as tetrahydrofuranyl group, tetrahydropyranyl group, pyrrolidinyl. Group, oxopyrrolidinyl group, imidazolidinyl group, dioxoimidazolidinyl group, piperidinyl group, morpholyl group and the like. Among these, preferred groups include a tetrahydrofuranyl group, a pyrrolidinyl group, an oxopyrrolidinyl group, and an imidazolidinyl group.

  In the present invention, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among these, a preferred atom is a fluorine atom.

In the present invention, the alkylene chain represented by — (CH ₂ ) _n — is an integer from 1 to 3, and the size of the ring is a 5- to 7-membered ring, preferably n is 2 ( (Ethylene group).

  In the present invention, when X and Y are bonded to form a cyclic structure, the number of carbon atoms is 3 to 5, and any of an alkylene chain, an alkenylene chain, and an alkynylene chain can be taken. Among these, a preferable chain includes an alkylene chain having 4 carbon atoms.

In the above general formulas (1) to (4), when A to A ₃ are lower alkyl groups, methyl group, ethyl group, n-propyl group, isopropyl group, dimethylpropyl group, isobutyl group, n-butyl group, sec A -butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group and the like can be taken. Among these, preferred groups include isopropyl group, dimethylpropyl group, and isobutyl group.

In formula (1) ~ (4), m~m 3 is an integer of 0 to 3, preferably m to m ₃ in the case of 0, 1 and 2.

In the general formulas (1) to (4), A to A ₃ can take an aryl group, a cycloalkyl group, a heterocycloalkyl group, or a heteroaryl group.

In the general formulas (1) to (4), when A to A ₃ are aryl groups, a phenyl group, a biphenyl group, a naphthyl group, an anthryl group, a phenanthryl group, and the like can be taken. Among these, a preferred group is a phenyl group. .

In the general formulas (1) to (4), when A to A ₃ are cycloalkyl groups, they can be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, or the like. Among these, a preferred group is a cyclopentyl group.

In the general formulas (1) to (4), when A to A ₃ are heterocycloalkyl groups, tetrahydrofuranyl group, tetrahydropyranyl group, pyrrolidinyl group, oxopyrrolidinyl group, imidazolidine group, piperidinyl group, morpholyl Groups can be taken. Among these, preferred examples include a tetrahydrofuranyl group, a pyrrolidinyl group, an oxopyrrolidinyl group, and an imidazolidinyl group.

In the general formulas (1) to (4), when A to A ₃ are heteroaryl groups, a furyl group, a thienyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, an indolyl group, A thiadiazolyl group, a furazanyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a quinoxalyl group, a thiadiazolyl group, a pyrazolopyrimidinyl group, etc. A pyrazolopyrimidinyl group, a furyl group, and a pyrazinyl group can be taken.

In the above general formulas (1) to (4), the substituents A to A ₃ are a halogen atom, a hydroxyl group, a carbonyl group, or a lower alkyl group, cycloalkyl group, or heterocycloalkyl which may have a substituent. A group, an aryl group, a heteroaryl group, or a lower alkoxy group.

In the general formulas (1) to (4), when the substituents A to A ₃ take a halogen atom, they can take a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Among these, a preferred atom is a fluorine atom.

In the above general formulas (1) to (4), when the substituents of A to A ₃ are lower alkyl groups, methyl group, ethyl group, n-propyl group, isopropyl group, dimethylpropyl group, isobutyl group, n-butyl group Group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group and the like. Among these, a preferred group is a methyl group.

In the general formulas (1) to (4), when the substituent of A to A ₃ is a lower alkoxy group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert -A butoxy group or the like can be taken. Among these, a preferred group is a methoxy group.

  Since the compounds represented by the general formulas (1) to (4) have an asymmetric carbon, they exist as a single optically active substance, a racemate or a mixture of optical isomers. Such compounds are obtained as optically active, racemic or optical isomer mixtures. The compounds of the present invention should be understood as encompassing any of these optically active, racemic or optical isomer mixtures.

  Examples of the pharmacologically acceptable hydrate of the compound of the present invention include those in a state of being associated with or bound to one or more water molecules. In addition, the hydrate of the compound of the present invention includes the hydrate of the pharmacologically acceptable salt of the compound of the present invention.

  Examples of the pharmacologically acceptable solvate of the compound of the present invention include alcohol solvents such as ethanol or propanol, organic acids such as acetic acid, esters such as ethyl acetate, ethers such as tetrahydrofuran or diethyl ether, And solvates such as dimethyl sulfoxide. The solvate is preferably non-toxic and water-soluble. Moreover, the solvate of the compound of the present invention includes a solvate of a pharmacologically acceptable salt of the compound of the present invention.

  The pharmacologically acceptable salts of the compounds of the present invention include salts with mineral acids such as hydrochloric acid and sulfuric acid, acetic acid, benzoic acid, succinic acid, fumaric acid, maleic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid And salts with organic acids such as benzenesulfonic acid. These salts can be produced according to a conventional method.

Examples of the compound represented by the general formula (1) include the following compounds.
(1) 2- (1- (4-Methoxyphenylacetyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (2) 2- (1- (3-methoxyphenylacetyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (3) 2- (1- (2-methoxyphenylacetyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (4) 2- (1- (2,2-dimethylpropionyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine-4- All (5) 2- (1-isobutyrylpiperi N-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (6) 2- (1- (3,5-difluorobenzoyl) ) Piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (7) 2- (1- (3,5-dichloro) Benzoyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (8) 2- (1- (cyclopentanecarbonyl) Piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (9) 2- (1- (4-hydroxyphenylacetyl) Piperidin-4-yl) -5,6,7,8-teto Hydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (10) 2- (1- (3-thiophenacetyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol

(11) 2- (1- (3- (tetrazolyltetrazol-1-yl) propionyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3 -D] pyrimidin-4-ol (12) 2- (1- (tetrazol-1-yl) acetylpiperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2, 3-d] pyrimidin-4-ol (13) 2- (1- (5-quinoxaloyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3- d] pyrimidin-4-ol (14) 2- (1- (tetrahydrofuran-2-yl) acetylpiperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3 -D] pyrimidin-4-ol 15) 2- (1- (Pyrrolidin-1-yl) acetylpiperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (16) 2- (1- (4-Methylfurazan-3-yl) acetylpiperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine- 4-ol (17) 2- (1- (2-oxopyrrolidin-1-yl) acetylpiperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3- d] pyrimidin-4-ol (18) 2- (1- (3- (2,5-dioxoimidazolidin-4-yl) propionyl) piperidin-4-yl) -5,6,7,8-tetrahydro Benzo [4,5] thieno [2,3-d Pyrimidin-4-ol (19) 2- (1- (4-methyl- [1,2,3] thiadiazol-5-carbonyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4 , 5] thieno [2,3-d] pyrimidin-4-ol (20) 2- (1- (3,5-difluorobenzoyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [ 4,5] thieno [2,3-d] pyrimidin-4-ol

(21) 2- (1- (2-pyrazincarbonyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol ( 22) 2- (1- (Cyclopentanecarbonyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (23) 2- (1-((Pyrrolidin-1-yl) acetyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (24) 2- (1- (pyrazolo [1,5-a] pyrimidin-3-carbonyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3 -D] pyrimidin-4-ol (25) 2- 1- (2,2-dimethylpropionyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (26) 2- (1- (4-Methoxyphenylacetyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (27) 2- (1- (3-Fluorophenylacetyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol (28) 2- (1- (2-thiophenecarbonyl) piperidine -3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol (29) 2- (1-isobutyrylpiperidin-3-yl) -5,6-dimethylthieno [2 , 3-d] pyrimidine 4-ol (30) 2- (1-furoyl-3-yl) -5,6-dimethyl-thieno [2,3-d] pyrimidin-4-ol

(31) 2- (1- (2,2-dimethylpropionyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol (32) 2- (1- ( 4-methoxyphenylacetyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol (33) 2- (1- (2-fluorophenylacetyl) piperidine-3- Yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol (34) 2- (1- (4-fluorophenylacetyl) piperidin-3-yl) -5,6-dimethylthieno [ 2,3-d] pyrimidin-4-ol (35) 2- (1- (cyclopentanecarbonyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol ( 36) 2 (1- (3-thiophenacetyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol (37) 2- (1- (4-methoxyphenylacetyl) pyrrolidine -3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (38) 2- (1- (3-methoxyphenylacetyl) pyrrolidine -3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (39) 2- (1- (2-methoxyphenylacetyl) pyrrolidine -3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (40) 2- (1- (2,2-dimethylpropionyl) Pyrrolidin-3-yl 5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol

(41) 2- (1-Isobutyrylpyrrolidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (42) 2 -(1- (3,5-difluorobenzoyl) pyrrolidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (43) 2- (1- (3,5-dichlorobenzoyl) pyrrolidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (44 ) 2- (1- (Cyclopentanecarbonyl) pyrrolidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (45) 2 -(1- (4-hydroxyphenylacetyl) Loridin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (46) 2- (1- (3-thiophenacetyl) pyrrolidine -3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (47) 2- (1- (3- (tetrazol-1- Yl) propionyl) pyrrolidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (48) 2- (1- (tetrazole 1) -Yl) acetylpyrrolidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (49) 2- (1- (5- Quinoxaloyl) pyrrolidin-3-yl) -5,6 7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (50) 2- (1- (tetrahydrofuran-2-yl) acetylpyrrolidin-3-yl) -5,6 , 7,8-Tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol

(51) 2- (1- (Pyrrolidin-1-yl) acetylpyrrolidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine-4- All (52) 2- (1- (4-Methylfurazan-3-yl) acetylpyrrolidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine -4-ol (53) 2- (1- (2-oxopyrrolidin-1-yl) acetylpyrrolidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3 -D] pyrimidin-4-ol (54) 2- (1- (3- (2,5-dioxoimidazolidin-4-yl) propionyl) pyrrolidin-3-yl) -5,6,7,8- Tetrahydrobenzo [4,5] thieno [2,3-d Pyrimidin-4-ol (55) 2- (1- (4-methyl- [1,2,3] thiadiazol-5-carbonyl) pyrrolidin-3-yl) -5,6,7,8-tetrahydrobenzo [4 , 5] thieno [2,3-d] pyrimidin-4-ol (56) 2- (1- (4-methoxyphenylacetyl) pyrrolidin-2-yl) -5,6,7,8-tetrahydrobenzo [4 , 5] thieno [2,3-d] pyrimidin-4-ol (57) 2- (1- (3-methoxyphenylacetyl) pyrrolidin-2-yl) -5,6,7,8-tetrahydrobenzo [4 , 5] thieno [2,3-d] pyrimidin-4-ol (58) 2- (1- (2-methoxyphenylacetyl) pyrrolidin-2-yl) -5,6,7,8-tetrahydrobenzo [4 , 5] thieno [2,3- Pyrimidin-4-ol (59) 2- (1- (2,2-dimethylpropionyl) pyrrolidin-2-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3- d] pyrimidin-4-ol (60) 2- (1- (3,5-difluorobenzoyl) pyrrolidin-2-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3 -D] pyrimidin-4-ol

(61) 2- (1- (5-Quinoxaloyl) pyrrolidin-2-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (62) ) 2- (1- (4-Methoxyphenylacetyl) azepan-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (63) ) 2- (1- (3-Methoxyphenylacetyl) azepan-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (64) ) 2- (1- (2-methoxyphenylacetyl) azepan-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (65) ) 2- (1- (2,2-Dimethylpropyi) Nyl) azepan-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (66) 2- (1- (3,5- Difluorobenzoyl) azepan-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (67) 2- (1- (5-quinoxaloyl) ) Azepan-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol

  The thieno [2,3-d] pyrimidin-4-ol derivative of the present invention can be synthesized by the following method. The following general formula (5)

（式中、ＸおよびＹは前記に記載の通りである。）で表される化合物、イソプロポキシナトリウムなどの強塩基性試薬を溶解した溶液に、下記一般式（６）

(Wherein X and Y are as described above) In a solution in which a strongly basic reagent such as isopropoxy sodium is dissolved, the following general formula (6)

（式中、（ＣＨ₂）_nは前記に記載の通りである。また、Ｐｒｏｔはアミノ基の保護基を示す。）で表される化合物を添加し、必要に応じて加熱し反応させることによって、下記一般式（７）

(Wherein (CH ₂ ) _n is as described above. In addition, Prot represents an amino-protecting group), and the reaction is carried out by heating as necessary. The following general formula (7)

（式中、Ｘ、Ｙ、（ＣＨ₂）_nおよびＰｒｏｔは前記に記載の通りである。）で表される化合物を得ることができる。このときアミノ基の保護基としては、「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ，Ｇｒｅｅｎ ａｎｄ Ｗｕｔｓ著、Ｊｏｈｎ Ｗｉｌｅｙ ＆ Ｓｏｎｓ，Ｉｎｃ．１９９９」に記載されている保護基が用いられ、好ましくはカルバメート型の保護基であり、より好ましくはｔ−ブトキシカルボニル基が挙げられる。

(Wherein, X, Y, (CH ₂ ) _n and Prot are as described above) can be obtained. In this case, as the protecting group for the amino group, a protecting group described in “Protective Group in Organic Synthesis, Green and Wuts, John Wiley & Sons, Inc. 1999” is used, preferably a carbamate-type protecting group. Yes, more preferably t-butoxycarbonyl group.

  Next, by deprotecting the protecting group of the amino group of the compound represented by the general formula (7) according to the method described in the non-patent literature,

（式中、Ｘ、Ｙおよび（ＣＨ₂）_nは前記に記載の通りである。）で表される化合物を得ることができる。

(Wherein, X, Y and (CH ₂ ) _n are as described above) can be obtained.

  Further, by reacting the compound represented by the general formula (12) with the corresponding carboxylic acid chloride, carboxylic acid anhydride and carboxylic acid active ester to amidate the amino group, the following general formula (1)

（式中、Ａ、Ｘ、Ｙ、（ＣＨ₂）_mおよび（ＣＨ₂）_nは前記に記載の通りである。）で表される目的の化合物を得ることができる。このとき対応するカルボン酸活性エステルは対応するカルボン酸、ジシクロヘキシルアミノカルボジイミドなどの縮合剤、Ｎ−ヒドロキシベンゾトリアゾールもしくはＮ−ヒドロキシスクシンイミドによって合成できる。

(Wherein, A, X, Y, (CH ₂ ) _m and (CH ₂ ) _n are as described above) can be obtained. At this time, the corresponding carboxylic acid active ester can be synthesized by the corresponding carboxylic acid, a condensing agent such as dicyclohexylaminocarbodiimide, N-hydroxybenzotriazole or N-hydroxysuccinimide.

  In order to isolate and purify the target product from the reaction mixture obtained by each of the above synthesis methods, solvent extraction, concentration, crystallization, distillation, suspension purification, various chromatographies, etc. are used as necessary. be able to.

  Various conventionally known methods can be applied to the formulation and administration method when the thieno [2,3-d] pyrimidin-4-ol derivative of the present invention is used as a pharmaceutical product. That is, as an administration method, for example, injection, oral, transdermal or rectal administration is possible.

  As long as the thieno [2,3-d] pyrimidin-4-ol derivative of the present invention, its hydrate, its solvate, or pharmacologically acceptable salt is not adversely affected during formulation Various pharmaceutical additives used for the purpose, that is, carriers and other auxiliaries such as stabilizers, preservatives, soothing agents, emulsifiers and the like may be used. In the preparation, the content of thieno [2,3-d] pyrimidin-4-ol derivative, its hydrate, its solvate, or pharmacologically acceptable salt can vary widely depending on the form of the preparation. Generally, the content is 0.01 to 100% (weight), preferably 0.1 to 70% (weight). In the case of an oral preparation, it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups and the like together with additives. Capsules, tablets, granules, and powders generally contain 5 to 100% (by weight), preferably 25 to 98% (by weight) of the active ingredient.

  The pharmaceutical comprising the thieno [2,3-d] pyrimidin-4-ol derivative, hydrate, solvate, or pharmacologically acceptable salt thereof of the present invention as an active ingredient is preferably cell growth inhibition Can be used as an agent. Alternatively, it is preferably used as an anticancer agent.

  Examples of the use of the thieno [2,3-d] pyrimidin-4-ol derivative of the present invention as an anticancer agent include kidney cancer, brain tumor, colon cancer, pancreatic cancer, liver cancer, ovarian cancer, prostate cancer, lung cancer, leukemia and the like. Treatment.

  The dose of the thieno [2,3-d] pyrimidin-4-ol derivative, hydrate, solvate, or pharmacologically acceptable salt of the present invention depends on the indication, symptoms, administration method, etc. Although it is different, it is about 0.01 to 800 mg per day per adult.

  EXAMPLES Next, the present invention will be specifically described with reference to synthesis examples and pharmacological experimental examples of the compound of the present invention as examples, but the present invention is not limited to these. Moreover, below, room temperature shows 10-30 degreeC. LCMS was analyzed by LCMS2010A manufactured by Shimadzu Corporation. LC used Inertsil ODS-3 (φ2.1 × 100 mm) as a column, 0.1% formic acid aqueous solution as eluent A, and acetonitrile as eluent B, respectively. The concentration of eluent B is 20 (0 min) -90% (5.5 min) -90% (6.5 min) -20% (6.51 min) -20% (10 min) with a gradient of 0.3 mL / min. Eluted with. The retention time (Rt) was the time to the UV detector, and MS was measured in ESI (Positive) mode.

Example 1
Synthesis of 2- (1- (4-methoxyphenylacetyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol ( First Step) 2- (1- (t-Butoxycarbonyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol Synthesis of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo [b] thiophene (8.) to a solution of metallic sodium (4.6 g, 0.2 mmol) added to 2-propanol (200 mL). 9 g, 0.05 mmol) and Nt-butoxycarbonylisonipecotic acid ethyl ester (18.0 g, 0.07 mmol) were added, and the mixture was heated to reflux for 5 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off until crystals were precipitated. Water (500 mL) was added to the residue, and hydrochloric acid was added to the reaction solution to adjust the pH to 4. The precipitated crystals were collected by filtration, washed with water, and recrystallized with 2-propanol-water (1: 5).

(Second Step) Synthesis of 2- (piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol In the first step The resulting 2- (1- (t-butoxycarbonyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol The mixture was added to a dioxane solution saturated with hydrochloric acid, heated to 50 ° C., and then cooled to room temperature. The precipitated crystals were collected by filtration, washed with 2-propanol and then with n-hexane, and dried to obtain the desired compound (3.7 g). The yield was 23% for 2 steps.

(Third Step) 2- (1- (4-Methoxyphenylacetyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine-4 Synthesis of 2-ol 2- (piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol obtained in the second step After adding potassium carbonate (0.28 g, 1.0 mmol) to a solution of (326 mg, 1.0 mmol) in water (10 mL), 4-methoxyphenylacetyl chloride (0.185 g, 1.0 mmol) was added to dichloromethane. A solution dissolved in (15 mL) was added and stirred under mild warming until dichloromethane disappeared. The reaction mixture was acidified with hydrochloric acid and then cooled. After removing the supernatant, the crystals were washed with water and recrystallized from methanol to obtain the target compound.

¹ H-NMR (DMSO-d ₆ , ppm): 1.1 (2H, m), 1.7 (6H, m), 2.3-2.6 (5H, m), 2.7 (1H, m), 2.9 (1H, m), 3.6 (2H, s), 3.7 (3H, s), 3.9 (1H, m), 4.4 (1H, m), 6. 8 (2H, m), 7.1 (2H, m), 11.4 (1H, brs)
LCMS: Rt = 6.757 min, m / z: 438 (M + H) ⁺

  The compounds of Examples 2 to 18 were synthesized according to the method of synthesizing the compound of Example 1, and using the corresponding acylating reagent instead of 4-methoxyphenylacetyl chloride in the third step. The physicochemical properties of each compound obtained for Examples 2 to 18 are shown below.

Example 2
2- (1- (2-methoxyphenylacetyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.834 min, m / z: 438 (M + H) ⁺

Example 3
2- (1- (2,2-dimethylpropionyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.835 min, m / z: 374 (M + H) ⁺

Example 4
2- (1-Isobutyrylpiperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.349 min , M / z: 360 (M + H) ⁺

Example 5
2- (1- (3,5-difluorobenzoyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.945 min, m / z: 430 (M + H) ⁺

Example 6
2- (1- (Cyclopentanecarbonyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6 939 min, m / z: 386 (M + H) ⁺

Example 7
2- (1- (4-hydroxyphenylacetyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 5.846 min, m / z: 424 (M + H) ⁺

Example 8
2- (1- (3-thiophenacetyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.598 min, m / z: 414 (M + H) ⁺

Example 9
2- (1- (3-methoxyphenylacetyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.683 min, m / z: 438 (M + H) ⁺

Example 10
2- (1- (3- (tetrazol-1-yl) propionyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine-4 -All LCMS: Rt = 5.619 min, m / z: 414 (M + H) ⁺

Example 11
2- (1- (tetrazol-1-yl) acetylpiperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 5.607 min, m / z: 400 (M + H) ⁺

Example 12
2- (1- (5-Quinoxaloyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 5 .938 min, m / z: 446 (M + H) ⁺

Example 13
2- (1- (Tetrahydrofuran-2-yl) acetylpiperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 5.847 min, m / z: 388 (M + H) ⁺

Example 14
2- (1- (Pyrrolidin-1-yl) acetylpiperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 3.690 min, m / z: 401 (M + H) ⁺

Example 15
2- (1- (4-Methylfurazan-3-yl) acetylpiperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.389 min, m / z: 414 (M + H) ⁺

Example 16
2- (1- (2-Oxopyrrolidin-1-yl) acetylpiperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine-4- All LCMS: Rt = 5.331 min, m / z: 415 (M + H) ⁺

Example 17
2- (1- (3- (2,5-dioxoimidazolidin-4-yl) propionyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2, 3-d] pyrimidin-4-ol LCMS: Rt = 4.996 min, m / z: 444 (M + H) ⁺

Example 18
2- (1- (4-Methyl- [1,2,3] thiadiazole-5-carbonyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3 -D] pyrimidin-4-ol LCMS: Rt = 6.362 min, m / z: 416 (M + H) ⁺

Example 19
Synthesis of 2- (1- (3,5-difluorobenzoyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol (First Step) 2- (1- (t-butoxycarbonyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine-4- Synthesis of Ole 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo [b] thiophene (8) to a solution of metallic sodium (4.6 g, 0.2 mmol) in 2-propanol (200 mL). 0.9 g, 0.05 mmol) and Nt-butoxycarbonylnipecotic acid ethyl ester (18.0 g, 0.07 mmol) were added, and the mixture was heated to reflux for 5 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off until crystals were precipitated. Water (500 mL) was added to the residue for dissolution, and then unnecessary substances were removed by filtration. Hydrochloric acid was added until the pH of the filtrate reached 4, and crystals were precipitated. The filtrate was removed, the crystals were washed with warm water, and then recrystallized with 2-propanol-water (1: 5).

(Second Step) Synthesis of 2- (piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol In the first step The resulting 2- (1- (t-butoxycarbonyl) piperidin-4-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol The mixture was added to a dioxane solution saturated with hydrochloric acid, heated to 50 ° C., and then cooled to room temperature. The precipitated crystals were collected by filtration, washed with 2-propanol and then with n-hexane, and dried to obtain the desired compound (3.5 g). The yield was 21.5% over 2 steps.

(Third Step) 2- (1- (3,5-Difluorobenzoyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine- Synthesis of 4-ol 2- (piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine-4- obtained in the second step To a solution of all (326 mg, 1.0 mmol) in water (10 mL) was added potassium carbonate (0.28 g, 2.0 mmol), dichloromethane (15 mL) and 3,5-difluorobenzoyl chloride (0.177 g, 1. 0 mmol) was added and stirred under mild warming until the dichloromethane disappeared. The reaction mixture was acidified with hydrochloric acid and then cooled. After removing the supernatant, the crystals were washed with cold water and recrystallized from methanol to obtain the target compound.

¹ H-NMR (DMSO-d ₆ , ppm): 1.5 (1H, m), 1.7 (6H, m), 2.0 (1H, m), 2.6 (2H, m), 2 .8 (2H, m), 3.0 (1H, m), 3.6-4.2 (4H, m), 7.0 (2H, m), 7.2 (1H, m), 11. 9 (1H, brs).
LCMS: Rt = 5.368 min, m / z: 430 (M + H) ⁺

The compounds of Examples 20 to 25 were synthesized according to the method of synthesizing the compound of Example 19, and using the corresponding acylating reagent instead of 3,5-difluorobenzoyl chloride in the third step. The physicochemical properties of each compound obtained for Examples 20-25 are shown below.
Example 20
2- (1- (2-pyrazincarbonyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 5.434 min, m / z: 396 (M + H) ⁺

Example 21
2- (1- (Cyclopentanecarbonyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6 946 min, m / z: 386 (M + H) ⁺

Example 22
2- (1-((Pyrrolidin-1-yl) acetyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 3.509 min, m / z: 401 (M + H) ⁺

Example 23
2- (1- (pyrazolo [1,5-a] pyrimidin-3-carbonyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] Pyrimidin-4-ol LCMS: Rt = 5.374 min, m / z: 435 (M + H) ⁺

Example 24
2- (1- (2,2-dimethylpropionyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.945 min, m / z: 374 (M + H) ⁺

Example 25
2- (1- (4-Methoxyphenylacetyl) piperidin-3-yl) -5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.656 min, m / z: 438 (M + H) ⁺

Example 26
Synthesis of 2- (1- (3-fluorophenylacetyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol (first step) 2- (1- ( Synthesis of t-butoxycarbonyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol Metallic sodium (4.6 g, 0.2 mmol) in 2-propanol (200 mL) To the solution to which 2-amino-3-cyano-4,5-dimethylthiophene (7.6 g, 0.05 mmol) and Nt-butoxycarbonylnipecotic acid ethyl ester (18.0 g, 0.07 mmol) were added. ) And heated to reflux for 5 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off until crystals were precipitated. Water (500 mL) was added to the residue for dissolution, and then unnecessary substances were removed by filtration. Hydrochloric acid was added until the pH of the filtrate reached 4, and crystals were precipitated. The filtrate was removed, the crystals were washed with warm water, and then recrystallized with 2-propanol-water (1: 5).

(Second Step) Synthesis of 2- (piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol 2- (1- (t -Butoxycarbonyl) piperidin-4-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol was added to a dioxane solution saturated with hydrochloric acid, heated to 50 ° C., and then cooled to room temperature. did. The precipitated crystals were collected by filtration, washed with 2-propanol and then with n-hexane, and dried to obtain the desired compound (3.6 g). The yield was 24% for 2 steps.

(Third Step) Synthesis of 2- (1- (3-fluorophenylacetyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol Obtained in the second step To a solution of the obtained 2- (piperidin-4-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol (300 mg, 1.0 mmol) in water (10 mL), potassium carbonate was added. (0.28 g, 2.0 mmol), dichloromethane (15 mL) and 3-fluorophenylacetyl chloride (0.173 g, 1.0 mmol) were added and stirred under mild warming until the dichloromethane disappeared. The reaction mixture was acidified with hydrochloric acid and then cooled. After removing the supernatant, the crystals were washed with cold water and recrystallized from methanol to obtain the target compound.

¹ H-NMR (DMSO-d ₆ , ppm): 1.4 (1H, m), 1.7 (2H, m), 1.9 (1H, m), 2.3 (3H, s), 2 .4 (3H, s), 2.7 (2H, m), 2.9-3.3 (3H, m), 3.8 (2H, m), 7.0 (3H, m), 7. 35 (1H, m), 12.0 (1H, brs).
LCMS: Rt = 6.306 min, m / z: 400 (M + H) ⁺

  The compounds of Examples 27 to 35 were synthesized according to the method of synthesizing the compound of Example 26, and using the corresponding acylating reagent instead of 3-fluorophenylacetyl chloride in the third step. The physicochemical properties of each compound obtained for Examples 27-35 are shown below.

Example 27
2- (1- (2-thiophenecarbonyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 5.979 min, m / z: 374 ( M + H) ⁺

Example 28
2- (1-Isobutyrylpiperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 5.744 min, m / z: 334 (M + H) ⁺

Example 29
2- (1-Furoylpiperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 5.649 min, m / z: 358 (M + H) ⁺

Example 30
2- (1- (2,2-dimethylpropionyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.294 min, m / z: 348 (M + H) ⁺

Example 31
2- (1- (4-methoxyphenylacetyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.156 min, m / z: 412 (M + H) ⁺

Example 32
2- (1- (2-fluorophenylacetyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.312 min, m / z: 400 (M + H) ⁺

Example 33
2- (1- (4-Fluorophenylacetyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.287 min, m / z: 400 (M + H) ⁺

Example 34
2- (1- (cyclopentanecarbonyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.398 min, m / z: 360 (M + H ) ⁺

Example 35
2- (1- (3-thiophenacetyl) piperidin-3-yl) -5,6-dimethylthieno [2,3-d] pyrimidin-4-ol LCMS: Rt = 6.034 min, m / z: 388 ( M + H) ⁺

Test Example 1 Cell Growth Inhibitory Action Using an RPMI 1640 medium (Iwaki) supplemented with 10% fetal bovine serum (manufactured by Moregate), human renal cancer cells UO-31 (NCI), human brain tumor cells U251, human breast cancer cells MDA-MB-231 (ATCC) was cultured at 37 ° C. under 5% CO ₂ . These cells were seeded in a 96-well plate and cultured for 1 day, after which various concentrations of the thieno [2,3-d] pyrimidin-4-ol derivative of the present invention were added. After further culturing for 3 days, the cells were fixed with methanol and stained with methylene blue dye. After staining, the dye was extracted with 0.3% hydrochloric acid, and the absorbance at 660 nm was measured.

For the growth inhibitory activity, a concentration-growth inhibition curve was prepared from the decrease rate of the absorbance of the compound addition group relative to the absorbance of the cells to which no compound was added. From this curve, the concentration at a growth rate of 50% was determined and used as the IC ₅₀ value, and the value is shown in Table 1.

Table 1
Cell growth inhibitory action of thieno [2,3-d] pyrimidin-4-ol derivatives
IC ₅₀ (μM)
Compound UO-31 U251 MDA-MB-231
Example 1 1.62 1.36 2.04
Example 2 11.7 7.27 12.5
Example 3> 20 13.5> 20
Example 5 8.74 43.8 31.5
Example 6 41.9 12.7 24.0
Example 7 12.5 6.69 11.5
Example 8 25.6 24.4 24.8
Example 9> 20 13.9 25.9
Example 12 6.49 27.4 21.2
Example 13> 20 38.9 37.1
Example 14 42.3 48.3 > 20
Example 19 4.01 33.8 24.8
Example 21 7.48 23.2 25.8
Example 23 8.73 36.9 > 20
Example 24 10.6 6.48 11.4
Example 25 18.0 32.9 29.9
Example 26 8.02>20> 20
Example 27 11.0 41.3 > 20
Example 30 14.7 46.0 > 20
Example 32 15.1>20> 20
Example 34 8.74 40.7 > 20
Example 35 9.05>20> 20
(Underline is extrapolated value)

  As is clear from Table 1, the thieno [2,3-d] pyrimidin-4-ol derivative showed a cell growth inhibitory effect on mammalian cancer cells.

Test example 2
Mouse lymphocytic leukemia cell P388 or its adriamycin resistant strain P388 / ADR was cultured at 37 ° C. under 5% CO ₂ using RPMI 1640 medium supplemented with 10% fetal bovine serum. The cells were seeded in a 96-well plate and cultured for 1 day, after which various concentrations of the thieno [2,3-d] pyrimidin-4-ol derivative of the present invention or adriamycin (manufactured by Kyowa Hakko) were added. After further culturing for 2 days, 0.16 mg / mL of WST-1 (manufactured by Dojindo) and 3.3 μg / mL of 1-methyl-5-methylphenylsulfate were added to the culture solution and cultured for 4 hours. The value obtained by subtracting the absorbance at 660 nm from the absorbance at 450 nm was determined, and the IC ₅₀ value was determined in the same manner as in Test Example 1.

Table 2
Cell growth inhibitory action of thieno [2,3-d] pyrimidin-4-ol derivatives
IC ₅₀ (μM)
Compound P388 P388 / ADR
Example 1 0.25 0.39
Example 2 0.62 1.48
Adriamycin 0.015 2.82

  As is clear from Table 2, the thieno [2,3-d] pyrimidin-4-ol derivative of the present invention has a cell growth inhibitory effect on mammalian cancer cells, and against adriamycin resistant cells (P388 / ADR). However, the cell growth inhibitory effect was almost the same as that of the sensitive cells (P388).

Claims (23)

General formula (1)

Wherein X and Y each independently represent a hydrogen atom, a lower alkyl group or a cycloalkyl group, or X and Y are an alkylene group having 3 to 5 carbon atoms for bonding to form a cyclic structure, alkenylene. N represents an integer of 1 to 3. A represents an optionally substituted lower alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, or heteroaryl group. And the substituent represents one or more selected from the group consisting of a halogen atom, a hydroxyl group, a carbonyl group, a lower alkyl group, and a lower alkoxy group, and m represents an integer of 0 to 3. [2,3-d] pyrimidin-4-ol derivatives, hydrates, solvates, or pharmacologically acceptable salts thereof. In the general formula (1), both X and Y represent a methyl group, or an alkylene group having 4 carbon atoms for bonding X and Y to form a cyclic structure. -D] Pyrimidin-4-ol derivative, its hydrate, its solvate, or pharmacologically acceptable salt. The thieno [2,3-d] pyrimidin-4-ol derivative, hydrate, solvate, or pharmacologically acceptable thereof according to claim 2, wherein n is 2 in the general formula (1). Salt. In the general formula (1), A is an alkyl group having 1 to 6 carbon atoms and 3 to 7 carbon atoms substituted with one or more selected from the group consisting of a halogen atom, a hydroxyl group, a carbonyl group, and a lower alkoxy group. Cycloalkyl group, phenyl group, naphthyl group, furyl group, thienyl group, imidazolyl group, triazolyl group, tetrazolyl group, tetrahydrobenzothieno group, quinoxalyl group, tetrahydrofuryl group, pyrrolidinyl group, flazanyl group, thiadiazolyl group, pyrazyl group, Or a thiano [2,3-d] pyrimidin-4-ol derivative according to any one of claims 1 or 3, a hydrate, a solvate thereof, or a pyrazolopyrimidyl group Pharmacologically acceptable salt. General formula (2)

(In the formula, A ₁ represents an optionally substituted lower alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, or heteroaryl group, and the substituent includes a halogen atom, a hydroxyl group, and a carbonyl group. 1 or more selected from the group consisting of a lower alkyl group and a lower alkoxy group, and m ₁ represents an integer of 0 to 3. ] Pyrimidin-4-ol derivative, its hydrate, its solvate, or pharmacologically acceptable salt. In the general formula (2), m ₁ is 0, and A ₁ is a lower alkyl group which may be substituted with one or more selected from the group consisting of a halogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxy group , A cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, the thieno [2,3-d] pyrimidin-4-ol derivative according to claim 5, a hydrate thereof, a solvate thereof, Or a pharmacologically acceptable salt. In the general formula (2), m ₁ is 1 or 2, and A ₁ is optionally substituted with one or more selected from the group consisting of a hydroxyl group, a carbonyl group, a lower alkyl group, and a lower alkoxy group. The thieno [2,3-d] pyrimidin-4-ol derivative according to claim 5, which is a cycloalkyl group, an aryl group or a heteroaryl group, a hydrate thereof, a solvate thereof, or a pharmacologically acceptable Salt. The thieno [2,3-d] pyrimidin-4-ol derivative according to claim 6, wherein A ₁ is an isopropyl group, a tert-butyl group, a cyclopentyl group, a tetrahydrofuryl group, a phenyl group, a quinoxalyl group or a thiadiazolyl group, Hydrates, solvates thereof, or pharmacologically acceptable salts. The thieno [2,3-d] pyrimidin-4-ol according to claim 7, wherein A ₁ is a pyrrolidinyl group, an oxopyrrolidinyl group, a phenyl group, a thienyl group, a tetrazolyl group, a dioxoimidazolidyl group or a flazanyl group. Derivatives, hydrates, solvates, or pharmacologically acceptable salts thereof. General formula (3)

(In the formula, A ₂ represents an optionally substituted lower alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, or heteroaryl group, and the substituent includes a halogen atom, a hydroxyl group, and a carbonyl group. 1 or more selected from the group consisting of lower alkyl groups and lower alkoxy groups, and m ₂ represents an integer of 0 to 3). -D] Pyrimidin-4-ol derivative, its hydrate, its solvate, or pharmacologically acceptable salt. The general formula (3), wherein m ₂ is 0 and A ₂ is a lower alkyl group, a cycloalkyl group, an aryl group, or a heteroaryl group, which may be substituted with one or more halogen atoms. Thieno [2,3-d] pyrimidin-4-ol derivatives, hydrates, solvates, or pharmaceutically acceptable salts thereof. In the general formula (3), thieno [2, 2, wherein m ₂ is 1 and A ₂ is a heterocycloalkyl group or an aryl group which may be substituted with one or more lower alkoxy groups. 3-d] pyrimidin-4-ol derivatives, hydrates, solvates, or pharmacologically acceptable salts thereof. The thieno [2,3-d] pyrimidin-4-ol derivative and hydrate thereof according to claim 11, wherein A ₂ is a tert-butyl group, a cyclopentyl group, a phenyl group, a pyrazyl group or a pyrazolopyrimidyl group. , Solvates or pharmaceutically acceptable salts thereof. The thieno [2,3-d] pyrimidin-4-ol derivative, hydrate, solvate or pharmacologically acceptable salt thereof according to claim 12, wherein A ₂ is a pyrrolidinyl group or a phenyl group. . General formula (4)

(In the formula, A ₃ represents an optionally substituted lower alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, or heteroaryl group, and the substituent includes a halogen atom, a hydroxyl group, and a carbonyl group. 1 or more selected from the group consisting of lower alkyl groups and lower alkoxy groups, and m ₃ represents an integer of 0 to 3. -D] Pyrimidin-4-ol derivative, its hydrate, its solvate, or pharmacologically acceptable salt. The general formula (4), wherein m ₃ is 0 and A ₃ is a lower alkyl group, a cycloalkyl group or a heteroaryl group, which may be substituted with one or more lower alkyl groups. Thieno [2,3-d] pyrimidin-4-ol derivatives, hydrates, solvates, or pharmaceutically acceptable salts thereof. In the general formula (4), m ₃ is 1, and A ₃ is an aryl group or heteroaryl group which may be substituted with one or more selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group The thieno [2,3-d] pyrimidin-4-ol derivative, hydrate, solvate, or pharmacologically acceptable salt thereof according to claim 15, wherein The thieno [2,3-d] pyrimidin-4-ol derivative, hydrate, and solvate thereof according to claim 16, wherein A ₃ is an isopropyl group, a tert-butyl group, a cyclopentyl group, a furyl group, or a thienyl group. Product or pharmacologically acceptable salt. The thieno [2,3-d] pyrimidin-4-ol derivative, hydrate, solvate or pharmacologically acceptable salt thereof according to claim 17, wherein A ₃ is a phenyl group or a thienyl group. . A preventive or therapeutic agent for a mammalian drug or disease comprising the compound according to any one of claims 1 to 19 or a hydrate, solvate or pharmacologically acceptable salt thereof as an active ingredient. . A cell growth inhibitor comprising the compound according to any one of claims 1 to 19 or a hydrate, solvate, or pharmacologically acceptable salt thereof as an active ingredient. The anticancer agent which uses the compound as described in any one of Claims 1 thru | or 19, its hydrate, its solvate, or a pharmacologically acceptable salt as an active ingredient. The anticancer agent according to claim 22, wherein the cancer is a drug resistant cancer.