JP2006022073A - Furylpyrimidine derivative or salt thereof, and application thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound having excellent antitumor activities. <P>SOLUTION: The medicinal composition or the antitumor agent contains a furylpyrimidine derivative represented by general formula (1) (wherein, Xs and Ys are each one or more atoms or substituents selected from a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an aryl or heteroaryl group which may have a substituent, a nitro group, a cyano group, -CZ3, -NR1R2, -CO2R3, -S(O)n-R4, -NHC(O)R5, -C(O)NR6R7, -COR8, -CH2-OR9, -CH=CH-R10, -CH=CH-COOR11 and -CH=CH-CONHR12; A is a diamino group which has a 2-10C straight chain, branched or cyclic alkyl chain between two nitrogen atoms, and in which one or more nitrogen atoms may form a 4- to 7-membered alicyclic heterocyclic group by bonding to the alkylene chain; B is a carbonyl group or a sulfonyl group; and C is an aryl or heteroaryl group which may have a substituent, or a benzyl group the α-position of which may be substituted with a lower alkyl group), or a salt thereof as an active ingredient. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a novel furyl pyrimidine derivative or a salt thereof.

  In 1942, Gilman and Philips used nitrogen mustard for the treatment of malignant lymphoma and observed significant tumor shrinkage. Since then, derivatives such as vinca alkaloids, epipodophyllotoxins, platinum compounds, taxanes, camptothecins have been developed as antitumor agents. However, most of these anti-tumor agents inhibit cell growth and division processes, and are known to act not only on actively proliferating cancer cells but also on normal cells. Therefore, the effects on cancer are still insufficient, that is, having resistance, toxicity to normal cells, and low selectivity for cancer cells are problems of conventional antitumor agents. . Therefore, for the development of cancer chemotherapy, development of an antitumor agent having excellent antitumor effect and selectivity for cancer cells is further desired.

Furyl pyrimidine derivatives have been widely studied as a basic structure of pharmaceuticals. An adenosine receptor antagonist in which the substituent at the 2-position of the pyrimidine ring of the furylpyrimidine derivative is an amino group or an alkylamino group having 1 to 6 carbon atoms which may have a substituent (Patent Document 1), pyrimidine ring 2 The 5-HT _2A receptor agonist (Non-Patent Documents 1 to 3), in which the substituent at the position is 4-methylpiperazine or ethylenediamine which may have a methyl group on one nitrogen atom, An anti-asthma drug (Patent Document 2) and the like in which the substituent is an amino group having a mono- or di-substituted phenyl group has been reported. Further, an Aurora kinase inhibitor having a pyrazole amino group on the pyrimidine ring (Patent Documents 3 and 4), a rho kinase inhibitor having an amino group substituted with an aromatic ring on the pyrimidine ring (Patent Document 5), and a furan ring A Raf kinase inhibitor (Patent Document 6), which is an aryl group, one of which is an aryl group, and the substituent at the 2-position of the pyrimidine ring is an ethylenediamine which may have a substituent. It has been reported that various kinase inhibitors such as glycogen synthase kinase 3 inhibitor (Patent Document 7) in which an aryl or heteroaryl group is bonded to a nitrogen atom are useful as an antitumor agent. However, a compound in which the substituent at the 2-position of the pyrimidine ring is an alkylamino group having an amide or sulfonamido group is not known.
WO03 / 035639 pamphlet U.S. Pat.No. 4,788,195 US Patent Application Publication No. 2003/055068 US Patent Application Publication No. 2003/064982 WO03 / 062225 pamphlet WO03 / 022840 pamphlet International Publication No. 02/20495 Pamphlet Journal of Medicinal Chemistry 2000, Vol. 43, No.10. 1901. Arch. Pharm. 328, 659 (1995). Pharmazie 1994, 49, H. 11.

  An object of the present invention is to provide a novel compound having excellent antitumor activity and high selectivity for cancer cells.

As a result of intensive studies to solve the above problems, the present inventors have found that a furylpyrimidine derivative represented by the following general formula has excellent antitumor activity, and completed the present invention.
That is, the present invention relates to the general formula (1)

[Wherein, X and Y are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an aryl or heteroaryl group which may have a substituent, a nitro group, a cyano group, -CZ ₃ , -NR ¹ R ² , -CO ₂ R ³ , -S (O) nR ⁴ , -NHC (O) R ⁵ , -C (O) NR ⁶ R ⁷ , -COR ⁸ , -CH _2- OR ⁹ , -CH = CH-R ¹⁰ , -CH = CH-COOR ¹¹ , and -CH = CH-CONHR ¹²
(Z represents a halogen atom; R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁹ are each independently a hydrogen atom, a lower alkyl group, an aryl group or heteroaryl group optionally having substituent (s) and an aralkyl optionally having substituent (s) An atom or a substituent selected from a group or a heteroarylalkyl group, R ⁶ and R ⁷ together form a 4- to 7-membered alicyclic heterocyclic group which may have a substituent; R ⁵ represents a lower alkyl group or an aryl group which may have a substituent; R ⁸ represents a hydrogen atom or a lower alkyl group; R ¹⁰ and R ¹² each independently have a substituent. An optionally substituted aryl group or heteroaryl group; R ¹¹ represents a hydrogen atom or a lower alkyl group; n represents an integer of 0 to 2)
A represents one or more atoms or substituents selected from: A represents a diamino group having a linear, branched or cyclic alkylene chain having 2 to 10 carbon atoms between two nitrogen atoms; Or two nitrogen atoms together with the alkylene chain may form a 4- to 7-membered alicyclic heterocyclic group; B represents a carbonyl group or a sulfonyl group; C represents a substituent. An aryl group or a heteroaryl group which may be substituted, or a benzyl group which may be substituted at the α-position with a lower alkyl group. The bonding position of the furyl group to the pyrimidine ring is the 2nd or 3rd position. ]
The furyl pyrimidine derivative represented by these, or its salt is provided.

The present invention also provides a compound selected from the following furyl pyrimidine derivatives:
4- (2-Furyl) -2- [1- [4- (2-methoxy-4-methylbenzenesulfonyl) piperazino]] pyrimidine
2- [1- [4- (2,4-Difluorobenzenesulfonyl) piperazino]]-4- (2-furyl) pyrimidine
4- (2-Furyl) -2- [1- [4- (2-phenylbutyroyl) piperazino]] pyrimidine
4- (2-Furyl) -2- [1- [4- (2,5-difluorobenzoyl) piperazino]] pyrimidine
4- (2-Furyl) -2- [1- [4- (quinoline-8-sulfonyl) piperazino]] pyrimidine
2- [1- [4- (3,4,5-trifluorobenzenesulfonyl) piperazino]]-4- (2-furyl) pyrimidine
4- (2-Furyl) -2- [1- [4- (pyridine-3-sulfonyl) piperazino]] pyrimidine
4- (2-Furyl) -2- [1- [4- (2,4-dimethoxybenzenesulfonyl) piperazino]] pyrimidine
2- [1- (4-{[2- (4-Chlorophenyl) -3-methyl] butyroyl} piperazino)]-4- (2-furyl) pyrimidine
2- (N-{[N- (2,4-Difluorobenzenesulfonyl) -N-methyl] amino} ethyl-N-methyl) amino-4- (2-furyl) pyrimidine
2- (4- {1-[(2,4-difluorobenzene) sulfonyl]} piperidine) amino-4- (2-furyl) pyrimidine
2- [1- [4- (2-Phenylbutyroyl) amino] piperidino] -4- (2-furyl) pyrimidine
2- {N- [N- (2,4-difluorobenzenesulfonyl) amino] ethyl} amino-4- (2-furyl) pyrimidine or a salt thereof is provided.

  The present invention also provides a pharmaceutical composition comprising a compound represented by the above general formula (1) or a salt thereof as an active ingredient.

  The present invention further provides an antitumor agent comprising a compound represented by the above general formula (1) or a salt thereof as an active ingredient.

  The furyl pyrimidine derivative of the present invention or a salt thereof has excellent antitumor activity, has high selectivity for cancer cells, and is useful as an antitumor agent.

  X and Y in the general formula (1) will be described.

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

  The “lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, etc. And a methyl group or an ethyl group is preferable.

  The “lower alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms. For example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy A methoxy group or an ethoxy group is preferable.

The “aryl group” in the “aryl group optionally having a substituent” means an aryl group having 6 to 20 carbon atoms. Examples include a phenyl group, a naphthyl group, an anthryl group, a benzanthryl group, a phenanthryl group, and the like, and a phenyl group is preferable.
The “heteroaryl group” of the “heteroaryl group optionally having substituent (s)” is a monocyclic group containing 1 to 3 of the same or different heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Alternatively, it means a bicyclic heteroaryl group having 4 to 9 carbon atoms. Examples of such heteroaryl groups include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isobenzofuryl. Group, indolizinyl group, isoindolyl group, indolyl group, indazolyl group, quinolyl group, isoquinolyl group, phthalazinyl group, naphthyridinyl group and the like, and a pyridyl group or a furyl group is preferable.

  Examples of the “substituent” in the “optionally substituted aryl group” and the “optionally substituted heteroaryl group” include, for example, the halogen atom, the lower alkyl group, and trifluoromethyl. Group, lower alkoxy group, hydroxyl group, nitro group, amino group, mono- or di-lower alkyl-substituted amino group, lower acyloxy group, lower acylamino group, cyano group, carboxyl group, carboxyamide group, lower alkoxycarbonyl group, mono- or di- Lower alkyl-substituted carbamoyl group, aryl group, heteroaryl group, arylcarbonyl group, heteroarylcarbonyl group, arylcarboxyl group, heteroarylcarboxyl group, arylcarboxamide group, aryl (N-lower alkyl) carboxamide group, heteroarylcarboxamide Group, hetero Reel (N- lower alkyl) carboxamide, arylcarbamoyl group, an aryl (N- lower alkyl) carbamoyl group, heteroarylthio carbamoyl group, heteroaryl (N- lower alkyl) carbamoyl group, and the like.

The mono- or di-lower alkyl-substituted amino group means an amino group substituted with one or two lower alkyl groups. Examples thereof include a methylamino group, an ethylamino group, an N, N-dimethylamino group, an N, N-diethylamino group, and an N-methyl-N-ethylamino group.
The lower acyloxy group means an acyloxy group having 2 to 7 carbon atoms having the lower alkyl group. For example, acetyloxy group, propionyloxy group, n-butyryloxy group, sec-butyryloxy group, pivaloyloxy group and the like can be mentioned.
The lower acylamino group means an acylamino group having 2 to 7 carbon atoms and having the lower alkyl group. Examples include acetylamino group, propionylamino group, n-butyrylamino group, sec-butyrylamino group, pivaloylamino group, and the like.
The lower alkoxycarbonyl group means a carbonyl group having the lower alkoxy. Examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, and an n-butoxycarbonyl group.
The mono- or di-lower alkyl-substituted carbamoyl group means a carbamoyl group substituted with one or two lower alkyl groups. Examples thereof include a methylcarbamoyl group, an ethylcarbamoyl group, an N, N-dimethylcarbamoyl group, an N, N-diethylcarbamoyl group, an N-methyl-N-ethylcarbamoyl group, and the like.
The arylcarbonyl group means a carbonyl group having the aryl group. For example, a benzoyl group, a naphthoyl group, etc. are mentioned.
The heteroarylcarbonyl group means a carbonyl group having the heteroaryl group. For example, a pyridylcarbonyl group, a furylcarbonyl group, etc. are mentioned.
The aryl carboxyl group means a carboxyl group having the aryl group. For example, a phenyl carboxyl group, a naphthyl carboxyl group, etc. are mentioned.
The heteroarylcarboxyl group means a carbonyl group having the heteroaryl group. For example, a pyridyl carboxyl group, a furyl carboxyl group, etc. are mentioned.
The arylcarboxamide group means a carboxamide group having the aryl group. For example, a phenyl carboxamide group etc. are mentioned.
The aryl (N-lower alkyl) carboxamide group means a carboxamide group having the aryl group and the lower alkyl group. For example, a phenyl-N-methylcarboxamide group etc. are mentioned.
The heteroaryl carboxamide group means a carboxamide group having the heteroaryl group. Examples thereof include a pyridylcarboxamide group and a furylcarboxamide group.
The heteroaryl (N-lower alkyl) carboxamide group means a carboxamide group having the heteroaryl group and the lower alkyl group. Examples thereof include a pyridyl-N-methylcarboxamide group and a furyl-N-methylcarboxamide group.
The arylcarbamoyl group means a carbamoyl group having the aryl group. An example is a phenylcarbamoyl group.
The aryl (N-lower alkyl) carbamoyl group means a carbamoyl group substituted with the aryl group and the lower alkyl group. For example, N-phenyl-N-methylcarbamoyl group, N-phenyl-N-ethylcarbamoyl group and the like can be mentioned.
The heteroarylcarbamoyl group means a carboxyl group having the aryl group. For example, a pyridylcarbamoyl group, a furylcarbamoyl group, etc. are mentioned.
The heteroaryl (N-lower alkyl) carbamoyl group means a carbamoyl group substituted with the heteroaryl group and the lower alkyl group. Examples thereof include an N-pyridyl-N-methylcarbamoyl group and an N-furyl-N-methylcarbamoyl group.

  Of these substituents, a halogen atom, a lower alkyl group or a lower alkoxy group is preferred. The number of substituents may be plural, and the plural substituents may be the same or different.

The lower alkyl group of R ^{1 to} R ^{12 and} the aryl group or heteroaryl group which may have a substituent are the same as described above. The aralkyl group of the aralkyl group which may have a substituent of R ^{1 to} R ⁴ , R ⁶ , R ⁷ and R ⁹ is composed of an aryl group having 6 to 20 carbon atoms and the lower alkyl group. Means a group. Examples of such an aralkyl group include a benzyl group and a phenethyl group, and a benzyl group is preferable. The heteroarylalkyl group which may have a substituent means a group composed of the heteroaryl group and the lower alkyl group. Examples of such heteroaralkyl groups include a pyridylmethyl group and a pyridylethyl group. The 4- to 7-membered alicyclic heterocyclic group which may have a substituent is a nitrogen atom such as a piperidyl group, piperazinyl group, pyrrolidinyl group, homopiperazinyl group, imidazolidinyl group, pyrazolidinyl group, morpholinyl group, thiomorpholinyl group, etc. And alicyclic heterocyclic groups containing 1 to 3 of the same or different heteroatoms selected from oxygen atoms and sulfur atoms.
The substituents of the aryl group, heteroaryl group, aralkyl group, heteroaralkyl group and alicyclic heterocyclic group are the same as described above, but a lower alkyl group is preferable, and a methyl group is particularly preferable.

Examples of —CZ ₃ include a trifluoromethyl group, a trichloromethyl group, and a tribromomethyl group.
-NR ¹ R ² includes an amino group, methylamino group, ethylamino group, n-propylamino group, N, N-dimethylamino group, N, N-diethylamino group, N-methyl-N-ethylamino group, N-methyl-Nn-propylamino group, phenylamino group, N, N-diphenylamino group, benzylamino group, pyridylamino group, pyridylmethylamino group, pyrrolidinyl group, piperidyl group, morpholino group, piperazinyl group, N-methylpipe Razinyl group and the like, amino group, methylamino group, ethylamino group, N, N-dimethylamino group, N, N-diethylamino group, phenylamino group, benzylamino group, pyridylamino group, pyridylmethylamino group, A pyrrolidinyl group, piperidyl group, morpholino group, piperazinyl group or N-methylpiperazinyl group is preferred.
As —CO ₂ R ³ , carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, phenoxycarbonyl Group, a naphthoxycarbonyl group, etc. are mentioned, A carboxyl group, a methoxycarbonyl group, or an ethoxycarbonyl group is preferable.
The -S (O) nR ^4, thiol group, methylthio group, ethylthio group, a sulfenic acid group, methylsulfinyl group, ethylsulfinyl group, a sulfinic acid group, a methylsulfonyl group, ethylsulfonyl group, phenylthio group, phenylsulfinyl group, A phenylsulfonyl group, a pyridylthio group, a pyridylsulfonyl group, etc. are mentioned, A phenylthio group, a phenylsulfonyl group, a pyridylthio group or a pyridylsulfonyl group is preferable.
Examples of —NHC (O) R ⁵ include a methylcarbonylamino group, an ethylcarbonylamino group, an n-propylcarbonylamino group, a phenylcarbonylamino group, a pyridylcarbonylamino group, and the like, and a phenylcarbonylamino group or a pyridylcarbonylamino group Is preferred.
-C (O) NR ⁶ R ⁷ includes aminocarbonyl group, methylaminocarbonyl group, N, N-dimethylaminocarbonyl group, ethylaminocarbonyl group, N, N-diethylaminocarbonyl group, N-methyl-N-ethyl Aminocarbonyl group, N-ethyl-N-ethylaminocarbonyl group, n-propylaminocarbonyl group, N-methyl-Nn-propylaminocarbonyl group, N-ethyl-Nn-propylaminocarbonyl group, phenylaminocarbonyl group, N -Methylphenylaminocarbonyl group, N-ethylphenylaminocarbonyl group, benzylaminocarbonyl group, N-methyl-N-benzylaminocarbonyl group, N-ethyl-N-benzylaminocarbonyl group, pyridylaminocarbonyl group, N-methyl- N-pyridylaminocarbonyl group, N-ethyl-N-pyridylaminocarbonyl group, pyridylmethylaminocarbonyl group, N -Methyl-N-pyridylmethylaminocarbonyl group, N-ethyl-N-pyridylmethylaminocarbonyl group, pyrrolidinylcarbonyl group, piperidylcarbonyl group, morpholinocarbonyl group, piperazinylcarbonyl group, N-methyl-piperazinyl A carbonyl group etc. are mentioned.
Examples of —COR ⁸ include a formyl group and an acetyl group.
Examples of —CH ₂ —OR ⁹ include a hydroxymethyl group, a phenoxymethyl group, a pyridyloxymethyl group, a benzyloxymethyl group, a pyridylmethyloxymethyl group, a phenethyloxymethyl group, and a pyridylethyloxymethyl group.
Examples of —CH═CH—R ¹⁰ include a styryl group and a pyridylethenyl group.
Examples of —CH═CH—COOR ¹¹ include an acryloyl group, a methoxycarbonylethenyl group, and an ethoxycarbonylethenyl group.
Examples of —CH═CH—CONHR ¹⁰ include a phenylaminocarboxyethenyl group and a pyridylaminocarboxyethenyl group.

Among the above atoms or substituents, X is a hydrogen atom, a halogen atom, a lower alkyl group, a nitro group, a cyano group, -NR ¹ R ² , -COR ⁸ , -CH ₂ -OR ⁹ , -CH = CH—R ¹⁰ , —CH═CH—COOR ¹¹ and —CH═CH—CONHR ¹² are preferable, a hydrogen atom, a halogen atom, a lower alkyl group, a nitro group or a cyano group is more preferable, and a hydrogen atom or a halogen atom is particularly preferable. .
Y represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an aryl group (for example, phenyl group) or heteroaryl group (for example, furyl group, thienyl group) which may have a substituent, nitro Group, cyano group, CZ ₃ , -NR ¹ R ² , -CO ₂ R ⁸ , -S (O) nR ⁴ , -NHCOR ⁵ , -CONR ⁶ R ⁷ , -COR ⁸ , -CH ₂ -OR ⁹ ,- CH = CH—R ¹⁰ , —CH═CH—COOR ¹¹ and —CH═CH—CONHR ¹² are preferred, a hydrogen atom, a halogen atom, a lower alkyl group, a nitro group or a cyano group is more preferred, particularly a hydrogen atom or a halogen atom. Is preferred.

A diamino group having a linear, branched or cyclic alkylene chain having 2 to 10 carbon atoms between two nitrogen atoms represented by A is two nitrogen atoms (one nitrogen atom is the 2-position of the pyrimidine ring) While the other nitrogen atom is bonded to B), ethylene group, propylene group, pentamethylene group, hexamethylene group, methylethylene group, ethylethylene group, methylpropylene group, ethylpropylene group, cyclopropylene group And a divalent diamino group derived from a diamine having a linear, branched or cyclic alkylene chain having 2 to 10 carbon atoms such as a cyclohexylene group.
One or two nitrogen atoms may form a 4- to 7-membered alicyclic heterocyclic group together with the alkylene chain. Examples of such alicyclic heterocycles include piperidine, piperazine, pyrrolidine, and homopiperazine.

  Therefore, as A, the general formula (2)

(In the formula, R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represents a hydrogen atom, a methyl group or an ethyl group.)
The group represented by these is preferable.

  Specifically, ethylenediamino group, ethylethylenediamino group, cyclopropylenediamino group, cyclohexylenediamino group, N, N-dimethylethylenediamino group, piperazino group, pyrrolidino group, 4-aminopiperidino group, 1,3-propanediamino group Group, 1,4-butanediamino group, 1,5-pentanediamino group, 1,6-hexanediamino group, 1,7-heptanediamino group and the like, ethylenediamino group, N, N-dimethylethylenediamino group A piperazino group or a 4-aminopiperidino group is preferred.

Examples of the aryl group and heteroaryl group represented by C include the same groups as described above. The aryl group is preferably a phenyl group, and the heteroaryl group is preferably a pyridyl group or a quinolyl group. The substituent that the aryl group or heteroaryl group has is the same as described above. As the substituent, a group selected from a halogen atom, a lower alkyl group and a lower alkoxy group is preferable. The number of substituents is preferably 1 to 3, and when a plurality of substituents are substituted, they may be the same or different.
Examples of the optionally substituted phenyl group, pyridyl group or quinolyl group include phenyl group, toluyl group, xylyl group, methoxyphenyl group, dimethoxyphenyl group, methylmethoxyphenyl group, fluorophenyl group and difluorophenyl. Group, trifluorophenyl group, chlorophenyl group, dichlorophenyl group, trichlorophenyl group, pyridyl group, methylpyridyl group, chloropyridyl group, quinolyl group, methylquinolyl group, chloroquinolyl group and the like.

The “benzyl group substituted at the α-position with a lower alkyl group” means a benzyl group substituted at the α-position with the lower alkyl group. The lower alkyl group is preferably a methyl group, an ethyl group, an n-propyl group or an isopropyl group. The lower alkyl group may be further substituted with a substituent selected from the halogen atom, the lower alkyl group, and the lower alkoxy group. Further, the benzene ring of the benzyl group may be further substituted with the lower alkyl group, the lower alkoxy group, the halogen atom, nitro group, amino group, hydroxyl group, carboxyl group or the like.
Examples of the benzyl group substituted at the α-position with a lower alkyl group include, for example, α-methylbenzyl group, α-ethylbenzyl group, α-n-propylbenzyl group, α-isopropylbenzyl group, α-n-butylbenzyl group. , Α- (1-methylbutyl) -p-chlorobenzyl group, α-pentylbenzyl group, α-hexylbenzyl group, and the like.

  As C, an optionally substituted phenyl group, pyridyl group or quinolyl group or a benzyl group optionally substituted at the α-position with a lower alkyl group is preferred, a halogen atom, a lower alkyl group and a lower alkoxy group. A phenyl group, a pyridyl group or a quinolyl group which may have a substituent selected from: or a lower alkyl group which may have a substituent selected from a halogen atom, a lower alkyl group and a lower alkoxy group at the α-position; A benzyl group substituted with is more preferable, and a phenyl group, a pyridyl group or a quinolyl group is particularly preferable.

  In the furyl pyrimidine derivative of the present invention, the furyl group is bonded to the 4-position of the pyrimidine ring at the 2- or 3-position of the furyl group, but the 2-position is preferred.

In the general formula (1), X is a hydrogen atom, a halogen atom, a lower alkyl group, a nitro group, a cyano group, —NR ¹ R ² , —COR ⁸ , —CH ₂ —OR ⁹ , —CH═CH—R ^10. , —CH═CH—COOR ¹¹ and —CH═CH—CONHR ¹² ; Y represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or an aryl group which may have a substituent (for example, Phenyl group) or heteroaryl group (for example, furyl group, thienyl group), nitro group, cyano group, -CZ ₃ , -NR ¹ R ² , -CO ₂ R ⁸ , -S (O) nR ⁴ , -NHCOR ⁵ , -CONR ⁶ R ⁷ , -COR ⁸ , -CH ₂ -OR ⁹ , -CH = CH-R ¹⁰ , -CH = CH-COOR ¹¹ and -CH = CH-CONHR ¹² ; A group represented by (2); B represents a carbonyl group or a sulfonyl group; C represents an aryl or heteroaryl group which may have a substituent, or the α-position is substituted with a lower alkyl group; Indicates a good benzyl group; Preferably point of attachment to the pyrimidine ring of groups is 2 or 3 position,
X and Y each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a nitro group or a cyano group; A represents a group represented by the general formula (2); B represents a carbonyl group or a sulfonyl group A phenyl group, a pyridyl group or a quinolyl group which may have a substituent selected from a halogen atom, a lower alkyl group and a lower alkoxy group, or the α-position is a halogen atom, a lower alkyl group and a lower alkoxy group A benzyl group substituted with a lower alkyl group which may have a substituent selected from: more preferably, the bonding position of the furyl group to the pyrimidine ring is the 2-position;
X and Y both represent a hydrogen atom; A represents a group represented by the general formula (2); B represents a carbonyl group or a sulfonyl group; C represents a phenyl group, a pyridyl group or a quinolyl group; The bonding position of the group to the pyrimidine ring is particularly preferably the 2-position.

  As described above, in the compound of the present invention represented by the general formula (1), the substituent at the 2-position of the pyrimidine ring is an alkylamino group having an amide or sulfonamide group formed by the above A and B. It is a feature.

  The compounds of the present invention can form pharmaceutically acceptable salts. For example, when an acidic group is present, an alkali or alkaline earth metal salt such as lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt; ammonium salt, methylammonium salt, dimethylammonium salt, trimethylammonium salt, etc. Ammonium salts can be formed. If basic groups are present, mineral salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate; acetate, propionate, tartrate, fumarate, maleate Organic acid salts such as malate, citrate, methanesulfonate, p-toluenesulfonate, and the like can be formed. Moreover, the compound of this invention or its salt can also exist as a solvate. Solvates include those formed by absorbing moisture in the air, in addition to solvates to which the solvent used for crystal crystallization is added. Examples of the solvent include lower alcohols such as methanol and ethanol, acetone, acetonitrile, water and the like.

  The compound of the present invention represented by the general formula (1) can be produced according to the following step 1.

(In the formula, M represents a halogen atom; X, Y and A are as defined above.)
The compound represented by the general formula (2) can be usually produced by a conventional synthesis method. For example, it can be synthesized according to the method described in the literature (Strekowski, L., et al Journal of Heterocyclic Chemistry, 1990, 27, 1393.).
The compound represented by the general formula (2) is converted to an amine corresponding to A by a method described in the literature (for example, Mokrosz, MJ, et al Arch. Pharm. 1995, 328, 659.) or a method analogous thereto. By making it react, the compound represented by General formula (3) is obtained.

  The amine may be any divalent diamino group derived from a diamine having a linear, branched or cyclic alkylene chain having 2 to 10 carbon atoms, or a protected form thereof. For example, piperazine, ethylenediamine, N, N-dimethylethylenediamine, 4-amino-1-piperidine-carboxylic acid ethyl ester, 4- (N-Boc amino) piperidine and the like can be mentioned. In the case of reacting the protector with the compound represented by the general formula (2), the protecting group is deprotected by a known method and converted into the compound (3), and then used in the following step 2. it can. The amount of amine to be used is not particularly limited as long as it does not affect the reaction, but it is usually 1 to 100 mol, preferably 1 to 20 mol, per 1 mol of the compound represented by the general formula (2).

  The amine or a protected form thereof can be reacted with a base. Examples of the base include sodium hydride, tert-butoxy potassium, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine and the like. Usually, it is 0.1-100 mol with respect to 1 mol of compounds represented by General formula (2), Preferably it is 1-10 mol.

  The reaction is carried out in a suitable solvent or non-solvent. The solvent is not particularly limited, but pyridine, toluene, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, N, N-dimethylformamide, dimethyl sulfoxide and the like are preferable, and pyridine or tetrahydrofuran is particularly preferable.

  The reaction temperature is −30 to 200 ° C., preferably 50 to 140 ° C., and the reaction time is 0.1 to 100 hours, preferably 1 to 50 hours.

  The compound represented by the general formula (3) can be isolated and purified as necessary, but can also be used in the next step 2 without purification.

(Wherein, X, Y, A, B and C are the same as described above.)
A compound represented by the general formula (1) can be obtained by amidation or sulfonamidation using the compound represented by the general formula (3). The condensation reaction may follow a known method. For example, a carboxylic acid or sulfonic acid corresponding to the BC is used together with a condensing agent, or an acid halide of the carboxylic acid or sulfonic acid is used together with a base.

When a carboxylic acid or sulfonic acid and a condensing agent are used, a condensing aid may be further added. The usage-amount of carboxylic acid or a sulfonic acid is 0.5-10 mol normally with respect to 1 mol with respect to the compound represented by General formula (3).
The condensing agent is not particularly limited. For example, 1,3-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (WSC), carbonyldiimidazole ( CDI), diphenylphosphoryl azide (DPPA) and the like. Condensation aids include 1-hydroxybenzotriazole hydrate (HOBT), N-hydroxysuccinimide (HONSu), N-hydroxy-5-norbornene-2,3-dicarboxylic imide (HONB), 4-dimethylaminopyridine (DMAP).
Usually, the condensing agent is 0.5 to 60 mol and the condensing aid is 0.01 to 10 mol, but preferably 1 to 20 mol of the condensing agent and the condensing aid is 0.1 to 5 with respect to 1 mol of the compound represented by the general formula (3). Is a mole.

  The reaction solvent is not particularly limited as long as it does not affect the reaction. Examples thereof include pyridine, dimethyl sulfoxide, N, N-dimethylformamide, dimethylacetamide, toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, diethyl ether, benzene and the like.

  The reaction temperature is generally −30 to 100 ° C., preferably −20 to 60 ° C., and the reaction time is 0.1 to 100 hours, preferably 1 to 80 hours.

When using the acid halide body and base of the said carboxylic acid or sulfonic acid, the usage-amount of an acid or an acid halide body is 1-10 mol normally with respect to 1 mol of compounds represented by General formula (3).
Examples of the base include sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine and the like. Usually, it is 0.1-100 mol with respect to 1 mol of compounds represented by General formula (2), Preferably it is 1-10 mol.

  The reaction solvent is not particularly limited as long as it does not affect the reaction. Examples thereof include pyridine, dimethyl sulfoxide, N, N-dimethylformamide, dimethylacetamide, toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, diethyl ether, benzene and the like.

  The reaction temperature is generally −30 to 100 ° C., preferably −20 to 60 ° C., and the reaction time is 0.1 to 100 hours, preferably 1 to 80 hours.

  The compound of the present invention or a salt thereof can be isolated and purified by using known separation and purification means such as concentration, solvent extraction, filtration, recrystallization, various chromatographies and the like.

  When the compound of the present invention or a salt thereof is used as a medicine, various administration forms can be adopted depending on the purpose of prevention or treatment. Examples of the form include oral preparations, injection preparations, suppositories, ointments, patches, and the like, and these preparations can be produced by conventional preparation methods known to those skilled in the art.

  When preparing an oral solid preparation, additives such as a binder, a disintegrant, a lubricant, a colorant, a flavoring and flavoring agent were added to the compound of the present invention or a salt thereof as necessary. Thereafter, tablets, coated tablets, granules, powders, capsules and the like can be produced by conventional methods. As such an additive, what is generally used in the said field | area should just be used.

Examples of excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like.
Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone.
Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
Examples of the lubricant include purified talc, stearate, borax, and polyethylene glycol.
Examples of the colorant include titanium oxide and iron oxide, and examples of the flavoring and flavoring agent include sucrose, orange peel, citric acid, and tartaric acid.

  When preparing an oral liquid preparation, a flavoring agent, a buffer, a stabilizer, a flavoring agent, etc. are added to the compound of the present invention or a salt thereof, and an oral solution, syrup, elixir or the like is produced by a conventional method. be able to. As the flavoring / flavoring agent, those listed above can be used. Examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.

  When preparing an injection, a pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. are added to the compound of the present invention or a salt thereof, and subcutaneous, intramuscular or intravenous are added by a conventional method. For injection. Examples of the pH adjuster and buffer in this case include sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.

  When preparing a suppository, a pharmaceutical carrier known to those skilled in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc., if necessary, Tween (registered trademark), etc. After adding the surfactant, etc., it can be produced by a conventional method.

  When preparing an ointment, bases, stabilizers, wetting agents, preservatives and the like that are usually used for the compound of the present invention or a salt thereof can be blended as necessary, and are mixed and formulated by a conventional method. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.

  When preparing a patch, the ointment, cream, gel, paste or the like may be applied to the support by a conventional method. The support is preferably a film or foam sheet of cotton, suf, woven fabric made of chemical fibers, non-woven fabric, soft vinyl chloride, polyethylene, polyurethane, or the like.

  The compound of the present invention or a salt thereof to be formulated in each of the above dosage unit forms is not constant depending on the symptoms of the patient, its dosage form, etc., but generally about 1-1000 mg for an oral dosage form per dosage unit injection It is desirable that the dosage is about 0.1 to 500 mg for suppositories and about 5 to 1000 mg for suppositories. The daily dose of the drug having the above dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., but is usually about 0.1 to 5000 mg, preferably 1-1000 mg per day for an adult. This is preferably administered once a day or divided into about 2 to 4 times a day.

  Examples of the diseases that can be treated by administering a pharmaceutical containing the compound of the present invention or a salt thereof include, for example, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer, Examples include lung cancer, breast cancer, ovarian cancer, bladder cancer, prostate cancer, bone / soft tissue sarcoma, malignant lymphoma, leukemia, multiple myeloma, cervical cancer, skin cancer, brain tumor, and other malignant tumors.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

[Reference Example 1]
4- (2-Furyl) -2-piperazinopyrimidine

  To 2.0 mL of toluene, 2.0 g (11 mmol) of 2-chloro-4- (2-furyl) pyrimidine produced by the method described in the literature (Strekowski, L., et al Journal of Heterocyclic Chemistry, 1990, 27, 1393.) A dissolved solution was obtained. Piperazine 19 g (220 mmol) was added, and the mixture was heated under reflux for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.5 g (yield 100%) of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.71-2.74 (4H, m), 3.67-3.70 (4H, m), 6.67 (1H, dd, J = 3.1, 1.5 Hz), 6.87 (1H , d, J = 5.1 Hz), 7.25 (1H, d, J = 3.1 Hz), 7.88 (1H, d, J = 1.5 Hz), 8.36 (1H, d, J = 5.1 Hz).

[Example 1]
4- (2-Furyl) -2- [1- [4- (2-methoxy-4-methylbenzenesulfonyl) piperazino]] pyrimidine

  To 100 mg (0.43 mmol) of 4- (2-furyl) -2-piperazinopyrimidine obtained in Reference Example 1, 4 mL of pyridine was added and stirred until dissolved. To the obtained solution, 143 mg (0.65 mmol) of 2-methoxy-4-methylbenzenesulfonyl chloride was added. After stirring at room temperature for 3 days, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (mobile bed; ethyl acetate: hexane = 2: 1 (v / v)) to obtain 180 mg (yield 100%) of the title compound as a white powder. It was.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.35 (3H, s), 3.13-3.15 (4H, m), 3.82-3.84 (4H, m), 3.87 (3H, s), 6.67 (1H , dd, J = 3.4, 1.7 Hz), 6.90 (1H, d, J = 8.3 Hz), 6.94 (1H, d, J = 5.0 Hz), 7.05 (1H, s), 7.28 (1H, d, J = 3.4 Hz), 7.61 (1H, d, J = 8.3 Hz), 7.89 (1H, d, J = 1.7 Hz), 8.38 (1H, d, J = 5.0 Hz).
mp: 162-163 ℃

[Example 2]
2- [1- [4- (2,4-Difluorobenzenesulfonyl) piperazino]]-4- (2-furyl) pyrimidine

  4 mL of pyridine was added to 250 mg (1.09 mmol) of 4- (2-furyl) -2-piperazinopyrimidine obtained in Reference Example 1, and stirred until dissolved. To the resulting solution, 0.22 mL (1.64 mmol) of 2,4-difluorobenzenesulfonyl chloride was added. After stirring at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (mobile bed; ethyl acetate: hexane = 2: 1 (v / v)) to obtain 380 mg (yield 86%) of the title compound as a white powder. It was.

¹ H-NMR (CDCl ₃ ) δ (ppm): 3.25-3.27 (4H, m), 3.98-4.01 (4H, m), 6.53 (1H, dd, J = 3.4, 1.7 Hz), 6.88 (1H, d , J = 5.1 Hz), 6.92-7.03 (2H, m), 7.13 (1H, d, J = 3.4 Hz), 7.55 (1H, d, J = 1.7 Hz), 7.85-7.91 (1H, m), 8.31 (1H, d, J = 5.1 Hz).
mp: 167-168 ° C

[Example 3]
4- (2-Furyl) -2- [1- [4- (2-phenylbutyroyl) piperazino]] pyrimidine

  To 250 mg (1.09 mmol) of 4- (2-furyl) -2-piperazinopyrimidine obtained in Reference Example 1, 5 mL of THF was added and stirred until dissolved. Triethylamine 0.16 mL (1.31 mmol) and 2-phenylbutyryl chloride 0.13 mL (1.31 mmol) were added to the resulting solution. After stirring at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (mobile bed; ethyl acetate: hexane = 2: 1 (v / v)) to obtain 290 mg (yield 88%) of the title compound as a white powder. It was.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.90 (3H, t, J = 7.3 Hz), 1.73-1.83 (1H, m), 2.10-2.21 (1H, m), 3.09-3.15 (1H, m ), 3.46-3.65 (5H, m), 3.84-4.03 (3H, m), 6.52 (1H, dd, J = 3.4, 1.7 Hz), 6.85 (1H, d, J = 5.1 Hz), 7.13 (1H, d, J = 3.4 Hz), 7.20-7.33 (5H, m), 7.54 (1H, d, J = 1.7 Hz), 8.30 (1H, d, J = 5.1 Hz).
mp: 116-117 ℃

[Example 4]
4- (2-Furyl) -2- [1- [4- (2,5-difluorobenzoyl) piperazino]] pyrimidine

  According to Example 3, the title was obtained from 150 mg (0.65 mmol) of 4- (2-furyl) -2-piperazinopyrimidine obtained in Reference Example 1 and 0.122 mL (0.98 mmol) of 2,5-difluorobenzoyl chloride. Compound 200 mg (yield 83%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ (ppm): 3.43 (2H, brs), 3.88-3.91 (4H, m), 3.99-4.01 (2H, m), 6.54 (1H, dd, J = 3.4, 1.7 Hz ), 6.92 (1H, d, J = 5.1 Hz), 7.06-7.14 (3H, m), 7.15 (1H, d, J = 3.4 Hz), 7.56 (1H, d, J = 1.7 Hz), 8.35 (1H , d, J = 5.1 Hz).
mp: 140-141 ℃

[Example 5]
4- (2-Furyl) -2- [1- [4- (quinoline-8-sulfonyl) piperazino]] pyrimidine

  The title compound was obtained from 100 mg (0.43 mmol) of 4- (2-furyl) -2-piperazinopyrimidine obtained in Reference Example 1 and 148 mg (0.65 mmol) of quinoline-8-sulfonyl chloride obtained in Reference Example 1 according to Example 1. 138 mg (76% yield) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ (ppm): 3.53-3.55 (4H, m), 3.94-3.96 (4H, m), 6.52 (1H, dd, J = 3.4, 1.7 Hz), 6.83 (1H, d , J = 5.1 Hz), 7.12 (1H, d, J = 3.4 Hz), 7.50 (1H, dd, J = 8.3, 4.3 Hz), 7.53 (1H, dd, J = 1.7, 0.7 Hz), 7.63 (1H , dd, J = 8.0, 7.4 Hz), 8.03 (1H, dd, J = 8.0, 1.5 Hz), 8.22 (1H, dd, J = 8.3, 1.7 Hz), 8.28 (1H, d, J = 5.1 Hz) , 8.52 (1H, dd, J = 7.4, 1.5 Hz), 9.06 (1H, dd, J = 4.3, 1.7 Hz).
mp: 155-156 ° C

[Example 6]
2- [1- [4- (3,4,5-trifluorobenzenesulfonyl) piperazino]]-4- (2-furyl) pyrimidine

  According to Example 1, 280 mg (1.22 mmol) of 4- (2-furyl) -2-piperazinopyrimidine obtained in Reference Example 1 and 0.203 mL (1.46 mL) of 3,4,5-trifluorobenzenesulfonyl chloride were obtained. mmol) gave 270 mg (52% yield) of the title compound as a white powder.

¹ H-NMR (CDCl ₃ ) δ (ppm): 3.11-3.14 (4H, m), 4.01-4.03 (4H, m), 6.53 (1H, dd, J = 3.6, 1.7 Hz), 6.89 (1H, d , J = 5.0 Hz), 7.13 (1H, d, J = 3.6 Hz), 7.42-7.45 (2H, m), 7.55 (1H, d, J = 1.7 Hz), 8.31 (1H, d, J = 5.0 Hz) ).
mp: 178-179 ° C

[Example 7]
4- (2-Furyl) -2- [1- [4- (pyridine-3-sulfonyl) piperazino]] pyrimidine

  According to Example 1, from 4- (2-furyl) -2-piperazinopyrimidine 100 mg (0.43 mmol) and 3-pyridylsulfonyl chloride hydrochloride 353 mg (0.65 mmol) obtained in Reference Example 1 40 mg (yield 25%) of the compound was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ (ppm): 3.13-3.16 (4H, m), 4.0-4.03 (4H, m), 6.53 (1H, dd, J = 3.4, 1.7 Hz), 6.87 (1H, d , J = 5.1 Hz), 7.12 (1H, d, J = 3.4 Hz), 7.48 (1H, dd, J = 7.9, 4.9 Hz), 7.54 (1H, d, J = 1.7 Hz), 8.06 (1H, d , J = 7.9 Hz), 8.30 (1H, d, J = 5.1 Hz), 8.82 (1H, dd, J = 4.9, 1.4 Hz), 9.00 (1H, d, J = 2.2 Hz).
mp: 145-146 ℃

[Example 8]
4- (2-Furyl) -2- [1- [4- (2,4-dimethoxybenzenesulfonyl) piperazino]] pyrimidine

  According to Example 1, from 100 mg (0.43 mmol) of 4- (2-furyl) -2-piperazinopyrimidine obtained in Reference Example 1 and 154 mg (0.65 mmol) of 2,5-dimethoxybenzenesulfonyl chloride. The title compound (180 mg, yield 97%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ (ppm): 3.33-3.35 (4H, m), 3.81 (3H, s), 3.87 (3H, s), 3.97-3.99 (4H, m), 6.55 (1H, dd , J = 3.3, 1.7 Hz), 6.90 (1H, d, J = 5.3 Hz), 6.93 (1H, d, J = 9.0 Hz), 7.05 (1H, dd, J = 9.0, 3.2 Hz), 7.18 (1H , d, J = 3.3 Hz), 7.45 (1H, d, J = 3.2 Hz), 7.58 (1H, brs), 8.35 (1H, d, J = 5.3 Hz).
mp: 133-136 ℃

[Example 9]
2- [1- (4-{[2- (4-Chlorophenyl) -3-methyl] butyroyl} piperazino)]-4- (2-furyl) pyrimidine

  According to Example 1, 150 mg (0.65 mmol) of 4- (2-furyl) -2-piperazinopyrimidine obtained in Reference Example 1 and 2- (4-chlorophenyl) -3-methylbutyroyl chloride 0.15 The title compound (212 mg, yield 77%) was obtained as a pale yellow powder from mL (0.98 mmol).

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.69 (3H, d, J = 6.7 Hz), 1.04 (3H, d, J = 6.4 Hz), 2.42-2.51 (1H, m), 3.35 (1H, d, J = 9.9 Hz), 3.32-3.38 (1H, m), 3.56-3.66 (4H, m), 3.80-3.94 (3H, m), 6.53 (1H, dd, J = 3.5, 1.8 Hz), 6.88 (1H, d, J = 5.0 Hz), 7.14 (1H, dd, J = 3.5, 0.8 Hz), 7.28 (4H, brs), 7.55 (1H, dd, J = 1.8, 0.8 Hz), 8.32 (1H, d, J = 5.0 Hz).
mp: 114-115 ℃

[Example 10]
2- (N-{[N- (2,4-Difluorobenzenesulfonyl) -N-methyl] amino} ethyl-N-methyl) amino-4- (2-furyl) pyrimidine

  According to Reference Example 1 and Example 1, 2-chloro-4- (2-furyl) pyrimidine was reacted with N, N-dimethylethylenediamine and 2,4-difluorobenzenesulfonyl chloride to obtain the title compound as an oily substance. It was.

¹ H-NMR (CDCl ₃ ) δ (ppm): 3.0 (3H, d, J = 1.7 Hz), 3.19 (3H, s), 3.45 (2H, t, J = 6.6 Hz), 3.87 (2H, t, J = 6.6 Hz), 6.53 (1H, dd, J = 3.4, 1.7 Hz), 6.83-6.95 (2H, m), 6.85 (1H, d, J = 5.0 Hz), 7.13 (1H, dd, J = 3.4 , 0.9 Hz), 7.54 (1H, dd, J = 1.7, 0.9 Hz), 7.83-7.89 (1H, m), 8.30 (1H, d, J = 5.0 Hz).

[Example 11]
2- (4- {1-[(2,4-difluorobenzene) sulfonyl]} piperidine) amino-4- (2-furyl) pyrimidine

  According to Reference Example 1 and Example 1, 2-chloro-4- (2-furyl) pyrimidine was reacted with 4-amino-1-piperidine-carboxylic acid ethyl ester, 2,4-difluorobenzenesulfonyl chloride, and the title The compound was obtained as an oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.59-1.68 (2H, m), 2.13-2.18 (2H, m), 2.85-2.91 (2H, m), 3.74-3.78 (2H, m), 3.91 -4.00 (1H, m), 5.03 (1H, d, J = 7.6 Hz), 6.53 (1H, dd, J = 3.4, 1.7 Hz), 6.89 (1H, d, J = 5.1 Hz), 6.96-7.04 ( 2H, m), 7.09 (1H, d, J = 3.4 Hz), 7.55 (1H, d, J = 1.7 Hz), 7.86-7.91 (1H, m), 8.27 (1H, d, J = 5.1 Hz).
mp: 176.5-177 ° C

[Example 12]
2- [1- [4- (2-Phenylbutyroyl) amino] piperidino] -4- (2-furyl) pyrimidine

  According to Reference Example 1 and Example 1, 2-chloro-4- (2-furyl) pyrimidine was reacted with 4- (N-Boc amino) piperidine and 2-phenylbutyryl chloride to give the title compound as an oily substance. Obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (3H, t, J = 7.3 Hz), 1.19-1.35 (2H, m), 1.73-1.82 (1H, m), 1.88-1.91 (1H, m ), 1.97-2.00 (1H, m), 2.14-2.25 (1H, m), 3.01-3.11 (2H, m), 3.19 (1H, brt, J = 7.5 Hz), 4.00-4.08 (1H, m), 4.61-4.68 (2H, m), 5.25 (1H, brd, J = 7.8 Hz), 6.52 (1H, dd, J = 3.4, 1.9 Hz), 6.82 (1H, d, J = 5.0 Hz), 7.13 (1H , dd, J = 3.4, 0.7 Hz), 7.23-7.34 (5H, m), 7.53 (1H, dd, J = 1.9, 0.7 Hz), 8.30 (1H, d, J = 5.0 Hz).
mp: 153-154 ℃

[Example 13]
2- {N- [N- (2,4-Difluorobenzenesulfonyl) amino] ethyl} amino-4- (2-furyl) pyrimidine

  According to Reference Example 1 and Example 1, 2-chloro-4- (2-furyl) pyrimidine was reacted with ethylenediamine and 2,4-difluorobenzenesulfonyl chloride to obtain the title compound as an oily substance.

¹ H-NMR (CDCl ₃ ) δ (ppm): 3.28-3.32 (2H, m), 3.57-3.61 (2H, m), 5.39 (1H, brs), 6.56 (1H, dd, J = 3.6, 1.7 Hz ), 6.70-6.86 (1H, brs), 6.80-6.86 (1H, m), 6.90-6.93 (1H, m), 6.94 (1H, d, J = 5.1 Hz), 7.17 (1H, d, J = 3.6 Hz), 7.59 (1H, d, J = 1.7 Hz), 7.84-7.90 (1H, m), 8.28 (1H, d, J = 5.1 Hz).
mp: 143.5-144 ℃

[Test Example 1]
In vitro cell killing test against JHH-7 cells (human hepatocellular carcinoma)
JHH-7 cell suspension suspended in ASF104 medium (Ajinomoto Co., Inc.) was seeded in 4 × 103 cells (0.1 mL) in each well of a 96-well flat-bottomed microplate, and 37% in an incubator containing 5% carbon dioxide gas. Culturing was performed for 1 day at 0 ° C. The compound of the present invention is dissolved in dimethyl sulfoxide to a concentration of 10 mM, and further diluted with ASF104 medium so that the final concentration of the compound of the present invention is 30, 10, 3, 0.3, and 0.1 μM, respectively. went. 0.1 mL of this was added to each well of the culture plate for JHH-7 cells described above, and cultured at 37 ° C. for 3 days in an incubator containing 5% carbon dioxide gas. After culturing, 20 μL of 25% glutaraldehyde aqueous solution (manufactured by Nacalai Tesque) was added to each well and allowed to stand at room temperature for 20 minutes to fix the cells. Thereafter, the plate was washed with water and dried. A 0.05% crystal violet / 20% aqueous methanol solution (manufactured by Wako Pure Chemical Industries, Ltd.) was added to each well in an amount of 100 μL and left at room temperature for 20 minutes to stain the cells. Thereafter, the plate was washed with tap water and dried. Crystal violet was extracted by adding 100 μL of 0.05 M NaH ₂ PO ₄ / ethanol (1/1 = v / v) to each well. The absorbance of the extracted crystal violet at 540 nm was measured with a microplate reader and used as an index of the number of living cells. The inhibition rate was calculated from the following formula, and the concentration (IC ₅₀ (μM)) of the test compound that was inhibited by 50% was determined.
An in vitro cell killing test was also conducted on the compound BAY 43-9006 (Curr. Pharm. Des. 2002, 8, 2255) which is useful as an antitumor agent.

Inhibition rate (%) = (C−T) / C × 100
T: Absorbance of well added with test compound
C: Absorbance of wells to which no test compound was added

  As is clear from Table 1, the compound of the present invention or a salt thereof exhibited a cell killing activity equivalent to or better than BAY 43-9006, and thus was confirmed to have excellent antitumor activity.

An in vitro cell killing test was performed on normal hepatocytes using the same method as in Test Example 1. The IC ₅₀ for normal hepatocytes was 3.46 μM for BAY 43-9006, whereas the compounds of the present invention (compounds of Examples 2 and 11) were 30 μM or more, which was excellent for cancer cells. It was confirmed to show selectivity.

Claims (11)

General formula (1)

[Wherein, X and Y are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an aryl or heteroaryl group which may have a substituent, a nitro group, a cyano group, -CZ ₃ , -NR ¹ R ² , -CO ₂ R ³ , -S (O) nR ⁴ , -NHC (O) R ⁵ , -C (O) NR ⁶ R ⁷ , -COR ⁸ , -CH _2- OR ⁹ , -CH = CH-R ¹⁰ , -CH = CH-COOR ¹¹ , and -CH = CH-CONHR ¹²
(Z represents a halogen atom; R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁹ are each independently a hydrogen atom, a lower alkyl group, an aryl group or heteroaryl group optionally having substituent (s) and an aralkyl optionally having substituent (s) An atom or a substituent selected from a group or a heteroarylalkyl group, R ⁶ and R ⁷ together form a 4- to 7-membered alicyclic heterocyclic group which may have a substituent; R ⁵ represents a lower alkyl group or an aryl group which may have a substituent; R ⁸ represents a hydrogen atom or a lower alkyl group; R ¹⁰ and R ¹² each independently have a substituent. An optionally substituted aryl group or heteroaryl group; R ¹¹ represents a hydrogen atom or a lower alkyl group; n represents an integer of 0 to 2)
A represents one or more atoms or substituents selected from: A represents a diamino group having a linear, branched or cyclic alkylene chain having 2 to 10 carbon atoms between two nitrogen atoms; Or two nitrogen atoms together with the alkylene chain may form a 4- to 7-membered alicyclic heterocyclic group; B represents a carbonyl group or a sulfonyl group; C represents a substituent. An aryl group or a heteroaryl group which may be substituted, or a benzyl group which may be substituted at the α-position with a lower alkyl group. The bonding position of the furyl group to the pyrimidine ring is the 2nd or 3rd position. ]
The furyl pyrimidine derivative represented by these, or its salt.   The furyl pyrimidine derivative or a salt thereof according to claim 1, wherein X and Y each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a nitro group or a cyano group. A is the general formula (2)

[Wherein, R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ each independently represents a hydrogen atom, a methyl group or an ethyl group. ]
The furyl pyrimidine derivative or a salt thereof according to claim 1 or 2, which represents a group represented by the formula:   C 1 represents a phenyl group, a pyridyl group or a quinolyl group which may have a substituent, or a benzyl group which may be substituted with a lower alkyl group at the α-position. Or a salt thereof.   C is a phenyl group, pyridyl group or quinolyl group which may have a substituent selected from a halogen atom, a lower alkyl group and a lower alkoxy group, or the α-position is selected from a halogen atom, a lower alkyl group and a lower alkoxy group The furyl pyrimidine derivative or a salt thereof according to any one of claims 1 to 4, which represents a benzyl group substituted with a lower alkyl group which may have a substituent. X is a hydrogen atom, a halogen atom, a lower alkyl group, a nitro group, a cyano group, -NR ¹ R ² , -COR ⁸ , -CH ₂ -OR ⁹ , -CH = CH-R ¹⁰ , -CH = CH-COOR ¹¹ and -CH = CH-CONHR ¹² ; Y is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an aryl or heteroaryl group which may have a substituent, a nitro group, a cyano group , -CZ ₃ , -NR ¹ R ² , -CO ₂ R ⁸ , -S (O) nR ⁴ , -NHCOR ⁵ , -CONR ⁶ R ⁷ , -COR ⁸ , -CH ₂ -OR ⁹ , -CH = CH -R ¹⁰ , -CH = CH-COOR ¹¹ and -CH = CH-CONHR ¹² ; A represents the general formula (2) [wherein R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are as defined above; It is as follows. B represents a carbonyl group or a sulfonyl group; C represents an aryl or heteroaryl group which may have a substituent, or the α-position may be substituted with a lower alkyl group. The furyl pyrimidine derivative or a salt thereof according to any one of claims 1 to 5, wherein the furyl pyrimidine derivative or a salt thereof is a good benzyl group; X and Y each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a nitro group or a cyano group; A represents the general formula (2) [wherein R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ is as defined above. B represents a carbonyl group or a sulfonyl group; C represents a phenyl group, a pyridyl group or a group optionally having a substituent selected from a halogen atom, a lower alkyl group and a lower alkoxy group A quinolyl group or a benzyl group substituted with a lower alkyl group which may have a substituent selected from a halogen atom, a lower alkyl group and a lower alkoxy group at the α-position; the bonding position of the furyl group to the pyrimidine ring is The furyl pyrimidine derivative or a salt thereof according to any one of claims 1 to 5, which is in the 2-position. X and Y both represent a hydrogen atom; A represents the general formula (2) [wherein R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are as defined above. Wherein B represents a carbonyl group or a sulfonyl group; C represents a phenyl group, a pyridyl group or a quinolyl group; and the bonding position of the furyl group to the pyrimidine ring is the 2-position. The furyl pyrimidine derivative of any one of -5, or its salt. A compound selected from the following furyl pyrimidine derivatives:
4- (2-Furyl) -2- [1- [4- (2-methoxy-4-methylbenzenesulfonyl) piperazino]] pyrimidine
2- [1- [4- (2,4-Difluorobenzenesulfonyl) piperazino]]-4- (2-furyl) pyrimidine
4- (2-Furyl) -2- [1- [4- (2-phenylbutyroyl) piperazino]] pyrimidine
4- (2-Furyl) -2- [1- [4- (2,5-difluorobenzoyl) piperazino]] pyrimidine
4- (2-Furyl) -2- [1- [4- (quinoline-8-sulfonyl) piperazino]] pyrimidine
2- [1- [4- (3,4,5-trifluorobenzenesulfonyl) piperazino]]-4- (2-furyl) pyrimidine
4- (2-Furyl) -2- [1- [4- (pyridine-3-sulfonyl) piperazino]] pyrimidine
4- (2-Furyl) -2- [1- [4- (2,4-dimethoxybenzenesulfonyl) piperazino]] pyrimidine
2- [1- (4-{[2- (4-Chlorophenyl) -3-methyl] butyroyl} piperazino)]-4- (2-furyl) pyrimidine
2- (N-{[N- (2,4-Difluorobenzenesulfonyl) -N-methyl] amino} ethyl-N-methyl) amino-4- (2-furyl) pyrimidine
2- (4- {1-[(2,4-difluorobenzene) sulfonyl]} piperidine) amino-4- (2-furyl) pyrimidine
2- [1- [4- (2-Phenylbutyroyl) amino] piperidino] -4- (2-furyl) pyrimidine
2- {N- [N- (2,4-difluorobenzenesulfonyl) amino] ethyl} amino-4- (2-furyl) pyrimidine or a salt thereof.   The pharmaceutical composition which uses the furyl pyrimidine derivative or its salt of any one of Claims 1-9 as an active ingredient. The antitumor agent which uses the furyl pyrimidine derivative or its salt of any one of Claims 1-9 as an active ingredient.