JPH08310952A - Medicine composition - Google Patents

Abstract

PURPOSE: To obtain a medicine preparation containing a heterocyclic group compound, showing excellent antitumor activity, effective for treating intractable tumor and for preventing distant metastasis to another organ, etc. CONSTITUTION: This medicine composition comprises a compound of the formula (R<1> and R<3> are each a halogen, H bondable through a hetero atom or a hydrocarbon residue; R<2> is a hydrocarbon residue; X is O or S; Z is a bifunctional group; Ar is an aromatic group) or its salt as an active ingredient. The compound of the formula has antitumor action on primal cancers of solid cancers such as prostatic cancer, pancreatic cancer, lung cancer, etc., controlling action on metastasis, preventing effect on relapse after surgical operation and improving action on symptoms such as pains followed by cancers, cachexia, etc. The compound of the formula has bacteria eliminating effect on Helicobacter pylori and is useful for preventing and treating diseases caused by the bacterium. The compound is pharmaceutically manufactured into an oral administration agent, solution, drop, injection, agent for external use (e.g. nasal medicine and percutaneous medicine), suppository, etc. A dose, for example, is 0.1-20mg/kg calculated as the compound of the formula in one administration and daily administered once to several times dividedly in the case of oral administration to a patient of prostatic cancer.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an antitumor agent containing a pyrimidine derivative.

[0002]

BACKGROUND OF THE INVENTION Pancreatic cancer, which is conventionally known as refractory solid cancer, is often inoperable because it may have metastasized or cancerous peritonitis at the time of discovery. Prognosis is not good even if surgery is possible. For such advanced cancer patients and post-operative patients, single-dose administration of 5-fluorouracil (5-FU) or multidrug combination therapy using chemotherapeutic agents such as 5-FU and mitomycin is performed. In addition, for hormone-independent cancers (especially prostate cancer, breast cancer, etc.) known as refractory solid tumors, and their recurrent or metastatic cancers, chemotherapeutic agents such as adriamycin, cisplatin, mitomycin, 5-FU, etc. Is being used alone or in combination with these drugs. In addition, the treatment of lung cancer is often given by combination therapy with cisplatin, carboplatin, etoposide, mitomycin and cyclophosphamide. However, at present, it cannot be said that the therapeutic methods using these anticancer agents are sufficiently satisfactory. On the other hand, JP-A-63-112566 and JP-A-1-19
0670, JP-A-1-261371 and JP-A-6-7
3022 describes that a compound having a pyridimidine skeleton can be used as an insecticide, acaricide, fungicide, or herbicide.

[0003]

The conventional antitumor agents include the following:
There is nothing that can be said to have a sufficient therapeutic effect.
It is desired to develop a drug having an excellent effect on the treatment of refractory solid tumors such as prostate cancer, breast cancer and lung cancer and the prevention of distant metastasis of these cancers to other organs.

[0004]

The present inventors have made various studies in view of the present situation, and as a result,

Embedded image [Wherein, R ¹ and R ³ are each (i) a halogen atom or (ii) a hydrogen atom which may be bonded via a hetero atom, or a hydrocarbon residue which may have a substituent; R ² is a hydrocarbon residue which may have a substituent;
X is an oxygen atom or a sulfur atom; Z is a divalent group; and A
r represents an aromatic group which may have a substituent. ] The compound represented by or a salt thereof shows an excellent growth inhibitory action on solid tumor cells such as pancreatic cancer cells, prostate cancer cells, breast cancer cells, and lung cancer cells, and has properties as a drug such as safety. Since it is excellent, it is useful for the prevention and treatment of refractory solid tumors and the remote transfer of these cancers to other organs, and has the eradication effect of Helicobacter pylori, and the prevention of diseases based on this. , It was found to be useful for treatment, and the present invention was completed based on these findings. That is, the present invention relates to (1) a pharmaceutical composition comprising compound [I] or a salt thereof, (2) R ¹ and R ³ are —O— or —S.
The composition according to (1) above, which is a C _1-6 alkyl group which may be bonded _via- , (3) the composition according to (1) above, wherein R ¹ is a C _1-6 alkylthio group, (4) The composition according to (1) above, wherein R ² is a C _1-6 alkyl group, (5) R ³ is C _1-6
The composition according to (1) above, which is an alkyl group, (6) the composition according to (1) above, wherein Z is a divalent aliphatic hydrocarbon residue having 1 to 10 carbon atoms, (7) Ar is substituted The composition according to (1) above, which is a phenyl group which may have a group, (8)
The substituent which the phenyl group may have is a C _6-14 aryloxy group, a C _7-16 aralkyloxy group, a C _6-14 arylthio group, a C _7-16 aralkylthio group, a C _6-14 arylsulfinyl group. , C _6-14 arylsulfonyl group, mono- or di-C _7-16 aralkylamino group, cyclic amino group, mono- or di-C _6-14 arylcarbamoyl group, C _7-16 aralkyl group, C _6-14 Aryl group, C _6-14 arylimino group, aromatic heterocyclic group, C _6-14 arylcarbonyl group (these substituents are 1 to 3 halogen atoms, C _1-6
Alkyl group, halo-C _1-6 alkyl group, carboxyl group, hydroxyl group, cyano group, nitro group, C _1-6 alkoxy group, halo-C _1-6 alkoxy group, amino group, mono- or di-C _{1 -6} alkylamino group, may have a cyclic amino group or a C _1-6 alkoxy-carbonyl group),

[Chemical 4] [In the formula, W ^a is a halogen atom, a C _1-6 alkyl group, a halo-
C _1-6 alkyl group, carboxyl group, hydroxyl group,
Cyano group, nitro group, C _1-6 alkoxy group, halo-C _1-6
Alkoxy group, amino group, mono- or di-C _1-6 alkylamino group, cyclic amino group or C _1-6 alkoxy-
Carbonyl group, m represents 0 to 5. ] The above is
(7) The composition as described above, (9) R ¹ is a C _1-6 alkyl group optionally bonded via —O— or —S—, and R ² is C _1-6.
Alkyl group; R ³ is C _1-6 alkyl group; X is oxygen atom or sulfur atom; Z is C _1-6 alkylene group; Ar is halogen, C _1-6 alkyl, halo-C _1-6 alkyl, C _{1 -6} alkoxy and halo-C _1-6 alkoxy, which is a phenyl group substituted with a C _6-14 arylcarbonyl group which may have 1 to 3 substituents. The present invention relates to a composition, (10) a composition according to (1) above for treating cancer, (11) a composition according to (1) above for eradicating Helicobacter pylori, and the like. In the compound [I], R ¹ and R ³ are each (i) a halogen atom,
(Ii) represents a hydrogen atom which may be bonded via a hetero atom or (iii) a hydrocarbon residue which may have a substituent which may be bonded via a hetero atom. The "hydrogen atom which may be bonded via a hetero atom" is
For example, it represents a hydrogen atom optionally through a hetero atom selected from nitrogen, oxygen, sulfur and the like, and specific examples thereof include a hydrogen atom, a hydroxyl group, an amino group and a mercapto group.

The "hydrocarbon residue which may have a substituent which may be bonded via a hetero atom" is, for example, -NR- [R is a hydrogen atom, a C _1-6 alkyl group ( For example, methyl, ethyl, propyl, isopropyl, etc.) or C _2-6 alkenyl group (eg, vinyl, allyl, etc.) is shown. R is preferably a hydrogen atom or a C _1-6 alkyl group. ], -O-, -S- and the like, which may be bonded via a hydrocarbon residue. It is preferably a hydrocarbon residue which may have a substituent which may be bonded via -O- or -S-. More preferably, it is a hydrocarbon residue which may have a substituent which may be bonded via -S-. In the compound [I], R ² represents a hydrocarbon residue which may have a substituent, for example, C _1-6
An alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.) and the like are preferable. In the compound [I], X represents an oxygen atom or a sulfur atom. Preferably,
It is an oxygen atom. In the compound [I], Z represents a divalent group. The “divalent group” is, for example, one having 1 to 1 carbon atoms.
A divalent aliphatic hydrocarbon residue of 0 (which may be linear or branched), etc., and specifically -CH ₂ -,-
C _1-6 alkylene such as CH ₂ CH ₂ — and —CH═CH— or C _2-6 alkenylene is shown. Preferably, it is a C _1-6 alkylene group (eg, —CH ₂ —) and the like. The “divalent group” is, for example, a C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), a C _1-6 alkylthio group (eg, methylthio, ethylthio, etc.), C _1-6 acyl. Having 1 to 3 substituents selected from groups (eg, formyl, acetyl, etc.), amino groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), hydroxyl groups, mercapto groups, oxo groups, etc. May be.

In the compound [I], Ar represents an aromatic group which may have a substituent. Preferable is a phenyl group which may have a substituent. The term "halogen atom" refers to, for example, fluorine, chlorine, bromine, iodine and the like. The term “hydrocarbon residue” in the term “hydrocarbon residue optionally having substituent (s)” means, for example, (1) a chain hydrocarbon group: a) a C _1-10 alkyl group (eg, methyl, Ethyl, propyl, isopropyl, 1-ethylpropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl Etc.), b) C _2-10 alkenyl groups (eg vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 5 - hexenyl, etc.), c) C _2-10 alkynyl groups (e.g., propargyl, ethynyl, butynyl, 1-hexynyl, 2-f Shin Il, 3
-Hexynyl, 4-hexynyl, etc.), (2) cyclic hydrocarbon: a) _C3-10 cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, 2-cyclopenten-1-yl, cyclohexyl, 2-cyclohexene-).
1-yl, cycloheptyl, adamantyl, etc.), b) C _6-14 aryl group (eg, phenyl, tolyl, xylyl, 1-naphthyl, 2-naphthyl, etc.) and the like are used. Preferred is (1) -a), and particularly C
_1-6 alkyl groups (eg, methyl, ethyl, propyl,
(Eg isopropyl) is commonly used.

The substituent which the "hydrocarbon residue" may have is, for example, a halogen atom (eg, fluorine,
Chlorine, bromine, iodine, etc.); alkyl group; halo-alkyl group; amino-alkyl group; mono- or di-alkylamino-alkyl group; cyclic amino-alkyl group; alkoxy group; halo-alkoxy group; amino-alkoxy group ;
Mono- or di-alkylamino-alkoxy group; cyclic amino-alkoxy group; alkylthio group; halo-alkylthio group; amino-alkylthio group; mono- or di-
Alkylamino-alkylthio group; cyclic amino-alkylthio group; oxo group; nitro group; cyano group; sulfo group;
Hydroxyl group; amino group; mono- or di-C _1-6 alkylamino (eg, methylamino, ethylamino,
Propylamino, dimethylamino, diethylamino, etc .; Cyclic amino groups optionally having C _1-6 alkyl groups (eg, pyrrolidino, piperidino, morpholino, N
-Methylpiperazino, N-phenylpiperazino, etc.);
Mercapto group; carbamoyl group; mono- or di-C
_1-6 alkyl-carbamoyl group (for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,
Diethylcarbamoyl etc.); C _1-6 alkoxy-carbonyl group (eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl etc.); C _1-6 alkylsulfonylamino group (eg methylsulfonylamino, ethyl Sulfonylamino, propylsulfonylamino, butylsulfonylamino, etc.); C _6-14 aryl group (eg, phenyl, tolyl, xylyl, 1-naphthyl, 2-
Naphthyl, biphenyl, 2-indenyl, 2-anthryl and the like); formyl group; carboxyl group; C _1-6 alkyl-carbonyl group (eg acetyl, propionyl,
Butyryl, valeryl, etc.); C _2-6 alkenyl-carbonyl group (eg, acryloyl etc.); C _2-6 alkynyl-carbonyl group (eg, propioloyl etc.); C
_6-14 aryl-carbonyl group (eg benzoyl etc.); C _1-6 alkylsulfonyl group (eg methylsulfonyl, ethylsulfonyl, propylsulfonyl etc.); C _6-14 arylsulfonyl group (eg benzenesulfonyl etc.); A C _1-7 acylamino group (eg formylamino, acetylamino, propionylamino,
Butyrylamino, benzoylamino etc.); C _1-3 acyloxy group (eg formyloxy, acetoxy, propionyloxy etc.); C _6-14 aryloxy group (eg phenoxy etc.) and the like are used.

These substituents are the above-mentioned "hydrocarbon residue".
Substituted at the substitutable position above, the number of substituents is 1
The number is 5 to 5, preferably 1 to 3. However,
When the number of the substituents is 2 or more, they may be the same or different. Specific examples of the substituents on these "hydrocarbon residues" are described below. The "alkyl group" is, for example, C ₁ such as methyl, ethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl. _{-6 represents} an alkyl group. The “halo-alkyl group” is, for example, a C _1-6 alkyl group having 1 to 5 halogen atoms (eg, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl, 2,2 , 2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl,
5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, etc.) and the like. The “amino-alkyl group” refers to an amino-C _1-6 alkyl group such as aminomethyl and aminoethyl. The "mono- or di-alkylamino-alkyl group" means, for example, mono- or di-C _1-6 alkylamino-C ₁ such as methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl and the like. _{-6 represents} an alkyl group.

The "cyclic amino-alkyl group" means a cyclic amino-C _1-6 alkyl group such as pyrrolidinomethyl, piperidinomethyl, morpholinomethyl and the like. The "alkoxy group" is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
C _1-6 alkoxy groups such as sec-butoxy, pentyloxy and hexyloxy are shown. The “halo-alkoxy group” is, for example, a C _1-6 alkoxy group having 1 to 5 halogen atoms (eg, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 4,4,4,4). 4-trifluorobutoxy) and the like. The “amino-alkoxy group” refers to an amino-C _1-6 alkoxy group such as aminoethoxy and aminopropoxy. The "mono- or di-alkylamino-
The “alkoxy group” refers to a mono- or di-C _1-6 alkylamino-C _1-6 alkoxy group such as methylaminoethoxy, dimethylaminoethoxy, dimethylaminopropoxy, diethylaminoethoxy, diethylaminopropoxy. The "cyclic amino-alkoxy group" is
Examples thereof include cyclic amino-C _1-6 alkoxy groups such as pyrrolidinoethoxy, piperidinoethoxy and morpholinoethoxy. The "alkylthio group" is, for example, a C _1-6 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio and the like.

The "halo-alkylthio group" is, for example, a C _1-6 alkylthio group having 1 to 5 halogen atoms (eg difluoromethylthio, trifluoromethylthio, 4,4,4-trifluorobutylthio etc.). Etc. The term "aromatic group optionally having substituent (s)"
“Aromatic group” refers to, for example, an aromatic hydrocarbon residue or an aromatic heterocyclic group. The "aromatic hydrocarbon group" represents, for example, a monocyclic or condensed polycyclic aromatic hydrocarbon, specifically, C _6-14 such as phenyl, 1-naphthyl, 2-naphthyl, indenyl or anthryl. An aryl group or the like is used, and a phenyl group is particularly preferable. Examples of the "aromatic heterocyclic group" include nitrogen atoms in addition to carbon atoms,
5 or 6 containing one or two, preferably 1 to 4 heteroatoms selected from oxygen atom and sulfur atom
A membered monocyclic heterocyclic group, which is condensed with another aromatic ring (for example, benzene etc.) to form a 2- or 3-cyclic condensed ring group is also used. Specifically 2
-Or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 4- or 5-pyrazolyl, 2-, 4- or 5-
Thiazolyl, 3-, 4- or 5-isothiazolyl, 2
-, 4- or 5-oxazolyl, 3-, 4- or 5
-Isoxazolyl, 2-, 3- or 4-pyridyl,
2-, 4- or 5-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, 1,2,3- or 1,2,
4-triazolyl, 5- or 6-membered monocyclic aromatic heterocyclic group such as 1H or 2H-tetrazolyl, benzofuryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, 1-indolyl, 2- or 3-quinolyl, 1-or Examples thereof include 2- or 3-cyclic condensed ring groups such as 3-isoquinolyl, imidazopyridinyl and thiazolopyridinyl.

The "aromatic group which may have a substituent (s)"
As the substituent which may have, for example, (1) halogen atom, (2) alkyl group, (3) alkenyl group, (4) alkynyl group, (5) cycloalkyl-alkyl group, (6) cyclo Alkyl-alkyl group, (7) alkoxy group, (8) alkenyloxy group, (9) alkynyloxy group, (10) aryloxy group, (11) aralkyloxy group, (12) alkylthio group,
(13) alkenylthio group, (14) alkynylthio group, (15) arylthio group, (16) aralkylthio group, (17) alkylsulfinyl group, (18) alkenylsulfinyl group, (19) alkynylsulfinyl group, (20 ) Arylsulfinyl group, (21) alkylsulfonyl group, (22) alkenylsulfonyl group, (23) arylsulfonyl group, (24) nitro group, (2
5) cyano group, (26) sulfo group, (27) hydroxyl group, (28)
Amino group, (29) mono- or di-alkylamino group, (3
(0) mono- or di-aralkylamino group, (31) cyclic amino group, (32) carboxyl group, (33) mercapto group, (34) carbamoyl group, (35) mono- or di-alkyl-carbamoyl group, ( 36) mono- or di-arylcarbamoyl group, (37) alkoxy-carbamoyl group, (38) alkoxy-carbonyl group, (39) alkylsulfonylamino group, (4
0) aralkyl group, (41) aryl group, (42) styryl group, (4
3) arylimino group, (44) aromatic heterocyclic group, (45) formyl group, (46) alkyl-carbonyl group, (47) alkenyl-
Carbonyl group, (48) alkynyl-carbonyl group, (49) arylcarbonyl group, (50) acylamino group, (51) acyloxy group,

Embedded image [W is a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.), C _1-6 alkoxy group (eg, methoxy, ethoxy, Propoxy, isopropoxy etc.), C _1-6 alkylthio group (eg methylthio, ethylthio, propylthio, isopropylthio etc.), C _3-6 cycloalkyl group (eg cyclopropyl, cyclobutyl etc.), halo-C _1-6 Alkyl group (eg, trifluoromethyl), halo-C _1-6 alkoxy group (eg, trifluoromethoxy), halo-C _1-6 alkylthio group (eg, trifluoromethylthio), C _1-6 alkoxy -Carbonyl group (eg, acetyl), nitro group, cyano group, hydroxyl group, carboxyl group, amino , Mono - or di -C
_1-6 alkylamino groups (eg, methylamino, dimethylamino, etc.), cyclic amino groups (eg, piperidino,
Piperazino, morpholino, etc.); m represents an integer of 0 to 5. When m is 2 to 5, they may be the same or different. W is a halogen atom, C _1-6 alkyl group, halo-C _1-6 alkyl group, carboxyl group, hydroxyl group, cyano group, nitro group, C _1-6 alkoxy group, halo-
C _1-6 alkoxy group, amino group, mono- or di-C _1-6
Alkylamino group, cyclic amino group, C _1-6 alkoxy-
A carbonyl group (these are represented by W ^a ) and the like are preferable. m is preferably 1 to 3. ] Etc. are mentioned. Preferable examples of these substituents include, for example,
(10), (11), (15), (16), (20), (23), (30), (31), (3
6), (40), (41), (43), (44), (49), (52), (53) and the like. Particularly preferred are (11) and (49). These substituents are substituted at substitutable positions on the aromatic ring, and the number of the substituents is 1 to 5, preferably 1 to 3. However, when the number of the substituents is 2 or more, they may be the same or different. Specific examples of the substituents on these "aromatic rings" are described below.

The "halogen atom" is, for example, fluorine,
Indicates chlorine, bromine, iodine, etc. The "alkyl group" is, for example, methyl, ethyl, propyl, isopropyl,
C _1-10 alkyl groups such as butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 1,1, -dimethylbutyl, 2,2-dimethylbutyl and the like are shown. The "alkenyl group" is, for example, C such as vinyl, allyl, 2-butenyl, isopropenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl. _{2-10 represents an} alkenyl group or the like. The "alkynyl group" is, for example, a C _2-10 alkynyl group such as ethynyl, 1-propynyl, probargyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and the like. The “cycloalkyl group” is, for example, a C _3-10 alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The "cycloalkyl-alkyl group"
Is, for example, a C _3-6 cycloalkyl-C _1-6 alkyl group such as cyclopropylmethyl. The "alkoxy group" is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-
C such as butoxy, pentyloxy, hexyloxy
_{1-10 represents an} alkoxy group or the like.

The "alkenyloxy group" is, for example, a C _2-10 alkenyloxy group such as allyloxy and isopropenyloxy. The "alkynyloxy group" is, for example, a C _2-10 alkynyloxy group such as propargyloxy. The "aryloxy group" is, for example, a C _6-14 aryloxy group such as phenoxy. The "aralkyloxy group" refers to, for example, a C _7-16 aralkyloxy group such as benzyloxy. The "alkylthio group" is, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio,
C _1-10 alkylthio groups such as pentylthio and hexylthio are shown. The "alkenylthio group" refers to, for example, a C _2-10 alkenylthio group such as allylthio and isopropenylthio. The “alkynylthio group” refers to a C _2-10 alkynylthio group such as propargylthio and the like. The "arylthio group" is, for example, a C _6-14 arylthio group such as phenylthio. The "aralkylthio group" is, for example, a C _7-16 aralkylthio group such as benzylthio.

The "alkylsulfinyl group" is, for example, C such as methylsulfinyl or ethylsulfinyl.
_{1-10 represents} an alkylsulfinyl group and the like. The "alkenylsulfinyl group" is, for example, allylsulfinyl,
A C _2-10 alkenylsulfinyl group such as isopropenylsulfinyl is shown. The “alkynylsulfinyl group” is, for example, C such as propargylsulfinyl.
_2-10 represents an alkynylsulfinyl group or the like. The “arylsulfinyl group” refers to, for example, a C _6-14 arylsulfonyl group such as benzenesulfinyl. The "alkylsulfonyl group" is, for example, C such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like.
_{1-10 represents} an alkylsulfonyl group or the like. The "alkenylsulfonyl group" is, for example, a C _2-10 alkenylsulfonyl group such as allylsulfonyl and isopropenylsulfonyl. The “alkynylsulfonyl group” refers to a C _2-10 alkynylsulfonyl group such as propargylsulfonyl and the like. The “arylsulfonyl group” refers to, for example, a C _6-14 arylsulfonyl group such as benzenesulfonyl. The “mono- or di-alkylamino group” is, for example, a C _1-10 alkylamino group such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like.

The "mono- or di-aralkylamino group" is, for example, a mono- or di-C _7-16 aralkylamino group such as benzylamino. The "cyclic amino group" refers to, for example, a 6-membered cyclic amino group such as pyrrolidino, piperidino, morpholino and the like. The "mono- or di-alkyl-carbamoyl group" means, for example, mono- or di-C such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and the like.
_1-10 alkyl-carbamoyl group etc. are shown. The "mono-
Alternatively, the “di-aryl-carbamoyl group” refers to a mono- or di-C _6-14 aryl-carbamoyl group such as phenylcarbamoyl. The "alkoxy-carbonyl group" is, for example, a C _1-10 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and the like. The “alkylsulfonylamino group” is, for example, C _1-10 such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, butylsulfonylamino and the like.
An alkylsulfonylamino group and the like are shown. The "aralkyl group" is, for example, benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2
And C _7-16 aralkyl groups such as naphthylmethyl, 2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, and 5-phenylpentyl. The “aryl group” is, for example, a C _6-14 aryl group such as phenyl, tolyl, xylyl, 1-naphthyl, 2-naphthyl, biphenyl, 2-anthryl and the like. The “arylimino” refers to a C _6-14 arylimino group such as phenylimino.

The "aromatic heterocyclic group" is, for example, a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom. Shown, specifically 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 4- or 5
-Pyrazolyl, 2-, 4- or 5-thiazolyl, 3
-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 3 -Or 4-pyridazinyl, pyrazinyl, 1,2,3- or 1,2,4-triazolyl, 1H or 2H-tetrazolyl, benzofuryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, 1-indolyl, 2- or 3-quinolyl , 1-
Alternatively, 3-isoquinolyl, imidazopyridinyl, thiazolopyridinyl and the like can be mentioned. The "alkyl-carbonyl group" refers to, for example, a C _1-10 alkyl-carbonyl group such as acetyl, propionyl, butyryl, valeryl and the like. The “alkenyl-carbonyl group” refers to a C _2-10 alkenyl-carbonyl group such as acryloyl. The “alkynyl-carbonyl group” refers to a C _2-10 alkynyl-carbonyl group such as propioloyl. The "arylcarbonyl group" is, for example, a C _6-14 arylcarbonyl group such as benzoyl, nicotinoyl, isonicotinoyl, indolylcarbonyl and the like. The "acylamino group" is, for example, a C _1-10 acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, benzoylamino and the like.

The "acyloxy group" is, for example, C such as formyloxy, acetoxy and propionyloxy.
_{1-10 represents an} acyloxy group and the like. The “alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkyl-alkyl group, alkoxy group, alkenyloxy group, alkynyloxy group, aryloxy group, aralkyloxy group, alkylthio group, alkenylthio group, alkynylthio group. , Arylthio group, aralkylthio group, alkylsulfinyl group, alkenylsulfinyl group, alkynylsulfinyl group, arylsulfinyl group, alkylsulfonyl group, alkenylsulfonyl group, alkynylsulfonyl group, arylsulfonyl group, mono- or di-alkylamino group, mono -Or di-aralkylamino group, cyclic amino group, carboxyl group, mercapto group, carbamoyl group, mono- or di-alkyl-carbamoyl group, mono- or di-aryl-carbamo Group, alkoxy-carbonyl group, alkylsulfonylamino group, aralkyl group, aryl group, styryl group, arylimino group, aromatic heterocyclic group, alkyl-carbonyl group, alkynyl-carbonyl group, aryl-carbonyl group, acylamino group, The “acyloxy group” further includes a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _{1-6 at} a substitutable position on these substituents.
Alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.), C _2-6 alkenyl group (eg, vinyl, allyl etc.), C _2-6 alkynyl group (eg, ethynyl, propargyl etc.), carboxyl group, hydroxyl group , Cyano group, nitro group, sulfo group, phosphono group,
Oxo group, C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy etc.), C _6-10 aryloxy group (eg, phenoxy etc.), C _7-14 aralkyloxy group (eg, benzyloxy etc.) ), C
_1-6 alkylthio group (eg methylthio, ethylthio, propylthio, isopropylthio etc.), C _6-10 arylthio group (eg phenylthio etc.), C _7-14 aralkylthio group (eg benzylthio etc.), amino group, mono -Or di-C _1-6 alkylamino group (for example, methylamino, ethylamino, dimethylamino, diethylamino, etc.), cyclic amino group (for example, pyrrolidino, piperidino, piperazino, morpholino, N-methylpiperazino, N-phenylpiperazino) No.), C _7-14 aralkylamino group (eg, benzylamino etc.), C
_6-10 aryl groups (eg phenyl, 1-naphthyl, 2
-Naphthyl etc.), C _1-6 alkyl-carbonyl groups (eg acetyl, propionyl, butyryl, valeryl etc.) and C _1-6 alkoxy-carbonyl groups (eg
It may have 1 to 3 substituents selected from methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and the like). Among these, halogen atom, C
_1-6 alkyl group, halo-C _1-6 alkyl group, carboxyl group, hydroxyl group, cyano group, nitro group, C _1-6 alkoxy group, halo-C _1-6 alkoxy group, amino group, mono- or di- -C _1-6 alkylamino group, cyclic amino group,
A C _1-6 alkoxy-carbonyl group and the like are preferable, and a halogen atom, a C _1-6 alkyl group, a halo-C _1-6 alkyl group, a C _1-6 alkoxy group, a halo-C _1-6 alkoxy group and the like are commonly used. To be done.

Compound [I] or a salt thereof can be produced by various methods.
-112566, JP-A-63-216877, JP-A-1-190670, JP-A-261371, JP-A-3-197467 and the like, or a method analogous thereto. can do. When the desired product is obtained in a free state by the above reaction, it may be converted into a salt according to a conventional method, and when it is obtained as a salt, it may be converted into a free form or another salt according to a conventional method. it can. The compound [I] or a salt thereof thus obtained can be isolated and purified from the reaction solution by known means such as phase transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization and chromatography. When the compound [I] exists as a diastereomer, a conformer or the like, it can be isolated by the above-mentioned separation and purification means, if desired. When compound [I] is a racemate, it can be separated into d-form and I-form by a usual optical resolution means.
When compound [I] contains a basic group, it can be obtained as an acid addition salt, particularly a pharmacologically acceptable acid addition salt, by a method known per se. Examples of such an acid include an inorganic acid (eg, hydrochloric acid, sulfuric acid, phosphoric acid, etc.) or an organic acid (eg, acetic acid, propionic acid, citric acid, tartaric acid, malic acid, oxalic acid, etc.). When the compound [I] has an acidic group, it can be used as a salt with a base, particularly a pharmacologically acceptable base. Such bases include alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.), organic bases (eg, triethylamine, piperidine, etc.).

Since the compound [I] of the present invention or a salt thereof has low toxicity and few side effects, it can be administered to mammals (eg, humans, cows, horses, dogs, cats, monkeys, mice, rats, etc.) For example, antitumor effect against primary cancer of solid cancer such as prostate cancer, pancreatic cancer, lung cancer, inhibition of metastasis, preventive effect on recurrence after surgery, and effect of improving various symptoms associated with cancer (eg, pain, cachexia, etc.) There is. Further, the therapy by administration of the compound [I] or a salt thereof of the present invention, various chemotherapeutic agents (for example, ifosfamide, estramustine phosphate, alkylating agents such as nimustine hydrochloride, fluorouracil, antimetabolites such as tegafur, Mitomycin, doxorubicin hydrochloride, bleomycin, peplomycin sulfate, aclarubicin hydrochloride, antibiotics such as neocarzinostatin, other cisplatin, carboplatin, etc.), BRM (IL-2, IFN-α, IFN-β,
IFN-γ, TNF-α, etc.), therapy with angiogenesis inhibitors, etc., hyperthermia, hormone therapy in the case of prostate cancer (exclusivity, estrogen, diethylstilbestrol phosphate phosphate, LHRH-agonist, LHRH-antagonist) Administration) etc. Furthermore, the compound [I] or a salt thereof is a Helicobacter pylori (H
Since it also has an excellent bactericidal effect against elicobacter Pylori), it can be used as a preventive and therapeutic agent for infectious diseases caused by Helicobacter pylori. Examples of the “infection” include duodenal ulcer, gastric ulcer, esophagitis,
Examples include gastritis and gastric cancer. Further, the combined use of the compound [I] or a salt thereof and 1 to 3 kinds of drugs selected from antiulcer agents and antibacterial agents is an excellent therapeutic method for digestive system diseases caused by Helicobacter pylori. Examples of the "anti-ulcer agent" include proton pump inhibitors (eg, lansoprazole, omeprazole, pantoprazole, paliprazole, reminoprazole, etc.), H ₂ -receptor antagonists (eg, cimetidine, ranitidine, famotidine, etc.) And so on. Examples of the "antibacterial agent" include amoxicillin, clarithromycin, tetracycline, metronidazole, tinidazole and the like. Examples of the "digestive system disease" include duodenal ulcer, gastric ulcer, esophagitis, gastritis, gastric cancer and the like. Compound [I] or a salt thereof is known per se or as such (eg, Japanese Pharmacopoeia 12th revision).
In accordance with the method of 1., a pharmaceutical composition containing a pharmaceutically acceptable carrier, such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, kaosels, capsules (including soft capsules), solvents, drip Orally or parenterally, as a drug, injection, external preparation (eg, nasal preparation, transdermal preparation, etc.), suppository (eg, rectal suppository, cavity suppository, etc.), sustained release preparation, etc. Although it can be safely administered, and its dose varies depending on the administration subject, administration route, disease, etc., for example, when it is orally administered to an adult patient with prostate cancer, the active ingredient ( The compound [I] or a salt thereof) is 0.1 to 20.
mg / kg, preferably 0.2 to 10 mg / kg daily
It is advisable to administer in divided doses.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances conventionally used as a formulation material are used, and an excipient, a lubricant, a binder, a disintegrating agent, a thickening agent in a solid formulation; a liquid form. It is used as a solvent, a dispersant, a solubilizing agent, a suspending agent, an isotonicity agent, a buffering agent, a soothing agent, etc. in the preparation. If necessary, additives such as antiseptics, antioxidants, coloring agents and sweeteners can be used. Suitable examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like. Preferable examples of the thickener include natural gums, cellulose derivatives, acrylic acid polymers and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, marcgor, sesame oil, corn oil and the like. Preferable examples of the dispersant include, for example, Tween 8
0, HCO 60, polyethylene glycol, carboxymethyl cellulose, sodium alginate and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Suitable examples of the suspending agent include, for example, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, surfactants such as xericerine monostearate; polyvinyl alcohol, Polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose,
Hydrophilic polymers such as hydroxyethyl cellulose and hydroxypropyl cellulose are included. Preferable examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Preferred examples of the soothing agent include benzyl alcohol and the like. Preferable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include phosphite, ascorbic acid and the like.

Specific examples of the pharmaceutical preparation of the present invention are shown below. (1) Tablets, powders, granules, kausels: Compound [I] or a salt thereof, for example, an excipient, a disintegrating agent, a binder, a lubricant or the like is added and compression-molded, and then, if necessary, taste. It can be produced by masking, enteric coating, or coating for the purpose of permanence. (2) Injection: A compound [I] or a salt thereof, for example, as an aqueous injection together with a dispersant, a preservative, an isotonicity agent,
Alternatively, it can be produced by dissolving, suspending or emulsifying in vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil and the like, propylene glycol or the like and molding as an oily injection. (3) External preparation: It is produced by making the compound [I] or a salt thereof into a solid, semi-solid or liquid composition. For example, the solid composition is produced by compounding the compound [I] or a salt thereof as it is, or by adding and mixing an excipient, a thickener and the like to give a powder. The above-mentioned liquid composition is almost the same as the case of the injection, and is produced by making it an oily or aqueous suspension. The semi-solid composition is preferably an aqueous or oily gel or an ointment. Further, any of these compositions may contain a buffering agent, a preservative and the like. (4) Suppository: Produced by making the compound [I] or a salt thereof into an oily or aqueous solid, semisolid or liquid composition. Examples of the oily base used in such a composition include, for example, glycerides of higher fatty acids (eg, cacao butter, witepsols, etc.), intermediate fatty acids (eg, migliols, etc.), or vegetable oils (eg, sesame oil, soybean oil, Cottonseed oil, etc.) and the like. As the aqueous gel base, for example, natural gums, cellulose derivatives,
Examples thereof include vinyl polymers and acrylic acid polymers.

[0022]

BEST MODE FOR CARRYING OUT THE INVENTION

EXAMPLES The present invention is explained in detail by the following reference examples, examples and test examples, but these examples are merely illustrative examples.
The present invention is not limited, and may be changed without departing from the scope of the present invention. Reference Example 1 3,5-Dimethyl-2-mercapto-6-hydroxy-
3H-pyrimidin-4-one sodium salt A solution of diethyl methylmalonate (39.0 g) and methylthiourea (19.9 g) in ethanol (100 ml) was added,
28% sodium methylate in methanol (45 ml)
Was added and the reaction was refluxed for 2 hours. The resulting precipitate was collected by filtration, washed with ethyl acetate and dried to give the title compound (35.73 g) as a colorless powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.58 (3H, s), 3.41 (3
4H, s), 10.34 (1H, brs) .IR (KBr): 3430, 1635, 16
00, 1525, 1280 cm ^-1 .

Reference Example 2 3,5-Dimethyl-2-methylthio-6-hydroxy-
3H-pyrimidin-4-one 3,5-dimethyl-2-mercapto-6-hydroxy-
3H-pyrimidin-4-one sodium salt (6.5 g)
Methyl iodide (5.7 g) was added to a 50% acetone (40 ml) solution of and the reaction mixture was stirred at room temperature for 5 hours.
The precipitate formed after distilling off acetone was collected by filtration, washed with water and dried to obtain the title compound (5.8 g) as a colorless powder. ¹ H-NMR (CDCl ₃ ): 1.97 (3H, s), 2.51 (3H, s),
3.49 (3H, s), 5.96 (1H, brs). IR (KBr): 3220, 1610, 1520, 1390, 1240, 1120
cm ⁻¹ . Reference Example 3 6-methyl-7-hydroxy-2,3-dihydro-5H
-Thiazolo [3,2-a] pyrimidin-5-one Diethyl methylmalonate (42.65 g) and 2-aminothiazolidine (25 g) in ethanol (170 ml) was added to a 28% sodium methylate methanol solution (51
ml) was added and the reaction was refluxed for 2 hours. The resulting precipitate was collected by filtration, washed with ethanol and ethyl acetate, and dried to give the title compound (27.15 g) as a colorless powder. ¹ H-NMR (DMSO-d ₆ ) δ: 1.72 (3H, s), 3.52 (2
H, t, J = 7.6Hz), 4.29 (2H, t, J = 7.6Hz), 11.20 (1H, br). IR (KBr): 2680, 1650, 1530, 1440 cm ^-1 .

Reference Example 4 6- [4- (4-chlorobenzoyl) benzyloxy]
-3,5-Dimethyl-2-methylthio-3H-pyrimidin-4-one 3,5-dimethyl-6-hydroxy-2-methylthio-
4- (4-Chlorobenzoyl) benzyl bromide (2.0 g) was added to a solution of 3H-pyrimidin-4-one (1.0 g) and potassium carbonate (750 mg) in dimethylformamide (15 ml), and the reaction solution was heated to 70 ° C. And allowed to stir for 1 hour. The reaction solution was concentrated, water-ethyl acetate was added to the residue, and the generated crystals were collected by filtration, washed with water and methanol, and dried to obtain the title compound (845 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 2.02 (3H, s), 2.50 (3H, s),
3.50 (3H, s), 5.50 (2H, s), 7.47 (2H, d, J = 8.0Hz), 7.49
(2H, d, J = 8.0Hz), 7.76 (2H, d, J = 8.0Hz), 7.79 (2H, d, J = 8.
IR (KBr): 1665, 1650, 1595, 1515 cm ^-1 .

Reference Example 5 7- [4- (4-chlorobenzoyl) benzyloxy]
-6-Methyl-2,3-dihydro-5H-thiazolo [3,
2-a] pyrimidin-5-one 7-hydroxy-6-methyl-2,3-dihydro-5H
-Thiazolo [3,2-a] pyrimidin-5-one (1.0
g) and potassium carbonate (750 mg) in dimethylformamide (15 ml), 4- (4-chlorobenzoyl) benzyl bromide (2.0 g) was added, and the reaction solution was stirred at 60 ° C. for 2 hours. The reaction mixture was concentrated and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) and recrystallized from isopropyl ether to give the title compound (200 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.97 (3H, s), 3.47 (2H, t, J
= 7.8Hz), 4.46 (2H, t, J = 7.8Hz), 5.43 (2H, s), 7.46 (2H,
d, J = 8.0Hz), 7.50 (2H, d, J = 8.0Hz), 7.76 (2H, d, J = 8.0H
z), 7.78 (2H, d, J = 8.0Hz). IR (KBr): 1650, 1515, 1390 cm ^-1 .

Reference Example 6 7- [4- (t-butyl) benzyloxy] -6-methyl-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidin-5-one 7-hydroxy-6 -Methyl-2,3-dihydro-5H
-Thiazolo [3,2-a] pyrimidin-5-one (1.0
g) and potassium carbonate (750 mg) in dimethylformamide (20 ml), 4- (t-butyl) benzyl bromide (1.48 g) was added, and the reaction solution was stirred at 50 ° C. for 2 hours. The reaction solution was concentrated and the resulting residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 1 /
The product was purified in 1) and recrystallized from isopropyl ether to give the title compound (234 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (9H, s), 1.97 (3H, s),
3.46 (2H, t, J = 7.6Hz), 4.45 (2H, t, J = 7.6Hz), 5.31 (2H,
s), 7.33 (2H, d, J = 8.4Hz), 7.40 (2H, d, J = 8.4Hz) .IR (KBr): 1650, 1510 cm ^-1 .

Reference Example 7 7- [4- (benzyloxy) benzyloxy] -6-
Methyl-2,3-dihydro-5H-thiazolo [3,2-
a] Pyrimidin-5-one 7-hydroxy-6-methyl-2,3-dihydro-5H
-Thiazolo [3,2-a] pyrimidin-5-one (1.0
g) and potassium carbonate (400 mg) in dimethylformamide (20 ml) was added with 4- (benzyloxy) benzyl chloride (1.52 g) and the reaction was allowed to stir at 50 ° C. for 3 hours. The reaction solution was concentrated and the resulting residue was subjected to silica gel column chromatography (hexane / ethyl acetate =
It was purified by 1/1) and recrystallized from ethyl acetate to obtain the title compound (598 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.91 (3H, s), 3.45 (2H, t, J
= 7.8Hz), 4.45 (2H, t, J = 7.8Hz), 5.07 (2H, s), 5.27 (2H,
s), 6.97 (2H, d, J = 8.6Hz), 7.30-7.50 (7H, m). IR (KBr): 1650, 1505 cm ^-1 .

Reference Example 8 7- (Biphenylmethyloxy) -6-methyl-2,3
-Dihydro-5H-thiazolo [3,2-a] pyrimidine-
5-one 7-hydroxy-6-methyl-2,3-dihydro-5H
-Thiazolo [3,2-a] pyrimidin-5-one (0.8
2 g) and potassium carbonate (600 mg) in dimethylformamide (15 ml), chloromethylbiphenyl (1.
0 g) was added and the reaction was allowed to stir at 70 ° C. for 24 hours.
The reaction mixture was concentrated and the obtained residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 1/1) and recrystallized from dichloromethane / isopropyl ether to give the title compound (394 mg) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 1.96 (3H, s), 3.46 (2H, t, J
= 7.8Hz), 4.46 (2H, t, J = 7.8Hz), 5.38 (2H, s), 7.30-7.50
(5H, m), 7.55-7.65 (4H, m). IR (KBr): 1650, 1590, 1505
cm ⁻¹ .

Reference Example 9 7- [4- (t-butyl) benzylthio] -6-methyl-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidin-5-one 7-hydroxy-6- Methyl-2,3-dihydro-5H
-Thiazolo [3,2-a] pyrimidin-5-one (2.0
g) and potassium carbonate (750 mg) in dimethylformamide (20 ml) was added p-toluenesulfonyl chloride (2.48 g), and the reaction mixture was allowed to stir at room temperature for 4 hours. The reaction solution was concentrated and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate / chloroform = 2/2/1) to give 7- (p-toluenesulfonyloxy) -6-methyl- as a colorless solid. 2,3-Dihydro-5H-thiazolo [3,2-a] pyrimidin-5-one (699 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.95 (3H, s), 2.47 (3H, s),
3.47 (2H, t, J = 7.9Hz), 4.42 (2H, t, J = 7.9Hz), 7.37 (2H,
. d, J = 8.6Hz), 7.92 (2H, d, J = 8.6Hz) IR (KBr):. 1660, 1595, 1630, 1360, 1170 cm -1 7- (p- toluenesulfonyloxy) -6- Methyl-
2,3-Dihydro-5H-thiazolo [3,2-a] pyrimidin-5-one (306 mg) and potassium carbonate (100 m
g) in dimethylformamide (10 ml), 4-
(T-Butyl) benzylthiol (190 mg) was added,
The reaction solution was allowed to stir at 80 ° C. for 24 hours. The reaction solution was concentrated and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 7- [4- (t-butyl) benzylthio] -6-methyl-2 as a colorless solid. , 3-Dihydro-5H-thiazolo [3,2-a]
Pyrimidin-5-one (42 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (9H, s), 1.98 (3H, s),
3.45 (2H, t, J = 7.7Hz), 4.34 (2H, s), 4.45 (2H, t, J = 7.7H
z), 7.29 (2H, d, J = 8.8Hz), 7.34 (2H, d, J = 8.8Hz). IR (KBr): 1645, 1555, 1500, 1380 cm ^-1 .

Reference Example 10 3,5-Dimethyl-2-methylthio-6- [4- (1,
2,3-thiadiazol-4-yl) benzyloxy]
Preparation of -4 (3H) -pyrimidinone 3,5-Dimethyl-6-hydroxy-2-methylthio-
4 (3H) -pyrimidinone (466 mg) was added to DMF (10 m).
l), 4- (4-bromomethylphenyl) -1,
Add 2,3-thiadiazole (765 mg) and potassium carbonate (525 mg), and stir at 70 ° C. for 30 minutes. The reaction solution is extracted with ethyl acetate, the organic layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. This is concentrated, and the residue is purified by silica gel chromatography (n-hexane-ethyl acetate (1: 1)), further washed with diethyl ether-dichloromethane and dried. White powder 1
19 mg ¹ H-NMR (CDCl ₃ ) δ: 2.02 (3H, s), 2.52
(3H, s), 3.49 (3H, s), 5.49 (2H, s), 7.51 (2H, d, J = 8.2H
z), 8.05 (2H, d, J = 8.2Hz), 8.65 (1H, s).

Reference Example 11 3,5-Dimethyl-2-methylthio-6- [4- (2-
Preparation of Pyridyl) benzyloxy] -4 (3H) -pyrimidinone 3,5-dimethyl-6-hydroxy-2-methylthio-
4 (3H) -pyrimidinone (466 mg) was added to DMF (10 m).
l), 2- (4-bromomethylphenyl) pyridine (744 mg) and potassium carbonate (525 mg) were added,
Stir at 70 ° C. for 30 minutes. The reaction solution is extracted with ethyl acetate, the organic layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. This is concentrated, the residue is purified by silica gel chromatography (n-hexane-ethyl acetate (1: 1)), then washed with diethyl ether and dried. White powder 180 mg ¹ H-NMR (CDCl ₃ ) δ: 2.01 (3H, s), 2.52 (3H, s),
3.49 (3H, s), 5.48 (2H, s), 7.20-7.28 (1H, m), 7.47 (2H,
d, J = 8.4Hz), 7.70-7.83 (2H, m), 7.99 (2H, d, J = 8.4Hz),
8.70 (1H, d, J = 4.4Hz).

Reference Example 12 Preparation of 6- [4- (4,6-dimethoxypyrimidin-2-yl) benzyloxy] 3,5-dimethyl-2-methylthio-4 (3H) -pyrimidinone 3,5-dimethyl- 6-hydroxy-2-methylthio-
4 (3H) -pyrimidinone (223 mg) in DMF (5 ml)
Dissolved in 2- (4-bromomethylphenyl) -4,6
-Add dimethoxypyrimidine (433 mg) and potassium carbonate (249 mg) and stir at 70 ° C for 30 minutes. The reaction solution is extracted with ethyl acetate, the organic layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. It is concentrated, the residue is purified by silica gel chromatography (dichloromethane-ethyl acetate (10: 1)), then washed with diethyl ether and dried. White powder 177 mg ¹ H-NMR (CDCl ₃ ) δ: 2.01 (3H, s), 2.51 (3H, s),
3.48 (3H, s), 4.05 (6H, s), 5.49 (2H, s), 5.98 (1H, s),
7.45 (2H, d, J = 8.6Hz), 8.45 (2H, d, J = 8.6Hz).

Example 1 (Dose per Tablet) (1) Compound of Reference Example 4 10.0 mg (2) Lactose 60.0 mg (3) Corn Starch 35.0 mg (4) Gelatin 3.0 mg (5) Stearic Acid Magnesium 2.0 mg A mixture of 10.0 mg of the compound of Reference Example 4, 60.0 mg of lactose and 35.0 mg of corn starch was added to 0.03 ml of 10% by weight gelatin aqueous solution (3.0 g as gelatin).
g) was used to interrogate a 1 mm mesh sieve for granulation, followed by drying at 40 ° C. and sieving again. The obtained granules were mixed with 2.0 mg of magnesium stearate and compressed. The obtained central tablet was coated with sugar coating of a suspension of sucrose, titanium dioxide, talc and gum arabic to give a coated tablet by glazing with a beeswax. Example 2 (Dose per tablet) (1) Compound of Reference Example 4 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3 0.0 mg The compound of Reference Example 4 (10.0 mg) and magnesium stearate (3.0 mg) were added to a soluble starch aqueous solution (0.07 ml).
Granulated with (7.0 mg as soluble starch), dried, lactose 70.0 mg and corn starch 5
Mixed with 0.0 mg. The mixture was compressed to give tablets.

[0034]

[Test Example] In vitro inhibition of cell growth of prostate cancer (Test method) Prostate cell line PC-3 in F-12K medium containing 10% fetal bovine serum (Flow Laboratories [Flow
Laboratories] or Dainippon Pharmaceutical Co., Ltd.) and suspended the cell suspension in a 96-well microplate (5
(000 cells / 50 or 75 μl / well) were cultured at 37 ° C. in a 5% carbon dioxide gas incubator. The next day, each compound solution (50 or 25 μl / well) dissolved in dimethylformamide and serially diluted 3-fold was added (final 100 μl), and the cells were further cultured for 3 days. MTT dye solution was added to quantify the number of surviving cells [Tada et al., Journal of Immunological Methods (J. Immunol. Meth
ods), 93, 157, (1986)]. Taking the cell amount of the control group to which the compound solution was not added as 100%, the ratio of the cell amount of each compound added group was calculated, and the compound concentration necessary to suppress the viable cell amount by 50% of the control group (IC ₅₀ value ) Was calculated. These are shown in [Table 1].

[Table 1] From Table 1, it can be seen that the compound of the present invention has an excellent antiproliferative effect on prostate cell line (PC-3).

[0035]

INDUSTRIAL APPLICABILITY The compound of the present invention exhibits excellent antitumor activity, and has excellent effects such as treatment of refractory solid tumors and prevention of distant metastasis to other organs.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location C07D 513/04 355 C07D 513/04 355 // (C07D 401/12 213: 16 239: 60) (C07D 417 / 12 239: 60 285: 06) (72) Inventor Masuo Yamaoka 2-5-10 Shoyama-cho, Nagata-ku, Kobe-shi, Hyogo Shoyama Villa-202 (72) Masafumi Nakao 720 Kose-cho, Ikoma-shi, Nara 74

Claims (11)

[Claims] 1. A general formula: [Wherein, R ¹ and R ³ are each (i) a halogen atom or (ii) a hydrogen atom which may be bonded via a hetero atom, or a hydrocarbon residue which may have a substituent; R ² is a hydrocarbon residue which may have a substituent; X
Is an oxygen atom or a sulfur atom; Z is a divalent group, and Ar
Represents an aromatic group which may have a substituent. ] The pharmaceutical composition containing the compound or its salt represented by these. 2. R ¹ and R ³ are C _1-6 alkyl groups which may be bonded via —O— or —S—.
The composition as described. 3. R ¹ is a C _1-6 alkylthio group.
The composition as described. 4. The composition according to claim 1, wherein R ² is a C _1-6 alkyl group. 5. The composition according to claim 1, wherein R ³ is a C _1-6 alkyl group. 6. The composition according to claim 1, wherein Z is a divalent aliphatic hydrocarbon residue having 1 to 10 carbon atoms. 7. The composition according to claim 1, wherein Ar is a phenyl group which may have a substituent. 8. The substituent which the phenyl group may have is C
_6-14 aryloxy group, C _7-16 aralkyloxy group, C
_6-14 arylthio group, C _7-16 aralkylthio group, C _6-14
Arylsulfinyl group, C _6-14 arylsulfonyl group, mono- or di-C _7-16 aralkylamino group, cyclic amino group, mono- or di-C _6-14 arylcarbamoyl group, C _7-16 aralkyl group, C _6-14 aryl group, C _6-14
Arylimino group, aromatic heterocyclic group, C _6-14 arylcarbonyl group (these substituents are 1 to 3 halogen atoms, C _1-6 alkyl group, halo-C _1-6 alkyl group, carboxyl group , Hydroxyl group, cyano group, nitro group,
It may have a C _1-6 alkoxy group, a halo-C _1-6 alkoxy group, an amino group, a mono- or di-C _1-6 alkylamino group, a cyclic amino group or a C _1-6 alkoxy-carbonyl group. Good), [In the formula, W ^a is a halogen atom, a C _1-6 alkyl group, a halo-
C _1-6 alkyl group, carboxyl group, hydroxyl group,
Cyano group, nitro group, C _1-6 alkoxy group, halo-C _1-6
Alkoxy group, amino group, mono- or di-C _1-6 alkylamino group, cyclic amino group or C _1-6 alkoxy-
Carbonyl group, m represents 0 to 5. ] The composition according to claim 7. 9. R ¹ is a C _1-6 alkyl group which may be bonded via —O— or —S—; R ² is a C _1-6 alkyl group; R ³ is a C _1-6 alkyl group. X is an oxygen atom or a sulfur atom; Z is a C _1-6 alkylene group; Ar is halogen, C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy and halo-C _1-6 alkoxy. The composition according to claim 1, which is a phenyl group substituted with a C _6-14 arylcarbonyl group which may have 1 to 3 selected substituents. 10. The composition according to claim 1, which is used for treating cancer. 11. The composition according to claim 1, which is for eradication of Helicobacter pylori.