WO2001072718A1

WO2001072718A1 - Pharmaceutical compositions containing as the active ingredient nitropyrimidine derivatives or salts thereof

Info

Publication number: WO2001072718A1
Application number: PCT/JP2001/002503
Authority: WO
Inventors: Keizo Miyata; Hirohiko Kimura; Toshio Ishikawa; Kazuhiro Yamamoto
Original assignee: Ishihara Sangyo Kaisha, Ltd.
Priority date: 2000-03-29
Filing date: 2001-03-27
Publication date: 2001-10-04
Also published as: AU2001242819A1

Abstract

Pharmaceutical compositions containing as the active ingredient nitropyrimidine derivatives of the general formula (I) or salts thereof wherein A is -C(R5)=N- or -CO-N(R?6)-; R1 and R4¿ are each hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or an optionally substituted heterocyclic group; and R?2 and R3¿ are each hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, an optionally substituted heterocyclic group, or -B-R7, or alternatively R?2 and R3¿ together with the nitrogen atom may form an N=CR8R9 group.

Description

Specification

TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing a nitropyrimidine derivative or a salt thereof as an active ingredient.

The present invention relates to a pharmaceutical composition containing a ditropyrimidine derivative or a salt thereof as an active ingredient. In addition, a part of the nitropyrimidine derivative or a salt thereof, which is an active ingredient of the pharmaceutical composition, is a novel compound, and the present invention also relates to the novel conjugate.

Matrix metaoral proteinase (MMP) is a major enzyme involved in the extracellular matrix. MMPs have a wide range of physiological actions in living organisms, and their overproduction disrupts the homeostasis of living organisms, causing new diseases or exacerbating their pathology. Therefore, MMP enzyme inhibitors are considered to be useful as therapeutic / preventive agents for various diseases.

Some of the nitropyrimidine derivatives represented by the following formula (I), which are the active ingredients of the pharmaceutical composition of the present invention, are compounds known from JP-A-48-40798 and JP-A-6-135943. However, it is not known that such known compounds have an MMP enzyme inhibitory action. That is, the compound described in JP-A-48-40798 relates to a pharmaceutical intermediate, and the compound described in JP-A-6-135943 relates to an active ingredient of a therapeutic agent for allergic disease. The present inventors have conducted intensive studies on the synthesis of compounds having MMP enzyme inhibitory activity and on their pharmacological activities. As a result, the inventors have found that non-MMP-9 has a potent and selective enzyme inhibitory activity for MMP-9. As a peptide compound, a ditropyrimidine derivative or a salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention, has been found. Some of the nitropyrimidine derivatives or salts thereof are novel compounds, and the present invention also includes the novel compounds and methods for producing the novel compounds.

Disclosure of the invention

The present invention provides a compound of formula (I):

[In the formula, A is —C (R ⁵ ) = N— group or one CO—N (R ⁵ ) group; R] and R ⁶ are each independently a hydrogen atom, a displaceable alkyl group, An alkenyl group, a substituted alkynyl group, a substituted cycloalkyl group, a substituted cycloalkenyl group, a substituted aryl group or a substituted heterocyclic group; R ² and R ³ are each independently a hydrogen atom, a substituted alkyl group, A substitutable alkenyl group, a substitutable alkynyl group, a substitutable cycloalkyl group, a substitutable cycloalkenyl group, a substitutable aryl group, a substitutable heterocyclic group or one B—R ⁷ group (B is S, SO, S 0 ₂ a S 0 _3, CO or C 0 _2, R ⁷ is a hydrogen atom, an optionally substituted alkyl group, a substitutable alkenyl group, a substitutable alkynyl group, a substitutable cycloalkyl group, a substitutable cycloalkenyl group, a substitutable Ariru Group or substituted heterocyclic group Or R ² and R ³ together with an N atom N = CR ⁸ R ⁹ group j R ⁸ and R ⁹ are each independently a hydrogen atom, a substitutable alkyl group, a substitutable alkenyl group, Alkynyl group, cycloalkyl group, cycloalkenyl group, cycloalkyl group, aryl group, heterocyclic group, cyano group, nitro group, alkoxy group, aryloxy group or 1B —R ⁷ group and R ⁷ are as defined above) may be formed; R ⁵ is a hydrogen atom or a displaceable amino group], or a nitropyrimidine derivative represented by the formula or a salt thereof as an active ingredient. As a pharmaceutical composition.

The salt of the ditropyrimidine derivative represented by the formula (I) may be a pharmaceutically acceptable salt, for example, a mineral acid salt such as hydrochloride, sulfate or nitrate; p-toluene sulfonate Organic salts such as propanesulfonate and methanesulfonate; alkali metal salts such as potassium salts and sodium salts; alkaline earth metal salts such as calcium salts; triethanolamine salts; Organic amine salts such as (hydroxymethyl) aminomethane salt. Some of these salts have water of crystallization.

In the formula (I), the alkyl moiety contained in ¹ to! ^ ⁴ and R ⁶ to R ⁹ ; In general, those having 1 to 18 carbon atoms, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, nonadecyl, etc. Also includes those having structural isomers of branched fatty chains. The alkenyl moiety contained in I ^ R ⁴ and R ^{6 to} R ⁹ in the formula (I) has 2 to 18 carbon atoms, for example, a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a Examples thereof include a xenyl group, a decenyl group and a nonadecenyl group, and these include those having a linear or branched aliphatic chain with structural isomerism.

The alkynyl moiety contained in i ^ to R ⁴ and R ^{6 to} R ⁹ in the formula (I) has 2 to 18 carbon atoms, for example, ethynyl, propynyl, petinyl, pentynyl, Hexynyl group, decynyl group, nonadecynyl group and the like;

They include those having structural isomers of linear or branched fatty chains.

The cycloalkyl moiety contained in R ¹ ! ^ ⁴ and: ^{6 to} R ⁹ in the formula (I) has 3 to 8 carbon atoms, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl And cyclooctyl groups.

In the formula (I), the cycloalkenyl moiety contained in E ^ to R ⁴ and R ^{6 to} R ⁹ has 5 to 8 carbon atoms, for example, a cyclopentenyl group, a cyclohexenyl group

And cyclooctenyl groups.

The Ariru portion included in the I ^ R ⁴ and R ⁶ to R ⁹ in the formula (I), phenyl group, naphthyl group, tetrahydronaphthyl group, indanyl group, Adamanchi group, Noruadamanchiru group, Noruporunaniru group, Noruborunanoniru group such as Are mentioned.

In formula (I); the heterocyclic moiety included in the E ^ R ⁴ and R ⁶ to R ^9, pin hole drill group, pyrrolinyl group, Pi port lysine two group, furanyl group, dihydrofuranyl group, tetrahydrofuranyl Nyl group, chenyl group, dihydrodichenyl group, tetrahydrophenyl group, pyrazolyl group, pyrazolidinyl group, pyrazolidinyl group, imidazolyl group, imidazolinyl group, imidazolidinyl group, oxazolyl group, oxazolinyl group, oxazolidinyl group , Isooxazolinyl group, isooxozazolidinyl group, thiazolyl group, thiazolinyl group, thiazolidinyl group, isothiazolyl group, isothiazolinyl group, isothiazolidinyl group, oxaziazolyl group, Oxadiazolinyl group, Oxadiazolidinyl group, Thiadiazolyl group, Thiadiazolidinyl group, Thiadiazolidinyl group, Triazolyl group, Triazolinyl group, Triazolidinyl group, Tetrazolyl group, Tetrazolinyl group, Tetrazolidinyl Group, dioxolyl group, dioxolanyl group, dithiolyl group, dithiolanyl group, pyridyl group, dihydropyridyl group, tetrahydropyridyl group, piperidinyl group, pyrimidyl group, dihydropyrimidyl group, tetrahydropyrimidyl group, hexahydropyrimidyl Group, pyridazinyl group, dihydropyridazinyl group, tetrahydropyridazinyl group, hexahydropyridazinyl group, virazinyl group, dihydrovirazinyl group, tetrahydrovirazinyl group, pyrazinyl group, viranyl Group, dihydropyranyl Monocyclic heterocyclic groups such as a group, a tetrahydroviranyl group, a dioxinyl group, a dioxenyl group, a dioxanyl group, a dithienyl group, a morpholinyl group; a thienochenyl group, a dihydrocyclopentachenyl group, an indolyl group, and a tetrahydroindolyl group , Isoindolyl group, tetrahydroisoindolyl group, benzochenyl group, tetrahydrobenzozoenyl group, benzofuranyl group, tetrahydrobenzozofuranyl group, benzoxoxazolyl group, tetrahydrobenzozoxazolyl group, benzoisoxazolyl group, tetrahydrobenzozo group Isoxazolyl, benzothiazolyl, tetrahydrobenzothiazolyl, benzothiazolyl, tetrahydrobenzoisothiazolyl, benzoimidazolyl, tetrahydrobenzoimidazolyl Group, benzodioxolyl, benzodithiolyl, benzodioxanyl, benzodithianyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, naphthyridinyl, purinyl, etc. A cyclic group; a crosslinked polycyclic heterocyclic group such as a quinuclidinyl group; The substituent of the substituted amino group contained in R ⁵ in the formula (I) includes a substituted alkyl group, a substituted alkenyl group, a substituted alkynyl group, a substituted cycloalkyl group, a substituted cycloalkenyl group, Substituted aryl group, substituted heterocyclic group, substituted alkoxy group, substituted alkenyloxy group, substituted alkynyloxy group, substituted cycloalkoxy group, substituted cycloalkenyloxy group, substituted aryloxy group, Substituted heterocyclic oxy group, substituted alkylcarbonyl group, substituted alkenylcarbonyl group, substituted alkynylcarbonyl group, substituted cycloalkylcarbonyl group, substituted Cycloalkenylcarbonyl group, substituted arylcarbonyl group, substituted heterocyclic carbonyl group, substituted alkoxycarbonyl group, substituted alkenyloxycarbonyl group, substituted alkynyloxycarbonyl group, substituted cycloalkyloxy group Rubonyl group, substituted cycloalkenyloxycarbonyl group, substituted aryloxycarbonyl group, substituted heterocyclic oxycarbyl group, substituted alkylsulfonyl group, substituted alkenylsulfonyl group, substituted alkynylsulfonyl group, substituted Cycloalkylsulfonyl group, substituted cycloalkenylsulfonyl group, substituted arylsulfonyl group, substituted heterocyclic sulfonyl group, substituted alkyloxysulfonyl group, substituted arylalkyloxysulfonyl group, substituted Alkynyloxysulfoni Group, substituted cycloalkyloxysulfonyl group, substituted cycloalkenyloxysulfonyl, substituted aryloxysulfonyl group, substituted heterocyclic oxysulfonyl group, substituted amino group, substituted aminocarbonyl group, substituted Examples thereof include an aminosulfonyl group and a hydroxyl group. The number of such substituents may be one or two or more. When the number of substituents is two or more, those substituents may be the same or different.

The secondary substituent of the substituted amino group contained in the above-mentioned R ⁵ includes alkyl, haloalkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, haloalkenyl, alkynyl, no, loalkynyl, cycloalkyl, cycloalkenyl, aryl, Heterocycle, alkylcarbonyl, haloalkylcarbonyl, alkoxyalkylcarbonyl, alkylthioalkylcarbonyl, alkenylcarbonyl, noloalkenylcarbonyl, alkynylcarbonyl, haloalkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heterocycle Luponyl, alkoxycarbonyl, haloalkoxycarbonyl, alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl, alk Alkoxycarbonyl, haloalkenyloxycarbonyl, alkynyloxycarbonyl, haloalkynyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryloxycarbonyl, heterocyclic oxycarbonyl, alkylsulfonyl , Haloalkylsulfonyl, alkoxyalkylsulfonyl, alkylthioalkylsulfonyl, alkenylsulfonyl, nodroal Kenylsulfonyl, alkynylsulfonyl, amino, loalkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkenylaminopropyl, alkynylaminocarbonyl , Cycloalkylaminocarbonyl, cycloalkenylaminocarbonyl, arylaminocarbonyl, heterocyclicaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, cycloalkylaminosulfonyl , Cycloalkenylaminosulfonyl, arylaminosulfonyl, heterocyclic aminosulfonyl , Shea Anomoto may be further substituted with tertiary substituent such as a hydroxyl group. The number of such substituents may be one or two or more.When the number of substituents is two or more, the tertiary substituents may be the same or different. Good.

In the formula (I)! Substitutable alkyl, substitutable alkenyl, substitutable alkynyl, substitutable cycloalkyl, substitutable cycloalkenyl, substitutable aryl, and substitutable heterocyclic groups contained in ^ to scale ⁴ and R ^{6 to} R ⁹ The substituent of the substituted alkoxy group and the substituted aryloxy group contained in R ⁸ and R ⁵ include, in addition to the substituent of the substituted amino group contained in R ⁵ , a substituted alkylthio group and a substituted aryl group; Dilthio group, Substitutable alkynylthio group, Substitutable cycloalkylthio group

, Substituted cycloalkenylthio group, substituted arylarylthio group, substituted heterocyclic thio group, substituted alkylcarbonyloxy group, substituted alkenylcarbonyloxy group, substituted alkynylcarbonyloxy group, substituted cycloalkylcarboxy group Roxy group, substituted cycloalkenyl carbonyl group, substituted aryl group, substituted heterocyclic carbonyl group, substituted alkylsulfonyl group, substituted alkenylsulfonyl group, substituted alkylsulfonyloxy group Group, substituted alkenylsulfonyloxy group, substituted alkynylsulfonyloxy group, substituted cycloalkylsulfonyloxy group, substituted cycloalkenylsulfonyloxy group, replaceable arylsulfonyloxy group, displaceable complex Ring sulfonyloxy group, Substitutable Examples include a droxyaminocarbonyl group, a halogen atom, a cyano group, a nitro group, a thiol group, a carboxyl group, and a sulfonic group. The number of those substituents is 1 Or two or more substituents. When the number of substituents is two or more, those substituents may be the same or different.

The secondary substituents of the respective substituents contained in the above-mentioned ¹ to! ^ ⁴ and R ^{6 to} R ⁹ include those listed as the tertiary substituents of the substitutable amino groups contained in R ⁵ , and alkoxy, haloalkoxy. , Alkoxyalkoxy, alkylthioalkoxy, alkenyloxy, noloalkenyloxy, alkynyloxy, haloalkynyloxy, cycloalkyloxy, cycloalkenyloxy, aryloxy, heterocyclicoxy, alkylthio, haloalkylthio, alkoxyalkylthio , Alkylthioalkylthio, alkenylthio, haloalkenylthio, alkynylthio, haloalkynylthio, cycloalkylthio, cycloalkenylthio, arylthio, heterocyclic thio, alkylcarbonyloxy, haloalkylcarbonyloxy, alkoxy Alkylcarbonyloxy, alkylthioalkylcarbonyloxy, alkenylcarbonyloxy, amino, loalkenylcarbonyloxy, alkynylcarboxy, haloalkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, arylyl Haloalkenyloxy, heterocyclic calponyloxy, alkoxysulfonyl, haloalkoxysulfonyl, alkoxyalkoxysulfonyl, alkylthioalkoxysulfonyl, alkenyloxysulfonyl, haloalkenyloxysulfonyl, alkynyloxysulfonyl, haloalkynyloxysulfonyl, cycloalkyloxy Xylsulfonyl, cycloalkenyloxysulfonyl, aryloxysulfonyl, heterocyclic oxysulfonyl , Alkylsulfonyloxy, haloalkylsulfonyloxy, alkoxyalkylsulfonyloxy, alkylthioalkylsulfonyloxy, alkenylsulfonyloxy, no, loalkenylsulfonyloxy, alkynylsulfonyloxy, haloalkynylsulfonyloxy, cycloalkylsulfonyl Oxy, cycloalkenylsulfonyloxy, arylsulfonyloxy, heterocyclic sulfonyloxy, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, Heterocyclic amino, Alkyl carbonyl amino, Haloalkylcarbonylamino, Alkoxyalkylcarbonylamino, Alkylthioalkylcarbo Rua Mino, alkenylcarbonylamino, haloalkenylcarbonylamino, alkynylcarbonylamino, haloalkynylcarbonylamino, cycloalkylcarbonylamino, cycloalkenylcarbonylamino, arylcarbonylamino

, Heterocyclic carbonylamino, alkoxycarbonylamino, haloalkoxycarponylamino, alkoxyalkoxycarbonylamino, alkylthioalkoxycarbonylamino, alkenyloxycarbonylamino, haloalkenyloxycarbonylamino, alkynyloxycarbonylamino Mino, haloalkynyloxycarbonylamino, cycloalkyloxyl ponylamino, cycloalkenyloxycarbonylamino, aryloxycarbonylamino, heterocyclic oxylupionylamino, alkylsulfonylamino, haloalkylsulfonylamino, Alkoxyalkylsulfonylamino, alkylthioalkylsulfonylamino, alkenylsulfonylamino, haloalkenylsulfonylamino, alkynyl Sulfonylamino, haloalkynylsulfonylamino, cycloalkylsulfonylamino, cycloalkenylsulfonylamino, arylsulfonylamino, complex ring sulfonylamino, hydroxyamino, alkoxyamino, hydroxyaminocarbonyl, alkoxyamino It may be further substituted with a tertiary substituent such as a carbonyl, halogen atom, nitro group, thiol group, carboxyl group or sulfonic acid group. The number of such substituents may be one, or two or more.When the number of substituents is two or more, the tertiary substituents may be the same or different. Good o

The alkyl moiety, alkenyl moiety, alkynyl moiety, cycloalkyl moiety, cycloalkenyl moiety, aryl moiety and heterocyclic moiety in the aforementioned secondary and tertiary substituents are defined as RR ⁴ and R ⁶ R ⁹ The same ones as mentioned above can be mentioned.

The compound represented by the formula (I) or a salt thereof includes a compound represented by the formula (1-1):

[Wherein, R ² , RR ⁴ and ⁵ are as described above], or a salt thereof, and a compound represented by the formula (I_2):

[Wherein, R ¹ R ² , R ³ , R ⁴ and R ⁶ are as defined above], or a salt thereof.

Further, among the compounds represented by the formula (I) or a salt thereof,

Wherein A is one C ( ⁵ ) = N— group or one CO—N (R ⁶ ) group; R ¹ ′ is a hydrogen atom; R ² ′ and R ³ ′ are each a hydrogen atom or Is a substituted heterocyclic group; or R ² ′ and R ³ ′ together with an N atom are N = CR ⁸ ′ R ⁹ group | R ⁸ ′ is a substituted heterocyclic group (provided that the benzodioxolyl group is R ⁹ is a hydrogen atom, a substituted alkyl group, a substituted alkenyl group, a substituted alkynyl group, a substituted cycloalkyl group, a substituted cycloalkenyl group, or a phenyl group substituted with a haloalkyl group; substitutable Ariru group, a substitutable heterocyclic group, Shiano group, a nitro group, a substitutable an alkoxy group, a substitutable Ariruokishi group or a B- R ⁷ group (B is _{S, SO, S0 2, SO} 3, CO or C0 is _2, R ⁷ is a hydrogen atom, an optionally substituted alkyl group, a substitutable Aruke group, a substitutable alkynyl group, location R ⁴ and R ⁶ may be a hydrogen atom, a substituted alkyl group, a substituted cycloalkyl group, a substituted cycloalkyl group, a substituted aryl group or a substituted heterocyclic group). An alkenyl group, a substituted alkynyl group, a substituted cycloalkyl group, a substituted cycloalkenyl group, a substituted aryl group or a substituted heterocyclic group; R ⁵ is a hydrogen atom or a substituted amino group; 1) When R ² ′ and R ³ ′ are hydrogen atoms at the same time, (2) one of R ² ′ and R ³ ′ is 3-methyl-15-two-row 2,4-dioxopyrimidine The nitropyrimidine derivative represented by the formula (1) or a salt thereof is a novel compound.

Desirable compounds represented by the formula (1 ′) are listed below.

(1) In the formula (Γ), A is one C (R ⁵ ) = N— group or one CO—N is ⁶ ) one group, wherein R ⁵ is a hydrogen atom, an amino group, an alkylamino group or R ⁶ is a hydrogen atom or an alkyl group); R ¹ ′ is a hydrogen atom; R ² ′ and R ³ ′ are each; R ² ′ and R ³ ′ together with N atom N = CR ⁸ ′ R ⁹ group 1 R ^S ′ is a heterocyclic group (excluding benzodioxolyl group) or haloalkyl group which may be substituted with a halogen atom or a haloalkyl group R ⁹ is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group, a heterocyclic group, a cyano group, a nitro group, an alkoxy group, an aryl group. Roxy or one B—R ⁷ (B Is S, a _{_{SO, S0 2, S0 3,}} CO or C 0 _2, R ⁷ is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, Ariru group or a heterocyclic group R ⁴ and R ⁶ are each a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group or a heterocyclic group; and R ⁵ is a hydrogen atom. A compound that is an atom or an amino group.

(2) R ¹ ′ and R ² ′ are hydrogen atoms; R ³ ′ is a substitutable heterocyclic group; R ⁴ is a hydrogen atom or a substitutable alkyl group; R ⁵ is a hydrogen atom, an amino group, A compound of (1), wherein R ⁶ is a hydrogen atom or a displaceable alkyl group;

(3) The compound according to (1) or (2), wherein the substituent of the substitutable heterocyclic group represented by R ³ ′ is a haloalkyl group or a halogen atom.

(4) The compound according to (1), (2) or (3), wherein the substituted heterocyclic group represented by R ³ ′ is a substituted pyridyl group.

(5) The compound according to (1), wherein R ⁸ ′ is a phenyl group substituted with a haloalkyl group, and R ⁹ is a hydrogen atom.

R ⁴ is a hydrogen atom or an alkyl group (1), (2), (3), (4) Or a compound of (5).

(7) The compound according to (1), (2), (3), (4), (5) or (6), wherein R ⁵ is a hydrogen atom or an amino group.

(8) The compound according to (1), (2), (3), (4), (5), (6) or (7), wherein R ⁶ is an alkyl group.

The compound represented by the formula (Γ) includes a compound represented by the formula (1′-1):

Wherein R ^r , R ² ′, R ³ ′, R ⁴ and R ⁵ are as defined above, or a pyrimidine derivative or a salt thereof, and a compound of the formula (I′-I 2):

[Wherein R ^] ′, R ² ′, R ³ ′, R ⁴ and R ⁶ are as defined above] or a pyrimidine derivative or a salt thereof.

Desirable compounds represented by the formula (1′-1) are listed below.

(1) In the formula (Ι′-1), R ¹ ′ and R ² ′ are a hydrogen atom, R ³ ′ is a substituted heterocyclic group, R ⁴ is a hydrogen atom or a substituted alkyl group, Compound when R ⁵ is a hydrogen atom, an amino group, an alkylamino group or a dialkylamino group o

(2) The compound according to (1), wherein the substituent of the substitutable heterocyclic group represented by R ³ ′ is a haloalkyl group or a halogen atom.

(3) The compound according to (1) or (2), wherein the substituted heterocyclic group represented by R ³ ′ is a substituted pyridyl group.

(4) The compound of (1), (2) or (3), wherein R ⁴ is a hydrogen atom or an alkyl group. (5) The compound according to (1), (2), (3) or (4), wherein R ⁵ is a hydrogen atom or an amino group.

Desirable compounds represented by the formula (1′-12) are listed below.

(1) In the formula (1′-1 2), R ¹ ′ and R ² ′ are hydrogen atoms, R ³ ′ is a substituted heterocyclic group, R ⁴ is a hydrogen atom or a substituted alkyl group, A compound in which R ⁶ is a hydrogen atom or a displaceable alkyl group.

(4) The compound according to (1), (2) or (3), wherein R ⁴ is an alkyl group. ,

(5) The compound according to (1), (2), (3) or (4), wherein R ⁶ is an alkyl group. The above-mentioned novel compounds are particularly excellent as effective components of matrix meta-oral proteinase enzyme inhibitors, and are selected from (1) MMP-1, MMP-2, MMP_3, MMP-7 and MMP-9 At least one matrix metallobrotinase enzyme inhibitor, especially MMP-9 enzyme inhibitor; ② angiogenesis inhibitor /, ③ anti-cancer agent; ④ cancer invasion inhibitor; ⑤ cancer metastasis inhibitor; ⑥ treatment for rheumatoid arthritis, etc. Can be used as an active ingredient of a pharmaceutical composition.

The compound of the formula (I) or a salt thereof can be produced by a known method for producing a similar compound or a method analogous thereto.

The production methods 1 to 4 will be exemplified.

OJ recipe 1

Formula (II):

Wherein R ⁴ and Α are as described above, and X is a leaving group such as a halogen atom, an alkylthio group, a benzylthio group, an alkylsulfonyloxy group, an arylsulfonyloxy group, or a dialkylamino group. And a compound represented by the formula (III): NN

R R 3

Wherein RR ² and R ³ are as described above, and Y is hydrogen or an alkali metal element, thereby producing a nitropyrimidine derivative of the formula (I). .

The compound of the formula (II) and the compound of the formula (III), which are the original products of the production method 1, can be produced by a known method or a method analogous thereto.

The reaction of Production Method 1 can be carried out in the presence of a suitable solvent. Specific examples of solvents used include alcohols such as methanol, ethanol, propanol, and butanol; aromatic hydrocarbons such as benzene, toluene, and xylene; pentane, hexane, heptane, petroleum ether, and lignin. , Aliphatic hydrocarbons such as petroleum benzine; ethers such as getyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran, and dioxane; nitriles such as acetonitrile and propionitrile; dimethylformamide, dimethyla Acid amides such as cetamide; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; phosphoric acid amides such as hexamethyl phosphoramide; chloroform, dichloromethane, tetrachloride Carbon, 1,2-dichloroethane Examples thereof include halogenated hydrocarbons and a mixed solvent thereof.

In production method 1, in order to carry out the reaction efficiently, it is desirable to carry out the reaction in the presence of a base. Specific examples of the base used include organic bases such as triethylamine, pyridine, p-methylmorpholine, 1,8-diazabicyclo [5,4,0] -17-p-decane, and p, p-dimethylaniline; lithium Alkali metals such as sodium, sodium and potassium; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metals such as lithium hydrogen carbonate, sodium charcoal, sodium charcoal lj Hydrogen carbonate; hydrides of alkali metal such as lithium hydride, sodium hydride, and lithium hydride; and alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide. The compound of the formula (III) also acts as a base.

The reaction of the production method 1 is generally carried out at a reaction temperature of 130 to 150 ° C, preferably 0 to 150 ° C. The reaction is performed at a reaction temperature of 100 ° C. The reaction time is generally between 0.1 and 48 hours. Further, the compound of the formula (III) can be used in a ratio of 1 to 1.2 equivalents to 1 mol of the compound of the formula (II), but there is no particular disadvantage even if it is used in excess. The various reaction conditions in Production Method 1 can be appropriately combined with each other.

(2) Manufacturing method 2

Formula (IV):

Wherein,; ^3,: R ⁴ and A are as defined above] is represented by the compound of the formula (V): in R ² -Z [wherein, R ² are as defined above, Z is halogen A leaving group such as an atom, an alkylsulfonyloxy group, or an arylsulfonyloxy group], to produce a nitropyrimidine derivative of the formula (I).

Γ3] Manufacturing method 3

Equation (VI):

Wherein RRR ⁴ and A are as defined above. Compound and Formula (VI I): ³ -Z wherein R ³ is as defined above, Z is a halogen atom, alkyl A leaving group such as a sulfonyloxy group or an arylsulfonyloxy group), to produce a nitropyrimidine derivative of the formula (I).

In addition, the compound of the formula (IV) and the compound of the formula (VI), which are the substance of the production methods 2 and 3, can be produced by the method of the production method 1, a known method or a method analogous thereto. The reactions of Production Method 2 and Production Method 3 can be performed in the presence of a suitable solvent. Specific examples include the same solvents as those used in Production Method 1. In order to carry out these reactions efficiently, it is desirable to carry out the reaction in the presence of a base. Specific examples include the same bases as those used in Production Method 1.

The reactions of Production Method 2 and Production Method 3 are generally carried out at a reaction temperature of 130 to 150 ° C, preferably at a reaction temperature of 0 to 100 ° C. The reaction time is generally between 0.1 and 48 hours. The compound of the formula (V) and the compound of the formula (VII) can be used in a proportion of 1 to 1.2 equivalents per 1 mol of the compound of the formula (IV) and the formula (VI). There is no particular disadvantage even when used. The reaction conditions in Production Method 2 and Production Method 3 can be appropriately combined with each other.

Wherein RR ⁴ , R ⁸ , R ⁹ and A are as described above, are included in the compound of the formula (I), wherein R ² and R ³ are N 2 CR together with an N atom. ^This is a compound that forms an ^S R ⁹ group, wherein R ⁸ and R ⁹ are as defined above. This compound can also be produced by the method shown in Production Method 4 below.

C 4J Manufacturing method 4

Formula (VIII)

[Wherein RR ⁴ and A are as described above] and a formula (IX): R ⁸ -CO-R ⁹ [wherein, R ⁸ and R ⁹ are as described above. A method for producing a nitropyrimidine derivative of the formula (1 ′ ″) by reacting the compound with the compound represented by the formula: The compound of the formula (VIII), which is a raw material of the production method 4, is obtained by the method of the production method 1 or a known method. Alternatively, it can be produced by a method corresponding thereto.

The reaction of Production Method 4 can be carried out in the presence of a suitable solvent. Specific examples of the solvent used include the same solvents as those used in Production Methods 1, 2 and 3.

In Production Method 4, in order to carry out the reaction efficiently, it is preferable to carry out the reaction in the presence of a base. Specific examples of the base used include organic bases such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -17-indene, and N, N-dimethylaniline; Alkali metal carbonates such as lithium, sodium carbonate and lithium carbonate; carbonic acid; alkali metal charcoal such as lithium carbonate, sodium sodium and potassium hydrogen carbonate ^! Examples thereof include chlorinated salts.

In production method 4, in order to carry out the reaction efficiently, it is desirable to carry out the reaction in the presence of a dehydrating agent such as molecular sieves. In addition, by using an appropriate solvent, it is possible to remove the components generated by azeotropic distillation out of the reaction system.

The reaction of Production Method 4 is generally carried out at a reaction temperature of 130 to 150 ° C, preferably at a reaction temperature of 0 to 100 ° C. The reaction time is generally between 0.1 and 4 hours. The compound of the formula (IX) can be used in a proportion of 1 to 1.2 equivalents per 1 mol of the compound of the formula (VIII), but there is no particular disadvantage even if it is used in excess. The various reaction conditions in Production Method 4 can be appropriately combined with each other.

The compound of the formula (I) obtained by the method described in the above-mentioned production methods 1 to 4 can be obtained by known means, for example, concentration, concentration under reduced pressure, distillation, fractional distillation, phase transfer, solvent extraction, crystallization, It can be isolated and purified by recrystallization, chromatography and the like.

When the compound of the formula (I) is obtained in a free form, a salt may be formed by a usual method. Further, the compound of the formula (I) may form an inner salt. The compound of the formula (I), its stereoisomer and tautomer alone each show a matrix meta-oral proteinase inhibitory action in any state of a mixture.

The ditropyrimidine derivative of the present invention or a salt thereof has an excellent inhibitory activity on matrix protein mouth proteinase as well as an angiogenesis inhibitor, an anticancer agent, and a cancer infiltration used for treating or preventing cancer and inflammatory diseases. Inhibitors, cancer metastasis inhibitors, chronic Treatment and prevention of joint-related diseases such as rheumatoid arthritis and osteoarthritis rheumatoid arthritis, as well as gingivitis, glomerulonephritis, interstitial nephritis, encephalomyelitis, arteriosclerosis, liver cirrhosis, revascularization of blood vessels Restenosis, diabetic retinopathy, neovascular glaucoma, corneal ulcer, epidermolysis bullosa, intervertebral disc herniation, osteoporosis and other bone resorption diseases, multiple sclerosis, bronchial asthma, Alzheimer's dementia, autoimmune diseases (Crohn's disease As an active ingredient of a pharmaceutical composition useful as an agent for treating or preventing various diseases such as Siggren's disease, etc., a compound represented by the following formula (X) or a salt thereof is also mentioned. Compounds of formula (X), pharmaceutical compositions containing compounds of formula (X) and matrix meta-oral proteinase enzyme inhibitors containing compounds of formula (X) are also within the scope of the present invention.

Equation (X):

Guang N0 ₂

. \

| Enter z

(L) _n

Wherein G is N or CH; L is a hydrogen atom, a halogen atom, a substituted aryl group, a substituted alkyl group or a substituted alkenyl group, n is 1 or 2; In the case where L is a substitutable alkyl group or a substitutable alkenyl group, two L may form a condensed ring.)

The alkyl moiety in the substitutable alkyl group represented by L in the compound represented by the formula (X) is the same as that in the formula (I). ^ To ⁴ and R ^{6 to} R ⁹ are defined similarly. Further, these substituents may be further substituted with the same secondary and tertiary substituents as in the compound of the formula (I). Among these substitutable alkyls, an alkyl group or a haloalkyl group is preferable.

Wherein alkenyl moiety Ariru unit content and in substitutable alkenyl groups in substitutable Ariru group represented by L in the compound represented by (X) is ^1-4 and R ⁶ to R in the formula (I) Defined similarly to what was defined as ⁹ . Further, these substituents may be further substituted with the same secondary and tertiary substituents as in the compound of the formula (I).

Examples of the halogen atom represented by L in the compound represented by the formula (X) include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a chlorine atom or a bromine atom Is desirable.

Desirable compounds represented by the formula (X) are described below.

(1) The compound of the formula (X), wherein G is N or CH, L is a hydrogen atom, a halogen atom, a substituted aryl group or a substituted alkyl group, and n is 1.

Equation (2) is):

(Wherein G is N or CH).

Example

Next, a specific synthesis example of the nitropyrimidine derivative represented by the formula (I) will be described.

Synthesis of 5-Nitro-6- (2- (5-chloro-2-pyridyl) hydrazino) -3H-pyrimidin-4-one

25 ml of methanol was added to 300 mg of 6-chloro-5-nitro-4- (3H) pyrimidone at room temperature, and then 490 mg of 5-chloro-2-pyridylhydrazine was added. Thereafter, the reaction was carried out at room temperature for 1 hour. After the completion of the reaction, the precipitated crystals are collected by filtration, washed with a small amount of methanol, and dried to give 5-nitro-6- (2- (5-chloro-2-pyridyl) having a melting point of 189 ° C (decomposition). 460 mg of hydrazino) -3H-pyrimidin-4-one (Compound No. 2) were obtained.

Synthesis of 2-Amino-5-nitro-6- (2- (5-chloro-2-pyridyl) hydrazino) -3H-pyrimidine-4-one (Compound No.)

10 ml of methanol was added to 340 mg of 2-amino-6-chloro-5-nitro-4- (3H) pyrimidone at room temperature, and then 300 mg of 5-chloro-2-pyridylhydrazine was added. Thereafter, the reaction was carried out at room temperature overnight. After the reaction is completed, the precipitated crystals are collected by filtration, washed with a small amount of methanol, and dried, and the melting point of 2-amino-5-nitro-6- (2- (5-chloro-2- Pyridyl) hydrazino) -3H-pyrimidin-4-one (Compound No. 4) 350 mg was obtained.

<Synthesis example 3> Synthesis of 4-trifluoromethylbenzaldehyde (1,3-dimethyl-5-nitro-2,4-dioxo-6-pyrimidinyl) hydrazone (Compound No. 9)

6-Hydrazino-1,3-dimethyl-5-ditropyrimidine-2,4-dion 40011¾, 330 mg of 4-trifluoroethanol and 8 ml of ethanol were stirred at room temperature for about 2 hours. After the reaction was completed, about 30 mL of water was added, and the precipitated crystals were collected by filtration. It was filtered and washed; water was dried after washing with water, and the melting point was 188 ° C (decomposition).

There were obtained 540 mg of aldehyde (1,3-dimethyl-5-nitro-2,4-dioxo-6-pyrimidinyl) hydrazone (Compound No. 9).

Synthesis of 3_nitromethyl-6-phenyl [1,2,41triazolo [4,3-a] pyridine (Compound No. 12)

To 868 mg of N- (l- (methylthio) -2-nitrothethenyl) methanesulfonamide was added 17 ml of ethanol at room temperature, and then 795 mg of 5-phenyl-2-pyridylhydrazine was added. Thereafter, the reaction was carried out for 30 minutes while heating under reflux. After completion of the reaction, the mixture was cooled to room temperature, and the precipitated crystals were purified by a silica gel column (methanol: ethyl acetate = 2: 1 distillation) to give 3-nitromethyl-6-phenyl having a melting point of 191 ° C (decomposition point). 231 mg of [1,2,4] triazolo [4,3-a] pyridine (Compound No. 12) were obtained.

The compounds of the formula (I) produced by the methods according to Synthesis Examples 1 to 3 and Production Methods 1 to 4 are shown in Tables 1 and 2 below.

table 1

Compound No. Structural formula Physical properties

1 Melting point 206 ° C (decomposition)

2 Melting point 189 ° C (decomposition)

, Table 2

Table 3 below shows the compound of the above formula (X) and analogous compounds thereof produced by a method according to Synthesis Example 4.

Table 3

The compound represented by the formula (I), the formula (Γ), the formula (1 ″) or the formula (X) or a salt thereof has an inhibitory effect on a matrix meta-oral proteinase enzyme, in particular, ΜΜΡ-1, MMP- 2, MMP- 3, has a MMP- 7, MM P- 9 inhibitory action, among them MM P- 3, MMP - 9 inhibitory action force ^5, are particularly good, MM P- 9 inhibitory action Is the best. Therefore, by using them as active ingredients and, if necessary, combining with the following carriers and the like, the matrix meta-oral proteinase enzyme inhibitor of the present invention is provided. Further, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the formula (I), the formula (Γ), the formula (I ′ ′) or the formula (X) or a salt thereof, and a pharmaceutically acceptable carrier. Is done. When the pharmaceutical composition of the present invention is clinically applied as, for example, an angiogenesis inhibitor, an anticancer agent, a cancer invasion inhibitor, a cancer metastasis inhibitor, a rheumatoid arthritis treatment or prevention agent used for treatment or prevention of cancer or inflammatory diseases. It is preferable to prepare a pharmaceutical composition comprising the above-mentioned active ingredient and a pharmaceutically acceptable carrier and further containing, if necessary, additives such as a diluent, an excipient and a stabilizer.

In the pharmaceutical composition of the present invention, the compounding ratio of the above-mentioned active ingredient to the carrier component is generally 1.0 to 90 WZW. The therapeutically effective dose depends on the administration method, the sex of the patient, body weight, age, target disease, and the like, but is generally 0.1 to 1000 mg Z days / person for adults.

Dosage forms and administration forms may be granules, fine granules, pills, tablets, capsules or liquids, and may be administered orally as raw powders, suppositories, Parenteral administration may be carried out using aerosols or topical preparations such as nasal drops. Injection may be administered intravenously, intramuscularly, subcutaneously, or intraarticularly. It may also be prepared as a powder for injection at the time of use.

Pharmaceutical organic or inorganic, solid or liquid carriers or diluents suitable for oral, enteral or parenteral administration can be used to formulate the pharmaceutical compositions of the invention. Representative carriers or diluents that can be incorporated into tablets, capsules, and the like include acacia, disintegrants such as corn starch and alginic acid, lubricants such as magnesium stearate, and sweeteners such as sucrose and lactose. When the dosage form is a capsule, it may contain, in addition to the above substances, a liquid carrier such as a fatty oil. Various other materials may be used as coatings or as agents to improve the physical form of the dosage unit. For example, it is desirable to dissolve or suspend the active ingredient in an excipient such as water and natural vegetable oils and in a synthetic fat excipient such as ethyl oleate. Buffers such as citrate, acetate and phosphate, and antioxidants such as ascorbic acid, can be incorporated according to accepted pharmaceutical methods.

Next, specific test examples will be described.

Measurement of inhibitory activity against human -9 (gelatinase B)

The inhibitory activity of each compound on human MMP-9 purified enzyme (Chemicon, Code No. CC079) was determined by using a fluorescent peptide substrate (7-methoxycoumarin-4-yl) Acetyl-Pro-Leu-Gly-Leu- ( The method of CG Knight et al. Using 3- [2,4-dinitrophenyl] -Ala_Arg-NH ₂ , manufactured by Pup Laboratories, Inc., Code. 3163-VC) [FEBS Letters, Vol. 296, No. 3, 263-266 (1992)]. Specifically, 180 μl of the MMP-9 enzyme solution, 101 of the compound of the present invention dissolved in DMS0, and 100 μl dissolved in DMS0 were placed on a fluoro Nunc plate (96C) white (No. 437842, manufactured by Nunc). and adding a fluorescent base peptide substrates 10 1 (highest concentration 5 _lambda Micromax), was reacted for 3 hours dark at 37 ° C. After the reaction was completed, the fluorescence intensity was measured (excitation wavelength: 327 mi, fluorescence wavelength: 400 nm) using a wavelength-tunable fluorescent plate reader Sectron FL-2575 (manufactured by Towa Kagaku Co., Ltd.). The MMP-9 enzyme activity is determined by measuring the amount of degradation products after the reaction based on the change in relative fluorescence intensity.The inhibition rate of the enzyme activity by the inhibitor is determined by the relative amount of the inhibitor-added group and the non-added group after the reaction. It was calculated by comparing the fluorescence intensities.

Since MMP-9 exists as an inactive precursor, 150 mM 4-aminophenylmercuric acetate (APMA, Tokyo Chemical Co., Code No. A0395) was added to 1490 μl of a 1 / g / ml enzyme solution in advance. After adding 1 (final concentration 1 mM), the mixture was allowed to stand at 37 ° C for 4 hours to convert to the active form, and then tested for enzyme inhibitory activity. The enzyme was diluted with 50 niM Tris-HCl (pH 7.5) containing 0.1 M NaCl, 10 mM CaCl, 0.05% Brij 35 and 0.02% NaN ₃ . MMP-9 inhibitory activity was measured once or twice each, and the results are shown in Tables 4 to 6. Table 4

MMP-9 inhibitory activity of the compound of formula (I-1)

1 Shiguchi Ύ / JIC ₅ . Value (/ imol / 1)

No. 1st 2nd average

1 10.5 11.6 11.1

2 9.0 9.2 9.1

4 20.0 20.0

7 26.3 28.9 27.6

MMP-9 inhibitory activity of the compound of formula (1-2)

Compound IC _5. Value (molZl)

No. 1st 2nd average

8 16.1 16.1

9 14.8 14.8

MMP-9 Inhibitory Activity Value of Formula (X) and Related Compounds Compound IC ₅ . Value (/ imol / 1)

No. 1st 2nd average

12 6. 1 4. 3 5.2

1 25. 1 20. 0 22. 6

16 14.9 9. 5 12.2

17 13.0 18.4 15.7

18 19.6 13. 7 16. 7

19 17.6 13.3 15.5

Claims

The scope of the claims

Wherein A is one C (R ⁵ ) = N— group or one CO—N (R ⁶ ) — group; R], R ⁴ and R ⁶ are each independently a hydrogen atom, a displaceable alkyl group, A substituted alkenyl group, a substituted alkynyl group, a substituted cycloalkyl group, a substituted cycloalkenyl group, a substituted aryl group or a substituted heterocyclic group; R ² and R ³ are each independently a hydrogen atom, a substituted alkyl group; Group, a substitutable alkenyl group, a substitutable alkynyl group, a substitutable cycloalkyl group, a substitutable cycloalkenyl group, a substitutable aryl group, a substitutable heterocyclic group or one B—R ⁷ group (B is S, S 0, S 0 _2, S 0 _3, a Rei_0 or (0 _2, R ⁷ is a hydrogen atom, an optionally substituted alkyl group, a substitutable alkenyl group, a substitutable alkynyl group, a substitutable cycloalkyl group, a substitutable cycloalkenyl group , Substitutable aryl group or substitutable complex Whether it is a group); or R ² and R ³ are both N = CR ⁸ R ⁹ group with the N atom | R ⁸ and R ⁹ are each independently a hydrogen atom, an optionally substituted alkyl group, a substitutable alkenyl group, A substitutable alkynyl group, a substitutable cycloalkyl group, a substitutable cycloalkenyl group, a substitutable aryl group, a substitutable heterocyclic group, a cyano group, a nitro group, a substitutable alkoxy group, a substitutable aryloxy group or —B—R ⁷ and R ⁷ are the same as those described above). 1 may be formed; R ⁵ is a hydrogen atom or a displaceable amino group.] Or a nitropyrimidine derivative represented by the formula Pharmaceutical composition containing.

2. A matrix meta-oral proteinase enzyme inhibitor comprising the ditropyrimidine derivative or a salt thereof according to claim 1 as an active ingredient.

3. Formula (I-1):

[Wherein, ² , ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1 above], or a nitropyrimidine derivative represented by the following formula or a salt thereof as an active ingredient: Inhibitors.

4. Formula (I_2):

Wherein RR ² , R ³ , R ⁴ and R ⁶ are as defined in claim 1 above, wherein the nitropyrimidine derivative represented by the formula or a salt thereof is used as an active ingredient. Enzyme inhibitor.

5. The matrix meta-oral proteinase according to claim 2, which inhibits at least one matrix metalloproteinase selected from MMP-1, MMP-2, MMP_3, MMP-7 and MMP-9. Enzyme inhibitors.

6. The matrix meta-oral proteinase enzyme inhibitor according to claim 2, wherein the inhibitor inhibits MMP-9.

7. An angiogenesis inhibitor comprising the ditropyrimidine derivative according to claim 1 or a salt thereof as an active ingredient.

8. An anticancer drug comprising the ditropyrimidine derivative or the salt thereof according to claim 1 as an active ingredient.

9. A cancer invasion inhibitor comprising the ditropyrimidine derivative or the salt thereof according to claim 1 as an active ingredient.

10. A cancer metastasis inhibitor comprising the ditropyrimidine derivative or the salt thereof according to claim 1 as an active ingredient.

11. The effective use of the ditropyrimidine derivative or the salt thereof according to claim 1 is described. A therapeutic and prophylactic agent for rheumatoid arthritis.

12. Formula (I '):

Wherein A is one C (R ⁵ ) 2 N— group or one CO—N (R ⁶ ) group; R ¹ ′ is a hydrogen atom; and ² ′ and R ³ ′ are each independently A hydrogen atom or a substituted heterocyclic group; or R ² ′ and R ³ ′ together with an N atom are N 2 CR ⁸ ′ R ⁹ group jR ⁸ ′ is a substituted heterocyclic group (provided that benzodioxolyl group Or a phenyl group substituted with a haloalkyl group; R ⁹ is a hydrogen atom, a substituted alkyl group, a substituted alkenyl group, a substituted alkynyl group, a substituted cycloalkyl group, a substituted cycloalkenyl group, a substituted Yes Ariru group, a substitutable heterocyclic group, Shiano group, a nitro group, a substitutable § alkoxy group, a substitutable Ariruokishi group or a B- R ⁷ group (B is S, SO, S_〇 _2, S0 _3, CO or C0 is _2, R ⁷ is a hydrogen atom, an optionally substituted alkyl group, a substitutable alkenyl group, a substitutable Al A quinyl group, a substitutable cycloalkyl group, a substitutable cycloalkenyl group, a substitutable aryl group or a substitutable heterocyclic group); R ⁴ and each independently represent a hydrogen atom, a substitutable alkyl group; R ⁵ is a hydrogen atom or a substituted amino group; a substituted alkenyl group, a substituted alkynyl group, a substituted cycloalkyl group, a substituted cycloalkenyl group, a substituted aryl group or a substituted heterocyclic group; However, when (1) R ² ′ and R ³ ′ are both hydrogen atoms, then (2) one of R ² ′ and R ³ ′ is 3-methyl-5-two-row 2, 4-— Excluding the case of dioxopyrimidine], or a pyrimidine derivative or a salt thereof

3. Equation (1'-1):

[Wherein, R ¹ ′ R ² ′, R ³ \ R ⁴ and R ⁵ are as defined in the above claim 12], or a salt thereof.

[Wherein, R ¹ ′ R ² ′, R ³ ′, R ⁴ and R ⁶ are as defined in claim 12 above] or a nitropyrimidine derivative or a salt thereof according to claim 12.