JPH09295939A - Phosphoric amide derivative, its production and use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a phosphoric amide derivative having an excellent antibacterial activity based on an excellent anti-urease activity, especially a strong antibacterial activity against bacteria belonging to genus Helicobacter and useful as an antibacterial agent against the bacteria belonging to genus Helicobacter for a prophylaxis and a treatment of a peptic disease. SOLUTION: An antibacterial agent against bacteria belonging to genus Helicobacter, especially Helicobacter pylori includes a compound of formula I [R is a (substituted) amino group] or its pharmacologically acceptable salt, and an antacid or a retarder of an acid secretion. N-(diaminophosphinyl)-2- thiophencarbonamide, etc., are exemplified as the compound of formula I. A compound of formula II R' is a (substituted) heterocyclic group [with the proviso that a (substituted) furyl, pyridyl or 3-amino-2-oxo-1-azetidinyl is removed], etc.} among the compounds of formula I is obtained by reacting a compound of formula III or its salt with ammonia.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a phosphoric acid amide derivative, a process for producing the same, and use thereof. More specifically, the present invention provides excellent antibacterial activity based on excellent anti-urease activity, especially Helicobacter pylori.
The present invention relates to a phosphoric acid amide derivative having strong antibacterial activity against Helicobacter spp.

[0002]

BACKGROUND OF THE INVENTION Bacteria which have a toxic effect in the digestive tract, such as Helicobacter pylori, are known as Helicobacter (Helico).
bacter) is a Gram-negative microaerobic bacterium belonging to the genus
It has been suggested that it may be a major cause of recurrence of gastritis, duodenal ulcer, gastric ulcer and the like. Helicobacter spp., In particular Helicobacter pylori, is said to exhibit strong urease activity and to produce ammonia from urea, thereby neutralizing the strong acidity around the bacteria in the stomach and enabling them to survive. ing. For the treatment of various diseases caused by this Helicobacter pylori, currently, a two-drug combination of a bismuth preparation and an antibiotic, a bismuth preparation, metronidazole (US Patent No. 2,944,061) and tetracycline (for example, US Patent No. 2,712,517) or amoxicillin. Chemotherapy is being performed by combining three drugs such as (US Pat. No. 3,192,198). The above-mentioned metronidazole is an imidazole derivative having an anti-Helicobacter pylori effect, and is used in combination with an antibiotic. These bismuth preparations, antibiotics, metronidazole, and the like are administered in the form of oral administration. However, the above-mentioned bismuth preparations, antibiotics, metronidazole and the like need to be administered in large amounts per day in order to maintain a sufficient concentration at the growth site to prevent the growth of Helicobacter pylori,
As a result, there are many problems such as side effects such as vomiting and diarrhea. On the other hand, a phosphoric acid amide derivative having an anti-urease activity is known (US Pat. No. 3,317,637,
US Patent 4,517,003, US Patent 4,528,020, EP210
703, U.S. Pat.No. 4,182,881, U.S. Pat.No. 4,221,730, JP-A-58-99490, JP-B-42-7379, U.S. Pat.
No., J. Pharm. Sci., 189, 57 (1968)), it is not known that the phosphoric acid amide derivative shows an antibacterial action in vivo, particularly an anti-Helicobacter action. .

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a phosphoramide derivative or a salt thereof having excellent antibacterial activity, particularly strong antibacterial activity against Helicobacter spp. Such as Helicobacter pylori, and anti-Helicobacter containing the same. It is intended to provide a genus fungus agent.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies in view of the above problems, and as a result, have found that bacteria (eg, Helicobacter spp., Such as Helicobacter pylori) that have toxic effects in the digestive tract. As a result, they found that a phosphoric acid amide derivative having an urease-inhibiting action had a strong anti-Helicobacter action in vivo, and further studied to complete the present invention. That is, the present invention provides (1) a compound represented by the general formula (I):

Embedded image [Wherein R represents an amino group which may be substituted] or a pharmaceutically acceptable salt thereof, and an anti-Helicobacter pylori containing an antacid or an acid secretion inhibitor An agent, (2) a combination preparation in which a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof and an antacid or an acid secretion inhibitor are packaged, (3) the general formula (IA):

Embedded image [In the formula, R'is (a) an optionally substituted heterocyclic group (provided that it may have an optionally substituted furyl, an optionally substituted pyridyl, and an optionally substituted 3-amino- 2-oxo-1-azetidinyl), (b) a hydrocarbon group substituted by an optionally substituted heterocyclic group (excluding phenyl substituted by an optionally substituted maleimide), ( c) a substituted phenoxy substituted hydrocarbon group, (d) an optionally substituted heterocyclic thio substituted hydrocarbon group, or (e) an optionally substituted arylsulfonylamino Or a salt thereof, wherein (4)
General formula (IA '):

Embedded image [In the formula, R ″ is halogen, cyano, formyl, lower (C _1-3 ) alkyl optionally substituted with halogen, lower (C _1-3 ) alkoxy optionally substituted with halogen, halogen May be substituted with (lower (C _1-3 ))
An alkoxy) carbonyl and a furyl or pyridyl group having 1 to 3 substituents selected from lower (C _1-3 ) alkylsulfonyl optionally substituted with halogen] or a salt thereof. , (5) General formula (IIIA):

Embedded image [Wherein R'is as defined above] or a salt thereof is reacted with ammonia; IIIA '):

Embedded image [Wherein R ″ is as defined above] or a salt thereof is reacted with ammonia, and relates to a process for producing a compound represented by the general formula (IA ′) or a salt thereof.

In the above general formula, examples of the substituent of the “optionally substituted amino group” represented by R include (1) an acyl group, (2) a carboxyl group which may be esterified, ( 3) An optionally substituted hydrocarbon group and the like may be mentioned, and these substituents may be the same or different and may be substituted with one or two (preferably one) amino groups. As the substituent, an acyl group or a carboxyl group which may be esterified is preferable.
More preferably, an acyl group is used.

(1) The acyl group as a substituent of the "optionally substituted amino group" represented by R includes carboxylic acid, thiocarboxylic acid, sulfonic acid, sulfinic acid, carbamic acid, thiocarbamic acid and the like. And an acyl group derived from, for example, each of the general formulas -COR
_{^{1, -CSR 2, -SO 2 R}} 3, -SOR 4, -CONHR 5
Or —CSNR ⁶ [R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group], and the like. And the like. The acyl group is preferably ^one derived from a carboxylic acid (—COR ¹ ), ^one derived from a sulfonic acid (—SO ₂ R ³ ), and more preferably one derived from a carboxylic acid.

The hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is a saturated or unsaturated aliphatic chain. Examples thereof include a hydrocarbon group, a saturated or unsaturated alicyclic hydrocarbon group, and an aryl group. As the saturated aliphatic hydrocarbon group, for example, a linear or branched saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.- Butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.-pentyl, hexyl, isohexyl,
A C _1-10 alkyl group such as heptyl and octyl), and preferably a straight-chain or branched saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. Examples of the unsaturated aliphatic hydrocarbon group include linear or branched unsaturated aliphatic hydrocarbon groups having 2 to 10 carbon atoms (eg, ethenyl,
-Propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl,
1-pentenyl, 2-pentenyl, 3-pentenyl, 4
-Pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-
C such as hexenyl, 1-heptenyl and 1-octenyl
_2-10 alkenyl groups, such as ethynyl, 1-propynyl, 2
-Propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, And a C _2-10 alkynyl group such as -heptynyl and 1-octynyl), and preferably a straight-chain or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms.
Examples of the saturated alicyclic hydrocarbon group include a saturated alicyclic hydrocarbon group having 3 to 12 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1]). Heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.
1] monocyclic or bicyclic such as octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, etc. Cyclic C _3-12 cycloalkyl group), and preferably a saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms. The unsaturated alicyclic hydrocarbon group has 5 to 5 carbon atoms.
12 unsaturated alicyclic hydrocarbon groups and the like (eg, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3
-Cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-
Cyclohexen-1-yl, 3-cyclohexen-1-
A C _5-12 cycloalkenyl group such as yl;
4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadiene-
C _5-12 such as 1-yl, 2,4-cycloheptadienyl
Cycloalkadienyl group). Further, as the hydrocarbon group of the "optionally substituted hydrocarbon group",
A saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms and substituted with the above-mentioned saturated or unsaturated alicyclic hydrocarbon group (eg, C
Specifically, for example, _3-7 cycloalkyl-C _1-8 alkyl or C _5-7 cycloalkenyl-C _1-8 alkyl,
Cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptyl Methyl, cycloheptylethyl, etc.). Examples of the aryl group include a monocyclic or condensed polycyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms. Examples of the aromatic hydrocarbon ring group include phenyl, 1- or 2-naphthyl, 1-, 2- or 9-anthryl, 1-, 2-, 3
-, 4- or 9-phenanthryl, 1-, 2-, 4
-, 5- or 6-azulenyl, acenaphthylenyl. Among them, phenyl, 1-naphthyl, C _6-10 aryl, such as 2-naphthyl preferred.

The hydrocarbon group in the “optionally substituted hydrocarbon group” may have 1 to 3 optional substituents at substitutable positions. As the substituent, (1)
Optionally substituted lower alkyl group, (2) optionally substituted lower alkoxy group, (3) optionally substituted aryl group, (4) optionally substituted lower cycloalkyl group or cyclo Alkenyl group, (5) optionally substituted heterocyclic group, (6) optionally esterified carboxyl group, (7) optionally substituted carbamoyl group, (8) optionally substituted. Amino group, (9) optionally substituted hydroxyl group, (10) optionally substituted thiol (mercapto) group, (11)
Examples thereof include an acyl group, (12) halogen (eg, fluorine, chlorine, bromine, etc.), (13) nitro, (14) cyano and the like. Examples of the lower alkyl group of the optionally substituted lower alkyl group (1) include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, And C _1-6 alkyl groups such as hexyl and isohexyl. Examples of the lower alkoxy group of the optionally substituted lower alkoxy group (2) include:
Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, tert.-butoxy, pentoxy, isopentoxy, neopentoxy,
Examples thereof include C _1-6 alkoxy groups such as hexyloxy and isohexyloxy. The lower alkyl group (1) and the lower alkoxy group (2) may have 1 to 3 substituents at substitutable positions. Examples of the substituent include halogen (eg, fluorine, chlorine) , Bromine, etc.) and lower (C _1-3 ) alkoxy (eg, methoxy, ethoxy, propoxy, etc.). Examples of the aryl group of the optionally substituted aryl group (3) include a C _6-14 aryl group such as phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, among which phenyl, 1-naphthyl and 2- Naphthyl and the like are preferred. Examples of the cycloalkyl group of the optionally substituted lower cycloalkyl group (4) include C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkenyl group of the optionally substituted lower cycloalkenyl group (4) includes C _3-6 such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.
And cycloalkenyl groups. The aryl group (3), lower cycloalkyl group (4) or lower cycloalkenyl group (4) has 1 to 5, preferably 1 to 3 optional substituents at substitutable positions. As the substituent, an alkoxy group (eg, C _1-3 alkoxy such as methoxy, ethoxy, propoxy, etc.);
Examples thereof include a halogen atom (eg, fluorine, chlorine, bromine, iodine), an alkyl group (eg, C _1-3 alkyl such as methyl, ethyl, propyl), an amino group, a nitro group and a cyano group.

The heterocyclic group of the optionally substituted heterocyclic group (5) has at least one heteroatom of oxygen, sulfur and nitrogen as an atom (ring atom) constituting a ring system. Examples thereof include an aromatic heterocyclic group, a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group), and an aromatic heterocyclic group is preferable. Examples of the aromatic heterocyclic group include a 5- to 7-membered aromatic heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom, and a 5- to 6-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms. And a 5- to 6-membered aromatic heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur atom or oxygen atom, and the like, and these aromatic heterocyclic groups are 2 or less nitrogen atoms. And a benzene ring or a 5-membered ring containing one sulfur atom. Examples of the aromatic heterocyclic group include, for example, an aromatic monocyclic heterocyclic group (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1, 2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.) and aromatic condensed heterocyclic groups (eg, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1
H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, Phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolinidinyl Pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a]
Pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1, 2,4-triazolo [4,3-b] pyridazinyl and the like), but furyl, condensed furyl, thienyl, condensed thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, azolyl or a condensed ring group thereof is preferable. . Examples of the azolyl group include a 5-membered aromatic heterocyclic group containing 1 to 4 nitrogen atoms (eg, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl), 1 to 2 nitrogen atoms and 1 sulfur atom or oxygen. 5-membered aromatic heterocyclic group containing an atom (eg, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl) and the like, and examples of the condensed azolyl group include a benzene ring and a 5-membered aromatic heterocyclic ring containing 1 to 2 nitrogen atoms. A group formed by condensation of (eg, benzimidazolyl, etc.), a group formed by condensation of a benzene ring and a 5-membered aromatic heterocycle containing one nitrogen atom and one sulfur atom or oxygen atom (example , Benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisoxazolyl, etc.) and the like. Among them, frills, thienyl,
Indolyl, isoindolyl, pyrazinyl, pyridyl,
Pyrimidinyl, benzofuranyl, benzimidazolyl,
Benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzo [b] thienyl, oxazolyl, isoxazolyl and the like are preferred, and furyl and thienyl are more preferred. As the non-aromatic heterocyclic group, a 5- to 7-membered non-aromatic heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom or one nitrogen atom and three or less hetero atoms (eg, nitrogen, A 3-7 membered non-aromatic heterocyclic group containing (oxygen, sulfur atom), for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl,
Examples include piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidyl, pyrrolinyl, imidazolidinyl and the like. The non-aromatic heterocyclic group includes a benzene ring, 6 or less nitrogen atoms.
It may be condensed with a membered ring or a five-membered ring containing one sulfur atom. Examples of the condensed non-aromatic heterocyclic group include chromanyl, isochromanyl, indolinyl, isoindolinyl, thiochromanyl, and isothiochromanyl. . The heterocyclic group may have 1 to 3 optional substituents at substitutable positions.
An alkoxy group (eg, C _1-4 alkoxy such as methoxy, ethoxy, propoxy) which may be substituted by three halogen atoms (eg, fluorine, chlorine, bromine, iodine), a halogen atom (eg, fluorine, chlorine) , Bromine, iodine), 1
An alkyl group optionally substituted by three halogen atoms (eg, fluorine, chlorine, bromine, iodine) (eg, methyl,
C _1-4 alkyl such as ethyl and propyl), and aryl group (eg, C such as phenyl, 1-naphthyl and 2-naphthyl)
_6-10 aryl), a nitro group and the like.

The carboxyl (6) which may be esterified includes a carboxyl group, (lower (C _1-6 )
Alkoxy) carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.-butoxycarbonyl, sec.-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxy) Carbonyl,
tert.-pentyloxycarbonyl, hexyloxycarbonyl, etc.), (C _6-10 aryl) oxycarbonyl (eg, phenoxycarbonyl, 1-naphthoxycarbonyl, etc.), (C _7-10 aralkyl) oxycarbonyl (eg, benzyloxy) Such as carbonyl (phenyl-C
_1-4 alkyloxy) carbonyl and the like. Among them, carboxyl group, methoxycarbonyl group,
An ethoxycarbonyl group is preferred. Examples of the substituent of the optionally substituted carbamoyl group (7) and the optionally substituted amino group (8) include, for example, an optionally substituted lower (C _1-6 ) alkyl (eg, methyl ,
Ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc., an optionally substituted C _3-6 cycloalkyl group (eg, cyclopropyl , Cyclobutyl, cyclopentyl, cyclohexyl, etc.), optionally substituted C
_6-10 aryl group (eg phenyl, 1-naphthyl, 2-naphthyl etc.), optionally substituted C _7-12 aralkyl group (eg phenyl-C _1-4 such as benzyl and phenethyl)
Alkyl, naphthyl-C _1-2 alkyl, etc.), and an optionally substituted C _6-10 arylsulfonyl group (eg, benzenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl, etc.) and the like. The groups may be the same or different and may be substituted by 1 or 2.
The optionally substituted lower (C _1-6 ) alkyl, the optionally substituted C _3-6 cycloalkyl group, the _optionally substituted C _6-10 aryl group, the _optionally substituted C
_The substituent in the _7-12 aralkyl group and the _optionally substituted C _6-10 arylsulfonyl group may be a halogen (eg, fluorine, chlorine, bromine, etc.), or may be substituted with 1 to 3 halogen atoms. A good alkoxy group (eg C _1-4 alkoxy such as methoxy, ethoxy, propoxy, etc.), 1
Alkyl groups (e.g., C _1-4 alkyl such as methyl, ethyl, propyl, etc.) which may be substituted with 3 to 3 halogen atoms, and nitro groups. Good. In the amino group which may be substituted, two substituents on the nitrogen atom may be combined with the nitrogen atom to form a cyclic amino group. Examples of such a cyclic amino group include , 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl and the like.

Examples of the substituent in the optionally substituted hydroxyl group (9) and the optionally substituted thiol group (10) include, for example, an optionally substituted hydrocarbon group and an optionally substituted hydrocarbon group. And a heterocyclic group.
The “optionally substituted hydrocarbon group” is the same as the “optionally substituted hydrocarbon group” defined for R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 above.} Preferably, for example, lower (C _1-6 ) alkyl which may be substituted (eg, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec.-butyl, te
rt.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl and the like, an optionally substituted C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like),
An optionally substituted C _6-10 aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.) and an optionally substituted C _7-12 aralkyl group (eg, phenyl-C such as benzyl, phenethyl and the like) _1-4 alkyl, naphthyl-C _1-2 alkyl, etc.). The lower (C _1-6 ) alkyl, C _3-6 cycloalkyl group, C _6-10 aryl group and C _7-12 aralkyl group have 1 to 5 substituents at any substitutable position. The substituent may be a halogen (eg, fluorine, chlorine, bromine, etc.), an alkoxy group optionally substituted with 1 to 3 halogen atoms (eg,
C _1-4 alkoxy such as methoxy, ethoxy, propoxy, etc.) and an alkyl group optionally substituted by 1 to 3 halogen atoms (eg, C _1-4 such as methyl, ethyl, propyl, etc.)
Alkyl), nitro, amino, cyano and the like.
Examples of the “optionally substituted heterocyclic group” include “optionally substituted heterocyclic group” defined by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ described below. Similar ones can be mentioned. Examples of the acyl group (11) include formyl,
A carbonyl group substituted with an optionally substituted hydrocarbon group, a sulfinyl group substituted with an optionally substituted hydrocarbon group, a sulfonyl group substituted with an optionally substituted hydrocarbon group, and the like. Can be As the “optionally substituted hydrocarbon group”, the aforementioned R ¹ , R ² ,
Examples include the same as the “optionally substituted hydrocarbon group” defined for R ³ , R ⁴ , R ⁵ and R ⁶ , but preferably, for example, optionally substituted lower (C _{1 -6} )
An alkyl group, an optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _6-10 aryl group (eg, phenyl, naphthyl, etc.), an optionally substituted C _7-12
Aralkyl groups (eg, phenyl-C _1-4 alkyl, naphthyl-C _1-2 alkyl, etc.); The acyl group is preferably a formyl group, (C _1-6 alkyl) carbonyl group, (C _3-6 cycloalkyl) carbonyl group, (C _6-10 aryl) carbonyl group, (C _7-12 aralkyl) Carbonyl group, (C _1-6 alkyl) sulfinyl group, (C _3-6 cycloalkyl) sulfinyl group, (C
_6-10 aryl) sulfinyl group, (C _7-12 aralkyl)
A sulfinyl group, a (C _1-6 alkyl) sulfonyl group,
(C _3-6 cycloalkyl) sulfonyl group, (C _6-10 aryl) sulfonyl group and (C _7-12 aralkyl) sulfonyl group. These acyl groups may have 1 to 5 substituents at any substitutable position. Examples of the substituent include a halogen atom and an alkoxy group (eg, C
_1-4 alkoxy group) and an alkyl group (eg, C _1-4 alkyl group).

As the heterocyclic group in the “optionally substituted heterocyclic group” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , an atom constituting a ring system (ring atom ) Includes an aromatic heterocyclic group having at least one heteroatom among oxygen, sulfur, and nitrogen, and a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group), and is preferably an aromatic heterocyclic group. Group heterocyclic group. Examples of the aromatic heterocyclic group include a 5- to 7-membered aromatic heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom, and a 5- to 5-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms.
A 6- or 6-membered aromatic heterocyclic group or a 5- or 6-membered aromatic heterocyclic group containing 1 or 2 nitrogen atoms and 1 sulfur atom or oxygen atom, and the like. 2
It may be condensed with a 6-membered ring containing not more than nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom. Examples of the aromatic heterocyclic group include, for example, an aromatic monocyclic heterocyclic group (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,
4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.) and aromatic condensed heterocyclic groups (eg, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, In drill, iso in drill, 1H-
Indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, Naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-
Carbolinyl, β-carbolinyl, γ-carbolinyl,
Acridinyl, phenoxazinyl, phenothiazinyl,
Phenazinyl, phenoxathiinyl, thianthrenyl,
Phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] Pyridyl, imidazo [1,2
-B] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl,
1,2,4-triazolo [4,3-b] pyridazinyl etc.)
But frills, thienyl, indolyl,
Isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, azolyl or a condensed ring group thereof are preferable, and among them, furyl, thienyl, indolyl, isoindolyl,
Pyrazinyl, pyridyl, pyrimidinyl, benzofuranyl, benzimidazolyl, benzoxazolyl, 1,2
-Benzoisoxazolyl, benzothiazolyl, benzo [b] thienyl, oxazolyl, isoxazolyl and the like are preferred, and furyl and thienyl are more preferred.

The non-aromatic heterocyclic group includes a 5- to 7-membered non-aromatic heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom or one nitrogen atom and three or less heteroatoms (eg, , Nitrogen, oxygen, sulfur atoms) containing 3 to 7 membered non-aromatic heterocyclic groups such as oxiranyl, azetidinyl,
Oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidyl, pyrrolinyl, imidazolidinyl and the like. The non-aromatic heterocyclic group is a benzene ring, 2
May be condensed with a 6-membered ring containing not more than one nitrogen atom or a 5-membered ring containing one sulfur atom, and the condensed non-aromatic heterocyclic group may be chromanyl, isochromanyl, indolinyl, isoindolinyl, thiochromanyl, Isothiochromanil and the like.

The heterocyclic group in the “optionally substituted heterocyclic group” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ may be any substituent at a substitutable position. 1 to 4
It may have one, preferably 1 to 3. Examples of the substituent include (i) an optionally substituted lower alkyl group, (ii) an optionally substituted lower alkoxy group,
(Iii) optionally substituted aryl group, (iv) optionally substituted lower cycloalkyl group or cycloalkenyl group, (v) optionally substituted heterocyclic group,
(Vi) an optionally esterified carboxyl group,
(Vii) an optionally substituted carbamoyl group, (vii
i) optionally substituted amino group, (ix) optionally substituted hydroxyl group, (x) optionally substituted thiol group, (xi) acyl group, (xii) halogen (eg, fluorine, chlorine , Bromine, etc.), (xiii) nitro, (xiv) cyano and the like. The optionally substituted lower alkyl group (i) and the optionally substituted lower alkoxy (i
i), optionally substituted aryl group (iii), optionally substituted lower cycloalkyl group or cycloalkenyl group (iv), optionally substituted heterocyclic group (v), esterified Carboxyl group (v
i), an optionally substituted carbamoyl group (vii), an optionally substituted amino group (viii), an optionally substituted hydroxyl group (ix), an optionally substituted thiol group (x) and Examples of the acyl group (xi) include those represented by the substituents in the “optionally substituted hydrocarbon group” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 above.} Similar ones can be cited.

Among the above, R ¹ , R ² , R ³ , R ⁴ , R
^{As 5} and R ⁶ , an optionally substituted alkyl group (preferably C _1-4 alkyl, etc.), an optionally substituted alkenyl group (eg, preferably C _2-4 alkenyl, etc.), _Optionally substituted aryl group (preferably C _6-10 aryl such as phenyl, 1-naphthyl and 2-naphthyl), and optionally substituted aromatic heterocyclic group (preferably furyl, benzofuranyl, thienyl, benzothienyl, Indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, azolyl, condensed azolyl, etc.)
Is preferred. The alkyl group, alkenyl group, and aryl group may have 1 to 3 (preferably, 1 to 2) arbitrary substituents at substitutable positions. Is (1) a lower (C _1-3 ) alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.) which may be substituted by 1 to 3 halogens (eg, fluorine, chlorine, bromine, iodine, etc.) ), (2) low grade (C
_1-3 ) _1-3 (preferably, selected from alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), (3) halogen (eg, fluorine, chlorine, bromine, iodine), amino, nitro and cyano Is a _C6-10 aryl group _optionally substituted with 1 to 2 substituents (e.g.,
Selected from lower (C _1-3 ) alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), halogen (eg, fluorine, chlorine, bromine, iodine), nitro, cyano and amino 1-3
C _6-10 aryloxy (eg, phenoxy and the like) which may be substituted with (preferably 1 to 2) substituents,
(5) A heterocyclic group (eg, thienyl, benzimidazolyl, benzoxa) which may be substituted with 1 to 3 (preferably 1 to 2) halogens (eg, fluorine, chlorine, bromine, iodine, etc.) Zolyl), (6) an amino group optionally substituted with p-toluenesulfonyl,
(6) C _6-10 optionally substituted with 1 to 3 (preferably 1 to 2) substituents selected from hydroxyl group, (8) halogen atom and lower (C _1-3 ) alkoxy group
It may be substituted with a thiol group which may be substituted with an aryl group, or 1 to 3 (preferably 1 to 2) substituents selected from a halogen atom and a lower (C _1-3 ) alkoxy group. A heterocycle (eg, benzoxazolyl,
Examples thereof include a thiol group optionally substituted with benzothiazolyl, etc., (9) halogen (eg, fluorine, chlorine, bromine, etc.), (10) nitro, (11) cyano and the like. The aromatic heterocyclic group may have 1 to 3 (preferably 1 to 2) arbitrary substituents at substitutable positions, but the substituent is preferably ( 1) 1-3
Lower (C _1-3 ) alkyl groups _optionally substituted with ₁ halogen (eg, methyl, ethyl, propyl, isopropyl, fluoromethyl, chloromethyl, etc.), (2) C
_6-10 aryl group (eg, phenyl, etc.), (3) lower (C _1-3 ) alkoxy optionally substituted by 1 to 3 halogens (eg, methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy) , Chloromethoxy, etc.),
(4) Halogen (eg, fluorine, chlorine, bromine, etc.),
(5) nitro, (6) cyano, (7) (lower (C _1-6 ).
Examples thereof include an alkyl) carbonyl group and a (8) (C _1-6 alkyl) sulfonyl group.

(2) The hydrocarbon group in the "optionally substituted hydrocarbon group" as the substituent of the "optionally substituted amino group" represented by R is the above-mentioned R ¹ ,
Examples are the same as those described for the hydrocarbon group in the “optionally substituted hydrocarbon group” for R ² , R ³ , R ⁴ , R ⁵ and R ⁶ . The hydrocarbon group may have 1 to 3 optional substituents at substitutable positions. As the substituent, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted aryl group, an optionally substituted lower cycloalkyl group or a cycloalkenyl group, Optionally substituted heterocyclic group, optionally esterified carboxyl group, optionally substituted carbamoyl group, optionally substituted amino group, optionally substituted hydroxyl group, optionally substituted And thiol group, acyl group, halogen (eg, fluorine, chlorine, bromine, etc.), nitro, cyano and the like. The optionally substituted lower alkyl group, optionally substituted lower alkoxy, optionally substituted aryl group, optionally substituted lower cycloalkyl group or cycloalkenyl group, optionally substituted Heterocyclic group, optionally esterified carboxyl group, optionally substituted carbamoyl group, optionally substituted amino group, optionally substituted hydroxyl group, optionally substituted thiol group and acyl As the group, R ¹ , R ² , and
The same groups as those represented by the substituents in the “optionally substituted hydrocarbon group” represented by R ³ , R ⁴ , R ⁵ and R ⁶ can be mentioned.

(3) Examples of the "optionally esterified carboxyl group" as a substituent of the "optionally substituted amino group" represented by R include, for example, the general formula -C.
OOR ⁷ [R ⁷ represents hydrogen or an optionally substituted hydrocarbon or heterocyclic group]. Examples of the hydrocarbon group include R ¹ , R ² , R ³ , R ⁴ ,
The same as those described for the hydrocarbon group in the “optionally substituted hydrocarbon group” for R ⁵ and R ⁶ can be mentioned. The hydrocarbon group may have 1 to 3 optional substituents at substitutable positions. As the substituent, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted aryl group, an optionally substituted lower cycloalkyl group or a cycloalkenyl group, Optionally substituted heterocyclic group, optionally esterified carboxyl group, optionally substituted carbamoyl group, optionally substituted amino group, optionally substituted hydroxyl group, optionally substituted And thiol group, acyl group, halogen (eg, fluorine, chlorine, bromine, etc.), nitro, cyano and the like. The optionally substituted lower alkyl group, optionally substituted lower alkoxy, optionally substituted aryl group, optionally substituted lower cycloalkyl group or cycloalkenyl group, optionally substituted Heterocyclic group, optionally esterified carboxyl group, optionally substituted carbamoyl group, optionally substituted amino group, optionally substituted hydroxyl group, optionally substituted thiol group and acyl Examples of the group are "optionally substituted hydrocarbon groups" represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 above.}
The same as those represented by the substituents in are mentioned.

Examples of the heterocyclic group include R ¹ , R ² and
The same as the heterocyclic group in the “optionally substituted heterocyclic group” for R ³ , R ⁴ , R ⁵ and R ⁶ can be mentioned. The heterocyclic group may have 1 to 3 optional substituents at substitutable positions. As the substituent, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted aryl group, an optionally substituted lower cycloalkyl group or a cycloalkenyl group, Optionally substituted heterocyclic group, optionally esterified carboxyl group, optionally substituted carbamoyl group, optionally substituted amino group, optionally substituted hydroxyl group, optionally substituted And thiol group, acyl group, halogen (eg, fluorine, chlorine, bromine, etc.), nitro, cyano and the like. The optionally substituted lower alkyl group, optionally substituted lower alkoxy, optionally substituted aryl group, optionally substituted lower cycloalkyl group or cycloalkenyl group, optionally substituted Heterocyclic group, optionally esterified carboxyl group, optionally substituted carbamoyl group,
The amino group which may be substituted, the hydroxyl group which may be substituted, the thiol group which may be substituted and the acyl group may be the above R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 respectively.} The same as those represented by the substituents in the "optionally substituted hydrocarbon group" represented by are mentioned. R ⁷ is an optionally substituted lower (C
_1-6 ) alkyl, lower (C _3-6 ) cycloalkyl, C _6-10
Aryl or a C _7-12 aralkyl group is preferable, and a lower (C _1-3 ) alkyl is more preferable.
The lower (C _1-6 ) alkyl is, for example, methyl,
Examples thereof include ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl and isohexyl. Examples of the lower (C _3-6 ) cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of the C _6-10 aryl group include phenyl, 1-naphthyl,
2-naphthyl and the like can be mentioned. Examples of the C _7-12 aralkyl group include phenyl-C _1-4 alkyl such as benzyl and phenethyl, and naphthyl-C _1-2 alkyl. The lower (C _1-6 ) alkyl, lower (C _3-6 ) cycloalkyl group, C _6-10 aryl group and C _7-12 aralkyl group have 1 to 3 substituents at any substitutable position. May have one, and as the substituent, halogen (eg,
Fluorine, chlorine, bromine, etc.) and the like.

In the general formula (I), R is
Preferably, a group represented by the formula R ¹ —CO—NH— or R ³ —SO ₂ —NH— [in the formula, R ¹ and R ³ have the same meanings as described above], more preferably, The group shown by the former is mentioned. Among the compounds represented by the general formula (I) above, among the compounds represented by the formula (IA)

Embedded image [In the formula, R'is (a) an optionally substituted heterocyclic group (provided that it may have an optionally substituted furyl, an optionally substituted pyridyl, and an optionally substituted 3-amino-2. -Oxo-1-azetidinyl) [referred to as group Ra], (b) hydrocarbon group substituted by an optionally substituted heterocyclic group (provided that it is phenyl substituted by an optionally substituted maleimide) Except) [referred to as a group Rb],
(C) Substituted phenoxy-substituted hydrocarbon group [referred to as group Rc], (d) optionally substituted heterocyclic thio-substituted hydrocarbon group [referred to as group Rd], or (e ) A compound represented by an alkyl group which is substituted with an optionally substituted arylsulfonylamino [indicated by a group Re]] or a formula (IA ')

Embedded image [In the formula, R ″ is halogen, cyano, formyl, 1 to 3
Lower halogen atom (eg, fluorine, chlorine, bromine, iodine) optionally substituted with lower (C _1-3 ) alkyl (eg, methyl, ethyl, propyl, etc.), 1 to 3 halogen atoms (eg, fluorine) , Lower (C _1-3 ) alkoxy optionally substituted with chlorine, bromine, iodine) (eg, methoxy, ethoxy, propoxy, etc.), 1 to 3 halogens (eg, fluorine, chlorine, bromine, iodine) Optionally substituted with (lower (C _1-3 ) alkoxy) carbonyl (eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl etc.) and 1 to 3 halogens (eg fluorine, chlorine, bromine, iodine). Optionally substituted lower (C
_1-3 ) represents a furyl or pyridyl group having 1 to 3 substituents selected from alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.)] is more preferable.

In the formula (IA), the heterocyclic group of the “optionally substituted heterocyclic group” defined by Ra is the above R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ The same as the heterocyclic group in the "optionally substituted heterocyclic group" shown in, but preferably thienyl (eg, 2- or 3-thienyl), azolyl [eg, oxazolyl (eg. , 2-, 4- or 5-oxazolyl),
Isoxazolyl (eg, 3-, 4- or 5-isoxazolyl) and the like], thienyl or azolyl condensed ring group [eg, benzothienyl (eg, 2- or 3-benzo [b] thienyl etc.), benzoxazolyl ( Example 2
-, 5- or 6-benz [d] oxazolyl),
Examples thereof include benzothiazolyl (eg, 2-benzo [d] thiazolyl, etc.) and condensed furanyl groups [eg, benzofuranyl (eg, 2- or 3-benzo [b] furanyl), etc.). The heterocyclic group in the “optionally substituted heterocyclic group” defined by Ra has 1 to 3 (preferably 1 to 3) optional substituents at substitutable positions.
2). Examples of the substituent include those similar to the substituents in the “optionally substituted heterocyclic group” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^6. Preferably, a lower (C _1-3 ) alkyl group (eg, methyl, ethyl, propyl, isopropyl, fluoro) which may be substituted with 1 to 3 halogens (eg, fluorine, chlorine, bromine, iodine, etc.) Methyl, chloromethyl, etc.), C _6-10 aryl group (eg, phenyl, etc.), 1 to 3 halogens (eg, fluorine, chlorine, bromine,
Lower (C _1-3 ) alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, chloromethoxy and the like) which may be substituted with iodine), halogen (eg, fluorine, chlorine, bromine and the like), Nitro, cyano, (C _1-6 alkyl) carbonyl group, (C _1-6
Alkyl) sulfonyl group and the like. Ra is preferably an optionally substituted thienyl group, and C
_A thienyl group which may be substituted with _1-3 alkyl group is more preferable.

The hydrocarbon group of the "hydrocarbon group substituted with an optionally substituted heterocyclic group" defined by Rb is R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Examples thereof include the same hydrocarbon group as the “optionally substituted hydrocarbon group” represented by R ⁶ . The hydrocarbon group has at least one heterocyclic group which may be substituted at a substitutable position, and examples of the heterocyclic group which may be substituted include R ¹ and R ² described above. , R ³ , R ⁴ , R ⁵ and R ⁶
The same as the "optionally substituted heterocyclic group" shown as the substituent of the "optionally substituted hydrocarbon group" shown in. The hydrocarbon group, in addition to the optionally substituted heterocyclic group, at a substitutable position,
Although it may have any substituent, the total number of substituents in the hydrocarbon group is preferably 1 to 3 (preferably 1).
~ 2). As the substituent, R ¹ , R ² , R
^{The same} groups as those represented by the substituents of the “optionally substituted hydrocarbon group” represented by ³ , R ⁴ , R ⁵ and R ⁶ can be mentioned. Rb is an optionally substituted aromatic heterocycle [eg, thienyl (eg, 2- or 3-thienyl), furyl (eg, 2- or 3-furyl), azolyl [eg, oxazolyl (eg, 2- , 4- or 5-oxazolyl), isoxazolyl (eg, 3-, 4- or 5
-Isoxazolyl) etc.], thienyl, furyl or azolyl condensed ring group [benzothienyl (eg, 2- or 3-benzo [b] thienyl etc.), benzofuranyl (eg, 2- or 3-benzo [b] furanyl etc.) , Benzoxazolyl (eg, 2-, 5- or 6-benz [d] oxazolyl etc.), benzisoxazolyl (eg, 3-, 4- or 5-benz [d] isoxazolyl), benzothiazolyl ( Example, 2-benzo [d]
Thiazolyl, etc.), benzimidazolyl (eg, 1-benz [d] imidazolyl, etc.], etc.]] are more preferable, and more preferably, they are substituted with an optionally substituted thienyl or furyl group. It is a hydrocarbon group. The hydrocarbon group is preferably C _1-10 alkyl (preferably C _1-3 alkyl such as methyl, ethyl or propyl), C _2-10 alkenyl group (preferably C _2- such as ethenyl). ₄ Alkenyl etc.) and the like. The aromatic heterocyclic group may have 1 to 3 arbitrary substituents at substitutable positions, and as the substituent, preferably 1 to 3 halogens (eg, fluorine, Lower (C _1-3 ) alkyl group _optionally substituted with chlorine, bromine, iodine (eg, methyl, ethyl, propyl, isopropyl, fluoromethyl, chloromethyl, etc.), C _6-10 aryl group (eg, , Phenyl, etc.), 1-3
Lower (C _1-3 ) alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, chloromethoxy, etc.) optionally substituted with one halogen (eg, fluorine, chlorine, bromine, iodine), halogen (Eg,
Fluorine, chlorine, bromine, iodine and the like), nitro and the like. The hydrocarbon group may have a substituent such as cyano in addition to the optionally substituted aromatic heterocyclic group.

The "substituted phenoxy-substituted hydrocarbon group" defined by Rc may be substituted with 1 to 3 halogens (eg, fluorine, chlorine, bromine, iodine, etc.). Alkoxy (eg, C _1-3 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, etc.), nitro, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), cyano, amino and 1 to 3 halogens (eg. , Fluorine, chlorine, bromine, iodine, etc.), optionally substituted with 1 to 3 substituents selected from alkyl groups (eg, C _1-3 alkyl such as methyl, ethyl, propyl, isopropyl, etc.) And a hydrocarbon group substituted with a substituted phenoxy group. The hydrocarbon group of the "hydrocarbon group substituted by a substituted phenoxy group" defined by Rc is "hydrocarbon group substituted by an optionally substituted heterocyclic group" defined by Rb above. And the same hydrocarbon groups as those mentioned above. The hydrocarbon group is preferably a lower (C _1-6 ) alkyl group. In addition to the substituted phenoxy group, the hydrocarbon group may further have 1 or 2 optional substituents at substitutable positions. Examples of the substituent include R ¹ , R ² and
Examples thereof include those similar to the substituents of the “optionally substituted hydrocarbon group” represented by R ³ , R ⁴ , R ⁵ and R ⁶ .

The hydrocarbon group of the "hydrocarbon group substituted with an optionally substituted heterocyclic thio" defined by Rd above includes R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Examples thereof include the same hydrocarbon group as the “optionally substituted hydrocarbon group” represented by R ⁶ . The hydrocarbon group has at least one "optionally substituted heterocyclic thio group" at a substitutable position, and is substituted in the "optionally substituted heterocyclic thio group". The heterocyclic ring which may be present is represented by the “optionally substituted hydrocarbon group” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 above.} The same as "the heterocyclic group which may be substituted" is mentioned. The hydrocarbon group may further have an optional substituent at a substitutable position in addition to the optionally substituted heterocyclic thio group, but the total number of the substituents in the hydrocarbon group is It is preferably 1 to 3 (preferably 1 to 2). The substituent may be the above R
^{The same} groups as those represented by the substituents of the “optionally substituted hydrocarbon group” represented by ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ can be mentioned. Rd is an optionally substituted aromatic heterocycle [eg, thienyl (eg, 2- or 3
-Thienyl), furyl (eg 2- or 3-furyl),
Azolyl [eg, oxazolyl (eg, 2-, 4- or 5
-Oxazolyl), isoxazolyl (eg, 3-, 4-
Or 5-isoxazolyl) and the like], thienyl, furyl or azolyl condensed ring group [benzothienyl (eg,
2- or 3-benzo [b] thienyl, etc.), benzofuranyl (eg, 2- or 3-benzo [b] furanyl, etc.), benzoxazolyl (eg, 2,-, 5- or 6-).
Benz [d] oxazolyl, etc.), benzisoxazolyl (eg, 3-, 4- or 5-benzo [d] isoxazolyl), benzothiazolyl (eg, 2-benzo [d] thiazolyl, etc.), benzimidazolyl (eg. , 1
-Benz [d] imidazolyl etc.) etc.] etc.] and a hydrocarbon group substituted with a thiol (mercapto) group substituted. The hydrocarbon group is preferably C
_Examples thereof include _1-10 alkyl (preferably C _1-3 alkyl such as methyl, ethyl and propyl), C _2-10 alkenyl group (preferably C _2-4 alkenyl such as ethenyl) and the like. The aromatic heterocyclic group of the optionally substituted aromatic heterocyclic group may have 1 to 3 (preferably 1 to 2) arbitrary substituents at substitutable positions, The substituent is preferably a lower (C _1-3 ) alkyl group which may be substituted with 1 to 3 halogens (eg, methyl, ethyl, propyl, isopropyl, etc.), C _6-10
Aryl group (eg, phenyl, etc.), lower (C _1-3 ) alkoxy optionally substituted by 1 to 3 halogens (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), halogen (eg, fluorine, Chlorine, bromine, iodine, etc.), nitro and the like.

As the "alkyl group substituted with optionally substituted arylsulfonylamino" defined by Re above, optionally substituted C _6-10 aryl (eg, phenyl, naphthyl, etc.) sulfonylamino And C _1-10 alkyl substituted with (preferably C _1-3 alkyl such as methyl, ethyl, propyl, etc.) and the like. The "alkyl group substituted with optionally substituted arylsulfonylamino" has 1 to 1 substituents at substitutable positions.
It may have 3 (preferably 1 to 2) arbitrary substituents, and the substituents are, for example, lower (C _1-3 which may be substituted with 1 to 3 halogens). ) Alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.), C _6-10 aryl group (eg, phenyl, etc.), 1 to 3
Lower (C _1-3 ) alkoxy optionally substituted with 1 halogen (eg methoxy, ethoxy, propoxy, isopropoxy etc.), halogen (eg fluorine, chlorine, bromine, iodine etc.), nitro etc. To be

In the formula (IA), R'is preferably C optionally substituted with 1 to 3 halogens.
_1-3 alkyl, C _1-3 alkoxy, halogen atom, nitro, cyano, (C _1-6 alkyl) carbonyl and (C
Examples thereof include a thienyl group which may be substituted with 1 to 3 (preferably 1 to 2) substituents selected from _1-6 alkyl) sulfonyl, and more preferably substituted with a C _1-3 alkyl group. And optionally a thienyl group. In the formula (IA ′), R ″ is preferably a furyl group substituted with halogen (eg, fluorine, chlorine, bromine, iodine, etc.). Further, as R ″, a furyl group substituted with C _1-3 alkyl is preferable. The salt of the compound represented by formula (I), (IA) or (IA ') in the present invention is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, Examples thereof include salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt. Preferred examples of the salt with an organic base include:
Examples thereof include ammonium salts, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, and salts with N, N′-dibenzylethylenediamine. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be These salts can be obtained according to a conventional method. Further, hydrates and non-hydrates of the compounds represented by formula (I), (IA) or (IA ') are also included in the scope of the present invention. In addition, as the salts of the compounds represented by the general formulas (II) and (III) shown below, those similar to the salts shown as the salts of the compounds represented by the above general formula (I) can be mentioned. .

The production method of the compound in the present invention is described below. For example, a compound or a salt thereof obtained by reacting a compound represented by the formula (II) RH (II) [wherein the symbols have the same meanings as above] or a salt thereof with phosphorus pentachloride, and formic acid And the resulting compound of the formula (I
II)

Embedded image The target compound can be produced by reacting a compound represented by the formula: [wherein the symbols have the same meaning as defined above] or a salt thereof with ammonia. Also, for example, by reacting the compound represented by the formula (II) or a salt thereof with phosphorus oxychloride, and reacting the obtained compound represented by the formula (III) or a salt thereof with ammonia The compound can be obtained. Formula (II)
In the reaction of the compound represented by or a salt thereof with phosphorus pentachloride or phosphorus oxychloride, as a solvent, a halogen-based solvent such as carbon tetrachloride, chloroform, cyclochloromethane, 1,2-dichloroethane, dioxane, tetrahydrofuran, Ether solvents such as diethyl ether,
Any solvent that does not interfere with the reaction, such as a hydrocarbon solvent such as benzene or toluene, may be used, and the reaction temperature is usually about −.
It is 50 to 100 ° C, preferably about -20 to 80 ° C. Further, with respect to 1 mol of the compound represented by the formula (II) or a salt thereof, phosphorus pentachloride or phosphorus oxychloride is usually used in an amount of 0.5 to 10 molar equivalents, preferably 1 to 2 molar equivalents. When the compound represented by the formula (II) or a salt thereof is reacted with phosphorus pentachloride and the compound or a salt thereof is reacted with formic acid, the solvent used is the same halogen-based solvent or ether as described above. A system solvent and a hydrocarbon solvent can be used, and the reaction temperature is usually about -50 to 50.
C, preferably about 0 to 30C. The formic acid used is usually 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to 1 mole of the compound obtained by reacting the compound represented by formula (II) or a salt thereof with phosphorus pentachloride. To use. In the reaction of the compound represented by the formula (III) or a salt thereof with ammonia, the same halogen-based solvent, ether-based solvent or hydrocarbon-based solvent as described above can be used, and the reaction temperature is usually about -50 to. 50 ° C, preferably
It is about -20 to 10 ° C.

The compound (I) or a salt thereof thus obtained is isolated by known means such as concentration, concentration under reduced pressure, distillation, fractional distillation, solvent extraction, chromatography, crystallization and recrystallization. It can be purified. In each of the above reactions, a protecting group may be used for an amino group, a carboxyl group, or a hydroxy group that does not participate in the reaction or a salt thereof, and addition and removal of the protecting group are known. Can be performed by the following means. Examples of the amino-protecting group include formyl, C _1-6 alkylcarbonyl (e.g., acetyl, propionyl, etc.), each of which may have a substituent, phenylcarbonyl, C _1-6 alkyl-oxycarbonyl ( For example, methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C _7-10 aralkyloxy-carbonyl (eg, phenyl-C _1-4 alkyloxy-carbonyl such as benzyloxycarbonyl), trityl, phthaloyl or N, N -Dimethylaminomethylene and the like are used. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, valeryl, etc.), a nitro group, etc. are used. The number of groups is about 1 to 3. The protecting group for the carboxyl group may be, for example, a C _1-6 alkyl _optionally having a substituent (for example, methyl, ethyl, propyl, isopropyl, butyl, tert.
-Butyl etc.), phenyl, trityl or silyl and the like are used. Examples of these substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl,
(Propionyl, valeryl, etc.), nitro group, etc. are used, and the number of substituents is about 1 to 3. Examples of the protecting group for the hydroxyl group include C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl, etc.), phenyl, C _7-10 Aralkyl (eg, phenyl-C _1-4 alkyl such as benzyl), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), phenyloxycarbonyl, benzoyl, (C _7-1
0 aralkyloxy) carbonyl (eg, phenyl-C _1-4 alkyloxy-, such as benzyloxycarbonyl)
Carbonyl etc.), pyranyl, furanyl or silyl and the like are used. Examples of these substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C
_1-6 alkyl (eg, methyl, ethyl, propyl, etc.), phenyl, C _7-10 aralkyl (eg, phenyl such as benzyl-C _1-4 alkyl, etc.), nitro group, etc. are used, and the number of substituents is It is about 1 to 4. As a method for removing the protecting group, a method known per se or a method analogous thereto is used. For example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride And a method of treating with palladium acetate or the like.

The Helicobacter genus agent in the present invention is
Containing a compound represented by the general formula (I), (IA) or (IA ') or a pharmaceutically acceptable salt thereof (hereinafter collectively referred to as a compound represented by the general formula (I) or a salt thereof) It is characterized by doing. The agent of the genus Helicobacter in the present invention can be produced according to the known means for producing a pharmaceutical preparation, except that it contains the compound represented by the general formula (I) or a salt thereof. The Helicobacter spp. Agent in the present invention can be used orally, parenterally, by inhalation method, rectal injection, or topical administration,
For example, it can be used as powders, granules, tablets, pills, capsules, injections, syrups, emulsions, elixirs, suspensions, solutions, etc., and they are represented by at least one general formula (I). The represented compound or a salt thereof can be used alone or in combination with a pharmaceutically acceptable carrier. When compounded with a carrier, the content of the compound represented by the general formula (I) or a salt thereof may be appropriately selected depending on the preparation, but is usually 1 to 100% by weight, preferably 1 to 20% by weight. %. As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances that are commonly used as a formulation material are used. Excipients, lubricants, binders, disintegrants in solid formulations; solvents and solubilizing agents in liquid formulations , A suspending agent, a tonicity agent, a buffering agent, a soothing agent, etc. are appropriately mixed in appropriate amounts. If necessary, appropriate amounts of pharmaceutical additives such as preservatives, antioxidants, coloring agents, sweeteners and the like can be used as appropriate. Preferred examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferred examples of the binder include, for example, crystalline cellulose, sucrose, D-mannitol,
Dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like can be mentioned. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.

Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine,
Examples thereof include sodium carbonate and sodium citrate. Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol ,
Examples include hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Suitable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like. Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include benzyl alcohol and the like. Suitable examples of preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,
Examples include sorbic acid. Preferable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

The pharmaceutical composition can be formulated according to a conventional method. In this specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion and the like. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as an aqueous solution. As the vehicles or solvents that can be used, water,
Examples thereof include Ringer's solution and isotonic saline solution. In addition, sterile, fixed oils may be conventionally employed as a solvent or suspending medium. For this purpose, any non-volatile oil and fatty acid can be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono- or di- or triglycerides. Suppositories for rectal administration consist of the drug and suitable nonirritating excipients, such as cocoa butter and polyethylene glycols, which are solid at room temperature but liquid at intestinal temperature and melt in the rectum. Can be manufactured by mixing with a substance that emits.

Examples of solid dosage forms for oral administration include powders, granules, tablets, pills, capsules and the like described above. In such dosage forms, the active ingredient compound may comprise at least one additive, such as sucrose,
Lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein,
It can be mixed with albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms may also comprise, as usual, further additives, such as inert diluents, lubricants such as magnesium stearate, parabens, preservatives such as sorbic acid, ascorbic acid, Examples include antioxidants such as α-tocopherol and cysteine, disintegrants, binders, thickeners, buffering agents, sweeteners, flavoring agents, perfumes and the like. Tablets and pills can also be prepared with enteric coating. The liquid for oral administration is
Examples include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which may contain inert diluents commonly used in the art, such as water. The anti-Helicobacter agent of the present invention may be an enteric preparation (preferably an oral enteric preparation).

The dose for a particular patient depends on age, weight,
It may be determined according to general health conditions, sex, diet, administration time, administration method, excretion rate, drug combination, the degree of the medical condition of the patient being treated at the time, and other factors. The compound represented by the general formula (I) or a salt thereof exhibits an antibacterial activity due to urease inhibitory activity, particularly an anti-Helicobacter genus activity, and can be used in mammals (eg, humans, dogs, cats, monkeys, rats, mice, etc.) It is useful for the prevention or treatment of digestive diseases such as gastritis, duodenal ulcer, gastric ulcer, and chronic gastritis which are considered to be caused by Helicobacter spp. In recent years, the correlation between Helicobacter spp., In particular, Helicobacter pylori and gastric cancer is large, and it is useful for prevention of gastric cancer and the like. Further, the compound represented by the general formula (I) or a salt thereof has low toxicity and can be used safely. Since the anti-Helicobacter agent of the present invention has an anti-Helicobacter effect, it exhibits an anti-Helicobacter effect against, for example, a Helicobacter that exerts a toxic effect in the digestive tract. The gastrointestinal tract includes, for example, stomach, duodenum and the like. Helicobacter species that have a toxic effect in the digestive tract include Helicobacter pylori. The dose of the anti-Helicobacter agent of the present invention is
The compound represented by the general formula (I) or a salt thereof is appropriately selected depending on the type and symptom of the disease, but the oral administration of the compound represented by the general formula (I) or a salt thereof is about 0.1 in an adult patient (50 kg) with gastric ulcer or duodenal ulcer. -10 g / day, preferably 0.2
2 g / day, about 0.01-1 g / day for parenteral administration,
Preferably 0.02 to 0.5 g / day can be administered. The dose for one dose is determined in consideration of such a daily dose and a dosage form. The frequency of administration is not particularly limited, but is preferably 1 to 5 times / day, more preferably 1 to 3 times / day.

The agent of the genus Helicobacter of the present invention prevents the decomposition of the compound represented by the general formula (I) or a salt thereof, which is an active ingredient thereof, by an acid under acidic conditions such as gastric environment. An antacid, an acid secretion inhibitor, etc. may be contained. Examples of the antacid include:
Examples thereof include aluminum hydroxide gel, sodium bicarbonate, aminoacetic acid, aluminum silicate, magnesium aluminometasilicate, magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium carbonate and calcium carbonate. Examples of the acid secretion inhibitor include a proton pump inhibitor and a histamine H ₂ blocker. The proton pump inhibitor refers to a drug that suppresses acid secretion by directly or indirectly inhibiting H / K-ATPase that functions as a proton pump in acid-secreting cells (parietal cells) of the gastric mucosa. . Examples include lansoprazole, omeprazole, pantoprazole, paliprazole sodium, reminoprazole,
TY-11345, TU-199, FPL-6537
2, BY-686, tannic acid (Tannic acid), ellagic acid (Ellagic acid), Ebselen (Ebselen), AH
R-9294, Cassigarol-A, Bafilomycin, Y-25942, Xantho
angelol E, SKF-96356, Epigallocatechin ga
llate, WY-27198, T-330 or SK &
F-20054 etc. are mentioned.

In particular, examples of the proton pump inhibitor include benzimidazole compounds and the like. The benzimidazole compounds have a proton pump inhibitory action and have low toxicity. As the benzimidazole compound, for example, 2-[(pyridyl) -methylsulfinyl or -methylthio] benzimidazole or a derivative thereof and a salt thereof are preferable. More preferably, a compound represented by the following general formula (α) and a salt thereof can be mentioned.

[Chemical 21] In the formulas, A ring may be substituted, R ^b is a hydrogen atom, an alkyl group, an acyl group, a carboalkoxy group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group or an alkylsulfonyl group, R ^c, R ^e
And R ^g are the same or different and each represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkoxy group;
^d is a hydrogen atom, an alkyl group, or a group of the formula -OR ^f or -S
R represents a group represented by R ^f (wherein, R ^f represents a hydrocarbon group which may have a substituent), and q represents 0 or 1, respectively. The benzimidazole compounds are described in, for example, JP-A-52-6
2275, JP-A-54-141783, JP-A-57-53406, JP-A-58-13588
No. 1, JP-A-58-192880, JP-A-5-192880
JP-A-9-181277, JP-A-61-50978, JP-A-62-116576, JP-A-62-2
77322, JP-A-62-258320,
JP-A-62-258316, JP-A-64-627
0, JP-A-64-79177, and JP-A-5-79177.
59043, JP-A-62-111980,
JP-A-5-117268, European Patent Publication 166287, European Patent Publication 51936.
No. 5 publication.

In the above general formula (α), when the ring A is substituted, examples of the substituent include a halogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, and a substituted group. Optionally substituted alkenyl group, optionally substituted alkoxy group, cyano group, carboxy group, carboalkoxy group, carboalkoxyalkyl group, carbamoyl group, carbamoylalkyl group, hydroxy group, hydroxyalkyl group, acyl group, carbamoyl Examples thereof include an oxy group, a nitro group, an acyloxy group, an aryl group, an aryloxy group, an alkylthio group and an alkylsulfinyl group. Hereinafter, each of the above substituents will be described. As a halogen atom,
Fluorine, chlorine, bromine, iodine and the like can be mentioned. Of these, fluorine and chlorine are preferred. Further, fluorine is particularly preferred. Examples of the alkyl group in the alkyl group which may be substituted include linear or branched ones having 1 to 10 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl) Tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.). Among them, a linear or branched one having 1 to 6 carbon atoms is preferable. Further, a linear or branched one having 1 to 3 carbon atoms is preferable. Examples of the substituent of the alkyl group include a halogen, a nitro, an amino group (which may have one or two substituents such as an alkyl group and an acyl group), a cyano group, a hydroxyl group, a carboxyl group, and an amidino. Group, guanidino group, carbamoyl group and the like.

The cycloalkyl group in the optionally substituted cycloalkyl group has, for example, 3 to 7 carbon atoms.
Cyclalkyl group. Specific examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The cycloalkyl group may have a substituent, for example, halogen, nitro,
Examples include an amino group (which may have one or two substituents such as an alkyl group and an acyl group), a cyano group, a hydroxyl group, a carboxyl group, an amidino group, a guanidino group, and a carbamoyl group. The alkenyl group in the alkenyl group which may be substituted is, for example, a linear or branched alkenyl group having 2 to 16 carbon atoms. Specific examples of the alkenyl group include, for example, allyl (ally
l), vinyl, crotyl, 2-penten-1-yl, 3-
Penten-1-yl, 2-hexen-1-yl, 3-hexen-1-yl, 2-methyl-2-propen-1-yl, 3-methyl-2-buten-1-yl and the like. Among them, a linear or branched alkenyl group having 2 to 6 carbon atoms is preferable. Further, a linear or branched alkenyl group having 2 to 4 carbon atoms is preferable. The alkenyl group may have a substituent, and examples of the substituent include a halogen, a nitro, an amino group (an alkyl group, an acyl group, etc.
It may have up to 2 substituents. ), Cyano group,
Examples thereof include amidino group and guanidino group. The alkenyl group includes isomers (E, Z isomers) related to the double bond. Examples of the alkoxy group in the optionally substituted alkoxy group include an alkoxy group having 1 to 10 carbon atoms. Specific examples of the alkoxy group include:
For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,
tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy and the like. Among them, an alkoxy group having 1 to 6 carbon atoms is preferable. Further, an alkoxy group having 1 to 3 carbon atoms is particularly preferred. The alkoxy group may have a substituent, as the substituent,
For example, a halogen, a nitro, an amino group (may have one or two substituents such as an alkyl group and an acyl group),
C _6-10 aryl groups such as amidino group, guanidino group, C _1-4 alkoxy group, phenyl, naphthyl (halogen, C
_1-4 substituents such as alkyl group, C _1-4 alkoxy group, etc.
May be present).

Examples of the halogen of the substituent on the above alkyl group, cycloalkyl group, alkenyl group and alkoxy group include chlorine, bromine, fluorine and iodine. As the alkyl group in the alkylamino group which is a substituent on the alkyl group, cycloalkyl group, alkenyl group and alkoxy group, for example, a linear or branched alkyl group having 1 to 6 carbon atoms is preferable. Specific examples thereof include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-
Butyl, n-pentyl, isopentyl, n-hexyl, isohexyl and the like. Among them, a linear or branched alkyl group having 1 to 4 carbon atoms is particularly preferred. Examples of the acyl group in the acylamino group which is a substituent on the alkyl group, cycloalkyl group, alkenyl group and alkoxy group include an acyl group derived from an organic carboxylic acid. Among them, an alkanoyl group having 1 to 6 carbon atoms is preferable. Specific examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like. Among them, an alkanoyl group having 1 to 4 carbon atoms is particularly preferred. The number of substituents on the alkyl, cycloalkyl, alkenyl and alkoxy groups is 1 to 6, preferably 1 to 3.

Specific examples of the substituted alkyl group include:
For example, trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, methoxyethyl, ethoxyethyl, 1-methoxyethyl, 2-
Methoxyethyl, 2,2-dimethoxyethyl, 2,2-diethoxyethyl, 2-diethylphosphorylethyl and the like can be mentioned. Of these, difluoromethyl, trifluoromethyl and hydroxymethyl are preferred. Further, trifluoromethyl is particularly preferred. Specific examples of the substituted cycloalkyl group include, for example, 2-aminocyclopropan-1-yl, 4-hydroxycyclopentane-1
-Yl, 2,2-difluorocyclopentan-1-yl and the like. Specific examples of the substituted alkenyl group include, for example, 2,2-dichlorovinyl, 3-hydroxy-2-propen-1-yl, 2-methoxyvinyl and the like. Specific examples of the substituted alkoxy group include, for example, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-methoxyethoxy, 4-chlorobenzyloxy, 2- (3,4-dimethoxyphenyl).
Examples include ethoxy and the like. Of these, difluoromethoxy is preferred.

The alkoxy group of the carboalkoxy group (alkoxycarbonyl group) has 1 to 7 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy). , N-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy and the like). The alkoxy group of the carboalkoxyalkyl group (alkoxycarbonylalkyl group) has 1 to 4 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, se)
The alkyl group of c-butoxy, tert-butoxy and the like has 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-
Butyl, tert-butyl, etc., and examples thereof include carbomethoxymethyl (methoxycarbonyl), 2
-Carbomethoxyethyl (2-methoxycarbonylethyl), 2-carbomethoxypropyl (2-methoxycarbonylpropyl), carboethoxymethyl (ethoxycarbonylmethyl), 2-carboethoxyethyl (2-ethoxycarbonylethyl), 1-carbo Methoxypropyl (1-methoxycarbonylpropyl), carbopropoxymethyl (propoxycarbonylmethyl), carbobutoxymethyl (butoxycarbonylmethyl) and the like can be mentioned. Examples of the alkyl group of the carbamoylalkyl group include those having 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.).

The alkyl group of the hydroxyalkyl group has 1 to 7 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl). , Neopentyl, hexyl, heptyl, etc.). Examples of the acyl group of the acyl group and the acyloxy group include alkanoyl groups each having 1 to 4 carbon atoms, and examples thereof include, for example, formyl, acetyl, propionyl,
Butyryl, isobutyryl and the like. The aryl group of the aryl group and the aryloxy group has 6 carbon atoms.
To 12 (eg, phenyl, naphthyl, etc.). The alkyl group of the alkylthio group and the alkylsulfinyl group each have 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, Isopentyl, neopentyl, hexyl, etc.). The number of substituents on the substituted ring A is preferably from 1 to 4, more preferably from 1 to 2. Examples of the position of the substituent on the benzene ring include positions 4 and 5 (positions 4 and 5 of the benzimidazole skeleton), with position 5 being preferred. Preferred examples of the ring A include a halogen atom, an alkyl group which may be substituted, a cycloalkyl group which may be substituted, an alkenyl group which may be substituted or an alkoxy group which may be substituted. A benzene ring which may be The alkyl group represented by R ^b has 1 to 5 carbon atoms (eg, methyl,
Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and the like, and acyl groups having 1 to 4 carbon atoms (eg, 1 carbon atoms) And alkanoyl groups such as alkanoyl group to alkoxycarboxy group (alkoxycarbonyl group) are those having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, etc.), and alkylcarbamoyl. As the alkyl of the group and the dialkylcarbamoyl group, the alkyl has 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.) Examples of the alkyl of the alkylsulfonyl group include those having 1 to 4 carbon atoms described above. As R ^b , hydrogen is preferable.

The alkyl group represented by R ^c , R ^e or R ^g is a linear or branched one having 1 to 10 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl,
n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like). Among them, straight or branched ones having 1 to 6 carbon atoms, particularly straight or branched ones having 1 to 3 carbon atoms are preferable. The alkoxy group represented by R ^c , ^Re or R ^g has 1 to 10 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Isobutoxy, sec-butoxy, tert-butoxy, n-
Pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, etc.). Among them, an alkoxy group having 1 to 6 carbon atoms is preferable. Further, an alkoxy group having 1 to 3 carbon atoms is particularly preferred. The alkoxy of the alkoxyalkoxy group represented by R ^c , ^Re or R ^g has 1 to 4 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
sec-butoxy, tert-butoxy, etc.). R ^c
Of these, a hydrogen atom, an alkyl group and an alkoxy group are preferable. The R ^e a hydrogen atom, an alkyl group, an alkoxy group are preferred. R ^g is preferably a hydrogen atom. Examples of the alkyl group represented by R ^d include those having 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.). Examples of the hydrocarbon group of the hydrocarbon group which may have a substituent represented by R ^f include a hydrocarbon group having 1 to 13 carbon atoms, for example, a linear or branched hydrocarbon group having 1 carbon atom.
To 6 alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.) and alkenyl groups having 2 to 6 carbon atoms (eg, vinyl, allyl, 2-butenyl) , Methyl allyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl, etc.), an alkynyl group having 2 to 6 carbon atoms (eg, ethynyl, propargyl, 2-butyn-1)
-Yl, 3-butyn-2-yl, 1-pentyn-3-yl, 3-pentyn-1-yl, 4-pentyn-2-yl, 3-hexyn-1-yl, etc.), having 3 to 6 carbon atoms. A cycloalkyl group (eg, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, etc.), carbon number 3-6
Cycloalkenyl group (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.), an aralkyl group having 7 to 13 carbon atoms (eg, benzyl,
1-phenethyl, 2-phenethyl, etc.), 6 to 1 carbon atoms
0 aryl groups (eg, phenyl-C _1-6 alkyl groups such as phenyl and naphthyl, naphthyl-C _1-3 alkyl groups, etc.) and the like. Among them, a linear or branched alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.) is preferable. Further, a linear or branched alkyl group having 1 to 4 carbon atoms is preferable.

Examples of the substituent in the hydrocarbon group having a substituent include a C _6-10 aryl group (eg, phenyl, naphthyl etc.), amino, and a C _1-6 alkylamino group (eg,
Methylamino, ethylamino, isopropylamino, etc.), di C _1-6 alkylamino group (eg, dimethylamino, diethylamino, etc.), N—C _7-14 aralkyl-N
-C _3-6 cycloalkylamino (eg, N-benzyl-N
N- (C _6-10 aryl-, such as cyclohexylamino
C _1-4 alkyl) -NC _3-6 cycloalkylamino, etc., NC _7-14 aralkyl-NC _1-6 alkylamino (eg, N- (1-naphthylmethyl) -N-ethyl N- (C _6-10 aryl-C _1-4 alkyl) -N such as amino
-C _1-6 alkylamino, etc.), azide, nitro, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), hydroxyl, C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, etc.), C _6-10 aryloxy group (eg, phenoxy, naphthyloxy, etc.), C _1-6
Alkylthio group (eg, methylthio, ethylthio, propylthio, etc.), C _6-10 arylthio group (eg, phenylthio, naphthylthio, etc.), cyano, carbamoyl group, carboxyl group, C _1-4 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxy Carbonyl, etc.), C _7-11
Aryloxycarbonyl group (eg, phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl, etc.), carboxy-C _1-4 alkoxy group (eg, carboxymethoxy, 2-carboxyethoxy, etc.), C _1-6 alkanoyl Group (eg, formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl, etc.), C _7-11 aroyl group (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C _6-10 arylsulfonyl group ( For example, benzenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, etc.), C _6-10 arylsulfinyl group (eg, benzenesulfinyl, 1
5 or 6 containing 1 to 4 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.), C _1-6 alkylsulfonyl groups (eg, methylsulfonyl, ethylsulfonyl, etc.), -naphthylsulfinyl, 2-naphthylsulfinyl, etc. Membered heterocyclic groups (eg, 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4-thiadiazol-2-yl, 1-methyl-5-tetrazolyl, etc.), hetero One atom (eg, nitrogen, oxygen, sulfur, etc.)
5- or 6-membered heterocyclic carbonyl group containing up to 4 (eg, 2-
Furoyl, 2-thenoyl, nicotinyl, isonicotinyl, etc.), 1 heteroatom (eg, nitrogen, oxygen, sulfur, etc.)
And a 5- or 6-membered heterocyclic thio group containing up to 4 (eg, 4-pyridylthio, 2-pyrimidylthio, 1,3,4-thiadiazol-2-ylthio, 1-methyl-5-tetrazolylthio, etc.), and the like. The heterocyclic thio group may be condensed with a benzene ring to form a bicyclic fused ring thio group (eg, 2-benzothiazolylthio, 8-quinolylthio, etc.). Among them, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), hydroxyl, C _1-4 alkoxy group (eg,
Methoxy, ethoxy, propoxy, butoxy, etc.). The number of the substituents is 1 to 5, preferably 1 to
3.

R ^d is preferably an optionally substituted alkoxy group or an optionally substituted alkoxyalkoxy group. The alkoxy group of the optionally substituted alkoxy group has 1 to 8 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n
-Butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, etc.), each of which may have a carbon atom as an alkoxy group. 1-4 (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.). As R ^d ,
In particular, an alkoxy group optionally having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, which may be halogenated with 1 to 9 halogens, or an alkoxy alkoxy group optionally halogenated with 1 to 5 halogens, preferable. Preferred examples of the optionally halogenated alkoxy group include, for example, 2,2,2-trifluoroethoxy, 2,2,3,3,3
-Pentafluoropropoxy, 1- (trifluoromethyl) -2,2,2-trifluoroethoxy, 2,2,3,3
-Tetrafluoropropoxy, 2,2,3,3,4,4,4-
Heptafluorobutoxy 2,2,3,3,4,4,5,5-
Octafluoropentoxy, methoxy and the like can be mentioned. Preferred examples of the alkoxyalkoxy group which may be halogenated include, for example, 3-methoxypropoxy. q is preferably 1.

As the benzimidazole compound,
More specifically, for example, the general formula (β)

Embedded image (In the formula, ring A may be substituted, R ^W , R ^Y and R ^Z may be the same or different and each represents a hydrogen, an alkyl group or an alkoxy group, and R ^X is an optionally substituted hydrocarbon. And n represents 0 or 1). In the general formula (β), examples of the ring A include those similar to the ring A in the general formula (α).

Examples of the alkyl group represented by R ^W , R ^Y or R ^Z include linear or branched alkyl groups having 1 to 10 carbon atoms. Specific examples of the alkyl group include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, Decyl and the like. Among them, a linear or branched alkyl group having 1 to 6 carbon atoms is preferable. Further, a linear or branched alkyl group having 1 to 3 carbon atoms is particularly preferred. The alkoxy group represented by R ^W , R ^Y or R ^Z includes, for example, one having 1 carbon atom.
And 10 to 10 alkoxy groups. Specific examples of the alkoxy group include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyl Oxy, nonyloxy,
Cyclobutoxy, cyclopentoxy, cyclohexyloxy and the like can be mentioned. Among them, an alkoxy group having 1 to 6 carbon atoms is preferable. Further, an alkoxy group having 1 to 3 carbon atoms is particularly preferred. Examples of the hydrocarbon group which may have a substituent represented by R ^X include the same as those represented by R ^f . R ^W is preferably a carbon number from 1 to 6
Or an alkoxy group having 1 to 6 carbon atoms. More preferably, it is an alkyl group having 1 to 3 carbon atoms. R ^Y is preferably hydrogen or an alkyl group having 1 to 6 carbon atoms. More preferably, it is hydrogen. ^RX is preferably 1) 1 to 5 halogens, 2) hydroxyl or 3) an alkyl group having 1 to 6 carbon atoms which may be substituted with an alkoxy group having 1 to 4 carbon atoms. More preferably, 1) 1 to 5 halogens or 2) 1 to 4 carbon atoms.
Is an alkyl group having 1 to 3 carbon atoms which may be substituted with an alkoxy group. R ^Z is preferably hydrogen.

Specific examples of the benzimidazole compound include 2- [2- [3-methyl-4- (2,2,3,3-
Tetrafluoropropoxy) pyridyl] methylthio] benzimidazole, 2- [2- [3-methyl-4- (2,
2,2-trifluoroethoxy) pyridyl] methylsulfinyl] benzimidazole (lansoprazole), 2
-[(2-pyridyl) methylsulfinyl] benzimidazole (thymoprazole), 2- [2- (3,5-dimethyl-4-methoxypyridyl) methylsulfinyl] -5
-Methoxy-1H-benzimidazole (omeprazole), 2- [2- [4- (3-methoxypropoxy) -3
-Methylpyridyl] methylsulfinyl] -1H-benzimidazole sodium salt, 2- [2- (3,4-dimethoxy) pyridyl] methylsulfinyl] -5-difluoromethoxy-1H-benzimidazole (pantoprazole) and the like. ..

The above-mentioned benzimidazole compound or a salt thereof can be produced, for example, by the method described in the above-mentioned publicly known Japanese and European patent publications and a method analogous thereto. The salt of the benzimidazole compound is preferably used as a physiologically acceptable salt. As physiologically acceptable salts, salts with inorganic bases, salts with organic bases, salts with basic amino acids and the like are used. Examples of the inorganic base used include alkali metals (eg, sodium, potassium, etc.) and alkaline earth metals (eg, calcium, magnesium, etc.). Examples of the organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, N, N -Dibenzylethylenediamine, ethanolamine, diethanolamine, trishydroxymethylaminomethane, dicyclohexylamine and the like, and basic amino acids include, for example, arginine and lysine. These salts can be prepared by a method known per se, for example, JP-A-64-7.
It is produced by a method described in Japanese Patent Application No. 9177 and Japanese Patent Application Laid-Open No. 59-167587 or a method similar thereto. Examples of the histamine H ₂ blocker as the acid secretion inhibitor include 2-cyano-1-methyl-3- [2-
[[5-Methylimidazol-4-yl) methyl] thio] ethyl] guanidine (cimetidine), N- [2-
[[5-[(Dimethylamino) methyl] furfuryl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine (ranitidine), (±) -2- (furfurylsulfinyl) -N -[4- [4- (Piperidinylmethyl) -2-pyridyl] oxy- (z) -2-butenyl]
Examples include acetamide (lectidine).

As described above, the present invention further provides an antacid in order to prevent the decomposition of the compound represented by the general formula (I) or the salt thereof as an active ingredient under acidic conditions such as gastric environment. The present invention also relates to a drug for anti-Helicobacter bacteria, which is characterized by using an agent, an acid secretion inhibitor, and the like in combination. A drug for an anti-Helicobacter genus characterized by using a compound represented by the general formula (I) or a salt thereof in combination with an antacid or an acid secretion inhibitor is represented by the general formula (I). The compound or a salt thereof is used in combination with an antacid or an acid secretion inhibitor, and the use form is not particularly limited. For example, (A) a compound represented by the general formula (I) or a salt thereof and (B) an antacid or an acid secretion inhibitor may be provided as a formulation which is usually administered, or both It may be a composition in which Examples of the drug for anti-Helicobacter of the present invention include, for example, a compound represented by the general formula (I) or a salt thereof and an antacid or an acid secretion inhibitor according to a known pharmaceutical production method, If desired, a pharmaceutically acceptable diluent, excipient, etc. are used and mixed to form one agent, each of which is separately, if desired, a pharmaceutically acceptable diluent,
Each formulation may be prepared by using an excipient or the like, or a combination formulation (set, kit, pack) in which each formulation is separately packaged may be packaged. For example, the drug for the genus Anti-Helicobacter of the present invention is (1) a preparation containing a compound represented by the general formula (I) or a salt thereof and a preparation containing an antacid or an acid secretion inhibitor are packaged. Or a composition containing the compound represented by the general formula (I) or a salt thereof and an antacid or an acid secretion inhibitor. Further, the medicament for the bacterium of the genus Anti-Helicobacter of the present invention may be a combination preparation or composition comprising a compound represented by the general formula (I) or a salt thereof, an antacid and an acid secretion inhibitor. .

The route of administration of the drug for the anti-Helicobacter genus of the present invention is the same as the route of administration of the above-mentioned anti-Helicobacter genus. Oral administration, parenteral administration (eg, intravenous administration, subcutaneous administration, intramuscular administration) Internal administration and the like). Specifically, it is determined in consideration of the target ulcer site and the like. When the compound represented by the general formula (I) or a salt thereof and the antacid or the acid secretion inhibitor are separately formulated, they are separately, simultaneously or with a time lag,
It may be administered to the same subject by the same route or different routes. When administering the drug for anti-Helicobacter spp. Of the present invention, the compound represented by the general formula (I) or a salt thereof and the antacid or acid secretion inhibitor are the same as those in the above-mentioned anti-Helicobacter spp. The prepared dosage form can be administered by a conventional method. For example, tablets and capsules include pharmaceutically acceptable carriers (eg, lactose, corn starch, light silicic acid anhydride, microcrystalline cellulose, sucrose), binders (eg, pregelatinized starch, methyl cellulose, carboxymethyl cellulose, hydroxy). Propylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone), disintegrants (eg, carboxymethylcellulose, starch, low-substituted hydroxypropylcellulose), surfactants [eg,
Tween80 (Kao-Atlas), Pluronic F68 (Asahi Denka,
Japan), polyoxyethylene-polyoxypropylene copolymer], antioxidant (eg, L-cysteine, sodium sulfite, sodium ascorbate), lubricant (eg,
Magnesium stearate, talc), and analogs thereof. When prepared as an injectable solution, the solution may be an aqueous solvent (eg, distilled water, saline, Ringer's solution) or an oily solvent (eg,
It is produced by a conventional method using a solvent such as sesame oil and olive oil. Further, one or more additives can be used, if desired. Examples of such additives include solubilizing agents (eg sodium salicylate, sodium acetate), buffering agents (eg sodium citrate, glycerin), isotonic agents (eg glucose, invert sugar), stabilizers ( (Eg, human serum albumin, polyethylene glycol), preservatives (eg, benzyl alcohol, phenol)
Alternatively, an analgesic (eg, benzalkonium chloride, procaine hydrochloride) can be mentioned. Also, when prepared as a solid preparation for injection, this preparation may include, for example, a diluent (eg,
Distilled water, saline, glucose), activator (eg, carboxymethylcellulose, sodium alginate), preservative (eg, benzyl alcohol, phenol) or analgesic (eg, benzalkonium chloride, procaine hydrochloride) It can be produced by a conventional method. On the other hand, in the case of an acid secretion inhibitor, the same method as the above can be adopted in principle, but the agent and the low-substituted hydroxypropylcellulose are blended by the method described in JP-A-63-301816. Nucleated granules coated with a powdery dusting agent or a method described in JP-A-3-163018, that is, stabilized with a stabilizer comprising a basic inorganic salt of magnesium and / or calcium. It can be preferably administered as a solid composition.

The composition for oral administration in the medicament for the genus Anti-Helicobacter of the present invention includes, for example, tablets, as in the above-mentioned agent for the genus Anti-Helicobacter.
Pills, granules, powders, capsules, syrups, emulsions,
Suspending agents and the like can be mentioned. Such a composition is produced by a method known per se, and lactose, starch, sucrose, magnesium stearate and the like are used as carriers or excipients. The composition for parenteral administration may be, for example, a suppository or an external preparation. Examples of suppositories include rectal suppositories, vaginal suppositories, and the like.
Examples of the external preparation include ointments (including cream), vaginal preparations, nasal preparations, transdermal preparations and the like. For example, in order to prepare a suppository, the composition of the present invention can be converted into an oily or aqueous solid, semi-solid or liquid suppository according to a method known per se.

The content of the compound represented by the general formula (I) or a salt thereof and the antacid or the acid secretion inhibitor in the medicine for anti-Helicobacter of the present invention may be appropriately selected depending on the preparation. For example, the compound represented by the general formula (I) or a salt thereof is about 1 to 20% by weight, preferably about 2 to
It is 10% by weight. The antacid is about 20 to 90% by weight, preferably about 30 to 80% by weight, more preferably about 50 to 70% by weight, and the acid secretion inhibitor is about 0.3.
-15% by weight, preferably about 1-10% by weight, more preferably about 2-5% by weight. The compound represented by the general formula (I) or a salt thereof to be used for the antacid and the acid secretion inhibitor is different depending on the individual combination,
For example, when combined with an antacid, about 0.0% of the antacid is used.
1 to 0.5 times (weight ratio), preferably about 0.1 to 0.3
When it is combined with an acid secretion inhibitor, it is about 3 to 70 times (weight ratio), preferably about 7 to 30 times (weight ratio) of the acid secretion inhibitor. In the drug for anti-Helicobacter of the present invention, a compound represented by the general formula (I) or a salt thereof and an antacid or an acid secretion inhibitor are separately formulated and administered to the same subject at the same time. be able to. Also, they can be administered to the same subject at different times. The frequency of administration of each component may be different. For example, the frequency of administration of the acid secretion inhibitor is preferably 1
~ 2 times / day, more preferably once / day, and the administration frequency of the compound represented by the general formula (I) or a salt thereof is
It is preferably 1 to 5 times / day, more preferably 1 to 3 times / day. The number of administrations of the antacid is preferably 1
-5 times / day, more preferably 1-3 times / day.

When the drug of the present invention is administered, for example, the compound represented by the general formula (I) or a salt thereof is usually in a state in which acid secretion is suppressed by administration of an acid secretion inhibitor (usually It is preferably administered about 30 to 60 minutes after the administration). When acid secretion is continuously suppressed by daily administration of an acid secretion inhibitor, simultaneous administration with an acid secretion inhibitor is also possible. The dose of the drug for the genus Anti-Helicobacter of the present invention is appropriately selected depending on the type and symptom of the disease, but the compound represented by the general formula (I) or a salt thereof is used for adult patients with gastric ulcer or duodenal ulcer. (50kg)
About 0.1 to 10 g / day for oral administration per day,
Preferably about 0.2-2 g / day, for parenteral administration about 0.01-1 g / day, preferably about 0.02-0.5 g / day.
1 day, one antacid is an adult patient (50 kg)
About 1 to 30 g / day, preferably about 2 to 5 g / day is administered per day for oral administration, and the acid secretion inhibitor is about 10 for oral administration per adult patient (50 kg) per day.
200 mg / day, preferably about 30-60 mg / day, and about 10 to 200 mg / day, preferably about 30-60 mg / day for parenteral administration. Each dose is determined in consideration of such a daily dose and a dosage form.

As described above, the phosphoric acid amide derivative of the present invention, the anti-Helicobacter bacterium agent, and the drug for the anti-Helicobacter bacterium are various digestive organs caused by bacteria having a toxic effect in the digestive tract, particularly Helicobacter pylori. It is effective in preventing or treating systematic diseases (eg, gastritis, duodenal ulcer, gastric ulcer, chronic gastritis, etc.). The phosphoric acid amide derivative, the anti-Helicobacter bacterium agent, and the anti-Helicobacter bacterium drug of the present invention are applied to the prevention / treatment of ulcers in animals (eg, mammals such as humans, dogs and cats), It is effective for the prevention and treatment of peptic ulcer in mammals including humans. Examples of such peptic ulcers include gastric ulcer, duodenal ulcer, reflux esophagitis, rostral ulcer or acute and chronic gastritis.

Further, the anti-Helicobacter genus agent and the medicine for anti-Helicobacter genus of the present invention may further contain a mucosa-protective antiulcer drug and the like. Examples of the mucosa-protective antiulcer drug include (z) -7-[(1R, 2R, 3
R) -2-[(E)-(3R) -3-hydroxy-4,
4-Dimethyl-1-octenyl] -3-methyl-5-oxocyclopentyl] -5-heptenoic acid (trimoprostil, wurster), 1-butyric acid-7-
(L-2-aminobutyric acid) -26-L-aspartic acid-27-L-valine-29-L-alanine calcitonin (elcatonin), 3-ethyl-7-
Isopropyl-1-azulene sulfonate sodium (egualen sodium) and the like.

[0055]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples, Test Examples and Formulation Examples, but the present invention is not limited to these. Hereinafter, room temperature means about 15 to 30 ° C., and% means weight &.

[0056]

【Example】

Reference Example 1 N-(diamino phosphinyl) -4-fluorobenzamide A
Flurofamide 4-fluorobenzamide (5 g) was added to chloroform (5 g).
5 ml) and phosphorus pentachloride (7.5 g) was added in small portions. After heating under reflux for 2 hours, the reaction solution was cooled to room temperature, and formic acid (1.7 g) was added dropwise. After stirring at room temperature for 20 hours, ammonia gas was introduced for 1 hour under ice cooling.
After the introduction, the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with water. The solid obtained by air drying was recrystallized from water. N-
Colorless crystals of (diaminophosphinyl) -4-fluorobenzamide (0.46 g) were obtained. Melting point 255-257
° C. Elemental analysis: C ₇ H ₉ N ₃ O ₂ FP Theoretical: C, 38.72; H, 4.18; N, 19.35. Found: C, 38.65; H, 4.08; N, 19.31.

[0057] Reference Example 2 N-(diamino phosphinyl) -3-pyridinecarboxylate down
Acid amide 3-pyridinecarboxylic acid amide (5 g) was suspended in chloroform (55 ml), and phosphorus pentachloride (8.5 g) was added little by little. After heating under reflux for 2 hours, the reaction solution was cooled to room temperature, and formic acid (1.9 g) was added dropwise. After stirring at room temperature for 20 hours, ammonia gas was introduced for 1 hour under ice cooling. After the introduction, the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with water. The solid obtained by air drying was recrystallized from water.
Colorless crystals of N- (diaminophosphinyl) -3-pyridinecarboxylic acid amide (0.46 g) were obtained. Melting point 280
-283 [deg.] C. Elemental analysis: C ₆ H ₉ N ₄ O ₂ P Theoretical: C, 36.01; H, 4.53; N, 27.99. Found: C, 35.71; H, 4.55; N, 27.91.

[0058] Reference Example 3 N-(diamino phosphinyl) -4- Nitorobenzua Mi
De- 4-nitrobenzamide (25.4 g) was suspended in carbon tetrachloride (150 ml) to give phosphorus pentachloride (32.9 g).
Was added in small portions at 40-50 ° C. 65-70 after addition
The mixture was heated and stirred at about 50 minutes. The reaction was cooled to room temperature and formic acid (7 g) was added dropwise. After stirring at room temperature for 4 hours, the precipitated crystals were collected by filtration. After washing with carbon tetrachloride, it was air-dried to obtain 40 g of crystals. The crystals (14.2 g) were suspended in chloroform (150 ml). Ammonia gas was introduced for about 30 minutes under ice cooling. After introduction, 1.
Stir for 5 hours. The precipitate was collected by filtration and washed with water. The solid obtained by air drying was recrystallized from water. Colorless crystals of N- (diaminophosphinyl) -4-nitrobenzamide (7 g) were obtained. 279-285 [deg.] C (decomposition). Elemental analysis value C ₇ H ₉ N ₄ O ₄ P Theoretical value: C, 34.44; H, 3.72; N, 22.95. Actual value: C, 34.33; H, 3.81; N, 22.63.

[0059] Reference Example 4 N-(diamino phosphinyl) - cinnamamide cinnamamide a (10 g) was suspended in toluene (50 ml), was added portionwise phosphorous pentachloride (15.6 g).
Heated to 70 ° C. and stirred for 25 minutes. The reaction was cooled to room temperature and formic acid (3.1 g) was added dropwise. After stirring at room temperature for 2 hours, the precipitated crystals were collected by filtration. After washing with toluene, it was air-dried to obtain 4.8 g of crystals. The crystals were dissolved in tetrahydrofuran (150 ml). Ammonia gas was introduced under ice cooling for 30 minutes. After the introduction, the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with water. The solid obtained by air drying was recrystallized from methanol. Colorless crystals of N- (diaminophosphinyl) -cinnamamide (0.8 g) were obtained. Melting point 176-178 [deg.] C. Elemental analysis: C ₉ H ₁₂ N ₃ O ₂ P Theoretical: C, 48.00; H, 5.37; N, 18.66. Found: C, 47.94; H 5.31; N, 18.62.

Reference Examples 5 to 36 The following compounds were synthesized in the same manner as in Reference Example 4.

[Table 1-1]

[Table 1-2]

[Table 1-3]

[0061] Reference Example 37 N-(diamino phosphinyl) -3- phenylpropionate
Acid amide N- (diaminophosphinyl) -cinnamamide (1
g) is dissolved in methanol (200 ml), and 10% P
dC (wet) (0.4 g) was added. Hydrogenation was performed at room temperature and normal pressure for 30 minutes. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration and washed with diethyl ether. Recrystallization from methanol gave the title compound (0.63).
g) colorless crystals were obtained. Melting point> 300 ° C. Elemental analysis: C ₉ H ₁₄ N ₃ O ₂ P Theoretical: C 47.58, H 6.21, N 18.49. Observed: C 47.39, H 6.14, N 18.28.

Reference Examples 38 to 44 The following compounds were synthesized in the same manner as in Reference Example 37.

[Table 2]

[0063] Reference Example 45 4-nitrophenoxy cell Toamido 4-nitrophenol (7.5 g), iodoacetamide (10 g), 15 hours a mixed solution at 50 ° C. of potassium carbonate (7.5 g), dimethylformamide (50ml) It was stirred. The reaction solution was poured into ice water and extracted with ethyl acetate.
It was washed successively with water and a saturated aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized from acetone-diisopropyl ether.
Colorless crystals of the title compound (7.9 g) were obtained. Melting point 160
-161 ° C.

Reference Examples 46 to 59 The following compounds were synthesized in the same manner as in Reference Example 45.

[Table 3]

Reference Example 60 2-Benzofurancarboxylic acid amide 2-Benzofurancarboxylic acid (6.0 g) was dissolved in tetrahydrofuran (50 ml), and N, N-dimethylformamide (3 drops) was added. Oxalyl chloride (4.9 g) was added dropwise at room temperature and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate (20 ml). 25% aqueous ammonia (30 ml),
The mixture was added dropwise to a mixture of ethyl acetate (100 ml) with stirring under ice cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours to separate an organic layer. The organic layer was washed successively with water and saturated saline and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the precipitated crystals were collected by filtration and washed with isopropyl ether. 2-benzofurancarboxamide (4.5 g) was obtained. 165-166 ° C.

Reference Examples 61 to 119 The following compounds were synthesized in the same manner as in Reference Example 60.

[Table 4-1]

[Table 4-2]

[Table 4-3]

1) The compound of Reference Example 80 was synthesized by the following method. 5-cyano-2-thiophene Nkarubon acid amide 5-formyl-2-thiophenecarboxylic acid (2.64
g) [Synthesized by the method described in [Tetrahedron, 41, 3803 (1985)]] was dissolved in tetrahydrofuran (30 ml), and N, N-dimethylformamide (3 drops) was added. Oxalyl chloride (2.2 ml) was added dropwise at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate (50 ml). The solution was added dropwise to a mixture of 25% aqueous ammonia (50 ml) and ethyl acetate (200 ml) with stirring under ice-cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour to separate an organic layer. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 5-Formyl-2-thiophenecarboxylic amide (1.77 g) was obtained. 5-formyl-2-thiophenecarboxamide (1.55
g), a mixture of N, O-bis (trifluoroacetyl) hydroxyamine (3.5 g), pyridine (2 ml), and toluene (110 ml) was stirred with heating under reflux for 1 hour. After cooling, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5-cyano-2-thiophenecarboxylic acid amide (0.6 g). Melting point 222-223 [deg.] C.

2) Reference Example 98 was synthesized by the following method. 5-chloro-3-thiophene Nkarubon acid amide 3-thiophenecarboxylic acid ethyl ester (1.98
g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.5 ml) was added under ice cooling. 30 at 10 ° C
After stirring for 10 minutes, a 10% aqueous solution of sodium thiosulfate (100%
(ml) was added and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with diethyl ether and washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give ethyl 5-chloro-3-thiophenecarboxylate and 2,5-dichloro-ethyl ester.
A mixture of ethyl 3-thiophenecarboxylate was obtained. Dissolve them in a mixed solvent of ethanol (15 ml) and tetrahydrofuran (15 ml) as a mixture,
A 1N aqueous sodium hydroxide solution (20 ml) was added. After stirring at room temperature for 2 hours, the mixture was washed with diethyl ether.
The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 5-chloro-3-thiophenecarboxylic acid and 2,5-dichloro-
A mixture of 3-thiophenecarboxylic acid (1.7 g) was obtained. The mixture was suspended in toluene (15 ml) and oxalyl chloride (1.56 ml) was added dropwise. N, N-Dimethylformamide (1 drop) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and ethyl acetate (10
ml). The solution was added to 25% aqueous ammonia (1
6 ml) and ethyl acetate (70 ml) were added dropwise with stirring under ice-cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 10 minutes to separate an organic layer. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-3-thiophenecarboxamide (0.76 g). 138-139
° C.

3) Reference Example 101 was synthesized by the following method. 5-chloro-2-methyl - 3-thiophenecarboxylic acid A
Synthesized 2-methyl in the same manner as bromide Reference Example 127 3-
Thiophenecarboxylic acid (5.69 g) was dissolved in N, N-dimethylformamide (50 ml), and ethyl iodide (3.2 ml) and potassium carbonate (5.52 g) were added.
After stirring at room temperature for 15 hours, the reaction solution was poured into water. The mixture was extracted with diethyl ether and washed with a 5% aqueous potassium hydrogen sulfate solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain a crude product of ethyl 2-methyl-3-thiophenecarboxylate. This crude product of ethyl 2-methyl-3-thiophenecarboxylate was dissolved in acetonitrile (50 ml) and sulfuryl chloride (3.0 m
A solution of l) in acetonitrile (20 ml) was added dropwise. After stirring for 1 hour while cooling in a water bath, a 10% aqueous sodium thiosulfate solution (100 ml) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with diethyl ether and washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give 5
A crude product of -chloro-2-methyl-3-thiophenecarboxylic acid ethyl ester was obtained. The crude product was dissolved in a mixed solvent of ethanol (25 ml) and tetrahydrofuran (25 ml), and a 1N aqueous sodium hydroxide solution (50 ml) was added.
ml) was added. After stirring at 65 ° C. for 2 hours, the mixture was washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A crude product of 5-chloro-2-methyl-3-thiophenecarboxylic acid was obtained. The 5-chloro-2-
The crude product of methyl-3-thiophenecarboxylic acid was suspended in toluene (50 ml) to prepare oxalyl chloride (4.6
ml) was added dropwise. N, N-dimethylformamide (3
) And stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate (20 ml). The solution was added dropwise to a mixture of 25% aqueous ammonia (56 ml) and ethyl acetate (150 ml) with stirring under ice cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 10 minutes to separate an organic layer. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-2-methyl-3-thiophenecarboxamide (1.6 g). 125-127 ° C.

Reference Example 120 4,5-Dibromo-2- thiophenecarboxylic acid 2-Thiophenecarboxylic acid (3.84 g) was mixed with bromine (9.3).
ml) and stirred at room temperature for 15 hours. Excess bromine was neutralized with an aqueous solution of ammonium carbonate, and then acidified with 1N hydrochloric acid. The precipitated crystals were collected by filtration. Dissolved in 1N sodium hydroxide and acidified with 1N hydrochloric acid. Extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure to obtain crystals of 4,5-dibromo-2-thiophenecarboxylic acid (7.48 g). Melting point 225-227
° C.

[0071] Reference Example 121 4-Bromo-2-thiophene Nkarubon acid silver nitrate (1.7 g) was dissolved in water (40 ml), was added an aqueous solution of sodium hydroxide (0.44g) (1ml). The precipitated silver oxide was collected by filtration and suspended in a 10% aqueous sodium hydroxide solution (20 ml). 60-
Heat to 65 ° C. and add 4-bromo-2-thiophenecarbaldehyde (1.91 g) dropwise. Thereafter, the mixture was stirred for 30 minutes, and the precipitate was separated by filtration. After washing the filtrate with diethyl ether, the aqueous layer was adjusted to pH 4 with 1N hydrochloric acid. After extraction with ethyl acetate, the extract was dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave crystals of 4-bromo-2-thiophenecarboxylic acid (1.39 g). 124-126 ° C.

[0072] Reference Example 122 5-ethyl-2-thiophene Nkarubon acid 1,3-dimethyl-2- (2-thienyl) imidazolidine (5.46g) [[Tetrahedron, 41 , 3803 (1985)]
, N, N, N ', N'-tetramethylethylenediamine (4.7 ml) was dissolved in tetrahydrofuran (150 ml). This solution was -78
After cooling to ° C, n-butyllithium (1.6 M hexane solution, 19.5 ml) was slowly added dropwise. After stirring at the same temperature for 2 hours, ethyl iodide (2.4 ml) was added.
The mixture was slowly heated to room temperature and stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and 10% sulfuric acid (200 m
l) was added and stirred for 24 hours. After extraction with ethyl acetate,
The organic layer was washed with water. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. An oil of 5-ethyl-2-thiophenecarbaldehyde (1.68 g) was obtained. This 5-
Ethyl-2-thiophenecarboxaldehyde (1.6
8 g) was dissolved in acetonitrile (20 ml), and an aqueous solution of sodium dihydrogen phosphate (0.54 g) (10 m
l), a 30% aqueous hydrogen peroxide solution (2.0 ml) was added. Then, an aqueous solution (20 ml) of sodium chlorite (3.0 g) was added dropwise under ice cooling. Thereafter, the mixture was stirred at room temperature for 2 hours. The mixture was made alkaline with a 1N aqueous sodium hydroxide solution and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystals of 5-ethyl-2-thiophenecarboxylic acid (1.48 g) were obtained. Melting point 65-6
6 ° C.

[0073] In Reference Example 123 5-nitro-2-thiophene Nkarubon acid 5-nitro-2-thiophene carboxaldehyde (7.86 g) was dissolved in acetonitrile (50 ml), sodium dihydrogen phosphate (1.6 g) Aqueous solution (2
0 ml) and 30% aqueous hydrogen peroxide solution (5.9 ml) were added. Then, under ice cooling, sodium chlorite (8.0 g)
Was added dropwise (70 ml). Thereafter, the mixture was stirred at room temperature for 2 hours. Sodium thiosulfate was added to the reaction solution to remove excess hydrogen peroxide. The mixture was made alkaline with a 1N aqueous sodium hydroxide solution and washed with diethyl ether. Water layer 1
The mixture was acidified with N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 5-nitro-2
Crystals of thiophenecarboxylic acid (7.83 g) were obtained.
158-159 ° C.

[0074] Reference Example 124 5-bromo-3-thiophene Nkarubon acid 3-thiophenecarboxylic acid (12.81 g), pyridinium bromide perbromide (35.54g), a mixture of acetic acid (50ml) at 45 ° C. 48 Stir for hours. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration. Dissolved in ethyl acetate,
It was dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to 5
-Bromo-3-thiophenecarboxylic acid (19.78 g)
Was obtained. 137-138 ° C.

Reference Example 125 5-Difluoromethyl-2 -thiophenecarboxylic acid 5-formyl-2-thiophenecarboxylic acid methyl ester (1.7 g) [J. Heterocyclic Chem., 28, 17 (199
Methylene chloride (10).
ml) solution with diethylaminosulfur trifluoride (DA
ST) (1.6 g) was slowly added dropwise to a methylene chloride (20 ml) solution at room temperature. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. Diethylamino sulfur trifluoride (DAS
T) (0.5 g) was added, and the mixture was stirred at room temperature for 1 hour. Water (10 ml) and saturated aqueous sodium hydrogen carbonate (10 ml) were added to the reaction solution in that order, and the mixture was left overnight. The organic layer was separated and washed with water.
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. 5-Difluoromethyl-2-thiophenecarboxylic acid methyl ester (0.81 g) was obtained. 5-Difluoromethyl-2-thiophenecarboxylic acid methyl ester (2.58 g) synthesized in this manner was treated with methanol (50%).
ml) and dissolved in a 1N aqueous sodium hydroxide solution (30 ml).
ml) was added. After stirring at room temperature for 2 hours, the reaction solution was washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with diethyl ether. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 5-difluoromethyl-2
Crystals of thiophenecarboxylic acid (2.13 g) were obtained.
111-112 ° C.

[0076] was synthesized by the method described in Reference Example 126 3-Chloro-2-thiophene Nkarubon acid [Heterocycles, 23, 1431 (1985 )].

[0077] cooling the Reference Example 127 2-Methyl-3-thiophene Nkarubon acid 3-thiophenecarboxylic acid (3.84 g) in dissolved to -78 ° C. in tetrahydrofuran (50ml).
n-butyllithium (1.6 M hexane solution, 41.3 m
l) was slowly added dropwise and stirred at the same temperature for 30 minutes.
Methyl iodide (3.7 ml) in tetrahydrofuran (1
0 ml) solution was added dropwise. After completion of the dropwise addition, the mixture was heated to room temperature and stirred for 15 hours. The reaction solution was poured into water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystals of 2-methyl-3-thiophenecarboxylic acid (3.98 g) were obtained. Mp 71-73 ° C.

[0078] suspended in Reference Example 128 3-Bromo-2-thiophene Nkarubon acid 3-amino-2-thiophenecarboxylic acid methyl ester (9.4 g) and hydrobromic acid (20ml) was stirred for 30 minutes at room temperature . The reaction solution was cooled to 0 ° C., and an aqueous solution (10 ml) of sodium nitrite (4.2 g) was added to the reaction solution.
The solution was added dropwise at 0 ° C or lower. After stirring for 1 hour, the mixture was poured into a solution of cuprous bromide (9.06 g) in hydrobromic acid (25 ml) under ice cooling. The mixture was heated and stirred at 60 ° C. for 1 hour. After extraction with diethyl ether, the extract was dried over anhydrous magnesium sulfate. It was concentrated under reduced pressure and the residue was distilled under reduced pressure. 3-bromo-2
-Thiophenecarboxylic acid methyl ester (7.99 g)
Was obtained. Boiling point 101 ° C / 8mmHg, melting point 47-
48 ° C. 3-Bromo-2-thiophenecarboxylic acid methyl ester (7.74 g) was dissolved in a mixed solvent of methanol (35 ml) -tetrahydrofuran (35 ml),
At room temperature, a 1N aqueous sodium hydroxide solution (53 ml) was added. After stirring at room temperature for 2 hours, the reaction solution was washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystals of 3-bromo-2-thiophenecarboxylic acid (7.05 g) were obtained. Melting point 200-201 [deg.] C.

[0079] Reference Example 129 5-Acetyl-2-Chiofu Enkarubon acid 2-methyl-2- (2-thienyl) -1,3-dioxolane (6.6g) [[Tetrahedron, 41 , 3803 (1985)]
Was dissolved in tetrahydrofuran (200 ml) and N, N, N ', N'-tetramethylethylenediamine (5.87 ml) was added. The solution was cooled to -78 ° C and n-butyllithium (1.6M
(Hexane solution, 25 ml) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 2 hours. The temperature of the reaction solution was slowly raised to room temperature over 2 hours while introducing carbon dioxide gas. After concentrating the reaction mixture under reduced pressure, 2N hydrochloric acid (200 m
l) was added and stirred for 3 hours. The precipitated crystals were collected by filtration, washed with water, and dried. Crystals of 5-acetyl-2-thiophenecarboxylic acid (3.87 g) were obtained. Melting point 283 [deg.] C.

Reference Example 130 5-Methanesulfonyl-2 -thiophenecarboxylic acid 5-methylthio-2-thiophenecarbaldehyde (4.48 g) [synthesized by the method described in [Tetrahedron, 41, 3803 (1985)]] Acetonitrile (20m
l) Sodium dihydrogen phosphate (1.2 g)
Aqueous solution (10 ml), 30% aqueous hydrogen peroxide solution (3.
5 ml) was added. Then, an aqueous solution (10 ml) of sodium chlorite (3.85 g) was added dropwise under ice cooling. Thereafter, the mixture was stirred at room temperature for 15 hours, and sodium sulfite (1 g) was added.
Was added. The mixture was made alkaline with a 1N aqueous sodium hydroxide solution and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Recrystallization from ethyl acetate-diisopropyl ether gave 5-methanesulfonyl-2-
Crystals of thiophene carboxylic acid (1.73 g) were obtained. 190-194 ° C (decomposition).

Reference Example 131 3-Difluoromethyl-2 -thiophenecarboxylic acid 3-Thiophenecarbaldehyde (22.43 g) was dissolved in toluene (200 ml) and N, N'-dimethylethylenediamine (22.3 ml) was added. . The mixture was stirred for 16 hours while separating azeotropic water with Gene Stark under heating and refluxing. The reaction solution was concentrated under reduced pressure, and the residue was distilled under reduced pressure to obtain 1,3-dimethyl-2- (3-thienyl) imidazolidine (5.88 g). Boiling point 63-
64 ° C / 0.8 mmHg, melting point 112-113 ° C. The 1,3-dimethyl-2- (3-thienyl) imidazolidine (9.06 g) thus obtained was dissolved in tetrahydrofuran (100 ml) to prepare N, N, N ′, N′-tetramethylethylenediamine ( 7.85 ml) was added and the temperature was -78 ° C.
And cooled. n-Butyllithium (1.6 M hexane solution, 32.5 ml) was slowly added dropwise, followed by stirring at the same temperature for 2 hours. The reaction solution was poured into a mixture of dry ice-diethyl ether, and the temperature was raised to room temperature with stirring. The solvent was distilled off under reduced pressure, 10% sulfuric acid (100 ml) was added to the residue, the mixture was stirred for 15 hours, and extracted with diethyl ether. The diethyl ether layer was extracted with a 1N aqueous sodium hydroxide solution, and the aqueous layer was washed with diethyl ether. 1N
The mixture was acidified with hydrochloric acid and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give 3-formyl-2.
-Crystals of thiophenecarboxylic acid (5.92 g) were obtained.
119-120 ° C. 3-Formyl-2-thiophenecarboxylic acid (3.12 g) was dissolved in N, N-dimethylformamide (30 ml), and ethyl iodide (1.76 m) was dissolved.
l), potassium carbonate (2.76 g) was added. 1 at room temperature
After stirring for 5 hours, the reaction solution was poured into water. The mixture was extracted with ethyl acetate and washed with a 5% aqueous potassium hydrogen sulfate solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The effective fraction was concentrated under reduced pressure to obtain ethyl 3-formyl-2-thiophenecarboxylate (2.91 g). 3-formyl-2-thiophenecarboxylic acid ethyl ester (1.
A solution of 84 g) in methylene chloride (10 ml) was added to diethylaminosulfur trifluoride (DAST) (1.45 ml).
Was slowly added dropwise at room temperature to a methylene chloride (10 ml) solution. After completion of dropping, the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the organic layer was separated. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. 3-Difluoromethyl-2-thiophenecarboxylic acid ethyl ester (1.58 g) was obtained. This 3-difluoromethyl-2
-Thiophenecarboxylic acid ethyl ester was dissolved in a mixed solvent of ethanol (10 ml) and tetrahydrofuran (10 ml), and a 1N aqueous sodium hydroxide solution (11 m
l) was added. After stirring at room temperature for 2 hours, the mixture was washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystals of 3-difluoromethyl-2-thiophenecarboxylic acid (1.12 g) were obtained. Melting point 119-12
0 ° C.

Reference Example 132 2-Difluoromethyl-3 -thiophenecarboxylic acid 3-Thiophenecarboxylic acid (3.48 g) was dissolved in tetrahydrofuran (50 ml) to prepare N, N, N ', N'-tetramethylethylenediamine (10 ml). ) Is added to -78
Cooled to ° C. n-Butyllithium (1.6M hexane solution, 41.3 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour. Then, N, N-dimethylformamide (4.6 m
l) was added dropwise. The mixture was heated to room temperature and stirred for 15 hours.
The reaction was acidified with 1N hydrochloric acid and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. 2-formyl-3-thiophenecarboxylic acid and 5-
Mixture of formyl-3-thiophenecarboxylic acid (2.1
1 g) was obtained. This mixture was dissolved in N, N-dimethylformamide (30 ml) and ethyl iodide (0.95) was dissolved.
ml) and potassium carbonate (1.66 g) were added. After stirring at room temperature for 15 hours, the reaction solution was poured into water. The mixture was extracted with diethyl ether and washed with a 5% aqueous potassium hydrogen sulfate solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The effective fraction was concentrated under reduced pressure to obtain ethyl 2-formyl-3-thiophenecarboxylate (1.75 g). A solution of ethyl 2-formyl-3-thiophenecarboxylate (1.66 g) in methylene chloride (20 ml) was treated with diethylaminosulfur trifluoride (DAST).
(1.32 ml) was slowly added dropwise to a solution of methylene chloride (10 ml) at room temperature. After the dropping was completed, the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the organic layer was separated. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. 2-Difluoromethyl-3-thiophenecarboxylic acid ethyl ester (1.08 g) was obtained. This ethyl 2-difluoromethyl-3-thiophenecarboxylate was dissolved in ethanol (10 ml) and tetrahydrofuran (1
0 ml), and 1N aqueous sodium hydroxide solution (7.8 ml) was added. After stirring at room temperature for 1 hour, the mixture was washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 2-difluoromethyl-3
-Crystals of thiophene carboxylic acid (0.88 g) were obtained.
127-128 ° C.

[0083] Nitric acid Reference Example 133 5-nitro-3-thiophene Nkarubon acid 3-thiophenecarboxylic acid (5.12 g) (20
ml) and sulfuric acid (11.5 ml) were added little by little at 5 ° C or less. After the addition, the mixture was stirred at that temperature for 30 minutes, and the reaction solution was poured into ice water. The mixture was made alkaline with a 1N aqueous sodium hydroxide solution and washed with diethyl ether. 1N water layer
The mixture was acidified with hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Recrystallization from ethyl acetate gave 5-nitro-3-thiophenecarboxylic acid (4.
45 g) of crystals were obtained. 117-118 ° C.

[0084] was cooled in Reference Example 134 5-Methoxy-2-Chiofu Enkarubon acid 2-methoxy-thiophene (4.0 ml) to dissolve to -78 ° C. in tetrahydrofuran (50ml). n
-Butyl lithium (1.6 M hexane solution, 31 ml)
Was slowly added dropwise, followed by stirring at the same temperature for 1 hour. The reaction solution was poured into a mixture of dry ice-diethyl ether, and the temperature was raised to room temperature with stirring. The solvent was distilled off and acidified with 1N hydrochloric acid. Extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 5-methoxy-2-thiophenecarboxylic acid (5.62 g). Melting point 167
-168 ° C.

[0085] Reference Example 135 3-cyano-2-thiophene Nkarubon acid 3-formyl-2-thiophenecarboxylic acid (4.68
g) was dissolved in N, N-dimethylformamide (30 ml), benzyl bromide (3.9 ml) and potassium carbonate (4.15 g) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into water, extracted with diethyl ether, and washed with a 5% aqueous potassium hydrogen sulfate solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The effective fraction is concentrated under reduced pressure to 3
-Formyl-2-thiophenecarboxylic acid benzyl ester (2.65 g) was obtained. 3-Formyl-2-thiophenecarboxylic acid benzyl ester (2.46 g) was dissolved in ethanol (50 ml), and hydroxylamine hydrochloride (0.83 g) and pyridine (0.97 ml) were added. The mixture was stirred under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was poured into water. Extracted with diethyl ether and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to 3-
Aldoxime-2-thiophenecarboxylic acid benzyl ester (2.61 g) was obtained. Acetic anhydride (20m
1) and stirred at 160 ° C. for 10 hours. The reaction mixture was cooled, poured into water (100 ml) and extracted with diethyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography. 3-Benzyl-2-thiophenecarboxylic acid benzyl ester (2.01 g) was obtained. This was dissolved in tetrahydrofuran (40 ml) and 5% Pd-C (wet) (0.25 g) was added. Hydrogenation was performed at normal temperature and normal pressure for 72 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain crystals of 3-cyano-2-thiophenecarboxylic acid (0.98 g). Melting point 204-
205 ° C.

[0086] was cooled in Reference Example 136 4-Methoxy-2-Chiofu Enkarubon acid 3-methoxy-thiophene (4.0 ml) to dissolve to -78 ° C. in tetrahydrofuran (50ml). n
-Butyl lithium (1.6 M hexane solution, 19.5 m
l) was slowly added dropwise, followed by stirring at the same temperature for 1 hour. The reaction solution was poured into a mixture of dry ice-diethyl ether, and the temperature was raised to room temperature with stirring. The solvent was distilled off and acidified with 1N hydrochloric acid. Extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to give 3-methoxy-2.
A mixture of -thiophenecarboxylic acid and 4-methoxy-2-carboxylic acid (6.0 g) was obtained. This mixture was dissolved in N, N-dimethylformamide (50 ml), and ethyl iodide (3.0 ml) and potassium carbonate (5.25 g) were added. After stirring at room temperature for 15 hours, the reaction solution was poured into water.
The mixture was extracted with diethyl ether and washed with a 5% aqueous potassium hydrogen sulfate solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The effective fraction was concentrated under reduced pressure to give 4-methoxy-
2-Thiophenecarboxylic acid ethyl ester (2.69
g) and 3-methoxy-2-thiophenecarboxylic acid ethyl ester (3.98 g) were obtained. Ethyl 4-methoxy-2-thiophenecarboxylic acid (2.69 g) was added to ethanol (25 ml) and tetrahydrofuran (25 m).
It was dissolved in the mixed solvent of l) and 1N aqueous sodium hydroxide solution (22 ml) was added. After stirring at room temperature for 3 hours, the mixture was washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystals of 4-methoxy-2-thiophenecarboxylic acid (2.11 g) were obtained. Melting point 172-1
73 ° C.

Reference Example 137 2,5-Dichloro-3-thiophenecarboxylic acid 3-thiophenecarboxylic acid ethyl ester (1.56)
g) was dissolved in acetonitrile (30 ml) and sulfuryl chloride (5.36 g) was added. After stirring at room temperature for 4 hours,
A 10% aqueous solution of sodium thiosulfate (100 ml) was added, and the mixture was stirred for 15 minutes. The mixture was extracted with diethyl ether and washed with saturated saline. After drying over anhydrous magnesium sulfate,
It was concentrated under reduced pressure to obtain 2,5-dichloro-3-thiophenecarboxylic acid ethyl ester (2.3 g). 2,5-dichloro-3-thiophenecarboxylic acid ethyl ester (2.
25 g) was dissolved in a mixed solvent of ethanol (10 ml) and tetrahydrofuran (10 ml), and a 1N aqueous sodium hydroxide solution (20 ml) was added. After stirring at room temperature for 2 hours, the mixture was washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 2,5-dichloro-3
-Crystals of thiophene carboxylic acid (1.89 g) were obtained.
140-141 ° C.

[0088] Reference Example 138 2-bromo-3-thiophene Nkarubon acid 2-bromo-3-methylthiophene (17.7 g), N
A mixture of -bromosuccinimide (17.7 g), 2,2'-azobis (isobutyronitrile) (0.32 g) and carbon tetrachloride (200 ml) was stirred for 4 hours while heating under reflux. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3-bromomethyl-2-bromothiophene (12.56 g). 3
-Bromomethyl-2-bromothiophene (6.30
g), potassium acetate (9.8 g), acetone (100 m
The suspension of 1) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give 3-acetoxymethyl-2-.
A crude product of bromothiophene (5.8 g) was obtained. This crude product was dissolved in tetrahydrofuran (50 ml), and a 1N aqueous sodium hydroxide solution (50 ml) and ethanol (20 ml) were added. After stirring at room temperature for 2 hours, the reaction solution was washed with diethyl ether, and the aqueous layer was acidified with 1N hydrochloric acid. Extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to give 3-hydroxymethyl-
A crude product of 2-bromothiophene (4.6 g) was obtained.
The crude product of 3-hydroxymethyl-2-bromothiophene was dissolved in methylene chloride (100 ml) and manganese dioxide (15 g) was added. After stirring at room temperature for 6 hours,
The insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to give 2-bromo-
Crude 3-thiophenecarbaldehyde (3.92)
g) was obtained. The crude product of 2-bromo-3-thiophenecarbaldehyde was dissolved in acetonitrile (50 ml), and an aqueous solution of sodium dihydrogen phosphate (1.0 g) (1
5 ml) and a 30% aqueous hydrogen peroxide solution (2.5 ml). Then, sodium chlorite (2.7 g) under ice cooling
Aqueous solution (30 ml) was added dropwise. Thereafter, the mixture was stirred at room temperature for 2 hours. The mixture was made alkaline with a 1N aqueous sodium hydroxide solution and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystals of 2-bromo-3-thiophenecarboxylic acid (2.89 g) were obtained. Melting point 151
-154 ° C.

[0089] Reference Example 139 3-ethyl-2-thiophene Nkarubon acid 3- acetylthiophene (20 g), ethylene glycol (10.54 g), p-toluenesulfonic acid (0.15
g) and a mixed solution of toluene (200 ml) were stirred for 16 hours while heating and refluxing while separating azeotropic water by Gene Stark. The reaction solution was cooled, washed with water, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography. 2-methyl-2-
(3-thienyl) -1,3-dioxolane (12.6 g)
I got This 2-methyl-2- (3-thienyl) -1,
3-Dioxolane (12.0 g) was dissolved in tetrahydrofuran (200 ml), and N, N, N ', N'-tetramethylethylenediamine (1.3 ml) was added. The solution was cooled to -78 ° C, and n-butyllithium (a 1.6 M hexane solution, 49 ml) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 2 hours. The temperature of the reaction solution was slowly raised to room temperature over 2 hours while introducing carbon dioxide gas. After concentrating the reaction mixture under reduced pressure, 2N hydrochloric acid (200 m
l) was added and stirred for 3 hours. The precipitated crystals were collected by filtration, washed with water, and dried. Crystals of 3-acetyl-2-thiophenecarboxylic acid (10 g) were obtained. Melting point 155-156
° C. 3-acetyl-2-thiophenecarboxylic acid (3.0
g) was dissolved in N, N-dimethylformamide (50 ml), and methyl iodide (4.0 ml) and potassium carbonate (6.0 g) were added. After stirring at room temperature for 3 hours, the reaction mixture was poured into water and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure to obtain crystals of methyl 3-acetyl-2-thiophenecarboxylate (3.07 g). 59-60 [deg.] C. 3 synthesized in this way
-Acetyl-2-thiophenecarboxylic acid methyl ester (3.87 g) was dissolved in methanol (50 ml),
Sodium borohydride (0.95 g) was added under ice cooling. After stirring at room temperature for 1 hour, 1N hydrochloric acid (50 ml) was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give 3- (1-hydroxyethyl).
-2-thiophenecarboxylic acid methyl ester (3.77
g) obtained. This was dissolved in ethyl acetate (100 ml), and methanesulfonyl chloride (2.86 g), triethylamine (3.5 g), and dimethylaminopyridine (0.2) were dissolved.
g) was added. After stirring at room temperature for 2 hours, 1N hydrochloric acid (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was dissolved in acetone (100 ml) and sodium iodide (10
g) was added. After stirring at room temperature for 2 hours, insolubles were filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography. The effective fraction was concentrated under reduced pressure to obtain methyl 3- (1-iodoethyl) -2-thiophenecarboxylate (3.0 g). This 3-
(1-Iodoethyl) -2-thiophenecarboxylic acid methyl ester was dissolved in dimethyl sulfoxide (10 ml), and sodium borohydride (0.4 g) was added at room temperature. After stirring for 1 hour, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. 3-Ethyl-2-thiophenecarboxylic acid methyl ester (1.0 g) was obtained. A mixture of 3-ethyl-2-thiophenecarboxylic acid methyl ester (1.0 g), 1N aqueous sodium hydroxide solution (15 ml), tetrahydrofuran (30 ml), and methanol (10 ml) was stirred at room temperature for 1 hour. After washing the reaction solution with diethyl ether, the aqueous layer was acidified with 1N hydrochloric acid. It was extracted with diethyl ether and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure to give 3-ethyl-2-thiophenecarboxylic acid (0.9).
The crystals of g) were obtained. 106-109 ° C.

[0090] was dissolved in Reference Example 140 4-Methyl-2-thiophene Nkarubon acid 5-bromo-4-methyl-2-thiophenecarboxylic acid (3.33 g) in dimethylformamide (50 ml), potassium carbonate (4.0 g ), Methyl iodide (4.0 ml) was added. After stirring at room temperature for 2 hours, the mixture was diluted with ethyl acetate (200 ml). Washed with 1N hydrochloric acid and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to
Bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (3.47 g) was obtained. This 5-bromo-4-
Methyl-2-thiophenecarboxylic acid methyl ester (2.36 g), zinc dust (1.65 g), acetic acid (10 m
A mixture of l) and water (10 ml) was stirred with heating under reflux for 3 hours. Zinc powder (1 g) and acetic acid (10 ml) were added, and the mixture was further stirred under heating and reflux for one day. After cooling, the reaction mixture was poured into concentrated aqueous ammonia and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give methyl 4-methyl-2-thiophenecarboxylate (1.4.
2 g) were obtained. This methyl 4-methyl-2-thiophenecarboxylate (1.42 g) was added to methanol (10
ml), dissolved in tetrahydrofuran (30 ml)
A 1N aqueous sodium hydroxide solution (15 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. After washing the reaction solution with diethyl ether, the aqueous layer was acidified with 1N hydrochloric acid. It was extracted with diethyl ether and dried over anhydrous magnesium sulfate.
The mixture was concentrated under reduced pressure to obtain 4-methyl-2-thiophenecarboxylic acid (1.16 g).

Reference Example 141 5-Bromo-4-methyl- 2-thiophenecarboxylic acid 2-Bromo-3-methylthiophene (8.85 g) and dichloromethyl methyl ether (6.27 g) in dichloromethane (100 ml) were chlorinated. Aluminum (14.
6g) was added little by little under ice cooling. Thereafter, the mixture was stirred at room temperature for 1 hour. The reaction was poured into ice water and acidified with 1N hydrochloric acid. Extracted with ethyl acetate and washed with aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5-bromo-4-methyl-2-thiophenecarbaldehyde (8.0 g). 5-Bromo-4-methyl-2-thiophenecarbaldehyde (6.18 g) was dissolved in acetonitrile (100 ml) and an aqueous solution of sodium dihydrogen phosphate (1.3 g) (20 ml) was added.
Aqueous hydrogen peroxide solution (3.8 ml) was added. Then, an aqueous solution of sodium chlorite (4.07 g) (5
0 ml) was added dropwise. Thereafter, the mixture was stirred at room temperature for 2 hours. 1
The mixture was made alkaline with an aqueous N sodium hydroxide solution and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystals of 5-bromo-4-methyl-2-thiophenecarboxylic acid (6.01 g) were obtained. Melting point 159
-161 ° C.

Reference Example 142 5-Difluoromethyl-3 -thiophenecarboxylic acid 5-Bromo-3-thiophenecarboxylic acid (4.14 g)
Was dissolved in tetrahydrofuran (50 ml) to give -78
Cooled to ° C. Add n-butyl lithium (1.6) to the solution.
M hexane solution, 27.5 ml) was slowly added dropwise.
After the addition, the mixture was stirred at the same temperature for 1 hour. N, N
-Dimethylformamide (3.1 ml) was added and the temperature was slowly raised to room temperature. After concentrating the reaction mixture under reduced pressure, 1N
Hydrochloric acid was added to make it acidic. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A crude product of 5-formyl-3-thiophenecarboxylic acid (3.12 g) was obtained. This 5-formyl-3-thiophenecarboxylic acid (3.12 g) was added to N, N-dimethylformamide (50
ml), and ethyl iodide (1.58 ml) and potassium carbonate (2.76 g) were added. After stirring at room temperature for 15 hours, the reaction solution was poured into water. The mixture was extracted with ethyl acetate and washed with a 5% aqueous potassium hydrogen sulfate solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The effective fraction was concentrated under reduced pressure to obtain ethyl 5-formyl-3-thiophenecarboxylate (0.71 g). A solution of the thus-formed ethyl 5-formyl-3-thiophenecarboxylate (1.47 g) in methylene chloride (10 ml) was treated with diethylaminosulfur trifluoride (DAST) (1.
2 ml) in methylene chloride (10 ml) was slowly added dropwise at room temperature. After the dropping was completed, the mixture was stirred at room temperature for 15 hours.
A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the organic layer was separated. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. 5-
Difluoromethyl-3-thiophenecarboxylic acid ethyl ester (0.7 g) was obtained. This 5-difluoromethyl-3-thiophenecarboxylic acid ethyl ester is dissolved in a mixed solvent of ethanol (5 ml) and tetrahydrofuran (5 ml), and a 1N aqueous sodium hydroxide solution (5 ml).
Was added. After stirring at room temperature for 1 hour, the mixture was washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystals of 5-difluoromethyl-3-thiophenecarboxylic acid (0.58 g) were obtained. Melting point 131-132
° C.

Reference Example 143 2,5-Dimethyl-3-thiophenecarboxylic acid Phosphorus oxychloride (10 ml) was slowly added dropwise to dimethylformamide (30 g) under ice cooling. 2,5-Dimethylthiophene (11.2 g) was added and the mixture was stirred at 100 ° C. for 15 hours. The reaction solution was poured into water and extracted with ethyl acetate.
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography.
2,5-Dimethyl-3-thiophenecarbaldehyde (1.41 g) was obtained. 2,5-dimethyl-3-thiophenecarbaldehyde synthesized in this way (3.89 g)
Was dissolved in acetonitrile (30 ml), and an aqueous solution (15 ml) of sodium dihydrogen phosphate (1.2 g) was added.
Aqueous hydrogen peroxide solution (3.5 ml) was added. Then, an aqueous solution of sodium chlorite (3.75 g) (2
0 ml) was added dropwise. Thereafter, the mixture was stirred at room temperature for 2 hours. 1
The mixture was made alkaline with an aqueous N sodium hydroxide solution and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystals of 2,5-dimethyl-3-thiophenecarboxylic acid (4.09 g) were obtained. Melting point 113-11
4 ° C.

Reference Example 144 4-chloro-5-methyl- 2-thiophenecarboxylic acid 5-methyl-2-thiophenecarboxylic acid (2.84 g)
Was dissolved in N, N-dimethylformamide (30 ml), ethyl iodide (1.68 ml) and potassium carbonate (2.
76 g) was added. After stirring at room temperature for 15 hours, the reaction solution was poured into water. The mixture was extracted with diethyl ether and washed with a 5% aqueous potassium hydrogen sulfate solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give 2-methyl-3-thiophenecarboxylic acid ethyl ester (1.84 g). 5-
Ethyl methyl-2-thiophenecarboxylate (1.84 g) was dissolved in acetonitrile (30 ml), and a solution of sulfuryl chloride (1.31 ml) in acetonitrile (20 ml) was added dropwise. While cooling in a water bath 1.
After stirring for 5 hours, a 10% aqueous solution of sodium thiosulfate (10%
0 ml) and stirred at room temperature for 2 hours. The mixture was extracted with diethyl ether and washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The effective fraction was concentrated under reduced pressure to obtain ethyl 4-chloro-5-methyl-2-thiophenecarboxylate (1.67 g). Part 4
-Chloro-5-methyl-2-thiophenecarboxylic acid ethyl ester (1.67 g) was added to ethanol (10 ml),
After dissolving in a mixed solvent of tetrahydrofuran (10 ml), a 1N aqueous sodium hydroxide solution (16 ml) was added. After stirring at 60 ° C. for 2 hours, the mixture was washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystals of 4-chloro-5-methyl-2-thiophenecarboxylic acid (0.98 g) were obtained. Melting point 164-165
° C.

Reference Example 145 5-Chloro-4-methyl- 2-thiophenecarboxylic acid 4-Methyl-2-synthesized by the same method as Reference Example 140
Thiophenecarboxylic acid ethyl ester (3.4 g) was dissolved in acetonitrile (30 ml), and a solution of sulfuryl chloride (2.4 ml) in acetonitrile (20 ml) was added dropwise. After stirring at room temperature for 30 minutes, a 10% aqueous sodium thiosulfate solution (100 ml) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with diethyl ether and washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The effective fraction was concentrated under reduced pressure to give ethyl 5-chloro-4-methyl-2-thiophenecarboxylate (4.09).
g) was obtained. The ethyl 5-chloro-4-methyl-2-thiophenecarboxylate (4.09 g) was dissolved in a mixed solvent of ethanol (20 ml) and tetrahydrofuran (20 ml), and a 1N aqueous sodium hydroxide solution (4
0 ml) was added. After stirring at 60 ° C. for 2 hours, the mixture was washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystals of 5-chloro-4-methyl-2-thiophenecarboxylic acid (2.37 g) were obtained. Melting point 14
4-145 ° C.

Reference Example 146 4,5-Dichloro-2-thiophenecarboxylic acid 5-chloro-2-thiophenecarboxylic acid (6.50 g)
Was dissolved in N, N-dimethylformamide (30 ml), ethyl iodide (3.2 ml), potassium carbonate (5.5).
2g) was added. After stirring at room temperature for 15 hours, the reaction solution was poured into water. The mixture was extracted with diethyl ether and washed with a 5% aqueous potassium hydrogen sulfate solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give ethyl 5-chloro-2-thiophenecarboxylate (5.27 g). 5-chloro-2-thiophenecarboxylic acid ethyl ester (2.
23 g) was dissolved in acetonitrile (30 ml) and sulfuryl chloride (1.4 ml) in acetonitrile (20 m
l) The solution was added dropwise. After stirring at room temperature for 48 hours, a 10% aqueous solution of sodium thiosulfate (100 ml) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with diethyl ether and washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The effective fraction is concentrated under reduced pressure to give ethyl 4,5-dichloro-2-thiophenecarboxylate (6.
21 g) was obtained. The ethyl 4,5-dichloro-2-thiophenecarboxylate (6.21 g) was dissolved in a mixed solvent of ethanol (25 ml) and tetrahydrofuran (25 ml), and a 1N aqueous sodium hydroxide solution (50 ml) was added.
ml) was added. After stirring at 60 ° C. for 15 hours, the mixture was washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystals of 4,5-dichloro-2-thiophenecarboxylic acid (2.14 g) were obtained. Melting point 162-1
63 ° C.

[0097] Reference Example 147 4-bromo-3-thiophene Nkarubon acid 3-bromo-4-methylthiophene (8.85 g), N
A mixture of -bromosuccinimide (8.85 g), 2,2'-azobis (isobutyronitrile) (0.16 g) and carbon tetrachloride (100 ml) was stirred for 6 hours while heating under reflux. The reaction mixture was concentrated under reduced pressure to obtain a crude product of 3-bromo-4-bromomethylthiophene. A suspension of the crude product of 3-bromo-4-bromomethylthiophene, potassium acetate (30 g), and acetone (100 ml) was stirred at room temperature for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain a crude product of 4-acetoxymethyl-2-bromothiophene. This crude product was dissolved in tetrahydrofuran (50 ml), and a 1N aqueous sodium hydroxide solution (50 ml) and ethanol (20 ml) were added. After stirring at room temperature for 2 hours, the reaction solution was washed with diethyl ether, and the aqueous layer was acidified with 1N hydrochloric acid. Extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to obtain an oil of 3-bromo-4-hydroxymethylthiophene (5.33 g). This 3-bromo-4-
Hydroxymethylthiophene is converted to methylene chloride (100m
Dissolved in 1) and added manganese dioxide (15 g).
After stirring at room temperature for 6 hours, insolubles were filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product of 4-bromo-3-thiophenecarbaldehyde. The crude product of 4-bromo-3-thiophenecarbaldehyde was converted to acetonitrile (50 m
l) Sodium dihydrogen phosphate (1.2 g)
Aqueous solution (15 ml), 30% hydrogen peroxide aqueous solution (3.
5 ml) was added. Then, an aqueous solution (40 ml) of sodium chlorite (3.7 g) was added dropwise under ice cooling. Thereafter, the mixture was stirred at room temperature for 2 hours. The mixture was made alkaline with a 1N aqueous sodium hydroxide solution and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 4-bromo-
Crystals of 3-thiophene carboxylic acid (3.40 g) were obtained. Melting point 161-162 [deg.] C.

[0098] Reference Example 148 2-chloro-3-thiophene Nkarubon acid 3-methyl thiophene (19.63g) was dissolved in acetonitrile (100ml) sulfuryl chloride (16.6
4 ml) was added dropwise. After stirring at room temperature for 1 hour, the mixture was stirred for 1 hour while heating under reflux. After cooling to room temperature, a 10% aqueous sodium thiosulfate solution (200 ml) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with diethyl ether and washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give 2-chloro-3-methylthiophene (21.52 g).
I got 2-chloro-3-methylthiophene (3.53
g), N-bromosuccinimide (4.73 g), 2,
2'-azobis (isobutyronitrile) (0.87 g),
A mixed solution of carbon tetrachloride (25 ml) was stirred for 4 hours while heating under reflux. After the reaction mixture was cooled to room temperature, insolubles were filtered off and the filtrate was concentrated under reduced pressure. A crude product of 2-chloro-3-bromomethylthiophene was obtained. This 2-chloro-
A suspension of a crude product of 3-bromomethylthiophene, potassium acetate (9.82 g), and acetone (50 ml) was stirred at room temperature for 48 hours. The reaction mixture was poured into water and extracted with diethyl ether. After drying over anhydrous magnesium sulfate,
After concentration under reduced pressure, a crude product of 3-acetoxymethyl-2-chlorothiophene was obtained. This crude product was dissolved in a mixed solvent of ethanol (25 ml) and tetrahydrofuran (25 ml), and a 1N aqueous sodium hydroxide solution (50 m
l) was added. After stirring at room temperature for 30 minutes, the aqueous layer was acidified with 1N hydrochloric acid. Extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography. The effective fraction was concentrated under reduced pressure to obtain 3-hydroxymethyl-2-chlorothiophene (3.22 g). 3-hydroxymethyl-2
-Chlorothiophene (3.16 g) in methylene chloride (5
0 ml) and manganese dioxide (9.66 g) was added. After stirring at room temperature for 15 hours, insolubles were filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product of 2-chloro-3-thiophenecarbaldehyde (3.16 g). Two
The crude product of -chloro-3-thiophenecarbaldehyde was dissolved in acetonitrile (20 ml) and an aqueous solution (10 ml) of sodium dihydrogen phosphate (0.67 g) was added.
A 0% aqueous hydrogen peroxide solution (2.6 ml) was added. Then, an aqueous solution (30 ml) of sodium chlorite (3.41 g) was added dropwise under ice cooling. Thereafter, the mixture was stirred at room temperature for 2 hours. The mixture was made alkaline with a 1N aqueous sodium hydroxide solution and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystals of 2-chloro-3-thiophenecarboxylic acid (1.92 g) were obtained. Melting point 166-16
7 ° C.

[0099] Reference Example 149 2-Methyl-3-Franca carboxylic acid 2-methyl-3-furancarboxylic acid ethyl ester (1
0 g) was dissolved in ethanol (70 ml), and a 1N aqueous sodium hydroxide solution (78 ml) was added. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The crystals precipitated by concentration under reduced pressure were collected by filtration with diisopropyl ether. Crystals of 2-methyl-3-furancarboxylic acid (5.5 g) were obtained. Melting point 101-102 [deg.] C.

[0100] Reference Example 150 5-Bromo-3- Franca carboxylic acid [J.Org.Chem., 41, 2350 ( 1976)] was synthesized by the method described.

[0102] Reference Example 151 5-Chloro-2-Franca carboxylic acid 5-chloro-2-furancarboxylic acid ethyl ester (8
g) [Synthesized by the method described in [Chem. Pharm. Bull., 40, 1966 (1992)]] was dissolved in ethanol (50 ml), and a 1N aqueous sodium hydroxide solution (50 ml) was added. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration and washed with diethyl ether-hexane. 5-chloro-2
-Crystals of furancarboxylic acid (5.3 g) were obtained. Melting point 1
82-183 ° C (decomposition).

[0102] Reference Example 152 5-methyl-2-Franca carboxylic acid [JCSPerkin 1, 1125 (1981) ] was synthesized by the method described.

[0103] Reference Example 153 5-ethyl-2-Franca carboxylic acid 2-ethyl-furan (9.1 g) was cooled to dissolved nitrogen stream -70 to ℃ diethyl ether n- butyl lithium (1.6M hexane The solution, 60 ml) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. Again -70
° C and introduce carbon dioxide gas into the reaction solution.
Stir for 0 minutes. Slowly raise the temperature to room temperature.
Stir for 0 minutes. The reaction solution was poured into ice water and acidified with concentrated hydrochloric acid. The mixture was extracted with diethyl ether and washed with saturated saline. After concentration under reduced pressure, the residue was crystallized from water and collected by filtration. 5-Ethyl-2-furancarboxylic acid (9 g) was obtained. 92-94 ° C.

[0104] Reference Example 154 2-chloro-3-Franca carboxylic acid 2-trimethylsilyl-3-furancarboxylic acid (16.
4g) [Synthesized by the method described in [JCSPerkin 1, 1125 (1981)]] was dissolved in N, N-dimethylformamide (50 ml), and potassium carbonate (12.3 g),
Ethyl iodide (13.9 g) was added. After stirring at room temperature for 15 hours, the reaction solution was poured into ice water. The mixture was extracted with diethyl ether and washed sequentially with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The effective fraction was concentrated under reduced pressure to obtain an oil of 2-trimethylsilyl-3-furancarboxylic acid ethyl ester (16.3 g). This ethyl 2-trimethylsilyl-3-furancarboxylate (16.3 g) was added to acetonitrile (75 ml).
And a solution of sulfuryl chloride (10.9 g) in acetonitrile (25 ml) was added dropwise. After the addition, the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with diethyl ether. The extract was washed successively with a 10% aqueous sodium thiosulfate solution and a saturated saline solution and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography. The effective fraction is concentrated under reduced pressure to give 2-chloro-3-furancarboxylic acid ethyl ester (3.5
g) was obtained. This ethyl 2-chloro-3-furancarboxylate (3.5 g) was added to ethanol (25 g).
dissolved in a 1N aqueous sodium hydroxide solution (25 ml).
ml) was added. After stirring at room temperature for 1.5 hours, the reaction solution was concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the precipitated crystals were collected by filtration and washed with diisopropyl ether-hexane. Two
Crystals of -chloro-3-furancarboxylic acid (2.2 g) were obtained. 138-141 ° C.

[0105] Reference Example 155 5-Chloro-3-Franca carboxylic acid 5-trimethylsilyl-3-furancarboxylic acid (4.1
g) [Synthesized by the method described in [Tetrahedron Lett. 25, 4451 (1984)]] and tetrahydrofuran (100
ml) and dissolved in N, N-dimethylformamide (3 ml).
Drops) were added. Oxalyl chloride (3.0 g) was added dropwise under cooling with water, and after completion of the addition, the mixture was stirred at room temperature for 30 minutes. Ethanol (100 ml) and triethylamine (4.7 g) were sequentially added to the reaction solution. Stirred at room temperature for 15 hours.
The reaction solution was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate and washed sequentially with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The effective fraction was concentrated under reduced pressure to obtain an oil of ethyl 5-trimethylsilyl-3-furancarboxylate (3 g). This 5-trimethylsilyl-3-furancarboxylic acid ethyl ester (3.0 g) was dissolved in acetonitrile (15 ml), and a solution of sulfuryl chloride (2.0 g) in acetonitrile (5 ml) was added dropwise. After completion of dropping, the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and extracted with diethyl ether. The extract was washed successively with a 10% aqueous sodium thiosulfate solution and a saturated saline solution and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography. The effective fraction is concentrated under reduced pressure to give 5-chloro-3.
-An oil of furancarboxylic acid ethyl ester (1.9 g) was obtained. This 5-chloro-3-furancarboxylic acid ethyl ester (1.9 g) was dissolved in ethanol (15 ml), and a 1N aqueous sodium hydroxide solution (12 ml) was added. After stirring at room temperature for 1.5 hours, the reaction solution was concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the precipitated crystals were collected by filtration and washed with hexane. Crystals of 5-chloro-3-furancarboxylic acid (1.1 g) were obtained. 124-125 ° C.

Reference Example 156 5-Difluoromethyl-2- furancarboxylic acid 5-Formyl-2-furancarboxylic acid (2.9 g) was added to N,
After dissolving in N-dimethylformamide (30 ml), potassium carbonate (2.9 g) and ethyl iodide (3.6 g) were added. After stirring at room temperature for 12 hours, the reaction solution was poured into ice water.
The mixture was extracted with diethyl ether and washed sequentially with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The effective fraction was concentrated under reduced pressure to obtain ethyl 5-formyl-2-furancarboxylate (1.3 g). A solution of this ethyl 5-formyl-2-furancarboxylate (1.3 g) in methylene chloride (5 ml) was slowly added dropwise to a solution of diethylaminosulfur trifluoride (DAST) (1.3 g) in methylene chloride (5 ml) at room temperature. . After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, which was extracted with diethyl ether. The extract was washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography. The effective fraction was concentrated under reduced pressure to give 5-difluoromethyl-2-furancarboxylic acid ethyl ester (0.1%).
7 g) was obtained. Ethyl 5-difluoromethyl-2-furancarboxylate thus synthesized (2.3 g)
Was dissolved in ethanol (20 ml) and 1N aqueous sodium hydroxide solution (15 ml) was added. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration and washed with hexane-isopropyl ether. Crystals of 5-difluoromethyl-2-furancarboxylic acid (1.2 g) were obtained. 112-113 ° C.

[0107] Reference Example 157 5-methyl-2-a trifluoromethyl-3- Franca Le
It was synthesized by the method described in boric acid [J. Heterocycl. Chem., 5, 95 (1968)].

Reference Example 158 2,5-Dimethyl-3-furancarboxylic acid 2,5-Dimethyl-3-furancarboxylic acid ethyl ester (14.6 g) [JACS, 59, 2525 (1937)] Was synthesized in ethanol] (100 ml) and 1N aqueous sodium hydroxide solution (100 ml) was added. After stirring at room temperature for 1 hour, the mixture was stirred for 30 minutes while heating under reflux. After concentrating the reaction solution under reduced pressure, the residue was dissolved in water and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The crystals precipitated by concentration under reduced pressure were recrystallized from acetone-hexane.
Crystals of 2,5-dimethyl-3-furancarboxylic acid (7.3 g) were obtained. 139-140 ° C.

Reference Example 159 5-Chloro-2-methyl- 3-furancarboxylic acid 2-methyl-3-furancarboxylic acid ethyl ester (1
0.5 g) was dissolved in acetonitrile (50 ml), and sulfuryl chloride (5.6 ml) was added under ice-cooling. 10 ℃
After stirring for 30 minutes, a 10% aqueous solution of sodium thiosulfate (100 ml) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with diethyl ether and washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The effective fraction was concentrated under reduced pressure to obtain an oil of ethyl 5-chloro-2-methyl-3-furancarboxylate (10 g). This 5-chloro-2-methyl-3-furancarboxylic acid ethyl ester (10 g) was dissolved in ethanol (100 ml), and a 1N aqueous sodium hydroxide solution (60 ml) was added. The mixture was stirred under reflux with heating for 30 minutes and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The crystals precipitated by concentration under reduced pressure were recrystallized from acetone-hexane. 5-chloro-2-methyl-
Crystals of 3-furancarboxylic acid (5.5 g) were obtained. 126-127 ° C.

[0110] Reference Example 160 2-ethyl-3 Franca carboxylic acid [JCSPerkin 1, 1125 (1981) ] was synthesized by the method described.

Reference Examples 161 to 169 The following compounds were synthesized in the same manner as in Reference Example 60.

[Table 5]

4) These compounds were synthesized by the following method. 5-chloro-4-methyl-3-thiophenecarboxylic acid
Mido 2,5-dichloro-4-methyl-3-thiophenecarbo
Synthesized 4-methyl in the same manner as phosphate amide Reference Example 171 3-
Thiophenecarboxylic acid (1.42 g) was dissolved in N, N-dimethylformamide (30 ml), and ethyl iodide (0.8 ml) and potassium carbonate (1.38 g) were added.
After stirring at room temperature for 15 hours, the reaction solution was poured into water. The mixture was extracted with diethyl ether and washed with a 5% aqueous potassium hydrogen sulfate solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain ethyl 4-methyl-3-thiophenecarboxylate (1.7 g). Ethyl 4-methyl-3-thiophenecarboxylate (1.70 g) was dissolved in acetonitrile (30 ml) to give sulfuryl chloride (1.2).
ml) in acetonitrile (20 ml) was added. After stirring at room temperature for 1 hour, a 10% aqueous sodium thiosulfate solution (100 ml) was added, and the mixture was stirred at room temperature for 2 hours. After extraction with ethyl acetate, drying over anhydrous magnesium sulfate, concentration under reduced pressure, ethyl 5-chloro-4-methyl-3-thiophenecarboxylate and 2,5-dichloro-4-methyl-3-thiophenecarboxylate A mixture of ethyl esters was obtained. Ethanol (10m
l) and dissolved in a mixed solvent of tetrahydrofuran (10 ml), and a 1N aqueous sodium hydroxide solution (20 ml) was added. After stirring at room temperature for 2 hours, the mixture was washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of 5-chloro-4-methyl-3-thiophenecarboxylic acid and 2,5-dichloro-4-methyl-3-thiophenecarboxylic acid was obtained. The mixture was dissolved in toluene (15
oxalyl chloride (1.31 ml)
Was dripped. N, N-Dimethylformamide (1 drop) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (5 ml). The solution was added dropwise to a mixture of 25% aqueous ammonia (16 ml) and ethyl acetate (50 ml) with stirring under ice-cooling.
After completion of the dropwise addition, the mixture was stirred at room temperature for 10 minutes to separate an organic layer.
The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-
Chloro-4-methyl-3-thiophenecarboxamide (0.83 g) and 2,5-dichloro-4-methyl-3-thiophenecarboxamide (0.61 g) were obtained.

[0113] Reference Example 170 4-Chloro-2-thiophene Nkarubon acid [J.Heterocyclic Chem., 13, 393 (1976)] was synthesized by the method described in.

[0114] Reference Example 171 4-Methyl-3-thiophene Nkarubon acid [J. Org. Chem., 51 , 230 (1986)] was synthesized by the method described in.

Reference Example 172 5-Bromo-2-chloro- 3-thiophenecarboxylic acid 2-chloro-3-thiophenecarboxylic acid (2.44)
A mixture of g), pyridinium bromide bromide (5.33 g) and acetic acid (15 ml) was stirred at 40 ° C. for 4 hours. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration. It was dissolved in ethyl acetate and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave crystals of 5-bromo-2-chloro-3-thiophenecarboxylic acid (2.81 g). Melting point 159-16
0 ° C.

Reference Example 173 2-Chloro-5-methyl- 3-thiophenecarboxylic acid 5-Bromo-2-chloro-3-thiophenecarboxylic acid (2.41 g) was dissolved in tetrahydrofuran (50 ml) and the temperature was adjusted to -78 ° C. Cooled. n-butyl lithium (1.
6M hexane solution, 14 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour, and then methyl iodide (1.4 ml) was added dropwise. After completion of the dropwise addition, the mixture was heated to room temperature and stirred for 15 hours. The reaction solution was poured into water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystals of 2-methyl-3-thiophenecarboxylic acid (1.7 g) were obtained.

Reference Example 174 3,5-Dimethyl-2-thiophenecarboxylic acid 3-Methyl-2-thiophenecarboxylic acid (7.11 g)
Was dissolved in tetrahydrofuran (100 ml) to give -78.
Cooled to ° C. After n-butyllithium (a 1.6 M hexane solution, 69 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour, methyl iodide (6.2 ml) was added dropwise. After completion of the dropwise addition, the mixture was heated to room temperature and stirred for 15 hours. The reaction solution was poured into water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 3,5-dimethyl-2-thiophenecarboxylic acid (4.
97 g) of crystals were obtained. 153-155 ° C.

[0118] Reference Example 175 3-methyl-2-Franca carboxylic acid [Org. Synth., IV, 628] was synthesized by the method described in.

[0119] Example 1 N-(diamino phosphinyl) -2-thiophenecarboxylic Cal Bo
Acid amide 2-Thiophenecarboxylic acid amide (3.82 g) was suspended in toluene (25 ml) to give phosphorus pentachloride (6.25 g).
g) was added in small portions. The mixture was heated to 65 ° C. and stirred for 3 hours. The reaction was cooled to room temperature and formic acid (1.38 g)
Was dripped. After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration. After washing with toluene, it was air-dried to obtain 6.67 g of crystals. The crystals are converted to tetrahydrofuran (100 m
l). Ammonia gas was introduced under ice cooling for 30 minutes. After the introduction, the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with water. The solid obtained by air drying was recrystallized from water. Colorless crystals of N- (diaminophosphinyl) -2-thiophenecarboxamide (1.56 g) were obtained. 272-280 ° C. Elemental analysis _{C 5 H 8 N 3 O 2} SP theoretically:. C, 29.27; H, 3.93; N, 20.48 Found:. C, 29.42; H, 4.00; N, 20.40 1 H-NMR (DMSO- d ₆ ) δ: 4.23 (4H, br s), 7.14-7.18 (1H,
m), 7.83-8.15 (1H, d, J = 5.2Hz), 8.13 (1H, m), 9.16
(1H, br s).

[0120] Example 2 N-(diamino phosphinyl) -3- thiophene Cal Bo
Acid amide 3-Thiophenecarboxylic acid amide (3.18 g) was suspended in toluene (25 ml) to give phosphorus pentachloride (5.21 g).
g) was added in small portions. The mixture was heated to 65 ° C. and stirred for 3 hours. The reaction was cooled to room temperature and formic acid (1.15 g)
Was dripped. After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration. After washing with toluene, it was air-dried to obtain 5.43 g of crystals. The crystals are converted to tetrahydrofuran (100 m
l). Ammonia gas was introduced under ice cooling for 30 minutes. After the introduction, the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with water. The solid obtained by air drying was recrystallized from methanol. Colorless crystals of N- (diaminophosphinyl) -3-thiophenecarboxamide (1.05 g) were obtained. 269-278 ° C. Elemental analysis _{C 5 H 8 N 3 O 2} SP theoretically:. C, 29.27; H, 3.93; N, 20.48 Found:. C, 29.12; H, 3.78; N, 20.62 1 H-NMR (DMSO- d ₆ ) δ: 4.20 (4H, br s), 7.57-7.64 (2H,
m), 8.48-8.50 (1H, m), 9.13 (1H, br s).

[0121] Example 3 N-(diamino phosphinyl) -5-methyl-2-Ji o
Phencarboxylic acid amide 5-methyl-2-thiophenecarboxylic acid amide (4.2
4 g) were suspended in toluene (25 ml), and phosphorus pentachloride (6.25 g) was added in small portions. Heat to 65 ° C and add 1
Stirred for hours. The reaction was cooled to room temperature and formic acid (1.38 g) was added dropwise. After stirring at room temperature for 2 hours,
The precipitated crystals were collected by filtration. After washing with toluene, it was air-dried to obtain 6.93 g of crystals. The crystals were dissolved in tetrahydrofuran (100 ml). Ammonia gas was introduced under ice cooling for 30 minutes. After the introduction, the mixture was stirred at room temperature for 1 hour.
The precipitate was collected by filtration and washed with water. The solid obtained by air drying was recrystallized from water-methanol. Colorless crystals of N- (diaminophosphinyl) -5-methyl-2-thiophenecarboxamide (3.86 g) were obtained. Melting point 284-293
° C. Elemental analysis _{C 6 H 10 N 3 O 2} SP theoretically:. C, 32.88; H, 4.60; N, 19.17 Found:. C, 32.68; H, 4.67; N, 19.17 1 H-NMR (DMSO- d ₆ ) δ: 2.49 (3H, s), 4.20 (4H, br s),
6.87 (1H, d, J = 3.6Hz), 7.94 (1H, d, J = 3.6Hz), 9.27
(1H, br s).

[0122] Example 4 N-(diamino phosphinyl) -3-methyl-2-Ji o
Phencarboxylic acid amide 3-Methyl-2-thiophenecarboxylic acid amide (4.2
4 g) were suspended in toluene (25 ml), and phosphorus pentachloride (6.25 g) was added in small portions. Heat to 65 ° C and add 1
Stirred for hours. The reaction was cooled to room temperature and formic acid (1.38 g) was added dropwise. After stirring for 1 hour at room temperature,
Hexane was added and stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with toluene, and air-dried to obtain 7.10 g of crystals. The crystals are washed with tetrahydrofuran (100 ml)
Was dissolved. Ammonia gas was introduced under ice cooling for 30 minutes. After the introduction, the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with water. Colorless crystals of N- (diaminophosphinyl) -3-methyl-2-thiophenecarboxamide (2.50 g) were obtained. Melting point 267-275 [deg.] C. Elemental analysis _{C 6 H 10 N 3 O 2} SP theoretically:. C, 32.88; H, 4.60; N, 19.17 Found:. C, 33.26; H, 4.55; N, 19.35 1 H-NMR (DMSO- d ₆ ) δ: 2.47 (3H, s), 4.20 (4H, br s),
6.84 (1H, d, J = 3.7Hz), 7.94 (1H, d, J = 3.7Hz), 9.50
(1H, d, J = 7.2Hz).

Examples 5 to 38 The following compounds were synthesized in the same manner as in Example 1.

[0124] Example 5 N-(diamino phosphinyl) -5-chloro-2- Ji o
Fencarboxylic acid amide Melting point 273-279 ° C Elemental analysis value C ₅ H ₇ N ₃ O ₂ SClP Theoretical value: C, 25.06; H, 2.94; N, 17.54. Actual value: C, 25.10; H, 2.88; N, 17.55. ¹ H-NMR (DMSO-d ₆ ) δ: 4.25 (4H, br s), 7.22 (1H, d, J
= 4.0Hz), 8.01 (1H, d, J = 4.0Hz), 9.48 (1H, br s).

[0125] EXAMPLE 6 N-(diamino phosphinyl) -5-bromo-2-Ji o
Fen-carboxylic acid amide mp 238-244 ° C. Elemental analysis _{C 5 H 7 N 3 O 2} SBrP theoretically:. C, 21.14; H, 2.48; N, 14.79 Found: C, 21.22; H, 2.45 ; N, 14.88. ¹ H-NMR (DMSO-d ₆ ) δ: 4.25 (4H, br s), 7.32 (1H, d, J
= 4.0Hz), 7.95 (1H, d, J = 4.0Hz), 9.47 (1H, d, J = 7.4H
z).

Example 7 N- (diaminophosphinyl ) -4,5-dibromo-2
- thiophenecarboxylic acid amide mp 257-266 ° C. Elemental analysis _{C 5 H 6 N 3 O 2} SBr 2 P theoretically:. C, 16.55; H, 1.67; N, 11.58 Found: C, 16.70; H, 1.55 ; N, 11.46. ¹ H NMR (DMSO-d ₆ ) δ: 4.28 (4H, br s), 8.14 (1H, s),
9.65 (1H, d, J = 6.4Hz).

[0127] Example 8 N-(diamino phosphinyl) -4-bromo-2-Ji o
Fencarboxylic acid amide Melting point 263-268 ° C Elemental analysis value C ₅ H ₇ N ₃ O ₂ SBrP theoretical value: C, 21.14; H, 2.48; N, 14.79. Found value: C, 21.27; H, 2.39; N, 14.75. ¹ H-NMR (DMSO-d ₆ ) δ: 4.24 (4H, br s), 7.96 (1H, d, J
= 1.4Hz), 8.13 (1H, d, J = 1.4Hz), 9.58 (1H, br s).

[0128] Example 9 N-(diamino phosphinyl) -5-ethyl-2-Ji o
Fencarboxylic acid amide Melting point 167-174 ° C Elemental analysis value C ₇ H ₁₂ N ₃ O ₂ SP Theoretical value: C, 36.05; H, 5.19; N, 18.02. Actual value: C, 35.97; H, 5.02; N, 18.16. ¹ H-NMR (DMSO-d ₆ ) δ: 1.24 (3H, t, J = 7.0Hz), 2.82 (2H,
q, J = 7.0Hz), 4.16 (4H, br s), 6.88 (1H, d, J = 4.0H
z), 7.91 (1H, d, J = 4.0Hz), 9.35 (1H, br d, J = 7.0 H
z).

[0129] Example 10 N-(diamino phosphinyl) -5-nitro-2-Ji o
Fencarboxylic acid amide Melting point 183-187 ° C Elemental analysis value C ₅ H ₇ N ₄ O ₄ SP Theoretical value: C, 24.01; H, 2.82; N, 22.40. Actual value: C, 24.44; H, 2.92; N, ^{. 22.35 1 H-NMR (DMSO} -d 6) δ: 4.36 (4H, br s), 8.04-8.32 (2H,
m), 10.01 (1H, br s).

[0130] Example 11 N-(diamino phosphinyl) -5-bromo-3- Ji o
Fen-carboxylic acid amide mp 193-196 ° C. Elemental analysis _{C 5 H 7 N 3 O 2} SBrP theoretically:. C, 21.14; H, 2.48; N, 14.79 Found: C, 21.38; H, 2.23 ; N, 15.04. ¹ H-NMR (DMSO-d ₆ ) δ: 4.17 (4H, br s), 7.68 (1H, d, J
= 1.6Hz), 8.40 (1H, d, J = 1.6Hz), 9.28 (1H, d, J = 6.8H
z).

[0131] Example 12 N-(diamino phosphinyl) -5-cyano-2- Ji o
Fencarboxylic acid amide Melting point 200-205 ° C (decomposition) Elemental analysis value C ₆ H ₇ N ₄ O ₂ SP Theoretical value: C, 31.31; H, 3.07; N, 2
4.34. Found: C, 31.42; H, 3.03; N, 2
4.17. ¹ H-NMR (DMSO-d ₆ ) δ: 4.28 (4H, s), 7.
98 (1H, d, J = 4.0Hz), 8.17 (1H, d, J = 4.0Hz), 9.84
(1H, br d, J = 7.0Hz).

[0132] EXAMPLE 13 N-(diamino phosphinyl) -5-difluoro methylation
2-Thiophenecarboxylic acid amide Melting point 165-169 ° C Elemental analysis value C ₆ H ₈ N ₃ O ₂ SF ₂ P Theoretical value: C, 28.24; H, 3.16; N, 16.47. Actual value: C, 28.24; H ^{, 2.92; N, 16.55 1 H} -NMR (DMSO-d 6) δ:. 4.23 (4H, br s), 7.31 (1H, t, J
= 56Hz), 7.47 (1H, m), 8.07 (1H, m), 9.64 (1H, br d,
J = 7.0Hz).

[0133] Example 14 N-(diamino phosphinyl) -3-chloro-2-Ji o
Fencarboxylic acid amide Melting point 154-164 ° C Elemental analysis value C ₅ H ₇ N ₃ O ₂ SClP Theoretical value: C, 25.06; H, 2.97; N, 17.54. Actual value: C, 25.15; H, 2.70; N, 17.62. ¹ H-NMR (DMSO-d ₆ ) δ: 4.33 (4H, br s), 7.20 (1H, d, J
= 5.3Hz), 7.93 (1H, d, J = 5.3Hz), 8.45 (1H, d, J = 6.0H
z).

[0134] Example 15 N-(diamino phosphinyl) -2-methyl-3- Ji o
Fencarboxylic acid amide Melting point 155-157 ° C Elemental analysis value C ₆ H ₁₀ N ₃ O ₂ SP 1 / 5H ₂ O Theoretical value: C, 32.34; H, 4.63; N, 19.13. Actual value: C, 32.15; . H, 4.63; N, 19.39 1 H-NMR (DMSO-d 6) δ: 2.62 (3H, s), 4.13 (4H, br s),
7.35 (1H, d, J = 5.4Hz), 7.54 (1H, d, J = 5.4Hz), 8.98
(1H, br s).

[0135] EXAMPLE 16 N-(diamino phosphinyl) -3-bromo-2-Ji o
Fencarboxylic acid amide Melting point 160-167 ° C Elemental analysis value C ₅ H ₇ N ₃ O ₂ SBrP Theoretical value: C, 21.14; H, 2.48; N, 14.79. Actual value: C, 21.38; H, 2.44; N, 14.85. ¹ H-NMR (DMSO-d ₆ ) δ: 4.31 (4H, br s), 7.22 (1H, d, J
= 5.2Hz), 7.90 (1H, d, J = 5.2Hz), 8.55 (1H, d, J = 6.6H
z).

Example 17 N- (diaminophosphinyl ) -5-acetyl-2- thi
Ofencarboxylic acid amide Melting point 185 ° C (decomposition) Elemental analysis value C ₇ H ₁₀ N ₃ O ₃ SP Theoretical value: C, 34.01; H, 4.08; N, 17.00. Actual value: C, 34.34; H, 4.12; N ^{, 17.03 1 H-NMR (DMSO} -d 6) δ:. 2.56 (3H, s), 4.28 (4H, br s),
7.92 (1H, d, J = 4.0Hz), 8.12 (1H, d, J = 4.0Hz), 9.68
(1H, br m).

[0137] EXAMPLE 18 N-(diamino phosphinyl) -5-methanesulfonyl Le
2-Thiophenecarboxylic acid amide Melting point 180-185 ° C (decomposition) Elemental analysis value C ₆ H ₁₀ N ₃ O ₄ S ₂ P Theoretical value: C, 25.44; H, 3.56; N, 14.83. Actual value: C, . 25.90; H, 3.31; N 14.56 1 H-NMR (DMSO-d 6) δ: 3.39 (3H, s), 4.28 (4H, br d, J
= 3.0Hz), 7.81 (1H, d, J = 4.0Hz), 8.13 (1H, d, J = 4.0H
z), 9.78 (1H, d, J = 7.0Hz).

[0138] Example 19 N-(diamino phosphinyl) -3-difluoro methylation
2-Thiophenecarboxylic acid amide Melting point 158-162 ° C Elemental analysis value C ₆ H ₈ N ₃ O ₂ SF ₂ P Theoretical value: C, 28.24; H, 3.16; N, 16.47. Actual value: C, 28.43; H ^{, 2.98; N, 16.58 1 H} -NMR (DMSO-d 6) δ:. 4.25 (4H, br s), 7.37 (1H, d, J
= 5.0Hz), 7.38 (1H, t, J = 55Hz), 7.87 (1H, d, J = 5.0H
z), 9.35 (1H, br s).

[0139] EXAMPLE 20 N-(diamino phosphinyl) -2-difluoro methylation
-3-Thiophenecarboxylic acid amide Melting point 168-173 ° C Elemental analysis value C ₆ H ₈ N ₃ O ₂ SF ₂ P Theoretical value: C, 28.24; H, 3.16; N, 16.47. Actual value: C, 28.56; H ^{, 2.93; N, 16.61 1 H} -NMR (DMSO-d 6) δ:. 4.22 (4H, br s), 7.67 (1H, t, J
= 55Hz), 7.78 (1H, d, J = 5.3Hz), 7.84 (1H, d, J = 5.3H
z), 9.42 (1H, d, J = 6.6Hz).

[0140] Example 21 N-(diamino phosphinyl) -5-nitro-3- Ji o
Fencarboxylic acid amide Melting point 181-184 ° C Elemental analysis value C ₅ H ₇ N ₄ O ₄ SP Theoretical value: C, 24.01; H, 2.82; N, 22.40. Actual value: C, 23.97; H, 2.76; N, 22.14. ¹ H-NMR (DMSO-d ₆ ) δ: 4.24 (4H, br s), 8.57 (1H, d, J
= 1.5Hz), 8.72 (1H, d, J = 1.5Hz), 9.60 (1H, d, J = 6.6H
z).

Example 22 N- (diaminophosphinyl ) -5-methoxy-2- thi
Ofencarboxylic acid amide Melting point 209-216 ° C Elemental analysis value C ₆ H ₁₀ N ₃ O ₃ SP Theoretical value: C, 30.64; H, 4.29; N, 17.87. Found value: C, 30.77; H, 4.17; N, 18.04. ¹ H-NMR (DMSO-d ₆ ) δ: 3.90 (3H, s), 4.14 (4H, br s),
6.35 (1H, d, J = 4.2Hz), 7.86 (1H, d, J = 4.2Hz), 9.25
(1H, br s).

[0142] Example 23 N-(diamino phosphinyl) -3-cyano-2-Ji o
Fencarboxylic acid amide Melting point 211-219 ° C Elemental analysis value C ₆ H ₇ N ₄ O ₂ SP Theoretical value: C, 31.31; H, 3.07; N, 24.34. Actual value: C, 31.27; H, 3.21; N, ^{. 23.99 1 H-NMR (DMSO} -d 6) δ: 4.29 (4H, br s), 7.57 (1H, d, J
= 5.2Hz), 7.98 (1H, d, J = 5.2Hz), 9.49 (1H, br s).

Example 24 N- (diaminophosphinyl ) -4-methoxy-2- thi
Ofencarboxylic acid amide Melting point 206-215 ° C Elemental analysis value C ₆ H ₁₀ N ₃ O ₃ SP Theoretical value: C, 30.64; H, 4.29; N, 17.87. Actual value: C, 30.65; H, 4.42; N, ^{. 17.70 1 H-NMR (DMSO} -d 6) δ: 3.75 (3H, s), 4.20 (4H, br s),
6.91 (1H, d, J = 1.8Hz), 7.82 (1H, d, J = 1.8Hz), 9.44
(1H, d, J = 7.0Hz).

Example 25 N- (diaminophosphinyl ) -2,5-dichloro-3
-Thiophenecarboxylic acid amide Melting point 168-172 ° C Elemental analysis value C ₅ H ₆ N ₃ O ₂ SCl ₂ P Theoretical value: C, 21.91; H, 2.21; N, 15.33. Actual value: C, 21.81; H, 2.38 ^{; N, 15.44 1 H-NMR} (DMSO-d 6) δ:. 4.19 (4H, br s), 7.51 (1H, s),
9.15 (1H, br s).

[0145] Example 26 N-(diamino phosphinyl) -2-bromo-3-Chi O
Fen-carboxylic acid amide mp 160-162 ° C. Elemental analysis _{C 5 H 7 N 3 O 2} SBrP theoretically:. C, 21.14; H, 2.48; N, 14.79 Found: C, 21.19; H, 2.53 ; N, 14.86. ¹ H-NMR (DMSO-d ₆ ) δ: 4.17 (4H, br s), 7.45 (1H, d, J
= 5.0Hz), 7.60 (1H, d, J = 5.0Hz), 9.11 (1H, m).

[0146] Example 27 N-(diamino phosphinyl) -3-ethyl-2-Ji o
Fencarboxylic acid amide Melting point 130-135 ° C Elemental analysis value C ₇ H ₁₂ N ₃ O ₂ SP Theoretical value: C, 36.05; H, 5.19; N, 18.02. Actual value: C, 35.80; H, 5.17; N, 17.81. ¹ H-NMR (DMSO-d ₆ ) δ: 1.16 (3H, t, J = 7.0Hz), 2.89 (2
H, q, J = 7.0Hz), 4.15 (4H, br s), 7.05 (1H, d, J = 5.
0Hz), 7.63 (1H, d, J = 5.0Hz), 8.65 (1H, br d, J = 9.0H
z).

[0147] Example 28 N-(diamino phosphinyl) -4-methyl-2-Ji o
Fencarboxylic acid amide Melting point 160-163 ° C Elemental analysis value C ₆ H ₁₀ N ₃ O ₂ SP Theoretical value: C, 32.88; H, 4.60; N, 19.17. Actual value: C, 32.73; H, 4.60; N, 18.76. ¹ H-NMR (DMSO-d ₆ ) δ: 2.21 (3H, s), 4.14 (4H, br s),
7.40 (1H, s), 7.89 (1H, s), 9.30 (1H, br m).

[0148] Example 29 N-(diamino phosphinyl) -5-bromo-4- main switch
Ru-2-thiophenecarboxylic acid amide Melting point 170-175 ° C Elemental analysis value C ₆ H ₉ N ₃ O ₂ SBrP Theoretical value: C, 24.18; H, 3.04; N, 14.10. Actual value: C, 24.39; H, ^{. 3.13; N, 14.22 1 H} -NMR (DMSO-d 6) δ: 2.14 (3H, s), 4.19 (4H, br s),
7.89 (1H, s), 9.44 (1H, br m).

[0149] Example 30 N-(diamino phosphinyl) -5-chloro-3- Ji o
Fencarboxylic acid amide Melting point 177-184 ° C Elemental analysis value C ₅ H ₇ N ₃ O ₂ SClP Theoretical value: C, 25.06; H, 2.94; N, 17.54. Actual value: C, 25.08; H, 3.08; N, 17.64. ¹ H-NMR (DMSO-d ₆ ) δ: 4.17 (4H, br
s), 7.59 (1H, d, J = 1.0H
z), 8.31 (1H, d, J = 1.0 Hz),
9.30 (1H, d, J = 6.8 Hz).

[0150] Example 31 N-(diamino phosphinyl) -5-difluoro methylation
3-thiophene carboxylic acid amide mp 149-153 ° C. Elemental analysis _{C 6 H 8 N 3 O 2} SF 2 P theoretically:. C, 28.24; H, 3.16; N, 16.47 Found: C, 28.19; H ^{, 3.11; N, 16.42 1 H} -NMR (DMSO-d 6) δ:. 4.17 (4H, br s), 7.31 (1H, t, J
= 55Hz), 7.90 (1H, s), 8.65 (1H, s), 9.38 (1H, d, J =
6.6Hz).

Example 32 N- (diaminophosphinyl ) -2,5-dimethyl-3
-Thiophenecarboxylic acid amide Melting point 159-162 ° C Elemental analysis value As C ₇ H ₁₂ N ₃ O ₂ SP Theoretical value: C, 36.05; H, 5.19; N, 18.02. Found value: C, 35.90; H, 5.04; N ^{, 17.75 1 H-NMR (DMSO} -d 6) δ:. 2.34 (3H, s), 2.57 (3H, s), 4.0
8 (4H, br s), 7.19 (1H, s), 8.76 (1H, br d, J = 7.0H
z).

[0152] Example 33 N-(diamino phosphinyl) -5-chloro-2- main switch
Le-3-thiophenecarboxylic acid amide Melting point 218-225 ° C Elemental analysis value C ₆ H ₉ N ₃ O ₂ SClP Theoretical value: C, 28.41; H, 3.58; N, 16.57. Found value: C, 28.13; H, ^{. 3.58; N, 16.68 1 H} -NMR (DMSO-d 6) δ: 2.60 (3H, s), 4.13 (4H, br s),
7.54 (1H, s), 9.01 (1H, br s).

[0153] Example 34 N-(diamino phosphinyl) -4-chloro-5- main switch
Lu-2-thiophenecarboxylic acid amide Melting point 225-233 ° C Elemental analysis value C ₆ H ₉ N ₃ O ₂ SClP Theoretical value: C, 28.41; H, 3.58; N, 16.57. Actual value: C, 28.58; H, ^{. 3.72; N, 16.69 1 H} -NMR (DMSO-d 6) δ: 2.39 (3H, s), 4.19 (4H, br s),
8.02 (1H, s), 9.44 (1H, br s).

[0154] Example 35 N-(diamino phosphinyl) -5-chloro-4- main switch
Ru-2-thiophenecarboxylic acid amide Melting point 182-184 ° C Elemental analysis value C ₆ H ₉ N ₃ O ₂ SClP Theoretical value: C, 28.41; H, 3.58; N, 16.57. Actual value: C, 28.02; H, ^{. 3.54; N, 16.47 1 H} -NMR (DMSO-d 6) δ: 2.15 (3H, s), 4.19 (4H, br s),
7.92 (1H, s), 9.19 (1H, br s).

Example 36 N- (diaminophosphinyl ) -4,5-dichloro-2
-Thiophenecarboxylic acid amide Melting point 276-278 ° C Elemental analysis value C ₅ H ₆ N ₃ O ₂ SCl ₂ P Theoretical value: C, 21.91; H, 2.21; N, 15.33. Actual value: C, 22.08; H, 2.29 ^{; N, 15.45 1 H-NMR} (DMSO-d 6) δ:. 4.26 (4H, br s), 8.16 (1H, s),
9.43 (1H, br s).

[0156] Example 37 N-(diamino phosphinyl) -4-bromo-3-Chi O
Fencarboxylic acid amide Melting point 149-153 ° C Elemental analysis value C ₅ H ₇ N ₃ O ₂ SBrP Theoretical value: C, 21.14; H, 2.48; N, 14.79. Actual value: C, 21.40; H, 2.56; N, 14.42. ¹ H-NMR (DMSO-d ₆ ) δ: 4.18 (4H, br s), 7.72 (1H, m),
8.28 (1H, m), 9.29 (1H, br m).

Example 38 N- (diaminophosphinyl ) -2-chloro-3-thiof
Encarboxylic acid amide Melting point 153-155 ° C Elemental analysis value C ₅ H ₇ N ₃ O ₂ SClP ・ 1 / 4H ₂ O Theoretical value: C, 24.60; H, 3.10; N, 17.21. Actual value: C, 24.70; H ^{, 3.21; N, 17.04 1 H} -NMR (DMSO-d 6) δ:. 4.17 (4H, br s), 7.40-7.50 (2H,
m), 9.03 (1H, br s).

[0158] Example 39 N-(diamino phosphinyl) -5-bromo-2- off La
Carboxylic acid amide 5-Bromo-2-furancarboxylic acid amide (5.0 g)
Was suspended in toluene (30 ml), and phosphorus pentachloride (5.
8g) was added in small portions. The mixture was heated to 70 ° C. and stirred for 30 minutes. The reaction was cooled to room temperature and the formic acid (1.2
g) was added dropwise. After stirring at room temperature for 30 minutes, the precipitated crystals were collected by filtration. After washing with toluene and hexane in that order, it was air-dried to obtain 7.9 g of crystals. The crystals were dissolved in tetrahydrofuran (150 ml). Ammonia gas was introduced under ice cooling for 30 minutes. After the introduction, the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with water. The solid obtained by air drying was recrystallized from methanol. Colorless crystals of N- (diaminophosphinyl) -5-bromo-2-furancarboxylic acid amide (2.0 g) were obtained. Melting point 175-176
° C. Elemental analysis C ₅ H ₇ N ₃ O ₃ theory as BrP:. C, 22.41; H , 2.63; N, 15.68 Found:. C, 22.44; H, 2.76; N, 15.71 1 H-NMR (DMSO- d ₆ ) δ: 4.22 (4H, s), 6.77 (1H, d, J = 3.
6Hz), 7.55 (1H, d, J = 3.6Hz), 9.28 (1H, d, J = 5.8H
z).

[0159] Example 40 N-(diamino phosphinyl) -2-methyl-3- off La
Carboxylic acid amide 2-Methyl-3-furancarboxylic acid amide (2.0 g)
Was suspended in toluene (30 ml), and phosphorus pentachloride (3.
5 g) were added in small portions. The mixture was heated to 70 ° C. and stirred for 30 minutes. The reaction was cooled to room temperature and formic acid (0.74
g) was added dropwise. After stirring at room temperature for 30 minutes, hexane (20 ml) was added and the mixture was stirred for 10 minutes. The precipitated crystals were collected by filtration, washed with hexane, and air-dried to obtain 3.3 g of crystals. The crystals are converted to tetrahydrofuran (100 m
l). Ammonia gas was introduced under ice cooling for 30 minutes. After the introduction, the mixture was stirred at room temperature for 1 hour. Diethyl ether (100 ml) was added and stirred for 10 minutes. The precipitate was collected by filtration and washed with water. The solid obtained by air drying was recrystallized from methanol. N- (diaminophosphinyl)-
2-methyl-3-furancarboxylic acid amide (0.85
g) colorless crystals were obtained. Melting point 249-253 [deg.] C (decomposition). Elemental analysis _{C 6 H 10 N 3 O 3} P theoretically:. C, 35.48; H, 4.96; N, 20.69 Found:. C, 35.41; H, 4.86; N, 20.68 1 H-NMR (DMSO- d ₆ ) δ: 2.52 (3H, s), 4.13 (4H, s), 7.1
7 (1H, d, J = 2.0Hz), 7.50 (1H, d, J = 2.0Hz), 9.00 (1
(H, d, J = 7.4Hz).

[0160] Example 41 N-(diamino phosphinyl) -5-bromo-3- off La
Carboxylic acid amide 5-Bromo-3-furancarboxylic acid amide (2.0 g)
Was suspended in toluene (30 ml), and phosphorus pentachloride (2.
3g) was added in small portions. The mixture was heated to 70 ° C. and stirred for 30 minutes. The reaction was cooled to room temperature and formic acid (0.48
g) was added dropwise. After stirring at room temperature for 30 minutes, hexane (20 ml) was added and the mixture was stirred for 10 minutes. The precipitated crystals were collected by filtration, washed with hexane, and air-dried to obtain 2.3 g of crystals. The crystals are converted to tetrahydrofuran (100 m
l). Ammonia gas was introduced under ice cooling for 30 minutes. After the introduction, the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with water. The solid obtained by air drying was recrystallized from methanol. Colorless crystals of N- (diaminophosphinyl) -5-bromo-3-furancarboxylic acid amide (1.0 g) were obtained. Melting point 181-183C. Elemental analysis C ₅ H ₇ N ₃ O ₃ theory as BrP:. C, 22.41; H , 2.63; N, 15.68 Found:. C, 22.46; H, 2.40; N, 15.76 1 H-NMR (DMSO- d ₆ ) δ: 4.18 (4H, s), 7.03 (1H, d, J = 1.
0Hz), 8.46 (1H, d, J = 1.0Hz), 9.25 (1H, d, J = 7.0H
z).

Examples 42 to 51 The following compounds were synthesized in the same manner as in Example 39.

[0162] Example 42 N-(diamino phosphinyl) -5-chloro-2- off La
Nkarubon acid amide mp 242-244 ° C. Elemental analysis C ₅ H ₇ N ₃ O ₃ theory as ClP:. C, 26.86; H , 3.16; N, 18.80 Found: C, 26.82; H, 2.96 ; N, 18.85 ^{. 1 H-NMR (DMSO-} d 6) δ: 4.22 (4H, d, J = 2.6Hz), 6.68 (1
H, d, J = 3.5Hz), 7.58 (1H, d, J = 3.5Hz), 9.26 (1H,
d, J = 7.0Hz).

[0163] Example 43 N-(diamino phosphinyl) -5-methyl-2- off La
Carboxylic acid amide Melting point 281-285 ° C (decomposition) Elemental analysis value C ₆ H ₁₀ N ₃ O ₃ P Theoretical value: C, 35.48; H, 4.96; N, 20.69. Actual value: C, 35.56; H, 4.94; N, 20.68. ¹ H-NMR (DMSO-d ₆ ) δ: 2.33 (3H, s), 4.16 (4H, s), 6.2
5 (1H, d, J = 3.0Hz), 7.37 (1H, d, J = 3.0Hz), 8.94 (1
(H, d, J = 7.0Hz).

[0164] Example 44 N-(diamino phosphinyl) -5-ethyl-2- off La
Carboxylic acid amide Melting point 151-153 ° C Elemental analysis value C ₇ H ₁₂ N ₃ O ₃ P ・ 1 / 4H ₂ O Theoretical value: C, 37.93; H, 5.68; N, 18.96. Actual value: C, 37.96; H ^{, 5.56; N, 18.77 1 H} -NMR (DMSO-d 6) δ:. 1.20 (3H, t, J = 7.6Hz), 2.70 (2
H, q, J = 7.6Hz), 4.16 (4H, s), 6.26 (1H, d, J = 3.3H
z), 7.37 (1H, d, J = 3.3Hz), 8.91 (1H, br s).

[0165] Example 45 N-(diamino phosphinyl) -2-chloro-3- off La
Carboxylic amide Melting point 153-155 ° C Elemental analysis value C ₅ H ₇ N ₃ O ₃ ClP Theoretical value: C, 26.86; H, 3.16; N, 18.80. Found value: C, 27.13; H, 3.14; N, 18.61 ^{. 1 H-NMR (DMSO-} d 6) δ: 4.20 (4H, s), 7.33 (1H, d, J = 2.
2Hz), 7.74 (1H, d, J = 2.2Hz), 9.14 (1H, d, J = 7.0H
z).

[0166] Example 46 N-(diamino phosphinyl) -5-chloro-3- off La
Nkarubon acid amide mp 170-171 ° C. Elemental analysis C ₅ H ₇ N ₃ O ₃ theory as ClP:. C, 26.86; H , 3.16; N, 18.80 Found: C, 26.76; H, 3.00 ; N, 18.70 ^{. 1 H-NMR (DMSO-} d 6) δ: 4.18 (4H, s), 6.94 (1H, s), 8.3
9 (1H, s), 9.23 (1H, d, J = 7.4Hz).

[0167] Example 47 N-(diamino phosphinyl) -5-difluoro methylation
-2-furancarboxylic acid amide Melting point 156-158 ° C Elemental analysis value C ₆ H ₈ N ₃ O ₃ F ₂ P Theoretical value: C, 30.14; H, 3.37; N, 17.57. Actual value: C, 30.06; H ^{, 3.14; N, 17.60 1 H} -NMR (DMSO-d 6) δ:. 4.23 (4H, s), 7.01-7.05 (1H,
m), 7.15 (1H, t, J = 53Hz), 7.57 (1H, d, J = 3.6Hz),
9.35 (1H, d, J = 6.0Hz).

[0168] Example 48 N-(diamino phosphinyl) -2-trifluoromethanesulfonyl Ji
Le-5-methyl-3-furancarboxylic acid amide Melting point 158-160 ° C Elemental analysis value C ₇ H ₉ N ₃ O ₃ F ₃ P Theoretical value: C, 31.01; H, 3.35; N, 15.50. C, 31.28; H, 3.40; N, 15.62.1 ¹ H-NMR (DMSO-d ₆ ) δ: 2.35 (3H, s), 4.19 (4H, s), 6.8
5 (1H, s), 9.37 (1H, d, J = 6.8Hz).

Example 49 N- (diaminophosphinyl ) -2,5-dimethyl-2
-Furancarboxylic acid amide Melting point 167-169 ° C Elemental analysis value C ₇ H ₁₂ N ₃ O ₃ P Theoretical value: C, 38.72; H, 5.57; N, 19.35. Found value: C, 38.95; H, 5.33; N ^{, 19.29 1 H-NMR (DMSO} -d 6) δ:. 2.20 (3H, s), 2.47 (3H, s), 4.0
9 (4H, s), 6.71 (1H, s), 8.80 (1H, br s).

[0170] Example 50 N-(diamino phosphinyl) -5-chloro-2- main switch
-3-furancarboxylic acid amide mp 270-275 ° C. (decomposition) Elemental analysis _{C 6 H 9 N 3 O 3} ClP theoretically:. C, 30.33; H, 3.82; N, 17.69 Found: C, 30.32 ; H, 3.96; N, 17.78 1 H-NMR (DMSO-d 6) δ:. 2.52 (3H, s), 4.15 (4H, s), 7.1
3 (1H, s), 9.04 (1H, d, J = 7.4Hz).

[0171] Example 51 N-(diamino phosphinyl) -2-ethyl-3- off La
Carboxylic acid amide Melting point 277-280 ° C (decomposition) Elemental analysis value C ₇ H ₁₂ N ₃ O ₃ P Theoretical value: C, 38.72; H, 5.57; N, 19.35. Actual value: C, 38.68; H, 5.67; N, 19.42. ¹ H-NMR (DMSO-d ₆ ) δ: 1.15 (3H, t, J = 7.6Hz), 2.98 (2
H, q, J = 7.6Hz), 4.09 (4H, s), 7.14 (1H, d, J = 2.2H
z), 7.51 (1H, d, J = 2.2Hz), 8.90 (1H, d, J = 7.0Hz).

[0172] Example 52 N-(diamino phosphinyl) -4-nitrophenoxy
Acetamide 4-nitrophenoxyacetamide (3.5 g) was suspended in toluene (30 ml) to give phosphorus pentachloride (3.9 g).
Was added in small portions. The mixture was heated to 70 ° C. and stirred for 3 hours.
The reaction was cooled to room temperature and formic acid (0.83 g) was added dropwise. After stirring at room temperature for 2 hours, the precipitated crystals were collected by filtration. After washing with toluene, it was air-dried to obtain 3.5 g of crystals. The crystals were dissolved in tetrahydrofuran (150 ml). Ammonia gas was introduced under ice cooling for 30 minutes.
After the introduction, the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with water. The solid obtained by air drying was recrystallized from water. N-
Colorless crystals of (diaminophosphinyl) -4-nitrophenoxyacetamide (0.5 g) were obtained. Melting point 174-
176 ° C. Elemental analysis _{C 8 H 11 N 4 O 5} P theoretically:. C, 35.05; H, 4.04; N, 20.43 Found:. C, 34.84; H, 3.97; N, 20.14 1 H-NMR (DMSO- d ₆ ) δ: 4.19 (4H, s), 4.79 (2H, s), 7.1
0-7.14 (2H, m), 8.18-8.23 (2H, m), 9.08 (1H, d, J =
8.0Hz).

Examples 53 to 81 The following compounds were synthesized in the same manner as in Example 52.

[0174] Example 53 N-(diamino phosphinyl) -4-methoxyphenyl key
Shiasetoamido mp 154-156 ° C. Elemental analysis _{C 9 H 14 N 3 O 4} P theoretically:. C, 41.70; H, 5.44; N, 16.21 Found: C, 41.59; H, 5.21 ; N, 16.14. ¹ H-NMR (DMSO-d ₆ ) δ: 3.70 (3H, s), 4.16 (4H, s), 4.4
9 (2H, s), 6.86 (4H, s), 8.75 (1H, d, J = 8.0Hz).

[0175] Example 54 N-(diamino phosphinyl) -4-fluoro-phenol key
Ciacetamide Melting point 156-158 ° C Elemental analysis value C ₈ H ₁₁ N ₃ O ₃ FP Theoretical value: C, 38.88; H, 4.49; N, 17.00. Actual value: C, 38.81; H, 4.42; N, 17.01. ¹ H-NMR (DMSO-d ₆ ) δ: 4.18 (4H, s), 4.56 (2H, s), 6.9
0-6.97 (2H, m), 7.07-7.16 (2H, m), 8.87 (1H, d, J =
7.0Hz).

[0176] Example 55 N-(diamino phosphinyl) -4-chlorophenoxy
Acetamide Melting point 155-157 ° C Elemental analysis value C ₈ H ₁₁ N ₃ O ₃ ClP Theoretical value: C, 36.45; H, 4.21; N, 15.94. Found value: C, 36.54; H, 4.17; N, 15.72. ¹ H-NMR (DMSO-d ₆ ) δ: 4.18 (4H, s), 4.59 (2H, s), 6.9
2-6.98 (2H, m), 7.31-7.35 (2H, m), 8.91 (1H, d, J =
7.8Hz).

Example 56 N- (diaminophosphinyl ) -2,3,5-trimethyl
Phenoxy acetamide mp 171-173 ° C. Elemental analysis _{C 11 H 18 N 3 O 3} P theoretically:. C, 48.71; H, 6.69; N, 15.49 Found: C, 48.54; H, 6.63 ; N, 15.12. ¹ H-NMR (DMSO-d ₆ ) δ: 2.07 (3H, s), 2.17 (3H, s), 2.2
1 (3H, s), 4.19 (4H, s), 4.53 (2H, s), 6.48 (1H,
s), 6.60 (1H, s), 8.69 (1H, d, J = 8.2Hz).

[0178] Example 57 N-(diamino phosphinyl) -4-cyanophenoxy
Acetamide Melting point 173-178 ° C Elemental analysis value C ₉ H ₁₁ N ₄ O ₃ P Theoretical value: C, 42.53; H, 4.36; N, 2
2.04. Found: C, 42.76; H, 4.38; N, 2
1.97. ¹ H-NMR (DMSO-d ₆ ) δ: 4.22 (4H, br s),
4.73 (2H, s), 7.08 (2H, d, J = 8.6Hz), 7.77 (2H, d,
J = 8.6Hz), 9.06 (1H, br s).

[0179] Example 58 N-(diamino phosphinyl) -3-chlorophenoxy
Acetamide mp 143-148 ° C. Elemental analysis C ₈ H ₁₁ N ₃ O ₃ theory as ClP:. C, 36.45; H , 4.21; N, 15.94 Found:. C, 36.12; H, 4.30; N, 16.08 1 H-NMR (DMSO-d ₆ ) δ: 4.21 (4H, s), 4.63 (2H, s),
6.87-6.93 (1H, m), 6.99-7.03 (2H, m), 7.33 (1H, d,
J = 8.4Hz), 8.93 (1H, br s).

[0180] Example 59 N-(diamino phosphinyl) -2-chlorophenoxy
Acetamide mp 141-148 ° C. Elemental analysis _{C 8 H 11 N 3 O 3} ClP · 1 / 4H 2 O theoretically:. C, 35.84; H, 4.32; N, 15.67 Found: C, 35.44; H, 4.15 ^{; N, 16.03 1 H-NMR} (DMSO-d 6) δ:. 4.21 (4H, br s), 4.71 (2H, s),
6.97-7.01 (2H, m), 7.23-7.32 (1H, m), 7.41-7.46 (1
H, m), 8.84 (1H, br s).

[0181] Example 60 N-(diamino phosphinyl) -3-fluoro phenol key
Ciacetamide Melting point 144-149 ° C Elemental analysis value C ₈ H ₁₁ N ₃ O ₃ FP Theoretical value: C, 38.88; H, 4.49; N, 17.00. Found value: C, 38.97; H, 4.58; N, 17.04. ¹ H-NMR (DMSO-d ₆ ) δ: 4.22 (4H, br s), 4.62 (2H, s),
6.74-6.82 (3H, m), 7.26-7.38 (1H, m), 8.95 (1H, d,
J = 8.4Hz).

[0182] Example 61 N-(diamino phosphinyl) - phenyl thioacetamide A
Bromide mp 156-162 ° C. Elemental analysis _{C 8 H 12 N 3 O 2} SP theoretically:. C, 39.18; H, 4.93; N, 17.13 Found:. C, 39.30; H, 4.97; N, 17.21 1 H-NMR (DMSO-d ₆ ) δ: 3.76 (2H, s), 4.13 (4H, br s),
7.17-7.46 (5H, m), 9.15 (1H, br s).

[0183] Example 62 N-(diamino phosphinyl) -4-fluoro-phenyl-
Thioacetamide Melting point 155-160 ° C Elemental analysis value C ₈ H ₁₁ N ₃ O ₂ SFP theoretical value: C, 36.50; H, 4.21; N, 15.96. Actual value: C, 36.42; H, 3.96; N, 15.98. ¹ H-NMR (DMSO-d ₆ ) δ: 3.71 (2H, s), 4.12 (4H, br s),
7.15 (1H, d, J = 8.8Hz), 7.19 (1H, d, J = 9.0Hz), 7.42
(1H, dd, J = 9.0Hz and 5.4Hz), 7.44 (1H, dd, J = 8.8Hz
and 5.2Hz), 9.11 (1H, br s).

[0184] Example 63 N-(diamino phosphinyl) -2-Benzookisazo Li
160-164 ° C. Elemental analysis Lucio acetamide mp _{C 9 H 11 N 4 O 3} SP theoretically:. C, 37.76; H, 3.87; N, 19.57 Found: C, 37.63; H, 3.78 ; N, 19.48. ¹ H-NMR (DMSO-d ₆ ) δ: 4.16 (4H, br
s), 4.27 (2H, s), 7.30-7.
37 (2H, m), 7.61-7.66 (2
H, m), 9.34 (1H, br s).

[0185] Example 64 N-(diamino phosphinyl) -2-benzothiazolyl Le
166-170 ° C. Elemental analysis thioacetamide mp _{C 9 H 11 N 4 O 2} S 2 P theoretically:. C, 35.76; H, 3.67; N, 18.53 Found: C, 35.75; H, 3.77 ; N, 18.58. ¹ H-NMR (DMSO-d ₆ ) δ: 4.17 (4H, br s), 4.28 (2H, s),
7.34-7.53 (2H, m), 7.84-7.88 (1H, m), 8.01-8.05 (1
H, m), 9.35 (1H, br s).

[0186] Example 65 N-(diamino phosphinyl) -5-chloro-2- Baie emissions
Zone benzothiazolylthio acetamide mp 165-171 ° C. Elemental analysis _{C 9 H 10 N 4 O 2} S 2 ClP theoretically:. C, 32.10; H, 2.99; N, 16.64 Found: C, 32.18; H, 2.94 ^{; N, 16.58 1 H-NMR} (DMSO-d 6) δ:. 4.19 (4H, br s), 4.29 (2H, s),
7.44 (1H, dd, J = 8.6Hz and 2.0Hz), 7.94 (1H, d, J = 2.
0Hz), 8.07 (1H, d, J = 8.6Hz), 9.38 (1H, br s).

[0187] Example 66 N-(diamino phosphinyl) -5-ethoxy-2-Baie
169-174 ° C. Elemental analysis emission zone benzothiazolylthio acetamide mp _{C 11 H 15 N 4 O 3} S 2 P · H 2 O theoretically:. C, 36.25; H, 4.70; N, 15.38 Found: C, . 36.20; H, 4.54; N 15.78 1 H-NMR (DMSO-d 6) δ: 1.33 (1H, t, J = 7.0Hz), 4.04 (2
H, q, J = 7.0Hz), 4.16 (4H, br s), 7.02 (1H, dd, J =
9.0Hz and 2.6Hz), 7.56 (1H, d, J = 2.6Hz), 7.71 (1H,
d, J = 9.0Hz), 8.32 (1H, br s).

[0188] Example 67 N-(diamino phosphinyl) -2-benzo Franca Le
172-174 ° C. Elemental analysis bon acid amide mp _{C 9 H 10 N 3 O 3} P theoretically:. C, 45.20; H, 4.21; N, 17.57 Found: C, 45.05; H, 4.24 ; N, 17.50 ^{. 1 H-NMR (DMSO-} d 6) δ: 4.27 (4H, s), 7.34 (1H, t, J = 7.
4Hz), 7.68 (1H, d, J = 8.4Hz), 7.79 (1H, d, J = 7.6H
z), 7.84 (1H, t, J = 7.0Hz), 7.90 (1H, s), 9.40 (1H,
d, J = 7.0Hz).

[0189] Example 68 N-(diamino phosphinyl) -2-methyl-5- base down
Zoxazolecarboxylic acid amide Melting point 250 ° C (decomposition) Elemental analysis value As C ₉ H ₁₁ N ₄ O ₃ P · H ₂ O Theoretical value: C, 39.71; H, 4.81; N, 20.58. Actual value: C, 39.48; H, 4.09; N, 20.45. ¹ H-NMR (DMSO-d ₆ ) δ: 2.66 (3H, s), 4.19 (4H, br s),
7.68 (2H, d, J = 9.0Hz), 8.03 (1H, dd, J = 9.0Hz and 2.
0Hz), 8.34 (1H, d, J = 2.0Hz), 9.52 (1H, br d, J = 7.0
Hz).

[0190] Example 69 N-(diamino phosphinyl) -3- (2- Benzoo key
Sazolyl) propenoic acid amide Melting point 180 ° C (decomposition) Elemental analysis value C ₁₀ H ₁₁ N ₄ O ₃ P Theoretical value: C, 45.12; H, 4.17; N, 21.05. Actual value: C, 45.00; H, 3.98; ^{. N, 20.97 1 H-NMR} (DMSO-d 6) δ: 4.24 (4H, br s), 7.35-7.52 (4H,
m), 7.74-7.83 (2H, m), 9.61 (1H, d, J = 6.0Hz).

[0191] Example 70 N-(diamino phosphinyl) -2 Benzochiazo Le
169-174 ° C. Elemental analysis carboxylic acid amide mp _{C 8 H 9 N 4 O 2} SP theoretically:. C, 37.50; H, 3.54; N, 21.87 Found: C, 37.42; H, 3.38 ; N, 21.86 ^{. 1 H-NMR (DMSO-} d 6) δ: 4.44 (4H, br s), 7.61-7.67 (2H,
m), 8.17-8.28 (2H, m), 8.90 (1H, br s).

[0192] Example 71 N-(diamino phosphinyl) -3-chloro-6- main switch
Rubenzothiophene carboxylic acid amide Melting point 173-178 ° C Elemental analysis value C ₁₀ H ₁₁ N ₃ O ₂ SClP ・ 1 / 5CH ₃ OH Theoretical value: C, 39.51; H, 3.71; N, 13.55. Found value: C, 39.30; H, 3.64; N, 13.15. ¹ H-NMR (DMSO-d ₆ ) δ: 2.48 (3H, s), 4.39 (4H, br s),
7.43 (1H, dd, J = 8.2Hz and 1.0Hz), 7.81 (1H, d, J = 8.
2Hz), 7.92 (1H, s), 8.38 (1H, br s).

Example 72 N- (diaminophosphinyl ) -3- (5-chloro- 2)
- benzoxazolyl) propenoic acid amide mp 210-211 ° C. (decomposition) Elemental analysis C ₁₀ H ₁₀ N ₄ O ₃ theory as ClP:. C, 39.95; H , 3.35; N, 18.64 Found: C, 39.79; H, 3.42; N, 18.49. ¹ H-NMR (DMSO-d ₆ ) δ: 4.23 (4H, br d, J = 2.0Hz), 7.35
(2H, m), 7.52 (1H, dd, J = 9.0Hz and 2.0Hz), 7.83 (1
H, d, J = 9.0Hz), 7.93 (1H, d, J = 2.0Hz), 9.55 (1H, br
m).

[0194] Example 73 N-(diamino phosphinyl) -5-methyl-3- off E
Nyl-4-isoxazolecarboxylic acid amide Melting point 230 ° C (decomposition) Elemental analysis value As C ₁₁ H ₁₃ N ₄ O ₃ P · 0.2H ₂ O Theoretical value: C, 46.55; H, 4.76; N, 19.74. :. C, 46.42; H, 4.78; N, 20.10 1 H-NMR (DMSO-d 6) δ: 2.56 (3H, s), 4.24 (4H, br s),
7.49 (3H, m), 7.70 (2H, m), 9.34 (1H, br m).

[0195] Example 74 N-(diamino phosphinyl) -3-chloro-2 base down
Zone thiophenecarboxylic acid amide mp 261-271 ° C. Elemental analysis _{C 9 H 9 N 3 O 2} SClP theoretically:. C, 37.27; H, 3.13; N, 14.51 Found: C, 36.92; H, 3.18 ; N , 14.5.9 ¹ H-NMR (DMSO-d ₆ ) δ: 4.38 (4H, br s), 7.56-7.64 (2H,
m), 7.88-7.93 (1H, m), 8.09-8.13 (1H, m), 8.68 (1
H, br s).

[0196] Example 75 N-(diamino phosphinyl) -3- Benzoisooki Sa
157-164 ° C. Elemental analysis benzisoxazolyl acetamide mp _{C 9 H 11 N 4 O 3} P theoretically:. C, 42.53; H, 4.36; N, 22.04 Found: C, 42.30; H, 4.31 ; N, 21.49 ^{. 1 H-NMR (DMSO-} d 6) δ: 4.06 (2H, s), 4.15 (4H, br s),
7.38 (1H, m), 7.67 (2H, m), 7.87 (1H, d, J = 8.0Hz),
9.43 (1H, br m).

Example 76 N- (diaminophosphinyl ) -N '-(4-methylbenzene
Benzenesulfonyl) glycinamide Melting point 161-169 ° C Elemental analysis value C ₉ H ₁₅ N ₄ O ₄ SP ・ 1 / 10H ₂ O theoretical value: C, 35.09; H, 4.97; N, 18.19. Actual value: C, 34.76 ; H, 4.94; N, 18.10 1 H-NMR (DMSO-d 6) δ:. 2.38 (3H, s), 3.52 (2H, s), 4.0
8 (4H, br s), 7.39 (2H, d, J = 8.0Hz), 7.68 (2H, d,
J = 8.0Hz), 7.77 (1H, br s), 8.77 (1H, br s).

Example 77 N- (diaminophosphinyl ) -3- (4-bromo- 2)
-Thienyl ) propenoic acid amide Melting point 176-184 ° C Elemental analysis C ₇ H ₉ N ₃ O _{2 As} SBrP Theoretical: C, 27.11; H, 2.93; N, 13.55. Found: C, 26.91; H, 2.86; N, 13.71. ¹ H-NMR (DMSO-d ₆ ) δ: 4.16 (4H, br s), 6.59 (1H, d, J
= 15.7Hz), 7.47 (1H, s), 7.63 (1H, d, J = 15.7Hz), 7.
76 (1H, s), 9.14 (1H, d, J = 7.4Hz).

Example 78 N- (diaminophosphinyl ) -3- (2-thienyl )
Propenoic acid amide Melting point 173-177 ° C Elemental analysis value C ₇ H ₁₀ N ₃ O ₂ SP Theoretical value: C, 36.36; H, 4.36; N, 18.17. Actual value: C, 36.16; H, 4.21; N, 18.16 ^{. 1 H-NMR (DMSO-} d 6) δ: 4.08 (4H, br s), 6.55 (1H, d, J
= 15.6Hz), 7.13 (1H, dd, J = 5.0Hz and 3.6Hz), 7.43
(1H, d, J = 3.6Hz), 7.60 (1H, d, J = 5.0Hz), 7.67 (1H,
d, J = 15.6Hz), 9.06 (1H, br s).

Example 79 N- (diaminophosphinyl ) -2-cyano-3- ( 2
- thienyl) propenoic acid amide mp 190-196 ° C. Elemental analysis _{C 8 H 9 N 4 O 2} SP theoretically:. C, 37.50; H, 3.54; N, 21.87 Found: C, 37.14; H, 3.56 ; N, 21.78. ¹ H-NMR (DMSO-d ₆ ) δ: 4.26 (4H, br s), 7.32-7.37 (1H,
m), 7.85 (1H, d, J = 4.3Hz), 8.15 (1H, d, J = 4.3Hz),
8.61 (1H, s), 9.08 (1H, br s).

[0201] Example 80 N-(diamino phosphinyl) -2-Chieniruaseto A
Bromide mp 179-184 ° C. Elemental analysis _{C 6 H 10 N 3 O 2} SP theoretically:. C, 32.88; H, 4.60; N, 19.17 Found:. C, 32.81; H, 4.48; N, 19.14 1 H-NMR (DMSO-d ₆ ) δ: 3.77 (2H, s), 4.11 (4H, br s),
6.93-6.99 (2H, m), 7.38 (1H, dd, J = 5.0Hz and 1.4H
z), 9.16 (1H, br s).

[0202] Example 81 N-(diamino phosphinyl) -3- Chieniruaseto A
Mid melting point 174-181 ° C Elemental analysis value C ₆ H ₁₀ N ₃ O ₂ SP Theoretical value: C, 32.88; H, 4.60; N, 19.17. Actual value: C, 32.55; H, 4.50; N, 18.92. ¹ H-NMR (DMSO-d ₆ ) δ: 3.54 (2H, s), 4.08 (4H, br s),
7.04 (1H, d, J = 4.8Hz), 7.27 (1H, d, J = 2.8Hz), 7.46
(1H, dd, J = 4.8Hz and 2.8Hz), 9.12 (1H, br s).

[0203] Example 82 N-(diamino phosphinyl) -3- (2- Benzoo key
Sazolyl) propionic acid amide N- (diaminophosphinyl) -3- (2-benzoxazolyl) propenoic acid amide (0.25 g) was dissolved by heating in methanol (30 ml), and 10% Pd-C (we
t) (0.05 g) was added. Hydrogenation was carried out at room temperature and atmospheric pressure for 1 hour. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration. N- (diaminophosphinyl) -3
Colorless crystals of-(2-benzoxazolyl) propionamide (0.17 g) were obtained. Melting point 176-178
° C (decomposition). Elemental analysis _{C 10 H 13 N 4 O 3} P theoretically:. C, 44.78; H, 4.89; N, 20.89 Found:. C, 44.71; H, 4.90; N, 20.82 1 H-NMR (DMSO- d ₆ ) δ: 2.83 (2H, m), 3.13 (2H, m), 4.0
0 (4H, br s), 7.35 (2H, m), 7.67 (2H, m), 9.05 (1
H, m).

[0204] Example 83 N-(diamino phosphinyl) -1-benzimidazolinyl
Ruasetoamido benzimidazole (10 g), ethyl bromoacetate (15.5 g), potassium carbonate (12.9g), N,
A mixture of N-dimethylformamide (50 ml) was added to 50
Stirred at 150C for 15 hours. The reaction solution was poured into water and extracted with diethyl ether. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to obtain an oily product of 1-benzimidazolyl acetic acid ethyl ester (12 g). 1-benzimidazolyl acetic acid ethyl ester (1
2 g) was dissolved in ethanol (200 ml), and ammonia gas was introduced under ice cooling for 30 minutes. After the introduction, the mixture was stirred at room temperature for 65 hours. The precipitated crystals were collected by filtration and washed with ethanol. Colorless crystals of 1-benzimidazolylacetamide (4.3 g) were obtained. Melting point 204-205
° C. 1-benzimidazolylacetamide (2.0 g)
Was suspended in toluene (30 ml), and phosphorus pentachloride (2.
5 g) were added in small portions. The mixture was heated to 70 ° C. and stirred for 1 hour. The reaction was cooled to room temperature and formic acid (0.52)
g) was added dropwise. Add tetrahydrofuran (30 m
l) was added and the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration, washed with toluene and hexane, and air-dried. The powder was suspended in tetrahydrofuran (150 ml), and ammonia gas was introduced under ice cooling for 50 minutes. After the introduction, the mixture was stirred at room temperature for 1 hour. Diethyl ether was added to the reaction solution, and the precipitate was collected by filtration and washed with diethyl ether. The obtained solid was purified by column chromatography using XAD-II. Eluting with water, the effective fraction was concentrated under reduced pressure. The residue was crystallized from ethanol and collected by filtration. Recrystallized from water-ethanol. Colorless crystals of N- (diaminophosphinyl) -1-benzimidazolylacetamide (0.19 g) were obtained. Melting point 186-188
° C. Elemental analysis: C ₉ H ₁₂ N ₅ O ₂ P ・ 1 / 4H ₂ O Theoretical: C, 41.95; H, 4.89; N, 27.18. Found: C, 42.14; H, 4.84; N, 26.99. ¹ H-NMR (DMSO-d ₆ ) δ: 4.17 (4H, s), 5.04 (2H, s), 7.1
6-7.29 (2H, m), 7.43-7.47 (1H, m), 7.63-7.67 (1H,
m), 8.15 (1H, s), 9.32 (1H, s).

Examples 84 to 91 The following compounds were synthesized in the same manner as in Example 1.

[0206] Example 84 N-(diamino phosphinyl) -4-chloro-2 Ji o
Phencarboxylic acid amide Melting point 278-280 ° C Elemental analysis value C ₅ H ₇ N ₃ O ₂ SClP Theoretical value: C, 25.06; H, 2.94; N, 17.54. Actual value: C, 24.95; H, 2.87; N, 17.57. ¹ H-NMR (DMSO-d ₆ ) δ: 4.23 (4H, br s), 7.86 (1H, d, J
= 1.4Hz), 8.11 (1H, d, J = 1.4Hz), 9.51 (1H, br s).

[0207] Example 85 N-(diamino phosphinyl) -4-methyl-3- Ji o
Fencarboxylic acid amide Melting point 145-147 ° C Elemental analysis value C ₆ H ₁₀ N ₃ O ₂ SP ・ 1 / 4H ₂ O Theoretical value: C, 31.94; H, 4.88; N, 18.64. Actual value: C, 32.21; . H, 4.73; N, 18.78 1 H-NMR (DMSO-d 6) δ: 2.36 (3H, s), 4.13 (4H, br s),
7.19 (1H, d, J = 3.2Hz), 8.32 (1H, d, J = 3.2Hz), 9.12
(1H, br s).

[0208] Example 86 N-(diamino phosphinyl) -2-chloro-5-Bed B
Mo-3-thiophenecarboxylic acid amide Melting point 181-183 ° C. Elemental analysis value C ₅ H ₆ N ₃ O _{2 As} SBrClP Theoretical value: C, 18.95; H, 1.90; N, 13.19. Found value: C, 19.05; H, ^{. 1.91; N, 13.37 1 H} -NMR (DMSO-d 6) δ: 4.19 (4H, br s), 7.16 (1H, s),
9.15 (1H, br s).

[0209] Example 87 N-(diamino phosphinyl) -5-chloro-4- main switch
Lu-3-thiophenecarboxylic acid amide Melting point 159-161 ° C Elemental analysis value C ₆ H ₉ N ₃ O ₂ SClP · 1 / 4H ₂ O Theoretical value: C, 27.91; H, 3.71; N, 16.28. C, 27.82; H, 3.57; N, 16.24. ¹ H-NMR (DMSO-d ₆ ) δ: 2.29 (3H, s), 4.14 (4H, br s),
7.18 (1H, s), 8.92 (1H, br s).

Example 88 N- (diaminophosphinyl ) -2,5-dichloro-4
- methyl-3-thiophene Nkarubon acid amide mp 178-180 ° C. Elemental analysis _{C 6 H 8 N 3 O 2} SCl 2 P theoretically:. C, 25.01; H, 2.80; N, 14.59 Found: C, 24.89 ; H, 2.81; N, 14.62 1 H-NMR (DMSO-d 6) δ:. 2.12 (3H, s), 4.21 (4H, br s),
9.42 (1H, br s).

[0211] Example 89 N-(diamino phosphinyl) -2-chloro-5- main switch
Le-3-thiophenecarboxylic acid amide Melting point 180-183 ° C Elemental analysis value C ₆ H ₉ N ₃ O ₂ SClP Theoretical value: C, 28.41; H, 3.58; N, 16.57. Actual value: C, 28.34; H, ^{. 3.39; N, 16.64 1 H} -NMR (DMSO-d 6) δ: 2.38 (3H, s), 4.17 (4H, br s),
7.16 (1H, s), 8.92 (1H, br s).

[0212] Example 90 N-(diamino phosphinyl) -3-chloro-4- main switch
Lu-2-thiophenecarboxylic acid amide Melting point 288-291 ° C Elemental analysis value C ₆ H ₉ N ₃ O ₂ SClP Theoretical value: C, 28.41; H, 3.58; N, 16.57. Actual value: C, 28.35; H, ^{. 3.45; N, 16.57 1 H} -NMR (DMSO-d 6) δ: 2.18 (3H, d, J = 0.8Hz), 4.31 (4
H, br s), 7.65 (1H, q, J = 0.8Hz), 8.37 (1H, d, J = 6.6
Hz).

Example 91 N- (diaminophosphinyl ) -3,5-dimethyl-2
-Thiophenecarboxylic acid amide Melting point 160-162 ° C Elemental analysis value C ₇ H ₁₂ N ₃ O ₂ SP Theoretical value: C, 36.05; H, 5.19; N, 18.02. Actual value: C, 35.86; H, 5.16; N ^{, 17.97 1 H-NMR (DMSO} -d 6) δ:. 2.37 (3H, s), 2.41 (3H, s), 4.1
3 (4H, br s), 6.68 (1H, s), 8.37 (1H, d, J = 6.6Hz).

Example 92 The following compounds were synthesized in the same manner as in Example 39. N- (diamino phosphinyl) -3-methyl-2- off La
Nkarubon acid amide mp 157-158 ° C. Elemental analysis _{C 6 H 10 N 3 O 3} P · 1 / 4H 2 O theoretically:. C, 34.71; H, 5.10; N, 20.24 Found: C, 34.75; H , 5.09; N, 20.38. ¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (3H, s), 4.16 (4H, br s),
6.53 (1H, d, J = 1.4Hz), 7.70 (1H, d, J = 1.4Hz), 8.31
(1H, br s).

Test Example 1 Effect of eradication of Flurofamide Crj: ICR, male, 5-week-old mouse was fasted for 30 hours, and then Helicobacter pylori (CPY-433 F)
4) was intragastrically inoculated with 10 ⁷ CFU per mouse. Infection 1
After a week, 100 mg / kg of the test compound suspended in 0.5% methylcellulose containing 1% sodium bicarbonate was orally administered twice a day for 7 days. The day after the end of administration, the stomach of the infected mouse was collected and crushed, and the 10-fold dilution series was modified with activated carbon S
Inoculate the Kirrow medium at 37 ° C under microaerobic conditions, 4
After culturing for a day, the eradication effect was determined based on the presence or absence of growth of the bacterium. Table 6 shows the results.

[0216]

[Table 6]

Test Example 2 Sterilization effect of urease inhibitor (in vivo) Helicobacter pylori (C
PY-433 F4) 1 ml of bacterial solution containing 1 × 10 ⁷ CFU
Was orally administered for infection. 0.1% containing 1% NaHCO ₃
Test sample suspended in 5% methylcellulose solution (10 mg
/ kg) was orally administered twice a day for 10 days after inoculation of the bacteria for 2 to 4 days. Also, lansoprazole 30 mg / kg was added to 0.1 mg.
The cells were suspended in a 5% methylcellulose solution and administered subcutaneously 10 minutes before the first sample administration each day. On the day after the final administration, the mouse was sacrificed, the stomach was excised, the stomach was washed with 5 ml of physiological saline, and a homogenate was prepared using 2 ml of Brucella medium. CFU per stomach was spread on a modified brucella agar medium with 0.1 ml of a 10-fold serial dilution of stomach homogenate in brucella medium, and incubated at 37 ° C in a microaerobic environment.
After culturing for one day, the measurement was performed. The results are shown in Table 7.

[0218]

[Table 7]

Test Example 3 Screening for urease inhibitor Test drug 2 dissolved in 0.1% dimethylformamide solution
0 μl of 100 mM Bis-Tris buffer (pH 6.
5) 100 μl and 60 μl of urease solution prepared from Helicobacter pylori were added and incubated at room temperature for 30 minutes, and then 20 μl of 100 mM urea was added and reacted at room temperature for 10 minutes. Ammonia generated in the reaction solution is a commercially available measurement kit (Ammonia Test Wako ^TM ,
Wako Pure Chemical Industries, Ltd.). The percent inhibition of the amount of ammonia generated in the solvent-added group was determined, and the IC ₅₀ value was calculated. The results are shown in Table 8-1 and Table 8-2.

[0220]

[Table 8-1]

[0221]

[Table 8-2]

Formulation Example The anti-Helicobacter genus agent and the medicine for anti-Helicobacter genus of the present invention can be produced, for example, by the following formulations. 1. Capsules (1) Flurofamide 100 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 270 mg (1), (2), (3) and 1/2 of (4) are mixed After doing
Granulate. Add the remaining (4) to this and encapsulate the whole in a gelatin capsule.

2. Tablets (1) Flurofamide 100 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 320 mg (1), (2), (3), and (4) 2/3 and 1 of (5)
And then granulating. The remaining (4) and (5) are added to the mixture and pressed into tablets.

3. Capsules (1) Flurofamide 100 mg (2) Lansoprazole 10 mg (3) Lactose 90 mg (4) Microcrystalline cellulose 70 mg (5) Magnesium stearate 10 mg 1 capsule 280 mg (1), (2), (3) and (4), Mix 1/2 of (5) and granulate. Add the remaining (5) to this and encapsulate the whole in a gelatin capsule.

[0225] Tablets (1) Flurofamide 100 mg (2) Lansoprazole 10 mg (3) Lactose 35 mg (4) Corn starch 150 mg (5) Microcrystalline cellulose 30 mg (6) Magnesium stearate 5 mg 1 tablet 320 mg (1), (2), (3), 2/3 of (4) and (5) and (6)
Mix 1/2 of the mixture and granulate. The rest of (5) and (6) is added to this and the mixture is pressed into tablets.

5. Combination preparation (kit) Capsules A and B containing each active ingredient are separately prepared and packed in one box. (A) Capsule A (1) Lansoprazole 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and (3), and (4) And then granulating. Add the remaining (4) to this and encapsulate the whole in a gelatin capsule. (B) Capsule B (1) Flurofamide 100 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 270 mg (1), (2) and (3), and 1 of (4) After mixing / 2, granulate. Add the remaining (4) to this and encapsulate the whole in a gelatin capsule.

6. Enteric coated non-pareil (sugar sugar 75 parts by weight coated with 25 parts by weight of corn starch by a method known per se, sugar nucleus
28 mesh) 1650 g, CF device (CF-360,
Rotor speed is 25, put in Freund Co., Japan)
Spraying agent 1 of the following composition obtained by premixing 1050 ml of hydroxypropylcellulose solution (2% (W / V)) at 30 ml / min at room temperature at 0 rpm, and then spraying agent 2 at 60 g / min Coating, vacuum drying at 40 ° C for 16 hours, and 1 using a round sieve
4-32 mesh spherical nucleated granules are obtained. [Spraying agent 1] Flurofamide 1500 g Magnesium carbonate 336 g Graniu sugar 297 g Corn starch 300 g L-HPC 354 g (Hydroxypropoxy group substitution degree: 10.0 to 13.0%)
(W / W), average particle size 30 μm or less) [Spraying agent 2] Graniu sugar 300 g Corn starch 246 g L-HPC (the same as above) 246 g The obtained granules 3800 g were put in a fluidized bed coating machine (manufactured by Okawara Co., Ltd.), Blower 65 ° C, controlled product temperature 40 ° C, 50 ml / min of enteric film solution having the following composition
And enteric coated to obtain enteric coated granules. Talc and light silicic acid anhydride are mixed with the granules and filled into No. 1 hard capsules using a capsule filling machine (Park Davis, USA) to produce capsules. [Enteric film liquid] Eudragit L30D-55 2018 g (solid content 650 g) Talc 182 g Polyethylene glycol 6000 60 g Titanium oxide 60 g Tween 80 27 g Water 4230 ml [Composition in one capsule] Enteric coated granules 438.8 mg Flurofamide 100.0 mg Magnesium carbonate 22 4 mg Nonpareil 110.0 mg Graniu sugar 59.8 mg Corn starch 36.4 mg L-HPC 40.0 mg Hydroxypropyl cellulose 1.4 mg Eudragit L30D-55 44.6 mg Talc 13.4 mg Polyethylene glycol 6000 4.4 mg Titanium oxide 4.4 mg Tween 80 2.0 mg Talc 0.6 mg Light anhydrous silicic acid 0.6 mg No. 1 hard capsule 79.0 mg Total 519 mg

[0228]

INDUSTRIAL APPLICABILITY The phosphoric acid amide derivative, the anti-Helicobacter genus agent and the drug for anti-Helicobacter genus of the present invention have anti-Helicobacter genus action, for example, Helicobacter genus which exerts a toxic action in the digestive tract. On the other hand, it exhibits anti-Helicobacter action. Therefore, it is useful for the prevention or treatment of peptic diseases caused by Helicobacter spp. Such as gastritis, duodenal ulcer, gastric ulcer and chronic gastritis. In recent years, it is said that there is a large correlation between Helicobacter spp., Especially Helicobacter pylori, and gastric cancer, and thus it is considered to be useful for prevention of gastric cancer and the like.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Hidefumi Yukimasa Inventor Hidefumi 3 of 683 Kiji Higashiguchi-cho, Nara City, Nara Prefecture

Claims (43)

[Claims] 1. General formula (I): [Wherein R represents an optionally substituted amino group] or a pharmaceutically acceptable salt thereof, and an anti-Helicobacter pylori containing an antacid or an acid secretion inhibitor Agent. 2. The anti-Helicobacter pylori agent according to claim 1, which is acid-resistant. 3. The anti-Helicobacter pylori agent according to claim 1, which is enteric-coated. 4. R is (1) -COR¹, -CSR^Two, -SO
_TwoR^Three, -SOR^Four, -CONHR^FiveAnd -CSNHR⁶
中 where R¹, R^Two, R^Three, R^Four, R^FiveAnd R⁶Are (1-1) a hydrogen atom, (1-2) (a) an alkyl group having 1 to 10 carbon atoms, (b) an alkenyl group having 2 to 10 carbon atoms, and (c) an alkynyl group having 2 to 10 carbon atoms. (D) a cycloalkyl group having 3 to 12 carbon atoms, (e) a cycloalkenyl group having 5 to 12 carbon atoms, (f) a cycloalkadienyl group having 5 to 12 carbon atoms, (g) C_3-7Cycloalkyl-C_1-8Alkyl group, (h) C_5-7Cycloalkenyl-C_1-8Alkyl group and
And (i) a hydrocarbon selected from aryl groups having 6 to 10 carbon atoms
Elementary groups [wherein the substituents (a) to (i) are (i) halogen and C, respectively._1-31 selected from alkoxy
~ C optionally substituted with 3 substituents_1-6Alkyl
A group, (ii) halogen and C_1-3Selected from alkoxy
C optionally substituted with 1 to 3 substituents_1-6Arco
Xy group, (iii) C_1-3Alkoxy, halogen, C_1-3Archi
1 to 5 selected from amino, nitro and cyano
C optionally substituted with a substituent of_6-14Aryl group, (iv) each C_1-3Alkoxy, halogen, C_1-3A
1 selected from alkyl, amino, nitro and cyano
C optionally substituted with 5 substituents_3-7Cycloal
Kill group or C_3-6A cycloalkenyl group, (v) C optionally substituted by halogen_1-4Alkoki
C, halogen, C optionally substituted with halogen_1-4
Alkyl, C_6-101 selected from aryl and nitro
To a heterocyclic group optionally substituted with 3 substituents, (vi) a carboxyl group, (C_1-6Alkoxy) carbo
Nyl group, (C_6-10Aryl) oxycarbonyl group or
(C_7-10Aralkyl) oxycarbonyl group, (vii) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Aralkyl and C_6-10Aryl
Substituted with 1 to 2 substituents selected from sulfonyl
A carbamoyl group (wherein each substituent is
Halogen, C optionally substituted with halogen_1-4Al
Coxy, C optionally substituted with halogen_1-4Archi
Substituted with 1 to 5 substituents selected from
May be included), (viii) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Aralkyl and C_6-10Aryl
Substituted with 1 to 2 substituents selected from sulfonyl
Amino group that may be present (Here, each substituent is a halogen
C optionally substituted by halogen_1-4Alkoki
C which may be substituted by halogen_1-4Alkyl
And substituted with 1 to 5 substituents selected from nitro
Or a cyclic amino group, (ix) C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10
Aryl, C_7-12Substituted with aralkyl and heterocycle groups
Optionally a hydroxyl group (here, C_1-6Alkyl, C_3-6Shi
Chloroalkyl, C_6-10Aryl and C_7-12Aralkyl
May be substituted with halogen or halogen, respectively
I C_1-4Optionally substituted with alkoxy and halogen
C_1-4Selected from alkyl, nitro, amino and cyano
A heterocycle which may be substituted with 1 to 5 substituents
The groups are (ix-1) halogen and C_1-3From alkoxy
C optionally substituted with 1 to 3 substituents selected
_1-6Alkyl group, (ix-2) halogen and C_1-3Al
Substituted with 1 to 3 substituents selected from
Good C_1-6Alkoxy group, (ix-3) C_1-3Alkoki
Si, halogen, C_1-3Alkyl, amino, nitro and
Substituted with 1 to 5 substituents selected from cyano,
Good C_6-14Aryl group, (ix-4) each C_1-3
Alkoxy, halogen, C_1-3Alkyl, amino, nitro
Substituted with 1 to 5 substituents selected from
May be C_3-7Cycloalkyl group or C_3-6Shiku
Alkenyl group, substituted with (ix-5) halogen
May be C_1-4Substitute with alkoxy, halogen, halogen
C that may be_1-4Alkyl, C_6-10Aryl and
Substituted with 1 to 3 substituents selected from
Optionally a heterocyclic group, (ix-6) carboxyl group, (C
_1-6An alkoxy) carbonyl group, (C_6-10Aryl) o
A xycarbonyl group or (C_7-10Aralkyl) oxyca
Rubonyl group, (ix-7) C_1-6Alkyl, C_3-6Cyclo
Alkyl, C_6-10Aryl, C_7-12Aralkyl and C
_6-101 to 2 substituents selected from arylsulfonyl
A carbamoyl group optionally substituted with
The groups may be substituted with halogen and halogen, respectively.
I C_1-4Optionally substituted with alkoxy and halogen
C_1-41 to 5 positions selected from alkyl and nitro
Optionally substituted with a substituent), (ix-8) C_1-6A
Luquil, C_3-6Cycloalkyl, C_6-10Aryl, C
_7-12Aralkyl and C_6-10Selected from arylsulfonyl
Amino optionally substituted with 1 to 2 substituents
Group (wherein each substituent is halogen,
C which may be replaced_1-4Substituted with alkoxy and halogen
C that may be_1-4Choose from alkyl and nitro
Optionally substituted with 1 to 5 substituents),
Is a cyclic amino group, (ix-9) C_1-6Alkyl, C_3-6Shi
Chloroalkyl, C_6-10Aryl, C_7-12Aralkyl and
And a hydroxyl group which may be substituted with a heterocyclic group (wherein C
_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Aryl
And C_7-12Aralkyl is halogen, halogen respectively
C optionally substituted with_1-4With alkoxy, halogen
Optionally substituted C_1-4Alkyl, nitro, amino
And substituted with 1 to 5 substituents selected from cyano
And the heterocyclic group is C_1-4Alkoxy, halogen
N, C_1-4Alkyl and C_6-10Selected from aryl
Optionally substituted with 1 to 3 substituents), (ix-
10) C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10A
Reel, C_7-12Substituted with aralkyl and heterocycle groups
Optional thiol group (where C_1-6Alkyl, C_3-6
Cycloalkyl, C_6-10Aryl and C_7-12Aralki
Each is halogen, even if substituted with halogen
Good C_1-4May be substituted with alkoxy or halogen
I C_1-4Select from alkyl, nitro, amino and cyano
Optionally substituted with 1 to 5 substituents
The ring group is C_1-4Alkoxy, halogen, C_1-4Alkyl and
And C_6-10Substituted with 1 to 3 substituents selected from aryl
), (Ix-11) formyl, (C
_1-6Alkyl) carbonyl, (C_3-6Cycloalkyl)
Rubonil, (C_6-10Aryl) carbonyl, (C_7-12A
Ralalkyl) carbonyl, (C_1-6Alkyl) sulfini
Le, (C_3-6Cycloalkyl) sulfinyl, (C_6-10
Aryl) sulfinyl, (C_7-12Aralkyl) Sulf
Inyl, (C_1-6Alkyl) sulfonyl, (C_3-6Cyclo
Alkyl) sulfonyl, (C_6-10Aryl) sulfonyl
And (C_7-12Aralkyl) A selected from sulfonyl
Silyl group (wherein each substituent is halogen, C_1-4A
Lucoxy and C_1-41 to 5 selected from alkyl
Optionally substituted with a substituent), (ix-12) halo
Gen, (ix-13) nitro, and (ix-14) si
Even if it is substituted with 1 to 4 substituents selected from ANO
Good), (x) C_1-6Alkyl, C_3-6Cycloalkyl,
C_6-10Aryl, C_7-12Aralkyl and heterocyclic groups
Optionally substituted thiol group (where C_1-6Archi
Le, C_3-6Cycloalkyl, C_6-10Aryl and C
_7-12Aralkyl substituted with halogen and halogen, respectively
C that may be_1-4Substituted with alkoxy, halogen
May be C_1-4Alkyl, nitro, amino and
Substituted with 1 to 5 substituents selected from cyano,
And the heterocyclic group is (x-1) halogen and C_1-3A
Substituted with 1 to 3 substituents selected from lucoxy
May be C_1-6An alkyl group, (x-2) halogen and
C_1-3Substituted with 1 to 3 substituents selected from alkoxy
C that may be_1-6Alkoxy group, (x-3) C_1-3
Alkoxy, halogen, C_1-3Alkyl, amino, nitro
Substituted with 1 to 5 substituents selected from
May be C_6-14Aryl group, (x-4) each
C_1-3Alkoxy, halogen, C_1-3Alkyl, amino,
Substituted with 1 to 5 substituents selected from nitro and cyano
C which may be replaced_3-7Cycloalkyl group or C_3-6
Cycloalkenyl group, substituted by (x-5) halogen
May be C_1-4Substituted with alkoxy, halogen, halogen
C which may be replaced_1-4Alkyl, C_6-10Aryl
And substituted with 1 to 3 substituents selected from nitro
An optionally substituted heterocyclic group, (x-6) carboxyl group, (C
_1-6An alkoxy) carbonyl group, (C_6-10Aryl) o
A xycarbonyl group or (C_7-10Aralkyl) oxyca
Rubonyl group, (x-7) C_1-6Alkyl, C_3-6Cycloa
Luquil, C_6-10Aryl, C_7-12Aralkyl and C
_6-101 to 2 substituents selected from arylsulfonyl
A carbamoyl group optionally substituted with
The groups may be substituted with halogen and halogen, respectively.
I C_1-4Optionally substituted with alkoxy and halogen
C_1-41 to 5 positions selected from alkyl and nitro
(X-8) C_1-6Al
Kill, C_3-6Cycloalkyl, C_6-10Aryl, C_7-12
Aralkyl and C_6-10Selected from arylsulfonyl
Amino group optionally substituted with 1 to 2 substituents
(Where each substituent is halogen,
C that may be_1-4Substituted with alkoxy, halogen
May be C_1-4Selected from alkyl and nitro
May be substituted with 1 to 5 substituents), or
Cyclic amino group, (x-9) C_1-6Alkyl, C_3-6Cyclo
Alkyl, C_6-10Aryl, C_7-12Aralkyl and multiple
A hydroxyl group which may be substituted with a ring group (here, C_1-6
Alkyl, C_3-6Cycloalkyl, C_6-10Aryl and
And C_7-12Aralkyl is halogen and halogen respectively
Optionally substituted C_1-4Substituted with alkoxy and halogen
C which may be replaced_1-4Alkyl, nitro, amino
And substituted with 1 to 5 substituents selected from cyano
And the heterocyclic group may be C_1-4Alkoxy, halogen,
C_1-4Alkyl and C_6-101 selected from aryl
(Optionally substituted with three substituents), (x-10)
C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Ally
Le, C_7-12Substituted with aralkyl and heterocyclic groups
Thiol group (where C_1-6Alkyl, C_3-6Shiku
Lower alkyl, C_6-10Aryl and C_7-12Aralkyl
Each may be substituted with halogen or halogen
C_1-4C which may be substituted by alkoxy or halogen
_1-4Selected from alkyl, nitro, amino and cyano
A heterocyclic group which may be substituted with 1 to 5 substituents
Is C_1-4Alkoxy, halogen, C_1-4Alkyl and C
_6-10Substituted with 1 to 3 substituents selected from aryl
(X-11) formyl, (C_1-6Al
Kill) carbonyl, (C_3-6Cycloalkyl) carboni
Le, (C_6-10Aryl) carbonyl, (C_7-12Aralki
Le) carbonyl, (C_1-6Alkyl) sulfinyl,
(C_3-6Cycloalkyl) sulfinyl, (C_6-10Ants
) Sulfinyl, (C_7-12Aralkyl) Sulfini
Le, (C_1-6Alkyl) sulfonyl, (C_3-6Cycloal
Kill) sulfonyl, (C_6-10Aryl) sulfonyl and
(C_7-12Aralkyl) acyl selected from sulfonyl
Group (where each substituent is halogen, C_1-4Arco
Xy and C_1-41 to 5 substitutions selected from alkyl
(X-12) halogen,
Selected from (x-13) nitro and (x-14) cyano
Optionally substituted with 1 to 4 substituents), (xi) formyl, (C_1-6Alkyl) carbonyl,
(C_3-6Cycloalkyl) carbonyl, (C_6-10Ally
Le) carbonyl, (C_7-12Aralkyl) carbonyl,
(C_1-6Alkyl) sulfinyl, (C_3-6Cycloalkyl
Le) sulfinyl, (C_6-10Aryl) sulfinyl,
(C_7-12Aralkyl) sulfinyl, (C_1-6Archi
Le) sulfonyl, (C_3-6Cycloalkyl) sulfoni
Le, (C_6-10Aryl) sulfonyl and (C_7-12Ara
Alkyl) sulfonyl acyl group (where each
The substituents are halogen, C_1-4Alkoxy and C_1-4
Substituted with 1 to 5 substituents selected from alkyl
May be used), (xii) halogen, (xiii) nitro, and (xiv) cyano substituted with 1 to 3 substituents.
Or a (1-3) heterocyclic group [wherein the heterocyclic group is (i) halogen and C_1-31 selected from alkoxy
~ C optionally substituted with 3 substituents_1-6Alkyl
A group, (ii) halogen and C_1-3Selected from alkoxy
C optionally substituted with 1 to 3 substituents_1-6Arco
Xy group, (iii) C_1-3Alkoxy, halogen, C_1-3Archi
1 to 5 selected from amino, nitro and cyano
C optionally substituted with a substituent of_6-14Aryl group, (iv) each C_1-3Alkoxy, halogen, C_1-3A
1 selected from alkyl, amino, nitro and cyano
C optionally substituted with 5 substituents_3-7Cycloal
Kill group or C_3-6A cycloalkenyl group, (v) C optionally substituted by halogen_1-4Alkoki
C, halogen, C optionally substituted with halogen_1-4
Alkyl, C_6-101 selected from aryl and nitro
To a heterocyclic group optionally substituted with 3 substituents, (vi) a carboxyl group, (C_1-6Alkoxy) carbo
Nyl group, (C_6-10Aryl) oxycarbonyl group or
(C_7-10Aralkyl) oxycarbonyl group, (vii) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Aralkyl and C_6-10Aryl
Substituted with 1 to 2 substituents selected from sulfonyl
A carbamoyl group (wherein each substituent is
Halogen, C optionally substituted with halogen_1-4Al
Coxy, C optionally substituted with halogen_1-4Archi
Substituted with 1 to 5 substituents selected from
May be included), (viii) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Aralkyl and C_6-10Aryl
Substituted with 1 to 2 substituents selected from sulfonyl
Amino group that may be present (Here, each substituent is a halogen
C optionally substituted by halogen_1-4Alkoki
C which may be substituted by halogen_1-4Alkyl
And substituted with 1 to 5 substituents selected from nitro
Or a cyclic amino group, (ix) C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10
Aryl, C_7-12Substituted with aralkyl and heterocycle groups
Optionally a hydroxyl group (here, C_1-6Alkyl, C_3-6Shi
Chloroalkyl, C_6-10Aryl and C_7-12Aralkyl
May be substituted with halogen or halogen, respectively
I C_1-4Optionally substituted with alkoxy and halogen
C_1-4Selected from alkyl, nitro, amino and cyano
A heterocycle which may be substituted with 1 to 5 substituents
The groups are (ix-1) halogen and C_1-3From alkoxy
C optionally substituted with 1 to 3 substituents selected
_1-6Alkyl group, (ix-2) halogen and C_1-3Al
Substituted with 1 to 3 substituents selected from
Good C_1-6Alkoxy group, (ix-3) C_1-3Alkoki
Si, halogen, C_1-3Alkyl, amino, nitro and
Substituted with 1 to 5 substituents selected from cyano,
Good C_6-14Aryl group, (ix-4) each C_1-3
Alkoxy, halogen, C_1-3Alkyl, amino, nitro
Substituted with 1 to 5 substituents selected from
May be C_3-7Cycloalkyl group or C_3-6Shiku
Alkenyl group, substituted with (ix-5) halogen
May be C_1-4Substitute with alkoxy, halogen, halogen
C that may be_1-4Alkyl, C_6-10Aryl and
Substituted with 1 to 3 substituents selected from
Optionally a heterocyclic group, (ix-6) carboxyl group, (C
_1-6An alkoxy) carbonyl group, (C_6-10Aryl) o
A xycarbonyl group or (C_7-10Aralkyl) oxyca
Rubonyl group, (ix-7) C_1-6Alkyl, C_3-6Cyclo
Alkyl, C_6-10Aryl, C_7-12Aralkyl and C
_6-101 to 2 substituents selected from arylsulfonyl
A carbamoyl group optionally substituted with
The groups may be substituted with halogen and halogen, respectively.
I C_1-4Optionally substituted with alkoxy and halogen
C_1-41 to 5 positions selected from alkyl and nitro
Optionally substituted with a substituent), (ix-8) C_1-6A
Luquil, C_3-6Cycloalkyl, C_6-10Aryl, C
_7-12Aralkyl and C_6-10Selected from arylsulfonyl
Amino optionally substituted with 1 to 2 substituents
Group (wherein each substituent is halogen,
C which may be replaced_1-4Substituted with alkoxy and halogen
C that may be_1-4Choose from alkyl and nitro
Optionally substituted with 1 to 5 substituents),
Is a cyclic amino group, (ix-9) C_1-6Alkyl, C_3-6Shi
Chloroalkyl, C_6-10Aryl, C_7-12Aralkyl and
And a hydroxyl group which may be substituted with a heterocyclic group (wherein C
_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Aryl
And C_7-12Aralkyl is halogen, halogen respectively
C optionally substituted with_1-4With alkoxy, halogen
Optionally substituted C_1-4Alkyl, nitro, amino
And substituted with 1 to 5 substituents selected from cyano
And the heterocyclic group is C_1-4Alkoxy, halogen
N, C_1-4Alkyl and C_6-10Selected from aryl
Optionally substituted with 1 to 3 substituents), (ix-
10) C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10A
Reel, C_7-12Substituted with aralkyl and heterocycle groups
Optional thiol group (where C_1-6Alkyl, C_3-6
Cycloalkyl, C_6-10Aryl and C_7-12Aralki
Each is halogen, even if substituted with halogen
Good C_1-4May be substituted with alkoxy or halogen
I C_1-4Select from alkyl, nitro, amino and cyano
Optionally substituted with 1 to 5 substituents
The ring group is C_1-4Alkoxy, halogen, C_1-4Alkyl and
And C_6-10Substituted with 1 to 3 substituents selected from aryl
), (Ix-11) formyl, (C
_1-6Alkyl) carbonyl, (C_3-6Cycloalkyl)
Rubonil, (C_6-10Aryl) carbonyl, (C_7-12A
Ralalkyl) carbonyl, (C_1-6Alkyl) sulfini
Le, (C_3-6Cycloalkyl) sulfinyl, (C_6-10
Aryl) sulfinyl, (C_7-12Aralkyl) Sulf
Inyl, (C_1-6Alkyl) sulfonyl, (C_3-6Cyclo
Alkyl) sulfonyl, (C_6-10Aryl) sulfonyl
And (C_7-12Aralkyl) A selected from sulfonyl
Silyl group (wherein each substituent is halogen, C_1-4A
Lucoxy and C_1-41 to 5 selected from alkyl
Optionally substituted with a substituent), (ix-12) halo
Gen, (ix-13) nitro, and (ix-14) si
Even if it is substituted with 1 to 4 substituents selected from ANO
Good), (x) C_1-6Alkyl, C_3-6Cycloalkyl,
C_6-10Aryl, C_7-12Aralkyl and heterocyclic groups
Optionally substituted thiol group (where C_1-6Archi
Le, C_3-6Cycloalkyl, C_6-10Aryl and C
_7-12Aralkyl substituted with halogen and halogen, respectively
C that may be_1-4Substituted with alkoxy, halogen
May be C_1-4Alkyl, nitro, amino and
Substituted with 1 to 5 substituents selected from cyano,
And the heterocyclic group is (x-1) halogen and C_1-3A
Substituted with 1 to 3 substituents selected from lucoxy
May be C_1-6An alkyl group, (x-2) halogen and
C_1-3Substituted with 1 to 3 substituents selected from alkoxy
C that may be_1-6Alkoxy group, (x-3) C_1-3
Alkoxy, halogen, C_1-3Alkyl, amino, nitro
Substituted with 1 to 5 substituents selected from
May be C_6-14Aryl group, (x-4) each
C_1-3Alkoxy, halogen, C_1-3Alkyl, amino,
Substituted with 1 to 5 substituents selected from nitro and cyano
C which may be replaced_3-7Cycloalkyl group or C_3-6
Cycloalkenyl group, substituted by (x-5) halogen
May be C_1-4Substituted with alkoxy, halogen, halogen
C which may be replaced_1-4Alkyl, C_6-10Aryl
And substituted with 1 to 3 substituents selected from nitro
An optionally substituted heterocyclic group, (x-6) carboxyl group, (C
_1-6An alkoxy) carbonyl group, (C_6-10Aryl) o
A xycarbonyl group or (C_7-10Aralkyl) oxyca
Rubonyl group, (x-7) C_1-6Alkyl, C_3-6Cycloa
Luquil, C_6-10Aryl, C_7-12Aralkyl and C
_6-101 to 2 substituents selected from arylsulfonyl
A carbamoyl group optionally substituted with
The groups may be substituted with halogen and halogen, respectively.
I C_1-4Optionally substituted with alkoxy and halogen
C_1-41 to 5 positions selected from alkyl and nitro
(X-8) C_1-6Al
Kill, C_3-6Cycloalkyl, C_6-10Aryl, C_7-12
Aralkyl and C_6-10Selected from arylsulfonyl
Amino group optionally substituted with 1 to 2 substituents
(Where each substituent is halogen,
C that may be_1-4Substituted with alkoxy, halogen
May be C_1-4Selected from alkyl and nitro
May be substituted with 1 to 5 substituents), or
Cyclic amino group, (x-9) C_1-6Alkyl, C_3-6Cyclo
Alkyl, C_6-10Aryl, C_7-12Aralkyl and multiple
A hydroxyl group which may be substituted with a ring group (here, C_1-6
Alkyl, C_3-6Cycloalkyl, C_6-10Aryl and
And C_7-12Aralkyl is halogen and halogen respectively
Optionally substituted C_1-4Substituted with alkoxy and halogen
C which may be replaced_1-4Alkyl, nitro, amino
And substituted with 1 to 5 substituents selected from cyano
And the heterocyclic group may be C_1-4Alkoxy, halogen,
C_1-4Alkyl and C_6-101 selected from aryl
(Optionally substituted with three substituents), (x-10)
C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Ally
Le, C_7-12Substituted with aralkyl and heterocyclic groups
Thiol group (where C_1-6Alkyl, C_3-6Shiku
Lower alkyl, C_6-10Aryl and C_7-12Aralkyl
Each may be substituted with halogen or halogen
C_1-4C which may be substituted by alkoxy or halogen
_1-4Selected from alkyl, nitro, amino and cyano
A heterocyclic group which may be substituted with 1 to 5 substituents
Is C_1-4Alkoxy, halogen, C_1-4Alkyl and C
_6-10Substituted with 1 to 3 substituents selected from aryl
(X-11) formyl, (C_1-6Al
Kill) carbonyl, (C_3-6Cycloalkyl) carboni
Le, (C_6-10Aryl) carbonyl, (C_7-12Aralki
Le) carbonyl, (C_1-6Alkyl) sulfinyl,
(C_3-6Cycloalkyl) sulfinyl, (C_6-10Ants
) Sulfinyl, (C_7-12Aralkyl) Sulfini
Le, (C_1-6Alkyl) sulfonyl, (C_3-6Cycloal
Kill) sulfonyl, (C_6-10Aryl) sulfonyl and
(C_7-12Aralkyl) acyl selected from sulfonyl
Group (where each substituent is halogen, C_1-4Arco
Xy and C_1-41 to 5 substitutions selected from alkyl
(X-12) halogen,
Selected from (x-13) nitro and (x-14) cyano
Optionally substituted with 1 to 4 substituents), (xi) formyl, (C_1-6Alkyl) carbonyl,
(C_3-6Cycloalkyl) carbonyl, (C_6-10Ally
Le) carbonyl, (C_7-12Aralkyl) carbonyl,
(C_1-6Alkyl) sulfinyl, (C_3-6Cycloalkyl
Le) sulfinyl, (C_6-10Aryl) sulfinyl,
(C_7-12Aralkyl) sulfinyl, (C_1-6Archi
Le) sulfonyl, (C_3-6Cycloalkyl) sulfoni
Le, (C_6-10Aryl) sulfonyl and (C_7-12Ara
Alkyl) sulfonyl acyl group (where each
The substituents are halogen, C_1-4Alkoxy and C_1-4
Substituted with 1 to 5 substituents selected from alkyl
May be used), (xii) halogen, (xiii) nitro, and (xiv) cyano substituted with 1 to 4 substituents.
May be included]. } An acyl group selected from the following: (2) Formula-COOR⁷中 where R⁷Is (2-1) a hydrogen atom, (2-2) (a) an alkyl group having 1 to 10 carbon atoms, (b) an alkenyl group having 2 to 10 carbon atoms, (c) an alkynyl group having 2 to 10 carbon atoms, (D) a cycloalkyl group having 3 to 12 carbon atoms, (e) a cycloalkenyl group having 5 to 12 carbon atoms, (f) a cycloalkadienyl group having 5 to 12 carbon atoms, (g) C_3-7Cycloalkyl-C_1-8Alkyl group, (h) C_5-7Cycloalkenyl-C_1-8Alkyl group and
And (i) a hydrocarbon selected from aryl groups having 6 to 10 carbon atoms
Elementary groups [wherein the substituents (a) to (i) are (i) halogen and C, respectively._1-31 selected from alkoxy
~ C optionally substituted with 3 substituents_1-6Alkyl
A group, (ii) halogen and C_1-3Selected from alkoxy
C optionally substituted with 1 to 3 substituents_1-6Arco
Xy group, (iii) C_1-3Alkoxy, halogen, C_1-3Archi
1 to 5 selected from amino, nitro and cyano
C optionally substituted with a substituent of_6-14Aryl group, (iv) each C_1-3Alkoxy, halogen, C_1-3A
1 selected from alkyl, amino, nitro and cyano
C optionally substituted with 5 substituents_3-7Cycloal
Kill group or C_3-6A cycloalkenyl group, (v) C optionally substituted by halogen_1-4Alkoki
C, halogen, C optionally substituted with halogen_1-4
Alkyl, C_6-101 selected from aryl and nitro
To a heterocyclic group optionally substituted with 3 substituents, (vi) a carboxyl group, (C_1-6Alkoxy) carbo
Nyl group, (C_6-10Aryl) oxycarbonyl group or
(C_7-10Aralkyl) oxycarbonyl group, (vii) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Aralkyl and C_6-10Aryl
Substituted with 1 to 2 substituents selected from sulfonyl
A carbamoyl group (wherein each substituent is
Halogen, C optionally substituted with halogen_1-4Al
Coxy, C optionally substituted with halogen_1-4Archi
Substituted with 1 to 5 substituents selected from
May be included), (viii) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Aralkyl and C_6-10Aryl
Substituted with 1 to 2 substituents selected from sulfonyl
Amino group that may be present (Here, each substituent is a halogen
C optionally substituted by halogen_1-4Alkoki
C which may be substituted by halogen_1-4Alkyl
And substituted with 1 to 5 substituents selected from nitro
Or a cyclic amino group, (ix) C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10
Aryl, C_7-12Substituted with aralkyl and heterocycle groups
Optionally a hydroxyl group (here, C_1-6Alkyl, C_3-6Shi
Chloroalkyl, C_6-10Aryl and C_7-12Aralkyl
May be substituted with halogen or halogen, respectively
I C_1-4Optionally substituted with alkoxy and halogen
C_1-4Selected from alkyl, nitro, amino and cyano
A heterocycle which may be substituted with 1 to 5 substituents
The groups are (ix-1) halogen and C_1-3From alkoxy
C optionally substituted with 1 to 3 substituents selected
_1-6Alkyl group, (ix-2) halogen and C_1-3Al
Substituted with 1 to 3 substituents selected from
Good C_1-6Alkoxy group, (ix-3) C_1-3Alkoki
Si, halogen, C_1-3Alkyl, amino, nitro and
Substituted with 1 to 5 substituents selected from cyano,
Good C_6-14Aryl group, (ix-4) each C_1-3
Alkoxy, halogen, C_1-3Alkyl, amino, nitro
Substituted with 1 to 5 substituents selected from
May be C_3-7Cycloalkyl group or C_3-6Shiku
Alkenyl group, substituted with (ix-5) halogen
May be C_1-4Substitute with alkoxy, halogen, halogen
C that may be_1-4Alkyl, C_6-10Aryl and
Substituted with 1 to 3 substituents selected from
Optionally a heterocyclic group, (ix-6) carboxyl group, (C
_1-6An alkoxy) carbonyl group, (C_6-10Aryl) o
A xycarbonyl group or (C_7-10Aralkyl) oxyca
Rubonyl group, (ix-7) C_1-6Alkyl, C_3-6Cyclo
Alkyl, C_6-10Aryl, C_7-12Aralkyl and C
_6-101 to 2 substituents selected from arylsulfonyl
A carbamoyl group optionally substituted with
The groups may be substituted with halogen and halogen, respectively.
I C_1-4Optionally substituted with alkoxy and halogen
C_1-41 to 5 positions selected from alkyl and nitro
Optionally substituted with a substituent), (ix-8) C_1-6A
Luquil, C_3-6Cycloalkyl, C_6-10Aryl, C
_7-12Aralkyl and C_6-10Selected from arylsulfonyl
Amino optionally substituted with 1 to 2 substituents
Group (wherein each substituent is halogen,
C which may be replaced_1-4Substituted with alkoxy and halogen
C that may be_1-4Choose from alkyl and nitro
Optionally substituted with 1 to 5 substituents),
Is a cyclic amino group, (ix-9) C_1-6Alkyl, C_3-6Shi
Chloroalkyl, C_6-10Aryl, C_7-12Aralkyl and
And a hydroxyl group which may be substituted with a heterocyclic group (wherein C
_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Aryl
And C_7-12Aralkyl is halogen, halogen respectively
C optionally substituted with_1-4With alkoxy, halogen
Optionally substituted C_1-4Alkyl, nitro, amino
And substituted with 1 to 5 substituents selected from cyano
And the heterocyclic group is C_1-4Alkoxy, halogen
N, C_1-4Alkyl and C_6-10Selected from aryl
Optionally substituted with 1 to 3 substituents), (ix-
10) C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10A
Reel, C_7-12Substituted with aralkyl and heterocycle groups
Optional thiol group (where C_1-6Alkyl, C_3-6
Cycloalkyl, C_6-10Aryl and C_7-12Aralki
Each is halogen, even if substituted with halogen
Good C_1-4May be substituted with alkoxy or halogen
I C_1-4Select from alkyl, nitro, amino and cyano
Optionally substituted with 1 to 5 substituents
The ring group is C_1-4Alkoxy, halogen, C_1-4Alkyl and
And C_6-10Substituted with 1 to 3 substituents selected from aryl
), (Ix-11) formyl, (C
_1-6Alkyl) carbonyl, (C_3-6Cycloalkyl)
Rubonil, (C_6-10Aryl) carbonyl, (C_7-12A
Ralalkyl) carbonyl, (C_1-6Alkyl) sulfini
Le, (C_3-6Cycloalkyl) sulfinyl, (C_6-10
Aryl) sulfinyl, (C_7-12Aralkyl) Sulf
Inyl, (C_1-6Alkyl) sulfonyl, (C_3-6Cyclo
Alkyl) sulfonyl, (C_6-10Aryl) sulfonyl
And (C_7-12Aralkyl) A selected from sulfonyl
Silyl group (wherein each substituent is halogen, C_1-4A
Lucoxy and C_1-41 to 5 selected from alkyl
Optionally substituted with a substituent), (ix-12) halo
Gen, (ix-13) nitro, and (ix-14) si
Even if it is substituted with 1 to 4 substituents selected from ANO
Good), (x) C_1-6Alkyl, C_3-6Cycloalkyl,
C_6-10Aryl, C_7-12Aralkyl and heterocyclic groups
Optionally substituted thiol group (where C_1-6Archi
Le, C_3-6Cycloalkyl, C_6-10Aryl and C
_7-12Aralkyl substituted with halogen and halogen, respectively
C that may be_1-4Substituted with alkoxy, halogen
May be C_1-4Alkyl, nitro, amino and
Substituted with 1 to 5 substituents selected from cyano,
And the heterocyclic group is (x-1) halogen and C_1-3A
Substituted with 1 to 3 substituents selected from lucoxy
May be C_1-6An alkyl group, (x-2) halogen and
C_1-3Substituted with 1 to 3 substituents selected from alkoxy
C that may be_1-6Alkoxy group, (x-3) C_1-3
Alkoxy, halogen, C_1-3Alkyl, amino, nitro
Substituted with 1 to 5 substituents selected from
May be C_6-14Aryl group, (x-4) each
C_1-3Alkoxy, halogen, C_1-3Alkyl, amino,
Substituted with 1 to 5 substituents selected from nitro and cyano
C which may be replaced_3-7Cycloalkyl group or C_3-6
Cycloalkenyl group, substituted by (x-5) halogen
May be C_1-4Substituted with alkoxy, halogen, halogen
C which may be replaced_1-4Alkyl, C_6-10Aryl
And substituted with 1 to 3 substituents selected from nitro
An optionally substituted heterocyclic group, (x-6) carboxyl group, (C
_1-6An alkoxy) carbonyl group, (C_6-10Aryl) o
A xycarbonyl group or (C_7-10Aralkyl) oxyca
Rubonyl group, (x-7) C_1-6Alkyl, C_3-6Cycloa
Luquil, C_6-10Aryl, C_7-12Aralkyl and C
_6-101 to 2 substituents selected from arylsulfonyl
A carbamoyl group optionally substituted with
The groups may be substituted with halogen and halogen, respectively.
I C_1-4Optionally substituted with alkoxy and halogen
C_1-41 to 5 positions selected from alkyl and nitro
(X-8) C_1-6Al
Kill, C_3-6Cycloalkyl, C_6-10Aryl, C_7-12
Aralkyl and C_6-10Selected from arylsulfonyl
Amino group optionally substituted with 1 to 2 substituents
(Where each substituent is halogen,
C that may be_1-4Substituted with alkoxy, halogen
May be C_1-4Selected from alkyl and nitro
May be substituted with 1 to 5 substituents), or
Cyclic amino group, (x-9) C_1-6Alkyl, C_3-6Cyclo
Alkyl, C_6-10Aryl, C_7-12Aralkyl and multiple
A hydroxyl group which may be substituted with a ring group (here, C_1-6
Alkyl, C_3-6Cycloalkyl, C_6-10Aryl and
And C_7-12Aralkyl is halogen and halogen respectively
Optionally substituted C_1-4Substituted with alkoxy and halogen
C which may be replaced_1-4Alkyl, nitro, amino
And substituted with 1 to 5 substituents selected from cyano
And the heterocyclic group may be C_1-4Alkoxy, halogen,
C_1-4Alkyl and C_6-101 selected from aryl
(Optionally substituted with three substituents), (x-10)
C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Ally
Le, C_7-12Substituted with aralkyl and heterocyclic groups
Thiol group (where C_1-6Alkyl, C_3-6Shiku
Lower alkyl, C_6-10Aryl and C_7-12Aralkyl
Each may be substituted with halogen or halogen
C_1-4C which may be substituted by alkoxy or halogen
_1-4Selected from alkyl, nitro, amino and cyano
A heterocyclic group which may be substituted with 1 to 5 substituents
Is C_1-4Alkoxy, halogen, C_1-4Alkyl and C
_6-10Substituted with 1 to 3 substituents selected from aryl
(X-11) formyl, (C_1-6Al
Kill) carbonyl, (C_3-6Cycloalkyl) carboni
Le, (C_6-10Aryl) carbonyl, (C_7-12Aralki
Le) carbonyl, (C_1-6Alkyl) sulfinyl,
(C_3-6Cycloalkyl) sulfinyl, (C_6-10Ants
) Sulfinyl, (C_7-12Aralkyl) Sulfini
Le, (C_1-6Alkyl) sulfonyl, (C_3-6Cycloal
Kill) sulfonyl, (C_6-10Aryl) sulfonyl and
(C_7-12Aralkyl) acyl selected from sulfonyl
Group (where each substituent is halogen, C_1-4Arco
Xy and C_1-41 to 5 substitutions selected from alkyl
(X-12) halogen,
Selected from (x-13) nitro and (x-14) cyano
Optionally substituted with 1 to 4 substituents), (xi) formyl, (C_1-6Alkyl) carbonyl,
(C_3-6Cycloalkyl) carbonyl, (C_6-10Ally
Le) carbonyl, (C_7-12Aralkyl) carbonyl,
(C_1-6Alkyl) sulfinyl, (C_3-6Cycloalkyl
Le) sulfinyl, (C_6-10Aryl) sulfinyl,
(C_7-12Aralkyl) sulfinyl, (C_1-6Archi
Le) sulfonyl, (C_3-6Cycloalkyl) sulfoni
Le, (C_6-10Aryl) sulfonyl and (C_7-12Ara
Alkyl) sulfonyl acyl group (where each
The substituents are halogen, C_1-4Alkoxy and C_1-4
Substituted with 1 to 5 substituents selected from alkyl
May be used), (xii) halogen, (xiii) nitro, and (xiv) cyano substituted with 1 to 3 substituents.
Or a (2-3) heterocyclic group [wherein the heterocyclic group is (i) halogen and C_1-31 selected from alkoxy
~ C optionally substituted with 3 substituents_1-6Alkyl
A group, (ii) halogen and C_1-3Selected from alkoxy
C optionally substituted with 1 to 3 substituents_1-6Arco
Xy group, (iii) C_1-3Alkoxy, halogen, C_1-3Archi
1 to 5 selected from amino, nitro and cyano
C optionally substituted with a substituent of_6-14Aryl group, (iv) each C_1-3Alkoxy, halogen, C_1-3A
1 selected from alkyl, amino, nitro and cyano
C optionally substituted with 5 substituents_3-7Cycloal
Kill group or C_3-6A cycloalkenyl group, (v) C optionally substituted by halogen_1-4Alkoki
C, halogen, C optionally substituted with halogen_1-4
Alkyl, C_6-101 selected from aryl and nitro
To a heterocyclic group optionally substituted with 3 substituents, (vi) a carboxyl group, (C_1-6Alkoxy) carbo
Nyl group, (C_6-10Aryl) oxycarbonyl group or
(C_7-10Aralkyl) oxycarbonyl group, (vii) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Aralkyl and C_6-10Aryl
Substituted with 1 to 2 substituents selected from sulfonyl
A carbamoyl group (wherein each substituent is
Halogen, C optionally substituted with halogen_1-4Al
Coxy, C optionally substituted with halogen_1-4Archi
Substituted with 1 to 5 substituents selected from
May be included), (viii) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Aralkyl and C_6-10Aryl
Substituted with 1 to 2 substituents selected from sulfonyl
Amino group that may be present (Here, each substituent is a halogen
C optionally substituted by halogen_1-4Alkoki
C which may be substituted by halogen_1-4Alkyl
And substituted with 1 to 5 substituents selected from nitro
Or a cyclic amino group, (ix) C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10
Aryl, C_7-12Substituted with aralkyl and heterocycle groups
Optionally a hydroxyl group (here, C_1-6Alkyl, C_3-6Shi
Chloroalkyl, C_6-10Aryl and C_7-12Aralkyl
May be substituted with halogen or halogen, respectively
I C_1-4Optionally substituted with alkoxy and halogen
C_1-4Selected from alkyl, nitro, amino and cyano
A heterocycle which may be substituted with 1 to 5 substituents
The groups are (ix-1) halogen and C_1-3From alkoxy
C optionally substituted with 1 to 3 substituents selected
_1-6Alkyl group, (ix-2) halogen and C_1-3Al
Substituted with 1 to 3 substituents selected from
Good C_1-6Alkoxy group, (ix-3) C_1-3Alkoki
Si, halogen, C_1-3Alkyl, amino, nitro and
Substituted with 1 to 5 substituents selected from cyano,
Good C_6-14Aryl group, (ix-4) each C_1-3
Alkoxy, halogen, C_1-3Alkyl, amino, nitro
Substituted with 1 to 5 substituents selected from
May be C_3-7Cycloalkyl group or C_3-6Shiku
Alkenyl group, substituted with (ix-5) halogen
May be C_1-4Substitute with alkoxy, halogen, halogen
C that may be_1-4Alkyl, C_6-10Aryl and
Substituted with 1 to 3 substituents selected from
Optionally a heterocyclic group, (ix-6) carboxyl group, (C
_1-6An alkoxy) carbonyl group, (C_6-10Aryl) o
A xycarbonyl group or (C_7-10Aralkyl) oxyca
Rubonyl group, (ix-7) C_1-6Alkyl, C_3-6Cyclo
Alkyl, C_6-10Aryl, C_7-12Aralkyl and C
_6-101 to 2 substituents selected from arylsulfonyl
A carbamoyl group optionally substituted with
The groups may be substituted with halogen and halogen, respectively.
I C_1-4Optionally substituted with alkoxy and halogen
C_1-41 to 5 positions selected from alkyl and nitro
Optionally substituted with a substituent), (ix-8) C_1-6A
Luquil, C_3-6Cycloalkyl, C_6-10Aryl, C
_7-12Aralkyl and C_6-10Selected from arylsulfonyl
Amino optionally substituted with 1 to 2 substituents
Group (wherein each substituent is halogen,
C which may be replaced_1-4Substituted with alkoxy and halogen
C that may be_1-4Choose from alkyl and nitro
Optionally substituted with 1 to 5 substituents),
Is a cyclic amino group, (ix-9) C_1-6Alkyl, C_3-6Shi
Chloroalkyl, C_6-10Aryl, C_7-12Aralkyl and
And a hydroxyl group which may be substituted with a heterocyclic group (wherein C
_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Aryl
And C_7-12Aralkyl is halogen, halogen respectively
C optionally substituted with_1-4With alkoxy, halogen
Optionally substituted C_1-4Alkyl, nitro, amino
And substituted with 1 to 5 substituents selected from cyano
And the heterocyclic group is C_1-4Alkoxy, halogen
N, C_1-4Alkyl and C_6-10Selected from aryl
Optionally substituted with 1 to 3 substituents), (ix-
10) C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10A
Reel, C_7-12Substituted with aralkyl and heterocycle groups
Optional thiol group (where C_1-6Alkyl, C_3-6
Cycloalkyl, C_6-10Aryl and C_7-12Aralki
Each is halogen, even if substituted with halogen
Good C_1-4May be substituted with alkoxy or halogen
I C_1-4Select from alkyl, nitro, amino and cyano
Optionally substituted with 1 to 5 substituents
The ring group is C_1-4Alkoxy, halogen, C_1-4Alkyl and
And C_6-10Substituted with 1 to 3 substituents selected from aryl
), (Ix-11) formyl, (C
_1-6Alkyl) carbonyl, (C_3-6Cycloalkyl)
Rubonil, (C_6-10Aryl) carbonyl, (C_7-12A
Ralalkyl) carbonyl, (C_1-6Alkyl) sulfini
Le, (C_3-6Cycloalkyl) sulfinyl, (C_6-10
Aryl) sulfinyl, (C_7-12Aralkyl) Sulf
Inyl, (C_1-6Alkyl) sulfonyl, (C_3-6Cyclo
Alkyl) sulfonyl, (C_6-10Aryl) sulfonyl
And (C_7-12Aralkyl) A selected from sulfonyl
Silyl group (wherein each substituent is halogen, C_1-4A
Lucoxy and C_1-41 to 5 selected from alkyl
Optionally substituted with a substituent), (ix-12) halo
Gen, (ix-13) nitro, and (ix-14) si
Even if it is substituted with 1 to 4 substituents selected from ANO
Good), (x) C_1-6Alkyl, C_3-6Cycloalkyl,
C_6-10Aryl, C_7-12Aralkyl and heterocyclic groups
Optionally substituted thiol group (where C_1-6Archi
Le, C_3-6Cycloalkyl, C_6-10Aryl and C
_7-12Aralkyl substituted with halogen and halogen, respectively
C that may be_1-4Substituted with alkoxy, halogen
May be C_1-4Alkyl, nitro, amino and
Substituted with 1 to 5 substituents selected from cyano,
And the heterocyclic group is (x-1) halogen and C_1-3A
Substituted with 1 to 3 substituents selected from lucoxy
May be C_1-6An alkyl group, (x-2) halogen and
C_1-3Substituted with 1 to 3 substituents selected from alkoxy
C that may be_1-6Alkoxy group, (x-3) C_1-3
Alkoxy, halogen, C_1-3Alkyl, amino, nitro
Substituted with 1 to 5 substituents selected from
May be C_6-14Aryl group, (x-4) each
C_1-3Alkoxy, halogen, C_1-3Alkyl, amino,
Substituted with 1 to 5 substituents selected from nitro and cyano
C which may be replaced_3-7Cycloalkyl group or C_3-6
Cycloalkenyl group, substituted by (x-5) halogen
May be C_1-4Substituted with alkoxy, halogen, halogen
C which may be replaced_1-4Alkyl, C_6-10Aryl
And substituted with 1 to 3 substituents selected from nitro
An optionally substituted heterocyclic group, (x-6) carboxyl group, (C
_1-6An alkoxy) carbonyl group, (C_6-10Aryl) o
A xycarbonyl group or (C_7-10Aralkyl) oxyca
Rubonyl group, (x-7) C_1-6Alkyl, C_3-6Cycloa
Luquil, C_6-10Aryl, C_7-12Aralkyl and C
_6-101 to 2 substituents selected from arylsulfonyl
A carbamoyl group optionally substituted with
The groups may be substituted with halogen and halogen, respectively.
I C_1-4Optionally substituted with alkoxy and halogen
C_{1 -Four}1 to 5 positions selected from alkyl and nitro
(X-8) C_1-6Al
Kill, C_3-6Cycloalkyl, C_6-10Aryl, C_7-12
Aralkyl and C_6-10Selected from arylsulfonyl
Amino group optionally substituted with 1 to 2 substituents
(Where each substituent is halogen,
C that may be_1-4Substituted with alkoxy, halogen
May be C_1-4Selected from alkyl and nitro
May be substituted with 1 to 5 substituents), or
Cyclic amino group, (x-9) C_1-6Alkyl, C_3-6Cyclo
Alkyl, C_6-10Aryl, C_7-12Aralkyl and multiple
A hydroxyl group which may be substituted with a ring group (here, C_1-6
Alkyl, C_3-6Cycloalkyl, C_6-10Aryl and
And C_7-12Aralkyl is halogen and halogen respectively
Optionally substituted C_1-4Substituted with alkoxy and halogen
C which may be replaced_1-4Alkyl, nitro, amino
And substituted with 1 to 5 substituents selected from cyano
And the heterocyclic group may be C_1-4Alkoxy, halogen,
C_1-4Alkyl and C_6-101 selected from aryl
(Optionally substituted with three substituents), (x-10)
C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Ally
Le, C_7-12Substituted with aralkyl and heterocyclic groups
Thiol group (where C_1-6Alkyl, C_3-6Shiku
Lower alkyl, C_6-10Aryl and C_7-12Aralkyl
Each may be substituted with halogen or halogen
C_1-4C which may be substituted by alkoxy or halogen
_1-4Selected from alkyl, nitro, amino and cyano
A heterocyclic group which may be substituted with 1 to 5 substituents
Is C_1-4Alkoxy, halogen, C_1-4Alkyl and C
_6-10Substituted with 1 to 3 substituents selected from aryl
(X-11) formyl, (C_1-6Al
Kill) carbonyl, (C_3-6Cycloalkyl) carboni
Le, (C_6-10Aryl) carbonyl, (C_7-12Aralki
Le) carbonyl, (C_1-6Alkyl) sulfinyl,
(C_3-6Cycloalkyl) sulfinyl, (C_6-10Ants
) Sulfinyl, (C_7-12Aralkyl) Sulfini
Le, (C_1-6Alkyl) sulfonyl, (C_3-6Cycloal
Kill) sulfonyl, (C_6-10Aryl) sulfonyl and
(C_7-12Aralkyl) acyl selected from sulfonyl
Group (where each substituent is halogen, C_1-4Arco
Xy and C_1-41 to 5 substitutions selected from alkyl
(X-12) halogen,
Selected from (x-13) nitro and (x-14) cyano
Optionally substituted with 1 to 4 substituents), (xi) formyl, (C_1-6Alkyl) carbonyl,
(C_3-6Cycloalkyl) carbonyl, (C_6-10Ally
Le) carbonyl, (C_7-12Aralkyl) carbonyl,
(C_1-6Alkyl) sulfinyl, (C_3-6Cycloalkyl
Le) sulfinyl, (C_6-10Aryl) sulfinyl,
(C_7-12Aralkyl) sulfinyl, (C_1-6Archi
Le) sulfonyl, (C_3-6Cycloalkyl) sulfoni
Le, (C_6-10Aryl) sulfonyl and (C_7-12Ara
Alkyl) sulfonyl acyl group (where each
The substituents are halogen, C_1-4Alkoxy and C_1-4
Substituted with 1 to 5 substituents selected from alkyl
May be used), (xii) halogen, (xiii) nitro, and (xiv) cyano substituted with 1 to 4 substituents.
May be included]. } Esterified
(3) (a) an alkyl group having 1 to 10 carbon atoms, (b) an alkenyl group having 2 to 10 carbon atoms, (c) an alkynyl group having 2 to 10 carbon atoms, and (d) ) C3-C12 cycloalkyl group, (e) C5-C12 cycloalkenyl group, (f) C5-C12 cycloalkadienyl group, (g) C_3-7Cycloalkyl-C_1-8Alkyl group, (h) C_5-7Cycloalkenyl-C_1-8Alkyl group and
And (i) a hydrocarbon selected from aryl groups having 6 to 10 carbon atoms
Elementary groups [wherein the substituents (a) to (i) are (i) halogen and C, respectively._1-31 selected from alkoxy
~ C optionally substituted with 3 substituents_1-6Alkyl
A group, (ii) halogen and C_1-3Selected from alkoxy
C optionally substituted with 1 to 3 substituents_1-6Arco
Xy group, (iii) C_1-3Alkoxy, halogen, C_1-3Archi
1 to 5 selected from amino, nitro and cyano
C optionally substituted with a substituent of_6-14Aryl group, (iv) each C_1-3Alkoxy, halogen, C_1-3A
1 selected from alkyl, amino, nitro and cyano
C optionally substituted with 5 substituents_3-7Cycloal
Kill group or C_3-6A cycloalkenyl group, (v) C optionally substituted by halogen_1-4Alkoki
C, halogen, C optionally substituted with halogen_1-4
Alkyl, C_6-101 selected from aryl and nitro
To a heterocyclic group optionally substituted with 3 substituents, (vi) a carboxyl group, (C_1-6Alkoxy) carbo
Nyl group, (C_6-10Aryl) oxycarbonyl group or
(C_7-10Aralkyl) oxycarbonyl group, (vii) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Aralkyl and C_6-10Aryl
Substituted with 1 to 2 substituents selected from sulfonyl
A carbamoyl group (wherein each substituent is
Halogen, C optionally substituted with halogen_1-4Al
Coxy, C optionally substituted with halogen_{1 -Four}Archi
Substituted with 1 to 5 substituents selected from
May be included), (viii) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Aralkyl and C_6-10Aryl
Substituted with 1 to 2 substituents selected from sulfonyl
Amino group that may be present (Here, each substituent is a halogen
C optionally substituted by halogen_1-4Alkoki
C which may be substituted by halogen_1-4Alkyl
And substituted with 1 to 5 substituents selected from nitro
Or a cyclic amino group, (ix) C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10
Aryl, C_7-12Substituted with aralkyl and heterocycle groups
Optionally a hydroxyl group (here, C_1-6Alkyl, C_3-6Shi
Chloroalkyl, C_6-10Aryl and C_7-12Aralkyl
May be substituted with halogen or halogen, respectively
I C_1-4Optionally substituted with alkoxy and halogen
C_1-4Selected from alkyl, nitro, amino and cyano
A heterocycle which may be substituted with 1 to 5 substituents
The groups are (ix-1) halogen and C_1-3From alkoxy
C optionally substituted with 1 to 3 substituents selected
_1-6Alkyl group, (ix-2) halogen and C_1-3Al
Substituted with 1 to 3 substituents selected from
Good C_1-6Alkoxy group, (ix-3) C_1-3Alkoki
Si, halogen, C_1-3Alkyl, amino, nitro and
Substituted with 1 to 5 substituents selected from cyano,
Good C_6-14Aryl group, (ix-4) each C_1-3
Alkoxy, halogen, C_1-3Alkyl, amino, nitro
Substituted with 1 to 5 substituents selected from
May be C_3-7Cycloalkyl group or C_3-6Shiku
Alkenyl group, substituted with (ix-5) halogen
May be C_1-4Substitute with alkoxy, halogen, halogen
C that may be_1-4Alkyl, C_6-10Aryl and
Substituted with 1 to 3 substituents selected from
Optionally a heterocyclic group, (ix-6) carboxyl group, (C
_1-6An alkoxy) carbonyl group, (C_6-10Aryl) o
A xycarbonyl group or (C_7-10Aralkyl) oxyca
Rubonyl group, (ix-7) C_1-6Alkyl, C_3-6Cyclo
Alkyl, C_6-10Aryl, C_7-12Aralkyl and C
_6-101 to 2 substituents selected from arylsulfonyl
A carbamoyl group optionally substituted with
The groups may be substituted with halogen and halogen, respectively.
I C_1-4Optionally substituted with alkoxy and halogen
C_1-41 to 5 positions selected from alkyl and nitro
Optionally substituted with a substituent), (ix-8) C_1-6A
Luquil, C_3-6Cycloalkyl, C_6-10Aryl, C
_7-12Aralkyl and C_6-10Selected from arylsulfonyl
Amino optionally substituted with 1 to 2 substituents
Group (wherein each substituent is halogen,
C which may be replaced_1-4Substituted with alkoxy and halogen
C that may be_1-4Choose from alkyl and nitro
Optionally substituted with 1 to 5 substituents),
Is a cyclic amino group, (ix-9) C_1-6Alkyl, C_3-6Shi
Chloroalkyl, C_6-10Aryl, C_7-12Aralkyl and
And a hydroxyl group which may be substituted with a heterocyclic group (wherein C
_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Aryl
And C_7-12Aralkyl is halogen, halogen respectively
C optionally substituted with_1-4With alkoxy, halogen
Optionally substituted C_1-4Alkyl, nitro, amino
And substituted with 1 to 5 substituents selected from cyano
And the heterocyclic group is C_1-4Alkoxy, halogen
N, C_1-4Alkyl and C_6-10Selected from aryl
Optionally substituted with 1 to 3 substituents), (ix-
10) C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10A
Reel, C_7-12Substituted with aralkyl and heterocycle groups
Optional thiol group (where C_1-6Alkyl, C_3-6
Cycloalkyl, C_6-10Aryl and C_7-12Aralki
Each is halogen, even if substituted with halogen
Good C_1-4May be substituted with alkoxy or halogen
I C_1-4Select from alkyl, nitro, amino and cyano
Optionally substituted with 1 to 5 substituents
The ring group is C_1-4Alkoxy, halogen, C_1-4Alkyl and
And C_6-10Substituted with 1 to 3 substituents selected from aryl
), (Ix-11) formyl, (C
_1-6Alkyl) carbonyl, (C_3-6Cycloalkyl)
Rubonil, (C_6-10Aryl) carbonyl, (C_7-12A
Ralalkyl) carbonyl, (C_1-6Alkyl) sulfini
Le, (C_3-6Cycloalkyl) sulfinyl, (C_6-10
Aryl) sulfinyl, (C_7-12Aralkyl) Sulf
Inyl, (C_1-6Alkyl) sulfonyl, (C_3-6Cyclo
Alkyl) sulfonyl, (C_6-10Aryl) sulfonyl
And (C_7-12Aralkyl) A selected from sulfonyl
Silyl group (wherein each substituent is halogen, C_1-4A
Lucoxy and C_1-41 to 5 selected from alkyl
Optionally substituted with a substituent), (ix-12) halo
Gen, (ix-13) nitro, and (ix-14) si
Even if it is substituted with 1 to 4 substituents selected from ANO
Good), (x) C_1-6Alkyl, C_3-6Cycloalkyl,
C_6-10Aryl, C_7-12Aralkyl and heterocyclic groups
Optionally substituted thiol group (where C_1-6Archi
Le, C_3-6Cycloalkyl, C_6-10Aryl and C
_7-12Aralkyl substituted with halogen and halogen, respectively
C that may be_1-4Substituted with alkoxy, halogen
May be C_1-4Alkyl, nitro, amino and
Substituted with 1 to 5 substituents selected from cyano,
And the heterocyclic group is (x-1) halogen and C_1-3A
Substituted with 1 to 3 substituents selected from lucoxy
May be C_1-6An alkyl group, (x-2) halogen and
C_1-3Substituted with 1 to 3 substituents selected from alkoxy
C that may be_1-6Alkoxy group, (x-3) C_1-3
Alkoxy, halogen, C_1-3Alkyl, amino, nitro
Substituted with 1 to 5 substituents selected from
May be C_6-14Aryl group, (x-4) each
C_1-3Alkoxy, halogen, C_1-3Alkyl, amino,
Substituted with 1 to 5 substituents selected from nitro and cyano
C which may be replaced_3-7Cycloalkyl group or C_3-6
Cycloalkenyl group, substituted by (x-5) halogen
May be C_1-4Substituted with alkoxy, halogen, halogen
C which may be replaced_1-4Alkyl, C_6-10Aryl
And substituted with 1 to 3 substituents selected from nitro
An optionally substituted heterocyclic group, (x-6) carboxyl group, (C
_1-6An alkoxy) carbonyl group, (C_6-10Aryl) o
A xycarbonyl group or (C_7-10Aralkyl) oxyca
Rubonyl group, (x-7) C_1-6Alkyl, C_3-6Cycloa
Luquil, C_6-10Aryl, C_7-12Aralkyl and C
_6-101 to 2 substituents selected from arylsulfonyl
A carbamoyl group optionally substituted with
The groups may be substituted with halogen and halogen, respectively.
I C_1-4Optionally substituted with alkoxy and halogen
C_1-41 to 5 positions selected from alkyl and nitro
(X-8) C_1-6Al
Kill, C_3-6Cycloalkyl, C_6-10Aryl, C_7-12
Aralkyl and C_6-10Selected from arylsulfonyl
Amino group optionally substituted with 1 to 2 substituents
(Where each substituent is halogen,
C that may be_1-4Substituted with alkoxy, halogen
May be C_1-4Selected from alkyl and nitro
May be substituted with 1 to 5 substituents), or
Cyclic amino group, (x-9) C_1-6Alkyl, C_3-6Cyclo
Alkyl, C_6-10Aryl, C_7-12Aralkyl and multiple
A hydroxyl group which may be substituted with a ring group (here, C_1-6
Alkyl, C_3-6Cycloalkyl, C_6-10Aryl and
And C_7-12Aralkyl is halogen and halogen respectively
Optionally substituted C_1-4Substituted with alkoxy and halogen
C which may be replaced_1-4Alkyl, nitro, amino
And substituted with 1 to 5 substituents selected from cyano
And the heterocyclic group may be C_1-4Alkoxy, halogen,
C_1-4Alkyl and C_6-101 selected from aryl
(Optionally substituted with three substituents), (x-10)
C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Ally
Le, C_7-12Substituted with aralkyl and heterocyclic groups
Thiol group (where C_1-6Alkyl, C_3-6Shiku
Lower alkyl, C_6-10Aryl and C_7-12Aralkyl
Each may be substituted with halogen or halogen
C_1-4C which may be substituted by alkoxy or halogen
_1-4Selected from alkyl, nitro, amino and cyano
A heterocyclic group which may be substituted with 1 to 5 substituents
Is C_1-4Alkoxy, halogen, C_1-4Alkyl and C
_6-10Substituted with 1 to 3 substituents selected from aryl
(X-11) formyl, (C_1-6Al
Kill) carbonyl, (C_3-6Cycloalkyl) carboni
Le, (C_6-10Aryl) carbonyl, (C_7-12Aralki
Le) carbonyl, (C_1-6Alkyl) sulfinyl,
(C_3-6Cycloalkyl) sulfinyl, (C_6-10Ants
) Sulfinyl, (C_7-12Aralkyl) Sulfini
Le, (C_1-6Alkyl) sulfonyl, (C_3-6Cycloal
Kill) sulfonyl, (C_6-10Aryl) sulfonyl and
(C_7-12Aralkyl) acyl selected from sulfonyl
Group (where each substituent is halogen, C_1-4Arco
Xy and C_1-41 to 5 substitutions selected from alkyl
(X-12) halogen,
Selected from (x-13) nitro and (x-14) cyano
Optionally substituted with 1 to 4 substituents), (xi) formyl, (C_1-6Alkyl) carbonyl,
(C_3-6Cycloalkyl) carbonyl, (C_6-10Ally
Le) carbonyl, (C_7-12Aralkyl) carbonyl,
(C_1-6Alkyl) sulfinyl, (C_3-6Cycloalkyl
Le) sulfinyl, (C_6-10Aryl) sulfinyl,
(C_7-12Aralkyl) sulfinyl, (C_1-6Archi
Le) sulfonyl, (C_3-6Cycloalkyl) sulfoni
Le, (C_6-10Aryl) sulfonyl and (C_7-12Ara
Alkyl) sulfonyl acyl group (where each
The substituents are halogen, C_1-4Alkoxy and C_1-4
Substituted with 1 to 5 substituents selected from alkyl
May be used), (xii) halogen, (xiii) nitro, and (xiv) cyano substituted with 1 to 3 substituents.
1 or 2 substitutions selected from
2. An amino group which may be substituted with a group.
Anti-Helicobacter pylori agent. 5. The anti-Helicobacter pylori agent according to claim 1, wherein R is an amino group which may be substituted with an acyl group. 6. R is of the formula —COR ¹ (wherein R ¹ is a hydrogen atom,
The anti-Helicobacter pylori agent according to claim 1, which is an acyl group represented by a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted). 7. The anti-Helicobacter pylori agent according to claim 6, wherein R ¹ is an optionally substituted furyl group or an optionally substituted thienyl group. 8. R ¹ (a) optionally substituted heterocyclic group (provided that optionally substituted furyl, optionally substituted pyridyl, and optionally substituted 3-amino-2). -Oxo-1-azetidinyl), (b) a hydrocarbon group substituted with an optionally substituted heterocyclic group (excluding phenyl substituted with an optionally substituted maleimide), (c ) Substituted phenoxy-substituted hydrocarbon group, (d) optionally substituted heterocyclic thio-substituted hydrocarbon group, or (e) optionally substituted arylsulfonylamino-substituted The anti-Helicobacter pylori agent according to claim 6, which is an alkyl group. 9. R ¹ is halogen, cyano, formyl, C _1-3 alkyl optionally substituted with halogen, C _1-3 alkoxy optionally substituted with halogen, or halogen substituted. Optionally C _1-3 alkoxycarbonyl and C optionally substituted by halogen
The anti-Helicobacter pylori agent according to claim 6, which is a furyl or pyridyl group having 1 to 3 substituents selected from _1-3 alkylsulfonyl. 10. R is --NHCOR ¹ or --NHSO ₂ R
³ {wherein R ¹ and R ³ are respectively (1) C _1-4 alkyl group, (2) C _2-4 alkenyl group, (3) C _6-10 aryl group, or (4) furyl, benzofuranyl , A thienyl, benzothienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, azolyl and fused azolyl heterocyclic group [wherein C
_{The 1-4} alkyl group, the C _2-4 alkenyl group and the C _6-10 aryl group are (a) a C _1-3 alkyl group optionally substituted with halogen, (b) a C _1-3 alkoxy group, (c ) halogen, amino, nitro or optionally substituted by cyano C _6-10 aryl group, (d) C _1-3 alkoxy, halogen, nitro, cyano or optionally C _6-10 aryl optionally substituted with amino An oxy group, (e) a heterocyclic group optionally selected from halogen, each selected from thienyl, benzimidazolyl, benzoxazolyl and benzisoxazolyl, (f) substituted with p-toluenesulfonyl. Good amino group, (g) hydroxyl group,
(H) a C _6-10 aryl optionally substituted with halogen or C _1-3 alkoxy, or a thiol group optionally substituted with a heterocyclic group selected from benzoxazolyl and benzothiazolyl; )halogen,
1 to 1 selected from (j) nitro group and (k) cyano group
The aromatic heterocyclic group which may be substituted with 3 substituents is (a) a C _1-3 alkyl group which may be substituted with a halogen, (b) a C _6-10 aryl group, (c) C _1-3 alkoxy group optionally substituted with halogen, (d) halogen, (e) nitro, (f) cyano, (g) (C _1-6 alkyl) carbonyl group and (h) (C _{1- 6} alkyl) sulfonyl group, which may be substituted with 1 to 3 substituents selected from the group].] The anti-Helicobacter pylori agent according to claim 1. 11. R is --NHCOR ¹ or --NHSO ₂ R
³ {wherein R ¹ and R ³ are respectively (1) C _1-4 alkyl group, (2) C _2-4 alkenyl group, (3) C _6-10 aryl group, or (4) furyl, thienyl. , Indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl,
Aromatic heterocyclic group selected from azolyl and condensed azolyl [wherein the C _1-4 alkyl group, C _2-4 alkenyl group and C _6-10 aryl group are (a) C ₁ which may be substituted with halogen. _-3 alkyl group, (b) C _1-3 alkoxy group,
(C) halogen optionally substituted C _6-10 aryl group, (d) C _1-3 alkoxy, halogen or optionally substituted C _6-10 aryloxy group nitro, (e)
Thienyl, each of which may be substituted with halogen,
Heterocyclic group selected from benzimidazolyl and benzoxazolyl, (f) amino group optionally substituted with p-toluenesulfonyl, (g) hydroxyl group, (h) heterocycle selected from benzoxazolyl and benzothiazolyl Group optionally substituted with 1 to 3 substituents selected from a thiol group optionally substituted with a group, (i) halogen, (j) nitro group and (k) cyano group, and an aromatic heterocyclic group Is (a) a C _1-3 alkyl group optionally substituted with halogen, (b) a C _6-10 aryl group, (c) a C _1-3 alkoxy group optionally substituted with a halogen, (d) Which may be substituted with 1 to 3 substituents selected from halogen and (e) nitro].] The anti-Helicobacter pylori agent according to claim 1. 12. The anti-Helicobacter pylori agent according to claim 1, which is an agent for preventing recurrence of ulcer. 13. General formula (I): A combined preparation comprising a compound represented by the formula: wherein R represents an amino group which may be substituted, or a pharmaceutically acceptable salt thereof, and an antacid or an acid secretion inhibitor. 14. General formula (IA): [In the formula, R'is (a) an optionally substituted heterocyclic group (provided that it may have an optionally substituted furyl, an optionally substituted pyridyl, and an optionally substituted 3-amino-2. -Oxo-1-azetidinyl), (b) a hydrocarbon group substituted with an optionally substituted heterocyclic group (excluding phenyl substituted with an optionally substituted maleimide), (c ) Substituted phenoxy-substituted hydrocarbon group, (d) optionally substituted heterocyclic thio-substituted hydrocarbon group, or (e) optionally substituted arylsulfonylamino-substituted Or a salt thereof. 15. R'is (1) (i) halogen and C _1-3.
A C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from alkoxy, (ii) substituted with 1 to 3 substituents selected from halogen and C _1-3 alkoxy also a C _1-6 alkoxy group, (iii) C _1-3 alkoxy, halogen, C _1-3 alkyl, amino, optionally substituted with 1-5 substituents selected from nitro and cyano C _{6 -14} aryl group, (iv) _{1 to 3} each selected from C _1-3 alkoxy, halogen, C _1-3 alkyl, amino, nitro and cyano.
C _3-7 cycloalkyl group or C _3-6 cycloalkenyl group optionally substituted with 5 substituents, (v) C _1-4 alkoxy optionally substituted with halogen, halogen, substituted with halogen _May be C _1-4
1 selected from alkyl, C _6-10 aryl and nitro
To a heterocyclic group which may be substituted with 3 substituents, (vi) a carboxyl group, a (C _1-6 alkoxy) carbonyl group, a (C _6-10 aryl) oxycarbonyl group or a (C _7-10 aralkyl) ) Oxycarbonyl group, (vii) C _1-6 alkyl, C _3-6 cycloalkyl, C
_A carbamoyl group which may be substituted with 1 to 2 substituents selected from _6-10 aryl, C _7-12 aralkyl and C _6-10 arylsulfonyl (wherein each substituent is substituted with halogen or halogen, respectively). which may be C _1-4 alkoxy, optionally substituted with 1-5 substituents selected from optionally C _1-4 alkyl and nitro substituted with halogen), (viii) C _{1- 6} alkyl, C _3-6 cycloalkyl, C
An amino group which may be substituted with 1 to 2 substituents selected from _6-10 aryl, C _7-12 aralkyl and C _6-10 arylsulfonyl (wherein each substituent is substituted with halogen, halogen) which may be C _1-4 alkoxy, 1-5 may be substituted with a substituent), or a cyclic amino group selected from optionally C _1-4 alkyl and nitro substituted with halogen, ( ix) C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10
Aryl, C _7-12 aralkyl and a hydroxyl group which may be substituted with a heterocyclic group (wherein C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl and C _7-12 aralkyl are, respectively, halogen, optionally substituted by halogen C _1-4 alkoxy, optionally C _1-4 alkyl optionally substituted by halogen, nitro, optionally substituted with 1-5 substituents selected from amino and cyano Alternatively, the heterocyclic group may be C which may be substituted with 1 to 3 substituents selected from (ix-1) halogen and C _1-3 alkoxy.
_1-6 alkyl group, (ix-2) halogen and C _1-3 1 to 3 substituents which may be substituted C _1-6 alkoxy group with a group selected from alkoxy, (ix-3) C _{1- 3} C _6-14 aryl group optionally substituted by 1 to 5 substituents selected from alkoxy, halogen, C _1-3 alkyl, amino, nitro and cyano, (ix-4) each C _1-3
A C _3-7 cycloalkyl group or a C _3-6 cycloalkenyl group which may be substituted with 1 to 5 substituents selected from alkoxy, halogen, C _1-3 alkyl, amino, nitro and cyano, (ix -5) halogen optionally substituted C _1-4 alkoxy, halogen, optionally substituted by halogen C _1-4 alkyl, one to three substituents selected from C _6-10 aryl and nitro A heterocyclic group which may be substituted with, (ix-6) carboxyl group, (C
_1-6 alkoxy) carbonyl group, (C _6-10 aryl) oxycarbonyl group or (C _7-10 aralkyl) oxycarbonyl group, (ix-7) C _1-6 alkyl, C _3-6 cycloalkyl, C _{6 -10} aryl, C _7-12 aralkyl and C
_A carbamoyl group optionally substituted by 1 to 2 substituents selected from _6-10 arylsulfonyl (wherein each substituent is halogen, C _1-4 alkoxy optionally substituted by halogen, halogen Optionally substituted with 1 to 5 substituents selected from C _1-4 alkyl and nitro), (ix-8) C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C
_An amino group which may be substituted with 1 to 2 substituents selected from _7-12 aralkyl and C _6-10 arylsulfonyl (wherein each substituent is halogen, or C ₁ which may be substituted with halogen, respectively) _-4 alkoxy, C _1-4 alkyl optionally substituted with halogen and optionally substituted with 1 to 5 substituents selected from nitro), or a cyclic amino group, (ix-9) C _{1 -6} alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C _7-12 aralkyl and a hydroxyl group _optionally substituted with a heterocyclic group (wherein C
_1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl and C _7-12 aralkyl are each halogen, C _1-4 alkoxy optionally substituted with halogen or optionally halogen substituted. It may be substituted with 1 to 5 substituents selected from C _1-4 alkyl, nitro, amino and cyano, and the heterocyclic group is C _1-4 alkoxy, halogen, C _1-4 alkyl and C _{6- 10} aryl, which may be substituted with 1 to 3 substituents), (ix-
10) C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C _7-12 aralkyl and a thiol group optionally substituted with a heterocyclic group (where C _1-6 alkyl, C _3-6
Cycloalkyl, C _6-10 aryl and C _7-12 aralkyl each of halogen, halogen substituted C _1-4 alkoxy, optionally C _1-4 alkyl optionally substituted by halogen, nitro, amino And 1 to 5 substituents selected from cyano, and the heterocyclic group may be 1 to 3 substituents selected from C _1-4 alkoxy, halogen, C _1-4 alkyl and C _6-10 aryl. Ix-11) formyl, (C-11)
_1-6 alkyl) carbonyl, (C _3-6 cycloalkyl) carbonyl, (C _6-10 aryl) carbonyl, (C _7-12 aralkyl) carbonyl, (C _1-6 alkyl) sulfinyl, (C _3-6 cycloalkyl) Alkyl) sulfinyl, (C _6-10
From aryl) sulfinyl, (C _7-12 aralkyl) sulfinyl, (C _1-6 alkyl) sulfonyl, (C _3-6 cycloalkyl) sulfonyl, (C _6-10 aryl) sulfonyl and (C _7-12 aralkyl) sulfonyl Selected acyl group (where each substituent may be substituted with 1 to 5 substituents selected from halogen, C _1-4 alkoxy and C _1-4 alkyl, respectively), (ix-12) halogen , (Ix-13) nitro, and (ix-14) cyano, which may be substituted with 1 to 4 substituents), (x) C _1-6 alkyl, C _3-6 cycloalkyl,
C _6-10 aryl, C _7-12 aralkyl and a thiol group optionally substituted with a heterocyclic group (here, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl and C _6-10 aryl
_7-12 aralkyl each of halogen, optionally substituted by halogen C _1-4 alkoxy, halogen optionally substituted C _1-4 alkyl, nitro, a 1-5 selected from amino and cyano A heterocyclic group which may be substituted with a substituent, (x-1) a C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from halogen and C _1-3 alkoxy, (X-2) a C _1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from halogen and C _1-3 alkoxy, (x-3) C _1-3
A C _6-14 aryl group optionally substituted with 1 to 5 substituents selected from alkoxy, halogen, C _1-3 alkyl, amino, nitro and cyano, and (x-4) each a C _1-3 alkoxy , Halogen, C _1-3 alkyl, amino,
C _3-7 cycloalkyl group optionally substituted with 1 to 5 substituents selected from nitro and cyano, or C _3-6
Cycloalkenyl group, selected from (x-5) may be substituted by halogen C _1-4 alkoxy, halogen, halogen optionally substituted C _1-4 alkyl, C _6-10 aryl and nitro 1 A heterocyclic group optionally substituted with up to 3 substituents, a (x-6) carboxyl group, a (C
_1-6 alkoxy) carbonyl group, (C _6-10 aryl) oxycarbonyl group or (C _7-10 aralkyl) oxycarbonyl group, (x-7) C _1-6 alkyl, C _3-6 cycloalkyl, C _{6 -10} aryl, C _7-12 aralkyl and C
_A carbamoyl group optionally substituted with 1 to 2 substituents selected from _6-10 arylsulfonyl (where each substituent is halogen, C _1-4 alkoxy optionally substituted with halogen, halogen, may be substituted with 1 to 5 substituents selected from optionally substituted C _1-4 alkyl optionally and nitro), (x-8) C 1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C _7-12
An amino group optionally substituted with one or two substituents selected from aralkyl and C _6-10 arylsulfonyl (where each substituent is halogen, C _1-4 alkoxy optionally substituted with halogen, respectively) , Optionally substituted with 1 to 5 substituents selected from C _1-4 alkyl optionally substituted with halogen and nitro), or a cyclic amino group, (x-9) C _1-6 alkyl , A C _3-6 cycloalkyl, a C _6-10 aryl, a C _7-12 aralkyl and a hydroxyl group _optionally substituted with a heterocyclic group (where C _1-6
Alkyl, C _3-6 cycloalkyl, C _6-10 respectively aryl and C _7-12 aralkyl, halogen, optionally substituted by halogen C _1-4 alkoxy, optionally substituted by halogen C _{1- 4} alkyl, nitro, amino and may be substituted with 1 to 5 substituents selected from cyano, a heterocyclic group is a C _1-4 alkoxy, halogen,
1 selected from C _1-4 alkyl and C _6-10 aryl
(Optionally substituted with three substituents), (x-10)
C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C _7-12 aralkyl and a thiol group optionally substituted with a heterocyclic group (here, C _1-6 alkyl, C _{3- 6} cycloalkyl, C _6-10 aryl and C _7-12 aralkyl are respectively halogen, C _1-4 alkoxy optionally substituted with halogen, C _1-4 alkoxy optionally substituted with halogen,
The heterocyclic group may be substituted with 1 to 5 substituents selected from _1-4 alkyl, nitro, amino and cyano, and the heterocyclic group may be C _1-4 alkoxy, halogen, C _1-4 alkyl or C _{1-4
(Optionally} substituted with 1 to 3 substituents selected from _6-10 aryl), (x-11) formyl, (C _1-6 alkyl) carbonyl, (C _3-6 cycloalkyl) carbonyl, ( C _6-10 aryl) carbonyl, (C _7-12 aralkyl) carbonyl, (C _1-6 alkyl) sulfinyl,
(C _3-6 cycloalkyl) sulfinyl, (C _6-10 aryl) sulfinyl, (C _7-12 aralkyl) sulfinyl, (C _1-6 alkyl) sulfonyl, (C _3-6 cycloalkyl) sulfonyl, (C ₆ Acyl groups selected from _-10 aryl) sulfonyl and (C _7-12 aralkyl) sulfonyl (where each substituent is 1 to 5 substituents selected from halogen, C _1-4 alkoxy and C _1-4 alkyl, respectively) ), (X-12) halogen,
(X-13) nitro, and (x-14) cyano, which may be substituted with 1 to 4 substituents), (xi) formyl, (C _1-6 alkyl) carbonyl,
(C _3-6 cycloalkyl) carbonyl, (C _6-10 aryl) carbonyl, (C _7-12 aralkyl) carbonyl,
(C _1-6 alkyl) sulfinyl, (C _3-6 cycloalkyl) sulfinyl, (C _6-10 aryl) sulfinyl,
Acyl group selected from (C _7-12 aralkyl) sulfinyl, (C _1-6 alkyl) sulfonyl, (C _3-6 cycloalkyl) sulfonyl, (C _6-10 aryl) sulfonyl and (C _7-12 aralkyl) sulfonyl (Wherein each substituent is halogen, C _1-4 alkoxy and C _1-4
Optionally substituted with 1 to 5 substituents selected from alkyl), (xii) halogen, (xiii) nitro, and (xiv) substituted with 1 to 4 substituents selected from cyano A heterocyclic group which may also be (2) each substituted with a heterocyclic group (a) having 1 to 1 carbon atoms
10 alkyl group, (b) alkenyl group having 2 to 10 carbon atoms, (c) alkynyl group having 2 to 10 carbon atoms, (d) cycloalkyl group having 3 to 12 carbon atoms, (e) 5 to 12 carbon atoms (F) a cycloalkadienyl group having 5 to 12 carbon atoms, (g) a C _3-7 cycloalkyl-C _1-8 alkyl group, (h) a C _5-7 cycloalkenyl-C _{1- 8} alkyl groups, and (i) hydrocarbon groups selected from aryl groups having 6 to 10 carbon atoms [wherein the heterocyclic group is optionally substituted with halogen, such as C _1-3 alkoxy, halogen, substituted with halogen, Optionally substituted C _1-3 alkyl and optionally substituted with 1 to 3 substituents selected from nitro], (3) halogen, C optionally substituted with halogen
_1-3 alkoxy, C _1-3 which may be substituted with halogen
1 selected from alkyl, nitro, amino and cyano
Phenoxy-substituted (a) alkyl group having 1 to 10 carbon atoms, (b) alkenyl group having 2 to 10 carbon atoms, (c) alkynyl group having 2 to 10 carbon atoms (D) cycloalkyl group having 3 to 12 carbon atoms, (e) cycloalkenyl group having 5 to 12 carbon atoms, (f) cycloalkadienyl group having 5 to 12 carbon atoms, (g) C _3-7 cyclo An alkyl-C _1-8 alkyl group, (h) a C _5-7 cycloalkenyl-C _1-8 alkyl group, and (i) a hydrocarbon group selected from an aryl group having 6 to 10 carbon atoms, (4) a hetero group (A) C1-C10 alkyl group substituted with a thiol group substituted with a ring group, (b) C2-C10 alkenyl group, (c) C2-C10 alkynyl group, (d) ) C3-C12 cycloalkyl group, (e) C5-C12 Kuroarukeniru group, (f) cycloalkadienyl group having 5 to 12 carbon atoms, (g) C _3-7 cycloalkyl -C _1-8 alkyl group, (h) C _5-7 cycloalkenyl -C _1-8 An alkyl group, and (i) a hydrocarbon group selected from an aryl group having 6 to 10 carbon atoms [wherein the heterocyclic group is (i) halogen and C _1-3.
C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from alkoxy, (ii) substituted with 1 to 3 substituents selected from halogen and C _1-3 alkoxy Good C _1-6 alkoxy group, (iii) C _1-3
A C _6-14 aryl group optionally substituted with 1 to 5 substituents selected from alkoxy, halogen, C _1-3 alkyl, amino, nitro and cyano, (iv) each C
_1-3 alkoxy, halogen, C _1-3 alkyl, amino, nitro and 1-5 may be substituted with a substituent C _3-7 cycloalkyl or C _3-6 cycloalkenyl group selected from cyano , 1-3 substituents selected (v) a halogen substituted C _1-4 alkoxy, halogen, optionally C _1-4 alkyl optionally substituted by halogen, C _6-10 aryl and nitro A heterocyclic group optionally substituted with a group, (vi) a carboxyl group, a (C _1-6 alkoxy) carbonyl group, a (C _6-10 aryl) oxycarbonyl group or a (C _7-10 aralkyl) oxycarbonyl group, (Vii) C _1-6 alkyl, C _3-6 cycloalkyl,
A carbamoyl group which may be substituted with one or two substituents selected from C _6-10 aryl, C _7-12 aralkyl and C _6-10 arylsulfonyl (where each substituent is halogen, halogen it may be substituted with 1 to 5 substituents selected from optionally C _1-4 alkyl and nitro substituted which may C _1-4 alkoxy, halogen have been), (viii) C _{1 -6} alkyl, C
1-2 selected from _3-6 cycloalkyl, C _6-10 aryl, C _7-12 aralkyl and C _6-10 arylsulfonyl
Pieces each substituted amino group which may be substituted with group (wherein each substituent is halogen, optionally substituted by halogen C _1-4 alkoxy, optionally C _1-4 alkyl optionally substituted by halogen And nitro), or a cyclic amino group, (ix) C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6
6-10 aryl, C _7-12 aralkyl and a hydroxy group _optionally substituted by a heterocyclic group (where C _1-6 alkyl, C
_3-6 cycloalkyl, C _6-10 aryl and C _7-12 aralkyl each of halogen, halogen substituted C _1-4 alkoxy, optionally C _1-4 alkyl optionally substituted by halogen, May be substituted with 1 to 5 substituents selected from nitro, amino and cyano;
The heterocyclic group may be substituted with 1 to 3 substituents selected from C _1-4 alkoxy, halogen, C _1-4 alkyl and C _6-10 aryl), (x) C _1-6 alkyl , C _3-6
Thiol groups optionally substituted with cycloalkyl, C _6-10 aryl, C _7-12 aralkyl and heterocyclic groups (wherein C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl and C _7-12 aralkyl each of halogen, optionally substituted by halogen C _1-4 alkoxy, optionally C _1-4 alkyl optionally substituted by halogen, nitro,
It may be substituted with 1 to 5 substituents selected from amino and cyano, and the heterocyclic group is 1 to 3 selected from C _1-4 alkoxy, halogen, C _1-4 alkyl and C _6-10 aryl. Optionally substituted with one substituent), (x
i) formyl, (C _1-6 alkyl) carbonyl, (C _3-6
Cycloalkyl) carbonyl, (C _6-10 aryl) carbonyl, (C _7-12 aralkyl) carbonyl, (C _1-6 alkyl) sulfinyl, (C _3-6 cycloalkyl) sulfinyl, (C _6-10 aryl) sulfinyl , (C _7-12
Aralkyl) sulfinyl, (C _1-6 alkyl) sulfonyl, (C _3-6 cycloalkyl) sulfonyl, (C _6-10
An acyl group selected from aryl) sulfonyl and (C _7-12 aralkyl) sulfonyl (wherein each substituent is substituted with 1 to 5 substituents selected from halogen, C _1-4 alkoxy and C _1-4 alkyl, respectively). May have been)
(Xiii) halogen, (xiii) nitro, and (x
iv) may be substituted with 1 to 4 substituents selected from cyano], or (5) with 1 to 5 substituents selected from halogen, C _1-4 alkoxy and C _1-4 alkyl The compound according to claim 14, which is a C _1-10 alkyl group substituted with an _optionally substituted C _6-10 arylsulfonylamino. 16. The compound according to claim 14, wherein R ′ is an optionally substituted thienyl group, azolyl group, condensed thienyl group, condensed azolyl group or condensed furanyl group. 17. 1 selected optionally R 'is optionally substituted with halogen, respectively C _1-3 alkyl, C _6-10 aryl, halogen optionally substituted C _1-3 alkoxy, halogen and nitro 1. A thienyl group, an oxazolyl group, an isoxazolyl group, a benzothienyl group, a benzofuranyl group, a benzoxazolyl group or a benzothiazolyl group which may be substituted with 3 to 3 substituents.
4. The compound according to 4. 18. The compound according to claim 14, wherein R ′ is an optionally substituted thienyl group, azolyl group, condensed thienyl group, condensed furanyl group or condensed azolyl group. 19. A C, wherein each R'is substituted with an aromatic heterocyclic group selected from thienyl, furyl, oxazolyl, isoxazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and benzimidazolyl. _{A 1-10} alkyl group or a C _2-10 alkenyl group (wherein the aromatic heterocyclic group may be halogen-substituted C _1-3 alkyl, C _6-10
15. A compound according to claim 14, which is optionally substituted with 1 to 3 substituents selected from aryl, C _1-3 alkoxy optionally substituted with halogen and nitro). 20. R 'is optionally C _1-3 alkoxy optionally substituted by halogen, nitro, halogen, cyano, 1-3, also selected from optionally C _1-3 alkyl substituted with amino and halogen 15. The compound according to claim 14, which is a phenoxy-substituted hydrocarbon group substituted with the substituent of. 21. The compound according to claim 14, wherein R ′ is an optionally substituted thienyl, furyl, azolyl, condensed thienyl, condensed furyl or a hydrocarbon group substituted with a thiol group substituted with condensed azolyl. . 22. A thiol group in which R'is substituted with an aromatic heterocyclic group selected from thienyl, furyl, oxazolyl, isoxazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and benzimidazolyl. C replaced by
_1-10 alkyl group or C _2-10 alkenyl group (wherein the aromatic heterocyclic group is C _1-3 alkyl optionally substituted with halogen, C _6-10 aryl, alkoxy optionally substituted with halogen) , Halogen and nitro 1
Is optionally substituted with 3 to 3 substituents). 23. R'is (1) thienyl, oxazolyl,
An aromatic heterocyclic group selected from isoxazolyl, benzothienyl, benzoxazolyl, benzothiazolyl and benzofuranyl (wherein the aromatic heterocyclic group is (a) a C _1-3 alkyl group optionally substituted with halogen, (b )
C _6-10 aryl group, (c) halogen-substituted C _1-3 alkoxy group, (d) halogen, (e) nitro, (f) cyano, (g) (C _1-6 alkyl) A carbonyl group and (h) may be substituted with 1 to 3 substituents selected from (C _1-6 alkyl) sulfonyl group], (2) Thienyl, furyl, oxazolyl, isoxazolyl, benzofuranyl, benzo C _1-10 alkyl group or C _2-10 alkenyl group substituted with an aromatic heterocyclic group selected from thienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and benzimidazolyl [wherein the aromatic heterocyclic group is Is (a) a C _1-3 alkyl group _optionally substituted with halogen, (b) a C _6-10
Aryl group, (c) C optionally substituted with halogen
_It may be substituted with 1 to 3 substituents selected from _1-3 alkenyl groups, (d) halogen, and (e) nitro. The C _1-10 alkyl group and C _2-10 alkenyl group are further cyano. Or (3) each is (a) C _1-3 alkoxy optionally substituted with halogen, (b) nitro, (c) halogen,
_1-3 selected from (d) cyano, (e) amino and (f) C _1-3 alkyl _optionally substituted with halogen.
C substituted with phenoxy groups substituted with 4 substituents
_1-10 alkyl group or C _2-10 alkenyl group, (4) aromatic hetero complex selected from thienyl, furyl, oxazolyl, isoxazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and benzimidazolyl. C _1-10 alkyl group or C _2-10 alkenyl group substituted with a thiol group substituted with a ring group [wherein the aromatic heterocyclic group is (a) C _1-3 alkyl optionally substituted with halogen] , (B) C _6-10 aryl, (c) C _1-3 alkoxy optionally substituted with halogen, (d) halogen and (e) substituted with 1 to 3 substituents selected from nitro. Or] (5) halogen, C optionally substituted with halogen
_1-4 alkoxy, C _1-4 optionally substituted with halogen
The compound according to claim 14, which is a C _1-10 alkyl group substituted with a C _6-10 arylsulfonylamino which may be substituted with 1 to 3 substituents selected from alkyl and nitro. 24. An aromatic heterocyclic group in which R'is selected from (1) thienyl, isoxazolyl, benzothienyl, benzoxazolyl, benzothiazolyl and benzofuranyl, wherein the aromatic heterocyclic group is substituted with (a) halogen. _{Optionally substituted} C _1-3 alkyl group, (b) C _6-10 aryl group, (c) C _1-3 alkoxy group, (d) halogen,
Substituted with 1 to 3 substituents selected from (e) nitro, (f) cyano, (g) (C _1-6 alkyl) carbonyl group and (h) (C _1-6 alkyl) sulfonyl group may also], (2) optionally substituted by C _1-3 alkoxy, respectively thienyl, benzoxazolyl, C substituted with an aromatic heterocyclic group selected from benzisoxazolyl and benzimidazolyl _{1- 10} alkyl group or C _2-10 alkenyl group (wherein the C _1-10 alkyl group and C _2-10 alkenyl group may be further substituted with cyano), (3) each (a) C _1-3 alkoxy C substituted with a phenoxy group substituted with 1 to 3 substituents selected from the group consisting of :, (b) nitro, (c) halogen, (d) cyano, (e) amino and (f) C _1-3 alkyl. _1-10 alkyl group or C _2-10 alkenyl Group, (4) C _1-10 substituted with a thiol group substituted with an aromatic heterocyclic group selected from benzoxazolyl and benzothiazolyl, each of which may be substituted with halogen.
Alkyl group or C _2-10 alkenyl group, or (5) C _6-10 optionally substituted with 1 to 3 C _1-4 alkyl, C _1-10 substituted with arylsulfonylamino
The compound according to claim 14, which is an alkyl group. 25. R ′ is (1) thienyl, oxazolyl,
An aromatic heterocyclic group selected from isoxazolyl, benzothienyl, benzoxazolyl, benzothiazolyl and benzofuranyl (wherein the aromatic heterocyclic group is (a) a C _1-3 alkyl group optionally substituted with halogen, (b )
A C _6-10 aryl group, (c) a C _1-3 alkoxy group which may be substituted with a halogen, (d) a halogen, (e) a nitro and (f) a cyano group selected from 1 to 3 substituents Optionally substituted], (2) an aromatic heterocyclic group selected from thienyl, furyl, oxazolyl, isoxazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and benzimidazolyl. A substituted C _1-10 alkyl group or a C _2-10 alkenyl group (wherein the aromatic heterocyclic group is (a) a C _1-3 alkyl group which may be substituted with halogen, (b) a C _6-10 group)
Aryl group, (c) C optionally substituted with halogen
_1-3 alkenyl group, (d) halogen, and (e) may be substituted with 1 to 3 substituents selected from nitro], (3) Each may be substituted with (a) halogen. A C _1-10 alkyl group or a C _2-10 alkenyl group substituted with a phenoxy group substituted with 1 to 3 substituents selected from C _1-3 alkoxy, (b) nitro and (c) halogen; 4) C ₁ substituted with a thiol group substituted with an aromatic heterocyclic group selected from thienyl, furyl, oxazolyl, isoxazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and benzimidazolyl _-10 alkyl group or C _2-10 alkenyl group (wherein the aromatic heterocyclic group is (a) C _1-3 alkyl, (b) C _6-10 aryl, (c)
C _1-3 alkoxy, (d) halogen and (e) nitro optionally substituted with 1 to 3 substituents], or (5) halogen, optionally substituted with halogen C
_1-4 alkoxy, C _1-4 optionally substituted with halogen
The compound according to claim 14, which is a C _1-10 alkyl group substituted with a C _6-10 arylsulfonylamino which may be substituted with 1 to 3 substituents selected from alkyl and nitro. 26. The compound according to claim 14, which is N- (diaminophosphinyl) -3-thiophenecarboxylic acid amide. 27. An N- (diaminophosphinyl) -5-methyl-2-thiophenecarboxylic acid amide.
4. The compound according to 4. 28. An N- (diaminophosphinyl) -3-methyl-2-thiophenecarboxylic acid amide.
4. The compound according to 4. 29. R ′ is C _1-3 alkyl optionally substituted with halogen, C _1-3 alkoxy, halogen, nitro,
The compound according to claim 14, which is a thienyl group optionally substituted with 1 to 3 substituents selected from cyano, (C _1-6 alkyl) carbonyl and (C _1-6 alkyl) sulfonyl. 30. The compound according to claim 14, wherein R ′ is a thienyl group optionally substituted by C _1-3 alkyl. 31. General formula (IA ′): [Wherein R ″ is halogen, cyano, formyl, C _1-3 alkyl optionally substituted with halogen, C _1-3 alkoxy optionally substituted with halogen, or optionally substituted with halogen Represents a furyl group or a pyridyl group substituted by 1 to 3 substituents selected from (C _1-3 alkoxy) carbonyl and C _1-3 alkylsulfonyl optionally substituted by halogen.] A compound or salt thereof. 32. The compound according to claim 31, wherein R ″ is a furyl group substituted with 1 to 3 substituents selected from halogen and C _1-3 alkyl optionally substituted with halogen. 33. The compound according to claim 31, wherein R ″ is a furyl group substituted with halogen. 34. The compound according to claim 31, which is N- (diaminophosphinyl) -5-bromo-3-furancarboxylic acid amide. 35. The compound according to claim 31, which is N- (diaminophosphinyl) -2-methyl-3-furancarboxylic acid amide. 36. A pharmaceutical composition comprising the compound according to claim 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 37. A pharmaceutical composition comprising the compound according to claim 14 or a pharmaceutically acceptable salt thereof, an antacid or an acid secretion inhibitor, and a pharmaceutically acceptable carrier. 38. A pharmaceutical composition comprising the compound according to claim 31 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 39. A pharmaceutical composition comprising the compound according to claim 31 or a pharmaceutically acceptable salt thereof, an antacid or an acid secretion inhibitor, and a pharmaceutically acceptable carrier. 40. Formula (IIIA): [In the formula, R ′ is (a) an optionally substituted heterocyclic group (provided that it may have an optionally substituted furyl, an optionally substituted pyridyl, and an optionally substituted 3-amino-2- Oxo-1-azetidinyl), (b) a hydrocarbon group substituted by an optionally substituted heterocyclic group (however, excluding phenyl substituted by an optionally substituted maleimide), (c). Substituted phenoxy substituted hydrocarbon group, (d) optionally substituted heterocyclic thio substituted hydrocarbon group, or (e) optionally substituted arylsulfonylamino substituted alkyl. A group represented by the formula] or a salt thereof and ammonia are reacted with the compound of the general formula (IA): [Wherein R'is the same as defined above] or a method for producing a salt thereof. 41. A compound represented by the formula (IIIA):
Formula (a): [Wherein R'is the same as defined in claim 40] or a salt thereof is reacted with phosphorus pentachloride, and the resulting compound or a salt thereof is reacted with formic acid, or Formula (b): The production method according to claim 40, which is obtained by reacting a compound represented by the formula: wherein R'is as defined in claim 40 or a salt thereof with phosphorus oxychloride. 42. Formula (IIIA '): [In the formula, R ″ is halogen, cyano, formyl, C _1-3 alkyl optionally substituted with halogen, C _1-3 alkoxy optionally substituted with halogen, or optionally substituted with halogen. Represents a furyl group or a pyridyl group substituted by 1 to 3 substituents selected from (C _1-3 alkoxy) carbonyl and C _1-3 alkylsulfonyl optionally substituted by halogen.] A compound of the general formula (IA '), characterized in that a compound or a salt thereof is reacted with ammonia: [Wherein R ″ is as defined above], or a method for producing a salt thereof. 43. A compound represented by the formula (IIIA ′):
Formula (a): [Wherein, R "has the same meaning as defined in claim 42] or a salt thereof is reacted with phosphorus pentachloride, and the resulting compound or salt thereof is reacted with formic acid, or , (B) Formula 43. The production method according to claim 42, which is obtained by reacting a compound represented by the formula [wherein R ″ has the same meaning as defined in claim 42] or a salt thereof with phosphorus oxychloride.