JPH10324632A - Pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject pharmaceutical composition that is useful as a preventive and therapeutic agent for digestive diseases that can be caused by Helicobacter pylori by formulating a phosphoric acid amide derivative or its salt and an antibiotic substance to this composition. SOLUTION: The objective composition contains (A) about 2-10 wt.% of a phosphoric acid amide of the formula R is a (substituted) amino, for example, -NHCOR<1> [R<1> is H, (substituted) hydrocarbon, a (substituted) heterocyclic ring]} and (B) about 5-90 wt.% of a penicillin, macrolide, nitroimidazole antibiotic agent (for example, amoxicillin, clarithromycin. In addition to the derivative of the formula or its salt and the antibiotic substance, 50-70 wt.% of an antacid and/or 2-5 wt.% of an acid secretion suppressor may be added thereto.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition. More specifically, the present invention comprises a phosphoric amide derivative having excellent antibacterial activity based on excellent anti-urease activity, particularly strong antibacterial activity against Helicobacter spp. Such as Helicobacter pylori, and an antibiotic. A pharmaceutical composition comprising:

[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 Helicobacter pylori, currently, two-drug combination of bismuth preparation and other antibiotics, bismuth preparation, metronidazole (US Pat. No. 2,944,061) and tetracycline (for example, US Pat. No. 2,712,517) Alternatively, chemotherapy using a combination of three drugs such as amoxicillin (US Pat. No. 3,192,198) has been performed. The above metronidazole,
A nitroimidazole antibiotic having an anti-Helicobacter pylori effect and used in combination with other antibiotics. These antibiotics are administered in oral form. However, the above antibiotics need to be administered in large amounts a day in order to maintain a concentration sufficient to inhibit the growth of Helicobacter pylori at the site of growth, which causes side effects such as vomiting and diarrhea. There are many problems. On the other hand, a phosphoric acid amide derivative having an anti-urease activity is known (US Pat. No. 3,317,637,
U.S. Pat.No. 4,517,003, U.S. Pat.No. 4,528,020, EP2107
03, U.S. Patent 4,182,881, U.S. Patent 4,221,730, JP-A-58-99490, JP-B-42-7379, U.S. Patent 4,629,491
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 relates to a pharmaceutical composition comprising a phosphoric acid amide derivative or a salt thereof having an excellent antibacterial activity, particularly a strong antibacterial activity against Helicobacter sp. Such as Helicobacter pylori, and a pharmaceutical comprising an antibiotic. It provides a composition.

[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 an anti-Helicobacter bacterium comprising a compound thereof, a salt thereof, and an antibiotic; (2) a general formula (Ia):

Embedded image Wherein R ^1a represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; or a pharmaceutical composition containing a salt thereof and an antibiotic; ) General formula (Ib):

Embedded image (In the formula, R ^1b is substituted with (i) an optionally substituted cyclic hydrocarbon group, (ii) an optionally substituted heterocyclic group, (iii) an optionally substituted cyclic hydrocarbon group. Hydroxyl group, (i
v) a hydroxyl group substituted with an optionally substituted heterocyclic group,
(v) a thiol group substituted with an optionally substituted cyclic hydrocarbon group, or (vi) a non-cyclic hydrocarbon group substituted with a thiol group substituted with an optionally substituted heterocyclic group (4) (i) a compound represented by the general formula (I) or a salt thereof, (ii) an antibiotic and (iii) an antacid A pharmaceutical composition comprising an agent or / and an acid secretion inhibitor, (5) a medicine comprising a combination of the compound represented by the general formula (Ia) or a salt thereof and an antibiotic,
(6) a medicament obtained by combining a compound represented by the general formula (Ib) or a salt thereof and an antibiotic; (7) (i) a compound represented by the general formula (I) or a salt thereof; (ii) an antibiotic (8) a medicine comprising a combination of a substance and (iii) an antacid or / and an acid secretion inhibitor, (8) an antidrug characterized by using an antibiotic and a compound represented by the general formula (I) or a salt thereof A drug for Helicobacter spp., And (9) a compound represented by the general formula (I) or a salt thereof,
The present invention relates to a medicine for anti-Helicobacter bacteria, which comprises using an antibiotic and an antacid or / and an acid secretion inhibitor in combination.

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 (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)
An optionally substituted lower alkyl group, (2) an optionally substituted lower alkoxy group, (3) an optionally substituted aryl group, (4) an optionally substituted lower cycloalkyl group or lower. Cycloalkenyl group,
(5) an optionally substituted heterocyclic group, (6) an optionally esterified carboxyl group, (7) an optionally substituted carbamoyl group, (8) an optionally substituted amino group, (9) an optionally substituted hydroxyl group, (1
0) an optionally substituted thiol (mercapto) group,
(11) 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,
C _1-6 such as sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.
And an alkyl group. The lower alkoxy group of the optionally substituted lower alkoxy group (2) includes
For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, ter
t.-C such as butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy, isohexyloxy
_1-6 alkoxy group and the like. 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 cyclopropyl,
And C _3-7 cycloalkyl groups such as cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of the cycloalkenyl group of the optionally substituted lower cycloalkenyl group (4) include C _3-6 cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. 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), a halogen atom (eg, fluorine, chlorine, bromine,
Iodine), an alkyl group (eg, C _1-3 alkyl such as methyl, ethyl and 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, with preference given to furyl, fused furyl, thienyl, fused thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, azolyl or fused azolyl groups. As the azolyl group, for example, a 5-membered aromatic heterocyclic group containing 1 to 4 nitrogen atoms (eg,
Pyrrolyl, imidazolyl, pyrazolyl, triazolyl,
Tetrazolyl), a 5-membered aromatic heterocyclic group containing 1-2 nitrogen atoms and one sulfur atom or oxygen atom (eg, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl) and the like. Examples of the condensed azolyl group include A group formed by condensing a benzene ring with a 5-membered aromatic heterocycle containing 1 to 2 nitrogen atoms (eg, benzimidazolyl); a benzene ring; one nitrogen atom and one sulfur atom or oxygen And a group formed by condensing a 5-membered aromatic heterocycle containing an atom (eg, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisoxazolyl, etc.). 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) (Phenyl-C such as carbonyl
_1-4 alkyl) oxycarbonyl 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, phenethyl and the like)
Alkyl, naphthyl-C _1-2 alkyl, etc.) and optionally substituted C _6-10 arylsulfonyl group (eg, benzenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl, etc.) and the like. One or two groups may be the same or different and may be substituted.
The optionally substituted lower (C _1-6 ) alkyl, an optionally substituted C _3-6 cycloalkyl group, an _optionally substituted C _6-10 aryl group, an _optionally substituted C
Examples of the substituent in the _7-12 aralkyl group and the _optionally substituted C _6-10 arylsulfonyl group include a halogen (eg, fluorine, chlorine, bromine, etc.) and a substituent substituted with 1 to 3 halogen atoms. Good alkoxy group (eg, C _1-4 alkoxy such as methoxy, ethoxy, propoxy), 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
, Preferably one to three. Examples of the substituent include (i) an optionally substituted lower alkyl group, (ii) an optionally substituted lower alkoxy group,
(Iii) optionally substituted aryl, (iv) optionally substituted lower cycloalkyl or lower cycloalkenyl, (v) optionally substituted heterocyclic, (vi) esterified An optionally substituted carboxyl group, (vii) an optionally substituted carbamoyl group, (v
iii) optionally substituted amino group, (ix) optionally substituted hydroxyl group, (x) optionally substituted thiol group, (xi) acyl group, (xii) halogen (eg, fluorine, chlorine , Bromine and the like), (xiii) nitro, (xiv) cyano and the like. The optionally substituted lower alkyl group (i), an optionally substituted lower alkoxy group (ii), an optionally substituted aryl group (iii), an optionally substituted lower cycloalkyl group or Lower cycloalkenyl group (iv), optionally substituted heterocyclic group (v), optionally esterified carboxyl group (vi), optionally substituted carbamoyl group (vi
i), the optionally substituted amino group (viii), the optionally substituted hydroxyl group (ix), the optionally substituted thiol group (x) and the acyl group (xi) are each the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , the same as the substituents in the “optionally substituted hydrocarbon group”.

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,
(7) C _6-10 which may be substituted by 1 to 3 (preferably 1 to 2) substituents selected from a hydroxyl group, (8) a halogen atom and a lower (C _1-3 ) alkoxy group.
A thiol group optionally substituted with an aryl group (eg, phenyl, etc.), or a halogen atom and a lower (C
_1-3 ) Even if substituted with a heterocyclic ring (eg, benzoxazolyl, benzothiazolyl, etc.) which may be substituted with 1 to 3 (preferably 1 to 2) substituents selected from alkoxy groups Good thiol group, (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, and the substituent is preferably ( 1) a lower (C _1-3 ) alkyl group _optionally substituted by 1 to 3 halogens (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 with 1 to 3 halogens (eg, methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, chloromethoxy) ), (4) halogen (eg, fluorine, chlorine, bromine, etc.), (5) nitro,
(6) cyano, (7) (lower (C _1-6 ) alkyl) carbonyl group, (8) (C _1-6 alkyl) sulfonyl group and the like.

(2) The “optionally esterified carboxyl group” as a substituent of the “optionally substituted amino group” represented by R includes, for example, a group represented by 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 lower cycloalkenyl group An optionally substituted heterocyclic group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted amino group, an optionally substituted hydroxyl group,
Examples include an optionally substituted thiol group, acyl group, halogen (eg, fluorine, chlorine, bromine, etc.), nitro, cyano and the like. The optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted aryl group, an optionally substituted lower cycloalkyl group or a lower cycloalkenyl group, Heterocyclic group, carboxyl group which may be esterified, carbamoyl group which may be substituted, amino group which may be substituted, hydroxyl group which may be substituted, thiol group which may be substituted And the acyl groups include R ¹ , R ² , R ³ , R ⁴ , R
^{The same} substituents as those described for the “optionally substituted hydrocarbon group” represented by ⁵ and R ⁶ can be mentioned.

The heterocyclic group includes R ¹ , R ² ,
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 lower cycloalkenyl group An optionally substituted heterocyclic group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted amino group, an optionally substituted hydroxyl group, And a thiol group, an acyl group, a halogen (eg, fluorine, chlorine, bromine and the like), nitro, cyano and the like. The optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted aryl group, an optionally substituted lower cycloalkyl group or a lower cycloalkenyl group,
An optionally substituted heterocyclic group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted amino group, an optionally substituted hydroxyl group, Examples of the preferable thiol group and acyl group include the aforementioned R ¹ , R ² , R ³ ,
The same substituents as those described for the “optionally substituted hydrocarbon group” represented by R ⁴ , R ⁵ and R ⁶ can be mentioned. R ⁷ is preferably an optionally substituted lower (C _1-6 ) alkyl, lower (C _3-6 ) cycloalkyl, C _6-10 aryl or C _7-12 aralkyl group, and more preferably Lower (C _1-3 ) alkyl is exemplified. Examples of the lower (C _1-6 ) alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl and the like. 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,
Examples thereof include 1-naphthyl and 2-naphthyl. The C
Examples of the _7-12 aralkyl group include phenyl-C _1-4 alkyl such as benzyl and phenethyl, and naphthyl-C _1-2
Alkyl and the like. The lower (C _1-6 ) alkyl, lower (C _3-6 ) cycloalkyl group, C _6-10 aryl group and C _7-12 aralkyl group may have a substituent group of 1 to 3 at any substitutable position. And the substituent may be halogen (eg, fluorine, chlorine, bromine, etc.).

(3) As the hydrocarbon group in the “optionally substituted hydrocarbon group” as a substituent of the “optionally substituted amino group” represented by R, 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 lower cycloalkenyl group ,
An optionally substituted heterocyclic group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted amino group, an optionally substituted hydroxyl group, Thiol group, acyl group, halogen (eg, fluorine, chlorine, bromine, etc.), nitro, cyano and the like. The optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted aryl group, an optionally substituted lower cycloalkyl group or a lower cycloalkenyl group, Heterocyclic group, carboxyl group which may be esterified, carbamoyl group which may be substituted, amino group which may be substituted, hydroxyl group which may be substituted, thiol group which may be substituted And an acyl group as R ¹ ,
Examples include the same substituents as those described for the “optionally substituted hydrocarbon group” represented by R ² , R ³ , R ⁴ , R ⁵ and R ⁶ .

In the general formula (I), R is
(1) -COR¹, -CSR^Two, -SO_TwoR^Three, -SO
R^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
Element group [where each substituent of (a) to (i) is
(I) halogen and C_1-31 selected from alkoxy
C optionally substituted with up to 3 substituents_1-6Alkyl
Group (ii) halogen and C_1-3Choose from alkoxy
C optionally substituted with 1 to 3 substituents_1-6A
Alkoxy group, (iii) C_1-3Alkoxy, halogen,
C_1-3Choose from alkyl, amino, nitro and cyano
C which may be substituted with 1 to 5 substituents_6-14A
Reel base, (iv) each C_1-3Alkoxy, halogen
N, C_1-3From alkyl, amino, nitro and cyano
C optionally substituted with 1 to 5 selected substituents
_3-7Cycloalkyl group or C_3-6Cycloalkenyl group,
(V) C optionally substituted with halogen_1-4Alkoki
C, halogen, C optionally substituted with halogen_1-4
Alkyl, C_6-101 selected from aryl and nitro
A heterocyclic group optionally substituted with up to 3 substituents, (v
i) carboxyl group, (C_1-6Alkoxy) carbonyl
Group, (C_6-10An aryl) oxycarbonyl group or (C
_7-10Aralkyl) oxycarbonyl group, (vii) C
_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Aryl,
C_7-12Aralkyl and C_6-10From arylsulfonyl
A cal optionally substituted with one or two selected substituents
Bamoyl group (where each substituent is halogen, halo
C optionally substituted with gen_1-4Alkoxy, halogen
C optionally substituted with_1-4Alkyl and nitro
May be substituted with 1 to 5 substituents selected from
I), (viii) C_1-6Alkyl, C_3-6Cycloalkyl
Le, C_6-10Aryl, C_7-12Aralkyl and C_6-10A
Substituted with one or two substituents selected from reelsulfonyl
An optionally substituted amino group (where 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
Or a cyclic amino group, (ix) C
_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Aryl,
C_7-12Optionally substituted with aralkyl and heterocyclic groups
Hydroxyl group (where C_1-6Alkyl, C_3-6Cycloalkyl
Le, C_6-10Aryl and C_7-12Aralkyl
And halogen, C optionally substituted with halogen_1-4
C which may be substituted by alkoxy or halogen_1-4A
1 selected from alkyl, nitro, amino and cyano
The heterocyclic group may be substituted with 5 substituents, and (i)
x-1) Halogen and C_1-3Selected from alkoxy
C optionally substituted with 1 to 3 substituents_1-6Archi
Group, (ix-2) halogen and C_1-3Alkoxy
C which may be substituted by 1 to 3 substituents selected from
_1-6Alkoxy group, (ix-3) C_1-3Alkoxy, halo
Gen, C_1-3Alkyl, amino, nitro and cyano
C which may be substituted with 1 to 5 substituents selected from
_6-14Aryl group, (ix-4) each C_1-3Alkoki
Si, halogen, C_1-3Alkyl, amino, nitro and
Substituted with 1 to 5 substituents selected from cyano,
Good C_3-7Cycloalkyl group or C_3-6Cycloalkene
Nyl group, which may be substituted with (ix-5) halogen
C_1-4Substituted with alkoxy, halogen, halogen
May be C_1-4Alkyl, C_6-10Aryl and nitro
May be substituted with 1 to 3 substituents selected from
Heterocyclic group, (ix-6) carboxyl group, (C_1-6Al
(Coxy) carbonyl group, (C_6-10Aryl) oxycal
Bonyl group or (C_7-10Aralkyl) oxycarbonyl
Group, (ix-7) C_1-6Alkyl, C_3-6Cycloalkyl
Le, C_6-10Aryl, C_7-12Aralkyl and C_6-10A
Substituted with one or two substituents selected from reelsulfonyl
Carbamoyl group (where each substituent is
Halogen and C which may be substituted with halogen, respectively
_1-4C which may be substituted by alkoxy or halogen_1-4
1 to 5 substituents selected from alkyl and nitro
(Optionally substituted), (ix-8) C_1-6Archi
Le, C_3-6Cycloalkyl, C_6-10Aryl, C_7-12A
Ralquil and C_6-10Selected from arylsulfonyl
An amino group optionally substituted with 1 to 2 substituents (this
Here, each substituent is substituted by halogen or halogen, respectively.
May be C_1-4Substituted with alkoxy, halogen
May be C_1-41 selected from alkyl and nitro
Or up to 5 substituents) or cyclic
Amino group, (ix-9) C_1-6Alkyl, C_3-6Cycloa
Luquil, C_6-10Aryl, C_7-12Aralkyl and complex
A hydroxyl group optionally substituted with a ring group (here, C_1-6A
Luquil, C_3-6Cycloalkyl, C_6-10Aryl and
C_7-12Aralkyl is replaced by halogen and halogen, respectively.
C which may be replaced_1-4Substituted with alkoxy and halogen
C that may be_1-4Alkyl, nitro, amino and
And 1 to 5 substituents selected from cyano
And the heterocyclic group may be C_1-4Alkoxy, halogen, C
_1-4Alkyl and C_6-101-3 selected from aryl
Ix-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
Ix-11) formyl, (C-11)_1-6A
Alkyl) carbonyl, (C_3-6Cycloalkyl) carbo
Nil, (C_6-10Aryl) carbonyl, (C_7-12Aral
Kill) 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
Kishi and C_1-41 to 5 substitutions selected from alkyl
(Ix-12) halogeno
, (Ix-13) nitro, and (ix-14) shea
May be substituted with 1 to 4 substituents selected from
I), (x) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Substituted with aralkyl and heterocyclic groups
Thiol group (where C is_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
C that may be_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
C that may be_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.
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 one or two substituents
(Where each substituent is halogen,
C that may be_1-4Substituted with alkoxy, halogen
C that may be_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
Kishi and C_1-41 to 5 substitutions selected from alkyl
(X-12) halogen,
Selected from (x-13) nitro and (x-14) cyano
May be 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
(Xiii) halogen, (xiii) nitrite
(B) and 1 to 3 positions selected from (xiv) cyano
Or (1-3) a heterocyclic group wherein the heterocyclic group is (i) halogen
And C_1-31 to 3 substituents selected from alkoxy
C optionally substituted with_1-6An alkyl group, (ii)
Logen and C_1-31-3 of selected from alkoxy
C optionally substituted with a substituent_1-6An alkoxy group,
(Iii) C_1-3Alkoxy, halogen, C_1-3Archi
1 to 5 selected from amino, nitro and cyano
C optionally substituted with a substituent_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_3-6Cycloalkenyl group, (v) halogen
C optionally substituted with_1-4Alkoxy, halogen
C optionally substituted by halogen_1-4Alkyl,
C_6-101-3 positions selected from aryl and nitro
A heterocyclic group optionally substituted with a substituent, (vi) carbo
A xyl group, (C_1-6An alkoxy) carbonyl group, (C
_6-10An aryl) oxycarbonyl group or (C_7-10Ara
Alkyl) oxycarbonyl group, (vii) C_1-6Archi
Le, C_3-6Cycloalkyl, C_6-10Aryl, C_7-12A
Ralquil and C_6-10Selected from arylsulfonyl
Carbamoyl optionally substituted by 1 to 2 substituents
Group (where each substituent is halogen, halogen, respectively)
C which may be replaced_1-4Substituted with alkoxy and halogen
C that may be_1-4Choose from alkyl and nitro
May be substituted with 1 to 5 substituents), (v
iii) C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10
Aryl, C_7-12Aralkyl and C_6-10Arylsul
Substituted with one or two substituents selected from honyl
An amino group (where each substituent is a halogen,
C which may be substituted with halogen_1-4Alkoxy, ha
C optionally substituted with a logen_1-4Alkyl and d
Even if substituted with 1 to 5 substituents selected from toro
Good) or a cyclic amino group, (ix) C_1-6Archi
Le, C_3-6Cycloalkyl, C_6-10Aryl, C_7-12A
Hydroxyl group optionally substituted by aralkyl and heterocyclic groups
(Where C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl and C_7-12Aralkyl is halo
C, which may be substituted with_1-4Alkoki
C which may be substituted by halogen_1-4Alkyl,
1 to 5 positions selected from nitro, amino and cyano
The heterocyclic group may be substituted with a substituent (ix-1)
Halogen and C_1-31-3 selected from alkoxy
C optionally substituted with a substituent_1-6Alkyl group,
(Ix-2) Halogen and C_1-3Choose from alkoxy
C optionally substituted with 1 to 3 substituents_1-6A
Alkoxy group, (ix-3) C_1-3Alkoxy, halogen
N, C_1-3From alkyl, amino, nitro and cyano
C optionally substituted with 1 to 5 selected substituents
_6-14Aryl group, (ix-4) each C_1-3Alkoki
Si, halogen, C_1-3Alkyl, amino, nitro and
Substituted with 1 to 5 substituents selected from cyano,
Good C_3-7Cycloalkyl group or C_3-6Cycloalkene
Nyl group, which may be substituted with (ix-5) halogen
C_1-4Substituted with alkoxy, halogen, halogen
May be C_1-4Alkyl, C_6-10Aryl and nitro
May be substituted with 1 to 3 substituents selected from
Heterocyclic group, (ix-6) carboxyl group, (C_1-6Al
(Coxy) carbonyl group, (C_6-10Aryl) oxycal
Bonyl group or (C_7-10Aralkyl) oxycarbonyl
Group, (ix-7) C_1-6Alkyl, C_3-6Cycloalkyl
Le, C_6-10Aryl, C_7-12Aralkyl and C_6-10A
Substituted with one or two substituents selected from reelsulfonyl
Carbamoyl group (where each substituent is
Halogen and C which may be substituted with halogen, respectively
_1-4C which may be substituted by alkoxy or halogen_1-4
1 to 5 substituents selected from alkyl and nitro
(Optionally substituted), (ix-8) C_1-6Archi
Le, C_3-6Cycloalkyl, C_6-10Aryl, C_7-12A
Ralquil and C_6-10Selected from arylsulfonyl
An amino group optionally substituted with 1 to 2 substituents (this
Here, each substituent is substituted by halogen or halogen, respectively.
May be C_1-4Substituted with alkoxy, halogen
May be C_1-41 selected from alkyl and nitro
Or up to 5 substituents) or cyclic
Amino group, (ix-9) C_1-6Alkyl, C_3-6Cycloa
Luquil, C_6-10Aryl, C_7-12Aralkyl and complex
A hydroxyl group optionally substituted with a ring group (here, C_1-6A
Luquil, C_3-6Cycloalkyl, C_6-10Aryl and
C_7-12Aralkyl is replaced by halogen and halogen, respectively.
C which may be replaced_1-4Substituted with alkoxy and halogen
C that may be_1-4Alkyl, nitro, amino and
And 1 to 5 substituents selected from cyano
And the heterocyclic group may be C_1-4Alkoxy, halogen, C
_1-4Alkyl and C_6-101-3 selected from aryl
Ix-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
Ix-11) formyl, (C-11)_1-6A
Alkyl) carbonyl, (C_3-6Cycloalkyl) carbo
Nil, (C_6-10Aryl) carbonyl, (C_7-12Aral
Kill) carbonyl, (C_1-6Alkyl) sulfinyl,
(C_3-6Cycloalkyl) sulfinyl, (C_6-10Ants
) Sulfinyl, (C_7-12Aralkyl) Sulfini
Le, (C_{1- 6}Alkyl) 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
Kishi and C_1-41 to 5 substitutions selected from alkyl
(Ix-12) halogeno
, (Ix-13) nitro, and (ix-14) shea
May be substituted with 1 to 4 substituents selected from
I), (x) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Substituted with aralkyl and heterocyclic groups
Thiol group (where C is_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
C that may be_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
C that may be_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.
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 one or two substituents
(Where each substituent is halogen,
C that may be_1-4Substituted with alkoxy, halogen
C that may be_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
Kishi and C_1-41 to 5 substitutions selected from alkyl
(X-12) halogen,
Selected from (x-13) nitro and (x-14) cyano
May be 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
(Xiii) halogen, (xiii) nitrite
B, and 1 to 4 positions selected from (xiv) cyano
May be substituted with a substituent]. Selected from｝
Acyl group, (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
Element group [where each substituent of (a) to (i) is
(I) halogen and C_1-31 selected from alkoxy
C optionally substituted with up to 3 substituents_1-6Alkyl
Group (ii) halogen and C_1-3Choose from alkoxy
C optionally substituted with 1 to 3 substituents_1-6A
Alkoxy group, (iii) C_1-3Alkoxy, halogen,
C_1-3Choose from alkyl, amino, nitro and cyano
C which may be substituted with 1 to 5 substituents_6-14A
Reel base, (iv) each C_1-3Alkoxy, halogen
N, C_1-3From alkyl, amino, nitro and cyano
C optionally substituted with 1 to 5 selected substituents
_3-7Cycloalkyl group or C_3-6Cycloalkenyl group,
(V) C optionally substituted with halogen_1-4Alkoki
C, halogen, C optionally substituted with halogen_1-4
Alkyl, C_6-101 selected from aryl and nitro
A heterocyclic group optionally substituted with up to 3 substituents, (v
i) carboxyl group, (C_1-6Alkoxy) carbonyl
Group, (C_6-10An aryl) oxycarbonyl group or (C
_7-10Aralkyl) oxycarbonyl group, (vii) C
_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Aryl,
C_7-12Aralkyl and C_6-10From arylsulfonyl
A cal optionally substituted with one or two selected substituents
Bamoyl group (where each substituent is halogen, halo
C optionally substituted with gen_1-4Alkoxy, halogen
C optionally substituted with_1-4Alkyl and nitro
May be substituted with 1 to 5 substituents selected from
I), (viii) C_1-6Alkyl, C_3-6Cycloalkyl
Le, C_6-10Aryl, C_7-12Aralkyl and C_6-10A
Substituted with one or two substituents selected from reelsulfonyl
An optionally substituted amino group (where 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
Or a cyclic amino group, (ix) C
_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Aryl,
C_7-12Optionally substituted with aralkyl and heterocyclic groups
Hydroxyl group (where C_1-6Alkyl, C_3-6Cycloalkyl
Le, C_6-10Aryl and C_7-12Aralkyl
And halogen, C optionally substituted with halogen_1-4
C which may be substituted by alkoxy or halogen_1-4A
1 selected from alkyl, nitro, amino and cyano
The heterocyclic group may be substituted with 5 substituents, and (i)
x-1) Halogen and C_1-3Selected from alkoxy
C optionally substituted with 1 to 3 substituents_1-6Archi
Group, (ix-2) halogen and C_1-3Alkoxy
C which may be substituted by 1 to 3 substituents selected from
_1-6Alkoxy group, (ix-3) C_1-3Alkoxy, halo
Gen, C_1-3Alkyl, amino, nitro and cyano
C which may be substituted with 1 to 5 substituents selected from
_6-14Aryl group, (ix-4) each C_1-3Alkoki
Si, halogen, C_1-3Alkyl, amino, nitro and
Substituted with 1 to 5 substituents selected from cyano,
Good C_3-7Cycloalkyl group or C_3-6Cycloalkene
Nyl group, which may be substituted with (ix-5) halogen
C_1-4Substituted with alkoxy, halogen, halogen
May be C_1-4Alkyl, C_6-10Aryl and nitro
May be substituted with 1 to 3 substituents selected from
Heterocyclic group, (ix-6) carboxyl group, (C_1-6Al
(Coxy) carbonyl group, (C_6-10Aryl) oxycal
Bonyl group or (C_7-10Aralkyl) oxycarbonyl
Group, (ix-7) C_1-6Alkyl, C_3-6Cycloalkyl
Le, C_6-10Aryl, C_7-12Aralkyl and C_6-10A
Substituted with one or two substituents selected from reelsulfonyl
Carbamoyl group (where each substituent is
Halogen and C which may be substituted with halogen, respectively
_1-4C which may be substituted by alkoxy or halogen_1-4
1 to 5 substituents selected from alkyl and nitro
(Optionally substituted), (ix-8) C_1-6Archi
Le, C_3-6Cycloalkyl, C_6-10Aryl, C_7-12A
Ralquil and C_6-10Selected from arylsulfonyl
An amino group optionally substituted with 1 to 2 substituents (this
Here, each substituent is substituted by halogen or halogen, respectively.
May be C_1-4Substituted with alkoxy, halogen
May be C_1-41 selected from alkyl and nitro
Or up to 5 substituents) or cyclic
Amino group, (ix-9) C_1-6Alkyl, C_3-6Cycloa
Luquil, C_6-10Aryl, C_7-12Aralkyl and complex
A hydroxyl group optionally substituted with a ring group (here, C_1-6A
Luquil, C_3-6Cycloalkyl, C_6-10Aryl and
C_7-12Aralkyl is replaced by halogen and halogen, respectively.
C which may be replaced_1-4Substituted with alkoxy and halogen
C that may be_1-4Alkyl, nitro, amino and
And 1 to 5 substituents selected from cyano
And the heterocyclic group may be C_1-4Alkoxy, halogen, C
_1-4Alkyl and C_6-101-3 selected from aryl
Ix-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
Ix-11) formyl, (C-11)_1-6A
Alkyl) carbonyl, (C_3-6Cycloalkyl) carbo
Nil, (C_6-10Aryl) carbonyl, (C_7-12Aral
Kill) 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
Kishi and C_1-41 to 5 substitutions selected from alkyl
(Ix-12) halogeno
, (Ix-13) nitro, and (ix-14) shea
May be substituted with 1 to 4 substituents selected from
I), (x) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Substituted with aralkyl and heterocyclic groups
Thiol group (where C is_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
C that may be_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
C that may be_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.
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 one or two substituents
(Where each substituent is halogen,
C that may be_1-4Substituted with alkoxy, halogen
C that may be_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
Kishi and C_1-41 to 5 substitutions selected from alkyl
(X-12) halogen,
Selected from (x-13) nitro and (x-14) cyano
May be 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
(Xiii) halogen, (xiii) nitrite
(B) and 1 to 3 positions selected from (xiv) cyano
Or (2-3) a heterocyclic group wherein the heterocyclic group is (i) halogen
And C_1-31 to 3 substituents selected from alkoxy
C optionally substituted with_1-6An alkyl group, (ii)
Logen and C_1-31-3 of selected from alkoxy
C optionally substituted with a substituent_1-6An alkoxy group,
(Iii) C_1-3Alkoxy, halogen, C_1-3Archi
1 to 5 selected from amino, nitro and cyano
C optionally substituted with a substituent_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_3-6Cycloalkenyl group, (v) halogen
C optionally substituted with_1-4Alkoxy, halogen
C optionally substituted by halogen_1-4Alkyl,
C_6-101-3 positions selected from aryl and nitro
A heterocyclic group optionally substituted with a substituent, (vi) carbo
A xyl group, (C_1-6An alkoxy) carbonyl group, (C
_6-10An aryl) oxycarbonyl group or (C_7-10Ara
Alkyl) oxycarbonyl group, (vii) C_1-6Archi
Le, C_3-6Cycloalkyl, C_6-10Aryl, C_7-12A
Ralquil and C_6-10Selected from arylsulfonyl
Carbamoyl optionally substituted by 1 to 2 substituents
Group (where each substituent is halogen, halogen, respectively)
C which may be replaced_1-4Substituted with alkoxy and halogen
C that may be_1-4Choose from alkyl and nitro
May be substituted with 1 to 5 substituents), (v
iii) C_1-6Alkyl, C_3-6Cycloalkyl, C_6-10
Aryl, C_7-12Aralkyl and C_6-10Arylsul
Substituted with one or two substituents selected from honyl
An amino group (where each substituent is a halogen,
C which may be substituted with halogen_1-4Alkoxy, ha
C optionally substituted with a logen_1-4Alkyl and d
Even if substituted with 1 to 5 substituents selected from toro
Good) or a cyclic amino group, (ix) C_1-6Archi
Le, C_3-6Cycloalkyl, C_6-10Aryl, C_7-12A
Hydroxyl group optionally substituted by aralkyl and heterocyclic groups
(Where C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl and C_7-12Aralkyl is halo
C, which may be substituted with_1-4Alkoki
C which may be substituted by halogen_1-4Alkyl,
1 to 5 positions selected from nitro, amino and cyano
The heterocyclic group may be substituted with a substituent (ix-1)
Halogen and C_1-31-3 selected from alkoxy
C optionally substituted with a substituent_1-6Alkyl group,
(Ix-2) Halogen and C_1-3Choose from alkoxy
C optionally substituted with 1 to 3 substituents_1-6A
Alkoxy group, (ix-3) C_1-3Alkoxy, halogen
N, C_1-3From alkyl, amino, nitro and cyano
C optionally substituted with 1 to 5 selected substituents
_6-14Aryl group, (ix-4) each C_1-3Alkoki
Si, halogen, C_1-3Alkyl, amino, nitro and
Substituted with 1 to 5 substituents selected from cyano,
Good C_3-7Cycloalkyl group or C_3-6Cycloalkene
Nyl group, which may be substituted with (ix-5) halogen
C_1-4Substituted with alkoxy, halogen, halogen
May be C_1-4Alkyl, C_6-10Aryl and nitro
May be substituted with 1 to 3 substituents selected from
Heterocyclic group, (ix-6) carboxyl group, (C_1-6Al
(Coxy) carbonyl group, (C_6-10Aryl) oxycal
Bonyl group or (C_7-10Aralkyl) oxycarbonyl
Group, (ix-7) C_1-6Alkyl, C_3-6Cycloalkyl
Le, C_6-10Aryl, C_7-12Aralkyl and C_6-10A
Substituted with one or two substituents selected from reelsulfonyl
Carbamoyl group (where each substituent is
Halogen and C which may be substituted with halogen, respectively
_1-4C which may be substituted by alkoxy or halogen_1-4
1 to 5 substituents selected from alkyl and nitro
(Optionally substituted), (ix-8) C_1-6Archi
Le, C_3-6Cycloalkyl, C_6-10Aryl, C_7-12A
Ralquil and C_6-10Selected from arylsulfonyl
An amino group optionally substituted with 1 to 2 substituents (this
Here, each substituent is substituted by halogen or halogen, respectively.
May be C_1-4Substituted with alkoxy, halogen
May be C_1-41 selected from alkyl and nitro
Or up to 5 substituents) or cyclic
Amino group, (ix-9) C_1-6Alkyl, C_3-6Cycloa
Luquil, C_6-10Aryl, C_7-12Aralkyl and complex
A hydroxyl group optionally substituted with a ring group (here, C_1-6A
Luquil, C_3-6Cycloalkyl, C_6-10Aryl and
C_7-12Aralkyl is replaced by halogen and halogen, respectively.
C which may be replaced_1-4Substituted with alkoxy and halogen
C that may be_1-4Alkyl, nitro, amino and
And 1 to 5 substituents selected from cyano
And the heterocyclic group may be C_1-4Alkoxy, halogen, C
_1-4Alkyl and C_6-101-3 selected from aryl
Ix-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
Ix-11) formyl, (C-11)_1-6A
Alkyl) carbonyl, (C_3-6Cycloalkyl) carbo
Nil, (C_6-10Aryl) carbonyl, (C_7-12Aral
Kill) 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
Kishi and C_1-41 to 5 substitutions selected from alkyl
(Ix-12) halogeno
, (Ix-13) nitro, and (ix-14) shea
May be substituted with 1 to 4 substituents selected from
I), (x) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Substituted with aralkyl and heterocyclic groups
Thiol group (where C is_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
C that may be_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
C that may be_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.
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 one or two substituents
(Where each substituent is halogen,
C that may be_1-4Substituted with alkoxy, halogen
C that may be_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
Kishi and C_1-41 to 5 substitutions selected from alkyl
(X-12) halogen,
Selected from (x-13) nitro and (x-14) cyano
May be 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
(Xiii) halogen, (xiii) nitrite
B, and 1 to 4 positions selected from (xiv) cyano
May be substituted with a substituent]. D represented by｝
(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, (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
Element group [where each substituent of (a) to (i) is
(I) halogen and C_1-31 selected from alkoxy
C optionally substituted with up to 3 substituents_1-6Alkyl
Group (ii) halogen and C_1-3Choose from alkoxy
C optionally substituted with 1 to 3 substituents_1-6A
Alkoxy group, (iii) C_1-3Alkoxy, halogen,
C_1-3Choose from alkyl, amino, nitro and cyano
C which may be substituted with 1 to 5 substituents_6-14A
Reel base, (iv) each C_1-3Alkoxy, halogen
N, C_1-3From alkyl, amino, nitro and cyano
C optionally substituted with 1 to 5 selected substituents
_3-7Cycloalkyl group or C_3-6Cycloalkenyl group,
(V) C optionally substituted with halogen_1-4Alkoki
C, halogen, C optionally substituted with halogen_1-4
Alkyl, C_6-101 selected from aryl and nitro
A heterocyclic group optionally substituted with up to 3 substituents, (v
i) carboxyl group, (C_1-6Alkoxy) carbonyl
Group, (C_6-10An aryl) oxycarbonyl group or (C
_7-10Aralkyl) oxycarbonyl group, (vii) C
_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Aryl,
C_7-12Aralkyl and C_6-10From arylsulfonyl
A cal optionally substituted with one or two selected substituents
Bamoyl group (where each substituent is halogen, halo
C optionally substituted with gen_1-4Alkoxy, halogen
C optionally substituted with_{1 -Four}Alkyl and nitro
May be substituted with 1 to 5 substituents selected from
I), (viii) C_1-6Alkyl, C_3-6Cycloalkyl
Le, C_6-10Aryl, C_7-12Aralkyl and C_6-10A
Substituted with one or two substituents selected from reelsulfonyl
An optionally substituted amino group (where 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
Or a cyclic amino group, (ix) C
_1-6Alkyl, C_3-6Cycloalkyl, C_6-10Aryl,
C_7-12Optionally substituted with aralkyl and heterocyclic groups
Hydroxyl group (where C_1-6Alkyl, C_3-6Cycloalkyl
Le, C_6-10Aryl and C_7-12Aralkyl
And halogen, C optionally substituted with halogen_1-4
C which may be substituted by alkoxy or halogen_1-4A
1 selected from alkyl, nitro, amino and cyano
The heterocyclic group may be substituted with 5 substituents, and (i)
x-1) Halogen and C_1-3Selected from alkoxy
C optionally substituted with 1 to 3 substituents_1-6Archi
Group, (ix-2) halogen and C_1-3Alkoxy
C which may be substituted by 1 to 3 substituents selected from
_1-6Alkoxy group, (ix-3) C_1-3Alkoxy, halo
Gen, C_1-3Alkyl, amino, nitro and cyano
C which may be substituted with 1 to 5 substituents selected from
_6-14Aryl group, (ix-4) each C_1-3Alkoki
Si, halogen, C_1-3Alkyl, amino, nitro and
Substituted with 1 to 5 substituents selected from cyano,
Good C_3-7Cycloalkyl group or C_3-6Cycloalkene
Nyl group, which may be substituted with (ix-5) halogen
C_1-4Substituted with alkoxy, halogen, halogen
May be C_1-4Alkyl, C_6-10Aryl and nitro
May be substituted with 1 to 3 substituents selected from
Heterocyclic group, (ix-6) carboxyl group, (C_1-6Al
(Coxy) carbonyl group, (C_6-10Aryl) oxycal
Bonyl group or (C_7-10Aralkyl) oxycarbonyl
Group, (ix-7) C_1-6Alkyl, C_3-6Cycloalkyl
Le, C_6-10Aryl, C_7-12Aralkyl and C_6-10A
Substituted with one or two substituents selected from reelsulfonyl
Carbamoyl group (where each substituent is
Halogen and C which may be substituted with halogen, respectively
_1-4C which may be substituted by alkoxy or halogen_1-4
1 to 5 substituents selected from alkyl and nitro
(Optionally substituted), (ix-8) C_1-6Archi
Le, C_3-6Cycloalkyl, C_6-10Aryl, C_7-12A
Ralquil and C_6-10Selected from arylsulfonyl
An amino group optionally substituted with 1 to 2 substituents (this
Here, each substituent is substituted by halogen or halogen, respectively.
May be C_1-4Substituted with alkoxy, halogen
May be C_1-41 selected from alkyl and nitro
Or up to 5 substituents) or cyclic
Amino group, (ix-9) C_1-6Alkyl, C_3-6Cycloa
Luquil, C_6-10Aryl, C_7-12Aralkyl and complex
A hydroxyl group optionally substituted with a ring group (here, C_1-6A
Luquil, C_3-6Cycloalkyl, C_6-10Aryl and
C_7-12Aralkyl is replaced by halogen and halogen, respectively.
C which may be replaced_1-4Substituted with alkoxy and halogen
C that may be_1-4Alkyl, nitro, amino and
And 1 to 5 substituents selected from cyano
And the heterocyclic group may be C_1-4Alkoxy, halogen, C
_1-4Alkyl and C_6-101-3 selected from aryl
Ix-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
Ix-11) formyl, (C-11)_1-6A
Alkyl) carbonyl, (C_3-6Cycloalkyl) carbo
Nil, (C_6-10Aryl) carbonyl, (C_7-12Aral
Kill) 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
Kishi and C_1-41 to 5 substitutions selected from alkyl
(Ix-12) halogeno
, (Ix-13) nitro, and (ix-14) shea
May be substituted with 1 to 4 substituents selected from
I), (x) C_1-6Alkyl, C_3-6Cycloalkyl, C
_6-10Aryl, C_7-12Substituted with aralkyl and heterocyclic groups
Thiol group (where C is_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
C that may be_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
C that may be_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.
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 one or two substituents
(Where each substituent is halogen,
C that may be_1-4Substituted with alkoxy, halogen
C that may be_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
Kishi and C_1-41 to 5 substitutions selected from alkyl
(X-12) halogen,
Selected from (x-13) nitro and (x-14) cyano
May be 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
(Xiii) halogen, (xiii) nitrite
(B) and 1 to 3 positions selected from (xiv) cyano
May be substituted with a substituent),
May be substituted with two (preferably one) substituents
Amino groups are preferred.

In the above general formula (I), R is
Preferably, a group represented by the formula R ¹ —CO—NH— or R ³ —SO ₂ —NH— (wherein R ¹ and R ³ have the same meanings as described above) is mentioned, but more preferably The group represented by the former (R ¹ -CO-NH-) is exemplified. Among the compounds represented by the above general formula (I), those represented by the formula (Ia)

Embedded image [Wherein, R ^1a represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group] or a compound represented by the formula (Ib):

Embedded image (In the formula, R ^1b is substituted with (i) an optionally substituted cyclic hydrocarbon group, (ii) an optionally substituted heterocyclic group, (iii) an optionally substituted cyclic hydrocarbon group. Hydroxyl group, (i
v) a hydroxyl group substituted with an optionally substituted heterocyclic group,
(v) a thiol group substituted with an optionally substituted cyclic hydrocarbon group, or (vi) a non-cyclic hydrocarbon group substituted with a thiol group substituted with an optionally substituted heterocyclic group Is more preferable. That is, R ¹ is preferably R ^1a or R ^1b . Also,
R ¹ is more preferably R ^1a .

In the formula (Ia), ^examples of the cyclic hydrocarbon group of the “optionally substituted cyclic hydrocarbon group” defined by R ^1a include the aforementioned R ¹ , R ² , R ³ , R ⁴ and R ⁵ And R ⁶
Examples of the saturated or unsaturated alicyclic hydrocarbon group and the aryl group (aromatic hydrocarbon group) exemplified as the hydrocarbon group in the “optionally substituted hydrocarbon group” shown in Preferably, phenyl, 1-naphthyl,
And C _6-10 aryl groups such as 2-naphthyl.

In the formula (Ia), the heterocyclic group of the "optionally substituted heterocyclic group" defined by R ^1a includes R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R Examples include the same as the heterocyclic group in the “optionally substituted heterocyclic group” shown in ⁶ , preferably thienyl (eg, 2- or 3-thienyl), furyl (eg, 2- Or 3-furyl), pyridyl (eg, 2-pyridyl, 3-
Pyridyl, 4-pyridyl), azolyl [eg, oxazolyl (eg, 2-, 4- or 5-oxazolyl), isoxazolyl (eg, 3-, 4- or 5-isoxazolyl), etc.], condensed ring group of thienyl or azolyl [Examples: benzothienyl (eg, 2- or 3-benzo [b] thienyl, etc.), benzoxazolyl (eg, 2
-, 5- or 6-benz [d] oxazolyl),
Aromatic heterocyclic groups such as benzothiazolyl (eg, 2-benzo [d] thiazolyl, etc.) or condensed furanyl groups (eg, benzofuranyl (eg, 2- or 3-benzo [b] furanyl, etc.)); . More preferably, a 5-membered aromatic heterocyclic group such as thienyl and furyl is exemplified. The cyclic hydrocarbon group in the “optionally substituted cyclic hydrocarbon group” and the heterocyclic group in the “optionally substituted heterocyclic group” as defined for R ^1a may have any substituent at a substitutable position. It may have 1 to 3 (preferably 1 to 2) groups. 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.

[0023] The heterocyclic group which may be substituted represented by R ^1a, optionally substituted with 1-3 substituents selected from for example (i) halogen and C _1-3 alkoxy C _{1 -6} alkyl group, (ii) halogen and C
_A C _1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from _1-3 alkoxy, (iii) C _1-3 alkoxy, halogen, C _1-3 alkyl, amino, nitro and cyano A C _6-14 aryl group _optionally substituted with 1 to 5 substituents selected from
_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 is a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from (ix-1) halogen and C _1-3 alkoxy, (ix-2) halogen and C _{1- Three}
A C _1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from alkoxy, (ix-3) C _1-3 alkoxy, halogen, C _1-3 alkyl, amino, nitro and cyano A C _6-14 aryl group _optionally substituted with 1 to 5 selected substituents, and (ix-4)
_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 , (Ix-5) _1-3 alkyl selected from C _1-4 alkoxy optionally substituted with halogen, halogen, C _1-4 alkyl optionally substituted with halogen, C _6-10 aryl and nitro A heterocyclic group which may be substituted with a substituent of (ix-6) a 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
A carbamoyl group optionally substituted with one or two substituents selected from cycloalkyl, C _6-10 aryl, C _7-12 aralkyl and C _6-10 arylsulfonyl (where each substituent is halogen, halogen optionally substituted C _1-4 alkoxy are selected from optionally C _1-4 alkyl and nitro substituted by halogen 1-5
Ix-8) C
_1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl,
An amino group which may be substituted with one or two substituents selected from C _7-12 aralkyl and C _6-10 arylsulfonyl (where each substituent is halogen, C _C1-4 alkoxy, optionally substituted with 1-5 substituents selected from optionally C _1-4 alkyl and nitro substituted by halogen), or cyclic amino group, (ix-9) C _1-6 alkyl, C _3-6
A hydroxy group _optionally substituted with cycloalkyl, C _6-10 aryl, C _7-12 aralkyl and heterocyclic group (wherein
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, optionally substituted with halogen The heterocyclic group may be substituted with 1 to 5 substituents selected from good C _1-4 alkyl, nitro, amino and cyano, and the heterocyclic group may be C _1-4 alkoxy, halogen, C _1-4 alkyl and C ₆ Ix-aryl may be substituted with 1 to 3 substituents selected from _-10 aryl), (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) may be substituted with 1 to 4 substituents selected from nitro and (x-14) cyano),
(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 by 1 to 5 substituents selected from alkyl), (xii) substituted by 1 to 4 substituents selected from halogen, (xiii) nitro, and (xiv) cyano And a heterocyclic group which may be substituted.

Examples of the optionally substituted cyclic hydrocarbon group represented by R ^1a include (i) halogen and C
_A C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from _1-3 alkoxy, (ii) substitution with 1 to 3 substituents selected from halogen and C _1-3 alkoxy An optionally substituted C _1-6 alkoxy group, (iii)
C _1-3 alkoxy, halogen, C _1-3 alkyl, amino,
A C _6-14 aryl group optionally substituted with 1 to 5 substituents selected from nitro and cyano, (iv) C _1-3 alkoxy, halogen, C _1-3 alkyl, amino, nitro and cyano, respectively A C _3-7 cycloalkyl group or a C _3-6 cycloalkenyl group optionally substituted with 1 to 5 substituents selected from: (v) a C _1-4 alkoxy optionally substituted with halogen, A heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen, C _1-4 alkyl _optionally substituted with halogen, C _6-10 aryl and nitro, (vi) a carboxyl group, (C
_1-6 alkoxy) carbonyl group, (C _6-10 aryl) oxycarbonyl group or (C _7-10 aralkyl) oxycarbonyl group, (vii) 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, (Optionally substituted by 1 to 5 substituents selected from C _1-4 alkyl and nitro), (viii) C _1-6 alkyl, C _3-6 cycloalkyl, C _{6 -10} aryl, C
_An amino group optionally substituted with one or two substituents selected from _7-12 aralkyl and C _6-10 arylsulfonyl (where each substituent is halogen, C ₁ optionally substituted with halogen, respectively) _-4 alkoxy, optionally substituted with 1 to 5 substituents selected from C _1-4 alkyl optionally substituted with halogen and nitro), or a cyclic amino group, (ix) 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 (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- The heterocyclic group may be substituted with 1 to 5 substituents selected from ₄ alkyl, nitro, amino and cyano, and the heterocyclic group is (ix-1) halogen and C
_1-3 1-3 substituents in the optionally substituted C _1-6 alkyl group selected from alkoxy, one to three substituents selected from (ix-2) halogen and C _1-3 alkoxy A C _1-6 alkoxy group optionally substituted with (ix
-3) a C _6-14 aryl group optionally substituted with 1 to 5 substituents selected from C _1-3 alkoxy, halogen, C _1-3 alkyl, amino, nitro and cyano, (ix-
4) a C _3-7 cycloalkyl group or a C _3-, each of which may be substituted with 1 to 5 substituents selected from C _1-3 alkoxy, halogen, C _1-3 alkyl, amino, nitro and cyano; ₆ cycloalkenyl group, (ix-5) may be substituted by halogen C _1-4 alkoxy, halogen, optionally C _1-4 alkyl optionally substituted by halogen,
A heterocyclic group optionally substituted with 1 to 3 substituents selected from C _6-10 aryl and nitro, (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
_A carbamoyl group which may be substituted with one or two substituents selected from _7-12 aralkyl and C _6-10 arylsulfonyl (where each substituent is halogen, C ₁ which may be substituted with halogen, respectively) _-4 alkoxy, C _1-4 alkyl optionally substituted with halogen, and 1 to 5 substituents selected from nitro), (ix-8) C _1-6 alkyl, C _An amino group optionally substituted with one or two substituents selected from _3-6 cycloalkyl, C _6-10 aryl, C _7-12 aralkyl and C _6-10 arylsulfonyl (where each substituent is each halogen, optionally substituted with 1-5 substituents selected from halogen optionally substituted C _1-4 alkoxy, optionally C _1-4 alkyl optionally substituted by halogen and nitro) Or circular ring Amino group, (ix-9)
C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C _7-12 aralkyl and a hydroxy 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,
_1-4 alkoxy, C _1-4 optionally substituted with halogen
1 selected from alkyl, nitro, amino and cyano
The heterocyclic group may be substituted with up to 5 substituents.
_1-4 alkoxy, halogen, C _1-4 alkyl and C _6-10
(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 (wherein
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, optionally substituted with halogen The heterocyclic group may be substituted with 1 to 5 substituents selected from good C _1-4 alkyl, nitro, amino and cyano, and the heterocyclic group may be C _1-4 alkoxy, halogen, C _1-4 alkyl and C ₆ Ix-aryl may be substituted with 1 to 3 substituents selected from _-10 aryl), (ix-
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
_6-10 aryl) sulfonyl and (C _7-12 aralkyl)
Acyl groups selected from sulfonyl (wherein 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 ) May be substituted with 1 to 4 substituents selected from halogen, (ix-13) nitro, and (ix-14) cyano), (x) C _1-6 alkyl, C _3-6 cyclo Alkyl, 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 are substituted with halogen and halogen, respectively) C _1-4 that may be
1 to 4 selected from alkoxy, C _1-4 alkyl optionally substituted with halogen, nitro, amino and cyano
The heterocyclic group may be substituted with 5 substituents, and (x
-1) 1 selected from halogen and C _1-3 alkoxy
C _1-6 alkyl group optionally substituted with 1 to 3 substituents, (x-2) halogen optionally substituted with 1 to 3 substituents selected from halogen and C _1-3 alkoxy _1-6
An alkoxy group, (x-3) C _1-3 optionally substituted with one to five substituents selected from C _1-3 alkoxy, halogen, C _1-3 alkyl, amino, nitro and cyano
_6-14 aryl group, (x-4), respectively C _1-3 alkoxy, halogen, C _1-3 alkyl, amino, 1-5 optionally substituted with a substituent C ₃ selected from nitro and cyano _-7 cycloalkyl group or C _3-6 cycloalkenyl group, (x-5) C which may be substituted with halogen
A heterocyclic group optionally substituted with 1 to 3 substituents selected from _1-4 alkoxy, halogen, C _1-4 alkyl optionally substituted with halogen, C _6-10 aryl and nitro, ( x-6) 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,
(X-7) C _1-6 alkyl, C _3-6 cycloalkyl, C
_A carbamoyl group optionally substituted with one or two substituents selected from _6-10 aryl, C _7-12 aralkyl and C _6-10 arylsulfonyl (wherein each substituent is halogen, which may be C _1-4 alkoxy, optionally substituted with 1 to 5 substituents may be selected from optionally C _{1 -4} alkyl and nitro substituted with halogen), (x-8) C _An amino group optionally substituted with one to two substituents selected from _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C _7-12 aralkyl and C _6-10 arylsulfonyl ( Here, each substituent is halogen, C _1-4 alkoxy optionally substituted with halogen, C _1-4 optionally substituted with halogen,
_1-4 substituted with 1 to 5 substituents selected from alkyl and nitro), or a cyclic amino group,
(X-9) C _1-6 alkyl, C _3-6 cycloalkyl, C
_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-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 each of halogen, optionally substituted by halogen C _1-4 alkoxy, optionally C _1-4 alkyl optionally substituted by halogen, nitro, amino and cyano The heterocyclic group may be substituted with 1 to 5 selected substituents, 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. ), (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 _6-10 aryl) sulfonyl and (C _7-12
An acyl group selected from aralkyl) sulfonyl (where each substituent may be substituted with 1 to 5 substituents selected from halogen, C _1-4 alkoxy and C _1-4 alkyl, respectively); -12) halogen, (x-1)
3) 1 selected from nitro and (x-14) cyano
(Optionally substituted with up 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, (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 an acyl group wherein each substituent is halogen, C _1-4 alkoxy And may be substituted with 1 to 5 substituents selected from C _1-4 alkyl),
(Xii) halogen, (xiii) nitro, and (x
iv) cyano, which may be substituted with 1 to 3 substituents selected from (a) a cycloalkyl group having 3 to 12 carbon atoms, (b) a cycloalkenyl group having 5 to 12 carbon atoms,
(C) a cycloalkadienyl group having 5 to 12 carbon atoms,
(D) an aryl group having 6 to 10 carbon atoms.

In the formula (Ia), R ^1a is preferably an “optionally substituted aromatic hydrocarbon group or aromatic heterocyclic group”, and more preferably an “optionally substituted 5-membered aromatic group”. Group heterocyclic group ", and specific examples thereof include, for example, C _1-3 alkyl, C _1-3 alkoxy, halogen, nitro, cyano, (C _{1- A} thienyl group or a furyl group, each of which may be substituted with 1 to 3 (preferably 1 to 2) substituents selected from ( _6alkyl ) carbonyl and ( _C1-6alkyl ) sulfonyl; 1-2 of C _1-3 substituted by alkyl groups include optionally furyl group optionally substituted in thienyl group or one to two C _1-3 alkyl groups. R ^1a is particularly preferably a thienyl group or a furyl group each substituted by one or two C _1-3 alkyl groups.

As defined for R ^1b , “an optionally substituted cyclic hydrocarbon group, an optionally substituted heterocyclic group,
A hydroxyl group substituted with an optionally substituted cyclic hydrocarbon group, a hydroxyl group substituted with an optionally substituted heterocyclic group, a thiol group substituted with an optionally substituted cyclic hydrocarbon group or The acyclic hydrocarbon group of the "acyclic hydrocarbon group substituted by a thiol group substituted by a heterocyclic group which may be substituted" includes the aforementioned R ¹ , R ² , R ³ , R ⁴ ,
The saturated or unsaturated aliphatic chain hydrocarbon group exemplified as the hydrocarbon group in the “optionally substituted hydrocarbon group” for R ⁵ and R ⁶ can be mentioned. The non-cyclic hydrocarbon group has at least one (preferably 1 to 2) at least one (i) a cyclic hydrocarbon group which may be substituted, and (ii) a heterocyclic group which may be substituted. Ring group,
(iii) a hydroxyl group substituted with an optionally substituted cyclic hydrocarbon group, (iv) a hydroxyl group substituted with an optionally substituted heterocyclic group, (v) an optionally substituted cyclic hydrocarbon group And / or (vi) a thiol group substituted with an optionally substituted heterocyclic group.
Examples of the “optionally substituted cyclic hydrocarbon group” (i) include the “optionally substituted hydrocarbon” described for R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 above.} "Optionally substituted aryl group" and "optionally substituted lower cycloalkyl group or lower cycloalkenyl group" exemplified as the substituent for the hydrocarbon group in the "group". The “optionally substituted heterocyclic group” (ii) includes the “optionally substituted hydrocarbon group” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^6. And the same as the "optionally substituted heterocyclic group" for the substituent. The "hydroxyl group substituted with an optionally substituted cyclic hydrocarbon group" (iii) and the "thiol group substituted with an optionally substituted cyclic hydrocarbon group"
As the cyclic hydrocarbon group in (v), R ¹ , R ² ,
The saturated or unsaturated alicyclic hydrocarbon group and the aryl group (aromatic group) exemplified as the hydrocarbon group in the “optionally substituted hydrocarbon group” for R ³ , R ⁴ , R ⁵ and R ⁶ Hydrocarbon group) and the like. The `` hydroxyl group substituted with an optionally substituted heterocyclic group '' (iv) and the `` thiol group substituted with an optionally substituted heterocyclic group '' (v
The heterocyclic group in i) includes R ¹ , R ² , R ³ ,
The same heterocyclic groups as those exemplified as the "optionally substituted heterocyclic group" for R ⁴ , R ⁵ and R ⁶ can be mentioned.

The “cyclic hydrocarbon group” is a substitutable position
Has 1 to 5 (preferably 1 to 3) optional substituents
It may be. As the substituent, the aforementioned R¹, R^Two, R
^Three, R^Four, R^FiveAnd R⁶"It may be substituted
Examples of substituents on hydrocarbon groups in "hydrocarbon groups"
The same ones as shown are mentioned, but preferably,
1 to 3 halogens (eg, fluorine, chlorine, bromine, iodine
Lower) (C)_1-3) Alkyl
Groups (eg, methyl, ethyl, propyl, isopropyl,
Fluoromethyl, chloromethyl, etc.), 1 to 3 halogen
(Eg, fluorine, chlorine, bromine, iodine, etc.)
Low-grade (C_1-3) Alkoxy (eg, methoxy
Si, ethoxy, propoxy, isopropoxy, fluoro
Methoxy, chloromethoxy, etc.), halogen (eg,
Nitrogen, chlorine, bromine, etc.), nitro, amino, cyano, etc.
No. The "heterocyclic group" is optionally substituted at a substitutable position.
1 to 4, preferably 1 to 3,
You may. As the substituent, the aforementioned R¹, R^Two, R^Three,
R^Four, R^FiveAnd R⁶May be substituted
Heterocyclic group "as an example of a substituent on a heterocyclic group
Although the same as those mentioned above are preferred,
(C _1-4) Alkyl group (eg, methyl, ethyl, propyl
, Isopropyl, etc.), low grade (C_1-4) Alkoxy
(Eg, methoxy, ethoxy, propoxy, isopropoxy
, Halogens (eg, fluorine, chlorine, bromine, etc.),
C_6-10Aryl (eg, phenyl, etc.)
You. The acyclic hydrocarbon group may be substituted as described above.
Cyclic hydrocarbon groups "," optionally substituted heterocyclic
In addition to “ring group”, any position can be substituted at a substitutable position.
A non-cyclic hydrocarbon group.
The total number of substituents is preferably 1 to 3 (more preferably
Is 1 to 2). As the substituent, the aforementioned R¹,
R^Two, R^Three, R^Four, R^FiveAnd R⁶"Replaced
Same as those shown for the substituent of "optionally hydrocarbon group"
Are included. R^1bAs "even if it is substituted
Acyclic hydrocarbon groups substituted with good cyclic hydrocarbon groups "
Examples of the cyclic hydrocarbon group include an aryl group
(Eg, C such as phenyl, 1-naphthyl, 2-naphthyl, etc.)
_6-14Aryl group, etc.), cycloalkyl having 3 to 7 carbon atoms
And a cycloalkenyl group having 3 to 6 carbon atoms is preferred.
No. The cyclic hydrocarbon group has 1 to 5 (preferably 1 to 3)
) Substituents, and the substituents include
For example, C_1-3Alkoxy, halogen, C_1-3Alkyl, a
Mino, nitro, cyano and the like are preferred. R^1bAs
Optionally substituted heterocycle [eg, thienyl (eg, 2-
Or 3-thienyl), furyl (eg, 2- or 3-free)
), Azolyl [eg, oxazolyl (eg, 2-, 4-
Or 5-oxazolyl), isoxazolyl (eg, 3
-, 4- or 5-isoxazolyl), etc.
, Furyl or azolyl condensed ring group [benzothienyl
(Eg, 2- or 3-benzo [b] thienyl),
Nzofuranyl (eg, 2- or 3-benzo [b] furani
Benzoxazolyl (eg, 2-, 5- or
6-benz [d] oxazolyl), benzisooki
Sazolyl (eg, 3-, 4- or 5-benz [d] iso
Oxazolyl), benzothiazolyl (eg, 2-ben
Zo [d] thiazolyl), benzimidazolyl (eg,
1-benz [d] imidazolyl etc.)
A heterocyclic group substituted with an aromatic heterocyclic group is preferred.
And more preferably an optionally substituted thienyl
Or a non-cyclic hydrocarbon group substituted with a furyl group. The
As the acyclic hydrocarbon group, preferably,_1-10Archi
Group (preferably C, such as methyl, ethyl, propyl, etc.)
_1-3Alkyl, etc.), C_2-10Alkenyl group (preferably
Is a C such as ethenyl_2-4Alkenyl), C_2-10A
A rukinyl group (preferably a C_2-4Archi
And the like). The aromatic heterocyclic group is
Even if it has 1 to 3 optional substituents at interchangeable positions
Often, the substituent is preferably 1 to 3 halo
Gen (eg, fluorine, chlorine, bromine, iodine, etc.)
Low-grade (C_1-3) Alkyl group (eg, methyl
, Ethyl, propyl, isopropyl, fluoromethyl
Chloromethyl), C_6-10Aryl group (eg,
Nil, etc.), 1 to 3 halogens (eg, fluorine, chlorine,
Lower (C) which may be substituted with bromine or iodine)_1-3)
Alkoxy (eg, methoxy, ethoxy, propoxy, i
Sopropoxy, fluoromethoxy, chloromethoxy
Etc.), halogens (eg, fluorine, chlorine, bromine, iodine
And nitro). The acyclic hydrocarbon group
Stands for “optionally substituted cyclic hydrocarbon group”, “substituted
A heterocyclic group which may be
It may have a substituent such as ノ.

R ^1b is preferably (i) a C _1-3 optionally substituted with one to five substituents selected from C _1-3 alkoxy, halogen, C _1-3 alkyl, amino, nitro and cyano. _6-14 aryl group, (ii) C _3-7 each optionally substituted with 1 to 5 substituents selected from C _1-3 alkoxy, halogen, C _1-3 alkyl, amino, nitro and cyano cycloalkyl group or C _3-6 cycloalkenyl group, and (iii) optionally substituted by halogen C _1-3 alkoxy, halogen, optionally C _1-3 alkyl optionally substituted by halogen, C _6-10 An aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from aryl and nitro, (iv) a _C1-3 alkyl optionally substituted with halogen, optionally substituted with halogen good C _1-3 alkoxy, Androgenic, nitro, amino and 1-5 may be substituted with a substituent C _3-6 cycloalkyl in each substituted hydroxy group or thiol group selected from cyano, optionally substituted by (v) halogen Good C _1-3 alkyl, C _1-3 alkoxy optionally substituted with halogen, C _6-10 aryl optionally substituted with 1 to 5 substituents selected from halogen, nitro, amino and cyano A hydroxyl group or a thiol group respectively substituted with (vi) C _1-4 alkyl, C _1-4
Substituted with 1 to 3 substituents selected from a hydroxyl group or a thiol group each substituted with a heterocyclic ring which may be substituted with 1 to 4 substituents selected from alkoxy, halogen and C _6-10 aryl (A) C
_Examples thereof include a _1-10 alkyl group, (b) a C _2-10 alkenyl group, and (c) a C _2-10 alkynyl group. The C _1-10
The alkyl group, C _2-10 alkenyl group and C _2-10 alkynyl group may be further substituted with one cyano group.
In the present invention, the compound represented by the general formula (I) or (Ia) is preferably N- (diaminophosphinyl) -5-methyl-2-thiophenecarboxamide, N- (diaminophosphinyl) ) -2-Methyl-3-
Furancarboxylic acid amide, N- (diaminophosphinyl) -5-methyl-3-furancarboxylic acid amide, N-
(Diaminophosphinyl) -3,5-dimethyl-2-furancarboxylic amide, and N- (diaminophosphinyl) -3,5-dimethyl-2-thiophenecarboxylic amide.

The salt of the compound represented by formula (I), (Ia) or (Ib) in the present invention is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base or a salt with an organic base. Examples thereof include salts, 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, for example, ammonium salt, trimethylamine, triethylamine, pyridine, picoline, ethanolamine,
Salts with diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like can be mentioned. 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. In addition, hydrates and non-hydrates of the compound represented by the general formula (I), (Ia) or (Ib) are also included in the scope of the present invention. The compounds represented by the following general formulas (II) and (I)
As the salt of the compound represented by II), those similar to the salts shown as the salt of the compound represented by the above general formula (I) can be mentioned.

The method for producing the compound represented by formula (I) will be described below. In addition, both the compound represented by the general formula (Ia) and the compound represented by the general formula (Ib) are included in the scope of the general formula (I). 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 compound represented by the general formula (I) can be produced, for example, by reacting a compound represented by the formula: or a salt thereof with ammonia, and the like. Further, for example, a compound represented by the formula (II) or a salt thereof is reacted with phosphorus oxychloride to obtain a compound represented by the formula (I)
The target compound can also be obtained by reacting the compound represented by II) or a salt thereof with ammonia. A compound represented by the formula (II) or a salt thereof,
In the reaction with phosphorus pentachloride or phosphorus oxychloride,
Solvents such as carbon tetrachloride, halogen solvents such as chloroform, cyclomethane and 1,2-dichloroethane, ether solvents such as dioxane, tetrahydrofuran and diethyl ether, and hydrocarbon solvents such as benzene and toluene do not hinder the reaction. Any solvent may be used,
The reaction temperature is usually about -50 to 100C, preferably about -100C.
20-80 ° C. Phosphorus pentachloride or phosphorus oxychloride is usually used in an amount of 0.5 to 10 molar equivalents, preferably 1 to 1 mol of the compound represented by the formula (II) or a salt thereof.
Use ~ 2 molar equivalents. When a compound or a salt thereof obtained by reacting the compound represented by the formula (II) or a salt thereof with phosphorus pentachloride is reacted with formic acid, the solvent to be used is the same as the above-mentioned halogen-based solvent or ether. A system solvent and a hydrocarbon solvent can be used, and the reaction temperature is usually about -50 to 50C, preferably about 0 to 30C. The formic acid used is a compound 1 obtained by reacting a compound represented by the formula (II) or a salt thereof with phosphorus pentachloride.
Usually 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, are used per mol. 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 and hydrocarbon-based solvent as described above can be used, and the reaction temperature is usually about -50 to -50.
It is 50 ° C, preferably about -20 to 10 ° C.

The compound (I) or a salt thereof thus obtained can be isolated by known means, for example, concentration, concentration under reduced pressure, distillation, fractionation, solvent extraction, chromatography, crystallization, recrystallization and the like. 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, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, valeryl, etc.), nitro groups and the like are used. The number of groups is about one to three. Examples of the carboxyl-protecting group include, for example, C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl, etc.), phenyl, trityl or silyl, each of which may have a substituent. Are used. As these substituents, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, valeryl, etc.), nitro groups and the like are used. The number of groups is about one to three. As the protecting group for the hydroxyl group, for example, a C _1-6 alkyl which may have a substituent (for example,
Methyl, ethyl, propyl, isopropyl, butyl, te
rt.-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.), phenyloxy Carbonyl, benzoyl, (C _7-10 aralkyloxy) carbonyl (for example, phenyl-C _1-4 alkyloxy-carbonyl such as benzyloxycarbonyl), pyranyl, furanyl, silyl and the like are used. 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, benzyl, etc.) Phenyl-C _1-4 alkyl), a nitro group and the like, and the number of substituents is 1
Or about four. 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 spp. Agent and the pharmaceutical composition of the present invention may be a compound represented by the general formula (I), the general formula (Ia) or the general formula (Ib) or a salt thereof (hereinafter, referred to as a compound thereof).
A compound represented by the general formula (I)) and an antibiotic. A drug for anti-Helicobacter, characterized by using the compound represented by the general formula (I) or a salt thereof in combination with an antibiotic, comprises a compound represented by the general formula (I) or a salt thereof: The form of use is not particularly limited as long as it is used in combination with the antibiotic. For example, (A) the compound represented by the general formula (I) or a salt thereof and (B) an antibiotic may be respectively distributed as a preparation which is usually administered, or a composition prepared by combining them in advance. There may be. Examples of the anti-Helicobacter medicaments of the present invention include a compound represented by the general formula (I) or a salt thereof and an antibiotic.
According to a known pharmaceutical manufacturing method, if necessary, using a pharmaceutically acceptable diluent, excipient, etc., and mixing to make one agent. Separately, if desired, a pharmaceutically acceptable diluent Each preparation may be prepared using an excipient, an excipient, or the like, or may be separately prepared into a combined preparation (set, kit, pack) in which the preparation is packaged in one container. For example, the medicament for anti-Helicobacter bacteria of the present invention,
(1) a combination preparation in which a preparation containing the compound represented by the general formula (I) or a salt thereof and a preparation containing an antibiotic are packed, or (2) the compound represented by the general formula (I) or a compound thereof It can be used as a composition containing a salt and an antibiotic. In addition, the pharmaceutical for anti-Helicobacter bacteria of the present invention may be a combination preparation or composition comprising the compound represented by the general formula (I) or a salt thereof and an antibiotic.

As antibiotics, substances having a natural antibacterial activity extracted from microorganisms and plants such as bacteria, molds and actinomycetes, and having an antibacterial activity obtained by chemically modifying the naturally occurring substance. Substances, substances having antibacterial activity obtained by chemical synthesis, and the like. Preferably, amoxicillin, piperacillin (piperacil)
lin), penicillin G, mecillinam (m
ecillinam) and other penicillins, cefaclor (cefaclor), cefotiam (cefotiam), cefixime (cefixime), ceftazidime (cefrazidime),
Cephalosporin antibiotics such as cefpirome, carbapenems such as imipenem, clarithromycin,
Erythromycin, roxithromycin, azithromyci
macrolide antibiotics such as n), lincomycin antibiotics such as clindamycin, chloramphenicol antibiotics such as chloramphenicol, tetracycline
yclin), tetracycline antibiotics such as minocyclin and doxycyclin, aminoglycoside antibiotics such as streptomycin, gentamycin, amikacin, norfloxacin (norflo)
quinolone antibiotics such as xacin), ofloxacin, ciprofloxacin,
Indolmycin antibiotics such as indolmycin, metronidazol
e), nitroimidazole antibiotics (antiprotozoal agents) such as tinidazole, colloidal bismuth subcitrate, bismuth subsalicylate and other bismuth compounds, fosfomycin, rifampicin (Rifampicin), nitrofurantoin (nitrofuran)
toin), furazolidone, etc., among which penicillin antibiotics such as amoxicillin, macrolide antibiotics such as clarithromycin, nitroimidazole antibiotics such as metronidazole and tinidazole, and indolmycins such as indolmycin Antibiotics and the like. The antibiotic is more preferably a penicillin antibiotic, a macrolide antibiotic, or a nitroimidazole antibiotic, and particularly preferably a penicillin antibiotic such as amoxicillin, or a macrolide antibiotic such as clarithromycin. One or more of these antibiotics (preferably one to three, more preferably one or two)
Seed) may be used.

The anti-Helicobacter bacterium according to the present invention,
The pharmaceutical composition and the medicament for the anti-Helicobacter genus can be produced according to a known method for producing a pharmaceutical preparation.
The anti-Helicobacter bacterium agent, the pharmaceutical composition and the drug for the anti-Helicobacter bacterium in the present invention can be used orally, parenterally, by inhalation, rectal injection, or topical administration, for example, powder. , Granules, tablets, pills, capsules, injections, syrups, emulsions, elixirs, suspensions, solutions and the like, which are at least one compound represented by the general formula (I) Alternatively, a salt thereof and an antibiotic can be blended, or they can be blended with a pharmaceutically acceptable carrier. When using such a carrier,
The content of the compound represented by the general formula (I) or the salt thereof and the antibiotic may be appropriately selected depending on the preparation, but the content of the compound represented by the general formula (I) or the salt thereof and the antibiotic is Usually about 1 to 99% by weight and 1 respectively
About 99% by weight, preferably about 1 to 20% by weight and about 1 to 90% by weight, respectively. As the pharmaceutically acceptable carrier, various organic or inorganic carrier materials commonly used as formulation materials are used, and excipients, lubricants, binders, disintegrants in solid formulations, solvents in liquid formulations,
An appropriate amount of a solubilizing agent, a suspending agent, a tonicity agent, a buffer, a soothing agent, etc. is appropriately compounded. 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 excipients include
Examples 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. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Suitable examples of disintegrants include, for example, starch,
Examples include carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like. Suitable examples of the solvent include, for example, water for injection, alcohol,
Propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. 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 And 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. Preferred examples of preservatives include:
For example, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like can be mentioned. Preferable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

The anti-Helicobacter agent, the pharmaceutical composition and the drug for the anti-Helicobacter can be formulated according to a usual 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 prepared 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. Examples of acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic saline and the like. 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 those described above such as powders, granules, tablets, pills and capsules. 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 bacterium of the present invention,
The pharmaceutical composition and the medicament for anti-Helicobacter may be an enteric-coated preparation. The compound represented by the general formula (I) or a salt thereof and / or an antibiotic can be adhered to the gastrointestinal (gastric) mucosa according to the method described in, for example, JP-A-5-132416, JP-A-7-126189, and the like. Formulation.

The dosage for a particular patient may include 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 action by an urease inhibitory action, in particular, an anti-Helicobacter action (elimination action of Helicobacter spp.), And is useful in mammals (eg, humans, dogs, cats). , Monkeys, rats, mice, etc.) are useful for the prevention or treatment of peptic diseases caused by Helicobacter spp. Such as gastritis, duodenal ulcer, gastric ulcer, chronic gastritis and the like. 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, the pharmaceutical composition and the anti-Helicobacter drug of the present invention have an anti-Helicobacter action, for example, the anti-Helicobacter bactericidal action and the bactericidal action of Helicobacter sp. Show. As a digestive tract,
For example, stomach, duodenum and the like can be mentioned. Helicobacter species that have a toxic effect in the digestive tract include Helicobacter pylori. The dose of the anti-Helicobacter bacterium agent, the pharmaceutical composition and the drug for the anti-Helicobacter bacterium 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 The salt is used, for example, in adult patients with gastric or duodenal ulcers (5
0 kg) per day, in the case of oral administration, about 0.1 to 10
g / day, preferably 0.2-2 g / day, for parenteral administration, about 0.01-1 g / day, preferably 0.02-0.5.
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 dosage of the antibiotic is appropriately selected depending on the type of disease, symptoms, type of antibiotic, etc. When the antibiotic is a penicillin antibiotic such as amoxicillin, for example, an adult patient with gastric ulcer or duodenal ulcer (50 kg)
About 0.1 to 10 g / day for oral administration per day,
Preferably 0.2 to 2 g / day, for parenteral administration about 0.2 g.
It can be administered at from 01 to 1 g / day, preferably from 0.02 to 0.5 g / day. 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 Helicobacter bacterium, the pharmaceutical composition and the anti-Helicobacter medicaments of the present invention may further comprise, in addition to the active ingredient, the compound represented by the general formula (I) or a salt thereof and an antibiotic, Antacid or /
And an acid secretion inhibitor. Examples of the antacid include agents that neutralize stomach acid, and more specifically, for example, aluminum hydroxide gel, sodium bicarbonate, aminoacetic acid, aluminum silicate, magnesium metasilicate aluminate, magnesium silicate, Magnesium oxide, magnesium hydroxide, magnesium carbonate,
Calcium carbonate and the like. Examples of the acid secretion inhibitor include agents that suppress gastric acid secretion, and more specifically, for example, proton pump inhibitors and histamine H ₂
Blockers. The proton pump inhibitor refers to a drug that suppresses gastric acid secretion by directly or indirectly inhibiting H / K-ATPase functioning as a proton pump in acid secreting cells (mural cells) of the gastric mucosa. . Examples include lansoprazole, omeprazole, pantoprazole, paliprazole sodium (rabeprazole sodium), reminoprazole,
TY-11345, TU-199, FPL-6537
2, BY-686, Tannic acid, Ellagic acid, Ebselen, A
HR-9294, Cassigarol-A, Bafilomycin, Y-25942, Xant
hoangelol E, SKF-96356, Epigallocatechin
gallate, WY-27198, T-330 or SK
& F-20054.

Particularly, examples of the proton pump inhibitor include, for example, benzimidazole compounds, and 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.

Embedded image 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 formula (α), when the ring A is substituted, examples of the substituent include a halogen atom, an alkyl group which may be substituted, a cycloalkyl group which may be substituted, 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.

Examples of the cycloalkyl group in the optionally substituted cycloalkyl group include, for example, those having 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,
Groups such as an amidino group and a guanidino group; The alkenyl group includes isomers related to double bonds (E and Z forms). 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} alkyl group, a substituent such as C _1-4 alkoxy group 1-3
May be present).

Examples of the halogen for the substituent on the alkyl, cycloalkyl, alkenyl and alkoxy groups 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. 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) 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, etc.). 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 (methoxycarbonylmethyl), 2-carbomethoxyethyl (2-methoxycarbonylethyl), and 2-carbomethoxypropyl (2-methoxycarbonylpropyl). Carboxyethoxymethyl (ethoxycarbonylmethyl), 2-carboethoxyethyl (2-ethoxycarbonylethyl), 1-carbomethoxypropyl (1-methoxycarbonylpropyl), carboxypropoxymethyl (propoxycarbonylmethyl),
And carbobutoxymethyl (butoxycarbonylmethyl). The alkyl group of the carbamoylalkyl group has 1 to 4 carbon atoms (eg, methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, sec
-Butyl, tert-butyl, etc.).

As the alkyl group of the hydroxyalkyl group, those having 1 to 7 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl) , Neopentyl, hexyl, heptyl and the like). 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.

As the alkyl group represented by R ^c , ^Re or R ^g , a linear or branched alkyl group 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, 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
Is preferably a hydrogen atom, an alkyl group or an alkoxy group. 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.), having 3 to 6 carbon atoms
Cycloalkenyl group (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.), an aralkyl group having 7 to 13 carbon atoms (eg, benzyl,
Phenyl-C such as 1-phenethyl and 2-phenethyl
_1-6 alkyl group, naphthyl-C _1-3 alkyl group, etc.), and an aryl group having 6-10 carbon atoms (eg, phenyl, naphthyl, etc.). 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 substituted hydrocarbon group include a C _6-10 aryl group (eg, phenyl, naphthyl, etc.), an amino, 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.

As R ^d , an optionally substituted alkoxy group and an optionally substituted alkoxyalkoxy group are preferred. 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).

The alkyl group represented by R ^W , R ^Y or R ^Z includes, for example, a linear or branched alkyl group 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.

As a specific example of the benzimidazole compound, 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 (paliprazole sodium, rabeprazole sodium), 2- [2- (3,4
-Dimethoxy) pyridyl] methylsulfinyl] -5-
And difluoromethoxy-1H-benzimidazole (pantoprazole). The benzimidazole-based compound or a salt thereof is produced, for example, by the method described in the above-mentioned known Japanese and European Patent Publications and a method analogous thereto.

The salts of the benzimidazole compounds are preferably used as physiologically acceptable salts. 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, in JP-A-64-79177 and JP-A-5-79177.
It is manufactured by the method described in JP-A-9-167587 or the like or a method analogous thereto. Examples of the histamine H ₂ blocker as the acid secretion inhibitor include 2-cyano-
1-methyl-3- [2-[[5-methylimidazole-
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] acetamide (Roctidine) and the like. The antacid and acid secretion inhibitor used in the anti-Helicobacter bacterium agent, the pharmaceutical composition and the anti-Helicobacter medicament of the present invention are one or more (preferably three or less) selected from them. ) An antacid or / and an acid secretion inhibitor are preferably used.
One or two antacids and / or acid secretion inhibitors are used. Among antacids and acid secretion inhibitors, acid secretion inhibitors are preferred, and proton pump inhibitors are more preferred.

As described above, the anti-Helicobacter bacterium agent and the pharmaceutical composition of the present invention contain, in addition to the active ingredient, the compound represented by the general formula (I) or a salt thereof and an antibiotic, an antacid or an antacid. And / or an acid secretion inhibitor. In the present specification, `` contains '' includes two cases where two or more active substances are mixed or not mixed, and both used at the same time or used with a time lag,
It includes the use in combination and the combined use. A drug for an anti-Helicobacter genus characterized by using a compound represented by the above general formula (I) or a salt thereof and an antibiotic together with an antacid and / or an acid secretion inhibitor is a compound of the general formula (I) ) Is not particularly limited as long as the compound or salt thereof, an antibiotic, an antacid and / or an acid secretion inhibitor are used in combination. For example, (A) a compound represented by the general formula (I) or a salt thereof, (B) an antibiotic, and (C) an antacid or / and an acid secretion inhibitor are each usually administered as a preparation which is usually administered. They may be arranged, or may be a composition obtained by combining them in advance. Anti-Helicobacter bacteria of the present invention,
Examples of the pharmaceutical composition and a drug for an anti-Helicobacter bacterium include a compound represented by the general formula (I) or a salt thereof, an antibiotic, an antacid and / or an acid secretion inhibitor. According to the pharmaceutical manufacturing method, if desired, a pharmaceutically acceptable diluent, excipient, or the like is used, and mixed to form a single agent. Two or more of the compound represented by the general formula (I) or a salt thereof, an antibiotic and an antacid or / and an acid secretion inhibitor, which are used as a pharmaceutical preparation in the form of a pharmaceutical preparation, are optionally pharmaceutically acceptable. The resulting active ingredients are mixed into a single agent using the resulting diluents, excipients, and the like, and the remaining active ingredients are optionally formulated into respective formulations using pharmaceutically acceptable diluents, excipients, or each is separately formulated. Combined products packed in one container Preparation (set, kit, pack)
It may be. For example, the medicament for anti-Helicobacter bacteria of the present invention comprises (1) a preparation containing a compound represented by the general formula (I) or a salt thereof, a preparation containing an antibiotic, an antacid and / or A combination preparation in which a preparation containing an acid secretion inhibitor is packed, or (2) a compound represented by the general formula (I) or a salt thereof, and an antibiotic;
It can be used as a composition containing an antacid and / or an acid secretion inhibitor. Also, in the medicament for anti-Helicobacter bacteria of the present invention, a combination preparation or composition comprising a compound represented by the general formula (I) or a salt thereof, an antibiotic, an antacid and / or an acid secretion inhibitor. It may be.

The route of administration of the anti-Helicobacter agent, the pharmaceutical composition and the drug for the anti-Helicobacter of the present invention includes the above-mentioned route of administration of the anti-Helicobacter agent, the pharmaceutical composition and the drug for the anti-Helicobacter. As in the above, any of oral administration and parenteral administration (eg, intravenous administration, subcutaneous administration, intramuscular administration, etc.) may be used. 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, an antibiotic and an antacid or / and an acid secretion inhibitor are separately formulated, they may be separately, simultaneously, or with a time lag, To the same or different routes. Anti-Helicobacter bacteria of the present invention,
Upon administration of a pharmaceutical composition and a medicament for anti-Helicobacter, the compound represented by the general formula (I) or a salt thereof, an antibiotic, and an antacid or acid secretion inhibitor each contain the above-mentioned anti-Helicobacter bacterium. It can be administered in a prepared dosage form in a conventional manner similar to that for an agent. For example, tablets and capsules are pharmacologically acceptable carriers (eg, lactose, corn starch, light silicic anhydride,
Microcrystalline cellulose, shucrose), binder (eg, pregelatinized starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone), disintegrant (eg, carboxymethylcellulose, starch, low-substituted hydroxypropylcellulose) ), Surfactants [eg, Tween80 (Kao-Atlas), Pluronic F6
8 (Asahi Denka, Japan), polyoxyethylene-polyoxypropylene copolymer], antioxidants (eg, L-cysteine, sodium sulfite, sodium ascorbate),
It is prepared by employing a lubricant (eg, magnesium stearate, talc), and the like. When formulated into a solution for injection, this solution is prepared by a conventional method using a solvent such as an aqueous solvent (eg, distilled water, physiological saline, Ringer's solution) or an oily solvent (eg, sesame oil, olive oil). . Further, one or more additives can be used, if desired. Such additives include solubilizers (eg, sodium salicylate, sodium acetate), buffers (eg, sodium citrate, glycerin), tonicity agents (eg, glucose, invert sugar), stabilizers (eg, Eg, human serum albumin, polyethylene glycol), preservative (eg, benzyl alcohol,
Phenol) or analgesics (eg, benzalkonium chloride, procaine hydrochloride). When prepared into a solid preparation for injection, the preparation may be, for example, a diluent (eg, distilled water, saline, glucose), an activator (eg, carboxymethylcellulose, sodium alginate), a preservative (eg, , Benzyl alcohol, phenol) or painkillers (eg, benzalkonium chloride,
Procaine hydrochloride) can be produced by a conventional method.

When the acid secretion inhibitor is a proton pump inhibitor, the same method as described above can be used in principle, but the method described in JP-A-63-301816 can be used to further reduce the degree of substitution with this agent. Nucleated granules coated with a powdered dusting agent mixed with hydroxypropylcellulose or the method described in JP-A-3-163018, that is, a stabilizer comprising a basic inorganic salt of magnesium and / or calcium. It can preferably be administered as a stabilized solid composition. The compound represented by the general formula (I) or a salt thereof and / or an antibiotic is prepared into a gastric mucosa-adhesive preparation according to the method described in, for example, JP-A-5-132416, JP-A-7-126189, and the like. You can also.

The composition for oral administration in the anti-Helicobacter agent of the present invention, the pharmaceutical composition and the medicament for the anti-Helicobacter bacterium may be, for example, a tablet in the same manner as in the above-mentioned anti-Helicobacter bacterium. Pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. 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. Compositions for parenteral administration include, for example, suppositories,
An external preparation or the like can be used. As a suppository, for example,
Rectal suppositories, vaginal suppositories, and the like, and examples of the external preparation include ointments (including creams), 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 compound represented by the general formula (I) or a salt thereof, an antibiotic, an antacid and / or an acid in the anti-Helicobacter bacterium agent, the pharmaceutical composition and the medicament for the anti-Helicobacter bacterium of the present invention. The content of the secretion inhibitor 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, it is about 2 to 10% by weight. The antibiotic is about 1 to 95% by weight, preferably about 5 to 90% by weight, depending on the kind of the antibiotic. The antacid is about 20 to 90% by weight, preferably about 30 to 80% by weight.
About 50 to 70% by weight, and the acid secretion inhibitor is about 0.3 to 15% by weight, preferably about 1 to 10% by weight, more preferably about 2 to 10% by weight.
It is about 5% by weight. With respect to the antacid and the acid secretion inhibitor, the compound represented by the general formula (I) or a salt thereof to be used varies depending on the individual combination. 0.01-0.5
Times (weight ratio), preferably about 0.1 to 0.3 times (weight ratio), and when combined with an acid secretion inhibitor, about 3 to 70 times (weight ratio) the acid secretion inhibitor, preferably , About 7 ~
30 times (weight ratio). For the antibiotic, the compound represented by the general formula (I) or a salt thereof to be used varies depending on the kind of the antibiotic.
It is 0 times (weight ratio), preferably about 0.1 to 5 times (weight ratio). In the anti-Helicobacter agent and the anti-Helicobacter drug of the present invention, the compound represented by the general formula (I) or a salt thereof, an antibiotic, an antacid or an acid secretion inhibitor are separately formulated. Can be simultaneously administered to the same subject. 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 administration frequency of the acid secretion inhibitor is preferably 1 to 2 times / day, more preferably,
Once / day, and the number of times of administration of the compound represented by the general formula (I) or a salt thereof is preferably 1 to 5 times / day, more preferably 1 to 3 times / day. The number of administrations of the antacid is preferably 1 to 5 times / day, more preferably
1-3 times / day. The administration frequency of the antibiotic is preferably 1 to 6 times / day, more preferably 1 to 4 times / day.

When the medicament 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 where acid secretion is suppressed by administration of an acid secretion inhibitor (usually, an acid secretion inhibitor is administered orally). Or about 30-60 minutes after parenteral administration)
It is preferred to administer 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 dosage of the anti-Helicobacter agent, the pharmaceutical composition and the anti-Helicobacter drug 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 compound thereof Salt is used in adult patients with gastric or duodenal ulcers (50k
g) about 0.1 to 10 g / day for oral administration per day
Days, preferably about 0.2 to 2 g / day, for parenteral administration, about 0.01 to 1 g / day, preferably about 0.02 to 0.2 g / day.
5 g / day, antibiotics for adult patients (50 kg) 1
Per day, about 0.1 to 10 g / day, preferably about 0.2 to 2 g / day for oral administration, and about 0.01 to 1 g / day, preferably about 0.02-g for parenteral administration. 0.5g
Antacid is administered in an amount of about 1 to 30 g / day, preferably about 2 to 5 g / day in the case of oral administration per adult patient (50 kg) per day. Approximately 10 to 2 for oral administration per patient (50 kg) per day
00 mg / day, preferably about 30-60 mg / day, for parenteral administration about 10-200 mg / day, preferably about 30-60 mg / day. Each 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.
Day.

As described above, the anti-Helicobacter agent, the pharmaceutical composition and the anti-Helicobacter drug of the present invention can be used in various digestive systems caused by bacteria having a toxic effect in the digestive tract, in particular, Helicobacter pylori. Diseases (eg,
Gastritis, duodenal ulcer, gastric ulcer, chronic gastritis, etc.). The anti-Helicobacter agent, the pharmaceutical composition and the medicine for the anti-Helicobacter bacterium of the present invention include animals (eg, humans, dogs,
It is applied to the prevention and treatment of ulcers in mammals such as cats, and is particularly effective in the prevention and treatment of peptic ulcers in mammals including humans. Examples of such peptic ulcers include gastric ulcer, duodenal ulcer, reflux esophagitis, rostral ulcer or acute and chronic gastritis.

The anti-Helicobacter agent, the pharmaceutical composition and the drug for the anti-Helicobacter bacterium of the present invention may further contain a mucosal protective anti-ulcer drug or the like. As the mucosal protective anti-ulcer drug, for example, (z) -7-[(1
(R, 2R, 3R) -2-[(E)-(3R) -3-hydroxy-4,4-dimethyl-1-octenyl] -3-methyl-5-oxocyclopentyl] -5-heptenoic acid (trimopro Still, Ulster), 1-butylic 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 (egualene sodium);

Further, the present invention relates to a novel phosphoric amide derivative. Examples of the phosphoric amide derivative include N- (diaminophosphinyl) -5-methyl-3-furancarboxylic acid amide or a salt thereof, and N- (diaminophosphinyl)-
Examples thereof include 3,5-dimethyl-2-furancarboxylic acid amide or a salt thereof, and N- (diaminophosphinyl) -3,5-dimethyl-2-thiophenecarboxylic acid amide or a salt thereof. These novel phosphoric amide derivatives are:
It has an antibacterial action, particularly an anti-Helicobacter action, by the urease inhibitory action, and has the above-mentioned general formula (I) or (Ia)
Or in the same manner as the compound represented by (Ib) or a salt thereof, for use in the prevention or treatment of peptic diseases caused by Helicobacter species such as gastritis, duodenal ulcer, gastric ulcer, chronic gastritis in mammals. it can.

[0062]

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% by weight.

[0063]

【Example】

Reference Example 1 N- (diaminophosphinyl) -4-fluorobenzamide (Flurofamide) 4-fluorobenzamide (5 g) was added to chloroform (5
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.

Reference Example 2 N- (diaminophosphinyl) -3-pyridinecarboxylic acid amide 3-pyridinecarboxylic acid amide (5 g) was suspended in chloroform (55 ml), and a small amount of phosphorus pentachloride (8.5 g) was added. Added one by one. 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.

Reference Example 3 N- (Diaminophosphinyl) -4-nitrobenzamide 4-Nitrobenzamide (25.4 g) was suspended in carbon tetrachloride (150 ml), and phosphorus pentachloride (32.9 g) was used.
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: C ₇ H ₉ N ₄ O ₄ P Theoretical: C, 34.44; H, 3.72; N, 22.95. Found: C, 34.33; H, 3.81; N, 22.63.

Reference Example 4 N- (Diaminophosphinyl) -cinnamamide Cinnamamide (10 g) was suspended in toluene (50 ml), and phosphorus pentachloride (15.6 g) was added little by little.
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]

Reference Example 37 N- (diaminophosphinyl) -3-phenylpropionamide 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]

Reference Example 45 4-Nitrophenoxyacetamide A mixture of 4-nitrophenol (7.5 g), iodoacetamide (10 g), potassium carbonate (7.5 g), and dimethylformamide (50 ml) was stirred at 50 ° C. for 15 hours. did. The reaction solution was poured into ice water and extracted with ethyl acetate.
Washed sequentially 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-thiophenecarboxylic 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). 222-223 ° C.

2) The compound of Reference Example 98 was synthesized by the following method. 5-chloro-3-thiophenecarboxylic 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) 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 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-thiophene carboxylic acids (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 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) The compound of Reference Example 101 was synthesized by the following method. 5-Chloro-2-methyl-3-thiophenecarboxylic acid amide 2-methyl-3- synthesized in the same manner as in Reference Example 127
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) and oxalyl chloride (4.6) was added.
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 converted to 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.

Reference Example 121 4-Bromo-2-thiophenecarboxylic acid Silver nitrate (1.7 g) was dissolved in water (40 ml), and an aqueous solution (1 ml) of sodium hydroxide (0.44 g) was added. 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.

Reference Example 122 1,3-Dimethyl-2- (2-thienyl) imidazolidine 5-ethyl-2-thiophenecarboxylate (5.46 g) [[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-thiophenecarbaldehyde (1.68
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.

Reference Example 123 5-Nitro-2-thiophenecarboxylic acid 5-nitro-2-thiophenecarbaldehyde (7.8
6 g) was dissolved in acetonitrile (50 ml) and an aqueous solution of sodium dihydrogen phosphate (1.6 g) (20 m
l), 30% aqueous hydrogen peroxide solution (5.9 ml) was added. Then, an aqueous solution (70 ml) of sodium chlorite (8.0 g) was added dropwise under ice cooling. 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. 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. 5-nitro-2-
Crystals of thiophene carboxylic acid (7.83 g) were obtained. 158-159 ° C.

Reference Example 124 5-Bromo-3-thiophenecarboxylic acid A mixture of 3-thiophenecarboxylic acid (12.81 g), pyridinium perbromide (35.54 g) and acetic acid (50 ml) was treated at 45 ° C. for 48 hours. Stirred 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 methyl 5-formyl-2-thiophenecarboxylate (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 thiophene carboxylic acid (2.13 g) were obtained.
111-112 ° C.

Reference Example 126 3-Chloro-2-thiophenecarboxylic acid was synthesized by the method described in Heterocycles, 23, 1431 (1985).

Reference Example 127 2-Methyl-3-thiophenecarboxylic acid 3-thiophenecarboxylic acid (3.84 g) was dissolved in tetrahydrofuran (50 ml) and cooled to -78 ° C.
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.

Reference Example 128 3-Bromo-2-thiophenecarboxylic acid methyl 3-amino-2-thiophenecarboxylate (9.4 g) was suspended in hydrobromic acid (20 ml) and stirred at room temperature for 30 minutes. . 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
-Methyl thiophenecarboxylate (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. 200-201 ° C.

Reference Example 129 2-Methyl-2- (2-thienyl) -1,3-dioxolane 5-acetyl-2-thiophenecarboxylate (6.6 g) [[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) and dissolved in 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 thus obtained 1,3-dimethyl-2- (3-thienyl) imidazolidine (9.06 g) was dissolved in tetrahydrofuran (100 ml) and N, N, N ', N'-tetramethylethylenediamine ( 7.85 ml) and add -78
Cooled to ° C. 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.
84 g) in methylene chloride (10 ml) was dissolved in diethylaminosulfur trifluoride (DAST) (1.45 ml).
Was slowly added dropwise at room temperature to a methylene chloride (10 ml) solution. After completion of the dropwise addition, 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 give N, N, N ', N'-tetramethylethylenediamine (10 ml). ) To add -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). This mixture was dissolved in N, N-dimethylformamide (30 ml) and ethyl iodide (0.95) was dissolved.
ml) and potassium carbonate (1.66 g). 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 completion of the dropwise addition, 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.

Reference Example 133 5-Nitro-3-thiophenecarboxylic acid 3-thiophenecarboxylic acid (5.12 g) was converted to nitric acid (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.

Reference Example 134 5-Methoxy-2-thiophenecarboxylic acid 2-methoxythiophene (4.0 ml) was dissolved in tetrahydrofuran (50 ml) and cooled to -78 ° C. 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.

Reference Example 135 3-cyano-2-thiophenecarboxylic 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 give 3-
Aldoxime-2-thiophenecarboxylic acid benzyl ester (2.61 g) was obtained. Acetic anhydride (20m
1) and stirred at 160 ° C. for 10 hours. After cooling, the reaction solution was 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-cyano-2-
Thiophenecarboxylic acid benzyl ester (2.01 g)
I got 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 20
4-205 ° C.

Reference Example 136 4-Methoxy-2-thiophenecarboxylic acid 3-methoxythiophene (4.0 ml) was dissolved in tetrahydrofuran (50 ml) and cooled to -78 ° C. 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-thiophenecarboxylic 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 (5.2).
5 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, and the residue was subjected to silica gel column chromatography. The effective fraction was concentrated under reduced pressure to obtain 4
-Methoxy-2-thiophenecarboxylic acid ethyl ester (2.69 g) and 3-methoxy-2-thiophenecarboxylic acid ethyl ester (3.98 g) were obtained. 4-methoxy-2-thiophenecarboxylic acid ethyl ester (2.6
9 g) was dissolved in a mixed solvent of ethanol (25 ml) and tetrahydrofuran (25 ml), and a 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 1
72-173 ° C.

Reference Example 137 Ethyl 2,5-dichloro-3-thiophenecarboxylate 3-thiophenecarboxylate (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.

Reference Example 138 2-Bromo-3-thiophenecarboxylic 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,
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 g) was added.
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.

Reference Example 139 3-Ethyl-2-thiophenecarboxylic acid 3-acetylthiophene (20 g), ethylene glycol (10.54 g), p-toluenesulfonic acid (0.15 g)
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. 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.

Reference Example 140 4-Methyl-2-thiophenecarboxylic acid 5-Bromo-4-methyl-2-thiophenecarboxylic acid (3.33 g) was added to N, N-dimethylformamide (50
ml), potassium carbonate (4.0 g) and methyl iodide (4.0 ml) were 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. It was concentrated under reduced pressure to obtain 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (3.47 g). This methyl 5-bromo-4-methyl-2-thiophenecarboxylate (2.36 g), zinc dust (1.65 g), acetic acid (10
ml) and water (10 ml) were stirred for 3 hours while heating under reflux. 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. 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 A solution of 2-bromo-3-methylthiophene (8.85 g) and dichloromethyl methyl ether (6.27 g) in a dichloromethane (100 ml) solution was chlorided. 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
Acidified with hydrochloric acid. 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 completion of the dropwise addition, 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 Phosphorus oxychloride (10 ml) was slowly added dropwise to 2,5-dimethyl-3-thiophenecarboxylic acid 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), and 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 obtain ethyl 5-methyl-2-thiophenecarboxylate (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 in the same manner as in 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.

Reference Example 147 4-bromo-3-thiophenecarboxylic 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) and dissolved in 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.

Reference Example 148 3-Methylthiophene 2-chloro-3-thiophenecarboxylate (19.63 g) was dissolved in acetonitrile (100 ml) to give 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
Manganese dioxide (9.66 g). 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). 2
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.

Reference Example 149 2-Methyl-3-furancarboxylic acid ethyl 2-methyl-3-furancarboxylate (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.

Reference Example 150 5-Bromo-3-furancarboxylic acid was synthesized according to the method described in J. Org. Chem., 41, 2350 (1976).

Reference Example 151 5-chloro-2-furancarboxylic acid ethyl 5-chloro-2-furancarboxylate (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).

Reference Example 152 5-Methyl-2-furancarboxylic acid synthesized according to the method described in [JCSPerkin 1, 1125 (1981)].

Reference Example 153 5-ethyl-2-furancarboxylic acid 2-ethylfuran (9.1 g) was dissolved in diethyl ether, cooled to -70 ° C under a nitrogen stream, and cooled with n-butyllithium (1.6M hexane). 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.
Stirred for 0 minutes. Slowly raise the temperature to room temperature.
Stirred 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.

Reference Example 154 2-Chloro-3-furancarboxylic 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. 2
Crystals of -chloro-3-furancarboxylic acid (2.2 g) were obtained. 138-141 ° C.

Reference Example 155 5-Chloro-3-furancarboxylic 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 ethyl 5-trimethylsilyl-3-furancarboxylate (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 the addition, 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) were obtained. Ethyl 5-difluoromethyl-2-furancarboxylate thus synthesized (2.3 g)
Was dissolved in ethanol (20 ml), and a 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.

Reference Example 157 Synthesized according to the method described in 5-Methyl-2-trifluoromethyl-3-furancarboxylic 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) [Method described in [JACS, 59, 2525 (1937)] Was synthesized in ethanol (100 ml), and a 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 ethyl 2-methyl-3-furancarboxylate (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.

Reference Example 160 2-ethyl-3-furancarboxylic acid [JCSPerkin 1, 1125 (1981)].

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 amide 2,5-dichloro-4-methyl-3-thiophenecarboxylic acid amide 4-methyl-3- synthesized by the same method as in Reference Example 171
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 added dropwise. N, N-dimethylformamide (1 drop) was added and 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.

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

Reference Example 171 Synthesized by the method described in 4-Methyl-3-thiophenecarboxylic acid [J. Org. Chem., 51, 230 (1986)].

Reference Example 172 5-bromo-2-chloro-3-thiophenecarboxylic acid 2-chloro-3-thiophenecarboxylic acid (2.44
g), a mixture of pyridinium perbromide 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 heated to -78 ° C. Cool. 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-chloro-5-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.

Reference Example 175 Synthesized by the method described in 3-Methyl-2-furancarboxylic acid [Org. Synth., IV, 628].

Reference Example 176 5-methyl-2-thiophenecarboxylic amide 2.6 g of 5-methyl-2-thiophenecarbaldehyde
(0.1 mol), 8.3 g of hydroxyamine hydrochloride (0.
12 mol), 9.8 g (0.12 mol) of sodium acetate
Was added to 50 ml of acetic acid and reacted under reflux for 13 to 15 hours. After confirming the disappearance of the raw material (retention time of about 13 minutes) by liquid chromatography (HPLC), the mixture was concentrated under reduced pressure to about half the volume, 100 ml of concentrated hydrochloric acid was added to the concentrated solution, and the mixture was heated at 60 ° C for 4 hours.
Reacted for hours. After completion of the reaction, 100 ml of water was added, and the mixture was stirred for 30 minutes under ice cooling. The precipitated crystals were collected by filtration and washed with 100 ml of ice water to obtain 11.6 g (82%) of 5-methyl-2-thiophenecarboxylic acid amide (retention time by HPLC: about 4 minutes). HPLC analysis conditions Column: Inertsil ODS-3 manufactured by GL Sciences, 5 μm,
4.6 × 150 mm Eluent: acetonitrile: 0.05 molar aqueous solution of potassium dihydrogen phosphate = 30: 70 Detection wavelength: 231 nm Flow rate: 1.0 ml / min ¹ H-NMR (DMSO-d ₆ ) δ: 2.54 (3H, d, CH ₃ ), 7.01 (1H, d
d, Thiophene-4-H), 7.78 (1H, dd, Thiophene-3-H).

Reference Examples 177 to 182 The following compounds were synthesized in the same manner as in Reference Example 60. [Table 6]----------------------------------Reference examples Compounds Melting point ([deg.] C) No.--- ----------------------------------------------------- 177 5-Methyl-3-furancarboxylic acid amide 123-124 178 3-methyl 2-furancarboxylic amide 66-68 179 3,5-dimethyl-2-furancarboxylic amide 141-142 180 5-methyl-3-thiophenecarboxylic amide 123-124 181 3,5-dimethyl-2-thiophene Carboxamides 114-116 182 2-Ethyl-3-thiophenecarboxamides 116-117 ------------------------------------------ −−−−−−

Example 1 N- (diaminophosphinyl) -2-thiophenecarboxylic acid amide 2-thiophenecarboxylic acid amide (3.82 g) was suspended in toluene (25 ml), and phosphorus pentachloride (6.25 g) was added.
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 added dropwise. 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).

Example 2 N- (diaminophosphinyl) -3-thiophenecarboxylic acid amide 3-thiophenecarboxylic acid amide (3.18 g) was suspended in toluene (25 ml), and phosphorus pentachloride (5.21) was used.
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 added dropwise. 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).

Example 3 N- (diaminophosphinyl) -5-methyl-2-thiophenecarboxylic 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).

Example 4 N- (diaminophosphinyl) -3-methyl-2-thiophenecarboxylic 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.

Example 5 N- (Diaminophosphinyl) -5-chloro-2-thiophenecarboxylic acid amide Melting point: 273-279 ° C. Elemental analysis: As C ₅ H ₇ N ₃ O ₂ SClP Theoretical: C, 25.06; . H, 2.94; N, 17.54 Found:. 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).

Example 6 N- (Diaminophosphinyl) -5-bromo-2-thiophenecarboxylic acid amide Melting point: 238-244 ° C. Elemental analysis: As C ₅ H ₇ N ₃ O ₂ SBrP Theoretical: 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).

Example 8 N- (Diaminophosphinyl) -4-bromo-2-thiophenecarboxylic acid amide Melting point: 263-268 ° C. Elemental analysis: As C ₅ H ₇ N ₃ O ₂ SBrP Theoretical: C, 21.14; . H, 2.48; N, 14.79 Found:. 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).

Example 9 N- (diaminophosphinyl) -5-ethyl-2-thiophenecarboxylic 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 Found:. 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).

Example 10 N- (Diaminophosphinyl) -5-nitro-2-thiophenecarboxylic acid amide Melting point: 183-187 ° C. Elemental analysis: As C ₅ H ₇ N ₄ O ₄ SP Theoretical: C, 24.01; . H, 2.82; N, 22.40 Found:. 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).

Example 11 N- (Diaminophosphinyl) -5-bromo-3-thiophenecarboxylic acid amide Melting point: 193-196 ° C. Elemental analysis: as C ₅ H ₇ N ₃ O ₂ SBrP Theoretical: 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 = 1.6H)
z), 8.40 (1H, d, J = 1.6 Hz),
9.28 (1H, d, J = 6.8 Hz).

Example 12 N- (Diaminophosphinyl) -5-cyano-2-thiophenecarboxylic acid amide Melting point: 200-205 ° C. (decomposition) Elemental analysis: C ₆ H ₇ N ₄ O ₂ SP Theoretical: C , 31.31; H, 3.07; N , 24.34 Found:.. C, 31.42; H , 3.03; N, 24.17 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 = 7.0
Hz).

Example 13 N- (Diaminophosphinyl) -5-difluoromethyl-2-thiophenecarboxylic acid amide Melting point 165-169 ° C. Elemental analysis value As C ₆ H ₈ N ₃ O ₂ SF ₂ P Theoretical value: C , 28.24; H, 3.16; N , 16.47 Found:.. 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).

Example 14 N- (Diaminophosphinyl) -3-chloro-2-thiophenecarboxylic acid amide Melting point: 154 to 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 Found:. 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 = 5.3H)
z), 7.93 (1H, d, J = 5.3 Hz),
8.45 (1H, d, J = 6.0 Hz).

Example 15 N- (Diaminophosphinyl) -2-methyl-3-thiophenecarboxylic acid amide Melting point 155-157 ° C. Elemental analysis value Theory as C ₆ H ₁₀ N ₃ O ₂ SP · 1 / 5H ₂ O values:. C, 32.34; H, 4.63; N, 19.13 Found:. 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).

Example 16 N- (Diaminophosphinyl) -3-bromo-2-thiophenecarboxylic acid amide Melting point 160-167 ° C. Elemental analysis value as C ₅ H ₇ N ₃ O ₂ SBrP Theoretical value: C, 21.14; . H, 2.48; N, 14.79 Found:. 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-thiophenecarboxylic acid amide Melting point: 185 ° C. (decomposition) Elemental analysis: C ₇ H ₁₀ N ₃ O ₃ SP Theoretical: C, 34.01 ; H, 4.08; N, 17.00 Found:.. C, 34.34; H , 4.12; N, 17.03 1 H-NMR (DMSO-d 6) δ: 2.56 (3H, s),
4.28 (4H, brs), 7.92 (1
H, d, J = 4.0 Hz), 8.12 (1H,
d, J = 4.0 Hz), 9.68 (1H, br)
m).

Example 18 N- (Diaminophosphinyl) -5-methanesulfonyl-2-thiophenecarboxylic acid amide Melting point: 180-185 ° C. (decomposition) Elemental analysis: C ₆ H ₁₀ N ₃ O ₄ S ₂ P Theory values:. C, 25.44; H, 3.56; N, 14.83 Found:. 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).

Example 19 N- (diaminophosphinyl) -3-difluoromethyl-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 Found:.. 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).

Example 20 N- (Diaminophosphinyl) -2-difluoromethyl-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 Found:.. 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).

Example 21 N- (Diaminophosphinyl) -5-nitro-3-thiophenecarboxylic acid amide Melting point 181-184 ° C. Elemental analysis value as C ₅ H ₇ N ₄ O ₄ SP Theoretical value: C, 24.01; . H, 2.82; N, 22.40 Found:. 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-thiophenecarboxylic 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:. 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).

Example 23 N- (Diaminophosphinyl) -3-cyano-2-thiophenecarboxylic 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 Found:. 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 = 5.2H)
z), 7.98 (1H, d, J = 5.2 Hz),
9.49 (1H, brs).

Example 24 N- (Diaminophosphinyl) -4-methoxy-2-thiophenecarboxylic 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 Found:. 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 mp 168-172 ° C. Elemental analysis _{C 5 H 6 N 3 O 2} SCl 2 P theoretically:. C, 21.91; H, 2.21; N, 15.33 Found: 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).

Example 26 N- (Diaminophosphinyl) -2-bromo-3-thiophenecarboxamide Melting point: 160-162 ° C. Elemental analysis: as C ₅ H ₇ N ₃ O ₂ SBrP Theoretical: 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 = 5.0H)
z), 7.60 (1H, d, J = 5.0 Hz),
9.11 (1H, m).

Example 27 N- (Diaminophosphinyl) -3-ethyl-2-thiophenecarboxamide Melting point: 130-135 ° C. Elemental analysis: as C ₇ H ₁₂ N ₃ O ₂ SP Theoretical: C, 36.05; . H, 5.19; N, 18.02 Found:. 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).

Example 28 N- (Diaminophosphinyl) -4-methyl-2-thiophenecarboxylic acid amide Melting point 160-163 ° C. Elemental analysis value as C ₆ H ₁₀ N ₃ O ₂ SP Theoretical value: C, 32.88; . H, 4.60; N, 19.17 Found:. 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).

Example 29 N- (Diaminophosphinyl) -5-bromo-4-methyl-2-thiophenecarboxylic acid amide Melting point 170-175 ° C. Elemental analysis value As C ₆ H ₉ N ₃ O ₂ SBrP Theoretical value: . C, 24.18; H, 3.04 ; N, 14.10 Found:. C, 24.39; H, 3.13; N, 14.22 1 H-NMR (DMSO-d 6) δ: 2.14 (3H, s),
4.19 (4H, brs), 7.89 (1
H, s), 9.44 (1H, brm).

Example 30 N- (diaminophosphinyl) -5-chloro-3-thiophenecarboxylic acid amide Melting point: 177-184 ° C. Elemental analysis: as C ₅ H ₇ N ₃ O ₂ SCLP Theoretical: C, 25.06; . H, 2.94; N, 17.54 Found:. 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
= 1.0Hz), 8.31 (1H, d, J = 1.0Hz), 9.30 (1H, d, J = 6.8H
z).

Example 31 N- (Diaminophosphinyl) -5-difluoromethyl-3-thiophenecarboxylic acid amide Melting point: 149-153 ° 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 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
- 159-162 ° C. Elemental analysis thiophenecarboxylic acid amide mp _{C 7 H 12 N 3 O 2} SP theoretically:. C, 36.05; H, 5.19; N, 18.02 Found: C, 35.90; H, 5.04 ; N , 17.75. ¹ H-NMR (DMSO-d ₆ ) δ: 2.34 (3H, s),
2.57 (3H, s), 4.08 (4H, b
rs), 7.19 (1H, s), 8.76
(1H, brd, J = 7.0 Hz).

Example 33 N- (Diaminophosphinyl) -5-chloro-2-methyl-3-thiophenecarboxylic acid amide Melting point: 218-225 ° C. Elemental analysis: As C ₆ H ₉ N ₃ O ₂ SCLP Theoretical value: . C, 28.41; H, 3.58 ; N, 16.57 Found:. 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).

Example 34 N- (Diaminophosphinyl) -4-chloro-5-methyl-2-thiophenecarboxylic acid amide Melting point 225-233 ° C. Elemental analysis value As C ₆ H ₉ N ₃ O ₂ SClP Theoretical value: . C, 28.41; H, 3.58 ; N, 16.57 Found:. 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).

Example 35 N- (Diaminophosphinyl) -5-chloro-4-methyl-2-thiophenecarboxylic acid amide Melting point: 182-184 ° C. Elemental analysis: As C ₆ H ₉ N ₃ O ₂ SClP Theoretical value: . C, 28.41; H, 3.58 ; N, 16.57 Found:. 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 mp 276-278 ° C. Elemental analysis _{C 5 H 6 N 3 O 2} SCl 2 P theoretically:. C, 21.91; H, 2.21; N, 15.33 Found: 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).

Example 37 N- (Diaminophosphinyl) -4-bromo-3-thiophenecarboxylic acid amide Melting point: 149-153 ° C. Elemental analysis: as C ₅ H ₇ N ₃ O ₂ SBrP Theoretical: C, 21.14; . H, 2.48; N, 14.79 Found:. 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-thiophenecarboxylic acid amide Melting point 153-155 ° C. Elemental analysis value C ₅ H ₇ N ₃ O ₂ SClP · 1 / 4H ₂ O Theory values:. C, 24.60; H, 3.10; N, 17.21 Found:. 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).

Example 39 N- (diaminophosphinyl) -5-bromo-2-furancarboxylic 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).

Example 40 N- (diaminophosphinyl) -2-methyl-3-furancarboxylic 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 the mixture was 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).

Example 41 N- (diaminophosphinyl) -5-bromo-3-furancarboxylic 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.

Example 42 N- (Diaminophosphinyl) -5-chloro-2-furancarboxylic acid amide Melting point: 242 ° -244 ° C. Elemental analysis: As C ₅ H ₇ N ₃ O ₃ ClP Theoretical: 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).

Example 43 N- (Diaminophosphinyl) -5-methyl-2-furancarboxylic acid amide Melting point 281-285 ° C. (decomposition) Elemental analysis value As C ₆ H ₁₀ N ₃ O ₃ P Theoretical value: C , 35.48; H, 4.96; N , 20.69 Found:.. 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).

Example 44 N- (Diaminophosphinyl) -5-ethyl-2-furancarboxylic acid amide Melting point: 151-153 ° C. Elemental analysis value: C ₇ H ₁₂ N ₃ O ₃ P · 1 / 4H ₂ O Theory values:. C, 37.93; H, 5.68; N, 18.96 Found:. C, 37.96; H, 5.56; N, 18.77 1 H-NMR (DMSO-d 6) δ: 1.20 (3H, t, J = 7.6 Hz), 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).

Example 45 N- (Diaminophosphinyl) -2-chloro-3-furancarboxylic acid amide Melting point 153-155 ° C. Elemental analysis value as C ₅ H ₇ N ₃ O ₃ ClP Theoretical value: C, 26.86; . H, 3.16; N, 18.80 Found:. 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).

Example 46 N- (Diaminophosphinyl) -5-chloro-3-furancarboxylic acid amide Melting point 170-171 ° C. Elemental analysis value as C ₅ H ₇ N ₃ O ₃ ClP Theoretical value: 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).

Example 47 N- (Diaminophosphinyl) -5-difluoromethyl-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 Found:.. 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).

Example 48 N- (Diaminophosphinyl) -2-trifluoromethyl-5-methyl-3-furancarboxylic acid amide Melting point: 158-160 ° C. Elemental analysis: C ₇ H ₉ N ₃ O ₃ F ₃ P theory as:. C, 31.01; H, 3.35; N, 15.50 Found:. C, 31.28; H, 3.40; N, 15.62 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-3
- furancarboxylic acid amide mp 167-169 ° C. Elemental analysis _{C 7 H 12 N 3 O 3} P theoretically:. C, 38.72; H, 5.57; N, 19.35 Found: 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).

Example 50 N- (Diaminophosphinyl) -5-chloro-2-methyl-3-furancarboxylic acid amide Melting point: 270-275 ° C. (decomposition) Elemental analysis: As C ₆ H ₉ N ₃ O ₃ ClP theory:. 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).

Example 51 N- (Diaminophosphinyl) -2-ethyl-3-furancarboxylic acid amide Melting point: 277-280 ° C. (decomposition) Elemental analysis: As C ₇ H ₁₂ N ₃ O ₃ P Theoretical value: C , 38.72; H, 5.57; N , 19.35 Found:.. 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).

Example 52 N- (Diaminophosphinyl) -4-nitrophenoxyacetamide 4-Nitrophenoxyacetamide (3.5 g) was suspended in toluene (30 ml), and phosphorus pentachloride (3.9 g) was added.
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.

Example 53 N- (Diaminophosphinyl) -4-methoxyphenoxyacetamide Melting point: 154 to 156 ° C. Elemental analysis value: C ₉ H ₁₄ N ₃ O ₄ P Theoretical value: 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).

Example 54 N- (Diaminophosphinyl) -4-fluorophenoxyacetamide 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 Found:.. 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).

Example 55 N- (Diaminophosphinyl) -4-chlorophenoxyacetamide Melting point: 155-157 ° C. Elemental analysis: as C ₈ H ₁₁ N ₃ O ₃ ClP Theoretical: C, 36.45; H, 4.21; N , 15.94. Found: 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-trimethylphenoxyacetamide Melting point 171-173 ° C. Elemental analysis value C ₁₁ H ₁₈ N ₃ O ₃ P Theoretical value: C, 48.71 H, 6.69; N, 1
5.49. Found: C, 48.54; H, 6.63; N, 1
5.12. ¹ H-NMR (DMSO-d ₆ ) δ: 2.07 (3H, s), 2.
17 (3H, s), 2.21 (3H, s), 4.19 (4H, s), 4.53 (2H,
s), 6.48 (1H, s), 6.60 (1H, s), 8.69 (1H, d, J = 8.2
Hz).

Example 57 N- (Diaminophosphinyl) -4-cyanophenoxyacetamide Melting point 173-178 ° C. Elemental analysis value as C ₉ H ₁₁ N ₄ O ₃ P Theoretical value: C, 42.53; H, 4.36; N , 22.04 Found:.. C, 42.76; H , 4.38; N, 21.97 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).

Example 58 N- (Diaminophosphinyl) -3-chlorophenoxyacetamide Melting point: 143 ° -148 ° C. Elemental analysis: C ₈ H ₁₁ N ₃ O ₃ ClP Theoretical: 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, br 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).

Example 59 N- (Diaminophosphinyl) -2-chlorophenoxyacetamide Melting point: 141-148 ° C. Elemental analysis value: C ₈ H ₁₁ N ₃ O ₃ ClP · 1 / 4H ₂ O Theoretical value: 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).

Example 60 N- (Diaminophosphinyl) -3-fluorophenoxyacetamide 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:.. 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).

Example 61 N- (Diaminophosphinyl) phenylthioacetamide Melting point: 156-162 ° C. Elemental analysis: C ₈ H ₁₂ N ₃ O ₂ SP Theoretical: 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).

Example 62 N- (Diaminophosphinyl) -4-fluorophenylthioacetamide Melting point: 155 to 160 ° C. Elemental analysis: As C ₈ H ₁₁ N ₃ O ₂ SFP Theoretical: C, 36.50; H, 4.21; . N, 15.96 Found:. C, 36.42; H, 3.96; N, 15.98 1 H-NMR (DMSO-d 6) δ: 3.71 (2H, s),
4.12 (4H, brs), 7.15 (1
H, d, J = 8.8 Hz), 7.19 (1H,
d, J = 9.0 Hz), 7.42 (1H, d
d, J = 9.0 Hz and 5.4 Hz), 7.
44 (1H, dd, J = 8.8 Hz and 5.
2 Hz), 9.11 (1H, brs).

Example 63 N- (Diaminophosphinyl) -2-benzoxazolylthioacetamide Melting point: 160-164 ° C. Elemental analysis: C ₉ H ₁₁ N ₄ O ₃ SP Theoretical: 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 (2H, m), 9.34 (1H, br
s).

Example 64 N- (Diaminophosphinyl) -2-benzothiazolylthioacetamide Melting point: 166-170 ° C. Elemental analysis: C ₉ H ₁₁ N ₄ O ₂ S ₂ P Theoretical: 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).

Example 65 N- (Diaminophosphinyl) -5-chloro-2-benzothiazolylthioacetamide Melting point 165-171 ° C. Elemental analysis value: C ₉ H ₁₀ N ₄ O ₂ S ₂ ClP Theoretical value: 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 (1
H, dd, J = 8.6 Hz and 2.0 Hz),
7.94 (1H, d, J = 2.0 Hz),
8.07 (1H, d, J = 8.6 Hz);
38 (1H, brs).

Example 66 N- (Diaminophosphinyl) -5-ethoxy-2-benzothiazolylthioacetamide Melting point 169-174 ° C. Elemental analysis value As C ₁₁ H ₁₅ N ₄ O ₃ S ₂ P.H ₂ O theory:. 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 = 7.0 Hz), 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).

Example 67 N- (Diaminophosphinyl) -2-benzofurancarboxylic acid amide Melting point 172-174 ° C. Elemental analysis value C ₉ H ₁₀ N ₃ O ₃ P Theoretical value: 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).

Example 68 N- (Diaminophosphinyl) -2-methyl-5-benzoxazolecarboxylic acid amide Melting point: 250 ° C. (decomposition) Elemental analysis: C ₉ H ₁₁ N ₄ O ₃ P.H ₂ O Theory values:. C, 39.71; H, 4.81; N, 20.58 Found:. 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).

Example 69 N- (diaminophosphinyl) -3- (2-benzoxazolyl) propenoic acid amide Melting point: 180 ° C. (decomposition) Elemental analysis: As C ₁₀ H ₁₁ N ₄ O ₃ P Theoretical value: . C, 45.12; H, 4.17 ; N, 21.05 Found:. 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).

Example 70 N- (diaminophosphinyl) -2-benzothiazolecarboxylic acid amide Melting point: 169-174 ° C. Elemental analysis value: C ₈ H ₉ N ₄ O ₂ SP Theoretical value: 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).

Example 71 N- (Diaminophosphinyl) -3-chloro-6-methyl-2-benzothiophenecarboxylic acid amide Melting point 173-178 ° C. Elemental analysis value C ₁₀ H ₁₁ N ₃ O ₂ SClP · 1 / 5CH ₃ OH Theoretical: C, 39.51; H, 3.71; N, 1
3.55. Found: C, 39.30; H, 3.64; N, 1
3.15. ¹ H-NMR (DMSO-d ₆ ) δ: 2.48 (3H, s), 4.
39 (4H, br s), 7.43 (1H, dd, J = 8.2Hzand 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 mp 210-212 ° C (decomposition) Elemental analysis: as C ₁₀ H ₁₀ N ₄ O ₃ ClP Theoretical: C, 39.95; H, 3.35; N, 18.64. . 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).

Example 73 N- (Diaminophosphinyl) -5-methyl-3-phenyl-4-isoxazolecarboxylic amide Melting point: 230 ° C. (decomposition) Elemental analysis: C ₁₁ H ₁₃ N ₄ O ₃ P · 0.2 H ₂ O theoretically:. C, 46.55; H, 4.76; N, 19.74 Found:. 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).

Example 74 N- (Diaminophosphinyl) -3-chloro-2-benzothiophenecarboxylic acid amide Melting point: 261-271 ° C. Elemental analysis: As C ₉ H ₉ N ₃ O ₂ SClP Theoretical: C, 37.27 ; H, 3.13; N, 14.51 Found:.. C, 36.92; H , 3.18; N, 14.59 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).

Example 75 N- (Diaminophosphinyl) -3-benzoisoxazolylacetamide Melting point 157-164 ° C. Elemental analysis value as C ₉ H ₁₁ N ₄ O ₃ P Theoretical value: 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-methylbenzenesulfonyl) glycinamide Melting point 161-169 ° C. Elemental analysis value C ₉ H ₁₅ N ₄ O ₄ SP · 1 / 10H ₂ O theory as:. C, 35.09; H, 4.97; N, 18.19 Found:. 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)
- 176-184 ° C. Elemental analysis thienyl) propenoic acid amide mp _{C 7 H 9 N 3 O 2} SBrP theoretically:. 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)
173-177 ° C. Elemental analysis propenoic acid amide mp _{C 7 H 10 N 3 O 2} SP theoretically:. C, 36.36; H, 4.36; N, 18.17 Found: 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).

Example 80 N- (Diaminophosphinyl) -2-thienylacetamide Melting point: 179-184 ° C. Elemental analysis value: C ₆ H ₁₀ N ₃ O ₂ SP Theoretical value: 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).

Example 81 N- (Diaminophosphinyl) -3-thienylacetamide 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. Found: 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).

Example 82 N- (Diaminophosphinyl) -3- (2-benzoxazolyl) propionic acid amide N- (Diaminophosphinyl) -3- (2-benzoxazolyl) propenoic acid amide (0.25 g) was dissolved in methanol (30 ml) by heating, and 10% Pd-C (we
t) (0.05 g) was added. Hydrogenated at room temperature and normal 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).

Example 83 N- (Diaminophosphinyl) -1-benzimidazolylacetamide Benzimidazole (10 g), ethyl bromoacetate (15.5 g), potassium carbonate (12.9 g), 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 oil of 1-benzimidazolylacetic 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.

Example 84 N- (Diaminophosphinyl) -4-chloro-2-thiophenecarboxylic acid amide Melting point: 278-280 ° C. Elemental analysis: As C ₅ H ₇ N ₃ O ₂ SClP Theoretical: C, 25.06; . H, 2.94; N, 17.54 Found:. 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).

Example 85 N- (Diaminophosphinyl) -4-methyl-3-thiophenecarboxylic acid amide Melting point 145-147 ° C. Elemental analysis value Theory as C ₆ H ₁₀ N ₃ O ₂ SP · 1 / 4H ₂ O Theory values:. C, 31.94; H, 4.88; N, 18.64 Found:. 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).

Example 86 N- (Diaminophosphinyl) -2-bromo-5-chloro-3-thiophenecarboxylic acid amide Melting point 181-183 ° C. Elemental analysis value As C ₅ H ₆ N ₃ O ₂ SBrClP Theoretical value: . C, 18.95; H, 1.90 ; N, 13.19 Found:. 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).

Example 87 N- (Diaminophosphinyl) -5-chloro-4-methyl-3-thiophenecarboxylic acid amide Melting point 159-161 ° C. Elemental analysis value C ₆ H ₉ N ₃ O ₂ SClP · 1 / 4H theory as _{2 O:. C, 27.91;} H, 3.71; N, 16.28 Found:. 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-thiophenecarboxamide Melting point: 178-180 ° C Elemental analysis: C ₆ H ₈ N ₃ O ₂ SCl ₂ P Theoretical: 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).

Example 89 N- (Diaminophosphinyl) -2-chloro-5-methyl-3-thiophenecarboxylic acid amide Melting point: 180-183 ° C. Elemental analysis: As C ₆ H ₉ N ₃ O ₂ SClP Theoretical value: C, 28.41; H, 3.58; N, 1
6.57. Found: C, 28.34; H, 3.39; N, 1
6.64. 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).

Example 90 N- (Diaminophosphinyl) -3-chloro-4-methyl-2-thiophenecarboxylic acid amide Melting point: 288-291 ° C. Elemental analysis: As C ₆ H ₉ N ₃ O ₂ SClP Theoretical value: . C, 28.41; H, 3.58 ; N, 16.57 Found:. 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
- 160-162 ° C. Elemental analysis thiophenecarboxylic acid amide mp _{C 7 H 12 N 3 O 2} SP theoretically:. C, 36.05; H, 5.19; N, 18.02 Found: 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
-(Diaminophosphinyl) -3-methyl-2-furancarboxylic acid amide Melting point: 157-158 ° C Elemental analysis: as C ₆ H ₁₀ N ₃ O ₃ P · 1 / 4H ₂ O Theoretical: 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).

Example 93 N- (Diaminophosphinyl) -5-methyl-2-thiophenecarboxylic acid amide 7.6 g (47 mmol) of 5-methyl-2-thiophenecarboxylic acid amide obtained in Reference Example 176 was dissolved in toluene. 50m
and 10 ml of phosphorus pentachloride at room temperature with good stirring.
9 g (50 mmol) were added. After stirring at 65 ° C. for 30 minutes, the mixture was cooled on ice and 2.0 ml of formic acid was added dropwise. After stirring at 25 ° C. for 30 minutes, toluene was removed under reduced pressure. The residue was dissolved in 100 ml of tetrahydrofuran (THF),
The mixture was added to 17.1 ml of 25% aqueous ammonia under ice-cooling. 25
After stirring at 30 ° C. for 30 minutes, 100 ml of toluene was added, and the precipitated crystals were collected by filtration. The crystals were taken up in 50 ml of THF and 5 ml of water.
Washed with 0 ml. Vacuum drying afforded 6.78 g (64%) of N- (diaminophosphinyl) -5-methyl-2-thiophenecarboxamide. 285-297 ° C
(Disassembly)

Example 94 N- (diaminophosphinyl) -5-methyl-3-furancarboxylic acid amide 5-methyl-3-furancarboxylic acid amide (0.94
g) was suspended in toluene (10 ml), and phosphorus pentachloride (1.6 g) was added little by little. Heat to 70 ° C for 30
Stirred for minutes. The reaction was cooled to room temperature and formic acid (0.35 g) was added dropwise. After stirring at room temperature for 20 minutes, hexane (30 ml) was added and the mixture was stirred for 15 minutes.
The precipitated crystals were collected by filtration. After washing with hexane, it was air-dried to obtain 1.1 g of crystals. The crystals were dissolved in tetrahydrofuran (50 ml). Add 3 ammonia gas under ice cooling
Introduced for 0 minutes. After the introduction, the mixture was stirred at room temperature for 50 minutes. Ethyl ether (50 ml) was added and stirred for 20 minutes.
The precipitate was separated by filtration and washed with water. The solid obtained by air drying was recrystallized from methanol-ethyl ether. Colorless crystals of N- (diaminophosphinyl) -5-methyl-3-furancarboxylic acid amide (0.39 g) were obtained. Mp 168-170 ° C. Elemental analysis _{C 6 H 10 N 3 O 3} P theoretically: C, 35.48; H, 4.96 ; N, 20.69 Found: C, 35.42; H, 4.90 ; N, 20.42 1 H-NMR (DMSO-d ₆ ) δ: 2.12 (3H, s), 4.12 (4H, br s),
7.48 (1H, s), 8.44 (1H, s), 9.07 (1H, d, J = 7.6Hz).

Examples 95 to 99 The following compounds were synthesized in the same manner as in Example 94.

Example 95 N- (diaminophosphinyl) -3-methyl-2-furancarboxylic acid amide Melting point: 157-158 ° C. Elemental analysis value: C ₆ H ₁₀ N ₃ O ₃ P 1 / 4H ₂ O Theoretical value : C, 35.48; H, 4.96; N, 20.69 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).

Example 96 N- (diaminophosphinyl) -3,5-dimethyl-2
- furancarboxylic acid amide mp 189-191 ° C. Elemental analysis _{C 7 H 12 N 3 O 3} P theoretically: C, 38.72; H, 5.57 ; N, 19.35 Found: C, 38.36; H, 5.31 ; N, 19.24 ¹ H-NMR (DMSO-d ₆ ) δ: 2.24 (2H, s), 2.28 (3H, s), 4.1
5 (4H, br s), 6.17 (1H, s), 8.09 (1H, d, J = 7.8Hz).

Example 97 N- (Diaminophosphinyl) -5-methyl-3-thiophenecarboxylic acid amide Melting point: 178-181 ° C. Elemental analysis value: C ₆ H ₁₀ N ₃ O ₂ SP 1 / 2H ₂ O Theoretical value : C, 32.61; H, 4.65; N, 19.01 Found: C, 32.37; H, 4.66; N, 19.28 ¹ H-NMR (DMSO-d ₆ ) δ: 2.44 (3H, d, J = 1.2 Hz), 4.15 (4
H, br s), 7.26 (1H, s), 8.01 (1H, m), 9.12 (1H, d,
J = 7.4Hz).

Example 98 N- (Diaminophosphinyl) -3,5-dimethyl-2
- 160-162 ° C. Elemental analysis thiophenecarboxylic acid amide mp _{C 7 H 12 N 3 O 2} SP theoretically: C, 36.05; H, 5.91 ; N, 18.02 Found: 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), 8.31 (1H, br s).

Example 99 N- (diaminophosphinyl) -2-ethyl-3-thiophenecarboxylic acid amide Melting point: 154-155 ° C. Elemental analysis value: C ₇ H ₁₂ N ₃ O ₂ SP 2 / 5H ₂ O Theoretical value : C, 34.96; H, 5.31; N, 17.49 Found: C, 35.36; H, 5.17; N, 17.10 ¹ H-NMR (DMSO-d ₆ ) δ: 1.23 (3H, t, J =
7.3 Hz), 3.13 (2H, q, J = 7H)
z), 4.11 (4H, brs), 7.28
(1H, d, J = 5.2 Hz), 7.53 (1
H, d, J = 5.2 Hz), 8.97 (1H,
brs).

Test Example 1 Eradication effect of urease inhibitor (in vivo) Helicobacter pylori (C) was administered to 5 male ICR mice.
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 drug 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. Table 7 shows the results.

[0233]

[Table 7]

Test Example 2 Screening of Urease Inhibitor Urease prepared from 100 μl of 100 mM Bis-Tris buffer (pH 6.5) and 20 μl of a test drug dissolved in 0.1% N, N-dimethylformamide solution and Helicobacter pylori Add 60 μl of the solution, and add
After incubating for 0 minutes, 100 mM urea 20μ
1 was added and reacted at room temperature for 10 minutes. Ammonia produced in the reaction solution was measured using a commercially available measurement kit (Ammonia Test Wako ^™ , 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 Tables 8-1, 8-2 and 8-3.
Shown in

[0235]

[Table 8-1]

[0236]

[Table 8-2]

[0237]

[Table 8-3]

Test Example 3 Five male ICR mice in each group were orally infected with 1 ml of a bacterial solution containing 1 × 10 ⁷ CFU of Helicobacter pylori (CPY 433 F4) and infected. A 0.5% methylcellulose solution or a drug (LPZ: lansoprazole) suspended in the same solution was subcutaneously administered, and 20 minutes later, 1% NaHCO ₃
Or a 0.5% methylcellulose solution or a drug suspended in the same solution was orally administered. Drug administration was performed twice a day for two days. The mouse was sacrificed the day after the final administration, 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. 0.1 ml of a 10-fold serial dilution of gastric homogenate in Brucella medium
Was spread on a modified Brucella agar medium, cultured for 4 days in a microaerobic environment at 37 ° C., and the CFU per stomach was measured.
Table 9 shows the results.

[0239]

[Table 9]

Formulation Examples The anti-Helicobacter agent and the medicament for anti-Helicobacter bacteria of the present invention can be produced, for example, by the following formulation.

[0241] 1. Capsule (1) Compound of Example 3 100 mg (2) Amoxicillin 500 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 680 mg (1), (2), (3) and (4) / 2 after mixing
Granulate. Add the remaining (4) to this and encapsulate the whole in a gelatin capsule.

[0242] 2. Tablets (1) Compound of Example 3 100 mg (2) Amoxicillin 500 mg (3) Microcrystalline cellulose 30 mg (4) Magnesium stearate 5 mg 1 tablet 635 mg 2/3 of (1), (2) and (3) and (4) )), And granulate. The remaining (3) and (4) are added to this and pressed into tablets.

[0243] 3. Capsules (1) Compound of Example 3 100 mg (2) Lansoprazole 10 mg (3) Amoxicillin 500 mg (4) Microcrystalline cellulose 70 mg (5) Magnesium stearate 10 mg 1 capsule 690 mg (1), (2), (3) After mixing 1/2 of (4) and (5), granulate. Add the remaining (5) to this and encapsulate the whole in a gelatin capsule.

[0244] 4. Tablets (1) Compound of Example 3 100 mg (2) Lansoprazole 10 mg (3) Amoxicillin 500 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg One tablet 645 mg (1), (2), (3) and (3) 2/3 of 4) and 1 / of (5)
After mixing 2, granulate. The remaining (4) and (5) are added to the mixture and pressed into tablets.

[0245] 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) Compound of Example 3 100 mg (2) Amoxicillin 500 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 680 mg (1), (2) and (3), and ( After mixing 1/2 of 4), granulate. Add the remaining (4) to this and encapsulate the whole in a gelatin capsule.

[0246] 6. 86.0 g of hexa (tetra) glyceride behenate (Sakamoto Pharmaceutical Co., Ltd., trade name: HB-310) was weighed, and 8 g
Heat and melt at 4 ° C. To this, 4 g of the compound of Example 3 and then 10.0 g of an acrylic acid-based polymer (Wako Pure Chemical Industries, Ltd., trade name: Hibiswako 104) were sequentially added, and 84 g of the compound was added.
Stir and disperse at 15 ° C for 15 minutes. 1 molten mixture
By dropping at a rate of 10 g / min onto a 15 cm diameter aluminum disc rotating at 950 rpm, 42
A spherical fine granule of / 60 mesh is obtained.

[0247] 7. Gastric mucosa-adhesive preparation containing phosphoric acid amide derivative 63 g of hardened castor oil (Freund Sangyo Co., Ltd., trade name: Raburi wax 101) and hexa (tetra) behenate
Glyceride (Sakamoto Yakuhin Co., Ltd., trade name HB-310)
Weigh 5.0 g and heat and melt at 84 ° C. Then, 4 g of the compound of Example 3 and then 8.0 of an acrylic acid polymer (Hibiswako 104, trade name, manufactured by Wako Pure Chemical Industries, Ltd.)
g and curdlan (Takeda Pharmaceutical Co., Ltd.) 20 g are sequentially added, and the mixture is stirred and dispersed at 84 ° C. for 15 minutes. By dropping the molten mixture at a rate of 10 g / min onto a 15 cm diameter aluminum disk rotating at 1950 rpm, a 42/60 mesh spherical fine granule is obtained.

[0248] 8. Gastric mucosa-adhesive preparation containing phosphoric acid amide derivative 63 g of hardened castor oil (Freund Sangyo Co., Ltd., trade name: Raburi wax 101) and hexa (tetra) behenate
Glyceride (Sakamoto Yakuhin Co., Ltd., trade name HB-310)
Weigh 5.0 g and heat and melt at 84 ° C. Then, 4 g of the compound of Example 3 and then 8.0 of an acrylic acid polymer (Hibiswako 104, trade name, manufactured by Wako Pure Chemical Industries, Ltd.)
g, low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd., trade name: L-HPC) 20 g,
Stir and disperse for 15 minutes while maintaining at 84 ° C. The molten mixture was added dropwise at a rate of 10 g / min to a 15 cm diameter aluminum disc rotating at 1950 rpm.
A 2/60 mesh spherical fine granule is obtained.

9. Gastric mucosa-adhesive preparation containing phosphoric acid amide derivative 81.5 g of hexa (tetra) glyceride behenate (Sakamoto Yakuhin Co., Ltd., trade name HB-310) was weighed, and 8
Heat and melt at 4 ° C. The compound 0.5 of Example 3 was added thereto.
g, then an acrylic acid polymer (Wako Pure Chemical Industries, Ltd.
8.0 g of brand name (Hibiswako 104) and 10 g of curdlan (Takeda Pharmaceutical Co., Ltd.) are sequentially added, and the mixture is stirred and dispersed at 84 ° C. for 15 minutes. 195 melt mixture
42/60 by dropping at a rate of 10 g / min onto a 15 cm diameter aluminum disc rotating at 0 rpm.
A spherical fine granule with a mesh is obtained.

10. Gastric mucosa-adhesive preparation containing phosphoric acid amide derivative Hardened castor oil (Freund Sangyo Co., Ltd., trade name: Raburi wax 101) 54 g and hexa (tetra) behenate
Glyceride (Sakamoto Yakuhin Co., Ltd., trade name HB-310)
1.0 g is weighed and melted by heating at 84 ° C. 35 g of the compound of Example 3 was added thereto, followed by an acrylic acid polymer (Wako Pure Chemical Industries, Ltd., trade name: Hibiswako 104) 5.0
g and curdlan (Takeda Pharmaceutical Co., Ltd.) (5 g) are sequentially added, and the mixture is stirred and dispersed at 84 ° C. for 15 minutes. By dropping the molten mixture at a rate of 10 g / min onto a 15 cm diameter aluminum disk rotating at 1950 rpm, a 42/60 mesh spherical fine granule is obtained.

[0251] 11. Gastric mucosa-adhesive preparation containing phosphoric acid amide derivative 35 g of hydrogenated castor oil (Freund Sangyo Co., Ltd., trade name Raburi wax 101) and hexa (tetra) behenate
Glyceride (Sakamoto Yakuhin Co., Ltd., trade name HB-310) 1
g, and heat and melt at 84 ° C. 35 g of the compound of Example 3, then 5.0 g of an acrylic acid polymer (Wako Pure Chemical Industries, Ltd., Hibiswako 104), low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd., trade name) L-HPC) 5.0 g was added successively, and 8
Stir and disperse for 15 minutes at 4 ° C. The molten mixture was dropped at a rate of 10 g / min onto a 15 cm diameter aluminum disc rotating at 1950 rpm by 42 g.
A spherical fine granule of / 60 mesh is obtained.

[0252] 12. Gastric mucosa-adhesive preparation containing phosphoric acid amide derivative 76 g of hardened castor oil (Freund Sangyo Co., Ltd., trade name Raburi Wax 101) is weighed and heated and melted at 84 ° C. To this, 4.0 g of the compound of Example 3, then 10.0 g of an acrylic acid polymer (Wako Pure Chemical Industries, Ltd., trade name: Hibiswako 104), low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.), Product name L-HPC) 1
Add 0.0 g sequentially and stir for 15 minutes while keeping at 84 ° C. to disperse. A 42/60 mesh spherical fine granule is obtained by dropping the molten mixture at a rate of 10 g / min onto a 15 cm diameter aluminum disk rotating at 1950 rpm.

13. Antibiotics-containing gastric mucosa-adhesive preparation 75 g of hydrogenated castor oil (Freund Sangyo Co., Ltd., trade name: Raburi wax 101) is weighed and heated and melted at 95 ° C. To this, 1.5 g of amoxicillin, 10.0 g of an acrylic acid polymer (Wako Pure Chemical Industries, Ltd., trade name: Hibiswako 104) and 13.5 g of curdlan (Takeda Pharmaceutical Co., Ltd.) were sequentially added. Keep at 95 ℃ 15
Stir and disperse for a minute. 10 g of the molten mixture on a 15 cm diameter aluminum disk rotating at 1950 rpm
By dropping at a rate of 1 / min, spherical fine granules of 42/60 mesh can be obtained.

14. 88.5 g of carnauba wax (trade name: Polishing Wax 103), an antibiotic-containing gastric mucosa-adhesive preparation, are weighed and melted at 95 ° C. by heating. To this, 1.5 g of amoxicillin and then 10.0 g of an acrylic acid polymer (Wako Pure Chemical Industries, Ltd., trade name: Hibiswako 104) are sequentially added, and the mixture is stirred and dispersed at 95 ° C. for 15 minutes. 1950 melt mixture
By dropping at a rate of 10 g / min onto an aluminum disk with a diameter of 15 cm rotating at rpm, spherical fine granules of 42/60 mesh can be obtained.

15. Gastric mucosa-adhesive preparation containing phosphoric acid amide derivative 78 g of hardened castor oil (Freund Sangyo Co., Ltd., trade name: Raburi wax 101) is weighed and heated and melted at 84 ° C. Then, 4 g of the compound of Example 3 and then an acrylic acid polymer (Wako Pure Chemical Industries, Ltd., trade name: Hibiswako 1)
04) 8.0 g, curdlan (Takeda Pharmaceutical Co., Ltd.) 1
Add 0.0 g sequentially and stir for 15 minutes while keeping at 84 ° C. to disperse. A 42/60 mesh spherical fine granule is obtained by dropping the molten mixture at a rate of 10 g / min onto a 15 cm diameter aluminum disk rotating at 1950 rpm.

[0256]

The anti-Helicobacter agent, the pharmaceutical composition and the drug for the anti-Helicobacter of the present invention have an anti-Helicobacter action, for example, against Helicobacter which exerts a toxic action in the digestive tract. It shows a disinfecting action and a bactericidal 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.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 33/42 A61K 33/42 C07F 9/655 C07F 9/655 9/6553 9/6553 // C07F 9/22 9/22

Claims (36)

[Claims] 1. A compound of the general formula [In the formula, R represents an amino group which may be substituted] or a salt thereof and an anti-Helicobacter bacterium containing an antibiotic. (Wherein, R ¹ represents a hydrogen atom, a heterocyclic group which may optionally be a hydrocarbon group or a substituted may be substituted) wherein R has the formula -NHCOR ¹ is a group represented by The anti-Helicobacter bacterium according to claim 1. 3. The anti-Helicobacter bacterium according to claim 1, wherein the antibiotic is a penicillin antibiotic, a macrolide antibiotic or a nitroimidazole antibiotic. 4. A compound of the general formula [Wherein R ^1a represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group] or a salt thereof, and a pharmaceutical composition containing an antibiotic. 5. The pharmaceutical composition according to claim 4, wherein R ^1a is an optionally substituted aromatic hydrocarbon group or aromatic heterocyclic group. 6. The pharmaceutical composition according to claim 4, wherein R ^1a is a 5-membered aromatic heterocyclic group which may be substituted. 7. The pharmaceutical composition according to claim 4, wherein R ^1a is a thienyl group or a furyl group each substituted with one or two C _1-3 alkyl groups. 8. The compound according to claim 1, wherein the compound is N- (diaminophosphinyl)-
The pharmaceutical composition according to claim 4, which is 5-methyl-2-thiophenecarboxylic amide. 9. The method according to claim 9, wherein the compound is N- (diaminophosphinyl)-
The pharmaceutical composition according to claim 4, which is 2-methyl-3-furancarboxylic acid amide or a salt thereof. 10. The pharmaceutical composition according to claim 4, wherein the antibiotic is a penicillin antibiotic, a macrolide antibiotic or a nitroimidazole antibiotic. 11. An anti-Helicobacter bacterium.
The pharmaceutical composition according to any one of the preceding claims. 12. The pharmaceutical composition according to claim 4, which is an agent for preventing recurrence of ulcer. 13. A compound of the general formula (In the formula, R ^1b is substituted with (i) an optionally substituted cyclic hydrocarbon group, (ii) an optionally substituted heterocyclic group, (iii) an optionally substituted cyclic hydrocarbon group. Hydroxyl group, (i
v) a hydroxyl group substituted with an optionally substituted heterocyclic group,
(v) a thiol group substituted with an optionally substituted cyclic hydrocarbon group, or (vi) a non-cyclic hydrocarbon group substituted with a thiol group substituted with an optionally substituted heterocyclic group And a salt thereof, and an antibiotic. 14. The pharmaceutical composition according to claim 13, wherein the antibiotic is a penicillin antibiotic, a macrolide antibiotic or a nitroimidazole antibiotic. (1) The general formula: [Wherein R represents an optionally substituted amino group] or a salt thereof, (2) an antibiotic, and (3) a drug containing an antacid or / and an acid secretion inhibitor Composition. 16. R is a group represented by the formula —NHCOR ¹ (wherein R ¹ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group). A pharmaceutical composition according to claim 15. 17. The pharmaceutical composition according to claim 16, wherein R ¹ is an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group. 18. R ¹ is substituted with (i) an optionally substituted cyclic hydrocarbon group, (ii) an optionally substituted heterocyclic group, and (iii) an optionally substituted cyclic hydrocarbon group. Hydroxyl group, (iv) hydroxyl group substituted with an optionally substituted heterocyclic group, (v) thiol group substituted with an optionally substituted cyclic hydrocarbon group, or (vi) substituted 17. The pharmaceutical composition according to claim 16, which is a noncyclic hydrocarbon group substituted with a thiol group substituted with a heterocyclic group. 19. The pharmaceutical composition according to claim 16, wherein R ¹ is an optionally substituted aromatic hydrocarbon group or aromatic heterocyclic group. 20. The pharmaceutical composition according to claim 16, wherein R ¹ is an optionally substituted 5-membered aromatic heterocyclic group. 21. The pharmaceutical composition according to claim 16, wherein R ¹ is a thienyl group or a furyl group each substituted with one or two C _1-3 alkyl groups. (22) the compound is N- (diaminophosphinyl);
The pharmaceutical composition according to claim 15, which is -5-methyl-2-thiophenecarboxylic amide. (23) the compound is N- (diaminophosphinyl);
The pharmaceutical composition according to claim 15, which is -2-methyl-3-furancarboxylic acid amide or a salt thereof. 24. The pharmaceutical composition according to claim 15, wherein the antibiotic is a penicillin antibiotic, a macrolide antibiotic, or a nitroimidazole antibiotic. 25. The pharmaceutical composition according to claim 15, wherein the acid secretion inhibitor is a proton pump inhibitor. 26. The pharmaceutical composition according to claim 25, wherein the proton pump inhibitor is a benzimidazole compound. 27. The method according to claim 1, which is an anti-Helicobacter bacterium.
5. The pharmaceutical composition according to 5. 28. The pharmaceutical composition according to claim 15, which is an agent for preventing recurrence of ulcer. 29. A compound of the general formula [Wherein R ^1a represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted] or a salt thereof and a medicine. 30. A compound of the general formula (In the formula, R ^1b is substituted with (i) an optionally substituted cyclic hydrocarbon group, (ii) an optionally substituted heterocyclic group, (iii) an optionally substituted cyclic hydrocarbon group. Hydroxyl group, (i
v) a hydroxyl group substituted with an optionally substituted heterocyclic group,
(v) a thiol group substituted with an optionally substituted cyclic hydrocarbon group, or (vi) a non-cyclic hydrocarbon group substituted with a thiol group substituted with an optionally substituted heterocyclic group And a salt thereof and an antibiotic. (1) A general formula: [Wherein R represents an amino group which may be substituted] or a salt thereof, (2) an antibiotic and (3) a medicine comprising a combination of an antacid or / and an acid secretion inhibitor . 32. A compound of the general formula [Wherein, R represents an amino group which may be substituted] or a salt thereof and an antibiotic in combination with an anti-Helicobacter drug. 33. A compound of the general formula Wherein R represents an amino group which may be substituted, or a salt thereof, an antibiotic, an antacid and / or an acid secretion inhibitor. Anti-Helicobacter bacteria. 34. N- (diaminophosphinyl) -5-methyl-3-furancarboxylic acid amide or a salt thereof. 35. N- (diaminophosphinyl) -3,5
-Dimethyl-2-furancarboxamide or a salt thereof. 36. N- (diaminophosphinyl) -3,5
-Dimethyl-2-thiophenecarboxylic amide or a salt thereof.