WO2000044707A1 - Novel substituted guanidine derivatives and process for the preparation thereof - Google Patents

Abstract

Compounds represented by general formula (1) or prodrugs thereof, or medicinally acceptable salts of both, useful as therapeutic and preventive drugs for diseases due to acceleration of the sodium/proton exchange system wherein R1 and R2 are each independently a substituted or unsubstituted aromatic group; X1 is nitrogen or ‰C-R3; X2 is oxygen, -N(R4)-, or -C(R5)(R6)-; X3 is oxygen, -N(R7)-, -C(R8)(R9)-, or a single bond; R3, R5, R6, R8 and R9 are each independently hydrogen, halogeno, alkyl, or the like; and R4 and R7 are each independently hydrogen, alkyl, or the like.

Description

 Description Novel substituted guanidine derivatives and their production

The present invention relates to a novel substituted guanidine derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a method for producing the same. The compound of the present invention has an inhibitory effect on sodium / proton (Na ⁺ ZH +) exchange transport system, and is a disease caused by enhancement of sodium / proton (Na ⁺ / H ⁺ ) exchange transport system, such as hypertension, arrhythmia, Organ damage due to angina pectoris, cardiac hypertrophy, diabetes, ischemia or reperfusion of ischemia (eg, myocardial ischemia-reperfusion injury, acute renal failure, surgical treatment (eg, organ transplantation or PTCA)

(Percutaneous Transluminal oronary Angioplasty)) i Involuntary disorders, etc.) ヽ Cerebral ischemic disorders (eg, disorders associated with cerebral infarction, disorders that occur as a sequela after stroke, cerebral edema, etc.), cell hyperproliferation (eg, fibroblast proliferation) Diseases caused by, for example, smooth muscle cell proliferation, mesangial cell proliferation, etc. (eg, atherosclerosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, renal glomerulosclerosis, organ hypertrophy, prostatic hypertrophy, diabetic complications) Disease, restenosis after PTCA, etc.), and treatment and prevention of diseases due to endothelial cell damage.

Background art

As a substituted guanidine derivative having an inhibitory action on the sodium Z proton (Na ⁺ ZH ⁺ ) exchange transport system, for example, a biradinoyl guanidine derivative represented by amyloid is known (for example, J Membrane Biol., Vol. 105, 1 (1988); Circulation, Vol. 79, 1257 (1989)). Benzoylguanidine derivatives have been reported to have an inhibitory effect on the sodium Z-proton (Na + /) exchange transport system and an antiarrhythmic effect (see, for example, J. Mol. Cell. Cardiol. , Vol. 24, Suppl. I, S.92 (1992); J. Mol. Cell. Cardiol., Vol. 24, Suppl. I, S. 117 (1992); Japanese Patent Application Laid-Open No. 5-339228; JP-A-6-9545; JP-A-6-3457; JP-A-7-109251). It has been reported that polycyclic arylylguanidine derivatives have an inhibitory effect on sodium / proton (Na ⁺ / H ⁺ ) exchange transport system (for example, JP-A-7-10839; JP-A-7-145149; JP-A-7-206823; JP-A 8-41028; JP-A 8-225513; JP-A 8-277269; - 77753 JP; Hei 9 ²⁹ 10 § 6 JP). It has been reported that indenylguanidine derivatives have an inhibitory effect on the sodium proton (Na ⁺ ZH +) exchange transport system (for example, JP-A-8-291131; JP-A-9-268172). In addition, it has been reported that a derivative of acryloylguanidine has an inhibitory effect on sodium proton (Na + / H ⁺ ) exchange transport system (for example, JP-A-8-319266; JP-A-9-52823). JP-A-9-59245; JP-A-9-67332; JP-A-9-67340; JP-A-9-249660).

 It has been reported that a substituted benzyloxycarbonyldanidine derivative and a substituted benzylaminodiamine derivative have an inhibitory effect on the sodium Z proton (Na + ZH +) exchange transport system (see, for example, JP-A-8-311012). No.). In addition, the phenyl-substituted alkylcarboguanidide derivative is sodium Z-proton.

It has been reported that (Na ⁺ / H ⁺ ) has an inhibitory effect on the exchange transport system (for example, JP-A-7-224022).

Disclosure of the invention

The present invention has a sodium noproton (Na + ZH ⁺ ) exchange transport system inhibitory effect, and is a disease caused by an enhanced sodium proton (Na + / H ⁺ ) exchange transport system, such as hypertension and arrhythmia. , Angina, cardiac hypertrophy, diabetes, organ damage due to ischemia or ischemia reperfusion (eg, myocardial ischemia reperfusion injury, acute renal failure, surgical treatment (eg, organ transplantation or PTCA (Percutaneous Transluminal Coronary Angioplasty)) Cerebral ischemic injury (eg, damage associated with cerebral infarction, a sequelae after stroke, cerebral edema, etc.), cell overproliferation (eg, fibroblast proliferation, smooth muscle cell proliferation, etc.) (Eg, atherosclerosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, renal glomerulosclerosis, organ hypertrophy, prostatic hyperplasia, diabetic complications, after PTCA) of Stenosis, etc.), the treatment of such diseases by disorder of endothelial cells, useful as a prophylactic, and an object thereof is to provide a novel substituted guanidine derivatives or salts thereof and their preparation.

The present invention relates to the following inventions [1] to [18]. [1] General formula (1)

[Wherein, and R ₂ independently represent an aromatic group which may have a substituent.

X 丄 represents a nitrogen atom or 3 C-R ₃ .

X ₂ represents an oxygen atom, —N (R ₄ ) — or 1 C (R ₅ ) (R ₆ ) _.

X ₃ represents an oxygen atom, one N (R ₇ ) _, one C (R ₈ ) (R ₉ ) — or a single bond.

R ₃ , R ₅ , R ₆ , R ₈ and R ₉ are each independently a hydrogen atom, a halogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic ring Group, carboxyl group, acyl group, _OR ₁₀ , _N (Rn) R ₁₂ , — S (〇) _n R ₁₃ , -C (0) N (R ₁ i) Ri

-S02NCR! I) Ri2 _Q— _Ra or

-A— CH N— R ₁₄

(A represents an oxygen atom, _S (O) _n _ or one N (R 丄₅ ) —, and R ₁₄ represents a hydrogen atom, an alkyl group, a substituted alkyl group, an acyl group, _S (O) _n R 丄₃ or — Q—Ra represents a ring, and the ring represents a saturated heterocyclic group consisting of one _3- to 8-membered nitrogen atom and a carbon atom.

R ₄ , 1 ^ _{7 and} 1 ^ ₁₅ are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a saturated heterocyclic group, an acyl group, —S (O) ₂ R _{1 3,} was or represents an Q-R _a.

R ₁₀ represents a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, an optionally substituted aromatic group, or an aromatic group. _{1 1 1 and} 1 _{1 2} each independently have a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, or a suitable substituent. an aromatic group, Ashiru group, one S (0) represent a _n R _{1 3} or _Q_R _a, or a ₂ are bonded to each other, they connexion such together with the nitrogen atom to which they are attached other in the ring represents the to cyclic amino group which may saturated 5-7 membered ring containing a hetero atom (cyclic amino group is one or more alkyl groups, substituted alkyl groups, may be substituted by a hydroxyl group or a oR i ₀₎ .

R ₁₃ represents an alkyl group, a substituted alkyl group or an aromatic group which may have a suitable substituent.

 Q represents a lower alkylene group which may be substituted.

_Ra represents an optionally substituted vinyl group or an optionally substituted ethyl group.

 n represents an integer of 0, 1 or 2.

] Or a prodrug thereof or a pharmaceutically acceptable salt thereof;

[2] The compound according to [1], wherein X ₃ is an oxygen atom, one N (R ₇ ) — or one C (R ₈ ) (R ₉ ) —, or a prodrug thereof, or a pharmaceutically acceptable salt thereof;

[3] the compound of [1], wherein X ₃ is a single bond, or a prodrug thereof, or a pharmaceutically acceptable salt thereof;

[4] the compound of [2], wherein X _{3 is} -C (R ₈ ) (R ₉ ) _, or a prodrug thereof, or a pharmaceutically acceptable salt thereof;

[5] The compound according to any one of [1] to [4], wherein X ₂ is one C (R ₅ ) (R ₆ ) —, a prodrug thereof, or a pharmaceutically acceptable salt thereof; 6] The compound according to any one of [1] to [5], wherein R 丄 is a phenyl group optionally having a substituent, a prodrug thereof, or a pharmaceutically acceptable salt thereof;

[7] The compound according to any one of [1] to [5], wherein R 丄 and R ₂ are a phenyl group optionally having a substituent, or a prodrug thereof, or Pharmaceutically acceptable salts thereof;

[8] salt X is acceptable compound if Kuwasono prodrug or pharmaceutical according to any one of three C one R ₃ [1] to [7];

[9] The compound according to any one of [1], [2], [3], [4], [6], [7], or [8], wherein X ₂ is _N (R ₄ ) — Or a prodrug thereof or a pharmaceutically acceptable salt thereof;

 [10] a medicament comprising the compound according to any one of [1] to [9] or a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient;

[11] a sodium Z proton exchange transport inhibitor comprising the compound according to any one of [1] to [9] or a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient;

 [1 2] Hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes mellitus containing the compound according to any of [1] to [9] or a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient A therapeutic or prophylactic agent for organ inhibition due to ischemia or ischemia reperfusion, cerebral ischemic injury, a disease caused by excessive cell proliferation, or a disease caused by endothelial cell damage;

 [13] The compound according to any one of [1] to [9] or a prodrug thereof or a pharmaceutically acceptable salt thereof for use as an active ingredient of a medicine;

 [14] use of the compound according to any one of [1] to [9], a prodrug thereof, or a pharmaceutically acceptable salt thereof for producing a sodium / proton exchange transport system inhibitor;

 [15] Hypertension, arrhythmia, angina, cardiac hypertrophy, diabetes, organ inhibition due to ischemia or ischemia reperfusion, cerebral ischemic injury, diseases caused by excessive cell proliferation, or diseases caused by endothelial cell damage Use of the compound according to any one of [1] to [9], a prodrug thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent;

(16) comprising administering to the subject an effective amount of the compound according to any of (1) to (9) or a prodrug thereof or a pharmaceutically acceptable salt thereof. How to inhibit the sodium / proton exchange transport system;

 (17) hypertension, arrhythmia, angina pectoris comprising administering to a subject an effective amount of the compound according to any one of (1) to (9) or a prodrug thereof or a pharmaceutically acceptable salt thereof. A method for treating or preventing cardiac hypertrophy, diabetes, organ inhibition due to ischemia or ischemia reperfusion, cerebral ischemic injury, a disease caused by excessive cell proliferation or a disease caused by endothelial cell disorder; and

 [18] General formula (2)

〇

^Rlヽ X ² , X

R ₂ (2)

Wherein R ₂ , X or X ₂ and X ₃ have the same meanings as in (1), and L represents a hydroxyl group or a leaving group that can be substituted by a nucleophile. Reacting in the presence of a condensing agent, if necessary, and converting the resulting product into a prodrug or a pharmaceutically acceptable salt thereof as necessary. A method for producing the prodrug or a pharmaceutically acceptable salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

 Various groups in the present invention will be described below.

The aromatic group includes an aryl group and a heteroaryl group, examples of the aryl group include aryl groups having 10 or less carbon atoms such as phenyl and naphthyl, and examples of the heteroaryl group include: Heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, virazolyl, pyridyl, pyrimidinyl, pyrazil, pyridazinyl, triazolyl, tetrazolyl, etc .; for example, indolyl, isoindolyl, benzoimidazolyl, quinolyl, Fused heterocyclic groups containing 1 to 4 nitrogen atoms such as isoquinolyl, indazolyl and benzotriazolyl; for example, 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as oxazolyl, isooxazolyl and oxdiazolyl; A heteromonocyclic group containing: for example, benzoxazolyl, A fused heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms such as benzoxazolyl; 1-2 sulfur atoms such as thiazolyl, isothiazolyl and thiadiazolyl; A heterocyclic monocyclic group containing 1 to 3 nitrogen atoms; a phenyl group; for example, benzothiazolyl, benzothiadiazolyl, etc., a fused heteroatom containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms. A ring group; a furyl group. Examples of the substituent of the aromatic group include a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, an aromatic group, an acyl group, a carboxyl group, and a halogen atom. Atom, nitro group, one OR ₁₀ , -N (R! I) R! ₂ One "CN ^ 2, One SOsN ^ ₂ ,

-QR _a (R ₁₀ , R! I R ₁₂ , Q and R _a have the same meaning as described above.), Or

A— CH N— R ₁₄

(A, R ₄ and the ring have the same meanings as described above).

 Examples of the alkyl group include straight-chain or branched groups such as methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl, heptyl, and octyl. Alkyl groups having 8 or less carbon atoms.

Cycloalkyl groups and is not substituted or 1-4 alkyl group, location substitution alkyl group, a hydroxyl group, or may be substituted from group one OR _6, for example shea Kuropuropinore, Shikuropuchi / Les, cyclopentyl / Cyclohexynole, Cycloheptyl, 2-Methylcyclopentyl, 3-Methylcyclopentyl, 2-Methylcyclohexynole, 3-Methynolecyclohexynole, 4-Methynolecyclohexynole, 2-Hydroxycyclopentynole, 3- Hydroxycyclopentinole, 2-hydroxycyclohexylene, 3-hydroxycyclohexole, 4-hydroxycyclohexyl ^^, 2-

(Hydroxymethyl) cyclopentyl, 3- (hydroxymethyl) cyclopentyl, 2- (hydroxymethyl) cyclohexyl, 3- (hydroxymethyl) cyclohexyl, 4- (hydroxymethyl) cyclohexyl, 2- (amino Methyl) Cyclopentyl, 3- (aminomethyl) cyclopentyl, 2- (aminomethyl) cyclohexyl, 3_ (aminomethyl) cyclohexyl, 4- (aminomethyl) cyclohexinole, 2- (methoxymethyl) cyclopentyl 、 ^, 3- to 8-membered cycloalkyl groups such as 3- (methoxymethyl) cyclopentyl, 2- (methoxymethyl) cyclohexyl, 3- (methoxymethylen) cyclohexyl, and 4- (methoxymethyl) cyclohexyl No.

Cycloalkenyl group, either unsubstituted, or 1-4 alkyl group, a substituted alkyl group, may be substituted by a hydroxyl group or formula one OR _6, such as 1-cyclopent two Honoré, 2-cyclopent two Honoré And 3-cyclopenteninole, 1-cyclohexeninole, 2-cyclohexeninole, 3-cyclohexeny, and the like, and a cycloalkenyl group having one 3- to 8-membered double bond.

Saturated heterocyclic group, unsubstituted or substituted with or 1-4 alkyl group, a substituted § alkyl group may be substituted by a hydroxyl group or formula one OR _6, such as 2-te Torahi Dorofuraniru, 3- Tetorahi Saturated heterocyclic groups having one 3- to 8-membered oxygen or sulfur atom, such as drofuranyl, 2-tetrahydro-12H-pyranyl and 4-tetrahydro-14H-viranyl, are exemplified.

 Examples of the alkenyl group include alkenyl groups having 6 or less carbon atoms, such as bier, aryl, propyl, 2-propenyl, butenyl, pentenyl, and hexenyl.

 Examples of the alkynyl group include alkynyl groups having 6 or less carbon atoms, such as ethynyl, propargyl, butyr, and pentenyl.

 Examples of the halogen atom include iodine, fluorine, chlorine and bromine atoms.

Examples of the acryl group include a formyl group, for example, an alkanoyl group having 2 to 6 carbon atoms such as acetyl and propanol, and a carbon atom having 4 to 7 carbon atoms such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanepropionyl and cyclohexanecarbonyl. A cycloalkanecarbonyl group having 3 to 6 carbon atoms such as cyclopentenecarbonyl and cyclohexanol, and a cycloalkanecarbonyl group having 3 to 6 carbon atoms such as benzoyl, toluoyl, and naphthoyl ~ 10 Royl group, for example, a saturated heterocyclic monocarbonyl group having a 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom such as 2-piperidinecarbonyl and 3_morpholinecarbonyl For example, heteroaromatic acyl groups having a 5- or 6-membered heteroaromatic ring containing 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur such as floyl, tenoyl, nicotinoyl, and isonicotinoyl, etc. No.

 The substituent in the substituted alkyl group includes a halogen atom, a hydroxyl group, an alkoxy group, a cycloalkyl group, a cyano group, a carboxyl group, an acyl group, an aromatic group, and a compound represented by the formula —CONRp Rq (Rp and Rq are each independently hydrogen, Represents an atom or an alkyl group, or Rp and Rq are bonded to each other to represent a saturated 5- to 7-membered cyclic amino group which may contain another heteroatom in the ring),

 -N (R !!) R ,. Or

• CH

(R "is a hydrogen atom, an alkyl group or a substituted alkyl group, the ring represents a saturated heterocyclic group consisting of one nitrogen atom and carbon atoms of 3-8 membered) _c thereof to include the group represented by Examples of the substituted alkyl group include an alkyl group having 1 to 5 carbon atoms substituted with a cycloalkyl having 3 to 6 carbon atoms, a polyhaloalkyl group having 1 to 5 carbon atoms, and an alkyl group having 1 to 6 carbon atoms. Droxyalkyl group, alkoxyalkyl group having 2 to 6 carbon atoms, cyanoalkyl group having 2 to 6 carbon atoms, carboxyalkyl group having 2 to 6 carbon atoms, alkoxycarbonylalkyl group having 3 to 8 carbon atoms, carbon An alkanolalkyl group having 3 to 8 atoms, an arylalkyl group having 16 or less carbon atoms, phenyl or naphthyl which may have a substituent—a C1 to C5 alkyl group, one nitrogen atom or May be substituted with two C1-C3 alkyl groups.Rbamoyl-C1-C3 alkyl group, one or two Cl-C3 alkyl or nitrogen atoms optionally substituted with one or two Cl-C3 aralkyl. To C5 alkyl groups, saturated 5- to 7-membered cyclic aminow C1-C3 alkyl groups and the like. Examples of the aralkyl group include an alkyl group substituted with an aryl group. Specific examples of typical substituted alkyl groups include polyhaloalkyl groups having 1 to 3 carbon atoms such as trifluoromethyl, trifluoroethyl, and trichloromethyl; carbon atoms such as hydroxymethyl, hydroxyxethyl, and 1-hydroxyxethyl. Number: 1 to 5 hydroxyalkyl groups, such as aminomethyl, aminoethyl, 1-aminoethyl, etc. 1 to 5 carbon atoms, such as aminoalkyl groups, 1 to 5 carbon atoms, such as methoxyl, ethoxyl, and methoxypropyl C2 to C6 carboxyalkyl groups such as alkoxyalkyl groups, carboxyshetyl and carboxypropyl, and C3 to C7 alkoxycarbonylalkyl groups such as methoxycarbonylmethyl, ethoxycarbonylmethyl and methoxycarbonylethyl Group, benzyl, Phenyl or naphthinole C 1 to C 5 anolequinole group (C 1 to C 3 alkyl group, halogen atom, nitro group, etc.) such as ninoleethynole, phenylpropyl, phenylbutinole, 1- or 2-naphthinolemethinole, etc. May have a substituent such as a group, an amino group, a hydroxyl group, a C 1 -C 3 alkoxy group), a rubamoylmethyl, a rubamoylethyl, a dimethylcarbamoylmethyl or the like. Carbamoyl which may be substituted with -C 3 alkyl C 1 -C 3 alkyl group, aminoethyl, aminopropyl, dimethylaminoethyl, dimethylaminopropyl, getylaminoethyl, N-methyl-1-N-benzylaminoethyl and the like A nitrogen atom having one or two C 1 -C 3 alkyl or Amino optionally substituted with C7-C11 aralkyl—Saturated 5- to 7-membered cyclic amino_C1-C3 alkyl group such as C1-C5 alkyl group, 1-pyrrolidinylethyl, piperidinoethyl, etc. Examples of R i and R ₂ include phenyl-CI to C 5 alkyl groups such as phenylethyl.

Bonded R ₁ E and ₂ to each other, as they form together with the nitrogen atom to which they are attached heteroatom may saturated 5 also contain heteroatoms others to in the ring to the cyclic amino group 7 membered ring, Examples include an oxygen atom, a nitrogen atom and a sulfur atom.Specific examples include a 5- to 7-membered ring group containing 1 to 3 nitrogen atoms or a 5- to 7-membered ring group containing 1 nitrogen atom and 1 oxygen atom. More specifically, 1-pyrrolidinyl, 1-piperidino, 1-piperazinyl, morpholino, 1_ (4-methyl) piperazi Nil and the like.

Examples of the saturated 5- to 7-membered cyclic amino group which Rp and Rq bind to each other and which may contain another hetero atom in the ring include a cyclic amino group formed by Ri and scale ₂ described above. Examples similar to the case of the group can be given.

Examples of the group represented by the formula one S (0) _n R丄_3, for example, methylsulfonyl group, E Chirusuruhoniru group, propylsulfonyl group, an alkylsulfonyl group and corresponding carbon atom number of 8 or less, such as isopropylsulfonyl group Examples thereof include an alkylsulfinyl group and an alkylthio group.

Examples of the substituent for the lower alkylene group for Q and the substituent for the butyl group and the ethur group for Ra include, for example, an alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, a carboxyl group, an alkoxycarbonyl group, and an aromatic group. And a group represented by the formula —CON (R ^) ₂ .

 Examples of the lower alkylene group include an alkylene group having 6 or less carbon atoms such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene.

Expression

Examples of the group represented by -A— CH N— R 14 include:

And preferably a group represented by the formula: (piperidin-1-3-yl) oxy, (piperidin-1-yl) oxy, (1-methylbiperidin-13-yl) oxy, (1 —Methylbiperidine-1 4-fyl) oxy, (pyrrolidine-1-3-yl) oxy, (1 _methylpyrrolidine-13-yl) oxy, (piperidin-1 3— ^ f1) thio, (piperidine-14-yl) ) Zeo, (1-Methylbiperidine-1-3-yl) Zio, (1-Methylbiperidine-14-yl) Zio, (Pyrrolidine-13-yl) Zio, (1-Methylpyrrolidine-12-yl) Zio, (Piperidine-1-3-yl) amino, (piperidine 1-4yl) amino, (1-methylpiperidin-3-yl) amino, (1-methylbiperidine-14-yl) amino, (pyrrolidine One 3-yl) amino, (1-methylpyrrolidine one-three) ) Amino, and the like.

Preferred combinations of X ₂ and X _{3 in} the general formula (1) include, for example, the following.

1. X 丄 represents a nitrogen atom or 3 C—R ₃ , X ₂ represents an oxygen atom, _N (R ₄ ) — or 1 C (R ₅ ) (R ₆ ) —, and X ₃ represents an oxygen atom , One N (R ₇ ) _ or

-C (R ₈ ) (R ₉ ) —

 Specifically, the following are mentioned.

1 - 1.丄represents a three Ji one R _3, X ₂ gar _{C (R 5) (R 6} ) - represents, X ₃ is _{-C (R 8) (R 9} ) - represents a. 1 -2. X; ^ ≡C— represents R ₃ , X ₂ represents one C (R ₅ ) (R ₆ ) — and X ₃ force S—N (R ₇ ) —.

1—3 represents 三 R ₃ , X ₂ represents one N (R ₄ ) —, and X ₃ represents

-C (R ₈ ) (R ₉ ) —

Represents a nitrogen atom, X ₂ represents _C (R ₅ ) (R ₆ ) —, and X ₃ represents

_C (R ₈ ) (R ₉ ) —.

1 -5. 丄 represents ₃ C-1 R ₃ , X ₂ represents 1 C (R ₅ ) (R ₆ ) —, and X ₃ represents an oxygen atom.

_1-6.1 is ≡. Represents over 1¾ _3, X ₂ represents an oxygen atom, is X ₃

—C (R ₈ ) (R ₉ ) —

2. X represents a nitrogen atom or 3 C-R ₃ , X ₂ represents an oxygen atom, 1 N (R ₄ ) — or 1 C (R ₅ ) (R ₆ ) —, and X ₃ is a single bond Represents

 Specifically, the following are mentioned.

2 - _1.1 represents ≡〇 one R _3, X ₂ gar _{C (R 5) (R 6} ) - represents, X ₃ represents a single bond.

2- 2. 丄 represents three-one R ₃ , X ₂ represents one N (R ₄ ) —, and X ₃ represents a single bond.

2-3. ₁ represents ≡ G 1 _3, X ₂ represents an oxygen atom, X ₃ represents a single bond. 2— 4. Xi represents a nitrogen atom, X ₂ represents —C (R ₅ ) (R ₆ ) —, and X ₃ represents a single bond.

 Furthermore, the present invention relates to a method for producing compound (1), and the method comprises reacting a compound of formula (2)

〇

^X l X L

R ₂ (2)

(Wherein Ri, R ₂ , XX ₂ and X ₃ have the same meaning as described above, and L represents a hydroxyl group or a leaving group that can be substituted by a nucleophile) Is reacted with guanidine, if necessary in the presence of a condensing agent, and a guanidinocarbonyl group shown in the formula (1) (one C (= 0) NHC (= NH) NH ₂ group) And optionally replacing the product with its prodrugs or their pharmaceutically acceptable salts.

 In this reaction, when the compound represented by the formula (2) has a group active in the reaction such as a hydroxyl group or a amino group, these groups may be protected with an appropriate protecting group in advance, if necessary. The desired acylguanidine derivative (1) can be prepared by removing the protecting group after performing this reaction.

 Leaving groups that can be displaced by a nucleophile include, for example, halogen atoms (eg, fluorine, chlorine, bromine), lower alkoxy groups (eg, methoxy, ethoxy, etc.), aralkyloxy groups (eg, benzyloxy group, etc.), Examples include an aryloxy group (for example, a phenoxy group) and a group formed by a compound in which L is a hydroxyl group and a condensing agent. The method for producing the compound of the formula (1) using a reactive derivative of the carboxylic acid represented by the formula (2) wherein L is one of these groups will be specifically described as follows.

 Examples of the reactive derivative of the carboxylic acid represented by the formula (2) in which L is a leaving group displaceable by a nucleophile include acid halides, acid anhydrides (including mixed acid anhydrides) and esters Derivatives include, for example, acid chlorides or acid bromides as acid halides, and ethyloxycarboyl chloride and isobutyloxycarbonyl chloride as mixed acid anhydrides. Mixed acid anhydrides with α-polyalkyl-substituted carboxylic acid chlorides such as 2-ethyl-n-butyryl chloride and trimethylacetyl chloride, and ρ- Active and methyl esters, such as ditrophenyl ester, Ν-hydroxysuccinimide ester, and pentafluorophenyl ester General esters such as esters. Such a reactive derivative of a carboxylic acid can be easily obtained from the corresponding carboxylic acid according to a commonly used general method.

When reacting an acid halide or an anhydride (including a mixed anhydride) with guanidine, the reaction is carried out in a solvent at a temperature between room temperature and room temperature in the presence of a base and an equimolar amount of guanidine or an excess of guanidine. be able to. Hydroxide as base Inorganic bases such as sodium, hydroxide hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and organic bases such as triethylamine, pyridine, etc., and solvents such as benzene, toluene, xylene, etc. Aromatic hydrocarbon solvents, ether solvents such as tetrahydrofuran, 1,4-dioxane, halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide, dimethyla Examples include amide solvents such as cetamide, basic solvents such as pyridine, and mixed solvents thereof.

 When reacting with an ester derivative, the reaction is carried out in a solvent in the presence of an equimolar or excess guanidine while cooling or heating. In the case of an active ester, for example, in the case of another ester in an ether solvent such as tetrahydrofuran, 1,2-dimethoxetane or dioxane, an ester solvent such as ethyl acetate, dimethylformamide or a mixed solvent thereof. For example, the reaction is preferably performed in an alcohol solvent such as methanol, ethanol, or isopropanol, an ether solvent such as tetrahydrofuran, 1,2-dimethyloxetane, or dioxane, dimethylformamide, or a mixed solvent thereof. In some cases, after the solvent is distilled off, heating at about 130 ° C for a short time is also possible.

 The compound of the present invention (1) preferably has the general formula (3) when L is a hydroxyl group in the formula (2).

〇

Ri ヽ γ2,

 xl x OH

^R 2 (3) (wherein, Ri, R ₂ , X and X ₂ have the same meanings as above, and X ₃ is

— Represents C (R ₈ ) (R ₉ ) —, or R ₂ and X 丄 have the same meaning as described above, X ₂ represents one C (R ₅ ) (R ₆ ) —, and X ₃ Represents a single bond. )

Can be obtained by reacting the carboxylic acid represented by the formula with guanidine, preferably in the presence of a condensing agent, in an inert solvent at room temperature or under heating. In this reaction, the compound represented by the formula (3) is not a carboxyl group, a hydroxyl group, or an amino group. If the compound has active groups for the reaction, these groups are protected with an appropriate protecting group in advance, and after carrying out the reaction, the protecting group is removed to obtain the desired acylguanidine derivative (1). Can be manufactured.

 Reactions include, for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (WSC), benzotriazole-1 —Yl tris (dimethylamino) phosphonium 'hexafluorophosphoride (BOP), diphenylphosphoninoleazide (DP PA), N, N-carbonyldiimidazole (Angew. Chem. Int. Ed. Engl., Vol. 1) , 351 (1962), and in some cases, for example, N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt), 3- Additives such as hydroxy-4-oxo-1,3,4-dihydro 1,2,3-benzotriazine (HOObt), for example, aromatic hydrocarbon solvents such as benzene, toluene and xylene; Ether solvents such as tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, and amide solvents such as dimethylformamide and dimethylacetamide It is preferable to carry out the reaction in a solvent, a basic solvent such as pyridine, or a mixed solvent thereof.

 In the above-mentioned production, as a protecting group for protecting a hydroxyl group, an amino group, a carboxyl group and the like active in the reaction, a usual protecting group used in the field of synthetic organic chemistry may be used. Removal can be performed according to a usual method (for example, Protective Groups in Organic Synthesis, JOHN WILLEY & SONS, 1991).

For example, examples of the protecting group for a hydroxyl group include a methoxymethyl group and a tetrahydrobilanyl group, and examples of the protecting group for an amino group include a tert-butyloxycarbonyl group. Such a hydroxyl-protecting group can be removed, for example, by reacting in a solvent such as aqueous methanol, aqueous ethanol, or aqueous tetrahydrofuran in the presence of an acid such as a base, sulfuric acid, or acetic acid. The protecting group can be reacted in a solvent such as aqueous tetrahydrofuran, methylene chloride, chloroform, or aqueous methanol in the presence of an acid such as hydrochloric acid or trifluoroacetic acid. More can be removed.

 When the carboxyl group is protected, the form of protection includes, for example, tert-butyl ester, ortho ester, acid amide and the like. In the case of tert-butyl ester, the removal of such a protecting group is carried out, for example, by reacting in the presence of hydrochloric acid in a water-containing solvent, and in the case of the ortho ester, for example, water-containing methanol, water-containing tetrahydrofuran, It is carried out by treating with an acid in a solvent such as water-containing 1,2-dimethoxetane and then with an alkali such as sodium hydroxide. In the case of an acid amide, for example, an acid such as hydrochloric acid or sulfuric acid is used. The reaction can be carried out in the presence of a solvent such as water, hydrated methanol, or hydrated tetrahydrofuran. The compounds represented by the general formulas (2) and (3), which are used as the starting compounds in the above-mentioned production method, are known in the literature or can be produced from compounds known in the literature according to known methods in the literature. (For example, Synth. Commun., 20 (1990) 9, 1387-1397; J. Chem. Soc. Perkin Trans. 1, (1985), 1527-1532; Chem. Pharm. Bull., 28 (1980) 5, 1394—1402; J. Organomet. Chem., 199 (1980) 1, 9-14; Tetrahedron Lett., 35 (1994) 4, 555-556; J. Prakt. Chem., 90 (1914), 273-275. J. Org. Chem., 41 (1976), 114-116; J. Med. Chem., 28 (1985) 11, 1621-1628; J. Org. Chem., 55 (1990), 4971-4973; J. Prakt. Chem./Chem.-Ztg., 337 (1995) 4, 292-298; J. Org. Chem., 16 (1951) 225-231; J. Org. Chem., 13 (1948), 830-833; J. Org. Chem., 42 (1977), 674-679; Indian J. Chem., 12 (1974), 31-37; J. Org. Chem., 39 (1974), 1589-1591. Synthesis, (1996), 495-501.).

The carboxylic acid represented by the general formula (3) is a corresponding ester (L = 〇R in the general formula (2), where R is a lower alkyl group such as methyl and ethyl, and an aralkyl group such as a benzyl group. Or an aryl group such as phenyl), which can be easily derived by a conventional hydrolysis reaction, wherein L is a leaving group displaceable by a nucleophile. The reactive derivative of the carboxylic acid can be synthesized from the haponic acid represented by the general formula (3) according to a general method commonly used. A compound in which X ₃ is an oxygen atom or one N (R ₇ ) — in the general formula (2), or X ₃ is a single bond, and X ₂ is an oxygen atom or —N (R ₄ ) _ In the case of a certain compound, the compound represented by the general formula (2) is represented by the general formula (4)

(Wherein Ri, R ₂ , and X ₂ have the same meaning as described above, and X ₃ represents an oxygen atom or one N (R ₇ ) —, or R ₂ and X 丄 represent the same as above. Has the same meaning, X ₂ represents an oxygen atom or 1 N (R ₄ ) —, and X ₃ represents a single bond.) A compound represented by the formula: Can be produced by reacting Examples of the inert solvent include solvents inert to the reaction reagent used, for example, aromatic hydrocarbon solvents such as benzene, toluene, and xylene; ether solvents such as tetrahydrofuran and 1,4-dioxane; Halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, etc .; amide solvents such as dimethylformamide and dimethylacetamide; basic solvents such as pyridine; or their solvents A mixed solvent is mentioned. Suitable carboxylic acid derivatives include, for example, phosgene, trichloromethyl chloroformate, bis (trichloromethinolecarbonate), ethyl / rechlorohonolemate, feninolechlorohonolemate, and isobutynolechlorohonolenate. Mate, bis (1-hydroxy 1H-benzotriazolyl) carbonate or N, N'-carbonyldiimidazole. The reaction can be carried out at a temperature between 20 ° C and the boiling point of the solvent, preferably between O ° C and 60 ° C.

The compound represented by the general formula (4) is publicly known in the literature, or can be produced from a publicly known compound in accordance with a publicly known method. (For example, Helv. Chim. Acta., 4 (1921) 212-217; J. Chem. Soc., (1933), 1493-1505; J. Amer. Chem. Soc., 55 (1933), 2051-2058 J. Amer. Chem. Soc., 71 (1949), 294-296; Chem. Ber., 57 (1924), 1645-1653; J. Org. Chem., 9 (1944), 529-536; J Org. Chem., 39 (1974), 1589-1591; Org. Synth., 56 (1977) 40; Tetrahedron Lett., 28 (1987), 4725-4728; J. Org. Chem., 61 (1996). J. Amer. Chem. Soc., 69 (1947), 858-859; J. Amer. Chem. Soc., 77 (1955), 2544-2545; J. Org. Chem., 3 ( 1938), 355-360; J. Amer. Chem. Soc., 71 (1949), 2734-2736; J. Amer. Chem. Soc., 81 (1959), 6423-6428; J. Amer. Chem. Soc. 63 (1941), 643-654, etc.).

 Examples of the compound represented by the general formula (1) produced as described above include the compounds exemplified in Table 19 below.

table 1

 X ゥ

■ 1 Y ■ 3 キ け け 2 — — CH 10- (+ n H J J or 2 チ ェ CH CH NH は 0 FHH ferri ま た は or 2 チ ェ CH CH NH Or 0 CH ₃ HH phenol or 2-CH CH NH or 0 ₂ H ₅ HH FER or 2-CH CH NH or 0 CH (CH ₃ ) ₂ HH FER or 2-CH CH NH or 0 CF ₃ HH ferr or 2 — Cher CH NH or 0 CH ₂ 0H HH ferr or 2 — Cher CH NH or 0 CH „NH ₂ HH ferr or 2 — Cher CH NH or 0 CHg (CH ₃ ) ₂ HH ferrule or 2-cell CH NH or 0 C (= CH ₂ ) CH ₃ HH ferr or 2-ch CH NH or 0 C (= 0) CH ₃ HH fer or 2-ch CH NH or 0 C0NH ₂ HH fer or 2-CH CH NH or 0 CON (CH3) ₂ HH full or 2-ch CH NH or 0 HH fer or 2-ch CH NH or 0 SO2N (CH ₃ ) ₂ HH Fe Rumata 2 one Choi Le CH NH or 0 OH HH Fe le or one Choi Le CH NH or 0 OCH3 HH full machining le or one Choi Le CH NH or 0 0¾Η ₅ HH Fe le or one Choi Le CH NH or 0 OCH (CH ₃ ) ₂ HH fer or 2 CH CH or NH (00) (CH ₂ ) ₂ NH ₂ HH fer or 2 — CH, CH CH or 00 (CH ₂ ) ₂ N (CH 3) ₂ HH Fe le or 2 one Choi 'Les CH NH or 0 N0 ₂ HH Fe le or 2 one Choi' Les CH NH or 0 C0 ₂ HHH Fe le or 2 one Choi 'Les CH NH or 0 NH ₂ HH Fe le or one Check CH NH or 0 N (CH ₃ ) ₂ HH 'Χ 2 thigh 2

R 2 腿 thigh Table 2

表 3 2 X ₂ Yi Y ₂ Y ₃ Fail or 2-Ch CH CH or 0 HCIH F-J or 2-Ch CH NH or 0 HFH F or 2 Ch CH or NH H CH ₃ H ferrule or 2-cell CH NH or 0 H ¾H ₅ H ferrule or 2-cell CH NH or 0 H CH (^ ₂ H-fer or 2-cell CH NH Or 0 H CF ₃ H fer or 2 — Chell CH NH or 0 H CHgOH H fer or 21 Ch CH NH or 0 H CH ₂ NH ₂ H Fer or 21 Ch CH CH or 0 H CHg (CH ₃ ) ₂ H fer or 2 CH CH or 0 HC (= CH ₂ ) CH ₃ H fer or 2 CH CH or 0 HC (= 0) CH ₃ H fer or 2 CH Cell CH NH or 0 H C0NH ₂ H ferrule or 2 — Cher CH NH or 0 H CON (CH ₃ ) ₂ H ferr or 2 CH CH NH or 0 H SO2N H2 H ferr or 2 Ch fer Le CH NH or 0H SO2 (CH ₃ ) ₂ H fer or 2 CH CH NH or 0 H OH H fer or 2 — Chell CH NH or 0 H OCH 3 H Fer or 2 — Chell CH NH or 0 H OC2H5 H Fer CH or CH 2 CH NH or 0 H 0CH (CH ^) ₂ H fer or CH ₂ CH ₂ CH ₂ NH ₂ H _{0 H 0 (CH 2) 2} N (CH3) 2 H Fe le or 2 - Choi / Les CH NH or 0 H N0 ₂ H Fe le or 2 - Choi, les CH NH or 0 H C0 ₂ HH Hue Le or 2 One cell CH NH or 0 H NH ₂ H fer or 2 — Cell CH NH or 0 HN (CH ₃ ) 2 H

Table 3

R ₂ X ₂ Yi 丫 2 Fail or 2 — Chell CH NH or 0 HH CI Fail or 2 — Chell CH NH or 0 HHF Fail or 2 Chell CH NH or 0 HH CH ₃ or CH 2 CH CH or 0 HH

Ferrite or 2-CH CH NH or 0 HH CH (CH ^) ₂ Fer J or 2-CH CH NH or 0 HH CF ₃ Fer or 2-CH CH NH or 0 HH CHgOH Ding II.

Roh X Norema 9 ^ Na one only 1 extra one Roh丄Honoré n WH toner f + o Π unr rl i Π click Fe les or one Choi Le CH NH or 0 HH CH2N (CH _{3) 2} Fe les or one Cher CH NH or 0 HHC (= CH ₂ ) CH ₃ ferr or 2 Chr CH NH or 0 HHC (= 0) CH ₃ ferr or 2 Chr CH NH or 0 HH C0NH ₂ Ferr or 2 —Chell CH NH or 0 HH CON (CH ₃ ) ₂ ferr or 2 —Chell CH NH or 0 HH S02 H ₂ ferr or 2 Ch GH NH or 0 HH SO2N (CH3) ₂ ferror or 2 One cell CH NH or 0 HH OH ferret or 2 — cell CH NH or 0 HH OCH3 ferr or 2 cell CH NH or 0 HH 0C ₂ H ₅ or 2 cell CH NH or 0 HH OCH (C¾) ₂ fer or 2 ch CH NH or 0 HH 0 (CH ₂ ) ₂ NH ₂ fer or 2 ch CH NH or 0 HH 0 (CH ₂ ) ₂ N (CH 3) ₂ fer Or 2 CH CH NH or 0 HH N0 ₂ fer or 2 ch CH NH or 0 HH C0 ₂ H fer or 2 — ch CH NH or 0 HH NH ₂ fer or 2 — ch CH CH or 0 HHN (C ^ _Z

表 4

Table 4

R ₂ X ₂ x ₃ YY ₂ Y ₃ Fail or 2 CH CH or N CH ₂ CH ₂ CIHH FH or 2 CH CH or N CH ₂ CH ₂ FHH FH or 2 —Chell CH or N CH ₂ CH ₂ CH ₃ HH Fern or 2 —Chel GH or N CH ₂ CH ₂ ¾Η ₅ HH Fer or 2 Ch GH or N CH ₂ CH ₂ CH (CH ₃ ) ₂ HH ferrule or 2-ch CH or N CH ₂ CH ₂ CF ₃ HH fer or 2-ch CH or N CH ₂ CH ₂ CHgOH HH fer or 2--ch CH or N CH ₂ CH ₂ HH ferrule or 2 CH CH or N CH ₂ CH ₂ CJ ^ N (CH ₃ ) ₂ HH ferrule or 2 — CH CH or N CH ₂ CH ₂ C (= CH ₂ ) CH ₃ HH CH or N CH ₂ CH ₂ C (= 0) CH ₃ HH ferret or ₂ CH CH or N CH ₂ CH ₂ C0NH ₂ HH fer or 2 CH CH or N CH ₂ CH ₂ CON (CH ₃ ) ₂ HH Fell or 2 — Chell CH or N C H ₂ CH ₂ S NH ₂ HH fer or 2 — Chell CH or N CH ₂ CH ₂ SOg (CH ₃ ) ₂ HH fer or 2 — Chell CH or N CH ₂ CH ₂ OH HH fer or 2 — CH or N CH ₂ CH ₂₀ CH ₃ HH fer or ₂ CH CH or N CH ₂ CH ₂ OCgHs HH FEL or 21 CH or N CH ₂ CH ₂₀ CH (CHg) ₂ HH fer Or 2 — Chell CH or N CH ₂ CH ₂₀ (CH2) ₂ H ₂ HH fer or 2 Ch CH or N CH ₂ CH ₂₀ (CH ₂ ) ₂ N (CH3) ₂ HH fer or 2 — Chell CH or N CH ₂ CH ₂ N0 ₂ HH Fer or 2 Ch CH or N CH ₂ CH ₂ C0 ₂ HHH Fer or 2 Ch Ch or N CH ₂ CH ₂ NH ₂ HH Fer Or 2 CH CH or N CH ₂ CH ₂ N (CH3> ₂ HH

表 6 Ferrule or 2-cell CH or N CH ₂ CH ₂ H CON (CHg) ₂ H Ferre or 2-ch GH or N CH ₂ CH ₂ H S02 H ₂ H Ferre or 2-ch CH or N CH ₂ CH ₂ H S0 ₂ N (CH3) ₂ H ferrule or 2 — chel GH or M GH ₂ CH ₂ H OH H phenol or 2 chel GH or N CH ₂ CH ₂ H OCH3 H ferrite or 2 chel CH or N CH ₂ CH ₂ H 0 C ₂ H ₅ H ferret or 2 — CH GH or N CH ₂ CH ₂ H OCH (CH3) ₂ H fer or 2 CH GH or N CH ₂ CH ₂ H 0 (CH ₂ ) ₂ NH ₂ H ferret or 2 ch CH or N CH ₂ CH ₂ H 0 (C) ₂ N (CH3) ₂ H fer or 2 ch GH or N CH ₂ CH ₂ H N0 ₂ H fer or 2 Ch CH or N CH ₂ CH ₂ H C0 ₂ HH Fer or 2 Ch CH or N CH ₂ CH ₂ H NH ₂ H Fer or 2 Ch CH or N CH ₂ CH ₂ HN (CH3> ₂ H

Table 6

表 7 R ₂ i ₂ x ₃ Yi Y ₂ Y ₃ F 3: レ or 2 CH CH or N CH ₂ CH ₂ HHCI ₂ or 2 GH or N CH ₂ CH ₂ HHF ま た は or 2 一Chell GH or N CH CH ₂ HH GH ₃ ferrules 2 — Chell CH or N CH ₂ CH ₂ HH Η ₅ ferrules or 21 ch CH or N CH CH ₂ HH CH (CHs) ₂ ferrules or 2 — chel CH or N CH ₂ CH ₂ HH CF ₃ ferrite or 2 GH or N CH ₂ CH ₂ HH CHgOH ferr or 2 ll CH or N CH ₂ CH ₂ HH CH2NH2 ferrile or 2 — chel GH or N CH ₂ CH ₂ HH CHg (CH ^ z ferr or 2 CH or N CH ₂ CH ₂ HHC (= (;) CH ₃ ferr or 2 1 CH GH or N CH ₂ CH ₂ HHC (= 0) CH ₃ ferret or ₂ CH CH or N CH ₂ CH ₂ HH C0N H ₂ F 3: CH or ₂ CH CH or N CH ₂ CH ₂ HH CON (CHgJg fer or 2 — Chell CH or N CH ₂ CH ₂ HHS (½NH2 ferret or 2-ch CH or N CH ₂ CH ₂ HH S¾N (CH3) _2- fer CH ₂ HCH or N CH ₂ CH ₂ HH OH file or _2- ch CH or N CH ₂ CH ₂ HH OCH3 ferrule or 2-cell GH or N CH ₂ CH ₂ HH 0¾Η ₅ fer or 2-ch CH or N CH ₂ CH ₂ HH OCH (01½) ₂ fer or 2 CH or N CH ₂ CH ₂ HH 0 (CH2> ₂ NH ₂ ferrule) ₂ CH or N CH ₂ CH ₂ HH 0 (CH2) ₂ N (CHgJg fer or 2 CH GH or N CH ₂ CH ₂ HH N0 ₂ fer or 2 GH GH or N CH ₂ CH ₂ HH CO2H fer or 2 GH or N CH ₂ CH ₂ HH NH ₂ FU or 2 — Chell CH or N CH ₂ CH ₂ HHN (GH3) ₂

Table 7

表 8 _{R 2 Χι 2 X3 Yi Y2 Y} 3 Fe two Honoré or one Choi Le CH or N CH (CH3) CH ₂ CIHH-phenyl or 2 - Choi Le CH or N CH (CHa) CH ₂ FHH-phenyl or 2 1 CH or N CH (CH3) CH ₂ CH ₃ HH FENO or 2 CH CH or N CH (CH3) CH ₂ C2H5 HH FER or 2 CH CH or N CH (CH3) CH ₂ CH (CH ₃ ) ₂ HH ferrule or 2 CH CH or N CH (CH3) CH ₂ CF ₃ HH ferr or 2 CH or N CH (CH3) CH ₂ C ^ OH HH ferret or 2 1-CH CH or N CH ₂ CH2 H2 HH ferret or _2- Ch CH or N CH iCHa) CH ₂ CH2N (083) 2 HH fer or _2- Ch CH or N CH (CH3) CH ₂ C ( = CH ₂ ) CH ₃ HH fer or _2- ch CH or N CH (CH3) CH ₂ C (= 0) CH ₃ HH fer or _2- ch CH or N CH (CH3) CH ₂ C0NH ₂ HH Fe le or 2 - Choi Le CH or _{N CH (CH3) CH 2 CON} (CH 3) 2 HH Fe Or one Choi Le CH or _{N CH (CH3) CH 2 SO2NH2} HH Fe le or 2 - Choi Le CH or _{N CH (GH3) CH 2 S0} 2 N (CH 3) 2 HH Fe le or one Choi Le CH or _{N CH (CH3) CH 2 OH} HH Fe le or one Choi Le CH or N CH iCHg) CH ₂ OCH3 HH Fe les or 2 - Choi Le CH or _{N CH (CH ^) OH 2} 0C 2 H 5 HH -off Engineering CH or N CH (CH3) CH ₂ OCH (CH3> ₂ HH ferret or 2 CH or N CH (CH3) CH ₂₀ (CH ₂ ) ₂ NH ₂ HH fer or 2 One CH or N CH (CH3> CH ₂₀ (CH ₂ ) ₂ (CH3) 2 HH fer or 2 CH CH or N CH (CHg) CH ₂ N 0 ₂ HH fer or 2 — CH CH Or N CH (CH3) GH ₂ C¾H HH fer or _2- ch CH or N CH (CH3) CH ₂ NH ₂ HH fer or _2- ch CH or N CH (CH3> CH ₂ N (CH ₃ ) ₂ HH

Table 8

表 9R ₂ Χι χ ₂ x ₃ Yi Y ₂ Y ₃ Fer-or 2-CH CH or N CH (CH3) CH ₂ HCIH Fer-Mel or 2-Ch CH or M CH (CH3) CH ₂ HFH Fail or 2-CH CH or N CH (CH3) CH ₂ H CH ₃ H FEL or 2-CH CH or N CH (CH3) CH ₂ H ¾H ₅ H FELL or 2-CH CH Or N CH (CH3) CH ₂ H CH (CH3) ₂ H Fer or 2 — Chell CH or N CH (CH3) CH ₂ H CF ₃ H Fer or 2 Ch Ch or N CH (CH3) CH ₂ H CHgOH H ferret or 2 CH GH or N CH (CH3 CH ₂ H CH2 H2 H fer or 2 — CH CH or N CH (CH3) CH ₂ H CH ₂ N (CH ₃ ) ₂ H fer Or 2 — CH CH or N CH (CH3) CH ₂ HC (= CH ₂ ) CH ₃ H phenol or 2 CH CH or N CH (CH3) CH ₂ HC (= 0) CH ₃ H fer Or 2 CH CH or N GH (CH3) CH ₂ Hz C0NH ₂ H ferrite or 2 CH GH or N CH (CH3) CH ₂ H CON (CH3) ₂ H ferret or 2 CH CH or N CH (CH3) CH ₂ H SQ2NH2 H fer or 2 — CH CH or N CH (CH3) CH ₂ H S02 ( CH3) ₂ H ferret or 2 — Chell CH or N CH (CH3) CH ₂ H OH H ferret or 2 — Chell CH or N CH (CH3) CH ₂ H 0 CH ₃ H ferret or 2 Chell CH or _{N CH (CH3) CH 2 H} 0 (½Η 5 H Fe Honoré or one Choi Le CH or _{N CH (CH3) CH 2 H} OCH (CH3> 2 H Fe les or one Choi Le CH or N CH ( CH3) CH ₂ H 0 (CH ₂ ) ₂ NH ₂ H fer or 2 CH CH or N CH (CH3) CH ₂ H 0 (CH ₂ ) ₂ N (CHs) 2 H fer or 2 CH CH or N CH (CH3) CH ₂ H N0 ₂ H Fer or 2-CH CH or N CH (CH ₃ ) CH ₂ HC (½H H Fer or 2-Ch CH or N CH (CH ₃ ) CH ₂ H NH ₂ H Fer or 2 CH CH or N CH (CH ₃ ) CH ₂ HH

Table 9

2 ι X ₂ X ₃ Yl Y ₂ Y ₃ Fer こ 2 1 CH 2 CH or N CH (CH 3) CH 2 HHC | Fer or 2 CH 2 CH or N CH (CH 3) CH 2 HHF ―R2 is CH2 or N CH (CH3) CH ₂ HH

Fail or 2-Cenyl GH or N CH (CH3) CH ₂ HH

Ferr or 2-Chenyl CH or N CH (CH3) CH ₂ HH CH (CHg) ₂ Ferr or 2-Chenyl CH or N CH (CH3) CH ₂ HH CF ₃ Fer or 2-Chenyl CH or N CH ( CH3) CH ₂ HH CHgOH Fe le or 2 one-thienyl GH or _{N CH (CH3) CH 2 HH} CH2 H 2 full machining le or 2 one-thienyl CH or _{N CH (CH3) CH 2 HH} CH2 (CH3> 2 Fe le or 2-Chenyl CH or N CH (CH3) CH ₂ HHC (= CH2> CH ₃ fer or 2-Chenyl CH or N CH (CH3) CH ₂ HHC (= 0) CH ₃ fer or 2-Chenyl CH or N CH (CH3) CH ₂ HH C0NH ₂ Fer or 2-Chenyl CH or N CH (CH3) CH ₂ HH CON (C) ₂ Fer or 2-Chenyl GH or N CH CCHg) CH ₂ HH S¾NH ₂ Fer or 2 Chenyl CH or N CH (CH3) CH ₂ HH S¾ (CH3) ₂ Fer or H N CH (CH3) CM

2 one-thienyl CH The CH ₂ HH OH Fe le or 2 one-thienyl CH or _{N CH (CH3) CH 2 HH} OCH3 Fe le or 2 one-thienyl CH or _{N CH (CH3) CH 2 HH} 0¾Η 5 Fe le or 2 - thienyl GH or N CH (CH3) CH ₂ HH OCH (C ^ 2 ferr or 2-Chenyl CH or N CH (CHa) CH ₂ HH 0 (CH ₂ ) ₂ NH ₂ ferr or 2-Chenyl CH or N CH ( CH3) CH ₂ HH 0 (CH ₂ ) ₂ N (CH3) ₂ Fer or 2-Chenyl CH or N CH (CH3) CH ₂ HH N0 ₂ Fer or 2-Chenyl CH or N CH (CH3) CH ₂ HH 0 (½Η Ferr or 2-Chenyl GH or N CH (CH3) CH ₂ HH NH ₂ Fer or 2-Chenyl CH or N CH (CH3) CH ₂ HH

In the substituted guanidine derivative of the present invention, the acylguanidine moiety is represented as in the above formula (1), but the compound may have tautomerism. That is, a tautomer in which the acylguanidine moiety is diaminomethyleneamino [1-C (O) N = C (N

H ₂ ) 2] and the tautomer [1-C (◦) NH-C (= NH) NH ₉ ], which is aminoiminomethylamino, may be the same compound only in a different state. is there. Therefore, the present invention includes any of these tautomers.

 The compounds of the general formula (1) include those having an optically asymmetric center, and therefore, they can be obtained as a racemate or in an optically active form when an optically active starting material is used. Can be. If necessary, the racemates obtained can be physically or chemically resolved into their optical antipodes by methods known per se. Preferably, the diastereomer is formed from the racemate by reaction using an optically active resolving agent. The diastereomers of different forms can be separated by methods known per se, for example by fractional crystallization.

 Examples of the “prodrug” include those that are easily hydrolyzed in vivo and regenerate the compound of the formula (1). For example, in the case of a compound having a carboxyl group, a compound in which the carboxyl group has become an alkoxycarbonyl group And compounds having an alkylthiocarbonyl group or compounds having an alkylaminocarbonyl group. For example, in the case of a compound having an amino group, a compound in which the amino group is substituted with an alkanol group to form an alkanoylamino group, a compound in which the amino group is substituted with an alkoxycarbonyl group to form an alkoxycarbonylamino group, A compound that has become a cimethylamino group or a compound that has become hydroxylyamine can be given. For example, in the case of a compound having a hydroxyl group, a compound in which the hydroxyl group has been substituted with the above-mentioned acyl group to form an acyloxy group, a compound which has become a phosphoric ester, or a compound which has become an acyloxymethyloxy group Is mentioned. Examples of the alkyl portion of the group used for these prodrugs include the aforementioned alkyl groups, and the alkyl group may be substituted (for example, by an alkoxy group having 1 to 6 carbon atoms). Preferable examples include, for example, a compound in which a carboxyl group is an alkoxycarbonyl group, for example, a lower (for example, having 1 to 6 carbon atoms) alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, etc., methoxymethoxycanoleboninole, ethoxymethoxy. Lower (eg, 1 to 6 carbon atoms) alkoxycarboyl substituted by an alkoxy group such as cicanoleboninole, 2-methoxyethoxycanoleboninole, 2-methoxyethoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl, and the like.

The compound represented by the general formula (1) or a prodrug thereof may be used as needed. It can be an acid addition salt with a pharmaceutically acceptable inorganic or organic acid. Such acid addition salts include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid; formic acid, acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, malic acid, tartaric acid, Salts with organic carboxylic acids such as aspartic acid and glutamic acid; salts with sulfonic acids such as methanesnolefonic acid, benzenesnolefonic acid, p-to / reensnolefonic acid, hydroxybenzenesulfonic acid, dihydroxybenzenesulfonic acid, etc. Are mentioned.

 The compound represented by the general formula (1) or a prodrug thereof may be a pharmacologically acceptable base addition salt as required. Examples of such base addition salts include ammonium salts, lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts and the like.

 Further, the compound represented by the general formula (1) or a prodrug thereof or a pharmaceutically acceptable salt thereof may be an anhydride, hydrate or solvate thereof.

The compound of the present invention has an inhibitory effect on sodium Z-proton (Na ^ H exchange transport system), and is a disease caused by abnormal sodium / proton (Na ⁺ / H +) exchange transport system, for example, hypertension, ischemia Or as a remedy or prophylactic for organ damage due to ischemia reperfusion, arrhythmia, angina pectoris, diabetes mellitus, cardiac hypertrophy, cerebral ischemia disorder, diseases caused by excessive cell proliferation or diseases caused by endothelial cell damage Useful.

The compound of the present invention, a prodrug thereof, or a pharmaceutically acceptable salt thereof can be administered orally or parenterally when using them as a medicine. That is, it can be orally administered in a commonly used dosage form such as a powder, granule, tablet, capsule, syrup, suspension or the like, or, for example, a solution, emulsion, or suspension thereof. Can be administered parenterally in the form of injections. It can also be administered rectally in the form of suppositories. The above-mentioned suitable dosage form can be produced, for example, by mixing the active compound with a usual acceptable carrier, excipient, binder, stabilizer, or diluent. When used in an injectable form, for example, an acceptable buffer, solubilizing agent, or isotonic agent can be added. The dose and frequency of administration vary depending on, for example, the target disease, symptoms, age, weight, and dosage form. Usually, however, 0.1 to 2000 mg, preferably 1 to 200 mg, per day for an adult can be administered once or in several divided doses.

 Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto. The compound names shown in the following Reference Examples and Examples do not always follow the IUPAC nomenclature.

Reference example 1

 (1) Synthesis of 2-benzhydrol

 Sodium borohydride (0.38 g, 10.Ommol) was added to a solution of 2-chlorobenzophenone (2.17g, 10.Ommol) in ethanol (44ml), and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into cold water, extracted with ethyl acetate (twice), the extract was washed with water (twice), then washed with a 5% aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.2 g of 2-chlorobenzhydrol.

_{1 H NM R (CDC 1 3} ) δ; 2.33~ 2.35 (1H, m), 6.23 (. 1H, d, J = 4 OHz), 7.19~7.41 (8H, m), 7.59~7.62 (1H, m) .

 The following compounds (2) and (3) were synthesized by using the same method as (1).

 (2) 3—Black mouth

_{1 HNMR (CD C 1 3)} δ; 2.28 (1H, d, J = 3.3Hz), 5.79 (1Η, d, J = 3.5Hz), 7.20~7.52 (9H, m).

 (3) 4 black mouth

_{^{1 HNMR (CD C 1 3)}} δ; 2.24 (1H, dd, J = 2.2Hz, 3.5 Hz), 5.81 (1H, d, J = 3.5Hz), 7.25~7.35 (9H, ra).

Reference example 2

 (1) Synthesis of 2,3'-dichrolic benzohydrol

A mixture of 3-bromochlorobenzene (1.91 g, 10. Ommol), magnesium (0.24 g, 10. Ommol), a catalytic amount of 1,2-dibromoethane and tetrahydrofuran (28 ml) was heated to reflux for 4 hours, and then the reaction mixture was refluxed. Cool to 0 ° C, then A solution of mouth aldehyde (1.41 g, 10. Ommol) in tetrahydrofuran (5 ml) was added dropwise. The reaction solution was stirred at 0 ° C for 1 hour and then left at room temperature for 2 days. The reaction solution was poured into a cooled 1N hydrochloric acid solution, extracted with getyl ether (twice), and the extract was washed with water, a 5% aqueous sodium hydrogencarbonate solution, and a 5% aqueous sodium chloride solution in that order, and then anhydrous magnesium sulfate. And dried. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluted with ethyl acetate n-hexane = 4/96) to give 2,3'-dichroic benzyl hydrochloride in 1.62. g obtained.

_{^{1 HNMR (CDC 1 3) δ}} ; 2.43 (1H, d, J = 3.9Hz), 6.21 (1H, d, J = 4.0Hz), 7.21~7.41 (7H, m), 7.55 (1H, dd, J = l.8Hz, 7.5 Hz).

 The following compounds (2) to (5) were synthesized by using the same method as (1).

 (2) 3.3 '-

_{^{1 HNMR (CDC 1 3) δ}} ; 2.28~ 2.30 (1H, m), 5.77 (1H, d, J = 3.5Hz), 7.22~7.38 (8Η, m).

(3) 2,3

_{^{1 HNMR (CDC 1 3) δ}} ; 2.38 (1Η, d, J = 3.7Hz), 6.22 (1H, d, J = 3.5Hz), 7.24~7.42 (7H, m), 7.58~7.61 (1H, m) .

 (4) 2-Penzinoleoxybenzhi draw / re

_{^{1 HNMR (CDC 1 3) δ}} ; 2.95~2.97 (1H, m), 5.03 (2Η, s), 6.06 (1H, d, J = 6.1Hz), 6.92~7.00 (2H, m), 7.18~7 · 37 (12 H, m).

 (5) 3_benzyloxybenzhi dronore

_{^{1 HNMR (CDC 1 3) 8}} ; 2.27~2.30 (1H, m), 5.02 (2Η, s), 5.77 (1H, d, J = 3.3Hz), 6.84~6.88 (1H, m), 6.95 (1H, d, J = 7.7Hz), 7.02-7.03 (1H, m), 7.21-7.42 (11H, m).

Reference example 3

 (1) Synthesis of 4-clozen benzhydrylamine

A mixture of 4_ benzophenone (4.33 g, 20. Ommol) and ammonium formate (12.61 g, 200 mmol) was heated and stirred at 160 to 170 ° C for 16 hours. After the reaction solution was cooled to room temperature, an aqueous ammonia solution was added, and extracted with ethyl acetate (twice). The extract was washed with water and a 5% aqueous sodium chloride solution and then dried over anhydrous sulfuric acid. The residue obtained by distilling off the solvent under reduced pressure is purified by silica gel gel chromatography (eluted with ethyl acetate / n-hexane = 1/1) to obtain N- (4-chlorobenzene). 4.37 g of formamide was obtained. Then, add this N- (4-benzhydryl) honolemamide (4.00 g, 16.3 ol) to a mixture of 35% hydrochloric acid (40 ml) and 1,4-dioxane (30 ml), and heat for 1 hour. Refluxed. The reaction solution was poured into ice water, washed with getyl ether, and the aqueous layer was made alkaline with a 28% aqueous ammonia solution. Subsequently, extraction was performed with getyl ether (twice), and the extract was washed with water and a 5% aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.6 g of 4-hydroxybenzhydrylamine.

_{^{1 HNMR (CDC 1 3) δ}} ; 1.73 (2Η, brs), 5.19 (1H, s), 7 · 20~7.36 (9 H, m).

 The following compounds (2) to (11) were synthesized by using the same method as (1).

 (2) 2—Black mouth Benzhydrylamine

_{^{1 HNMR (CDC 1 3) δ}} ; 1.76 (2H, brs), 5.64 (1H, s), 7 · 14~7.20 (1H, m), 7.21~7 · 40 (7Η, m), 7.50~7.53 (1H , m).

 (3) 3—black mouth Benzhydrylamine

_{1 HNMR (CDC 1 3) δ} ; 1.73 (2H, brs), 5.18 (1H, s), 7.17~7.27 (4H, m), 7.29~7.37 (4H, m), 7.40~7.41 (1H, m).

 (4) 2-Methylbenzhydrylamine

^{1 HNMR (CDC 1 3) δ} ; 1.72 (2H, brs), 2.25 (3H, s), 5.37 (1H, s), 7.11~7.30 (8H, m), 7.53 (1H, d, J = 7.5Hz) .

(5) 3-Methylbenzhydrylamine

_{^{1 HNMR (CD C 1 3)}} 6; 1.74 (2H, brs), 2.32 (3H, s), 5.17 (1H, s), 7.03 (1H, d, J = 7.0Hz), 7.14~7.25 (4H, m ), 7.28 to 7.39 (4H, m).

(6) 4-Methylbenzhydrylamine

^{1 HNMR (CD C 1 3)} δ; 1.74 (2H, brs), 2.31 (3H, s), 5.17 (1H, s), 7.10 to 7.13 (2H, m), 7.18 to 7.38 (7H, m).

 (7) a- (2-Chenyl) benzylamine

_{^{1 HNMR (CDC 1 3) δ}} ; 1.87 (2H, brs), 5.41 (1H, s), 6.82~6.84 (1H, m), 6.92 (1H, dd, J = 3.5Hz, 5.0Hz), 7.20 (1H , dd, J = 1.3 Hz, 5.1 Hz), 7.23 to 7.29 (1H, m), 7.32 to 737 (2H, m), 7.40 to 7.43 (2H, m).

 (8) a_ (2-pyridyl) benzylamine

_{^{1 HNMR (CDC 1 3) δ}} ; 2.17 (2Η, brs), 5.24 (1H, s), 7.11~7.15 (1H, m), 7 · 20~ 7.27 (2H, m), 7.28~ 7.34 (2H, m ), 7.38 to 7 · 42 (2H, m), 7.56 to

7.62 (1H, m), 8.55-8.58 (1H, m).

(9) a— (3-pyridyl) benzylamine

_{^{1 HNMR (CDC 1 3) δ}} ; 1.81 (2H, brs), 5.26 (1H, s), 7 · 21~7.28 (2H, m), 7 · 31~7 · 39 (4H, m), 7.68~7.72 (1H, m), 8.47 (1H, dd, J = l.7Hz, 4.8Hz),

8.65 (1H, d, J = 2.2Hz).

 (10) a_ (4-pyridyl) benzylamine

_{1 HNMR (CDC 1 3) δ} ; 1.84 (2H, brs), 5.17 (1H, s), 7.23~7, 30 (1H, m), 7.31~7.34 (6H, m), 8.52 (2H, dd, J = l.7Hz, 4.4Hz).

 (11) 3-Nitrovens hydrylamine

_{^{1 HNMR (CDC 1 3) δ}} ; 1.77 (2H, brs), 5.32 (1H, s), 7.23~7.29 (1H, m), 7.31~7.39 (4H, m), 7.44~7.50 (1H, m), 7.74 (1H, d, J = 7.7Hz), 8.06 to 8.10 (1H, m), 8.32 to 8.33 (1H, m).

Reference example 4

 (1) Synthesis of 2,3'-jikuguchibenzhydrylamine

Reference Example 2 A mixture of 2,3'-dichlorobenzhydrol (1.00 g, 3.95 mmol), triethylamine (1.20 g, 11.9 mmol) and tetrahydrofuran (40 ml) obtained in (1) was heated to 0 ° C. After cooling, a solution of methanesulfoyluc mouth ride (0.91 g, 7.90 mmol) in tetrahydrofuran (10 ml) was slowly added dropwise with stirring. After the reaction solution was stirred at 0 ° C. for 1 hour, the temperature was raised to room temperature. The residue obtained by distilling off the solvent under reduced pressure was dissolved in 1-methyl-2-pyrrolidinone (20 ml), sodium azide (0.77 g, 11.9 mraol) was added, and the mixture was heated and stirred at 80 ° C for 2 hours. Ice water The mixture was poured into the mixture, extracted with getyl ether (twice), and the extract was washed with water and a 5% aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in tetrahydrofuran (15 ml), and this solution was cooled to 0 ° C and suspended in lithium aluminum hydride (0.15 g, 3.95 mmol) in tetrahydrofuran (30 ml). Dropped in. After the reaction solution was stirred at 0 ° C. for 2 hours, it was poured into cold 2N hydrochloric acid and washed with getyl ether (twice). Next, the aqueous layer is made alkaline with a 2N aqueous sodium hydroxide solution, extracted with getyl ether (twice), and the extract is washed with a 5% aqueous sodium chloride solution (twice), and then dried over anhydrous magnesium sulfate. Dried. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel gel column chromatography (eluted with ethyl acetate-hexane = 1/1) to reduce 2,3'-dichlorobenzhydrylamine to 0.51%. g obtained.

_{^{1 HNMR (CDC 1 3) δ}} ; 1.70 (2Η, brs), 5.61 (1H, s), 7.17~7.29 (5H, m), 7.35 (1H, dd, J = l.5Hz, 7.7Hz), 7.41 ( 1H, s), 7.48 (1H, dd, J = 1.7 Hz, 7.5 Hz).

 The following compounds (2) to (4) were synthesized by using the same method as (1).

 (2) 3, 3'-dichlorobenzhydrylamine

_{^{1 HNMR (CDC 1 3) δ}} ; 1.70 (2H, brs), 5.15 (1H, s), 7.19~ 7.38 (8H, m).

(3) 2, 3-dichlorobenzhydrylamine

_{^{1 HNMR (CDC 1 3) δ}} ; 1.72 (2H, brs), 5.66 (1H, s), 7.18~7.39 (7H, m), 7.48~7.51 (1H, m).

 (4) 2-benzyloxybenzhi dolinoleamine

_{^{1 HNMR (CDC 1 3) δ}} ; 1.69 (2H, brs), 5.03 (2H, s), 5.18 (1H, s), 6.82~ 6.85 (1H, m), 6.97 (1H, d, J = 7.7Hz) , 7.03-7.04 (1H, m), 7.20-7.42 (1H, m).

Reference example 5

 Synthesis of N, N-diphenylglycineethyl ester

Diphenylamine (1.69 g, 10. Ommol), 60% sodium hydride (0.40 _g , A mixture of 10. Oramol) and dimethylformamide (34 ml) was stirred at room temperature for 4 hours, and then ethyl bromoacetate (1.67 g, 10. Ommol) was added dropwise. The reaction mixture was heated and stirred at 80 ° C for 2 hours, poured into a 5% aqueous sodium chloride solution, extracted with ethyl acetate (twice), and the extract was washed with water and a 5% aqueous sodium chloride solution and then dried. Dried over sodium sulfate. By purifying the residue obtained by evaporation of the solvent under reduced pressure was in silica gel column chromatography (eluted with hexane = ^2/98 to acetic acid Echiru Zn-), Ν, Ν - diphenyl glycine E chill ester 0.23 g obtained.

_{^{1 HNMR (CDC 1 3) δ}} ; 1.24 (3Η, t, J = 7.2Hz), 4.19 (2Η, q, J = 7.2Hz), 4.44 (2H, s), 6.93~7 · 09 (6Η, m) , 7 · 24 to 7.30 (4H, m).

Reference example 6

 Synthesis of N_ (2_carboxyethyl) _N-phenylayurin

 (a) Synthesis of N- (2-cyanoethyl) -1-N-phenylaniline

 A mixture of N- (2-chloroethyl) -N-phenylaniline (1.00 g, 4.32 ramol), sodium cyanide (0.42 g, 8.63 mmol) and dimethylformamide (20 ml) was stirred at 50 ° C for 10 hours. did. The reaction solution was poured into a 5% aqueous sodium chloride solution, extracted with ethyl acetate (twice), and the extract was washed with water and a 5% aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluted with ethyl acetate / n-hexane = 4/96) to give N- (2-cyanoethyl) -N-phenylaniline. Was obtained in an amount of 0.26 g.

^{1 H NMR (CDC 1 3)} δ; 2.65~ 2.70 (2H, m), 4.06 (2H, t, J = 7.2Hz), 6.97~7 · 05 (6Η, m), 7 · 27~7.34 (4H, m).

 (b) Synthesis of N- (2-carboxyethyl) -N-phenylaniline

A mixture of N- (2-cyanoethyl) -1-N-phenylaniline (0.25 g, 1.12 mmol ol), a 50% aqueous sulfuric acid solution (5 ml) and acetic acid (5 ml) was heated and stirred at 80 to 100 ° C for 3 hours. . The reaction solution was diluted with a 5% aqueous sodium chloride solution, extracted with getyl ether (twice), and the extract was washed with a 5% aqueous sodium chloride solution. Subsequently, the organic layer was extracted with a 1N aqueous solution of sodium hydroxide (twice), the aqueous layer was acidified with 1N hydrochloric acid, and then extracted with getyl ether (twice). Wash the eluate with 5% aqueous sodium chloride solution After cleaning, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.08 g of N- (2-carboxyethyl) -N-phenylaniline.

_{^{1 HNMR (CDC 1 3) δ}} ; 2.70~2.75 (2H, m), 4.03~4.08 (2H, m), 6.95 ~7 · 01 (6Η, m), 7.24~7.30 (4H, m).

Reference Example 7

 (1) Synthesis of 4,4-diphenylbutanoic acid ethyl ester

 (a) Synthesis of 4,4-diphenyl-13-butenoic acid ethyl ester

 To a suspension of 60% sodium hydride (0.60 g, 15. Ommol) in dimethylformamide (40 ml) was added dropwise ethyl phosphonoethylate (3.36 g, 15.0 mmol) in a suspension, and the mixture was stirred at 0 ° C for 15 minutes. Thereafter, diphenylacetoaldehyde (1.96 g, 10. Omraol) was added dropwise, and the mixture was stirred at 0 ° C for 1 hour. The reaction solution was poured into a 5% aqueous sodium chloride solution, extracted with ethyl acetate (twice), and the extract was washed with water and a 5% aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluted with ethyl acetate: Zn-hexane = 1/99) to give 2.63 g of 4,4-diphenyl-3-butenoic acid ethyl ester. Obtained.

_{^{1 HNMR (CDC 1 3) δ}} ; 1.26 (3H, t, J = 7.2Hz), 3.15 (2H, d, J = 7.3Hz), 4.15 (2H, q, J = 7.2Hz), 6.24~6.29 (1H , m), 7.16 to 7.41 (10H, m).

 (b) Synthesis of ethyl 4-, 4-diphenylbutanoate

A mixture of 4,4-diphenyl-3-ethyl butenoate (2.00 g, 7.51 ol), ammonium formate (4.74 g, 75.lmmol 10% palladium on carbon (0.20 g) and ethanol (40 ml) was heated at 50 ° C. at stirred for 5 hours. the catalyst and the filtrate was concentrated under reduced pressure obtained was filtered off and the resulting concentrated residue was purified by silica gel column chromatography (acetic Echiru / n-to-hexane two 1/9 ⁹⁾ As a result, 1.60 g of 4,4-diphenyl ethyl butyrate was obtained.

^{1 HNMR (CD C 1 3)} 8; 1.23 (3H, t, J = 7.2Hz), 2.23~ 2.30 (2H, m), 2.34~ 2 · 42 (2H, m), 3.90~ 3.95 (1H, m) , 4.09 (2H, q, J = 7.2Hz), 7.14 to 7.30 (10H, m).

By using the same method as (1), the following compound (2) was synthesized. (2) 4,4-diphenyl-1,3-methylbutanoic acid ethyl ester

_{^{1 HNMR (CDC 1 3) δ}} ; 0.91 (3Η, d, J = 6.4Hz), 1.22 (3Η, t, J = 7.2Hz), 1.96- 2.04 (1H, m), 2.38 (1H, dd, J = 3.5Hz, 15.2 Hz), 2.85 to 2.95 (1H, m), 3.57 (1H, d, J = 11.0Hz), 4.04 to 4.11 (2H, m), 7.16 to 7.18 (2H, m), 7.23 7.32 (8H, m).

Reference Example 8

 Synthesis of N- (diphenylmethyl) glycineethyl ester

 A mixture of benzhydrinoleamine (1.83 g, 10. Ommol), ethyl bromoacetate (1.67 g, 10. Ommol), potassium carbonate (6.91 g, 50. Ommol) and 1-methyl-12-pyrrolidinone (40 ml) was added at room temperature. For 11 hours. The reaction solution was poured into water, extracted with ethyl acetate (twice), and the extract was washed with a 5% aqueous sodium hydrogen carbonate solution and a 5% aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel gel chromatography (elution with ethyl acetate / hexane = 4/96) to give N- (diphenylmethyl) glycineethyl ester. 2.24 g was obtained.

_{^{1 HNMR (CDC 1 3) δ}} ; 1.25 (3Η, t, J = 7.2Hz), 2.22 (1H, brs), 3.37 (2H, s), 4.18 (2H, q, J = 7.2Hz), 4.88 (1H , s), 718-18.24 (2H, m), 7.26-7.32 (4H, m), 7.38-7.42 (4H, m).

Reference Example 9

Synthesis of N-Methoxycarbonyl-2- (2-pyridyl) benzylamine

Reference Example 3 In a solution of α- (2-pyridyl) benzylamine (0.10 g, 0.54 mmol) synthesized in (8) in dimethylformamide (2 ml), methyl chloroformate (0.051 g) was added at 0 ° C. , 0.54 corruptol) in dimethylformamide (0.5 ml) was added dropwise. The reaction solution was stirred at 0 ° C for 1 hour, further dried at room temperature for 2 hours, then poured into a 5% aqueous sodium chloride solution, and extracted with ethyl acetate (twice). The extract was washed with water and a 5% aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was silica gel column outlet Matogurafi one purified by (eluted with black port Holm Z methanol == ⁹ 9/1) N-menu Tokishikarubo two Lou alpha-(2-pyridyl ) 0.068 g of benzylamine was obtained. Melting point: 97 101 ° C (recrystallized from a mixed solvent of getyl ether and _n- xane)

_{^{1 HNMR (CDC 1 3) δ}} ; 3.67 (3Η, s), 5.90 (1H, d, J = 6.4Hz), 6.78 (1H, brs), 7.16 7.35 (7H m), 7.59 7.64 (1H, m) 8.56 (1H, d J = 4.4Hz)-Reference example 10

Synthesis of N-phenoxycanolepon / le N-meth / lebenzhydrinoleamine

(a) Synthesis of N-phenoxyl-norrebonylbenzhydrisleamine

 A mixture of benzhydrylamine (L83 g, 10. Ommol), phenyl chloroformate (1.57 g 10. Ommol) 4-dimethylaminopyridine (1.47 g, 12. Ommol) and tetrahydrofuran (73 ml) was added at room temperature for 1 hour. Stirred. The reaction solution was poured into a 5% aqueous sodium chloride solution, extracted with getyl ether (twice), and the extract was washed with water and a 5% aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was crystallized from a mixed solvent of getyl ether and n-hexane to obtain 2.73 g of N-phenoxycarbonylbenzhydrylamine.

Melting point: 132 134C

_{^{1 HNMR (CDC 1 3) δ}} ; 5.67 (1H, m), 6.05 (1H, d, J = 8.3Hz), 7.13 7.21 (3H, m), 7.27 7.40 (12H, m).

 (b) Synthesis of N-phenoxycarbonyl N-methinolebenzhydrylamine

 After stirring a mixture of N-phenoxycarberbenzhydrylamine (2.50 g, 8.24 mmol) 60% sodium hydride (0.36 g, 9.07 mmol) and dimethylformamide (50 ml) at room temperature for 10 minutes, Methyl iodide (2.34 g 16.5 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was poured into a 5% aqueous sodium chloride solution, extracted with ethyl acetate (twice), and the extract was washed with water and a 5% aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluted with ethyl acetate / n-hexane = 2/98) to give N-phenoxycarbonyl N-methylbenzhydrylamine. 0.13 g was obtained.

_{^{X HNMR (CDC 1 3) δ}} ;. 2.89 (3Η, s), 6.78 (1H, s) 7.13 7 · 51 (15H, m) Reference Example 11 (1) Synthesis of 3- (2-chlorophenyl) -1-phenylpropionic acid

 (a) Synthesis of 3- (2-cyclohexyl) -1-3-phenyl-2-hydroxypropionic acid

A solution of n_butyllithium in hexane (L53M, 20 ml) was added dropwise to a solution of diisopropylamine (3.04 g, 30. Omraol) in tetrohydrofuran (60 ml) at 0 ° C, and the mixture was stirred at 0 ° C for ³⁰ minutes. after acetate (0. ⁹ 0g, 15. Ommol) was added dropwise as tetrahydrofuran (10ml) solvent solution. The reaction solution was stirred at 0 ° C for 30 minutes, and further stirred at 45 ° C for 1 hour. Next, the reaction solution was cooled to 0 ° C, and a solution of 2-chloro-benzophenone (3.25 g, 15.Ommol) in tetrahydrofuran (20 ml) was added dropwise, followed by stirring at 0 ° C for 1 hour. The mixture was stirred at room temperature. The reaction solution was poured into cold 1 N hydrochloric acid, extracted with getyl ether (twice), and then extracted from the ether layer with a 0.1 N aqueous sodium hydroxide solution. The separated aqueous layer was washed with getyl ether (twice), acidified with 2N hydrochloric acid, and extracted with getyl ether (twice). The extract was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was crystallized from a mixed solvent of chloroform and n-hexane to give 3- (2-chlorophene-ole) -13-phenylenol-3-hydroxypropione. 3.19 g of the acid were obtained.

Melting point: 153-155. C

_{^{1 HNMR (CDC 1 3) δ}} ; 3.48 (2Η, dd, J = 16.5Hz, 44.0Hz), 7.25~7.39 (8H, m), 7.83 (1H, dd, J = l.5Hz, 7.9Hz).

 (b) Synthesis of 3- (2-chlorophenyl) -1-phenylpropionic acid

A mixture of triethylsilane (4.20 g, 36.2 mmol) and trifluoroacetic acid (40 ml) was cooled to 0 ° C., and then 3- (2-chloropheninole) -13-phenyl-13-hydroxypropionic acid was added. (1.00 g, 3.62 mmol) was added, followed by stirring at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, water was added to the residue obtained, extracted with getyl ether (twice), and then extracted from the ether layer with a 0.5N aqueous sodium hydroxide solution. The separated aqueous layer was washed with dimethyl ether, acidified with 2N hydrochloric acid, and extracted with dimethyl ether. The extract was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue obtained is n-hexane. By crystallizing from styrene, 0.64 g of 3_ (2-chlorophenyl) -13-phenylpropionic acid was obtained.

_{^{1 HNMR (CDC 1 3) δ}} ; 3.05~3.08 (2H, m), 5.01~5.06 (1H, m), 7.12~ 7.36 (9H, m).

 The following compounds (2) and (3) were synthesized by using the same method as (1).

 (2) 3— (3_chlorophenyl) -1-phenylpropionate; ^ acid

_{^{1 HNMR (CDC 1 3) δ}} 3.07 (2Η, d, J = 7.9Hz), 4.49 (1Η, t, J = 7.9Hz), 7.10~7.32 (9H, m).

(3) 3— (4—black mouth)

_{^{1 HNMR (CD C 1 3)}} δ; 3.04~ 3.06 (2Η, m), 4.49 (1H, t, J = 7.9Hz), 7.14~7.39 (9H, m).

Reference Example 12

Synthesis of dipheninolemethoxyacetic acid ethynoleate

 A mixture of benzhydrinole (1.84 g, 10.0 fractions 1), 60% sodium hydride (0.44 g, ll. Omraol) and dimethylformamide (40 ml) was stirred at room temperature for 1 hour and then stirred. Then, ethyl bromoacetate (2.51 g, 15.Ommol) was added, and the mixture was further stirred at room temperature for 2 hours. The reaction solution was poured into a 5% aqueous solution of sodium chloride, extracted with ethyl acetate (twice), and the extract was washed with water and a 5% aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluted with ethyl acetate η-hexane = 2/98) to obtain 1.46 g of diphenylmethoxyacetic acid ethyl ester.

_{^{1 HNMR (CD C 1 3)}} δ; 1.27 (3H, t, J = 7.2Hz), 4.09 (2H, s), 4.21 (2H, q, J = 7.2Hz), 5.58 (1H, s), 7.23~ 7.39 (10H, m).

Reference Example 13

Synthesis of N-phenoxycarbonyl-1-benzyloxybenzhydrylamine 2-benzyl / reoxybenzhydrol (1.00 g, 3.44 mmol) and phenylcarbamate (0.71 g, 5.17 mmol) synthesized in Reference Example 2 (4) ), Trifluoroacetic acid (20 ml) and chloroform (10 ml) were stirred at 0 ° C for 2 hours. Reaction liquid Was poured into cold water, extracted with chloroform (twice), and the extract was washed with water, a 5% aqueous sodium hydrogen carbonate solution and a 5% aqueous sodium chloride solution in that order, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was separated by silica gel force chromatography (eluted with ethyl acetate Zn-hexane = 4/96) to give N-phenoxy force bonyl- 1-benzinoleoxybenz. 0.60 g of a crude product of hydrylamine was obtained. This crude product can be used in the next step without further purification

(Example 34).

Example 1

 Synthesis of 3-methylbenzhydryloxycarbonyldanidine methanesulfonate

Reference Example 1 3-benzobenzene hydrol (1.00 g, 4.57 mmol 1,1'_carbonyldiimidazole (0.82 g, 5.03 ol)) synthesized in (2) and dimethylformamide (20 ml) ) Was stirred at 0 ° C for 30 minutes, and further stirred at room temperature overnight.Next, a solution of guanidine in dimethylformamide (guanidine hydrochloride (1.75 g, 18.3 ol) was added. ), Sodium methoxide (0.99 g, 18.3 ol) and dimethylformamide (20 ml) were stirred at room temperature and added to the reaction mixture, and further stirred at room temperature for 2 hours. The reaction solution was poured into a 5% aqueous sodium chloride solution, extracted with ethyl acetate (twice), the extract was washed with water and a 5% aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. By leaving 3 _ black mouth Benzdrilloxycarbonyl Then I got this gin Treating benzhydric / reoxycanolevonii / regazine with methanesulfonic acid in isopropinoleanolone / re. 0.94 g of 3-chlorobenzhydroxycarboxylguanidine methanesulfonate Obtained.

Melting point: 125-126. C

_{^{X HNMR (DMS O- d 6)}} δ; 2.40 (3Η, s), 6.85 (1H, s), 7.32~7.47 (8H, m), 7.55 (1H, s), 7.94 (2H, brs), 8.34 ( 2H, brs), 11.51 (1H, brs).

 By using the same method as in Example 1, the following compounds of Examples 2 to 26 were synthesized.

Example 2

 4 Benzhydrylcarbonylcarbonyldanidine. Methane sulfonate

融点： 132〜134。C

Melting point: 132-134. C

_{^{1 HNMR (DMS O- d 6)}} δ; 2.41 (3Η, s), 6.85 (1Η, s), 7.31~7.45 (5Η, m), 7.47 (4Η, s), 7.93 (2Η, brs), 8.36 ( 2Η, brs), 11.53 (1H, brs).

Example 3

N_ (3j 3-diphenylpropionyl) guanidine '' methanesulfone

Melting point: 194 ~ 196 ° C

丄 HNMR (DMS O- d ₆ ) δ; 2.44 (3H, s), 3.27 (2H, d, J = 7.9 Hz), 4.48 to 4.54 (1H, m), 7.15 to 7.23 (2H, m), 7.26 to 7.33 (8H, m), 8.21 (4H, brs), 11.42 (1H, brs).

Example 4

Benzhi-dori-no-reoxy power / reponinoleguanidine / methanesulfonate

Melting point: 131-133 ° C (decomposition)

^ NMR (DMSO-d ₆ ) δ; 2.39 (3Η, s), 6.83 (1H, s), 7.30 to 7.45 (10H, m), 7.92 (2H, brs), 8.32 (2H, brs), 11.50 (1H , brs).

Example 5

Benzhydrylaminocarbonylguanidine. Methanesulfonate

(1- (Aminoiminomethyl) -3-diphenylmethylperyl methanesulfonate)

Melting point: 190-194 ° C

_{^{1 HNMR (DMS O- d 6)}} δ; 2.39 (3H, s), 5.96 (1H, d, J = 7.7Hz), 21 ~7.39 (10H, m), 8.15 (4H, brs), 8.44 (1H, d, J = 7.7Hz), 9.71 (1H, brs).

Example 6

 2-chlorobenzhydryloxycarbonyldanidine .hydrochloride

実施例 1と同様の方法を用いることにより合成した 2—クロ口べンズヒ ドリル ォキシカルボニルダァニジンを、 テトラヒ ドロフラン中にて、 ェ一テル性の塩酸 で処理することによって 2—クロ口べンズヒ ドリルォキシ力ルボニルグァ二ジン •塩酸塩を得た。

2-Chlorobenzhydryloxycarbonyldanidine synthesized by using the same method as in Example 1 was treated with ethereal hydrochloric acid in tetrahydrofuran to obtain 2-chlorobenzhydryl. Drilloxy power rubonylguanidine • Hydrochloride was obtained.

Melting point: 151-152 ° C

_{^{1 HNMR (DMS O- d 6)}} δ; 7.05 (1H, s), 7 · 34~7 · 47 (7H, m), 7.48~ 7.55 (2H, m), 8.04 (2H, brs), 8.48 (2H , brs), 11.88 (1H, brs).

Example 7

4 Benzhydrylaminocarbonylguanidine methanesulfonate

融点： 162〜164°C

Melting point: 162-164 ° C

_{^{1 HNMR (DMS O- d 6)}} δ; 2.39 (3H, s), 5.97 (1H, d, J = 7.7Hz), 7.24 ~7.44 (9H, m), 8.14 (4H, brs), 8.46 (IH, d, J = 7.7Hz), 9.71 (IH, brs).

Example 8

 2, 2-diphenylethylaminocarbodiguanidine. Methanesulfonate (1-1 (aminoiminomethyl) 13- (2) 2-diphenylethyl) perylene. Methanesulfonate

Melting point: 158-159 ° C

丄 HNMR (DMS O-d 6) δ; 2.35 (3H, s), 3.78 (2H, dd, J = 5.7 Hz, 7.9 Hz), 4.18 to 4.24 (1H, m), 7.18 to 7.25 (2H, m) , 7.28-7.32 (8H, m), 7.36-7.40 (IH, m), 8.08 (4H, brs), 9.71 (IH, brs).

Example 9

2—Black mouth _Drillaminocarbonyldanidine 'Methanesulfonic acid H

融点： 198〜204°C

Melting point: 198-204 ° C

_{^{1 HNMR (DMS O- d 6)}} δ; 2.38 (3H, s), 6.27 (IH, d, J = 7.5Hz), 7.23 ~7.48 (9H, m), 8.15 (4H, brs), 8.49 (IH, d, J = 7.7Hz), 9.70 (IH, brs).

Example 10

 3-Mouth Benzhydrylaminocarbonylguanidine. Methanesulfonate

Melting point: 171-174. C

_{^{1 HNMR (DMS O- d 6)}} δ; 2.41 (3H, s), 5.99 (1H, d, J = 7.7Hz), 7.28 ~7.43 (9H, m), 8.14 (4H, brs), 8.49 (IH, d, J = 7.7Hz), 9.77 (IH, brs).

Example 11

融点： 176〜178°C 2-Methylbenzhydrylaminocarboylguanidine methanesulfonate

Melting point: 176-178 ° C

_{^{1 HNMR (DMS O- d 6)}} δ 2.26 (3H, s), 2.37~2.38 (3H, m), 6.10 (1H, d, J = 7.7Hz), 7.15~ 7 · 25 (6H, m), 7.28 ~ 7.39 (4H, m), 8.15 (4H, brs), 8.35 (1H, d, J = 7.7Hz), 9.62 (1H, brs).

Example 12

 3-Methylbenzhydrylaminocarboylguanidine. Methanesulfonate

Melting point: 179-dish. C

^ HNMR (DMS O— d ₆ ) δ 2.28 (3Η, s), 2.40 (3H, s), 5.91 (1H, d, 1 = 7.7 Hz), 7.07 to 7.12 (3H, m), 7 · 21 to 7.38 (6H, m), 8.14 (4H, brs), 8.40 (1H, d, J = 8.1Hz), 9.72 (1H, brs).

Example 13

4-Methylbenzhydrylaminocarbonyldanidine · methanesulfonate

融点： 184〜188。C

Melting point: 184-188. C

^{1 H NMR (DM SO - d} 6) δ; 2.27 (3H, s), 2.36 (3H, s), 5.90 (1H, d, J = 7.7Hz), 7.17 (4H, brs), 7.24~7.29 (3H , m), 7.33 to 7.38 (2H, m), 8.12 (4H, brs), 8.38 (1H, d, J = 7.7Hz), 9.61 (1H, brs).

Example 14

 [a-_ (2-Chenyl) _benzyl] aminocarbonyldananidin hydrochloride

((Amino iminomethyl) _— 3— [α (2-Chenyl) -benzyl]

'Hydrochloride)

_{^{1 HNMR (DMS 0- d 6)}} δ; 6.19 (1H, d, J = 8.1Hz), 6.90~6.92 (1H, m), 6.96~6 · 99 (1Η, m), 7 · 29~ 7.34 (1H , m), 7.36 to 7.41 (4H, m), 7.47 (1H, dd, J = 1.3Hz, 5.1Hz), 8.23 (4H, brs), 8.99 (1H, d, J = 8.1Hz), 10.23 (1H , brs).

a-(3-pyridyl) benzylaminocarbonyl danidine · dihydrochloride

2HC1

_{^{1 HNMR (DMS O- d 6)}} δ; 6.23 (1H, d, J = 7.9Hz), 7.31~7.35 (1H, m), 7 · 37~ 7.45 (4H, ra), 7 · 84~ 7.88 (1H , m), 8.30 (4H, brs), 8.31 (1H, d, J = 8.3Hz), 8.75 (1H, brs), 8.89 (1H, brs), 9.29 (1H, d, J = 7.9Hz), 10.49 (1H, brs).

Example 16

a-(4_pyridyl) benzylaminocarbonyl danidine · dihydrochloride

_{^{1 HNMR (DMS O- d 6)}} δ; 6.42 (1Η, d, J = 7.3Hz), 7.32~7.48 (5H, m), 7.97 (2H, d, J = 6.1Hz), 8.31 (4H, brs) , 8.84 (2H, d, J = 5.1Hz), 9.41 (1H, d, J = 7.3Hz), 10.61 (1H, brs).

Example 17

2, 3'-Dichlorobenzhydrylaminocarbanolguanidine 'hydrochloride

_{^{1 HNMR (DMS O- d 6)}} 6; 6.29 (1H, d, J = 7.9Hz), 7.22~7.26 (1H, m), 7.33~7.51 (7H, m), 8.24 (4H, brs), 9.01 ( 1H, d, J = 7.9Hz), 10.20 (1H, brs).

3,3, Jikro-Ven's Hydride / Reaminocanolepol-L-guanidine.

Melting point: 136-137. C

丄 HNMR (DMS O- d ₆ ) δ; 2.39 (3Η, s), 6.03 (1H, d, J = 7.7 Hz), 7.29 to 7.31 (2H, m), 7.35 to 7.44 (6H, m), 8.12 ( 4H, brs), 8.54 (1H, d, J = 7.5Hz), 9.75 (1H, brs).

Example 19

3-dichlorobenzhydrylaminocarbonyldanidine 'hydrochloride

Melting point: 228-229 ° C

_{^{1 HNMR (DMS O- d 6)}} δ; 6.29 (IH, d, J = 7.7Hz), 7.27~7.30 (2H, m) 7.32~ 7.41 (3H, m), 7.43~ 7.54 (2H, m), 7.63 (IH, dd, J = l.8Hz, 7.7Hz) 8.24 (4H, brs), 9.00 (IH, d, J = 7.5Hz), 10.25 (IH, brs).

Example 20

 3-Nitrobenzhydrylaminocarbonylguanidine .hydrochloride

_{^{1 HNMR (DMS 0- d 6)}} δ; 6.19 (IH, d, J = 7.7Hz), 7.28~7.33 (1H, m), 7.36~7.44 (4H, m), 7.65~7.70 (1H, m), 7.87 (IH, d, J = 7.5Hz), 8.15 (IH, d, J = 8.1Hz), 8.26 (IH, s), 8.32 (4H, brs), 9.27 (IH, d, J = 7.9Hz), 10.52 (1H, brs).

Example 21 〔· [3- (diphenylamino) propionyl] guanidine. Methanesulfonic acid

Melting point: 145-146. C

1H NMR (DMS O-d ₆ ) δ; 2.34 (3Η, s), 2.74 (2H, t, J = 7.0 Hz), 3.99 to 4.03 (2H, m), 6.94 to 7.00 (6H, m), 7.28 (4H, dd, J = 7.2Hz, 8.6Hz), 8.14 (4H, brs), 11.26 (1H, brs).

Example 22

 N— [3-(2—Feninole) 1 3—Feninolepropionin] Guanidine.

融点： 215〜220°C

Melting point: 215-220 ° C

_{^{1 HNMR (DMS O- d 6)}} δ; 2.40 (3H, s), 3.22~3.38 (2H, m), 4.92~ 4.97 (1H, m), 7.18~ 7.46 (8H, m), 7.51~ 7.54 (1H , M), 8.19 (4H, brs), 11.42 (1H, brs).

Example 23 N— [3— (3-cloth feninole) _ 3 _ feninolepropioninole] guanidine methanesulfonate

Melting point: 138-140 ° C

_{1 HNMR (DMS O- d 6)} 6; 2.41 (3H, s), 3.23~3.39 (2H, m), 4.53 (1H, t, J = 7.9Hz), 7.18~7.36 (8H, m), 7.41 ( 1H, m), 8.19 (4H, brs), 11.38 (1H, brs).

Example 24

 N- [3- (4-—Feninole) 1-3-Feninolepropionyl] guanidine-methanesulfonate

融点： 169〜175°C

Melting point: 169-175 ° C

_{^{1 HNMR (DM SO - d 6}} ) δ; 2.41 (3H, s), 3.27 (2H, d, J = 7.7Hz), 4.52 (1H, t, J = 7.9Hz), 7 · 17~ 7.24 (1H, m), 7.27 to 7.32 (4H, m), 7.35 (4H, brs), 8.18 (4H, brs), 11.38 (1H, brs).

Example 25

 2. _2—diphenylethoxycarbonyldanidine _ acid salt

Melting point: 170-172 ° C

_{^{1 HNMR (DMS O- d 6)}} δ 2.33 (3Η, s), 4.40~4 · 46 (1H, m), 4.77 (2H, d, J = 7.7Hz), 7.20~ 7.26 (2H, m), 7.30 ~ 7.39 (8H, m), 7.73 (1H, brs), 8.23 (1H, brs), 11.04 (1H, brs).

Example 26

3-benzyloxybenzhydrylaminocarbonyldanidine .hydrochloride

¹ HNMR (DMS 0- d ₆ ) δ 5.09 (2Η, s), 5.94 (1H, d, J = 8.1 Hz), 6.89 to 6.95 (2H, m), 7.07 (1H, s), 7.23 to 7.46 (11H , m), 8.28 (4H, brs), 9.09 (1H, brs), 10.50 (1H, brs).

Example 27 N— [2- (diphenylamino) acetyl] guanidine methanesulfonate

H

H

 N, N-diphenyldaricinethyl ester (0.23 g, 0.90 mmol) synthesized in Reference Example 5, guanidine hydrochloride (0.34 g, 3.60 mmol), sodium methoxide (0.19 g, 3.60 mmol) and dimethyl A mixture of formamide (5 ml) was stirred at room temperature for 3 hours and then left at room temperature overnight. The reaction solution was poured into cold water, extracted with ethyl acetate (twice), and the extract was washed with water and a 5% aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N- [2- (diphenylamino) acetyl] guanidine. The N— [2- (diphenylamino) acetyl] guanidine is treated with methanesulfonic acid in isopropyl alcohol to obtain 0.17 g of N— [2- (diphenylamino) acetyl] guanidine ′ methanesulfonic acid salt. Was.

Melting point: 135-137 ° C

_{^{1 HNMR (DMS O- d 6)}} δ; 2.40 (3Η, s), 4.67 (2H, s), 6.96~7.03 (6H, m), 7.26~7.32 (4H, m), 8.30 (4H, brs), 11.32 (1H, brs).

 By using the same method as in Example 27, the following compounds of Examples 28 to 34 were synthesized.

Example 28

N— (4, _4-diphenylbutyryl) guanidine · _methanesulfonate

融点： 150〜157。C

Melting point: 150-157. C

_{^{1 HNMR (DMS O- d 6)}} δ; 2.31~2.34 (4H, ra), 2.37 (3H, s), 3.93~ 3.98 (1H, m), 7 · 15~ 7.22 (2H, m), 7.26~ 7.32 (8H, m), 8.16 (4H, brs), 11.16 (1H, brs).

Example 29

 N— [2- (diphenylmethylamino) acetyl] guanidine'2 methanesulfonate

Melting point: 206-208 ° C

_{^{1 HNMR (DMS O- d 6)}} δ; 2.37 (3H, s), 2.38 (3H, s), 3.58 (1H, brs), 3.89 (2H, brs), 5.58 (1H, brs), 7.35~ 7.47 ( 6H, m), 7.57 to 7.59 (4H, m), 8.34 (2H, brs), 8.54 (2H, brs), 10.29 (1H, brs).

Example 30

N- (4 ュ 4-diphenyl-1-methylbutyryl) guanidine '' methanesulfone

Melting point: 169-170 ° C

_{^{1 HNMR (DMSO- d 6) δ}} ; 0.84 (3H, d, J = 6.4Hz), 2.12~2.21 QH, m), 2.33 (1H, d, J = 3.5Hz), 2.38 (3H, s), 2.92 ~ 2.95 (1H, m), 3.69 (1H, d, J = ll.2Hz), 7.13 to 7.18 (2H, m), 7.28 (4H, t, J = 7.5Hz), 7.38 (4H, d, J = (7.3Hz) _: 8.15 (4H, brs), 11.09 (1H, brs).

Example 31

 [A __ (2-pyridyl) benzyl] aminocarbonyldananidin dihydrochloride

_{1 HNMR (DMSO- d 6) δ} ; 6.06 (1H, d, J = 7.3Hz), 7.23~7.41 (6H, m), 7.59 (1H, d, J = 7.9Hz), 7.86~ 7.91 (1H, m ), 8.20 (4H, brs), 8.60 (1H, d, J = 4.2Hz), 8.81 (1H, d, J = 7.3Hz), 10.45 (1H, brs).

Example 32

N-diphenylmethyl _N-methylaminocarbonylcarbazine .hydrochloride

_{^{1 HNMR (DM SO - d 6}} ) δ; 2.85 (3H, brs), 6.75 (1H, brs), 7.18~ 7.20 (4H, m), 7.32~7.43 (6H, m), 8.20 (2H, brs), 8.58 (2H, brs), 10.50 (1H, brs).

Example 33

N- [2- (diphenylmethoxy) acetyl] guanidine methanesulfonate

Melting point: 175-176 ° C

丄 HNMR (DMS O— d ₆ ) δ; 2.33 (3Η, s), 4.16 (2Η, s), 5.64 (1H, s): 7.26 to 7.31 (2H, m), 7.34 to 7.43 (8H, m), 8.32 (4H, brs), 10.77 (1H, brs).

2 Benzyloxybenzhydrylaminocarbonyl danidine hydrochloride

_{^{1 HNMR (DMS O- d 6)}} δ; 5.13 (2H, s), 6.32 (. 1H, d, J = 8 lHz), 6.95 ~7.00 (1H, m), 7.07 (1H, d, J = 8.1Hz ), 7.26 to 7.31 (12H, ra), 8.26 (4H, brs), 8.85 (1H, brs), 10.54 (1H, brs).

Test example

 Inhibitory effect on Na + / H + exchange transport system (in vitro test)

 Test method

 The test was performed according to the method of Iemori et al. (J. Hypertension, 8, 153 (1990)). That is, isolated ventricular myocytes (rats) were used to evaluate the inhibitory effect of the Na + ZH + exchange transport system on the index of intracellular PH change during acid loading.

Test results

Table 10

Example Inhibitory effect of Na + / H + exchange transport system

IC _{5 0} (μΜ)

0 2 5

 2 1 8 0

 3 4 4 0

 4 9 0 0

 5 0 3 9

 6 0 1 6

 7 5, 5 0

 8 4, 4 0

 9 0.3 2

 0 0.1 4 Possibility of industrial use

 The compound of the present invention has an inhibitory effect on the sodium-proton (Na + ZH +) exchange transport system, and is a disease caused by enhanced sodium / proton (Na + / H +) exchange transport system, for example, hypertension, arrhythmia, Organ damage due to angina pectoris, cardiac hypertrophy, diabetes, ischemia or ischemia reperfusion (eg, myocardial ischemia reperfusion injury, acute renal failure, surgical treatment (eg, organ transplantation “PTCA”) Cerebral ischemic injury (eg, a disorder associated with cerebral infarction, a disorder that occurs as a sequela after a stroke, cerebral edema, etc.), cell hyperproliferation (eg, fibroblast proliferation, smooth muscle cell proliferation, mesangium) Diseases caused by cell proliferation (eg, atherosclerosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, renal glomerulosclerosis, organ hypertrophy, prostatic gland hypertrophy, diabetic complications, after PTCA Is useful as a therapeutic or prophylactic agent for diseases caused by endothelial cell damage.

Claims

The scope of the claims 1. General formula (1)

[In the formula, R i and R ₂ independently represent an aromatic group which may have a substituent. X! Represents a nitrogen atom or 3 C-R ₃ . X ₂ represents an oxygen atom, one N (R ₄ ) — or one C (R ₅ ) (R ₆ ) _. X ₃ represents an oxygen atom, —N (R ₇ ) —, —C (R ₈ ) (R ₉ ) —, or a single bond. R ₃ , R ₅ , R ₆ , R ₈ and R ₉ are each independently a hydrogen atom, a halogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic ring Group, carboxyl group, acyl group, — OR ₁₀ , —

— S (0) _n R _{1 3} , — C (O) N (R 丄 R 丄 -SO NCRi _x ) Ri _Q— _Ra or -A— CH N— R ₁₄ (A represents an oxygen atom, one S (0) _n _ or one NCR ₅ ) —, and R ₁₄ represents a hydrogen atom, an alkyl group, a substituted alkyl group, an acyl group, one S (〇) _n R ₁₃ or — Q — Represents _Ra , and the ring represents a saturated heterocyclic group consisting of one _3- to 8-membered nitrogen atom and carbon atom. R ₄ , R ₇ and ₅ each independently represent a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a saturated heterocyclic group, an acyl group, one S (0) ₂ R ₁₃ , or _Q- representing the R _a. R ₁₀ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, It represents an alkenyl group, a saturated heterocyclic group or an aromatic group which may have a suitable substituent. R i and ₂ each independently represent a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, or an aromatic group which may have a suitable substituent. , An acyl group, one S (0) _n R ₁₃ or one Q—R _a , or i and R ₂ are bonded to each other, and together with the nitrogen atom to which they are bonded, A saturated 5- to 7-membered cyclic amino group which may contain a heteroatom (wherein the cyclic amino group is at least one alkyl group, a substituted alkyl group, a hydroxyl group or OR 丄₀ ). R ₁₃ represents an alkyl group, a substituted alkyl group or an aromatic group which may have a suitable substituent.  Q represents a lower alkylene group which may be substituted. Ra represents _a vinyl group which may be substituted or an ethynyl group which may be substituted.  n represents an integer of 0, 1 or 2.  Or a prodrug thereof, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein X ₃ is an oxygen atom, one N (R ₇ ) — or one C (R ₈ ) (R ₉ ) _, or a prodrug thereof or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, wherein X ₃ is a single bond, a prodrug thereof, or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 2, wherein X ₃ is one C (R ₈ ) (R ₉ ) —, a prodrug thereof, or a pharmaceutically acceptable salt thereof. _5.2 is -. (1¾ ₅₎ (R ₆₎ acceptable salts compound or a prodrug thereof or a pharmaceutically reduction according to any one of claims 1 to 4 _ a is.  6. The compound according to any one of claims 1 to 5, wherein R is a phenyl group optionally having a substituent, a prodrug thereof, or a pharmaceutically acceptable salt thereof. 7. and R ₂ is a phenyl group optionally having a substituent Item 6. The compound according to any one of Items 1 to 5, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. 8. salt X is acceptable compound if Kuwasono prodrug or pharmaceutical according to any one of claims 1 to 7 three C _ R _3. 9. The compound according to any one of claims 1, 2, 3, 4, 6, 7, 7 or 8, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein X ₂ is one N (R ₄ ) —. Salt.  10. A medicament comprising the compound according to any one of claims 1 to 9, or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.  11. A sodium Z-proton exchange inhibitor comprising the compound according to any one of claims 1 to 9 or a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient.  12. Hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes mellitus, which contains the compound according to any one of claims 1 to 9 or a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic or preventive agent for organ inhibition due to ischemia or ischemia reperfusion, cerebral ischemic injury, a disease caused by excessive cell proliferation, or a disease caused by endothelial cell damage.  13. The compound according to any one of claims 1 to 9, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, for use as an active ingredient of a medicament.  14. Use of a compound according to any one of claims 1 to 9 or a prodrug thereof or a pharmaceutically acceptable salt thereof for producing a sodium proton exchange transport system inhibitor.  15. Hypertension, arrhythmia, angina, cardiac hypertrophy, diabetes, organ inhibition due to ischemia or ischemia reperfusion, cerebral ischemic injury, diseases caused by excessive cell proliferation or diseases caused by endothelial cell damage Use of the compound according to any one of claims 1 to 9, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, for producing a therapeutic or prophylactic agent for the drug. 16. administering to the subject an effective amount of the compound according to any one of claims 1 to 9, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. A method to inhibit the sodium proton exchange transport system.  17. Hypertension, arrhythmia, angina pectoris comprising administering to a subject an effective amount of the compound according to any one of claims 1 to 9 or a prodrug thereof or a pharmaceutically acceptable salt thereof. A method for treating or preventing cardiac hypertrophy, diabetes, organ inhibition due to ischemia or ischemia reperfusion, cerebral ischemic injury, a disease caused by excessive cell proliferation, or a disease caused by endothelial cell damage.  18. —General formula (2) 〇 ^Rl , X ^X 2, _X R ₂ (2) Wherein R ₂ , XX ₂ and X ₃ have the same meaning as in claim 1 and L represents a hydroxyl group or a leaving group that can be substituted by a nucleophile. 2. The compound of the formula (1) or a prodrug thereof according to claim 1, comprising reacting in the presence of a condensing agent, and converting the obtained product into a prodrug or a pharmaceutically acceptable salt as necessary. Or a method for producing a pharmaceutically acceptable salt thereof.