JPH0789957A - Biphenylmethylamine derivative - Google Patents

Abstract

PURPOSE:To obtain the compound derivative useful as an active ingredient for a preventive and a therapeutic agent for congestive heart failure, chronic renal disease, etc., having antagonism on angiotensin II, having excellent safety, comprising a biphenylmethylamine derivative. CONSTITUTION:A new biphenylmethylamine derivative of formula I {R<1> is H, (substituted) 1-6C alkyl, (substituted) 2-6C alkeny 1, (substituted)3-6C cycloalkyl, (substituted)phenyl, etc.; R<2> is carboxyl, sulfonic acid, sulfonic acid amide, tetrazolyl, etc.; R<3> and R<4> are H, (substituted)1-6C alkyl, (substituted)2-6C alkenyl, (substituted)phenyl or group of the formula (CH2)mX ((m) is 0, 1 or 2; X is halogen, cyano, etc.); Z is group of formula II [R<9> to R<12> are H, (substituted)l-6C alkyl, (substituted)2-6C alkenyl, (substituted)phenyl, etc.}. The compound is obtained by reacting an aminomethylbiphenyl of formula III (R<28> is as shown for R<2>) with a compound of formula IV (V is halogen).

Description

Detailed Description of the Invention

[0001]

The present invention relates to various cardiovascular diseases,
Especially treatment of hypertension, heart failure and venous failure, and glaucoma,
The present invention relates to a novel substituted biphenylmethylamine compound useful as an angiotensin II antagonist in the treatment of diabetic retinopathy and various central nervous system diseases such as anxiety, depression, memory loss, Alzheimer's disease or chronic renal disease.

[0002]

BACKGROUND OF THE INVENTION The renin-angiotensin system plays a central role in normal blood pressure regulation and is greatly involved in the development of hypertension and congestive heart failure. Angiotensin II is an octapeptide hormone, and angiotensin I, which is a decapeptide by angiotensin converting enzyme (ACE)
Are mainly produced in blood by being cleaved. This ACE is localized on the vascular endothelium of the lung, kidney and many other organs. Angiotensin II, a potent arterial constrictor of the renin-angiotensin system, acts on specific receptors on the cell membrane surface. Therefore, one method of controlling the renin-angiotensin system is antagonism at the angiotensin II receptor. It is known that some angiotensin II peptide analogs inhibit the action of this hormone by antagonistically blocking the receptor, but these peptide analogs show partial agonist activity and oral absorption. Poor availability has limited experimental and clinical applications [M. Antona
ccio, Clin. Exp. Hypertens., A4, 27-46 (1982)].

Recently, some non-peptidic compounds have been reported as angiotensin II antagonists [US Pat. Nos. 4,207,324, 4,340,598, 4,576,958, 4,58].
2,847 and 4,880,804, European patent application 028,834, 24
5,637, 253,310 and 291,969 etc. AT Chiu et al., E
ur. J. Pharm. Exp. Therap., 157, 13-21 (1988) and
PC Wong et al., J. Pharm. Exp. Therap., 247, 1-7 (19
88) etc.].

However, the biphenylmethylamine compound of the present invention is not disclosed in all US patent specifications, European patent application specifications and all papers.

The present invention relates to novel biphenylmethylamine compounds and their derivatives which are useful as antihypertensive agents as angiotensin II antagonists in the treatment of congestive heart failure, chronic renal disease and the like.

[0006]

Means for Solving the Problems As a result of intensive studies made by the present inventors, it was surprisingly found that a biphenylmethylamine compound of the present invention and its derivatives, which are different from any of the compounds disclosed in the above-mentioned documents, are antagonistic to angiotensin II. The present invention was found to be useful as a drug, and as an antihypertensive agent, it was a more excellent compound and found to be an active ingredient of a preventive or therapeutic drug for the above-mentioned congestive heart failure, chronic kidney disease, etc., and completed the present invention. did.

That is, the present invention uses the formula [1]

[0008]

[Chemical 5]

[Wherein R ¹ represents a hydrogen atom, a C _{1 to} C ₆ linear or branched alkyl group (the alkyl group is a halogen atom, or a halogen atom, a nitro group, a carboxyl group,
It may be optionally substituted with a phenyl group which may be optionally substituted with a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group. ), A C _{2 to} C ₆ linear or branched alkenyl group (the alkenyl group may be optionally substituted with a halogen atom), a C _{2 to} C ₆ linear or branched alkynyl group. (The alkynyl group may be optionally substituted with a halogen atom.), A C _{3 to} C ₆ cycloalkyl group (the cycloalkyl group may be optionally substituted with a halogen atom or a phenyl group. ) Or a phenyl group (the phenyl group may be optionally substituted with a halogen atom, a nitro group, a carboxyl group, a C _{1 to} C ₄ alkyl group or a C _{1 to} C ₄ alkoxy group). Meaning,

R ² is a carboxyl group (the carboxyl group may be esterified with a C ₁ -C ₄ alkyl group), a sulfonic acid group (the sulfonic acid group is a C ₁ -C ₄ alkyl group). Esterified), sulfonic acid amide group, PO ₂ H ₂ (may be esterified with C _{1 to} C ₄ alkyl group), PO ₃ H ₂ (C _{1 to} C ₄ alkyl group) Or a tetrazolyl group (the tetrazolyl group may be optionally substituted with a benzyl group, a methoxymethyl group or a triphenylmethyl group),

R ³ and R ⁴ are each independently a hydrogen atom, a C ₁ -C ₆ linear or branched alkyl group (the alkyl group is a halogen atom, or a halogen atom, a nitro group, a carboxyl group). , A C ₁ -C ₄ alkyl group or C ₁ ~
It may be optionally substituted with a phenyl group, which may be optionally substituted with a C ₄ alkoxy group. ), A C _{2 to} C ₆ linear or branched alkenyl group (the alkenyl group may be optionally substituted with a halogen atom), C _{2 to} C ₆
A straight-chain or branched alkynyl group (the alkynyl group may be optionally substituted with a halogen atom),
A C _{3 to} C ₆ cycloalkyl group (the cycloalkyl group may be optionally substituted with a halogen atom or a phenyl group), a phenyl group (the phenyl group is a halogen atom,
Nitro group, an alkyl group or a C ₁ carboxyl group, C ₁ -C ₄
It may be optionally substituted with a C ₄ -alkoxy group. )
Or (CH ₂ ) _m X {in the formula, m represents 0, 1 or 2, and X represents a halogen atom, a cyano group, a nitro group, CH (CN) ₂ , CH (CO ₂ Me)
₂ , CH (CO ₂ Et) ₂ , a C _{1 to} C ₈ linear or branched acyl group, a carboxyl group which may be esterified with a C _{1 to} C ₄ alkyl group, a sulfonic acid group, or- YR ⁶ [Y is O,
S (O) _n (n represents 0, 1 or 2) or NR (R represents a hydrogen atom or a C _{1 to} C ₄ linear or branched alkyl group), and R ⁶ represents Hydrogen atom, C ₁ -C ₇ linear or branched alkyl group (wherein the alkyl group is a halogen atom,
Or a halogen atom, a nitro group, a carboxyl group, C _{1 to} C ₄
Optionally substituted with a phenyl group which may be optionally substituted with an alkyl group or a C ₁ -C ₄ alkoxy group. ), A C _{2 to} C ₆ linear or branched alkenyl group (the alkenyl group may be optionally substituted with a halogen atom), a C _{2 to} C ₆ linear or branched alkynyl group. (The alkynyl group may be optionally substituted with a halogen atom.), A C _{3 to} C ₆ cycloalkyl group (the cycloalkyl group may be optionally substituted with a halogen atom or a phenyl group. ), A phenyl group (the phenyl group may be optionally substituted with a halogen atom, a nitro group, a carboxyl group, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group), C. (O) A (A is a hydrogen atom, a C _{1 to} C ₆ linear or branched alkyl group (the alkyl group is a halogen atom, or a halogen atom, a nitro group, a carboxyl group, C _{1 to} C ₄ Alkyl group or C ₁ ~
It may be optionally substituted with a phenyl group, which may be optionally substituted with a C ₄ alkoxy group. ), A C _{2 to} C ₆ linear or branched alkenyl group (the alkenyl group may be optionally substituted with a halogen atom), C _{2 to} C ₆
A straight-chain or branched alkynyl group (the alkynyl group may be optionally substituted with a halogen atom),
A C _{3 to} C ₆ cycloalkyl group (the cycloalkyl group may be optionally substituted with a halogen atom or a phenyl group), a phenyl group (the phenyl group is a halogen atom,
Nitro group, an alkyl group or a C ₁ carboxyl group, C ₁ -C ₄
It may be optionally substituted with a C ₄ -alkoxy group. ), Or NR ⁷ R ⁸ (R ⁷ and R ⁸ are each independently a hydrogen atom, a C _{1 to} C ₆ linear or branched alkyl group (the alkyl group is a halogen atom, a halogen atom, a nitro group, Group, a carboxyl group, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group, which may be optionally substituted with a phenyl group), and C ₂ -C. ₆
A straight-chain or branched alkenyl group (wherein the alkenyl group may be optionally substituted with a halogen atom),
A C _{2 to} C ₆ linear or branched alkynyl group (the alkynyl group may be optionally substituted with a halogen atom), a C _{3 to} C ₆ cycloalkyl group (the cycloalkyl group is It may be optionally substituted with a halogen atom or a phenyl group.), A phenyl group (the phenyl group is a halogen atom, a nitro group, a carboxyl group, a C _{1 to} C ₄ alkyl group or a C _{1 to} C ₄ alkoxy group). It may be optionally substituted with a group). ) Means. ) Means. ]
Means },

Z is

[0013]

[Chemical 6]

(R⁹, R^Ten, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R
¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R^{twenty one}, R^{twenty two}, R ^{twenty three}And R^{twenty four}Is that
Each independently, hydrogen atom, C₁~ C₆Straight or branched
An alkyl group (the alkyl group is a halogen atom, or
Halogen atom, nitro group, carboxyl group, C₁~ C_FourA
Rukiru group or C₁~ C_FourOptionally substituted with an alkoxy group of
Optionally substituted with a phenyl group
Yes. ), C₂~ C₆A straight-chain or branched alkenyl group
(The alkenyl group is optionally substituted with a halogen atom.
You may stay. ), C₂~ C₆Linear or branched alky
Nyl group (the alkynyl group is optionally substituted with a halogen atom)
It may have been done. ), C₃~ C₆A cycloalkyl group of
The cycloalkyl group is a halogen atom or a phenyl group.
It may be replaced at will. ), A phenyl group (the phenyl group
Group is a halogen atom, nitro group, carboxyl group, C₁
~ C_FourAlkyl group or C₁~ C_FourThe alkoxy group of
It may be replaced. ) Or (CH₂)_oX¹{Where o is 0,
1 or 2 and X¹Is a halogen atom, cyano group, nitro
Group, CH (CN)₂, CH (CO₂Me)₂, CH (CO₂Et)₂, C₁~ C₈Straight chain of
Or a branched acyl group, C₁~ C_FourBy the alkyl group of
Optionally esterified carboxyl group, sulfone
Acid group, or -Y¹-R^{twenty five}[Y¹Is O, S (O)_p(P is 0, 1 or 2
Show. ) Or NR (R is a hydrogen atom or C₁~ C_FourStraight chain or minutes
A branched alkyl group is shown. ) And R^{twenty five}Is the hydrogen source
Child, C₁~ C₇A straight-chain or branched alkyl group of
A kill group is a halogen atom, or a halogen atom, nitro.
Group, carboxyl group, C₁~ C_FourAlkyl group or C₁~
C_FourOptionally substituted with an alkoxy group of
May be optionally substituted with a phenyl group. ), C₂~ C₆Straight chain of
Alternatively, a branched alkenyl group (the alkenyl group is
It may be optionally substituted with a logen atom. ), C₂~ C₆
A linear or branched alkynyl group (the alkynyl group
May be optionally substituted with a halogen atom. ),
C₃~ C₆A cycloalkyl group of
It may be optionally substituted with a rogen atom or a phenyl group
Yes. ), A phenyl group (the phenyl group is a halogen atom,
Nitro group, carboxyl group, C₁~ C_FourAlkyl group or C₁
~ C_FourOptionally substituted with an alkoxy group of
Yes. ), C (O) A¹(A¹Is a hydrogen atom, C₁~ C₆Straight chain
Is a branched alkyl group (the alkyl group is a halogen source
Child, or halogen atom, nitro group, carboxyl group, C₁
~ C_FourAlkyl group or C₁~ C_FourAny alkoxy group
Optionally substituted with a phenyl group which may be substituted with
You may stay. ), C₂~ C₆Straight or branched alke
Nyl group (the alkenyl group is optionally substituted with a halogen atom)
It may have been done. ), C₂~ C₆Straight or branched
Alkynyl group (the alkynyl group is a halogen atom
May be substituted with. ), C₃~ C₆Cycloalkyl
Group (the cycloalkyl group is a halogen atom or phenyl
It may be optionally substituted with groups. ), A phenyl group (the
Phenyl group is a halogen atom, nitro group, carboxyl
Base, C₁~ C_FourAlkyl group or C₁~ C_FourWith the alkoxy group of
It may be replaced at will. ), Or NR²⁶R²⁷(R²⁶Over
And R²⁷Are each independently a hydrogen atom, C₁~ C ₆Straight chain
Or a branched alkyl group (wherein the alkyl group is a halogen
Atom or halogen atom, nitro group, carboxyl group,
C₁~ C_FourAlkyl group of or or C₁~ C_FourAlkoxy group
Optionally substituted with a phenyl group which may be optionally substituted with
It may have been done. ), C₂~ C₆Straight or branched
Alkenyl group (The alkenyl group may be a halogen atom.
May be substituted with. ), C₂~ C₆Straight or minute
A branched alkynyl group (the alkynyl group is a halogen atom
May be optionally substituted. ), C₃~ C₆Cycloa
Alkyl group (the cycloalkyl group is a halogen atom or a fluorine atom).
It may be optionally substituted with a phenyl group. ), Phenyl
A group (the phenyl group is a halogen atom, a nitro group, a carbo
Xyl group, C₁~ C_FourAlkyl group or C₁~ C_FourThe alkoxy
It may be optionally substituted with groups. ) Means. )
means. ) Means. ] Means } Means
It ) Is shown. ] The compound represented by
And salts and pharmaceutical compositions containing these as active ingredients
Regarding

The substituents in the compound of the present invention represented by the general formula [1] will be described below.

Specific examples of R ¹ include hydrogen atom, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, Pentyl group, hexyl group, ethylene group, 1-propylene group, 2-propylene group, 1-butylene group, 2-butylene group, 3-butylene group, 1-pentylene group, 2-pentylene group, 3-pentylene group, 4-pentylene group, 1-hexylene group, 2-hexylene group, 3-hexylene group, 4-hexylene group, 5-hexylene group, c-propyl group, c-butyl group, c-pentyl group, c-hexyl group , Phenyl group, benzyl group, 2-phenylethyl group and the like, preferably, n-propyl group, n-butyl group, c-propyl group and the like. Both may be optionally substituted with halogen atoms.

R²Specific examples of
Toxycarbonyl group, ethoxycarbonyl group, n-propo
Xycarbonyl, n-butoxycarbonyl, SO₃Me, SO₃E
t, SO ₃ ⁿPr, SO₃ ⁿBu, SO₃H, SO₂NH₂, PO₂Me₂, PO₂Et₂, P
O₂ ⁿPr₂, PO₂ ⁿBu₂, PO₂H₂, PO₃Me₂, PO₃Et₂, PO₃ ⁿPr₂, P
O₃ ⁿBu₂, PO₃H₂, 1-triphenylmethyl-5-tetrazolyl
Group, 2-triphenylmethyl-5-tetrazolyl group, 1-meth
Xymethyl-5-tetrazolyl group, 2-methoxymethyl-5-thero
Trazolyl group, 1-benzyl-5-tetrazolyl group, 2-ben
Examples include dil-5-tetrazolyl group and 5-tetrazolyl group.
Preferably a 5-tetrazolyl group, a carboxyl group, etc.
Can be mentioned.

R³And R^FourExamples of are hydrogen atom,
Cyl group, ethyl group, n-propyl group, i-propyl group, n-bu
Cyl group, i-butyl group, sec-butyl group, t-butyl group, pen
Cyl group, hexyl group, ethylene group, 1-propylene group, 2-
Propylene group, 1-butylene group, 2-butylene group, 3-butylene
Group, 1-pentylene group, 2-pentylene group, 3-pentylene group
Group, 4-pentylene group, 1-hexylene group, 2-hexylene
Group, 3-hexylene group, 4-hexylene group, 5-hexylene
Group, c-propyl group, c-butyl group, c-pentyl group, c-hexyl group
Syl group, phenyl group, benzyl group, 2-phenylethyl
Group, hydroxy group, methoxy group, ethoxy group, n-propo group
Xy group, i-propoxy group, n-butoxy group, i-butoxy group
Group, sec-butoxy group, t-butoxy group, pentyloxy
Group, hexyloxy group, 1-propyleneoxy group, 2-pro
Pyreneoxy group, 1-butyleneoxy group, 2-butyleneoxy
Si group, 3-butyleneoxy group, 3-butyleneoxy group, 1-pe
Pentyleneoxy group, 2-pentyleneoxy group, 3-pentylene
Group, 4-pentyleneoxy group, 1-hexyleneoxy group
Si group, 2-hexyleneoxy group, 3-hexyleneoxy group,
4-hexyleneoxy group, 5-hexyleneoxy group, c-pro
Pyroxy group, c-butoxy group, c-pentyloxy group, c-
Hexyloxy group, phenyloxy group, benzyloxy
Group, 2-phenylethoxy group, thiol group, methylthio
Group, ethylthio group, n-propylthio group, i-propylthio group
Group, n-butylthio group, sec-butylthio group, t-butylthio group
Group, pentylthio group, hexylthio group, amino group, methyl
Ruamino group, ethylamino group, n-propylamino group, i-
Propylamino group, n-butylamino group, i-butylamino group
Group, sec-butylamino group, t-butylamino group, benzyl
Amino group, 3-ethoxy-4-methoxybenzylamino group, 2
-Pyridylmethylamino group, 3-pyridylmethylamino group
Group, 4-pyridylmethylamino group, fluorine atom, chlorine source
Child, bromine atom, iodine atom, cyano group, nitro group, met
Xycarbonyl group, ethoxycarbonyl group, carboxy
Group, methoxycarbonylmethyl group, ethoxycarbonyl
Group, hydroxycarbonylmethyl group, 2-methoxy group
Sicarbonylmethyl group, 2-ethoxycarbonylmethyl
Group, hydroxycarbonylethyl group, CH (CN)₂, CH (CO₂M
e)₂, CH (CO₂Et)₂, Methylcarbonyl group, ethylcarbo
Nyl group, i-propylcarbonyl group, n-propylcarbonyl group
Group, n-butylcarbonyl group, i-butylcarbonyl group,
sec-Butylcarbonyl group, t-Butylcarbonyl group, n-Petro
N-ethylcarbonyl group, c-pentylcarbonyl group, n-hexyl group
Sylcarbonyl group, c-hexylcarbonyl group, NHC (O) NH
₂, NHC (O) NHMe, NHC (O) NHEt, NHC (O) NHⁿPr, NHC (O) NHⁱP
r, NHC (O) NHⁿBu, NHC (O) NHⁱBu, NHC (O) NH^secBu, NHC (O)
NH^tBu, NHC (O) NHⁿPent, NHC (O) NHⁿHex, NHC (O) NH^cPen
t, NHC (O) NH^cHex, NHC (O) NMe₂, NHC (O) N (Et)₂, NHC (O) N
HPh, NHC (O) NHCH₂Ph, NHC (O) Me, NHC (O) Et, NHC (O) CH₂P
h, NHC (O) CHPh₂, NHCH (CH₂Ph) CO₂H, NHCH (Ph) CO₂H, NⁿP
entC (O) NHMe, NⁿPentC (O) NHEt, NHC (O) Ph, NHC (O) Ph-2-
Cl, NHC (O) Ph-2-NO₂, NHC (O) Ph-2-CO₂H and the like,
Preferably, a hydrogen atom, an ethyl group, an n-propyl group, an i-propyl group
Ropyl group, n-butyl group, hydroxy group, ethoxy group, n-
Propoxy group, i-propoxy group, n-butoxy group, amino
Group, n-propylamino group, n-butylamino group, 3-ethoxy group
Si-4-methoxybenzylamino group, 2-pyridylmethyl group
Mino group, 3-pyridylmethylamino group, 4-pyridylmethyl
Amino group, cyano group, nitro group, chlorine atom, bromine atom,
Methoxycarbonyl group, ethoxycarbonyl group, carbo
Xyl group, methoxycarbonylmethyl group, ethoxycarl
Bonylmethyl group, hydroxycarbonylmethyl group, CH (C
N)₂, CH (CO₂Me)₂, CH (CO₂Et) ₂, A methylcarbonyl group,
Ethylcarbonyl group, c-hexylcarbonyl group, NHC (O)
NHMe, NHC (O) NHEt, NHC (O) NHⁱPr, NHC (O) NH^cHex, NHC
(O) Me, NHC (O) Et, NHC (O) CH₂Ph, NHC (O) CHPh₂, NHCH (CH
₂Ph) CO₂H, NHCH (Ph) CO₂H, NⁿPentC (O) NHMe, NⁿPentC (O)
NHEt, NHC (O) Ph-2-Cl, NHC (O) Ph-2-NO₂, NHC (O) Ph-2-CO
₂H etc. can be mentioned.

R⁹, R^Ten, R¹¹, R¹², R¹³, R¹⁴, R¹⁵,
R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R^{twenty one}, R^{twenty two}, R ^{twenty three}And R^{twenty four}Ingredient
Examples of the body include hydrogen atom, methyl group, ethyl group, n-pro
Pill group, i-propyl group, n-butyl group, i-butyl group, sec-
Butyl, t-butyl, pentyl, hexyl, ethyl
Ren group, 1-propylene group, 2-propylene group, 1-butylene
Group, 2-butylene group, 3-butylene group, 1-pentylene group, 2-
Pentylene group, 3-Pentylene group, 4-Pentylene group, 1-He
Xylene group, 2-hexylene group, 3-hexylene group, 4-hex
Silen group, 5-hexylene group, c-propyl group, c-butyl
Group, c-pentyl group, c-hexyl group, phenyl group, benzyl
Group, 2-phenylethyl group, hydroxy group, methoxy
Group, ethoxy group, n-propoxy group, i-propoxy group, n-
Butoxy group, i-butoxy group, sec-butoxy group, t-butoxy group
Si group, pentyloxy group, hexyloxy group, 1-propyi group
Renoxy group, 2-propyleneoxy group, 1-butylene oxy group
Si group, 2-butyleneoxy group, 3-butyleneoxy group, 3-butene
Tyleneoxy group, 1-Pentyleneoxy group, 2-Pentylene
Oxy group, 3-pentyleneoxy group, 4-pentyleneoxy
Group, 1-hexyleneoxy group, 2-hexyleneoxy group, 3-
Hexyleneoxy group, 4-hexyleneoxy group, 5-hexyl
Renoxy group, c-propyloxy group, c-butoxy group, c-
Pentyloxy group, c-hexyloxy group, phenyloxy
Si group, benzyloxy group, 2-phenylethoxy group, thio
Group, methylthio group, ethylthio group, n-propylthio group
Group, i-propylthio group, n-butylthio group, sec-butylthio group
O group, t-butylthio group, pentylthio group, hexylthio group
Group, amino group, methylamino group, ethylamino group, n-type
Ropylamino group, i-propylamino group, n-butylamino group
Group, i-butylamino group, sec-butylamino group, t-butyl
Amino group, benzylamino group, 3-ethoxy-4-methoxy
Benzylamino group, 2-pyridylmethylamino group, 3-pyridyl group
Dilmethylamino group, 4-pyridylmethylamino group, fluorine
Elementary atom, chlorine atom, bromine atom, iodine atom, cyano group,
Nitro group, methoxycarbonyl group, ethoxycarbonyl
Group, carboxyl group, methoxycarbonylmethyl group,
Toxycarbonylmethyl group, hydroxycarbonylmethyl
Group, 2-methoxycarbonylmethyl group, 2-ethoxycarl
Bonylmethyl group, hydroxycarbonylethyl group, CH (C
N)₂, CH (CO₂Me)₂, CH (CO₂Et)₂, A methylcarbonyl group,
Ethylcarbonyl group, i-propylcarbonyl group, n-pro
Pyrcarbonyl group, n-butylcarbonyl group, i-butylcarbonyl group
Rubonyl group, sec-butylcarbonyl group, t-butylcarbo group
Nyl group, n-pentylcarbonyl group, c-pentylcarbonyl
Group, n-hexylcarbonyl group, c-hexylcarbonyl
Group, NHC (O) NH₂, NHC (O) NHMe, NHC (O) NHEt, NHC (O) NHⁿP
r, NHC (O) NHⁱPr, NHC (O) NHⁿBu, NHC (O) NHⁱBu, NHC (O) NH
^secBu, NHC (O) NH^tBu, NHC (O) NHⁿPent, NHC (O) NHⁿHex, N
HC (O) NH^cPent, NHC (O) NH^cHex, NHC (O) NMe₂, NHC (O) N (E
t)₂, NHC (O) Me, NHC (O) Et, NHC (O) CH₂Ph, NHC (O) CHP
h₂, NHCH (CH₂Ph) CO₂H, NHCH (Ph) CO₂H, NⁿPentC (O) NHM
e, NⁿPentC (O) NHEt, NHC (O) NHPh, NHC (O) NHCH₂Ph, NHC
(O) Ph, NHC (O) Ph-2-Cl, NHC (O) Ph-2-NO₂, NHC (O) Ph-2-C
O₂H and the like, preferably a hydrogen atom, an ethyl group, n
-Propyl group, i-propyl group, n-butyl group, hydroxy
Group, ethoxy group, n-propoxy group, i-propoxy group, n-
Butoxy group, amino group, n-propylamino group, n-butyl
Amino group, 3-ethoxy-4-methoxybenzylamino group, 2
-Pyridylmethylamino group, 3-pyridylmethylamino group
Group, 4-pyridylmethylamino group, cyano group, nitro group,
Chlorine atom, bromine atom, methoxycarbonyl group, ethoxy
Carbonyl group, carboxyl group, methoxycarbonyl group
Cyl group, ethoxycarbonylmethyl group, hydroxycal
Bonylmethyl group, CH (CN)₂, CH (CO₂Me)₂, CH (CO₂Et) ₂,
Methylcarbonyl group, ethylcarbonyl group, c-hexyl
Carbonyl group, NHC (O) NHMe, NHC (O) NHEt, NHC (O) NHⁱP
r, NHC (O) NH^cHex, NHC (O) Me, NHC (O) Et, NHC (O) CH₂Ph,
NHC (O) CHPh₂, NHCH (CH₂Ph) CO₂H, NHCH (Ph) CO₂H, NⁿPent
C (O) NHMe, NⁿPentCONHEt, NHC (O) Ph-2-Cl, NHC (O) Ph-2-
NO₂, NHC (O) Ph-2-CO₂H etc. can be mentioned.

Examples of the compound of the present invention include the compounds described in Table 1 and the pharmacologically acceptable salts thereof, in addition to the compounds described in the examples relating to the production method described below. In the present specification, n is normal, i is iso, c is cyclo, sec is secondary, t is tertiary, Me is methyl group, Et is ethyl group, Pr is propyl group, Bu is butyl group, and Pent is Pentyl group, Hex represents a hexyl group, and Ph represents a phenyl group.

Further, Q in the table means the following substituents.

[0022]

[Chemical 7]

In the table, it is the substituent Z of the compound of the present invention.

[0024]

[Chemical 8]

[0025]

[0026]

[Chemical 9]

It is represented by

Table 1

[0029]

[Chemical 10]

[0030]

[Table 1] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Pr Q COOH H CH CH CH CH ⁿ Pr Q COOH H CH CH CNO ₂ CH ⁿ Pr Q COOH H CH CH CNH ₂ CH ⁿ Pr Q COOH H CH CH CNHCOCH ₃ CH ⁿ Pr Q COOH H CH CH CNHCOEt CH ⁿ Pr Q COOH H CH CH CNHCOCHPh ₂ CH ⁿ Pr Q COOH H CH CH CNHCOPh-2-COOH CH ⁿ Pr Q COOH H CH CH CNHCOPh-2-Cl CH ⁿ Pr Q COOH H CH CH CNHCOPh-2-NO ₂ CH ⁿ Pr Q COOH H CH CH CNHCONHN ⁱ Pr CH ⁿ Pr Q COOH H CH CH CNHCONHMe CH ⁿ Pr Q COOH H CH CH CNHCONHM ^c Hex CH ⁿ Pr Q COOH H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Pr Q COOH H CH CH CNCH (COOH) Ph CH ⁿ Pr Q COOH H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Pr QQH CH CH CH CH ⁿ Pr QQH CH CH CNO ₂ CH ⁿ Pr QQH CH CH CNH ₂ CH ⁿ Pr QQH CH CH CNHCOCH ₃ CH ⁿ Pr QQH CH CH CNHCOEt CH ⁿ Pr QQH CH CH CNHCOCHPh ₂ CH ⁿ Pr QQH CH CH CNHCOPh-2-COOH CH ⁿ Pr QQH CH CH CNHCOPh-2-Cl CH ── ──────────────────────────────────

[0031]

[Table 2] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Pr QQH CH CH CNHCOPh-2-NO ₂ CH ⁿ Pr QQH CH CH CNHCONHN ⁱ Pr CH ⁿ Pr QQH CH CH CNHCONHMe CH ⁿ Pr QQH CH CH CNHCONHM ^c Hex CH ⁿ Pr QQH CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Pr QQH CH CH CNCH (COOH) Ph CH ⁿ Pr QQH CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Pr Q CH ₂ COOH H CH CH CH CH ⁿ Pr Q CH ₂ COOH H CH CH CNO ₂ CH ⁿ Pr Q CH ₂ COOH H CH CH CNH ₂ CH ⁿ Pr Q CH ₂ COOH H CH CH CNHCOCH ₃ CH ⁿ Pr Q CH ₂ COOH H CH CH CNHCOEt CH ⁿ Pr Q CH ₂ COOH H CH CH CNHCOCHPh ₂ CH ⁿ Pr Q CH ₂ COOH H CH CH CNHCOPh-2-COOH CH ⁿ Pr Q CH ₂ COOH H CH CH CNHCOPh-2-Cl CH ⁿ Pr Q CH ₂ COOH H CH CH CNHCOPh-2-NO ₂ CH ⁿ Pr Q CH ₂ COOH H CH CH CNHCONHN ⁱ Pr CH ⁿ Pr Q CH ₂ COOH H CH CH CNHCONHMe CH ⁿ Pr Q CH ₂ COOH H CH CH CNHCONHM ^c Hex CH ⁿ Pr Q CH ₂ COOH H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Pr Q CH ₂ COOH H CH CH CNCH (COOH) Ph CH ⁿ Pr Q CH ₂ COOH H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Pr Q CH ₂ OH H CH CH CH CH ────────── ─────────────────────────

[0032]

[Table 3] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Pr Q CH ₂ OH H CH CH CNO ₂ CH ⁿ Pr Q CH ₂ OH H CH CH CNH ₂ CH ⁿ Pr Q CH ₂ OH H CH CH CNHCOCH ₃ CH ⁿ Pr Q CH ₂ OH H CH CH CNHCOEt CH ⁿ Pr Q CH ₂ OH H CH CH CNHCOCHPh ₂ CH ⁿ Pr Q CH ₂ OH H CH CH CNHCOPh-2-COOH CH ⁿ Pr Q CH ₂ OH H CH CH CNHCOPh-2-Cl CH ⁿ Pr Q CH ₂ OH H CH CH CNHCOPh-2-NO ₂ CH ⁿ Pr Q CH ₂ OH H CH CH CNHCONHN ⁱ Pr CH ⁿ Pr Q CH ₂ OH H CH CH CNHCONHMe CH ⁿ Pr Q CH ₂ OH H CH CH CNHCONHM ^c Hex CH ⁿ Pr Q CH ₂ OH H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Pr Q CH ₂ OH H CH CH CNCH (COOH) Ph CH ⁿ Pr Q CH ₂ OH H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Pr Q CHO H CH CH CH CH ⁿ Pr Q CHO H CH CH CNO ₂ CH ⁿ Pr Q CHO H CH CH CNH ₂ CH ⁿ Pr Q CHO H CH CH CNHCOCH ₃ CH ⁿ Pr Q CHO H CH CH CNHCOEt CH ⁿ Pr Q CHO H CH CH CNHCOCHPh ₂ CH ⁿ Pr Q CHO H CH CH CNHCOPh-2-C OOH CH ⁿ Pr Q CHO H CH CH CNHCOPh-2-Cl CH ⁿ Pr Q CHO H CH CH CNHCOPh-2-NO ₂ CH ────────────────────── ──────────────

[0033]

[Table 4] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Pr Q CHO H CH CH CNHCONHN ⁱ Pr CH ⁿ Pr Q CHO H CH CH CNHCONHMe CH ⁿ Pr Q CHO H CH CH CNHCONHM ^c Hex CH ⁿ Pr Q CHO H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Pr Q CHO H CH CH CNCH (COOH) Ph CH ⁿ Pr Q CHO H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Pr COOH COOH H CH CH CH CH ⁿ Pr COOH COOH H CH CH CNO ₂ CH ⁿ Pr COOH COOH H CH CH CNH ₂ CH ⁿ Pr COOH COOH H CH CH CNHCOCH ₃ CH ⁿ Pr COOH COOH H CH CH CNHCOEt CH ⁿ Pr COOH COOH H CH CH CNHCOCHPh ₂ CH ⁿ Pr COOH COOH H CH CH CNHCOPh-2-COOH CH ⁿ Pr COOH COOH H CH CH CNHCOPh-2-Cl CH ⁿ Pr COOH COOH H CH CH CNHCOPh-2-NO ₂ CH ⁿ Pr COOH COOH H CH CH CNHCONHN ⁱ Pr CH ⁿ Pr COOH COOH H CH CH CNHCONHMe CH ⁿ Pr COOH COOH H CH CH CNHCONHM ^c Hex CH ⁿ Pr COOH COOH H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Pr COOH COOH H CH CH CNCH (COOH) Ph CH ⁿ P r COOH COOH H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Pr COOH QH CH CH CH CH ⁿ Pr COOH QH CH CH CNO ₂ CH ──────────────────── ────────────────

[0034]

[Table 5] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Pr COOH QH CH CH CNH ₂ CH ⁿ Pr COOH QH CH CH CNHCOCH ₃ CH ⁿ Pr COOH QH CH CH CNHCOEt CH ⁿ Pr COOH QH CH CH CNHCOCHPh ₂ CH ⁿ Pr COOH QH CH CH CNHCOPh-2-COOH CH ⁿ Pr COOH QH CH CH CNHCOPh-2-Cl CH ⁿ Pr COOH QH CH CH CNHCOPh-2-NO ₂ CH ⁿ Pr COOH QH CH CH CNHCONHN ⁱ Pr CH ⁿ Pr COOH QH CH CH CNHCONHMe CH ⁿ Pr COOH QH CH CH CNHCONHM ^c Hex CH ⁿ Pr COOH QH CH CH CN ( ⁿ Pen ) CONHMe CH ⁿ Pr COOH QH CH CH CNCH (COOH) Ph CH ⁿ Pr COOH QH CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Pr COOH CH ₂ COOH H CH CH CH CH ⁿ Pr COOH CH ₂ COOH H CH CH CNO ₂ CH ⁿ Pr COOH CH ₂ COOH H CH CH CNH ₂ CH ⁿ Pr COOH CH ₂ COOH H CH CH CNHCOCH ₃ CH ⁿ Pr COOH CH ₂ COOH H CH CH CNHCOEt CH ⁿ Pr COOH CH ₂ COOH H CH CH CNHCOCHPh ₂ CH ⁿ Pr COOH CH ₂ COOH H CH CH CNHCOPh-2-COOH CH ⁿ Pr COOH CH ₂ COOH H CH CH CNHCOPh-2-Cl CH ⁿ Pr COOH CH ₂ COOH H CH CH CNHCOPh-2-NO ₂ CH ⁿ Pr COOH CH ₂ COOH H CH CH CNHCONHN ⁱ Pr CH ──────────── ────────────────────────

[0035]

[Table 6] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Pr COOH CH ₂ COOH H CH CH CNHCONHMe CH ⁿ Pr COOH CH ₂ COOH H CH CH CNHCONHM ^c Hex CH ⁿ Pr COOH CH ₂ COOH H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Pr COOH CH ₂ COOH H CH CH CNCH (COOH) Ph CH ⁿ Pr COOH CH ₂ COOH H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Pr COOH CH ₂ OH H CH CH CH CH ⁿ Pr COOH CH ₂ OH H CH CH CNO ₂ CH ⁿ Pr COOH CH ₂ OH H CH CH CNH ₂ CH ⁿ Pr COOH CH ₂ OH H CH CH CNHCOCH ₃ CH ⁿ Pr COOH CH ₂ OH H CH CH CNHCOEt CH ⁿ Pr COOH CH ₂ OH H CH CH CNHCOCHPh ₂ CH ⁿ Pr COOH CH ₂ OH H CH CH CNHCOPh-2-COOH CH ⁿ Pr COOH CH ₂ OH H CH CH CNHCOPh-2-Cl CH ⁿ Pr COOH CH ₂ OH H CH CH CNHCOPh-2-NO ₂ CH ⁿ Pr COOH CH ₂ OH H CH CH CNHCONHN ⁱ Pr CH ⁿ Pr COOH CH ₂ OH H CH CH CNHCONHMe CH ⁿ Pr COOH CH ₂ OH H CH CH CNHCONHM ^c Hex CH ⁿ Pr COOH CH ₂ OH H CH CH CN ( ⁿ Pen) CONH Me CH ⁿ Pr COOH CH ₂ OH H CH CH CNCH (COOH) Ph CH ⁿ Pr COOH CH ₂ OH H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Pr COOH CHO H CH CH CH CH ⁿ Pr COOH CHO H CH CH CNO ₂ CH ⁿ Pr COOH CHO H CH CH CNH ₂ CH ────────────────────────────────────

[0036]

[Table 7] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Pr COOH CHO H CH CH CNHCOCH ₃ CH ⁿ Pr COOH CHO H CH CH CNHCOEt CH ⁿ Pr COOH CHO H CH CH CNHCOCHPh ₂ CH ⁿ Pr COOH CHO H CH CH CNHCOPh-2-COOH CH ⁿ Pr COOH CHO H CH CH CNHCOPh-2-Cl CH ⁿ Pr COOH CHO H CH CH CNHCOPh-2-NO ₂ CH ⁿ Pr COOH CHO H CH CH CNHCONHN ⁱ Pr CH ⁿ Pr COOH CHO H CH CH CNHCONHMe CH ⁿ Pr COOH CHO H CH CH CNHCONHM ^c Hex CH ⁿ Pr COOH CHO H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Pr COOH CHO H CH CH CNCH (COOH) Ph CH ⁿ Pr COOH CHO H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Bu Q COOH H CH CH CH CH ⁿ Bu Q COOH H CH CH CNO ₂ CH ⁿ Bu Q COOH H CH CH CNH ₂ CH ⁿ Bu Q COOH H CH CH CNHCOCH ₃ CH ⁿ Bu Q COOH H CH CH CNHCOEt CH ⁿ Bu Q COOH H CH CH CNHCOCHPh ₂ CH ⁿ Bu Q COOH H CH CH CNHCOPh-2 -COOH CH ⁿ Bu Q COOH H CH CH CNHCOPh-2-Cl CH ⁿ Bu Q COOH H CH CH CNHCOP h-2-NO ₂ CH ⁿ Bu Q COOH H CH CH CNHCONHN ⁱ Pr CH ⁿ Bu Q COOH H CH CH CNHCONHMe CH ─────────────────────── ─────────────

[0037]

[Table 8] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Bu Q COOH H CH CH CNHCONHM ^c Hex CH ⁿ Bu Q COOH H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Bu Q COOH H CH CH CNCH (COOH) Ph CH ⁿ Bu Q COOH H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Bu QQH CH CH CH CH CH ⁿ Bu QQH CH CH CNO ₂ CH ⁿ Bu QQH CH CH CNH ₂ CH ⁿ Bu QQH CH CH CNHCOCH ₃ CH ⁿ Bu QQH CH CH CNHCOEt CH ⁿ Bu QQH CH CH CNHCOCHPh ₂ CH ⁿ Bu QQH CH CH CNHCOPh-2-COOH CH ⁿ Bu QQH CH CH CNHCOPh-2-Cl CH ⁿ Bu QQH CH CH CNHCOPh-2-NO ₂ CH ⁿ Bu QQH CH CH CNHCONHN ⁱ Pr CH ⁿ Bu QQH CH CH CNHCONHMe CH ⁿ Bu QQH CH CH CNHCONHM ^c Hex CH ⁿ Bu QQH CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Bu QQH CH CH CNCH (COOH) Ph CH ⁿ Bu QQH CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Bu Q CH ₂ COOH H CH CH CH CH ⁿ Bu Q CH ₂ COOH H CH CH CNO ₂ CH ⁿ Bu Q CH ₂ COOH H CH CH CNH ₂ CH ⁿ Bu Q CH ₂ COOH H CH CH CNHCOCH ₃ CH ── ──────────────────────────────────

[0038]

[Table 9] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Bu Q CH ₂ COOH H CH CH CNHCOEt CH ⁿ Bu Q CH ₂ COOH H CH CH CNHCOCHPh ₂ CH ⁿ Bu Q CH ₂ COOH H CH CH CNHCOPh-2-COOH CH ⁿ Bu Q CH ₂ COOH H CH CH CNHCOPh-2-Cl CH ⁿ Bu Q CH ₂ COOH H CH CH CNHCOPh-2-NO ₂ CH ⁿ Bu Q CH ₂ COOH H CH CH CNHCONHN ⁱ Pr CH ⁿ Bu Q CH ₂ COOH H CH CH CNHCONHMe CH ⁿ Bu Q CH ₂ COOH H CH CH CNHCONHM ^c Hex CH ⁿ Bu Q CH ₂ COOH H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Bu Q CH ₂ COOH H CH CH CNCH (COOH) Ph CH ⁿ Bu Q CH ₂ COOH H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Bu Q CH ₂ OH H CH CH CH CH ⁿ Bu Q CH ₂ OH H CH CH CNO ₂ CH ⁿ Bu Q CH ₂ OH H CH CH CNH ₂ CH ⁿ Bu Q CH ₂ OH H CH CH CNHCOCH ₃ CH ⁿ Bu Q CH ₂ OH H CH CH CNHCOEt CH ⁿ Bu Q CH ₂ OH H CH CH CNHCOCHPh ₂ CH ⁿ Bu Q CH ₂ OH H CH CH CNHCOPh-2-COOH CH ⁿ Bu Q CH ₂ OH H CH CH CNHCOPh-2-Cl CH ⁿ Bu Q CH ₂ OH H CH CH CNHCOPh-2-NO ₂ CH ⁿ Bu Q CH ₂ OH H CH CH CNHCONHN ⁱ Pr CH ⁿ Bu Q CH ₂ OH H CH CH CNHCONHMe CH ⁿ Bu Q CH ₂ OH H CH CH CNHCONHM ^c Hex CH ───────────────────────────────────

[0039]

[Table 10] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Bu Q CH ₂ OH H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Bu Q CH ₂ OH H CH CH CNCH (COOH) Ph CH ⁿ Bu Q CH ₂ OH H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Bu Q CHO H CH CH CH CH ⁿ Bu Q CHO H CH CH CNO ₂ CH ⁿ Bu Q CHO H CH CH CNH ₂ CH ⁿ Bu Q CHO H CH CH CNHCOCH ₃ CH ⁿ Bu Q CHO H CH CH CNHCOEt CH ⁿ Bu Q CHO H CH CH CNHCOCHPh ₂ CH ⁿ Bu Q CHO H CH CH CNHCOPh-2-COOH CH ⁿ Bu Q CHO H CH CH CNHCOPh-2-Cl CH ⁿ Bu Q CHO H CH CH CNHCOPh-2-NO ₂ CH ⁿ Bu Q CHO H CH CH CNHCONHN ⁱ Pr CH ⁿ Bu Q CHO H CH CH CNHCONHMe CH ⁿ Bu Q CHO H CH CH CNHCONHM ^c Hex CH ⁿ Bu Q CHO H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Bu Q CHO H CH CH CNCH (COOH) Ph CH ⁿ Bu Q CHO H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Bu COOH COOH H CH CH CH CH ⁿ Bu COOH COOH H CH CH CNO ₂ CH ⁿ Bu COOH COOH H CH CH CNH ₂ CH ⁿ Bu COOH COOH H CH CH CNHCOCH ₃ CH ⁿ Bu COOH COOH H CH CH CNHCOEt CH ───────────────────────────────────

[0040]

[Table 11] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Bu COOH COOH H CH CH CNHCOCHPh ₂ CH ⁿ Bu COOH COOH H CH CH CNHCOPh-2-COOH CH ⁿ Bu COOH COOH H CH CH CNHCOPh-2-Cl CH ⁿ Bu COOH COOH H CH CH CNHCOPh-2-NO ₂ CH ⁿ Bu COOH COOH H CH CH CNHCONHN ⁱ Pr CH ⁿ Bu COOH COOH H CH CH CNHCONHMe CH ⁿ Bu COOH COOH H CH CH CNHCONHM ^c Hex CH ⁿ Bu COOH COOH H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Bu COOH COOH H CH CH CNCH (COOH) Ph CH ⁿ Bu COOH COOH H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Bu COOH QH CH CH CH CH ⁿ Bu COOH QH CH CH CNO ₂ CH ⁿ Bu COOH QH CH CH CNH ₂ CH ⁿ Bu COOH QH CH CH CNHCOCH ₃ CH ⁿ Bu COOH QH CH CH CNHCOEt CH ⁿ Bu COOH QH CH CH CNHCOCHPh ₂ CH ⁿ Bu COOH QH CH CH CNHCOPh-2-COOH CH ⁿ Bu COOH QH CH CH CNHCOPh-2-Cl CH ⁿ Bu COOH QH CH CH CNHCOPh-2-NO ₂ CH ⁿ Bu COOH QH CH CH CNHCONHN ⁱ Pr CH ⁿ Bu COOH QH CH CH CNHCONHMe CH ⁿ Bu COOH QH CH CH CNHCONHM ^c Hex CH ⁿ Bu COOH QH CH CH CN ( ⁿ Pen) CONHMe CH ──────────────────────── ───────────

[0041]

[Table 12] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Bu COOH QH CH CH CNCH (COOH) Ph CH ⁿ Bu COOH QH CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Bu COOH CH ₂ COOH H CH CH CH CH ⁿ Bu COOH CH ₂ COOH H CH CH CNO ₂ CH ⁿ Bu COOH CH ₂ COOH H CH CH CNH ₂ CH ⁿ Bu COOH CH ₂ COOH H CH CH CNHCOCH ₃ CH ⁿ Bu COOH CH ₂ COOH H CH CH CNHCOEt CH ⁿ Bu COOH CH ₂ COOH H CH CH CNHCOCHPh ₂ CH ⁿ Bu COOH CH ₂ COOH H CH CH CNHCOPh-2-COOH CH ⁿ Bu COOH CH ₂ COOH H CH CH CNHCOPh-2-Cl CH ⁿ Bu COOH CH ₂ COOH H CH CH CNHCOPh-2-NO ₂ CH ⁿ Bu COOH CH ₂ COOH H CH CH CNHCONHN ⁱ Pr CH ⁿ Bu COOH CH ₂ COOH H CH CH CNHCONHMe CH ⁿ Bu COOH CH ₂ COOH H CH CH CNHCONHM ^c Hex CH ⁿ Bu COOH CH ₂ COOH H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Bu COOH CH ₂ COOH H CH CH CNCH (COOH) Ph CH ⁿ Bu COOH CH ₂ COOH H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Bu COOH CH ₂ OH H CH CH CH CH ⁿ Bu COOH CH ₂ OH H CH CH CNO ₂ CH ⁿ Bu COOH CH ₂ OH H CH CH CNH ₂ CH ⁿ Bu COOH CH ₂ OH H CH CH CNHCOCH ₃ CH ⁿ Bu COOH CH ₂ OH H CH CH CNHCOEt CH ⁿ Bu COOH CH ₂ OH H CH CH CNHCOCHPh ₂ CH ────────────────────────────────────

[0042]

[Table 13] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Bu COOH CH ₂ OH H CH CH CNHCOPh -2-COOH CH ⁿ Bu COOH CH ₂ OH H CH CH CNHCOPh-2-Cl CH ⁿ Bu COOH CH ₂ OH H CH CH CNHCOPh-2-NO ₂ CH ⁿ Bu COOH CH ₂ OH H CH CH CNHCONHN ⁱ Pr CH ⁿ Bu COOH CH ₂ OH H CH CH CNHCONHMe CH ⁿ Bu COOH CH ₂ OH H CH CH CNHCONHM ^c Hex CH ⁿ Bu COOH CH ₂ OH H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Bu COOH CH ₂ OH H CH CH CNCH ( COOH) Ph CH ⁿ Bu COOH CH ₂ OH H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Bu COOH CHO H CH CH CH CH ⁿ Bu COOH CHO H CH CH CNO ₂ CH ⁿ Bu COOH CHO H CH CH CNH ₂ CH ⁿ Bu COOH CHO H CH CH CNHCOCH ₃ CH ⁿ Bu COOH CHO H CH CH CNHCOEt CH ⁿ Bu COOH CHO H CH CH CNHCOCHPh ₂ CH ⁿ Bu COOH CHO H CH CH CNHCOPh-2-COOH CH ⁿ Bu COOH CHO H CH CH CNHCOPh -2-Cl CH ⁿ Bu COOH CHO H CH CH CNHCOPh-2-NO ₂ CH ⁿ Bu COOH CHO H CH CH CNHCONHN ⁱ Pr CH ⁿ Bu COOH CHO H CH CH CNHCONHMe CH ⁿ Bu COOH CHO H CH CH CNHCONHM ^c Hex CH ⁿ Bu COOH CHO H CH CH CN ( ⁿ Pen) CONHMe CH ⁿ Bu COOH CHO H CH CH CNCH (COOH) Ph CH ── ──────────────────────────────────

[0043]

[Table 14] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Bu COOH CHO H CH CH CNCH (COOH ) CH ₂ Ph CH ^c Pr Q COOH H CH CH CH CH ^c Pr Q COOH H CH CH CNO ₂ CH ^c Pr Q COOH H CH CH CNH ₂ CH ^c Pr Q COOH H CH CH CNHCOCH ₃ CH ^c Pr Q COOH H CH CH CNHCOEt CH ^c Pr Q COOH H CH CH CNHCOCHPh ₂ CH ^c Pr Q COOH H CH CH CNHCOPh-2-COOH CH ^c Pr Q COOH H CH CH CNHCOPh-2-Cl CH ^c Pr Q COOH H CH CH CNHCOPh-2- NO ₂ CH ^c Pr Q COOH H CH CH CNHCONHN ⁱ Pr CH ^c Pr Q COOH H CH CH CNHCONHMe CH ^c Pr Q COOH H CH CH CNHCONHM ^c Hex CH ^c Pr Q COOH H CH CH CN ( ⁿ Pen) CONHMe CH ^c Pr Q COOH H CH CH CNCH (COOH) Ph CH ^c Pr Q COOH H CH CH CNCH (COOH) CH ₂ Ph CH ^c Pr QQH CH CH CH CH ^c Pr PrQQH CH CH CNO ₂ CH ^c Pr QQH CH CH CNH ₂ CH ^c Pr QQH CH CH CNHCOCH ₃ CH ^c Pr QQH CH CH CNHCOEt CH ^c Pr QQH CH CH CNHCOCHPh ₂ CH ^c Pr QQH CH CH CNHCOPh-2 -COOH CH ───────────────────────────────────

[0044]

[Table 15] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ^c Pr QQH CH CH CNHCOPh-2-Cl CH ^c Pr QQH CH CH CNHCOPh-2-NO ₂ CH ^c Pr QQH CH CH CNHCONHN ⁱ Pr CH ^c Pr QQH CH CH CNHCONHMe CH ^c Pr QQH CH CH CNHCONHM ^c Hex CH ^c Pr QQH CH CH CN ( ⁿ Pen) CONHMe CH ^c Pr QQH CH CH CNCH (COOH) Ph CH ^c Pr QQH CH CH CNCH (COOH) CH ₂ Ph CH ^c Pr Q CH ₂ COOH H CH CH CH CH ^c Pr Q CH ₂ COOH H CH CH CNO ₂ CH ^c Pr Q CH ₂ COOH H CH CH CNH ₂ CH ^c Pr Q CH ₂ COOH H CH CH CNHCOCH ₃ CH ^c Pr Q CH ₂ COOH H CH CH CNHCOEt CH ^c Pr Q CH ₂ COOH H CH CH CNHCOCHPh ₂ CH ^c Pr Q CH ₂ COOH H CH CH CNHCOPh-2-COOH CH ^c Pr Q CH ₂ COOH H CH CH CNHCOPh-2-Cl CH ^c Pr Q CH ₂ COOH H CH CH CNHCOPh-2-NO ₂ CH ^c Pr Q CH ₂ COOH H CH CH CNHCONHN ⁱ Pr CH ^c Pr Q CH ₂ COOH H CH CH CNHCONHMe CH ^c Pr Q CH ₂ COOH H CH CH CNHCONHM ^c Hex CH ^c Pr Q CH ₂ COOH H CH CH CN ( ⁿ Pen) CONHMe CH ^c Pr Q CH ₂ COOH H CH CH CNCH (COOH) Ph CH ^c Pr Q CH ₂ COOH H CH CH CNCH (COOH) CH ₂ Ph CH ────────── ──────────────────────────

[0045]

[Table 16] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ^c Pr Q CH ₂ OH H CH CH CH CH ^c Pr Q CH ₂ OH H CH CH CNO ₂ CH ^c Pr Q CH ₂ OH H CH CH CNH ₂ CH ^c Pr Q CH ₂ OH H CH CH CNHCOCH ₃ CH ^c Pr Q CH ₂ OH H CH CH CNHCOEt CH ^c Pr Q CH ₂ OH H CH CH CNHCOCHPh ₂ CH ^c Pr Q CH ₂ OH H CH CH CNHCOPh-2-COOH CH ^c Pr Q CH ₂ OH H CH CH CNHCOPh-2-Cl CH ^c Pr Q CH ₂ OH H CH CH CNHCOPh -2-NO ₂ CH ^c Pr Q CH ₂ OH H CH CH CNHCONHN ⁱ Pr CH ^c Pr Q CH ₂ OH H CH CH CNHCONHMe CH ^c Pr Q CH ₂ OH H CH CH CNHCONHM ^c Hex CH ^c Pr Q CH ₂ OH H CH CH CN ( ⁿ Pen) CONHMe CH ^c Pr Q CH ₂ OH H CH CH CNCH (COOH) Ph CH ^c Pr Q CH ₂ OH H CH CH CNCH (COOH) CH ₂ Ph CH ^c Pr Q CHO H CH CH CH CH CH ^c Pr Q CHO H CH CH CNO ₂ CH ^c Pr Q CHO H CH CH CNH ₂ CH ^c Pr Q CHO H CH CH CNHCOCH ₃ CH ^c Pr Q CHO H CH CH CNHCOEt CH ^c Pr Q CHO H CH CH CNHCOCHPh ₂ C H ^c Pr Q CHO H CH CH CNHCOPh-2-COOH CH ^c Pr Q CHO H CH CH CNHCOPh-2-Cl CH ───────────────────────── ─────────────

[0046]

[Table 17] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ^c Pr Q CHO H CH CH CNHCOPh-2 -NO ₂ CH ^c Pr Q CHO H CH CH CNHCONHN ⁱ Pr CH ^c Pr Q CHO H CH CH CNHCONHMe CH ^c Pr Q CHO H CH CH CNHCONHM ^c Hex CH ^c Pr Q CHO H CH CH CN ( ⁿ Pen) CONHMe CH ^c Pr Q CHO H CH CH CNCH (COOH) Ph CH ^c Pr Q CHO H CH CH CNCH (COOH) CH ₂ Ph CH ^c Pr COOH COOH H CH CH CH CH ^c Pr COOH COOH H CH CH CNO ₂ CH ^c Pr COOH COOH H CH CH CNH ₂ CH ^c Pr COOH COOH H CH CH CNHCOCH ₃ CH ^c Pr COOH COOH H CH CH CNHCOEt CH ^c Pr COOH COOH H CH CH CNHCOCHPh ₂ CH ^c Pr COOH COOH H CH CH CNHCOPh-2-COOH CH ^c Pr COOH COOH H CH CH CNHCOPh-2-Cl CH ^c Pr COOH COOH H CH CH CNHCOPh-2-NO ₂ CH ^c Pr COOH COOH H CH CH CNHCONHN ⁱ Pr CH ^c Pr COOH COOH H CH CH CNHCONHMe CH ^c Pr COOH COOH H CH CH CNHCONHM ^c Hex CH ^c Pr COOH COOH H CH CH CN ( ⁿ Pen) CONHMe CH ^c Pr COOH COOH H CH CH CNCH (COOH) Ph CH ^c Pr COOH COOH H CH CH CNCH (COOH) CH ₂ Ph CH ^c Pr COOH QH CH CH CH CH ──────────────── ────────────────────

[0047]

[Table 18] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ^c Pr COOH QH CH CH CNO ₂ CH ^c Pr COOH QH CH CH CNH ₂ CH ^c Pr COOH QH CH CH CNHCOCH ₃ CH ^c Pr COOH QH CH CH CNHCOEt CH ^c Pr COOH QH CH CH CNHCOCHPh ₂ CH ^c Pr COOH QH CH CH CNHCOPh-2-COOH CH ^c Pr COOH QH CH CH CNHCOPh-2-Cl CH ^c Pr COOH QH CH CH CNHCOPh-2-NO ₂ CH ^c Pr COOH QH CH CH CNHCONHN ⁱ Pr CH ^c Pr COOH QH CH CH CNHCONHMe CH ^c Pr COOH QH CH CH CNHCONHM ^c Hex CH ^c Pr COOH QH CH CH CN ( ⁿ Pen) CONHMe CH ^c Pr COOH QH CH CH CNCH (COOH) Ph CH ^c Pr COOH QH CH CH CNCH (COOH) CH ₂ Ph CH ^c Pr COOH CH ₂ COOH H CH CH CH CH ^c Pr COOH CH ₂ COOH H CH CH CNO ₂ CH ^c Pr COOH CH ₂ COOH H CH CH CNH ₂ CH ^c Pr COOH CH ₂ COOH H CH CH CNHCOCH ₃ CH ^c Pr COOH CH ₂ COOH H CH CH CNHCOEt CH ^c Pr COOH CH ₂ COOH H CH CH CNHCOCHPh ₂ CH ^c Pr COOH CH ₂ COOH H CH CH C NHCOPh-2-COOH CH ^c Pr COOH CH ₂ COOH H CH CH CNHCOPh-2-Cl CH ^c Pr COOH CH ₂ COOH H CH CH CNHCOPh-2-NO ₂ CH ────────────── ──────────────────────

[0048]

[Table 19] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ^c Pr COOH CH ₂ COOH H CH CH CNHCONHN ⁱ Pr CH ^c Pr COOH CH ₂ COOH H CH CH CNHCONHMe CH ^c Pr COOH CH ₂ COOH H CH CH CNHCONHM ^c Hex CH ^c Pr COOH CH ₂ COOH H CH CH CN ( ⁿ Pen) CONHMe CH ^c Pr COOH CH ₂ COOH H CH CH CNCH (COOH) Ph CH ^c Pr COOH CH ₂ COOH H CH CH CNCH (COOH) CH ₂ Ph CH ^c Pr COOH CH ₂ OH H CH CH CH CH ^c Pr COOH CH ₂ OH H CH CH CNO ₂ CH ^c Pr COOH CH ₂ OH H CH CH CNH ₂ CH ^c Pr COOH CH ₂ OH H CH CH CNHCOCH ₃ CH ^c Pr COOH CH ₂ OH H CH CH CNHCOEt CH ^c Pr COOH CH ₂ OH H CH CH CNHCOCHPh ₂ CH ^c Pr COOH CH ₂ OH H CH CH CNHCOPh-2-COOH CH ^c Pr COOH CH ₂ OH H CH CH CNHCOPh-2-Cl CH ^c Pr COOH CH ₂ OH H CH CH CNHCOPh-2-NO ₂ CH ^c Pr COOH CH ₂ OH H CH CH CNHCONHN ⁱ Pr CH ^c Pr COOH CH ₂ OH H CH CH CNHCONHMe CH ^c Pr COOH CH ₂ OH H CH CH CNHCONHM ^c Hex CH ^c Pr COOH CH ₂ OH H CH CH CN ( ⁿ Pen) CONHMe CH ^c Pr COOH CH ₂ OH H CH CH CNCH (COOH) Ph CH ^c Pr COOH CH ₂ OH H CH CH CNCH (COOH) CH ₂ Ph CH ^c Pr COOH CHO H CH CH CH CH ^c Pr COOH CHO H CH CH CNO ₂ CH ──────────────────────────────── ────

[0049]

[Table 20] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ^c Pr COOH CHO H CH CH CNH ₂ CH ^c Pr COOH CHO H CH CH CNHCOCH ₃ CH ^c Pr COOH CHO H CH CH CNHCOEt CH ^c Pr COOH CHO H CH CH CNHCOCHPh ₂ CH ^c Pr COOH CHO H CH CH CNHCOPh-2-COOH CH ^c Pr COOH CHO H CH CH CNHCOPh -2-Cl CH ^c Pr COOH CHO H CH CH CNHCOPh-2-NO ₂ CH ^c Pr COOH CHO H CH CH CNHCONHN ⁱ Pr CH ^c Pr COOH CHO H CH CH CNHCONHMe CH ^c Pr COOH CHO H CH CH CNHCONHM ^c Hex CH ^c Pr COOH CHO H CH CH CN ( ⁿ Pen) CONHMe CH ^c Pr COOH CHO H CH CH CNCH (COOH) Ph CH ^c Pr COOH CHO H CH CH CNCH (COOH) CH ₂ Ph CH ⁿ Pr Q COOH HN CH CH CH ⁿ Pr Q COOH HN CH CNO ₂ CH ⁿ Pr Q COOH HN CH CNH ₂ CH ⁿ Pr Q COOH HN CH CNHCOCH ₃ CH ⁿ Pr Q COOH HN CH CNHCOEt CH ⁿ Pr Q COOH HN CH CNHCOCHPh ₂ CH ⁿ Pr Q COOH HN CH CNHCOPh-2-COOH CH ⁿ Pr Q COOH HN CH CNHCOPh-2-Cl CH ⁿ Pr Q C OOH HN CH CNHCOPh-2-NO ₂ CH ⁿ Pr Q COOH HN CH CNHCONHN ⁱ Pr CH ─────────────────────────────── ─────

[0050]

[Table 21] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Pr Q COOH HN CH CNHCONHMe CH ⁿ Pr Q COOH HN CH CNHCONHM ^c Hex CH ⁿ Pr Q COOH HN CH CN ( ⁿ Pen) CONHMe CH ⁿ Pr Q COOH HN CH CNCH (COOH) Ph CH ⁿ Pr Q COOH HN CH CNCH (COOH) CH ₂ Ph CH ⁿ Pr Q COOH H CH N CH CH ⁿ Pr Q COOH H CH N CNO ₂ CH ⁿ Pr Q COOH H CH N CNH ₂ CH ⁿ Pr Q COOH H CH N CNHCOCH ₃ CH ⁿ Pr Q COOH H CH N CNHCOEt CH ⁿ Pr Q COOH H CH N CNHCOCHPh ₂ CH ⁿ Pr Q COOH H CH N CNHCOPh-2-COOH CH ⁿ Pr Q COOH H CH N CNHCOPh-2-Cl CH ⁿ Pr Q COOH H CH N CNHCOPh-2-NO ₂ CH ⁿ Pr Q COOH H CH N CNHCONHN ⁱ Pr CH ⁿ Pr Q COOH H CH N CNHCONHMe CH ⁿ Pr Q COOH H CH N CNHCONHM ^c Hex CH ⁿ Pr Q COOH H CH N CN ( ⁿ Pen) CONHMe CH ⁿ Pr Q COOH H CH N CNCH (COOH ) Ph CH ⁿ Pr Q COOH H CH N CNCH (COOH) CH ₂ Ph CH ⁿ Pr Q COOH H CH CH CH N ⁿ Pr Q COOH H CH CH CNO ₂ N ⁿ Pr Q COOH H CH CH CNH ₂ N ────────────────────────────────────

[0051]

[Table 22] ─────────────────────────────────── R ¹ R ² R ³ R ⁴ W ¹ W ² W ³ W ⁴ ─────────────────────────────────── ⁿ Pr Q COOH H CH CH CNHCOCH ₃ N ⁿ Pr Q COOH H CH CH CNHCOEt N ⁿ Pr Q COOH H CH CH CNHCOCHPh ₂ N ⁿ Pr Q COOH H CH CH CNHCOPh-2-COOH N ⁿ Pr Q COOH H CH CH CNHCOPh-2-Cl N ⁿ Pr Q COOH H CH CH CNHCOPh-2-NO ₂ N ⁿ Pr Q COOH H CH CH CNHCONHN ⁱ Pr N ⁿ Pr Q COOH H CH CH CNHCONHMe N ⁿ Pr Q COOH H CH CH CNHCONHM ^c Hex N ⁿ Pr Q COOH H CH CH CN ( ⁿ Pen) CONHMe N ⁿ Pr Q COOH H CH CH CNCH (COOH) Ph N ⁿ Pr Q COOH H CH CH CNCH (COOH) CH ₂ Ph N ─────────────────── ─────────────────

The biphenylmethylamine compound of the general formula [1] of the present invention and, if possible, a pharmaceutically acceptable salt thereof can be produced by the following method.

Reaction formula (1)

[0054]

[Chemical 11]

(In the formula, R ³ , R ⁴ and Z are the same as defined above. V is halogen such as chlorine atom, bromine atom or iodine atom and methanesulfonyloxy group, paratoluenesulfonyloxy group, trifluoromethanesulfonyloxy group, etc. Means a leaving group, R ²⁸ is a methyl group, an ethyl group, a carboxyl group which may be protected by a t-butyl group, a sulfonic acid group, a sulfonic acid amide group, PO ₂ H, PO ₃ H ₂ or A 5-tetrazolyl group which may be protected by a triphenylmethyl group, a methoxymethyl group, a benzyl group or the like is used.) The reaction formula (1) includes a compound represented by the general formula [2b] and a general formula [3a]. This is a method of producing a compound of the present invention [1] in which R ¹ is hydrogen, by reacting the compound represented by the above and leading it to [5], followed by deprotection if necessary.

This reaction can usually be carried out in the presence of an inorganic base such as potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, lithium hydroxide or sodium hydroxide. In addition to the above inorganic bases, metal hydrides such as sodium hydride, potassium hydride and n-butyllithium, metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide, sodium amide, lithium diisopropylamide, Examples thereof include metal amides such as lithium hexamethyldisilazide and lithium 2,2,6,6-tetramethylpiperidide, and organic bases such as trimethylamine, triethylamine, pyridine and diisopropylethylamine.

Any reaction solvent may be used as long as it does not participate in the reaction, such as hydrocarbon solvents such as benzene, toluene and hexane, ether solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane, formamide and N. , N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and other amide solvents, methanol, ethanol, propanol and other alcohol solvents, chloroform, methylene chloride, ethylene dichloride and other halogen solvents, and others, acetonitrile , A solvent such as dimethyl sulfoxide, water, or a mixed solvent thereof.

The reaction temperature may be in the range of -78 ° C to the boiling point of the solvent used in the reaction. Although the molar ratio of the raw materials can be arbitrarily set, the compound represented by the general formula [2b] is added to the compound represented by the general formula [3a] at 0.
It is sufficient to use 8 to 1.5 times the molar amount. Deprotection can be performed by a known method. For example, methyl ester and ethyl ester can be eliminated by reacting with sodium hydroxide, potassium hydroxide and the like in a water-alcohol solvent under ice cooling to room temperature. The triphenylmethyl group can be eliminated with aqueous acetic acid, hydrochloric acid-ethanol, or ethanol reflux conditions.

The benzyl group can be eliminated by hydrogenolysis with hydrogen gas using a Pd-carbon catalyst, and methoxymethyl ether can be eliminated by hydrochloric acid-ethanol.

Reaction formula (2)

[0061]

[Chemical 12]

(Wherein R ³ , R ⁴ , Z, R ²⁸ and V are the same as above) The reaction formula (2) is represented by the compound represented by the general formula [3b] and the general formula [2a]. This is a method of producing a compound of the present invention [1] in which R ¹ is hydrogen, by reacting the compound and leading it to [5], and then deprotecting if necessary. This reaction can be carried out under the same conditions as in reaction formula (1).
The deprotection conditions are the same as described above.

Although the molar ratio of the raw materials can be set arbitrarily, it is sufficient to use the compound represented by the general formula [3b] in an amount of 0.8 to 1.5 times the molar amount of the compound represented by the general formula [2a]. is there.

Reaction formula (3)

[0065]

[Chemical 13]

(In the formula, R ¹ , R ³ , R ⁴ , Z and R ²⁸ are the same as above. When R ¹ is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or an aralkyl group, V ¹ is Chlorine atom,
A halogen and a leaving group such as a bromine atom, an iodine atom, a methanesulfonyloxy group, a paratoluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group, and R ¹
Is an acyl group, V ¹ means halogen such as chlorine atom, bromine atom, iodine atom and methoxy group, ethoxy group, methylthio group, ethylthio group, etc.) Reaction formula (3) is represented by the general formula [5]. The compound represented by the general formula [1a] is reacted with the compound represented by the general formula [4a].
And then deprotecting as necessary to produce a compound of the present invention compound [1] in which R ¹ is other than hydrogen. This reaction can be carried out under the same conditions as in reaction formula (1). The deprotection conditions are the same as described above.

Reaction formula (4)

[0068]

[Chemical 14]

(Wherein R ¹ , R ³ , R ⁴ , Z, R ²⁸ and V have the same meanings as described above) The reaction formula (4) is the compound represented by the general formula [6] and the general formula [6]. 3a] is reacted to give a compound of the general formula [1a]
And then deprotecting as necessary to produce a compound of the present invention compound [1] in which R ¹ is other than hydrogen. This reaction can be carried out under the same conditions as in reaction formula (1). The deprotection conditions are the same as described above.

Reaction formula (5)

[0071]

[Chemical 15]

(In the formula, R ¹ , R ³ , R ⁴ , Z, R ²⁸ and V have the same meanings as described above.) The reaction formula (5) is the compound represented by the general formula [7] and the general formula [7]. 2a] is reacted to give a compound of the general formula [1a]
And then deprotecting as necessary to produce a compound of the present invention compound [1] in which R ¹ is other than hydrogen. This reaction can be carried out under the same conditions as in reaction formula (1). The deprotection conditions are the same as described above.

The compounds represented by the general formulas [6] and [7], which are the starting materials for the above-mentioned production method, can be produced by the following method.

Reaction formula (6)

[0075]

[Chemical 16]

(Wherein R ¹ , R ²⁸ and V ¹ have the same meanings as described above) The reaction formula (6) is a compound represented by the general formula [2b] and a compound represented by the general formula [4a]. To react with the general formula [6]
Is a method for producing a compound represented by. This reaction can be carried out under the same conditions as in reaction formula (3).

Reaction formula (7)

[0078]

[Chemical 17]

(Wherein R ¹ , R ²⁸ and V have the same meanings as described above) The reaction formula (7) is the same as the compound represented by the general formula [4b] and the compound represented by the general formula [2a]. The reaction is allowed to proceed to the general formula [6]
Is a method for producing a compound represented by. This reaction can be carried out under the same conditions as in reaction formula (1).

Reaction formula (8)

[0081]

[Chemical 18]

(Wherein R ¹ , R ³ , R ⁴ , Z and V ¹ have the same meanings as described above) The reaction formula (8) is the compound represented by the general formula [3b] and the general formula [4a]. The compound represented by the general formula [7] is reacted.
Is a method for producing a compound represented by. This reaction can be carried out under the same conditions as in reaction formula (2).

Reaction formula (9)

[0084]

[Chemical 19]

(In the formula, R ¹ , R ³ , R ⁴ , Z and V have the same meanings as described above.) The reaction formula (9) is the compound represented by the general formula [4b] and the general formula [3a]. A compound represented by the general formula [7] is reacted.
Is a method for producing a compound represented by. This reaction can be carried out under the same conditions as in reaction formula (1).

Next, the compound [3, which is a raw material of the compound of the present invention,
The production methods [a] and [3b] will be described.

In the compound [3a], Z is

[0088]

[Chemical 20]

(Wherein R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same as defined above), the production method of compound [16] is
edron Lett. , P2045 (1978), T
etrahedron Lett. , P3111 (19
79), Chem. Lett. , P891 (197)
7), Helv. Chim. Acta, 53 , p798
(1970), J. Am. Chem. Soc. C. , P153
3 (1967), Tetrahedron Let
t. , P2655 (1977), Chem. Phar
m. Bull. , 14 , p1144 (1966), J. Am.
Chem. Soc. , P3207 (1951), J. Am. O
rg. Chem. , 12 , p456 (1947), J. Am.
Amer. Chem. Soc. , 72 , p1723 (1
950), J. Amer. Chem. Soc. , 63 ,
p2367 (1941), J. Chem. Soc. , P
3185 (1949), J. Med. Chem. , 2
3 , p981 (1980), J. Am. Med. Chem. ，
29 , p291 (1986), Org. Synth. c
ol. Vol. III, p194 (1955), J. Am.
Chem. Soc. Perkin Trans. I, p
1537 (1981), Angew. Chem. In
t. Ed. Engl. , 11 , p315 (1972) and J. Am. Amer. Chem. Soc. , 68 , p181
0 (1946) etc. can be used.

[0090]

[Chemical 21]

(Wherein R ³ , R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and V
Is the same as above. That is, the compound [8] is reacted with phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide or the like to give the compound [16], or

Compound [16] is prepared by reacting [9] with phosphorus trichloride or phosphorus tribromide, or compound [16] is prepared by reacting compound [10] with hydrochloric acid or iron trichloride. Compound [16] is obtained by reacting phosphorus chloride or phosphorus oxybromide, or compound [1]
2] is reacted with phosgene to give compound [16], or compound [13] is reacted with DMF and phosphorus oxychloride or phosphorus oxybromide to give compound [16] (R ⁴ = H), or Compound [16] can be obtained by reacting [14] with compound [15].

In the compound [3a], Z is

[0093]

[Chemical formula 22]

(Wherein R ¹³ , R ¹⁴ and R ¹⁵ are the same as defined above), the production method is as follows:
thesis, p691 (1976) and J. Org.
Chem. , 37 , p3101 (1972) and the like.

[0095]

[Chemical formula 23]

(Wherein R ³ , R ⁴ , R ¹³ , R ¹⁴ , R ¹⁵ and V are
Same as above. That is, the compound [17] is reacted with phosphorus oxychloride or phosphorus oxybromide to give the compound [19], or the compound [1]
Compound [19] can be obtained by reacting 8] with phosphorus oxychloride or phosphorus oxybromide.

In the compound [3a], Z is

[0098]

[Chemical formula 24]

(Wherein R ¹⁶ , R ¹⁷ and R ¹⁸ are the same as defined above), the method for producing compound [22] is as follows.
m. Abstr. 82 , 111959i and J. Or
g. Chem. , 37 , p3101 (1972) and the like.

[0100]

[Chemical 25]

(Wherein R ³ , R ⁴ , R ¹⁶ , R ¹⁷ , R ¹⁸ and V are
Same as above. That is, the compound [20] is reacted with phosphorus oxychloride or phosphorus oxybromide to give the compound [22], or the compound [2]
The compound [22] can be obtained by reacting 1] with phosphorus oxychloride or phosphorus oxybromide.

In the compound [3a], Z is

[0103]

[Chemical formula 26]

(Wherein R ¹⁹ , R ²⁰ and R ²¹ are the same as defined above), a method for producing the compound [24] is described in J. H
etherocycl. Chem. , 9 , p1151 (1
972) and the like can be used.

[0105]

[Chemical 27]

(Wherein R ³ , R ⁴ , R ¹⁹ , R ²⁰ , R ²¹ and V are
Same as above. That is, compound [23] can be reacted with phosphorus oxychloride or phosphorus oxybromide to give compound [24].

In the compound [3a], Z is

[0108]

[Chemical 28]

(Wherein R ²² , R ²³ and R ²⁴ are the same as defined above)
m. Abstr. 92 , 76357, J. Am. Org. Ch
em. , 36 , p450 (1971), J. Am. Org. C
hem. 36 , p1720 (1971) and J. Ch
em. Soc. The method described in p1879 (1954) and the like can be used.

[0110]

[Chemical 29]

(Wherein R ³ , R ⁴ , R ²² , R ²³ , R ²⁴ and V are
Same as above. ) That is, compound [25] is reacted with chlorine or bromine to give compound [28], or compound [26] is reacted with phosphorus oxychloride or phosphorus oxybromide to give compound [28], or compound [27] is added. Compound [28] can be obtained by reacting phosphorus oxychloride or phosphorus oxybromide.

In the compound [3b], Z is

[0113]

[Chemical 30]

(Wherein R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same as defined above), the method for producing the compound [40] is described in J. H
etherocycl. Chem. , 9 , p161 (19
72), J. Chem. Soc. p316 (194
3), J. Chem. Soc. p381 (1942),
J. Chem. Soc. p1284 (1948), Sy
nth. Commun. 21 (18-19), p184
1 (1991), Tetrahedron, 45 , p2.
03 (1989), Synth. Commun. 15 ,
p451 (1985), Chem. Scripta, 1
8 , p240 (1981), Chem. Ber. , 10
9 , p723 (1976), J. Am. Heterocyc
l. Chem. , 8 , p111 (1971), J. Or
g. Chem. , 7 , p497 (1942), Rec.
Trav. Chim. P-B, 86 , p187 (196
7), Chem. Ber. , 71 , p2226 (193
8), Chem. Abstr. 22 , 3663, J. A
mer. Chem. Soc. , 55 , p1748 (19
34) and Helv. Chim. Acta, 9 , p98
0 (1926) and the like.

[0115]

[Chemical 31]

(In the formula, R ³ , R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are
Same as above. That is, the compound [29] is reduced with iron to give the compound [40], or the compound [30] is reacted with an alkali to give the compound [40], or the compound [31] is reduced with H ₂ and Pd—C. To give compound [40] or compound [3]
2] is reacted with KNH _{2 in} liquid ammonia to give compound [40], or compound [33] and compound [34] are reacted with phosphorus tribromide, NaNH ₂ or Py to give compound [40]. Alternatively, the compound [35] is reductively closed with nickel, hydrogen, tin, or hydrochloric acid to give a compound [4].
0], the compound [36] is reacted with ammonium chloride, phosphorus pentoxide or tri-n-butylamine to give the compound [40], or the compound [37] is reacted with NaOBr to give the compound [40]. , Compound [3
8] can be reacted with KNH ₂ or Ba (NH ₂ ) ₂ in liquid ammonia to give compound [40].

In the compound [3b], Z is

[0118]

[Chemical 32]

(Wherein R ¹³ , R ¹⁴ and R ¹⁵ are the same as defined above), the method for producing the compound [47] is described in J. O
rg. Chem. , 30 , p1607 (1965),
J. Chem. Soc. C, p315 (1966),
J. Amer. Chem. Soc. , 69 , p1151
(1947), Chem. Abstr. , 3096 (1
943), J. et al. Org. Chem. , 46 , p2134
(1981), J. Am. Med. Chem. , 22 , p30
1 (1979), Tetrahedron Let
t. , P2087 (1977), Synthesis,
p691 (1976), J. Chem. Soc. C, p
2985 (1971), J. Chem. Soc. C, p
2991 (1971) and J. Org. Chem. , 3
3 , p. 1384 (1968) and the like.

[0120]

[Chemical 33]

(In the formula, R ³ , R ⁴ , R ¹³ , R ¹⁴ and R ¹⁵ are the same as above.) That is, the compound [41] is added to KNH _{2 in} liquid ammonia.
To give compound [47], or to react compound [42] with compound [34] in the presence of piperidine to give compound [47], or to react compound [43] in liquid ammonia to give compound [47] Alternatively, compound [45] and compound [46] are reacted in the presence of phosphoric acid to give compound [4
7].

In the compound [3b], Z is

[0123]

[Chemical 34]

(Wherein R ¹⁶ , R ¹⁷ and R ¹⁸ are the same as defined above), the method for producing the compound [50] is described in J. O
rg. Chem. , 46 , p2134 (1981) and Rec. Trav. Chim. , P-B, 96 , p15
1 (1977) and the like can be used.

[0125]

[Chemical 35]

(In the formula, R ³ , R ⁴ , R ¹⁶ , R ¹⁷ and R ¹⁸ are the same as above.) That is, compound [48] or compound [49] is reacted with KNH _{2 in} liquid ammonia to give compound [50 ] Can be used.

In the compound [3b], Z is

[0128]

[Chemical 36]

(Wherein R ¹⁹ , R ²⁰ and R ²¹ are the same as defined above), the method for producing the compound [54] is described in J. H
etherocycl. Chem. , 9 , p703 (19
72), J. Org. Chem. , 46 , p2134
(1981), Chem. Abstr. , 92 , 763
55, J. Heterocycl. Chem. , 11 ,
p151 (1974) and J. Org. Chem. , 3
3 , p. 1384 (1968) and the like.

[0130]

[Chemical 37]

(In the formula, R ³ , R ⁴ , R ¹⁹ , R ²⁰ and R ²¹ are the same as above.) That is, compound [51] or compound [53] is reacted with KNH _{2 in} liquid ammonia to give compound [54 Or a compound [52] and a compound [34] are reacted in the presence of sodium hydroxide or piperidine to give a compound [54].

In the compound [3b], Z is

[0133]

[Chemical 38]

(Wherein R ²² , R ²³ and R ²⁴ are the same as defined above), the method for producing compound [57] is described in J. O
rg. Chem. , 46 , p2134 (1981), R
ocz. Chem. , 47 , p549 (1973),
J. Org. Chem. , 33 , p1384 (196
8), Rec. Trav. Chim. , P-B, 82 ,
p997 (1963), J. Chem. Soc. , P2
04 (1958) and J. Org. Chem. , 46 ,
The method described in p2134 (1981) and the like can be used.

[0135]

[Chemical Formula 39]

(In the formula, R ³ , R ⁴ , R ²² , R ²³ and R ²⁴ are the same as above.) That is, compound [55] or compound [57] is reacted with KNH _{2 in} liquid ammonia to give compound [57 ] Can be used.

The administration form of the compound of the present invention includes parenteral administration by injection (subcutaneous, intravenous, intramuscular, intraperitoneal injection), ointment, suppository, aerosol, etc. or tablets, capsules, granules, Oral administration by pills, syrups, solutions, emulsions, suspensions and the like can be mentioned.

The above-mentioned pharmaceutical composition containing a compound of the present invention comprises about 0.1% of the compound of the present invention, based on the weight of the total composition.
1-99.5%, preferably about 0.5-95%.

In addition to the compounds of the present invention or compositions containing the compounds of the present invention, other pharmaceutically active compounds can be included. Alternatively, these compositions may include multiple compounds of the invention.

The clinical dose of the compound of the present invention varies depending on the age, body weight, susceptibility of the patient, degree of symptoms, etc., but the effective dose is usually 0.003 to 1.5 g / day for an adult. It is about 0.01 to 0.6 g. However, if necessary, an amount outside the above range can be used.

The compounds of the present invention are formulated for administration by conventional pharmaceutical means. That is, tablets, capsules, granules and pills for oral administration include excipients such as sucrose, lactose, glucose, starch, mannitol; binders such as syrup, acacia, gelatin, sorbit, tragacanth, methylcellulose, Polyvinylpyrrolidone; disintegrants such as starch, carboxymethyl cellulose or its calcium salt, microcrystalline cellulose, polyethylene glycol; lubricants such as talc, magnesium or calcium stearate, silica; lubricants such as sodium laurate, glycerol And then prepared.

Injectables, solutions, emulsions, suspensions, syrups and aerosols include active ingredient solvents such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol; surface active agents. Agents such as sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor oil, lecithin; suspending agents, for example, carboxymethylcellulose sodium salt, cellulose derivatives such as methylcellulose, tragacanth, Natural gums such as gum arabic; prepared by using preservatives such as esters of paraoxybenzoic acid, benzalkonium chloride, sorbate and the like.

For the ointment which is a transdermal preparation, for example, white petrolatum, liquid paraffin, higher alcohol, macrogol ointment, hydrophilic ointment, aqueous gel base and the like are used.
Suppositories are prepared, for example, using polyethylene glycol, lanolin, coconut oil and the like.

[0144]

EXAMPLES The compounds of the present invention will be described in more detail below with reference to examples, but these examples do not limit the present invention. Synthesis example

Synthesis Example 1 N- (3-ethoxycarbonylquinolin-2-yl)-
N-[(2 '-(N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-propylamine 2-n-propylamino-3-ethoxycarbonylquinoline 369 .2 mg and 1,3-dimethyl-3,4
5,6-Tetrahydro-2 (1H) -pyrimidinone 18
A 8.5 mg THF solution (2 mL) was cooled to −78 ° C., 1.0 M lithium hexamethyldisilazide THF solution (1.60 mL) was added, and the mixture was stirred for 10 minutes. 4-Bromomethyl-2 ′-(N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl 1.15 g TH
The F solution (5 mL) was stirred at −78 ° C. for 1 hour and further at room temperature for 16 hours. After adding 10 mL of an ammonium chloride aqueous solution to this reaction solution, THF was distilled off under reduced pressure, and the mixture was extracted with 60 mL of dichloromethane. After drying over anhydrous calcium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to give the title compound 757.
3 mg was obtained as a pale yellow amorphous solid.

¹ H-NMR (60 MHz, CDCl ₃ ):
δ 0.76 (t, J = 7 Hz, 3H), 1.35 (t,
J = 7 Hz, 3H), 1.50-1.80 (m, 2
H), 3.25 (t, J = 7 Hz, 2H), 4.29.
(Q, J = 7 Hz, 2H), 4.72 (s, 2H),
7.60-8.10 (m, 27H), 8.25 (s, 1
H) MS (EI): 420 (49%), 635 (52%),
678 (M ⁺ -56, 59%)

Synthesis Example 2 N- (3-ethoxycarbonylquinolin-2-yl)-
N-[(2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -n-propylamine N- (3-ethoxycarbonylquinolin-2-yl) -obtained in Synthesis Example 1 N-[(2 '-(N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-propylamine 726.
9 mg was suspended in 15 mL of ethanol, heated under reflux for 4.5 hours, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 9: 1 → 2: 1 → 1: 2) to give the title compound (446.0 mg) as a yellow amorphous solid.

¹ H-NMR (60 MHz, CDCl ₃ ):
δ 0.84 (t, J = 7 Hz, 3H), 1.37 (t,
J = 7 Hz, 3H), 1.40-1.90 (m, 2
H), 3.35 (t, J = 7 Hz, 2H), 4.31
(Q, J = 7 Hz, 2H), 4.74 (s, 2H),
6.90-7.73 (m, 11H), 7.90-8.1
5 (m, 1H), 8.24 (s, 1H), 8.30-
8.60 (m, 1H) MS (EI): 375 (20%), 449 (73%),
492 (M ⁺ , 25%)

Synthesis Example 3 N- (3-ethoxycarbonylquinolin-2-yl)-
N-[(2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -n-propylamine potassium salt N- (3-ethoxycarbonylquinolin-2-yl obtained in Synthesis Example 2 ) -N-[(2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -n-
Propylamine (39.3 mg) was dissolved in methanol (3 mL) to give a 0.1 M potassium hydroxide methanol solution (0.80 m).
L was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and dried to give the title compound (41.3 mg) as a yellow powder.

MS (FAB): 531 (M + H)

Synthesis Example 4 N- (3-Carboxyquinolin-2-yl) -N-
[(2 '-(1H-Tetrazol-5-yl) biphenyl-4-yl) methyl] -n-propylamine N- (3-ethoxycarbonylquinolin-2-yl) -N- obtained in Synthesis Example 2 [(2 '-(1H-Tetrazol-5-yl) biphenyl-4-yl) methyl] -n-
347.2 mg of propylamine was suspended in a mixed solution of 10 mL of water and 10 mL of ethanol, 1.05 g of potassium hydroxide was added, and the mixture was heated under reflux for 4.5 hours. The reaction solution was neutralized with dilute hydrochloric acid to precipitate crystals. The obtained crystals were washed with water and dichloromethane, and the residue was dissolved in warm ethanol. This solution was filtered while hot, and the obtained filtrate was concentrated under reduced pressure and dried to give the title compound (391.9 mg) as a yellow amorphous solid.

¹ H-NMR (60 MHz, CDCl ₃ ):
δ 0.95 (t, J = 7 Hz, 3H), 1.50-2.
10 (m, 2H), 3.66 (t, J = 7Hz, 2
H), 4.95 (s, 2H), 6.90-8.20.
(M, 12H), 8.94 (s, 1H) MS (EI): 377 (39%), 420 (91%),
464 (M ⁺ , 12%)

Synthesis Example 5 N- (3-carboxyquinolin-2-yl) -N-
[(2 '-(1H-Tetrazol-5-yl) biphenyl-4-yl) methyl] -n-propylamine dipotassium salt N- (3-carboxyquinoline-2 obtained in Synthesis Example 4
-Yl) -N-[(2 '-(1H-tetrazole-5-
196.0 mg of (yl) biphenyl-4-yl) methyl] -n-propylamine was dissolved in 3 mL of methanol, and 8.4 mL of a 0.1 M potassium hydroxide methanol solution was added thereto.
After adding, the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and dried to give the title compound (180.0 mg) as a pale-yellow powder.

MS (FAB): 541 (M + H)

Synthesis Example 6 N- (3-ethoxycarbonylquinolin-2-yl)-
N-[(2 '-(N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-butylamine 2-n-butylamino-3-ethoxycarbonylquinoline 500 mg and 1,3-dimethyl-3,4,5,6
-Tetrahydro-2 (1H) -pyrimidinone 0.175
Cool the mL solution of THF (5 mL) to −78 ° C. and
0M lithium hexamethyldisilazide THF solution 2.2
mL was added and stirred for 10 minutes. 4-bromomethyl-
A THF solution (12 mL) of 2 '-(N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl (1.54 g) was stirred at -78 ° C for 1 hour, and further stirred at room temperature for 16 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution for neutralization, and the solvent was distilled off under reduced pressure.
The residue was extracted with 200 mL of dichloromethane, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 9: 1) to give the title compound 24
Obtained 3.9 mg as a pale yellow amorphous solid.

¹ H-NMR (60 MHz, CDCl ₃ ):
δ 0.87 (t, J = 7 Hz, 3H), 1.21-1.
70 (m, 7H), 3.24 (t, J = 7Hz, 2
H), 4.34 (q, J = 7 Hz, 2H), 4.72.
(S, 2H), 6.73-7.92 (m, 27H),
8.27 (s, 1H) MS (FAB): 749 (M + H)

Synthesis Example 7 N- (3-ethoxycarbonylquinolin-2-yl)-
N-[(2 '-(1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-butylamine N- (3-ethoxycarbonylquinolin-2-yl) -obtained in Synthesis Example 6 N-[(2 '-(N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-butylamine 240.0
After suspending mg in ethanol (5 mL) and heating under reflux for 4.5 hours, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 9: 1 → 2: 1 → 1: 2) to give the title compound (148.2 mg) as a yellow powder.

MS (FAB): 507 (M + H)

Synthesis Example 8 N- (3-Carboxyquinolin-2-yl) -N-
[(2 '-(1H-Tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-butylamine N- (3-ethoxycarbonylquinolin-2-yl) -N- obtained in Synthesis Example 7. [(2 '-(1H-Tetrazol-5-yl)) biphenyl-4-yl) methyl] -n
-Butylamine 110.0 mg was suspended in a mixed solution of water 1.5 mL and ethanol 4 mL, and potassium hydroxide 4
After adding 00 mg, the mixture was heated under reflux for 3 hours. The reaction solution was neutralized with 2% hydrochloric acid to precipitate crystals. The obtained crystals were washed with water and dichloromethane, and the residue was dissolved in warm ethanol. The solution is filtered while hot,
The obtained filtrate was concentrated under reduced pressure and dried to give the title compound 5
8 mg was obtained as a yellow powder.

MS (FAB): 479 (M + H)

Synthesis Example 9 N- (3-carboxyquinolin-2-yl) -N-
[(2 '-(1H-Tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-butylamine dipotassium salt N- (3-carboxyquinoline-2 obtained in Synthesis Example 8
-Yl) -N-[(2 '-(1H-tetrazole-5-
I))) Biphenyl-4-yl) methyl] -n-butylamine (44.5 mg) was dissolved in methanol (2 mL), and 0.1 M potassium hydroxide methanol solution (1.78 mL) was dissolved therein.
After adding, the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried to obtain the title compound (53.4 mg) as a pale yellow powder.

MS (FAB): 555 (M + H)

Synthesis Example 10 N- (3-ethoxycarbonyl-6-nitroquinoline-
2-yl) -N-[(2 '-(N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4
-Yl) methyl] -n-butylamine 2-chloro-3-ethoxycarbonyl-6-nitroquinoline 100 mg and 4-n-butylaminomethyl-
2 '-(N-triphenylmethyl- (1H) -tetrazol-5-yl)) biphenyl 196.0 mg DMF
0.075 mL of triethylamine was added to the solution (8 mL), and the mixture was stirred at 80 ° C. for 10 hours while heating. The reaction solution was allowed to cool, neutralized with saturated aqueous ammonium chloride solution, extracted with 100 mL of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give 226.0 mg of the title compound as a yellow amorphous solid.

¹ H-NMR (60 MHz, CDCl ₃ ):
δ 0.90 (t, J = 7 Hz, 3H), 1.00-1.
62 (m, 7H), 3.39 (t, J = 7Hz, 2
H), 4.33 (q, J = 7 Hz, 2H), 4.79.
(S, 2H), 6.87-8.01 (m, 24H),
8.20 (m, 1H), 8.32 (s, 1H), 8.5
9 (m, 1H) MS (FAB): 794 (M + H)

Synthesis Example 11 N- (3-ethoxycarbonyl-6-nitroquinoline-
2-yl) -N-[(2 '-(1H-tetrazole-5
-Yl)) Biphenyl-4-yl) methyl] -n-butylamine N- (3-ethoxycarbonyl-obtained in Synthesis Example 10
6-nitroquinolin-2-yl) -N-[(2 '-(N
226.0 mg of -triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-butylamine was suspended in 5 mL of ethanol,
After heating under reflux for 4.5 hours, the solvent was distilled off under reduced pressure.
The obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 2 → ethyl acetate) to give the title compound (148.8 mg) as a yellow powder.

¹ H-NMR (60 MHz, CDCl ₃ ):
δ1.00 (t, J = 7 Hz. 3H), 1.29-2.
00 (m, 7H), 3.50 (t, J = 7Hz, 2
H), 4.38 (q, J = 7 Hz, 2H), 4.90
(S, 2H), 6.90-8.59 (m, 12H) MS (FAB): 552 (M + H).

Synthesis Example 12 N- (3-ethoxycarbonyl-6-nitroquinoline-
2-yl) -N-[(2 '-(1H-tetrazole-5
-Yl)) Biphenyl-4-yl) methyl] -n-butylamine potassium salt N- (3-ethoxycarbonyl-obtained in Synthesis Example 11
6-nitroquinolin-2-yl) -N-[(2 '-(1
H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-butylamine (50.5 mg) was dissolved in methanol (2 mL), 0.1 M potassium hydroxide methanol solution (0.9 mL) was added, and the mixture was allowed to stand at room temperature for 1 hour. It was stirred. The reaction solution was concentrated under reduced pressure and dried to give the title compound 58.
2 mg was obtained as a yellow amorphous solid.

MS (FAB): 590 (M + H)

Synthesis Example 13 N- (3-carboxy-6-nitroquinolin-2-yl) -N-[(2 '-(1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n -Butylamine N- (3-ethoxycarbonyl-obtained in Synthesis Example 11
6-nitroquinolin-2-yl) -N-[(2 '-(1
H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-butylamine (260.0 mg) was suspended in a mixed solution of water (3.5 mL) and ethanol (9.5 mL), and potassium hydroxide (80 mg) was added. The mixture was heated under reflux for 4 hours. The reaction solution was neutralized with 2% hydrochloric acid to precipitate crystals. The obtained crystals were washed with water and dichloromethane, and the residue was dissolved in warm ethanol. The solution was filtered while hot, and the resulting filtrate was concentrated under reduced pressure and dried to give the title compound (237.1 mg) as a yellow powder.

¹ H-NMR (60 MHz, CDCl ₃ ):
δ 0.83 (t, J = 7 Hz, 3H), 1.01-1.
81 (m, 4H), 3.61 (brs, 2H), 4.6
9 (brs, 2H), 6.63-8.70 (m, 12
H) MS (FAB): 524 (M + H)

Synthesis Example 14 N- (3-Carboxy-6-nitroquinolin-2-yl) -N-[(2 '-(1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n -Butylamine dipotassium salt N- (3-carboxy-6-nitroquinolin-2-yl) -N-[(2 '-(1H-tetrazol-5-yl)) biphenyl-4-obtained in Synthesis Example 13 174.7 mg of (yl) methyl] -n-butylamine was added to methanol 7
It melt | dissolved in mL, 6.3M 0.1M potassium hydroxide methanol solution was added, and it stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried to give the title compound 187.2.
mg was obtained as a pale yellow amorphous solid.

MS (FAB): 600 (M + H)

Synthesis Example 15 N- (3-ethoxycarbonyl-6-nitroquinoline-
2-yl) -N-[(2 '-(N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4
-Yl) methyl] -n-propylamine 2-chloro-3-ethoxycarbonyl-6-nitroquinoline 150 mg and 4-n-butylaminomethyl-
0.12 mL of triethylamine was added to a DMF solution (12 mL) of 286.0 mg of 2 ′-(N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl, and the mixture was stirred at 80 ° C. for 10 hours while heating. The reaction solution was allowed to cool, neutralized with saturated aqueous ammonium chloride solution,
After extraction with 150 mL of ethyl acetate, the extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give the title compound (271.5 mg) as a yellow amorphous solid.

¹ H-NMR (60 MHz, CDCl ₃ ):
δ 0.79 (t, J = 7 Hz, 3H), 1.20-1.
88 (m, 4H), 3.34 (t, J = 7Hz, 2
H), 4.37 (q, J = 7 Hz, 2H), 4.81
(S, 2H), 6.77-8.66 (m, 27H) MS (FAB): 780 (M + H).

Synthesis Example 16 N- (3-ethoxycarbonyl-6-nitroquinoline-
2-yl) -N-[(2 '-(1H-tetrazole-5
-Yl)) Biphenyl-4-yl) methyl] -n-propylamine N- (3-ethoxycarbonyl-obtained in Synthesis Example 15
6-nitroquinolin-2-yl) -N-[(2 '-(N
271.5 mg of -triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-propylamine was suspended in 8 mL of ethanol,
After heating under reflux for 16 hours, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (n
-Hexane: ethyl acetate = 1: 2 → ethyl acetate) to obtain 148.1 mg of the title compound as a yellow amorphous solid.

¹ H-NMR (60 MHz, CDCl ₃ ):
δ 0.85 (t, J = 7 Hz, 3H), 1.39 (t,
J = 7 Hz, 3H), 1.60-1.96 (m, 2
H), 3.45 (t, J = 7 Hz, 2H), 3.37
(Q, J = 7 Hz, 2H), 4.89 (s, 2H),
6.93-8.62 (m, 12H) MS (FAB): 538 (M + H).

Synthesis Example 17 N- (3-Carboxy-6-nitroquinolin-2-yl) -N-[(2 '-(1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n -Propylamine N- (3-ethoxycarbonyl-obtained in Synthesis Example 16)
6-nitroquinolin-2-yl) -N-[(2 '-(1
H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-propylamine (148.0 mg) was suspended in a mixed solution of water (2 mL) and ethanol (6 mL), and potassium hydroxide (46 mg) was added thereto. Heated to reflux for hours. The reaction solution was neutralized with 2% hydrochloric acid to precipitate crystals. The obtained crystals were washed with water and dichloromethane, and the residue was dissolved in warm ethanol. This solution was filtered while hot, and the obtained filtrate was concentrated under reduced pressure and dried to obtain 142.5 mg of the title compound as a yellow powder.

¹ H-NMR (60 MHz, CDCl ₃ ):
δ 0.88 (t, J = 7 Hz, 3H), 1.12-1.
77 (m, 2H), 3.61 (brt, J = 7Hz, 2
H), 4.69 (brs, 2H), 6.80-8.19.
(M, 12H), 11.2 (brs, 1H) MS (FAB): 510 (M + H)

Synthesis Example 18 N- (3-Carboxy-6-nitroquinolin-2-yl) -N-[(2 '-(1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n -Propylamine dipotassium salt N- (3-carboxy-6-nitroquinolin-2-yl) -N-[(2 '-(1H-tetrazol-5-yl)) biphenyl-4 obtained in Synthesis Example 13 -Yl) methyl] -n-butylamine 112.5 mg in methanol 6
It melt | dissolved in mL, 4.2 M 0.1 M potassium hydroxide methanol solution was added, and it stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried to give the title compound (114.2 m).
g was obtained as a pale yellow amorphous solid.

MS (FAB): 586 (M + H)

Synthesis Example 19 N- (3-ethoxycarbonyl-6-aminoquinoline-
2-yl) -N-[(2 '-(1H-tetrazole-5
-Yl)) Biphenyl-4-yl) methyl] -n-propylamine N- (3-ethoxycarbonyl-obtained in Synthesis Example 16
6-nitroquinolin-2-yl) -N-[(2 '-(1
H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-propylamine 550 mg and 1.16 g stannous chloride in ethanol (30 mL) are heated to 60 ° C. and 20 mg sodium borohydride is added. Add ethanol solution (9 mL) slowly and stir for 3.5 hours. The reaction solution is cooled to 0 ° C., 20 mL of cold water is added, and a 3.5 M sodium hydroxide solution is further added to neutralize. The reaction mixture solution was filtered through Celite and extracted with 300 mL of chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 4 → ethyl acetate) to give the title compound 216.
7 mg was obtained as a dark green powder.

¹ H-NMR (60 MHz, CDCl ₃ ):
δ 0.80 (t, J = 7 Hz, 3H), 1.43 (t,
J = 7 Hz, 3H), 1.45-1.82 (m, 2
H), 3.23 (t, J = 7 Hz, 2H), 4.32
(Q, J = 7 Hz, 2H), 4.60 (s, 2H),
5.63 (brs, 2 or 3H), 6.60-7.99
(M, 12H) MS (FAB): 508 (M + H)

Synthesis Example 20 N- (3-ethoxycarbonyl-6-aminoquinoline-
2-yl) -N-[(2 '-(1H-tetrazole-5
-Yl)) Biphenyl-4-yl) methyl] -n-propylamine potassium salt N- (3-ethoxycarbonyl-obtained in Synthesis Example 19
6-aminoquinolin-2-yl) -N-[(2 '-(1
H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-propylamine (76.7 mg) was dissolved in methanol (6 mL), and 0.1 M potassium hydroxide methanol solution (1.44 mL) was added. Stir for hours. The reaction solution was concentrated under reduced pressure and dried to obtain the title compound (85.5 mg) as a dark yellow powder.

MS (FAB): 546 (M + H)

Synthesis Example 21 N- (3-Carboxy-6-aminoquinolin-2-yl) -N-[(2 '-(1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -N -Propylamine N- (3-ethoxycarbonyl-obtained in Synthesis Example 19)
6-aminoquinolin-2-yl) -N-[(2 '-(1
H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n-propylamine (100 mg) in water (1 m)
The mixture was suspended in a mixed solution of L and ethanol (4 mL), potassium hydroxide (33 mg) was added, and the mixture was heated under reflux for 2 hr. The reaction solution was neutralized with 2% hydrochloric acid to precipitate crystals. The obtained crystals were washed with water and dichloromethane, and the residue was dissolved in warm ethanol. This solution was filtered while hot, and the resulting filtrate was concentrated under reduced pressure and dried to obtain 81.4 mg of the title compound as a yellow powder.

¹ H-NMR (60 MHz, CDCl ₃ ):
δ 0.95 (t, J = 7 Hz, 3H), 1.23-1.
80 (m, 2H), 3.58 (t, J = 7Hz, 3
H), 4.37 (s, 2H), 6.81-7.91.
(M, 12H) MS (FAB): 480 (M + H)

Synthesis Example 22 N- (3-Carboxy-6-aminoquinolin-2-yl) -N-[(2 '-(1H-tetrazol-5-yl)) biphenyl-4-yl) methyl] -n -Propylamine dipotassium salt N- (3-carboxy-6-aminoquinolin-2-yl) -N-[(2 '-(1H-tetrazol-5-yl)) biphenyl-4 obtained in Synthesis Example 21. -Yl) methyl] -n-propylamine 57.0 mg in methanol 4
It melt | dissolved in mL, 2.26 mL of 0.1-M potassium hydroxide methanol solutions were added, and it stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried to give the title compound (66.5 m).
g was obtained as a dark green powder.

MS (FAB): 556 (M + H)

Formulation example

Formulation Example 1 Tablet Compound of the present invention 10 g Lactose 20 g Starch 4 g Starch (for paste) 1 g Magnesium stearate 100 mg Carboxymethyl 7 g Cellulose calcium Total amount 42.1 g After mixing the above components by a conventional method, A sugar-coated tablet containing 50 mg of the active ingredient was prepared.

Formulation Example 2 Capsule Compound of the present invention 10 g Lactose 20 g Microcrystalline cellulose 10 g Magnesium stearate 1 g Total amount 41 g The above ingredients were mixed by a conventional method and filled in a gelatin capsule to obtain 50 mg of the active ingredient per capsule. The capsule was contained.

Formulation Example 3 Soft capsule formulation Compound of the present invention 10 g Corn oil 35 g Total amount 45 g After mixing the above components, a soft capsule formulation was prepared by a conventional method.

Formulation Example 4 Ointment Compound of the present invention 1.0 g Olive oil 20 g White petrolatum 79 g Total amount 100 g The above components were mixed by a conventional method to give a 1% ointment.

Formulation Example 5 Aerosol suspension (A) Compound of the present invention 0.25% Isopropyl myristate 0.10% Ethanol 26.40% (B) 1,2-dichlorotetrafluoroethane and 1-chloropentafluoro Mixture of 60-40% of ethane 73.25% The above composition (A) is mixed, the resulting mixture is charged into a container equipped with a valve, and the propellant (B) is added at about 2.46 at 20 ° C.
A pressure of 2.81 mg / cm ² cage was applied from a valve nozzle to obtain an aerosol suspension.

Test example

Test Example 1 Angiotensin Antagonist Test [0196] Rabbits were killed by exsanguination under pentobarbital anesthesia, and the thoracic aorta was immediately removed. The aorta was used as a ring sample, kept at 37 ° C., suspended in a nutrient solution (Krebs-Henseleit solution) aerated with a mixed gas of 95% oxygen and 5% carbon dioxide, and its isometric contraction was measured. The sample was stabilized for 1 hour while exchanging the nutrient solution every 20 minutes, and then contracted by angiotensin II (AngII: 10 ⁻⁸ M). In the evaluation of the compound of the present invention, the compound of the present invention (10 ⁻⁶ M or 10 ⁻⁷ M) was pretreated 20 minutes before the fourth administration of AngII, and the inhibition rate was calculated assuming that the contraction of AngII at the third time was 100%. The compounds of the present invention were corrected by dimethyl sulfoxide (DMSO).

[0197]

[Table 23] ────────────────────────── Inhibition rate (%) Synthesis example of the compound of the present invention 1 × 10 ⁻⁶ M 1 × 10 ^{− 7} M ────────────────────────── 4 62 16 15 5 69 12 8 8 47 9 57 ───────────── ──────────────

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/47 ABN 9454-4C ABU 9454-4C ACV 9454-4C C07D 471/04 113 114 A C07F 9 / 60 9155-4H 9/6561 Z 9155-4H (72) Inventor Tsutomu Higashiyama 722, Tsuboi-cho, Funabashi-shi, Chiba 1 Central Research Laboratory, Nissan Chemical Industries, Ltd. (72) Masayuki Sato 722, Tsuboi-cho, Funabashi, Chiba Address 1 Nissan Chemical Industry Co., Ltd. Central Research Laboratory (72) Inventor Yukinori Masuda 1470 Shiraoka, Shiraoka-cho, Minamisaitama-gun, Saitama Nissan Chemical Industry Co., Ltd.

Claims (8)

[Claims] 1. A formula [1]:[In the formula, R¹Is a hydrogen atom, C₁~ C₆Straight or branched
Alkyl group (the alkyl group is a halogen atom, or
Rogen atom, nitro group, carboxyl group, C₁~ C_FourThe al
Kill group or C₁~ C_FourOptionally substituted with an alkoxy group of
Optionally substituted with a phenyl group
Yes. ), C₂~ C₆A straight-chain or branched alkenyl group
(The alkenyl group is optionally substituted with a halogen atom.
You may stay. ), C₂~ C₆Linear or branched alky
Nyl group (the alkynyl group is optionally substituted with a halogen atom)
It may have been done. ), C₃~ C₆A cycloalkyl group of
The cycloalkyl group is a halogen atom or a phenyl group.
It may be replaced at will. ), Or a phenyl group (the group
A phenyl group is a halogen atom, a nitro group, or a carboxyl group.
Base, C₁~ C_FourAlkyl group or C₁~ C_FourWith the alkoxy group of
It may be replaced at will. ) Means R²Is a carboxyl group (the carboxyl group is C₁~ C_FourA
Alkyl group, which may be esterified with a rualkyl group), sulfonic acid
Group (the sulfonic acid group is C₁~ C_FourEsterified with the alkyl group of
), Sulfonic acid amide group, PO₂H₂(C₁
~ C_FourMay be esterified with an alkyl group of), PO
₃H₂(C₁~ C_FourMay be esterified with the alkyl group of
Or a tetrazolyl group (the tetrazolyl group is benzyl
Group, methoxymethyl group, triphenylmethyl group
May be substituted with. ) Means R³And R^FourAre each independently a hydrogen atom, C₁~ C₆Directly
A chain or branched alkyl group (wherein the alkyl group is a halo
Gen atom, halogen atom, nitro group, carboxyl
Base, C₁~ C_FourAlkyl group or C₁~ C_FourAlkoxy group
Optionally substituted with a phenyl group which may be optionally substituted with
It may have been done. ), C₂~ C₆Straight or branched
Alkenyl group (The alkenyl group may be a halogen atom.
May be substituted with. ), C₂~ C₆Straight or minute
A branched alkynyl group (the alkynyl group is a halogen atom
May be optionally substituted. ), C₃~ C₆Cycloa
Alkyl group (the cycloalkyl group is a halogen atom or a fluorine atom).
It may be optionally substituted with a phenyl group. ), Phenyl
A group (the phenyl group is a halogen atom, a nitro group, a carbo
Xyl group, C₁~ C_FourAlkyl group or C₁~ C_FourThe alkoxy
It may be optionally substituted with groups. ) Or (CH₂)_mX {expression
In the formula, m represents 0, 1 or 2, and X represents a halogen atom or a cyanide.
Group, nitro group, CH (CN)₂, CH (CO₂Me)₂, CH (CO₂Et)₂, C
₁~ C₈A linear or branched acyl group, C₁~ C_FourThe al
Carboxyl optionally esterified by a kill group
Group, sulfonic acid group, or -Y-R⁶[Y is O, S (O)_n(N is 0,
Indicates 1 or 2. ) Or NR (R is a hydrogen atom or C₁~ C_Fourof
A straight-chain or branched alkyl group is shown. ) And R⁶Is
Hydrogen atom, C₁~ C₇Linear or branched alkyl group of
(The alkyl group is a halogen atom, or a halogen atom,
Nitro group, carboxyl group, C₁~ C_FourThe alkyl group of
Is C₁~ C_FourOptionally substituted with an alkoxy group of
It may be optionally substituted with a phenyl group. ), C₂~ C₆
A straight-chain or branched alkenyl group (the alkenyl group
May be optionally substituted with a halogen atom. ),
C₂~ C₆A linear or branched alkynyl group of
The nyl group may be optionally substituted with a halogen atom.
Yes. ), C₃~ C₆A cycloalkyl group of (the cycloalkyl
The group is optionally substituted with a halogen atom or a phenyl group
You may stay. ), A phenyl group (the phenyl group is a halogen
Group atom, nitro group, carboxyl group, C₁~ C_FourThe alkyl
Group or C₁~ C_FourEven if it is optionally substituted with an alkoxy group of
Good. ), C (O) A (A is a hydrogen atom, C₁~ C₆Straight chain
Is a branched alkyl group (the alkyl group is a halogen source
Child, or halogen atom, nitro group, carboxyl group, C₁
~ C_FourAlkyl group or C₁~ C_FourAny alkoxy group
Optionally substituted with a phenyl group which may be substituted with
You may stay. ), C₂~ C₆Straight or branched alke
Nyl group (the alkenyl group is optionally substituted with a halogen atom)
It may have been done. ), C₂~ C₆Straight or branched
Alkynyl group (the alkynyl group is a halogen atom
May be substituted with. ), C₃~ C₆Cycloalkyl
Group (the cycloalkyl group is a halogen atom or phenyl
It may be optionally substituted with groups. ), A phenyl group (the
Phenyl group is a halogen atom, nitro group, carboxyl
Base, C₁~ C_FourAlkyl group or C₁~ C_FourWith the alkoxy group of
It may be replaced at will. ), Or NR⁷R⁸(R⁷And R⁸
Are each independently a hydrogen atom, C₁~ C₆Straight chain or
A branched alkyl group (wherein the alkyl group is a halogen atom,
Or halogen atom, nitro group, carboxyl group, C₁~ C_Four
Alkyl group of or or C₁~ C_FourAny alkoxy group
Optionally substituted with a phenyl group which may be substituted with
You may stay. ), C₂~ C₆Straight or branched alke
Nyl group (the alkenyl group is optionally substituted with a halogen atom)
It may have been done. ), C₂~ C₆Straight or branched
Alkynyl group (the alkynyl group is a halogen atom
May be substituted with. ), C₃~ C₆Cycloalkyl
Group (the cycloalkyl group is a halogen atom or phenyl
It may be optionally substituted with groups. ), A phenyl group (the
Phenyl group is a halogen atom, nitro group, carboxyl
Base, C₁~ C_FourAlkyl group or C₁~ C_FourWith the alkoxy group of
It may be replaced at will. ) Means. ) Means
It ) Means. ] Means }, And Z is(R⁹, R^Ten, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷,
R¹⁸, R¹⁹, R²⁰, R^{twenty one}, R^{twenty two}, R ^{twenty three}And R^{twenty four}Are each German
Stand up, hydrogen atom, C₁~ C₆Straight chain or branched al
Kill group (the alkyl group is a halogen atom or a halogen atom)
Atom, nitro group, carboxyl group, C₁~ C_FourAlkyl group of
Or C₁~ C_FourOptionally substituted with an alkoxy group of
Optionally substituted with a phenyl group. ),
C₂~ C₆A straight-chain or branched alkenyl group of
The nyl group may be optionally substituted with a halogen atom.
Yes. ), C₂~ C₆Linear or branched alkynyl group
(The alkynyl group is optionally substituted with a halogen atom.
You may stay. ), C₃~ C₆A cycloalkyl group of
The alkyl group is a halogen atom or a phenyl group, and is optionally
It may be replaced. ), A phenyl group (the phenyl group
Is a halogen atom, nitro group, carboxyl group, C₁~ C_Four
Alkyl group or C₁~ C_FourOptionally substituted with an alkoxy group of
It may be. ) Or (CH₂)_oX¹{Where o is 0, 1 or
Indicates 2, X¹Is a halogen atom, cyano group, nitro group,
CH (CN)₂, CH (CO₂Me)₂, CH (CO₂Et)₂, C₁~ C₈Straight chain if
C-branched acyl group, C₁~ C_FourThe alkyl group of
Carboxyl group which may be tellurized, sulfonic acid
Group or -Y¹-R^{twenty five}[Y¹Is O, S (O)_p(P is 0, 1 or 2
You ) Or NR (R is a hydrogen atom or C₁~ C_FourStraight or branched
Is an alkyl group. ) And R^{twenty five}Is a hydrogen atom, C
₁~ C₇A linear or branched alkyl group of
The group is a halogen atom, or a halogen atom, a nitro group, or a group.
Ruboxyl group, C₁~ C_FourAlkyl group or C₁~ C_FourA
A phenyl group optionally substituted with a lucoxy group
It may be optionally substituted. ), C₂~ C₆Straight chain
Is a branched alkenyl group (the alkenyl group is a halogen
It may be optionally substituted with atoms. ), C₂~ C₆Straight chain of
Alternatively, a branched alkynyl group (the alkynyl group is
It may be optionally substituted with a logen atom. ), C₃~ C₆
A cycloalkyl group of (wherein the cycloalkyl group is a halogen
Optionally substituted with atoms or phenyl groups
Yes. ), A phenyl group (the phenyl group is a halogen atom,
Nitro group, carboxyl group, C₁~ C_FourAlkyl group or C₁
~ C_FourOptionally substituted with an alkoxy group of
Yes. ), C (O) A¹(A¹Is a hydrogen atom, C₁~ C₆Straight chain
Is a branched alkyl group (the alkyl group is a halogen source
Child, or halogen atom, nitro group, carboxyl group, C₁
~ C_FourAlkyl group or C₁~ C_FourAny alkoxy group
Optionally substituted with a phenyl group which may be substituted with
You may stay. ), C₂~ C₆Straight or branched alke
Nyl group (the alkenyl group is optionally substituted with a halogen atom)
It may have been done. ), C₂~ C₆Straight or branched
Alkynyl group (the alkynyl group is a halogen atom
May be substituted with. ), C₃~ C₆Cycloalkyl
Group (the cycloalkyl group is a halogen atom or phenyl
It may be optionally substituted with groups. ), A phenyl group (the
Phenyl group is a halogen atom, nitro group, carboxyl
Base, C₁~ C_FourAlkyl group or C₁~ C_FourWith the alkoxy group of
It may be replaced at will. ), Or NR²⁶R²⁷(R²⁶as well as
R²⁷Are each independently a hydrogen atom, C₁~ C₆Straight chain if
Or a branched alkyl group (the alkyl group is a halogen source
Child, or halogen atom, nitro group, carboxyl group, C₁
~ C_FourAlkyl group of or or C₁~ C_FourWith the alkoxy group of
Optionally substituted with an optionally substituted phenyl group
It may be. ), C₂~ C₆A straight or branched chain of
A lukenyl group (the alkenyl group is a halogen atom
It may be substituted. ), C₂~ C₆Straight or branched
Alkynyl group (the alkynyl group is a halogen atom)
It may be optionally substituted. ), C₃~ C₆The cycloal
Kill group (the cycloalkyl group is a halogen atom or a phenyl group).
It may be optionally substituted with a nyl group. ), Phenyl group
(The phenyl group is a halogen atom, a nitro group, a carboxyl group.
Sil group, C₁~ C_FourAlkyl group or C₁~ C_FourAlkoxy group
May be optionally substituted. ) Means. )
To taste. ) Means. ] Means } Means
It ) Is shown. ] The compound represented by
Salt. 2. R ¹ is a C ₁ -C ₆ linear or branched alkyl group, and R ² is a carboxyl group (wherein the carboxyl group is esterified with a C ₁ -C ₄ alkyl group. Or a tetrazolyl group (the tetrazolyl group may be optionally substituted with a benzyl group, a methoxymethyl group or a triphenylmethyl group), and R ⁴ is a hydrogen atom. 3. R ¹ is a normal propyl group, a normal butyl group or a cyclopropyl group, and R ² is a carboxyl group (the carboxyl group may be esterified with a C _{1 to} C ₄ alkyl group). Or a tetrazolyl group (the tetrazolyl group may be optionally substituted with a benzyl group, a methoxymethyl group or a triphenylmethyl group), and R ⁴ is a hydrogen atom. 4. R¹Is a normal propyl group, normal buty
R group or cyclopropyl group, R²Is carboxy
Group (the carboxyl group is C₁~ C_FourWith an alkyl group of
May be tellurized) or a tetrazolyl group (the
The tetrazolyl group is a benzyl group, a methoxymethyl group,
Optionally substituted with a phenylmethyl group)
R³Is a carboxyl group or a tetrazolyl group
R^FourIs a hydrogen atom and Z is[In the formula, R⁹, R^TenAnd R¹²Means a hydrogen atom, R¹¹Is water
Elementary atom, C₁~ C₆A linear or branched alkyl group of
The alkyl group is a halogen atom, a halogen atom, or nit
B group, carboxyl group, C₁~ C_FourAlkyl group or C₁
~ C_FourOf the alkoxy group, which may be optionally substituted with an alkoxy group of
It may be optionally substituted with a nyl group. ), C₂~ C₆Directly
A chain or branched alkenyl group (the alkenyl group is
It may be optionally substituted with a halogen atom. ), C₂~
C₆A straight-chain or branched alkynyl group of
The group may be optionally substituted with a halogen atom.
Yes. ), C₃~ C₆A cycloalkyl group of (the cycloalkyl
The group is optionally substituted with a halogen atom or a phenyl group
You may stay. ), A phenyl group (the phenyl group is a halogen
Group atom, nitro group, carboxyl group, C₁~ C_FourThe alkyl
Group or C₁~ C_FourEven if it is optionally substituted with an alkoxy group of
Good. ) Or (CH₂)_oX¹{In the formula, o represents 0, 1 or 2
Then X¹Is a halogen atom, cyano group, nitro group, CH (C
N)₂, CH (CO₂Me)₂, CH (CO₂Et) ₂, C₁~ C₈Straight chain or
Branched acyl group, C₁~ C_FourBy the alkyl group of
An optionally converted carboxyl group, sulfonic acid group, or
Is-Y¹-R^{twenty five}[Y¹Is O, S (O)_p(P represents 0, 1 or 2.)
Or NR (R is hydrogen atom or C₁~ C_FourA straight or branched chain of
Indicates a rukyl group. ) And R^{twenty five}Is a hydrogen atom, C₁~ C₇
A linear or branched alkyl group (wherein the alkyl group is
Halogen atom, halogen atom, nitro group, carboxy
Sil group, C₁~ C_FourAlkyl group or C₁~ C_FourThe Archoki
Optionally substituted with a phenyl group optionally substituted with a phenyl group
It may be substituted. ), C₂~ C₆Straight or branched
Alkenyl group (the alkenyl group is a halogen atom)
It may be optionally substituted. ), C₂~ C₆Straight chain
Is a branched alkynyl group (the alkynyl group is a halogen
It may be optionally substituted with atoms. ), C₃~ C₆Shiku
Alkyl group (the cycloalkyl group is a halogen atom or
May optionally be substituted with a phenyl group. ), Fe
Nyl group (the phenyl group is a halogen atom, a nitro group,
Ruboxyl group, C₁~ C_FourAlkyl group or C₁~ C_FourArco
It may be optionally substituted with an xy group. ), C (O) A¹(A¹
Is a hydrogen atom, C₁~ C₆Linear or branched alkyl of
Group (the alkyl group is a halogen atom or a halogen atom)
Child, nitro group, carboxyl group, C₁~ C_FourThe alkyl group of
Or C₁~ C_FourEven if it is optionally substituted with an alkoxy group of
It may be optionally substituted with a good phenyl group. ), C₂
~ C₆A straight-chain or branched alkenyl group of
Radicals may be optionally substituted with halogen atoms.
Yes. ), C₂~ C₆Linear or branched alkynyl group
(The alkynyl group is optionally substituted with a halogen atom.
You may stay. ), C₃~ C₆A cycloalkyl group of
The alkyl group is a halogen atom or a phenyl group, and is optionally
It may be replaced. ), A phenyl group (the phenyl group
Is a halogen atom, nitro group, carboxyl group, C₁~ C_Four
Alkyl group or C₁~ C_FourOptionally substituted with an alkoxy group of
It may be. ), Or NR²⁶R²⁷(R²⁶And R²⁷Is that
Independently hydrogen atom, C₁~ C₆Straight or branched
Alkyl group (the alkyl group is a halogen atom, or
Rogen atom, nitro group, carboxyl group, C₁~ C_FourThe al
Kill group or C₁~ C_FourOptionally substituted with the alkoxy group of
Optionally substituted with a phenyl group
Good. ), C₂~ C₆A straight-chain or branched alkenyl group
(The alkenyl group is optionally substituted with a halogen atom.
You may stay. ), C₂~ C₆Linear or branched alky
Nyl group (the alkynyl group is optionally substituted with a halogen atom)
It may have been done. ), C₃~ C₆A cycloalkyl group of
The cycloalkyl group is a halogen atom or a phenyl group.
It may be replaced at will. ), A phenyl group (the phenyl group
Group is a halogen atom, nitro group, carboxyl group, C₁
~ C_FourAlkyl group or C₁~ C_FourThe alkoxy group of
It may be replaced. ) Means. ) Means. )
Means ] Means } Is meant. ] Is the contract
The compound according to claim 1. 5. R ¹ is a normal propyl group, a normal butyl group or a cyclopropyl group, and R ² is a carboxyl group (the carboxyl group may be esterified with a C _{1 to} C ₄ alkyl group). Or a tetrazolyl group (the tetrazolyl group may be optionally substituted with a benzyl group, a methoxymethyl group, a triphenylmethyl group), R ³ is a carboxyl group or a tetrazolyl group, and R ⁴ is a hydrogen atom. , Z is (In the formula, R ⁹ , R ¹⁰ and R ¹² represent a hydrogen atom, and R ¹¹ represents a hydrogen atom, NO ₂ , NH ₂ , NHC (O) Me, NHC (O) Et, NHC (O) CH ₂ Ph.
, NHC (O) CHPh ₂ , NHC (O) NHMe, NHC (O) NHEt, NHC (O) NH ⁱ P
r, NHC (O) NH ^c Hex, N ⁿ PentC (O) NHMe or N ⁿ PentC (O) N
Means HEt. ) Is a compound according to claim 1. 6. An antihypertensive drug comprising the compound according to claim 1. 7. A therapeutic agent for congestive heart failure, which comprises the compound according to claim 1. 8. A therapeutic agent for chronic renal failure, which comprises the compound according to claim 1.