JPH07300414A - Therapeutic agent for cardiac insufficiency - Google Patents

Abstract

PURPOSE:To obtain a benzopyran derivative useful as a therapeutic agent for cardiac insufficiency having strongly enhancing action on contractive force of cardiac muscle and reducing action on a heart rate. CONSTITUTION:This compound is expressed by formula I [X<1> and X<2> each is absent or O; X is O, S, N (may be replaced with H or an alkyl), CO, CS, etc.; A is H, OH, OC(O)R<5> (R<5> is an alkyl); B is H or forms a single bond with A; R<1> and R<2> each is H, a 1-4C alkyl or form 1,4-butylene or 1,5-pentylene which may be substituted with a 1-4C alkyl; R<3> and R<4> each is a 1-6C alkyl, a 2-6C alkenyl, a 2-6C alkynyl, a 3-6C cycloalkyl or phenyl which may be substituted or form 1,4-butylene or 1,5-pentylene which may be substituted] such as 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-diethylamino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazol-1-3-oxide of formula II as an active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to use of a benzopyran derivative having pharmacological activity as a therapeutic agent for heart failure in mammals including humans.

[0002]

Prior Art and Problems to be Solved by the Invention
2-4791, JP-A-2-49788, JP-A-2-152974
JP-A-5-43432, U.S. Pat.No. 4,500,752, U.S. Pat.No. 4900752, European Patent 327127, and European Patent No. 492391 disclose that a benzopyran derivative is a circulatory system disorder such as hypertension, angina, or arrhythmia. , And the possibility of being used as a hair growth promoter in the treatment of alopecia and the like, but does not mention the possibility of treating heart failure pathology.

[0003]

Means for Solving the Problems Among the benzopyran derivatives, the present inventors have earnestly searched for a compound that has a low potassium channel activating effect, has no cardiac depressant effect, and can rather enhance cardiac contractile force. The present invention has been completed by finding that the compound represented by the formula (I) has a strong cardiotonic action.

The compounds used in the present invention have the formula (I)

[0005]

[Chemical 3]

[Wherein X¹And X²Is absent or oxygen
Means an atom; X is an oxygen atom, a sulfur atom, a nitrogen atom (the
Nitrogen atom is hydrogen atom or C₁-C_FourSubstituted with alkyl
), C (O), C (S) or C (N-CN)
Means A is a hydrogen atom, a hydroxy group or OC (O) R^Five(R^Five
Is C₁-C_FourMeans alkyl. ) Means one with B
In a chain means a single bond; B means a hydrogen atom
Or together with A means a single bond; R¹And R²Are mutual
Identical to or different from each other, hydrogen atom or C₁-C_FourAlkyl
Or R¹And R²Together, C₁-C_FourAl
1,4-butylene young optionally substituted by kill
Means 1,5-pentylene; R³And R^FourAre the same as each other
Differently, hydrogen atom, C₁-C₆Alkyl group of {the al
Kill group is a halogen atom, carboxyl group, C₂-C_FiveAl
Coxycarbonyl group, hydroxy group, C₁-C_FourAlkoxy
Group, CH (OR)₂ (R is C₁-C_FourMeans an alkyl group. ), F
Phenyl group (the phenyl group is a halogen atom, a hydroxy group
Group or C₁-C_FourOptionally substituted by an alkoxy group
Group), a formyl group, a cyano group or a nitro group.
It may be optionally substituted. }, C₂-C₆Archeni
Group (the alkenyl group is a halogen atom, a carboxyl group
Base, C₂-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-
C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
Optional), formyl group, cyano group or
It may be optionally substituted with a toro group. }, C₂-C₆
An alkynyl group of {the alkynyl group is a halogen atom,
Ruboxyl group, C₂-C_FiveAlkoxycarbonyl group, hydro
Xy group, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourArchi
Means a radical. ), A phenyl group (the phenyl group is
Rogen atom, hydroxy group or C₁-C _FourBy an alkoxy group
Optionally substituted), formyl group, cyano
Optionally substituted by groups or nitro groups
Yes. }, C₃-C₆Cycloalkyl group {the cycloalkyl group
Is a halogen atom, carboxyl group, C₂-C_FiveAlkoxy
Carbonyl group, hydroxy group, C₁-C_FourAlkoxy group, CH
(OR)₂(R is C₁-C_FourMeans an alkyl group. ), Phenyl
Group (the phenyl group is a halogen atom, a hydroxy group or
C₁-C_FourOptionally substituted by an alkoxy group
), Formyl group, cyano group or nitro group
It may be replaced at will. }, A phenyl group (the phenyl group
Group is a halogen atom, a hydroxy group or C₁-C_FourArco
Optionally substituted by a xy group), or C (=
Y) ZR⁶(Y is an oxygen atom, a sulfur atom or NR⁷(R⁷Is hydrogen
Child, cyano group, nitro group, C₁-C_FourAlkyl, C₁-C_FourArco
Kisshi or CO₂R⁸ (R⁸Is C₁-C_FourMeans alkyl. )
Means ), And Z is an oxygen atom or a sulfur atom.
Ku NR⁹(R⁹Is a hydrogen atom, C₁-C₆Alkyl group of {the al
Kill group is a halogen atom, carboxyl group, C₂-C_FiveAl
Coxycarbonyl group, hydroxy group, C₁-C_FourAlkoxy
Group, CH (OR)₂ (R is C₁-C_FourMeans an alkyl group. ), F
Phenyl group (the phenyl group is a halogen atom, a hydroxy group
Group or C₁-C_FourOptionally substituted by an alkoxy group
Group), a formyl group, a cyano group or a nitro group.
It may be optionally substituted. }, C₂-C₆Archeni
Group (the alkenyl group is a halogen atom, a carboxyl group
Base, C₂-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-
C_FourAlkoxy group, CH (OR)₂ (R is C₁-C_FourMeans an alkyl group
To do. ), A phenyl group (the phenyl group is a halogen source
Child, hydroxy group or C₁-C_FourOptionally by an alkoxy group
(May be substituted), formyl group, cyano group or
May optionally be substituted by a nitro group. }, C₂
-C₆An alkynyl group of
Child, carboxyl group, C₂-C_FiveAn alkoxycarbonyl group,
Hydroxy group, C₁-C_FourAlkoxy group, CH (OR)₂ (R is C₁-C
_FourMeans an alkyl group. ), A phenyl group (the phenyl
The group is a halogen atom, a hydroxy group or C₁-C_FourArcoki
Si group optionally substituted), formyl
Optionally substituted by groups, cyano groups or nitro groups
You may stay. }, C₃-C₆Cycloalkyl group (the cycloalkyl
The alkyl group is a halogen atom, a carboxyl group, C₂-C_FiveA
Lucoxycarbonyl group, hydroxy group, C₁-C_FourArcoki
Si group, CH (OR)₂ (R is C₁-C_FourMeans an alkyl group. ),
Phenyl group (the phenyl group is a halogen atom, a hydroxy group
Si group or C₁-C_FourOptionally substituted by an alkoxy group
, Formyl group, cyano group or nitro group
It may be optionally substituted. }, A phenyl group (the
Phenyl group is a halogen atom, hydroxy group or C₁-C_Four
Optionally substituted with an alkoxy group)
To taste. ) Means R⁶Is a hydrogen atom, C₁-C₈The alkyl
Group {the alkyl group is a halogen atom, a carboxyl group,
C₂-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourA
Lucoxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
Optional), formyl group, cyano group or
It may be optionally substituted with a toro group. }, C₂-C₆
An alkenyl group of {the alkenyl group is a halogen atom,
Ruboxyl group, C₂-C_FiveAlkoxycarbonyl group, hydro
Xy group, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourAl
Means a kill group. ), A phenyl group (the phenyl group is
Halogen atom, hydroxy group or C₁-C_FourOn an alkoxy group
More optionally substituted), formyl group, sia
May be optionally substituted by a nitro group or a nitro group
Yes. }, C₂-C₆An alkynyl group of
Rogen atom, carboxyl group, C₂-C_FiveAlkoxy carbo
Nyl group, hydroxy group, C₁-C_FourAlkoxy group, CH (OR)₂(R
 Is C₁-C_FourMeans an alkyl group. ), Phenyl group
(The phenyl group is a halogen atom, a hydroxy group or C₁
-C_FourOptionally substituted by an alkoxy group
), Formyl group, cyano group or nitro group
It may be replaced at will. }, C₃-C₆Cycloalkyl
Group {the cycloalkyl group is a halogen atom, carboxy
Lu group, C₂-C_FiveAlkoxycarbonyl group, hydroxy group, C
₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
To taste. ), A phenyl group (the phenyl group is a halogen source
Child, hydroxy group or C₁-C_FourOptionally by an alkoxy group
(May be substituted), formyl group, cyano group or
May optionally be substituted by a nitro group. }, H
Phenyl group (the phenyl group is a halogen atom, a hydroxy group
Group or C₁-C_FourOptionally substituted by an alkoxy group
Also means). ) Means or R³And R^FourTogether
Become 1,4-butylene or 1,5-pentylene (the butylene and
And pentylene are each C₁-C_FourAlkyl, phenyl group
(Arbitrarily halogen atom, hydroxy group, C₁-C_FourAlkyl
Optionally substituted by a coxy group), halogen
Atom, OR^Ten(R^TenIs a hydrogen atom, C₁-C_FourAlkyl, COR¹¹(R
¹¹Is C₁-C_FourMeans alkyl. ), Nitro group, SO₃H young
Or PO₃H₂Means ) Arbitrarily replaced by
May be used or R³And R^FourTogether (C
H₂)_mX^Four(CH₂)_l(m and l mean 1, 2 or 3 respectively
However, the total is 3, 4 or 5. X^FourIs an oxygen atom, sulfur
Atom, NR¹²(R¹²Is a hydrogen atom, C₁-C_FourAlkyl, phenyl
Group (the phenyl group is a halogen atom, a hydroxy group or
C₁-C_FourOptionally substituted by an alkoxy group
Meaning). ) Means. ), Or
R³And R^FourTogether (CH₂)_nZC (= Y) (n is 2, 3, younger
Means 4 and Z and Y have the same meanings as described above. )
means. ] And the optical isomers thereof
Body, stereoisomer, or compound capable of forming a salt
Is a pharmaceutically acceptable salt thereof.

The present invention relates to a therapeutic agent for heart failure containing these compounds as active ingredients.

The present invention also relates to a heart failure drug containing the following compound as an active ingredient. Formula (II)

[Chemical 4](In the formula, X⁶Means absent or an oxygen atom; X^FiveIs
Oxygen atom, sulfur atom or nitrogen atom (the nitrogen atom is hydrogen
Atom or C₁-C_FourWhich may be substituted with alkyl)
Taste; A¹Is a hydrogen atom, a hydroxy group or OC (O) R¹⁷(R¹⁷Is
C₁-C_FourMeans alkyl. ) Means; B¹Is a hydrogen atom
Means; R¹³And R¹⁴Are the same or different from each other and are hydrogen
Atom or C₁-C_FourMeans alkyl; R¹⁵And R¹⁶Each other
Same or different, hydrogen atom, C₁-C₆Alkyl group of
{The alkyl group is a halogen atom, a carboxyl group, C₂
-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourA
Lucoxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C _FourOptionally substituted by an alkoxy group
May be). ), Formyl group, shea
May be optionally substituted by a nitro group or a nitro group
Yes. }, C₃-C₆Cycloalkyl group {the cycloalkyl group
Is a halogen atom, carboxyl group, C₂-C_FiveAlkoxy
Carbonyl group, hydroxy group, C₁-C_FourAlkoxy group, CH
(OR)₂(R is C₁-C_FourMeans an alkyl group. ), Phenyl
Group (the phenyl group is a halogen atom, a hydroxy group or
C₁-C_FourOptionally substituted by an alkoxy group
), Formyl group, cyano group or nitro group
It may be replaced at will. }, A phenyl group (the phenyl group
Group is a halogen atom, a hydroxy group or C₁-C_FourArco
Optionally substituted by xy groups), or C (= Y
¹) Z¹R¹⁸(Y¹Is an oxygen atom, a sulfur atom or NR¹⁹(R¹⁹Is water
Elementary atom, cyano group, nitro group, C₁-C_FourAlkyl or
C₁-C_FourMeans alkoxy. ) Means Z¹Is oxygen source
Child, sulfur atom or NR²⁰(R²⁰Is a hydrogen atom, C₁-C₆of
Alkyl group (The alkyl group is a halogen atom,
Sil group, C₂-C_FiveAlkoxycarbonyl group, hydroxy
Base, C₁-C_FourAlkoxy group, CH (OR)²(R is C₁-C_FourAlkyl group
Means ), A phenyl group (the phenyl group is a halogen
Atom, hydroxy group or C₁-C_FourDepends on the alkoxy group
Optionally substituted), formyl group, cyano group
Or optionally substituted by a nitro group
Yes. }, C₃-C₆Cycloalkyl group {the cycloalkyl group
Is a halogen atom, carboxyl group, C₂-C_FiveAlkoxy
Carbonyl group, hydroxy group, C₁-C_FourAlkoxy group, CH
(OR)₂ (R is C₁-C_FourMeans an alkyl group. ), Phenyl
Group (the phenyl group is a halogen atom, a hydroxy group or
C₁-C_FourOptionally substituted by an alkoxy group
), Formyl group, cyano group or nitro group
It may be replaced at will. }, A phenyl group (the phenyl group
Group is a halogen atom, a hydroxy group or C₁-C_FourArco
Optionally substituted with xy groups)
It ) Means R¹⁸Is a hydrogen atom, C₁-C₈Alkyl group of
{The alkyl group is a halogen atom, a carboxyl group, C₂
-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourA
Lucoxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
Optional), formyl group, cyano group or
It may be optionally substituted with a toro group. }, C₃-C₆
Cycloalkyl group (the cycloalkyl group is a halogen atom
Child, carboxyl group, C₂-C_FiveAn alkoxycarbonyl group,
Hydroxy group, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C
_FourMeans an alkyl group. ), A phenyl group (the phenyl
The group is a halogen atom, a hydroxy group or C₁-C_FourArcoki
Si group optionally substituted), formyl
Optionally substituted by groups, cyano groups or nitro groups
You may stay. }, A phenyl group (the phenyl group is a halogen
Atom, hydroxy group or C₁-C_FourDepends on the alkoxy group
It may be replaced by any means). ) Means
Or R¹⁵And R¹⁶Together with 1,4-butylene or 1,5-pen
Tylene {The butylene and pentylene are each C₁-C_Four
Alkyl, phenyl groups (the phenyl group is a halogen source
Child, hydroxy group or C₁-C_FourOptionally by an alkoxy group
(May be substituted), halogen atom, OR^{twenty one}(R^{twenty one}Is water
Elementary atom, C₁-C_FourAlkyl, COR^{twenty two}(R^{twenty two}Is C₁-C_FourAlkyl
means. ), Nitro group, SO₃H or PO₃H₂Means
It ), Optionally substituted by
Ruka, R¹⁵And R¹⁶Together (CH₂)_OX⁷(CH₂)_P(O and P are
Each means 1, 2 or 3, but the sum is 3, 4
Or it becomes 5. X⁷Is oxygen atom, sulfur atom, NR^{twenty three}(R^{twenty three}Is water
Elementary atom, C₁-C_FourAlkyl, phenyl group (the phenyl group
Is a halogen atom, a hydroxy group or C₁-C_FourAlkoxy
Optionally substituted by a group). )
Means ) Or R¹⁵And R¹⁶Together
Become (CH₂)_QZ¹C (= Y¹) (Q means 2, 3, or 4
Then Z¹, Y¹Has the same meaning as described above. ) Means
It ] The compound and its optical isomer represented by
Isomers and, if it is a compound capable of forming a salt,
A therapeutic agent for heart failure comprising a pharmaceutically acceptable salt as an active ingredient.

In formula (II), R ¹⁵ is a hydrogen atom and R ¹⁶ is
C (= Y ² ) NHR ²⁴ (Y ² is an oxygen atom, a sulfur atom or N-CN
Means R ²⁴ is a phenyl group, a benzyl group or C ₁ -C
₈ means an optionally branched alkyl. ) Is a remedy for heart failure.

In formula (II), R ¹⁵ and R ¹⁶ are taken together to form (CH ₂ ) _K NHC (= Y ³ ) (K is 2, 3 or 4; Y ³ is an oxygen atom, a sulfur atom or N-CN is meant.) The therapeutic agent for heart failure according to.

In the formula (II), R ¹⁵ and R ¹⁶ are both C ₁ -C
_The therapeutic agent for heart failure according to ₆ alkyl.

The therapeutic agent for heart failure according to the formula (II), wherein R ¹⁵ and R ¹⁶ together are (CH ₂ ) ₄ or (CH ₂ ) ₅ .

The compound used in the present invention enhances myocardial contractility, is useful for improving cardiac function, and can be used as a therapeutic agent for heart failure. Further, the compound not only exerts a cardiotonic action, but also exerts a strong heart rate reducing action.

Next, each substituent of the compound (I) will be described more specifically. In the present specification, "n-" is normal, "i-" is iso, "sec-" is secondary, "t-" is tertiary (tertiary-) and "c-" is cyclo (cyclo- ) Is meant. Also, "Me" is methyl, "Et" is ethyl,
"Pr" means propyl, "Bu" means butyl, "Pen" means pentyl, "Hex" means hexyl and "Ph" means phenyl.

Examples of R ¹ and R ² are hydrogen atom, Me, Et, n-
Pr, i-Pr, n-Bu, i-Bu, sec-Bu and t-Bu. There is also an example in which R ¹ and R ² are taken together to form a spiro ring as (CH ₂ ) ₄ or (CH ₂ ) ₅ .

Examples of A include OH, OC (O) Me and OC (O) Et.
, OC (O) -n-Pr, OC (O) -i-Pr, OC (O) -n-Bu, OC (O) -iB
u, OC (O) -sec-Bu, OC (O) -t-Bu and the like.

Further, A together with B may mean a single bond.

Examples of X include oxygen atom, sulfur atom, C
(O), C (S), NH, NMe, NEt, Nn-Pr, Ni-Pr, NcP
r, Nn-Bu, Ni-Bu, N-sec-Bu, Nt-Bu and the like can be mentioned.

Examples of R ³ and R ⁴ include a hydrogen atom, Me, E
t, n-Pr, i-Pr, c-Pr, n-Bu, i-Bu, sec-Bu, t-Bu, n-
Pen, c-Pen, n-Hex, c-Hex, Ph, benzyl, parachlorophenylmethyl, parafluorophenylmethyl, parabromophenylmethyl, phenylethyl, parachlorophenylethyl, parafluorophenylethyl, parabromophenylethyl, CH ₂ CO ₂ H, CH ₂ CO ₂ Me, CH ₂ CO ₂ Et, (CH
₂ ) ₂ CO ₂ Me, (CH ₂ ) ₂ CO ₂ Et, (CH ₂ ) ₂ CH (OMe) ₂ , (CH ₂ ) ₂ CH (O
_{Et) 2, (CH 2)} 3 OH, (CH 2) 3 OMe, (CH 2) 3 OEt, (CH 2) 3 Cl, (C
_{H 2) 3 Br, (CH} 2) 3 F, (CH 2) 3 CO 2 H, (CH 2) 3 CO 2 Me, (CH 2) 3 CO
₂ Et, (CH ₂ ) ₃ CH (Me) ₂ , (CH ₂ ) ₃ CH (Et) ₂ , C (O) OMe, C (O) OE
t, C (O) On-Pr, C (O) Oi-Pr, C (O) Oc-Pr, C (O) OnB
u, C (O) Oi-Bu, C (O) O-sec-Bu, C (O) Ot-Bu, C (O) OnP
en, C (O) Oc-Pen, C (O) On-Hex, C (O) Oc-Hex, C (O) O (C
_{H 2) 2 Cl, C (} O) O (CH 2) 2 Br, C (O) O (CH 2) 3 Cl, C (O) O (CH 2) 3 B
r, C (O) OPh, C (O) OCH ₂ Ph, C (O) NHMe, C (O) NHEt, C (O) NH
-n-Pr, C (O) NH-i-Pr, C (O) NH-c-Pr, C (O) NH-n-Bu, C (O)
NH-i-Bu, C (O) NH-sec-Bu, C (O) NH-t-Bu, C (O) NH-n-Pen
, C (O) NH-c-Pen, C (O) NH-n-Hex, C (O) NH-c-Hex, C (O)
NH (CH ₂ ) ₂ Cl, C (O) NH (CH ₂ ) ₂ Br, C (O) NH (CH ₂ ) ₃ Cl, C (O) NH
(CH ₂ ) ₃ Br, C (O) NHPh, C (O) NHCH ₂ Ph, C (O) NHC (O) CCl ₃ ,
C (S) NHMe, C (S) NHEt, C (S) NH-n-Pr, C (S) NH-i-Pr, C (S)
NH-c-Pr, C (S) NH-n-Bu, C (S) NH-i-Bu, C (S) NH-sec-Bu,
C (S) NH-t-Bu, C (S) NH-n-Pen, C (S) NH-c-Pen, C (S) NH-
n-Hex, C (S) NH-c-Hex, C (S) NH (CH ₂ ) ₂ Cl, C (S) NH (CH ₂ ) ₂ B
r, C (S) NH (CH ₂ ) ₃ Cl, C (S) NH (CH ₂ ) ₃ Br, C (S) NHPh, C (S) N
HCH ₂ Ph, C (N-CN) NHMe, C (N-CN) NHEt, C (N-CN) NH-nP
r, C (N-CN) NH-i-Pr, C (N-CN) NH-c-Pr, C (N-CN) NH-n-
Bu, C (N-CN) NH-i-Bu, C (N-CN) NH-sec-Bu, C (N-CN) NH
-t-Bu, C (N-CN) NH-n-Pen, C (N-CN) NH-c-Pen, C (N-CN) N
Hn-Hex, C (N-CN) NH-c-Hex, C (N-CN) NH (CH ₂ ) ₂ Cl, C (N
_{-CN) NH (CH 2) 2} Br, C (N-CN) NH (CH 2) 3 Cl, C (N-CN) NH (C
H ₂ ) ₃ Br, C (N-CN) NHPh, C (N-CN) NHCH ₂ Ph, or the like, or R ¹ and R ⁴ together form a nitrogen atom to which each is bonded Q1-Q36 And a substituent that represents

[0020]

[Chemical 5]

[0021]

[Chemical 6]

The examples of the compounds according to the present invention are shown below.
Of X ¹ and X ² "-" indicates that no. Also, in the table,
Q1~Q36 representing the R ³ and R ⁴ are as defined above.

[0023]

[Chemical 7]

[0024]

[Table 1] ───────────────────────────────── No. XX ¹ X ² ABR ¹ R ² R ³ R ⁴ ───────────────────────────────── 1 O-O OH H Me Me Et Et 2 O-O OH H Me Me Q8 3 O--OH H Me Me Q8 4 O--OH H Me Me Q1 5 O--OH H Me Me H Me 6 O--OH H Me Me H CH ₂ Ph (pF) 7 O-- OH H Me Me H CH ₂ Ph 8 O--OH H Me Me Me CH ₂ Ph 9 O--OH H Me Me H n-Hex 10 O--OH H Me Me Q22 11 O--OH H Me Me Q21 12 O--OH H Me Me Q23 13 O--OH H Me Me Q17 14 O--OH H Me Me Q19 15 O--OH H Me Me Q20 16 O--OH H Me Me H (CH ₂ ) ₃ OMe 17 O--OH H Me Me H (CH ₂ ) ₃ CO ₂ Et 18 O--OH H Me Me H CH ₂ CO ₂ Et 19 O--OH H Me Me H (CH ₂ ) ₃ Cl 20 O- -OH H Me Me H (CH ₂ ) ₂ OH 21 O--OH H Me Me HH 22 O--OH H Me Me HC (O) NHMe 23 O--OH H Me Me HC (S) NHMe ─── ──────────────────────────────

[0025]

[Table 2] Table 1 (continued) ───────────────────────────────── No. XX ¹ X ² ABR ¹ R ² R ³ R ⁴ ───────────────────────────────── 24 O--OH H Me Me HC ( O) NHPh 25 O--OH H Me Me HC (O) NHC (O) CCl ₂ 26 O--OH H Me Me HC (O) NH (CH ₂ ) ₃ Cl 27 O--OH H Me Me HC ( O) NH (CH ₂ ) ₂ Cl 28 O--OH H Me Me HC (O) NH-i-Pr 29 O--OH H Me Me HC (O) OEt 30 O--OH H Me Me HC (O ) O (CH ₂ ) ₂ Cl 31 O--OH H Me Me Q26 32 O--OH H Me Me Q25 33 O--OH H Me Me HC (O) NH-c-Hex 34 O--OH H Me Me HC (O) NH-t-Bu 35 O--OH H Me Me HC (O) OMe 36 O--OH H Me Me HC (S) NH-t-Bu 37 O--OH H Me Me Q31 38 O--OH H Me Me HC (O) O (CH ₂ ) ₃ Cl 39 O--OH H Me Me Q32 40 O-O OC (O) Me H Me Me Et Et 41 O--OH H Me Me Et Et 42 O--OC (O) Me H Me Me Et Et 43 O--OC (O) Me H Me Me Q8 44 O--OH H Me Me H (CH ₂ ) ₃ CH (OEt) ₂ 45 O- -OH H Me Me Q2 ───────────── ───────────────────

[0026]

[Table 3] Table 1 (continued) ───────────────────────────────── No. XX ¹ X ² ABR ¹ R ² R ³ R ⁴ ───────────────────────────────── 46 O--OH H Me Me H ( CH ₂ ) ₃ CO ₂ H 47 O--OC (O) Me H Me Me HH 48 O--OH H Et Et Q8 49 O--OH H Et Et HH 50 O--OH H Et Et HC (O) NHMe 51 O--OC (O) Me H Et Et HH 52 O--OH H Me Me HC (N-CN) NH-t-Bu 53 NH--OH H Me Me Q8 54 NH--OH H Me Me Q1 55 NH--OH H Me Me Et Et 56 S--OH H Me Me Q8 57 S--OH H Me Me Q1 58 S--OH H Me Me Et Et 59 O--OH H Me Me Q3 60 O --OH H Me Me Q4 61 O--OH H Me Me Q5 62 O--OH H Me Me Q6 63 O--OH H Me Me Q7 64 O--OH H Me Me Q9 65 O--OH H Me Me Q10 66 O--OH H Me Me Q11 67 O--OH H Me Me Q12 ─────────────────────────────── ───

[0027]

[Table 4] Table 1 (continued) ───────────────────────────────── No. XX ¹ X ² ABR ¹ R ² R ³ R ⁴ ───────────────────────────────── 68 O--OH H Me Me Q13 69 O--OH H Me Me Q14 70 O--OH H Me Me Q15 71 O--OH H Me Me Q16 72 O--OH H Me Me Q18 73 O--OH H Me Me Q24 74 O--OH H Me Me Q27 75 O--OH H Me Me Q28 76 O--OH H Me Me Q29 77 O--OH H Me Me Q30 78 O--OH H Me Me Q33 79 O--OH H Me Me Q34 80 O --OH H Me Me Q35 81 O--OH H Me Me Q36 82 O--OH H Me Me Me Me 83 O--OH H Me Me n-Pr n-Pr 84 O--OH H Me Me i- Pr i-Pr 85 O--OH H Me Me c-Pr c-Pr 86 O--OH H Me Me n-Bu n-Bu 87 O--OH H Me Me i-Bu i-Bu 88 O-- OH H Me Me sec-Bu sec-Bu 89 O--OH H Me Me t-Bu t-Bu ─────────────────────────── ───────

[0028]

[Table 5] Table 1 (continued) ───────────────────────────────── No. XX ¹ X ² ABR ¹ R ² R ³ R ⁴ ───────────────────────────────── 90 O--OH H Me Me n- Pen n-Pen 91 O--OH H Me Me n-Hex n-Hex 92 O--OH H Me Me c-Pen c-Pen 93 O--OH H Me Me c-Hex c-Hex 94 O-- OH H Me Me Ph Ph 95 O--OH H Me Me CH ₂ Ph CH ₂ Ph 96 O--OH H Me Me HC (S) NHEt 97 O--OH H Me Me HC (S) NH-n-Pr 98 O--OH H Me Me HC (S) NH-i-Pr 99 O--OH H Me Me HC (S) NH-c-Pr 100 O--OH H Me Me HC (S) NH-n- Bu 101 O--OH H Me Me HC (S) NH-i-Bu 102 O--OH H Me Me HC (S) NH-sec-Bu 103 O--OH H Me Me HC (S) NH-n -Pen 104 O--OH H Me Me HC (S) NH-c-Pen 105 O--OH H Me Me HC (S) NH-n-Hex 106 O--OH H Me Me HC (S) NH- c-Hex 107 O--OH H Me Me HC (S) NHPh 108 O--OH H Me Me HC (S) NHCH ₂ Ph 109 O--OH H Me Me HC (N-CN) NHMe 110 O-- OH H Me Me HC (N-CN) NHEt 111 O--OH H Me Me HC (N-CN) NHEt ────────────────────────────────

[0029]

[Table 6] Table 1 (continued) ───────────────────────────────── No. XX ¹ X ² ABR ¹ R ² R ³ R ⁴ ───────────────────────────────── 112 O--OH H Me Me HC ( N-CN) NH-n-Pr 113 O--OH H Me Me HC (N-CN) NH-i-Pr 114 O--OH H Me Me HC (N-CN) NH-c-Pr 115 O- -OH H Me Me HC (N-CN) NH-n-Bu 116 O--OH H Me Me HC (N-CN) NH-i-Bu 117 O--OH H Me Me HC (N-CN) NH -sec-Bu 118 O--OH H Me Me HC (N-CN) NH-n-Pen 119 O--OH H Me Me HC (N-CN) NH-c-Pen 120 O--OH H Me Me HC (N-CN) NH-n-Hex 121 O--OH H Me Me HC (N-CN) NH-c-Hex 122 O--OH H Me Me HC (N-CN) NH-Ph 123 O- -OH H Me Me HC (N-CN) NH-CH ₂ Ph 124 O--OH H Me Me Me n-Pr 125 O--OH H Me Me Et n-Pr 126 O--OH H Me Me n- Pr n-Bu 127 O--OH H Me Me n-Pr n-Pen 128 O--OH H Me Me n-Pr c-Pen 129 O--OH H Me Me Et n-Hex 130 O--OH H Me Me Et Ph 131 O--OH H Me Me n-Pr CH ₂ Ph ────────────── ────────────────────

The compound used in the present invention has a pyran ring of 3
Although it has an asymmetric carbon atom at the 4-position and an optically active substance based on the asymmetric carbon, it can be used for the purpose of the present invention in the same manner as the racemate. Also, the third and fourth positions of the pyran ring
Position-based stereoisomers can also be used. Further, when the compound is capable of forming a salt, a pharmaceutically acceptable salt thereof can also be used as an active ingredient.

Next, a method for producing the compound used in the present invention will be described. Of the compounds represented by the general formula (I), those in which X is an oxygen atom and both R ³ and R ⁴ are not C (= Y) ZR ⁶ are represented by the general formula (3) It is obtained by reacting the compound represented by and the compound represented by the general formula (4) in an inert solvent. The case where A is OH is shown by the general formula (5), and the compound when A means a single bond together with B is shown by the general formula (6).

[0032]

[Chemical 8]

Examples of the solvent used for the reaction between the compound (3) and the compound (4) include the following. Sulfoxide solvents represented by dimethyl sulfoxide, amide solvents represented by dimethylformamide or dimethylacetamide, ether solvents represented by ethyl ether, dimethoxyethane or tetrahydrofuran, and represented by methanol, ethanol or isopropanol. Examples thereof include alcohol solvents.
Of these, alcohol solvents are preferred.

The reaction temperature is usually under ice-cooling to the reflux temperature of the reaction solvent used, preferably the reflux temperature of the solvent used. In some cases, it is carried out under pressure.

The molar ratio of the reaction raw materials is such that the compound (4) / compound (3) (molar ratio) is in the range of 0.5 to 2.0, preferably 1.0 to 1.1. Which of the compounds represented by the general formula (5) or the general formula (6) is obtained depends on the reaction conditions or the post-treatment conditions after completion of the reaction, as described below. The compound represented by the general formula (6) can be obtained by reacting the compound represented by the general formula (3) with the compound represented by the general formula (4) in tetrahydrofuran in the presence of sodium hydride. However, the compound represented by the general formula (5) may be obtained depending on the reaction conditions (reaction time, reaction temperature, etc.).

Dehydration also occurs depending on the difference in the post-treatment method. For example, when an acid or alkali is present in the reaction solution, the acid or alkali may not be removed by washing treatment in the post-treatment, and the reaction solution may be directly heated and concentrated to be dehydrated. However, this dehydration condition tends to depend on the type of compound, reaction condition, and post-treatment condition.

Of the compounds used in the present invention, those in which X is an oxygen atom and either R ³ or R ⁴ is C (= Y) ZR ⁶ are represented by the general formula (3 ) And a compound represented by the general formula (7) are reacted in an inert solvent to obtain a compound (8), which is converted to R ⁶ NCY (R ⁶ NC
O, R ⁶ NCS) or ClCO ₂ R ⁶ is reacted to obtain the compound represented by the general formula (9) or (10).

[Chemical 9]

[0038]

[Chemical 10]

[In the reaction formula, Z means N (R ⁹ ) or an oxygen atom or a sulfur atom, W is a chlorine atom, a bromine atom,
It means an iodine atom, a lower alkyl sulfonate, a benzene sulfonate or a toluene sulfonate. ]

The compound in which R ³ and R ⁴ together form a ring can be obtained by cyclizing the compound represented by the general formula (11) according to the above procedure. General formula (3) which is an intermediate raw material of the compound according to the present invention

[0041]

[Chemical 11]

[In the formula, R ¹ and R ² have the same meanings as described in the general formula (I). ] The compound represented by the following is obtained by the following method. The relationship of the whole process is shown in the following flow.

[0043]

[Chemical 12]

General formula (13)

[0045]

[Chemical 13]

[In the formula, R ¹ and R ² have the same meanings as described in the general formula (I). ] The compound represented by general formula (3) by treating the compound represented by the formula with sodium hypochlorite (NaOCl), wherein X ¹ is absent and X ² is an oxygen atom. (compound ^{3 (X 1 = -, X} 2 = O)) in, and oxygen N- oxide type represented by the nitride sodium compound (NaN ₃₎ or triethyl phosphite (P (OEt) _3), etc. A compound represented by the general formula (3), which comprises reacting with a reducing agent capable of removing X ¹ and
Compound in which X ² does not exist (Compound 3 (X ¹ , X ² =-))
Is obtained. Also, compound 3 (X ¹ , X ² =-) is treated with about 1 equivalent of a suitable peracid (for example, represented by m-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, and so on). Then, a compound represented by the general formula (3), wherein X ¹ is an oxygen atom and X ² is absent (compound 3 (X ¹ =
O, X ² = −)) is obtained. In this case, when 1 equivalent or more of peracid is used, the compound represented by the general formula (3), wherein X ¹ and X ² are both oxygen atoms (compound 3 (X ¹ , X ² =
O)) is obtained. The compound represented by the general formula (13) can be obtained by a known method (for example, J. Med. Chem., 27 , 1).
127 (see 1987)). Compound 3
^{(X 1 = O, X 2} = -) is the general formula (14)

[0047]

[Chemical 14]

[In the formula, R ¹ and R ² have the same meanings as described for the general formula (I). ] It can also be obtained by treating the compound represented by the following with sodium hypochlorite. General formula (1
The compound represented by 4) can be obtained by a known method (the above document).

Compound (8) and the general formula Y = C = NR ⁶ or Cl
Examples of the solvent used for the reaction of C (O) OR ⁶ include the following. Sulfoxide solvents represented by dimethylsulfoxide, amide solvents represented by dimethylformamide or dimethylacetamide, ether solvents represented by ethyl ether, dimethoxyethane or tetrahydrofuran, and halogens represented by methylene chloride and chloroform. Examples include system solvents. Of these, halogen-based solvents are preferable.

The reaction temperature is usually under ice-cooling to the reflux temperature of the reaction solvent used, preferably the reflux temperature of the solvent used. In some cases, it is carried out under pressure.
The molar ratio of the reaction raw materials is compound (8) / Y = C = NR ⁶ or ClC
The (O) OR ⁶ compound (molar ratio) is in the range of 0.5 to 2.0, preferably 1.0 to 1.1.

Of the compounds of the present invention represented by the general formula (I), those in which X is a sulfur atom or a nitrogen atom (which may be substituted with a hydrogen atom or C ₁ -C ₉ alkyl) are It is synthesized from the compound represented by the formula (15) through 3 or 4 steps. The conversion of the compound of the general formula (15) into the compound of the general formula (17) is known and can be achieved according to the methods described in, for example, JP-A-56-57785 and JP-A-56-122380. General formula (17)
The compound (1) is subjected to a usual diazotization reaction represented by a method of reacting sodium nitrite in an aqueous solution in the presence of an inorganic acid such as hydrochloric acid or sulfuric acid or an organic acid such as acetic acid, and then 5 to
The general formula (18) in which X is a nitrogen atom can be synthesized by ring closure by heating at 100 ° C, preferably 50 to 100 ° C.

When A represents a single bond together with B, the compound is sometimes produced only by heating the compound of the general formula (18), and thus it is obtained during the synthetic reaction of the general formula (18) or the post-treatment after the synthesis. Sometimes. It can also be synthesized by allowing an acid anhydride such as benzoic anhydride or acetic anhydride or a base such as potassium carbonate to act and dehydrate. When X in the general formula (I) is alkylamino, the compound (1
It can be obtained by reacting 8) or its dehydrated product with diazomethane or with an alkyl halide in the presence of potassium carbonate.

The compound of the general formula (17) can be synthesized by reacting thionylaniline in an inert solvent such as benzene, toluene, xylene or dichlorobenzene to synthesize the compound of the general formula (20) in which X is a sulfur atom. .

The reaction temperature is 5 to 120 ° C., preferably 50.
The reaction can be carried out at -100 ° C.

The compound in the case where A means a single bond together with B is sometimes produced only by heating the compound of the general formula (20), and thus is obtained during the synthetic reaction of the general formula (20) or the post-treatment after the synthesis. Sometimes. It can also be synthesized by allowing an acid anhydride such as benzoic anhydride or acetic anhydride or a base such as potassium carbonate to act and dehydrate.

[Chemical 15]

[0056]

[Chemical 16]

[In the reaction formula, Z means N (R ⁹ ), oxygen atom or sulfur atom, W is chlorine atom, bromine atom,
It means an iodine atom, a lower alkyl sulfonate, a benzene sulfonate or a toluene sulfonate. ]

Among the compounds represented by the general formula (15), the compounds represented by the general formula (24) in which both R ³ and R ⁴ are not C (= Y) ZR ⁶ (in this case, R ³ and R 4 ⁴ does not include C (= Y) ZR ⁶ both are obtained by reacting the compound represented by the general formula (23) with the compound represented by the general formula (4) in an inert solvent.

Examples of the solvent used for the reaction of the compound (23) and the compound (4) include the following.

By a sulfoxide solvent represented by dimethyl sulfoxide, an amide solvent represented by dimethylformamide or dimethylacetamide, an ether solvent represented by ethyl ether, dimethoxyethane or tetrahydrofuran, and methanol, ethanol or isopropanol. Typical examples include alcoholic solvents. Of these, alcohol solvents are preferred.

The reaction temperature is usually under ice-cooling to the reflux temperature of the reaction solvent used, preferably the reflux temperature of the solvent used. In some cases, it is carried out under pressure.

The molar ratio of the reaction raw materials is such that compound (4) / compound (23) (molar ratio) is in the range of 0.5 to 2.0,
It is preferably in the range of 1.0 to 1.1.

Among the compounds represented by the general formula (15),
The compounds represented by the general formula (26) and the general formula (27), in which either R ³ or R ⁴ is C (═Y) ZR ⁶ , are represented by the general formula (26) The compound (25) obtained by reacting the compound represented by 23) with the compound represented by the general formula (7) in an inert solvent is converted into R ⁶
A compound represented by the general formula (26) or (27) can be obtained by reacting NCY (R ⁶ NCO, R ⁶ NCS) or ClCO ₂ R ⁶ .

The compound in which R ³ and R ⁴ are taken together to form a ring can be obtained by cyclizing the compound represented by the general formula (28) according to the above procedure.

[0065]

[Chemical 17]

Compound (25) and the general formula Y = C = NR ⁶ or
Examples of the solvent used for the reaction of ClC (Y) OR ⁶ include the following. Sulfoxide solvents represented by dimethylsulfoxide, amide solvents represented by dimethylformamide or dimethylacetamide, ether solvents represented by ethyl ether, dimethoxyethane or tetrahydrofuran, and halogens represented by methylene chloride and chloroform. Examples include system solvents. Of these, halogen-based solvents are preferable.

The reaction temperature is usually from under ice cooling to the reflux temperature of the reaction solvent used, preferably the reflux temperature of the solvent used. In some cases, it is carried out under pressure.
The molar ratio of the reaction raw materials is compound (25) / Y = C = NR ⁶ or Cl
The C (Y) OR ⁶ compound (molar ratio) is in the range of 0.5 to 2.0, preferably 1.0 to 1.1.

Among the compounds of the present invention represented by the general formula (I), those in which A is an acyl group do not react with the compound represented by the general formula (30) as shown by the following reaction formula. It is obtained by reacting an acylating agent in the presence of a suitable base in an active solvent.

[0069]

[Chemical 18]

Examples of the solvent used in the reaction include the followings. Sulfoxide solvent represented by dimethyl sulfoxide, amide solvent represented by dimethylformamide or dimethylacetamide, ethyl ether, dimethoxyethane or ether solvent represented by tetrahydrofuran, halogen system represented by dichloromethane, chloroform, dichloroethane The reaction can be carried out under the condition of a solvent or no solvent. Examples of the salt used in the reaction include triethylamine, pyridine, diisopropylethylamine, DBU
(Diazabicycloundecene) and the like. Examples of the acylating agent include acid halides such as acid chloride and acid bromide, and acid anhydrides. The reaction temperature is usually from under ice cooling to the reflux temperature of the reaction solvent used.

The molar ratio of the reaction raw materials is in the range of 0.5 to 2.0 for the acylating agent relative to compound 30, preferably 1.
It is in the range of 0 to 1.1.

Among the compounds of the present invention represented by the general formula (I), those in which R ⁴ is NC (N-CN) NHR ⁹ are represented by the general formula (32) as shown by the following reaction formula. ) Is reacted with carbodiimide in an inert solvent.

[0073]

[Chemical 19]

After desulfurization, the compound represented by the general formula (33) can be obtained by reacting with cyanamide. A compound represented by the general formula (34) in which R ³ and R ⁴ are combined to form a cyclic thiourea can be converted into a compound represented by the general formula (35) by using the same conditions. .

Of the compounds represented by the general formula (I) to be used in the present invention, the optically active substance is synthesized by a method of optically resolving a racemate (Japanese Patent Laid-Open No. 3-141286, US Pat. No. 5,970,37). European Patent Publication No. 409165) and a method by asymmetric synthesis (Japanese Patent Laid-Open No. 5-301878)
Publication, European Patent No. 535377 publication).

As described above, the present inventors have found that the compound represented by the general formula (I) has a strong myocardial contractile force increasing action and heart rate decreasing action. The compound according to the present invention, which has no cardiac depressant effect and can rather enhance the contractile force of the heart, has a strong heart rate reducing effect at a dose equivalent to the onset of cardiotonic effect, and the decrease in myocardial oxygen consumption based on this effect is due to this effect. It is thought that it reduces the exercise load, exhibits an antianginal effect, and has an antiarrhythmic effect by prolonging the effective refractory period. Therefore, the compound according to the present invention is expected to be useful for the treatment of cardiovascular diseases in consideration of oxygen consumption or energy consumption or metabolism related to heart exercise and the treatment mainly considering the heart rate reducing action. To be done.
For example, as an anti-heart failure agent for mammals including humans, or a therapeutic agent for cardiovascular disease that induces heart failure, for example, a therapeutic agent for ischemic heart disease, a therapeutic agent for hypertension, an antibody liquid retention agent, a therapeutic agent for pulmonary hypertension, and valvular membrane. Disease treatment agent, congenital heart disease treatment agent,
Myocardial disease therapeutic agent, pulmonary edema therapeutic agent, exertional angina therapeutic agent,
It is useful as a myocardial infarction therapeutic agent, antiarrhythmic agent, and anti-atrial fibrillation agent.

The present invention provides pharmaceutical compositions containing an effective amount of a compound of general formula (I) for these treatments.

The administration form of the compound according to the present invention is as follows:
Injection (subcutaneous, intravenous, intramuscular, intraperitoneal injection), parenteral administration by ointment, suppository, aerosol, etc. or tablets,
Capsules, granules, pills, syrups, solutions, emulsions,
Oral administration such as suspension may be mentioned. The above-mentioned pharmaceutical or veterinary composition containing the compound according to the invention contains about 0.01-99.5%, preferably about 0.1-30% of the compound according to the invention, based on the weight of the total composition. To do.

In addition to the compounds of the present invention or compositions containing the compounds, other pharmaceutically or veterinary active compounds can be included. In addition, these compositions may contain a plurality of the compounds according to the present invention. The clinical dose of the compound used in the present invention varies depending on the age, body weight, patient sensitivity, degree of symptoms, etc., but usually an effective dose is 0.003 to 1.5 g per day for an adult, preferably
It is about 0.01 to 0.6 g. However, if necessary, amounts outside the above range can be used.

The compounds provided herein are formulated for administration by conventional pharmaceutical means. That is, tablets, capsules, granules and pills for oral administration are excipients such as sucrose,
Lactose, glucose, starch, mannitol; binders such as hydroxypropyl cellulose, syrup, gum arabic, gelatin, sorbit, tragacanth, methylcellulose, polyvinylpyrrolidone; disintegrants such as starch, carboxymethylcellulose or its calcium salt, microcrystalline cellulose, Prepared using polyethylene glycol; lubricants such as talc, magnesium or calcium stearate, silica; lubricants such as sodium laurate, glycerol and the like.

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 esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene ethers of hydrogenated castor oil, lecithin; suspending agents, such as carboxymethyl 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.

As the ointment which is a transdermal preparation, for example, white petrolatum, liquid paraffin, higher alcohols, macrogol ointment, hydrophilic ointment, aqueous gel base and the like are used.
Suppositories are prepared using, for example, cocoa butter, polyethylene glycol, lanolin, fatty acid triglyceride, coconut oil, polysorbate and the like.

[0083]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. [Synthesis Example] Hereinafter, a synthesis example of a compound that can be used for pharmaceutical use of the present invention will be shown.

Reference Example 1 Optically active 7,8-dihydro-6,6-dimethyl-7,8
-Epoxy-6H-pyrano [2,3-f] benzo-2,
40 g of 1,3-oxadiazole 6,6-dimethyl-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole (198 mmo
le) in 300 ml of methylene chloride solution (R, R)-
[1,2-Bis (3,5-di-t-butylsalicylideamino) cyclohexane] -manganese (III) acetate (Production method is described in JP-A-5-507645 and European Patent 521099). 2.44.
g (3.7 mmole) was added. To this, add 1.2 l of sodium hypochlorite aqueous solution (active chlorine 5%) to adjust the pH.
0.5N aqueous sodium hydroxide solution was added while adjusting the pH to 11.3 with a stat. 10 at room temperature
After stirring for an hour, stirring was stopped and left overnight. After extracting the reaction solution with chloroform (300 ml x 1, 200 ml x 1,
50 ml × 1) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (benzene: ethyl acetate = 5: 1) and again subjected to silica gel column chromatography (benzene → benzene: ethyl acetate = 5: 1), and the obtained crystals were ethanol (60 ml). Recrystallization from (1) gave 15.7 g (yield 36%) of the title compound. Optical purity> 99% ee [Column: Chiralcel OJ (manufactured by Daicel Chemical Industries), mobile phase: Hexane: Isopropanol = 4: 1, Detection: UV
254 nm, flow rate: 1 ml / min, column temperature: 40 ° C.,
Hold time 9.2 minutes]

Reference Example 2 Enantiomer of the compound of Reference Example 1 (S, S)-[1,2-bis (3,5-di-t-butylsalicylideamino) cyclohexane] -manganese (III)
The same operation as in Reference Example 1 was performed using acetate to synthesize an enantiomer of the compound of Reference Example 1. 20.8 g (yield 48%), optical purity> 99% ee
[Retention time 12.5 minutes]

Synthesis Example 1 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-diethylamino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole-3- Oxide

[0087]

[Chemical 20]

3,4-dihydro-2,2-dimethyl-3
-Hydroxy-4-diethylamino-6-amino-7-
Nitro-2H-benzo [b] pyran 465 mg (1.50 mmol
e), sodium hydroxide 102mg (2.56mmole), ethanol 32
ml, 6 ml of water and 0.1 ml of polyethylene glycol were stirred at 40 ° C, and 2.59 g (2.10 mmole) of 6% NaOCl aqueous solution was added to this solution.
Was added and stirred for 15 minutes. The reaction solution was poured into water and extracted with ethyl acetate three times. The ethyl acetate layers were collected, washed with water and then saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (elution solvent, ethyl acetate: hexane = 1: 2).
(V / v)) to give the title compound (189 mg, yield: 41%
) Got. Dissolve a portion of this in ethanol and add HCl-EtOH
The solution was added and anhydrous ether was added to give the hydrochloride of the title compound as yellow crystals.

Mp 160-164 ° C. (decomposition) NMR (CDCl ₃ ) δ (ppm): 1.15 (6H), 1.26 (3H), 1.52 (3H),
2.64-3.14 (5H), 3.56 (1H), 3.85 (1H), 6.57 (1H), 7.30
(1H)

Synthesis Example 2 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (1-piperidinyl) -6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole-3-oxide

[0091]

[Chemical 21]

3,4-dihydro-2,2-dimethyl-3
-Hydroxy-4- (1-piperidinyl) -6-amino-7-nitro-2H-benzo [b] pyran 924 mg (2.8
8 mmole), 0.7% 50% potassium hydroxide, 4 ml dichloromethane, and 10 mg Bu ₄ N ⁺ Br ⁻ were stirred at room temperature while adding 4.97 g (4.03 mmole) of a 6% NaOCl aqueous solution and reacted for 9 hours. After separating the organic layer, the aqueous layer was extracted twice with methylene chloride. The methylene chloride layers were combined, washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography (elution solvent, ethyl acetate: hexane = 1: 3 (v / v)) to give the expressed compound (297 m
g, yield: 43%) as an oil. A part of this was dissolved in ethanol, HCl-EtOH was added, and dry ether was added to give the hydrochloride of the title compound as yellow crystals.

Mp 210-213 ° C

Synthesis Example 3 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (1-piperidinyl) -6H-pyrano [2,3-
f] benzo-2,1,3-oxadiazole

[0095]

[Chemical formula 22]

7,8-Dihydro-obtained in Synthesis Example 2
6,6-Dimethyl-7-hydroxy-8- (1-piperidinyl) -6H-pyrano [2,3-f] benzo-2,
1,3-Oxadiazole-3-oxide 297 mg (0.93 mm
ole), ethylene glycol 6 ml, NaN ₃ 60 mg (0.93 mmole)
Was heated to 140 ° C. and reacted for 1.2 hours. After cooling, the reaction solution was poured into water and extracted three times with chloroform. The chloroform layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was subjected to column chromatography (eluting solvent, ethyl acetate: hexane = 1: 3 (v / v)) to give the title compound (84 mg, yield: 30%) as an oil. A part of this was dissolved in ethanol-ethyl ether, and HCl-EtOH was added.
Was added to give the hydrochloride of the title compound as pale yellow crystals.

Mp 202-205 ° C

Synthesis Example 4 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (1-pyrrolidinyl) -6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole

[0099]

[Chemical formula 23]

7,8-Dihydro-6,6-dimethyl-
7,8-Epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole 150 mg (0.687 mmole),
63 μl (0.756 mmole) of pyrrolidine and 2 ml of ethanol were refluxed for 31 hours while stirring. After distilling off the solvent, the residue was subjected to preparative thin layer chromatography (eluting solvent, ethyl acetate: hexane = 1: 1 (V / V)) to give the title compound (12
0 mg, yield 60%) was obtained. A portion of this was dissolved in dry ether and HCl-EtOH was added to give the hydrochloride of the title compound as pale yellow crystals.

Mp 208-209 ° C

Synthesis Example 5 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-methylamino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

[0103]

[Chemical formula 24]

7,8-Dihydro-6,6-dimethyl-
7,8-Epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole 300 mg (1.37 mmole), 40
% Methylamine aqueous solution 0.53 g and ethanol 15 ml were stirred at 60 ° C. for 3 days (using pressure resistant tube). After the reaction, the solvent was distilled off, and the residue was subjected to preparative thin layer chromatography (eluting solvent, ethyl acetate: methanol = 10: 1) to obtain the title compound (263 mg: yield 77%). A portion of this was dissolved in dry ether and HCl-EtOH was added to give the hydrochloride of the title compound as colorless crystals.

Mp 244.5-260 ℃

Synthesis Example 6 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (4-fluorobenzyl) amino-6H-pyrano [2,3-f] benzo-2,1,3- Oxadiazole

[0107]

[Chemical 25]

7,8-Dihydro-6,6-dimethyl-
7,8-epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole 150 mg (0.687 mmole),
86 μl (0.756 mmole) of 4-fluoroberdylamine and 2 ml of ethanol were refluxed for 20 hours while stirring. After the solvent was distilled off, the residue was subjected to preparative thin layer chromatography (eluting solvent, ethyl acetate: hexane = 1: 2) to give the title compound (204 mg, yield: 86%) as an oil. A portion of this was dissolved in dry ether and HCl-EtOH was added to give the hydrochloride of the title compound as colorless crystals.

Mp 207-210 ° C

Synthesis Example 7 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-benzylamino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

[0111]

[Chemical formula 26]

The title compound was obtained by the same procedures as in Synthesis Example 6 using benzylamine. NMR (60MHz, CDCl ₃ , δppm): 7.77 (1H), 7.37-6.92 (5H),
6.81 (1H), 3.9-3.8 (4H), 2.73 (2H), 1.51 (3H), 1.25 (3
H)

Synthesis Example 8 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (N-benzyl-N-methyl) amino-6H-pyrano [2,3-f] benzo-2,1 , 3-oxadiazole

[0114]

[Chemical 27]

The title compound was obtained in the same manner as in Synthesis Example 6 using N-methylbenzylamine. Hydrochloride of the title compound mp 148-150 ℃

Synthesis Example 9 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-cyclohexylamino-6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole

[0117]

[Chemical 28]

The title compound was obtained in the same manner as in Synthesis Example 6 using cyclohexylamine. Hydrochloride of the title compound mp 208-210 ℃

Synthesis Example 10 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (4-methyl-1-piperazinyl) -6H-pyrano [2,3-f] benzo-2,1, 3-oxadiazole

[0120]

[Chemical 29]

The title compound was obtained as yellow crystals by the same procedure as in Synthesis Example 6 using N-methylpiperazine. (7
5%) mp 225-226 ℃ MS: 70 (100%), 246 (56%), 318 (M ⁺ , 13%)

Synthesis Example 11 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (1-piperazinyl) -6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole

[0123]

[Chemical 30]

The title compound was obtained as pale yellow crystals by the same procedure as in Synthesis Example 6 using piperazine. (72%) mp 245-246 ℃ MS: 56 (67%), 232 (100%), 304 (M ⁺ , 8%)

Synthesis Example 12 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (4-phenyl-1-piperazinyl) -6H-pyrano [2,3-f] benzo-2,1, 3-oxadiazole

[0126]

[Chemical 31]

Synthesis Example 6 using N-phenylpiperazine
The title compound was obtained by performing the same operation as described above. (75%) MS: 132 (100%), 308 (36%), 380 (M ⁺ , 32%) The hydrochloride of the title compound was obtained as colorless crystals. mp 198-201 ℃

Synthesis Example 13 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (4-phenyl-1-piperidinyl) -6H-pyrano [2,3-f] benzo-2,1, 3-oxadiazole

[0129]

[Chemical 32]

Synthesis Example 6 using 4-phenylpiperidine
The title compound was obtained by performing the same operation as described above. (87%) MS: 186 (21%), 307 (100%), 379 (M ⁺ , 4%) The hydrochloride of the title compound was obtained as colorless crystals. mp 195-197 ℃

Synthesis Example 14 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (1,2,3,4-tetrahydroisoquinoline-
2-yl) -6H-pyrano [2,3-f] benzo-2,
1,3-oxadiazole

[0132]

[Chemical 33]

Using 1,2,3,4-tetrahydroisoquinoline, the title compound was obtained in the same manner as in Synthesis Example 6. (80%) MS: 262 (32%), 279 (100%), 351 (M ⁺ , 4%) The hydrochloride of the title compound was obtained as colorless crystals. mp 188.5-190 ℃

Synthesis Example 15 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (4-morpholinyl) -6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole

[0135]

[Chemical 34]

The title compound was obtained in the same manner as in Synthesis Example 6 using morpholine. (11%) mp 185-186.5 ℃

Synthesis Example 16 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (3-methoxypropylamino) -6H-pyrano [2,3-f] benzo-2,1,3- Oxadiazole

[0138]

[Chemical 35]

The title compound was obtained by the same procedure as in Synthesis Example 6 using 3-methoxypropylamine. (60%) MS: 177 (100%), 235 (100%), 289 (M ⁺ -18, 1%) mp 175.5-178 ℃

Synthesis Example 17 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (3-ethoxycarbonylpropylamino) -6
H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

[0141]

[Chemical 36]

The title compound was obtained in the same manner as in Synthesis Example 6 using ethyl 4-aminobutyrate. (38%) The hydrochloride of the title compound was obtained as colorless crystals. mp 189-191 ℃

Synthesis Example 18 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-ethoxycarbonylmethylamino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

[0144]

[Chemical 37]

Synthesis Example 6 using glycine ethyl ester
The title compound was obtained by performing the same operation as described above. (5%) The hydrochloride salt of the title compound was obtained as an orange oil.

Synthesis Example 19 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (3-chloropropylamino) -6H-pyrano [2,3-f] benzo-2,1,3- Oxadiazole

[0147]

[Chemical 38]

The title compound was obtained in the same manner as in Synthesis Example 6 using 3-chloropropylamine. (20%) The hydrochloride of the title compound was obtained as colorless crystals. mp 216-220 ℃

Synthesis Example 20 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (2-hydroxyethylamino) -6H-pyrano [2,3-f] benzo-2,1,3- Oxadiazole

[0150]

[Chemical Formula 39]

The title compound was obtained in the same manner as in Synthesis Example 6 using ethanolamine. (89%) The hydrochloride of the title compound was obtained as colorless crystals. mp 200-204 ℃

Synthesis Example 21 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-
2,1,3-oxadiazole

[0153]

[Chemical 40]

7,8-Dihydro-6,6-dimethyl-
7,8-Epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole 0.82g (3.8mmole)
It was dissolved in 25 ml of 6.7% NH ₃ -EtOH and reacted in a pressure-resistant glass tube at 60 ° C. for 48 hours. The reaction solution was evaporated, and the residue was subjected to silica gel column chromatography (eluting solvent, ethyl acetate: methanol = 5: 1) to give the title compound (0.77 g,
Yield: 87%) was obtained as a brown solid. A portion of this was recrystallized from ethanol to give the pure title compound as colorless crystals.

Mp 223-225 ° C. NMR (CDCl ₃ + DMSO-d ⁶ ) δ (ppm): 1.26 (3H), 1.49 (3H),
2.80-3.30 (5H), 3.33 (1H), 3.78 (1H), 6.82 (1H), 7.98
(1H) MS: 133 (50%), 163 (100%), 235 (M ⁺ , 3%)

Synthesis Example 22 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-methylureido-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

[0157]

[Chemical 41]

7,8-Dihydro-6,6-dimethyl-7
-Hydroxy-8-amino-6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole 200 mg (0.85
0 ml) and 20 ml of dichloromethane were stirred at room temperature, 55 μl (0.935 mmole) of methyl isocyanate was added to this solution, and the mixture was stirred for 23 hours. The precipitated crystals were filtered to give the title compound (227 mg, yield: 92%) as colorless crystals.

Mp 213-215 ° C MS: 44, 202 (30%), 274 (M ⁺ -H ₂ O, 6%)

Synthesis Example 23 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-methylthioureido-6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole

[0161]

[Chemical 42]

7,8-Dihydro-6,6-dimethyl-7
-Hydroxy-8-amino-6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole 200 mg (0.85
(0 mmole) and 20 ml of dichloromethane were stirred at room temperature, 68 mg (0.935 mmole) of methyl isothiocyanate was added to this solution, and the mixture was stirred for 23 hours. The precipitated crystals were filtered to give the title compound (122 mg, yield: 47%) as colorless crystals.

Mp 213-215 ° C MS: 91 (62%), 202 (67%), 290, 308 (M ⁺ , 27%)

Synthesis Example 24 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-phenylureido-6H-pyrano [2,3-f]
Benzo-2,1,3-oxadiazole

[0165]

[Chemical 43]

7,8-Dihydro-6,6-dimethyl-7
-Hydroxy-8-amino-6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole 200 mg (0.85
0 ml) and 20 ml of dichloromethane were stirred at room temperature, and 102 μl (0.935 mmole) of phenyl isocyanate was added to this solution, followed by stirring for 4 hours. The precipitated crystals were filtered to obtain the title compound (203 mg, yield: 67%) as colorless crystals.

Mp 215-217 ° C MS: 93, 163 (56%), 321 (20%), 354 (M ⁺ , 10%)

Synthesis Example 25 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-trichloroacetylureido-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

[0169]

[Chemical 44]

7,8-Dihydro-6,6-dimethyl-7
-Hydroxy-8-amino-6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole 200 mg (0.85
(0 mmole), 20 ml of dichloromethane was stirred at room temperature, and 100 μl of trichloroacetyl isocyanate (0.935
mmole) was added and stirred for 5 hours. The precipitated crystals were filtered to give the title compound (90 mg, yield: 25%) as colorless crystals.

Mp 248-250 ° C MS: 44, 163 (43%), 422 (M ⁺ , 2%)

Synthesis Example 26 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (3-chloropropylureido) -6H-pyrano [2,3-f] benzo-2,1,3- Oxadiazole

[0173]

[Chemical formula 45]

7,8-Dihydro-6,6-dimethyl-7
-Hydroxy-8-amino-6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole 400 mg (1.70
mmole), 40 ml of dichloromethane was stirred at room temperature, and 192 μl of 3-chloropropyl isocyanate (1.87 mm) was added to this solution.
ole) was added and stirred for 5 hours. The precipitated crystals are filtered,
The title compound (250 mg, yield: 41%) was obtained as pale yellow crystals.

Mp 83-85 ° C MS: 41 (53%), 163, 318 (93%), 354 (M ⁺ , 5%)

Synthesis Example 27 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (2-chloroethylureido) -6H-pyrano [2,3-f] benzo-2,1,3- Oxadiazole

[0177]

[Chemical formula 46]

7,8-Dihydro-6,6-dimethyl-7
-Hydroxy-8-amino-6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole 400 mg (1.70
mmole), 40 ml of dichloromethane were stirred at room temperature, and 200 μl of 2-chloroethyl isocyanate (1.87 mmol) was added to this solution.
e) was added and stirred for 6 hours. The precipitated crystals were filtered to obtain the title compound as colorless crystals (480 mg, yield: 83%).

Mp 178-180 ° C MS: 87 (57%), 163, 304 (78%), 340 (M ⁺ , 8%)

Synthesis Example 28 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-isopropylureido-6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole

[0181]

[Chemical 47]

7,8-Dihydro-6,6-dimethyl-7
-Hydroxy-8-amino-6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole 200 mg (0.85
(0 mmole) and 20 ml of dichloromethane were stirred at room temperature, and 92 μl (0.935 mmole) of isopropyl isocyanate was added to this solution.
Was added and stirred for 6 hours. The precipitated crystals were filtered to give the title compound (120 mg, yield: 44%) as colorless crystals.

Mp 201-203 ° C MS: 43 (40%), 202, 302 (20%), 320 (M ⁺ , 12%)

Synthesis Example 29 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-ethoxycarbonylamino-6H-pyrano [2,2]
3-f] benzo-2,1,3-oxadiazole

[0185]

[Chemical 48]

7,8-Dihydro-6,6-dimethyl-7
-Hydroxy-8-amino-6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole 200 mg (0.85
(0 mmole), 166 μl (1.19 mmole) of triethylamine, and 20 mg of dichloromethane were stirred at room temperature, 114 μl (1.19 mmole) of ethyl chloroformate was added to this solution, and the mixture was stirred for 21 hours. The reaction solution was washed with water three times and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (elution solvent ethyl acetate: methanol =
20: 1 (v / v)) to give the title compound (227 mg, yield: 87%) as a yellow oil.

MS: 133 (48%), 235,307 (M ⁺ , 25%)

Synthesis Example 30 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (2-chloroethoxycarbonylamino) -6H
-Pyrano [2,3-f] benzo-2,1,3-oxadiazole

[0189]

[Chemical 49]

7,8-Dihydro-6,6-dimethyl-7
-Hydroxy-8-amino-6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole 400 mg (1.70
mmole), 260 μl (1.87 mmole) of triethylamine, and 40 mg of dichloromethane were stirred at room temperature, 193 μl (1.87 mmole) of 2-chloroethyl chloroformate was added to this solution, and the mixture was stirred for 21 hours. The reaction solution was washed with water three times and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was recrystallized from chloroform to obtain the title compound (507 mg, yield: 87%) as pale yellow crystals.

Mp 164-166 ° C MS: 133 (48%), 235, 307 (M ⁺ , 25%)

Synthesis Example 31 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (2-oxo-3-oxazolin-1-yl)-
6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

[0193]

[Chemical 50]

400 mg (1.17 mm) of the compound obtained in Synthesis Example 30
ole), potassium carbonate 3.24 g (23.4 mmole), potassium iodide
388 mg (2.34 mmole) and 50 ml of anhydrous acetone were heated to reflux at room temperature for 26 hours in a nitrogen atmosphere. After returning to room temperature,
The insoluble material was filtered off, ethyl acetate was added to the filtrate, and the mixture was washed 3 times with water. The residue obtained by drying over anhydrous magnesium sulfate and distilling off the solvent was subjected to silica gel column chromatography (eluting solvent, ethyl acetate: methanol = 10: 1 (v / v)) to give the title compound (339 mg, yield) as a brown oil. Rate: 94%). A part of this was recrystallized from ethyl acetate to obtain yellow crystals.

Mp 177.5-180 ° C MS: 43 (25%), 272, 287 (65%), 305 (M ⁺ , 8%)

Synthesis Example 32 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (2-oxo-3-imidazolin-1-yl)-
6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

[0197]

[Chemical 51]

The compound obtained in Synthesis Example 27 was synthesized as Synthesis Example 31.
The same operation as the above was performed to obtain the title compound as colorless crystals. (34%) mp 251-252.5 ° C

Synthesis Example 33 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-cyclohexylureido-6H-pyrano [2,3]
-F] Benzo-2,1,3-oxadiazole

[0200]

[Chemical 52]

Using cyclohexyl isocyanate,
The same operation as in Synthesis Example 22 was performed to obtain the title compound as colorless crystals. (28%) mp 203-206 ℃

Synthesis Example 34 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (t-butylureido) -6H-pyrano [2,3
-F] Benzo-2,1,3-oxadiazole

[0203]

[Chemical 53]

The title compound was obtained as colorless crystals by the same procedure as in Synthesis Example 22 using t-butylisocyanate. (52%) mp 203-205 ℃

Synthesis Example 35 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-methoxycarbonylamino-6H-pyrano [2,2]
3-f] benzo-2,1,3-oxadiazole

[0206]

[Chemical 54]

The title compound was obtained as a yellow oil by the same procedure as in Synthesis Example 29 using methyl chloroformate. (19%)

Synthesis Example 36 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (t-butylthioureido) -6H-pyrano [2,3-f] benzo-2,1,3- Oxadiazole

[0209]

[Chemical 55]

Using t-butyl isothiocyanate,
The same operation as in Synthesis Example 23 was performed to obtain the title compound. (Five
7%)

Synthesis Example 37 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (2-oxohexahydropyrimidin-1-yl) -6H-pyrano [2,3-f] benzo-2 , 1, 3
-Oxadiazole

[0212]

[Chemical 56]

The compound obtained in Synthesis Example 26 was synthesized as Synthesis Example 31.
The same operation as the above was performed to obtain the title compound as colorless crystals. (39%) mp 233-234 ° C

Synthesis Example 38 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (3-chloropropoxycarbonylamino) -6
H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

[0215]

[Chemical 57]

Using 3-chloropropyl chloroformate and the same procedures as in Synthesis Example 30, the title compound was obtained as a yellow oil. (100%)

Synthesis Example 39 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (2-oxotetrahydrooxazin-3-yl) -6H-pyrano [2,3-f] benzo-2, 1,3
-Oxadiazole

[0218]

[Chemical 58]

The compound obtained in Synthesis Example 38 was synthesized as Synthesis Example 31.
The same operation as the above was performed to obtain the title compound as colorless crystals. (34%) mp 220-223 ° C

Synthesis Example 40 7,8-Dihydro-6,6-dimethyl-7-acetoxy-8-diethylamino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole-3- Oxide

[0221]

[Chemical 59]

103 mg (0.34 mmo of the compound obtained in Synthesis Example 1)
1 ml of pyridine and 130 mg (1.27 mmol) of acetic anhydride were added to (l) and the mixture was stirred at 80-90 ° C for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent, ethyl acetate: n-hexane = 1: 3).
(V / v) Rf = 0.3), and 90.4 mg (yield 77%) of the title compound were obtained as a yellow solid.

Synthesis Example 41 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-diethylamino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

[0224]

[Chemical 60]

310 mg (1.01 mmo of the compound obtained in Synthesis Example 1)
l) is dissolved in 3 g of benzene, and triethylphosphite 0.2
0 g (1.2 mmol) was added, the mixture was heated at 60 ° C. for 1 hour, then returned to room temperature and stirred overnight. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent, ethyl acetate: n-hexane = 1: 3 (v / v) Rf = 0.3), 267 mg of the title compound (yield 91% ) Was obtained as a yellow solid.

Synthesis Example 42 7,8-Dihydro-6,6-dimethyl-7-acetoxy-8-diethylamino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

[0227]

[Chemical formula 61]

220 mg (0.75 mm) of the compound obtained in Synthesis Example 41
ol) with 2 ml of pyridine and 0.29 g (2.8 mmol) of acetic anhydride,
Heated at 80-90 ° C for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent, ethyl acetate: n-hexane = 1: 3 (v
/ V) Rf = 0.3), and 209.1 mg (yield 83%) of the title compound was obtained as a pale yellow solid.

Synthesis Example 43 7,8-Dihydro-6,6-dimethyl-7-acetoxy-8- (1-piperidinyl) -6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole

[0230]

[Chemical formula 62]

Using the compound obtained in Synthetic Example 3, the same operation as in Synthetic Example 42 was carried out to obtain the title compound as yellow crystals. (100%) mp 158-160 ℃

Synthesis Example 44 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (4-diethoxybutylamino) -6H-pyrano [2,3-f] benzo-2,1,3 -Oxadiazole

[0233]

[Chemical formula 63]

Using 4-aminobutyraldehyde diethyl acetal and following the same procedure as in Synthesis Example 6 the title compound was obtained as a brown oil. (93%)

Synthesis Example 45 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (2-hydroxypyrrolidin-1-yl) -6H
-Pyrano [2,3-f] benzo-2,1,3-oxadiazole

[0236]

[Chemical 64]

316 mg (0.832 m) of the compound obtained in Synthesis Example 44
1 ml of 2.5N hydrochloric acid and 2 ml of 1,4-dioxane were added to (mol) and reacted at room temperature for 3 hours. Aqueous sodium carbonate solution was added, and the mixture was hydrated and extracted with diethyl ether. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluting solvent, ethyl acetate: n-hexane = 1: 1 (v / v) Rf = 0.5) to give the title compound as a yellow oil. (40%)

Synthesis Example 46 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (3-carboxypropylamino) -6H-pyrano [2,3-f] benzo-2,1,3- Oxadiazole

[0239]

[Chemical 65]

Hydrochloric acid salt of the compound obtained in Synthesis Example 17 80.6
Sodium hydroxide 18.4mg (0.460mmol) to mg (0.209mmol)
A solution consisting of 1 ml of water and 4 ml of ethanol was added and the reaction was carried out at room temperature for 3 hours. The mixture was acidified with 1N hydrochloric acid and extracted with diethyl ether. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound as a colorless oil.

Synthesis Example 47 7,8-Dihydro-6,6-dimethyl-7-acetoxy-8-amino-6H-pyrano [2,3-f] benzo-
2,1,3-oxadiazole

[0242]

[Chemical formula 66]

7,8-Dihydro-6,6-dimethyl-
240 mg (1.10 mmol) of 7,8-epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole was dissolved in 5 ml of dichloromethane and acetonitrile was added to 5 ml of BF _3-.
Add 0.5 ml of diethyl ether complex. After reacting for 30 minutes at room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluting solvent, ethyl acetate: n-hexane = 1: 1 (v / v) Rf = 0.3) to obtain 152 mg (yield 50%) of the title compound as a yellow oily substance.

MS: 163 (53%), 188 (100%), 277 (M ⁺ , 4%)

Synthesis Example 48 7,8-Dihydro-6,6-diethyl-7-hydroxy-8- (1-piperidinyl) -6H-pyrano [2,3-
f] Benzo-2,1,3-oxadiazole

[0246]

[Chemical formula 67]

7,8-Dihydro-6,6-diethyl-
7,8-Epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole 87.7 g (0.36 mmol), piperidine 61 mg (0.72 mmol) and ethanol 2 ml were refluxed for 20 hours with stirring. Let After distilling off the solvent, the residue was subjected to silica gel column chromatography (eluting solvent, ethyl acetate: n-hexane = 1: 1 (v / v) Rf = 0.3),
30 mg (25% yield) of the title compound was obtained as a yellow oil.

Synthesis Example 49 7,8-Dihydro-6,6-diethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-
2,1,3-oxadiazole

[0249]

[Chemical 68]

7,8-Dihydro-6,6-diethyl-
Using 7,8-epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, the same operation as in Synthesis Example 21 was carried out to obtain the title compound as colorless crystals.
(44%) mp 122-124 ℃

Synthesis Example 50 7,8-Dihydro-6,6-diethyl-7-hydroxy-8-methylureido-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

[0252]

[Chemical 69]

The title compound was obtained as a brown oil by the same procedure as in Synthesis Example 22 using the compound obtained in Synthesis Example 49. (89%)

Synthesis Example 51 7,8-Dihydro-6,6-diethyl-7-acetoxy-8-amino-6H-pyrano [2,3-f] benzo-
2,1,3-oxadiazole

[0255]

[Chemical 70]

7,8-Dihydro-6,6-diethyl-
The same operation as in Synthesis Example 47 was performed using 7,8-epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole to obtain the title compound as pale yellow crystals. (62%) mp 92-95 ° C

Synthesis Example 52 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (2-cyano-3-t-butyl-1-guadinino) -6H-pyrano [2,3-f] Benzo-2,1,3
-Oxadiazole

[0258]

[Chemical 71]

100 mg (0.29 mm) of the compound obtained in Synthesis Example 36
ol), 97 mg (0.37 mmol) of triphenylphosphine, 40 μl of carbon tetrachloride, 40 μl (0.29 mmol) of triethylamine, and 1 ml of dichloromethane were heated under reflux for 4 hours. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent, ethyl acetate: n-hexane = 1: 2 (v / v) Rf = 0.1) to obtain 77 mg of pale yellow crystals.

122 mg (0.39 mmol) of this compound, cyanamide
A solution consisting of 21 mg (0.50 mmol), 2 ml of tetrahydrofuran and 20 mg of diisopropylethylamine was stirred at room temperature for 14 hours. The precipitated crystals were collected by filtration to give the title compound (112 mg, yield 80%).
%) As pale yellow crystals. mp 146-148 ℃

Synthesis Example 53 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (1-piperidinyl) -6H-pyrano [2,3-
f] Benzo-1,2,3-triazole

[0262]

[Chemical 72]

3,4-dihydro-2,2-dimethyl-3
-Hydroxy-4- (1-piperidinyl) -6-amino-7-nitro-2H-benzo [b] pyran 0.14 g (0.44 mm
ol) was dissolved in 23.7 g of ethanol, and hydrogenation was carried out at room temperature and 1 atm for 3 hours with stirring using 0.10 g of 5% palladium-carbon as a catalyst. When the reaction solution is suction filtered to remove the catalyst and the solvent is distilled off, 3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (1-piperidinyl) -6,6 is obtained.
0.12 g of 7-diamino-2H-benzo [b] pyran (yield 9
5%) as a dark red oil. Since it was unstable, it was used immediately for the next diazotization.

The total amount of the above diamino compound was adjusted to 0.13 g of acetic acid and 0.23 of water.
Sodium nitrite 35mg (0.51mmo
A solution prepared by dissolving l) in 0.15 g of water was added all at once at room temperature. After confirming the generation of heat, the mixture was heated on a water bath at 80 ° C for 1 minute. 20 ml of water, 0.13 g of sodium hydroxide and 4.0 g of sodium chloride were added to this reaction mixture, which was then extracted 3 times with 40 ml of ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and the filtration solvent was distilled off to obtain 0.10 g of yellow-red powder. When 90 mg of this was purified by silica gel column chromatography (ethyl acetate-ethanol = 5: 1), 80 mg of the title compound (yield 72% in the total of 2 steps) was obtained as a pale yellowish brown powder.

MS: 284 (M ⁺ -H ₂ O, 18%), 230 (M ⁺ -72, 100
%), 84 (5%)

Synthesis Example 54 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (1-pyrrolidinyl) -6H-pyrano [2,3-
f] Benzo-1,2,3-triazole

[0267]

[Chemical formula 73]

3,4-Dihydro-2,2-dimethyl-3
-Hydroxy-4- (1-pyrrolidinyl) -6-amino-7-nitro-2H-benzo [b] pyran 0.20 g (0.65 mm
ol) was dissolved in 34.9 g of ethanol, and hydrogenation was carried out at room temperature and 1 atm for 3 hours with stirring using 0.15 g of 5% palladium-carbon as a catalyst. When the reaction solution is suction filtered to remove the catalyst and the solvent is distilled off, 3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (1-pyrrolidinyl) -6,6 is obtained.
170 mg of 7-diamino-2H-benzo [b] pyran (yield 9
4%) as a dark red oil.

The total amount of this diamino compound was 0.19 g of acetic acid and 0.34 of water.
Sodium nitrite 52mg (0.75mmo
A solution prepared by dissolving l) in 0.22 g of water was added all at once at room temperature. After confirming the generation of heat, the mixture was heated on a water bath at 80 ° C for 3 minutes. Thereafter, the same post-treatment as in Synthesis Example 53 was carried out to obtain 160 mg (2
A total yield of 85%) was obtained as a yellowish brown powder.

MS: 288 (M ⁺ , 3%), 270 (M ⁺ -H ₂ O, 3%), 216
(M ⁺ -72, 88%), 188 (M ⁺ -100, 100%), 70 (22%)

Synthesis Example 55 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-diethylamino-6H-pyrano [2,3-f] benzo-1,2,3-triazole

[0272]

[Chemical 74]

3,4-dihydro-2,2-dimethyl-3
-Hydroxy-4-diethylamino-6-amino-7-
Nitro-2H-benzo [b] pyran 0.20 g (0.65 mmol) was dissolved in ethanol 34.9 g, and 5% palladium-carbon 0.15 was added.
Hydrogenation was carried out at room temperature and 1 atm for 2.5 hours with stirring using g as a catalyst. When the reaction solution is suction filtered to remove the catalyst and the solvent is distilled off, 3,4-dihydro-2,2-dimethyl-3 is obtained.
0.15 g (83% yield) of -hydroxy-4-diethylamino-6,7-diamino-2H-benzo [b] pyran was obtained as a black brown oily residue.

The total amount of this diamino compound was 0.19 g of acetic acid and 0.34 of water.
Sodium nitrite 52mg (0.75mmo
A solution prepared by dissolving l) in 0.22 g of water was added all at once at room temperature. After confirming the generation of heat, the mixture was heated on a water bath at 80 ° C for 3 minutes. Thereafter, the same post-treatment as in Synthesis Example 53 was carried out to obtain 70 mg of the title compound (yield: 37% over 2 steps) as a pale brown powder. MS (FAB): 291 ((M + H) ⁺ )

Synthesis Example 56 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (1-piperidinyl) -6H-pyrano [2,3-
f] Benzo-2,1,3-thiadiazole

[0276]

[Chemical 75]

3,4-Dihydro-2,2-dimethyl-3
-Hydroxy-4- (1-piperidinyl) -6-amino-7-nitro-2H-benzo [b] pyran 0.28 g (0.87 mm)
ol) was dissolved in 44.8 g of ethanol, and hydrogenation was carried out at room temperature and 1 atm for 3 hours with stirring using 0.20 g of 5% palladium-carbon as a catalyst. When the reaction solution is suction filtered to remove the catalyst and the solvent is distilled off, 3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (1-piperidinyl) -6,6 is obtained.
0.24 g of 7-diamino-2H-benzo [b] pyran (yield 9
5%) as a dark red oil. To this product, 0.12 g (0.86 mmol) of thionylaniline and 4 g of benzene were added, and the mixture was heated under reflux for 2.5 hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate-ethanol = 1: 3) to give the title compound (60 mg, yield 23%) as a yellow solid.

MS: 84 (85%), 247 (100%), 319 (M ⁺ , 2%)

Synthesis Example 57 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (1-pyrrolidinyl) -6H-pyrano [2,3-
f] Benzo-2,1,3-thiadiazole

[0280]

[Chemical 76]

3,4-Dihydro-2,2-dimethyl-3
Using -hydroxy-4- (1-pyrrolidinyl) -6-amino-7-nitro-2H-benzo [b] pyran, the same procedure as in Synthesis Example 56 was carried out to obtain the title compound as pale brown crystals ( Yield 25%).

Synthesis Example 58 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-diethylamino-6H-pyrano [2,3-f] benzo-2,1,3-thiadiazole

[0283]

[Chemical 77]

3,4-Dihydro-2,2-dimethyl-3
-Hydroxy-4-diethylamino-6-amino-7-
Synthesis Example 56 using nitro-2H-benzo [b] pyran
The title compound was obtained as a brown oil by the same procedure as in (17% yield).

Synthesis Example 59 (−)-7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (1-pyrrolidinyl) -6H-pyrano [2,3-f] benzo-2,1, 3-Oxadiazole [optically active (−) form of compound of Synthesis Example 4]

[Chemical 78] 14.7 g of pyrrolidine in a solution of 15.0 g (68.7 mmole) of the compound of Reference Example 1 in ethanol (60 ml).
(206.2 mmole) was added and the mixture was heated under reflux for 2 hours.
The solvent was distilled off under reduced pressure, 100 ml of water was added, and the mixture was extracted with chloroform (100 ml × 1, 30 ml × 2). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (benzene: ethyl acetate = 5: 1 → 4: 1), and the obtained crystals were recrystallized from benzene-hexane (1: 2) to give the title compound (13.8 g, yield). Rate 69%) was obtained as yellow crystals. A solution of 13 g (44.9 mmole) of the title compound in ethanol (240 ml) was added with hydrochloric acid-methanol (10
%) 240 ml, and the mixture was stirred at room temperature for 3 hours, and the solvent was evaporated under reduced pressure. Crystallization was performed from 250 ml of 2-propanol to give 11.5 g of the hydrochloride of the title compound (yield 78
%) As colorless crystals. mp> 200 ℃ (decomp.)

Synthesis Example 60 (+)-7,8-Dihydro-6,6-dimethyl-7-hydroxy-8- (1-pyrrolidinyl) -6H-pyrano [2,3-f] benzo-2,1, 3-Oxadiazole [optically active (+) form of the compound of Synthesis Example 4]

[Chemical 79] By the same operation as in Synthesis Example 59, 15.0 g of the title compound
(Yield 58%) was obtained as yellow crystals. Similarly, 12.9 g (yield: 82%) of the hydrochloride of the title compound was obtained as colorless crystals. mp> 200 ℃ (decomp.)

[Formulation Example]

Formulation Example 1 Tablets Synthetic Example Compound 4 10 g Lactose 260 g Microcrystalline cellulose 600 g Corn starch 350 g Hydroxypropyl cellulose 100 g CMC-Ca 150 g Magnesium stearate 30 g Total amount 1,500 g The above ingredients were mixed by a conventional method and then in one tablet. 10,000 sugar-coated tablets containing 1 mg of the active ingredient are prepared.

Formulation Example 2 Capsule Synthetic Example Compound 4 10 g Lactose 440 g Microcrystalline cellulose 1,000 g Magnesium stearate 50 g Total amount 1,500 g The above ingredients were mixed by a conventional method and filled into a gelatin capsule. 10,000 capsules containing 1 mg of active ingredient are prepared.

Formulation Example 3 Soft Capsule Synthesis Example Compound 4 10 g PEG400 479 g Saturated fatty acid triglyceride 1,500 g Mint oil 1 g Polysorbate 80 10 g Total amount 2,000 g Soft gelatin capsule No. 3 was mixed by the conventional method after the above ingredients were mixed. To prepare 10,000 soft capsules containing 1 mg of active ingredient per capsule.

Formulation Example 4 Ointment Synthetic Example Compound 4 1.0 g Liquid paraffin 10.0 g Cetanol 20.0 g White petrolatum 68.4 g Ethylparaben 0.1 g l-Menthol 0.5 g Total amount 100.0 g The above components were prepared by a conventional method. Mix to make 1% ointment.

Formulation Example 5 Suppository Synthetic Example Compound 4 1 g Wittepsol H15 ^* 478 g Wittepsol W35 ^* 520 g Polysorbate 80 1 g Total amount 1,000 g “ ^* Trade name of triglyceride compound Witepsol = Witepsol” The above components are melt-mixed by a conventional method, poured into a suppository container, and cooled and solidified to prepare 1,000 1 g suppositories containing 1 mg of the active ingredient.

Formulation Example 6 Injectable Compound 4 1 mg Distilled water for injection 5 mL Used, dissolved.

[Pharmacological Test Example]

Effect on myocardial contractile force Test method Heart was removed from a Hartley male guinea pig and 95% O ₂ /
The left atrium was separated in Krebs Henseleit solution aerated with 5% CO ₂ . The sample was suspended in an organ bath filled with nutrient solution maintained at 31 ° C under a tension of 0.5 g. The myocardial contraction force is obtained by transmural electrical stimulation of the left atrium through a bipolar platinum electrode [stimulation condition: voltage; twice the threshold potential at which contraction is obtained (V), stimulation time; 3 (msec), stimulation interval. ; 1 (H
z)] was added and the contraction tension generated was recorded.

Following equilibration with nutrient exchange, specimens were cumulatively applied with isoproterenol to determine maximal contractile response. After washing with the drug, equilibration was performed for 60 minutes while exchanging the nutrient solution, and then each compound was applied to observe the action. As a result, the action when each compound was applied at 100 μM and 300 μM was expressed as a percentage change with the maximum reaction of isoproterenol obtained in advance as 100%.

Results The compounds of the present invention showed a strong concentration-dependent myocardial contractile force increasing action.

[0298]

[Table 7]

Effect on Heart Rate Test Method Heart was removed from a male Hartley guinea pig and 95% O ₂ /
The right atrium was separated in Krebs Henseleit solution which was aerated with 5% CO ₂ . The specimens were suspended in an organ bath filled with nutrient solution maintained at 31 ° C under a tension of 1 g.

After equilibration with exchange of nutrient solution, isoproterenol was cumulatively applied to the specimens to determine the maximum response. After washing with the drug, equilibration was performed for 60 minutes while exchanging the nutrient solution, and then each compound was applied to observe the action.
As a result, the action when each compound was applied at 100 μM and 300 μM was expressed as a percentage change with the maximum reaction of isoproterenol obtained in advance as 100%.

Results The compound according to the present invention showed a concentration-dependent heart rate reducing action.

[0302]

[Table 8]

Effect on cardiac function in anesthetized dogs Test method Male and female miscellaneous dogs were anesthetized with sodium pentobarbital and placed under artificial respiration. The blood pressure was measured by inserting a cannula from the right femoral artery into the abdominal aorta and using a strain pressure amplifier via a pressure transducer. The heart rate was measured by the instantaneous heartbeat pattern with the blood pressure waveform as a trigger. Left ventricular pressure was measured via a strain pressure amplifier by inserting a catheter pressure transducer into the left ventricle through the left carotid artery. The left ventricular pressure temporary differential value (rise rate of left ventricular systolic pressure, LV dp / dl _max ) was obtained by differentiating the left ventricular pressure via a differentiating unit. The drug is
It was dissolved in polyethylene glycol 400, ethanol, and water (mixing ratio 2: 3: 5), and administered as a bolus from a cannula inserted into the left cephalic vein. It was confirmed that the solvent alone had no effect on cardiac function and blood pressure.

Results The compounds according to the invention show that without affecting blood pressure,
It showed a strong cardiac contractile force increasing action and a strong heart rate reducing action.

[Table 9]

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] June 28, 1994

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 1

[Correction method] Change

[Correction content]

[Chemical 1](In the formula, X¹And X²Means absent or an oxygen atom
X is an oxygen atom, a sulfur atom, a nitrogen atom (the nitrogen atom
Is a hydrogen atom or C₁-C_FourMay be substituted with alkyl
I), C (O), C (S) or C (N-CN)
A; hydrogen atom, hydroxy group or OC (O) R^Five(R^FiveIs C₁-C
_FourMeans alkyl. ) Means or with B
Means a single bond; B means a hydrogen atom, or
Taken together means a single bond; R¹And R²Are the same as each other
Are different, hydrogen atom or C₁-C_FourMeans alkyl
Or R¹And R²Together, C₁-C_FourBy alkyl
Optionally substituted 1,4-butylene or 1,5-pepylene
Means nethylene; R³And R^FourAre the same or different from each other
Becomes, hydrogen atom, C₁-C₆Alkyl group of {the alkyl group
Is a halogen atom, carboxyl group, C₂-C_FiveAlkoxy
Carbonyl group, hydroxy group, C₁-C_FourAlkoxy group, CH
(OR)₂(R is C₁-C_FourMeans an alkyl group. ), Phenyl group
(The phenyl group is a halogen atom, a hydroxy group or C₁
-C_FourOptionally substituted by an alkoxy group
), Formyl group, cyano group or nitro group
It may be replaced at will. }, C₂-C₆Alkenyl group of
{The alkenyl group is a halogen atom, a carboxyl group,
C₂-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourA
Lucoxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
Optional), formyl group, cyano group or
It may be optionally substituted with a toro group. }, C₂-C₆
An alkynyl group of {the alkynyl group is a halogen atom,
Ruboxyl group, C₂-C_FiveAlkoxycarbonyl group, hydro
Xy group, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourArchi
Means a radical. ), A phenyl group (the phenyl group is
Rogen atom, hydroxy group or C₁-C _FourBy an alkoxy group
Optionally substituted), formyl group, cyano
Optionally substituted by groups or nitro groups
Yes. }, C₃-C₆Cycloalkyl group {the cycloalkyl group
Is a halogen atom, carboxyl group, C₂-C_FiveAlkoxy
Carbonyl group, hydroxy group, C₁-C_FourAlkoxy group, CH
(OR)₂(R is C₁-C_FourMeans an alkyl group. ), Phenyl
Group (the phenyl group is a halogen atom, a hydroxy group or
C₁-C_FourOptionally substituted by an alkoxy group
), Formyl group, cyano group or nitro group
It may be replaced at will. }, A phenyl group (the phenyl group
Group is a halogen atom, a hydroxy group or C₁-C_FourArco
Optionally substituted by a xy group), or C (=
Y) ZR⁶(Y is an oxygen atom, a sulfur atom or NR⁷(R⁷Is hydrogen
Atom, cyano group, nitro group, C₁-C_FourAlkyl, C₁-C_FourAl
COXY or CO₂R⁸(R⁸Is C₁-C_FourMeans alkyl
It ) Means. ), Z is an oxygen atom, sulfur source
Child or NR⁹(R⁹Is a hydrogen atom, C₁-C₆Alkyl group of
{The alkyl group is a halogen atom, a carboxyl group, C₂
-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourAl
Coxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
Optional), formyl group, cyano group or
It may be optionally substituted with a toro group. }, C₂-C₆
An alkenyl group of {the alkenyl group is a halogen atom,
Ruboxyl group, C₂-C_FiveAlkoxycarbonyl group, hydro
Xy group, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourArchi
Means a radical. ), A phenyl group (the phenyl group is
Rogen atom, hydroxy group or C₁-C_FourBy an alkoxy group
Optionally substituted), formyl group, cyano
Optionally substituted by groups or nitro groups
Yes. }, C₂-C₆An alkynyl group of
Rogen atom, carboxyl group, C₂-C_FiveAlkoxy carbo
Nyl group, hydroxy group, C₁-C_FourAlkoxy group, CH (OR)₂(R
Is C₁-C_FourMeans an alkyl group. ), A phenyl group (the group
A phenyl group is a halogen atom, a hydroxy group or C₁-C_FourA
Optionally substituted with a lucoxy group),
Optionally substituted by a mil, cyano or nitro group
It may be. }, C₃-C₆Cycloalkyl group
The alkyl group is a halogen atom, a carboxyl group, C₂-C
_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourArco
Xy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group. ),
Phenyl group (the phenyl group is a halogen atom, a hydroxy group
Si group or C₁-C _FourOptionally substituted by an alkoxy group
, Formyl group, cyano group or nitro group
It may be optionally substituted. }, A phenyl group (the
Phenyl group is a halogen atom, hydroxy group or C₁-C_Four
Optionally substituted with an alkoxy group)
To taste. ) Means R⁶Is a hydrogen atom, C₁-C₈The alkyl
Group {the alkyl group is a halogen atom, a carboxyl group,
C₂-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourA
Lucoxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
Optional), formyl group, cyano group or
It may be optionally substituted with a toro group. }, C₂-C₆
An alkenyl group of {the alkenyl group is a halogen atom,
Ruboxyl group, C₂-C_FiveAlkoxycarbonyl group, hydro
Xy group, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourArchi
Means a radical. ), A phenyl group (the phenyl group is
Rogen atom, hydroxy group or C₁-C_FourBy an alkoxy group
Optionally substituted), formyl group, cyano
Optionally substituted by groups or nitro groups
Yes. }, C₂-C₆An alkynyl group of
Rogen atom, carboxyl group, C₂-C_FiveAlkoxy carbo
Nyl group, hydroxy group, C₁-C_FourAlkoxy group, CH (OR)₂(R
Is C₁-C_FourMeans an alkyl group. ), A phenyl group (the
Phenyl group is a halogen atom, hydroxy group or C₁-C_Four
Optionally substituted by an alkoxy group),
Arbitrarily substituted by rumil group, cyano group or nitro group
It may have been done. }, C₃-C₆Cycloalkyl group
Chloroalkyl groups include halogen atoms, carboxyl groups, C₂
-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourAl
Coxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
Optional), formyl group, cyano group or
It may be optionally substituted with a toro group. }, Pheny
Group (the phenyl group is a halogen atom, a hydroxy group or
Is C₁-C_FourOptionally substituted by an alkoxy group
Meaning). ) Means or R³And R^FourTogether
1,4-butylene or 1,5-pentylene (the butylene and petroleum
N is each C₁-C_FourAlkyl, phenyl group
Halogen atom, hydroxy group, C₁-C _FourARukoXy group
Optionally substituted by), a halogen atom,
OR^Ten(R^TenIs a hydrogen atom, C₁-C_FourAlkyl, COR¹¹(R¹¹Is C₁-C
_FourMeans alkyl. ), Nitro group, SO₃H or PO₃
H₂Means ) May be optionally substituted by
I mean} or R³And R^FourTogether (CH₂)_mX^Four(C
H₂)_l(m and l mean 1, 2 or 3 respectively, but
The total is 3, 4 or 5. X^FourIs oxygen atom, sulfur atom, NR
¹²(R¹²Is a hydrogen atom, C₁-C_FourAlkyl, phenyl group
A phenyl group is a halogen atom, a hydroxy group or C₁-C_FourA
Means optionally substituted by a lucoxy group)
To do. ) Means. ) Or R³And R^FourIs one
Ties (CH₂)_nZC (= Y) (n means 2, 3, or 4
However, Z and Y have the same meanings as described above. ) Means
It ] The compound and its optical isomer represented by
Isomers and, if it is a compound capable of forming a salt,
A therapeutic agent for heart failure comprising a pharmaceutically acceptable salt as an active ingredient.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 2

[Correction method] Change

[Correction content]

[Chemical 2](In the formula, X⁶Means absent or an oxygen atom; X^FiveIs
Oxygen atom, sulfur atom or nitrogen atom (the nitrogen atom is hydrogen
Atom or C₁-C_FourWhich may be substituted with alkyl)
Taste; A¹Is a hydrogen atom, a hydroxy group or OC (O) R¹⁷(R¹⁷Is
C₁-C_FourMeans alkyl. ) Means; B¹Is a hydrogen atom
Means; R¹³And R¹⁴Are the same or different from each other and are hydrogen
Atom or C₁-C_FourMeans alkyl; R¹⁵And R¹⁶Each other
Same or different, hydrogen atom, C₁-C₆Alkyl group of
{The alkyl group is a halogen atom, a carboxyl group, C₂
-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourAl
Coxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
May have been),Formyl group, cyano group or
It may be optionally substituted with a toro group. }, C₃-C₆
Cycloalkyl group (the cycloalkyl group is a halogen atom
Child, carboxyl group, C₂-C_FiveAn alkoxycarbonyl group,
Hydroxy group, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C_Four
Means an alkyl group. ), A phenyl group (the phenyl group
Is a halogen atom, a hydroxy group or C₁-C_FourAlkoxy
Optionally substituted by a group), a formyl group,
Optionally substituted by cyano or nitro groups
Good. }, A phenyl group (the phenyl group is a halogen source
Child, hydroxy group or C₁-C_FourOptionally by an alkoxy group
May be substituted), or C (= Y¹) Z¹R¹⁸(Y¹Is oxygen source
Child, sulfur atom or NR¹⁹(R¹⁹Is a hydrogen atom, a cyano group,
Nitro group, C₁-C_FourAlkyl or C₁-C_FourMeans alkoxy
To taste. ) Means Z¹Is an oxygen atom, a sulfur atom or
NR²⁰(R²⁰Is a hydrogen atom, C₁-C₆Alkyl group of {the alky
Group is a halogen atom, carboxyl group, C₂-C_FiveArco
Xycarbonyl group, hydroxy group, C₁-C_FourAlkoxy
Group, CH (OR)²(R is C₁-C_FourMeans an alkyl group. ), Fe
Nyl group (the phenyl group is a halogen atom, a hydroxy group
Or C₁-C_FourEven if optionally substituted by an alkoxy group
Good), a formyl group, a cyano group or a nitro group
It may be optionally substituted. }, C₃-C₆Cycloalk
Group (the cycloalkyl group is a halogen atom, a carboxyl group
Sil group, C₂-C_FiveAlkoxycarbonyl group, hydroxy
Base, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourAlkyl group
Means ), A phenyl group (the phenyl group is a halogen
Atom, hydroxy group or C₁-C_FourDepends on the alkoxy group
Optionally substituted), formyl group, cyano group
Or optionally substituted by a nitro group
Yes. }, A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C _FourOptionally substituted by an alkoxy group
May be). ) Means R ¹⁸Is water
Elementary atom, C₁-C₈Alkyl group of {wherein the alkyl group is halogen
Group atom, carboxyl group, C₂-C_FiveAlkoxy carbonyl
Group, hydroxy group, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁
-C_FourMeans an alkyl group. ), A phenyl group (the phenyl group
Group is a halogen atom, a hydroxy group or C₁-C_FourArco
Optionally substituted by xy groups), formyl
Optionally substituted by groups, cyano groups or nitro groups
You may stay. }, C₃-C₆Cycloalkyl group (the cycloalkyl
The alkyl group is a halogen atom, a carboxyl group, C₂-C_FiveA
Lucoxycarbonyl group, hydroxy group, C₁-C_FourArcoki
Si group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group. ), F
Phenyl group (the phenyl group is a halogen atom, a hydroxy group
Group or C₁-C_FourOptionally substituted by an alkoxy group
Group), a formyl group, a cyano group or a nitro group.
It may be optionally substituted. }, A phenyl group (the group
A phenyl group is a halogen atom, a hydroxy group or C₁-C_FourA
Means optionally substituted by a lucoxy group)
To do. ) Means or R¹⁵And R¹⁶Together, 1,4-bu
Tylene or 1,5-pentylene {the butylene and pentylene
Are each C₁-C_FourAlkyl, phenyl group (the phenyl
The group is a halogen atom, a hydroxy group or C₁-C_FourArcoki
Si group optionally substituted), halogen atom
Child, OR^{twenty one}(R^{twenty one}Is a hydrogen atom, C₁-C_FourAlkyl, COR^{twenty two}(R^{twenty two}Is
C₁-C_FourMeans alkyl. ), Nitro group, SO₃H young
Is PO₃H₂Means ) Has been arbitrarily replaced by
Means good or R¹⁵And R¹⁶Together (CH₂)_O
X⁷(CH₂)_P(O and P mean 1, 2 or 3, respectively,
Will be 3, 4 or 5. X⁷Is oxygen atom, sulfur source
Child, NR^{twenty three}(R^{twenty three}Is a hydrogen atom, C₁-C_FourAlkyl, phenyl group
(The phenyl group is a halogen atom, a hydroxy group or C₁
-C_Four(It may be optionally substituted with an alkoxy group)
Means ) Means. ), Or
R¹⁵And R¹⁶Together (CH₂)_QZ¹C (= Y¹) (Q is 2, 3, young
Actually means 4, Z¹, Y¹Has the same meaning as above.
It ) Means. ] The compound represented by
Optical isomers, stereoisomers, and compounds capable of forming salts
In some cases, a heart containing the pharmaceutically acceptable salt as an active ingredient
Dysfunction drug.

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0006

[Correction method] Change

[Correction content]

[Wherein X¹And X²Is absent or oxygen
Means an atom; X is an oxygen atom, a sulfur atom, a nitrogen atom (the
Nitrogen atom is hydrogen atom or C₁-C_FourSubstituted with alkyl
), C (O), C (S) or C (N-CN)
Means A is a hydrogen atom, a hydroxy group or OC (O) R^Five(R^Five
Is C₁-C_FourMeans alkyl. ) Means one with B
In a chain means a single bond; B means a hydrogen atom
Or together with A means a single bond; R¹And R²Are mutual
Identical to or different from each other, hydrogen atom or C₁-C_FourAlkyl
Or R¹And R²Together, C₁-C_FourAl
1,4-butylene young optionally substituted by kill
Means 1,5-pentylene; R³And R^FourAre the same as each other
Differently, hydrogen atom, C₁-C₆Alkyl group of {the al
Kill group is a halogen atom, carboxyl group, C₂-C_FiveAl
Coxycarbonyl group, hydroxy group, C₁-C_FourAlkoxy
Group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group. ), Fe
Nyl group (the phenyl group is a halogen atom, a hydroxy group
Or C₁-C_FourEven if optionally substituted by an alkoxy group
Good), a formyl group, a cyano group or a nitro group
It may be optionally substituted. }, C₂-C₆Alkenyl
Group {The alkenyl group is a halogen atom, a carboxyl group
Base, C₂-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-
C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
Optional), formyl group, cyano group or
It may be optionally substituted with a toro group. }, C₂-C₆
An alkynyl group of {the alkynyl group is a halogen atom,
Ruboxyl group, C₂-C_FiveAlkoxycarbonyl group, hydro
Xy group, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourArchi
Means a radical. ), A phenyl group (the phenyl group is
Rogen atom, hydroxy group or C₁-C _FourBy an alkoxy group
Optionally substituted), formyl group, cyano
Optionally substituted by groups or nitro groups
Yes. }, C₃-C₆Cycloalkyl group {the cycloalkyl group
Is a halogen atom, carboxyl group, C₂-C_FiveAlkoxy
Carbonyl group, hydroxy group, C₁-C_FourAlkoxy group, CH
(OR)₂(R is C₁-C_FourMeans an alkyl group. ), Phenyl group
(The phenyl group is a halogen atom, a hydroxy group or C₁
-C_FourOptionally substituted by an alkoxy group
), Formyl group, cyano group or nitro group
It may be replaced at will. }, A phenyl group (the phenyl group
Group is a halogen atom, a hydroxy group or C₁-C_FourArco
Optionally substituted by a xy group), or C (=
Y) ZR⁶(Y is an oxygen atom, a sulfur atom or NR⁷(R⁷Is hydrogen
Child, cyano group, nitro group, C₁-C_FourAlkyl, C₁-C_FourArco
Kisshi or CO₂R⁸(R⁸Is C₁-C_FourMeans alkyl. )
Means ), And Z is an oxygen atom or a sulfur atom.
Ku NR⁹(R⁹Is a hydrogen atom, C₁-C₆Alkyl group of {the al
Kill group is a halogen atom, carboxyl group, C₂-C_FiveAl
Coxycarbonyl group, hydroxy group, C₁-C_FourAlkoxy
Group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group. ), Fe
Nyl group (the phenyl group is a halogen atom, a hydroxy group
Or C₁-C_FourEven if optionally substituted by an alkoxy group
Good), a formyl group, a cyano group or a nitro group
It may be optionally substituted. }, C₂-C₆Alkenyl
Group {The alkenyl group is a halogen atom, a carboxyl group
Base, C₂-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-
C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
Optional), formyl group, cyano group or
It may be optionally substituted with a toro group. }, C₂-C₆
An alkynyl group of {the alkynyl group is a halogen atom,
Ruboxyl group, C₂-C_FiveAlkoxycarbonyl group, hydro
Xy group, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourArchi
Means a radical. ), A phenyl group (the phenyl group is
Rogen atom, hydroxy group or C₁-C_FourBy an alkoxy group
Optionally substituted), formyl group, cyano
Optionally substituted by groups or nitro groups
Yes. }, C₃-C₆Cycloalkyl group {the cycloalkyl group
Is a halogen atom, carboxyl group, C₂-C_FiveAlkoxy
Carbonyl group, hydroxy group, C₁-C_FourAlkoxy group, CH
(OR)₂(R is C₁-C_FourMeans an alkyl group. ), Phenyl group
(The phenyl group is a halogen atom, a hydroxy group or C₁
-C _FourOptionally substituted by an alkoxy group
), Formyl group, cyano group or nitro group
It may be replaced at will. }, A phenyl group (the phenyl group
Group is a halogen atom, a hydroxy group or C₁-C_FourArco
Optionally substituted with xy groups)
It ) Means R⁶Is a hydrogen atom, C₁-C₈Alkyl group of
{The alkyl group is a halogen atom, a carboxyl group, C₂
-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourAl
Coxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
Optional), formyl group, cyano group or
It may be optionally substituted with a toro group. }, C₂-C₆
An alkenyl group of {the alkenyl group is a halogen atom,
Ruboxyl group, C₂-C_FiveAlkoxycarbonyl group, hydro
Xy group, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourArchi
Means a radical. ), A phenyl group (the phenyl group is
Rogen atom, hydroxy group or C₁-C_FourBy an alkoxy group
Optionally substituted), formyl group, cyano
Optionally substituted by groups or nitro groups
Yes. }, C₂-C₆An alkynyl group of
Rogen atom, carboxyl group, C₂-C_FiveAlkoxy carbo
Nyl group, hydroxy group, C₁-C_FourAlkoxy group, CH (OR)₂(R
Is C₁-C_FourMeans an alkyl group. ), A phenyl group (the
Phenyl group is a halogen atom, hydroxy group or C₁-C_Four
Optionally substituted by an alkoxy group),
Arbitrarily substituted by rumil group, cyano group or nitro group
It may have been done. }, C₃-C₆Cycloalkyl group
Chloroalkyl groups include halogen atoms, carboxyl groups, C₂
-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourAl
Coxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
Optional), formyl group, cyano group or
It may be optionally substituted with a toro group. }, Pheny
Group (the phenyl group is a halogen atom, a hydroxy group or
Is C₁-C_FourOptionally substituted by an alkoxy group
Meaning). ) Means or R³And R^FourTogether
1,4-butylene or 1,5-pentylene (the butylene and petroleum
N is each C₁-C_FourAlkyl, phenyl group
Halogen atom, hydroxy group, C₁-C_FourARukoXy group
Optionally substituted by), a halogen atom,
OR^Ten(R^TenIs a hydrogen atom, C₁-C_FourAlkyl, COR¹¹(R¹¹Is C₁-C
_FourMeans alkyl. ), Nitro group, SO₃H or PO₃
H₂Means ) May be optionally substituted by
I mean} or R³And R^FourTogether (CH₂)_mX^Four(C
H₂)_l(m and l mean 1, 2 or 3 respectively, but
The total is 3, 4 or 5. X^FourIs oxygen atom, sulfur atom, NR
¹²(R¹²Is a hydrogen atom, C₁-C_FourAlkyl, phenyl group
A phenyl group is a halogen atom, a hydroxy group or C₁-C_FourA
Means optionally substituted by a lucoxy group)
To do. ) Means. ) Or R³And R^FourIs one
Ties (CH₂)_nZC (= Y) (n means 2, 3, or 4
However, Z and Y have the same meanings as described above. ) Means
It ] The compound and its optical isomer represented by
Isomers and, if it is a compound capable of forming a salt,
It is a pharmaceutically acceptable salt.

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0008

[Correction method] Change

[Correction content]

The present invention also relates to a heart failure drug containing the following compound as an active ingredient. Formula (II)

[Chemical 4] [In the formula, X ⁶ does not exist or means an oxygen atom; X ⁵ is an oxygen atom, a sulfur atom or a nitrogen atom (the nitrogen atom may be substituted with a hydrogen atom or C ₁ -C ₄ alkyl) A ¹ is a hydrogen atom, a hydroxy group or OC (O) R ¹⁷ (R ¹⁷ is
Means C ₁ -C ₄ alkyl. B ¹ represents a hydrogen atom; R ¹³ and R ¹⁴ are the same or different from each other and represent a hydrogen atom or C ₁ -C ₄ alkyl; R ¹⁵ and R ¹⁶ are the same or different from each other; Differently, a hydrogen atom, a C ₁ -C ₆ alkyl group (the alkyl group is a halogen atom, a carboxyl group, C ₂
-C ₅ alkoxycarbonyl group, hydroxy group, C ₁ -C ₄ alkoxy group, CH (OR) ₂ (R means C ₁ -C ₄ alkyl group), phenyl group (the phenyl group is a halogen atom,
Optionally substituted with a hydroxy group or a C ₁ -C ₄ alkoxy group ), formyl group, cyano group or nitro group. }, C ₃ -C ₆
Cycloalkyl group (the cycloalkyl group is a halogen atom, a carboxyl group, a C ₂ -C ₅ alkoxycarbonyl group,
Hydroxy group, C ₁ -C ₄ alkoxy group, CH (OR) ₂ (R is C ₁ -C ₄
Means an alkyl group. ), A phenyl group (the phenyl group may be optionally substituted with a halogen atom, a hydroxy group or a C ₁ -C ₄ alkoxy group), a formyl group,
It may be optionally substituted with a cyano group or a nitro group. }, A phenyl group (the phenyl group may be optionally substituted with a halogen atom, a hydroxy group or a C ₁ -C ₄ alkoxy group), or C (= Y ¹ ) Z ¹ R ¹⁸ (Y ¹ is oxygen. Atom, sulfur atom or NR ¹⁹ (R ¹⁹ is a hydrogen atom, a cyano group,
It means a nitro group, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy. ), Z ¹ is an oxygen atom, a sulfur atom or
NR ²⁰ (R ²⁰ is a hydrogen atom, a C ₁ -C ₆ alkyl group (the alkyl group is a halogen atom, a carboxyl group, a C ₂ -C ₅ alkoxycarbonyl group, a hydroxy group, a C ₁ -C ₄ alkoxy group, CH (OR) ² (R means a C ₁ -C ₄ alkyl group), a phenyl group (the phenyl group may be optionally substituted with a halogen atom, a hydroxy group or a C ₁ -C ₄ alkoxy group) Optionally, substituted with a formyl group, a cyano group or a nitro group.}, A C ₃ -C ₆ cycloalkyl group {wherein the cycloalkyl group is a halogen atom, a carboxyl group, a C ₂ -C ₅ alkoxy group. Carbonyl group, hydroxy group, C ₁ -C ₄ alkoxy group, CH (OR) ₂ (R means C ₁ -C ₄ alkyl group), phenyl group (the phenyl group is a halogen atom, a hydroxy group or C may be optionally substituted by ₁ -C ₄ alkoxy group), Mill group may be optionally substituted by a cyano group or a nitro group.}, A phenyl group (the phenyl group, a halogen atom,
Optionally substituted with a hydroxy group or a C ₁ -C ₄ alkoxy group). R ¹⁸ is a hydrogen atom, a C ₁ -C ₈ alkyl group (the alkyl group is a halogen atom, a carboxyl group, a C ₂ -C ₅ alkoxycarbonyl group, a hydroxy group, a C ₁ -C ₄ alkoxy group , CH (OR) ₂ (R is C ₁
It refers to -C ₄ alkyl group. ), A phenyl group (the phenyl group may be optionally substituted with a halogen atom, a hydroxy group or a C ₁ -C ₄ alkoxy group), a formyl group, a cyano group or a nitro group. Good. }, C ₃ -C ₆ cycloalkyl group {wherein the cycloalkyl group is a halogen atom, a carboxyl group, a C ₂ -C ₅ alkoxycarbonyl group, a hydroxy group, a C ₁ -C ₄ alkoxy group, CH (OR) ₂ (R Means a C ₁ -C ₄ alkyl group), a phenyl group (the phenyl group may be optionally substituted by a halogen atom, a hydroxy group or a C ₁ -C ₄ alkoxy group), a formyl group, a cyano group. It may be optionally substituted with a group or a nitro group. }, A phenyl group (the phenyl group may be optionally substituted with a halogen atom, a hydroxy group or a C ₁ -C ₄ alkoxy group). Or R ¹⁵ and R ¹⁶ together form 1,4-butylene or 1,5-pentylene (the butylene and pentylene are each a C ₁ -C ₄ alkyl, a phenyl group (the phenyl group is Halogen atom, hydroxy group or C ₁ -C ₄ alkoxy group may be optionally substituted), halogen atom, OR ²¹ (R ²¹ is a hydrogen atom, C ₁ -C ₄ alkyl, COR ²² (R ²² is
Means C ₁ -C ₄ alkyl. ), A nitro group, SO ₃ H or PO ₃ H ₂ . ) Optionally substituted by)} or R ¹⁵ and R ¹⁶ together are (CH ₂ ) _O
X ⁷ (CH ₂ ) _P (O and P mean 1, 2 or 3, respectively, and the total thereof is 3, 4 or 5. X ⁷ is an oxygen atom, a sulfur atom, NR ²³ (R ²³ is hydrogen. Atom, C ₁ -C ₄ alkyl, phenyl group (the phenyl group is a halogen atom, a hydroxy group or C ₁
(Optionally substituted by -C ₄ alkoxy group)
Means ) Means. ), Or
R ¹⁵ and R ¹⁶ are taken together to form (CH ₂ ) _Q Z ¹ C (= Y ¹ ) (Q means 2, 3, or 4 and Z ¹ and Y ¹ have the same meanings as described above. ) Means. ] A compound represented by the following formula and its optical isomers, stereoisomers, and, when it is a compound capable of forming a salt, a therapeutic agent for heart failure containing a pharmaceutically acceptable salt thereof as an active ingredient.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/495 31/505 31/535 // C07D 491/052 7019-4C 498/04 101 513 / 04 301 (72) Inventor Kazuhiko Ikuyori 722 Tsuboi-cho, Funabashi-shi, Chiba 1 Central Research Laboratory, Nissan Chemical Industry Co., Ltd. In-house (72) Inventor Yukinori Masuda 1470 Shiraoka, Shiraoka-cho, Minamisaitama-gun, Saitama Nissan Chemical Industry Co., Ltd.

Claims (6)

[Claims] 1. Formula (I):(In the formula, X¹And X²Means absent or an oxygen atom
X is an oxygen atom, a sulfur atom, a nitrogen atom (the nitrogen atom
Is a hydrogen atom or C₁-C_FourMay be substituted with alkyl
I), C (O), C (S) or C (N-CN)
A; hydrogen atom, hydroxy group or OC (O) R^Five(R^FiveIs C₁-C
_FourMeans alkyl. ) Means or with B
Means a single bond; B means a hydrogen atom, or
Taken together means a single bond; R¹And R²Are the same as each other
Are different, hydrogen atom or C₁-C_FourMeans alkyl
Or R¹And R²Together, C₁-C_FourBy alkyl
Optionally substituted 1,4-butylene or 1,5-pepylene
Means nethylene; R³And R^FourAre the same or different from each other
Becomes, hydrogen atom, C₁-C₆Alkyl group of {the alkyl group
Is a halogen atom, carboxyl group, C₂-C_FiveAlkoxy
Carbonyl group, hydroxy group, C₁-C_FourAlkoxy group, CH
(OR)₂ (R is C₁-C_FourMeans an alkyl group. ), Phenyl
Group (the phenyl group is a halogen atom, a hydroxy group or
C₁-C_FourOptionally substituted by an alkoxy group
), Formyl group, cyano group or nitro group
It may be replaced at will. }, C₂-C₆Alkenyl group of
{The alkenyl group is a halogen atom, a carboxyl group,
C₂-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourA
Lucoxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
Optional), formyl group, cyano group or
It may be optionally substituted with a toro group. }, C₂-C₆
An alkynyl group of {the alkynyl group is a halogen atom,
Ruboxyl group, C₂-C_FiveAlkoxycarbonyl group, hydro
Xy group, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourArchi
Means a radical. ), A phenyl group (the phenyl group is
Rogen atom, hydroxy group or C₁-C _FourBy an alkoxy group
Optionally substituted), formyl group, cyano
Optionally substituted by groups or nitro groups
Yes. }, C₃-C₆Cycloalkyl group {the cycloalkyl group
Is a halogen atom, carboxyl group, C₂-C_FiveAlkoxy
Carbonyl group, hydroxy group, C₁-C_FourAlkoxy group, CH
(OR)₂(R is C₁-C_FourMeans an alkyl group. ), Phenyl
Group (the phenyl group is a halogen atom, a hydroxy group or
C₁-C_FourOptionally substituted by an alkoxy group
), Formyl group, cyano group or nitro group
It may be replaced at will. }, A phenyl group (the phenyl group
Group is a halogen atom, a hydroxy group or C₁-C_FourArco
Optionally substituted by a xy group), or C (=
Y) ZR⁶(Y is an oxygen atom, a sulfur atom or NR⁷(R⁷Is hydrogen
Child, cyano group, nitro group, C₁-C_FourAlkyl, C₁-C_FourArco
Kisshi or CO₂R⁸ (R⁸Is C₁-C_FourMeans alkyl. )
Means ), And Z is an oxygen atom or a sulfur atom.
Ku NR⁹(R⁹Is a hydrogen atom, C₁-C₆Alkyl group of {the al
Kill group is a halogen atom, carboxyl group, C₂-C_FiveAl
Coxycarbonyl group, hydroxy group, C₁-C_FourAlkoxy
Group, CH (OR)₂ (R is C₁-C_FourMeans an alkyl group. ), F
Phenyl group (the phenyl group is a halogen atom, a hydroxy group
Group or C₁-C_FourOptionally substituted by an alkoxy group
Group), a formyl group, a cyano group or a nitro group.
It may be optionally substituted. }, C₂-C₆Archeni
Group (the alkenyl group is a halogen atom, a carboxyl group
Base, C₂-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-
C_FourAlkoxy group, CH (OR)₂ (R is C₁-C_FourMeans an alkyl group
To do. ), A phenyl group (the phenyl group is a halogen source
Child, hydroxy group or C₁-C_FourOptionally by an alkoxy group
(May be substituted), formyl group, cyano group or
May optionally be substituted by a nitro group. }, C₂
-C₆An alkynyl group of
Child, carboxyl group, C₂-C_FiveAn alkoxycarbonyl group,
Hydroxy group, C₁-C_FourAlkoxy group, CH (OR)₂ (R is C₁-C
_FourMeans an alkyl group. ), A phenyl group (the phenyl
The group is a halogen atom, a hydroxy group or C₁-C_FourArcoki
Si group optionally substituted), formyl
Optionally substituted by groups, cyano groups or nitro groups
You may stay. }, C₃-C₆Cycloalkyl group (the cycloalkyl
The alkyl group is a halogen atom, a carboxyl group, C₂-C_FiveA
Lucoxycarbonyl group, hydroxy group, C₁-C_FourArcoki
Si group, CH (OR)₂ (R is C₁-C_FourMeans an alkyl group. ),
Phenyl group (the phenyl group is a halogen atom, a hydroxy group
Si group or C₁-C_FourOptionally substituted by an alkoxy group
, Formyl group, cyano group or nitro group
It may be optionally substituted. }, A phenyl group (the
Phenyl group is a halogen atom, hydroxy group or C₁-C_Four
Optionally substituted with an alkoxy group)
To taste. ) Means R⁶Is a hydrogen atom, C₁-C₈The alkyl
Group {the alkyl group is a halogen atom, a carboxyl group,
C₂-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourA
Lucoxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
Optional), formyl group, cyano group or
It may be optionally substituted with a toro group. }, C₂-C₆
An alkenyl group of {the alkenyl group is a halogen atom,
Ruboxyl group, C₂-C_FiveAlkoxycarbonyl group, hydro
Xy group, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourAl
Means a kill group. ), A phenyl group (the phenyl group is
Halogen atom, hydroxy group or C₁-C_FourOn an alkoxy group
More optionally substituted), formyl group, sia
May be optionally substituted by a nitro group or a nitro group
Yes. }, C₂-C₆An alkynyl group of
Rogen atom, carboxyl group, C₂-C_FiveAlkoxy carbo
Nyl group, hydroxy group, C₁-C_FourAlkoxy group, CH (OR)₂(R
 Is C₁-C_FourMeans an alkyl group. ), Phenyl group
(The phenyl group is a halogen atom, a hydroxy group or C₁
-C_FourOptionally substituted by an alkoxy group
), Formyl group, cyano group or nitro group
It may be replaced at will. }, C₃-C₆Cycloalkyl
Group {the cycloalkyl group is a halogen atom, carboxy
Lu group, C₂-C_FiveAlkoxycarbonyl group, hydroxy group, C
₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
To taste. ), A phenyl group (the phenyl group is a halogen source
Child, hydroxy group or C₁-C_FourOptionally by an alkoxy group
(May be substituted), formyl group, cyano group or
May optionally be substituted by a nitro group. }, H
Phenyl group (the phenyl group is a halogen atom, a hydroxy group
Group or C₁-C_FourOptionally substituted by an alkoxy group
Also means). ) Means or R³And R^FourTogether
Become 1,4-butylene or 1,5-pentylene (the butylene and
And pentylene are each C₁-C_FourAlkyl, phenyl group
(Arbitrarily halogen atom, hydroxy group, C₁-C_FourAlkyl
Optionally substituted by a coxy group), halogen
Atom, OR^Ten(R^TenIs a hydrogen atom, C₁-C_FourAlkyl, COR¹¹(R
¹¹Is C₁-C_FourMeans alkyl. ), Nitro group, SO₃H young
Or PO₃H₂Means ) Arbitrarily replaced by
May be used or R³And R^FourTogether (C
H₂)_mX^Four(CH₂)_l(m and l mean 1, 2 or 3 respectively
However, the total is 3, 4 or 5. X^FourIs an oxygen atom, sulfur
Atom, NR¹²(R¹²Is a hydrogen atom, C₁-C_FourAlkyl, phenyl
Group (the phenyl group is a halogen atom, a hydroxy group or
C₁-C_FourOptionally substituted by an alkoxy group
Meaning). ) Means. ), Or
R³And R^FourTogether (CH₂)_nZC (= Y) (n is 2, 3, younger
Means 4 and Z and Y have the same meanings as described above. )
means. ] And the optical isomers thereof
Body, stereoisomer, or compound capable of forming a salt
Treatment of heart failure with pharmaceutically acceptable salt as an active ingredient
medicine. 2. Formula (II):(In the formula, X⁶Means absent or an oxygen atom; X^FiveIs
Oxygen atom, sulfur atom or nitrogen atom (the nitrogen atom is hydrogen
Atom or C₁-C_FourWhich may be substituted with alkyl)
Taste; A¹Is a hydrogen atom, a hydroxy group or OC (O) R¹⁷(R¹⁷Is
C₁-C_FourMeans alkyl. ) Means; B¹Is a hydrogen atom
Means; R¹³And R¹⁴Are the same or different from each other and are hydrogen
Atom or C₁-C_FourMeans alkyl; R¹⁵And R¹⁶Each other
Same or different, hydrogen atom, C₁-C₆Alkyl group of
{The alkyl group is a halogen atom, a carboxyl group, C₂
-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourA
Lucoxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C _FourOptionally substituted by an alkoxy group
May be). ), Formyl group, shea
May be optionally substituted by a nitro group or a nitro group
Yes. }, C₃-C₆Cycloalkyl group {the cycloalkyl group
Is a halogen atom, carboxyl group, C₂-C_FiveAlkoxy
Carbonyl group, hydroxy group, C₁-C_FourAlkoxy group, CH
(OR)₂(R is C₁-C_FourMeans an alkyl group. ), Phenyl
Group (the phenyl group is a halogen atom, a hydroxy group or
C₁-C_FourOptionally substituted by an alkoxy group
), Formyl group, cyano group or nitro group
It may be replaced at will. }, A phenyl group (the phenyl group
Group is a halogen atom, a hydroxy group or C₁-C_FourArco
Optionally substituted by xy groups), or C (= Y
¹) Z¹R¹⁸(Y¹Is an oxygen atom, a sulfur atom or NR¹⁹(R¹⁹Is water
Elementary atom, cyano group, nitro group, C₁-C_FourAlkyl or
C₁-C_FourMeans alkoxy. ) Means Z¹Is oxygen source
Child, sulfur atom or NR²⁰(R²⁰Is a hydrogen atom, C₁-C₆of
Alkyl group (The alkyl group is a halogen atom,
Sil group, C₂-C_FiveAlkoxycarbonyl group, hydroxy
Base, C₁-C_FourAlkoxy group, CH (OR)²(R is C₁-C_FourAlkyl group
Means ), A phenyl group (the phenyl group is a halogen
Atom, hydroxy group or C₁-C_FourDepends on the alkoxy group
Optionally substituted), formyl group, cyano group
Or optionally substituted by a nitro group
Yes. }, C₃-C₆Cycloalkyl group {the cycloalkyl group
Is a halogen atom, carboxyl group, C₂-C_FiveAlkoxy
Carbonyl group, hydroxy group, C₁-C_FourAlkoxy group, CH
(OR)₂ (R is C₁-C_FourMeans an alkyl group. ), Phenyl
Group (the phenyl group is a halogen atom, a hydroxy group or
C₁-C_FourOptionally substituted by an alkoxy group
), Formyl group, cyano group or nitro group
It may be replaced at will. }, A phenyl group (the phenyl group
Group is a halogen atom, a hydroxy group or C₁-C_FourArco
Optionally substituted with xy groups)
It ) Means R¹⁸Is a hydrogen atom, C₁-C₈Alkyl group of
{The alkyl group is a halogen atom, a carboxyl group, C₂
-C_FiveAlkoxycarbonyl group, hydroxy group, C₁-C_FourA
Lucoxy group, CH (OR)₂(R is C₁-C_FourMeans an alkyl group
It ), A phenyl group (the phenyl group is a halogen atom,
Hydroxy group or C₁-C_FourOptionally substituted by an alkoxy group
Optional), formyl group, cyano group or
It may be optionally substituted with a toro group. }, C₃-C₆
Cycloalkyl group (the cycloalkyl group is a halogen atom
Child, carboxyl group, C₂-C_FiveAn alkoxycarbonyl group,
Hydroxy group, C₁-C_FourAlkoxy group, CH (OR)₂(R is C₁-C
_FourMeans an alkyl group. ), A phenyl group (the phenyl
The group is a halogen atom, a hydroxy group or C₁-C_FourArcoki
Si group optionally substituted), formyl
Optionally substituted by groups, cyano groups or nitro groups
You may stay. }, A phenyl group (the phenyl group is a halogen
Atom, hydroxy group or C₁-C_FourDepends on the alkoxy group
It may be replaced by any means). ) Means
Or R¹⁵And R¹⁶Together with 1,4-butylene or 1,5-pen
Tylene {The butylene and pentylene are each C₁-C_Four
Alkyl, phenyl groups (the phenyl group is a halogen source
Child, hydroxy group or C₁-C_FourOptionally by an alkoxy group
(May be substituted), halogen atom, OR^{twenty one}(R^{twenty one}Is water
Elementary atom, C₁-C_FourAlkyl, COR^{twenty two}(R^{twenty two}Is C₁-C_FourAlkyl
means. ), Nitro group, SO₃H or PO₃H₂Means
It ), Optionally substituted by
Ruka, R¹⁵And R¹⁶Together (CH₂)_OX⁷(CH₂)_P(O and P are
Each means 1, 2 or 3, but the sum is 3, 4
Or it becomes 5. X⁷Is oxygen atom, sulfur atom, NR^{twenty three}(R^{twenty three}Is water
Elementary atom, C₁-C_FourAlkyl, phenyl group (the phenyl group
Is a halogen atom, a hydroxy group or C₁-C_FourAlkoxy
Optionally substituted by a group). )
Means ) Or R¹⁵And R¹⁶Together
Become (CH₂)_QZ¹C (= Y¹) (Q means 2, 3, or 4
Then Z¹, Y¹Has the same meaning as described above. ) Means
It ] The compound and its optical isomer represented by
Isomers and, if it is a compound capable of forming a salt,
A therapeutic agent for heart failure comprising a pharmaceutically acceptable salt as an active ingredient. 3. In the formula (II), R ¹⁵ is a hydrogen atom and R ¹⁶ is
C (= Y ² ) NHR ²⁴ (Y ² is an oxygen atom, a sulfur atom or N-CN
Means R ²⁴ is a phenyl group, a benzyl group or C ₁ -C
₈ means an optionally branched alkyl. ) Is a therapeutic agent for heart failure according to claim 2. 4. In formula (II), R ¹⁵ and R ¹⁶ are taken together to form (CH ₂ ) _K NHC (= Y ³ ) (K is 2, 3 or 4; Y ³ is an oxygen atom or sulfur. It means an atom or N-CN.) The therapeutic agent for heart failure according to claim 2. 5. In the formula (II), R ¹⁵ and R ¹⁶ are both C ₁ -C.
_The therapeutic agent for heart failure according to claim 2, which is ₆ alkyl. 6. The therapeutic agent for heart failure according to claim 2, wherein in the formula (II), R ¹⁵ and R ¹⁶ together are (CH ₂ ) ₄ or (CH ₂ ) ₅ .