WO1997023209A1

WO1997023209A1 - Therapeutic agent for cardiac failure

Info

Publication number: WO1997023209A1
Application number: PCT/JP1996/003761
Authority: WO
Inventors: Keizo Tanikawa; Kazuhiko Ohrai; Masayuki Sato; Toru Yamashita
Original assignee: Nissan Chemical Industries, Ltd.
Priority date: 1995-12-25
Filing date: 1996-12-24
Publication date: 1997-07-03

Abstract

A therapeutic agent for cardiac failure comprising as the active ingredient either a benzopyran derivative represented by general formula (I) or a pharmacologically acceptable salt thereof, wherein R?1 and R2¿ each independently represent hydrogen, halogeno, nitro, cyano, amino, C¿1-6? alkylcarbonylamino, etc.; R?3 and R4¿ each independently represents hydrogen, C¿1-6? alkyl, or phenyl, or R?3 and R4¿ are bonded together to form C¿3-6? cycloalkyl in cooperation with the carbon atom bonded thereto; R?5¿ represents hydroxy, C¿1-6? alkoxy, or C1-6 alkylcarbonyloxy, or R?5¿ is bonded to R6 to form a bond; R6 represents hydrogen, or R6 is bonded to R5 to form a bond; and R?7 and R8¿ each independently represent hydrogen or C¿1-6? alkyl, or R?7 and R8¿ are bonded together to form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, etc. in cooperation with the nitrogen atom bonded thereto, or R?7 and R8¿ are bonded together to form, in cooperation with the nitrogen atom bonded thereto, pyrrole ring optionally substituted with R9 (where R9 has the same meaning as R1).

Description

Description Heart failure therapeutic drug Technical field

The present invention relates to the use of pharmacologically active benzopyran shoes for treating heart failure in mammals, including humans. Background art

JP-A-51-14777 (UK Patent No. 1 495 526, U.S. Pat.No. 4,048,317, JP-A-56-57778 ^ g Leaked Patent 2 No. 864, U.S. Pat.No. 4,336,811), Japanese Patent Application Laid-Open No. 56-57776 86

No. 49, U.S. Pat. No. 4,366,163), WO85001290 ^ (related patent 1

(57, 843, published ^^) discloses that benzopyran induction can be used in the treatment of JlilEE ^ but mentions the potential for treating heart failure. Absent.

Heart failure, which is a function of the heart, is a disease based on a decrease in cardiac fiber strength, and a drug that increases myocardial TO strength is used clinically to treat it. However, these ^ flJs are considered to have a problem with excessive consumption of myocardial energy based on the effect of increasing heart rate, and it is said that there is a problem with the postnatal improvement effect in long-term administration. Therefore, there is a demand for a drug that reduces the heart muscle energy consumption burden by reducing the heart rate. Disclosure of the invention

The present inventors have found that among the benzopyran derivatives, the antihypertensive effect is low and the heart rate is reduced. As a result of an exploratory search for the compound represented by the formula (I), it was found that the compound represented by the formula (I) has a strong bradycardia effect and was useful as a treatment for heart failure, and thus the present invention was made.

The present invention provides a compound of the formula (I)

[In the formula, R ¹ and 0¾2 are respectively: hydrogen atom, halogen atom, nitrocyanoformyl! ^ Amino d-alkyl amino di-C physician _β alkylamino C physician _β alkylcarbonyl § amino d -!, Alkylsulfonyl § amino ¾ Ami Nokarubo sulfonyl ¾ ^ alkyl § amino carboxymethyl sulfonyl ^ di ^ -, alkyl § Mino Cal Boniru alkyl Cal Poni group or C, -! a _β alkoxycarbonyl two Le group S *, and

! R |及cffi * are, respectively it: tmfc a hydrogen atom, c, alkyl ^ = properly is E a phenyl group * to whether or R 'and R ⁴ such in the H¾ go-between Ci - the «cycloalkyl group ,

R ⁶ represents a τ »¾C, alkoxy group or a Ci-« alkylcarbonyloxy group, or forms a bond with 〖± R ^e ,

Represents a hydrogen atom; ^ or becomes R ⁶ and H を to «I *

R ^T and U ^ each represent a hydrogen atom or a C, alkyl group, or R ^T and R «together with the atom to which they are attached, pyrrolidinyl, imi Dazolidinyl, birazolidinyl, biberidyl, piperazinyl, perhydroazepinyl, 1,3-oxazolidinyl, morpholinyl, 1,3-belhydroxazebine, 1,4-perhydrooxazepinyl, 1,3-thiazolidinyl, 1,4-peridin Hydrothiazolinyl, 1,3-perhydride α-thiazolidinyl, 1,4 Or a pyrrolyl ring optionally substituted by R ⁹ together with the nitrogen atom to which they are attached such that R ⁷ and R ⁸ are "" ^ (R ⁸ has the same meaning as R ^1. ) ] The benzopyran derivative represented by the formula (I) or a salt thereof that is H-tolerant is an active ingredient.

The compound provided by the present invention has a strong heartbeat-lowering effect, is effective in improving the ability of the patient, and can be used as a therapeutic agent for heart failure.

Next, each substituent of the compound (I) used in the present invention will be described more specifically. In this specification, "nj is the normal" ij means iso, the r _s j is secondary, RTJ is r _c "tertiary means cyclo.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Preferably, a fluorine atom, a chlorine atom and a bromine atom are mentioned.

- The _β alkyl group, methyl, Echiru, .pi.-propyl, i- propyl, n- Petit Le, i- butyl, s- butyl, t- butyl, 1-pentyl, 2-pentyl, 3-Benchiru, i- Pentyl, neobentyl, t-bentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-π-pentyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl Examples include -n-propyl and 3-dimethyl-n-butyl.

Preferably, methyl, ethyl, n-propyl, i-propyl, π-butyl and the like are mentioned.

C -! The _e alkoxy group, methoxy, ethoxy, .pi. Purobokishi, i- Puroboki shea, n- butoxy, i- butoxy, s- butoxy, t-butoxy, 1-Penchiruokishi, 2- Penchiruokishi, 3- Penchiruokishi, i-pentyloxy, neopentyloxy, t-bentyloxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 1-methyl-n-pentyloxy, 1,1,2-trimethyl-n-propoxy, 1, 2,2-trimethyl-n-propoxy and 3,3-dimethyl-n-butoxy.

Preferably, methoxy, ethoxy, π-propoxy and i-propoxy are preferred You.

C ₈ - The _e sik n alkyl group, Shikurobu port pills, cyclobutyl, cyclohexyl, and the like to Shikuropen chill and cycloalkyl. Preferably, cyclobutyl pill, cyclobutyl and cyclohexyl are used.

Examples of d- _e alkylamino groups include methylamino, ethylamino, n-propylamino, i-propylamino, c-propylamino, π-butylamino, i-butylamino, s-butylamino, t-butylamino, c-butylamino, and 1-pentylamino. 2-pentylamino, 3-pentylamino, i-pentylamino, neopentylamino, t-pentylamino, c-pentylamino, 1-hexylamino, 2-hexylamino, 3-hexylamino, c-hexylamino, 1- Methyl-n-pentylamino, 1,1,2-trimethyl-π-propylamino, 1,2,2-trimethyl-n-propylamino, 3 »3-dimethyl-n-butylamino and the like.

Preferably, methylamino, ethylamino, n-propylamino, i-propylamino and π-butylamino are used.

Examples of the dialkylamino group include dimethylamino, getylamino, di-n-propylamino, di-i-butylamino, di-C-α-pyramino, di-η-butylamino, di-i-butylamino, and di-s-amino. Butylamino, di-t-butylamino, di-C-butylamino, di-1-pentylamino, di-2-pentylamino, di-3-pentylamino, di-i-pentylamino, di-neopentylamino, di-t-amino Pentylamino, di-C-pentylamino, di-1-hexylamino, di-2-hexylamino, di-3-hexylamino, di-C-hexylamino, di- (1-methyl-n-pentyl) amino , Di-α, 2-trimethyl-η-propyl) amino, di- (1,2 »2-trimethyl-η-propyl) amino, di- (¾3-dimethyl-η-butyl) amino, methyl (ethyl) ) Amino, Methyl (η-propyl) Amino, Methyl (i-propyl) amino, methyl (c-propyl) amino, methyl (n-butyl) amino, methyl (i-butyl) amino, methyl (s-butyl) amino, Methyl (t-butyl) amino, methyl (c-butyl) amino, ethyl (n-propyl) amino, ethyl (i-propyl) amino, ethyl (c-propyl) amino, ethyl (n-butyl) amino, ethyl (i-butyl) amino, ethyl (s-butyl) amino, ethyl (t-butyl) amino, ethyl (c-butyl) amino, π-propyl (i-propyl) amino, n-propyl (c-propyl) amino N-Propyl (π-butyl) amino, n-propyl (i-butyl) amino, n-propyl (s-butylin) amino, n-propyl (t-butyl) amino, Π-propyl (c-butyl) amino Amino, i-propyl (c-propyl) amino, i-propyl (n-butyl) amino, i-propyl (i-butyl) amino, i-propyl (s-butyl) amino, i-bromo (t- Butyl) amino, i-p α-pill (c-butyl) amino, c-propyl (η-p Le) amino, c-propyl (i-butyl) amino, c-propyl (s-butyl) amino, c-butyl α-pill (t-butyl) amino, C-propyl (c-butyl) amino, n- Butyl (i-butyl) amino, π-butyl (S-butyl) amino, n-butyl (t-butyl) amino, π-butyl (c-butyl) amino, i-butyl (s-butyl) amino, i- Butyl (t-butyl) amino, i-butyl (c-butyl) amino, S-butyl (t-butyl) amino, s-butyl (c-butyl) amino, t-butyl (c-butyl) amino, etc. I can do it.

Preferably, dimethylamino, getylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino are used.

Examples of the dealkylcarbonylamino group include methylcarbonylamino, ethylcarbonylamino, π-propylcarbonylamino, i-propylcarbonylamino, π-butylcarbonylamino, i-butylcarbonylamino, and s-butyl. Carbonylamino, t-butylcarbonylamino, 1-pentylcarbonylamino, 2-pentylcarbonylamino, 3-pentylcarbonylamino, i-pentylcarbonylamino, neopentylcarbonylamino, t-pentylcarbonylamino, Examples thereof include 1-hexylcarbonylamino, 2-hexylcarbonylamino, and 3-hexylcarbonylamino. Preferably, methylcarbonylamino, ethylcarbonylamino, π-propylαcarbonylcarbonylamino, i-propylcarbonylamino, and n-butylcarbonylamino are exemplified.

Examples of the _β- alkylsulfonylamino group include methylsulfonylamino, ethylsulfonylamino, η-propylsulfonylamino, i-propylsulfonylamino, n-butylsulfonylamino, i-butylsulfonylamino, s -Butylsulfonylamino, t-butylsulfonylamino, 1-pentylsulfonylamino, 2-pentylsulfonylamino, 3-pentylsulfonylamino, i-pentylsulfonylamino, neopentylsulfonylamino, t-pentylsulfonylamino Mino, 1-hexylsulfonylamino, 2-hexylsulfonylamino, 3-hexylsulfonylamino and the like; ^.

Preferred examples include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, i-propylsulfonylamino, and n-butylsulfonylamino.

Examples of the alkylaminocarbonyl group include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, i-propylaminocarbonyl, n-butylaminocarbonyl, i-butylaminocarbonyl, and s-butylamino. Carbonyl, t-butylaminocarbonyl, 1-pentylaminocarbonyl, 2-pentylaminocarbonyl, 3-pentylaminocarbonyl, i-pentylaminocarbonyl, neopentylaminocarbonyl, t-pentylaminocarbonyl, Examples include 1-hexylaminocarbonyl, 2-hexylaminocarbonyl, and 3-hexylaminocarbonyl.

Preferably, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, i-propylaminocarbonyl and n-butylaminocarbonyl are used. Examples of dialkylaminocarbonyl groups include dimethylaminocarbonyl, diethylaminocarbonyl, di-π-propylaminocarbonyl, di-i-propylaminocarbonyl, di-C-propylaminocarbonyl, di-n- Butylaminocarbonyl, di-i-butylaminocarbonyl, di-s-butylaminocarbonyl, di-t-butylaminocarbonyl, di-C-butylaminocarbonyl, di-1-pentylaminocarbonyl, Di-2-bentylaminocarbonyl, di-3-pentylaminocarbonyl, di-i-pentylaminocarbonyl, di-neopentylaminocarbonyl, di-t-pentylaminocarbonyl, di-C-pentyl Aminocarbonyl, di-1-hexylaminocarbonyl, di-2-hexylaminocarbonyl, di-3-hexylaminocarbonyl and the like. Can be

Preferably, dimethylaminocarbonyl, acetylaminocarbonyl, di-π-propylaminocarbonyl, di-i-propylaminocarbonyl, di-C-propylaminocarbonyl, di-n-butylaminocarbonyl Is reduced.

The C have _e alkyl group, methylcarbonyl, E chill carbonyl, n- propyl carbonyl, i- propyl carbonyl, n- Puchirukaruponiru, i- butyl carbonyl, s- butylcarbonyl, t- butyl, 1- pentylcarbonyl , 2-pentylcarbonyl, 3-pentylcarbonyl, i-pentylcarbonyl, neopentylcarbonyl, t-pentylcarbonyl, 1-hexylcarbonyl, 2-hexyl carbonyl, and 3-hexylcarbonyl Can be

Preferably, methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, i-propyl carbonyl and II-butyl carbonyl are used.

Examples of the dealkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, and 1-butoxycarbonyl. Pentyloxycarbonyl, 2-pentyloxycarbonyl, 3-pentyloxyka Luponyl, i-pentyloxycarbonyl, neopentyloxycarbonyl, t_pentyloxycarbonyl, 1-hexyloxycarbonyl, 2-hexyloxycarbonyl, 3-hexyloxycarbonyl, etc.

Is mentioned.

Preferably, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i_butoxycarbonyl, s-butoxycarbonyl and t-butoxycarbonyl are exemplified.

Preferred compounds used in the present invention include the following compounds.

(1)

Ri and o- ² are each a hydrogen atom, a hydrogen atom, a logen atom, a nitro group, a cyanoformyl amino group, a C-alkylamino group, a di-dealkylamino group, and a Cl-6 alkylcarbonylamino group. A minocarbonyl group, a _β- alkylaminocarbonyl group or a di-C ((alkylaminocarbonyl group;

R ⁸ and R ⁴ are each independently a -alkyl group or a C ₈ _-e cycloalkyl group together with the atoms to which R ^s and R ⁴ are attached, and

R ⁶ is meant bonded in or R ^e and one cord means hydroxyl group or _d-e alkyl carbonylation Ruokishi group,

R ^e represents a hydrogen atom or together with R ⁶ a bond,

R ⁷及0¾ ^beta is, do you mean respectively elevational a hydrogen atom or a _d-e alkyl group, a pyrrolidinyl together with the nitrogen atom to which they become R ⁷ and R ⁸ gar cord is attached, I Mi Dazorijiniru , Bisazolidinyl, piperidyl, piberazinyl, morpholinyl, 1,3-thiazolidinyl group, or R ⁷ may be optionally substituted with R ⁷ together with the nitrogen atom to which they are attached A benzopyran derivative represented by the formula (I) or a pyrrole ring (R ^e has the same meaning as R ¹ ): Pharmaceutically acceptable salts of

(2)

R ⁷ and R ⁸ together form a pyrrolidinyl, imidazolidinyl, virazolidinyl, piperidyl, piperazinyl, morpholinyl group together with the nitrogen atom to which they are attached, or ΙΓ and R ⁸ together nitrogen atom linked co a R ^e optionally substituted which may be pyrrole ring by (R ⁸ has the same meaning as R ^1.) the to the (1) compound described.

(3)

It said R ⁸及0¾ ⁴ are the same _d-e alkyl group (2) compounds according.

(Four)

R ² is a hydrogen atom, Bruno, androgenic atom, Shiano Amino C, - an _e alkylcarbonylamino § iminocarbonyl _{d-e-alkylaminocarbonyl} group or gripping ^ § Le kills aminocarbonyl group (3) word S mounting the reduction ^ .

(Five)

R ² is a hydrogen atom, a halogen atom, an amino group or a C, - ₆ alkyl carbonyl § amino group above (4) according spoon ^.

(6)

R ¹ is a hydrogen atom, hagen atom, nitro cyano formyl amino

C is _beta alkylamino! ^ Di de alkylamino ¾ ^ - _beta alkylcarbonyl amino § amino carbonyl group, C -! A _e alkylcarbonyl § amino group or a di CI- _e Aruki Rua amino group (5) compounds according.

(7)

R ¹ is a hydrogen atom, a nitro group, Shiano ¾ ^ C physician _β alkylcarbonyl § amino group, amino Nokarubo sulfonyl ^ - is a _β alkyl § amino carbonyl or grip _d-6 Arukiruamino force Ruponiru group (6>, wherein Compound. (8)

The compound according to the above (7), wherein R ² is a hydrogen atom.

(9)

R ¹ is a hydrogen atom, R ² is methylcarbonyl § amino R ^s及0¾ ⁴ is methyl R ⁶ is water, R ^e is a hydrogen atom,驟which R ⁷及Arufa¾ ^beta are attached they Te summer together A benzopyran derivative represented by the formula (I) which is a pyrrolidinyl group together with an atom, or a freshly acceptable salt thereof.

(Ten)

Ri is nitro! ^ R ² is methylcarbonylamino R ⁸ and R ⁴ are methyl R ⁶ is a hydroxyl group, ^Re is a hydrogen atom, and R ⁷ and R ⁸ are A benzopyran derivative represented by the formula (I), which is a pyrrolidinyl group together with a nitrogen atom, or a pharmaceutically acceptable salt thereof.

(11)

R ¹ is Nitro R ² is Amino! ^ R ⁸及^ ⁴ is a methyl group, R ⁶ is ^ Βί R ^e is hydrogen atom, taken R ⁷ and R ⁸ guard ^ is H. Jiniru group together with the nitrogen atom to which they are attached formula Benzopyran-induced or pharmaceuticals represented by (I) ± tolerable ^ ULO

(12)

R ¹ is nitro R ² is a hydrogen atom, R ⁸ and R ⁴ is methyl R ⁶ is hydroxyl R ^e is hydrogen atom, together with the nitrogen atom to which R ^T及Y¾ ⁸ are attached they become H¾ A benzopyran derivative represented by the formula (I), which is a pyrrolidinyl group, or a pharmaceutically acceptable salt thereof.

(13)

R 'is Nito. R ² is?! Elementary atom, R ³ and R ⁴ are methyl R ⁶ is hydroxyl! ^ R ^e is a hydrogen atom, together with the nitrogen atom to which they become R ⁷及0¾ ⁸ guard cord is attached to the R » A benzopyran derivative represented by the formula (I), which means an optionally substituted pyr σ-ring (R ^e has the same meaning as R ¹ ), or ¾ ^ 0 ^

In the following, chemical compounds that can be used in the present invention! Specific examples are shown below, but the present invention is not limited thereto. Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, Bu represents a butyl group, and Ac represents an acetyl group (COCH ₈ ).

One 1 — ゥ

R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ R ⁷ R ⁸ -N0 ₂ H Me Me OH H Me Me-N0 ₂ H Me Me OH H Et Et-N0 ₂ H Me Me OH H-(CH ₂ ) ₄ --N0 ₂ H Me Me OH H-(CH ₂ ) ₃ --N0 ₂ H Me Me OH H-(CH ₂ ) ₆ -μ nι Mo Ivlc Jf C π l レ π ₂ --N0 ₂ H Et Et OH H Me Me-N0 ₂ H Me Me OH H Me Me-N0 ₂ H Me Me OH H Et Et-N0 ₂ H Me Me OH H-(CH ₂ ) ₄ --N0 ₂ H Me Me OH H-(CH ₂ ) ₅ --N0 ₂ H Me Me OH H-(CH ₂ ) ₆ --N0 ₂ H Me Me OAc H-(CH ₂ ) ₃ --N0 ₂ H Et Et OH H Me Me -N0 ₂ 7-AcHN Me Me OH H-(CH ₂ ) ₄ --N0 ₂ 7-NH ₂ Me Me OH H-(CH ₂ ) ₄ --AcHN 7-N0 ₂ Me Me OH H-(CH ₂ ) ₄ --NH ₂ 7- _{N0 2 Me Me OH H - (} CH 2) 4 -

-NH ₂ H Me Me OH H Me Me-NH ₂ H Me Me OH H Et Et-NH ₂ H Me Me OH H-(CH ₂ ) ₄ --NH ₂ H Me Me OH H-(CH ₂ ) _3- -NH ₂ H Me Me OH H-(CH ₂ ) ₆ --NH ₂ H Me Me OAc H-(CH ₂ ) ₃ --NH ₂ H Et Et OH H Me Me -NH ₂ H Me Me OH H Me Me -NH ₂ H Me Me OH H Et Et -NH ₂ H Me Me OH H-(CH ₂ ) ₄ --NH ₂ H Me Me OH H-(CH ₂ ) ₃ --NH ₂ H Me Me OH H-( CH2) ₆ --NH ₂ H Me Me OAc H-(CH ₂ ) ₃ --NH ₂ H Et Et OH H Me Me-AcHN H Me Me OH H Me Me-AcHN H Me Me OH H Et Et-AcHN H Me Me OH H-(CH ₂ ) ₄ --AcHN H Me Me OH H-(CH ₂ ) ₅ --AcHN H Me Me OH H-(CH ₂ ) ₆ --AcHN H Me Me OAc H-(CH ₂ ) ₃ --AcHN H Et Et OH H Me Me

-AcHN H Me Me OH H Me Me-AcHN H Me Me OH H tl tt-AcHN H Me Me OH H "(CH ₂ ) ₄ --AcHN H Me Me OH H-(CH ₂ ) ₃ --AcHN H Me Me OH H-(CH ₂ ) ₆ --AcHN H Me Me OAc H-(CH ₂ ) ₅ --AcHN H Et Et OH H Me Me

6-NH ₂ H n-Pr n-Pr OH H Me Me

6-NH ₂ H-(CH ₂ ) ₂ -OH H Et Et

_{_{6-NH 2 7-N0 2}} - (CH 2) 2 - OH H - (CH 2) 4 -

6-N0 ₂ H-(CH ₂ ) ₄ -OH H-(CH ₂ ) _3-

6-N0 ₂ H n-Pr n-Pr OAc H-(CH ₂ ) _6-

6-N0 ₂ 7-AcHN n-Bu n-Bu OH H Me Me-AcHN H n-Pr n-Pr OH H-(CH ₂ ) ₄ --AcHN H-(CH ₂ ) ₄ -OAc H-(CH _{_{2) 4 - -AcHN 7-N0}} 2 - (CH 2) 2 - OH H - (CH 2) 4 -

1 Λ

— ゥ

R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ R ⁹ -AcHN H Me Me OH H 3'-Me-AcHN H Me Me OH H H-AcHN H Me Me OH H 3'-Br-AcHN H Me Me OH H 3'-F-AcHN H Me Me OH H CHO-AcHN H Me Me OAc H H-AcHN H Et Et OH HH -NH ₂ H n-Pr n-Pr OH H 2'-Me -NH ₂ H-( CH ₂ ) ₂ -OH H 3'-Et

6-NH ₂ 7-N0 _2- (CH ₂ ) ₂ -OH H 2'-Me -N0 ₂ H-(CH ₂ ) ₅ -OH HH -N0 ₂ H Me Me OAc HH

6-N0 ₂ 7-AcHN n-Bu n-Bu OH H 3'-Me

7-N0 ₂ H Me Me OH H H-AcHN H n-Pr n-Pr OH H 2'- e-AcHN H-(CH ₂ ) ₅ -OAc H 3'-Br-AcHN 7-N0 ₂ Me Me OH HH The compound KKl used in the present invention has asymmetry at the 3- and 4-positions of the silane ring, and there is an optical isomer based on the asymmetric weave. Can be used for applications. The relative configuration of the 3- and 4-positions of the pyran ring is trans. When the salt can be formed, a freshly acceptable salt can also be used as the active ingredient.

Next, a method for producing the compound used in the present invention will be described.

-, represented reduction ^ R ⁷及0¾ * is each it out of the by (I); h ^ & fi to the hydrogen atoms properly - they become the «or an alkyl group or R ^T and R ^e Pyrrolidinyl, imidazolidinyl, birazolidinyl, piperidyl, piperazinyl, perhydroazepinyl, 1,3-oxazolidinyl, morpholinyl, 1,3-perhydrooxazepinyl, 1,4-perhydrooxy with attached ^ ^ atoms Sazepinyl, 1,3-thiazolidinyl, 1,4-perhydrothiazolinyl, 1,3-perhydroαthiazolidinyl, 1,4-perhydrothiazolidinyl group (H »S¾i (IV) Is represented by HK¾ (U), as shown by ®S ® below! It can be obtained by inactivating 化 ^ which is represented by and と δ¾ (Ι 〖Ι). In the formula (〖V), R ⁶ is a fiber group, and R * is a hydrogen atom.

(Π) (IV) i (formation represented by ID ^ and "^ (iii) Examples of the solvent used for the above include the following.

Sulfoxides represented by dimethylsulfoxide, amides represented by dimethylformamide or dimethylacetamide, ethers, dimethoxyethane or ethers represented by tetrahydrofuran, dichloromethane, Halogen compounds represented by oral form and dichloroethane, and alcohol compounds represented by methanol, ethanol, or propanol are obtained. You can also perform ^; Preferably, an alcohol solvent is used.

The Sitv Sitl usually ranges from 20 to the difficulty of the machine used, preferably from 60 to 100.

As for the molar ratio of the raw materials, the chemical formula (III) and the chemical formula (I) are in the range of 0.5 to 0, and preferably in the range of 1.0 to 2.0.

Compounds represented by Hl¾¾ (II) can be prepared by known methods (eg, J. Med. Chem. 1 9 8 3, 26, 15 8 2 and J. Med. Chem. 19) 8 4, 2 7, 1 1 2 7).

In the compound represented by HIS¾ (I), R ⁷ and R * are linked together to form a pyrrole ring together with the nitrogen atom to which they are attached ^ (~ ^ (νΐ). ) Is obtained by centering the compound represented by (II) and the compound represented by "^ (V) ^ under a base as shown by the following. In the formula (V 〖), R ⁶ is a τ Κ group, and R ^{e is a} hydrogen atom _c

(ID (VI) Solvents used for the compound represented by (II) and the compound represented by "^ (V)" include the following.

Sulfoxides represented by dimethylsulfoxide ^ !, amide solvents represented by dimethylformamide or dimethylacetamide, ether solvents represented by ethyl ether, dimethoxyethane or tetrahydrofuran, dichloropimethane, chloromethane Mouth Holm, represented by dichloroethane. Examples include alcoholic solvents typified by genous, methanol, ethanol, or propanol. Also, sis can be performed without solvent. Preferably, sulfoxide and amide solvents are used.

Examples of the base include sodium hydride, hydrogen hydride, and lithium t-butoxide, and preferably sodium hydride.

Sf SKiiii atmospheric - 2 is up to the reaction solvent used from 0, the preferred properly 0 'C～6 is 0 ^e C.

As for the molar ratio of the raw materials, the ratio of base / compound (V) is in the range of 0.5 to 2.0, and preferably in the range of 1.0 to 1.5.

The molar ratio of the raw materials is such that compound (V) / compound (II) is in the range of 0.5 to 2.0, preferably in the range of 1.0 to 2.0.

-Λ ^ ζ (I) represented by ^! Of which R ^T and R ^e become, which together form the pyrrole ring with the nitrogen atom to which they are bonded, represented by H ^ (VI), is represented by Thus, the conversion of a compound represented by (VII) to (a compound of (II) into a compound of (VII)) which is easily obtained by treating (II) with ammonia is «I, for example, IifiR according to the method described in JP-A-58-67683, JP-A-58-18880 and JP-A-58-2101776 ^. Yes.) And

The compound represented by (VI II) can be obtained in the presence of Can be In the formula (V 〖), R ⁶ is a group, and R ^e is a hydrogen atom.

(VII) (VI) Chemical ^! The following Nadas are used for SJS of (VII) and Chemical (VI II). Sulfoxides represented by dimethylsulfoxide ^^ Amides based on dimethylformamide or dimethylacetamide, ethers based on ethyl ether, dimethoxyethane, or ethers based on tetrahydrofuran.Represented by dichloromethane, chloroform, and dichloroethane. It is also possible to perform ^ with a halogen-based compound or with ^. Also, ljSitt may be used as it is as a solvent.

SJSSEtiii Normally from ice-cooled to used.

The SJSW molar ratio is: ^^ (VIII) / ^^! (VU) is in the range of 0.5 to 4.0, preferably (gffl) of 1.0 to 2.0.

For use, m-fiber and propionic acid are used.

-, (vn), the optical compound is synthesized by a method of optically resolving a racemate (Japanese Patent Application Laid-Open No. 8-141,286, US Pat. No. 5,097,037) issue

Is done. In addition, the synthesis of the photopolymer represented by the formula (10) is performed by asymmetric synthesis.

1 g The method is disclosed by using the method (Japanese Patent Laid-Open No. Hei 5-3108778, KfcH "(Patent No. 5357377, published US Pat. No. 5,420,314 ^^).

As described above, the present inventors have found that the compound represented by-^ (I) has a strong heart rate effect. It has no heart rate-lowering effect because it is not used for production. Can be Therefore, the compound according to the present invention is also useful for the treatment of cardiac HUfiL tract disease taking into account metabolism, oxygen consumption or energy consumption related to heart movement, and treatment mainly considering heart rate decreasing action. Is expected. For example, tSX in mammals including humans, as a drug for deficiency, or in the reversal of cardiovascular disease that induces heart failure, such as ぱ ^ jfii ¾¾ ¾¾ mm, mm im, lung ΙΜΕ ΙΜΕ 治、, ^ m m .

It is useful as a therapeutic agent, for controlling myocardial diseases, for controlling lungs, for exertion, for controlling rnmu myocardial infarction, and as an active agent.

The present invention provides a medicament comprising an effective amount of a compound of formula (I) for these treatments.

Examples of the dosage form of the compound according to the present invention include parenteral administration by mm (subcutaneous, intravenous, intramuscular, intraperitoneal injection), ointment, suppository, aerosol, etc., or capsule, granule, Oral administration by syrup u, liquid preparation, mu suspension, etc. can be provided.

The above-mentioned pharmaceutical or non-pharmaceutical products containing the compound according to the present invention contain the compound of the present invention in an amount of about 0.01 to 99.5%, preferably about 0. 1-30

%.

Other pharmaceutically or silently active compounds can be included in the compounds according to the invention or in addition to the authentics containing said compounds. These objects can include a plurality of compounds according to the present invention. The clinical dosage of the compounds provided in the present invention may be increased or decreased depending on age, body weight, patient's condition, fiber of symptoms or administration method. Usually the effective dose is 0.001 mg / kg to 50 mg / k daily, preferably 0.01 mgZKg to 20 mg / kgSS. However, amounts outside the above range can also be used depending on

The compounds provided by the present invention are formulated for administration by pharmaceutical means. That is, capsules, granules, and pills for oral administration are excipients, such as sucrose, lactose, glucose, starch, mannitol; binders, such as hydroxypropyl cellulose, syrup, gum arabic, and gelatin. Sorbitol, tragacanth, methylcellulose, polyvinylpyrrolidone; disintegration, for example, starch, carboxymethylcellulose or its calcium salt, microcrystalline cellulose, polyethylene glycol; lubricating, for example, talc, magnesium or calcium stearate, silicic acid Force; prepared using lubricants, such as sodium laurate, glycerol, etc. mm, solutions, emulsions, suspensions, syrups and aerosols are solvents for pirates, such as water, ethyl alcohol, isopropyl alcohol , Propylene glycol, 1,3-butane Lenglycol, polyethylene glycol; surfactant, for example, sorbitan H fatty acid ester, polyoxoxylene sorbitan B fatty acid ester, boroxixylene fatty acid ester, hydrogenated castor oil boroxixylene Teru, lecithin; hanging drops such as carboxymethyl sodium salt, cellulose-induced tragacanth such as methylcellulose, natural gums such as gum arabic; preservatives such as esters of paraoxybenzoic acid, benzalkonium chloride, sorbic acid salt, etc. It is prepared by

For example, white vaseline, fine fiber paraffin, high-grade alcohol, macrogol soft blue, mm, aqueous gel base, etc. are used for the ointment which is a pure adjuvant. Suppositories are, for example, cocoa butter, polyethylene glycol, lanolin, fatty acid triglycerides. It is prepared using celite, coconut oil, borisorbate, etc. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail using difficult examples, but the present invention is not limited to these examples.

Synthesis example 1

^ ims, 4-epoxy-1,3,4-dihydro-2,2-dimethyl-7-two-row 2H-1 1-benzopyran

2,2-dimethyl-7-nitro- 1 H-benzopyran (1.026 g, 5.0 mmo 1), 4-phenylpyridine-N-oxide (17.lmg, 0.1 Ommo 1), manganese-salen ^ (IX) (See ^ UX below)) 51.8 mg. 0.05 mmo 1 (this compound is known and can be synthesized according to US Pat. No. 5,420,814) in methylene chloride (7.5 ml) and sodium acid 3.4 m 1 at 0 (1.77mo 11) for 10 minutes. After 1 hour, 0.6 ml of sodium phosphate was added, and 2 hours later, 0.3 ml of sodium acid was added. The mixture was further stirred at 0'C for 1 hour. After separating the methylene salt from Shii-Dani, 7k® was extracted twice with a black-mouthed form. After combining β with β and purifying with water “e¾fe” and performing I ^ with sodium acid, the residue was distilled off to obtain a brown oil. The oil: ^ was subjected to silica gel column chromatography (elution).鹏, Hexane: diethyl = 9: 1 (v / v)) mm ^^ (1.026 g, 93%) was obtained as oil: ^ quality. ^l H-NMR (CDCl ₈ ) <5: 1.27 (s, 3H), 1.59 (s, 3H), 3.48 (d, J = 4.5Hz,), 3.89 (d, J = 4.5Hz, 1H), 7.32 ( d, J = 8Hz, 1H), 7.48-7.81 (m, 2H)

Optical purity> 995¾ [Column: Chiral Cell OJ (manufactured by Daicel F ^ Industry), mobile phase: Hexane Zisov-panorol = / K Detection wavelength: 254 nm, Flow rate: 0.5 ml Z min, Column temperature: 40 ^e C, retention time: 17.0 minutes (35.9 minutes for light-active substances)]

Synthesis example 2

3,4-dihydro-2,2-dimethyl-1-6-nitro-trans-1-4-1 (1-pyrrolidinyl) 1-2H-1-1-benzopyran-1-3-ol

3,4-epoxy-1,3,4-dihydro-2,2-dimethyl-6-two-trough 2H-1 1 Benzopyran (79 Omg, 8.6 mmo 1) dissolved in ethanol (9 ml) After dissolving, pyrrolidine (450 jti 1, 5.4 mmo 1) was added, and the mixture was heated for 1 hour. After ^ J to room temperature, Nada was distilled off to obtain brown oil: ^ quality. This oil is subjected to silica gel column chromatography (elution solvent, hexane: ff¾S? Ethyl -5: 1 (V / V)). (624 mg, 59½) was obtained as ¾fe crystals.

lH-N R (CDCl ₈ ) δ: 1.26 (s, 3H), 2.03 (s, 8H), 1.75-2.05 (¾H), 2.71-3.19 (5H), 3.55 (d, J = 10Hz, 1H ), 3.99 (d, J = 10Hz, 1H), 6.75 (4 J = 9Hz, 1H), 7.78-7.83 (¾ 2H)

MS: 292 (M ⁺ ), 221 (禱, 203 (53¾), 163 (43¾)

Synthesis example 3

6-Acetylamino-3,4-dialdehyde α-2,2-Dimethyl-1-trans-1- (1-pyrrolidinyl) -1 2H-1-Venzopyran-1-3-ol

6-Acetylamino-3,4-epoxy-1,3,4-dialdehyde π-2,2-Dimethyl-2Η-1 Benzopyran (96 Omg, 4.lmmo 1) was dissolved in ethanol (20 ml), and then dissolved in ethanol (20 ml). α-lysine (410, 4.9 mmo 1) was added, and the clinic was held for 1.5 hours. After cooling to room temperature, the solvent was distilled off to obtain a brown oily substance. The oil was subjected to silica gel column chromatography (elution f, methanol: ethyl = 20: 1 (V / V)) ^ it (1.229 g 9896) as yellow crystals. 'H-NMRCCDCh) δ: 1.20 (s, 8H), 1.48 (s, 3H), 1.71- ^ 21 (in, 4H), 2.11 (s, 3H), 2.68-3.23 (¾5H), 3.51 (d , J = 10Hz, IH), 3.92 (d, J = 10Hz, IH), 6.64 (d, J = 9Hz, IH), 6.84-7.09 (¾IH), 7.12-7.42 (nv IH), 7.51-7.67 ( m, IH)

MS: 304 ( ⁺ ), 232 (return, 173 (45¾)

Synthesis example 4

6-Acetylamino-3,4-dihydro-2,2-dimethyl-trans-1-4-1 (1-pyrrolidinyl) -2H-1 Benzopyran-1-3-ol

7-Acetylamino-8,4-epoxy-1,3,4-dihydro-2,2-dimethyl-1-6-nitro-1H-1-benzopyran (606 mg, 2.2 mmo1) was dissolved in ethanol (23 ml). Thereafter, pyrrolidine (275/1, aSmmo 1) was added and the mixture was heated for 1 hour. After cooling to room temperature, the separation was distilled off to obtain a brown oily substance. The oily substance was subjected to silica gel column chromatography (eluted with hexane: uglyethyl = 3: 1 (V / V)) to obtain 化 (58 2 mg, 76%) as ^ crystals.

(H-NMRCCDCh) 6: 1.25 (s, 8H), 1.52 (s, 3H), 1.70-2.12 (¾ 4H), 2.22 (s, 3H), 2.83-3.16 (¾ 5H), 3.50 (d, J = 10Hz _f 1H), 3.93 (d, J = 10Hz, IH), 8.10 (s, 2H), 10.33-10.56 (brs, IH)

MS: 350CM + 1), 277α00¾), 232 (68¾) _f 162 (56¾) Synthesis example 5

6-Acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-trans-1-41- (1-pyrrolidinyl) -1 2H-1-benzopyran-1 3-ol

6-Acetylamino-3,4-epoxy-1,3,4-dihydro-2,2-dimethyl-7-Nitro 2H-1 Benzopyran (1.11 g, 4.0 mmo 1) dissolved in ethanol (2 Oml) After that, pyrrolidine (0.57 g, 8.0 mmo 1) was added and the mixture was heated for 1 hour. After cooling to room temperature, Nada was distilled off to obtain a brown oily substance. This oil was subjected to silica gel column chromatography.

(Eluted person, hexane :, ethyl = 2: 1 (v / v)) i ^ (i 97 mg, 14%) was obtained as crystals.

lH-wake (CDC1,) δ: 1.22 (s, 3H), 1.49 (s, 8H) _f 1.75-2.08 (m, H), 2.21 (s, 3H), 2.62-3.29 (¾ 5H), 3, 50 (d, J = 10Hz, IH), 3.95 (d, J = 10Hz, IH), 7.47 (s, IH), 8.54 (s, IH), 9.62-10.02 (brs, IH)

MS: 349 (M ⁺ ), 277 (100¾), 218 (41¾), 162 (2850 Synthesis Example 6

6-Amino-3,4-dihydro-2,2-dimethyl-7-Nitro-trans-1-4-1 (1-pi α-ridinyl) -1 2Η-1 Benzopyran-1 3-ol

6-Acetylamino-3,4-dihydro-2,2-dimethyl-7-nitrothranth 4- (1-pi-α-ridinyl) -1-2H-1-benzovirane-3-ol (2.54 g, 7.3mmo1) ) Was dissolved in ethanol (2 Oml), 3% i (1.50 g) and water (1.5 g) were added, and the mixture was heated for 2 hours. After ^ ifl to room temperature, water was added, the mixture was neutralized with an aqueous solution of sodium hydrogen difficult, and extracted four times with a black-mouthed form. The solvent was distilled off after the combined form layers were combined and observed with sodium acid. The obtained residue was subjected to silica gel column chromatography (elution, hexane: ethyl acetate = 1: 2 (V / V)) to give the title compound (2.22 g, 99%) as brown feijg crystals. Was.

'H-NM CCDCh) δ: 1.20 (s, 3H), 1.46 (s, 3H), 1.65-2.20 (¾ 4H), 2.71-3.26 (ι¾ 5H), 8.63 ((ί J = 10Hz, 1H), 4.43 (d, J = 10Hz, 1H), 5.54-6.05 (brs, 2H), 6.88 (s, 1H), 7.46 (s, 1H) Synthesis Example 7

3,4-dihydro-2,2-dimethyl-1- 7-nitro-trans-1- 4- (1-pi-α-ridinyl) —2H-1-benzopyran-1--3-ol

3,4-epoxy-1,3,4-dihydro-1,2-dimethyl-7-nitro-2,11-benzopyran (812 mg, 8.7 mmol) was dissolved in ethanol (8 ml), and then pyrrolidine (620 1, 7.4mmo 1) was added and heating δ¾ was performed for 1 hour. After cooling to room temperature, the oil was distilled off to obtain a brown oily substance. This oil ^ was subjected to silica gel column chromatography (elution solvent, hexane: ugly ethyl = 3: 1 (V / V)) ^ Mi ^ (816 mg, 76%) was orange-colored oil As obtained.

lH-Nlfi (CDCl ₈ ) δ: 1.24 (s, 8H), 1.51 (s, 3H), 1.68-2.09 (¾ 4H), 2.58-3.31 (5H), 3.61 (d, J = 10Hz, 1H), 3.99 (d, J = 10Hz, 1H), 7.20-7.75 (m, 8H)

MS: 292C +), 220 (100¾), 203 (14¾), 163 (13¾)

Synthesis Example 8

Light ^ 3,4-dihydro-2,2-dimethyl-17-nitro-1-trans-1- (1-pyrrolidinyl) — 2H—1-benzopyran-3-ol

Light 3,4-epoxy-1,3,4-dihydro-2,2-dimethyl-7-twotro 2H-1-benzopyran (664 mg, 3.Ommo 1) obtained in Synthesis Example 1 was added to ethanol (6 ml). After digestion at 50, piperidine (500 1, 6. Ommo 1) was added, and the mixture was heated under reflux for 1 hour. After returning to room temperature, the solvent was distilled off, and the oil residue was subjected to silica gel column chromatography (elution: hexane: uglyethyl = 3: 1 (V / V)) ¾S-formation! 757 mg, 86%) as an orange oil. Spectral data match with Synthesis Example 7 Synthesis Example 9

0k N

8,4-Dihydro-2,2-dimethyl-7-Nitrotrans-1-41- (1-piral) 1-2H-1 Benzopyran-1-3-ol

4Amino-3,4-dihydro-2,2-dimethyl-7-nitrotrans-1H-2 Benzopyran-3-ol (31 lmg, l.Smmo 1) was dissolved in sleep (6 ml), 5- dimethoxytetrahydrofuran (0.19ml, 1.44 mmo 1) was stirred for 1.5 hours at added 60 ^e C. After returning to room temperature,

Thorium was added, and the mixture was extracted three times with a black hole form and dried over sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (elution). Solvent, hexane: ugly ethyl = 3: 1 (V / V)) ¾ @ 化 ^ (299 mg, 80¾) was obtained as yellow fei * -like substance.

'H-NMRCCDCU) <5: 1.30 (s, 3H), 1.53 (s, 3H), 2, 49-2.94 (brs, IH), 3.86 (d _f J = 10Hz, IH), 4.87 (d, J = 10Hz, IH), 5.94-6.23 (i¾2H), 6.39-6.84 (¾3H), 7.30-7.65 (¾2H)

MS: 289CM + 1), 288 (M ⁺ ), 217 (22¾), 180 (38¾), 68 (35¾)

[Adaptation]

Adaptation 1

Transliteration

Synthesis Example Compound 410 g

Lactose 260 g

600 g microcrystalline cellulose

350 g corn starch

Hydroxybut pi-pyrucellulose 100 g

CMC-Ca 150 g

Magnesium stearate 30 g

1,500 g

After mixing the above with, stabilize 100,000 sugar-coated tablets containing 1 mg per tablet.

Adaptation 2

Cabsell agent

Synthesis Example Compound 4 10 g

Lactose 440 g

Microcrystalline cellulose 1,000 g

Magnesium stearate 50 g 1,500 g

After mixing the Xiao Xiao component in a conventional manner, the mixture is filled into gelatin capsules to produce 10,000 capsules containing 1 mg of active ingredient per capsule.

Adaptation 3

Soft capsule

Synthesis Example Compound 410 g

PEG 400 479 g

1 ^ 1 fatty acid triglyceride 1,500 g

Nozzle oil l g

Polysorbate 80 1 0 g

Total weight 2,000 g

After mixing the above components, the mixture is filled into No. 3 soft gelatin capsules by a conventional method to produce 10 000 soft capsules containing 1 mg of the active ingredient in one capsule.

Adaptation 4

Ointment

Synthesis example ^) 4 1.0 g

¾¾¾ paraffin 10.0 g

Cetanol 20.0 g

White Pserin 6 & 4 g

Etylparaben 0.1 g

1 mentor tore _0.5

Total amount 100.0 g

Overstrike Makoto content mixed by餓, _t to 1% ointment

Adaptation 5 Suppository

Synthesis Example Compound 4 1 g

Wittubesol H 15 * 478 g

ゥ Itetuvazole W35 * 520 g

Polysorbate 80 1 g

Total weight 1,000 g

Γ * Trade name of triglyceride compound

Wittebuzul = \ 1 ^ i t e p s 01 J

The upper portion is mixed in a conventional manner, poured into a suppository container, solidified, and 1,00 D 1 g of suppository containing 1 mg of active pirates are fibred.

Formulation Example 6

mm

Chemically ^ BJ 4 1 mg

5mL of distilled water for

When used, dissolve and use.

m

Effects on heart rate

Fiber method

From Hartley strain male guinea pigs were excised organ was divided female right atrium in 95¾0 _₂ / 5¾C0 ₂ Krebs Henseleit solution which was bubbled. Specimens were suspended in a filled organ bath maintained at 31 under 1 g tension.

After equilibration, the samples were cumulatively applied with isoproterenol to find the maximum. After washing with the drug, ⁵ W of 60 minutes was performed while exchanging nutrients, and then each compound was applied to act.

The results show the effect of applying each z ^ 00 zM and 300 iM. The isoproterenol obtained was expressed in% of change with 100% of IS

Result

The compound according to the present invention exhibited a port rate-dependent heart rate decreasing effect.

Table 1 Compound heart rate change (%)

(Synthesis example number) 1 00 300

1 -5.2-24.4

2 1 1.6 -27.5

3 14.2-19.9

4 18.6-31.7

5 26.3-57.2

6 281-57.6

23.8 -28.1

Difficult to use

The compound provided in the present invention is useful for enhancing cardiac muscle strength and improving cardiac function. <Therefore, the present invention can be a useful therapeutic agent for heart failure.

Claims

The scope of the claims

1. Formula (I)

[In the formula, R ¹ and α¾ ² are each ω: hydrogen atom, halogen atom, nitrocyanoformyl! ^ Amino ^ dealkylamino alkylamino 3, d- «alkylcarbonylamino, alkyl Suruhoniruamino § Mi Nokarubo sulfonyl ¾ ^ C doctor "alkyl § amino carboxymethyl sulfonyl di C physician _β alkyl § amino Cal Boniru C Bok" Arukirukarupo sulfonyl or d - means _β alkoxycarbonyl two group,

^及^4, respectively ifcfc a hydrogen atom, c 〖_ _e alkyl properly will either boat a phenyl group, or R ⁸ and R * is H ^: made by with sickle atom to which they are attached

Ci- _β cycloalkyl group;

R ⁶ is a y &. D-, alkoxy or d- * alkylcarbonyl group or forms a bond with R ′ and H¾,

R * is a hydrogen atom or forms a bond with R ⁶ and H¾,

R ⁷ and R are respectively: l & fc to form a hydrogen atom or d-, alkyl group, or R ⁷ and R ⁸ become H and pyrrolidinyl, imidazolidinyl together with the nitrogen atom to which they are attached , Bisazolidinyl, piberidyl, piperazinyl, perhydroazepinyl, 1,3-oxazolidinyl, morpholinyl, 1,3-perhydrooxazepinyl, 1,4-perhydrooxazepinyl, 1,3-thiazolidinyl, 1, 4 one perhydro-thiazolyl sulfonyl, 1, 3-perhydro thiazolidinyl Le, 1, 4 or one base Le hydroperoxide thiazolidinyl group, or taken R ⁷ and R ⁸ gar cord their formation A pyrrole ring (R * has the same meaning as R ¹ ) which may be optionally substituted by R ⁹ together with the nitrogen atom being combined. Therapeutic treatment for heart failure comprising a benzopyran-inducing or acceptable salt represented by the following formula:

2. Ri and ² are each a hydrogen atom, a halogen atom, a nitrocyano group, a formyl group, an amino group, a d-ealkylaminodialkylamino d-ealkylcarbonylamino, a ^ aminocarbonyl group, d- ₆ alkylamino carbonyl group or di- _β alkylamino carbonyl group,

R ⁸及are each independently - ₆ C ₈ with an alkyl group or R ⁸ and R ⁴ forces it we weave is bound atoms Te summer together - the _e consequent α alkyl group,

R ⁶ represents a hydroxyl group or a C- _β- alkylcarbonyloxy group, or represents a bond together with R ^E ,

R ^E represents a hydrogen atom or forms a bond together with R ⁶ ,

R ⁷ and ^β each represent a hydrogen atom or a CH alkyl group, or R ⁷ and R ⁸ are linked together to form a pyrrolidinyl, Midazolidinyl, birazolidinyl, piperidyl, piperazinyl, morpholinyl, 1,

Three to thiazolidinyl or means a group, or R ⁷ and R ⁸ gar cord since it may pyrrole ring optionally substituted by R ^E together with the nitrogen atom to which they are attached (R ⁸ and R ¹全する表す表す表す表す表す表す表す全

3. R ⁷ and R ⁸ are H. together with the nitrogen atom to which they are attached Te the previously explained Jiniru, is imidazolidinyl, Birazorijiniru, piperidyl, piperazinyl, or means the molar Horiniru group, or R ^T and R ^E gar cord good pyro Ichiru ring optionally substituted (R ⁹ by R ^E together with the nitrogen atom to which they are attached Te represents the same «as R ^1., heart failure treatment means according to claim 2, wherein

^{4. The} treatment for heart failure according to claim 3, wherein R ⁸ and R ⁴ are the same _-β- alkyl group! ^

. 5 R ² is a hydrogen atom, a halogen atom, Shiano group, amino d - the «claim 4 wherein the alkyl § amino group - _e alkyl force Ruponiruamino group, § amino carbonyl group,-beta alkylaminocarbonyl group or a di ^ 5 All treatment Ho

6. The method according to claim 5, wherein R ^{2 is a} sulfur atom, a halogen atom, an amino group or a _β- alkylcarbonylamino group.

7. R ¹ is 7j atom, a halogen atom, a nitro Shiano group, Horuminore § H d -e alkylamino group, di C -! _E alkylamino de alkylcarbonyl Niruamino § amino carbonyl group, _de alkylcarbonyl § amino group Or a dialkylaminocarbonyl group.

8. R ¹ is a hydrogen atom, a nitro Shiano d -e alkylcarbonyl § amino group, § amino carbonyl groups, C WINCH _β alkyl § amino carbonyl or gripping alkyl Aminokaruponiru heart failure treatment Ho of claim 7 wherein the group

9. The treatment for heart failure according to claim 8, wherein R ² is a hydrogen atom.

10. R ¹ is a hydrogen atom, R ² is a methylcarbonylamino group, 1 to ⁸ and 0 to ⁴ are methyl groups, R ⁶ is hydroxyl R ⁶ is a hydrogen atom, and R ⁷ and 0 to ⁸ are 2. The ^^ total treatment according to claim 1, wherein the compound is a pyridinyl group together with the atom to which it is bonded.

1 1. R ¹ is nitro R ² is methylcarbonylamino R ⁸ and 0¾ ⁴ is methyl ¾ ^ R ⁶ is hydroxyl R ⁸ is hydrogen atom and R ⁷ and R- are linked to form a bond Claim 1 is a pyrrolidinyl group together with the nitrogen atom

1 2. R ¹ is nitro R ² is amino R3 and y ^ is a methyl group, is; ^

R ^e is a hydrogen atom, heart failure therapeutic agent according to claim 1, wherein they become R ⁷及0¾ ⁸ guard cord are both pyrrolidinyl group with the nitrogen atom to which they are bonded.

1 3. R ¹ is Nit. R ² is a hydrogen atom, R ⁸及0¾ ⁴ is a methyl group,

R ^e is a hydrogen atom, R ^T and Ri are H¾ and the nitrogen atom to which they are bonded 2. The therapeutic agent for heart failure according to claim 1, wherein both are pyrrolidinyl groups.

1 4. R ¹ is a nitro group, R ² is a hydrogen atom, R ⁸ and R ⁴ is a methyl group, R ⁶ is hydroxyl R ^e is a hydrogen atom, they become R ⁷及0¾ ⁸ gar cord bound good pyrrole ring optionally substituted by both R ^e and the nitrogen atom to which (R ⁸ represent. the same meanings as R ¹⁾ of claim 1 «¾ meaning, W total treatment