WO2009110468A1 - Potassium channel opener - Google Patents

Abstract

Disclosed is a compound represented by formula (in the formula, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and X are as defined in the description), a salt thereof that is permissible as a medical drug, or a solvate of the compound.

Description

Potassium channel opener

The present invention relates to a compound that acts as a potassium channel opener, particularly a Ca ²⁺ -dependent potassium channel opener, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Furthermore, this invention relates to the manufacturing method of the said compound, and the synthetic intermediate useful for manufacture of the said compound. The present invention further relates to pharmaceutical compositions comprising the compounds and the use of the compounds as potassium channel openers.

A Ca ²⁺ -dependent potassium channel (large conductance Ca ²⁺ -activated K ⁺ channel; Maxi K ⁺ channel or BK channel) expressed in smooth muscle cells is an ion channel involved in the relaxation of smooth muscle and is a cerebral vascular disorder including cerebral infarction. Involved in a wide range of diseases directly related to our quality of life, such as blood and ischemic heart disease, overactive bladder, frequent urination / urinary incontinence and bronchial asthma. Modulation of BK channel opening by compounds has attracted attention as a target for drug discovery.

The BK channel is a kind of biological defense mechanism that responds to depolarization of the biological membrane due to an increase in intracellular Ca ²⁺ concentration, opens quickly and causes hyperpolarization of the membrane, reduces Ca ²⁺ inflow, and avoids cell death. As a role. The BK channel is composed of four molecules each of an α subunit and a β subunit. The α subunit forms the main body of the channel, and the β subunit modifies the function of the α subunit. It is known that K ⁺ channels including BK channels have four-fold rotational symmetry (homo-tetramers) (Non-Patent Document 1). For this reason, it is considered that four binding sites for the BK channel opener are also arranged in rotational symmetry.

Although the binding mechanism of α and β subunits and the mechanism of functional regulation at the molecular level are unknown, natural compounds that bind to α subunits and exhibit open activity have already been found. It was confirmed that pimaric acid (formula A) interacts with the α subunit of the BK channel and has an opening activity, but abietic acid (formula B), which is highly similar in structure to pimaric acid, has no opening activity. (Non-Patent Document 2). On the other hand, it has been confirmed that dichlorodehydroabietic acid (formula C) has an opening activity via the α subunit (Patent Document 1, Non-Patent Document 3).

Furthermore, as a compound having BK channel opening activity, a compound having a 1,3,4,5-tetrahydrobenzo [b] azepin-2-one skeleton (for example, a compound of formula D) has been reported (Patent Document) 2 and Non-Patent Document 4).

International Publication No. WO2002 / 087559 JP 2007-186480 A

None of the existing compounds having BK channel opening activity can be said to have sufficient activity, and further improvement in activity is required. In addition, there is no pharmaceutical that is marketed as a BK channel opener and is used in clinical practice, and there is a demand for discovery of a novel compound having BK channel opener activity.

The present inventor has intensively studied to achieve the above-mentioned problems. As a result, a novel compound having a 2,3,4,5-tetrahydrobenzo [c] azepin-1-one skeleton has BK channel opening activity. This was discovered and the present invention was completed.

An object of the present invention is to provide a novel compound having potassium channel opening activity, particularly BK channel opening activity, and useful as a pharmaceutical product. A further object of the present invention is to provide a pharmaceutical composition comprising the compound.

That is, according to one aspect of the present invention, the formula (I):

^{Wherein, R 1, R 2, R} 3 and ^{R 4} are independently hydrogen atom, halogen atom, hydroxy, cyano, nitro, _{carboxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6} Selected from alkynyl, C _1-6 alkoxy, —NR ¹¹ R ¹² , —S (O) _n C _1-6 alkyl (where n is an integer selected from 0 to 2) and C _1-6 alkylcarbonyl Wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy and —S (O) _n C _1-6 alkyl are one or more halogen atoms on a carbon atom Optionally substituted by atoms or hydroxy;
R ¹¹ and R ¹² are independently selected from a hydrogen atom, C _1-6 alkyl and C _1-6 alkylcarbonyl, or together with a nitrogen atom to form a 5- to 7-membered heterocycle Well;
R ⁵ is —COOR ¹³ , —CONR ¹⁴ R ¹⁵ or tetrazol-5-yl;
R ¹³ is a hydrogen atom or C _1-6 alkyl optionally substituted by one or more Ra;
R ¹⁴ and R ¹⁵ are independently selected from a hydrogen atom and C _1-6 alkyl optionally substituted by one or more Ra, or together with the nitrogen atom to which it is attached a 5- to 7-membered heterocycle May form;
R ⁶ and R ⁷ are independently selected from a hydrogen atom, hydroxy and C _1-10 alkyl;
X is a hydrogen atom, C _1-10 alkyl optionally substituted by one or more Ra, C _2-10 alkenyl optionally substituted by one or more Ra, or substituted by one or more Ra. _May be C _2-10 alkynyl;
Ra is independently, a halogen atom, hydroxy, carboxy, cyano, one or more optionally substituted by Rb _{C 1-6} alkoxycarbonyl, one or more optionally substituted by Rb _{C 1-6} alkoxy, C _3-10 cycloalkyl _optionally substituted by one or more Rb, aryl optionally substituted by one or more Rc, heterocyclyl optionally substituted by one or more Rc, substituted by one or more Rc Optionally substituted aryloxy, one or more heterocyclyloxy optionally substituted by Rc, —NR ²¹ R ²² , and —S (O) _n R ^23, wherein n is an integer selected from 0 to 2 Is selected from;
R ²¹ and R ²² are independently a hydrogen atom, C _1-6 alkyl optionally substituted by one or more Rb, aryl optionally substituted by one or more Rc, and substituted by one or more Rc Selected from optionally substituted heterocyclyl;
R ²³ is C _1-6 alkyl optionally substituted by one or more Rb;
Rb is independently a halogen atom, hydroxy, cyano, C _1-6 alkoxy, hydroxy C _1-6 alkoxy, aryl optionally substituted by one or more Rc, and optionally substituted by one or more Rc Heterocyclyl, aryloxy optionally substituted by one or more Rc, heterocyclyloxy optionally substituted by one or more Rc, C _7-14 aralkyloxy optionally substituted by one or more Rc, heterocyclyl C _1-6 alkoxy (the heterocyclyl moiety contained in the group may be substituted by one or more Rc), C _1-6 alkoxy C _1-6 alkoxy, hydroxy C _1-6 alkoxy C _1-6 alkoxy, C _1-6 alkoxy _{C 1-6} alkoxy _{C 1-6 alkoxy, C 7 - 14} aralkyl Carboxymethyl _{C 1-6} alkoxy (the aryl moiety included in the group may be substituted by one or more Rc), heterocyclyl _{C 1-6} alkoxy _{C 1-6} alkoxy (heterocyclyl moiety included in the group, may be substituted by one or more Rc), ^- in ^NR 24 ^{R 25} and -S _(O) ^{n R 26} _(wherein n is selected from an integer selected from 0 to 2); wherein, The alkoxy moiety contained in the group may be substituted with one or more halogen atoms;
R ²⁴ and R ²⁵ are independently selected from a hydrogen atom and C _1-6 alkyl;
R ²⁶ is C _1-6 alkyl _optionally substituted with a halogen atom;
Rc is, independently, a halogen atom, hydroxy, cyano, nitro, _{carboxy, C 1-6 alkoxycarbonyl, C 1-6} alkylcarbonyloxy, one or more halogen atoms optionally substituted by a _{C 1-6} alkoxy, C _1-6 alkyl _optionally substituted with one or more halogen atoms, phenoxy optionally substituted with one or more halogen atoms, phenyl optionally substituted with one or more halogen atoms, one or more halogens Heterocyclyloxy optionally substituted with one atom, heterocyclyl optionally substituted with one or more halogen atoms, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkoxy, hydroxy C _{1 -6} alkyl, hydroxy _{C 1-6} alkoxy, amino _{C 1-6} alkyl, and amino _{C 1-} It is selected from alkoxy;
Further, the substitutable carbon atom contained in the cyclohexane ring in the formula may be independently substituted with a substituent selected from hydroxy, C _1-6 alkyl and oxo, and the substitution contained in the azepine ring in the formula Possible carbon atoms may be independently substituted with substituents selected from hydroxy and C _1-6 alkyl]
Or a pharmaceutically acceptable salt or solvate thereof.

According to another aspect of the present invention, the formula (Ia):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and X are independently as defined herein]
Or a pharmaceutically acceptable salt or solvate thereof.

According to another aspect of the present invention there is provided a compound of formula (I) or formula (Ia) comprising:
[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [ c, e] azepine-4-carboxylic acid methyl ester;
[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [ c, e] azepine-4-carboxylic acid;
[4R, 4aR, 11bS] -8-chloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] Azepine-4-carboxylic acid methyl ester;
[4R, 4aR, 11bS] -8-chloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] Azepine-4-carboxylic acid;
[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,6,11b-trimethyl-7-oxo-2,3,4,4a, 5,6,7,11b-octahydro-1H- Dibenzo [c, e] azepine-4-carboxylic acid methyl ester;
[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,6,11b-trimethyl-7-oxo-2,3,4,4a, 5,6,7,11b-octahydro-1H- Dibenzo [c, e] azepine-4-carboxylic acid;
[4R, 4aR, 11bS] -8-chloro-9-isopropyl-4,6,11b-trimethyl-7-oxo-2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [ c, e] azepine-4-carboxylic acid methyl ester;
[4R, 4aR, 11bS] -8-chloro-9-isopropyl-4,6,11b-trimethyl-7-oxo-2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [ c, e] azepine-4-carboxylic acid;
[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- (pent-4-ynyl) -2,3,4,4a, 5,6 7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester;
[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- (pent-4-ynyl) -2,3,4,4a, 5,6 7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid;
[4R, 4aR, 11bS] -8,10-dichloro-6- [5- (4-iodophenyl) -pent-4-ynyl] -9-isopropyl-4,11b-dimethyl-7-oxo-2,3 , 4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester;
[4R, 4aR, 11bS] -8,10-dichloro-6- [5- (4-iodophenyl) -pent-4-ynyl] -9-isopropyl-4,11b-dimethyl-7-oxo-2,3 , 4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid;
[4R, 4aR, 11bS] -8,10-dichloro-6- [5- (3-iodophenyl) -pent-4-ynyl] -9-isopropyl-4,11b-dimethyl-7-oxo-2,3 , 4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester;
[4R, 4aR, 11bS] -8,10-dichloro-6- [5- (3-iodophenyl) -pent-4-ynyl] -9-isopropyl-4,11b-dimethyl-7-oxo-2,3 , 4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid;
[4R, 4aR, 11bS] -8,10-dichloro-6- [5- (2-iodophenyl) -pent-4-ynyl] -9-isopropyl-4,11b-dimethyl-7-oxo-2,3 , 4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester;
[4R, 4aR, 11bS] -8,10-dichloro-6- [5- (2-iodophenyl) -pent-4-ynyl] -9-isopropyl-4,11b-dimethyl-7-oxo-2,3 , 4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid;
[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- (5-phenylpent-4-ynyl) -2,3,4,4a, 5 , 6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester;
[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- (5-phenylpent-4-ynyl) -2,3,4,4a, 5 , 6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid is provided.

In one embodiment of the invention, R ⁴ in formula (I) and formula (Ia) is a halogen atom, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, or —S (O) _n C _{1 -6} alkyl (where n is an integer selected from 0 to 2), wherein the C _1-6 alkyl, C _1-6 alkoxy and —S (O) _n C _1-6 alkyl are: The carbon atom may be substituted with one or more halogen atoms or hydroxy.

In a further aspect of the invention, X of formula (I) and formula (Ia) is C _2-4 alkyl optionally substituted by one or more Ra, C ₂ optionally substituted by one or more Ra _-4 alkenyl, or C _2-4 alkynyl optionally substituted by one or more Ra; Ra is as previously defined.

In a further aspect of the invention, X of formula (I) and formula (Ia) is C _2-4 alkyl optionally substituted by one or more Ra, C ₂ optionally substituted by one or more Ra by _-4 alkenyl or one or more Rd, be a _{C 2-4} alkynyl substituted; Rd is independently, a halogen atom, hydroxy, carboxy, cyano, one or more optionally substituted by Rb _{C 1 -6} alkoxycarbonyl, C _1-6 alkoxy optionally substituted by one or more Rb, C _3-10 cycloalkyl optionally substituted by one or more Rb, optionally substituted by one or more Rc Good aryl, heterocyclyl optionally substituted by one or more Rc, aryloxy optionally substituted by one or more Rc, one or more Rc Ri optionally substituted ^{heterocyclyloxy,} is selected from ^-NR 21 ^{R 22,} and -S _(O) ^{n R 23} _(where n is an integer selected from 0 ~ 2); Ra, Rb , R ²¹ , R ²² and R ²³ are as defined above.

In a further aspect of the invention, X in formula (I) and formula (Ia) is C _2-10 alkyl optionally substituted by one or more Ra, or C optionally substituted by one or more Ra. _2-10 alkenyl.

In a further embodiment of the invention R ² in formula (I) and formula (Ia) is a hydrogen atom or a halogen atom.

In a further embodiment of the invention R ⁴ in formula (I) and formula (Ia) is a halogen atom.

In a further aspect of the invention, R ⁵ of formula (I) and formula (Ia) is —COOR ¹³ .

According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound represented by formula (I) or formula (Ia), a pharmaceutically acceptable salt thereof, or a solvate thereof. The pharmaceutical composition is not particularly limited, for example, for treating or preventing a disease selected from cerebral infarction, cerebrovascular ischemia, ischemic heart disease, frequent urination, urinary incontinence disease, overactive bladder and bronchial asthma Can be used for.

According to a further aspect of the invention, it acts on a potassium channel opener comprising a compound of formula (I) or formula (Ia), a pharmaceutically acceptable salt thereof, or a solvate thereof, in particular a BK channel. A potassium channel opener is also provided.

In the present specification, “C _1-10 alkyl” means a linear, branched, cyclic or partially cyclic alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl. I-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, and 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, etc., for example, C _2-10 alkyl C _1-6 alkyl, C _1-3 alkyl and the like are also included. In the present specification, “C _1-6 alkyl” includes, for example, C _1-3 alkyl and the like.

In the present specification, “C _2-10 alkenyl” means a linear, branched, cyclic or partially cyclic alkenyl group having 2 to 10 carbon atoms, such as vinyl, 1-propenyl, 2 -Propenyl (allyl), 1-methylvinyl, cyclopentenyl, cyclohexenyl and the like, for example, C _2-6 alkenyl, C _2-4 alkenyl and the like.

In the present specification, “C _2-10 alkynyl” means a linear, branched, cyclic or partially cyclic alkenyl group having 2 to 10 carbon atoms, such as ethynyl, 1-propynyl, 2 -Propynyl (propargyl), 2-cyclopropylethynyl and the like, for example, C _2-6 alkynyl and C _2-4 alkynyl and the like.

In the present specification, “C _1-10 alkoxy” means an alkyloxy group having an alkyl group having 1 to 10 carbon atoms already defined as an alkyl moiety, and includes, for example, methoxy, ethoxy, n-propoxy, i-propoxy N-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpen Toxic, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy and the like, for example, C _1-6 alkoxy and C ₁ Also included are _-3 alkoxy and the like. In the present specification, “C _1-6 alkoxy” includes, for example, C _1-3 alkoxy and the like.

In this specification, “—S (O) _n C _1-6 alkyl” means C _1-6 alkylthio, C _1-6 alkylsulfenyl, or C _1-6 alkylsulfonyl, and the alkyl of these groups The moiety is an already defined C _1-6 alkyl group. —S (O) _n C _1-6 alkyl also includes —S (O) _n C _1-3 alkyl.

As used herein, “C _1-6 alkylcarbonyl” means an alkylcarbonyl group having a C _1-6 alkyl group already defined as the alkyl moiety, and includes, for example, C _1-3 alkylcarbonyl.

In the present specification, “C _7-14 aralkyl” means an arylalkyl group having 7 to 14 carbon atoms including an aryl group, such as benzyl, 1-phenethyl, 2-phenethyl, 1-naphthylmethyl, 2- Naphthylmethyl and the like are included.

In the present specification, the “aryl” is not particularly limited, but means an aryl group having an aromatic hydrocarbon ring having 6 to 14 carbon atoms, such as 6 to 10 carbon atoms, such as phenyl, 1-naphthyl and 2 -Includes naphthyl and the like.

In the present specification, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the present specification, when forming a 5- to 7-membered heterocycle together with a nitrogen atom, the “5- to 7-membered heterocycle” means a saturated, partially unsaturated, or unsaturated nitrogen-containing 5- to 7-membered heterocycle. By means of a ring, the heterocycle may contain one or more additional nitrogen atoms and / or may contain one or more heteroatoms selected from oxygen and sulfur atoms. Examples of 5- to 7-membered heterocycles include pyrrole, pyrazole, imidazole, pyrrolidine, piperidine, piperazine, homopiperidine, homopiperazine and morpholine.

As used herein, “heterocyclyl” refers to a saturated, partially unsaturated, or unsaturated 4- to 10-membered heterocyclic group containing one or more heteroatoms selected from, for example, a nitrogen atom, an oxygen atom, and a sulfur atom Means. Examples of heterocyclyl include pyridyl, pyrimidyl, pyrazyl, triazinyl, quinolyl, quinoxalyl, quinazolyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolidyl, piperidyl, piperazinyl, homopiperidyl, homopiperazinyl and morpholyl.

In the present specification, “aryl”, “heterocyclyl” and “C _7-14 aralkyl” included in “aryloxy”, “heterocyclyloxy” and “C _7-14 aralkyloxy” are as defined above, respectively. is there.

The compound of the present invention includes various stereoisomers such as tautomers, geometric isomers and optical isomers, and mixtures thereof.

The “pharmaceutically acceptable salt” in the present specification is not particularly limited as long as it is a salt that can be used as a pharmaceutical. The compounds of the above formulas (I) and (Ia) are, for example, a carboxylic acid when R ⁵ is carboxy. It may be an acid salt. Examples of the salt formed by the compound of the present invention with a base include salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine and ethanolamine; bases such as lysine and ornithine Salts with acidic amino acids and ammonium salts. The salt may be an acid addition salt. Specific examples of the salt include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and other mineral acids; formic acid, acetic acid, Organic acids such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid; acidic amino acids such as aspartic acid, glutamic acid Examples include acid addition salts.

The compound of the present invention includes hydrates, various pharmaceutically acceptable solvates (for example, hydrates), crystal polymorphs, and the like.

The compound of formula (I) according to the present invention can be synthesized, for example, by the steps shown in the following scheme.

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined herein, and R ¹⁰ is a hydrogen atom or —SO ₂ —R ¹⁶ And R ¹⁶ is C _1-6 alkyl, C _1-6 haloalkyl, phenyl (wherein the phenyl may be substituted by C _1-6 alkyl or a halogen atom)].

Step 1-1 uses an appropriate oxidizing agent (for example, CrO ₃ , SeO ₂ , KMnO ₄ , O ₂ / CuCl ₂ (CuCl), NaIO ₄ , NaBrO ₃ , H ₂ O ₂ , tBuOOH, etc.) It can be carried out in a suitable solvent (for example, acetic acid, acetonitrile and the like), and it is preferable that an additive (for example, acetic anhydride and the like) is present in the system. For example, the oxidation in this step can be performed using CrO ₃ in acetic acid in the presence of acetic anhydride. The step is not particularly limited, but can be performed at a reaction temperature of 0 to 150 ° C., preferably 40 to 60 ° C., and a reaction time of 1 to 17 hours, preferably 5 to 10 hours.

In Step 1-2, the ketone and hydroxyamine hydrochloride obtained in Step 1-1 are mixed with a base (eg, pyridine, tertiary amine, NaHCO 3) in a suitable solvent (eg, ethanol, water, t-butanol, acetonitrile, etc.). ₃ and NaOH). The step is not particularly limited, but can be performed at a reaction temperature of 0 to 150 ° C., preferably 50 to 100 ° C., and a reaction time of 30 minutes to 17 hours, preferably 2 hours to 5 hours. The obtained oxime can be used as it is in the next reaction. However, in order to carry out step 1-3 with a higher yield, R ¹⁰ is -SO ₂ -R ¹⁶ (for example, mesyl, tosyl, benzenesulfonyl, trifluoro) May be converted to a compound such as lomethanesulfonyl. The conversion is carried out using an appropriate reagent (eg, tosyl chloride, mesyl chloride, benzenesulfonyl chloride, trifluoromethanesulfonic anhydride, etc.) in a suitable solvent (eg, pyridine, etc.) and a base (eg, pyridine, 3 Secondary amine, sodium hydroxide, etc.). The reaction conditions are not particularly limited, but the reaction can be performed at a reaction temperature of 0 to 150 ° C., preferably 20 to 50 ° C., and a reaction time of 1 hour to 3 days, preferably 10 hours to 20 hours.

Step 1-3 can be performed by reacting the oxime obtained in Step 1-2 or a derivative thereof under acidic conditions. Examples of the acid that can be used include H ₃ PO ₄ , CF ₃ CO ₂ H, P ₂ O _{5 and the} like, and the reaction conditions are not particularly limited, but are 0 to 150 ° C., preferably 10 to 30 ° C. The reaction can be carried out at a reaction temperature and a reaction time of 10 minutes to 17 hours, preferably 30 minutes to 2 hours.

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and X are as defined herein, L is a leaving group (eg, a halogen atom, A mesyl group, a tosyl group, and a trifluoromethanesulfonyl group).

Step 2-1 can be carried out in a suitable solvent (eg, DMF, THF, methanol, ethylene glycol, etc.) in the presence of a suitable base (eg, sodium hydride, potassium hydroxide, etc.), and further suitable Additives such as crown ethers (such as 18-crown ether-6) may be used. The reaction conditions are not particularly limited, but the reaction can be carried out at a reaction temperature of 0 to 200 ° C., preferably 50 to 80 ° C., and a reaction time of 1 hour to 3 days, preferably 15 hours to 20 hours. In this scheme, preferred leaving groups L include halogen atoms (for example, iodine atom and bromine atom), trifluoromethanesulfonyloxy, tosyloxy, mesyloxy and the like.

Examples of the reagent LX used in this step include a C _1-10 alkyl halide which may have a substituent, a C _2-10 alkynyl halide which may have a substituent, and a substituent. C _2-10 alkenyl halide having a substituent, preferably a C _1-10 alkyl bromide having a substituent, a C _2-10 alkynyl bromide having a substituent, and a C _1-10 alkenyl bromide having a substituent. . Reagent LX is commercially available, known in the literature, or can be prepared by standard synthetic means.

In the above scheme, a protecting group may be introduced for a functional group that needs to be protected. It will be appreciated that selection of the protecting group and methods for its introduction can be readily accomplished by one of ordinary skill in the art. For example, when R ⁵ is carboxy in the formulas (I) and (Ia), the carboxy is converted to an appropriate ester (eg, C _1-10 alkyl ester, C _7-14 aralkyl ester, etc.) Followed by deprotection under suitable conditions (acid or alkaline hydrolysis, hydrogenation, etc.) to give the desired compound.

The pharmaceutical composition of the present invention can be used in various dosage forms such as tablets, capsules, powders, granules, pills, solutions, emulsions, suspensions, solutions, spirits, syrups for oral administration. And parenteral agents include, for example, injections such as subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and the like; transdermal administration or patches , Ointments or lotions; sublingual and buccal patches for buccal administration; and aerosols for nasal administration, but not limited thereto. These preparations can be produced by known methods usually used in the preparation process.

The pharmaceutical composition may contain various commonly used components, such as one or more pharmaceutically acceptable excipients, disintegrants, diluents, lubricants, flavoring agents, and coloring agents. , Sweeteners, flavoring agents, suspending agents, wetting agents, emulsifying agents, dispersing agents, adjuvants, preservatives, buffering agents, binders, stabilizers, coating agents and the like. The pharmaceutical composition of the present invention may be in a sustained or sustained release dosage form.

The dosage of the pharmaceutical composition of the present invention can be appropriately selected depending on the administration route, the patient's body shape, age, physical condition, degree of disease, elapsed time after onset, etc. An effective amount and / or a prophylactically effective amount of a compound of formula (I) or (Ia) above may be included. In the present invention, the compound of the above formula (I) or (Ia) is generally used at a dose of 0.1 to 20000 mg / day / adult, for example, 10 to 200 mg / day / adult, preferably 30 to 100 mg / day / adult. sell. The pharmaceutical composition may be administered in a single dose or multiple doses, such as an antihypertensive drug (calcium antagonist, angiotensin converting enzyme inhibitor, angiotensin receptor antagonist), bronchodilator (β2 receptor agonist) Drug), urinary incontinence drug (muscarinic receptor antagonist), and the like, and can also be used in combination with other drugs having activity.

FIG. 1 is a graph showing an example of a test result obtained by the automation patch clamp method, showing the human BK channel opening activity of the compound of the present invention.

Hereinafter, preferred examples of the present invention will be described in more detail, but the present invention is not limited to these examples.

Reagents and data measurement Unless otherwise stated, purchased reagents were used without further purification. ¹ H-NMR displays chemical shift in ppm. When deuterated chloroform (CDCl ₃ ) is used as a measurement solvent, tetramethylsilane (TMS) is used as an internal standard, and deuterated dimethyl sulfoxide ((CD ₃ ) ₂ SO). When used, its own peak was taken as the internal standard. Mass spectrometry used a JEOL MStation JMS-700 spectrometer, and elemental analysis used a Yanaco CHN CORDER spectrometer. For flash column chromatography, Kanto Chemical silica gel 60N (40-50 μm) was used. Melting points were measured using a hot-stage microscope and no correction was made. Yield represents the isolated yield after purification.

Example 1: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6,7,11b-octahydro- 1H-Dibenzo [c, e] azepine-4-carboxylic acid methyl ester

6,8-dichloro-7-isopropoxy-1,4a-dimethyl-9-tosyloxyimino-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carboxylic acid methyl ester ( Production Example 1; 3.39 g, 5.98 mmol) was added to trifluoroacetic acid (27.2 mL) at 0 ° C., and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off by concentrating under reduced pressure and azeotroping with toluene. The residue was purified by flash chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a colorless solid (1.98 g, 80.3% yield).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.15 (1H, s), 4.04 (1H, m), 3.62 (3H, s), 3.36 (1H, m), 2 .86 (1H, dd, J = 16.1 Hz, J = 6.4 Hz), 2.60-2.78 (1H, brs), 2.46 (1H, d, J = 7.3 Hz), 2. 36-2.51 (1H, m), 1.55-1.90 (8H, m), 1.31-1.50 (9H, m).

6,8-Dichloro-7-isopropoxy-1,4a-dimethyl-9-tosyloxyimino-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1- used as starting material Carboxylic acid methyl ester was produced by the following method.

Production Example 1
[Step 1] Preparation of 6,8-dichloro-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carboxylic acid

Of 7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carboxylic acid (6.00 g, 20 mmol) in carbon tetrachloride (18 mL) To the solution was added 10% FeCl ₃ / SiO ₂ (300 mg) and 1% DDQ / SiO ₂ (300 mg). The reaction mixture was stirred at room temperature and a Cl ₂ / carbon tetrachloride solution (2.4M, 120 ml) was added in one portion at 0 ° C. in the dark and then stirred overnight at room temperature. The resulting solution was poured into saturated aqueous Na ₂ SO ₃ (100 mL) and extracted with CHCl ₃ (70 × 3 ml). The organic layer was washed with water, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was washed by flash chromatography (hexane: AcOEt = 7: 1) to give the title compound as a colorless solid (4.71 g, 63.8% yield).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.23 (1H, s), 3.88 (1H, brs), 2.91 (1H, dd, J = 19.6 Hz, 5.3 Hz), 2.65-2.78 (1H, m), 2.22 (1H, d, J = 13.0 Hz), 2.11 (1H, d, J = 13.0 Hz), 1.71-1.75 (5H, m), 1,61-1.66 (2H, m,), 1.37 (6H, d, J = 7.20 Hz), 1.25 (3H, s), 1.10-1. 25 (1H, m).

[Step 2] Preparation of 6,8-dichloro-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carboxylic acid methyl ester

6,8-Dichloro-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carvone in methanol (25 mL) and toluene (50 mL) To a solution of acid (4.71 g, 12.7 mmol), TMSCHN ₂ / Et ₂ O solution (2.0 M, 8.6 ml) was added dropwise and the reaction mixture was stirred at room temperature for 15 minutes. Then, it was quenched by adding acetic acid and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane: AcOEt = 20: 1) to give the title compound as a colorless solid (4.60 g, 87% yield).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.13 (1H, s), 4.00 (1H, m), 3.68 (3H, s), 3.45 (1H, d, J = 13.2 Hz), 2.68-2.87 (2H, m), 2.05 (1H, d, J = 11.6 Hz), 1.58-1.77 (5H, m), 1.46 ( 3H, s), 1.38 (6H, d, J = 7.20 Hz), 1.27 (3H, s), 1.10-1.25 (1H, m).

[Step 3] 6,8-Dichloro-7-isopropyl-1,4a-dimethyl-9-oxo-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carboxylic acid methyl ester Preparation of

6,8-Dichloro-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carboxylic acid methyl ester (4) in acetic acid (75 mL) To a solution of CrO ₃ (1.52 g, 15.2 mmol, 1.2 eq) in Ac ₂ O (60 mL) and acetic acid (30 mL) was added dropwise at 0 ° C. over 10 min. Added. The reaction mixture was stirred at 50 ° C. overnight, then cooled, poured into ice water (200 mL) and extracted with CHCl ₃ (100 mL × 3). The combined organic layers were washed with water (100 mL), saturated aqueous NaHCO ₃ (100 mL × 3) and brine (100 mL), dried over Na ₂ SO ₄ , filtered and then evaporated under reduced pressure. . The residue was washed by flash chromatography (hexane: AcOEt = 7: 1) to give the title compound as a colorless solid (3.17 g, 72.5% yield).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.15 (1H, s), 4.04 (1H, m), 3.67 (3H, s), 3.46 (1H, d, J = 13.6 Hz), 2.61-2.72 (2H, m), 2.36-2.46 (1H, m), 1.61-1.82 (5H, m), 1.54 (3H, s), 1.40 (6H, d, J = 6.8 Hz), 1.31 (3H, s).

[Step 4] Methyl 6,8-dichloro-9-hydroxyimino-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carboxylate Preparation of esters

6,8-Dichloro-7-isopropyl-1,4a-dimethyl-9-oxo-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1- in EtOH (33.5 mL) A mixture of carboxylic acid methyl ester (3.17 g, 7.98 mmol), pyridine (1.05 mL), NH ₂ OH · HCl (864 mg, 12.4 mmol, 1.5 eq) was stirred at 100 ° C. overnight, then Cooled down. The solvent was distilled off under reduced pressure and the residue was purified by flash chromatography (hexane: AcOEt = 7: 1) to give the title compound as a colorless solid (3.17 g, 96.4% yield). .

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.15 (1H, s), 4.06 (1H, m), 3.67 (3H, s), 3.41 (1H, d, J = 12.0 Hz), 2.95-3.01 (1 H, m), 2.31 (1 H, dd, J = 18.7 Hz, 13.8 Hz), 2.21 (1 H, dd, J = 18.7 Hz) 5.7 Hz), 1.55-1.75 (5H, m), 1.41 (6H, d, J = 16.0 Hz), 1.35 (3H, s), 1.25 (3H, s) ).

[Step 5] 6,8-Dichloro-7-isopropyl-1,4a-dimethyl-9-tosyloxyimino-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carboxylic acid Preparation of methyl ester

6,8-Dichloro-9-hydroxyimino-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carvone in pyridine (24 mL) To a solution of acid methyl ester (3.17 g, 7.69 mmol) was added tosyl chloride (2.20 mg, 11.54 mmol, 1.5 eq) at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water (50 mL) and extracted with CHCl ₃ (50 mL × 3). The organic phase was washed with hydrochloric acid (50 mL) and water (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane: AcOEt = 7: 1) to give the title compound as a colorless solid (3.39 g, yield 77.8%).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.87 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 3.96 (1H, m ), 3.67 (3H, s), 3.37 (1H, d, J = 13.6 Hz), 2.96 (1H, dd, J = 13.6 Hz, 19.2 Hz), 2.47 (1H) , D, J = 5.6 Hz), 2.43 (3H, s), 2.14 (1H, dd, J = 13.7 Hz, 5.7 Hz), 1.5-1.68 (5H, m) 1.50-1.80 (9H, m), 1.21 (3H, s).

Example 2: [4R, 4aR, 11bS] -8,10,11-trichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6,7,11b- Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester

Methyl 5,6,8-trichloro-7-isopropoxy-1,4a-dimethyl-9-tosyloxyimino-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carboxylate The ester (Preparation Example 2; 2.50 g, 4.17 mmol) was added to trifluoroacetic acid (17 mL) at 0 ° C., and the mixture was stirred at room temperature for 2.5 hours. The solvent was removed azeotropically with toluene under reduced pressure, and the residue was purified by flash chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a colorless solid (1.50 g, yield 81). %).

5,6,8-trichloro-7-isopropoxy-1,4a-dimethyl-9-tosyloxyimino-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene- used as starting material 1-carboxylic acid methyl ester was produced by the following method.

Production Example 2
[Step 1] Preparation of 5,6,8-trichloro-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carboxylic acid

7-Isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carboxylic acid (2.01 g, 6.69 mmol) in carbon tetrachloride (7 mL) ) Was added FeCl ₃ (503 mg, 3.10 mmol) and 1% DDQ / SiO ₂ (119 mg). The reaction mixture was stirred at room temperature and a Cl ₂ / carbon tetrachloride solution (2.4M, 40 ml) was added in one portion at 0 ° C. in the dark and then stirred overnight at room temperature. The resulting solution was poured into saturated aqueous Na ₂ SO ₃ (100 mL) and extracted with CHCl ₃ (70 × 3 ml). The organic layer was washed with water, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was washed by flash chromatography (hexane: AcOEt = 7: 1) to give the title compound as a colorless solid (0.97 g, 35% yield).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 4.01 (1H, m), 3.45 (1H, d, J = 1.24 Hz), 2.81-2.90 (2H, m), 2.06 (1H, d, J = 11.2 Hz), 1.60-1.90 (5H, m), 1.51-1.59 (2H, m), 1,48 (3H, s), 1.38 (6H, d, J = 7.20 Hz), 1.29 (3H, s), 1.10-1.25 (1H, m).

[Step 2] Preparation of 5,6,8-trichloro-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carboxylic acid methyl ester

5,6,8-Trichloro-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1 in methanol (26 mL) and toluene (52 mL) -A solution of TMSCHN ₂ / Et ₂ O (2.0 M, 5.4 ml, 10.8 mmol) was added dropwise to a solution of carboxylic acid (2.51 g, 6.20 mmol) and the reaction mixture was stirred at room temperature for 15 minutes. did. Then, it was quenched by adding acetic acid and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane: AcOEt = 20: 1) to give the title compound as a colorless solid (2.26 g, 87% yield).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 4.00 (1H, m), 3.68 (3H, s), 3.45 (1H, d, J = 13.2 Hz), 2.68- 2.87 (2H, m), 2.05 (1H, d, J = 11.6 Hz), 1.58-1.77 (5H, m), 1.46 (3H, s), 1.38 ( 6H, d, J = 7.20 Hz), 1.27 (3H, s), 1.10-1.25 (1H, m).

[Step 3] 5,6,8-trichloro-7-isopropyl-1,4a-dimethyl-9-oxo-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carboxylic acid Preparation of methyl ester

5,6,8-Trichloro-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carboxylic acid methyl ester in acetic acid (100 mL) (6.82 g, 14.6 mmol) in a solution of CrO ₃ (2.30 g, 23.0 mmol, 1.5 eq) in Ac ₂ O (100 mL) and acetic acid (50 mL) at 0 ° C. for 10 min. Added dropwise. The reaction mixture was stirred at 50 ° C. overnight, then cooled, poured into ice water (200 mL) and extracted with CHCl ₃ (100 mL × 3). The combined organic layers were washed with water (100 mL), saturated aqueous NaHCO ₃ (100 mL × 3) and brine (100 mL), dried over Na ₂ SO ₄ , filtered and then evaporated under reduced pressure. . The residue was washed by flash chromatography (hexane: AcOEt = 7: 1) to give the title compound as a colorless solid (3.19 g, 51% yield).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 4.04 (1H, m), 3.67 (3H, s), 3.46 (1H, d, J = 13.6 Hz), 2.61- 2.72 (2H, m), 2.36-2.46 (1H, m), 1.61-1.82 (5H, m), 1.54 (3H, s), 1.40 (6H, d, J = 6.8 Hz), 1.31 (3H, s); MS m / z 453.1 ([M ( ³⁵ Cl ₃ ) + H] ⁺ ), 455.1 ([M ( ³⁵ Cl ₂ ³⁷ Cl) + H] ⁺ ), 456.1 ([M ( ³⁵ Cl ³⁷ Cl ₂ ) + H] ⁺ ), 458.1 ([M ( ³⁷ Cl ₃ ) + H] ⁺ ), 469.1 ([M ( ³⁵ Cl ₃ ) + Na] ⁺ ), 471.1 ([M ( ³⁵ Cl ₂ ³⁷ Cl) + Na] ⁺ ), 473.1 ([M ( ³⁵ Cl ³⁷ Cl ₂ ) + Na] ⁺ ), 475.1 ([M ( ³⁷ Cl ₃ ) + Na] ⁺ ), 497.1 ([M ( ³⁵ Cl ₃ ) + K] ⁺ ), 499.1 ([M ( ³⁵ Cl ₂ ³⁷ Cl ) + K] ⁺ ), 501.1 ([M ( ³⁵ Cl ³⁷ Cl ₂ ) + K] ⁺ ), 503.1 ([M ( ³⁷ Cl ₃ ) + K] ⁺ ).

[Step 4] 5,6,8-trichloro-9-hydroxyimino-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1-carvone Preparation of acid methyl ester

5,6,8-trichloro-7-isopropyl-1,4a-dimethyl-9-oxo-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene in ethanol (3.7 mL) A mixture of 1-carboxylic acid methyl ester (354 mg, 0.851 mmol), pyridine (0.14 mL), NH ₂ OH · HCl (102 mg, 1.46 mmol, 1.7 eq) was stirred at 100 ° C. overnight, then Cooled down. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (hexane: AcOEt = 7: 1) to give the title compound as a colorless solid (334 mg, 91% yield).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 4.06 (1H, m), 3.67 (3H, s), 3.41 (1H, d, J = 12.0 Hz), 2.95- 3.01 (1H, m), 2.31 (1H, dd, J = 18.7 Hz, 13.8 Hz), 2.21 (1H, dd, J = 18.7 Hz, 5.7 Hz), 1.55 −1.75 (5H, m), 1.41 (6H, d, J = 16.0 Hz), 1.35 (3H, s), 1.25 (3H, s); MS m / z 446.1 ( [M ( ³⁵ Cl ₃ ) + H] ⁺ ), 448.1 ([M ( ³⁵ Cl ₂ ³⁷ Cl) + H] ⁺ ), 450.1 ([M ( ³⁵ Cl ³⁷ Cl ₂ ) + H] ⁺ ), 452. _{^{1 ([M (37 Cl 3}} ) + H] +), 468.1 ([M (35 Cl 3) + Na] +), 470.1 ([M _{^{35 Cl 2 37 Cl) + Na}} ] +), 472.1 ([M (35 Cl 37 Cl 2) + Na] +), 474.1 ([M (37 Cl 3) + Na] +), 484.1 ([ M ( ³⁵ Cl ₃ ) + K] ⁺ ), 486.1 ([M ( ³⁵ Cl ₂ ³⁷ Cl) + K] ⁺ ), 488.1 ([M ( ³⁵ Cl ³⁷ Cl ₂ ) + K] ⁺ ), 490.1 _{^{([M (37 Cl 3)}} + K] +).

[Step 5] 5,6,8-Trichloro-7-isopropyl-1,4a-dimethyl-9-tosyloxyimino-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1- Preparation of carboxylic acid methyl ester

5,6,8-Trichloro-9-hydroxyimino-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydro-phenanthrene-1 in pyridine (8 mL) To a solution of carboxylic acid methyl ester (986 mg, 2.29 mmol) was added tosyl chloride (640.2 mg, 3.358 mmol, 1.5 eq) at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water (50 mL) and extracted with CHCl ₃ (50 mL × 3). The organic phase was washed with hydrochloric acid (50 mL) and water (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane: AcOEt = 7: 1) to give the title compound as a colorless solid (1.15 g, 86% yield).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.87 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 3.96 (1H, m ), 3.67 (3H, s), 3.37 (1H, d, J = 13.6 Hz), 2.96 (1H, dd, J = 13.6 Hz, 19.2 Hz), 2.47 (1H) , D, J = 5.6 Hz), 2.43 (3H, s), 2.14 (1H, dd, J = 13.7 Hz, 5.7 Hz), 1.5-1.68 (5H, m) , 1.50-1.80 (9H, m), 1.21 (3H, s); MS m / z600.1 ([M (35 Cl 3) + H] +), 602.1 ([M (35 Cl ₂ ³⁷ Cl) + H] ⁺ ), 604.1 ([M ( ³⁵ Cl ³⁷ Cl ₂ ) + H] ⁺ ), 606.1 ([M ( ³⁷ Cl ₃ ) + H] _{^{+), 622.1 ([M (}} 35 Cl 3) + Na] +), 624.1 ([M (35 Cl 2 37 Cl) + Na] +), 626.1 ([M (35 Cl 37 Cl 2) + Na] ⁺ ), 628.1 ([M ( ³⁷ Cl ₃ ) + Na] ⁺ ), 638.1 ([M ( ³⁵ Cl ₃ ) + K] ⁺ ), 640.1 ([M ( ³⁵ Cl ₂ ³⁷ Cl) + K] ⁺ ), 642.1 ([M ( ³⁵ Cl ³⁷ Cl ₂ ) + K] ⁺ ), 644.1 ([M ( ³⁷ Cl ₃ ) + K] ⁺ ).

Example 3: [4R, 4aR, 11bS] -6- [2- (benzyloxy) ethyl] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4 4a, 5,6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester

To a suspension of sodium hydride (60% mineral oil suspension, 24.0 mg, 0.6 mmol, 1.5 eq) in DMF (4 mL) at 0 ° C. in [4R in DMF (1.0 mL). , 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] Azepine-4-carboxylic acid methyl ester (165 mg, 0.4 mmol) was added dropwise. 2-Benzyloxyethyl bromide (107 mg, 0.5 mmol, 1.25 equiv) was added and the mixture was stirred at 70 ° C. for 40 hours. The reaction mixture was then poured into water and extracted with Et ₂ O (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane: AcOEt = 3: 1) to give the title compound as a colorless solid (138.5 mg, 63% yield).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.26-7.33 (5H, m), 7.19 (1H, bs), 4.51 (2H, s), 4.42-4. 49 (1H, m), 3.94 (1H, bs), 3.66-3.80 (3H, m), 3.56 (3H, s), 3.10-3.17 (1H, m) , 3.03 (1H, d, J = 12.3 Hz), 2.16 (1H, d, J = 8.4 Hz), 1.69-1.93 (6H, m), 1.39 (12H, m); MS m / z 546.2 ([M + H] ⁺ ).

Example 4: [4R, 4aR, 11bS] -6- [2- (benzyloxy) ethyl] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4 4a, 5,6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid

[4R, 4aR, 11bS] -6- [2- (Benzyloxy) ethyl] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3, in methanol (3 mL) 4,4a, 5,6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester (138.5 mg, 0.25 mmol), potassium hydroxide (140 mg, 2.5 mmol, 10 equivalents) and 18-crown ether-6 (166 mg, 0.63 mmol, 2.5 equivalents) were stirred at 80 ° C. for 40 hours and the solvent was removed under reduced pressure. The residue was diluted with water (5 mL), acidified with 2N hydrochloric acid and extracted with CHCl ₃ (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography to give the title compound as a colorless solid (155.0 mg, 95% yield).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.26-7.33 (5H, m), 7.17 (1H, bs), 4.49 (2H, s), 4.27-4. 40 (1H, m), 3.98 (1H, bs), 3.68-3.80 (3H, m), 3.10-3.18 (2H, m), 2.13 (1H, d, J = 8.4 Hz), 1.69-1.93 (6H, m), 1.45 (3H, s), 1.39-1.42 (9H, m); MS m / z 530.1865 ([ MH] ⁻ ).

Example 5: [4R, 4aR, 11bS] -6- [4- (benzyloxy) butyl] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4 4a, 5,6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester

The title compound was obtained as a colorless solid in the same manner as in Example 3 except that 4-benzyloxybutyl bromide was used instead of 2-benzyloxyethyl bromide (yield 67%).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.26-7.33 (5H, m), 7.17 (1H, bs), 4.53 (2H, s), 4.39-4. 46 (1H, m), 3.96 (1H, bs), 3.64 (3H, s), 3.57-3.60 (4H, m), 2.77-2.95 (2H, m) 2.21 (1H, d, J = 8.4 Hz), 1.69-1.95 (9H, m), 1.45 (3H, s), 1.39-1.42 (9H, m) MS m / z 574.491 ([M + H] ⁺ ).

Example 6: [4R, 4aR, 11bS] -6- [4- (benzyloxy) butyl] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4 4a, 5,6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid

[4R, 4aR, 11bS] -6- [4- (Benzyloxy) butyl] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a as starting material , 5,6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester was used in the same manner as in Example 4 to obtain the title compound as a colorless solid. (Yield 95%).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.29-7.32 (5H, m), 7.17 (1H, bs), 4.48 (2H, s), 4.24-4. 35 (1H, m), 3.93 (1H, bs), 3.61-3.70 (2H, m), 3.42-3.54 (2H, m), 2.80-2.89 ( 2H, m), 2.17 (1H, d, J = 8.4 Hz), 1.63-1.94 (9H, m), 1.40 (6H, d, J = 10.0 Hz), 39 (6H, d, J = 6.8 Hz); MS m / z 558.2 ([M−H] ⁻ ).

Example 7: [4R, 4aR, 11bS] -6- [5- (benzyloxy) pentyl] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4 4a, 5,6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester

The title compound was obtained as a colorless solid in the same manner as in Example 3 except that 5-benzyloxypentyl bromide was used instead of 2-benzyloxyethyl bromide (yield 75%).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.26-7.35 (5H, m), 7.17 (1H, bs), 4.48 (2H, s), 4.24-4. 32 (1H, m), 3.94 (1H, bs), 3.61 (3H, s), 3.57-3.61 (1H, m), 3.42-3.50 (3H, m) 2.71-2.83 (2H, m), 2.18 (1H, d, J = 14.3 Hz), 1.59-1.92 (11H, m), 1.41 (6H, d, J = 10.0 Hz), 1.38 (6H, d, J = 6.8 Hz); MS m / z 588.2647 ([M + H] ⁺ ).

Example 8: [4R, 4aR, 11bS] -6- [5- (benzyloxy) pentyl] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4 4a, 5,6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid

[4R, 4aR, 11bS] -6- [5- (Benzyloxy) pentyl] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a as starting material , 5,6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester was used in the same manner as in Example 4 to obtain the title compound as a colorless solid. (Yield 95%).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.27-7.33 (5H, m), 7.17 (1H, bs), 4.47 (2H, s), 4.24-4. 34 (1H, m), 3.93 (1H, bs), 3.61-3.64 (1H, m), 3.42-3.50 (3H, m), 2.78-2.83 ( 2H, m), 2.16 (1H, d, J = 8.3 Hz), 1.59-1.96 (11H, m), 1.44 (3H, m), 1.37-1.41 ( 9H, m); MS m / z 572.2334 ([M−H] ⁻ ).

Example 9: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-6- [3- (4-methylbenzyloxy) propyl] -7-oxo-2,3 , 4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester

The title compound was obtained as a colorless solid in the same manner as in Example 3 except that 3- (4-methylbenzyloxy) propyl bromide was used instead of 2-benzyloxyethyl bromide (yield 87%) .

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.11-7.27 (5H, m), 4.49 (2H, s), 4.34-4.45 (1H, m), 3. 93 (1H, bs), 3.77-3.89 (3H, m), 3.10-3.18 (2H, m), 2.24 (3H, s), 2.13 (1H, d, J = 8.4 Hz), 1.69-1.93 (9H, m), 1.39-1.46 (12H, m); MS m / z 574.2491 ([M + H] ⁺ ).

Example 10: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-6- [3- (4-methylbenzyloxy) propyl] -7-oxo-2,3 , 4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid

[4R, 4aR, 11bS] -6- [3- (4-Methylbenzyloxy) propyl] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3 as starting material 4,4a, 5,6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester was prepared in the same manner as in Example 4 except that Obtained as a solid (55% yield).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.26-7.33 (5H, m), 4.50 (2H, s), 4.39-4.46 (1H, m), 3. 94 (1H, bs), 3.68-3.80 (2H, m), 3.11-3.16 (2H, m), 2.34 (3H, s) 2.13 (1H, d, J = 8.4 Hz), 1.69-1.92 (9H, m), 1.57 (3H, m), 1.37-1.45 (9H, m); MS m / z 558.2 ([M -H] ^- ).

Example 11: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-6- [3- (2-naphthyl) pentyl] -7-oxo-2,3,4 , 4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester

The title compound was obtained as a colorless solid in the same manner as in Example 3 except that 5- (2-naphthyl) pentyl bromide was used in place of 2-benzyloxyethyl bromide (yield 62%).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.73-7.80 (3H, m), 7.58 (1H, s), 7.37-7.45 (2H, m), 7. 30 (1H, d, J = 8.4 Hz), 7.17 (1H, bs), 4.27-4.36 (1H, m), 3.93 (1H, bs), 3.60 (3H, s), 2.76-2.82 (1H, m), 2.65-2.73 (3H, m), 2.16 (1H, d, J = 8.4 Hz), 1.59-1. 91 (13H, m), 1.53 (3H, m), 1.41 (6H, s), 1.38 (3H, s).

Example 12: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-6- [3- (2-naphthyl) pentyl] -7-oxo-2,3,4 , 4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid

[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-6- [3- (2-naphthyl) pentyl] -7-oxo-2,3,4, 4a, 5,6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester was used as a colorless solid in the same manner as in Example 4 except that methyl ester was used. Obtained (yield 77%).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.73-7.80 (3H, m), 7.58 (1H, s), 7.37-7.45 (2H, m), 7. 30 (1H, d, J = 8.4 Hz), 7.17 (1H, bs), 4.27-4.36 (1H, m), 3.93 (1H, bs), 2.76-2. 82 (1H, m), 2.65-2.73 (3H, m), 2.16 (1H, d, J = 8.4 Hz), 1.64-1.92 (13H, m), 1. 47 (3H, m), 1.38-1.42 (9H, m); MS m / z 592.2 ([M−H] ⁻ ).

Example 13: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-6- [5- (pentafluorophenyl) pentyl] -7-oxo-2,3,4 , 4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester

The title compound was obtained as a colorless solid in the same manner as in Example 3 except that 5- (pentafluorophenyl) pentyl bromide was used instead of 2-benzyloxyethyl bromide (yield 63%).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.17 (1H, bs), 4.27-4.36 (1H, m), 3.94 (1H, bs), 3.63 (3H, s), 2.76-2.82 (1H, m), 2.65-2.73 (3H, m), 2.19 (1H, d, J = 8.4 Hz), 1.57-1. 96 (13H, m), 1.39-1.44 (12H, m).

Example 14: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-5- [3,5-bis (trifluoromethyl) phenyl] pentyl-7-oxo-2 , 3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester

The title compound was obtained as a colorless solid in the same manner as in Example 3, except that 5- [3,5-bis (trifluoromethyl) phenyl] pentyl bromide was used instead of 2-benzyloxyethyl bromide. (Yield 70%).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 7.65 (1H, s) 7.58 (1H, s), 7.60 (1H, s), 7.19 (1H, bs); 80-3.92 (1H, m), 3.40-3.63 (3H, m), 2.60-2.75 (3H, m), 2.47 (1H, dd, J = 2.4 Hz) 10.8 Hz), 2.23 (1 H, d, J = 8.4 Hz), 1.55-1.94 (11 H, m), 1.45 (3 H, m), 1.38 (6 H, m) ), 1.27 (3H, s).

Examples 15-31
The compounds of Examples 15 to 31 were synthesized by the following method.

To a suspension of sodium hydride (60% mineral oil suspension; 19 mg, 0.405 mmol, 1.5 eq) in DMF (2 mL) at 0 ° C. in [4R, 4aR in DMF (1.3 mL). , 11bS] -8,10,11-trichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] A solution of azepine-4-carboxylic acid methyl ester (120 mg, 0.270 mmol) was added dropwise, followed by the corresponding benzyl bromide (0.484 mmol, 1.870) in DMF (1.3 mL). Equivalent) was added dropwise. The reaction mixture was stirred at room temperature overnight, then poured into water and extracted with CHCl ₃ (30 mL × 3). The combined organic layers were washed with water (10 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by open chromatography (hexane: AcOEt = 5: 1) to obtain the target compound.

The physical property data of the obtained compounds (Examples 15 to 31) are shown below.

Examples 32-47
The compounds of Examples 32-47 were synthesized by the following method.

A solution of the methyl ester prepared in Examples 15-31, KOH (0.4 M, 10 eq) and 18-crown ether-6 (0.1 M, 2.5 eq) in methanol / THF (15/1). Stir at 80 ° C. overnight. After cooling, the solvent was removed under reduced pressure and the residue was diluted with water (5 mL), acidified with 2N hydrochloric acid and extracted with CHCl ₃ (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (hexane: AcOEt = 2: 1) to obtain the desired carboxylic acid corresponding to the raw material. In Examples 36, 37, 40, 42, and 43, the reaction was performed at 145 ° C. for 45 minutes under microwave irradiation.

The physical property data of the obtained carboxylic acids (Examples 32-47) are shown below.

Example 48: [4R, 4aR, 11bS] -8,10,11-trichloro-6-cyclohexylmethyl-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6 , 7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester

To a suspension of sodium hydride (60% mineral oil suspension; 32 mg, 0.67 mmol, 1.5 eq) in DMF (4 mL) at 0 ° C. in [4R, 4aR in DMF (1.5 mL). , 11bS] -8,10,11-trichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] A solution of azepine-4-carboxylic acid methyl ester (200 mg, 0.45 mmol) was added dropwise. Bromomethylcyclohexane (100 μL, 1.4 g / mL, 0.82 mmol, 1.8 equiv) in DMF (1.5 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature overnight, then poured into water and extracted with CHCl ₃ (30 mL × 3). The combined organic phases were washed with water (10 mL), dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by open column (hexane: AcOEt = 5: 1) to give the title compound as a colorless solid (227.7 mg, 94% yield).

¹ H-NMR (400 MHz / CDCl ₃ ): δ = 4.14 (1H, m), 4.03 (1H, m), 3.68 (1H, m), 2.78 (1H, m), 2 .50-2.70 (3H, m), 2.37 (1H, d, J = 7.6 Hz), 1.56-1.95 (12H, m), 1.34-1.50 (9H, s), 1.06-1.31 (4H, m), 0.88-1.05 (2H, m).

Example 49: [4R, 4aR, 11bS] -8,10,11-trichloro-6-cyclohexylmethyl-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6 , 7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid

[4R, 4aR, 11bS] -8,10,11-trichloro-6-cyclohexylmethyl-9-isopropyl-4,11b-dimethyl-7-oxo- in methanol (3.7 mL) and THF (0.7 mL) 2,3,4,4a, 5,6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester (158.8 mg, 0.298 mmol), KOH (168 mg, 3. 00 mmol, 10 eq) and 18-crown ether-6 (198 mg, 0.7 mmol, 2.5 eq) were stirred at 80 ° C. overnight. After cooling, the solvent was distilled off under reduced pressure, the residue was diluted with water (5 mL), acidified with 2N hydrochloric acid, and extracted with CHCl ₃ (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (hexane: AcOEt = 2: 1) to give the title compound as a colorless solid (114.2 mg, 0.218 mmol, 73% yield).

Melting point: 229.5-231.0 ° C. (recrystallized from CH ₂ Cl ₂ / hexane); ¹ H-NMR (400 MHz / CDCl ₃ ): δ = 4.14 (1H, m), 4.03 (1H, m), 3.68 (1H, m), 2.78 (1H, m), 2.50-2.70 (3H, m), 2.37 (1H, d, J = 7.6 Hz), 1 .56-1.95 (12H, m), 1.34-1.50 (9H, s), 1.06-1.31 (4H, m), 0.88-1.05 (2H, m) MS m / z 528.17 ([M ( ³⁵ Cl ₃ ) + H] ⁺ ), 532.177 ([M ( ³⁵ Cl ³⁷ Cl ₂ ) + H] ⁺ ), 542.19 ([M ( ³⁵ Cl ₃ ) + Na ^{_{] +), 544.18 ([M}} (35 Cl 2 37 Cl) + Na] +), 546.18 ([M (35 Cl 3 ^{_{Cl 2) + Na] +)}} ; elemental analysis calcd _{(C 28 H 32 Cl 3 NO} 3: C, 62.64; H, 6.01; N, 2.61; Found: C, 62.81; H, 6.18; N, 2.53.

Example 50: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6-pent-4-ynyl-2,3,4,4a, 5 6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester

[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6,7,11b- in DMF (10 ml) To a solution of octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester (596 mg, 1.45 mmol) at 0 ° C. was added sodium hydride (76.0 mg, 1.90 mmol) at 0 ° C. For 10 minutes. Thereafter, 5-iodopent-1-yne (1.40 g, 7.22 mmol) was added and stirred overnight at room temperature. The reaction was quenched by adding water and extracted with Et ₂ O. The organic phase was washed with water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 7: 1 v / v) to give the title compound as a white solid (562 mg, 81%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.17 (1H, bs), 4.24-4.31 (1H, m), 3.93 (1H, bs), 3.62-3. 70 (1H, m), 3.62 (3H, s), 3.01-3.08 (1H, m), 2.86 (1H, d, J = 16.2 Hz), 2.17 (1H, d, J = 8.5 Hz), 2.24-2.29 (2H, m), 1.96-1.98 (1H, m), 1.72-1.90 (5H, m), 1. 63-1.72 (3H, m), 1.43 (3H, s), 1.38 (9H, m).

Example 51: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6-pent-4-ynyl-2,3,4,4a, 5 6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid

[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6-pent-4-ynyl-2,3,4,4a, in methanol (50 ml) To a solution of 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester (2.00 g, 4.18 mmol) was added potassium hydroxide (2.35 g, 41.9 mmol). ), 18-crown ether-6 (2.76 g, 10.4 mmol) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was extracted with CHCl ₃ and the organic phase was washed with 2M hydrochloric acid followed by water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 3: 1 v / v) to give the title compound as a white solid (1.86 g, 96%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.17 (1H, bs), 4.28 (1H, m), 3.92 (1H, bs), 3.69 (1H, dd, J = 16.1 Hz, J = 8.6 Hz), 3.04 (1H, m), 2.97 (1H, d, J = 16.3 Hz), 2.26 (2H, m), 2.14 (2H, d, J = 8.4 Hz), 1.81-2.00 (6H, m), 1.72 (2H, m), 1.37-1.43 (12H, m).

Example 52: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- [5- (2-pyridyl) pent-4-ynyl] -2 , 3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid

[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6-pent-4-ynyl-2,3,4, in Et ₃ N (3 ml) 4a, 5,6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid (100 mg, 0.215 mmol) in a solution of 2-iodopyridine (52.9 mg, 0.258 mmol, 1.2 eq), [Pd (Ph ₃ )] ₂ Cl ₂ (20.0 mg, 0.0285 mmol), and CuI (20.0 mg, 0.105 mmol) were added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched by adding water and extracted with Et ₂ O. The organic phase was washed with 2M hydrochloric acid and then with water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 3: 1 v / v) to give the title compound as a colorless oil (19.7 mg, 17% yield). The resulting oil solidified later.

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 8.49 (1H, m), 7.72 (1H, t, J = 6.2 Hz), 7.42 (1H, d, J = 7.9 Hz) ), 7.27-7.31 (1H, m), 7.18 (1H, bs), 4.28-4.35 (1H, m), 3.92 (1H, bs), 3.80 ( 1H, d, J = 16.2 Hz), 3.50-3.65 (2H, m), 2.58-2.65 (1H, m), 2.44-2.52 (1H, m), 2.25-2.40 (1H, m), 1.78-2.05 (6H, m), 1.60-1.64 (2H, m), 1.52 (3H, s), 1. ^{45 (3H, s), 1.37-1.43} (6H, m); 13 C-NMR (100MHz, CDCl 3): δ = 179.6,168.1,147.8,146.7,1 2.0, 141.0, 137.9, 135.9, 133.5, 128.2, 123.3, 92.5, 79.8, 53.6, 50.6, 48.5, 46. 7, 40.8, 38.9, 35.7, 26.1, 23.2, 19.6, 19.3, 19.2, 18.6, 16.2; ESI-HRMS: calculated value (C ₃₀ H ₃₃ Cl ₂ N ₂ O ₃ ) ([M−H] ⁻ ): 539.1868; Found: 539.1872; Melting point: 135.5-136.0 ° C.

Example 53: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- [5- (3-thienyl) pent-4-ynyl] -2 , 3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid

The title compound was obtained in the same manner as in Example 52 except that 3-iodothiophene was used instead of 2-iodopyridine (yield 14%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.29 (1H, dd, J = 3.0 Hz, J = 1.1 Hz), 7.12 (1H, dd, J = 5.0 Hz, J = 3.0 Hz), 7.17 (1H, bs), 7.00 (1H, dd, J = 5.0 Hz, J = 1.2 Hz), 4.30 (1H, m), 3.94 (1H, bs), 3.57 (1H, dd, J = 16.0 Hz, J = 8.7 Hz), 3.09 (1H, m), 2.88 (1H, d, J = 16.3 Hz), 2. 45 (2H, t, J = 7.1 Hz), 2.06 (1H, d, J = 8.4 Hz), 1.97-2.04 (1H, m), 1.75-1.95 (5H , m), 1.70 (2H, m), 1.37-1.46 (12H, m); 13 C-NMR (100MHz, CDCl 3): δ = 182.8,1 8.3, 146.1, 141.2, 136.1, 133.8, 129.9, 127.9, 125.0, 122.5, 88.4, 76.6, 50.5, 49. 6, 48.5, 47.2, 39.7, 39.0, 37.0, 27.2, 21.8, 19.6, 19.3, 18.1, 17.9, 16.8; mass calcd _{(C 29 H 33 Cl 2 NO} 3 S): C: 63.73, H: 6.09, N: 2.56; Found C: 64.11, H: 6.49, N: 2.41; ESI-HRMS: (C ₂₉ H ₃₂ Cl ₂ NO ₃ S ([M−H] ⁻ )): 544.1480; Found: 544.1484; Melting point: 124.0-124.3 ° C. Recrystallized from AcOEt / hexane, colorless cubic crystals).

Example 54: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6-pent-4-ynyl-2,3,4,4a, 5 6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methoxymethyl ester

[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6-pent-4-ynyl-2,3,4,4a, in triethylamine (4 ml) To a solution of 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid (261 mg, 0.562 mmol) was added methoxymethyl chloride (91.0 mg, 1.13 mmol), Stir at room temperature for 30 minutes. Water was added to the reaction mixture and extracted with Et ₂ O, and the organic phase was washed with 2M hydrochloric acid then water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 5: 1 v / v) to give the title compound as a white solid (258 mg, 90%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.17 (1H, bs), 5.17 (2H, dd, J = 20.2 Hz, J = 5.9 Hz), 4.27 (1H, m ), 3.92 (1H, bs), 3.68 (1H, dd, J = 16.1 Hz, J = 8.6 Hz), 3.41 (3H, s), 3.04 (1H, m), 2.93 (1H, d, J = 16.2 Hz), 2.25 (2H, td, J = 7.1 Hz, J = 1.7 Hz), 2.19 (1H, d, J = 8.5 Hz) 1.80-2.00 (7H, m), 1.72 (2H, m), 1.44 (3H, s), 1.37-1.40 (9H, m).

Example 55: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- [5- (pyrazin-2-yl) pent-4-ynyl] -2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methoxymethyl ester

[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6-pent-4-ynyl-2,3,4,4a, in triethylamine (3 ml) To a solution of 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methoxymethyl ester (100 mg, 0.197 mmol) was added 2-iodopyrazine (48.7 mg, 0.236 mmol). 1.2 equivalents), [Pd (Ph ₃ )] ₂ Cl ₂ (20.0 mg, 0.0285 mmol), and CuI (20.0 mg, 0.105 mmol) were added and stirred at room temperature overnight. Water was added to the reaction mixture, extracted with Et ₂ O, washed with 2M hydrochloric acid and then with water. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 3: 1 v / v) to give the title compound as a white solid (94.6 mg, 82% yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 8.62 (1H, m), 8.46 (1H, m), 8.42 (1H, m), 7.18 (1H, bs), 5 .12 (2H, m), 4.37 (1H, m), 3.93 (1H, bs), 3.71 (1H, dd, J = 16.1 Hz, J = 8.7 Hz), 3.37 (3H, s), 3.06 (1H, m), 2.90 (1H, d, J = 16.1 Hz), 2.57 (2H, t, J = 7.2 Hz), 2.20 (1H , D, J = 8.6 Hz), 1.75-2.10 (6H, m), 1.71 (2H, m), 1.45 (3H, s), 1.35-1.45 (9H) , M).

Example 56: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- [5- (pyrazin-2-yl) pent-4-ynyl] -2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid

[4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- [5- (pyrazin-2-yl) in 3M hydrochloric acid / THF (2 ml / 2 ml) ) Pent-4-ynyl] -2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methoxymethyl ester (100 mg, 0.17 mmol) The solution of was stirred at 50 ° C. for 8 hours. The reaction mixture was diluted with water and extracted with Et ₂ O. The organic phase was washed with water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 4: 1 v / v) to give the title compound as a white solid (66.4 mg, 72% yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 8.68 (1H, m), 8.51 (1H, m), 8.46 (1H, m), 7.16 (1H, bs), 4 .34 (1H, m), 3.93 (1H, bs), 3.64 (1H, m), 3.52 (1H, m), 3.38-3.47 (1H, m), 2. 65 (1H, m), 2.54 (1H, m), 2.20-2.30 (1H, m), 1.75-2.00 (6H, m), 1.63-1.66 ( 2H, m), 1.49 (3H, s), 1.35 to 1.45 (9H, m); ¹³ C-NMR (100 MHz, CDCl ₃ ): δ = 180.1, 168.3, 148. 0, 146.3, 143.4, 142.6, 141.1, 139.8, 136.0, 133.5, 95.4, 78.0, 51.7, 50.1, 4 .3, 47.0, 40.1, 38.9, 36.4, 26.2, 22.3, 19.5, 19.2, 18.4, 18.2, 16.6; ESI-HRMS : Calculated value (C ₂₉ H ₃₄ Cl ₂ N ₃ O ₃ ([M + H] ⁺ )): 542.9777; found: 542.1972; melting point: 134.6-135.0 ° C.

Example 57: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- [5- {4-[(tert-butoxy) carbonylaminomethyl] Phenyl} pent-4-ynyl] -2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methoxymethyl ester

The title compound was obtained in the same manner as in Example 55 except that 1- (tert-butoxycarbonylaminomethyl) -4-iodobenzene was used instead of 2-iodopyrazine (yield 39%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.33 (2H, m), 7.15-7.21 (3H, m), 4.97-5.22 (2H, m), 4. 82 (1H, bs), 4.35 (1H, m), 4.26 (2H, d, J = 5.5 Hz), 3.94 (1H, bs), 3.72 (1H, dd, J = 16.1 Hz, J = 8.7 Hz), 3.34 (3 H, s), 3.09 (1 H, m), 2.93 (1 H, d, J = 16.2 Hz), 2.47 (2 H, t, J = 6.9 Hz), 2.20 (1H, d, J = 8.4 Hz), 1.50-2.10 (8H, m), 1.35-1.50 (21H, m).

Example 58: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- [5- {4- (aminomethyl) phenyl} pent-4- Inyl] -2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid

[4R, 4aR, 11bS] -8,10-Dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- [5- {4-[(tert-butoxy) carbonylaminomethyl] phenyl as starting material } Pent-4-ynyl] -2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methoxymethyl ester The title compound was obtained in the same manner as in Example 56 (yield 66%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.36 (2H, d, J = 8.3 Hz), 7.25 (3H, m), 4.18 (1H, m), 3.80- 3.96 (3H, m), 3.54 (1 H, dd, J = 16.0 Hz, J = 8.9 Hz), 3.22 (1 H, m), 3.14 (1 H, m), 3. 07 (1H, d, J = 16.0 Hz), 2.42 (2H, t, J = 7.0 Hz), 2.23 (1H, d, J = 8.6 Hz), 1.75-2.00 (4H, m), 1.50-1.75 (4H, m), 1.30-1.50 (12H, m); ¹³ C-NMR (100 MHz, CD ₃ OD): δ = 185.3, 170.9, 149.6, 142.2, 137.6, 134.7, 134.6, 133.6, 130.1, 126.3, 91.5, 81.9 53.4, 51.5, 51.4, 50.2, 44.4, 41.5, 40.9, 39.2, 28.4, 22.7, 20.3, 20.1, 20 .. 0, 17.9; ESI-HRMS: Calculated (C ₃₂ H ₃₉ Cl ₂ N ₂ O ₃ ([M + H] ⁺ )): 569.2338; Found: 569.2342; Melting point: 196.4-197. 0 ° C.

The automation patch clamp method using a biological activity test Ion Works Quattro (Molecular Device Co.), the activity evaluation of compounds using human BK channels CHO cells expressing the α-subunit (obtained from RIKEN Bioresource Center) Went. The test was performed based on the description of VHJohn et al. J Biol Screen 2007; 12; 50-60, A.Finkel et al. J Biol Screen 2006; 11; 488-496. Measurements are also given in Finke, A .; Wittel, A .; Yang, N .; Handram, S .; Hughes, J .; Costantin, J., Journal of Biomolecular Screening, 2006, 11 (5), 488-496. According to the described Population Patch Clamp method.

The test was performed using a 384 well PatchPlate PPC ^™ device. Add 10 μL of External buffer (NaCl 137 mM, KCl 4 mM, MgCl ₂ / 6H ₂ O 1 mM, CaCl ₂ / 2H ₂ O 2 mM, Glucose 10 mM, HEPES 10 mM (pH 7.4)) to each well, and then CHO cell suspension 5 mL of BAPTA-AM (Dojindo Chemicals) was added to 20 μM (cell concentration of 2.0 × 10 ⁶ cells / ml in the external buffer). After that, Amphotericin B (Ionophore) (Sigma-Aldrich) was added to Internal buffer (KCl 140 mM, MgCl ₂ / 6H ₂ O 1 mM, HEPES 20 mM (pH 7.3)) to a final concentration of 108 μM, and ions were added to the cell membrane. A permeating pore was formed, and the Pre current was measured. Thereafter, DIDS (inhibitor of Ca ²⁺ -dependent Cl ⁻ Channel, Sigma-Aldrich) is adjusted to a final concentration of 300 μM, and Ionomycin (increasing intracellular Ca ²⁺ concentration, Sigma-Aldrich) is added to a final concentration of 1 Each was added to an external buffer so as to be 2 μM, and the Post-1st current was measured. Thereafter, the test compound (DMSO solution, final concentration 30 μM) was added to the external buffer, and the post-2nd current was measured. Note that each measurement of current was performed with the potential fixed at 100 mV. FIG. 1 shows the value of the current at the time of adding the test compound as the human BK channel opening activity value of the test compound when the measured pre-current before the addition of the compound is 100.

[Test results]
As a comparative example, IpA (the following formula):

It was used. From the test results, it was confirmed that the compound according to the present invention has human BK channel opening activity.

The novel compound provided by the present invention has potassium channel opening activity, particularly BK channel opening activity, and is useful as a pharmaceutical product. Furthermore, the synthesis method of the compound and the intermediate useful for the synthesis of the compound provided by the present invention are useful in the production of the present invention.

Claims (11)

1. Formula (I):
   

   

   ^{Wherein, R 1, R 2, R} 3 and ^{R 4} are independently hydrogen atom, halogen atom, hydroxy, cyano, nitro, _{carboxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6} Selected from alkynyl, C _1-6 alkoxy, —NR ¹¹ R ¹² , —S (O) _n C _1-6 alkyl (where n is an integer selected from 0 to 2) and C _1-6 alkylcarbonyl Wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy and —S (O) _n C _1-6 alkyl are one or more halogen atoms on a carbon atom Optionally substituted by atoms or hydroxy;
   R ¹¹ and R ¹² are independently selected from a hydrogen atom, C _1-6 alkyl and C _1-6 alkylcarbonyl, or together with a nitrogen atom to form a 5- to 7-membered heterocycle Well;
   R ⁵ is —COOR ¹³ , —CONR ¹⁴ R ¹⁵ or tetrazol-5-yl;
   R ¹³ is a hydrogen atom or C _1-6 alkyl optionally substituted by one or more Ra;
   R ¹⁴ and R ¹⁵ are independently selected from a hydrogen atom and C _1-6 alkyl optionally substituted by one or more Ra, or together with the nitrogen atom to which it is attached a 5- to 7-membered heterocycle May form;
   R ⁶ and R ⁷ are independently selected from a hydrogen atom, hydroxy and C _1-10 alkyl;
   X is a hydrogen atom, C _1-10 alkyl optionally substituted by one or more Ra, C _2-10 alkenyl optionally substituted by one or more Ra, or substituted by one or more Ra. _May be C _2-10 alkynyl;
   Ra is independently, a halogen atom, hydroxy, carboxy, cyano, one or more optionally substituted by Rb _{C 1-6} alkoxycarbonyl, one or more optionally substituted by Rb _{C 1-6} alkoxy, C _3-10 cycloalkyl _optionally substituted by one or more Rb, aryl optionally substituted by one or more Rc, heterocyclyl optionally substituted by one or more Rc, substituted by one or more Rc Optionally substituted aryloxy, one or more heterocyclyloxy optionally substituted by Rc, —NR ²¹ R ²² , and —S (O) _n R ^23, wherein n is an integer selected from 0 to 2 Is selected from;
   R ²¹ and R ²² are independently a hydrogen atom, C _1-6 alkyl optionally substituted by one or more Rb, aryl optionally substituted by one or more Rc, and substituted by one or more Rc Selected from optionally substituted heterocyclyl;
   R ²³ is C _1-6 alkyl optionally substituted by one or more Rb;
   Rb is independently a halogen atom, hydroxy, cyano, C _1-6 alkoxy, hydroxy C _1-6 alkoxy, aryl optionally substituted by one or more Rc, and optionally substituted by one or more Rc Heterocyclyl, aryloxy optionally substituted by one or more Rc, heterocyclyloxy optionally substituted by one or more Rc, C _7-14 aralkyloxy optionally substituted by one or more Rc, heterocyclyl C _1-6 alkoxy (the heterocyclyl moiety contained in the group may be substituted by one or more Rc), C _1-6 alkoxy C _1-6 alkoxy, hydroxy C _1-6 alkoxy C _1-6 alkoxy, C _1-6 alkoxy _{C 1-6} alkoxy _{C 1-6 alkoxy, C 7 - 14} aralkyl Carboxymethyl _{C 1-6} alkoxy (the aryl moiety included in the group may be substituted by one or more Rc), heterocyclyl _{C 1-6} alkoxy _{C 1-6} alkoxy (heterocyclyl moiety included in the group, may be substituted by one or more Rc), ^- in ^NR 24 ^{R 25} and -S _(O) ^{n R 26} _(wherein n is selected from an integer selected from 0 to 2); wherein, The alkoxy moiety contained in the group may be substituted with one or more halogen atoms;
   R ²⁴ and R ²⁵ are independently selected from a hydrogen atom and C _1-6 alkyl;
   R ²⁶ is C _1-6 alkyl _optionally substituted with a halogen atom;
   Rc is, independently, a halogen atom, hydroxy, cyano, nitro, _{carboxy, C 1-6 alkoxycarbonyl, C 1-6} alkylcarbonyloxy, one or more halogen atoms optionally substituted by a _{C 1-6} alkoxy, C _1-6 alkyl _optionally substituted with one or more halogen atoms, phenoxy optionally substituted with one or more halogen atoms, phenyl optionally substituted with one or more halogen atoms, one or more halogens Heterocyclyloxy optionally substituted with one atom, heterocyclyl optionally substituted with one or more halogen atoms, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkoxy, hydroxy C _{1 -6} alkyl, hydroxy _{C 1-6} alkoxy, amino _{C 1-6} alkyl, and amino _{C 1-} It is selected from alkoxy;
   Further, the substitutable carbon atom contained in the cyclohexane ring in the formula may be independently substituted with a substituent selected from hydroxy, C _1-6 alkyl and oxo, and the substitution contained in the azepine ring in the formula Possible carbon atoms may be independently substituted with substituents selected from hydroxy and C _1-6 alkyl]
   Or a pharmaceutically acceptable salt or solvate thereof.
2. R ⁴ is a halogen atom, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, or —S (O) _n C _1-6 alkyl (where n is an integer selected from 0 to 2) Wherein the C _1-6 alkyl, C _1-6 alkoxy and —S (O) _n C _1-6 alkyl may be substituted on the carbon atom by one or more halogen atoms or hydroxy Or a pharmaceutically acceptable salt or solvate thereof.
3. X is C _2-4 alkyl optionally substituted by one or more Ra, C _2-4 alkenyl optionally substituted by one or more Ra, or C optionally substituted by one or more Ra _2-4 alkynyl; Ra is as defined in claim 1; a compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof.
4. The compound according to any one of claims 1 to 3, wherein R ² is a hydrogen atom or a halogen atom, a pharmaceutically acceptable salt thereof, or a solvate thereof.
5. The compound according to any one of claims 1 to 4, wherein R ⁴ is a halogen atom, a pharmaceutically acceptable salt thereof, or a solvate thereof.
6. The compound according to any one of claims 1 to 5, wherein R ⁵ is -COOR ¹³ , a pharmaceutically acceptable salt thereof, or a solvate thereof.
7. Formula (Ia):
   

   

   Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and X are independently as defined in any one of claims 1 to 6
   The compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or a solvate thereof, represented by:
8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, or a solvate thereof.
9. The pharmaceutical composition according to claim 8, which is used for treatment or prevention of a disease selected from cerebral infarction, cerebral vascular ischemia, ischemic heart disease, frequent urination, urinary incontinence disease, overactive bladder and bronchial asthma. .
10. A potassium channel opener comprising the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
11. The potassium channel opener according to claim 10, which acts on a BK channel.

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