JP4873614B2 - Potassium channel opener - Google Patents

Description

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⁺ -dependent 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, 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 the binding sites of the BK channel opener are also arranged in four places in a rotationally symmetrical manner.

  The binding mechanism of α and β subunits and the molecular mechanism of functional regulation are unknown, but natural compounds that bind to α subunits and exhibit open activity have already been found. 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 dichlorodihydroabietic acid (formula C) has an opening activity via the α subunit (Patent Document 1, Non-Patent Documents 3 and 3).

International Publication WO2002 / 087559 Pamphlet J. et al. Pharmacol. Sci. 94 (4): 339-347, 2004; Molecular Pharmacology, 62, 836-846, 2002; Bioorganic Medicinal Chemistry Letters, Vol. 13, pp. 3971-3974, 2003

  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 conducted extensive research to achieve the above-mentioned problems, and as a result, discovered that a group of compounds having a benzazepine skeleton and dimers thereof had BK channel opening activity, and completed the present invention. .

  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 method for synthesizing the compound, an intermediate useful for the synthesis of the compound, and a pharmaceutical composition containing the compound.

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

[Wherein R ¹ , R ² and R ³ independently represent a hydrogen atom, a halogen atom, hydroxy, cyano, nitro, carboxy, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C Selected from _1-10 alkoxy, —NR ¹¹ R ¹² , —S (O) _n C _1-10 alkyl (where n is an integer selected from 0 to 2) and C _1-10 alkylcarbonyl, wherein And the C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkoxy may be substituted on the carbon atom by one or more halogen atoms or hydroxy;
R ¹¹ and R ¹² are independently selected from a hydrogen atom, C _1-6 alkyl and C _1-10 alkylcarbonyl, or together with a nitrogen atom to form a 5- to 6-membered heterocycle Well;
R ⁴ is selected from —COOR ¹³ , —CONR ¹⁴ R ¹⁵ and tetrazol-5-yl;
R ¹³ represents a hydrogen atom, C _1-6 alkyl (wherein the alkyl is a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _7-14 aralkyloxy and C ₁ Optionally substituted by one or more substituents selected from _-6 alkoxycarbonyl) and C _7-14 aralkyl (wherein the aralkyl is selected from halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy) And optionally substituted on the benzene ring by one or more substituents selected from
R ¹⁴ and R ¹⁵ may be independently selected from a hydrogen atom, hydroxy and C _1-6 alkyl, or together with a nitrogen atom to be bonded to form a 5-6 membered heterocycle;
R ⁵ and R ⁶ are independently selected from a hydrogen atom, hydroxy and C _1-10 alkyl;
X is selected from a hydrogen atom, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, wherein the C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl is carbon The atom may be substituted by one or more C _1-10 alkoxy, halogen atom, hydroxy, aryl or heterocyclyl, wherein the aryl and heterocyclyl are halogen atom, C _1-6 alkyl, C _1-6 alkoxy, cyano , Nitro, carboxy, hydroxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, —NR ¹¹ R ¹² , —S (O) _n C _1-10 alkyl (where n is an integer selected from 0 to 2) And optionally substituted by one or more substituents selected from C _1-10 alkylcarbonyl;
Further, the substitutable carbon atom contained in the cyclohexane ring in the formula may be independently substituted with a substituent selected from hydroxy and C _1-6 alkyl, and the substitutable carbon atom contained in the azepine ring in the formula 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 yet another aspect of the present invention, the formula (II):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above;
Y represents the formula (III):
^{-X 1 -Q-X 2 - (} III)
Wherein Q is a direct bond, arylene or heteroarylene,
X ¹ and X ² are independently selected from C _2-10 alkylene, C _2-10 alkenylene and C _2-10 alkynylene, wherein X ¹ and X ² are attached to Q via an oxygen or sulfur atom. The arylene and heteroarylene may be a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, cyano, nitro, carboxy, hydroxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, — Substituted by one or more substituents selected from NR ¹¹ R ¹² , —S (O) _n C _1-10 alkyl (where n is an integer selected from 0 to 2) and C _1-10 alkylcarbonyl. May be)
A divalent linking group represented by:
The substitutable carbon atom contained in the cyclohexane ring in the formula may be independently substituted with a substituent selected from hydroxy and C _1-6 alkyl, and the substitutable carbon contained in the azepine ring in the formula 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 following steps a) to d):
a) Formula (XI):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in formula (I), or each substituent capable of protection is protected by a protecting group. It is good]
Is oxidized to formula (XII):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in formula (XI)]
Obtaining
b) A compound of formula (XII) is represented by formula (XIII):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in formula (XI), R ¹⁰ is a hydrogen atom, or —SO ₂ —R ¹⁶ (where And R ¹⁶ is C _1-6 alkyl, C _1-6 haloalkyl, phenyl or 4-tolyl)]
Converting to:
c) A compound of formula (XIII) is represented by formula (XIV):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in formula (XI)]
And d) converting the compound of formula (XIV) to formula (XV) or (XVI):
L-X (XV)
L-Y-L (XVI)
[Wherein, X is as defined in claim 1, Y is as defined in claim 2, and L is a leaving group (including a halogen atom, a mesyl group, a tosyl group, a trifluoromethanesulfonyl group)] Each substituent selected independently from or capable of protection may be protected by a protecting group]
A compound represented by the formula (I) or (II), which comprises a step of reacting with a compound and deprotecting in the presence of a protecting group to obtain a compound represented by the formula (I) or (II) A method is also provided.

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

[Wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in formula (I);
R ⁷ and R ⁸ are hydrogen atoms or together with the carbon atoms to which they are attached form a carbonyl group;
R ²¹ and R ²² independently represent a hydrogen atom, C _1-6 alkyl, C _1-10 alkylcarbonyl and —S (O) _n C _1-10 alkyl (where n is an integer selected from 0 to 2) Together with the nitrogen atom to which it is attached may form a 5-6 membered heterocycle;
The substitutable carbon atom contained in the octahydronaphthalene ring in the formula may be independently substituted with a substituent selected from hydroxy and C _1-6 alkyl]
Or a pharmaceutically acceptable salt or solvate thereof. The compound can be used as a synthetic intermediate for producing the formulas (I) and (II), and is a compound represented by the formula (VI) of the step a) in the above synthesis method or the formula (b) VII). Furthermore, the compound of formula (IV) is also useful in that it itself has potassium channel opening activity.

In certain embodiments of the present invention, R ¹ and R ³ in formulas (I), (II) and (IV) are independently selected from hydrogen and halogen atoms; R ⁴ is —COOR ¹³ May be. In the formula, R ² may be C _1-10 alkyl.

  The compounds according to the present invention also include compounds having the stereochemistry represented by the following formulas (Ia), (IIa) and (IVa):

  According to a further aspect of the invention, there is also provided a pharmaceutical composition comprising a compound of formula (I), (II) or (IV), or a pharmaceutically acceptable salt thereof, or a solvate thereof. . The compound is not particularly limited, but for example for the 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 Can be used.

  According to a further aspect of the invention, a potassium channel opener comprising a compound of formula (I), (II) or (IV), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in particular BK Potassium channel openers that act on the channels are 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, and the like, for example, C _1-6 alkyl And C _1-3 alkyl are also included.

As used herein, “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 are also included.

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 are included, 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, such as 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 are included, for example, C _1-6 alkoxy and C _{1 -3} alkoxy and the like are also included. Further, in the present specification, “C _1-6 alkoxy” includes, for example, C _1-3 alkoxy and the like.

As used herein, “C _1-6 haloalkyl” means C _1-6 alkyl substituted with one or more halogen atoms, and includes, for example, C _1-3 haloalkyl, specifically trifluoromethyl and the like. .

As used herein, “C _1-6 alkoxy” means C _1-6 alkoxy substituted with one or more halogen atoms, and includes, for example, C _1-3 haloalkoxy, specifically trifluoromethoxy and the like. It is.

In the present specification, “—S (O) _n C _1-10 alkyl” means C _1-10 alkylthio, C _1-10 alkylsulfenyl, or C _1-10 alkylsulfonyl. The moiety is a C _1-10 alkyl group as defined above. The -S _{(O) n C 1-10} alkyl also includes _{-S (O) n C 1-6} alkyl.

As used herein, “C _1-10 alkylcarbonyl” means an alkylcarbonyl group having a C _1-10 alkyl group already defined as an alkyl moiety, and includes, for example, C _1-6 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, “aryl” means an aryl group having an aromatic hydrocarbon ring having 6 to 10 carbon atoms, and includes, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.
In this specification, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

As used herein, “C _1-6 haloalkyl” means a C _1-6 haloalkyl group substituted with one or more halogen atoms having a C _1-6 alkyl group as an alkyl moiety. Fluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, pentafluoroethyl and the like are included. Preferable C _1-6 haloalkyl groups include, for example, linear or branched ones having 1 to 3 carbon atoms, and include trifluoromethyl, trifluoroethyl, pentafluoroethyl and the like.

In the present specification, the “5- to 6-membered heterocycle” includes, for example, pyrrole, pyrazole, imidazole, pyrrolidine, piperidine, piperazine and morpholine.
As used herein, “arylene” means a divalent linking group composed of an aromatic carbocycle, and includes phenylene (including ortho, meta, and para substitution) and naphthylene. Particularly preferred arylene groups in the present invention are o-phenylene and p-phenylene.

  In the present specification, “heteroarylene” means a divalent linking group composed of an aromatic heterocycle, such as pyridinylene (2,3-, 2,4-, 2,5-, 2,6-, 3). , 4- and 3-5-substituted), thiophenylene (including 2,3-, 2,4-, 2,5- and 3,4-substituted) and the like.

The compounds of the above formulas (I), (II) and (IV) include various stereoisomers such as tautomers, geometric isomers and optical isomers, and mixtures thereof.
In the present specification, the “pharmaceutically acceptable salt” is not particularly limited as long as it is a salt that can be used as a pharmaceutical. In the compounds of the above formulas (I), (II), and (IV), for example, R Carboxylates where ⁴ is carboxy are included. 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; and acidic amino acids such as aspartic acid, glutamic acid Examples include acid addition salts.

Furthermore, the compound of the present invention includes hydrates, various pharmaceutically acceptable solvates and crystal polymorphs.
The compounds of formulas (I) and (II) according to the present invention can be synthesized, for example, by the steps shown in the following scheme.

In the above scheme, formulas (XI) to (XIV) are as previously defined.
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. Although the process is not particularly limited, it 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 hydroxylamine 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 , NaOH, etc.). Although the process is not particularly limited, it 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, but in order to carry out step 1-3 with a higher yield, R ¹⁰ is converted to —SO ₂ —R ¹⁶ (eg, mesyl, tosyl, benzenesulfonyl, trifluoro). It may be converted to lomethanesulfonyl. The transformation 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, and P ₂ O _{5. 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.

In the above scheme, formulas (I), (II) and (XIV) are as defined above, and X, Y and L are also as defined above.
Both steps 2-1 and 2-2 can be carried out in a suitable solvent (eg, methanol, ethylene glycol, etc.) in the presence of a suitable base (eg, potassium hydroxide, etc.), and further suitable additives. (For example, crown ether (18-crown-6-ether etc.) etc.) may be used. The reaction conditions are not particularly limited, but the reaction can be performed 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, preferable L includes a halogen atom (for example, an iodine atom and a bromine atom), trifluoromethanesulfonyloxy, tosyloxy, mesyloxy and the like.

[Wherein m is an integer selected from 1 to 8, and R ^{1 to} R ⁶ are as defined above in formula (XIV)]
Step 3-1 can be performed using a halogenated alkyne (eg, 5-iodopent-1-yne) under the same conditions as in Step 2-1.

Step 3-2 uses an appropriate arylene compound (for example, o-diiodobenzene, m-diiodobenzene, p-diiodobenzene, 2,7-diiodofluorene, etc.) and a suitable catalyst (for example, Pd (PPh ₃ ), Pd (PPh ₃ ) ₂ Cl ₂ / CuI and the like) and additives (for example, triethylamine and the like) can be used. 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 100 ° C., and a reaction time of 5 hours to 3 days, preferably 15 hours to 25 hours.

In the above scheme, a protecting group may be introduced for a functional group that needs to be protected. It will be appreciated that the selection of such protecting groups and methods for their introduction can be readily accomplished by those skilled in the art of technical distribution. For example, in the formulas (I), (II) and (IV), when R ⁴ is carboxy, the carboxy is converted to an appropriate ester (eg, C _1-10 alkyl ester, C _7-14 aralkyl ester, etc.) The desired compound can be obtained by carrying out the reaction and then deprotecting under appropriate conditions (such as acid or alkali hydrolysis or hydrogenation).

  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 preparations include, for example, injections such as subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections; 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 and / or prophylactically effective amount of a compound of formula (I), (II) or (IV) above may be included. In the present invention, the compound of the above formula (I), (II) or (IV) is generally 0.1 to 20000 mg / day / adult, for example, 10 to 200 mg / day / adult, preferably 30 to 100 mg / day / adult. Can be used in doses. 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.

  EXAMPLES Hereinafter, although the preferable Example of this invention is described in detail, this invention is not limited to these Examples.

Reagents and data measurement Unless otherwise stated, purchased reagents were used without further purification. ¹ H-NMR was measured using a Brucker advanced spectrometer (400 MHz). Chemical shifts are expressed in ppm. When heavy chloroform (CDCl ₃ ) is used as the measurement solvent, tetramethylsilane (TMS) is used as an internal standard, and when heavy methanol (CD ₃ OD) is used, its own peak is displayed. Used as an 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: 13-amino-13-deisopropyldehydroabietic acid methyl ester

  [Step 1] Preparation of 12-bromodehydroabietic acid

  12- (sodium sulfo) dehydroabietic acid (prepared based on Journal of Chemical Society of Japan, Vol. 8, pp. 874-876, 1992; 10.0 g, 0.020 mol) in a solution of bromine (230 mL) A solution of 5.5 g, 0.035 mol, 1.7 eq.) And KBr (9.2 g, 0.077 mol, 3.8 eq.) In water (230 mL) was added at 120 ° C. over 1 hour. After stirring at 120 ° C. for 30 minutes, the reaction mixture was stirred at ambient temperature for 1.5 hours and filtered. Ethyl acetate (600 mL) was added to the filtrate, the organic layer was separated, the organic layer was washed with water and brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized with ethanol / water to give the title compound as a colorless powder (6.4 g, 4.497 mmol, 82% yield).

Melting point: 200-203 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.20 (3H, d, J = 8.4 Hz, C H ₃ CH), 1.21 (3H, s, CH ₃ ), 1.22 (3H, d, J = 7.1 Hz, C H ₃ CH), 1.28 (3H, s, CH ₃ ), 1.54-1.57 (2H, m, CH × 2), 1 .76-1.86 (5H, m, CH × 5), 2.19 (1H, d, J = 10.3 Hz, CH), 2.26 (1H, d, J = 12.8 Hz, CH), _{2.84-2.88 (2H, m, CH 2} ), 3.23-3.30 (1H, m, CH 3 C H), 6.92 (1H, s, ArH), 7.36 (1H ^{, s, ArH); LRMS (} FAB) m / z378 ([M (79 Br) + H] +), 380 ([M (81 Br) + H] +); original Elementary analysis, calculated value C ₂₀ H ₂₇ BrO ₂ : C; 63.33, H; 7.17. Measurement: C; 63.12, H; 7.08.

[Step 2] Preparation of 12-bromodehydroabietic acid methyl ester To a solution of 12-bromoabietic acid (6.3 g, 0.017 mol) in methanol (15 mL) and PhMe (22 mL), trimethylsilyldiazomethane (hereinafter also referred to as TMSCHN _2). 2.0M diethyl ether solution (10.8 mL, 0.022 mol, 1.3 eq.) Was added at room temperature, and the mixture was stirred at room temperature for 20 minutes. After quenching excess TMSCHN ₂ with acetic acid, the reaction mixture was concentrated under reduced pressure and then purified by flash SiO ₂ column chromatography ( n -hexane only → n -hexane: AcOEt = 10: 1) to give the title compound Obtained as a colorless solid (6.0 g, 015 mol, 92% yield).

Colorless needle-like crystals ( n -hexane); melting point 139-141 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.19 (3H, d, J = 7.1 Hz, C H ₃ CH), 1 .19 (3H, s, CH ₃ ), 1.21 (3H, d, J = 7.5 Hz, C H ₃ CH), 1.26 (3H, s, CH ₃ ), 1.43-1.48 (2H, m, CH × 2), 1.64-1.80 (5H, m, CH × 5), 2.18 (1H, dd, J = 12.6 Hz, 2.2 Hz, CH), 2. 24 (1H, d, J = 11.6 Hz, CH), 2.81-2.84 (2H, m, CH × 2), 3.24-3.27 (1H, m, CH ₃ C H ), _{3.66 (3H, s, CO 2} CH 3), 6.91 (1H, s, ArH), 7.35 (1H, s, ArH); LRMS (FAB ^{m / z393 ([M (79} Br) + H] +), 395 ([M (81 Br) + H] +); elemental analysis, Calcd _{C 21 H 29 BrO 2 · 1} / 4H 2 O: C; 63. 39, H; 7.47. Measurement: C; 63.34, H; 7.32.

[Step 3] Preparation of 12-bromo-13-deisopropyl-13-nitrodehydroabietic acid methyl ester and 12-bromo-13-deisopropyl-11,13-dinitrodehydroabietic acid methyl ester Fuming nitric acid (89%, 12 mL ) And concentrated sulfuric acid (0.6 mL) were added 12-bromoabietic acid methyl ester powder (2.00 g, 5.084 mmol) at −5 ° C. over 30 minutes. Thereafter, the reaction mixture was stirred at −5 ° C. for 30 minutes, poured into ice water (50 mL), neutralized to pH 8-9 with potassium carbonate, and extracted with diethyl ether (40 mL × 3). The organic layers were combined, washed with water (100 mL × 1), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 5: 1) to give the title mononitrate (1.07 g, 2.709 mmol, 53% yield) as a yellow solid and replicate organisms The dinitro compound (0.23 g, 0.517 mmol, yield 10%) was obtained as a colorless solid.

Mononitro body: colorless powder ( n -hexane); melting point 131-133 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.22 (3H, s, CH ₃ ), 1.28 (3H, s, _{CH 3), 1.44-1.54 (2H,} m, CH × 2), 1.71-1.88 (5H, m, CH × 5), 2.17 (1H, dd, J = 12. 5 Hz, 2.2 Hz, CH), 2.27 (1H, d, J = 13.1 Hz, CH), 2.88-2.94 (2H, m, CH × 2), 3.68 (3H, s , CO ₂ CH ₃ ), 7.55 (1H, s, ArH), 7.58 (1H, s, ArH); LRMS (FAB) m / z 396 ([M ( ⁷⁹ Br) + H] ⁺ ), 398 ( ^{[M (81 Br) + H} ] +); elemental analysis, calcd _{C 18 H 22 BrO 4 · 1} / 4H 2 O: C; 53.94, H; 5.65, N; 3.49. Measurement: C; 53.76, H; 5.57, N; 3.76.

By-product: pale yellow columnar crystals ( n -hexane / AcOEt); melting point 64-66 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.25 (3H, s, CH ₃ ), 1.28 ( _{3H, s, CH 3),} 1.53-1.56 (2H, m, CH × 2), 1.73-1.80 (5H, m, CH × 5), 2.18 (1H, d, J = 10.2 Hz, CH), 2.29 (1H, d, J = 12.6 Hz, CH), 2.82-2.89 (2H, m, CH × 2), 3.69 (3H, s , CO ₂ CH ₃ ), 7.71 (1H, s, ArH); LRMS (FAB) m / z 441 ([M ( ⁷⁹ Br) + H] ⁺ ), 443 ([M ( ⁸¹ Br) + H] ⁺ ); elemental analysis calculated _{C 18 H 22 BrO 4: C} ; 48.99, H; 4.80, N; 6.35. Measurements: C; 48.87, H; 4.83, N; 6.36.

[Step 4] Preparation of 13-amino-13-deisopropyldehydroabietic acid methyl ester 12-Bromo-13-deisopropyl-13-nitrodehydroabietic acid methyl ester (1.02 g, 2.563 mmol), triethylamine (0. A suspension of 18 mL, 1.307 mmol, 0.5 eq.) And 10% Pd—C (0.10 g) in methanol (12 mL) was stirred at room temperature for 3 hours under a balloon atmosphere of hydrogen. The reaction mixture was filtered, concentrated under reduced pressure, and then purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 3: 2) to give the title compound as a pale yellow solid (507 mg, 1.763 mmol, Yield 69%).

Pale yellow needle-like crystal ( n -hexane / AcOEt); melting point 105 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.17 (3H, s, CH ₃ ), 1.26 (3H, s, CH ₃ ), 1.34-1.39 (1H, m, CH), 1.45 (1H, m, CH), 1.61-1.82 (5H, m, CH × 5), 2.19 ( 1H, dd, J = 12.5 Hz, 2.2 Hz, CH), 2.23 (1H, d, J = 16.7 Hz, CH), 2.78-2.82 (2H, m, CH × 2) 3.49 (2H, bs, NH ₂ ), 3.65 (3H, s, CO ₂ CH ₃ ), 6.36 (1H, d, J = 2.4 Hz, ArH), 6.48 (1H, dd, J = 8.4 Hz, 2.6 Hz, ArH), 7.02 (1H, d, J = 8.2 Hz, ArH); LRMS (FA B) m / z 288 ([M + H] ⁺ ); elemental analysis, calculated C ₁₈ H ₂₅ NO ₂ : C; 75.22, H; 8.77, N; 4.87. Measurement: C; 74.98, H; 8.72, N; 4.88

Example 2: 13-acetylamino-13-deisopropyldehydroabietic acid

[Step 1] Preparation of 13-acetylamino-13-deisopropyldehydroabietic acid methyl ester 13-Amino-13-deisopropyldehydroabietic acid methyl ester (150 mg, 0.522 mmol) and triethylamine (0.219 mL, 1.566 mmol) , 3.0 eq.) In methylene chloride (2 mL) was added a solution of acetyl chloride (0.041 mL, 0.574 mmol, 1.1 eq.) In methylene chloride (2 mL) at −78 ° C. over 6 minutes. The reaction mixture was stirred at −78 ° C. for 2 hours, diluted with water (20 mL) and extracted with CHCl ₃ (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 1: 1) to give the title compound as a pale yellow oil (140 mg, 0.425 mmol, 81% yield).

_{^{1 H-NMR (400MHz / CDCl}} 3 /TMS)δ1.18(3H,s,CH 3), 1.27 (3H, s, CH 3), 1.38-1.50 (2H, m, CH × 2), 1.60-1.81 (5H, m, CH × 5), 2.14 (3H, s, COCH ₃ ), 2.19 (1H, d, J = 12.6 Hz, CH), 2 .28 (1H, d, J = 12.8 Hz, CH), 2.85-2.87 (2H, m, CH × 2), 3.67 (3H, s, CO ₂ CH ₃ ), 7.10 (1H, s, NH), 7.17-7.20 (3H, m, ArH); LRMS (FAB) m / z 330 ([M + H] ⁺ ).

[Step 2] Preparation of 13-acetylamino-13-deisopropyldehydroabietic acid 13-acetylamino-13-deisopropyldehydroabietic acid methyl ester (44 mg, 0.132 mmol), potassium hydroxide (77 mg, 1.369 mmol, 10.3 eq.) And dicyclohexano-18-crown ether-6 (118 mg, 0.317 mmol, 2.4 eq.) In methanol (4 mL) were stirred at 80 ° C. for 14 hours. After cooling, the mixture was concentrated under reduced pressure, diluted with water (10 mL), acidified with 2N hydrochloric acid (2 mL), and then extracted with chloroform (15 mL × 3). The organic layers were combined, washed with brine (15 mL × 1), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash SiO ₂ column chromatography (CHCl ₃ : MeOH = 30: 1) to give the title compound as a colorless amorphous substance (42 mg, 0.127 mmol, yield 100%).

_{^{1 H-NMR (400MHz / CDCl}} 3 /TMS)δ1.18(3H,s,CH 3), 1.27 (3H, s, CH 3), 1.43-1.55 (2H, m, CH × 2), 1.73-1.79 (5H, m, CH × 5), 2.15 (3H, s, COCH ₃ ), 2.19 (1H, d, J = 12.4 Hz, CH), 2 .28 (1H, d, J = 12.8 Hz, CH), 2.85-2.87 (2H, m, CH × 2), 7.15-7.17 (2H, m, ArH), 7. 23 (1H, d, J = 8.4 Hz, ArH), 7.30 (1H, s, NH); LRMS (FAB) m / z 316 ([M + H] ⁺ ); HRMS (FAB) Measured value: 316.1895 (-1.8mmu for [M + H] ⁺ )

  The following compounds were prepared by the same procedure as in Example 2, starting from 13-amino-13-deisopropyldehydroabietic acid methyl ester and the appropriate acid chloride.

Example 3: 13-butyrylamino-13-deisopropyldehydroabietic acid

Colorless needles (n - hexane); mp ^{45-49 ℃; 1 H-NMR (} 400MHz / CDCl 3 /TMS)δ1.00(3H,t,J=9.3Hz,CH 2 CH 2 C H 3 ), 1.19 (3H, s, CH ₃ ), 1.27 (3H, s, CH ₃ ), 1.47-1.51 (2H, m, CH × 2), 1.72-1.86 (7H, m, CH × 5 and _{CH 2 C H 2 CH 3)} , 2.20 (1H, dd, J = 11.8Hz, 1.8Hz, CH), 2.29-2.31 (1H, m , CH), 2.30 (2H, t, J = 7.5 Hz, C H ₂ CH ₂ CH ₃ ), 2.87-2.91 (2H, m, CH × 2), 7.03 (1H, s, NH), 7.17 (1H, d, J = 8.4 Hz, ArH), 7.16-7.22 (2H, m, ArH); LRMS ( AB) m / z315 ([M + H] +); elemental analysis, Calcd _{C 21 H 30 O 2: C} ; 80.21, H; 9.62. Measurement value: C; 80.07, H; 9.82

Example 4: 13-Methanesulfonylamino-13-deisopropyldehydroabietic acid

Yellow _{^{oil, 1 H-NMR (400MHz /}} CDCl 3 /TMS)δ1.20(3H,s,CH 3), 1.28 (3H, s, CH 3), 1.47 (1H, m, CH ), 1.57 (1H, m, CH), 1.77-1.79 (5H, m, CH × 5), 2.19 (1H, d, J = 10.4 Hz, CH), 2.29 (1H, d, J = 12.1 Hz, CH), 2.90 (2H, m, CH × 2), 3.00 (3H, s, SO ₂ CH ₃ ), 6.60 (1H, bs, NHSO) ₂ ), 6.89 (1H, s, ArH), 6.99 (1H, dd, J = 8.4 Hz, 2.6 Hz, ArH), 7.21 (1H, d, J = 8.6 Hz, ArH) ); LRMS (FAB) m / z352 ([M + H] +); HRMS (FAB) measurements: 352.1587 ([M + H] Against + 0.4mmu)

Example 5: 13-Cyclopropylcarbonylamino-13-deisopropyldehydroabietic acid

Orange oil, ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 0.81-0.82 (2H, m, CH × 2), 1.07 (2H, m, CH × 2), 1.18 _{(3H, s, CH 3)} , 1.27 (3H, s, CH 3), 1.40-1.53 (3H, m, CH × 2 and CHCO), 1.72-1.79 (5H, m, CH × 5), 2.19 (1H, d, J = 12.3 Hz, CH), 2.28 (1H, d, J = 12.5 Hz, CH), 2.87 (2H, m, CH × 2), 7.17-7.27 (3H, m, ArH), 7.38 (1H, s, NH); HRMS (FAB) m / z 342 ([M + H] ⁺ ); HRMS (FAB) 342. 2086 (+1.7 mm for [M + H] ⁺ )

Example 6: 13-Cyclohexylcarbonylamino-13-deisopropyldehydroabietic acid

Colorless amorphous material, ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.18 (3H, m, CH ₃ ), 1.21-1.30 (3H, m, CH × 3), 1.27 _{(3H, m, CH 3)} , 1.47-1.53 (4H, m, CH × 4), 1.69-1.83 (8H, m, CH × 8), 1.92 (2H, d , J = 12.1 Hz, CH × 2), 2.19 (2H, dd, J = 11.9 Hz, 2.4 Hz, CH × 2), 2.28 (1H, d, J = 12.5 Hz, CH ), 2.85-2.89 (2H, m, CH × 2), 7.16 (1H, d, J = 8.4 Hz, ArH), 7.22 (1H, d, J = 11.0 Hz, ArH), 7.23 (1H, s, CH); LRMS (FAB) m / z 384 ([M + H] ⁺ ); HRMS (FAB) Measured value: 38 4.2564 (+2.5 mmu for [M + H] ⁺ )

Example 7: 13-amino-13-deisopropyldehydroabietic acid

13-amino-13-deisopropyldehydroabietic acid methyl ester (38 mg, 0.116 mmol), potassium hydroxide (44 mg, 0.784 mmol, 6.7 eq.) In ethylene glycol (1 mL) at 170 ° C. for 1.5 Stir for hours. After cooling, the reaction mixture was diluted with water (10 mL), acidified with 2N hydrochloric acid (2 mL), and extracted with chloroform (20 mL × 3). The separated aqueous layer was neutralized with sodium bicarbonate to pH 8 and extracted with chloroform (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography (CHCl ₃ : MeOH = 30: 1) to give the title compound as a light orange amorphous material (22 mg, 0.080 mmol, 69% yield).

_{^{1 H-NMR (400MHz / CDCl}} 3 /TMS)δ1.18(3H,s,CH 3), 1.26 (3H, s, CH 3), 1.46-1.52 (2H, m, CH × 2), 1.68-1.85 (5H, m, CH × 5), 2.14-2.27 (2H, m, CH × 2), 2.77-2.85 (2H, m, CH × 2), 5.71 (2H, bs, NH ₂ ), 6.38 (1H, s, ArH), 6.51 (1H, d, J = 8.4 Hz, ArH), 7.03 (1H, d, J = 8.4 Hz, ArH); LRMS (FAB) m / z 274 ([M + H] ⁺ ); HRMS (FAB); measured value: 274.1758 (−4.9 mmu against [M + H] ⁺ ).

Example 8: 13-amino-13-deisopropyl-12,14-dichlorodehydroabietic acid methyl ester

To a suspension of 13-amino-13-deisopropyldehydroabietic acid methyl ester (50 mg, 0.174 mmol) in 2N hydrochloric acid (2 mL) was added NCS (35 mg, 0.261 mL, 1.5 eq.) At 45 ° C. Added over 2 minutes. The reaction mixture was stirred at 45 ° C. for 30 minutes, cooled, neutralized to pH 8 by adding saturated aqueous sodium hydrogen carbonate (10 mL), and then extracted with chloroform (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 3: 2) to give the title compound as a dark brown amorphous material (29 mg, 0.081 mmol, 46% yield).

_{^{1 H-NMR (400MHz / CDCl}} 3 /TMS)δ1.17(3H,s,CH 3), 1.25 (3H, s, CH 3), 1.45-1.50 (2H, m, CH × 2), 1.65 to 1.81 (5H, m, CH × 5), 2.11 (1H, d, J = 12.6 Hz, CH), 2.20 (1H, d, J = 12.5 Hz) , CH), 2.65-2.70 (1H, m, CH), 2.84 (1H, dd, J = 17.8 Hz, 6.6 Hz, CH), 3.67 (3H, s, CO ₂ CH ₃ ), 4.46 (2H, s, NH ₂ ), 7.29 (1H, s, ArH); LRMS (FAB) m / z 356 ([M ( ³⁵ Cl ₂ ) + H] ⁺ ), 358 ([[ M ( ³⁵ Cl ³⁷ Cl) + H] ⁺ ), 360 ([M ( ³⁷ Cl ₂ ) + H] ⁺ )

Example 9: [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro- 5H-Dibenzo [b, d] azepine-8-carboxylic acid

  [Step 1] Preparation of 12,14-dichloro-8-oxodehydroabietic acid methyl ester

To a solution of CrO ₃ (287 mg, 2.867 mmol, 1.1 eq.) In acetic anhydride (9 mL) and acetic acid (4 mL), 12,14-dichlorodehydroabietic acid methyl ester (corresponding to the non-patent document 2 above) A suspension of 999 mg, 2.606 mmol) in acetic acid (15 mL) was added dropwise at 0 ° C. over 10 minutes. The reaction mixture was stirred at 50 ° C. for 9 hours, cooled, poured into ice water (40 mL), and then extracted with chloroform (30 mL × 3). The organic layers were combined, washed with water (30 mL × 1), saturated aqueous sodium hydrogen carbonate (30 mL × 2) and brine (30 mL × 1), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 5: 1) to obtain the title compound as a pale yellow amorphous substance (847 mg, 2.130 mmol, yield 82%).

_{^{1 H-NMR (400MHz / CDCl}} 3 /TMS)δ1.17(3H,s,CH 3), 1.34 (3H, s, CH 3), 1.41 (6H, d, J = 7.3Hz, C H ₃ CH × 2), 1.75-1.79 (5H, m, CH × 5), 2.20 (1H, d, J = 12.5 Hz, CH), 2.51 (1H, dd, J = 16.9 Hz, 5.2 Hz, CH), 2.64 (2H, m, CH × 2), 3.66 (3H, s, CO ₂ CH ₃ ), 3.94 (1H, bs, CH ₃ C H ), 7.19 (1H, bs, ArH)

[Step 2] Preparation of 12,14-dichloro-8- (N-hydroxy) iminodehydroabietic acid methyl ester 12,14-dichloro-8-oxodehydroabietic acid methyl ester in ethanol (2 mL) (198 mg. 498 mmol), pyridine (0.06 mL) and hydroxyamine hydrochloride (54 mg, 0.772 mmol, 1.6 eq.) Were stirred at 100 ° C. for 3.5 hours, cooled, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 5: 1) to give the title compound as a colorless amorphous material (207 mg, quantitative).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.06 (3H, s, CH ₃ ), 1.22 (6H, d, J = 8.4 Hz, C H ₃ CH × 2), 1.26 ( 1H, dd, J = 18.7 Hz, 6.4 Hz, CH), 1.72-1.77 (5H, m, CH × 5), 2.15 (2H, dd, J = 12.1 Hz, 6. 1 Hz, CH), 2.38 (1 H, dd, J = 18.7 Hz, 6.4 Hz, CH), 3.09 (1 H, dd, J = 18.7 Hz, 13.0 Hz, CH), 3.66 _{(3H, s, CO 2 CH} 3), 3.69 (1H, bs, CH 3 C H), 7.15 (1H, s, ArH).

[Step 3] 12,14-Dichloro-8- (N-tosyloxy) iminodehydroabietic acid methyl ester 12,14-Dichloro-8- (N-hydroxy) iminodehydroabietic acid methyl ester (207 mg, 0.503 mmol) Tosyl chloride (144 mg, 0.754 mmol, 1.5 eq.) Was added to a pyridine (1 mL) solution at room temperature. The reaction mixture was stirred at room temperature for 17 hours and then concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 5: 1) to give the title compound as a colorless oil (282 mg, 0.497 mmol, yield 99%).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.03 (3H, s, CH ₃ ), 1.25 (3H, d, J = 7.1 Hz, C H ₃ CH), 1.27 (3H, d, J = 7.1 Hz, C H ₃ CH), 1.37 (3H, s, CH ₃ ), 1.74-1.77 (5H, m, CH × 5), 2.06-2.15 (2H, m, CH × 2), 2.46 (3H, s, CH ₃ ), 2.51 (1H, dd, J = 13.8 Hz, 5.0 Hz, CH), 3.02 (1H, dd _{, J = 19.0Hz, 12.9Hz, CH} ), 3.67 (3H, s, CO 2 CH 3), 3.94 (1H, bs, CH 3 C H), 7.12 (1H, bs, ArH), 7.35 (2H, d, J = 8.4 Hz, ArH), 7.94 (2H, d, J = 8.2 Hz, ArH)

[Step 4] [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro- 5 H -dibenzo [ b , d ] azepine-8-carboxylic acid methyl ester 12,14-dichloro-8- (N-tosyloxy) iminodehydroabietic acid methyl ester (282 mg, 0.497 mmol) in TFA (2 mL) The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 1: 1) to give the title compound as a colorless amorphous substance (166 mg, 0.403 mmol, 81% yield).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.42 (6H, d, J = 7.1 Hz, C H ₃ CH × 2), 1.45 (3H, s, CH ₃ ), 1.58 ( _{3H, s, CH 3),} 1.67-1.76 (2H, m, CH × 2), 1.81-1.83 (2H, m, CH × 2), 1.90-1.93 ( 2H, m, CH × 2), 2.29 (1H, d, J = 8.6 Hz, CH), 2.92 (1H, dd, J = 15.9 Hz, 6.8 Hz, CH), 3.47 _{-3.55 (1H, m, CH)} , 3.64 (3H, s, CO 2 CH 3), 3.96 (1H, bs, CH 3 C H), 7.26 (1H, bs, ArH) , 7.85 (1H, bs, NH); LRMS (FAB) m / z 412 ([M ( ³⁵ Cl ₂ ) + H] ⁺ ), 414 ([M ( ³⁵ Cl ^{3 7} Cl) + H] ⁺ ), 416 ([M ( ³⁷ Cl ₂ ) + H] ⁺ )

[Step 5] [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro- 5 H - dibenzo [b, d] azepine-8-carboxylic acid in methanol (2 mL) solution of 2,4-dichloro-3-isopropyl -8,11a, - dimethyl-6-oxo -6,7,7a, 8, 9,10,11,11a- octahydro -5 H - dibenzo [b, d] azepine-8-carboxylic acid methyl ester (80mg, 0.194mmol), potassium hydroxide (109mg, 3.068mmol, 10.0eq.) And 18-crown ether-6 (128 mg, 0.485 mmol, 2.5 eq.) Was stirred at 80 ° C. for 7.5 hours. The reaction mixture was cooled, concentrated under reduced pressure, diluted with water (10 mL), acidified with 2N hydrochloric acid (2 mL), and extracted with chloroform (20 mL × 3). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography (AcOEt only → AcOEt: MeOH = 10: 1) to give the title compound as a colorless solid (35 mg, 0.087 mmol, 45% yield).

Colorless powder ( n -hexane / AcOEt / MeOH); melting point 192-197 ° C .; ¹ H-NMR (400 MHz / CD ₃ OD) δ 1.32 (6H, d, J = 7.1 Hz, C H ₃ CH × 2) 1.36 (3H, s, CH ₃ ), 1.47 (3H, s, CH ₃ ), 1.60 (2H, m, CH × 2), 1.70 (2H, m, CH × 2) , 1.70 (2H, m, CH × 2), 1.85 (2H, m, CH × 2), 2.10 (1H, d, J = 8.4 Hz, CH), 2.86 (1H, dd, J = 15.9Hz, CH) , 3.27 (1H, m, CH), 3.90 (1H, bs, CH 3 C H), 7.23 (1H, bs, ArH); LRMS (FAB _{^{) m / z398 ([M (}} 35 Cl 2) + H] +), 400 ([M (35 Cl 37 Cl) + H] +), 4 _{^{2 ([M (37 Cl 2}} ) + H] +); elemental analysis, Calcd _{C 20 H 25 Cl 2 NO 3} · 3 / 4H 2 O: C; 58.33, H; 6.30, N; 3. 40. Measurement: C; 58.29, H; 6.39, N; 3.39

Example 10: [7aR, 8R, 11aS] -2-chloro-3-isopropyl-8,11a-dimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro-5H- Dibenzo [b, d] azepine-8-carboxylic acid

[Step 1] Preparation of 12-chloro-8-oxodehydroabietic acid methyl ester 12-chlorodehydroabietic acid methyl ester (Helvetica Chimica Acta, 65, 1351-1358, can be prepared based on 1992; 600 mg , 1.720 mmol) to give the title compound as a yellow oil (394 mg, 1.086 mmol, 63% yield) in a manner similar to Step 1 of Example 9.

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.24 (3H, d, J = 7.0 Hz, C H ₃ CH), 1.26 (3H, s, CH ₃ ), 1.27 (3H, d, J = 6.8 Hz, C H ₃ CH), 1.34 (3H, s, CH ₃ ), 1.66 to 1.80 (5H, m, CH × 5), 2.30-2.39. (2H, m, CH × 2 ), 2.68-2.71 (2H, m, CH × 2), 3.34-3.37 (1H, m, CH 3 C H), 3.65 (3H , S, CO ₂ CH ₃ ), 7.33 (1H, s, ArH), 7.94 (1H, s, ArH); LRMS (FAB) m / z 363 ([M ( ³⁵ Cl) + H] ⁺ ), 365 ([M ( ³⁷ Cl) + H] ⁺ ).

[Step 2] Preparation of 12-chloro-8- (N-hydroxy) iminodehydroabietic acid methyl ester Example 9 using 12-chloro-8-oxodehydroabietic acid methyl ester (300 mg, 0.827 mmol) In the same manner as in Step 2, the title compound was obtained as colorless amorphous (272 mg, 0.720 mmol, yield 87%).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.12 (3H, s, CH ₃ ), 1.24 (3H, d, J = 7.0 Hz, C H ₃ CH), 1.27 (3H, d, J = 6.8 Hz, C H ₃ CH), 1.37 (3H, s, CH ₃ ), 1.63-1.77 (5H, m, CH × 5), 2.24 (1H, d , J = 12.1 Hz, CH), 2.30 (1H, dd, J = 10.8 Hz, 7.7 Hz, CH), 2.64 (1H, d, J = 3.7 Hz, CH), 2. _{66 (1H, s, CH)} , 3.33-3.36 (1H, m, CH 3 C H), 3.66 (3H, s, CO 2 CH 3), 7.24 (1H, s, ArH ), 7.79 (1H, s, ArH).

[Step 3] Using 12-chloro-8- (N-tosyloxy) iminodehydroabietic acid methyl ester 12-chloro-8- (N-hydroxy) iminodehydroabietic acid methyl ester (272 mg, 0.720 mmol), The title compound was obtained as a pale-yellow oil by a method similar to that in Step 3 of Example 9 (387 mg, quantitative).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.05 (3H, s, CH ₃ ), 1.18 (3H, d, J = 6.8 Hz, C H ₃ CH), 1.25 (3H, dd, J = 7.0 Hz, 2.0 Hz, CH), 1.33 (3H, s, CH ₃ ), 1.64-1.74 (5H, m, CH × 5), 2.34 (2H, dd, J = 11.7 Hz, 6.8 Hz, CH × 2), 2.45 (3H, s, CH ₃ ), 2.63 (1H, d, J = 7.5 Hz, ArH), 2.66 ( _{1H, d, J = 2.6Hz,} CH), 3.29-3.33 (1H, m, CH 3 C H), 3.67 (3H, s, CO 2 CH 3), 7.21 (1H , S, ArH), 7.36 (1H, d, J = 7.9 Hz, ArH), 7.63 (1H, s, ArH), 7.95 (1H, d, J = .2Hz, ArH)

[Step 4] [7aR, 8R, 11aS] -2-Chloro-3-isopropyl-8,11a, -dimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro-5 H -Dibenzo [ b , d ] azepine-8-carboxylic acid methyl ester 12-Chloro-8- (N-tosyloxy) iminodehydroabietic acid methyl ester (387 mg, 0.727 mmol) was used for the process of Example 9. 4 gave the title compound as a colorless solid (198 mg, 0.523 mmol, 72% yield).

Colorless needle-like crystals ( n -hexane / AcOEt); melting point 66-69 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.21 (3H, d, J = 6.8 Hz, C H ₃ CH) _{, 1.23 (3H, d, J} = 6.8Hz, CH 3 CH), 1.42 (3H, s, CH 3), 1.45 (3H, s, CH 3), 1.78-1. 90 (6H, m, CH × 6), 2.15 (1H, dd, J = 14.8 Hz, 2.2 Hz, CH), 2.55 (1H, dd, J = 14.8 Hz, 8.6 Hz, CH), 2.76 (1H, dd , J = 8.6Hz, 3.3Hz, CH), 3.28-3.35 (1H, m, CH 3 C H), 3.65 (3H, s, _{CO 2 CH 3), 6.74 (} 1H, s, ArH), 7.34 (1H, s, ArH), 7.41 (1H, bs ^{NH); LRMS (FAB) m} / z378 ([M (35 Cl) + H] +), 380 ([M (37 Cl) + H] +); elemental analysis, Calcd _{C 21 H 28 ClNO 3 · 1} / 4H ₂ O: C; 65.95, H; 7.51, N; 3.66. Measurements: C; 66.10, H; 7.30, N; 3.78

[Step 5] [7aR, 8R, 11aS ] -2- chloro-3-isopropyl--8,11a- dimethyl-6-oxo -6,7,7a, 8,9,10,11,11a- octahydro -5 H -Dibenzo [ b , d ] azepine-8-carboxylic acid [7aR, 8R, 11aS] -2-chloro-3-isopropyl-8,11a, -dimethyl-6-oxo-6,7,7a, 8,9, 10,11,11a- octahydro -5 H - dibenzo [b, d] azepine-8-carboxylic acid methyl ester (80 mg, 0.212 mmol) was used to the same manner as step 5 of example 9, the title As a colorless solid (61 mg, 0.168 mmol, 79% yield).

Colorless columnar crystals (CHCl ₃ / MeOH); melting point 199-204 ° C .; ¹ H-NMR (400 MHz / CD ₃ OD) δ 1.22 (3H, d, J = 7.0 Hz, C H ₃ CH), 1. _{24 (3H, d, J =} 6.8Hz, C H 3 CH), 1.40 (3H, s, CH 3), 1.45 (3H, s, CH 3), 1.71-1.91 ( 6H, m, CH × 6), 2.14 (1H, dd, J = 14.7 Hz, 2.9 Hz, CH), 2.54 (1H, dd, J = 14.7 Hz, 2.9 Hz, CH) , 2.73 (1H, dd, J = 9.0Hz, 2.9Hz, CH), 3.32 (1H, m, CH 3 C H), 6.96 (1H, s, ArH), 7.38 (1H, s, ArH); LRMS (FAB) m / z 364 ([M ( ³⁵ Cl) + H] ⁺ ), 366 ([M ( ³⁷ Cl) + H] ⁺ ); elemental analysis, calculated C ₂₀ H ₂₆ ClNO ₃ · 1 / 12H ₂ O: C; 65.74, H; 7.17, N; 3.83. Measurement: C; 65.45, H; 6.91, N; 3.86.

Example 11: [7aR, 8R, 11aS] -4-chloro-3-isopropyl-8,11a-dimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro-5H- Dibenzo [b, d] azepine-8-carboxylic acid

[Step 1] Preparation of 14-chloro-8-oxodehydroabietic acid methyl ester 14-chlorodehydroabietic acid methyl ester (Helvetica Chimica Acta, 65, 1351-1358, can be prepared based on 1992; 600 mg , 1.720 mmol) to give the title compound as a yellow oil (434 mg, 1.197 mmol, 70% yield) by a method similar to step 1 of Example 9.

Colorless mica-like solid ( n -hexane / AcOEt); melting point 85-89 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.18 (3H, s, CH ₃ ), 1.21 (3H, d , J = 7.0 Hz, C H ₃ CH), 1.25 (3H, d, J = 6.8 Hz, C H ₃ CH), 1.35 (3H, s, CH ₃ ), 1.76-1 .77 (5H, m, CH × 5), 2.27 (1H, d, J = 12.1 Hz, CH), 2.51 (1H, dd, J = 17.4 Hz, 4.9 Hz, CH), 2.59-2.74 (2H, m, CH × 2), 3.55-3.58 (1H, m, CH 3 C H), 3.66 (3H, s, CO 2 CH 3), 7 .23 (1H, d, J = 8.2 Hz, ArH), 7.41 (1H, d, J = 8.4 Hz, ArH); LRMS (FAB ^{m / z363 ([M (35} Cl) + H] +), 365 ([M (37 Cl) + H] +); elemental analysis, Calcd _{C 21 H 27 ClO 3: C} ; 69.50, H; 7. 50. Measurement: C; 69.29, H; 7.51

[Step 2] Preparation of 14-chloro-8- (N-hydroxy) iminodehydroabietic acid methyl ester Example 9 using 14-chloro-8-oxodehydroabietic acid methyl ester (300 mg, 0.827 mmol) In the same manner as in Step 2, the title compound was obtained as a yellow amorphous substance (337 mg, quantitative).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.05 (3H, s, CH ₃ ), 1.23 (3H, d, J = 6.6 Hz, C H ₃ CH), 1.27 (3H, d, J = 7.1 Hz, C H ₃ CH), 2.05 (3H, s, CH ₃ ), 1.64-1.74 (5 H, m, CH × 5), 2.07-2.20 (2H, m, CH × 2), 2.45 (3H, s, CH ₃ ), 2.52 (1H, dd, J = 18.9 Hz, 6.4 Hz, CH), 3.04 (1H, dd _{, J = 19.0Hz, 12.9Hz, CH} ), 3.43-3.46 (1H, m, CH 3 C H), 3.67 (3H, s, CO 2 CH 3), 7.13 ( 1H, d, J = 8.2 Hz, ArH), 7.27 (1H, d, J = 8.4 Hz, ArH), 7.34 (1H, d, J = 8.1 Hz) ArH), 7.95 (2H, d, J = 8.4Hz, ArH)

[Step 3] 14-Chloro-8- (N-tosyloxy) iminodehydroabietic acid methyl ester 14-Chloro-8- (N-hydroxy) iminodehydroabietic acid methyl ester (303 mg, 0.802 mmol) was used. The title compound was obtained as a colorless amorphous substance by the same method as in Step 3 of Example 9 (166 mg, 313 mmol, yield 39%).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.19 (3H, s, CH ₃ ), 1.22 (6H, d, J = 7.1 Hz, C H ₃ CH × 2), 1.27 ( _{3H, s, CH 3),} 1.38-1.51 (2H, m, CH × 2), 1.65-1.80 (5H, m, CH × 5), 2.16-2.25 ( 2H, m, CH × 2) , 2.84 (2H, dd, J = 9.0Hz, 4.6Hz, CH × 2), 3.28-3.32 (1H, m, CH 3 C H), 3.66 (3H, s, CO ₂ CH ₃ ), 6.91 (1H, s, ArH), 7.17 (1H, s, ArH)

[Step 4] [7aR, 8R, 11aS] -4-chloro-3-isopropyl-8,11a-dimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro-5 H -Dibenzo [ b , d ] azepine-8-carboxylic acid methyl ester 14-chloro-8- (N-tosyloxy) iminodehydroabietic acid methyl ester (321 mg, 0.604 mmol) was used, step 4 of Example 9. The title compound was obtained as a colorless solid by the same procedure as (154 mg, 0.408 mmol, yield 68%).

Colorless needle-like crystals ( n -hexane / AcOEt); melting point 57-60 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.24 (3H, d, J = 4.0 Hz, C H ₃ CH) _{, 1.26 (3H, d, J} = 4.0Hz, C H 3 CH), 1.44 (3H, s, CH 3), 1.62 (3H, s, CH 3), 1.68-1 .70 (2H, m, CH × 2), 1.82-1.84 (2H, m, CH × 2), 1.96-1.97 (2H, m, CH × 2), 2.23 ( 1H, d, J = 8.4Hz, CH), 2.86 (1H, dd, J = 16.0Hz, 6.9Hz, CH), 3.46-3.55 (2H, m, CH 3 C H And CH), 3.62 (3H, s, CO ₂ CH ₃ ), 6.71 (1H, bs, NH), 7.22 (1H, d, J = 8.4H) z, ArH), 7.33 (1H, d, J = 8.4 Hz, ArH); LRMS (FAB) m / z 378 ([M ( ³⁵ Cl) + H] ⁺ ), 380 ([M ( ³⁷ Cl) + H ] ⁺ ); Elemental analysis, calculated value C ₂₁ H ₂₈ ClNO ₃ : C; 66.74, H; 7.47, N; 3.71. Measurement: C; 66.52, H; 7.49, N; 3.81

[Step 5] [7aR, 8R, 11aS] -4-chloro-3-isopropyl-8,11a-dimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro-5 H -Dibenzo [ b , d ] azepine-8-carboxylic acid [7aR, 8R, 11aS] -4-chloro-3-isopropyl-8,11a-dimethyl-6-oxo-6,7,7a, 8,9,10 , 11,11A- octahydro -5 H - dibenzo [b, d] azepine-8-carboxylic acid methyl ester (80 mg, 0.212 mmol) was used to the same manner as step 5 of example 9, the title The compound was obtained as a colorless solid (61 mg, 0.168 mmol, yield 79%).

Colorless needle-like crystals ( n -hexane / AcOEt); melting point 198-203 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.26 (6H, dd, J = 6.9 Hz, 1.7 Hz, C H ₃ CH × 2), 1.47 (3H, s, CH ₃ ), 1.58 (3H, s, CH ₃ ), 1.70-1.74 (2H, m, CH × 2), 1. 82-1.84 (2H, m, CH × 2), 1.94-2.04 (2H, m, CH × 2), 2.20 (1H, d, J = 8.6 Hz, CH), 2 .94 (1H, d, J = 16.1 Hz, CH), 3.32-3.35 (1H, m, CH), 3.47-3.50 (1H, m, CH ₃ C H ), 7 .33 (1H, d, J = 8.2 Hz, ArH), 7.44 (1H, d, J = 8.2 Hz, ArH); LRMS (FAB) m / z ^{64 ([M (35 Cl)} + H] +), 366 ([M (37 Cl) + H] +); elemental analysis, Calcd _{C 20 H 26 ClNO 3: C} ; 66.01, H; 7.20, N; 3.85. Measurement: C; 65.77, H; 7.14, N; 3.72

Example 12: [7aR, 8R, 11aS] -3-Isopropyl-8,11a-dimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro-5H-dibenzo [b, d] Azepine-8-carboxylic acid

[Step 1] Preparation of 8-oxodehydroabietic acid methyl ester Dehydroabietic acid methyl ester (Preparable by esterifying the corresponding carboxylic acid disclosed in Non-Patent Document 2 above; 2.35 g, 7.456 mmol) To give the title compound as a pale yellow oil (570 mg, 1.746 mmol, 23% yield).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ1.24-1.26 (9H, m, C H ₃ CH × 2 and CH ₃ ), 1.34 (3H, s, CH ₃ ), 1.61 -1.80 (5H, m, CH x 5), 2.32-2.38 (2H, m, CH x 2), 2.71-2.73 (2H, m, CH x 2), 2. _{91-2.95 (1H, m, CH 3} C H), 3.65 (3H, s, CO 2 CH 3), 7.29 (1H, d, J = 8.1Hz, ArH), 7.40 (1H, dd, J = 8.2 Hz, 2.1 Hz, ArH), 7.87 (1H, d, J = 2.0 Hz, ArH); LRMS (FAB) m / z 329 ([M + H] ⁺ ). ^{by-product: 1 H-NMR} (400MHz / CDCl 3 /TMS)δ1.26(3H,s,CH 3), 1.34 (3H, s, CH 3), 1.72-1.79 (1H, m, CH × 5 and C H ₃ CPh × 2), 2.10 (3H, s, CH ₃ CO), 2.32-2.36 (2H, m, CH × 2), 2.70-2. 74 (2H, m, CH × 2), 3.66 (3H, s, CO ₂ CH ₃ ), 7.33 (1H, d, J = 8.2 Hz, ArH), 7.52 (1H, dd, J = 8.3 Hz, 2.3 Hz, ArH), 7.97 (1H, d, J = 2.4 Hz, ArH)

[Step 2] Preparation of 8- (N-hydroxy) iminodehydroabietic acid methyl ester Using 8-oxodehydroabietic acid methyl ester (598 mg, 1.667 mmol) in the same manner as in Step 2 of Example 9. The title compound was obtained as colorless amorphous (390 mg, 1.137 mmol, 68% yield).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.12 (3H, s, CH ₃ ), 1.25 (6H, d, J = 7.0 Hz, C H ₃ CH × 2), 1.38 ( 3H, s, CH ₃ ), 1.42-1.76 (5H, m, CH × 5), 2.28-2.35 (2H, m, CH × 2), 2.64-2.67 ( _{2H, m, CH × 2)} , 2.88-2.91 (1H, m, CH 3 C H), 3.65 (3H, s, CO 2 CH 3), 7.21 (2H, m, ArH ), 7.70 (1H, s, ArH); LRMS (FAB) m / z 344 ([M + H] ⁺ )

[Step 3] 8- (N-tosyloxy) iminodehydroabietic acid methyl ester Similar to step 3 of Example 9 using 8- (N-hydroxy) iminodehydroabietic acid methyl ester (390 mg, 1.137 mmol). The title compound was obtained as a colorless solid (545 mg, 1.095 mmol, yield 96%).

Colorless powder ( n -hexane / AcOEt); melting point 158-160 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.04 (3H, s, CH ₃ ), 1.20-1.28 (6H) , M , C H ₃ CH × 2), 1.34 (3H, s, CH ₃ ), 1.68-1.74 (5H, m, CH × 5), 2.26 (2H, t, J = 9.3 Hz, CH ₂ ), 2.45 (3H, s, PhC H ₃ ), 2.66 (2H, d, J = 8.6 Hz, CH ₂ ), 2.85-2.88 (1 H, m _{, CH 3 C H), 3.66} (3H, s, CO 2 CH 3), 7.18 (1H, d, J = 8.2Hz, ArH), 7.25 (1H, dd, J = 8. 2 Hz, 2.0 Hz, ArH), 7.35 (2H, d, J = 8.6 Hz, ArH), 7.58 (1H, d, J = 1.8) Hz, ArH), 7.95 (2H, d, J = 8.4 Hz, ArH); LRMS (FAB) m / z 498 ([M + H] ⁺ ); elemental analysis, calculated value C ₂₈ H ₃₅ NO ₅ S: C 67.58, H; 7.09, N; 2.81. Measurement: C; 69.39, H; 7.21, N; 2.91

[Step 4] [7aR, 8R, 11aS ] -3- isopropyl -8,11a- dimethyl-6-oxo -6,7,7a, 8,9,10,11,11a- octahydro -5 H - dibenzo [b , D ] azepine-8-carboxylic acid methyl ester 8- (N-tosyloxy) iminodehydroabietic acid methyl ester (505 mg, 1.015 mmol) was prepared in a similar manner as in step 4 of Example 9 using the title The compound was obtained as a colorless amorphous (392 mg, quantitative).

Colorless needle-like crystals ( n -hexane / AcOEt); melting point 148-149 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.24 (6H, d, J = 7.0 Hz, C H ₃ CH × 2), 1.42 (3H, s, CH ₃ ), 1.45 (3H, s, CH ₃ ), 1.69-1.93 (6H, m, CH × 6), 2.18 (1H, d, J = 14.8 Hz, CH), 2.57 (1H, dd, J = 14.7 Hz, 8.2 Hz, CH), 2.78-2.81 (1H, dd, J = 8.2 Hz, _{3.6Hz, CH), 2.85-2.88 (1H} , m, CH 3 C H), 3.65 (3H, s, CO 2 CH 3), 6.76 (1H, d, J = 2 0.0 Hz, ArH), 7.04 (1H, d, J = 8.2 Hz, ArH), 7.33 (1H, d, J = 8.4 Hz, rH), 8.62 (1H, s , NH); LRMS (FAB) m / z343 ([M + H] +); elemental analysis, Calcd _{C 21 H 29 NO 3: C} ; 73.44, H; 8. 51, N; 4.08. Measurement: C; 73.21, H; 8.29, N; 4.10

[Step 5] [7aR, 8R, 11aS ] -3- isopropyl -8,11a- dimethyl-6-oxo -6,7,7a, 8,9,10,11,11a- octahydro -5 H - dibenzo [b , D ] azepine-8-carboxylic acid [7aR, 8R, 11aS] -3-isopropyl-8,11a, -dimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro- 5 H - dibenzo [b, d] using azepine-8-carboxylic acid methyl ester (100 mg, 0.291 mmol), in the same manner as step 5 of example 9, the title compound as a solid oil Obtained (75 mg, 0.228 mmol, 78% yield).

Colorless powder ( n -hexane / AcOEt); melting point 135-140 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.22 (6H, d, J = 6.8 Hz, C H ₃ CH × 2) , 1.42 (3H, s, CH ₃ ), 1.45 (3H, s, CH ₃ ), 1.74-1.88 (5H, m, CH × 5), 1.95 (1H, d, J = 11.3 Hz, CH), 2.28 (1 H, dd, J = 14.9 Hz, 3.4 Hz, CH), 2.67 (1 H, dd, J = 14.9 Hz, 7.8 Hz, CH) , 2.80 (1H, dd, J = 7.9 Hz, 3.7 Hz, CH), 2.83-2.86 (1H, m, CH ₃ C H ), 6.70 (1H, d, J = 1.8 Hz, ArH), 7.00 (1H, dd, J = 8.0 Hz, 1.8 Hz, ArH), 7.31 (1H d, J = 8.4Hz, ArH) , 7.99 (1H, s, ArH); LRMS (FAB) m / z330 ([M + H] +); elemental analysis, Calcd _{C 20 H 27 NO 3 · 1} / 6H ₂ O: C; 72.26, H; 8.28, N; 4.21. Measurement: C; 72.21, H, 8.15, N; 4.16

Example 13: [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-5,8,11a-trimethyl-6-oxo-6,7,7a, 8,9,10,11,11a- Octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid

[Step 1] [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-5,8,11a-trimethyl-6-oxo-6,7,7a, 8,9,10,11,11a- octahydro -5 H - dibenzo [b, d] using 60% dispersion of NaH (in mineral oil in the preparation of DMF azepine-8-carboxylic acid methyl ester (1 mL) was washed twice with hexane; 10 mg, 0. 244 mmol, 1.1 eq.) Into a suspension of [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-6,7,7a, 8,9 , 10,11,11A- octahydro -5 H - dibenzo [b, d] azepine-8-carboxylic acid methyl ester (91mg, 0.222mmol) DMF of (1 mL) solution for 2 minutes at 0 ℃ the Only and was dropped. After stirring at 0 ° C. for 2 minutes, methyl iodide (0.07 mL, 1.108 mmol, 5.0 eq.) Was added at 0 ° C. The reaction mixture was stirred at room temperature for 7 hours, then concentrated under reduced pressure, diluted with 1N hydrochloric acid (10 mL), and extracted with chloroform (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 2: 1) to give the title compound as a colorless oil (73 mg, 0.171 mmol, yield 77%).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.36 (3H, s, CH ₃ ), 1.42 (6H, d, J = 7.1 Hz, C H ₃ CH × 2), 1.46 ( 3H, s, CH ₃ ), 1.72-1.73 (2H, m, CH ₂ ), 1.82-1.91 (4H, m, CH × 4), 2.21 (1H, d, J = 8.6Hz, CH), 2.74 ( 1H, d, J = 16.3Hz, CH), 3.19 (3H, s, NCH 3), 3.64 (3H, s, CO 2 CH 3) , 3.81 (1H, dd, J = 16.2 Hz, 8.8 Hz, CH), 4.09 (1H, bs, CH ₃ C H ), 7.20 (1H, bs, ArH)

[Step 2] [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-5,8,11a-trimethyl-6-oxo-6,7,7a, 8,9,10,11,11a- octahydro -5 H - dibenzo [b, d] - azepine-8-carboxylic acid [7aR, 8R, 11aS] -2,4- dichloro-3-isopropyl--5,8,11a- trimethyl-6-oxo - 6,7,7a, 8,9,10,11,11a- octahydro -5 H - dibenzo [b, d] azepine-8-carboxylic acid methyl ester (73mg, 0.171mmol), potassium hydroxide (96 mg, 1 .705 mmol, 10.0 eq.) And 18-crown ether-6 (113 mg, 0.426 mmol, 2.5 eq.) In methanol (1 mL) In the mixture was stirred for 13 hours. The reaction mixture was cooled, concentrated under reduced pressure, diluted with water (10 mL), acidified with 2N hydrochloric acid (2 mL), and then extracted with chloroform (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography (AcOEt only) to give the title compound as a colorless solid (65 mg, 0.156 mmol, 92% yield).

Colorless powder ( n -hexane); melting point 155-159 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.34 (3H, s, CH ₃ ), 1.39 (6H, d, J = 7) .1 Hz, C H ₃ CH × 2), 1.43 (3H, s, CH ₃ ), 1.54 (2H, m, CH × 2), 1.73-1.88 (4H, m, CH ×) 4), 2.18 (1H, d, J = 8.6 Hz, CH), 2.83 (1H, d, J = 16.3 Hz, CH), 3.19 (3H, s, NCH ₃ ), 3 _{.79-3.85 (1H, m, CH)} , 3.94 (1H, bs, CH 3 C H), 7.19 (1H, bs, ArH), 10.03 (1H, bs, CO 2 H _{^{); LRMS (FAB) m /}} z412 ([M (35 Cl 2) + H] +), 414 ([M (35 Cl 37 Cl) + _{^{] +), 416 ([M}} (37 Cl 2) + H] +); elemental analysis, Calcd _{C 21 H 27 Cl 2 NO 2} · 1 / 4H 2 O: C; 60.51, H; 6.64, N; 3.36. Measurement: C; 60.72, H; 6.82, N: 3.26

Example 14: [7aR, 8R, 11aS] -2-chloro-3-isopropyl-8,11a-trimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro-5H- Dibenzo [b, d] azepine-8-carboxylic acid

[Step 1] [7aR, 8R, 11aS] -2-chloro-3-isopropyl-5,8,11a-trimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro- 5 H - dibenzo [b, d] - azepine-8-carboxylic acid methyl ester [7aR, 8R, 11aS] -2- chloro-3-isopropyl--8,11a- dimethyl-6-oxo -6,7, 7a, 8,9,10,11,11A- octahydro -5 H - dibenzo [b, d] azepine-8-carboxylic acid methyl ester (107 mg, 0.282 mmol) was used to the step 1 of example 13 The same procedure gave the title compound as a pale orange oil (106 mg, 0.271 mmol, 96% yield).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.25 (6H, d, J = 7.0 Hz, C H ₃ CH × 2), 1.30 (3H, s, CH ₃ ), 1.47 ( 3H, s, CH ₃ ), 1.67 (2H, m, CH × 2), 1.74-1.79 (2H, m, CH × 2), 1.90-2.05 (3H, m, CH × 3), 2.50-2.62 (2H , m, CH × 2), 3.25 (3H, s, NCH 3), 3.35-3.38 (1H, m, CH 3 C H ), 3.61 (3H, s, CO ₂ CH ₃ ), 7.05 (1H, s, ArH), 7.31 (1H, s, ArH).

[Step 2] [7aR, 8R, 11aS] -2-chloro-3-isopropyl-5,8,11a-trimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro- 5 H - dibenzo [b, d] - azepine-8-carboxylic acid [7aR, 8R, 11aS] -2- chloro-3-isopropyl--5,8,11a--trimethyl-6-oxo -6,7, 7a, 8,9,10,11,11A- octahydro -5 H - dibenzo [b, d] - azepine-8-carboxylic acid methyl ester (106 mg, 0.271 mmol) using, for example 13 step 2 The title compound was obtained as a colorless solid by the same procedure as (88 mg, 0.232 mmol, yield 86%).

Colorless cotton-like substance (CHCl ₃ / n -hexane); melting point 192-196 ° C .; ¹ H-NMR (400 MHz / CD ₃ OD) δ 1.16 (3H, d, J = 6.8 Hz, C H ₃ CH) 1.17 (3H, d, J = 6.8 Hz, C H ₃ CH), 1.20 (3H, s, CH ₃ ), 1.33 (3H, s, CH), 1.56-1. 71 (4H, m, CH × 4), 1.85-1.91 (3H, m, CH × 3), 2.40-2.51 (2H, m, CH × 2), 3.15 (3H _{, s, NCH 3), 3.25-3.30} (1H, m, CH 3 C H), 7.15 (1H, s, ArH), 7.27 (1H, s, ArH); LRMS (FAB ) M / z 378 ([M ( ³⁵ Cl) + H] ⁺ ), 378 ([M ( ³⁷ Cl) + H] ⁺ ); elemental analysis, calculated value C ₂₁ H ₂₈ ClNO ₃ : C; 66.74, H; 7.47, N: 3.71. Measurement value: C; 66.44, H: 7.23, N: 3.65

Example 15: [7aR, 8R, 11aS] -4-chloro-3-isopropyl-5,8,11a-trimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro- 5H-Dibenzo [b, d] azepine-8-carboxylic acid

[Step 1] [7aR, 8R, 11aS] -4-chloro-3-isopropyl-5,8,11a-trimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro- 5 H - dibenzo [b, d] - azepine-8-carboxylic acid methyl ester [7aR, 8R, 11aS] -4- chloro-3-isopropyl--8,11a- dimethyl-6-oxo -6,7, 7a, 8,9,10,11,11A- octahydro -5 H - dibenzo [b, d] azepine-8-carboxylic acid methyl ester (65 mg, 0.173 mmol) was used to the step 1 of example 13 The same procedure gave the title compound as a colorless oil (66 mg, 0.168 mmol, 97% yield).

_{^{1 H-NMR (400MHz / CDCl}} 3 /TMS)δ1.23(3H,d,J=6.8Hz,C H 3 CH), 1.25 (3H, d, J = 6.8Hz, C H 3 CH ), 1.38 (3H, s, CH ₃ ), 1.47 (3H, s, CH ₃ ), 1.71-1.73 (2H, m, CH × 2), 1.78-1.99 (4H, m, CH × 4), 2.22 (1H, d, J = 8.7 Hz, CH), 2.73 (1H, d, J = 16.1 Hz, CH), 3.21 (3H, _{s, NCH 3), 3.47-3.50 (} 1H, m, CH 3 C H), 3.64 (3H, s, CO 2 CH 3), 3.83 (1H, dd, J = 16. 1 Hz, 8.8 Hz, CH), 7.19 (1H, d, J = 8.4 Hz, ArH), 7.29 (1H, d, J = 8.2 Hz, ArH)

[Step 2] [7aR, 8R, 11aS] -4-chloro-3-isopropyl-5,8,11a-trimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro- 5 H - dibenzo [b, d] - azepine-8-carboxylic acid [7aR, 8R, 11aS] -4- chloro-3-isopropyl--5,8,11a--trimethyl-6-oxo -6,7, 7a, 8,9,10,11,11A- octahydro -5 H - dibenzo [b, d] - azepine-8-carboxylic acid methyl ester (66 mg, 0.168 mmol) using, for example 13 step 2 The title compound was obtained as a colorless solid by the same procedure as (57 mg, 0.150 mmol, yield 89%).

Scale crystals ( n -hexane / AcOEt); melting point 185-189 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.21 (3H, d, J = 7.0 Hz, C H ₃ CH), 1. _{23 (3H, d, J =} 7.0Hz, C H 3 CH), 1.36 (3H, s, CH 3), 1.44 (3H, s, CH 3), 1.73-1.74 ( 2H, m, CH × 2), 1.78-1.96 (4H, m, CH × 4), 2.17 (1H, d, J = 8.4 Hz, CH), 2.82 (1H, d _{, J = 16.3Hz, CH),} 3.20 (3H, s, NCH 3), 3.44-3.51 (1H, m, CH 3 C H), 3.83 (1H, dd, J = 16.1 Hz, 8.6 Hz, CH), 7.17 (1H, d, J = 8.4 Hz, ArH), 7.28 (1H, d, J = 7. 9 Hz, ArH), 9.64 (1H, bs, CO ₂ H); LRMS (FAB) m / z 378 ([M ( ³⁵ Cl) + H] ⁺ ), 378 ([M ( ³⁷ Cl) + H] ⁺ ); elemental analysis calculated _{C 21 H 28 ClNO 3 · 1} / 4H 2 O: C; 65.96, H; 7.51, N; 3.66. Measurement: C; 66.10, H; 7.30, N; 3.70

Example 16: [7aR, 8R, 11aS] -3-Isopropyl-5,8,11a, -trimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro-5H-dibenzo [B, d] azepine-8-carboxylic acid

[Step 1] [7aR, 8R, 11aS ] -3- isopropyl -5,8,11a--trimethyl-6-oxo -6,7,7a, 8,9,10,11,11a- octahydro -5 H - dibenzo Preparation of [ b , d ] -azepine-8-carboxylic acid methyl ester [7aR, 8R, 11aS] -3-isopropyl-8,11a-dimethyl-6-oxo-6,7,7a, 8,9,10, 11,11a- octahydro -5 H - dibenzo [b, d] using azepine-8-carboxylic acid methyl ester (100 mg, 0.291 mmol), by the same procedure as step 1 of example 13, the title compound Obtained as a pale orange oil (90 mg, 0.252 mmol, 87% yield).

Colorless plate crystal ( n -hexane / AcOEt); melting point 149-150 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.26 (6H, d, J = 7.0 Hz, C H ₃ CH × 2), 1.31 (3H, s, CH ₃ ), 1.48 (3H, s, CH ₃ ), 1.65 to 1.68 (2H, m, CH × 2), 1.74-1. 77 (2H, m, CH × 2), 1.90 (1H, d, J = 13.6 Hz, CH), 1.89-1.98 (3H, m, CH × 3), 2.50-2 .63 (2H, m, CH × 2), 2.88-2.92 (1H, m, CH 3 C H), 3.27 (3H, s, NCH 3), 3.60 (3H, s, _{CO 2 CH 3), 7.01 (} 1H, d, J = 1.8Hz, ArH), 7.07 (1H, dd, J = 8.2Hz, 1.9Hz, A H), 7.28 (1H, d , J = 8.2Hz, ArH); LRMS (FAB) m / z358 ([M + H] +); elemental analysis, Calcd _{C 22 H 31 NO 3: C} ; 73. 91, H; 8.74, N; 3.92. Measurement: C; 73.78, H; 8.89, N; 3.97.

[Step 2] [7aR, 8R, 11aS ] -3- isopropyl -5,8,11a--trimethyl-6-oxo -6,7,7a, 8,9,10,11,11a- octahydro -5 H - dibenzo Preparation of [ b , d ] -azepine-8-carboxylic acid [7aR, 8R, 11aS] -3-isopropyl-5,8,11a-trimethyl-6-oxo-6,7,7a, 8,9,10 11,11a- octahydro -5 H - dibenzo [b, d] - azepine-8-carboxylic acid methyl ester (50 mg, 0.141 mmol) was used to the same manner as step 2 of example 13, the title The compound was obtained as colorless amorphous (42 mg, 0.121 mmol, 86% yield).

Colorless flake crystals ( n -hexane / AcOEt); melting point 123-127 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.24 (6H, d, J = 7.0 Hz, C H ₃ CH × 2), 1.31 (3H, s, CH ₃ ), 1.50 (3H, s, CH ₃ ), 1.67-1.78 (4H, m, CH × 2), 1.98-2. 04 (3H, m, CH × 3), 2.50-2.62 (2H, m, CH × 2), 2.86-2.90 (1H, m, CH ₃ C H ), 3.28 ( 3H, s, NCH ₃ ), 6.97 (1H, d, J = 1.8 Hz, ArH), 7.06 (1H, dd, J = 8.2 Hz, 1.9 Hz, ArH), 7.26 ( 1H, d, J = 8.2Hz, ArH); LRMS (FAB) m / z344 ([M + H] +); elemental analysis, calcd _{C 21 29 NO 3: C; 73.44,} H; 8.51, N; 4.08. Measurement: C; 73.28, H; 8.31, N; 4.03

Example 17: [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5-pent-4-ynyl-6,7,7a, 8,9, 10,11,11a-Octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid methyl ester

[Step 1] Methylene chloride of toluene-4-sulfonic acid pento-4-ynyl ester 4-pentyn-1-ol (1.10 mL, 0.012 mol) and triethylamine (1.81 mL, 0.013 mol, 1.1 eq.) To a (8 mL) solution, a solution of tosyl chloride (2.49 g, 0.0113 mol, 1.1 eq.) In methylene chloride (20 mL) was added at 0 ° C. over 20 minutes. The reaction mixture was stirred at room temperature for 20 hours and poured into ice water (50 mL). The separated aqueous layer was extracted with chloroform (30 mL × 3). The organic layers were combined, washed with water (30 mL × 1) and brine (30 mL × 1), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 4: 1) to obtain the title compound as a colorless liquid (2.37 g, 0.010 mol, yield 84%).

_{^{1 H-NMR (400MHz / CDCl}} 3 /TMS)δ1.85-1.89(2H,m,CH 2 C H 2 CH 2), 1.89 (1H, t, J = 2.7Hz, HCC), 2.26 (2H, dt, J = 6.9 Hz, 2.7 Hz, CCH ₂ ), 2.45 (3H, s, CH ₃ ), 4.15 (2H, t, J = 6.1 Hz, CH ₂ O), 7.35 (2H, d, J = 8.2 Hz, ArH), 7.80 (2H, d, J = 8.4 Hz, ArH)

[Step 2] Preparation of 5-iodopent-1-yne Toluene-4-sulfonic acid pento-4-ynyl ester (817 mg, 3.430 mmol) and sodium iodide (1.234 g, 8.232 mmol, in acetone (8 mL)) 2.4 eq.) Was stirred at 70 ° C. for 1 h, cooled, poured into water (20 mL) and extracted with diethyl ether (20 mL × 3). The organic layers were combined, washed with a saturated aqueous sodium bicarbonate solution (20 mL × 1) and brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow liquid. (600 mg, 3.093 mmol, 90% yield).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 2.00 (1H, t, J = 2.6 Hz, HCC), 2.01 (2H, tt, J = 6.7 Hz, 6.7 Hz, C H ₂ CH ₂ I), 2.35 (2H, dt, J = 6.7 Hz, 2.6 Hz, CCH ₂ ), 3.32 (2H, t, J = 6.7 Hz, CH ₂ I)

[Step 3] [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5-pent-4-ynyl-6,7,7a, 8,9, Preparation of 10,11,11a-octahydro- 5H -dibenzo [ b, d ] azepine-8-carboxylic acid methyl ester Sodium hydride in DMF (1 mL) (60% dispersion in mineral oil washed twice with hexane; 6 mg, 0.138 mmol, 1.1 eq.) Into a suspension of [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-6,7,7a , 8,9,10,11,11A- octahydro - 5H - dibenzo [b, d] azepine-8-carboxylic acid methyl ester (52 mg, 0.125 mmol) in DMF (1.5 mL It was added over 2 minutes at 0 ℃ a. After stirring for 30 minutes at 0 ° C., a solution of 5-iodopent-1-yne (122 mg, 0.627 mmol, 5.0 eq.) In DMF (1.5 mL) was added at 0 ° C. The mixture was stirred at room temperature for 17 hours, concentrated under reduced pressure, diluted with water (20 mL), and then extracted with chloroform (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 4: 1) to give the title compound as a colorless oil (44 mg, 0.093 mmol, 74% yield).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.42 (3H, s, CH ₃ ), 1.42 (6H, d, J = 7.0 Hz, C H ₃ CH × 2), 1.47 ( 3H, s, CH ₃ ), 1.72 (2H, m, CH × 2), 1.83-1.91 (5H, m, CH × 5), 2.01 (1H, t, J = 2. 3 Hz, HCC), 2.21 (1H, d, J = 8.5 Hz, CH), 2.30 (2H, t, J = 7.0 Hz, CCH ₂ ), 2.90 (1H, d, J = 16.2 Hz, CH), 3.05-3.12 (1 H, m, CH), 3.66 (3 H, s, CO ₂ CH ₃ ), 3.70 (1 H, dd, J = 16.4 Hz, _{8.9Hz, CH), 3.96 (1H} , bs, CH 3 C H), 4.11-4.28 (1H, m, CH), 7.21 (1H, bs, Ar H); LRMS (FAB) m / z 478 ([M ( ³⁵ Cl ₂ ) + H] ⁺ ), 480 ([M ( ³⁵ Cl ³⁷ Cl) + H] ⁺ ), 482 ([M ( ³⁷ Cl ₂ ) + H] ⁺ )

Example 18: [7aR, 8R, 11aS] -3-Isopropyl-8,11a-dimethyl-6-oxo-5-pent-4-ynyl-6,7,7a, 8,9,10,11,11a- Octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid methyl ester

[7aR, 8R, 11aS] -3-Isopropyl-8,11a-dimethyl-6-oxo-6,7,7a, 8,9,10,11,11a-octahydro- 5H -dibenzo [ b, d ] azepine- The title compound was obtained as a colorless oil in the same manner as in Step 3 of Example 17 using 8-carboxylic acid methyl ester (91 mg, 0.265 mmol) (76 mg, 0.85 mmol, yield). 70%).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.27 (6H, d, J = 6.9 Hz, C H ₃ CH × 2), 1.32 (3H, s, CH ₃ ), 1.48 ( _{3H, s, CH 3),} 1.66-1.68 (2H, m, CH × 2), 1.75-1.78 (2H, m, CH × 2), 1.90 (1H, d, J = 13.3 Hz, CH), 1.95-2.04 (2H, m, CH × 2), 1.96 (1H, t, J = 2.6 Hz, HCC), 2.10-2.17. (1H, m, CH), 2.19-2.37 (2H, m, CH × 2), 2.50-2.59 (2H, m, CH × 2), 2.88-2.96 ( _{1H, m, CH 3 C H} ), 3.48-3.56 (1H, m, CH), 3.60 (3H, s, CO 2 CH 3), 3.90-3.97 (1H, m , CH) 7.08 (1H, dd, J = 8.2 Hz, 1.9 Hz, ArH), 7.11 (1H, d, J = 1.9 Hz, ArH), 7.29 (1H, d, J = 8. 2 Hz, ArH); LRMS (FAB) m / z 410 ([M + H] ⁺ )

Example 19: [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5- [5- (4-iodophenyl) pent-4-ynyl]- 6,7,7a, 8,9,10,11,11a-Octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid methyl ester

[7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5-pent-4-ynyl-6,7,7a, 8,9,10,11 11a-octahydro- 5H -dibenzo [ b, d ] azepine-8-carboxylic acid methyl ester (44 mg, 0.093 mmol), p -diiodobenzene (34 mg, 0.102 mmol, 1.1 eq.), Pd (PPh _{3 ) 2 Cl 2 (1mg, 0.001mmol} , 0.02eq.) and CuI (1mg, 0.005mmol, 0.06eq. ) a mixture of triethylamine (2 mL) was stirred under an argon atmosphere for 39 hours in. The reaction mixture was filtered, concentrated under reduced pressure, the residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 2: 1), and the mixture of the title compound and p -diiodobenzene was obtained as a pale yellow oil (55 mg) as well as the dimer (1,4-bis [[[7aR, 8R, 11aS] -5- (2,4-dichloro-3-isopropyl-8,11a-dimethyl-8-methoxycarbonyl- 6-oxo -6,7,7a, 8,9,10,11,11a- octahydro -5 H - dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene) as a pale yellow Obtained as an amorphous material (14 mg, 0.013 mmol, 28% yield). The mixture containing the title compound was further purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 4: 1) to give the title compound as a pale orange amorphous material (32 mg, 0.046 mmol, yield). 50%).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.41 (6H, d, J = 5.3 Hz, C H ₃ CH × 2), 1.42 (3H, s, CH ₃ ), 1.46 ( 3H, s, CH ₃ ), 1.70 (2H, m, CH × 2), 1.81-1.97 (5H, m, CH × 5), 2.02-2.09 (1H, m, CH), 2.21 (1H, d, J = 8.5 Hz, CH), 2.50 (2H, t, J = 6.9 Hz, CH ₂ ), 2.86 (1H, d, J = 16. 2 Hz, CH), 3.06-3.50 (1 H, m, CH), 3.51 (3 H, s, CO ₂ CH ₃ ), 3.72 (1 H, dd, J = 16.1 Hz, 8. _{6Hz, CH), 3.95 (1H} , bs, CH 3 C H), 4.33-4.39 (1H, m, CH), 7.14 (2H, d, J = 8.1Hz, ArH), 7.20 (1H, bs, ArH), 7.62 (2H, d, J = 8.1 Hz, ArH); LRMS (FAB) m / z 680 ([M ( ³⁵ Cl ₂ ) + H] ⁺ ) , 682 ([M ( ³⁵ Cl ³⁷ Cl) + H] ⁺ ), 684 ([M ( ³⁷ Cl ₂ ) + H] ⁺ )

Dimer: ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ1.43 (12H, d, J = 6.0 Hz, C H ₃ CH × 4), 1.44 (6H, s, CH ₃ × 2 ), 1.48 (6H, s, CH ₃ × 2), 1.71 (4H, m, CH × 4), 1.83-1.99 (10H, m, CH × 10), 2.04- 2.09 (2H, m, CH × 2), 2.22 (2H, d, J = 8.5 Hz, CH × 2), 2.53 (4H, d, J = 6.9 Hz, CH × 4) , 2.89 (2H, d, J = 16.3 Hz, CH × 2), 3.09-3.16 (2H, m, CH × 2), 3.53 (6H, s, CO ₂ CH ₃ × 2), 3.74 (2H, dd , J = 16.1Hz, 8.6Hz, CH × 2), 3.97 (2H, bs, CH 3 C H × 2), 4.35-4.41 ( 2H, m CH × 2), 7.22 (2H , bs, ArH), 7.35 (4H, s, ArH); LRMS (FAB) m / z1029 ([M (35 Cl 4) + H] +), 1031 ([ M ( ³⁵ Cl ₃ ³⁷ Cl) + H] ⁺ ), 1033 ([M ( ³⁵ Cl ₂ ³⁷ Cl ₂ ) + H] ⁺ ), 1035 ([M ( ³⁵ Cl ³⁷ Cl ₃ ) + H] ⁺ )

Example 20: 1,4-bis [[[7aR, 8R, 11aS] -5- (2,4-dichloro-3-isopropyl-8,11a-dimethyl-8-methoxycarbonyl-6-oxo-6,7 , 7a, 8,9,10,11,11a-octahydro-5H-dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene

[7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5-pent-4-ynyl-6,7,7a, 8, in triethylamine (2 mL) 9,10,11,11a-Octahydro- 5H -dibenzo [ b, d ] azepine-8-carboxylic acid methyl ester (17 mg, 0.036 mmol), [7aR, 8R, 11aS] -2,4-dichloro-3- Isopropyl-8,11a-dimethyl-6-oxo-5- [5- (4-iodophenyl) pent-4-ynyl] -6,7,7a, 8,9,10,11,11a-octahydro-5H- dibenzo [b, d] azepine-8-carboxylic acid methyl ester _{(32mg, 0.047mmol, 1.3eq.)} , Pd (PPh 3) 2 Cl 2 (1mg, 0 001mmol, 0.04eq.) And CuI (1mg, 0.005mmol, 0.14eq.) And the mixture was stirred for 72 hours at room temperature under argon atmosphere. The reaction mixture was filtered, concentrated under reduced pressure, and purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 2: 1) to give the title compound as a colorless oil (32 mg, 0.031 mmol). 84% yield).

Example 21: 1,4-bis [[[7aR, 8R, 11aS] -5- (2,4-dichloro-3-isopropyl-8,11a-dimethyl-8-carboxy-6-oxo-6,7, 7a, 8,9,10,11,11a-octahydro-5H-dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene

1,4-bis [[[7aR, 8R, 11aS] -5- (2,4-dichloro-3-isopropyl-8,11a-dimethyl-8-methoxycarbonyl-6-oxo-6] in methanol (2 mL) , 7,7a, 8,9,10,11,11a-octahydro-5H-dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene (46 mg, 0.045 mmol), potassium hydroxide A mixture of (25 mg, 0.445 mmol, 10.0 eq.) And 18-crown ether-6 (59 mg, 0.223 mmol, 5.0 eq.) Was stirred at 80 ° C. for 19 hours. After cooling, the reaction mixture was concentrated, diluted with water (20 mL), acidified with 2N hydrochloric acid (2 mL) and then extracted with chloroform (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography (AcOEt: MeOH = 10: 1) to give the title compound as a colorless solid (29 mg, 0.029 mmol, yield 65%).

Colorless powder ( n -hexane / AcOEt); melting point 211-214 ° C .; ¹ H-NMR (400 MHz / CD ₃ OD) δ 1.31 (6H, s, CH ₃ × 2), 1.43-1.49 ( 12H, m, C H ₃ CH × 2 and CH ₃ × 2), 1.76-2.18 (14H, m, CH × 14), 2.27 (2H, d, J = 8.6 Hz, CH × 2), 2.54-2.55 (4H, m, CH × 4), 3.15 (2H, d, J = 16.5 Hz, CH × 2), 3.65-3.72 (2H, m , CH × 2), 4.02 ( 2H, bs, CH 3 C H × 2), 4.30 (2H, m, CH × 2), 7.32 (4H, s, ArH), 7.35 ( 2H, bs, ArH); LRMS (FAB) m / z 1001 ([M ( ³⁵ Cl ₄ ) + H] ⁺ ), 1003 ([M ( ³⁵ Cl ₃ ³⁷ Cl) + H] ⁺ ), 1005 ([M ( ³⁵ Cl ₂ ³⁷ Cl ₂ ) + H] ⁺ ), 1007 ([M ( ³⁵ Cl ³⁷ Cl ₃ ) + H] ⁺ ), 1009 ([M ( ³⁷ Cl ₄ ) + H] ⁺ ); HRMS (FAB) measured value: 1001.3432 (-1.7 mmu for [M ( ³⁵ Cl ₄ ) + H] ⁺ ), 1003.3444 ([M ( ³⁵ Cl ₃ ³⁷ Cl) + H] ⁺ relative _{^{-1.3mmu), 1005.3637 (M (35}} Cl 2 37 Cl 2) + H) + relative ^{+ 1.0mmu), 1007.3604 ([M} (35 Cl 37 Cl 3) + H] + in + 0.9mmu) _{^{for, 1009.3651 ([M (35 Cl}} 4) + H] + against ^{+ 1.7mmu);} elemental analysis, calcd _{C 56 H 64 Cl 4 N 2} O 6 · 3/2 _{2 O: C; 65.30, H} ; 6.56, N; 2.72. Measurements: C; 65.34, H; 6.59, N; 2.60.

Example 22: [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5- [5- (3-iodophenyl) pent-4-ynyl]- 6,7,7a, 8,9,10,11,11a-Octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid methyl ester

[7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5-pent-4-ynyl-6,7,7a, 8, in triethylamine (3 mL) 9,10,11,11a-octahydro- 5H -dibenzo [ b, d ] azepine-8-carboxylic acid methyl ester (62 mg, 0.129 mmol), m -diiodobenzene (21 mg, 0064 mmol, 0.5 eq.), A mixture of Pd (PPh ₃ ) ₂ Cl ₂ (1 mg, 0.001 mmol, 0.01 eq.) And CuI (1 mg, 0.005 mmol, 0.04 eq.) Was stirred at room temperature for 49 hours under an argon atmosphere. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 4: 1) to give the title compound as an orange oil (32 mg, 0.046 mmol, Yield 36%) and the dimer (1,3-bis [[[7aR, 8R, 11aS] -5- (2,4-dichloro-3-isopropyl-8,11a-dimethyl-8-methoxycarbonyl)]. 6-oxo -6,7,7a, 8,9,10,11,11a- octahydro -5 H - dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene) of orange Obtained as an oil (31 mg, 0.030 mmol, 47% yield).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.41 (6H, d, J = 5.9 Hz, C H ₃ CH × 2), 1.42 (3H, s, CH ₃ ), 1.47 ( 3H, s, CH ₃ ), 1.70-1.71 (2H, m, CH × 2), 1.82-1.93 (5H, m, CH × 5), 2.03-2.10 ( 1H, m, CH), 2.20 (1H, d, J = 8.5 Hz, CH), 2.51 (2H, t, J = 7.0 Hz, CH ₂ ), 2.87 (1H, d, J = 16.2Hz, CH), 3.07-3.14 (1H, m, CH), 3.52 (3H, s, CO 2 CH 3), 3.72 (1H, dd, J = 16. _{1Hz, 8.6Hz, CH), 3.96} (1H, bs, CH 3 C H), 4.32-4.39 (1H, m, CH), 7.02 (1H, t, J = 7 .9 Hz, ArH), 7.20 (1H, bs, ArH), 7.37 (1H, td, J = 7.8 Hz, 1.2 Hz, ArH), 7.61 (1H, td, J = 8. 5 Hz, 1.4 Hz, ArH), 7.77 (1H, t, J = 1.6 Hz, ArH); LRMS (FAB) m / z 680 ([M ( ³⁵ Cl ₂ ) + H] ⁺ ), 682 ([M ( ³⁵ Cl ³⁷ Cl) + H] ⁺ ), 684 ([M ( ³⁷ Cl ₂ ) + H] ⁺ )

Dimer: ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.41 (6H, s, CH ₃ × 2), 1.41 (12H, d, J = 6.3 Hz, C H ₃ CH × 4 ), 1.47 (6H, s, CH ₃ × 2), 1.69-1.70 (4H, m, CH × 4), 1.81-1.93 (10H, m, CH × 10), 2.03-2.08 (2H, m, CH × 2), 2.20 (2H, d, J = 8.5 Hz, CH × 2), 2.50 (4H, d, J = 7.0 Hz, CH × 4), 2.88 (2H, d, J = 16.2 Hz, CH × 2), 3.07-3.14 (2H, m, CH × 2), 3.51 (6H, s, CO _{2 CH 3 × 2), 3.73} (2H, dd, J = 16.2Hz, 8.7Hz, CH × 2), 3.96 (2H, bs, CH 3 C H × 2), 4.32- 4.39 2H, m, CH × 2), 7.20 (2H, bs, ArH), 7.21 (2H, t, J = 7.7 Hz, ArH), 7.32 (2H, d, J = 7.8 Hz) , ArH), 7.44 (1H, s, ArH); LRMS (FAB) m / z 1029 ([M ( ³⁵ Cl ₄ ) + H] ⁺ ), 1031 ([M ( ³⁵ Cl ₃ ³⁷ Cl) + H] ⁺ ) , 1033 ([M ( ³⁵ Cl ₂ ³⁷ Cl ₂ ) + H] ⁺ ), 1035 (M ( ³⁵ Cl ³⁷ Cl ₃ ) + H) ⁺ )

Example 23: 1,3-bis [[[7aR, 8R, 11aS] -5- (2,4-dichloro-3-isopropyl-8,11a-dimethyl-8-methoxycarbonyl-6-oxo-6,7 , 7a, 8,9,10,11,11a-octahydro-5H-dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene

[7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5-pent-4-ynyl-6,7,7a, 8, in triethylamine (2 mL) 9,10,11,11a-Octahydro- 5H -dibenzo [ b, d ] azepine-8-carboxylic acid methyl ester (22 mg, 0.046 mmol), [7aR, 8R, 11aS] -2,4-dichloro-3- Isopropyl-8,11a-dimethyl-6-oxo-5- [5- (3-iodophenyl) pent-4-ynyl] -6,7,7a, 8,9,10,11,11a-octahydro-5H- dibenzo [b, d] azepine-8-carboxylic acid methyl ester _{(32mg, 0.046mmol), Pd (} PPh 3) 2 Cl 2 (1mg, 0.001mmo , 0.03 eq.) And CuI (1mg, 0.005mmol, 0.1eq.) And the mixture was stirred for 48 hours at room temperature under argon atmosphere. The reaction mixture was filtered, concentrated under reduced pressure, and purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 2: 1) to give the title compound as an orange oil (33 mg, 0.032 mmol). , Yield 70%).

Example 24: 1,3-bis [[[7aR, 8R, 11aS] -5- (2,4-dichloro-3-isopropyl-8,11a-dimethyl-8-carboxy-6-oxo-6,7, 7a, 8,9,10,11,11a-octahydro-5H-dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene

4-bis [[[7aR, 8R, 11aS] -5- (2,4-dichloro-3-isopropyl-8,11a-dimethyl-8-methoxycarbonyl-6-oxo-6,7 in methanol (2 mL) , 7a, 8,9,10,11,11a-octahydro-5H-dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene (69 mg, 0.067 mmol), potassium hydroxide (38 mg , 0.672 mmol, 10.0 eq.) And 18-crown ether-6 (89 mg, 0.336 mmol, 5.0 eq.) Were stirred at 80 ° C. for 18 hours. After cooling, the reaction mixture was concentrated, diluted with water (20 mL), acidified with 2N hydrochloric acid (2 mL) and then extracted with chloroform (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography (AcOEt: MeOH = 10: 1) to give the title compound as a colorless solid (50 mg, 0.050 mmol, 75% yield).

Colorless powder ( n -hexane / CHCl ₃ ); melting point 207-213 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.29 (6H, s, CH ₃ × 2), 1.32 (12H, d, J = 7.1 Hz, C H ₃ CH × 4), 1.33 (6H, s, CH ₃ × 2), 1.61 (4H, m, CH × 4), 1.75-1.89 (10H, m, CH × 10), 2.13 (2H, d, J = 8.6 Hz, CH × 2), 2.21 (4H, m, CH × 4), 2.92-3.00 ( 2H ,, m, CH × 2), 2.98 (2H, d, J = 16.7 Hz, CH × 2), 3.50-3.57 (2H, m, CH × 2), 3.91 ( _{2H, bs, CH 3 C H} × 2), 4.13-4.20 (2H, m, CH × 2), 7.09 (3H, m, ArH), 7.24 (2H, bs ^{ArH), 7.30 (1H, s} , ArH); LRMS (FAB) m / z1001 ([M (35 Cl 4) + H] +), 1003 ([M (35 Cl 3 37 Cl) + H] +), 1005 ([M ( ³⁵ Cl ₂ ³⁷ Cl ₂ ) + H] ⁺ ), 1007 ([M ( ³⁵ Cl ³⁷ Cl ₃ ) + H] ⁺ ), 1009 ([M ( ³⁷ Cl ₄ ) + H] ⁺ ); HRMS (FAB ) Measurements: 1001.4380 (+7.8 mmu for [M ( ³⁵ Cl ₄ ) + H] ⁺ , 1003.4284 (+7.1 mmu for [M ( ³⁵ Cl ₃ ³⁷ Cl) + H] ⁺ ), ^{_{1005.3859 ([M (35 Cl 2}} 37 Cl 2) + H] + against ^{+ 3.7mmu), 1007.3920 ([M} (35 Cl 37 Cl 3) + H] + against + 4.1 m ^{u), 1009.3856 ([M (} 35 Cl 4) + H] + against ^{+ 3.7mmu);} elemental analysis, Calcd _{C 56 H 64 Cl 4 N 2} O 6 · 3 / 2H 2 O: C; 65 .30, H; 6.56, N; 2.72. Measurement: C; 65.03, H; 6.78, N; 2.62

Example 25: [7aR, 8R, 11aS] -3-isopropyl-8,11a-dimethyl-6-oxo-5- [5- (3-iodophenyl) pent-4-ynyl] -6,7,7a, 8,9,10,11,11a-Octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid methyl ester

[7aR, 8R, 11aS] -3- isopropyl -8,11a- dimethyl-6-oxo-5-pent-4-ynyl -6,7,7a, 8,9,10,11,11a- octahydro - 5H - Dibenzo [ b, d ] azepine-8-carboxylic acid methyl ester (66 mg, 0.161 mmol), m -diiodobenzene (53 mg, 0.161 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (1 mg, 0.001 mmol, 0.01 eq.) And CuI (1 mg, 0.005 mmol, 0.03 eq.) In triethylamine (2 mL) were stirred under an argon atmosphere for 19 hours. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 4: 1 → 2: 1) to give the title compound as a yellow oil (63 mg, 0.103 mmol, yield 64%), and dimer (1,3-bis [[[7aR, 8R, 11aS] -5- (3-isopropyl-8,11a-dimethyl-8-methoxycarbonyl-6- oxo -6,7,7a, 8,9,10,11,11a- octahydro -5 H - dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene: example 26) as a yellow As an oil (26 mg, 0.029 mmol, 36% yield).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.23 (6H, d, J = 6.9 Hz, C H ₃ CH × 2), 1.34 (3H, s, CH ₃ ), 1.50 ( 3H, s, CH ₃ ), 1.68-1.69 (2H, m, CH × 2), 1.77-1.79 (2H, m, CH × 2), 1.92 (1H, d, J = 8.3 Hz, CH), 1.97-2.00 (2H, m, CH × 2), 2.09 (1H, m, CH), 2.22-2.23 (1H, m, CH ), 2.46-2.64 (4H, m, CH × 4), 2.83-2.90 (1H, m, CH 3 C H), 3.55-3.61 (1H, m, CH ), 3.62 (3H, s, CO ₂ CH ₃ ), 3.95-4.02 (1H, m, CH), 7.00 (1H, t, J = 7.9 Hz, ArH), 7. 08 (1H dd, J = 8.2 Hz, 1.8 Hz, ArH), 7.13 (1H, d, J = 1.8 Hz, ArH), 7.30 (1H, t, J = 8.3 Hz, ArH), 7 .32 (1H, dt, J = 8.0 Hz, 1.4 Hz, ArH), 7.60 (1H, td, J = 7.9 Hz, 1.2 Hz, ArH), 7.73 (1H, t, J = 1.6 Hz, ArH); LRMS (FAB) m / z 612 ([M + H] ⁺ )

Example 26: 1,3-bis [[[7aR, 8R, 11aS] -5- (3-isopropyl-8,11a-dimethyl-8-methoxycarbonyl-6-oxo-6,7,7a, 8,9 , 10,11,11a-octahydro-5H-dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene

Dimer obtained in Example 25: ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.19 (12H, d, J = 6.9 Hz, C H ₃ CH × 4), 1.33 (6H , S, CH ₃ × 2), 1.48 (6H, s, CH ₃ × 2), 1.67-1.68 (4H, m, CH × 4), 1.75-1.77 (4H, m, CH × 4), 1.90 (2H, d, J = 7.3 Hz, CH × 2), 2.01-2.11 (2H, m, CH × 2), 2.17-2.24 (2H, m, CH × 2 ), 2.40-2.62 (8H, m, CH × 8), 2.80-2.90 (2H, m, CH 3 C H × 2), 3.42 −3.60 (2H, m, CH × 2), 3.61 (6H, s, CO ₂ CH ₃ × 2), 3.92-4.00 (2H, m, CH × 2), 7.05 (2H, dd, J = 8. Hz, 1.9 Hz, ArH), 7.11 (2H, d, J = 1.9 Hz, ArH), 7.16 (1H, d, J = 8.4 Hz, ArH), 7.24 (2H, dd) , J = 8.6 Hz, 1.5 Hz, ArH), 7.28 (2H, d, J = 8.3 Hz, ArH), 7.36 (1H, m, ArH); LRMS (FAB) m / z 893 ( [M + H] ⁺ )

Example 27: 1,3-bis [[[7aR, 8R, 11aS] -5- (3-isopropyl-8,11a-dimethyl-8-carboxy-6-oxo-6,7,7a, 8,9, 10,11,11a-octahydro-5H-dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene

1,3-bis [[[7aR, 8R, 11aS] -5- (3-isopropyl-8,11a-dimethyl-8-methoxycarbonyl-6-oxo-6,7,7a, 8 in methanol (2 mL) , 9,10,11,11a-octahydro-5H-dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene (26 mg, 0.029 mmol), potassium hydroxide (16 mg, 0.289 mmol) , 10.0 eq.) And 18-crown ether-6 (38 mg, 0.145 mmol, 5.0 eq.) Were stirred at 80 ° C. for 17 hours. After cooling, the reaction mixture was concentrated, diluted with water (20 mL), acidified with 2N hydrochloric acid (2 mL) and then extracted with chloroform (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography (AcOEt: MeOH = 10: 1) to give the title compound as a colorless amorphous substance (9 mg, 0.010 mmol, 36% yield).

Colorless solid ( n -hexane / CHCl ₃ ); melting point 159-163 ° C .; ¹ H-NMR (400 MHz / CD ₃ OD / TMS) δ 1.04 (12H, d, J = 6.9 Hz, C H ₃ CH × 4), 1.22 (6H, s, CH ₃ × 2), 1.33 (6H, s, CH ₃ × 2), 1.57-1.68 (8H, m, CH × 8), 1. 84-1.88 (8H, m, CH × 8), 2.21-2.27 (2H, m, CH × 2), 2.38-2.48 (8H, m, CH × 8), 2 _{.73-2.78 (2H, m, CH 3} C H × 2), 3.30-3.38 (2H, m, CH × 2), 3.80 (2H, m, CH × 2), 7 .01-7.08 (6H, m, ArH), 7.23-7.25 (4H, m, ArH); LRMS (FAB) m / z 866 ([M + H] ⁺ ); elemental content Analysis, calcd _{C 56 H 68 N 2 O 6} · 2H 2 O: C; 74.64, H; 8.05, N; 3.11. Measurement: C; 74.45, H; 8.31, N; 2.83.

Example 28: [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,
11a-dimethyl-6-oxo-5- [5- (2-iodophenyl) pent-4-ynyl] -6,7,7a, 8,9,10,11,11a-octahydro-5H-dibenzo [b, d] Azepine-8-carboxylic acid methyl ester

[7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5-pent-4-ynyl-6,7,7a, 8, in triethylamine (2 mL) 9,10,11,11a-Octahydro- 5H -dibenzo [ b, d ] azepine-8-carboxylic acid methyl ester (77 mg, 0.161 mmol), o -diiodobenzene (0.010 mL, 0.080 mmol, 0. 0). 5 eq.), Pd (PPh ₃ ) ₂ Cl ₂ (1 mg, 0.001 mmol, 0.01 eq.) And CuI (1 mg, 0.005 mmol, 0.03 eq.) Were stirred at room temperature for 48 hours under an argon atmosphere. . The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 2: 1) to give the title compound as an orange oil (17 mg, 0.025 mmol, (Yield 15%), and a raw dimer of alkyne (1,10-bis [[7aR, 8R, 11aS] -5- (2,4-dichloro-3-isopropyl-8,11a-dimethyl-8) - methoxycarbonyl-6-oxo -6,7,7a, 8,9,10,11,11a- octahydro -5 H - dibenzo [b, d] azepin-5-yl)] decane-4,6-diyne) Was obtained as an orange oil (52 mg, 0.054 mmol, 67% yield).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ1.43 (6H, d, J = 7.5 Hz, C H ₃ CH × 2), 1.44 (3H, s, CH ₃ ), 1.49 ( _{3H, s, CH 3),} 1.70 (2H, m, CH × 2), 1.85-1.92 (4H, m, CH × 2), 2.02-2.03 (1H, m, CH), 2.12-2.17 (1H, m, CH), 2.22 (1H, d, J = 8.5 Hz, CH), 2.61 (2H, t, J = 6.9 Hz, CH ₂ ), 2.91 (1H, d, J = 16.3 Hz, CH), 3.20-3.27 (1H, m, CH), 3.52 (3H, s, CO ₂ CH ₃ ), 3 .77 (1H, dd, J = 16.1 Hz, 8.6 Hz, CH), 3.98 (1H, bs, CH ₃ C H ), 4.34-4.38 (1H, m, CH) 6.98 (1H, dt, J = 7.7 Hz, 1.7 Hz, ArH), 7.22 (1H, bs, ArH), 7.29 (1H, dt, J = 7.6 Hz, 1.2 Hz) , ArH), 7.44 (1H, dd, J = 7.7 Hz, 1.6 Hz, ArH), 7.84 (1H, dd, J = 8.0 Hz, 1.6 Hz, ArH); LRMS (FAB) _{^{m / z680 ([M (35}} Cl 2) + H] +), 682 ([M (35 Cl 37 Cl) + H] +), 684 ([M (37 Cl 2) + H] +).

Homodimer obtained in Example 28: ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.40 (6H, s, CH ₃ × 2), 1.41 (12H, d, J = 5. 8 Hz, C H ₃ CH × 4), 1.46 (6H, s, CH ₃ × 2), 1.71 (4H, m, CH × 4), 1.79-1.92 (10H, m, CH × 10), 1.95-2.04 (2H, m, CH × 2), 2.20 (2H, d, J = 8.5 Hz, CH × 2), 2.36 (4H, d, J = 7.1 Hz, CH × 4), 2.83 (2H, d, J = 16.2 Hz, CH × 2), 2.98-3.05 (2H, m, CH × 2), 3.67 (6H _{, s, CO 2 CH 3 ×} 2), 3.69 (2H, dd, J = 16.0Hz, 8.6Hz, CH × 2), 3.94 (2H, bs, CH 3 C H × 2), 4). 6-4.32 (2H, m, CH × 2), 7.19-7.23 (2H, bs, ArH); LRMS (FAB) m / z1029 ([M (35 Cl 4) + H] +), 1031 ([M ( ³⁵ Cl ₃ ³⁷ Cl) + H] ⁺ ), 1033 ([M ( ³⁵ Cl ₂ ³⁷ Cl ₂ ) + H] ⁺ ), 1035 ([M ( ³⁵ Cl ³⁷ Cl ₃ ) + H] ⁺ ), 1037 _{^{([M (37 Cl 4)}} + H] +)

Example 29: 1,2-bis [[[7aR, 8R, 11aS] -5- (2,4-dichloro-3-isopropyl-8,11a-dimethyl-8-methoxycarbonyl-6-oxo-6,7 , 7a, 8,9,10,11,11a-octahydro-5H-dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene

[7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5-pent-4-ynyl-6,7,7a, 8 in triethylamine (1 mL) 9,10,11,11a-Octahydro- 5H -dibenzo [ b, d ] azepine-8-carboxylic acid methyl ester (15 mg, 0.032 mmol), [7aR, 8R, 11aS] -2,4-dichloro-3- Isopropyl-8,11a-dimethyl-6-oxo-5- [5- (2-iodophenyl) pent-4-ynyl] -6,7,7a, 8,9,10,11,11a-octahydro-5H- Dibenzo [b, d] azepine-8-carboxylic acid methyl ester (22 mg, 0.032 mmol), Pd (PPh ₃ ) ₄ (2 mg, 0.002 mmol, 0. 05 eq.) And CuI (1 mg, 0.005 mmol, 0.2 eq.) Were stirred at 100 ° C. for 19 hours under an argon atmosphere. The reaction mixture was filtered, concentrated under reduced pressure, and purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 2: 1) to give the title compound as an orange oil (11 mg, 0.011 mmol). , Yield 33%).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.41 (6H, s, CH ₃ × 2), 1.42 (12H, d, J = 6.6 Hz, C H ₃ CH × 4), 1. 46 (6H, s, CH ₃ × 2), 1.68 (4H, m, CH × 4), 1.81-1.92 (8H, m, CH × 8), 1.95-2.00 ( 2H, m, CH × 2), 2.07-2.14 (2H, m, CH × 2), 2.20 (2H, d, J = 8.0 Hz, CH × 2), 2.57 (4H , T, J = 6.9 Hz, CH ₂ × 2), 2.89 (2H, d, J = 16.2 Hz, CH × 2), 3.13-3.20 (2H, m, CH × 2) , 3.47 (6H, s, CO ₂ CH ₃ × 2), 3.74 (2H, dd, J = 16.2 Hz, 8.6 Hz, CH × 2), 3.96 (2H, bs, CH ₃ C H × 2 4.33-4.38 (2H, m, CH × 2), 7.20 (2H, dd, J = 5.7 Hz, 3.3 Hz, ArH), 7.19-7.20 (2H, m , ArH), 7.41 (2H, dd, J = 5.7 Hz, 3.4 Hz, ArH); LRMS (FAB) m / z 1029 ([M ( ³⁵ Cl ₄ ) + H] ⁺ ), 1031 ([M ( ³⁵ Cl ₃ ³⁷ Cl ₃ ) + H] ⁺ ), 1033 ([M ( ³⁵ Cl ₂ ³⁷ Cl ₂ ) + H] ⁺ ), 1035 ([M ( ³⁵ Cl ³⁷ Cl ₃ ) + H] ⁺ )

Example 30: 1,2-bis [[[7aR, 8R, 11aS] -5- (2,4-dichloro-3-isopropyl-8,11a-dimethyl-8-carboxy-6-oxo-6,7, 7a, 8,9,10,11,11a-octahydro-5H-dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene

1,2-bis [[[7aR, 8R, 11aS] -5- (2,4-dichloro-3-isopropyl-8,11a-dimethyl-8-methoxycarbonyl-6-oxo-6] in methanol (2 mL) , 7,7a, 8,9,10,11,11a-octahydro-5H-dibenzo [b, d] azepin-5-yl)] pent-1-ynyl] benzene (11 mg, 0.011 mmol), potassium hydroxide A mixture of (60 mg, 0.108 mmol, 10.0 eq.) And 18-crown ether-6 (14 mg, 0.054 mmol, 5.0 eq.) Was stirred at 80 ° C. for 16 hours. After cooling, the reaction mixture was concentrated, diluted with water (20 mL), acidified with 2N hydrochloric acid (2 mL) and then extracted with chloroform (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography (AcOEt: MeOH = 20: 1) to give the title compound as a colorless solid (4 mg, 0.004 mmol, 41% yield).

Pale yellow powder ( n -hexane / AcOEt); melting point 181-184 ° C .; ¹ H-NMR (400 MHz / CD ₃ OD) δ 1.28 (6H, s, CH ₃ × 2), 1.34 (12H, m , C H ₃ CH × 2 and CH ₃ × 2), 1.73 (14H, m, CH × 14), 2.21 (6H, m, CH × 6), 2.98 (4H, m, CH × 4), 3.54 (2H, m , CH × 2), 3.91 (2H, bs, CH 3 C H × 2), 4.15 (2H, m, CH × 2), 7.06 (2H , s, ArH), 7.27 ( 4H, m, ArH); LRMS (FAB) m / z1001 ([M (35 Cl 4) + H] +), 1003 ([M (35 Cl 3 37 Cl) + H] ⁺ ), 1005 ([M ( ³⁵ Cl ₂ ³⁷ Cl ₂ ) + H] ⁺ ), 1007 ([M ( ³⁵ Cl _{^{37 Cl 3) + H] +}} ), 1009 ([M (37 Cl 4) + H] +); elemental analysis, Calcd _{C 56 H 64 Cl 4 N 2} O 6 · 3 / 2H 2 O: C; 65.30 , H; 6.56, N; 2.72. Measurement: C; 65.17, H; 6.79, N; 2.69

Example 31: [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5-pent-4-ynyl-6,7,7a, 8,9, 10,11,11a-Octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid

[7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5-pent-4-ynyl-6,7,7a, 8 in methanol (1 mL) 9,10,11,11a-octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid methyl ester (41 mg, 0.086 mmol), potassium hydroxide (48 mg, 0.863 mmol, 10.0 eq.) And A mixture of 18-crown ether-6 (57 mg, 0.216 mmol, 2.5 eq.) Was stirred at 80 ° C. for 17 hours. The reaction mixture was cooled, concentrated under reduced pressure, diluted with water (10 mL), acidified with 2N hydrochloric acid (2 mL), and then extracted with chloroform (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography (AcOEt: MeOH = 10: 1) to give the title product as a colorless solid (29 mg, 0.0624 mmol, 72% yield).

Colorless glassy solid ( n -hexane / AcOEt); melting point 122-126 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.39 (3H, s, CH ₃ ), 1.40 (6H, d , J = 5.5 Hz, C H ₃ CH × 2), 1.44 (3H, s, CH ₃ ), 1.69-1.74 (2H, m, CH × 2), 1.73 (1H, t, J = 2.4 Hz, HCC), 1.81-1.89 (5H, m, CH × 5), 2.16 (1H, d, J = 8.5 Hz, CH), 2.50-2 .53 (2H, m, CH × 2), 2.94-3.01 (1H, s, CH), 3.04 (1H, d, J = 16.4 Hz, CH), 3.74 (1H, _{dd, J = 15.9Hz, 9.0Hz,} CH), 3.95 (1H, bs, CH 3 C H), 4.36-4.43 (1H, m ^{CH), 7.19 (1H, bs} , ArH); LRMS (FAB) m / z464 ([M (35 Cl 2) + H] +), 466 ([M (35 Cl 37 Cl) + H] +), 468 _{^{([M (37 Cl 2)}} + H] +); elemental analysis, calcd _{C 25 H 31 Cl 2 NO 3} : C; 64.65, H; 6.73, N; 3.02. Measurement: C; 64.63, H; 6.87, N; 2.94.

Example 32: [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5- (5-phenylpent-4-ynyl) -6,7,7a , 8,9,10,11,11a-octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid methyl ester

[7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5-pent-4-ynyl-6,7,7a, 8 in triethylamine (1 mL) 9,10,11,11a-Octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid methyl ester (20 mg, 0.063 mmol), iodobenzene (0.008 mL, 0.075 mmol, 1.2 eq.) , Pd (PPh ₃ ) ₂ Cl ₂ (1 mg, 0.001 mmol, 0.02 eq.) And CuI (1 mg, 0.005 mmol, 0.08 eq.) Were stirred at room temperature for 14 hours under an argon atmosphere. The reaction mixture was filtered, concentrated under reduced pressure, and purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 5: 1) to give the title compound as a pale yellow amorphous (37 mg, quantitative).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.42 (6H, d, J = 6.7 Hz, C H ₃ CH × 2), 1.42 (3H, s, CH ₃ ), 1.47 ( 3H, s, CH ₃ ), 1.69 (2H, m, CH × 2), 1.81-1.98 (5H, m, CH × 5), 2.06-2.11 (1H, m, CH), 2.20 (1H, d, J = 8.5 Hz, CH), 2.52 (2H, t, J = 7.0 Hz, CH ₂ ), 2.89 (1H, d, J = 16. 3 Hz, CH), 3.10-3.17 (1 H, m, CH), 3.48 (3 H, s, CO ₂ CH ₃ ), 3.73 (1 H, dd, J = 16.2 Hz, 8. _{5Hz, CH), 3.96 (1H} , bs, CH 3 C H), 4.32-4.39 (1H, m, CH), 7.20 (1H, bs, ArH), 7. 27-7.29 (3H, m, ArH), 7.41 (2H, dd, J = 7.9 Hz, 1.9 Hz, ArH); LRMS (FAB), m / z 554 ([M ( ³⁵ Cl ₂ ) + H] ⁺ ), 556 ([M ( ³⁵ Cl ³⁷ Cl) + H] ⁺ ), 558 ([M ( ³⁷ Cl ₂ ) + H] ⁺ )

Example 33: [7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5- (5-phenylpent-4-ynyl) -6,7,7a , 8,9,10,11,11a-octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid

[7aR, 8R, 11aS] -2,4-dichloro-3-isopropyl-8,11a-dimethyl-6-oxo-5- (5-phenylpent-4-ynyl) -6,7 in methanol (1 mL) , 7a, 8,9,10,11,11a-octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid methyl ester (37 mg, 0.067 mmol), potassium hydroxide (38 mg, 0.669 mmol, 10 0.0 eq.) And 18-crown ether-6 (44 mg, 0.167 mmol, 2.5 eq.) Were stirred at 80 ° C. for 16 h. The reaction mixture was cooled, concentrated under reduced pressure, diluted with water (10 mL), acidified with 2N hydrochloric acid (2 mL), and then extracted with chloroform (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 10: 1) to obtain the title compound as a colorless oil (31 mg, 0.058 mmol, yield 87%).

Colorless powder ( n -hexane / AcOEt); melting point 127-130 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.37-1.44 (12H, m, CH ₃ × 4), 1.70 (2H, m, CH × 2), 1.79-1.88 (5H, m, CH × 5), 1.90-2.04 (1H, m, CH), 2.11 (1H, d, J = 8.5 Hz, CH), 2.47 (2H, t, J = 6.9 Hz, CH ₂ ), 2.89 (1H, d, J = 16.3 Hz, CH), 3.07-3. 14 (1H, m, CH) , 3.48 (1H, dd, J = 16.1Hz, 8.6Hz, CH), 3.94 (1H, bs, CH 3 C H), 4.27-4. 36 (1H, m, CH) , 7.13-7.36 (6H, m, ArH); LRMS (FAB) m / z540 ([M (3 _{^{Cl 2) + H] +)}} , 542 ([M (35 Cl 37 Cl) + H] +), 544 ([M (37 Cl 2) + H] +); elemental analysis, Calcd _C 22 _H 29 _Cl 2 NO ₃ : C; 68.88, H; 6.53, N; 2.59. Measurement: C; 68.62, H; 6.65, N; 2.58.

Example 34: [7aR, 8R, 11aS] -3-isopropyl-8,11a-dimethyl-6-oxo-5- (5-phenylpent-4-ynyl) -6,7,7a, 8,9,10 , 11,11a-Octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid methyl ester

[7aR, 8R, 11aS] -3-isopropyl-8,11a-dimethyl-6-oxo-5- (5-pent-4-ynyl) -6,7,7a, 8,9, in triethylamine (1 mL) 10,11,11a-octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid methyl ester (88 mg, 0.215 mmol), iodobenzene (0.029 mL, 0.258 mmol, 1.2 eq.), Pd (PPh ₃ ) ₂ Cl ₂ (2 mg, 0.002 mmol, 0.01 eq.) And CuI (1 mg, 0.005 mmol, 0.02 eq.) Were stirred at room temperature for 21 hours under an argon atmosphere. The reaction mixture was filtered, concentrated under reduced pressure, and purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 2: 1) to give the title compound as an orange amorphous material (81 mg, 0.167 mmol). Yield 78%).

¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.20 (6H, d, J = 6.9 Hz, C H ₃ CH × 2), 1.33 (3H, s, CH ₃ ), 1.49 ( _{3H, s, CH 3),} 1.66-1.68 (2H, m, CH × 2), 1.74-1.77 (2H, m, CH × 2), 1.91 (1H, d, J = 13.3 Hz, CH), 1.92-1.98 (2H, m, CH × 2), 2.05-2.12 (1H, m, CH), 2.16-2.27 (1H) , m, CH), 2.41-2.62 ( 4H, m, CH × 4), 2.79-2.90 (1H, m, CH 3 C H), 3.56-3.63 (1H , M, CH), 3.60 (3H, s, CO ₂ CH ₃ ), 3.95-4.02 (1H, m, CH), 7.06 (1H, dd, J = 8.2 Hz, 1 .7Hz ArH), 7.13 (1H, d, J = 1.9 Hz, ArH), 7.24-7.26 (3H, m, ArH), 7.28 (1H, d, J = 8.3 Hz, ArH) ), 7.34-7.37 (2H, m, ArH); LRMS (FAB) m / z 486 ([M + H] ⁺ ).

Example 35: [7aR, 8R, 11aS] -3-Isopropyl-8,11a-dimethyl-6-oxo-5- (5-phenylpent-4-ynyl) -6,7,7a, 8,9,10 , 11,11a-Octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid

[7aR, 8R, 11aS] -3-Isopropyl-8,11a-dimethyl-6-oxo-5- (5-phenylpent-4-ynyl) -6,7,7a, 8,9 in methanol (1 mL) , 10, 11, 11a-octahydro-5H-dibenzo [b, d] azepine-8-carboxylic acid methyl ester (67 mg, 0.139 mmol), potassium hydroxide (93 mg, 0.167 mmol, 1.2 eq.) And 18 A mixture of crown ether-6 (92 mg, 0.347 mmol, 2.5 eq.) Was stirred at 80 ° C. for 15 hours. The reaction mixture was cooled, concentrated under reduced pressure, diluted with water (20 mL), acidified with 2N hydrochloric acid (2 mL), and then extracted with chloroform (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO ₂ column chromatography ( n -hexane: AcOEt = 1: 1) to give the title compound as a colorless amorphous material (32 mg, 0.068 mmol, yield 49%), which was unreacted at the same time. The raw material was recovered as a colorless amorphous substance (24 mg, 0.049 mmol, recovery rate 35%).

Pale yellow powder ( n -hexane); melting point 76-79 ° C .; ¹ H-NMR (400 MHz / CDCl ₃ / TMS) δ 1.24 (6H, d, J = 7.0 Hz, C H ₃ CH × 2), 1 .26 (3H, s, CH ₃ ), 1.46 (3H, s, CH ₃ ), 1.65-1.77 (4H, m, CH × 4), 1.88-2.03 (2H, m, CH × 2), 1.97 (1H, d, J = 13.3 Hz, CH), 2.05-2.12 (1H, m, CH), 2.46-2.57 (4H, m _{, CH × 4), 2.84-2.91 (} 1H, m, CH 3 C H), 3.23-3.31 (1H, m, CH), 3.74-3.80 (1H, m , CH), 7.05 (1H, dd, J = 8.2 Hz, 1.8 Hz, ArH), 7.08 (1H, d, J = 1.8 Hz, ArH), 7.18 (2 , D, J = 8.2 Hz, ArH), 7.21-7.25 (2H, m, ArH), 7.29 (1H, d, J = 7.4 Hz, ArH); LRMS (FAB) m / ^{z472 ([M + H] +} ); elemental analysis, calcd _{C 31 H 37 Cl 2 NO 3} : C; 78.95, H; 7.91, N; 2.97. Measurement: C; 78.65, H; 8.07, N; 2.80

Bioactivity test 1) Electrophysiological test Using the inside-out patch clamp method, the effect of the compound of the present invention as a BK channel opener was evaluated.

Expression vector, pcDNA3 (Invitrogen, CA, USA ) and pTracer-CMV2 (Invitrogen), which incorporates human BK slo a gene and beta ₁ gene, respectively. The expression vector was used together with FuGENE6 transfection reagent (Roche Diagnostics Corporation, USA) and the BK slo α gene and β ₁ gene introduced were temporarily co-expressed in human embryonic kidney tsA201 cells. Using inside-out patch clamp (patch / hole cell clamp amplifier CEZ-2400, Nihon Kohden) at room temperature (20-25 ° C.), recording K ⁺ flow from HEK cells 24-48 hours after transfection did. Intracellular fluid (K-Mes (Alfa Aesar, USA): 140 mM, HEPES (Sigma-Aldrich, Inc., USA): 10 mM, HEDTA (Nacalai Tesque, Japan) ): 5 mM, free Ca ²⁺ 100 nM or 1 μM; pH = 7.4) and diluted from the intracellular side of the patch membrane. When the pipette was filled with the solution, the resistance of the pipette was 2-5 MΩ. The stimulation potential was changed from -100 mV to 190 mV with a positive width of 10 mV. The tail current value of the BK channel current at each measured potential was plotted to obtain a conductance-potential curve. Based on the Boltzmann analysis, V _1/2 (half value of maximum activation potential) was calculated from the curve and compared.

[Test results]
The potential dependence curve by the inside-out patch clamp method of the compound manufactured in Example 33 (hereinafter referred to as Compound 1) is shown (FIG. 1). From this test result, it was confirmed that at any Ca ²⁺ concentration (100 nM and 1 μM), the addition of Compound 1 (10 μM) shifts the potential dependence curve to the lower potential side by about −24 mV. Addition showed that even small depolarizations facilitated opening of the BK channel, and the V _1/2 value also decreased (FIG. 2). Thereby, it was confirmed that this invention compound has an effect as a BK channel opening agent.

  Further, FIG. 3 shows a change in the BK channel current when the stimulation potential is increased stepwise and then changed from 190 mV to 100 mV. In the system to which Compound 1 was added, it was confirmed that the tail current range was widened compared to the system in which Compound 1 was not present, and it was shown that the opening time of the BK channel was extended by the addition of Compound 1.

  Furthermore, the opening action (G / Gmax) of the compound of the present invention on the human BK channel when the membrane potential is 100 mV is shown (FIGS. 4 and 5). For the test, Compound 1, the compound produced in Example 13 (hereinafter referred to as Compound 2), the compound produced in Example 31 (hereinafter referred to as Compound 3), the compound produced in Example 35 (hereinafter referred to as Compound 4) ), The compound produced in Example 30 (hereinafter referred to as Compound 5), the compound produced in Example 21 (hereinafter referred to as Compound 6) and the compound produced in Example 27 (hereinafter referred to as Compound 7). )It was used. In addition, the percentage displayed in the figure indicates the rate of increase when the control value is 100%. In addition, wash in the figure indicates the value of G / Gmax after washing out the compound. From the results shown in FIGS. 4 and 5, it was confirmed that the human BK channel opening action of the compound according to the present invention is a reversible action. The washout operation was performed by substituting with an intracellular solution containing no drug.

2) Test using isolated micturition smooth muscle The bladder was removed from male Japanese white rabbits (3-4 kg, age 3-4 months) anesthetized with an excessive amount of pentobarbital, and immediately, Krebs solution (NaCl: 118 mM, KCl: 4.7 mM, MgSO ₄ : 1.2 mg, CaCl ₂ : 2.6 mg, KH ₂ PO ₄ : 1.2 mM, NaHCO ₃ : 25 mM, glucose: 11 mM). The bladder mucosa was removed, and the bladder smooth muscle was vertically cut into strips (length 5 to 7 mm, width 2 to 3 mm) to prepare bladder smooth muscle strips. This bladder smooth muscle strip was placed in a tissue bath containing Krebs solution (10 mL), and kept at 37 ° C. and bubbled with 95% O ₂ /5% CO ₂ gas. One end of the strip is fixed to the support rod, the other end is connected to a force-displacement transducer (TB-612T, Nihon Kohden, Japan), and tension is applied via a strain pressure amplifier (AP-601G, Nihon Kohden). Changes were measured. A load of about 2 g weight was applied as the initial tension. This bladder smooth muscle strip was equilibrated for 1 hour and then used for experiments. This strip was pre-contracted with a high concentration K ⁺ (30 mM or 120 mM) krebs solution by replacement of the tissue bath solution, and then the test compound was added to a final concentration of 10 μM and activity was measured by measuring the relaxation effect. Evaluated. When a high concentration K ⁺ solution was used to shrink the strip, the same molar concentration of Na ⁺ in the Krebs solution was replaced with K ⁺ to maintain isotonicity. When the K ⁺ concentration in the tissue bath (extracellular) is 30 mM, a part of the voltage-dependent Ca ²⁺ channel is opened to depolarize compared to the physiological K ⁺ concentration of 5.4 mM. Although contraction of bladder smooth muscle due to Ca ²⁺ inflow is observed, when the K ⁺ channel including the BK channel is opened by the test compound, the resting membrane potential is hyperpolarized to around −40 mV which is the equilibrium potential of K ^+. In addition, the voltage-dependent Ca ²⁺ channel is closed and relaxation of the bladder smooth muscle is observed. On the other hand, when the K ⁺ concentration is 120 mM, even if the BK channel is opened, the equilibrium potential is around 0 mV, so that relaxation of the bladder smooth muscle is not observed while the voltage-dependent Ca ²⁺ channel remains open. That is, when the test compound exhibits a relaxation reaction at a K ⁺ concentration of 30 mM and the action disappears at a K ⁺ concentration of 120 mM, it means that the test compound has an effect of opening the K ⁺ channel.

[Test results]
Test results for the compounds of the present invention are shown in FIGS. For the test, compounds 1 to 4, the compound produced in Example 2 (hereinafter referred to as Compound 8), the compound produced in Example 4 (hereinafter referred to as Compound 9), the compound produced in Example 6 (hereinafter referred to as “Compound 8”) , Referred to as Compound 10), the compound prepared in Example 9 (hereinafter referred to as Compound 11), the compound prepared in Example 12 (hereinafter referred to as Compound 12), and the compound prepared in Example 14 (hereinafter referred to as “Compound 11”). Compound 13) was used. As a comparative example, the following formula:

The test results for the compound represented by (dichlorodihydroabietic acid) are shown in FIG. In each figure, the tension of the strip measured after equilibrating the bladder smooth muscle strip for 1 hour was defined as 100%, and the decrease in tension due to the subsequent treatment was shown as a ratio. From the test results, it was confirmed that the compound according to the present invention has a bladder smooth muscle relaxing action due to the K ⁺ channel opening action.

It is a figure which shows an example of the test result by the inside-out patch clamp method for investigating the influence with respect to the human BK channel of the compound of this invention. It is a figure which shows the influence which the compound of this invention has on V1 _{/ 2} in a human BK channel. It is a figure which shows an example of the test result for confirming the influence which the compound of this invention has on the tail electric current at the time of closing of a human BK channel. It is a figure which shows an example of the test result for confirming the influence which the compound of this invention has on the opening effect | action (G / Gmax) with respect to a human BK channel when a membrane potential is 100 mV. It is a figure which shows an example of the test result for confirming the influence which the compound of this invention has on the opening effect | action (G / Gmax) with respect to a human BK channel when a membrane potential is 100 mV. It is a figure which shows an example of the result of the test for investigating the influence with respect to the contraction / relaxation of the rabbit urinary smooth muscle of dichlorodihydroabietic acid. It is a figure which shows an example of the result of the test for investigating the influence with respect to the contraction / relaxation of the rabbit urinary smooth muscle of the compound of this invention. It is a figure which shows an example of the result of the test for investigating the influence with respect to the contraction / relaxation of the rabbit urinary smooth muscle of the compound of this invention. It is a figure which shows an example of the result of the test for investigating the influence with respect to the contraction / relaxation of the rabbit urinary smooth muscle of the compound of this invention. It is a figure which shows an example of the result of the test for investigating the influence with respect to the contraction / relaxation of the rabbit urinary smooth muscle of the compound of this invention. It is a figure which shows an example of the result of the test for investigating the influence with respect to the contraction / relaxation of the rabbit urinary smooth muscle of the compound of this invention.

Claims (9)

Formula (I):

[Wherein R ¹ , R ² and R ³ independently represent a hydrogen atom, a halogen atom, hydroxy, cyano, nitro, carboxy, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C Selected from _1-10 alkoxy, —NR ¹¹ R ¹² , —S (O) _n C _1-10 alkyl (where n is an integer selected from 0 to 2) and C _1-10 alkylcarbonyl, wherein And the C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkoxy may be substituted on the carbon atom by one or more halogen atoms or hydroxy;
R ¹¹ and R ¹² are independently selected from a hydrogen atom, C _1-6 alkyl and C _1-10 alkylcarbonyl, or together with a nitrogen atom to form a 5- to 6-membered heterocycle Well;
R ⁴ is selected from —COOR ¹³ , —CONR ¹⁴ R ¹⁵ and tetrazol-5-yl;
R ¹³ represents a hydrogen atom, C _1-6 alkyl (wherein the alkyl is a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _7-14 aralkyloxy and C ₁ Optionally substituted by one or more substituents selected from _-6 alkoxycarbonyl) and C _7-14 aralkyl (wherein the aralkyl is selected from halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy) And optionally substituted on the benzene ring by one or more substituents selected from
R ¹⁴ and R ¹⁵ are independently selected from a hydrogen atom, hydroxy and C _1-6 alkyl, or together with the nitrogen atom to which they are attached may form a 5-6 membered heterocycle;
R ⁵ and R ⁶ are independently selected from a hydrogen atom, hydroxy and C _1-10 alkyl;
X is selected from a hydrogen atom, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, wherein the C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl is carbon The atom may be substituted by one or more C _1-10 alkoxy, halogen atom, hydroxy, aryl or heterocyclyl, wherein the aryl and heterocyclyl are halogen atom, C _1-6 alkyl, C _1-6 alkoxy, cyano , Nitro, carboxy, hydroxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, —NR ¹¹ R ¹² , —S (O) _n C _1-10 alkyl (where n is an integer selected from 0 to 2) And optionally substituted by one or more substituents selected from C _1-10 alkylcarbonyl;
Further, the substitutable carbon atom contained in the cyclohexane ring in the formula may be independently substituted with a substituent selected from hydroxy and C _1-6 alkyl, and the substitutable carbon atom contained in the azepine ring in the formula Carbon atoms may be independently substituted with substituents selected from hydroxy and C _1-6 alkyl]
Or a pharmaceutically acceptable salt or solvate thereof. Formula (II):

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in claim 1;
Y represents the formula (III):
^{-X 1 -Q-X 2 - (} III)
Wherein Q is a direct bond, arylene or heteroarylene,
X ¹ and X ² are independently selected from C _2-10 alkylene, C _2-10 alkenylene and C _2-10 alkynylene, wherein X ¹ and X ² are attached to Q via an oxygen or sulfur atom. The arylene and heteroarylene may be a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, cyano, nitro, carboxy, hydroxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, — Substituted by one or more substituents selected from NR ¹¹ R ¹² , —S (O) _n C _1-10 alkyl (where n is an integer selected from 0 to 2) and C _1-10 alkylcarbonyl. May be)
A divalent linking group represented by:
R ¹¹ and R ¹² are as defined in claim 1;
The substitutable carbon atom contained in the cyclohexane ring in the formula may be independently substituted with a substituent selected from hydroxy and C _1-6 alkyl, and the substitutable carbon contained in the azepine ring in the formula Atoms may be independently substituted with substituents selected from hydroxy and C _1-6 alkyl]
Or a pharmaceutically acceptable salt or solvate thereof. a) Formula (XI):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in claim 1, or each substituent capable of protection may be protected by a protecting group. Good]
Is oxidized to formula (XII):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in formula (XI)]
Obtaining
b) A compound of formula (XII) is represented by formula (XIII):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in formula (XI), R ¹⁰ is a hydrogen atom, or —SO ₂ —R ¹⁶ (where And R ¹⁶ is C _1-6 alkyl, C _1-6 haloalkyl, phenyl or 4-tolyl)]
Converting to:
c) A compound of formula (XIII) is represented by formula (XIV):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in formula (XI)]
And d) converting the compound of formula (XIV) to formula (XV) or (XVI):
L-X (XV)
L-Y-L (XVI)
[Wherein, X is as defined in claim 1, Y is as defined in claim 2, and L is a leaving group (including a halogen atom, a mesyl group, a tosyl group, a trifluoromethanesulfonyl group)] Each substituent selected independently from or capable of protection may be protected by a protecting group]
The method for producing a compound according to claim 1 or 2, comprising a step of reacting with the compound and deprotecting when a protecting group is present to obtain the compound according to claim 1. R ¹ and R ³ are independently selected from hydrogen and halogen atoms;
The compound according to claim 1 or 2 , wherein R ⁴ is -COOR ¹³ , or a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to claim 1, wherein R ² is a C _1-10 alkyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof. A pharmaceutical composition comprising the compound according to any one of claims 1, 2, 4 and 5 , or a pharmaceutically acceptable salt thereof, or a solvate thereof. The pharmaceutical composition according to claim 6 , 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. . A potassium channel opener comprising the compound according to any one of claims 1, 2, 4, and 5 , or a pharmaceutically acceptable salt thereof, or a solvate thereof. The potassium channel opener according to claim 8 , which acts on a BK channel.

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