WO1998015269A1 - Drugs containing rotenoids - Google Patents

Abstract

Drugs containing as the active ingredient rotenoids represented by general formula (1) wherein R?2 and R3¿ represent each hydroxy, C¿1-3? alkoxy, etc.; R?8 and R10¿ represent each hydrogen, C¿1-6? alkyl or C2-6 alkenyl; R?9¿ represents hydroxy, C¿1-3? alkoxy, etc.; R?11 and R12a¿ represent each hydrogen, hydroxy or C¿1-3? alkoxy; X represents -C(=O)-, etc.; and Y represents -CH(R)- (wherein R represents hydrogen, hydroxy or C1-3 alkoxy), etc. These drugs exert antibacterial effects specifically on microorganisms belonging to the genus Helicobacter, such as H. pylori, and are usable in the treatment of gastric ulcer, gastric cancer, etc.

Description

 Specification

Pharmaceuticals containing oral tendon

Technical field

 The present invention relates to the invention of a medicament containing an oral tenod as an active ingredient. The oral tenod, which is an active ingredient of the medicament of the present invention, has a specific antibacterial activity against microorganisms belonging to the genus Helicobacter, such as Helicobacter pylori, and is useful for treating gastric ulcers and gastric cancer. Useful for such things. Background art

 Helicobacter pylori is a gram-negative microaerobic bacterium isolated from human gastric mucosa in recent years, and has been suggested to be associated with ulcer formation and recurrence in the gastrointestinal tract and also with gastric cancer .

Previously, the treatment of peptic ulcer, have been drug is used having an effect such as H ₂ blockers and professional ton pump inhibitor coater, Rikopakuta pillow Li infection has been implicated in its development to the above Since this was suggested, antibacterial agents represented by amoxicillin have been used in combination. There are few cases where Helicobacter pylori can be completely eliminated by using any of the antibacterial agents, and diarrhea etc., because the antibacterial agents show antibacterial activity against intestinal bacteria. There is a problem that side effects occur frequently. Therefore, development of a better anti-Helicobacter pylori agent is desired.

 Rotenone, on the other hand, is an active ingredient in legume roots of legumes and has been used around the world as an excellent natural insecticide with low toxicity to humans and animals and little phytotoxicity to plants. In addition, related compounds of rotenone are collectively called rotenoids, and the structure-activity relationship of their insecticidal activity has been studied in detail (J. Environmental Pathology and

Toxicology, III, 315-337 (1978)).

However, the fact that these compounds have anti-Helicobacter pylori action No report has been made so far as far as the present inventors know. Disclosure of the invention

 The present inventors have focused on the fact that natural organic compounds have various physiological activities, and as a result of repeatedly examining various kinds of natural organic compounds, as a result, it has been found that the mouth tenode is a microorganism belonging to the genus Helicobacter, in particular, a helicobacter. They found that they had specific antibacterial activity against H. pylori, and completed the present invention.

 That is, according to the present invention, the following formula (1):

Wherein R ² and R ³ are each independently a hydroxyl group or C i -C

Or R ² and R ³ together

(Where n represents an integer from 1 to 3)

May be formed.

R ⁸ and R ^{1 G} are each independently a hydrogen atom, an alkyl group of Ci Ce, or C ₂ -C represents a ₆ alkenyl group (the alkyl group or alkenyl group, hydroxyl group, C R ⁹ may be substituted with one or more substituents selected from the group consisting of a halogen atom, an alkoxy group of Ci Cs, and an acyloxy group of ci to c ₄ ), and R ⁹ is a hydroxyl group or Ci Cg Or R ⁹ is taken together with R ⁸ or R ¹⁰

[Wherein R ⁵ ′ represents an alkyl group of C i Ce or an alkenyl group of C _{2 to} C ₆ (the alkyl group or alkenyl group is a hydroxyl group, a halogen atom, an alkoxy group of C Cg, and C i to C ₄ may be substituted with one or two or more substituents selected from the group consisting of the acyloxy group ₄ ), but the dotted line indicates that a double bond may be present].

R ¹¹ and R ^12a each independently represent a hydrogen atom, a hydroxyl group, or an alkoxy group of Ci Cg.

X represents a group C (= 0) or a group —CH (OR ′) 1 (where R ′ represents a hydrogen atom or an acyl group of CiCs), and Y represents a group —CH (R) 1 (Wherein, R represents a hydrogen atom, a hydroxyl group, or a C i -C ₃ alkoxy group) or a group c (= o). ]

Or a hydrate or solvate thereof as an active ingredient.

The medicament of the present invention includes, for example, microorganisms belonging to the genus Helicobacter, preferably Treatment and / or prevention of infectious diseases caused by H. pylori, and microorganisms belonging to the genus Helicobacter, preferably diseases associated with infection or proliferation of H. pylori (for example, gastrointestinal ulcers such as gastric ulcer and duodenal ulcer, gastric cancer, etc. For gastrointestinal cancer or gastritis).

According to a preferred embodiment of the present invention, the above-mentioned medicament wherein R ² and R ³ in the formula (1) are each a methoxy group; and R ⁸ and R ⁹ in the formula (1) together.

(Where the dotted line indicates that a double bond may be present); R ⁸ and R ⁹ in the above formula (1) together form a group

[Where R ⁵ ′ represents an alkyl group of Ci Ce or an alkenyl group of C _{2 to} C ₆ (the alkyl group or alkenyl group is a hydroxyl group, a halogen atom, an alkoxy group of Ci Cg, and an acyloxy group of Ci C R ⁵ ′ may be substituted with one or more substituents selected from the group consisting of groups, and the dotted line indicates that a double bond may be present. Or a drug as described above, which is a C _{2 to} C ₆ alkenyl group substituted with an alkoxy group of Ci Cg; R ¹¹ and R ^12a are hydrogen atoms, X is a group of CH (OH) or C (= 0) 1 and Y is a group of CH ₂ —; ) Wherein R ¹ ° is a hydrogen atom.

According to a further preferred aspect of the present invention, there is provided a medicine comprising a compound of any one of the following formulas (2) to (25).

Ϊ / 86 Ο 69ΚΛν, 8ss

vD OdeJdA iV

00 One—. CNJ CO

01

LSS £ 0 / L6d £ / lDd

6dr / 13d

69 1/86 OAV

The compound represented by the above formula (13) is a novel compound. Accordingly, another aspect of the present invention provides a compound represented by the above formula (13), or a hydrate or solvate thereof.

 From yet another aspect, the present invention provides a method for preventing and / or treating a disease associated with infection or proliferation of a microorganism belonging to the genus Helicobacter, preferably Helicobacter pylori, which comprises administering an effective amount of the oral tenoid. A method comprising the step of administering to a mammal including a human; and the use of the above-mentioned oral tenod for the manufacture of the medicament. BEST MODE FOR CARRYING OUT THE INVENTION

The medicament of the present invention is useful for treating and / or preventing an infection caused by a microorganism belonging to the genus Helicobacter, preferably Helicobacter pylori, and a Helicobacter. The present invention can be used as an anti-helicobacter for preventing or treating diseases associated with infection or proliferation of a microorganism belonging to the genus, preferably Helicobacter pylori, for example, gastric ulcer or gastric cancer. As used herein, the term "anti-helicopter agent" refers to a microorganism belonging to the genus Helicobacter, such as Helicobacter pylori, that inhibits the growth of or against the microorganism in humans, including humans. It is used in a concept that includes all agents capable of exerting a bactericidal action, and needs to be interpreted in the broadest sense based on the common general technical knowledge of those skilled in the art.

 The medicament of the present invention comprises, as an active ingredient, one or two or more substances selected from the group consisting of a mouth tendon represented by the above formula (1) and hydrates and solvates thereof. Features.

In the formula (1), the ^{R 2 R 3 R 5 'R} 8 R 9 R 10 R 1 \ R 1 2 R 12a X, and atoms and functional groups in the definition of Y, that describes a specific example below .

Examples of the alkoxy group ci C _3, for example, main butoxy group, an ethoxy group, n- propoxy group, and isopropoxy group, main butoxy group is preferred among these. Examples of the alkyl group of Ci Ce include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an n-pentynole group, an isopentyl group, an n-xyl group, and an isohexyl group. No.

Examples of the C ₂ C ₆ alkenyl group include a vinyl group, a 1-propenyl group, an aryl group, an isopropyl group, a 1-butenyl group, a 2-butenyl group, a 1-pentenyl group and a 2-pentenyl group. , 13-pentagenenyl group and 2-isopentyl group.

 The halogen atom may be any one of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and among them, a chlorine atom is preferred.

Examples of the acetyl group of C! Cs include an acetyl group, a formyl group, a propionyl group, a butyryl group, an isoptyryl group, a valeryl group, an isovaleryl group, and a bivaloyl group. The Ashiruokishi group C! ~C _4, Horumiruokishi group, Asetokishi group, flop opening Pioniruokishi group, Puchiriruokishi group, and the like.

The substituent on the C ₁ -C ₆ alkyl group and the C ₂ -C ₆ alkenyl group is, for example, selected from the group consisting of a hydroxyl group, a halogen atom, a C i Cg alkoxy group, and a C i C alkoxy group. And one or more substituents. As the halogen atom, the alkoxy group of Ci Cg, and the acyloxy group of Ci to C _{4 which} are present as the substituent, those specifically described above can be used. When two or more substituents on the alkenyl group of the alkyl group and C ₂ ~ C ₆ of ~ C ₆ to exist, they may be the same or different.

Specific examples of these C is substituted with a substituent, Arukeniru group of the alkyl group and C ₂ ~ C ₆ of ~ C _6, for example, i-chloro - i Mechiruechiru group, 1 over human Doroki Shimechirueteniru group, 1-arsenide Dorokishechiru Group, 1-bromoethyl group, 1-hydroxymethyl 2-chloroethyl group, 1,2-dihydroxyethyl group, 1-hydroxymethyl-2-hydroxyethyl group, 1,2-dichloroethyl group, etc. . However, the atoms and functional groups in the definitions of R ² , R ³ , R ⁵ ′, R ⁸ , RR ¹⁰ , R ″, R ¹² , R ^12a , X, and Y are exemplified in the above specific description. The present invention is not limited to this, and it goes without saying that it can be arbitrarily selected according to the technical common sense of those skilled in the art.

In the above formula (1), it is most preferred that both R ² and R ³ are methoxy groups, and R ⁸ and R ⁹ are a group formed by joining these groups together.

(Where the dotted line indicates that a double bond may be present), or

Wherein R ⁵ ′ represents a C ₁ -C ₆ alkyl group or a C ₂ -C ₆ alkenyl group (the alkyl group or alkenyl group is a hydroxyl group, a halogen atom, an alkoxy group of Ci Cg, it to C ₄ of which may be substituted with 1 or more substituents selected from the group consisting of Ashiruokishi group), most preferably an alkenyl group substituted with an alkoxy group for a hydroxyl group or a Ci Cg among these . A dotted line indicates that a double bond may be present]. Further, preferably a hydrogen atom as R ^{1 1} and R ^12a, X one CH (OH) one or group group - C (= 0) one is preferably, Y Groups In one CH ₂ - is preferred.

Specific examples of particularly preferred compounds include the compounds of the above formulas (2) to (25). Of these, compounds of the formula (17) or (18), wherein R ⁵ ′ is an isopropenyl group substituted with a hydroxyl group, and the above-mentioned groups formed by R ⁸ and R ⁹ The compounds of the formulas (20) to (23) which are formed are particularly preferred. However, the active ingredient of the medicament of the present invention is not limited to the preferred compounds, compounds or particularly preferred compounds specifically described above.

The compound represented by the above formula (1) has a plurality of asymmetric carbons (carbon atoms at 6a position, 12a position, 12 position, 5 'position and the like), and has many isomers. Exists. For example, rotenone having a configuration represented by the above formula (2) and its epimer, epirotenone (Eur. J. Biochem., 225, # 1, 411 (1994)), and the above formula (20) Deguelin having the indicated configuration and its epimer, trans-deguelin, and the like are known (J. Chem. So Perkin Trans. I, 2605 (1993)). The active ingredient of the medicament of the present invention includes pure optical isomers, diastereoisomers, Alternatively, in addition to geometric isomers, an arbitrary mixture or racemate of these isomers may be used.

 As the active ingredient of the medicament of the present invention, any hydrate or solvate can be used in addition to the free form compound represented by the above formula (1). Solvents that can form solvates include methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride and the like.

 Among the mouth tents represented by the above formula (1) used in the present invention, rotenone represented by the above formula (2) is commercially available from A1drich and the like. The rotenone of the formula (2), the deguelin of the formula (20), the toxicalol of the formula (21), and the tefucine of the formula (22) are natural products (Fortschr. Chem. Org. Naturst., 43). 98-120 (1983)), and can be extracted and purified from plants containing them (such as deris roots) in accordance with conventional methods.

 The other rotenoide represented by the above formula (1) can be chemically totally synthesized, but usually, the rotenone of the above formula (2), the deguelin of the above formula (20), or an analog thereof ( From other natural rotenoides), for example, Indian J. Chem., Sect. B, 28B (10), p868 (1989); Bull. Chem. So Japan, 31, p268, p271,

p397 (1958);. Chem Ber , 10, p2044 (1958);.... Bull Agr Chem So Japan, 22, pl28, P 335, p337 (1958);... Appl Environ Microbiol, 45 (2), p616 (1983); Appl. Environ. Microbiol., 49 (2), p451 (1985); J. Chem. So,

Agr. Biol. Chem., 37, p387 (1973); Agr. Biol. Chem., 37, pl937 (1973), J. Chem. So Perkin Trans. 1, 2605 (1993); Appl. Environ. Microbiol., 49 (2), p451 (1985); the method described in J. Org. Chem., 44 (14), 2578 (1979), etc., or a chemical synthesis method or a microorganism similar thereto. It can be manufactured by a conversion method.

The method for synthesizing the compounds of the formulas (3) to (19) and (25) from the rotenone of the formula (2) is specifically shown in Production Examples 1 to 13 and 20 described below. A method for purifying the mouth tenoids of the formulas (20) to (22) from delis root, and the formula The methods for synthesizing the compounds of (23) and (24) from the deguelin of the formula (20) are specifically shown in Production Examples 14 to 19 below. Therefore, by referring to the methods described in the above-mentioned documents and the examples of the present specification, and by making appropriate modifications and alterations to these methods as necessary, those skilled in the art can obtain the formula (1) It is possible to easily obtain any compound included in the above. As far as the present inventors know, the compound of the formula (13) is a novel compound, and its production method is specifically shown in Production Example 7 of Examples.

 The medicament of the present invention can be prepared as a pharmaceutical composition according to the administration route together with a usual pharmaceutical carrier. For example, for oral administration, it can be administered as a preparation in the form of tablets, capsules, granules, powders, or liquids. In preparing a solid preparation for oral administration, conventional excipients, binders, lubricants, coloring agents, disintegrating agents and the like can be used.

 Excipients include, for example, lactose, starch, talc, magnesium stearate, crystalline cellulose, methinoresenorelose, carboxymethylcellulose, glycerin, sodium alginate, acacia, and the like. Anoreconore, polyvinylinoethenore, etinoresenorelose, gum arabic, shellac, sucrose and the like, and examples of lubricants include magnesium stearate and talc. In addition, colorants and disintegrants that are commonly used in the art can be used.

Tablets may be coated by known methods. Liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, or other forms of preparations, which are prepared by commonly used methods. When preparing an injection, use a pH adjuster, buffer, stabilizing agent, isotonic agent, local anesthetic, etc., and subcutaneously, intramuscularly or intravenously using a conventional method. Forms of the preparation can be manufactured. As a base for producing suppositories, for example, an oily base such as cocoa butter, polyethylene glycol, lanolin, fatty acid triglyceride, witebsol (registered trademark of Dynamite Nobel) can be used. . The medicament of the present invention containing the oral tenod represented by the above formula (1) may be blended with another medicament, for example, another anti-helicopter agent. Not required. For example, a preparation containing an antibacterial agent such as amoxicillin can be prepared.

 The medicament of the present invention exerts an excellent preventive effect and / or therapeutic effect on, for example, ulcers and cancers in the gastrointestinal tract. It is needless to say that the present invention is applicable to any disease involving infection or proliferation of a microorganism belonging to the genus Helicobacter, preferably Helicobacter 1-pylori. The dose is preferably increased or decreased as appropriate according to the condition of the patient such as symptoms, weight, age, etc., the type of disease, the purpose of prevention or treatment, and the like. In general, the amount of rotenoide of the above formula (1) is usually preferably in the range of about 10 to 3000 mg per day, and it is usually desirable to administer it in 1 to 4 times a day. Example

 Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. Production Example 1 Synthesis of compound of formula (3)

 1.3 g of rotenone was added to a mixture of 10 ml of chloroform and 10 ml of ethyl acetate, and 0.5 g of cupric bromide was added. This reaction solution was heated under reflux in a nitrogen atmosphere for 5 hours, cooled, and filtered through celite. The obtained filtrate was concentrated and separated by silica gel column chromatography (n-hexanemonoacetate) to obtain 30 mg of the compound of the formula (3). This was recrystallized from methanol to obtain 21 mg of a crystal. The physicochemical properties of the obtained compound were as follows.

: H-NMR (in _{CDC 1 3; ppm): 1.80} (3H, s, 8; -H),

3.02 (1H, dd, J = 8.2Hz, 15.7Hz, 4'-H), 3.34 (1H, dd, J = 9.7Hz, 15.7Hz, 4'-H), 3.84 (3H, s, 2 or 3- 0CH ₃ ), 3.93 (3H, s, 2 or 3— 0CH ₃ ), 3.95 (1H, d, J = 12.4Hz, 12a- H), 4.19 (1H, dd, J = 10.2Hz, 10.2Hz, 6-H), 4.55 (1H, dd, J = 4.1Hz, 10.0Hz, 6-H),

4.71 (1H, ddd, J = 4.1Hz, 10.5Hz, 12.4Hz, 6a-H), 4.96 (1H, d, J = l.2Hz, V-H),

5.11 (1H, d, J = 1.2Hz, 7 ^/ -H), 5.33 (1H, dd, J = 8.9Hz, 8.9Hz, 5'-H), 6, 44 (1H, s, 4-H),

6.58 (1H, d, J = 8.6Hz, 10-H), 7.63 (1H, s, 1-H), 7.85 (1H, d, J = 8.6Hz, 11-H)

Melting point: 159-163 ° C Production Example 2 Synthesis of compounds of formula (4) and formula (11)

 394 mg (1. Ommo 1) of rotenone was dissolved in 10 ml of dioxane, and Omg of 10% PdZC4 was added. After stirring the reaction solution under a hydrogen atmosphere at room temperature for 13 hours, the catalyst was removed by filtration and the solvent was distilled off. The resulting residue was separated by silica gel column chromatography (form-form methanol) to obtain 318 mg of the compound of the formula (4) and 66 mg of a mixture of the compounds of the formulas (4) and (11). Was. Expression

 The mixture of (4) and the compound of the formula (11) was further separated by preparative thin-layer chromatography (silica gel / developing solvent: chloroform) to obtain 56 mg of the compound of the formula (11). The compounds of formulas (4) and (11) were recrystallized from methanol to give 107 mg and 41 mg of crystals, respectively. The physicochemical properties of the obtained compound were as follows.

Compound of formula (4)

'H-NMR (in _{CDC 1 3; p pm):} 0.98 (3H, d, J = 6.7Hz, T or 8' - H), 1.03 (3H, d, J = 6.7Hz, T or 8 '- H ), 1.98 (1H, Septet, J = 6.7Hz, 6'-H),

2.86 (1H, dd, J = 8.5Hz, 15.8Hz, 4 '-H), 3.17 (1H, dd, J = 9.3Hz, 15.8Hz, 4-H),

3.77 (3H, s, 2 or 3— 0CH ₃ ), 3.82 (3H, s, 2 or 3— 0CH ₃ ), 3.85 (1H, d, J = 4.0 Hz, 12a—H), 4.19 (1H, d, J = 12. LHz, 6-H), 4.60 (2H, m, 6—H, 5'-H),

 4.93 (1H, dd, J = 3.1Hz, 4.0Hz, 6a-H), 6.46 (1H, s, 4-H), 6.47 (1H, d, J = 8.5Hz, 10-H), 6.78 (1H, s, 1—H), 7.83 (1H, d, J = 8.5Hz, 11-H)

Melting point: 16 1 to 1 64 ° C Compound of Formula (11)

iH-NMR (in CDC 13; ppm): 0.98 (3H, d, J = 6.7Hz, To or 8'-H), 1.04 (3H, d, J = 6.7Hz, 7, or 8'-H) , 1.97 (1H, Septet, J = 6.7Hz, 6, -H),

2.85 (1H, dd, J = 8.5Hz, 15.7HZ.4 '-H), 3.14 (1H, dd, J = 9.2Hz, 15.7Hz, 4' — H),

3.38 (1H, brt. J = 4.8Hz, 12a-H), 3.84 (3H, s, 2 or 3— 0CH ₃ ), 3.86 (3H, s, 2 or 3-0CH ₃ ), 4.23 (1H, dd, J = 9.7Hz, 5.1Hz, 6-H), 4.57 (1H, m, 5 '— H),

 4.64 (1H, d, J = 9.7Hz, 6-H), 4.82 (1H, m, 6a-H), 4.91 (1H, d, J = 3.6Hz, 12-H),

6.4K1H, d, J = 8.1Hz, 10-H), 6.46 (1H, s, 4-H), 6.70 (1H, s, 1—H),

 7.02 (1H, d, J = 8.1Hz, 11—H)

Melting point: 141-142 ° C Production Example 3 Synthesis of compounds of formulas (5), (6), (7) and (9)

 To 2.0 g of rotenone, 6 ml of acetic acid and 2 ml of concentrated hydrochloric acid were added, and the mixture was heated under reflux in a nitrogen atmosphere for 2 hours, cooled, poured into water, and the precipitate was collected by filtration and washed with water. The obtained precipitate was separated by silica gel column chromatography (ethyl n-hexane monoacetate) to obtain a crude fraction of 1 O mg of the compound of the formula (6), the compound of the formula (5) and the compound of the formula (9) 1.69 g of a mixture of the above and 550 mg of the compound of the formula (7) were obtained. Further, 1 Omg of the crude fraction of the compound of the formula (6) was separated by HPLC (ODS column: water-acetonitrile) to obtain 4.Omg of the compound of the formula (6). The mixture of the compound of the formula (5) and the compound of the formula (9) was again separated by silica gel column chromatography (ethyl n-hexane monoacetate) to give 200 mg of the compound of the formula (5) and 1 mg of the compound of the formula (5). .11 g of the compound of formula (9) was obtained. Each compound was crystallized from methanol to give 170 mg of the compound of formula (5), 2.3 mg of the compound of formula (6), 42 Omg of the compound of formula (7), and 94 mg of the compound of formula (7). Crystals of the compound of formula (9) were obtained. The physicochemical properties of the obtained compound were as follows.

Compound of formula (5)

iH—NMR (in CDC 13; P pm): 1.30 (3H, d, J = 6.9Hz, or 8'-

or 3- 0CH ₃ ), 3.85 (IH, d, J = 3.9Hz, 12a-H), 4.19 (IH, d, J = 12. OHz, 6-H),

 4.63 (IH, dd, J = 2.8Hz, 12.OHz, 6-H), 4.81 (1H, t like, J = 8.7Hz, 5'-H), 4.96 (IH, t like, J = 3.4Hz, 6a-H), 6.45 (1H, s, 4-H), 6.50 (1H, d, J = 8.6Hz, 10-H),

 6.76 (lH, s, 1-H), 7.84 (1H, d, J = 8.6Hz, 11-H)

Melting point: 186 to 188 ° C Preparation Example 4 Synthesis of compound of formula (8)

 2.0 g of rotenone and 1 g of activated manganese dioxide were stirred in Acetone 5 Om 1 under a nitrogen atmosphere for 60 hours, and then filtered through celite. The obtained filtrate was concentrated and separated by silica gel column chromatography (form-form-methanol) to obtain crude compound (16 mg) of the formula (8) and 1.27 g of a crude fraction of the compound of the formula (8). Obtained. 1.27 g of the crude fraction of the compound of the formula (8) was further separated by silica gel column chromatography (n-hexane monoethyl acetate) to obtain 488 mg of the compound of the formula (8). Both were combined and crystallized from methanol to obtain 640 mg of crystals. The physicochemical properties of the obtained compound were as follows.

^X H-NMR (in _{CDC 1 3; p pm):} 1.76 (3H, s, 8 '-H),

 2.94 (IH, dd, J = 8.1Hz, 15.8Hz, 4 '-H), 3.29 (1H, dd, J = 9.6Hz, 15.7Hz, -H),

3.73 (3H, s, 2 or 3-0CH ₃ ), 3.82 (3H, s, 2 or 3 0CH ₃ ),

 4.49 (1H, dd, J = 1.6Hz, 17.5Hz, 6-H), 4.59 (IH, brs, 6a-H),

 4.60 (IH, dd, J = 2.3Hz, 17.5Hz, 6-H), 4.94 (IH, s, 1'-H), 5.07 (IH, s, 1'-H), 5.24 (1H, t like, J = 8.9Hz, 5'-H), 6.49 (1H, s, 4-H), 6.52 (IH, d, J = 8.6Hz, 10-H), 6.55 (IH, s, 1-H), 7.82 (IH, d, J = 8.6Hz, 11-H)

Melting point: 80-81 ° C Production Example 5 Synthesis of compound of formula (10)

Rotenone 394mg dissolved in methanol 1 Om 1 and as tetrahydrofuran (THF) 1 Om l, was added and stirred under ice-cooling Na BH ₄ 76 mg 2 hours. Small amount The acetic acid was added and the solvent was removed by filtration.The residue was partitioned between chloroform and saturated aqueous sodium bicarbonate.The _c- form layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off to remove 390 mg. A compound of the formula (10) was obtained. This was crystallized from methanol to obtain 27 Omg of crystals. The physicochemical properties of the obtained compound were as follows.

^X H-NMR (in _{CDC 1 3; ppm): 1.76} (3H, s, 8 ' one H),

 2.93 (1H, dd, J = 8.1Ηζ, 15.7Hz, 4'-H), 3.27 (1H, dd, J = 9.6Hz, 15.7Hz, 4'-H),

3.31 (1H, brt, J = 4.9Hz, 12a-H), 3.77 (3H, s, 2 or 3- 0CH 3), 3.80 (3H, s 2 or 3- 0CH 3), 4.18 (1H, dd, J = 4.8Hz, 9.6Hz, 6-H), 4.59 (1H, t, J = 10.4Hz, 6-H),

 4.75 (lH, m, 6a-H), 4.87 (1H, d, J = 4.0Hz, 12-H), 4.89 (1H, s, T-H),

 5.07 (1H, s, 1'-H), 5.16 (1H, t, J = 8.8Hz, 5'-H), 6.40 (1H, s, 4—H),

 6.40 (1H, d, J = 8. LHz, 10-H), 6.69 (1H, s, 1_H), 7.00 (1H, d, J = 8.1Hz, ll-H) Melting point: 92-93 ° C Production Example 6 Synthesis of compound of formula (12)

 In the same manner as in Production Example 5, 495 mg of a crude compound of the formula (12) was obtained from 50 Omg of the compound of the formula (7). This was crystallized from water-methanol (2: 1) to obtain 302 mg of the compound of the formula (12). The physicochemical properties of the obtained compound were as follows.

'H-NMR (Ji 0_Rei 1 ₃ in; 111): 1.23 (3H, s, T or 8' - H), 1.36 (3H, s, 7 'or 8' - H), 1.71 (1H, s, OH), 1.90 (1H, s, OH),

3.07 (1H, dd, J = 8.9Hz, 16.7Hz, 4 ^r — H), 3.13 (1H, dd, J = 9.2Hz, 16.7Hz, 4'-H), 3.40 (1H, t like, J = 4.3 Hz, 12a—H), 3.86 (3H, s, 2 or 3— 0CH ₃ ), 3.87 (3H, s, 2 or 3— 0CH ₃ ), 4.24 (1H, dd, J = 5.0 Hz, 11.5 Hz, 6 -H), 4.62 (1H, t like, J = ll.5Hz, 6-H),

4.66 (lH, t like, J = 9.2Hz, 5 ^/ -H), 4.85 (1H, quintet like, J = 6.2Hz, 6a-H), 4.93 (1H, d, J = 3.7Hz, 12-H) , 6.45 (1H, d, J = 8.2Hz, 10-H), 6.48 (1H, s, 4-H),

6.71 (1H, s, 1-H), 7.05 (1H, d, J = 8.2Hz, ll-H) Melting point: 118-120 ° C Production Example 7 Synthesis of compound of formula (13)

In a similar manner to Production Example 5, 1.4 g of the compound of the formula (13) was obtained from 1.05 g of the compound of the formula (9). This was separated by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 1.13 _g of a compound of the formula (13). Crystallization from methanol gave 0.99 g of the compound of formula (13). The physicochemical properties of the obtained compound were as follows.

^X H-NMR (Ji 0_Rei 1 in _{3; 111): 1.62 (3H} , s, T or 8 '- H), 1.66 (3H, s, 7' or 8 '-H), 1.71 (1H, s, 0H), 3.20 (1H, dd, J = 8.2Hz, 16.7Hz, 'one H),

3.26 (1H, dd, J = 9.2Hz, 16.7Hz, 4'-H), 3.42 (1H, t like, J = 5.0Hz, 12a-H),

3.86 (3H, s, 2 or 3— 0CH ₃ ), 3.87 (3H, s, 2 or 3— 0CH ₃ ),

 4.24 (1H, dd, J = 5.1Hz, 9.9Hz, 6-H), 4.62 (1H, t like, J = 10.5Hz, 6-H), 4.81 (1H, t like, J = 8.6Hz, 5 ' -H), 4.85 (1H, m, 6a-H), 4.93 (1H, d, J = 3.7Hz, 12-H),

 6.46 (1H, d, J = 8.1Hz, 10-H), 6.48 (1H, s, 4-H), 6.70 (1H, s, 1-H),

 7.06 (1H, d, J = 8.1Hz, 11— H)

Melting point: 114-116 ° C Production Example 8 Synthesis of compound of formula (14)

 Compound 23 Omg of the formula (14) was obtained from 20 Omg of the compound of the formula (5) in the same manner as in Production Example 5. This was separated by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 20 Omg of the compound of the formula (14). Crystallization from methanol gave 12 Omg of the compound of formula (14). The physicochemical properties of the obtained compound were as follows.

'H-NMR (0 Ji 1 ₃ in; 111): 1.34 (6H, d, J = 6.9Hz, V and 8' -H), 1.95 (lH, s, 0H), 3.06 (1H, Sept, J = 6.9Hz, 6 '-H), 3.45 (1H, t like, J = 4.8Hz, 12a- H), 3.84 (3H, s, 2 or 3- 0CH ₃ ), 3.86 (3H, s, 2 or 3- 0CH ₃ ), 4.28 (1H, dd, J = 5.1Hz, 9.7Hz, 6—H), 4.66 (1H, dd, J-9.7Hz, 11.3Hz, 6—H),

4.92 (1H, quintet like, J = 5.7Hz, 6a-H), 5.03 (1H, d, J = 3.9Hz, 12-H), 6.47 (2H, s, 4 and A '-H), 6.73 (1H , s, 1-H), 7.05 (1H, d, J = 8.3Hz, 10-H),

 7.10 (1H, d, J = 8.3Hz, 11-H)

Melting point: 191-193 ° C Production Example 9 Synthesis of compound of formula (15)

1.3 g of rotenone and 1.0 g of cupric bromide were heated and refluxed for 5 hours in a mixed solution of form 1 Om 1 and 10 ml of ethyl acetate. The reaction solution was cooled, filtered through celite, and the filtrate was concentrated and separated with a 50 g column of silica gel H (manufactured by Merck). After washing with 25 mL of ethyl acetate n-hexane mixed solution (3: 7), the fraction eluted with 100 mL of ethyl acetate-n-hexane mixed solution (2: 3) was distilled off to remove 160 mg residue was obtained. This was separated on a reversed-phase HPLC column (Capcellpakc 18 ø30 x 250 mm; manufactured by Shiseido Co., Ltd.) using a linear concentration gradient (flow rate 9 ml / min) at 80% for 3 minutes to 70% tetrahydrofuran water. Then, the fraction eluted between 53 minutes and 57 minutes was distilled off to obtain 42.5 mg of a residue. This was again separated on the above HP LC column using a linear gradient (flow rate 9 ml / min) of 40% to 50% tetrahydrofuran water for 80 minutes, and the fraction eluted between 50 minutes and 54 minutes was distilled. The crystals were crystallized from methanol to give 12.6 mg of crystals. Connexion with the out 8. Omg, in N a BH ₄ and room temperature mixture of 2. Omg methanol lm 1 and as tetrahydrofuran lm l reacted for 1 hour. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and chloroform, and the mixture was partitioned. The chloroform layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was separated on the reverse phase HP LC column using a linear gradient of 30% to 50% aqueous tetrahydrofuran (80 minutes, flow rate 9 ml / min) and eluted between 35 and 37 minutes. The fraction was distilled off and crystallized from methanol to obtain 2.8 _mg of crystals of the compound of the formula (15). The physicochemical properties of the obtained compound were as follows. - NMR (in _{CDC 1 3; p pm):} 1.77 (3H, s, T or 8 '- H),

1.83 (3H, s, T or 8,-H), 3.24 (2H, m, '-H), 3.41 (1H, t like, J = 4.9Hz, 12a-H),

3.84 (3H, s, 2 or 3- 0CH 3), 3.85 (3H, s, 2 or 3- 0CH 3),

 4.23 (1H, dd, J = 4.9Hz, 9.8Hz, 6-H), 4.61 (1H, t like, J = 10.5Hz, 6-H), 4.75 (1H, t like, J = 8.6Hz, 5 ' — H), 4.83 (1H, m, 6a— H), 4.92 (1H, d, J = 3.8Hz, 12-H),

 6.43 (1H, d, J = 8.1Hz, 10-H), 6 · 46 (1H, s, 4-H), 6.70 (1H, s, 1—H),

 7.05 (1H, d, J = 8.1Hz, 11— H)

Melting point: Synthesis of 1 1 9 to 1 21 ⁰ C Production Example 1 0 compounds of formula (1 6)

Rotenone (2.0 g) and manganese dioxide (10 g) were stirred vigorously in acetone 5 Om1 at room temperature for 60 hours. The insolubles were filtered through celite, washed with acetone, and the filtrate was distilled off. The residue was separated with 5 Og of silica gel H (manufactured by Merck). After washing with 250 ml of black-mouthed form, the fraction eluted with 100 ml of 2% methanol-containing chloroform was distilled off to obtain 1.27 g of a residue. This was separated again with 50 g of silica gel H. Ethyl acetate-n-hexane mixed solution (1: 1) After washing with 25 Oml, the fraction eluted with 250 ml of ethyl acetate and 250 ml of chloroform were distilled off to obtain 484 mg of a residue. . For these 429 mg, it was reacted at room temperature for 1 hour the N a BH ₄ 100 mg dissolved in Metanonore 1 0 m 1 and as tetrahydrofuran 10 m 1. A saturated aqueous sodium hydrogen carbonate solution and chloroform-form were added to the reaction mixture, and the mixture was partitioned. The foam-form layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was separated on the reversed-phase HP LC column used in Production Example 9 using a linear gradient of 30% to 50% aqueous tetrahydrofuran for 80 minutes (flow rate: 9 m1Z). The fraction eluted between 65 minutes and 70 minutes was distilled off to obtain 22.7 mg of a residue.

This was then separated on a reversed-phase HP LC column (YMC polymer C18030X300 mm) using a linear gradient (flow rate 9 m1 / min) of 35% to 55% tetrahydrofuran water for 80 minutes. . The fraction eluted between 76 and 79 minutes The residue was crystallized from methanol to obtain 9. O mg of a compound of the formula (16). The physicochemical properties of the obtained compound were as follows.

^ -NMR (in CD C 13; p p m): 1.78 (3H, s, T T),

 2.97 (1H, dd, J = 8.0Hz, 15.8Hz, 4'-H), 3.29 (1H, dd, J = 9.7Hz, 15.8Hz, 4'-H),

3.40 (1H, t like, J = 4.5Hz, 12a-H), 3.85 (3H, s, 2 or 3 - 0CH 3), 3.87 (3H, s, 2 or 3-0CH 3), 4.23 (1H, dd , J = 5.2Hz, 9.8Hz, 6-H), 4.61 (1H, dd, J = 9.8Hz, 11.3Hz, 6-H),

4.84 (1H, m, 6a-H), 4.92 (2H, m, 12-H, 7'-H), 5.09 (1H, brs, 7'-H), 5.25 (1H, t like, J = 8.7Hz , 5'-1H), 6.46 (1H, d, J = 8.1Hz, 10-H), 6.48 (1H, s, 4-H),

 6.71 (1H, s, 1-H), 7.06 (1H, d, J = 8.1 Hz, 11-H)

Melting point: 107-: 108 ° C Production Example 11 Synthesis of compound of formula (17)

 Ammonolefin l lOmg (manufactured by Latoxan) was dissolved in 25 ml of water, and the mixture was mixed with 55 mg of rambarite IR-120 (H + type) and heated under reflux for 6 hours. The reaction solution was cooled and extracted with methylene chloride. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. Crystallization from methanol gave 53. O mg of the compound of formula (17). The physicochemical properties of the obtained compound were as follows.

i H- NMR (in _{CD C 1 3; ppm):} 1.87 (lH, s, 8 '-OH),

 3.06 (1H, dd, J = 8.5Hz, 15.8Hz, 4'-H), 3.37 (1H, dd, J = 9.8Hz, 15.8Hz, 4'-H),

3.75 (3H, s, 2- OCH3 or 3- 0CH 3), 3.79 (3H, s, 2-0CH 3 or 3- 0CH 3),

 3.83 (lH, d, J = 4.2Hz, 12a-H), 4.14-4.25 (3H, m, 6-H and 8'-H),

 4.60 (1H, dd, J = 2.9Hz, 12.1Hz, 6-H), 4.92 (1H, t like, J = 3.0Hz, 6a-H),

 5.24 (1H, s, T — H), 5.27 (lH, s, 7 '— H), 5.38 (lH, t like, J = 9.0Hz, 5'-H),

6.44 (1H, s, 4-H), 6.50 (1H, d, J = 8.5Hz, 10-H), 6.75 (1H, s, 1-H),

 7.83 (1H, d, J = 8.5Hz, 11-H)

Melting point: 19 1 ~ 192 ° C Preparation Example 1 2 Synthesis of Compound of Formula (18)

Crude compound of formula from the compound 20 m _g of formula (1 7) in the same manner as in Production Example 5 (1 8) 20. was obtained 5 mg. This was separated on the reverse phase HP LC column used in Production Example 9 with a linear concentration gradient of 30% to 45% tetrahydrofuran water for 80 minutes (flow rate of 9 m1Z), and then separated from 34 minutes to 37 minutes. The fraction eluted in between was distilled off and crystallized from methanol to give 19.6 mg of compound (18). The physicochemical properties of the obtained compound were as follows.

^ -NMR (in _{CDC 1 3; p pm):} 1.74 (2H, s, 8 '-OH and 12-0H), 3.07 (1H, dd, J = 8.5Hz, 15.7Hz, 4' - H), 3.37 (1H, dd, J = 9.6Hz, 15.7Hz, \ 'one H),

3.41 (1H, m, 12a- H), 3.85 (3H, s, 2 - 0CH 3 or 3- 0CH 3), 3.87 (3H, s, 2 - 0CH 3 or 3- 0CH 3), 4.21-4.30 (3H , m, 6-H and 8 '-H), 4.62 (1H, dd, J = 9.8Hz, 11.1Hz, 6-H),

4.83 (lH, m 6a-H), 4.94 (1H, d, J = 3.7Hz, 12-H), 5.27 (1H, s, T — H),

 5.28 (1H, s, 1'-H), 5.37 (1H, t like, J = 9.0Hz, 5'-H), 6.47 (1H, d, J = 8.lHz, 10-H), 6.48 (1H , s, 4-H), 6.71 (1H, s, 1-H), 7.07 (1H, d, J-8.1Hz, 11-H)

Melting point: 147-149 ° C Preparation Example 13 Synthesis of compound of formula (19)

 420 mg of the compound of the formula (10), 124 μl of acetic anhydride, 176 μl of triethylamine and 10 ml of a dichloromethane solution containing 5 mg of dimethylaminopyridine were allowed to stand at room temperature for 15 hours. The solution was washed successively with water, saturated aqueous sodium bicarbonate and saturated saline, then dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 460 mg of a residue. This was crystallized from methanol to obtain 206 mg of crystals. The physical and chemical properties of the obtained compound were as follows.

'H-NMR (in _{CDC 1 3; p pm):} 1.75 (3H, s, 12 - 0C0CH 3 or 8' - H), 1.79 (3H, s, I2-OCOCH3 or 8 '- H), 2.96 (1H , dd, J = 8.1Hz, 15.7Hz, 4'-H), 3.31 (1H, dd, J = 9.3Hz, 15.7Hz, 4'-H), 3.54 (1H, brt, J = 5.3Hz, 12a- H), 3.84 (6H, s, 2 and 3- 0CH 3), 4.27 (1H, dd, J = 4.4Hz, 9.6Hz, 6H),

4.48 (1H, t, J = 10.6Hz, 6-H), 4.87 (1H, m, 6a-H), 4.92 (1H, s, 7'-H),

 5.09 (1H, s, 7'-H), 5.22 (1H, t, J = 8.8Hz, 5'-H), 6.30 (1H, d, J = 4.4Hz, 12-H), 6.41 (1H, s , 4-H), 6.44 (1H, d, J = 8.3Hz, 10-H), 6.66 (1H, s, 1-H),

 7.10 (1H, d, J = 8.3Hz, 11— H)

Melting point: 87-89 ° C Production Example 14 Purification of compounds of formulas (20)-(22) from delis root

 25.23 g of finely ground deris root was infiltrated with 126 ml of methanol, allowed to stand at room temperature for 1 week, and the supernatant was decanted. To the residue was added 126 ml of methanol again,

The supernatant was collected after one week. This was repeated once again, and the supernatant for three times was collected and distilled off under reduced pressure to obtain 2.21 g of a methanol extract. This methanol extract is

The mixture was partitioned between 500 ml and 500 ml of ethyl acetate, and the ethyl acetate layer was distilled off to obtain 0.86 g of an ethyl acetate extract. This was applied to a 50 g column of MC I gel ODS 1 MY (manufactured by Mitsubishi Chemical Corporation), washed with 40% acetonitrile water 25 Om 1 and then fractionated with 60% acetonitrile water 25 Om 1 Fraction 1, fractions eluted with 250 ml of 80% aqueous acetonitrile were collected as fraction 2, and the solvents were separately distilled off to obtain 390 mg and 210 mg residues, respectively.

 Next, fraction 1 is divided into two halves, and the mixture is separated into 35% acetonitrile water and 65% acetonitrile using an HP LC column I for separation of ODS (C apeel 1 pak C 18 030 X 250 mm (manufactured by Shiseido)). 80 min linear gradient to water, flow rate

Separated at 9 ml / min. Retention time Fraction between 64 and 67 minutes 3, 67 to 7

Fraction 4 was collected during 7 minutes, and fraction 5 was collected between 81 and 89 minutes.

 Fraction 2 was extracted from 50% aqueous acetonitrile

Separation was performed at a flow rate of 9 m 1 / min on a linear concentration gradient of 80% to acetonitrile water for 80 minutes. Fraction 6 was collected during a retention time of 34 minutes to 36 minutes, and fraction 7 was collected between 44 minutes to 56 minutes. Preparation Example 15 Purification of the compound of formula (20) (deguelin)

 Fraction 5 was distilled off under reduced pressure to obtain 49 mg of a residue. This was passed through a preparative HP LC column II (YMC polymer C18, 030 x 300 mm (YMC)) with a linear gradient from 60% acetonitrile to 80% acetonitrile in 80 minutes. Separated in 9 m 1 Z minutes.

 The retention time was 50 minutes to 53 minutes, and the solvent was distilled off, followed by crystallization from methanol to obtain 29.8 mg of the compound of the formula (20) (deguelin). In addition, 39 mg of the residue obtained by evaporating Fraction 7 was also collected on a preparative HP LC column II at a flow rate of 9 m 1 Z with a linear concentration gradient from 50% acetonitrile water to 90% acetonitrile water for 80 minutes. Minutes. Fractions were collected between a retention time of 37 minutes and 41 minutes, and the solvent was distilled off, followed by crystallization from methanol to obtain 75.8 mg of the compound of the formula (20) (deguelin). The physicochemical properties of the obtained compound were as follows.

'H-NMR (in _{CDC 1 3; ppm): 1.39} (3H, s, 7' or8, - H), 1.46 (3H, s, T or8 '-H), 3.78 (3H, s, 2 or 3- _{0CH 3), 3.82 (3H,} s, 2 or 3-OCH 3), 3.85 (1H, d, J = 4. lHz, 12a- H), 4.20 (1H, d, J = 12.0Hz, 6

H), 4.65 (1H, dd, J = 3.lHz, 12.0Hz, 6-H), 4.93 (1H, t like, J = 3.5Hz, 6a-H), 5.57 (1H, d, J = 10.0Hz) , 5'-H), 6.46 (1H, d, J = 8.6Hz, 10-H), 6.46 (3H, s, 4-H), 6.66 (1H, d, J = 10.0Hz, 4'-H) , 6.80 (1H, s, 1-H), 7.75 (1H, d, J = 8.6Hz, 11-H) Melting point: 170 ° C Production Example 16 Purification of compound (Toxicarol) of formula (21)

 In the separation of the fraction 7 using the preparative HP LC column II, a fraction having a retention time of 67 to 69 minutes was fractionated, and after evaporating the solvent, crystallizing from methanol to obtain 1.2 mg of the compound of the formula (21) ( Toxicalol) was obtained. The physicochemical properties of the obtained compound were as follows.

'H-NMR (in CDC 13; ppm): L 39 (3H, s, 7'-H or 8 '- H), 1.46 (3H, s , 7'-H or 8 '- H), 3 · 82 (3H, s, 2- 0CH 3 or 3- 0CH 3), 3.81 (3H, s, 2- 0CH 3 or 3-0CH ₃ ), 3.87 (1H, d, J = 4.2Hz, 12a-H), 4.19 (1H, d, J = 12.3Hz, 6-

H), 4.64 (1H, dd, J = 3.2Hz, 12.3Hz, 6-H), 4.89 (1H, t like, J = 4.lHz, 6a-

H), 5.49 (1H, d, J = 10.2Hz, 5'-H), 5.98 (1H, s, 10-H), 6.48 (1H, s, 4-

H), 6.58 (1H, d, J = 10.2Hz, 4'-H), 6.89 (1H, s, 1-H), 12.22 (1H, s, 1 l-OH)

Melting point: 125-127 ° C Preparation Example 17 Purification of the compound of formula (22) (Tefguchi Shin)

Fraction 3 was distilled off and crystallized from methanol to obtain 34.2 _mg of the compound of the formula (22) (Tefguchi Shin). In addition, 12.5 mg of the residue obtained by evaporating fraction 4 was subjected to a linear concentration gradient over 80 minutes from 35% aqueous acetonitrile to 65% aqueous acetonitrile using the preparative HPLC column II. Separation was performed at a flow rate of 9 ml / min. A retention time between 84 minutes and 88 minutes was collected, and the solvent was distilled off, followed by crystallization from methanol to obtain 82.8 mg of the compound of the formula (22) (Tefguchi Shin). Fraction 6 was distilled off, and the residue was crystallized from methanol to obtain 1.1 mg of the compound of the formula (22) (Tefguchi Shin). The physicochemical properties of the obtained compound were as follows.

^ -NMR (in Rei_0_rei _{1 3; 111): 1.39 (} 3H, s, 7 'or 8' -H), 1.45 (3Η, s, 7 'or 8'- H), 3.73 (3H, s, 2- 0CH ₃ ), 3.82 (3H, s, 3-0CH ₃ ), 4.47 (1H, s, J = 13.6Hz, 6-H), 4.57 (1H, d, J = l.9Hz, 6a-H) , 4.63 (1H, dd, Jl.9Hz, 13.6Hz, 6

H), 5.56 (1H, d, J = 10.2Hz, 5'-H), 6.47 (1H, d, J = 8.8Hz, 10-H), 6.48 (1H, s, 4-

H), 6.56 (1H, s, 1-H), 6.60 (1H, d, J = 10.2Hz, 4'-H), 7.72 (1H, d, J = 8.8Hz, 11-H) Melting point: 19 6—198 ° C Production Example 18 Synthesis of compound of formula (23)

The compound is dissolved 3 Omg of formula (20) in methanol 800 mu 1 and as tetrahydrofuran (THF) 800 mu 1, under ice-cooling N a ΒΗ ₄ 8 mg was added for 1 hour攪拌. A saturated aqueous solution of sodium bicarbonate and black-mouthed form are added, and the mixture is partitioned. , And dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The resulting residue was separated on the preparative HP LC column I using a linear gradient from 40% acetonitrile to 80% acetonitrile for 80 minutes at a flow rate of 9 mlZ. The mixture was fractionated between 56 minutes and 60 minutes, the solvent was distilled off, and the residue was crystallized from methanol to obtain 16.1 mg of the compound of the formula (23). The physicochemical properties of the obtained compound were as follows.

iH- NMR (in _{CDC 1 3; ppm): 1.42} (3H, s, 7 'or 8'- H), 1.43 (3H, s, 7' or 8'-H), 1.72 (1H, brs, 12- OH), 3.38 (1H, t like, J = 5. OHz, 12a- H), 3 ・ 84 (3H, s, 2 or

3-OCH 3), 3.86 (3H, s, 2 or 3-OCH 3), 4.23 (1H, dd, J = 5.2Hz, 9.8Hz, 6-

H), 4.59 (1H, dd, J = 9.9Hz, 10.9Hz, 6-H), 4.84 (1H, dd, J = 5.4Hz, 11.3Hz, 6a-

H), 4.89 (1H, d, J = 3.8Hz, 12-H), 5.58 (1H, d, J = 10. OHz, 5,-

 H), 6.43 (1H, d, J = 8.3Hz, 10H), 6.47 (1H, s, 4-H), 6.66 (1H, d, J = 10. OHz, 4 '-

H), 6.71 (1H, s, 1-H), 7.01 (1H, d, J = 8.3Hz, 11—H)

Melting point: 179-180 ° C Preparation Example 19 Synthesis of compound of formula (24)

 After stirring 30 mg of the compound of the formula (20) together with 10 mg of 10% palladium / carbon in 10 ml of dioxane under a hydrogen stream for 3.5 hours, the catalyst was removed by filtration through celite. The obtained solution was distilled off and crystallized with methanol to obtain 2 lmg of 4 ', 5'-dihydroxydeguelin. Subsequently, 5.1 mg of the compound of the formula (24) was obtained in the same manner as in the synthesis example of the compound of the above formula (23) using 14 mg of the 4, 4, 5, and dihydroxydegueline obtained here. I got The physicochemical properties of the obtained compound were as follows.

'H-NMR (in _{CDC 1 3; ppm): 1.32} (3H, s, 7' or 8 '-H), 1.34 (3H, s, 7' or 8 ' one H), 1.66 (1H, d , J = l.9Hz, 12-0H), 1.79 (2H, t, J = 6.8Hz, 5'-1

H), 2.66 (2H, t, J = 6.8Hz, 4'-1H), 3.39 (1H, t like, J = 4.9Hz, 12a-H), 3.86 (3H, s, 2 or 3-0CH ₃ ) , 3.87 (3H, s, 2 or 3-0CH ₃ ), 4.24 (1H, dd, J = 5.2Hz, 9.7Hz, 6- H), 4.61 (1H, dd, J = 9.7Hz, 11.4Hz, 6-H), 4.86 (1H, dd, J = 5.2Hz, 11.5Hz, 6a-

H), 4.91 (1H, dd, J = 1.9Hz, 4.1Hz, 12-H), 6.45 (1H, d, J = 8.4Hz, 10—H), 6.48 (1H, s, 4—

H), 6.71 (1H, s, 1-H), 7.02 (1H, d, J = 8.4Hz, 11-H)

Melting point: 16 3— 16 5 ° C Preparation Example 20 Synthesis of compound of formula (25)

2.0 g of rotenone (manufactured by Aldrich) was heated and refluxed for 2 hours in a mixture of 6 ml of acetic acid and 2 ml of concentrated hydrochloric acid. After cooling, the reaction solution was poured into water, the precipitate was collected by filtration, washed with water, and separated with a 100 g column of silica gel H (manufactured by Merck) using a mixed solution of n-hexane monoethyl acetate. After washing the column with 500 ml of an ethyl acetate-n-hexane mixed solution (3: 7), the fraction eluted with 500 ml of an ethyl acetate-n-hexane mixed solution (2: 3) was concentrated to 1.0. 5 g of residue were obtained. This was dissolved in a mixture of methanol 20 m 1 and Tetorahi de port furan (THF) 20m l, was stirred at room temperature for 1 hour the N a BH ₄ 250 mg. 20 ml of saturated aqueous sodium hydrogencarbonate solution and 20 ml of chloroform-form were added and partitioned. The chloroform layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 1.4 g of a residue. This was separated again by column chromatography on silica gel H 50 g. After washing with ethyl acetate- _n- hexane (1: 1) 150 ml, the fraction eluted with 100 ml of the same solvent was distilled off to obtain 2 Omg residue. This was separated on the above-mentioned preparative HP LC column I by a linear concentration gradient of 40% acetonitrile water to 80% acetonitrile water for 80 minutes at a flow rate of 9 m 1 / min. The fraction between 56 and 60 minutes was concentrated and crystallized from methanol to give 8.7 mg of compound (25). The physicochemical properties of the obtained compound were as follows.

- NMR (in _{CDC 1 3; p pm):} 1.74 (3H, s, 7 'or 8, -H), 1.82 (3H, s, 7' or 8'- H), 3.3-3.5 (3H, m, 4'- H and 12a - H), 3.85 (3H, s, 3- OCH 3), 3.86 (3H, s, 2-OCH 3), 4.22 (1H, dd, J = 4.2Hz, 9.5Hz, 6- H), 4.57 (1H, t like, J = 10.6Hz, 6-H), 4.84 (1H, m, 6a-H), 4.94 (1H, d, J = 3.9Hz, 12-H), 5.24 (1H , t like, J = 6.7Hz, 5'-1 H), 5.34 (IH, brs, 12-OH), 6.46 (1H, d, J = 8.2Hz, 10-H), 6.47 (IH, s, 4-H), 6.72 (1H, s, 1-H) ), 7.02 (IH, d, J = 8.2Hz, 11-H)

Melting point: 1 20-1 21 ° C Example 1 Evaluation as a helicopter agent for piles

 (1) Measurement of helicopter activity to pile

Helicobacter pylori 31A strain (obtained from the Tokyo Metropolitan Institute of Health, Microbiology Department, Bacteria I) isolated from human was used as a brain heart infusion medium (Difco) containing 10% fetal bovine serum. ) 5 m l was dispensed into a test tube, the aforementioned 3 1 inoculated a strain, under microaerophilic conditions _{(0 2: 5%, C0} 2: 10%, N 2: 85%), 48 with 3 7 ° C The cells were cultured with shaking for a time.

 The above culture was inoculated into brain heart infusion medium containing 10% fetal bovine serum at 5% and separately dissolved in 10% dimethyl sulfoxide according to the formula (2).

The compound of (25) and amoxicillin (Sigma) were added, and the cells were cultured under shaking under microaerobic conditions at 37 ° C for 48 hours, and the growth of Helicobacter pylori was examined. The results are shown in Table 1 (MIC: minimum growth inhibitory concentration).

Test agent MIC (μgκm 1) Compound of formula (2) 1.3 Compound of formula (3) 1.0 Compound of formula (4) 1.0 Compound of formula (5) 1.0 Compound of formula (5) 6) Compound of formula 1.0 Compound of formula (7) 1.3 Compound of formula (8) 1.0 Compound of formula (9) 1.3 Compound of formula (10) 0.08 Compound of formula (11) Compound 0.2 Compound of formula (12) 0.2 Compound of formula (13) 0.2 Compound of formula (14) 2.0 Compound of formula (15) 0.3 Compound of formula (16) 1.0 Compound of formula (17) 2.6 Compound of formula (18) 0.3 Compound of formula (19) 3.0 Compound of formula (20) 0.6 Compound of formula (21) 3 Compound of formula (22) 0.3 Compound of formula (23) 0.25 Compound of formula (24) 0.6 Compound of formula (25) 0.25 Amoxicillin 0.015 (2) Measurement of antibacterial activity

Conventional manner, 1 0 over ⁶ cells / ml were added to bacterial solution prepared in nutrient agar medium (manufactured Sakaekensha), a hole, after injection the test drug 5 0 mu 1 prepared in various concentrations, After leaving it to stand at 4 ° C for 2 hours, the test drug was allowed to penetrate into the agar medium, and cultured at 37 ° C for 24 hours to examine the strength of the antibacterial activity. The results are shown in Table 1 [Numerical values indicate the minimum inhibitory concentration (MIC, μg / m 1)].

 Table 1 2

Based on the above results, rotenoide has an excellent antibacterial activity against Helicobacter pylori, but has no antibacterial activity against Pacteria other than Helicobacter, and has excellent selectivity. It turns out that it is a lycactor agent. In contrast, it can be seen that the conventionally used amoxicillin has antibacterial activity against bacteria other than Helicobacter. Industrial applicability

The mouth tenoid represented by the above formula (1) used in the present invention, particularly the rotenoid of the above formulas (2) to (25), selectively has an anti-helicobacter action at a low concentration (for example, an anti-helicobacter lipase). Pylori action). Therefore, the above rotenoide is useful as an active ingredient of a medicament, and prevents or treats an infectious disease caused by a microorganism belonging to the genus Helicobacter, and various diseases involving infection or proliferation of a microorganism belonging to the genus Helicobacter ( For example, gastrointestinal ulcers such as gastric ulcer and duodenal ulcer, digestion of gastric cancer Utsuwagan, or useful in the prevention and Z or treatment of gastritis, etc.) ₍

Claims

The scope of the claims

The following formula (1)

[Wherein R ² and R ³ each independently represent a hydroxyl group or a C i Cs alkoxy group, or R ² and R ³ are taken together to form a group

(Where n represents an integer from 1 to 3)

May be formed.

R ⁸ and R ^{1 Q} each independently represent a hydrogen atom, an alkyl group of Ct Ce, or an alkenyl group of C _{2 to} C ₆ (the alkyl group or alkenyl group is a hydroxyl group, a halogen atom, an alkoxy group of Ci Cg, R ⁹ may be substituted with one or more substituents selected from the group consisting of an alkoxy group of CL and an alkoxy group of CL), R ⁹ represents a hydroxyl group or an alkoxy group of Ci Cs, or R ⁹ Is combined with R ⁸ or R ¹⁰

[Wherein R ⁵ ′ represents an alkyl group of C i Ce or an alkenyl group of C _{2 to} C ₆ (the alkyl group or alkenyl group is a hydroxyl group, a halogen atom, an alkoxy group of C _{1 to} C ₃ , and Ci may be substituted with 1 or more substituents selected from the group consisting of Ashiruokishi group -C _4), even if the dotted line to form a] indicates that in some cases the presence of a double bond Good.

R ¹¹ and R ^12a each independently represent a hydrogen atom, a hydroxyl group, or an alkoxy group of Ci Cg.

 X represents a group C (= 0) — or a group CH (OR ′) 1 (where R ′ represents a hydrogen atom or an acyl group of CiCs), and Y represents a group CH (R). (Where R represents a hydrogen atom, a hydroxyl group, or an alkoxy group represented by ^) or a group c (= o). ]

Or a hydrate or solvate thereof as an active ingredient.

 2. The medicament according to claim 1, which is used for treating and / or preventing an infection caused by a microorganism belonging to the genus Helicobacter.

 3. The medicament according to claim 1, which is used for prevention and / or treatment of a disease associated with infection or proliferation of a microorganism belonging to the genus Helicobacter.

 4. The medicament according to claim 3, wherein the disease is gastric ulcer, duodenal ulcer, gastric cancer, or gastritis.

5. The claim that the microorganism belonging to the genus Helicobacter is Helicobacter pylori. 5. The medicament according to any one of items 2 to 4.

6. The drug according to any one of claims 1 to 5, wherein in the formula (1), R ² and R ³ are each a methoxy group.

7. In the above formula (1), R ⁸ and R ⁹ are linked together to form a group.

(Where the dotted line indicates that a double bond may be present). The pharmaceutical agent according to any one of claims 1 to 6, which forms a double bond.

8. In the above formula (1), R ⁸ and R ⁹ are linked together to form a group.

[Where R ⁵ ′ represents an alkyl group of C Ce or an alkenyl group of C _{2 to} C ₆ (the alkyl group or alkenyl group is a hydroxyl group, a halogen atom, an alkoxy group of C Cg, and C i to C ₄ may be substituted with one or two or more substituents selected from the group consisting of an acyloxy group), and the dashed line indicates that a double bond may be present.] Item 8. The medicament according to any one of items 7 to 7.

9. The medicament according to any one of R ⁵ 'is hydroxyl or Ci Cg of claim 1, wherein an alkenyl group of C ₂ -C ₆ substituted with an alkoxy group to paragraph 8.

10. In the above formula (1), R ¹¹ and R ^12a are hydrogen atoms, X is a group CH (OH) — or a group —C (〇), and Y is a group —CH ₂ — Range number

10. The medicament according to any one of items 1 to 9.

1 1. The medicament according to any one of claims ^{1 to} 10, wherein R ^{1 Q} in the formula (1) is a hydrogen atom.

1 2. A compound selected from the group consisting of the following formulas (2) to (25):

t

cn ¾

N3 O

Dimension

CD 00

LSSZ0 / L6d £ / lDd

The medicament according to any one of claims 1 to 5, comprising:

 1 3. Compound represented by the following formula (13), or hydrate or solvate thereof

14. A method for preventing and / or treating a disease associated with infection or proliferation of a microorganism belonging to the genus Helicobacter, wherein the compound of formula (1) according to claim 1 is effective. Administering a quantity to a mammal, including a human.

 1 5. Use of a compound of the above formula (1) for the manufacture of a medicament according to claim 1.