KR20040071530A - A novel farnesyl transferase inhibitors - Google Patents

Abstract

PURPOSE: Farnesyl transferase inhibitors are provided. The compounds are useful for treatment of diseases mediated with ras farnesylation, particularly, useful as anti-cancer agent, anti-growth agent, anti-inflammatory agent, immune-suppressive drug, auto-immune disease treating agent and muscle relaxants. CONSTITUTION: The carbohydrate ring lactone derivatives of the formula(I) as farnesyl transferase inhibitors or salts thereof are provided, wherein R1 is hydrogen, alkyl or aryl; A is CH2, CH(alkyl), C(alkyl)2, CH(aryl), C(aryl)2, C=CH2, C=CH(alkyl), C=C(alkyl)2, C=CH(aryl), or C=C(aryl)2; B binds with hydrogen, hydroxy, alkoxy or halogen, binds with C or F in double, or binds with epoxy, imine oxy or thioxy; C binds with hydrogen, hydroxy, alkoxy or halogen, binds with B in double, or binds with epoxy, imine oxy or thioxy; D binds with hydrogen, hydroxy, alkoxy, alkyl(except methyl), aryl or halogen, binds with E in double, or binds with epoxy, imine oxy or thioxy; E binds with hydrogen, hydroxy, alkoxy or halogen, binds with D or F in double, or binds with epoxy, imine oxy or thioxy; F binds with hydrogen, hydroxy, alkoxy or halogen, binds with B or E in double, or binds with epoxy, imine oxy or thioxy; X is selected from hydrogen, hydroxy, alkoxy, silyloxy, amine, sulfur compound or halogen; and n is an integer from 1 to 3.

Description

A novel farnesyl transferase inhibitors

The present invention relates to a novel hydrocarbon ring lactone derivative compound having farnesyl transferase inhibitory activity, a method for preparing the compound and a novel intermediate material used in the method. In addition, the present invention comprises a novel hydrocarbon ring lactone derivatives and pharmaceutically acceptable salts thereof as an active ingredient and therapeutic effects of diseases mediated through farnesylation, in particular anti-cancer, anti-proliferation, anti-inflammatory, immunosuppressive, autologous The present invention relates to a pharmaceutical composition having an immune disease treatment and muscle relaxation effect.

ras is a procarcinogenic gene that encodes a 21kDa GTP binding protein that acts on signaling systems involved in cell growth and differentiation. ras protein is synthesized as a plasma precursor, Annu. Rev. Cell. Biol. , 1991, vol. 7, 601-632, located on the cytoplasmic surface of the plasma membrane after a series of transcriptional processes. The importance of farnesylation after transcription of this ras protein has been studied in the study of tumor cell function. Farnesylation of ras catalyzed by farnesyl transferase is believed to be an essential step in ras processing. Inhibition of farnesyl transferase and consequently inhibition of the farnesylation of the ras protein interferes with the ability of the ras protein to convert normal cells into cancer cells. The system in which the farnesylation of proteins is best expressed is in the ras protein.

Many farnesyl transferase inhibitors have been developed, one of which farnesyl pyrophosphate derivatives complementarily inhibits the binding of farnesyl enzyme to the farnesyl pyrophosphate binding site.

The amino acid sequence of the ras protein all ends with CAAX, where C is cystine, A is an aliphatic amino acid and X is another amino acid. The first transcription process of the ras protein is the attachment of the fatty 15-carbon farnesyl end to the cystine end of the CAAX box via farnesyl enzyme catalysis. Through these findings, many farnesyl transferase inhibitors including CAAX tetrapeptide have been found, which act as substrate or complementary inhibitors to farnesyl enzyme.

Recently, hydrocarbon ring lactone compounds have been developed as farnesyl enzyme inhibitors, and effective anticancer effects have been reported. Known hydrocarbon ring lactone compounds include aglabin, ixerin, ambrosenolides, cilostakianolide, cardinalolide, eremanolide and the like. Among them, as known in US Pat. No. 6,197,767, aglabine is of great interest as an anticancer agent due to its in vivo efficacy and low toxicity, such as acting only on farnesyl transferase and not on other classes of enzymes such as geranyl enzyme. I am getting it.

Conventional anticancer agents, on the other hand, can be used as immunosuppressants, rheumatoid arthritis, autoimmune diseases, and anti-inflammatory agents in organ transplantation as reported in the Journal of Neuroimmunology , 2001, 120, 1-9.

As a result of a long study, the present inventors have completed the present invention by synthesizing a hydrocarbon ring lactone derivative having a novel structure comparable to the in vivo efficacy of the existing aglabin.

An object of the present invention is to provide a novel hydrocarbon ring lactone derivative having farnesyl transferase inhibitory action.

Still another object of the present invention is to provide a method for preparing the novel hydrocarbon ring lactone derivative.

It is another object of the present invention to provide a novel intermediate material for use in the preparation of the novel hydrocarbon ring lactone derivatives.

Still another object of the present invention is to provide a farnesyl transferase inhibitor composition comprising the novel hydrocarbon ring lactone derivative and a pharmaceutically acceptable salt thereof.

It is also an object of the present invention to include the novel hydrocarbon ring lactone derivatives and pharmaceutically acceptable salts thereof as an active ingredient and to prevent or treat diseases mediated through farnesylation, in particular, anti-cancer, anti-proliferation, anti-inflammatory, It is to provide a pharmaceutical composition having an immunosuppressive, autoimmune disease and muscle relaxation effect.

According to one aspect, the present invention provides a hydrocarbon ring lactone derivative represented by the following formula (I):

In the above formula,

R ¹ is hydrogen, alkyl and an aryl group,

A is CH ₂ , CH (alkyl), C (alkyl) ₂ , CH (aryl), C (aryl) ₂ , C═CH ₂ , C═CH (alkyl), C═C (alkyl) ₂ , C = CH (Aryl), C = C (aryl) ₂ ,

B bonds with hydrogen, hydroxide, alkoxy or halogen or forms a double bond with C or F or an epoxy, imineoxy, thioxy bond,

C bonds with hydrogen, hydroxide, alkoxy or halogen or double bonds with B or forms an epoxy, imineoxy, thioxy bond,

D is combined with hydrogen, hydroxide, alkoxy, alkyl (but not methyl), aryl or halogen, or a double bond with E or an epoxy, imineoxy, thioxy bond,

E combines with hydrogen, hydroxide, alkoxy or halogen or a double bond with D or F or an epoxy, imineoxy, thioxy bond,

F bonds with hydrogen, hydroxide, alkoxy or halogen or forms a double bond with B or E or an epoxy, imineoxy, thioxy bond,

X selects one of hydrogen, hydroxide, alkoxy, silyloxy, amine, sulfur compound or halogen,

n is one of the integers of 1-3.

Also provided in the present invention are hydrocarbon ring lactone derivatives represented by the following general formula (II):

In the above formula,

R ¹ is hydrogen, alkyl or aryl,

A is CH ₂ , CH (alkyl), C (alkyl) ₂ , CH (aryl), C (aryl) ₂ , C = CH ₂ , C = CH (alkyl), C = C (alkyl) ₂ , C = CH (Aryl), or C = C (aryl) ₂ ,

B bonds with hydrogen, hydroxide, alkoxy or halogen or forms a double bond with C or F or an epoxy, imineoxy, thioxy bond,

C combines with hydrogen, hydroxide, alkoxy or halogen or forms a double bond with B or an epoxy, imineoxy or thioxy bond,

D is bonded to hydrogen, hydroxide, alkoxy, alkyl (but not methyl), aryl or halogen, or a double bond with E or an epoxy, imineoxy, or thioxy bond,

E combines with hydrogen, hydroxide, alkoxy or halogen or forms a double bond with D or F or an epoxy, imineoxy or thioxy bond,

F bonds with hydrogen, hydroxide, alkoxy or halogen or forms a double bond with B or E or an epoxy, imineoxy or thioxy bond,

X is oxygen,

n is one of the integers of 1-3.

Also provided in the present invention are hydrocarbon ring lactone derivatives represented by formula (III):

In the above formula,

R ¹ and R ² are hydrogen, alkyl or aryl groups,

A is CH ₂ , CH (alkyl), C (alkyl) ₂ , CH (aryl), C (aryl) ₂ , C═CH ₂ , C═CH (alkyl), C═C (alkyl) ₂ , C = CH (Aryl), or C = C (aryl) ₂ ,

B combines with hydrogen, hydroxide, alkoxy or halogen or forms a double bond with C, F or G or an epoxy, imineoxy or thioxy bond,

C combines with hydrogen, hydroxide, alkoxy or halogen or a double bond with B or an epoxy, imineoxy or thioxy bond,

D is bonded to hydrogen, hydroxide, alkoxy, alkyl (but not methyl), aryl or halogen, or a double bond with E or an epoxy, imineoxy, or thioxy bond,

E combines with hydrogen, hydroxide, alkoxy or halogen or forms a double bond with D or F or an epoxy, imineoxy or thioxy bond,

F bonds with hydrogen, hydroxide, alkoxy or halogen or forms a double bond with B or E or an epoxy, imineoxy or thioxy bond,

G forms a double bond with hydrogen, hydroxide, alkoxy, halogen, alkyl, aryl, B, or an epoxy, imineoxy, or thioxy bond,

X selects one of hydrogen, hydroxide, alkoxy, silyloxy, amine, sulfur compound or halogen,

n is one of the integers of 1-3.

Hydrocarbon ring lactone derivative compounds of formulas (I), (II) and (III) may form pharmaceutically acceptable salts that fall within the scope of the present invention. Specifically, when the compound contains a basic moiety, it is possible to form pharmaceutically acceptable salts with various inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid or maleic acid. have. When the compound contains an acidic moiety, salts with sodium bases, potassium salts, calcium salts, or inorganic bases such as magnesium salts or ammonium salts; Salts with organic bases such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine, and the like.

According to another aspect of the present invention, there is provided a method for stereoselectively preparing the hydrocarbon ring lactone derivatives of the above formulas (I), (II) and (III).

The process for preparing the hydrocarbon ring lactone derivatives of the present invention can be prepared via intermediate materials of the general formula (IX) and the following general formula (XI), as represented in Scheme 1.

Scheme 1: Preparation of intermediate material of formula (IX) and formula (XI)

In formulas (IV) to (IX), R ¹ , A, B, C, D, E, F and n are as defined in the hydrocarbon ring lactone compound of formula (I), and P and Q are hydrogen , Alkyl, aryl, and in the above formulas (X) and (XI), R ¹ , A, B, C, D, E, F, G, X and n are the hydrocarbon ring lactone compounds of formula (III) As defined.

Referring to Scheme 1, the cyclopropane reaction of a furan of formula (IV) and a diazo compound of formula (V) is carried out to produce a propaneated furan of formula (VI) in which a tricyclic ring is bound, and the product is ozonated. To synthesize a tricyclic compound of formula (VII) (first step reaction). The allylsilane of the formula (VIII) is reacted with the compound (VII) thus obtained, followed by lactonation under basic conditions to synthesize a vinylcyclolactone compound of the formula (IX) (second step reaction). In addition, a compound of formula (XI) is synthesized by reacting a compound of formula (IX) with allylsilane of formula (X) (third step reaction).

In the first stage reaction, a bisoxazoline derivative of formula (A) may be used as a catalyst to increase stereoselectivity, which is used in an amount of 0.01 to 0.1 equivalents based on the compound of formula (IV).

Wherein R and R ¹ are hydrogen, alkyl, aryl or silyl, X is CH ₂ , CH (alkyl), C (alkyl) ₂ , CH (aryl), C (aryl) ₂ , NH, N (alkyl), O or S.

The ratio of diazo compound to furan is used in an amount of 1 to 20 equivalents, and the reaction is slowly added dropwise at a temperature of 0 ° C. to 60 ° C. for 2 to 24 hours to give the desired compound of formula (VI) with high yield and high stereoselectivity. Can be synthesized. In this reaction, compounds having opposite stereostructures can be synthesized in high yield and high stereoselectivity by changing the stereostructure of the bisoxazoline derivative of formula (A). Cyclopropaneated furan compounds of formula (VI) can be readily obtained. The compound of formula (VI) thus obtained is produced as a stereoselective tricyclic compound of formula (VII) by ozone decomposition reaction.

In the second stage reaction, the compound of formula (VII) obtained in the first stage reaction forms an intermediate compound through a carbonyl-ene reaction under the allylsilane of formula (VIII) and an inorganic acid catalyst and lactoneization of the intermediate compound under base. By reaction, a vinylcyclolactone compound of formula (IX) is synthesized. By this reaction, a cyclopropane compound in which the tridentate carbon position of the tricyclic ring is stereoselectively controlled can be obtained.

Inorganic acids used in this reaction include trifluoroboron, diethylzinc, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride and the like. In addition, bases used in the lactonation reaction include inorganic bases such as barium hydroxide, potassium hydroxide and sodium hydroxide.

In the third stage reaction, the compound of formula (IX) obtained in the second stage reaction is reacted with allylsilane of the formula (X) to form a compound of formula (XI).

The compounds of the formulas (IX) and (XI) synthesized in Scheme 1 can be used as the main intermediate for synthesizing the hydrocarbon ring lactone derivative of the present invention which is the final material.

The hydrocarbon ring lactone derivatives of formula (I) and formula (II) of the present invention are prepared by the reactions shown in Scheme 2 from compounds of formula (IX):

Scheme 2: Preparation of hydrocarbon ring lactone derivatives of formula (I) and formula (II)

In the formula (IX), R ¹ , A, B, C, D, E, F and n are as defined in the hydrocarbon ring lactone derivative compound of formula (I).

Looking at Scheme 2, the compound of formula (IX) is formed by the carbonyl-ene reaction under an inorganic acid catalyst to produce the compound of formula (I). As the inorganic acid, trifluoroboron diethyl ether, tetramethyltin, tin tetrachloride, trimethylsilyl triflate, trimethylsilyl acetate, titanium tetrachloride and the like can be used.

The resulting compound of formula (I) is rearranged under an organic acid catalyst to give a compound of formula (II) in high yield. Paratoluenesulfonic acid, methanesulfonic acid, parabenzoylsulfonic acid, pyridinium paratoluenesulfonate, acetic acid, benzoic acid and the like can be used as the organic acid.

In addition, the solvent used in this reaction is a methyl halide solvent or an aromatic solvent such as toluene or dichlorobenzene. The reaction is carried out at -80 ~ 45 ℃, and the reaction product ratio and yield vary depending on the reaction temperature, the type of inorganic acid used and the solvent.

Compounds of formula (I) and formula (II) prepared by the present invention can be easily separated by column chromatography, there is an advantage that can be easily purified even in a mixture state.

The compound of formula (I) and the compound of formula (II) obtained in Scheme 2 can be selectively synthesized by five stereoselection sites by easily adjusting the stereoselectivity from the compound intermediate obtained in Scheme 1. There is an advantage that can be easily separated by column chromatography or recrystallization method.

Since the method of Scheme 1 can be easily controlled to a hydrocarbon ring lactone derivative having a stereoselectivity similar to or opposite to that of aglabin or iserine-Y, which is known to have high anticancer activity, various hydrocarbon ring lactone compounds can be synthesized. There are advantages to it.

Hydrocarbon ring lactone derivatives of formula (III) of the present invention can be synthesized by the following scheme 3.

Scheme 3: Preparation of hydrocarbon ring lactone derivative of formula (III)

In Formula (XI), R ¹ , A, B, C, D, E, F, G, X and n are as defined in the hydrocarbon ring lactone derivative compound of Formula (III).

In Scheme 3, metathesis reaction of an intermediate compound of Formula (XI) under a Grubbs catalyst produces a hydrocarbon ring lactone derivative of Formula (III). Various hydrocarbon ring lactone derivatives can also be synthesized from the resulting compounds of formula (III).

Hydrocarbon ring lactone derivatives produced by the methods of Scheme 2 and Scheme 3 can be separated and purified using conventional methods such as column chromatography, recrystallization and the like.

According to another aspect of the present invention, a disease mediated through the farnesylation of ras comprising a hydrocarbon ring lactone derivative of formula (I), (II) and (III) or a pharmaceutically acceptable salt thereof as an active ingredient A therapeutic composition is provided. Specifically, the pharmaceutical composition of the present invention has the effect of anticancer, antiproliferative, anti-inflammatory, immunosuppressive agent, autoimmune disease treatment agent and muscle relaxant.

The pharmaceutical composition of the present invention may be prepared by oral administration such as tablets, capsules, troches, liquids, suspensions, or the like, or solutions for injection or distilled water upon injection. It may be formulated into various preparations, such as injectable preparations in the form of dry powder for use, and external preparations such as ointments and creams. The pharmaceutical compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients such as colorants, sweeteners, flavors and / or preservatives.

The dosage of the pharmaceutical composition of the present invention is determined depending on the nature and severity of the symptoms, the age and sex of the individual, and the route of administration, but is preferably administered so that 0.1 mg to 200 mg / kg body weight is taken per day.

Example

The invention is illustrated in more detail by the following examples. The following examples illustrate the invention and should not be construed as limiting the invention to these examples.

Example 1

(1 R / S, 2 R / S, 3 S) -2- (2- methylene-cyclopentyl) -5-oxo-tetrahydrofuran-3-carbonitrile synthesis of the aldehyde

In a nitrogen atmosphere was dissolved in dichloromethane 100 ㎖ (1 S, 2 S , 3 S) - oxalate 2-ethoxycarbonyl-3-formyl-cyclopropyl-methyl ester (4.84 g, 20 mmol) and the solution -78 After cooling to C, trifluoroboron diethyl ether (2.64 mL, 21 mmol, 1.05 equiv) was added. After 30 minutes cyclophen-1-enylmethyltrimethylsilane (3.70 g, 24 mmol, 1.2 equiv) was added and stirred for 18 h. The reaction was terminated with 6 ml of saturated sodium bicarbonate solution at -78 ° C and then left to 0 ° C. The filtered filtrate was dried over magnesium sulfate and concentrated under reduced pressure. The resulting reaction intermediate was dissolved in 60 mL of methanol, cooled to 0 ° C., and a solution of barium hydroxide hydrate (6.62 g, 21 mmol, 1.05 eq) completely dissolved in 200 mL of methanol was slowly added dropwise. After dropping, the solution was further exchanged at 0.degree. C. for 1.75 hours and 350 ml of water was added thereto. The precipitate was filtered off and the immediately filtered solution was extracted with dichloromethane (4 × 250 mL). The combined organic layers were dried over magnesium sulfate and the filtered filtrate was concentrated under reduced pressure under vacuum. A pale yellow oily compound (3.228 g, 16.62 mmol, 83%) was obtained. (Structural isomer: dr = 95: 5)

Enantiomeric derivatives (1 S / R , 2 S / R , 3 R from enantiomeric starter (1 R , 2 R , 3 R ) -oxalic acid-2-ethoxycarbonyl-3-formyl-cyclopropyl-methylester ) -2- (2-methylene-cyclopentyl) -5-oxo-tetrahydro-furan-3-carboaldehyde was obtained by silica gel chromatography in 44% yield. (Structural isomer: dr = 90:10)

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.52 (m, 4H, 2 CH ₂ ), 2.23 (m, 2H), 2.70 (m, 1H), 2.76 (dd, J = 18.1, 10.2 Hz, 1H , 4-H), 2.92 (dd, J = 18.1, 7.4 Hz, 1 H, 4-H), 3.31 (dddd, J = 10.2, 7.4, 6.4, 1.3 Hz, 1 H, 3-H), 4.75 (dd, J = 6.1, 6.0 Hz, 1H, 2-H), 4.99 (m, 1H, CH ₂ ), 5.06 (m, 1H, CH ₂ ), 9.70 (d, J = 1.3 Hz, CHO, minor) & 9.74 ( d, J = 1.3 Hz, 1H, CHO, major); ¹³ C-NMR (75.4 MHz, CDCl ₃ ): δ = 23.02, 26.98, 32.67, 46.82, 49.16, 79.58, 108.08, 149.86, 173.25, 196.63; IR (film, cm ⁻¹ ): = 3426, 2955, 2873, 1771, 1653, 1435, 1198, 882; MS (CI, NH ₃ ): m / z (%) = 212.2 (100.0) [M + NH ₄ ⁺ ]

Example 2

(1 R / S, 2 R / S, 3 S) -2- (2- methylene-cyclohexyl) -5-oxo-tetrahydrofuran-3-carbonitrile synthesis of the aldehyde

(1 S , 2 S , 3 S )-(-)-oxalic acid-2-ethoxy-carbonyl-3-formyl-cyclopropyl-methyl-ester (3.5 g) dissolved in 100 ml of purified dichloromethane under a nitrogen stream. , 14.3 mmmol) solution was cooled to -78 ° C and borontrifluorate diethyl ether (2.0 mL, 15.9 mmol, 1.1 equiv.) Was added. After 10 minutes cyclohex-1-enylmethyl-trimethylsilane (4.0 g, 21.5 mmol, 1.5 equiv.) Was added and stirred for 12 hours. The reaction was terminated with 40 ml of saturated aqueous sodium bicarbonate solution at -78 ° C and left to 0 ° C. The reaction solution was extracted with dichloromethane (5 x 100 mL) and the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The resulting reaction intermediate was dissolved in 56 ml of methanol, cooled to 0 ° C., and a solution of barium hydroxide hydrate (4.8 g, 15.1 mmol, 1.05 equiv.) Completely dissolved in 26 ml of methanol was slowly added dropwise. After dropping, the solution was further stirred at 0 ° C. for 2 hours, and 50 ml of water was added thereto. After layer separation, the aqueous layer was extracted with dichloromethane (5 × 50 mL, 2 × 100 mL, 1 × 200 mL), the combined organic layers were dried over magnesium sulfate, and the filtered filtrate was concentrated under reduced pressure under vacuum. An oily mixture (2.9 g, 13.9 mmol, 97%) was obtained, which was purified by silica gel chromatography with chloroform as the developing solvent to two structural isomers (1.7 g, 8.2 mmol, 57%, dr = 91: 9). Purified.

Enantiomeric (1 S / R , 2 from enantiomeric starter (1 R , 2 R , 3 R )-(-)-oxalic acid-2-ethoxy-carbonyl-3-formyl-cyclopropyl-methyl-ester S / R , 3R ) -2- (2-methylene-cyclohexyl) -5-oxo-tetrahydrofuran-3-carboaldehyde was obtained in 97% yield.

1 H-NMR (300 MHz, CDCl 3): δ = 1.14 (m, 8 H, 4 CH 2), 2.36 (dt, J = 10.0, 3.9 Hz, 1 H, 1-H), 2.73 (dd, J = 18.0, 10.0 Hz, 1 H, 4-H), 2.91 (dd, J = 18.0, 7.5 Hz, 1 H, 4-H), 3.30 (dddd, J = 9.8, 7.4, 6.3, 1.0 Hz, 1 H, 3- H), 4.79 (bs, 1H, = CH 2), 4.88 (bs, 1 H, = CH 2), 4.92 (dd, J = 10.0, 6.2 Hz, 1 H, 2-H), 9.69 (d, J = 1.0 Hz, 1 H, CHO, major) and 9.79 (d, J = 1.6 Hz, CHO, minor); 13 C-NMR (75.4 MHz, CDCl 3): δ = 21.66, 27.95, 28.61, 29.55, 33.48, 49.13, 51.34, 78.70, 111.57, 147.28, 174.28, 197.86; IR (film, cm- ¹ ): = 3435, 2934, 2859, 1645, 1771, 1448, 1020; MS (CI, NH 3): m / z (%) = 226.2 (100.0) [M + NH 4+]

Example 3

Synthesis of (3a S , 4 S , 8a R , 8b S ) -4-hydroxy-3,3a, 4,5,7,8,8a, 8b-octahydro-1-oxa-indasen-2-one

(1 R / S, 2 R / S , 3 S ) -2- (2-methylenecyclohexyl) -5-oxo-tetrahydrofuran-3-carboaldehyde (50) dissolved in 5 ml of purified dichloromethane under a nitrogen stream. mg, 0.26 mmol) was added borontrifluorate diethyl ether (0.99 mL, 7.8 mmol, 30 equiv.). After stirring for 12 hours at room temperature, the reaction was terminated with 3.5 ml of saturated aqueous sodium bicarbonate solution. The separated aqueous layer was extracted with dichloromethane, the combined organic layers were dried over sodium sulfate, and the filtered filtrate was concentrated under reduced pressure under vacuum to obtain (3a S , 4 S , 8a R , 8b S ) -4-hydroxy-3,3a in solid state. , 4,5,7,8,8a, 8b-octahydro-1-oxa-indasen-2-one (42 mg, 0.21 mmol, 84%) was obtained.

Mirror-like starting with impurities (1 S / R, 2 S / R , 3 R ) -2- (2-methylenecyclohexyl) -5-oxo-tetrahydrofuran-3-carboaldehyde (338 mg, 1.74 mmol ) And a mirror derivative (3a R , 4 R , 8a S , 8b R ) -4-hydroxy-3,3a, 4,5 from borontrifluorate diethyl ether (240 μl, 1.91 mmol, 1.1 equiv.) , 7,8,8a, 8b-octahydro-1-oxa-as-indacen-2-one was obtained in 15% (50 mg, 0.26 mmol) yield.

= 11.5 (c = 1.035, CH 2 Cl 2); 1 H-NMR (300 MHz, CDCl 3): δ = 1.68 (m, 2H, 7-H, 8-H), 2.18 (m, 4H, 7-H, 8-H, 5-H), 2.43 ( dd, J = 16.2, 6.6 Hz, 1 H, 3-H), 2.60 (m, 1 H), 8a-H), 2.64 (dd, J = 16.2, 13.4 Hz, 1 H, 3-H), 2.76 (m, 1 H), 4.02 (dd, J = 10.1, 10.0 Hz, 1 H, 8b-H), 4.18 (m, 1 H, 4-H), 5.64 (m, 1 H, 6-H); 13 C-NMR (75.4 MHz, CDCl 3): δ = 27.50, 31.32, 32.02, 36.70, 47.73, 51.13, 65.57, 84.21, 130.18, 137.03, 176.48; IR (KBr, cm ⁻¹ ): = 3469, 2923, 2363, 1767, 1105, 1019; MS (EI, 70 eV)): m / z (%) = 194.1 (16.6) [M < + >], 176.1 (9.8) [M-H2O], 130.1 (15.2), 117.1 (100.0) [M- (CH2CO2H + H2O). )], 113.1 (28.0), 81.1 (66.8)

Example 4

(3a S , 4 S , 9a R , 9b S ) -4-hydroxy-3a, 4,5,7,8,9,9a, 9b-octahydro-3H-naphtho [1,2-b] furan Synthesis of 2-one

(1 S / R , 2 S / R , 3R ) -2- (2-methylene-cyclohexyl) -5-oxo-tetrahydrofuran-3-carboaldehyde dissolved in 30 ml of purified dichloromethane under a nitrogen stream ( To 338 mg, 1.62 mmol) solution was added borontrifluorate diethyl ether (612 μL, 4.86 mmol, 3.0 equiv.). After stirring for 12 hours at room temperature, the reaction was terminated with 7 ml of saturated aqueous sodium bicarbonate solution. The separated aqueous layer was extracted with dichloromethane, the combined organic layers were dried over sodium sulfate, and the filtered filtrate was concentrated under reduced pressure under vacuum to obtain (3a S , 4 S , 9a R , 9b S ) -4-hydroxy-3a, 4 in solid form. , 5,7,8,9,9a, 9b-octahydro-3H-naphtho [1,2-b] furan-2-one (210 mg, 1.01 mmol, 62%) was obtained.

= 28.1 (c = 0.645, CH 2 Cl 2); 1 H-NMR (600 MHz, CDCl 3): δ = 1.36 (m, 2H, 7-H, 9-H), 1.68 (m, 1H, 9-H), 1.99 (m, 2H, 8-H ), 2.09 (m, 1H, 7-H), 2.24 (dddd, J = 13.2, 11.1, 6.5, 1.9 Hz, 1H, 3a-H), 2.32 (m, 3H, 5-CH2, 9a- H), 2.42 (dd, J = 16.2, 6.5 Hz, 1 H, 3-H), 2.63 (dd, J = 16.2, 13.2 Hz, 1 H, 3-H), 3.99 (dd, J = 11.0, 11.0 Hz, 1 H, 9b-H), 4.15-4.20 (m, 1H, 4-H), 5.73 (bs, 1H, 6-H); 13 C-NMR (100.6 MHz, CDCl 3): δ = 20.22, 25.40, 26.77, 31.94, 42.43, 42.94, 48.08, 65.5, 83.18, 129.16, 131.1, 176.42; IR (film, cm- ¹ ): = 3438, 2928, 1770, 1423, 988; MS (CI, NH 3): m / z (%) = 226.1 (100.0) [M + NH 4+].

Example 5

( Z )-(3a R , 4 S , 4a R , 8a S ) -4-hydroxy-3,3a, 4,4a, 5,6,8,8a-octahydro-1-oxa-s-indacene Synthesis of 2-one

To 5 mL dichloromethane purified under nitrogen stream (1 R / S , 2 R / S , 3 S ) -2- (2-methylenecyclopentyl) -5-oxo-tetrahydrofuran-3-carboaldehyde (50 mg , 0.26 mmol) was cooled to −78 ° C., and boron trifluorate diethyl ether (46 μl, 0.36 mmol, 1.37 equiv.) Was slowly added thereto, and stirred at −78 ° C. for 12 hours. Thereafter, the mixture was left to 0 deg. C and the reaction was terminated with 5 ml of saturated aqueous sodium bicarbonate solution. The separated aqueous layer was extracted with dichloromethane (3 x 15 mL), the combined organic layers were dried over sodium sulfate, and the filtered filtrate was concentrated under reduced pressure under vacuum. Petroleum ether / ethyl acetate = 3: 1 using silica gel chromatography as a developing solvent to give a colorless solid (3a S , 4 S , 8a R , 8b S ) -4-hydroxy-3,3a, 4,5,7 ( Z )-(3a R , 4 S , 4a R , 8a S with, 8,8a, 8b-octahydro-1-oxa-as-indasen-2-one (20 mg, 0.103 mmol, 40%) ) -4-hydroxy-3,3a, 4,4a, 5,6,8,8a-octahydro-1-oxa-as-indasen-2-one (13 mg, 0.67 mmol, 26%) was obtained. .

1 H-NMR (300 MHz, CDCl 3): δ = 1.66 (m, 1 H), 2.10 (m, 1 H), 2.25 (m, 4 H), 2.44 (m, 2 H), 2.67 (m, 2 H ), 3.05 (dd, J = 10.1, 10.0 Hz, 1 H, 4-H), 4.60 (m, 1 H, 8a-H), 5.48 (m, 1 H, 7-H); 13 C-NMR (75.4 MHz, CDCl 3): δ = 26.42, 29.27, 31.36, 36.0, 43.72, 51.83, 76.15, 80.69, 127.17, 136.85, 176.96; IR (film, cm- ¹ ): = 3367, 2928, 2856, 2361, 1769, 1177, 1155, 1021, 916; MS (CI, NH 3): m / z (%) = 212.1 (100.0) [M + NH 4+]

Example 6

( Z )-(3a R , 4 S , 4a R , 9a S ) -4-hydroxy-3a, 4,4a, 5,6,7,9,9a-octahydro-3H-naphtho [2,3 -b] Synthesis of furan-2-one

Purified 7 mL of toluene under nitrogen stream (3a S , 4 S , 9a R , 9b S ) -4-hydroxy-3a, 4,5,7,8,9,9a, 9b-octahydro-3H- To a solution of naphtho [1,2-b] furan-2-one (50 mg, 0.24 mmol) was added p -toluenesulfonic acid (23 mg, 0.12 mmol, 0.5 equiv.) And refluxed at 80 ° C. for 20 hours. I was. The reaction mixture was concentrated under reduced pressure, dissolved in 30 ml of dichloromethane, and washed with saturated aqueous sodium bicarbonate solution. The separated aqueous layer was extracted with dichloromethane (15 mL), and the combined organic layers were dried over sodium sulfate, and the filtered filtrate was concentrated under reduced pressure under vacuum. Petroleum ether / ethyl acetate = 1: 1 using ( Z )-(3a R , 4 S , 4a R , 9a S ) -4-hydroxy-3a, 4,4a as a colorless solid via silica gel chromatography with developing solvent , 5,6,7,9,9a-octahydro-3H-naphtho [2,3-b] furan-2-one (12 mg, 0.058 mmol, 24%) was obtained.

1 H-NMR (300 MHz, CDCl 3): δ = 1.37 (m, 4 H), 1.83 (m, 4 H), 2.27 (m, 2 H), 2.63 (m, 2 H), 3.12 (dd, J = 10.1, 10.0 Hz, 1 H, 4-H), 4.63 (ddd, J = 4.5, 4.4, 1.7 Hz, 1 H, 9a-H), 5.60-5.72 (m, 1H, 8-H); 13 C-NMR (75.4 MHz, CDCl 3): δ = 19.72, 25.06, 25.12, 35.87, 36.30, 41.83, 43.65, 74.64, 80.31, 126.39, 130.98, 177.20; IR (film, cm- ¹ ): = 3453, 2945, 2858, 2361, 1753, 1416, 1207, 1179, 928; MS (CI, NH 3): m / z (%) = 226.1 (100.0) [M + NH 4+]

Example 7

Of furan-2-one - (1 R / S, 1 R, 4 S, 5 R) -4- (1- hydroxy-boot-3-enyl) -5- (2-methylene-cyclopentyl) -dihydro synthesis

In 90 ml of dichloromethane purified under a nitrogen stream, aldehyde (1 R / S , 2 R / S , 3 S ) -2- (2-methylenecyclopentyl) -5-oxo-tetrahydrofuran-3-carboaldehyde ( 1.5 g, 7.68 mmol) was dissolved and then cooled to -78 ° C. To this solution allyltrimethylsilane (2.44 mL, 15.36 mmol, 2.0 equiv.) Was added and after 10 minutes borontrifluorate diethylether (1.078 mL, 8.46 mmol, 1.1 equiv.) Was added. The reaction was stirred at −78 ° C. for 12 hours and then terminated with 12 ml of saturated aqueous sodium bicarbonate solution. The reaction was terminated to 0 ℃ and extracted with dichloromethane (3 x 100 mL, 1x 200 mL), the combined organic layer was dried over sodium sulfate and the filtered filtrate was concentrated under reduced pressure under a vacuum to give a colorless oil (1 R / S , 1 R, 4 S , 5 R ) -4- (1-hydroxy-but-3-enyl) -5- (2-methylenecyclopentyl) -dihydro-furan-2-one (1.20 g, 5.08 mmol , 66%, dr = 80:20).

Mirror-like starting with impurities (1 S / R , 2 S / R , 3 R ) -2- (2-methylenecyclopentyl) -5-oxo-tetrahydrofuran-3-carboaldehyde (900 mg, 4.63 mmol ) And allyl derivatives (1 S / R, 1 S, 4 R , 5 S ) -4- (1-hydroxy-but-3-enyl) from allyltrimethylsilane (1.06 g, 9.27 mmol, 2.0 equiv.) -5- (2-Methylene-cyclopentyl) -dihydro-furan-2-one was obtained in 22% (237 mg, 1.00 mmol, dr = 80:20) yield.

1 H-NMR (300 MHz, CDCl 3): δ = 1.51 (m, 2 H, CH 2), 1.73 (m, 2 H, CH 2), 2.04 (m, 3 H, CH 2, 4-H), 2.31 (m, 2 H, CH2), 2.51 (dd, J = 17.2, 9.3 Hz, 1 H, 3-H), 2.72 (dd, J = 17.2, 7.0 Hz, 1 H, 3-H), 2.60 (m, 1 H , CH), 3.71 (m, 1H, CHOH), 4.62 (dd, J = 6.0, 4.7 Hz, 1H, 5-H), 4.93 (m, 2H, = CH2), 5.18 (m, 2H , = CH2), 5.67 (m, 1H, CH = CH2); 13C-NMR (75.4 MHz, CDCl 3): δ = 24.30 (CH2, minor: 24.39), 27.11 (CH2, minor: 26.67), 28.98 (CH2, minor: 32.34), 33.90 (CH2, minor: 34.04), 40.36 ( CH2, minor: 39.89), 43.27 (CH, minor: 42.89), 47.04 (CH, minor: 47.72), 70.12 (CH, minor: 72.31), 83.77 (CH, minor: 84.19), 107.44 (= CH2, minor: 107.06), 119.32 (= CH2, minor: 119.63), 133.64 (= CH, minor: 133.42), 151.90 (Cquat, minor: 152.35), 176.93 (Cquat, minor: 176.61); IR (film, cm- ¹ ): = 3439, 2929, 1768, 1418, 1199; MS (CI, NH 3): m / z (%) = 254.2 (100.0) [M + NH 4 +], 237.0 (11.7) [MH +]

Example 8

(1 R / S, 1 R , 4 S, 5 R) -5- (2- methylene-cyclopentyl) -4- (1-trimethylsilanyl-oxy-boot-3-enyl) -dihydro-furan-2-one Synthesis of

(1 R / S, 1 R, 4 S , 5 R ) -4- (1-hydroxy-but-3-enyl) -5- (2-methylenecyclopentyl with 10 ml of dichloromethane purified under nitrogen stream ) -Dihydro-furan-2-one (450 mg, 1.90 mmol) was dissolved in triethylamine (542 μl, 3.90 mmol, 2.0 equiv.) And trimethylsilyl chloride (436 μl, 3.42 mmol, 1.8 equiv. ) Was added sequentially at 0 ° C. The reaction mixture was stirred at room temperature for 20 minutes and then terminated with 10 ml of saturated sodium bicarbonate aqueous solution. The separated aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtered filtrate was concentrated under reduced pressure under vacuum to give a colorless oil (1 R / S, 1 R, 4 S , 5 R ). -5- (2-methylenecyclopentyl) -4- (1-trimethylsilanyloxy-but-3-enyl) -dihydrofuran-2-one (433 mg, 1.40 mmol, 74%, dr = 80:20 )

Starting mirror (1 S / R, 1 S, 4 R , 5 S ) -4- (1-hydroxy-but-3-enyl) -5- (2-methylenecyclopentyl) -dihydro-furan- Mirror derivatives (1 S / R, 1 S, from 2-one (203 mg, 0.86 mmol), triethylamine (240 μl, 1.72 mmol) and trimethylsilyl chloride (136 μl, 1.075 mmol, 1.25 equiv.) 4R , 5S ) -5- (2-methylene-cyclopentyl) -4- (1-trimethylsilanyloxy-but-3-enyl) -dihydro-furan-2-one in 81% (214 mg, 0.694 mmol, dr = 80:20).

1 H-NMR (300 MHz, CDCl 3): δ = 0.08 (s, 9 H, SiMe 3), 1.50 (m, 2 H, CH 2), 1.72 (m, 2 H, CH 2), 2.04 (m, 6 H, 2 CH 2, 3-H, 4-H), 2.57 (m, 2H, 3-H, 2-H), 3.74 (m, 1H, C H OH), 4.42 (dd, J = 5.7, 4.8 Hz, 1 H, 5-H), 4.86 (m, 4 H, = CH 2), 5.58 (m, 1 H, C H = CH 2); 13 C-NMR (75.4 MHz, CDCl 3): δ = 0.57 (3 C, Si (CH 3) 3), 24.43 (CH 2, minor: 24.50), 27.23 (CH 2, 6a-minor: 26.68), 28.82 (CH 2, minor: 32.64), 34.03 (CH2, minor: 34.19), 41.00 (CH2, minor: 39.89), 43.08 (CH, minor: 42.35), 47.00 (CH, minor: 47.82), 71.15 (CH, minor: 74.47), 83.87 ( CH, minor: 83.92), 107.45 (= CH2, minor: 107.06), 118.30 (= CH2, minor: 118.35), 133.85 (= CH, minor: 133.61), 152.07 (Cquat, minor: 152.39), 177.03 (Cquat, minor: 176.66).

Example 9

(3a S , 4 R , 9a R , 9b S ) -4-hydroxy-3a, 4,5,7,8,9,9a, 9b-octahydro-3H-azuleno [4,5-b] furan Synthesis of 2-one

To 113 mL of dichloromethane purified under a nitrogen stream (1 R / S, 1 R, 4 S , 5 R ) -5- (2-methylenecyclopentyl) -4- (1-trimethylsilanyloxy-but-3 (4,5-DihydroIMES) (PCy ₃ ) Cl ₂ Ru = CHPh (40.5 mg, 0.0475 mmol, 5 mol%) in a solution of -enyl) -dihydrofuran-2-one (295 mg, 0.954 mmol) Added. The solution was refluxed for 28 hours and then the reaction was terminated by adding concentrated aqueous hydrochloric acid solution (52.2 mg, 1.5 equiv.). The solution was further refluxed for 1 hour, allowed to stand at room temperature, and then 2.5 ml of saturated aqueous sodium bicarbonate solution was added thereto. After 5 minutes, the filtered filtrate was concentrated to dryness with sodium sulfate. Colorless solid product (3a S , 4 R , 9a R , 9b S ) -4-hydroxy-3a, 4,5,7,8,9, using silica gel chromatography with petroleum ether / ethyl acetate developing solvent 9a, 9b-octahydro-3H-azuleno [4,5-b] furan-2-one (68 mg, 0.327 mmol, 34%, dr = 53: 47) was obtained. The main structural isomer ( 4R ) was separated into crystals with dichloromethane / n -hexane.

Starting mirror (1 S / R, 1 S, 4 R , 5 S ) -5- (2-methylenecyclopentyl) -4- (1-trimethylsilanyloxy-but-3-enyl) -dihydrofuran 2-one (190 mg, 0.622 mmol) and (4,5-DihydroIMES) Cl2Ru = CH- O- OiPrC6H4 (39 mg, 0.062 mmol, 10 mol%) were dissolved in purified 80 ml of dichloromethane for 6 days. Reactions with enantiomeric derivatives (3a R , 4 S , 9a S , 9b R ) -4-hydroxy-3a, 4,5,7,8,9,9a, 9b-octahydro-3H-azuleno [4, 5-b] furan-2-one was obtained in 28% (37 mg, 0.178 mmol, dr = 80:20) yield. The main structural isomer (4S) was dissolved in a minimum amount of dichloromethane, n -hexane was added until the solution became cloudy, and then shaken until it became clear. When the container was left open, the main structural isomer slowly crystallized, and then the crystal and the liquid phase were separated.

mp = 133-135 ° C .; = 70.4 (c = 0.625, CH 2 Cl 2); 1 H-NMR (600 MHz, CDCl 3): δ = 1.47 (m, 1 H, 8-H), 1.63-1.68 (m, 1 H, 9-H), 1.69 (m, 1 H, 8-H), 2.12-2.19 (m, 1H, 9-H), 2.20 (m, 2H, 5-H, 7-H), 2.33 (m, 2H, 3a-H, 7-H), 2.42 (ddd, J = 14.5, 9.3, 3.3 Hz, 1 H, 5-H), 2.51 (dd, J = 17.0, 12.8 Hz, 1 H, 3-H), 2.61 (m, 1 H, 9a-H), 2.80 ( dd, J = 17.0, 7.3 Hz, 1 H, 3-H), 3.54 (ddd, J = 10.2, 10.1, 3.1 Hz, 1 H, 4-H), 3.74 (dd, J = 10.1, 10.1 Hz, 1 H, 9b-H), 5.58-5.66 (m, 1H, 6-H); 13 C-NMR (150.9 MHz, CDCl 3): δ = 25.02, 32.33, 35.54, 38.07, 47.10, 54.23, 70.66, 84.21, 116.42, 146.70, 175.78; IR (KBr, cm- ¹ ): = 3425, 2958, 1757, 1438, 1227, 1192, 981, 953; MS (EI, 70 eV): m / z (%) = 208.1 (69.3) [M +], 190.1 (50.3) [M-H 2 O], 131.1 (43.7) [M- (H 2 O + CH 2 CO 2 H)], 113.0 (36.6) , 95.0 (100), 79.1 (60.5), 57.1 (46.3); MS (HR-EI, 70 eV): 208.1099 (C12H16O3: calc. 208.1099).

Example 10

(1 R / S, 2 R , 4 S, 5 R) -4- (1- hydroxy-3-methyl-3-boot-enyl) -5- (2-methylene-cyclopentyl) - dihydro-furan-2 Synthesis of On

In dichloromethane of 30 ㎖ purified in a nitrogen stream (1 R / S, 2 R / S, 3 S) -2- (2- methylene-cyclopentyl) -5-oxo-tetrahydro-furan-3-carbonyl aldehyde (620 mg, 3.192 mmol), and trimethyl- (2-methylallyl) -silane (820 mg, 6.384 mmol, 2.0 equiv.) was added at 50 ° C., and after 1.5 hours, borontrifluorate diethyl ether (421 μl, 3.352 mmol) was added. , 1.05 equiv.) Was then added. The reaction mixture was refluxed at 50 ° C. for 16 hours and then terminated with 1 ml of saturated aqueous sodium bicarbonate solution. The reaction product was cooled to 0 ° C., dried over magnesium sulfate, the filtered filtrate was concentrated, and petroleum ether / ethyl acetate = 4: 1 was developed as a colorless oil product through silica gel chromatography (1 R / S, 2 R). , 4 S , 5 R ) -4- (1-hydroxy-3-methylbut-3-enyl) -5- (2-methylenecyclopentyl) -dihydrofuran-2-one (491 mg, 1.961 mmol, 61%, dr = 71:29).

Mirror-like starting with impurities (1 S / R , 2 S / R , 3 R ) -2- (2-methylenecyclopentyl) -5-oxo-tetrahydrofuran-3-carboaldehyde (900 mg, 4.63 mmol ) And a mirror derivative (1 S / R, 2 S, 4 R , 5 S ) -4- (1-hydroxy) from trimethyl- (2-methylallyl) -silane (1.19 g, 9.27 mmol, 2.0 equiv.) 3-Methyl-but-3-enyl) -5- (2-methylenecyclo-pentyl) -dihydro-furan-2-one was obtained in 51% (592 mg, 2.37 mmol, dr = 70:30) yield .

1 H-NMR (300 MHz, CDCl 3): δ = 1.54 (m, 2 H, CH 2), 1.72 (m, 2 H, CH 2), 1.76 (s, 3 H, CH 3), 1.93 (m, 3 H, CH 2 , 4-H), 2.31 (m, 2H, CH 2), 2.51 (dd, J = 17.5, 9.4 Hz, 1 H, 3-H), 2.72 (dd, J = 17.5, 7.0 Hz, 1 H, 3 -H), 2.65 (m, 1H, CH), 3.78 (m, 1H, CH), 4.64 (dd, J = 6.0, 4.7 Hz, 1H, 5-H), 4.79 (m, 4H, = CH2); 13C-NMR (75.4 MHz, CDCl 3): δ = 22.21 (CH3, minor: 22.92), 24.29 (CH2, minor: 24.43), 27.11 (CH2, minor: 26.63), 28.88 (CH2, minor: 32.37), 33.90 ( CH2, minor: 34.09), 43.43 (CH, minor: 43.28), 44.29 (CH2, minor: 43.96), 47.05 (CH, minor: 47.67), 67.29 (CH, minor: 70.40), 83.78 (CH, minor: 84.23 ), 107.39 (CH2, minor: 107.00), 114.40 (CH2, minor: 114.65), 141.46 (Cquat, minor: 141.39), 151.94 (Cquat, minor: 152.33), 177.00 (Cquat, minor: 176.69); IR (film, cm- ¹ ): = 3437, 2938, 1765, 1198, 887; MS (CI, NH 3): m / z (%) = 268.2 (100.0) [M + NH 4+].

Example 11

(1 R / S, 2 R , 4 S, 5 R) -5- (2- methylene-cyclopentyl) -4- (3-methyl-1-trimethylsilyl oxy-carbonyl-3-boot ennil) - dihydro-furan Synthesis of 2-one

In dichloromethane of 10 ㎖ purified in a nitrogen stream (1 R / S, 2 R , 4 S, 5 R) -4- (1- hydroxy-3-methyl-3-boot-enyl) -5- (2- Triethylamine (700 μl, 4.993 mmol, 2.0 equiv.) And trimethylsilyl chloride (400 μl, 3.121 mmol, 1.25) in a solution of methylenecyclopentyl) -dihydrofuran-2-one (625 mg, 2.497 mmol) equiv.) were each added at 0 ° C. The reaction mixture was stirred at room temperature for 3 hours and then quenched with 10 ml of saturated aqueous sodium bicarbonate solution. The separated aqueous layer was extracted with dichloromethane (3 × 25 mL), the combined organic layers were dried over sodium sulfate, the filtered filtrate was concentrated under reduced pressure, and petroleum ether / ethyl acetate = 2: 1 was purified by silica gel chromatography using a developing solvent. (1 R / S, 2 R, 4 S , 5 R ) -5- (2-methylenecyclopentyl) -4- (3-methyl-1-trimethylsilanyloxy-but-3-enyl) as colorless oil -Dihydrofuran-2-one (750 mg, 2.526 mmol, 93%, dr = 70:30) was obtained.

Start of enantiomer (1 S / R, 2 S, 4 R , 5 S ) -4- (1-hydroxy-3-methylbut-3-enyl) -5- (2-methylenecyclopentyl) -dihydro Mirror-like derivatives (1 S / R, 2 S, 4 R ) from furan-2-one (500 mg, 1.997 mmol), triethylamine (550 μl, 3.994 mmol) and trimethylsilyl chloride (317 μl, 2.496 mmol) , 5 S ) -5- (2-methylene-cyclopentyl) -4- (3-methyl-1-trimethylsilanyloxy-but-3-enyl) -dihydro-furan-2-one 84% (542 mg, 1.68 mmol, dr = 70: 30).

1 H-NMR (300 MHz, CDCl 3): δ = 0.13 (s, 9 H, SiMe 3), 1.51 (m, 2 H, CH 2), 1.71 (s, 3 H, CH 3), 1.76 (m, 2 H, CH 2 ), 2.13 (m, 6 H, 2 CH 2, 4-H, 3-H), 2.59 (m, 1 H, C 1 -H), 2.71 (dd, J = 20.7, 11.1 Hz, 1 H, 3-H ), 3.90 (ddd, J = 8.8, 5.5, 1.6 Hz, 1 H, C H OTMS), 4.42 (dd, J = 5.5, 5.4 Hz, 1 H, 5-H), 4.69 (m, 1 H, = CH2), 4.76-4.86 (m, 1H, = CH2), 4.86 (m, 1H, = CH2), 4.99 (m, 1H, = CH2); 13 C-NMR (75.4 MHz, CDCl 3): δ = 0.54 (3 C, (CH 3) 3, minor: 0.56), 22.77 (CH 3, minor: 23.31), 24.42 (CH 2, minor: 24.50), 27.28 (CH 2, minor : 26.75), 28.45 (CH2, minor: 32.95), 34.00 (CH2, minor: 34.17), 42.66 (CH, minor: 42.57), 45.04 (CH2, minor: 43.92), 47.02 (CH, minor: 48.04), 69.59 (CH, minor: 73.24), 83.89 (CH, minor: 83.38), 107.46 (CH2, minor: 107.17), 114.08 (CH2, minor: 114.30), 141.44 (Cquat, minor: 141.51), 152.08 (Cquat, minor: 152.28), 177.09 (Cquat, minor: 176.84).

Example 12

(3a S , 4 R / S , 9a R , 9b S ) -4-hydroxy-6-methyl-3a, 4,5,7,8,9,9a, 9b-octahydro-3H-azuleno [4 , 5-b] Synthesis of furan-2-one

13 ml of toluene purified under argon stream ( 1R / S, 2R, 4S , 5R ) -5- (2-methylenecyclopentyl) -4- (3-methyl-1-trimethylsilanyloxy- (4,5-DihydroIMES) Cl ₂ Ru = CH- o -OiPrC ₆ H ₄ (19.3 mg, 0.031 mmol) in a solution of but-3-enyl) -dihydrofuran-2-one (295 mg, 0.954 mmol) , 5 mol%) was added. The solution was refluxed at 80 ° C. for 24 hours before further 5 mol% Grubbs catalyst was added. The solution refluxed for 5 more days was concentrated to remove toluene, and the remaining reaction was dissolved in 20 ml of chloroform, and then concentrated aqueous hydrochloric acid solution (140 mg, 2.3 equiv.) Was added and stirred at room temperature for 1 hour.

3 ml of saturated aqueous sodium bicarbonate solution was added, and after 5 minutes, dried over magnesium sulfate, and the filtered filtrate was concentrated under reduced pressure. Colorless solid product (3a S , 4 R / S , 9a R , 9b S ) -4-hydroxy-6-methyl-3a, 4,5, by silica gel chromatography with petroleum ether / ethyl acetate developing solvent 7,8,9,9a, 9b-octahydro-3H-azuleno [4,5-b] furan-2-one (66 mg, 0.297 mmol, 48%, dr = 71:29) was obtained.

Starting point of the mirror image (1 S / R, 2 S, 4 R , 5 S ) -5- (2-methylenecyclopentyl) -4- (3-methyl-1-trimethylsilanyloxy-but-3-enyl) -Dihydrofuran-2-one (490 mg, 1.519 mmol) and Grubbs catalyst (94 mg, 0.152 mmol, 10 mol%) were dissolved in purified 40 ml of toluene and reacted for 6 days to obtain a mirror derivative (3a R , 4 S / R , 9a S , 9b R ) -4-hydroxy-6-methyl-3a, 4,5,7,8,9,9a, 9b-octahydro-3H-azuleno [4,5- b] furan-2-one was obtained in 17% (57 mg, 0.256 mmol, dr = 62:38) yield.

1 H-NMR (300 MHz, CDCl 3): δ = 1.41 (m, 4 H, 2 CH 2), 1.75 (s, 3 H, CH 3), 2.07 (m, 5 H, 2 CH 2, CH), 2.47 (dd, J = 16.5, 12.9 Hz, 1 H, 3-H), 2.59 (m, 1 H), 2.79 (dd, J = 16.5, 6.6 Hz, 1 H, 3-H), 3.54 (ddd, J = 10.1, 10.1, 2.5 Hz, 1 H, 4-H), 3.75 (dd, J = 10.2, 10.2 Hz, 1 H, 9b-H); 13C-NMR (75.4 MHz, CDCl 3): δ = 24.12 (CH3, minor: 25.46), 24.83 (CH2, minor: 25.04), 32.06 (CH2, minor: 29.65), 32.95 (CH2, minor: 33.05), 35.56 ( CH2, minor: 33.47), 45.56 (CH2, minor: 42.05), 46.79 (CH, minor: 48.02), 54.67 (CH, minor: 52.11), 69.78 (CH, minor: 65.44), 84.06 (CH, minor: 81.09 ), 124.11 (Cquat, C-6, minor: 123.49), 139.05 (Cquat, C-6a, minor: 139.91), 175.73 (Cquat, C-2, minor: 175.90); MS (CI, NH 3): m / z (%) = 240.2 (100.0) [M + NH 4+], 222.9 (30.7) [MH +], 205.0 (15.4); MS (HR-EI, 70 eV): 222.1255 (C12H16O3: calc. 222.1256).

Example 13

(3a S , 4 R / S , 6 R / S , 6a R / S , 9a S , 9b R ) -6,6a-epoxy-4-hydroxydecahydro-azuleno [4,5-b] furan- 2-one synthesis

To 1 ml of dichloromethane purified under nitrogen stream (3a S , 4 R , 9a R , 9b S ) -4-hydroxy-3a, 4,5,7,8,9,9a, 9b-octahydro-3H TBuOOH (72.3 μl, 0.36 mmol, 1.5 equiv.) And VO (acac) ₂ (6.4 mg, 0.024 mmol) in a solution of azuleno [4,5-b] furan-2-one (50 mg, 0.24 mmol) , 0.1 equiv.), Respectively. The reaction mixture was stirred at 0 ° C. for 4.5 days. The completed reaction mixture was concentrated under reduced pressure in vacuo and a derivative (8 mg, 0.036 mmol, 15%) was obtained as a structural isomer mixture through silica gel chromatography using petroleum ether / ethyl acetate as a developing solvent. (Main structural isomer: dr = 70: 30).

1 H-NMR (300 MHz, CDCl 3): δ = 1.42 (m, 4 H), 1.76-1.93 (m, 2 H), 1.97 (m, 3 H), 2.15-2.53 (m, 2 H), 2.43 ( dd, J = 16.9, 7.0 Hz, 1 H, 3-H), 2.65 (m, 1 H), 2.82 (dd, J = 16.9, 13.3 Hz, 1 H, 3-H), 3.88 (m, 1 H ); 13 C-NMR (75.4 MHz, CDCl 3): δ = 22.47, 30.60, 32.36, 33.38, 33.95, 46.56, 50.00, 65.73, 71.27, 79.85, 175.92; MS (PI-EI, 70 eV): m / z (%) = 224.2 (1.0) [M < + >], 206.1 (4.0) [MH 2 O], 150.1 (75.1), 95.1 (100.0), 55.1 (80.9).

Reference example: ras farnesyl transferase inhibitory efficacy test

Substrate pentapeptide N-dansyl-GCVLS and expected product

N-dansil-G [S-farnesyl-C] VLS was synthesized by solid phase synthesis using an ABI peptide synthesizer and analyzed for the structure of purified peptide derivatives by instrumental analysis. Incubating N-dansil-GCVLS with recombinant human farnesyl transferase results in the farnesyl pyrophosphonate results over time increased by fluorescence appearing at 505 nm when excited at 340 nm. The covalent bond of farnesyl end groups to the cystine thiol group of N-dansil-GCVLS changes the nonpolar and hydrophobic environment around the end of the single thread, resulting in a dramatic change in fluorescence properties. The spectrum after complete conversion to the fluorescence emission spectrum and the product before the enzyme injection is 13 times higher in fluorescence intensity at 505 nm with a decrease in maximum wavelength from 565 nm to 515 nm. Using N-single-GCVLS, farnesyl transferase is according to Michaels-Menten equation, and the time-related change in fluorescence is linearly proportional to enzyme concentration. From this is obtained a value that indicates a 50% efficacy was determined IC ₅₀ value.

Example 14

Farnesyl Transferase Inhibitory Effect of the Compound of the Present Invention

The farnesyl transferase inhibitory effect of the compound of the present invention was tested according to the method described in the reference example and the results are shown in Table 1.

Table 1

The novel hydrocarbon ring lactone derivative compounds of the formulas (I), (II) and (III) of the present invention can be used as farnesyl transferase inhibitors, and include the compound or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition exhibits excellent effects as a disease mediated by farnesylation of ras, in particular as an anticancer agent, an antiproliferative agent, an anti-inflammatory agent, an immunosuppressive agent, an autoimmune disease treatment agent, and a muscle relaxant.

Claims (10)

Hydrocarbon ring lactone derivatives represented by formula (I) or salts thereof: In the above formula, R ¹ is hydrogen, alkyl or aryl group; A is CH ₂ , CH (alkyl), C (alkyl) ₂ , CH (aryl), C (aryl) ₂ , C = CH ₂ , C = CH (alkyl), C = C (alkyl) ₂ , C = CH (Aryl), or C═C (aryl) ₂ ; B bonds with hydrogen, hydroxide, alkoxy or halogen or forms a double bond with C or F or an epoxy, imineoxy, thioxy bond; C combines with hydrogen, hydroxide, alkoxy or halogen or forms a double bond with B or an epoxy, imineoxy or thioxy bond; D is bonded to hydrogen, hydroxide, alkoxy, alkyl (but not methyl), aryl or halogen or to a double bond with E or an epoxy, imineoxy, or thioxy bond; E bonds with hydrogen, hydroxide, alkoxy or halogen or forms a double bond with D or F or an epoxy, imineoxy or thioxy bond; F bonds with hydrogen, hydroxide, alkoxy or halogen or forms a double bond with B or E or an epoxy, imineoxy or thioxy bond; X selects one of hydrogen, hydroxide, alkoxy, silyloxy, amine, sulfur compound or halogen, n is one of the integers of 1-3. Hydrocarbon ring lactone derivatives represented by formula (II) or salts thereof: Wherein R ¹ , A, B, C, D, E, F, and n are as defined in claim 1 and X is oxygen. Hydrocarbon ring lactone derivatives represented by formula (III) or salts thereof: Wherein R ¹ , A, C, D, E, F, X and n are as defined in claim 1, and B is bonded to hydrogen, hydroxide, alkoxy or halogen or a double bond with C, F or G Or an epoxy, imineoxy, thioxy bond, G is a double bond with hydrogen, hydroxide, alkoxy, halogen, alkyl, aryl, B, or an epoxy, imineoxy, or thioxy bond, and R ² is Hydrogen, alkyl or aryl groups. A composition having a farnesyl transferase inhibitory activity comprising the hydrocarbon ring lactone derivative according to any one of claims 1 to 3 or a salt thereof. A pharmaceutical composition having a therapeutic or prophylactic effect of a disease mediated by farnesylation of ras comprising the hydrocarbon ring lactone derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient. According to claim 5, wherein the therapeutic or prophylactic effect of the disease is characterized in that the anti-cancer, anti-proliferative, anti-inflammatory, immunosuppressive, autoimmune disease or muscle relaxation effect. The method for preparing a hydrocarbon ring lactone derivative of formula (I) according to claim 1, wherein the method is a) reacting a furan of formula (IV) with a diazo compound of formula (V) to stereoselectively produce a cyclopropaneated furan of formula (VI); b) ozonation of the compound of formula (VI) to produce a tricyclic cyclic compound of formula (VII); c) reacting a compound of formula (VII) with allylsilane of formula (VIII) to produce a lactone compound of formula (IX); d) reacting a lactone compound of formula (IX) with allylsilane of formula (X) to yield formula (XI); And e) A process consisting of carbonyl-ene-reacting the obtained compound of formula (IX) under an inorganic acid catalyst to produce a compound of formula (I). In the above formulas (IV) to (IX), R ¹ , A, B, C, D, E, F and n are as defined in claim 1, P and Q are hydrogen, alkyl, aryl, and In formulas (X) and (XI), R ¹ , A, B, C, D, E, F, G, X and n are as defined in claim 3. A process for preparing a hydrocarbon ring lactone derivative of formula (II) according to claim 2, wherein the method consists of reacting a compound of formula (I) according to claim 1 with an organic acid. A process for the preparation of a hydrocarbon ring lactone derivative of formula (III) according to claim 3, wherein the process comprises metathesis reaction of a compound of formula (XI) produced by steps a) to d) of claim 7 Stereo-selectively producing a hydrocarbon ring lactone derivative of a). Intermediate Compounds of Formula (IX) or Formula (XI): , In formula (IX), R ¹ , A, B, C, D, E, F and n are as defined in claim ¹ and in formula (XI) R ¹ , R ² , A, B, C , D, E, F, G, X and n are as defined in claim 3.