KR20020019136A - Diterpene derivatives and anti-inflammatory analgesic agents comprising the same - Google Patents

Abstract

PURPOSE: Provided are diterpene derivatives which are synthesized from the material extracted from Acanthopanax Koreanum, and antiphlogistics containing the derivatives. CONSTITUTION: The diterpene derivatives are represented by the formula 1, wherein R1 is a vinyl group or phenylethyl group; and R2 is carboxyl group, carboxy homoallyl group, carboxy pentadienyl group, carboxy hexyl group, carboxy hexatrienyl group, carboxy heptadienyl group, carboxy methyl butadienyl group, carboxy dimethyl pentadienyl group, carboxy methyl pentadienyl group, carboxy methyl pentenyl group, carboxy methyl pentyl group, carbamoyl pentadienyl group, (N-methoxy)carbamoyl pentadienyl group, (N-pipsyl)carbamoyl pentadienyl group, (N-methanesulfonyl)carbamoyl pentadienyl group, or (N-chloropyridine)carbamoyl pentadienyl group.

Description

Diterpene derivatives and anti-inflammatory analgesic agents comprising the same

The present invention relates to a diterpene derivative and an anti-inflammatory analgesic agent comprising the same, and more particularly, to a diterpene derivative of the following Chemical Formula 1 prepared from a component extracted from Acanthopanax Koreanum and an anti-inflammatory analgesic agent comprising the same.

One

(Wherein R ₁ represents vinyl or phenylethyl group, R ₂ represents carboxyl, carboxy homoallyl, carboxypentadienyl, carboxyhexyl, carboxyhexatriene, carboxyheptadienyl, carboxymethylbutadienyl, carboxydimethylpenta Dienyl, carboxymethylpentadienyl, carboxymethylpentenyl, carboxymethylpentyl, carbamoylpentadienyl, (N-methoxy) carbamoylpentadienyl, (N-propyl) carbamoylpentadienyl, (N- Methanesulfonyl) carbamoylpentadienyl, (N-chloropyridine) carbamoylpentadienyl.)

Island Ogalpi Tree is a natural product native to Jeju Island in Korea, and is a deciduous shrub belonging to the elm family. The bark and the bark of this tree have long been proven to be effective in the treatment of musculoskeletal pain, etc. in oriental medicine.

Recently, the inventors of the present invention have described (-)-pimara-9 (11), 15-diene-4-carboxylic acid [(-)-pimara-9 (11), 15-diene-4-carboxylic acid] and its novel derivatives have excellent anti-inflammatory effects by inhibiting the conversion of arachidonic acid to PGE ₂ , an inflammatory agent in vivo. Has been found and applied for a patent (Patent Registration No. 112194, Patent Publication No. 1999-072290, PCT / KR99 / 00038)

The inventors continued the study to find compounds with better anti-inflammatory action and reduced side effects. Specifically, cyclooxygenase-2 (COX-2) is selectively induced in an in vitro test, and then cyclooxygenase-2 is examined to examine the deactivation of cyclooxygenase-2. The aim was to develop novel derivatives that reduce the inhibitory activity of 1 and selectively inhibit cyclooxygenase-2 alone (Nature, 1994, 367, 215). Therefore, in the first step, derivatives patented in 2441 in 1998 and 37600 in 1999 were further reviewed for the inhibitory activity, anti-inflammatory analgesic effect and cytotoxicity of cyclooxygenase-2. The present invention was completed by further developing a substance having an excellent inhibitory effect on PGE ₂ production.

The present invention relates to a diterpene derivative represented by the following Chemical Formula 1, and a pharmaceutically acceptable salt thereof and an anti-inflammatory analgesic agent comprising the same.

One

(Wherein R ₁ represents vinyl or phenylethyl group, R ₂ represents carboxyl, carboxy homoallyl, carboxypentadienyl, carboxyhexyl, carboxyhexatriene, carboxyheptadienyl, carboxymethylbutadienyl, carboxydimethylpenta Dienyl, carboxymethylpentadienyl, carboxymethylpentenyl, carboxymethylpentyl, carbamoylpentadienyl, (N-methoxy) carbamoylpentadienyl, (N-propyl) carbamoylpentadienyl, (N- Methanesulfonyl) carbamoylpentadienyl, (N-chloropyridine) carbamoylpentadienyl.)

The obtained Formula 1 is reacted as in Schemes 1 to 9 to form various derivatives.

As shown in Scheme 1, the conjugated ester of Formula 2 (compound of Formula 20 of Patent Publication No. 1999-072290) is reduced in methanol to magnesium in double bond, and the ester is reduced to diisobutylaluminum hydride and then tetrapropyl Oxidation with ammonium ferruthenate yields Formula 5 (R ₂ = CH ₂ CH ₂ CH ₂ CHO).

The aldehyde group of the obtained compound of formula 5 was subjected to Wittig reaction in tetrahydrofuran with triethylphosphonoacetate anion to obtain a double bond, and then the conjugated ester was directly hydrolyzed with potassium hydroxide or magnesium in methanol. The double bond is reduced and then hydrolyzed to obtain a compound of Formula 9 (R ₂ = CH ₂ CH ₂ CH ₂ CHCHCOOH) or a compound of Formula 7 (R ₂ = CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ COOH).

In addition, the above formula (2) is reduced to diisobutylaluminum hydride and then oxidized with tetrapropylammonium ferruthenate to obtain formula (11) (R ₂ = CH ₂ CHCHCHO), and in tetrahydrofuran as a triethylphosphonoacetate anion. After a (Wittig) reaction to obtain a double bond, the conjugated ester is directly hydrolyzed with potassium hydroxide to obtain a compound of formula 13 (R ₂ = CH ₂ CHCHCHCHCOOH).

As shown in Scheme 2, the conjugated ester of Formula 14 (compound of Formula 30 of Patent Publication No. 1999-072290) is reduced to diisobutylaluminum hydride, and then oxidized to tetrapropylammonium ferruthenate to formula (R _2). = CH ₂ CH ₂ CH ₂ CH ₂ CHO)

Get

The aldehyde group of the obtained compound of Formula 16 was subjected to Wittig reaction in tetrahydrofuran with triethylphosphonoacetate anion to obtain a double bond, followed by reduction of the double bond with magnesium in methanol and hydrolysis. (R ₂ = CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ COOH).

As shown in Scheme 3, an aldehyde group represented by Chemical Formula 20 (Formula 24 of Patent Publication No. 1999-072290) was subjected to a Wittig reaction in tetrahydrofuran with triethylphosphonoacetate anion to obtain a double bond, and then to isobutyl Reduction with aluminum hydride followed by oxidation with tetrapropylammonium ferrunate yields Formula 23 (R ₂ = CHCHCHCHCHO).

The aldehyde group of the obtained compound of Formula 23 is subjected to Wittig reaction in tetrahydrofuran with triethylphosphonoacetate anion to obtain a double bond, followed by hydrolysis to obtain a compound of formula 25 (R ₂ = CHCHCHCHCHCHCOOH).

In addition, the aldehyde group of the compound of Formula 20 is subjected to Wittig reaction in tetrahydrofuran with a carboxybutyltriphenylphosphonoacetate anion to obtain a compound of Formula 26 (R ₂ = CHCHCHCHCH ₂ CH ₂ CH ₂ COOH).

As shown in Scheme 4, the aldehyde group of the compound of formula 20 is subjected to Wittig reaction in toluene with triethylphosphonopropionate anion to obtain a double bond, and then hydrolyzed to obtain a compound of formula 28 (R ₂ = CHCHCHC ( CH ₃ ) COOH).

As shown in Scheme 5, the aldehyde group of the compound of Chemical Formula 29 (Formula 19 of Patent Publication No. 1999-072290) was subjected to a Wittig reaction in toluene with triethylphosphonopropionate anion to obtain a double bond, Reduction with isobutylaluminum hydride followed by oxidation with tetrapropylammoniumferrunate yields Formula 32. (R ₂ = CH ₂ CHC (CH ₃ ) CHO).

The aldehyde group of the obtained compound of formula 32 was subjected to Wittig reaction in toluene with triethylphosphonopropionate anion and then hydrolyzed to obtain a compound of formula 34 (R ₂ = CH ₂ CHC (CH ₃ ) CHC (CH ₃ ) COOH) Get

As shown in Scheme 6, after the aldehyde group of the compound of formula 11 is Wittig reacted in toluene with triethylphosphonopropionate anion, the conjugated ester is directly hydrolyzed with potassium hydroxide or magnesium in methanol The double bond is reduced and then hydrolyzed to obtain a compound of Formula 36 (R ₂ = CH ₂ CHCHCHC (CH ₃ ) COOH) or a compound of Formula 38.

As shown in Scheme 7, the aldehyde group of the compound of formula 5 is reacted with Wittig in toluene with triethylphosphonopropionate anion, and then the double bond is reduced with magnesium in methanol to hydrolyze the compound of formula 41 (R ₂ = CH ₂ CH ₂ CH ₂ CH ₂ CH (CH ₃ ) COOH) is obtained.

As shown in Scheme 8, the aldehyde group of the compound of formula 42 (compound of formula 45 of JP-A-1999-072290) was reacted with phenylmagnesium bromide in tetrahydrfuran, and 10% palladium / activated carbon was treated in hydrogen gas. Obtaining a compound of formula 44 (R ₁ = CH ₂ CH ₂ Ph) and deprotection with tetrabutylammonium fluoride in dimethylsulfoxide gave compound of formula 45 (R ₁ = CH ₂ CH ₂ Ph, R ₂ = CO ₂ H Get)

As shown in Scheme 9, the carboxyl group of the compound of Formula 13 was directly reacted with oxalyl chloride in benzene to obtain a compound of Formula 46 (R ₂ = CH ₂ CHCHCHCHCOCOOH), and reacted with ammonia water in ethyl acetate or in benzene. Treatment with an aqueous oxytamine solution yields a compound of formula 47 (R ₂ = CH ₂ CHCHCHCHCONH ₂ ) or a compound of formula 48 (R ₂ = CH ₂ CHCHCHCHCONHOCH ₃ ).

The compound of formula 49 (R ₂ = CH ₂ CHCHCHCHCONHSO ₂ PhI) and the compound of formula 50 (R) ₂ = CH ₂ CHCHCHCH-CONHSO ₂ CH ₃ ) and the compound of formula 51 are obtained.

The dosage of the compound of Formula 1 is an anti-inflammatory analgesic agent of 0.01 to 1000 mg per day for adults, and the dosage may be changed depending on the age and weight of the patient as well as the degree of symptoms.

Anti-inflammatory analgesic of the present invention can be prepared in a form suitable for oral or parenteral administration in accordance with conventional preparation methods. That is, in the case of oral administration, it may be prepared in the form of tablets, capsules, solutions, syrups, suspensions, etc., and in the case of parenteral administration, it may be prepared in the form of injections for intraperitoneal, subcutaneous, muscle, and transdermal.

The present invention will be described in more detail with reference to the following Examples, but the present invention is not limited thereto.

Example 1: Preparation of 4-hydroxybutyl-(-)-pimara-9 (11), 15-diene

22 mg of 4-carbomethoxypropyl-(-)-pimara-9 (11), 15-diene was dissolved in 2 ml of dichloromethane, and 0.15 ml of 1 molar solution of diisobutyl aluminum hydride was added at -78 ° C, followed by stirring for 30 minutes. It was. After completion of the reaction with a few drops of methanol, 20 ml of dichloromethane and 20 ml of saturated solution of potassium sodium tartrate tetrahydrate were added thereto, and the mixture was stirred vigorously at room temperature for 2 hours. The organic solvent layer was washed with water and saturated aqueous sodium chloride solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure to obtain 13 mg (66%) of 4-hydroxybutyl-(-)-pimara-9 (11) and 15-diene.

1 H-NMR (300 MHz, CDCl ₃ ): 5.75 (dd, 1H, J = 17.4, 10.7 Hz), 5.27 (m, 1H), 4.89 (d, 1H, J = 17.5 Hz), 4.80 (d, 1H, J = 10.7 μs), 3.57 (t, 2H, J = 6.6 μs), 0.73-1.97 (m, 22H), 1.02 (s, 3H), 0.90 (s, 3H), 0.77 (s, 3H)

Example 2: Preparation of 4-formylpropyl-(-)-pimara-9 (11), 15-diene

13 mg of 4-hydroxybutyl-(-)-pimara-9 (11), 15-diene prepared by the method of Example 1, catalytic amount of tetrapropylammonium perruthenate, and 7 mg of N-methylmorpholine-N-oxide , The molecular powder was dissolved in 2 ml of dichloromethane and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, diluted with diethyl ether, and filtered through silica gel. The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography with a mixture of ethyl acetate-hexane 1:30 to obtain 4-formylpropyl-(-)-pimara-9 (11), 12 mg (89%) of 15-diene. .

1 H-NMR (300 MHz, CDCl ₃ ): 9.71 (t, 1 H, J = 3.4 Hz), 5.75 (dd, 1H, J = 18.0, 10.7 Hz), 5.27 (m, 1H), 4.86 (dd, 1H, J = 17.7, 1.5 Hz), 4.79 (dd, 1H, J = 10.5, 1.4 Hz), 0.73-2.36 (m, 22H), 1.00 (s, 3H), 0.90 (s, 3H), 0.80 (s, 3H)

Example 3: Preparation of 4-Carbetoxyhomallyl-(-)-pimara-9 (11), 15-diene

0.02 ml of triethylphosphonoacetate and 4 mg of 60% sodium hydride were dissolved in 1 ml of tetrahydrofuran and stirred at room temperature for 1 hour. 12 mg of 4-formylpropyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 2 was dissolved in 1 ml of tetrahydrofuran, and stirred at room temperature for 1 hour. The solution was concentrated to remove tetrahydrofuran, diluted with 20 ml of ethyl acetate, washed with saturated aqueous sodium chloride solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a mixed eluent of ethyl acetate-hexane 1:30, 4-carbetoxy homoallyl-(-)-pimara-9 (11), 15 mg diene 10 mg (71 %) Was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 6.90 (dtd, 1H, J = 2.7, 6.8, 15.6 Hz), 5.75 (m, 2H), 5.27 (m, 1H), 4.86 (dd, 1H, J = 17.4, 1.2 Hz), 4.79 (dd, 1H, J = 10.6, 1.2 Hz), 4.12 (q, 2H, J = 7.1 Hz), 0.70-2.10 (m, 24H), 1.01 (s, 3H), 0.90 (s, 3H), 0.77 (s, 3H)

Example 4: Preparation of 4-carbomethoxypentyl-(-)-pimara-9 (11), 15-diene

10 mg of 4-carbetoxy homoallyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 3 was dissolved in 2 ml of methanol, and 2 mg of magnesium turning was added thereto, followed by stirring at room temperature for 12 hours. 2 mol hydrochloric acid was added to the reaction solution to dissolve the remaining magnesium, concentrated under reduced pressure to remove methanol, extracted with 20 ml of ethyl acetate, and the organic solvent layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a mixed solution of ethyl acetate-hexane 1:30, 4-carbomethoxypentyl-(-)-pimara-9 (11), 15-diene 9.5 mg (97 %) Was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 5.75 (dd, 1H, J = 17.3, 10.8 Hz), 5.26 (m, 1H), 4.89 (dd, 1H, J = 17.5 Hz), 4.82 (dd, 1H, J = 10.7 Hz), 0.73-2.24 (m, 29H), 1.01 (s, 3H), 0.90 (s, 3H), 0.77 (s, 3H)

Example 5: Preparation of 4-carboxypentyl-(-)-pimara-9 (11), 15-diene

4-carbomethoxypentyl-(-)-pimara-9 (11), 15-diene prepared by the method of Example 4 was added with 9.5 mg of 85% potassium hydroxide and ethanol, and refluxed for 2 hours. It was. The reaction solution was diluted with 20 ml of ethyl acetate and the aqueous layer was washed with water and saturated aqueous sodium chloride solution, acidified to pH 4 with 1 molar hydrochloric acid solution, and then filtered by drying with magnesium sulfate. The residue obtained after concentration of the filtrate under reduced pressure was purified by silica gel column chromatography with a 1: 3 mixed eluent of ethyl acetate and nucleic acid, and 4-carboxypentyl-(-)-pimara-9 (11), 15-diene 6.8 mg (77%). )

1 H-NMR (300 MHz, CDCl ₃ ): 5.75 (dd, 1H, J = 17.6, 10.7 Hz), 5.27 (m, 1H), 4.86 (dd, 1H, J = 17.3 Hz), 4.79 (dd, 1H, J = 10.7 Hz), 0.74-2.31 (m, 25H), 1.02 (s, 3H), 0.90 (s, 3H), 0.76 (s, 3H)

Example 6: Preparation of 4-carboxyhomallyl-(-)-pimara-9 (11), 15-diene

5.8 mg of 85% potassium hydroxide and ethanol were added to 23 mg of 4-carbetoxy homoallyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 3, followed by reflux for 2 hours. . The reaction solution was diluted with 20 ml of ethyl acetate and the aqueous layer was washed with water and saturated aqueous sodium chloride solution, acidified to pH 4 with 1 molar hydrochloric acid solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a mixed solution of ethyl acetate-hexane 1: 3, 4-carboxy homoallyl-(-)-pimara-9 (11), and 15-diene 16 mg (77%). Got.

1 H-NMR (300 MHz, CDCl ₃ ): 6.96 (dtd, 1H, J = 2.7, 6.8, 15.6 Hz), 5.75 (m, 2H), 5.27 (m, 1H), 4.86 (dd, 1H, J = 17.4, 1.2 Hz), 4.79 (dd, 1H, J = 10.6, 1.2 Hz), 0.74-3.64 (m, 23H), 1.01 (s, 3H), 0.90 (s, 3H), 0.77 (s, 3H)

Example 7: Preparation of 4-hydroxymethylallyl-(-)-pimara-9 (11), 15-diene

43 mg of 4-carbetoxyallyl-(-)-pimara-9 (11), 15-diene was dissolved in 3 ml of dichloromethane, and 0.05 ml of diisobutyl aluminum hydride 1 mol solution was added at -78 ° C, followed by stirring for 30 minutes. . After completion of the reaction with a few drops of methanol, 20 ml of dichloromethane and 20 ml of saturated solution of potassium sodium tartrate tetrahydrate were added thereto, and the mixture was stirred vigorously at room temperature for 2 hours. The organic solvent layer was washed with water and saturated aqueous sodium chloride solution, and then filtered by drying with magnesium sulfate. Example 8 was carried out with 4-hydroxymethylallyl-(-)-pimara-9 (11), 15-diene obtained by concentrating the filtrate under reduced pressure.

Example 8: Preparation of 4-formylallyl-(-)-pimara-9 (11), 15-diene

4-hydroxymethylallyl-(-)-pimara-9 (11), 37.4 mg of 15-diene, the catalytic amount of tetrapropylammonium perruthenate, N-methylmorpholine-N- prepared according to the method of Example 7 18 mg of oxide and molecular powder were dissolved in 4 ml of dichloromethane and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, diluted with diethyl ether, and filtered through silica gel. The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography with a mixed mixture of ethyl acetate-hexane 1:30 to obtain 4-formylallyl-(-)-pimara-9 (11), 31 mg (84%) of 15-diene. .

1 H-NMR (300 MHz, CDCl ₃ ): 9.44 (d, 1 H, 7.8 Hz), 6.79 (dtd, 1 H, J = 3.5, 7.8, 16.8 Hz), 6.04 (m, 1H), 5.75 (dd, 1H, J) = 17.6, 10.7 Hz), 5.31 (m, 1H), 4.86 (dd, 1H, J = 17.4, 1.2 Hz), 4.79 (dd, 1H, J = 10.6, 1.2 Hz), 0.81-2.57 (m, 17H) , 1.01 (s, 3H), 0.91 (s, 3H), 0.86 (s, 3H)

Example 9: Preparation of 4-Carbetoxypentadienyl-(-)-pimara-9 (11), 15-diene

0.06 ml of triethylphosphonoacetate and 12 mg of 60% sodium hydride were dissolved in 1 ml of tetrahydrofuran and stirred at room temperature for 1 hour. 31 mg of 4-formylallyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 8 was dissolved in 1 ml of tetrahydrofuran, and stirred at room temperature for 1 hour. The solution was concentrated to remove tetrahydrofuran, diluted with 20 ml of ethyl acetate, washed with saturated aqueous sodium chloride solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with a mixed eluent of ethyl acetate-hexane 1:30, 4-carbetoxypentadienyl-(-)-pimara-9 (11), 15 mg of diene 37 mg ( 98%).

1 H-NMR (300 MHz, CDCl ₃ ): 7.19 (m, 1 H), 6.07 (m, 2 H), 5.75 (dd, 1 H, J = 18.0, 10.7 Hz), 5.71 (d, 1H, J = 15.1 Hz), 5.29 (m, 1H), 4.86 (dd, 1H, J = 17.4, 1.2 Hz), 4.79 (dd, 1H, J = 10.6, 1.2 Hz), 4.13 (q, 2H, J = 7.1 Hz) 0.78-2.35 ( m, 17H), 1.22 (t, 3H, J = 7.1 Hz), 1.03 (s, 3H), 0.90 (s, 3H), 0.80 (s, 3H)

Example 10 Preparation of 4-carboxypentadienyl-(-)-pimara-9 (11), 15-diene

37 mg of 4-carbetoxypentadienyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 9 was dissolved in a mixed solution of 1.5 ml of tetrahydrofuran and 1.5 ml of water, followed by lithium hydride. 12 mg of rock seed was added and refluxed for 12 hours. The reaction solution was diluted with 20 ml of ethyl acetate and the aqueous layer was washed with water and saturated aqueous sodium chloride solution, acidified to pH 4 with 1 molar hydrochloric acid solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a mixed mixture of ethyl acetate-hexane 1: 3, 4-carboxypentadienyl-(-)-pimara-9 (11), and 15 mg of diene (29%). )

1 H-NMR (300 MHz, CDCl ₃ ): 7.26 (m, 1 H), 6.11 (m, 2 H), 5.75 (dd, 1 H, J = 17.6, 10.7 Hz), 5.72 (d, 1H, J = 15.1 Hz), 5.30 (m, 1H), 4.86 (dd, 1H, J = 17.5, 1.2 Hz), 4.79 (dd, 1H, J = 10.6, 1.2 Hz), 0.71-2.43 (m, 17H), 1.04 (s, 3H) , 0.90 (s, 3H), 0.81 (s, 3H)

Example 11: Preparation of 4-hydroxypentyl-(-)-pimara-9 (11), 15-diene

45 mg of 4-carbomethoxybutyl-(-)-pimara-9 (11), 15-diene was dissolved in 3 ml of dichloromethane, and 0.05 ml of diisobutyl aluminum hydride 1-mol solution was added at -78 ° C, followed by stirring for 30 minutes. It was. After completion of the reaction with a few drops of methanol, 20 ml of dichloromethane and 20 ml of saturated solution of potassium sodium tartrate tetrahydrate were added thereto, and the mixture was stirred vigorously at room temperature for 2 hours. The organic solvent layer was washed with water and saturated aqueous sodium chloride solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure to give 38 mg (90.3%) of 4-hydroxypentyl-(-)-pimara-9 (11) and 15-diene.

1 H-NMR (300 MHz, CDCl ₃ ): 5.75 (dd, 1H, J = 17.3, 10.7 Hz), 5.27 (m, 1H), 4.86 (dd, 1H, J = 17.4, 1.4 Hz), 4.79 (dd, 1H , J = 10.7, 1.4 Hz), 3.57 (t, 2H, J = 6.6 Hz), 0.69-2.24 (m, 24H), 1.02 (s, 3H), 0.90 (s, 3H), 0.77 (s, 3H)

Example 12 Preparation of 4-formylbutyl-(-)-pimara-9 (11), 15-diene

38 mg of 4-hydroxypentyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 11, catalytic amount of tetrapropylammonium perruthenate, 20 mg of N-methylmorpholine-N-oxide , The molecular powder was dissolved in 4 ml of dichloromethane and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, diluted with diethyl ether, and filtered through silica gel. The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography with a mixed mixture of ethyl acetate-hexane 1:30 to obtain 4-mg of butyl-(-)-pimara-9 (11), 15-diene 34mg (90%). .

1 H-NMR (300 MHz, CDCl ₃ ): 9.70 (t, 1H, 2.0 Hz), 5.75 (dd, 1H, J = 18.0, 10.7 Hz), 5.27 (m, 1H), 4.86 (dd, 1H, J = 17.4 , 1.2 Hz), 4.79 (dd, 1H, J = 10.6, 1.2 Hz), 0.74-2.39 (m, 23H), 1.02 (s, 3H), 0.90 (s, 3H), 0.76 (s, 3H)

Example 13: Preparation of 4-carbetoxyhomallyl-(-)-pimara-9 (11), 15-diene

0.06 ml of triethylphosphonoacetate and 12 mg of 60% sodium hydride were dissolved in 2 ml of tetrahydrofuran and stirred at room temperature for 1 hour. 34 mg of 4-formylbutyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 12 was dissolved in 1 ml of tetrahydrofuran, and stirred at room temperature for 1 hour. The solution was concentrated to remove tetrahydrofuran, diluted with 20 ml of ethyl acetate, washed with saturated aqueous sodium chloride solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a mixed eluent of ethyl acetate-hexane 1:30, 4-carbetoxy homoallyl-(-)-pimara-9 (11), 15-diene 30 mg (73 %) Was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 6.90 (dtd, 1H, J = 2.7, 6.8, 15.6 Hz), 5.75 (m, 2H), 5.27 (m, 1H), 4.86 (dd, 1H, J = 17.4, 1.2 Hz), 4.79 (dd, 1H, J = 10.6, 1.2 Hz), 4.12 (q, 2H, J = 7.1 Hz), 1.22 (t. 3H, J = 7.3 Hz), 0.75-2.15 (m, 23H) , 1.01 (s, 3H), 0.90 (s, 3H), 0.76 (s, 3H)

Example 14 Preparation of 4-carbomethoxyhexyl-(-)-pimara-9 (11), 15-diene

25 mg of 4-carbetoxy homoallyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 13 was dissolved in 2 ml of methanol, and 3 mg of magnesium turning was added thereto, followed by stirring at room temperature for 12 hours. 2 mol hydrochloric acid was added to the reaction solution to dissolve the remaining magnesium, concentrated under reduced pressure to remove methanol, extracted with 20 ml of ethyl acetate, and the organic solvent layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The residue obtained after the filtrate was concentrated under reduced pressure was purified by silica gel column chromatography with a mixed solution of ethyl acetate-hexane 1:30 to give 4-carbomethoxyhexyl-(-)-pimara-9 (11), 20 mg (82%). )

1 H-NMR (300 MHz, CDCl ₃ ): 5.75 (dd, 1H, J = 18.0, 10.8 Hz), 5.27 (m, 1H), 4.86 (dd, 1H, J = 17.4, 1.2 Hz), 4.79 (dd, 1H , J = 10.6, 1.2 Hz), 3.60 (s, 3H), 0.69-2.26 (m, 28H), 1.02 (s, 3H), 0.90 (s, 3H), 0.76 (s, 3H)

Example 15 Preparation of 4-carboxyhexyl-(-)-pimara-9 (11), 15-diene

To 20 mg of 4-carbomethoxyhexyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 14, 5 mg of 85% potassium hydroxide and ethanol were refluxed for 1 hour. The reaction solution was diluted with 20 ml of ethyl acetate and the aqueous layer was washed with water and saturated aqueous sodium chloride solution, acidified to pH 4 with 1 molar hydrochloric acid solution, and then filtered by drying with magnesium sulfate. The residue obtained after concentration of the filtrate under reduced pressure was purified by silica gel column chromatography with a mixed mixture of ethyl acetate-hexane 1: 3, and 4-carboxyhexyl-(-)-pimara.

8 mg (41%) of -9 (11), 15-diene was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 5.75 (dd, 1H, J = 18.0, 10.8 Hz), 5.27 (m, 1H), 4.86 (dd, 1H, J = 17.4, 1.2 Hz), 4.79 (dd, 1H , J = 10.6, 1.2 Hz), 0.74-2.31 (m, 27H), 1.02 (s, 3H), 0.90 (s, 3H), 0.76 (s, 3H)

Example 16: Preparation of 4-hydroxypentadienyl-(-)-pimara-9 (11), 15-diene

Dissolve 33.5 mg of 4-carbetoxybutadienyl-(-)-pimara-9 (11), 15-diene in 3 ml of dichloromethane and add 0.05 ml of 1 mole solution of diisobutyl aluminum hydride at -78 ° C. Stirred for a minute. After completion of the reaction with a few drops of methanol, 20 ml of dichloromethane and 20 ml of saturated solution of potassium sodium tartrate tetrahydrate were added thereto, and the mixture was stirred vigorously at room temperature for 2 hours. The organic solvent layer was washed with water and saturated aqueous sodium chloride solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure to obtain 14 mg (47%) of 4-hydroxypentadienyl-(-)-pimara-9 (11) and 15-diene.

1 H-NMR (300 MHz, CDCl ₃ ): 6.21 (m, 1H), 5.96 (m, 2H), 5.75 (m, 2H), 5.33 (m, 1H), 4.86 (dd, 1H, J = 17.5, 1.2 Hz ), 4.80 (dd, 1H, J = 10.6, 1.2 Hz), 0.76-2.28 (m, 15H), 1.00 (s, 3H), 0.91 (s, 3H), 0.86 (s, 3H)

Example 17 Preparation of 4-formylbutadienyl-(-)-pimara-9 (11), 15-diene

4-hydroxypentadienyl-(-)-pimara-9 (11), 15-diene, 14 mg of tetrapropylammonium perruthenate, N-methylmorpholine-N- prepared according to the method of Example 16 7.5 mg of oxide and molecular powder were dissolved in 4 ml of dichloromethane and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, diluted with diethyl ether, and filtered through silica gel. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography with a mixture of ethyl acetate-hexane 1:30, 4-formylbutadienyl-(-)-pimara-9 (11), and 15-diene 13 mg (87%). Got.

1 H-NMR (300 MHz, CDCl ₃ ): 9.52 (d, 1H, J = 8.0 Hz), 7.10 (m, 1H), 6.59 (d, 1H, J = 15.6 Hz), 6.20 (m, 1H), 6.07 ( m, 1H), 5.75 (dd, 1H, J = 18.0, 10.7 Hz), 5.36 (m, 1H), 4.86 (dd, 1H, J = 17.4, 1.2 Hz), 4.80 (dd, 1H, J = 10.6, 1.2 Hz), 0.81-2.04 (m, 15H), 1.00 (s, 3H), 0.94 (s, 3H), 0.87 (s, 3H)

Example 18 Preparation of 4-Carbetoxyhexatriene-(-)-pimara-9 (11), 15-diene

0.04 ml of triethylphosphonoacetate and 25 mg of 60% sodium hydride were dissolved in 2 ml of tetrahydrofuran and stirred at room temperature for 1 hour. 13 mg of 4-formylbutadienyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 17 was dissolved in 1 ml of tetrahydrofuran, and stirred at room temperature for 1 hour. After concentration under reduced pressure, tetrahydrofuran was removed, diluted with 20 ml of ethyl acetate, washed with saturated aqueous sodium chloride solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography with a mixed eluent of ethyl acetate-hexane 1:30, 4-kebetoxyhexatriene-(-)-pimara-9 (11), 15-diene 10mg ( 60%).

1 H-NMR (300 MHz, CDCl ₃ ): 7.24 (m, 1 H), 6.49 (m, 1 H), 6.10 (m, 3 H), 5.75 (m, 2 H), 5.29 (m, 1 H), 4.86 (dd, 1 H) , J = 17.4, 1.2 Hz), 4.79 (dd, 1H, J = 10.6, 1.2 Hz), 0.76-1.98 (m, 18H)

Example 19 Preparation of 4-carboxyhexatriene-(-)-pimara-9 (11), 15-diene

To 10 mg of 4-carbetoxyhexatriene-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 18, 2.5 mg of 85% potassium hydroxide and ethanol were refluxed for 1 hour. It was. The reaction solution was diluted with 20 ml of ethyl acetate and the aqueous layer was washed with water and saturated aqueous sodium chloride solution, acidified to pH 4 with 1 molar hydrochloric acid solution, and then filtered by drying with magnesium sulfate. The residue obtained after concentration of the filtrate under reduced pressure was purified by silica gel column chromatography with a mixed mixture of ethyl acetate-hexane 1: 3, 4-carboxyhexatriene-(-)-pimara-9 (11), 15-diene 6.5 mg (70 %) Was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 7.32 (dd, 1H, J = 15.2, 11.2 Hz), 6.54 (dd, 1H, J = 14.7, 10.2 Hz), 6.13 (m, 3H), 5.75 (m, 2H ), 5.30 (m, 1H), 4.86 (dd, 1H, J = 17.4, 1.2 Hz), 4.79 (dd, 1H, J = 10.6, 1.2 Hz), 0.62-2.23 (m, 15H), 1.00 (s, 3H), 0.90 (s, 3H), 0.78 (s, 3H)

Example 20 Preparation of 4-carboxyheptadienyl-(-)-pimara-9 (11), 15-diene

77 mg of carboxybutyl triphenylphosphonoacetate was dissolved in 2 ml of tetrahydrofuran, and 0.1 ml of 1.0 M potassium butoxide was added thereto, followed by stirring at room temperature for 1 hour. 18 mg of 4-formylvinyl-(-)-pimara-9 (11), 15-diene was dissolved in 1 ml of tetrahydrofuran, stirred at room temperature for 1 hour, and then concentrated under reduced pressure to remove tetrahydrofuran and ethyl. Diluted with 20 ml of acetate, washed with saturated aqueous solution of sodium chloride and dried over filtered with magnesium sulfate. The residue obtained after concentration of the filtrate under reduced pressure was purified by silica gel column chromatography with a mixed eluent of ethyl acetate-hexane 1:30, 4-carboxyheptadienyl-(-)-pimara-9 (11), 15 mg of diene 18 mg (79 %) Was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 6.15 (dd, 1H, J = 15.0, 10.9 Hz), 5.96 (m, 2H), 5.75 (dd, 1H, J = 18.0, 10.7 Hz), 5.28 (m, 1H ), 5.22 (m, 1H), 4.86 (dd, 1H, J = 17.4, 1.2 Hz), 4.80 (dd, 1H, J = 10.6, 1.2 Hz), 0.64-2.34 (m, 21H), 0.99 (s, 3H), 0.91 (s, 3H), 0.83 (s, 3H)

Example 21 Preparation of 4-Carbetoxymethylbutadienyl-(-)-pimara-9 (11), 15-diene

0.06 ml of triethyl phosphono propionate and 6 mg of 95% sodium hydride were dissolved in 2 ml of toluene and stirred at room temperature for 1 hour. 24 mg of 4-formylvinyl-(-)-pimara-9 (11), 15-diene was dissolved in 1 ml of toluene, and the mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure to remove toluene, and diluted with 20 ml of ethyl acetate. Washed with water and saturated aqueous sodium chloride solution, and then filtered through dryness with magnesium sulfate. The residue obtained after concentration of the filtrate under reduced pressure was purified by silica gel column chromatography with a mixed eluent of ethyl acetate-hexane 1:30, 4-carbetoxymethylbutadienyl-(-)-pimara-9 (11), 15-diene 23mg. (75.5%) was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 7.12 (d, 1H, J = 10.7 Hz), 6.27 (m, 2H), 5.75 (dd, 1H, J = 18.0, 10.7 Hz), 5.29 (m, 1H), 4.86 (dd, 1H, J = 17.5, 1.2 Hz), 4.80 (dd, 1H, J = 10.7, 1.2 Hz), 4.14 (q, 2H, J = 7.1 Hz), 0.62-2.24 (m, 16H), 1.87 (s, 3H), 1.24 (t, 3H, J = 7.2 Hz), 1.00 (s, 3H), 0.90 (s, 3H), 0.78 (s, 3H)

Example 22 Preparation of 4-carboxymethylbutadienyl-(-)-pimara-9 (11), 15-diene

To 23 mg of 4-carbetoxymethylbutadienyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 21, 6 mg of 85% potassium hydroxide and ethanol were refluxed for 1 hour. It was. The reaction solution was diluted with 20 ml of ethyl acetate and the aqueous layer was washed with water and saturated aqueous sodium chloride solution, acidified to pH 4 with 1 molar hydrochloric acid solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a mixture of ethyl acetate-hexane 1: 3, and 4-carboxymethylbutadienyl-(-)-pimara-9 (11), 15-diene 20mg (94 %) Was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 7.24 (d, 1H, J = 9.5 Hz), 6.41 (d, 1H, J = 15.6 Hz), 6.24 (m, 1H), 5.75 (dd, 1H, J = 18.0 , 10.7 Hz), 5.29 (m, 1H), 4.86 (dd, 1H, J = 17.5, 1.2 Hz), 4.80 (dd, 1H, J = 10.7, 1.2 Hz), 1.88 (s, 3H), 0.62-2.28 (m, 18H), 1.00 (s, 3H), 0.90 (s, 3H), 0.78 (s, 3H)

Example 23 Preparation of 4-Carbetoxymethylallyl-(-)-pimara-9 (11), 15-diene

0.06 ml of triethyl phosphono propionate and 20 mg of 95% sodium hydride were dissolved in 3 ml of toluene and stirred at room temperature for 1 hour. 25 mg of 4-formylmethyl-(-)-pimara-9 (11), 15-diene was dissolved in 1 ml of toluene, and the mixture was stirred at room temperature for 10 minutes, concentrated under reduced pressure to remove toluene, and diluted with 20 ml of ethyl acetate. Washed with water and saturated aqueous sodium chloride solution, and then filtered through dryness with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a mixed eluent of ethyl acetate-hexane 1:30, 4-carbetoxymethylallyl-(-)-pimara-9 (11), 15-diene 30 mg (78 %) Was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 6.76 (t, 1H, J = 7.5 Hz), 5.75 (dd, 1H, J = 17.6, 10.7 Hz), 5.30 (m, 1H), 4.86 (dd, 1H, J = 17.5, 1.2 Hz), 4.80 (dd, 1H, J = 10.7, 1.2 Hz), 4.12 (q, 2H, J = 7.1 Hz), 1.53 (s, 3H), 1.22 (t, 3H, J = 7.1 Hz) ), 0.68-2.43 (m, 17H), 1.02 (s, 3H), 0.90 (s, 3H), 0.81 (s, 3H)

Example 24 Preparation of 4-hydroxymethylmethylallyl-(-)-pimara-9 (11), 15-diene

70 mg of 4-carbetoxymethylallyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 23 was dissolved in 4 ml of dichloromethane and 1 mol of diisobutylaluminum hydride at -78 ° C. After adding 0.08 ml of the solution, the mixture was stirred for 1 hour. After completion of the reaction with a few drops of methanol, 20 ml of dichloromethane and 20 ml of saturated solution of potassium sodium tartrate tetrahydrate were added thereto, and the mixture was stirred vigorously at room temperature for 2 hours. The organic solvent layer was washed with water and saturated aqueous sodium chloride solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure to give 70 mg (93%) of 4-hydroxymethylmethylallyl-(-)-pimara-9 (11) and 15-diene.

1 H-NMR (300 MHz, CDCl ₃ ): 5.75 (dd, 1H, J = 17.6, 10.5 Hz), 5.42 (t, 1H, J = 7.1 Hz), 5.34 (m, 1H), 4.86 (dd, 1H, J = 17.5, 1.2 Hz), 4.80 (dd, 1H, J = 10.7, 1.2 Hz), 4.00 (s, 2H), 1.67 (s, 3H), 0.74-2.34 (m, 19H), 1.11 (s, 3H) , 0.95 (s, 3H), 0.83 (s, 3H)

Example 25 Preparation of 4-formylmethylallyl-(-)-pimara-9 (11), 15-diene

70 mg of 4-hydroxymethylmethylallyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 24, catalytic amount of tetrapropylammoniumperruthenate, N-methylmorpholine-N- 38 mg of oxide and molecular powder were dissolved in 4 ml of dichloromethane and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, diluted with diethyl ether, and filtered through silica gel. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography with a mixed mixture of ethyl acetate-hexane 1:30, and 4-formylmethylallyl-(-)-pimara-9 (11) and 70 mg (91%) of 15-diene were obtained. Got it.

1 H-NMR (300 MHz, CDCl ₃ ): 9.39 (d, 1H, J = 2.4 Hz), 6.55 (t, 1H, J = 7.8 Hz), 5.80 (dd, 1H, J = 17.4, 15.0 Hz), 5.36 ( m, 1H), 4.92 (dd, 1H, J = 18.0, 1.4 Hz), 4.85 (dd, 1H, J = 12.0, 1.2 Hz), 1.55 (s, 3H), 0.75-2.67 (m, 17H), 1.13 (s, 3H), 0.96 (s, 3H), 0.83 (s, 3H)

Example 26 Preparation of 4-Carbetoxydimethylpentadienyl-(-)-pimara-9 (11), 15-diene

0.15 ml of triethyl phosphono propionate and 16 mg of 95% sodium hydride were dissolved in 3 ml of toluene and stirred at room temperature for 1 hour. 70 mg of 4-formylmethylallyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 25 was dissolved in 1 ml of toluene, and stirred at room temperature for 10 minutes, and then concentrated under reduced pressure. Toluene was removed, diluted with 20 ml of ethyl acetate, washed with water and saturated aqueous sodium chloride solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a mixed eluent of ethyl acetate-hexane 1:30, 4-carbetoxydimethylpentadienyl-(-)-pimara-9 (11), 15-diene 76 mg. (87%) was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 7.06 (s, 1 H), 5.75 (dd, 1 H, J = 18.0, 10.7 Hz), 5.58 (t, 1H, J = 7.8 Hz), 5.30 (m, 1H), 4.87 (dd, 1H, J = 17.5, 1.5 Hz), 4.80 (dd, 1H, J = 10.5, 1.4 Hz), 4.14 (q, 2H, J = 7.1 Hz), 1.94 (s, 3H), 1.78 (s , 3H), 1.24 (t, 3H, J = 7.1 Hz), 0.67-2.40 (m, 17H), 1.03 (s, 3H), 0.91 (s, 3H), 0.82 (s, 3H)

Example 27 Preparation of 4-carboxydimethylpentadienyl-(-)-pimara-9 (11), 15-diene

25 mg of 4-carbetoxydimethylpentadienyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 26 was added with 9 mg of 85% potassium hydroxide and ethanol and refluxed for 1 hour. It was. The reaction solution was diluted with 20 ml of ethyl acetate and the aqueous layer was washed with water and saturated aqueous sodium chloride solution, acidified to pH 4 with 1 molar hydrochloric acid solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a mixture of ethyl acetate-hexane 1: 3, and 4-carboxydimethylpentadienyl-(-)-pimara-9 (11), 26.5 mg of 15-diene ( 91%).

1 H-NMR (300 MHz, CDCl ₃ ): 5.80 (dd, 1H, J = 15.0, 10.5 Hz), 5.72 (t, 1H, J = 7.6 Hz), 5.35 (m, 1H), 4.91 (d, 1H, J = 17.5 μs), 4.84 (d, 1H, J = 10.7 μs), 1.94 (s, 3H), 1.79 (s, 3H), 1.22 (t, 3H, J = 7.1 μs), 0.81-2.46 (m, 17H ), 1.01 (s, 3H), 0.91 (s, 3H), 0.81 (s, 3H)

Example 28 Preparation of 4-Carbetoxymethylpentadienyl-(-)-pimara-9 (11), 15-diene

0.08 ml of triethyl phosphono propionate and 8.5 mg of 95% sodium hydride were dissolved in 2 ml of toluene and stirred at room temperature for 1 hour. 36.5 mg of 4-formylallyl-(-)-pimara-9 (11), 15-diene was dissolved in 1 ml of toluene, stirred at room temperature for 10 minutes, concentrated under reduced pressure to remove toluene, and 20 ml of ethyl acetate. The mixture was diluted, washed with water and saturated aqueous sodium chloride solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with a mixed eluent of ethyl acetate-hexane 1:30, 4-carbetoxymethylpentadienyl-(-)-pimara-9 (11), 15-diene 39.7 mg (87%) was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 7.10 (d, 1H, J = 11.2 Hz), 6.23 (ddt, 1H, J = 3.0, 6.8, 15.0 Hz), 6.00 (m, 1H), 5.75 (dd, 1H , J = 18.0, 10.5 Hz), 5.30 (m, 1H), 4.86 (dd, 1H, J = 17.5, 1.2 Hz), 4.80 (dd, 1H, J = 10.7, 1.2 Hz), 1.86 (s, 3H) , 1.23 (t, 3H, J = 7.1 Hz), 0.68-2.45 (m, 17H), 1.01 (s, 3H), 0.91 (s, 3H), 0.79 (s, 3H)

Example 29 Preparation of 4-carboxymethylpentadienyl-(-)-pimara-9 (11), 15-diene

To 20.7 mg of 4-carbetoxymethylpentadienyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 28, 5% of 85% potassium hydroxide and ethanol were added for 1 hour. It was refluxed. The reaction solution was diluted with 20 ml of ethyl acetate and the aqueous layer was washed with water and saturated aqueous sodium chloride solution, acidified to pH 4 with 1 molar hydrochloric acid solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a mixed mixture of ethyl acetate-hexane 1: 3, 4-carboxymethylpentadienyl-(-)-pimara-9 (11), 15-diene 18mg (93 %) Was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 7.20 (d, 1H, J = 7.3 Hz), 6.25 (ddt, 1H, J = 3.0, 6.8, 15.0 Hz), 6.06 (m, 1H), 5.75 (dd, 1H) , J = 18.0, 10.7 Hz), 5.30 (m, 1H), 4.86 (dd, 1H, J = 17.5, 1.2 Hz), 4.80 (dd, 1H, J = 10.7, 1.2 Hz), 0.71-2.46 (m, 17H), 1.87 (s, 3H), 1.01 (s, 3H), 0.91 (s, 3H), 0.81 (s, 3H)

Example 30 Preparation of 4-Carbetoxymethylpentenyl-(-)-pimara-9 (11), 15-diene

8 mg of 4-carbetoxymethylpentadienyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 28 was dissolved in 1 ml of methanol, and then 1 mg of magnesium turning was added and stirred at room temperature for 12 hours. It was. 2 mol hydrochloric acid was added to the reaction solution to dissolve the remaining magnesium, concentrated under reduced pressure to remove methanol, extracted with 20 ml of ethyl acetate, and the organic solvent layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The residue obtained after concentration of the filtrate under reduced pressure was purified by silica gel column chromatography with a mixed solution of ethyl acetate-hexane 1:30 to 4-carbetoxymethylpentenyl-(-)-pimara-9 (11), 15-diene 6mg (75 %) Was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 5.75 (dd, 1H, J = 18.0, 10.7 Hz), 5.37 (m, 3H), 4.86 (dd, 1H, J = 17.4, 1.2 Hz), 4.79 (dd, 1H , J = 10.6, 1.2 Hz), 3.61 (s, 3H), 0.69-2.43 (m, 20H), 1.50 (s, 3H), 1.02 (s, 3H), 0.90 (s, 3H), 0.81 (s, 3H)

Example 31 Preparation of 4-carboxymethylpentenyl-(-)-pimara-9 (11), 15-diene

10 mg of 4-carbetoxymethylpentenyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 30 was added with 1 mg of 85% potassium hydroxide and ethanol, followed by reflux for 1 hour. . The reaction solution was diluted with 20 ml of ethyl acetate and the aqueous layer was washed with water and saturated aqueous sodium chloride solution, acidified to pH 4 with 1 molar hydrochloric acid solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with a mixed solution of ethyl acetate-hexane 1: 3, 4-carboxymethylpentenyl-(-)-pimara-9 (11), and 7.5 mg of 80-diene. %) Was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 5.75 (dd, 1H, J = 18.0, 10.7 Hz), 5.33 (m, 3H), 4.86 (dd, 1H, J = 17.5, 1.2 Hz), 4.80 (dd, 1H , J = 10.7, 1.2 Hz), 1.77 (s, 3H), 0.68-2.49 (m, 18H), 1.01 (s, 3H), 0.90 (s, 3H), 0.81 (s, 3H)

Example 32 Preparation of 4-Carbetoxymethyl Homoallylmethyl-(-)-pimara-9 (11), 15-diene

0.1 ml of triethyl phosphono propionate and 8 mg of 95% sodium hydride were dissolved in 2 ml of toluene and stirred at room temperature for 1 hour. To the reaction solution, 33 mg of 4-formylpropyl-(-)-pimara-9 (11), 15-diene were dissolved in 1 ml of toluene, stirred at room temperature for 10 minutes, concentrated under reduced pressure to remove toluene, and diluted with 20 ml of ethyl acetate. Washed with water and saturated aqueous sodium chloride solution, and then filtered through dryness with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a mixed eluent of ethyl acetate-hexane 1:30, 4-carbetoxymethyl homoallylmethyl-(-)-pimara-9 (11), 15-diene 37 mg. (93%) was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 6.69 (t, 1H), 5.75 (dd, 1H, J = 17.6, 10.7 Hz), 5.27 (m, 1H), 4.86 (dd, 1H, J = 17.4, 1.2 Hz ), 4.79 (dd, 1H, J = 10.6, 1.2 Hz), 4.05 (q, 2H, J = 7.3 Hz), 1.51 (s, 3H), 1.19 (t, 3H, J = 7.1 Hz), 0.76-2.04 (m, 22H), 1.01 (s, 3H), 0.90 (s, 3H), 0.77 (s, 3H)

Example 33 Preparation of 4-Carbomethoxymethylpentyl-(-)-pimara-9 (11), 15-diene

37 mg of 4-carbetoxymethyl homoallylmethyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 32 was dissolved in 2 ml of methanol, followed by 2 mg of magnesium turning, followed by stirring at room temperature for 12 hours. It was. 2 mol hydrochloric acid was added to the reaction solution to dissolve the remaining magnesium, concentrated under reduced pressure to remove methanol, extracted with 20 ml of ethyl acetate, and the organic solvent layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a mixed solution of ethyl acetate-hexane 1:30, 4-carbomethoxymethylpentyl-(-)-pimara-9 (11), 15-diene 28mg (75 %) Was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 5.75 (dd, 1H, J = 18.0, 10.7 Hz), 5.27 (m, 1H), 4.86 (dd, 1H, J = 17.5, 1.2 Hz), 4.80 (dd, 1H , J = 10.7, 1.2 Hz), 3.60 (s, 3H), 1.51 (s, 3H), 0.69-2.40 (m, 24H), 1.01 (s, 3H), 0.90 (s, 3H), 0.75 (s, 3H)

Example 34 Preparation of 4-carboxymethylpentyl-(-)-pimara-9 (11), 15-diene

28 mg of 4-carbomethoxymethylpentyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 33 was added with 11 mg of 85% potassium hydroxide and ethanol, and the mixture was refluxed for 1 hour. . The reaction solution was diluted with 20 ml of ethyl acetate and the aqueous layer was washed with water and saturated aqueous sodium chloride solution, acidified to pH 4 with 1 molar hydrochloric acid solution, and then filtered by drying with magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a mixture of ethyl acetate-hexane 1: 3, and 4-carboxymethylpentyl-(-)-pimara-9 (11), 15-diene 20mg (77%) Got.

1 H-NMR (300 MHz, CDCl ₃ ): 5.75 (dd, 1H, J = 17.5, 10.7 Hz), 5.27 (m, 1H), 4.86 (dd, 1H, J = 17.5, 1.2 Hz), 4.80 (dd, 1H , J = 10.7, 1.2 Hz), 0.69-2.40 (m, 24H), 1.01 (s, 3H), 0.90 (s, 3H), 0.76 (s, 3H)

Example 35 Preparation of 2-(trimethylsilyl) ethyl 16-hydroxyphenyl-(-)-pimara-9 (11) -ene-4-carboxylate

35 mg of 2- (trimethylsilyl) ethyl 15-formyl-(-)-pimara-9 (11) -ene-4-carboxylate was dissolved in tetrahydrofuran and 0.03 ml of 1.0 M phenylmagnesium bromide Put and stirred for 30 minutes. The reaction solution was terminated with an aqueous saturated ammonium chloride solution, concentrated under reduced pressure to remove tetrahydrofuran, extracted with 20 ml of ethyl acetate, and the organic solvent layer was washed with saturated aqueous sodium chloride solution and dried over filtered with magnesium sulfate. The residue obtained after concentration of the filtrate under reduced pressure was subjected to silica gel column chromatography with a mixed mixture of ethyl acetate-hexane 1: 8, and then 2- (trimethylsilyl) ethyl 16-hydroxyphenyl-(-)-pimara-9 (11) -ene. 25.5 mg (61%) of 4-carboxylate were obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 7.30 (d, 4H, J = 4.1 Hz), 5.31 (m, 1H), 4.86 (m, 1H), 4.08 (m, 4H), 0.77-2.27 (m, 17H ), 1.13 (s, 3H), 0.87 (s, 3H), 0.83 (s, 3H), 0.00 (s, 9H)

Example 36 2- (trimethylsilyl) ethyl 16-phenyl-(-)-pimara-9 (11) -ene-4-carboxy

Preparation of Silates

2-(trimethylsilyl) ethyl 16-hydroxyphenyl-(-)-pimara-9 (11) -ene-4-carboxylate 15.5 prepared according to the method of example 35 was dissolved in anhydrous methanol 1 and 10% Palladium / activated carbon was placed in a catalytic amount, replaced with hydrogen, and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with diethyl ether, and filtered through silica gel. The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography with a mixed eluent of ethyl acetate-hexane 1: 3 to give 2- (trimethylsilyl) ethyl 16-phenyl-(-)-pimara-9 (11) -ene-. 8.5 mg (57%) of 4-carboxylate were obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 7.17 (m, 4H), 5.34 (m, 1H), 4.08 (m, 2H), 2.54 (m, 2H), 0.71-2.58 (m, 17H), 1.14 (s , 3H), 0.89 (s, 3H), 0.83 (s, 3H), 0.00 (s, 9H)

Example 37 Preparation of 16-phenyl-(-)-pimara-9 (11) -ene-4-carboxylic acid

2-(trimethylsilyl) ethyl 16-phenyl-(-)-pimara prepared according to the method of Example 6

10.5 mg of -9 (11) -ene-4-carboxylate was dissolved in 1 ml of dimethylformamide, 0.8 ml of tetrabutylammonium fluoride was added, followed by stirring at room temperature for 2 hours. The reaction solution was diluted with 20 ml of ethyl acetate, washed with 0.5 mol of hydrochloric acid solution and saturated aqueous sodium chloride solution, and then filtered by drying with magnesium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography with ethyl acetate, and 16-phenyl-(-)-pima.

9 mg (91%) of La-9 (11) -ene-4-carboxylic acid was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 7.17 (m, 4H), 5.32 (m, 1H), 2.50 (m, 2H), 0.81-2.12 (m, 18H), 1.20 (s, 3H), 0.94 (s , 3H), 0.84 (s, 3H)

Example 38 Preparation of 4-Chloroformylpentadienyl-(-)-pimara-9 (11), 15-diene

10 mg of 4-carboxypentadienyl-(-)-pimara-9 (11), 15-diene prepared according to the method of Example 10 was dissolved in 2 ml of benzene, and 30 µl of oxalyl chloride was added thereto at room temperature. After stirring for some time, the reaction mixture was concentrated under reduced pressure to obtain an unstable 4-chloroformylpentadienyl-(-)-pimara-9 (11), 15-diene.

Example 39 Preparation of 4-carbamoylpentadienyl-(-)-pimara-9 (11), 15-diene

1 ml of ammonia water was added to the residue obtained by distillation under reduced pressure of the reaction solution of Example 38, and 4-carbamoylpentadienyl-(-)-pimara-9 (11) and 15-diene 9.8 were prepared in the same manner as in Example 39. mg (98%) was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 7.14 (m, 1 H), 6.05 (m, 2 H), 5.75 (m, 2 H), 5.41 (s, 2 H), 5.29 (m, 1 H), 4.86 (dd, 1 H) , J = 17.5, 1.2 Hz), 4.79 (dd, 1H, J = 10.6, 1.2 Hz), 0.77-2.41 (m, 18H), 1.04 (s, 3H), 0.90 (s, 3H), 0.80 (s, 3H)

Example 40 Preparation of 4- (N-methoxy) carbamoylpentadienyl-(-)-pimara-9 (11), 15-diene

To the residue obtained by distilling the reaction solution of Example 38 under reduced pressure, 1 ml of methoxyamine aqueous solution was added, and 2 ml of acyl acetate was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was extracted with 20 ml of ethyl acetate, and the organic solvent layer was washed with water and saturated aqueous sodium chloride solution, and then filtered by drying with magnesium sulfate. The residue obtained by concentration of the filtrate under reduced pressure was purified by silica gel column chromatography with a mixture of ethyl acetate-hexane 1: 3, and 4- (N-methoxy) carbamoyl-(-)-pimara-9 (11), 15-diene 10.3 mg (95%) was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 7.20 (m, 1H), 6.07 (m, 2H), 5.75 (m, 2H), 5.29 (m, 1H), 4.86 (dd, 1H, J = 17.5, 1.2 Hz ), 4.79 (dd, 1H, J = 10.6, 1.2 Hz), 3.67 (s, 3H), 0.70-2.24 (m, 19H), 1.03 (s, 3H), 0.90 (s, 3H), 0.80 (s, 3H)

Example 41 Preparation of 4- (N-Phillyl) carbamoylpentadienyl-(-)-pimara-9 (11), 15-diene

article

9.6 mg of pipsyl amide and 1.5 mg of 60% sodium hydride prepared according to the method of Example 36 of Patent Publication No. 1999-072290 were dissolved in 1 ml of tetrahydrofuran and stirred at room temperature for 30 minutes. The reaction solution of Example 38 was dissolved in 1 ml of tetrahydrofuran in a residue obtained by distillation under reduced pressure, and then stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, tetrahydrofuran was removed, diluted with 20 ml of dichloromethane, washed with saturated aqueous sodium chloride solution, and dried over filtered with magnesium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography with a mixed mixture of ethyl acetate-hexane 1: 3, and 4- (N-propyl) carbamoylpentadienyl-(-)-pimara-9 (11), 15- 11 mg (64%) of diene was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 7.83 (d, 2H, J = 8.8 Hz), 7.71 (d, 2H, J = 8.8 Hz), 7.60 (s, 1H), 7.20 (m, 1H), 6.08 ( m, 2H), 5.72 (m, 2H), 5.29 (m, 1H), 4.86 (dd, 1H, J = 17.4, 1.2 Hz), 4.79 (dd, 1H, J = 10.7, 1.2 Hz), 0.74-2.24 (m, 18H), 1.01 (s, 3H), 0.89 (s, 3H), 0.78 (s, 3H)

Example 42 Preparation of 4- (N-methanesulfonyl) carbamoylpentadienyl-(-)-pimara-9 (11), 15-diene

4- (N-methanesulfonyl) carbamoylpentadienyl-(-)-pimara from 6 mg of methanesulfonamide prepared according to Example 36 of Patent Publication No. 1999-072290 in the same manner as in Example 41 9.2 mg (76%) of -9 (11) and 15-diene were obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 7.84 (s, 1 H), 7.31 (m, 1 H), 6.19 (m, 2 H), 5.78 (m, 2 H), 5.34 (m, 1 H), 4.91 (dd, 1 H) , J = 18.0, 1.4 Hz), 4.84 (dd, 1H, J = 10.5, 1.4 Hz), 3.32 (s, 3H), 0.74-2.50 (m, 18H), 1.08 (s, 3H), 0.91 (s, 3H), 0.84 (s, 3H)

Example 43: 4- (N-Chloropyridine) carbamoylpentadienyl-(-)-pimara-9 (11), 15-

Manufacture of dienes

4- (N-chloropyridine) carbamoylpentadienyl-(-)-pimara- from 8 mg of chloropyridineamide prepared according to the method of Example 36 of Patent Publication No. 1999-072290 in the same manner as in Example 41 9 (11), 15-diene 11.2 mg (86%) was obtained.

1 H-NMR (300 MHz, CDCl ₃ ): 8.23 (d, 1H, J = 8.7 Hz), 8.15 (d, 1H, J = 2.4 Hz), 7.85 (s, 1H), 7.30 (m, 1H), 6.12 ( m, 2H), 5.81 (d, 1H, J = 9.7 Hz), 5.75 (dd, 1H, J = 18.0, 10.7 Hz), 5.30 (m, 1H), 4.86 (dd, 1H, J = 17.7, 1.4 Hz ), 4.80 (dd, 1H, J = 10.5, 1.4 Hz), 0.77-2.25 (m, 18H), 1.01 (s, 3H), 0.90 (s, 3H), 0.79 (s, 3H)

Experimental Example 1 PGE of a Natural Single Component and Its Synthetic Derivative ₂ Synthetic inhibitory action

Novel derivatives synthesized according to the method of the present invention from (-)-pimara-9 (11), 15-diene-4-carboxylic acid, which are diterpine compounds isolated from the roots of the islands of Agadir, cyclooxygena in vitro Experiments were conducted to inhibit PGE ₂ synthesis by inhibiting the activity of _II-2 .

The experimental method is as follows.

3 units of purified COX-2 (manufactured by Layman Chemical Co., Ltd.) separated from both placenta and 1.0mM of hematin, 1.95mM of 1-epiteprine, and 0.49mM of reduced glutathion were mixed After standing on ice for 5 minutes, a sample for measuring COX-2 activity was added and pre-cultured on ice for 10 minutes. After the completion of the preculture, 0.02μ Ci [1-14C] arachidonic acid was added as a substrate, and the reaction was performed at 37 ° C. for 20 minutes. To terminate the reaction, 10 µl of 2M HCl was added to terminate the reaction, and the resulting prostaglandin was extracted twice with ethyl ether, combined, the ethyl ether was evaporated in a 37 ° C. aqueous phase, the concentrated solution was dissolved in acetone, and the solvent was added to a TLC plate, and then (CHCl ₃ : methanol: acetic acid = 18: 1: 1). The developed TLC plate was identified by PGR ₂ using autoradiography (PACKARD), and the amount of PGE ₂ lowered by the sample was compared with the control to measure the COX-2 inhibitory activity of the sample.

The result of measuring 50% inhibition of PGE ₂ synthesis using IC50 is shown in Table 1 below.

Inhibition of PGE ₂ Synthesis by Inhibiting COX-2 Activity of Natural Single Component and Its Synthetic Derivatives Substance R ₂ R ₁ IC50 (μM) Natural ingredients CO ₂ vinyl 790.4 aspirin - 33865.7 Indomethacin - 82.0 NS-398 - 38.4 Celecoxib - 9.0 Example 5 CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ COOH vinyl 13.2 Example 6 CH ₂ CH ₂ CH ₂ CHCHCOOH vinyl 13.2 Example 10 CH ₂ CHCHCHCHCOOH vinyl 40.7 Example 15 CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ COOH vinyl 60.1 Example 19 CHCHCHCHCHCHCOOH vinyl 581.4 Example 20 CHCHCHCHCH ₂ CH ₂ CH ₂ COOH vinyl > 2000 Example 22 CHCHCHC (CH ₃ ) COOH vinyl 197.0 Example 27 CH ₂ CHC (CH ₃ ) CHC (CH ₃ ) COOH vinyl 83.2 Example 29 CH ₂ CHCHCHC (CH ₃ ) COOH vinyl 503.7 Example 31 CH ₂ CH ₂ CHCHC (CH ₃ ) COOH vinyl 81.7 Example 34 CH ₂ CH ₂ CH ₂ CH ₂ CH (CH ₃ ) COOH vinyl > 2000 Example 37 CO ₂ H CH ₂ CH ₂ Ph

From the above measurement results, the compound of the present invention is 6 times as indomethacin as the compound of the present invention is sufficient as at least 13 micromoles compared to the conventional anti-inflammatory analgesic indomethacin, which is required to inhibit PGE ₂ synthesis by 50%. It can be seen that it has a strong anti-inflammatory action.

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Formulation example

1. Preparation of Tablets

2.5 mg of compound of Example 5

Lactose BP 151.0 mg

Starch BP 30.0 mg

Pregelatinized Corn Starch BP 15.0 mg

The compound of Example 5 was sieved and mixed with lactose, starch and pregelatinized corn starch, then a suitable volume of purified water was added and granulated into a powder. The granules were dried and then mixed with magnesium stearate and compressed to obtain tablets.

2. Preparation of Injectables

800 μg / ml of the compound of Example 15

Dilute hydrochloric acid BP until pH 3.5

Physiological saline BP up to 1 ml for injection

The compound of Example 15 was dissolved in an appropriate volume of sodium chloride BP for injection, and the pH of the resulting solution was adjusted to pH 3.5 with diluted hydrochloric acid BP, then the volume was adjusted with sodium chloride BP for injection and thoroughly mixed. . The solution was filled into a 5 ml Type 1 ampoule of clear glass, dissolved in glass and enclosed under an upper grid of air, then sterilized by autoclaving at 120 ° C. for at least 15 minutes to obtain an injection.

The present inventors have found that novel derivatives synthesized according to the method of the present invention from (-)-pimara-9 (11), 15-diene-4-carboxylic acid, which are diterpine compounds isolated from the root and bark of the island of Orgapi In vitro tests showed that the effect of inhibiting PGE ₂ synthesis was superior to indomethacin and up to 6.2-fold physiological activity.

In addition, these compounds showed better or comparable effects to ketoprofen in most animal anti-inflammatory studies.

Claims (2)

A compound of formula 1 and a pharmaceutically acceptable salt thereof. One (Wherein R ₁ represents vinyl or phenylethyl group, R ₂ represents carboxyl, carboxy homoallyl, carboxypentadienyl, carboxyhexyl, carboxyhexatriene, carboxyheptadienyl, carboxymethylbutadienyl, carboxydimethylpenta Dienyl, carboxymethylpentadienyl, carboxymethylpentenyl, carboxymethylpentyl, carbamoylpentadienyl, (N-methoxy) carbamoylpentadienyl, (N-propyl) carbamoylpentadienyl, (N- Methanesulfonyl) carbamoylpentadienyl, (N-chloropyridine) carbamoylpentadienyl) Anti-inflammatory analgesic comprising a compound of Formula 1 as an active ingredient.