KR100345047B1 - Novel taxaneterpine compounds - Google Patents

Abstract

PURPOSE: Novel taxane terpenes are provided, which compounds are useful as anticancer agents. Also, provided are a method for manufacturing the same and anticancer agents containing the same as an active ingredient. CONSTITUTION: Taxane terpenes represented by the formula(1) are provided, wherein R1 is isopropyl, isobutyl, isobutenyl, tetrahydrofuranyl, phenyl, furyl or thiophenyl; R2 is phenyl, furyl, cyclopropyl or t-butoxy; R3 and R4 are independently hydrogen, or form the cyclic carbonate structure together; and R5 is phenyl. A method for manufacturing the taxane terpenes of the formula(1) comprises reducing a ketone group at the C9-site of a compound of the formula(6), wherein a reducing agent used is samarium iodide; and the reaction is carried out in a solvent selected from methanol, ethanol, tetrahydrofuran, 1,4-dioxane and amide.

Description

New Taxane Terpine Compounds {Novel taxaneterpine compounds}

The present invention relates to a novel taxane terpine-based compound represented by the following formula (1) useful as an anticancer agent, a method for preparing the same, and an anticancer composition containing the same as an active ingredient.

In the above formula

R ¹ represents substituted or unsubstituted straight or branched chain alkyl, alkenyl or alkynyl, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl Indicate,

R ² represents substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl, RO-, RS- or RR ⁶ N- Radicals, wherein R represents substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl, and R ⁶ represents hydrogen or the above It may have the same meaning as R defined in the above, or R and R ⁶ may combine together to form a cyclic structure.

R ³ is hydrogen, acyl, alkyl, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, substituted or unsubstituted aryl, heteroaryl or hydroxy protecting group Indicate,

R ⁴ is hydrogen, acyl, alkyl, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, substituted or unsubstituted aryl, heteroaryl or hydroxy protecting group Or R ³ and R ⁴ can be joined together to form a cyclic carbonate, cyclic thiocarbonate, or acetonide structure,

R ⁵ represents aryl.

Taxane terpine-based compounds are known as anti-cancer active substances that exhibit excellent effects in treating various cancers, leukemias and tumors by inhibiting the growth of various cancer cells and tumor cells, and representative compounds thereof include paclitaxel represented by the following formula (2) Taxol ^?? ) may be mentioned.

Paclitaxel of Formula 2 is a substance extracted and isolated from the bark of the Pacific coast of Taxus brevifolia , called Taxus brevifolia , and has been used for the treatment of ovarian cancer, breast cancer, lung cancer, etc. in recent years. However, paclitaxel can only be supplied in a limited amount from a very slow-growing yew tree, so that it does not meet the clinical requirements, but also has solubility in water [0.0008 mg / ml; RM Straubinger, et al., Taxane Anticancer Agents, Basic Science and Current Status, ACS Symposium Series 583, 1995 , p. 111 to 123], have very low usage due to formulation and bioavailability problems. have. In other words, to dissolve paclitaxel in water, special means or supplements should be used and the dosage should be limited. However, the supplements used at this time cause many side effects.

As a result of the research to improve the problems of paclitaxel, French researchers removed acetyl group present in the 10-position of paclitaxel, and the dositaxel (taxotere ^?? International Patent No. 94/12482).

However, even though doxytaxel significantly improved water solubility and anticancer activity compared to paclitaxel, it did not completely solve the problem of solubility in water.

Recently, as a result of another study to increase the solubility of water in paclitaxel, a compound of formula (4) was disclosed in which a 9-position ketone group having a taxane terpine structure was reduced and converted to a hydroxyl group. TP Pulicani, et al., Tetrahedron Letters 1994 , 35 , 4999 and GI Georg, et al., Tetrahedron Letters 1995 , 3 6, 1783].

As shown in Formula 4, the taxane terpine-based compound in which the ketone group in the 9-position is reduced to 9β-hydroxy group has a 10-fold increase in water solubility than doxytaxel, and its in vitro anticancer activity is known to be almost equivalent to paclitaxel.

As another effort to increase the solubility of water in the taxane terpine-based compound, a compound of formula 5 having a hydroxyl group introduced at the 14-position of the taxane terpine structure was disclosed (International Patent No. 94/22856). That is, when the hydroxyl group is introduced at the 14-position of the taxane terpine structure as shown in Chemical Formula 5, it is known that the solubility in water may be increased, thereby improving pharmacological activity and thus reducing toxicity and side effects. [Ojima, et al., J. Bioorg. Med. Chem. 1994 , 4 , 1571 and J. Kant, et al., J. Bioorg. Med. Chem. 1994 , 4 , 1565.

However, as mentioned above, despite various efforts to increase the solubility of the taxane terpine-based compound having anticancer activity in water, the new anticancer agent has not only increased the solubility in water but also has excellent anticancer effect. It does not appear until now. In addition, conventional taxane terpine-based anticancer agents such as paclitaxel of Formula 2 and docetaxel of Formula 3, which are currently used in the clinic, have very low solubility in water, and thus are formulated using a mixture of 50% ethanol and 50% polyoxyethyl castor oil. Dosage should be administered by instillation for a long time. In addition, the adjuvant used in combination with the harmful effects on the human body, as well as paclitaxel and docetaxel, neutropenia, leukopenia, anemia, hypersensitivity, peripheral neuropathy, myalgia, arthralgia, stomach Serious side effects, including relationship disorders (nausea and vomiting). Therefore, there is an urgent need for the development of a new substance that can solve various problems related to the existing taxane terpine-based anticancer agent, thereby remarkably improving the anticancer activity and solubility in water, and thus eliminating the side effect problem.

Accordingly, the present inventors have conducted extensive and continuous research to develop a new structure of anticancer agent which has a low solubility in water, which is a problem of existing taxane terpine-based anticancer agents, and also enhances anticancer effect. It was confirmed that the 10-deacetyl-9-deketo-9β, 14β-dihydroxytaxane compounds represented by the above formula (1) having a hydroxyl group introduced at the 9β-position and 14β-position have excellent solubility in water and an anticancer effect. This invention was completed.

In the present invention, a hydroxyl group is introduced at the 9β-position and 14β-position of the taxane terpin structure, and is a taxane terpine-based compound represented by Formula 1 useful as an anticancer agent, that is, 10-deacetyl-9-deketo-9β, 14β- It is an object to provide dihydroxytaxane derivatives.

[Formula 1]

In the above formula

R ¹ represents substituted or unsubstituted straight or branched chain alkyl, alkenyl or alkynyl, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl Indicate,

R ² represents substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl, RO-, RS- or RR ⁶ N- Radicals, wherein R represents substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl, and R ⁶ represents hydrogen or the above It may have the same meaning as R defined in the above, or R and R ⁶ may combine together to form a cyclic structure.

R ³ is hydrogen, acyl, alkyl, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, substituted or unsubstituted aryl, heteroaryl or hydroxy protecting group Indicate,

R ⁴ is hydrogen, acyl, alkyl, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, substituted or unsubstituted aryl, heteroaryl or hydroxy protecting group Or R ³ and R ⁴ can be joined together to form a cyclic carbonate, cyclic thiocarbonate or acetonide structure,

R ⁵ represents aryl.

Preferred compounds according to the invention indicate that R ¹ represents alkyl, alkenyl, heterocycloalkyl, aryl or heteroaryl, R ² represents aryl, heteroaryl, cycloalkyl or RO- radicals, R represents alkyl, R ³ and R ⁴ each independently represent hydrogen or R ³ and R ⁴ together form a cyclic structure, and R ⁵ is a compound of Formula 1 wherein phenyl represents.

Particularly preferred compounds according to the invention are those wherein R ¹ represents C ₁ -C ₄ alkyl, C ₂ -C ₆ alkenyl, heterocycloalkyl, phenyl or heteroaryl, and R ² is phenyl, heteroaryl, cycloalkyl or RO- Radicals, R represents C ₁ -C ₄ alkyl, R ³ and R ⁴ each independently represent hydrogen, or R ³ and R ⁴ together form a cyclic carbonate or cyclic thiocarbonate structure, R ⁵ is a compound of formula 1 representing phenyl.

Most preferred compounds according to the invention are those in which R ¹ represents isopropyl, isobutyl, isobutenyl, tetrahydrofuranyl, phenyl, furyl, thiophenyl or pyridyl and R ² represents phenyl, furyl, cyclopropyl or t-part Oxy, R ³ and R ⁴ each independently represent hydrogen, or R ³ and R ⁴ together form a cyclic carbonate structure, and R ⁵ represents phenyl.

The 10-deacetyl-9-deketo-9β, 14β-dihydroxytaxane derivatives represented by Formula 1 of the present invention exhibit an excellent solubility in water compared to paclitaxel or docetaxel, which is a conventional taxane terpine-based anticancer agent. In addition, it has been shown to have excellent anticancer activity against various cancer cells.

Still another object of the present invention is to provide a novel method for preparing a taxane terpine-based compound represented by Chemical Formula 1, which is useful as an anticancer agent.

According to the method of the present invention, the taxane terpineic compound of Formula 1, that is, 10-deacetyl-9-deketo-9β, 14β-dihydroxytaxane derivative is 10-deacetyl-14β-hydride represented by Formula 6 It can be prepared by reducing the ketone group at the 9-position of the oxytaxane derivative.

In the above formula

R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each as defined above.

Reducing agents that can be used to reduce the 9-position ketone group of the compound of formula 6 according to the method of the present invention as described above include sodium borohydride (NaBH ₄ ), sodium cyanoborohydride (NaBH ₃ CN), Lithium borohydride (LiBH ₄ ), tetrabutylammonium borohydride (n-Bu ₄ NBH ₄ ), alan (AlH ₃ ), diisobutylalan (AlH [CH ₂ CH (CH ₃ ) ₂ ] ₂ ) A reducing agent such as boron or aluminum series, or a lanthanide series reducing agent such as samarium iodide. Reducing agents that can be preferably used in the reduction reaction of the present invention include tetrabutylammonium borohydride (n-Bu ₄ NBH ₄ ) or samarium iodide, and particularly preferably samarium iodide is used.

In the case of using samarium iodide as a reducing agent, the reaction can be carried out directly using samarium iodide obtained by reacting samarium metal with iodine in a tetrahydrofuran solvent, or using a commercially available samarium iodide solution. Can be performed. In this case, the reaction is usually carried out in the presence of a solvent, and examples of the solvent used include a mixed solvent of water and an organic solvent that can be mixed with water. As an organic solvent that can be mixed with water that can be used for this purpose, it is possible to use a solvent that can dissolve all the compounds used in the reaction, minimize the side reactions and maximize the reactivity without participating in the reaction under the reaction conditions. For example, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and 1,4-dioxane or solvents such as amides. In this reaction, a mixed solvent of water and tetrahydrofuran in a ratio of 1: 5 to 1:50 (v / v) is preferably used. The temperature of the reduction reaction is generally suitable at a temperature of -30 ° C to room temperature, preferably -10 ° C to 10 ° C.

The 10-deacetyl-14β-hydroxytaxane derivative represented by the formula (6) used as a starting material in the method of the present invention is known from International Patent No. 94/03215 or the like, or can be prepared similarly to these known methods. . For example, the functional group of the 14β-hydroxy-10-deacetylbaccatin (III) derivative of the formula (7) is protected to prepare a derivative of the formula (8), which is represented by the formula (9) as a side chain substituent of the taxane terpine derivative. The derivative of Formula 10 may be prepared by combining the betalactam structure of the serine derivative by a coupling reaction, and then protecting groups may be removed to prepare a compound of Formula 6 wherein R ³ and R ⁴ each represent hydrogen.

The above method can be represented by the following Scheme 1.

In Reaction Scheme 1, R ¹ , R ² and R ⁵ are the same as defined above, Troc represents 2,2,2-trichloroethoxycarbonyl, TES represents triethylsilyl, and Et represents an ethyl group. it means.

In addition, another method for preparing the compound of Formula 6 includes protecting the functional group of the compound of Formula 7 as defined above and cyclizing hydroxy present at the 1 and 14-positions of the taxane terpine structure with carbonate to form A derivative is prepared, and the derivative of Formula 12 is prepared by coupling the derivative with a beta-lactam structure of the isoserine derivative represented by Formula 9 as a side chain substituent of the taxane terpine derivative, and then removing the protecting groups to remove R ^3. It is also possible to prepare a compound of formula (6) in which R ⁴ and R ⁴ together form a cyclic carbonate.

The above method can be represented by the following scheme 2.

R ¹ , R ² and R ⁵ in Scheme 2 are as defined above, respectively, Troc represents 2,2,2-trichloroethoxycarbonyl, and TES means triethylsilyl group.

The novel taxane terpine-based compound of Formula 1 prepared according to the method of the present invention can be used as an anticancer agent useful for treating various cancer diseases because it has excellent solubility in water and shows an excellent anticancer effect. Accordingly, another object of the present invention is to provide an anticancer composition containing the compound of Formula 1 as an active ingredient.

The novel taxane terpine-based compound of formula 1 according to the present invention not only shows excellent anticancer activity compared to the conventional taxane compounds, but also has been used in the formulation of the conventional taxane terpine-based compound because of its excellent solubility in water. It can be formulated and administered using pure water without using a solvent such as a mixture of ethanol and polyoxyethyl castor oil, or it can be formulated with a minimum amount of solvent such as a mixture of ethanol and polyoxyethyl castor oil. This provides the advantage of minimizing the side effects caused by ethanol or polyoxyethyl castor oil.

Due to this improvement in water solubility, the anticancer active compound of formula 1 according to the present invention can be formulated into an injectable preparation and used effectively in the clinic. Injectable preparations can be prepared, for example, with aqueous or oily sterile injectable suspensions using suitable dispersing, wetting or suspending agents according to known techniques. Aqueous solvents that can be used include pharmaceutically acceptable water, glucose solutions, Ringer's solution and isotonic salt solutions, and sterile fixed oils are conventionally employed as a solvent or suspending medium.

In order to express sufficient anticancer effect when administering the compound of the present invention for clinical purposes, the total daily dose to be administered to the patient is preferably in the range of 0.5 mg to 50 mg per m 2 of body surface, but the specific dose level for a particular patient May be appropriately increased or decreased by a specialist depending on the specific compound to be used, the individual's weight, sex, health condition, diet, time of administration, method of administration, rate of excretion, the type or severity of the combination or cancer.

The present invention is explained in more detail based on the following examples and experimental examples. However, the present invention is not limited in any way by these examples or experimental examples.

Example 1

10-deacetyl-9-deketo-9β, 14β-dihydroxypaclitaxel

828 mg (1 mmol) of 10-deacetyl-14β-hydroxypaclitaxel prepared by the method described in International Patent 94/03215 was dissolved in 10 ml of a 9/1 (v / v) mixed solvent of tetrahydrofuran and water. . After nitrogen was injected into the resulting solution for 10 minutes, 50 ml of fresh dark blue samarium iodide (0.1 M tetrahydrofuran solution) prepared by reacting samarium metal with iodine in tetrahydrofuran was slowly added. The color of the solution changes from dark blue to colorless. When the color of the reaction solution no longer changed, air was injected for 10 minutes, and then 50 ml of 5% ammonium chloride solution was added and extracted three times (100 ml × 3) with ethyl acetate. The organic layer was washed twice with saturated sodium thiosulfate solution (100 mL × 2), dried over anhydrous magnesium sulfate, and the organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent: ethyl acetate / dichloromethane / methanol = 50: 50: 3, v / v / v] to give 620 mg (yield 75%) of the title compound.

Elemental Analysis C ₄₅ H ₅₁ NO ₁₄ calc. C 65.61%; H 6.21%; N 1.69%

Found C 65.62%; H 6.21%; N 1.68%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.20 (s, 3H, H17), 1.68 (s, 3H, H16), 1.73 (s, 3H, H19), 1.85 (s, 1H, OH ), 2.04 (s, 3H, H18), 2.05 (b, 1H, OH), 2.09 (m, 1H, H6β), 2.40 (m, 1H, H6α), 2.48 (s, 3H, OAc), 3.16 (d , J = 5.2 Hz, 1H, H3), 3.98 (m, 1H, H7), 4.05 (d, 1H, H9), 4.18 (d, J = 8.0 Hz, 1H, H20β), 4.22 (d, J = 8.0 Hz, 1H, H20α), 4.34 (m, 3H, 30H), 4.59 (m, 1H, H14), 4.91 (b, 1H, OH), 5.00 (m, 2H, H2 'and H10), 5.15 (m, 1H, H5), 6.11 (m, 2H, H3 'and H13), 6.29 (d, J = 5.3 Hz, 1H, H2), 7.42-7.68 (m, 11H), 7.96 (d, J = 7.1 Hz, 2H ), 8.17 (d, J = 7.1 Hz, 2H), 8.36 (d, J = 8.6 Hz, 1H, NH)

The title compound of Examples 2 to 36 was prepared by using the corresponding 10-deacetyl-14β-hydroxytaxane derivative represented by Formula 6 as a starting material according to a method analogous to that of Example 1.

Example 2

13-{(2 R , 3 S ) -3-benzoylamino-5-methyl-2-hydroxyhexanoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III)

Yield: 78%

Elemental Analysis C ₄₃ H ₅₅ NO ₁₄ calc. C 65.51%; H 6.21%; N 1.69%

Found C 65.60%; H 6.19%; N 1.69%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 0.99 (d, J = 6.4 Hz, 3H, CH ₃ ), 1.01 (d, J = 6.5 Hz, 3H, CH ₃ ), 1.21 (s, 3H, H17), 1.47 (m, 2H, CH ₂ ), 1.67 (s, 3H, H16), 1.70 (s, 3H, H19), 1.96 (s, 3H, H18), 1.96 (m, 2H, CHMe ₂ And H6β), 2.48 (m, 1H, H6α), 2.51 (s, 3H, OAc), 3.15 (d, J = 5.3 Hz, 1H, H3), 3.98 (m, 1H, H7), 4.02 (m, 1H , H3 '), 4.18-4.34 (m, 6H, H9, H14, H20β, H20α and 20H), 4.45 (m, 1H, OH), 4.45 (m, 1H, OH), 4.59 (m, 2H, 20H) , 5.12 (m, 2H, H10 and H2 '), 5.23 (m, 1H, H5), 6.02 (d, J = 6.8 Hz, 1H, OH), 6.26 (m, 2H, H2 and H13), 7.42-7.87 (m, 6H), 7.89 (d, J = 7.1 Hz, 2H), 8.06 (d, J = 8.6 Hz, NH), 8.16 (d, J = 7.1 Hz, 2H)

Example 3

13-{(2 R , 3 S ) -3-benzoylamino-4-methyl-2-hydroxypentanoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III)

Yield: 70%

Elemental Analysis C ₄₂ H ₅₃ NO ₁₄ calc. C 63.38%; H 6.71%; N 1.76%

Found C 63.21%; H 6.65%; N 1.70%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.09 (d, J = 6.7 Hz, 3H, CH ₃ ), 1.23 (d, J = 6.7 Hz, 3H, CH ₃ ), 1.23 (s, 3H, H17), 1.68 (s, 3H, H16), 1.71 (s, 3H, H19), 1.82 (s, 3H, H18), 1.83 (m, 1H, H6β), 1.91 (m, 2H, CHMe ₂ ) , 2.45 (m, 1H, H6α), 2.56 (s, 3H, OAc), 2.89 (b, 1H, OH), 3.11 (d, J = 5.3 Hz, 1H, H3), 3.97 (m, 1H, H7) , 4.05 (m, 1H, H3 '), 4.22 (d, J = 3.7 Hz, 1H, H9), 4.25-4.35 (m, 4H, H20β, H20α and 20H), 4.40 (m, 2H, H14 and H2' ), 4.72 (m, 1H, OH), 4.89 (b, 1H, 0H), 5.14 (m, 1H, H5), 6.01 (d, J = 6.5 Hz, 1H, H13), 6.17 (d, J = 3.3 Hz, 1H, OH), 6.27 (d, J = 5.4 Hz, 1H, H2), 7.45-7.65 (m, 6H), 7.89 (d, J = 7.1 Hz, 2H), 7.98 (d, J = 7.8 Hz , 1H, NH), 8.17 (d, J = 7.0 Hz, 2H)

Example 4

9-deketo-9β, 14β-dihydroxydosidaxel

Yield: 80%

Elemental Analysis C ₄₃ H ₅₅ NO ₁₅ calcd C 62.53%; H 6.47%; N 1.69%

Found C 62.51%; H 6.45%; N 1.64%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.29 (s, 3H, H17), 1.40 (s, 9H, CH ₃ ), 1.68 (s, 3H, H16), 1.75 (s, 3H, H19), 1.85 (s, 3H, H18), 1.88 (m, 1H, H6β), 2.42 (m, 1H, H6α), 2.44 (s, 3H, OAc), 2.91 (b, 1H, OH), 3.15 ( d, J = 5.3 Hz, 1H, H3), 3.92 (m, 1H, H7), 4.05 (d, J = 4.0 Hz, 1H, H9), 4.17 (d, J = 7.9 Hz, 1H, H20β), 4.24 (d, J = 7.9 Hz, 1H, H20α), 4.33 (m, 3H, H14 and OH), 4.36 (m, 1H, H10), 4.78 (b, 2H, OH), 4.92 (m, 1H, H2 ' ), 5.15 (m, 1H, H5), 5.41 (m, 1H, OH), 5.83 (d, J = 3.9 Hz, 1H, H3 '), 5.83 (d, J = 6.9 Hz, 1H, H13), 6.29 (d, J = 5.3 Hz, 1H, H2), 6.72 (d, J = 8.7 Hz, 1H, NH), 7.32-7.63 (m, 8H), 8.13 (d, J = 7.2 Hz, 2H)

Example 5

13-{(2 R , 3 S ) -3- (t-butoxycarbonyl) amino-5-methyl-2-hydroxyhexanoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III)

Yield: 75%

Elemental Analysis C ₄₁ H ₅₉ NO ₁₅ calcd. C 61.10%; H 7.38%; N 1.74%

Found C 60.00%; H 7.25%; N 1.64%

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 0.98 (d, J = 7.1 Hz, 3H, CH ₃ ), 1.01 (d, J = 7.3 Hz, 3H, CH ₃ ), 1.29 (s, 3H, H17), 1.33 (m, 1H, CHMe ₂ ), 1.40 (s, 9H, CH ₃ ), 1.65 (s, 3H, H16), 1.70 (s, 3H, H19), 1.81 (s, 3H, H18), 1.86 (m, 3H, CH ₂ and H6β), 2.44 (s, 3H, OAc), 2.49 (m, 1H, H6α), 3.15 (d, J = 4.8 Hz, 1H, OH), 4.02 (d, J = 7.15 Hz, 1H, H3), 4.06 (b, 1H, OH), 4.18-4.41 (m, 8H, H7, H9, H14, H20α, H20β, H3 ', 2OH), 4.63 (m, 1H, H5), 4.93 (d, J = 8.0 Hz, 1H, H2 '), 5.18 (m, 1H, OH), 5.82 (m, 2H, H10 and OH), 6.04 (d, J = 6.6 Hz, 1H, H2), 6.25 -6.28 (m, 2H, H13 and NH), 7.52-7.65 (m, 3H), 8.15 (d, J = 7.3 Hz, 2H)

Example 6

13-{(2 R , 3 S ) -3- (t-butoxycarbonyl) amino-4-methyl-2-hydroxypentanoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III)

Yield: 60%

Elemental Analysis C ₄₀ H ₅₇ NO ₁₅ calcd C 60.67%; H 7.25%; N 1.77%

Found C 60.67%; H 7.24%; N 1.75%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.04 (d, J = 6.7 Hz, 3H, CH ₃ ), 1.13 (d, J = 6.7 Hz, 3H, CH ₃ ), 1.27 (s, 3H, H17), 1.43 (s, 9H, CH ₃ ), 1.68 (s, 3H, H16), 1.73 (s, 3H, H19), 1.83 (s, 3H, H18), 1.84 (m, 1H, H6β) , 2.08 (m, 1H, CHMe ₂ ), 2.43 (s, 3H, OAc), 2.45 (m, 1H, H6α), 2.89 (b, 1H, 20H), 3.08 (d, J = 5.3 Hz, 1H, H3 ), 3.83 (m, 1H, H7), 3.94 (m, 1H, H3 '), 3.98 (d, J = 3.6 Hz, 1H, H9), 4.18 (d, J = 8.3 Hz, H20β), 4.22 (d , J = 8.3 Hz, H20α, 4.33 (m, 2H, OH), 4.46 (d, 2H, OH), 4.58 (m, 2H, H2 'and OH), 4.94 (m, 1H, H10), 5.13 ( m, 1H, H5), 5.81 (b, 1H, OH), 6.04 (d, J = 7.2 Hz, 1H, H13), 6.28 (d, J = 5.3 Hz, 1H, H2), 6.30 (d, J = 8.6 Hz, 1H, NH), 7.48-7.58 (m, 3H), 8.13 (d, J = 7.2 Hz, 2H)

Example 7

13-{(2 R , 3 S ) -3- (furyl-2-carbonyl) amino-5-methyl-2-hydroxyhexanoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III)

Yield: 79%

Elemental Analysis C ₄₁ H ₅₃ NO ₁₅ calcd. C 61.57%; H 6.68%; N 1.75%

Found C 61.63%; H 6.70%; N 1.80%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 0.96 (d, J = 6.9 Hz, 3H, CH ₃ ), 1.01 (d, J = 6.9 Hz, 3H, CH ₃ ), 1.23 (s, 3H, H17), 1.56 (m, 2H, CH ₂ ), 1.58 (s, 3H, H16), 1.71 (s, 3H, H19), 1.77 (m, 1H, CHMe ₂ ), 1.82 (s, 3H, H18 ), 1.88 (m, 1H, H6β), 2.50 (s, 3H, OAc), 2.47 (m, 1H, H6α), 2.83 (b, 1H, 0H), 3.13 (d, J = 5.4 Hz, 1H, H3 ), 4.03 (m, 2H, H2 and H3 '), 4.21 (d, J = 3.8 Hz, 1H, H9), 4.26-4.33 (m, 4H, H20β, H20α and 20H), 4.45 (m, 1H, OH ), 4.61 (m, 1H, H2 '), 4.65 (d, d, J = 6.2 Hz, H14), 4.90 (m, 2H, H10 and OH), 5.14 (m, 1H, H5), 6.03 (m, 2H, H13 and OH), 6.27 (d, J = 5.4 Hz, 1H, H2), 6.60 (dd, J = 3.5 Hz, J = 1.7 Hz, 1H), 7.14 (d, J = 3.4 Hz, 1H), 7.54-7.72 (m, 5H), 8.15 (d, J = 7.1 Hz, 2H)

Example 8

13-{(2 R , 3 S ) -3- (furyl-2-carbonyl) amino-4-methyl-2-hydroxypentanoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III)

Yield: 66%

Elemental Analysis C ₄₀ H ₅₁ NO ₁₅ calcd. C 61.14%; H 6.54%; N 1.78%

Found C 61.11%; H 6.53%; N 1.64%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.03 (d, J = 6.57 Hz, 3H, CH ₃ ), 1.21 (d, J = 6.7 Hz, 3H, CH ₃ ), 1.23 (s, 3H, H17), 1.67 (s, 3H, H16), 1.70 (s, 3H, H19), 1.76 (s, 3H, H18), 1.92 (m, 1H, H6β), 2.30 (m, 1H, CHMe ₂ ) , 2.46 (m, 1H, H6α), 2.53 (s, 3H, OAc), 2.87 (b, 1H, 0H), 3.10 (d, J = 5.3 Hz, 1H, H3), 3.99 (m, 1H, H7) , 4.04 (m, 1H, H3 '), 4.17-4.25 (m, 3H, H20β, H20α and H9), 4.32 (m, 2H, 2OH), 4.52 (m, 1H, H14), 4.58 (m, 1H, H2 '), 4.71 (b, 2H, 20H), 4.93 (m, 1H, H10), 5.13 (m, 1H, H5), 5.96 (d, J = 3.7 Hz, 1H, OH), 6.00 (d, J = 6.9 Hz, 1H, H13), 6.26 (d, J = 5.4 Hz, 1H, H2), 6.60 (dd, J = 3.4 Hz, J = 1.7 Hz, 1H), 7.14 (d, J = 3.3 Hz, 1H ), 7.54-7.65 (m, 3H), 7.73 (d, J = 1.7 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H, NH), 8.15 (d, J = 7.1 Hz, 2H)

Example 9

13-{(2 R , 3 S ) -3- (furyl-2-carbonyl) amino-3-phenyl-2-hydroxypropionyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III)

Yield: 70%

Elemental Analysis C ₄₃ H ₄₉ NO ₁₅ calcd C 63.00%; H 6.02%; N 1.71%

Found C 63.22%; H 5.99%; N 1.68%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.23 (s, 3H, H17), 1.68 (s, 3H, H16), 1.70 (s, 3H, H19), 1.83 (s, 3H, H18 ), 1.89 (m, 1H, H6β), 2.43 (m, 1H, H6α), 2.45 (s, 3H, OAc), 2.95 (b, 1H, OH), 3.15 (d, J = 5.3 Hz, 1H, H3 ), 3.95 (m, 1H, H7), 4.17 (d, 1H, J = 8.0 Hz, H20β), 4.22 (d, 1H, J = 8.0 Hz, H20α), 4.29-4.35 (m, 4H, 3OH, and H9 ), 4.59 (m, 1H, H14), 4.90-4.97 (m, 2H, H2 'and H5), 5.12-5.17 (m, 2H, H10 and OH), 5.96 (bd, 1H, H3'), 6.04 ( d, J = 4.8 Hz, 1H, OH), 6.11 (d, J = 5.7 Hz, 1H, H13), 6.29 (d, J = 5.4 Hz, 1H, H2), 6.61 (dd, J = 3.4 Hz, J = 1.7 Hz, 1H), 7.19 (d, J = 3.4 Hz, 1H), 7.32-7.65 (m, 8H), 7.75 (d, J = 1.72 Hz, 1H), 8.05 (d, J = 9.5 Hz, 1H , NH), 8.14 (d, J = 7.1 Hz, 2H)

Example 10

13-[(2 R , 3 S ) -3- (t-butoxycarbonyl) amino-2-hydroxy-3-{( RS ) -2-tetrahydrofuranyl} propionyl] -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III)

Yield: 65%

Elemental Analysis C ₄₁ H ₅₇ NO ₁₆ calc. C 60.06%; H 7.01%; N 1.71%

Found C 60.00%; H 6.95%; N 1.76%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.19 (s, 3H, H17), 1.34 (s, 9H, CH ₃ ), 1.36 (s, 3H, H16), 1.74 (s, 3H, H19), 1.80-2.18 (m, 5H), 1.88 (s, 3H, H18), 2.45 (s, 3H, OAc), 2.45 (m, 1H, H6α), 2.88 (b, 2H), 3.79 (m, 1H, H7), 3.89 (m, 2H), 4.12-4.38 (m, 8H), 4.44 (m, 1H), 4.52 (d, J = 5.6 Hz, 1H, H2 '), 4.64 (m, 1H), 4.95 (m, 1H, H5), 5.22 (m, 1H), 5.79 (m, 1H), 5.98 (d, J = 5.3 Hz, 1H, H2), 6.07 (1H, J = 5.6 Hz, H13), 6.43 (d, J = 8.4, 1H, NH), 7.50-7.65 (m, 3H), 8.10 (d, J = 7.1 Hz, 2H)

Example 11

13-{(2 R , 3 S ) -3-benzoylamino-2-hydroxy-3- (2-furyl) propionyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III)

Yield: 69%

Elemental Analysis C ₄₃ H ₄₉ NO ₁₅ calcd C 63.00%; H 6.02%; N 1.71%

Found C 62.87%; H 5.88%; N 1.77%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.27 (s, 3H, H17), 1.39 (s, 9H, CH ₃ ), 1.67 (s, 3H, H16), 1.73 (s, 3H, H19), 1.83 (m, 1H, H6β), 1.83 (s, 3H, H18), 2.45 (s, 3H, OAc), 2.45 (m, 1H, H6α), 3.16 (d, J = 5.3 Hz, 1H, H3), 4.05 (m, 2H), 4.18-4.35 (m, 5H), 4.56 (b, 1H), 4.88-4.96 (m, 5H), 5.14 (m, 1H, H5), 6.08 (1H, J = 5.5 Hz, H13), 6.17 (m, 1H, H3 '), 6.28 (d, J = 5.3 Hz, 1H, H2), 6.46 (dd, J = 3.2 Hz, J = 1.7 Hz, 1H), 6.61 (d , J = 3.2 Hz, 1H), 7.45-7.63 (m, 7H), 7.95 (d, J = 7.0 Hz, 2H), 8.17 (d, J = 7.1 Hz, 2H), 8.34 (b, 1H, NH)

Example 12

13-{(2 R , 3 S ) -3- (t-butoxycarbonyl) amino-2-hydroxy-3- (2-furyl) propionyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin ( III)

Yield: 56%

Elemental Analysis C ₄₁ H ₅₃ NO ₁₆ calc. C 60.36%; H 6.55%; N 1.72%

Found C 60.18%; H 6.72%; N 1.68%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.27 (s, 3H, H17), 1.39 (s, 9H, CH ₃ ), 1.67 (s, 3H, H16), 1.73 (s, 3H, H19), 1.83 (m, 1H, H6β), 1.83 (s, 3H, H18), 2.45 (s, 3H, OAc), 2.45 (m, 1H, H6α), 3.19 (d, J = 5.3 Hz, 1H, H3), 4.05 (m, 1H, H7), 4.11-4.32 (m, 4H), 4.61 (m, 1H), 4.84-4.96 (m, 6H), 5.16 (m, 1H, H5), 5.46 (m, 1H), 5.78 (m, 1H), 6.07 (1H, J = 5.5 Hz, H13), 6.25 (d, J = 5.3 Hz, 1H, H2), 6.43 (dd, J = 3.2 Hz, J = 1.7 Hz, 1H), 6.48 (d, J = 3.2 Hz, 1H), 6.84 (d, J = 8.4, 1H, NH), 7.38-7.76 (m, 5H), 8.13 (d, J = 7.0 Hz, 2H)

Example 13

13-{(2 R , 3 S ) -3- (cyclopropylcarbonyl) amino-2-hydroxy-3- (2-furyl) propionyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III)

Yield: 44%

Elemental Analysis C ₄₀ H ₄₉ NO ₁₅ calcd C 61.29%; H 6.30%; N 1.79%

Found C 61.33%; H 6.22%; N 1.72%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 0.85-0.89 (m, 4H, cyclopropyl), 1.21 (s, 3H, H17), 1.62 (s, 3H, H16), 1.68 (s, 3H, H19), 1.83 (m, 1H, H6β), 1.83 (s, 3H, H18), 2.45 (s, 3H, OAc), 2.45 (m, 1H, H6α), 3.21 (d, J = 5.4 Hz, 1 H, H 3), 3.49 (m, 1 H). 4.05 (m, 1H, H7), 4.21-4.35 (m, 6H), 4.46 (m, 1H), 4.82 (m, 1H), 4.97 (m, 1H, H5), 5.01 (b, 2H), 5.18 ( m, 1H), 5.78 (m, 1H), 5.83 (m, 1H), 6.07 (1H, J = 5.5 Hz, H13), 6.25 (d, J = 5.3 Hz, 1H, H2), 6.51 (m, 2H ), 6.84 (d, J = 8.4, 1H, NH), 7.26-7.55 (m, 4H), 8.13 (d, J = 7.0 Hz, 2H)

Example 14

13-{(2 R , 3 S ) -3-benzoylamino-2-hydroxy-3- (2-thiophenyl) propionyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III)

Yield: 46%

Elemental Analysis C ₄₃ H ₄₉ NO ₁₄ S Est. C 61.78% H 5.91%; N 1.68%; S 3.84%

Found C 61.52%; H 5.99%; N 1.70%; S 3.68%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.28 (s, 3H, H17), 1.64 (s, 6H, H16), 1.72 (s, 6H, H19), 1.84 (s, 3H, H18 ), 1.86 (m, 1H, H6β), 2.08 (b, 2H, OH), 2.45 (m, 1H, H6α), 2.46 (s, 3H, OAc), 3.14 (d, J = 5.3 Hz, 1H, H3 ), 4.01 (m, 1H, H7), 4.16-4.33 (m, 5H), 4.46 (m, 1H), 4.56 (m, 1H), 4.73 (m, 1H), 4.91 (m, 1H), 5.14 ( m, 1H, H5), 5.43 (m, 2H), 6.08 (d, J = 6.5 Hz, 1H, H13), 6.26 (m, 2H, H2, and H3 '), 7.41-7.63 (m, 9H), 7.88 (d, J = 7.0 Hz, 2H), 7.93 (d, J = 8.3 Hz, 1H, NH), 8.16 (d, J = 7.2 Hz, 2H)

Example 15

13-{(2 R , 3 S ) -3- (t-butoxycarbonyl) amino-2-hydroxy-3- (2-thiophenyl) propionyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III)

Yield: 40%

Elemental Analysis C ₄₁ H ₅₃ NO ₁₅ S Est. C 59.19% H 6.42%; N 1.68%; S 3.85%

Found C 59.30%; H 6.29%; N 1.71%; S 3.70%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.32 (s, 3H, H17), 1.41 (s, 9H, CH ₃ ), 1.72 (s, 6H, H16 and H19), 1.84 (s, 3H, H18), 1.86 (m, 1H, H6β), 2.08 (b, 2H, OH), 2.38 (s, 3H, OAc), 2.38 (m, 1H, H6α), 2.95 (b, 1H, OH), 3.14 (d, J = 5.3 Hz, 1H, H3), 4.14-4.47 (m, 7H), 4.86 (d, J = 3.5 Hz, 1H, H3 '), 5.00 (m, 1H, H2'), 5.23 ( m, 1H, H5), 5.52 (m, 1H, OH), 5.69 (m, 2H), 6.04 (d, J = 6.5 Hz, 1H, H13), 6.25 (d, J = 5.3, 1H, H2), 7.05 (dd, J = 3.5 Hz, J = 5.1 Hz, 1H), 7.23 (dd, J = 0.9 Hz, J = 3.5 Hz), 7.32 (dd, J = 0.9 Hz, J = 5.1 Hz, 1H), 7.49 -7.63 (m, 3H), 8.17 (d, J = 7.2 Hz, 2H)

Example 16

13-{(2 R , 3 S ) -3-benzoylamino-2-hydroxy-5-methyl-4-hexenoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III)

Yield: 42%

Elemental Analysis C ₄₃ H ₅₃ NO ₁₄ calcd. C 63.93% H 6.61%; N 1.73%

Found C 63.87%; H 6.72%; N 1.83%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.28 (s, 3H, H17), 1.67 (s, 3H, H16), 1.72 (s, 3H, H19), 1.79 (s, 3H, CH ₃ ), 1.81 (s, 3H, CH ₃ ), 1.86 (m, 1H, H6β), 2.01 (s, 3H, H18), 2.08 (b, 2H, OH), 2.47 (s, 3H, OAc), 2.47 (m, 1H, H6α), 3.15 (d, J = 5.2 Hz, 1H, H3), 3.62 (m, 2H), 3.97 (m, 1H, H7), 4.18-4.31 (m, 5H), 4.56 (b , 1H), 4.92 (m, 2H), 5.15 (m, 2H), 6.07 (d, J = 6.2 Hz, 1H, H13), 6.31 (m, 2H, H2, and H3 '), 7.44-7.63 (m, 6H), 7.92 (d, J = 7.0 Hz, 2H), 8.14 (d, J = 7.1 Hz, 2H), 8.33 (d, J = 8.3 Hz, 1H, NH)

Example 17

13-{(2 R , 3 S ) -3- (t-butoxycarbonyl) amino-2-hydroxy-5-methyl-4-hexenoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin ( III)

Yield: 48%

Elemental Analysis C ₄₁ H ₅₇ NO ₁₅ calcd. C 61.26% H 7.15%; N 1.74%

Found C 61.31%; H 7.25%; N 1.68%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.30 (s, 3H, H17), 1.41 (s, 9H, CH ₃ ), 1.62 (s, 3H, H16), 1.72 (s, 3H, H19), 1.79 (s, 3H, CH ₃ ), 1.81 (s, 3H, CH ₃ ), 1.86 (m, 1H, H6β), 1.89 (s, 3H, H18), 2.08 (b, 2H, OH), 2.30 (s, 3H, OAc), 2.49 (m, 1H, H6α), 2.92 (b, 1H, OH), 4.14-4.47 (m, 8H), 4.96-5.01 (m, 3H), 5.64-5.68 (m , 2H), 6.04 (d, J = 6.6 Hz, 1H, H13), 6.25 (d, J = 5.3 Hz, 1H, H2), 7.38-7.61 (m, 3H), 8.13 (d, J = 7.2 Hz, 2H)

Example 18

13-{(2 R , 3 S ) -3- (t-butoxycarbonyl) amino-2-hydroxy-3- (4-pyridyl) propionyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III)

Yield: 31%

Elemental Analysis C ₄₂ H ₅₄ N ₂ O ₁₅ Cal. C 61.01% H 6.58%; N 3.39%

Found C 60.98%; H 6.67%; N 3.43%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.22 (s, 3H, H17), 1.33 (s, 9H, CH ₃ ), 1.67 (s, 6H, H16), 1.75 (s, 6H, H19), 1.82 (m, 1H, H6β), 1.98 (s, 3H, H18), 2.08 (b, 2H, OH), 2.32 (s, 3H, OAc), 2.52 (m, 1H, H6α), 3.17 ( d, J = 5.3 Hz, 1H, H3), 4.02 (m, 1H, H7), 4.21-4.33 (m, 5H), 4.40 (m, 1H), 4.63 (m, 2H), 4.98 (m, 1H) , 5.16 (m, 1H), 5.48 (m, 2H), 6.11 (d, J = 6.1 Hz, 1H, H13), 6.26 (d, J = 5.3 Hz, 1H, H2), 6.35 (m, 1H, H3 '), 7.37 (m, 2H), 7.43-7.65 (m, 3H), 8.09 (d, J = 7.1 Hz, 2H), 8.67 (m, 2H)

Example 19

10-deacetyl-9-deketo-9β, 14β-dihydroxypaclitaxel-1,14-carbonate

Yield: 45%

Elemental Analysis C ₄₆ H ₄₇ NO ₁₅ calcd C 64.55%; H 5.53%; N 1.64%

Found C 64.51%; H 5.57%; N 1.71%

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.26 (s, 3H, H17), 1.66 (s, 3H, H16), 1.73 (s, 3H, H19), 1.85 (s, 1H, OH), 2.04 (s, 3H, H18), 2.05 (m, 1H, H6β), 2.22 (m, 1H, H6α), 2.38 (s, 3H, OAc), 2.76 (d, J = 5.2 Hz, 1H, H3), 3.66 (b, 2H, OH), 3.88 (m, 1H, H7), 3.90 (d, J = 8.4 Hz, 1H, NH), 4.27 (m, 1H, H9), 4.28 (d, J = 8.4 Hz, 1H, H20β), 4.35 (d, J = 8.4 Hz, 1H, H20α), 4.58 (d, J = 3.4 Hz, 1H, OH), 4.68 (d, J = 5.7 Hz, 1H, H14), 4.82 (m , 1H, H2 '), 5.00 (m, 1H, H5), 5.14 (m, 1H, H10), 5.88 (m, 1H, H3'), 6.32 (d, J = 5.4 Hz, 1H, H13), 6.52 (d, J = 5.2 Hz, 1H, H2), 7.32-7.62 (m, 11H), 7.80 (d, J = 7.2 Hz, 2H), 8.03 (d, J = 7.2 Hz, 2H)

Example 20

13-{(2 R , 3 S ) -3-benzoylamino-5-methyl-2-hydroxyhexanoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III) -1,14-carbonate

Yield: 49%

Elemental Analysis C ₄₄ H ₅₃ NO ₁₅ calcd C 63.22%; H 6.39%; N 1.68%

Found C 63.31%; H 6.30%; N 1.71%

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 0.82 (d, J = 5.9 Hz, 3H, CH ₃ ), 0.84 (d, J = 5.9 Hz, 3H, CH ₃ ), 1.15 (s, 3H, H17), 1.41 (m, 2H, CH ₂ ), 1.46 (s, 3H, H16), 1.56 (s, 3H, H19), 1.64 (m, 2H, CHMe ₂ and H6β), 1.72 (s, 3H, H18 ), 2.11 (m, 1H, H6α), 2.26 (s, 3H, OAc), 2.63 (b, 1H, OH), 2.69 (d, J = 5.3 Hz, 1H, H3), 3.86 (m, 1H, H7 ), 3.98 (m, 1H, H3 '), 4.04 (d, J = 8.2 Hz, 1H, H20β), 4.13 (d, J = 8.2 Hz, 1H, H20α), 4.27 (b, 1H, OH), 4.33 (d, J = 3.2 Hz, 1H, H2 '), 4.43 (d, J = 4.9 Hz, 1H, H9), 4.56 (b, 2H, OH), 4.67 (d, J = 5.9 Hz, 1H, H14) , 4.78 (d, J = 5.6 Hz, 1H, H10), 4.93 (m, 1H, H5), 5.27 (d, J = 7.5 Hz, NH), 6.20 (d, J = 5.9 Hz, 1H, H13), 6.31 (d, J = 5.3 Hz, 1H, H2), 7.21-7.44 (m, 6H), 7.67 (d, J = 7.1 Hz, 2H), 7.85 (d, J = 7.3 Hz, 2H)

Example 21

13-{(2 R , 3 S ) -3-benzoylamino-4-methyl-2-hydroxypentanoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III) -1,14-carbonate

Yield: 31%

Elemental Analysis C ₄₃ H ₅₁ NO ₁₅ calcd. C 62.84%; H 6.25%; N 1.70%

Found C 62.80%; H 6.30%; N 1.67%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.08 (d, J = 6.7 Hz, 3H, CH ₃ ), 1.15 (d, J = 6.7 Hz, 3H, CH ₃ ), 1.25 (s, 3H, H17), 1.51 (s, 3H, H16), 1.60 (s, 3H, H19), 1.72 (s, 3H, H18), 1.85 (m, 1H, H6β), 2.24 (m, 2H, H6α, and CHMe ₂ ), 2.48 (s, 3H, OAc), 2.79 (d, J = 5.2Hz, 1H, H3), 3.46 (b, 1H, OH), 3.56 (d, J = 5.3Hz, 1H, OH), 3.84 (m, 2H, H3 'and H7), 4.31-4.40 (m, 4H, H2', H9, H20β and H20α), 4.69 (b, 2H, 0H), 4.78 (d, J = 5.9 Hz, 1H, H14 ), 5.02 (d, J = 5.6 Hz, 1H, H10), 5.17 (m, 1H, H5), 6.30 (d, J = 5.9 Hz, 1H, H13), 6.52 (d, J = 5.2 Hz, 1H, H2), 7.39-7.63 (m, 6H), 7.75 (d, J = 7.2 Hz, 2H), 8.06 (d, J = 7.3 Hz, 2H)

Example 22

9-deketo-9β, 14β-dihydroxydocetaxel-1,14-carbonate

Yield: 53%

Elemental Analysis C ₄₄ H ₅₃ NO ₁₆ calc. C 62.04%; H 6.27%; N 1.64%

Found C 61.97%; H 6.32%; N 1.63%

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.35 (s, 3H, H17), 1.39 (s, 9H, CH ₃ ), 1.59 (s, 3H, H16), 1.72 (s, 3H, H19) , 1.91 (s, 3H, H18), 1.85 (s, 1H, OH), 2.13 (m, 1H, H6β), 2.28 (m, 1H, H6α), 2.37 (s, 3H, OAc), 2.83 (d, J = 5.0 Hz, 1H, H3), 2.87 (b, 1H, OH), 3.39 (b, 1H, OH), 3.54 (b, 1H, OH), 3.94 (m, 1H, H7), 4.09 (1H, OH), 4.29 (m, 1H, H9), 4.32 (d, J = 8.4 Hz, 1H, H20β), 4.36 (d, J = 8.4 Hz, 1H, H20α), 4.68 (d, J = 5.7 Hz, 1H , H14), 4.68 (m, 1H, H2 '), 5.02 (m, 1H, H5), 5.29 (m, 1H, H10), 5.35 (d, J = 9.8 Hz, 1H, NH), 5.68 (m, 1H, H3 '), 6.40 (d, J = 5.4 Hz, 1H, H13), 6.56 (d, J = 5.0 Hz, 1H, H2), 7.32-7.65 (m, 8H), 8.03 (d, J = 7.1 Hz, 2H)

Example 23

13-{(2 R , 3 S ) -3- (t-butoxycarbonyl) amino-5-methyl-2-hydroxyhexanoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III) -1 14-carbonate

Yield: 48%

Elemental Analysis C ₄₂ H ₅₇ NO ₁₆ calc. C 60.64%; H 6.91%; N 1.68%

Found C 60.57%; H 6.87%; N 1.72%

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 0.90 (d, J = 6.2 Hz, 3H, CH ₃ ), 0.91 (d, J = 6.2 Hz, 3H, CH ₃ ), 1.29 (s, 3H, H17), 1.35 (s, 9H, CH ₃ ), 1.41 (m, 2H, CH ₂ ), 1.56 (s, 3H, H16), 1.63 (m, 1H, CHMe ₂ ), 1.76 (s, 3H, H19) , 1.89 (s, 3H, H18), 1.90 (m, 1H, H6β), 2.37 (s, 3H, OAc), 2.40 (m, 1H, H6α), 2.97 (d, J = 5.2 Hz, 1H, H3) , 3.24 (b, 1H, OH), 3.82 (m, 1H, H7), 4.03 (m, 1H, H3 '), 4.07 (d, J = 8.0 Hz, 1H, H20β), 4.18 (d, J = 8.0 Hz, 1H, H20α), 4.25 (d, J = 3.2 Hz, 1H, H2 '), 4.49 (d, J = 5.5 Hz, 1H, H9), 4.89 (b, 3H, OH), 4.90 (d, J = 5.6 Hz, 1H, H14), 4.93 (m, 1H, H5), 5.03 (d, J = 5.5 Hz, 1H, H10), 6.19 (d, J = 9.6 Hz, 1H, NH), 6.32 (d, J = 5.6 Hz, 1H, H13), 6.49 (d, J = 5.3 Hz, 1H, H2), 7.44-7.49 (m, 2H), 7.58-7.60 (m, 1H), 8.00 (d, J = 7.3 Hz , 2H)

Example 24

13-{(2 R , 3 S ) -3- (t-butoxycarbonyl) amino-4-methyl-2-hydroxypentanoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III) -1 14-carbonate

Yield: 34%

Elemental Analysis C ₄₁ H ₅₅ NO ₁₆ calc. C 60.21%; H 6.78%; N 1.71%

Found C 60.24%; H 6.69%; N 1.68%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.03 (d, J = 6.7 Hz, 3H, CH ₃ ), 1.08 (d, J = 6.7 Hz, 3H, CH ₃ ), 1.36 (s, 3H, H17), 1.42 (s, 9H, CH ₃ ), 1.71 (s, 3H, H16), 1.73 (s, 3H, H19), 1.84 (m, 1H, CHMe ₂ ), 1.90 (s, 3H, H18 ), 1.99 (m, 1H, H6β), 2.32 (m, 1H, H6α), 2.43 (s, 3H, OAc), 2.85 (d, J = 5.1 Hz, 1H, H3), 3.80 (b, 2H, OH ), 3.80 (m, 1H, H7), 3.97 (m, 1H, H3 '), 4.28 (d, J = 8.2 Hz, 1H, H20β), 4.35 (b, 2H, OH), 4.36 (d, J = 8.0 Hz, 1H, H20α), 4.57 (d, J = 3.1 Hz, 1H, H2 '), 4.75 (d, J = 5.8 Hz, 1H, H9), 4.98 (d, J = 5.6 Hz, 1H, H14) , 5.01 (m, 1H, H5), 5.28 (d, J = 5.8 Hz, 1H, H10), 6.37 (d, J = 5.6 Hz, 1H, H13), 6.54 (d, J = 5.1 Hz, 1H, H2 ), 7.46-7.51 (m, 2H), 7.60-7.65 (m, 1H), 8.04 (d, J = 7.2 Hz, 2H)

Example 25

13-{(2 R , 3 S ) -3- (furyl-2-carbonyl) amino-5-methyl-2-hydroxyhexanoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III) -1 14-carbonate

Yield: 51%

Elemental Analysis C ₄₂ H ₅₁ NO ₁₆ calc. C 61.08%; H 6.22%; N 1.70%

Found C 61.11%; H 6.23%; N 1.65%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 0.96 (d, J = 6.9 Hz, 3H, CH ₃ ), 0.99 (d, J = 6.9 Hz, 3H, CH ₃ ), 1.23 (s, 3H, H17), 1.42 (s, 2H, CH ₂ ), 1.54 (s, 3H, H16), 1.63 (s, 3H, H19), 1.67 (m, 1H, CHMe ₂ ), 1.70 (s, 3H, H18 ), 1.88 (m, 1H, H6β), 2.53 (s, 3H, OAc), 2.60 (m, 1H, H6α), 2.79 (d, J = 5.7 Hz, 1H, H3), 2.82 (b, 2H, OH ), 3.81 (m, 1H, H7), 4.27-4.36 (m, 3H, H20β, H20α, and H3 '), 4.43 (b, 1H, OH), 4.61 (d, J = 6.0 Hz, 1H, H9), 4.68 (m, 1H, H2 '), 4.91 (d, J = 5.5 Hz, 1H, H14), 4.91 (b, 1H, OH), 5.05 (m, 1H, H5), 5.24 (d, J = 6.9 Hz , 1H, H10), 6.28 (d, J = 5.5 Hz, 1H, H13), 6.32 (d, J = 5.7 Hz, 1H, H2), 6.60 (dd, J = 3.3 Hz, J = 1.7 Hz, 1H) , 7.08 (d, J = 3.3 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H, NH), 7.60-7.75 (m, 4H), 8.16 (d, J = 7.2 Hz, 2H)

Example 26

13-{(2 R , 3 S ) -3- (furyl-2-carbonyl) amino-4-methyl-2-hydroxypentanoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III) -1 14-carbonate

Yield: 43%

Elemental Analysis C ₄₁ H ₄₉ NO ₁₆ calc. C 60.66%; H 6.08%; N 1.73%

Found C 60.64%; H 6.03%; N 1.75%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.04 (d, J = 6.9 Hz, 3H, CH ₃ ), 1.15 (d, J = 6.9 Hz, 3H, CH ₃ ), 1.23 (s, 3H, H17), 1.53 (s, 3H, H16), 1.62 (s, 3H, H19), 1.68 (s, 3H, H18), 2.05 (m, 1H, CHMe ₂ ), 2.15 (m, 1H, H6β) , 2.58 (m, 1H, H6α), 2.60 (s, 3H, OAc), 2.82 (d, J = 5.7 Hz, 1H, H3), 2.89 (b, 2H, OH), 3.78 (m, 1H, H7) , 4.30 (d, J = 8.3 Hz, 1H, H20β), 4.37 (d, J = 8.3 Hz, 1H, H20α), 4.37 (b, 2H, OH), 4.41 (m, 1H, H3 '), 4.78 ( d, J = 5.1 Hz, 1H, H2 '), 4.82 (b, 1H, OH), 4.90 (d, J = 6.2 Hz, 1H, H9), 4.98 (m, 2H, H5 and H14), 5.28 (d , J = 5.1 Hz, 1H, H10), 6.26 (d, J = 5.5 Hz, 1H, H13), 6.30 (d, J = 5.7 Hz, 1H, H2), 6.51 (d, J = 5.7 Hz, 1H, H2), 6.51 (dd, J = 3.4 Hz, J = 1.7 Hz, 1H), 7.07 (d, J = 3.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H, NH), 7.62-7.74 ( m, 4H), 8.16 (d, J = 7.2 Hz, 2H)

Example 27

13-{(2 R , 3 S ) -3- (furyl-2-carbonyl) amino-3-phenyl-2-hydroxypropionyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III) -1 14-carbonate

Yield: 52%

Elemental Analysis C ₄₄ H ₄₇ NO ₁₆ calc. C 62.48%; H 5.84%; N 1.66%

Found C 60.51%; H 5.71%; N 1.60%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.23 (s, 3H, H17), 1.66 (s, 3H, H16), 1.68 (s, 3H, H19), 1.92 (m, 1H, H6b ), 1.97 (s, 3H, H18), 2.47 (m, 1H, H6a), 2.47 (s, 3H, OAc), 3.34 (d, J = 5.4 Hz, 1H, H3), 3.91 (m, 1H, H7) ), 4.10 (d, J = 7.9 Hz, 1H, H20b), 4.17 (d, J = 7.9 Hz, 1H, H20a), 4.32 (d, J = 4.0 Hz, 1H, OH), 4.46 (d, J = 6.7 Hz, 1H, H9), 4.63 (m, 2H, OH, and H2 ′), 4.90 (d, J = 6.1 Hz, 1H, H14), 5.00 (m, 2H, H5, and H10), 5.12 (m, 1H , OH), 5.56 (bd, 1H, OH), 5.77 (dd, J = 4.0 Hz, J = 8.9 Hz, 1H, H3 '), 6.37 (d, J = 6.1 Hz, 1H, H13), 6.58 (d , J = 5.4 Hz, 1H, H2), 6.62 (dd, J = 3.4 Hz, J = 1.7 Hz, 1H), 7.13 (d, J = 3.4 Hz, 1H), 7.57-7.75 (m, 9H), 7.96 (d, J = 8.9 Hz, 1H, NH), 8.11 (d, J = 7.2 Hz, 2H)

Example 28

13-[(2 R , 3 S ) -3- (t-butoxycarbonyl) amino-2-hydroxy-3-{( RS ) -2-tetrahydrofuranyl} propionyl] -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III) -1,14-carbonate

Yield: 63%

Elemental Analysis C ₄₂ H ₅₅ NO ₁₇ calcd. C 59.64% H 6.55%; N 1.66%

Found C 59.26%; H 6.60%; N 1.65%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.21 (s, 1H, H17), 1.36 (s, 9H, CH ₃ ), 1.38 (s, 3H, H16), 1.74 (s, 3H, H19), 1.80-2.18 (m, 5H), 1.88 (s, 3H, H18), 2.45 (s, 3H, OAc), 2.45 (m, 1H, H6α), 2.87 (d, J = 5.2 Hz, 1H, H3), 3.79 (m, 1H, H7), 3.94 (m, 2H), 4.12 (d, J = 8.0 Hz, 1H, H20α), 4.20-4.38 (m, 6H), 4.44 (m, 1H), 4.52 (d, J = 5.6 Hz, 1H, H2 '), 4.64 (m, 1H), 4.95 (m, 1H, H5), 5.22 (m, 1H), 5.67 (m, 1H), 5.79 (m, 1H) , 6.36 (1H, J = 5.6 Hz, H13), 6.54 (d, J = 5.3, 1H, H2), 7.45-7.65 (m, 3H), 8.05 (d, J = 7.2 Hz, 2H)

Example 29

13-{(2 R , 3 S ) -3-benzoylamino-2-hydroxy-3- (2-furyl) propionyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III) -1,14- Carbonate

Yield: 58%

Elemental Analysis C ₄₄ H ₄₇ NO ₁₆ calcd. C 62.48% H 5.60%; N 1.66%;

Found C 62.80%; H 5.60%; N 1.65%;

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.33 (s, 3H, H17), 1.68 (s, 6H, H16), 1.72 (s, 6H, H19), 1.84 (m, 1H, H6β ), 2.04 (s, 3H, H18), 2.45 (m, 1H, H6α), 2.50 (s, 3H, OAc), 2.78 (m, 1H), 3.05 (d, J = 5.4 Hz, 1H, H3), 3.08 (b, 1H, OH), 3.91 (m, 1H, H7), 4.15 (d, J = 7.9 Hz, 1H, H20β), 4.25 (d, J = 7.9 Hz, 1H, H20α), 4.25 (m, 1H), 4.42 (m, 1H), 4.63 (d, J = 6.1 Hz, 1H, H14), 4.97 (m, 2H), 5.04 (d, J = 4.7 Hz, 1H, H2 '), 5.12 (d, J = 5.4 Hz, 1H, H10), 5.48 (m, 1H), 5.93 (m, 1H, H3 '), 6.42 (m, 2H, H13 and furan), 6.48 (d, J = 3.2 Hz, 1H), 6.55 (d, J = 5.4, 1H, H2), 7.45-7.70 (m, 7H), 8.00 (m, 1H, NH), 8.00 (d, J = 7.1Hz, 2H), 8.12 (d, J = 7.2 Hz, 2H)

Example 30

13-{(2 R , 3 S ) -3- (t-butoxycarbonyl) amino-2-hydroxy-3- (2-furyl) propionyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin ( III) -1,14-carbonate

Yield: 65%

Elemental Analysis C ₄₂ H ₅₁ NO ₁₇ calcd. C 59.92% H 6.11%; N 1.66%

Found C 60.03%; H 6.06%; N 1.75%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.36 (s, 3H, H17), 1.46 (s, 9H, CH3), 1.69 (s, 6H, H16), 1.72 (s, 6H, H19 ), 1.84 (m, 1H, H6β), 1.91 (s, 3H, H18), 2.35 (m, 1H, H6α), 2.40 (s, 3H, OAc), 2.73 (m, 1H), 2.85 (d, J = 5.3 Hz, 1H, H3), 3.42 (m, 1H), 3.49 (m, 1H), 3.98 (m, 1H, H7), 4.07 (m, 1H), 4.30 (m, 1H), 4.30 (d, J = 8.2Hz, 1H, H20β), 4.37 (d, J = 8.2Hz, 1H, H20α), 4.74 (m, 2H), 5.00 (m, 1H), 5.31 (m, 1H), 5.41 (m, 2H ), 6.34-6.39 (m, 3H, H13 and furan), 6.48 (d, J = 3.2 Hz, 1H), 6.54 (d, J = 5.3, 1H, H2), 7.27 (m, 1H), 7.41-7.62 (m, 3H), 8.04 (d, J = 7.3 Hz, 2H)

Example 31

13-{(2 R , 3 S ) -3- (cyclopropylcarbonyl) amino-2-hydroxy-3- (2-furyl) propionyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III) -1,14-carbonate

Yield: 48%

Elemental Analysis C ₄₁ H ₄₇ NO ₁₆ calcd. C 60.81% H 5.85%; N 1.73%

Found C 60.96%; H 5.76%; N 1.72%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 0.72 (m, 2H, cyclopropyl), 0.83 (m, 2H, cyclopropyl), 1.35 (s, 3H, H17), 1.68 (s, 6H , H16), 1.79 (s, 6H, H19), 1.84 (m, 1H, H6β), 2.05 (s, 3H, H18), 2.47 (m, 1H, H6α), 2.49 (s, 3H, OAc), 2.85 (b, 1H), 2.85 (d, J = 5.5 Hz, 1H, H3), 3.93 (m, 1H, H7), 4.13 (d, J = 8.0 Hz, 1H, H20β), 4.23 (d, J = 8.0 Hz, 1H, H20α), 4.30 (d, J = 4.1 Hz, 1H, OH), 4.43 (d, J = 6.8 Hz, 1H, OH), 4.58 (d, J = 5.1 Hz, 1H, H9), 4.65 (m, 1H, H2 '), 4.90-4.98 (m, 3H), 5.20 (m, 1H, H5), 5.36 (d, J = 5.2 Hz, 1H, H10), 5.67 (m, 1H), 6.36- 6.39 (m, 3H, H13 and furan), 6.57 (d, J = 5.4 Hz, 1H, H2), 7.51-7.78 (m, 5H), 8.10 (d, J = 7.7 Hz, 2H)

Example 32

13-{(2 R , 3 S ) -3-benzoylamino-2-hydroxy-3- (2-thiophenyl) propionyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III) -1,14 Carbonate

Yield: 53%

Elemental Analysis C ₄₄ H ₄₇ NO ₁₅ S calculated C 61.32% H 5.60%; N 1.66%; S 3.72%

Found C 61.20%; H 5.60%; N 1.65%; S 3.86%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.29 (s, 3H, H17), 1.67 (s, 6H, H16 and H19), 1.86 (m, 1H, H6β), 1.93 (s, 3H , H18), 1.96 (b, 2H, OH), 2.46 (m, 1H, H6α), 2.51 (s, 3H, OAc), 3.08 (d, J = 5.3Hz, 1H, H3), 3.86 (m, 1H , H7), 4.16 (d, J = 8.0 Hz, 1H, H20β), 4.24 (d, J = 8.0 Hz, 1H, H20α), 4.28 (m, 1H), 4.39 (m, 1H), 4.55 (m, 1H), 4.62 (m, 1H), 4.95 (m, 2H), 5.02 (m, 1H), 5.13 (m, 1H), 5.65 (d, J = 5.8 Hz, 1H), 6.09 (dd, J = 3.9 Hz, J = 8.7 Hz, 3'H), 6.38 (1H, J = 5.8 Hz, H13), 6.58 (d, J = 5.1, 1H, H2), 7.26 (dd, J = 1.1 Hz, J = 3.4 Hz , 1H), 7.39 (dd, J = 1.1 Hz, J = 5.1 Hz), 7.46-7.70 (m, 6H), 7.95 (d, J = 7.6 Hz, 2H), 8.09 (d, J = 7.7 Hz, 2H )

Example 33

13-{(2 R , 3 S ) -3- (t-butoxycarbonyl) amino-2-hydroxy-3- (2-thiophenyl) propionyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III) -1,14-carbonate

Yield: 49%

Elemental Analysis C ₄₂ H ₅₁ NO ₁₆ S Est. C 58.80% H 5.99%; N 1.63%; S 3.74%

Found C 58.60%; H 6.11%; N 1.65%; S 3.82%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.30 (s, 3H, H17), 1.43 (s, 9H, CH ₃ ), 1.72 (s, 6H, H16 and H19), 1.84 (s, 3H, H18), 1.86 (m, 1H, H6β), 2.38 (m, 1H, H6α), 2.41 (s, 3H, OAc), 2.83 (d, J = 5.2 Hz, 1H, H3), 3.08 (b, 1H, OH), 3.52 (b, 1H, OH), 3.70 (m, 1H, H7), 3.93 (m, 1H, OH), 4.30 (d, J = 8.8 Hz, 1H, H20β), 4.38 (d, J = 8.8 Hz, 1H, H20α), 4.29-4.39 (m, 2H), 4.72 (m, 2H), 5.02 (m, 1H), 5.26 (m, 1H), 5.57 (m, 2H), 6.38 (d , J = 5.6Hz, H13), 6.55 (d, J = 5.3Hz, 1H, H2), 7.00 (dd, J = 3.5Hz, J = 5.1Hz, 1H), 7.12 (dd, J = 0.9Hz, J = 3.5 Hz), 7.28 (m, 1H), 7.46-7.65 (m, 3H), 8.05 (d, J = 7.7 Hz, 2H)

Example 34

13-{(2 R , 3 S ) -3-benzoylamino-2-hydroxy-5-methyl-4-hexenoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III) -1,14- Carbonate

Yield: 60%

Elemental Analysis C ₄₄ H ₅₁ NO ₁₅ calcd. C 63.38% H 6.16%; N 1.68%

Found C 63.29%; H 6.09%; N 1.53%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.34 (s, 3H, H17), 1.67 (s, 6H, H16), 1.76 (s, 3H, CH ₃ ), 1.77 (s, 6H, H19), 1.80 (s, 6H, CH ₃ ), 1.85 (m, 1H, H6β), 1.97 (s, 3H, H18), 2.44 (m, 1H, H6α), 2.49 (s, 3H, OAc), 2.78 (b, 1H), 3.03 (d, J = 5.4 Hz, 1H, H3), 3.90 (m, 1H, H7), 4.13 (d, J = 8.0 Hz, 1H, H20β), 4.22 (d, J = 8.0 Hz, 1H, H20α), 4.26 (m, 1H), 4.36 (m, 1H), 4.62 (m, 3H), 4.95 (m, 2H), 5.30 (m, 2H), 5.48 (m, 1H), 6.38 (d, J = 6.1 Hz, 1H, H13), 6.57 (d, J = 5.4 Hz, 1H, H2), 7.45-7.69 (m, 6H), 8.78 (d, J = 8.4 Hz, 1H, NH), 7.92 (dd, J = 7.0 Hz, J = 1.5 Hz, 2H), 8.07 (d, J = 7.7 Hz, 2H)

Example 35

13-{(2 R , 3 S ) -3- (t-butoxycarbonyl) amino-2-hydroxy-5-methyl-4-hexenoyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin ( III) -1,14-carbonate

Yield: 66%

Elemental Analysis C ₄₂ H ₅₅ NO ₁₆ calcd. C 60.79% H 6.68%; N 1.69%

Found C 60.85%; H 6.72%; N 1.56%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ 1.30 (s, 3H, H17), 1.41 (s, 9H, CH ₃ ), 1.62 (s, 3H, H16), 1.72 (s, 3H, H19), 1.79 (s, 3H, CH ₃ ), 1.81 (s, 3H, CH ₃ ), 1.86 (m, 1H, H6β), 1.89 (s, 3H, H18), 2.08 (b, 2H, OH), 2.30 (s , 3H, OAc), 2.49 (m, 1H, H6α), 2.92 (b, 1H, OH), 4.14-4.47 (m, 8H), 4.96-5.01 (m, 3H), 5.64-5.68 (m, 2H) , 6.04 (d, J = 6.6 Hz, 1H, H13), 6.25 (d, J = 5.3, 1H, H2), 7.38-7.61 (m, 3H), 8.13 (d, J = 7.2 Hz, 2H)

Example 36

13-{(2 R , 3 S ) -3- (t-butoxycarbonyl) amino-2-hydroxy-3- (4-pyridyl) propionyl} -10-deacetyl-9-deketo-9β, 14β-dihydroxybacatin (III) -1,14-carbonate

Yield: 39%

Elemental Analysis C ₄₃ H ₅₂ N ₂ O ₁₆ calc. C 60.56%; H 6.15%; N 3.28%

Found C 60.33%; H 6.09%; N 3.20%

¹ H-NMR (300 MHz, acetone-d ₆ ) δ (ppm) 1.56 (s, 3H, H17), 1.62 (s, 9H, CH ₃ ), 1.90 (s, 6H, H16), 2.02 (s, 6H, H19), 2.15 (m, 1H, H6β), 2.20 (s, 3H, H18), 2.49 (m, 1H, H6α), 2.67 (s, 3H, OAc), 3.27 (d, J = 5.3 Hz, 1H, H3), 4.14 (m, 1H, H7), 4.36 (d, J = 7.9 Hz, 1H, H20β), 4.45 (d, J = 7.9 Hz, 1H, H20α), 4.52 (m, 1H), 4.64 (m , 1H), 4.80 (m, 1H), 4.86 (m, 1H), 5.11-5.20 (m, 3H), 5.20 (d, 1H, J = 5.3 Hz), 5.48 (m, 1H), 6.60 (d, J = 6.1 Hz, 1H, H13), 6.76 (m, 1H, H3 '), 6.80 (d, J = 5.3 Hz, 1H, H2), 7.71 (m, 2H), 7.73-7.92 (m, 3H), 8.30 (d, J = 7.1 Hz, 2H), 8.80 (m, 2H)

Experimental Example 1 Measurement of In Vitro Anticancer Activity

The anticancer activity of the compound of formula 1 according to the present invention is known as a sulfohodamine B (SRB) method as described below [P. Skehan, et al., New colorimetric cytotoxicity assay for anti-cancer drug screening , J. Natl. Cancer Inst., 1990 , 82 , 1107-1112], measured in vitro experiments.

The cancer cell lines tested in this experiment were A549 (human lung cancer cell line), HCT15 (human colon cancer cell line), SKOV-3 (human ovarian cancer cell line), XF498 (human CNS cancer cell line), and SK-MEL-2 (human melanoma cell line). ) And paclitaxel (taxol ^?? ) was used as a control compound.

Each cancer cell line was incubated for 48 hours in an incubator at 37 ° C. in the presence of 5% CO ₂ using Sigma's RPMI1640 medium, and the test drug was added to dimethyl sulfoxide (DMSO) along with the control compound, paclitaxel. The solution was dissolved at a concentration of 1 mg / ml, and this solution was added by diluting in a 10-fold dilution unit, and then incubated for 48 hours, and then the culture medium was removed. 50% trichloroacetic acid (TCA) was added thereto at a concentration of 50 μl per well, and the cells were fixed for 1 hour (final concentration 10%). After TCA was removed and the plate was washed with distilled water and dried, 50 μl of 0.4% sulforhodamine B (SRB) dissolved in 1% acetic acid as a dye was added per well. After 20 minutes sulforhodamine B was removed and washed four times with 1% acetic acid solution and then dried. 150 μl of 10 mmol / L unbuffered trisbase {tris (hydroxymethyl) aminomethane} was added to each well, and the mixture was mixed well and absorbance was measured at 540 nm. From the measured absorbance, the concentration of a drug that inhibits the proliferation of cancer cells by 50% using a microplate reader was calculated as anticancer activity (ED ₅₀ ). Table to calculate the anticancer activity of the tested compound according to the present invention on the basis of the results of the measurements ED ₅₀ ratio for the anti-cancer activity of paclitaxel control compound 1 (cytotoxicity: ED ₅₀ of ED ₅₀ / paclitaxel of test compound) It is described in.

As can be seen from the results shown in Table 1, the anticancer active compounds according to the present invention showed an equivalent or rather better anticancer activity compared to the control compound paclitaxel. Therefore, it can be seen that the compound of the present invention can be usefully used as an anticancer agent.

Experimental Example 2 Measurement of Solubility in Water

Compounds of formula (1) according to the present invention exhibit significantly increased water solubility compared to conventional taxane compounds. In order to prove this, the standard solution and the sample solution were prepared according to the method described below, and the water solubility of each test compound was measured by High Performance Liquid Chromatography (HPLC).

Preparation of Standard Solution

5 mg of the sample was precisely measured and dissolved in 10 ml of methanol to prepare a standard solution. A solution of paclitaxel was prepared in the same manner as a control compound in the preparation of the standard solution.

Preparation of the sample solution

The sample was dissolved in a constant amount of water, shaken vigorously for 30 minutes at 5 minute intervals to form a saturated state, and the sample that was no longer dissolved was filtered through a 0.45 μm membrane semipermeable membrane to prepare a sample solution. In preparing the sample solution, an aqueous solution of paclitaxel was always prepared and used together as a control compound.

HPLC analysis conditions

1) Eluent: 50% -65% acetonitrile solution

2) Column: Capcell-pak C18 4.6 × 150mm

3) Detector: UV 235nm

4) Flow rate: 1.5 ml / min

5) Injection amount: 10µl

6) Calculation Method: The solubility in water was measured by calculating the HPLC area of the sample in HPLC area / standard solution ㎎ / mL concentration, and the measured results are shown in Table 2.

As can be seen from the results shown in Table 2, the compound of formula 1 according to the present invention wherein the ketone group at the 9-position is reduced to a hydroxyl group is 4 to 383 times higher than paclitaxel and up to 35 times higher than docetaxel to have a significantly higher water solubility. Indicates.

In addition, in order to prove that the water solubility is increased by reducing the 9-position ketone group to a hydroxy group, a representative compound of the 9β-hydroxytaxane terpine derivatives of the general formula (1) as the compound of the present invention (Examples 1, 4, 19) And 22) and the water solubility with the compound of the formula (6) used as a corresponding starting material, that is, the taxane terpine derivatives before the 9-position ketone group was reduced. Solubility was measured in the same manner as above, and the results are shown in Table 3 below.

As shown in Table 3, the 9β-hydroxy derivatives of the compounds of the present invention can be seen that the water solubility is improved 4 to 16 times compared to the 9-keto derivatives.

Due to this increased water solubility the compounds according to the invention offer many advantages when administered to the human body. That is, when actual paclitaxel is administered to a patient, paclitaxel is dissolved in 50% ethanol and 50% polyoxyethyl castor oil mixture to dissolve the solution in 5% glucose injection, 0.9% sodium chloride injection, 5% glucose injection and 0.9% sodium chloride injection. Or diluted to a concentration of 0.3-1.2 mg / ml in 5% glucose ring gel injection solution or the like. However, considering that the recommended daily dose of paclitaxel, suggested by the US Food and Drug Administration (FDA), is 170 to 300 mg for adults weighing 60 kg, most of the compounds of formula 1 according to the present invention are 50% ethanol. And a 50% polyoxyethyl castor oil mixture, which can be directly dissolved in 5% glucose injection, 0.9% sodium chloride injection, 5% glucose injection and 0.9% sodium chloride injection, or 5% glucose ring gel injection.

As mentioned above, the dihydroxy group was introduced at the 9β-position and 14β-position of the taxane terpine structure by reducing the 9-position ketone group of the 14β-hydroxytaxane terpine structure according to the present invention with a 9β-hydroxy group. The novel taxane terpine-based compounds represented by Formula 1 can be prepared, and these compounds exhibit excellent anticancer activity, and show much improved water solubility compared to conventional taxane terpine-based compounds. The anticancer activity and improved water solubility of these compounds were confirmed by the experiments of Experimental Examples 1 and 2 above. Therefore, the novel taxane terpineic compounds of the formula (1) provided in the present invention make a clear advance in the art by improving the problem of poor solubility in water of the existing taxane terpineic anticancer agents and the resulting side effects in the clinic. It became.

Claims (13)

Taxane terpine compound of Formula 1 [Formula 1] In the above formula R ¹ represents isopropyl, isobutyl, isobutenyl, tetrahydrofuranyl, phenyl, furyl or thiophenyl, R ² represents phenyl, furyl, cyclopropyl or t-butoxy, R ³ and R ⁴ each independently represent hydrogen, or R ³ and R ⁴ together form a cyclic carbonate structure, R ⁵ represents phenyl. delete delete delete A method for preparing a compound of Formula 1, characterized by reducing the ketone group at the 9-position of the compound of Formula 6: [Formula 1] [Formula 6] Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each as defined in claim 1. delete delete A method according to claim 5, characterized in that samarium iodide is used as the reducing agent. 10. The process of claim 8, wherein the reaction is carried out in the presence of a solvent. 10. The process according to claim 9, wherein a mixed solvent of water and an organic solvent which can be mixed with water is used as a solvent. The process according to claim 10, wherein a solvent selected from methanol, ethanol, tetrahydrofuran, 1,4-dioxane and amide solvent is used as an organic solvent that can be miscible with water. The method according to claim 10, wherein a mixed solvent of water and tetrahydrofuran in a ratio of 1: 5 to 1:50 (v / v) is used as a solvent. An anticancer agent composition comprising as an active ingredient one or more compounds of the formula (I) together with a pharmaceutically acceptable carrier.