JP2003026673A - Osteoplasty accelerator - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an osteoplasty accelerator useful for prevention and therapy of bone disease, fracture of the bone, refracture, osteoporosis, osteomalacia, Paget disease, bone tissue restoring after myeloma, osteosarcoma, bone tissue restoring after extirpating metastatic lesion such as carcinoma mammae, pulmonary cancer and restoring of periodontal tissue in periodontosis. SOLUTION: This osteoplasty accelerator includes taxiods as an active ingredient expressed by general formula (I).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an osteogenesis promoter useful as a preventive or therapeutic agent for bone diseases such as bone fracture, re-bone fracture, osteoporosis, osteomalacia and Paget's disease.

[0002]

2. Description of the Related Art Bone defects due to tumor resection such as osteosarcoma or complicated fractures cannot be completely cured or require a long healing period. Further, a bone fracture is a disorder that can occur across generations due to various causes, and its healing requires a relatively long period of time, which seriously hinders daily life. Furthermore, in recent years, the number of patients with osteoporosis has increased with the aging of the population, and fractures of limbs due to osteoporosis have increased. In the case of patients with osteoporosis, if long-term bed rest due to a fracture is forced, passive bone atrophy is added and susceptibility to fracture is further accelerated. It is becoming more and more bedridden with medical complications such as dementia, which is becoming a serious social and economic problem.

It is a very important task to get a fractured patient out of bed early in various aspects such as patient prognosis and QOL. Fracture healing is a phenomenon that occurs locally and changes over time with inflammation, callus formation, and remodeling. Various local factors work effectively in each step to promote their healing. Bone morphology inducer (BMP) and fibroblast growth factor (FG) are factors that promote fracture healing.
F), transforming growth factor (TGF-β) and the like are known, and their effects have been proved in animal experiments. On the other hand, as low molecular weight osteogenesis promoting substances, prostaglandins, vitamin D3 derivatives, benzylphosphonic acid derivatives, phenolsulfophthalene derivatives and the like have been reported.

[0004]

All of the above-mentioned peptidic physiologically active substances are peptides or proteins having a molecular weight of 5000 or more, and they are rapidly metabolized in vivo and lack stability. Therefore, the formulation which tried to stabilize is created,
Satisfactory quality has not been obtained for clinical application. In addition, there is no report that non-peptidic bone formation-promoting substances are sufficiently effective in promoting healing of bone fractures or bone defects. For the above-mentioned reasons, there has been a strong demand for an excellent quality bone disease therapeutic agent having a high activity and a low-molecular-weight bone formation-promoting action that can be applied to the promotion of repair of bone defects. .

[0005]

Means for Solving the Problems As a result of intensive studies by the present inventors, the following general formula (I)

[0006]

[Chemical 2] The present invention was completed by discovering that the taxoid represented by (3) has a remarkable bone formation promoting action.

That is, the present invention relates to formula (I) wherein R1 is alkyl, alkenyl, alkynyl, aryl or heteroaryl, R2 is alkyl, aryl, heteroaryl, alkyloxy or alkylamino and R3 Is hydrogen, alkylcarbonyl, alkyloxycarbonyl, dialkylaminocarbonyl or alkyl, and X and Y are the same or different and each represents a hydroxyl group or a group capable of imparting a hydroxyl group.) A bone formation promoter containing a taxoid as an active ingredient. It is about.

In the taxoid represented by the general formula (I), X and Y mean a hydroxyl group, and R1 is isobutyl, isopropyl, tert-butyl, cyclopropyl, 3
-Pentyl, 2-methylpropenyl, 1-methylpropenyl or phenyl, R2 is pentyl, phenyl, 3-furyl, benzyloxy, tert-butyloxy, tert-amyloxy, isopropyloxy, adamantyloxy, 2,2-dimethyl. Derivatives selected from propyl, tert-butylamino and R3 selected from hydrogen, acetyl, benzoyl, butanoyl, methoxycarbonyl, N, N-dimethylaminocarbamoyl, methyl are more preferred osteogenic promoters.

Specific examples of the compound represented by the formula (I) in the present invention include the following compounds (both X and Y mean a hydroxyl group).

AZ42001; 3'-desphenyl-
3'-isobutyl-10-acetyl docetaxel (R1
= Isobutyl, R2 = tertiary butyloxy, R3 = acetyl), AZ42002; 3'-desphenyl-3'-
(2-Methylpropenyl) -10-acetyl docetaxel (R1 = 2-methylpropenyl, R2 = tertiary butyloxy, R3 = acetyl), AZ42003; 3'-desphenyl-3'-isobutyl docetaxel (R1 = Isobutyl, R2 = tertiary butyloxy, R3 = hydrogen),

AZ42004; 3'-desphenyl-
3 '-(2-methylpropenyl) docetaxel (R1 =
2-methylpropenyl, R2 = tert-butyloxy, R3
= Hydrogen), AZ42005; 3'-desphenyl-3 '.
-(1-Methylpropenyl) -10-acetyl docetaxel (R1 = 1-methylpropenyl, R2 = tert-butyloxy, R3 = acetyl), AZ42007; 3'-desphenyl-3'-isobutyl-10- (N , N-dimethylaminocarbonyl) docetaxel (R1 = isobutyl, R2 = tert-butyloxy, R3 = N, N-dimethylaminocarbonyl),

AZ42008; 3'-desphenyl-
3'-isobutyl-10-methyl docetaxel (R1 =
Isobutyl, R2 = tert-butyloxy, R3 = methyl), AZ42009; 3'-desphenyl-3'-isobutyl-10-benzoyl docetaxel (R1 = isobutyl, R2 = tert-butyloxy, R3 = benzoyl), AZ42010; 3'-desphenyl-3'-isobutyl-10-butanoyl docetaxel (R1 = isobutyl, R2 = tertiary butyloxy, R3 = butanoyl),

AZ42011; 3'-desphenyl-
3'-isobutyl-10-methoxycarbonyl docetaxel (R1 = isobutyl, R2 = tertiary butyloxy, R
3 = methoxycarbonyl), AZ42012; 3'-desphenyl-3'-tert-butyl-10-acetyldocetaxel (R1 = tert-butyl, R2 = tert-butyloxy,
R3 = acetyl), AZ42014; 3'-desphenyl-3'-cyclopropyl-10-acetyl docetaxel (R1 = cyclopropyl, R2 = tertiary butyloxy,
R3 = acetyl),

AZ42016; 3'-desphenyl-
3'-isopropyl-10-acetyl docetaxel (R
1 = isopropyl, R2 = tert-butyloxy, R3 = acetyl), AZ42018; 3'-desphenyl-3 '.
-(3-Pentyl) -10-acetyl docetaxel (R
1 = 3-pentyl, R2 = tert-butyloxy, R3 = acetyl), AZ42020; N-debenzoyl-N-tertiaryamyloxycarbonyl-3'-desphenyl-3 '.
-Isobutyl paclitaxel (R1 = isobutyl, R2
= Tertiary amyloxy, R3 = acetyl),

AZ42021; N-debenzoyl-N-
Isopropyloxycarbonyl-3'-desphenyl-
3'-isobutyl paclitaxel (R1 = isobutyl,
R2 = isopropyloxy, R3 = acetyl), AZ4
2022; N-debenzoyl-N-benzyloxycarbonyl-3'-desphenyl-3'-isobutyl paclitaxel (R1 = isobutyl, R2 = benzyloxy,
R3 = acetyl), AZ42023; N-debenzoyl-N-adamantyloxycarbonyl-3'-desphenyl-3'-isobutylpaclitaxel (R1 = isobutyl, R2 = adamantyloxy, R3 = acetyl),

AZ42024; N-debenzoyl-N-
(3,3-Dimethylbutanoyl) -3'-desphenyl-3'-isobutylpaclitaxel (R1 = isobutyl, R2 = 2,2-dimethylpropyl, R3 = acetyl), AZ42025; N-debenzoyl-N- Hexanoyl-3'-desphenyl-3'-isobutyl paclitaxel (R1 = isobutyl, R2 = pentyl, R3 =
Acetyl), AZ42026; N-debenzoyl-N-
Tert-Butylaminocarbonyl-3'-desphenyl-
3'-isobutyl paclitaxel (R1 = isobutyl,
R2 = tertiary butylamino, R3 = acetyl),

AZ42027; N-debenzoyl-N-
(3-furyl) -3'-desphenyl-3'-isobutyl paclitaxel (R1 = isobutyl, R2 = 3-furyl, R3 = acetyl), paclitaxel (R1 = phenyl, R2 = phenyl, R3 = acetyl), Docetaxel (R1 = phenyl, R2 = tertiary butyloxy, R3 = hydrogen).

These taxoids can be prepared by a known method such as O.
jima et al. , Bioorg. Med. Chem. Le
tt. , 1994, 4,2631-2934, Geor
g et al. , Bioorg. Med. Chem. Let
t. , 4,1825-1830, Georg et al. , Bi
oorg. Med. Chem. Lett. , 1994,
4,335-338, Kant et al. , Tetrahed
ron Lett. , 1994, 35, 5543-55.
46, Ojima et al. , Tetrahedron, 19
92, 48, 6985-7012, Ojima et al. , T
etrahedron Lett. , 1993, 34,
4149-4152 and the like.

A specific synthetic route is shown in process drawings 1, 2, and 3. R1, R2 and R3 in these figures are as defined above. (Process drawing 1)

[0020]

[Chemical 3]

(-)-(1R, 2S) -2-phenyl-
After treating 1-cyclohexyl triisopropylsilyloxyacetate (II) with lithium diisopropylamide, aldimine (III) prepared by condensation of various aldehydes R1-CHO and p-anisidine is reacted to obtain azetidinone (IV). 1 of azetidinone
The p-methoxyphenyl group at the 1-position was first removed with cerium diammonium nitrate in order to exchange the protecting groups at the 3-position and 3-position with those suitable for the coupling reaction with the bacatin skeleton carried out in Process Diagram 2, and then tetra- The TIPS (triisopropylsilyl) group at the 3-position is removed with -n-butylammonium fluoride to obtain azetidinone (V). Further, tert-butyldimethylsilyl chloride (TBS-Cl) and then di-tert-butyl dicarbonate ((Boc) 2 O) are reacted to obtain azetidinone (VI) which is subjected to the coupling reaction with the bakatin skeleton. However, the TIPS group can be used as it is for the coupling reaction without exchanging the protective group for the 3-position hydroxyl group. (Process drawing 2)

[0022]

[Chemical 4]

7-trimethylsilyl baccatin III (V
Reacting II) with n-butyllithium and R3X 1
It is assumed that the 0-hydroxyl group is modified to baccatin (VIII).
The reaction reagent shown here as R3X is a corresponding acid halide when R3 is an acyl group, a corresponding alkyloxy halide when R3 is alkyloxycarbonyl, and a corresponding alkyloxyhalide when R3 is dialkylaminocarbonyl. Refers to the corresponding dialkylaminocarbonyl halide and, where R3 is alkyl, the corresponding alkyl halide or dialkylsulfate. Thus obtained 1
0-modified baccatin (VIII) and azetidinone (VI)
Is coupled in the presence of hexamethyldisilazane sodium salt to give a taxane derivative (IX) having a protecting group. Further, the protective groups for the 2'-position and the 7-position hydroxyl group are removed with hydrogen fluoride-pyridine to obtain a taxane derivative (X). (Process drawing 3)

[0024]

[Chemical 5] The taxane derivative (XI) having various substituents (R2-CO-) on the 2'-position amino group was obtained by removing the Boc (tertiary butyloxycarbonyl) group of the above taxane derivative (X) with trifluoroacetic acid. After that, it is obtained by reacting R2COY or by reacting carboxylic acid R2COOH in the presence of a condensing agent such as carbodiimide.
The reaction reagent shown here as R2COY is a corresponding carboxylic acid halide or carboxylic acid anhydride when R2 is alkyl, aryl or heteroaryl, and a corresponding dialkyl dicarbonate or alkyl dicarbonate when R2 is an alkyloxy group. An oxyhalide refers to the corresponding alkyl isocyanate when R2 is an alkylamino group.

Of the compounds listed as specific examples, AZ4
2005, AZ42009, AZ42010, AZ42
018, AZ42020, AZ42021, AZ420
22, AZ42023, AZ42024, AZ4202
5, AZ42026 and AZ42027 are novel derivatives, and the synthetic method is shown in Example 3 described later.

The sources of other known derivatives are shown below.

AZ42001, AZ42002, AZ4
2003, AZ42004 (Ojima et al., Biot.
rg. Med. Chem. Lett. , 1994, 4,
2631-2934).

AZ42007, AZ42008, AZ4
2011 (Ojima et al., J. Med. Chem.,
1996, 39, 3889-3896).

AZ42012, AZ42014, AZ4
2016 (Japanese Patent Laid-Open No. 8-508469).

Docetaxel (Ojima et al., Tetr
ahedron Lett. , 1993, 34, 414
9-4152).

The thus-obtained osteogenesis promoting agent comprising the taxoid represented by the general formula (I) as a main component prevents and treats bone diseases such as fracture, re-fracture, osteoporosis, osteomalacia, Paget's disease, and the like. It is useful for bone tissue repair after surgery such as myeloma and osteosarcoma, bone tissue repair after removal of bone metastases such as breast cancer and lung cancer, and regeneration of periodontal tissue in periodontal disease.

The taxoid in the present invention is represented by the general formula (I) (wherein R 1 is alkyl, alkenyl, alkynyl, aryl or heteroaryl, and R 2 is alkyl, aryl, heteroaryl, alkyloxy or alkylamino). R3 is hydrogen, alkylcarbonyl, alkyloxycarbonyl, dialkylaminocarbonyl or alkyl, and X and Y are the same or different and each represents a hydroxyl group or a group capable of providing a hydroxyl group. The group capable of providing a hydroxyl group in Y and Y is preferably a protective group for a hydroxyl group, but is not particularly limited as long as it is a group capable of providing a hydroxyl group.

More preferred examples of the taxoid represented by the general formula (I) are the same hydroxyl group for X and Y, R 1 is alkyl having 1 to 6 carbons, alkenyl having 2 to 6 carbons, and carbon. Selected from alkynyl having 2 to 6 carbon atoms, phenyl, naphthyl, furyl, and thienyl, and R2 has alkyl having 1 to 6 carbon atoms, phenyl, naphthyl, furyl, thienyl, alkyloxy having 1 to 10 carbon atoms, or 1 carbon atom.
Selected from alkylamino having 6 to 6 carbon atoms, R3 is hydrogen, alkylcarbonyl having 1 to 6 carbon atoms in the alkyl portion, alkyloxycarbonyl having 1 to 6 carbon atoms in the alkyl portion, and 2 to 6 carbon atoms in the dialkyl portion. It is selected from dialkylaminocarbonyl or alkyl having 1 to 6 carbons.

More preferred examples of the taxoid represented by the formula (I) are the same hydroxyl group for X and Y, and R1 is isobutyl, isopropyl, tert-butyl, cyclopropyl, 3-pentyl, 2- Selected from methylpropenyl, 1-methylpropenyl or phenyl, R2 is pentyl, phenyl, 3-furyl, benzyloxy, tert-butyloxy, tert-amyloxy, isopropyloxy, adamantyloxy, 2,2-dimethylpropyl, tert-butyl. And derivatives in which R3 is selected from amino, R3 is selected from hydrogen, acetyl, benzoyl, butanoyl, methoxycarbonyl, N, N-dimethylaminocarbamoyl, methyl.

As the taxoid used as the osteogenesis promoter in the present invention, as described above, all compounds represented by the general formula (I) are included in the taxoid of the present invention. The taxoids used for the purpose of the present invention are also included in the present invention in addition to these examples.

For example, as a preferred example, AZ42001; 3'-desphenyl-3'-isobutyl-10-acetyl docetaxel (R1 = isobutyl, where X and Y are the same hydroxyl group,
R2 = tert-butyloxy, R3 = acetyl): AZ42002; 3'-desphenyl-3 '-(2-methylpropenyl) -10-acetyl docetaxel (R1
= 2-methylpropenyl, R2 = tert-butyloxy, R
3 = acetyl): AZ42003; 3'-desphenyl-3'-isobutyl docetaxel (R1 = isobutyl, R2 = tert-butyloxy, R3 = hydrogen): AZ42004; 3'-desphenyl-3 '-(2- Methylpropenyl) docetaxel (R1 = 2-methylpropenyl, R2 = tertiary butyloxy, R3 = hydrogen):

AZ42005; 3'-desphenyl-
3 '-(1-Methylpropenyl) -10-acetyl docetaxel (R1 = 1-methylpropenyl, R2 = tertiary butyloxy, R3 = acetyl): AZ42007; 3'-desphenyl-3'-isobutyl-10-. (N, N-dimethylaminocarbonyl) docetaxel (R1 = isobutyl, R2 = tertiary butyloxy, R3 = N, N-dimethylaminocarbonyl): AZ42008; 3'-desphenyl-3'-isobutyl-10-methyl doceta Xcel (R1 = isobutyl, R
2 = tert-butyloxy, R3 = methyl): AZ42009; 3'-desphenyl-3'-isobutyl-10-benzoyl docetaxel (R1 = isobutyl, R2 = tert-butyloxy, R3 = benzoyl):

AZ42010; 3'-desphenyl-
3′-isobutyl-10-butanoyl docetaxel (R
1 = isobutyl, R2 = tert-butyloxy, R3 = butanoyl): AZ42011; 3'-desphenyl-3'-isobutyl-10-methoxycarbonyl docetaxel (R1 = isobutyl, R2 = tert-butyloxy, R3 = methoxycarbonyl). ): AZ42012; 3'-desphenyl-3'-tertiary butyl-10-acetyl docetaxel (R1 = tert-butyl,
R2 = tert-butyloxy, R3 = acetyl):

AZ42014; 3'-desphenyl-
3'-cyclopropyl-10-acetyl docetaxel (R1 = cyclopropyl, R2 = tertiary butyloxy, R
3 = acetyl): AZ42016; 3'-desphenyl-3'-isopropyl-10-acetyl docetaxel (R1 = isopropyl, R2 = tert-butyloxy, R3 = acetyl): AZ42018; 3'-desphenyl-3 '. -(3-Pentyl) -10-acetyl docetaxel (R1 = 3-pentyl, R2 = tertiary butyloxy, R3 = acetyl):

AZ42020; N-debenzoyl-N-
Tertiary amyloxycarbonyl-3'-desphenyl-
3'-isobutyl paclitaxel (R1 = isobutyl,
R2 = tertiary amyloxy, R3 = acetyl): AZ42021; N-debenzoyl-N-isopropyloxycarbonyl-3'-desphenyl-3'-isobutylpaclitaxel (R1 = isobutyl, R2 = isopropyloxy, R3 = acetyl). : AZ42022; N-debenzoyl-N-benzyloxycarbonyl-3'-desphenyl-3'-isobutyl paclitaxel (R1 = isobutyl, R2 = benzyloxy, R3 = acetyl):

AZ42023; N-debenzoyl-N-
Adamantyloxycarbonyl-3'-desphenyl-
3'-isobutyl paclitaxel (R1 = isobutyl,
R2 = adamantyloxy, R3 = acetyl): AZ42024; N-debenzoyl-N- (3,3-dimethylbutanoyl) -3'-desphenyl-3'-isobutylpaclitaxel (R1 = isobutyl, R2 = 2.
2-dimethylpropyl, R3 = acetyl): AZ42025; N-debenzoyl-N-hexanoyl-3'-desphenyl-3'-isobutylpaclitaxel (R1 = isobutyl, R2 = pentyl, R3 = acetyl):

AZ42026; N-debenzoyl-N-
Tert-Butylaminocarbonyl-3'-desphenyl-
3'-isobutyl paclitaxel (R1 = isobutyl,
R2 = tert-butylamino, R3 = acetyl): AZ42027; N-debenzoyl-N- (3-furyl) -3'-desphenyl-3'-isobutylpaclitaxel (R1 = isobutyl, R2 = 3-furyl, R3 =
Acetyl):

Paclitaxel (R1 = phenyl, R2 =
Phenyl, R3 = acetyl): docetaxel (R1 = phenyl, R2 = tertiary butyloxy, R3 = hydrogen), more preferably paclitaxel (R1 = phenyl, R2 = phenyl, R3 = acetyl), docetaxel (R1 =). Phenyl, R2 = tert-butyloxy, R3 =
Hydrogen), and most preferred examples include paclitaxel (R1 = phenyl, R2 = phenyl, R3 = acetyl).

The taxoid in the present invention is not limited by the production method, and for example, taxoid extracted from nature, taxoid chemically synthesized and the like can be used.

The osteogenesis promoter is a general term for substances that act on osteoblasts to promote osteogenic functions, and their biological activity is, for example, alkaline phosphatase (in alkaline phosphatase in osteoblast-like cells derived from neonatal rat calvaria). ALP) activity-promoting action, cell layer calcium-increasing action, and most suitably, bone-like nodule formation-promoting action can be evaluated as an index. Examples of the use of the osteogenesis promoter include a bone disease, for example, a repair agent for a bone defect and a bone lesion due to surgical damage, a preventive and therapeutic agent for metabolic bone disease, a periodontal tissue regenerating agent, and the like. Examples of uses for surgical injuries include fractures and re-fractures due to mechanical load, or primary malignant tumors such as myeloma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma, fibrosarcoma, lung cancer, and gastric cancer. , Bone repair and bone reconstruction after surgical removal of bone metastases such as breast cancer and liver cancer.

Further, as the use for metabolic bone disease,
It can be used as a prophylactic and therapeutic agent for osteoporosis, osteomalacia, Paget's disease and the like. In addition, prevention of metabolic bone diseases thought to be caused by various causative diseases and factors such as diabetic osteoporosis, osteoporosis during adrenal steroid therapy, bone loss caused by hyperparathyroidism, and renal bone dystrophy. It can also be used as an agent and a therapeutic agent. Further, it can also be used as a regenerating agent for periodontal tissue to the alveolar bone absorption-promoting site or defective site due to periodontitis, periodontal abscess malignant tumor, etc.

Examples of the drug form of the present invention include injections, rectal absorption agents, vaginal agents, transdermal absorption agents, nasal absorption agents, pulmonary absorption agents, buccal absorption agents, oral administration agents and the like. However, these dosage forms are not limited in any way.

The injection is preferably used for intramuscular administration or intravenous administration.
Vaginal agents are generally used in the form of suppositories, nasal absorbents and transdermal agents are used in the form of preparations to which appropriate absorption enhancers are added, and transpulmonary agents are used as appropriate dispersants or water and It is used in the form of an aerosol composition containing a propellant.
The oral absorbent is used in the form of, for example, a sublingual tablet or a tape by adding an appropriate absorption promoter, and the orally administered agent is used in the form of oral preparation such as liposome preparation and microcapsule preparation. .

Further, the agent of the present invention is blended in a suitable carrier such as gelatin sponge, porous hydroxyapatite, lactic acid-glycolic acid copolymer, glycolic acid-caprolactone copolymer, and the like to prepare rod-shaped, needle-shaped, spherical, film-shaped. It is also possible to use by embedding it in a bone injury site or a defect site in the form of orthopedic or ointment-like form. The carrier used for this purpose is in no way limited to these examples.

Further, these drugs are prepared into dosage forms suitable for each drug form by adding a pharmacologically acceptable auxiliary agent. As this auxiliary agent, for example, a base material,
Stabilizers, preservatives, preservatives, suspending agents, solubilizers, solubilizers, emulsifiers, lubricants, tackifiers, excipients, binders, flavoring agents, colorants, fragrances, soothing agents. , Buffering agents and the like. When preparing the drug of the present invention using these auxiliary ingredients, for example, it is found in the list of pharmaceutical additives (published by the Tokyo Pharmaceutical Industry Association Medical Law and Regulation Committee and the Osaka Pharmaceutical Industry Association Medical Law and Regulation Research Committee). As described above, the auxiliary component may be appropriately selected and used. The amount of the auxiliary component used may be appropriately selected depending on the dosage form and the like within a pharmaceutically acceptable range.

The drug of the present invention can be used in combination with other therapeutic agents for bone diseases. Examples of drugs to be combined include calcium preparations and vitamin D.
Preparations, vitamin K preparations, parathyroid hormone, sex hormones, bisphosphonic acids, ipriflavones, fluorine compounds, prostaglandins, transforming growth factor (TGF-β), insulin-like growth factors-1 and -2 (IGF- 1 and IGF-2), fibroblast growth factor (FGF), bone morphogenetic induction factor (BMP) and the like.

In principle, the administration period of the drug of the present invention is clinically the period in which bone lesions, disorders and defects are observed, and the administration may be continued after recovery according to the judgment of the clinician according to the etiology and condition. It is possible. Furthermore, when osteoporosis is expected to occur as in the case of adrenal steroid therapy, the drug of the present invention can be administered prophylactically. For example, when paclitaxel is used as a bone defect repairing agent, the dose of the agent of the present invention is a single dose for adults (body weight 5
0 kg), about 1 ng to 500 mg of the active ingredient is 1
It may be administered once every week to 3 months (lethal dose: rat 85 mg / kg intravenous injection).

Other preparations or other taxoids represented by the general formula (I) may be administered according to the weight of paclitaxel. Further, the blending amount may be appropriately changed depending on the sustained release of the active ingredient of the carrier used. The taxoid thus produced / prepared is useful as an osteogenesis promoter which markedly promotes bone formation and prevents or maintains bone diseases satisfactorily, as shown in the following examples.

[0054]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will now be described in detail with reference to Examples, but the present invention is not limited thereto. Example 1 Paclitaxel is a reagent manufactured by Wako Pure Chemical Industries (lot number JCQ9
354) was dissolved in dimethyl sulfoxide and used. A calvaria was aseptically collected from an 1-day-old SD rat (Charles River Japan, Inc.) and cut into small pieces. Add 0.1% collagenase, 0.05% trypsin, 4 mM EDTA.
By shaking in phosphate buffered saline containing Na for 20 minutes at room temperature, the released cells were collected.

This operation was repeated 6 times, and the collected cells in the latter 4 times were treated as osteoblast-like cells and cultured in an αMEM culture medium containing 10% fetal bovine serum at 37 ° C. in a CO 2 incubator. After 5 days of culture, the osteoblast-like cells were added to 0.1
% Collagenase, 0.05% trypsin, 4 mM ED
3.73 × 10 ⁴ cells / cm ^{2 were} detached from the culture dish with phosphate buffered saline containing TA / 2Na.
Falcon 6-well plates were seeded at a cell density of.
Subsequent culture medium is 10% fetal bovine serum, 5 mM
An αMEM culture solution containing β-glycerophosphate and 50 μg / ml ascorbic acid was used.

Paclitaxel was added 2 days after the cells were seeded, and then, on the second and fifth days after the addition, the medium was exchanged with a culture solution containing the same concentration of paclitaxel. Seven days after the addition of paclitaxel, the alkaline phosphatase (ALP) activity in the cell layer, the amount of calcium, and the number of bone-like nodules were determined by Ishi.
zuya et al. J. Clin. Invest. , 199
It measured based on the method of 7,99,2961-2970. The measurement results are shown in FIG. 1 (effect of paclitaxel on ALP activity of rat calvaria-derived osteoblast-like cells;
The abscissa shows the added concentration of paclitaxel) and FIG. 2 (the action of paclitaxel on the amount of calcium in the cell layer of rat calvaria-derived osteoblast-like cells and bone-like nodule formation; the abscissa shows the added concentration of paclitaxel). .

In FIG. 1,-○-indicates ALP activity,
In FIG. 2,-●-represents the amount of calcium and-□-represents the number of bone-like nodules, respectively. Paclitaxel is 0.3 ng /
Dose-dependent promotion of ALP activity, calcium content, and bone-like nodule formation in the cell layer in a concentration range of at least 1 ml is found to be useful as a preventive or therapeutic agent for bone diseases. There was found.

Further, a photomicrograph (40 times) of rat calvaria-derived osteoblast-like cells in the paclitaxel-free group on day 7 of culture is shown in FIG. 3, and FIG. 4 shows paclitaxel concentration 0 on day 7 of culture. Micrograph of rat calvaria-derived osteoblast-like cells in the addition group of 0.3 ng / ml (40 times; black portion is v
on KOSSA staining-positive calcified bone-like nodules) are shown in FIG. 5, and the paclitaxel concentration on the 7th day of culture is 1 ng /
A micrograph (40 times) of rat calvaria-derived osteoblast-like cells in the ml addition group is shown in FIG. 6, and a microscope of rat calvaria-derived osteoblast-like cells in the paclitaxel concentration 3 ng / ml addition group on day 7 of culture is shown in FIG. The photograph (40 times) is shown. as a result,
Compared to the paclitaxel-free group, paclitaxel 0.
In the 3 to 3 ng / ml addition group, it was confirmed that the number of calcified bone-like nodules shown in the black portion increased in a dose-dependent manner.

Example 2 Docetaxel was prepared by a known method (Ojima et al., Tetr).
ahedron Lett. , 1993, 34, 414
9-4152), dissolved in dimethyl sulfoxide and used. A calvaria was aseptically collected from an 1-day-old SD rat (Charles River Japan, Inc.) and cut into small pieces. Add this to 0.1% collagenase, 0.05% trypsin, 4 mM
The cells were released by shaking in phosphate buffered saline containing EDTA · 2Na for 20 minutes at room temperature.

This operation was repeated 6 times, and the cells collected in the latter 4 times were used as osteoblast-like cells and cultured in an αMEM culture medium containing 10% fetal bovine serum at 37 ° C. in a CO 2 incubator. After 5 days of culture, the osteoblast-like cells were added to 0.1
% Collagenase, 0.05% trypsin, 4 mM ED
3.73 × 10 ⁴ cells / cm ^{2 were} detached from the culture dish with phosphate buffered saline containing TA / 2Na.
Falcon 6-well plates were seeded at a cell density of.
Subsequent culture medium is 10% fetal bovine serum, 5 mM
An αMEM culture solution containing β-glycerophosphate and 50 μg / ml ascorbic acid was used.

Docetaxel was added 2 days after the cells were seeded, and thereafter, on the second and fifth days after the addition, the medium was exchanged with a culture solution containing docetaxel at the same concentration. Seven days after the addition of docetaxel, the number of bone-like nodules was measured as in Example 1 herein. The measurement results are shown in Table 1 below.

[0062]

[Table 1]

As is clear from the measurement results in Table 1, docetaxel markedly increased bone-like nodule formation in the concentration range of 1 to 3 ng / ml, and an osteogenesis promoting effect was recognized. From this fact, it was revealed that it is useful as a preventive or therapeutic agent for bone diseases.

Example 3 3'-desphenyl-3 '-(1-methylpropenyl)
Synthesis of -10-acetyl docetaxel (AZ42005) 1.23 g (10 mmol) of p-anisidine was dissolved in 10 ml of dichloromethane, and anhydrous magnesium sulfate 850 was used.
After adding mg, the mixture was cooled to -78 ° C, and a dichloromethane solution (10 ml) of 4.85 ml (50 mmol) of trans-2-methyl-2-butenal was added dropwise. After stirring overnight at room temperature, magnesium sulfate was filtered off, the solvent was distilled off under reduced pressure, and N- (4-methoxyphenyl) -2-methyl-2 was used.
-Butene aldimine was obtained.

1.37 ml of diisopropylamine (11
(mmol) was dissolved in 10 ml of distilled THF, cooled to -30 ° C under an argon atmosphere, and 6.55 ml (11 mmol) of a 1.6 M n-butyllithium hexane solution was dissolved.
Was dripped. After stirring at 0 ° C. for 30 minutes, the mixture was cooled to −78 ° C., and then (−)-(1R, 2S) -2-phenyl-1-cyclohexyl triisopropylsilyloxyacetate (Ojima et al., Tetrahedron, 199).
2,48,6985-7012) 3.91 g (10 mm
10 ml of THF solution of ol) was added dropwise over 1.5 hours. After stirring for 2 hours, 10 ml of the above-mentioned N- (4-methoxyphenyl) -2-methyl-2-butenealdimine in THF was added dropwise over 30 minutes, and the reaction solution was returned to room temperature and stirred overnight.

The reaction mixture was ice-cooled, saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) (3R, 4S) -1-
(4-Methoxyphenyl) -3-triisopropylsilyloxy-4- (1-methylpropenyl) azetidine-
2-one 2.89 g (7.16 mmol, 71.6%)
Got The enantiomeric excess of this product is chiral HPL.
According to C analysis, it was 69.9%.

TLC (Merck silica gel 60 (same below), hexane: ethyl acetate = 20: 1, developed twice)
Rf = 0.52, FAB-MASS; 404 (MH +)

This (3R, 4S) -1- (4-methoxyphenyl) -3-triisopropylsilyloxy-4-
(1-Methylpropenyl) azetidin-2-one 80.
Dissolve 7 mg (0.20 mmol) in 2 ml of acetonitrile, and under ice cooling, diammonium cerium nitrate (IV)
3 ml of an aqueous solution of 334 mg (0.61 mmol) was slowly added dropwise. After stirring for 30 minutes, 15 ml of water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium sulfite solution, 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.

The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) (3
R, 4S) -3-Triisopropylsilyloxy-4-
(1-Methylpropenyl) azetidin-2-one 40.
2 mg (0.135 mmol, 67.5%) was obtained.

TLC (hexane: ethyl acetate = 5: 1)
Rf = 0.36, FAB-MASS; 297 (M +)

This (3R, 4S) -3-triisopropylsilyloxy-4- (1-methylpropenyl) azetidin-2-one (845 mg, 2.84 mmol) was dissolved in dichloromethane (20 ml) to prepare a catalytic amount of 4-dimethylaminopyridine. And ice-cooled, triethylamine 950 μl
(6.82 mmol) and di-tert-butyl dicarbonate (Di-t
-Butyl Dicarbonate) 744mg
(3.41 mmol) was added. After stirring at room temperature for 1 hour, the mixture was ice-cooled, ice water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.

The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) (3
R, 4S) -1-tert-Butoxycarbonyl-3-triisopropylsilyloxy-4- (1-methylpropenyl) azetidin-2-one 840 mg (2.11 mmo
1, 74%).

TLC (hexane: ethyl acetate = 10:
1) Rf = 0.54, FAB-MASS; 398 (MH
+)

This (3R, 4S) -1-tert-butoxycarbonyl-3-triisopropylsilyloxy-4-
(1-Methylpropenyl) azetidin-2-one 16
9.9 mg (0.428 mmol) and 200 mg (0.
285 mmol) 7-triethylsilyl baccatin II
I (Kant et al., Tetrahedron Let
t. , 1994, 35, 5543-5546) was dissolved in 6 ml of distilled THF under an argon atmosphere. -30
The mixture was cooled to 0 ° C., 1M concentration of hexamethyldisilazane sodium salt THF solution (428 μl, 0.428 mmol) was added dropwise, and the mixture was stirred for 1.5 hours. A saturated ammonium chloride aqueous solution was added, the mixture was extracted with ether, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.

The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3 '.
-Desphenyl-3 '-(1-methylpropenyl)-
2'-triisopropylsilyl-10-acetyl-7-
214 mg of triethylsilyl docetaxel (0.195
mmol, 68.4%) was obtained.

TLC (hexane: ethyl acetate = 3: 1,
(Development twice) Rf = 0.55, FAB-MASS; 109
8 (MH +)

This 3'-desphenyl-3 '-(1-methylpropenyl) -2'-triisopropylsilyl-1
0-Acetyl-7-triethylsilyl docetaxel 13
5 mg (0.123 mmol) was dissolved in 2 ml of pyridine, and 1 ml of hydrogen fluoride-pyridine (7: 3) was added under ice cooling. After stirring at room temperature for 4.5 hours, 0.5 ml of hydrogen fluoride-pyridine was further added, and the mixture was stirred for 6 hours. The reaction mixture was ice-cooled, ether was added, and 2N hydrochloric acid was further added. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.

The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and 3'-
Desphenyl-3 '-(1-methylpropenyl) -10
-Acetyl docetaxel (AZ42005) 35.5m
g (0.0429 mol, 34.9%) was obtained. This chromatography separated the coexisting (2'S, 3'R) isomers.

TLC (hexane: ethyl acetate = 1: 1)
Rf = 0.34, FAB-MASS; 828 (MH +)

3'-desphenyl-3 '-(3-pentyl) -10-acetyl docetaxel (AZ42018)
In the same manner as in the synthesis of AZ42005, 501 mg (5.0 mmol) of 2-ethylbutyraldehyde was used to synthesize (3R, 4S) -1- (4-methoxyphenyl) -3-.
Triisopropylsilyloxy-4- (1-ethylpropyl) azetidin-2-one 1.03 g (2.44 mm)
ol, 48.8%). The enantiomeric excess of this product was 53.5% by chiral HPLC analysis.

TLC (hexane: ethyl acetate = 10:
1) Rf = 0.41, FAB-MASS; 420 (MH
+)

This (3R, 4S) -1- (4-methoxyphenyl) -3-triisopropylsilyloxy-4-
(1-Ethylpropyl) azetidin-2-one 976.
4 mg (2.33 mmol) was (3R, 4S) -3-triisopropylsilyloxy-4- (1-ethylpropyl) azetidin-2-one 481 mg (1.53 mmol, 65.7) by a method similar to the synthesis of AZ42005.
%).

TLC (hexane: ethyl acetate = 5: 1)
Rf = 0.23, FAB-MASS; 314 (MH +)

409 mg (1.30 mmol) of this (3R, 4S) -3-triisopropylsilyloxy-4- (1-ethylpropyl) azetidin-2-one was dissolved in 10 ml of THF under an argon atmosphere to prepare 1M tetra-. n
-Butyl ammonium fluoride / THF solution 2.4
6 ml (2.46 mmol) was added. After stirring at room temperature for 30 minutes, the reaction solution was ice-cooled, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) and (3R, 4S) -3-hydroxy-4- (1-ethylpropyl) azetidin-2-one 191 mg (1.22 m)
mol, 93.8%).

TLC (hexane: ethyl acetate = 1: 2)
Rf = 0.35, FAB-MASS; 158 (MH +)

This (3R, 4S) -3-hydroxy-4
-(1-Ethylpropyl) azetidin-2-one 190
mg (1.21 mmol) under argon atmosphere 10 ml
Dissolved in DMF of 206 mg of imidazole (3.02 m
mol) and tert-butyldimethylsilyl chloride 20
1 mg (1.33 mmol) was added. After stirring overnight at room temperature, hexane was added and the mixture was washed with water, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) (3R, 4S) -3-tert-butyldimethylsilyloxy-4- (1-ethylpropyl).
Azetidin-2-one 322 mg (1.19 mmol,
98.1%) was obtained.

TLC (hexane: ethyl acetate = 10:
1) Rf = 0.36, FAB-MASS; 272 (MH
+)

This (3R, 4S) -3-tert-butyldimethylsilyloxy-4- (1-ethylpropyl) azetidin-2-one (319 mg, 1.18 mmol) was dissolved in dichloromethane (15 ml) and ice-cooled, and the atmosphere was argon. Under triethylamine 395 μl (2.83 mmol),
Di-t-butyl Dica
325 μl (1.42 mmol) of rbonate) and a catalytic amount of 4-dimethylaminopyridine were added. 5 at room temperature
After stirring for an hour, 160 μl of ditert-butyl dicarbonate (0.70
(mmol) and added and stirred overnight.

The reaction mixture was ice-cooled, ice water was added, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated brine. It was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) (3R, 4S) -1-tert-butoxycarbonyl-3-tert-butyldimethylsilyloxy-4- (1-ethylpropyl). Azetidin-2-one 4
Obtained 48 mg (quantitative).

TLC (hexane: ethyl acetate = 3: 1)
Rf = 0.77, FAB-MASS; 372 (MH +)

This (3R, 4S) -1-tert-butoxycarbonyl-3-tert-butyldimethylsilyloxy-4-
(1-Ethylpropyl) azetidin-2-one 146.
6 mg (0.395 mmol) and 184 mg (0.26
3 mmol) of 7-triethylsilyl baccatin III was dissolved in 6 ml of distilled THF under an argon atmosphere.
The mixture was cooled to -30 ° C, and 452 µl of a 1 M solution of hexamethyldisilazane sodium salt in THF (0.452 mmo
1) was added dropwise and the mixture was stirred for 1.5 hours. A saturated ammonium chloride aqueous solution was added, the mixture was extracted with ether, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.

The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) and 3′-
Desphenyl-3 '-(1-ethylpropyl) -2'
-Tert-Butyldimethylsilyl-10-acetyl-7-triethylsilyl docetaxel 170 mg (0.159 m
mol, 60.5%) was obtained.

TLC (hexane: ethyl acetate = 3: 1)
Rf = 0.62, FAB-MASS; 1072 (MH
+)

This 3'-desphenyl-3 '-(1-ethylpropyl) -2'-tert-butyldimethylsilyl-1
0-Acetyl-7-triethylsilyl docetaxel 13
7 mg (0.128 mmol) was dissolved in 2 ml of pyridine, and 1 ml of hydrogen fluoride-pyridine (7: 3) was added under ice cooling. After stirring at room temperature for 5 hours, the reaction solution was ice-cooled, ether was added, and 1N hydrochloric acid was further added. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.

The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and 3'-
Desphenyl-3 '-(1-ethylpropyl) -10-
Acetyl docetaxel (AZ42018) 72mg
(0.085 mmol, 67%) was obtained. This chromatography separated the coexisting (2'S, 3'R) isomers.

TLC (hexane: ethyl acetate = 1: 1)
Rf = 0.20, FAB-MASS; 844 (MH +)

3'-desphenyl-3'-isobutyl-
Synthesis of 10-benzoyl docetaxel (AZ42009) (3R, 4S) -3-triisopropylsilyloxy-
4-isobutylazetidin-2-one (Ojima
Et al. , Tetrahedron, 1992, 48, 69.
85-7012) (830 mg, 2.77 mmol) was dissolved in 10 ml of THF under an argon atmosphere, and 3.50 ml (3.50 mmol) of a 1M tetra-n-butylammonium fluoride THF solution was added. After stirring at room temperature for 2.5 hours, the reaction solution was ice-cooled, saturated brine was added, and the mixture was extracted with ethyl acetate.

The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate) (3R, 4S)-
363 mg (2.54 mmol, 91.7%) of 3-hydroxy-4-isobutylazetidin-2-one were obtained.

TLC (hexane: ethyl acetate = 2: 1)
Rf = 0.1, FAB-MASS; 144 (MH +)

This (3R, 4S) -3-hydroxy-4
-Isobutylazetidin-2-one 430 mg (3.0
0 mmol) was dissolved in 20 ml of DMF under an argon atmosphere and 511 mg (7.50 mmol) of imidazole and 543 mg (3.
60 mmol) was added and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture and extracted with hexane, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) and (3R, 4S) -3-tert-butyldimethylsilyloxy-4-isobutylazetidin-2-one 717 mg (2.78 mmol, 92.8
%) Was obtained.

TLC (hexane: ethyl acetate = 2: 1)
Rf = 0.80, FAB-MASS; 258 (MH +)

700 mg (2.72 mmol) of this (3R, 4S) -3-tert-butyldimethylsilyloxy-4-isobutylazetidin-2-one was added to dichloromethane 3
It was dissolved in 0 ml and ice-cooled, and 910 μl (6.53 mmol) of triethylamine and Di-t-butyl Dicarbonat were added under an argon atmosphere.
e) 875 μl (3.81 mmol) and catalytic amount of 4-dimethylaminopyridine (21 mg) were added. After stirring overnight at room temperature, the reaction solution was ice-cooled, ice water was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. It was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) (3
R, 4S) -1-tert-Butoxycarbonyl-3-tert-butyldimethylsilyloxy-4-isobutylazetidin-2-one 959 mg (2.68 mmol, 98.6)
%) Was obtained.

TLC (hexane: ethyl acetate = 2: 1)
Rf = 0.90, FAB-MASS; 358 (MH +)

(3R, 4S) -1-tert-butoxycarbonyl-3-tert-butyldimethylsilyloxy-4-isobutylazetidin-2-one 91.2 mg (0.26 m)
mol) and 130 mg (0.17 mmol) of 7-triethylsilyl-10-benzoyl-10-deacetylbaccatin III (Kant et al., Tetrahedron.
Lett. , 1994, 35, 5543-5546).
Was dissolved in 6 ml of distilled THF under an argon atmosphere. The mixture was cooled to −30 ° C., and 1 μM of hexamethyldisilazane sodium salt THF solution 255 μl (0.26 mm
ol) was added dropwise and the mixture was stirred for 1 hour. Then, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ether. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 1: 1) to give 3'-desphenyl-3'-isobutyl-2'-tert-butyldimethylsilyl-10-benzoyl. 172 mg of -7-triethylsilyl docetaxel (0.24 mmo
1, 90.5%).

TLC (hexane: ethyl acetate = 2: 1)
Rf = 0.70, FAB-MASS; 1120 (MH
+)

160 mg of this 3'-desphenyl-3'-isobutyl-2'-tert-butyldimethylsilyl-10-benzoyl-7-triethylsilyl docetaxel
(0.14 mmol) was dissolved in 10 ml of pyridine, and 2 ml of hydrogen fluoride-pyridine (7: 3) was added under ice cooling. After stirring for 1 hour under ice cooling, the mixture was stirred for 5 hours at room temperature. Ether was added to the reaction solution, the organic layer was washed with water, 1N hydrochloric acid and water in that order, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 3: 2) and 3'-desphenyl-3'-isobutyl-10-benzoyl docetaxel (AZ42009) 118 mg.
(0.13 mmol, 94.6%) was obtained.

TLC (hexane: ethyl acetate = 2: 1)
Rf = 0.20, FAB-MASS; 892 (MH +)

3'-desphenyl-3'-isobutyl-
Synthesis of 10-butanoyl docetaxel (AZ42010) 7-triethylsilyl-10-deacetylbaccatin II
I (Kant et al., Tetrahedron Let
t. , 1994, 35, 5543-5546) 537m
g (0.815 mmol) THF1 under argon atmosphere
It was dissolved in 0 ml, cooled to -40 ° C., and 696 μl of a 1.64 M concentration n-butyllithium / hexane solution (1.1
4 mmol) and then butanoyl chloride 118μ
1 (1.14 mmol) was added dropwise. After 10 minutes, the cooling temperature was raised to 0 ° C., and the mixture was further stirred for 1 hour. Ice water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and 7-triethylsilyl-10-butanoyl-10-deacetylbaccatin III, 481 mg (0.660 mm)
ol, 81.0%).

TLC (hexane: ethyl acetate = 1: 1)
Rf = 0.62, FAB-MASS; 729 (MH +)

96.5 mg (0.27 m) of (3R, 4S) -1-tert-butoxycarbonyl-3-tert-butyldimethylsilyloxy-4-isobutylazetidin-2-one
mol) and 131 mg of 7-triethylsilyl-10-
Butanoyl-10-deacetylbaccatin III (0.1
8 mmol) was distilled under an argon atmosphere in THF 7 m
dissolved in 1. 270 μl of a 1 M solution of hexamethyldisilazane sodium salt in THF, cooled to −30 ° C.
(0.27 mmol) was added dropwise and stirred for 2 hours. A saturated aqueous ammonium chloride solution was added, the mixture was extracted with ether, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 3: 2) and 3'-desphenyl-3'-isobutyl-2'-tert-butyldimethylsilyl-10-butanoyl. 174 mg of -7-triethylsilyl docetaxel (0.24 mmo
1, 89.4%).

TLC (hexane: ethyl acetate = 2: 1)
Rf = 0.80, FAB-MASS; 1086 (MH
+)

160 mg of this 3'-desphenyl-3'-isobutyl-2'-tert-butyldimethylsilyl-10-butanoyl-7-triethylsilyl docetaxel
(0.15 mmol) was dissolved in 10 ml of pyridine, and 2 ml of hydrogen fluoride-pyridine (7: 3) was added under ice cooling. After stirring under ice cooling for 0.5 hours, the mixture was stirred at room temperature for 4.5 hours. Ether was added to the reaction solution, and the organic layer was added to water, 1N hydrochloric acid,
After washing with water in that order, it was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 1) and 100 mg of 3'-desphenyl-3'-isobutyl-10-butanoyl docetaxel (AZ42010).
(0.12 mmol, 77.9%) was obtained.

TLC (hexane: ethyl acetate = 1: 1)
Rf = 0.20, FAB-MASS; 858 (MH +)

Synthesis of N-debenzoyl-N-tertiaryamyloxycarbonyl-3'-desphenyl-3'-isobutylpaclitaxel (AZ42020) N-debenzoyl-N-tertiarybutyloxycarbonyl-
3'-desphenyl-3'-isobutyl paclitaxel (Ojima et al., Bioorg. Med. Chem.
Lett. , 1994, 4,2631-2934) 33.
6 mg (0.404 mmol) was dissolved in 4 ml of methylene chloride, cooled to -5 ° C, added with 1 ml of trifluoroacetic acid, and stirred for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to neutralize the reaction solution, which was then extracted with chloroform.

The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1) to give N-debenzoyl-3'-desphenyl. -3'-isobutyl paclitaxel 194 mg (0.266 mmo
1, 65.8%) was obtained.

TLC (ethyl acetate: methanol: triethylamine = 20: 1: 0.1) Rf = 0.31, FA
B-MASS; 730 (MH +)

18 mg (25 μm) of this N-debenzoyl-3′-desphenyl-3′-isobutylpaclitaxel
mol) was dissolved in 1.5 ml of ethyl acetate, 1.5 ml of saturated aqueous sodium hydrogen carbonate solution and ditertiary amyl dicarbonate (Di-t-
Amyl-dicarbonate) 7.9 mg (32
(μmol) was added and the mixture was stirred at room temperature for 5 hours. Water and ethyl acetate were added for liquid separation, the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and N-debenzoyl-N-tertiaryamyloxycarbonyl-3′-desphenyl-3′-isobutyl. Paclitaxel (AZ4202
0) was obtained in an amount of 21.7 mg (quantitative).

TLC (ethyl acetate: methanol: triethylamine = 20: 1: 0.1) Rf = 0.88, FA
B-MASS; 844 (MH +)

Synthesis of N-debenzoyl-N-isopropyloxycarbonyl-3'-desphenyl-3'-isobutylpaclitaxel (AZ42021) N-debenzoyl-3'-desphenyl-3'-isobutylpaclitaxel 30 mg ( 41 μmol) was dissolved in 1.5 ml of ethyl acetate, and saturated aqueous sodium hydrogencarbonate solution was added under ice-cooling 1.5.
ml and isopropyl chlorocarbonate 6.6 mg (53 μ
mol) was added. After stirring at room temperature for 1 hour, 6.6 mg (53 μmol) of isopropyl chlorocarbonate was added, and 2
Stir for hours. Water and ethyl acetate were added to the reaction solution for partitioning, the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Purified in 1), N-debenzoyl-N-isopropyloxycarbonyl-3'-desphenyl-3'-isobutylpaclitaxel (AZ42021) 12.2 mg (1
5 μmol, 36.5%) was obtained.

TLC (ethyl acetate: methanol: triethylamine = 20: 1: 0.1) Rf = 0.57, FA
B-MASS; 816 (MH +)

Synthesis of N-debenzoyl-N-benzyloxycarbonyl-3'-desphenyl-3'-isobutylpaclitaxel (AZ42022) N-debenzoyl-3'-desphenyl-3'-isobutylpaclitaxel 30 mg ( 41 μmol) was dissolved in 1.5 ml of ethyl acetate, and saturated aqueous sodium hydrogencarbonate solution was added under ice-cooling 1.5.
ml and benzyl chlorocarbonate (Z-chloride) 9.0
mg (53 μmol) was added. After stirring at room temperature for 1 hour, water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
1) Purified in 1) N-debenzoyl-N-benzyloxycarbonyl-3'-desphenyl-3'-isobutylpaclitaxel (AZ42022) 20.1 mg (23μ)
mol, 56.6%).

TLC (hexane: ethyl acetate = 1: 1)
Rf = 0.37, FAB-MASS; 864 (MH +)

Synthesis of N-debenzoyl-N-adamantyloxycarbonyl-3'-desphenyl-3'-isobutylpaclitaxel (AZ42023) N-debenzoyl-3'-desphenyl-3'-isobutylpaclitaxel 22 mg ( (30 μmol) was dissolved in 1.5 ml of ethyl acetate, and saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling 1.5.
ml and 1-adamantyl fluoroformate (1-A
damantylfluoroformat) 18m
g (91 μmol) was added. After stirring at room temperature for 1 hour, water and ethyl acetate were added for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
1) purified by 1) N-debenzoyl-N-adamantyloxycarbonyl-3'-desphenyl-3'-isobutylpaclitaxel (AZ42023) 12.8 mg (1
4.1 μmol, 46.7%) was obtained.

TLC (hexane: ethyl acetate = 1: 1)
Rf = 0.43, FAB-MASS; 908 (MH +)

Synthesis of N-debenzoyl-N- (3,3-dimethylbutanoyl) -3'-desphenyl-3'-isobutylpaclitaxel (AZ42024) N-debenzoyl-3'-desphenyl-3'- Isobutyl paclitaxel 18.7 mg (27.4 μmol)
Was dissolved in 1.5 ml of ethyl acetate, and 1.5 ml of saturated aqueous sodium hydrogen carbonate solution and tert-butyl acetyl chloride (t-
Butyl acetyl chloride) 4.8m
g (36 μmol) was added. After stirring at room temperature for 1 hour, water and ethyl acetate were added for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
1) Purified in 1) N-debenzoyl-N- (3,3-dimethylbutanoyl) -3'-desphenyl-3'-isobutylpaclitaxel (AZ42024) 20 mg (24
μmol, 88%) was obtained.

TLC (ethyl acetate: methanol: triethylamine = 20: 1: 0.1) Rf = 0.80, FA
B-MASS; 828 (MH +)

N-debenzoyl-N-hexanoyl-
Synthesis of 3′-desphenyl-3′-isobutylpaclitaxel (AZ42025) N-debenzoyl-3′-desphenyl-3′-isobutylpaclitaxel 30 mg (41 μmol) was dissolved in ethyl acetate 1.5 ml and iced. Saturated sodium bicarbonate solution under cold 1.5
ml and hexanoyl chloride 7.2 mg (54 μmo
l) was added. After stirring at room temperature for 1 hour, water and ethyl acetate were added for liquid separation, and the organic layer was washed with saturated brine,
It was dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Purified in 1), N-debenzoyl-N-hexanoyl-
3'-desphenyl-3'-isobutyl paclitaxel (AZ42025) 14.6 mg (17.6 μmol,
42.8%) was obtained.

TLC (ethyl acetate: methanol: triethylamine = 20: 1: 0.1) Rf = 0.83, FA
B-MASS; 828 (MH +)

Synthesis of N-debenzoyl-N-tert-butylaminocarbonyl-3'-desphenyl-3'-isobutylpaclitaxel (AZ42026) N-debenzoyl-3'-desphenyl-3'-isobutylpaclitaxel 25 mg (34 μmol) and 4
-Dimethylaminopyridine (4 mg, 34 μmol) was dissolved in ethyl acetate (3 ml), and tert-butyl isocyanate (3.3 mg, 34 μmol) was added under ice cooling. After stirring overnight at room temperature, the mixture was ice-cooled again and ice water was added to the reaction solution. After extraction with dichloromethane and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and N-debenzoyl-N-tert-butylaminocarbonyl-3′-
Desphenyl-3'-isobutyl paclitaxel (AZ
42026) 24.8 mg (29.9 μmol, 88.
7%).

TLC (hexane: ethyl acetate = 1: 1)
Rf = 0.20, FAB-MASS; 829 (MH +)

N-debenzoyl-N- (3-furyl)-
Synthesis of 3'-desphenyl-3'-isobutyl paclitaxel (AZ42027) 3-Pyroic acid 4.6
mg (41 μmol), water-soluble carbodiimide hydrochloride (1-Ethyl-3- (3′dimethylamine)
nopropyl) carbodiimide ・ HC
l) 19 mg (45 μmol) and 1-hydroxybenzotriazole 6.1 mg (45 μmol) were added to DMF.
Dissolve in 1.5 ml, and under ice cooling, N-debenzoyl-3'-
Desphenyl-3'-isobutyl paclitaxel 30m
1.5 ml of DMF solution of g (41 μmol) was added dropwise.

After stirring overnight at room temperature, the mixture was ice-cooled again and ice water was added to the reaction solution. The mixture was extracted with ethyl acetate, the organic layer was washed 3 times with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3), and N-debenzoyl-N- (3-furyl) -3′-desphenyl-
3'-isobutyl paclitaxel (AZ42027) 1
Obtained 3.4 mg (16.3 μmol, 39.7%).

TLC (hexane: ethyl acetate = 1: 1)
Rf = 0.44, FAB-MASS; 824 (MH +)

Example 4 Taxoid was synthesized by the method shown in Example 3 or by the method shown in the above-mentioned publicly known document, and dissolved in dimethyl sulfoxide to be used. A calvaria was aseptically collected from an 1-day-old SD rat (Charles River Japan, Inc.) and cut into small pieces. Add this to 0.1% collagenase, 0.05
% Trypsin, 4 mM EDTA · 2Na in phosphate buffered saline, shaken at room temperature for 20 minutes, and the released cells were collected. This operation was repeated 6 times, and the collected cells from the latter 4 times were treated as osteoblast-like cells and cultured in an αMEM culture medium containing 10% fetal bovine serum at 37 ° C. in a CO 2 incubator.

After 5 days of culture, the osteoblast-like cells were treated with 0.1% collagenase, 0.05% trypsin, 4 mM EDTA.
The cells were detached from the culture dish with a phosphate buffered saline containing 2Na and seeded in a Falcon 6-well plate at a cell density of 3.73 × 10 ⁴ cells / cm ² . Subsequent culture medium includes α containing 10% fetal bovine serum, 5 mM β-glycerophosphate, and 50 μg / ml ascorbic acid.
A MEM culture medium was used. Each taxoid was added from 2 days after seeding the cells, and thereafter, on the second and fifth days after the addition, the medium was exchanged with a culture solution containing each taxoid at the same concentration.

After 7 days of culture, the cells were fixed with a phosphate buffered formalin solution, stained with von Kossa, and then examined under a microscope to count the number of calcified bone-like nodules formed. The results are shown in Table 2 below. In Table 2, ND: Not evaluated.

[0149]

[Table 2]

In Table 2 above, for example, AZ42003
No effect of promoting bone-like nodule formation was observed at a concentration of 0.3 ng / ml, but a strong effect of promoting bone-like nodule formation was observed in the concentration range of 1 to 3 ng / ml. in this way,
Bone-like nodule formation promoting action was observed in all the evaluated taxoids, and an osteogenesis promoting effect was observed. From this fact, it was proved that it is useful as a preventive or therapeutic agent for bone diseases.

Example 5 Paclitaxel (Wako Pure Chemical Industries, Ltd.) was adjusted to 20 mg / ml and 6 mg / ml solutions with a 1: 1 solution of Cremophor EL (Sigma) and ethanol (Wako Pure Chemical Industries), and immediately before administration. 8 times diluted with physiological saline solution (2.5m each)
g, 0.75 mg / ml; the final concentration of ethanol and cremophor were both 6.25%), and a volume of 4 ml / kg was slowly intravenously injected. 7 under ether anesthesia
Ovariectomy and left sciatic nerve resection were performed on week-old female SD rats, and paclitaxel 3 mg / kg and 10 m
g / kg was administered intravenously twice a week.

After the double labeling of bones (tetracycline and calcein) was performed, the mice were sacrificed 2 weeks after the start of the experiment, and the left tibia was excised. After fixing the left tibia with 70% ethanol,
Non-decalcified bone tissue sections were obtained by staining with Vila Nueva Born stain and embedding in methyl methacrylate resin. Using this, the bone morphology of the cancellous bone of the metaphysis of the tibia was measured, and the labeled surface and the bone formation rate were measured. The results are shown in Table 3 below.

[0153]

[Table 3]

As is clear from the results in Table 3 above, the parameters (marking plane and bone formation rate) showing the activity of bone formation (bone calcification) in the cancellous bone of the metaphysis of the tibiae are as follows. Although decreased by resection, administration of paclitaxel significantly increased bone formation (bone calcification) in a short period in a dose-dependent manner.

[0155]

The osteogenesis promoter containing the taxoid represented by the general formula (I) of the present invention as an active ingredient is a bone disease such as bone fracture, re-fracture, osteoporosis, osteomalacia and Pag.
Prevention and treatment of et disease, bone tissue repair after surgery for myeloma and osteosarcoma, bone tissue repair after removal of bone metastases such as breast cancer and lung cancer, and periodontal tissue for periodontal disease It is useful for reproduction.

[Brief description of drawings]

FIG. 1 is a graph showing the action of paclitaxel for promoting ALP activity of rat calvaria-derived osteoblast-like cells.

FIG. 2 is a graph showing the effect of paclitaxel on the amount of calcium in the cell layer of rat calvaria-derived osteoblast-like cells and the promotion of bone-like nodule formation.

FIG. 3 is a view showing a micrograph (40 ×) of rat calvaria-derived osteoblast-like cells in the paclitaxel-free group on day 7 of culture.

FIG. 4 Paclitaxel concentration on day 7 of culture: 0.3 ng /
It is a figure which shows the micrograph (40 times) of the rat calvaria origin osteoblast-like cell of the ml addition group.

FIG. 5: Paclitaxel concentration 1 day / ml on day 7 of culture
It is a figure which shows the micrograph (40 times) of the rat calvaria origin osteoblast-like cell of the addition group.

FIG. 6: Paclitaxel concentration 3 days / ml on day 7 of culture
It is a figure which shows the micrograph (40 times) of the rat calvaria origin osteoblast-like cell of the addition group.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Uenozawa Toyonobu             1 Asahi, 632, Mifuku, Ohito-cho, Takata-gun, Shizuoka Prefecture             Kasei Industry Co., Ltd. (72) Inventor Masayuki Hori             1 Asahi, 632, Mifuku, Ohito-cho, Takata-gun, Shizuoka Prefecture             Kasei Industry Co., Ltd. F-term (reference) 4C048 TT08 UU01 XX01 XX04                 4C086 AA01 AA02 AA03 BA02 GA16                       MA01 MA04 NA14 ZA67 ZA96                       ZA97 ZB22

Claims (6)

[Claims] 1. The following general formula (I): Where R1 is alkyl, alkenyl, alkynyl, aryl or heteroaryl, R2 is alkyl, aryl, heteroaryl, alkyloxy or alkylamino, and R3 is hydrogen, alkylcarbonyl, alkyloxycarbonyl, dialkylamino. Carbonyl or alkyl, X and Y are the same or different and mean a hydroxyl group or a group capable of imparting a hydroxyl group), and a bone formation promoting agent comprising a taxoid as an active ingredient. 2. In the general formula (I), X and Y mean a hydroxyl group, and R1 is isobutyl, isopropyl, tert-butyl, cyclopropyl, 3-pentyl, 2-methylpropenyl, 1-methylpropenyl or phenyl. R2 is selected from pentyl, phenyl, 3-furyl, benzyloxy, tert-butyloxy, tert-amyloxy, isopropyloxy, adamantyloxy, 2,2-dimethylpropyl, tert-butylamino, R3 is hydrogen, acetyl. The osteogenesis promoter according to claim 1, which is selected from benzoyl, butanoyl, methoxycarbonyl, N, N-dimethylaminocarbamoyl and methyl. 3. In the general formula (I), X and Y mean a hydroxyl group, 3'-desphenyl-3 'in which R1 = isobutyl, R2 = tertiary butyloxy and R3 = acetyl.
-Isobutyl-10-acetyl docetaxel (AZ42
001): 3'-desphenyl-3 '-(2-methylpropenyl) -10-acetyl docetaxel (AZ42002): R1 = 2-methylpropenyl, R2 = tert-butyloxy, R3 = acetyl: R1 = isobutyl. , R
2'-tert-butyloxy, R3 = hydrogen 3'-desphenyl-3'-isobutyl docetaxel (AZ4200
3): 3'-desphenyl-3'- where R1 = 2-methylpropenyl, R2 = tert-butyloxy, R3 = hydrogen.
(2-Methylpropenyl) docetaxel (AZ4200
4); 3'-desphenyl-wherein R1 = 1-methylpropenyl, R2 = tert-butyloxy, R3 = acetyl.
3 '-(1-methylpropenyl) -10-acetyl docetaxel (AZ42005): R1 = isobutyl, R2
= Tert-butyloxy, R3 = N, N-dimethylaminocarbonyl 3'-desphenyl-3'-isobutyl-10- (N, N-dimethylaminocarbonyl) docetaxel (AZ42007): R1 = isobutyl, R2 =
Tertiary butyloxy, 3'-desphenyl-3'-isobutyl-10-methyl docetaxel (AZ42008) where R3 = methyl: 3'-desphenyl where R1 = isobutyl, R2 = tert-butyloxy, R3 = benzoyl. -3'-isobutyl-10-benzoyl docetaxel (AZ42009): 3'-desphenyl-3'-isobutyl-10-butanoyl docetaxel (R1 = isobutyl, R2 = tert-butyloxy, R3 = butanoyl). AZ42010): R1 = isobutyl, R2 = tert-butyloxy, R3 = methoxycarbonyl 3'-desphenyl-3'-isobutyl-10-methoxycarbonyl docetaxel (AZ42011): R1 = tert-butyl, R2 = tert-butyl. Tributyloxy, 3'-desphenyl-3'-tert-butyl-10 where R3 = acetyl -Acetyl docetaxel (AZ42012): R1 = cyclopropyl, R2 = tert-butyloxy, R3 = acetyl 3'-desphenyl-3'-cyclopropyl-10-acetyl docetaxel (AZ42014): R1 = isopropyl. , R2 = tert-butyloxy, R3 = acetyl 3'-desphenyl-3'-isopropyl-10-acetyl docetaxel (AZ42016): R1 = 3-pentyl, R2 = tert-butyloxy, R3 = acetyl. 3'-desphenyl-3 '-(3-pentyl) -10
-Acetyl docetaxel (AZ42018): N-debenzoyl-N-tertiary amyloxycarbonyl-3'-desphenyl-3'-isobutyl paclitaxel (where R1 = isobutyl, R2 = tertiary amyloxy, R3 = acetyl. AZ42020): N-debenzoyl-N-isopropyloxycarbonyl-3'-desphenyl-3'-isobutylpaclitaxel (AZ42) where R1 = isobutyl, R2 = isopropyloxy, R3 = acetyl.
021): R1 = isobutyl, R2 = benzyloxy,
N-debenzoyl-N-benzyloxycarbonyl-3'-desphenyl-3'-isobutylpaclitaxel (AZ42022) where R3 = acetyl: R1 = isobutyl, R2 = adamantyloxy, R3 = acetyl N-debenzoyl- N-adamantyloxycarbonyl-3'-desphenyl-3'-isobutyl paclitaxel (AZ42023): R1 = isobutyl, R2 =
2,2-Dimethylpropyl, N- with R3 = acetyl
Debenzoyl-N- (3,3-dimethylbutanoyl)-
3'-desphenyl-3'-isobutylpaclitaxel (AZ42024): N-debenzoyl-N-hexanoyl-3'-desphenyl-3'-isobutylpaclitax, where R1 = isobutyl, R2 = pentyl, R3 = acetyl. Cell (AZ42025): R1 = isobutyl, R
N-debenzoyl-N-tert-butylaminocarbonyl-3'-desphenyl-3'-isobutylpaclitaxel (AZ4 where 2 = tert-butylamino and R3 = acetyl)
2026): R1 = isobutyl, R2 = 3-furyl, R
N-debenzoyl-N- (3-furyl) -3'-desphenyl-3'-isobutyl paclitaxel (AZ42027) where 3 = acetyl: paclitaxel and R where R1 = phenyl, R2 = phenyl, R3 = acetyl.
The osteogenesis promoter according to claim 1, which is selected from the group consisting of docetaxel in which 1 = phenyl, R 2 = tert-butyloxy and R 3 = hydrogen. 4. In the general formula (I), X and Y mean a hydroxyl group, R1 is isobutyl, R2 is tertiary amyloxy, isopropyloxy, benzyloxy, adamantyloxy, 2,2-dimethylpropyl, pentyl. , Tert-butylamino or 3-furyl,
A taxoid in which R3 is acetyl. 5. In the general formula (I), X and Y represent a hydroxyl group, and R1 is 1-methylpropenyl or 3-.
A taxoid selected from pentyl wherein R2 is tert-butyloxy and R3 is acetyl. 6. A taxoid selected from the group consisting of X and Y in the general formula (I), wherein R1 is isobutyl, R2 is tert-butyloxy and R3 is benzoyl or butanoyl.