CA2253443A1 - 7-o-methoxymethyl paclitaxel - Google Patents
7-o-methoxymethyl paclitaxel Download PDFInfo
- Publication number
- CA2253443A1 CA2253443A1 CA002253443A CA2253443A CA2253443A1 CA 2253443 A1 CA2253443 A1 CA 2253443A1 CA 002253443 A CA002253443 A CA 002253443A CA 2253443 A CA2253443 A CA 2253443A CA 2253443 A1 CA2253443 A1 CA 2253443A1
- Authority
- CA
- Canada
- Prior art keywords
- paclitaxel
- compound
- methoxymethyl
- ethyl acetate
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
The present invention concerns the novel compound 7-O-methoxymethyl paclitaxel, its use as an antitumor agent and pharmaceutical compositions containing the novel compound.
Description
CA 022~3443 1998-11-02 W 097/42948 PCTrUS97108079 FIELD OF THE INVENTION
The present invention concerns the novel antitumor compound, 7-O-methoxymethyl paclitaxel, pharmaceutical compositions thereof, and its use as an antitumor agent.
BACKGROUND OF TH~ INVENTION
Taxol~) (paclitaxel) is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia. It has been shown to have excellent 15 antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It has been recently approved for the treatment of ovarian cancer; and studies involving breast, colon, and lung cancers have shown promising results. The 20 results of paclitaxel clinical studies are reviewed in Rowinsky and Donehower, "The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics" Pharmac. Ther. 52:35-84,1991.
Recently, a semi-synthetic analog of paclitaxel named Taxotere~) 25 has also been found to have good antitumor activity in animal models.
Taxotere(~) is also currently undergoing clinical trials in Europe and the United States. The structures of paclitaxel and Taxotere(~) are shown below along with the conventional numbering ~y~tem of taxane molecules; such numbering system is also employed in this application.
R'O~ ~ OH
RCONH O \ /1 Ph~O
PhC(O)O
, _ CA 022~3443 1998-11-02 Taxol(E~): R = Ph; R' = acetyl Taxotere(~): R = t-butoxy; R' = hydrogen DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the novel compound 7-O-methoxymethyl paclitaxel, having the formula (I):
011~
OAC
wherein Ph is phenyl;
Ac is acetyl; and Bz is-C(O)Ph.
Representative In vivo antitumor activity Balb/c x DBA/2 F1 hybrid mice were implanted intraperitoneally, 20 as described by William Rose in Evaluation of Madison 109 Lung Carcinoma as a Model for Screening Antitumor Drugs, Cancer Treatment Reports 65, No. 3-4 (1981), with 0.5 mL of a 2% (w/v) brei of M109 lung carcinoma.
Mice were treated with compound (I) under study by receiving intraperitoneal injections of various doses on days 5 and 8 post-tumor implant. Mice were followed daily for survival until approximately 75 -90 days post-tumor implant. One group of mice per experiment remained untreated and served as the control group.
CA 022~3443 1998-11-02 W O 97/42948 PCTrUS97/08079 Median survival times of compound-treated (T) mice were compared to the median survival time of the control (C) mice. The ratio of the two values for each compound-treated group of mice was multiplied by 100 and expressed as a percentage (i.e. % T/C). Any % T/C
value 2 125 is considered significant antitumor activity.
Compound (I) exhibited a % T/C value of 192 at a dose of 50 mg/kg/injection.
The compound of formula (I) of the instant invention is an effective tumor inhibiting agent, and thus is useful in human and/or veterinary medicine. Thus, another aspect of the instant invention concerns a method for inhibiting human and/or other mammalian tumors which comprises administering to a tumor bearing host an antitumor effective amount of a compound of formula (I).
The compound of formula (I) of the present invention may be used in a manner similar to that of paclitaxel; therefore, an oncologist skilled in the art of cancer treatment will be able to ascertain, without undue experimentation, an appropriate treatment protocol for administering a compound of the present invention. The dosage, mode and schedule of administration for the compound of this invention is not particularly restricted. Thus the compound of the present invention may be administered via any suitable route of administration, preferably parenterally; the dosage may be, for example, in the range of about 1 to about 100 mg/kg of body weight, or about 20 to about 500 m g/ m2. The actual dose used will vary according to the particular composition formulated, the route of administration, and the particular site, host and type of tumor being treated. Many factors that modify the action of the 30 drug will be taken into account in determining the dosage including age, weight, sex, diet and the physical condition of the patient.
The present invention also provides pharmaceutical compositions (formulations) containing an antitumor effective amount of the compound of formula (I) in combination with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants.
CA 022~3443 1998-11-02 W 097/42948 PCTrUS97/08079 Examples of formulating paclitaxel or derivatives thereof may be found in, for example, United States Patents Nos. 4,960,790 and 4,814,470, and such examples may be followed to formulate the compound of this invention. For example, the compound of the present invention may be 5 formulated in the form of tablets, pills, powder mixtures, capsules, injectables, solutions, suppositories, emulsions, dispersions, food premix, and in other suitable forms. It may also be manufactured in the form of sterile solid compositions, for example, freeze dried and, if desired, combined with other pharmaceutically acceptable excipients. Such solid 10 compositions can be reconstituted with sterile water, physiological saline, or a mixture of water and an organic solvent, such as propylene glycol, ethanol, and the like, or some other sterile injectable medium immediately before use for parenteral administration.
Typical of pharmaceutically acceptable carriers are, for example, manitol, urea, dextrans, lactose, potato and maize starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethyl cellulose, poly(vinylpyrrolidone), calcium carbonate, ethyl oleate, isopropyl myristate, benzyl benzoate, sodium carbonate, gelatin, potassium 20 carbonate, silicic acid. The pharmaceutical preparation may also contain nontoxic auxiliary substances such as emulsifying, preserving, wetting agents, and the like as for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium sulfosuccinate, and the like.
In the following experimental procedures, all temperatures are understood to be in Centigrade (C) when not specified. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (~) expressed in parts per million (ppm) versus tetramethylsilane (TMS) 30 as re~lence standard. The relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs or br s), broad doublet (bd or br d), broad triplet (bt or br t), broad quartet (bq or br q), 35 singlet (s), multiplet (m), doublet (d), quartet (q), triplet (t), doublet of doublet (dd), doublet of triplet (dt), and doublet of quartet (dq). The CA 022~3443 1998-11-02 solvents employed for taking NMR spectra are acetone-d6 (deuterated acetone). DMSO-d6 (perdeuterodimethylsulfoxide), D20 (deuterated water), CDC13 (deuterochloroform) and other conventional deuterated solvents. The infrared (IR) spectral description include only absorption 5 wave numbers (cm~1) having functional group identification value.
The compound of formula (I) can be prepared from paclitaxel according to the following process scheme and procedure.
Note that the following abbreviations are used and have the following meanings:
"TES" means triethylsilyl "TESCl" means triethylsilylchloride WO 97142g48 ¦ The Synthesis of Compound of Formula (I) ¦
J~ AcO O
CH2CI2, 0 ~C
BzO _ O
OAc p~rli ~AY~'I
J~ AcO O
Ph NH O \ ~~4 OH
BZ202~ DMS
OTES ~ C(gs30/CO)N
BzO ~ O
II OAc Ph~ NH O ~~ ~ ~
=TES ~ 2) Cl 130H, z BzO (82%) OAc III
o ~~0' BzO ~ O
OAc I
CA 022~3443 1998-11-02 2'-O-TES p~1it~
To a solution of paclitaxel (8.1g, 9.49 mmol) in 40 mL of pyridine and 40 mL of methylene chloride at 0~ C was added TESCl (6.3 mL, 37.8 ~ 5 mmol). The solution was stirred at 0~ C for 1 hour and then diluted with ethyl acetate and washed with water and brine. The organic fraction was dried over MgSO4, concentrated and the residue chromatographed over silica gel (3:1 hexane/ethyl acetate, then 2:1 and finally with 1:1 hexane/ethyl acetate) to give 9.34 g of 2'-O-TES paclitaxel (95%).
2'-O-TES-7-O-methylthiomethyl p~litA~el (III) To a solution of 2'-O-TES paclitaxel (15.0 g, 15.5 mmol) in 150 mL of anhydrous acetonitrile at 0~ C was added dimethylsulfide (11.4 mL, 154 mmol) and benzoyl peroxide (18.7 g, 77.3 mmol). The solution was stirred at 0~ C for 30 minutes and then warmed to room temperature and stirred until the reaction was complete by TLC analysis. A saturated solution of sodium bicarbonate was added and the mixture extracted with ethyl acetate. The organic fraction was dried over MgSO4, filtered and concentrated and the residue chromatographed over silica gel, eluting with 25% ethyl acetate/hexane and then 33% ethyl acetate/hexane to give 15.14 g of product (95%).
Anal. Calcd. for CssH6gNSiSO14; C, 64.24; H, 6.76; N, 1.36.
Found: C, 63.87; H, 6.70; N, 1.31.
FABMS (NOBA) M+Na calcd for CssH6gNSiSOl4 1050.
Found: 1050.
IR(KBr) 3442, 1724, 1242, 1066 cm~
.
CA 022~3443 1998-11-02 lH NMR (CDCl3, 300 MHz) ~ 8.11 (d, J=6.9 Hz, 2H), 7.73 (d, J=6.9 Hz, 2H), 7.60-7.23 (m, 11H), 7.11 (d, J=8.7 Hz, lH), 6.54 (s, lH), 6.22 (t, J=9.3 Hz, lH), 5.69 (d, J=7.5 Hz, 2H), 4.95 (d, J=8.1 Hz, lH), 4.68 (d, J=2.0 Hz, lH), 4.65 (s, lH), 4.27 (m, 3H), 3.88 (d, J=6.9 Hz, lH), 2.80 (m, lH), 2.52 (s, 3H), 2.39 (m, lH), 2.16 (s, 3H), 2.10 (s, 3H), 2.04 (s, 3H), 1.85 (m, 2H), 1.75 (s, 3H), 1.19 (s, 3H), 1.17 (s, 3H), 0.80 (t, J=7.8 Hz, 9H), 0.43 (m, 6H).
7-O-methoxymethyl paclitaxel (I) To a solution of 2'-O-T~S-7-O-methylthiomethyl paclitaxel (10.48 g, 10.2 mmol) in 100 mL of acetonitrile at 0~ C was added 20.5 mL of lN HCl (20.5 mmol) and stirred for 1 hour at 0~ C. A saturated solution of sodium bicarbonate was added and the mixture extracted with ethyl acetate. The 15 organic fraction was washed with brine and dried over MgSO4, filtered and concentrated to give 10.1 g (quant.) of 7-methylthiomethyl paclitaxel that was pure by 1H NMR.
To a solution of 7-methylthiomethyl paclitaxel (6.54g, 7.16 mmol) 20 in 125 mL of anhydrous methanol (distilled over CaH2) with 1 g of whole 4A sieves was added I2 (8.2g, 32.3 mmol). The solution was stirred at room temperature for 1 hour and the solution decanted off into ethyl acetate and the sieves rinsed with ethyl acetate. The solution was then washed twice with a saturated solution of sodium thiosulfate and 25 once with brine, dried over MgSO4 and concentrated. The residue was chromatographed over silica gel, eluting with 40% ethyl acetate/hexane and then 50% ethyl acetate/hexane to give 660 mg of product >90% pure by HPLC (10%) and 4.67 g of product which was 98.1% pure by HPLC (72%~.
A portion of the 98% pure material (2.38g) was crystalized from a minimal 30 amount of hot ethyl acetate to which hexane was added until cloudy and then set aside at 0~ C to give 1.98 g of white solid.
CA 022~3443 1998-11-02 ESIMS M + HcalcdforC4gHs6NOls;898.
Found:898.
~ 5 IR(KBr)3436,1724,1242,1106,1026cm-l lH NMR(CDCl3,300 MHz)~8.09(d,J=7.2Hz,2H),7.75(d,J=7.2Hz, 2H),7.62-7.30(m,11H),7.06(d,J=8.5Hz,lH),6.30(s,lH),6.16(t,J=8.7Hz, lH),5.78(d,J=9.0Hz,lH),5.64(d,J=6.9Hz,lH),4.90(d,J=8.1Hz,lH),4.77 (m,lH),4.65(ABq,J=15.6,7.8Hz,2H),4.28(d,J=8.2Hz,lH),4.16(d,J=8.2 Hz,lH),4.08(mlH),3.81(d,J=6.9Hz,lH),3.63(d,J=4.8Hz,lH),3.28(s, 3H),2.77(m,lH),2.34(s,3H),2.29(d,J=8.4Hz,2H),2.21(s,3H),1.94(m, lH),1.79(s,3H),1.74(s,3H),1.17(s,6H).
The present invention concerns the novel antitumor compound, 7-O-methoxymethyl paclitaxel, pharmaceutical compositions thereof, and its use as an antitumor agent.
BACKGROUND OF TH~ INVENTION
Taxol~) (paclitaxel) is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia. It has been shown to have excellent 15 antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It has been recently approved for the treatment of ovarian cancer; and studies involving breast, colon, and lung cancers have shown promising results. The 20 results of paclitaxel clinical studies are reviewed in Rowinsky and Donehower, "The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics" Pharmac. Ther. 52:35-84,1991.
Recently, a semi-synthetic analog of paclitaxel named Taxotere~) 25 has also been found to have good antitumor activity in animal models.
Taxotere(~) is also currently undergoing clinical trials in Europe and the United States. The structures of paclitaxel and Taxotere(~) are shown below along with the conventional numbering ~y~tem of taxane molecules; such numbering system is also employed in this application.
R'O~ ~ OH
RCONH O \ /1 Ph~O
PhC(O)O
, _ CA 022~3443 1998-11-02 Taxol(E~): R = Ph; R' = acetyl Taxotere(~): R = t-butoxy; R' = hydrogen DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the novel compound 7-O-methoxymethyl paclitaxel, having the formula (I):
011~
OAC
wherein Ph is phenyl;
Ac is acetyl; and Bz is-C(O)Ph.
Representative In vivo antitumor activity Balb/c x DBA/2 F1 hybrid mice were implanted intraperitoneally, 20 as described by William Rose in Evaluation of Madison 109 Lung Carcinoma as a Model for Screening Antitumor Drugs, Cancer Treatment Reports 65, No. 3-4 (1981), with 0.5 mL of a 2% (w/v) brei of M109 lung carcinoma.
Mice were treated with compound (I) under study by receiving intraperitoneal injections of various doses on days 5 and 8 post-tumor implant. Mice were followed daily for survival until approximately 75 -90 days post-tumor implant. One group of mice per experiment remained untreated and served as the control group.
CA 022~3443 1998-11-02 W O 97/42948 PCTrUS97/08079 Median survival times of compound-treated (T) mice were compared to the median survival time of the control (C) mice. The ratio of the two values for each compound-treated group of mice was multiplied by 100 and expressed as a percentage (i.e. % T/C). Any % T/C
value 2 125 is considered significant antitumor activity.
Compound (I) exhibited a % T/C value of 192 at a dose of 50 mg/kg/injection.
The compound of formula (I) of the instant invention is an effective tumor inhibiting agent, and thus is useful in human and/or veterinary medicine. Thus, another aspect of the instant invention concerns a method for inhibiting human and/or other mammalian tumors which comprises administering to a tumor bearing host an antitumor effective amount of a compound of formula (I).
The compound of formula (I) of the present invention may be used in a manner similar to that of paclitaxel; therefore, an oncologist skilled in the art of cancer treatment will be able to ascertain, without undue experimentation, an appropriate treatment protocol for administering a compound of the present invention. The dosage, mode and schedule of administration for the compound of this invention is not particularly restricted. Thus the compound of the present invention may be administered via any suitable route of administration, preferably parenterally; the dosage may be, for example, in the range of about 1 to about 100 mg/kg of body weight, or about 20 to about 500 m g/ m2. The actual dose used will vary according to the particular composition formulated, the route of administration, and the particular site, host and type of tumor being treated. Many factors that modify the action of the 30 drug will be taken into account in determining the dosage including age, weight, sex, diet and the physical condition of the patient.
The present invention also provides pharmaceutical compositions (formulations) containing an antitumor effective amount of the compound of formula (I) in combination with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants.
CA 022~3443 1998-11-02 W 097/42948 PCTrUS97/08079 Examples of formulating paclitaxel or derivatives thereof may be found in, for example, United States Patents Nos. 4,960,790 and 4,814,470, and such examples may be followed to formulate the compound of this invention. For example, the compound of the present invention may be 5 formulated in the form of tablets, pills, powder mixtures, capsules, injectables, solutions, suppositories, emulsions, dispersions, food premix, and in other suitable forms. It may also be manufactured in the form of sterile solid compositions, for example, freeze dried and, if desired, combined with other pharmaceutically acceptable excipients. Such solid 10 compositions can be reconstituted with sterile water, physiological saline, or a mixture of water and an organic solvent, such as propylene glycol, ethanol, and the like, or some other sterile injectable medium immediately before use for parenteral administration.
Typical of pharmaceutically acceptable carriers are, for example, manitol, urea, dextrans, lactose, potato and maize starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethyl cellulose, poly(vinylpyrrolidone), calcium carbonate, ethyl oleate, isopropyl myristate, benzyl benzoate, sodium carbonate, gelatin, potassium 20 carbonate, silicic acid. The pharmaceutical preparation may also contain nontoxic auxiliary substances such as emulsifying, preserving, wetting agents, and the like as for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium sulfosuccinate, and the like.
In the following experimental procedures, all temperatures are understood to be in Centigrade (C) when not specified. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (~) expressed in parts per million (ppm) versus tetramethylsilane (TMS) 30 as re~lence standard. The relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs or br s), broad doublet (bd or br d), broad triplet (bt or br t), broad quartet (bq or br q), 35 singlet (s), multiplet (m), doublet (d), quartet (q), triplet (t), doublet of doublet (dd), doublet of triplet (dt), and doublet of quartet (dq). The CA 022~3443 1998-11-02 solvents employed for taking NMR spectra are acetone-d6 (deuterated acetone). DMSO-d6 (perdeuterodimethylsulfoxide), D20 (deuterated water), CDC13 (deuterochloroform) and other conventional deuterated solvents. The infrared (IR) spectral description include only absorption 5 wave numbers (cm~1) having functional group identification value.
The compound of formula (I) can be prepared from paclitaxel according to the following process scheme and procedure.
Note that the following abbreviations are used and have the following meanings:
"TES" means triethylsilyl "TESCl" means triethylsilylchloride WO 97142g48 ¦ The Synthesis of Compound of Formula (I) ¦
J~ AcO O
CH2CI2, 0 ~C
BzO _ O
OAc p~rli ~AY~'I
J~ AcO O
Ph NH O \ ~~4 OH
BZ202~ DMS
OTES ~ C(gs30/CO)N
BzO ~ O
II OAc Ph~ NH O ~~ ~ ~
=TES ~ 2) Cl 130H, z BzO (82%) OAc III
o ~~0' BzO ~ O
OAc I
CA 022~3443 1998-11-02 2'-O-TES p~1it~
To a solution of paclitaxel (8.1g, 9.49 mmol) in 40 mL of pyridine and 40 mL of methylene chloride at 0~ C was added TESCl (6.3 mL, 37.8 ~ 5 mmol). The solution was stirred at 0~ C for 1 hour and then diluted with ethyl acetate and washed with water and brine. The organic fraction was dried over MgSO4, concentrated and the residue chromatographed over silica gel (3:1 hexane/ethyl acetate, then 2:1 and finally with 1:1 hexane/ethyl acetate) to give 9.34 g of 2'-O-TES paclitaxel (95%).
2'-O-TES-7-O-methylthiomethyl p~litA~el (III) To a solution of 2'-O-TES paclitaxel (15.0 g, 15.5 mmol) in 150 mL of anhydrous acetonitrile at 0~ C was added dimethylsulfide (11.4 mL, 154 mmol) and benzoyl peroxide (18.7 g, 77.3 mmol). The solution was stirred at 0~ C for 30 minutes and then warmed to room temperature and stirred until the reaction was complete by TLC analysis. A saturated solution of sodium bicarbonate was added and the mixture extracted with ethyl acetate. The organic fraction was dried over MgSO4, filtered and concentrated and the residue chromatographed over silica gel, eluting with 25% ethyl acetate/hexane and then 33% ethyl acetate/hexane to give 15.14 g of product (95%).
Anal. Calcd. for CssH6gNSiSO14; C, 64.24; H, 6.76; N, 1.36.
Found: C, 63.87; H, 6.70; N, 1.31.
FABMS (NOBA) M+Na calcd for CssH6gNSiSOl4 1050.
Found: 1050.
IR(KBr) 3442, 1724, 1242, 1066 cm~
.
CA 022~3443 1998-11-02 lH NMR (CDCl3, 300 MHz) ~ 8.11 (d, J=6.9 Hz, 2H), 7.73 (d, J=6.9 Hz, 2H), 7.60-7.23 (m, 11H), 7.11 (d, J=8.7 Hz, lH), 6.54 (s, lH), 6.22 (t, J=9.3 Hz, lH), 5.69 (d, J=7.5 Hz, 2H), 4.95 (d, J=8.1 Hz, lH), 4.68 (d, J=2.0 Hz, lH), 4.65 (s, lH), 4.27 (m, 3H), 3.88 (d, J=6.9 Hz, lH), 2.80 (m, lH), 2.52 (s, 3H), 2.39 (m, lH), 2.16 (s, 3H), 2.10 (s, 3H), 2.04 (s, 3H), 1.85 (m, 2H), 1.75 (s, 3H), 1.19 (s, 3H), 1.17 (s, 3H), 0.80 (t, J=7.8 Hz, 9H), 0.43 (m, 6H).
7-O-methoxymethyl paclitaxel (I) To a solution of 2'-O-T~S-7-O-methylthiomethyl paclitaxel (10.48 g, 10.2 mmol) in 100 mL of acetonitrile at 0~ C was added 20.5 mL of lN HCl (20.5 mmol) and stirred for 1 hour at 0~ C. A saturated solution of sodium bicarbonate was added and the mixture extracted with ethyl acetate. The 15 organic fraction was washed with brine and dried over MgSO4, filtered and concentrated to give 10.1 g (quant.) of 7-methylthiomethyl paclitaxel that was pure by 1H NMR.
To a solution of 7-methylthiomethyl paclitaxel (6.54g, 7.16 mmol) 20 in 125 mL of anhydrous methanol (distilled over CaH2) with 1 g of whole 4A sieves was added I2 (8.2g, 32.3 mmol). The solution was stirred at room temperature for 1 hour and the solution decanted off into ethyl acetate and the sieves rinsed with ethyl acetate. The solution was then washed twice with a saturated solution of sodium thiosulfate and 25 once with brine, dried over MgSO4 and concentrated. The residue was chromatographed over silica gel, eluting with 40% ethyl acetate/hexane and then 50% ethyl acetate/hexane to give 660 mg of product >90% pure by HPLC (10%) and 4.67 g of product which was 98.1% pure by HPLC (72%~.
A portion of the 98% pure material (2.38g) was crystalized from a minimal 30 amount of hot ethyl acetate to which hexane was added until cloudy and then set aside at 0~ C to give 1.98 g of white solid.
CA 022~3443 1998-11-02 ESIMS M + HcalcdforC4gHs6NOls;898.
Found:898.
~ 5 IR(KBr)3436,1724,1242,1106,1026cm-l lH NMR(CDCl3,300 MHz)~8.09(d,J=7.2Hz,2H),7.75(d,J=7.2Hz, 2H),7.62-7.30(m,11H),7.06(d,J=8.5Hz,lH),6.30(s,lH),6.16(t,J=8.7Hz, lH),5.78(d,J=9.0Hz,lH),5.64(d,J=6.9Hz,lH),4.90(d,J=8.1Hz,lH),4.77 (m,lH),4.65(ABq,J=15.6,7.8Hz,2H),4.28(d,J=8.2Hz,lH),4.16(d,J=8.2 Hz,lH),4.08(mlH),3.81(d,J=6.9Hz,lH),3.63(d,J=4.8Hz,lH),3.28(s, 3H),2.77(m,lH),2.34(s,3H),2.29(d,J=8.4Hz,2H),2.21(s,3H),1.94(m, lH),1.79(s,3H),1.74(s,3H),1.17(s,6H).
Claims (3)
1. The compound, 7-O-methoxymethyl paclitaxel, having the formula (I) wherein Ph is phenyl;
Ac is acetyl; and Bz is -C(O)Ph.
Ac is acetyl; and Bz is -C(O)Ph.
2. A pharmaceutical composition which comprises an antitumor effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
3. A method for inhibiting tumor growth in a mammalian host which comprises administering to said mammal a tumor-growth inhibiting amount of a compound of claim 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1791996P | 1996-05-16 | 1996-05-16 | |
| US60/017,919 | 1996-05-16 | ||
| PCT/US1997/008079 WO1997042948A1 (en) | 1996-05-16 | 1997-05-08 | 7-o-methoxymethyl paclitaxel |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2253443A1 true CA2253443A1 (en) | 1997-11-20 |
Family
ID=21785279
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002253443A Abandoned CA2253443A1 (en) | 1996-05-16 | 1997-05-08 | 7-o-methoxymethyl paclitaxel |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0906095A1 (en) |
| JP (1) | JP2000510148A (en) |
| AU (1) | AU706955B2 (en) |
| CA (1) | CA2253443A1 (en) |
| WO (1) | WO1997042948A1 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4960790A (en) * | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
| US5646176A (en) * | 1992-12-24 | 1997-07-08 | Bristol-Myers Squibb Company | Phosphonooxymethyl ethers of taxane derivatives |
| NZ288802A (en) * | 1994-06-28 | 1998-05-27 | Upjohn Co | Ether taxol derivatives, preparation and pharmaceutical compositions thereof |
-
1997
- 1997-05-08 JP JP09541052A patent/JP2000510148A/en active Pending
- 1997-05-08 AU AU31240/97A patent/AU706955B2/en not_active Ceased
- 1997-05-08 CA CA002253443A patent/CA2253443A1/en not_active Abandoned
- 1997-05-08 WO PCT/US1997/008079 patent/WO1997042948A1/en not_active Application Discontinuation
- 1997-05-08 EP EP97926480A patent/EP0906095A1/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| EP0906095A1 (en) | 1999-04-07 |
| AU3124097A (en) | 1997-12-05 |
| AU706955B2 (en) | 1999-07-01 |
| EP0906095A4 (en) | 1999-05-12 |
| JP2000510148A (en) | 2000-08-08 |
| WO1997042948A1 (en) | 1997-11-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU722082B2 (en) | 6-halo-or nitrate-substituted paclitaxels | |
| US5977386A (en) | 6-thio-substituted paclitaxels | |
| US5821263A (en) | Sulfenamide taxane derivatives | |
| CA2163706C (en) | Amino acid derivatives of paclitaxel | |
| US5635531A (en) | 3'-aminocarbonyloxy paclitaxels | |
| AU706155B2 (en) | 7-deoxy-6-substituted paclitaxels | |
| US5840929A (en) | C4 methoxy ether derivatives of paclitaxel | |
| US5739359A (en) | Methods for preparing 1-deoxy paclitaxels | |
| US5773464A (en) | C-10 epoxy taxanes | |
| AU706955B2 (en) | 7-O-methoxymethyl paclitaxel | |
| CA2328771A1 (en) | 2-aroyl-4-acyl paclitaxel (taxol) analogs | |
| EP1263749B1 (en) | Taxane anticancer agents | |
| AU724591B2 (en) | 7-methylthiooxomethyl and 7-methylthiodioxomethyl paclitaxels | |
| AU2001245582A1 (en) | Taxane anticancer agents | |
| WO1999032109A1 (en) | 7-deoxy-6-nitrogen substituted paclitaxels | |
| WO1998000419A1 (en) | Ortho-ester analogs of paclitaxel | |
| KR20030049023A (en) | Paclitaxel derivatives for radio-sensitizer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |