WO2018001270A1 - Palbociclib prodrugs and composition thereof - Google Patents
Palbociclib prodrugs and composition thereof Download PDFInfo
- Publication number
- WO2018001270A1 WO2018001270A1 PCT/CN2017/090534 CN2017090534W WO2018001270A1 WO 2018001270 A1 WO2018001270 A1 WO 2018001270A1 CN 2017090534 W CN2017090534 W CN 2017090534W WO 2018001270 A1 WO2018001270 A1 WO 2018001270A1
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- WO
- WIPO (PCT)
- Prior art keywords
- palbociclib
- compound
- present
- formula
- prodrugs
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- 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.)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to Palbociclib prodrugs.
- Palbociclib (trade name Ibrance) (IUPAC name: 6-Acetyl-8-cyclopentyl-5-methyl-2- ⁇ [5- (1-piperazinyl) -2-pyridinyl] amino ⁇ pyrido [2, 3-d] pyrimidin-7 (8H) -one) is a drug for treating ER-positive and HER2-negative breast cancer, which has the following formula:
- Palbociclib is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6.
- the present invention provides a compound having the formula:
- the present invention provides a compound having the formula:
- the compounds of Formulae (I) and (II) may be used as Palbociclib prodrugs in treating breast cancer.
- the present invention provides a pharmaceutical composition, which comprises a compound of the present invention, and a pharmaceutically acceptable excipient.
- Fig. 1 shows the concentration of Palbociclib in the blood samples from Group K (administered with Palbociclib) .
- Fig. 2 shows the concentration of Palbociclib in the blood samples from Group L (administered with compound of Formula (I)) .
- Fig. 3 shows the concentration of Palbociclib in the blood samples from Group M (administered with compound of Formula (II)) .
- Fig. 4 shows the averaged concentrations of Palbociclib in the blood samples from Groups K, L, and M, respectively.
- the present invention provides a compound having the formula:
- the present invention provides a compound having the formula:
- the compounds of Formulae (I) and (II) may be used as Palbociclib prodrugs in treating breast cancer.
- the present invention provides a pharmaceutical composition, which comprises a compound of the present invention, and a pharmaceutically acceptable excipient.
- the compound of Formula (I) may be prepared by the following process:
- the compound of Formula (I) may be prepared by the following process:
- the pharmaceutical composition of the present invention can be manufactured by conventionally known methods with one or more pharmaceutically acceptable excipients or carriers.
- pharmaceutically acceptable excipient encompasses any of the standard pharmaceutical carriers. Excipients include, by way of illustration and not limitation, solvents, thickening agents, wetting agents, lubricants, penetration enhancers. Such excipients include but are not limited to: saline, buffered saline, dextrose, water, glycerol, ethanol, propylene glycol, cremophor, nanoparticles, liposome, polymer, and combinations thereof.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Disclosed herein are Palbociclib prodrugs, and pharmaceutical compositions comprising the Palbociclib prodrugs.
Description
The present invention relates to Palbociclib prodrugs.
Palbociclib (trade name Ibrance) (IUPAC name: 6-Acetyl-8-cyclopentyl-5-methyl-2- { [5- (1-piperazinyl) -2-pyridinyl] amino} pyrido [2, 3-d] pyrimidin-7 (8H) -one) is a drug for treating ER-positive and HER2-negative breast cancer, which has the following formula:
It is known that Palbociclib is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6.
BRIEF SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound having the formula:
In another aspect, the present invention provides a compound having the formula:
According to the present invention, the compounds of Formulae (I) and (II) may be used as Palbociclib prodrugs in treating breast cancer.
In a further aspect, the present invention provides a pharmaceutical composition, which comprises a compound of the present invention, and a pharmaceutically acceptable excipient.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred.
In the drawings:
Fig. 1 shows the concentration of Palbociclib in the blood samples from Group K (administered with Palbociclib) .
Fig. 2 shows the concentration of Palbociclib in the blood samples from Group L (administered with compound of Formula (I)) .
Fig. 3 shows the concentration of Palbociclib in the blood samples from Group M (administered with compound of Formula (II)) .
Fig. 4 shows the averaged concentrations of Palbociclib in the blood samples from Groups K, L, and M, respectively.
In one aspect, the present invention provides a compound having the formula:
In another aspect, the present invention provides a compound having the formula:
According to the present invention, the compounds of Formulae (I) and (II) may be used as Palbociclib prodrugs in treating breast cancer.
In a further aspect, the present invention provides a pharmaceutical composition, which comprises a compound of the present invention, and a pharmaceutically acceptable excipient.
According to the present invention, the compound of Formula (I) may be prepared by the following process:
According to the present invention, the compound of Formula (I) may be prepared by the following process:
The pharmaceutical composition of the present invention can be manufactured by conventionally known methods with one or more pharmaceutically acceptable excipients or carriers. The term “pharmaceutically acceptable excipient” as used herein encompasses any of the standard pharmaceutical carriers. Excipients include, by way of illustration and not limitation, solvents, thickening agents, wetting agents, lubricants, penetration enhancers. Such excipients include but are not limited to: saline, buffered saline, dextrose, water, glycerol, ethanol, propylene glycol, cremophor, nanoparticles, liposome, polymer, and combinations thereof.
The present invention is further illustrated by the following examples, which are provided for the purpose of demonstration rather than limitation.
Examples
Example 1: Pharmacokinetic Examination
Materials and Methods
Nine male SD rats were randomly assigned to one of three groups: Group K, Group L, and Group M, which were administered intragastrically (i. g. ) with 5 mg/kg of Palbociclib, compound of Formula (I) , and compound of Formula (II) , respectively. The concentration of Palbociclib in blood samples collected at different time points after administration was determined by LC-MS/MS (Agilent G6410B, ESI) . Pharmacokinetic parameters were calculated using WinNonlin (6.3) software, non-compartmental model.
Results
The results are shown in the following Figs. 1-4 and Table 1 below. Compound of Formula (I) and Compound of Formula (II) were not detectable in the blood samples from Groups L and M, respectively.
Table 1. Pharmacokinetic parameters of Palbociclib
It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims.
Claims (4)
- A compound having the formula:
- A compound having the formula:
- A pharmaceutical composition comprising the compound of claim 1, and a pharmaceutically acceptable excipient.
- A pharmaceutical composition comprising the compound of claim 2, and a pharmaceutically acceptable excipient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662357130P | 2016-06-30 | 2016-06-30 | |
| US62/357,130 | 2016-06-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2018001270A1 true WO2018001270A1 (en) | 2018-01-04 |
Family
ID=60785092
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2017/090534 Ceased WO2018001270A1 (en) | 2016-06-30 | 2017-06-28 | Palbociclib prodrugs and composition thereof |
Country Status (2)
| Country | Link |
|---|---|
| TW (1) | TW201803875A (en) |
| WO (1) | WO2018001270A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005005426A1 (en) * | 2003-07-11 | 2005-01-20 | Warner-Lambert Company Llc | Isethionate salt of a selective cdk4 inhibitor |
| WO2013142427A1 (en) * | 2012-03-19 | 2013-09-26 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
| WO2015022609A1 (en) * | 2013-08-14 | 2015-02-19 | Novartis Ag | Combination therapy for the treatment of cancer |
| WO2016015598A1 (en) * | 2014-07-26 | 2016-02-04 | Sunshine Lake Pharma Co., Ltd. | 2-amino-pyrido[2,3-d]pyrimidin-7(8h)-one derivatives as cdk inhibitors and uses thereof |
| WO2016065980A1 (en) * | 2014-10-30 | 2016-05-06 | 康朴生物医药技术（上海）有限公司 | Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof |
-
2017
- 2017-06-28 WO PCT/CN2017/090534 patent/WO2018001270A1/en not_active Ceased
- 2017-06-29 TW TW106121845A patent/TW201803875A/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005005426A1 (en) * | 2003-07-11 | 2005-01-20 | Warner-Lambert Company Llc | Isethionate salt of a selective cdk4 inhibitor |
| WO2013142427A1 (en) * | 2012-03-19 | 2013-09-26 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
| WO2015022609A1 (en) * | 2013-08-14 | 2015-02-19 | Novartis Ag | Combination therapy for the treatment of cancer |
| WO2016015598A1 (en) * | 2014-07-26 | 2016-02-04 | Sunshine Lake Pharma Co., Ltd. | 2-amino-pyrido[2,3-d]pyrimidin-7(8h)-one derivatives as cdk inhibitors and uses thereof |
| WO2016065980A1 (en) * | 2014-10-30 | 2016-05-06 | 康朴生物医药技术（上海）有限公司 | Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| TW201803875A (en) | 2018-02-01 |
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