WO2006098628A1 - Oral dosage forms of gemcitabine derivatives - Google Patents

Oral dosage forms of gemcitabine derivatives Download PDF

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Publication number
WO2006098628A1
WO2006098628A1 PCT/NO2006/000085 NO2006000085W WO2006098628A1 WO 2006098628 A1 WO2006098628 A1 WO 2006098628A1 NO 2006000085 W NO2006000085 W NO 2006000085W WO 2006098628 A1 WO2006098628 A1 WO 2006098628A1
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gemcitabine
dosage form
oral dosage
pharmaceutical acceptable
formula
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PCT/NO2006/000085
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French (fr)
Inventor
Finn Myhren
Marit Liland Sandvold
Ole Henrik Eriksen
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Clavis Pharma ASA
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Clavis Pharma ASA
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Priority to NZ561377A priority Critical patent/NZ561377A/en
Priority to CA002600399A priority patent/CA2600399A1/en
Priority to JP2008501829A priority patent/JP2008533135A/en
Priority to US11/908,364 priority patent/US20080280851A1/en
Priority to EP06716760A priority patent/EP1858527A4/en
Priority to AU2006223757A priority patent/AU2006223757A1/en
Publication of WO2006098628A1 publication Critical patent/WO2006098628A1/en
Priority to IL185866A priority patent/IL185866A0/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to oral dosage forms of certain long chain saturated and monounsaturated fatty acid derivatives of 2',2'-difluorodeoxycytidine (Gemcitabine).
  • the present invention relates to the use of the said gemcitabine derivatives or a pharmaceutical acceptable salt thereof for preparing an oral dosage form ameliorating compliance in treatment of cancer.
  • Gemcitabine has the formula:
  • R 1 , R 2 and R 3 are independently selected from hydrogen and C 18 - and C 2 o- saturated and monounsaturated acyl groups, with the proviso that R 1 , R 2 and R 3 cannot all be hydrogen.
  • gemcitabine is a well known cytostatic compound, marketed under the trade name Gemzar by Eli Lilly & Co.
  • Gemzar is administered intravenously (i.v.).
  • the reason for choosing a parenteral administration route is due to the toxicity of gemcitabine.
  • gemcitabine Like a lot of drugs, it obviously would have been desirable to be able to administer gemcitabine orally.
  • oral administration usually is much more pleasant than intravenous administration.
  • R 1 , R 2 and R 3 are independently selected from hydrogen and C 18 - and C 2 o- saturated and monounsaturated acyl groups, with the proviso that R 1 , R 2 and R 3 cannot all be hydrogen or a pharmaceutical acceptable salt thereof, for preparing an oral dosage form ameliorating compliance in treatment of cancer, is provided.
  • Gemcitabine has three derivatisable functions, namely the 5'- and 3'-hydroxyl groups and the N 4 -amino group. Each group can selectively be transformed into an ester or amide derivative, but di-adducts (di-esters or ester-amides) and tri-adducts may be formed as well. In the case of the di- and tri-adducts the acyl substituent groups need not necessarily be the same.
  • the mono-acyl derivatives of this invention i.e. with two of R 1 , R 2 and R 3 being hydrogen, are preferred. It is especially preferred that the monosubstitution with the acyl group should be in the 3'-0 and 5'-O positions of the sugar moiety, with 5'-0 substitution being most preferred.
  • the double bond of the mono-unsaturated acyl groups may be in either the cis or the trans configuration, although the therapeutic effect may differ depending on which configuration is used.
  • the position of the double bond in the monounsaturated acyl groups also seem to affect the activity.
  • esters or amides having their unsaturation in the ⁇ -9 position.
  • the position ⁇ of the double bond of a monounsaturated fatty acid is counted from the terminal methyl group, so that, for example, eicosenoic acid (C 2 o: 1 ⁇ -9) has 20 carbon atoms in the chain and a single double bond is formed between carbon 9 and 10 counting from the methyl end of the chain.
  • Esters, ester-amides and amides of gemcitabine derived from stearic acid (C 18 :0) and eicosanoic acid (C 2O ⁇ O) are advantageously used in some cases.
  • elaidic acid (5')-gemcitabine ester for preparing an oral dosage form ameliorating compliance in treatment of cancer.
  • the present invention relates to an oral dosage form useful for ameliorating compliance in treatment of cancer, comprising a gemcitabine derivative of formula (I) or a pharmaceutical acceptable salt thereof.
  • the present invention also provides a method for ameliorating compliance in treatment of cancer, in a subject in need of such treatment, which comprises orally administering to such subject a therapeutically effective amount of a gemcitabine derivative of formula (T) as defined in claim 1 or a pharmaceutical acceptable salt thereof.
  • terapéuticaally effective amount refers to from about 0,1 mg to 20 grams per day of a gemcitabine derivative of formula (I) or a pharmaceutical acceptable salt thereof, more preferred from about 100 mg to 2 grams per day of a gemcitabine derivative of formula (I) or a pharmaceutical acceptable salt thereof, in a formulation containing 0,001 - 100% of the said derivative or salt thereof formulated in capsule, tablet, mixture, colloidal suspension or others for oral administration.
  • a gemcitabine derivative of formula (I) or a pharmaceutical acceptable salt thereof in a formulation containing 0,001 - 100% of the said derivative or salt thereof formulated in capsule, tablet, mixture, colloidal suspension or others for oral administration.
  • Fig. 1 shows antitumour activity of elaidic acid (5')-gemcitabine ester and gemcitabine in colon cancer xenograft Co5776.
  • Fig. 2 shows antitumour activity of elaidic acid (5')-gemcitabine ester and gemcitabine after intraperitoneal administration to mice with human colon cancer xenograft Co6044.
  • Fig. 3 shows oral effect of elaidic acid (5')-gemcitabine ester in Co6044 xenograft.
  • Fig. 4 shows mean body weight of treated animals.
  • the maximum tolerated dose for gemcitabine is approximately 120 mg/kg per injection compared to 40 mg/kg per injection for elaidic acid (5')-gemcitabine ester. This is shown below by the experiments presented in table 1 and table 2 using different mice strains and also different human colon xenografts.
  • BWC body weight change
  • T/C volume of treated tumour versus volume of control tumour
  • Ncr nu/nu female mice, 8 per group, were inserted with the human colon cancer xenograft Co6044 and treated IP every third day for five times with elaidic acid (5')- gemcitabine ester (40mg/kg) or gemcitabine (120 mg/kg) . Treatment started when the tumours reached a mean volume of 100 mm 3 . Excellent antitumor effect was obtained for elaidic acid (5')-gemcitabine ester and gemcitabine.
  • Antitumour activity after oral administration of elaidic acid (5')-gemcitabine ester and gemcitabine was tested for the first time in NCR:nu/nu mice. The lowest starting dose was selected based on IP data. A dose of gemcitabine that is well tolerated and active when administered intraperitoneally (120 mg/kg per injection) was highly toxic and it was impossible to evaluate antitumour activity as gemcitabine was toxic at all tested doses. On the contrary and to our great surprise, a dose of elaidic acid (5')-gemcitabine ester (40 mg/kg) that was shown to be highly active after intraperitoneal administration was also highly active and tolerable when given orally. These results are shown in Table 3.

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  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

The present invention relates to oral dosage forms of certain long chain saturated and monounsaturated fatty acid derivatives of 2',2'-difluorodeoxycytidine (Gemcitabine). In particular, the present invention relates to the use of the said gemcitabine derivatives or a pharmaceutical acceptable salt thereof for preparing an oral dosage form ameliorating compliance in treatment of cancer.

Description

Oral dosage forms of gemcitabine derivatives
The present invention relates to oral dosage forms of certain long chain saturated and monounsaturated fatty acid derivatives of 2',2'-difluorodeoxycytidine (Gemcitabine). In particular, the present invention relates to the use of the said gemcitabine derivatives or a pharmaceutical acceptable salt thereof for preparing an oral dosage form ameliorating compliance in treatment of cancer.
Gemcitabine has the formula:
Figure imgf000002_0001
The derivatives of the present invention can be represented by the formula I:
Figure imgf000002_0002
(D wherein R1, R2 and R3 are independently selected from hydrogen and C18- and C2o- saturated and monounsaturated acyl groups, with the proviso that R1, R2 and R3 cannot all be hydrogen.
It is known from WO 98/32762 that compounds of formula (I) are useful in treatment of cancer.
Furthermore, gemcitabine is a well known cytostatic compound, marketed under the trade name Gemzar by Eli Lilly & Co.
Gemzar is administered intravenously (i.v.). The reason for choosing a parenteral administration route is due to the toxicity of gemcitabine. Like a lot of drugs, it obviously would have been desirable to be able to administer gemcitabine orally. For the patient oral administration usually is much more pleasant than intravenous administration.
Normally the dose in terms of mg/kg must be increased when administering enterally (orally) compared to parenterally due to bioavailability less than 100%. Therefore, drugs having a high degree of toxicity are not suitable for oral administration.
This is also the case for gemcitabine. Experiments have shown that the toxicity of gemcitabine is greatly enhanced after oral administration. That is, the toxicity of gemcitabine is largely increased after oral administration compared to the toxicity after intraperitoneal (parenteral) administration.
We have now surprisingly found that the toxicity after oral administration of derivatives of formula (I) resembles the toxicity of intraperitoneal (parenteral) dosing of the said compound.
It is a main object of the present invention to find a way to be able to orally administer gemcitabine derivatives being as efficacious as, or more efficacious than gemcitabine itself, in the treatment of cancer.
This and other objects by the present invention are obtained by the attached claims.
According to an embodiment of the present invention the use of a gemcitabine derivative of formula (T):
Figure imgf000004_0001
(D
wherein R1, R2 and R3 are independently selected from hydrogen and C18- and C2o- saturated and monounsaturated acyl groups, with the proviso that R1, R2 and R3 cannot all be hydrogen or a pharmaceutical acceptable salt thereof, for preparing an oral dosage form ameliorating compliance in treatment of cancer, is provided.
Gemcitabine has three derivatisable functions, namely the 5'- and 3'-hydroxyl groups and the N4-amino group. Each group can selectively be transformed into an ester or amide derivative, but di-adducts (di-esters or ester-amides) and tri-adducts may be formed as well. In the case of the di- and tri-adducts the acyl substituent groups need not necessarily be the same.
Currently, the mono-acyl derivatives of this invention, i.e. with two of R1, R2 and R3 being hydrogen, are preferred. It is especially preferred that the monosubstitution with the acyl group should be in the 3'-0 and 5'-O positions of the sugar moiety, with 5'-0 substitution being most preferred.
The double bond of the mono-unsaturated acyl groups may be in either the cis or the trans configuration, although the therapeutic effect may differ depending on which configuration is used.
The position of the double bond in the monounsaturated acyl groups also seem to affect the activity. Currently, we prefer to use esters or amides having their unsaturation in the ω-9 position. In the ω-system of nomenclature, the position ω of the double bond of a monounsaturated fatty acid is counted from the terminal methyl group, so that, for example, eicosenoic acid (C2o: 1 ω-9) has 20 carbon atoms in the chain and a single double bond is formed between carbon 9 and 10 counting from the methyl end of the chain. We prefer to use esters, ester-amides and amides derived from oleic acid (C18: 1 ω-9, cis), elaidic acid (C18: 1 ω-9, trans), eicosenoic acid(s) (C2o:l ω-9, cis) and (C2o".l ω-9, trans), and the amides and 5 '-esters are currently the most preferred derivatives of this invention.
Esters, ester-amides and amides of gemcitabine derived from stearic acid (C18:0) and eicosanoic acid (C2O^O) are advantageously used in some cases.
Elaidic acid (N4)-Gemcitabine amide, elaidic acid (5')-gemcitabine ester and elaidic acid (3')-gemcitabine ester among the most preferred derivatives of the invention.
In a preferred embodiment of the invention the use of elaidic acid (5')-gemcitabine ester for preparing an oral dosage form ameliorating compliance in treatment of cancer, is provided.
According to another embodiment, the present invention relates to an oral dosage form useful for ameliorating compliance in treatment of cancer, comprising a gemcitabine derivative of formula (I) or a pharmaceutical acceptable salt thereof.
The present invention also provides a method for ameliorating compliance in treatment of cancer, in a subject in need of such treatment, which comprises orally administering to such subject a therapeutically effective amount of a gemcitabine derivative of formula (T) as defined in claim 1 or a pharmaceutical acceptable salt thereof.
The derivatives of formula (I) are prepared according to methods known in the prior art (see WO 98/32762 for further details).
The term "therapeutically effective amount" as used herein refers to from about 0,1 mg to 20 grams per day of a gemcitabine derivative of formula (I) or a pharmaceutical acceptable salt thereof, more preferred from about 100 mg to 2 grams per day of a gemcitabine derivative of formula (I) or a pharmaceutical acceptable salt thereof, in a formulation containing 0,001 - 100% of the said derivative or salt thereof formulated in capsule, tablet, mixture, colloidal suspension or others for oral administration. In the following the invention will be further explained by examples and attached figures (Fig.1-4). The examples are only meant to be illustrative and shall not be considered as limiting.
Fig. 1 shows antitumour activity of elaidic acid (5')-gemcitabine ester and gemcitabine in colon cancer xenograft Co5776.
Fig. 2 shows antitumour activity of elaidic acid (5')-gemcitabine ester and gemcitabine after intraperitoneal administration to mice with human colon cancer xenograft Co6044.
Fig. 3 shows oral effect of elaidic acid (5')-gemcitabine ester in Co6044 xenograft.
Fig. 4 shows mean body weight of treated animals.
EXAMPLES
EXAMPLE 1 Background experiments
When test compounds are administered every third day, repeated five times, both test compounds at their maximum tolerated doses (MTD), the maximum tolerated dose for gemcitabine is approximately 120 mg/kg per injection compared to 40 mg/kg per injection for elaidic acid (5')-gemcitabine ester. This is shown below by the experiments presented in table 1 and table 2 using different mice strains and also different human colon xenografts.
Antitumor activity of elaidic acid (5')-gemcitabine ester and gemcitabine in a human colon xenograft model Co5776
Human colon cancer Co5776 was inserted to Ncr:nu/nu female mice subcutaneously, and treatment started when tumours reached a mean volume of 100 mm3. Treatment was IP with gemcitabine (120 mg/kg) or elaidic acid (5')-gemcitabine ester (40mg/kg). As can be seen from Fig. 1, high antitumour activity in terms of reductions in tumour growth is obtained for both gemcitabine and elaidic acid (5')-gemcitabine ester. Toxicity in terms of weight loss is similar, with slightly more toxicity seen with gemcitabine but both are considered to be at the maximum tolerated dose. Table 1 Antitumour activity in NCR:nu/nu female mice implanted with Colon 5776 (human colon carcinoma) treated IP with elaidic acid (5' - emcitabine ester or emcitabine
Figure imgf000007_0001
* significant different from Saline control 1
BWC = body weight change, T/C = volume of treated tumour versus volume of control tumour
Antitumor activity of elaidic acid (5')-gemcitabine ester and gemcitabine in human colon cancer xenograft model
Ncr:nu/nu female mice, 8 per group, were inserted with the human colon cancer xenograft Co6044 and treated IP every third day for five times with elaidic acid (5')- gemcitabine ester (40mg/kg) or gemcitabine (120 mg/kg) . Treatment started when the tumours reached a mean volume of 100 mm3. Excellent antitumor effect was obtained for elaidic acid (5')-gemcitabine ester and gemcitabine.
Table 2 Antitumour activity in NMRI male mice implanted with Co6044 (human colon carcinoma) treated IP with elaidic acid 5' - emcitabine ester or emcitabine
Figure imgf000007_0002
* significant different from Saline control BWC = body weight change, T/C = volume of treated tumour versus volume of control tumour EXAMPLE 2
Antitumour activity of elaidic acid (5')-gemcitabine ester and gemcitabine in Co6044 after oral administration
Antitumour activity after oral administration of elaidic acid (5')-gemcitabine ester and gemcitabine was tested for the first time in NCR:nu/nu mice. The lowest starting dose was selected based on IP data. A dose of gemcitabine that is well tolerated and active when administered intraperitoneally (120 mg/kg per injection) was highly toxic and it was impossible to evaluate antitumour activity as gemcitabine was toxic at all tested doses. On the contrary and to our great surprise, a dose of elaidic acid (5')-gemcitabine ester (40 mg/kg) that was shown to be highly active after intraperitoneal administration was also highly active and tolerable when given orally. These results are shown in Table 3.
This surprising finding has been confirmed by the data shown in Table 4, where it is demonstrated that oral administration of elaidic acid (5')-gemcitabine gives high antitumour activity at tolerable doses with different dosing schedules.
Table 3 Antitumour activity in NCR:nu/nu female mice implanted with Colon 6044 (human colon carcinoma) treated orall with elaidic acid (5')- emcitabine ester or emcitabine
Figure imgf000008_0001
! significant different from Saline control Antitumour activity of elaidic acid (5')-gemcitabine ester in Co6044 after oral administration
Table 4 Antitumour activity in NCR:nu/nu female mice implanted with Colon 6044 (human colon carcinoma) treated orall with elaidic acid (S' - emcitabine ester
Figure imgf000009_0001
* significant different from Saline control
High dose dependent activity was seen in all tested schedules after oral administration of elaidic acid (5')-gemcitabine ester. Significant antitumour activity was observed for all the tested schedules.

Claims

C 1 a i m s
1.
Use of a gemcitabine derivative of formula I:
Figure imgf000010_0001
(D
wherein R1, R2 and R3 are independently selected from hydrogen and C18- and C2o- saturated and monounsaturated acyl groups, with the proviso that R1, R2 and R3 cannot all be hydrogen or a pharmaceutical acceptable salt thereof, for preparing an oral dosage form ameliorating compliance in treatment of cancer.
2.
Use according to claim 1, wherein the oral dosage form comprises from about 0,1 mg to 20 grams per day, more preferred from about 100 mg to 2 grams per day, of a gemcitabine derivative of formula (I) or a pharmaceutical acceptable salt thereof.
3.
Use according to claim 1, wherein the gemcitabine derivative of formula (I) is elaidic acid (5')-gemcitabine ester.
4.
Use according to claim 1, wherein the oral dosage form further comprises pharmaceutical acceptable exipients, diluents and/or carriers.
5.
Oral dosage form useful for ameliorating compliance in treatment of cancer, comprising a gemcitabine derivative of formula (I) as defined in claim 1 or a pharmaceutical acceptable salt thereof.
6.
Oral dosage form according to claim 5, wherein the said the dosage form comprises from about 0,1 mg to 20 grams per day, more preferred from about 100 mg to 2 grams per day, of a gemcitabine derivative of formula (I) as defined in claim 1 or a pharmaceutical acceptable salt thereof.
7.
Oral dosage form according to claim 6, wherein the said the dosage form comprises from about 0,1 mg to 20 grams per day, more preferred from about 100 mg to 2 grams per day, of elaidic acid (5')-gemcitabine ester.
8.
Oral dosage form according to claim 5, wherein the said the dosage form further comprises pharmaceutical acceptable exipients, diluents and/or carriers.
9.
A method for ameliorating compliance in treatment of cancer, in a subject in need of such treatment, which comprises orally administering to such subject a therapeutically effective amount of a gemcitabine derivative of formula (I) as defined in claim 1 or a pharmaceutical acceptable salt thereof.
PCT/NO2006/000085 2005-03-18 2006-03-07 Oral dosage forms of gemcitabine derivatives Ceased WO2006098628A1 (en)

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NZ561377A NZ561377A (en) 2005-03-18 2006-03-07 Oral dosage forms of gemcitabine derivatives
CA002600399A CA2600399A1 (en) 2005-03-18 2006-03-07 Oral dosage forms of gemcitabine derivatives
JP2008501829A JP2008533135A (en) 2005-03-18 2006-03-07 Oral dosage form of gemcitabine derivative
US11/908,364 US20080280851A1 (en) 2005-03-18 2006-03-07 Oral Dosage Forms of Gemcitabine Derivatives
EP06716760A EP1858527A4 (en) 2005-03-18 2006-03-07 Oral dosage forms of gemcitabine derivatives
AU2006223757A AU2006223757A1 (en) 2005-03-18 2006-03-07 Oral dosage forms of gemcitabine derivatives
IL185866A IL185866A0 (en) 2005-03-18 2007-09-10 Oral dosage forms of gemcitabine derivatives

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NO20051467 2005-03-18
NO20051467A NO322682B1 (en) 2005-03-18 2005-03-18 Use of gemcitabine derivatives for the preparation of oral dosage forms in cancer treatment, as well as such oral dosage forms

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JP (1) JP2008533135A (en)
KR (1) KR20070120539A (en)
AU (1) AU2006223757A1 (en)
CA (1) CA2600399A1 (en)
IL (1) IL185866A0 (en)
NO (1) NO322682B1 (en)
NZ (1) NZ561377A (en)
RU (1) RU2007138582A (en)
UA (1) UA90893C2 (en)
WO (1) WO2006098628A1 (en)
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WO2010039039A1 (en) * 2008-10-03 2010-04-08 Clavis Pharma Asa Oral formulations of gemcitabine derivatives
WO2010121486A1 (en) 2009-04-21 2010-10-28 济南圣鲁金药物技术开发有限公司 Prodrugs based on gemcitabine structure as well as synthetic method and application thereof
CN102432654A (en) * 2011-09-26 2012-05-02 宋云龙 Gemcitabine amide derivative and preparation method and application thereof
US8497292B2 (en) 2005-12-28 2013-07-30 Translational Therapeutics, Inc. Translational dysfunction based therapeutics
US8956613B2 (en) 2012-11-13 2015-02-17 BoYen Therapeutics, Inc. Gemcitabine prodrugs and uses thereof
CN107184592A (en) * 2017-05-17 2017-09-22 广东艾时代生物科技有限责任公司 Application of the gemcitabine in treatment medicine for treating rheumatoid arthritis is prepared

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US10517822B2 (en) 2013-11-06 2019-12-31 The University Of Chicago Nanoscale carriers for the delivery or co-delivery of chemotherapeutics, nucleic acids and photosensitizers
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EP3439666A4 (en) 2016-05-20 2019-12-11 The University of Chicago NANOPARTICLES FOR CHEMOTHERAPY, TARGETED THERAPY, PHOTODYNAMIC THERAPY, IMMUNOTHERAPY AND ANY COMBINATION THEREOF
EP3638367A4 (en) 2017-08-02 2021-07-21 The University of Chicago NANOSCALE METAL ORGANIC LAYERS AND METAL ORGANIC NANOPLATES FOR X-RAY INDUCED PHOTODYNAMIC THERAPY, RADIOTHERAPY, DYNAMIC RADIATION THERAPY, CHEMOTHERAPY, IMMUNOTHERAPY AND ANY COMBINATION THEREOF
AU2019216531A1 (en) 2018-02-02 2020-09-24 Maverix Oncology, Inc. Small molecule drug conjugates of gemcitabine monophosphate

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* Cited by examiner, † Cited by third party
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US8497292B2 (en) 2005-12-28 2013-07-30 Translational Therapeutics, Inc. Translational dysfunction based therapeutics
US10472677B2 (en) 2005-12-28 2019-11-12 Translational Therapeutics, Inc. Translational dysfunction based therapeutics
WO2010039039A1 (en) * 2008-10-03 2010-04-08 Clavis Pharma Asa Oral formulations of gemcitabine derivatives
WO2010121486A1 (en) 2009-04-21 2010-10-28 济南圣鲁金药物技术开发有限公司 Prodrugs based on gemcitabine structure as well as synthetic method and application thereof
EP2423215A4 (en) * 2009-04-21 2013-05-22 Sanlugen Pharmatech Ltd Prodrugs based on gemcitabine structure as well as synthetic method and application thereof
US8653048B2 (en) 2009-04-21 2014-02-18 Sanlugen Pharmatech Ltd. Prodrugs based on gemcitabine structure and synthetic methods and applications thereof
CN102432654A (en) * 2011-09-26 2012-05-02 宋云龙 Gemcitabine amide derivative and preparation method and application thereof
US8956613B2 (en) 2012-11-13 2015-02-17 BoYen Therapeutics, Inc. Gemcitabine prodrugs and uses thereof
US9540410B2 (en) 2012-11-13 2017-01-10 BoYen Therapeutics, Inc. Gemcitabine prodrugs and uses thereof
US9890189B2 (en) 2012-11-13 2018-02-13 BoYen Therapeutics, Inc. Gemcitabine prodrugs and uses thereof
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