WO2001087283A2 - New use of citreamicins - Google Patents

New use of citreamicins Download PDF

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Publication number
WO2001087283A2
WO2001087283A2 PCT/GB2001/002148 GB0102148W WO0187283A2 WO 2001087283 A2 WO2001087283 A2 WO 2001087283A2 GB 0102148 W GB0102148 W GB 0102148W WO 0187283 A2 WO0187283 A2 WO 0187283A2
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Prior art keywords
coch
citreamicin
formula
citreamicins
group
Prior art date
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Ceased
Application number
PCT/GB2001/002148
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French (fr)
Other versions
WO2001087283A3 (en
Inventor
José Luis FERNANDEZ PUENTES
Librada Maria CAÑEDO FERNANDEZ
Dolores Garcia Gravalos
Julia Perez-Baz
Francisco Romero-Millan
Fernando Espliego-Vazquez
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Instituto Biomar SA
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Instituto Biomar SA
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Filing date
Publication date
Application filed by Instituto Biomar SA filed Critical Instituto Biomar SA
Priority to AT01929832T priority Critical patent/ATE263560T1/en
Priority to US10/276,343 priority patent/US20030236291A1/en
Priority to EP01929832A priority patent/EP1292299B1/en
Priority to AU2001256512A priority patent/AU2001256512A1/en
Priority to DE60102695T priority patent/DE60102695D1/en
Priority to CA002408837A priority patent/CA2408837A1/en
Priority to JP2001583751A priority patent/JP2003533474A/en
Publication of WO2001087283A2 publication Critical patent/WO2001087283A2/en
Publication of WO2001087283A3 publication Critical patent/WO2001087283A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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 citreamicins, and in particular to a new use of the citreamicins.
  • citreamicins are known comopunds, see: Pearce, C.J.; Carter, G.T.; Nietsche, J.A.; Borders, D.B.; Greenstein, M.and Maiese, W.M. J. Antibiotics, 1991, 44(11), 1247-1250.
  • the citreamicins thus include compounds of the formula: wherein Ri is selected from the group consisting of COCH 2 CH(CH 3 ) 2 , COCH(CH 3 ) 2 , COCH 3 or H when R 2 is CH 3) or wherein Ri is COCH 2 CH(CH 3 ) 2 and R 2 is H.
  • citreamicin ⁇ is a compound of formula (I) where Riis COCH 2 CH(CH 3 ) 2 and R 2 is CH 3 .
  • compositions for treatment of tumors which include a citreamicin and a pharmaceutically acceptable carrier.
  • a method for treating a mammal affected by a malignant tumor sensitive to a citreamicin compound such as a compound of formula (I), which comprises administering to the affected individual a therapeutically effective amount of the citreamicin compound or a pharmaceutical composition thereof
  • compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable formulation of oral, topical or parenteral administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. These compositions may need to be sterile when administered parenterally.
  • a pharmaceutical composition comprising a citreamaicin compound
  • the correct dosage of a pharmaceutical composition will vary according to the pharmaceutical formulation, the mode of application, and the particular situs, host and tumor being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.
  • citreamicin ⁇ exhibits in vitro antitumor activity against a cell line derived from mouse lymphoma.
  • Citreamicin ⁇ displays good antitumor activity. Its antitumor activity has been detected in vitro by culturing the tumor cells following the methodology described by
  • a screening procedure has been carried out to determine and compare the antitumor activity of citreamicin CL, using an adapted form of the method described by Bergeron et al.
  • the antitumor cells employed were P388 (ATCC CCL-46, suspension culture of a lymphoid neoplasm from DBA/2 mouse), A549 (ATCC CCL- 185, monolayer culture of a human lung carcinoma) and HT-29 (ATCC HTB-38, monolayer culture of a human colon carcinoma).
  • P388 cells were seeded into 16 mm wells at 1 x 104 cells per well in 1 ml aliquots of MEM 5FCS containing the indicated concentration of drug. A separate set of cultures without drug was seeded as control growth to ensure that cells remained in exponential phase of growth. All determinations were carried out in duplicate. After three days of incubation at 37°C, 10% CO in a 98% humid atmosphere, an approximate IC 5 0 was determined by comparing the growth in wells with drug to the growth in wells control.
  • A549 and HT-29 cells were seeded into 16 mm wells at 2 x ⁇ o cells per well in 1 ml aliquots of MEM lOFCS containing the indicated concentration of drug.
  • a separate set of cultures without drug was seeded as control growth to ensure that cells remained in exponential phase of growth. All determinations were carried out in duplicate. After three days of incubation at 37°C, 10% CO 2 in a 98% humid atmosphere, the wells were stained with 0.1 % Crystal Violet. An approximate IC 50 was determined by comparing the growth in wells with drug to the growth in wells control.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Cosmetics (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Citreamicins possess useful antitumor activity. Typically they are of formula (I), wherein R1 is selected from the group consisting of COCH2CH(CH3)2, COCH(CH3)2, COCH3 or H when R2 is CH3, or wherein R1 is COCH2CH(CH3)2 and R2 is H.

Description

NEW USE OF CITREAMICINS
The present invention relates to citreamicins, and in particular to a new use of the citreamicins.
BACKGROUND
The citreamicins are known comopunds, see: Pearce, C.J.; Carter, G.T.; Nietsche, J.A.; Borders, D.B.; Greenstein, M.and Maiese, W.M. J. Antibiotics, 1991, 44(11), 1247-1250. The citreamicins thus include compounds of the formula:
Figure imgf000003_0001
wherein Ri is selected from the group consisting of COCH2CH(CH3)2, COCH(CH3)2 , COCH3 or H when R2 is CH3) or wherein Ri is COCH2CH(CH3)2 and R2 is H. In particular, citreamicin α is a compound of formula (I) where Riis COCH2CH(CH3)2 and R2 is CH3.
SUMMARY OF INVENTION We have now found a new use of the known citreamicins, especially those of the formula (I). We have found that they exhibit antitumor activity.
Thus, we provide pharmaceutical compositions for treatment of tumors and which include a citreamicin and a pharmaceutically acceptable carrier.
We further provide methods of making such pharmaceutical compositions, including the use of a citreamicin in the preparation of a medicament for use in treating a tumor.
Additionally, we provide a method for treating a mammal affected by a malignant tumor sensitive to a citreamicin compound such as a compound of formula (I), which comprises administering to the affected individual a therapeutically effective amount of the citreamicin compound or a pharmaceutical composition thereof
DETAILS OF THE INVENTION
Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable formulation of oral, topical or parenteral administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. These compositions may need to be sterile when administered parenterally.
The correct dosage of a pharmaceutical composition comprising a citreamaicin compound will vary according to the pharmaceutical formulation, the mode of application, and the particular situs, host and tumor being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose. We have found in particular that citreamicin α exhibits in vitro antitumor activity against a cell line derived from mouse lymphoma.
BIOLOGICAL ACΠVITY
Citreamicin α displays good antitumor activity. Its antitumor activity has been detected in vitro by culturing the tumor cells following the methodology described by
(1): Raymond I. Bergeron, Paul F. Cavanaugh, Jr., Steven J. Mine, Robert G. Hughes, Jr., Gary T. Elliot and Carl W. Porter. Antineoplastic and antiherpetic activity of spermidine catecholamide iron chelators. Biochem. Bioph. Res. Comm. 1984, 121(3): 848-854; and
(2). Alan C. Schroeder, Robert G. Hughes, Jr. and Alexander Bloch. Effects of Acycic Pyrimidine Nucleoside Analoges. J. Med. Chem. 1981, 24:1078-1083.
Cells were maintained in logarithmic phase of growth in Eagle's Minimum Essential Medium, with Earle's Balanced Salts, with 2.0 mM L-glutamine, with non- essential amino acids, without sodium bicarbonate (EMEM/neaa); supplemented with 10% Fetal Calf Serum (FCS), lO"2 M sodium bicarbonate and 0.1 g/1 penicillin-G + streptomycin sulfate.
A screening procedure has been carried out to determine and compare the antitumor activity of citreamicin CL, using an adapted form of the method described by Bergeron et al. The antitumor cells employed were P388 (ATCC CCL-46, suspension culture of a lymphoid neoplasm from DBA/2 mouse), A549 (ATCC CCL- 185, monolayer culture of a human lung carcinoma) and HT-29 (ATCC HTB-38, monolayer culture of a human colon carcinoma).
P388 cells were seeded into 16 mm wells at 1 x 104 cells per well in 1 ml aliquots of MEM 5FCS containing the indicated concentration of drug. A separate set of cultures without drug was seeded as control growth to ensure that cells remained in exponential phase of growth. All determinations were carried out in duplicate. After three days of incubation at 37°C, 10% CO in a 98% humid atmosphere, an approximate IC50 was determined by comparing the growth in wells with drug to the growth in wells control.
A549 and HT-29 cells were seeded into 16 mm wells at 2 x ιo cells per well in 1 ml aliquots of MEM lOFCS containing the indicated concentration of drug. A separate set of cultures without drug was seeded as control growth to ensure that cells remained in exponential phase of growth. All determinations were carried out in duplicate. After three days of incubation at 37°C, 10% CO2 in a 98% humid atmosphere, the wells were stained with 0.1 % Crystal Violet. An approximate IC50 was determined by comparing the growth in wells with drug to the growth in wells control.
The activity results, IC50 (μM), for citreamicin α are given in the following table:
Figure imgf000006_0001

Claims

Claims
l. The use of a citreamicin in the preparation of a medicament for the treatment of a tumor.
2. The use according to claim l, wherein the citreamicin is of the formula (I),
Figure imgf000007_0001
wherein Ri is selected from the group consisting of COCH2CH(CH3)2, COCH(CH3)2 , COCH3 or H when R2 is CH3, or wherein Ri is COCH2CH(CH3)2 and R2 is H.
3. The use according to claim 2, wherein the citreamicin is citreamicin α which is of formula (I) where Riis COCH2CH(CH3)2 and R2is CH3.
A method of treating a tumor which comprises administration of an effective amount of a citreamicin compound.
5. A method according to claim 4, wherein the citreamicin is of the formula (I),
Figure imgf000008_0001
wherein Ri is selected from the group consisting of COCH2CH(CH3)2, COCH(CH3)2 , COCH3 or H when R2 is CH3) or wherein Ri is COCH2CH(CH3)2 and R2 is H.
6. A method according to claim 5, wherein the citreamicin is citreamicin α which is of formula (I) where Riis COCH2CH(CH3)2 and R2is CH3.
7. A pharmaceutical composition with antitumor activty comprising a citreamicin and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition according to claim 7, wherein the citreamicin is of the formula (I),
Figure imgf000009_0001
wherein Ri is selected from the group consisting of COCH2CH(CH3)2, COCH(CH3)2 , COCH3 or H when R2 is CH3> or wherein Ri is COCH2CH(CH3)2 and R2 is H.
9. A pharmaceutical compostion according to claim 8, wherein the citreamicin is citreamicin α which is of formula (I) where Riis COCH2CH(CH3)2and R2is CH3.
PCT/GB2001/002148 2000-05-17 2001-05-17 New use of citreamicins Ceased WO2001087283A2 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AT01929832T ATE263560T1 (en) 2000-05-17 2001-05-17 NEW USE OF CITREAMICINS
US10/276,343 US20030236291A1 (en) 2000-05-17 2001-05-17 Use of citreamicins
EP01929832A EP1292299B1 (en) 2000-05-17 2001-05-17 New use of citreamicins
AU2001256512A AU2001256512A1 (en) 2000-05-17 2001-05-17 New use of citreamicins
DE60102695T DE60102695D1 (en) 2000-05-17 2001-05-17 NEW USE OF CITREAMICINES
CA002408837A CA2408837A1 (en) 2000-05-17 2001-05-17 New use of citreamicins
JP2001583751A JP2003533474A (en) 2000-05-17 2001-05-17 Novel use of citreamycin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0011927.1 2000-05-17
GBGB0011927.1A GB0011927D0 (en) 2000-05-17 2000-05-17 New use of citreamicins

Publications (2)

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WO2001087283A2 true WO2001087283A2 (en) 2001-11-22
WO2001087283A3 WO2001087283A3 (en) 2002-04-25

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US (1) US20030236291A1 (en)
EP (1) EP1292299B1 (en)
JP (1) JP2003533474A (en)
AT (1) ATE263560T1 (en)
AU (1) AU2001256512A1 (en)
CA (1) CA2408837A1 (en)
DE (1) DE60102695D1 (en)
GB (1) GB0011927D0 (en)
WO (1) WO2001087283A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6812245B2 (en) 2000-06-29 2004-11-02 Instituto Biomar S.A. Polycylic xanthones and their use

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009085360A2 (en) * 2007-10-04 2009-07-09 Novobiotic Pharmaceuticals Llc Citreamicin antibiotic with a sugar residue
HRP20231233T1 (en) 2017-04-27 2024-01-19 Pharma Mar, S.A. Antitumoral compounds

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU599650B2 (en) * 1986-05-16 1990-07-26 Taiho Pharmaceutical Co., Ltd. Substance 4181-2 and its derivatives
EP0353381A3 (en) * 1988-08-04 1991-01-02 American Cyanamid Company Antibiotic ll-e19085 alpha
EP0405151A1 (en) * 1989-06-29 1991-01-02 American Cyanamid Company Antibiotic LL-E19085
EP0442003A1 (en) * 1990-02-13 1991-08-21 American Cyanamid Company Antibiotic LL-E 19085 alpha
US5919816A (en) * 1994-11-14 1999-07-06 Bionumerik Pharmaceuticals, Inc. Formulations and methods of reducing toxicity of antineoplastic agents

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6812245B2 (en) 2000-06-29 2004-11-02 Instituto Biomar S.A. Polycylic xanthones and their use

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Publication number Publication date
CA2408837A1 (en) 2001-11-22
DE60102695D1 (en) 2004-05-13
JP2003533474A (en) 2003-11-11
EP1292299B1 (en) 2004-04-07
US20030236291A1 (en) 2003-12-25
EP1292299A2 (en) 2003-03-19
GB0011927D0 (en) 2000-07-05
WO2001087283A3 (en) 2002-04-25
ATE263560T1 (en) 2004-04-15
AU2001256512A1 (en) 2001-11-26

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