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WO1997004783A2 - Alcaloides de bis-1 oxaquinolizidine provenant d'une eponge marine et presentant une activite antitumorale - Google Patents

Alcaloides de bis-1 oxaquinolizidine provenant d'une eponge marine et presentant une activite antitumorale Download PDF

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Publication number
WO1997004783A2
WO1997004783A2 PCT/GB1996/001852 GB9601852W WO9704783A2 WO 1997004783 A2 WO1997004783 A2 WO 1997004783A2 GB 9601852 W GB9601852 W GB 9601852W WO 9704783 A2 WO9704783 A2 WO 9704783A2
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WO
WIPO (PCT)
Prior art keywords
compound
compounds
formula
alkaloids
group
Prior art date
Application number
PCT/GB1996/001852
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English (en)
Other versions
WO1997004783A3 (fr
Inventor
Jun-Ichi Tanaka
Tatsuo Higa
Dolores Garcia Gravalos
Original Assignee
Pharma Mar, S.A.
Ruffles, Graham, Keith
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Pharma Mar, S.A., Ruffles, Graham, Keith filed Critical Pharma Mar, S.A.
Priority to AU66256/96A priority Critical patent/AU6625696A/en
Publication of WO1997004783A2 publication Critical patent/WO1997004783A2/fr
Publication of WO1997004783A3 publication Critical patent/WO1997004783A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems

Definitions

  • the present invention relates to bis-1-oxaquinolizidine alkaloids from a marine sponge. Such compounds have antitumor activity.
  • quinolizidine alkaloids known as xestospongins and araguspongines have been isolated from sponges of the genus Xestospongia [Tet. Lett., 25, 3227, 1984; Tet. Lett. 30, 4149, 1989; and Chem. Pharm. Bull. 37, 1667, 1989].
  • the present invention provides antitumor compounds with a core bis-1-oxaquinolizidine structure found in the known compounds.
  • the core bis-1-oxaquinolizidine structure is of formula (I), as follows:
  • the invention also provides antitumor compositions and methods using an antitumor compound incorporating the core structure of formula (I).
  • the compounds of this invention have optical centres, and the present invention extends to the individual isomers as well as mixtures including the racemic compounds.
  • antitumor compounds of the present invention are of the formula (II):
  • groups R 1 and R 1 are the same or different and each group is -H or -OH.
  • the group R 2 is -H or -CH 3
  • the group R 3 is -H or -CH 3 .
  • Demethylxestospongin B and Araguspongine A. C and D are known compounds within this general formula.
  • the compounds of this invention are identified as compounds in the series "LT", and structures for individual LT compounds are given later in this description.
  • the antitumor compound is one of the known compounds, especially araguspongine C (LT-1). or one of the new compounds LT -5 to LT-10.
  • the compounds of the invention can be easily transformed into physiologically acceptable salts by methods known in the art.
  • Such salts include acid addition salts formed with inorganic or organic acids, such as HBr, HCl, H 2 SO 4 or HOAc.
  • the compounds LT-1 and LT-5 show promising antitumor activity, indicating similar activity for other compounds with the core bis-1-oxaquniolizine structure of formula (II).
  • compositions provided by this invention include solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) formulations with a suitable composition for oral, topical or parenteral administration. They may contain the pure compound or in combination with any other pharmacologically active compound. These compositions may need to be sterile when administered parentally.
  • a pharmaceutical composition comprising a compound of formula (II)
  • 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.
  • the marine sponge is of the genus Xestospongia sp. and was obtained in the Bay of Thailand and also at Kohama Island in Okinawa [which is very close to Aragusuku Island, which is the site of collection of the sponge discussed in Tet. Lett. 30. 4149. 1989; and Chem. Pharm. Bull. 37, 1667, 1989].
  • a specimen of the sponge has been deposited at Chulalongkorn University, Bangkok, Thailand (deposit number PH-5-94-008). The alkaloids isolated from this sponge have been found to have antitumor activity.
  • a fresh sample of a sponge belonging to the genome Xestospongia sp. (wet 77g) [deposited at Chulalongkorn University, Bangkok, Thailand, deposit number PH-5-94-008] was collected by hand using SCUBA at sandy-rocky bottom (7m) of Coral Island near Dahl. Thailand. This species belonged to the class Demospongiae and resembles the Okinawan sponge Xestospongia sp. which yielded similar compounds.
  • the sponge sample was extracted with acetone (3L) three times. After filtration and concentration, the resulting aqueous residue was partitioned between EtOAc and water. MeOH was added to the water layer, filtered and concentrated to give MeOH soluble extract of 1.3g.
  • Compound LT-7 amorphous; IR (CHCl 3 ) 3500, 2910, 2845, 1130. 1015 cm -1 ; MS m/z 490 (M + , 100); HREIMS obsd. 490.4113, calcd. for C 30 H 54 N 2 O 3 490.4131.
  • Compound LT-8 amorphous: IR (CHCl 3 ) 2910, 2860. 2810, 1460, 1095. 1015 cm -1 MS m/z 474 (M + , 100); HREIMS obsd. 474.4173. calcd for C 30 H 54 N 2 O 2 474.4182.
  • Compound LT-10 amorphous, IR (CHCl 3 ) 3550, 2950, 2850, 1460, 1430, 975 cm -1 ; El m/z 490(M + ); HREIMS obsd 490.4149, calcd for C 28 H 50 N 2 O 4 490.4131.
  • FCS Calf Serum
  • the antitumor cells employed were P-388 (suspension culture of a lymphoid neoplasm from DBA/2 mouse). A-549 (monolayer culture of a human lung carcinoma). HT-29 (monolayer culture of a human colon carcinoma) and MEL-28 (monolayer culture of a human melanoma).
  • P-388 were seeded into 16 mm wells at 1 ⁇ 10 4 cells per well in 1 ml aliquots of MEM 5FCS containing the indicated concentration of drug. A separate set of cultures without drug were seeded as control growth to ensure that these 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 an atmosphere of 98% humidity, 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.
  • HT-29 and MEL-28 cells were seeded into 16 mm wells at 2 ⁇ 10 cells per well in 1 ml aliquots of MEM 10FCS 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 an atmosphere of 98% humidity, 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. Results:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (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)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne les composés présentant la formule générale (II) ou un sel pharmaceutiquement acceptable de ces derniers, et leur utilisation comme agents anti-tumoraux. Dans la formule, R1 et R2 sont similaires ou différents, et chaque groupe représente -H ou -OH; le groupe R2 représente -H ou -CH¿3? et le groupe R?3¿ représente -H ou -CH¿3?. Ces composés peuvent être isolés dans des éponges marines.
PCT/GB1996/001852 1995-07-28 1996-07-29 Alcaloides de bis-1 oxaquinolizidine provenant d'une eponge marine et presentant une activite antitumorale WO1997004783A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU66256/96A AU6625696A (en) 1995-07-28 1996-07-29 Bis-1-oxaquinolizidine alkaloids from a marine sponge with antitumor activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9515469.6A GB9515469D0 (en) 1995-07-28 1995-07-28 Bis-1-oxaquinolizidine alkaloids from a marine sponge with antitumor activity
GB9515469.6 1995-07-28

Publications (2)

Publication Number Publication Date
WO1997004783A2 true WO1997004783A2 (fr) 1997-02-13
WO1997004783A3 WO1997004783A3 (fr) 1997-04-17

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1996/001852 WO1997004783A2 (fr) 1995-07-28 1996-07-29 Alcaloides de bis-1 oxaquinolizidine provenant d'une eponge marine et presentant une activite antitumorale

Country Status (3)

Country Link
AU (1) AU6625696A (fr)
GB (1) GB9515469D0 (fr)
WO (1) WO1997004783A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999059592A1 (fr) * 1998-05-15 1999-11-25 National University Of Singapore Alcaloides beta-carbolines ayant une activite antipaludique
WO2002038140A3 (fr) * 2000-11-09 2003-03-13 Contrimmune Biotechnology Inc Utilisations therapeutiques de modulateurs du canal calcique induits par le recepteur ip¿3?
US9845067B2 (en) 2015-08-28 2017-12-19 Autoliv Asp, Inc. Frontal airbag systems for oblique crash protection
WO2023147678A1 (fr) * 2022-02-07 2023-08-10 Universidad Mayor Procédé de synthèse du composé desméthyl xestospongine b (dmxeb)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59227885A (ja) * 1983-06-09 1984-12-21 Suntory Ltd １−オキサキノリチジン類

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 6, no. 12, 1996, pages 1313-1318, XP000617820 PETTIT, G.R. ET AL: "Isolation and X-ray crystal structure of racemic Xestospongin D from the singapore marine sponge Niphates sp." *
CANCER CHEMOTHERAPY AND PHARMACOLOGY, vol. 30, no. 5, 1992, pages 401-406, XP000617821 STINGL, J. ET AL: "In vitro screening of crude extracts and pure metabolites obtained from marine invertebrates for the treatment of breast cancer" *
CHEM. PHARM. BULL., vol. 37, no. 6, 1989, pages 1676-1678, XP000617987 KOBAYASHI, M. ET AL: "Araguspongines B, C, D, E, F, G, H, and J. New vasodilative bis-1-oxaquinolizidine alkaloids from an Okinawan marine sponge, Xestospongia sp." *
DATABASE WPI Week 8506 Derwent Publications Ltd., London, GB; AN 85-034355 XP002025798 & JP 59 227 885 A (SUMITOMO RUBBER IND KK) , 9 June 1983 *
JOURNAL OF NATURAL PRODUCTS, vol. 55, no. 10, 1992, pages 1505-1508, XP000617818 QUIRION, J.-C. ET AL: "Two new alkaloids from Xestospongia sp., a New Caledonian sponge" *
JOURNAL OF NATURAL PRODUCTS, vol. 57, no. 9, 1994, pages 1283-1285, XP000617823 VENKATESWARLU, Y. ET AL: "bis-1-Oxaquinolizidines from the sponge Haliclona exigua" *
JOURNAL OF ORGANIC CHEMISTRY, vol. 59, no. 23, 1994, pages 6904-6910, XP000644369 HOYE, T.R. ET AL: "Conformational considerations in 1-oxaquinolizidines related to the xestospongin/araguspongine family: Reassignment of stereostructures for araguspongines B and E" & JOURNAL OF ORGANIC CHEMISTRY, vol. 60, no. 15, 1995, page 4958 HOYE, T.R. ET AL: "Additions and corrections" *
PLANTA MEDICA, vol. 62, no. 1, February 1996, pages 28-30, XP000617775 VASSAS, A. ET AL: "Naturally occurring somatostatin and vasoactive intestinal peptide inhibitors. Isolation of alkaloids from two marine sponges." *
TETRAHEDRON LETTERS, vol. 25, no. 30, 1984, pages 3227-3230, XP000615875 NAKAGAWA, M. ET AL: "Structures of xestospongin A,B,C and D novel vasodilative compounds from marine sponge, Xestospongia exigua" cited in the application *
TETRAHEDRON LETTERS, vol. 30, no. 31, 1989, pages 4149-4152, XP000615876 KOBAYASHI, M. ET AL: "Aragopetrosine A, a new vasodilative macrocyclic quinolizidine alkaloid from an Okinawan marine sponge Xestospongia sp." cited in the application *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999059592A1 (fr) * 1998-05-15 1999-11-25 National University Of Singapore Alcaloides beta-carbolines ayant une activite antipaludique
WO2002038140A3 (fr) * 2000-11-09 2003-03-13 Contrimmune Biotechnology Inc Utilisations therapeutiques de modulateurs du canal calcique induits par le recepteur ip¿3?
US9845067B2 (en) 2015-08-28 2017-12-19 Autoliv Asp, Inc. Frontal airbag systems for oblique crash protection
WO2023147678A1 (fr) * 2022-02-07 2023-08-10 Universidad Mayor Procédé de synthèse du composé desméthyl xestospongine b (dmxeb)

Also Published As

Publication number Publication date
WO1997004783A3 (fr) 1997-04-17
AU6625696A (en) 1997-02-26
GB9515469D0 (en) 1995-09-27

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