AU663312B2 - Creación de Inventos y Patentes con Inteligencia Artificial

AU663312B2 – Treatment of ovarian cancer
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AU663312B2 – Treatment of ovarian cancer
– Google Patents
Treatment of ovarian cancer

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Publication number
AU663312B2

AU663312B2
AU14616/92A
AU1461692A
AU663312B2
AU 663312 B2
AU663312 B2
AU 663312B2
AU 14616/92 A
AU14616/92 A
AU 14616/92A
AU 1461692 A
AU1461692 A
AU 1461692A
AU 663312 B2
AU663312 B2
AU 663312B2
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AU
Australia
Prior art keywords
course
therapy
day
hydroxy
document
Prior art date
1991-02-21
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AU14616/92A
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AU1461692A
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Inventor
Randall Keith Johnson
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SmithKline Beecham Corp

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SmithKline Beecham Corp
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1991-02-21
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1992-02-07
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1995-10-05

1992-02-07
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SmithKline Beecham Corp

1992-09-15
Publication of AU1461692A
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patent/AU1461692A/en

1995-10-05
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1995-10-05
Publication of AU663312B2
publication
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patent/AU663312B2/en

2012-02-07
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Expired
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Classifications

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

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07D—HETEROCYCLIC COMPOUNDS

C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 – C07D459/00, C07D463/00, C07D477/00 or C07D489/00

C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 – C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings

C07D491/16—Peri-condensed systems

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

A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom

A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

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

A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom

A61K31/47—Quinolines; Isoquinolines

A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems

A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline

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

A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom

A61K31/47—Quinolines; Isoquinolines

A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems

A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines

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

A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines

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

C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 – C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Abstract

The invention relates to a pharmaceutical composition comprising topotecan, for use in the treatment of ovarian cancer in a human afflicted therewith, wherein the composition is for parenteral administration to such human employing a course of therapy of from 1.0 to 2.5 mg (e.g. about 1.5 to about 2 mg) of topotecan/m 2 of body surface area per day for about five consecutive days. The invention also relates to a pharmaceutical composition comprising topotecan, for use in the treatment of ovarian cancer in a human afflicted therewith, wherein the composition is for oral administration to such human employing a course of therapy of from 1.5 to 5.0 mg of topotecan/m 2 of body surface area per day for about five consecutive days. The pharmaceutical composition can be an oral or parenteral pharmaceutical composition comprising topotecan and an inert, pharmaceutically acceptable carrier or diluent.

Description

OPI DATE 15/09/92 PCT AOJP DATE 29/10/92 APPLN. ID 14616 92 PCT NUMBER PCT/US92/01028 INTERNATIONAL A.n. u.n- I-iii vrI,-. IIti- ix ci f (PCT) (51) International Patent Classification 5 (1i) International Publication Number: WO 92/14469 A61K 31/535, 31/495, 31/44 Al (43) International Publication Date: 3 September 1992 (03.09.92) (21) International Application Number: PCT/US92/01028 (72) inventor; and Inventor/Applicant (for US only) JOHNSON, Randall, (22) International Filing Date: 7 February 1992 (07.02.92) Keith [US/US]; 71 Llanfair Circle, Ardmore, PA 19003
(US).
Priority data: (74) Agents: SUTTON, Jeffrey, A. et al.; Corporate Patents, 658,948 21 February 1991 (21.02.91) US UW2220, SmithKline Beecham Corporation, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406
(US).
Parent Application or Grant (63) Related by Continuation US 658,948 (CON) (81) Designated States: AT (European patent), AU, BE (Euro- Filed on 21 February 1991 (21.02.91) pean patent), CA, CH (European patent), DE (European patent), DK (European patent), ES (European patent), FR (European patent), GB (European patent), GR (71) Applicant (for all designated States except US): SMITH- (European patent), IT (European patent), JP, KR, LU KLINE BEECHAM CORPORATION [US/US]; 709 (European patent), MC (European patent), NL (Euro- Swedeland Road, P.O. Box 1539, King of Prussia, PA pean patent), SE (European patent), US.
19406 (US).
Published With international search report.
Before the expiration of the time limit for amending the claims and to be republished in the event of the receipt of amendn ts.
(54) Title: TREATMENT OF OVARIAN CANCER (57) Abstract A method of treating ovarian cancer in a human afflicted therewith which comprises administering to such human an effective amount of a compound of the water soluble camptothecin analog class.
r I I-I WO 92/14469 PCT/US92/01028 -1- TREATMENT OF OVARIAN CANCER BACKGROUND OF THE INVENTION This invention relates to a method of treating ovarian cancer in a human afflicted therewith which comprises administering to such human an effective amount of a compound of the water soluble camptothecin analog class, such as topotecan.
The structure of the DNA helix within eukaryotic cells imposes certain topological problems that the cellular apparatus must solve in order to use its genetic material as a template. The separation of the DNA strands is fundamental to cellular processes such as DNA replication and transcription. Since eukaryotic DNA is organized into chromatin by chromosomal proteins, the ends are constrained and the strands cannot unwind without the aid of enzymes that alter topology. It has long been recognized that the advancement of the transcription or replication complex along the DNA helix would be facilitated by a swivel point which would relieve the torsional strain generated during these processes.
Topoisomerases are enzymes that are capable of altering DNA topology in eukaryotic cells. They are critical for important cellular functions and cell Sproliferation. There are two classes of topoisomerases in eukaryotic cells, type I and type II.
Topoisomerase I is a monomeric enzyme of approximately 100,000 molecular weight. The enzyme binds to DNA and introduces a transient single-strand break, unwinds the double helix (or allows it to unwind), and subsequently reseals the break before SUBSTITUTE
SHEET
WO 92/14469 PCT/US92/01028 2 dissociating from the DNA strand.
Camptothecin, a water-insoluble alkaloid produced by trees indigenous to China and India, and a few other congeners thereof, are the only class of compounds known to inhibit topoisomerase I.
Camptothecin and other topoisomerase I inhibiting congeners have not proven to be attractive for clinical drug development as cytolytic agents because of lack of clinical efficacy, unacceptable doselimiting toxicity, unpredictable toxicity, poor aqueous solubility, and/or unacceptable shelf life stability.
Therefore, there is a need for topoisomerase I inhibiting agents which avoid the aforementioned undesirable features of camptothecin and related topoisomerase I inhibiting congeners. Topotecan,-or any compound of the water soluble camptothecin analog class, is a specific inhibitor of DNA topoisomerase I which fulfills such need.
SUMMARY OF THE INVENTION This invention relates to a method of treating ovarian cancer in a human afflicted therewith which comprises administering to such human an effective amount of a compound of the water soluble camptothecin analog class.
This invention also relates to a method of treating ovarian cancer in a human afflicted therewith which comprises administering to such human an effective amount of topotecan.
DETAILED DESCRIPTION OF THE INVENTION By the t.erm «a compound of the water soluble camptothecin analog class» is meant any compound claimed in U.S. Patent Number 5,004,758, the entire disclosure of which is hereby incorporated by reference. The preparation of any compound of the water soluble camptothecin analog class (including pharmaceutically acceptable salts, hydrates and solvates thereof) as well as the preparation of oral and parenteral pharmaceutical SUBSTITUTE
SHEET
L 1 1 WO 92/14469 PCT/US92/01028 3 compositions comprising a compound of the water soluble camptothecin analog class and an inert, pharmaceutically acceptable carrier or diluent, is extensively described in U.S. Patent Number 5,004,758. The same extensive description is found in European Patent Application Number 88311366.4, published on June 21, 1989 as Publication Number EP 0 321 122, the entire disclosure of which is hereby incorporated by reference. Preferred compounds of the water soluble camptothecin analog class include those compounds of the formula:
R
S
A B C ‘N N ~D
EO
OHO
wherein: a) X is hydroxy and R is trimethylammoniummethyl; b) X is hydroxy and R is Nmethylpiperazinylmethyl; c) X is hydroxy and R is N-methylanilinomethyl; d) X is hydroxy and R is cyclohexylaminomethyl; e) X is hydroxy and R is N,Ndimethylaminoethyloxymethyl; f) X is hydroxy and R is cyclopropylaminomethyl; g) X is hydroxy and R is morpholinomethyl; h) X is iydroxy and R is aminomethyl; and i) X is hydroxy and R is cyanomethyl; and j) X is hydroxy and R is dimethylaminomethyl or any pharmaceutically acceptable salts, hydrates and solvates thereof.
Topotecan is the most preferred compound of the water soluble camptothecin analog class. By the term SUBSTITUTE SHEET
I
WO 92/14469 PCT/US92/01028 4 «topotecan» as used herein is meant the compound of the formula:
CH
3
CH
OH
O
A B C N D E 0
OHO
(S)-9-dimethylaminomethyl-10-hydroxycamptothecin and any pharmaceutically acceptable salt, hydrate or solvate thereof. Topotecan’s chemical name is 10[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-lHpyrano[3′,4′:6,7]indolizino[1,2-b]quinolone- 3,14(4H,12H)-dione.
Topotecan is water-soluble by virtue of the presence of the basic side-chain at position 9 which forms salts with acids. Preferred salt forms of topotecan include the hydrochloride salt, acetate salt and methanesulfonic acid salt. A alkali metal salt form of the carboxylate formed on alkaline hydrolysis of the E-ring lactone of topotecan would also yield a soluble salt, such as the sodium salt.
The preparation of topotecan (including pharmaceutically acceptable salts, hydrates and solvates thereof) as well as the preparation of oral and parenteral pharmaceutical compositions comprising topotecan and an inert, pharmaceutically acceptable carrier or diluent, is extensively described in U.S.
Patent Number 5,004,758. The same extensive description is found in European Patent Application Number 88311366.4, published on June 21, 1989 as Publication Number EP 0 321 122.
This invention relates to a method of treating SUBSTITUTE
SHEET
WO 92/14469 PCT/US92/01028 ovarian cancer in a human afflicted therewith which comprises administering to such human an’effective amount of a compound of the water soluble camptothecin analog class. One preferred aspect of this invention relates to a method of treating ovarian cancer in a human afflicted therewith which comprises administering to such human an effective amount of topotecan.
By the term «ovarian cancer» as used herein is meant adenocarcinoma of the ovary.
By the term «treating ovarian cancer» as used herein is meant the inhibition of the growth of ovarian cancer cells. Preferably such treatment also leads to the regression of tumor growth, the decrease in size of a measurable tumor. Most preferably,, such treatment leads to the complete regression of the-tumor.
By the term «administering» is meant parenteral or oral administration. By «parenteral» is meant intravenous, subcutaneous and intramuscular administration.
By the term «effective amount of a compound of the water soluble camptothecin analog class» and «effective amount of topotecan» as used herein is meant a course of therapy which will result in treating ovarian cancer. It will be appreciated that the actual preferred course of therapy will vary according to, inter ali, the mode of administration, the particular formulation of a compound of the water soluble camptothecin analog class (such as topotecan) being utilized, the mode of administration and the particular host being treated. The optimal course of therapy for a given set of conditions can be ascertained by those skilled in the art using conventional course of therapy determination tests in view of the information set out herein, as well as the information outlined in US.
Patent Number 5,004,758. The same information is found in European Patent Application Number 88311366.4, published on June 21, 1989 as Publication Number EP 0 SUBSTITUTE SHEET I .W1 WO 92/14469 PCT/US92/01028 6 321 122.
For parenteral administration of a compound of the water soluble camptothecin analog class, the course of therapy generally employed is from about 0.5 to about 25.0 mg/m 2 of body surface area per day for about one to about five consecutive days. More preferably, the course of therapy employed is from about 1.0 to about 2 mg/m 2 of body surface area per day for about five consecutive days. Most preferably, the course of therapy employed is from about 1.5 to about 2 mg/m 2 of body surface area per day for about five consecutive days. Preferably, the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval (from the date of initiation ofitherapy) depending upon the initial dosing schedule and the patient’s recovery of normal tissues. Most preferably, the course of therapy continues to be repeated based on tumor response.
Preferably, the parenteral administration will be by short 30 minute) or prolonged 24 hour) intravenous infusion. More preferably, the topotecan will be administered by a 30 minute intravenous infusion.
At this time, it is believed that the most preferred course of parenteral therapy to be employed with topotecan for a previously non-treated or lightly pretreated patient is an initial course of therapy of mg of topotecan/m 2 of body surface area per day administered by short intravenous infusion for five consecutive days.. When the patient has recovered sufficiently from the drug-related effects of this initi,,.l course, an additional course of therapy of mg of topotecan/m 2 of body surface area per day is administered by short intravenous infusion for five consecutive days, to be repeated based on tumor response.
At this time, it is believed that the most SUBSTITUTE
SHEET
i~i~ii~B~ WO 92/14469 PCT/US92/01028 7 preferred course of parenteral therapy to be employed with topotecan for a heavily pretreated patient is an 2 initial course of therapy of 1.0 mg of topotecan/m of body surface area per day administered by short intravenous infusion for five consecutive days. When the patient has recovered sufficiently from the drugrelated effects of this initial course, an additional 2 course of therapy of 1.5 mg of topotecan/m of body surface area per day is administered by short intravenous infusion for five consecutive days, such course of therapy to be repeated based on tumor response.
For oral administration of a compound of the water soluble camptothecin analog class, the course of therapy generally employed is from about 1.0 to about 2 50.0 mg/m 2 of body surface area per day for about one to five consecutive days. More preferably, the course of 2 therapy employed is from about 1.5 to about 5.0 mg/m 2 of body surface area per day for about five consecutive days. Preferably, the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval (from the date of initiation of therapy) depending upon the initial dosing schedule and the patient’s recovery of normal tissues. Most preferably, the course of therapy continues to be repeated based on tumor response.
Clinical Pharmaceutical Information Topotecan is currently undergoing Phase I clinical investigation. The following pharmaceutical information is being supplied to the clinicians: How supplied As a vial containing 5 mg (of the base) with 100 mg mannitol. The pH is adjusted to with HCl/NaOH. Lyophilized powder is light yellow in color. Intact vials should be stored under refrigeration (2-8 degrees Centigrade).
Solution Preparation -When the 5 mg vial is reconstituted with 2 ml of Sterile Water for Injection, SUBSTITUTE SHEBT WO 92/14469 PCT/US92/01028 8 USP, each ml will contain 2.5 mg of topotecan as the base and 50 mg of mannitol, USP. Topotecan must not be diluted or mixed with buffered solutions because of solubility and stability considerations.
Stability Shelf life surveillance of the intact vials is ongoing. Because the single-use lyophilized dosage form contains no antibacterial preservatives, it is advised that the reconstituted solution be discarded eight hours after initial entry into the vial. Futher dilutions of the reconstituted solution to concentrations of 0.02 mg/ml and 0.1 mg.ml in 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, in plastic bags stored at room temperature yielded the following stability results: Percentaae of Initial Topotecan Remaining in Solution Concentration Dilueant Time (hrs) 0.02 mg/ml _1_m 0 100.00 100.00 6 99.29 99.68 24 102.30 98.16 48 101.98 97.91 NS 0 100.00 100.00 6 98.58 97.71 24 96.01 98.30 48 102.03 98.35 Topotecan diluted in saline (10 ug/ml or 500 ug/ml) or dextrose (6.7 ug/ml or 330 ug/ml) is stable in a hang-bag for 24 hours with at least 95% recovery.
Treatment dose The treatment dose is to be diluted in a final volume of 150 ml of Sodium Chloride Injection, USP (without preservatives) and administered over a 30 minute period. The treatment dose is to be kept under refrigeration and protected from light and it is to be used within 24 hours.
Utility One human patient with ovarian cancer, who was SUBSTITUTE
SHEET
i
U_
-9refractory to two previous platinum-containing regimens cisplatin-cyclophosphamide combination regimen and treatment with single agent carboplatin), received a course of therapy comprising intravenous administration of 1.5 mg of topc,.ecan/m 2 of body surface area per day for five consecutive days. This course of therapy was repeated weekly nine more times to date at twenty-one day intervals (from the date of initiation of therapy) for a total of ten treatments.
Tumor size regression was evaluated by CAT (computerized axial tomography) scan. Tumor size regression was observed following two courses of therapy of the above-outlined treatment regimen. An even greater response was observed following four courses. At least until the tenth treatment, this clinically significant response was sustained, a greater than fifty percent tumor size regression was obtained.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word «comprise», or variations such as «comprises» or «comprising», will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
C r i 4 95808,p:\opcdab, 14616-92.220,9 r I

Claims (18)

1. A method of’treating ovarian cancer in a human afflicted therewith which comprises administering to such human an effective amount of a compound of the formula: R x o A B C 0 C 0 wherein: a) X is hydroxy and R is trimethylammoniummethyl; b) X is hydroxy and R is N- methylpiperazinylmethyl; c) X is hydroxy and R is N-methylanilinomethv.; d) X is hydroxy and R is cyclohexylaminometh.’,; e) X is hydroxy and R is N,N- dimethylaminoethyloxymethyl; f) X is hydroxy and R is cyclopropylaminomethyl; g) X is hydroxy and R is morpholinomethyl; h) X is hydroxy and R is aminomethyl; i) X is hydroxy and R is cyanomethyl; or j) X is hydroxy and R is dimethylaminomethyl or any pharmaceutically acceptable salts, hydrates and ‘solvates thereof.

2. The method of Claim 1 wherein the administration is oral.

3. The method of Claim 1 wherein the administration is parenteral.

4. The method of Claim 3 wherein the course of therapy employed is from about 0.5 to about 25.0 mg/m 2 SUBSTITUTE SHEET i I i I lb- WO 92/14469 PCT/US92/01028 11 of body surface area per day for about one to about five consecutive days.

The method of Claim 4 wherein the course of therapy employed is from about 1.0 to about 2.5 mg/m 2 of body surface area per day for about five consecutive days.

6. The method of Claim 5 wherein the course of therapy employed is frorr about 1.5 to about 2 mg/m 2 of body surface area per day for about five consecutive days.

7. The method of Claim 4 wherein the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval.

8. The method of Claim 5 wherein the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval.

9. The method of Claim 6 wherein the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval.

10. The method of Claim 3 wherein the administration is via short or long intravenous infusion.

11. The method of Claim 10 wherein the administration is via a 30 minute intravenous infusion.

12. The method of Claim 10 wherein the administration is via a 24 hour intravenous infusion.

13. The method of Claim 3wherein the course of therapy employed is from about 1.0 to about 50.0 mg/m 2 of body surface area per day for about one to about five consecutive days.

14. The method of Claim 13 wherein the course of therapy employed is from about 1.5 to about 5.0 mg/m 2 of body surface area per day for about five consecutive days.

15. The method of Claim 13 wherein the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval. SHEET I SUBSTiituE SHEETF 12-

16. The method of Claim 14 wherein the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval.

17. The method of Claim 1 wherein the compound is topotecan.

18. The method of Claim 10 wherein the compound is topotecan. Dated this 9th day of August, 1995 SMITHKLINE BEECHAM CORPORATION by DAVIES COLLISON CAVE Patent Attorneys for the Applicant. Kj, 0* *O C a SO S 5 9-r41 9588,poctdab,14616.92.22O,12 r INTERNATIONAL SEARCH REPORT International Application No. PCT/US92/01028 I. CLASSIFICATION OF SUBJECT MATTER (if several classification symools aoply, indicate all) According to International Patent Cilaaification (IPC) or to both National Classification and IPC IPC A61K 31/535; A61K 31/495; A61K 31/44 U.S.C1.: 514/233.2; 514/253; 514/283 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols U.S. 514/233.2; 514/253; 514/283 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in the Fields Searched I CEMICAL ABSTRACTS; CHEMICAL SUBSTANCES 1972 PRESENT III. DOCUMENTS CONSIDERED TO ME RELEVANT Category Citation ol Document. i» with indication, where appropriate, of the relevant passages 12 Relevant to Claim No. I3 X,P US, A, 5,004,758 (BOEHM ET AL.) 02 April 1991 1-30 See the entire document. Speciil categories of cited documents: 10 later document published after the international filing date or priority date and not in conflict with the application but docunnt defining the general tate of the art which is not cited to understand the principle or theory underlying the cone dared to be of particular relevance’ invention earl ra document but published on or after the international document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw double on priority claim(s) or involve an inventive step which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specifile) cannot be considered to involve an inventive steo when the document referring to an oral disclosure, use, exhibition or document is combined with ono or more other such docu- other means menta. such combination being obvious to a person skilled document published Prior to the international filing date but in m memer of the m p later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of M iltg Search Report 04 June 1992 International Searching Authority Signatu o on Ofer ISA/US Jerome D. Goldberg Form PCTlSAO od aM (Rf.11-4~ II fI

AU14616/92A
1991-02-21
1992-02-07
Treatment of ovarian cancer

Expired

AU663312B2
(en)

Applications Claiming Priority (3)

Application Number
Priority Date
Filing Date
Title

US65894891A

1991-02-21
1991-02-21

US658948

1991-02-21

PCT/US1992/001028

WO1992014469A1
(en)

1991-02-21
1992-02-07
Treatment of ovarian cancer

Publications (2)

Publication Number
Publication Date

AU1461692A

AU1461692A
(en)

1992-09-15

AU663312B2
true

AU663312B2
(en)

1995-10-05

Family
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Priority Date
Filing Date

AU14616/92A
Expired

AU663312B2
(en)

1991-02-21
1992-02-07
Treatment of ovarian cancer

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EP
(3)

EP1707568B1
(en)

JP
(1)

JP2778632B2
(en)

KR
(1)

KR930702983A
(en)

AT
(2)

ATE444755T1
(en)

AU
(1)

AU663312B2
(en)

CA
(1)

CA2103708C
(en)

DE
(2)

DE69233773D1
(en)

DK
(2)

DK1707568T3
(en)

ES
(2)

ES2349037T3
(en)

HK
(1)

HK1012265A1
(en)

MX
(1)

MX9200754A
(en)

PT
(1)

PT100156B
(en)

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WO1992014469A1
(en)

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CN101255406B
(en)

2005-04-22
2010-05-26
李红霞
Human ovarian cancer drug-resistant cell strain

ES2371171B1
(en)

2010-06-08
2012-11-16
Consejo Superior De Investigaciones Científicas (Csic)

CAMPTOTECHINE DERIVATIVES AS ANTITUMOR AGENTS.

CN102477042A
(en)

2010-11-26
2012-05-30
复旦大学
10-hydroxyamptothecin derivative, and its preparation method and application

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Publication date
Assignee
Title

EP0321122A2
(en)

1987-12-01
1989-06-21

Smithkline Beecham Corporation

Water soluble camptothecin analogs

1992

1992-02-07
KR
KR1019930702490A
patent/KR930702983A/en
not_active
Application Discontinuation

1992-02-07
CA
CA002103708A
patent/CA2103708C/en
not_active
Expired – Lifetime

1992-02-07
DK
DK05076845.6T
patent/DK1707568T3/en
active

1992-02-07
DE
DE69233773T
patent/DE69233773D1/en
not_active
Expired – Lifetime

1992-02-07
AT
AT92907833T
patent/ATE444755T1/en
active

1992-02-07
ES
ES05076845T
patent/ES2349037T3/en
not_active
Expired – Lifetime

1992-02-07
ES
ES92907833T
patent/ES2334178T3/en
not_active
Expired – Lifetime

1992-02-07
DK
DK92907833.5T
patent/DK0572557T3/en
active

1992-02-07
EP
EP05076845A
patent/EP1707568B1/en
not_active
Expired – Lifetime

1992-02-07
EP
EP05076846A
patent/EP1690542A3/en
not_active
Withdrawn

1992-02-07
EP
EP92907833A
patent/EP0572557B1/en
not_active
Expired – Lifetime

1992-02-07
WO
PCT/US1992/001028
patent/WO1992014469A1/en
active
Application Filing

1992-02-07
DE
DE69233793T
patent/DE69233793D1/en
not_active
Expired – Lifetime

1992-02-07
JP
JP4507268A
patent/JP2778632B2/en
not_active
Expired – Lifetime

1992-02-07
AU
AU14616/92A
patent/AU663312B2/en
not_active
Expired

1992-02-07
AT
AT05076845T
patent/ATE476182T1/en
active

1992-02-21
MX
MX9200754A
patent/MX9200754A/en
unknown

1992-02-21
PT
PT100156A
patent/PT100156B/en
not_active
IP Right Cessation

1998

1998-12-15
HK
HK98113535.8A
patent/HK1012265A1/en
not_active
IP Right Cessation

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Publication number
Priority date
Publication date
Assignee
Title

EP0321122A2
(en)

1987-12-01
1989-06-21
Smithkline Beecham Corporation
Water soluble camptothecin analogs

Also Published As

Publication number
Publication date

JP2778632B2
(en)

1998-07-23

PT100156B
(en)

1999-09-30

ES2349037T3
(en)

2010-12-22

MX9200754A
(en)

1992-08-01

DK1707568T3
(en)

2010-11-08

WO1992014469A1
(en)

1992-09-03

DK0572557T3
(en)

2010-02-01

HK1012265A1
(en)

1999-07-30

EP1690542A2
(en)

2006-08-16

PT100156A
(en)

1993-05-31

ES2334178T3
(en)

2010-03-05

ATE444755T1
(en)

2009-10-15

AU1461692A
(en)

1992-09-15

JPH06505740A
(en)

1994-06-30

DE69233793D1
(en)

2010-09-16

EP0572557A1
(en)

1993-12-08

ATE476182T1
(en)

2010-08-15

EP1707568B1
(en)

2010-08-04

CA2103708A1
(en)

1992-08-22

KR930702983A
(en)

1993-11-29

EP0572557B1
(en)

2009-10-07

DE69233773D1
(en)

2009-11-19

EP1707568A3
(en)

2008-03-26

EP0572557A4
(en)

1993-12-29

CA2103708C
(en)

2004-04-27

EP1707568A2
(en)

2006-10-04

EP1690542A3
(en)

2008-03-26

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