Title:
THERAPEUTIC ACRIDONE AND ACRIDINE COMPOUNDS
Document Type and Number:
WIPO Patent Application WO2002008193
Kind Code:
A3
Abstract:
The present invention pertains to acridone and acridine compounds of formula (I), wherein either: (a) K is =O, L is -H, alpha is a single bond, beta is a double bond, gamma is a single bond (acridones); or, (b) K is a 9-substituent, L is absent, alpha is a double bond, beta is a single bond, gamma is a double bond (acridines); and wherein: J<1> is a 2- or 3-substituent; J<2> is a 6- or 7-substituent; J<1> and J<2> are each independently a group of the formula -NHCO(CH2)nNR<1>R<2>, wherein: n is an integer from 1 to 5; and, R<1> and R<2> are independently hydrogen, C1-7alkyl, C3-20heterocyclyl, or C5-20aryl, or R<1> and R<2>, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 3 to 8 ring atoms; and wherein, when K is a 9-substituent, K is a group of the formula -N(R)Q, wherein: R is an amino substituent and is hydrogen, C1-7alkyl, C3-20heterocyclyl, or C5-20aryl; and, Q is C1-7alkyl, C3-20heterocyclyl, or C5-20aryl, and is optionally substituted; and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit telomerase, to regulate cell prol iferation, and in the treatment of proliferative conditions, such as cancer.
Inventors:
NEIDLE STEPHEN (GB)
HARRISON RICHARD JOHN (GB)
KELLAND LLOYD ROYSTON (GB)
GOWAN SHARON MICHELE (GB)
READ MARTIN (GB)
RESZKA TONY (GB)
HARRISON RICHARD JOHN (GB)
KELLAND LLOYD ROYSTON (GB)
GOWAN SHARON MICHELE (GB)
READ MARTIN (GB)
RESZKA TONY (GB)
Application Number:
PCT/GB2001/003046
Publication Date:
October 02, 2003
Filing Date:
July 06, 2001
Export Citation:
Assignee:
CANCER REC TECH LTD (GB)
NEIDLE STEPHEN (GB)
HARRISON RICHARD JOHN (GB)
KELLAND LLOYD ROYSTON (GB)
GOWAN SHARON MICHELE (GB)
READ MARTIN (GB)
RESZKA TONY (GB)
NEIDLE STEPHEN (GB)
HARRISON RICHARD JOHN (GB)
KELLAND LLOYD ROYSTON (GB)
GOWAN SHARON MICHELE (GB)
READ MARTIN (GB)
RESZKA TONY (GB)
International Classes:
A61K31/473; A61K31/496; A61K31/5377; A61K31/55; A61P35/00; C07D219/06; C07D219/08; C07D219/10; C07D219/12; C07D401/12; (IPC1-7): C07D219/06; A61K31/473; A61P35/00; C07D219/08; C07D219/10
Other References:
HARRISON R J ET AL: "Human Telomerase Inhibition by Substituted Acridine Derivatives", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 9, no. 17, 6 September 1999 (1999-09-06), pages 2463 - 2468, XP004188844, ISSN: 0960-894X
M A READ ET AL: "Molecular Modeling ...", JOURNAL OF MEDICINAL CHEMISTRY, vol. 42, no. 22, 1999, pages 4538 - 46, XP000926704
DENNY W A ET AL: "Potential antitumor gents. 26. Quantitative relationships between experimental antitumor activity, toxicity, and structure for the general class of 9-anilinoacridine antitumor agents", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 25, no. 3, 1 March 1982 (1982-03-01), pages 276 - 315, XP002081503, ISSN: 0022-2623
G KLOPMAN ET AL: "Computer-Automated ...", MOLECULAR PHARMACOLOGY, vol. 31, no. 4, 1987, pages 457 - 76, XP000926707
CAIN B F ET AL: "POTENTIAL ANTITIMOR AGENTS. 19. MULTIPLY SUBSTITUTED 4'-(9- ACRIDINYLAMINO)METHANESULFONANILIDES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 19, no. 9, 1976, pages 1124 - 1129, XP001041428, ISSN: 0022-2623
CAIN B F ET AL: "POTENTIAL ANTITUMOR AGENTS. 17. 9-ANILINO-10-METHYLACRIDINIUM SALTS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 19, no. 6, 1976, pages 772 - 777, XP001041427, ISSN: 0022-2623
CAIN B F ET AL: "POTENTIAL ANTITUMOR AGENTS. 14. ACRIDYLMETHANESULFONANILIDES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 17, no. 9, 1974, pages 922 - 930, XP001041425, ISSN: 0022-2623
D J HAGAN ET AL: "Antitumour polycyclic acridines. Part 1. ...", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANS. 1, 1997, pages 2739 - 46, XP002188534
M JULINO ET AL: "Antitumour polycyclic acridines. Part 5. ...", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANS. 1, 1998, pages 1677 - 84, XP002188535
D SUN ET AL: "Inhibition of Human ...", JOURNAL OF MEDICINAL CHEMISTRY, vol. 40, no. 14, 1997, pages 2113 - 16, XP002188536
P J PERRY ET AL: "1,4- and 2,6-Disubstituted ...", JOURNAL OF MEDICINAL CHEMISTRY, vol. 41, no. 17, 1998, pages 3253 - 60, XP002188537
P J PERRY ET AL: "Human Telomerase ...", JOURNAL OF MEDICINAL CHEMISTRY, vol. 41, no. 24, 1998, pages 4873 - 84, XP002188538
P J PERRY ET AL: "2,7-Disubstituted ...", JOURNAL OF MEDICINAL CHEMISTRY, vol. 42, no. 14, 1999, pages 2679 - 84, XP002188539
GAMAGE S A ET AL: "SYNTHESIS AND IN VITRO EVALUATION OF 9-ANILINO-3,6-DIAMINOACRIDINESA CTIVE AGAINST A MULTIDRUG-RESISTANT STRAIN OF THE MALARIA PARASITEPLASMODIUM FALCIPARUM", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 37, no. 10, 1994, pages 1486 - 1494, XP001041426, ISSN: 0022-2623
MOISAN M ET AL: "NEW ALPHA,OMEGA-DIAMIDO AND ALPHA,OMEGA-DIAMINO MONO-AND BI-BRIDGEDACRIDINE DIMERS", MONATSHEFTE FÜR CHEMIE, SPRINGER VERLAG. WIEN, AT, vol. 124, no. 1, 1993, pages 23 - 35, XP001041424, ISSN: 0026-9247
S HOFFAMNN ET AL: "Synthese bisbasisch-substituierter ...", ZEITSCHRIFT FÜR CHEMIE, vol. 26, no. 9, 1986, pages 331 - 2, XP000926708
M A READ ET AL: "Molecular Modeling ...", JOURNAL OF MEDICINAL CHEMISTRY, vol. 42, no. 22, 1999, pages 4538 - 46, XP000926704
DENNY W A ET AL: "Potential antitumor gents. 26. Quantitative relationships between experimental antitumor activity, toxicity, and structure for the general class of 9-anilinoacridine antitumor agents", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 25, no. 3, 1 March 1982 (1982-03-01), pages 276 - 315, XP002081503, ISSN: 0022-2623
G KLOPMAN ET AL: "Computer-Automated ...", MOLECULAR PHARMACOLOGY, vol. 31, no. 4, 1987, pages 457 - 76, XP000926707
CAIN B F ET AL: "POTENTIAL ANTITIMOR AGENTS. 19. MULTIPLY SUBSTITUTED 4'-(9- ACRIDINYLAMINO)METHANESULFONANILIDES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 19, no. 9, 1976, pages 1124 - 1129, XP001041428, ISSN: 0022-2623
CAIN B F ET AL: "POTENTIAL ANTITUMOR AGENTS. 17. 9-ANILINO-10-METHYLACRIDINIUM SALTS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 19, no. 6, 1976, pages 772 - 777, XP001041427, ISSN: 0022-2623
CAIN B F ET AL: "POTENTIAL ANTITUMOR AGENTS. 14. ACRIDYLMETHANESULFONANILIDES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 17, no. 9, 1974, pages 922 - 930, XP001041425, ISSN: 0022-2623
D J HAGAN ET AL: "Antitumour polycyclic acridines. Part 1. ...", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANS. 1, 1997, pages 2739 - 46, XP002188534
M JULINO ET AL: "Antitumour polycyclic acridines. Part 5. ...", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANS. 1, 1998, pages 1677 - 84, XP002188535
D SUN ET AL: "Inhibition of Human ...", JOURNAL OF MEDICINAL CHEMISTRY, vol. 40, no. 14, 1997, pages 2113 - 16, XP002188536
P J PERRY ET AL: "1,4- and 2,6-Disubstituted ...", JOURNAL OF MEDICINAL CHEMISTRY, vol. 41, no. 17, 1998, pages 3253 - 60, XP002188537
P J PERRY ET AL: "Human Telomerase ...", JOURNAL OF MEDICINAL CHEMISTRY, vol. 41, no. 24, 1998, pages 4873 - 84, XP002188538
P J PERRY ET AL: "2,7-Disubstituted ...", JOURNAL OF MEDICINAL CHEMISTRY, vol. 42, no. 14, 1999, pages 2679 - 84, XP002188539
GAMAGE S A ET AL: "SYNTHESIS AND IN VITRO EVALUATION OF 9-ANILINO-3,6-DIAMINOACRIDINESA CTIVE AGAINST A MULTIDRUG-RESISTANT STRAIN OF THE MALARIA PARASITEPLASMODIUM FALCIPARUM", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 37, no. 10, 1994, pages 1486 - 1494, XP001041426, ISSN: 0022-2623
MOISAN M ET AL: "NEW ALPHA,OMEGA-DIAMIDO AND ALPHA,OMEGA-DIAMINO MONO-AND BI-BRIDGEDACRIDINE DIMERS", MONATSHEFTE FÜR CHEMIE, SPRINGER VERLAG. WIEN, AT, vol. 124, no. 1, 1993, pages 23 - 35, XP001041424, ISSN: 0026-9247
S HOFFAMNN ET AL: "Synthese bisbasisch-substituierter ...", ZEITSCHRIFT FÜR CHEMIE, vol. 26, no. 9, 1986, pages 331 - 2, XP000926708
Download PDF: