AU676992B2 - Adenosine diphosphoribose polymerase binding nitroso aromatic compounds useful as anti-tumor and anti-retroviral agents - Google Patents
Adenosine diphosphoribose polymerase binding nitroso aromatic compounds useful as anti-tumor and anti-retroviral agents Download PDFInfo
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- AU676992B2 AU676992B2 AU12609/92A AU1260992A AU676992B2 AU 676992 B2 AU676992 B2 AU 676992B2 AU 12609/92 A AU12609/92 A AU 12609/92A AU 1260992 A AU1260992 A AU 1260992A AU 676992 B2 AU676992 B2 AU 676992B2
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- nitroso
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- compound
- hydrogen
- viral
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Classifications
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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
- A61K31/435—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
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- 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
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/18—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted otherwise than in position 3 or 7
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
OPI DATE 21/05/93 '"AOJP DATE 22/07/93 APPLN. ID 12609/92 IllllllIll Il l 111111 I PCT NUMBER PCT/US91/08902 111111 I ll111 111111111111111 AU9212609 (51) International Patent Classification 5 (11) International Publication Number: WO 93/07868 A61K 31/37, 31/47, 31/165 C07C 233/22, C07D 217/22 Al (43) International Publication Date: 29 April 1993 (29.04.93) C07D 311/0 (21) International Application Number: PCT/US91/08902 (74) Agent: HALLUIN, Albert, Limbach Limbach, 2001 Ferry Building, San Francisco, CA 94111 (US).
(22) International Filing Date: 26 November 1991 (26.11.91) (81) Designated States: AT, AU, BB, BG, BR, CA, CH, DE, Priority data: DK, ES, FI, GB, HU, JP, KP, KR, LK, LU, MC, MG, 780,809 22 October 1991 (22.10.91) US MW, NL, NO, PL, RO, SD, SE, SU, European patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LU, NL, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, (71) Applicant: OCTAMER, INC. [US/US]; 4 Embarcadero ML, MR, SN, TD, TG).
Center, 14th Floor, San Francisco, CA 94111 (US).
ApplieaAt-nd Inventor: KUN, Ernest [US/US]; 8 Hel- Published ens Lane, Mill Valley, CA 94941 With international search report.
With amended claims and statement.
(72) Inventors: MENDELEYEV, Jerome 1292 Stanyan Street, San Francisco, CA 94117 RICE, William, G. 2848 Cordite Loop, Sneelville, CA 30278 (54) Title: ADENOSINE DIPHOSPHORIBOSE POLYMERASE BINDING NITROSO AROMATIC COMPOUNDS USE- FUL AS ANTI-TUMOR AND ANTI-RETROVIRAL AGENTS (57) Abstract The subject invention provides for novel anti-tumor and anti-viral compounds. These compounds include 6-nitroso- 1,2-benzopyrone, 3-nitrosobenzamide, 5-nitroso-l(2H)-isoquinolinone, 7-nitroso-l(2H)-isoquinolinone, 8-nitroso-l(2H)-isoquinolinone. The invention also provides for compositions containing one or more of the compounds, and for methods of treating viral infections and cancer with these compounds and compositions.
I ADENOISE DIPHOSPHORIBOSE POLY!ERASE BINDING NITROSO AROMATIC COMPOUNDS USEFUL AS ANTI-TUMOR AND ANTI-RETROVIRAL AGENTS oil f t h&~rti~ The present invention relates generally to the f ield of retroviral therapeutic agents and their use in treatinq viral infections and cancers.
More specifically it relates to those therapeutic agents w~hich inhibit ADP-ribose transferase, and in particular various nitrosobenzamides.
aound of the Inventign The enzyme ADP-ribase transfarase (ADPRT) 4.2. 30) is a chrbmatirL-bound enzyme located in the nucleus of most eukaryotic cells. The enzyme catalyzes the polymerization of the ADPribose moiety of rzicotinamide adenine dinucleotide (NAD') to form poly (ADP-ribosa).
The loolymer is covalantly attached to various *nuclear proteins, including the polymerase itself.
Temany vaidrlsthat ADP-ribosylation Th vaz e o e 2 5 plays in cellular metabolism have made ADP9T a target for drugs essentially useful for combating neoplasia and viral infections.
Numerous physiological activities have been deteted for compounds that inhibit the carcinogen- induced malignant transformation of S human fibroblasts (sun, Rirsten, Milo, G.E. Kurian, P. and Kumazi, Hi. L. (1983) Prg N~tI.- AciaA- mi. UA .Q.7219-7223), conferring also carcinogen resistance (Milo, Nurian, Kirsteno E. and Kun, E. (1985) 11:332-336), inhibition of malignant xl _P 41 Ztransformation in hamster embryo and moune OOOJ 808'ON t'50d 0StNS8Z 9 19 SN3U NOIS134S TEtET WO 93/07868 WO 9307868PCI/US 91 /0890,2 -2- C3H10T1/2 cell cultures (Borek, Morgan, W. F. Ong, A. and Cleaver, J.E. (1984) Rrc Natl. Acad. Sci. USA -UJ:243-247), deletion of transfected oncogenes from NIl- 3T3 cells (Nakayashu, Shima, Aonuma, Nakagama, H. Nagao. M. and Sugimara, T. (1988) Prc Nat.l. Acad. Sci. USA B.:9066-9070), suppression of the mitogenic stimulation of tumor promoters (Romano, Menapace, L. and Armato, V. (1983) Carcinogenesis 92:2147-2154), inhibition of illegitimate DNA recombinations (Waldman, B.C.
and Waldman, A. (1990) NullcdsRs 5981- 5988) and integration (Farzaneh, Panayotou, Bowler, Hardas, Broom, T., Walther, C. and Shall, S. (1988) Nucl. acids Egg. 16: 1131?-11326), induction of sister chromatid exchange (Ikushima, T. (1990) C~aroinosoma 9-2:360-364) and the loss of certain amplified oncogenes (Grosso, L.E. and Pitot, H.C. (1984) Biochem, Bioxhv,. Res. Commun.
119: 473-480; Shima, H. Nakayasu, M. Aonums, S. Sugimura, T. and Nagao, M. (1989) .ErD.ro Nal....Acad. -Sci, USA 86.:7442-.7445).
Compounds known to inhibit ADPRT polymerase activity include benzamide (Run, Kirsten, E. Milo, G.E. Kurian, P. and Kumari, H. L.
(1983) Proc. Natl. Acad. Sci. USA .".:7219-7223), substituted benzamides (Borek, C. Morgan, W. F., Ong, A. and Cleaver, J.E. (1984) Rrc Nt- Acad. Sci. USA 812:243-247; Romano, F. Menapace, L. and Armato, V. (1983) Carcinogenesis 2147- 2154; Farzaneh, Panayotou, Bowler, Hardas, Broom, Walther, C. and Shall, S. (1988) Nucl. Acids Res. 11:11319- 11326.; Grosso, L.E. and Pitot, H.C. (1984) jiochem. Biophys. Res. Coln.n. .L-S.473-480; -3- Shima, Nakayasu, Aonums, Sugimura, T. and Nagao, M. (1989) Proc. Nalt.
Aca.i. SA 86~: 7442-7445), 3-aminonaphthylhydrazide (Waldman, B.C. and Waldman, A. (1990) NucI. Acids Res. 1i:5981-5988), isoquinoline, quercetin, and coumnarin (l,2-benzopyrone) (Milo, Kurian, Kirsten, E. and Kun, E. (1985) EEBS Lg I. 172: 332-336). The anti-transformning and anti-neoplastic effect of 1,2 benzopyrone were demonstrated in yitr and in vivo (Tseng, gt al, (1987) Pro.NatiL Other known ADPRT polymerase activity inhibitors include 5-ia do-6-amino- 1,2benzopyrone as described in WO 92/06687 published April 30, 1992 and entitled "Novel 5-Iodo-6-Amino-1,2-Benzopyrones and their Mjetabolites Useful as Cystostatic and Anti-Viral Agents" for use as anti-tumor and anti-viral agents. The cited patent discusses the possibility of using 5-iodo-6-nitroso-l, 2-benzopyrone as an anti-tumor or anti-viral agent.
The 6-nitroso-benzopyrones have been hitherto known or described. The only remotely related compounds found in the literature are 6-nitro-1, 2-benzopyrone and 6aamino-i, 2-benzopyrone (6-ABP) Eharm, SOI. M2:615 (1923)) for which, only scarce medicinal evaluation has been reported. In particular, testing was done for sedative and hypnotic effects Pharmn. Soc Lapa, 73,:351 (1953); Hbid, 74:271 (1954)), "Dotehypothermal action (JYak1.gakuLZasshi, 7B.:491 (1958)), and antipyretic, hypnotic, hypotensive and adrenolytic action (bidk, K- 1124 (1963)). No significant application for any of these compounds has been described except for 6-ABP.
2-nitrosobenzamide (Ime-Rasa, K.M. and Koubek, E. (1963) LQrg..Ch=in 28:3240-324 and 4-nitrosobenzamide (Wubbels, Kalhomn, Johnson, D.E.
16283.40 DOci -4and Campbell, D. (1982) 1 OrgJlChem. 47:4664-4670), have been reported in the chemical literature, but no commercial use of these isomers is known. Neither of these articles suggest the use of nitrosobenzamides as ADPRT inhibitors.
The anti-viral and anti-tumorigenic actions of substituted and unsubstituted 6amino-1,2-benzopyrone and 5-iodo-6-amino-1,2-benzopyrone is the subject of WO 9i/04663 published on September 18, 1994 entitled "6-Amino-i, 2-Benzopyrones Useful for Treatment of Viral Diseases" and WO 92/06687 published orn April 30, 1992 entitled "Novel 5-Iodo-6-Amino-1I,2-Benzopyrones and Their Metabolites Useful as Cytostatic and Antiviral Agents", which are incorporated herein by refere, ze.
The precursor molecule, 1,2-benzopyrone (coumnarin), was shown to be an inhibitory ligand of adenosinediphosphoribosyl transferase (ADPRT), a DNA-binding nuclear protein present in all mammalian cells (Tseng, et al., (1987) PrEQS1NaAcad., LJaA, 84.1107-1111).
4 Hakam, et al., FIEBSLett., M12:73 (1987) has shown that 6-amino-1,2is benzopyrone (6-ABP) binds specifically to ADRPT at the site that also *l.go 16283-80 DOCAkjc binds to DNA, indicating that both 6-ABP and DNA compete for the same site on ADPRT. Synthetic 1igands of ADPRT inhibit DNA proliferation, particularly in tumorigenic cells, (Kirsten, gt A. (1991) Ex g ~Res.
L93:1-4). Subsequently, these ligands were found to inhibit viral replication and are the subject of the WO 91/4663 entitled "GAio12Bnoyoe Useful for Treatment of 'Vit~al Diseases, 1 published on April 18, 1994 which is hereby incorporated by reference.
IQ Thus it is of interest to provid' ADPRT polymerase activity inhibitors for use as anti-viral and anti-tumor agents. The subj ect invention provides for novel nitroso-1, 2-benzopyrone, nitroso-benzamide and nitroso-isoquinolinone compounds, and various structurally related other nitroso compounds for usk- as anti-viral and anti-tumor therapeutic agents. The compounds taught for use in the subject invention are believed to be significantl less toxic and far more OV. (500 to 1000 fold) potent than structurally analogous amino compounds.
The subject invention provides for novel anti-tumor and anti-viral conpounds. These compounds include 3-nitrosobenzamide. bfeinvention also provides for compositions containing one or more of the compounds, and for methods of treating viral infections and cancer with these *0 ~r L~ SOW SM"ON SO~~d er69MOZ S 9~ 19 SdBJ.UM NOISIS WO 93/07868 PCT/US91/08902 -6compounds and compositions.
Also provided for are methods of treating cancer and viral infections with 2nitrosobenzamide and 4-nitrosobenzamide.
Composition containing one or more of these compounds is also provided for.
Description of Figures Figure 1 is a graph comparing the degree of ADRPT polymerase activity (ADPRP) inactivation exhibited by different concentrations of 6nitroso-1,2-benzopyrone, 3-nitroso-benzamide, and nitroso-1(2H)-isoquinolinones (NOQ) (a mixture of the 5 and 7 nitroso isomers).
Figure 2 is a composite of graphs displaying the inhibitory effects of the ADRPT ligands on 855-2 cells (a cell line of human B-cell lineage acute lymphoblastic leukemia), H9 cells (a cell line of human T-cell lineage acute lymphoblastic leukemia), HL-60 cells (a cell line of human acute nonlymphoblastic leukemia) and K562 cells (a cell line of human chronic myelogenous leukemia). These cells were cultured while under the influence of the growth factors in 10% fetal bovine serum (FCS), whereas in and the 855-2 cells were cultured in the presence of autocrinr growth factor activity (AGF) or low molecular weight-B-cell growth factor (BCGF, a T-cell derived lymphokine), respectively.
Figure 3 is a graph showing the inhibition of increasing levels of leukemic cell growth (in response to increasing concentrations of FCS) of WO 93/07868 PCT/US91/08902 -7- 855-2 cells by 6-nitroso-1,2-benzopyrone
(NOBP)
and 3-nitrosobenzamide (NOBA).
Figure 4 is a graph showing that NOBP and NOBA inhibit the ability of human leukemic cells (855-2 and HL-60) to form colonies (CFU) from single cells in a semi-solid medium.
Figure 5 shows graph of the relative inhibitory effects of anti-leukemic doses of ADRPT ligands on the ability of normal rhesus bone marrow stem cells or human peripheral blood stem cells to form colonies in soft agar. Note that the NOBP and NOBA had minimal effect on normal cells.
Figure 6 shows graphs displaying the inhibitory effects of NOBP, NOBA and NOQ on four human brain tumor cell lines.
Figure 7 is a graph comparing the effectiveness of NOBP with vincristine.
Figure 8 is a graph displaying the effects of NOBP, NOBA and NOQ on human breast tumor cell line MDA 468.
Figure 9 is a graph displaying the effects of NOBP, NOBA and NOQ on murine leukema cell line L 1210.
Description of Specific Embodiments The subject invention provides for several nitroso compounds that are ADPRT polymerase activity inhibitors. These compounds find use as anti-tumor and anti-viral compounds.
-8- According to a first aspect the present invention consists in a compound selected from the group consisting of: a compound having the structural formula:
R
4
R
R
3
R
2
NH
R
1 0 wherein RI, R 2
R
3
R
4 and R 5 are selected from the group consisting of hydrogen and nitroso, and only one of R, R 2
R
3 R, and R 5 is a nitroso group; and a compound having the structural formula: O NH2
I
NO
According to a second aspect the present invention consists in an anti-viral composition comprising an anti-viral effective amount of a compound, or a pharmaceutical salt thereof, in combination with a pharmaceutically effective amount of an inert carrier, wherein the compound is selected from the group consisting of: S(a) a compound having the structural formula:
R
4
RS
R
3 R 2
R
1 0 1628l.0O DOC'jap -9wherein RI, R 2
R
3
R
4 and R 5 are selected from the group consisting of hydrogen and nitroso, and only one of RI, R 2
R
3
R
4 and R 5 is a nitroso group; and a compound having the structural formula: 0 NH 2
R,
R
2
R
3 wherein R 2 and R 3 are selected from the group consisting of hydrogen and nitroso, and only one of RI, R 2 and R 3 is a nitroso.
According to a third aspect the present invention consists in an anti-cancer composition comprising an anti-cancer effective amount of a compound, or a •pharmaceutical salt thereof, in combination with a pharmaceutically effective amount of an inert carrier, wherein the c,.lpound is selected from the group consisting of: a compound having the structural formula: R4
*R
R,.H
N
SR2 H
R
1 0 wherein RI, R 2
R
3 R,1, and Rs are selected from the group consisting of hydrogen and nitroso, and only one of R, R2, R 3
R
4 and Rs is a nitroso group; and 1628l.O DOCjap 9a a compound having the structural formula: O NH2 R2
R
3 wherein RI, R 2 and R 3 are selected from the group consisting of hydrogen and nitroso, and only one of R, R 2 and R 3 is a nitroso; and a compound having the structural formula:
R
6 R4
RTI
R3 R2 wherein RI, R 2
R
3 R4, R and R 6 are selected from the group consisting of hydrogen and nitroso, and only one of R, R 2
R
3
R
4 R5 and R 6 is a nitroso group.
S. According to a fourth aspect the present invention consists in a method of inhibiting viral growth and replication within a cell in the substantial absence of cellular toxicity comprising contacting the cell with an anti-viral composition, wherein the antiviral composition comprises a compound, or a pharmaceutical salt thereof, in .combination with a pharmaceutically effective amount of an inert carrier, and wherein V the compound is selected from the group consisting of: a compound having the structural formula:
R
4
R
R
3 R H
R
2 N H 1621.80 DOCjap -9b The disclosed synthesis for 5-nitroso-1 (2Ii)-isoquinolinorie may produce 2 closely related structural isomers, 7-nitroso-! (211)- isoquirlolinone and 8-nitroso-lI(2H)isoquinolinione. Although experiments testirg the biological activity of 5-nitroso-l x qoquinolinone mnay have contained significant quantities of 8-nitroso-lI(2.H)isoquinolinone or 7-nitroso-) (28)-isoquinolinone, all three isomers are believed to possess similar anti-t'irnor and anti -viral activity on the basis of their close structural similarity. This hypothesis may be conveniently tested by sepairating the isomers by thn layer chromatography or similar methods, and comparing the anti-twlmor and anti-virai activities of the separated compounds, Detailed synthesis of 6-nitroso-1I,2-beftzopyrone, 3-nitroso-benzamide, l(214,)-isoquinolinone, 7-nitroso-1(2H)-isoqu~inolinone, and 8-nitroso-1(2H)isoquinolinone, are provided in the exaxnpl' section 14\: *4 At. C) 900d 60e"QN USESSC 9 T9 S831UM NCJJ.S'IBHS 9c a compound having the structural formula: O NHz
R,
R2
R
3 wherein RI, R 2 and R 3 are selected from the group consisting of hydrogen and nitroso, and only one of R, R 2 and RT is a nitroso; and a compound having the structural formula:
R
6
R
5 0 0 4 R
R
3
R
2 wherein RI, R 2
R
3
R
4
R
5 and R 6 are selected from the group consisting of hydrogen o Jand nitroso, and only one of R, R 2
R
3
R
4 Rs and R 6 is a nitroso group.
According to a final aspect the present invention consists in a method for the treatment of viral infections comprising the step of administering to a subject an antiviral effective amount of an anti-viral composition, wherein the anti-viral composition comprises a compound, or a pharmaceutical salt thereof, in combination with a pharmaceutically effective amount of an inert carrier, wherein the compound is selected *from the group consisting of: a compou having the structural formula: a cornpound having the structural formula: 16213.«ODOCIp 9d wherein R 1
R
2
R
3
R
4 and R 5 are selected from the group consisting of hydrogen and nitroso, and only one of R 1
R
2
R
3
R
4 and R 5 is a nitroso group; and a compound having the structural formula: O NH2
R
R
2
R
3 wherein RI, R 2 and R 3 are selected from the group consisting of hydrogen and nitroso, and only one of R 1
R
2 and R 3 is a nitroso.
In preferred embodiments the compound is selected from the group consisting of S: 5-nitroso- 1 (2H)-isoquinolinone and 7-nitroso- (2H)-isoquinolinone and 8-nitrosoo* C e 1(2H)-isoquinolinone.
The disclosed synthesis for 5-nitroso-l(2H)-isoquinolinone may produce 2 closely related structural isomers, 7-nitroso-1(2H)- isoquinolinone and 8-nitroso-1(211)isoquinolinone. Although experiments testing the biological activity of 5-nitrcso-l(2H)- S* isoquinolinone may have contained significant quantities of 8-nitroso-1(2H)isoquinolinone or 7-nitroso-l(2H)-isoquinolinone, all three isomers are believed to possess similar anti-tumor and anti-viral activity on the basis of their close structural similarity. This hypothesis may be conveniently tested by separating the isomers by thin layer chromatography or similar methods, and comparing the anti-tumor and anti-viral activities of the separated compounds.
Detailed synthesis of 6-nitroso-1,2-benzopyrone, 3-nitroso-benzamide, s 1 (2H)-isoquinolinone, 7-nitroso-l(2H)-isoquinolinone, and 8-nitroso-1(2H)i 11 isoquinolinone, are provided in the example section below.
.O DOC/kje WOQ 93/078168 PCr/US91/08902 In general, the nitroso compounds of the subject of invention may be synthesized by oxidizing a corresponding amino compound to a compound of the subject invention by oxidation with 3-chloroperoxybenzoic acid (or other peroxyacids) in ethyl acetate or a halocarbon solvent. Syntheses of these precursor amino compounds are described in the chemical literature and some of the compounds are commercially available. Some precursor amino compounds for oxidation to nitroso compounds of the subject invention are as follows: 3-amino- 1,2-benzopyrone (Spectrum Chemical Mfg. Corp., Gardena, CA 90248); 4-amino-1,2-benzopyrone (Aldrich, Rare Chemical Catalog); 5-amino-1,2benzopyrone (by reduction of 5-nitro-1,2benzopyrone, Chem. Abst,. 57 16536d (1962)); 7amino-1,2-benzopyrone (Gottlieb, .t al., L.
Chem. Soc. Perkin. Trans. II 435 (1979)); 8amino-1,2-benzopyrone (by reduction of 8-amino- 1,2-benzopyrone, Abdel-Megid, et al., Egypta J Chem. 20:453-462 (1977)), and 4-amino-i(2H)isoquinolinone, by reduction of the corresponding 4-nitro analog (Horning, et Ai., (1971) Can. J. Chem. 49:2785-2796).
In addition to compounds to (III), the subject invention contemplates various structurally related compounds that have similar carcinostatic and/or anti-viral activities.
These structurally related compounds could be conveniently screened on the basis of their highly potent inhibitory effect on ADPRT polymerase activity. Structurally related compounds of interest include derivatives substituted by additional nitroso groups and small, C 1 alkyl groups. Also of WO 93/07868 PC/US91/0890z -11interest are various nitroso substituted structurally related heterocyclic rings such as 3,4-dihydro-1(2H)-isoquinolinones, nicotinamides, pthalhydrazides, and 1,3benzoxazine-2,4-diones.
Another aspect of the compounds of the subject invention are the ease with which they permeate cell membranes and their relative absence of non-specific binding to proteins and nucleic acid.
In practice, the ADPRT polymerase inhibitors of this invention, namely compounds to (III), and any of their pharmaceutically acceptable salts, may be administered in amounts, either alone or in combination with each other, and in the pharmaceutical form which will be sufficient and effective to inhibit neoplastic growth or viral replication or prevent the development of the cancerous growth or viral infection in the mammalian host.
Administration of the active compounds and salts described herein can be yiJ any of the accepted modes of administration for therapeutic agents. These methods include systemic or local administration such as oral, parenteral, transdermal, subcutaneous, or topical administration modes. The preferred method of administration of these drugs is intravenous, except in those cases where the subject has topical tumors or lesions, where the topical administration may be proper. In other instances, it may be necessary to administer the composition in other parentera 1 or even oral forms.
,WO 9q/07868 PCT/US91/08902 -12- Depending on the intended mode, the compositions may be in the solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, powders, liquids, suspensions, or the like, preferably in unit dosages. The compositions will include an effective amount of at least one of compounds to (III), or pharmaceutically acceptable salts thereof, and in addition it may include any conventional pharmaceutical excipients and other medicinal or pharmaceutical drugs or agents, carriers, adjuvants, diluents, etc., as customary in the pharmaceutical sciences.
For solid compositions, in addition to the compounds to (III), such excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, m-gnesium carbonate, and the like may be used.
The compounds of the subject invention may be also formulated as suppositories using, for example, polyalkylene glycols, for example, propylene glycol, as the carrier.
Liquid, particularly injectable compositions can, for example, be prepared by dissolving, dispersing, etc., at least one of active compounds to (III) in a pharmaceutical solution such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, DMSO and the like, to thereby form the injectable solution or uuspension.
WO 93/07868 PCT/US91/08902 -13- If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and other substances such as, for example, sodium acetate, triethanolamine oleate, etc.
Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
A more recently devised approach for parenteral administration employs the implantation of a slow-release or sustainedrelease systems, which assures that a constant level of dosage is maintained, according to U.S.
Patent No. 3,710,795, which is incorporated herein by reference.
Any of the above pharmaceutical compositions may contain 0.1-99%, preferably 1-70% of the active ingredient.
Actual methods of preparing such dosage forms are known, or will be apparent to those skilled in this art, and are described in detail in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 17th Edition, 1985. The composition or formulation to be administered will, in any event, contain auch quantity of the active compound(s) that will assure that a therapeutically effective amount will be delivered to a patient. A WO 93/07868 PCT/US91/08902 -14therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated.
The amount of active compound administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. However, an effective dosage may be in the range of 1 to 12 mg/kg/day, preferably 1 to 5 mg/kg/day, given only for 1- 2 days at one treatment cycle. Generally, the upper limit for the drug dose determination is its efficacy balanced with its possible toxicity.
The invention having been described, the following examples are offered to illustrate the subject invention by way of illustration, not by way of limitation.
EXAMPLES
I. Synthesis and Characterization of 6- Nitroso-1,2-Benzopyr.g An example of a method for the preparation of 6-nitroso-1,2-benzopyrones is provided as follows: To a stirred solution of 6-amino-1,2benzopyrone hydrochloride (4.00 g, 20 mmol) in water (40 ml) at 22'C was added a solution of sodium tungstate (5.93 g, 20 mmol) in water ml) followed by 30% aqueous hydrogen peroxide ml) ,aid stirring was continued for 1.5 hours.
The oxidation product was extracted from the WO 93/07868 PCT/US91/08902 green-colored mixture with two 100 ml volumes of ethyl acetate, the combined extracts washed with 0.1 N HC1 (50 ml) and then water (100 ml). The ethyl acetate was removed by rotary evaporation and the residue recrystallized from warm ethanol (250 ml).
Analysis of Reaction Product The green crystals obtained from the recrystallization step (1.48 g, 42s yield) displayed light absorption at 750 1m characteristic of monomeric arylnitroso compounds. Mass spectrum: m/z (relative intensity): 175 '100), 161 (16.88), 145 (33.77), 133 (10.38), 117 (56.09), 89 (79.71), 63 (57.13). High resolution data for the M* peak: calculated for C 0
HNO
3 175.0268; found: 175.0271 (deviation 1.1 ppm). 1 H-NMR (CDCl 3 300 MHz) 6 (ppm) from TMS: doublet (6.572 and 6.604) H-4 split by H-3; doublet (7.472 and 7.501) H-8 split by H-7; doublet of doublets (7.860/7.866 and 7.889/7.798) H-7 split by H-8 and finely split by H-5; doublet (7.910 and 7.942) H-3 split by H-4; doublet (8.308 and 8.315) H-3 finely split by H-7. UV/VIS spectrum in ethanol, A max 750 nm 316 nm (8.96 x 10 3 274 nm (2.24 x 104). Melting Point: The compound polymerizes above blackens and melts in the range of 325-340'C, This nitroso-compound may also be prepared by reacting 6-amino-i,2-benzopyrone (as the free base) with 3-chloroperoxybenzoic acid in ethyl acetate or halocarbon solvents.
WO 93/07868 PCTI/US91/08902 -16- II. Synthesis of 3-nitrosobenzamide To a stirred solution of 3-aminobenzamide (Aldrich Chemical Co.) (0.476 g, 3.50 mmol) in ethyl acetate (50 mL) at ambient temperature was added 1.208 g of 3-chloroperoxybenzoic acid (commercial grade, 50-60% purity, Aldrich), whereupon the solution turned green. After minutes the mixture was extracted with 0.14M aqueous sodium bicarbonate (58 mL), washed with three successive 40-mL portions of water, dried over sodium sulfate, then reduced in volume to mL by rotary evaporation and placed in the freezer whereupon the product slowly deposited as a light yellow solid during a period of 72 hours (0.180 g, 34% yield).
The 2-nitrosobenzamide and 4-nitrosobenzamide isomers may be similarly prepared by performing the above oxidation on 2-aminobenzamide and 4aminobenzamide, respectively.
Analysis of Reaction Product Melting point: The substance darkens above 135'C, softens and apparently polymerizes in the range 150-160'C, and melts at 240-250'C (with decomposition). In solution the compound is green-blue. Mass spectrum: m/z (relative intensity): 150 136 120 103 92 85 71 High resolution data for the M' peak: calculated for CyHN 2 0 2 150.042928; found: 150.042900 (deviation 0.2 ppm). NMR spectrum: iH-NMR (DMSO-de, 300 MHz) 6 (ppm) from TMS: broad singlet (7.737) N-H; t (7.824, 7.850, 7.875) H- 5 split by H-4 and H-6; d (8.059 and 8.086) H- 6 split by H-5; d (8.357 and 8.383) H-4 split by s (8.472) H-2. The singlet at 7.737 WO 93/07868 PCT/US91/08902 -17corresponds to 1 proton; the second N-H proton, spectrally non-equivalent in this compound, is overlaid by the doublet of H-4. This doublet integrates to 2 protons and can be resolved by addition of D 2 0 to the DMSO solution. UV-VIS absorption spectrum in absolute ethanol, Xmax 750nm 304nm (5.35 x 103) and 218nm (1.50 x 104). An absorption maximum at 750nm is characteristic of monomeric arylnitroso compounds.
III. Synthesis of Ni troso- 1( 2 H)isoquinolinones (a mixture of and 7-nitroso-isomers) 1(2H)-Isoquinoinonone (isocarbostyril) (Aldrich) was nitrated using a general method for isoquinoline compounds LeFevre and R.J.W. LeFevre, J. Chem. eSc. 1470 (1935)). The nitration product (a mixture of the 5-nitro and 7-nitro isomers, as assigned by Y. Kawazoe and Y. Yoshioka, Chem. Pharm. Bull. (Tokyo) 1 :715- 720 (1968), although one of the isomers could be the 8-nitro isomer) was then reduced to the corresponding amino-1(2H)-isoquinolinones using a combination of potassium borohydride and palladium-on-carbon catalyst in aqueous methanol. To the resultant amino-1(2H)isoquinolinones (as free bases) (0.560 g, 3.50 mmol) in ethyl acetate (175 mL) at 30'C was added 1.208 g of 3-chloroperoxybenzoic acid (Aldrich). The mixture became cloudy and after minutes it was filtered, extracted with 0.14M sodium bicarbonate (58 mL), washed with two mL portions of water, and dried over dodium sulfate. The volume of the solution was reduced to 50 mL by rotary evaporation and then placed in the freezer whereupon an orange solid product was deposited (0.102 g).
WO 93/07868 PCT/US91/08902 -18- Analysis of Reaction Product Melting point: substance darkens above 175'C, softens, blackens and apparently polymerizes above 195'C, and finally melts in the range 310- 335'C. NMR analysis: 'H-NMR (DMSO-d 6
/D
2 0, 300 MHz) S (ppm) from TMS: m (6.723, 6.741, 6.752); m (7.511, 7.518, 7.533, 7.539, 7.547, 7.559, 7.577, 7.585); m (7.663, 7.674, 7.686. 7.698, 7.707); d (7.818, 7.846). In the absence of the compound also displays a broad singlet at 11.90 ppm. The isomeric components were analytically resolved by thin-layer chromatography (silica gel plates, ethyl acetate solvent), giving two bands, R1 0.82 and R 0.72.
Mass spectrum for R 1 0.82: m/z (relative intensity): 174 (M 100), 160 144 117 97 89 71 High resolution data for the M peak: calculated for CoHN~ 2 0: 174.042928; found: 174.043200 (deviation -0.3 ppm). For the component having R, 0.72, M calculated for CHHcN 2 02: 174.042928; Found: 174.043200 (deviation -1.6 ppm). These data confirm that the compounds are mono-nitroso isomers.
IV. ADPRT Inactive Studies The compounds of the subject invention were tested for their ability to inactivate the polymerase activity of adenosinediphosphoribosyl transferase (ADPRT). Assays were performed according to the method of Buki and Kun, Bighetm. 27:5990-5995 (1988), using calf thymus ADPRT. The assay results as given in Table I provide the I (the concentration of the compound that inhibits enzyme activity values for ADPRT of the nitroso precursor (6- WO 93/67868 PCr/US91/08902 -19amino-1,2-benzopyrone) and the more potent iodo-derivative (Table I, compounds 1 and 2, respectively). The nitroso compounds (3,4,5 in Table I) are all highly active as anti-tumor and anti-HIV molecules (as shown in later sections) and are effective even after exposure of cells for a period as short as 30 minutes. 5-1-6nitroso-1,2-benzopyrone (compound 6) in these studies has been shown to be a relatively poor inhibitor of ADRPT (It is believed that the iodo substitution deactivates the NO group as an electrophile) and its biological action is times weaker than that of 6-NO-1,2-benzopyrone.
For these reasons, the compositions of the present invention are believed to be superior to 5-I-6-nitroso-1,2 benzopyrone, which has been shown to be A poor permeant molecule.
TABLEI.
Ig data for aromatic inhibitors of ADPRT 9IL. Inhibitor Leam 1 6-NH 2 -1,2-benzopyrone* 370 2 5-I-6-NH2-1,2-benzopyrone* 41 3 3-NO-benzamide 4 5(7)-nitroso-(2H)-isoquinolinone** 13 5 6-NO-1,2-benzopyrone 6 5-I-6-NO-1,2-benzopyrone 400 *biochemical precursor of nitroso compounds and 6 mixture of the 5- and 7-nitroso compounds Assay conditions: ADPRT, 0.4 pg; coDNA, 4 Ag; inhibitor diluted between 0.8 and 600 AM, in pl of 50 mM Tris-HC-1, 50 mM KC1, 5 mM 2mercaptoethanol, 0.5 mM EDTA, 0.1 mM NAD ((32- P)-labelled), pH 7.5. Polymerization at for 4 minutes.
WO 93/07868 PCT/US91/08902 Figure 1 illustrates the inactivation of ADPRT polymerase activity observed after 2 hours of incubation with the nitroso-compound inhibitors at several concentrations.
Additional experiments involving the equilibration between 6SZn+2 and ADPRT-bound Zn 2 suggest that the ADPRT inhibition activity of the nitroso compounds appears to act by destabilizirg the protein through the ejecting of Zn 2 (Buki Bauer Mendeleyev, F.; Hakam, H. and Kun E. (1991) E.'IS Lett. 290:181- 185). The above mechanism of action for ADPRT inhibitors is speculative and does not constitute any limitation on claimed subject matter.
V. 'ioloaical Anti-Cancer Activities of litosobenzopyrones. Nitroobenzamides and Nicroso-isoquinolinones Experiments were perfomed in which various human leukemia cell lines were exposed to increasing concentrations of 6-amino-1,2benzopyrone (ABP), 5-iodo-6-amino-1,2benzopyrone (IABP), 6-nitro-1,2-benzopyrone
(NO
2 BP), 6-nitroso-1,2-benzopyrone (NOBP), 3nitrosobenzamide (NOBA) or 5(7)-nitroso-1(2H)isoquinolinone (MOQ) (a mixture of the nitroso and 7 nitroso isomers), and the level of thymidine uptake was determined as a measure of cellular proliferation. As shown in Figure 2, for each of the cell lines tested (855-2 cells, Fig. 2A; H9 cells, Fig. 2B; HLcells, Fig. 2C; K562 cells, Fig. 2D) the nitroso-containing ligands (NOBP, NOBA, NOQ) were able to inhibit "H-thymidine uptake in lower molar concentrations than the other compounds. NOBP, NOBA and NOQ powerfully WO 93/07868 PCT/US91/08902 -21inhibited "H-thymidine uptake at a concentration of r1l JM, a concentration at which the other compounds exhibited comparatively slight inhibitory effects.
Experiments with H9 cells grown in 10% fetal boviae serum (FCS) (Fig. 2B) found NOQ to be the most potent inhibitor, demonstrating almost complete inhibition at 10 AM levels. NOBP demonstrated about a 30% decrease in thymidine uptake at 10 IM, and an almost complete inhibition of uptake at 100 AM. NOBA demonstrated about 75% level of inhibition at AM, about 85% inhibition at 100 JM, and almost complete inhibition at 250 IM. The remaining amino and nitro compounds were significantly less potent and did not display complete inhibition until concentrations of 1000 jM were reached.
Experiments with K562 cells grown in 10% fetal bovine serum (Fig. 2D) found NOQ and NOBP to be the most potent inhibitors of cell growth. Both NOQ and NOBP resulted in the almost complete inhibition at concentrations of 10 pM. NOBP was almost as potent as NOQ and produced about inhibition at a concentration of 10 AM, and almost complete inhibition at a concentration of 100 AM. The other 3 compounds tested were significantly less potent.
Experiments with 855-2 cells grown in fetal bovine serum (Fig. 2A) found that NOQ, and NOBP produced almost complete inhibition at a concentration of 10 IM. At a concentration of 1 AM, NOQ produced somewhat more inhibition than NOBP, and NOBP produced somewhat more inhibition WO 93/07868 PCT/US91/08902 -22than NOBA. Experiments using HL-60 cells (Fig.
2C) provided similar conclusions. The other 3 compounds tested were significantly less potent.
The effect of different growth factors on the growth inhibitory effects of NOBP was tested.
855-2 cells that were grown in media with (1) fetal bovine serum, autocrine growth factor (AGF) and low molecular weight-BCGF (a T cell derived lymphokine) were exposed to increasing concentrations of the ADRPT ligands.
The results are provided in Figure 2(A, E, F).
Cells grown in each of the growth factors were all potently inhibited by the nitroso-containing rompounds, with concentrations of 5 to 10 pM resulting in 100% inhibition, Thus, NOBP, NOBA and NOQ exurt potent inhibitory effects regardless of the source of growth factor activity.
In order to exclude the possibility that NOBP and NOBA manifest their growth inhibitory effects through inactivation of growth factors, the effects of 10 IM NOBP or NOBA (constant concentration) on 855-2 cells in the presence of 2E increasing concentrations of fetal bovine serum (FCS) were tested (PCS) contains growth factors for 855-2 cells). The data are provided in Figure 3. Growth arrest occurs irrespective of the concentration of FCS, Thus, the mode of action of NOBP, does not appear to be by antagonism of growth factors but at ADPRT sites related to DNA-replication.
Tumor cell inhibitory concentrations of NOBP and NOBA were shown not to affect adversely the viability of normal cells. Experiments were WOs 93/67868 PCT/US91/08902 -23performed in which the functions of various cancer cells (855-2 and HL-60 leukemia cells, D32, D37 and CRL 7712 glioblastoma cell lines, 186 medulla tumor cell line, L1210 murine leukemia cell line, MDA-468 human breast tumor cell line) and normal cells (neutrophil leukocytes and bone marrow or peripheal blood stream cells) were assessed in the absence or presence of the compounds. The results are shown in Figures 4-9. Together, the data indicate that a concentration of 10 AM of the nitroso-containing ligands effectively suppressed cancer cell growth but demonstrated only modest effects the functions on normal cells.
VI. Toxicity of NOBP The cytotoxicity of 0, 2 lM, 4 8 pM and IM NOBP was measured by examining the effect of the compound on the colony formation (CFU-GM) of normal human stem cells (PBSC). The results of the experiments are provided in figure Toxicity was not detected, even though levels of NOBP sufficient to block 855-2 cell proliferation completely were tested.
A similar CFU stem cell toxicity assay was performed in which comparisons were made between (ABP) 6-amino-1,2-benzopyrone 1 mM, (IABP) I-6-amino-1,2-benzopyrone 250 pM, (NO 2 BP) 6nitro-1,2-benzopyrone (weakly active) 250 JM, NCOP 10 AM, and NOBA 10 AM. The results of the experiments are provided in figure 5A. Whereas the 6-amino-1,2-benzopyrone, 5-I-6-amino-1,2benzopyrone and the 6-nitro derivative were toxic at the tested given doses, the almost ineffective (against tumor cells) G-nitro WO 93/07868 PCT/US91/08902 -24derivative and the highly effective (against tumor cells) NOBP and NOBA were non-toxic.
The effects of 10/m NOBP and NOBA on superoxide generation by normal human peripheral blood neutrophil leukocytes was tested. The results are provided in table II. Only minor reductions in superoxide generation were observed.
2f.bl. i1 Effects of 10 AM NOBP and NOBA on the Generation of Superoxide by Human Neutrophils nmol 0O/hr/10 5 cells Imean n=11) 5 PMN PMA: 55.9 7.7 pM NOBP 34.1 14.1 M NOBA 44.4 10.0 VII. Comparative Efficacy Studies Vincristine, a highly toxic chemetherapeutic compound, is the currently used in the treatment of leukemia and other malignancies. Studies were performed in order to determine the concentration of vincristine that produces the same level of growth inhibition as 10 LM NOBP, when assayed on 855-2 leukemia cells grown in vitro. Vincristine was tested in doses of 0.1, 1, 10 and 100 AM. As shown in FigUre 7. 100 AM of vincristine (a highly toxic concentration) was required to produce the same level of inhibition as 10 iM of NOBP, thus NOBP is about times more potent than an equal concentration of vincristine, and is not toxic to normal cells.
Thus certain aromatic nitroso molecules that are alto inhibitors of ADPRT polymerase activity WO 9307868 PCT/US91/08902 may be useful chemotherapeutic cytostatic agents because of their effectiveness combined with low toxicity.
VIII. Anti-HIV action of NOBP. NOBA and NQOon stimulated human lymphoblasts.
The ability of NOBP (6-nitroso-1,2benzopyrone) and NOBA (3-nitrosobenzamide) to inhibit HIV infections were tested using the methods described in the Journal of Immunological Methods 76:171-183 (1985).
Exposure to the two drugs was only for minutes at the commencement of viral infection, and drugs were never re-added. The results given in Table III provide the ID, of HIV titer days after infection of cell cultures with HIV. The data in Table III demonstrate that JM of the nitroso-containing ligands causes a three log decrease in the HIV-1 infectivity titer.
TABLE III Lst Sampl.e Virus Titer (log ID g) 10 days Virus Alone 5.25 +500 VM ABP 4.50 +250 AM IABP 4.66 +250 JM NO 2 BP 4.93 JM NOBP 2.01 IM NOBA 1.05 AM NOQ 1.73 IX. Cytocidal Activity of ADRPT ligands MTT Experimets were perfornted to determine if the inhibition of proliferation of 855-2 cells seen in culture and in soft agar is due to the cytostatic or cytocidal effect of the nitroso compounds NOBP, NOBA, and NC'. Cells at WO 93/07868 PCI/US91/08902 -26- 1xl10/ml (concentration used in bone marrow assay) were treated with NOBP, NOBA and NOQ at 1, 2.5, 5 and 10/m for 2 hours then stimulated with 10% fetal calf serum and incubated for 24 hours. MTT (3-[4,5-Dimethyl-2-yl]-2,5diphenyltetrazolium bromide) at 1 mg/ml was then added for 16 hours. The absorbance of the pelleted cell was then measured at 550nm after adding DMSO to solubilze the cells.
Results: With 10pM NOBP, NOBA and NOQ, complete killing was observed in 855-2 cells at 100,000/ml.
All publications, patents, and patent applications cited above are herein incorporated by reference.
The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention.
Indeed, various modifications of the abovedescribed modes for carrying out the invention which a'e obvious to those skilled in the field of pharmaceutical formulation or related fields are intended to be within the scope of the following claims.
Claims (5)
- 5.5. S S 5 5 S THE CLAIMS DEFINING THE INVEN' 1 10N ARE AS FOLLOWS:- 1. A compound selected from the group consisting of: a compound having the structural formula: R 4 R, R(3 R, 0 wherein R 1 'R 2 R 3 R 4 and R 5 are selected from the group consisting of hydrogen and nitroso, and only one of R 1 R 2 R 3 R4, and R(5 is a nitroso group; and a compound having the structural formula: 0I-H &~NO 2. The compound of Claim 1, wherein the compound is selected from the group consisting of: 5-nitroso- 1(2H)-isoquinolinone;, 7-nitroso- 1(2H)-isoquiinolinone; and 8-nitroso- I (2H)-isoquinolinone, 3. The compound of Claim 1, wherein the compound is 3-nitroso-benzamide, 28 4. An anti-viral composition comprising an ani-viral effective amount of a cori.pound, or a pharmaceutical salt thereof, in combinatin with a pharmaceutically effective amount of an inert carrier, wherein the compound is selectcd from the group consisting of: a compound having the structural formula: R 4 R R 3 2N1 R, 0 wherein RI, R 2 R 3 R 4 arid R 5 are selected from the group consisting of hydrogen and nitroso, and only one of RI, R 2 R 3 R 4 and Rs is a nitroso group; and a compound having the structural formula: 0o NH 2 0* R3 "0:0wC...I 2 adR r eetdfo tegopcnitn fhyrgnadntoo n 0 onyoeo I 2 adR santoo Th copsto fCam4Shri h opudi eetdfo h ru cossigo:5ntoo12)iounlnn;.-itoo12)iounlnn;ad8ntoo whdei R6. The andompreselecte ofrolam theri rou comstngofuydonad nitroso, obn ad R.* 4 29
- 7. An anti-cancer composition comprising an anti-cancer effective amount of a compound, or a pharmaceutical salt thereof, in combination with a pharmaceutically effective amount of an inert carrier, wherein the compound is selected from the group consisting of: a compound having the structural formula: R 4 R R 3 41 R 2 H R 1 O wherein Ri, R 2 R 3 R 4 and R 5 are selected from the group consisting of hydrogen and nitroso, and only one of R, R R 4 and R 5 is a nitroso group; and a compound having the structural formula: O NH 2 R2 R3 wherein RI, R 2 and R, are selected from the group consisting of hydrogen and nitroso, and only 'ne of RI, R 2 and R 3 is a nitroso; and *too a a 0*a4 *a a 0...0 0 a aa a a a a a.. *a a a a a a 14, An anti-viral composition according to claim 2, and substantially as herein described with reference to any one of the Examples.V An anti-cancer composition ac~cording to claim 4, and substantially as herein kitscribcd with reference to any one of the Examnples. 1 A method of inhibiting viral growth and. replication wiin a cell in the substantial absceuce of cellular toxicity according to claim 6 and substantially as herein described vithxvfettence to any one of the Examples b.L excluding any comparative examples,
- 17. A method for the treatment of cancer according to claim 9 and substantially as herein dewribed with reference to any one of the E~xamnples but excluding any examples.
- 18. 'A inetho~i for the treatment of viral infections according to claim 11 and substantially as herein described with reference to any one of the Examples but excl1uding any comparative examples, Dated this 12 dlay of February, 1997 15OCTAMER, INC. and EMORY UN! VERSJ"7Y Attorney-. IAN T. ERNST Fellow Institue of Patent Attorneys of Australia of SHELSTON WATERS F 4~00d eeO
- 965-9 9 T9 f- S j.131 NOIS13H~S M!al 46/zo/aT 31 wherein Ri, R, R R 4 and R 5 are selected from the group consisting of hydrogen and nitroso, and only one of R 1 R, R R 4 and Rs is a nitroso group; and a compound having the structural formula: 0 NH 2 R2 R3 wherein Ri, R 2 and R 3 are selected from the group consisting of hydrogen and nitroso, and only one of RI, R 2 and R 3 is a nitroso. 12. The method of Claim 11 wherein the compound is selected fro". the group consisting of: 5-nitroso-l(2H)-isoquin ;one; 7-nitroso-l(2H)-isoquinolinone; and 8-nitroso- 1(2H)-isoquinolinone. 13. The method of Claim 11, wherein the compound is 3-nitroso-benzamide. 14, The method of Claims 12 or 13, wherein the virus is human immunodeficiency virus. 15. A method for 'ie treatment of cancer comprising the step of administering to a subject an anti-cancer effective amount of an anti-cancer composition, wherein the anti- cancer composition comprises a compound, or a pharmaceutical salt thereof, in combination with a pharmaceutically effective amount of an inert carrier, wherein the compound is selected from the group consisting of: a compound having the structural formula: R 3 4 R S* R34 RR N H R, O 32 wherein RI, R 2 R 3 R4, and R 5 are selected from the group consisting of hydrogen and nitroso, and only one of R 2 R 3 R 4 and R 5 is a nitroso group; a compound having the structural formula: 0 N11 2 R, R 2 R 3 wherein RI, R 2 and R 3 are selected from the group consisting of hydrogen and nitroso, and only one of RI, R 2 and R 3 is a nitroso; and a compound having the structural formula: so 0. R 6 0 0R ob es R3 R2 S '040 hri I 2 RRR.n.,aesletdfo h ru onitn fhdoe n S. 0 a' nirsadol nSfRRR, 4 5adR santoogop 16 Th*ehdo.li 5 weentecmon s eetdfo h ru cosstn of -irS(H-sqioioe -iroo12)iounlnn;ad8ntoo whri 1 The metho of lan 15, are eednro the grmoupd cisting tof hydroenoarn nirsadolI n fRRR, 4 5 adR santoogop .O 33 19. A method for the treatment of viral infections comprising the step of administering to a subject an anti-viral effective amount of an anti-viral composition, wherein the anti-viral composition comprises a compound, or a pharmaceutical salt thereof, in combination with a pharmaceutically effective amount of an inert carrier, wherein the compound is selected from the group consisting of: a compound having the structural formula: R 4 RS R 3 R2 H R 1 O wherein Ri, R 2 R 3 R 4 and R 5 are selected from the group consisting of hydrogen and nitroso, and only one of RI, R2, R 3 R 4 and R, is a nitroso group; and a compound having the structural formula: 0 NH 2 R2 R3 R wherein RI, R2, and R3 are selected from the group consisting of hydrogen and nitroso, and only one of R 1 R 2 and R 3 is a nitroso. 20. The method of Claim 19, wherein the compound is selected from the group consisting of: 5-nitroso-1(2H)-isoquinolinone; 7-nitroso-l(2H)-isoquinolinone; and 8-nitroso- 1(2H)-isoquinolinone. 21. The method of Claim 19, wherein the compound is 3-nitroso-benzamide, R4"AJ) a b /r u o l h -34- 22. A compound according to claim 1, substantially as herein described with reference to any one of the Examples. 23. An anti-viral composition according to claim 4, substantially as herein described with reference to any one of the Examples. 24. An anti-cancer composition according to claim 7, substantially as herein described with reference to any one of the Examples. A method of inhibiting viral growth and replication within a cell in the substantial absence of cellular toxicity which method is substantially as herein described with reference to any one of the Examples but excluding any comparative examples, 26. A method for the treatment of cancer which method is substantially as herein describec with reference to any one of the Examples but excluding any comparative examples. s 27. A method for the treatment of viral infections which method is substantially as herein describes with reference to any one of the Examples but excluding any comparative examples. Dated this 30th day of January, 1996. OCTAMER, INC. and EMORY UNIVERSITY Attorney: IAN T. ERNST Fellow Institue of Patent Attorneys of Australia of SHELSTON WATERS /f (hi "S U T^ I62 .ltO )0O('0jit WO 93/07868 Pr/US9 1/08902 86 R RI R3 R2 in combination with a pharnaceutically acceptable amount of an inert carrier wherein R 1 R 2 R 3 R 4 Rg and R 6 are selected from the group consisting of hydrogen and nitroso and only one of R1, R 2 R 4 Rg and R 6 is a nitroso group. 13. The method of claim 12 wherein R 4 is a nitroso group. 14. A method of inhibiting viral growth and replication within a cell in the substantial absence of cellular toxicity comprising contacting the cell with an anti-viral effective amount of a composition of a compound of the formula or pharmaceutically acceptable salt thereof: R3 R2 in combination with a pharmaceutically acceptable amount of an inert carrier wherein Rz, R 2 R 3 R 4 Rs WO 93/07868 Pcr/vssli/08s02 36 and R 6 are selected from the group consisting of hydrogen and nitroso and only one of R 1 R 3 R 4 Rg and R 6 is a nitroso group. The method of claim 14 wherein R4 is a nitroso group. 16. The method of claim 14 wherein the virus is human immunodeficiency virus. 17. A method for the treatment of cancer said method comprising the step of administering an anti- cancer effective amount of a composition of a compound of the chemical formula or a pharmaceutical salt thereof: -NB 2 2 R3 in combination with a pharmaceutically acceptable amount of an inert carrier wherein R 1 R 2 and R 3 are selected from the group consisting.of hydrogen and nitroso and only one of R 1 R 2 and R3 is a nitroso group. 18. The method of claim 17 wherein R 2 is a nitroso group. WO 93/07868 PC@T/US91/08902 37 19. A method of inhibiting viral growth and replication within a cell in the substantial absence of cellular toxicity comprising contacting the cell with an anti-viral effective amount of a composition of a compound of the formula or pharmaceutically acceptable salt thereof: 0 II 2 R 3 in combination with a pharmaceutically acceptable amount of an inert carrier wherein R 1 R 2 and R3 are selected from the group consisting of hydrogen and nitroso and only one of R 1 R 2 and R 3 is a nitroso group. The method of claim 19 wherein R 2 is a nitroso group. 21. The method of claim 19 wherein the virus is human immunodeficiency virus. 22. A mthod for the treatment of cancer said method comprising the step of administering an anti- cancer effective amount of a composition of a compound of the chemical formula or a pharmaceutical salt thereof: WO 93/07868 IIF/US1/08902 38 R4 R o R1 O in combination with a pharmaceutically acceptable amount of an inert carrier wherein RL, R 2 R 3 R 4 and R s are selected from the group consisting of hydrogen and nitroso and only one of R 1 R 2 R 3 R 4 and R 5 is a nitroso group. 23. The method of claim 22 wherein R 2 or R 4 is a nitroso group. 24. A method of inhibiting viral growth and replication within a cell in the substantial absence cf cellular toxicity comprising contacting the cell with an anti-viral effective amount of a composition of a compound of the formula or pharmaceutically acceptable salt thereof: R4 R in combination with a pharmaceutically acceptable amount of an inert carrier wherein R 1 R 2 R 3 R and Rs are selected from the group consisting of hydrogen WO 93/07868 PCT/S91/08902 3 9 and nitroso and only one of RV, R 2 ,F RV, R4 and R. is a nitroso group. The method of claim 24 wherein R 2 or R4is a nitroso group. 26. The method of claim 24 wherein the virus is human immunodeficiency virus. WO 93/07868 PCT/US91/08902 STATEMENT UNDER ARTICLE 19 The cancelation of claims 1-11 and the addition of new claims 1-26 were made in order to more clearly define the invention. The amendment does not go beyond the disclosure of the international application as filed since full support for these claims can be found in the specification. In particular, support for new claims 1-26 can be found at page 1, lines 4-7 and page 8 lines 1-30.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US78080991A | 1991-10-22 | 1991-10-22 | |
| US780809 | 1991-10-22 | ||
| PCT/US1991/008902 WO1993007868A1 (en) | 1991-10-22 | 1991-11-26 | Adenosine diphosphoribose polymerase binding nitroso aromatic compounds useful as anti-tumor and anti-retroviral agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU1260992A AU1260992A (en) | 1993-05-21 |
| AU676992B2 true AU676992B2 (en) | 1997-04-10 |
Family
ID=25120767
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU12609/92A Ceased AU676992B2 (en) | 1991-10-22 | 1991-11-26 | Adenosine diphosphoribose polymerase binding nitroso aromatic compounds useful as anti-tumor and anti-retroviral agents |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0609211A4 (en) |
| JP (1) | JP3070767B2 (en) |
| AU (1) | AU676992B2 (en) |
| CA (1) | CA2121900A1 (en) |
| WO (1) | WO1993007868A1 (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5877185A (en) * | 1991-10-22 | 1999-03-02 | Octamer, Inc. | Synergistic compositions useful as anti-tumor agents |
| US5652260A (en) * | 1991-10-22 | 1997-07-29 | Octamer, Inc. | Adenosine diphosphoribose polymerase binding nitroso aromatic compound useful as retroviral inactivating agents, anti-retroviral agents and anti-tumor agents |
| US5464871A (en) | 1993-05-12 | 1995-11-07 | Octamer, Inc. | Aromatic nitro and nitroso compounds and their metabolites useful as anti-viral and anti-tumor agents |
| CA2148455A1 (en) * | 1992-11-02 | 1994-05-11 | Ernest Kun | Adenosine diphosphoribose polymerase binding nitroso aromatic compounds useful as anti-retroviral agents and anti-tumor agents |
| GB9404485D0 (en) | 1994-03-09 | 1994-04-20 | Cancer Res Campaign Tech | Benzamide analogues |
| IL129871A (en) * | 1994-05-06 | 2003-11-23 | Pharmacia & Upjohn Inc | Process for preparing 4-phenyl-substituted octanoyl-oxazolidin-2-one intermediates that are useful for preparing pyran-2-ones useful for treating retroviral infections |
| CN101233121A (en) * | 2005-06-10 | 2008-07-30 | 彼帕科学公司 | PARP modulators and treatment of cancer |
| AU2007292302A1 (en) * | 2006-09-05 | 2008-03-13 | Bipar Sciences, Inc. | Methods for designing PARP inhibitors and uses thereof |
| EP3655418A4 (en) | 2017-06-22 | 2021-05-19 | Triact Therapeutics, Inc. | Methods of treating glioblastoma |
| EP3687501A4 (en) | 2017-09-29 | 2021-06-23 | Triact Therapeutics, Inc. | Iniparib formulations and uses thereof |
-
1991
- 1991-11-26 JP JP4505220A patent/JP3070767B2/en not_active Expired - Lifetime
- 1991-11-26 AU AU12609/92A patent/AU676992B2/en not_active Ceased
- 1991-11-26 EP EP92904892A patent/EP0609211A4/en not_active Ceased
- 1991-11-26 CA CA002121900A patent/CA2121900A1/en not_active Abandoned
- 1991-11-26 WO PCT/US1991/008902 patent/WO1993007868A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CA2121900A1 (en) | 1993-04-29 |
| EP0609211A1 (en) | 1994-08-10 |
| AU1260992A (en) | 1993-05-21 |
| EP0609211A4 (en) | 1995-02-01 |
| JPH07502975A (en) | 1995-03-30 |
| JP3070767B2 (en) | 2000-07-31 |
| WO1993007868A1 (en) | 1993-04-29 |
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