WO1996030336A1 - Substituted 1,3,9,11-tetraoxa-4,5,7,8-tetraazaundecadiene-4,7-dioxides-5,7, their preparation and application - Google Patents
Substituted 1,3,9,11-tetraoxa-4,5,7,8-tetraazaundecadiene-4,7-dioxides-5,7, their preparation and application Download PDFInfo
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- WO1996030336A1 WO1996030336A1 PCT/LV1996/000001 LV9600001W WO9630336A1 WO 1996030336 A1 WO1996030336 A1 WO 1996030336A1 LV 9600001 W LV9600001 W LV 9600001W WO 9630336 A1 WO9630336 A1 WO 9630336A1
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- tetraazaundecadiene
- tetraoxa
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
- C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
- C07C291/08—Azoxy compounds
Definitions
- the present invention relates to new chemical compounds - substituted 1,3,9, 1 1 - tetraoxa-4,5,7,8-tetraazaundecadiene-4,7-dioxides-5,7 with general structure Fl , to methods of their preparation, and to pharmaceutical compositions, containing these compounds.
- such compounds can act as potential donors of nitric oxide NO in living organisms, and as strong cytostatic agents they can be employed in cancer chemotherapy
- Second group of known related compounds are by F2 alkylation obtained substituted alkoxydialkyltriazene-N-oxides with general structure F3, where Ri - R . . are different organic residues (Keefer L. K. et. al., WO 93/071 14, publ. 15.04. 1993 ).
- A represents oxygen or nitrogen containing substituent, but B is photolytically unstable group
- Compounds F2 show cytostatic activity (WO 93/20806), they inhibit 3 H- thymidine incorporation in DNA of human melanoma A-375-C6 cells to 50% at concentrations 24 - 280 ⁇ M.
- Aerosols comprising compounds Fl in therapeutically active amounts, which are sprayed by pulverizator or pressurized propellant, as freon, propane, etc
- Galenic forms for parenteral use include sterile injection solutions of compounds Fl in therapeutically active amounts in water or other solvents, as well as microcrystalline compounds Fl suspensions, which additionally may contain conserving, bacteriostatic, buffering agents, antioxidants, salts, as well as other pharmaceutically acceptable ingredients for galenic drug preparation This includes also ex tempore prepared injection solutions and suspensions
- Mouse lympholeucosis P-388 (mouse line DBA/2) cell suspension was made in RPMI-1640 medium with 5% serum, cell concentration 10 5 cells/ml. Incubation with compounds 2 hr, incubation with ⁇ -thymidine ( l ⁇ Ci/ml medium) - 1 hr
- NMU N-methyl-N-nitrosourea
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to new chemical compounds - substituted 1,3,9,11-tetraoxa-4,5,7,8-tetraazaundecadiene-4,7-dioxides-5,7 with general structure F1, to methods of their preparation, and to pharmaceutical compositions, containing these compounds. Specifically, such compounds can act as potential donors of nitric oxide NO in living organisms, and as strong cytostatic agents they can be employed in cancer chemotherapy.
Description
Substituted 1,3,9,1 l-tetraoxa-4,5,7,8-tetraazaundecadiene-4,7- dioxides-5,7 , their preparation and application
Field of the invention
The present invention relates to new chemical compounds - substituted 1,3,9, 1 1 - tetraoxa-4,5,7,8-tetraazaundecadiene-4,7-dioxides-5,7 with general structure Fl , to methods of their preparation, and to pharmaceutical compositions, containing these compounds.
Fl
Specifically, such compounds can act as potential donors of nitric oxide NO in living organisms, and as strong cytostatic agents they can be employed in cancer chemotherapy
Background of the invention
Malignant tumors still remain between the leading human death factors in most of the industrial countries. Therefore elaboration of new, more effective malignant tumors therapy methods, including new anticancer drugs, is a vital necessity One of possible methods to solve such problem is employment of chemical compounds, which are capable to liberate in vivo nitric oxide NO - an unique biological mediator, having cytotoxic properties (Hibbs J. B. et. al., Biochem Biophys. Res Comm., 1988., vol. 157., nr. 1 , pp. 87-94 ).
From structural analogues to the claimed compounds F l in scientific and patent information as nitric oxide NO donors, cytostatic agents and wide spectrum medicines are offered nitric oxide NO and nucleophile adducts of the general structure F2 Here J is a radical, connected with an active moiety via heteroatom, but M is metal, etc cation (Maragos C M. et. al., WO 93/20806, publ. 28.10.1993 ).
0 M+
N .0 N
F2
Chemically they represent nitric oxide NO adducts with primary and secondary amines, etc
Second group of known related compounds are by F2 alkylation obtained substituted alkoxydialkyltriazene-N-oxides with general structure F3, where Ri - R.. are different organic residues (Keefer L. K. et. al., WO 93/071 14, publ. 15.04. 1993 ).
Compounds with similar structure, substituted l ,7-dioxa-2,3,5,6- tetraazaheptadiene-2,5-dioxides-3,5 (see F4) are known as chemical substances
CHHUOBCKHH B. H. H jφ., >K. Opr. XHM., 1980., T. 16.,Bbiπ. 5., crp. 933-936 ),
F4
but we cannot found any biomedical information about them Published analogues (see F4) have Rι=R4 and they are lower alkyls, any further transformations were done at the central carbon atom.
Compounds with structure F5 are offered (Tsien R. Y. et. al., WO 94/27957) as nitric oxide NO donors after photochemical activation.
N 0
0"
F5
In this structure A represents oxygen or nitrogen containing substituent, but B is photolytically unstable group
Compounds with general structures F2 and F3 have some serious disadvantages
1. During F2 and F3 decomposition in solutions strongly carcinogenic N- nitrosa ines are formed as by-products; this fact is confirmed in literature (Saavedra J E et. al., J Org Chem., 1992 , vol 57., nr.23., pp 6134-6138 )
2 Compounds F2 and F3 stability is not sufficient enough for galenic drugs preparation Published half-lifes of adducts F2 in buffered solution with pH=7,4 and 37°C temp, are few minutes up to half a hour (Keefer L. K. et al., J Med Chem , 1991 , vol 34., nr. 1 1., pp. 3242-3247 ). This fact corresponds to the authors conception about direct nitric oxide NO donors, but seriously burdens application of these compounds and galenic forms preparation for medical purposes
Any biomedical information, as far as we know, is not published on compounds with general structure F4
In compounds with general structure F5 substituent B (see F5) must be photolytically unstable, which seriously limits their medical application
For solving mentioned drawbacks we offer as anticancer drugs and potential nitric oxide NO donors substituted 1,3,9, 1 l-tetraoxa-4,5,7,8-tetraazaundecadiene-4,7- dioxides-5,7 (see Fl) In comparison with known F2 and F3 they have the following advantages:
1 Nitrosamine formation during destruction of the compound selfsame is ruled out, because molecules Fl do not contain chains from three interconnected nitrogen atoms
2. Half-life of compounds Fl in aqueous buffer with pH=7,4 and 37°C temp exceeds 24 hours, which is sufficient for infusion
3 In comparison with structures F2 and F3, compounds with general structure Fl have additional modification possibilities. By suitable radicals Ri - R8 (see F l ) selection the whole molecule may be constructed asymmetric at central carbon atom This gives additional chances for biological activity variation
Compounds F2 show cytostatic activity (WO 93/20806), they inhibit 3H- thymidine incorporation in DNA of human melanoma A-375-C6 cells to 50% at concentrations 24 - 280 μM.
In our structure-activity relation investigations of diazene oxides compounds with general structure Fl showed high cytostatic activity Thus, compound with (see Fl ) at concentration 4 μM shows
in DNA of mouse P-388 cells Standart compound N-methyl-N-n trosourea oes * not showed "Η-thymidine incorporation inhibition on this model at cone 1 μM
Obtained results together with mentioned compounds Fl advantages describes them as promising anticancer pharmaceuticals
Physico-chemical properties (see experimental part) of claimed compounds with general structure Fl allow their various application for galenic form preparation Galenic forms for oral use include
1 Solutions, comprising compounds Fl in therapeutically active amounts in suitable solvents, as water, ethanol, ethanol - water mixtures, dimethylsulfoxide, oils, etc., which in turn may contain other pharmaceutically acceptable ingredients, as well as conservants and stabilizing agents
2 Tablets, capsules or powders, which contain compounds Fl in therapeutically active amounts. In these forms employment of various colouring, diluting, conserving, etc modifying components, as microcrystalline cellulose, starch, saccharose, lactose, mannit, gelatin, sihcagel, as well as combination with other pharmaceutically acceptable ingredients is allowed
3 Aerosols, comprising compounds Fl in therapeutically active amounts, which are sprayed by pulverizator or pressurized propellant, as freon, propane, etc
Galenic forms for parenteral use include sterile injection solutions of compounds Fl in therapeutically active amounts in water or other solvents, as well as microcrystalline compounds Fl suspensions, which additionally may contain conserving, bacteriostatic, buffering agents, antioxidants, salts, as well as other pharmaceutically acceptable ingredients for galenic drug preparation This includes also ex tempore prepared injection solutions and suspensions
Experimental part
Example 1
1, 1 1 -dimethyl- 1,3, 9, 1 l-tetraoxa-4,5,7,8-tetraazaundecadiene-4,7-dioxide-5,7 (A)
In structure F 1 R , =R.=methyl , R2=R3=R-I=R5-=R6=R7 *=H
Saturated sodium ethylate solution in anhydrous ethanol was bubbled through with argon, after which gaseous NO was few hours bubbled through, until quantity of precipitate does not more increases Obtained precipitate was filtered, washed with anhydrous ethanol and dried
2,0 g of such obtained dry intermediate was suspended in 50 ml of acetonitrile, 5 ml methoxymethylchloride added and resulting suspension was stirred for 6 hr at room temp After filtration solution was vacuum-evaporated Remaining oil crystallizes Product was few times recrystallized from methylethylketone-heptane 1/1 Colourless crystals 0,25 g
PMR (CDC1. -TMS) 3,49 (s, 6H, CH,-O)
5,36 (s, 4H, O-CH.-O) 5,89 (s, 2H, N-CH.-N)
Elem analysis C5H12N4O6 M = 224, 175 calc % N 24,99 C 26,79 H 5,40 found N 24,73 C 26,91 H 5.4 I
Example 2 l , l l-dimethyl-6-ethyl-l,3,9, 1 l-tetraoxa-4,5,7,8-tetraazaundecadiene-4,7-dioxide-5,7
(B) In structure Fl
Saturated sodium n-butylate solution in n-butanol was bubbled through with argon, after which gaseous NO was few hours bubbled through, until quantity of precipitate does not more increases Obtained precipitate was filtered off, washed with n- butanol and dried
2,0 g of thus obtained dry intermediate was suspended in 50 ml of acetonitrile, 5 ml methoxymethylchloride added and resulting suspension was stirred for 6 hr at room temp After filtration solution was vacuum-evaporated Remaining oil does not crystallizes, therefore few ml of heptane-chloroform 1 1 was added and cooled at - 18°C Precipitated crystals on the next day were filtered off 0,2 g
Final purification was done by crystallization from anhydrous ethanol Colourless crystals, m p 41°C
PMR (CDCI..-TMS) 1 ,07 (t, 3H, CH?-C)
2,51 (m, 2H, C-CH.-C) 3,51 (s, 6H, CH3-O-) 5,35 (s, 4H, O-CH2-O) 5,93(t, 1H, central -CH-)
Elem analysis
M = 252,229 calc % N 22,21 C 33,33 H 6,39 found N 21,95 C 33,34 H 6,35
Example 3 Cytostatic activity.
Mouse lympholeucosis P-388 (mouse line DBA/2) cell suspension was made in RPMI-1640 medium with 5% serum, cell concentration 105 cells/ml. Incubation with compounds 2 hr, incubation with Η-thymidine ( lμCi/ml medium) - 1 hr
cone (M) inhibition %
4,5 x 10"4 89
4,5 x 10-6 0 B 4 4 xx 1 l0o"-4 48
4 x lo-6 27 NMU 1l0o"-4* 35
1 Q-6 0
NMU = N-methyl-N-nitrosourea
Substituted 1,3,9,1 l-tetraoxa-4, 5,7, 8-tetraazaundecadiene-4, 7- dioxides-5,7 , their preparation and application
References
1. Hibbs J. B et. al., Biochem. Biophys. Res. Comm., 1988 , vol. 157., nr. 1., pp 87-94
2. Maragos C M. et. al., WO 93/20806, publ 28 10. 1993
3. Keefer L K. et. al., WO 93/071 14, publ. 15.04.1993
4 fl αoBCKHH B. H. H zip., )K. Opr. XHM., 1980., T. 16.,B_>IΠ . 5., crp. 933-936 5. Tsien R Y et al., WO 94/27957
6 Saavedra J E. et. al , J Org Chem., 1992 , vol.57 , nr 23., pp 6134-6138
7 Keefer L K et al , J Med Chem , 1991 , vol 34 , nr 1 1 , pp 3242-3247
Claims
Substituted 1,3,9,1 l-tetraoxa-4,5,7,8-tetraazaundecadiene-4, 7- dioxides-5,7 , their preparation and application
We claim
1 Chemical compounds, substituted 1,3,9, 1 l-tetraoxa-4,5, 7,8- tetraazaundecadiene-4,7-dioxides-5,7 of the general structure Fl
F l
2 Pharmaceutical compositions for human and veterinary medicine, which contain in therapeutically active amount specified in claim 1 compounds
3 Compounds, specified in claim 1 , where groups Ri - Rs are H or lower alkyls C 1 - C4
4 Pharmaceutical compositions for human and veterinary medicine, which contain in therapeutically active amount specified in claim 3 compounds
5 Compounds, specified in claim 3, where groups Ri and R8 are methyl, groups R2, R3, R. and R7 are H, but groups R» and R5 are H or lower alkyls C 1 - C4
6 Pharmaceutical compositions for human and veterinary medicine, which contain in therapeutically active amount specified in claim 5 compounds
7 Compounds, specified in claim 5, where group
but group R5 is H or ethyl
8 Pharmaceutical compositions for human and veterinary medicine, which contain in therapeutically active amount specified in claim 7 compounds
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LVP-95-84 | 1995-03-30 | ||
| LVP-95-84A LV11542B (en) | 1995-03-30 | 1995-03-30 | Substituted 1,3,9,11-tetraoxa-4,5,7,8-tetraazaundecadien-4,7-dioxides-5,7, preparation and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996030336A1 true WO1996030336A1 (en) | 1996-10-03 |
Family
ID=19735911
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/LV1996/000001 Ceased WO1996030336A1 (en) | 1995-03-30 | 1996-03-19 | Substituted 1,3,9,11-tetraoxa-4,5,7,8-tetraazaundecadiene-4,7-dioxides-5,7, their preparation and application |
Country Status (2)
| Country | Link |
|---|---|
| LV (1) | LV11542B (en) |
| WO (1) | WO1996030336A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003074082A1 (en) * | 2002-03-06 | 2003-09-12 | Cellegy Pharmaceuticals, Inc. | Formulations and methods of using nitric oxide mimetics in cancer treatment |
| EP1502604A1 (en) * | 2000-04-26 | 2005-02-02 | Cellegy Pharmaceuticals, Inc | Use of nitric oxide mimetics in cancer treatment |
| WO2005056048A1 (en) * | 2003-12-10 | 2005-06-23 | Georg Bauer | Method for specifically increasing the sensitivity of tumor cells |
| US6946484B2 (en) | 2000-04-26 | 2005-09-20 | Cellegy Pharmaceuticals, Inc. | Formulations and methods of using nitric oxide mimetics against a malignant cell phenotype |
| US7678391B2 (en) | 2000-04-26 | 2010-03-16 | Queen's University At Kingston | Formulations and methods of using nitric oxide mimetics against a malignant cell phenotype |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993020806A1 (en) * | 1992-04-13 | 1993-10-28 | The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Use of nitric oxide/nucleophile complexes for the treatment of cancer |
| WO1994027957A1 (en) * | 1993-05-26 | 1994-12-08 | The Regents Of The University Of California | Compounds which release nitric oxide |
-
1995
- 1995-03-30 LV LVP-95-84A patent/LV11542B/en unknown
-
1996
- 1996-03-19 WO PCT/LV1996/000001 patent/WO1996030336A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993020806A1 (en) * | 1992-04-13 | 1993-10-28 | The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Use of nitric oxide/nucleophile complexes for the treatment of cancer |
| WO1994027957A1 (en) * | 1993-05-26 | 1994-12-08 | The Regents Of The University Of California | Compounds which release nitric oxide |
Non-Patent Citations (7)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 093, no. 17, 27 October 1980, Columbus, Ohio, US; abstract no. 167536, YANDOVSKII V N ET AL: "Azo- and azoxy compounds. V. Alkylation of bis(nitrosohydroxylamino)methane salts. Synthesis of 1,7-dialkyl-1,7-dioxa-2,3,5,6-tetraaza-2,5-heptadiene 3,5-dioxides" XP002005358 * |
| CHEMICAL ABSTRACTS, vol. 104, no. 25, 23 June 1986, Columbus, Ohio, US; abstract no. 224533, MARCHENKO G A ET AL: "Derivatives of N'-alkoxydiazene N-oxides. II. Reaction of 2,2-bis(2-methoxy-1-oxodiazenyl)ethanol esters with nucleophiles" XP002005359 * |
| CHEMICAL ABSTRACTS, vol. 113, no. 11, 10 September 1990, Columbus, Ohio, US; abstract no. 096995, MARCHENKO G A ET AL: "N'-alkoxydiazene N-oxides. VI. Ethers of N'-alkoxydiazene N-oxides" XP002005651 * |
| WOODWARD R B ET AL: "Methoxazonyl group", TETRAHEDRON LETT. (TELEAY);69; (32); PP.2689-92, 1969, HARVARD UNIV.;CAMBRIDGE; MASS., XP002005357 * |
| ZH. ORG. KHIM. (ZORKAE,05147492);80; VOL.16 (5); PP.933-6, LENINGR. GOS. UNIV.;LENINGRAD; USSR * |
| ZH. ORG. KHIM. (ZORKAE,05147492);85; VOL.21 (7); PP.1429-31, USSR (SU) * |
| ZH. ORG. KHIM. (ZORKAE,05147492);90; VOL.26 (2); PP.276-9, USSR (SU) * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1502604A1 (en) * | 2000-04-26 | 2005-02-02 | Cellegy Pharmaceuticals, Inc | Use of nitric oxide mimetics in cancer treatment |
| US6946484B2 (en) | 2000-04-26 | 2005-09-20 | Cellegy Pharmaceuticals, Inc. | Formulations and methods of using nitric oxide mimetics against a malignant cell phenotype |
| US7678391B2 (en) | 2000-04-26 | 2010-03-16 | Queen's University At Kingston | Formulations and methods of using nitric oxide mimetics against a malignant cell phenotype |
| US8168232B2 (en) | 2000-04-26 | 2012-05-01 | Queen's University At Kingston | Formulations and methods of using nitric oxide mimetics in cancer treatment |
| WO2003074082A1 (en) * | 2002-03-06 | 2003-09-12 | Cellegy Pharmaceuticals, Inc. | Formulations and methods of using nitric oxide mimetics in cancer treatment |
| WO2005056048A1 (en) * | 2003-12-10 | 2005-06-23 | Georg Bauer | Method for specifically increasing the sensitivity of tumor cells |
Also Published As
| Publication number | Publication date |
|---|---|
| LV11542B (en) | 1997-02-20 |
| LV11542A (en) | 1996-10-20 |
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