Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-05
2003-04-22
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S233000, C544S251000, C544S343000
Reexamination Certificate
active
06552021
ABSTRACT:
The present invention relates to heteroaromatic[a]phenazine carboxamides and derivatives thereof. These compounds are cytotoxic agents which have demonstrated topoisomerase I and topoisomerase II inhibition and have the ability to circumvent multidrug resistance mechanisms. They are therefore potential anticancer agents.
The topoisomerases are important cellular targets for a number of successful chemotherapeutic agents (Wang, Ann. Rev. Biochem, 65, 635-692, 1996) and are essential enzymes in the regulation of DNA topology which is required if cells are to divide and proliferate (Wang, loc cit). Drugs that target topoisomerase II, for example doxorubicin and etoposide, have been widely used in cancer chemotherapy (Hande, Biophys. Acta 1400, 173-184, 1998) while those that specifically target topoisomerase I, principally the camptothecin analogues, have made an important impact more recently, an example being CPT-11 for the treatment of colon cancer (Dancey et al, Br. J. Cancer 74, 327-338, 1996). More recently, topoisomerases have been shown to be therapeutic targets for antifungal, antibacterial and antiviral drugs (Chen et al, Rev. Pharmacol. Toxicol, 34, 191-218, 1994).
In addition to those compounds that specifically target topoisomerase I or II, several joint inhibitors of topoisomerase I and II have been identified and may also be beneficial in the treatment of solid tumours. These compounds include intoplicine (Riou et al , Cancer Res. 53, 5987-5993, 1993), DACA/XR5000 (Finlay et al, Eur. J. Cancer 32A, 708-714, 1996) and TAS-103 (Utsugi et al, J. Cancer Res, 88, 992-1002 1997) which are all in clinical evaluation. The advantage of joint inhibitors of topoisomerase I and II is their ability to avoid drug resistance and to target two key enzymes that affect the topology of DNA which are active at different points in the cell cycle.
It has now been found that a class of novel heteroaromatic[a]phenazine carboxamides are inhibitors of topoisomerase I and topoisomerase II. Accordingly, the present invention provides a compound which is a heteroaromatic[a]phenazine carboxamide derivative of formula (I)
wherein X is a five- or six-membered heteroaromatic ring which contains one or two nitrogen atoms and which is unsubstituted or substituted by C
1
-C
6
alkyl, hydroxyl or
C
1
-C
6
alkoxy;
Q is C
1
-C
6
alkylene which is unsubstituted or substituted by C
1
-C
6
alkyl which is unsubstituted or substituted by a hydroxy group; and
R
1
and R
2
, which are the same or different are each C
1
-C
6
alkyl;
or a pharmaceutically acceptable salt thereof.
In a preferred aspect of the invention the heteroaromatic[a]phenazine carboxamide derivative is of formula (Ia)
wherein R
1
and R
2
are as defined above and R
4
is C
1
-C
6
alkyl which is unsubstituted or substituted by hydroxy.
When X in formula (I) and (Ia) is a six-membered heteroaromatic ring which is substituted, it is typically substituted on a ring carbon atom. Preferably it is substituted at this position by C
1
-C
6
alkoxy or hydroxy. When X in formula (I) or (Ia) is a five-membered heteroaromatic ring it is typically substituted on a ring nitrogen atom by C
1
-C
6
alkyl. Suitable examples of six-membered heteroaromatic rings are pyridine and pyrazine. Suitable examples of five-membered heteroaromatic rings are pyrrole and pyrazole.
A C
1
-C
6
alkyl group may be linear or branched. A C
1
-C
6
alkyl group is typically a C
1
-C
4
alkyl group, for example a methyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl or tert-butyl group. A C
1
-C
6
alkyl group is unsubstituted or substituted, typically by one or more groups selected from hydroxy, hydroxy-C
1
-C
6
alkyl wherein the alkyl moiety is unsubstituted or substituted as specified herein for C
1
-C
6
alkyl. Examples of hydroxy-C
1
-C
6
-alkyl include, for instance, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl. C
1
-C
6
alkylene is a C
1
-C
6
alkyl group as defined above which is divalent.
A C
1
-C
6
alkoxy group may be linear or branched. It is typically a C
1
-C
4
alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy, n-propoxy, n-butoxy, sec-butoxy or tert-butoxy group.
In formula (Ia) R
4
is preferably C
1
-C
6
alkyl, more preferably methyl.
In formulae (I) and (Ia) a preferred option for Q is a C
2
- or C
3
-alkylene chain which is substituted &agr; to the adjacent amide nitrogen atom by C
1
-C
6
alkyl which is unsubstituted or substituted as defined above. Preferably the substituent on Q is unsubstituted C
1
-C
6
alkyl or hydroxy-C
1
-C
6
alkyl such as hydroxymethyl. Typically the C
2
- or C
3
-alkylene chain is substituted &agr; to the adjacent amide nitrogen atom by methyl, ethyl, isopropyl, hydroxymethyl, substituted hydroxymethyl or 1-hydroxyethyl.
Examples of preferred compounds of the invention are as follows.
Compound
Compound Name
number
Pyrido[2,3-&agr;]phenazine-11-carboxylic acid (2-
1
dimethylamino-ethyl)-amide
Pyrido[4,3-&agr;]phenazine-11-carboxylic acid (2-
2
dimethylamino-ethyl)-amide
Pyrido[3,2-&agr;]phenazine-11-carboxylic acid (2-
3
dimethylamino-ethyl)-amide
Pyrazino[2,3-&agr;]phenazine-11-carboxylic acid (2-
4
dimethylamino-ethyl)-amide
4-Methoxypyrido[4,3-&agr;]phenazine-11-carboxylic
5
acid (2-dimethylamino-ethyl)-amide
4-Methoxypyrido[4,3-&agr;]phenazine-11-carboxylic
6
acid (2-dimethylamino-1-(R)-methyl-ethyl)-
amide
Pyrido[3,4-&agr;]phenazine-11-carboxylic acid (2-
7
dimethylamino-ethyl)-amide
4-Methoxypyrido[2,3-&agr;]phenazine-11-carboxylic
8
acid (2-dimethylamino-ethyl)-amide
4-Methoxypyrido[4,3-&agr;]phenazine-11-carboxylic
9
acid (2-dimethylamino-1-(S)-hydroxymethyl-
ethyl)-amide
4-Hydroxypyrido[4,3-&agr;]phenazine-11-carboxylic
10
acid (2-dimethylamino-ethyl)-amide
4-Hydroxypyrido[2,3-&agr;]phenazine-11-carboxylic
11
acid (2-dimethylamino-ethyl)-amide
3-Methyl-3H-Pyrazolo[4,3-&agr;]phenazine-10-
12
carboxylic acid (2-dimethylamino-ethyl)-amide
1-Methyl-1H-pyrazolo[3,4-&agr;]phenazine-10-
13
carboxylic acid (2-dimethylamino-ethyl)-amide
1H-Pyrazolo[3,4-&agr;]phenazine-10-carboxylic acid
14
(2-dimethylamino-ethyl)-amide
3H-Pyrazolo[4,3-&agr;]phenazine-10-carboxylic acid
15
(2-dimethylamino-ethyl)-amide
1H-Imidazo[4,5-&agr;]phenazine-10-carboxylic acid
16
(2-dimethylamino-ethyl)-amide
3-Methyl-3H-pyrrolo[3,2-&agr;]phenazine-10-
17
carboxylic acid (2-dimethylamino-ethyl)-amide
Compounds of formula (I) may be prepared by a process which comprises:
a) treating an activated derivative of a compound of formula (II)
wherein X is as defined above, with a compound of formula (III)
wherein Q, R
1
and R
2
are as defined above; and
(b) if desired, converting one resulting heteroaromatic (a)phenazine carboxamide derivative of formula (I) into another such derivative, and/or converting a heteroaromatic[a]phenazine carboxamide derivative of formula (I) into a pharmaceutically acceptable salt thereof.
The optical purity of resulting compounds that have an optically active centre, for instance the heteroaromatic[a]phenazine carboxamide derivatives of formula (Ia) and the salts thereof, may be determined by the addition of an NMR shift reagent such as 2,2,2-trifluoro-1 (9-anthryl) ethanol to NMR samples of the homochiral compounds.
The starting compounds of formula (II) are novel and thus constitute a further aspect of the present invention.
In step (a) the carboxylic acid grouping in formula (II) may be activated as the corresponding acid chloride which may be obtained by treating the free carboxylic acid of formula (II) with thionyl chloride. Alternatively the carboxylic acid grouping can be activated by treatment with an appropriate amide-coupling reagent such as 1,1′-carbonyldiimidazole.
The reaction between the activated derivative of the compound of formula (II) and the amine of formula (III) is typically conducted in an organic solvent. Suitable solvents include dimethylformamide and
Denny William Alexander
Gamage Swarnalatha Akuratiya
Milton John
Spicer Julie Ann
Vicker Nigel
McKenzie Thomas
Nixon & Vanderhye P.C.
Xenova Limited
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