Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-09
2001-04-17
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S255050, C514S307000, C514S308000, C514S311000, C514S314000, C544S353000, C544S405000, C546S146000, C546S152000
Reexamination Certificate
active
06218393
ABSTRACT:
This application is a 35 U.S.C. § 371 national phase entry application of PCT/GB97/02885 filed Oct. 17, 1997.
The present invention relates to compounds useful as modulators of multi-drug resistance (MDR), in particular MDR caused by over-production of P-glycoprotein (P-gp), to their preparation and to pharmaceutical and veterinary compositions containing them.
The resistance of tumours to treatment with certain cytotoxic agents is an obstacle to the successful chemotherapeutic treatment of cancer patients. A tumour may acquire resistance to a cytotoxic agent used in a previous treatment. A tumour may also manifest intrinsic resistance, or cross-resistance, to a cytotoxic agent to which it has not previously been exposed, that agent being unrelated by structure or mechanism of action to any agent used in previous treatments of the tumour.
Analogously, certain pathogens may acquire resistance to pharmaceutical agents used in previous treatments of the diseases or disorders to which those pathogens give rise. Pathogens may also manifest intrinsic resistance, or cross resistance, to pharmaceutical agents to which they have not previously been exposed. Examples of this effect include multi-drug resistant forms of malaria, tuberculosis, leishmaniasis and amoebic dysentery. These phenomena are referred to collectively as multi-drug resistance (MDR).
The most common form of MDR is caused by over-production in the cell membrane of P-gp, a protein which is able to reduce the accumulation of drugs in cells by pumping them out. This protein has been shown to be a major cause of multidrug resistance in tumour cells (Beck, W. T.
Biochem. Pharmacol,
1987, 36,2879-2887).
In addition to cancer cells, p-glycoprotein has been found in many normal human tissues including the liver, small intestine, kidney, and blood-brain endothelium. P-gps are localised to the secretory domains of the cells in all these tissues. This localisation suggests that P-gp may play a role in limiting the absorption of foreign toxic substances across biological barriers.
Consequently, in addition to their ability to increase the sensitivity of cancer cells to cytotoxic agents, P-gp inhibitors are expected to increase the net oral absorption of certain drugs and improve the transport of drugs through the blood-brain barrier. Indeed, administration of cyclosporin, a P-gp inhibitor, has been shown to increase the intestinal absorption of acebutolol and vinblastine in rats by 2.6 and 2.2-fold respectively (Tereo, T. et al.
J. Pharm. Pharmacol,
1996, 48, 1083-1089), while mice deficient in mdr la P-gp gene exhibit up to 100-fold increased senstivity to the centrally neurotoxic pesticide ivermectin (Schinkel, A. H. et al
Cell
1994, 77, 491-502). Besides increased drug levels in the brain, the P-gp deficient mice were shown to have elevated drug levels in many tissues and decreased drug elimination.
Disadvantages of drugs which have so far been used to modulate MDR, termed resistance modifying agents or RMAs, are that they frequently possess a poor pharmacokinetic profile and/or are toxic at the concentrations required for MDR modulation.
It has now been found that a series of anthranilic acid derivatives have activity as inhibitors of P-gp and may therefore be used in overcoming the multi-drug resistance of tumours and pathogens. They also have potential utility in improving the absorption, distribution, metabolism and elimination characteristics of certain drugs.
The present invention therefore provides a compound which is an anthranilic acid derivative of formula (I):
wherein
each of R, R
1
and R
2
, which are the same or different, is H, C
1
-C
6
alkyl, OH, C
1
-C
6
alkoxy, halogen, nitro, or N(R
10
R
11
) wherein each of R
10
and R
11
, which are the same or different, is H or C
1
-C
6
alkyl, or R
1
and R
2
, being attached to adjacent positions of ring b, together form a methylenedioxy or ethylenedioxy group;
R
3
is H or C
1
-C
6
alkyl
R
4
is C
1
-C
6
alkyl or R
4
represents —CH
2
— or —CH
2
CH
2
— which is attached either (i) to position 2 of ring b to complete a saturated 5- or 6-membered nitrogen-containing ring fused to ring b, or (ii) to the position in ring a adjacent to that to which X, being a single bond, is linked, thereby completing a saturated 5- or 6-membered nitrogen-containing ring fused to ring a;
R
5
is H, OH or C
1
-C
6
alkyl;
X is a direct bond, O, S, —S—(CH
2
)
p
— or —O—(CH
2
)
p
— wherein p is an integer of 1 to 6;
R
6
is H, C
1
-C
6
alkyl or C
1
-C
6
alkoxy;
q is 0 or 1;
Ar is an unsaturated carbocyclic or heterocyclic group;
each of R
7
and R
8
, which are the same or different, is H, C
1
-C
6
alkyl which is unsubstituted or substituted, C
1
-C
6
alkoxy, hydroxy, halogen, phenyl, —NHOH, nitro, a group N(R
10
R
11
) as defined above or a group SR
12
wherein R
12
is H or C
1
-C
6
alkyl or R
7
and R
8
, when situated on adjacent carbon atoms, form together with the carbon atoms to which they are attached a benzene ring or a methylenedioxy substituent;
R
9
is phenyl or an unsaturated heterocyclic group, either of which is unsubstituted or substituted by C
1
-C
6
alkyl, OH, C
1
-C
6
alkoxy, halogen, C
3
-C
6
cycloalkyl, phenyl, benzyl, trifluoromethyl, nitro, acetyl, benzoyl or N(R
10
R
11
) as defined above, or two substituents on adjacent ring positions of the said phenyl or heterocyclic group together complete a saturated or unsaturated 6-membered ring, or form a methylenedioxy group;
n is 0 or 1; and
m is 0 or an integer of 1 to 6;
or a pharmaceutically acceptable salt thereof.
The group X is linked to any one of the positions 2 to 6 in ring a which are not occupied by R
6
. Preferably it is linked to position 3 or 4. In a preferred series of compounds R
6
is at position 2 and X is at position 3 or 4 in ring a. When X is at position 3 or 4 in ring a R
6
may alternatively occupy position 5. Owing to the free rotation of ring a, position 6 is equivalent to position 2.
The value of m is preferably 0 or an integer of 1 to 3, more preferably 1 or 2. The value of q is preferably 1.
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 halogen is F, Cl, Br or I. Preferably it is F, Cl or Br. A C
1
-C
6
alkyl group which is substituted is typically substituted by one or more halogen atoms, for instance by 1, 2 or 3 halogen atoms. It may be a perhaloalkyl group, for instance trifluoromethyl.
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. The integer m is from 1 to 6 and is typically 1, 2 or 3.
An unsaturated carbocyclic group is typically a C
5
-C
10
carbocyclic group which contains at least one unsaturated bond, for instance a C
6
-C
10
aryl group such as a phenyl or naphthyl group. An unsaturated heterocyclic group is typically a 5 or 6-membered heterocyclic ring with at least one unsaturated bond, which contains one or more heteroatoms selected from N, S and O and which is optionally fused to a benzene ring or to a second such 5 or 6-membered heterocyclic ring.
An unsaturated heterocyclic group may be, for example, a furan, thiophene, pyrrole, indole, isoindole, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, pyridine, quinoline, quinoxaline, isoquinoline, thienopyrazine, pyran, pyrimidine, pyridazine, pyrazine, purine or triazine group. The aforesaid heterocyclic ring may be unsubstituted or substituted by one or more substituents, for instance one or more substituents selected from OH, halogen, C
1
-C
6
alkyl which is unsubstituted or substituted, for example by halogen, such as CF
3
, C
1
-C
6
alkoxy, nitro and an amino group N(R
10
R
11
) as defined above.
Preferably the heterocyclic group represented by R
9
includes at least one nitrogen atom and the heterocyclic group represented by Ar includes at least one nitrogen or sulphur atom.
In a preferre
Ashworth Philip Anthony
Brumwell Julie Elizabeth
Folkes Adrian John
Hunjan Sukhjit
Maximen Levi Michael
Davis Zinna Northington
Nixon & Vanderhye
Xenova Limited
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