Fused imidazole derivatives as multidrug resistance modulators

Details Fused imidazole derivatives as multidrug resistance modulators Fused imidazole derivatives as multidrug resistance modulators

2001-02-02

2002-11-05

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S214020, C514S292000, C514S293000

Reexamination Certificate

active

06476018

ABSTRACT:

This invention relates to fused imidazole derivatives having multidrug resistance modulating properties, and processes for their preparation; it further relates to compositions comprising them, as well as their use as a medicine.
Chemotherapy is one of the most frequently used forms of cancer therapy and has found clinical applications in the treatment of almost every type of cancer. One of the major problems in cancer chemotherapy is the development of resistance to cytotoxic drugs. Patients who did respond to a first course of chemotherapy frequently relapse because tumor cells seem to develop resistance against chemotherapeutic agents or may acquire resistance to a cytotoxic agent used in a previous treatment. A tumor may also manifest 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 tumor. Examples of these effects can be seen in, for example, haematological tumors (leukemias, lymphomas), renal carcinoma and breast carcinoma.
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 resistance to pharmaceutical agents to which they have not previously been exposed. Examples of this effect include multidrug resistance forms of malaria, tuberculosis, leishmaniasis and amoebic dysentery.
The above phenomena by which cancer cells or pathogens become resistant to multiple drugs that have little similarity in their structure or mechanism of action, are referred to collectively as multidrug resistance (MDR).
As used throughout the text, MDR modulators or compounds having MDR modulating properties are defined as compounds which are able to decrease, avoid, eliminate, inhibit or reverse the effects of multidrug resistance.
Since MDR is a major problem for the chemotherapeutic approach of the above-mentioned disorders, compounds capable of inhibiting or reversing the effects of multidrug resistance would be very useful.
EP-0,518,435 and EP-0,518,434, published on Dec. 16 1992, disclose fused imidazole compounds having antiallergic activity. WO-94/13680 published Jun. 23, 1994, discloses substituted imidazo[1,2-a](pyrrolo, thieno and furano) [2,3-d]azepine derivatives having antiallergic activity. Also, WO 95/02600, published on Jan. 26, 1995, discloses other piperidinyl- or piperidinylidene substituted imidazoazepine derivatives also having antiallergic activity.
The compounds of the present invention differ from the cited art-known compounds structurally, by the nature of the substituents on the nitrogen of the piperidine moiety, and pharmacologically by the fact that, unexpectedly, these compounds have MDR modulating properties.
This invention concerns compounds of formula
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
the dotted line is an optional bond;
n is 1 or 2;
R
1
is hydrogen; halo; formyl; C
1-4
alkyl; C
1-4
alkyl substituted with 1 or 2 substituents each independently selected from hydroxy, C
1-4
alkyloxy, C
1-4
alkylcarbonyloxy, imidazolyl, thiazolyl or oxazolyl; or a radical of formula
—X—CO—OR
5
  (a-1);
—X—CO—NR
6
R
7
  (a-2);
or
—X—CO—R
10
  (a-3);
 wherein
—X— is a direct bond, C
1-4
alkanediyl or C
2-6
alkenediyl;
R
5
is hydrogen; C
1-12
alkyl; Ar; Het; C
1-6
alkyl substituted with C
1-4
alkyloxy, C
1-4
alkyloxycarbonylC
1-4
alkyloxy, Ar or Het;
R
6
and R
7
each independently are hydrogen or C
1-4
alkyl;
R
10
is imidazolyl, thiazolyl or oxazolyl,
R
2
is hydrogen, halo, C
1-4
alkyl, hydroxyC
1-4
alkyl, C
1-4
alkyloxycarbonyl, carboxyl, formyl or phenyl;
R
3
is hydrogen, C
1-4
alkyl or C
1-4
alkyloxy;
R
4
is hydrogen, halo, C
1-4
alkyl, C
1-4
alkyloxy or haloC
1-4
alkyl;
Z is Z
1
or Z
2
;
 wherein
Z
1
is a bivalent radical of formula —CH
2
—, —CH
2
—CH
2
— or —CH═CH—; provided that when the dotted line is a bond, then Z
1
is other than —CH
2
—;
Z
2
is a bivalent radical of formula —CHOH—CH
2
—, —O—CH
2
—, —C(═O)—CH
2
— or —C(═NOH)—CH
2
—;
—A—B— is a bivalent radical of formula
—Y—CR
8
═CH—  (b-1);
—CH═CR
8
—Y—  (b-2);
—CH═CR
8
—CH═CH—  (b-3);
—CH═CH—CR
8
═CH—  (b-4);
or
—CH═CH—CH═CR
8
—  (b-5);
 wherein
each R
8
independently is hydrogen, halo, C
1-4
alkyl, C
1-4
alkyloxy, hydroxyC
1-4
alkyl, hydroxycarbonylC
1-4
alkyl, formyl, carboxyl, ethenyl substituted with carboxyl, or ethenyl substituted with C
1-4
alkyloxycarbonyl;
each Y independently is a bivalent radical of formula —O—, —S— or —NR
9
—; wherein R
9
is hydrogen, C
1-4
alkyl or C
1-4
alkylcarbonyl;
—A
1
— is a direct bond; C
1-6
alkanediyl; C
1-6
alkanediyl-oxy-C
1-6
alkanediyl; C
1-6
alkanediyloxy; carbonyl; C
1-6
alkanediylcarbonyl; C
1-6
alkanediyloxy substituted with hydroxy; or C
1-6
alkanediyl substituted with hydroxy or ═NOH;
—A
2
— is a direct bond or C
1-6
alkanediyl;
Q is phenyl; phenyl substituted with one or two substituents selected from hydrogen, hydroxy, C
1-4
alkyl, C
1-4
alkyloxy or haloC
1-4
alkyl; naphthalenyl; naphthalenyl substituted with one or two substituents selected from hydrogen, hydroxy, C
1-4
alkyl, C
1-4
alkyloxy or haloC
1-4
alkyl; pyridinyl; pyridinyl substituted with one or two substituents selected from hydrogen, hydroxy, C
1-4
alkyl, C
1-4
alkyloxy or haloC
1-4
alkyl; quinolinyl; or quinolinyl substituted with one or two substituents selected from hydrogen, hydroxy, C
1-4
alkyl, C
1-4
alkyloxy or haloC
1-4
alkyl;
Ar is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from hydrogen, halo, C
1-4
alkyl or C
1-4
alkyloxy;
Het is furanyl; furanyl substituted with C
1-4
alkyl, C
1-4
alkyloxy or hydroxyC
1-4
alkyl; oxazolyl; oxazolyl substituted with C
1-4
alkyl or C
1-4
alkyloxy; or quinolinyl.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C
1-4
alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C
1-6
alkyl includes C
1-4
alkyl and the higher homologues thereof having from 5 to 6 carbon atoms such as, for example, pentyl, hexyl, 3-methylbutyl, 2-methylpentyl and the like; C
1-12
alkyl includes C
1-6
alkyl and the higher homologues thereof having from 7 to 12 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl and the like; C
1-4
alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like; C
1-5
alkanediyl includes C
1-4
alkanediyl and the higher homologues thereof having 5 carbon atoms such as, for example, 1,5-pentanediyl and the like; C
1-6
alkanediyl includes C
1-5
alkanediyl and the higher homologues thereof having 6 carbon atoms such as, for example, 1,6-hexanediyl and the like; C
2-6
alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like; C
2-6
alkenediyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenediyl, 2-propenediyl, 3-butenediyl, 2-pentenediyl, 3-pentenediyl, 3-methyl-2-butenediyl, and the like; haloC
1-4
alkyl is defined as mono- or polyhalosubstituted C
1-4
alkyl; C
1-6
alkanediyl-oxy-C
1-6
alkanediyl defines bivalent radicals of formula such as, for example, —CH
2
—CH
2
—O—CH
2
—CH
2
—, —CH
2
—CH(CH
2
CH
3
)—O—CH(CH
3
)—CH
2
—, —CH(CH
3
)—O—CH
2
— and the like.
Whenever the bivalent radical A
1
is defined as a C
1-6
alkanediylc

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