Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-15
2003-04-08
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S214020, C514S292000, C514S293000, C540S548000, C540S578000, C540S579000, C546S082000, C546S083000, C546S084000
Reexamination Certificate
active
06544979
ABSTRACT:
This invention relates to fused imidazole derivatives having multidrug resistance modulating properties, and their use for improving oral bioavailability of pharmaceutical agents that are poorly absorbed from the gastrointestinal tract.
Many valuable pharmaceutical agents cannot be effectively administered by the oral route because of poor systemic absorption from the gastrointestinal tract. All these pharmaceutical agents are, therefore, generally administered via intravenous or intramuscular routes, requiring intervention by a physician or other health care professional, entailing considerable discomfort and potential local trauma to the patient and even requiring administration in a hospital setting with surgical access in the case of certain iv infusions.
It has been suggested that, in some cases, the poor bioavailability of pharmaceutical agents after oral administration is a result of the activity of a cell surface protein P-glycoprotein P-gp, which acts as an energy-dependent transport or efflux pump to decrease intracellular accumulation of said agent by extruding it from the cell. This P-glycoprotein has been identified in secretory epithelial cells of the liver, pancreas, small intestine, colon, and kidney; endothelial capillary cells of the brain and testis, placental trophoblasts; and the adrenal gland.
It is believed that the P-glycoprotein efflux pump prevents certain pharmaceutical compounds from transversing the mucosal cells of the small intestine and, therefore, from being absorbed into the systemic circulation.
Furthermore, it is believed that a major cause of multidrug resistance (MDR) is overexpression of the mdr-1 gene which codes for the expression of P-glycoprotein. P-glycoprotein decreases the intracellular concentration of cytotoxic drugs by binding the drug and actively pumping it out of the cell before it reaches a critical cytotoxic concentration (Dalton W. S.,
Seminars in oncology,
20:66-69, 1993). The term multidrug resistance (MDR) describes the phenomenon by which cells, in particular cancer cells, become resistant to multiple drugs that may have little similarity in the structure or mechanism of action.
Therefore, it has been suggested that compounds that are able to decrease, avoid, eliminate, inhibit or reverse the effects of multidrug resistance (i.e. so-called MDR reversing agents or compounds having MDR reversing properties) exert their action by blocking, inhibiting or suppressing the function of the P-glycoprotein efflux pump.
Since it is believed that the presence of P-glycoprotein in the gut epithelium can limit the uptake of certain orally administered pharmaceutical agents from the intestine, it is suggested that MDR inhibitors would be very useful to improve the bioavailability of orally administered pharmaceutical agents which are themselves poorly absorbed or not absorbed at all from the gastrointestinal tract.
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 having antiallergic activity.
WO-93/16044, published on Aug. 19, 1993, discloses triphenyl-azacycloalkane derivatives effective in reversing drug resistance in multi-drug resistant tumors. WO-94/22842, published on Oct. 13, 1994, encompasses 1-amino-3-phenoxy propane derivatives as modulators of multi-drug resistance.
WO-97/34897, published on Sep. 25, 1997, discloses the fused imidazole derivatives of formula (I) as multidrug resistance modulators.
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.
The present invention relates to the use of a first pharmaceutical compound of formula (I) for the manufacture of a medicine to improve the oral bioavailability of a second pharmaceutical agent that is poorly absorbed or not absorbed at all from the gastrointestinal tract or gut by pre-administering and/or simultaneously co-administering a first pharmaceutical compound of formula (I) to a warm-blooded animal by the oral route.
The phrases “oral bioavailability” and “bioavailability upon oral co-administration” as used herein refer to the systemic availability (i.e. blood/plasma levels) of a given amount of a pharmaceutical agent administered orally to a warm-blooded animal, in particular a human.
This invention concerns the use of a first pharmaceutical compound of formula
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein
the dotted line represents 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— (c-1);
—CH═CR
8
—Y— (c-2);
—CH═CR
8
—CH═CH— (c-3);
—CH═CH—CR
8
═CH— (c-4);
or
—CH═CH—CH═CR
8
— (c-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 dependently 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, halo, 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, halo, 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, halo, 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, halo, 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; for the manufacture of a medicine for improving the bioavailability of a second pharmac
Janssen Pharmaceuticals N.V.
McKenzie Thomas
Shah Mukund J.
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