Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-03-11
1997-07-15
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514323, 514330, C07D21116, C07D40106, A61K 31445, A61K 3140
Patent
active
056483651
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Effective tumor treatment is frequently thwarted by the lack of sensitivity of certain tumors to standard chemotherapeutic agents (intrinsic resistance) or by the ability of certain tumors to develop a lack of chemotherapeutic sensitivity during the course of treatment (acquired or extrinsic resistance). The cause of these phenomena has been linked to the existence of an energy dependent efflux pump which acts to remove the chemotherapeutic agent from the target cell. The pump consists of the P-glycoprotein found as a constituent of cell membrane, and it has been suggested that the normal function of the P-glycoprotein is to remove toxins from within the cell. This theory is supported by the observation that P-glycoprotein is found as a cell membrane constituent in cells of liver, kidney, colon, and jejunum tissues. It has been suggested that P-glycoprotein in the cell membrane of such normal tissues could act to remove toxins or to assist in the transport of nutrients and solutes and to secrete a variety of protein and steroid substances. The natural presence of P-glycoprotein in tumor cells derived from these tissues as well as its presence in tumor cells derived from other tissue types could explain, at least in part, resistance of various tumors to therapy with standard chemotherapeutic agents. The use of agents which inactivate the P-glycoprotein pump could be therapeutic and valuable in the treatment of multi-drug resistant tumors.
SUMMARY OF THE INVENTION
This invention relates to novel diarylalkyl piperidines of Formula 1 ##STR2## wherein m is an integer selected from the group consisting of 0, 1 or 2, consisting of hydrogen, halogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy, and from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, halogen, OCH.sub.2 O, CF.sub.3, OCF.sub.3, OH, CN, NO.sub.2, and NH.sub.2 ; and indolyl, their effectiveness in the treatment of multi-drug resistant tumors.
DETAILED DESCRIPTION OF THE INVENTION
This invention concerns the use of the compounds of Formula 1 as agents effective in reversing drug resistance in multi-drug resistant tumors. The compounds of Formula 1 can be administered together with standard chemotherapeutic agents, can be used in the treatment of tumors which are intrinsically or extrinsically multi-drug resistant, and can be used to reverse resistance in experimental multi-drug resistant tumor cell lines. Multi-drug resistance is defined to be that condition of a tumor cell in which the cell is resistant to a wide variety of unrelated anticancer drugs such as vinca alkaloids, epipodophyllotoxins, dactinomycin, and anthracycline classes as well as colchicine. (Goodman and Gilman, 7th Ed., p. 1278.) This broad based, cross resistance can develop after administration of a single agent of either the vinca alkaloid, epipodophyllotoxins, dactinomycin, and anthracycline classes as well as colchicine and is characterized by resistance to the other members of these drug classes. Examples of antitumor drugs of the vinca alkaloid class include the naturally occurring vincristine and vinblastine as well as the synthetic derivative vindesine. Examples of antitumor drugs of the epipodophyllotoxins class include etoposide and teniposide. An example of an antitumor drug of the anthracycline class is daunorubicin. Examples of antitumor drugs of the dactinomycin class include actinomycin A and actinomycin D.
As used herein, the term "(C.sub.1 -C.sub.4)alkoxy" means a straight or branched chain alkoxy group having from one to four carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
The compounds of Formula 1 contain one or more asymmetric centers and will therefore exist as enantiomers and diastereomers. In particular the carbon atom of the piperidine ring to which the diphenylalkyl group is attached is an asymmetric center. Moreover, when those phenyls are substituted, not identically, the carbon atom to which
REFERENCES:
patent: 2898339 (1959-08-01), Wheeler et al.
patent: 3956296 (1976-05-01), Duncan et al.
patent: 4035372 (1977-07-01), Deason et al.
patent: 4851423 (1989-07-01), Girijavallab-han et al.
patent: 4990511 (1991-02-01), Nakajima et al.
Wu, et al, Cancer Research, 52, pp. 3029-3034, Jun. 1, 1992.
Chemical Abstracts, vol. 67, 32621c, 1967.
Kartner et al., Scientific American, 44-51 (1989).
Tsuruo et al., Cancer Research 43, 2905-2910 (1983).
Helson, Cancer Drug Delivery vol. 1, No. 4, 353-361 (1984).
Tsuruo et al., Cancer Research 43, 2267-2272 (1983).
Gottesman et al., TIPS Reviews vol. 9, 54-58 (1988).
Endicott et al., Annual Review Biochem 58, 137-171 (1989).
Ford, et al., Pharmacological Review, Am. Soc. for Pharmacology and Experimental Therapeutics vol. 42, No. 3, 155-199 (1990).
Chemical Abstracts vol. 102:45760p (1985).
Chemical Abstracts vol. 102:2490F 19(9), 671-675 (1983).
Chemical Abstracts 67:3262c Ghiringhelli et al., (1967).
Freedman Jules
Sunkara Sai P.
Lentz Nelsen L.
Merrell Pharmaceuticals Inc.
Raymond Richard L.
LandOfFree
Diarylalkyl piperidines useful as multi-drug resistant tumor age does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Diarylalkyl piperidines useful as multi-drug resistant tumor age, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Diarylalkyl piperidines useful as multi-drug resistant tumor age will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1492535