Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-02
2003-09-09
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S140000
Reexamination Certificate
active
06617335
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The invention relates to the field of isoquinoline alkaloids. Specifically, the invention relates to preparations and formulations of derivatives of bis-isoquinoline alkaloids. More specifically, the invention relates to the use of derivatives of bis-isoquinoline alkaloids with reduced toxicity in rebersing multi drug resistance (MDR) activity.
BACKGROUND OF THE INVENTION
Alkaloids are alkali-like organic compounds that form salts with acids and contain nitrogen, generally in heterocyclic and/or ring structure. Found in a wide variety of plants, alkaloids have medicinal and toxic properties. Alkaloids that possess an isoquinoline skeleton are among the most common of all alkaloids. These are derived from a 3,4-dihydroxytyramine (dopamine) precursor that undergoes a Schiff base addition with aldehydes of different origin. At least 4000 compounds of this structural type are known. The simplest type of isoquinoline alkaloids is based on carbonyl compounds such as glyoxylic acid, pyruvic acid, and an aldehyde derived from leucine. Isoquinoline alkaloids sometimes occur as dimers and oligomers. (see Isoquinoline Alkaloids, by Kenneth W. Bentley and K. W. Bentley (Gordon & Breach Publishing Group (April 1998)).
Isoquinoline alkaloids are found in plants from a wide group of genera. Plants containing isoquinoline alkaloids include the following: Argemone species (prickly poppy), Chelidonium species (celandine poppy), Corydalis species (fitweed), Dicentra species (dutchman's breeches), Papaver species (poppy), and Sanguinera species (bloodroot). Isoquinoline alkaloids are most common in the cactus family, Cactaceae, but also are found in the Chenopodiaceae, Fabaceae, Musaceae, Nympheaceae, and Sterculiaceae.
The isoquinoline alkaloids papaverine, sanguinarine, protoverine, and chelidonine are gastrointestinal (GI) tract irritants and central nervous system (CNS) stimulants. Many have varying degrees of neurologic effects, ranging from relaxation and euphoria to seizures. They are also known to cause vasodilation. About 4000 bis-benzyl-isoquinoline (BIQ) alkaloids of many important structural types are known. Many BIQ alkaloids are important in medicine. Others are highly toxic and some are used as arrow poisons. BIQ alkaloids are found in the Annonaceae, Aristolochiaceae, Berberidaceae, Eupomatiaceae, Hernandiaceae, Fabaceae, Fumariaceae, Lauraceeae, Magnoliaceae, Menispermaceae, Monimiaceae, Nelumbonaceae, Papaveraceae, Ranunculaceae, Winteraceae, Euphorbiaceae (Croton), Rhamnaceae, Phellinaceae, Symplocaceae, Rutaceae, Combretaceae, Araliaceae, Apiaceae, Caprifoliaceae, Rubiaceae, and Araceae families.
Bis-isoquinoline class alkaloids have been shown to possess a variety of biological activities (reviewed in Gao Guang Yao, Res. & Dev. Nat. Prod. (1999), 11 (3):96-103; He Li Wen et al., Progress in Pharm Sci (1996), 20(4):193-197). It has been reported that these compounds possess anti-bacterial, anti-tumor, analgesic, immunomodulator, anti-platelet agglutination, anti-arrhythmic and anti-hypertensive activities.
Natural bis-isoquinoline class alkaloids include, for example, tetrandrine, fangchinoline, etc. Fangchinoline and tetrandrine are the major alkaloids from
Stephania tetrandrae
which has been used traditionally for the treatment of inflammatory diseases in oriental countries including Korea. Both fangchinoline and tetrandrine show anti-inflammatory effects (Hong-Serck Choi, et al. Journal of Ethnopharmacology, 69(2): 173-179 (February 2000)); inhibition of platelet aggregation and thrombosis (Kim H. S., et al. Journal of Ethnopharmacology, 66(2): 241-246 (August 1999)); and effects on vasodilations and on calcium movement in vascular smooth muscle, and hypotensive effects (H. Kim, et al. Journal of Ethnopharmacology, 58(2): 117-123 (October 1997)). However, natural bis-isoquinoline class alkaloids possess significant toxic side effects.
Multiple drug resistance (MDR) mediated by the human mdr-1 gene product was initially recognized during the course of developing regimens for cancer chemotherapy (Fojo et al., 1987, Journal of Clinical Oncology 5:1922-1927). A multiple drug resistant cancer cell line exhibits resistance to high levels of a large variety of cytotoxic compounds. Frequently these cytotoxic compounds will have no common structural features nor will they interact with a common target within the cell. Resistance to these cytotoxic agents is mediated by an outward directed, ATP-dependent pump encoded by the mdr-1 gene. By this mechanism, toxic levels of a particular cytotoxic compound are not allowed to accumulate within the cell.
MDR-like genes have been identified in a number of divergent organisms including numerous bacterial species, the fruit fly
Drosophila melanogaster, Plasmodium falciparum
, the yeast
Saccharomyces cerevisiae, Caenorhabditis elegans, Leishmania donovanii
, marine sponges, the plant
Arabidopsis thaliana
, as well as
Homo sapiens
. Extensive searches have revealed several classes of compounds that are able to reverse the MDR phenotype of multiple drug resistant human cancer cell lines rendering them susceptible to the effects of cytotoxic compounds. These compounds, referred to herein as “MDR inhibitors”, include for example, calcium channel blockers, anti-arrhythmics, antihypertensives, antibiotics, antihistamines, immuno-suppressants, steroid hormones, modified steroids, lipophilic cations, diterpenes, detergents, antidepressants, and antipsychotics (Gottesman and Pastan, Annual Review of Biochemistry 62:385-427 (1993)). Clinical application of human MDR inhibitors to cancer chemotherapy has become an area of intensive focus for research.
Recently, bis-isoquinoline class alkaloid compounds have been shown to reverse multi drug resistance (MDR). (Ye Zu Guang et al., Chin. J. Trad. Chin. Med. (1998), 23(7): 427-428; Tian Hui et al., Acta Pharmaceutica Acad Sinica (1997) 32(4):245-250; Tian Hui et al.,
Acta Pharmacologica Sinica
(1997), 18(5): 455-458; Xia Wei et al., Acta Nanjing Med. Univ. (1995), 15(3):543-546; Ono M et al., Cancer Chemotherapy Pharmacol. (1994), 35(1):10-16). However, natural bis-isoquinoline class alkaloid compounds are generally toxic to humans. Also, none of these studies report any enhancer activity of these compounds with the anti-cancer agents in clinical cancer chemotherapy.
BRIEF SUMMARY OF THE INVENTION
This invention relates to methods for carrying out structural modifications of bis-isoquinoline class alkaloids. These structurally modified bis-isoquinoline class alkaloids are used as agents for reversing multiple drug resistance (MDR), especially when used as synergistic enhancers of anti-cancer drugs with improved therapeutic efficacy. The advantage of using structurally modified derivatives of bis-isoquinoline class alkaloids is that, in general, the structurally modified bis-isoquinoline class alkaloids of the invention are considerably less toxic than their natural counterparts.
This invention relates to the bis-isoquinoline class alkaloid compound of general formula (I), which is as follows:
In formula (I), R
1
represents hydrogen, or a straight chain or branched chain alkane of 1 to 10 carbon atoms. R
2
and R
3
represent hydrogen or substituted acyl group, or straight chain or branched chain alkanes, which can be interrupted by placement of heterogeneous atoms like O, N, and S. R
2
and R
3
can also be O or S. R
4
and R
5
represent hydrogen, substituted acyl group, straight chain or branched chain alkanes or an alkane group which may be interrupted by the replacement of heterogeneous atoms like O, N, and S. R
4
and R
5
can also be O or S. X
1
, X
2
, X
3
and X
4
can be the same or different and also individually replaced by halogen atom or straight chain or branched chain alkaneoxy or acyloxy groups with 1 to 10 carbon atoms; and n is an integral of 1 to 4. C(1) and C(1′) include all stereo isomers of RR, SS, 1S1′R and 1R1′S. The compound does not include the natural isoquinoline bis-alkaloids tetrandrine, fangchinoline, berbamine, c
Chen Donglin
Jian Xixian
Wang Fengpeng
Wang Li
Yang Jinsong
Davis Zinna Northington
Kanghong USA, Inc.
Morrison & Foerster / LLP
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