Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-14
2003-06-03
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S211070, C514S245000, C514S356000, C514S357000, C514S487000, C514S492000, C514S565000, C514S585000, C514S587000, C514S595000, C514S599000
Reexamination Certificate
active
06573284
ABSTRACT:
The present invention relates to novel compounds useful as therapeutic agents and assay reagents. More specifically, the present invention relates to a drug targeting and especially to a novel method of delivery of therapeutically active agents to tumour cells, in particular melanoma cells.
BACKGROUND TO THE INVENTION
Malignant melanoma is an important cancer with a rising incidence world-wide affecting people of all ages, including a relatively young population. Whilst progress is being made in prevention and in early diagnosis, the major problem is the difficulty of treating the disease in its disseminated state. Therapeutic agents with improved effectiveness are urgently required if the number of deaths resulting from malignant melanoma is to be reduced. Melanoma has the potential of rapid metastasis and remains a difficult neoplasm to treat. Conventional antineoplastic agents continue to be of value in the management of this malignancy but improved clinical results can be achieved if established or newly discovered agents are modified to allow them to act more selectively. The delivery of cytotoxic agents to the site of tumour cells is much desired because systemic administration of these agents often results in the killing of normal cells within the body as well as the tumour cells sought to be eliminated.
Sadly, treatment of disseminated melanoma is currently inadequate, remaining incurable. Targeted chemotherapy seems a feasible approach for this neoplasm because in the adult human melanogenesis is uniquely a property of melanocytes. Previous attempts at utilization of the melanogenic pathway to activate prodrugs have made use of the formation of reactive quinone intermediates which rely on thiol depletion for their toxic effect and initial attempts to treat melanoma in the clinic have been unsuccessful due to unfavourable pharmacokinetics, low potency and systemic toxicity.
In developing the compounds of the invention, reliance was placed on the realisation that the tyrosinase enzyme is differentially associated with certain target cells, especially melanoma cells.
Thus, tyrosinase (monophenol, 3,4-dihydroxyphenylalanine: oxygen oxidoreductase, EC 1. 14.18. 1) is generally exclusive to pigment-producing cells (melanocytes) and is frequently unregulated in melanoma. Use of the catalytic potential of tyrosinase to generate a highly toxic compound from a non-toxic substrate or “prodrug” has been suggested [see Riley P A (1991) Eur J Cancer, 27: 1172-1177] and so far, a number of potential melanoma prodrugs have been studied, but with limited success. Examples of such agents include analogues of tyrosine which are oxidised by tyrosinase to generate cytotoxic quinones [see e.g. Naish S, Cooksey C J & Riley P A (1988) Pig. Cell Res., 1:3 79-381; Naish S, Holden J L, Cooksey C J & Riley P A (1988) Pig. Cell Res, 1:382-385] which act through mechanisms leading to thiol depletion [see e.g. Alena F, Iwashina T, Gili A & Jimbow K (1994) Cancer Res., 54(10): 2661-2666; Alena F, Dixon W, Thomas P & Jimbow K (1995) J. Invest. Dermatol., 104(5): 792-797; Riley P A, Cooksey C J, Johnson C I, Land E J, Latter A M & Ramsden C A (1996) Eur. J. Canc. (in press)].
Initial studies indicated that compounds such as 4-hydroxyanisole held promise in targeted melanoma chemotherapy [see Morgan B D G, O'Neill T, Dewey D L, Galpine A R & Riley P A (1981) Clin. Oncol., 7:227-234], but a number of serious difficulties have been encountered in the clinic, notably the relatively limited cytotoxicity of the resulting cytotoxic quinone, necessitating the use of high serum levels of the prodrug and complications from systemic actions [see Rustin G J, Stratford M R, Lamont A, Bleehen N, Philip P A, Howells N, Wafta R R & Slack J A (1992) Eur. J. Canc., 28A, 1362-1364; Belcher H J, Nizam M & ONeill T J (1992) Br. J. Plast. Surg., 45:208-210] due to alternative metabolism, particularly hepatic and renal toxicity [see Schiller C D, Gesher A & Jheeta P (1991) Eur. J. Canc., 27:1017-1022; Stolze K & Nohl H (1991) Free Rad. Res. Comm., II:321-327. Refs. 17,18].
Therefore, in order for tyrosinase-dependent activation of cytotoxic pro-drugs is to become an effective and realistic chemotherapeutic targeting strategy for the treatment of melanoma, there has been a need for agents to be developed that produce their action by a mechanism that does not rely for its cytotoxic effect on thiol depletion.
The basis of our new approach to lethal synthesis in melanogenic cells, which to our knowledge has not hitherto been studied, is the utilization of the reductive cyclization process associated with the tyrosinase enzyme to initiate the specific intracellular release of cytotoxic agents. By this approach, we have succeeded in incorporating in a prodrug known cytotoxic compounds whose behaviour on release are well understood and which have been proven as potent inhibitors of tumour growth. The modification of the chemical structure of the active agent by incorporation in the prodrug is designed to moderate its cytotoxicity whilst it is in the form of the prodrug by diminishing its reactivity and by reduction of systemic bioavailability through effects on half-life or altered cellular uptake characteristics. The targetted release mechanism proposed is aimed at selectively liberating the drug from these constraints.
It is one aim of the present invention to produce and screen a novel category of anti-melanoma compounds. A further object is to provide novel compounds useful as assay or diagnostic agents. The approach that we adopted was based on our appreciation that the structural requirements for compounds to act as substrates for tyrosinase could be adapted to the synthesis of prodrugs.
SUMMARY OF THE INVENTION
The present invention provides a novel class of compounds which depend upon the action of tyrosinase for their conversion to desired products, including therapeutically active substances and assayable metabolites, e.g. indicator molecules.
Thus according to one aspect of the invention there is provided a pro-drug which is capable of releasing a therapeutically active agent at a desired location, characterised in that the pro-drug is a substrate for tyrosinase wherein in the presence of tyrosinase, the compound is oxidised to a quinone, which undergoes cyclisation and hydrolysis to release therapeutically active agent.
According to a further aspect of the invention there is provided a compound which is capable of conversion to an assayable substance such as an indicator molecule, characterised in that the compound is a substrate for tyrosinase wherein in the presence of tyrosinase, the compound is oxidised to a quinone, which undergoes cyclisation and hydrolysis to release said assayable substance.
More specifically, the invention provides a compound, in particular a prodrug, which is capable of releasing a therapeutically active agent or assayable substance (ThrAg) at a desired location, characterised in that the compound is a substrate for the tyrosinase enzyme and has the formula:
TyrX—B—ThrAg*
wherein TyrX— is a residue of an optionally substituted tyrosine analogue of the structure
wherein each of the symbols ═Z— is independently selected from ═CH—, ═C—, ═N—, and —N
+
═O,
B represents a linking group or single bond linking TyrX and ThrAg*,
ThrAg* represents a residue of a therapeutically active agent ThrAg or a residue of an indicator molecule, and
Y represents —O—, —S— or a group
n is 1, 2, 3 or 4 (preferably 1 or 2),
and either NQ— represents —N— and the dotted line represents a bond linking the nitrogen atom to the indicated ring atom or NQ— represents —NR
6
— and the dotted line is to be ignored,
R
1
and R
2
independently represents hydrogen, halogen (e.g. F, Cl, Br or I) or —OH,
R
3
, R
4
, and R
5
independently represent hydrogen, halogen (e.g. F, Cl, Br or I), C
1-4
alkyl, C
1-4
alkenyl, CF
3
, NO
2
, —OH, —COOH, —COOR, or —CH
2
OH, wherein R represents C
1-4
alkyl, and
R
6
represents hydrogen, halogen
Khan Tariq Hussain
Osborn Helen Mary
Photiou Andrew
Riley Patrick Anthony
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