Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1992-04-03
1995-02-07
Kim, Kay K. A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 8, 4249811, 525 541, 5303911, 530399, 530408, 530409, 536 64, 536 221, 540304, 540350, 540351, 540478, 549298, A61K 3700, C07K 1706, C07H 15252, C07H 1906
Patent
active
053875788
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to conjugates of therapeutically useful anthracyclines with carriers such as polyclonal and monoclonal antibodies or proteins or peptides of natural or synthetic origin; methods for their preparation, pharmaceutical compositions containing them and use thereof in treating certain mammaliam tumors. The invention also relates to new anthracycline derivatives and their preparation.
In recent years, many highly cytotoxic anthracyclines have been synthesized. For example, those bearing a morpholino or substituted morpholino ring linked at C-3' position of the sugar moiety have shown promising antitumor activity on experimental murine tumors [see: Bioactive molecules, 55-101, vol 6, Edited by J. William Lown, Elveiser 1988].
The present invention is concerned with new linkers for releasing therapeutically useful drugs from bioactive agents in order to improve the therapeutic efficacy of the drugs and to reduce their toxic effects upon administration in humans. More particularly, the bioactive agents comprise drugs bearing free primary or secondary hydroxyl groups and belonging to therapeutic classes such as antibiotics, antitumorals or antiviral compounds, conjugated to carriers such as antibodies reactive with a selected cell population or to proteins, peptides or polymers of natural or synthetic origin reactive with receptor tissues.
Each drug containing at least a primary or secondary hydroxyl group is covalently bound to the carrier via a linker arm and is bound to that linker arm via an acid-sensitive acetalic bond at its primary or secondary hydroxyl position. The acid sensitive acetalic bond of the bioactive agent of this invention allows the release of active drug in the acidic external or internal environment of the target tissue.
Accordingly the present invention provides conjugates of general formula 1 which --O--H is a primary or secondary hydroxyl group; a is an integer of from 1 to 30; W is a group of general formula 2: ##STR2## wherein b is an integer of from 1 to 4, B represents a C.sub.1 -C.sub.3 alkylene group and R.sub.1 and R.sub.2 each independently represent hydrogen, halogen, alkyl, phenyl or substituted phenyl; Z is a spacer group and T is a carrier moiety.
Preferably a is from 1 to 5. B suitably represents --(CH.sub.2).sub.2 --. In the definition of R.sub.1 and R.sub.2, halogen is typically chlorine, bromine or iodine and alkyl may be C.sub.1 -C.sub.4 such as methyl or ethyl. Substituted phenyl may be halogen or alkyl-substituted phenyl in which case the halogen and alkyl may be as above. Preferred Z groups are: 4; is an integer of from 2 to 4, --O--(CH.sub.2).sub.f -- in which f is 1 or 2, or which g is an integer of from 2 to 6; which g is an integer of from 2 to 6 or ##STR3##
In the above formula 1 the drug A--O--H preferably represents an antitumor agent belonging to the class of anthracyclines such as doxorubicin, its 3'-deamino-3'-morpholinyl derivatives in which the morpholino ring optionally is substituted at position 2" with alkoxy residues such as a C.sub.1 -C.sub.4 alkoxy group; pyrimidine analogs such as 5-fluorodeoxyuridine or arabinofuranosylcytosine (cytarabine); derivatives of vinca alkaloids such as 4-desacetylvinylblastine; or other antitumor agents such as podophyllotoxin or illudines. Alternatively, the drug A--O--H may be an antiviral agent such as 3'-azido-3'-deoxythymidine (AZT), bromovinyldeoxy-uridine (BVDU), 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir) or 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (gancyclovir) or an antibiotic such as thienamycin or our new penem derivatives such as (5R,6S)-2-carbamoyloxymethyl-6-[(1R-hydroxyethyl]-2-penem-3-carboxylic acid and acetoxymethyl (5R,6S)-2-carbamoyloxymethyl-6-[(1R)-hydroxyethyl]-2-penem-3-carboxylate.
When the moiety A--O-- is derived from an anthracycline A--O--H typically the moiety A--O-- represents ##STR4## in which R.sub.10 is a hydrogen atom or a hydroxy or methoxy group, one of R.sub.11 and R.sub.12 is a hydrogen atom and the other is a hydroxy group or R.sub.11 is a hydrogen
REFERENCES:
Takahashi et al (1984) Iyo Masu Kenkyu Kai Koenshu 9: 77-82.
Webb et al. (1990) Polymer Prepr. (Am. Chem. Soc.) Div. Polym. Chem) 31 (2);204-205.
The Journal of Biological Chemistry, vol. 264, No. 25, Sep. 1989, (US) D. M. Neville et al.: "Enhancement of immunotoxin efficacy by acid-clevable crossagents utilizing diphteria toxin and toxen mutants", pp. 14653-14661, see the whole article.
Angelucci Francesco
Bersani Laura
Caruso Michele
Ripamonti Marina
Ruggieri Daniela
Farmitalia Carlo Erba S.r.l.
Kim Kay K. A.
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