Basf Aktiengesellschaft

Boehringer Mannheim Gmbh

Other

Bayer Aktiengesellschaft

Georg-august-universitat Gottingen Stiftung Offentlichen Rechts

Syntarga Bv

Georg-august-universitaet Goettingen Stiftung Oeffentlichen Rechts

Georg-august-universität Göttingen

Lutz F Tietze

Michael Joseph Powell

Jochem Henkelmann

Matthias Beller

Pyare L Khanna

Patrick Henry Beusker

Franciscus Marinus Hendrikus De Groot

Henri Johannes Spijker

Johannes Albertus Frederikus Joosten

Adrian Steinmetz

Scott J Eisenbeis

Roland Fischer

David Lingenfelter

Felix Major

Tobias Herzig

Anja Fecher

Kamala Penchalaiah

A first aspect of the invention relates to novel compounds and more precisely to novel bifunctional prodrugs and drugs. An additional aspect of the invention relates to antibody compound conjugates, wherein the compound is a claimed compound, and to pharmaceutical compositions containing the compound or antibody compound conjugate. The invention lastly relates to the use of this compound or antibody compound conjugates according to the invention in order to treat tumour diseases, particularly in mammals.

Bifunctional prodrugs

The present invention relates to a method for the synthesis of compounds useful in the preparation of antibody drug conjugates (ADC), namely, monoprotected dimeric bifunctional prodrugs based on duocarmycin analogs. In a further aspect, compounds obtained by the method according to the present invention are provided. The monoprotected bifunctional prodrug is used for preparing antibody drug conjugates composed of an antibody moiety and the monoprotected bifunctional prodrug. The antibody compound conjugates thus obtained are provided. Further, a method of preparing an antibody drug conjugate composed of two identical or two different antibody moieties is provided as well as the antibody compound conjugate containing two different antibody moieties accordingly. These conjugates can be used in pharmaceutical compositions, in particular, for use in treatment of tumors, e.g. for use in ADC therapy.

Method for the synthesis of monoprotected bifunctional prodrugs and antibody drug conjugates based thereon as well as a method for preparing antibody drug conjugates

This invention relates to novel analogs of the DNA-binding alkylating agent CC-1065 and to their conjugates. Furthermore this invention concerns intermediates for the preparation of said agents and their conjugates. The conjugates are designed to release their (multiple) payload after one or more activation steps and/or at a rate and time span controlled by the conjugate in order to selectively deliver and/or controllably release one or more of said DNA alkylating agents. The agents, conjugates, and intermediates can be used to treat an illness that is characterized by undesired (cell) proliferation. As an example, the agents and the conjugates of this invention may be used to treat a tumor.

Water-soluble CC-1065 analogs and their conjugates

The chemotherapy of malignant tumours is greatly restricted by the generally slight differentiation of the available cytostatic agents between normal and malignant tissue. In order to achieve an improvement of the selectivity in cancer therapy, novel prodrugs have been developed from 6-hydroxy-2,3-dihydro-1H-indolene, 5-hydroxy-1,2-dihydro-3H-pyrrolo[3,2-e]indolene and 5-hydroxy-1,2-dihydro-3H-benzo[e]indolene as well as from 6-hydroxy-1,2,3,4-tetrahydro-benzo[f]-quinolines, that may be used within the framework of the ADEP therapy (antibody directed enzyme prodrug therapy). The new prodrugs are characterised by a high difference in toxicity between the prodrug and underlying drug and by a very high efficacy of the drug. After splitting off of the glycosidic and/or acetal group on the phenolic hydroxy groups of the prodrugs, a spirocyclopropacyclohexadiene is formed which, being a highly toxic group, effects an alkylation of the DNA or RNA.

Prodrugs for a selective cancer therapy

The invention relates to cycloalkyl derivatives, a process for their preparation and their use.

Cycloalkyl derivatives and the solid-phase synthesis of such derivatives

Formation of an intramolecular cross-link in enzyme donor polypeptide fragments of .beta.-galactosidase, thereby forming a cyclic enzyme donor which is hindered from complementation with an enzyme acceptor fragment to form active of .beta.-galactosidase. The cyclic enzyme donor can be linearized by cleaving to restore complementation ability. Assays in which such cyclic enzyme donors are linearized by specific analytes are disclosed, as well as novel homobifunctional bis-maleimido cross-linking agents of the formula ##STR1## wherein R is hydroxy or acetate.

Bis-maleimido cross-linking agents

Cross-linked polypeptide fragments of .beta.-galactosidase

A process for the preparation of .alpha.,.beta.-unsaturated .beta.-oxycarboxylic acid chlorides of the formula I ##STR1## where R.sup.1 is a C-organic radical, and R.sup.2 and R.sup.3, independently of one another, are hydrogen or a C-organic radical, comprises carrying out the addition reaction of an enol derivative of the formula II ##STR2## with a compound of the formula IIIa, IIIb or IIIc ##STR3## and converting the resultant acid chloride of the formula ##STR4## into I by elimination of hydrogen chloride (HCl).

Preparation of .alpha.,.beta.-unsaturated .beta.-oxycarboxylic acid

Compounds of the formula (I) ##STR1## wherein R.sup.1 represents a pyranosyl radical and R.sup.4, R.sup.2, and R.sup.3 are as specified herein, compositions containing the compounds, methods of using the compounds to selectively kill tumor cells, and a process for the preparation of the compounds.

Ketophosphamide glycosides

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Göttingen, Germany

Lutz F Tietze