Novartis Ag

Sandoz Gmbh

Debiopharm S.a.

Debio Recherche Pharmaceutique S.a.

Roland M Wenger

Manfred Mutter

Hans Kobel

Dieter Seebach

Pietro Bollinger

Rene P Traber

Soo Young Ko

Brigitte Besemer-Rosenwirth

Sylvain Cottens

Robert Paul Hof

Thomas Ruckle

Hans Hofmann

Grégoire Vuagniaux

Rafael Crabbé

Patrick Garrouste

Valerie Quesniaux

Joachim Rosenthaler

Max H Schreier

Michael Keller

Robert Lysek

Jean-Fran&ccedil;ois Guichou

Torsten Woehr

Olivier Turpin

Ren&eacute;P Traber

Valérie Nicolas

Fran&ccedil;ois Legay

Philipp E Ball

Amaud Hamel

Laura Novaroli Zanolari

Francis Hubler

Thomas Rückle

At least one embodiment of the present invention relates to new cycloundecadepsipeptide compounds and to the use of said compounds as a medicament, in particular as antiviral agents, more particularly for preventing or treating Hepatitis C infections or HCV induced disorders.

Cycloundecadepsipeptide compounds and use of said compounds as a medicament

The invention relates to a novel cyclosporin, the pharmaceutical use thereof and a pharmaceutical composition containing it.

Cyclosporin with improved activity profile

A pro-drug comprising a cyclic undecapeptide wherein the peptide chain thereof comprises at least one amino acid residue, useful as a medicinal product, including use for treatment of pathological conditions of the eye.

Cyclic undecapeptide pro-drugs and uses thereof

The invention relates to cyclosporin derivatives, whereby the peptide chain thereof comprises at least one pseudo-proline type non-natural amino acid radical. The invention also relates to a method for the production of said derivatives.

Cyclosporin derivatives and method for the production of said derivatives

Use for 1,3-propanediol derivatives

Use of a compound of formula (I) wherein R,is an optionally substituted straight- or branched carbon chain having 12 to 22 carbon atoms which may be optionally interrupted by an optionally substituted phenylene, and each of R,, R,, R,and R,, independently, is H or lower alkyl, in free form or in pharmaceutically acceptable salt form, in the prevention or treatment of chronic rejection in a recipient of organ or tissue allo- or xenotransplant, or of acute rejection in a xenograft transplant recipient.

It has been found that nonimmunosuppressive, cyclophilin-binding cyclosporins are useful in the treatment and prevention of AIDS and AIDS-related disorders. Such cyclosporins include novel Ciclosporin derivatives modified at the 4- and/or 5-positions.

Cyclosporin fermentation process

A new method of measuring blood levels of immunophilin-binding pharmaceuticals, e.g., cyclosporins, rapamycins, and FK506 compounds is provided, comprising the novel step of displacing the pharmaceutical from its immunophilin by using a binding competitor, thereby eliminating the need for an extraction step and enhancing the simplicity and accuracy of the assay. Assay kits comprising a binding competitor and a receptor, e.g., a monoclonal antibody, which binds to the pharmaceutical but not significantly to the binding competitor are also provided, as are new uses of immunophilin-binding compounds as binding competitors in such assays.

Assay kit

Cyclosporins

Nonimmunosuppressant cyclosporin derivatives having cyclophilin-binding activity, for example, the compound, �MeIle!.sup.4 -ciclosporin, are useful in inhibiting HIV-1 replication in treating AIDS and AIDS related disorders.

Novel monoclonal antibodies capable of distinguishing between cyclosporins, e.g. Cyclosporine, and metabolites, e.g. Cyclosporins 17 and 18, are produced, e.g. starting from novel cyclosporins having an activated coupling group, e.g. activated carboxy group, e.g. (i) [(O-succinimidooxysuccinyl)-Thr].sup.2 -Cyclosporine and (ii) [(N-.epsilon.-succinimidooxysuccinyl)-(D)Lys].sup.8 -Cyclosporine. Cyclosporin starting materials required for the production of cyclosporins of type (ii), e.g. [(D)Lys].sup.8 -Cyclosporine are also new and additionally have utility in the preparation of novel labelled cyclosporin derivatives, as well as antibodies and antisera generally. Also claimed are novel antigenic conjugates and hybridoma cell lines used in the production of antibodies and antisera as aforesaid as well as assay kits comprising novel antisera, antibodies and/or labelled cyclosporins as aforesaid.

Monoclonal antibodies to cyclosporins

Cyclosporins wherein the amino acid residue at the 8-position is a (D)-acyloxy-.alpha.-amino acid residue, typically of formula ##STR1## wherein X=--MeBmt-- or --dihydro--MeBmt--, Y=--.alpha.Abu--, --Ala--, --Thr--, --Val-- or --Nva--, Z=--Val-- or --Nva-- and Q=R.sub.1 --CO--O--CH(R.sub.2)--CH(CO--)--NH-- wherein R.sub.1 =H, C.sub.1-4 alkyl or phenyl and R.sub.2 =H or CH.sub.3, possess immunosuppressive, anti-inflammatory and anti-parasitic activity.

Novel cyclosporins

Cyclosporins wherein the amino acid residue at the 8-position is a (D)-acyloxy-.alpha.-amino acid residue, typically of formula ##STR1## wherein X=-MeBmt- or -dihydro-MeBmt-, Y=-.alpha.Abu-, -Ala-, -Thr-, -Val- or -Nva-, Z=-Val- or -Nva- and Q=R.sub.1 --CO--O--CH(R.sub.2)--CH(CO--)--NH--wherein R.sub.1 =H, C.sub.1-4 alkyl or phenyl and R.sub.2 =H or CH.sub.3, possess immunosuppressive, anti-inflammatory and anti-parasitic activity.

A method for the total synthesis of cyclosporins, in particular Cyclosporin A, cyclosporins produced in accordance with the method of the invention and novel intermediates, in particular novel [1S, 2R, 3R]- and [1R, 2S, 3S]-1-nitrilo-1-carbonyl-3-methyl-2-oxy-heptanes and -hept-5-enes, employed in the method of the invention.

Growing community of inventors

Riehen, Switzerland

Roland M Wenger