Janssen Pharmaceutica Nv

Polyphor Ag

Takeda Pharmaceutical Company Limited

Philipp Ermert

Daniel Obrecht

Anatol Luther

Lieven Meerpoel

Gustaaf Maria Boeckx

Christophe Francis Robert Nestor Buyck

Jean-Pierre André Marc Bongartz

Guy Rosalia Eugeen Van Lommen

Said Oumouch

Kerstin Möhle

Karsten Marx

Franck Lach

Pierre-Henri Storck

Virginie Sophie Poncelet

Bruno Schoentjes

Martin Eberle

Felix Bachmann

Marc Thommen

Alessandro Strebel

Imre Christian Francis Csoka

Jean-François Gosalbes

Arnaud Piettre

Arnaud Marcel Pierre Piettre

Frank Lach

Allessandro Strebel

Jean-Pierre Andre Marc Bongartz

Jean-Francois Gosalbes

Arnaud Marcel Piettre

Kerstin Mohle

Imre Christian Csoka

The conformationally restricted, spatially defined macrocyclic ring system of formula (I) is constituted by three distinct molecular parts: Template A, conformation Modulator B and Bridge C. Macrocycles described by this ring system I are readily manufactured by parallel synthesis or combinatorial chemistry in solution or on solid phase. They are designed to interact with a variety of specific biological target classes, examples being agonistic or antagonistic activity on G-protein coupled receptors (GPCRs), inhibitory activity on enzymes or antimicrobial activity. In particular, these macrocycles show inhibitory activity on endothelin converting enzyme of subtype 1 (ECE-1) and/or the cysteine protease cathepsin S (CatS), and/or act as antagonists of the oxytocin (OT) receptor, thyrotropin-releasing hormone (TRH) receptor and/or leukotriene B4 (LTB4) receptor, and/or as agonists of the bombesin 3 (BB3) receptor, and/or show antimicrobial activity against at least one bacterial strain. Thus they are showing great potential as medicaments for a variety of diseases. 

Conformationally constrained, fully synthetic macrocyclic compounds

Conformationally restricted, spatially defined 12-30 membered macrocyclic ring systems of type (I) are constituted by three distinct building blocks: an aromatic template a, a conformation modulator b and a spacer moiety c as detailed in the description and the claims. Macrocycles of type (I) are readily manufactured by parallel synthesis or combinatorial chemistry. They are designed to interact with specific biological targets. In particular, they show agonistic or antagonistic activity on the motilin receptor (MR receptor), on the serotonin receptor of subtype 5-HT(5-HTreceptor), and on the prostaglandin F2&#x2022;receptor (FP receptor). They are thus potentially useful for the treatment of hypomotility disorders of the gastrointestinal tract such as diabetic gastroparesis and constipation type irritable bowl syndrome; of CNS related diseases like migraine, schizophrenia, psychosis or depression; of ocular hypertension such as associated with glaucoma and preterm labour. 

The invention further relates to a DGAT inhibitor of formula including any stereochemically isomeric form thereof, wherein A represents CH or N; the dotted line represents an optional bond in case A represents a carbon atom; X represents &#x2014;NR&#x2014;C(&#x2550;O)&#x2014;; &#x2014;Z&#x2014;C(&#x2550;O)&#x2014;; &#x2014;Z&#x2014;NR&#x2014;C(&#x2550;O)&#x2014;; &#x2014;S(&#x2550;O)p-; &#x2014;C(&#x2550;S)&#x2014;; &#x2014;NR&#x2014;C(&#x2550;S)&#x2014;; &#x2014;Z&#x2014;C(&#x2550;S)&#x2014;; &#x2014;Z&#x2014;NR&#x2014;C(&#x2550;S)&#x2014;; &#x2014;O&#x2014;C(&#x2550;O)&#x2014;; &#x2014;C(&#x2550;O)&#x2014;C(&#x2550;O)&#x2014;; Rrepresents a 5-membered monocyclic heterocycle containing at least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle; or a 5-membered heterocycle containing at least 2 heteroatoms fused with phenyl, cyclohexyl or a 5- or 6-membered heterocycle; wherein each of said heterocycles may optionally be substituted; Rrepresents R; Rrepresents Ccycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said Ccycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle may optionally be substituted; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use as a medicine of said compounds.

Piperidine/piperazine derivatives

Conformationally restricted, spatially defined 12-30 membered macrocyclic ring systems of formulae Ia and Ib are constituted by three distinct molecular parts: Template A, conformation Modulator B and Bridge C. These macrocycles Ia and Ib are readily manufactured by parallel synthesis or combinatorial chemistry in solution or on solid phase. They are designed to interact with a variety of specific biological target classes, examples being the agonistic or antagonistic activity on G-protein coupled receptors (GPCRs), ion channels and signal transduction pathways. In particular, these macrocycles act as antagonists of the motilin receptor, the FP receptor and the purinergic receptors P2Y, as modulators of the serotonin receptor of subtype 5-HT, as blockers of the voltage-gated potassium channel K1.3 and as inhibitors of the &#x3b2;-catenin-dependent 'canonical' Wnt pathway. Thus they are showing great potential as medicaments for a variety of diseases. 

The invention further relates to a DGAT inhibitor of formula including any stereochemically isomeric form thereof, wherein A represents CH or N; X represents &#x2014;NR&#x2014;C(&#x2550;O)&#x2014;; &#x2014;Z&#x2014;C(&#x2550;O)&#x2014;; &#x2014;Z&#x2014;NR&#x2014;C(&#x2550;O)&#x2014;; &#x2014;S(&#x2550;O)p-; &#x2014;C(&#x2550;S)&#x2014;; &#x2014;NR&#x2014;C(&#x2550;S)&#x2014;; &#x2014;Z&#x2014;C(&#x2550;S)&#x2014;; &#x2014;Z&#x2014;NR&#x2014;C(&#x2550;S)&#x2014;; &#x2014;O&#x2014;C(&#x2550;O)&#x2014;; &#x2014;C(&#x2550;O)&#x2014;C(&#x2550;O)&#x2014;; Rrepresents a 5-membered monocyclic heterocycle containing at least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle; or a 5-membered heterocycle containing at least 2 heteroatoms fused with phenyl, cyclohexyl or a 5- or 6-membered heterocycle; wherein each of said heterocycles may optionally be substituted; Rrepresents R; Rrepresents Ccycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said Ccycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzo-dioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle may optionally be substituted; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use as a medicine of said compounds.

The invention further relates to a DGAT inhibitor of formula (I), including any stereochemically isomeric form thereof, wherein A represents CH or N; the dotted line represents an optional bond in case A represents a carbon atom; X represents &#x2014;NR&#x2014;C(&#x2550;O)&#x2014;; &#x2014;Z&#x2014;C(&#x2550;O)&#x2014;; &#x2014;Z&#x2014;NR&#x2014;C(&#x2550;O)&#x2014;; &#x2014;S(&#x2550;O)p&#x2014;; C(&#x2550;S)&#x2014;; &#x2014;NR&#x2014;C(&#x2550;S)&#x2014;; &#x2014;Z&#x2014;C(&#x2550;S)&#x2014;; &#x2014;Z&#x2014;NR&#x2014;C(&#x2550;S)&#x2014;; &#x2014;O&#x2014;C(&#x2550;O)&#x2014;; &#x2014;C(&#x2550;O)&#x2014;C(&#x2550;O)&#x2014;; Rrepresents a 5-membered monocyclic heterocycle containing at least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle; or a 5-membered heterocycle containing at least 2 heteroatoms fused with phenyl, cyclohexyl or a 5-or 6-membered heterocycle; wherein each of said heterocycles may optionally be substituted; Rrepresents R; Rrepresents Ccycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxlyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said Ccycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzo-dioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle may optionally be substituted; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use as a medicine of said compounds. 

The present invention provides compounds of formula (I), their use as an inhibitor of a p53-MDM2 interaction as well as pharmaceutical compositions comprising said compounds: wherein n, s, t, R, R, R, R, R, X, Y, Q, Z, G, E and D have defined meanings.

Inhibitors of the interaction between MDM2 and p53

The invention relates to compounds of formula (I) wherein Rrepresents aryl, aralkyl or heteroaryl, Ris aryl or heteroaryl and Ris aryl, heteroaryl or optionally substituted aminomethyl, to methods of synthesis of such compounds, to pharmaceutical compositions containing compounds of formula (I), to the use of a compounds of formula (I) for the preparation of a pharmaceutical composition for the treatment of neoplastic and autoimmune diseases, and to methods of treatment of neoplastic and autoimmune diseases using compounds of formula (I) or of pharmaceutical compositions containing same.

Sulfopyrroles

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Allschwil, Switzerland

Philipp Ermert