Merck + Co., Inc.

Merck Sharp + Dohme Corp.

Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa

Instituto Di Ricerche Di Biologia Molecolare P. Angeletti S.p.a.

Msd Italia S.r.l.

Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.r.l.

Philippe L Durette

William K Hagmann

Malcolm MacCoss

Soumya P Sahoo

Sander G Mills

Ihor E Kopka

Thomas J Lanza, Jr

Timothy Francis Gallagher

Tsung-Ying Shen

Shrenik K Shah

Bruce E Witzel

Kathleen M Rupprecht

Charles G Caldwell

Craig K Esser

Richard L Tolman

Conrad P Dorn

Gary H Rasmusson

Mitree M Ponpipom

Arsenio A Pessolano

Paul E Finke

James B Doherty

Robert K Baker

Richard A Mumford

Derek J Von Langen

Allan N Tischler

Jeffrey John Hale

Ravindra N Guthikonda

Malcolm Maccoss

Kevin Tyler Chapman

Frank Narjes

Cristina Gardelli

Debra L Allison

Marvin M Goldenberg

Scott A Polo

William F Hoffman

Donald W Graham

Joshua S Boger

Ping Chen

Thomas R Beattie

Janos Kollonitsch

Robert L Bugianesi

Shu S Yang

Laura C Meurer

Nathan G Steinberg

Joung L Goulet

Francis J Dumont

Kothandaraman Shankaran

Barbara Pacini

Monica Donghi

Kenny Kin Wong

Albert J Robichaud

Edward Holson

Richard T Dean

Robert A Frankshun

Barbara Attenni

Nolan H Sigal

Jack A Schmidt

Stephan K Grant

Malte Meppen

Renee Chabin

Gail A Van Riper

Howard M Katzen

Plato A Magriotis

The present invention provides nucleoside cyclic phosphoramidates of formula (I), pharmaceutical compositions comprising the compounds of formula (I) and methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection using the compounds of formula (I). 

Nucleoside cyclic phosphoramidates for the treatment of RNA-dependent RNA viral infection

The present invention provides nucleoside aryl phosphoramidates of structural formula (I) which are precursors to inhibitors of RNA-dependent RNA viral polymerase. These compounds are precursors to inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as precursors to inhibitors of hepatitis C virus (HCV) NS5B polymerase, as precursors to inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside aryl phosphoramidates alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside aryl phosphoramidates of the present invention. (I) 

Nucleoside aryl phosphoramidates for the treatment of RNA-dependent RNA viral infection

Compounds of Formula I are antagonists of VLA-4 and/or &#x3b1;&#x3b2;, and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of asthma, allergies, inflammation, multiple sclerosis, and other inflammatory and autoimmune disorders.

Heterocyclic amide compounds as cell adhesion inhibitors

&bgr;-Alanine derivatives of Formula I are antagonists of VLA-4 and/or &agr; &bgr; , and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of asthma, allergies, inflammation, multiple sclerosis, and other inflammatory and autoimmune disorders.

Substituted &bgr;-alanine derivatives as cell adhesion inhibitors

Compounds of Formula I are antagonists of VLA-4 and/or &agr;,&bgr;,, and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of asthma, allergies, inflammation, multiple sclerosis, and other inflammatory and autoimmune disorders.

Biarylalkanoic acids as cell adhesion inhibitors

Sulfonamides as cell adhesion inhibitors

16-substituted-4-aza-androstane 5-&agr;-reductase isozyme 1 inhibitors

Novel N-carboxyalkylpeptidyl compounds represented by the formula ##STR1## which are found to be useful inhibitors of matrix metalloendoproteinases which degrade major components of articular cartilage and basement membranes causing degenerative diseases such as arthritis, periodontal disease, corneal ulceration and the like, and certain cancers, are described.

Substituted N-carboxyalkylpeptidyl derivatives as antidegenerative agents

Substituted 2-aminopyridines as inhibitors of nitric oxide synthase

New substituted azetidinones of the general Formula (I) which have been found to be potent elastase inhibitors and thereby useful anti-inflammatory and antidegenerative agents are described, wherein n is

Substituted azetidinones as anti-inflammatory and antidegenerative agents

Novel N-carboxyalkylpeptidyl compounds of formula I are found to be useful inhibitors of matrix metalloendoproteinase-mediated diseases including osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion in certain cancers, periodontal disease, corneal ulceration, proteinuria, dystrophobic epidermolysis bullosa, and coronary thrombosis associated with atherosclerotic plaque rupture. The matrix metalloendoproteinases are a family of zinc-containing proteinases including but not limited to stromelysin, collagenase, and gelatinase, that are capable of degrading the major components of articular cartilage and basement membranes. The inhibitors claimed herein may also be useful in preventing the pathological sequelae following a traumatic injury that could lead to a permanent disability. These compounds may also have utility as a means for birth control by preventing ovulation or implantation. ##STR1##

Substituted N-carboxyalkylpeptidyl derivatives as antidegenerative

The present invention is directed to certain novel compounds represented by structural formula I: ##STR1## or a pharmaceutically acceptable salt thereof, wherein R.sup.3, R.sup.6, R.sup.7, R.sup.8, R.sup.11, R.sup.12, R.sup.13, A, m, n and the dashed lines are defined herein. The invention is also concerned with pharmaceutical formulations comprising these novel compounds as active ingredients and the use of the novel compounds and their formulations in the treatment of certain disorders. The compounds of this invention are tachykinin receptor antagonists and are useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis.

Heteroaryl spiroethercycloalkyl tachykinin receptor antagonists

Compounds of the Formula I ##STR1## are inhibitors of the 5.alpha.-reductase 1 isozyme, and are useful alone, or in combination with a 5.alpha.-reductase 2 inhibitor, for the treatment of androgenic sensitive disorders such as acne vulgaris, seborrhea, female hirsutism, male pattern baldness, and benign prostatic hyperplasia.

16-pyrazinyl-substituted-4-aza-androstane 5-.alpha.-reductase isozyme 1

Substituted 2-acylamino-pyridines as inhibitors of nitric oxide synthase

Disclosed herein are compounds of Formula (I) ##STR1## and pharmaceutically acceptable salts thereof which have been found useful in the treatment of nitric oxide synthase mediated diseases and disorders, including neurodegenerative disorders, disorders of gastrointestinal motility and inflammation. These disease and disorders include hypotension, septic shock, toxic shock syndrom, hemodialysis, IL-2 therapy such as in cancer patients, cachexia, immnunosuppression such as in transplant therapy, autoimmune and/or inflammatory indications including sunburn or psoriasis and respiratory conditions such as bronchitis, asthma, and acure respiratory distress (ARDS), myocarditis, heart failure, atherosclerosis, arthritis, rheumatoid arthritis, chronic or inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE), ocular conditions such as ocular hypertension and uveitis, type 1 diabetes, insulin-dependent diabetes mellitus and cystic fibrosis. Compounds of Formula I are also useful in the treatment of hypoxia, hyperbaric oxygen convulsions and toxicity, dementia, Sydenham's chorea, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Korsakoffs disease, imbecility related to cerebral vessel disorder, ischemic brain edema, sleeping disorders, schizophrenia, depression, PMS, anxiety, drug addiction, pain, migraine, immune complex disease, as immunosupressive agents and for preventing or reversing tolerance to opiates and diazepines.

Substituted saturated aza heterocycles as inhibitors of nitric oxide

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New Providence, NJ, United States of America

Philippe L Durette