Sri International

Syntex (u.s.a.) Inc.

Astraea Therapeutics, LLC

Japan Tobacco Inc.

Roche Palo Alto LLC

F. Hoffmann-La Roche Ag

Dennis Mitsugu Yasuda

Counde O'Yang

Masato Tanabe

Paul Francis Keitz

Richard Leo Cournoyer

Alexander Victor Muehldorf

Mitchell A Avery

John G Johansson

Lee Edwin Lowrie, Jr

Wan-Ru Chao

Nurulain Zaveri

Wesley K Chong

John A Lawson

George Detre

Anjali Pandey

The present invention provides novel piperidinyl-containing nociceptin receptor ligand compounds and pharmaceutical compositions useful in the treatment of neurological diseases and conditions where such ligands mediate the negative effects of the condition. Such neurological diseases and conditions include acute and chronic pain, substance abuse/dependence, alcohol addiction, anxiety, depression, sleep disorders, gastrointestinal disorders, renal disorders, cardiovascular disorders and Parkinson's disease.

Piperidinyl nociceptin receptor compounds

Piperdinyl nociceptin receptor compounds

This invention relates to compounds which are generally IP receptor antagonists and which are represented by Formula I: wherein:

Carboxylic acid derivatives as IP antagonists

The present invention concerns novel compounds represented by the Formula: ##STR1## wherein: A is R.sup.1.sub.q (R.sup.3 R.sup.60 N).sub.m (Z)(NR.sup.2).sub.n ; m and q are each 0 or 1, with the proviso that when q is 1, m is 0 and when q is 0, m is 1; Z is C.dbd.O or SO.sub.2 ; n is 1 with the proviso that, when Z is C.dbd.O, m is 1; X is --NH--, --CH.sub.2 --, or --OCH.sub.2 --; Y is [2-imidazoline, 2-oxazolin] 2-thiazoline, [or 4-imidazole] R.sup.1 is H, lower alkyl, or phenyl, with the proviso that, when R.sup.1 is H, m is 1; R.sup.2, R.sup.3, R.sup.60 are each independently H, lower alkyl, or phenyl; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are each independently hydrogen, lower alkyl, --CF.sub.3, lower alkoxy, halogen, phenyl, lower alkeny, hydroxyl, lower alkylsulfonamido, or lower cycloalkyl, wherein R.sup.2 and R.sup.7 optionally may be taken together to form alkylene or alkenylene of 2 to 3 atoms in an unsubstituted or optionally substituted 5- or 6-membered ring, wherein the optional substituents on the ring are halo, lower alkyl, or --CN, with the proviso that, when R.sup.7 is hydroxyl or lower alkylsulfonamido, then X is not --NH-- when Y is 2-imidazoline. The compounds include pharmaceutically acceptable salts of the above. In the above formula A may be, for example, (R.sup.1 SO.sub.2 NR.sup.2 --), (R.sup.3 R.sup.60 NSO.sub.2 NR.sup.2 --), or (R.sup.3 R.sup.60 NCONR.sup.2 --). The invention also includes the use of the above compounds, and compositions containing them, as alpha.sub.1A/1L agonists in the treatment of various disease states such as urinary incontinence, nasal congestion, priapism, depression, anxiety, dementia, senility, Alzheimer's, deficiencies in attentiveness and cognition, and eating disorders such as obesity, bulimia, and anorexia.

2-imidazoline, 2-oxazoline, 2-thiazoline, and 4-imidazole derivatives of

The present invention concerns novel compounds represented by the Formula: ##STR1## wherein: A is R.sup.1.sub.q (R.sup.3 R.sup.60 N).sub.m (Z)(NR.sup.2).sub.n ; m and q are each 0 or 1, with the proviso that when q is 1, m is 0 and when q is 0, m is 1; Z is C.dbd.O or SO.sub.2 ; n is 1 with the proviso that, when Z is C.dbd.O, m is 1; X is --NH--, --CH.sub.2 --, or --OCH.sub.2 --; Y is 2-imidazoline, 2-oxazoline, 2-thiazoline, or 4-imidazole; R.sup.1 is H, lower alkyl, or phenyl, with the proviso that, when R.sup.1 is H, m is 1; R.sup.2, R.sup.3, R.sup.60 are each independently H, lower alkyl, or phenyl; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are each independently hydrogen, lower alkyl, --CF.sub.3, lower alkoxy, halogen, phenyl, lower alkeny, hydroxyl, lower alkylsulfonamido, or lower cycloalkyl, wherein R.sup.2 and R.sup.7 optionally may be taken together to form alkylene or alkenylene of 2 to 3 atoms in an unsubstituted or optionally substituted 5- or 6-membered ring, wherein the optional substituents on the ring are halo, lower alkyl, or --CN, with the proviso that, when R.sup.7 is hydroxyl or lower alkylsulfonamido, then X is not --NH-- when Y is 2-imidazoline. The compounds include pharmaceutically acceptable salts of the above. In the above formula A may be, for example, (R.sup.1 SO.sub.2 NR.sup.2 --), (R.sup.3 R.sup.60 NSO.sub.2 NR.sup.2 --), or (R.sup.3 R.sup.60 NCONR.sup.2 --). The invention also includes the use of the above compounds, and compositions containing them, as alpha.sub.1A/1L agonists in the treatment of various disease states such as urinary incontinence, nasal congestion, priapism, depression, anxiety, dementia, senility, Alzheimer's, deficiencies in attentiveness and cognition, and eating disorders such as obesity, bulimia, and anorexia.

Novel antihypercholesterolemic agents are provided. An exemplary group of compounds has the structural formula (I) ##STR1## wherein R is a C-17 side chain, R.sup.1 is --OH, .dbd.O, or the like, and X and Y are CH, C--OH, C--OCH.sub.3 or C--Z. Methods of using the compound of formula (I) or other novel oxysterol analogs to treat hypercholesterolemia are provided, as are pharmaceutical compositions containing the compounds.

Antihypercholesterolemic compounds and related pharmaceutical

Novel antihypercholesterolemic agents are provided. An exemplary group of compounds has the structural formula (I) ##STR1## wherein R is a C-17 side chain, R.sup.1 is --OH, .dbd.O, or the like, and X and Y are N, N.fwdarw.O, CH, C--OH, C--OCH.sub.3 or C--Z. Methods of using the compound of formula (I) or other novel oxysterol analogs to treat hypercholesterolemia are provided, as are pharmaceutical compositions containing the compounds.

A method is provided for isolating 5,7-diene-containing steroids, particularly 3.beta.-ols and esters of 3.beta.-ols, from a sterol mixture. The method involves (1) treating the mixture with a dienophile or with an oxidizable dienophile precursor in combination with an oxidizing agent so as to provide a Diels-Alder adduct of the 5,7-diene to be isolated, followed by (2) removal of the adduct from the mixture and (3) regeneration of the 5,7-diene with a suitable reducing agent. The invention also encompasses subsequent purification steps and intermediate modification of the Diels-Alder intermediate, e.g., wherein chemical conversion of the Diels-Alder adduct is effected prior to regeneration of the 5,7-diene. Novel compounds which are Diels-Alder adducts of 5,7-diene-containing steroids are provided as well.

Isolation of steroids containing a 5,7-diene functionality from a sterol

Compounds of formula I ##STR1## wherein X is ##STR2## or .dbd.N--O--, in which R.sub.4 is hydrogen or halogen, R.sub.1, R.sub.2, and R.sub.3 independently represent hydrogen or a C.sub.1-4 alkyl group, and n has a value of zero to four are disclosed. Also disclosed are pharmaceutically acceptable salts of these compounds, pharmaceutical compositions of these compounds or salts with a pharmaceutically acceptable carrier, the use of these materials as N-methyl-D-aspartate receptor antagonists, processes for preparing these compounds and salts, and methods to treat cerebral diseases by administering an effective amount of these compounds, salts or compositions.

2-piperidinecarboxylic acid derivatives useful as NMDA receptor

Introduction of a C-12 substituent and especially a .beta. C-12 substituent into glucocorticoids improves their usefulness as topical antiinflammatories by increasing their topical activity relative to their systemic activity, thus reducing systemic side effects such as adrenal suppression.

Growing community of inventors

Campbell, CA, United States of America

Dennis Mitsugu Yasuda