Merck + Co., Inc.

Synaptic Pharmaceutical Corporation

Ben E Evans

Mark G Bock

Roger M Freidinger

Paul S Anderson

Kevin F Gilbert

Kenneth E Rittle

Peter D Williams

Marcia E Christy

Douglas J Pettibone

David C Remy

Joshua S Boger

Doug W Hobbs

Daniel F Veber

Dhanapalan Nagarathnam

Jacob M Hoffman

Bharat Lagu

Kanyin E Zhang

Kamlesh P Vyas

J Christopher Culberson

Hanumath P Kari

Donghui Cui

Michael Dunn

Margaret R Davis

George D Hartman

Gerald S Ponticello

Raymond S Chang

Steven M Pitzenberger

Robert M DiPardo

Joseph M Pawluczyk

George F Lundell

Roger M Friedinger

James B Hoffman

Douglas W Hobbs

This invention is directed to dihydropyrimidines which are selective antagonists for human &agr; receptors. This invention is also related to uses of these compounds for relaxing lower urinary tract tissue, treating benign prostatic hyperplasia and for the treatment of any disease where the antagonism of the &agr; receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

Dihydropyrimidines and uses thereof

Spirotricyclic azacycloalkyl compounds and pharmaceutically acceptable salts thereof are disclosed. The synthesis of these compounds is also described. One application of these compounds, which are alpha 1a adrenergic receptor antagonists, is in the treatment of benign prostatic hyperplasia. These compounds are selective in their ability to relax smooth muscle tissue enriched in the alpha 1a receptor subtype without at the same time inducing hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia can be achieved.

Spirotricyclic substituted azacycloalkane derivatives and uses thereof

Lactam and cyclic urea derivatives and their pharmaceutically acceptable salts are disclosed. The synthesis of these compounds and their use as alpha 1,adrenergic receptor antagonists is also described. One application of these compounds is in the treatment of benign prostatic hyperplasia. These compounds are typically selective in their ability to relax smooth muscle tissue enriched in the alpha 1,receptor subtype without at the same time inducing hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia can be achieved.

Lactam and cyclic urea derivatives useful as alpha 1a adrenoceptor antagonists

This invention is directed to dihydropyrimidines which are selective antagonists for human &agr;,receptors. This invention is also related to uses of these compounds for relaxing lower urinary tract tissue, treating benign prostatic hyperplasia and for the treatment of any disease where the antagonism of the &agr;,receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

Alpha 1a adrenergic receptor antagonists

Tocolytic oxytocin receptor antagonists

Hydantoin and succinimide-substituted derivatives of

Compounds of the formula ##STR1## X is --O--, --NH-- and --NR.sup.8 --; Y is --CH.sub.2 --, --CHR.sup.8 -- and --C(R.sup.8).sub.2 --; R.sup.1 is camphor-10-yl, C.sub.1-5 alkoxyl, styryl, hydroxystyryl, furyl, unsubstituted or substituted thienyl, naphthyl, indolyl, tetrahydronaphthyl, unsubstituted, mono- or di-substituted pyridyl, pyrazinyl, unsubstituted or substituted cyclohexyl where the substituent is R.sup.4, and unsubstituted or substituted phenyl where the substituents on phenyl are R.sup.5, R.sup.6 and R.sup.7 ; R.sup.2 is hydrogen, C.sub.1-5 alkoxy, C.sub.1-5 alkyl, amino, C.sub.1-5 alkylcarbonylamino, nitro or halogen; R.sup.3 is hydrogen, C.sub.1-5 alkoxycarbonyl, cyano or carbamoyl; R.sup.4 is one to two of hydrogen, oxo, hydroxy, C.sub.1-5 alkoxy, C.sub.1-5 alkoxycarbonylamino-C.sub.1-5 alkyl and amino-C.sub.1-5 alkyl; R.sup.5, R.sup.6 are each independently selected from hydrogen, halogen, C.sub.1-5 alkyl, hydroxyl and C.sub.1-5 alkoxy; R.sup.7 is ##STR2## W is CO or SO.sub.2 ; and m is an integer from 0 to 1. Such compounds as useful as oxytocin and vasopressin receptor antagonists.

Benzoxazinone and benzopyrimidinone piperidinyl tocolytic oxytocin

Compounds of the formula X--Y--R, or the pharmaceutically acceptable salts and esters thereof, wherein X is ##STR1## Y is --SO.sub.2 --, --(CH.sub.2).sub.p -- or --CO--(CH.sub.2).sub.p --; R is unsubstituted or substituted phenyl where said substitutents are one or more of R.sup.5, R.sup.6 or R.sup.7 ; R.sup.1 is hydrogen, cyano, phenyl,--CONHR.sup.2, --CONR.sup.2 R.sup.2, --(CH.sub.2).sub.m --OR.sup.2, --(CH.sub.2).sub.p --S(O).sub.r --R.sup.2, --(CH.sub.2).sub.m --CO.sub.2 R.sup.2, --(CH.sub.2).sub.m --N.sub.3, --(CH.sub.2).sub.m --NH.sub.2 or --(CH.sub.2).sub.m --NR.sup.2 R.sup.2 ; R.sup.2 is hydrogen, C.sub.3-8 cycloalkyl or C.sub.1-5 alkyl; R.sup.5 and R.sup.6 are each independently selected from hydrogen, C.sub.1-5 alkoxy, halogen or --(CH.sub.2).sub.n --N(R.sup.2)--C(O)--R.sup.18 ; R.sup.7 is hydrogen or ##STR2## R.sup.11 is selected from hydrogen, C.sub.1-5 alkylcarbonyl, ##STR3## or substituted C.sub.1-5 alkyl wherein said alkyl substituent is unsubstituted, mono-, di- or tri-substituted pyridyl wherein said substitutents on said pyridyl are independently selected from halogen, C.sub.1-5 alkyl or C.sub.1-5 alkoxyl; R.sup.13 is unsubstituted or substituted C.sub.1-10 alkyl wherein the substituent is selected from --N(R.sup.2).sub.2, --NHR.sup.2 or imidazolyl; R.sup.14 and R.sup.15 are each independently selected from C.sub.1-5 alkyl, C.sub.1-5 alkoxy or halogen; R.sup.16 is hydrogen or oxo; R.sup.18 is C.sub.1-5 alkoxyl, unsubstituted or substituted C.sub.1-5 alkyl where said substituent is Het, unsubstituted or substituted C.sub.2-5 alkenyl where said subsituent is Het or Het; Het is benzimidazolyl, carboxymethyl-substituted benzimidazolyl or indolyl; m is an integer of from 1 to 5; p is an integer of from 1 to 3; and r is an integer of from 0 to 2. Such compounds as useful as oxytocin and vasopressin receptor antagonists.

Benzodiazepine analogs of the formula: ##STR1## wherein: R.sup.3 is ##STR2## --NH(CH.sub.2).sub.2 --.sub.3 NHCOR.sup.7, ##STR3## or --X.sup.11 NR.sup.18 SO.sub.2 (CH.sub.2).sub.q R.sup.7 ; R.sup.7 is O,S,HH, or NR.sup.15 with the proviso that X.sup.7 can be NR.sup.15 only when R.sup.1 is not H. are disclosed which are antagonists of gastrin and cholecystokinin (CCK) with enhanced aqueous solubility and have properties useful in the treatment of disorders of gastric secretion, appetite regulation, gastrointestinal motility, pancreatic secretion, and dopaminergic function, as well as in treatment producing potentiation of morphine and other opiate analgesics.

Benzodiazepine analogs

This invention relates to certain .beta.-carbolines, which are antagonists of the functions of cholecystokinin (CCK) and gastrin, to pharmaceutical compositions comprising these compounds, and to the use of these compounds in the prevention and treatment of disorders of the gastrointestinal, central nervous and appetite-regulatory systems of mammals, especially of humans.

.beta.-carbolines as cholecystokinin and gastrin antagonists

Pharmaceutical compositions containing aromatic 2-benzazepines with fused 5- or 6-membered heterocyclic rings are disclosed which are useful in the treatment of panic disorder or anxiety disorder.

2-benzazepines with 5- and 6-membered heterocyclic rings to treat pain

Pharmaceutical compositions containing benzodiazepines of the formula: ##STR1## are disclosed which are useful in the treatment of panic disorder or anxiety disorder.

Benzolactam analogs of the formula: ##STR1## are disclosed which are antagonists of gastrin and cholecystokinin (CCK).

Benzolactam analogs as antagonists of CCK

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Lansdale, PA, United States of America

Ben E Evans