G.d. Searle & Company

Daniel R Pilipauskas

Donald W Hansen, Jr

Michael John Clare

Barnett S Pitzele

Timothy J Hagen

E Ann Hallinan

Sofya Tsymbalov

Karen B Peterson

Srinivasan Babu

James R Behling

Robert W Hamilton

Robert H Mazur

Sean T Nugent

Kevin A Babiak

Donald E Korte

John R Medich

Payman N Farid

Kimberly J Cain-Janicki

Wendel W Doubleday

Mark L Boys

Vlasdislav Orlovski

Jung M Park

Glenn L Stahl

Kathleen T McLaughlin

Kathleen T Mc Laughlin

The present invention relates to a novel process for the preparation of ethyl 3S-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentyno ate and pharmaceutically acceptable acid addition salt thereof.

Process for the preparation of ethyl

The present invention relates to a novel process for the preparation of ethyl 3S-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentyno ate and pharmaceutically acceptable acid addition salt thereof which comprises treating (trimethylsilyl)acetylene sequentially with n-butyllithium and 4-formylmorpholine followed by acid hydrolysis to give 3-(trimethylsilyl)-2-propynal; treating 3-(trimethylsilyl)-2-propynal with lithium bis(trimethylsilyl)amide to give in situ N,3-bis(trimethylsilyl)-2-propyn-1-imine; condensation of N,3-bis(trimethylsilyl)-2-propyn-1-imine with lithium t-butyl acetate to give (.+-.)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate; treating (.+-.)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate- with p-toluenesulfonic acid to give (.+-.)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate, mono p-toluenesulfonic acid salt, treatment of resulting salt with ethanol in the presence of p-toluenesulfonic acid to give (.+-.)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate; desilylation of (.+-.)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate to give in situ (.+-.)ethyl 3-amino-4-pentynoate; resolution of (.+-.)ethyl 3-amino-4-pentynoate using (R)-(-)-mandelic acid and treatment of the resolved product with gaseous hydrochloric acid to give ethyl 3S-amino-4-pentynoate, monohydrochloride; coupling the ethyl 3S-amino-4-pentynoate, monohydrochloride to 4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid, monohydrochloride in the presence of isobutyl chloroformate and N-methylmorpholine to give ethyl 3S-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentyno ate, monohydrochloride.

This invention relates to compounds of the formula: ##STR1## and the pharmaceutically acceptable acid addition salts thereof wherein R.sup.1 is ##STR2## where X is oxygen or sulfur, Y is oxygen or nitrogen, and R.sup.11 represents straight or branched chain lower alkenyl having 2-6 carbon atoms, or phenyl, benzyl, and their equivalents such as nitro, halogen, or lower alkyl or lower alkoxy substituted phenyl or benzyl; wherein R.sup.2 and R.sup.3 may be the same or different and represent straight or branched chain lower alkyl having 1-6 carbon atoms, wherein R.sup.4 -R.sup.9 may be the same or different and represent hydrogen, or straight or branched chain lower alkyl having 1-6 carbon atoms; wherein C.sub.w is an asymmetric carbon atom when R.sup.7 and R.sup.8 are not the same and may be racemic or have the D or L configuration; and wherein C.sup.v is an asymmetric carbon atom and may be racemic or may have the D or L configuration. The compounds of this invention are useful because they possess analgesic activity in mammals.

O-substituted tyrosyl dipeptide amides

This invention relates to novel substituted tyrosyl alanine dipeptide amides of the formula: ##STR1## and the pharmaceutically acceptable addition salts thereof, wherein R.sup.1 is --OH, --OCH.sub.3 or lower alkoxy of 1-6 carbon atoms; wherein R.sup.2 and R.sup.3 may be the same or different and represent straight or branched chain lower alkyl of 1-6 carbon atoms; wherein R.sup.4, R.sup.5 R.sup.9 may be the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms; wherein R.sup.6 represents hydrogen, or straight or branched chain lower alkyl of 1-6 carbon atoms, or R.sup.6 may act together with N.sup.6, C.sup.w and either R.sup.7 R.sup.8 to form a cycloamine of the formula: ##STR2## such that between R.sup.7 and R.sup.8, when one acts to form said cycloamine, the other is hydrogen, or straight or branched chain lower alkyl of 1-6 carbon atoms; wherein when neither R.sup.7 nor R.sup.8 is acting to form said cycloamine, R.sup.7 R.sup.8 act together with C.sup.w to form a cycloalkyl of the formula: ##STR3## where n=3, 4, 5; wherein C.sup.w represents an asymmetric carbon atom when R.sup.7 and R.sup.8 are not the same and may be racemic or have the D or L configuration; and wherein C.sup.v represents an asymmetric carbon atom that may be racemic or that may hve the D or L configuration. These compounds are useful because they possess analgesic activity in mammals.

Substituted tyrosyl methionyl dipeptide amides

This invention encompasses compounds of the formula ##STR1## and the pharmaceutically acceptable acid addition salts thereof wherein R.sup.1 is lower alkoxy or --O--(CH.sub.2).sub.n -phenyl where the phenyl may be optionally substituted with halogen, --NO.sub.2, --CN, --NH.sub.2 or lower alkyl wherein n is 1 to 4; R.sup.2 and R.sup.3 represent lower alkyl, halogen, lower alkoxy or one of R.sup.2 or R.sup.3 is hydrogen and the other is lower alkyl, lower alkoxy, or halogen; R.sup.4, R.sup.5, R.sup.7, R.sup.8, and R.sup.9 represent hydrogen or lower alkyl, R.sup.6 represents hydrogen, lower alkyl, lower alkenyl, or --(CH.sub.2).sub.m -cycloalkyl wherein m is 1 to 4 and the cycloalkyl has 3 to 8 carbon atoms; R.sup.10 is --(CH.sub.2).sub.p -phenyl wherein p is 1 to 4; and v represents an asymmetric carbon that may be racemic or have the D or L Configuration; w represents an asymmetric carbon when R.sup.7 and R.sup.8 are not the same that may be racemic or have the D or L configuration. This invention also encompasses compounds where R.sup.1 is hydroxy, provided at least one of R.sup.4, R.sup.5, R.sup.6 or R.sup.9 is lower alkyl. The compounds of this invention are useful analgesic agents.

N-terminally substituted dipeptide amides

The invention relates to novel substituted tyrosyl alanine dipeptide amides of the formula: ##STR1## and the pharmaceutically acceptable acid addition salts thereof wherein R.sup.1 is hydrogen, lower alkyl, hydroxy, lower alkoxy, --O(CH.sub.2).sub.n phenyl with the phenyl optionally substituted by halogen, --NO.sub.2, --CN, --NH.sub.2 or lower alkyl wherein n is 1 to 4; R.sup.2 and R.sup.3 represent lower alkyl, halogen, or lower alkoxy, or either one of R.sup.2 or R.sup.3 is hydrogen and the other is lower alkyl, lower alkoxy or halogen; R.sup.4, R.sup.5, R.sup.6, and R.sup.9 may be the same or different and represent hydrogen, lower alkyl, cycloalkyl having 3 to 8 carbons, unsaturated lower alkyl, or --(CH.sub.2).sub.m cycloalkyl with the cycloalkyl having 3 to 8 carbons and m is 1 to 4; R.sup.10 is hydrogen or --(CH.sub.2).sub.p phenyl or with the phenyl optionally substituted with --NH.sub.2, --OH, halogen, --NO.sub.2, or lower alkyl or --(CH.sub.2).sub.p thienyl wherein p is 1 to 4; one of R.sup.7 or R.sup.8 is --(CH.sub.2).sub.f --S(O).sub.z --(CH.sub.2).sub.q --CH.sub.3 where f is 1 to 3 and q is 0 to 3, z is 0, 1 or 2 and the other is hydrogen or lower alkyl, or R.sup.7 and R.sup.8 together with carbon w is ##STR2## where x and y are independently 1 to 3 and z is 0, or 2. V represents an asymmetric carbon that may be recemic or have the D or L configuration; W represents an asymmetric carbon when R.sup.7 and R.sup.8 are not the same that may be recemic or have the D or L configuration. The compounds of this invention are useful as analgesic and/or antihypertensive agents.

Sulfide, sulfinyl and sulfone dipeptide amides

The invention relates to novel substituted tyrosyl alanine dipeptide amides of the formula: ##STR1## and the pharmaceutically acceptable acid addition salts thereof wherein R.sub.1 represents straight or branched lower alkyl having 1 to 4 carbons;

Substituted tyrosyl alanine dipeptide amides

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Glenview, IL, United States of America

Daniel R Pilipauskas