Merrell Toraude Et Compagnie

Richardson-merrell Inc.

Merrell Dow France Et Cie.

Merrell-toraude Et Cie

Marion Merrell Et Compagnie C/o Merrell Pharmaceuticals Inc.

Merrell Toruade Et Compagnie

Michel Jung

Philippe Bey

Brian W Metcalf

Fritz E Gerhart

Charles Danzin

Patrick Casara

Daniel Schirlin

Albert Sjoerdsma

Michael Kolb

.alpha.-Fluoromethyl- or .alpha.-difluoromethylornithine, and certain derivatives thereof, can be used alone or in combination with cytotoxic agents for the treatment of neoplastic diseases.

Method of controlling tumor growth rate

2-(Fluoromethyl or chloromethyl)-2,5-diaminopentanoic acid, 2-(fluoromethyl or chloromethyl)-2,6-diaminohexanoic acid, and 2-fluoromethyl-2-amino-5-guanidinopentanoic acid, and certain derivatives thereof, are inhibitors of ornithine decarboxylase. Methods of preparing the compounds and derivatives are also described.

2-Halomethyl derivatives of 2-amino acids

2-halomethyl derivatives of 2-amino acids

Novel halomethyl derivatives of .alpha.-amino acids of the following general structure: ##STR1## wherein Y is F.sub.2 CH--, F.sub.3 C--, Cl.sub.2 CH--; Z is .beta.-methylthioethyl, .beta.-thioethyl, .beta.-benzylthioethyl; S-(5'-desoxyadenosin-5'-yl)-S-methylthioethyl, .gamma.-guanidinopropyl, R.sub.a HN(CH.sub.2).sub.n -- wherein n is the integer 3 or 4 or ##STR2## wherein Y.sub.2 is F.sub.2 CH--, or F.sub.3 C--; each of R.sub.a and R.sub.b can be the same or different and is hydrogen, alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, alkoxycarbonyl wherein the alkoxy moiety has from 1 to 4 carbon atoms and is straight or branched, or ##STR3## wherein R.sub.2 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl; R.sub.1 is hydroxy, a straight or branched alkoxy group of from 1 to 8 carbon atoms, --NR.sub.4 R.sub.5 wherein each of R.sub.4 and R.sub.5 is hydrogen or a lower alkyl group of from 1 to 4 carbon atoms, or ##STR4## wherein R.sub.3 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl; and the lactams thereof when Z is R.sub.a HN(CH.sub.2).sub.n -- and each of R.sub.a and R.sub.b is hydrogen; with the provisos that when Z is .gamma.-guanidinopropyl or .beta.-methylthioethyl, Y is FCH.sub.2 --, F.sub.2 CH-- or F.sub.3 C--; when Z is .gamma.-guanidinopropyl, R.sub.1 is hydroxy; and when Z is .beta.-thioethyl, .beta.-benzylthioethyl, S-(5'-desoxyadenosin-5'-yl)-S-methylthioethyl or ##STR5## Y and Y.sub.2 are FCH.sub.2 --, F.sub.2 CH--, or F.sub.3 C-- and are the same, each of R.sub.a and R.sub.b is hydrogen and R.sub.1 is hydroxy; and pharmaceutically acceptable salts and individual optical isomers thereof.

.alpha.-Halomethyl derivatives of .alpha.-amino acids

A novel method of treating psoriasis which comprises administering a halomethyl derivative of .alpha.-amino acids of the following general structure: ##STR1## wherein Y is FCH.sub.2 --, F.sub.2 CH--, F.sub.3 C--, ClCH.sub.2 --, Cl.sub.2 CH--; Z is .gamma.-guanidinopropyl or R.sub.a HN(CH.sub.2).sub.n -- wherein n is the integer 3 or 4; each of R.sub.a and R.sub.b can be the same or different and is hydrogen, alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, alkoxycarbonyl wherein the alkoxy moiety has from 1 to 4 carbon atoms and is straight or branched, or ##STR2## wherein R.sub.2 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl; R.sub.1 is hydroxy; a straight or branched alkoxy group of from 1 to 8 carbon atoms, --NR.sub.4 R.sub.5 wherein each of R.sub.4 and R.sub.5 is hydrogen or a lower alkyl group of from 1 to 4 carbon atoms, or ##STR3## wherein R.sub.3 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl; and the lactams thereof when Z is R.sub.a HN(CH.sub.2).sub.n -- and each of R.sub.a and R.sub.b is hydrogen; with the proviso that when Z is .gamma.-guanidinopropyl Y is FCH.sub.2 --, F.sub.2 CH-- or F.sub.3 C-- and R.sub.1 is hydroxy; and pharmaceutically acceptable salts and individual optical isomers thereof.

Method of treating psoriasis

Fluorinated alkenylene diamine compounds are inhibitors of ornithine decarboxylase enzyme in vivo and have the following formula: ##STR1## wherein: R.sub.a represents hydrogen or R.sub.2, where R.sub.2 is as defined below;

Fluorinated pentene diamine derivatives

Novel halomethyl derivatives of .alpha.-amino acids of the following general structure: wherein Y is ClCH.sub.2, F.sub.2 CH--, F.sub.3 C--, ClCH.sub.2 --, Cl.sub.2 CH--; Z is .beta.-methylthioethyl, .beta.-thioethyl, .beta.-benzylthioethyl; S-(5'-desoxyadenosin-5'-yl)-S-methylthioethyl, .gamma.-guanidinopropyl, R.sub.a HN(CH.sub.2).sub.n -- wherein n is the integer 3 or 4 or ##STR1## wherein Y.sub.2 is F.sub.2 CH--, or F.sub.3 C--; each of R.sub.a and R.sub.b can be the same or different and is hydrogen, alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, alkoxycarbonyl wherein the alkoxy moiety has from 1 to 4 carbon atoms and is straight or branched, or ##STR2## wherein R.sub.2 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or .rho.-hydroxybenzyl; R.sub.1 is hydroxy, a straight or branched alkoxy group of from 1 to 8 carbon atoms, --NR.sub.4 R.sub.5 wherein each of R.sub.4 and R.sub.5 is hydrogen or a lower alkyl group of from 1 to 4 carbon atoms, or ##STR3## wherein R.sub.3 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or .rho.-hydroxybenzyl; and the lactams thereof when Z is R.sub.a HN(CH.sub.2).sub.n -- and each of R.sub.a and R.sub.b is hydrogen; with the provisos that when Z is .gamma.-guanidinopropyl or .beta.-methylthioethyl, Y is FCH.sub.2 --, F.sub.2 CH-- or F.sub.3 C--; when Z is .gamma.-guanidinopropyl, R.sub.1 is hydroxy; and when Z is .beta.-thioethyl, .beta.-benzylthioethyl, S-(5'-desoxyadenosin-5'-yl)-S-methylthioethyl ##STR4## Y and Y.sub.2 are FCH.sub.2 --, F.sub.2 CH--, or F.sub.3 C-- and are the same, each of R.sub.a and R.sub.b is hydrogen and R.sub.1 is hydroxy; and pharmaceutically acceptable salts and individual optical isomers thereof.

Fluorinated diaminobutane derivatives

Fluorinated aminobutyric acid and diaminobutane compounds in vivo are inhibitors of gamma-aminobutyric acid transaminase and have the following formula: ##STR1## wherein: Y represents hydrogen or fluorine;

Fluorinated amino-butyric acid and diaminobutane derivatives

This invention relates to 2-(difluoromethyl)-2,5-diaminopentanoic acid, or a pharmaceutically acceptable acid addition salt thereof, and to the methods for the preparation and use thereof.

2-(Difluoromethyl)-2,5-diaminopentanoic acid

Novel halomethyl derivatives of amino acids of the following general structure ##STR1## wherein Y is FCH.sub.2 --, F.sub.2 CH.sub.2 --, F.sub.3 C--, ClCH.sub.2 -- or Cl.sub.2 CH--; R.sub.1 is hydroxy, a straight or branched alkoxy group of from 1 to 8 carbon atoms, --NR.sub.11 R.sub.12 wherein each of R.sub.11 and R.sub.12 is hydrogen or a straight or branched lower alkyl group of from 1 to 4 carbon atoms, ##STR2## wherein R.sub.5 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl; R.sub.2 is hydrogen, alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, alkoxycarbonyl wherein the alkoxy moiety has from 1 to 4 carbon atoms and is straight or branched or ##STR3## wherein R.sub.6 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl; each of R.sub.3 and R.sub.4 is hydrogen, halogen selected from fluorine, chlorine, bromine and iodine, or a straight or branched lower alkyl of from 1 to 4 carbon atoms and may be the same or different with the proviso that when both R.sub.3 and R.sub.4 are halogen R.sub.3 and R.sub.4 are the same; and pharmaceutically acceptable salts thereof.

.alpha.-Halomethyl derivatives of amino acids

Novel compounds of the following general Formula I are useful pharmacological agents: ##STR1## wherein: Ado represents 5'-deoxyadenosin-5'-yl;

Substituted deoxyadenosine derivatives

2-Amino-2-fluoromethyl-3-(substituted)phenyl propionic acids and derivatives thereof are coadministered with dopamine for the treatment of schizophrenia, mania, tardive dyskinesia, anxiety, or depression.

Method of depleting endogenous monoamines

There is described a method for treating benign prostatic hypertrophy comprising the administration of 2,5-di-amino-2-(mono-,di-, or trifluoromethyl)pentanoic acid or derivative thereof.

Method of treating benign prostatic hypertrophy

Novel compounds of the following general formula are useful pharmacological agents: ##STR1## wherein Y is FCH.sub.2 - or F.sub.2 CH-; R.sub.1 is hydroxy, a straight or branched alkoxy group of from 1 to 8 carbon atoms, -NR.sub.10 R.sub.11 wherein each of R.sub.10 and R.sub.11 is hydrogen or a straight or branched alkyl group of from 1 to 4 carbon atoms or ##STR2## wherein R.sub.12 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl; R.sub.2 is hydrogen, alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, alkoxycarbonyl wherein the alkoxy moiety has from 1 to 4 carbon atoms and is straight or branched or ##STR3## wherein R.sub.8 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl; and n is the integer 2 or 3; pharmaceutically acceptable salts and individual optical isomers thereof.

Growing community of inventors

Illkirch Graffenstaden, France

Michel Jung