Hoechst Aktiengesellschaft

Ulrich Lerch

Wilhelm Bartmann

Gerhard Beck

Rainer Henning

Milos Babej

Bernward Scholkens

Joachim Kaiser

Hansjorg Urbach

Rudolf Kunstmann

Susanne Grabley

Manfred Schudok

Gerhard Kretzschmar

Wolfgang Ruger

Johannes Meiwes

Peter Hammann

Franz Hock

Wolf-Ulrich Nickel

Elmar Konz

Josef Scholtholt

Bernhard Kammermeier

Hermann Teufel

Martin Bickel

Ernold Granzer

Klaus Kuhlein

Wolfgang Linz

Hermann J Gerhards

Richard H Rupp

Heiner Jendralla

Gabriele Wiemer

Dieter-Bernd Reuschling

Bernhard Seuring

Bernward Schokens

Raymond Oekonomopulos

Henning Rainer

Process for the biotechnological preparation of L-thienylalanines in enantiomerically pure form from 2-hydroxy-3-thienylacrylic acids, and their use. L-Thienylalanines are prepared via the hydantoin or the azlactone route. The starting substances used for the biotransformation are 2-hydroxy-3-thienylacrylic acids. The innovative step consists in the transamination of the enol form of the 2-hydroxy-3-thienylacrylic acids to give L-thienylalanines with the aid of biotransformation. The transaminiation is carried out in the presence of L-aspartic acid or L-glutamic acid as amino donor.

Process for the biotechnological preparation of L-thienylalanines in

Process for the biotechnological preparation of L-thienylalanines in enantiomerically pure form from 2-hydroxy-3-thienylacrylic acids L-Thienylalanines are prepared via the hydantoin or the azlactone route. The starting substances used for the biotransformation are 2-hydroxy-3-thienylacrylic acids. The innovative step consists in the transamination of the enol form of the 2-hydroxy-3-thienylacrylic acids to give L-thienylalanines with the aid of biotransformation. The transaminiation is carried out in the presence of L-aspartic acid or L-glutamic acid as amino donor.

L-Thienylalanines are prepared via the hydantoin or the azlactone route. The starting substances used for the biotransformation are 2-hydroxy-3-thienylacrylic acids. The innovative step consists in the transamination of the enol form of the 2-hydroxy-3-thienylacrylic acids to give L-thienylalanines with the aid of biotransformation. The transaminiation is carried out in the presence of L-aspartic acid or L-glutamic acid as amino donor.

Process for the biotechnological preparation of l-thienylalanines in

A process for the preparation of racemic and optically active 1,2.3,4-tetrahydroisoquinoline-3-carboxylic acid is described, in which dihalo-o-xylylenes are cyclized to dicarboxylic acid esters in basic medium using dialkyl N-acylamidomalonates of the formula (CO.sub.2 R.sup.1).sub.2 CHNHCOR.sup.2, in which R.sup.1 is (C.sub.1 -C.sub.4)-alkyl and R.sup.2 is H, (C.sub.1 -C.sub.4)-alkyl or (C.sub.6 -C.sub.12)-aryl, decarboxylated by basic hydrolysis and subsequent acid work-up and then reacted in acid medium to give (D,L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, or dihalo-o-xylylenes are cyclized in basic medium to give the dicarboxylic acid esters and these are reacted directly without isolation in a one-pot process to give (D,L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, if desired the racemic 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is reacted with (-)menthol and p-toluenesulfonic acid to give (-)menthyl (D)- or (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate, then the diastereomers are separated by column chromatography and subjected to basic hydrolysis to give (D)-or (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, or (D,L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is esterified by means of benzyl alcohol and p-toluenesulfonic acid, reacted with D(-)mandelic acid to give benzyl (D)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (D)-mandelate and benzyl (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (D)-mandelate or with L(+)mandelic acid to give benzyl (D)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (L)-mandelate and benzyl (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (L)-mandelate and then the compounds obtained are separated into the optical antipodes by fractional crystallization in an inert solvent and the enantiomers (D)- or (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are liberated by basic hydrolysis, the chiral auxiliary reagent being recovered.

Process for the preparation of racemic and optically active

Two processes are described for the preparation of the optically pure compounds of formula 1: ##STR1## in which R.sup.1 and R.sup.2 are e.g. alkyl, R.sup.3 and R.sup.4 are e.g. hydrogen and R.sup.5 is e.g. hydrogen. Both processes include, as key steps, the enantioselective hydrogenation of a C.dbd.C double bond and the regioselective formation of a dicarboxylic acid monoamide derivative. In one process a phenylitaconic acid derivative is asymmetrically hydrogenated to give an optically active (R)-benzylsuccinic acid which is then converted to a diester, said diester being converted to the monoamide compound of formula 1. In the second process, a phenylitaconic acid derivative is converted to its anhydride, and the anhydride is then converted to a monoamide which is then asymmetrically hydrogenated to give the compound of formula 1.

Process for the enantioselective synthesis of 2(R)-benzylsuccinic acid

A process for the preparation of racemic and optically active 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is described, in which dihalo-o-xylylenes are cyclized to dicarboxylic acid esters in basic medium using dialkyl N-acylamidomalonates of the formula (CO.sub.2 R.sup.1).sub.2 CHNHCOR.sup.2, in which R.sup.1 is (C.sub.1 -C.sub.4)-alkyl and R.sup.2 is H, (C.sub.1 -C.sub.4)-alkyl or (C.sub.6 -C.sub.12)-aryl, decarboxylated by basic hydrolysis and subsequent acid work-up and then reacted in acid medium to give (D,L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, or dihalo-o-xylylenes are cyclized in basic medium to give the dicarboxylic acid esters and these are reacted directly without isolation in a one-pot process to give (D,L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, if desired the racemic 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is reacted with (-)menthol and p-toluenesulfonic acid to give (-)menthyl (D)- or (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate, then the diastereomers are separated by column chromatography and subjected to basic hydrolysis to give (D)- or (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, or (D,L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is esterified by means of benzyl alcohol and p-toluenesulfonic acid, reacted with D(-)mandelic acid to give benzyl (D)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (D)-mandelate and benzyl (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (D)-mandelate or with L(+)mandelic acid to give benzyl (D)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (L)-mandelate and benzyl (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (L)-mandelate and then the compounds obtained are separated into the optical antipodes by fractional crystallization in an inert solvent and the enantiomers (D)- or (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are liberated by basic hydrolysis, the chiral auxiliary reagent being recovered.

The invention relates to new comoounds having a cognition adjuvant action, to the use of ACE inhibitors as medicaments having a cognition adjuvant action, to agents containing them, and to the use thereof for the treatment and prophylaxis of cognitive dysfunctions.

Compounds having a cognition adjuvant action, agents containing them,

The invention relates to compounds of the formula I ##STR1## in which R.sup.1, R.sup.2 and R.sup.4 represent optionally substituted aliphatic, alicyclic, alicyclic-aliphatic, aromatic, araliphatic, heteroaromatic or heteroaromatic-aliphatic radicals, with R.sup.2, if not already covered by the above-mentioned definitions, denoting the side-chain, which is protected if necessary, of a naturally occurring .alpha.-amino acid, R.sup.4 can additionally represent ##STR2## R.sup.3 denotes an optionally substituted aliphatic, alicyclic, aromatic or araliphatic radical, or R.sup.3 and R.sup.4 form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system,

Piperazinediones having a psychotropic action

The invention relates to amino acid esters of the formula I ##STR1## in which n is 2 and R, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the meaning indicated in the description, to a process and intermediates for the preparation thereof, to agents containing them, and the use thereof.

Amino acid esters, pharmaceuticals containing them, and the use thereof

A description is given of compounds I ##STR1## with R(1) equal to H, alkyl, alkoxy, Hal, NO.sub.2, OH, acetamido or amino; R(2) equal to H, alk(en)yl or phenylalkyl; R(3) equal to H, (cyclo)alk(en)yl(alkyl), phenyl or phenylalkyl; R(4) equal to H, alkyl, alkoxy, Hal CF.sub.3, NO.sub.2, OH, acetamido or amino; A equal to --C.tbd.C-- or --CH.dbd.CH--; R(5) equal to various amines; m and n equal to 1-3; and their salts. Preparation processes are also described. Compounds I are excellent calcium agonists or calcium antagonists. They also act to regulate the blood glucose.

Benzothiazinone derivatives, and pharmaceuticals containing them

Compounds I ##STR1## in which R(1) and R(4) equal H, alkyl, alkoxy, Hal, CF.sub.3, NO.sub.2, OH, acetamido or amino;

Benzothiazinone oxides, processes for their preparation, medicaments

Calcium antagonists of the formula ##STR1## with R(1), R(2), R(3) and R(4) being, inter alia, H, alkyl, alkoxy, halogen, in some cases phenyl; m being 1-4; n being 0-3; X being CH.sub.2, O, S, CO, CHOH or CR.sub.2, and R(5) being various groups containing nitrogen atoms, are described. They are obtained by reaction of compounds II which are likewise new and which contain in place of R(5) a leaving group Y (Cl, Br, I) with the appropriate (cyclic) amino compound. Another synthesis comprises reaction of the appropriate indollinone derivative IV which has a non-etherified hydroxyl group with a side chain which contains a terminal leaving group Z (Cl, Br, I) in the presence of a base. Furthermore, indolinone derivatives VI with an ether side chain with a terminal epoxide group can be reacted with (cyclic) amines to give compounds I.

3-phenyl indolinone derivatives, processes for their preparation,

Calcium antagonists of the formula ##STR1## with R(1), R(2), R(3) and R(4) being, inter alia, H, alkyl, alkoxy, halogen, in some cases phenyl; m being 1-4; n being 0-3; X being CH.sub.2, O, S, CO, CHOH or CR.sub.2, and R(5) being various groups containing nitrogen atoms, are described. They are obtained by reaction of compounds II which are likewise new and which contain in place of R(5) a leaving group Y (Cl, Br, I) with the appropriate (cyclic) amino compound. Another synthesis comprises reaction of the appropriate indolinone derivative IV which has a non-etherified hydroxyl group with a side chain which contains a terminal leaving group Z (Cl, Br, I) in the presence of a base. Furthermore, indolinone derivatives VI with an ether side chain with a terminal epoxide group can be reacted with (cyclic) amines to give compounds I.

Alkoxyphenylindolinone derivatives, medicaments containing them and

Benzothiazinone derivatives I ##STR1## with R.sup.1 and R.sup.4 being H, alkyl, alkoxy, Hal, CF.sub.3, NO.sub.2, OH, acetamido or amino,

Novel benzothiazinone derivatives, processes for their preparation,

Compounds of the formula I ##STR1## where R(1), R(2), R(3), R(4) and R(5) are, inter alia, hydrogen and alkyl, m is 1-4, n is 0 or 1, p is 0-4 and R(6) is identical or different dialkylamine derivatives, and salts thereof, have a calcium-antagonistic action. They are obtained by reacting corresponding amines with a compound II which carries, on the side chain, a leaving group which can be displaced nucleophilically, or from a hydroxyphenyl-dihydroquinolin-2-one compound by reaction with a corresponding side chain compound which has a leaving group which can be displaced nucleophilically.

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Hofheim am Taunus, Germany

Ulrich Lerch