NO863582L - PROCEDURE FOR THE PREPARATION OF N-ALKYLATED TRIPEPTIDES. - Google Patents

Abstract

A process wherein, in a first step, a highly nucleated polyester is prepared with addition of from 2x10<-><2> mol to 1 mol of alkali metal or alkaline earth metal, an alkali metal compound or an alkaline earth metal compound per kg of the polyester to be prepared, at any desired point of the synthesis and subsequently, in a second step, this highly nucleated polyester is admixed with a non-nucleated polyester of the same or different chemical composition to give a rapidly crystallising polyester. The polyesters according to the invention are distinguished, in particular, by improved colour quality and increased processing stability.

Description

The invention relates to a method for the production of N-alkylated tripeptides with formula I

in which

n means 1 or 2,

R means hydrogen,

an optionally substituted aliphatic residue with 1 to 8 C atoms,

an optionally substituted alicyclic residue with 3-9 C atoms, an optionally substituted aromatic residue with 6-12 C atoms, an optionally substituted araliphatic residue with 7-14 C atoms,

an optionally substituted alicyclic-aliphatic residue with 7-14 C atoms,

a residue OR cl or SR cl, wherein

R means an optionally substituted aliphatic residue with 1-4 C atoms, an optionally substituted aromatic residue with 6-12 C atoms, or an optionally substituted heteroaromatic residue with 5-12 ring atoms,

R"*" means hydrogen

an optionally substituted aliphatic residue with 1 to 6 C atoms,

an optionally substituted alicyclic residue with 3-9 C atoms, an optionally substituted alicyclic-aliphatic residue with 4-13 C atoms,

an optionally substituted aromatic residue with 6-12 C atoms, an optionally substituted araliphatic residue with 7-16 C atoms, an optionally substituted heteroaromatic residue with 5-12 ring atoms, or

if necessary protected side chain of naturally occurring α-amino acids.

2 3

R and R are the same or different and mean hydrogen,

an optionally substituted aliphatic residue with 1-6 C atoms, an optionally substituted alicyclic residue with 3-9 C atoms, an optionally substituted aromatic residue with 6-12 C atoms, an optionally substituted araliphatic residue with 7-16 C- atoms, and

4 5

R and R together with the atoms bearing a heterocyclic bi- or tricyclic ring system of the group

octahydrocyclopenta/ b7pyrrole, (A), 2-aza-bicyclo/ 2,2,2/- octane (B), 2-azabicyclo/ 2,2,1/heptane (C), spiro/ (bicyclo-/ 2,2 , l/heptane)-2,3'-pyrrolidine/ (D), spiro/ (bicyclo/~2,2,27-octane)-2,21-pyrrolidine/ (E), 2-azatricyclo/~4,3 ,0,l<6>'^/decane decahydrocyclohepta/"b/ pyrrole (G), 2,3,3a,4,5,7a-hexabydroindole (H), 2-azabicyclo/ 3,1,0/hexane ( I), trans-octahydroindole (J), trans-octahydroisoindole (K), 1,2,3,3a,4,6a,-hexahydrocyclo-

and

A means the residue of an optionally protected natural amino acid,

as well as their physiologically tolerable salts with acids and bases.

In the case of the compounds having several chiral atoms, all possible diastereomers such as racemates or en-enantiomers or mixtures of different diastereomers come into consideration.

Preference is given to compounds of formula I, wherein

n = 1 or 2,

R means hydrogen,

alkyl with 1-8 C atoms,

alkenyl with 2-6 C atoms,

cycloalkyl with 3-9 C atoms,

aryl with 6-12 C atoms,

which can be mono-, di- or tri-substituted with (C-^-C^ )-alkyl, (C^-C^)- alkoxy, hydroxy, halogen, nitro, amino, aminomethyl, (C^-C^)- alkylamino, di-(C-^-C^)-alkylamino, (C-^-C^ )-acylamino, preferably (C^-C^)-alkanoylamino, methylene dioxide, carboxy, cyano, and/or sulfamoyl,

alkoxy with 1-4 C atoms,

aryloxy with 6-12 C atoms,

which may be substituted as described above by aryl,

mono-, resp. bicyclic heteroaryloxy with 5-7 resp. 8-10 ring atoms, of which 1 to 2 ring atoms represent sulfur or oxygen atoms, and/or 1 to 4 ring atoms represent nitrogen,

which may be substituted as described above by aryl,

amino-(C 1 -C 4 )-alkyl,

(C 1 -C 4 )-alkanoylamino-(C 1 -C 4 )-alkyl,

(C7_ci3 ^~aroylamino-(ci~C4)~aiky1, (C^-C^)-Alkoxy-carbonylamino-(ci~ c^)-alkyl, ^C6~C12 ^ -ary-1-- ^ci~C4 ) -al^oxycarbonylamino-(C^~C4 )-alkyl, (C5~C12)-aryl-(C^-C^)-alkylamino-(C1~C4)-alkyl, (C1~C4)-alkylamino-( C1-C4)-alkyl, di-(C1-C4)-alkylamino-(C-^-C^-alkyl, guanidino-(C]-C4)-alkyl,

imidazolyl, indolyl,

(C1-C4)-alkylthio,

(C1-C4)-alkylthio-(C-L-C4)-alkyl,

(C6-C2)-arylthio-(C1-C4)-alkyl,

which may be substituted in the aryl part as described above by aryl,

(C6-C12)-aryl-(C1-C4)-alkylthio,

which in the aryl part may be substituted as described above by aryl,

carboxy-(C 1 -C 4 ) alkyl,

carboxy, carbamoyl,

carbamoyl-(C 1 -C 4 )alkyl,

(C1-C4)-Alkoxycarbonyl-(C1-C4)-Alkyl, (C6-C12)-Aryloxy-(C1-C4)-Alkyl

which in the aryl part may be substituted as described above by aryl, or

(C 8 -C 12 )-aryl-(C 1 -C 4 )-alkoxy,

which in the aryl part may be substituted as described above by aryl,

R"*" means hydrogen,

alkyl with 1-6 C atoms,

alkenyl with 2-6 C atoms,

alkynyl with 2-6 C atoms,

cycloalkyl with 3-9 C atoms,

cycloalkenyl with 5-9 C atoms,

(C3-C9)-cycloalkyl-(C1-C4)-alkyl, (C5-C9)-cycloalkenyl-(C1-C4)-alkyl,

optionally partially hydrogenated aryl with 6-12 C atoms, which may be substituted as described above by R,

(C6-C12)-aryl-(C1-C4)-alkyl or (C7-C13)-aroyl-

{C1 or C2)alkyl

both of which can be substituted as the above-mentioned aryl, mono- or bicyclic, optionally partially hydrogenated heteroaryl with 5-7 resp. 8-10 ring atoms, of which 1 to 2 ring atoms represent sulfur or oxygen atoms, and/or 1 to 4 ring atoms represent nitrogen atoms,

which may be substituted as the above aryl,

the optionally protected side chains have a naturally occurring α-amino acid R^"-CH (NH2 )-COOH,

2 3

R and R are the same or different and mean

hydrogen,

alkyl with 1-6 C atoms,

alkenyl with 2-6 C atoms, di-(C-L-C4)-allylamino-(C1~C4)-alkyl,

(C1-C5)-alkanoyloxy-(C1~C4)-alkyl,

(C 1 -C 8 )-Alkoxy-carbonyloxy-(C 1 -C 4 )-alkyl, (C 7 -C 13 )-aroyloxy-(C 1 -C 4 )-alkyl,

(C6~C12)-aroyloxycarbonyloxy(C1~C4)-alkyl,

aryl with 6-12 C atoms,

(<C>6<-C>12)-aryl-(C1-C4)-alkyl,

(C3-C9)-cycloalkyl, or

(C3-C8)-cycloalkyl-(C1-C4)-alkyl,

4 5

R and R have the above meaning, and

A means an amino acid residue from the group

alanyl, leucyl, isoleucyl, arginyl, glycyl, histidyl, methionyl, phenylalanyl, seryl, threonyl, tyrosyl, valyl, lysyl, O-methyltyrosyl, O-ethyltyrosyl, N£-tert-butoxycarbonyl-lysyl, N£-benzyloxycarbonyl-lysyl .

Particularly preferred are compounds of formula I, wherein

n means 1 or 2,

R means (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, (C 3 -C 9 )-cycloalkyl, amino-(C-L-C 4 )-alkyl, (C 2 -C 1 -)-acylamino-(C- (C^-C^)-alkyl, (C^-C^^)-aroylamino-(C^-C^ )-alkyl, (C-^-C^ )-Alkoxycarbonylamino-(C^-C^)-alkyl, (Cg-C^2 ^-ary1-(Ci-C4 ^~Alkoxycarbonylamino-(C-^-C^)-alkyl, (Cg-C^2)-aryl, which may be mono-, di- or tri-substituted with (C-^-C^)-alkyl, (C1~C4)- alkoxy, hydroxy, halogen, nitro, amino, (C^-)-alkylamino, di-(c-^-C^ )-alkylamino, and /or methylenedioxy, or 3-indolyl, especially methyl, ethyl, cyclohexyl, tert-butoxycarbonylamino-(C^-C^)-alkyl, benzyl-oxycarbonylamino-(C^-C4)-alkyl or phenyl, which may be mono - or disubstituted or in the case of methoxy, tri substituted with phenyl, (C-^-C^)-alkyl, (C-^or C 2 )-alkoxy, hydroxy, fluoro, chlorine, bromo, amino, (C^-C ^)-alkylamino, di-(C^-C^)-alkylamino, nitro, and/or methylenedioxy,

R"*" means hydrogen or (C-^-Cg)-alkyl, which may optionally be substituted with amino, (C-^-Cg)-acylamino or benzoylamino, (C2-Cg)-alkenyl, (C^ -C^)-cycloalkyl, (C5-C9)~cycloalkenyl, (C3~C7)-cycloalkyl-(C1~C4)-alkyl, (C6-c12)-aryl or partially hydrogenated aryl, which resp. may be substituted by (C-L-C4)-alkyl, (C-1 or C2)-alkoxy or halogen, (<C>g<->C12)-aryl-(Cx to C4)-alkyl or (C7~c13)~ aroyl-(C 1 -C 2 )-alkyl, both of which may be substituted in the aryl residue as defined above, a mono- or bicyclic heterocyclene residue with 5 to 7, resp. 8 to 10 ring atoms, of which 1 to 2 ring atoms represent sulfur or oxygen atoms, and/or 1 to 4 ring atoms represent nitrogen atoms, or a side chain of naturally occurring optionally protected ot-amino acid, especially however hydrogen, (C^-C3)-alkyl , (C2 or C3)-alkenyl, the optionally protected side chain of lysine, benzyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-amino-butyl or benzoylmethyl,

2 3

R and R are the same or different residues and mean hydrogen,

(C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl or (C 8 -C 12 )-aryl-(C 8 -C 8 )-alkyl, especially however hydrogen, (C 8 -C 8 )-alkyl or benzyl, and

R and R^ have the above meaning, and

A means an amino acid residue from the group

alanyl, phenylalanyl, lysyl, N-benzyloxycarbonyl-lysyl or seryl.

Particularly preferred are compounds of formula I, wherein

n = 2,

R means phenyl,

R1 means methyl,

R 2 and R 3 mean hydrogen, or the same or different (ci~cg)~

alkyl radicals or (C₁-C₁q)-aralkyl radicals such as benzyl or nitrobenzyl, and

R^, R^ and A have the above meaning.

By aryl, here as in the following, it is preferably understood to mean optionally substituted phenyl, diphenylyl or naphthyl. The same applies to residues derived from aryl such as aryloxy, arylthio. Under aroyl is understood in particular benzoyl. Aliphatic residues can be straight or branched.

With a mono or bicyclic heterocyclene residue with 5 to 7, resp. 8 to 10 ring atoms, of which 1 to 2 ring atoms mean sulfur or oxygen atoms, and/or of which 1 to 4 ring atoms mean nitrogen atoms, for example thienyl, benzo/ b/ thienyl, furyl, furanyl, benzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indazolyl, iso-indolyl, indolyl, pyrinyl, quinolizinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl, teridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl. These residues can also be partially or completely hydrogenated. Naturally occurring α-amino acid is e.g. mentioned in Houben-Weyl, Methoden der Organischen Chemie, volumes XV/1 and XV/2 and is e.g. Ala, Ser, Thr, Val, Leu, Ile, Asp, Asn, Glu, Gin, Cys, Met. Arg, Lys, Hyl, Orn, Cit, Tyr, Phe, Trp and His.

If R''" means a side chain of a protected naturally occurring α-amino acid such as protected Ser. Thr, Asp,

Asn, Glu, Gin, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp are

as protecting groups in the peptide chemistry usual group preferred. In the case of R"*" means the protected lysine side chain, the known amino protecting groups are preferred, especially however Z, Boe or (C-^-C8)-alkanoyl. The 0-protecting groups for tyrosine are preferably (C-^-Cg)-alkyl, especially methyl or ethyl. Suitable protecting groups are described, for example, in Schroder, Lubke, The Peptides, Volume I, New York, London 1965, page 3 -270 and

in Contact Merck 3/79 14-22 and 1/80 23-35.

Of particular importance are the following compounds: N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS-6aS)-octahydrocyclopenta/b7pyrrole-2-carbonyl-S-phenylalanine, N-(1-S -ethoxycarbonyl-3-phenylpropyl)-S_alanyl-(2S,3aR,6aS)-octahydrocyclopenta/ b7pyrroic-2-carbonyl-S-phenylalanine, N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S ,3aS,6aS)-octahydrocyclopenta/~b7pyrroi-2-carbonyl-S-phenylalanine, N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aR,6aS)-octahydrocyclopenta/ fc >7pyrrole-2-carbonyl-S-phenylalanine, N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/ b7pyrrole-2-carbonyl-S-alanine, N -(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3a,6aS)-octahydrocyclopenta/b7pyrrole-2-carbonyl-S-alanine,

N -/~N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/b/pyrrole-2-carbonyl7_N-benzyloxycarbonyl-S-lysine,

N -/~N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/b7pyrrole-2-carbonyl7-S-lysine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/ b7pyrrole-2-carbonyl-S-serine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-0-methyl-tyrosyl-(2S,3aS,6aS)-octahydrocyclopenta/b7pyrrole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-O-ethyl-tyrosyl-(2S,3aS,6aS)-octahydrocyclopheta/~b7pyrro1-2-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenylpropyl)-S-lysyl-(2S,3aS,6aS)-octahydrocyclopenta/~b7pyrrole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-azabicyclo-/ 2,2,27octane-2S-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-azabicyclo/~2,2, 2J-octane-2S-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-azabicyclo/~2,2,17heptane-2S-exo-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl-azabicyclo/2,2,17heptane-2S-endo-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-alanyl-spiro/~bicyclo/ 2,2,2_7octane-2 ,3 1 -pyrrolidine7~5' -S-exo-carbonyl-S-phenylalanine , N-( 1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-spiro/~bicyclo/2,2,2/octane-2,3<1->pyrrolidine/-5'-S-endo-carbonyl-S-phenylalanine ,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-spiro/bicyclo/2,2,1/heptane-2,3'-pyrrolidine/-5<1->S-carbonyl-S-phenylalanine ,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-spiro)/~bicyclo/2,2,2_7-octane-2,3'-pyrrolidine7_5'-S-exo-carbonyl-S-f enylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-spiro/ bicyclo/ 2,2 27-octane-2,3'-pyrrolidine/-5<1->S-endo-carbonyl-S- phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-spiro/bicyclo/_2 , 2 , 2_7octane-2 , 3 1 -pyrrolidine7~5' -S-exo-carbonyl-S-alanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-spiro/bicyclo/~2,2,2-7octane-2,3'-pyrrolidine/-5'-S-endo-carbonyl-S-alanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-spiro/bicyclo/2,2,2_7octane-2,31-pyrrolidine7-5'-S-exo-carbonyl-S-serine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-spiro-/bicyclo/2,2,2/octane-2,31-pyrrolidine7-5'-S-endo-carbonyl-S-serine ,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(1R,2S,4S,6S,7S)-tricyclo[5,2,1,0<2>'^7-3-aza -decane-4-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(1R,2S,4S,6S,7S)-bi-26 — cyclo/ 5,2,1,0 '_/-3 -aza-decane-4-carbonyl-S-phenylalanine, N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(1S,2S,4S,6R,7R)-bicyclo/~5.2, 1,0<2>'^7-3-aza-decane-4-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(1S,2S,4S,6R,7R)-tricyclo/ — 5,2,1,0 2 ' 6 /—-3-aza- decane-4-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(1R,2S,4S,6R,7S)-tricyclo[5,2,1,0<2>'^7"3 -aza-decane-4-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(IR,2S,4S,6R,7S)-

— 2 6 —

tricyclo[5,2,1,0'_7~3-aza-decane-4-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-1S,2R,4S,6S,7R-tricyclo(/~5 ,2 ,1,02 ' ^7~3-aza-decane -4-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(1S,2R,4R,6S,7R)-tricyclo/ — 5,2,1,0 2 ' 6 /—-3-aza- decane-4-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-(S-alanyl-2S,3aS,8aS)-decahydrocyclohepta/~b7pyrrole-2-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,8aS)-deca-hydrocyclohepta/ b7pyrrole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-2S,3aR,8aR-decahydrocycloheptane/k>7pyrrole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-1-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-2,2,3a,4,5,7a-hexahydroindole-2-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-2,3,3a,4,5,7a-hexahydroindole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-1-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aR)- 2,3,3a,4,5,7a-hexahydroindole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-2,3,3a,4,5,7a-hexahydroindole-2-carbonyl-S-alanine,

N-(1-S-ethoxycarbonyl-3-phenyl-porpyl)-S-alanyl-(2S,3aS,7aS)-2,3,3a,4,5,7a-hexahydroindole-2-carbonyl-S-serine,

Na-/ N-(1S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-2,3,3a,4,5,7a-hexahydrindole-2-carbonyl/-N£ -benzyloxycarbonyl-S-lysine,

Na-/~N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-2,3,3a,4,5,7a-hexahydroindole-2-carbonyl7~S- lysine,

N-(1-S-ethoxycarbonyl-1-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-2,3,3a,4,5,7a-hexahydroindole-2-carbonyl-S-alanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-2S,3S,5S,2-azabicyclo/3,1,O/hexane-3-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(1R,3S,5R,2)-azabicyclo/~3,1,07hexane-3-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-lysyl-(2S,3aR,7aS)-octa-hydroindo1-2-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2-carbonyl-S-alanine, N-(1-S-ethoxycarbonyl-1-3-phenyl-propyl )-S-alanyl-(2S,3aR,7aS-octahydroindole-2-carbonyl-S-serine,

Na-/~N-(1S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aR-7aS)-octahydroindole-2-carbonyl/-N£-benzyloxycarbonyl-S-lysine,

Na-/~N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2-carbonyl/-S-lysine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-O-ethyl-tyrosyl-(2S,3aR,7aS)-octahydroindole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aR)-octahydroindole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(IS,3aR,7aR)-octahydroisoindole-1-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(1S,3aR,7aR)-octahydroindole-1-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl1-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-1,2,3,3a,4,6a-hexahydrocyclopenta/ b7pyrrole-2-carbonyl-S- phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-1,2,3,3a,4,Ga-hexahydrocyclopenta/b7pyrrole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aR,6aR)-1,2,3,3a,4,Ga-hexahydrocyclopenta/b/pyrrole-2-carbonyl-S- phenylalanine-

The method according to the invention for the preparation of compound of formula I is characterized by

a) a compound of formula II

in which the residues R, R''', R^, R^, R^ and n have the same meaning as in formula I, are reacted with an amino acid ester of formula

III

in which A is defined as formula I, and R 3 means an esterifying group, preferably a benzyl or tert-butyl group, under known per se peptide linking conditions (see e.g. Houben-Weyl, Methoden der Organischen Chemie, vol. XV, part II, page 1-364, further Angew. Chemie 92 129 (1980), as well as US patent no. 4 331 592) and optionally the protecting group R 3 is cleaved off under the appropriate conditions, and optionally residues R 2 are removed hydrolytically or hydrogenolytically as resp. in particular hydrogenolysis comes into consideration for benzyl esters, treatment with trifluoroacetic acid for tert-butyl esters and alkaline cleavage for alkyl esters, or

b) a compound of formula IV

in which R 1 , R 3 , R 4 and R 5 have the same meaning as for formula

I, is reacted with a compound of formula V

in which R and R 2 have the same meaning as in formula I, in a manner known per se in a Michael reaction (Organikum, 6. oppi. page 492, 1967), the carbonyl group is hydrogenated, e.g. by an acidic alcoholic solution in a precious metal catalyst, especially palladium or platinum on activated carbon at pressures from 20 to 120 bar, and optionally residues R 2 and/or R-73 are split off after

suitable conditions, (see above), or

c) compounds of formula IV are reacted with compounds of formula VI, in which R 2 has the same meaning as for formula I,

and a compound of formula VII

wherein R has the same meaning as formula I, in a known manner in a Mannich reaction (Bull. Soc. Chim. France, 1975, page 625) and further forward as discussed under b), or

d) a compound of formula IV is reacted with a compound of formula VIII, in which n, R and R 2 have the same meaning as in

formula I

for example according to that in J. Amer. Chem. SOc. 93, 2897 (1971), mentioned methods, the Schiff base formed is reduced, preferably using sodium cyanoborohydride, and optionally residues R 2 and/or RJ ^ are cleaved off under suitable conditions (see above), or e) a compound of formula IV with is reacted with a compound of formula IX

2

wherein n, R and R have the same meaning as for formula I, e.g. analogously to the method described in US patent 4,525,301, and residues R 2 and R 3 are optionally cleaved off under suitable conditions

and the thus formed compounds of formula I are optionally transferred in their physiologically tolerable salts.

US patent 4,483,850 mentions N-alkyl oligopeptides which are inhibitors of angiotensin-converting enzyme. The compound according to the invention differs from the residues R<4>Qq R<5> mentioned there.

Compounds of formula II are known (see e.g. EP-A 79 022, 105 102, 113 880, 116 276, 84 164, 90 362),

Compounds with formula IV are tripeptides which must be built up from the individual amino acid components according to methods known per se from peptide chemistry (see e.g. Houben-Weyl, Methoden der Organischen Chemie, volume XV, part II, pages 1-364).

The compounds prepared according to the invention with formula I exist if R 3 = hydrogen as internal salts. As amphoteric compounds, they can form salts with acids or bases. These salts are prepared in the usual way by reaction with an equivalent acid or base.

The compounds of formula I and their salts have long-lasting, intense blood pressure-lowering action. They are strong inhibitors of the angiotensin-converting enzyme (ACE inhibitor). They can be used to combat high blood pressure of various origins. Their combination with other blood pressure-lowering vasodilator or diuretic active compounds is also possible. Typical representatives of these active classes are e.g. discussed in Erhardt-Ruschig, Arzneimittel, 2nd edition, Weinheim 1972. The application can take place intravenously, subcutaneously or perorally.

The dosage for oral administration is 1-100 mg, preferably 1-40 mg per single dose in an adult patient of normal weight, then it is approx. 15-1300 yg/kg/day, preferably 15-500 yg/kg/day. In more severe cases, it can also be increased, as toxic properties have not been observed so far. A reduction of the doses is also possible, and above all appropriate when diuretics are administered at the same time.

The compounds according to the invention can be administered orally or parenterally in a corresponding pharmaceutical preparation. For an oral form of application, the active compounds are mixed with the usual additives such as carriers, stabilizers or inert diluents, and are brought by usual methods into suitable administration forms, such as tablets, dragees, injectable capsules, aqueous alcoholic or oil suspensions, or aqueous alcohols or oil solutions. As inert carriers, it can e.g. gum arabic, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, are used. Thereby, the preparation can take place as well as dry or moist granules. For example, plant or animal oils, such as sunflower oils or cod liver oil, come into consideration as oily carriers or solvents.

For subcutaneous or intravenous application, the active compounds or their physiologically tolerable salts are brought, if desired, with the usual substances such as dissolution mediators, emulsifiers or further auxiliaries in solution, suspension or emulsion. As a solvent for the new active compounds and the corresponding physiologically tolerable salts, e.g. in question: Water, physiological saline solutions, or alcohols, e.g. ethanol, propanediol or glycerol, in addition also sugar solutions, such as glucose or mannitol solutions or also a mixture of the various solvents mentioned.

Example 1

N-(1-S-ethoxycarbonyl-1-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/ b/ pyrrole- 2- carbonyl- S- phenylalanine,

a) N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/b/pyrrole-2-carbonyl-S-phenyl-1-alanine tert-butyl ester

1.04 g of N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/~b7pyrrole-2-carboxylic acid and 0.65 g

phenylalanine tert-butyl ester hydrochloride is added to 10 ml of dry dichloromethane cooled to -10°C, 2.4 ml of triethylamine and then 1.6 ml of n-propylphosphonic anhydride (dropwise added to 50% dichloromethane). After 1 hour at -10°C, stir again 3

hours at 20°C, diluted with dichloromethane, and washed each time once with ice water, 5% KHSO^ solution and 5% NaHCO^ solution, dried with MgSO^ and evaporated. The crude product is purified by chromatography on silica gel with toluene/ethyl acetate (1:1) as eluent. You get 0.9 g of colorless oil.

1~ a/ D = -20.9° (c = 1, CH 3 OH).

b) N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/b/pyrrole-2-carbonyl-S-phenylalanine.

0.8 g of tert-butyl ester of a) is stirred with 5 ml of trifluoroacetic acid for 90 minutes. After evaporation, 20 ml of toluene is added dropwise and evaporated again. The residue is dissolved in 20 ml of methanol/H20 (4:1) and brought to a pH value with "Amberlite" IRA 93

of 4.5. After extraction from the ion exchanger, it is evaporated and crystallized from vinegar. You get 0.5 g of colorless crystals of m.p. 142-143°C

^ -/D = +9.4° (c = 0.5/CH 3 OH).

Using suitable starting materials, prepare according to the instructions given in example 1: N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aR,6aS)-octahydrocyclopenta/~b/pyrrole-2-carbonyl -S-phenylalanine, N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/b/pyrroic-2-carbonyl-S-alanine,

Na -/~N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/b7pyrrole-2-carbonyl7N-benzyloxycarbonyl-S-lysine, N-(1-S -ethoxycarbonyl-1-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/b/pyrrole-2-carbonyl-S-serine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-O-methyl-tyrosyl-(2S,3aS,6aS)-octahydrocyclopenta/~b7pyrrole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-0-ethyl-tyrosyl-2S,3aS,6aS-octahydrocyclopenta/b7pyrrole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-azabicyclo/2,2,27octane-2S-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-azabiscyclo/~2,2,17heptane-2S-exo-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-azabicyclo/ 2,2,17heptane-2S-endo-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-spiro/bicyclo/2,2,2_7octane-2,31-pyrrolidine7~5'-S-exo-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-spiro/bicyclo/2,2,2-7octane-2,3'-pyrrolidine/-5'-S-endo-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-spiro/~bicyclo/~2,2,17heptane-2,3'-pyrrolidine/-5'-S-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-spiro/ bicyclo / 2,2, 2_7octane-2 , 2 1 -pyrrolidine/-5 1 -S-exo-carbonyl-S-alanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-spiro/ bicyclo / 2,2, 2_7octane-2 , 3 1 -pyrrolidine7~5' -S-endo-carbonyl-S-alanine, N- (1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-spiro/bicyclo/2,2,2-7octane-2,3'-pyrrolidine/-5'-S-exo-carbonyl-S-serine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-spiro/bicyclo/2,2,2/octane-2,31-pyrrolidine7-5'-S-endo-carbonyl-S-serine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl(1R,2S,4S-6S,7S)-tricyclo[5,2,1,0<2>'^7~3-aza- decane-4-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(1S,2S,4S-6R,7R)-tricyclo[5,2,1,02'^7"-3-aza-decane -4-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(1R,2S,4S-6R,7S)-tricyclo/~5,2,1,0<2>'^7~3 -aza-decane-4-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(1S-2R,4S-6S,7R)-tricyclo/~5,2,1,0<2>'^7~3 -aza-decane-4-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,8aS)-decahydrocyclohepta/b7pyrrole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aR,8aR)-decahydrocyclohepta/b7pyrrole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-2,3,3a,4,5,7a-hexahydroindole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aR)-2,3,3a,4,5,7a-hexahydroindole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-2,3,3a,4,5,7a-hexahydroindole-2-carbonyl-S-alanine, N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-2,3,3a,4,5,7a-hexahydroindole-2-carbonyl-S-serine,

Na-/ N-(1S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-2 , 3 , 3a, 4 , 5 , 7a-hexahydroindole-2-carbonyl-17-N^- benzyloxycarbonyl-S-lysine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-2,3,3a,4,5,7a-hexahydroindole-2-carbonyl-S-alanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(1S,3S,5S)-2-azabicyclo/3,1,0_7hexane-3-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(1R,3S,5R)-2-azabicyclo/3,1,o7hexane-3-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2-carbonyl-S-alanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2-carbonyl-1-S-serine,

Na~Z N~(1S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2-carbonyl7-Ne-benzyloxycarbonyl-S-lysine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-O-ethyl-tyrosyl-(2S,3aR,7aS)-octahydroindole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aR)-octahydroindole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(IS,3aR,7aR)-octahydroisoindole-1-carbonyl-S-phenylalanine, N-(1-S-ethoxycarbonyl-3-phenyl-propyl )-S-alanyl-(2S,3aS,6aS)-1,2,3,3a,4,6a-hexahydrocyclopenta/b/pyrrole-2-carbonyl-S-phenylalanine,

N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aR,6aR)-1,2,3,3a,4,6a-hexahydrocyclopenta/b/pyrrole-2-carbonyl-S- phenylalanine,

Example 2

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/ b7pyrrole-2-carbonyl-S-phenylaniline.

0.23 g of N-(1-S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/b/pyrrole-2-carbonyl-S-phenyl-aniline is dissolved in 3 ml I^O/dioxane (1:1), mixed with 1.1 equivalents IN KOH, and stirred for 5 hours at room temperature. Neutralize with 0.1 N HCl and evaporate. The crude product is taken up in H2O, applied to 10 ml "Dowex" 50 and eluted with 0.5% pyridine in water. After evaporation, 0.16 g of colorless, amorphous powder is obtained.

Analogous to the regulation stated in example 2, the following compounds can be prepared using the corresponding starting materials: N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aR,6aS)-octahydrocyclopenta/ b7pyrrole-2-carbonyl-S-phenylalanine, M-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/ b7pyrrole-2-carboxy-S-alanine, Na- /~N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/ b7pyrrole-2-carbonyl7s-lysine, N-(1-S-carboxy-3-phenylpropyl)- S-lysyl-2S,3aS,6aS-octahydrocyclopenta/ b7pyrrole-2-carbonyl-S-phenylalanine, N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-azabicyclo/ 2,2,2/ octane- 2S-carbonyl-S-phenylalanine, N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-spiro/ bicyclo/ 2,2, 2/octane-2,3<1->pyrrolidine/-5' -S-exo-carbonyl-S-phenylalanine, N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-spiro/bicyclo/ 2,2 2/octane-2,3<1->pyrrolidine/- 5<1->S-endo-carbonyl-S-phenylalanine, N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(IR,2S,4S,6S,7S)-tricyclo/ — 5,2,1,0 2 '_ 6 /—-3-aza-decane-4-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(1S,2S,4S,6R,7R)-

— 2 6 —

tricyclo[5,2,1,0'_/-3-aza-decane-4-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(IR,2S,4S,6R,7S)-

— 2 6 —

tricyclo/5,2,1,0'_/-3-aza-decane-4-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(1S,2R,4S,6S,7R)-

— 2 6 —

tricyclo/5,2,1,0'_/-3-aza-decane-4-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,8aS)-deca-hydrocyclohepta/ b7pyrrole-2-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-2,3,3a-4,5,7a-hexahydroindole-2-carbonyl-S-phenylalanine,

Not-/~ (1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S , 3aS , 7aS)-2 , 3 , 3a,4,5-7a-hexahydroindole-2-carbonyl7-S-lysine ,

N-(1-S-carboxy-3-phenyl-propyl)-S-lysyl-(2S,3aR,7aS)-octahydroindole-2-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2-carbonyl-S-phenylalanine, Na-/-N-(1S-carboxy-3-phenyl -propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2-carbonyl/-S-lysine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(1S,3aR,7aR)-octa-hydroisoindole-1-carbonyl-S-phenylalanine,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-1,2,3,3a-4,6a-hexahydrocyclopenta/b/pyrrole-2-carbonyl-S- phenylalanine,

Example 3

N-(1-S-ethoxycarbonyl-1-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/b7pyrrole-2-carbonyl-S-phenylalanine

a) N-(1-S-ethoxycarbonyl-3-phenyl-3-oxy-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/b7pyrrole-2-carbonyl-S-phenylalanine benzyl ester. 7 mmol of S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/b7pyrrole-2-carbonyl-S-phenylalanine benzyl ester are stirred together with 7 mmol of 3-benzoyl acrylic acid ethyl ester and 8 mmol of triethylamine in ethanol (50 ml) in 2 4 hours at 2 0°C. After evaporation, the diastereomers formed are separated by chromatography on silica gel with ethyl acetate/cyclohexane (1:2) as eluent. b) N-(1S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS, 6aS)-octahydrocyclopenta/b7pyrrole-2-carbonyl-S-phenylalanine, 3 mmol of compound from a) dissolve in ethanol (30 ml). After adding 1 ml conc. ^SO^ is hydrogenated with Pd/C (10%) as catalyst at 25 atm. hydrogen pressure 4 hours. After filtering off, neutralize with sodium carbonate and evaporate. The physical properties of the product correspond to the compound from example 1.

Example 4

N-(1S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/b/ pyrrole-2-carbonyl-S-phenylalanine. 10 mmol of acetophenone, 10 mmol of glyoxylic acid ethyl ester and 10 mmol of S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/~b/pyrrole-2-carbonyl-S-phenylalanine-benzyl ester are heated in 30 ml of glacial acetic acid for 36 hours at 45°C . After evaporation in a vacuum, neutralize with sodium carbonate solution and extract with acetic acid. The acetate phase is evaporated and chromatographed on silica gel with acetate/cyclohexane (1:2) as eluent. The product (corresponds to the product from example 3a) is reacted further as described in example 3b).

Example 5

N-(1S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/~ b7pyrrole-2-carbonyl-S-phenylalanine. 5 mmol of S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/~b/pyrrole-2-carbonyl-S-phenylalanine tert-butyl ester are dissolved in 15 ml of anhydrous ethanol. The solution is adjusted to pH 7.0 with ethanolic potassium hydroxide and 0.7 g of powdered molecular sieve (4Å) is added, followed by 5 mmol of 2-keto-4-phenyl-butyric acid ethyl ester. A solution of 0.6 g of sodium cyanoborohydride in 6 ml of anhydrous ethanol is slowly added dropwise. After a reaction time of 20 hours at 20 to 25°C, the solution is filtered and the solvent is distilled off. The residue is taken up in vinegar/water. After evaporation of the acetate phase, the residue is chromatographed on silica gel using acetate/cyclohexane (1:2).

The purified product is reacted as described in example 1b with trifluoroacetic acid.

The physical properties of the thus formed product agree with those of the compound from example lb.

Example 6

N-(1S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl-(2S,3aS,6aS)-octahydrocyclopenta/b/ pyrrole-2-carbonyl-S-phenylalanine.

9.4 mmol of S-alanyl-(2S, 3aS, 6aS)-octahydrocyclopenta/t>7pyrrole-2-carbonyl-S-phenylalanine tert-butyl ester are dissolved together with 3.4 mmol of triethylamine in 10 ml of dry dichloromethane. At 20°C, 5.16 g (3.4 mmol) of 4-phenyl-2-R-trifluoromethylsulfonyloxybutyric acid ethyl ester dissolved in 5 ml of dry dichloromethane are added dropwise. After 1 hour, wash at 20°C with water, dry over sodium sulphate and evaporate. The product formed is reacted as described in example 1b with trifluoroacetic acid.

The physical properties of the product thus formed agree with those of the compound with example lb.

Analogous to the methods mentioned in examples 3 to 6, resp. the compounds listed according to example 1 are prepared using suitable starting materials.

Claims (5)

1. Process for preparing a compound of formula I in which n means 1 or 2, R means hydrogen, an optionally substituted aliphatic residue with 1 to 8 C atoms, an optionally substituted alicyclic residue with 3-9 C atoms, an optionally substituted aromatic residue with 6-12 C atoms, an optionally substituted araliphatic residue with 7-14 C atoms, an optionally substituted alicyclic-aliphatic residue with 7-14 C atoms, a residue OR cl or SR cL, wherein Ra means an optionally substituted aliphatic residue with 1-4 C- atoms, an optionally substituted aromatic residue with 6-12 C atoms, or an optionally substituted heteroaromatic residue with 5-12 ring atoms, R"*" means hydrogen, an optionally substituted aliphatic residue with 1-6 C atoms, an optionally substituted alicyclic residue with 3-9 C atoms, an optionally substituted alicyclic-aliphatic residue with 4-13 C atoms, an optionally substituted aromatic residue with 6-12 C atoms, an optionally substituted araliphatic residue with 7-16 C atoms, an optionally substituted heteroaromatic residue with 5-12 ring atoms, or an if necessary protected side chain of a naturally occurring amino acid, R 2 and R 3 are the same or different and mean hydrogen, an optionally substituted aliphatic residue with 1-6 C atoms, an optionally substituted alicyclic residue with 3-9 C atoms, an optionally substituted aromatic residue with 6-12 C atoms, an optionally substituted araliphatic residue with 7-16 C atoms, and 4 5 R and R together with the atoms that bear them mean a hetero cyclic bi- or tricyclic ring system from the group Octahydrocyclopenta/ b/pyrrole (A), 2-aza-bicyclo/ 2, 2, 2/-octane (B), 2-azabicyclo/~2,2, l/heptane, (C ), spiro/ (bicyclo/ 2,2,17heptane)-2,3'-pyrrolidine/ (D), spiro/~(bicyclo/ 2,2,2/-octane)-2,3'-pyrrolidine/ (E ), 2-azatricyclo / 4,3,0,1 "_/-decane (F), decahydrocyclohepta/b/pyrrole (G), 2,3,3a,4,5,7a-hexahydroindole (H), 2- azabicyclo / 3,1,o7hexane (I), trans-octahydroindole (J), trans-octahydroisoindole (K), 1,2,3,3a,4,6a-hexahydrocyclo-penta/b/pyrrole (L) and A means the residue of an optionally protected natural amino acid, as well as their physiologically tolerable salts with acids or bases, characterized by ata) a compound of formula II 12 4 5 in which the residues R, R , R , R and R as well as n have the above meaning, are reacted with an amino acid ester of formula III in which A has the above meaning, and R 3 means an esterifying group, possibly cleaved protective group R 3 and optionally the residue R 2 is removed, orb) a compound of formula IV 13 4 5 in which R , R , R and R have the above meaning, are exchanged with a compound of formula V in which R and R 2 have the above meaning, the carbonyl group is hydrogenated and optionally residues R <2> and/or R <3> are split off, or c) a compound of formula IV is reacted with a compound of formula VI and a compound of formula VII in which R and R 2 have the above meaning, and are further obtained as described under b), d) a compound of formula IV is reacted with a compound of formula VIII in which n, R and R 2 have the above meaning, the Schiff base formed is reduced and optionally residues R 2 and/or R 3 are split off, or) a compound of formula IV is reacted with a compound of formula IX in which n, R and R 2 have the above meaning, and optionally av-2 3 residues R and/or R are cleaved, and the thus formed compound of formula I is optionally transferred in its physiologically tolerable salts. 2. Method according to claim 1, characterized in that a compound of formula I is prepared, wherein n means 1 or 2, R means hydrogen, alkyl with 1-8 C atoms, alkenyl with 2-6 C atoms, cycloalkyl with 3-9 C atoms, aryl with 6-12 C atoms, which can be mono-, di--i or tri-substituted with (C^ -C^ )-alkyl, (C-^ -C^ )-alkoxy, hydroxy, halogen, nitro, amino, aminomethyl, (C^ -C^ ) -alkylamino, di-(C^ -C^ )-alkylamino, (C^ -C^ )-acylamino, preferably (C^ -C^ )-alkanoylamino, methylenedioxy, carboxy, cyano and/or sulfamoyl, alkoxy with 1- 4 C atoms, aryloxy with 6-12 C atoms, which may be substituted as described above by aryl, mono- or bicyclic heteroaryloxy with 5-7, resp. 8-10 ring atoms, of which 1 to 2 ring atoms mean sulfur or oxygen atoms, and/or 1 to 4 ring atoms mean nitrogen, which may be substituted as described above by aryl, amino-(C^ -C^ )-alkyl, ^Cl-C4 ^ ~alkanoylamino-(C^~C4)-alkyl, (C7~ C13 )-aroylamino-(C^ -C^ )-alkyl, ^C1~C4 ^ ~alk°oxy-carbonylamino- ^ci~C4 )-alkyl, (Cg-C-^2 ) -aryl- ( C^"C4 )-Alkoxycarbonylamino-(C^"C4 )-alkyl, (C6 -C12 )-aryl-(C1~ C4 )-alkylamino-(C^-C^ )-alkyl, ( C-^- C^ ) -alkylamino-(C1-C4)-alkyl, di-(C1~ C4 )-alkylamino-(C1~ C4 )-alkyl, guanidino-(C^ -C4 )-alkyl, imidazolyl, indolyl, (C1 -C4 )-alkylthio, (C1-C4)-alkylthio-('C^-C^)-alkyl, (C6-C12 )-arylthio-(C-j^-C^ )-alkylthio, which in the aryl part may be substituted as described above by aryl, (C 6 -C 12 )-aryl-(C 1 -C 2 )-alkylthio, which in the aryl part may be substituted as described above by aryl, carboxy-(C 1 -C 4 )-alkyl, carboxy, carbamoyl, carbamoyl-(C 1 -C 4 )-alkyl, (C-]_-C 4 )-alkoxycarbonyl-(C 1 -C 4 )-alkyl, (C 6 -C 12 )-aryloxy-(C 1 -C 4 )-alkyl, which in the aryl part may be substituted as described above by aryl, (C6 -C12 )-aryl-(C1~C4 )-Alkoxy, which in the aryl part may be substituted as described above by aryl, R"*" means hydrogen, alkyl with 1-6 C atoms, alkenyl with 2-6 C atoms, alkynyl with 2-6 C atoms, cycloalkyl with 3-9 C atoms, cycloalkenyl with 5-9 C atoms, (C3 -C9 )-cycloalkyl-(C1~ C4 )-alkyl, (C5 -Cg)-cycloalkenyl-(C1~ C4 )-alkyl, optionally partially hydrogenated aryl with 6-12 C atoms which may be substituted as described above by R' (C6 -C12 )-aryl-(C1 -C4 )-alkyl or (C7~ C13 )-aroyl-(C, or C )alkyl, as both <2> e can be substituted as in the case above aryl, mono or bicyclic optionally partially hydrogenated heteroaryl with 5-7 resp. 8-10 ring atoms, of which 1 to 2 ring atoms represent sulfur or oxygen atoms, and/or 1 to 4 ring atoms represent hydrogen atoms, which can be substituted as with the above aryl, the optionally protected side chain of a naturally occurring α-amino acid R -CH(NH2 )-COOH, 2 3 R and R are the same or different and mean hydrogen, alkyl with 1-6 C atoms, alkenyl with 2-6 C atoms, di-(C -C4)-alkylamino-(C1~C4)-alkyl, (C1 -C5 )-alkanoyloxy-(C1~C4 )-alkyl, (C-^-Cg)-Alkoxy-carbonyloxy- (C-^-C4 )-alkyl, (C7-C13)-aroyloxy-(C1-C4)-alkyl, (Cg-C12)-aryloxycarbonyloxy(Ci-C^ )-alkyl, aryl with 6-12 C atoms, (C6 -C12 )-aryl-(C1 -C4 )-alkyl, (C3 -Cg)-cycloalkyl or (C3 -Cg)-cycloalkyl-(C1~ C4 )-alkyl, and 4 5 R and R have the above meaning, and A means an amino acid residue from the group alanyl, leucyl, isoleucyl, arginyl, glycyl, histidyl, methionyl, phenylalanyl, seryl, threonyl, tyrosyl, valyl, lysyl, O-methyltyrosyl, O-ethyltyrosyl, N-E-tert-butoxy-carbonyl-lysyl, N£-benzyloxycarbonyl- lysyl, as well as their physiologically tolerable salts with acids and bases. 3. Method according to claim 1 or 2, characterized in that a compound of formula I is prepared, wherein n means 1 or 2, R means (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, (C 3 -C 8 )-cycloalkyl, amino-(C-^-C^ )-alkyl, (C2~C5)-acylamino-(C-^-C^)-alkyl, (c7~c13)-aroylamino-(C-^-C^)-alkyl . -C^2 )-aryl, which may be mono-, di- or tri-substituted with (C-^ -C^)-alkyl, (C^-C4 )-alkoxy, hydroxy, halogen, nitro, amino, (C^ -C4 )-alkylamino, di-(C-j_-C4 )-alkylamino, and/or methylenedioxy or means 3-indolyl, especially methyl, ethyl, cyclohexyl, tert, -butoxycarbonylamino-(C-^-C4)-alkyl, benzoyloxycarbonylamino-(C-^-C4 )-alkyl or phenyl, which may be mono- or disubstituted with phenyl-(C-^-C2 )-alkyl, (C-^ or C^)-Alkoxy, hydroxy, fluorine, chlorine, bromine, amino, (C-^-C4)-alkylamino, di-(C-^-C^)-alkylamino, nitro, and/or methylene dioxide , or in the event that methoxy may be trisubstituted, R"*" means hydrogen or (C-^-Cg)-alkyl, which may optionally be substituted with amino, (C-^-Cg)-acylamino or benzoylamino, or means (C2~Cg)-alkenyl, ( C^ -Cg)-cycloalkyl, (C5 -Cg)-cycloalkenyl, (C3~ C7 )-cycloalkyl-(C1~ <C> 4) <-> alkyl, (Cg-C^2 )-aryl or partially hydrogenated aryl which respectively may be substituted by (C 1 -C 4 )-alkyl, (C 3 or C 2 )- alkoxy or halogen, or means (C 8 -C 2 )-aryl-(C 3 to C 4 )-alkyl or (C 3 - C,^)-aroyl-(C-^-C,^ )-alkyl, both of which may be substituted in the aryl residue as defined above, a mono- or resp. bicyclic heterocyclene residue with 5 to 7 resp. 8 to 10 ring atoms, of which 1 to 2 ring atoms mean sulfur or oxygen atoms, and/or 1 to 10 ring atoms mean nitrogen atoms, or a side chain of a naturally occurring optionally protected α-amino acid, especially however hydrogen, (C^ -C3 )- alkyl, (C 2 or C 1 )-alkenyl, the optionally protected side chain of lysine, benzyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-amino-butyl or benzoylmethyl, 2 3 R and R are the same or different residues and mean hydrogen, (C 1 -C 8 )-alkyl, (C 2 - C 6 )-alkenyl or (C 8 -C 12 )-aryl-(C 1 -C 4 )-alkyl, however hydrogen, (C 1 -C %)-alkyl or benzyl, and 4 5 R and R have the above meaning, and A means an amino acid residue from the group alanyl, phenylalanyl, lysyl, N£ -benzyloxycarbonyl-lysyl, or seryl, as well as their physiologically tolerable salts or bases. 4. Method according to one of claims 1 to 3, characterized in that a compound of formula I is prepared, wherein n means 2, R means phenyl, R"1" means methyl, R 2 and R 3 mean hydrogen or the same or different (C 1 -C 8 )-alkyl radicals or (C 1 -C 3 q )-aralkyl radicals, and R<4> , R^ and A have the above meaning, as well as their physiologically tolerable salts with acids or bases. 5. Process for the production of a pharmaceutical agent containing a compound of formula I according to one of claims 1-4, characterized in that these and a carrier are brought into a suitable administration form.