| PATENT ASSIGNEE'S COUNTRY | Germany |
| UPDATE | 11.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 14.11.00 |
| PATENT TITLE |
Amino acid derivatives, processes for the manufacture thereof and pharmaceutical compositions containing these compounds |
| PATENT ABSTRACT |
The invention relates to new amino acid derivatives of general formula I and the pharmaceutically acceptable salts thereof, wherein group B is --A.sup.2 --NR.sup.2 R.sup.3 or R.sup.5, wherein group R.sup.5 is ##STR1## and R.sup.1, A.sup.1, A.sup.2, R.sup.2, R.sup.3, R.sup.6, R.sup.7, R.sup.8, R.sup.9, X, Y, Z, t and u have the meanings described in the specification, as well as the preparation and use thereof. The novel compounds are valuable neurokinin (tachykinin) antagonists. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 08.07.98 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED | This data is not available for free |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound of formula ##STR355## wherein T is methyl or methoxy and Q is an arylalkanoyl selected from the group consisting of ##STR356## pharmaceutically acceptable salt thereof. 2. A compound of formula ##STR357## wherein T is methyl or methoxy and Q' is an alkanoyl selected from the group consisting of ##STR358## or a pharmaceutically acceptable salt thereof. 3. A compound of formula ##STR359## wherein T is methyl or methoxy and Q" is an aryloxyacetyl selected from the group consisting of ##STR360## or a pharmaceutically acceptable salt thereof |
| PATENT DESCRIPTION |
The invention relates to new amino acid derivatives of general formula I, ##STR2## wherein B represents the group --A.sup.2 --NR.sup.2 R.sup.3 or R.sup.5, and the pharmaceutically acceptable salts thereof, processes for their preparation and pharmaceutical compositions containing these compounds. The compounds are valuable neurokinin (tachykinin)-antagonists. European Patent Applications EP 394 989 and EP 443 132 disclose peptides with a neurokinin-antagonistic action. The compounds according to the invention differ significantly from these peptides in the members A.sup.2, R.sup.5 and ##STR3## The abbreviations used for the amino acids in this specification and the claims correspond to the conventional three letter code described for example in Europ. J. Biochem., 138, 9 (1984). The other abbreviations are explained as follows: Boc=t-Butoxycarbonyl Bzl=Benzyl CDI=Carbonyldiimidazole Cha=3-Cyclohexylalanine DCCI=Dicyclohexylcarbodiimide DCH=Dicyclohexylurea HOBt=1-Hydroxybenzotriazole Hpa=Homophenylalanine Hyp=(2S,4R)-Hydroxyproline Pal=3-(1-Pyrrolyl)alanine THF=Tetrahydrofuran TFA=Trifluoroacetic acid Z=Benzyloxycarbonyl Me=Methyl Ac=Acetyl Et=Ethyl DMF=Dimethylformamide DPPA=Diphenylphosphorylazide PPA=Polyphosphoric acid RT=ambient temperature Unless explicitly indicated otherwise in the following text, the expression amino acid covers natural and unnatural amino acids, both of the D- and L-form, more particularly .alpha.-amino acids as well as the isomers thereof. If an amino acid is given without prefix (e.g. Orn) this indicates the L-form of the amino acids. The D-form is explicitly indicated. The invention relates to new amino acid derivatives of general formula I ##STR4## and the pharmaceutically acceptable salts thereof, wherein R.sup.1 is vinyl, aryl, heteroaryl, aralkyl, heteroaralkyl, arylvinyl, heteroarylvinyl, aryloxyalkyl, arylalkyloxy, (C.sub.3-8)cycloalkyl, (C.sub.3-8)cycloalkylalkyl, bicycloheptyl or bicycloheptylalkyl (either unsubstituted or substituted by 1-3 methyl groups), adamantyl, adamantylalkyl, decalin, decalinalkyl, tetraline, tetralinalkyl, diphenylalkyl, di(arylalkyl)aminoalkyl or arylalkylaminoalkyl (wherein aryl is phenyl, mono-, di- or trisubstituted phenyl or naphthyl; the substituents of the phenyl group represent, independently of each other, halogen, trihalomethyl, alkoxy, alkyl, hydroxy, nitro, alkylcarbonyl or cyano; heteroaryl is indolyl, indolyl substituted in position 1 by alkyl or benzyl, pyridyl, pyrrolyl, imidazolyl or thienyl; and the alkyl or alkoxy group contains 1 to 3 carbon atoms; A.sup.1 is D- or L-alanine (Ala, (D- or L-valine (Val), D- or L-leucine (Leu), D- or L-isoleucine (Ile), D- or L-serine (Ser), D- or L-threonine (Thr), D- or L-allothreonine, D- or L-cysteine (Cys), D- or L-methionine (Met), D- or L-phenylalanine (Phe), D- or L-tryptophan (Trp), N-formyl protected Trp, D- or L-tyrosine (Tyr), D- or L-proline (Pro), D- or L-didehydroproline (.DELTA.Pro) such as 3,4-didehydroproline (.DELTA.3,4)-Pro), D- or L-hydroxyproline (Pro(OH)) such as 3-hydroxyproline (Pro(3OH)) and 4-hydroxyproline (Pro(4OH)), D- or L-azetidin-2-carboxylic acid (Azt), D- or L-thioproline (Tpr), D- or L-aminoproline (Pro(NH.sub.2)) such as 3-aminoproline (Pro(3NH.sub.2)) and 4-aminoproline (Pro(4NH.sub.2)), D- or L-pyroglutamic acid (pGlu), D- or L-2-aminoisobutyric acid (Aib), D- or L-2,3-diaminopropionic acid, D- or L-2,4-diaminobutyric acid, D- or L-glutamic acid (Glu), D- or L-aspartic acid (Asp), D- or L-glutamine (Gln), D- or L-asparagine (Asn), D- or L-lysine (Lys), D- or L-arginine (Arg), D- or L-histidine (His), D- or L-ornithine (Orn), D- or L-hydroxy piperidine carboxylic acid such as 5-hydroxypiperidine-2-carboxylic acid, D- or L-mercaptoproline (Pro(SH)) such as 3-mercaptoproline (Pro(3SH)) and 4-mercaptoproline (Pro)4SH)), Tpr(O), Met(O), Tpr(O.sub.2) or Met(O.sub.2), and the geometric isomers thereof, whereby the hydroxy and amino groups contained therein may be protected by usual protective groups (e.g. acyl, carbamoyl or aralkyl (in particular benzyl)); B is group --A.sup.2 --NR.sup.2 R.sup.3 -- or --R.sup.5 ; A.sup.2 is a lipophile .alpha.-amino acid which contains a phenyl, 1-, 2- or 3-substituted phenyl, heteroaryl, cyclohexyl or cyclopentyl group, a naphthyl group or a mono- or di-C.sub.1-3 -alkylamino group, and this cyclic group or amino group is separated by 1- to 8-membered chain from the backbone of the amino acid, (whereby the substituents of the phenyl group may, independently of each other, be halogen, trihalomethyl, alkoxy, alkyl, cyano or 1-pyrrolidinyl and whereby in the 1- to 8-membered chain, the members of the chain may be --CHR.sup.4, --C(O)--, --O--, --S-- and/or --NR.sup.4 -- which are arranged such that they result in one of the following three types of chains --(CHR.sup.4).sub.1-8 -- --(CHR.sup.4).sub.0-p --G.sup.1 --(CHR.sup.4).sub.0-q -- --(CHR.sup.4).sub.1-p --G.sup.2 --(CHR.sup.4).sub.0-q -- wherein G.sup.1 is --C(O)O-- or --C(O)--NR.sup.4 --, G.sup.2 is --O--, --S--, --NR.sup.4 --C(O)--O--, --NR.sup.4 --C(O)--, --NR.sup.4 --C(O)--NR.sup.4 -- or --O--C(O)--NR.sup.4 -- and p and q are whole numbers from 1 to 6 which are chosen such that the total number of the chain members is 1 to 8, and R.sup.4 is hydrogen, alkyl, aryl or aralkyl, wherein aryl is phenyl, mono-, di- or trisubstituted phenyl or naphthyl; the substituents of the phenyl group are, independently of each other halogen, trihalomethyl, alkoxy, alkyl or cyano, and the alkyl group contains 1 to 3 carbon atoms; (whereby, if one chain contains more than one --CHR.sup.4 -group, R.sup.4 can only be alkyl, aryl or aralkyl in one of these --CHR.sup.4 -groups and whereby the chain is not CH.sub.2, if R.sup.2 and R.sup.3 are alkyl or aralkyl and if ##STR5## together form the group ##STR6## and m and n are each 0, 1, 2 or 3, wherein the sum thereof is 2, 3, 4 or 5) or A.sup.2 is Leu, Ile, Nle, Val, Met or one of the groups ##STR7## (wherein x and y independently of each other are 1 or 2); R.sup.2 and R.sup.3 independently of each other are alkyl, arylalkyl, heteroaryl or hydroxy (wherein aryl is phenyl, mono-, di- or trisubstituted phenyl or naphthyl; the substituents of the phenyl group are, independently of each other halogen, trihalomethyl, alkoxy, alkyl, alkylthio, hydroxy, nitro, trifluoromethoxy, dialkylamino or cyano or 2 adjacent positions of the phenyl group are linked by --O--(CH.sub.2).sub.1 or 2 --O--; heteroaryl is indolyl, pyridyl, pyrrolyl, imidazolyl or thienyl; and the alkyl or alkoxy group contains 1 to 3 carbon atoms) or the group ##STR8## is a ring of general formula ##STR9## wherein m and n are each 0, 1, 2 or 3, whereby the sum thereof is 2, 3, 4 or 5, s is 2 or 3, W is the group ##STR10## (CH.sub.2).sub.0-2 -aryl, CH(aryl).sub.2, cyclopentyl, (CH.sub.2).sub.0-2 -cyclohexyl, pyridyl or ##STR11## (wherein aryl is phenyl, mono-, di- or trisubstituted phenyl or naphthyl; the substituents of the phenyl group independently of each other are halogen, trihalomethyl, alkoxy, alkyl, cyano, hydroxy, nitro or alkylthio or 2 adjacent positions of the phenyl group are linked by --O--(CH.sub.2).sub.1-2 --O-- and alkyl contains 1 to 3 carbon atoms); R.sup.5 is an amine of formula ##STR12## wherein R.sup.6 is aralkyl, diarylalkyl (in these groups aryl is phenyl or naphthyl and alkyl (C.sub.1-5)alkyl), heteroaryl-(C.sub.1-5)alkyl (wherein heteroaryl is 2-, 3- or 4-pyridyl or 2- or 3-thienyl), phenylamino-(C.sub.1-5) alkyl, nephthylamino-(C.sub.1-5) alkyl or N-phenylalkylpiperidinyl (wherein the phenyl groups listed are not substituted or contain 1, 2 or 3 substituents which are, independently of each other (C.sub.1-5)alkyl, preferably methyl, (C.sub.1-5)alkoxy, preferably methoxy, dimethylamine, halogen, trifluoromethyl, --CN or OCF.sub.3); R.sub.7 is hydrogen or (C.sub.1-5)-alkyl; X is O or H.sub.2 ; Y and Z independently of each other are hydrogen, (C.sub.1-5)alkyl; (C.sub.1-5)alkyloxy, benzyloxy (wherein the phenyl group is not substituted or contains 1, 2 or 3 substituents which are independently of each other (C.sub.1-5)alkyl, preferably methyl, (C.sub.1-5)alkoxy, preferably methoxy, dimethylamine, halogen, trifluoromethyl, --CN or OCF.sub.3), OCF.sub.3, halogen, CF.sub.3, CN, CH.sub.2 NH.sub.2, CONH.sub.2, N-(C.sub.1-5 -alkyl).sub.2, NH-(C.sub.1-4) alkylcarbonyl, N-(C.sub.1-5) alkyl-N-(C.sub.1-4) alkylcarbonyl, NH.sub.2 or NH-(C.sub.1-5) alkyl or if Y and Z are in a vicinal position to one another, both together represent --OCH.sub.2 O--, OCH.sub.2 CH.sub.2 O-- or (CH).sub.4 ; t and u have one of the following meanings (a) t and u are zero (b) t is one and u is zero (c) t and u are each one (d) t is two and u is zero; and if t is one and u is zero, R.sup.5 is also an amine of formula IV ##STR13## wherein R.sup.6, R.sup.7, Y and Z have the above meanings and R.sup.8 is hydrogen and R.sup.9 is hydroxy, (C.sub.1-5)alkoxy, phenyl-(C.sub.1-5)alkyloxy, naphthyl-(C.sub.1-5)alkyloxy or (C.sub.1-4)alkylcarbonyl, or wherein R.sup.8 and R.sup.9 are both oxygen or --OCH.sub.2 CH.sub.2 O--; and the chirality to C* may be R or S. Compounds of general formula I may have acid groups, mainly carboxyl groups or phenolic hydroxy groups, and/or alkaline groups such as guanidino or amino functions. Therefore, compounds of general formula I may be present either as inner salts, as salts with pharmaceutically usable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (e.g. maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically usable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as diethylamine, triethylamine, triethanolamine and the like. The chiral centres in the new amino acid derivatives may have an R-, S- or R,S-configuration. The expression "heteroaryl group" contained in the definition of A.sup.2 represents a mono-, bi- or tricyclic aromatic ring system which contains 1 or 2 heteroatoms, namely one or two nitrogen atoms or one nitrogen atom and one sulphur atom. The group may optionally contain 1 or 2 substituents (C.sub.1-3 alkyl) or one oxo group or one alkoxy group. Examples of suitable heteroaryl groups are ##STR14## It must be noted that the above heteroaryl groups may also be bound to the chain in positions other than those mentioned. As mentioned above, the "1- to 8-membered chain" contained in A.sup.2 comprises 1 to 8 members denoting the following groups: --CHR.sup.4 --, --C(O)--, --O--, --S--, --NR.sup.4 --. The chain is bound to the .alpha.-carbon atom of the amino acid (A.sup.2). R.sup.4 represents (as indicated above) hydrogen, alkyl, aryl or aralkyl, R.sup.4 is preferably hydrogen, methyl or phenyl. Examples of suitable chains are --(CH.sub.2).sub.1-4 -- --CH.sub.2 --O--CH.sub.2 --, --CH.sub.2 --O-- --CH.sub.2 --S--CH.sub.2 --, --CH.sub.2 --S-- --CH(CH.sub.3)--O--CH.sub.2 --, --CH(CH.sub.3)--O-- --(CH.sub.2).sub.1-2 --C(O)--O--CH.sub.2 --, --C(O)--NH-- --(CH.sub.2).sub.4 --NH--C(O)--O--CH.sub.2 -- --CH.sub.2 --C(O)--NH-- --CH.sub.2 --C(O)--NH--CH.sub.2 -- --CH.sub.2 --C(O)--N(CH.sub.3)--CH.sub.2 -- --CH.sub.2 --C(O)--O-- --CH.sub.2 --NH--C(O)--CH.sub.2 -- --CH.sub.2 --NH--C(O)--O-- --CH.sub.2 --NH--C(O)--O--CH.sub.2 -- --CH.sub.2 --NH--C(O)--NH-- --(CH.sub.2).sub.2 --C(O)--NH--(CH.sub.2).sub.2 -- --(CH.sub.2).sub.4 --NH--C(O)--CH.sub.2 -- --(CH.sub.2).sub.3 --NH--C(O)--O--CH.sub.2 -- The chain contains preferably 1 to 5, more particularly 1 to 4 members. Those compounds of formula I, according to the invention, are preferred, wherein R.sup.1 is vinyl, aryl, heteroaryl, aralkyl, heteroaralkyl, arylvinyl, heteroarylvinyl, aryloxyalkyl, arylalkyloxy, di(arylalkyl)aminoalkyl or arylalkylaminoalkyl (wherein aryl is phenyl, mono-, di- or trisubstituted phenyl or naphthyl; the substituents of the phenyl group, independently of each other are halogen, trihalomethyl, alkoxy, alkyl or cyano; heteroaryl is indolyl, indolyl substituted in position 1 by alkyl or benzyl, pyridyl, pyrrolyl, imidazolyl or thienyl; and the alkyl or alkoxy group contains 1 to 3 carbon atoms); A.sup.1 is D- or L-alanine (Ala), (D- or L-valine (Val), D- or L-leucine (Leu), D- or L-isoleucine (Ile), D- or L-serine (Ser), D- or L-threonine (Thr), D- or L-allothreonine, D- or L-cysteine (Cys), D- or L-methionine (Met), D- or L-phenylalanine (Phe), D- or L-tryptophan (Trp), N-formyl protected Trp, D- or L-tyrosine (Tyr), D- or L-proline (Pro), D- or L-didehydroproline (.DELTA.Pro) such as 3,4-didehydroproline (.DELTA.(3,4)-Pro), D- or L-hydroxyproline (Pro(OH)) such as 3-hydroxyproline (Pro(3OH)) and 4-hydroxyproline (Pro(4OH)), D- or L-azetidin-2-carboxylic acid (Azt), D- or L-thioproline (Tpr), D- or L-aminoproline (Pro(NH.sub.2)) such as 3-aminoproline (Pro(3NH.sub.2)) and 4-aminoproline (Pro(4NH.sub.2)), D- or L-pyroglutamic acid (pGlu), D- or L-2-aminoisobutyric acid (Aib), D- or L-2,3-diaminopropionic acid, D- or L-2,4-diaminobutyric acid, D- or L-glutamic acid (Glu), D- or L-aspartic acid (Asp), D- or L-glutamine (Gln), D- or L-asparagine (Asn), D- or L-lysine (Lys), D- or L-arginine (Arg), D- or L-histidine (His), D- or L-ornithine (Orn), D- or L-hydroxy piperidine carboxylic acid such as 5-hydroxypiperidine-2-carboxylic acid, D- or L-mercaptoproline (Pro(SH)) such as 3-mercaptoproline (Pro(3SH)) and 4-mercaptoproline (Pro(4SH)), Tpr(O), Met(O), Tpr(O.sub.2) or Met (O.sub.2), and the geometric isomers thereof, whereby the hydroxy and amino groups contained therein may be protected by usual protective groups (e.g. acyl, carbamoyl or aralkyl (in particular benzyl)); and if B is group --A.sup.2 --NR.sup.2 R.sup.3 A.sup.2 is a lipophilic amino acid which contains a phenyl-, mono-, di- or trisubstituted phenyl-, heteroaryl-, cyclohexyl- or cyclopentyl group or a mono- or di-C.sub.1-3 -alkylamino group, and this cyclic group or amino group is separated by a 1- to 8-membered chain from the backbone of the amino acid (whereby the substituents of the phenyl group independently of each other are halogen, trihalomethyl, alkoxy, alkyl, cyano or 1-pyrrolidinyl and the chain is defined as in claim 1) or A.sup.2 is Leu, Ile, Nle, Val, Met or one of the groups ##STR15## (wherein x and y independently of each other are 1 or 2); R.sup.2 and R.sup.3 independently of each other are alkyl, arylalkyl, heteroaryl or hydroxy (wherein aryl represents phenyl, mono-, di- or trisubstituted phenyl or naphthyl; the substituents of the phenyl group independently of each other denote halogen, trihalomethyl, alkoxy, alkyl or cyano; heteroaryl represents indolyl, pyridyl, pyrrolyl, imidazolyl or thienyl; and the alkyl or alkoxy groups contains 1 to 3 carbon atoms) or the group ##STR16## is a ring of general formula ##STR17## wherein m, n and s are defined as in claim 1 and W is the group ##STR18## --(CH.sub.2).sub.0-2 -aryl, CH(aryl).sub.2, cyclopentyl or (CH.sub.2).sub.0-2 -cyclohexyl (wherein aryl represents phenyl, mono-, di- or trisubstituted phenyl or naphthyl; the substituents of the phenyl group independently of each other are halogen, trihalomethyl, alkoxy, alkyl or cyano). Of the compounds, according to the invention, of formula Ia R.sup.1 --C(O)--A.sup.1 --A.sup.2 --NR.sup.2 R.sup.3 Ia those are preferred wherein R.sup.1 represents aryl, heteroaryl, aralkyl, heteroaralkyl, aryloxyalkyl, arylalkyloxy, di(arylalkyl)aminoalkyl (wherein aryl denotes phenyl or mono- or disubstituted phenyl; the substituents of the phenyl group independently of each other are halogen or alkoxy; heteroaryl denotes indolyl, indolyl or pyridyl substituted by alkyl or benzyl in position 1; and the alkyl or alkoxy group contains 1 to 3 carbon atoms; particularly ##STR19## and/or A.sup.1 is an amino acid which carries one or 2 polar functional group(s) in the side chain such as OH, COOH, NH.sub.2, guanidine, CONH.sub.2, SH; particularly wherein the functional group in the side chain of A.sup.1 is OH and/or wherein A.sup.1 is Pro, 4-hydroxyproline, 3-hydroxyproline, Ser, Thr, Trp(For) or Tyr; preferably 4-hydroxyproline with 2-S-configuration, particularly ##STR20## and/or wherein A.sup.2 represents an acyclic or cyclic amino acid such as (O-benzyl)Ser, (O-subst. benzyl)Ser, (O-benzyl)Thr, cyclohexylalanine, homophenylalanine, 3-(1-pyrrolyl)-alanine, 3-(2,5-dimethyl-1-pyrrolyl)alanine, 3-(1-indolyl)alanine, 2-amino-4-(1-pyrrolyl)-butyric acid, 2-amino-5-(1-pyrrolyl)valeric acid, 2-amino-6-(1-pyrrolyl)caproic acid, Leu, Lys(Z), 3-(2-thienyl)alanine, 3-(3-benzothienyl)alanine, 3-(1-isoindolinonyl)alanine, (O-benzyl)Asp, (O-benzyl)Glu, Trp, (N-Me)Trp, His, 3-(2-thiazolyl)-alanine, or 3-dimethylamino-alanine, -(O-methyl)Tyr, 2-naphthylalanine, ##STR21## wherein the phenyl groups contained in the amino acids may be mono-, di- or trisubstituted and the substituents independently of each other are halogen, trihalomethyl, alkoxy, alkyl or cyano, the alkyl or alkoxy group contains 1 to 3 carbon atoms; and wherein the above amino acids are preferably present in S-configuration; special mention must be made of compounds wherein A.sup.2 ##STR22## and/or wherein R.sup.2 and R.sup.3 independently of each other represent methyl, benzyl, phenethyl (wherein the phenyl groups contained therein are substituted by one or two methoxy groups) or pyridylmethyl; preferably a compound wherein R.sup.2 is methyl and R.sup.3 is benzyl or alkoxybenzyl, more particularly wherein R.sup.3 is alkoxybenzyl, preferably 2-methoxybenzyl; or wherein the group ##STR23## represents a ring ##STR24## wherein m is 1 and n is 1 or 2; or wherein the group ##STR25## is a ring ##STR26## wherein s is 2 or 3 (preferably 2) and W is as hereinbefore defined; preferably wherein W ##STR27## is cyclohexyl, phenyl or CH(phenyl).sub.2 wherein the phenyl groups are substituted; wherein if W is phenyl, this is preferably monosubstituted by halogen, alkoxy, alkyl, cyano, hydroxy, nitro or alkylthio, particularly by methoxy, chlorine, methyl, ethyl, cyano, hydroxy, nitro or methylthio, preferably by methoxy, chlorine, methyl, cyano or methylthio, wherein the substituent of the phenyl group is preferably in position 2 and if W represents the group --CH(phenyl).sub.2, the phenyl group is substituted by one halogen each, preferably by fluorine, wherein in the --CH(phenyl).sub.2 group the two phenyl groups are preferably substituted identically, preferably in p-position. Of the compounds, according to the invention, of formula Ib R.sup.1 --C(O)--A.sup.1 --R.sup.5 Ib those are preferred wherein R.sup.1 represents aryl, heteroaryl, aralkyl, heteroaralkyl, aryloxyalkyl, arylalkyloxy, di(arylalkyl)aminoalkyl (wherein aryl represents phenyl or mono- or polysubstituted phenyl; the substituents of the phenyl groups independently of each other are halogen or alkoxy; heteroaryl denotes indolyl, indolyl or pyridyl substituted by alkyl or benzyl in position 1; and the alkyl or alkoxy group contains 1 to 3 carbon atoms); particularly ##STR28## and/or A.sup.1 is an amino acid which carries one or 2 polar functional group(s) in the side chain such as OH, COOH, NH.sub.2, guanidine, CONH.sub.2, SH; particularly wherein the functional group in the side chain of A.sup.1 represents OH and/or wherein A.sup.1 is Pro, 4-hydroxyproline, 3-hydroxyproline, Ser, Thr, Trp(For) or Tyr; preferably 4-hydroxyproline with 2-S-configuration, particularly ##STR29## Of the compounds according to the invention, those are preferred wherein R.sup.5 is a group of general formula II ##STR30## particularly those wherein t is one and u is zero or t is two and u is zero or t and u is one each, and R.sup.6, R.sup.7, X, Y and Z are specified as hereinbefore. Special mention must be made of those compounds wherein R.sup.6 is benzyl or methoxybenzyl and/or wherein R.sup.7 is hydrogen and/or wherein X is oxo and/or wherein Y and Z independently of each other represent methoxy, hydrogen, CF.sub.3 or tert.butyl or together --(CH).sub.4 --. The above amino acids are preferably in S-configuration. Test results of the compounds according to the invention: The receptor affinity to the NK.sub.1 -receptor (substance P-receptor) was determined with cloned NK.sub.1 -receptors on human lymphoblastoma cells (IM-9), whereby the displacement of .sup.125 I-labelled substance P is measured. The IC.sub.50 -values thus obtained are: Compound A: 60 nM Compound B: 21 nM Compound C: 90 nM Compound D: 45 nM Compound E: 6 nM Compound F: 15 nM Compound G: 1.7 nM ##STR31## The compounds according to the invention are valuable neurokinin (tachykinin)-antagonists which have, in particular substance P-antagonism, but also neurokinin A- and neurokinin-B antagonistic properties. They are useful for treating and preventing neurokinin-receptive diseases such as respiratory tract diseases e.g. asthma, bronchitis, rhinitis, cough or expectoration as well as inflammatory eye diseases such as conjunctivitis, inflammatory skin diseases such as dermatitis and urticaria, other inflammatory diseases such as polyarthritis or osteoarthritis as well as painful conditions and vomiting. The invention also relates to the use of the compounds according to the invention as drugs and pharmaceutical preparations containing these compounds. It is preferred if the compounds are used for human beings. They may be given intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, inhalationally, transdermally, optionally assisted by iontophoresis or new enhancers, and orally. For the parenteral administration, the compounds of formula I or the physiologically compatible salts thereof are placed in solution, suspension or emulsion, optionally with the substances normally used for this purpose such as solubilisers, emulsifiers or other excipients. The solubilisers used are for example: water, physiological sodium chloride solutions or alcohols such as ethanol, propanediol or glycerin, sugar solutions such as glucose or mannitol solutions or else a mixture of different solubilisers. Furthermore, the compounds may be administered by implants, for example of polylactide, polyglycolide or polyhydroxybutyric acid or intranasal preparations. The compounds may be prepared using generally known methods of amino and peptide chemistry, by condensing, step by step, the relevant amino acids or peptide derivative part sequences, carboxylic acids and amines and isolating the compound thus obtained in free form or in the form of the desired salt. The dipeptide derivatives of formula Ia R.sup.1 --C(O)--A.sup.1 --A.sup.2 --NR.sup.2 R.sup.3 Ia may be synthesised from the parts R.sup.1 --COOH, H--A.sup.1 --OH, H--A.sup.2 --OH and HN(R.sup.3)R.sup.2, whereby the sequence of the couplings may be from right to left, from left to right or by coupling the units R.sup.1 --CO--A.sup.1 --OH and H--A.sup.2 --N(R.sup.3)R.sup.2 (fragment couplings). The compounds according to the invention may be prepared using generally known methods of peptide chemistry such as described in "Houben-Weyl, Methoden der organischen Chemie, Vol. 15/2", or using the solid phase peptide synthesis (e.g. R. C. Sheppard, Int. J. Pept. Prot. Res., 21, 118 [1983]) or similar known methods. Here, the relevant amino acids or amino acid partial sequences are condensed step by step and the resultant peptides are isolated in free form or in the form of the desired salts. The amino protective groups used as those described in "Houben-Weyl, Methoden der organischen Chemie, Vol. 15/1", whereby the benzyloxycarbonyl group (Z) is preferred in conventional syntheses and the fluorenylmethoxycarbonyl group (Fmoc) in solid phase syntheses. In the case of the conventional synthesis the side chain of the arginine was protected by protonation, in the case of the solid phase synthesis, the Mtr-group was used. In the solid phase peptide synthesis the following amino acids with protected side chains were for example used: Lys(Boc), His(Bum), Ser(tBu) and Asp(tBu). The specific synthesis conditions are apparent from the following Examples. For the synthesis of the compounds of general formula I using the solid phase synthesis, those dipeptide carboxylic acids are initially synthesised which are reacted in solution to form dipeptide amides. The following anchor groups are suitable 1. Benzylester (G. Barang, R. B. Merrifield, Peptides 2, 1 (1980) Eds. E. Gross, J. Meienhofer, Academic Press, New York) 2. PAM-Anker (R. B. Merrifield, J. Am. Chem. Soc. 85, 2149 (1966)) 3. Wang-Anker (S.-S. Wang, J. Am. Chem. Soc. 95, 1328 (1973)) 4. SASRIN-Anker (M. Mergler, R. Tanner, J. Gostuli, P. Grogg, Tetrah. Lett. 29, 4005 (1988)). For preparing the compounds of formula Ib R.sup.1 --C(O)--A.sup.1 --R.sup.5 Ib the components R.sup.1 --COOH, the amino acid H--A.sup.1 --OH and the amine H--R.sup.5 are bonded to one another. Optionally, the carboxylic acid of R.sup.1 --COOH may first be coupled with a suitably protected form of H--A.sup.1 --OH and concentrated with the amine H--R.sup.5 using the protective group cleavage, or the suitably protected amino acid H--A.sup.1 --OH may first be reacted with H--R.sup.5 and this product may be coupled with R.sup.1 --COOH after deprotection. The basic bodies of the amines H--R.sup.5 may be obtained using known methods: if H--R.sup.5 is ##STR32## with t=1 and u=0 and R.sup.6, Y and Z are as hereinbefore described, the preparation is carried out using known methods as described by A. L. Davis et al., J. Med. Chem. 18, 752 (1975) or H. Merz, DE 38 23 576 (C.A. 114 (21), 207 052 m). The introduction of the group R.sup.6 into a compound of general formula XI is carried out by the reaction with NaH and BrR.sup.6. This reaction may take place by either using a protective group (Sch) on the exocyclic N or not. This preparation may be demonstrated by the following reaction scheme: ##STR33## Suitable protective groups (Sch) are base-stable protective groups such as the Boc-group. In order to prepare a compound of general formula XI, a compound of general formula X is reduced under cyclisation (e.g. analogous to the method described by A. L. Davis et al. (J. Med. Chem. 9, 826 (1966)) by means of Pd-Mohr). The compound X may be prepared from the correspondingly substituted 1-nitrobenzylalcohol (VIII) and via the intermediary stages VIII and IX (by halogenation with e.g. SOCl.sub.2 and subsequent reaction with acetamidomalonic acid diethylester according to (J. Med. Chem. 9, 828 (1966)). An amine H--R.sup.5 of general formula IIb ##STR34## wherein t=1 and u=0 and R.sup.6, Y and Z are as specified hereinbefore for formula IIa may be prepared by reduction of a corresponding compound IIa by means of e.g. LiAlH.sub.4. For preparing a compound IIa, wherein t=u=0 and R.sup.6, Y and Z are as specified hereinbefore, the method according to A. L. Davis et al., J. Med. Chem. 16, 1043 (1973) is suitable. Here, starting from .alpha.-bromo-o-nitrophenylacetic acid methylester, the phthalimido group is introduced and after cleavage of the protective groups and the reduction of the nitro group, the cyclisation takes place to form (substituted or unsubstituted) 3-amino-2-indolinone: ##STR35## The introduction of R.sup.6 and reduction to form the analogous compound of general formula IIb may be carried out as indicated above. The preparation of compound IIa with t=2, u=0, wherein R.sup.6, Y and Z is as defined above may be summarised by the following reaction scheme: ##STR36## The introduction of R.sup.6 and reduction to form the analogous compound IIb may be carried out as indicated above. When using this preparation method, the correspondingly substituted 2-(2-nitrophenyl)-ethylbromide (XVIII) may be reacted with acetamidomalonic acid diethylester to form compound XIX and then XX, analogously to the methods described above. The reduction of compound XX to form compound XXI may be carried out under pressure in a solution of MeOH and water, for example by hydrogen in the presence of Pd-Mohr. The cyclisation to prepare compound XXII may be carried out by polyphosphoric acid whilst stirring and heating. The preparation of compound IIa with t=u=1, wherein R.sup.6, Y and Z is as defined above, may be carried out as follows: unsubstituted or substituted phthaloyl-phenylalanine is coupled with the amine H.sub.2 N--R.sup.6 and then cyclised with formaldehyde in a reaction of the Pictet-Spengler kind. Finally, the phthaloyl group is cleaved off, for example by treating with hydroxylamine: ##STR37## The reduction to form the analogous compound of general formula IIb may be carried out as indicated above. The preparation of an amine HR.sup.5 of general formula IIIa ##STR38## wherein R.sup.6, Y and Z are as defined above may be carried out according to G-Leclerc et al., J. Med. Chem. 29, 2427 (1986). For this purpose, substituted or unsubstituted 3-bromoquinoline is first converted into the corresponding N-oxide, then transposed to the quinolin-2-one and finally the amino group is introduced with ammonium under pressure (in the carrier tube): ##STR39## The introduction of the substituents R.sup.6 may be carried out as described above with respect to compound IIa. The preparation of a compound HR.sup.5 of general formula IVa ##STR40## wherein R.sup.6 is as defined above and R.sup.8 represents hydroxy and R.sup.9 is hydrogen, may be carried out according to R. Weichert, Arkiv Kemi 25, 231 (1966). Here, acetaminomalonic acid monoethylether is reacted with substituted or unsubstituted 2-nitrobenzaldehyde, finally it is hydrolysed, the nitro group is reduced and finally the cyclisation is carried out: ##STR41## The introduction of R.sup.6 is carried out as described above. In order to prepare a compound IVa wherein R.sup.9 represents (C.sub.1-5)alkoxy, phenyl-(C.sub.1-5)alkyloxy, naphthyl-(C.sub.1-5)alkyloxy or (C.sub.1-4)alkylcarbonyl or wherein R.sup.8 and R.sup.9 both represent oxygen or --OCH.sub.2 CH.sub.2 O--, the above compound IVa wherein R.sup.8 represents hydrogen and R.sup.6 represents hydroxy, may be reacted as follows: a) for preparing a compound IVa, wherein R.sup.9 is alkyloxy, phenyl or naphthylalkyloxy: etherication according to Williamson; b) for preparing a compound IVa, wherein R.sup.9 is alkylcarbonyl; reaction with the corresponding acid anhydride; c) for preparing a compound IVa, wherein R.sup.8 and R.sup.9 both represent oxygen: oxidation according to e.g. Oppenauer; d) for the preparation to form compound IVa, wherein R.sup.8 and R.sup.9 both represent --OCH.sub.2 CH.sub.2 O--: reaction of the keto compound obtained according to (c) with ethyleneglycol. In order to prepare amines of general formula H--R.sup.5, wherein R.sup.7 is alkyl, the compounds of general formula IIa, IIb, IIIa and IVa are alkylated. This alkylation may be carried out by protecting the exocyclic N initially by e.g. trifluoroacetyl, carrying out the alkylation with e.g. alkylbromide and then cleaving the protective group by e.g. hydrolysis. ______________________________________ Pharmaceutical Preparations: ______________________________________ Injection solution 200 mg active substance * 1.2 mg potassium dihydrogen phosphate = KH.sub.2 PO.sub.4) 0.2 mg sodium dihydrogen phosphate = (buffer) NaH.sub.2 PO.sub.4.2H.sub.2 O 94 mg sodium chloride or (isotonic) 520 mg glucose 4 mg albumin (protease protection) q.s. sodium hydroxide solution to pH 6 q.s. hydrochloric acid to 10 ml water for injection purposes Injection solution 200 mg active substance* 94 mg sodium chloride or 520 mg glucose 4 mg albumin q.s. sodium hydroxide solution to pH 9 q.s. hydrochloric acid to 10 ml water for injection purposes Lyophilisate 200 mg active substance* 520 mg mannitol (isotonic/structure builders) 4 mg albumin Solvent 1 for lyophilisate 10 ml water for injection purposes Solvent 2 for lyophilisate 20 mg Polysorbat .RTM. 80 = Tween .RTM. 80 (surface-active substance) 10 ml water for injection purposes ______________________________________ * Active substance: compounds according to the invention, for example the compound of Example 1 or 201. Dosage for human beings of 67 kg: 1 to 500 mg |
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