AU615516B2 - Renin inhibitors - Google Patents

Description

this 6th day of January 1989 W.G. BARB i k j i:;q 'i r

S

6 *0 so wow W mo Mii-- P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990 6 ms6 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

NOTICE

1. The specification should describe the invention in full and the best method of performing it known to the applicant.

2. The specification should be typed on as many sheets of good quality A4 International size paper as are necessary and inserted inside this form.

3. The claims defining the invention must start on a new pge. if there is insufficient space on this form for the claims, use separate sheets of paper.

The words "The claims defining the invention are as follows" should appear before claim 1. After the claims the date and the name of the applicant should appear in block letters.

4. This form must be accompanied by a true and exact copy of the description, claims and drawings (if any) and an additional copy of the claims.

(see Pamphlets explaining formal requirements of specifications and drawings) TO BE COMPLETED BY APPLICANT Name of Applicant: RCKGesellschaft mit beschrankter Haf Ac a Inventor(s) Dr. Alfred Jonczyk, Dr. Peter Raddatz, Dr. Gunter Actual Inventor(s):. ."o.ze iY b.."Sg C"icen cEmitqes Dr. Klaus-Otto Minck and Dr. Joachim Gante Address for Service: A C Invention Title: Details of Associated Provisional Applications: Nos: 7 -,The following statement Is a full description of this invention, including the best S 4ehod of performing it known to me:a, la The invention relates to new amino acid derivatives of the formula I R Z-MR -_CHR -_CR 4_(CHR 5 )n-CO-E-Q-Y An"e 444* 4 44 *4 4 .4 4 4 4*4* 444.

4 4 4 4. 4 .4 4 *4 4* 4 7***44 4 44 94 9 4.

4 4 4.

*44 4 4 444444 4 in which Ri is R 6

R

6 O0CmH 2 m-CO 1

R

6 _CmH 2 mO~CO_ R 6 CmH 2 m-COt, R 6

_S

2

(R

6 _CmH2m(T)Xi(G) yCrH 2 r)-

L(R

7 _C pH 2 p)-CtH 2 t-COi, R 6

(NHCH

2

CH

2 mNHCH 2 Ca-, or 9 -fluorenylCmH 2 m-O-CO-,I Z is 0 to 3 amino acid residues which are linked together in the manner of a peptide and are selected from the group comprising Abu, Ada, Ala., BAla, *Arg, Asn, Asp, Bia, Cal, Dab, Gin, Glu, Gly, His, N(im)-A-His, Ile, Leu, tert.- Leu, Lys, Met, aNal, i3Nal, Nbg, Nle, Orn, Phe, Pia, Pro, Pya, Ser, Thr, Tic, Trp, Tyr and, Val, M is 3A-la, Gly, Pia orPya, or else His if an R1Sgroup replaces an N atom in a Het-ylene group in the radical Y E is 0 to 2 amino acid residues which are linked together in the manner of a peptide and are selected from the group comprising Abu, Ala, Cal, His, Ile, Leu, Met, Nle, Nva, Phe, Trp, Ty-r and Val, Q is 0or NH, Y is an alkyl group in which it is also possible for a CH 2 group to be replaced by an Ar-ylene group or Het.-ylene group and which has a total of 1-20 C atoms and is substituted by an R 8

R

9

R

1 0 bP group or a pyrIdInium -group which -is.unsubstituted or substituted one or more times by A, AO and/or Hal, and/or in which an R 8

NP

group replaces an N atom in a Het-ylene group, y ill 4, I if 2 An 0

.R

3

R

6 4.9.

*6 6

S

S.

9 6 20

S

*5 a *SS 6

R

2 and

R

4 R8, R 9

R

1 1

R

I

I

L

T

G

n m, p, x and Ar is an anion, which can also be absent if, in its stead, a carboxyl group contained in the compound of the formula I is in the form of a carboxylate ion, and R 7 are each H, A, Ar, Ar-alkyl, Het, Hetalkyl, unsubstituted or singly or multiply, by A, AO and/or Hal, substituted cycloalkyl having 3-7 C atoms, cycloalkylalkyl having 4-11 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms or bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C atoms, R5 are each H or A, is OH), NH 2 or =0, and R 0 are each alkyl having 1-18 C atoms or Ar-alkyl, two of the radicals R 8

R

9 and R 1 0 together are also an alkylene group which has 2-8 C atoms and can be interrupted by an O atom or by an NR11 group, is H, A, Ar or Ar-alkyl, is CH or N, is O, S, NH or NA, is CO, S, SO or SO02 is 1 or 2, and t are each 0, 1, 2, 3, 4 or Sare each 0 or 1, is phenyl which is unsubstituted or substituted one or more times by A, AO, Hal, CF 3

OH,

H

2

NSO

2 and/or NH 2 or is unsubstituted naphthyl, is a saturated or unsaturated 5- or 6-membered heterocyclic radical which has 1-4 N, 0 and/or S atoms and can be fused with a benzene ring and/or can be substituted one or more times by A, AO, Hal, CF 3 HO, 0 2 N, carbonyl oxygen, H 2 N, HAN,

A

2 N, AcNH, AS, ASO, ASO 2 HOOC, AOOC, CN,

H

2 NCO, H 2

NSO

2

ASO

2 NH, Ar, Ar-alkyl, Aralkenyl, hydroxyalkyl and/or aminoalkyl each having 1-8 C atoms and/or whose N and/or S heteroatoms can also be oxidized, is F, Cl, Br or I, Het Hal .1h 1 o -3- Ac is A-CO-, Ar-CO- or A-NH-CO-, -alkyl- is an alkylene group having 1-4 C atoms, and A is alkyl having 1-8 C atoms, and in which, furthermore, it is also possible for one or more -NH-CO- groups to be replaced by one or more -NA-CO- groups, as well as the salts thereof.

Similar compounds are disclosed in EP-A 163237, EP-A 173481 and EP-A 209897.

The invention has the object of finding new compounds with valuable properties, in particular those which can be used for the preparation of medicaments.

It has been found that the compounds of the formula I and the salts thereof have very valuable properties. In particular, they inhibit the activity of human plasma renin. This action can be detected, for example, by the method of F. Fyhrquist et al., Clin.Chem. 22, 250-256 (1976). The noteworthy point is that these compounds are very specific inhibitors of renin; as a rule, considerably higher concentrations of these compounds are necessary to inhibit other aspartyl-proteinases (for example pepsin and cathepsin

D).

The compounds can be used as pharmaceutically active substances in human and veterinary medicine, in particular for the prophylaxis and for the treatment of diseases of the heart, circulation and vessels, especially of hypertension, cardiac insufficiency and hyperaldosteronism. In addition, the compounds can be used for diagnostic purposes in order to determine, in patients with hypertension or hyperaldosteronism, the possible contribution of the renin activity to maintaining the pathological state.

The abbreviations quoted hereinbefore and hereinafter for amino acid residues represent the radicals as a rule -NH-CHR-CO- (in which R, R' and R" have the specific meaning known for each amino acid), of the following amino acids: Abu 2-Aminobutyric acid .t 'lm 4' 8' 4.

-4 Ada Ala I3Aia Arg Asn Asp Bia Cal Dab Gin Giu Giy His N(im) -A-His Ile Leu tert. -Leu Lys Met a Nai BNai Nbg Nie N-Me-His N-Me-Phe Nva Orn Phe Pia Pro Pya 3- -Adamantyl) -alanine Alanine B-Alanine Arginine Asparagine Aspaz~tic acid 3 (2 -Benz imidazoiyi) -alanine 3 -Cyclohexylalanine 2, 4-Diaminobutyric acid Glutainine Giutamic acid Giycime Histidine histidine substituted in the 1 or 3 position of the imidazole ring by A Isoleucine Leucine tert -Leucime Lysine Methionine 3 (at -Naphthyi) -aianine 3- (B-Naphthyi) -aianine (2-Norbornyl) -glycine Norleucine N-Methyl-his tidine N-Methyi -phenylalanine Norvaline Ornithine Phenylalanine 3-(Piperidyi)-alanine 2- Pia 3- (2-piperidyl) -aianine) Proline 3-(Pyridyl)-aianine [e.g.

3-Pya 3,;,3-Pyridyl) -alanine] Serine Threonine 1, 2, 3, 4 -Tetrahydroisoquinoline-1-carboxylic acid Ser Thr Tic L_ t i I Trp Tryptophan Tyr Tyrosine Val Valine.

Further meanings hereinafter are: ADPA 2-Amino-5,6-dimethyl-3pyrazinyl-methylamino AMPA 4-amino-2-methyl-5pyrimidinyl-methylamino BOC tert.-Butoxycarbonyl imi-BOM Benzyloxymethyl in the 1 position of the imidazole ring CBZ Benzyloxycarbonyl DNP 2,4-Dinitrophenyl imi-DNP 2,4-Dinitrophenyl in the 1 position of the imidazole ring ETNC N-Ethylcarbamoyl ETOC Ethoxycarbonyl FMOC 9-Fluorenylmethoxycarbonyl IPNC N-Isopropylcarbaimoyl IPOC Isopropoxycarbonyl MAC Morpholinoacetyl MC Morpholinocarbonyl OMe Methyl ester OEt Ethyl ester POA Phenoxyacetyl DCCI Dicyclohexylcarboditide HOBt l-Hydroxybenzotriazole.

If the abovementioned amino acids can occur in more than one enantiomeric form, then all these forms, as well as mixtures thereof (for example the DL forms), are included hereinbefore and hereinafter, for example as constituent of the compounds of the formula I. The L-forms are preferred. Where individual compounds are mentioned hereinafter, then the abbreviations of these amino acids each relate to the L-form unless expressly indicated otherwise.

The invention furthermore relates to a process for the preparation of an amino acid derivative of the formula I, and of the salts thereof, characterized in 6 that it is liberated from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, or in that a carboxylic acid of the formula II R1-GI-OH II in which G is Z 1

Z,

Z-M,

Z-M-W,

Z-M-W-E

1 Z-M-W-E and W is -NR2-CHR3CR 4

-(CHR

5 is reacted with an amino compound of the formula III

H-G

2

III

in which

G

2 is -Z 2

-M-W-E-Q-Y,

-M-W-E-Q-Y,

-W-E-Q-Y,

-E-Q-Y,

-E2Q-Y,

-NH-Y,

E E are together E, and Z Z 2 are together Z, or in that a tertiary amine which otherwise corresponds to formula I is treated with a quaternizing agent, and in that a functionally modified amino and/or hydroxyl group in a compound of the formula I is liberated where appropriate by treatment with solvolyzing or hydrogenolyzing agents, and/or for the preparation of a compound of the formula I in which R is OH) or NH 2 an amino keto acid derivative of the formula I in which R4 is 0 is reduced or reductively aminated, and/or a compound of the formula I is converted by treatment with an acid into one of the salts thereof, and/or an anion ArP in a compound of the formula I is replaced by another anion An(.

Hereinbefore and hereinafter the radicals and parameters R to R 1 Z, M, E, Q, Y, An L, T, G, m, n, p, r, t, x, y, Ar, Het, Hal, Ac, A, G 1

G

2

E

l

E

2 I* i

Z

1

Z

2 and W have the meanings indicated for the formulae I, II or III unless expressly indicated otherwise.

A in the formulae mentioned hereinbefore has 1- 8, preferably 1, 2, 3 or 4 C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl, as well as pentyl, 1, 2- or 3-methylbutyl, 1,2- or 2,2dimethyipropyl, 1-ethyipropyl, hexyl, 3- or 4methylpentyl, 2,3- or 3,3dimethylbutyl, 1- or 2-ethylbutyl, l-ethyl-lmethylpropyl, 1l-ethyl -2 -methylpropyl 1,1,2- or 1,2,2trimethylpropyl, heptyl or octyl.

Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but is also, for example, 2- or 3-methylcyclopentyl, or 3- or 4-methylcyclohexyl.

I Correspondingly, cycloalkylalkyl is preferably cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 2 -cyc lohexyl ethyl, but is also, for example 2- or 3-methylcyclopentylmethyl, or 3- or 4-methylcyclohexylmethyl.

Bicycloalkyl is preferably 1- or 2-decalyl, 2bicyclo[2.2.1]heptyl or 6,6-dimethyl-2-bicyclo[3..1]heptyl.

Tricycloalkyl is preferably 1-adamantyl.

Hal is preferably F, Cl or Br, but is also I.

Ac is preferably A-CO-, such as acetyl, ~130 propionyl or butyryl, A-t-CO- such as benzoyl, m- or p-methoxybenzoyl or 3,4-dimethoxybenzoyl, or A-NH-COsuch as N-methyl- or N-ethylcarbamoyl.

Ar is preferably phenyl and is furthermore preferably m- or p-tolyl, m- or p-ethylphenyl, o-,m-or p-chlorophenyl, or p-bromophenyl, o-, m- or p- metoxphenyl, orptilorometflurphenyl, t o- -or p-hydroxyphenyl, m- or p-sulfamoylphenyl, 23,2,4-, 3,4- or -8- 3,4,5-trimethoxyphenyl, m- or p-aminophenyl, 1- or 2-naphthyl.

Correspondingly, Ar-alkyl is preferably benzyl, 1- or 2-phenylethyl, m- or p-methylbenzyl, 1- or 2- -in- or -p-tolylethyl, m- or p-ethylbenzyl, 1or -in- or -p-ethylphenylethyl, in- or pmethoxybenzyl, 1- or -in- or p methoxyphenylethyl, mn- or p-f luorobenzyl, 1- or 2o,-in- or -p-f luorophenylethyl, o- i- or pchlorobenzyl, 1- or -mn- or chl orophe nyl ethyl, mn- or p-bromobenzyl, 1- or -mn- or -pbromophenylethyl, mn- or p-iodobenzyl, 1- or 2-o-, -in- or -p-iodophenylethyl, mn- or p-trifluoronethylbenzyl, m- or p-hydroxybenzyl, 3,4- or 3,5-dimethoxybenzyl, 3 14,5trimethoxybenzyl, mn- or p-aminobenzyl, 1- or 2naphthylmethyl.

Het is preferably 2- or 3-furyl, 2- or 3thienyl, 2- or 3-pyrrolyl, 4- or iinidazolyl, 4- or 5-pyrazolyl, 4- or oxazolyl, 4- or 5-isoxazolyl, 4- or thiazolyl, 4- or 5-isothiazolyl, 3- or 4pyridyl, 5- or 6-pyrimidinyl, furthermore preferably l,2,3-triazol-l-, or -5-yl, 1,2,4triazol-1-, or -5-yl, 1- or 5-tetrazolyl, 1,2,3oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or l,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or 2,l,5-thiadiazol-3- or -4-yl, 5- or 6-2H-thiopyranyl, 3- or 4-4H-thiopyranyl, 3- or 4pyridazinyl, pyrazinyl, 6- or 7benzofuryl, 6- or 7-benzothienyl, 1-, 6- or 7-indolyl, 6or 7-isoindolyl, 4- or 5-benziinidazolyl, 1-, 6- or 7-benzopyrazolyl, 6- or 7-benzoxazolyl, 6- or 7-benzisoxazolyl, 2-, 6- or 7-benzthiazolyl, 6- or 7-J benzisothiazolyl, 6- or 7-benz-2,l,3oxadiazolyl, 7- or 8-quinolyl, 1-, 7- or 8-isoguinolyl, 4- or -9- 9-carbazolyl, 8- or 9acridinyl, 7- or 8-cinnolyl, 4-, 7- or 8-quinazolyl. The heterocyclic radicals can also be partially or completely hydrogenated. Thus, Het can also be, for example, 2,3-dihydro-2-, -4or -5-furyl, 2,5-dihydro-2-, or tetrahydro-2- or -3-furyl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-l-, or -5-pyrrolyl, dihydro-l-, or -5-pyrrolyl, 2- or 3pyrrolidinyl, tetrahydro-l-, or -4-imidazolyl, 2,3dihydro-l-, or -5-pyrazolyl, tetrahydroor -4-pyrazolyl, l,4-dihydro-l-, or -4-pyridyl, l,2,3,4-tetrahydro-l-, or -6-pyridyl, l,2,3,6-tetrahydro-1-, or -6-pyridyl, 3- or 4-piperidinyl, 3- or 4-morpholinyl, tetrahydro-2-, or -4-pyranyl, 1,4dioxanyl, l,3-dioxan-2-, or -5-yl, hexahydro-l-, or -4-pyridazinyl, hexahydro-l-, or pyrimidinyl, 2- or 3-piperazinyl, 1,2,3,4tetrahyd1ro-l-, or -8quino.'ylf l,2,3,4-tetrahydro-l-, or -8-isoquinolyl.

The heterocyclic radicals can also be substitued as indicated. Het can also preferably be, for example 2-amino-4-thiazolyl, 4-carboxy-2-thiazolyl, 4-carbainoyl-2-thiazolyl, 2-axninoethyl)-2-thiazolyl, 2-amino- 6-dimethyl-3-pyrazinyl, 4-carbamoylpiperidino, furthermore, for example, 4- or 5-methyl-2furyl, 4- or 5-methyl-3-furyl, 2,4-dimethyl-3furyl, 5-nitro-2-furyl, 5-styryl-2-furyl, 4- or methyl-2-thienyl, 4- or 5-methyl-3-thienyl, 3- -butyl-2-thienyl, 5-chloro-2-thienyl, phenyl-2- or -3-thienyl, 4- or 5-methyl-2pyrrolyl, l-methyl-4- or -5-nitro-2-pyrrolyl, dimethyl-4-ethyl-2-pyrrolyl, 4-methyl-5-pyrazolyl, methyl-3-isoxazolyl, 3 ,4-di-methyl-5-isoxazolyl, 4- or 5-methyl-2-thiazolyl, 2- or 5-methyl-4-thiazolyl, 2- or 2 ,4-dimethyl-5-thiazolyl, 4-, or 6-methyl-.2-pyridyl, 5- or 6-methyl-3pyridyl, 2- or 3-methyl-4-pyridyl, c*6chloro-2-pyridyl, 5- or 6-chloro-3-pyridyl, 2or 3-chloro-4-pyridyl, 2, 6-dimethyl-3- or -4-pyridyl, 2,6-dichloro-3- or -4-pyridyl, 2-hydroxy-3-, or -6-pyridyl 1H-2-pyridon-3-, or -6-yl),2hydroxy-4, 6-dimethyl-3-pyridyl, 5pey-H2prdn 3-yl, 5-p-methoxyphenyl-1H-2-pyridon-3-yl, 2-methyl-3- 2-hydroxy-4-amino-6methyl-3-pyridyl, 3-N' 4-methyl-2-pyrimidinyl, 4, 6-dixnethyl-2-pyrimidinyl, 2-, or 6-methyl-4-pyrimidinyl, 2,6-dimethyl-4pyrimidinyl, 2, 6-dihydroxy-4-pyrimidinyl, 5-chloro-2- 4methyl-4-pyrimidinyl, 2-methyl-4-amino-5-pyrimidinyl, 3 -methyl-2-benzofuryl, 2 -ethyl- 3-benzof uryl, 7-methyl- 2-benzothienyl, 2-, 6- or 7-methyl-3-indolyl, l-methylt-5- or -6benzimidazolyl, l-ethyl-5- or -6-benzimidazolyl, 3-, 44-, 7- or 8-hydroxy-2-quinolyl, 2-oxopyrrolidino, 2-oxo-piperidino, 2,5-dioxopyrrolidino, or :120 3-benzyl-2,-ixprodn.

L spreferably CH. T is preferably 0 or S. G is preferably CO. The parameters m, p, r and t are ft preferably each 0, 1 or 2; n is preferably 1; x is preferably 0; y is preferably 0 or 1.

Ri is preferably H, POA, alkoxycarbonyl such as ETOC, IPOC or BOC; Ar-alkoxycarbonyl such as CBZ; Hetalkoxycarbonyl such as 3- or 4-pyridyl)ethoxycarbonyl; alkanoyl preferably having 2-7 C atoms such as acetyl, propionyl, butyryl, isobutyryl, pivaloyl (trimethylacetyl) hexanoyl, 3,3dimethylbutyryl (tert.-butylacetyl), heptanoyl, 2propylvaleryl, (dipropylacetyl); amino-alkanoyl such as aminoacetyl (H-Gly), 3-aminopropionyl (H-J3Ala), Haminobutyryl, 6-aminoheianoyl, 8-aminooctanoyl; dialkylamino-alkanoyl such as 4-dimethylaminobutyryl, 4 -diethyl aminobutyryl or 5 -dimet~ayl aminopentanoyl; axido-alkanoyl, for example BOC-Gly, ETOC-Gly, IPOC- Gly, BOC-J3Ala, 4-BOC-aminobutyryl, 6-BOC-aminohexanoyl, 8-BOC-aminooctanoyl, N-benzoyl-N-benzyl-aminoacetyl; 4 Mwr-

I

21 11 cycloalkylcarbonyl such as cyclopentylcarbonyl or cyclonexylcarbonyl; Ar-('0 such as benzoyl; Ar-alkanoyl such as phenylacetyl, 2- or 3-phenyipropionyl, 4pheniylbLtyryl, 2-benzyl-butyryl, 2-benzyl-hexanoyl, 2benzyl-5-methylhexanoyl, 2-benzyl-heptanoyl, 2- or 3-oor -p-f luorophenyipropiolyl, 2- or -mn- or p-chlorophenylpropiolyl; (jxo-Ar-alkanoyl, in particular groups of the formula R 1 2

-CO-CH

2

-CH(CH

2

C

6

H

5 in which R2is A, cycloalkyl having 3-7 C atoms or cycloalkylalkyl having 4-11 C atoms, for example butyl, isubutyl, tert.-butyl, pentyl, isopentyl, 2,2dimethyipropyl, hexyl, 4-methylpentyl, 3,3dimethylbutyl. heptyl, 5-methyihexyl, cyclohexyl, cyclohexylmethyl or 2 -cyc lohexyl -ethyl, such as 2benzyl-4-oxo-5 ,5-dimethyl-hexanoyl, 2-benzyl-4-oxo-6, 6dimethyl-heptanoyl, 2-benzyl-4 .oxo-6-methyl-heptanoyl, 2-benzyl-4-oxo-G-cyclohexyl-hexaloyl; Ar-alkanoyl substituted by amino groups, in particular dialkylamino groups, for example 2-benzyl-4-dimethylaminobutyryl, 2benzyl-5-dimethylamirtopentanoyl; Di-Ar-alkanoyl such as 2-benzyl-3-phenylpropionyl, 2-benzyl-4-phenylbutyryl, 2- (2-phe~yl-ethyl-)-4-phanylbutyryl, or 2-naphthylmethyrl) -4-phenylbutyryl; Het-alkaa'oyl such as pyrzolidino .acetyl, 4-pyrrolidinobutyryl, piperidinoacetyl, 4-aminopiperidinoacetyl, MAC; Di-Het-alkanoyl such as 2-(2 ,5-dioxopyrrolidino) 3-indolyl) -propionyl, 2- (3-benzyl-2, 5-dioxopyrrolidino-3- (3-indolyl) propionyl; cycloalkylalkanoyl such as cyclohexylacetyl, 2- or 3-cyclohexylpropionyl; FMOC; arylalkanoyl with a heterocyclic substituent such as 2-benzyl-4-(2-, 3- or 4-pyridyl.) -butyryl, 2-benzyl-4- (2-o.-.opyrrolidino) -butyryl, 2- (2 ,5-dioxopyrrolidilo) -3-pihenyipropionyl, 2- 5-dio; opyrrolidino) -3-p-hydroxyphenyl-propionyl, 2- 5-dioxopyrrolidino) or 2-naphthyl) -propionyl, 3-benzyl-2, 5-dioxopyrrolidino) -3-phenyl-propionyl, 2- (3-benzyl-2 ,5-'dioxopyrrolicdlno) -3-hydroxyphenylpropionyl, 3-benzyl-2,5-dioxopyrrolidilo)-3-( 1- or 2-naphtayl) -propionyl; 11-Bubstituted carbainoyl such as ETNCr IPNC, X-benzylcarbamoyl, 3- or 4-pyridyl- -12methyl)-carbamoyl; N,N-disubstituted carbamoyl such as N, N-dibenzyl-carbamoyl, N-benzyl-N-2-phenylethyl-carbamoyl, N-benzyl-N-butyl-carbamoyl, N-benzyl-N-isopentylcarbamoyl, N,N-bis-2-phenylethyl-carbanoyl, N-2-morpholinoethyl-N-1-naphthylmethyl-carbamoyl, pyrrolidino- Ccarbonyl, piperidinocarbonyl, 4-aminopiperidinocarbonyl, MC; arylalkanoyl substituted by alkoxycarbonyl, such as 2-benzyl-3-ethoxycarbonyl-propionyl, 2-(1naphthylmethyl) -3-ethoxycarbonyl-propionyl; -1rylalkanoyl substituted by substituted carbamoyl, such as 2-benzyl-3-(N-isopropyl-carbamoyl)-propionyl, 1naphthyl-methyl) (N-isopropyl-carbamoyl) -propionyl, 2- 1-naphthylmethyl) 2-phenyl ethyl carb aoyl)propionyl, 2 -benzyl-3-piperidinocarbonyl-propionyl, 2- 1s benzy1-3-morpholinocarbony-propiony., 2- (1naphthylmethyl) -3-morpholinocarbonyl-propionyl; arylalkanoyl substituted by acyl, such as 2-benzyl-4oxo-hexanoyl, 2-benzyl-4-oxo-5, 5-dixnethylhexanoyl, 2benzyl-4-oxo-6-methyl-heptanoyl, 2-benzyl-4-oxo-4phenylbutyryl, 2-benzyl-4-oxo-4-(2-, 3- or 4-pyridyl)butyryl; alkylsulfonyl such as tert.-butylsulfonyl; arylalkanoyl substituted by alkylsulfonyl, such as 2q tert. -butylsulfonylmethyl-3-pheny.propionyl.

iiSome particularly preferred radicals R 1 are BOC, furthermore pivaloyl, 3,3-dimethylbutyryl, 4aminobutyryl, 6-aminohexanoyl, 8-aninooctanoyl 4dimethylaminobutyryl, 5 -dimethylaminopentanoyl, 2- MAC, 2-(2,5-dioxopyrrolidino) -3-phenylpropionyl, 2- (3-benzyl-2, pyrrolidino) -3-phenylpropionyl, 4-amino-piperidinocarbonylf 4-aminopiperidinoacetyl.

Z is preferably one, but also 0 or 2, furthermore 3, amino acid residues which are linked i together or to the groups R 1 and NR 2 in the manner of a peptide, especially the group Phe, furthermore one of the groups aNal, M3al, Trp or Tyr, f urtlirmore preferably one of the groups Abu, Ada, Asn, Bia, Cal, Gin, Gly, His, N(im)-methyl-His, Leu, Nie, Pia, Pya, Abu-His, Ada-His, Ala-His, Ala-Phe, Asn-His, Bia-His, -13 Cal-His, Dab-His, Glu-His, Gly.-His, His-His, Ile-His, Leu-His, tert.-Leu-His, Lys-His, Met-His, Nal-His, I3Nal-His, Nbg-His, Nie-His (N-Me-His) -His, (N-Me-Phe)- His, Orn-His, Phe-Abu, Phe-Ada, Phe-Ala, Phe-Arg, Phe- Asn, Phe-Bia, Phe-Cal, Phe-Dab, Phe-Gin, Phe-Glu, Phe- Gly, Phe-(N-im-methyl-His), Phe-Ile, Phe-Leu, Phetert. -Leu, Phe-Lys, Phe-Met, Phe-ciNal, Phe-3Nal, Phe- Nbg, Phe-Nie, Phe-(N-Me-His) Phe-(N-Me-Phe), Phe-Orn, Phe-Phe, Phe-Pro, Phe-Ser, Phe-Thr, Phe-Tic, Phe-Trp, Phe-Tyr, Phe-Val, Pro-His, Ser-His, Thr-His, Tic-His, Trp-His, Tyr-His, Val-His, furthermore Ada-Phe-His, Pro-Ala-His, Pro-Ala-Phe, Pro-Phe-Ala, Pro-Phe-Phe, furthermore Pro-Abu-His, Pro-Ada-His, Pro-Arg-His, Pro- Asn-His, Pro-Bia-His, Pro-Dab-His, Pro-Glu-His, Pro- His-His, Pro-Ile-His, Pro-Leu-His, Pro-tert.-Leu-His, Pro-Lys -His, Pro-Met-His, Pro-Nbg-His, Pro-Nie-His, Pro- (N-Me-His) -His, Pro- (N-Me-Phe) -His, Pro-Orn-His, Pro-Phe-Abu, Pro-Phe-Ada, Pro-Phe-Arg, Pro-Phe-Asn, Pro-Phe-Bia, Pro-Phe-Dab, Pro-Phe-Gin, Pro-Phe-Glu, Pro-Phe-His, Pro-Phe-(N-im-methyl-His) Pro-Phe-Ile, Pro-Phe-Leu, Pro-Phe-tert.-Leu, Pro-Phe-Lys, Pro-Phe- Met, Pro-Phe-Nbg, Pro-Phe-Nie, Pro-Phe- (N-Me-His), Pro- Phe-(N-Me-Phe) Pro-Phe-Orn, Pro-Phe-Pro, Pro-Phe-Ser, Pro-Phe-Thr, Pro-Phe-Tic, Pro-Ph'e-Trp, Pro-Phe-Tyr, Pro-Phe-Val, Pro-Pro-His, Pro-Ser-His, Pro-Thr-His, Pro-Tic-His, Pro-Trp-His, Pro-Tyr-His, Pro-Val-His.

If R 1 is one of the groups R -CH(CH 2

C

6

H

5

)-CO-

in which R 0 is R 6 _CH2m-(T)X'(G)y-CrH2rI but is preferably pyrrolidino, 2-oxo-pyrrolidino, 2, pyrrol1idino, 3 -benzyl -2,5 -dioxopyrrol idino, piperidino, morphlino, alkyl, alkoxy or alkyithio each having 1-8 C atoms, or A2N-CrH 2 r, Z is preferably absent.

M is preferably Gly, furthermore preferably I3Ala or 3-Pya.

E is preferably absent or is preferably Ile or Leu, furthermore preferably Abu, Cal, Met, Nle, Phe or Val.

Details of Associated Provisional Applications: Nos: he following statement is a full description of this invention, including the best hod of performing it known to me:- 14 14 Q is preferably NH.

R

2 and R 5 are preferably H or methyl, furthermore ethyl, propyl, isopropyl, butyl or isobutyl. If n is 2, the two radicals R 5 can be identical or different from one another; in this case preferably one radical R 5 is H and the other is A, especially isopropyl.

R

3 is preferably cyclohexylmethyl, furthermore preferably A, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, pentyl, isopentyl (3-methylbutyl) or 2-methylbutyl, phenyl, benzyl, pchlorobenzyl, 2-cyclohexylethyl, bicyclo[2.2.1]heptyl- 2-methyl or 6,6-dimethylbicyclo[ 3.1.1]heptyl-2-methyl.

R

4 is preferably OH).

R

6 and R 7 are preferably A, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.butyl, furthermore preferably cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, pyrrolidino, piperidino or morpholino.

R

8

R

9

R

10 are preferably each A; they are preferably identical and are each methyl or ethyl, and one of these radicals is preferably higher alkyl having, preferably, 6-18 C atoms or benzyl, and two of these radicals are preferably tetramethylene, pentamethylene, 3-oxapentamethylene or 3-NR 11 pentamethylene.

R is preferably H, A, phenyl or benzyl.

The group R 8 R R 10 0, called "Am" hereinafter for brevity, is accordingly preferably trialkylammonium, especially trimethyl- or triethylammonium, furthermore preferably dimethyl-butyl-, -pentyl-, hexyl-, -heptyl, -octyl-, -nonyl-, -decyl-, -undecyl-, -dodecyl-, -tetradecyl-, hexadecyl- or -octadecylammonium, N-alkylpyrrolidinium, N-alkyl-piperidinium or N-alkylmorpholinium.

The group Y is preferably -alkylene-Am, especially -CH 2

CH

2 -Am or -CH 2

CH

2

CH

2 -Am, furthermore preferably -CH 2

-P-C

6 H4- H 2 -Am; -alkylene-(l-pyridinium), especially -CH 2

CH

2 -(l-pyridinium) or an R 8

R

9 RlI goprapridinium.*group which is.

unsubstituted or substituted one or more times by A, AO and/or Hal, and/or in which an FI Agroup replaces an N atom in a Het-.ylene group, -C AL

-CH

2

CH

2

CH

2 -(1-pyridinium); -alkylene-(2-, or j N-alkyl-pyridinium; N, N-dialkyl-2-, or -4-piperidinium; N-alkyl-N-Ar-alkyl-2-, or -4-piperidinium; alkylene-2-, or -4-N,N-dialkyl-piperidiniui; alkylene-2-, or -4-N-alkyl-N-Ar-alkyl-piperidinium. The group Y is furthermore preferably 1-(or 3-)A-4-amino-2- 1-A-2, 6-dimethylpyridinium-3-methyl, 1A-2-hydroxy-4, 6-dimethyl-pyridinium- 3-methyl, 3-A-thiazoliun-4- or -5-methyl, 3-Abenzothiazoliun-2-methyl.

The group W is preferably -NH-CHR -CHOH-CH 2 CO-, especially -NH-CH( cyclohexylmethyl) -CHOH-CH 2

-CO-

("AHCP'

t derived from 4 -amino- 3-hydroxy-5 -cyc lohexyl pentanoic acid), furthermore -NH-CH (CH CH 2 -cyclohexyl)

CHOH-CH

2 -CO- ("AHCH"; derived from 4 -amino- 3-hydroxy-6 cyclohexylhexanoic acid), -NH-CH(isobutyl)-CHOH-CH 2

-CO-

("Stall; derived from statin) or -NH-CH(benzyl)-CHOH-

CH

2 -CO- ("AHPP"; derived from 4-amino-3-hydroxy-5phenylpentanoic acid). The group W is furthermore preferably -NH-CHR 3 -CH (NH 2

-CH

2 especially -NH- CH( cyclohexylmethyl) -CH(NH 2

-CH

2 -CO- ("1DACP11; derived from 3,4-diamino-5-cyclohexylpentanoic acid), -NH- CH (CH CH 2 -yloey)-CH (NH 2 )-Gl 2 -CO- ("1DACH"; derived from 3, 4-diamino-6-cyclohexylhexanoic acid), -NH- CH(isobutyl)-CH(NH 2

)-CH

2 -CO- ("1DAMH'1; derived from 3,4diamino- 6-methylheptanoic acid) or -NH-CH (benzyl) CH(NH)-HC- ("1DAPP11; derived from 3,4-diamino-5- 4phenylpentanoic acid.

The group W has at least one chiral centre.

Further chiral centres may be present in the groupsRI Z, M, E and Y. The compounds of the formula I can' theref ore occur in various, optically inactive or optically active, forms. The formula I embraces all these forms. If W is -NH-CHR -CR -CH 2 -CO- with R 4 being OH) or N),the 3S-hydroxy-4S-amino enantiomers and 3S,4S-diamino enantiomers are preferred.

Unless indicated otherwise in the naming of individual substances, the abbreviations AHCP, AHCH, Sta, AHPP, DACP, DACH, DAMH and DAPP always relate to the 3S,4S

H

2 NCO, H 2

NSO

2

ASO

2 NH, ArX, Ar-alkyl, Aralkenyl, hydroxyalkyl and/or aminoalkyl each having 1-8 C atoms and/or whose N and/or S heteroatoms can also be oxidized, is F, Cl, Br or I, Hal 4 16 forms.

Accordingly, the invention particularly relates to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated hereinbefore. Some preferred groups of compounds can be represented by the following partformulae Ia to Ih, which correspond to the formula I but in which in Ia Rl is A-O-CO-, A-CO-, A 2 N-CtH 2 t-CO- orR_

CH(CH

2

CH

6

H

5 in lb Rl is BOC; in Ic Z is Phe; in Id M is J3Ala, Gly or 3-Pya; in le -N2CRRCR -O W) is AHCP; in If E is Ile or Leu; in Ig R 1 -Z is A-O-CO-Phe, A-CQ-Phe, -A-CO-CH 2 CH( CH 2

-C

6 H -CO- or 2,

(CH

2

-C

6

H

5 M is 13-Ala, Gly or 3-Pya, W is AHCP or 2-isopropyl-3-hydroxy-4amino- 5-cyc lohexylpentanoyl and E denotes Ile or Leu; in Ih R 1 -Z is BOC-Phe, M is 13-Ala, Gly or 3-Pya, W is AHCP and E is Ile or Leu.

Particularly preferred are compounds of the part-formulae: I* and Ia* to Ih*, which correspond to the formulae I and Ia to Ih but in which Q-Y is -NH- (CH 2 -A -NH-CH 2 -P-C0H -CH 2 AM, -NH-

(CH

2 )z-(l-pyridinium) or -NH-(CH 2 -3or -4-pyridinium), z is 1, 2, 4 or 5 and Am is tris-Cl- 1 8 -alkyl-anmonium, l-A-pyrrolidinium, 1-A-piperidinium or 1-A-morpholinium; V' and Ia' to Ih', which correspond to the formulae I and Ia to Ih but in which Q-Y is -NH-(CH 2 )z-NA 3 and

I

'1 Ii

L

17 z is 2 or 3.

I" and Ia" to Ih", which correspond to the formulae Ia to Ih but in which Q-Y -NH-CH 2 or 3-A-4-amino-2-methyl-5pyrimidinium) or

-NH-CH

2 3- or 4-pyridinium).

The compounds of the formula I, as well as the 1, starting materials for the preparation thereof, are furthermore prepared by methods which are known per se and as are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie, (Methods of Organic Chemistry), published by Georg-Thieme, Stuttgart; as well as EP-A 45665, EP-A 77028, EP-A 77029 and EP-A 81783) specifically under reaction conditions which are known and suitable for the said reactions. In this connection it is also possible to make use of variants which are known per se and which are not mentioned in detail herein.

It is also possible, if desired, to form the starting materials in situ so that they are not isolated from the reaction mixture but are immediately reacted further to give the compounds of the formula I.

The compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.

Preferred starting materials for the solvolysis or hydrogenolysis are those which correspond to the formula I apart from containing, in place of one or 4 more free amino and/or hydroxyl groups, corresponding protected amino and/or hydroxyl groups, preferably those which carry an amino protective group in place of an H atom bonded to an N atom, for example those which correspond to the formula I but contain in place of a His group an N(im)-R'-His group (in which R' is an amino protective group, for example BOM or DNP), or those of the formula RI--M-NR2CHR3-CH(NHR'

)-(HR

5 )n-

CO-E-Q-Y.

'i 61_ S 18 Further preferred, starting materials are those which carry, in place of the H atom of a hydroxyl group, a hydroxyl protective group, for example those of the formula R 1

-Z-M-NR

2

-CHR

3

-CHOR

1 1

-(CHR

5 )n-CO-E-Q-Y, in which R" is a hydroxyl protective group.

It is also possible for more than one identical or different protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protective groups which are present differ from one another it is possible in many cases to eliminate them selectively.

The term "amino protective group" is generally known and relates to groups which are suitable for protecting (blocking) an amino group from chemical reactions but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl-, aryl- (for example DNP), aralkoxymethyl (for example BOM) or aralkyl groups (for example benzyl, 4nitrobenzyl, triphenylmethyl). Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size are not otherwise critical; however, those which are preferred have 1-20, in particular 1-8, atoms. The term "acyl group" in connection with the present process is to be interpreted in the widest sense. It embraces acyl groups derived from aliphatic, aryliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, as well as, in particular, alkoxycarbonyl, aryloxycarbonyl and, especially, arylkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ETOC, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC. Preferred amino protective groups are BOC, DNP and BOM, as well as CBZ,

I

f .f 19- FMOC, benzyl and acetyl.

The term "hydroxyl protective group" is likewise generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, as well as alkyl groups.

The nature and size of the hydroxyl protective groups are not critical because they are removed again after the desired chemical reaction or reaction sequence; preferred groups have 1-20, especially 1-10, C atoms.

Examples of hydroxyl protective groups are, inter alia, tert.-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, with benzyl and acetyl being particularly preferred.

The functional derivatives of the compounds of the formula I which are to be used as starting materials can be prepared by customary methods of amino acid and peptide synthesis as are described, for example, in the said standard works and patent applications, for example also by the solid-phase method of Merrifield.

The liberation of the compounds of the formula I from their functional derivatives is effected depending on the protective group used for example with strong acids, preferably with trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulphuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzeneor p-toluenesulfonic acid. The presence of an additional inert solvent is possible but not always necessary. Suitable and preferred inert solvents are organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, as well as i L =LU L..LV .L Y CLLIL.Lu, L I I/u.L a JL L UL Ji uju. L LJj- iUU.L I is converted by treatment with an acid into one of the salts thereof, and/or an anion Ar 3 in a compound of the formula I is replaced by another anion AiP.

Hereinbefore and hereinafter the radicals and parameters R 1 to R 1 1 Z, M, E, Q, Y, An L, T, G, m, n, p, r, t, x, y, Ar, Het, Hal, Ac, A, G 1

G

2

E

1

E

2 I tl i sl~ i: r t1 F~:E iQ P1

NO

1QICI--_ 20 alcohols such as methanol, ethanol or isopropanol, and water. Furthermore suitable are mixtures of the Sabovementioned solvents. Trifluoroacetic acid is preferably used in excess without the addition of another solvent, and perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures for the cleavage are preferably between about 0 and about 500, preferably between 15 and 300 (room temperature).

The BOC group can be eliminated, for example, preferably with 40% trifluoroacetic acid in methylene chloride or with about 3 to 5 N HCI in dioxane at 300, and the FMOC group with an approximately 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15-300. Elimination of the DNP group is effected, for example, also with an approximately 3-10% solution of 2-mercaptoethanol in DMF/water at 15-300.

Protective groups which can be removed by hydrogenolysis (for example BOM, CBZ or benzyl) can be eliminated, for example by treatment with hydrogen in the presence of a catalyst (for example a noble metal catalyst such as palladium, preferably on a support such as carbon). Solvents suitable for this are those mentioned above, especially, for example, alcohols such as methanol or ethanol or amides such as DMF.

Hydrogenolysis is, as a rule, carried out at temperatures between about 0 and 1000 under pressures between about 1 and 200 bar, preferably at 20-300 and under 1-10 bar. Hydrogenolysis of the CBZ group is effected satisfactorily, for example, on 5-10% Pd-C in methanol at 20-300.

Compounds of the formula I can also be obtained by direct peptide synthesis from a carboxylic acid component (formula II) and an amine component (formula III). Examples of suitable carboxylic acid components are those of the part-formulae R 1 -Z-OH, R 1 M-OH, R

I

Z-M-W-OH or RI-Z-M-W-E-OH, and of amine components are those of the part-formulae H-M-W-E-Q-Y, H-W-E-Q-Y, H-E- Q-Y or H 2 N-Y. The peptide linkage can, however, also be

I~

-I

,ru~ i i preferably m- or p-tolyl, m- or p-ethylphenyl, m- or p-methoxyphenyl, m- or p-fluorophenyl, m- or p-chlorophenyl, or p-bromophenyl, o-, m- or p-iodophenyl, m- or p-trifluoromethylphenyl, m- or p-hydroxyphenyl, m- or p-sulfamoylphenyl, J 3,4- or Al Ipiiii. TTL-T-n T--7T- 17 -21r formed within the group Z or E; this entails a carboxylic acid of the formula R_-ZIOH or R 1

-Z-M-W-E

1 OH being reacted with an amino compound of the formula I H-Z 2 -M-W-E-Q-Y or H-E 2 where Z 1

Z

2 Z and E

E

2 E. The methods preferably used for this are those customary in peptide synthesis, as are described, for example in Houben-Weyl, Vol. 15/II, pages 1-806 (1974).

The reaction is preferably effected in the presence of a dehydrating agent, for example a carbodiimide such as DCCI or dimethylaminopropylethylcarbodiimide, or else propanephosphonic anhydride (compare Angew. Chem. 92, 129 (1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-l,2dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or dimethylacetamide, or a nitrile such as acetonitrile, at temperatures between about -10 and preferably between 0 and 300.

It is also possible, in place of II or III, to use suitable reactive derivatives of these substances in the reaction, for example those in which reactive groups have undergone intermediate blocking with protective groups. The amino acid derivatives III can be used, for example, in the form of their activated esters which are preferably formed in situ, for example by addition of HOBt or N-hydroxysuccinimide.

The starting materials of formulae II and III are mostly known. Those which are unknown can be prepared by known methods, for example the abovementioned methods of peptide synthesis and of elimination of protective groups.

The compounds of the formula I can also be obtained by treating a tertiary amine, which otherwise corresponds to formula I, with a quaternizing agent.

Examples of suitable tertiary amines are (a) compounds which correspond to the formula I but contain in place of the radical Y an alkylene chain in which a L I 22

CH

2 group can also be replaced by an Ar-ylene group or Het-ylene group, which has a total of 1-20 C atoms and which is substituted by an RR 10 N group or a pyridyl group which is unsubstituted or substituted one or more times by A, AO and/or Hal. Also suitable are (b) pyridine or amines of the formula R 8

R

9

R

10 N. Suitable as quaternizing agents in case are halides of the formula R 8 X (X=C1, Br or for example alkyl halides such as methyl iodide or ethyl bromide or Ar-alkyl halides such as benzyl chloride, and in case on the other hand are, for example, halides of the formula R 1 Z-M-W-E-Q-alkylene-X, for example BOC-Phe-Gly-AHCP-Ile- N-(2-bromoethyl)amide or 2-(2,5-dioxopyrrolidino)-3phenylpropionyl-Gly-AHCP-Ile-N-(3-chloropropyl)amide.

The quaternization is preferably carried out in the presence of one of the abovementioned inert solvents, for example acetonitrile, at temperatures between about -10 and +400.

If desired, it is possible for a functionally modified amino and/or hydroxyl group in a compound of the formula I to be liberated by solvolysis or hydrogenolysis by one of the methods described above.

Thus, in particular, a compound of the formula I in which R 1 differs from H can be converted into a compound of the formula I (R 1 preferably by hydrogenolysis if R 1 is CBZ, otherwise by selective solvolysis. If R 1 is BOC, the BOC group can be eliminated, for example, with HC1 in dioxane at room temperature.

Furthermore, for example, keto compounds of the formula I (R 4 0) can be reduced to compounds of the formula I (R 4 for example with a complex metal hydride such as NaBH 4 which does not simultaneously reduce the peptide carbonyl groups, in an inert solvent such as methanol at temperatures between about -10 and Keto compounds of the formula I (R 4 0) can also be converted into compounds of the formula I (R 4 H, NH 2 by reductive amination. The reductive amination phenyl-2- or -3-thienyl, 4- or 5-methyl-2pyrrolyl, l-methyl-4- or -5-nitro-2-pyrrolyl, dimethyl-4-ethyl-2-pyrrolyl, 4-methyl-5-pyrazolyl, 5- i methyl-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 4- or 5-methyl-2-thiazolyl, 2- or 5-methyl-4-thiazolyl, 2- or 2,4-dimethyl-5-thiazolyl, 4-, or 6-methyl-2-pyridyl, 5- or 6-methyl-3- 23 can be carried out in one or more stages. Thus, for example, the keto compound can be treated with ammonium salts, for example ammonium acetate and NaCNBH 3 preferably in an inert solvent, for example an alcohol such as methanol, at temperatures between about 0 and 500, in particular between 15 and 30°. It is furthermore possible initially to convert the keto compound into the oxime, using hydroxylamine in a customary manner, and to reduce the oxime to the amine, for example by catalytic hydrogenation on Raney nickel.

A base of the formula I can be converted into the relevant acid addition salt using an acid.

Particularly suitable acids for this reaction are those which provide physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, as well as organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and disulfonic acids and lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify the compounds of the formula I.

It is furthermore possible to exchange an anion An® in a compound of the formula I for another anion AAG. Suitable anions An® are the anions of the abovementioned acids; the chlorides, bromides, methanesulfonates, acetates, citrates, fumarates, maleates and succinates are preferred. For the anion i i 1 24exchange, it is possible, for example, to subject the starting material to gel chromatography using as eluent a solvent mixture which contains the desired anion in excess. Suitable and preferred as support is a crosslinked polydextran. If it is desired to obtain an acetate, then the eluent is, for example, acetic acid/water or methanol/acetic acid/water.

i The new compounds of the formula I and the physiologically acceptable salts thereof can be used to prepare pharmaceutical products by converting them, together with at least one vehicle or auxiliary and, if desired, together with one or more other active substance(s), into a suitable dosage form. The Icompositions obtained in this way can be used as medicaments in human or veterinary medicine. Suitable vehicles are organic or inorganic substances which are if suitable for enteral (for example oral or rectal) or parenteral administration or for administration in the form of a spray for inhalation and which do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc and cellulose. Used orally are, in particular, tablets, coated tablets, capsules, syrups, elixirs or drops; specifically of interest are lacquered tablets and capsules with enteric coatings or capsule shells. Used rectally are suppositories, and for parenteral administration are solutions, preferably oily or aqueous solutions as well as suspensions, emulsions or implants. For administration by spray for inhalation, it is possible to use sprays which contain the active substance either dissolved or suspended in a propellant gas mixture (for example chlorofluorohydrocarbons). The active substance is preferably used for this in micronized form, with one or more additional physiologically tolerated solvents possibly

I,

being present, for example ethanol. Solutions for inhalation can be administered with the aid of f 1

•IIL

33 C- 1 J~W~dlyj±L J -iJUj.uALJy L ^.J.Uj.LI I -J .j-k*j[Ls uf f 2-(3-benzyl-2,5-dioxopyrrolidino)-3-hydroxyphenylpropionyl, 2-(3-benzyl-2,5-dioxopyrrolidino)-3-(l- or 2-naphtnyl)-propionyl; N-substituted carbamoyl such as ETNC, IPNC, I-benzylcarbamoyl, 3- or 4-pyridylcustomary inhalers The new compounds can also be freeze-dried and the resulting lyophilisates used, for example, to prepare products for injection. The stated compositions ca. be sterilized and/or contain auxiliaries such as preservatives, stabilizers and/or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, colorants and/or flavourings. They can, if desired, also contain one or more other active substances, for example one or iiiore vitamins.

The substances according to the invention are, as a rule, administered in analogy to other known, commercially available peptides, but especially in analogy to the compounds described in EP-A 163227, EP-A 173481 and EP-A 209897, preferably in dosages between about 100 mg and 30 g, in particular between 500 mg and g, per dosage unit. The daily dosage is preferably between about 2 and 600 mg/kg of bodyweight. The specific dose for each particula patient depends, however, on a wide variety of factors, for example on the activity of the specific compound used, on the age, body weight, general state of health and sex, on the diet, on the time and route of administration and on the rate of excretion, medicinal substance, conmination and severity of the particular disease for which the therapy is applied. Parenteral administration is preferred.

All temperatures stated hereinbefore and hereinafter are in oC. In the examples which follow, "usual work:ing up" means: if necessary, water is added, the pH is adjusted to between 2 and 8, depending on the constitution of the final product, extraction is carried out with etayl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate, filtered and concentrated, and the crude product, which is usually oily, is subjected to g filtration on crosslinked polydextran using methanol/water or acetic acid/water as eluent, and, after concentration, purification is carried out by A. f -1 -26chromatography on silica gel and/or crystallization.

When the eluent in the gel filtration contains acetic acid. the quaternary acetates of the formula I, An

CH

3 COO, are obtained. The Rf values are obtained by thin-layer chromatography on silica gel; eluent methanol/acetic acid/water 7:2:1, unless otherwise indicated.

Example 1 A mixture of 1.079 g of N-2-[3S-hydroxy-4S-(Ntert. -butoxycarbonyl-L-phelylalanyl-N( imi) ,4-dinitrophenyl) -L-histidyl-glycyl-amino) noyl-L-isoleucyl-amino] -ethyl-N,N,,N-trimethyl-aimnonium acetate ["N-2-(BOC-Phe-(imi-DNP-His )-Gly-AHCP-Ileamino) -ethyl N, N- trimethyl ammonium acetate"; obtainable by reaction of BOC-Ile-N-2-dimethylaminoethylamide 100-1050) with CH 3 I to give N-2-(BOC-Ile-amino)ethyl-N,N,N-trimethylammonium iodide (oil; Rf 0.45, trichloroethane /methanol /acetic acid. elimination of the BOC group wi~th HCl/dioxane to give N-2-(H- Ile-amino) -ethyl-N, N,N, -trimethylai,.monium chloride hydrochloride 89-1200) and condensation with BOC- Phe-(imi-DNP-His)-Gly-AHCP-OH), 2 g -of 2-mercaptoethanol, 20 ml of DMF and 20 ml of water is, while stirring at 200, adjusted to pH 8 with aqueous Na 2

CO

3 solution and is stirred at 200 for 2 h. After the usual working up there ic, obtained N-2-[3S-hydroxy-4S-(Ntert btxcroy Lpeyaay--hsiy-lc amino) -5-cyclohexyl-pentanoyl-L-isoleucyl-ahi no] -ethyl- N, N,N-trimethylammonium acetate 2- (BOC-Phe-His-Gly- A}CP-Ile-amino) -ethyl-N,N,N-trimethylammoliul acetate"].

Example 2 1 g of N--BCPe(B--i)AC-l-mn]phl N, N ,N-trimethylammonium acetate [obtanable by hydrogenation of BOC-Phe-3-Pya-AHCP-OH to give B0C-Phe- 3-Pia-AHCP-OH, reaction with CBZ-Cl to give BCC-Phe- (CBZ-3-Pia)-AHCP-OH, condensation with N-(2-H-Ileaminoethyt) N, N-trimethylammonium chloride hydrochloride and HPLC with ammonium acetate) is dissolved

I

27 in 15 ml of ethanol and hydrogenated on 0.5 g of Pd-C at 200 and under 1 bar for 3 h, the mixture is filtered, the filtrate is concentrated and, after purification by chromatography, N-2- (BOC-Phe-3-Pia- AHCP-Ile-amino) -ethyl-N, N, N-trimethyl ammonium acetate is obtained.

The following are obtained analogously by hycrogenolysis of the corresponding CBZ derivatives: N-2-(BOC-Phe-2-Pia-AHCP-Ile-amin)-ethyl-NNNtrimethylammonium acetate N-2-(BOC-Phe-4-Pia-AHCP- Ile-amino)-ethyl-N,N,Ntrimethylammonium acetate N-3-(BOC-Phe-2-Pia-AHCP-Ile-amino)-propyl-NNNtrimethylammonium acetate N-3-(BOC-Phe-3-Pia-AHCP-Ile-amino)-propyl-NNNtrimethylammonium acetate N-3-(BOC-Phe-4-Pia-AHCP-Ile-amino)propyl-NNNtrimethylanmonium acetate N-2-(BOC-Phe-Gly-DACP-Leu-amino)-ethyl-NNNtrinethylammonium acetate N-2-(BOC-Phe-Gly-DACH-Leu-amino)-ethyl-NN,Ntrimethylammonium acetate N-2- (BOC-Phe-Gly-DAMH-Leu-amino) -ethyl-N,N,Ntrimethylammonium acetate N-2 (BOC -Phe-Gly-DAPP-Leu-amino) -ethyl N, N.

trimethylaxmonium acetate.

Example 3 1.01 g of N-methylmorpholine are added to a solution of 2.88 g of N-2-(H-Ile-amino) -ethyl-NN,N-trimethylanmmonium chloride hydrochloride 89-1200, obtainable by reaction of BOC- I le N- 2 -dinmethyaminoethylamide 100-1050) with CH 3 I to give N-(2-BOC-Ileaminoethyl) N, N-trimethyl ammonium iodide (oil) and elimination of the BOC group with HC1 in dioxane] in V 160 ml of DMF. While stirring, 5.19 g of BOC-Phe-Gly- AHCP-OH, 1.35 g of HOBt and a solution of 2.06 g of DCCI in 50 ml of CH 2 Cl 2 are added, the .re is stirred at 40 for 14 h, the precipitated dicyclohexylurea is filtered off, and the filtrate is concentrated.

It N-alkylmorpholinium.

The group Y is preferably -alkylene-Am, especially -CH CH 2 -Am or -CH 2

CH

2

CH

2 -Am, furthermore preferably -CH 2 -p-C 6 2

H

2 -Am; -alkylene-(l-pyridinium), especially -CH 2

CH

2 -(l-pyridinium) or -28- After the usual working up there is obtained N-2-(BOC- Phe-Gly-AHCP-Ile-ailo) -ethyl-N,N,N-trimethylammonium acetate m.p. 55-670, Rf 0.68.

The following are obtained analogously: N-2- (BOC-Phe-BAla-AHCP-Ile-amino) -ethyl-N,N,Ntrimethylammonium acetate N-2-(BOC-Phe-2-Pya-AHCP-Ile-amino) -ethyl-N,N,Ntrimethylanimonium acetate N-2-(BOC-Phe-3-Pya-AHCP-Il-ano) -ethyl-N,N,Ntriiethylammonium acetate N-2-(BOC-Phe-4-Pya-AHCP-Ile-amino) -ethyl-N,N,Ntrimethylaimonium acetate N-3-(BOC-Phe-Gly-AHCP-Ile-amino)-rplN,- 1 15 trimethylaimoniun acetate, m.p. 61-720, Rf 0.63 N-3-(BOC-Phe-BAla-AHCP-Ile-amiino) -propyl-N,N,N-trimethylanimonium acetate N-3-(BOC-Phe-2-Pya-AHCP-Ile-aino) -propyl-N,N,Ntrimethylaimoniui acetate iq 20 N-3-(BOC-Phe-3-Pya-AHCP-Ile-anino) -propyl-N,N,Ntrimethylanunonium acetate N-3-(BOC-Phe-4-Pya-AHCP-Ile-amino)-propyl-N,N,Ntrimethylainmonium acetate N-4-(BOC-Phe-Gly-AHCP-Ile-amino) -butyl-NN,N- U trimethylainmonium acetate N-4- (BOC-Phe-I3Ala-AHCP-Ile-amino) -butyl-N N- U trimethylanimonium acetate N-4-(BOC-Phe-3-Pya-AHCPrIle-amino) -butyl-N,N,Ntrimethylammonium acetate (BOC-Phe-Gly-AHCP-I le-amino) -pentyl-N, N,Ntrimethylammonium acetate -pentyl-N,N',Ntrimethylanmonium acetate N-5-(BOC-Phe-3-Pya-AHCP-Ile-amino)-pentyl-N,N,Ntrimethylammonium acetate.

Example 4 N-.2-(BOC-Pro-Phe-Gly-AHCP-Ile-amino)-ethyl-N,N,N- -29 triethyl ammonium chloride is obtained from BOC-Pro-OH and N-2- (H-Phe-Gly-AHCP-Ile-amino) -ethyl-N, N, N-tniethylammoriium chloride in analogy to Example 3.

*1 Example m.p. 55-670, is obtained from BOC-Phe-OH and N-2- (H-Gly-AHCP- I le-ainino) -ethyl-N,N, N-trimethyl ammonium chloride in analogy to Example 3.

The following are obtained analogously: N-2 (B0C- aNal-Gly-AHCP- I e-amino) -ethyl-N, N, N-trimethylammonium, acetate N- 2- (BOC-INal -Gly-AHCP -I le-amino) -ethyl N, Ntrinethyl ammoniumn acetate N- 2- (BOC-Trp-Gly-AHCP- le-amino) -ethyl N, Ntnimethyl ammonium acetate N-2 (BOC-Tyr-Gly-AHCP- Ile-amino) -ethyl N, Ntrimethylaimonium acetate Ji N-2- (P ivaloyl -Phe -Gly-AHCP- Ile- amino) -ethyl-N, N, Ntrimethylammonium acetate N- 2 3 -Dimethylbutyryl -Phe-Gly-AHCP- I le -amino) -ethyl- N,N,N-tnimethylammonium. acetate, Rf 0.70 N-2- 3-Dimethylbutyryl-Phe-la-AHCP- Ile-amino) ethyl -N IN, N- trimethyl amonium acetate N-2- 3-Dimethylbutyryl-Phe-3-Pya-AHCP-Ile-amino) ethyl N, N-trimethyl ammonium. acetate N-3 3 -Dimethylbutyryl -Phe-Gly-AHCP-I11e- amino) propyl N, N-trimethyl amonium acetate N- 3- (3,3 -Dimethylbutyry -Phe-3Ala-AHCP -I le- amino) propyl-N,N,N-trimethylammonium. acetate N- 3- 3 -Dimethylbutyryl-Phe- 3-Pya-AHCP-I11e- amino) propyl N, N-trimethyl ammonium acetate N- 2- (MAC-Phe-Gly-AHCP -Iie-amino) -ethyl N, Ntrimethylanmonium acetate N-2 (MAC-Phe-JAla-AHCP- Ile-amino) -ethyl N, Ntrimethylammonium acetate

V

N-2- (MAC-Phe-3-Pya-AHCP-Ile-amino) -ethyl-N, N, Ntrimethylammonium acetate I Li Am is tris-Cl 1 8 -alkyl-ammonium, 1-A-pyrrolidi- 1 nium, 1-A-piperidinium or 1-A-morpholinium; V' and Ia' to Ih', which correspond to the formulae I andi Ia to Ih but in which Q-Y is -NH-(CH 2 )z-NA~ and N-3- (MAC-Phe-Gly-AHCP-Ile-amino) -propyl-N,N,Ntrimethylammonium acetate N-3- (MAC-Phe-I3Ala-AHCP-Ile-amino) -propyl-N,N,Ntrimethylammonium acetate N-3- (MAC-Phe- 3-Pya-AHCP- Ile- amino) -propyl-N, N, Ntrimethylammonium. acetate N-2- (MAC-Phe-Gly-AHCP-Leu-amino) -ethyl-N,N,Ntrimethylaxnmonium acetate N-2-(MAC-Phe-3Ala-AHCP-Leu-amilo) -ethyl-N,N,Ntrimethylanumonium acetate N-2-(MAC-Phe-3-Pya-AHCP-Leu-auino)-ethyl-N,N,Ntrimethylammonium acetate N-2- 3-Dimethylaminopropionyl-Phe-Gly-AHCP-Ile-amino) ethyl-N, N,N-trimethylanmonium acetate N-2 (3 -Dimethylaminopropionyl -Phe-3Ala-AHCP-Ile-amino) ethyl N, N-trimethylammonium acetate N-2- (3-Dimethylaminopropionyl-Phe-3-Pya-AHCP-Ileamino) -ethyl-N,N,N-trimethylammonium acetate N-2- (4 -Dimethyl aminobutyryl -Phe-Gly-AHCP- Ile- amino) ethyl N,N-trimethylammonium acetate N-2- 5-Dimethylaminopentanoyl-Phe-Gly-AHCP-Ile-amino) ethyl-N, N, N-trimethylammonium acetate N-2- (5 -Dimethyl aminopentanoyl -Phe-3Ala-AHCP- Ile- amino) ethyl-N, N, N-trimethylanmonium acetate4 N-2- (5-Dimethylaminopentanoyl-Phe-3-Pya-AHCP-Ileamino) -ethyl-N, N, N-trimethylammonium acetate N-2 -Benzyl- 3-dimethylaniinopropionyl-Phe-Gly-AHCPle-amino) -ethyl-N,N,N-trimethylammonium acetate N-2- (2-Benzyl-3-dimethylaminopropionyl-Phe-Ala-AHCPle-amino) -ethyl-N,N,N-trimethylammonium acetate N-2- (2-Benzyl-3-dimethylaminopropionyl-Phe-3-Pya-AHCPle-amino) -ethyl-N, N, N-trimethylaumonium acetate correspond to the formula I but contain in place of a His group an N(im)-R'-His group (in which R, is an amino protective group, for example BOM or DNP), or thos ofthe ormla 1

-Z-M-NR

2

-CHR

3

_CH(NHR')-(CHR

5 CO-E-Q-Y.4 -31- N-2- amino) -ethyl-N, N, N-trimethylanmonium acetate N-2- (2-Benzyl-5-dimethylaminopentanoyl-3Ala-AHCP-Ileamino) -ethyl N, N-trimethyl ammonium acetate N-2- (2-Benzyrl-5-dimethylaminopentanoyl-3-Pya-AHCP-Ileamino) -ethyl-N, N, N-trimethylammonium acetate N-2- 5-Dioxopyrrolidino) -3-phenylpropionyl-Gly- AIICP-Ile-amino] -ethyl-N,N, N-trimethylammonium acetate N-2- (2 ,5-Dioxopyrrolidino) -3-phenylpropionyl-3Ala- AHCP-Ile-amino]-ethyl-N,N,N-trimethylammuolium acetate N-2- 5-Dioxopyrrolidino) -3-phenylpropionyl-3-Pya- AHCP-Ile-amino] -ethyl-N,N,N-trimethylanmonium acetate 2,5-Dioxopyrrolidino)-3-phenylpropionyl-Gly- AHCP-Leu-amino] -ethyl-N,N,N-trimethylaumonium acetate N-2- 5-Dioxopyrrolidino) -3-phenylpropionyl-3Ala- AHCP-Leu-amino] -ethyl-N,N,N-trimethylaimonium acetate N-2- (2 ,5-Dioxopyrrolidino) -3-phenylpropionyl-3-Pya- AHCP-Leu-amino] -ethyl-N, N,N-trimethylammonium acetate N-2- (3-Benzyl-2 ,5-dioxopyrrolidino) -3phenylpropionyl-Gly-AHCP-Ile-amino] -ethyl-N,N,Ntrimethylanmonium acetate N-3- 5-Dioxopyrrolidino) -3-phenylpropionyl-Gly- AHCP-Ile-amino] -propyl-N,N, N-trimethylaimonium acetate, Rf 0,55 ii N-3- 5-Dioxopyrrolidino) -3-phenylpropionyl-3Ala- 30 AHCP-Ile-amino]J-propyl-N,N, N-trimethylammonium acetate N-3- 5-Dioxopyrrolidino) -3-phenylpropionyl-3-Pya- AHCP-Ile-amino] -propyl-N,N, N-trimethylaumonium acetate N-2- (CBZ-Phe-Gly-AHCP-Ile-amino) -ethyl-NN,Ntrimethylaimonium acetate.

Example 6 N-2- (BOC-Phe-3-Pya-AHCP-Ile-amino) -ethyl-N,N,N-V trimethyl ammonium chloride, m.p. 225-2300, is obtained from BOC-Phe-3-Pya-OH and N-2-(H-AHCP-Ile-amino)-ethylaroyl such as benzoyl or -toluyl; aryloxyalkanoyl suchi as POA; alkoxycarbonyl such as methoxycarbonyl, ETOC, 2,2,2-trichloroethoxycarboflyl, BOC, 2-jodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ ('carbobeflzoxyl) 4-methoxybenzyloxycarbonyl, FMOC. Preferred amino protective groups are BOC, DNP and BOM, as well as CBZ, -32- N,N,N-trimethylamofliumf chloride in analogy to Example 3.

The following are obtained analogously: N- 2- (BOC-Phe-Gly-AHCP-Leu-amiflo) -ethyl-N, N,Ntrimethylaunonium chloride, m.p. 141-1420.

N- 2 (BOC -Phe-J3Ala-AHCP -Leu- amino) -ethyl N, Ntrimethylanmonium chloride N- 2- (BOC -Phe- 2-Pya-AHCP -Leu- amlino) -ethyl N, Ntrimethylanmonium chloride N- 2 -(BOC -Phe- 3-Pya-AHCP-Leu- amfino) -ethyl N, Ntrimethylammonium chloride N- 2 -(BOC-Phe- 4-Pya-AHCP-Lel- amlino) -ethyl-N, N, Ntrimethylamonium chloride N-3- (BOC-Phe-Gly-AHCP-Leu- amlino)-royNNN trimethylanmonium chloride N-3- (BOC-Phe-l3Ala-AHCP-Leu- amlino) -propyl-N, N,Ntrimethylammoniuni chloride N-3- (BOC-Phe- 2 -Pya-AHCP-Leu- amino) -propyl N, Ntrimethylammonium chloride N- 3- (BOC-Phe- 3 -Pya-AHCP-Leu- amino) -propyl-N, N,Ntrimethylanmoniun chloride N-3- (BOC-Phe-4 -Pya-AHCP-Leu-amino) -propyl-N, N ,Ntrimethylammonium chloride N-2 (BOC-Phe-Gly-AHCP-Nle- amino) -ethyl-N, N, Ntrimethylammonium chloride N-2 (BOC-Phe-l3Ala-AHCP-Nle -amuino) -ethyl-N, N, N- 1 trimethylaunonium chloride N- 2- (BOC-Phe -3 -Pya -AHCP-Nle amino) -ethyl N, Ntrimethylammonium chloride N- 2- (BOC -Phe -Gly-AHCP -Phe -amino) ethyl N, Ntrimethylanmonium chloride N -2 (S3OC -Phe -JAl a-AHCP -Phe amino) -ethyl NI Ntrimethylaimonium chloride N- 2-(BOC-Phe- 3-Pya-AHCP-Phe-amino) -ethyl-N, NNtrimethylaunonium chloride JVI L V aLJ.LL LJL lut J.MJ L wa necessary. Suitable and preferred inert solvents are organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide (DMF), halogenatedV hydrocarbons such as dichioromethane, as well as 1' -33- 1, 4N-2- (BOC-Phe-Gly-AHCP-Val-anino) -ethyl-N,N,N- 'if trimethylammonium chloride N-2-(BOC-Phe-3Ala-AHCP-Val-ahino) -ethyl-N,N,Ntrimethylanimonium chloride N-2-(BOC-Phe-3-Pya-AHCP-Val-amino)-ethyl-NN,N- I trimethylammonium, chloride N-2-(BOC-Phe-Gly-Sta-Ile-amino) -ethyl-N,N,Ntrimethylammonium, chloride N-2-(BOC-Phe-Gly-AHCH-Ile-amfino)-ethyl-N,N,Ntrimethylaimoniun chloride N-2-(BOC-Phe-Gly-AHPP-Ile-amino) -ethyl-N,N,Nft trimethylammonium, chloride 11 15 2-Benzyl-4-oxo-5, amino) -ethyl-N, N,N-trimethylanmoniun actt, Rf 0,68 N-2 sopropyl-4S-hydroxy-5S-BOC-Phe-3Ala-amino-6 cyclohexyl-hexanoyl-amino) -ethyl-N, N, Ntrimethylammonium. chloride, Im.p. 129-1300 N-2- (N-Benzoyl-N-benzyl-Gly-AHCP-Ile-amino) -ethylpyridinium bromide N-2-[2-(2,5-dioxopyrrolidino)-3-(p-hydroxyphenyl)propionyl-Gly-AHCP-Ile-amino] -ethyl-N,N,Ntrimethylainmonium methanesulfonate N-2- 5-Dioxopyrrolidino) (3-indolyl) -propionyl- Gly-AHCP-Ile-amino] -ethyl-N,N, N-tripropylammonium chloride N-2-[2-(2,5-Dioxopyrrolidino)-3-(1-naphthyl)-propiolyl- Gly-AHCP-Ile-amino 3-ethyl N, N-tributylalnmonium chloride N-2- 5-Dioxopyrrolidino) (2-naphthyl) -propionyl- Gly-AHCP-Ile-amino] -ethyl-N-2-phenylethyl-morpholinium chl~oride (3-Benzyl-2 ,5-dioxopyrrolidino) -acetyl-AHCP-Ileamino] -ethyl-N, N, N-trimethylanuuonium acetate N-2- (3-Benzyl-2 ,5-dioxopyrrolidino) -propionyl-AHCPle-amino] -ethyl-N,N,N-trimethylaxmonium acetate component (formula II) and an amine component (formula 111)., Examples of suitable carboxylic acid components are those of the part-formulae R -Z-OH, R -Z-M-OH, R- Z-M-W-OH or R -Z-M-W-E-OH, and of amine components are those of the part-formulae H-M-W-E-Q-Y, H-W-E-Q-Y, H-E- Q-Y or H 2 N-Y. The peptide linkage can, however, also be 43 r N-2- 3-Benzyl-2, 5-dioxopyrrolidino) (4imidazolyl) -propionyl-A{CP-Ile-amino] -ethyl-N, N, Ntrimethylammonium acetate N-2- -Benzyl- 4 -dimethyl amino- 4 -oxobutyryl-Gly-AHCP- Ile-amino) -ethyl-N, N, N-trimethylammonium acetate N-2 (2 -Benzyl-4 -dimethylamino-4 -oxobutyryl-3A-la-AHCPle-amino) -ethyl-N,N,N-trimethylammonium acetate N-2- (2-Benzyl-4-dimethylamino-4-oxobutyryl-3-Pya-AHCPle-amino) -ethyl-N,N,N-trimethylammonium acetate N-2 -Benzyl (3 -diinethylaminopropyl) -4-oxobutyryl- Gly-AHCP-Ile-amino) -ethyl-N,N, N-trimethylammonium acetate N-2- -Benzyl- 4- (3 -dimethylaminopropyl) -4-oxobutyryl- BAla-AHCP-Ile-amino) -ethyl-N, N, N-trimethylammonium acetate Ii N-2- 2-.Benzyl-4- 3-di-methylaminopropyl) -4-oxobutyryl-3- Pya-AHCP-Ile-amino) -ethyl N, N-trimethylammonium acetate a 04 N-2- (2-Benzyl-4-oxo-5 **amino) -ethyl-NNNtrimethylamonium acetate N-2- (2-Benzyl-4-oxo-5 ,5-dimethyl-hexanoyl-3Ala-AHCP- 2 le-amino) -ethyl-N,N,N-trimethylamonium acetate Ile-aiuino)-ethyl-N,N,N-trimethyanmonium acetate N-2 (2 2-Bieyl4-o- 3 -phetyl -heainyl-3-y-AHCP- e N-2- (2-Dimethylamino-3-phenyl-propionyl-Gl-AHCP-Ileamino) -ethyl-N,N,N-trimethylanmoniun acetate4 N-2 -Dimethylamitno-3 -phenyl-propiony-3-la-AHCP-leamino) -ethyl N N-trimethylanmoniuu acetate.

Eamn)lethlN 7,-r tyamoimaeae 560,i bandfrmBCPeGy EamCp-le-O an7- aioty-,NNtie lamnu chloride in analogy to Example 3.

PT

0 The following are obtained analogously: N-4- (BOC-Phe-Gly-AHCP-Ile-amino) -butyl-N,N,Ntrimethylammonium. acetate (BOC -Phe-Gly-AHCP- Ile- aino) -pentyl-N, N, Ntrimethylaimonium acetate N- 6- (BOC-Phe-Gly-AHCP- Ile- amino) -hexyl N, Ntrimethyl ammonium acetate N-7-(BOC-Phe-Gly-AHCP-Ile-amino) -heptyl-N,N,Ntrimethylammonium. acetate N-8-(BOC-Phe-Gly-AHCP-Ile-amino)-octyl-N,N,Ntrimethylanmonjium acetate N-9-(BOC-Phe-Gly-AHCP-Ile-ainino) -nonyl-N,N,Ntrimethyl amonium acetate trimethyl ammoniumn acetate N-p- (BOC-Phe-Gly-AHCP-Ile-aiinomethyl) -benzyl-N, N,Ntrimethylammonium, acetate N- 2 -(BOC -Phe -Gly-AHCP- Ile -amnino) -ethyl N-dimethyl -Nhexyl-ammonium acetate N-2- (BOC -Phe -Gly-AHCP- Ile -amino) -ethyl N-dimethyl -Noctyl-aunonium. acetate N-2- (BOC-Phe-j3Ala-AHCP- Ile- amino) -ethyl-N, N-dimethyl-Noctyl-aimonium. acetate N- 2- (BOC -Phe 3-Pya-AHCP- Ile -amnino) -ethy N-dimethy. N-octyl -ammoniumi acetate N- 3- (BOC -Phe-Gly-AHCP- Ile -amino) -propyl N-dimethyl. -Nfl octyl-axnmonium acetate N-3- (BOC-Phe-I3Ala-AHCP-Ile-ar;A4no) -propyl-N, N-dimethyl- 430 N-octyl -amnmonium acetate N-3- (BOC-Phe-3-Pya-AHCP-Ile-amino) -propyl-N, N-diniethyl- N-octyJ.-ammonium acetate N- 5- (BOC-Phe-Gly-AHCP- Ile- amino) -pentyl -N N-dimethyl-Noctyl-aimonium. ar.etate N-5- (BOC-Phe-J)Ala-AHCP-Ile-amino)-pentyi-N,N-dimethyl- N-octyl -ammonium acetate (BOC-Phe-3-Pya-AHCP-Ile-amino) -pentyl-N,N-dimethyl- N-octyl- ammoniumn acetate N-2- (BOC-Phe-Gly-AHCP-Ile-amino) -ethyl-N,N-dimethyl-N- -36decyl-anmonium acetate N-2 (BOC-Phe-Gly-AHCP- Ile- amino) -ethyl -N-methyl pyrrolidinium acetate N-3- (BOC -Phe -Gly-AHCP- Ile -amino) -propyl-N-methylpyrrolidinium acetate N-2 (BOC-Phe-Gly-AHCP- Ile- amino) -ethyl -N-methyl piperidinium acetate 4 N- 3- (BOC-Phe -Gly-AHCP- Ile- amino) -propyl -N-methylpiperidiniuu acetate N- 2- (BOC -Phe-Gly-AHCP- Ile- amino) -ethyl -N-methyl morpholinium acetate N- 3- BOC- Phe -Gly-AHCP- Ile -amino) -propyi-N-methylmorpholinium acetate N-Benzyi- 4- (BOC-Phe-Giy-AHCP -Ile -amino) -N-methylpiperidinium acetate 3- BOC-Phe-Gly-.AHCP-Ile-aminomethyl) -N-methylpyridinium chloride, m.p. 1380 N-2 (BOC-Phe -Gly-AHCP- Ile -amino) -ethyl -pyridinium acetate.

Example 8 N-2 (BOC -Phe-Gly-A}ICP-Al a-Leu- amino) -ethyl- NNN-trimethylammonium chloride is obtained from BOC- Phe-Gly-AHCP-Ala-OH and N-2-(H-Leu-amino)-ethyl-N,NfNtrimethyl ammonium chloride in analogy to Example 3.

Example 9 A solution of 0.4 g of CH 3 T~ in 2 ml of acetonitrile is added dropwise, at 00 with stirring, to a suspension of 1 g of BOC-Phe-Gly-AHCP-Ile N-(2dimethylaminoethyl )-amide in 12 ml of acetonitrile, the mixture is stirred at 200 for a further 4 h and then evaporated, the crude product is washed several times with ether, the usual working-up is carried out, and "All is obtained, m.p. 55-67o The same product is obtained analogously from 37 equimolar amounts of BOC-Phe-Gly-AHCP-Ile N- (2chloroethyl)-amide and trimethylamine.

N-3- (IPOC-Phe-Gly-AHCP-Ile-oxy) -propyl-Nmethyl-morpholinium bromide is obtained analogously from IPOC-Phe-Gly-AHCP-Ile 3-bromopropyl ester and Nmethyl-morpholine.

Example A solution of 1 g of N-2- (BOC-Phe-Gly-AHCP-Ileamino) -ethyl-NN,N-trimethylammonium acetate in 20 ml of 4 N HC1 in dioxane is stirred at 200 for 30 min and then evaporated. N-2- (H-Phe-Gly-AHCP-Ile-amino) -ethyl- N,N,N-trimethylammonium chloride hydrochloride is obtained.

Example 11 N-2-(H-Phe-Gly-AHCP-Ile-amino) -ethyl-N, NNtrimethylammonium acetate is obtained from N-2-(CBZ- Phe-Gly-AHCP- Ile-amino) -ethyl-N, NoN-trimethylammonium acetate by hydrogenolysis in analogy to Example 2.

Example 12 70 mg of hydroxylamine hydrochloride are added to a solution of 751 mg of N-2-[N-(3-oxo-4S-BOC-Phe- -Ile-amino] -ethyl- NN,N-trimethylammonium chloride and 1.43 g of Na 2

CO

3

H

2 0 in 5 ml of methanol and 5 ml of water, and the mixture is stirred at 200 for 14 h. The precipitated oxime is filtered off, dried, dissolved in 10 ml of methanol and hydrogenated on 0.5 g of Raney Ni at 200 under 5 bar. The catalyst is removed by filtration, the filtrate is evaporated, the resulting mixture is separated on silica gel, and N-2-[N-(3S-amino-4S-BOClohexylpentanoyl) -lie-amino -ethyl- NIN,N-trimethylammonium chloride ["N-2-(BOC-Phe-Gly- DACP-Ile-amino) -ethyl-N, I N N-trimethylammonium chloride"] is obtained; the 3R amino epimer is also obtained.

The following are obtained analogously from the appropriate oxo compounds: N-2-(BOC-Phe-Gly-DACH-Ile-amino) -ethyl-NNNtrimethylammonium chloride, the active substance either dissolved Or suspendled in a propellant gas mixture (for example chiorofluorohydrocarbons) The active substance is preferably used for this in micronized form, with one or more additional. physiologically tolerated solvents possibly being present, for example ethanol. Solutions for inhalation can be administered with the aid of -38- N-2 (BOC-Phe -Gly-DAMH- Ile- amino) -ethyl-N, N, Mtrimethylaimonium chloride, N- 2- (BOC-Phe -Gly-DAPP- Ile- amino) -tehyl N, Ntrimethylammnonium chloride.

Example 13 BOC-Phe-His-AHCP-Ile-AMPA methoacetate, m.p. 1210, is obtained in analogy to Example 2, but in acetic acid instead of ethanol, by hydrogenolysis of BOC-Phe-imi- BOM-His-AHCP-Ile-AMPA methoiodide.

The methoacetates of the following compounds are obtained analogously by hydrogenolysis of the methoiodides of the corr-sponding imi-BOM derivatives: 6 -Aminohexanoyl-Phe-His -AIICP- Ile-AMPA 6 -Aminohexanoyl-Phe-His-AHCP-Leu-AJPA 6-Dimethylaminohexanoyl-Phe-His-AHCP-Ile-AMPA 6 -Dixethylaniinohexanoyl -Phe -His -AHCP-Leu-AMPA 6 -Aminohexanoyl -Phe-His -AHCP- Ile 2-pyridylmethylamide) 6 -Arinohexanoyl-Phe-His -AHCP-Leu 2-pyridylmethylamide) 6 -Aminohexanoyl-Phe-His -AHCP-Ile 3-pyridyimethylainide) 6 -Aminohexanoyi-Phe-His-AIICP-Leu (N-3 -pyridylmethylamide) 6 -Aminohexyanoyl-Phe-His -AHCP-Ile (N-4 -pyridylmethylamide) 6 -Aminohexanoyl-Phe-His -AHiCP-Leu (N-4 -pyridyimethyl aiuide) 6 -Aminohexanoyl-Phe-His -AHCP- Ile 2-hydroxy-4, 6dimethyl-3-pyridylmothylamide) 6-Azinohexanoyl-Phe-His-AHCP-Leu (N-2-hydroxy-4, 6dimethyl-3-pyridylmethylamide).

Example 14 4 -Dimethylaminobutyryl-Phe-Gly-AHCP- Ile-AMPA methoiodide is obtained in analogy to Example 3 from 4dimethylaminobutyric acid and H-Phe-Gly-AHCP-Ile-AMPA methoiodide.

The following are obtained analogously: 4 -Dimethylaminobutyryl-Phe-Gly-AHCP- Ile-ADPA 4 -39methoiL lide 4-Dimethylaminobutyryl-Phe-Gly-AHCP-Leu-AMPA metho iodide- 4 -Dimethyl.aminobutyryl -Phe-Gly-AHCP-Leu-ADPA metho iodide ihvl amir ,obutyryl -Phe-3Ala-AICP- Ile-AMPA methoiodL~de 4 -Dime thylaminobuty-y1-Php- Ala-AHCP-Ile-ADP'A methoi,_r,- de Dimethylaminobtyr-yl-T-ihe-3Ala--AHCP-Leu-AMPA methoiodide 4-Dixnethyl aminobutyryl-Phe-3Ala-AHCP-Leu-ADPA metho iodide 6-Dixethylaminohexanoyl-Phe-Gly-AHCP-I le-AMPA methoiodide 6- Dimethylaminohexanoyl -Phe -Gly-AHCP -Leu-AMPA metho iodide 6-Dimethylaminohexanoyl-Phe-3Ala-AlCP-Ile-AMPA metho iodide 6-Dirnethylaminohexanoyl-Phe-Ala-AHCP-Leu-AMPA metho iodide.

Example The met,-oiodids corresponding to 6-BOCaminohexanoyl-Phe-Gly-AHCP-Ile (N-3-pyridylmethylauide) is obtained it and CH 3 1 in analogy to Example 9, decomposition at 960.

The following are obtained analogously: BOC-Phe-Gly-AIICP-Ile-AMPA methochioride, m.p. 1500 4-BOC-aminobutyryl-Phe-Gly-AHCP-IleAMPA methoiodide 4 -BOC-aminobutyryl-Phe-Gly-AHCP-I le-ADPA niethoiodide 4 -BOC-aminobuty,&yl-Phe-Gly-AHCP-Leu-AMPA methoiodide 4 -BOC-aminobutyryl -Phe -Gly-AHCP-Leu-ADPA niethoiodide 6 -BOC-aminohexanoyl-Plhe-Gly-AHCP-I le-AMPA methoiodide, M.P. 1110 6 -BOC-aminohexanoyl-Phe-Gly-AHCP- Ile-ADPA, methoiodide 6-BOC-aminohexanoyl-Phe-Gly-AHCP-Ile (N-2pyridylmethyla-tido) motholodide 6 -B0C-amintohex&.oyl-Phe-Gly-AHCP- Ile (N-4 pyridylmethylamide) methoiodide 6-BOC-aminohexanoyl-Phe-Gly-AHCP-Ile (N-2-hydroxy-4, 6dimethyl-3-pyridylmethylamide) methoiodide 6-BOC-aminohexanoyl-Phe-Gly-AHCP-Leu-AMPA methoiodide 6 -BOC-aminohexanoyl -Phe-Gly-AHCP -Leu-ADPA metho iodide 6 -BOC -amino hexanoyl -Phe -Gly-A{CP -Leu (N-2 pyridylmethylamide) metho iodide 6 -BOC-aminohexanoyl-Phe-Gly-AHCP-Leu 3pyridylmethylamide) methoiodide 6 -BOC -amino hexanoyl -Phe -Gly-AHCP -Leu (N-4pyridylmethylamide) methoiodide 6 -BOC-aminohexanoyl-Phe-Gly-AICP-Leu 2-hyciroxy- 4,6 dimethyl-3-pyridylmethylamide) methoiodide methoiodide 6-BOC-aminohexanoyl-Phe-3Ala-AHCP-Ile-ADPA methoiodide 6-BOC-aminohexanoyl-Phe-i3Ala-AHCP-Ile (N-2pyridylmethylamide) nietho iodide 6-BOC-aminohexanoyl-Phe-J3Ala-AHCP-Ile (N-3pyridylmethylamid) methoiodide 6-BOC-axinohexanoyl-Phe-I3Ala-AHCP-Ile (N-4pyridylmethylainide) methoiodide 6-BOC-aminohexanoyl-Phe-3Ala-AHCP-Ile (N-2-hydroxy-4,6dimethyl -3 -pyridylmethyl amid) methoiodide 6-BOC-aminohexanoyl-Phe-BAla-AHCP-Leu-AMPA methoiodide 6 -BOC-aiinohexanoyl-Phe-3Ala-AHCP-Leu-ADPA methoiodide 6-BOC-aminohexanoyl-Phe-3Ala-AICP-Leu (N-2pyridylmethylamide) metho iodide 6-BOC-aminohexanoyl-Phe-BAla-AHCP-Leu (N-3pyridylmethylamide) metho iodide 6-BOC-aminohqLxanoy1-Phe-I3Ala-AHCP-Leu (N-4 pyridylmethylamide) methoiodide 6-BOC-aminohexanoyl-Phe-3Ala-AHCP-Leu (N-2-hydroxy-4, 6diniethyl-3-pyridylnethylwnide) methoiodide 8-BOC-aminooctanoyl-Phe-Gly-AHCP-Ile-AMPA methoiodide 8-BOC-aminooctanoyl ,.Phe-Gly-AHCP- Ile-ADPA methoiodide 8-BOC-aminooctanioyl-Phe-Gly-AHCP-Leu-AMPA methoiodide 8-BOC-aminooctanoyl-Phe-Gly-AHCP-Leu-AlPA methoiodide.

Example 16 The (mono)methoiodide corresponding to ?,-tert.butylamino-3-phenylpropiony1-Gly-AHCP-Ile-Al ,A is J 41 obtained by leaving an ethanolic solution of it to stand with excess CH 3 I for one week, m.p. 1800.

Example 17 A solution of 1 g of (2-benzyl-4-oxo-5,5dimethyl-hexanoyl) -imi-tert. -butoxy-methyl-His-AHCP- Ile-AMPA methoiodide [obtainable by condensation of 2benzyl-4-oxo-5,5-dimethylhexanoic acid with H-(imitert. -butoxymethyl-His) -AHCP-Ile-AMPA followed by reaction with CH 3 I] in 20 ml of 4 N HCl in dioxane is stirred at 200 for 30 min and then evaporatedf. 2methochloride hydrochloride is obtained, decomposition at 1020.

Cleavage of the methoiodides of the corresponding BOC-amino derivatives analogously yields: 4-mnbtrlPe-l-HPIeAP meho.or *4 -Aminobutyryl-Phe-Gly-A'HCP-1 le-AIPA methochloride 4-Aminobutyryl-Phe-Gly-AHCP-Le-APA methochloride 4 -Aminobutyryl -Phe-Gly-AHCP-Leu-A{PA methochloride 6-Aminohexanoyl-Phe-Gly-AHCP-Ile-APA methochloride, dihydxrochloride, decomposition at 1020 6 -Aiinohexanoyl-Phe-Gly-AHCP-I le-AJPA methochloride 6-Aminohexanoyl-Phe-Gly-AHCP-Ile pyridylmethylamide) methochloride 0'.25 6 -Aminohexanoyl--Phe-Gly-AHCP-Ile (N-3pyridylImethylanide) methochioride, dihycirochioride, decomposition at 1050 6 -Aminohexanoyl-Phe-Gly-AHCP- le (N-4 pyridylmethylamide) methochloride O 30 G -Aminoht anoyl-Phe-Gly-AHCP -Ile (N-2 -hydroxy-4 ,6dimethyl-3-pyridylnethylamide) methochioride 6 -Aminohexanoyl-Phe-Gly-AHCP-Leu-APA methochloride 6 -Aminohexanoyl-Phe-Gly-AHCP-Leu-AJPA methochioride 6 -Aminohexanoyl-Phe-Gly-AHCP-Leu (N-2 pyridylmethylanide) methochioride 6 -Aminohexanoyl-Phe-Gly-AHCP-Leu (N-3pyridylmethylamide) methochlorideJ 6 -Anminohexanoyl-Phe-Gly-AHCP-Leu (N-A pyridylmethylamide) methochioride 4I1 4, 41

S

I I 42 6-Aminohexanoyl-Phe-Gly-AHCP-Leu (N-2-hydroxy-4,6dimethyl-3-pyridylmethylamide) methochloride y-Aminooctanoyl-Phe-Gly-AHCP-Ile-AMPA methochloride 8-Aminooctanoyl-Phe-Gly-AHCP-Ile-ADPA methochloride 8-Aminooctanoyl-Phe-Gly-AHCP-Leu-AMPA methochloride 8-Aminooctanoyl-Phe-Gly-AHCP-Leu-ADPA methochloride.

The examples which follow relate to pharmaceutical compositions: Example A: Injection ampoules A solution of 100 g of N-2-(BOC-Phe-Gly-AHCP- Ile-amino)-ethyl-N,N,N-trimethylammonium acetate and g of disodium hydrogen phosphate in 4 1 of doubledistilled water is adjusted to pH 6.5 with 2 N hydrochloric acid, filtered sterile and dispensed into injection ampoules. After lyophilization under sterile conditions they are sealed sterile. Each injection ampoule contains 500 mg of active substance.

Example B: Suppositories A mixture of 50 g of N-2-(BOC-Phe-Gly-AHCP-Ileamino)-ethyl-N,N,N-trimethylammonium chloride with 10 g of soya lecithin and 140 g of cocoa butter is melted, poured into moulds and left to cool. Each suppository contains 250 mg of active substance.

Example C: Tablets 56 A mixture of 1 kg of 6-aminohexanoyl-Phe-Gly- AHCP-Ile-AMPA methochloride dihydrochloride, 4 kg of lactose, 1,2 kg of maize starch, 200 g of talc and 100 g of magnesium stearate is compressed to tablets in the customary manner so that each tablet contains 100 mg of active substance.

Example D: Coated tablets Tablets are compressed in analogy to Example C and are then coated in a customary manner with a coating composed of sucrose, maize starch, talc, tragacanth and colorant.

Example E: Capsules 500 g of 6-aminohexanoyl-Phe-Gly-AHCP-Ile (N-3pyridylmethylamide) methochloride dihydrochloride are dispensed in a customary manner into hard gelatine

W.

T

-43 capsules so that each capsule contains 500 mg of active substance.

Claims (4)

1. Amino acid derivatives of the formula I R 1 Z-M-NR 2 -CHR -_CR -_(CUR in whic] 00 S0 0 S. S 9 000 S .5 15 560S S S S S. S S. S *5 S q 55 *5 S 90* is R 6 R 6 O0CmH 2 mCO, R 6 _CmH 2 mOCO- 1 R 6 CmH2mCO, R6_S0 2 (R 6 -CmH2m(T)x(G)y-CrHi 2 r)- L(R 7 _C pH 2 p) -CtH 2 t-CO-, R 6 _-(NICH 2 CH 2 )MIICH 2 CO-, or 9 -fluorenyl-CmH 2 m-O-CO.-, is 0 to 3 amino acid residues which are linked together in the manner of a peptide and are selected from the group comprising Abu, Ada, Ala, I3Ala, Arg, Asn, Asp, Bia, Cal, Dab, Gin, Glu, Gly, His, N(im)-A-His, Ile, Leu, tert.- Leu, Lys, Met, Nal, BNal, Nbg, Nie, Orn, Phe, Pia, Prol Pya, Ser, Thr, Tic, Trp, Tyr and Val, is BAla, Gly, Pia or Pya, or else His if an R84 group replaces an N atom in a Het-ylene group in the radical Y is 0 to 2 amino acid residues which are linked together in the manner of a peptide and are selected from the group comprising Abu, Ala, Cal, His, Ile, Leu, Met, Nie, Nva, Phe, Trp, Tyr and Val, is 0 or NH, is an alkyl group which it is also possible for a CH 2 -group to be replaced by an Ar-ylene group or Het-ylene group and which has a total of 1-20 C atoms and. is substituted by an R 8 R9R101$@ group or a pyridinium group which is unsubstituted or substituted one or more times by A, AO and/or Hal, and/or in which an R8nG group replaces an N atom in a Het-ylene group, 0* S. S S S S I Q y r 1 45 ArP is an anion, which can also be absent if, in its stead, a carboxyl group contained in the compound of the formula I is in the form of a carboxylate ion, R 3 R 6 and R 7 are each H, A, Ar, Ar-alkyl, Het, Het- alkyl, unsubstituted or singly or multiply, by A, AO and/or Hal, substituted cycloalkyl having

3-7 C atoms, cycloalkylalkyl having 4-11 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms or bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C atoms, R 2 and RS are each H or A, R 4 is OH), NH2) or =0, R 8 R 9 and R 1 0 are each alkyl having 1-18 C atoms or 15 Ar-alkyl, two of the radicals R 8 R 9 and R 1 0 together are also an alkylene group which has 2-8 C atoms and can be interrupted by an O atom

6. or by an NR 1 1 group, S" R is H, A, Ar or Ar-alkyl, L is CH or N, T is O, S, NH or NA, G is CO, S, SO or S02, n is 1 or 2, p, r and t are each 0, 1, 2, 3, 4 or 25 x and y are each 0 or 1, Ar is phenyl which is unsubstituted or substituted one or more times by A, AO, Hal, CF 3 OH, H 2 NSO 2 and/or NH 2 or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered 30 heterocyclic radical which has 1-4 N, O and/or S atoms and can be fused with a benzene ring and/or can be substituted one or more times by A, AO, Hal, CF 3 HO, 0 2 N, carbonyl oxygen, H 2 N, HAN, A 2 N, AcNH, AS, ASO, ASO 2 HOOC, AOOC, CN, H 2 NCO, H 2 NSO 2 ASO 2 NH, Ar, Ar-alkyl, Ar- alkenyl, hydroxyalkyl and/or aminoalkyl each having 1-8 C atoms and/or whose N and/or S heteroatoms can also be oxidized, Hal is F, Cl, Br or I, 1 44 I8 Ac is A-CO-, Ar-CO- or A-NH-CO-, -alkyl- is an alkylene group having 1-4 C atoms, and A is alkyl having 1-8 C atoms, jand in which, furthermore, it is also possible for one or more -NH-CO- groups to be replaced by one or more -NA-CO- groups, as well as the salts thereof. 2. a) Salts of N-2-(BOC-Phe-Gly-AHCP-Ile-amino)- ethyl-N,N,N-trimethylammonium hydroxide. b) Salts of N-3-(BOC-Phe-Gly-AHCP-Ile-amino)- pronyl-N,N,N-trimethylammonium hydroxide. c) Salts of N-2-(BOC-Phe-3-Pya-AHCP-Ile-amino)- ethyl-N,N,N-trimethylammonium hydroxide. d) Salts of N-methyl-3-(6-aminohexanoyl-Phe-Gly- AHCP-Ile-aminomethyl)-pyridinium hydroxide. e) Salts of 1,2-(or 2,3-)dimethyl-4-amino-5-(6- aminohexanoyl-Phe-Gly-AHCP-Ile-aminomethyl)- pyrimidinium hydroxide. 3. Process for the preparation of an amino acid derivative of the formula I, and of the salts thereof, characterized in that it is liberated from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, or in that a carboxylic acid of the formula II R 1 -G 1 -OH II in which G is Z 1 Z, Z-M, Z-M-W, Z-M-W-E, Z-M-W-E and W is -NR2CHR 3 CR4-(CHR 5 )n-CO-I is reacted with an amino compound of the formula III H-G 2 7 II in which 2 is -Z 2 -M-W-E-Q-Y, -M-W-E-Q-Y, -W-E-Q-Y, -E-Q-Y, Example 7 m.p. 55-67°, is obtained from BOC-Phe-Gly- AHCP-Ile-OH and N-2-aminoethyl-N,N,N-trimethylammonium chloride in analogy to Example 3. r 47 -E 2 -Q-Y, NH-Y, E l E 2 are together E, and Z Z 2 are together Z, or in that a tertiary amine which otherwise corresponds to formula I is treated with a quaternizing agent, and in that a functionally modified amino and/or hydroxyl group in a compound of the formula I is liberated where appropriate by treatment with solvolyzing or hydrogenolyzing agents, and/or for the preparation of a compound of the formula I in which R 4 is OH) or NH 2 an amino keto acid derivative of the formula I in which R 4 is O is reduced or reductively aminated, and/or a compound of the formula I is converted by treatment with an acid into one of S* the salts thereof, and/or an anion An in a compound of the formula I is replaced by another anion A. Process for the preparation of pharmaceutical compositions, characterized in that a compound of the formula I and/or one of the physiologically acceptable salts thereof is converted, together with at least one solid, liquid or semi-liquid vehicle or auxiliary and, *r where appropriate, in combination with one or more other active substance(s), into a suitable dosage form. 5. Pharmaceutical composition characterized by ti contain,.:g at least one compound of the formula I and/or one of the physiologically acceptable salts thereof. S" 6. Use of compounds of the formula I or of 30 physiologically acceptable salts thereof for the preparation of a medicament. 0218p:mmb -48

7. Use of compounds of the formula I or of physiologically acceptable salts thereof for controlling renin-dependent hypertension or hyperaldosteronism. DATED this 14th day of May, 1991. MERCK PATENT Gesellschaft mit beschrankter Haftuni By Its Patent Attorneys ARTHUR S. CAVE CO. I I S