AU626835B2 - Amino acid derivatives - Google Patents

Description

AUSTRALIA

PATENTS AC6 9 COMPLETE SPECIC7

(ORIGINAL)

FOR OFFICE USE Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art: r j TO BE COMPLETED BY APPLICANT Name of Applicant: Address of Applicant: Actual Inventors: Merck Patent Gesellschaft Mit Beschrankter Haftung Frankfurter Strasse 250, D-6100 Darmstadt, Federal Republic of Germany Dr. Peter Raddatz, Dr. Johannes Sombroek, Dr. Joachim Gante, Dr. Claus J. Schmitges and Dr. Klaus-Otto Minck ARTHUR S. CAVE CO.

Patent Trade Mark Attorneys Level Barrack Street SYDNEY N.S.W. 2000

AUSTRALIA

Address for Service: Complete Specification for the J C .L T invention entitled NMwe u:eth f3 Avo acand m.v\v oves The following statement is a full description of this invention including the best method of performing it known to me:- 1 ASC 49 ,TA:2217T i;l The invention relates to new amiino acid derivatives of the formula I R -Z-NR 2_CUR -_CR -_(CUR 5)n -CO-E-Q-Y I in which Ri is [R 6

R

7 N-CmH 2 x-.C0) y-CrH 2 r]>L(R 8 -C PH 2 p)- Co- 8or L(R _C PH 2 p) -GO-, Z is Abu, Ada, Ala, I3Aia, Arg,, Asn, Asp, Bia, Cal, Dab, Ftr, Gin, Giu, Gly, His, Hph, N(im)- A-His, Ile, Leu, tert.-Le", Lys, Met, Nal, J3Nai, Nbg, Nie, Nva, Orn, Phe, Pia, Pro, Pya, Ser, Thr, Tia, Tic, Trp, Tyr or Val, 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, o Cal, His, Ile, Leu, Met, Nie, Nva, Phe, Trp, Tyr and Val, *Q is 0 or R0 11 12 Y is -CtH 2 t-R 11 -CtH 2 t-R 1 or -CwH2w-(CR1 3 s-CtH 2 t-R 11 T isO0 or N1 'L is CU or N,

**R

2 R, R R 1 and R 1 are each H or A,

R

3

R

8 and R are each H, A, Ar, Ar-alkyl, Het, Hetalkyl, cycloalkyl having 3 7 C atoms which is dnsubstituted or substituted one or more times by A, AO and/or Hal, cycloalkylalkyl having 4-11 C atoms, bicycloalkyl or tricycloalkyl. each having 7-14 C atoms, bicycloalkylalkyl or tricycloaikylaikyl each having 8-18 C atoms, Rand R 13 are each OH), NH 2 or =0,

R

6 and R 7 are each H, A, -C(=NI)-N1 2 or -C(=NHi)-NHCN, R 6 can also be Ac, R2 is -SO 3 H, -S0 2

NH

2

-SO

2 NH{A1 -SO 2

A

2 -i 2 2 -2- NHA, -NA 2

-NH-C(=NH)-NH

2 -NH-C(=NH)-NHCN,

NH-CO-NH

2 -NH-CO-NHA, -NH-CO-NA 2

-NH-CS-NH

2 -NH-CS-NHA or -NH-CS-NA 2 n and s are each 1 or 2, m, p, r, t and w are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or x, y and z are each 0 or 1, Ar is phenyl which is unsubstituted or substituted one or more times by A, OA, Hal, CF 3 OH, NO 2 hydroxyalkyl, NH 2 NHA, NA 2 NHAc, SA, SO-A,

SO

2 S0 2

NH

2

SO

2 NHA, COOH, COOA, CONH 2

CN,

Aminoalkyl, HAN-alkyl, A 2 N-alkyl, A 3 N lkyl Ane and/or guanidinylalkyl or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical which has 1-4 N, 0 and/or S atoms and is fused with a benzene ring and/or can be substituted one or more times by A, OA, Hal, CF 3 OH, NO 2 carbonyl oxygen, NH 2

NHA,

NA

2 NHAc, SA, SO-A, SO 2 S0 2

NH

2 S02NHA, COOH, COOA, CONH 2 CN, NH-SO 2 Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl and/or aminoalkyl and/or whose N and/or S hetero atoms can also be oxidized, Hal is F, Cl, Br or I, SAc is A-CO-, Ar-CO-, Ar-alkyl-CO-, A--CO- Ar-O-CO-, Ar-alkyl-O-CO- or A-NH-CO-, An O 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 anion, -alkyl- is an alkylene group having 1-8 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 249096.

The invention had the object of finding new compounds with valuable properties, in particular those Si.

i l I C .a' 9* 9 9 99 99 9 3 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, the concentrations of these compounds necessary for the inhibition of other aspartyl proteinases (for example pepsin and cathepsin D) are about 100 to 1000 times as high as for renin inhibition. The actions of the compounds on the blood pressure and/or on the heart rate, as well as the inhibition of renin activity in blood plasma can furthermore be determined in conscious monkeys, for example female monkeys (Macaca fascicularis); it is possible in this for the blood pressure and heart rate to be measured by a modification of the method of M.J.

Wood et al., J. Hypertension 4, 251-254 (1985). In order to stimulate renin activity in this, the animals are preferably pretreated with a saluretic. Blood samples for the determination of the plasma renin activity can be obtained by puncture of the femoral vein.

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 procedure for such diagnostic tests can be similar to that indicated in EP-A 77 028.

The abbreviations quoted hereinbefore and hereinafter for amino acid residues represent the 9 -4radicals 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 Ada 3- -Adamantyl) -alanine AHCH 4S-Amino-3S-hydroxy-6-cyclohexyl-hexanoic acid AIICP 4 -Amino-3S-hydroxy-5-cyclohexyl-pentanoic acid AHPP 4S-Amino-3S-hydroxy-5-phenyl-pentanoic acid Ala Alanine I3Ala B1-Alanine Arg Arginine Asn Asparagine Asp Aspartic acid Bia 3- (2-Benzimidazolyl) -alanine Cal 3-Cyclohexylalanine 0 Dab 2,4-Diaminobutyric acid DACH 3S, 4S-Diaxnino-6-cyclohexyl-hexanoic acid DACP 3S, 4S-Diamino-5-cyclohexyl-pentanoic acid DAMH 3S, 4S-Diamino-6-methyl-heptanoic acid DAPP 3S, 4S-Diamino-5-phenyl-pentanoic acid Ftr N-Formyl-tryptophan 6:*Gin Glutamine Glu Glutamic acid 0 4 Gly Glycine :000,His Histidine N(im)-A-His Histidine substituted in the 1 or 3 position of the imidazole ring by A 0 0.,Hph Homo-phenylalanine (=2-Amino-4-phenylbutyric -009 acid) Ile Isoleucine Leu Leucime tert. -Leu tert-Leucine Lys Lysine Met Methionine ciNal 3-(ai-Naphthyl)-alanine J3Nal 3- (J-Naphthyl) -alanineL Nbg (2-Norbornyl) -glycine Nle Norleucine N-Me-His N-Methyl-histidine r ,4, 0 S S N-Me-Phe N-lMethyl-phenylalanine Nva Norvalime Orn Ornithine Phe Phenylalanine Pia 3-(Piperidyl)-alanine 2- Pia 3- (2-piperidyl) -alanine 3 Pro Proline Pya 3-(Pyridyl)-alanine [e.g.

3-Pya 3- (3-pyridyl) -alanine] Ser Serine Sta Statine Thr Threonine Tia 3-(Thienyl)-alanine 2- Tia 2-thienyl) -alanine] Tic 1, 2, 3, 4 -Tetrahydroisoquinoline-1-carboxylic acid Trp Tryptophan Tyr Tyrosine Val Valine.

Further meanings hereinafter are: ADPA N-2-Amino-5, 6-dimethyl-3-pyrazinylmethyl-amide AMPA N-4-Amino-2-methyl-5-pyrimidinylmethyl-auide BDP 2-Benzyl-3- (N-3-dimethylaminopropyl-carbamoyl) prop ionyl BOC tert. -Butoxycarbonyl BOM Benzyloxymethyl imi-BOM Benzyloxymethyl in the 1 position of the imidazole ring CBZ Benzyloxycarbonyl DCCI Dicyclohexylcarbodiimide DLMF Dimethyl formamide DNP 2, 4-Dinitrophenyl imi-DNP 2,4-Dinitrophenyl in the 1 position of the imidazole ring ETOC Ethoxycarbonyl FMOC 9 -Fluorenylmethoxyc arbonyl HOBt 1-Hydroxybenzotriazole IPOC I sopropoxycarbonyl NDP 2- -Naphthylmethyl) (N-3-dimethylamino- 5 5S S S

S

6propyl-carbamoyl)-propionyl OMe Methyl ester OEt Ethyl ester POA Phenoxyacetyl 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 e that it is liberated from one of its functional S* 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 1 is absent,

Z,

Z-W,

Z-W-E

1 Z-W-E- and W is -NR2-CHR3CR4-(CHR 5 is reacted with an amino compound of the formula III 2 H-G III in which

G

2 is -Z-W-E-Q-Y,

-W-E-Q-Y,

-E-Q-Y,

-E

2

-Q-Y,

-NR

10

-Y,

El E 2 are together E and in that a functionally modified amino and/or hydroxyl gruup in a compound of the formula I is liberated where appropriate by treatment with i. I -7solvolyzing or hydrogenolyzing agents, and/or for the preparation of a compound of the formula I, R4 (H, OH) or NH 2 an amino keto acid derivative of the formula I, R4 O 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.

Hereinbefore and hereinafter the radicals and parameters R to R 14 Z, E, Q, Y, T, L, m, n, p, r, s, t, w, x, y, z, Ar, Het, Hal, Ac, An, A, G 1

G

2

E

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, inobutyl, sec.-butyl or tert.-butyl, as well as pentyl, 2- or 3-methylbutyl, 1,2- or 2,2dimethylpropyl, l-ethylpropyl, hexyl, 3- or 4methylpentyl, 2,3- or 3,3dimethylbutyl, 1- or 2-ethylbutyl, l-ethyl-l- *methylpropyl, 1-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.

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

Bicycloalkyl is preferably 1- or 2-decalyl, 2bicyclo[2.2.]heptyl or 6,6-dimethyl-2-bicyclo[3.1.1]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, propionyl or butyryl, Ar-CO- such as benzoyl, m- or p-methoxybenzoyl or 3,4-dimethoxybenzoyl, or A-NH-COj.

8such as N-methyl- or N-ethylcarbanoyl.

Ar is preferably phenyl and is furthermore preferably m- or p-tolyl, m- or p-ethylphenyl, m- or p-methoxyphenyl, m- or p-f luorophenyl, m- or p-chlorophenyl, m- or p-bromophenyl, o-, m- or p-iodophenyl, m- or p-trifluoromethylphenyl, m- or p-hydroxyphenyl, m- or p-sulfamoylphenyl, 3,4- or 3,4,5-trimethoxyphenyl, m- or p-aminophenyl, mor p-aminomethylphenyl, m- or p dimethylaminomethylphenyl, m- or p guanidinomethylphenyl, or 1- or 2-naphthyl.

Correspondingly, Ar-alkyl is preferably benzyl, 0 1- or 2-phenylethyl, m- or p-methylbenzyl, 1- or 2o- -in- or -p-tolylethyl, in- or p-ethylbenzyl, 1or -mn- or -p-ethylphenylethyl, m- or pmethoxybenzyl, 1- or -in- or p methoxyphenylethyl, in- or p-f luorobenzyl, 1- or 2- -in- or -p-f luorophenylethyl, in- or p- *chlorobenzyl, 1- or -in- or chlorophe nyl ethyl, in- or p-bromobenzyl, 1- or -in- or p bromophenylethyl, in- or p-iodobenzyl, 1- or -mn- or -p-iodophenylethyl, in- or p-trifluoromethylbenzyl, in- or p-hydroxybenzyl, 2b, 3,4- or 3,5-diinethoxybenzyl, 3,4,5trimethoxybenzyl, in- or p-aminobenzyl, in-, or p-aininoiethylbenzyl, in- or p-diinethylaminoineth-,lbenzyl, mn- or p-guanidinoinethylbenzyl, or 1or 2-naphthylinethyl.

Het is preferably 2- or 3-furyl, 2- or 3thienyl, 2- or 3-pyrrolyl, 4- or imidazolyl, 4- or 5-pyrazolyl, 4- or oxazolyl, 4- or 5-isoxazolyl, 4- or thiazolyl, 4- or 5-isothiazolyl, 3- or 4pyridyl, 5- or 6-pyriinidinyl, furthermore preferably 1,2,3-triazol-1-, or -5-yl, 1,2,4-L triazol-l-, or -5-yl, 1- or 5-tetrazolyl, 1,2,3oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,4 1,3,4-thiadiazol-2- or -S-yl, 1,2,4-thiadiazol-3- or ww -9- 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-benzimidazolyl, l-, 6- or 7-benzopyrazolyl, 6- or 7-benzoxazolyl, 6- or 7-benzisoxazolyl, 2-, 6- or 7-benzothiazolyl, 6- or 7benzisothiazolyl, 6- or 7-benz-2,1,3oxadiazolyl, 7- or 8-quinolyl, 1-, 7- or 8-isoquinolyl, 4- or 9-carbazolyl, 8- or 9- 0 acridinyl, 7- or 8-cinnolyl, 4-, 7- or 8-quinazolyl. The heterocyclic radicals *can also be partially or complately hydrogenated. Thus, Het can also be, for example, 2,3-dihydro-2-, -4- 6 or -5-furyl, 2,5-dihydro-2-, or tetrahydro-2- or -3-furyl, tetrahydro-2- or -3-thienyl, 3-iyro.* 4*r*5proy,25 2dihydro-i-, or -5-pyrrolyl, 2,5 pyrrolidinyl, tetrahydro-l-, or -4-imidazolyl, 2,3dihydro-l-, or -5-pyrazolyl, tetrahydroor -4-pyrazolyl, 1,4-dihydro-l-, or -4-pyridyl, l,2,3,4-tetrahydro-l-, or -6-pyridyl, 1,2,3,6-tetrahydro-l-, or -6-pyridyl, 3- or 4-piperidinyl, 3or 4-morpholinyl, tetrahydro-2-, or -4-pyranyl, 1,4-dioxanyl, l,3-dioxan-2-, or -5-yl, hexahydro-lor -4-pyridazinyl, hexahydro-l-, or pyrimidinyl, 2- or 3-piperazinyl, 1,2,3,4tetrahydro-1-, or -8quinolyl, 1,2,3,4-tetrahydro-l-, or -8-isoquinolyl.

The heterocyclic radicals can also be substituted as indicated. Het can also preferably be, for example 2-amino-4-thiazolyl, 4-carboxy-2-thiazolyl, 4-carbaxnoyl-2-thiazolyl, 2-aminoethyl)-2-thiazolyl, 4-amino-2-methyl-5-pyrimidinyl, 2-amino-5, 6-dimethyl-3- 0 eSe S S S. S

S.

*S S

S

S

S

OS

S S

S

5555 5* 5* S

S.

S

*5 59 S

S

10 pyrazinyl, 4-carbamoylpiperidino, furthermore, for example, 4- or 5-methyl-2-furyl, 4- or methyl-3-furyl, 2,4-dimethyl-3-furyl, 5-nitro--2-furyl, 5-styryl-2-furyl, 4- or 5-methyl-2-thienyl, 4or 5-methyl-3-thienyl, 3-methyl-5-tert. -butyl-2thienyl, 5-chloro-2-thienyl, 5-phenyl-2- or -3-thienyl, 4- or 5-methyl-2-pyrrolyl, l-methyi-4- or nitro-2-pyrrolyl, 3, 5-dimethyl-4-ethyl-2-pyrrolyl, 4- 5-methyl-3-isoxazolyl, 3,4- 4- or 5-methyl-2-thiazolyl, 2or 5-methyl-4-thiazolyl, 2- or 2,4-dimethyl-5-thiazolyl, 5- or 6-methyl-2pyridyl, 5- or 6-methyl-3-pyridyl, 2- or 3methyl-4-pyridyl, 5- or 6-chloro-2-pyridyl, 2-, 5- or 6-chloro-3-pyridyl, 2- or 3-chloro-4-pyridyl, 2,6-dichioropyridyl, 2-hydroxy-3-, or -6pyridyl 1H-2-pyridon-3-, or phenyl- 1H-2-pyridon-3-yl, 5-p-methoxyphenyl-1H-2pyridon-3-yl, 2-methyl-3-hydroxy-4-hydroxymethyl-5pyridyl, 2-hydroxy-4-amino-6-methyl-3-pyridyl, 3-N' methylureido-1H-4-pyridon-5-yl, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 5- or 6-methyl-4pyrixuidinyl, 2, 6-dimethyl-4-pyrimidinyl, 2, 6-dihydroxy- 4-pyrimidinyl, 5-chloro-2-methyl-4-pyrimidinyl, 3methyl-2-benzofuryl, 2 -ethyl- 3-benzof uryl, 7-methyl-2benzothienyl, 6- or 7-methyl-3-indolyl, or -6-benzimidazolyl, l-ethyl-5- or -6benzimidazolyl, 7- or 8-hydroxy-2quinolyl, 2-oxo-pyrrolidino, 2-oxo-piperidino, dioxopyrrolidino or 3-benzyl-2 Z is preferably Gly, I3Ala or His, and is furthermore preferably Abu, Ada, Asn, Bia, Cal, Gln, Gly, N(im)-methyl-His, Leu, Nal, J3Nal, Nie, Phe, Pia, Pya, Tia, Trp or Tyr.

The parameters n and s are each preferably 1, and m, p and r each 0,1,2,3,4,5 or 6; specifically, m is preferably 2, 3, 4, 5 or 6 (especially 4, 5 or p is preferably 0 and r is preferably 1 or 2. The groups CtH 2 t and CwH 2 w are preferably each -CH 2

-(CH

2 2 absent The parameters x, y and z are each preferably 1.

T is preferably NR 14 especially NH, and furthermore

N(CH

3 or N(C 2

H

5 L is preferably CH.

Accordingly, R' is preferably (R 6

R

7 N-CmH 2 m-

NR'

4 -COCrH 2 r)-L(R 8 -Cp H 2 p)-COi, and on the other hand preferably (RRNCm~ -O-r~)CH(R 8 -C pH 2 p)-C0,1 particularly preferably (R 6

R

7 N-CmH 2 m-NR 14 _CO-CrH 2 r) CHR- More restricted preferred meanings of R are (RRNCHmN-OCH -HR- c-

[R

6

R

7

N-(CH

2 )m-NHCO(CH 2 )r]CH.R 8

_(CH

2 )p]CO- 1

[R

6

R

7

N-

(CH

2 )M-NHCO(CH )rCH[A(CH 2

[R

6

R

7

N-(CH

2 00,NH-CO-(CH 2 )r]-CH(ArCH 2

[R

6

R

7

N-(CH

2 )mINHCO-

*(CH

2 and [R 6

R

7

N(CH

2

)NC

(CH

2 )]-CH[ArCH 2 wherein m is preferably 2 or 3 *and Ar is preferably phenyl or 1- or 2-naphthyl.

Particularly preferred radicals Riare BDP and NDP.

*R

2

R

5

R

6

R

7 Rio and R 14 are preferably H or methyl, fvrthermore ethyl, propyl, isopropyl, butyl or *.isobutyl, and R 6 is preferably -C(=NH)-NH 2 or *0 ~eNH-CN; in these two latter cases, R 7 is preferably simultaneously H. The group R 6

R

7 N- is accordingly 00preferably dimethylamino, furthermore amino, 0 methylamino, ethylamino, diethylamino, guanidino or N'cyanoguanidino. If n is 2, the two radicals R 5 can be goo.

00identical or different from one another; it is preferable in this case for one radical R 5 to be H and the other A, in particular isopropyl, the group (CHR )n Is preferably -CH 2 -CHA-, in particular -CH 2 (H(isopropyl)-.

R

3 is preferably cyclohexylmethyl, furthermnore preferably A, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, pentyl, isopentyl, (3-methylbutyl) or 2-methylbutyl, phenyl, benzyl, p-chlorobenzyl, 2-cyclohexylethyl, bicyclo- [2,2,1 ]heptyl-2-methyl or 6, 6-dimethylbicyclo- -12 [3.1.1]heptyl-2-methyl.

R

4 and R 1 3 are each preferably OH).

R is preferably Ar, in particular phenyl, m- or pmethoxyphenyl or 1- or 2-naphthyl.

R

9 is preferably H.

The group W is preferably -NH-CHR 3

-CHOH-CH

2 in particular AHCP, AHCH, Sta or AHPP. The group W is furthermore preferably -NH-CHR -CH(NH 2

)-CH

2 in particular DACP, DACH, DAMH or DAPP.

The group W has at least one chiral centre.

Further chiral centres may be present in the groups R- Z, E, Q and Y. The compounds of the formula I can therefore occur in various, optically inactive or optically active, forms. The formula I embraces all these forms. If W is -NH-CHR 3

-CR

4

-CH

2 -CO- with R 4 being OH) or NH 2 the 3S-hydroxy-4S-amino enantiomers and 3S,4S-diamino enantiomers are preferred.

0*@SS* The abbreviations AHCP, AHCH, Sta, AHPP, DACP, DACH, DAMH and DAPP always relate to the 3S,4S forms.

The abovementioned substituted cycloalkyl and phenyl groups preferably have 1 to 3, in particular 1 or 2, substituents.

E is preferably one of the said amino acid residues, in particular Ile or Leu; furthermore, E is preferably absent or is preferably Abu, Cal, Met, Nle, Nva, Phe or Val.

Q is preferably NR 10 in particular NH or N(CH3).

C)Y is preferably -CtH 2 t-R 1 1 or CtH2t-R 1 2 in 11 12 1 particular -CH 2

R

1 1

-CH

2 Rl or -CH 2

CH

2 R1. In these, Rii is preferably H, A, Ar or Het, specifically and preferably H, alkyl having 3-5 C atoms, phenyl, mor p-aminomethylphenyl, m- or p-guanidinomethylphenyl, m- or p-dialkylaminomethylphenyl such as m- or p-dimethylaminomethylphenyl, 3- or 4pyridyl, 2-hydroxy-4,6-dimethyl-3-pyridyl, 4-amnino-2or 2-amino-5,6-dimethyl-3- 12 pyrazinyl. R 12 is preferably -SO 3 H, -S0 2

NH

2

-NA

2 -NA3An, -NH-C(=NH)-NH 2 -NH-CO-NHA or -NH-CS-NHA, _N3A nv.(=H-N2 'Vr T ILIUC C- I~ I~C1 13 wherein A is preferably CH 3 Some particularly preferred meanings of the group Q-Y are -NH-CH 2 (4-amino-2-methyl-5-pyrimidinyl)

-NH-CH

2 -(2-amino-5,6-dimethyl-3-pyrazinyl) ("ADPA") and -NH-CH 2 -(3-pyridyl), furthermore -NH-A.

Accordingly, the invention particularly ralates 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 Ii, which correspond to the formula I, but in which in Ia R is (R 7N-"H)TnNH-O-C-,H3r)

-CH-

S eS

SO

S. C

S

S

0 in Ib 67 (Ar-C pH2p)-CO-1

R

6

R

7 N is amino, methylamino, dimethylamino, ethylamino, diethylamino, guanidino or N'-cyanoguanidino and Ar is phenyl, methoxyphenyl or naphthyl; Rl is [R 6

R

7

N-(CH

2 )mNH-CO(CH 2 )r]-CH- (Ar-CH 2

R

6

R

7 N ii amino, methylaminc, dimethylamino, ethylamino or diethylamino, e.g.

ties gas* A890 *4

S

in Ic in Id in Ie m is 2 or iana Ar is phenyl or naphthyl; Rl is NDP; Z is Gly, BAla or His; R2 is H, R3 is cyclohexylmethyl, R4 is OH) and

-(CHR

5 is -CH 2 or -CH 2 CH(isopropyl)-;

NR

2

-CHR

3

-CR

4

-(CHR

5 nCO is AHCP; E is absent or is Ile or Leu; R is (R 6

R

7 N-CmH 2 m-NHCO-CH 2 -CH(ArCH 2

)C

R

6

R

7 N-CmH 2 mN(ArCH 2 or HO-CmH2m- N(ArCH 2

R

6

R

7 N is amino: methylamino, dimethylamino, ethylamino or diethylamino, m is2, 3, 4, 5 or 6, Ar is phenyl or naphthyl,

I

Li -14-

R

2 is H, R3 is cyclohexylmethyl, R4 is OH),

-(CHR

5 is -CH 2 or -CH 2 -CH(Isopropyl)- and E is Ile or Leu; in Ii R 1 is NDP, Z is Gly, BAla or His,

R

2 is H,

R

3 is cyclohexylmethyl,

R

4 is OH),

-(CHR

5 )n is -CH 2 or -CH 2 -CH(isopropyl)- an E is absent or is Ile.

Particularly preferred are compounds of the S part-formulae: I* and Ia* to Ii*, which correspond to the formulae I and Ia to Ii but in which Q is NH, Y is H, A or -CH 2 R and R1 is m- or p-aminomethylbenzyl, m- or pguanidinomethylbenzyl, 3-pyridyl, 4-amino-2or 2-amino-5,6-dimethyl-3pyrazinyl.

I' and Ia' to Ii', which correspond to the formulae I 6 and Ia to Ii but in which Q is NH and Y is H, A, 4-amino-2-methyl-5-pyrimidinylmethyl or 2-amino-5,6-dimethyl-3-pyrazinylmethyl.

The compounds of the formula I, as well as the starting materials for the preparation thereof, are, by the way, 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, EP-A 81783, EP-A 249096) 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

J

*4 4Oi

S

*04045 4 .4' S £4 *6 5" &c S 15 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 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 R1--NR2CHR3-CH(NHR')-(CHR5)n-CO-

E-Q-Y.

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 RI-Z-NR 2

-CHR

3 -CHOR' 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-, L- 16 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, C 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, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, as well as, in particular, alkoxycarbonyl, aryloxycarbonyl and, especially, aralkoxycarbonyl 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, 2,2,2trichloroethoxycarbonyl, IPOC, BOC, 2-iodoethoxycar- S"bonyl; aralkyloxycarbonyl such as CBZ, 4methoxybenzyloxycarbonyl, FMOC. Preferred amino protective groups are BOC, DNP and BOM, as well as CBZ, I 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 Sfe 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.

_I_

0ti s.

es 0 *00 0 0* *0 ft 17 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 alcohols such as methanol, ethanol or isopropanol, and water. Furthermore suitable are mixtures of the abovementioned 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 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 HC1 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.

ift 18 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 -OH, R 1 -Z-OH, R1-Z-W- OH or R 1 -Z-W-E-OH, and of amine components are those of the part-formulae H-Z-W-E-Q-Y, H-W-E-Q-Y, H-E-Q-Y or H-

NR

10 The peptide linkage can, however, also be formed within the group E; this entails a carboxylic acid of the formula R 1

-Z-W-E

1 -OH being reacted with an 2 1 2F *.amino compound of the formula H-E 2 where E E E. The methods preferably used for this are those O 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 L

I

19acetonitrile, 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 carboxylic acids II 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 I are mostly known. Those which are unknown can be prepared by known methods, for example the f*t abovementioned methods of peptide synthesis and of elimination of protective groups.

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 S* hydrogenolysis by one of the methods described above.

Thus, for example, a compound of the formula I which contains an AcNH or an AOOC group can be converted into the corresponding compound of the formula I which contains in its stead an H 2 N or an HOOC group, preferably by selective solvolysis by one of the methods indicated above.

Furthermore, for example, keto compounds of the Sformula 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 +300.

Keto compounds of the formula I (R 4 0) can also be converted into compounds of the formula I (R 4 H, NH2) by reductive amination. The reductive amination 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

I-

T_

20 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 Ssulfuric 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, S. 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.

The new compounds of the formula I and the 1 5 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 compositions obtained in this way can be used as medicaments in human or veterinary medicine. Suitable vehicles are organic or inorganic substances which are suitable for enteral (for example oral or rectal) or ,i V.

21 0 so *00.

I

409 0 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 ad.ninistration 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 being present, for example ethanol. Solutions for inhalation can be administered with the aid of customary inhalers. The new compounds can also be freeze-dried and the resulting lyophilisates used, for example, to prepare products for injection. The stated compositions can 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 more 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 163237, EP-A 173481 and EP-A 209897, preferably in dosagGs between about 100 mg and 30 g, in particular between 500 mg and g, per dosage unit. The daily dosage is preferably I 22 between about 2 and 600 mg/kg, in particular between about 2 and 200 mg/kg, of bodyweight. The specific dose for each particular patient depends, however, on a wide variety of factors, for example on the activity of the specific compound used, on the age, body weigh-, general state of health and sex, on the diet, on the time and route of administration and on the rate of excretion, medicinal substance, combination and severity of the particular disease for which the therapy is applied. Parenteral administration is preferred.

e Renin-dependent hypertension and hyperaldosteronism can be effectively treated by administration of dosages between, in particular, about 1 and 300, preferably between 5 and 50, mg/kg of bodyweight. For diagnostic purposes, it is possible and preferable for Sthe new compounds to be administered in single doses, particularly in about 0.1 and 10 mg/kg of bodyweight.

All temperatures stated hereinbefore and hereinafter are in oC. In the examples which follow, "usual working 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 ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate, filtered and concentrated, and purification is carried out by chromatography on silica gel and/or crystallization. The statements "R Form", "S Form" and "RS Form" relate to the chiral C atom in the radical R 1 especially in the BDP or NDP group.

Example 1 A mixture of 953 mg of 2S-isopropyl-4S-hydroxy- 5S-[2-(l-naphthylmethyl)-3-(N-3-dimethylaminopropylcarbamoyl)-propionyl-N-imi-(2,4-dinitrophenyl)-Lhistidyl-amino]-6-cyclohexylhexanoic acid N-butylamide ["2S-is( 6-cyclohexyl)-hexanoic acid N-butylamide"; obtainable by reaction of 2-(l-naphthylmethyl)-3-(N-3dimethylaminopropyl-carbamoyl)-propionic acid ("NDP-

V

LI F

S.

*.SSt.

23 OH"; m.p. 122-1230) with 2S-isopropyl-4S-hydroxy-5S- (imi-DNP-His-amino) -6-cyclohexyihexanoic acid Nbutylamide], 2 g of 2-mercaptoethanol, 20 ml of DMF and ml of water is stirred at 200 while the PH is adjusted to 8 with aqueous Na 2

CO

3 solution, and is then stirred at 200 for 2 hours. The usual working-up results in 2S-isopropyl-4S-hydroxy-5S-(NDP-His-anino) 6-cyclohexyihexanoic acid N-butylamide, RS Form, m.p.

168-1690.

Example 2 g of 2S-isopropyl-4S-hydroxy-5S-[NDP-N-(imi- BOM-His )-amino] -6-cyclohexyl-hexanoic acid N-butylamide (obtainable by reaction of NDP-OH with 2S-isopropyl-4Shydroxy-5S- (imi-BOM-His-amino) -6-cyclohexyl-hexanoic acid N-butylamide] are dissolved in 150 ml of ethanol and hydrogenated on 5 g of 10% Pd-C at 200 and under 1 bar until H 2 uptake ceases. The mixture is filtered out, evaporated and purification by chromatography results in 2S-isopropyl-4S-hydroxy-5S-(NDP-His-amino)- 6-cyclohexyl-hexanoic acid N-butylamide, RS form, m.p.

168-169o. R form, dihydrochioride, M.P. 1780 (decomposition). S form, dihydrochloride, m.p. 1450 (decomposition).

The following are obtained analogously from the corresponding imi-BOM-His derivatives: BDP-His-AHCP- Ile-OMe BDP-His-A}CP-I le-QEt BDP-His-AHCP-I le-NH 2 BDP-His-AHCP-Ile N-methylamide BDP-His-AHCP-Ile N-ethylamide BDP-His-AHCP-Ile N-butylamide BDP-His-AHCP-Ile-AMPA BDP-His -AHCP-I le-ADPA NDP-His-AHCP-Ile-OMe NDP-His -AHCP- Ile-OEt NDP-His-AHCP-Ile-NH 2 RS form, dihydrochloride p. 2090 (decomposition) NDP-His-AHCP-Ile N-methylamide 9' 9. 9 *9t .9 9. 9 *9 9 9.99 9 4.99 *999 9* 24 NDP-His-AHCP-Ile N-ethylamide NDP-His-AHCP-Ile N-butylamide NDP-His-AHCP-I1e-AMPA NDP-His-AHCP-Ile-ADPA.

3Saio4-D-l-mn--ylhxl pentanoyl-Ile-AMPA ("NDP-Gly-DACP-Ile-AMPA") is obtained analogously from 3S-CBZ-amino-4S-NDP-Gly-aminoby hydrogenolysis.

The following can be prepared analogously from the corresponding CBZ derivatives: NDP-Gly-DACH- Ile-AMPA NDP-Gly-DAMH-Ile-AMPA NDP-Gly-DAPP-Ile-AMPA.

Example 3 A solution of 1 g of N-benzyl-N-(6-BOCaminohexyl) -carbamoyl-Gly-AHCP-Ile-AMPA 1350; obtainable by reaction of BOC-AIICP-Ile-AMPA; 218- 2200) with HCl/dioxane to give H-AHCP-Ile-AMPA and reaction with N-benzyl-N- (6-BOC-aminohexyl) -carbamoyl- Gly-OH] in 20 ml of 4 N HCl in dioxane is stirred at 200 for 30 min and then evaporated. N-benzyl-N-(6aminohexyl) -carbamoyl-Gly-AHCP-Ile-AMPA dihydrochloride is obtained. Free base, m.p. 1090 (RS form).

The following are obtained analogously by cleavage of the corresponding N-BOC derivatives: N-Benzyl-N- (6-aminohexyl) -carbamoyl-Gly-AHCP-Ile-ADPA N-Benzyl (6-aminohexyl) -carbamoyl-J3Ala-AHCP-Ile-AMPA N-Benzyl-N- (6-aminohexyl) -carbamoyl-BAla-AHCP-Ile-ADPA 2-Benzyl-3-N- (6-aminohexyl) -carbamoyl-propionyl-Gly- AHCP-Ile-AMPA 2-Benzyl-3-N- (6-aminohexyl) -carbamoyl-propionyl-3Ala- AHCP- Ile-AMPA 2-Benzyl-3-N- (6-aminohexyl) -carbamoyl-propionyl-Gly- AHCP -Leu-AMPA 2-Benzyl-3-N- (6-aminohexyl) -carbaxnoyl-propionyl-J3Ala- AHCP-Leu-A.MPA.

The following are obtainable via 2-(lnaphthylmethyl) (6-BOC-aminohexyl) -carbamoylpropionyl-Gly-OH or -l3Ala-OH: 25 *0 C C

C

2 SCeeCS 2- -Naphthylmethyl) (6-aminohexyl) -carbamoylpropionyl-Gly-AHCP-Ile-AMPA ,S form, dihydrochioride, M.P. 1880 (decomposition); R form, dihydrochioride, M.P. 171' (decomposition) 2- -Naphthylmethyl) (6-aminohexyl) -carbamoylpropionyl-J3Ala-AHCP-Ile- AMPA, RS form, dihydrochioride, M.P. 1790 (decomposition) -Naphthylmethyl) (6-aminohexyl) -carbamovlpropionyl -BA.a-AHCP-AMPA 2- -Naphthylmethyl) (6-aininohexyl) -carbamoylpropionyl -BA.a-AHCP-AMPA 2- -Naphthylmethyl) (6-aminohexyl) -carbamoylpropionyl -BAla-AHCP-Cal -AMPA 2- (l-Naphthylmethyl) (6-aminohexyl) -carbamoylpropionyl -BAla-AHCP-Leu-AMPA 2- -Naphthylmethyl) (6-aminohexyl) -carbamoylpropionyl -BAl.a -AHCP-Met-AMPA 2- (l-Naphthylmethyl) (6-aminohexyl )-carbamoylpropionyl -BAla-AHCP-Nle-AMPA 2- (l-Naphthylmethyl) (6-aminohexyl) -carbamoylprop ionyl -BAla-AHCP -Nva-AMPA 2- (l-Naphthylmethyl) (6-aminohexyl) -carbamoylpropionyl-BAla-AHCP-Val-AMPA.

The following are obtained analogously: 2 -Benzyl-3-N- (8-aininooctyl) -carbamoyl-propionyl-Gly- AHCP-Ile-AMPA 2-Benzyl-3-N- (8-aminooctyl) -carbamoyl-propionyl-BAla- AHCP-Ile-AMPA 1-Naphthylmethyl) 8-aminooctyl) -propionylcarbamoyl -Gly-AHCP- Ile-AMPA 2- -Naphthylmethyl) (8-aminooctyl) -propionylcarbamoyl-BAla-AHCP-Ile-AMPA.

2 -Benzyl-4-(N-BOC-N-methyl-amino) -butyryl-fAla- AHCP-Ile-AMPA, RS form, acetate, Rf 0.61 (silica gel; 1 1, 1-tri chloroethane/methanol /acetic acid 75:15:10) i

I

I

25A (N-BOC-N-methyl-amino) -pentanoyl 4Ala- AHCP-Ile-AMPA, RS form, acetate, Rf 0.63 (silica gel; 1 ,1 ,1 -trichloroethane/methanol/acetic acid 75:15:10).

Example 4 1.01 g of N-methylmorpholine are added to a solution of 5.05 g of H-Gly-AHCP.-Ile-AMPA (obtainable by condensation of BOC-Gly-AHCP-Ile-OH with ami- nomethyl-2-methyl-pyrimidine to give BOC-Gly-AHCP- Ile-A-MPA followed by elimination of the BOC group) in 160 ml of DMF. While stirring, 3.44 g of NDP-OH, 1.35 g of HOBt and 'a solution of 2.06 g of DCCI in 50 ml of

CH

2 C1 2 are added. The mixture is stirred at 40 for 12 hours, the precipitated dicyclohexylurea is filtered e.g.

C

C. 9

C

CO COOS

C

CC 509 CC SC C S

C

CC..

9 0*

*C

C S 55 9C SC C C 9CC

C

*S9C SC -26off, and the filtrate is evaporated. The usual workingup results in NDP-Gly-AHCP-Ile-AMPA, RS form, m.p.

1520; dihydrochioride, m.p. 1860 (decomposition) R form, M.P. 1420; dihydrochioride, M.P. 1820 (decomposition). S form, dihydrochioride, m.p. 1780 (decomposition).

The following are obtained analogously: BDP-Gly-AHCP-I le-NH 2 BDP-Gly.-AHCP-Ile N-butylamide BDP-Gly-AHCP-Ile N-pentylamide BDP-Gly-AHCP-Ile N,N-diethylamide E BDP-Gly-AHCP-Ile-AMPA, R Form, m.p. 1180 (decomposition); S Form, M.p. 1220 (decomposia aa...tion) BDP-Gly-AHCP- Ile-ADPA, NDP-Gly-AIICP-Ile-NH 2 NDP-Gly-AHCP-Ile N-butylamide NDP-Gly-AHCP- Ile N-pentylamide :.NDP-Gly-AHCP-Ile N, N-dimethylamide NDP-Gly-AHCP- Ile-ADPA 2-Benzyl-3-(N-2-dimethylaminoethyl-carbamoyl) propionyl-Gly-AHCP- I li-AMPA 2-Benzyl-3- (N-2-dimethylaminoethyl-carbamoyl) propionyl-I3Ala-AHCP-I le-AMPA 2- -Naphthylmethyl) (N-2-dimethylaminoethylc arbamoyl) -propionyl-Gly-AHCP- Ile-AMPA A,2- -Naphthylmethyl) (N-2-dimethylaminoethylcarbamoyl) -propionyl-I3Ala-AHCP-Ile-AMPA 2-Benzyl-3..(N-5-dimethylaminopentyl-carbamoyl) propionyl-Gly-AHCP- I :-AMPA 2-Benzyl-3- (N-5-dime-thylaminopentyl-carbamoyl) propionyl-I3Ala-AHCP- Ile-AMPA 2- -Naphthylmethyl) carbamoyl) -propiony].-Gly-AHCP-Ile AMPA 2- -Naphthylmethyl) carbamoyl) -propionyl-I3Ala-AHCP-Ile-AMPA b SOO S S *5 S

S

S.

S

S

*SSS

5* 0 0* 0 0 0@ *0 *S 0 0

S

S

27- 2-Benzyl-3- (N-6-dimethylarinohexyl-carbamoyl) propionyl-Gly-AHCP- Ile-AMPA 2-Benzyl-3- (N-6-dimethylaminohexyl-carbamoyl) propionyl-I3Ala-AHCP- Ile-AMPA 2- -Naphthylmethyl) (N-6-dimethylaminohexylcarbamoyl) -propionyl-Gly-AHCP-Ile-AMPA 2- -Naphthylmethyl) (N-6-dimethylaminohexylcarbamoyl) -propionyl-l3Ala-AHCP-Ile-AM4PA 2-Benzyl-3- (N-6-gjuanidinohexyl-carbamoyl) -propionyl- Gly-AHCP- Ile-AMPA 2-Benzyl-3- (N-6-guanidinohexyl-carbamoyl) -propionyl- BAla-AHCP- Ile-AMPA 2- -Naphthylmethyl) (N-6-guanidinohexyl-.carbamoyl) propionyl-Gly-AHCP- Ile-AMPA 2- -Naphthylmethyl) (N-6-guanidinohexyl-carbamoyl) propionyl-J3Ala-AHCP-I le-AMPA 2-Benzyl-3- -cyanoguanidino) -hexyl-carbamoyl] propionyl -Gly-AHCP- Ile-AMPA 2-Benzyl-3- -cyanoguanidino) -hexyl-catrbamoyl] propionyl-I3Ala-AHCP-I le-AMPA 2- -Naphthylmethyl) -cyanoguanidino) -hexylcarbamoyl ]-propionyl-Gly-AHCP-Ile-AMPA 2- -Naphthylmethyl) -cyanoguanidino) -hexylcarbamoyl ]-propionyl-I3Ala-AHCP-Ile-AMPA Example NDP-Gly-AHCP-Ile-AMPA, RS form, m.p. 1520, is obtained from NDP-Gly-OH and H-AHCP-Ile-AMPA in analogy to Example 3.

Analogously, N-benzyl-N- (2-hydroxyethlyl )-carbamoyl-Gly-AHCP-Ile-AMPA 116-1180) is obtained from N-benzyl-N- (2-hydroxyethiyl) -carbamoyl-Gly-OH (in.p. 106- 1070), and N-benzyl-N- (2-ethoxyethyl) -carbamoyl-Gly- AHCP-Ile-AMPA 100-1020) is obtained from Nbenzyl (2-ethoxyethyl) -carbainoyl-Gly-OH.

The following are obtained analogously: N-Benzyl-N- (6-dimethylamnino-hexyl) -carbamoy:l-Gly-AHCP- I le-AMPA N-Benzyl-N- (6-diinethylainino-hexyl) -carbamoyl-BAla-AHCp- I. -28le -AMPA N- -Naphthylmethyl) (6-dimethylamino-hexyl) carbamoyl-Gly-AHCP- Ile-AMPA N- -Naphthylmethyl) (6-dimethylamino-hexyl) carbamoyl-I3Ala-AHCP- Ile-AMPA N-Benzyl-N- (8-dimethylamino-octyl) -carbamoyl-Gly-AHCP- Ile-AMPA N-Benzyl-N- (8-dimethylamino-octyl) -carbamoyl-3Ala-AlCP- I le-AMPA N- -Naphthylmethyl) (8-dimethylamino-octyl) carbamoyl-Gly-AHCP-I le-AXPA N- -Naphthylmethyl) (8-dimethylamino-octyl) carbamoyl-3Ala-A}ICP-Ile-AMPA.

BDP-Gly-AHCH- Ile-AMPA BDP-J3Ala-AHCH-Ile-AMPA .:see: BDP-Gly-Sta-I le-AMPA 5 BDP-I3Ala-Sta-Ile-AMPA 0 BDP-Gly-.AHPP-I le-AMPA BDP-I3Ala-AHPP-I le-AMPA 0609: NDP-Gly-AHCH- Ile-AMPA 0 S.

NDP-I3Ala-SAC- Ile-AMPA 00 NDP-Glyr-taH-I le-AMPA NDP-JIAla-SaHP-Ile-AMPA.

NDP-Gly-AHCP-Ile-AMPA ,mp 150 isotne by condensation of NDP-Gly-AHCP-OH with H-Ile-AMPA in analogy to Exxmple 3.

The following are obtained analogously: NDP-Gly-AHCP -Abu-IVMPA NDP-Gly-ALHCP-Al a-AMPrA NDP-Gly-AHCP-Cal-AMPA NDP-Gly-AHCP -Leu-AMPA NDP-Gly-AHCP-Met-AMPA NDP-Gly-AHCP-Nle-AMPA NDP-Gly-AHCP-Nva-AMPA NDP-Gl-AHCP-he-AMi 29 S S SO

S

*555*O 0 0 500555 0

OS

S

S

*055 S S *5 S

S.

PS 0 00 5 0 0 NDP-Gly-AHCP-Trp-AMPA NDP-Gly-AHCP-Tyr-A4PA NDP-Gly-AflCP-Val-AMPA.

Example 7 NDP-Gly-AHCP-Ile-Ala-AMPA are obtained from NDP-Gly-AHCP-Ile-OH and H-Ala-AMPA in analogy to Example 3.

Example 8 NDP-l3Ala-AHCP-Ile-AMPA, RS Form, rn.p. 1810 is obtained from NDP-BAla-AHCP-Ile-OH and aminomethyl-2-methyl-pyrimidine in analogy to Example 3.

The following are obtained analogously: BDP-Gly-AHCP-Ile N-2-pyridylmethyl amide BDP-l3Ala-AHCP-Ile N-2-pyridylmethyl amide BDP-Gly-AHCP-Ile N-3-pyridylmethyi, amide BDP-J3A-a-AHCP-Ile N-3-pyridylmethyl amide BDP-Gly-AHCP-Ile N-m-aminomethyl-benzyl-amide BDP-J3Ala-AHCP-Ile N-m-aminomethyl-benzyi-amide BDP-Gly-AHCP-Ile N-2-hydroxy-4, methyl -amide BDP-l3Ala-AHCP-Ile N-2-hydroxy-4, methylamide BDP-Gly-AHCP-Ile p-sulfamoyl-anilide BDP-I3Ala-AHCP-Ile p-sulfamoyl-anilide NDP-Gly-AH.CP-Ile N-2-pyridylmethyl-amide NDP-f3Ala-AHCP-Ile N-2-pyridylmethyl-amide NDP-Gly-AHCP-Ile N-3-pyridylmethyl-amide NDP-I3Ala-AHCP-Ile N-3-pyridylmethyl.-amide NDP-Gly-AHCP-I le N-m-aminomethyl-benzyl-amide NDP-I3Ala-AHCP-Ile N-m-aminomethyl-benzyl-amide NDP-Gly-AHCP-Ile N-2-hydroxy-4, methyl amide NDP-i3Ala-AHCP-Ile N-2-hydroxy-4, methyl-amide NDP-Gly-AHCP-Ile p-sulfamoyl-anilide NDP-I3Ala-AHCP-Ile p-sulfamoyl-anilide.

0500

S

0050 0 SOS @5 5 30 Example 9 a) 3-Oxo-4S(NDP-Gly-amino)-5-cyclohexyl-pentanoyl- Ile-AMPA is obtained from NDP-Gly-OH and 3-oxo-4Sin analogy to Example 3.

b) A solution of 1 g of the abovementioned keto amide in 25 ml of CH 3 0H is hydrogenated on 0.1 g of Pd-C at 200 and under 1 bar until H 2 uptake ceases. Filtration and evaporation result in a mixture of 3R- and 3S-hydroxy-4S-(NDP-Gly-amino)- Example mg of hydroxylamine hydrochloride are added to a solution of 829 mg of 3-oxo-4S-(NDP-Gly-amino)-5cyclohexylpentanoyl-Ile-AMPA and 1.43 g of Na 2

CO

3 10H 2 0 in 5 ml of methanol and 5 ml of water, and the mixture is stirred at 200 for 14 hours. The precipitated oxime is filtered off, dried, dissolved in 10 ml of methanol and hydrogenated on 0.5 g of Raney-Ni at 200 and under bar. The catalyst is removed by filtration, the filtrate is evaporated, the resulting mixture is separated on silica gel, and 3S-amino-4S-(NDP-Gly- S4.. amino)-5-cyclohexylpentanoyl-Ile-AMPA ("NDP-Gly-DACP- Ile-AMPA") is obtained; the 3R-amino epimer is also obtained.

The examples which follow relate to pharmaceutical compositions.

Example A: Tablets A mixture of 1 kg of NDP-BAla-AHCP-Ile-AMPA, 4 kg of lactose, 1.2 kg of maize starch, 200 g of talc and 100 g of magnesium stearate are compressed in a customary manner to give tablets in such a way that each tablet contains 200 mg of active compound.

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

Example C: Capsules fi 117^ 31 500 g of NDP-Gly-AHCP-Ile-AMPA are dispensed in a customary manner into hard gelatin and capsules so that each capsule contains 500 mg of active compound.

Example D: Injection ampoules A solution of 100 g of 2S-isopropyl-4S-hydroxy-5S-(NDP- His-amino)-6-cyclohexyl-hexanoic acid N-butylamide (RS Form) in 4 1 of distilled water is adjusted to pH with 2N hydrochloric acid, filtered sterile and dispensed into injection ampoules. These are lyophilized under sterile conditions and sealed sterile. Each injection ampoule contains 100 mg of active compound.

Example E: Suppositories A mixture of 50 g of NDP-Gly-AHCP-Ile-AMPA 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 compound.

aa *a a a a rt

Claims (3)

1. Amino acid derivatives of the formula I R -Z-NR -_CH -_CR -_(CHR in which R 1 isR 6 R m 2 m -N-O-CH 2 -L(Ar-CH 2 R N-C mH 2 -L(Ar-CH 2 R 9-0-CO-NR TA-C rH -rL(Ar-CH2)C-o R 9-0-C rH 2-N(Ar-CH 2 Z is Abu, Ada, Ala, BlAa, Arg, Asn, Asp, Bia, Cal, Dab, Ftr, Gin, Glu, Gly, His, IHph, N(im)- A-His, Ile, Leu, tert.-Leu, Lys, Met, Nr l BNal, Nbg, Nie, Nva, Orn, Phe, Pia, Pro, Pya, r Thr, Tia, Tic, Trp, Tyr or Val, E is 0 to 2 amino acid rosidues 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, Q is 0Oor Nr Y is -C H -tR 11 ,-tH2tR 12 o 13 11 -C wH 2 w- (CR )s tH2R L is CH orN, 2 R 9 R 10 14 RR R and R are each Hor A, R 3and R 11 are each H, A, Ar, Ar-alkyl, Het, Het- alkyl, cycloalkyl having 3-7 C atoms, which is un- substituted or substituted one or more times by A,AO and/or Hal, cycloalkylalkyl having 4-Il C atoms, bicycloalkyl or tricycloalkyl each having

7-14 C atoms, bicycloalkylalkyl or tricyclo- alkylalkyl each having 8-18 C atoms, R 4and R 13are each OH), NH 2 or =0, Rand R 7are each H, A, -C(=NH)-NH 2or -C(=NH)-NHCN, R 6can also be Ac, R 12 is -SO 3 H, -SO 2 NH 2 1 -S0 2 NHA, -SO 2 NA 2 1 -NH 2 -NHA, -NA 2 -NH-C(=NH)-NH 2 P" 2le/VMJ -oQ IT0

33- -NH-C(=NH)-NHCN, -NH-CO-NH 2 -NH-CO-NHA, -NH-CO-NA 2 -NH-CS-NH2, -NH-CS-NHA or -NH-CS-NA 2 n and s are each 1 or 2, m, p, r, t and w are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 cr x, y and z are each 0 or 1, Ar is phenyl which is unsubstituted or substituted one or more times by A, OA, Hal, CF 3 OH, NO 2 hydroxyalkyl, NH 2 NHA, NA 2 NHAc, SA, SO-A, SO 2 SO 2 NH 2 SO 2 NHA, COOH, COOA, CONH 2 CN, Aminoalkyl, HAN-alkyl, A 2 N-alkyl, A3N+alkyl An and/or guanidinylalkyl or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical which has 1-4 N, O and/or S atoms and is fused with a benzene ring and/or can be substituted one or more times by A, OA, Hal, CF3, OH, NO 2 carbonyl oxygen, NH 2 NHA, NA2, NHAc, SA, SO-A, SO 2 SO 2 NH 2 SO 2 NHA, COOH, COOA, CONH 2 CN, NH-SO 2 Ar, i Ar-alkyl, Ar-alkenyl, hydroxyalkyl and/or aminoalkyl and/or whose N and/or S hetero atoms can *i also be oxidised, Hal is F, Cl, Br or I, Ac is A-CO-, Ar-CO-, Ar-alkyl-CO-, A-O-CO, AR-O-CO-, Ar-alkyl-O-CO- or A-NH-CO-, An 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 anion, -alkyl- is an alkylene group having 1-8 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, with the proviso that R is different from a (CH3 2 N-(CH 2 2 -NH-CO-CH 2 I T/ o 04 2 1 e/VMJ -34- CH(Ar-CH when, at the same time, Z is Leu, Nie, Phe, Cal, Gin or His, and -(CHR 5 n is -CH -CHisopropyl-. and E is missing, and Q is -NR 2. a) 2-(l-Naphithylmethyl)-3-(N-3-dimethylamflopropyl- carbamoyl)-propionyl-I3Ala-AHCP-Ile N-4-amino- b) 2-(l-Naphthylmethyl)-3-(N-3- dimethylaminopropylcarbamoyl) -propionyl-Gly-AHCP- Ile N-4-amino-2-methyl-5-pyrimidinyl-methyl-amide; c) 2-Benzyl-3-(N-3-dimethylaminopropyl-carbamoyl) propionyl-Gly-AHCP-Ile N-4-amino-2-methyl-5-pyri- midinyl-methyl-amide; d) 2-Isopropyl-4-hydroxy-5-(2-( l-naphthylmethyl)- 3- (N-3-dimethyVlaminopropyl-carbamoyl) -propionyl- His-amino] -6-cyclohexyl-hexanoic acid N-butyl- amide. 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 R1-G 1 -OH I which G 1 1 is absent Z, Z-W, Z-W-E 1 Z-W-E and W is -N2CRRCR nC- is reac- ted with an amino compound of the formula III H-G 2 III in which G2is -Z-W-E-Q-Y, -W-E-Q-Y, -E-Q-Y, -E 2 -Q-Y, -NR' 0 Y and, 7) 042le/VMJ 35 1 2 E E are together E, 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, R 4 OH) or NH 2 an amino keto acid derivative of the formula I, R 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. 4. 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 semiliquid vehicle or auxiliary and, where appropriate, in combination with one or more other active compound(s) into a suitable dosage form. 5. Pharmaceutical composition characterized by containing at least one compound according to claim 1 or claim 2 and/or one of the physiologically acceptable salts thereof, and a pharmaceutically suitable excipient or carrier. 6. A method of treating a condition responsive to the inhibition of human plasma resin activity in a human, which comprises administering to said human an effective amount of an amino acid derivative according to claim 1 or claim 2. 7. The method of claim 6, wherein the condition is hypertension. 8. An amino acid derivative of the formula I shown in claim 1, said derivative substantially as herein described with reference to any one of Examples 1 to 9. A pharmaceutical composition substantially as herein described with reference to Examples A to E. DATED this 3rd day of March, 1992. t MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER By Their Patent Attorneys DAVIES COLLISON CAVE 421e/VMJ T