AU615216B2 - Amino acid derivatives - Google Patents

Description

r l i;

AUSTRALIA

PATENTS ACT 1952 ,6,1 1 2A COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art: TO BE COMPLETED BY APPLICANT Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: t 4 i I t t 4's MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG Postfach 4119, D-6100 Darmstadt 1, Frankfurter StraBe 250, Germany 1. Dr Peter Raddatz 2. Dr Claus J. Schmitges 3. Dr Klaus-Otto Minck ARTHUR S. CAVE CO.

Patent Trade Mark Attorneys Level 10 Barrack Street SYDNEY N.S.W. 2000

AUSTRALIA

ft 14 "eomplete Specification for the invention entitled AMINO ACID

DERIVATIVES.

The following statement is a full description of this invention .inb'luding the best method of performing it known to me:s A 0 I 1 1 ASC 49 la Amino acid derivatives The invention reLates to new amino acid derivatives of the formula I X-Z-NR 3

_CHR

4

.CR

5

ICHR

6 )n.E w he rein X is H, R 1 0OCmH 2 m-CO-, R 1

R

1 _CmH2m-CO-, R 1 S0 2 (R 1 CmH2m)-

L(R

2 -cpH 2 p)-C rH2r-CO-, R 1

-(NHCH

2

CH

2 )m-

NH-CH

2 CO-, 9-f Iuo renyL-CmH2m-O-CO-, ER 1 CMH2m-(T X-C tHat I-L R 2 _C H 2p CrH2r-CO- or A3N _CmH2m-CO- Ane Z is 1 to 4 amino acid radicals bonded to one 0 0 a 00 another in peptidle form and selected from the 00 0 0 group cons isting of Abu, Ada, Ala, 0-AL a, Arg, 00 15 Asn, Asp, Bia, Cal, Dab, Ftr, G~n, GLu, GLy, 000 His, Hph, N(im)-A-His, Ie, Leu, tert.-Leu, 0 00 0 1 Lys, Met, caNaL, $NaL, Nbg, NLe,Nva, Orn, Phe, Pro, 0 00 Pyr, Ser, Thr, Tia,Tic, Trp, Tyr, O-A-Tyr and Val, E is S-R 7

SO-R

7 S0 2

-R

7 S0 2 -0R 7 or 0 0078 0 0 20 1 S0 2 -NR R, 0o R 2

R

4 are each H, A, Ar, Ar-aLkyL, Het, Het-alkyL 0 0 0 7 and R 8 or cycLoalkyL with 3-7 C atoms, cycLo- 00- aLkylaLkyL with 4-11 C atoms, bicycLoaLkyl or tricycLoalkyL with in each case 7-14 C or bicycLoaLkyLaLkyL or tricycLoa~ky~aLky 00 with in each case 8-18 C atorsis, in each case 00 00 unsubstituted or mono- or poLysubstituted by A, AO and/or Hal, R 3is H or A, R5 is in each case OH), NH 2 or =0, R 6 s H, A or ai kenyL with 2-8 C atoms, -2 m, p, r and t are each 0, 1, 3, 4 or n is 1 or 2, x is 0 or 1, L is CH or N, T is 0 or NH, V is CO or SO2, An 0 is one equivalent of an anion, Ar is phenyl which is unsubstituted or mono- or poLysubstituted by A, AO, HaL, CF 3

HO,

hydroxyaLkyL with 1-8 C atoms, H 2 N and/or aminoaLkyL with 1-8 C atoms, or unsubstituted naphthyL, Het is a saturated or unsaturated 5- or 6-membered heterocycLic radical which has 1-4 N, 0 and/or S atoms, can be fused with a benzene ring and/ or can be mono- or poLysubstituted by A, AO, Hal, CF 3 HO, 0 2 N, carbonyL oxygen, H 2

N,

HAN, A 2 N, AcNH, AS, ASO, AS0 2 AOOC, CN,

H

2 NCO, H 2 NS0 2

ASO

2 NH, Ar, Ar-alkenyl, hydroxyalkyL and/or aminoaLkyL with in each case 1-8 C atoms and/or the N and/or S hetero atoms of which can aLso be oxidized, Hal is F, CL, Br or I, Ac is A-CO-, Ar-CO- or A-NH-CO- and 25 A is alkyL with 1-8 C atoms, and wherein furthermore one or more -NH-CO- groups can also be replaced by one or more -NA-CO- groups, and salts thereof.

Similar compounds are known from European Patent A-163,237.

The invention was based on the object of discovering new compounds with useful 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 their salts have very useful properties.

Above all, they inhibit the activity of human plasma renin. This action can be demonstrated, for example, by the method of F. Fyhrquist et al., CLin.Chem. 22, 250-256 i St t Ii II I Ii i i iiI.

I I os 00 0 0 3 (1976). It is remarkable that these compounds are very specific inhibitors of renin; as a rule considerably higher concentrations of these compounds are needed for inhibition of other aspartyLproteinases (for example pepsin and cathepsin D).

The compounds can be used as medicament active compounds in human and veterinary medicine, in particular for the prophylaxis and treatment of cardiac, circulatory and vascular diseases, above all hypertension, cardiac insufficiency and hyperaldosteronism. The compounds can also be used for diagnostic purposes in order to determine the possible contribution of the renin activity towards maintaining the pathological state in patients with hypertension or hyperaldosteronism.

The abbreviations given above and below for amino acid radicals stand for the radicals as a rule -NH-CHR-CO- (wherein R, R' and R' have the specific meaning known for each amino acid) of the following amino acids: It C 'i 20 Abu 2-aminobutyric acid Ada 3-(1-adamantyl)-alanine Ala alanine B-Ala 2 Arg arginine 25 Asn asparagine Asp aspartic acid Bia 3-(2-benzimidazolyl)-alanine o Cal 3-cyclohexyLalanine Dab 2,4-diaminobutyric acid 30 Ftr N(ind)-formyl-tryptophan Gin glutamine GLu glutamic acid GLy glycine H* His histidine Hph homo-phenylalanine (2-amino-4-phenylbutyric acid) N(im)-A-His histidine substituted by A in the 1- or 3position of the imidazole ring -4 Ite isoLeucine Leu Leucine tert.-Lou tert.-LeucinEj Lys Lysine Mal 3- (p-me-thoxyphenyl) -alanine 0-me thyl-tyrosine) Met methionine aNa 1 3-(c -naphthyl )-alanine ANaL 3-.(-naphthyl)-aianine Nbg (2-norbornyL)-gtycine N~e norLeucine Nva norvaline Orn ornithine Phe phenyLaLanine Pro proLine Pyr 3-CpyridyL)-aLanine, for exampLe 3-Pyr 3-C 3-pyr idy 1)-a Lan ine Ser serine Thr threonine Tia 3-(thienyl)-alanine, for example 3-Tia= 3--(2-thienyl)-alanine Ticll l234etayrioinie-1-carboxylic acid 4 t Trp tryptophan Tyr tyrosine 0-A-Tyr 0-alkyt-tyrosime Vat vaLine.

The other abbreviations furthermore have the meanings given below: BOC tert.-butoxycarbonyL imi-BOM benzyLoxymethyL in the 1-position of the imidazote ring CBZ benzyLoxycarbonyL DNP 2,4-dinitrophenyt *'.imi-DNP 2,4-dinitrophenyL in the 1-position of the o imidazoLe ring FMOC 9-f Luor(eny Lme thoxyc arbony I IPOC i sopropoxycarboryl MC iorphoLinocarbonyL POA phenoxyacetyL PyOC 2-C2-pyr idyL )-ethoxy-carbonyL DCCI dicycLohexyLcarbodi imide HOBt 1-hydroxybenzotriazoLe.

r -r~---~rrrrr~ar Whero the abovementioned amino acids can occur in several enantiomeric forms, aLL these forms and aLso their mixtures (for example the DL-forms) are incLuded above and below, for example as a constituent of the compounds of the formuLa I. The L-forms are preferred.

Where individual compounds are Listed below, the abbreviations of these amino acids in each case relate to the L-form, unless expressly indicated otherwise.

The invention relates to the amino acid derivatives of the formula I and salts thereof, and furthermore to a process for the preparation of an amino acid derivative of the formula I and of its salts, 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 X-G 1

-OH

#4 t 4i r* 4 44 44 4 .4, *i 0 04 0 *4 4 0 4 *r 0 4* 4 4 4 4 4 4 4 4, *4 4,4.

4 44 44 44,.

44i 44 4 44 4 4 4 4 1 1 wherein G is -Z or and X has the meaning given, or one of its reactive derivatives is reacted with a 20 compound of the formula III

H-G

2 wherein

G

2 is -Z2-NR3-CHR -CR 5

-(CHR

6 )n-E or -NR3CHR CR5-(CHR 6 )n-E, Z1 Z 2 together are Z and R R R R 6 n and E have the meanings given, or one of its reactive derivatives, and/or in that, if appropriate, to prepare compounds of the formula I wherein E is SO-R or -S0 2 -R a sulfide 30 of the formula I wherein E is S-R 7 is treated with an oxidizing agent, and/or in that, if appropriate, in a compound of the formula I, a functionally modified amino and/or hydroxyl group is liberated by treatment with solvolyzing or hydrogenolyzing agents, and/or a keto 6 group is reduced to a CHOH group or aminated reductively to a CH(NH 2 group and/or a compound of the formula I is converted into one of its salts by treatment with an acid.

The radicals and parameters X, Z, E, R to RS m, n, p, r, t, x, L, T, An, Ar, Het, Hal, Ac, A, G 1 G S2 1 and Z above and below have the meanings given in the case of formuLae I, II or III, unless expressLy indicated 6 otherwise. If two radicals R are present in a compound of the formula I, they can be identical to or different from one another.

In the above formulae, A has 1 8, preferably 1, 2, 3 or 4, C atoms. A is preferably methyl, or moreover ethyl, propyl, isopropyL, butyl, isobutyl, sec.-butyl or tert.-butyL, or furthermore also pentyl, 2- or 3methylbutyl, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyL, 3- or 4-methylpentyl, 1,2-, 2,3- or 3,3-dimethybutyl, 1- or 2-ethyl- 000 butyl, 1-ethyl-1-methylpropyl, 1-ethy-2-methylpropyl, 00 20 1,1,2- or 1,2,2-trimethyLpropyL, heptyl or octyl.

00 0 Cycloalkyl is preferably cyclopropyl, cyclobutyl, 00 cyclopentyl, cyclohexyl or cycloheptyl, but also, for 0o 0 example, 2- or 3-methylcyclopentyl or 3- or 0 4-methylcyclohexyl.

Cycloalkyl-alkyl accordingly is preferably cyctopropylmethyl, 2-cyclopropylethyl, cycLobutylmethyl, 2- 0. o cyclobutylethyl, cyclopentylmethyl, 2-cyclopentyethyL, 00 0 cyclohexylnethyl or 2-cyclohexylethyl, but also, for example, 2- or 3-methylcyclopentylmethyl or 2-, 30 3- or.4-methyLcycLohexyLmethyL.

Bicycloalkyl is preferably 1- or 2-decalyl, 2bicyclo[2,2, 1heptyL or 6,6-dimethyl-2-bicyclo[3,1,1 "o0 ~heptyl.

Tricycloalkyl is preferably 1- or 2-adamantyL.

Hal is preferably F, CL or Br, but 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-CO-, such as i -7- N-methyl- or N-ethyLcarbainoyL.

Ar is preferabLy phenyL, or furthermore preferably r-or p-toLyL, r-or p-ethyLphenyL, o-,inor p-inethoxyphenyL, mn- or p-fLuorophenyL, mn- or p-chLorophenyL, mn- or p-bromophenyL, mn- or piodophen-yL, in- or p-trifLuoroinethyLphenyL, in- or p-hydroxyphenyL, in- or p-hydroxyinethylphenyL, 2,3-, 3,4- or 3,5-diinethoxyphenyL, 3,4,5triinethoxyphenyL, in- or p-aininophenyL, in- or paininorethyLphonyL or 1- or 2-naphthyL.

Ar-aLkyL accordingly is preferabLy 1v-nzyL, 1- or 2-phenyLethyl, r-or p-rethyLbenzyl, 1- or -inor -p-toLyLethyL, r-or p-ethyLbenzyL, 1- or 2-o-, -in- or -p-ethyLphenylethyL, in- or p-inethoxybenzyL, 1- or -in- or -p-rnethoxyphenyLethyL, in- or pfLuorobenzyL, 1- or -r-or -p-fLuorophenyLethyL, r-or p-chtorobenzyL, 1- or -in- or -p-chLorophenyLethyL, mn- or p-brornobenzyL, 1- or -mn- or -p-broinophenyLethyL, r-or p-iodobenzyL, 1- or 2-o-, -mn- or -p-iodophenyLethyL, rn- or p-trifLuorornethyLt tbenzyL, mn- or p-hydroxybenzyL, mn- or p-hydroxyrethyLbenzyL, 3,4- or tdiinethoxybenzyt, 3,4,5-triinethoxybenzyL, mn- or p- *4aininobenzyL, mn- or p-aininorethyLbenzyL or 1- or 2naphthyLniethyL.

Het is preferably 2- or 3-furyL, 2- or 3-thienyL, 2- or 3-pyrryL, 4- or 5-irnidazolyL, 3-, 4 4 44- or 5-pyrazoLyL, 4- or 5-oxazoLyL, 4- or isoxazoLyl, 4- or 5-thiazoLyL, 4- or 30 LyL, 3- or 4-pyridyL or 5- or 6-pyrirnidyL, or moreover preferably 1,2,3- triazoLl-, or -S-yL, 1,2,4-triazoL-1-, or -5-yL, 1- or .56 1,2,3-oxadiazoL-4- or -5-yL, 1,2,4-oxad'ia3:oL-3- or 4, 4- 1,3,4-thiadiazoL-2- or -5-yL, 1,2,4-thiadiazoL-3- or yL, 2,1,5-thiadiazoL-3- or -4-yL, 5- or 6-2HthiopyranyL, 3- or 4-4H-thiopyranyL, 3- or 4-pyridazinyl, pyrazinyL, 6- or 7-benzofuryL, 2-, 6- or 7-benzoth ienyi, 6or 7-indoLyL, 6- or 7-isoiricoLyL, 1-, 4- or 5-benz imidazoLyL, 6- or 7benzopyrazoLyL, 6- or 7-benzoxazoLyL, 4-, 6- or 7-benzisoxazoLyL, 6- or 7-benzthiazolyL, 6- or 7-benzisothiazoLyL, 6- or 7-benz-2,1,3-oxadiazoLyL, 7- or 8-quinoLyL, 7- or 8-isoquinoLyl, 1-, 4- or 9-carbazoLyL, 7-, 8- or 9-acridinyL, 7- or 8-cinnoLyL or 7- or 8-quinazoLyL. The heterocycLic radicaLs can aLso be partly or completeLy hydrogenated.

Het can thus also be, for example, 2,3-dihydro-Z-, or -5-furyL, 2,5-dihydro-2-, or tetrahydro-2- or -3-furyL, tetrahydro-2- or -3-thienyL, 2,3-cdihydro-1-, or -5-pyrryL, or -5-pyrryL, 2- or 3-pyrrolidinyL, tetrahydro-l-, or -4-imidazoLyL, 2,3-dihydro-1-, or -5-pyrazoLyL, 2,5-dihydro-1-, -4or -5-pyrazoLyL, tetrahydro-1-, or -4-pyrazoLyl, 1,4dihydro-1-, or -4-pyridyl, 1,2,3,4-tetrahydroor -6-pyridyL, 1,2,3,6-tetrahydroor -6-pyridyL, 3- or 4piperidinyL, 3- or 4-rorphoLinyL, tetrahydro-2-, -3or -4-pyranyL, 1,4-dioxanyL, 1,3-dioxan-2-, or hexahydro-1-, or -4-pyridazinyL, hexahydro-l-, or -5-pyrimidyL, 2- or 3-piperazinyL, 1,2,3,4tetrahydro-1-, or -8-quino- LyL or 1,2,3,4-tetrahydro-l-, or -8-isoquinoLyL.

0-1 301 The heterocycLic radicals can also be substituted as described. Het can thus aLso preferably be: 2-amino- 4-th iazoLyL, 4-carboxy-2-th jazoLyl, 4-carbamoyL-2-th iazo- LyL, 4-(2-aminoethyL)-2-thiazoLyL, 2-amino-5,6-dimethyL- 3-pyrazinyL or 4-carbamoyLpiperidino, or 'furthermore, for 4 35 exampLe, 4- or 5-methyL-2-furyL, 4- or 3-furyL, 2,4-dimethyL-3-furyL, 5-ni tro-2-furyL, 2-furyL, 4- or 5-methyL-2-thienyL, 4- or 3-thienyL, 3-methyL-5-tert.-butyL-2-th ienyL, 5-chloro-2- Ii -9thienyL, 5-phenyL-2- or -3-thienyL, 4- or methyL-2-pyrryL, 1-methyL-4- or -5-nitro-2-pyrryL. dimethyL-4-ethyL-2-pyrryL, 4-methyL-5-pyrazoLyL, 4- or methyt-2--thiazoLyL, 2- or 5-methyL-4-thiazoLyL, 2- or 4methyL-5-thiazoLyL, 2,4-dimeth,'L-5-thiazoLyL, or 6-methyL-2-pyridyl, 5- or 6-methyL-3-pyridyL, 2- or 3-methyL-4-pyridyL, 5- or 6-chLoro-2-pyridyL, 5- or 6-chLoro-3-pyridyL, 2- or 3-chLoro-4pyridyL, 2,6-dichLoropyridyL, 2-hydroxy-3-, or -6-pyridyL 1H-2-pyridon-3-, or phenyL-1H-2-pyr idon-3-yL, 5-p-methoxyphenyL-1H-2-pyr idon- 3-yL, 2-methyL-3-hydroxy-4-hydroxymethyL-5-pyr idyL, 2hydroxy-4-amino-6-methyL-3-pyridyL, 3-N '-methyLureido-lH- 5- or 6-methyL-4-pyrimidyL, ?,6-dihydroxy-4-pyrimidyL, 5-chLoro-2-methyL-4-pyr imidyL, 2- 3-methyL-2-benzofuryL, 2ethyL-3-benzofuryL, 7-methyL-2-benzothienyL, 4-, 6- or 7-methyL-3-indoLyL, 1-methyL-5- or -6-benzimidazolyl, 1-eth)/L-5- or -6-benzimidazoLyL or 4-, 7- or 8-hydroxy-2-quinoLyL.

R 1and R 2 are preferabLy A, in particuLar methyL, ethyL, propyl, isopropyL, butyL, isobutyL or t e rt.-butyL, or furthermore preferabLy cycLopropyL, cycLopentyL, cycLohexyL, rethyLcyc~ohexyL, such as trans- 4-methyLcycLohexyL, tert.-butyLcycLohexyL, such as trans- 4-tert.-butyLcycLohexyL, phenyL or benzyL.

4 43 4. is preferabLy H or methyL, or furthermore 44 preferabLy ethyl, propyl, isopropyL, butyL or isobutyL.

R 4 is preferabLy isobutyL or cycLohoxyLmethyL, or furthermore preferably A, in particular methyl, ethyl, propyL, isopropyL, butyL, sec.-butyL, pentyL, isopentyL (3-methyLbutyL) or 2-methyLbutyL, phenyL, benzyL, pchLorobenzyL, 1- or 2-naphthyLmethyL, 2-phenyLethyL, 3phenyLpropyL, 2-cycLohexyLethyL, 1- or 2-decaLyLmethyL, bicycLo[2,2,1]heptyL-2-methyL or 6,6-dimethyLbicyc Lo- E3,1,llheptyL-2-methyL.

R 5is preferabLy OH).

R 6is preferabLy H or isopropyL, or furthermore preferabLy methyL, ethyL, propyL, butyL, isobutyL or sec butyL If E is S-R SO-R 7 or (preferabLy) S0 2

-R

7 R 7 is preferabLy A, Ar or Het, in particuLar phenyL or a saturated 5- or 6--membered heterocycLic radicaL., such as pyrroLidlino, piperidlino, morphoLino, piperazino, 4-Apiperazino (for example 4-methyLpiperazino), 4-Arpiperazino (for example 4-phenyLpiperazino) or 4- (hydroxyaLkyL iperazimo [for exampLe 4-(2-hydroxyethyL piperazinol. If E is S0 2 -OR R 1 is preferably A or Ar. If E is S0 2 -NR R R 7 and R are preferably indlependlently of one another each H. A, Ar or Ar-aLkyL.

E is accordingly preferabLy morphoLinosuLfonyL, or furthermore pyrroL idinosuLfonyL, piperidinosuLfonyL, piperaz inosuLfonyL, 4-methyLpiperaz inosuLforiyL, phenyLsuLfonyL, suLfamoyL, N-methyLsuLfamoyL, N-ethyLsuLfamoyL, N-propyLsuLfamoyL, N-i sopropyLsuLfamoyL, N-butyLsuLfamoyL, N-isobutyLsuLfamoyL, N-sec butyLsuLfamoyL, NpentyLsuLfamoyL, N-isopentyLsuLfamoyL, N-hexyLsuLfamoyL, N,N-dimethyLsuLfamoyL, N,N-diethiyLsuLfamoyL, N,N-dipropyl suLfamoyL, N,N-dibutyLsuL famoyL, N-benzyL-N-methyLsuLfamoyL, N-benzyL-N-ethyL-suLfamoyL, N-benzyl-N-propyLsuLfamoyL, N-benzyl-N-butyL-suLfanoyL, furthermore for example morphoL inosuLfinyL, pyrroL idinosuLfinyL, piperidlinosuLfinyL, piperazinosuLfinyL, phenylsuLfinyL, morphoLinothio or phenyLthia.

L is preferably CH. T is preferabLy NH. An is A, t preferably CL, Br, HCOO or CH 3

COO.

The parameters m, p, r and t are preferably 0,1 or 2;.n is preferably 2; x is preferably 1.

ILIX is preferably H, POA, aLkoxycarbonyL, such as IPOC or BOC, CBZ, aLkanoyL, such as acetyL, propionyL, butyryL, isobutyryl, isovaLeryL or 3,3-diroethyLbutyryL, cycLoaLkyLcarbonyL, such as cycLopentyLcarbonyL or cycLohexyLcarbonyL, aroyL, such as benzoyL, aryLaLkanoyL, such as phenyLacetyL, 2- or 3-phenyLpropionyL, 4-phenyLbutyryl, 2-benzyLheptanoyL, 2-benzyL-3-phenyLpropionyL, 2-benzyL- 4-phenyLbutyryL, 2-(2-phenyLethyL )-4-phenyLbutyryL, 2-(2f niaphthyLmethyi)-4-phenyLbutyryL, bis-( 1-naphthyLmethyL)acetyL), 2- or -in- or -p-fLuorophenyLpropionyL or 2- cr -in- or -p-chiorophenyLpropionyL, cycLoaLkyLaLkanoyi, such as cycLohexyLacetyL or 2- or 3-cycLohexyLpropionyL, Het-aikanoyL, such as MC, morphoLinoacetyL, or 4-(4-pyridyL)-butyryL or PyOC, aminoaLkanoyL, such as 6-aminohexanoyL, 4-dimethyLaminobutyryL, 6-dimethyLaminohexanoyL or FMOC. ParticuLarLy preferred radicaLs X are BOG and bis-(1-naphthyLmethyL)-acetyL, or furthermore POA, 4-phenyLbutyryL, 2-benzyL-3-phenyLpropionyL, 2-benzyL-4-phenyLbutyryL, 2-(2-phenyLethyL phenyLbutyryL, 2-(2-naphithyLinethyL )-4-phenyLbutyryL and CB 8 Z is preferabLy 2, or aLso 1, or moreover 3 or 4 amino acid radicaLs bonded to one another in peptidle form, in particuLar one of the groups His, Phe-His or Phe-GLy, or furthermore preferabLy the groups Abu, Ada, Asn, Bia, CaL, Gin, N-(im)-methyL-His, Leu, ctNaL, NaL, Nie, Pte, Trp, Tyr, Abu-His, Ada-His, ALa-His, ALa-Phe, Arg-His, Asn-His, Bia-His, CaL-His, Dab-His, GLu-His, His-His, Hph-His, Lie-His, Leu-His, tert.-Leu-His, Lys- His, Met-His, caNaL-His, NaL-His, Nbg-His, Nie-His, (N- Me-His)-His, (N-Me-Phe)-His, Orn-His, Phe-Abu, Phe-Adla, Phe-ALa, Phe- ALa, Phe-Arg, Phe-Asn, Phe-Bia, Phe-CaL, Phe-Dab, Phe-Gin, Phe-Giu, Phe-(N-im-methyi-His), Phe-lie, Phe-Leu, Phe-tert.-Leu, Phe-Lys, Phe-Met, Phe-ct-NaL, Phe-$ NaL, Phe-Nbg, Phe-Nie, Phe-(N-Me-His), Phe-(N-Me-Phe), a419 Phe-Orn, Phe-Phe, Phe-Pro, Phe-(2-Pyr), Phe-(3-Pyr), Phe- (4-Pyr), Phe-ser, Phe-Thr, Phe-Tic, Phe-Trp, Phe-Tyr, Phe-Vai, Pro-His, Ser-His, Thr-His, Tic-His, Trp-His, Tyr-His, (0-Me-Tyr)-His or VaL-His, or furthermore Ada- Phe-His, Pro-Ala-His, Pro-ALa-Phe, Pro-Phe-ALa, Pro-Phe- His, Pro-Phe-Phe, Ftr-Pro-Phe-His, His-Pro-Ala-His, His- Pro-ALa-Phe, His-Pro-Phe-ALa or His-Pro-Phe-Phe, or moreover 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-li s, Pro-tert Leu-His, Pro-Lys-H is, Pro-Met-His, Pro-Nbg-His, Pro-Nie-His, Pro-(N-Me-H is)-His, kh- 12 Pro-CN-Me-Phe)-H is, 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-(N-im-methyL-H is), Pro-Phe- ILe, Pro-Phe-Leu, Pro-Phe-tert.-Leu, Pro-Phe-Lys, Pro- Phe-Met, Pro-Phe-Nbg, Pro-Phe-NLe, Pro-Phe-CN-Me-His), Pro-Phe-(N-Me-Phe), Pro-Phe-Orn, Pro-Phe-Pro, Pro-Phe-Ser, Pro-Phe-Thr, Pro-Phe-Tic, Pro-Phe-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, His-Pro-Abu- His, His-Pra-Ada-His, His-Pro-Arg-His, His-Pro-Asn-His, His-Pro-Bi a-His, His-Pro-Dab-His, H is-Pro-GLu-His, His- Pro-His-His, H is-Pro-I Le-His, His-Pro-Leu-His, His-Protert.-Leu-H is, His-Pro-Lys-His, His-Pro-Met-His, His-Pro- Nbg-His, H is-Pro-NLe-H is, H is-Pro-(N-Me-His )-His, His- Pro-(N-Me-Phe)-His, H is-Pro-Oin-His, His-Pro-Phe-Abu, H is-Pro-Phe-Ada, H is-P ro-Phe-Aing, H is-Pro-Phe-Asn, His- Pro-Phe-Bia, H is-P ro-Phe-Dab, His-Pro-Phe-Gin, H is-Pro- Phe-GLu, His-Pro-Phe-His, H is-Pro-Phe(N-im-methyL-His), His-Pro-Phe-I Le, His-Pro-Phe-Leu, H is-Pro-Phe-tert.-Leu, His-Pro-Phe-Lys, His-Pro-Phe-Met, His-Pro-Phe-Nbg, His- Pro-Phe-Nie, His-Pro-Phe-(N-Me-His), His-Pro-Phe-(N-Me- Phe), His-Pro-Phe-Orn, His-Pro-Phe-Pro, His-Pro-Phe-Ser, His-Pro-Phe-Thr, His-Pro-Phe-Tic, His-Pro-Phe-Trp, His- Pro-Phe-tyr, His-Pro-Phe-Val, His-Pro-Pro-His, His-Pro- Ser-His, His-Pro-Thr-His, His-Pro-Tic-His, His-Pro-Trp- His, His-Pro-Tyr-His or His-Pro-Vat-His.

The group -N _CR4 R n is preferably -NH-CHR -_CHOH-CH 2 in particuLar -NH-CH(cycLohexyLmethyL)-CHOH-CH 2 or furthermore -NH-CH(CH 2

CH

2 44V30 cyciohexyL)-CHOH-CH 2 -CO-NH-CH~isobutyL)CHOHiCH2- or -NH-CH(benzyL)-CHOH-CH 2 or furthermore preferabLy

-NH-CHR

4

_-CH(NH

2 in particular -NH-CH(cycLo- 4: hexyLmethyL)-CH(NH 2

-NH-CH(CH

2

CH

2 -cycLohexYL

CH(NH

2

)-CH

2 -NH-CH(isobutyL)-CH(NH2)-CH2- or 0035 -NH-CH(benzyL)-CH(NH 2 )CH2-, or moreover preferably -NH-CHR 4 _CHOH-CH2-CHA-, in part icuLar -NH-CH( cycLohexyLmethyL)-CHOHCH 2 -CH(isopropyL)-.

This group as a ruLe has two chiraL centres. The -13 compounds of the formuLa I can therefore occur in various -opticaLLy inactive or opticaLly active forms.

Formula I inctudes aLL these forms. The substituent X-Z-NR 3_ is preferabLy in the form of the S-enantiomer.

group E is prcferabLy S0 2 -R and preferabLy S0 2 -Het, in particuLar S0 2 -morphoLino, or furthermore preferably S0 2 -pyrroLidlino, S0 2 -piperidlino or S2 piperazino; E is moreover preferabLy S0 2 -NR 7 R 8 in particuLar S0 2

-N(A)

2 such as S0 2

-N(CH

3 2 S0 2 -NHA, such as S0 2

-NH-C

4 Hq or S02-NH-isopentyL; or S0 2 -NAAr-aLkyL, such as S0 2

-N(CH

2

C

6

H

5

)C

4

H

9 The invention accordingly particuLarLy reLates to those compounds of the formuLa I in which at Least one of the radicals mentioned has one of the abovernentioned preferred meanings. Some preferred groups of compounds can be expressed by the folLowing part formuLae Ia to Ig, which correspond to the formuLa I but wherein in Ia X is 6CC, isovaLeryL, 3,3-dimethyLbutyryL, bis-( 1-naphthyLmethyL )-acetyL, 2-benzyL- 4-phenyL-butyryL, POA, 2-(1-naphthyLmethyL)-3-N-isopropyLcarbamoyL-propionyL, 2-benzyL-3-MC-propionyL, N-benzyL-N-butyLcarbamoyL, 6-aminohexanoyL, morphoLinoacetyL, PyOC, IPOC, MC, 4-(4-pyridyL)butyryL, 4-dimethyLamino-butyryL, 6dim,-eth'yiariiinohexanecyL, 4-tr imethyLammonium butyryL-formate, 6-tr imethyLammonium-hexanoyL-formate or CBZ; in lb X is BOG or bis-(1-naphthyLmethyL)-acetyL; ~j 30 i n .1c. X is in Id Z is His, Bia-His, CaL-His, Hph-His, cNaL-His, NLe-His, Phe-Abu, Phe-ALa, Phe-BALa, Phe- Asn, Phe-G~n, Phe-GLY, Phe-His, Phe-Leu, Phe-Met, Phe-NLe, Phe-(N-Me-His), Phe-(3- Pyr), Trp-His, (O-Me-Tyr)-His, Pro-Phe- His, P ro-Phe-N (Me) -His, His-P ro-Phe-H is or Ftr-Pro-Phe-His; in Ie Z is His or Phe-His; 14 in If R 3 is H, R is isobutyl or cyclohexylmethyl,

R

5 is OH,

R

6 is H or isopropyl and n is 2; in Ig X is BOC or bis-(1-naphthyLmethyl)-acetyl, Z is His or Phe-His,

R

3 is H, R is isobutyl or cyclohexylmethyl,

R

5 is OH, R is H or isopropyL and n is 2.

Compounds which are moreover preferred are those which correspond to the formulae I and la to Ig but wherein in each case, in addition, E is S-R E is SO-R 7 E is S0 2

-R

7 E is S0 2

-OR

7 E is S0 2

-NR

7

R

8 E is S0 2 -Het; E is S02-morpholino, SO2-pyrrolidino, SO2piperidino, S0 2 -piperazino, S0 2

-NHA,

S0 2

N(A)

2 or S02NA-araLkyL; E is S0 2 -morphoLino.

The compounds of the formula I and also the starting substances for their preparation are moreover prepared by methods which are known per se such as are described in the Literature (for example in the standard works, such as Houben-WeyL, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme- Verlag, Stuttgart; and furthermore European Patent A- 45,665, European Patent A-77,028, European Patent Az 77,029 and European Patent A-81,783), and in particular under reaction conditions which are known and suitable for the reactions mentioned. It is also thereby possibLe to utilize variants which are known per se and are not mentioned here in more detail.

1 1 1 -L 15 If desired, the starting substances can also be formed 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 thus be obtained by Liberating them from their functional derivatives by solvoLysis, in particular hydrolysis, or by hydrogenoLysis.

Preferred starting substances for the solvolysis or hydrogenoLysis are those which, instead of one or more free amino and/or hydroxyL groups, contain corresponding protected amino and/or hydroxyL groups, preferabLy those which carry an amino-protective group instead of an H atom bonded to an N atom, for example those which correspond to the formula I but which contain an N(im)-R 9 9 His group (wherein R is an amino-protective group, for example BOM or DNP) instead of an His group, or those of the formula X-Z-NR3-CHR4-CH(NHR9)-(CHR6)n-E.

Starting substances which carry a hydroxyl- 20 protective group instead of the H atom of a hydroxyL group, for example those of the formuLa X-Z-NR -CHR

CH(R

10

)-(CHR

6 wherein R 10 is a hydroxylprotective group, are furthermore preferred.

S It is also possible for several identicaL or i« 25 different protected amino and/or hydroxyL groups to be present in the molecule of the starting substance. If the protective groups present differ from one another, they can in many cases be split off selectively.

The expression "amino-protective group" is generot- 30 ally known and relates to groups which are suitable for protecting an amino group from chemical reactions (blocking the amino group), but can easily be removed when the ni', desired chemical reaction elsewhere in the moLecule has t been carried out. Typical examples of such groups are, in particular, unsubstituted or substituted acyl, aryl (for example 2,4-dinitrophenyl), aralkoxymethyl (for example benzyloxymethyl) or aralkyl groups (for example benzyL, 4-nitrobenzyL or triphenylmethyl). Since the

W

16 amino-protective groups are reacted after the desired reaction (or reaction sequence), their nature and size is otherwise not critical; however, those with 1-20, in particular 1-8, C atoms are preferred. The expression "acyl group" in connection with the present process is to be interpreted in the broadest sense. It includes acyL groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or suLfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and above all aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and butyryL; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyL or toluyL; aryloxyaLkanoyl, such as phenoxyacetyl; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, and 2-iodoethoxycarbonyl; and aralkoxycarbonyL, such as CBZ .0 ("carbobenzoxy"), 4-methoxybenzyLoxycarbonyL or FMOC.

0 St Preferred amino-protective groups are DNP, BOM, CBZ, FMOC, benzyL and acetyl.

V4 20 The expression "hydroxyl-protective group" is also generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions but can easily be removed when the desired chemical reaction eLsewhere in the molecule has been 25 carried out. Typical examples of such groups are the unsubstituted or substituted aryL, aralkyl or acyl groups mentioned above, and furthermore also alkyl groups. The 0 nature and size of the hydroxyL-protective groups is not critical, since they are removed again after the desired 30 chemical reaction or reaction sequence; groups with 1-20, 0 0. 0 in particular 1-10, C atoms are preferred. Examples of 0 hydroxyl-protective groups are, inter alia, benzyl, pnitrobenzoyl, p-toluenesulfonyl and acetyL, benzyL and acetyL being particularly preferred.

The functional derivatives of the compounds of the formula I to be used as starting substances can be prepared by customary methods of amino acid and peptide synthesis, such as are described, for example, in the 17 standard works and patent applications mentioned.

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 sulfuric acid, strong organic carboxylic acids, such as trifluoroacetic acid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible but not always necessary. Suitable inert solvents are, preferably, organic solvents, for example carboxylic acias, such as acetic acid, ethers, such as tetrahydrofuran (THF) or dioxane, amides, such as dimethyLformamide (DMF), phosphoric acid hexamethyLtriamide (HMPT), halogenated hydrocarbons, such as methylene f chloride, or furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are furthermore possible. Trifluoroacetic acid is preferably used in excess without the addition of a further solvent, and perchloric acid is used in the form of a mixture of acetic acid and perchloric acid in a ratio of 9 1. The reaction temperatures for the cleavage are preferably between 25 about 0 and about 500, and the reaction is preferably carried out at between 15 and 300 (room temperature).

4& The BOC group can preferably be split off, for 1 example, with 40% trifluoroacetic acid in methylene chloride or with about 3 to 5 N HCL in dioxane at 15-300, and the FMOC group can be split off with an approximately o 5 to 20% solution of dimethylamine, diethylamine or *o piperidine in DMF at 15-30°. The DNP group is also split off, for example, with an approximately 3 to solution of 2-mercaptoethanoL in DMF/water at 15-300.

Protective groups which can be removed hydrogenolytically (for example BOM, CBZ or benzyl) can be split off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble metal cata- L- i_ iii* ii ICIIII)- 18 lyst, such as palladium, preferably on a support, such as charcoal). Suitable solvents here are those mentioned above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. 'he 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 1-10 bar.

Hydrogenolysis of the CBZ group is carried out particularly well, for example, on 5 to 10% Pd-C in methanol at 20-30 Compounds of the formula I can also be obtained by direct peptide synthesis from a carboxylic acid and an amine component. Suitable carboxylic acid components are, for example, those of the part formula X-Z-OH, and suitable amine components are those of the part formula H-NR3CHR4 CR5-(CHR 6 The peptide bond can furthermore be linked within the group Z, if Z consists of at least two of the amino acid radicals mentioned; a carboxylic acid of the formula X-Z -OH is thereby reacted with an amine of the formula H-Z 2

-NR

3

-CHR-CR

5 (CHR6)n-E, wherein Z1 and Z 2 in each case denotes at least one of the amino acid radicals mentioned in the definition of Z and Z Z Z. The reaction is thereby preferably carried out by customary methods 25 of peptide synthesis, such as are described, for example, in Houben-Weyl, loc. cit., Volume 15/II, pages 1 to 806 (1974).

The reaction preferably takes place in the presence of a dehydrating agent, for example a carbodiimide, such as DCCI or dimethylaminopropylethyl-carbodiimide, or furthermore propanephosphonic anhydride (compare Angew.Chem. 92, 129 (1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon, such as methylene chloride, an ether, such as THF or dioxane, an amide, such as DMF or dimethylacetamide, or a nitrile, such as acetonitrile, at temperatures between about -10 and 40, preferably between 0 and 300.

U

19 Instead of II or III, suitable reactive derivatives of these substances can also be used in the reaction, for example those in which reactive groups are intermediately blocked by 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 1-hydroxybenzotriazole or N-hydroxysuccinimide.

The starting substances of the formulae II and III are known in some cases. Where they are not known, they can be prepared by known methods, for example by the methods described above or in the examples or analogously thereto.

If desired, a sulfide of the formula I in which E is S-R can be oxidized to the corresponding suLfoxide E SO-R 7 or sulfone E S0 2

-R

7 for example with hydrogen peroxide or a peracid, such as mchloroperoxybenzoic acid, in an inert solvent, such as chloroform, at temperatures between about -10 and +200 Approximately stoichiometric amounts of the oxidizing agent are used for the preparation of the sulfoxide. The sulfone is predominantly obtained with the amount of oxidizing agent calculated for the formation of the sulfone or with an excess thereof.

25 If desired, a functionally modified amino and/or .I4 hydroxyl group in a compound of the formula I can be liberated by solvolysis or hydrogenolysis by one of the methods described above.

Thus, in particular, a compound of the formula I 30 wherein X is other than H can be converted into a com- 4t pound of the formula I (X advantageously by hydro- U genolysis if X is CBZ, and otherwise by selective solvolysis. If X is BOC, the BOC group can be split off, for example, with HCL in dioxane at room temperature.

A keto group in a compound of the formula I can also be reduced to a CHOH group, for example with a complex metal hydride, such as NaBH 4 which does not simultaneously reduce the peptide carbonyl groups, in an inert r solvent, such as methanoL, at temperatures between about and +300.

A keto group in a compound of the formula I can also be converted into a CH(NH 2 group by reductive amination. The reducci e 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, such as methanol, at temperatures between about 0 and 500, in particular between 15 and 300. It is furthermore possible for the keto compound first to be converted into the oxime with hydroxylamine in the customary manner and for this to be reduced to the amine, for example by catalytic hydrogenation on Raney nickel.

A base of the formula I can be converted with an acid into the associated acid addition salt. Acids which give physiologically acceptable salts are particularly suitable for this reaction. It is thus possible to use inorganic acids, for example sulfuric acid or nitric acid, hydrogen halide acids, such as hydrochloric acid or hydrobromic acid, phospnoric acids, such as orthophosphoric acid, or sulfamic acid, and furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic S, carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, SdiethyLacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid,.malic acid, benzoic acid, salicylic acid, 2- or 3- K phenylpropionic acid, citric acid, gluconic acid, ascorr Cbic 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 Laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for isolating and/or purifying the compounds of the formula I.

21 The new compounds of the formula I and their physiologically acceptable salts can be used for the manufacture of pharmaceutical preparations by bringing them into a suitable dosage form together with at least one excipient or auxiliary and, if desired, together with one or more other active compound(s). The formulations thus obtained can be used as medicaments in human or veterinary medicine. Possible carrier substances are organic or inorganic substances which are suitable for enteral (for example oral or rectal) or parenteral administration or for administration in the form of an inhalation spray 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, gelatine, soya lecithin, carbohydrates, such as Lactose or starch, magnesium stearate, talc or celLuLose. TabLets, coated tablets, capsules, syrups, elixirs or drops are particula'ly suitable for oral use; lacquered tablets and capsules with coatings or capsule shells resistant to gastric juice are of particular interest. Suppositories are suitable for rectal use, and solutions, preferably oily or aqueous solutions, and furthermore suspensions, emulsions or implants are suitable for parenteral administration.

•25 Sprays which contain the active compound either dissolved S or suspended in a propellant gas mixture (for example fluorochlorohydrocarbons) can be used for administration oas an inhalation spray. The active compound is thereby preferably used in micronized form, it being possible for one or more additional physiologically tolerated solvents to be present, for example ethanol. Inhalation *i solutions can be administered with the aid of customary inhalers. The new compounds can also be Lyophilized and the resulting lyophilisates can be used, for example, for the manufacture of injection preparations.

The formulations described can be sterilized and/ or contain auxiliaries, such as preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing 22 the osmotic pressure, buffer substances, dyestuffs and/or aroma substances. If desired, they can also contain one or more other active compounds, for example one or more vitamins.

The substances according to the invention are as a rule administered anaLogousLy to other known commerciaLLy avaiLabLe peptides, but in particular anaLogousLy to the compounds described in European Patent A-163,237, preferabLy in dosages of between about 100 mg and 30 g, in particular between 500 mg and 5 g per dosage unit.

The daily dosage is preferably between about 2 and 600 mg/kg of body weight. However, the specific dose for each particular patient depends on the most diverse factors, for example on the effectiveness of the specific compound used, and on the age, body weight, general state of health, sex, diet, administration time and route, rate of excretion, drug combination and severity of the particuLar disease to which the therapy appLies. ParenteraL administration is preferred.

ALL the temperatures above and below are given in oC. In the foLLowing exampLes, "customary working up" means: water is added if necessary, the mixture is neutralized and extracted with ether or methyLene chloride, the organic phase is separated off, dried over 25 sodium sulfate, fiLtered and evaporated and the residue is purified by chromatography on siLica gel and/or crystallization.

S* I ExampLe 1 A mixture of 844 mg of 3S-hydroxy-4S-CN-tert.butoxycarbonyl-L-phenyLaLanyL-N(imi)-(2,4-dinitrophenyL)- L-histidyl-aminol-6-methyl-heptane-suLfonic acid morphofLide ["3S-hydroxy-4S-(BOC-Phe-(imi-DNP-His)-amino)-6methyL-heptane-sulfonic acid morpholide" obtainable by reduction of 1-bromo-3S-CBZ-amino-5-methyl-hexan-2-one with LiAl-(0-tert.-C 4

H

9 3 H to give 1-bromo-3S-CBZamino-5-methyL-hexan-2S-oL (in addition the 2R-epimer, melting point 880; chromatographic separation), reaction with 2,2-dimethoxypropane/p-toluenesuLfonic acid in *1 23 methyLene chLoridle to give 2,2-dimethyL-3-CBZ-4S-isobutyLreaction with Nal in acetone to give 2,2-dimethyL-3-CBZ-4S-isobutyL-5S-iodonethyLoxazoLidline (melting point 570), reaction with methanesuLfonic acid morpholidle (melting point 'n5 0 )/Lithium diisopropyLamide/HMPT/THF to give 2,2-dimethyL-3-C8Z--4SsobutyL-5S-(2-morphoL inosuL fonyL-ethyL )-oxazoL idine, hydrogenoLysis on 5% Pd/c in methanoL to give 3S-hydroxy- 4s-amino-6--methyL-heptane-suLfonic acid morphoL ide and condensation with BOC-Phe-( imi-DNP-His)-OH/DCCI/HOBt], 860 mg of 2-mercaptoethanoL, 10 mL of DMF and 10 mL of water is brought to pH 8 with aqueous Na 2

CO

3 soLution at 200, while stirring, and the mixture is stirred at 200 for 2 hours. Customary working up gives 3Shydroxy-4S-(N-tert butoxycarbonyL-L-phenyLaLanyL-LhistidyL-amino)-6-methyL-heptane-suLfonic acid morphoL ide ("3S-hydroxy-4S-BOC-Phe-H is-amino-6-methyL--heptanesuLfonic acid morphoLide'), melting point 1653.

The following compounds are obtained anaLogousLy by cLeavage of the corresponding (imi-DNP--His) dlerivat i ye s: 1-phenyLthio-3S-hydroxy-4S-80G-Phe-His-amino-6-methyLheptane 1-phenyLthio-3S-hydroxy-4S-80C-Phe--His-amino-5-cycLo- 2 25 hexyL-pentane 1R-isopropyvL-1-phenyL th io-3S-hydroxy-4S-BOC-Phe-His- 1S-isopropyL-1-phenyL th io-3S-hydroxy-4S-BOC-Phe-Hisam ino-5-cyc LohexyL-pentane 1-phenyLsuLf inyL-3S-hydroxy-4S-BOC-Phe-His9-amilo-6methyL-heptane 1-phenyLsuLf inyL-3S-hydroxy-4S-BOC-Phe-H cyc IohexyL-pentane 1R-isopropyL-1-phenyLsuLfinyL-3S-hydroxy-4S-BCPhe-His5 am 1S-isopropyL-1-phenyLsuLfinyL-3S-hydroxy4SBOCPhe-Hisam ino-S-c yc Iohe xy I-pent an e 3S-hydroxy-4S-(2-benzyL-4-oxo-5,5-dimethyL-hexanoyL-His -24 amino)-6-methyL-heptane-suLfonic acid morphoLidle 3 S -h yd rox y-4 S-(2-benz yL -4-a xo 5- d imet h'L hex ano>'L-H i s acid morphoL ide 3S-hydroxy-4S-BOC-Ftr-Pro-Phe-His-amjno-6-methyL-heptanesuLfonic acid morphoLide 3S-hydroxy-4S-BOC--Ftr-Pro-Phe-His-amino-5-cycLohexyLpentane-suLfonic acid morphoLidle 1R-isopropyL-3S-hydroxy-4S-BOC-Ftr-Pro-Phe-His-amino-6mirthLheptane-suLfonic acid morphoLidle isrropyL-3S-hydroxy-4S-BOC-Ftr-Pro-Phe-H is-amino-6methyL-heptane-suLfon ic acid morphoL ide 1R-isopropyL-3S-hydroxy-4S-BOC-Ftr-Pro-Phe-His-amino-5cycLohexyL-pentane-sulfonic acid morphoL ide 1S-isopropyL-3S-hydroxy-4S-BOC-Ftr-Pro-Phe-H is-am cycLohexyL-pentane-suLfonic acid morphoLidle 3S-hydroxy-4S-isovaLeryL-Ftr-Pro-Phe-Hi s-amino-6-methyLheptane-suLfonic acid morphoLidle 3S-hydroxy-4S-isovaLeryL-Ftr-Pro-Phe-His-amino-5-cyc LohexyL-pentane-sulfonic acid morphoL ide.

ExampLe 2 1 g of 3S-hydroxy-4S--bis-(1-naphthyL .ethyL)acetyL-( imi-BOM-His)-amino-6-methyL-heptane-suLfonic acid amorphoLide Emelting point 110 0; obtainable by reaction *8 of 3S-hydroxy-4S-amino-6-methyL-heptane-suLfonic acid 25 morphoLidle with BOC-(imi-E3OM-His)-OH/DCCI/HOBt to give 3S-hydroxy-4-BOC-(imi-BOM-His)-amino-6-methyL-heptane- @8 a suLfonic acid morphoLidle (melting point 560), splitting a aa off of the BOC group with 4N HCL in dioxane and acyLat ion with bis-(1-naphthyLmethyL)-acetic acid] is dlissolved in S30 10 mL-of methanol and hydrogenated on 0.5 g of 10% Pd-C a oa aO a* at 200 under 1 bar, the mixture is filtered and the fiLtrate is evaporated to give 3S-hydroxy-4S-bis-6(1naphthyLrnethyL )-acetyL-His-amino-6-methyL-heptane2suLfonic acid morphoLide, meLting point 1300 (dlecomposition) a aThe folLowing compounds are obtainable analogously by hydrogenoLysis of the corresponding BOM derivatives: 3S-hydrox:,-4Sbis-(-naphthyLmethyL)-acetyL-Hisamino-5 25 cycLohexyL-pentane-suLfIonic acid morphoL ide, melting point 1330 [obtainabLe via 1-bromo-3S-BOC-amino-4-cycLohexyL-butan-2-one (melting point 860), 1-bromo-3S-BOCamino-4-cycLohexyL-butan-2S-oL (oiL; in addition the 2Repimer), 2,2-dimethyL-3-BOC-4S-cycLohexyLmethyL-5S-bromomethyL-oxazoLidine (melting point 102-1030), 2,2d ime t h>'L-3-BOC -4 S -c yc 1o h e xy m e th y -5 S -i odo m et h>I- o xa z 1i dine (melting point 930), 2,2-dlimethyL-3-BOC-4S-cycLohexyLmethyL-5S-(2-morphoLino-suLfonyL-ethyL)-oxazoLidine, 3S-hydroxy-4S-amino-5-cycLohexyL-pentane-suLfonic acid morphoL ide, 3S-hydroxy-4S-Boc-( imi-BOM-His cycLohexyL-pentane-suLfonic acid morphoL ide (meLting point 1650) and 3S-hydroxy-4S-bis-(1-naphthyLmethyL)acid morpholidle (meLting point 114-1150)1; 3S-hydroxy-4S-BOC-P 1 ,Hi suLfonic acid morphoLidle, melting point 1320 [obtainable from 3S-hydroxy-4S-BOC-Phe-( hexyL-pentane-suLfonic acid morphoLidle, meLting point 940] 1R-isopropyL-3S-hydroxy-4S-BOC-Phe-H is-amino-6-methyL- Iz heptane-sulfonic acid morphoLidle, I 1S-isopropyL-3S-hydroxy-4S-BOC-Phe-H is-amino-6-methyLheptane-sulfonic acid morphoLidle, iR- i suropyL-3S-hydroxy-4S-B0C-Phe-Hi s-am ino-5-cyc LohexyL-pientane-suLfonic acid morphoLidle, melting point 116-117' [obtainabL2- via 1-bromo-3S-CBZ-amino-4-cycLohexyL-butan-2-one (melting point 660), 1-bromo-3S-CBZamino-4-cycLohexyL-butan-2S-oL (oil; in addition the 2Repimer, melting point 1250), 2,2-dimethyL-3-CBZ-4S- (oiL), 2,2dimethyL-3-CBZ-4S--cycLohexyLmethyL-5S-iodomethyL-oxazoLi- 14 dine (melting point 670), reaction thereof with 2methyL-propane-suLfonic acid morphoLidle (melting point 82 0 )/lithium diisopropyLamide/HMPT to give 2,2-di- II methyL-3-CBZ-4S-cycLohexyLmethyL-5S-(2R-isopropyL-2- II,. morphoLinosuLfonyL-ethyL)-oxazoLidine (oil; in addition the 2S-isopropyL epirner meLting point 840), 1R- -26 isopropyL-3S-hydroxy-4S-amino--5-cycLohexyL-pentanesuLfonic acid morpholidle and reaction thereof with BOC- Phe-(imi-BOM-His)-OH (meLting point 1820) to give iRisopropyL-3S-hydroxy-4S-BOC-Phe-(imi-Bom-His)-amino-5cycLohexyL-pentane-suLfonic acid morphoLidle (meLting point 118-120o)3I; 1S-isopropyL-3S-hydroxy-4S-BOC-Pheacid morphoL ide, meLting point 114-1160 [obtainabLe via iS-isoprop>'L -3 S -h 'd rox y-4 amino-S-c yc Lohe xy L -pent an e -s uL fon ic acid morphoLidle and 1S-isopropyL-3S-hydroxy-4S-BOC-Pheacid morphoLide (meLting point 108-109o0)1; 3S-hydroxy-4S--BOC-Phe-His-amino-6-methyL-heptanesuLfonic acid pyrroLidide 3S-hydroxy-4S-BOC-Phe-H is-am ino-5-cyc LohexyL-pentanesuLfonic acid pyrro~liide 1R-isopropyL-3S-hydroxy-4S-BOC-Phe-His-amino-6-methyLheptane-suLfonic acid pyrroLidlide 1S-isopropyL-3S-hydroxy-4S-BOC-Phe-His-amino-6-methyLheptane-suLfonic acid pyrroLidlide 1R-isopropyL-3S-hydroxy-4S-BOC-Phe-His-amino-5-cycLohexyL-pentane-suLfonic acid pyrroLidlide is-i sopropyL-3S-hydroxy-4S-BOC-Phe-His-aino-5-cyc LohexyL-pentane-suLfonic acid pyrroLidlide 3S-hydroxy--4S-BOC-Phe-Hi s-arnino-6-methyL-heptanesuLfonic acid piperidlide 3S-hydroxy-4S-BOC-Phe-H is-amino-5-cyc LohexyL-pentanesuLfonic acid piperidlide 1R-isopropyL-3S-hydroxy-4S-BOC-Phe-His-aino-6-methyL- 30 heptarie-suLfonic acid piperidlide 1S-i sopropyL-3S-hydroxy-4S-BOC-Phe-Hi s-amino-6-methyLheptane-sulfonic acid piperidlide 1R- isopropyL-3S-hydroxy-4S-BOC-Phe-H is-am ino-5-cyc LahexyL-pentane-suLfonic acid piper ididle iS- isopropyL-3S-hydroxy-4S-BOC-Phe-His-amfino-5-cycLohexyl-pentane-suLfonic acid piperidlide 3S-hydroxy-4S-OCPhe-Hi s-am ino-6-methyt-heptanesutfonic acid piperazide -27 3S-hydroxy-4S-BOC-Phe-His-amino-5-cycLohexyL-pentanesuLfonic acid piperazidle 1R-isopropyL-3S-hydroxy-4S-BOC-Phe-His-amino-6-methyLheptane-suLfonic acid piperazide 1S-i sopropyL-3S-hydroxy-4S-BOC-Phe-H is-amino-6-methyLheptane-suLfonic acid piperazide 1R-isopropyL-3S-hydroxy-4S-BOC-Phe-His-amino-5-cycLohexyL-pentane-suLfonic acid piperazidle 1S-isopropyL-3S-hydroxy-4S-BOC-Phe-His-amino-5-cycLohexyL-pentane-suLfonic acid piperazide 3S-hydroxy-4S-BOC-Phe-His-anino-6-methyL-heptalesuLfonic acid dimethyLamide 3S-hydroxy-4S-BOC-Phe-His-amino-5-cycLohexyL-peltaesuLfonic acid dimethylamide 1R-isopropyL-3S-hydroxy-4S-BOC-Phe-Hi s-amino-6-methyLheptane-suLfonic acid dimethyLamide 1S-isopropyL-3S-hydroxy-4S-BOC-Phe-H is-amino-6-methyLheptane-suLfonic acid dimethyLamide 1R-isopropyL-3S-hydroxy-4S-BOC-Phe-His-amiflo-5-cycLo hexyL-pentane-suLfonic acid dimethyLaniide 1S-isopropyL-3S-hydroxy-4S-BOC-Phe-His-amfiflo-5-cycLohexyt-pentane-suLfonic acid dimethyLamide 3S-hydroxy-4S-BOC-Phe-H is-ami no-6-methyL-heptanesuLfonic acid (N-benzyL-N-butytamide) 3S-hydroxy-4S-BOC-Phe-His-amino-5-cyc LohexyL-pentanesuLfonic acid (N-benzyL-N-butyLamide) 1R-isopropyL-3S-hydroxy-4S-BOC-Phe-H is-amino-6-methyLheptane-suLfonic acid CN-benzyL-N-butyLamfide) 1S-isopropyL-3S-hydroxy-4S-BOCPhe-His-ami no-6-methyL- 4 44 30 heptane-suLfonic acid (N-benzyL-N-butyLamfide) 441 1R-isopropyL-3S-hydroxy-4S-BOC-Phe-H is-ani no-5-cyc Lo- 4 4 hexyt-pentane-suLfonic acid (N-benzyL-N-butyLamide) 1S-isopropyL-3S-hydroxy-4S-BOC-Phe-H hexyL-pentane-sutfonic acid (N-benzyL-N-butyLamide) 3S-hydroxy-4S-BOC-Phe-H is-amino-6-methyL-heptale- 494 suLfonic acid CN-butyLarnide) 3S-hydroxy-4S-BOC-Phe-H is-am ino-5-cyc LohexyL-pentanesuLfonic acid (N-butytamide) 28 1R-isopropyL-3S-hydroxy-4S-BOC-Phe-H is-amino-6--methyLheptane-suLfonic acid (N-butyLamide) 1S-i sopropyt-3S-hydroxy-4S-BOC-Phe-H is-arnino-6-methyLheptane-suLfonic acid (N-bUtyLamidle) 1R-isopropyt-3S-hydroxy-4S-BOC-Phe-His-amino-5-cyc LohexyL-pentane-suLfonic acid (N-butyLamide) 1S-isopropyL-3S-hydroxy-4S-BOC-Phe-His-amino-5-cycLohexyL-pentane-suLfonic acid (N-butyLamide) 3S-hydroxy-4S-BOC-Phe-H is-arino-6-methyL-heptanesuLfonic acid (N-isopentyLamide) 3S-hydroxy-4S-BOC-Phe-H is-amino-5-cyc LohexyL-pentanesuLfonic acid (N-isopentyLamide) 1R-isopropyL-3S-hydroxy-4S-BOC-Phe-H is-amino--6-methyLheptane-suLfoni c acid (N-isopentyLamide) iS-i sopropyL-3S-hydroxy-4S-80C-Phe-H is-arnino-6-methyLheptane-suLfonic acid CN-isopentyLamide) 1R-isopropyL-3S-hydroxy-4S-BOC-Phe-His-amino-5-cycLohexyL-pentane-suLfonic acid (N-isopentyLaiide) 1S-isopropyL-3S-hydroxy-4S-BOC-Phe-His-amino-5-cycLohexyL-pentane-suLfonic acid (N-isopentyLamide) 1-ph en yL s uL f o>L -3 h yd rox y-4 S-BOG -P h e -Hi s -am ino-6methyL-heptane 1-phenyLsuLfonyL-3S-hydroxy-4S-BOC-Phe-His-amino-5cycLohexyL-pentane i 25 1R-isopropyL-1-phenyLsuLfonyL-3S-hydroxy-4S-BOC-Phe-Hi amino-6-methyL-heptane 1S-isopropyL-1-phenyLsuLfonyL-3S-hydroxy-4S-BOC-Phe-H isamino-6-rnethyL-heptane 1R-isopropyL-l-phenyLsutfonyL-3S-hydroxy-4S-BOC-Phe-His- Q 30 i1S-i sopropyt-i-phenyLsuLfonyL-3S-hydroxy-4S-BOC-Phe-H is- The foLLowing 6-methyL-heptane-suLfonic acid morphoLidles are obtained anaLogousLy: 3S-hydroxy-4S-BOC-a-His-anino- 3S-hydroxy-4S-BOC-Hph-H is-amino- 3S-hydroxy-4S-BOC-Hpha-H is-amino- 29 3S-hydroxy-4S-BOC-NLe-H is-amino- 3S-hydroxy-4S-BOC-Trp-H is-amino- 3S-hydroxy-4S-BOC-Tyr-H is-amino- 3S-hydroxy-4S-BOC-(0-methylu-Typ)-H is-amino- 3S-hydroxy-4S-(2-benzyL-heptanoyL-H is-amino)- 3S-hydroxy-4S-(2-benzyL-3-phenyL-propionyL-H is-amino)- 3S-hydroxy-4S-C2-benzyL-4-phenyL-butyryL-His-amino)- 3S-hydroxy-4S-POA-H is-amino- 3S-hydroxy-4S-[2-(l-naphthyLmethyL)-3-N-isopropyLcarbamoyL-propionyL-H is-amino]- 3S-hydroxy-4S-C2-benzyL-3-MC-prop ionyL-H is-amino)- 3S-hydroxy-4S-(N-benzyL-N-butyL-carbamoyL-H is-amino)- 3S-hydroxy-4S-BOC-Phe-(N-methyL-His)-amino- 3S-hydroxy-4S-B0C-Pro-Phe-H is-amino- 3S-hydroxy-4S-BOC-Pro-Phe-CN-methyL-H is )-amino- 3S-hydroxy-4S-80C-H is-Pro-Phe-His-amino- (from the bism i-BOM-H is derivative) 1R-isopropyL-3S-hydroxy-4S-BOC-Phe-(N-methyL-His)amilo- 1S-isopropyL-3S-hydroxy-4S-BOC-Phe-(N-methyL-His)-amilo-.

The foLLowing 5-cycLohexyL-pentane-suLfonic acid morpholidles are obtained anaLogousLy: 3S-hydroxy-4S-BOC-B ia-His-am ino- 3S-hydroxy-4S-BOC-Ca 1-H is-amino- 3S-hydroxy-4S-B0C-Hph-His-amino- 3S-hydroxy-4S-BOC-ctNaL-Hi s-aminotat, C 3S-hydroxy-4S-BQC-NLe-H is-aminoat I 3S-hydroxy-4S-BOC-Trp-Hi s-amino- 4 I I 3S-hydroxy-4S-BOC-Tyr-H is-amino- 3S-hydroxy-4S-BOC-CO-methyL-Tyr)-His-amilo- 3S-hydroxy-4S-(2-benzyL-heptanoyL-His-amino)- 3S h d o y-S -en y -he y r pi n L H s-m n 3S-hydroxy-4S-(2-benzyL-3-phenyL-rOP ioyL-H is-amino)- It 3S-hydroxy-4S-POA-H is-amino- 3S-hydroxy-4S-E2-(l-naphthyLmethyL)-3-N-isopropyLcarbamoyL-propionyL-H is-amino]- '4 3S-hydroxy-4S-(2-benzyL-3-MCpropiofyL-H is-amino)- 3S-hydroxy-4S-(N-benzyL-N-butyL-carbaloyL-H is-amino)- 3S-hydroxy-4S-BOC-Phe-( N-methyl-H is) -amino-

LL

30 3S-hydroxy-4S-BOC-Pro-Phe-His-amino- 3S-hydroxy-4S-BOC-Pro-Phe-(N-methyL-His)-amino- 3S-hydroxy-4S-BOC-H is-Pro-Phe-His-amino- (from bis-imi- BOM-His derivative) 1R-i sopropyl-3S-hydroxy-4S-BOC-Phe-(N-methyL-His )-amino- 1S-isopropyL-3S-hydroxy-4S-BOC-Phe-(N-rnethyL-His)-amino-.

ExampLe 3 3S-Hydroxy-4S-C6-amino-hexanoyL-Phe-H is-amino)acid morphoLidle is obtained analogously to ExampLe 2 by hydrogenoLysis of 3S-hydroxy- 4S-[5-CBZ-amino-hexanoyL-Phe-(imi-BQM-His)-aminoJ-5cycLohexyL-pentane-suLfonic acid morphoL ide EobtainabLe by splitting off the BOC group from 3S-hydroxy-4S-BOCacid morpholide and reaction with 6-CBZ-amino-hexanoic ac id] the 3S-hydroxy-4S-(6-amino-hexanoyL-Phe-H is-amino)acid morphoL ide.

Example 4 100 mg of 10% Pd-c and 500 mg of ammonium formate are added to a solution of 100 mg of 3S-hydroxy-4S-E4cycLohexyL-pentane-suLfonic acid morphoLidle chLoridle in 10 ml of methanol and the mixture is stirred at 200 for 8 hours. it is filtered,. the filtrate is evaporated and 25 the residue is chromatographed on silica gel with methylene chloride/methanol to give 3S-hydroxy-4S-C4-trimethyLammon ium-butyryL-Phe-H is-amino) -5-cyc LohexyL-pentanesuLfonic acid morphoLidle-formate.

The following 5-cycLohexyL-pentane-suLfonic acid 30 morphoLidles are obtained analogously: 3S-hydroxy-4S-( isovaLeryL-Phe-H is-amino)- 3S-hydroxy-4S-(3,3-dimethyLbutyryL-Phe-His-amino)- 3 S- hy d rox y-4 S -(morph o Ii no ace t yI-Phe -Hi s -amino) 3S-hydroxy-4S-(PyOC-Phe-H is-amino)- 35 3S-hydroxy-4S-( IPOC-Phe-His-amino)- 3S-hydroxy-4S-(MC-Phe-H is-amino)- 3S-hydroxy-4S-E4-(4-pyridyL)-butyryL-Phe-His-amino)- 3S-hydroxy-4S-(6-am ino-hexanoyL-Phe-H is-amino) 3 S iyd rox y-4 S-(4-dime thyIm in ob ut yr yI- Ph e- His -amino) it 4 4 4 1 4 44 I ii I 4 4 ii Li 14 1 4 1 ii I 44 1 I 4 1 4 ii 44 4 I I I *1 t( t I Ii,, Ii II ii

I

CI

II I 4 1 1 I Ii 31 3S-hydroxy-4S-(6--dimethyLarninohexanoyL-Phe-H is-amino)- 3 S- h yd rox y-4 S-(6-t r imet h>'La mmon iurnh a xa no y ,L -Ph e -His -amino) formate.

The foLLowing 6-methyL-heptane-suLfonic acid morphoLidles are obtained anaLogously: 3 S-hydroxy-4S-(4-trimethyLammonium-butyryL-Phe-His-aminoforruate 3S-hydroxy-4S-(jsovaLeryL-Phe-H is-amino)- 3S-hydroxy-4S-(3,3-d irethyLbutyryL-Phe-Hi s-ami no)- 3S-hydroxy-4S-(morphoL inoacetyL-Phe-H is-amino)- 3 S -hy d rox y-4 S y0C -Ph e -Hi s -amino) 3S-hydroxy-4S-(IPOC-Phe-H is-amino)- 3S-hydroxy-4S-(MC-Phe-H is-amino)- 3S-hydroxy-4S-C4-(4-pyridyL)-butyryL- Phe-His-amino)- 3S-hydroxy-4S-C6-ami no-hexanoyL-Phe-H is-amino)- 3S-hydroxy-4S-(4-dimethyLaminobutyryL-Phe-His-amino)- 3S-hydroxy-4S-(6-dimethyLaminohexanoyL-Phe-His-amino)- 3S-hydroxy-4S-(6-trimtethyLammoniumhexanoyL-Phe-Hisamino)-, formate.

Example 2.65 g of BOC-Phe-OH, 1.25 g of HOBt and a solution of 2.06 g of DCCI in 50 mL of methylene chloridle are added to a solution of 3.51 g of 3S-hydroxy-4S-(H-GLyamino)-6-methyL-heptane-suLfonic acid morphol ide (obtainable by condensation of BOC-GLy-OH with 3S-hydroxy- 4S-amino-6-methyL-heptane-suLfonic acid morphoLidle and f t subsequent splitting off of the BOC group with 4N HCL) in ml of methyLene chloridle, with stirring. The mixture is stirred at 2-60 for 14 hours, the dicycLohexyLurea 30 which-has precipitated is filtered off and the filtrate is evaporated and worked up in the customary manner to give 3S-hydroxy-4S-60C-Phe-gLy-arnino-6-methyL-heptanetuon acid tExample 5 from BOC-Phe--Abu-OH and 3S-hydroxy-4S-aminoacid morphoL ide.

32 The foLLowing 6-methyL-heptane--suLfonic acid morphoLides are obtained anaLogousLy: 3S-hydroxy-4S-BOC-Phe-Abu-am ino- 3S-hydroxy-4S-BOC-Phe-ALa-amino- 3S-hydroxy-4S-BOC-Phe- AL a-8m ino- 3 S- h >d ro xy -4 S-60 C-P h e -A sn -a mi no 3S-hydroxy-4S-BOC-Phe-G Ln-am ino- 3S-hydroxy-4S-BOC-Phe-GLy-amino- 3 S -h yd roaxy-4S-BOG -Ph e- Le u -am in 3S-hydroxy-4S-BOC-Phe-Met-ami no- 3S-hydroxy-4S-BOC-Phe-NLe-amino- 3S-hydroxy-4S-BOC-Phe-(3-Pyr)-amino-; the foLLowing 5-cycLohexyL-pentane-suLfoniC acid morpho- Lides are obtained anaLogousLy: 3S-hydroxy-4S-BOC-Phe-ALa-ami no- 3S-hydroxy--4S-BOC-Phe-SALa-amino- 3S-hydroxy-4S-BOC-Phe-Asn-ali no- 3S-hydroxy-4S-BQC-Phe-GLn-amino- 3S-hydroxy-4S-BOC-Phe-GLy-amino- 3S-hydroxy-4S-BOC-Phe-Leu-am ino- 3S-hydroxy-4S-BOC-Phe-Met-amfino- 253S-hydroxy-S-BOC-Phe-NLe-amino; the foLLowing iR-isopropyL- and lS-isopropyL-6-methyLacid morphoLides are obtained anaLogo u sL y -3S-hydroxy-4S-BOC-Phe-AbUj-amino- -3S-hydroxy-4S-BOC-Phe-ALa-amino- -3S-hydroxy-4S-BOC-Phe-aALa-amino- 2 30 -3S-hydroxy-4S-BOC-Phe-Asn-amino- .lit-3S-hydroxy-4S-BOC-Phe-GLfl-amino- -3S-hydroxy-4S-BOC-Phe-GLy-amino- -3S-hydroxy-4S-BOC-Phe-Leu-all o- -3S-hydroxy-4S-BOC-Phe-Met-amino- -3S-hydroxy-4S-BOC-Phe-NLe-ali no- -3S-hydroxy-4S-BOC-Phe-(3Pyr)amino-; and the foLlowing 1R-isopropyL- and hexyL-pentane-SULfoniC acid norphoLides are obtained 33 analogous Ly: -3S-hydroxy-4S-BOC-Phe-Abu-am ino- -3S-hydroxy-4S-BOC-Phe-ALa-amino- -3S-hydroxy-4S-BOC-Phe-5ALa-amino- -3S-hydroxy-4S-BOC-Phe-Asn-am ino- -3S-hydroxy-4S-BOC-Phe-GLn-am ino- -3S-hydroxy-4S-BOC-Phe-GLy-amino- -3S-hydroxy-4S-BOC-Phe-Leu-am ino- -3S-hydroxy-4S-BOC-Phe-Met-amino- -3S-hydroxy-4S-BOC-Phe-NLe-am ino- -3S-hydroxy-4S-BOC-Phe-(3-Pyr)-arnino-.

ExampLe 7 A solution of 677 mg of 1-phenyLthio-3S-hydroxyand 190 mg of 3-chLoroperbenzoic acid in 8 ml of chLoroform is Left to stand at 00 for 16 hours. Customary working up gives 1-phenyLsuLfinyL-3S-hydroxy-4S-BOC-Ph.o-His-amino-5-cycLohexyL-pentane.

ExampLe 8 1-PhenyLsuLfonyL-3S-hydroxy-4S-BOC-Phe-H is-aminois obtained anaLogously to Example 7 but with 440 mg of 3-chLoroperbenzoic acid.

ExampLe 9 A solution of 1 g of 3S-hydroxy-4S-80C-Phe-Hisamino-6-methyL-heptane-suLfonic acid morphoLidle in 20 ml of 4 N HCL in dlioxane 4S stirred at 200 for 30 minutes it and then evaporated. 3S-Hydroxy-4S-H-Phe-His-amino-6methyL-heptane-suLfonic acid morphoLidle is obtained.

The following compounds are obtained analogously from the corresponding BOG derivatives: 3S-hydroxy-4S-H-Phe-His-amino-5-cycLohexyL-pentanesuLfonic acid rorphoLide 4 ~1R-isopropyL-3S-hydroxy-4S-H-Phe-His-amino6methyLheptane-sulfonic acid morpholide is- isopropyL-3S-hydroxy-4S-H-Phe-H is-amino-6-methyLheptane-.sulfonic acid morpholide.

Example 1 g of '3S-hydroxy-4S-CBZ-Phe-GLy-amin-6-methyL- 34 heptane-suLfonic acid morphoLide is dissoLved in 10 mL of ethanoL and hydrogenated on 0.5 g of 10% Pd-C at 200 under 1 bar untiL the uptake of H 2 has ended, and the mixture is fiLtered and evaporated to give, after purification by chromatography, 3S-hydroxy-4S-H-Phe-Glyamino-6-methyL-heptane-suLfonic acid morphoLide.

ExampLe 11 a) 3-Oxo-4S-(BOC-Phe-GLy-amino)-5-cycLohexyLpentanesulfonic acid morphoLide is obtained anaLogousLy to Example 5 from BOC-Phe-GLy-OH and 3-oxo-4S-amino-5-cycLohexyLpentanoyL-suLfonic acid morphoLide (obtainable by oxidation of 3S-hydroxy-4S-BOC-amino-5-cycLohexyLpentane-suLfonic acid morpholide with Cr03/pyridine and spLitting off of the BOC group).

b) A soLution of 1 g of the above amide in 25 mL of

CH

3 0H is hydrogenated on 0.1 g of 10% Pd-C at 200 under 1 bar until the reaction stops. FiLtration and evaporation gives a mixture of 3R- and 3S-hydroxy-4S-(BOC-Pheacid morphoLide, which can be separated by chromatography.

ExampLe 12 mg of hydroxyLamine hydrochLoride are added to a solution of 636 mg of 3-oxo-4S-(BOC-Phe-GLy-amino)acid morpholide and 1.43 g of Na 2

CO

3 10 H 2 0 in 5 mL of methanol and 5 mL of water and the mixture is stirred at 200 for 14 hours.

The oxime which has precipitated 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 mixture is fil- 30 tered-and the filtrate is evaporated to give, after customary working up, a mixture of 3R- and 3S-amino-4Sacid a morpholide, which can be separated by chromatography.

C

i Example 13 Analogously to Example 1, the following cyclohexyl-pentane-sulfonic acid morpholides are obtained by cleavage of the correspunanii±- imi-DNP-His derivatives: 2S-isopropyl-4S-(2R, S-'oenzyl-4-oxo-5,5-dimethyl-hexanoyl- His-amino)-, m.p. 123-124 0 2S-isopropyl-4S- (l-napthylmethyl )-3-MC-propionyl-Hisamino]-, methanesulfonate, 2 epimers, m.p. 160-161 0 (dec.) and 176-177 0 (dec.) 2S-isopropyl-4S-bis-(l-naphthylmethyl)-acetyl-His-amino-, methanesulfonate, m.p. 166 0 (dec.) 2S-isopropyl-4S-(2-benzyl-3-tert. -butyl-sulfonyl-propionyl- His-amino)-, 2 epimers, m.p. 103 0 (methanesulfonate, m.p.

81 0) and 110 0 (methanesulfonate, m.p. 83 0 2 epimers, m.p. 120 0 (hydrochloride, m.p. 113-114 0) and 113 (hydrochloride, m.p. 116-117 0 4S-[2-(l-naphthylmethyl)-3-MC-propionyl-His-amino] 2 epimers, m.p. 120 0 (hydrochloride, m.p. 126-127 0) and 130 0(hydrochloride, m.p. 101-120 lR, S-methyl-4S-(2-benzyl-3-tert.-butylsulfonyl-propiony1- His-amino)-, 2 epimers, m.p. 104 0 (hydrochloride, m.p.

'tl135 0) and 123 o(hydrochloride, m.p. 150 0 (1Inaphthylmethy1 (N-3-dimethylaminopropyl-carbamoyl)-propionyl-His-amino]-, dihydrochloride, 2 epimers, m.p. 127-129 0 and 133-136 0 dinocarbonyl )-propionyl-His-amino] 4S-BOC-Mal-His-amino-, m.p. 153 *(dec.) -36- 43- 4 -BOC-amino-piperidinocarbony.PheHis..amino)- 43- 4 -BOC-amino-piperidinocarbony-MalHis-.amino) 1R, S-methyl-4S- (4-BOC-amino-piperidinocarbonyl-Phe-Hisamino) iR, S-methyl-4S-(4-BOC-amino-piperidinocarbony...Mal1Hisamino') iR, S-isopropyl-4S-(4-BOC-amino-piperidinocarbonyl-Phe- His-amino) iR, S-isopropy.-4S- (4-BOC-amino-piperidinocarbonyl-Mal- His-amino)- 4S-(2-BOC-amino-2-methyl-propionyl-Phe-His-anino)- 4S- (2-BOC-amino-2-methyl-propionyl-Mal-His-amino 1R, S-methyl-4S- (2-BOC-aw~tino-2-methyl-propionyl-Phe-Hisamino)iR, S-methyl-4S-(2-BOC-amino-2-methyl-propionyl-Mal-Hisamino)iR, S-isopropyl-4S- (2-BOC-amino-2-methyj.-propionyl-Phe- His-aim-ino) iR, S-isopropyl-4S- (2-BOC-amino-2-methyl-propionyl-Mal- His-amino)- 4S- (3-BOC-amino-3-methyl-butyryl-Phe-His-amino 4S- (3-BOC-amino-3-methyl-butyryl-Mal-His-amino iR, S-methyl-4S- (3-BOC-amino-3-methyl-butyryl-Phe-Hisamino),- 2P25 iR, S-w.ethyl-4S- (3-BOC-amino-3-methyl-butyryl-Mal-Hisamino tit R, S-isopropylL-4S- (3-BOC-amino-3-methyl-butyryl-Phe- His-amino)- R, S-isopropyl-4S-(3-BOC-amino-3-methyl-butyryl-Mal- His-amino)- 4S- (8-BOC-amino-octanoyl-Phe-His-amino) 43- (8-BOC-amino-octanoyl-Mal-His-amino) 9 37 1R, S-methyl-4S-(B-BOC-anino-octanoyL-Phe-His-amino 1R, S-methyl-4S-(8-BOC-amino-actanoyl-Mal-His-amino)iR, S-isopropyl-4S-(8-BOC-amino-octanoyl-Phe-His-aminio)- 1R, S-isopropyl-4S-(8-BOC-amino-octanoyl-Mal-His-amino)- 4S-[4-BOC-amino-piperidinocarbonyl-Phe-(2-Tia)-amino] 4S-[4-BOC-amino-piperidinocarbonyl-Mal-(2-Tia)-amino] iR, S-methyl-4S-[4-BOC-amino-piperidinocarbonyl-Phe- (2-Tia)-amino] iR, S-methyl-4S-[4-BOC-amino-piperidinocarbonyl-Mal- (2-Tia)-amino]- 1R, S-isopropyil-4S- [4-BOC-amino-piperidinocarbonyl-Phe- (2-Tia)-amino] iR, S-isopropyl-4S-[4-BOC-amino-piperidinocarbonyl-Mal- (2-Tia)-amino] as well as the following sulfonic acid N-butylamides: 4S-(2-benzyl-3.-tert.-butylsulfonyl-propiolyl-His-amilo)- 1R, S-methyl-4S-(2-benzyl-3-tert.-butylsulfonyl-propioflyl- His-amino)iR, S-isopropyl-4S-(2-benzyl-3-tert.-butylsulfolyl-propionyl-His-amino)- 4S-(2-benzyl-3'-MC-propionyl--His-amino)- VittiR, S-methyl-4S.-(2-benzyl-3MC-propionyl-His-amilo)- 1R, S-isopropyl-4S-(2-benzyl-3MC-propiolyl-His-amilo)- 4S- (3-BOC-amino-3-methyl-butyryl-Mal-His-amilo)- 1R, S-rethyl-4S- (3-BOC-amino-3-methyl-butyryl-Mal-His-amino iR, S-isopropyl-4S-(3-BOC-amilo-3-methyl-butyryl-M1al-His-.

amino)- 4S- (4-BOC-amino-piperidinocarbonyl-Mal-Hi-afiflo)iR, S-methyl-4S-(4-BOC-amilo-piperidil()%carboilyl-Mal-Hisamino)iR, S-i sopropyl-4S- (4-BOC-amino-piperidinocarbonyl-Mal- His-amino)- 38 Example 14 Analogously to Example 9, the following cyclohexyl-pentane-sulfonic acid morpholides are obtained from the corresponding BOG derivatives with 4 n HCl in dioxane: lR, S-methyl-4S- (l-naphthylmethyl (4-arinopiperidinocarbonyl )-propionyl-His-aminol dihydrochioride, 2 epimers, m.p. 158 0 and 167 4s- (4-amino-piperidinocarbonyl-Phe-His-amino 4S- (4-amino-piperidinocarbonyl-Mal-His-amino lR, S-methyl-4S-(4-ainino-piperidinocarbonyl-Phe-His-amino)- 1R, S-methyl-4S-(4-amino-piperidinocarbonyl-Mal-His-amino)iR, S-isopropyl-4S- (4-amino-piperidinocarbonyl-Phe-His-amilo lR, S-isopropyl-4S-(4-amino-piperidinocarbonyl-Mal-His-anino)- 4S-(2-amino-2-methyl-propionyl-Phe-His-anino)- 4S- (2-amino-2-methyl-propionyl-Mal-His-amino lR, S-methyl-4S-(2-amino-2-methyl-propionyl-Phe-His-amino)iR, S-methyl-4S- (2-arino-2-methyl-propionyl-Mal-His-anino 1R, S-isopropyl-4S-(2-amino-2-methyl-propionyl-Phe-His-amilo)- 1R, S-isopropyl-4S-(2-amino-2-methyl-propionyl-Mal-His-amino)- 4S- (3-axino-4-methyl-butyryl-Phe-His-amino) 4S-(3-amino-4-methyl-butyryl-Mal-His-amino)iR, S-methyl-4S-(3-amino-3-methyl-butyryl-Phe-Hi-amino iR, S-methyl-4S- (3-axnino-3-methyl-butyryl-Ma-is-amfino)- 1R, S-isopropyl-4S-(3-amino-3-methy1-butyry-Phe-Hisamino)iR, S-isopropyl-4S- (3-amino-3-methyl-butyryl-Mal-His-amino 4S- (8-arninooctanoyl -Phe-His-amino 4S- -aminooctanoyl-Mal-HiS;-amino iR, S-methyl-4S-(8-aminooctanoyl-Phe-HiS-amino)iR, S-methyl-4S-(8-aminooctanoyl-Mal-His-amino)iR, S-isopropyl-4S- (8-aminooctanoyl-Phe-His-amilo)iR, S-isopropyl-4S- (8-aminooctanoyl-Mal-His-amilo)- -39 4S-[4-amino-piperidinocarbonyl-Phe-(2-Tia)-aminol 4S-114-amino-piperidinocarbonyl--Mal-(2-Tia)-amino] 1R, S-methyl-4S-[4-amino-piperidinocarbonyl-Phe-(2-Tia)amino] 1R, S-methyl-4S-[4--amino-piperidinocarbonyl-Mal-(2-Tia)amino] iR, S-isopropyl-4S-[4-amino-piperidinocarbonyl-Phe-(2-Tia)amino] lR, S-isopropyl-4S-[4-amino-piperidinocarbonyl-Mal-(2-Tia)amino]as well as the following sulfonic acid N-butylamides: 4S- (3-amino-3-methyl-butyryl-Mal-His-amino iR, S-methyl--4S-(3-amino-3-methyl-butyryl-Mal-His-amilo)iR, S-isoprdpyl-4S-(3-amino-3-methyl-butyryl-Mal-Hi-ailo)- 4S- (4-amino-piperidinocarbonyl-Mal-His-amino) iR, S-methyl-4S- (4-amino-piperidinocarbonyl-Mal-His-amino lR, S-isopropyl-4S-(4-amino-piperidinocarbonyl-Mal-HiS-amino)-.

The following examples relate to the pharmaceutical formulations.

Example A: Tablets A mixture of 1 kg of lR,S-methyl-3S-hydroxy-4S-i2-(lnaphthylmethyl )-3-(4-aminopiperidinocarbonyl )-propionyl- His-amino] -5-cyclohexyl-pentane-sulfonic acid morpholide dihydrochloride 167 4 kg of lactose, 1.2 kg of potato starch, 200 g of talc and 100 g of magnesium stearate are granulated in a customary manner and then compressed into tablets, so that each tablet contains mg of active compound.

40 Example B: Coated tablets Tablets are compressed analogously to Example A and are then coated in a customary manner with a coating consisting of sucrose, potato starch, talc, tragacanth, colorant and vanilla aroma.

Example C: Capsules 1 kg of 1R,S-methyl-3S-hydroxy-4S-(2-benzyl-3-tert.sulfonic acid morpholide hydrochloride 150 0) are filled in a customary manner into hard gelatine capsules so that each capsule contains 100 mg of active compound.

Example D Injection bottles SA solution of 100 g of 3S-hydroxy-4S-BOC-Phe-His- 0 0 0 0 .0 amino-5-cycLohexyL-pentane-sulfonic acid morpholide and NO

O

5 g of disodium hydrogen phosphate in 3 L of doubLydistilled water is brought to pH 6.5 with 2 N hydroqo0° chloric acid, subjected to sterile filtration, introduced o, into injection bottles, lyophilized under sterile conditions and sealed under sterile conditions. Each injeco 20 tion bottle contains 500 mg of active compound.

Example E: Suppositories A mixture of 50 g of 3S-hydroxy-4S-BOC-Phe-His- Y amino-6-methyl-heptane-sulfonic acid morpholide is melted o. with 10 g of soya Lecithin and 140 g of cocoa butter and 25 the mixture is poured into moulds and allowed to cool.

Each suppository contains 500 mg of active compound.

Claims (3)

1. Amino acid derivatives of the formula I 3 4 5 (H6n X-Z-NR -CHR -CR5(CHR6)n-E I wherein 1 1 X is H, R -0-C H R -C H -0-CO-, 1 m2m 1 m m R -CH R -SO (R -CH 2 m)- L(R -CH)-C H 2r-CO-, 1 pC 2 p) r 2r R -(NHCH 2 CH 2 NH-CH 2 CO-, 9-fluorenyl- CR 1 CH 2m-O-CO-,[R -CH 2 V-- CH 2t -L(R 2 -CH )-CH 2 r CO- or A3N -CH 2 m-CO- An Z is 1 to 4 amino acid radicals bonded to one another in peptide form and selected from the group consisting of Abu, Ada, Ala, B-Ala, Arg, Asn, Asp, Bia, Cal, Dab, Ftr, Gln, Glu, Gly, His, Hph, N(im)-A-His, Ile, Leu, tert.-Leu, Lys, Met, c>Nal, BNal, Nbg, Nle, Nva, Orn, Phe, Pro, Pyr, Ser, Thr, Tia, Tic, Trp, Tyr, O-A-Tyr and Val, E is S0 2 -morpholino, SO2-pyrrolidino, SO2 piperidino, SO 2 -piperazino, S0 2 -NHA, SO2-NA2 or SO2-NA-aralkyl wherein aralkyl is a hydrocarbon aralkyl of 7 to 11 C atoms, 1, R2 4 and R are each H, A, Ar, Ar-alkyl, Het, Het-alkyl or cycloalkyl with 3-7 C atoms, cycloalkylalkyl with

4-11 C atoms, bicycloalkyl or tricycloalkyl with in each case 7-14 C atoms or bicycloalkylalkyl or tricycloalkylalkyl with in each case 8-18 C atoms, in each case unsubstituted or mono- or polysubstituted by A, AO and/or Hal, R is H or A, 5 R is in each case OH), NH 2 or =0, 6 R is H, A or alkenyl with 2-8 C atoms, m, p, r and t are each 0, 1, 2, 3, 4 or n is 1 or 2 x is 0 or 1, L is CH or N, T is 0 or NH, V is CO or SO An is one equivalent of an anion, yrs 42 Ar is phenyl which is unsubstituted or mono- or polysubstituted by A, AO, Hat, CF 3 HO, hydroxyalkyl with 1-8 C atoms, H 2 N and/or aminoalkyL with 1-8 C atoms, or unsubstituted naphthyL, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical which has 1-4 N, 0 and/or S atoms, can be fused with a benzene ring and/ or can be mono- or polysubstituted by A, AO, Hat, CF 3 HO, 0 2 N, carbony oxygen, H 2 N, HAN, A-N, AcNH, AS, ASO, ASO 2 AOOC, CN, H 2 NCO, H 2 NSO 2 ASO 2 NH, Ar, Ar-alkenyl, hydroxyalkyl and/or aminoalkyl with in each case 1-8 C atoms and/or the N and/or S hetero atoms of which can also be oxidized, Hal is F, CL, Br or I, Ac is A-CO-, Ar-CO- or A-NH-CO- and A is alkyl with 1-8 C atoms, and wherein furthermore one or more -NH-CO- groups can also be replaced by one or more -NA-CO- groups, and salts thereof. 2. a) 3S-Hydroxy-4S-BOC-Phe-His-amino-6-methy-heptane- sulfonic acid morpholide; b) 3S-Hydroxy-4S-Cbis-(1-naphthylmethy)-acetyL-His]- amino-6-methyl-heptane-sulfonic acid morpholide; c) 1R-IsopropyL-3S-hydroxy-4S-BOC-Phe-His-amino-5- cyclohexyL-pentane-sulfonic acid morpholide; d) 1S-Isopropyl-3S-hydroxy-4S-BOC-Phe-His-amino-5- cycLohexyl-pentane-sulfonic acid morpholide. 3. -Process for the preparation of an amino acid derivative of the formula I and of its salts, character- ized in that it is liberated from one of its functional derivatives by treatment with a soLvolyzing or hydrogeno- lyzing agent, or in that a carboxylic acid of the formula t a t t I lilA I At t* 4 A l X-G -OH v"" G /lci (i 43 wherein G is -Z or and X has the meaning given, or one of its reactive derivatives is reacted with a compound of the formula III H-G 2 III wherein G is -Z 2 -NR -CHR -CR -(CHR6 n-E or -NR3-CHR4-CR5-(CHR 6 )n-E, Z Z together are Z and 3 4 5 6 R R R R n and E have the meanings given, or one of its reactive derivatives, and/or in that, if appropriate, in a compound of. the formula 1, a functionaLLy modified amino and/or hydroxyl group is Liberated by treatment with solvolyzing or hydrogenolyzing agents, and/or a keto group is reduced to a CHOH group or aminated reductively to a CH(NH 2 group and/or a compound of the formula I is converted into one of its salts by treatment with an acid. 4. Process for the preparation of pharmaceutical for- mulations, characterized in that a compound of the S* formuLa I and/or one of its physiologically acceptable salts is brought into a suitable dosage form together with at Least one solid, liquid or semi-Liquid excipient .r or auxiliary and if appropriate in combination with one I* or more other active compound(s). Pharmaceutical formulation, characterized in that it contains at Least one compound of the formula I and/or one of its physiologically acceptable salts.

6. Use of compounds of the formula I or of physio- LogicaLLy acceptable s ts thereof for the preparation of a medicament. A f 43 j7. Use of compounds of the formula I or of physio- Logically acceptabLe saLts thereof in combating renin- related hypertension or hyperaldosteronism. DATED this 19th day of June 1991. MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER By Its Patent Attorneys, ARTHUR S. CAVE CO. it t E M[V