AU614951B2

AU614951B2 - Amino acid derivatives

Info

Publication number: AU614951B2
Application number: AU12617/88A
Authority: AU
Inventors: Joachim Gante; Klaus Otto Minck; Peter Raddatz; Claus J. Schmitges; Johannes Sombroek
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1987-03-12
Filing date: 1988-03-01
Publication date: 1991-09-19
Anticipated expiration: 2008-03-01
Also published as: EP0286813A3; HU204848B; EP0286813A2; JPS63258451A; AU1261788A; DE3721855A1; KR880011196A; HUT49147A

Description

The Commissioner of Patents ARTHUR S. CAVE CO.

PATENT AND TRADE MARK ATTORNEYS

SYDNEY

A,:erciK raienT u lpenualnIaI mit beschrankter Hafting ir nf Si nature of Declarant(s) Pnamam r.e oumanM

I

I: i

AUSTRALIA

PATENTS ACT 1952 614951 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: fo Actual Inventor: Address for Service: t MERCK PATENT Gesellschaft beschrankter Haftung mit Frankfurter Strasse 250, D-6100 Darmstadt, Federal Republic of Germany 1. Dr Joachim GANTE 2. Dr Peter RADDATZ 3. Dr Johannes SOMBROEK 4. Dr Claus- J SCHMITGES Dr Klaus Otto MINCK ARTHUR S. CAVE CO.

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

AUSTRALIA

Complete Specification for the invention entitled AMINO ACID

DERIVATIVES.

The following statement is a full description of this invention including the best method of performing it known to me:- 1 ASC 49 V -la- Merck PatentGesellschaft mit beschr~nkter Haftung 6100D a r ms t ad t Amino acid derivatives The invention relates to new amino acid derivatives of the formula I

X-Z-N

2

_CHR

3 _C 4 -(CHR 5 l-CO-E-NR 6 _D I X is H, R -0-C H-CO-, R' C H -OC~ R M2m' o-o 2m 0 0 1-CH 2

-CO-

1 or 7 r-LRCPH2)CtHtC_ Z is 0 to 4 amino acid radicals attached to one another by a peptidle Linkage and selected from *the group consisting of Abu, Ada, Ala, OALa, Arg, Asn, *Asp, Bia, Cal, Dab, G~n, GLu, GLy, His, N(im)-aLkyL- His, ILe, Leu, tert.-Leu, Lys, Met, ctNaL, BNaL, Nbg, N Le Orn, Phe, Pro, Ser, Thr, Tic, Trp, Tyr and VaL, 0:E is 0 to 2 amino acid radicals attached to one ano- 0ther by a peptidle Linkage and selected from the group consisting of Abu, Ala, Cal, His, Ie,.Leu, Met, N~e, Phe, Trp, Tyr and VaL, 0 20 u is -CH2-CHOH-LI120H, -LCfl2z-SU2-Rl, a phenyL- 800CH 2 furyL-C H 2 thienyL-CyH 2 y- or pyri- 0 08 dyLVCyH2y- radlical which is substituted by one or 0 8two R 14_S2 groups or an R l4C group or an

(R

14 2 -PO- group and, if appropriate, additionaLLy by an Hal atom, or 0 is i A kl.' 2

R

13

-CHR

8 R9-- O R 10

R

3

R

7 and R 8 are each H, A, Ar, Ar-aLkyL, Het, Het-aLkyL or cycLoaLkyL having 3-7 C atoms, cycloalkylalkyl having 4-11 C atoms, bicycloaLkyL or tricycloalkyl having in each case 7-14 C atoms or bicycLoaLkyLaLkyl or tricycLoaLkylaLkyL having in each case 8-18 C atoms, each of which is unsubsti- ;tuted or monosubstituted or poLysubstituted by A, AO and/or Hal,

R

2

R

5 and R 6 are each H or A,

R

4 is OH), NH 2 or =0,

R

9 is H, NH 2 NHA or NA 2

R

1 0

R

1 1

R

12 and R 13 are each H, HaL, OH, OA, NH 2

SH,

SA, S02NH 2

CF

3 CN, COOH or COOA, 15 R 1 4 is OH, OA, NH 2 NHA, NA 2 NHcycloalkyl having S3-7 C atoms, N(cycloalkyl)2 having 6-14 C atoms, pyrrolidino, piperidino, hexahydroazepino, morpho- Slino, thiomorpholino, piperazino, N-A-piperazino, SNHAr or NHHet, y 20 L is CH or N, S.T is 0, S, NH or NA, n is 1 or 2, m, p, r and t are each 0, 1, 2, 3, 4 or x is 0 or 1, 25 y is 0, 1 or 2, z is 2, 3, 4, 5 or 6, Ar is phenyl which is unsubstituted or monosubstituted S" or polysubstituted by A, AO, Hal, CF 3 OH, H 2

NSO

2 and/or NH 2 or unsubstituted naphthyL, Het is a saturated or unsaturated 5-membered or 6-membered heterocyclic radical which has 1-4 N, 0 and/or S atoms, which can be condensed with a-benzene ring I t 3 and/or can be monosubstituted or polysubstituted by A, AO, Hal, CF 3 HO, 02N, carbonyl oxygen,

H

2 N, HAN, A 2 N, AcNH, AS, ASO, AS02, HOOC, AOOC, CN, H 2 NCO, H 2

NSO

2

ASO

2 NH, Ar or Ar-aLkenyl, hydroxyalkyl and/or aminoalkyL having in each case 1-8 C atoms, and/or in which the N and/or S heteroatoms can also be oxidized, Hal is F, CL, Br or I, Ac is A-CO-, Ar-CO- or A-NH-CO-, -alkyl- is an alkylene group having 1-4 C atoms and A is alkyl having 1-8 C atoms, and wherein it is also possible for one or more -NA-COgroups to replace one or more -NH-CO- groups, and to salts thereof.

Similar compounds are known from EP-A-77,028.

The invention was based on the object of finding new compounds having valuable properties, especially compounds which can be used for the preparation of medicaments.

It has been found that the compounds of the formula 20 I and their salts possess very valuable properties. Above all, they inhibit the activity of human plasma renin. This effect can be demonstrated, for example, by the method of F. Fyhrquist et al., Clin. Chem. 22, 250-256 (1976). It is remarkable that these compounds are very specific inhibitors 25 of renin; as a rule substantially higher concentrations of Sthese compounds are necessary for the inhibition of other aspartylproteinases (for example pepsin and cathepsin D).

The compounds can be employed as active compounds for medicaments in human and veterinary medicine, especially i 30 for the prophylaxis and treatment of cardiac, circulatory and vascular diseases, above all hypertension, cardiac insufficiency and hyperaldosteronism. In addition, the compounds can be used for diagnostic purposes in order to determine, in the case of patients with hypertension or hyperaldosteronism, the possible contribution made by the renin activity towards maintaining the pathological state.

The abbreviations of amino acid radicals listed above and below represent the radicals as a I. -4ruLe -NH-CHR-CO-, (wherein R, R' and R" have the specific meaning known for each amino acid) of the foLLowing amino ac ids: Abu 2-aminobutyric acid Ada 3-adamantyLaLanine ALa aLanine aALa $-aLanine Arg arginine Asn asparagine Asp aspartic acid Bia 3-(Z-benz imidazoLyL )-aLanine Cal 3-cyc LohexyLaL anime Dab 2,4-dliaminobutyric acid G~n gLutamine GLu gLutamic acid GLy gLycine His histidine N( im)-aLkyL-H is histidline which is substituted by A in the 1-posi- 20 tion or 3-position of the imidlazoLe ring I e isoLeucine Leu Le uc in e tert.-Leu tert.-Leucine Lys L y s ine S 25 Met methionine ctNaL ot-naphthyLaLanine NaL B-naphthyiaLanine Nbg C2-norbornyL)-gLycine N Le norLeucine N-Me-His N-methyLhistidine N-Me-Phe N-methyLphenyL alanine Orn ornithine Phe phenyLaLanine CPro proLine Ser serine Thr threonine Tic tetrahydroisoquinoLine-1-carboxyLic acid Trp tryptophane Tyr tyrosine, VaL 5 vaLine.

The abbreviations beLow also have the foLLowing 9* 9

*L

4 I I 9 te., meanings: BOC tert.-butoxycarbonyL imi-BOM benzyLoxymethyl in the 1-position of the imidazole ring CBZ benzyLoxycarbonyl DNP 2,4-dinitrophenyl imi-DNP 2,4-dinitrophenyL in the 1-position of the imidazoLe ring ETNC N-ethylcarbamoyl ETOC ethoxycarbonyl FMOC 9-fluorenylmethoxycarbonyl IPNC N-isopropylcarbamoyl IPOC isopropoxycarbonyL MC morpholinocarbonyL OMe methyL ester OEt ethyL ester PBB 4-phenyL-2-benzyLbutyryl POA phenoxyacetyL DCCI dicyclohexylcarbodiimide HOBt 1-hydroxybenzotriazoLe.

Insofar as the amino acids mentioned above can exist in several enantiomeric forms, all these forms and also mixtures thereof (for example the DL-forms) are included in the above and following text, for example as a constituent of the compounds of the formula I. The L-forms are preferred. Where individual compounds are listed in the following text, the abbreviations of these amino acids relate in each case to the L-form, unless anything to the contrary is expressly indicated.

The invention also relates to a process for the preparation of an amino acid derivative of the formula I and salts thereof, characterized in that it is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent, or in that a carboxylic acid of the formula II X-G OH f '0104d/NNG 1 1 6 wherein G is Z

Z,

Z-W,

Z-W-E

1 Z-W-E and 2 3 4 5 W is -NR -CHR -CR -(CHR5) -COis reacted with an amino compound of the formula III

H-G

2

III

wherein G 2 is -Z2-W-E-NR -D, -W-E-NR -D, -E-NR -D, 2 6 -E -NR -D, -NR -D, 1 2 E and E are each one amino acid radical selected from the group conisting of Abu, Ala, Cal, His, Ile, Leu, Met, Nle, Phe, Trp, Tyr and Val in such a manner that E

E

2 together are E, 1 2 Z and Z are each 1 to 3 amino acid radicals selected from the group consisting of Abu, Ada, Ala, BAla, "Arg, Asn, Asp, Bia, Cal, Dab, Gln, Glu, Gly, His N(im)- *:~aikyl-His, Ile, Leu, tert -Leu, Lys, Met, aNal, BNal, Nbg, S.Ne, Orn, Phe, Pro, Ser, Thr, Tic, Trp, Tyr and Val in such .1 2 .*a:manner that Z Z together are Z, and in that, if apropriate, a functionally modified amino and/or hydroxyl group in a compound of the formula I is liberated by treatment with solvolysing or hydrogenolysing agents and/or, *ii order to prepare a compound of the Formula I wherein R OH) or NH an aminoketo acid derivative of the formula I wherein R 0 is reduced or reductively "aminated and/or a radical D is converted into another radical D by treatment with esterifying, solvolysing or .educing agents and/or a compound of the formula I is converted into one of its salts by treatment with an acid.

In the preceding and following text, the radicals or 1 14 parameters X, Z, E, D, R to R L, T, m, n, p, r, t, 1 2 1 2 1 x, y, z, Ar, Het, Hal, Ac, A, G G 2 E E Z, 2

Z

2 and W have the meanings indicated in the formulae I, II or III, unless anything to the contrary is expressly indicated.

OlO4a/NN'G -6a In the formulae above, A has 1 8, preferably 1, 2, 3 or 4, C atoms. A is preferably methyl and also ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl, and also pentyl, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 3or c t -7- 4-methyLpentyL, 2,3- or 3,3-dimethyLbutyL, 1-ethyLbutyL, 2-ethyLbutyL, 1-ethyL-1-methyLpropyL, 1-ethyL-2-methyLpropyL, 1, 1,2-trimethyLpropyL, 1,2,2-tnimethyLpropyL, heptyl or octyL.

CycLoaLkyL is preferably cycLopropyL, cycLobutyL, cycLopentyL, cycLohexyL. or cycLoheptyL, but is also, for example, 2- or 3-methyLcycLopentyL or 3- or 4methyLcycLohexyL.

AccordingLy, cycLoaLkyLaLkyL is preferably cycLopropyLmethyL, 2-cycLopropyLethyL, cycLobutyLmethyL, 2cyc LobutyLethyL, cycLopentyLmethyL, 2-cyc LopentyLethyL, cycLohexyLmethyl or 2-cycLohexyLethyL, but is also, for ex- I ample, 2- or 3-methyLcycLopentyLmethyL or 3- or 4-methyL cycLohexyLmethyL.

BicycLoaLkyL is preferably 1-decaLyL, 2-decaLyL, 2-bicycLo[2,2, 1]heptyL or 6,6-dirnethyL-2-bicycLoE3,1, lihept y L.

Tricycloalkyl is preferably 1-adarnantyL.

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

Ac is preferably A-CO-, such as acetyL, prop ionyL or butyryL, Ar-CO-, such as benzoyL, m- or p-rnethoxy- :9 benzoyL or 3,4-dimethoxybenzoyL, or A-NH-CO-, such as N- Ar i orfray N-e hcarand also preferably mor p-toLyL, rn- or p-ethyLphenyL, mn- or p-rnethoxyphenyL, m- or p-fLuorophenyL, mn- or p-chLorophenyL, mn- or p-brornophenyL, m- or p-iodophenyL, m- or p-trifLuoromethyLphenyL, mn- or p-hydroxyphenyL, mor p-suLfarnoyLphenyL, 3,4- or dl*imethoxyphenyL, 3,4,5-trimethoxyphenyL, m- or p-aminoo phenyL, 1-naphthyL or 2-naphthyL.

Accordingly, Ar-aLkyL is preferably benzyL, 1phenyLethyL, 2-phenyLethyL, r-or p-methyLbenzyL, 1-o-, -in- or -p-toLyLethyL, -in- or -p-toLyLethyL, mor p-ethyLbenzyL, -in- or -p-ethyLphenyLethyL, 2-o-, -in- or -p-ethyLphenyLethyL, r-or p-methoxybenzyL, 1-o-, -in- or -p-iethoxyphenyLethyL, -in- or -p-methoxyphenyLethyL, r-or p-fLuorobenzyL, -in- or -p-fLuoro-

I

0@ o oQ~ 0060.0 0 0 0 00 00 6 6000 *0 0 66 6 000066 6 6 4 p 06 00 6 o 6,, 0 06 6 66 6 0 6 6 -8 phenyLethyL, -in- or -p-fLuorophenyLethyL, in- or p-chLorobenzyL, -in- or -p-chLorophenyLethyL, 2-o-, -in- or -p-chLorophenyLethyL, mn- or p-broinobenzyL, 1-o-, -mn- or -p;-broinophenylethyl, -in- or -p-broinophenylethyl, mn- or p-iodobenzyl, -mn- or -p-iodophenyLethyL, -mn- or -p-iodophenylethyl, in- or p-tnifLuoroinethyLbenzyL, in- or p-hydroxybenzyl, 2,4-, 3,4- or 3,5-diinethoxybenzyL, 3,4,5-triinethoxybenzyL, in- or p-aininobenzyL, 1-naphthyLinethyL or 2-naphthyLinethyl.

Het is preferably 2-furyL, 3-furyL, 2-thienyL, 3thienyL, 2- or 3-pyrryL, 4- or 5-iinidazoLyL, 1-, 4- or 5-pyrazoLyL, 4- or 5-oxazoliyL, 4- or isoxazoLyL, 4- or 5-thiazoLyL, 4- or 3- or 4-pyridyL or 5- or 6-pyriinidyL, aind is.

also preferably 1,2,3-triazoL-1-yL, -4-yL or -5-yL, 1,2,4triazoL-1-yL, -3-yL or -5-yL, 1-tetrazoLyl, 1 ,2,3-oxadiazoL-4-yL, 1,2,3-oxadiazoL-5-yL, 1,2,4-oxadiazoL- 3-yL, 1,2,4-oxadiazoL-5-yL, 1,3,4-thiadi azoL-2-yL, 1,3,4- 20 th iadiazoL-5-yL, 1,2,4-thiadiazoL-3-yL, 1,2,4-thiadiazoL-5yL, 2,1,5-thiadiazot-3-yL, 2,1,5-thiadiazoL-4-yL, 3-, 5- or 6-2H-thiopyranyL, 3- or 4-4H-thiopyranyL, 3pyridazinyl, 4-pyridazinyL, pyrazinyL, 6or 7-benzofuryL, 6- or 7-benzothienyL, 1-, 25 6- or 7-indoLyL, 6- or 7-isoindoLyL, 4- or 5-benzimidazoLyL, 4-, 6- or 7-benzopyrazoLyL, 6- or 7-benzoxazoLyL, 6- or 7-benzisoxazoLyL, 6- or 7benzthiazoLyL, 6- or 7-benzisothiazoLyL, 4-, 30 6- or 7-benz-2,1,3-oxadiazotyL, 7or 8-quinoLyL, 7- or 8-isoquinoLyL, 1-, 4- or 9-carbazoLyL, 8or 9-acridinyL, 7- or 8-cinnoLyL, 4-, 7- or 8-quinazoLyl. The heterocycLic radicals can also be partLy or completely hydrogenated. Het can, therefore, also be, for example: 2,3-dihydro-2-, or furyl, 2,5-dihydro-2-, or 5-fury-L, tetrahydro-2furyL, tetrahydro-3-furyL, tetrahydro-2-th jenyl, tetrahydro- -9- 3-thienyL, 2,3-dihydro-1-, or -5-pyrryL, dihydro-1-, or -5-pyrryL, 2- or 3-pyrroLidinyL, tetrahydro-1-, or -4-imidazoLyL, 2,3-dihydro-1-, or -5-pyrazotyL, 2,5-dihydro-l-, or 5-pyrazoLyL, tetrahydro-1-, or -4-pyrazoLyL, 1,4-dihydro-l-, or -4-pyridyL, 1,2,3,4-tetrahydroor -6-pyridyL, 1,2,3,6-tetrahydro-1-, or -6-pyridyL, 3- or 4-piperidinyL, 3- or 4-morphoLinyL, tetrahydro-2-, or -4pyranyL, 1,4-dioxanyL, 1,3-dioxan-2-, or -5-yL, hexahydro-l-, or -4-pyridazinyL, hexahydro-l-, or 2- or 3-piperazinyL, 1,2,3,4-tetrahydroor -8-quinoLyL, 1,2,3,4tetrahydro-i-, or 8-isoquinoLyL.

The heterocycLic. radicaLs can aLso be substituted as indicated. Het can, therefore, preferabLy aLso be: 2amino-4-thiazoLyL, 4-carboxy-2-th iazoLy L, 4-carbamoy L-2thiazoLyt, 4-(2-aminoethyL )-2-thiazoLyL, 2-amino-5,6-dimethyL-3-pyrazinyt or 4-carbamoyLpiperidino, and aLso, for 20 exampLe, 4- or 5-methyL-2-furyL, 4- or 5-methyL-3furyL, 2,4-dimethyL-3-furyL, 5-nitro-2-furyL, 5-styryL-2furyL, 4- or 5-methyL-2-thienyL, 4- or 5-methyL-3thienyL, 3-methyL-5-tert.-butyL-2-thienyL, 5-chLoro-2-thienyL, 5-phenyL-2- or -3-thienyt, 4- or 5-methyL-2pyrryL, 1-methyL-4-nitro-2-pyrryL, 1-methyL-5-nitro-2pyrryL, 3,5-dimethyL-4-ethyL-2-pyrryL, 4-methyL-5-pyrazoLy 1, 5-methyL-3-isoxazoLyL, 3,4-dimethyt-5-isoxazotyL, 4-methyL- 2-thiazoLyL, 5-methyL-2-thiazoLyk, 2-methyL-4-th iazotyL, a 645-methyL-4-thiazoLyL, 2-rethyt-5-thiazoLyL, 30 azoLyL, 2,4-dimethyt-5-thiazoLyL, 5- 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 a 6-chLoro-3-pyridyL, 2-chLoro-4-pyridyL, 3-chLoro-4-pyr idyL, 2,6-dichioropyridyL, 2-hydroxy-3-, or -6-pyridyL C=1H-2-pyridon-3-, or 5-phenyL-lH-2-pyriv idon-3-yL, 5-p-methoxyphenyL-1H-2-pyr idon-3-yL, 2-rnethyL-3hydroxy-4-hydroxymethyL-S-pyr idyL, 2-hydroxy-4-arnino-6methyL-3-pyridyL, 3-N'-rnethyLureido-1H-4-pyr idon-5-yL, 4rnethyL-a--pyrirnidyL, 4,6-dimethyL-2-pyrimidyL, 5- or 6methyl-4+--pyrimidyL, 2,6-dirnethyL-4-pyr imidyL, 2,6-di hydroxy- 4-pyrimic-yl, 5--chLoro-2-methyL-4-pyrimidyL, 2-methyL-4- 3-methyL-2-benzofuryL, 2-eti yL-3-benzofuryl, 7-inmethyL-2-benzothienyL, 6- or 7methyL-3-indotyL, 1-methyl-5- or -6-benzimidazoLyL, 1-ethyl- 1-ethyL-6-benzimidazoLyLan3- 7- or 8-hydroxy-2-quinoLyL.

Rand R 7 are preferably A, espacia~Ly methyl, ethyl, propyL, isopropyl, butyl, isobutyL or tert.-butyL, and aLso, preferably, cyclopropyL, cycLopentyL, cycLohexyL, phenyl, benzyL, pyrroLidino, piperidino or morphoLino.

F2, R 5and R6 are preferably H or methyl, and also ethyl, pr'opyL, isopropyL, butyL or isobutyL.

3 R is preferably cycLohexyLmethyL, and also preferably A, especially meth)., ethyl, propyL, isopropyL, butyL, isobutyL, sec.-butyL, pentyL, isopentyL (3-methyLbutyL) or 2-methyLbutyL, phenyL, benzyL, p-chLorobenzyL, 2-cycLohexyLethyL, bi cycLoE2,2, ljheptyL-2-methyL or 6,6- 20 dimethyLbicycLo[3,1,1]!ieptyL-2-methyL.

Ris preferably OH).

R

8 is preferably isopropyL, isobutyL, sec.-butyL or benzyL, and also preferably H, methyl, ethyl, propyL, butyL or cycLohexyLmethyL.

R9is preferably H or NH 2 R and R 13are preferably H.

R is preferably H or SO 2

NH

2 R is preferably H or CL.

444 R is preferably NH 2

NHCH

3 or N(CH 3 2 and also preferably 2-thiazoLyLamino, 3-isoxazoLyLamino, 4 3-isoxazoLyLamino,3,4-dimethyL-5-isoxazoyLamilo, 2-pyrimidyLamino, 4-methyL-2-pyrimidytamino, 4,6-dimethyL-2-pyrim idybamino or 2,6-dimet'iyL-4-pyrimidyLamino.

6* L is preferably CH.

T is preferably 0 or S.

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

V

X is preferably H, POA, aLkoxycarbonyL, such as ETOC, IPOC or 60C, CBZ, aLkanoyL, such as acetyL, propionyL, butyryL or isobutyryL, cycLoaLkyLcarbonyL, such as cycLopentyLcarbonyL or cycLohexyLcarbonyL, aroyL, such as benzoyL, aryLaLkanoyL, such as phenyLacetyL, 2-phenyLpropionyL, 3-phenyLprop jonyL, 4-phenyLbutyryL, 2-benzyL-3-phenyLpropionyL, PB6, 2-(2-phenyLet.hyL )-4-phenyLbutyryL, 2-(2-naphthyLmethyL)-4--phenyLbutyryL, -mn- or -p-fLuorophenyLpr DpionyL, -mn- or -p-fLuorophenyLpropionyL, -mnor -p-chLorophenyLpropionyL, or -mn- or -p-chLorophenyLpropionyL, or cycLoaLkyLaLkanoyL, such as cycLohexyLacetyL, 2-cycLohexyLpropionyL or 3-cycLohexyipropionyL, or N-aLkyLcarbamoyL, such as ETNC or IPNC or MC. RadlicaLs X which are particuLarLy preferred are BOC and MC, and aLso ETOC, IPOC, ETNC, IPNC and P86, and also H, POA, 4-phenyLbutyryL, 2-benzyL-3-phenyLprop ionyL, 2-C2-phenyLethyL )-4-phenyLbutyryl, 2-(2-naphthiyLmethyL)-4-phenyLbutyryL and C8Z. A further group of particularly preferred radicaLs X corresponds to the formuLa R0- CH(CH 2

C

6

H

5 wherein R 0is pyrrolidlino, piperidlino, morpholino, aLkyL, aLkoxy or alkylthio each of which has 1-8 C atoms.

Z is preferably 2, but also 0 or 1 and also 3 or 4, amino acid radicals which are attached to one another by a peptidle Linkage, in particular one of the groups GLy, His, S 25 Phe-GLy, Phe-His, Pro-Phe-His or His-Pro-Phe-His, and also preferably one of the groups Abu, Ada, Asn, Bia, Cal, G~n, N-(im)-methyL-His, Leu, aNal, BNaL, N~e, Phe, Trp, Tyr, Abu-His, Ada-His, Ala-His, ALa-Phe, Arg-His, Asn-His, Bia- 0 4 4 His, Cal-His, Dab-His, GLu-His, GLy-His, His-His, Lie-His, Leu-His, tert.-Leu-His, Lys-His, Met-His, aNal-His, $NaL- His, Nbg-His, N~e-His, (N-Me-His)-His, (N-Me-Phe)-His, Orn- His, Phe-Abu, Phe-Ada, Phe-ALa, Phe-Arg, Phe-Asn, Phe-Bia, Phe-CaL, Phe-Dab, Phe-G~n, Phe-GLu, Phe-CN-im-methyL-His), Phe-ILe, Phe-Leu, Phe-tert.Leu, Phe-Lys, Phe-Met, Phe-ct-NaL, Phe-$NaL, Phe-Nbg, Phe-N~e, Phe-CN-Me-His), Phe-CN-Me-Phe), 'Phe-Orn, Phe-Phe, Phe-Pro,' Phe-Ser, Phe-Thr, Phe-Tic, Phe- Trp, Phe-Tyr, Phe-VaL, Pro-His, Ser-His, Thr-His, Tic-His, Trp-His, Tyr-His, VaL-His, and also Ada-Phe-His, Pro-Ala- His, Pro-ALa-Phe, Pro-Phe-ALa, Pro-Phe-Phe, His-Pro-ALa-His, and aLso Pro-Abu-His, Pro-Ada-His, Pro-Arg-His, Pro-Asn-His, Pro-Bia-His, Pro-Dab-His, Pro-GLu-His, Pro-His-His, Pro- ILe-His, -Pro-Leu-His, Pro-tert.-Leu-His, Pro-Lys-His, Pro- Met-His, Pro--Nbg-His, Pro-Nie-His, Pro-(N-Me-His)-His, Pro-(N-Me-Phe)-His, Pro-Orn-H is, 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-CN-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-Nie, Pro-Phe-CN-Me-His), Pro-Phe- CN-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-Vat-His, His-Pro-Abu-His, His- Pro-Ada-His, His-Pro-Arg-His, His-Pro-Asn-His, His-Pro-Bia- His, His-Pro-Dab-His, His-Pro-Gtu-His, His-Pro-His-His, His-Pro-ILe-His, His-Pro-Leu-His, His-Pro-tert.-Leu-His, His-Pro.-Lys-His, His-Pro-Met-His, His-Pro-Nbg-His, His-Pro- Nie-His, His-Pro-(N-Me-His )-His, His-Pro-(N-Me-Phe)-His, V. 20 His-Pro-Orn-His, His-Pro-Phe-Abu, His-Pro-Phe-Ada, His-Pro- Phe-Arg, His-Pro-Phe-Asn, His-Pro-Phe-Bia, His-Pro-Phe-Dab, H is-Pro-Phe-Gin, His-Pro-Phe-GLu, H is-Pro-Phe(N-im-methyL- His), His-Pro-Phe-ILe, His-Pro-Phe-Leu, His-Pro-Phe-tert.- Leu, His-Pro-Phe-Lys, His-Pro-Phe-Met, His-Pro-Phe-Nbg, :K 25 H i s-Pro-Phe-Nie, His-Pro-Phe-CN-Me-H is), His-Pro-Phe-CN-Me- Phe), His-Pro-Phe-Orn, His-Pro-Phe-Pro, His-Pro-Phe-Ser, H is-Pro-Phe-Thr, His-Pro-Phe-Tic, Hi s-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-Pr.o-Trp-His, His-Pro- Tyr-His, His-Pro-Vat-His.

If X is one of the gro,.ips R 0

-CHCCH

2

C

6

H

5 Z is preferably GLy or His.

E is preferably absent or is preferably I~e or Leu, ::and also preferably Abu, Cal, Met or N~e.

D is preferably -CH 2

-CHOH-CH

2 0H, -CCH 2 2 S0 2

NH

2 -mn- or especially -P-C 6

H

4 -SO2NH2, -mn- or especially -p-

CH

2

C

6

H

4

-SO

2

NH

2 -mn- or especially -P-C 6

H

4

-SO

2

NHCH

3 -mn- or especially -p-C 6

H

4

-SO

2 N(CH3)2, -in-j or especially -13

-P-C

6

H

4

SO

2 NHHet, -in- or especialLy P-C 6

H

4

CONH

2 suLfamoyL-2-pyridyL, 2-suLfamoyL--5-thienyL or 3-suLfamoyL- 3H-quinazoL in-4--on-2-yL-CHR 8 3-amino--3H-quinazoL in-4-o-n-2-yL-CHR 8 6-aminosuLfonyL-7-chLoro-3H-quina- 88 3H-ciuinazoLin--4-on-2-yL-CHR.

The group W is preferabLy -NH-CHR 3

_CHOH-CH

2

-CO-,

espec iaLLy -NH-CH(cycLohexyLmethyL)-CHOH-CH 2 -CO- ("AHCP", derived from 4-amino-3-hydroxy-5-cycLohexyLpentanoic acid) and aLso -NH-CH(CH 2

CH

2 -cycIohexyL)-CHOH-CH 2 -CO- ("AHCH"; derived from 4 -amino-3-hydroxy-6-cycLohexyLhexanoic acid>,, -NH-CH(isobutyL)-CHOH-CH 2 -CO- derived from statin) or -NH-CH(berIzyL)-CHOH-CH 2 -CO- C"AHPP"; derived from 4acid). The group W is aLso preferably -NH-CHR 3

_CH(NH

2

)-CH

2 especiaLLy -NH-.

CH(cycLohexyLmethyl

)-CHCNH

2

)-CH

2 -CO- ("DACP"; derived from 3 1 4 -diamino-5-cycLohexyLpentanoic acid), -NH-CH- CCH2CH 2 -cycLohexyL )-CH(NH 2

)-CH

2 -CO- ("DACH"; derived from 3 4 -diamino-6-cycLohexythexanoic acid), -NH-CH-( isobutyL)-CH(NH 2

)-CH

2 -CO- ("DAMH"; dleri-ved from 3,4-diamino- 0:444:6-methyLheptanoic acid) or -NH-CH(benzyL)-CH(NH 2

)-CH

2

-CO-

C"DAPP"; derived from 3,4-diamino-5-phenyLpentanoic acid).

The group W has at Least one chiral centre. Further chiral centres; can be present in the groups X, R 6 and D.

25 The compounds of the formula I can, therefore, exist in various forms optically inactive or optically active.

The formula I embraces all these forms. If W is -NH-CHR 3 CR-4_CH 2 -CO- in which R 4is OH) or NH 2 3.@.the 3S-hydlroxy-4S-amino enantiomners or' 3S,4S-diamino enantiorners are preferred. Unless anything to the contrary is indicated in the designation of indlividlual substances, the abbreviations AHCP, AHCH, Sta, AHPP, DACP, DACH, DAMH and DAPP relate in each case to the 3S,4Sf for ms Accordingly, the invention relates particularly to compounds of the formula I in which at Least one of the radicals mentioned has one of the preferr-ed meanings indlicated above. Some preferred groups of compounds can be I I k 4, 4 4 *44 0.~44, o 4*4 00 4 4*04 40 0 *4 04 4442(1 4 4 4 I 44 44 4! 4 4~ 14 expressed by means of the partiaL formuLae la to IL foLLowing, which correspond to the formuLa 1, but in which in Ia X is H, BOC or R_ -CHCCH 2

C

6

H

5 in Ib X- is BOC; in Ic Z is GLy, His, Phe-GLy or Phe-His; i n Id Z is Phe-Gly or Phe-His; in le 7 is Phe-H is; in If -NR2 H _C 4 CR5) -O W) is AHCP; in Ig E is absent; i n I h R6is H; in Ii X is H, BOC or R 0

-CH(CH

2

C

6

H

5 Z is GLy, His, Phe-GLy or Phe.-His, W is AHCP, Ris Hand E is absent; in Ij X i's BOC, Z is Phe-His or Phe-GLy, W is AHCP, R 6is H and E is absent; 20 in Ik X is BOC and Z is Phe-GLy or Phe-His; and in IL X is R -CH(CH 2

C

6

H

5 and Z is GLy or His.

Compounds of the folLowing partiaL formuLae are particuLarLy preferred: I* and Ia* to IL*, which correspond to the formuLae I and Ia to IL, but in which D is -CH 2

-CHOH-CH

2 0H, -P-C 6

H

4

-SQ

2

NH

2 or 3-R 9 -5-R 1 0 -6-R l- 7-R 1 2 _8-R 1 3 _-3H-quinazoLin-4-on- 2-yL-CHR 8

-;J

I' and Ia' to IL', which correspond to the formuLae I and 13~ to IL, but in which D is -CH 2

-CHOH-CH

2

OH;

I" and la" to IL", which correspond to the formuLae I and a to IL, but in which D is -P-C 6

H

4

-SO

2

NH

2 and Ia'" to which correspond to the formulaeI and Ia to IL, but in which D is 3-R 9 5-R 10 -6-R 1 1 -7-R 12 13 _3H-qu inazoL in-4- 4.- 4 I''4

(I

15 8 on-2-yL-CHR 8 R is H, alkyl having 1-4 C atoms or benzyl,

R

9 is H or NH 2 10 13

R

0 and R 1 3 are H, R is H or SONH 2 and 12 R is H or Cl; and Ia 0 to II which correspond to the formulae I and Ia to IL, but in which D is 3H-quinazolin-4-on-2-yl-CHR or 8 3-amino-3H-quinazolin-4-on-2-yl-CHR and R is H, alkyL having 1-4 C atoms or benzyl; and 00 00 00 and Ia to IL which correspond to the formulae I and Ia to IL, but in which 8 U is 3H-quinazoLin-4-on-1-yl-CHR or 3-amino-3H-quinazolin-4-on-2-yl-CHR and 8 R is sec.-butyl or isobutyl.

The compounds of the formula I and also the starting materials for their preparation are, incidentaLLy, prepared by methods known per se, such as are described in the 20 Literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie ("Methods of o, Organic Chemistry"), Georg-Thieme-Verlag, Stuttgart; and also EP-A-45,665, EP-A-77,028, EP-A-77,029 and EP-A-81,783), oi* Sin particular under reaction conditions which are known and j 25 suitable for the reactions mentioned. In this regard it is also possible to make use of variants which are known per St se, but are not mentioned here in detail.

If desired, the starting materials can also be Sformed in situ, so that they are not isolated from the reac- 30 tion mixture, but are immediately reacted further to give the compounds of the formula I.

The compounds of the formula I are preferably obe tained 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 otherwise correspond to the formula I, but, instead of one or more free amino and/or c A 16 hydroxyl groups, contain corresponding protected amino and/ or hydroxyL groups, preferably groups of this type which, instead of an H atom attached to an N atom, carry an amino protective group, for example those which correspond to the formula I, but, instead of an His group, contain an N-(im)- 15 15

R

15 -His group (wherein R 15 is an amino protective group, for example BOM or DNP), or those of the formula X-Z-NR 2 CHR3-CH(NHR15)-(CHR 5 n-CO-E-NR6-D.

Preferred starting materials are also those which, instead of the H atom of a hydroxyl group, carry a hydroxyl protective group, for example those of the formula X-Z-NR 2

CHR

3

-CHOR

16 -(CHR )n-CO-E-NR6-D, wherein R 1 is a hydroxyL protective group.

It is also possible for several identical or different protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protective groups present are different from one another, they can in many cases be split off selectively.

The term "amino protective group" is generally S 20 known and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, S* but which can be removed readily after the desired chemical reaction has been carried out at another point on the molecule. Typical representatives of groups of this kind are, tj 25 in particular, unsubstituted or substituted acyl, aryl (for example DNP), aralkoxymethyl (for example BOM) or aralkyl (for example benzyl, 4-nitrobenzyl or triphenylmethyl) groups. Since the amino protective groups are removed after Sthe desired reaction (or reaction sequence), their nature and size is, incidentally, not critical; groups having S1-20, in particular 1-8, C atoms are, however, preferred.

In the context of the present process, the term "acyl group", is to be understood in the widest sense. It embraces acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and also, in particular, alkoxycarbonyl, aryloxycarbonyl and, above all, aralkoxycrbonyl groups. Examples of acyl groups of this type are alkanoyl, such as acetyl, propionyl or buty- 77.4 7- 17 ryL; aralkanoyl, such as phenyLacetyl; aroyL, such as benzoyL or toluyL; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ETOC, 2,2,2-trichloroethoxycarbonyl, BOC or 2-iodoethoxycarbonyL; and aralkyLoxycarbonyL, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyL or FMOC. Preferred amino protective groups are DNP and BOM, and also CBZ, FMOC, benzyl and acetyL.

The term "hydroxyL protective group" is also generally known and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which can be removed readily after the desired chemical reaction has been carried out at another point in the molecute. Typical representatives of such groups are the unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, and also alkyL groups. The nature and size.

of the hydroxyl protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups having 1-20, in particular 1-10, C atoms are preferred. Examples of hydroxyl protec- 20 tive groups are, inter alia: benzyl, p-nitrobenzoyl, ptoluenesulfonyl and acetyl, benzyl and acetyl being particularly preferred.

The functional derivatives of the compounds of the formula I to be used as starting materials can be prepared 25 by customary methods of amino acid and peptide synthesis, such as are described, for example, in the standard works and patent applications mentioned, and also, for example, S' by the Merrifield solid phase method.

|I The liberation of the compounds of the formula I from their functional derivatives is effected depending L on the protective group used with, for example, strong acids, preferably trifluoroacetic acid or perchloric acid, but also other strong inorganic acids, such as hydrochloric S acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzenesulfonic or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic 18solvents, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as dimethylformamide (DMF), halogenated hydrocarbons, such as methyl-ene chloride, and also alcohols, such as methanot, ethanol or isopropanol, and also water. Mixtures of the abovementioned solvents are also suitable. Trifluoroacetic acid is preferably used in excess without the addition of a further solvent; perchloric acid is used in the form of a mixture of acetic acid and 70% perchlori'c acid in a 9 1 ratio. The reaction temperatures for the cleavage are preferably between about 0 and about 500; the reaction is preferably carried out between 15 and 300 (room temperature).

The BOC group can be split off, for example, preferably by means of 40% trifluoroacetic acid in methylene.

chloride or by means of about 3 N to 5 N HCL in dioxane at 15-300, while the FMOC group can be split off by means of an approximately 5 to 20% solution of dimethylamine, diethylamine or piperidine in DMF at 15-300. Splitting off 20 the DNP group is possible, for example, also by means of an a approximately 3 to 10% solution of 2-mercaptoethanol in DMF/ water at 15-30°.

bo ~Protective groups which can be removed by hydrogens olysis (for example BOM, CBZ or benzyl) can be split off, 25 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 charcoal). Suitable solvents for this reaction are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. As a rule, the hydrogenolysis is carried out at temperatures between about 0 and 1000 and pressures between about 1 and 200 bar, preferably at 20-300 and 1-10 bar. Hydrogenolysis of the CBZ group can be effected readily, for example, over 5 to 10% Pd/C in methanol at 20-300 Compounds of the formula I can also be obtained by direct peptide synthesis from a carboxyli.c acid component (formula II) and an amine component (formula III). Examples I I 19 of suitable carboxylic acid components are those of the partial formuLae X-Z-OH, X-Z-W-OH or X-Z-W-E-OH, while suitable amine components are those of the partial formulae H-W-E-

NR

6 H-E-NR -D or H-NR6-D. The peptide bond can, however, also be made within the group Z or E; in this case a carboxylic acid of the formulae X-Z -OH or H-Z-W-E-OH with an amino compound of the formula H-Z 2

-W-E-NR

6 -D or H-E -NR -D, respectively, Z Z 2 being Z or E E being E, respectively. This reaction is preferably carried out by customary methods of peptide synthesis, such as are described, for example, in Houben-Weyl, Loc. cit., volume 15/II, pages 1 to 806 (1974).

The reaction is preferably carried out in the presence of a dehydrating agent, for example a carbodiimide, such as DCCI or dimethylaminopropylethylcarbodiimide, and also 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 chlor- 20 ide, an ether, such as tetrahydrofuran or dioxane, an amide, such as DMF or dimethylacetamide, or a nitrile, such as aceo tonitrile, at temperatures between about -10 and 400, preferably between 0 and 300.

Instead of II or III, it is also possible to employ it 4 It t in the reaction suitable reactive derivatives of these compounds, for example compounds in which reactive groups are 7 blocked in the meantime by protective groups. The amino acid derivatives III can, for example, be used in the form of their activated esters, which are preferably formed in situ, for example by the addition of HOBt or N-hydroxysuccinimide.

The starting materials of the formulae II and III t are for the most part known. Insofar as they are not known, they can be prepared by known methods, for example the abovementioned methods of peptide synthesis and of splitting protective groups.

If desired, a functionally modified amino and/or hydroxyl group in a compound of the formula I can be liberated 20 by soLvoLysis or hydrogenolysis in accordance with one of the methods described above.

Thus it is possible, in particular, to convert a compound of the formula I wherein X is other than H into a compound of the formula I (X preferably by hydrogenoLysis, if X is CBZ, otherwise by selective soLvolysis. If X is BOC, the BOC group can be split off, for example by means of HCL in dioxane at room temperature.

Furthermore, it is possible, for example, to reduce keto compounds of the formula I (R 4 0) to compounds of the formula I (R H, for example by means of a complex metal hydride, such as NaBH 4 which does not simul- ~j taneously reduce the peptide carbonyl groups, in an inert solvent such as methanol at temperatures between about and +300.

Keto compounds of the formula I (R 0) can also be converted into compounds of the formula I (R H, NH 2 by reductive amination. Reductive amination can be carried out in a single stage or in several stages. Thus it is S 20 possible, for example, to treat the keto compound with ammonium salts, for example ammonium acetate, and NaCNBH 3 o preferably in an inert solvent, for example an alcohol such as methanol, at temperatures between about 0 and 500, in 8 particular between 15 and 30°. It is also possible first to convert the keto compound into the oxime in a customary manner by means of hydroxylamine, and to reduce this oxime to the amine, for example by catalytic hydrogenation over e a O Raney nickel.

o e 0 It is also possible to convert a radical D into an- 30 other radical D by treatment with esterifying, solvolysing B or reducing agents. Thus an acid can be esterified, for example by means of an alcohol of the formula A-OH or a diazoalkane, for example diazomethane, or an ester can be saponified to give the corresponding acid, for example by means of sodium hydroxide in aqueous dioxane solution at room temperature. It is also possible, for example, to convert a radical R NlH 2 into a radical R H by treatment with reducing agents, preferably with Raney nickel in an urcll i

[I

I I 1:) 21 alcohol such as isopropanol at temperatures between 20 and 1200 A base of the formula I can be converted into the appropriate acid addition salt by means of an acid. Acids suitable for this reaction are, in particular, those which afford physiologically acceptable salts. Thus it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrogen halide acids, such as hydrochloric or hydrobromic acid, phosphoric acids, such as orthophosphoric 10 acid, or sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, 3-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic S 20 acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemonosulfonic and naphthalenedisulfonic acids or Laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or 25 purify the compounds of the formula I.

(The new compounds of the formula I and their physiologically acceptable salts can be used for the preparation of pharmaceutical formulations by bringing them into a suitable dosage form together with at least one excipient or auxiliary and, if desired, together with one or more further active compound(s). The formulations thus obtained can be employed as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral or rectal) administration 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 gly- 22coLs, 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 especially used for oraL administration; Lacquered tablets and capsules having coatings or capsule casings resistant to gastric juices are of particular interest. Suppositories are used for rectal administration; solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants are used for parenteral application.

Sprays containing the active compound either dissolved or suspended in a propellent gas mixture (for exampLe fluorochlorohydrocarbons) can be used for administration as an inhalation spray. It is preferable in this regard to use the active compound in a micronized form, and one or more.

additional physiologically tolerable solvents can be present, for example ethanol. Inhalation solutions can be administered by means of customary inhalers. The new compounds can also be lyophilized and the resulting lyophilis- 20 ates can be used, for example, for the preparation of injection formulations. The formulations indicated can be steriLized and/or can contain auxiLiaries, such as preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substan- 25 ces, colorants and/or aroma substances. If desired, they can also contain one or more further active compounds, for example one or more vitamins.

As a rule, the substances according to the invention are administered analogously to other known, commercially 30 available peptides, but, in particular, analogously to the compounds described in EP-A-77,028, preferably in dosages between about 100 mg and 30 g, especially between 500 mg and 5 g, per dosage unit. The daily dosage is preferably i between about 2 and 600 mg/kg of body weight. The particu- Lar dose for each specific patient depends, however, on a very wide variety of factors, for example on the effectiveness of the particular compound employed, on the age, body weight, general state of health, sex, diet, time and means I -23 of administration, excretion rate, combination of medicaments and the severity of the particular disease to which the therapy applies. Parentera administration is preferred.

In the preceding and following text aLL temperatures are quoted in OC. In the following examples "customary working up" means as foLLows: if necessary, water is added, the mixture is neutraLized and extracted with ether or methylene chloride, the phases are separated, the organic phase is dried over sodium sulfate, filtered and evaporated, and the residue is purified by chromatography over silica 20 gel and/or crystallization. [ac] 20 in methanol, c 1.

Example 1 The pH of a mixture of 978 mg of 2-C1S-(3S-hydroxy- 4S-(N-tert.-butoxycarbonyl-L-phenylaanyL-N(imi)-(2,4-di- 3-methyLbutyl]-3H-quinazolin-4-one C"2-E1S-(BOC-Phe-imi- DNP-His-AHCP-amino)-3-methylbutyl]-3H-quinazoLin-4-one"; o 20 obtainable by reacting BOC-Leu-OH with methyl anthranilate to give methyl 2-(BOC-Leu-amino)-benzoate (oil), reacting the latter with hydrazine hydrate to give 2-(1S-BOC-amino- 3-methylbutyl)-3-amino-3H-quinazolin-4-one 110-1150 (decomp.); [a]C -47.10), boiling the latter for 5 hours with Raney Ni in isopropanol with the formation of 2-(1S- BOC-amino-3-methybuty)-3H-quinazoin-4-oie 2150 (decomp.); -48.50), splitting off the BOC group by means of 4N HCL in dioxane to give 2-(1S-amino-3-methyLbutyl)- 3H-quinazolin-4-one (dihydrochloride, m.p. 2750 (decomp.); -28.40), reacting the latter with BOC-AHCP-OH/DCCI/ HOBt to give 2-(1S-BOC-AHCP-amino-3-methylbutyL)-3H-quinazolin-4-one, splitting off the BOC group and subjecting the product to a condensation reaction with BOC-imi-DNP-His- OH to give 2-(S-BOC-imi-DNP-His-AHCP-amino-3-methyLbutyL)- 3H-quinazoin-4-one, splitting off the BOC group again and reacting the product with BOC-Phe-OH3, 2 g of 2-mercaptoethanol, 20 mL of DMF and 20 mL of water .is adjusted to 8 by stirring with aqueous Na 2 CO3 solution at 200, and the -24 mixture is stirred for 2 hours at 200 Working up in the customary manner gives 2-E1S-C3S-hydroxy-4S-(N-tert.

hexyLpentanoyLamino)-3-methytbutyL]-3H-quinazoLin-4-one E"2-[lS-(BOC-Phe-His-AHCP-amino)-3-methyLbutyLJ-3H-qu inazoLin-4-one"], m.p. 147-1490.

The foLLowing are obtained anaLogousLy by cLeaving the corresponding imi-DNP derivatives: 3-(BOC-Phe-His-AHCP-ILe-armino) -propane-1,2-dioL, m.p. 180- 1820 3-(B0C-Phe-His-AHCP-Leu-amino)-propane-1,2-dio', 2-(BOC-Phe-H is-AHCP-ILe--amino)-ethanesuLfonamide, m.p. 1820 2-CBOC-Phe-His-AHCP-Leu-amino)-ethanesuLfonamide o-(BOC-Phe-His-AHCP--ILe--amino)-benzenesuLfonamide o-(BOC-Phe-H is-AHCP-Leu--arino)-benzenesuLfonamide m-(BOC-Phe-H is-AHCP-ILe-amino)-benzenesuLfonamide m-(BOC-Phe-His-AHCP-Leu-amino)-benzenesuLfonamide 0 N 4 -(BOC-Phe-His-AHCP-ILe)-suLfaniLamide 00 20 N 4 -(BOC-Phe-His-AHCP-Leu)-suLfaniLamide, m.p. 146-1470 p-(BOC-Phe-His-AHCP-ILe-aminomethyt )-benzenesuLfonamide, m.p. 2270 0 0: p-[2-(BOC-Phe-His-AHCP-I Le-amino)-ethyL]-benzenesuLfonamide, o-(BOC-Phe-His-AHCP-ILe-amino)-benzenesuLfon ic acid Nmethytamidle o-(BOC--Phe-His-"AHCP-Leu-amino)--benzenesuLfon ic acid Na ;methyLamide m-CBOC-Phe-His-AHCP-ILe-amino)-benzenesuLfonic acid Nme thy Iam ide 3 m-(BOC-Phe-His-AHCP-Leu-amino)-benzenesuLfonic acid Nmethyl amidle p-CBOC-Phe-His-AHCP-Iie-amino)-benzenesuLfonic acid NmethyLamide, mn.p. 1570 p-(BOC-Phe-t.'is-AHCP-Leu-aniino)-benzeresuLfonic acid NmethyLamidoe o-(BOC-Phe-His-AH1CP-ILe-aimino)-benzenesuLfonic acid N,NdimethyLamidle o-(BOC-Phe-His-AHCP-Leu-amino)-benzenesuLfonic acid N,Nt. 25 diniethytamide m-(BOC-Phe-His-AHCP-ILe-amino)-benzenesuLfoflic acid N,NdiniethyLamide r-(BOC-Phe--His-AHCP-Leu-amino)--benzenesuLfoflic acid N,NdirethyLamide p-CBOC-Phe-His-AHCP-ILe-amino)-benzenesutfonic acid N,NdirnethyLaniide m.p. 1680 p-CBQC-Phe-His-AHCP-Leu-amino)-benzenesuLfonic acid N,Ndime thy Lamnide o-(morphoL inoacetyL-Phe-His-AHCP-ILe-ainino)-benzenesuLfonamidle o -(miorphoL inoacetyL-Phe-His-AHCP-Leu-amino)-benzenesuLfonamidle m-(niorphoL inoacetyL-Phe-His-AHCP-ILe-amino)-benzenesuLfol amiide i-(iorphoLinoacetyL-Phe-His-AHCP-Leu-amino)belzelesuLfofl amidle inoacetyL-Phe-His-AHCP-e-amino)-belzelesuLfol p-(morphoLinoacetyL-Phe-His-AHCP-Leu-anino)-belzelesu~fon amidle 0: o-CmorphoL inoacetyL-Phe-His-AHCP-ILe-amino)-benzeneuLfofliC acid N-methyLamide o-(niorphoL inoacetyL-Phe-His-AHCP-Leu-amino)-belzelesuLfolic acid N-mnethyLamide :hit m-(inorphoL inoacetyL-Phe-liis-AHCP-ILe-anino)-belzeesuLfoflic acid N-mnethyLamide m-(molphoLinoacetyL-Phe-His-AHCP-Le-aio)-belzelesuLfoflic 30 acid N-methyLamide p-Cmnorphot inoacetyL-Phe-His-AHCP-Le-amilo)belzelesuLfoflic acid N-methyLamide inoacetyL-Phe-His-AHCP---aliflo)-belzeflesuLfoflic acid N,N-dimethyLainide o-(morphoL inoacetyL-Phe-His-AHCP-Leuamio)belzelesuLfofic acid N,N-dimethyLamide -26m-(morphoLinoacetyL-Phe-His-AHCPILeaml)-belzelesuLfoflic acid N,N-dirnethyLamide m-(morphoLinoacetyL-Phe-His-AHCP-Leuami0)belzelesuLfolic acid N,N-dimethyLamide p-(rnorphoL inoacetyL-Phe-His-AHCP-ILeamio)-elzelesuLfolic acid N,N-dimethyLamlide p-(morphoLinoacetyL-Phe-HisAHCPLeuam0)bezeesuLfoflic acid N,N-dirnethyLarnide 5-(BOC-Phe-H is-AHCP-ILe-amino)-furan-2-suLfolamide 5-(BOC-Phe-His-AHCP-Leu-amino)-furafl2-suLfoflamide 5.-(BOC-Phe-His-AHCP-ILe-amino)-thiophele2-suLfolamide 5-(BOC-Phe-His-AHCP-Leu-amino)-thiophele-2-suLfoflamide is-AHCP-I Le-arnino )-th iophene-3-suL fonarnide 5-(BOC-Phe-H is-AHCP-Leu-amino)-thiophene-3-su1fonamide 2-CBOC-Phe-H is-,-.HCP-I~e-amino)-pyridine-5-suLfoflami de, p-(BOC-Phe-H is-AHCP-ILe-arnino)-benzarnide, m.p. 2280 p-CBOC-Phe-His-AHCP-Leu-amino)-belzamide p-(BOC-Phe-His-AHCP-ILe-amino)-belzelephospholic acid dliamidle p-(B0C-Phe-His-AHCP-Leu-amin)-belzeleph0sphofic acid diamidle 2-l-BCPeHi-HPaio-thL Hqiaoin-4-one 4-one Lobtainable via methyl 2-CBOC-ALa-amino)-benzoate L in-4-one 2-[1S-(BOC-Phe-His-AHCP-amino)-2-methyLpropyL ]-3-amino-3HquinazoLin-4-one, 1270 Cobtainable via methyL 2-(BOC- VaL-amino)-benzoate (ru.p. 151-1550)] 2-l-BCPeHsAC-mn)2-eh~uy]3-unz~n 4-one 2-E1S-(BOC-Phe-His-AHCP-amino)-2Smethy~butyL)3-amilo-3Hquinazolin-4-one, m.p. 1200 Edecomp.; obtainable via 2- (lS-BOC-arino2SmethuyL)3amifl3HquinazoLin4-one -27- (ni.p. 110-115 0 [a]l -41.90) and 2-(lS-amino-2S-rnethyLbutyL)-3-amino-3H-quinazoLin-4-one 1050 (decomp.); -4.40] 2-[lS-(BOC-Phe-His-AHCP-amino)-3-methyLbutyt ]-3-amino--3HquinazoLin-4-one, m.p. 125-128o 2-C1S-CBOC-Phe-His-AHCP-amino)-2-phenyLethyL]-3H-quinazoL in- 4-one 2-C 1S-CBOC-Phe-His-AHCP-amino)-2-phenyLethyL 1-3-am ino-3HquinazoLin-4-one, m.p. 1980 [obtainabLe via methyL 2-(BOC- II Phe-amino)-benzoate (rn.p. 145-1470)] 2-E1S-(BOC-Phe-His-AHCP-amino)-2S-methyLbutyL]-6-suLfamoyL- 7 -chLoro-3H-quinazoL in-4-one 2-[1S-CBOC-Phe-His-AHCP-amino)-2S-methyLbutyL 1-3-ami no-6suLfamoyL-7-chLoro-3H-quinazoL in-4-one 2-[lS-CBOC-Phe-His-AHCP-amino)-3-methyLbutyLi1-6-suLfamoyL- I7-chtoro-3H-quinazoLi-on 2 -[lS-(BOC-Phe-His-AHCP-amino)-3-methyLbutyL]J-3-amino-6suLfamoyL-7-chLoro-3H-quinazoLin-4-one I 2-[1S-(N-(2-pyrroL idino-3-phenyL-propionyL )-His-AHCP-amino)- I :.2S-methyLbutyL]-3H-quinazoLin-4-one I a. 2-[1S-(N-(2-pyrroL idino-3-phenyt-propionyL )-His-AHCP-amino)- 2S-methyLbutyL ]-3-amino-3H-quinazoL in-4-one 2-E1S--(N-(2-pyrroL idino-3-phenyL-propionyL )-His-AHCP-arnino)- 3-methyLbutyLJ-3fi-quinazoL in-4-one ii2-C1S-CN-(2-pyrroL idino-3-phenyL-propionyL)HsAC-mn- 3-iethyLbutyL]-3-amino-3H-quinazoLin-4-one 2-[lS-(N-C2-piperidino-3-phenyt-propionyt)-His-AHCP-amino)- Z S-methyLbutyL]-311-quinazoLin-4-one 2-E1S-(N-(2-piperidino-3-phenyL-propionyL)-His-AHCP-amino)- 2S-methyLbutyL]-3-amino-3H-quinazoLin-4-one 2-E1S-CN-(2-piperidino-3-phenyL-propionyL )-His-AHCP-amino)- 3-methyLbutyL]-3H-quinazoLin-4-one 2-[1S-CN-(2-piperidino-3-phenyL-propionyL )-His-AHCP-amino)- 3-methyLbutyL]-3-amino-3H-quinazoLin-4-one 2-[1S-(N-(2-morphoLino-3-phenyL-propionyL)-His-AHCP-amino)- 2S-methyLbutyL]-3H-quinazoLin-4-one -28 2-E1S-(N-(2-morphoLino-3--phenyL-propionyL)-His-AHCP-amino)- 2S-rethyLbutyL]-3-amino-3H-quinazoL in-4-one 2-E1S-(N-(2-morphoL ino-3-phenyL-propionyL )-His-AHCP-amino)- 3-methyLbutyLJ-3H-quinazolin-4-one 2-[1S-(N-(2-morphoL ino-3-phenyL-propionyL )-His--AHCP-amino)- 3-methyLbutyL]-3-amino-3H-quinazoLin-4-one 2-[1S-(N-(2-benzyL-hexanoyL )-His-AHCP-amino)-2S-methyLbutyl ]-3H-quinazoL in-4-one 2-E1S-(N-(2-benzyL-hexanoyl )-His-AHCP-amino)-2S-methyLbutyL]-3-amino-3H-quinazoL in-4-orie 2-E1S-CN-(2-benzyL-hexanoyL )-His-AHCP-amino)-3--methyLbutyLJ-3H-quinazoL in-4-one 2-[lS--(N-(2-benzyL-hexanoyL )-His-AHCP-amino)-3--methyLbutyLJ-3-amino-3H-quinazoL in-4-one 2-C 1S-(N-(2-butoxy-3-phenyL--propionyL )-His-AHCP-amino)-2SmethyLbutyLJ-3H-quinazoL in-4--one 2-[1S-(N-(2--butoxy-3-phenyL-propionyL)-His-AHCP-amino)-2SmethyLbutyL]-3-amino-3H-quinazoL in-4-one 2-EIS-CN-(2-butoxy-3-phenyL-propionyL )-His-AHCP-amino)- 3-methyLbutyL]-3H-quinazoLjn-4-orne 2-E1S-(N-(2-butoxy-3-phenyL-propionyL )-His-AHCP-amino)- 3-methytbutyL]-'3-amino-3H-quinazoL in-4--one 2-[1S-(N-(2-butyLthio-3-phenyL-propionyL )-His-AHCP-amino)- 2S-methyLbutyLJ-3H-quinazoL in-4-one 2-[1S-(N-(2-butyLthio-3-phenyL-propionyL )-His-AHCP-amino)- 2S-methyLbutyL]-3--amino-3H-quinazoLin-4-one 2-E1S-(N-C2-butyLthio-3-phenyL-propionyL )-His-AHCP-amino)- 3 -methyLbutyL]-3H-qu inazoL in-4-one 2-E1S-CN-C2-butyLthio-3-phenyL-propionyL)-His-AHCP-amino)- 3-methyLbutyL]-3-amino-3H-quinazoL in-4-one Example 2 1 g of 2-E1S-(80C-Phe-(imj-B0M-Hjs)-AHCP--amjno)-2SmethyLbutyL]-3-amino-3H--quinazoLine-4-one Cm.p. 1460; [ca] -37.20; obtainable from 2-C1S-amino-2S-methyLbutyL)- 3-amino-3H-quinazoLin-4-one and BOC-Phe-Cimi-BOM-His)-AHCP- OH) is dlissolved in 15 ml of methanol, and the mixture is hydrogenated over Pd/C at, 200 and 1. bar until absorption ceases, and is filtered and evaporated to give 2-ElS- -29 (BOC-Phe-His-AHCP-amino)-2S-methyLbutyL ]-3-amino-3H-quinazoLin-4--one, m.p. 1200 (dlecomp.).

The other compounds indicated in ExampLe 1 are obtained anaLogousLy by cLeaving the corresponding imi-BOM derivatives, as are aLso the foLLowing: p-CBOC--Phe-His-AHCP-ILe-amino)-benzenesuLfonani Lide p-CBOC-Phe-His-AHCP-ILe-amino)--benzenesuLfonic acid o-suLfaroyLanitide p-(BOC-Phe-His-AHCP-ILe-amino)-benzenesuLfonic acid p-sulfamoyLaniLide p-(BOC-Phe-His--AHCP-ILe-amino)-benzenesuLfoni c acid N-(2thienyL)-amide I p-(BOC--Phe-His-AHCP-ILe--arino)-benzenesuLfonic acid N-(2thiazoLyL)-amide p-(BOC-Phe-His-AHCP-ILe-amino)-benzenesuLfonic acid N-(3isoxazoLyl )-amide acid N-CSmethyL-3-isoxazoLyL)-amide p-(B0C-Phe-His-AHCP-ILe-amino)-benzenesuLfonic acid N-(3,4acid N-(4pyridyL)-amide p-(BOC-Phe-His-AHCP-ILe-amino)-benzenesuLfonic acid N-(2pyrimidinyL)-anide, m.p. 192 0 p-CBOC--Phe-His-AHCP-ILe-amino)-benzenesuLfonic acid N-(4methyL-2-pyrimidinyt)-amide p-(BOC-Phe--His-AHCP-ILe-amino)-benzenesuLfonic acid N-(4,6ditethyL-2-pyrimidinyL )-amide p-CBOC-Phe-His-AHCP-ILe-amino)-benzenesuLfonic acid N-C2,6dimethyL-4-pyrimidinyL)-anide.

Example 3 1.01 g of N-methyLmorphoLine is added to a soLution, in 60 mL of CH 2

CL

2 of 4.58 g of 3-(H-GLy-AHCP-ILeamino)-propane-1,2-dioLl[obtainable by reacting AHCP-OH with 3-(H-ILe--amino)-propane-1,2-dioL to give 3- (BOC-GLy-AHCP-ILe-amino)-propane-1,2-dioL and spL itt ing off the 30C group]. 2.65 g of BOC-Phe-OH, 1.35 g of HOBt and a soLution of 2.06 g of DCCI in 50 mL of CH 2

CL

2 are added with stirring, the mixture is stirred for 14 hours at 40, the precipitated dicycLohexyLurea is fiLtered off and the fiLtrate is 'evaporated. Customary working up gives 3-(BOC- Phe-GLy-AHCP-ILe-amino)-propane-1,2-dioL, m.p. 104-106'.

ExampLe 4

N

4 -CBOC-Phe-GLy-AHCP-Leu)-suLfani Lamide, m.p. 142- 1440, is obtained anaLogousLy to ExampLe 3 from BOC-Phe- 4 GLy-OH and N _-CH-AHCP-Leu)-suLfaniLamide.

The folLowing are obtained anaLogously:

N

4 -(BOC-Phe-GLy-AHCP-I Le)-suLfani Lamide

N

4 _(POA-Phe-Abu-AHCP-Leu)-suLfani Lamide 4_(E

O

N-TO-Phe-Ada-AHCP-Leu)-suLfani Lamide N I POC -Phe--ALa-AHCP-Leu)-suLfani Lamide 1 N 4 -CCBZ-Phe-CaL-AHCP-Leu)-suLfani Lamide

N

4 _CacetyL-Phe-(N-im-methyL-His)-AHCP-Leu)-suLfaniamd

N

4 -EN-PeIeAC-e)s~aiLmd

N

4 _-(INC-Phe-ILe-AHCP-Leu)-suLfani Lamide

N

4 _C4-PhnyC yy-Phe-a-AHCP-Leu)-suLfaniLamide N 4 _-(MC-bezyL-3-heyAHProinLe-Phe-faL-aHCPeu)s~ i1 V 4 -(morphlioety-hAj-AHCP-Leu)-su Lailaiemp.12 N-(2pnehL) 4 -phenyLbutyryL-Phe-eta-HPLu-ufnbg-aHmpeuJ tit N 4 -[2--enaphhyL ety)4henypoi nyLbutyryNL-He-Leu-suH fnpalesuanaid N (mpoioyL -Ph(e-Hi)-AHCP-LeusufsuLai Lamide92 N 4 _-(tyy-phe-(NtyL-M -phe-A uyrL-heNbpACPLeu)lufniLmd sfaiouya LPemieAdpLues~ai~md N 4 _-ycoptyLarboyL)-ph-pronyAbutprLuhesuLe-Ani Leul-su~aLamided N N-pycohexlcboyL-(-pe-se-AHCP-Leu-suLfani Lamide N 4 CbezyL-Phe-Thre-e-AHCP-Leu-suLfanide N~ 4 -Cphnyo atyL-Phe-i-AHCP-Leu)-suLfani Lamide N 4 C2peny pro o y l-h-h-HP-eTr -sHuL u -suif n lam N 4 3-phenypropionyL-Phe-Tyr-AHCP-Leu)-.suLfaniLamide N 4 2-p-fLuorophenyLpropionyL-Phe-VaL-AHCP-Leu).suLfan iLam ide.

31 ExampLe N 4 _(BOC-Phe-GLy-AHCP--Leu)-suLfani Larnide, m.p. 142- 1440, is obtained anaLogously to Example 3 from BOC-Phe- GLy-AHCP-OH and N 4 _-(H-Leu)-suLfani Lamide.

The folLowing are obtained anaLogously: N 4 _(BOC-Phe-BALa-AHCP-Leu)-suLfani Lamide, m.p. 1960 N 4 _(BOC-Phe-GLy-AHCP--ILe)-suLfaniLamide 5-(BOC-Phe-GLy-AHCP-ILe-amino)-thiophene-3-suLfonamide 2-C1S-CBOC-Phe-GLy-AHCP-amino)-2-methyLpropyL]-3H-quinazo- L in-4-one 2-C1S-(BOC-Phe-GLy-AHCP-amino)-2-methyLpropyL]-3-amino-3HquinazoLin-4-one 2-E1S-(BOC-Phe-GLy-AHCP--amino)-2S-methyLbutyL ]-3H-quinazoLi n-4-one 2-C 1S-(BOC-Phe-GLy-AHCP-amino)-2S-methyLbutyL]-3-amino-3HquinazoLin-4-one, m.p. 1150 (decomp.) 2-[lS-(BOC-Phe-GLy-AHCP-amino)-3-methyLbutyL]-3H-quinazoi in- 4-one 2( O -h -G y A C -m n -e h~ u yL -m n -H 20quinazoLin-4-one 2-C 1S-(BOC-Phe-GLy-AHCP-amino)-2-rntyLtyL-6H--ul famoyl- 7-hoo3unzLin-4-one 2-[1IS-(BOC-Phe-GLy-AHCP-amino)-2S-hethyLtyL]-3-amino-3HsfayL7cor-HquinazoLin-4-one 302-C1S-(BOC-Phe-GLy-AHCP-amino)-3-methyLbuty )-6-suLfamoyL- 7-chLoro-3H-quinazoLin-4-one 2-C1S-CBOC-Phe-GLy-AHCP-amino)-2-methyLbutyL-3-amino-6suLfamoyL-7-chLoro-3H-quinazoL in-4-one 302--(BOC-Phe-G -HC- e-aminohl)-3-quinazLbutyn--one amy -(B~oO.Pr GyAC-~-mnmty)3ao-3H-quinazolin4-oe, -p.188 2 -ClS-(NO-Ph-y-AHolid inohny-propioyL)-y-A-amino 2s-~motyLbutyhLJr-3H-quinazoLin-4-one 2 -[lS-CN-C 2 -pyrroLidino-3-phenyL-propionyL)-GLyAHCPamn)- 2S-methyLbutyLJ--n-3H-quinazouin-4-one

'A

-32- 2-C1S-(N-(2-pyrroLidino-3-pheriyL-propionyt)-GLy-AHCP-amino)- 3-methyLbutyL ]-3H-qu inazol in-4-one 2-E1S-(N-C2-pyrroLidino-3-phenyL-propionyL)-GLy-AHCP-amino)- 3-rethytbutyL]-3-amino-3H-quinazoLin-4-one 2-[1S-(N-C2-piperidino-3-phenyL-propionyL )-GLy-AHCP-amino)- 2S-methyLbutyL]-3H--quinazoLin-4-one 2-ClS-(N-(2-piperidino-3-phenyL-propionyL)-GLy-AHCP-amino)- 2S-methy~butyL]-3-amino-3H-quinazoL in-4--one 2-C1S-(N-(2-piper idino-3-phenyL-prop ionyL )-GLy-AHCP-amino)- 3-methyLbutyL]-3H-quinazoL in-4--one 2-C1S-(N-C2-piperidino-3-phenyL-propionyL )-GLy-AH-CP-amino)- 3-methyLbutyL]-3-amino-3H-quiniazoLin-4-one 2-C1S-(N-(2-morphoL ino-3-phenyL-propionyL )-GLy-AHCP-amino)- 2S-methyLbutyL]-3H-quinazoLin-4-one 2-[1S-(N-(2-morphoL ino-3-phenyL-propionyL)-GLy-AHCP-amino)- 2S-methyLbutytj-3-amino-3H-quinazoLin-4-one 2-[lS-(N-(2-morphoLino-3-phenyt-propionyL)-Gly-AHCP-amino)- 3-methytbutyL]-3H-quinazoL in-4-one 2-[1S-(N-(2-morj~hoLino-3-pheny1-propionyL)-GLy-AHCP-amino)- 20 3-methyLbutyL)-3-amino-3H-quinazoLin-4-one 2-C 1S-(N-C2-benzyL-hexanoyL )-GLy-AHCP-amino)-2S-methyLbutyLI-3H-quinazoLin-4-one 2-C 1S-CN-C2-benzyt-hexanoyL )-GLy-AHCP-amino)-2S-methytbutyL )-3-arnino-3H-quinazot in-4-one 2-C 1S-(N-(2-benzyL-hexanoyL )-GLy-AHCP--amino)-3-methyLbutyLJ-3H-quinazoiin--4-one 2-C1S-CN-(2-benzyL-hexanoyL )-GLy-AHCP-amino)-3-methyLbutyt)-3-amino-3H-quinazoLin-4-one *o 30 2-C1S-(N-(2-butoxy-3-phenyt-propionyL)-GLy-AHCP-amino)- 2S-methyLbutyL]-3H-quinazot in-4-one 2-C 1S-(N-C2-butoxy-3-phenyL-propionyt)-GLy-AHCP-aniino)- 2S-methyLbutyL]-3-amino-3H-quinazotin-4-one 2-C 1S-(N-(2-butoxy-3-phenyL-propionyL)-GLy-AHCP-amino)- 3-methyLbutyL]-3H-quinazoLin-4-one 2-C 1S N -(C2-b uto x y-3-p hen y p rap iony 1) G Iy-A H CP -am ino) 3-methyLbutyL)-3-amino-3H-quinazoLin-4-one 2-CIS-(N-(a-butyLthio-3-phenyL-propionyL)-Gty-AHCP-amino)- 7A

I

-33 2S-methy LbutyL ]-3H-qu inazol in-4-one 2-[1S-(N-(2-butyLthio-3-phenyL-propionyL )-GLy--AHCP-amino)- 2S-methyLbutyLJ-3-arnino-3H-quinazoLin-4-one 2-[lS-(N-(2-butyLthio-3-phenyL-propionyL)-GLy-AHCP-amino)- 3-methyLbutyLJ-3H--quinazoL in-4--one 2-E1S-CN-C2-butyLthio-3-phenyL-propionyL)-GLy-AHCP-amino)- 3-methyLbutyL]-3-amino-3H1-quinazoLin-4-one Example 6 3-(BOC-Phe--GLy-AHCP-ILe-Met-amino)-propane-1,2-dioL is obtained analogously to Example 3 from BOC-Phe-GLy-AHCP- Ie-OH and 3-(H-Met-amino)-propane-1,2-dioL.

Example 7 3 -(BOC-Phe-GLy-AHCP-ILe-amino)-propane-1,2-dioL, r.p. 104-1060, is obtained analogously to Example 3 from BOC-Phe-GLy--AHCP-ILe-OH and 3-aminopropane-1,2-dioL.

The following are obtained analogously: 3-(B0C-Phe-GLy-AHCP-Abu-amino)-propane-1,2-dioL 3-(BOC-Phe-GLy-AHCP-ALa--amino)-propane-1,2-dioL 3-(BOC-Phe-GLy-AHCP-CaL-amino)-propane-1 ,2-d ioL 3-(BOC-Phe-GLy-AHCP-His-amino)-propane-1 ,2-dioL 3-(BOC-Phe-GLy-AHCP-Leu-amino)-propane-1 ,2-dioL o.P e- H P- e -m no r p ne 1 2 d o o 3-(BOC-Phe--GLy-AHCP-et-amino)-propane-1 ,2-d ioL 3-(BOC--Phe-GLy-AHCP-Nle-amino)-propane-1 ,2-dioL 3-(BOC-Phe-GLy-AHCP-Tph-amino)-propane-1,2-dioL 3-CBOC-Phe-GLy-AHCP-Tr-amino)-propane-1,2-d joL 0 0 ov 03-CBOC-Phe-GLy-AHCP-Tyr-amino)-propane-1 ,2-d ioL 0 3-CBOC-Phe-GLy-AHCP-aLe-amino)-propane-1 ,2-d joL 3-CBOC-Phe-GLy-S,ta-I Le-amino)-propane-1,2-d ioL 3-(BOC-Phe-GLy-AHPP-ILe--amino)-propane-1,2-dioL.

Example 8 0 099999 6 9 A solution of 1 g of 2-[1S-(BOC-Phe-His-AHCP-amino)- 3-methyLbutyLJ-3H-quinazoLin-4-one in 20 ml of 4N HCI in dioxane is stirred for 30 minutes at 200 and is then evaporated. This gives 2-E1S-(H-Phe-His-AHCP-amino)-3-methyLbutyt)-3H-quinazoL in-4-one.

The fo~Lowing are obtained analogously by cleaving the corresponding BOC derivatives: -34- 3-(H-Phe-GLy-AHCP-I Le-ami no)-propane-1,2-dioL 3-CH-Phe-H is-AHCP-I Le-amino)-propane-1,2-dioL N 4 -(H-Phe-GLy--AHCP-Leu )-suLfani Lami de N 4 -(H-Phe-His-AHCP-Leu)-suLfaniLamide 2-ClS-(H-Phe--His-AHCP-amino)-3-methyLbutyL]-3--amino-3HquinazoLin-4-one 2-E1S-CH-Phe-His-AHCP-amino)-2S-methyLbutyLj--3H-quinazoL in- 4-one 2-[IS-(H-Phe-H is-AHCP-amino)-2S--methyLbutyL J-3-amino-3HquinazoL in-4-one.

Example 9 1 g of 2-[1S-CCBZ-Phe-His-AHCP-amino)-3-methyLbutylI-3H-quinazoLin-4-one is dissolved in 15 ml of ethanol, and the mixture is hydrogenated over 0.5 g of 10% Pd/C at 200 and 1 bar for 3 hours and is filtered and evaporated to give, after purification by chroma.tography, 2-EIS-(H- Phe-His-AHCP-amino)-3-methyLbutyL]-3H-quinazoLin-4-one.

Example 70 mg of hydroxyLamine hydrochloridle are added to a solution of 826 mg of 2-E1S-(3-Oxo-4S-BOC-Phe-His-amino- 5-cycLohexyLpentanoyLamino)-3-methyLbutyLJ-3H-quinazoL in- 4-one and 1.43 g of Na 2

CO

3 10 H 2 0 in 5 ml of methanol and ml of water, and the mixture is stirred for 14 hours at 200. The precipitated oxime is filtered off, dried, dissolved in 10 ml of methanol and hydrogenated over 0.5 g of Raney Ni at 200 and 5 bar. The catalyst is filtered off, the filtrate is evaporated and the resulting mixture is separated over silica gel to give 2-C1S-(3S-amino-4S-BOC- Phe-H is-amino-5-cycLohexyLpentanoyLami no)-3-methyLbutyL 3H-quinazoL in-4-one E"2-E1S-(BOC-Phe-His-DACP-amino)-3methyLbutyLJ-3H-quinazoLin-4-ine"J; the 3R-amino epimer is also obtained.

The following are obtained analogously from the corresponding oxo compounds: 2-E1S-(BOC-Phe-His-DACH-amino)-3-methyLbutyL]-3H-quinazoLin- 4-one 1 r I- 35 2 -C1S-(BOC-Phe-His-DAMH-amino)-3-methyLbutyL]-3H-quinazolin- 4-one 2-[1S-(BOC-Phe-His-DAPP-amino)-3-methylbutyLJ-3H-quinazolin- 4-one.

Example 11 g of Raney nickel, moistened with 0.5 g of isopropanol, is added to a solution of 1 g of 2-C1S-(BOC-Phe- His-AHCP-amino)-3-methylbutyl]-3-amino-3H-quinazolin-4-one in 500 ml of isopropanol, and the mixture is boiled for 5 hours. After filtration, the mixture is evaporated and worked up in the customary manner to give 2-C1S-(BOC-Phe- His-AHCP-amino)-3-methylbutyl]-3H-quinazolin-4-one, m.p.

147-1490 The examples below relate to pharmaceutical formulations.

Example A: Injection vials The pH of a solution of 100 g of 2-E1S-(BOC-Phe- His-AHCP-amino)-3-methylbutyl]-3H-quinazolin-4-one and 5 g S° of disodium hydrogenphosphate in 4 L of twice distilled water is adjusted to 6.5 with 2N hydrochloric acid, and the solution is filtered under sterile conditions and filled *oo° into injection vials. These are lyophilized under sterile conditions and closed in a sterile manner. Each injection vial contains 500 mg of active compound.

Example B: Suppositories A mixture of 50 g of 2-C1S-(BOC-Phe-His-A!CP-amino)- 3-methylbutyl]-3-amino-3H-quinazolin-4-one with 10 g of soya 60 lecithin and 140 g of cocoa butter is melted, poured into so moulds and allowed to cool. Each suppository contains 250 S 30 mg of active compound.

0 9 0000 a eI

Claims

1. Amino acid derivatives of the fo'rmuLaI X-- 2 -CHR 3 -R 4 -(CHR 5 n) -CO-E-NR 6 -D w h ere i n x z E is H, R 1 -0-C mH 2m-CO-, R 1 -C u mOC- R 1-C H -mCO-,R- so- or (R 1-C mH 2m-(T) x-C rH 2r)-L(R 7-C pH2)-C tH -tG o-, is 0 to 4 amino acid radicaLs attached to one ano- ther by a peptide Linkage and selected from the group cons isting of Abu, Ada, ALa, BALa, Arg, Asn, Asp, Bia, Cal, Dab, G~n, GLu, GLy, His, N(im)-aLkyL- His, ILe, Leu, tert.-Leu, Lys, Met, aNaL, BNaL, Nbg, N~e, Orn, Phe, Pro, Ser, Thr, Tic, Trp, Tyr and VaL, is 0 to 2 amino acid radicals attached to one ano- ther by a peptide Linkage and selected from the group consisting of Abu, Ala, Cal, His, I~e, Leu, Met, N~e, Phe, Trp, Tyr and Val, is -CH 2 -CHOH-CH 2 OH, -CZH2z-S02-R14, a phenyL- CYH 2 furyL-CyH 2 thienyL-CyH 2 y- or pyri- dyL-CvH 2 y- radical which is substituted by one or two R 14_S2 groups or an R 14_ O group or an (Rt 4 2 -PO- group and, if desired additionally by an Hal atom, or D is .4. a *$SF~4 04 4 o 5 4* 4 a. .4.404 '.0t4 St *444 td 0s .4, 4,44, 4,1J4 o R 1 R 3 R 7 and R 8 are each H, A, Ar, Ar-aLkyL, Het, C 37 Het-alkyL or cycLoaLkyL having 3-7 C atoms, cyclo- aLkylalkyL having 4-11 C atoms, bicycloaLkyL or tricycLoaLkyL having in each case 7-14 C atoms or bicycLoalkyLaLkyL or tricycloaLkyLaLkyl having in each case 8-18 C atoms, each of which is unsubsti- tuted or monosubstituted or poLysubstituted by A, AO and/or Hat, 2 5 6 R R and R are each H or A, 4 R is OH), NH 2 or =0, 9 R is H, NH 2 NHA or NA 2 10D R 11 123 R, R, R and R are each H, HaL, OH, OA, NH 2 SH, SA, SO 2 NH 2 CF 3 CN, COOH or COOA, R 14 is OH, OA, NH 2 NHA, NA 2 NHcycLoaLkyL having

3-7 C atoms, N(cycLoaLkyL) 2 having 6-14 C atoms, pyrrolidik g piperidino, hexahydroazepino, morpho- Lino, thiomorphoLino, piperazino, N-A-piperazino, NHAr or NHHet, L is CH or N, I T is 0, S, NH or NA, m n is 1 or 2, m, p, r and t are each 0, 1, 2, 3, 4 or x is 0 or 1, 4 y is 0, 1 or 2, r z is 2, 3, 4, 5 or 6, Ar is phenyL which is unsubstituted or monosubstituted or polysubstituted by A, AO, HaL, CF 3 OH, H 2 NSO 2 and/or NH 2 or unsubstituted naphthyl, Het is a saturated or unsaturated 5-membered or 6-mem- bered heterocycLic radical which has 1-4 N, 0 and/or S atoms, which can be condensed with a benzene ring and/or can be monosubstituted or poLysubstituted by A, AO, Hat, CF 3 HO, 0 2 N, carbony', oxygen, H 2 N, HAN, A 2 N, AcNH, AS, ASO, ASO 2 HOOC, AOOC, CN, H 2 NCO, H 2 NSO 2 AS02NH, Ar or Ar-alkenyl, hydroxyalkyl and/or aminoalkyl having in each case 1-8 C atoms, and/or in which the N and/or S hetero- atoms can also be oxidized, Hat is F, CL, Br or I, I olo4d/NNG 38 Ac is A-CO-, Ar-CO- or A-NH-GO-, alkyl- is an alkylene group having 1-4 C atoms and A is alkyl having 1-8 C atoms, and wherein it is also possible for one or more -NA-CO- groups to replace one or more -NH-GO- groups, and salts thereof. 2. a) 2-[lS--(BOC-Phe-His--AHCP-amino)-2S-methyl- butyl] -3H-quinazol in-4-one; b) 2-LlS-(BOC-Phe--His-AHCP-amino)-2S-methyl- butyl]-3-amino-3H-quinazol in-4-one; c) 2-.[S-(BOC-Phe-His-AHCP-amino)-3-methyl- butylll-3H-quinazol in-4-one; or d) 2- [1S-(BOC-Phe-His-AHCP-amiino) -3-methyl- butylll-3-amino-3H-quinazol in-4-one. 3. Process for the preparation of an amino acid derivative of the formula I and salts thereof, characterized in that this amino acid derivative is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent, or in that a carboxylic acid of the 'formula II ,G 1-OH I 11 :V"ierein G is Z Z, Z -W, Z-W-E 1 Z-W-E and W is is reacted with 2 wherein G2is -NR -_CHR -_CR 4_(CHR an amino compound of the formula III -Z 2_W-E-NR 6_D, S 0104d/NNG 39 -W-E-NR6-D, -E-NR 6 -D, 2 6 -E -NR -D, -NR6-D, 1 2 E and E are each one amino acid radical selected from the group conisting of Abu, Ala, Cal, His, Ile, Leu, Met, Nle, Phe, Trp, Tyr and Val in such a manner that E 1 E together are E, 1 2 Z and Z are each 1 to 3 amino acid radicals selected from the group consisting of Abu, Ada, Ala, IAla, Arg, Asn, Asp, Bia, Cal, Dab, Gln, Glu, Gly, His N(im)- alkyl-His, Ile, Leu, tert -Leu, Lys, Met, aNal, BNal, Nbg, Nle, Orn, Phe, Pro, Ser, Thr, Tic, Trp, Tyr and Val in such 1 2 a manner that Z Z together are Z, and in that, if appropriate, a functionally modified amino and/or hydroxyl group in a compound of the formula I is Liberated by treatment with solvolysing or hydrogenolysing agents and/or, in order to prepare a compound of the formula I wherein R 4 OH) or NH an aminoketo acid derivative of the °'formula I wherein R 0 is reduced or reductively *:"'aminated and/or a radical D is converted into an- other ,;adical D by treatment with esterifying, solvolysing or I reducing agents and/or a compound of the formula I is Sconverted into one of its salts by treatment with an acid.

4. Process for the preparation of pharmaceutical i formulations, characterized in that a compound of the 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 or Sauxiliary and, if appropriate, in combination with one or more further 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. The use of compounds of the formula I or of physiologically acceptable salts thereof for the preparation of a medicament. 0ol4d/NrNG 40

7. The use of compounds of the formula I or of physiologically acceptable salts thereof in combating renin-dependent hypertension or hyperaldosteronism. DATED this 1st day of July, 1991. MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HUNETUNG By Its Patent Attorneys ARTHUR S. CAVE CO. a *9* o O4 0 oft a S 0 #08* 04 a 0 0t 001 C 0 0 *0* alt.