IE920655A1 - Peptide analogues - Google Patents

Peptide analogues

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Publication number
IE920655A1
IE920655A1 IE065592A IE920655A IE920655A1 IE 920655 A1 IE920655 A1 IE 920655A1 IE 065592 A IE065592 A IE 065592A IE 920655 A IE920655 A IE 920655A IE 920655 A1 IE920655 A1 IE 920655A1
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Ireland
Prior art keywords
amino
dihydroxy
cyclohexylhexyl
formula
alkyl
Prior art date
Application number
IE065592A
Inventor
Horst Juraszyk
Peter Raddatz
Johannes Sombroek
Joachim Gante
Claus J Schmitges
Klaus-Otto Minck
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Merck Patent Gmbh
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Publication of IE920655A1 publication Critical patent/IE920655A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0227—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the (partial) peptide sequence -Phe-His-NH-(X)2-C(=0)-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6 see C07K5/06 - C07K5/10
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

Peptide analogues of the formula I R<1>-Z-NR<2>-CHR<3>-CR<4>-CH2-CR<5>R<6>-Y I in which R<1> to R<6>, Z and Y have the meanings stated in Claim 1, and the salts thereof, inhibit the activity of human plasma renin.

Description

Peptide analogues March 3, 1991 The invention relates to new peptide analogues of the formula I r1-z-nr2-chr3-cr4-ch2-cr5r6-y 1 in which R1 is H, R7-O-CeH2ffl-CO-, R'-C^-O-CO-, R'-CJI^-CO-, r7-so2-, rVn-c^-co-, R10-NH-C (=NH) -NH-C^-CO-, R’OOC-C^-CO-, R®O3S-CfflH2a-CO- or R11-CBH2m- (T),- (V) ,-C^-L (R7-CpH2p) C^-CO-, Z is 0 to 4 amino acid residues which are linked together in the manner of a peptide and are selected from the group comprising Abu, Ada, Ala, 0Ala, Arg, Asn, Asp, Bia, Cal, Dab, Gin, Glu, Gly, His, N(im)-A-His, Hph, lie, Isoser, Leu, tert.-Leu, Lys, Mai, Met, aNal, 0Nal, Nbg, Nle, Nva, Orn, Phe, Pia, Pro, Pya, Ser, Thr, Tia, Tic, Trp, Tyr and Val, Y is -CN, -NO2, -CH2-NR12R13, -CH2-NR12-SO2Ru, -ch2-nr12-cor1* , -ch2-nr12-co-nh-r14 , -CH2-NR12-CS-NH-Ru or -COR16, R2, R®, R9 and R13 are each H or A, R* is (H, R17) or =0, R5 is OH, OR7, OCOR7, OSiR18R19R20, NR®R9 or -0-(2-tetrahydropyranyl), R® is H, A, Ar or aralkyl, R3 and R® together are also (=0), R1® is H, OH, OR7, NR*R9, OSiRieR19R20 or -O-(2-tetrahydropyranyl), R17 is OH or NH2, - 3 Rs and R17 together are also -T1-(CR3R7)-T2-, R3, R7, Ru, R12 and R1* are each H, A, Ar, Ar-alkyl, Het or Het-alkyl, unsubstituted or singly or multiply, by A, AO and/or Hal, substituted cycloalkyl having 3-7 C atoms, cycloalkylalkyl having 4-11 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms, or bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C atoms, Rn is also R®0-, R8R®N-, R®OOC- or A3N+ An®, R18, R19 and R20 are each A, Ar or aralkyl, R10 is H, A or CN, L is CH or N, T, T1 and T2 are each O or NR®, V is CHOR2, CO, S, SO or SO2, ReR®N and NR12R13 are also each a pyrrolidino, piperidino, morpholino or piperazino group which is unsubstituted or is substituted by A, OH, NH2, NHA, NAj, NHAc, NH-CO-C^-O-R15, NH20 CO-O-C^-R15, hydroxyalkyl, COOH, COOA, CONH2, aminoalkyl, HAN-alkyl, AjN-alkyl, A3N+ alkyl An®, NH-CO-NH2, NH-CO-NHA, guanidinyl or guanidinylalkyl, R15 is A or Ar-alkyl, s and y are each 0 or 1, m, n, p, r and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or , Ar is phenyl which is unsubstituted or is substituted one or more times by A, OA, 30 Hal, CFj, OH, N02, hydroxyalkyl, NH2, NHA, NAa, NHAc, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, aminoalkyl, HANalkyl, AaN-alkyl, A3N+ alkyl An® and/or guanidinyl-alkyl, or is unsubstituted 35 naphthyl, is a saturated or unsaturated 5- or 6membered heterocyclic radical which has 14 N, 0 and/or S atoms and can be fused Het with a benzene ring and/or be substituted one or more times by A, OA, Hal, CF3, OH, NO2, carbonyl oxygen, NH2, NHA, NA2, NHAc, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, NH-SO2-A, Ar, Ar-alkyl, Aralkenyl, hydroxyalkyl, aminoalkyl, HANalkyl and/or AaN-alkyl, and/or whose N and/or S hetero atoms can also be oxidized, Hal is F, Cl, Br or I, Ac is A-CO-, Ar-CO-, Ar-alkyl-CO- or A-NH-CO, An® is an anion, which can also be absent if, in its place, a carboxyl group contained in the compound of the formula I is in the form of a carboxylate anion, -alkyl- is an alkylene group having 1-8 C atoms, and A is alkyl having 1-8 C atoms, in which, furthermore, it is also possible for one or more -NH-CO- groups to be replaced by one or more -NA-COgroups, with the provisos that a) in the case R1 = (TJ.-V-C^-Li R7-CpH2p)C^-CO- with V = S, SO or SO2, and Y = -CH2NR12R13 with R12 = R13 = H, R3 then is OCOR7, OSiR18R1BR20, NR*Re or -0- (2-tetrahydropyranyl), b) in the case R1 = R11-CBH2,-(T).-V-CnH2n-L(R7-CHpH2p) CJI^-CO- with V - S, SO or SO2, and Y » COR18, R18 then is H, OH, OR7, OSiR18R19R20 or -0-(2-tetrahydropyranyl) , as well as the salts thereof.
Similar compounds are disclosed in EP-A 249,096. The invention had the object of finding new compounds with valuable properties, in particular those which can be used for the preparation of medicaments.
It has been found that the compounds of the formula I and the salts thereof have very valuable properties. In particular, they inhibit the activity of human plasma renin. This action can be detected, for example, by the method of F. Fyhrquist et al., Clin.Chem. 22. 250-256 (1976). The noteworthy point is that these compounds are very specific inhibitors of renin; as a rule, the concentrations of these compounds necessary for the inhibition of other aspartyl proteinases (for example pepsin and cathepsin D) are about 100 to 1000 times as high as for renin inhibition. The actions of the compounds on the blood pressure and/or on the heart rate, as well as the inhibition of renin activity in blood plasma can furthermore be determined in conscious monkeys, for example female monkeys (Macaca fascicularis); it is possible in this for the blood pressure and heart rate to be measured by a modification of the method of M.J. Wood et al., J. Hypertension 4, 251-254 (1985). In order to stimulate renin activity in this, the animals are preferably pretreated with a saluretic. Blood samples for the determination of the plasma renin activity can be obtained by puncture of the femoral vein.
The compounds can be used as pharmaceutically active substances in human and veterinary medicine, in particular for the prophylaxis and for the treatment of diseases of the heart, circulation and vessels, especially of hypertension, cardiac insufficiency and hyperaldosteronism. In addition, the compounds can be used for diagnostic purposes in order to determine, in patients with hypertension or hyperaldosteronism, the possible contribution of the renin activity to maintaining the pathological state. The procedure for such diagnostic tests can be similar to that Indicated in EP-A 77,028.
The abbreviations quoted hereinbefore and hereinafter for amino acid residues represent the radicals —NR'—R-CO—, as a rule -NH-CHR-CO- (in which R, R' and R have the specific meaning known for each amino acid), of the following amino acids: Abu 2-aminobutyric acid Ada 3-(1-adamantyl)-alanine Ala alanine 0Ala ^-alanine Arg arginine Asn asparagine Asp aspartic acid Bia 3-(2-benzimidazolyl)-alanine Cal 3-cyclohexylalanine Dab 2,4-diaminobutyric acid Gin glutamine Glu glutamic acid Gly glycine His histidine N( im)-A-His histidine substituted in the 1 or 3 position of the imidazole ring by A Hph homophenylalanine (2-amino-4-phenylbu tyr ic acid) He isoleucine Isoser isoserine Leu leucine tert.-Leu tert.-leucine Lys lysine Mai 3-(p-methoxyphenyl)-alanine Met methionine aNal 3-(α-naphthyl)-alanine £Nal 3-(0-naphthyl)-alanine Nbg 2-norborny1-glyc ine Nle norleucine Nva norvaline N-Me-His N-methyl-histidine N-Me-Phe N-methyl-phenylalanine Orn ornithine Phe phenylalanine Pia 3-(piperidyl)-alanine [e.g. 2-Pia = 3-(2piperidyl)-alanine] Pro proline Pya 3-(pyridyl)-alanine [e.g. 3-Pya = 3-(3pyridyl)-alanine] Ser serine Thr threonine Tia 3-(thienyl)-alanine [e.g. 2-Tia = 3-(2thienyl)-alanine] Tic 1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid Trp tryptophan Tyr tyrosine Val valine.
Further meanings hereinafter are: BOC tert.-butoxycarbonyl BOM benzyloxymethyl imi-BOM benzyloxymethyl in the 1 position of the imidazole ring CBZ benzyloxycarbonyl DAPECI dimethylaminopropylcarbodiimide DCCI dicyclohexylcarbodiimide DMF dimethyl formamide DNP 2,4-dinitrophenyl imi-DNP 2,4-dinitrophenyl in the 1 position of the imidazole ring ETOC ethoxycarbonyl FMOC 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole IPOC isopropoxycarbonyl NMM N-methylmorpholine POA phenoxyacetyl THF tetrahydrofuran.
If the abovementioned amino acids can occur in several enantiomeric forms, then all these forms, as well as mixtures thereof (for example the DL forms), are included hereinbefore and hereinafter, for example as constituent of the compounds of the formula I. The L30 forms are preferred. Where individual compounds are mentioned hereinafter, then the abbreviations of these amino acids each relate to the L-form unless expressly indicated otherwise.
The invention furthermore relates to a process for the preparation of a peptide analogue of the formula I, and of the salts thereof, characterized in that it is liberated from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, or in that a carboxylic acid of the formula 11 RX-GX-OH II in which G1 is (a) absent, (b) Z, (c) Zx, or one of the reactive derivatives thereof, is reacted with an amino compound of the formula III h-g2-nr2-chr3-cr4-ch2-cr5r6-Y 111 in which G2 is (a) Z, (b) absent, (c) Z2 and Zx + Z2 are together Z, and in that a functionally modified amino and/or hydroxyl group in a compound of the formula I is liberated where appropriate by treatment with solvolyzing or hydrogenolyzing agents, and/or a free amino group is acylated by treatment with an acylating agent and/or for the preparation of a compound of the formula I, R* (H, OH) or (H, NH2), an amino keto acid derivative of the formula I, R* = 0, is reduced or reductively aminated, and/or a radical Rx is converted to another radical Rx, and/or a compound of the formula I is converted by treatment with an acid into one of the salts thereof.
Hereinbefore and hereinafter the radicals and parameters Rx to R20, Z, Y, I», T, T1, T2, V, m, n, p, r, s, x, y, Ar, Het, Hal, Ac, An, A, Gx, G2, Z1 and Z2 have the meanings indicated for the formulae I, II or III unless expressly indicated otherwise.
A in the abovementioned formulae has 1-8, preferably 1, 2, 3 or 4 C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl, as well as pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl1-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2- or 1,2,2IE 920655 trimethylpropyl, heptyl or octyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but is also, for example, 1-, 2- or 3-methylcyclopentyl, or 1-, 2-, 3- or 4-methylcyclohexyl. -alkyl- is an alkylene group having 1-8 C atoms, preferably 1, 2, 3 or 4 C atoms, -alkyl- is preferably methylene, ethylene, propylene, butylene, and furthermore pentylene, hexylene, heptylene, octylene, isopropylene, 1-ethylpropylene or 1-, 2- or 3-methylbutylene.
Correspondingly, cycloalkylalkyl is preferably cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2 -eye lobutylethy 1, eye lopentylmethyl, 2 -eye lopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, but is also, for example 1-, 2- or 3-methyleyelopentylmethyl, or 1-, 2-, 3- or 4-methylcyclohexylmethyl.
Bicycloalkyl is preferably 1- or 2-decalyl, 2-bicyclo[2.2.1]heptyl or 6,6-dimethyl-2-bicyclo[3,1,1]heptyl20 Tricycloalkyl is preferably 1-adamantyl.
Hal is preferably F, Cl or Br, but is also I.
Ac is preferably A-CO-, such as acetyl, propionyl or butyryl, Ar-CO- such as benzoyl, ο-, m- or p-methoxybenzoyl or 3,4-dimethoxybenzoyl, or A-NH-CO- such as N25 methyl- or N-ethylcarbamoyl.
Ar is preferably phenyl and is furthermore preferably ο-, m- or p-tolyl, ο-, m- or p-ethylphenyl, ο—, m- or p-methoxyphenyl, ο-, m- or p-fluorophenyl, ο-, m- or p-chlorophenyl, ο-, m- or p-bromophenyl, ο-, m- or p-iodophenyl, ο-, m- or p-trifluoromethylphenyl, ο-, mor p-hydroxyphenyl, ο-, m- or p-sulfamoylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl, 3,4,5trimethoxyphenyl, ο-, m- or p-aminophenyl, ο-, m- or paminomethylphenyl, ο-, m- or p-dimethylaminomethylphenyl, o—, m- or p-guanidinomethylphenyl, or 1- or 2-naphthyl.
Correspondingly, Ar-alkyl is preferably benzyl, 1- or 2-phenylethyl, ο-, m- or p-methylbenzyl, 1- or 2o—, -m- or -p-tolylethyl, ο-, m- or p-ethylbenzyl, 1- or 2- 0-, -m- or -p-ethylphenylethyl, o-, m- or p-methoxybenzyl, - 10 1- or 2-ο-, -m- or -p-methoxyphenylethyl, ο-, m- or pfluorobenzyl, 1- or 2-ο-, -m- or -p-fluorophenylethyl, ο-, m- or p-chlorobenzyl, 1- or 2-ο-, -ra- or -p-chlorophenylethyl, ο-, m- or p-bromobenzyl, 1- or 2-ο-, -m- or -p-bromophenylethyl, ο-, m- or p-iodobenzyl, 1- or 2-0-, -m- or -p-iodophenylethyl, ο-, m- or p-trifluoromethylbenzyl, ο-, ra- or p-hydroxybenzyl, 2,3-, 2,4-, 2,5-, 2,63.4- or 3,5-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, ο-, m- or p-aminobenzyl, ο-, m- or p-aminomethylbenzyl, ο-, m- or p-dimethylaminomethylbenzyl, ο-, m- or p-guanidinomethylbenzyl, or 1- or 2-naphthylmethyl.
Het is preferably 2- or 3-furyl, 2- or 3-thienyl, 1- , 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3- , 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 515 isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-l-, -4- or -5-yl, 1.2.4- triazol-l-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, l,2,4-oxadiazol-3- or -5-yl, 20 l,3,4-thiadiazol-2- or -5-yl, l,2,4-thiadiazol-3- or 5yl, 2,l,5-thiadiazol-3- or -4-yl, 2-, 3-, 4-, 5- or 6-2Hthiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2- , 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, -, 6- or 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, - , 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4- , 5-, 6- or 7- benzothiazolyl, 2-, 4-, 5-, 6- or 730 benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6- , 7- or 8-isoquinolyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, - , 6-, 7- or 8-cinnolyl, 2-, 4-, 5-, 6-, 7- or 835 quinazolyl. The heterocyclic radicals can also be partially or completely hydrogenated. Thus, Het can also be, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or 3furyl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro1-, -2- or -4-imidazolyl, 2,3-dihydro-l-, -2-, -3-, -4or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,45 dihydro-Ι-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro1- , -2-, -3-, -4-, -5- or -6-pyridyl, 1,2,3,6tetrahydro-Ι-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2- , 3- or 4-piper idinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,310 dioxan-2-, -4- or -5-yl, hexahydro-Ι-, -3- or -4-pyridazinyl, hexahydro-Ι-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3- piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl.
The heterocyclic radicals can also be substituted as indicated. Het can also preferably be, for example, 2amino-4-thiazolyl, 4-carboxy-2-thiazolyl, 4-carbamoyl-2thiazolyl, 4-(2-aminoethyl)-2-thiazolyl, 4-amino-2methyl-5-pyrimidinyl, 2-amino-5,6-dimethyl-3-pyrazinyl, 4-carbamoylpiperidino, furthermore, for example, 3-, 4or 5-methyl-2-furyl, 2-, 4- or 5-methyl-3-furyl, 2,4dimethyl-3-furyl, 5-nitro-2-furyl, 5-styryl-2-furyl, 3-, 4- or 5-methyl-2-thienyl, 2-, 4- or 5-methyl-3-thienyl, 3- methyl-5-tert.-butyl-2-thienyl, 5-chloro-2-thienyl, 525 phenyl-2- or -3-thienyl, 1-, 3-, 4- or 5-methyl-2-pyrrolyl, l-methyl-4- or -5-nitro-2-pyrrolyl, 3,5-dimethyl4- ethyl-2-pyrrolyl, 4-methyl-5-pyrazolyl, 5-methyl-3isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 4- or 5-methyl-2thiazolyl, 2- or 5-methyl-4-thiazolyl, 2- or 4-methyl-530 thiazolyl, 2,4-dimethyl-5-thiazolyl, 3-, 4-, 5- or 6-methyl-2-pyridyl, 2-, 4-, 5- or 6-methyl-3-pyridyl, 2or 3-methyl-4-pyridyl, 3-, 4-, 5- or 6-chloro-2-pyridyl, 2- , 4-, 5- or 6-chloro-3-pyridyl, 2- or 3-chloro-4pyridyl, 2,6-dichloropyridyl, 2-hydroxy-3-, -4-, -5- or -6-pyridyl (= lH-2-pyridon-3-, -4-, -5- or -6-yl), 5phenyl-lH-2-pyridon-3-yl, 5-p-methoxyphenyl-lH-2-pyridon3- yl, 2-methyl-3-hydroxy-4 -hydroxymethyl-5-pyridyl, 2hydroxy-4-amino-6-methyl-3-pyridyl, 3-N'-methylureido-lH4- pyridon-5-yl, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-2IE 920655 pyrimidinyl, 2-, 5- or 6-methyl-4-pyrimidinyl, 2,6dimethyl-4-pyrimidinyl, 2,6-dihydroxy-4-pyrimidinyl, 5chloro-2-methyl-4-pyrimidinyl, 3-methyl-2-benzofuryl, 2ethyl-3-benzofuryl, 7-methyl-2-benzothienyl, 1-, 2-, 4-, -,6- or 7-methyl-3-indolyl, l-methyl-5- or -6-benzimidazolyl, 1-ethyl-5- or -6-benzimidazolyl, 3-, 4-, -, 6-, 7- or 8-hydroxy-2-quinolyl, 2-oxo-pyrrolidino, 2oxo-piperidino, 2,5-dioxopyrrolidino or 3-benzyl-2,5dioxopyrrolidino.
R1 is, in general, preferably R8R9N-CdH2oi-CO- or R7-CmH2m-O-CO-, furthermore preferably r’-C^^-CO- , ReOOCC^-CO- or R11-CnH2ll-(T),-(V)y-CnH2n-L(R7-CpH2p)-CrH2r-CO-.
The group Z preferably consists of one or two of the stated amino acid residues; however, it can also contain three or four amino acid residues or be absent.
Z is preferably His, Phe or Phe-His, furthermore preferably Cal-His, Mal-His, aNal-His, ^Nal-His, Phe-Abu, Phe-Ala, Phe-^Ala, Phe-Ser, Phe-Asn, Phe-Gln, Phe-Glu, Phe-Gly, Phe-Nle, Phe-Pya (especially Phe-3-Pya), Phe-Tia (especially Phe-3-Tia), Tia-His (especially 3-Tia-His), Trp-His, Tyr-His or Pro-Phe-His.
Y is, in general, preferably -CN or -CH2-NR12SOjR1*, furthermore preferably -CHj-NR^-CO-NHR1* or -CH2-NR12-CS-NHRu .
R2, Re, Re and Rn are each preferably H and furthermore preferably methyl. ReR®N is also preferably pyrrolidino, piperidino, morpholino, amino-piperidino such as 4-aminopiperidino, alkylaminopiper idino such as 4-methylaminopiperidino, or dialkylaminopiperidino such as 4-dimethylaminopiperidino.
R3 is preferably cycloalkylalkyl, especially cyclohexylmethyl, furthermore preferably alkyl, especially isobutyl; Ar-alkyl, especially benzyl; cycloalkyl, especially cyclohexyl.
R* is preferably (H, R17), in which R17 is OH or NH2.
R* is especially preferably (H, OH).
R3 is preferably OH, OR7, OCOR7 or OSiR18R18R20. Preferably, R3 together with R17 also is -T1- (CR3R7) -t2- .
R® is preferably H or A, particularly methyl.
R5 and R® together are also preferably (=0).
R7 is preferably A, especially methyl, ethyl, isopropyl or tert.-butyl; or Ar, especially phenyl, 1- or 2-naphthyl.
R10 is preferably H, methyl or CN.
R11 is preferably H; A, especially methyl or tert.-butyl; R®ReN, especially A2N such as (CH3)2N, piperi10 dino or 4-aminopiperidino.
R12 and R13 are preferably H or A, especially methyl.
R1* is preferably A, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.15 butyl, pentyl or isopentyl; cycloalkylalkyl, especially cyclohexylmethyl; Ar-alkyl, especially benzyl; Ar, especially phenyl or aminophenyl such as p-aminophenyl.
R1S is preferably A having 1-4 C atoms, especially isopropyl or tert.-butyl; or Ar-alkyl, especially benzyl.
R1’ is preferably H, OH or OR7.
R17 is preferably OH.
R1’, R18 and R20 independently of one another are each preferably A, particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl or isopentyl; Ar, particularly phenyl or Ar-alkyl, particularly benzyl.
L is preferably CH, furthermore preferably N.
T is preferably O or NR®, in which R® is H or A.
T1 and T2 are preferably O.
V is preferably CO or SO2.
The parameter 8 is preferably 0 but also 1; y is preferably 1 but also 0. The sum s + y is preferably 1 but also 0 or 2. The parameter m is preferably 1, 2, 3, or 5; n is preferably 1; pH is preferably 1; r is preferably 1 or 0. The groups C^Hj., C^H^, CpHjj, and CjH^ are preferably straight-chain and thus are preferably -(CH2).-, -(CH2)b-, -(CH2)p- or -(CH2)r-.
Accordingly, the group R1 is specifically and preferably R®R8N-(CH2).-CO-, especially HjN-C.Hj.-CO- such as aminocarbonyl, aminoacetyl (H-Gly)-, 3-aminopropionyl (H-0Ala-), 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl, 11-aminoundecanoyl, but also, for example, 2-amino-propionyl (Ala), 2-amino-2-methylpropionyl; ANH-C.H2.-CO- such as methylaminocarbonyl, methylaminoacetyl (sarcosyl), 3-methylaminopropionyl, 4methylaminobutyryl, 5-methylaminopentanoyl, 6-methylaminohexanoyl, 6 -ethylaminohexanoyl, 7 -methylaminoheptanoyl, 8-methylaminooctanoyl, 9-methylaminononanoyl, 10-methylaminodecanoyl, 11-methylaminoundecanoyl; A2N-C.H2.-COsuch as dimethylaminocarbonyl, dimethylaminoacetyl, 3-dimethylaminopropionyl, 4-dimethylaminobutyryl, 5-dimethylaminopentanoyl, 6-dimethylaminohexanoyl, 6-diethylamino15 hexanoyl, 7-dimethylaminoheptanoyl, 8-dimethylaminooctanoyl, 9-dimethylaminononanoyl, 10-dimethylaminodecanoyl, 11-dimethylaminoundecanoyl; A-O-CO-NH-CJij.-CO- such as BOC-Gly, ETOC-Gly-, IPOC-Gly, BOC-^Ala, ETOC-^Ala, IPOC-ySAla, 4-BOC-amino-butyryl, 5-BOC-amino-pentanoyl, 620 BOC-amino-hexanoyl, 7-BOC-amino-heptanoyl, 8-BOC-aroinooctanoyl, 9-BOC-amino-nonanoyl, 10-BOC-amino-decanoyl, 11-BOC-amino-undecanoyl; ArCHj-O-CO-NH-CJH^-CO- such as CBZ-Gly-, CBZ-^Ala, 4-CBZ-amino-butyryl, 5-CBZ-aminohexanoyl, 7-CBZ-amino-heptanoyl, 8-CBZ-amino-octanoyl, 925 CBZ-amino-nonanoyl, 10-CBZ-amino-decanoyl, 11 -CBZ-aminounde canoyl; pyrrolidino-C.H2.-CO- such as pyrrolidinocar- bonyl, pyrrol idino-acetyl, 3-pyrrolidino-propionyl, 4- pyrrol idi no-butyryl, 5-pyrrolidino-pentanoyl, 6- pyrrolidino-hexanoyl, 4-pyrrolidino-heptanoyl, 8- 30 pyrrol idino-octanoyl, 9-pyrrolidino-nonanoyl, 10- pyrrolidino-decanoyl; piperidino-C.H21.~CO- such as piperidinocarbonyl, piperidinoacetyl, 3-piperidino-propionyl, 4-piperidino-butyryl, 5-piperidino-pentanoyl, 6-piperidino-hexanoyl, 7-piperidino-heptanoyl, 8-piperidino35 octanoyl, 9-piperidino-nonanoyl, 10-piperidino-decanoyl; morpholino-C.H2.-CO- such as morpholinocarbonyl, morpholinoacetyl, 3-morpholino-propionyl, 4-morpholinobutyryl, 5-morpholino-pentanoyl, 6-morpholino-hexanoyl, 7-morpholino-heptanoyl, 8-morpholino-octanoyl, 9-morIE 920655 pholino-nonanoyl, 10-morpholino-decanoyl; 4-amino-piperidino-CaH2a-CO- such as 4-amino-piper idino-carbonyl, 4amino-piperidino-acetyl, 3-(4-amino-piperidino)-propionyl, 4-(4-amino-piper idino) -butyryl, 5-(4-amino-piperi5 dino) -pentanoyl, 6-(4-amino-piperidino) -hexanoyl, - (4-amino-piperidino) -heptanoyl, 8- (4-amino-piperidino) octanoyl, 9-(4-amino-piperidino)-nonanoyl, 10-(4-aminopiperidino) -decanoyl; 4-dialkylamino-piperidino-CBH2a-COsuch as 4-dimethylamino-piperidinocarbonyl, 4-dimethyl10 amino-piperidino-acetyl; 4-guanidino-piperidino-CBH2a-COsuch as 4-guanidino-piperidino-carbonyl, 4-guanidinopiperidino-acetyl; 4-carboxy-piper idino-CaHja-CO- such as 4-carboxy-piper idino-carbonyl, 4-carboxy-piper id inoacetyl; 4-alkoxycarbonyl-piperidino-CaH2a-CO- such as 415 methoxycarbonyl-piperidino-carbonyl, 4-ethoxycarbonylpiperidino-carbonyl, 4-methoxycarbonyl-piper idino-acetyl, 4-ethoxycarbonyl-piperidino-acetyl; 4-Ac NH-piper idinoCaH^-CO- such as 4-acetamido-piper idino-carbonyl, 4acet amido-piper idino-acetyl; H2N-C(=NH)-ΝΗ-Ο,Η^-ΟΟ- such as guanidinoacetyl, 3-guanidino-propionyl, 4-guanidinobutyryl, 5-guanidino-pentanoyl, 6-guanidino-hexanoyl, 7guanidino-heptanoyl, 8-guanidino-octanoyl; NC-NH-C (=NH) NH-CaHja-CO- such as N *-cyanoguanidino-acetyl, 3-(N'cyanoguanidino) -propionyl, 4 - (N' -cyanoguanidino) -butyryl, -(Ν'-cyanoguanidino)-pentanoyl, 6-(Ν'-cyanoguanidino)hexanoyl, 7-(Ν'-cyanoguanidino)-heptanoyl, 8-(Ν'-cyanoguanidino) -octanoyl; HOOC-CaHja-CO- such as malonyl, succinyl, glutaryl, adipyl, 6-carboxyhexanoyl, 7-carboxyheptanoyl, 8-carboxyoctanoyl, 9-carboxynonanoyl, 1030 carboxy-decanoyl, 11-carboxyundecanoyl; AOOC-CaH^-COsuch as methoxycarbonyl-acetyl, 3-methoxycarbonyl-propionyl, 4-methoxycarbonyl-butyryl, 5-methoxycarbonylpentanoyl, 6-methoxycarbonyl-hexanoyl, 7-methoxycarbonylheptanoyl, 8-methoxycarbonyl-octanoyl, 9-methoxycarbonyl35 nonanoyl, 10-methoxycarbonyl -decanoyl, ethoxycarbonylacetyl, 3-ethoxycarbonyl-propionyl, 4-ethoxycarbonylbutyryl, 5-ethoxycarbonyl -pentanoyl, 6-ethoxycarbonylhexanoyl, 7-ethoxycarbonyl-heptanoyl, 8-ethoxycarbonyloctanoyl, 9-ethoxycarbonyl-nonanoyl, 10-ethoxycarbonylIE 920655 decanoyl; H-SOj-C^H^-CO- such as sulfo-acetyl, 3-sulfopropionyl, 4-sulfo-butyryl, 5-sulfo-pentanoyl, 6-sulfohexanoyl, 7-sulfo-heptanoyl, 8-sulfo-octanoyl, 9-sulfononanoyl, 10-sulfo-decanoyl; A-SOj-C^H^-CO- such as methoxysulfonyl-acetyl, 3-methoxy sulfonyl -propionyl, 4-methoxysulfonyl-butyryl, 5-methoxysulfonyl-pentanoyl, 6-methoxysulfonyl-hexanoyl, 7-methoxysulfonyl-heptanoyl, 8-methoxysulfonyl-octanoyl, 9-methoxysulfonyl-nonanoyl, 10-methoxysulfonyl-decanoyl, ethoxysulfonyl-acetyl, 310 ethoxysulfonyl-propionyl, 4-ethoxysulfonyl-butyryl, 5ethoxysulfonyl-pentanoyl, 6-ethoxysulfonyl-hexanoyl, 7ethoxysulfonyl-heptanoyl, 8-ethoxysulfonyl-octanoyl, 9ethoxysulfonyl-nonanoyl, 10-ethoxysulfonyl-decanoyl; ^'-C^-Co-C^-CHiR’-CpH^) -CrH2r-C0-, especially A-CO-CH2-CH(Ar-CH2)-CO- such as 2-benzyl-4-oxo-5,5-dimethylhexanoyl, 2-(1-naphthylmethyl)-4-oxo-5,5-dimethylhexanoyl; furthermore R8R9N-CO-CH2-CH(Ar-CH2)-CO- such as 2 -benzyl-3- (4 -aminopiper idinocarbonyl) -propionyl, 2-(1naphthylmethyl) -3- (4-aminopiperidinocarbonyl) -propionyl; R11-CmH2B-SO2-CBH2a-CH(R7-CpH2p)-CrH2r-CO-, especially A-SO2-CH2-CH(Ar-CH2)-CO such as 2-benzyl-3-tert.-butylsulfonylpropionyl, 2- (l-naphthylmethyl)-3-tert.-butylsulf onylpropionyl; RU-CbH2.-NH-C0-CbH2b-CH( R7-CpH2p) -C^-CO-, especially R8R9N-(CH2)1,-NH-CO-CH2-CH(Ar-CH2) -CO- such as 225 benzyl-3- (N-3-dimethylaminopropyl-carbamoyl) -propionyl, 2-(1-naphthylmethyl)-3-(N-3-dimethylaminopropyl-carbamoyl)-propionyl, 2-benzyl-3-(N-5-dimethylaminopentylcarbamoyl) -propionyl; A-CH( R7-CpH2p) -CrH^-CO-, especially A-CH(Ar-CH2)-CO- such as 2-benzylhexanoyl, 2-benzyl30 heptanoyl; R11-C„H2e-NH-CO-, especially R8R9N-(CH2)„-NH-COsuch as N-3-dimethylaminopropyl-carbamoyl, N-5-dimethylaminopentyl-carbamoyl; R11-CBH2a-N (R7-CpH2p) -CrH2t-CO-, especially A-N(Ar-CH2)-CO- such as N-benzyl-N-butylcarbamoyl, N-benzyl-N-isopentyl-carbamoyl; R7-CeH2a-O-CO35 especially A-O-CO- such as ETOC, IPOC, BOC as well as Ατ-Ο,,,Η^-Ο-ΟΟ- such as CB2; R7-C1DH2lI1-CO- such as 3,3-dimethylbutyryl.
Accordingly, the group Y is specifically and preferably -CN; -CH2NH-SO2RU, especially -CH2-NH-SO2-A such as methane-, ethane-, propane-, 2-methylpropane- and butane-sulfonamidomethyl, furthermore, for example, phenylmethane- and cyclohexylmethane-sulfonamidomethyl; -CHj-NH-CO-NH-R1*-, especially -CH2-NH-CO-NH-A such as N'methylureidomethyl, N'-propylureidomethyl, N'-butylureidomethyl, N'-isopentylureidomethyl, furthermore -CH2-NH-CO-NH-Ar such as N'-phenylureidomethyl and N'-paminophenylureidomethyl; -CH2-NH-CS-NH-Rl*, especially -CH2-NH-CS-NH-A such as N'-methylthioureidomethyl; -CH2-NH-CORU, especially -CH2-NH-CO-A such as acetamidomethyl, propionamidomethyl and butyramidomethyl.
If R1 = R^-C^-iTJ.-V-CJi^-LiR'-CjJLpJ-C.H^-COwith V = S, SO or S02 and at the same time Y = -CH2-NH2, R5 is OCOR7, OSiRieR19R20, NRaR9 or -O-(2-tetrahydropyranyl).
Furthermore, R18 is H, OH, OR7, OSiR18R19R20 or -0-(2-tetrahydropyranyl), if R1 = R11-CBH2l,-(T),-V-CnH2nL(R7-CpH2p)-CrH2l-C0- with V = S, SO or S02 and Y is COR16.
The compounds of the formula I may have one or more chiral centres and therefore exist in various, optically active or optically inactive, forms. The formula I embraces all these forms, the S enantiomers generally being preferred.
The abovementioned cycloalkyl and phenyl groups are preferably unsubstituted or carry preferably 1 to 3, especially 1 or 2, substituents.
Accordingly, the invention particularly relates to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated hereinbefore. Some preferred groups of compounds can be represented by the following part-formulae la to Ik: la R7-C Ho -0-C0-Z-NH-CHR3-CH0H-CHo-CHOH-Y; m 2m *· lb R7—C Ho -CO-Z-NH-CHR3-CHOH-CH0-CHOH-Y; m 2m Ic R8R9N-C Ho -CO-Z-NH-CHR3-CHOH-CH,-CHOH-Y; m 2m * Id R10-NH-C(=NH)-NH-CmH2m-CO-Z-NH-CHR3-CHOH-CH2-CHOH-Y; Ie R8OOC-C Ho -CO-Z-NH-CHR3-CHOH-CH_-CHOH-Y; m 2m * If R8R9N-C H~-CO-Z-NH-CHR3-CH-CH--CH-Y m 2m 2 3 7 2 T-CRR-T CHR3 -CHOH- CH2-CHR -Y ; Ih 4-Aminopiperidinocarbonyl-Z-NH-CHR3-CHOH-CH2-CHOH-Y; Ii A-CO-CH2-CH(ArCH2 )-CO-Z-NH-CHR3-CHOH-CH2-CHOH-Y; Ij Ik A-SO2-CH2-CH(ArCH2 ) -CO-Z-NH-CHR3-CHOH-CH2-CHR5-Y; R8R9N-C H„ -NH-CO-CH--CH(ArCH^)-CO-Z-NH-CHR3-CHOHm 2m 2 £. ch2-chr -Y.
Particularly preferred are compounds of the partformulae: (a) Iaa to Ika, which correspond to the formulae la to Ik but in which additionally Z is His, Phe, Phe-^Ala, Phe-Ser or Phe-His; (b) lab to Ikb and Iaab to Ikab, which correspond to the formulae la to Ik and Iaa to Ika but in which additionally R3 is isobutyl or cyclohexylmethyl.
Especially preferred are compounds of the partformulae: I* and la* to Ik*, which correspond to the formulae I and la to Ik, as well as those compounds which correspond to the other abovementioned part-formulae but in which additionally Y is -CN, -CHj-NH-CO-NH-R1*, -CHj-NH-CO-R1* or -CH2-NHSOj-R1* and R1* is A, Ar-alkyl or cycloalkylalkyl; I' and la' to Ik', which correspond to the formulae I and la to Ik, as well as those compounds which correspond to the other abovementioned part-formulae but in which additionally Y is -CH2-NH-SO2-A.
The compounds of the formula I, as well as the - 19 starting materials for the preparation thereof, are furthermore prepared by methods which are known per se and as are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), published by Georg Thieme, Stuttgart; as well as EP-A 45665, EP-A 77028, EP-A 77029, EP-A 81783, EP-A 249096), specifically under reaction conditions which are known and suitable for the said reactions. In this connection it is also possible to make use of variants which are known per se and which are not mentioned in detail herein.
It is also possible, if desired, to form the starting materials in situ so that they are not isolated from the reaction mixture but are immediately reacted further to give the compounds of the formula I.
The compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenoly20 sis.
Preferred starting materials for the solvolysis or hydrogenolysis are those which correspond to the formula I apart from containing, in place of one or more free amino and/or hydroxyl groups, corresponding protec25 ted amino and/or hydroxyl groups, preferably those which carry an amino protective group in place of an H atom bonded to an N atom, for example those which correspond to the formula I but contain in place of an His group an N(im)-R'-His group (in which R' is an amino protective group, for example BOM or DNP), or those of the formula R1-Z-NR2-CHR3-CH (NHR') -CH2-CR8 (NHR' ) -Y.
Further preferred starting materials are those which carry, in place of the H atom of a hydroxyl group, a hydroxyl protective group, for example those of the formula R1-2-NRa-CHRs-CHOR-CHa-CReOR-Y in which R is a hydroxyl protective group.
It is also possible for more than one - identical or different - protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protective groups which are present differ from one another it is possible In many cases to eliminate them selectively.
The term amino protective group is generally 5 known and relates to groups which are suitable for protecting (blocking) an amino group from chemical reactions but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, In par10 ticular, unsubstituted or substituted acyl, aryl (for example DNP), aralkoxymethyl (for example BOM) or aralkyl groups (for example benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size are not otherwise critical; however, those which are preferred have 1-20, in particular 1-8, C atoms. The term acyl group in connection with the. present process Is to be interpreted In the widest sense. It embraces acyl groups derived from aliphatic, aralipha20 tic, aromatic or heterocyclic carboxylic acids or sulfonic acids, as well as, in particular, alkoxycarbonyl, aryloxycarbonyl and, especially, aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ETOC, 2,2,2trichloroethoxycarbonyl, IPOC, BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ, 4-methoxybenzyloxycarbonyl, FMOC. Preferred amino protective groups are BOC, DNP and BOM, as well as CBZ, FMOC, benzyl and acetyl.
The term hydroxyl protective group is likewise generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions but which can easily be removed after the desired cheml35 cal reaction has been carried out elsewhere in the molecule. Typical of such groups are the abovementloned unsubstituted or substituted aryl, aralkyl or acyl groups, as well as alkyl groups. The nature and size of the hydroxyl protective groups are not critical because they are removed again after the desired chemical reaction or reaction sequence; preferred groups have 120, especially 1-10, C atoms. Examples of hydroxyl protective groups are, inter alia, tert.-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, with benzyl and acetyl being particularly preferred.
The functional derivatives of the compounds of the formula I which are to be used as starting materials can be prepared by customary methods of amino acid and peptide synthesis as are described, for example, in the said standard works and patent applications, for example also by the solid-phase method of Merrifield.
The liberation of the compounds of the formula I from their functional derivatives is effected - depending on the protective group used - for example with strong acids, preferably with trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic 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 and preferred inert solvents are organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or diox25 ane, amides such as dimethyl formamide (DMF), halogenated hydrocarbons such as dichloromethane, as well as alcohols such as methanol, ethanol or isopropanol, and water. Furthermore suitable are mixtures of the abovementioned solvents. Trifluoroacetic acid is preferably used in excess without the addition of another solvent, and perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures for the cleavage are preferably between about 0 and about 50°, preferably between 15 and 30° (room temperature).
The BOC group can be eliminated, for example, preferably with 40% trifluoroacetic acid in dichloromethane or with about 3 to 5 N HCl in dioxane at 15-30°, and the FMOC group with an approximately 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°. Elimination of the DNP group is effected, for example, also with an approximately 3-10% solution of 2-mercaptoethanol in DMF/water at 15-30°.
Protective groups which can be removed by hydrogenolysis (for example BOM, CBZ or benzyl) can be eliminated, for example by treatment with hydrogen in the presence of a catalyst (for example a noble metal catalyst such as palladium, preferably on a support such as carbon). Solvents suitable for this are those mentioned above, especially, for example, alcohols such as methanol or ethanol or amides such as DMF. Hydrogenolysis is, as a rule, carried out at temperatures between about 0 and 100° under pressures between about 1 and 200 bar, prefer15 ably at 20-30° and under 1-10 bar. Hydrogenolysis of the CBZ group is effected satisfactorily, for example, on 510% Pd-C in methanol at 20-30°.
Compounds of the formula I can also be obtained by direct peptide synthesis from a carboxylic acid component (formula II) and an amine component (formula III) . Examples of suitable carboxylic acid components are those of the part-formulae (a) RX-OH, (b) R1-Z-OH, and of amine components are those of the part-formulae (a) H-ZNR2-CHR3-CR*-CH2-CR5R6-Y, (b) H-NR2-CHR3-CR*-CH2-CRsRe-Y. The peptide linkage can, however, also be formed within the group Z; this entails a carboxylic acid of the formula Rx-Zl-OH being reacted with an amino compound of the formula H-Z2-NR2-CHR3-CR*-CH2-CR5Re-Y, where Z1 + Z2 = Z. The methods preferably used for this are those customary in peptide synthesis, as are described, for example, in Houben-Weyl, l.c., Volume 15/11, pages 1-806 (1974).
The reaction is preferably effected in the presence of a dehydrating agent, for example a carbodiimide such as DCCI or dimethylaminopropylethylcarbodi35 imide, or else propanephosphonlc anhydride (compare Angew. Chem. 92. 129 (1980)), diphenyl phosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon such as diehloromethane, 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 30°.
It is also possible, In place of II or III, to use suitable reactive derivatives of these substances in the reaction, for example those in which reactive groups have undergone intermediate blocking with protective groups. The acid derivatives II can be used, for example, in the form of their activated esters which are preferably formed in situ, for example by addition of HOBt or N-hydroxysuccinimide.
Urea derivatives of the formula I [R1 = R®-NH-COor R11-CnH2B-(T),-(V)y-CnH2n-NH-CO-] can be obtained, for example, by reacting an appropriate isocyanate (for example of the formula R*-NCO; can be prepared from an amine of the formula Re-NH2 and phosgene) with an amine of the formula H-Z-NR2-CHR3-CR*-CH2-CRSR*-Y (Ila), preferably in an inert solvent such as THF at temperatures between about -10 and 40°, preferably between 10 and 30°.
The starting materials of the formulae II and III are mostly known. Those which are unknown can be prepared by known methods, for example the abovementioned methods of peptide synthesis and of elimination of protective groups.
The amino component of the formula Illb can be obtained, for example, in accordance with the following general scheme.
R -CH-CH-CH2-CHO I I BOC-H 0 X I (b) ch3mo23 XCT2\ RJ-CH-CH-CH2-CH no2 (·) I I BOC-H p Λ I OH - 24 ir-CH-CH-CH2-CH-ai I I I BOC-N y> OH A 3 R-CH-CH-CH2-CH no2 ( I BOC-N 0 X 0siR18R19R2° R -CH-CH-CH2-CH-CN R -CH-CH-CH2-CH ZH2\ NIL BOC-N 0 \ / c OSiR18R19R2° BOC-N 0 \ / 0SiR18R19R2° (c) The compound (c) can be varied as required on the substituent CH2NH2 (corresponds to Y) by known methods. Elimination of the silyl group, of the BOC protective group and cleavage of the oxazolidinyl ring result in, for example, the amine component H2N-CHR3-CHOH-CH2-CHOHCH2NH2. Peptide coupling with, for example, R1-Z-OH is then subsequently carried out by customary methods.
If desired, it is possible for a functionally modified amino and/or hydroxyl group in a compound of the formula I to be liberated by solvolysis or hydrogenolysis by one of the methods described above.
Thus, for example, a compound of the formula I which contains an R13-CxH2x-0-C0-NH-, an AcNH-, an ArCH2SO3- or an AOOC- group can be converted into the corresponding compound of the formula I which contains in its stead an H2N-, an HSOs- or an HOOC- group, preferably by selective solvolysie by one of the methods indicated above. AOOC- groups can be hydrolyzed, for example, with NaOH or KOH in water/dioxane at temperatures between 0 and 40°, preferably 10 and 30°.
It is also possible to acylate a compound of the formula I which contains a free primary or secondary amino group. Thus, in particular, compounds of the formula I in which Y is a CH2-NH-RU group can be reacted with acylating agents of the formulae RW-SO2C1, RU-COC1 or R1*-NCO, preferably in the presence of an inert solvent such as THF and/or of a base such as pyridine or triethylamine at temperatures between -10 and +30°.
Furthermore, for example, keto compounds of the 10 formula I (R* 3 0 and/or RSR® = 0) can be reduced to compounds of the formula I (R* = (H, OH) and/or RSR® = H, OH), for example with a complex metal hydride such as NaBHA which does not simultaneously reduce the peptide carbonyl groups, in an inert solvent such as methanol at temperatures between about -10 and +30°.
Keto compounds of the formula I (R* 3 0 and/or R5R® - 0) can also be converted into compounds of the formula I (R* 3 H, NH2 and/or RSR® 3 H, NH2) by reductive amination. The reductive amination can be carried out in one or more stages. Thus, for example, the keto compound can be treated with ammonium salts, for example ammonium acetate and NaCNBH3, preferably in an inert solvent, for example an alcohol such as methanol, at temperatures between about 0 and 50°, in particular between 15 and 30°.
It is furthermore possible initially to convert the keto compound into the oxime, using hydroxylamine in a customary manner, and to reduce the oxime to the amine, for example by catalytic hydrogenation on Raney nickel.
A base of the formula I can be converted into the relevant acid addition salt using an acid. Particularly suitable acids for this reaction are those which provide physiologically acceptable salts, thus it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, as well as organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and -disulfonic acids and lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify the compounds of the formula I.
The new compounds of the formula I and the physiologically acceptable salts thereof can be used to prepare pharmaceutical products by converting them, together with at least one vehicle or auxiliary and, if desired, together with one or more other active compound(s), into a suitable dosage form. The compositions obtained in this way can be used as medicaments in human or veterinary medicine. Suitable vehicles are organic or inorganic substances which are suitable for enteral (for example oral or rectal) or parenteral administration or for administration in the form of a spray for inhalation and which do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatine, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc and cellulose. Used orally are, in particular, tablets, coated tablets, capsules, syrups, elixirs or drops; specifically of interest are lacquered tablets and capsules with enteric coatings or capsule shells. Used rectally are suppositories, and for parenteral administration are solutions, preferably oily or aqueous solutions as well as suspensions, emulsions or implants. For administration by spray for inhalation, it is possible to use sprays which contain the active substance either dissolved or suspended in a propellant gas mixture (for example chlorofluorohydrocarbons). The active substance is preferably used for this in micronized form, with one or more additional physiologically tolerated solvents possibly being present, for example ethanol. Solutions for inhalation can be administered with the aid of customary inhalers. The new compounds can also be freeze-dried and the resulting lyophilisates used, for example, to prepare products for injection. The stated compositions can be sterilized and/or contain auxiliaries such as preservatives, stabilizers and/or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, colorants and/or flavourings. They can, if desired, also contain one or more other active substances, for example one or more vitamins.
The substances according to the Invention are, as a rule, administered in analogy to other known, commercially available peptides, but especially In analogy to the compounds described in EP-A 249,096, preferably In dosages between about 10 mg and 1 g, in particular between 50 and 500 mg, per dosage unit. The daily dosage Is preferably between about 0.2 and 20 mg/kg, in particular between 1 and 10 mg/kg, of body weight. The specific dose for each particular patient depends, however, on a wide variety of factors, for example on the activity of the specific compound used, on the age, body weight, general state of health and sex, on the diet, on the time and route of administration and on the rate of excretion, medicinal substance combination and severity of the particular disease for which the therapy is applied. Parenteral administration is preferred.
Renin-dependent hypertension and hyperaldosteronism can be effectively treated by administration of dosages between, in particular, about 1 and 300, preferably between 5 and 50, mg/kg of body weight. For diagnostic purposes, it is possible and preferable for the new compounds to be administered in single doses, particularly in about 0.1 and 10 mg/kg of body weight.
All temperatures stated hereinbefore and hereinafter are In °C. In the examples which follow, usual working up means: if necessary, water is added, the pH is adjusted to between 2 and 8, depending on the constitution of the final product, extraction is carried out with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate, filtered and concentrated, and purification is carried out by chromatography on silica gel and/or crystallization.
Example 1 a) A mixture of 380 mg (0.45 mmol) of N-[5S-(BOC-Phe(imi-BOM-His)-amino)-6-cyclohexyl-2S,4S-dihydroxy10 hexyl]-propanesulfonamide (m.p. 159-161*) [obtainable by reaction of (4S,5S)-3-BOC-4-cyclohexylmethyl-2,2-dimethyl-5-oxazolidinyl-acetaldehyde with NaCN in the presence of glacial acetic acid in THF at 4“ to give 2-[ (4S,5S)-3-BOC-4-cyclohexyl15 methyl-2,2 -dimethyl-5-oxazolidinyl ] - (IR, S) 1-hydroxy-propionitrile; reaction with tert, butyldimethylchlorosilane in the presence of imidazole at room temperature to give 2-[ (4S,5S)-3-BOC-4-cyclohexylmethyl-2,2-dimethyl-5-oxazolidinyl]-(IR,S) 20 l-(trimethylsilyloxy) -propionitrile; hydrogenation in methanol on Raney Ni at room temperature to give 3-[(4S,5S) -3-BOC-4-cyclohexylmethyl-2,2-dimethyl5-oxazolidinyl]-(2R,S) -2- (trimethyl silyloxy) -propylamine; reaction with 1-propanesulfonyl chloride in THF in the presence of triethylamine at 10* to give N- [ 3-{(4S, 5S)-3-BOC-4-cyclohexylmethyl-2,2-dimethyl5-oxazolidinyl} - (2R, S) - 2-trimethyls ilyloxy-propyl ] propanesulfonamide, separation of the diastereomere by chromatography; elimination of the trimethylsilyl group from the 2S epimer by reaction with tetrabutylammonium fluoride in ether, cleavage with HC1saturated ethyl acetate to give N-(5S-amino-6-cyclohexyl-2S, 4 S-dihydroxy-1-hexyl) -propanesulfonamide (m.p. 102-104*); condensation with BOC-(imi-BOM35 His)-OH in the presence of HOBt, NMM and DAPECI in DMF to give N-[5S-BOC-( imi-His)amino-6-cyclohexyl2S, 4S-dihydroxy-l-hexyl) -propanesulfonamide (m.p. 131-133*); elimination of the BOC group with HCl/ethyl acetate and condensation with BOC-Phe-OH - 29 in the presence of HOBt, NMM and DAPECI hydrochloride in DMF], 590 mg (9.3 mmol) of ammonium formate and 480 mg of Pd-carbon In 38 ml of methanol is stirred at room temperature for 20 hours. The mixture is filtered, the solution is concentrated, ml of a 5% NaHCO3 solution are added, and the mixture is stirred and filtered with suction. Purification of the crystals results in N-[5S-(BOCPhe-His-amino ) -6-cyclohexyl-2S,4S-dihydroxyhexyl]10 propanesulfonamide, m.p. 125-127*. b) This and the following compounds can likewise be obtained from the corresponding imi-DNP-His derivatives by elimination of the DNP group in the following way: a mixture of the corresponding DNP derivative with 2-mercaptoethanol in DMF and water is adjusted to pH 8 with aqueous Na2CO3 solution while stirring at 20* and is stirred for 2 hours. The usual working up results in the required final product.
The following are obtained analogously from the corresponding imi-BOM or imi-DNP derivatives: N- [ 5S- (BOC-Phe-His-amino) -2R,4S-dihydroxy-6-cyclohexylhexyl]-propanesulfonamide, m.p. 165-168* N- [ 2S, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonyl25 Phe-His-amino) -6-cyclohexylhexyl ] -propanesulfonamide N- [ 2S, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonylPhe-His-amino) -6-cyclohexylhexyl ]-3-methylbutanoamide, m.p. 120-130* (decomposition) N- [ 2R, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonyl3 0 Phe-His -amino) - 6 -eye lohexy lhexy 1 ] - 3 -me thy lbut anoamide, m.p. 120-130* (decomposition, N- [ 2S, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonylPhe-His-amino) -6-cyclohexylhexyl ] -N' -isopropylurea, m.p. 137-140* N-[2R, 4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonylPhe-His-amino)-6-cyclohexylhexyl]-3-methylbutanoamide, m.p. 137-140* N- [ 2S, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonylPhe-His-amino)-6-cyclohexylhexyl]-N'-ethylurea, m.p. 129* (decomposition) N- [ 2R, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonylPhe-His-amino)-6-cyclohexylhexyl ]-N'-ethylurea, m.p. 143* (decomposition) N- [ 2S, 4S-dihydroxy-5S- (2-benzyl-3-tert. -butyl-sulfonylpropionyl -His -amino) -6-cyclohexylhexyl] -methanesulf onamide N— [ 2S, 4S-dihydroxy-5S- (2-benzyl-3-tert. -buty 1-sulfonyl propionyl-His-amino) -6-cyclohexylhexyl ] -propanesulfon10 amide N- [ 2S, 4S-dihydroxy-5S-(2-benzyl-3-tert.-butyl-sulfonylpropionyl-His-amino) -6-cyclohexylhexyl ] -butanesulf onamide N-[2S,4S-dihydroxy-5S-(2-benzyl-heptanoyl-His-amino) 6-cyclohexylhexyl ] -propanesulf onamide N-[2S,4S-dihydroxy-5S-(2-benzyl-4-oxo-5,5-dimethylhexanoyl-His-amino) -6-cyclohexylhexyl ] -propanesulf onamide N- [ 2S, 4S-dihydroxy-5S-( 2-benzyl-3-tert. -butyl-sulfonylpropionyl-His-amino)-6-cyclohexylhexyl] -propanesulf onamide N-[2S,4S-dihydroxy-5S-(2-benzyl-3-morpholinocarbonylpropionyl-His-amino)-6-cyclohexylhexyl ]-propanesulf onamide N- [ 2S, 4S-dihydroxy-5S- (2- (1-naphthylmethyl) - 3 -mo rp ho linocarbony 1 -propionyl -His -amino) -6-cyclohexylhexyl ] -propane25 sulfonamide N- [ 2S, 4S-dihydroxy-5S- (N-benzyl-N-isopentyl-carbamoylHi 8-amino) -6-cyclohexylhexyl]-propanesulf onamide N - [ 2S , 4S-dihydroxy-5S-(2-(1-naphthylmethyl)-3-(N(3-dimethyl aminopropyl) -carbamoyl-propionyl-His-amino) 30 6 -cyclohexylhexyl ] -propanesulf onamide N- [ 2S, 4S-dihydroxy-5S- (2-benzyl-3-(4-BOC-aminopiper idinocarbonyl ) -propionyl-His-amino) -6-cyclohexylhexyl ] propane s ulfonamide N-[2S,4S-dihydroxy-5S-(2-(1-naphthylmethyl)-3-(4-BOC35 amino-piperidinocarbonyl)-propionyl-His-amino) -6-cyclohexylhexyl ] -propanesulf onamide N-[ 2S, 4S-dihydroxy-5S - (CBZ-Phe-His-amino) -6-cyclohexylhexyl ]-propanesulfonamide N- [ 2S,4S-dihydroxy-5S-(3,3-dimethylbutyryl-Phe-Hisamino)-6-eyelohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(2-BOC-amino-2-methyl-ρropionylPhe-His-amino )-6-cyclohexylhexyl ] -propanesul f onamide N-[2S,4S-dihydroxy-5S-(6-BOC-amino-hexanoyl-Phe-Hisamino) -6-cyclohexylhexyl ] -propane sulfonamide N-[2S,4S-dihydroxy-5S-(6-methoxycarbonyl-hexanoyl-PheHis-amino)-6-eyelohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(N-(3-dimethylaminopropyl) 10 carbamoyl-Phe-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(N-(5-dimethylaminopentyl) carbamoyl-Phe-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N- [ 2S, 4S-dihydroxy-5S- (BOC-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[ 2S, 4S-dihydroxy-5S-(CBZ-Mai-His-amino) - 6-cyclohexylhexyl ]-propanesulfonamide N-[ 2S, 4S-dihydroxy-5S-(3,3-dimethylbutyryl-Mal-His20 amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(2-BOC-amino-2-methyl-propionylMal-His-amino)-6-cyclohexylhexyl)-propanesulfonamide N-[2S,4S-dihydroxy-5S-(6-BOC-amino-hexanoyl-Mal-Hisamino) -6-cyclohexylhexyl ]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonylMal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N- [2S,4S-dihydroxy-5S-(6-methoxycarbonyl-hexanoyl-MalHis-amino)-6-cyclohexylhexyl)-propanesulfonamide N-(2S,4S-dihydroxy-5S-(N-(3-dimethylaminopropyl) 30 carbamoyl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2S,4S-dihydroxy-5S-(N-(5-dimethylaminopentyl) carbamoyl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N- [ 2S, 4S-dihydroxy-5S- (4-BOC-aminopipe ridinocarbo nyl -MaiHi s—amino)-6-cyclohexylhexyl]-methaneeulfonamide N- [ 2S, 4S-dihydroxy-5S- (BOC-Phe-His-amino) -6-cycloIE 920655 hexylhexyl ]-2-me thylpropane sulfonamide N-[2S,4S-dihydroxy-5S- (BOC-Cal-His-amino)-6-cyclohexylhexyl ] -2 -methylpropane sulfonamide N-[2S, 4S-dihydroxy-5S-(BOC-aNal-His-amino) -6-cyclo5 hexylhexyl ] -2 -methylpropanesul f onamide N- [ 2S, 4S-dihydroxy-5S-(BOC-2-Tia-His-amino)-6-cyclohexylhexyl ] -2-methylpropanesulf onamide N-[2S,4S-dihydroxy-5S-(BOC-Trp-His-amino)-6-cyclohexylhexyl ] -2-methylpropanesulf onamide N-[2S, 4S-dihydroxy-5S-(BOC-Pro-Phe-His-amino) -6-cyclohexylhexyl ] -2-methylpropanesulfonamide N- [ 2S, 4S-dihydroxy-5S- (3,3-dimethylbutyryl-Pro-Phe-N-MeHis-amino) -6-cyclohexylhexyl ] - 2-methylpropanesulfonamide N- [ 2S, 4S-dihydroxy-5S- (4-CBZ-amino-piperidinocarbonyl15 Phe-His-amino) -6-cyclohexylhexyl ] -propanesulf onamide.
N- [ 2S, 4S-dihydroxy-5S- (2-benzyl-2-tert. -butylsulf onylpropionyl-His-amino) -6-cyclohexylhexyl]-methanesulfonamide N- [ 2S, 4S-dihydroxy-5S- (2-benzyl-3-tert. -butylsulfonyl20 propionyl-His-amino)-6-cyclohexylhexyl ]-butanesulf onamide N- [ 2S, 4S-dihydroxy-5S- (2-benzyl-3-tert. -butylsul f onylpropionyl-His-amino) -6-cyclohexylhexyl ]-2-methylpropanesul f onamide N-[ 2S, 4S-dihydroxy-5S- (2-benzyl-3-tert. -butylsulfonyl25 propionyl-His-amino) -6-cyclohexylhexyl)-phenylmethanesulfonamlde N-[2S,4S-dihydroxy-5S-(2-benzyl-3-tert. -butylsulf onylpropionyl-His-amino) -6-cyclohexylhexyl]-cyclohexylmethanesuIfonamide N-[2S, 4S-dihydroxy-5S-(2-benzyl-3-tert. -butylsulfonylpropionyl-His-amino) -6-cyclohexylhexyl ]-N*-propylurea N- [ 2S, 4S-dihydroxy-5S- (2-benzyl-3-tert. -butylsulf onylpropionyl-His-amino) -6-cyclohexylhexyl ]-N'-butylurea N- [ 2S, 4S-dihydroxy-5S- (2-benzyl-3-tert. -butylsulf onyl35 propionyl-His-amino) -6-cyclohexylhexyl ] -N' -propyl thiourea N- [ 2S, 4S-dlhydroxy-5S- (2-benzyl-3-tert. -butylsulf onylpropionyl-His-amino ) -6-cyclohexylhexyl]-N'-(p-aminoIE 920655 phenyl)-urea N- [2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butylsulfonylpropionyl-His-amino) -6-cyclohexylhexyl ] -4-methyl-pent anoamide Example 2 0.01 mol of N-methylmorpholine is added to a solution of 0.01 mol of N-[2S,4S-dihydroxy-5S-(H->9Ala-amino)-6-cyclohexylhexyl]-propanesulfonamide [obtainable by condensation of BOC-0Ala-OH with N-(2S,4S-dihydroxy10 5S-amino-6-cyclohexylhexyl)-propanesulf onamide to give N-[2S,4S-dihydroxy-5S-(BOC-/?Ala-amino)-6-cyclohexylhexyl] -propanesulf onamide and elimination of the BOC group with 4 N HC1 in dioxane] in 60 ml of dichloromethane. While stirring, 0.01 mol of 4-dimethylamino15 piperidinocarbonyl-Phe-OH, 1.35 g of HOBt and a solution of 2.06 g of DCCI in 50 ml of dichloromethane is added, the mixture is stirred at 2-6* for 14 h, the precipitated dicyclohexylurea is filtered off, and the filtrate is evaporated. The usual working up results in N-[2S,4S-dihydroxy-5S-(4-dimethylamino-piperidinocarbonyl-Phe-^Ala-amino)-6-cyclohexylhexyl]-propanesulfonamide.
N-[2S,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbony1-Phe-^Ala-amino)-6-cyclohexylhexyl]-propane25 sulfonamide is analogously obtained as a colorless foam with 4-BOC-amino-piperidinocarbonyl-Phe-OH.
The following are obtained analogously: N-[2S,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonylPhe-£Ala-amino) - 6-cyclohexylhexyl ] -2-propanesulf onamide, colourless foam N- [2S, 4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonylPhe-2-Tia-amino) -6-cyclohexylhexyl ] -propanesulf onamide N-[2S,4S-dihydroxy-5S-(N-(5-dimethylaminopentyl)carbamoyl-Phe-β Ala-amino) -6-cyclohexylhexyl ] -propane35 sulfonamide N- [ 2S, 4S-dihydroxy-5S-(N- (5-dimethylaminopentyl) -carbamoyl-Phe-2-Tia-amino) -6-cyclohexylhexyl ]-propanesulfonamide Example 3 In analogy to Example 2, N-(2S,4S-dihydroxy5S- (BOC-Phe-Gly-amino)-6-cyclohexylhexyl) -propanesulfonamide is obtained from BOC-Phe-Gly-OH and N- (2S, 4S-dihydroxy-5S-amino-6-cyclohexylhexyl) -propanesulfonamide.
The following are obtained analogously N- ( 2S , 4S-dihydroxy-5S- (BOC-Phe-Abu-amino) -6-cyclohexylhexyl ) -propanesulf onamide N- ( 2S, 4S-dihydroxy-5S - (BOC-Phe-Ala-amino) -6-eyelohexylhexyl )-propanesulfonamide N- ( 2S, 4S-dihydroxy-5S- (BOC-Phe-y9Ala-amino) - 6-cyclohexylhexyl )-propanesulfonamide N- ( 2S, 4S-dihydroxy-5S - (BOC-Phe-Asn-amino)-6-cyclo15 hexylhexyl)-propanesulfonamide N- ( 2S, 4S-dihydroxy-5S- (BOC-Phe-Gln-amino) -6-cyclohexylhexyl)-propanesulfonamide N- ( 2S , 4S-dihydroxy-5S- (BOC-Phe-Nle-amino)-6-cyclohexylhexyl)-propanesulfonamide N-2R, 4S-dihydroxy-5S-(BOC-Phe-Ser-amino) -6-cyclohexylhexyl )-propanesulfonamide N-2R, 4S-dihydroxy-5S-( BOC-Phe) -6-cyclohexylhexyl) propanesul f onamide N- ( 2S, 4S-dihydroxy-5S- (BOC-Phe-3-Pya-amino) -6-cyclo2 5 hexylhexyl) -propanesul f onamide N- (2S, 4S-dihydroxy-5S-(BOC-Phe-2-Tia-amino)-6-cyclohexylhexyl )-propanesulfonamide Example 4 In analogy to Example 2, N-[2S,4S-dihydroxy30 5S - ( 4-BOC - aminopiper idinocarbonyl-Phe-Gly-amino) 7-methyl-octyl]-ethanesulfonamide is obtained from 4-BOCaminopiperidinocarbonyl-Phe-OH and N-[2S,4S-dihydroxy5S- (H-Gly-amino) -7-methyl-octyl ] -ethanesulf onamide.
Example 5 A solution of 1 g of N-[2S,4S-dihydroxy5S- ( 4-BOC-aminopiperidinocarbonyl-Phe-His-amino) 6-eyelohexylhexyl]-propanesulfonamide in 20 ml of 4 N HC1 in dioxane is stirred at 20* for 30 min and then evaporated . N- [ 2S, 4S-dihydroxy-5S-(4-amino-piperidinocarbonylPhe-His-amino)-6-cyclohexylhexyl ] -propanesulfonamide, dihydrochloride is obtained.
The following are obtained analogously by cleavage of the corresponding BOC derivatives: N-[2S,4S-dihydroxy-5S-(2-benzyl-3-(4-aminopiperidinocarbonyl) -propionyl-His-amino) -6-cyclohexylhexyl ] propanesulfonamide N-[2S, 4S-dihydroxy-5S- (2-( 1-naphthylmethyl) -3- (4-aminopipe rid i nocarbonyl ) -propionyl-His-amino)-6-cyclohexylhexyl ]-propanesulfonamide N- [2S, 4S-dihydroxy-5S- (4-aminopiperidinocarbonyl-Phe£Ala-amino) - 6-cyclohexylhexyl ] -propanesulfonamide N- [ 2S, 4S-dihydroxy-5S- (4-aminopiperidinocarbonyl-Phe2 -Tia-amino) -6-cyclohexylhexyl ] -propanesulfonamide N- [ 2S, 4S-dihydroxy-5S- (4-aminopiperidinocarbonyl-Phe-Hisamino) -6-cyclohexylhexyl ] -propanesulfonamide N-[2S, 4S-dihydroxy-5S- (4-aminopiperidinocarbonyl-Mal-His20 amino) -6-cyclohexylhexyl]-propanesulfonamide N- [ 2S, 4S-dihydroxy-5S- (2-amino-2-methyl-propionyl-PheHis -amino) -6 -eye lohexylhexyl ] -propanesul f onamide N- [ 2S, 4S-dihydroxy-5S- (2-amino-2 -methyl- [propionyl -MalHis-amino) -6-cyclohexylhexyl ] -propanesulfonamide N- [ 2S, 4 S-dihydroxy-5 S- (6-aminohexanoyl-Phe-His-amino) 6-cyclohexylhexyl]-propanesulfonamide N- [ 2S, 4S-dihydroxy-5S- (6-aminohexanoyl-Mal-His-amino) 6-cyclohexylhexyl]-propanesulfonamide N- [ 2S, 4S-dihydroxy-5S- (4-aminopiperidinocarbonyl-Phe3 0 ^Ala-amino )-6 -eye lohexylhexyl ] -2 -propanesul f onamide N- [ 2S, 4S-dihydroxy-5S- (4-aminopiperidinocarbonyl-Phe-Hisamino)-6-cyclohexylhexyl]-3-methylbutanoamide N- [ 2S, 4S-dihydroxy-5S- (4-aminopiper idinocarbonyl-Phe-Hisamino)-6-cyclohexylhexyl]-N'-isopropylurea N— [ 2 S, 4 S -dihydroxy-5S- (4 -aminopiper idinocarbonyl -Phe-Hisamino) - 6-cyclohexylhexyl ] -methaneeulf onamide N- [ 2S, 4S-dihydroxy-5S- (4-aminopiper idinocarbonyl-Mal-Hisamino) - 6-cyclohexylhexyl ] -methaneeulf onamide. - 36 Example 6 Hydrogenolysis (on 10% Pd-C in ethanol at 20*) of N- [ 2S, 4S-dihydroxy-5S- (4-CBZ-aminopiper idinocarbonyl-PheHis-amino) -6-cyclohexylhexyl]-propanesulfonamide results in N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-PheHi s - ami no, - 6 -eye 1 ohexy 1 hexyl ] -propanes u 1 f onamide.
Example 7 The following are obtained in analogy to Example 1 from the corresponding imi-BOM-His derivatives: N- (2R, 4S-dihydroxy-5S- (3-BOC-amino-3-methylbutyryl-PheHis-amino) -6-cyclohexylhexyl]-propanesulfonamide N- [ 2R, 4S-dihydroxy-5S- (3-BOC-ami no-3-me thy 1 butyryl-MaiHi s-ami no ) -6-cyclohexylhexyl ] -propanesulfonamide N- [ 2R, 4 S-dihydroxy-5 S- (3-BOC-amino-3-methylbutyryl-Phe15 N-Me-His-amino) -6-cyclohexylhexyl ] -propanesulfonamide N- [ 2R, 4S-dihydroxy-5S- (3-BOC-amino-3-methylbutyryl-PheHis-amino) -6-cyclohexylhexyl ]-1-methylethanesuIfonamide N- [ 2R, 4 S-dihydroxy-5S- (3-BOC-amino-3-methylbutyryl-MalHis-amino) -6-cyclohexylhexyl ] -1-methylethanesulf onamide N- [ 2R, 4S-dihydroxy-5S- (3-BOC-amino-3-methylbutyryl-PheN-Me-His-amino) -6-cyclohexylhexyl ] -1-methylethanesulf onamide N- [ 2R, 4S-dihydroxy-5S- (3-BOC-amino-3-methylbutyryl-PheHis-amino)-6-cyclohexylhexyl ]-cyclohexanesulf onamide N- [ 2 R, 4 S -d i hydroxy- 5 S - (3 -BOC-amino- 3 -me t hy lbutyryl-PheHi s -amino) - 6 -eye lohexylhexyl ] -N' -ethyl -urea N- [ 2R,4S-dihydroxy-5S- (3-BOC-amino-3-methylbutyryl-PheN-Me-His-amino) -6-cyclohexylhexyl ] -N · isopropyl-urea N- (2R, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonyl30 Phe-His-amino) -6-cyclohexylhexyl J-l-methylethanesulfonamide N-[2R, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonylMal-His-amino) -6-cyclohexylhexyl]-1-methylethanesulf onamide N- [ 2R, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonylPhe-His -amino )-6 -eye lohexylhexyl ] -eye lohexane-sul f onamide N- [ 2R, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonylMal-His-amino) -6-cyclohexylhexyl ] -cyclohexane-sulfonamide N-[2R, 4S-dihydroxy-5S-( 4-BOC-amino-piperidinocarbonyl Phe-His-amino) -6-cyclohexylhexyl ] -N' -ethyl-urea N- [ 2R, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonyl Ma 1 -Hi s - amino) - 6 -eye lohexy lhexy 1 ] -N' -ethyl -urea N- (2R, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonyl Phe-His-amino) -6-cyclohexylhexyl ] -N' -isopropyl-urea N- [ 2R, 4S-dihydroxy-5S-( 4-BOC-amino-piperidinocarbonyl Mai-His-amino) -6-cyclohexylhexyl ] -N' -isopropyl-urea N-[2R, 4S-dihydroxy-5S-( 4-BOC-amino-piperidinocarbonyl Phe-His-amino)-6-cyclohexylhexyl ] -N'-phenyl-urea N- [ 2R, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonyl Mal-His-amino) -6-cyclohexylhexyl ] -N' -phenyl-urea N- [ 2R, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonyl Phe-His-amino) -6-cyclohexylhexyl ] -3-methylbutyramide N- [ 2R, 4S-dihydroxy-5S- (4-BOC-amino-piperidinocarbonyl Mai-His-amino) -6-cyclohexylhexyl ] -3-methylbutyramide N- [ 2R, 4S-dihydroxy-5S-( 2R-benzyl-4-(4-BOC-amino-piper i dinocarbonyl) -propionyl-His-amino) -6-cyclohexylhexyl] propanesulfonamide N- [ 2R, 4S-dihydroxy-5S- (2S-benzyl-4-(4-BOC-amino-piper i dinocarbonyl) -propionyl-His-amino) -6-cyclohexylhexyl] propanesulfonamide N-[2R, 4S-dihydroxy-5S- (2R- (1-naphthylmethyl )-3-( 4-BOC amino-piper idinocarbonyl) -propionyl-His-amino) -6-cyclo hexy lhexy 1 ] -propanesul f onamide N- [ 2R, 4 S-dihydroxy-5S- (2S- (1-naphthylmethyl) -3- (4-BOC amino-piperidinocarbonyl) -propionyl-His-amino) -6-cyclo hexylhexyl ] -propanesulf onamide N- [ 2R, 4S-dihydroxy-5S- (2R-benzyl-5-N-BOC-N-methyl-amino pentanoyl-His-amino)-6-cyclohexylhexyl ]-propanesulf on amide N- [ 2R, 4 S-dihydroxy-5 S-( 2S-benzyl-5-N-BOC-N-methyl-amino pentanoyl-His-amino) -6-cyclohexylhexyl ] -propanesulf on amide N- (2R, 4S-dihydroxy-5S- (2R-benzyl-5-N-BOC-N-methyl-amino pentanoyl-His-amino) -6-cyclohexylhexyl ] -1-methylethane sulfonamide N- [ 2R, 4S-dihydroxy-5S- (2S-benzyl-5-N-BOC-N-methyl-amino - 38 pentanoyl-His-amino)-6-cyclohexylhexyl ]-l-methylethanesulfonamide N- [ 2R, 4S-dihydroxy-5S-(2R-benzyl-5-N-BOC-N-methyl-aminopentanoyl-His-amino)-6-cyclohexylhexyl]-N’-ethyl-urea N- [ 2R, 4S-dihydroxy-5S-(2S-benzyl-5-N-BOC-N-methyl-aminopentanoyl-His-amino)-6-cyclohexylhexyl]-N'-ethyl-urea N- (2R,4S-dihydroxy-5S- (2R-benzyl-3-tert. -butylsulfonylpr opiony 1 -Hi s -amino) - 6 -eye lohexylhexyl ] -1 -met hylethanesulfonamide N-[2R, 4S-dihydroxy-5S- (2S-benzyl-3-tert. -butylsulfonylpropionyl-His-amino) -6-cyclohexylhexyl ] -1-methyl-ethanesulfonamide N- [ 2R, 4S-dihydroxy-5S- (2R-benzyl-3-tert. -butylsulfonylpropionyl-His-amino)-6-cyclohexylhexyl]-cyclohexane15 sulfonamide N- [ 2R, 4S-dihydroxy-5S- (2S-benzyl-3-tert. -butylsulfonylpropionyl-His-amino)-6-cyclohexylhexyl]-cyclohexanesulfonamide N- [ 2R, 4S-dihydroxy-5S- (2R-benzyl-3-tert. -butylsulfonyl20 propionyl-His-amino)-6-cyclohexylhexyl]-N'-ethyl-urea N- [ 2R, 4S-dihydroxy-5S- (2S-benzyl-3-tert. -butylsulfonylpropionyl-His-amino)-6-cyclohexylhexyl]-N'-ethyl-urea N- [ 2R, 4S-dihydroxy-5S- (2R-benzyl-3-tert. -butylsulfonylpropionyl-His-amino) -6-cyclohexylhexyl ] -N' -isopropyl-urea N- [ 2R, 4S-dihydroxy-5S- (2S-benzyl-3-tert. -butylsulfonylpropionyl-His-amino) -6-cyclohexylhexyl ] -N ’ -isopropyl-urea N-[2R,4S-dihydroxy-5S-(2R-benzyl-heptanoyl-His-amino)6-cyclohexylhexyl]-propanesulfonamide N-[2R,4S-dihydroxy-5S-(2S-benzyl-heptanoyl-His-amino)30 6-cyclohexylhexyl]-propanesulfonamide N-[2R,4S-dihydroxy-5S-{2R—(1-naphthylmethyl) 3-morpholinocarbonyl-propionyl-His-amino)6-eyelohexylhexyl]-propanesulfonamide N-[2R, 4S-dihydroxy-5S-(2S-(1-naphthylmethyl) 35 3-morpholinocarbonyl-propionyl-His-amino)6-eyelohexylhexyl]-propanesulfonamide N- (2R, 4S-dihydroxy-5S-(2R-benzyl-3-tert.-butylthiopropionyl-His-amino)-6-cyclohexylhexyl]-propanesulfonIE 920655 amide N-[2R,4S-dihydroxy-5S-(2S-benzyl-3-tert.-butylthiopropionyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2R, 4S-dihydroxy-5S-( 2R-benzyl-3-tert.-butylsulfinyl5 propionyl-His-amino)-6-cyclohexylhexyl] -propanesulf onamide N- [ 2R, 4S-dihydroxy-5S- (2S-benzyl-3-tert. -butylsulf inyl propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N-[2R,4S-dihydroxy-5S-(2R-benzyl-4-oxo-5,5-dimethylhexanoyl-His -amino) -6-cyclohexylhexyl ] -propanesul f onamide N-[2R,4S-dihydroxy-5S-(2S-benzyl-4-oxo-5,5-dimethylhexa noy 1 -His-amino)-6 -eye lohexylhexy 1 ] -propanesu 1 f onamide N-[2R, 4S-dihydroxy-5S- (2R-benzyl-4-hydroxy-5,5-dimethyl15 hexanoyl-His-amino) -6-cyclohexylhexyl ] -propanesulf onamide N- [ 2R, 4S-dihydroxy-5S- (2 S-benzyl-4-hydroxy-5, 5-dimethylhexanoyl-His-amino) -6-cyclohexylhexyl] -propanesulf onamide N-[2R,4S-dihydroxy-5S-(4-dimethylamino-piperidinocarbonyl-Phe-His-amino)-6-cyclohexylhexyl]-propane20 sulfonamide N-[2R,4S-dihydroxy-5S-(4-dimethylamino-piperidinocarbonyl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide N- [ 2R, 4S-dihydroxy-5S- (N- (5-dimethylaminopentyl) -car2 5 bony1-Phe-His-amino)-6-eyelohexylhexyl]-propanesulfonamide N- [ 2R, 4S-dihydroxy-5S- (N- (5-dimethylaminopentyl) -carbonyl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide .
Example 8 The following are obtained in analogy to Example 5 from the corresponding BOC derivatives: N- [2R,4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-PheHis-amino)-6-eyelohexylhexyl]-propanesulfonamide, hydro35 chloride N- [2R,4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-MalHis-amino)-6-cyclohexylhexyl]-propanesulfonamide N- [ 2R, 4S-dihydroxy-5S- (3-amino-3-methylbutyryl-Phe-HisIE 920655 amino) -6-cyclohexylhexyl ] -propanesulf onamide N- [ 2R, 4S-dihydroxy-5S- (3-amino-3-methylbutyryl-Mal-Hisamino)-6-cyclohexylhexyl]-propanesulfonamide N-[2R,4S-dihydroxy-5S-( 3-amino-3-methylbutyryl-Phe-N-Me5 His-amino)-6-cyclohexylhexyl ]-propanesulf onamide N- [ 2R, 4S-dihydroxy-5S-( 3-amino-3-methylbutyryl-Phe-Hisamino) -6-cyclohexylhexyl ]-l-methyl-ethanesul f onamide N- [ 2R, 4S-dihydroxy-5S- (3-amino-3-methylbutyryl-Mal-Hisamino)-6-eyelohexylhexy1]-1-methyl-ethanesu1fonamide N-[2R,4S-dihydroxy-5S-( 3-amino-3-methylbutyryl-Phe-N-MeHis-amino)-6-cyclohexylhexyl ]-1-methyl-ethanesulfonamide N-[2R,4S-dihydroxy-5S-(3-amino-3-methylbutyryl-Phe-Hisamino)-6-cyclohexylhexyl]-eyelohexanesulfonamide N- [ 2R, 4S-dihydroxy-5S- (3-amino-3-methylbutyryl-Phe-Mal15 amino) -6-cyclohexylhexyl]-cyclohexanesulfonamide N- [ 2R, 4S-dihydroxy-5S- (3-amino-3-methylbutyryl-Phe-Hisamino) -6-cyclohexylhexyl ] -N · -ethyl-urea N- [ 2R, 4S-dihydroxy-5S- (3-amino-3-methylbutyryl-Phe-Malamino) - 6-cyclohexylhexyl ] -N' -ethyl-urea N-[2R,4S-dihydroxy-5S-( 3-amino-3-methylbutyryl-Phe-N-MeHis-amino)-6-cyclohexylhexyl]-N'-isopropylurea N- [2R, 4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-PheHis-amino) -6-cyclohexylhexyl ] -1-methylethanesulf onamide N- [ 2R, 4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-Mai25 His-amino)-6-cyclohexylhexyl J-l-methylethaneeulf onamide N- [ 2R, 4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-PheHis-amino) -6-cyclohexylhexyl ] -cyclohexanesulf onamide N- [2R, 4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-MaiHi s -amino) - 6 -cyclohexylhexyl ] -eye lohexanes u 1 f onamide N- [2R, 4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-PheHis-amino)-6-cyclohexylhexyl]-N'-ethyl-urea N-[2R, 4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-MalHis-amino)-6-cyclohexylhexyl]-N'-ethyl-urea N- [2R, 4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-Phe35 His - amino) - 6 -eye lohexylhexy 1 ] -N' - isopropyl -urea N- [2R, 4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-MalHis-amino)-6-cyclohexylhexyl]-N'-isopropyl-urea N- [ 2R, 4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-PheHis-amlno) -6-cyclohexylhexyl ]-N·-phenyl-urea N- [ 2R, 4S-dihydroxy-5S- (4-amino-piperidinocarbonyl-Mal His -amino) - 6 -eye lohexylhexyl ] -N ' -phenyl -urea N- [ 2R, 4S-dihydroxy-5S- (4-amino-piperidinocarbonyl-Phe His -amino) - 6 -eye lohexylhexyl ] - 3 -me thy lbu tyr amide N- [ 2R, 4S-dihydroxy-5S- (4-amino-piperidinocarbonyl-Mal His-amino) -6-cyclohexylhexyl ] -3-me thy lbu tyr amide N- [ 2R, 4S-dihydroxy-5S- (2R-benzyl-3-(4-amino- [piper idino carbonyl) -propionyl-His-amino) -6-cyclohexylhexyl ] propanesulfonamide N- [ 2R, 4S-dihydroxy-5S- (4-aminopiperidinocarbonyl-Phe 0Ala-amino) -6-cyclohexylhexyl ] -2-propanesul f onamide N- [ 2R, 4S-dihydroxy-5S- (2S-benzyl-3-(4-amino-piperidino carbonyl) -propionyl-His-amino) -6-cyclohexylhexyl ] propanesulfonamide N- [ 2R, 4S-dihydroxy-5S- (2R- (1-naphthylmethyl )-3-( 4-amino piperidinocarbonyl)-propionyl-His-amino)-6-cyclo hexylhexyl ] -propanesul f onamide N-[2R, 4S-dihydroxy-5S- (2S- (1-naphthylmethyl )-3-( 4-amino piperidinocarbonyl)-propionyl-His-amino)-6-cyclo 0 hexylhexyl ] -propanesul f onamide N- [ 2R, 4S-dihydroxy-5S- (2R-benzyl-5-N-methyl-amino pentanoyl-His-amino) -6-cyclohexylhexyl ] -propanesul f on amide N- [2R,4S-dihydroxy-5S- ( 2S-benzyl-5-N-methyl-amino pentanoyl-His-amino)-6-cyclohexylhexyl ]-propanesul f on amide N- [2R,4S-dihydroxy-5S-( 2R-benzyl-5-N-methyl-amino pentanoyl-His-amino) -6-cyclohexylhexyl]-1-methylethanesulfonamide N- [ 2R, 4S-dihydroxy-5S- (2S-benzyl-5-N-methyl-aminopentanoyl-His-amino)-6-cyclohexylhexyl]-1-methylethanesulfonamide N- [ 2R, 4S-dihydroxy-5S- (2R-benzyl-5-N-methyl-aminopentanoyl-His-amino) -6-cyclohexylhexyl ] -N' -ethyl-urea N- [ 2R, 4S-dihydroxy-5S- (2S-benzyl-5-N-methyl-aminopentanoyl-His-amino) -6-cyclohexylhexyl ] -N' -ethyl-urea.
Example 9 A mixture of 730 mg of N-[2R,4S-dihydroxy-5S (4 -aminopiper idino-carbonyl -Phe-His -amino) - 6 -eye lohexyl hexyl]-propanesulfonamide, 90 mg of S-methylisothiourea, 5 ml of ethanol and 5 ml of water is stirred at 50* for 2 h. The usual working up results in N-[2R,4S-dihydroxy5 5S- ( 4-guanidino-piperidinocarbonyl-Phe-His-amino) 6-eye lohexylhexyl ] -propanesulfonamide.
N- [ 2R, 4S-dihydroxy-5S-(4-guanidino-piperidinocarbonyl-Mal-His-amino) -6-cyclohexylhexyl ] -propanesulfonamide is obtained analogously.
Example 10 A mixture of 730 mg of N-[2R,4S-dihydroxy5S-(4-aminopiperidino-carbonyl-Phe-His-amino) -6-cyclohexylhexyl]-propanesulfonamide, 115 mg of trimethylsilyl isocyanate and 10 ml of THF is stirred at 20* for 16 h.
It is then stirred into water, and worked up in the usual way to result in N-[2R,4S-dihydroxy-5S-(4-ureido-piperidinoc arbony 1 - Phe-His - amino) - 6 -cyclohexyl hexyl ] -propanesulfonamide.
N- [ 2R, 4S-dihydroxy-5S- (4-ureido-piperidino20 carbonyl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide Is obtained analogously, and, using ethyl isocyanatei N- [ 2R, 4S-dihydroxy-5S- (4-N' -ethylureido-piperidinocarbonyl-Phe-His-amino) -6-cyclohexylhexyl ] -propane25 sulfonamide N- [ 2R, 4S-dihydroxy-5S- (4-N' -ethylureido-piperidinocarbonyl-Mal -His -amino) -6-cyclohexylhexyl ] -propanesulfonamide.
Example 11 a) 0.48 g (0.53 mmol) of 2,2-dimethyl-4S-[2-cyclohexyl1S- (BOC-Phe-His (DNP) -amino) -ethyl ] -6R- (3-isopropylureido)-methyl-1,3-dioxane [obtainable by reaction of 3- [ (4S, 5S) -3-BOC-4-cyclohexylmethyl-2,2-dimethy 15-oxazolidinyl ] - (2R, S) -2-trimethylsilyloxy) -propylamine (see Example 1) with isopropyl isocyanate in THF in the presence of triethylamine at 0* to give N- [ 3-{(4S, 5S) -3-BOC-4-cyclohexylmethyl-2,2-dime thy 135 -oxazolidinyl} - (2R, S) -tr imethylsilyloxypropyl ] -N' isopropylurea, separation of the diastereomers by chromatography; elimination of the trimethylsilyl groups from the 2R epimer by reaction with tetra5 butyl ammonium fluoride at 0‘, this product is stirred in ethyl acetate with HCl-saturated ethyl acetate at 0* for 48 hours, water is added and extraction is carried out with 32% NaOH, the organic phase is worked up and, after purification by chromatography on silica gel, 2,2-dimethyl4S-[2-cyclohexyl-lS-aminoethyl]-6R-(3-isopropylureido)-methyl-1,3-dioxane is obtained; condensation with BOC-Phe-His(DNP)-OH in DMF in the presence of HOBt, NMM and DAPECI] in 5 ml of DMF is mixed with 0.2 ml of 5% NaHCOa solution, and then 0.14 ml (2 mmol) of 2-mercaptoethanol Is added. After 12 hours, 50 ml of H20 are added, and the precipitate which forms is taken up in CH2C12. The crystalline residue is purified on silica gel to result in 2,2-dimethyl-4S-[2-cyclohexyl-lS-(BOC-Phe-Hisamino ) - ethyl ]-6R-( 3-isopropylureido)methyl1,3-dioxane, m.p. 134-140* (decomposition).
The following is obtained analogously: 4S-(2-cyclohexyl-lS-{( 4-BOC-amino-piperidino25 carbonyl)- Phe-His-ami no}- ethyl] -2-methyl6R- (3-methylbutyryl-aminomethyl )-1,3-dioxane. b) The following are obtained by elimination of the BOC group in a known manner 2,2 -dimethyl-4S- [ 2-cyclohexyl-lS- (Phe-His-amino) 30 ethyl ]-6R-(3-isopropylureido)-methyl-1,3-dioxane and 4S - (2-eyelohexy1-IS-{(4-aminopiperidinocarbonyl)Phe-His-amino} -ethyl ] -2-methyl-6R- (3-methylbutyrylaminomethyl )-1,3-dioxane.
The examples which follow relate to pharmaceu35 tical compositions.
Example A: Tablets A mixture of 1 kg of N-[2R,4S-dihydroxy-5S(4-aminopiper idinocarbonyl-Phe-His-amino) -6-cycloIE 920655 hexylhexyl ]-3-methyl-butyramide, 4 kg of lactose, 1.2 kg of maize starch, 200 g of talc and 100 g of magnesium stearate is compressed in a customary manner to give tablets in such a way that each tablet contains 100 mg of active compound.
Example B: Coated tablets Tablets are compressed in analogy to Example A and are then coated in a customary manner with a coating composed of sucrose, maize starch, talc, tragacanth and colorant.
Example C: Capsules 500 g of N-[2S-,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-j9Ala-amino) -6-cyclohexylhexyl ] -propanesulfonamide hydrochloride are dispensed in a customary manner into hard gelatine capsules so that each capsule contains 500 mg of active compound.
Example D: Injection ampoules A solution of 100 g of N-[2S,4S-dihydroxy5S- (4-aminopiperidinocarbonyl-Phe-His-amino) -6-cyclo20 hexylhexyl] -propanesulfonamide dihydrochloride in 4 1 of double distilled water is adjusted to pH 6.5 with 2 N hydrochloric acid, filtered sterile and dispensed into injection ampoules. These are lyophilized under sterile conditions and sealed sterile. Each injection ampoule contains 50 mg of active compound.
Example E: Suppositories A mixture of 50 g of N-(2S,4S-dihydroxy5S- (2-benzyl-3-tert. -butylsulfonylpropionyl-His-amino) 6-eyelohexylhexyl ]-methanesulfonamide hydrochloride with g of soya lecithin and 140 g of cocoa butter is melted, poured into moulds and left to cool. Each suppository contains 250 mg of active compound.

Claims (6)

1. Patent Claims Peptide analogues of the formula I in which nl r 1 -z-nr 2 -chr 3 -cr 4 -ch 2 -cr 5 r 6 -y 1 is H, R 7 -O-CaH2a-CO—, R’-C.Hj.-O-CO-, R'-C.Ha.-CO-, R 7 -SO2-, R e R e N-C IB H a ,-CO-, R 10 -NH-C ( -NH) -NH-C^-CO-, R®OOC-C e H 2a -CO-, R®O 3 S-C b H 2b -CO- or (T).- (V) ,-C^-L (R 7 -CpH 2p ) C^-CO-, Z is 0 to 4 amino acid residues which are linked together in the manner of a peptide and are selected from the group comprising Abu, Ada, Ala, ;9Ala, Arg, Asn, Asp, Bia, Cal, Dab, Gin, Glu, Gly, His, N(im)-A-His, Hph, lie, Isoser, Leu, tert.-Leu, Lys, Mai, Met, aHal, £Nal, Nbg, Nle, Nva, Orn, Phe, Pia, Pro, Pyr, Ser, Thr, Tia, Tic, Trp, Tyr and Val, Y is -CN, -NO 2 , -CH 2 -NR 12 R 13 , -CH2-NR 12 -SO2R u , -CH 2 -NR l2 -C0R l * , -ch 2 -nr 12 -co-nh-r x * , -CHj-NR^-CS-NH-R 1 * or -COR 18 , R 2 , R®, R e and R 13 are each H or A, R* is (H, R 17 ) or -0, R 5 is OH, OR 7 , OCOR 7 , OSiR ie R ie R 20 , NR 8 R e or -O-(2-tetrahydropyranyl), R® is H, A, Ar or aralkyl, R s and R® together are also (-0), is H, OH, OR 7 , NR®R e , OSiR 18 R 19 R 20 or -0-(2-tetrahydropyranyl), R 17 is OH or NH a , R 5 and R 17 together are also -T l -(CR 3 R 7 )-T 2 -, R 3 , R 7 , R 11 , R 12 and R 1 * are each H, A, Ar, Ar-alkyl, Het or Het-alkyl, unsubstituted or singly or multiply, by A, AO and/or Hal, substituted cycloalkyl having 3-7 C atoms, cycloalkylalkyl having 4-11 C atoms, ,ιβ bicycloalkyl or tricycloalkyl each having 7-14 C atoms, or bicycloalkylalkyl or trlcycloalkylalkyl each having 8-18 C atoms, R 11 is also R*0-, R e R®N-, R e OOC- or A^N* An®, R 18 , R 1 ’ and R 20 are each A, Ar or aralkyl, R 10 is H, A or CN, L is CH or N, T, T 1 and T 2 are each 0 or NR®, V is CHOR 2 , CO, S, SO or S0 2 , R 8 R®N and NR 12 R 13 are also each a pyrrolidino, piperidino, morpholino or piperazino group which is unsubstituted or is substituted by A, OH, NH2, NHA, NAa, NHAc, NH-CO-C^-O-R 15 , NHC0-O-CxH 2x -O-R 15 , hydroxyalkyl, COOH, COOA, C0NH 2 , aminoalkyl, HAN-alkyl, AjN-alkyl, AaN* alkyl An®, NH-CO-NH 2 , NH-CO-NHA, guanidinyl or guanidinylalkyl, R 13 is A or Ar-alkyl, s and y are each 0 or 1, m, n, p, r and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, Ar is phenyl which is unsubstituted or is substituted one or more times by A, OA, Hal, CF 3 , OH, NO 2 , hydroxyalkyl, NH 2 , NHA, NAj, NHAc, SA, SO-A, SO 2 -A, SO 2 NH 2 , SO 2 NHA, COOH, COOA, CONHj, CN, aminoalkyl, HANalkyl, A^N-alkyl, AjN + alkyl An® and/or guanidinyl-alkyl, or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6membered heterocyclic radical which has 14 N, 0 and/or S atoms and can be fused with a benzene ring and/or be substituted one or more times by A, OA, Hal, CF 3 , OH, NO 2 , carbonyl oxygen, NH 2 , NHA, NAj, NHAc, SA, SO-A, SO 2 -A, SO 2 NH 2 , SO 2 NHA, COOH, COOA, CONHj, CN, NH-SO 2 -A, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalk/L, aminoalkyl, Hal Ac An® -alkyland A HAN-alkyl and/or AjN-alkyl, and/or whose N and/or S hetero atoms can also be oxidized, is F, Cl, Br or I, is A-CO-, Ar-CO-, Ar-alkyl-CO- or A-NH CO-, is an anion, which can also be absent if, in its place, a carboxyl group contained in the compound of the formula I is in the form of a carboxylate anion, is an alkylene group having 1-8 C atoms, is alkyl having 1-8 C atoms in which, furthermore, it is also possible for one or more -NH-CO- groups to be replaced by one or more -NA-COgroups, with the provisos that a) in the case R 1 = R 11 -CJi2B-(T),-V-CnH2n-L(R 7 -CpH 2p )CjHj^-CO- with V » S, SO or SOj, and Y » -CH 2 NR 12 R 13 with R u = R 13 » H, R 3 then is OCOR 7 , OSiR ie R ie R 20 , NR e R® or -0-(2-tetrahydropyranyl), b) in the case R 1 - R u -C1IH2.-(T),-V-CnH2n-L(R 7 -CHpH 2p )CrH^-CO- with V - S, SO or SO 2 , and Y » COR 1 ’, R 1 ’ then is H, OH, OR 7 , OSiR ie R ie R 20 or -0-(2-tetrahydropyranyl), as well as the salts thereof.
2. Process for the preparation of a peptide analogue of the formula I, and of the salts thereof, characterized in that it is liberated from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, or in that a carboxylic acid of the formula II R l -G x -OH II in which G 1 is (a) absent (b) Z, (C) or one of the reactive derivatives thereof, is reacted with an amino compound of the formula III H-G 2 -NR 2 -CHR 3 -CR 4 -CH 2 -CR 5 R 6 -Y hi in which G 2 is (a) Z, (b) absent, (c) Z 2 and Z 1 + Z 2 are together Z, and in that a functionally modified amino and/or hydroxyl group in a compound of the formula I is liberated where appropriate by treatment with solvolyzing or hydrogenolyzing agents, and/or a free amino group is acylated by treatment with an acylating agent and/or for the preparation of a compound of the formula I, R* = (H, OH) or (H, NH 2 ), an amino keto acid derivative of the formula I, R* « 0, is reduced or reductively aminated, and/or a radical R 1 is converted into a compound of the formula I is converted by another radical R l and/or treatment with an acid into one of the salts thereof
3. Process for the preparation of pharmaceutical compositions, characterized in that a compound of the formula I and/or one of the physiologically acceptable salts thereof is converted together with at least one solid, liquid or semi-liquid vehicle or auxiliary and, where appropriate, in combination with one or more other active compound(s) into a suitable dosage form. 4. , substantially as hereinbefore described and exemplified . 11. Use hereinbefore according to Claim described.
4. Pharmaceutical composition characterized by containing at least one compound of the formula I and/or one of the physiologically acceptable salts thereof. 5. , substantially as 12. Use hereinbefore according described to Claim
5. Use of compounds of the formula I or of physiologically acceptable salts thereof for the preparation of a medicament. 6. Use of compounds of the formula I or of the physiologically acceptable salts thereof for controlling renin-dependent hypertension or hyperaldosteronism. -497. A compound as claimed in Claim 1, substantially as hereinbefore described and exemplified. 8. A process for the preparation of a compound as claimed in Claim 1, substantially as hereinbefore described and exemplified. 9. A compound as claimed in Claim 1, whenever prepared by a process claimed in Claim 2 or 8. 10. A pharmaceutical composition according to Claim
6. , substantially as
IE065592A 1991-03-01 1992-02-28 Peptide analogues IE920655A1 (en)

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DE4106488A DE4106488A1 (en) 1991-03-01 1991-03-01 PEPTIDE ANALOGS

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JP (1) JPH05117297A (en)
KR (1) KR920018073A (en)
AU (1) AU1130292A (en)
CA (1) CA2062065A1 (en)
CS (1) CS56992A3 (en)
DE (1) DE4106488A1 (en)
HU (1) HU9200678D0 (en)
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MX (1) MX9200862A (en)
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AU1130292A (en) 1992-09-03
CA2062065A1 (en) 1992-09-02
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HU9200678D0 (en) 1992-05-28
JPH05117297A (en) 1993-05-14
EP0501280A2 (en) 1992-09-02

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