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IE912343A1 - Amino acid derivatives - Google Patents

Amino acid derivatives

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Publication number
IE912343A1
IE912343A1 IE234391A IE234391A IE912343A1 IE 912343 A1 IE912343 A1 IE 912343A1 IE 234391 A IE234391 A IE 234391A IE 234391 A IE234391 A IE 234391A IE 912343 A1 IE912343 A1 IE 912343A1
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IE
Ireland
Prior art keywords
amino
hydroxy
acid
cyclohexyl
aminopiperidinocarbonyl
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Application number
IE234391A
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Merck Patent Gmbh
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Publication of IE912343A1 publication Critical patent/IE912343A1/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
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Novel amino acid derivatives of the formula I X-W-CR<1>R<2>-CO-Y-NH-CHR<4>-CR<5>-CH2-(CR<6>R<7>)rS(O)t-CH2-CO-V-R<3> I in which X, W, R<1>, R<2>, Y, R<4>, R<5>, R<6>, R<7> r, t, V and R<3> have the meanings given in Patent Claim 1, inhibit the activity of human plasma renin and can be used for the treatment of cardiac, circulatory and vascular diseases.

Description

Merck Patent Gesellschaft mit beschrankter Haftung 6100 Darmstadt Amino acid derivatives The invention relates to novel amino acid derivatives of the formula I X-W-CR1R2-C0-Y-NH-CHR4-CR5-CH2-6R7)rS(0)t-CH2CO-V-R3 I in which X R9 and R R2, R3, R R9R10N is R8, R8-0-CmH2ni-C0-, R8-CmH2m-O-CO-, R8-CmH2m-CO-, R8-SO2-, R’R^N-CJIa.-CO-, Rn-NH-C ( =NH) -NH-CmH2m-CO-, R9OOC-CmH2n-CO- , R^S-C^-CO-, R9-O-(CH2CH2O)n-CmH2ni-CO-, or Aa^-CJi^-CO-An', is 0, NH, CH2 or S, is 0 or 1 amino acid radical selected from the group comprising Abu, Ada, Ala, £Ala, Arg, Asn, Asp, Bia, Cal, Cys, S-A-Cys, Dab, Gin, Glu, Gly, His, N(im)-A-His, Hph, lie, Leu, tert.- Leu, Lys, Mai, Met, aNal, £Nal, Nbg, Nle, Nva, Orn, Phe, Pia, Pro, Pya, Ser, Thr, Tia, Tic, Tiz, Trp, Tyr and Val, is 0 or NH, R7, are each H or A, and R8 are each H, A, Ar, Ar-alkyl, Het, Het-alkyl, cycloalkyl having 3-7 C atoms, which is unsubstituted or cycloalkyl which is monosubstituted or polysubstituted by A, AO and/or Hal, 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, is (H, OH), (H, NH2) or =0, also is an unsubstituted pyrrolidino, piperidino, morpholino or piperazino group or one which is substituted by A, OH, NH2, NHA, NA2, NHAc, NH-CO-CIH2l-O-R11, NH-C0-0-CxH2l-Rn, hydroxyalkyl, COOH, COOA, CONH2, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N®alkyl An®, NH-CO-NH2, NH-CO-NHA, guanidinyl or guanidinylalkyl, R11 is A or Ar-alkyl, m and x are each 0, 1, 2, 3, 4, 5, 6, n is 1, 2, 3, 4 or 5, r is 0, 1, 2 or 3, t is 0, 1 or 2, Ar is unsubstituted phenyl or Het monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, hydroxyalkyl, NH2, NHA, NA2, NHAc, NH-SO2-A, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, aminoalkyl, HAN-alkyl, AjN-alkyl, A3N®-alkyl Αηθ and/or guanidinylalkyl or unsubstituted naphthyl, is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N, 0 and/or S atoms, which can be fused to a benzene ring and/or monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, carbonyl oxygen, NH2, NHA, NA2, NHAc, NH-COOA, NHCOOAr, NHCOOCH2Ar, NH-SO2-A, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN-alkyl, AaN-alkyl and/or A3N®-alkyl An® and/or whose N and/or S heteroatoms can also be oxidised, Hal is 30 Ac is An® is an anion, which can also be absent, if instead of this a carboxyl group contained in the compound of the formula I is present 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 in addition instead of one or more -CO-NH groups there can also be one or more -CO-ΝΑ groups, and their salts. - 3 Similar compounds are disclosed in EP-A-249,096. The invention was based on the object of finding novel compounds having useful properties, in particular those which can be used for the preparation of medica5 ments.
It has been found that the compounds of the formula I and their salts have very useful 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). It is noteworthy that these compounds are very specific inhibitors of renin; as a rule about 100 to 1000 times as high concentrations of these compounds are necessary for the inhibition of other aspartylproteinases (for example pepsin and cathepsin D) as for renin inhibition. The actions of the compounds on the blood pressure and/or on the heart rate and the inhibition of the renin activity in the blood plasma can additionally be determined in conscious monkeys, for example female monkeys (Macaca fascicularis); in this connection blood pressure and heart rate can be measured following the method of M.J. Wood et al., J. Hypertension 4, 251-254 (1985). To stimulate renin activity, the animals are in this case expediently pretreated with a saluretic. Blood samples for determining the plasma renin activity can be obtained by puncture of the femoral vein.
The compounds can be employed as medicament active compounds in human and veterinary medicine, in particular for the prophylaxis and for the treatment of cardiac, circulatory and vascular diseases, in particular hypertension, cardiac insufficiency and hyperaldosteronism. In addition, the compounds can be used for diagnostic purposes in patients with hypertension or hyperaldosteronism in order to determine the possible contribution of the renin activity to the maintenance of the pathological condition. Such diagnostic tests can be carried out in a similar manner to that given in EP-A-77,028.
The abbreviations of amino acid radicals - 4 mentioned above and below are for the radicals -NR'-RC0-, 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 £Ala y9-alanine Arg arginine Asn asparagine Asp aspartic acid Bia 3-(2-benzimidazolyl)alanine Cal 3-cyclohexylalanine Cys cysteine S-A-Cys S-alkylcysteine S-Me-Cys S-methylcysteine 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-phenylbutyric acid) lie isoleucine 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-norbornylglycine Nle norleucine N-Me-His N-methylhistidine N-Me-Phe N-methylphenylalanine Nva norvaline Orn ornithine Phe phenylalanine Pia 3-(piperidyl)alanine [for example 3-(2-piperidyl) alanine] 2-Pia = Pro proline 5 Pya 3-(pyridyl)alanine [for example 3-(3-pyridyl) alanine] 3-Pya = Ser serine Thr threonine Tia 3-(thienyl)alanine [for example 2-Tia = 10 3-(2-thienyl) alanine] Tic 1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid Tiz 3-(thiazolyl)alanine [for example 3-(2-thiazolyl) alanine] 2-Tiz = 15 Trp tryptophan Tyr tyrosine Val valine. In addition, the following have the meaning below: 20 BOC tert.-butoxycarbonyl BOM benzyloxymethyl imi-BOM benzyloxymethyl in the 1-position imidazole ring of the CBZ benzyloxycarbonyl 25 DCCI dicyclohexylcarbodiimide DMF dimethylformamide DNP 2,4-dinitrophenyl imi-DNP 2,4-dinitrophenyl in the 1-position imidazole ring of the 30 ETOC ethoxycarbonyl FMOC 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole IPOC i s opropoxyc arbony1 Pla the radical of phenyllactic acid 35 POA -O-CH(CH2CeH5)-CO- (S-form) phenoxyacetyl THF tetrahydrofuran.
If the abovementioned amino acids can occur in several enantiomeric forms, all these forms and also - 6 their mixtures (for example the DL-forms) are included above and below, for example as constituents of the compounds of the formula I. The L-forms are preferred. If individual compounds are mentioned below, the abbrevia5 tions of these amino acids in each case relate to the L-form, if not expressly stated otherwise.
The invention further relates to a process for the preparation of an amino acid of the formula I and of its salts, characterised in that it is set free from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent or in that a carboxylic acid of the formula II X-Gx-OH II in which Gx (a) is absent, (b) is -W-CRXR2-CO-, (c) is -W-CRXR2-CO-Y-, (d) is -W-CRXR2- -CO-Y-NH-CHR4-CR5-CH2- (CR8R7) r-S (0) t-CH2-CO- or one of its reactive derivatives is reacted with a compound of the formula III H-G2-V-R3 III in which G2 (a) is -W-CRXR2-CO-Y-NH-CHR*-CR5-CH2- (CR6R7) r-S (0) t-CH2-CO-, (b) is -Y-NH-CHR4-CR5-CH2-(CR8R7)r-S(O)t-CH2-CO-, (c) is -NH-CHR*-CR5-CH2-(CR®R7)r-S(0)t-CH2-CO-, (d) is absent, and W' is 0, NH or S, and in that a functionally modified amino and/or hydroxy group is optionally set free in a compound of the formula I by treating with solvolysing or hydrogenolysing agents and/or a free amino group is acylated by treating with an acylating agent and/or an aminoketo acid derivative of the formula I, R5 = 0, is reduced or reductively aminated - 7 to prepare a compound of the formula I, R5 = (H, OH) or (H, NH2) and/or a thioether group is oxidised to a sulfoxide or sulfone group and/or a compound of the formula I is converted into one of its salts by treating with an acid.
Above and below, the radicals or parameters R1 to R11, V, W, X, Y, m, n, x, r, t, Ar, Het, Hal, Ac, An, A, G1, G2 and W' have the meanings indicated in the formulae 1, II or III unless expressly stated otherwise.
In the above formulae, A 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, additionally also 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-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, heptyl, octyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, 20 cyclopentyl, cyclohexyl or cycloheptyl, but also, for example, 1-, 2- or 3-methylcyclopentyl, or 1-, 2-, 3- or 4- methylcyclohexyl.
Accordingly, cycloalkylalkyl is preferably cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, eye lopenty Ime thyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, but 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]heptyl.
Tricycloalkyl is preferably 1-adamantyl.
Hal is preferably F, Cl or Br, but also I.
Ac is preferably A-CO-, such as acetyl, propionyl or butyryl, Ar-CO- such as benzoyl, ο-, m- or p-methoxybenzoyl or 3,4-dimethoxybenzoyl, or A-NH-CO- such as N-methyl- or N-ethylcarbamoyl.
Ar is preferably phenyl, in addition preferably ο-, m- or p-tolyl, ο-, m- or p-ethylphenyl, ο-, m- or - 8 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, 3,4,5-trimethoxyphenyl, ο-, m-, or p-aminophenyl, ο-, mor p-aminomethylphenyl, ο-, m- or p-dimethylaminomethylphenyl, ο-, m- or p-guanidinomethylphenyl, 1- or 2-naphthyl.
Accordingly, Ar-alkyl is preferably benzyl, 1- or 2-phenylethyl, ο-, m- or p-methylbenzyl, 1- or 2-0-, -mor -p-tolylethyl, ο-, m- or p-ethylbenzyl, 1- or 2-o-, -m- or -p-ethylphenylethyl, ο-, m- or p-methoxybenzyl, 1or 2-0-, -m- or -p-methoxyphenylethyl, ο-, m- or p-fluorobenzyl, 1- or 2-o-, -m- or -p-fluorophenylethyl, ο-, m- or p-chlorobenzyl, 1- or 2-ο-, -m- or -p-chlorophenylethyl, ο-, m- or p-bromobenzyl, 1- or 2-o-, -m- or -p-bromophenylethyl, ο-, m- or p-iodobenzyl, 1- or 2-o-, -m- or -p-iodophenylethyl, ο-, m- or p-trifluoromethyl20 benzyl, ο-, m- or p-hydroxybenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, o—, m- or p-aminobenzyl ο-, m- or p-aminomethylbenzyl, ο-, m- or p-dimethylaminomethylbenzyl, ο-, m- or p-guanidinomethylbenzyl, 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 - 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, 1.3.4- thiadiazol-2- or -5-yl, l,2,4-thiadiazol-3- or -5-yl, 2,l,5-thiadiazol-3- or -4-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 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-, 5-, 6- or 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, - 9 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3- , 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7- benzothiazolyl, 2-, 4-, 5-, 6- or 7-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-, - , 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8- cinnolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolyl. The heterocyclic radicals can also be partially or completely hydrogenated. Het can thus also be, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4or -5-furyl, tetrahydro-2- or -3-furyl, 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, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-l-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-l-, -2-, -3or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5or -6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, -3-, -4-, -520 or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-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-l-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-l-, -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: 2- amino-4-thiazolyl, 4-carboxy-2-thiazolyl, 4-carbamoyl30 2-thiazolyl, 4-(2-aminoethyl)-2-thiazolyl, 4-amino-2methyl-5-pyrimidinyl, 2-amino-5,6-dimethyl-3-pyrazinyl, 4- carbamoylpiperidino, in addition, for example, 3-, 4or 5-methy1-2-furyl, 2-, 4- or 5-methyl-3-furyl, 2,4-dimethyl-3-furyl, 5-nitro-2-furyl, 5-styryl-2-furyl, 3-, 435 or 5-methyl-2-thienyl, 2-, 4- or 5-methyl-3-thienyl, 3- methyl-5-tert.-butyl-2-thienyl, 5-chloro-2-thienyl, - phenyl-2- or -3-thienyl, 1-, 3-, 4- or 5-methyl-2pyrrolyl, l-methyl-4- or -5-nitro-2-pyrrolyl, 3,5-dimethyl-4-ethyl-2-pyrrolyl, 4-methyl-5-pyrazolyl, - 10 5-methyl-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 4- or 5-methyl-2-thiazolyl, 2- or 5-xnethyl-4-thiazolyl, 2- or 4- methyl-5-thiazolyl, 2,4-dimethyl-5-thiazolyl, 3-, 4-, - or 6-methyl-2-pyridyl, 2-, 4-, 5- or 6-methyl-35 pyridyl, 2- or 3-methyl-4-pyridyl, 3-, 4-, 5- or 6chloro-2-pyridyl, 2-, 4-, 5- or 6-chloro-3-pyridyl, 2- or 3-chloro-4-pyridyl, 2,6-dichloropyridyl, 2-hydroxy-3-, -4-, -5- or -6-pyridyl (= lH-2-pyridon-3-, -4-, -5- or -6-yl), 5-phenyl-lH-2-pyridon-3-yl, 5-p-methoxyphenyl-lH10 2-pyridon-3-yl, 2-methyl-3-hydroxy-4-hydroxymethyl-5pyridyl, 2-hydroxy-4-amino-6-methyl-3-pyridyl, 3-N'methylureido-1H-4-pyridon-5-y1, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 2-, 5- or 6-methyl-4-pyrimidinyl, 2,6-dimethyl-4-pyrimidinyl, 2,6-dihydroxy-4-pyrim15 idinyl, 5-chloro-2-methyl-4-pyrimidinyl, 3-methyl-2benzofuryl, 2-ethyl-3-benzofuryl, 7-methyl-2-benzothienyl, 1-, 2-, 4-, 5-, 6- or 7-methyl-3-indolyl, l-methyl-5- or -6-benzimidazolyl, l-ethyl-5- or -6-benzimidazolyl, 3-, 4-, 5-, 6-, 7- or 8-hydroxy-2-quinolyl, 2-oxopyrrolidino, 2-oxopiperidino, 2,5-dioxopyrrolidino or 3-benzyl-2,5-dioxopyrrolidino.
X is generally preferably R8, R8-CmH2m-O-CO-> R9R10N-CmH2n-CO-, in particular 4-BOC-aminopiperidinocarbonyl, 4-aminopiperidinocarbonyl, 3-BOC-amino-325 methylbutyryl or 3-amino-3-methylbutyryl, or R8-SO2-, in particular A-SO2- such as tert.-butylsulfonyl or isopropylsulfonyl.
The group Y is preferably one of the amino acid radicals Indicated; however, it can also be absent. Y is preferably 0Ala, His, S-Me-Cys or Nva, in addition preferably Asn, Dab, Gin, Gly, N-Me-His, lie, Leu, tert.Leu, Lys, Met, Nle, Orn, Pya (particularly 3-Pya), Ser, Tia or Val.
V is preferably NH.
R1, R8, R7, Re and R10 are each preferably H, in addition preferably methyl; R8 is preferably also isopropyl or isobutyl. R9R10N is preferably also pyrrolidino, piperidino, morpholino, aminopiperidino such as 4-aminopiperidino, alkylaminopiperidino such as - 11 10 4-methylaminopiperidino, dialkylaminopiperidino such as 4-dimethylaminopiperidino or BOC-aminopiperidino such as 4-BOC-aminopiperidino. CR6R7 is preferably CH2.
R2 is preferably Ar-alkyl, in particular benzyl or p-methoxybenzyl; in addition preferably A, in particular n-butyl or isobutyl; cycloalkylalkyl, in particular eyelohexylmethyl; or Het-alkyl, in particular 2-thienylmethyl. The group -W-CR1R2-CO- is preferably one of the radicals Phe or Pla, in addition Ada, Bia, Cal, Hph, Leu, Mai, Tia or Trp.
R3 is preferably H or A.
R4 is preferably cycloalkylalkyl, in particular eyelohexylmethyl, in addition preferably alkyl, in particular n-butyl or isobutyl; Ar-alkyl, in particular benzyl or p-methoxybenzyl; Het-alkyl, for example 2thienylmethyl; or cycloalkyl, in particular cyclohexyl.
R5 is preferably (H, OH).
The group -(CR6R7)r- is preferably -CH2- or -CH2CH2-.
Ru is preferably H, methyl or CN.
The parameter m is preferably 1, 2, 3, 4 or 5; n is preferably 1; r is preferably 0 or 1; t is preferably 0 or 2; x is preferably 1 or 2.
CnHan and ΟχΗ^ are preferably straight-chain, that is to say preferably -(CH2)m- or -(CH2)X-.
Accordingly, the group X is in particular preferably A, for example isopropyl or isobutyl; Ar, for example phenyl; Ar-alkyl, for example benzyl; R9R10N(CHa^-CO-, in particular HjN-CnHan-CO- such as aminocarbonyl, aminoacetyl (H-Gly-), 3-aminopropionyl (H-ySAla-), 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl, 11-aminoundecanoyl, but also, for example, 2-aminopropionyl (Ala), 2-amino-2-methylpropionyl, 3-amino-3-methylbutyryl; ANH-CJi^-CO- such as methylaminocarbonyl, methylaminoacetyl (sarcosyl), 3-methylaminopropionyl, 4-methylaminobutyryl, 5-methylaminopentanoyl, 6-methylaminohexanoyl, 6-ethylaminohexanoyl, 7-methylaminoheptanoyl, 8-methylaminooctanoyl, -129- methylaminononanoyl, 10-methylaminodecanoyl, 11-methylaminoundecanoyl, A2N-CmH2m-CO- such as dimethylaminocarbonyl, dimethylaminoacetyl, 3-dimethylaminopropionyl, 4-dimethylaminobutyryl, 5-dimethylaminopentanoyl, 6-di5 methylaminohexanoyl, 6-diethylaminohexanoyl, 7-dimethylaminoheptanoyl, 8-dimethylaminooctanoyl, 9-dimethylaminononanoyl, 10-dimethylaminodecanoyl, 11-dimethylaminoundecanoyl; pyrrol idino-CmH2m-CO- such as pyrrolidinocarbonyl, pyrrolidinoacetyl, 3-pyrrolidinopropionyl, 4-pyrrolidinobutyryl, 5-pyrrolidinopentanoyl, 6-pyrrolidinohexanoyl, 7-pyrrolidinoheptanoyl, 8-pyrrolidinooctanoyl, 9-pyrrolidinononanoyl, 10-pyrrolidinodecanoyl; piperidino-CmH2m-CO- such as piperidinocarbonyl, piperidinoacetyl, 3-piperidinopropionyl, 4-piperidinobutyryl, -piperidinopentanoyl, 6-piperidinohexanoyl, 7-piperidinoheptanoyl, 8-piperidinooctanoyl, 9-piperidinononanoyl, - piperidinodecanoyl; morpholino-CmHan-CO- such as morpholinocarbonyl, morpholinoacetyl, 3-morpholinopropionyl, 4-morpholinobutyryl, 5-morpholinopentanoyl, 6-morpholinohexanoyl, 7-morpholinoheptanoyl, 8-morpholinooctanoyl, 9-morpholinononanoyl, 10-morpholinodecanoyl; 4-aminopiper idino-CnHan-CO- such as 4-aminopiperidinocarbonyl, 4-aminopiperidinoacetyl, 3-(4-aminopiperidino)propionyl, 4-(4-aminopiperidino)butyryl, 5-(4-aminopiper25 idino)pentanoyl, 6-(4-aminopiperidino)hexanoyl, 7-(4aminopiperidino)heptanoyl, 8-(4-aminopiperidino)octanoyl, 9- (4-aminopiperidino)nonanoyl, 10-(4-aminopiperidino)decanoyl; 4-BOC-aminopiperidino-CmH2n>“CO- such as 4-BOCaminopiperidinocarbonyl, 4-BOC-aminopiperidinoacetyl; A-dialkylaminopiperidino-CmHaj-CO- such as 4-dimethylaminopiperidinocarbonyl, 4-dimethylaminopiperidinoacetyl; 4-guanidinopiper idino-CJI^-CO- such as 4-guanidinopiperidinocarbonyl, 4-guanidinopiperidinoacetyl; 4-carboxypiperidino-C^^-CO- such as 4-carboxypiperidino35 carbonyl, 4-carboxypiperidinoacetyl; 4-alkoxycarbonylpiperidino-C^H^-CO- such as 4-methoxycarbonylpiperidinocarbonyl, 4-ethoxycarbonylpiperidinocarbonyl, 4-methoxycarbonylpiperidinoacetyl, 4-ethoxycarbonylpiperidinoacetyl; 4-AcNH-piperidino-CmH2m-CO- such as - 13 4-acetamidopiperidinocarbonyl, 4-acetamidopiperidinoacetyl; H2N-C(=NH) -CJi^-CO- such as guanidinoacetyl, 3- guanidinopropionyl, 4-guanidinobutyryl, 5-guanidinopentanoyl, 6-guanidinohexanoyl, 7-guanidinoheptanoyl, 8-guanidinooctanoyl; NC-NH-C(=NH)-NH-C^H^-CO- such as N'-cyanoguanidinoacetyl, 3-(N'-cyanoguanidino) propionyl, 4- (N'-cyanoguanidino) butyryl, 5-(N'-cyanoguanidino)pentanoyl, 6-(N'-cyanoguanidino)hexanoyl, 7-(N'-cyanoguanidino )heptanoyl, 8-(N'-cyanoguanidino)octanoyl; HOOC-C^H^-CO- such as malonyl, succinyl, glutaryl, adipyl, 6-carboxyhexanoyl, 7-carboxyheptanoyl, 8-carboxyoctanoyl, 9-carboxynonanoyl, 10-carboxydecanoyl, 11-carboxyundecanoyl; AOOC-^H^-CO- such as methoxycarbonylacetyl, 3-methoxycarbonylpropionyl, 4-methoxycar15 bonylbutyryl, 5-methoxycarbonylpentanoyl, 6-methoxycarbonylhexanoyl, 7-methoxycarbonylheptanoyl, 8-methoxycarbonyloctanoyl, 9-methoxycarbonylnonanoyl, 10-methoxycarbony Idee anoyl, ethoxycarbonylacetyl, 3-ethoxycarbonylpropionyl, 4-ethoxycarbonylbutyryl, 5-ethoxycarbonyl2 0 pentanoyl, 6-ethoxycarbonylhexanoyl, heptanoyl, 8-ethoxycarbonyloctanoyl, nonanoyl, 10-ethoxycarbonyldecanoyl; H-SOa-C^Han-CO- such as sulfoacetyl, 3-sulfopropionyl, 4-sulfobutyryl, - sulfopentanoyl, 6-sulfohexanoyl, 7-sulfoheptanoyl, 8-sulfooctanoyl, 9-sulfononanoyl, 10-sulfodecanoyl; A-SO3CmHan-CO- such as methoxysulfonylacetyl, 3-methoxysulfonylpropionyl, 4-methoxysulfonylbutyryl, 5-methoxysulfonylpentanoyl, 6-methoxysulfonylhexanoyl, 7-methoxysulfonylheptanoyl, 8-methoxysulfonyloctanoyl, 9-methoxy30 sulfonylnonanoyl, 10-methoxysulfonyldecanoyl, ethoxy3-ethoxysulfonylpropionyl, 4-ethoxy5-ethoxysulfonylpentanoyl, 6-ethoxy7-ethoxysulfonylheptanoyl, 8-ethoxy9-ethoxysulfonylnonanoyl, 10-ethoxy35 sulfonyldecanoyl; ^-C^^-O-CO-, in particular A-O-COsuch as ETOC, IPOC, BOC and also Ar-CJHaj-O-CO- such as CBZ; R^C^-CO-, in particular A-CO- such as acetyl, trimethylacetyl or 3,3-dimethylbutyryl.
The compounds of the formula I can have one or 7-ethoxycarbonyl9-ethoxycarbonylsulfonylacetyl, sulfonylbutyryl, sulfonylhexanoyl, sulfonyloctanoyl, sulfonyldecanoyl; - 14 more chiral centres and therefore occur in different - optically active or optically inactive - forms. The formula I includes all these forms. If R4 differs from H and/or R5 is (H, OH) or (H, NH2), for r = 0 the 5S-hydroxy, 5S-amino, 6S-amino, 5S-hydroxy-6S-amino and 5S,6S-diamino enantiomers or for r = 1 the 6S-hydroxy, 6S-amino, 7S-amino, 6S-hydroxy-7S-amino and 6S,7S-diamino enantiomers are preferred (the C atom which carries the radical R5 being allocated the 5-position for r = 0 and the 6-position for r = 1, and the C atom which carries the radicals X-W-CR1R2-CO-Y-NR3 and R4 being allocated the 6-position for r = 0 and the 7-position for r = 1).
The abovementioned cycloalkyl and phenyl groups are preferably unsubstituted or preferably carry 1 to 3, in particular 1 or 2 substituents.
The invention accordingly relates in particular to those compounds of the formula I in which at least one of the said radicals has one of the abovementioned preferred meanings. Some preferred groups of compounds can be expressed by the following sub-formulae Ia to Ik: I a RS-W-CfVRZ-CO- Y-NH-CHR*-CR5-CH2- (CR6R7) r-S (0) t CH2CO-V-R3; lb R8-O-CJi2ra-CO-W2-CO-Y-NH-CHR<-CR5CH2-(CR6R7) r-S(0) t-CH2CO-V-R3; I c R8-CBH2n,-0-C0-W-CR1R2-C0-Y-NH-CHR«-CR5CH2- (CR6R7) r-S (0) t-CH2C0-V-R3; Id R8-CniH2n,-C0-W-CR1Rz-C0-Y-NH-CHR*-CR5-CH2- (CR6R7) rS(0) t-CH2CO-V-R3; Ie R^'ON-CJi^-CO-W-CR^z-CO-Y-NH-CHR^-CR5CH2- (CR6R7) r-S (0) t-CH2C0-V-R3; If R11-NH-C(=NH) -NH-C^^-CO-W-CR'RZ-CO-Y-NH-CHR4CR5-CH2- (CR6R7) r-S(0) t-CH2CO-V-R3; I g R900C-CmH2n-C0-W-CR1R2-C0-Y-NH-CHR4-CR5CHZ- (CR6R7) r-S (0) t -CHZCO-V-R3; *E 912343 - 15 Ih R9O3S-CnH2n|-CO-W-CR1R2-CO-Y-NH-CHR*-CR5CH2- (CR6R7) r-S(0) t-CH2CO-V-R3; I i R9-0- (CH2CH2O) n-C„H2a-C0-W-CRiR2-C0-Y-NH-CHR5-CH2- (CR6R7) r-S(0) t-CH2C0-V-R3; I j R9R10N-C0-W-CR‘R2-C0-Y-NH -CHR<-CR5-CH2- (CR6R7) rS(O)t-CH2CO-V-R3; Ik 4-Aminopiperidinocarbonyl-W-CR1R2-C0-Y-NH-CHR4CR5-CH2-(CR6R7) r-S(0) t-CH2C0-V-R3.
Particularly preferred compounds are those of the sub-formulae: (a) Iaa to Ika which correspond to the formulae Ia to Ik, but in which additionally -W-CR1R2-C0- is Phe, Pla, Mai or -CH2-CH (CH2C6H5) -CO- ? (b) lab to Ikb and also Iaab to Ikab, which correspond to the formulae Ia to Ik and also Iaa to Ika, but in which additionally Y is 0Ala, His, Leu or S-Me-Cys. (c) lac to Ike, Iaac to Ikac and also Iabc to Ikbc, which correspond to the formulae Ia to Ik, Iaa to Ika and also lab to Ikb, but in which additionally R* is cyclohexylmethyl.
Particularly preferred compounds are those of the sub-formulae: I* and Ia* to Ik*, which correspond to the formulae I and also Ia to Ik and those compounds which correspond to the other abovementioned sub-formulae, but in which additionally R5 is (H, OH); I' and Ia' to Ik', which correspond to the formulae I and also Ia to Ik and those compounds which correspond to the other abovementioned sub-formulae, but in which additionally (CR6R7)r is CH2 or CH2CH2; I and also Ia to Ik, which correspond to the formulae I and also Ia to Ik and those compounds which correspond *E 912343 - 16 10 to the other abovementioned sub-formulae, but in which additionally V is 0 or NH and R3 is H or A.
A particularly preferred group of compounds corresponds to the formula I in which X is 4-BOC-aminopiperidinocarbonyl, 4-aminopiperidinocarbonyl, morpholinocarbonyl or A-SO2-, -W-CR1R2-CO- is Phe, Pla or -CH2-CH(CH2C6H5)-CO-, V is £Ala, His or S-Me-Cys, R3 is H or A, R* is cyclohexylmethyl, R5 is (H, OH), (CR6R7)r is CH2 or CH2CH2, V is 0 or NH and t is 0 or 2.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; and in addition EP-A-45,665, EP-A-77,028, EP-A-77,029, EP-A-81,783 and EP-A-249,096), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made of here of variants which are known per se but are not mentioned here in greater detail.
The starting substances, if desired, can also be formed in situ, such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
The compounds of the formula I can be obtained by setting them free from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis .
Preferred starting substances for the solvolysis or hydrogenolysis are those which otherwise correspond to - 17 the formula I, but instead of one or more free amino and/or hydroxy groups contain correspondingly protected amino and/or hydroxy groups, preferably those which instead of an H atom which is bonded to an N atom, carry an amino protective group, for example those of the formula I, but instead of an His group contain an N(im)-R'-His group (in which R' is an amino protective group, for example BOM or DNP), those of the formula X-W-CR1R2-CO-Y-NH-CHR4-CH (NHR') -CHZ- (CR6R7) r-S (0) t-CH2CO-V-R3 or those which instead of a Dab, Lys or Orn group contain a corresponding group which instead of the terminal NH2 group contains an NH-R' group (for example NH-CBZ).
In addition, starting substances are preferred which instead of the H atom of a hydroxy group carry a hydroxy protective group, for example those of the formula X-W-CR1R2-CO-Y-NH-CHR4-CHOR -CH2- (CR6R7 ) r-S (0) t-CH2CO-V-R3 in which R is a hydroxy protective group.
Several - identical or different - protected amino and/or hydroxy groups can also be present in the molecule of the starting substance. If the protective groups present are different from one another, they can in many cases be removed selectively.
The expression 'amino protective group' is generally known and relates to groups which are suitable for protecting an amino group from chemical reactions (for blocking), but which are easily removable after the desired chemical reaction has been carried out in another site of the molecule. Typical of such groups are in particular unsubstituted or substituted acyl, aryl (for example DNP), aralkoxymethyl (for example BOM) or aralkyl groups (for example benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise not critical; but those with 1-20 C atoms, in particular 1-8 C atoms, are preferred. The expression acyl group is to be interpreted in the widest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and also in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl such as acetyl, propionyl or butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ETOC, 2,2,2-trichloroethoxycarbonyl, IPOC, BOC, 2-iodoethoxycarbonyl; aralky loxycarbonyl such as CBZ, 4-methoxy10 benzyloxycarbonyl and FMOC. Preferred amino protective groups are BOC, DNP and BOM, and in addition CBZ, FMOC, benzyl and acetyl.
The expression 'hydroxy protective group' is likewise generally known and relates to groups which are suitable for protecting a hydroxy group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out in another site of the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and in addition also alkyl groups. The nature and size of the hydroxy protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10 C atoms are preferred. Examples of hydroxy protective groups are, among others, tert.-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, benzyl and acetyl being particularly preferred.
The functional derivatives of the compounds of the formula I to be used as starting substances can be prepared by customary methods of amino acid and peptide synthesis, such as, for example, are described in the said standard works and patent applications, for example also by the solid phase method according to Merrifield.
The compounds of the formula I are set free from their functional derivatives - depending on the protective group used - for example with strong acids, expediently with trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic - 19 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 inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and in addition also alcohols such as methanol, ethanol or isopropanol and also water. In addition, mixtures of the abovementioned solvents are suitable. Trifluoroacetic acid is preferably used in excess without addition of a further solvent, 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 expediently between about 0 and about 50°C; the reaction is preferably carried out between 15 and 30° (room temperature) .
The BOC group can, for example, preferably be removed with 40 % trifluoroacetic acid in dichloromethane or with about 3 to 5 N HCl in dioxane at 15-30°C, the FMOC group with an about 5-20 % solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°. The DNP group is also removed, for example, with an about 3-10 % solution of 2-mercaptoethanol in DMF/water at -30°.
Protective groups which can be removed by hydrogenolysis (for example BOM, CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst (for example a noble metal catalyst such as palladium, expediently on a support such as carbon). Suitable solvents in this case are the abovementioned, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. The hydrogen35 olysis is as a rule carried out at temperatures between 0 and 100° and at pressures between about 1 and 200 bar, preferably at 20-30° and at 1-10 bar. The CBZ group is easily hydrogenolysed, for example, on 5-10 % Pd-C in methanol at 20-30°.
Compounds of the formula I can also be obtained by direct condensation (peptide synthesis) from a carboxylic acid component (formula II) and a hydroxyl or amino component (formula III). Suitable carboxylic acid components are, for example, those of the sub-formulae (a) X-OH, (b) X-W-CR1R2-COOH (c) X-W-CR1R2-CO-Y-OH or (d) H-W-CR1R2-C0-Y-NH-CHR4-CR5-CH2- (CR6R7) r-S (0) t-CH2-COOH, suitable hydroxy or amino components are those of the sub-formulae (a) HW-CR1R2-CO-Y-NH-CHR',-CR5-CH2-(CR6R7)r-S(O)t-CH2CO-V-R3 (in which W is NH or 0), (b) H-Y-NH-CHR*-CR5-CH2- (CR6R7) r-S (0) t-CH2CO-V-R3 (c) H2N-CHR4-CR5-CH2-(CR6R7)r-S(O)t-CH2CO-V-R3 or (d) H-V-R3. The reaction is expediently carried out in this case by customary methods of peptide synthesis, such as are described, for example, in Houben-Weyl, loc.cit., Volume 15/11, pages 1-806 (1974); these methods can also be transferred, if W = 0, to the condensation according to (a), an ester bond being formed.
The reaction is preferably carried out in the presence of a dehydrating agent, for example of a carbodiimide such as DCCI or dimethylaminopropylethylcarbodiimide, and in addition propanephosphonic anhydride (cf. 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 dichloromethane, 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°.
Instead of II or III, suitable reactive derivatives of these substances can also be employed in the reaction, for example those in which reactive groups are intermediately blocked by protective groups. The acid derivatives II can be used, for example, in the form of their activated esters, which are expediently formed in situ, for example by addition of HOBt or N-hydroxysuccinimide.
The starting substances of the formulae II and - 21 III are for the greatest part known. If they are not known, they can be prepared by known methods, for example the abovementioned methods of condensation and removal of protective groups.
If desired, the functionally modified amino and/or hydroxy group in a compound of the formula I can be set free by solvolysis or hydrogenolysis according to one of the methods described above.
Thus, for example, a compound of the formula I 10 which contains an R11-CxH2x-O-CO-NH-, an AcNH- or an AOOCgroup can be converted into the corresponding compound of the formula I which instead of this contains an H2N- or an HOOC-group, expediently by selective solvolysis according to one of the abovementioned methods. AOOC15 groups can be hydrolysed, 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 Ra is H, can be reacted with acylating agents of the formula X-Cl (in which X is different from h), expediently 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, keto compounds of the formula I (R5 = 0) can be reduced to compounds of the formula I (R = (H, OH)), for example with a complex metal hydride such as NaBH4, 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 (R5 = 0) can also be converted into compounds of the formula I (R5 = H, NH2) by reductive amination. Reductive amination can be carried out in one or more steps. Thus, for example, the keto compounds 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 - 22 between 15 and 30°. It is furthermore possible to convert the keto compound into the oxime first with hydroxylamine in a customary manner and to reduce this, for example by catalytic hydrogenation on Raney nickel, to the amine.
If desired, a sulfide of the formula I in which t = 0 can be oxidised to the corresponding sulfoxide (I, t = 1) or sulfone (I, t = 2), for example with hydrogen peroxide or a peracid such as m-chloroperoxybenzoic acid or a salt of a peracid such as magnesium monoperoxyphthalate hexahydrate, in an inert solvent such as chloroform or THF at temperatures between about -10 and +20°. Approximately stoichiometric amounts of the oxidising agent are expediently used to prepare the sulfoxide. On the other hand, predominantly the sulfone is obtained when using the amounts of oxidising agents calculated for the formation of the sulfone or when using an excess.
A base of the formula I can be converted into the respective acid addition salt using an acid. Suitable acids for this reaction are in particular those which give physiologically acceptable salts, thus inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophos25 phoric acid, sulfamic acid, and in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, trifluoroacetic 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, naphthalenemono- and -disulfonic acids, and laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and/or purification of the - 23 compounds of the formula I.
The novel compounds of the formula I and their physiologically acceptable salts can be used for the production of the pharmaceutical preparations by bringing them into a suitable dosage form together with at least one excipient or auxiliary and, if desired, together with one or more other active compound(s). The preparations 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) or parenteral administration or for administration in the form of an inhalation spray and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose. For oral administration, tablets, coated tablets, capsules, syrups, juices or drops are used; especially of interest are coated tablets and capsules having enteric-resistant coatings or capsule shells. Suppositories are used for rectal administration, and solutions, preferably oily or aqueous solutions, and in addition suspensions, emulsions or implants are used for parenteral administration. For administration as inhalation sprays, sprays can be used which contain the active compound either dissolved or suspended in a propellant gas mixture (for example fluorochlorohydrocarbons). The active compound in this case is expediently used in micronised form, it being possible for one or more additional physiologically tolerable solvents to be present, for example ethanol. Inhalation solutions can be administered with the aid of customary inhalers. The novel compounds can also be lyophilised and the lyophilisates obtained used, for example, for the production of injection preparations.
The preparations mentioned can be sterilised and/or can contain auxiliaries such as preservatives, stabilisers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants - 24 and/or flavourings. If desired, they can also contain one or more other active compounds, for example one or more vitamins.
The substances according to the invention are as 5 a rule administered in analogy to other known commercially available peptides, but in particular 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 specific patient, however, depends on a wide variety of factors, for example on the activity of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, and on the excretion rate, medicament combination and severity of the particular disease to which the treatment applies. Parenteral administration is preferred. Renin-dependent hypertension and hyperaldosteronism can be effectively treated by administration of dosages between, in particular, about 0.2 and 20, preferably between 1 and 10 mg/kg of body weight. For diagnostic purposes the novel compounds can expediently be administered in individual doses between about 0.1 and 10 mg/kg of body weight.
Above and below, all temperatures are indicated in “C. In the following examples 'customary working up' means: water is added if necessary, the pH is adjusted to between 2 and 8, depending on the constitution of the final product, the mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or crystallisation. TFA = trifluoroacetate.
Example 1 g of 6S-[2RS-benzyl-3-tert.-butylsulfonylpropionyl-L- (N-imi) -benzyloxymethylhistidyl) amino] -7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide [= 6S-[2RS-benzyl-3-tert.-butylsulfonylpropionyl•Ε 912343 - 25 (imi-BOM-His) amino]-7-cyclohexyl-5S-hydroxy-3-thiaheptano ic acid N-isobutylamide; obtainable by reaction of 3-BOC-4-cyclohexylmethyl-5-iodomethyl-2, 2-dimethyloxazolidine (m.p. 89°) with thioglycolic acid in the presence of NaH in DMF to give 3-BOC-5-(3-carboxy-2thiapropyl)-4-cyclohexylmethyl-2,2-dimethyloxazolidine (m.p. 115-116°), condensation with isobutylamine to give 3-BOC-4-cyclohexylmethyl-5- (3-N-isobutylcarbamoyl-2-thiapropyl)-4-cyclohexylmethyl-2,2-dimethyloxazolidine, hydrolysis to give 6S-amino-7-cyclohexyl-5S-hydroxy-3thiaheptanoic acid N-isobutylamide and condensation with 2-RS-benzyl-3-tert. -butylsulfonylpropionyl- (imi-BOM-His) OH analogously to Example 4] are dissolved in 26 ml of ethanol, the solution is hydrogenated on 0.4 g of 10 % Pd-C at 20’ and at 1 bar until uptake of hydrogen has stopped, filtered and evaporated, and 6S-(2RS-benzyl-3tert.-butylsulfonylpropionyl-His-amino)-7-cyclohexyl-5Shydroxy-3-thiaheptanoic acid N-isobutylamide hydrochloride, 2 isomers, m.p. 136-137° and m.p. 99-100°, is obtained after chromatographic purification.
Example 2 6S-(4-BOC-aminopiperidinocarbonyl-Pla-His-amino)7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide, m.p. 149°, is obtained from 6S-[4-BOC-aminopiper25 idinocarbonyl-Pla-(imi-BOM-His) amino]-7-cyclohexyl-5Shydroxy-3-thiaheptanoic acid N-isobutylamide by hydrogenolysis analogously to Example 1.
Example 3 6S-(4-BOC-aminopiperidinocarbonyl-Phe-His-amino)30 7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide, m.p. 116-117°, is obtained from 6S-[4-BOC-aminopiperidinocarbonyl-Phe- (imi-BOM-His) amino ] - 7-cyclohexyl5S-hydroxy-3-thiaheptanoic acid N-isobutylamide by hydrogenolysis analogously to Example 1.
The following are obtained analogously 6S-(4-BOC-aminopiperidinocarbonyl-Phe-His-amino )-7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide- 3 ,3-dioxide methyl 6S-acetyl-Cal-His-amino-7-cyclohexyl-5S-hydroxyIE 912343 - 26 3-thiaheptanoate methyl 6S-BOC-Bia-His-amino-7-cyclohexyl-5S-hydroxy-3 thiaheptanoate methyl 7-eyelohexy1-5S-hydroxy-6 S-isopropylsu1fony1-Phe 5 His-amino-3-thiaheptanoate methyl 7-cyclohexyl-5S-hydroxy-6S-morpholinocarbonyl-Ada His-amino-3-thiaheptanoate methyl 7-cyclohexyl-5S-hydroxy-6S-morpholinocarbonyl-Hph His-amino-3-thiaheptanoate methyl 7-cyclohexyl-5S-hydroxy-6S-morpholinocarbonyl-Leu His-amino-3-thiaheptanoate methyl 7-eyelohexyl-5S-hydroxy-6S-morpholinocarbonyl-Mal His-amino-3-thiaheptanoate methyl 7-cyclohexyl-5S-hydroxy-6 S-morpholinoc arbonyl-Phe His-amino-3-thiaheptanoate methyl 7-eyelohexyl-5 S-hydroxy-6 S-morpholinocarbonyl-Tia His-amino-3-thiaheptanoate methyl 7-eye1ohexy1-5S-hydroxy-6 S-morpholinoc arbonyl-Trp His-amino-3-thiaheptanoate methyl 7-cyclohexyl-5S-hydroxy-6S-morpholinosul£onyl-Phe His-amino-3-thiaheptanoate methyl 6S-(4-BOC-aminopiperidinocarbonyl-Phe-His-amino) 7-cyclohexyl-5S-hydroxy-3-thiaheptanoate methyl 6S-(4-BOC-aminopiperidinocarbonyl-Pla-His-amino) 7-eyelohexyl-5S-hydroxy-3-thiaheptanoate methyl 6S-(4-BOC-aminopiperidinocarbonyl-Phe-His-amino) 7-cyclohexyl-5S-hydroxy-3-thiaheptanoate-3,3-dioxide methyl 6S-(4-BOC-aminopiperidinocarbonyl-Pla-His-amino) 7- eyelohexyl-5S-hydroxy-3-thiaheptanoate-3,3-dioxide methyl 7S-(4-BOC-aminopiperidinocarbonyl-Phe-His-amino) 8- cyclohexyl-6S-hydroxy-3-thiaoctanoate methyl 7S-(4-BOC-aminopiperidinocarbonyl-Pla-His-amino) 8-cyclohexyl-6S-hydroxy-3-thiaoctanoate methyl 7S-(4-BOC-aminopiperidinocarbonyl-Phe-His-amino) 8-cyclohexyl-6S-hydroxy-3-thiaoctanoate-3,3-dioxide methyl 7S-(4-BOC-aminopiperidinocarbonyl-Pla-His-amino) 8-cyclohexyl-6S-hydroxy-3-thiaoctanoate-3,3-dioxide methyl 7-eyelohexyl-5 S-hydroxy-6 S-morpholinocarbonyl-Phe His-amino-3-thiaheptanoate-3,3-dioxide methyl 7-cyclohexyl-5S-hydroxy-6S-morpholinocarbonyl-PlaHis-amino-3-thiaheptanoate-3,3-dioxide methyl 6S-(2-RS-benzyl-3-tert.-butylsulfonylpropionylHis-amino)-7-cyclohexyl-5S-hydroxy-3-thiaheptanoate-3,35 dioxide.
Example 4 A mixture of 992 mg of 6S-[4-BOC-aminopiperidinocarbonylamino-L-phenylalanyl-L-(N-(imi)-2,4-dinitrophenylhistidyl) amino]-7-cyclohexyl-5S-hydroxy-3-thiahep10 tanoic acid N-isobutylamide [= 6S-[4-BOC-aminopiperidinocarbonyl-Phe- (imi-DNP-His) amino] -7-cyclohexyl-5S-hydroxy3-thiaheptanoic acid N-isobutylamide; obtainable via 6S-BOC-(imi-DNP-His)amino-7-cyclohexyl-5S-hydroxy-3thiaheptanoic acid N-isobutylamide (m.p. 95-96°)], 2 g of 2-mercaptoethanol, 20 ml of DMF and 20 ml of water is adjusted to pH 8 with aqueous NazCO3 solution while stirring at 20° and the mixture is stirred at 20° for a further 2 hours. Customary working-up gives 6S-(4-BOCaminopiperidinocarbonyl-Phe-His-amino) -7-cyclohexyl-5S20 hydroxy-3-thiaheptanoic acid N-isobutylamide, m.p. 116117°.
Example 5 6S- (4-BOC-aminopiperidinocarbonyl-Phe-Lys-amino)7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-2-phenyl25 ethylamide is obtained by hydrogenolysis of 6S-(4-BOCaminopiper idinocarbonyl-Phe- (N5-CBZ-Lys) amino) -7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-2-phenylethylamide analogously to Example 1.
Example 6 A solution of 3.96 g of 7-cyclohexyl-5S-hydroxy6S-H- (S-Me-Cys) amino-3-thiaheptanoic acid N-isobutylamide [obtainable by condensation of 6S-amino-7-cyclohexyl-5Shydroxy-3-thiaheptanoic acid N-isobutylamide with BOC-(SMe-Cys) -OH to give 6S-[BOC- (S-Me-Cys) amino] -7-cyclohexyl35 5S-hydroxy-3-thiaheptanoic acid N-isobutylamide (m.p. 107°) and removal of the BOC group] in 60 ml of dichloromethane is treated with 1.01 g of N-methylmorpholine. 3.79 g of 4-BOC-aminopiperidinocarbonyl-Phe-OH, 1.35 g of HOBt and a solution of 2.06 g of DCCI in 50 ml of - 28 dichloromethane are added with stirring, the mixture is stirred at 0-5° for 12 hours, the precipitated dicyclohexylurea is filtered off and the filtrate is evaporated. Customary working-up gives 6S-[4-BOC-aminopiperidino5 carbonyl-Phe-(S-Me-Cys) amino]-7-cyclohexyl-5S-hydroxy-3thiaheptanoic acid N-isobutylamide, m.p. 101-102°.
Example 7 6S- [ 4-BOC-aminopiperidinocarbonyl-Pla- ( S-MeCys ) amino]-7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide, m.p. 172-173°, is obtained using 4-BOCaminopiperidinocarbonyl-Pla-OH (m.p. 123-124°) analogously to Example 6.
Example 8 6S - ( 4 - BOC-aminopiperidinocarbonyl-Phe-Ala15 amino)-7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid Nisobutylamide, m.p. 100-101°, is obtained from 4-BOCaminopiperidinocarbonyl-Phe-^Ala-OH and 6S-amino-7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide analogously to Example 6.
Analogously, there are obtained with methyl 6S-amino-7-cyclohexyl-5S-hydroxy-3-thia-heptanoate or its S,S-dioxide, respectively: methyl 6S-(4-BOC-amino-piperidinocarbonyl-PheBAla-amino)-7-cyclohexyl-5S-hydroxy-3-thia-heptanoate, m.p. 140-141° methyl 6S-(4-BOC-amino-piperidinocarbonyl-PheBAla-amino)-7-cyclohexyl-5S-hydroxy-3-thia-heptanoate» 3,3-dioxide,m.p. 113-114°. - 28AExample 9 7S-[4-BOC-aminopiperidinocarbonyl-Phe-(S-MeCys)amino]-8-cyclohexyl-6S-hydroxy-3-thiaoctanoic acid N-isobutylamide, m.p. 149-150°, is obtained using 8-cyclohexyl-6S-hydroxy-7S-H-(S-Me-Cys)amino-3-thiaoctanoic acid N-isobutylamide [obtainable from 3-BOC-4cyclohexylmethyl-5-(2-iodoethyl)-2,2-dimethyloxazolidine via 3-BOC-4-cyclohexylmethyl-5-(4-carboxy-3-thiabutyl)2,2-dimethyloxazolidine, 3-BOC-4-cyclohexylmethyl-5-(41 0 isobutylaminocarbonyl-3-thiabutyl )-2,2-dimethyloxazolidine (m.p. 61-62°) and 8-cyclohexyl-6S-hydroxy-7SBOC-(S-Me-Cys)amino-3-thiaoctanoic acid N-isubutylamide (m.p. 124-125’)] analogously to Example 6.
Example 10 15 Methyl 6S-[4-BOC-aminopiperidinocarbonyl-Pla-(SMe-Cys) amino] -7-cyclohexyl-5S-hydroxy-3-thiaheptanoate, m.p. 104-105°, is obtained from 4-BOC-aminopiperidinocarbonyl-Pla-OH and methyl 7-cyclohexyl-5S-hydroxy-6S-H(S-Me-Cys)amino-3-thiaheptanoate [obtainable via 3-BOC20 4 -eye lohexy lmethyl - 5 - iodomethyl-2,2 -dimethyloxazolidine (m.p. 67°) and 3-BOC-4-cyclohexylmethyl-5-(3-methoxycarbonyl-2-thiapropyl)-2,2-dimethyloxazolidine (m.p. 67°)] analogously to Example 6.
Example 11 Methyl 6S-[4-BOC-aminopiperidinocarbonyl-Phe-(SMe-Cys ) amino ] -7-cyclohexyl-5S-hydroxy-3-thiaheptanoate, m.p. 90-91°, is obtained using 4-BOC-aminopiperidinocarbonyl-Phe-OH analogously to Example 10.
Example 12 The following are obtained using morpholinocarbonyl-Phe-OH or using morpholinocarbonyl-Pla-OH analogously to Example 10: methyl 7-cyclohexyl-5S-hydroxy-6S-[morpholinocarbonylPhe-(S-Me-Cys) amino]-3-thiaheptanoate methyl 7-cyclohexyl-5S-hydroxy-6S-[morpholinocarbonylPla-(S-Me-Cys) amino]-3-thiaheptanoate.
Example 13 - Cyc lohexy 1 - 6 S - hydroxy- 7 S - [ morpho 1 inoc ar bony 1 Pla- (S-Me-Cys) amino] -3-thiaoctanoic acidN-isobutylamide, m.p. 97-98°, is obtained from morpholinocarbonyl-Pla-OH and 8-cyclohexyl-6S-hydroxy-7S-H-(S-Me-Cys) amino-3thiaoctanoic acid N-isobutylamide analogously to Example 6.
Example 14 7S- [ 4-BOC-aminopiperidinocarbonyl-Pla- ( S-MeCys ) amino] -8-cyclohexyl-6S-hydroxy-3-thiaoctanoic acid Nisobutylamide, m.p. 171-172’, is obtained using 4-BOCaminopiperidinocarbonyl-Pla-OH analogously to Example 13. Example 15 Methyl 7S- [ 4-BOC -aminopiperidinocarbonyl-Pla- (SMe-Cys) amino)-8-cyclohexyl-6S-hydroxy-3-thiaoctanoate, m.p. 58-59°, is obtained from 4-BOC-aminopiperidinocarbonyl-Pla-OH and methyl 8-cyclohexyl-6S-hydroxy-7S-H(S-Me-Cys )amino-3-thiaoctanoate analogously to Example 6.
Methyl 7S-[4-BOC-aminopiperidinocarbonyl-Phe-(SMe-Cys) amino]-8-cyclohexyl-6S-hydroxy-3-thiaoctanoate, m.p. 175-176°, is obtained analogously using 4-BOCaminopiperidinocarbonyl-Phe-OH.
Example 16 Methyl 8-cyclohexyl-6 S-hydroxy-7 S-morpholinocarbonyl-Phe- (S-Me-Cys )amino-3-thiaoctanoate, m.p. 135136°, is obtained from morpholinocarbonyl-Phe-(S-Me-Cys)5 OH and methyl 8-cyclohexyl-6S-hydroxy-7S-amino-3-thiaoctanoate analogously to Example 6.
Example 17 Methyl 7-cyclohexyl-5S-hydroxy-6S-[3-phenylpropionyl-(S-Me-Cys) amino]-3-thiaheptanoate-3,3-dioxide, m.p. 132-133°, is obtained from 3-phenylpropionic acid and methyl 7-cyclohexyl-5S-hydroxy-6S-(S-Me-Cys)amino-3thiaheptanoate-3,3-dioxide analogously to Example 6.
The following are obtained analogously: methyl 7-cyclohexyl-5S-hydroxy-6S-[POA-(S-Me-Cys) amino]15 3-thiaheptanoate-3,3-dioxide, m.p. 138-139°, using phenoxyacetic acid (POA-H); methyl 6S-BOC-Phe-(S-Me-Cys)amino-7-cyclohexyl-5Shydroxy-3-thiaheptanoate-3,3-dioxide, m.p. 154-155°, using BOC-Phe-OH; methyl 6S-[4-BOC-aminopiperidinocarbonyl-Phe-(S-MeCys ) amino] -7-cyclohexyl-5S-hydroxy-3-thiaheptanoate-3 , 3dioxide, m.p. 139-140°, using 4-BOC-aminopiperidinocarbonyl-Phe-OH. methyl 6S-[4-BOC-aminopiperidinocarbonyl-Pla-(S-Me2 5 Cys) amino]-7-cyclohexyl-5S-hydroxy-3-thiaheptanoate-3,3dioxide, m.p. 178-179°, using 4-BOC-aminopiperidinocarbonyl-Pla-OH. methyl 7-cyclohexyl-5S-hydroxy-6S-morpholinocarbonyl-Phe(S-Me-Cys)amino-3-thiaheptanoate-3,3-dioxide, m.p. 13930 141°, using morpholinocarbonyl-Phe-OH.
Example 18 Methyl 7S-[4-BOC-aminopiperidinocarbonyl-Pla-(SMe-Cys) amino]-8-cyclohexyl-6S-hydroxy-3-thiaoctanoate, m.p. 167-168°, is obtained from 4-BOC-aminopiperidino35 carbonyl-Pla-OH and methyl 8-cyclohexyl-6S-hydroxy-7S-(SMe-Cys)amino-3-thiaoctanoate-3,3-dioxide analogously to Example 6.
The following are obtained analogously: methyl 7S-[4-BOC-aminopiperidinocarbonyl-Phe-(S-MeIE 912343 - 31 Cys) amino] -8-cyclohexyl-6S-hydroxy-3-thiaoctanoate-3,3dioxide, m.p. 151-152°, using 4-BOC-aminopiperidinocarbonyl-Phe-OH; methyl 8-cyclohexyl-6S-hydroxy-7S-morpholinocarbonyl-Phe5 (S-Me-Cys)amino-3-thiaoctanoate-3,3-dioxide, m.p. 155156°, using morpholinocarbonyl-Phe-OH; methyl 8-cyclohexyl-6S-hydroxy-7S-POA-(S-Me-Cys)amino-3thiaoctanoate-3,3-dioxide, m.p. 134-135°, using POA; methyl 8-cyclohexyl-6S-hydroxy-7S-[2-indolylcarbonyl-(S10 Me-Cys)amino]-3-thiaoctanoate-3,3-dioxide, m.p. 175-176°, using indole-2-carboxylic acid; methyl 7S-[4-BOC-aminopiperidinocarbonyl-Pla-(S-MeCys )amino-3-thiaoctanoate-3, 3-dioxide, m.p. 112-113°, using morpholinocarbonyl-Pla-OH.
Example 19 6-[4-BOC-aminopiperidinocarbonyl-Phe-(S-MeCys ) amino]-7-cyclohexyl-5R,S-hydroxy-3-thiaheptanoic acid N-isobutylamide-3,3-dioxide, m.p. 118-119°, is obtained from 4-BOC-aminopiperidinocarbonyl-Phe-OH and 7-cyclo20 hexyl-5R,S-hydroxy-6-H-(S-Me-Cys)amino-3-thiaheptanoic acid N-isobutylamide-3,3-dioxide analogously to Example 6.
The corresponding 5S-diastereomer, m.p. 154-155°, is obtained analogously from 7-cyclohexyl-5S-hydroxy-625 H-(S-Me-Cys)amino-3-thiaheptanoic acid N-isobuty1amide3, 3-dioxide. 6-[4-BOC-aminopiperidinocarbonyl-Pla-(S-MeCys) amino]-7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide-3,3-dioxide, m.p. 96-97°, is obtained analogously using 4-BOC-aminopiperidinocarbonyl-Pla-OH.
Example 20 6S-(4-BOC-aminopiperidinocarbonyl-Phe-Leu-amino)7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide-3,3-dioxide is obtained from 4-BOC-aminopiperidino35 carbonyl-Phe-Leu-OH and 6S-amino-7-cyclohexyl-5S-hydroxy3-thiaheptanoic acid N-isobutylamide-3,3-dioxide analogously to Example 6.
The following are obtained analogously using the corresponding compounds of the type 4-BOC-aminopiperIE 912343 - 32 idinocarbonyl-Phe-Y-OH (Y = Ala, £Ala, Met, Nle, Nva, 3-Pya, Tia or 2-Tiz): S — (4-BOC-aminopiperidinocarbonyl-Phe-Ala-amino )-7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutyl5 amide-3,3-dioxide 6S-(4-BOC-aminopiperidinocarbonyl-Phe-/9Ala-amino)-7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide-3,3-dioxide 6S-(4-BOC-aminopiperidinocarbonyl-Phe-Met-amino )-710 cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide- 3 , 3-dioxide 6S-(4-BOC-aminopiperidinocarbonyl-Phe-Nle-amino)-7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide-3,3-dioxide 6S-(4-BOC-aminopiperidinocarbonyl-Phe-Nva-amino)-7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide-3,3-dioxide 6S-(4-BOC-aminopiperidinocarbonyl-Phe-(3-Pya) amino)-7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutyl20 amide-3,3-dioxide 6S-(4-BOC-aminopiperidinocarbonyl-Phe-Tia-amino)-7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide- 3 ,3-dioxide 6S-(4-BOC-aminopiperidinocarbonyl-Phe-(2-Tiz) amino)-725 cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide- 3 ,3-dioxide.
Example 21 7-Cyclohexyl-5S-hydroxy-6 S-morpho1inoc arbony1Phe-(S-Me-Cys)amino-3-thiaheptanoic acid N-methylamide is obtained from morpholinocarbonyl-Phe-(S-Me-Cys)-OH and 6S-amino-7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid Nmethylamide analogously to Example 6.
The following are obtained analogously using 6S-amino-7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N35 propylamide, its isopropyl ester, N-methylamide-3,3dioxide or N-propylamide-3,3-dioxide: 7-cyclohexyl-5S-hydroxy-6S-morpholinocarbonyl-Phe-(S-MeCys)amino-3-thiaheptanoic acid N-propylamide isopropyl 7-cyclohexyl-5S-hydroxy-6S-morpholinocarbonylIE 912343 - 33 Phe-(S-Me-Cys) amino-3-thiaheptanoate 7-cyclohexyl-5S-hydroxy-6 S-morpho1inocarbony1-Phe-(S-MeCys)amino-3-thiaheptanoic acid N-methylamide-3,3-dioxide 7-cyclohexyl-5S-hydroxy-6S-morpholinocarbonyl-Phe-(S-Me5 Cys) amino-3-thiaheptanoic acid N-propylamide-3,3-dioxide.
The following are obtained analogously using morpholinocarbonyl-Pla-(S-Me-Cys)-OH: 7-eyelohexy1-5 S-hydroxy-6 S-morpho1inocarbony1-P1a-(S-MeCys)amino-3-thiaheptanoic acid N-methylamide 7-cyclohexyl-5S-hydroxy-6S-morpholinocarbonyl-Pla-(S-MeCys )amino-3-thiaheptanoic acid N-propylamide i s opropy1 7-cyclohexyl-5S-hydroxy-6 S-morpho1inoc arbony1Pla-(S-Me-Cys) amino-3-thiaheptanoate 7-cyclohexyl-5S-hydroxy-6S-morpholinocarbonyl-Pla-(S-Me15 Cys)amino-3-thiaheptanoic acid N-methylamide-3,3-dioxide 7-cyclohexyl-5S-hydroxy-6S-morpholinocarbonyl-Pla-(S-MeCys )amino-3-thiaheptanoic acid N-propylamide-3,3-dioxide Example 22 The following are obtained from 4-BOC-aminopiper20 idinocarbonyl-Phe-Leu-OH or 4-BOC-aminopiperidinocarbonyl-Pla-Leu-OH using methyl 6S-amino-7-cyclohexyl5S-hydroxy-3-thiaheptanoate-3,3-dioxide or using methyl 7S-amino-8-cyclohexyl-6S-hydroxy-3-thiaoctanoate-3,3dioxide analogously to Example 6: methyl 6S-(4-BOC-aminopiperidinocarbonyl-Phe-Leu-amino)7-cyclohexyl-5S-hydroxy-3-thiaheptanoate-3,3-dioxide methyl 6S-(4-BOC-aminopiperidinocarbonyl-Pla-Leu-amino)7- cyclohexyl-5S-hydroxy-3-thiaheptanoate-3,3-dioxide methyl 7S-(4-BOC-aminopiperidinocarbonyl-Phe-Leu-amino)30 8-cyclohexyl-6S-hydroxy-3-thiaoctanoate-3,3-dioxide methyl 7S-(4-BOC-aminopiperidinocarbonyl-Pla-Leu-amino)8- cyclohexyl-6S-hydroxy-3-thiaoctanoate-3,3-dioxide Example 23 The following are obtained from 2-benzyl-3-tert.35 butylsulfonylpropionyl-(S-Me-Cys)-OH using methyl 6Samino-7-cyclohexyl-5S-hydroxy-3-thiaheptanoate-3,3dioxide, methyl 7S-amino-8-cyclohexyl-6S-hydroxy-3thiaoctanoate or its 3-oxide or 3,3-dioxide analogously to Example 6: methyl 6S-[2-benzyl-3-tert.-butylsulfonylpropionyl-(S-MeCys) amino]-7-cyclohexyl-5S-hydroxy-3-thiaheptanoate-3,3dioxide methyl 7S-[2-benzyl-3-tert.-butylsulfonylpropionyl-(S-Me5 Cys) amino]-8-cyclohexyl-6S-hydroxy-3-thiaoctanoate methyl 7S-[2-benzyl-3-tert.-butylsulfonylpropionyl-(S-MeCys) amino ] -8-cyc lohexyl-6 S-hydroxy-3- thiaoc tanoate-3oxide methyl 7S-[2-benzyl-3-tert.-butylsulfonylpropionyl-(S-Me10 Cys) amino ]-8-cyclohexyl-6S-hydroxy-3-thiaoctanoate-3,3dioxide.
Example 24 The following are obtained analogously to Example 6 from 4-B0C-aminopiperidinocarbonyl-Phe-£Ala-0H 4-BOC-aminopiperidinocarbonyl-Pla-^Ala-OH morpholinocarbonyl-Phe-0Ala-OH morpholinocarbonyl-Pla-^Ala-OH morpholinocarbonyl-Phe-(S-Me-Cys)-OH morpholinocarbonyl-Pla-(S-Me-Cys)-OH using methyl 7S-amino-8-cyclohexyl-6S-hydroxy-3-thiaoctanoate or its 3,3-dioxide: methyl 7S- (4-BOC-aminopiperidinocarbonyl-Phe-j3Ala-amino) 8-cyclohexyl-6S-hydroxy-3-thiaoctanoate methyl 7S-(4-BOC-aminopiperidinocarbonyl-Pla-^Ala-amino)8-eyelohexyl-6S-hydroxy-3-thiaoctanoate methyl 8-cyclohexyl-6S-hydroxy-7S-(morpholinocarbonylP he-β Ala-amino) —-——-6S-hydroxy-3-thiaoctanoate methyl 8-cyclohexyl-6S-hydroxy-7S-(morpholinocarbonyl30 Pla-^Ala-amino)----6S-hydroxy-3-thiaoctanoate methyl 8-cyclohexyl-6S-hydroxy-7S-[morpholinocarbonylPhe- (S-Me-Cys) amino ] — -—6 S-hydroxy-3-thiaoctanoate methyl 8-cyclohexyl-6S-hydroxy-7S-[morpholinocarbonyl35 Pla- (S-Me-Cys) amino]—---«6S-hydroxy-3-thiaoctanoate methyl 7S-(4-BOC-aminopiperidinocarbonyl-Phe-^Ala-amino)8-cyclohexyl-6S-hydroxy-3-thiaoctanoate-3,3-dioxide - 35 methyl 7S-(4-BOC-aminopiperidinocarbonyl-Pla-^Ala-amino)8-cyclohexyl-6S-hydroxy-3-thiaoctanoate-3,3-dioxide methyl 8-cyclohexy1-6 S-hydroxy-7S-(morpho1inocarbonylPhe-/) Ala-amino)-— ----?-6S-hydroxy-3-thiaoctanoate5 3,3-dioxide methyl 8-cyclohexy1-6 S-hydroxy-7 S-(morpholinoc arbonylPla-£Ala-amino)---------6S-hydroxy-3-thiaoctanoate3,3-dioxide methyl 8-cyclohexy1-6 S-hydroxy-7 S-[morpho1inoc arbonyl10 Phe- (S-Me-Cys) amino]---—— -6S-hydroxy-3-thiaoctanoate-3,3-dioxide methyl 8-cyclohexyl-6S-hydroxy-7S-[morpholinocarbonylPla- (S-Me-Cys )amino]——-----6S-hydroxy-3-thiaoctanoate-3,3-dioxide, m.p. 112° (dec.).
Example 25 6S-(4-BOC-aminopiperidinocarbonyl-Phe-^Alaamino)-7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid Nisobutylamide, m.p. 100-101°, is obtained from 6S-(4-BOCaminopiperidinocarbonyl-Phe-^S Ala-amino) -7-cyclohexyl-5S20 hydroxy-3-thiaheptanoic acid and isobutylamine analogously to Example 6.
Example 26 A solution of 1 g of 6S-[4-BOC-aminopiperidinocarbonyl-Phe-(S-Me-Cys) amino]-7-cyclohexyl-5S-hydroxy-325 thiaheptanoic acid N-isobutylamide in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid is stirred at 20’ for 1 hour and then evaporated. 6S-[4-Aminopiperidinocarbonyl-Phe- (S-Me-Cys) amino ] -7-cyclohexyl-5S-hydroxy3-thiaheptanoic acid N-isobutylamide, TFA, m.p. 159-160°, is obtained.
The following are obtained analogously from the corresponding BOC-amino derivatives using trifluoroacetic acid: 6S- [ 4-aminopiper idinocarbonyl-Phe- (S-Me-Cys) amino ] -735 cyclohexyl-5R-hydroxy-3-thiaheptanoic acid N-isobutylamide, TFA, m.p. 145’ (dec.) 6S- [ 4-aminopiperidinocarbonyl-Pla- (S-Me-Cys ) amino ] -7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide, TFA, m.p. 112° (dec.) - 36 6S-[4-aminopiperidinocarbonyl-Phe-£Ala-amino)-7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide, TFA, m.p. 141° 6S-[4-aminopiperidinocarbonyl-Pla-^Ala-amino)-7-cyclo5 hexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide 6S- [4-aminopiperidinocarbonyl-Phe-His-amino) -7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide, bis-TFA, m.p. 149-150° 6S- [4-aminopiperidinocarbonyl-Pla-His-amino) -7-cyclo10 hexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide, bis-TFA, m.p. 125-126° methyl 6S-[4-aminopiperidinocarbonyl-Phe-(S-Me-Cys)amino]-7-cyclohexyl-5S-hydroxy-3-thiaheptanoate, hydrochloride, m.p. 184-185° methyl 6S-[4-aminopiperidinocarbonyl-Pla-(S-Me-Cys)amino]-7-cyclohexy1-5S-hydroxy-3-thiaheptanoate, hydrochloride, m.p. 124-125° methyl 6S-[4-aminopiperidinocarbonyl-Phe-Hisaminq7-7-cyclohexyl-5S-hydroxy-3-thiaheptanoate methyl 6S-/4-aminopiperidinocarbonyl-Pla-His-aminq7-7cyclohexyl-5S-hydroxy-3-thiaheptanoate methyl 6S-(4-amino-piperidinocarbonyl-Phe-flAla-amino)-7cyclohexyl-5S-hydroxy-3-thia-heptanoate, TFA, m-p. 215-217 methyl 6S-(4-amino-piperidinocarbonyl-Phe-flAla-amino)-725Cyclohexyl-5S-hydroxy-3-thia-heptanoate—3,3-dioxide, TFA, m.p. 126-127° -36A Cys) amino]-7-cyclohexyl-5S-hydroxy-3-thiaheptanoate methyl 6 S —[4-aminopiperidinocarbonyl-Pla-His-(S-Me Cys) amino]-7-cyclohexyl-5S-hydroxy-3-thiaheptanoate 7S-[ 4-aminopiperidinocarbonyl-Phe- (S-Me-Cys) amino ] -8 cyclohexyl-6S-hydroxy-3-thiaoctanoic acid N-isobutyl amide, TFA, m.p. 148-149“ 7S- [ 4-aminopiperidinocarbonyl-Pla- (S-Me-Cys ) amino ] -8 cyclohexyl-6S-hydroxy-3-thiaoctanoic acid N-isobutyl amide, TFA, m.p. 106-107’ 0 7S-( 4-aminopiper idinocarbonyl-Phe-/3Ala-amino) -8-cyclo hexyl-6S-hydroxy-3-thiaoctanoic acid N-isobutylamide 7S-(4-aminopiperidinocarbonyl-Pla-^Ala-amino)-8-cyclo hexyl-6S-hydroxy-3-thiaoctanoic acid N-isobutylamide TFA, m.p. 130-131’ 7S- [ 4-aminopiperidinocarbonyl-Phe-His-amino ]-8-cyclo hexyl-6S-hydroxy-3-thiaoctanoic acid N-isobutylamide 7S-[ 4-aminopiper idinocarbonyl-Pla-His-amino] - 8-cyclo hexyl-6S-hydroxy-3-thiaoctanoic acid N-isobutylamide methyl 7S-[4-aminopiperidinocarbonyl-Phe-(S-Me-Cys) amino]-8-cyclohexyl-6S-hydroxy-3-thiaoctanoate, TFA m.p. 162-163° - 37 methyl 7S-[4-aminopiperidinocarbonyl-Pla-(S-Me-Cys)amino]-8-cyclohexyl-6S-hydroxy-3-thiaoctanoate, TFA, m.p. 88-89“ methyl 6S-[4-aminopiperidinocarbonyl-Phe-(S-Me-Cys)5 amino]-7-cyclohexyl-5S-hydroxy-3-thiaheptanoate3,3-dioxide, TFA, m.p. 154-155° methyl 6S-[4-aminopiperidinocarbonyl-Pla-(S-Me-Cys)amino]-7-cyclohexyl-5S-hydroxy-3-thiaheptanoate-3,3dioxide, TFA, m.p. 161-162° methyl 6S-[4-aminopiperidinocarbonyl-Phe-His-amino]-7cyclohexyl-5S-hydroxy-3-thiaheptanoate-3,3-dioxide methyl 6S-[4-aminopiperidinocarbonyl-Pla-His-amino]-7cyclohexyl-5S-hydroxy-3-thiaheptanoate-3,3-dioxide methyl 6S-[4-aminopiperidinocarbonyl-Phe-Leu-amino]-715 cyclohexyl-5S-hydroxy-3-thiaheptanoate-3,3-dioxide methyl 6S-[4-aminopiperidinocarbonyl-Pla-Leu-amino]-7cyclohexyl-5S-hydroxy-3-thiaheptanoate-3,3-dioxide methyl 7S-[4-aminopiperidinocarbonyl-Phe-(S-Me-Cys)amino]-8-eyelohexy1-6S-hydroxy-3-thiaoctanoate-3,320 dioxide, TFA, m.p. 170-171° methyl 7S-[4-aminopiperidinocarbonyl-Pla-(S-Me-Cys)amino]-8-cyclohexyl-6S-hydroxy-3-thiaoctanoate-3,3dioxide, TFA, m.p. 130-131’ methyl 7S-[4-aminopiperidinocarbonyl-Phe-His-amino]-825 cyclohexyl-6S-hydroxy-3-thiaoctanoate-3,3-dioxide methyl 7S-[4-aminopiperidinocarbonyl-Pla-His-amino]-8cyclohexyl-6S-hydroxy-3-thiaoctanoate-3,3-dioxide methyl 7S-[4-aminopiperidinocarbonyl-Phe-Leu-amino]-8cyclohexyl-6S-hydroxy-3-thiaoctanoate-3,3-dioxide methyl 7S-[4-aminopiperidinocarbonyl-Pla-Leu-amino]-8cyclohexyl-6S-hydroxy-3-thiaoctanoate-3,3-dioxide 6S- [ 4-aminopiperidinocarbonyl-Phe- (S-Me-Cys) amino ] -7 cyclohexyl-5R,S-hydroxy-3-thiaheptanoic acid N-isobutylamide- 3 , 3-dioxide 6S- [4-aminopiperidinocarbonyl-Phe- (S-Me-Cys) amino ] -7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide- 3, 3-dioxide, TFA, m.p. 176-177° 6S-[4-aminopiperidinocarbonyl-Pla-(S-Me-Cys ) amino] -7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylIE 912343 - 38 amide-3,3-dioxide, TFA, m.p. 130-131° methyl 7-cyclohexyl-5S-hydroxy-6S-H-Phe-(S-Me-Cys)amino3-thiaheptanoate-3,3-dioxide, TFA, m.p. 110’ 6S- (4-aminopiperidinocarbonyl-Phe-His-amino) -7-cyclo5 hexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide3,3-dioxide 6S- (4-aminopiperidinocarbonyl-Phe-Ala-amino) -7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide3,3-dioxide 6S-(4-aminopiperidinocarbonyl-Phe-^Ala-amino)-7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide3,3-dioxide S — (4-aminopiperidinocarbonyl-Phe-Leu-amino) -7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide15 3,3-dioxide 6S-( 4-aminopiperidinocarbonyl-Phe-Met-amino) -7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide3,3-dioxide 6S- (4-aminopiper idinocarbonyl-Phe-Nle-amino) -7-cyclo20 hexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide3,3-dioxide 6S-( 4-aminopiper idinocarbonyl-Phe-Nva-amino) -7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide3, 3-dioxide 6S- (4-aminopiperidinocarbonyl-Phe-3-Pya-amino) -7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide3,3-dioxide 6S- (4-aminopiperidinocarbonyl-Phe-Tia-amino) -7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide30 3,3-dioxide 6S-[4-aminopiperidinocarbonyl-Phe-(2-Tiz) amino]-7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide3,3-dioxide methyl 7S-(4-aminopiperidinocarbonyl-Phe-^Ala-amino)-835 cyclohexyl-6S-hydroxy-3-thiaoctanoate methyl 7S-(4-aminopiperidinocarbonyl-Pla-^Ala-amino)-8cyclohexyl-6S-hydroxy-3-thiaoctanoate - 39 methyl 7S-(4-aminopiperidinocarbonyl-Phe-0Ala-amino)-8cyclohexyl-6S-hydroxy-3-thiaoctanoate-3, 3-dioxide methyl 7S- (4-aminopiperidinocarbonyl-Pla-jSAla-amino) -8cyclohexyl-6S-hydroxy-3-thiaoctanoate-3, 3-dioxide Example 27 A mixture of 1 g of methyl 7-eyelohexy1-5Shydroxy-6S-[3-phenylpropionyl-(S-Me-Cys) amino]-3-thiaheptanoate-3,3-dioxide, 50 ml of dioxane and 20 ml of 2N aqueous NaOH solution is stirred at 20° for 3 hours.
Customary working-up gives 7-cyclohexyl-5S-hydroxy-6S-[ 3phenylpropionyl-(S-Me-Cys) amino]-3-thiaheptanoate-3,3dioxide, m.p. 106-107°.
The following are obtained analogously by alkaline hydrolysis of the corresponding methyl ester: 7-cyclohexyl-5S-hydroxy-6S-[POA-(S-Me-Cys) amino]-3thiaheptanoic acid 3,3-dioxide, m.p. 101-102°. 6S-(4-BOC-aminopiperidinocarbonyl-Phe-His-amino)-7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid 3,3-dioxide 6S-(4-BOC-aminopiperidinocarbonyl-Pla-His-amino )-720 cyclohexyl-5S-hydroxy-3-thiaheptanoic acid 3,3-dioxide 6S-(4-BOC-aminopiperidinocarbonyl-Phe-Leu-amino)-7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid 3,3-dioxide 6S-(4-BOC-aminopiperidinocarbonyl-Pla-Leu-amino)-7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid 3,3-dioxide 6S- [ 4-BOC-aminopiperidinocarbonyl-Phe- (S-Me-Cys) amino ] 7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid 3,3-dioxide 6S- [ 4-BOC-aminopiperidinocarbonyl-Pla- (S-Me-Cys) amino ] 7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid 3,3-dioxide 6S- (4-aminopiperidinocarbonyl-Phe-His-amino) -7-cyclo30 hexyl-5S-hydroxy-3-thiaheptanoic acid 3,3-dioxide 6S- (4-aminopiperidinocarbonyl-Pla-His-amino) -7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid 3,3-dioxide 6S- (4-aminopiperidinocarbonyl-Phe-Leu-amino) -7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid 3,3-dioxide 6S- (4-aminopiperidinocarbonyl-Pla-Leu-amino) -7-eyelohexyl-5S-hydroxy-3-thiaheptanoic acid 3,3-dioxide -406S-[4-aminopiperidinocarbonyl-Phe- (S-Me-Cys) amino ] - 7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid 3,3-dioxide S— [ 4-aminopiperidinocarbonyl-Pla- (S-Me-Cys) amino] - 7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid 3,3-dioxide 7S-(4-BOC-aminopiperidinocarbonyl-Phe-^Ala-amino)-8cyclohexyl-6 S-hydroxy-3-thiaoctano ic ac id 7S-(4-BOC-aminopiperidinocarbonyl-Pla-^Ala-amino)-8cyclohexyl-6S-hydroxy-3-thiaoctanoic acid 7S- [ 4-BOC-aminopiperidinocarbonyl-Phe- (S-Me-Cys) amino ] 10 8-cyclohexyl-6S-hydroxy-3-thiaoctanoic acid S—[ 4-BOC-aminopiperidinocarbonyl-Pla- (S-Me-Cys) amino ] 8-cyclohexyl-6S-hydroxy-3-thiaoctanoic acid, m.p. 71-72° 7S- ( 4-BOC-aminopiperidinocarbonyl-Phe-0Ala-amino)-8cyclohexyl-6S-hydroxy-3-thiaoctanoic acid 3,3-dioxide 7S-(4-BOC-aminopiperidinocarbonyl-Pla-^Ala-amino)-8cyclohexyl-6S-hydroxy-3-thiaoctanoic acid 3,3-dioxide 7 S— [ 4-BOC-aminopiper idinocarbonyl-Phe- (S-Me-Cys) amino ] 8-cyclohexyl-6S-hydroxy-3-thiaoctanoic acid 3,3-dioxide 7S- [ 4-BOC-aminopiperidinocarbonyl-Pla- (S-Me-Cys) amino ] 20 8-cyclohexyl-6S-hydroxy-3-thiaoctanoic acid 3,3-dioxide 7S-(4-aminopiperidinocarbonyl-Phe-j0 Ala-amino)-8-cyclohexyl-6S-hydroxy-3-thiaoctanoic acid 7S-(4-aminopiperidinocarbonyl-Pla-^Ala-amino)-8-cyclohexyl -6 S-hydroxy-3-thiaoctanoic ac id 7S- [ 4-aminopiperidinocarbonyl-Phe- (S-Me-Cys) amino ] -8cyclohexyl-6S-hydroxy-3-thiaoctanoic acid 7S- [4-aminopiperidinocarbonyl-Pla- (S-Me-Cys) amino ] -8cyclohexyl-6S-hydroxy-3-thiaoctanoic acid, TFA, m.p. 152-153° 7S- (4-aminopiperidinocarboyl-Phe-0 Ala-amino) -8-cyclo30 hexyl-6S-hydroxy-3-thiaoctanoic acid 3,3-dioxide 7S-( 4-aminopiperidinocarboyl-Pla-^Ala-amino) -8-cyclohexyl-6S-hydroxy-3-thiaoctanoic acid 3,3-dioxide 7S- [ 4-aminopiper idinocarbonyl-Phe- (S-Me-Cys) amino ] -8cyclohexyl-6S-hydroxy-3-thiaoctanoic acid 3,3-dioxide 7S- [ 4-aminopiperidinocarbonyl-Pla- (S-Me-Cys) amino ] -8cyclohexyl-6S-hydroxy-3-thiaoctanoic acid 3,3-dioxide - 41 8-cyclohexyl-6S-hydroxy-7S-morpholinocarbonyl-Phe-0Alaamino-3-thiaoctanoic acid 8-cyclohexyl-6S-hydroxy-7S-morpholinocarbonyl-Pla-/3Alaamino-3-thiaoctanoic acid 8-cyclohexyl-6S-hydroxy-7S-morpholinocarbonyl-Phe-(S-MeCys) amino- 3-thiaoctanoic acid, m.p. 133-134° 8-cyclohexyl-6S-hydroxy-7S-morpholinocarbonyl-Pla-(S-MeCys ) amino-3-thiaoctanoic acid, m.p. 95-96° 8-cyclohexyl-6S-hydroxy-7S-morpholinocarbonyl-Phe-(s Ala10 amino-3-thiaoctanoic acid 3,3-dioxide -cyc lohexyl- 6 S-hydroxy-7 S-morphol inocarbonyl-Pla-£Alaamino-3-thiaoctanoic acid 3,3-dioxide 8-cyclohexyl-6S-hydroxy-7S-morpholinocarbonyl-Phe-(S-MeCys) amino- 3-thiaoctanoic acid 3,3-dioxide 8-cyclohexyl-6S-hydroxy-7S-morpholinocarbonyl-Pla-(S-MeCys )amino-3-thiaoctanoic acid 3,3-dioxide 7S- [ 2-benzyl-3-tert. -butylsulfonylpropionyl- (S-Me-Cys) amino]-8-cyclohexyl-6S-hydroxy-3-thiaoctanoic acid, 2 epimers m.p. 136-137° and 138-139°, respectively 7 s- [ 2-benzyl-3-tert. -butylsulfonylpropionyl- (S-Me-Cys) amino]-8-cyclohexyl-6S-hydroxy-3-thiaoctanoic acid 3-oxide 7S- [ 2-benzyl-3-tert. -butylsulfonylpropionyl- (S-Me-Cys) amino]-8-cyclohexyl-6S-hydroxy-3-thiaoctanoic acid 3,3-dioxide Example 28 6S-[4-aminopiperidinocarbonyl-Phe-(S-Me-Cys)amino]-7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid Nisobutyl amide, TFA, m.p. 159-160°, is obtained from 6S- [ 4-CBZ-aminopiper idinocarbonyl-Phe- (S-Me-Cys) amino ] 7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide analogously to Example 1.
Example 29 a) 6S-[ 4-BOC-aminopiperidinocarbonyl-Phe-Leu-amino ]-7cyclohexyl-5-oxo-3-thiaheptanoic acid N-isobutylamide- 3, 3-dioxide is obtained from 4-BOC-aminopiperidinocarbonyl-Phe-Leu-OH and 6S-amino-7-cyclohexyl-5-oxo-3-thiaheptanoic acid N-isobutylamideIE 912343 - 42 3,3-dioxide analogously to Example 6. b) A solution of 1 g of the above ketoamide in 25 ml of methanol is hydrogenated on 0.1 g of 10 % Pd-C at 20° and at 1 bar until absorption of H2 has stopped.
After filtering and evaporating, a mixture of 5Rand 5S-hydroxy-6S-(4-BOC-aminopiperidinocarbonylPhe-Leu-amino)-7-cyclohexyl-3-thiaheptanoic acid N-isobutylamide-3,3-dioxide is obtained, which can be separated on silica gel.
Example 30 A solution of 804 mg of the ketoamide obtainable according to Example 29 a) and 1.43 g of Na2C03«10H20 in 5 ml of methanol and 5 ml of water is treated with 70 mg of hydroxylamine hydrochloride and the mixture is stirred at 20° for 14 hours. The precipitated oxime is filtered off, dried, dissolved in 10 ml of methanol and hydrogenated on 0.4 g of Raney Ni at 20° and at 5 bar. The catalyst is filtered off, the filtrate is evaporated and the mixture of 5R- and 5S-amino-6S-[4-BOC-aminopiperid20 inocarbonyl-Phe-Leu-amino] -7-cyclohexyl-3-thiaheptanoic acid N-isobutylamide-3,3-dioxide obtained is separated. Example 31 A solution of 1 mmol of 6S-(4-BOC-aminopiperidinocarbonyl-Phe-0Ala-amino)-7-cyclohexyl-5S-hydroxy-325 thiaheptanoic acid N-isobutylamide and 1 mmol of 3-chloroperbenzoic acid in 10 ml of chloroform is allowed to stand at 0’ for 16 hours. Customary working-up gives 6S- ( 4-BOC-aminopiperidinocarbonyl-Phe-0Ala-amino)-7cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutyl30 amide-3-oxide.
Example 32 6S-(4-BOC-aminopiperidinocarbonyl-Phe-jflAlaamino)-7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide-3,3-dioxide is obtained analogously to Example 31, but using 2.5 mmol of 3-chloroperbenzoic acid.
The following examples relate to pharmaceutical preparations. - 43 Example A: Tablets A mixture of 1 kg of 6S-[4-aminopiperidinocarbonyl-Phe-(S-Me-Cys) amino]-7-cyclohexyl-5S-hydroxy-3thiaheptanoic acid N-isobutylamide trifluoroacetate, 4 kg of lactose, 1.2 kg of maize starch, 200 g of talc and 100 g of magnesium stearate is compressed to give tablets in a customary manner in such a way that each tablet contains 100 mg of active compound.
Example B: Coated tablets Tablets are pressed analogously to Example A, and are then coated in a customary manner with a coating of sucrose, maize starch, talc, tragacanth and colourant. Example C: Capsules 500 g of 6S-[4-aminopiperidinocarbonyl-Phe-(S-Me15 Cys)amino]-7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide-S,S-dioxide trifluoroacetate are filled into hard gelatin capsules in a customary manner in such a way that each capsule contains 500 mg of active compound.
Example D: Injection vials A solution of 100 g of 6S-(4-aminopiperidinocarbonyl-Phe-His-amino) -7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide-bis-trifluoroacetate in 4 1 of doubly distilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered and poured into injection vials. The solution is lyophilised under sterile conditions and the vials are sterile sealed. Each injection vial contains 50 mg of active compound.
Example E: Suppositories A mixture of 50 g of 6S-[4-aminopiperidinocarbonyl-Pla-(S-Me-Cys) amino]-7-cyclohexyl-5S-hydroxy-3thiaheptanoic acid N-isobutylamide-trifluoroacetate is fused with 10 g of soya lecithin and 140 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 250 mg of active compound.
Merck Patent Gesellschaft mit beschrankter Haftung 6100 Darmstadt

Claims (13)

1. 5 1. Amino acid derivatives of the formula I X-W-CR 1 R 2 -C0-Y-NH-CHR 4 -CR 5 -CH2- (CR 6 R 7 ) r S(0) t -CH 2 CO-V-R 3 in which X is R 8 , R^O-CJ^-CO-, R 8 -CmH2ni-O-CO-, R 8 -CQIH 2ffl -CO-, R 8 -SO2-, R®R 10 N-CbH^-CO-, R n -NH-C (=NH) -NH-C^-CO-, R^OC-C^-CO-, R^S-C^-CO-, R 9 -O-(CH2CH2O) q-C^H^-CO-, or A3N + -CmH 2m -CO-An’, W is O, NH, CH 2 or S, Y is 0 or 1 amino acid radical selected from the group comprising Abu, Ada, Ala, ^Ala, Arg, Asn, Asp, Bia, Cal, Cys, S-A-Cys, Dab, Gin, Glu, Gly, His, N(im)-A-His, Hph, lie, Leu, tert.Leu, Lys, Mai, Met, aNal, £Nal, Nbg, Nle, Nva, Orn, Phe, Pia, Pro, Pya, Ser, Thr, Tia, Tic, Tiz, Trp, Tyr and Val, V is 0 or NH, R 1 , R 6 , R 7 , R 9 and R 10 are each H or A, R 2 , R 3 , R* and R 8 are each H, A, Ar, Ar-alkyl, Het, Het-alkyl, cycloalkyl having 3-7 C atoms, which is unsubstituted or cycloalkyl which is monosubstituted or polysubstituted by A, AO and/or Hal, cycloalkylalkyl having 4-11 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms, or bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C atoms, R 5 is (H, OH), (H, NH 2 ) or =0, R e R 10 N also is an unsubstituted pyrrolidino, piperidino, morpholino or piperazino group or one which is substituted by A, OH, NH 2 , NHA, NAj, NHAc, NH-CO-CJi^-O-R 11 , NH-CO-O-CJi^-R 11 , hydroxyalkyl, COOH, COOA, CONH 2 , aminoalkyl, HAN-alkyl, A^N-alkyl, A 3 N®alkyl An 9 , NH-CO-NH 2 , NH-CO-NHA, guanidinyl or guanidinylalkyl, R n is A or Ar-alkyl, 5 m and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, n is 1, 2, 3, 4 or 5, r is 0, 1, 2 or 3, t is 0, 1 or 2, Ar is unsubstituted phenyl or phenyl which is 10 monosubstituted or polysubstituted by A, OA, Hal, CF 3 , OH, NO 2 , hydroxyalkyl, NH 2 , NHA, NA^, NHAc, NH-SO 2 -A, SA, SO-A, SO 2 -A, SO 2 NH 2 , SO 2 NHA, COOH, COOA, CONH 2 , CN, aminoalkyl, HAN-alkyl, A^-alkyl, A^-alkyl An® and/or guanidinylalkyl 15 or unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N, O and/or S atoms, which can be fused to a benzene ring and/or monosubstituted or polysubstituted by A, 20 OA, Hal, CF 3 , OH, NO 2 , carbonyl oxygen, NH 2 , NHA, NAa, NHAC, ΝΗ-COOA, NHCOOAr, NHCOOCH^Ar, NH-SO 2 -A, SA, SO-A, SO 2 -A, SO 2 NH 2 , SO 2 NHA, COOH, COOA, CONH 2 , CN, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN-alkyl, AjN-alkyl 25 and/or A 3 N*-alkyl An® and/or whose N and/or S heteroatoms can also be oxidised, is F, Cl, Br or I, is Α-CO-, Ar-CO-, Ar-alkyl-CO- or A-NH-CO-, an anion, which can also be absent, if 30 instead of this a carboxyl group contained in the compound of the formula I is present 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, 35 in which in addition instead of one or more -CO-NH groups there can also be one or more -CO-ΝΑ groups, and their salts.
2. a) 6S-(4-aminopiperidinocarbonyl-Phe-(S-Me-Cys)amino)-7-cyclohexyl-5S-hydroxy-3-thiaheptanoic Hal is Ac is An® is acid N-isobutylamide and its salts; b) 6S-(4-aminopiperidinocarbonyl-Phe-(S-Me-Cys) amino) -7-cyc lohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide-S/S-dioxide and its salts; c) 7S-(4-aminopiperidinocarbonyl-Phe-(S-Me-Cys)amino)-8-cyclohexyl-6S-hydroxy-3-thiaoctanoic acid N-isobutylamide and its salts; d) 6S-(4-aminopiperidinocarbonyl-Pla-(S-Me-Cys)amino) -7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide and its salts; e) 6S-(4-aminopiperidinocarbonyl-Pla-(S-Me-Cys)amino)-7-cyclohexyl-5S-hydroxy-3-thiaheptanoic acid N-isobutylamide-S,S-dioxide and its salts.
3. Process for the preparation of an amino acid derivative of the formula I and of its salts, characterised in that it is set free from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent or in that a carboxylic acid of the formula II X-G^OH II in which G l (a) is absent, (b) is -W-CR 1 R 2 -CO-, (c) is -W-CR 1 R 2 -CO-Y-, (<υ is -W-CR^ 2 - -CO-Y-NH-CHR*-CR 5 -CH2- (CR 6 R 7 ) r-S (0) t -CH 2 -CO- or one of its reactive derivatives is reacted with a compound of the formula III H-G 2 -V-R 3 III 30 in which G 2 (a) is -W-CR 1 R 2 -CO-Y-NH-CHR*-CR 5 -CH2- (CR 6 R 7 ) r-S (O) t -CH z -CO-, (b) is -Y-NH-CHR*-CR 5 -CH2-(CR 6 R 7 )r-S(O) t -CH 2 -CO-, (C) is -NH-CHR*-CR 5 -CH2-(CR 6 R 7 )r-S(O) t -CH 2 -CO-, (d) is absent, and W' is 0, NH or S, and in that a functionally modified amino and/or hydroxy group is optionally set free in a compound of the formula I by treating with solvolysing or hydrogenolysing agents 5 and/or a free amino group is acylated by treating with an acylating agent and/or an aminoketo acid derivative of the formula I, R 5 = 0, is reduced or reductively aminated to prepare a compound of the formula I, R 5 = (H, OH) or (H, NH 2 ) and/or a thioether group is oxidised to a sulf10 oxide or sulfone group and/or a compound of the formula I is converted into one of its salts by treating with an acid.
4. Process for the production of pharmaceutical preparations, characterised in that a compound of the 15 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 auxiliary.
5. Pharmaceutical preparation, characterised in that 20 it contains at least one compound of the formula I and/or one of its physiologically acceptable salts.
6. Use of compounds of the formula I or of their physiologically acceptable salts for the production of a medicament. 25
7. Use of compounds of the formula I or of their physiologically acceptable salts in the control of renindependent hypertension or hyperaldosteronism. - 48
8. An amino acid derivative of the formula I given and defined in Claim 1, or a salt thereof, substantially as hereinbefore described and exemplified.
9. A process for the preparation of an amino acid derivative of the formula I given and defined in Claim 1, or a salt thereof, substantially as hereinbefore described and exemplified.
10. An amino acid derivative of the formula I given and defined in Claim 1, or a salt thereof, whenever prepared by a process claimed in Claim 3 or 9.
11. A pharmaceutical preparation according to Claim 5, substantially as hereinbefore described.
12. Use according to Claim 6, substantially as hereinbefore described.
13. Use according to Claim 7, substantially as hereinbefore described.
IE234391A 1990-07-05 1991-07-04 Amino acid derivatives IE912343A1 (en)

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