GB2212158A - Trialkylsilymethyl-substituted peptides; renin inhibitors - Google Patents
Trialkylsilymethyl-substituted peptides; renin inhibitors Download PDFInfo
- Publication number
- GB2212158A GB2212158A GB8828982A GB8828982A GB2212158A GB 2212158 A GB2212158 A GB 2212158A GB 8828982 A GB8828982 A GB 8828982A GB 8828982 A GB8828982 A GB 8828982A GB 2212158 A GB2212158 A GB 2212158A
- Authority
- GB
- United Kingdom
- Prior art keywords
- butyl
- trimethylsilylmethyl
- triaza
- acid
- cyclohexylmethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000002461 renin inhibitor Substances 0.000 title claims description 11
- 229940086526 renin-inhibitors Drugs 0.000 title claims description 10
- 108090000765 processed proteins & peptides Proteins 0.000 title claims description 6
- 102000004196 processed proteins & peptides Human genes 0.000 title description 2
- -1 N-protected amino Chemical group 0.000 claims description 74
- 150000001875 compounds Chemical class 0.000 claims description 54
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 18
- 150000002431 hydrogen Chemical group 0.000 claims description 18
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 15
- 229920006395 saturated elastomer Polymers 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 150000003254 radicals Chemical class 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 206010019280 Heart failures Diseases 0.000 claims description 7
- 206010020772 Hypertension Diseases 0.000 claims description 6
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 5
- 150000001413 amino acids Chemical group 0.000 claims description 5
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical group [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
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- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
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- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000005640 glucopyranosyl group Chemical group 0.000 claims description 3
- 229930182470 glycoside Natural products 0.000 claims description 3
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
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- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000005182 hydroxyalkylcarbonyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims description 2
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims 7
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- 239000003085 diluting agent Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 120
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 25
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 19
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- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 9
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- 125000006341 heptafluoro n-propyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)* 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- YSTDSWVFMNLAHU-UHFFFAOYSA-N methoxymethanedithioic acid Chemical compound COC(S)=S YSTDSWVFMNLAHU-UHFFFAOYSA-N 0.000 description 5
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 description 5
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- 125000004432 carbon atom Chemical group C* 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 4
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- 150000001844 chromium Chemical class 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- TWLCEYWYILDCDA-UHFFFAOYSA-N chromium(6+) oxygen(2-) pyridine Chemical compound [O-2].[O-2].[O-2].[Cr+6].C1=CC=NC=C1.C1=CC=NC=C1 TWLCEYWYILDCDA-UHFFFAOYSA-N 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- LEVJVKGPFAQPOI-UHFFFAOYSA-N phenylmethanone Chemical compound O=[C]C1=CC=CC=C1 LEVJVKGPFAQPOI-UHFFFAOYSA-N 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- PTMBWNZJOQBTBK-UHFFFAOYSA-N pyridin-4-ylmethanol Chemical compound OCC1=CC=NC=C1 PTMBWNZJOQBTBK-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000001926 trapping method Methods 0.000 description 1
Classifications
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- 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
- C07K5/0205—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)3-C(=0)-, e.g. statine or derivatives thereof
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Genetics & Genomics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Crystallography & Structural Chemistry (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
A_ 1 C I- AI CASE 100-7250 New silicon-containing peptides, their
production and use The invention relates to silicon-containing renin inhibitors, their preparation, their use and pharmaceutical compositions containing them. Especially the invention provides silicon-containing renin inhibitors of formula 0 H 1 A-N Si(R1)3 B-D I wherein R, signifies (CI-5)alkyl, A is a N-protected amino acid radical or a peptide or signifies a group of formula X R2 whereby X denotes 0, S, or H2 and R2 denotes a straight-chain or branched (Cl-IO)alkyl radical, which may be optionally substitu ted by amino, hydroxy or (C2-5)alkyl or (Cl-6)aryloxy; a 5- or 6-membered heteroaryl radical containing one or two nitrogen at oms, oxygen or sulphur atoms or one nitrogen atom and one oxygen atom and/or one sulphur atom; or a heteroaryl(Cl-s)alkyl radical, in which the heteroaryl moiety is 5- or 6-membered and contains one or two nitrogen atoms, oxygen or sulphur atoms or one nitro- n 2 2 12 15 u 100-7250 gen atom and one oxygen atom and/or one sulphur atom; a straight-chain or branched (Cj_5)alkoxy radical or a (C6-10)aryl-(C,-B)alkoxy radical, or A signifies a group of formula X 0 R3-0-(CH2CH2-0).-(CH2 wherein v is -0-, NR7- or -CH2, whereby R7 signifies hydrogen or a straight-chain or branched (Cl-5)alkyl radical, R3 is hydrogen, a straight-chain or branched (Cl-20)alkyl radi cal or a sugar radical which is bonded as a glycoside, an optionally substituted, saturated or unsaturated, straight -chain or branched (C2-30)alkylcarbonyl group, a (C3-6)P01Y hydroxyalkylcarbonyl, a phosphoroyl, a bis-(dimethylamino) phosphoroyl, a sulpho, an aroyl, a heteroaroyl, an arylalkyl, an arylalkylcarbonyl or a heteroarylalkylcarbonyl group, or the biotinoyl-group, or R3 signifies a group of formula R6 R4 N RS 0 wherein R4 is hydrogen or a side chain of a D- or L-amino acid, and R5 and R6 are the same or different and respectively signify hydrogen, (Cl-5)alkyl, (C2-5)hydroxyalkyl or (C2-5)aminoalkyl, or f Cl f 6 t c 1 C R3 signifies a group of formula R6 Rs wherein \ N-(CH2)p-E- 1.1e RS and R6 are defined as above, p is a whole number from 0 to 5 and 0 H E signifies a bond or the group -C-, or R3 signifies a group of formula F-(CH2)p-E-, wherein p F and E are defined as above, and denotes groups of formulae R7 N N-, 0 N- or whereby R7 is defined as above.
m is a whole number from 1 to 20, n is a whole number from 0 to 5, and B signifies a group of formula Re 11.1 N 1 R7 0 100-7250 or a group of formula R 8 "' C H "' "' wherein 2 R7 is defined as above and Re signifies a hydrophilic or lipophilic amino acid side chain, D signifies a group of formula 100-7250 H RIO R,, / R14 N Y Ris R9R12 R13 X wherein X is defined as above, R9 has the same significance as R8, RIO is a hydroxyl or amino group and R,, is hydrogen, or RIO and R,, together form an oxo group, R12 and R13, independently of one another, signify fluorine or hydrogen, R14 and R15 are the same or different and respectively signify hydrogen, a straight-chain or branched (Cl-6)alkyl radical, or respectively signify a group of formula R, 6 RI-7 1 U wherein R16 signifies a straight-chain or branched (Cl-5)alkyl radical or a straight-chain or branched (Cl-5)hydroxyalkyl radical, R17 is a hydroxyl radical, a straight-chain or branched (Cl-5)alkoxy group, an amino or a (Cl-5)alkylamino group, an aminomethylpyridyl group, a benzyl group or a protected or unprotec- Lw 11 v - 5 c 1..
IL 100-7250 ted amino acid, Y signifies a bond or is -0-, -N- or -C- 1 H RIB wherein R18 and R19, independently of one another, denote hydrogen or fluorine, or respectively possess the significance given above for R8, or D signifies a group of formula RIO R,, H (W 2),,CF3 R9 wherein Rg, RIO, R,, and n are defined as above.
The renin inhibitors according to the invention contain as their component a trimethylsilyl-substituted amino acid. Surprisingly, the presence of this trimethylsilyl-substituted amino acid gives the peptide molecule remarkable stability towards the proteolytic activity of chymotrypsin. This surprisingly leads to a great improvement in the bio- availability of the compounds according to the invention.
The compounds described above are referred to hereinafter as compounds according to the invention.
In formula I, A signifies in particular BOC-proline and R, signifies in particular ethyl, propyl or isobutyl. If R2 is a straight-chain or branched alkyl with 1 to 10 carbon atoms, it is in particular methyl, ethyl, propyl, isopropyl, butyl, tert.butyl, 2,2-dimethylethyl, pentyl, hexyl etc., especially methyl, tert, 6 - 100-7250 butyl and 2,2-dimethylethyl. If it is substituted by aryloxy, it is in particular phenoxymethyl or 1- or 2-naphtyloxymethyl, preferably 1- naphtyloxymethyl. Heteroaryl signifies in particular pyridyl, thienyl or furyl. In the heteroarylalkyl radical, the heteroaryl moiety and the alkyl moiety preferably have the above-mentioned definitions. A straight- chain or branched alkoxy radical signifies in particular ethoxy or tert. butoxy, and a (C6_jo)aryl-(Cj_5)-alkoxy radical possesses in particular the definitions given above for aryl and alkyl and is preferably benzyloxy.
If A signifies the group X 11 R3 0-(CH2 CH2 -0),,(CH2),-Y-C- then R3 is a straight-chain or branched alkyl, especially an alkyl with 1 to 5 carbon atoms, especially ethyl, propyl or isobutyl, the sugar radical which is bonded as a glycoside is for example glucopyranosyl which may be optionally 0-acylated, e.g. tetra-0-acetylglucopyranosyl, an optionally substituted saturated or unsaturated (C2-30)alkylcarbonyl group is in particular a corresponding (C4-20)alkylcarbonyl group, for example a palmitoyl, an oleyl, linoyl, stearoyl or pivaloyl radical, whereby the alkylcarbonyl group may be substituted by a cyclopentaphenanthrene radical and may denote a cholyl radical, a (C3- 6)polyhydroxyalkylcarbonyl radical, for example a glycerinoyl or a gluconoyl radical which may be optionally substituted, and may denote for example a penta-0-acetyl-gluconyl or a dibutyroy1glycerinoyl radical, an aroyl radical for example the benzoyl radical, a heteroaroyl for example the 2-, 3- or 4-pyridinoyl radical, an aryl alkyl radical for example the benzyl, phenethyl, naphtylmethyl, p-chlorophenoxy-propyl-2 radical, an arylalkylcarbonyl radical for example a phenylacetyl, bis(lnaphtylmethyl)acetyl or a 11 W \1 11 z 1 - 7 100-7250 p-chlorophenoxy-l,l-dimethylacety1 radical, a heteroarylalkylcarbonyl group for example a bis-(3-pyridylmethyl)acetyl or a bis(4quinolinylmethyl)acetyl radical. In R4, a side chain of a D- or L-amino acid is in particular methyl, isopropyl, isobutyl, benzyl, hydroxy(C15)alkyl, 4-aminobutyl or 2-carboxyethyl.
The hydrophilic or lipophilic amino acid side chain in the significance of R$ may be for example a n-butyl, isobutyl, benzyl, 4-imidazolylmethyl, 2-methylthioethyl, trimethylsilylmethyl, cyclohexylmethyl or pyridylmethyl radical.
Hydroxyalkyl with 1 to 5 carbon atoms in the significance Of R16 is preferably hydroxyethyl or hydroxypropyl, and an alkoxy group with 1 to 5 carbon atoms in the significance of R17 preferably signifies methoxy or ethoxy.
Preferred compounds of the compounds according to the invention are of formula IY 0 H BY -DY t AY -N SiMe3 whereby AY signifies a group of formula XY 1 2 Y '-^ whereby XY signifies S or 0, 100-7250 R2Y denotes tert.-butyloxy, benzyloxy, 5-aminopentyl or isobu tyl, or AY signifies a group of formula xy 11 R3y-0-(CH2CH20)m-(CH2),-C- whereby xy is defined as above, R3Y denotes hydrogen, methyl, glucopyranosyl, pyridinoyl, 3,4,5-trimethoxybenzoyl, MY signifies a whole number from 2-7 and ny signifies a whole number from 0-2, BY signifies a group of formula R8Y -N 1 R7Y 0 wherein R7Y denotes hydrogen or methyl and Rey denotes n-butyl, isobutyl, 2-butenyl, phenylmethyl, 4-imidazolyImethyl, pyridinemethyl or trimethylsilylmethyl, DY signifies a group of formula R14y Rjoy Ril Y H YY N alsy Rgy R12y R13y 0 a r, 100-7250 whereby Rgy denotes isobutyl, benzyl or cyclohexylmethyl, and either Rjoy signifies a hydroxy radical and R11 Y signifies hydrogen, when R12y and R13y respectively denote hydrogen, or R10y and Rlly together form the oxo group, when R12y and R13y respectively denote fluorine, R14y signifies hydrogen and R15Y signifies hydrogen, methyl, i-propyl, i-butyl or a group of f ormula R16y 0 R17y whereby R16y denotes i-butyl or 2-butyl and R17y denotes aminomethylpyridyl, YY denotes a bond or a group of formula R, sy,R, 9 Y c whereby R1BY and R19y respectively signify fluorine, or Rjay has the definition n-butyl, isobutyl, 2"butenyl, methyl, methylthiomethyl, benzyl, isopropyl or chlorine, and Rjoy denotes hydrogen.
The preparation of compounds of formula I is characterised in that a) a compound of formula II 0 H 1 A-N 1//"", B-OH Si(R1)3 100-7250 II wherein A, B and R, possess the definitions given above is reacted with a compound of formula H-D, wherein D possesses the definition given above or b) a compound of formula III 0 H2N B-D Si(RI)3 III wherein R1, B and D possess the definitions given above is reacted with a compound of formula A-OH wherein A has the significances given above or a compound of formula I, wherein R10 is a hydroxyl radical and R,, is hydrogen, is oxidised to a compound of formula I, wherein R10 and R,, together form an oxo group.
The process according to stage a) is preferably carried out such that a compound of formula II is reacted with an amine of formula H-D using processes which are known in peptide chemistry, e.g. in the presence of N, NI-dicyclohexylcarbodiimide (DCC) (adding 1-hydroxybenzotriazole (HOBT)) in an appropriate solvent, such as methylene chloride or dimethylformamide at temperatures between 01 and room temperature.
a a C 11 c 100-7250 The process according to stage b) is carried out under the same conditions as those of the process according to stage a).
The process according to stage c) is carried out such that alcohols of the compounds according to the invention are oxidised to the corresponding ketones using a chromium trioxide dipyridine complex (CrO3PY2 = Collins' reagent) in a solvent such as methylene chloride or dimethyl formamide.
The starting compounds used in the above processes are either known or may be produced by known processes, for example as described in the following examples.
The compounds of formula I produced according to the invention may be isolated and purifies by known processes. Racemic and/or diastereoisomeric mixtures can be separated in known manner.
If the compounds of formula I contain acidic or basic groups, then these may optionally also form salts, for example metal salts such as sodium salts, or acid addition salts such as hydrochlorides.
In the following examples, all temperatures are given in degrees celsius and are uncorrected. The optical activity was measured at 200 centigrade.
The compounds given in abbreviated form in the examples are described fully in claim 3 in the order of the examples.
A 12 - 100-7250 In the following examples, the following abbreviations are used:
H-Bly-OH 7EG-OH 3EG-OH H-Chatin-OR H-F2Chatin-OH H-F2.Chaton-OH Tmsal H-Aca-OH Niacin-OH H-3eg-OH H-2eg-OH H-Cha(OH)Bly-OH HOBT H-Cha(N)Ala-0H (X-Pie 4-PySAc T pac-OH H-Cha-(OH)CH2CHCl-OH MPA H-2egs-OH H-Cha-(OH)CF2CF2CF3 (2S)-2-amino-hex-(4)-enecarboxylic acid 2,6,9,12,15,18,21,24-octaoxa- pentacosanic acid 3,6,9,12-tetraoxatridecanoic acid (3S,4S)-4-amino-5cyclohexyl-3-hydroxyvalerianic acid (3R,4S)-4-amino-5-cyclohexyl-2,2difluoro-3-hydroxy-valerianic acid (4S)-4-amino-5-cyclohexyl-2,2-difluoro3-oxa-valerianic acid (2R)-2-amino-3-trimethylsilyl-propionic acid 6aminocaproic acid 3-pyridinecarboxylic acid 2,5,8,11-tetraoxaundecanoic acid 2,5,8-trioxaoctanoic acid (2R,4S,SS)-5-amino-Z-(E-2-butenyl)6cyclohexyl-4-hydroxycaproic acid 1-hydroxybenzotriazol (2R,4S,5S)-5-amino6-cyclohexyl-4-hydroxy-2-methyl caproic acid 2-aminomethyl-pyridine (4pyridylthio)acetyl (3,4,5-trimethoxy)phenyl acetic acid (2R,4S,5S)-5amino-2-chloro-6-cyclohexyl4-hydroxy caproic acid 3-(4-morpholinyl)propylamine 2,5,8-trioxaoktanethiono acid (4S,SS)-5-amino-6-cyclohexyl-1, 1,1,2,2,3, 3-heptafluoro-4-hydroxy hexanoic acid C H-Cha-CF2CF2CF3 H-Leu-(S)-a-Pic, 3EGS-OH 7EGS-OH H-Leu-R-Tmsal-OH H-Cha(H)Thiobly-OH EXI 100-7250 (5S)-5-amino-6-cyclohexyl-1,1,1,2,2,3,3heptafluoro-4-oxo-hexanoic acid (2S)-2-amino-4-methylpentanthionic acid cc-picolylamide 3,6,9,12-tetraoxa- tridecanthionic acid 2,6,9,12,15,18,21,24-oktaoxa-pentacosanthionic acid (2R,SS)-5-amino-3-aza-7-methyl-2-trimethylsilylmethyl-oktanoic acid (2R, 4S,5S)-5-amino-2-(E-2-butenyl)-6-cyclohexyl-4-hydroxy-thionocaproic acid N-Ethyl-N'-(dimethylaminopropyl)-carbodiimide 1 EXAMPLES
Intermediate products:
L-N-BOC-P--trimethylsilylalanine 100-7250 Dissolve 24 g of (2P,)-2,5-dihydro-3,6-dimethoxy-2-isopropylp-yrazine in 400 ml of tetrahydrofuran. 82 C of n-butyl-lithium are added in drops at - 70', stirred for 15 minutes, 30 g of iodotrimethylsilane are added and allowed to warm to room temperature over night. The reaction solution is partitioned between ether and water, washed until neutral, dried (M9S04), concentrated by evaporation, and chromatographed on silica gel with 7% ether in hexane. The product (24 g) is dissolved in 200 C of methanol, mixed at 0-5 with 20 ml of conc. hydrochloric acid in 50 ml of water, and stirred for 2 hours. The product is then concentrated under vacuum, the residue dissolved in methylene chloride and extracted with 2N soda solution. The organic phase is dried (K2C03) and concentrated by evaporation. The residue is dissolved in tetrahydrofuran, mixed with 35 g of di-tert.-butyldicarbonate, left to stand over night at room temperature and then concentrated by evaporation. The residue is dissolved in methanol (0.5 1), and is mixed, whilst cooling with ice, with a solution of 15 g of sodium hydroxide in 100 M1 Of H20/methanol 1:1. After 3 hours, the methanol is distilled off, and the residue is partitioned between ether and water and 40 g of phosphoric acid (85%). The organic phase is dried (M9S04) and concentrated by evaporation. 36 g of a 1:1 mixture of the title compound and D-BOC-Valine are obtained. The mixture is used without further purification for the synthesis of dipeptides.
BOC-Tmsal-His-OH 100-7250 29 g of acid mixture (BocTmsal-OH + D-BOC-Val-OH) are dissolved in 100 ml of dimethyl formamide. 19.2 g of H-HisOCH3.2HCl are added, the mixture cooled to 0-51, mixed with 50 C of N-methyl-morpholine, and then 52 ml of propanephosphoric acid anhydride (50% in CH2C12) are added in drops at Cl. After 15 hours at room temperature, the product is concentrated by evaporation under vacuum, and the residue is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The crude product is chromatographed on silica gel with methanol/methylene chloride 2-5%. 10 g of this methylester are dissolved in methanol, and a solution of 10 g of barium hydroxide. 8H20 in 100 C of water is added. After 2 hours at room temperature, an aqueous solution of 3.25 g of sulphuric acid conc. is added, the barium sulphate is centrifuged off, the remaining solution is evaporated to dryness and the residue is crystallised from methanol/methylene chloride/ether.
BOC-Tmsal-Nle-OH Analogously to the preceding example, 25 g of acid mixture and 19 g of H- Nle-OCH3.Rl in 100 ml of dimethyl formamide are reacted with 55 ml of N- methylmorpholine and 70 ml of propanephosphoric acid anhydride. In this example, the methylester can also be hydrolysed with aqueous.sodium hydroxide.
H 1 Example 1: BOC-Tmsal-Nle-Cha(OH)BlyNBu 166 mg of BOC-Tmsal-Nle-OH are dissolved in methylene chloride together with 150 mg o,f H-CHa(OH)BlyMu and 100 mg ok hydroxybenzotriazole. 96 mg of dicyclohexylcarbodiimide are added at 100-7250 0-5". The mixture is stirred for 15 hours at room temperature, the precipitated dicyclohexylurea is filtered off and the crude product is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase is dried (M9S04) and concentrated by evaporation. The residue is recrystallised from methylene chloride/hexane. [0-f1D = -39.1 (c = 0.2 in CH2C12).
H 1 Example 2: BOC-Tmsal-Nle-Cha(OH)Nle-NBu The title compound of example 1 is dissolved in ethanol and is hydrogenated for 3 hours over palladium-charcoal catalyst at normal pressure. The catalyst is filtered off, and the residue is concentrated by evaporation and crystallised from methylene chloride/hexane. loc]D = - 30.9' (c = 0.2 in CH2C12).
Example 3: BOC-Tmsal-Nle-F2-Chatin-NH-iBu mg of BOC-Tmsal-Nle-OH and 163 mg of H-F2-Chatin-NHiBu are reacted analogously to example 1 with 144 mg of hydroxybenzotriazole and 113 mg of dicyclohexylcarbodiimide. 10ID -2-010 (c 1.5 in CH2C12).
Example 4: BOC-Tmsal-Nle-F2-Chaton-NH-iBu 33 mg of alcohol of example 3 are dissolved in 1 ml of dry methylene chloride and mixed with 200 mg of Cr03'PY2 (Collins, reagent). Stirring is effected for 201 at room temperature, the chromium salts are precipitated by adding ethyl acetate and the product is filtered over Hyflo and silica gel. The filtrate is concentrated by evaporation and the residue is lyphilised from z 100-7250 benzene. 10-1D = -35.8 (c = 0.35 in CH2C12).
Example 5: BOC-Tmsal-Nle-Chatin-Leu-a-Pic mg of BOC-Tmsal-Nle-OH and 223.5 mg of H-Chatin-Leu-oc-Pic are reacted analogously to example 1 with 140 mg of hydroxybenzotriazole and 111 mg of dicyclohexylcarbodiimide. The product is crystallised from methylene chloride/hexane. [OCID = -12.9' (c = 0.15 in CH2C12).
Example 6: BOC-Tmsal-His-Cha(OH)Bly-NH-Bu 230 mg of BOC-Tmsal-His-OH and 195 mg of H-Cha(OH)BlyNHBu are reacted analogously to example 1 in dimethyl formamide with 150 mg of hydroxybenzotriazole and 120 mg of dicyclohexylcarbodiimide. The product is crystallised from methylene chloride/methanol/ether.
-32.50 (c = 0.1 in MeOH/CH2C12 1.1).
Example 7: BOC-Tmsal-His-CHa(OH)Nle-NH-Bu mg of the title compound of example 6 are dissolved in 2 ml of alcohol analogously to example 2 and hydrogenated over 3 mg of palladium-charcoal catalyst (U). 1OCID = -38.6 (c = 0.1 in MeOH/CH2C12 1.1).
Example 8: BOC-Tmsal-Bly-F2-Chatin-NH-iBu 248 mg of BOC-Tmsal-Bly-OH and 204 mg of H-F2-Chatin-NH-iBu are reacted analogously to example 1 with 182 mg of hydroxybenzotriazole and 141 mg of dicyclohexylcarbodiimide. The crude product is chromatographed on silica gel with methylene chloride/ether 8:2 and is lyphilised from benzene. 1OCID = -29.8' (c. 0.5 in CH2C12).
Example 9: BOC-Tmsal-B1Y-F2-Chaton-NH-iBu 100-7250 29 mg of alcohol of example 8 are oxidised analogously to example 4 with 250 mg of Collin's reagent. [cc]D = -47.9 (c = 0.24 in CH2C12).
Example 10: 7EG-Tmsal-B1Y-F2-Chatin-NH-iBu 59 mg of H-Tmsal-Bly-F2Chatin-NH-iBu and 43 mg of 7EG-OH are reacted analogously to example 7 with 29 mg of hydroxybenzotriazole and 23 mg of dicyclohexylcarbodiimide. The crude product is purified over silica gel with methylene chloride/ether 8:2. IOID -18.80 (c = 1.8 in CH2C12).
Example 11: 7EG-Tmsal-Bly-F2Chaton-NH-iBu 23 mg of the alcohol of example 10 are oxidised analogously to example 4 with 130 mg of Collins' reagent. 1OCID = -20.6 (c = 0.34 in CH2C12).
Example 12: 3 EG-Tmsal-His-Cha(OH)-BlyNH-Bu 206 mg of 3 EG-OH and 500 mg of H-Tmsal-His-Cha(OH)-Bly-NH-Bu are reacted analogously to example 1 in dimethyl formamide with 0.144 ml of diisopropylcarbodiimide. The crude product is chromatographed on silica gel with methanol/methylene chloride 2-10%. 10]D = -27.6' (c = 0.1 in CH2C12).
C Example 13: 7EG-Tmsal-His-Cha(OH)-Bly-NH-nBu 100-7250 338 mg of 7EG-OH and 500 mg of H-Tmsal-His-Cha(OH)Bly-M-nBu are reacted analogously to example 7 in dimethyl formamide with 110 mg of hydroxybenzotriazole and 0.13 C of diisopropylcarbodiimide. The product is crystallised from methylene chloride/ether/hexane. [ID = -21.0 (c = 0. 1 in CH2C12).
Example14: BOC-Tmsal-His-Chatin-Leu-cc-Pic 2.9 g of BOC-Tmsal-His-OH and 3.1 g of H-Chatin-Leu-oc-Pic are reacted analogously to example 1 in dimethyl formamide with 2 g of hydroxybenzotriazole and 1.2 ml of diisopropylcarbodiimide, and chromatographed on silica gel with methanol/methylene chloride 0-10%. [cc]D = -27.20 (c = 0.2 in CH2C12).
Example 15: Me-3eg-Tmsal-His-Chatin-Leu-a-Pic 350 mg of Me-3eg-p-nitrophenol and 700 mg of H-Tmsal-His-Chatin-Leu-tx- Pic are dissolved in dimethyl formamide. After 3 hours, the solution is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic phase is dried and concentrated by evaporation and the residue is chromatographed on silica gel with methanol/methylene chloride 0-10%. The title compound has an [CCID = -26. 5' (c = 0.2 in CH2C12), Example 16: Me-3egTmsal-(me-3eg)-His-Chatin-Leu-oc-Pic The diacylated compound of this example can be isolated as a by-product from example 15.
[OAD = -4.7 (c = 0 2 in CH2C12).
Example 17: BOC-Aca-Tmsal-His-Chatin-Leu-cc-Pic 100-7250 300 mg of BOC-Aca-p-nitrophenol and 600 mg of H-Tmsal-His-ChatinLeu-a-Pic are reacted analogously to example 15 in the presence of 100 mg of imidazole. The crude product is chromatographed with methanol/methylene chloride 0-12. [0JD = -21.5 (c = 0.2 in CH2C12).
Example 18: H-Aca-Tmsal-His-Chatin-Leu-a-Pic.3HCl 500 mg of title compound of example 17 are treated for 1 hour with trifluoroacetic acid/methylene chloride 1:1. The reaction mixture is partitioned between methylene chloride and aqueous sodium carbonate solution. The organic phase is separated, dried, mixed with 0.3 ml of conc. hydrochloric acid and evaporated to dryness. The residue is lyophilised from t-butanol. 1OCID = -23.41 (c = 0.2 in MeOH/CH2C12 1:1).
Example 19: Niacin-2eg-Tmsal-Nle-F2-Chatin-NH-iBu 381 mg of Niacin-2eg-p-nitrophenol and 523 mg of H-Tmsal-Nle-F2chatin-NH- iBu are reacted analogously to example 15. IOID = -24,5 (c = 0,1 in CH2C12).
Example 20: Niacin-2eg-Tmsal-Nle-F2-Cha_ton-NH-iBu mg of the alcohol of example 19 are oxidised analogously to example 4 with 241 mg Collins, reagent. [a]D = -31,6 (c = 0.4 in CH2C12).
j Example 21: BOC-Aca-Tmsal-Nle-Chatin-Leu-a.-Pic 100-7250 275 mg of N-t-BOC-6-aminocaproic-acid-p-nitrophenylester and 500 mg of HTmsal-Nle-Chatin-Leu-a-Pic are reacted analogously to example 15. The crude product is crystallised from ethylacetate/ether. 10AD -47,011 (c = 0.1 in CH2C12).
Example 22: H-Aca-Tmsal-Nle-Chatin-Leu-a-Pic.2HCl The title compound of example 21 is deprotected with trifluoroacetic acid/methylene chloride analogously to example 18 and transformed in the dihydrochloride. [CdD = -15,4 (c = 0,2 in CH2C12) Example 23: 7EG-Tmsal-Nle-Chatin-Leu-a-Pic 400 mg of H-Tmsal-Nle-Chatin-Leu-a-Pic are reacted with 260 mg 7EGOH, 80 mg HOBT and 130 mg DCC analogously to example 1. The crude product is chromatographed with 5% methanol in methylene chloride. ICID = -3.9 (c = 0.8 in CH2C12) Example 24: Niacin-2eg-Tmsal-Nle-Chatin-Leu-a-Pic 500 mg of H-Tmsal-Nle-Chatin-Leu-oc-Pic are reacted with 300 mg of Niacin2egp-nitrophenol in DMF analogously to example 15. The crude product is crystallised from methylene chloride/ether. ICID = -27.2' (c = 0.25 in CH2C12).
Example 25: H-2eg-Tmsal-Nle-Chatin-Leu-a-Pic mg of nicotinic acid ester (example 24) are dissolved in C_ 100-7250 methanol and environ 50 mg of Na OH are added. After 15 minutes repartition between water and methylene chloride. The organic phase is separated, dried (M9S04) and evaporated. The residue is crystallised from methylene chloride/ether/hexane. 10ID = 15,5' (c = 0.1 in CH2C12).
Example 26: 4-PySAc-Tmsal-Nle-F2-Chatin-NH-iBu 511 mg of H-Tmsal-Nle-F2-Chatin-NH-iBu are reacted with 155 mg of (4pyridylthio)acetic acid, 245 mg HOBT and 197 mg DCC in 40 ml DMF analogously to example 1. 10AD = -38,1' (c = 0.1 in methanol).
Example 27: Biotinoyl-Tmsal-Nle-F2-Chatin-NH-iBu 244 mg of (+) Biotin are reacted with 560 mg of H-Tmsal-Nle-F2Chatin-NH- iBu, 269 mg HOBT and 215 mg DCC analogously to example 1. [a]D = -22,9' (c = 0,33 in CH2C12).
Example 28: H-2egTmsal-Nle-Chaton-NH-iBu 32 mg of the title compound of example 20 are dissolved in methanol and hydrolysed with 4 mg NaOH. The reaction mixture is partitioned between aqueous Na-bicarbonate-solution and methylene chloride, the organic phase dried and evaporated. [CID -21.10 (c = 0.6 in C112C12).
Example 29: Tmpac-2eg-Tmsal-Nle-F2-Chatin-NH-iBu 44o mg of H-Tmsal-Nle-F2-Chatin-M-iBu are reacted with 370 mg of H-Tmpac2eg-p-nitrophenol analogously to example 15. The crude product is purified by chromatography on silica gel.
t C, lOdD = -19,3 (c = 0.1 in CH2C12).
Example 30: Tmpac-2eg-Tmsal-Nle-F2-Chaton-NH-iBu 100-7250 mg of the title compound of example 29 are oxidised analogously to example 4 with 100 mg Collin's reagent. 10AD = -21.0 (c = 0.2 in CH2C12).
Example 31: BOC-Tmsal-Nle-Cha(OH)CH2CHCl-NHBu 636,7 mg of BOC-Tmsal-Nle-OH and 479,8 mg of H2NCH(Chm)-a-chlorolacton. HCl are reacted with 1.05 ml N-ethylmorpholine and 1.14 ml propanephosphonic acid anhydride (50% in CH2C12) in DMF. The reaction solution is evaporated and the residue partitioned between ethylacetate and 2N hydrochlorid acid. The organic phase is washed once with saturated aqueous sodiumcarbonate solution and once with saturated aqueous sodiumchloride solution, dried over NaS04 and evaporated. The residue is chromatographed on silica gel with hexane/ethylacetate (2:1).
The obtained pure BOC-Tmsal-Nle-NHCH(Chm)-(x-chlorolacton is reacted subsequently with 3,6 ml of n-butylamine at room temperature. The reaction solution is evaporated and the residue crystallised from methylene chloride/hexane. 10AD = -38,9 (c = 0.48 in MeOH).
Example 32: BOC-Tmsal-Nle-Cha(OH)Ala-NH-Bu 1,5 g of BOC-Tmsal-Nle-OH + 1,2 g of H-Cha(OH)Ala-NH-Bu and 0,7 g of HOBT are reacted analogously to example 1 in methylene chloride. Crude product crystallises from methanol/methylenechloride/ether. ICID = -39,5' (c = 0. 2 in CH2C12).
(- 1 Example 33: 3EG-Tmsal-Nle-Cha(OH)ThioblyNH-nBu 100-7250 117,8 mg of 3 EG-OH and 350 mg of H-Tmsal-Nle-Cha(OH)Thiobly-NHnBu are reacted in THP/DMF (1:1) with 105.5 mg of hydroxybenzotriazol and 111,8 mg of EDCI. The reaction mixture is evaporated, at 511, a saturated aqueous sodiumcarbonate solution is added and the mixture taken up in ethylacetate. The organic phase is washed with diluted hydrochloric acid and dried over M9S04. The crude product is chromatographed on silica gel with ethylacetate/alcohol (99:1). ICdD = -18.4 (c = 0.5 in CH2C12).
Example 34: 3 Eg-Tmsal-Nle-Cha(OH)Bly-NHBu 502 mg of H-Tmsal-Nle-Cha(OR)Bly-MBu are reacted analogously to example 1 in 2.3 ml of tetrahydrofuran/DMF 1:1 with 2.8 mg of HOBT, 151 mg 3 EG-OH and 143 mg N-ethyl-NI-(3-dimethylaminopropyl)-carbodiimide.HCl. The crude product is crystallised from methylenechloride/hexane. PYID = -31.4 (c = 0.5 in CH2C12).
Example 35: Me-3egs-Tmsal-His-Cha(OH)Bly-NHBu mg of the methylxanthat of triethylenglykolmonomethylether are reacted with 400 mg of H-Tmsal-His-Cha(OH)Bly-MBu in DMF in presence of 100 mg of imidazol. After 15 hours the reaction mixture is diluted with ethylacetate, washed with water and the crude product is chromatographed on silica gel with methanol in methylene chloride (2-10%). 1OCID = -49.8' (c = 0.2 in CH2C12).
1 C - Example 36: 3EG-Tmsal-Nle-Cha(OH)C-2CHCl-NHBu 100-7250 338 mg of H-Tmsal-Nle-Cha(OH)CH2CHCl-NHBu.HCl are reacted analogously to example 1 with 127 mg of HOBT, 0.0862 C of N-ethylmorpholine, 184 mg of 3EG-OH and 111 mg of N-ethyl-NI-(3-dimethylaminopropyl)carbodiimide.HCl. The crude product is chromatographed on Lichroprep PR-18 with methanol/water (8:2). [OAD = -22.8' (c = 0.6 in CH2C12).
Example 37: 4-PyCH2OCS-Tmsal-Nle-F2-Chatin-NH-iBu mg of the methylxanthate of 4-hydroxymethylpyridine are reacted analogously to example 35 in dimethy1formamide with 410 mg of H-Tmsal-Nle- F2-Chatin-NHiBu- The crude product is chromatographed with methanol/methylene chloride 1-5%. [CYID = -53,0 (c = 0.1 in CH2C12).
Example 38: MPA-CS-Tmsal-Nle-ChatinLeu-oc-Pic 400 mg of H-Tmsal-Nle-Chatin-Leu-a-Pic are reacted in DMF with 115 mg of the isothiocyanide of 3-(4-morpholino)propylamine. After 2 hours the ractionmixture is diluted with ethylacetate, ether is added and the precipitated product is filtered off. 10ID = -68,6' (c = 0.2 in CH2C12).
Example 39: 4-PyCH2OCS-Tmsal-Nle-F2-Chaton-NH-iBu 300 mg of the alcohol of example 37 are dissolved in DMSO/benzene 1:1. At 0-5 443 mg of DCC and 17 mg of dichloroacetic acid are added. After 24 hours 200 mg of oxalic acid dissolved in methanol are added, 1 hour later the mixture is filtered off and the filtrate distributed between ethylacetate and saturated sodiumcarbo- 100-7250 nate solution. The organic phase is dried (M9S04) and evaporated. 10AD - 19.10 (c = 0,1 in CH2C12).
Example 40: Niacin-2egs-Tmsal-Nle-F2-Chatin-NH-iBu 514 mg of H-Tmsal-Nle-F2-Chatin-NH-iBu are reacted analogously to example 35 in presence of 40 mg of dimethylaminopyridine with 302 mg of the methylxanthat of diethylenglycolmononicotinic acid ester. [CdD = -71,211 (c = 0.1 in CH2C12).
Example 41: Niacin-2egs-Tmsal-Nle-F2-Chaton-NH-iBu 28 mg of the alcohol of example 40 are oxidised analogously to example 39 with 35 mg of DCC and 0.5 equivalents of dichloroacetic acid. [0dD = -13, 5 (c = 0.05 in CH2C12).
Example 42: Tmpac-2egs-Tmsal-Nle-F2-Chatin-NH-iBu 610 mg of H-Tmsal-Nle-F2-Chatin-M-iBu are reacted analogously to ex ample 35 after addition of 100 mg of dimethylaminopyridine with 500 mg of the methylxanthat of diethylenglykolmono(3,4,5-trimethoxy)phenylacetic acid ester. 114]D = -49.11 (c = 0.1 in CH2C12).
Example 43: Tmpac-2egs-Tmsal-Nle-F2-Chaton-NH-iBu 300 mg of the alcohol of example 42 are oxidised analogously to example 39 with 33 mg of DCC and 1.5 mg of dichloroacetic acid. [C-rlD = +1.80 (c 0,1 in CH2C12), C Example 44: BOC-Tmsal-Nle-Cha(H)CF2CF2CF3 100-7250 94 mg of (4R,5S)-5amino-6-cyclohexyl-1,1,1,2,2,3,3-heptafluoro4-hexanol are reacted analogously to example 1 with 108 mg of BOC-Tmsal-NleOH, 78 mg of HOBT and 61 mg of DCC. bXID = -28,9' (c = 2,0 in CH2C12).
Example 45: Niacin-2egs-Tmsal-Nle-Cha(OH)-CF2CF2CF3 mg of the t-BOC-deprotected product of example 44 are reacted analogously to example 35 in presence of 5 mg of dimethylaminopyridin with 15 mg of the methylxanthate of diethylenglykolmononicotinic acid ester. 10ID = -38. 5 (c = 0.7 in CH2C12).
Example 46: 3EG-Tmsal-Nle-Cha(OH)CF2CF2CF3 mg of t-BOC deprotected product of example 44 are reacted analogously to example 1 with 20 mg of 3EG-OH, 12 mg of HOBT and 18 mg of DCC. IOID = - 26,8' (c = 0.2 in CH2C12).
Example 47: 3EG-Tmsal-Nle-Cha-CF2CF2CF3 mg of the title product of example 46 are oxidises analogously to example 4 with 130 mg of Collin's reagent. [CID = 15.80 (c = 0.1 in CH2C12).
Example 48: 3EGS-Tmsal-Nle-Cha(OH)Thiobly-NH-nBu 380 mg of 3EGS-OEt and 790 mg of H-Tmsal-Nle-Cha(OH)-Thiobly-NHnBu are reacted in methylene chloride with 15.8 mg of N-dimethylaminopyridine (DMAP). After 1.5 hours at room temperature the C 100-7250 mixture is heated for 1.5 hours to reflux. The reaction mixture is diluted with further methylene chloride, washed once with 1 N sodiumhydrogensulfate-solution and once with saturated aqueous sodiumhydrogencarbonate-solution and once with saturated aqueous sodiumchloride-solution and dried over Na2S04. After filtration and evaporation, the obtained residue is chromatographed on silica gel with hexane/ethylacetate (30:70 to 0:100). 10'1D = -56.80 (c = 0.5 in CH2C12).
Example 49: BOC-Tmsal-Nle-Chatin 235 mg of H-Chatin-Leu(S)-a-Pic are reacted analogously to example 1 with 210 mg of BOC-Tmsal-Me-OH, 90 mg of HOBT and 115 mg of DCC. The crude product is chromatographed with 0.5 to 3% methanol in methylene chloride. 10'1D = -13,0' (c = 0.2 in CH2C12) Example 50: 3EGS-Tmsal-Nle-Chatin- mg of H-Tmsal-Nle-Chatin-Leu(S)-cc-Pic are reacted in methylene chloride with 80 mg of 3EGS-OEt. After 24 hours the reaction mixture is chromatographed with 0.5-5% methanol in methylene chloride. lOdD = -66,71 (c = 0.1 in CH2C12).
Example 51: 7EGS-Tmsal-Nle-Chatin-Leu(S)-(z-Pic mg of H-Tmsal-Nle-Chatin-Leu(S)-a-Pic are reacted analogously to example 50 with 120 mg of 7EGS-OEt. lOdD = -58.3' (C 012 in CH2C12), C ' Example 52: BOC-Leu-R-Tmsal-Nle-Chatin-Leu-a-Pic 100-7250 To a solution of 550 mg of H-Tmsal-Nle-Chatin-Leu-ct-Pic In 1.6 ml of methanol and 0.33 ml of 5 N HCl in methanol a solution of 180 mg of BOC- 1eucinal in 0.6 C of methanol and subsequently 31 mg of sodiumcyanoborhydrid are added and the obtained mixture is stirred during 24 hours at room temperature. The reaction mixture is poured on ice-water, made alkaline with aqueous 2 N sodiumbicarbonate solution and subsequently extracted with methylene chloride. The organic phase is dried and evaporated and the obtained residue chromatographed on silica gel with 5% ethanol in methylene chloride. The title compound has an 10f1D = -33.1' (c = 0.38 in ethanol).
Example 53: H-Leu-R-Tmsal-Nle-Chatin-Leu-cc-Pic To 250 mg of BOC-Leu-R-Tmsal-Nle-Chatin-Leu-oc-Pic 3 ml of 10% conc. hydrochloric acid in glacial acetic acid are added at OC and the obtained mixture heated to room temperature. After 3 hours the mixture is evaporated. The residue is partitioned between saturated aqueous sodiumbicarbonate solution and 5% ethanol in methylene chloride. The organic phase is dried and evaporated and the residue chromatographed on silica gel with 10% ethanol in 1% conc. ammoniak solution. The title compound has an [a.]D = -25.00 (c = 0.34 in ethanol).
C - 100-7250 The compounds according to the invention exhibit pharmacological activity and are, therefore, useful as pharmaceuticals.
They are inhibitors of renin activity, e.g. on human tetradecapeptide substrate and they inhibit at a concentration of 10-5 M to 10-11 M the enzyme activity of pure human renin by 50 % according to the method of F. Cumin et al. (Bioch. Biophys. Acta 913, 10 to 19 (1987)) or in a renin binding assay.
In the antibody-trapping method of K. Poulsen and J. Jorgensen (J. Clin. Endocrin. Metab. 39, [19741 816 - 825), they inhibit human plasma renin activity at a concentration of 10-5 M to 10-11 M.
The compounds according to the invention are therefore useful for the prophylaxis and treatment Of conditions which are characterised by enzymatic malfunction and for which an inhibition of enzymatic activity is indicated.
As renin inhibitors they are suitable e.g. for use in the prophylaxis and treatment of hypertension and cardiac insufficiency Ccongestive heart failure").
The compounds which are preferred for the prophylaxis and treatment of hypertension and cardiac insufficiency are the title compounds of examples 1,22,23,24,35 and 51 especially of examples 22 and 23.
The title compound of example 23 is the most preferred compound for the renin inhibition, it has for example been determined in the antibody trapping test having the lowest inhibiting concentration 0,15 nM/1, the highest inhibiting concentration 15 nM/1, C.
100-7250 ICso = 1,5 nM/l, it is therefore indicated that -the compound of example 23 may be administered to larger mammals such as humans at daily dosage from 1 mg to 10 mg.
The compounds according to the invention exhibit also an antiretroviral activity and are therefore useful for the treatment of diseases caused by retroviruses including HTLV-I and -III. This activity can be demonstrated in the FeLV cat model [Cerny and Essex, CRC press in 1979, pp. 233 - 256; Cockerell et al., J. Natl. Cancer Inst. 57, 1095 - 1099 (1976); Cotter et al. J. Am. Vet. med. Assoc. 166, 449-453 (1975); Essex et al. Science 190, 790 - 792 (1975)] - a disease model for human AIDS.
It has been reported e.g. (25th ICAAC in Minneapolis, Sept. 30th - Oct. 2nd) that with a 30 mg treatment of 31-azido31-deoxy-thymidine over 14 days a reduction of FeLV-titres by a factor of 10 could be shown, but no cure was achieved. On administration of the compounds of the invention, eradication of the virus can be observed. Dosage ranges for the antiretro-viral activity are those conventionally employed and lie e.g. in the range of 5 - 20 mg/kg/day.
For above indications, the dosage to be administered depends on the compound respectively used, the type of administration and the desired treatment. In general, satisfactory results are obtained if the compounds are administered in a daily dosage of 0.02 mg/kg to ca. 20 mg/kg animal body weight. For larger mammals, for example humans an indicated daily dosage is from about 1 mg to about 500 mg, conveniently administered e.g. orally in doses of 0.25 mg to ca. 500 mg up to 4 times daily e.g. in divided form or in retard form.
Ck 100-7250 The compounds according to the invention may be administered in free form, or if acidic or basic groups are present, in pharmacologically acceptable salt form. Such salt forms have the same order of activity as the free forms and can be produced in known manner. The present invention similarly relates to pharmaceutical preparations containing a compound according to the invention in free form or in pharmaceutically acceptable salt form, optionally together with pharmaceutically adjuvants and/or carrier substances. Such pharmaceutical preparations may be formulated for use in enteral, preferably oral administration, e.g. at tablets, or for use in parenteral administration, e.g. as injectable solutions or suspensions. Further a nasal administration of the compounds according to the invention is also possible. An appropriate nasal spray can be prepared in a manner known per se.
1 C A
Claims (15)
1. Silicon-containing renin inhibitors.
100-7250
2. Renin inhibitors according to claim 1, of formula 0 H 1 /" A-N Si (R,)
3 B-D I wherein R, signifies (Cl-5)alkyl, A is a N-protected amino acid radical or a peptide or signifies a group of formula X 1 whereby X denotes 0, S or H2 and R2 denotes a straight-chain or branched (Cl-10)alkyl radical, which may be optionally substituted by amino, hydroxy or (C2-5)alkyl or (C6_10)aryloxy; a 5- or 6-membered heteroaryl radical containing one or two nitrogen atoms, oxygen or sulphur atoms or one nitrogen atom and one oxygen atom and/or one sulphur atom; or a heteroaryl(Cl-5)alkyl radical, in which the heteroaryl moiety is 5- or 6membered and contains one or two nitrogen atoms, oxygen or sulphur atoms or one nitrogen atom and one oxygen atom and/or one sulphur atom; a straightchain or branched (Cl-5)alkoxy radical or a (C6-10)aryl-(Cl5)alkoxy radical, or A signifies a group of formula X 11 R3-0-(CH2CH2-0),-(CH2)n-TJC- wherein C 1 - 34 100-7250 is -0-, NR7- or -CH21 whereby R7 signifies hydrogen or a straight-chain or branched (Cl-5)alkyl radical, R3 is hydrogen, a straight-chain or branched (Cl-20)alkyl radi cal or a sugar radical which is bonded as a glycoside, an op tionally substituted, saturated or unsaturated, straight chain or branched (C2-30)alkylcarbonyl group, a (C36)P01Y hydroxyalkylcarbonyl, a phosphoroyl, a bis-(dimethylamino) phosphoroyl, a sulpho, an aroyl, a heteroaroyl, an arylalkyl, an arylalkylcarbonyl or a heteroarylalkylcarbonyl group, or the biotinoylgroup or signifies a group of formula R6 R4 N RS 0 wherein R4 is hydrogen or a side chain of a D- or L-amino acid, and R5 and R6 are the same or different and respectively signify hydrogen, (Cl-5)alkyl, (C2-5)hydroxyalkyl or (C2-5)aminoalkyl, or R3 signifies a group of formula R6 \\ N(CH2)p-E- ..I R5 wherein R5 and R6 are defined as above, p is a whole number from 0 to 5 and 0 U E signifies a bond or the group -C-, or R3 signifies a group of formula F-(CM2)p-E-, wherein 3 A p and E are defined as above, and F denotes groups of formulae R7-N N-, 0 N-, N- or \_J c whereby R7 is defined as above m is a whole number from 1 to 20, n is a whole number from 0 to 5, and B signifies a group of formula Ra 1\ N..I 1 R7 0 or a group of formula R8 1---. CH2 0 100-7250 EN- wherein R7 is defined as above and R8 signifies a hydrophilic. or lipophilic amino acid side chain, D signifies a group of formula H Rjo R,, / R14 -N \\y YV \\ R15 11 R9 R12 R13 X wherein X is defined as above, 100-7250 Rg has the same significance as R8, RIO is a hydroxyl or amino group and R,, is hydrogen, or RIO and R,, together form an oxo group, R12 and R13t independently of one another, signify fluorine or hydrogen, R14 and Rls are the same of different and respectively signify hydrogen, a straight-chain or branched (Cl-6)alkyl radical, or respectively signify a group of formula R16 --L R17 0 wherein R16 signifies a straight-chain or branched (Cl-5)alkyl radical or a straight-chain or branched (Cl-5)hydroxyalkyl radical, R17 is a hydroxyl radical, a straight-chain or branched (Cl-5)al koxy group, an amino or a (Cl-5)alkylamino group, an aminome thylpyridyl group, a benzyl group or a protected or unprotec ted amino acid, Y signifies a bond or is -0-, -N- or -C 1 h M18 Rig wherein R18 and Rig, independently of one another, denote hydrogen or fluorine, or respectively possess the significancesgiven above for Re, or D signifies a group of formula RIO R,, H 1 -N-- (CF2MF3 Rg I- k 1 k_ wherein Rg, Rio, R,, and n are defined as above.
100-7250 3. A compound according to claims 1 and 2 of formula H 1 Ay- N 0 BY -DY SiMe3 whereby AY signifies a group of formula xy R 2 Y") JY whereby XY signifies S or 0, R2Y denotes tert.-butyloxy, benzyloxy, 5-aminopentyl or isobutyl, or AY signifies a group of formula xy h R3y-0-(CH2CH20),-(CH2)11-C- whereby XY is defined as above, R3Y denotes hydrogen, methyl, glucopyranosyl, pyridinoyl, 3,4,5-trimethoxybenzoyl, MY signifies a whole number from 2-7 and ny signifies a whole number from 0-2, - 1 38 - BY signifies a group of formula Ray N K77 0 100-7250 wherein R7Y denotes hydrogen or methyl and Rey denotes n-butyl, isobutyl, 2-butenyl, phenylmethyl, 4-imidazolylmethyl, pyridinemethyl or trimethylsilylmethyl, DY signifies a group of formula Rjoy Rily H 1 N YY N \IY/ \ R1SY Rgy R12y R1 3Y 0 R14 Y whereby Rgy denotes isobutyl, benzyl or cyclohexylmethyl, and either Rjoy signifies a hydroxyl radical and Rlly signifies hydrogen, when R12y and R13y respectively denote hydrogen, or Rjoy and Rlly together form the oxo group, when R12y and R13y respectively denote fluorine, R14y signifies hydrogen and R1r,y signifies hydrogen, methyl, i-propyl, ibutyl, 2-butyl or a group of formula R16y whereby 39 R16y denotes i-butyl or 2-butyl and R17y denotes aminomethylpyridyl, YY denotes a bond of a group of formula RISY R Y c 100-7250 whereby Rjay and R1gy respectively signify fluorine. or R18Y has the definition n-butyl, isobutyl, 2-butenyl, methyl, methylthiomethyl, benzyl, isopropyl or chlorine, and Rjoy denotes hydrogen.
4.
Compounds of claims 1 to 3 selected from (2R,4S,5S,8S,11R)-6,9,12-triaza-2-(2-E-butenyl)-8-butyl-Scyclohexylmethyl-4-hydroxy-15,15-dimethyl-ll-trimethylsilylmethyl-14oxa-7, 10,13-trioxo-hexadecanoic acid butylamide.
(2R,4S,5S,8S,11R)-6,9,12-triaza-2,8-dibutyl-5-cyclohexylmethyl-4hydroxy15,15-dimethyl-ll-trimethylsilylmethyl-14-oxa-7,10,13trioxo-hexadecanoic acid butylamide.
(3R,4S,7S,10R)-5,8,11triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-3hydroxy-14,14-dimethyl-10-trimethylsilylmethyl13-oxa6,9,12-trioxopentadecanoic acid isobutylamide.
(4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-14,14dimethyl-10-trimethylsilylmethyl-13-oxa-3,6,9,12-tetraoxo-pentadecanoic acid isobutylamide.
(3S,4S,7S,10R)-5,8,11-triaza-7-butyl-4-eyclohexylmethyl-3-hydro- 100-7250 xy-14,14-dimethyl-10-trimethylsilylmethyl-13-oxa-6,9,12trioxopentadecanoyl(L)-leucine-a-picolylamide.
(2R,4S,SS,8S,11R)-6,9,12-triaza-2-(2-B-butenyl)-5-cyclohexylmethyl-4hydroxy-8-(4-imidazolyl)-methyl-15,15-dimethyl-ll-trimethylsilylmethyl-14oxa-7,10,13-trioxo-hexadecanoic acid butylamide.
(2R,4S,SS,8S,11R)-6,9,12-triaza-2-butyl-S-cyclohexylinethyl-4-hydroxy-8(4-imidazolyl)-methyl-15,15-dimethyl-ll-trimethylsilylmethyl-14-oxa-7,10, 13-trioxo-hexadecanoic acid butylamide.
(3R,4S,7S,10R)-5,8,11-triaza-7-(2-E-butenyl)-4-eyclohexylmethyl2,2difluoro-3-hydroxy-14,14-dimethyl-10-trimethylsilylmethyl-13oxa-6,9,12trioxo-pentadecanoic acid isobutylamide.
(4S,7S,10R)-5,8,11-triaza-7-(2-E-butenyl)-4-cyclohexylmethyl-2,2difluoro14,14-dimethyl-10-trimethylsilylmethyl-13-oxa-3,6,9,12tetraoxopentacarboxylic acid isobutylamide.
(3R,4S,7S,10R)-5,8,11-triaza-7-(2-E-butenyl)-4-cyclohexylmethyl2,2difluoro-3-hydroxy-10-trimethylsilylmethyl-14,17,20,23,26,29, 32,35octaoxa-6,9,12-trioxo-hexatriacontanic acid isobutylamide.
(4S,7S,10R)-5,8,11-triaza-7-(2-E-butenyl)-4-eyclohexylmethyl-2,2difluoro10-trimethylsilylmethyl-14,17,20,23,26,29,32,35-octaoxa3,6,9,12-tetraoxahexatriacontanic acid isobutylamide.
(2R,4S,5S,8S,11R)-6,9,12-triaza-2-(2-E-butenyl)-5-cyclohexylmethyl-4hydroxy-8-(4-imidazolyl)-methyl-ll-trimethylsilylmethyl15,18,21,24tetraoxa-7,10,13-trioxo-pentacosanic acid butylamide.
(2R,4S,SS,8S,11R)-6,9,12-triaza-2-(2-E-butenyl)-5-cyclohexylme- 1 " 1 l I_ 1 100-7250 thyl-4-hydroxy-8-(4-imidazolyl)-methyl-ll-trimethylsilylmethyl15,18,21,24, 27,30,33,36-octaoxa-7,10,13-trioxo-heptatricontanic acid butylamide.
(3S,4S,7S,10R)-5,8,11-triaza-4-cyclohexylmethyl-3-hydroxy-7-(4imidazolyl)methyl-14,14-dimethyl-10-trimethylsilylmethyl-13-oxa6,9,12trioxopentadecanoyl-(L)-leucine-a.-picolylamide.
(3S,4S,7S,10R)-5,8,11-triaza-4-cyclohexylmethyl-3-hydroxy-7-(4imidazolyl)methyl-10-trimethylsilylmethyl-13,16,19,22-tetraoxa-6,9,12-trioxotricosanoyl-(L)-leucine-(x-picolylamide.
(3S,4S,7S,10R)-5,8,11-triaza-4-cyclohexylmethyl-3-hydroxy-7-[4(1-(2,5,8, 11-tetraoxa-lauroyl))-imidazolyllmethyl-10-trimethylsilylmethyl13,16,19, 22-tetraoxa-6,9,12-trioxo-tricosanoyl-(L)leucine-a-picolylamide.
(3S,4S,7S,10R)-5,8,11,18-tetraaza-4-cyclohexylmethyl-3-hydroxy7-(4imidazolyl)-methyl-21,21-dimethyl-10-trimethylsilylmethyl20-oxa-6,9,12,19tetraoxo-docosanoyl(L)-leucineot-picolylamide.
(3S,4S,7S,10R)-17-amino-5,8,11-triaza-4-cyclohexylmethyl-3-hydroxy-7-(4imidazolyl)-methyl-10-trimethylsilylmethyl-6,9,12-trioxoheptadecanoyl-(L)leucine-a-picolylamide.
(3R,4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexymethy.1-2,2-difluoro-3hydroxy-19-nicotinoyl-10-trimethylsilylmethyl13,16,19-trioxa-6,9,12. trioxo-nonadecanoic acid-isobutylamide.
(4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-19-nicotinoyl-10-trimethylsilylmethyl-13,16,19-trioxa-3,6,9, 12tetraoxo-nonadecanoic acid-isobutylamide.
100-7250 (3S,4S,7S,10S)-5,8,11,18-tetraaza-4-cyclohexylmethyl-7-butyl-3hydroxy-21, 21-dimethyl-10-trimethylsilylmethyl-20-oxa-6,9,12,19tetraoxo-docosanoyl(L)-Ieucine-a.-picolylamide.
(3S,4S,7SylOR)-17-amino-5,8,11-triaza-7-butyl-4-cyclohexylmethyl3-hydroxy10-trimethylsilylmethyl-6,9,12-trioxoheptadecanoyl-(L)leucine-apicolylamide.
(3S,4S,7S,10R)-5,8,11-triaza-7-butyl-4-eyclohexylmethyl-3hydroxy-10trimethylsilylmethyl-14,17,20,23,26,29,32,35-oktaoxa-6,9,12-trioxohexatriacontanoyl-(L)-leucine-a-picolylamid.
(3S,4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-3-hydroxy -19nicotinoyl-10-trimethylsilylmethyl-13,16,19-trioxa-6,9,12trioxononadecanoyl-(L)-leucine-a-picolylamide.
(3S,4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-3-hydroxy -10trimethylsilylmethyl-13,16,19-trioxa-6,9,12-trioxo-nonadecanoyl-(L)leucine-a-picolylamide.
(3R,4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-3hydroxy-10-trimethylsilylmethyl-6,9-dioxo-ll-(4-pyridylthio)acetylundecanoic acid-isobutylamide.
(3R,4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-3hydroxy-10-trimethylsilylmethyl-6,9-dioxo-11-biotinoylundecanoic acidisobutylamide.
(4S,7S,10R)-5,8,11triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-10trimethylsilylmethyl-13,16,19-trioxa-3,6,9,12-tetraoxononadecanoic acidisobutylamide.
(3R,4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-di- a 1:
100-7250 fluoro-3-hydroxy-19-(3,4,5-trimethoxyphenyl)-acetyl-10trimethylsilylmethyl-13,16,19-trioxa-6,9,12-trioxo-nonadecanoic acidisobutylamide.
(4S,7S,IOR)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-19(3,4, 5-trimethoxyphenyl)acetyl-10-trimethylsilylmethyl-13, 16,19-trioxa-3,6,9, 12-tetraoxo-nonadecanoic acid-isobutylamide.
(2R,4S,5S,8S,11R)-6,9,12-triaza-2-chloro-8-butyl-S-cyclohexylmethyl-4hydroxy-15,15-dimethyl-ll-trimethylsilylmethyl-14-oxa-7, 10,13-trioxohexadecanoic acid-butylamide.
(2R,4S,SS,8S,11R)-6,9,12-triaza-8-butyl-5-cyclohexylmethyl-4-hydroxy-2,15, 15-trimethyl-ll-trimethylsilylmethyl-14-oxa-7,10,13trioxo-hexadecanoic acid-butylamide.
(2R,4S,5S,8S,11R)-6,9,12-triaza-11-trimethylsilylmethyl-2-(E-2butenyl)-5eyclohexylmethyl-8-butyl-4-hydroxy-7,10,13-trioxo-15, 18,21,24tetraoxapentacosanthionoic acid-butylamide.
(2R,4S,SS,8S,11R)-6,9,12-triazall-trimethylsilylmethyl-2-(E-2butenyl)-5cyclohexylmethyl-8-butyl-4-hydroxy-7,10,13-trioxo-15, 18,21,24-tetraoxapentacosanoic acid-butylamide.
(2R,4S,5S,8S,11R)-6,9,12-triaza-2-(2-E-butenyl)-5-cyclohexylmethyl-4hydroxy-8-(4-imidazolyl)-methyl-ll-trimethylsilylmethyl14,17,20,23tetraoxa-7,10-dioxo-13-thioxo-tetracosanoic acidbutylamide.
(2R,4S,5S,8S,11R)-6,9,12-triaza-11-trimethylsilylmethyl-2-chloro5cyclohexylmethyl-8-butyl-4-hydroxy-7,10,13-trioxo-15,18,21,24tetraoxapentacosanoic acid-butylamide.
1 1 100-7250 (3R,4S,7S,10R)-5,8,11-triaza-7-butyl-4-eyclohexylmethyl-2,2-difluoro-3hydroxy-10-trimethylsilylmethyl-13-oxa-6,9-dioxo-14(4-pyridyl)-12-thioxotetradecanoic acid-isobutylamide.
(3S,4S,7S,10R)-5,8,11,13-tetraaza-7-butyl-4-cyclohexylmethyl-3hydroxy-10trimethylsilylmethyl-16-(4-morpholinyl)-6,9-dioxo-12thioxo-hexadecanoyl(L)-leucine-a.-picolylamide.
(4S,7S,10R)-5,8,11-triaza-7-butyl-4-eyclohexylmethyl-2,2-difluoro-10trimethylsilylmethyl-13-oxa-3,6,9-trioxo-14-(4-pyridyl)12-thioxotetradecanoic acid-isobutylamide.
(3R,4S,7S,10R)-.5y8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2difluoro-3hydroxy-19-nicotinoyl-10-trimethylsilylmethyl-13, 16,19-trioxa-6,9-dioxo12-thioxo-nonadecanoic acid-isobutylamide.
(4S,7S,IOR)-5,8,11triaza-7-butyl-4-eyclohexylmethyl-2,2-difluoro-19nicotinoyl-10-trimethylsilylmethyl-13,16,19-trioxa-3,6, 9-trioxo-12thioxo-nonadecanoic acid-isobutylamide.
(3R,4S,7S,10R)-5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-3hydroxy-19-(3,4,5-trimethoxyphenyl)acetyl-10-trimethylsilylmethyl-13,16, 19-trioxa-6,9-dioxo-12-thioxo-nonadecanoic acid isobutylamide.
(4S,7S,10R)5,8,11-triaza-7-butyl-4-eyclohexylmethyl-2,2-difluoro-19-(3,4, 5-trimethoxyphenyl)acetyl-10-trimethylsilylmethyl-13, 16,19trioxa-3,6,9trioxo-12-thioxo-nonadecanoic acid-isobutylamide.
(4R,SS,8S,11R)-6,9,12-triaza-8-butyl-5-cyclohexylmethyl-1,1,1,2, 2,3,3heptafluoro-4-hydroxy-12-tert.-butyloxycarbonyl-ll-trimethylsilylmethyl-7, 10-dioxododecanoic acid-isobutylamide.
b 1 100-7250 (4R,5S,8S,11R)-6,9,12-triaza-8-butyl-5-cyclohexylmethyl-1,1,1,2, 2,3,3heptafluoro-4-hydroxy-11-trimethylsilylmethyl-14,17,20-trioxa-7,10-dioxo13-thioxo-20-nicotinoyl-eicosanoic acid-isobutylamide.
(4R,5S,8S,11R)-6,9,12-triaza-8-butyl-S-cyclohexylmethyl-1,1,1,2, 2,3,3,heptafluoro-4-hydroxy-11-trimethylsilylmethyl-15,18,21,24tetraoxa-7,10,13trioxo-pentacosanoic acid-isobutylamide.
(SS,8S,11R)-6,9,12-triaza-8-butyl-5-cyclohexylmethyl-1,1,1,2,2,3, 3heptafluoro-11-trimethylsilylmethyl-15,18,21,24-tetraoxa-4,7, 10,13tetraoxo-pentacosanoic acid-isobutylamide.
(2R,4S,SS,8S,11R)-6,9,12-triaza-11-trimethylsilylmethyl-2-(E-2butenyl)-5cyclohexylmethyl-8-butyl-4-hydroxy-13-thioxo-7,10-dioxo-15,18,21,24tetraoxa-pentacosanthionoic acid-butylamide.
(2S,6S,7S,10S,13R)-3,8,11,14-tetraaza-10-butyl-7-cyclohexylmethyl-6hydroxy-2-isobutyl-17,17-dimethyl-13-trimethylsilylmethyl-16-oxa-4,9,12, 15-tetraoxo-oktadecathionocarbonic acid-a-picolylamide.
(2S,6S,7S,10S,13R)-3,8,11,14-tetraaza-10-butyl-7-cyclohexylmethyl -6hydroxy-2-isobutyl-13-trimethylsilylmethyl-17,20,23,26-tetraoxa-4,9,12trioxo-15-thioxo-heptacosanthionocarbonic acid-m-picolylamide.
(2S,6S,7S,10S,13R)-3,8,11,14-tetraaza-10-butyl-7-cyclohexylmethyl -6hydroxy-2-isobutyl-13-trimethylsilylmethyl-17,20,23,26,29,32, 35,38tetraoxa-4,9,12-trioxo-15-thioxo-nonatriacontanthionoic-(xpicolylamide.
g 100-7250 (3S,4S,7S,10R)-5,8,11,14-tetraaza-7-butyl-4-cyclohexylmethyl-3hydroxy-13isobutyl-10-trimethylsilylmethyl-14-tert.-butyloxycarbonyl-6,9-dioxotetradecanoyl-(L)-leucine-a.-picolylamide.
(3S,4S,7S,10R)-5,8,11,14-tetraaza-7-butyl-4-eyclohexylmethyl-3hydroxy-13isobutyl-10-trimethylsilylmethyl-6,9-dioxotetradecanoyl-(L)-leucine-xxpicolylamide.
il A J 1 11 100-7250
5. Process for the production of compounds of formula I, characterised in that a) a compound of formula II 0 H /", ' B-OH A-N-1::: c4 "1,-,^ Si (R,)3 II wherein A, B and R, possess the definitions given in claim 2, is reacted with a compound of formula H-D, wherein D possesses the definitions given in claim 2, or b) a compound of formula III H2N Si (R,) 3 B-D III wherein R,, B and D possess the definitions given in claim 2, is reacted with a compound of formula A-OH, wherein A possesses the definitions given in claim 2 or c) a compound of formula I, wherein R10 is a hydroxyl radical and R,, is hydrogen, is oxidised to a compound of formula I, wherein Rjo and R,, together form an oxo group.
100-7250
6. A compound according to anyone of claims 1 to 4 for use as a medicament.
A compound according to anyone of claims 1 to 4 for use as a renin inhibitor.
8. A compound according to anyone of claims 1 to 4 for use against hypertension and cardiac insufficiency.
9. A compound according to anyone of claims 1 to 4 for use against hypertension and cardiac insufficiency.
10. Pharmaceutical compositions containing a compound according to claims 1 to 4 in pharmaceutically acceptable form in association with pharmacologically acceptable adjuvants and/or diluents -
11. Use of hydrophilic renin inhibitors according to claims 1 to 4 for the preparation of medicaments for the treatment of hypertension and cardiac insufficiency.
12. Use of hydrophilic renin inhibitors according to claims 1 to 4 for the preparation of medicaments for the treatment of diseases caused by retroviruses.
-i 19 100-7250 1 Use of the pharmaceutical composition according to claim 10 for the preparation of medicaments for the treatment of hypertension and consestive heart failure.
14. Use of the pharmaceutical composition according to claim 10 for the preparation of medicaments for the treatment of diseases caused by retroviruses.
15. A compound of anyone of claims 1 to 4 for use as a pharmaceutical.
Published 1989 at The Patent Office. State House. 66 711-hg. Ho'borr_. LondorWCIR4TP PurLherc0P'esxnkv be obtamedfrorn7"Irie Patent Office Sales Branch. St Mary Crkv. Orpington. Kent BP.5 3RL. Printed by Mu3taplex techinques Itd, St, Mary Cray, Kent. Con. 1-87
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3742474 | 1987-12-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB8828982D0 GB8828982D0 (en) | 1989-01-25 |
| GB2212158A true GB2212158A (en) | 1989-07-19 |
Family
ID=6342652
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8828982A Withdrawn GB2212158A (en) | 1987-12-15 | 1988-12-12 | Trialkylsilymethyl-substituted peptides; renin inhibitors |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPH01199983A (en) |
| CH (1) | CH677877A5 (en) |
| FR (1) | FR2624513A1 (en) |
| GB (1) | GB2212158A (en) |
| IT (1) | IT1235166B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5559140A (en) * | 1991-01-02 | 1996-09-24 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
| US5716973A (en) * | 1991-01-02 | 1998-02-10 | Merrell Pharmaceuticals Inc. | Anti-viral compounds |
| US5717093A (en) * | 1993-07-08 | 1998-02-10 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
| US5831094A (en) * | 1993-09-09 | 1998-11-03 | Merrell Pharamceuticals Inc. | Difluoro statone antiviral analogs |
| US6114380A (en) * | 1995-12-18 | 2000-09-05 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
| EP2261662A1 (en) * | 2009-06-10 | 2010-12-15 | Forschungszentrum Borstel Leibniz-Zentrum für Medizin und Biowissenschaften | Novel synthetic blocking reagents |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5220047A (en) * | 1990-09-17 | 1993-06-15 | Union Carbide Chemicals & Plastics Technology Corporation | Carbamate silicon compounds as latent coupling agents and process for preparation and use |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU573735B2 (en) * | 1983-02-07 | 1988-06-23 | Aktiebolaget Hassle | Peptide analogue enzyme inhibitors |
-
1988
- 1988-12-12 GB GB8828982A patent/GB2212158A/en not_active Withdrawn
- 1988-12-12 FR FR8816432A patent/FR2624513A1/en not_active Withdrawn
- 1988-12-13 IT IT8848638A patent/IT1235166B/en active
- 1988-12-13 CH CH4597/88A patent/CH677877A5/de not_active IP Right Cessation
- 1988-12-14 JP JP63316097A patent/JPH01199983A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5559140A (en) * | 1991-01-02 | 1996-09-24 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
| US5716973A (en) * | 1991-01-02 | 1998-02-10 | Merrell Pharmaceuticals Inc. | Anti-viral compounds |
| US5717093A (en) * | 1993-07-08 | 1998-02-10 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
| US5831094A (en) * | 1993-09-09 | 1998-11-03 | Merrell Pharamceuticals Inc. | Difluoro statone antiviral analogs |
| US5948778A (en) * | 1993-09-09 | 1999-09-07 | Merrel Pharmaceuticals Inc. | Difluoro statone antiviral analogs |
| US6114380A (en) * | 1995-12-18 | 2000-09-05 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
| EP2261662A1 (en) * | 2009-06-10 | 2010-12-15 | Forschungszentrum Borstel Leibniz-Zentrum für Medizin und Biowissenschaften | Novel synthetic blocking reagents |
| US8501199B2 (en) | 2009-06-10 | 2013-08-06 | Forschungszentrum Borstel | Synthetic blocking reagents |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2624513A1 (en) | 1989-06-16 |
| IT8848638A0 (en) | 1988-12-13 |
| JPH01199983A (en) | 1989-08-11 |
| CH677877A5 (en) | 1991-07-15 |
| GB8828982D0 (en) | 1989-01-25 |
| IT1235166B (en) | 1992-06-22 |
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| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |