NO177351B - Analogous Process for the Preparation of Renin-Inhibiting Aminodiol Derivatives - Google Patents
Analogous Process for the Preparation of Renin-Inhibiting Aminodiol Derivatives Download PDFInfo
- Publication number
- NO177351B NO177351B NO894663A NO894663A NO177351B NO 177351 B NO177351 B NO 177351B NO 894663 A NO894663 A NO 894663A NO 894663 A NO894663 A NO 894663A NO 177351 B NO177351 B NO 177351B
- Authority
- NO
- Norway
- Prior art keywords
- amino
- cyclohexyl
- pyridine
- residue
- fab
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 28
- 238000002360 preparation method Methods 0.000 title claims description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 53
- -1 methoxy, 2-naphthylmethyl Chemical group 0.000 claims description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 239000007858 starting material Substances 0.000 claims description 7
- 239000012634 fragment Substances 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 210000004899 c-terminal region Anatomy 0.000 claims description 3
- 125000000524 functional group Chemical group 0.000 claims description 3
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
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- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- 125000003275 alpha amino acid group Chemical group 0.000 abstract 1
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Classifications
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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
- C07K5/08—Tripeptides
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—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-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- 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
-
- 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
- C07K5/0207—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)4-C(=0), e.g. 'isosters', replacing two amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyridine Compounds (AREA)
- Pyrrole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Foreliggende oppfinnelse vedrører en analogifremgangsmåte for fremstilling av terapeutisk aktive renin-hemmende aminodiolderivater. The present invention relates to an analogue method for the production of therapeutically active renin-inhibiting aminodiol derivatives.
Fra de europeiske patentene EP-A 184 855, 189 203, 202 571, 229 667, 230 266 samt 237 202 og den internasjonale patent-søknaden WO 87/05302 er aminodiolderivater med renin-hemmende virkning kjent. From the European patents EP-A 184 855, 189 203, 202 571, 229 667, 230 266 and 237 202 and the international patent application WO 87/05302, aminodiol derivatives with renin-inhibiting action are known.
Videre er renin-hemmende aminodiol-derivat beskrevet i Biochem. Biophys. Res. Commun. 132, 155 - 161 (1985), i Biochem. Biophys. Res. Commun. 146. 959 - 963 (1987), i FEBS Lett. 230, 38 - 42 (1988) og i J. Med. Chem. 30, 976 - 982 (1987 ). Furthermore, the renin-inhibiting aminodiol derivative is described in Biochem. Biophys. Res. Commun. 132, 155-161 (1985), in Biochem. Biophys. Res. Commun. 146. 959 - 963 (1987), in FEBS Lett. 230, 38 - 42 (1988) and in J. Med. Chem. 30, 976-982 (1987).
Det ble nå overraskende oppdaget at slike forbindelser, som er forskjellige i forhold til de som er beskrevet i de nevnte dokumentene, idet de ved den C-terminale enden bærer en heterocyklus, er meget virksomme renin-hemmere in vitro og in vivo og som i forhold til de kjente forbindelsene utviser fordelaktige egenskaper. It was now surprisingly discovered that such compounds, which are different from those described in the aforementioned documents, in that they carry a heterocycle at the C-terminal end, are very effective renin inhibitors in vitro and in vivo and that in compared to the known compounds exhibit advantageous properties.
Foreliggende oppfinnelse vedrører følgelig en analogifremgangsmåte for fremstilling av en terapeutisk aktiv forbindelse med formel I The present invention therefore relates to an analogue method for the production of a therapeutically active compound of formula I
hvor A er en rest med formel II where A is a residue of formula II
hvor where
<R5> er fenyl eller benzyl, som eventuelt kan være substituert <R5> is phenyl or benzyl, which may optionally be substituted
med metoksy, 2-naftylmetyl, 2-fluorbenzyl eller 2-thienyl E er en CH2~gruppe eller en -NH-gruppe, with methoxy, 2-naphthylmethyl, 2-fluorobenzyl or 2-thienyl E is a CH2~ group or an -NH group,
G er en rest fra gruppen SO2, CO eller CS eller betyr en G is a residue from the group SO2, CO or CS or means one
direkte binding, direct binding,
R<6> er (C1-C7 )-alkyl, (C3-C7)-cykloalkyl, 1-piperazinyl, som eventuelt kan være substituert med amino, ( C^- C^)-alkoksy, R<6> is (C1-C7 )-alkyl, (C3-C7)-cycloalkyl, 1-piperazinyl, which may optionally be substituted with amino, (C^-C^)-alkoxy,
4-morfolinyl, 1-naftyl, 2-fluorfenyl eller 3-pyridylmetyl, B er en N-terminal med A og C-terminal med -NH- med formel I 4-morpholinyl, 1-naphthyl, 2-fluorophenyl or 3-pyridylmethyl, B is N-terminal with A and C-terminal with -NH- of formula I
koblet rest av en aminosyre fra rekken histidin, norvalin linked residue of an amino acid from the series histidine, norvaline
eller norleucin, or norleucine,
R<2> er isopropyl eller sykloheksyl, R<2> is isopropyl or cyclohexyl,
D er en 2-pyridylrest, en 2-imidazolyl-rest, som er substituert med metyl eller en 2-oxazolinyl-rest, som er D is a 2-pyridyl residue, a 2-imidazolyl residue, which is substituted with methyl or a 2-oxazolinyl residue, which is
substituert med metyl og propyl, substituted with methyl and propyl,
samt fysiologiske tålbare salter, kjennetegnet ved at man kobler et fragment med endestående karboksylgrupper eller reaktive deriavter derav med et tilsvarende fragment med fri aminogruppe, avspalter eventuelt for beskyttelse av ytterligere funksjonelle grupper (en) temporær innført beskyt-telsesgruppe(er) og overfører den på denne oppnådde forbindelsen eventuelt til deres fysiologiske tålbare salt. as well as physiologically tolerable salts, characterized by connecting a fragment with terminal carboxyl groups or reactive derivatives thereof with a corresponding fragment with a free amino group, possibly cleaving off (a) temporarily introduced protecting group(s) for the protection of further functional groups and transferring it onto this obtained the compound eventually to their physiologically tolerable salt.
Chiralitetssentrene i forbindelsene med formel I kan oppvise R-, S- eller R,S-konfigurasjon. The centers of chirality in the compounds of formula I may exhibit R, S or R,S configuration.
Alkyl kan være lineær eller forgrenet. Tilsvarende gjelder for rester avledet derav, som f.eks. alkoksy. Alkyl can be linear or branched. The same applies to residues derived from it, such as e.g. Alkoxy.
Under cykloalkyl forstås også alkylsubstituerte rester, som f.eks. 4-metylcykloheksyl eller 2,3-dimetylcyklopentyl. Cycloalkyl also means alkyl-substituted residues, such as e.g. 4-methylcyclohexyl or 2,3-dimethylcyclopentyl.
Under salter av forbindelsene med formel I forstås spesielt farmasøytisk anvendbare eller ikke-toksiske salter. By salts of the compounds of formula I is meant particularly pharmaceutically usable or non-toxic salts.
Slike salter blir eksempelvis dannet fra forbindelser med formel I, som inneholder sure grupper, f.eks. karboksy, med alkali- eller jordalkalimetaller, som Na, K, Mg og Ca, samt med fysiologisk tålbare organiske aminer, som f.eks. trietylamin og tri-(2-hydroksy-etyl)-amin. Such salts are, for example, formed from compounds of formula I, which contain acidic groups, e.g. carboxy, with alkali or alkaline earth metals, such as Na, K, Mg and Ca, as well as with physiologically tolerable organic amines, such as e.g. triethylamine and tri-(2-hydroxyethyl)amine.
Forbindelser med formel I som inneholder basiske grupper, f.eks. en aminogruppe, danner salter med uorganiske syrer, som f.eks. saltsyre, svovelsyre eller fosforsyre og med organiske karboksyl- eller sulfonsyrer, som f.eks. eddiksyre, sitronsyre, benzosyre, maleinsyre, fumarsyre, vinsyre og p-toluensulfonsyre. Compounds of formula I containing basic groups, e.g. an amino group, forms salts with inorganic acids, such as e.g. hydrochloric acid, sulfuric acid or phosphoric acid and with organic carboxylic or sulphonic acids, such as e.g. acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid.
Fragmenter av en forbindelse med formel I med en endestående karboksylgruppe har de nedenfornevnte formlene Illa og IIIb: Fragments of a compound of formula I with a terminal carboxyl group have the formulas Illa and IIIb below:
Fragmenter av en forbindelse med formel I med en endestående aminogruppe har de nedenfornevnte formlene IVa og IVb: Fragments of a compound of formula I with a terminal amino group have the formulas IVa and IVb below:
Metoder som er egnede for fremstilling av en amidbinding er f.eks. beskrevet i Houben-Weyl, Methoden der organischen Chemie, bind 15/2; Bodanszky et al., Peptide synthesis, 2. utg. (Wiley & Sons, New York 1976) eller Gross, Meienhofer, The Peptides. Analysis, synthesis, biology (Academic Press, New York 1979). Følgende fremgangsmåte blir fortrinnsvis anvendt: Aktivestermetode med N-hydroksy-succinimid som esterkomponenter, kobling med et karbodiimid som dicykloheksylkarbodiimid eller med propanfosfonsyreanhydrid og blandet-anhydrid-metoden med pivaloylklorid. Methods that are suitable for producing an amide bond are e.g. described in Houben-Weyl, Methoden der organischen Chemie, volume 15/2; Bodanszky et al., Peptide synthesis, 2nd ed. (Wiley & Sons, New York 1976) or Gross, Meienhofer, The Peptides. Analysis, synthesis, biology (Academic Press, New York 1979). The following method is preferably used: active ester method with N-hydroxysuccinimide as ester components, coupling with a carbodiimide such as dicyclohexylcarbodiimide or with propanephosphonic anhydride and the mixed-anhydride method with pivaloyl chloride.
Fremstilling av de anvendte optisk aktive aminodiolene med formel V anvendt som utgangsforbindelse Preparation of the used optically active aminodiols of formula V used as starting compound
kan eksempelvis i det tilfellet hvor n er 2 foregå ved omsetning av en forbindelse med formel VI med en forbindelse med formel VII etter deprotoneringen derav. can, for example, in the case where n is 2 take place by reaction of a compound of formula VI with a compound of formula VII after its deprotonation.
I formel VI betyr P^ en uretanbeskyttelsesgruppe, fortrinnsvis N-tert.-butoksykarbonyl- og benzyloksykarbonyl. In formula VI, P₁ means a urethane protecting group, preferably N-tert-butoxycarbonyl and benzyloxycarbonyl.
Som baser for deprotonering av heteroarylalkylkomponenten kan alkalimetallalkoholater, som kalium-O-tert.-butylat, natriummetylat, alkalimetallhydrider, som natrium- eller kaliumhydrid, metallorganiske baser, som n-butyllitium, s-butyllitium, metyllitium eller fenyllitium, natriumamid samt alkalimetallsalter av organiske nitrogenbaser, som litiiim-diisopropylamid anvendes. As bases for deprotonation of the heteroarylalkyl component, alkali metal alcoholates, such as potassium O-tert.-butylate, sodium methylate, alkali metal hydrides, such as sodium or potassium hydride, organometallic bases, such as n-butyllithium, s-butyllithium, methyllithium or phenyllithium, sodium amide and alkali metal salts of organic nitrogen bases such as lithium diisopropylamide are used.
Addisjon av forbindelsene med formel VII på de nevnte N-beskyttede epoksydene foregår i et overfor basen inert oppløsningsmiddel som eter, THF, toluen, DMF,. DMSO eller dimetoksyetan. Addition of the compounds of formula VII to the aforementioned N-protected epoxides takes place in a base-inert solvent such as ether, THF, toluene, DMF. DMSO or dimethoxyethane.
Forbindelser med formel VI er kjent fra EP-A 189 203. Compounds of formula VI are known from EP-A 189 203.
Videre kan de forskjellige isomerene av forbindelser med formel V bli fremstilt ifølge skjema 1 vist nedenfor: Furthermore, the various isomers of compounds of formula V can be prepared according to scheme 1 shown below:
Dersom den valgte synteseveien fører til diastereomerer med hensyn på OR^ Qg or^ bærende sentrene, kan disse separeres på i seg selv kjent måte, eksempelvis ved fraksjonert krystallisasjon eller ved kromatografi. Overprøving av diastereomer-renheten foregår ved hjelp av HPLC og enantiomerrenheten kan overprøves på kjent måte ved overprøving i Mosher-derivater (H. S. Mosher et al., J. Org. Chem. 34, 2543 (1969)). If the chosen synthesis route leads to diastereomers with regard to the OR^ Qg or^ bearing centers, these can be separated in a manner known per se, for example by fractional crystallization or by chromatography. Testing of the diastereomeric purity takes place by means of HPLC and the enantiomeric purity can be tested in a known manner by testing in Mosher derivatives (H. S. Mosher et al., J. Org. Chem. 34, 2543 (1969)).
I en oppnåelig forbindelse med formel I kan man oksidere en tiogruppe til en sulfinyl- eller sulfonylgruppe eller en sulfinylgruppe til en sulfonylgruppe. In an obtainable compound of formula I, a thio group can be oxidized to a sulfinyl or sulfonyl group or a sulfinyl group to a sulfonyl group.
Oksidasjonen til sulfonylgruppen kan bli gjennomført ved hjelp av de fleste vanlige oksidasjonsmidlene. Man anvender fortrinnsvis slike oksidasjonsmidler som oksiderer tiogruppen eller sulfinylgruppen selektivt i nærvær av andre funksjonelle grupper av forbindelsen med formel I, f.eks. amid-funksjonen og hydroksygruppen, eksempelvis aromatiske eller alifatiske peroksykarboksylsyrer, f.eks. perbenzosyre, monoperftalsyre, m-klorperbenzosyre, pereddiksyre, permaur-syre eller trifluorpereddiksyre. The oxidation to the sulfonyl group can be carried out using most common oxidizing agents. Such oxidizing agents are preferably used which oxidize the thio group or the sulfinyl group selectively in the presence of other functional groups of the compound of formula I, e.g. the amide function and the hydroxy group, for example aromatic or aliphatic peroxycarboxylic acids, e.g. perbenzoic acid, monoperphthalic acid, m-chloroperbenzoic acid, peracetic acid, permauric acid or trifluoroperacetic acid.
De for fremstilling av forbindelser med formel I nødvendige for- og etteroperasjoner som innføring og avspaltning av beskyttelsesgrupper er kjent i litteraturen og er f.eks. beskrevet i T.W. Greene, "protective Groups in Organic Synthesis". Salter av forbindelser med formel I med salt-dannende grupper blir fremstilt på kjent måte, idet man f.eks. omsetter en forbindelse med formel I med en basis-gruppe med en støkiometrisk mengde av en egnet syre. Stereoisomerblandinger, spesielt diastereomerblandinger, som oppstår ved anvendelse av de rasemiske syrene A eller B kan på kjent måte bli separert ved fraksjonert krystallisasjon eller ved kromatografi. The pre- and post-operations necessary for the preparation of compounds of formula I, such as the introduction and removal of protective groups, are known in the literature and are e.g. described in T.W. Greene, "Protective Groups in Organic Synthesis". Salts of compounds of formula I with salt-forming groups are prepared in a known manner, e.g. reacts a compound of formula I with a base group with a stoichiometric amount of a suitable acid. Mixtures of stereoisomers, in particular mixtures of diastereomers, which occur when the racemic acids A or B are used can be separated in a known manner by fractional crystallization or by chromatography.
Forbindelsene med formel I fremstilt ifølge oppfinnelsen viser enzymhemmende egenskaper; de hemmer spesielt virkningen av det naturlige enzymet renin. Renin er et protolyttisk enzym fra aspartyl-proteaseklassen som på grunn av forskjellige stimuli (volumdeplesjon, natriummangel, p-reseptor-stimulering) av de jukstaglomulære cellene til nyrene blir sezernert i blodomløpet. Dette blir gjennom "angiotensin-omdannende enzym" (ACE) overført til Angiotensin II. Angiotensin II spiller en vesentlig rolle ved blodtrykks-regulering da det direkte øker blodtrykket ved vene-kontraksjon. Det stimulerer først utskillingen av aldosteron fra binyrene og forhøyer på denne måten over hemmingen av natrium-utskillingen det ekstracellulære væskevolumet, som innebærer en stigning av blodtrykket. Hemming av den enzymatiske aktiviteten av renin fører til en mindre dannelse av Angiotensin I som medfører en forminsket dannelse av Angiotensin II. Senkingen av konsentrasjonen av dette aktive peptidhormonet er en direkte årsak for den blodtrykkssenkende virkningen av renin-hemmere. The compounds of formula I prepared according to the invention show enzyme-inhibiting properties; they specifically inhibit the action of the natural enzyme renin. Renin is a protolytic enzyme from the aspartyl protease class which, due to various stimuli (volume depletion, sodium deficiency, p-receptor stimulation) by the juxtaglomular cells of the kidneys is secreted into the bloodstream. This is transferred through "angiotensin-converting enzyme" (ACE) to Angiotensin II. Angiotensin II plays an important role in blood pressure regulation as it directly increases blood pressure during vein contraction. It first stimulates the secretion of aldosterone from the adrenal glands and in this way, over the inhibition of sodium excretion, increases the extracellular fluid volume, which entails a rise in blood pressure. Inhibition of the enzymatic activity of renin leads to a smaller formation of Angiotensin I which leads to a reduced formation of Angiotensin II. The lowering of the concentration of this active peptide hormone is a direct cause of the blood pressure-lowering effect of renin inhibitors.
Virkningen av renin-hemmere kan overprøves ved in-vitro-tester. Her blir forminskningen av dannelse av Angiotensin I målt i forskjellige systemer (humanplasma, svine-renin). Her blir f.eks. humanplasma, som både inneholder renin og angiotensinogen, inkubert ved 37° C med forbindelsen som skal testes. Til slutt blir konsentrasjonen av de i løpet av inkubasjonen dannede Angiotensin I målt med en radio-immunoanalyse. De i foreliggende oppfinnelse beskrevne forbindelser med generell formel I viser i anvendte in-vitro-tester hemmevirkninger ved konsentrasjoner på omtrent IO"<5> til 10_10 mol/l. The effect of renin inhibitors can be verified by in vitro tests. Here, the reduction in the formation of Angiotensin I is measured in different systems (human plasma, pig renin). Here, e.g. human plasma, containing both renin and angiotensinogen, incubated at 37°C with the compound to be tested. Finally, the concentration of the Angiotensin I formed during the incubation is measured with a radio-immunoassay. The compounds of general formula I described in the present invention show inhibitory effects in applied in vitro tests at concentrations of approximately 10"<5> to 10_10 mol/l.
Renin-hemmere fører til senkning av blodtrykket i dyr som er utarmet på salt. På grunn av at menneskelig renin er forskjellig fra renin i andre arter blir primater anvendt for in-vivo-test av renin-hemmerene (marmosets, rhesus-aper). Primat-renin og human-renin har stort sett homologe sek-venser. Ved i. v. injeksjon av furosemid blir en endogen renin-utskilling stimulert. Til slutt blir testforbindelsene gjennom kontinuerlig infusjon gjennom engangsintravenøse bolusdoser, gjennom intraduodenale eller gjennom perorale doser administrert og deres virkning på blodtrykket og hjertefrekvensen blir målt. Forbindelsene fremstilt ifølge foreliggende oppfinnelse er herved virksomme i et doserings-område på omtrent 0,1-5 mg/kg i. v. henholdsvis 1-50 mg/kg i.d. eller p.o. De i foreliggende oppfinnelse beskrevne forbindelsene med generell formel I kan anvendes som antihypertensive midler samt for behandling av hjerte-insuffisiens. Renin inhibitors lead to lowering of blood pressure in salt-depleted animals. Because human renin is different from renin in other species, primates are used for in-vivo testing of the renin inhibitors (marmosets, rhesus monkeys). Primate renin and human renin have largely homologous sequences. When furosemide is injected i.v., endogenous renin secretion is stimulated. Finally, the test compounds are administered by continuous infusion through single intravenous bolus doses, through intraduodenal or through oral doses and their effect on blood pressure and heart rate is measured. The compounds produced according to the present invention are thereby effective in a dosage range of approximately 0.1-5 mg/kg i.v., respectively 1-50 mg/kg i.d. or p.o. The compounds of general formula I described in the present invention can be used as antihypertensive agents as well as for the treatment of heart insufficiency.
Farmasøytiske preparater inneholder en virksom mengde av det virksomme stoffet med formel I sammen med et uorganisk eller organisk farmasøytisk anvendbart bærerstoff. Anvendingen kan foregå intranasalt, intravenøst, subkutant eller peroralt. Doseringen av det virksomme stoffet avhenger av den varmblo-dige arten, kroppsvekten, alderen og av applikasjonsmåten. Pharmaceutical preparations contain an effective amount of the active substance of formula I together with an inorganic or organic pharmaceutically usable carrier substance. The application can take place intranasally, intravenously, subcutaneously or orally. The dosage of the active substance depends on the warm-blooded species, body weight, age and the method of application.
For en oral anvendelsesform blir de aktive forbindelsene blandet med de dertil egnede tilsetningsstoffene som bærerstoffer, stabilisatorer eller inerte fortynningsmidler og brakt ifølge vanlige metoder til egnede administrerings-former, som tabletter drageer, stikkapsler, vandige, alkoholiske eller oljeholdige suspensjoner eller vandige, alkoholiske eller oljeholdige oppløsninger. Som Inert bærer kan f.eks. gummi arabikum, magensia, magnesiumkarbonat, kaliumfosfat, melkesukker, glukose, magnesiumstearylfumarat eller stivelse, spesielt maisstivelse anvendes. Tilberednin-gen kan foregå både som tørr- og fuktgranulat. Som oljeholdige bærerstoffer eller oppløsningsmidler kommer oljer fra planter eller dyr i betraktning, som solsikkeolje eller levertran. For subkutan eller intravenøs applikasjon blir de aktive forbindelsene eller de fysiologisk tålbare saltene derav, om ønskelig, med den dertil vanlige substansen som oppløsningsformidler, emulgatorer eller ytterligere hjelpe-stoffer brakt i oppløsninger, suspensjoner eller emulsjoner. Som oppløsningsmiddel kan f.eks. nevnes: Vann, fysiologiske koksaltoppløsninger eller alkoholer, f.eks. etanol, propan-diol eller glyserin, og også sukkeroppløsninger som glukose-eller mannittoppløsninger men også en blanding av de forskjellige nevnte oppløsningsmidlene. For an oral application form, the active compounds are mixed with the appropriate additives such as carriers, stabilizers or inert diluents and brought according to usual methods into suitable administration forms, such as tablets, dragees, suppositories, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily suspensions resolutions. As Inert carrier can e.g. gum arabic, magnesia, magnesium carbonate, potassium phosphate, milk sugar, glucose, magnesium stearyl fumarate or starch, especially corn starch are used. The preparation can take place both as dry and wet granules. As oily carriers or solvents, oils from plants or animals come into consideration, such as sunflower oil or cod liver oil. For subcutaneous or intravenous application, the active compounds or the physiologically tolerable salts thereof, if desired, are brought into solutions, suspensions or emulsions with the usual substance such as solubilizers, emulsifiers or further auxiliaries. As a solvent, e.g. mentioned: Water, physiological saline solutions or alcohols, e.g. ethanol, propane-diol or glycerin, and also sugar solutions such as glucose or mannitol solutions but also a mixture of the various solvents mentioned.
Fortegnelse over anvendte forkortelser: List of abbreviations used:
Forkortelsene anvendt for aminosyrene tilsvarer de i peptidkjemien vanlige tre bokstavkodene som f.eks. er beskrevet i Europ. J. Biochem 138, 9-37 (1984). Dersom ikke annet uttrykkelig er angitt dreier det seg alltid om aminosyrer med L-konfigurasjon. The abbreviations used for the amino acids correspond to the three letter codes common in peptide chemistry, e.g. is described in Europ. J. Biochem 138, 9-37 (1984). If not expressly stated otherwise, it is always about amino acids with L-configuration.
Eksemplene nedenfor skal forklare foreliggende oppfinnelse. The examples below shall explain the present invention.
Eksempel 1 Example 1
a) 2-[(3S,4R,5S)-5-tert.-butoksykarbonylamino-3,4-dihydroksy-6-cykloheksyl-heksyl]-pyridin 93 mg (1 mmol) 2-picolin i 10 ml THF blir omsatt ved -78° C med 1,4 ml (1 mmol) n-buli. Etter oppvarming ved romtemperatur blir dette omrørt i 30 minutter og deretter avkjølt ved-40°C. 1 mmol (2RS,3R,4S)-3-tert.-butyldimetylsilyloksy-4-tert. -butoksykarbonylamino-5-cykloheksyl-l,2-oksopentan (kjent fra EP-A 189 203, eksempel 6) blir tilsatt (løst opp i 5 ml THF). Etter 10 timer ved romtemperatur blir dette fortynnet med vann og ekstrahert med MTB. Råproduktet (0,4 g) blir løst i THF og rørt med 5 ml av en 1 M oppløsning av tetrabutylammoniumf luorid i THF i 1 time ved 0°C. Etter fortynning med vann og ekstrahering med eddiksyre oppnår man 0,15 g av (3S,4R,5S)-isomeren [MS (FAB): 391 (M + 1)] og 0,12 g av (3S,4S,5S)-isomeren [MS (FAB): 391 (M + 1)]. a) 2-[(3S,4R,5S)-5-tert.-butoxycarbonylamino-3,4-dihydroxy-6-cyclohexyl-hexyl]-pyridine 93 mg (1 mmol) of 2-picoline in 10 ml of THF are reacted at -78° C with 1.4 ml (1 mmol) n-buli. After heating at room temperature, this is stirred for 30 minutes and then cooled at -40°C. 1 mmol (2RS,3R,4S)-3-tert-butyldimethylsilyloxy-4-tert. -butoxycarbonylamino-5-cyclohexyl-1,2-oxopentane (known from EP-A 189 203, example 6) is added (dissolved in 5 ml of THF). After 10 hours at room temperature, this is diluted with water and extracted with MTB. The crude product (0.4 g) is dissolved in THF and stirred with 5 ml of a 1 M solution of tetrabutylammonium fluoride in THF for 1 hour at 0°C. After dilution with water and extraction with acetic acid, 0.15 g of the (3S,4R,5S) isomer is obtained [MS (FAB): 391 (M + 1)] and 0.12 g of (3S,4S,5S) -isomer [MS (FAB): 391 (M + 1)].
b ) ( 3S , 4R , 5S )-2- [N- [ I va-Phe-His (DNP )-5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl]-pyridin b) (3S, 4R, 5S)-2-[N-[Iva-Phe-His (DNP)-5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl]-pyridine
0,5 mmol av (3S,4R,5S)-isomeren i eksempel la blir rørt med 5 ml HC1 i DMF (mettet) i 2 timer. Etter inndamping i vakuum blir resten løst i 3 ml absolutt DMF. 0,5 mmol Iva-Phe-His(DNP)-0H, dicykloheksylkarbodiimid og 1-hydroksybenzotriazol blir tilsatt. Oppløsningen blir stilt inn til pH 9 med N-etylmorfolin og omrørt i 24 timer. Etter filtreringen blir dette fortynnet med EE og vasket en gang med 3$ natriumbikarbonatoppløsning, vann og mettet koksaltoppløs-ning, tørket med magnesiumsulfat og inndampet. Kromatografi på kiselgel (MeOH/CH2Cl2 =1 : 30) tilveiebringer tittelforbindelsen som gult harpiks: 0.5 mmol of the (3S,4R,5S) isomer of Example 1a is stirred with 5 ml of HCl in DMF (saturated) for 2 hours. After evaporation in vacuo, the residue is dissolved in 3 ml of absolute DMF. 0.5 mmol of Iva-Phe-His(DNP)-OH, dicyclohexylcarbodiimide and 1-hydroxybenzotriazole are added. The solution is adjusted to pH 9 with N-ethylmorpholine and stirred for 24 hours. After filtration, this is diluted with EE and washed once with 3% sodium bicarbonate solution, water and saturated sodium bicarbonate solution, dried with magnesium sulfate and evaporated. Chromatography on silica gel (MeOH/CH2Cl2 =1 : 30) affords the title compound as a yellow resin:
Rf (Si02; CH2Cl2/MeOH (10 : 1) = 0,6) Rf (SiO 2 ; CH 2 Cl 2 /MeOH (10 : 1) = 0.6)
MS (FAB): 827 (M + 1) MS (FAB): 827 (M + 1)
c ) ( 3S , 4R , 5S )-2- [N-( Iva-Phe-His )-5-amino-6-cykloheksyl-3 ,4-dihydroksy-heksyl]-pyridin c) (3S, 4R, 5S)-2-[N-(Iva-Phe-His)-5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl]-pyridine
0,1 g av forbindelsen i eksempel lb blir rørt med 30 mg tiofenol i 2 ml acetonitril i 2 timer. Etter inndamping blir det kromatografert på kiselgel med CH2Cl2/MeOH/met. NH3 (10 : 1 : 0,1). Man oppnår 60 mg av tittelforbindelsen som harpiks. 0.1 g of the compound in example 1b is stirred with 30 mg of thiophenol in 2 ml of acetonitrile for 2 hours. After evaporation, it is chromatographed on silica gel with CH2Cl2/MeOH/met. NH3 (10:1:0.1). 60 mg of the title compound is obtained as a resin.
Rf (CH2C1 : MeOH (10 : 1); Si02) : 0,05 Rf (CH 2 Cl : MeOH (10 : 1); SiO 2 ) : 0.05
MS (FAB): 661 (M + 1) MS (FAB): 661 (M + 1)
Ved anvendelse av egnede utgangsmaterialer ble følgende forbindelser fremstilt analogt med fremgangsmåten beskrevet i ovennevnte eksempler: Eksempel 2 Using suitable starting materials, the following compounds were prepared analogously to the method described in the above-mentioned examples: Example 2
( 3S,4R,5S )-2-[N-(Boc-Phe-His)-5-amino-6-cykloheksy1-3,4-dihydroksy-heksyl]-pyridin ( 3S,4R,5S )-2-[N-(Boc-Phe-His)-5-amino-6-cyclohexy1-3,4-dihydroxy-hexyl]-pyridine
MS (FAB): 677 (M + 1 ) MS (FAB): 677 (M + 1 )
Eksempel 3 Example 3
(3S,4R,5S)-2-[N-(EtOC-Phe-His)-5-amino-6-cykloheksyl-3 ,4-dihydro-heksyl]-pyridin (3S,4R,5S)-2-[N-(EtOC-Phe-His)-5-amino-6-cyclohexyl-3,4-dihydro-hexyl]-pyridine
MS (FAB) : 649 (M + 1) MS (FAB) : 649 (M + 1)
Eksempel 4 Example 4
( 3S,4R,5S)-2-[N-(Iva-Phe-Nva)-5-amino-6-cykloheksy1-3,4-dihydroksy-heksyl]-pyridin ( 3S,4R,5S )-2-[N-(Iva-Phe-Nva)-5-amino-6-cyclohexy1-3,4-dihydroxy-hexyl]-pyridine
MS (FAB): 623 (M + 1) MS (FAB): 623 (M + 1)
Eksempel 5 Example 5
(3S,4R,5S)-2-[N-(Iva-Phe-Nle)-5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl]-pyridin (3S,4R,5S)-2-[N-(Iva-Phe-Nle)-5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl]-pyridine
MS (FAB): 637 (M + 1) MS (FAB): 637 (M + 1)
Eksempel 6 Example 6
(3S,4R, 5S )-2-[N-( Iva-Phe-(NMe )-his ) -5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl]pyridin (3S,4R,5S)-2-[N-(Iva-Phe-(NMe)-his)-5-amino-6-cyclohexyl-3,4-dihydroxyhexyl]pyridine
MS (FAB): 675 (M + 1) MS (FAB): 675 (M + 1)
Eksempel 7 Example 7
a) 4(S)-cykloheksylmetyl-5(R)-[3-(2-pyridyl)-l-(R,S)-hydroksy-propyl]-2-oksazolidinon 1 mmol 2-pikolin blir omsatt med 1 mmol 4(s)-cykloheksyl-metyl-5(R)-[l(R,S)-2-oksoetyl]-2-oksazolidinon (kjent fra EP-A 189 203, eksempel 2) ifølge fremgangsmåten angitt i eksempel 1. Kromatograf i på Si02 med EE/cykloheksan (2 : 1) tilveiebringer begge diastereomerene (0,15 og 0,13 g). a) 4(S)-cyclohexylmethyl-5(R)-[3-(2-pyridyl)-1-(R,S)-hydroxy-propyl]-2-oxazolidinone 1 mmol 2-picoline is reacted with 1 mmol 4 (s)-Cyclohexyl-methyl-5(R)-[1(R,S)-2-oxoethyl]-2-oxazolidinone (known from EP-A 189 203, example 2) according to the method indicated in example 1. Chromatograph in on SiO2 with EE/cyclohexane (2 : 1) affords both diastereomers (0.15 and 0.13 g).
b) (3S,4R,5S)-2-[N-( I va-Phe-His )-5-amino-6-cykloheksyl-3 ,4-dihydroksyl-heksyl]-pyridin b) (3S,4R,5S)-2-[N-( Iva-Phe-His )-5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl]-pyridine
0,2 mmol 4(S)-cykloheksylmetyl-5-(R)-[3-(2-pyridyl-l-(S)-hydroksy-propyl]-2-oksazolidinon (eksempel 7a) blir kokt med 0,4 mmol Ba(0H)2 * 8 H20 i 4 ml dioksan og 4 ml H20 i 9 timer ved tilbakeløp. Etter fortynning med dioksan blir dette sugd av og inndampet. Råproduktet blir videre omsatt som beskrevet i eksemplene lb og lc. 0.2 mmol of 4(S)-cyclohexylmethyl-5-(R)-[3-(2-pyridyl-1-(S)-hydroxy-propyl]-2-oxazolidinone (Example 7a) is boiled with 0.4 mmol Ba(OH) 2 * 8 H 2 O in 4 ml of dioxane and 4 ml of H 2 O for 9 hours at reflux. After dilution with dioxane, this is sucked off and evaporated. The crude product is further reacted as described in examples lb and lc.
Eksempel 8 Example 8
a) 1,l-dibrom-3-cykloheksyl-l-propen a) 1,1-dibromo-3-cyclohexyl-1-propene
I en oppløsning bestående av 0,2 mol cykloheksylacetaldehyd In a solution consisting of 0.2 mol of cyclohexyl acetaldehyde
og 104,8 g trifenylfosfin i 150 ml CH2C12 tilsetter man and 104.8 g of triphenylphosphine in 150 ml of CH2C12 are added
dråpevis ved -10°C en oppløsning av 76,36 g tetrabrommetan i 100 ml CH2C12- Etter omrøring i 30 min ved romtemperatur blir dette sugd av, inndampet og renset på kiselgel med petroleter som løpemiddel. Man oppnår 48 g av tittelforbindelsen som en olje. dropwise at -10°C a solution of 76.36 g tetrabromomethane in 100 ml CH2C12- After stirring for 30 min at room temperature, this is suctioned off, evaporated and purified on silica gel with petroleum ether as eluant. 48 g of the title compound are obtained as an oil.
MS (EI): 292 (M<+>) MS (EI): 292 (M<+>)
b) 2-(6-cykloheksyl-3-hydroksy-4-heksinyl)-pyridin b) 2-(6-cyclohexyl-3-hydroxy-4-hexynyl)-pyridine
En oppløsning av 0,1 mol 1,l-dibrom-3-cykloheksyl-l-propen i A solution of 0.1 mol of 1,1-dibromo-3-cyclohexyl-1-propene in
THF blir ved -78°C omsatt med 2 ekvivalenter av en oppløsning av n-butyllitium i heksan (1,4 M). Etter oppvarming ved romtemperatur blir dette omrørt i enda 1 time, deretter avkjølt ved -78°C og en oppløsning av 0,1 mol 2-(2-pyridyl )-propionaldehyd (fremstilt ifølge J. Pract. Chem..19, 226 THF is reacted at -78°C with 2 equivalents of a solution of n-butyllithium in hexane (1.4 M). After heating at room temperature, this is stirred for another 1 hour, then cooled at -78°C and a solution of 0.1 mol of 2-(2-pyridyl)-propionaldehyde (prepared according to J. Pract. Chem..19, 226
(1963) blir tilsatt. Etter fornyet oppvarming ved romtemperatur blir det tilsatt is og ekstrahert med MTB. Etter tørking, inndamping og kromatografi på kiselgel (EE/cyklo-heksan (1 : 1)) oppnår man 20,4 g av tittelforbindelsen som olje. (1963) is added. After renewed heating at room temperature, ice is added and extracted with MTB. After drying, evaporation and chromatography on silica gel (EE/cyclohexane (1:1)), 20.4 g of the title compound is obtained as an oil.
MS (EI): 257 (M<+>) MS (EI): 257 (M<+>)
c) E-2-(6-cykloheksyl-3-hydroksy-4-heksenyl)-pyridin c) E-2-(6-cyclohexyl-3-hydroxy-4-hexenyl)-pyridine
136 ml (0,5 mol) av en 70$ oppløsning av natrium-bis-metoksyetoksyaluminiumhydrid i toluen blir fortynnet med 250 ml eter. Ved 0°C blir 0,312 mol av forbindelsen i eksempel 8b dråpevis tilsatt. Etter 1 time ved romtemperatur blir det ved avkjøling dråpevis tilsatt 400 ml 2N H2SO4. Etter opparbei-ding med eter blir dette tørket med MgS04 og inndampet. 136 ml (0.5 mol) of a 70% solution of sodium bis-methoxyethoxyaluminum hydride in toluene is diluted with 250 ml of ether. At 0°C, 0.312 mol of the compound in example 8b is added dropwise. After 1 hour at room temperature, 400 ml of 2N H2SO4 is added dropwise upon cooling. After working up with ether, this is dried with MgSO 4 and evaporated.
MS (El): 259 (M<+>) MS (El): 259 (M<+>)
d) 2 - ( 6-cykloheksyl-3-(S)-hydroksy-(4R,5S)-okso-heksyl)-pyridin (A) og d) 2 - (6-cyclohexyl-3-(S)-hydroxy-(4R,5S)-oxo-hexyl)-pyridine (A) and
E-2-(6-cykloheksyl-3(R)-hydroksy-4-heksenyl)-pyridin (B) E-2-(6-cyclohexyl-3(R)-hydroxy-4-hexenyl)-pyridine (B)
Til en oppløsning av 0,1 mol av forbindelsen i eksempel 13 og 15 mmol L-( +)-diisopropyltartrat i 480 ml abs. CH2CI2 tilsetter man 10 g pulverformig molekylærsikt (3 Å). Ved-10°C tilsettes dråpevis 10 mmol titan(IV)isopropylat og dette blir omrørt i 30 min. 23 ml (0,07 mol) tert. -butylhydroper-oksyd (3 M i isooktan) blir dråpevis tilsatt. Oppløsningen blir tilsatt i en 0°C kald oppløsning av 73 g FeS04 • 7 H20 og 11 g sitronsyre i 100 ml vann. Den vandige fasen blir ekstrahert med eter. De samlede organiske fasene blir omrørt med 10 ml av en oppløsning av 5 g NaCl og 30 g NaOH i 90 ml vann i 1 time. Etter fortynning med H2O blir dette ekstrahert med MTB, tørket og inndampet. Råproduktet blir kromatografert på kiselgel hvorved A og B blir adskilt fra hverandre. To a solution of 0.1 mol of the compound in example 13 and 15 mmol of L-(+)-diisopropyl tartrate in 480 ml of abs. 10 g of powdered molecular sieve (3 Å) is added to CH2CI2. At -10°C, 10 mmol of titanium (IV) isopropylate is added dropwise and this is stirred for 30 min. 23 mL (0.07 mol) tert. -butyl hydroperoxide (3 M in isooctane) is added dropwise. The solution is added to a 0°C cold solution of 73 g FeS04 • 7 H20 and 11 g citric acid in 100 ml water. The aqueous phase is extracted with ether. The combined organic phases are stirred with 10 ml of a solution of 5 g of NaCl and 30 g of NaOH in 90 ml of water for 1 hour. After dilution with H2O, this is extracted with MTB, dried and evaporated. The raw product is chromatographed on silica gel, whereby A and B are separated from each other.
e) 2-[(3S,4R,5R)-5-amino-3,4-dihydroksy-6-cykloheksy1)-heksyl]-pyridin 1 mmol av forbindelsen i eksempel 8d A blir tilsatt i en 5 ml toluen til en oppløsning av 1,2 mmol diazidotitan(IV)diiso-propylat i 10 ml toluen ved 70° C. Etter 10 min. blir dette avkjølt og oppløsningsmiddelet fjernet. Resten blir tatt opp i Et20 og rørt med 8 ml 8$ H2SO4 i 1 time. Etter ekstraksjon med CH2CI2 blir dette tørket med MgS04 og inndampet. Råproduktet blir hydrert i 20 ml MeOE med Pd/C som katalysator ved 1,1 bar og romtemperatur i 2 timer. Man oppnår tittelforbindelsen som en olje. e) 2-[(3S,4R,5R)-5-amino-3,4-dihydroxy-6-cyclohexyl)-hexyl]-pyridine 1 mmol of the compound in example 8d A is added in a 5 ml toluene to a solution of 1.2 mmol of diazidotitanium(IV) diisopropylate in 10 ml of toluene at 70° C. After 10 min. this is cooled and the solvent removed. The residue is taken up in Et20 and stirred with 8 ml of 8$ H2SO4 for 1 hour. After extraction with CH 2 Cl 2 , this is dried with MgSO 4 and evaporated. The crude product is hydrated in 20 ml of MeOE with Pd/C as catalyst at 1.1 bar and room temperature for 2 hours. The title compound is obtained as an oil.
MS (FAB): 299 (M + 1) MS (FAB): 299 (M + 1)
f) (3S ,4R , 5R )-2-[N-( Iva-Phe-His )-5-amino-6-cykloheksyl-3 ,4-dihydroksy-heksyl]-pyridin f) (3S ,4R ,5R )-2-[N-( Iva-Phe-His )-5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl]-pyridine
Denne forbindelsen blir oppnådd fra eksempel 8e analogt med fremgangsmåten angitt i eksemplene lb og lc ved omsetning med This compound is obtained from example 8e analogously to the method indicated in examples lb and lc by reaction with
Iva-Phe-His(DNP)0H og tiofenol. Man oppnår tittelforbindelsen som blassgult harpiks. Iva-Phe-His(DNP)OH and thiophenol. The title compound is obtained as a pale yellow resin.
MS (FAB): 661 (M + 1) MS (FAB): 661 (M + 1)
Eksempel 9 Example 9
a) (3S,4R,5S)-2-[5-amino-6-cykloheksyl-3 , 4-dihydroksy-heksyl]-pyridin • hydroklorid a) (3S,4R,5S)-2-[5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl]-pyridine • hydrochloride
12,9 mmol av forbindelsen i eksempel 8d blir rørt i 50 ml CH2CI2 med 4,6 ml titan(IV)isopropylat ved romtemperatur i 5 min. En oppløsning av 3,79 g lutidiniumtosylat i 50 ml CH2CI2 blir tilsatt og rørt i 15 min. Etter fortynning med eter blir dette omrørt med 80 ml 5% svovelsyre i 1 time, ekstrahert med CH2CI2, tørket med MgSC>4 og inndampet. Råproduktet blir kokt med 5 ml dimetoksypropan og 40 mg p-toluensulfonsyre i 100 ml toluen i 3 timer i en vannavskiller. Etter avkjøling blir dette vasket med 1 N NaHCC^-oppløsning og inndampet. Resten blir rørt i 30 ml DMF med 5 ekvivalenter NaN3 i 3 timer ved 40°C. Etter fortynning med vann blir dette ekstrahert med MTB. Ekstraktet blir vasket 3 ganger med vann, tørket med MgS04 og inndampet. Råproduktet blir hydrert i 30 ml metanol med Pd/C (10$) som katalysator ved romtemperatur og 1,1 bar H2~trykk. Etter filtrering og inndamping blir resten rørt i mettet HC1/DMF i 30 min ved 20" C og oppløsningen blir inndampet til tørrhet. 12.9 mmol of the compound in example 8d is stirred in 50 ml of CH 2 Cl 2 with 4.6 ml of titanium (IV) isopropylate at room temperature for 5 min. A solution of 3.79 g of lutidinium tosylate in 50 ml of CH 2 Cl 2 is added and stirred for 15 min. After dilution with ether, this is stirred with 80 ml of 5% sulfuric acid for 1 hour, extracted with CH 2 Cl 2 , dried with MgSO 4 and evaporated. The crude product is boiled with 5 ml of dimethoxypropane and 40 mg of p-toluenesulfonic acid in 100 ml of toluene for 3 hours in a water separator. After cooling, this is washed with 1 N NaHCC 3 solution and evaporated. The residue is stirred in 30 ml of DMF with 5 equivalents of NaN3 for 3 hours at 40°C. After dilution with water, this is extracted with MTB. The extract is washed 3 times with water, dried with MgSO 4 and evaporated. The crude product is hydrogenated in 30 ml of methanol with Pd/C (10$) as catalyst at room temperature and 1.1 bar H2 pressure. After filtration and evaporation, the residue is stirred in saturated HCl/DMF for 30 min at 20°C and the solution is evaporated to dryness.
MS (FAB): 292 (M + 1) MS (FAB): 292 (M + 1)
b) B0C-Eis(DNP )-(3S,4R,5S)-2-[5-amino-6-cykloheksy1-3,4-dihydroksy-heksyl]-pyridin b) B0C-Eis(DNP )-(3S,4R,5S)-2-[5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl]-pyridine
Denne forbindelsen blir fremstilt ifølge fremgangsmåten angitt i eksempel lb ved omsetning av (3S,4R,5S)-2-[5-amino-6-cykloheksyl-3 ,4-dihydroksy-j;sksyl]-pyridin (eksempel 9a) med B0C-His(DNP)0H. This compound is prepared according to the method indicated in example 1b by reacting (3S,4R,5S)-2-[5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl]-pyridine (example 9a) with BOC -His(DNP)0H.
MS (FAB): 696 (M + 1) MS (FAB): 696 (M + 1)
c ) H-hi s- ( DNP ) - ( 3S , 4R , 5S )-2- ( 5-amino-6-cykloheksy 1 -3 ,4-dihydroksy-heksyl]-pyridinhydroklorid c ) H-hi s-( DNP )-( 3S , 4R , 5S )-2-( 5-amino-6-cyclohexy 1 -3,4-dihydroxy-hexyl]-pyridine hydrochloride
400 mg av forbindelsen i eksempel 9b blir rørt i 10 ml DME/HC1 (mettet) i 2 timer. Etter inndamping blir dette tatt opp to ganger i toluen og videre inndampet. Man oppnår tittelforbindelsen som gult skum. 400 mg of the compound in Example 9b is stirred in 10 ml of DME/HCl (saturated) for 2 hours. After evaporation, this is taken up twice in toluene and further evaporated. The title compound is obtained as a yellow foam.
MS (FAB): 596 (M + 1) MS (FAB): 596 (M + 1)
d) N-(2(S)-benzyl-tert.-butylsulfonyl-propionyl ) - his-(3S,4R,5S)-(5-amino-6-cykloheksy1-3,4-dihydroksy-heksyl]-pyridin d) N-(2(S)-benzyl-tert-butylsulfonyl-propionyl)-his-(3S,4R,5S)-(5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl]-pyridine
0,8 mmol av forbindelsen i eksempel 9c, 2(S)-benzyl-3-tert.-butylsulfonyl-propionsyre (kjent fra EP-A 236 734), 1 hydroksybenztriazol og dicykloheksylkarbodiimid blir løst i 3 ml DMF. pH-verdien blir innstilt til 9 med N-etylmorfolin og omrørt i 24 timer. 0.8 mmol of the compound in example 9c, 2(S)-benzyl-3-tert-butylsulphonyl-propionic acid (known from EP-A 236 734), 1 hydroxybenztriazole and dicyclohexylcarbodiimide are dissolved in 3 ml of DMF. The pH value is adjusted to 9 with N-ethylmorpholine and stirred for 24 hours.
Utfelt dicykloheksylurinstoff blir filtrert av, filtratet fortynnet med EE og vasket med 1 N NaHCO^-oppløsning, vann og mettet koksaltoppløsning, tørket med MgS04 og inndampet. Råproduktet blir løst i 3 ml acetonitril og rørt med 45 mg tiofenol i 3 timer. Etter inndamping blir dette kromatograf ert på kiselgel med CH2Cl2/MeOH/kons. NH3 (10 : 1 : 0,1). Man oppnår tittelforbindelsen som en blassgul harpiks. Precipitated dicyclohexylurea is filtered off, the filtrate diluted with EE and washed with 1 N NaHCO 3 solution, water and saturated sodium chloride solution, dried with MgSO 4 and evaporated. The crude product is dissolved in 3 ml of acetonitrile and stirred with 45 mg of thiophenol for 3 hours. After evaporation, this is chromatographed on silica gel with CH2Cl2/MeOH/conc. NH3 (10:1:0.1). The title compound is obtained as a pale yellow resin.
MS (FAB): 664 (M + 1) MS (FAB): 664 (M + 1)
Eksempel 10 Example 10
a) 2-( 6-cykloheksyl-3-(R)-hydroksy-(4S,5R)-okso-heksyl)-pyridin a) 2-(6-cyclohexyl-3-(R)-hydroxy-(4S,5R)-oxo-hexyl)-pyridine
Denne forbindelsen oppnår man fra E-2-(6-cykloheksyl-3-(R)-hydroksy-4-heksenyl )-pyridin (Eksempel 8d B) ifølge fremgangsmåten angitt i eksempel 8d under anvendelse av D-(-)-vinsyrediisopropyleter og 1,2 ekvivalenter tert.-butyl-hydroperoksyd. This compound is obtained from E-2-(6-cyclohexyl-3-(R)-hydroxy-4-hexenyl)-pyridine (Example 8d B) according to the method indicated in Example 8d using D-(-)-tartaric diisopropyl ether and 1.2 equivalents of tert-butyl hydroperoxide.
MS (El): 275 (M<+>) MS (El): 275 (M<+>)
b) 2-[(3R,4S,5S)-5-amino-3 , 4-dihydroksy-6-cykloheksyl-heksyl]-pyridin b) 2-[(3R,4S,5S)-5-amino-3,4-dihydroxy-6-cyclohexyl-hexyl]-pyridine
Denne forbindelsen blir fremstilt ifølge fremgangsmåten angitt i eksempel 8e fra forbindelsen i eksempel 10a. This compound is prepared according to the method indicated in example 8e from the compound in example 10a.
c) ( 3R ,4S , 5S )-2-[N-( Iva-Phe-His )-5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl]-pyridin c) (3R,4S,5S)-2-[N-(Iva-Phe-His)-5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl]-pyridine
Denne forbindelsen blir fremstilt ifølge fremgangsmåten angitt i eksemplene lb og lc fra forbindelsen i eksempel 10b; farveløs harpiks. This compound is prepared according to the method indicated in examples 1b and 1c from the compound in example 10b; colorless resin.
MS (FAB): 661 (M + 1) MS (FAB): 661 (M + 1)
Eksempel 11 Example 11
a) (3R,4S,5R)-2-[5-amino-6-cykloheksyl-3 , 4-dihydroksy-heksyl] -pyridin a) (3R,4S,5R)-2-[5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl]-pyridine
Denne forbindelsen blir fremstilt ifølge fremgangsmåten angitt i eksempel 9a fra forbindelsen i eksempel 10a. This compound is prepared according to the method indicated in example 9a from the compound in example 10a.
b ) ( 3R ,4S , 5R )-2-[N-( Iva-Phe-His)-5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl]-pyridin b) (3R,4S,5R)-2-[N-(Iva-Phe-His)-5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl]-pyridine
Denne forbindelsen blir fremstilt ifølge fremgangsmåten angitt i eksemplene la og lb fra forbindelsen i eksempel lia. This compound is prepared according to the method indicated in examples la and lb from the compound in example lia.
MS (FAB): 661 (M + 1) MS (FAB): 661 (M + 1)
Analogt med forskriftene angitt i eksempel 9d blir følgende forbindelser fremstilt ved anvendelse av egnede utgangsmaterialer: Eksempel 12 N-[2-(S)-( 2-t ienyl -metyl )-3-tert. -butylsulfonyl-propionyl )-his-(3S,4R,5S)-2-(5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl] -pyridin Analogous to the regulations stated in example 9d, the following compounds are prepared using suitable starting materials: Example 12 N-[2-(S)-(2-thienyl-methyl)-3-tert. -butylsulfonyl-propionyl)-his-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl]-pyridine
MS (FAB): 670 (M + 1) MS (FAB): 670 (M + 1)
Eksempel 13 Example 13
N-[2-(S )-(1-naf tyl-metyl )-3-tert.-butylsulfonyl-propionyl )-his-(3S,4R,5S)-2-(5-amino-6-cykloheksy1-3,4-dihydroksy-heksyl] -pyridin N-[2-(S )-(1-naphthyl-methyl )-3-tert-butylsulfonyl-propionyl )-his-(3S,4R,5S)-2-(5-amino-6-cyclohexy1-3 ,4-dihydroxyhexyl]-pyridine
MS (FAB): 714 (M + 1) MS (FAB): 714 (M + 1)
Eksempel 14 Example 14
N - [2 - (S ) - ( 2-f enyl-metyl - 3-isobutylsulf onyl-propionyl )-his-( 3S , 4R , 5S )-2-( 5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl]-pyridin N - [2 - ( S ) - ( 2-phenyl-methyl - 3-isobutylsulfonyl-propionyl )-his-( 3S , 4R , 5S )-2-( 5-amino-6-cyclohexyl-3,4- dihydroxyhexyl]pyridine
MS (FAB: 664 (M + 1) MS (FAB: 664 (M + 1)
Eksempel 15 Example 15
N - [ ( 2 - ( S ) - f enyl-metyl-3-tert. -butylsulfonyl-propionyl )-Nva-(3S , 4R , 5S )-2-(5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl)]-pyridin N - [ ( 2 - ( S ) - phenyl-methyl-3-tert. -butylsulfonyl-propionyl )-Nva-(3S , 4R , 5S )-2-(5-amino-6-cyclohexyl-3,4- dihydroxyhexyl)]-pyridine
MS (FAB): 626 (M + 1) MS (FAB): 626 (M + 1)
Eksempel 16 Example 16
N-[(2-(S)-fenyl-metyl-3-tert.-butylsul f onyl-propionyl)-3-pyrazolyl-alanyl-(3S,4R,5S)-2-(5-amino-6-cykloheksyl-3 ,4-dihydroksy-heksyl)]-pyridin N-[(2-(S)-phenyl-methyl-3-tert-butylsulfonyl-propionyl)-3-pyrazolyl-alanyl-(3S,4R,5S)-2-(5-amino-6-cyclohexyl -3,4-dihydroxyhexyl)]-pyridine
MS (FAB): 664 (M + 1) MS (FAB): 664 (M + 1)
Eksempel 17 Example 17
N- [bis-( 1-naftyl-metyl )-acetyl]-his-(3S,4R,5S )-2-(5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl)-pyridin N-[bis-(1-naphthyl-methyl)-acetyl]-his-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl)-pyridine
Fremstilt analogt eksempel 9d fra forbindelsen i eksempel 9c og bis-(1-naftyl-metyl)-eddiksyre (kjent fra EP-A 228 182). Prepared analogous example 9d from the compound in example 9c and bis-(1-naphthyl-methyl)-acetic acid (known from EP-A 228 182).
MS (FAB): 766 (M + 1) MS (FAB): 766 (M + 1)
Eksempel 18 Example 18
N- [bis- ( 2-f luo r benzyl )-acetyl]-his-(3S,4R,5S)-2-(5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl)-pyridin N-[bis-(2-fluorobenzyl)-acetyl]-his-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxyhexyl)-pyridine
Fremstilt analogt eksempel 9d fra forbindelsen fra eksempel 9c og bis-(2-fluorbenzyl)eddiksyre (kjent fra EP-A 252 727). Prepared analogous example 9d from the compound from example 9c and bis-(2-fluorobenzyl)acetic acid (known from EP-A 252 727).
MS (FAB): 702 (M + 1) MS (FAB): 702 (M + 1)
Eksempel 19 Example 19
N-[3-morfolinokarbonyl-2-(1-naftyl)-propionyl]-his-(3S,4R,5S)-2-( 5-amino-6-cykloheksyl-3 ,4-dihydroksy-heksyl )-pyridin N-[3-morpholinocarbonyl-2-(1-naphthyl)-propionyl]-his-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl)-pyridine
Fremstilt analogt eksempel 9d fra forbindelsen fra eksempel 9c og 3-morfolinokarbonyl-2-(1-naftyl)-propionsyre (kjent fra EP-A 200 406) Prepared analogous example 9d from the compound from example 9c and 3-morpholinocarbonyl-2-(1-naphthyl)-propionic acid (known from EP-A 200 406)
MS (FAB): 739 (M + 1) MS (FAB): 739 (M + 1)
Eksempel 20 Example 20
N- ( 2-benzyl-5 , 5-dimetyl-4-okso-heksanoyl )-his-(3S,4R , 5S )-2-(5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl)-pyridin N-(2-benzyl-5,5-dimethyl-4-oxo-hexanoyl)-his-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl)- pyridine
Fremstilt analogt eksempel 9d fra forbindelsen fra eksempel 9c og 2-benzyl-5,5-dimetyl-4-okso-heksansyre (kjent fra EP-A 184 550). Prepared analogous example 9d from the compound from example 9c and 2-benzyl-5,5-dimethyl-4-oxo-hexanoic acid (known from EP-A 184 550).
MS (FAB): 660 (M + 1) MS (FAB): 660 (M + 1)
Eksempel 21 Example 21
N-[3-(piperazin-l-yl)-karbonyl-2-(1-naftyl)metyl-propionyl]-his-(3S,4R,5S)-2-(5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl )-pyridin N-[3-(piperazin-1-yl)-carbonyl-2-(1-naphthyl)methyl-propionyl]-his-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3, 4-dihydroxy-hexyl )-pyridine
Fremstilt analogt eksempel 9d fra forbindelsen fra eksempel 9c og 3-(4-boc-piperazin-l-yl)-karbonyl-2-(1-naftyl)metyl-propionsyre (kjent fra EP-A 278 158) og etterfølgende avspaltning av BOC-gruppen med trifluoreddiksyre. Prepared analogous example 9d from the compound from example 9c and 3-(4-boc-piperazin-1-yl)-carbonyl-2-(1-naphthyl)methyl-propionic acid (known from EP-A 278 158) and subsequent cleavage of BOC -group with trifluoroacetic acid.
MS (FAB): 715 (M + 1) MS (FAB): 715 (M + 1)
Eksempel 22 Example 22
a) H-Phe-Eis ( DNP )- ( 3S , 4R , 5S )-2-( 5-amino-6-cykloheksyl-3 ,4-dihydroksy-heksyl)-pyridin-trifluoracetat 1 mmol av forbindelsen i eksempel 9c blir løst sammen med 1 mmol Boc-Phe-OH, 1-hydroksybenzotriazol og dicykloheksylkarbodiimid i 4 ml DMF; oppløsningen blir innstilt til pH 9 med N-etylmorfol in og omrørt i 24 timer. Etter avfiltrering av det utfelte dicykloheksylurinstoffet blir dette fortynnet med eddikester og vasket en gang med 1 N NAHCC^-oppløsning, vann og mettet koksaltoppløsning, tørket med MgSC^ og inndampet. Råproduktet blir løst i 2 ml trifluoreddiksyre og omrørt i 30 min. Etter inndamping oppnår man tittelforbindelsen som et gult skum. a) H-Phe-Eis (DNP)-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl)-pyridine-trifluoroacetate 1 mmol of the compound in example 9c is dissolved together with 1 mmol Boc-Phe-OH, 1-hydroxybenzotriazole and dicyclohexylcarbodiimide in 4 ml DMF; the solution is adjusted to pH 9 with N-ethylmorpholine and stirred for 24 hours. After filtering off the precipitated dicyclohexylurea, this is diluted with acetic acid and washed once with 1 N NAHCC^ solution, water and saturated sodium chloride solution, dried with MgSC^ and evaporated. The crude product is dissolved in 2 ml of trifluoroacetic acid and stirred for 30 min. After evaporation, the title compound is obtained as a yellow foam.
MS (FAB): 577 (M + 1) MS (FAB): 577 (M + 1)
b) N-[3-(3-pyridyl)-propionyl]-Phe-His-(3S,4R,5S)-2-(5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl)-pyridin b) N-[3-(3-pyridyl)-propionyl]-Phe-His-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl)-pyridine
Fremstilt fra forbindelsen i eksempel 22a ifølge fremgangsmåten angitt i eksempel 9d ved omsetning med 3-(3-pyridyl )-propionsyre. Prepared from the compound in example 22a according to the method indicated in example 9d by reaction with 3-(3-pyridyl)-propionic acid.
MS (FAB): 720 (M + 1 ) MS (FAB): 720 (M + 1 )
Eksempel 23 Example 23
f3-Val-Phe-His-(3S,4R,5S)-2-( 5-amino-6-cykl oheksy 1-3 , 4-dihydroksy-heksyl)-pyridin f3-Val-Phe-His-(3S,4R,5S)-2-( 5-amino-6-cyclohexy 1-3 , 4-dihydroxy-hexyl)-pyridine
Fremstilt fra forbindelsen i eksempel 22a ved omsetning med N-benzyloksykarbonyl-3-amino-3-metylsmørsyre (kjent fra EP-A 258 289) ifølge fremgangsmåten angitt i eksempel 9d og påfølgende hydrogenolyttisk avspaltning av benzyloksykarbonyl-beskyttelsesgruppen med Hg; Pd/C ( 10%) i eddiksyre. Prepared from the compound in example 22a by reaction with N-benzyloxycarbonyl-3-amino-3-methylbutyric acid (known from EP-A 258 289) according to the method indicated in example 9d and subsequent hydrogenolytic cleavage of the benzyloxycarbonyl protecting group with Hg; Pd/C (10%) in acetic acid.
MS (FAB): 664 (M + 1) MS (FAB): 664 (M + 1)
Eksempel 24 Example 24
N-morf olinokarbonyl-Phe-His-( 3S , 4R , 5S)-2-(5-amino-6-cykloheksyl-3 ,4-dihydroksy-heksyl)-pyridin N-morph olinocarbonyl-Phe-His-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl)-pyridine
Fremstilt fra forbindelsen i eksempel 9c og N-morfolino-karbonyl-Phe-OH (kjent fra EP-A 258 289) ifølge fremgangsmåten angitt i eksempel 9d. Prepared from the compound in example 9c and N-morpholino-carbonyl-Phe-OH (known from EP-A 258 289) according to the method indicated in example 9d.
MS (FAB): 678 (M + 1) MS (FAB): 678 (M + 1)
Eksempel 25 Example 25
a) 2 [ ( 3S , 4R ,5S)-5-tert.-butyloksykarbonylamino-3,4-dihydrok-sy-7-metyl-oktyl]-pyridin a) 2 [ ( 3S , 4R , 5S )-5-tert-butyloxycarbonylamino-3,4-dihydroxy-cy-7-methyl-octyl]-pyridine
Fremstilt ifølge fremgangsmåten angitt i eksempel 1 med utgangspunkt i (2RS,3R,4S)-3-tert.-butyldimetylsilyl-4-tert.-butoksykarbonylamino-6-metyl-l,2-oksoheptan, som er tilgjen-gelig analogt med den i eksempel 1 anvendte utgangsforbindelse fra Boc-leucinal. Produced according to the method indicated in example 1 starting from (2RS,3R,4S)-3-tert-butyldimethylsilyl-4-tert-butoxycarbonylamino-6-methyl-1,2-oxoheptane, which is available analogously to the in example 1 used starting compound from Boc-leucinal.
MS (FAB ) : 353 (M + 1) MS (FAB ) : 353 (M + 1)
b) Iva-Phe-His-(3S,4R,5S)-2-( 5 -am i no-3 , 4-dihydroksy-7-metyloktyl)-pyridin b) Iva-Phe-His-(3S,4R,5S)-2-(5-amino-3,4-dihydroxy-7-methyloctyl)-pyridine
Fremstilt fra fremgangsmåten angitt i eksemplene lb og lc under anvendelse av forbindelsen i eksempel 25a som ut-gangsmateri ale. Prepared from the method indicated in examples 1b and 1c using the compound in example 25a as starting material.
MS (FAB): 601 (M + 1) MS (FAB): 601 (M + 1)
Eksempel 26 Example 26
N-(2-(S)-benzyl-3-tert.-butylsulfonyl-propi onyl) -His-(3S,4R,5S)-(5-amino-3,4-dihydroksy-7-metyl-oktyl)-pyridin N-(2-(S)-benzyl-3-tert-butylsulfonyl-propionyl)-His-(3S,4R,5S)-(5-amino-3,4-dihydroxy-7-methyl-octyl)- pyridine
Fremstilt ifølge fremgangsmåten angitt i eksemplene 9b - 9d fra forbindelsen i eksempel 25a. Prepared according to the method indicated in examples 9b - 9d from the compound in example 25a.
MS (FAB): 576 (m + 1) MS (FAB): 576 (m + 1)
Eksempel 27 Example 27
a) 2-[(3S,4R,5S)-5-tert.-butoksykarbonylamino-6-cykloheksyl-3,4-dihydroksy-heksyl]-1-metyl-imidazol a) 2-[(3S,4R,5S)-5-tert-butoxycarbonylamino-6-cyclohexyl-3,4-dihydroxy-hexyl]-1-methyl-imidazole
Fremstilt analogt med forskriften angitt i eksempel 1 under anvendelse av 1,2-dimetylimidazol som nukleofil. Prepared analogously to the prescription given in example 1 using 1,2-dimethylimidazole as nucleophile.
MS (FAB): 382 (M + 1) MS (FAB): 382 (M + 1)
b) Iva-Phe-His-(3S,4R,5S )-2-( 5-amino-6-cykloheksyl-3 ,4-dihydroksy-heksyl)-1-metyl-imidazol b) Iva-Phe-His-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl)-1-methyl-imidazole
Fremstilt fra forbindelsen i eksempel 27a analogt med fremgangsmåten angitt i eksempel lb og lc. Prepared from the compound in example 27a analogously to the method indicated in examples lb and lc.
MS (FAB): 664 (M + 1) MS (FAB): 664 (M + 1)
Eksempel 28 Example 28
a) 2-[(3S,4E,5S)-5-tert.-butoksykarbonylamino-6-cykloheksyl-3,4-dihydroksy-heksyl]-4-(S)-l(S) -metyl-propyl-1 , 3-oksazolin a) 2-[(3S,4E,5S)-5-tert.-butoxycarbonylamino-6-cyclohexyl-3,4-dihydroxy-hexyl]-4-(S)-1(S)-methyl-propyl-1, 3-oxazoline
Fremstilt analogt som angitt i forskriften i eksempel 1 under anvendelse av 2-litio-metyl-4-(S)-l(S)-metyl-propyl-oksazolin som nukleofil. Prepared analogously to the instructions in example 1 using 2-lithio-methyl-4-(S)-1(S)-methyl-propyl-oxazoline as nucleophile.
MS (FAB): 441 (M + 1) MS (FAB): 441 (M + 1)
b ) N- [Iva-Phe-His-( 3S , 4R , 5S )-2-( 5-amino-6-cykloheksyl-3 ,4-dihydroksy-heksyl)]-4-(S)-l(S)-metyl-propyl-1,3-oksazolin b ) N- [Iva-Phe-His-( 3S , 4R , 5S )-2-( 5-amino-6-cyclohexyl-3 ,4-dihydroxy-hexyl)]-4-(S)-1(S) -methyl-propyl-1,3-oxazoline
Fremstilt analogt med forskriftene angitt i eksemplene lb og lc fra forbindelsen i eksempel 28. Prepared analogously to the regulations stated in examples lb and lc from the compound in example 28.
MS (FAB); 708 (M + 1) MS (FAB); 708 (M + 1)
Eksempel 29 Example 29
N-[3-morfolinokarbonyl)-2-fenyl-propionyl]-his-(3S,4R,5S)-(5-amino-6-cykloheksyl-3,4-dihydroksy)-pyridin N-[3-morpholinocarbonyl)-2-phenyl-propionyl]-his-(3S,4R,5S)-(5-amino-6-cyclohexyl-3,4-dihydroxy)-pyridine
MS (FAB): 689 (M + 1) MS (FAB): 689 (M + 1)
Eksempel 30 Example 30
N-[ 3-mor f olinotiokarbonyl-2-fenyl-propionyl]-his-(3S,4R,5S )-(5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl)-pyridin MS (FAB): 705 (M + 1) N-[3-morpholinothiocarbonyl-2-phenyl-propionyl]-his-(3S,4R,5S)-(5-amino-6-cyclohexyl-3,4-dihydroxyhexyl)-pyridine MS (FAB): 705 (M + 1)
Eksempel 31 Example 31
N- [3-mo r f ol inokarbonyl - 2- ( 4-me tok sy-f enyl )-propionyl] -his-( 3S,4R,5S )-5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl)-pyridin N- [3-morpholinecarbonyl-2-(4-methoxy-phenyl)-propionyl]-his-(3S,4R,5S)-5-amino-6-cyclohexyl-3,4-dihydroxy- hexyl)-pyridine
MS (FAB): 719 (M + 1) MS (FAB): 719 (M + 1)
Eksempel 32 Example 32
p-val-0-metyl-tyrosyl-hi s-(3S,4R,5S)-2-(5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl)-pyridin p-val-O-methyl-tyrosyl-his-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl)-pyridine
MS (FAB): 694 (M + 1) MS (FAB): 694 (M + 1)
Eksempel 33 Example 33
N-morfolinokarbonyl-0-metyl-tyrosyl-his-(3S,4R, 5S)-2-(5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl)-pyridin MS (FAB): 708 (M + 1) N-morpholinocarbonyl-0-methyl-tyrosyl-his-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl)-pyridine MS (FAB): 708 (M + 1)
Eksempel 34 Example 34
N-morfol i not iokarbonyl-Phe-His- ( 3S,4R,5S)-2-(5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl)-pyridin N-morphol i notiocarbonyl-Phe-His-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl)-pyridine
MS (FAB): 694 (M + 1) MS (FAB): 694 (M + 1)
Eksempel 35 Example 35
4- aminobutyryl-Phe-His- ( 3S ,4R, 5S )-2-( 5-amino-6-cykloheksy 1-3,4-dihydroksy-heksyl)-pyridin 4-aminobutyryl-Phe-His-(3S,4R,5S)-2-(5-amino-6-cyclohexy 1-3,4-dihydroxy-hexyl)-pyridine
MS (FAB): 650 (M + 1) MS (FAB): 650 (M + 1)
Eksempel 36 Example 36
5- aminovaleroyl-Phe-His-(3S,4R,5S)-2-(5-amino-6-cykloheksy1-3,4-dihydroksy-heksyl)-pyridin 5- aminovaleroyl-Phe-His-(3S,4R,5S)-2-(5-amino-6-cyclohexy1-3,4-dihydroxy-hexyl)-pyridine
MS (FAB): 664 (M + 1) MS (FAB): 664 (M + 1)
Eksempel 37 Example 37
4-aminobutyryl-0-metyl -tyrosyl-His-(3S ,4R, 5S )-2-( 5-amino-6-cykloheksyl-2,4-dihydroksy-heksyl)-pyridin 4-aminobutyryl-0-methyl-tyrosyl-His-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-2,4-dihydroxy-hexyl)-pyridine
MS (FAB): 680 (M + 1) MS (FAB): 680 (M + 1)
Eksempel 38 Example 38
5-aminovaleroyl-0-metyl-tyrosyl-His-(3S, 4R,5S)-2-(5-amino-6-cykloheksyl-3,4-dihydroksyl)-pyridin 5-aminovaleroyl-0-methyl-tyrosyl-His-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxyl)-pyridine
MS (FAB): 694 (M + 1) MS (FAB): 694 (M + 1)
Eksempel 39 Example 39
(3 - Val-Phe-(NMe) -His-(3S,4R,5S)-2-(5-amino-6-cykloheksyl-3 ,4-dihydroksy-heksyl )-pyridin (3-Val-Phe-(NMe)-His-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl)-pyridine
MS (FAB): 678 (M + 1) MS (FAB): 678 (M + 1)
Eksempel 4 0 Example 4 0
N-morfolinokarbonyl-Phe-(NMe)- His-(3S,4R,5S)-2-(5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl)-pyridin N-morpholinocarbonyl-Phe-(NMe)-His-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxy-hexyl)-pyridine
MS (FAB): 692 (M + 1) MS (FAB): 692 (M + 1)
Eksempel 41 Example 41
5-aminovaleroyl-Phe-(NMe)-His-(3S,4R,5S)-2-(5-amino-6-cykloheksyl-3,4-dihydroksy-heksyl)pyridin 5-aminovaleroyl-Phe-(NMe)-His-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxyhexyl)pyridine
MS (FAB): 678 (M + 1) MS (FAB): 678 (M + 1)
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DE3839559A DE3839559A1 (en) | 1988-11-24 | 1988-11-24 | RENIN-INHIBITING AMINODIOL DERIVATIVES |
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JP (1) | JPH02193968A (en) |
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AU (1) | AU628109B2 (en) |
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ES (1) | ES2054989T3 (en) |
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HU (1) | HU204262B (en) |
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GB8827308D0 (en) * | 1988-11-23 | 1988-12-29 | British Bio Technology | Compounds |
IE68045B1 (en) * | 1990-05-11 | 1996-05-15 | Abbott Lab | Renin inhibitors |
IE911774A1 (en) * | 1990-06-11 | 1991-12-18 | Akzo Nv | Pyridinylpiperazine derivatives |
CA2018801C (en) * | 1990-06-12 | 2000-08-22 | Pierre Louis Beaulieu | Antiherpes peptide derivatives having a 1,4-dioxo c n-terminus |
DE4021007A1 (en) * | 1990-07-02 | 1992-01-09 | Hoechst Ag | Amino diol DERIVATIVES |
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US5032577A (en) * | 1986-12-31 | 1991-07-16 | Abbott Laboratories | Peptidylaminodiols |
EP0309766B1 (en) * | 1987-09-29 | 1998-04-15 | Banyu Pharmaceutical Co., Ltd. | N-acylamino acid derivatives and their use |
IL90184A0 (en) * | 1988-05-09 | 1989-12-15 | Abbott Lab | Functionalized peptidyl aminodiols and-triols |
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1988
- 1988-11-24 DE DE3839559A patent/DE3839559A1/en not_active Withdrawn
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1989
- 1989-11-21 DE DE58907505T patent/DE58907505D1/en not_active Expired - Fee Related
- 1989-11-21 AT AT8989121499T patent/ATE104678T1/en active
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ATE104678T1 (en) | 1994-05-15 |
FI895568A0 (en) | 1989-11-22 |
DE58907505D1 (en) | 1994-05-26 |
DK589589A (en) | 1990-05-25 |
DK589589D0 (en) | 1989-11-23 |
FI93645C (en) | 1995-05-10 |
JPH02193968A (en) | 1990-07-31 |
PT92388B (en) | 1995-07-18 |
HU896173D0 (en) | 1990-02-28 |
IL92405A0 (en) | 1990-07-26 |
HUT52524A (en) | 1990-07-28 |
PT92388A (en) | 1990-05-31 |
NO894663D0 (en) | 1989-11-23 |
NZ231485A (en) | 1993-03-26 |
PH27267A (en) | 1993-05-04 |
EP0370454A2 (en) | 1990-05-30 |
EP0370454B1 (en) | 1994-04-20 |
KR900007867A (en) | 1990-06-02 |
NO177351C (en) | 1995-08-30 |
FI93645B (en) | 1995-01-31 |
EP0370454A3 (en) | 1990-10-24 |
HU204262B (en) | 1991-12-30 |
AU628109B2 (en) | 1992-09-10 |
NO894663L (en) | 1990-05-25 |
DE3839559A1 (en) | 1990-05-31 |
ZA898990B (en) | 1990-08-29 |
ES2054989T3 (en) | 1994-08-16 |
AU4547589A (en) | 1990-09-13 |
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