EP0423170A1 - Synthese de dipeptide hydroxyethylenique isostere et ses intermediaires - Google Patents

Synthese de dipeptide hydroxyethylenique isostere et ses intermediaires

Info

Publication number
EP0423170A1
EP0423170A1 EP19890907510 EP89907510A EP0423170A1 EP 0423170 A1 EP0423170 A1 EP 0423170A1 EP 19890907510 EP19890907510 EP 19890907510 EP 89907510 A EP89907510 A EP 89907510A EP 0423170 A1 EP0423170 A1 EP 0423170A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
benzyl
hydroxy
het
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Withdrawn
Application number
EP19890907510
Other languages
German (de)
English (en)
Inventor
Peter G. M. Wuts
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of EP0423170A1 publication Critical patent/EP0423170A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

Definitions

  • the present invention provides novel processes and intermediates for the synthesis of the hydroxyethylene isostere dipeptide leu-val and similar transition state moieties. These compounds are useful in the synthesis of a large number of renin inhibitory peptides having this moiety in the 10,11 position corresponding to the renin substrate. See, e.g., published European patent application 173,481, published 5 March 1986, which is incorporated by reference herein. The sequence may readily be modified for the preparation of a large variety of both the N-terminal and C-terminal variants. When hydroxy ethylene isosteres of this type are incorporated into a variety of peptides they have enhanced or altered biological activity which makes them useful for treatment of a variety of disease states, particularly the treatment of hypertension.
  • the present invention particularly provides:
  • aryl is phenyl or naphthyl substituted by zero to 3 of the following:
  • Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, which heterocyclic moiety is substituted with zero to three of the following:
  • n 1 to 5 ; wherein aryl is phenyl or naphthyl substituted by zero to 3 of the following:
  • Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, which heterocyclic moiety is substituted with zero to three of the following:
  • the present invention provides an efficient and stereospecific means to prepare intermediates for renin inhibitory peptides.
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix (C i -C j ) indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • (C 1 -C 10 )alkyl refers to alkyl of one to 4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl and isomeric (cyclic, acylic, branched) forms thereof.
  • aryl examples include phenyl, naphthyl, (o-, m-, p-)tolyl, (o-, m-, p-)ethylphenyl, 2-ethyl-tolyl, 4-ethyl-o-tolyl, 5-ethyl-m- tolyl, (o-, m-, or p-)propylphenyl, 2-pro ⁇ yl- (o-, m-, or p-)tolyl, 4- isopropyl-2,6-xylyl, 3-propyl-4-ethylpyhenyl, (2,3,4- 2,3,6-, or 2,4,5-)trimethylphenyl, (o-, m-, or p-) fluorophenyl, (o-, m-, or p- trifluoromethyl)phenyl, 4-fluoro-2 ,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-,
  • Examples of -Het include: 2-, 3-, or 4-pyridyl, imidazolyl, indolyl, N in -formyl-indolyl, N in -C 2 -C 5 alkyl-C(O) -indolyl, [1,2,4]-triazolyl, 2-, 4-, 5-pyrimidinyl, 2-, 3-thienyl, piperidinyl, pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, Imidazolidinyl, pyrazinyl, piperazinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl
  • the intermediates herein and inhibitory peptides prepared therefrom can occur in several isomeric forms, depending on the configuration around the asymmetric carbon atoms . All such isomeric forms are included within the scope of the present invention.
  • the stereochemistry of the amino acids corresponds to that of the naturally-occurring amino acids.
  • a heterocycle as defined herein for -Het would not be bonded through oxygen or sulfur or through nitrogen which is within a ring and part of a double bond.
  • hydroxyethylene isostere dipeptides prepared herein are incorporated into renin-inhibitory peptides by conventional means.
  • the renin inhibiting polypeptides may be prepared by either polymer assisted or solution phase peptide synthetic procedures analogous to those described hereinafter or to those methods known in the art.
  • the carboxylic moiety of N ⁇ -t-butyloxycarbonyl (Boc)-substituted amino acid derivatives having suitable side chain protecting groups may be condensed with the amino functionality of a suitably protected amino acid, peptide or polymer-bound peptide using a conventional coupling protocol such as dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) or diethylphosphoryl cyanide (DEPC) and triethylamine (Et 3 N) in methylene chloride or dimethylformamide.
  • DCC dicyclohexylcarbodiimide
  • HOBT 1-hydroxybenzotriazole
  • DEPC diethylphosphoryl cyanide
  • Et 3 N triethylamine
  • Compound 3 is prepared from isopropyloxazolidinone, butyllithium and isovaleryl chloride according to Evans (see Aldrichimica Acta, 15:23 (1982).
  • a solution of LDA (Lithium diisopropylamide) in THF (tetrahydrofuran) is prepared from 0.25 ml of diisopropyl amine and n-butyllithium (1.6 M) at -78oC.
  • imide 3 in THF After 40 min., bromide 2 is added and the reaction is warmed to -30oC after stirring at -78o for 1.5 h.
  • the mixture is placed in the freezer overnight after stirring at -30o for 3 hours.
  • the mixture is poured Into water and isolated with MTBE (Methyl t-butyl ether) to afford the crude adduct 4.
  • MTBE Metal t-butyl ether
  • amide bases such as KN(TMS) 2 (potassium hexamethyldisilazide) and NaN(TMS) 2 (sodium hexamethyldisilazide) also work in the reaction.
  • the preferred temperature range is between -30 and- 20o C. Lower temperatures stall the reaction and higher temperatures cause decomposition of the enolate through its ketene. The optimum time has also not been established.
  • the product is isolated by extraction with MTBE from 10% KOH.
  • the organic extracts are dried over magnesium sulfate and concentrated to afford the epoxides 5 and 6 as a viscous oil.
  • peracids such as trifluoroperoxyacetic, peroxyacetic, perphathalic acid and magnesium perphthalate also work in this reaction. Again temperature merely changes the rate of the reaction.
  • Other solvents such as toluene, dichloroethane, butyl chloride will also work.
  • the crude mixture of epoxides 5 and 6 from above is taken up in THF and 10% sulfuric acid and heated to reflux overnight.
  • the product is isolated with MTBE and chromatographed on silica gel with 25% ethyl acetate/cyclohexane to afford the lactones as a mixture of the (2S, 4R, 5S)-isomer and the (2S, 4S, 5R)-isomer in a ratio of 56:40 as determied by capillary GC. Retention times are 4.52 and 4.72, respectively, 150oC 15 meter column.
  • the mixture of lactones 7 and 8 (ratio «4:1, minor isomer is desired) is dissolved in methylene chloride, cooled to -10oC and treated with triethylamine. The mixture is cooled to -16oC and methanesulfonyl chloride (22.8 g, 0.20 mol) is added over a 2 h period.
  • TLC shows the reaction to be complete, the mixture is washed with 5% sodium bicarbonate (NaHCO 3 ), dried over sodium sulfate (NaSO 4 ) and concentrated under reduced pressure to afford an oil.
  • the NMR spectrum shows the mesylate methyl at 3.2 ppm. If desired, the mesylates are separated by silica gel chromatography with 15% ethyl acetate/hexane.
  • Leavlng groups such as tosylate, trifluoromethanesulfonate should be just as effective in the inversion reaction. NaOH will also work. It does not matter what acid is used to acidify the mixture. The ratio of isomers varies somewhat, but, in general, it comes out the reverse of what went in.
  • the crude mesylate from above is dissolved in DMS0 and treated with 59.9 g of PEG-300, and 43.2 g of sodium azide.
  • the mixture is heated to 70oC overnight under a nitrogen atmosphere, cooled to room temperature and poured into 250 ml of half saturated brine and 250 ml of ethyl acetate.
  • the organic layers are washed with one-half saturated brine, dried over sodium sulfate and concentrated to afford the azides 10a and 10b.
  • Amines 11a and lib A solution of the azides 10a and 10b in absolute ethanol and 10% Pd/C is hydrogenated at 28 psi for 4 hours. The catalyst is removed by filtration through solka flock and the filtrate is concentrated to a viscous oil which is not characterized further. TLC in 25% ethyl acetate/hexane shows a red (characteristic of primary amine) origin spot when developed in ninhydrin.
  • the reduction may be performed with a variety of catalysts such as Pt and Ni or by chemical means such as vanadous chloride, sodium hydrosulfite, aluminum amalgam, titanium trichloride, hydrogen sulfide and 1,3-propanedithiol.
  • catalysts such as Pt and Ni
  • chemical means such as vanadous chloride, sodium hydrosulfite, aluminum amalgam, titanium trichloride, hydrogen sulfide and 1,3-propanedithiol.
  • T-butoxycarbonyl (T-Boc) amino lactones la and lb are prepared as follows: The crude oil from above is taken up in THF and saturated sodium bicarbonate and T-Boc anhydride. The mixture is stirred at room temperature overnight. Extraction with ethyl acetate from water affords a mixture of lactones la and lb. Crystallization from 1:1 ethyl acetate/heptane affords the pure (2S, 4S, 5S)-lactone 1b. Mp: 146-148oC.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Furan Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des procédés et des intermédiaires permettant une préparation du dipeptide hydroxyéthylénique isostère de leu-val lequel est lui-même utile dans la préparation de peptides inhibiteurs de la rénine. Le procédé emploie certains nouveaux oxazolidènes.
EP19890907510 1988-06-30 1989-06-08 Synthese de dipeptide hydroxyethylenique isostere et ses intermediaires Withdrawn EP0423170A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US21378788A 1988-06-30 1988-06-30
US213787 1988-06-30

Publications (1)

Publication Number Publication Date
EP0423170A1 true EP0423170A1 (fr) 1991-04-24

Family

ID=22796508

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19890907510 Withdrawn EP0423170A1 (fr) 1988-06-30 1989-06-08 Synthese de dipeptide hydroxyethylenique isostere et ses intermediaires

Country Status (4)

Country Link
EP (1) EP0423170A1 (fr)
JP (1) JPH03505577A (fr)
AU (1) AU3832089A (fr)
WO (1) WO1990000166A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5175298A (en) * 1988-06-30 1992-12-29 The Upjohn Company Dipeptide hydroxy ethylene isostere synthesis and intermediates therefor
GB8912659D0 (en) * 1989-06-02 1989-07-19 Ici Plc Process
US5229518A (en) * 1991-03-06 1993-07-20 Abbott Laboratories Isomerically pure 2-piperidone compounds
US5342981A (en) * 1991-03-06 1994-08-30 Abbott Laboratories Substantially isomerically pure hexane or hexene compounds
US5606078A (en) * 1994-04-18 1997-02-25 Ciba-Geigy Corporation 3,5-Disubstituted tetrahydrofuran-2-ones

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK356085A (da) * 1984-08-06 1986-02-07 Upjohn Co Reninhaemmende peptid eller et farmaceutisk acceptabelt syreadditionssalt deraf

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9000166A1 *

Also Published As

Publication number Publication date
AU3832089A (en) 1990-01-23
JPH03505577A (ja) 1991-12-05
WO1990000166A1 (fr) 1990-01-11

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