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FI90346B - Förfarande för framställning av terapeutiskt användbara nor-statin- och nor-cyklostatin derivat - Google Patents

Förfarande för framställning av terapeutiskt användbara nor-statin- och nor-cyklostatin derivat Download PDF

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Publication number
FI90346B
FI90346B FI874787A FI874787A FI90346B FI 90346 B FI90346 B FI 90346B FI 874787 A FI874787 A FI 874787A FI 874787 A FI874787 A FI 874787A FI 90346 B FI90346 B FI 90346B
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product
give
sta
mixture
nmr
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FI874787A
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English (en)
Finnish (fi)
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FI874787A (sv
FI90346C (sv
FI874787A0 (sv
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Dennis Jay Hoover
Robert Louis Rosati
Ronald Thure Wester
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Pfizer
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/14—Angiotensins: Related peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • 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
    • C07K5/0227—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
    • 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
    • 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
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Claims (9)

1. Förfarande för framställning av terapeutiskt användbara nor-statin- och nor-syklostatinpolypeptider '> mod formeLn Xn^Xw/ (1) il = H 10. r2 eller (11) H H Ξ H H o R5 oh där Z är Ri-(Y)m-( A)p, där Rx är amino, (C1_4 )alkylamino, 20 (Cj^.3 )alkoxi( C2.4 )alkylenamino, karboxiiCi^ )alkyl, hydroxi- (C2_4 )alkylenamino, ()alkoxiCOCH2N( CH3), aminoiC^ )al-kyl, morfolino, piperidyl, hydroxipiperidino, 4-oxopipe-ridino, piperazino, 4-oxopiperidino-etylenketal, 4-((^.3)-alkylpiperazino, tiomorfolino, tiomorfolino-l-oxid, tio-25 morfolino-1,1-dioxid, N-(C1.4 )alkoxikarbonylpiperidyl, 4-()alkoxikarbonylpiperazino, 3-oxomorfolino, 3,5-dioxo-morfolino, hydroxipyridyl, pyridyl, (s)-pyrrolid-2-yl, N-t-butoxikarbonyl-( s )-pyrrolid-2-yl, (Cx_3 )alkoxikarbonyl-( s )-pyrrolid-2-yl eller 4-( C:.4 )alkanoylpiperazino; Y är 30 C=0, P(0CH3)=0 eller S02; A är N(CH3), NH eller O; m och p är bäda heltalen 0 eller 1; M är fenyl, bensyl, naftyl, tienyl, metoxifenyl, hydroxifenyl, klorfenyl eller (C6_7)-cykloalkyl; Q är metyl eller väte; R2 är (C^) alkyl, (C1.3)alkyltio(C1.2)alkyl, (C1.3)alkoxi(C1.2)alkyl, bensyl-35 oxi( Cj.j )alkyl, bensyl, hydroxi()alkyl, karboxi-(C1.2)- 167 90 3 45 alkyl, guanidofCj..,)alkyl, (^.3 )alkylsulfinyl(C^2 )alkyl, (Ci.3 )alkylsulfonyl( )alkyl, 4-bensyloxikarbonylaminobu-tyl, 4-aminobutyl, imidazol-4-ylmetyl, N-t-butoxikarbo-nyl-imidazsol-4-ylmetyl eller karbamyl(¢3.3)alkyl; X är 5 cyklohexsyl, i-propyl eller fenyl; W är CH III OCO( 03_3 )al-kyldi(Ci.j )alkylamlno, CH III OCOiC^j )alkylpiperldino, CH III OH, C=0, CHIIIN3, CH-^N3, CH-^NH2, CHI|lNH2, C(CH3)i|iOH, C(CH3)-^OH, CHIU OCO-(C1.2)alkyl eller CH III OCO( Cr.2 )alkylen-C02H; Z1 är CH20H eller R-S-T, där R är C=0, S är O, NH,
10 N(CH3), CH2 eller en kemisk bindning, som binder R och T; T är (C^g)alkyl, hydroxi(C1.4)alkyl, CONH( ^_4 )alkyl, väte, trifluoretyl, (C6_7 )cykloalkyl, (C6_7 )cykloalkylmetyl, fenyl, benzyl, amino (C2_5) alkyl, 0-(C1_2)alkyl-hydroxylamino, morfolino, 4-( ΰ3.2 )alkylpiperazino eller omega-di(C1_2 )al-15 kylamino(C3,5) alkyl; L är CH eller N; R5 är imidazol-4- ylmetyl eller (C2_5) alkyl; och R6 är (C1.4)alkoxi eller (C3. 4)alkylamino, förutsatt att när m är 0, sä är p = 0; när A är O sä är Y=C=0; när T är CONHfC^)alkyl sä är S = NH, N(CH3) eller CH2; när T är (C2_5 )alkylamino, O-(C1.2)alkyl-20 hydroxylamino, morfolino eller 4-(C1.2)alkylpiperazino, sä är S = CH2 eller en kemisk bindning, som binder R och T; och när Z1 är CHO eller CH20H sä är Rx morfolino, k ä n-netecknat därav, att man bildar en amidbindning C(O)N, med hjälp av en dehydreringskoppling, varvid de 25 funktionella grupper som inte deltar i reaktionen kan vara skyddade, varefter man eventuellt utför följande steg, där man 1) selektivt avlägsnar skyddsgrupperna, 2. oxiderar en sulfidgrupp tili sulfoxid eller sulfon, 3. oxiderar W dä det är CH l|| OH eller CH^eOH tili en 30 grupp C=0, 4) acylerar W, dä det är CH l|l OH och om sä önskas bildar man ett farmaceutiskt godtagbart sait av produkten.
2. Förfarande enligt patentkravet 1 för framställ-ning av en förening med formeln I, känneteck-35 n a t därav, att amidbindningen bildas mellan delarna
168. O 3 ‘' 6 / - u jC / Z CO-H V \n/\W I H *2
3. Förfarande enligt patentkravet 1 för framstäl-lning av en förening med formeln I, känneteck-n a t därav, att amidbindningen bildas mellan delarna 10 /M /X ji ? n { / Z/XNVCX 0H OCh 0 _R2 15 4. Förfarande enligt patentkravet 1 för framstäl- lning av en förening med formeln II, känneteck-n a t därav, att amidbindningen bildas mellan delarna COxc/S^a ooh f® H |i = H-N OR- z Ξ OH 25 5. Förfarande enligt patentkravet 1, känne- t e c k n a t därav, att kopplingsreagenset är 1-hydrox-ibensotriazol och dicyklohexylkarbodiimid.
6. Förfarande enligt patentkravet 1, känne-t e c k n a t därav, att kopplingsreagenset är 1-hydrox- 30 ibensotriazol och dimetylaminopropyletylkarbodiimid.
7. Förfarande enligt patentkravet 1, känne-t e c k n a t därav, att det eventuella oxideringsskedet av en sulfidgrupp utförs med m-klorperbensoesyra.
8. Förfarande enligt patentkravet 1, känne- 35 tecknat därav, att det eventuella oxideringsskedet 169 av gruppen CH l|| OH eller CH^OH utförs med hjälp av pyri-dium-dikromat och ättiksyraanhydrid.
9. Förfarande enligt patentkravet 1, k ä n n e -* t e c k n a t därav, att det eventuella acyleringsskedet 5 av gruppen CH III OH utförs med en syra och de i patentkravet 5 eller 6 nämnda koppiingsreagensen eller med en sy-rahalogenid och en organisk tertiär amin.
FI874787A 1986-10-31 1987-10-30 Förfarande för framställning av terapeutiskt användbara nor-statin- och nor-cyklostatin derivat FI90346C (sv)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US92544986A 1986-10-31 1986-10-31
US92544986 1986-10-31
US6898287A 1987-07-01 1987-07-01
US6898287 1987-07-01

Publications (4)

Publication Number Publication Date
FI874787A0 FI874787A0 (sv) 1987-10-30
FI874787A FI874787A (sv) 1988-05-01
FI90346B true FI90346B (sv) 1993-10-15
FI90346C FI90346C (sv) 1994-01-25

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FI874787A FI90346C (sv) 1986-10-31 1987-10-30 Förfarande för framställning av terapeutiskt användbara nor-statin- och nor-cyklostatin derivat

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EP (1) EP0266950B1 (sv)
JP (1) JPH07108901B2 (sv)
KR (1) KR910002544B1 (sv)
CN (1) CN1027271C (sv)
AR (1) AR245732A1 (sv)
AU (1) AU585180B2 (sv)
CA (1) CA1310793C (sv)
DE (1) DE3788626T2 (sv)
DK (1) DK568487A (sv)
EG (1) EG18378A (sv)
ES (1) ES2061512T3 (sv)
FI (1) FI90346C (sv)
HU (1) HU207869B (sv)
IE (1) IE61087B1 (sv)
IL (1) IL84270A0 (sv)
MY (1) MY103189A (sv)
NO (1) NO173017C (sv)
NZ (1) NZ222373A (sv)
PH (1) PH25231A (sv)
PL (1) PL151679B1 (sv)
PT (1) PT86024B (sv)
YU (1) YU46819B (sv)

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ES2061512T3 (es) 1994-12-16
JPH07173134A (ja) 1995-07-11
KR880005152A (ko) 1988-06-28
CN87101499A (zh) 1988-05-11
CA1310793C (en) 1992-11-24
YU198087A (en) 1989-02-28
MY103189A (en) 1993-05-29
IL84270A0 (en) 1988-03-31
EP0266950B1 (en) 1993-12-29
DK568487A (da) 1988-05-01
AU585180B2 (en) 1989-06-08
CN1027271C (zh) 1995-01-04
NZ222373A (en) 1989-09-27
FI874787A (sv) 1988-05-01
EG18378A (en) 1993-04-30
EP0266950A2 (en) 1988-05-11
KR910002544B1 (ko) 1991-04-23
DE3788626D1 (de) 1994-02-10
IE61087B1 (en) 1994-09-21
JPH07108901B2 (ja) 1995-11-22
AU8054187A (en) 1988-05-05
NO173017B (no) 1993-07-05
YU46819B (sh) 1994-06-10
FI90346C (sv) 1994-01-25
NO874530D0 (no) 1987-10-30
AR245732A1 (es) 1994-02-28
DE3788626T2 (de) 1994-04-28
PL268521A1 (en) 1988-09-01
PL151679B1 (en) 1990-09-28
HU207869B (en) 1993-06-28
PT86024B (pt) 1990-07-31
DK568487D0 (da) 1987-10-30
PT86024A (en) 1987-11-01
FI874787A0 (sv) 1987-10-30
HUT45270A (en) 1988-06-28
NO173017C (no) 1993-10-13
PH25231A (en) 1991-03-27
IE872929L (en) 1988-04-30
NO874530L (no) 1988-05-02
EP0266950A3 (en) 1990-04-11

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