FI106197B - Förfarande för framställning av farmaceutiskt användbara alfa-metyltryptofanderivat av dipeptoidtyp - Google Patents

Förfarande för framställning av farmaceutiskt användbara alfa-metyltryptofanderivat av dipeptoidtyp Download PDF

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FI106197B
FI106197B FI916060A FI916060A FI106197B FI 106197 B FI106197 B FI 106197B FI 916060 A FI916060 A FI 916060A FI 916060 A FI916060 A FI 916060A FI 106197 B FI106197 B FI 106197B
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amino
methyl
oxo
indol
mmol
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FI916060A0 (fi
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Julian Aranda
David Christopher Horwell
Martyn Clive Pritchard
Reginald Stewart Richardson
Edward Roberts
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Warner Lambert Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • 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
    • C07K5/06156—Dipeptides with the first amino acid being heterocyclic and Trp-amino acid; 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
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • 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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  • Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)
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Claims (12)

1. Förfarande för framställning av a-metyltryptofanderivat av dipeptoidtyp med formeln I A). * I R'-A-NH^TcONHv Sk Me Ph R3 eller deras farmaceutiskt godtagbara salter, i vilken formel R1 är en cykloalkyl- eller polycykloalkylkolväte med 3-12 kolatomer, som har 0-4 substituenter, vilka är valda av en rak eller förgrenad Cj-Cg-alkyl, halogen och CF3, A är -OC(=0) -SO,- eller -CH,CO-, R3 och R4 är oberoende av varandra H, en C1-C4-alkylgrupp eller -(CH2)n-B-D, i vilken n är ett helt tai 0-3, B är en bindning, -0C0 (CH2) n-, -O (CH2) n-, —NHCO (CH2) n—, -CONH (CH2) n—, -NHCOCH=CH-, -S (CH2) n-, -S(=0)-(CH,)n- eller -S02 (CH,) n-f i vilka n betecknar detsamma som ovan, och D är H, -C00R*, -OH eller tetrazol, väri R* är H eller en rak eller förgrenad Cj-C.j-alkyl och Ph är en fenylgrupp, som är eventuellt substituerad med en halogenatom, kännetecknat därav, att a) en förening med formeln Ia 187 106197 CO {ia) Π,Η+ΟΟΙΠΚγΛρπ R3 i vilken R3 och R4 betecknar detsamma som ovan, omsättes med en förening med formeIn IV R:-A-C1 (IV) i vilken Rl och A betecknar detsamma som ovan, eller b) för framställning av sädana föreningar med formeln I, i vilka A är -00(=0)-, en förening med formeln VI XX) R1 -OCONH I'C00H Me i vilken R1 betecknar detsamma som ovan, omsättes med en amin med formeln VII H2N-CHR3-CHR4 -Ph (VII) i vilken R3 och R4 betecknar detsamma som ovan, eller dess trifluoracetatsalt, och, vid behov, den erhällna föreningen frigörs frän sitt sait, eller c) för framställning av sädana föreningar med formeln I, i vilka A är -00(=0)-, R1 betecknar detsamma som ovan, R3 är -CH2OCOCH2CH2COOH och R4 är väte, en alkohol med formeln VIII 188 1 06 1 97 XX) ™, R1 - OCONH 'l' CONHn. v Me Ph ^OH omsättes med en succinanhydrid, eller d) för framställning av sädana föreningar med formeln I, i vilka R1 betecknar detsamma som ovan och A är -0C(=0)-, R3 är ~CH2NHCOCH=CHCOOCH3/ -CH2NHCOCH2CH,COOH eller -CH2NHCOCH=CHCOOH och R4 är H, en azid med formeln IX XX) S (ix) R1 OCONH "T* CONHv. Me y^Ph ^N3 omsättes med succinanhydrid eller ett sait eller en ester av furoarsyra, eller e) för framställning av sädana föreningar med formeln I, i vilka R1 betecknar detsamma som ovan, A är -0C(=0)-, R3 är H och R4 är -NHCOCH2CH2COOH eller -NHCOCH=CHCOOH, en förening med formeln VI yo R1 -OCONH'l COOH Me omsättes med en amin med formeln X 189 1 06 1 97 Bz°2c γ^ΝΗ2 (x) Ph varefter erhällen bensylester hydreras till en fri syra, och, om sa önskas, de sälunda erhallna föreningarna med formeln I omvandlas, till sina farmaceutiskt godtagbara salter, och/eller deras möjliga alkylestergrupper hydro-lyseras till fria syragrupper.
2. Förfarande enligt patentkravet l, kännetecknat därav, att man framställer (±)trans-2-klorcyklohexyl[1-(lH-indol-3-ylmetyl)-l-metyl-2-oxo-2-[(2-fenyletyl)amino]etyl]karbamat, (+)- eller (-)-2-klorcyklohexyl[l-(lH-indol-3-yl-metyl)-l-metyl-2-oxo-2-[(2-fenyletyl)amino]-etyl]karbamat eller 2-klorcyklohexyl[2-[[1-(hydroximetyl)-2-fenyl-etyl]amino]- 1- (lH-indol-3-ylmetyl)-1-mety1-2-oxo-etyl]karbamat.
3. Förfarande enligt patentkravet l, kännetecknat därav, att man framställer 2- [[2-[[[(2-klorcyklohexyl)oxi]karbonyl]amino]-3-(lH-indol-3-yl)-2-metyl-l-oxopropyl]amino]-3-fenylpropyl-butandioat eller 2— [[2-[[[(2-metylcyklohexyl)oxi]karbonyl]amino]-3-(lH-indol- 3- yl)-2-metyl-l-oxopropyl]amino]-3-fenylpropyl-butandioat.
4. Förfarande enligt patentkravet 1 kännetecknat därav, att man framställer (±) -tricyklo[3.3.1. l3,7]dek-2-yl- [ l- (lH-indol-3-ylmetyl) -1-metyl-2-oxo-2-[(2-fenyletyl)amino]etyl]karbamat, tricyklo[3.3.1. l3'7] dek-2-y 1- [2- [ [ 1- (hydroximetyl) -2-fenyletyl ]amino]-1-(lH-indol-3-ylmetyl)-1-metyl-2-oxoetyl]karbamat «o 106197 eller (R) -tricyklo[3.3.1. l3,7]dek-2-yl-[l- (lH-indol-3-ylmetyl) -1-metyl-2-[metyl-(2-fenyletyl)amino]-2-oxoetylkarbamat.
5. Förfarande enligt patentkravet 1, kännetecknat därav, att man framställer 2-[[3-(lH-indol-3-yl)-2-metyl-l-oxo-2-[[(tricyklo-[3.3.1.13'7]dek-2-yloxi)karbonyl]amino]propyl]amino]-3-fenyl-propyl-butandioat eller 2-[[3-(lH-indol-3-yl)-2-metyl-l-oxo-2-[[(tricyklo- [3.3.1.I3,7 ]dek-2-yloxi)karbonyl]amino]propyl]amino]-1-fenyl- etyl-butandioat.
6. Förfarande enligt patentkravet 1, kännetecknat därav, att man framställer [R-(R*,R*)]-4-[[2—[[3-(lH-indol-3-yl)-2-metyl-l-oxo-2 [ [ (tricyklo[3.3.1. I3,7 ] dek-2-yloxi) karbonyl] amino] propyl ]-amino]-1-fenyletyl]amino]-4-oxobutansyra.
7. Förfarande enligt patentkravet 1, kännetecknat därav, att man framställer [R-[R*,S*-(E)]]-4-[[2—[[3-(lH-indol-3-yl)-2-metyl-l-oxo-2 [ [ (tricyklo [3.3.1.13,7] dek-2-yloxi) karbonyl]amino]propyl]-amino]-3-fenylpropyl]amino]-4-oxo-2-butensyra, [R-[R*,R*-(E)]]-4-[[2-[[3-(lH-indol-3-yl)-2-metyl-l-oxo-2 [ [ (tricyklo[3.3.1.13,7]dek-2-yloxi) karbonyl]amino] -propyl]amino]-1-fenyletyl]amino]-4-oxo-2-butensyra eller [R-[R*,S*)]-4-[[2 — [[3-(lH-indol-3-yl)-2-metyl-l-oxo-2 [ [ (tricyklo[3.3. l. l3,7]dek-2-yloxi)karbonyl]amino]-propy1]amino]-3-fenylpropyl]amino]-4-oxobutansyra.
8. Förfarande enligt patentkravet 1, kännetecknat därav, att 191 106197 man framställer metylester av [lS-[la,2p[S*[S*(E) ]],4a]]-4-[[2—[[3-(lH-indol-3-yl)-2-metyl-l-oxo-2-[[[(1,7,7-trimetylbicyklo[2.2.l]hept-2-yl)-oxi]karbonyl]amino]propyl]amino]-l-fenylety1]amino]- 4-oxo-2-butensyra (bicyklosystemet är lS-endo) eller [lS-[la,2P[S*[S*(E)]],4a]]-4-[[2-[[3-(lH-indol-3-yl)-2-metyl-l-oxo-2-[[[(1,7,7-trimetylbicyklo[2.2.1Jhept-2-y1)oxi]karbonyl]amino]propyl]amino]-l-fenylety1]amino]- 4-oxo-2-butensyra (bicyklosystemet är lS-endo).
9. Förfarande enligt patentkravet 1, kännetecknat därav, att man framställer [R-(R*,S*)]-p-[[3-(lH-indol-3-yl)-2-metyl-l-oxo-2-[[(tri-cyklo[3.3. l. l3,7]dek-2-yloxi) karbonyl] amino] propyl] amino] -bensenbutansyra.
10. Förfarande enligt patentkravet 1, kännetecknat därav, att man framställer [R-(R*,S*)]-[[2-[[3-(lH-indol-3-yl)-2-metyl-l-oxo-2-[ [ (tricyklo[3.3.1.13,7]dek-2-yloxi)karbonyl]amino]propyl]-amino]-3-fenylpropyl]sulfinyl]ättiksyra eller dess etylester, [R-(R*,S*)]-[[2-[[3-(lH-indol-3-yl)-2-metyl-l-oxo-2-[[(tri-cyklo[3.3 ,l.l3,7]dek-2-yloxi)karbonyl]amino]propyl]amino]-3-fenylpropyl]sulfonyl]attiksyra eller dess etylester, eller [R-(R*,S*)]—[[2—[[3-(lH-indol-3-yl)-2-metyl-l-oxo-2-[ [ (tricyklo[ 3.3.1.13,7] dek-2-yloxi) karbonyl]amino]propyl]-amino]-3-fenylpropyl]tio]ättiksyra.
11. Mellanproduktförening med formeln VI 106197 192 ΧΌ „„ R1 - OCONH "T^ COOH Me i vilken resten R1 betecknar detsamma som i patentkravet 1.
12. Mellanproduktförening enligt patentkravet 11, i vilken R1 betecknar 2-adamantyl, 4-protoadamantyl, exobornyl, endobor-nyl, exonorbornyl, endonorbornyl, 2-klorcyklohexyl, 2-metyl-cyklohexyl eller kamfanyl.
FI916060A 1989-06-29 1991-12-20 Förfarande för framställning av farmaceutiskt användbara alfa-metyltryptofanderivat av dipeptoidtyp FI106197B (sv)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US37432789A 1989-06-29 1989-06-29
US37432789 1989-06-29
US42248689A 1989-10-16 1989-10-16
US42248689 1989-10-16
US53081190A 1990-06-05 1990-06-05
US53081190 1990-06-05
PCT/US1990/003553 WO1991000274A1 (en) 1989-06-29 1990-06-28 N-substituted cycloalkyl and polycycloalkyl alpha-substituted trp-phe- and phenethylamine derivatives
US9003553 1990-06-28

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FI916060A0 FI916060A0 (fi) 1991-12-20
FI106197B true FI106197B (sv) 2000-12-15

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FI916060A FI106197B (sv) 1989-06-29 1991-12-20 Förfarande för framställning av farmaceutiskt användbara alfa-metyltryptofanderivat av dipeptoidtyp

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EP (2) EP0479910A1 (sv)
JP (1) JP2972331B2 (sv)
KR (2) KR0167315B1 (sv)
CN (1) CN1049165A (sv)
AT (1) ATE275546T1 (sv)
AU (1) AU644088B2 (sv)
CA (2) CA2060652C (sv)
DE (1) DE69034162T2 (sv)
DK (1) DK0405537T3 (sv)
ES (1) ES2229202T3 (sv)
FI (1) FI106197B (sv)
IE (1) IE902347A1 (sv)
IL (1) IL94903A0 (sv)
NO (1) NO301831B1 (sv)
NZ (1) NZ234264A (sv)
PT (1) PT94543B (sv)
WO (1) WO1991000274A1 (sv)

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PT94543A (pt) 1991-03-20
KR920702678A (ko) 1992-10-06
ATE275546T1 (de) 2004-09-15
AU5962890A (en) 1991-01-17
KR0180539B1 (en) 1999-05-01
CN1049165A (zh) 1991-02-13
EP0479910A1 (en) 1992-04-15
EP0405537B1 (en) 2004-09-08
DK0405537T3 (da) 2005-01-10
CA2060652A1 (en) 1990-12-30
NO915122L (no) 1992-02-27
CA2344707A1 (en) 1991-01-10
JPH04506079A (ja) 1992-10-22
PT94543B (pt) 1997-04-30
NO915122D0 (no) 1991-12-27
JP2972331B2 (ja) 1999-11-08
CA2060652C (en) 2001-08-21
DE69034162D1 (de) 2004-10-14
EP0405537A1 (en) 1991-01-02
DE69034162T2 (de) 2005-09-22
IE902347L (en) 1990-12-29
KR0167315B1 (ko) 1999-01-15
NZ234264A (en) 1993-05-26
FI916060A0 (fi) 1991-12-20
CA2344707C (en) 2002-07-30
WO1991000274A1 (en) 1991-01-10
IE902347A1 (en) 1991-01-16
NO301831B1 (no) 1997-12-15
AU644088B2 (en) 1993-12-02
ES2229202T3 (es) 2005-04-16
IL94903A0 (en) 1991-04-15

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