FI105024B - Förfarande för framställning av terapeutiskt användbara N-(amidinobensoyl- eller amidinopyridylkarbonyl)-alfa-aminosyraderivat - Google Patents

Förfarande för framställning av terapeutiskt användbara N-(amidinobensoyl- eller amidinopyridylkarbonyl)-alfa-aminosyraderivat Download PDF

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FI105024B
FI105024B FI921163A FI921163A FI105024B FI 105024 B FI105024 B FI 105024B FI 921163 A FI921163 A FI 921163A FI 921163 A FI921163 A FI 921163A FI 105024 B FI105024 B FI 105024B
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acid
acetic acid
piperidinyl
oxy
group
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FI921163A
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FI921163A (fi
FI921163A0 (fi
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Marcel Mueller
Leo Alig
Paul Hadvary
Marianne Huerzeler
Beat Steiner
Thomas Weller
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Hoffmann La Roche
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Claims (16)

1. Förfarande för framställning av terapeutiskt an-vändbara N- (amidinobensoyl- eller amidinopyridylkarbonyl) -5 α-aminosyraderivat med formeln I HaN>. ___ O R" j^\ n i i X = Y R· S
2. Förfarande enligt patentkrav 1, k ä n n e -tecknat av att man framställer [[1-(N-(p-amidino-30 bensoyl)-L-alanyl]-4-piperidinyl]oxi]attiksyra. · 3. Förfarande enligt patentkrav l, kanne- tecknat av att man framställer [[1—[N—[(5-amidino- 2-pyridyl) karbonyl] -L-alanyl] - 4-piperidinyl ] oxi ] ättiksyra. • · 60 105024
3. X=Y R· J) « · A 59 105024 omvandlas cyangruppen till en amidinogrupp pä ett i och för sig känt sätt, eller c) en amin med formeln
4. Förfarande enligt patentkrav 1, kanne- tecknat av att man framställer [[1-[N-(p-amidi-nobensoyl)-3-(4-hydroxi-3-jodfenyl)-L-alanyl]-4-piperidinyl] oxi]ättiksyra. 5 5. Förfarande enligt patentkrav 1, k ä n n e - tecknat av att man framställer [[1-[3-acetoxi-N-(p-amidinobensoyl)-L-alanyl]-4-piperidinyl]oxi]ättiksyra.
5 R'-NHCH(R")CO-Q IV omsätts med en syra med formeln XIII 10 \-COOH XUI HN ' eller ett reaktivt derivat därav pä ett i och för sig känt sätt, 15 och eventuellt underkastas den erhällna föreningen med formeln I en eller flera av följande reaktioner: i) en primär eller sekundär lägre alkoxikarbonyl-grupp eller fenyl-lägre-alkoxikarbonylgrupp -COOT eller -COOT' spjälkas till en fri karboxylgrupp, 20 ii) en karboxylgrupp -COOT eller -COOT' förestras till en primär eller sekundär lägre alkoxikarbonylgrupp eller fenyl-lägre-alkoxikarbonylgrupp, iii) en fenylgrupp i gruppen R" joderas, iv) en förening med formeln I omvandlas till ett 25 fysiologiskt användbart salt, och v) ett salt av en förening med formeln I omvandlas till en fri syra eller bas.
6. Förfarande enligt patentkrav 1, k ä n n e - tecknat av att man framställer [p-[[1-(p-amidino- 10 bensoyl)-2-pyrrolidinyl]karbonyl]fenoxi]ättiksyra.
7. Förfarande enligt patentkrav 1, k ä n n e - tecknat av att man framställer [[1-[N-[(5-amidino-2-pyridyl)karbonyl]-L-tyrosyl]-4-piperidinyl]oxi]ättiksyra. 15
8. Förfarande enligt patentkrav 1, kanne- tecknat av att man framställer [[1-[N-(p-amidino-bensoyl)-L-tyrosyl]-4-piperidinyl]oxi]ättiksyra.
9. Förfarande enligt patentkrav 1, k ä n n e - tecknat av att man framställer (S)-1-[2-(5-amidino- 20 pyridin-2-ylkarbonylamino)-3-(4-metoxifenyl)propionyl]pi pe r idin- 4 -yloxi ättiksyra .
10. Förfarande enligt patentkrav 1, k ä n n e -tecknat av att man framställer (S)-1-[2-(4-amidino-bensamido) -3- (4-metoxifenyl) propionyl ] piperidin-4-yloxiät- 25 tiksyraetylester.
10 HN väri den ena av X och Y är CH och den andra är CH eller N, R' är väte eller metyl,
15 R" är väte, lägre alkyl, fenyl eller lägre alkyl med en substituent ur gruppen hydroxi, lägre alkoxi, lägre alka-noyloxi, amino, karboxyl, fenyl, med lägre alkoxi, jod och/eller hydroxi substituerad fenyl och indolyl, eller R' och R" tillsammans med de N- och C-atomer, vid vilka de är 20 bundna, bildar en 5- eller 6-ledad ring, Q är en grupp med formeln: /(CHa)n-v o COO-T —N Y ^ , • \ / O 25 '-' eller * « eller, dä R' och R" tillsammans med de N- och C-atomer, vid vilka de är bundna, bildar en ring, sä kan Q ytterli-gare vara en grupp med formeln 58 105024 Rz '}==\ Q9 -(\ /)—O COO-T V 5 n är ett tai 0 eller 1, R2 betecknar väte eller en grupp -OCH2COO-T', T och Τ' betecknar väte, primär eller sekundär lägre alkyl 10 eller fenyl-lägre-alkyl, samt deras hydrater och solvater och deras fysiologiskt användbara salter, kännetecknatav att a) i en förening med formeln 15
0 E" f/ λ II I A (/ \ C-N-CH-C-G II \ / I II X = Y E' O 20 vari A är en eventuellt skyddad amidinogrupp, E', E" och G betecknar samma som R', R" respektive Q i formeln I, varvid G ändä i stället för gruppen -COOT inne-häller en tert-butoxikarbonylgrupp -COO-tBu och E' och E" I · 25 kan innehälla en karboxylsyraestergrupp och/eller eter- grupp och/eller skyddad aminogrupp, spjälkas den i G närvarande gruppen -COO-tBu och en eventuellt i A, E1 eller E" närvarande etergrupp, skyddad amino- eller amidinogrupp eller karboxylsyraestergrupp pä ett 30 i och för sig känt sätt, eller · b) i en nitril med formeln ___ O R" // \ « 1 TTT NsC—f x)-C-N-CH-C-Q 111
11. Förfarande enligt patentkrav 1, k ä n n e -tecknat av att man framställer (S)-1-[2-(4-amidino-bensamido) -3- (4-metoxifenyl) propionyl ]piperidin-4-yloxiät-tiksyra. 30
12. Förfarande enligt patentkrav 1, känne- t e c k n a t av att man framställer [l-[N-(4-amidino-bensoyl)-4 '-hexyloxi-L-fenylalanyl]piperidin-4-yloxi]ättiksyra . 4 . · ·
FI921163A 1991-03-26 1992-03-18 Förfarande för framställning av terapeutiskt användbara N-(amidinobensoyl- eller amidinopyridylkarbonyl)-alfa-aminosyraderivat FI105024B (sv)

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CH91091 1991-03-26
CH91091 1991-03-26
CH17692 1992-01-22
CH17692 1992-01-22

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FI921163A FI921163A (fi) 1992-09-27
FI105024B true FI105024B (sv) 2000-05-31

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NO921169D0 (no) 1992-03-25
BG60796B2 (bg) 1996-03-29
ATE127800T1 (de) 1995-09-15
TW198011B (sv) 1993-01-11
UA39849C2 (uk) 2001-07-16
IL101311A (en) 2000-07-16
IE920953A1 (en) 1992-10-07
IE70601B1 (en) 1996-12-11
ES2078570T3 (es) 1995-12-16
HU211978A9 (en) 1996-01-29
IS3825A (is) 1992-09-27
SK279688B6 (sk) 1999-02-11
FI921163A (fi) 1992-09-27
US5747522A (en) 1998-05-05
EP0505868B1 (de) 1995-09-13
CA2061661A1 (en) 1992-09-27
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IL101311A0 (en) 1992-11-15
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US5670515A (en) 1997-09-23
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NO921169L (no) 1992-09-28
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AU659629B2 (en) 1995-05-25
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