DK2776404T3 - Heterocykliske analoger af propargyl-bundne inhibitorer af dihydrofolat-reduktase - Google Patents

Heterocykliske analoger af propargyl-bundne inhibitorer af dihydrofolat-reduktase Download PDF

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DK2776404T3
DK2776404T3 DK12846926.9T DK12846926T DK2776404T3 DK 2776404 T3 DK2776404 T3 DK 2776404T3 DK 12846926 T DK12846926 T DK 12846926T DK 2776404 T3 DK2776404 T3 DK 2776404T3
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alkyl
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phenyl
halogen
hydrogen
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Amy C Anderson
Dennis L Wright
Kathleen M Frey
Janet L Paulsen
Eric W Scocchera
Kishore Viswanathan
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Univ Connecticut
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen 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
    • C07D401/10—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 aromatic rings
    • 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
    • C07D403/10—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 carbon chain containing aromatic rings
    • 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
    • C07D413/10—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 aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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Claims (15)

1. Forbindelse med formel V
formel V hvor R er valgt fra gruppen bestående af H, Ci til Cs alkyl, Ci til C3 alkoxy, og hydroxy; hvor Ri, R2, R3, R4, uafhængigt er valgt fra gruppen bestående af hydrogen, og Ci til Cs alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, arylalkyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, alkoxyalkylcarbonyl, alkoxyalkoxyalkylcarbonyl, arylcarbonyl, pyridinylcarbonyl, aryloxyalkyl, haloalkylcarbonyl, og cyanoalkylcarbonyl; hvor A og B hver uafhængigt er valgt fra gruppen bestående af hydrogen, Ci til Cs alkyl, halogen, hydroxy, lavere haloalkyl, lavere alkoxy, lavere haloalkoxy, lavere alkoxyalkyl, carboxy, lavere alkoxycarbonyl, cyano, nitro, aminocarbonyl, lavere alkylsulfinyl, lavere alkylcarbonylamino, lavere alkylsulfonylamino, lavere alkylthio, lavere alkylsulfonyl, formyl, lavere alkoxycarbonyl, dialkylsilyloxy, phenyl, phenoxy, arylalkoxy, og aryloxyalkoxy, hvor phenyl-, phenoxy-, aryloxy-, og aryloxyalkoxysubstituenterne i sig selv eventuelt kan substitueres med halogen, lavere haloalkyl, lavere alkyl, lavere alkoxy, eller lavere alkylsulfonyl, hvor "lavere" anvendt i forbindelse med hvilken som helst af de ovennævnte grupper betegner Ci til Ce alkyl; hvor en af V og W er en methoxygruppe og den anden er valgt fra gruppen bestående af hydrogen, Ci til Cs alkyl, halogen, hydroxy, lavere haloalkyl, lavere alkoxy, lavere haloalkoxy, lavere alkoxyalkyl, carboxy, lavere alkoxycarbonyl, cyano, nitro, aminocarbonyl, lavere alkylsulfinyl, lavere alkylcarbonylamino, lavere alkylsulfonylamino, lavere alkylthio, lavere alkylsulfonyl, formyl, lavere alkoxycarbonyl, dialkylsilyloxy, phenyl, phenoxy, arylalkoxy, og aryloxyalkoxy, hvor phenyl-, phenoxy-, aryloxy-, og aryloxyalkoxy-substituenterne i sig selv kan være eventuelt uafhængigt substitueret én eller flere gange med halogen, lavere haloalkyl, lavere alkyl, lavere alkoxy, eller lavere alkylsulfonyl, hvor "lavere" anvendt i forbindelse med hvilken som helst af de ovennævnte grupper betegner Ci til Ce, hvor to af J, L, og M, er valgt fra gruppen bestående af hydrogen, Ci til C5 alkyl, halogen, hydroxy, lavere haloalkyl, lavere alkoxy, lavere haloalkoxy, lavere alkoxyalkyl, carboxy, lavere alkoxycarbonyl, cyano, nitro, aminocarbonyl, lavere alkylsulfinyl, lavere alkylcarbonylamino, lavere alkylsulfonylamino, lavere alkylthio, lavere alkylsulfonyl, formyl, lavere alkoxycarbonyl, dialkylsilyloxy, phenyl, phenoxy, arylalkoxy, og aryloxyalkoxy, hvor phenyl-, phenoxy-, aryloxy-, og aryloxyalkoxysubstituenterne i sig selv kan være eventuelt uafhængigt substitueret én eller flere gange med halogen, lavere haloalkyl, lavere alkyl, lavere alkoxy, eller lavere alkylsulfonyl, hvor "lavere" anvendt i forbindelse med hvilken som helst af de ovennævnte grupper betegner Ci til Ce, og hvor (a) den anden af J, L, og M er en substituent valgt fra gruppen bestående af piperidin, perhydropyrimidin, morpholin, pyridin, pyrimidin, indol, isoindol, quinolin, isoquinolin, oxazol, thiazol, og imidazol, hvor piperidin, perhydropyrimidin, morpholin, pyridin, pyrimidin, indol, isoindol, quinolin, isoquinolin, oxazol, thiazol, eller imidazol i sig selv kan eventuelt være substitueret én eller flere gange med Ci til Cs alkyl, halogen, hydroxy, lavere haloalkyl, lavere alkoxy, lavere haloalkoxy, lavere alkoxyalkyl, carboxy, lavere alkoxycarbonyl, cyano, nitro, aminocarbonyl, lavere alkylsulfinyl, lavere alkylcarbonylamino, lavere alkylsulfonylamino, lavere alkylthio, lavere alkylsulfonyl, formyl, lavere alkoxycarbonyl, dialkylsilyloxy, phenyl, phenoxy, arylalkoxy, eller aryloxyalkoxy, hvor phenyl-, phenoxy-, arylalkoxy-, eller aryloxyalkoxy-substituenterne i sig selv kan være eventuelt uafhængigt substitueret én eller flere gange med halogen, lavere haloalkyl, lavere alkyl, lavere alkoxy, eller lavere alkylsulfonyl, hvor "lavere" anvendt i forbindelse med hvilken som helst af de ovennævnte grupper betegner Ci til Ce, eller (b) den anden af J, L, og M er valgt fra gruppen bestående af formel VIA and formel VIB
formel VIA formel VIB hvor mindst én af R32, R33, R34, R35, og R36 er N og hvilke som helst af R32, R33, R34, R35, og R36 så er N ikke CRx, hvor for hver af R32, R33, R34, R35, og R36 ikke er N, Rx er uafhængigt valgt fra hydrogen, Ci til Cs alkyl, halogen, hydroxy, lavere haloalkyl, lavere alkoxy, lavere haloalkoxy, lavere alkoxyalkyl, carboxy, lavere alkoxycarbonyl, cyano, nitro, aminocarbonyl, lavere alkylsulfinyl, lavere alkylcarbonylamino, lavere alkylsulfonylamino, lavere alkylthio, lavere alkylsulfonyl, formyl, lavere alkoxycarbonyl, dialkylsilyloxy, phenyl, phenoxy, arylalkoxy, og aryloxyalkoxy, hvor phenyl-, phenoxy-, aryloxy-, og aryloxyalkoxy-substituenterne i sig selv kan være eventuelt uafhængigt substitueret én eller flere gange med halogen, lavere haloalkyl, lavere alkyl, lavere alkoxy, eller lavere alkylsulfonyl, hvor "lavere" anvendt i forbindelse med hvilken som helst af de ovennævnte grupper betegner Ci til C6; hvor R37 er O, NH, eller NCH3; hvor R38 er N eller CH, og når R38 er CH R37 er NH eller NCH3; og hvor R39 og R40 uafhængigt er hydrogen eller CH3 og farmaceutisk acceptable salte deraf.
2. Forbindelsen med valg (a) i krav 1, hvor R er methyl eller ethyl, én af A og B er hydrogen og den anden af A og B er hydrogen eller Ci til Ce alkyl, én af V og W er methoxy, og den anden af V og W er hydrogen.
3. Forbindelsen med formel 1, hvor den anden af J, L, og M er valgt fra gruppen bestående af formel VIA og formel VIB
formel VIA formel VIB hvor mindst én af R32, R33, R34, R35, og R36 er N og hvilke som helst af R32, R33, R34, R35, og R36 så er N ikke CRx, hvor for hver af R32, R33, R34, R35, og R36 ikke er N, Rx er uafhængigt valgt fra hydrogen, Ci til Cs alkyl, halogen, hydroxy, lavere haloalkyl, lavere alkoxy, lavere haloalkoxy, lavere alkoxyalkyl, carboxy, lavere alkoxycarbonyl, cyano, nitro, aminocarbonyl, lavere alkylsulfinyl, lavere alkylcarbonylamino, lavere alkylsulfonylamino, lavere alkylthio, lavere alkylsulfonyl, formyl, lavere alkoxycarbonyl, dialkylsilyloxy, phenyl, phenoxy, arylalkoxy, og aryloxyalkoxy, hvor phenyl-, phenoxy-, aryloxy-, og aryloxyalkoxy-substituenterne i sig selv kan være eventuelt uafhængigt substitueret én eller flere gange med halogen, lavere haloalkyl, lavere alkyl, lavere alkoxy, eller lavere alkylsulfonyl, hvor "lavere" anvendt i forbindelse med hvilken som helst af de ovennævnte grupper betegner Ci til C6j hvor R37 er O, NH, eller NCH3; hvor R38 er N eller CH, og når R38 er CH R37 er NH eller NCH3; og hvor R39 og R40 uafhængigt er hydrogen eller CH3.
4. Forbindelsen med formel 3, hvor en af J, L, og M er formel VIA, og hvor mindst én af R32, R33, R34, R35, og R36 er N, og hvilke som helst af R32, R33, R34, R35, og R36 der ikke er N er CH.
5. Forbindelsen med formel 4, hvor mindst to af R32, R33, R34, R35, og R36 er N.
6. Forbindelsen med formel 3, hvor en af J, L, og M er formel VI B, hvor R38 er N, R37 er O, og R39 og R40 er den samme og er enten hydrogen eller CH3.
7. Forbindelsen med formel 3, hvor en af J, L, og M er formel VI B, hvor R38 er N, R37 er NH eller NCH3, og R39 og R40 er hydrogen.
8. Forbindelsen med valg (a) of krav 1, hvor to af J, L, og M er valgt fra gruppen bestående af hydrogen, Ci til C5 alkyl, halogen, hydroxy, lavere haloalkyl, lavere alkoxy, lavere haloalkoxy, lavere alkoxyalkyl, carboxy, lavere alkoxycarbonyl, cyano, nitro, aminocarbonyl, lavere alkylsulfinyl, lavere alkylcarbonylamino, lavere alkylsulfonylamino, lavere alkylthio, lavere alkylsulfonyl, formyl, lavere alkoxycarbonyl, diaIkylsilyloxy, phenyl, phenoxy, arylalkoxy, og aryloxyalkoxy, hvor phenyl-, phenoxy-, aryloxy-, og aryloxyalkoxy-substituenterne i sig selv kan være eventuelt uafhængigt substitueret én eller flere gange med halogen, lavere haloalkyl, lavere alkyl, lavere alkoxy, eller lavere alkylsulfonyl, hvor "lavere" anvendt i forbindelse med hvilken som helst af de ovennævnte grupper betegner Ci til C6; hvor den anden af J, L, og M er valgt fra gruppen bestående af formel VIC, formel VID, og formel VIE
Formel VIC formel VID formel VIE hvor en af R41 og R42 er N og den anden er CH; hvor R43 er H eller C1-C6 alkyl; hvor en af R44, R45, og R46 er N, en anden af R44, R45, og R46 er O, S, NH, eller N(Ci-Cealkyl), og den tredje af R44, R45, og R46 er CH; og hvor hvilket som helst methincarbon på den heterocykliske gruppe kan tjene som vedhæftningspunktet af den heterocykliske gruppe til forbindelsen med formel V.
9. Farmaceutisk sammensætning omfattende en forbindelse ifølge et hvilket som helst af kravene 1-8 i kombination med ét eller flere farmaceutisk acceptable fortyndingsmidler, excipienser eller bærere.
10. Forbindelse ifølge et hvilket som helst af kravene 1-8 eller en sammensætning ifølge krav 9 til anvendelse i behandling af et individ der har en bakterieinfektion, en svampeinfektion, eller en protozoinfektion.
11. Forbindelse ifølge et hvilket som helst af kravene 1-8 eller en sammensætning ifølge krav 9 til anvendelse i behandling af et individ der har en infektion af Bacillus anthracis, methicillin-resistent Staphylococcus aureus, Streptococcus pyogenes, Candida glabrata, Candida albicans, Cryptococcus neoformans, Cryptosporidium bom in is eller Toxoplasma gondii.
12. Forbindelse ifølge et hvilket som helst af kravene 1-8 eller en sammensætning ifølge krav 9 til anvendelse i behandling af et individ der har en neoplastisk sygdom.
13. Forbindelse ifølge et hvilket som helst af kravene 1-8 eller en sammensætning ifølge krav 9 til anvendelse i behandling af et individ der har cancer.
14. Farmaceutisk sammensætning ifølge krav 9, yderligere omfattende en sulfaforbindelse der udviser høj aktivitet mod patogene bakterier.
15. Farmaceutisk sammensætning ifølge krav 14 til anvendelse i behandling af et individ der har en bakterieinfektion, en svampeinfektion, en protozoinfektion, en neoplastisk sygdom eller cancer.
DK12846926.9T 2011-11-07 2012-11-06 Heterocykliske analoger af propargyl-bundne inhibitorer af dihydrofolat-reduktase DK2776404T3 (da)

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US13/290,741 US8853228B2 (en) 2007-06-04 2011-11-07 Heterocyclic analogs of propargyl-linked inhibitors of dihydrofolate reductase
PCT/US2012/063729 WO2013070620A1 (en) 2011-11-07 2012-11-06 Heterocyclic analogs of propargyl-linked inhibitors of dihydrofolate reductase

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US9382213B2 (en) 2014-02-12 2016-07-05 Promiliad Biopharma Inc. Heterocyclic and cyclic analogs of propargyl-linked inhibitors of dihydrofolate reductase
CN109071511B (zh) * 2016-01-08 2022-06-07 康涅狄格大学 可用于治疗细菌感染的两性离子性炔丙基连接的抗叶酸剂
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EP0639075A1 (en) * 1990-11-14 1995-02-22 Chiron Corporation Specific inhibition of dihydrofolate reductase and compounds therefor
US5622954A (en) 1994-05-11 1997-04-22 Fmc Corporation 5[W(substituted aryl)alkenylene and alkynylene]-2,4-diaminopyrimidines as pesticides
PL320458A1 (en) * 1994-11-24 1997-09-29 Hoffmann La Roche Novel benzyl pyrimidines
WO2009025919A2 (en) 2007-06-04 2009-02-26 University Of Connecticut 5-propargyl-pyrimidine derivatives as inhibitors of dihydrofolate reductase with antibacterial antiprotozoal, antifungal and anticancer properties

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