NO165398B - Analogifremgangsmaate og fremstilling av terapeutisk aktive nitrofuranderivater. - Google Patents
Analogifremgangsmaate og fremstilling av terapeutisk aktive nitrofuranderivater. Download PDFInfo
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- NO165398B NO165398B NO872831A NO872831A NO165398B NO 165398 B NO165398 B NO 165398B NO 872831 A NO872831 A NO 872831A NO 872831 A NO872831 A NO 872831A NO 165398 B NO165398 B NO 165398B
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- imidazo
- pyridin
- hydrazide
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- 238000002360 preparation method Methods 0.000 title claims abstract 3
- 238000000034 method Methods 0.000 title claims description 10
- 230000001225 therapeutic effect Effects 0.000 title abstract 2
- 229940027988 antiseptic and disinfectant nitrofuran derivative Drugs 0.000 claims abstract description 3
- IAIWVQXQOWNYOU-FPYGCLRLSA-N nitrofural Chemical class NC(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 IAIWVQXQOWNYOU-FPYGCLRLSA-N 0.000 claims abstract description 3
- -1 imidazo[2,1-b]thiazol-6- yl Chemical group 0.000 claims description 38
- SXINBFXPADXIEY-UHFFFAOYSA-N 5-Nitrofurfural Chemical compound [O-][N+](=O)C1=CC=C(C=O)O1 SXINBFXPADXIEY-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- DXWCZMGIIFEEPU-OWOJBTEDSA-N (e)-3-(5-nitrofuran-2-yl)prop-2-enal Chemical compound [O-][N+](=O)C1=CC=C(\C=C\C=O)O1 DXWCZMGIIFEEPU-OWOJBTEDSA-N 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 17
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 2
- RHZQESDITRQWDU-UHFFFAOYSA-N imidazo[1,2-a]pyridine-2-carbohydrazide Chemical compound C1=CC=CC2=NC(C(=O)NN)=CN21 RHZQESDITRQWDU-UHFFFAOYSA-N 0.000 description 2
- WQLJLPDGSLZYEP-UHFFFAOYSA-N imidazo[1,2-a]pyridine-2-carboxylic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CN21 WQLJLPDGSLZYEP-UHFFFAOYSA-N 0.000 description 2
- POWQZFXZDXTXIO-UHFFFAOYSA-N imidazo[1,5-a]pyridine-1-carboxylic acid Chemical compound C1=CC=CC2=C(C(=O)O)N=CN21 POWQZFXZDXTXIO-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- DXWCZMGIIFEEPU-UHFFFAOYSA-N 3-(5-nitrofuran-2-yl)prop-2-enal Chemical compound [O-][N+](=O)C1=CC=C(C=CC=O)O1 DXWCZMGIIFEEPU-UHFFFAOYSA-N 0.000 description 1
- UCDLZUUCNFTQQY-UHFFFAOYSA-N 7-acetyl-6,8-dihydro-5h-imidazo[1,2-a]pyrazine-2-carboxylic acid Chemical compound C1N(C(=O)C)CCN2C=C(C(O)=O)N=C21 UCDLZUUCNFTQQY-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 241000588767 Proteus vulgaris Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000224526 Trichomonas Species 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 239000003904 antiprotozoal agent Substances 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 208000010227 enterocolitis Diseases 0.000 description 1
- QXVVXFZKXXPMCZ-UHFFFAOYSA-N ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate;hydrochloride Chemical compound Cl.C1CNCC2=NC(C(=O)OCC)=CN21 QXVVXFZKXXPMCZ-UHFFFAOYSA-N 0.000 description 1
- GNFACXDTRBVZJE-UHFFFAOYSA-N ethyl imidazo[1,2-a]pyridine-2-carboxylate Chemical compound C1=CC=CC2=NC(C(=O)OCC)=CN21 GNFACXDTRBVZJE-UHFFFAOYSA-N 0.000 description 1
- KLRVWFZTEPQRKB-UHFFFAOYSA-N ethyl imidazo[1,5-a]pyridine-1-carboxylate Chemical compound C1=CC=CC2=C(C(=O)OCC)N=CN21 KLRVWFZTEPQRKB-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- NSFLWPSOFWTQEQ-UHFFFAOYSA-N imidazo[1,5-a]pyridine-1-carbohydrazide Chemical compound C1=CC=CC2=C(C(=O)NN)N=CN21 NSFLWPSOFWTQEQ-UHFFFAOYSA-N 0.000 description 1
- MIOPOILJVITUGW-UHFFFAOYSA-N imidazo[1,5-a]pyridine-1-carbonitrile Chemical compound C1=CC=CC2=C(C#N)N=CN21 MIOPOILJVITUGW-UHFFFAOYSA-N 0.000 description 1
- YYEWLWDRYKBIKH-UHFFFAOYSA-N imidazo[2,1-b][1,3]thiazole-6-carbohydrazide Chemical compound C1=CSC2=NC(C(=O)NN)=CN21 YYEWLWDRYKBIKH-UHFFFAOYSA-N 0.000 description 1
- BAKIBSRDBASFAQ-UHFFFAOYSA-N imidazo[2,1-b][1,3]thiazole-6-carboxylic acid Chemical compound C1=CSC2=NC(C(=O)O)=CN21 BAKIBSRDBASFAQ-UHFFFAOYSA-N 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229940007042 proteus vulgaris Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229940118696 vibrio cholerae Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
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- A—HUMAN NECESSITIES
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- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- A61P33/10—Anthelmintics
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- 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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Nitrofuranderivater med generell formel (I). hvori n er 0 eller 1 og R er et heterosyk1 isk radikal. Deres fremstilling er beskrevet.Derivatene har terapeutisk anvendelse.
Description
Foreliggende oppfinnelse vedrører en analogifremgangsmåte for fremstilling av terapeutisk aktive nitrofuranderivater med generell formel (I)
hvori
n er 0 eller 1 og R er et radikal imidazo[1,2-a]pyridin-2-yl, imidazo[2,1-b]tiazol-6-yl, imidazo[1,2-a]pyrazin-2-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl, 7-acetyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl, imidazo[1,5-a]pyridin-1-yl, imidazo[1,5-a]pyridin-3-yl, pyrazolo[1,5-a]pyridin-3-
yl, 1-indolizinyl, 3-indolizinyl, 5,6,7,8-tetrahydroindolizin-1-yl, 5,6,7,8-tetrahydroindolizin-2-yl, 6H-tieno[2,3-b]pyrrol-5-yl, 4H-tieno[3,2-b]pyrrol-5-yl, 4-okso-4H-pyrido[1,2-a]-pyrimidin-3-yl, 2H-benzimidazol-2-yl, imidazo[1,2-a]pyridin-3-yl, og det særegne ved fremgangsmåten i henhold til oppfinnelsen er at et hydrazid med formel (II)
hvori R har den ovennevnte betydning,
kondenseres med 5-nitro-2-furankarboksaldehyd eller 3-(5-nitro-2- furyl)-2-propenal, i et alkoholisk løsningsmiddel, ved en temperatur mellom 20°C og tilbakeløpstemperaturen for løsnings-middelet.
I henhold til fremgangsmåten for den foreliggende oppfinnelse fremstilles forbindelsene med formel I i henhold til reak-sjonsskjemaet som vist i det etterfølgende. Det alkoholiske løsningsmiddel er f.eks. metanol, etanol eller 2-metoksy-etanol. De oppnådde derivater krystalliserer spontant i reaksj onsmilj øet.
3- (5-nitro-2-furyl)-2-propenal fremstilles ved en aldolreaksjon mellom 5-nitro-2-furankarboksaldehyd og acetaldehyd, etterfulgt av rensing ved kromatografering på en silikagelkolonne.
Hydrazidene med formel II kan fremstilles ved reaksjon mellom syrene eller tilsvarende syreestere beskrevet i litteraturen, og tørt hydrazin eventuelt i nærvær av kondensasjonsmidler (f.eks. dicykloheksylkarbodiimid, 2-etoksy-l-etoksykarbonyl-1,2-dihydrokinolin, o.s.v.).
Følgende eksempler illustrerer den foreliggende oppfinnelse.
IR og NMR spektra bekrefter strukturen av forbindelsene.
Eksempel 1 ((5-nitrofuran-2-yl)metylen)hydrazid av imidazo-[ 1,2-a]pyridin-2-karboksylsyre.
1.1. Imidazo[1,2-a]pyridin-2-karboksylsyrehydrazid.
4,2 ml trietylamin tilsettes til en suspensjon, av 8,1 g av hydrobromidet av etylimidazo[1,2-a]pyridin-2-karboksylat (beskrevet av J.G. Lombårdino, J.Org.Chem. 30, 2403, 1965) i 7 5 ml toluen. Etter avdamping og filtrering av toluen, oppløses resten ved hjelp av 75 ml etanol og 6 ml hydrazin
hvorpå blandingen holdes ved tilbakeløpstemperatur i fire timer.
Presipitatet filtreres og imidazo [ 1, 2-a] pyridin-2-ka.rboksyl-syrehydrazidet oppnås. Smp. = 195-198°C.
1.2. ((5-nitrofuran-2-yl)metylen)hydrazid av imidazo[1,2-a]-pyridin-2-karboksylsyre.
En suspensjon av 5,2 g (0,037 mol) 5-nitro-2-furankarboksalde-hyd og 6 g (0,034 mol) av hydrazidet oppnådd i det foregående i 150 ml metanol holdes ved tilbakeløpstemperatur i tre timer. Etter avkjøling filtreres presipitatet hvorpå det løses opp med kokende metanol, filtreres og tørkes. Den ovennevnte forbindelse oppnås. Smp. = 280°C.
Eksempel 2 ((5-nitrofuran-2-yl)-2-propen-2-yliden)hydrazid
av imidazo[2,1-b]tiazol-6-karboksylsyre.
I overensstemmelse med fremgangsmåten i eksempel 1.2. omsettes 1,1 g (0,065 mol) 3-(5-nitrofuran-2-yl)-2-propenal og 1,2 g imidazo[2,1-b]tiazol-6-karboksylsyrehydrazid i metanol. Tittelforbindelsen oppnås med smp. 332°C.
Eksempel 3 ((5-nitrofuran-2-yl)metylen)hydrazid av 7-acetyl -5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-karboksylsyre.
3.1. 7-acetyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2
karboksylsyrehydrazid.
5,9 g (0,03 mol) etyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-karboksylat (beskrevet hos J.P. Chapat, J. Chem. Research, 1984, 468-80), tilsettes til 8,3 ml eddiksyreanhydrid avkjølt til 0-5°C og blandingen får stå i to timer.
Blandingen helles over i isavkjølt vann og ekstraheres med metylenklorid, hvoretter den organiske fase vaskes med vann til nøytral pH. Den organiske fase tørkes, filtreres og avdampes. Forbindelse etyl-7-acetyl-5,6,7,8-tetrahydro-imidazo [1 , 2-a] pyrazin-2-karboksylat oppnås. Smp. = 97°C. 6 g av den oppnådde ester i 10 ml hydrazin holdes ved til-bakeløpstemperatur i 20 min. Overskuddshydrazinet avdampes og den oppnådde olje renses, ved kromatografering på en silikagelkolonne (metylenklorid, metanol, ammoniakk 19/10/1) idet hydrazidet oppnås. Smp. = 182°C.
3.2. ((5-nitrofuran-2-yl)metylen)hydrazid av 7-acetyl-5,6,7,8-tetrahydroimidazo [ 1 ,.2-a] pyrazin-2-karboksylsyre.
På samme måte som i eksempel 1.2., omsettes 1,9 g av hydrazidet oppnådd i det foregående-, og 1,3 g 5-nitro-2-furankarboksaldehyd i metanol. Tittelforbindelsen med smp. 255°C oppnås.
Eksempel 4 ((5-nitrofuran-2-yl)metylen)hydrazid av
imidazo[1,5-a]pyridin-l-karboksylsyre.
4.1. Etylimidazo[1,5-a]pyridin-l-karboksylat.
11,2 g (0,078 mol) imidazo[1,5-a]pyridin-l-karbonitril
(Y.A. Saednya, Synthesis. 1983, 748) i 300 ml etanol holdes ved tilbakeløpstemperatur i 16 timer idet blandingen gjennombobles med HCL-gass.
Løsningen avdampes til tørrhet, oppløses i vann og ekstraheres med eter. Den organiske- fase vaskes med vann, bikarbonat og vann.. Etter avdamping oppnås produktet med smp. lik 141°C.
4.2. Imidazo [1, 5-a] pyridin-1-karb'oksylsyrehydrazid. Fremgangsmåten som er béskrevet i eksempel 1 anvendes, idet ved å utgå fra 10,2 g (0,05 mol) av esteren oppnådd i det foregående og 20 ml hydrazin. Man oppnår produktet med smp. 189°C.
4.3. ((5-nitrofuran-2-yl)metylen)hydrazid av imidazo[1,5-a]-pyridin-l-karboksylsyre.
Produktet fremstilles i overensstemmelse med eksempel 1, ved å utgå fra 1,3 g (0,007 mol) av hydrazidet oppnådd i det foregående og 1,1 g (0,008 mol) 5-nitro-2-furankarboksaldehyd.
Det oppnås et produkt med smp. 300°C (spalting).
Hydrazidene II, d.v.s. utgangsforbindelsene, er vist i den etterfølgende tabell I.
Sluttforbindelsene I fremstilt i overensstemmelse med de ovennevnte eksempler er representert i den etterfølgende tabell
II.
Forbindelsene fremstilt i overensstemmelse med fremgangsmåten for den foreliggende oppfinnelse er underkastet farmakologiske tester innen antibakterie-, antiparasitt- og antisoppområdet.
Forbindelsene viste en inhiberende aktivitet "in vitro" og "in vivo" overfor et stort antall mikroorganismer, særlig omfat-tende: Staphylococcus aureus, Escherichia Coli, Mycobacterium ranea, Pseudomonas aeruginosa, Proteus Vulgaris, Vibrio Cholerae, Klebsielle pneumoniae, Trichomonas, Salmonella, Shighella Flexneri, Candida Albicans, noe som viser at forbindelsene kan anvendes ved ulike bakterie- og parasitt-infeksjoner, særlig i tarmen.
Den minimale inhiberende konsentrasjon "in vitro", bestemt etter at forbindelsene er oppløst i dimetylformamid (0,1%) varierer fra 0,05 ug/ml til 20 ug/ml.
Eksperimentelle forsøk utført "in vivo" på infeksjoner hos mus viste at forbindelsene hadde oral aktivitet ettersom de inhiberte dødligheten som var indusert ved hjelp av en rekke bakteriekilder, og bevirket en fullstendig sterilisering av fordøyelseskanalen hos mus.
Forbindelsene viste svært liten giftighet, idet denne generelt er svært stor ved 1 g/kg.
Forbindelsene fremstilt i overensstemmelse med oppfinnelsen kan anvendes klinisk i mennesker i doser fra 20 mg til 1 g/dag, idet enhetsdosen er mellom 5 og 200 mg, og forbindelsene kan anvendes i dyr i doser fra 1 til 20 mg/kg/dag.
Forbindelsene fremstilt ifølge fremgangsmåten for oppfinnelsen kan være i alle passende former for oral, rektal eller parenteral tilførsel, f.eks. i form av kapsler, tabletter, granuler, geler eller flytende oppløsninger, siruper eller drikkbare suspensjoner som kan inneholde passende hjelpe-stoffer.
Forbindelsene fremstilt i henhold til fremgangsmåten for oppfinnelsen kan anvendes i dyr og mennesker som aktibak-teriemidler, tarmantiseptiske midler, antisoppmidler og/eller antiprotozomidler. I mennesketarmen kan forbindelsene anvendes for å helbrede infeksiøse tarmsykdommer som diaré, enteritt, enterokolitt og bakteriedysenteri.
Claims (1)
- Analogifremgangsmåte for fremstilling av terapeutisk aktive nitrofuranderivater med generell formel (I) hvori n er 0 eller 1 og R er et radikal imidazo[1,2-a]pyridin-2-yl, imidazo[2,1-b]tiazol-6-yl, imidazo[1,2-a]pyrazin-2-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl, 7-acetyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl, imidazo[1,5-a]pyridin-1-yl, imidazo[1,5-a]pyridin-3-yl, pyrazolo[1,5-a]pyridin-3-yl, 1-indolizinyl, 3-indolizinyl, 5,6,7,8-tetrahydroindolizin-1-yl, 5,6,7,8-tetrahydroindolizin-2-yl, 6H-tieno[2,3-b]pyrrol-5-yl, 4H-tieno[3,2-b]pyrrol-5-yl, 4-okso-4H-pyrido[1,2-a] - pyrimidin-3-yl, 2H-benzimidazol-2-yl, imidazo[1,2-a]pyridin-3-yl,karakterisert ved at et hydrazid med formel (II) hvori R har den ovennevnte betydning, kondenseres med 5-nitro-2-furankarboksaldehyd eller 3-(5-nitro-2-furyl)-2-propenal, i et alkoholisk løsningsmiddel, ved en temperatur mellom 20°C og tilbakeløpstemperaturen for løsnings-middelet .
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8609886A FR2601368B1 (fr) | 1986-07-08 | 1986-07-08 | Derives de nitrofuranne, leur preparation et leur application en therapeutique. |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO872831D0 NO872831D0 (no) | 1987-07-07 |
| NO872831L NO872831L (no) | 1988-01-11 |
| NO165398B true NO165398B (no) | 1990-10-29 |
| NO165398C NO165398C (no) | 1991-02-06 |
Family
ID=9337175
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO872831A NO165398C (no) | 1986-07-08 | 1987-07-07 | Analogifremgangsmaate og fremstilling av terapeutisk aktive nitrofuranderivater. |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4794120A (no) |
| EP (1) | EP0252809A3 (no) |
| JP (1) | JPS6323879A (no) |
| KR (1) | KR880001641A (no) |
| CN (1) | CN87104648A (no) |
| AU (1) | AU594170B2 (no) |
| CA (1) | CA1287049C (no) |
| DK (1) | DK349387A (no) |
| FI (1) | FI873010A (no) |
| FR (1) | FR2601368B1 (no) |
| HU (1) | HU196413B (no) |
| IL (1) | IL83093A (no) |
| MA (1) | MA21029A1 (no) |
| NO (1) | NO165398C (no) |
| NZ (1) | NZ220986A (no) |
| PT (1) | PT85279B (no) |
| TN (1) | TNSN87086A1 (no) |
| ZA (1) | ZA874939B (no) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8901423D0 (en) * | 1989-01-23 | 1989-03-15 | Fujisawa Pharmaceutical Co | Pyrazolopyridine compound and processes for preparation thereof |
| ES2081747B1 (es) * | 1993-09-07 | 1997-01-16 | Esteve Labor Dr | Amidas derivadas de tienopirroles, su preparacion y su aplicacion como medicamentos. |
| US6711297B1 (en) * | 1998-07-03 | 2004-03-23 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Methods and apparatus for dynamic transfer of image data |
| GB0021831D0 (en) * | 2000-09-06 | 2000-10-18 | Astrazeneca Ab | Chemical compounds |
| GB0205175D0 (en) * | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
| GB0205166D0 (en) * | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
| GB0205162D0 (en) * | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
| GB0205165D0 (en) * | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
| GB0205176D0 (en) * | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
| GB0205170D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
| GB0318463D0 (en) * | 2003-08-07 | 2003-09-10 | Astrazeneca Ab | Chemical compounds |
| GB0318464D0 (en) * | 2003-08-07 | 2003-09-10 | Astrazeneca Ab | Chemical compounds |
| GB0319759D0 (en) * | 2003-08-22 | 2003-09-24 | Astrazeneca Ab | Chemical compounds |
| GB0319690D0 (en) * | 2003-08-22 | 2003-09-24 | Astrazeneca Ab | Chemical compounds |
| US7632928B2 (en) * | 2004-04-19 | 2009-12-15 | Charm Sciences, Inc | Method and antibodies for detecting nitrofuran |
| GB0710121D0 (en) | 2007-05-25 | 2007-07-04 | F2G Ltd | Antifungal agents |
| DK2283006T3 (en) | 2008-04-24 | 2015-05-26 | F2G Ltd | Pyrrole-based antifungal agents |
| CN101624376B (zh) * | 2009-08-19 | 2011-09-14 | 沈阳中海药业有限公司 | 取代酰肼类化合物及其应用 |
| US8518968B2 (en) | 2009-12-04 | 2013-08-27 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Hydrazone and diacyl hydrazine compounds and methods of use |
| US20140200241A1 (en) * | 2011-05-24 | 2014-07-17 | Northeastern University | Prodrugs for treating microbial infections |
| CN111096967B (zh) | 2014-11-21 | 2023-03-10 | F2G有限公司 | 抗真菌剂 |
| GB201609222D0 (en) | 2016-05-25 | 2016-07-06 | F2G Ltd | Pharmaceutical formulation |
| CN107417673B (zh) * | 2017-04-25 | 2019-10-01 | 西华大学 | N-(2-吡啶基)亚甲基-2-氰基-3-杂环基丙烯酰肼类衍生物及其应用 |
| US11819503B2 (en) | 2019-04-23 | 2023-11-21 | F2G Ltd | Method of treating coccidioides infection |
| CN110590771B (zh) * | 2019-09-05 | 2021-11-12 | 南通大学 | 一种[1,5-a]-吡啶并咪唑-1-腈及其化学合成方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH479615A (de) * | 1959-12-24 | 1969-10-15 | Ciba Geigy | Verfahren zur Herstellung neuer Methylidenverbindungen |
| US3424845A (en) * | 1967-05-25 | 1969-01-28 | Salsbury Lab | 3,5-dinitrosalicylic acid, 5-nitrofurfurylidene hydrazide and compositions containing and methods employing the same for the control of histomoniasis |
| LU71111A1 (no) * | 1974-10-15 | 1976-08-19 |
-
1986
- 1986-07-08 FR FR8609886A patent/FR2601368B1/fr not_active Expired
-
1987
- 1987-07-01 EP EP87401522A patent/EP0252809A3/fr not_active Withdrawn
- 1987-07-06 IL IL83093A patent/IL83093A/xx unknown
- 1987-07-07 ZA ZA874939A patent/ZA874939B/xx unknown
- 1987-07-07 JP JP62169609A patent/JPS6323879A/ja active Pending
- 1987-07-07 NO NO872831A patent/NO165398C/no unknown
- 1987-07-07 CA CA000541476A patent/CA1287049C/en not_active Expired - Fee Related
- 1987-07-07 HU HU873055A patent/HU196413B/hu unknown
- 1987-07-07 AU AU75293/87A patent/AU594170B2/en not_active Ceased
- 1987-07-07 FI FI873010A patent/FI873010A/fi not_active Application Discontinuation
- 1987-07-07 PT PT85279A patent/PT85279B/pt not_active IP Right Cessation
- 1987-07-07 KR KR1019870007252A patent/KR880001641A/ko not_active Application Discontinuation
- 1987-07-07 MA MA21266A patent/MA21029A1/fr unknown
- 1987-07-07 TN TNTNSN87086A patent/TNSN87086A1/fr unknown
- 1987-07-07 US US07/070,541 patent/US4794120A/en not_active Expired - Fee Related
- 1987-07-07 CN CN198787104648A patent/CN87104648A/zh active Pending
- 1987-07-07 DK DK349387A patent/DK349387A/da not_active Application Discontinuation
- 1987-07-07 NZ NZ220986A patent/NZ220986A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL83093A (en) | 1991-07-18 |
| IL83093A0 (en) | 1987-12-31 |
| ZA874939B (en) | 1988-03-30 |
| FI873010A0 (fi) | 1987-07-07 |
| JPS6323879A (ja) | 1988-02-01 |
| CA1287049C (en) | 1991-07-30 |
| PT85279A (fr) | 1987-08-01 |
| FR2601368A1 (fr) | 1988-01-15 |
| EP0252809A2 (fr) | 1988-01-13 |
| AU594170B2 (en) | 1990-03-01 |
| NO165398C (no) | 1991-02-06 |
| US4794120A (en) | 1988-12-27 |
| EP0252809A3 (fr) | 1989-07-19 |
| HU196413B (en) | 1988-11-28 |
| AU7529387A (en) | 1988-01-14 |
| DK349387A (da) | 1988-01-09 |
| NO872831D0 (no) | 1987-07-07 |
| HUT44787A (en) | 1988-04-28 |
| KR880001641A (ko) | 1988-04-25 |
| NZ220986A (en) | 1989-09-27 |
| PT85279B (pt) | 1990-03-30 |
| DK349387D0 (da) | 1987-07-07 |
| MA21029A1 (fr) | 1988-04-01 |
| TNSN87086A1 (fr) | 1990-01-01 |
| FI873010A (fi) | 1988-01-09 |
| CN87104648A (zh) | 1988-04-13 |
| FR2601368B1 (fr) | 1989-04-07 |
| NO872831L (no) | 1988-01-11 |
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