DK154429B - Analogifremgangsmaade til fremstilling af imidazooe1,2-aaapyridinderivater eller syreadditionssalte heraf - Google Patents
Analogifremgangsmaade til fremstilling af imidazooe1,2-aaapyridinderivater eller syreadditionssalte heraf Download PDFInfo
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- DK154429B DK154429B DK465181A DK465181A DK154429B DK 154429 B DK154429 B DK 154429B DK 465181 A DK465181 A DK 465181A DK 465181 A DK465181 A DK 465181A DK 154429 B DK154429 B DK 154429B
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- 238000000034 method Methods 0.000 title claims abstract description 14
- 150000003839 salts Chemical class 0.000 title claims abstract description 6
- 239000002253 acid Substances 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 title claims description 3
- 239000000460 chlorine Substances 0.000 claims description 51
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 150000002825 nitriles Chemical class 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 claims description 3
- 150000003140 primary amides Chemical class 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 34
- 230000000147 hypnotic effect Effects 0.000 abstract description 3
- 230000000694 effects Effects 0.000 description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 230000007958 sleep Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- IYGYMKDQCDOMRE-QRWMCTBCSA-N Bicculine Chemical compound O([C@H]1C2C3=CC=4OCOC=4C=C3CCN2C)C(=O)C2=C1C=CC1=C2OCO1 IYGYMKDQCDOMRE-QRWMCTBCSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000001773 anti-convulsant effect Effects 0.000 description 4
- 230000000949 anxiolytic effect Effects 0.000 description 4
- AACMFFIUYXGCOC-UHFFFAOYSA-N bicuculline Natural products CN1CCc2cc3OCOc3cc2C1C4OCc5c6OCOc6ccc45 AACMFFIUYXGCOC-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- IYGYMKDQCDOMRE-UHFFFAOYSA-N d-Bicucullin Natural products CN1CCC2=CC=3OCOC=3C=C2C1C1OC(=O)C2=C1C=CC1=C2OCO1 IYGYMKDQCDOMRE-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 206010021143 Hypoxia Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000002249 anxiolytic agent Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- SNGFSJIEFYKMQP-UHFFFAOYSA-N 2-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]acetamide Chemical compound N1=C2C=CC=CN2C(CC(=O)N)=C1C1=CC=C(Cl)C=C1 SNGFSJIEFYKMQP-UHFFFAOYSA-N 0.000 description 2
- ZOUWHRHJCHJSGJ-UHFFFAOYSA-N 2-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]acetamide Chemical compound N1=C2C=CC(Cl)=CN2C(CC(=O)N)=C1C1=CC=C(Cl)C=C1 ZOUWHRHJCHJSGJ-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010002660 Anoxia Diseases 0.000 description 2
- 241000976983 Anoxia Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000007953 anoxia Effects 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 235000012631 food intake Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- IMKILIAPBKFUTO-UHFFFAOYSA-N 2-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]acetic acid Chemical compound N1=C2C=CC(Cl)=CN2C(CC(=O)O)=C1C1=CC=C(Cl)C=C1 IMKILIAPBKFUTO-UHFFFAOYSA-N 0.000 description 1
- PAPIVHGHEPOCNK-UHFFFAOYSA-N 2-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]acetonitrile Chemical compound C1=CC(Cl)=CC=C1C1=C(CC#N)N2C=C(Cl)C=CC2=N1 PAPIVHGHEPOCNK-UHFFFAOYSA-N 0.000 description 1
- YDHIMEXEGOCNHU-UHFFFAOYSA-N 2-pyridin-3-ylacetamide Chemical compound NC(=O)CC1=CC=CN=C1 YDHIMEXEGOCNHU-UHFFFAOYSA-N 0.000 description 1
- CFINUJBABHRHDT-UHFFFAOYSA-N 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine Chemical compound C1=CC(Cl)=CC=C1C1=CN(C=C(Cl)C=C2)C2=N1 CFINUJBABHRHDT-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000026680 Metabolic Brain disease Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 101100133466 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) nit-4 gene Proteins 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000496 anti-anoxic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008129 cerebral palsy Diseases 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000002566 electrocorticography Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 230000000803 paradoxical effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 230000037322 slow-wave sleep Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Neurology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
DK 154429 B
Opfindelsen angår en analogifremgangsmåde til fremstilling af hidtil ukendte imidazo[1,2-a]pyridin-de-rivater med den almene formel (I) fi^Y=Ny/~\_x1 Y-1¾. N- ^ch2-conr1r2 10 hvori betegner halogen, methyl eller methylthio, Y betegner hydrogen, halogen eller methyl, betegner hydrogen, C^_^-alkyl eller hydroxy-C^_^-al-kyl, og R2 betegner C^_^-alkyl eller hydroxy-C^_^-alkyl, 15 eller farmaceutisk acceptable syreadditionssalte heraf.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav 1's kendetegnende del anførte.
Foretrukne forbindelser blandt de omhandlede opnås ved udføreis es former for fremgangsmåden ifølge 20 opfindelsen som angivet i krav 2-5.
Ifølge opfindelsen foretrukne forbindelser er således forbindelser med formlen (I), hvori R^ og R2 begge er C^_^-alkyl. Blandt disse foretrækkes forbindelser, hvori Y er halogen, specielt chlor, eller methyl.
25 Blandt disse sidste kan specielt fremhæves de forbindelser, hvori er halogen eller methyl.
Imidazo[1,2-a]pyridiner er allerede blevet beskrevet i litteraturen, f.eks. i beskrivelserne til de engelske patentskrifter nr. 991 589 og 1 076 089 samt 30 i forskellige andre publikationer. Fra engelsk patentskrift nr. 1 076 089 samt fra J. Med. Chem., Vol. 12, 1969, side 122-126, kendes således en med de her ariiandlede forbindelser nært beslægtet forbindelse, nemlig 2—(4— chlor-phenyl)-imidazo[1,2-a]pyridin-3-acetamid. Denne 35 kendte forbindelse har lige som de her omhandlede forbindelser bl.a. anticonvulsiv virkning og hypnotisk virkning. Som det vil fremgå af nedenstående forsøgsdata 1 i 2
DK 154429 B
(Tabel 2), har de her omhandlede forbindelser imidlertid generelt en højere anticonvulsiv virkning, men desuden har de overraskende, hvad der er mere væsentligt, en betydningsfuld virkning på centralnervesystemet, hvilken 5 virkning ikke findes hos den nævnte kendte forbindelse, jf. Tabel 2.
Fremgangsmåden ifølge opfindelsen kan gengives ved følgende reaktionsskema.
^ N Z N Z
frj —»
Y_L N-Il ^ Y_k N-IL
^CH.CN \CHpCONH
(II) 2 (III) „ rr rr y v L Å_il Y—L N-U CH2CONR1R2 (IV) ^CH2COOH (I) hvori Z betegner gruppen 20
Reaktionen til omdannelse af nitrilet (II) til det primære amid gennemføres i overensstemmelse 25 med en af de velkendte fremgangsmåder, f.eks. ved hjælp af en syre, såsom tør gasformig hydrogenchlorid, i et opløsningsmiddel, såsom myresyre, ved en temperatur i området fra 15-50°C.
Hydrolyse af det primære amid (III) til syren (IV) 30 kan gennemføres i ethanolisk kaliumhydroxid ved tilbagesvalingstemperatur .
Omdannelsen af syren (IV) til amidet med formlen (I) kan gennemføres ved hjælp af enhver af de dertil egnede velkendte fremgangsmåder, f.eks. ved omsætning 35 af syren (IV) med en amin med formlen HNR-^R,,, hvor R^ og R2 har den før angivne betydning, i nærværelse af carbonyldiimidazol eller ved omsætning af chloridet af syren (IV) med aminen HNR^R2.
3
DK 154429 B
Den almindelige fremgangsmåde til fremstilling af de som udgangsmaterialer anvendte nitriler (II) er beskrevet i litteraturen, specielt i beskrivelsen til engelsk patent nr. 1 076 089.
5 Fremgangsmåden ifølge opfindelsen belyses nærmere ved de efterfølgende eksempler. Analyserne og IR- og NMR-spektrene bekræfter forbindelsernes struktur.
Eksempel 1 N,N-dimethyl-6-chlor-2-(4-chlor-phenyl)-imidazo[1,2-a]-10 pyridin-3-acetamid.
[y = Cl, ΧΊ = Cl, R1 = R2 = CH3J
1. 22 g (0,0788 mol) 6-chlor-2-(4-chlor-phenyl)-15 imidazo[1,2-a]pyridin-3-acetonitril sættes til 85 ml 99%'s myresyre, og opløsningen behandles med en strøm af tør gasformig hydrogenchlorid i 3-4 timer. Når nitrilen er omdannet, opvarmes opløsningen lidt med henblik på afgasning, hvorpå den afkølede opløsning 20 hældes i 1 liter vand. Der omrøres i 10 minutter, hvorefter der gøres alkalisk med 200 ml koncentreret ammoniakvand. Det faste stof frafiltreres og vaskes rigeligt med vand, hvorpå det tørres ved hjælp af vandstrålepumpe. Det opnåede 6-chlor-2-(4-chlor-25 phenyl)-imidazo[1,2-a]pyridin-3-acetamid omkrystallise res. Smp. 285-287°C.
2. Til 550 ml 75%’s ethanol sættes successivt 19,2 g 6-chlor-2-(4-chlor-phenyl)-imidazo[l,2-a]pyridin- 3-acetamid og 19 g KOH. Suspensionen opvarmes til til- 30 bagesvalingstemperatur i 10-16 timer. Efter reaktionens afslutning koncentreres opløsningen i vakuum, og remanensen opløses i 1/2 liter vand. Den lille mængde uopløselige stof frafiltreres, og filtratet behandles med 50 ml eddikesyre. Den ventede syre udfældes, og 35 den filtreres og tørres let. Det opnåede produkt optages i 500 ml acetone, og der filtreres varmt, hvorved opnås 6-chlor-2-(4-chlor-phenyl)-imidazo[1,2-a]pyridin-
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4 3-eddikesyre. Smp. 258-260°C.
3. 4 g (12,45 mmol) 6-chlor-2-(4-chlor-phenyl)-imidazo[l,2-a]pyridin-3-eddikesyre og 2,42 g (14,94 mmol) carbonyldiimidazol suspenderes i 60 ml tør 5 tetrahydrofuran. Reaktionsblandingen omrøres ved 20°C, indtil kulsyreudviklingen er ophørt, hvorefter der opvarmes svagt til 40°C i 15 minutter og derpå afkøles til 0°C. Der tilsættes derefter 14,94 mmol dimethylamin opløst i 5 ml tetrahydrofuran. Suspensionen omrøres i 10 15 minutter ved 20°C, hvorefter den koncentreres.
Remanensen behandles med 300 ml vand og 50 ml af en mættet vandig opløsning af NaHCOg. Det uopløste stof frafiltreres, vaskes med vand og tørres. Den opnåede forbindelse omkrystalliseres i et opløsningsmiddel, 15 såsom ethanol. Smp. 230°C.
Den opnåede forbindelse er nr. 11 i nedenstående Tabel 1, der indeholder en række yderligere, på analog måde fremstillede forbindelser blandt de omhandlede.
20 TABEL 1 _ y—L Nit—4 ^CH2CONR1R2 25
Forbin- v _ ,o~» delse * X1 nr1E2 Smp· ‘( C) nr._______ 30 1 H Cl NHCH 234 2 H Cl N(CH3}2 179 3 Cl Cl NHCH3 >290 ^ 35 4 Cl Cl . NHC2H5- 28°-2 5 Cl Cl HH-n-C3H7 229-30 6 Cl Cl NH-i-C3H7 259 5
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Tabel 1 (fortsat) delse”” * X1 SmP· <Pc> 5 nr.______ 7 Cl Cl - NH-n-C4H9 225 8 Cl Cl NH-t-C4H9 , 224 9 Cl Cl NHCH2CH2OH 260-1 10 10 Cl CH3 NHC2H5 238 11 Cl Cl N(CH3)2 230 12 Cl Cl N(C2H5)2 149 13 Cl Cl N(n-C3H?)2 140-1 /CH3 15 14 Cl Cl N 160 n-C3H7 /CH3 15 Cl Cl N 185-6 ^ ch(ch3)2 20 16 Cl Cl N(n-C4H9)2 149-150 17 CH3 Cl NHCH3 261-2 18 CH3 Cl NHC2H5 224-5 19 CH3 Cl NB-CH2CH2OH 246 20 CH3 Cl N(CH3)2 215 25 21 Cl CH3 NHCH3 277-8 22 Cl CH3 N(CH3)2 185-6 23 Cl Br NHC2H5 287 24 Cl Br N(C2H5}2 168 25 Cl F N(CH3)2 210 30 26 Cl F N(n-C4H9)2 129 27 CH3 F N(CH3)2 195 28 Cl Br N(CH3)2 228-9 29 CH3 CH3 N(CH3)2 196 30 CH3 Cl N(n-C4H9)2 116 35 31 H Cl N(n-C3H7)2 136 32 H Cl N(n-C4H9)2 105 33 Cl Cl N(n-C5H11)2 92-3 34 CH3 CH3 NHCH3 187
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6
Tabel 1 (fortsat) delse"' T Smp. (°C) nr. __ 5 35 CH3 CH3 NHC2H5 184 /CH3 36 CH3 CH3 N 108 ^NC3H7 37 CH3 CH3 N(n-C3H?)2) 115 10 38 CH3 Br NHC2H5 232-4 39 CH3 Br N(ch3)2 203,5-205 40 CH3 Br N(n-C3H7)2 138-9 /CH3 41 Cl Cl N 173 1 5 g ___ 2a5
Forbindelserne fremstillet ifølge opfindelsen er blevet underkastet farmakologiske forsøg, som har vist deres interessante farmakologiske egenskaber på forskel-20 lige områder, og til sammeligning undersøgtes den fra bl.a. engelsk patentskrift nr 1 076 089 kendte forbindelse 2-(4-chlor-phenyl)-imidazo[1,2-a]pyridin-3-acetamid. Resultaterne er angivet i nedenstående Tabel 2, hvori den nævnte kendte forbindelse er betegnet med "Ref.".
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7
Tabel 2
Forb. Toxicitet Anxiolytisk Anti- Anticonv. Sedat./hyp^· nr. virkning anoxia virkning notisk virkning
Ref. >1000 (>10) (*) 30-40 _ _ +21(10) 476 9 1 5 2 300<<60Ό +41(1) - 4,5 10-30 (i.p.) 3 >1000 +25(0,1) 2 0,6 3 (i.p.) 4 >1000 +58(0,3) 1,2 0,9 30 (p.o.) 5 - +24(3) 2,3 6 10 (i.p.) 6 >1000 +45(3) 9,3 6 10 7 - (>10) >32 7 30 (i.p.) 8 >1000 +29(3) - >10 30 (i.p.) 9 >1000 +50(10) >32 >10 >30 (i.p.) 10 >1000 (>10)(p.o.) - . 9 (p.o.) 30 (i.p.) 11 >1000 +46(0,3) 0,6 0,3 3 (i.p.) 15 3 (p.o.) 12 - 03) 2,2 2 30 (p.o.) 13 >1000 +42(3) 4,7 8 10 (i.p.) 30 (p.o.) 14 >1000 +20(1) 1,3 4,5 30 (i.p.) 20 15 300» 1000 - 4,2 10 16 - (>30)(p.o.) - 10 (p.o.) >30 (p.o.) 17 - +46(1) (p.o.) 0,8 2,8 (p.o.) 3 (i.p.) 18 650 +41(3) (p.o.) 0,7 13 (p.o.) 10 (p.o.) 25 20 300«600 +27(3) (p.o.) 1,15 2,5 (p.o.) 1 (i.p.) 1 (p.o.) 21 >1000 +28(3) 0,66 5 (p.o.) 22 >1000 +69(10) (p.o.) 0,56 15 (p.o.) 3 (p.o.) 23 >1000 O10) (p.o.) 14 3 (p.o.) - 30 24 - (>10)(p.o.) 3,1 8 (p.o.) 25 >1000 +34(1) (p.o.) - 2 (p.o.) 27 100«300 (>10) (p.o.) - 5 (p.o.) 3 (i.p.) 28 >1000 +26( 1 ) - 2 (p.o.) 3 (i.p.) 29 - +31(1) (p.o.) - 10 (p.o.) 0,3(i.p.) 35 0,3(p.o.) (m)
Resultaterne for den kendte forbindelse er ikke reproducerbare t c
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s
Tabel 2 (fortsat)
Forb. Toxicitet Anxiolytisk Anti- Anticonv. Sedat./hypo- nr. virkning anoxia virkning tetisk _______virkning 30 - - >20 (p.o.) - 5 31 - (>10) - 10 30 (i.p.) 32 >1000 (>10) 30 33 >1000 (>10) - >30 30 (i.p.) 34 600«1000 +24(3) (p.o.) - 20 (p.o.) 3 (I.p.) 35 >1000 (>10) 0,52 >30 3 (i.p.) 10 36 100«300 (>10) - >10 1 (i.p.) 37 600«1000 O10) (p.o.) - >30 (p.o.) 10 (i.p.) 38 >1000 O10) (p.o.) - .25 (p.o.) 3 (i.p.) 39 100«300 (>10) (p.o.) - 3-10 (p.o.)3 (i.p.) 15 40 >1000 O10) (p.o.) - >30 (p.o.) 10 (i.p.) 41 - (>10) (p.o.) - 3 (p.o.) J -
Forbindelsernes toxicitet blev bestemt på mus ved intraper i toneal indgift. DI»5Q ligger, som det vil 2fl ses, ofte over 1000 mg/kg.
Den anxiolytiske virkning blev bestemt ved den såkaldte "eating test" (Stephens, R.J. (1973) Brit.
J. Pharmac., 49, 146 P). Ved denne test varierer de doser, som forøger musenes fødeoptagelse, fra 0,1 til 10 mg/kg. i tabellen er der angivet fødeoptagelsesforøgelsen i procent, og i parentes den pågældende dosis i mg/kg enten intraperitonealt (ikke angivet i tabellen) eller oralt (angivet ved p.o. i tabellen).
Forbindelsernes virkning på det cerebrale kreds-30 løb blev bestemt ved test for hypobar hypoxi: Mus af stammen CD1 holdes i en atmosfære, hvis oxygenindhold er formindsket ved opretholdelse af et partielt vakuum (190 mmHg svarende til 5,25% oxygenindhold).
Dyrets overlevelsestid noteres. Disse tider forøges 35 ved hjælp af midler, der er i stand til at fremme vævets 9
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og især hjernevævets forsyning med oxygen. De undersøgte forbindelser indgives intraperitonealt i flere doser 10 min. før forsøget. De procentvise forøgelser af overlevelsestiderne i forhold til de værdier, der 5 opnås for kontroldyrene, beregnes. Den aktive middeldosis (AMD), som er den dosis, der forøger overlevelsestiden med 100%, bestemmes grafisk. AMD i mg/kg er angivet i tabellen.
Anticonvulsionsvirkningen blev bestemt ved 10 test for antagonisme overfor den med bicucullin hos mus forårsagede mortalitet (Worms, P., Depoortere, H. and Lloyd, K.G. (1979) Life Sci., 25, 607-614).
De undersøgte produkter injiceres intraperitonealt (ikke angivet i tabellen) eller oralt (angivet ved p.o.
15 i tabellen) 30 minutter før bicucullin (0,9 mgAg i.v.). Da kriteriet, som man skal være opmærksom på, er letaliteten, noteres mortalitetsprocenterne for hver gruppe 2 timer efter indgivelse af bicucullinet (kontrolgruppe: 100% mortalitet). For hvert produkt bestemmes DA,-q 2° (den dosis der beskytter 50% af dyrene mod den dødelige virkning af bicucullin) grafisk. da5q i mg/kg er angivet i tabellen.
Den sedative eller hypnotiske virkning blev bestemt ved at iagttage forbindelsernes virkning på 25 curariserede rotters ECoG samt virkningen på vågen-søvn-tilstanden hos frie implanterede rotter og katte (Depoortere, H., Rev. E.E.G. Neurophysiol., (1980) 10, 3, 207-214; Da Costa, L.M., Depoortere, H. et Naquet, R. Rev. E.E.G. Neurophysiol., (1977), 1_, 2, 158-164).
30 De undersøgte forbindelser blev hos curariserede rotter indgivet intraperitonealt eller oralt i voksende doser fra 0,1 til 30 mg/kg. De fremkalder søvnkurver ved doser fra 0,1 til 10 mg/kg i.p. eller p.o. For frie implanterede rotters vedkommende blev de undersøgte 35 forbindelser indgivet intraperitonealt eller oralt i en enkelt dosis fra 1 til 10 mg/kg. Ved disse doser nedsætter forbindelserne opvågningens totale varighed med 13-44% uden nogen væsentlig ændring af varigheden / i 10
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af paradoks-søvnen. Visse forbindelser forøger også den totale varighed af denne søvnperiode. For frie implanterede kattes vedkommende blev de undersøgte forbindelser indgivet intraperitonealt eller oralt i 5 en enkeltdosis på 10 mg/kg. De forøger forbigående opvågningen efter injektion på lignende måde som de:n, der ledsager en urotilstand af benzodiazepin-typen, og de nedsætter den totale varighed af paradoks-søvnen med 40-100¾. Visse forbindelser giver imidlertid en 10 forøgelse af den totale varighed af SPOL (søvn med langsomme bølger med periodiske fænomener: P.G.O.-spidser) af størrelsesordenen 50%. I tabellen er der angivet den søvnfremkaldende dosis i mg/kg, intraperitonealt (i.p.) eller oralt (p.o.).
15 Resultaterne af disse forskellige forsøg viser, at forbindelserne fremstillet ifølge opfindelsen besidder anxiolytiske, antianoxiske, søvnfremkaldende, hyp-=·-notiske og anticonvulsiviske egenskaber. Forbindelserne fremstillet ifølge opfindelsen er nyttige til behand-20 ling af angsttilstande, søvnbesvær og andre neurologiske og psykiatriske lidelser, til behandling af vigilitets-besvær, navnlig til bekæmpelse af adfærdsvanskeligheder, der skyldes beskadigelser af hjerne-blodkar og alderdansforkalkninger i hjernen, samt til behandling af absence-tilstande, 25 der forårsages af hjerne-traumer, og til behandling af metaboliske encephalopatier.
Forbindelserne fremstillet ifølge opfindelsen kan anvendes i enhver egnet form for indgivelse oralt eller parenteral t, f.eks. i form af tabletter, drageer, gelatine-30 kapsler, drikkelige eller injicerbare opløsninger etc., sammen med ethvert egnet hjælpemiddel.
Daglig dosis kan andrage fra 0,5 til 2000 mg.
Claims (5)
1. Analogifremgangsmåde til fremstilling af imidazo[1,2-a]pyridin-derivater med den almene formel (I) ' ... ^CH2-CONR1R2 10 hvori X.j betegner halogen, methyl eller methylthio, Y betegner hydrogen, halogen eller methyl, R1 betegner hydrogen, C^^-alkyl eller hydroxy~C^ alkyl, og 15 r2 betegner C^-alkyl eller hydroxy-C^alkyl, eller farmaceutisk acceptable syreadditionssalte heraf, kendetegnet ved,, at man omdanner en nitril med formlen (II) " xop- .... 25 til et primært amid med formlen (III) , rrvCH ,,,
30 Y-N- ^CH2 C0NH2 og derpå omdanner dette amid til en syre med formlen (IV) , ΓΤγΟ“ ™ Y-L N-- x:h2cooh 12 DK 154429 B i hvilke formler og Y har de ovennævnte betydninger, hvorpå man omdanner syren med formlen (IV) til et amid med formlen (I), hvorefter man om ønsket omdanner det opnåede amid (I) 5 til et farmaceutisk acceptabelt syreadditionssalt heraf.
2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at man fremstiller derivater med formlen (I), hvori R.J og begge er C-j_,-~alkyl.
3. Fremgangsmåde ifølge krav 1, kendeteg-10 n e t ved, at man fremstiller derivater med formlen (I), hvori Y er chlor eller methyl.
4. Fremgangsmåde ifølge krav 1, kendetegnet ved, at man fremstiller derivater med formlen (I), hvori X.j er halogen eller methyl.
5. Fremgangsmåde ifølge krav 1, kendeteg net ved, at man fremstiller derivater med formlen (I), hvori og R£ begge er C^_g-alkyl, Y er halogen eller methyl, og X^ er halogen eller methyl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8022537 | 1980-10-22 | ||
| FR8022537A FR2492382A1 (fr) | 1980-10-22 | 1980-10-22 | Derives d'imidazo (1,2-a) pyridine, leur preparation et leur application en therapeutique |
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| Publication Number | Publication Date |
|---|---|
| DK465181A DK465181A (da) | 1982-04-23 |
| DK154429B true DK154429B (da) | 1988-11-14 |
| DK154429C DK154429C (da) | 1989-04-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK465181A DK154429C (da) | 1980-10-22 | 1981-10-21 | Analogifremgangsmaade til fremstilling af imidazooe1,2-aaapyridinderivater eller syreadditionssalte heraf |
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| US (2) | US4382938A (da) |
| EP (1) | EP0050563B1 (da) |
| JP (1) | JPS5798283A (da) |
| AT (1) | ATE7393T1 (da) |
| AU (1) | AU544345B2 (da) |
| CA (1) | CA1157470A (da) |
| DE (1) | DE3163524D1 (da) |
| DK (1) | DK154429C (da) |
| ES (1) | ES8207537A1 (da) |
| FI (1) | FI71143C (da) |
| FR (1) | FR2492382A1 (da) |
| GR (1) | GR74701B (da) |
| IE (1) | IE51686B1 (da) |
| IL (1) | IL64091A (da) |
| LU (1) | LU88228I2 (da) |
| MX (1) | MX6463E (da) |
| NL (1) | NL930044I2 (da) |
| NO (1) | NO155664C (da) |
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| JP5433508B2 (ja) * | 2009-06-25 | 2014-03-05 | 高田製薬株式会社 | ゾルピデム酒石酸塩含有内用液剤 |
| CN102234275B (zh) * | 2010-04-27 | 2015-12-16 | 溧阳合誉药物科技有限公司 | 治疗失眠的氘代咪唑并[1,2-a]吡啶衍生物、制备方法及其应用 |
| US8741888B2 (en) | 2010-11-09 | 2014-06-03 | Carl A. Forest | Sleep aid composition and method |
| IN2013MU02428A (da) * | 2013-07-22 | 2015-06-19 | 3A Chemie Private Ltd | |
| US10202376B2 (en) | 2014-12-24 | 2019-02-12 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
| EP3468545A4 (en) | 2016-06-08 | 2020-07-22 | President and Fellows of Harvard College | METHODS AND COMPOSITIONS FOR REDUCING TACTILE DYSFUNCTION AND ANXIETY ASSOCIATED WITH AUTISM SPECTRUM DISORDER, RETT SYNDROME AND FRAGILE X SYNDROME |
| US10807987B2 (en) * | 2018-03-28 | 2020-10-20 | Takeda Pharmaceutical Company Limited | Heterocyclic compound and use thereof |
| CA3099751A1 (en) | 2018-05-22 | 2019-11-28 | President And Fellows Of Harvard College | Compositions and methods for reducing tactile dysfunction, anxiety, and social impairment |
| EP3801512A4 (en) * | 2018-05-29 | 2022-01-19 | President and Fellows of Harvard College | COMPOSITIONS AND METHODS TO REDUCE TACTILE DYSFUNCTION, ANXIETY AND SOCIAL DISABILITIES |
| WO2020198275A1 (en) | 2019-03-25 | 2020-10-01 | President And Fellows Of Harvard College | Compositions and methods for reducing tactile dysfunction, anxiety, and social impairment |
| JP2021050161A (ja) | 2019-09-25 | 2021-04-01 | 武田薬品工業株式会社 | 複素環化合物及びその用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3336194A (en) * | 1963-04-30 | 1967-08-15 | Merck & Co Inc | Indolyl acid amides |
| GB1076089A (en) * | 1965-11-09 | 1967-07-19 | Selvi & C Lab Bioterapico | New derivatives of imidazo [1,2-a]-pyridine and a process for the manufacture thereof |
-
1980
- 1980-10-22 FR FR8022537A patent/FR2492382A1/fr active Granted
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1981
- 1981-10-15 EP EP81401606A patent/EP0050563B1/fr not_active Expired
- 1981-10-15 DE DE8181401606T patent/DE3163524D1/de not_active Expired
- 1981-10-15 AT AT81401606T patent/ATE7393T1/de active
- 1981-10-15 LU LU88228C patent/LU88228I2/xx unknown
- 1981-10-19 MX MX81101627U patent/MX6463E/es unknown
- 1981-10-21 US US06/313,601 patent/US4382938A/en not_active Expired - Lifetime
- 1981-10-21 CA CA000388385A patent/CA1157470A/en not_active Expired
- 1981-10-21 GR GR66315A patent/GR74701B/el unknown
- 1981-10-21 JP JP56169392A patent/JPS5798283A/ja active Granted
- 1981-10-21 NO NO813551A patent/NO155664C/no not_active IP Right Cessation
- 1981-10-21 NZ NZ198722A patent/NZ198722A/xx unknown
- 1981-10-21 IL IL64091A patent/IL64091A/xx not_active IP Right Cessation
- 1981-10-21 ES ES506412A patent/ES8207537A1/es not_active Expired
- 1981-10-21 FI FI813288A patent/FI71143C/fi not_active IP Right Cessation
- 1981-10-21 AU AU76687/81A patent/AU544345B2/en not_active Expired
- 1981-10-21 DK DK465181A patent/DK154429C/da not_active IP Right Cessation
- 1981-10-21 IE IE2470/81A patent/IE51686B1/en not_active IP Right Cessation
- 1981-10-21 PT PT73863A patent/PT73863B/pt unknown
- 1981-10-21 ZA ZA817297A patent/ZA817297B/xx unknown
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1982
- 1982-04-21 OA OA57664A patent/OA07076A/xx unknown
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1983
- 1983-02-10 US US06/465,605 patent/US4460592A/en not_active Expired - Lifetime
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1993
- 1993-05-28 NL NL930044C patent/NL930044I2/nl unknown
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