NO301162B1 - Imidazolylpyridinderivater - Google Patents
Imidazolylpyridinderivater Download PDFInfo
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- NO301162B1 NO301162B1 NO923653A NO923653A NO301162B1 NO 301162 B1 NO301162 B1 NO 301162B1 NO 923653 A NO923653 A NO 923653A NO 923653 A NO923653 A NO 923653A NO 301162 B1 NO301162 B1 NO 301162B1
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- acid addition
- free base
- addition salt
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- alkyl
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- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 150000003839 salts Chemical group 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 11
- 239000012458 free base Substances 0.000 claims abstract description 9
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 206010039966 Senile dementia Diseases 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- -1 imidazolylmethyl group Chemical group 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 206010003591 Ataxia Diseases 0.000 claims description 3
- 208000033647 Classic progressive supranuclear palsy syndrome Diseases 0.000 claims description 3
- 201000010374 Down Syndrome Diseases 0.000 claims description 3
- 208000023105 Huntington disease Diseases 0.000 claims description 3
- 206010020651 Hyperkinesia Diseases 0.000 claims description 3
- 208000000269 Hyperkinesis Diseases 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 206010043118 Tardive Dyskinesia Diseases 0.000 claims description 3
- 206010044688 Trisomy 21 Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 206010028417 myasthenia gravis Diseases 0.000 claims description 3
- 208000032207 progressive 1 supranuclear palsy Diseases 0.000 claims description 3
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims description 3
- 208000020401 Depressive disease Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 239000008024 pharmaceutical diluent Substances 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 5
- 230000001430 anti-depressive effect Effects 0.000 abstract description 4
- 239000000935 antidepressant agent Substances 0.000 abstract description 3
- 229940005513 antidepressants Drugs 0.000 abstract description 3
- 229910052736 halogen Inorganic materials 0.000 abstract description 3
- 150000002367 halogens Chemical class 0.000 abstract 2
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 5
- 230000003902 lesion Effects 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 210000000627 locus coeruleus Anatomy 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000036385 rapid eye movement (rem) sleep Effects 0.000 description 3
- 230000007958 sleep Effects 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- SZXUTTGMFUSMCE-UHFFFAOYSA-N 2-(1h-imidazol-2-yl)pyridine Chemical class C1=CNC(C=2N=CC=CC=2)=N1 SZXUTTGMFUSMCE-UHFFFAOYSA-N 0.000 description 1
- SQEUYNQLUMQWKJ-UHFFFAOYSA-N 2-(1h-imidazol-2-ylmethyl)pyridine Chemical class C=1C=CC=NC=1CC1=NC=CN1 SQEUYNQLUMQWKJ-UHFFFAOYSA-N 0.000 description 1
- NJWIMFZLESWFIM-UHFFFAOYSA-N 2-(chloromethyl)pyridine Chemical compound ClCC1=CC=CC=N1 NJWIMFZLESWFIM-UHFFFAOYSA-N 0.000 description 1
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 238000011672 OFA rat Methods 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000036626 alertness Effects 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 238000009227 behaviour therapy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000003931 cognitive performance Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 210000004283 incisor Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring 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
- C07D401/06—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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Veterinary Medicine (AREA)
- Neurology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Psychiatry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Luminescent Compositions (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Foreliggende oppfinnelse vedrører imidazolylpyridinderivater, deres anvendelse som farmasøytika, og farmasøytiske preparater inneholdende de nevnte forbindelser. The present invention relates to imidazolylpyridine derivatives, their use as pharmaceuticals, and pharmaceutical preparations containing the aforementioned compounds.
Mere spesielt tilveiebringer foreliggende oppfinnelse forbindelser med formel I, More particularly, the present invention provides compounds of formula I,
hvori in which
Rx er C1-C4 alkyl, Rx is C1-C4 alkyl,
R2 og R3 er uavhengig av hverandre hydrogen eller Cx-C4 alkyl, R2 and R3 are independently hydrogen or Cx-C4 alkyl,
og and
R4 er hydrogen eller C-l-C,} alkyl, R 4 is hydrogen or C-1-C, } alkyl,
i form av fri base eller syreaddisjonssalt. in the form of free base or acid addition salt.
Forbindelsene benevnes heretter som nye forbindelser. The connections are hereafter referred to as new connections.
Forsåvidt som de ovennevnte alkylgrupper er tilstede i de nye forbindelsene, har disse foretrukket en eller to karbonatomer og betyr særlig metyl. Insofar as the above-mentioned alkyl groups are present in the new compounds, these preferably have one or two carbon atoms and mean particularly methyl.
Imidazolylalkylradikalet er foretrukket i 2-stillingen på pyridinet, men kan også være i 4-stillingen på pyridinet. The imidazolylalkyl radical is preferred in the 2-position of the pyridine, but can also be in the 4-position of the pyridine.
Rx er foretrukket metyl. R2 og R3 er hver foretrukket hydrogen. R4 er foretrukket hydrogen. Forbindelsen i eksempel 1 er foretrukket. Rx is preferably methyl. R 2 and R 3 are each preferably hydrogen. R 4 is preferably hydrogen. The compound in example 1 is preferred.
De nye forbindelsene kan fremstilles ved at en forbindelse The new compounds can be produced by a compound
med formel II, with formula II,
hvori R4 er som angitt over og X er halogen, reageres med en forbindelse med formel III, wherein R 4 is as defined above and X is halogen, is reacted with a compound of formula III,
hvori Rx, R2 og R3 er som angitt over, where Rx, R2 and R3 are as above,
og med oppnåelse av den endelige forbindelse med formel I i form av fri base eller i form av et syreaddisjonssalt. and with obtaining the final compound of formula I in the form of a free base or in the form of an acid addition salt.
Reaksjonen av forbindelsen med formel II med forbindelsen med formel III kan gjennomføres på kjent måte, i et løsnings-middel som er inert under reaks j onsbetingelsene, f . eks-, i dimetylformamid eller lavere alkohol. I formel II er X foretrukket klor. The reaction of the compound of formula II with the compound of formula III can be carried out in a known manner, in a solvent which is inert under the reaction conditions, e.g. ex-, in dimethylformamide or lower alcohol. In formula II, X is preferably chlorine.
Bearbeiding av de oppnådde reaksjonsblandinger og rensing av de således dannede forbindelser med formel I kan gjennomføres i henhold til kjente metoder. Processing of the obtained reaction mixtures and purification of the thus formed compounds of formula I can be carried out according to known methods.
Forbindelsene med formel I kan være tilstede i fri form eller i form av deres syreaddisjonssalter. Syreaddisjonssaltene kan dannes fra de frie basene på kjent måte og vice versa. The compounds of formula I may be present in free form or in the form of their acid addition salts. The acid addition salts can be formed from the free bases in a known manner and vice versa.
Utgangsforbindelsene med formel II og III er kjente forbindelser eller de kan fremstilles i overensstemmelse med kjente prosedyrer, henholdsvis analoge med kjente prosedyrer. The starting compounds of formulas II and III are known compounds or they can be prepared in accordance with known procedures, respectively analogous to known procedures.
Forbindelsene med formel I og deres fysiologisk tålbare salter som i det etterfølgende er betegnet som forbindelser i henhold til oppfinnelsen, utviser fordelaktige farmakologiske aktiviteter og de kan derfor anvendes som farmasøytika. The compounds of formula I and their physiologically tolerable salts, which are hereinafter referred to as compounds according to the invention, exhibit beneficial pharmacological activities and they can therefore be used as pharmaceuticals.
I syklusen med søvn/våken tilstand hos langsiktig implantert rotte (for metoden, se J.M. Vigouret et al., J. Pharmacol 10, 503 (1978)), vil forbindelsene i henhold til oppfinnelsen, når de tilføres peritonealt i 1 til 100 mg/kg, bevirke en økning i våkenhet ved at de våkne fasene forlenges. In the sleep/wake cycle of the long-term implanted rat (for the method, see J.M. Vigouret et al., J. Pharmacol 10, 503 (1978)), the compounds of the invention, when administered peritoneally at 1 to 100 mg/ kg, cause an increase in alertness by lengthening the awake phases.
I denne test reduserte alle forbindelser REM-søvnen og forlenget de våkne faser signifikant. Testen er basert på den anerkjennelse at en berøvelse av total søvnmengde (som svarer til forlengelse av de våkne faser) eller en berøvelse av selektiv REM-søvn har antidepressiv effekt (se f.eks. W.B. Mendelson et al., Human Sleep and its Disorders, Plenum Press, New York and London, side 173), og at ulike anti-depressive midler undertrykker REM-søvn i normale og deprimerte pasienter (se den samme artikkel, side 178). In this test, all compounds significantly reduced REM sleep and prolonged the awake phases. The test is based on the recognition that a deprivation of the total amount of sleep (which corresponds to the prolongation of the awake phases) or a deprivation of selective REM sleep has an antidepressant effect (see e.g. W.B. Mendelson et al., Human Sleep and its Disorders , Plenum Press, New York and London, page 173), and that various anti-depressants suppress REM sleep in normal and depressed patients (see the same article, page 178).
De etterfølgende minimale effektive doser (MED) er blitt oppnådd: The following minimal effective doses (MED) have been obtained:
Etter peritoneal tilførsel av 1 til 100 mg/kg til rotter med bilaterale lesjoner i locus coeruleus (LC) og nucleus basalis Meynert (NBM) vil dessuten forbindelsene i henhold til oppfinnelsen forbedre kognitiv opptreden betydelig som målt ved evnen til å unngå et elektrisk sjokk i skyttelkassen. Furthermore, after peritoneal administration of 1 to 100 mg/kg to rats with bilateral lesions in the locus coeruleus (LC) and nucleus basalis Meynert (NBM), the compounds according to the invention will significantly improve cognitive performance as measured by the ability to avoid an electric shock in the shuttle box.
Metoden er den samme som beskrevet av V. Haroutunian et al. i Brain Research 507 (1990) 261-266. OFA-hannrotter 300 g bedøves med pentobarbital og plasseres i et stereotaksisk apparat med den øvre "incisor bar" satt til 5 mm (LC) eller 3,3 mm (NBM) under interaurallinjen. Lesjonene ble gjennomført med en radiofrekvenslesjonsgenerator ved 60°C i løpet av ti sekunder. Fem uker etter lesjondannelse ble det gjennomført tester vedrørende opptreden ved anvendelse av den aktive unngåelsetest i skyttelkassen som beskrevet av A.R. Dravid, A.L. Jaton og E.B. Van Deusen og Experimental Brain Research, Suppl. 13, side 249 (1986). The method is the same as described by V. Haroutunian et al. in Brain Research 507 (1990) 261-266. Male OFA rats 300 g are anesthetized with pentobarbital and placed in a stereotaxic apparatus with the upper incisor bar set at 5 mm (LC) or 3.3 mm (NBM) below the interaural line. The lesions were performed with a radiofrequency lesion generator at 60°C within ten seconds. Five weeks after lesion formation, behavioral tests were conducted using the active avoidance test in the shuttle box as described by A.R. Dravid, A.L. Jaton and E.B. Van Deusen and Experimental Brain Research, Suppl. 13, page 249 (1986).
US-PS 4.230.714 vedrører imidazolylmetylpyridiner og -kinoliner som ikke er substituerte i 2-stillingen på imidazolenheten. Mens disse forbindelser er anvendbare for behandling av ischemisk hjertesykdom, slag og migrene, utviser de 2-substituerte imidazoler i henhold til oppfinnelsen en uventet farmakologisk profil som indikerer sentralaktivi-tet. US-PS 4,230,714 relates to imidazolylmethylpyridines and -quinolines which are not substituted in the 2-position of the imidazole unit. While these compounds are useful for the treatment of ischemic heart disease, stroke and migraine, the 2-substituted imidazoles according to the invention exhibit an unexpected pharmacological profile indicating central activity.
Forbindelsene i henhold til oppfinnelsen kan derfor anvendes for behandling av senil demens, Alzheimers sykdom og ytter-ligere degenererende sykdommer som Huntingtons chorea, Morbus Parkinson, Steel-Richardson syndrom, tardive dyskinesier, hyperkinesi, akutte konfusjonsforstyrrelser, Downs syndrom, myasteni gravis og Friedrichs ataksi, og videre som anti-depressive midler. The compounds according to the invention can therefore be used for the treatment of senile dementia, Alzheimer's disease and further degenerative diseases such as Huntington's chorea, Morbus Parkinson, Steel-Richardson syndrome, tardive dyskinesias, hyperkinesia, acute confusional disorders, Down's syndrome, myasthenia gravis and Friedrich's ataxia , and further as anti-depressants.
En indikert daglig dose av en forbindelse i henhold til oppfinnelsen er i området fra 1 mg til 100 mg som passende f.eks. tilføres i flere doser opptil fire ganger pr. døgn. An indicated daily dose of a compound according to the invention is in the range from 1 mg to 100 mg as appropriate e.g. administered in several doses up to four times per day and night.
Forbindelsene i henhold til oppfinnelsen kan tilføres på enhver vanlig anvendt måte, særlig enteralt, foretrukket oralt, f.eks. i form av tabletter eller kapsler, eller parenteralt, f.eks. i form av injiserbare oppløsninger eller suspensjoner. The compounds according to the invention can be administered in any commonly used way, in particular enterally, preferably orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions.
I overensstemmelse med det foregående tilveiebringer den In accordance with the foregoing, it provides
foreliggende oppfinnelse også anvendelse av en forbindelse i henhold til oppfinnelsen for fremstilling av et farmasøytisk preparat for behandlingen av senil demens, Alzheimers sykdom, Huntingtons chorea, Morbus Parkinson, Steel-Richardson syndrom, tardiv dyskinesi, hyperkinesi, akutte konfusjonsforstyrrelser, Downs syndrom, myasteni gravis og Friedrichs ataksi, og for behandling av depresjon. present invention also use of a compound according to the invention for the production of a pharmaceutical preparation for the treatment of senile dementia, Alzheimer's disease, Huntington's chorea, Morbus Parkinson, Steel-Richardson syndrome, tardive dyskinesia, hyperkinesia, acute confusional disorders, Down's syndrome, myasthenia gravis and Friedrich's ataxia, and for the treatment of depression.
Den foreliggende oppfinnelse tilveiebringer videre et farma-søytisk preparat som omfatter en forbindelse i henhold til oppfinnelsen sammen med minst en farmasøytisk tålbar bærer eller, fortynningsmiddel. Slike preparater kan fremstilles på vanlig måte. Enhetsdoseformer inneholder f.eks. fra 0,2 5 mg til 50 mg av en forbindelse i henhold til oppfinnelsen. The present invention further provides a pharmaceutical preparation comprising a compound according to the invention together with at least one pharmaceutically acceptable carrier or diluent. Such preparations can be prepared in the usual way. Unit dosage forms contain e.g. from 0.25 mg to 50 mg of a compound according to the invention.
De etterfølgende eksempler illustrerer oppfinnelsen. Temperaturene er gitt i grader Celsius og er ukorrigerte. The following examples illustrate the invention. Temperatures are given in degrees Celsius and are uncorrected.
EKSEMPEL 1: [2-(2-metylimidazol-l-yl)metyl] pyridin EXAMPLE 1: [2-(2-methylimidazol-1-yl)methyl]pyridine
9,7 g (75 mM) 2-(klormetyl)pyridin og 42 g (512 mM) 2-metyl-imidazol suspenderes i 40 ml dimetylformamid, og blandingen omrøres deretter i tre timer ved 105°C. Dimetylformamidet avdestilleres og den krystallinske rest fortynnes med etyl-acetat og litt heksan. Etter filtrering konsentreres moder-væsken ved avdamping og dimetylformamidet avdestilleres, og rystes deretter ut flere ganger mellom vann og metylenklorid. Det oppnås 10,3 g av den oljeaktige tittelforbindelse. 9.7 g (75 mM) of 2-(chloromethyl)pyridine and 42 g (512 mM) of 2-methylimidazole are suspended in 40 ml of dimethylformamide, and the mixture is then stirred for three hours at 105°C. The dimethylformamide is distilled off and the crystalline residue is diluted with ethyl acetate and a little hexane. After filtration, the mother liquor is concentrated by evaporation and the dimethylformamide is distilled off, and then shaken out several times between water and methylene chloride. 10.3 g of the oily title compound are obtained.
9,3 g av den oppnådde base i etanol blandes med 12,7 g fumarsyre. Det oppnådde bis(base)-tris(hydrogenfumarat) krystalliseres fra etanol/etylacetat og rekrystalliseres en gang fra etanol/etylacetat. Det er ensartet ved tynnsjiktkromatografi og smelter ved 109 - 110°C. 9.3 g of the obtained base in ethanol are mixed with 12.7 g of fumaric acid. The bis(base)-tris(hydrogen fumarate) obtained is crystallized from ethanol/ethyl acetate and recrystallized once from ethanol/ethyl acetate. It is uniform by thin layer chromatography and melts at 109 - 110°C.
De etterfølgende [2-(imidazol-l-yl)metyl]pyridiner fremstilles analogt med eksempel 1: såvel som det etterfølgende [4-(imidazol-1-yl)metyl]pyridin: The following [2-(imidazol-1-yl)methyl]pyridines are prepared analogously to example 1: as well as the following [4-(imidazol-1-yl)methyl]pyridine:
Claims (6)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4131584A DE4131584A1 (en) | 1991-09-23 | 1991-09-23 | IMIDAZOLYLMETHYL-PYRIDINE, THEIR PRODUCTION AND USE AS A PHARMACEUTICAL |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO923653D0 NO923653D0 (en) | 1992-09-21 |
| NO923653L NO923653L (en) | 1993-03-24 |
| NO301162B1 true NO301162B1 (en) | 1997-09-22 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO923653A NO301162B1 (en) | 1991-09-23 | 1992-09-21 | Imidazolylpyridinderivater |
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| Country | Link |
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| EP (1) | EP0534904B1 (en) |
| JP (1) | JP2568356B2 (en) |
| KR (1) | KR100254085B1 (en) |
| AT (1) | ATE144509T1 (en) |
| AU (1) | AU650569B2 (en) |
| CA (1) | CA2078700C (en) |
| CZ (1) | CZ281675B6 (en) |
| DE (2) | DE4131584A1 (en) |
| DK (1) | DK0534904T3 (en) |
| ES (1) | ES2092666T3 (en) |
| FI (1) | FI103887B (en) |
| GR (1) | GR3021444T3 (en) |
| HU (2) | HUT61993A (en) |
| IL (1) | IL103229A (en) |
| MX (1) | MX9205365A (en) |
| MY (1) | MY110450A (en) |
| NO (1) | NO301162B1 (en) |
| NZ (1) | NZ244420A (en) |
| RO (1) | RO109337B1 (en) |
| RU (1) | RU2058312C1 (en) |
| SG (1) | SG43079A1 (en) |
| SK (1) | SK279224B6 (en) |
| TW (1) | TW222630B (en) |
| ZA (1) | ZA927279B (en) |
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| JPH10165349A (en) * | 1996-12-06 | 1998-06-23 | Matsushita Electric Ind Co Ltd | Dish washer |
| DE10000161A1 (en) * | 2000-01-06 | 2001-07-19 | Boehringer Ingelheim Pharma | Determining test substances that inhibit protease, involves incubating cells expressing fusion protein having substrate with cleavage site for protease and reporter, measuring cleaved reporter and comparing with standard |
| GB0009037D0 (en) * | 2000-04-13 | 2000-05-31 | Novartis Ag | Organic compounds |
| KR101146807B1 (en) | 2005-07-29 | 2012-05-21 | 반다 파마슈티칼즈, 인코퍼레이티드. | Method of improving wakefulness |
| WO2007095523A2 (en) * | 2006-02-13 | 2007-08-23 | Vanda Pharmaceuticals, Inc. | Stable dosage formulations of imidazolylalkyl-pyridines |
| WO2009097416A1 (en) * | 2008-01-29 | 2009-08-06 | Vanda Pharmaceuticals, Inc. | Imidazolylalkyl- pyridines as dbh inhibitors |
| JP6265583B2 (en) | 2008-10-17 | 2018-01-24 | ウィスコンシン アルムニ リサーチ ファンデイション | Method for producing bioactive alpha beta peptide |
| US9394290B2 (en) * | 2010-10-21 | 2016-07-19 | Universitaet Des Saarlandes Campus Saarbruecken | Selective CYP11B1 inhibitors for the treatment of cortisol dependent diseases |
| JP2020520952A (en) * | 2017-05-22 | 2020-07-16 | トーリー パインズ インスティテュート フォー モレキュラー スタディーズＴｏｒｒｅｙ Ｐｉｎｅｓ Ｉｎｓｔｉｔｕｔｅ Ｆｏｒ Ｍｏｌｅｃｕｌａｒ Ｓｔｕｄｉｅｓ | Compositions, methods of use and methods of treatment |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0003732B1 (en) * | 1978-02-01 | 1983-10-19 | The Wellcome Foundation Limited | Imidazole derivatives and salts thereof, their synthesis, and pharmaceutical formulations thereof |
| GB2028317B (en) * | 1978-08-15 | 1982-11-10 | Pfizer Ltd | 2-(imidazol-1-ylmethyl)-pyridine and -quinoline thromboxane synthetase inhibitors |
| US4634711A (en) * | 1985-08-02 | 1987-01-06 | Smithkline Beckman Corporation | Pyridylalkyl imidazole-2-thiols |
| DE3811574A1 (en) * | 1988-03-31 | 1989-10-19 | Schering Ag | N-SUBSTITUTED IMIDAZOLES, METHODS FOR THEIR PRODUCTION AND THEIR USE IN MEDICINAL PRODUCTS |
-
1991
- 1991-09-23 DE DE4131584A patent/DE4131584A1/en not_active Withdrawn
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1992
- 1992-09-09 HU HU9202886A patent/HUT61993A/en unknown
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- 1992-09-21 DE DE59207425T patent/DE59207425D1/en not_active Expired - Lifetime
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- 1992-09-21 EP EP92810719A patent/EP0534904B1/en not_active Expired - Lifetime
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- 1992-09-21 AU AU25226/92A patent/AU650569B2/en not_active Ceased
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- 1992-09-21 ES ES92810719T patent/ES2092666T3/en not_active Expired - Lifetime
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1995
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1996
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