CA2078700C - Imidazolylmethyl-pyridines - Google Patents
Imidazolylmethyl-pyridines Download PDFInfo
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- CA2078700C CA2078700C CA002078700A CA2078700A CA2078700C CA 2078700 C CA2078700 C CA 2078700C CA 002078700 A CA002078700 A CA 002078700A CA 2078700 A CA2078700 A CA 2078700A CA 2078700 C CA2078700 C CA 2078700C
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- SQEUYNQLUMQWKJ-UHFFFAOYSA-N 2-(1h-imidazol-2-ylmethyl)pyridine Chemical class C=1C=CC=NC=1CC1=NC=CN1 SQEUYNQLUMQWKJ-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 8
- 206010039966 Senile dementia Diseases 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 13
- 150000003839 salts Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000012458 free base Substances 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 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
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 206010028417 myasthenia gravis Diseases 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- 208000020401 Depressive disease Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- -1 imidazolylmethyl group Chemical group 0.000 claims 2
- 239000001530 fumaric acid Substances 0.000 claims 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 230000003902 lesion Effects 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
- 241000700159 Rattus Species 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 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
- 238000012360 testing method Methods 0.000 description 2
- 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
- 241001363655 Jaton Species 0.000 description 1
- 238000011672 OFA rat Methods 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 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
- 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
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 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
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 230000000144 pharmacologic 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
- 238000004809 thin layer chromatography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- Veterinary Medicine (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Luminescent Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Compounds of formula I, (see formula I) wherein R1 to R4 possess the significances given in the description, may be used in the treatment of senile dementia, Alzheimer's disease and depression.
Description
recv inn ~s~~t I!lIDAZOLYL?iETHYL-PYRIDINES
The present invention relates to imidazolylmethyl-pyridines, their production, their use as pharmaceuticals and pharmaceutical compositions containing them.
More particularly the present invention provides compounds of formula I, N _N
(I) wherein R1 is alkyl (1-4 C), halogen with an atomic number of 9 to 35 or amino optionally mono- or disubstituted by alkyl (1-4 C), Rz and R3 independently of one another are hydrogen or alkyl (1-4 C) and R9 is hydrogen, hydroxy, alkyl (1-4 C), alkoxy (1-4 C) or halogen with an atomic number of 9 to 35, in free base or acid addition salt form, hereinafter referred to as new compounds.
The present invention relates to imidazolylmethyl-pyridines, their production, their use as pharmaceuticals and pharmaceutical compositions containing them.
More particularly the present invention provides compounds of formula I, N _N
(I) wherein R1 is alkyl (1-4 C), halogen with an atomic number of 9 to 35 or amino optionally mono- or disubstituted by alkyl (1-4 C), Rz and R3 independently of one another are hydrogen or alkyl (1-4 C) and R9 is hydrogen, hydroxy, alkyl (1-4 C), alkoxy (1-4 C) or halogen with an atomic number of 9 to 35, in free base or acid addition salt form, hereinafter referred to as new compounds.
Insofar as above-defined alkyl or alkoxy groups are present in the new compounds, these preferably have one or two carbon atoms and especially signify methyl or methoxy.
The imidazolylmethyl radical is preferably in position 2 of the pyridine.
R1 is preferably methyl. Rz and R3 are preferably each hydrogen. R9 is preferably hydrogen. The compound of Example 1 is preferred.
In a particular group of new compounds, R1 is alkyl (1-4 C), RZ and R3 independently of one another are hydrogen or alkyl (1-4 C) and R~, is hydrogen, alkyl (1-4 C) or halogen with an atomic number of 9 to 35.
In accordance with the invention, the new compounds are obtained by reacting a compound of formula II, /N \X
(II) R~
wherein R4 is defined as above, and X is halogen, with a compound of formula III, Rl HN N
(III) wherein R1, RZ and R3 are defined as above, P
The imidazolylmethyl radical is preferably in position 2 of the pyridine.
R1 is preferably methyl. Rz and R3 are preferably each hydrogen. R9 is preferably hydrogen. The compound of Example 1 is preferred.
In a particular group of new compounds, R1 is alkyl (1-4 C), RZ and R3 independently of one another are hydrogen or alkyl (1-4 C) and R~, is hydrogen, alkyl (1-4 C) or halogen with an atomic number of 9 to 35.
In accordance with the invention, the new compounds are obtained by reacting a compound of formula II, /N \X
(II) R~
wherein R4 is defined as above, and X is halogen, with a compound of formula III, Rl HN N
(III) wherein R1, RZ and R3 are defined as above, P
and recovering the resulting compound of formula I in free base form or in acid addition salt form.
The reaction of the compound of formula II with the compound of formula II may take place in known manner, in a solvent which is inert under the reaction conditions, e.g. in dimethylformamide or a lower alcohol. In formula II, X is preferably chlorine.
Working up of the reaction mixtures obtained and purification of the compounds of formula I thus produced may take place in accordance with known methods.
The compounds of formula I may be present in free form or in the form of their acid addition salts. Acid addition salts may be produced from the free bases in known manner, and vice versa.
The starting compounds of formulae II and III are known or may be produced in accordance with known processes, resp. analogously to known processes.
The compounds of formula I and their physiologically acceptable salts, hereinafter referred to as compounds according to the invention, exhibit interesting pharmacological activities and may therefore be used as pharmaceuticals.
In the sieep/wake cycle of the long-term implanted rat [for the method, see J.-M. Vigouret et al., J. Pharmacol 10, 503 (1978)], the compounds according to the invention when administered at 1 to 100 mg/kg p.o. effect an increase in vigilance by prolonging the wake phases.
~ ~'~ ~'~ ~;
The reaction of the compound of formula II with the compound of formula II may take place in known manner, in a solvent which is inert under the reaction conditions, e.g. in dimethylformamide or a lower alcohol. In formula II, X is preferably chlorine.
Working up of the reaction mixtures obtained and purification of the compounds of formula I thus produced may take place in accordance with known methods.
The compounds of formula I may be present in free form or in the form of their acid addition salts. Acid addition salts may be produced from the free bases in known manner, and vice versa.
The starting compounds of formulae II and III are known or may be produced in accordance with known processes, resp. analogously to known processes.
The compounds of formula I and their physiologically acceptable salts, hereinafter referred to as compounds according to the invention, exhibit interesting pharmacological activities and may therefore be used as pharmaceuticals.
In the sieep/wake cycle of the long-term implanted rat [for the method, see J.-M. Vigouret et al., J. Pharmacol 10, 503 (1978)], the compounds according to the invention when administered at 1 to 100 mg/kg p.o. effect an increase in vigilance by prolonging the wake phases.
~ ~'~ ~'~ ~;
Moreover after administration of 1 to 100 mg/kg p.o. to rats with bilateral lesions of the Locus coeruleus (LC) and the Nucleus basalis Meynert (NBM), the compounds according to the invention improve significantly the cognitive performance as measured by the ability to avoid an electric shock in the shuttle box.
The method is similar to that described by V. Haroutunian et al. in Brain Research SU7 (1990) 261 - 266. Male OFA rats (300 g) are anaesthetized with pentobarbital and positioned in a stereotaxic apparatus with the upper incisor bar set 5 mm (LC) or 3.3 rnm (NBM) below the interaural line. The lesions are carried out with a radia frequency lesion generator ar 60 ° C during 10 seconds. 5 weeks after lesioning, behavioral testing is performed, using the active avoidance test in the shuttle box as described by A.R. Dravid, A.-L. Jaton and E.B. Van Deusen in Experimental Brain Research, suppl. 13, p. 249 (1986).
The compounds according to the invention are therefore useful 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 confusion disorders, Down's syndrome, myasthenia gravis and Friedrich's ataxia, furthermore as antidepressants.
An indicated daily dosage is in the range from about 1 mg to about 100 mg of a compound according to the invention, conveniently administered, for example, in divided doses up to four tunes a day.
'fhe compounds according to the invention may be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.
~~~~~G' In accordance with the foregoing, the present invention also provides a compound according to the invention, for use as a pharmaceutical, e.g. 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 confusion disorders, Down's syndrome, myasthenia gravis and Friedrich's ataxia, and for the treatment of depression.
The present invention furthermore provides a pharmaceutical composition cornprising a compound according to the invention in association with at least one pharmaceutical carrier or diluent. Such compositions may be manufactured in conventional manner. Unit dosage forms contain, for example, from about 0.25 mg to about 50 mg of a compound according to this invention.
The following examples illustrate the invention. The temperatures are given in degrees Celsius and are uncorrected.
The method is similar to that described by V. Haroutunian et al. in Brain Research SU7 (1990) 261 - 266. Male OFA rats (300 g) are anaesthetized with pentobarbital and positioned in a stereotaxic apparatus with the upper incisor bar set 5 mm (LC) or 3.3 rnm (NBM) below the interaural line. The lesions are carried out with a radia frequency lesion generator ar 60 ° C during 10 seconds. 5 weeks after lesioning, behavioral testing is performed, using the active avoidance test in the shuttle box as described by A.R. Dravid, A.-L. Jaton and E.B. Van Deusen in Experimental Brain Research, suppl. 13, p. 249 (1986).
The compounds according to the invention are therefore useful 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 confusion disorders, Down's syndrome, myasthenia gravis and Friedrich's ataxia, furthermore as antidepressants.
An indicated daily dosage is in the range from about 1 mg to about 100 mg of a compound according to the invention, conveniently administered, for example, in divided doses up to four tunes a day.
'fhe compounds according to the invention may be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.
~~~~~G' In accordance with the foregoing, the present invention also provides a compound according to the invention, for use as a pharmaceutical, e.g. 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 confusion disorders, Down's syndrome, myasthenia gravis and Friedrich's ataxia, and for the treatment of depression.
The present invention furthermore provides a pharmaceutical composition cornprising a compound according to the invention in association with at least one pharmaceutical carrier or diluent. Such compositions may be manufactured in conventional manner. Unit dosage forms contain, for example, from about 0.25 mg to about 50 mg of a compound according to this invention.
The following examples illustrate the invention. The temperatures are given in degrees Celsius and are uncorrected.
EXAHPLE l: (2-(2-methylimidazol-1-yl)methyl]pyridine 9.7 g (75 mM) of 2-(chloromethyl)pyridine and 42 g (512 mM) of 2-methyl-imidazole are suspended in 40 ml dimethylformamide, then stirred for 3 hours at 105 °. The dimethylformamide is distilled off and the crystalline residue is diluted with ethyl acetate and a little hexane. Following filtration, the mother solution is concentrated by evaporation and the dimethylformamide distilled off, and then shaken out several times between water and methylene chloride. 10.3 g of the oily title cornpound are obtained.
9.3 g of the obtained basa_ i.n ethanol are mixed with 12.7 g of furnaric acid. The resulting bis(base)-tris(hydrogen fumarate)crystallizes from ethanol/ethyl acetate and is recrystallized once from ethanol/ethyl acetate. It is uniform upon thin-layer chromatography and melts at 109 - 110 °.
The following [2-(imidazol-1-yl)methyl]pyridines are produced analogously to example 1:
~Example R I R4 M.p.
I
i T ~
I ~
~ ~ ~
I 3 I CH3 CH3 H H I 250 - 253 (decomp.) I I **
I 4 I CE33 H CH3 I H 213 - 220 (decomp.) I I I **
m * fumarate ** dihydrochloride ~~~~~~~~!
9.3 g of the obtained basa_ i.n ethanol are mixed with 12.7 g of furnaric acid. The resulting bis(base)-tris(hydrogen fumarate)crystallizes from ethanol/ethyl acetate and is recrystallized once from ethanol/ethyl acetate. It is uniform upon thin-layer chromatography and melts at 109 - 110 °.
The following [2-(imidazol-1-yl)methyl]pyridines are produced analogously to example 1:
~Example R I R4 M.p.
I
i T ~
I ~
~ ~ ~
I 3 I CH3 CH3 H H I 250 - 253 (decomp.) I I **
I 4 I CE33 H CH3 I H 213 - 220 (decomp.) I I I **
m * fumarate ** dihydrochloride ~~~~~~~~!
as well as the following [4-(imidazol-1-y1)methyl]pyridine:
Example ~ Rz R3 R9 M.p.
R1 ~ ~ ~ ~
i i i i i i ~ CH3 ~ H H H ~ 155 - 156 *
~ ~
* fumarate
Example ~ Rz R3 R9 M.p.
R1 ~ ~ ~ ~
i i i i i i ~ CH3 ~ H H H ~ 155 - 156 *
~ ~
* fumarate
Claims (8)
1. A process for the production of a compound of formula I, wherein R1 is alkyl (1-4 C), halogen with an atomic number of 9 to 35 or amino optionally mono- or disubstituted by alkyl (1-4 C), R2 and R3 independently of one another are hydrogen or alkyl (1-4 C) and R4 is hydrogen, hydroxy, alkyl (1-4 C), alkoxy (1-4 C) or halogen with an atomic number of 9 to 35, in free base or acid addition salt form, which includes the step of reacting a compound of formula II, wherein R4 is defined as above, and X is halogen, with a compound of formula III, wherein R1, R2 and R3 are defined as above, and recovering the resulting compound of formula I in free base form or in acid addition salt form.
2. A compound of formula I in free base form or acid addition salt form, as defined in claim 1.
3. A compound of claim 2 wherein R1 is alkyl (1-4 C), R2 and R3 independently of one another are hydrogen or alkyl (1-4 C) and R4 is hydrogen, alkyl (1-4 C) or halogen with an atomic number of 9 to 35, in free base or acid addition salt form.
4. A compound of claim 2. which is the [2-(2-methylimidazol-1-yl)methyl]pyridine, in free base or acid addition salt form.
5. A compound of claim 4 in acid addition salt form, wherein the acid is fumaric acid.
6. A compound of claim 2 wherein - R1 = CH3, R2 = H, R3 = H, R4 = 6-CH3, or - R1 = CH3, R2 = CH3, R4 = H, R4 = H, or - R1 = CH3, R2 = H, R3 = CH3, R4 = H, and the imidazolylmethyl group is in position 2, or - R1 = CH3, R2 = H, R3 = H, R4 = H
and the imidazolylmethyl group is in position 4, in free base or acid addition salt form.
and the imidazolylmethyl group is in position 4, in free base or acid addition salt form.
7. A compound of any one of claims 2 to 6 in physiologically acceptable form, for use in the treatment of senile dementia, Alzheimer's disease, Huntington's chorea, Morbus Parkinson, Steel-Richardson syndrome, tardive dyskinesia, hyperkinesia, acute confusion disorders, Down's syndrome, myasthenia gravis or Friedrich's ataxia, or in the treatment of depression.
8. A pharmaceutical composition comprising a compound according to any one of claims 2 to 6 in physiologically acceptable form, in association with a pharmaceutical carrier or diluent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4131584.7 | 1991-09-23 | ||
| DE4131584A DE4131584A1 (en) | 1991-09-23 | 1991-09-23 | IMIDAZOLYLMETHYL-PYRIDINE, THEIR PRODUCTION AND USE AS A PHARMACEUTICAL |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2078700A1 CA2078700A1 (en) | 1993-03-24 |
| CA2078700C true CA2078700C (en) | 2005-09-13 |
Family
ID=6441240
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002078700A Expired - Fee Related CA2078700C (en) | 1991-09-23 | 1992-09-21 | Imidazolylmethyl-pyridines |
Country Status (24)
| Country | Link |
|---|---|
| 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) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018217631A1 (en) * | 2017-05-22 | 2018-11-29 | Torrey Pines Institute For Molecular Studies | Compositions, methods of use, and methods of treatment |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10165349A (en) * | 1996-12-06 | 1998-06-23 | Matsushita Electric Ind Co Ltd | Dishwasher |
| DE10000161A1 (en) * | 2000-01-06 | 2001-07-19 | Boehringer Ingelheim Pharma | Method of identifying a protease inhibitor |
| GB0009037D0 (en) * | 2000-04-13 | 2000-05-31 | Novartis Ag | Organic compounds |
| AU2005215134B2 (en) * | 2004-02-19 | 2009-01-29 | Novartis Ag | Use of cholinesterase inhibitors for treating vascular depression |
| AU2006275824B2 (en) * | 2005-07-29 | 2010-12-16 | Vanda Pharmaceuticals, Inc. | Method of improving wakefulness |
| JP5044572B2 (en) * | 2006-02-13 | 2012-10-10 | ヴァンダ ファーマシューティカルズ インコーポレイテッド | Stable dosage formulation of imidazolylalkyl-pyridine |
| 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 |
| WO2012052540A1 (en) * | 2010-10-21 | 2012-04-26 | Universitaet Des Saarlandes | Selective cyp11b1 inhibitors for the treatment of cortisol dependent diseases |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2862340D1 (en) * | 1978-02-01 | 1983-11-24 | Wellcome Found | 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
-
1992
- 1992-09-09 HU HU9202886A patent/HUT61993A/en unknown
- 1992-09-18 MY MYPI92001673A patent/MY110450A/en unknown
- 1992-09-21 DE DE59207425T patent/DE59207425D1/en not_active Expired - Lifetime
- 1992-09-21 ES ES92810719T patent/ES2092666T3/en not_active Expired - Lifetime
- 1992-09-21 NO NO923653A patent/NO301162B1/en not_active IP Right Cessation
- 1992-09-21 CZ CS922896A patent/CZ281675B6/en not_active IP Right Cessation
- 1992-09-21 NZ NZ244420A patent/NZ244420A/en not_active IP Right Cessation
- 1992-09-21 EP EP92810719A patent/EP0534904B1/en not_active Expired - Lifetime
- 1992-09-21 AU AU25226/92A patent/AU650569B2/en not_active Ceased
- 1992-09-21 AT AT92810719T patent/ATE144509T1/en active
- 1992-09-21 FI FI924233A patent/FI103887B/en not_active IP Right Cessation
- 1992-09-21 CA CA002078700A patent/CA2078700C/en not_active Expired - Fee Related
- 1992-09-21 SK SK2896-92A patent/SK279224B6/en not_active IP Right Cessation
- 1992-09-21 DK DK92810719.2T patent/DK0534904T3/en active
- 1992-09-21 SG SG1996003366A patent/SG43079A1/en unknown
- 1992-09-21 IL IL10322992A patent/IL103229A/en not_active IP Right Cessation
- 1992-09-22 MX MX9205365A patent/MX9205365A/en unknown
- 1992-09-22 KR KR1019920017228A patent/KR100254085B1/en not_active Expired - Fee Related
- 1992-09-22 JP JP4252692A patent/JP2568356B2/en not_active Expired - Fee Related
- 1992-09-22 RO RO92-01218A patent/RO109337B1/en unknown
- 1992-09-22 RU SU925052552A patent/RU2058312C1/en active
- 1992-09-23 ZA ZA927279A patent/ZA927279B/en unknown
- 1992-09-24 TW TW081107550A patent/TW222630B/zh active
-
1995
- 1995-06-13 HU HU95P/P00198P patent/HU211261A9/en unknown
-
1996
- 1996-10-24 GR GR960402593T patent/GR3021444T3/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018217631A1 (en) * | 2017-05-22 | 2018-11-29 | Torrey Pines Institute For Molecular Studies | Compositions, methods of use, and methods of treatment |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |