Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-25
2001-09-11
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S399000
Reexamination Certificate
active
06288101
ABSTRACT:
This invention relates compounds having serotonin receptor binding activity, to pharmaceutical compositions containing them and to their medical use, particularly in the treatment of CNS conditions.
According to one aspect of the invention, there are provided compounds of Formula I and salts, solvates or hydrates thereof:
wherein
R
1
is selected from H, C
1-6
alkyl and benzyl;
R
2
is selected from H and C
1-6
alkyl;
R
3
is selected from H and C
1-6
alkyl;
R
4
is selected from C
1-6
alkyl and halo;
R
5
is selected from H and OH; and
with the proviso that when R
1
is H and R
2
and R
3
are methyl, R
4
is not t-butyl.
According to another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of Formula II, in an amount effective to stimulate 5-HT
1D
-like receptors, and a pharmaceutically acceptable carrier:
wherein
R
1
is selected from H, C
1-6
alkyl and benzyl;
R
2
is selected from H and C
1-6
alkyl;
R
3
is selected from H and C
1-6
alkyl;
R
4
is selected from C
1-6
alkyl and halo;
R
5
is selected from H and OH; and
and salts, solvates or hydrates thereof.
In another aspect of the invention, there are provided compositions containing the present compounds in amounts for pharmaceutical use to treat CNS conditions where a 5-HT
1D
-like ligand is indicated. These and other aspects of the present invention are described in greater detail hereinbelow.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
The term “C
1-6
alkyl” as used herein means straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
The term “halo” as used herein means halide and includes fluoro, chloro, bromo and iodo.
In embodiments of the invention, compounds of Formula I and II include those in which R
1
is selected from H, C
1-6
alkyl and benzyl. In preferred embodiments, R
1
is H.
In another embodiment of the invention, compounds of Formula I and II include those in which R
2
and R
3
are selected from H and C
1-6
alkyl. In preferred embodiments, one of R
2
and R
3
is H and the other is methyl or R
2
and R
3
are both methyl.
In another embodiment of the invention, compounds of Formula I and II include those in which R
4
is selected from C
1-6
alkyl and halo. In preferred embodiments of the invention, R
4
is selected from t-butyl, isopropyl and bromo. In the most preferred embodiment of the invention, R
4
is t-butyl or isopropyl.
In a further embodiment of the invention, R
5
is selected from H and OH; preferably, R
5
is H.
In specific embodiments of the invention, the compounds of Formula I and Formula II include:
2-[(4-t-butyl-2,6-dimethylphenyl)methyl]-1H-imidazole;
2-[(4-bromo-2,6-dimethylphenyl)methyl]-1H-imidazole;
2-[(2,4,6-trimethylphenyl)methyl]-1H-imidazole;
2-[(2,6-dimethyl-4-isopropylphenyl)methyl]-1H-imidazole;
2-[(4-t-butyl-2,6-dimethylphenyl)methyl]-1-methylimidazole;
2-[(4-t-butyl-2,6-dimethylphenyl)methyl]-1-benzylimidazole;
2-[(4-t-butyl-2-methylphenyl)methyl]-1H-imidazole; and
2-[(4-t-butyl-2,6-dimethylphenyl-3-hydroxy)methyl]-1H-imidazole.
Preferred compounds of Formula I and II include:
2-[(4-t-butyl-2,6-dimethylphenyl)methyl]-1H-imidazole;
2-[(4-bromo-2,6dimethylphenyl)methyl]-1H-imidazole;
2-[(2,4,6-trimethylphenyl)methyl]-1H-imidazole;
2-[(2,6-dimethyl-4-isopropylphenyl)methyl]-1H-imidazole;
2-[(4-t-butyl-2-methylpheny)methyl]-1H-imidazole; and
2-[(4-t-butyl-2,6-dimethylphenyl-3-hydroxy)methyl]-1H-imidazole.
Particularly preferred compounds of Formula I and II include:
2-[(4-t-butyl-2,6-dimethylphenyl)methyl]-1H-imidazole;
2-[(4-t-butyl-2-methylphenyl)methyl]-1H-imidazole; and
2-[(2,6-dimethyl-4-isopropylphenyl)methyl]-1H-imidazole.
Acid addition salts of the compound of Formula I and II are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e.g. hydrochloric, sulphuric or phosphoric acids and organic adds e.g. succinic, maleic, acetic or fumaric acid. Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I and II for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included within the scope of the invention are solvates and hydrates of the invention.
The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, in which an aqueous solution of the given salt is treated with a solution of base e.g. sodium carbonate or potassium hydroxide, to liberate the free base which is then extracted into an appropriate solvent such as ether. The free base is then separated from the aqueous portion, dried, and treated with the requisite acid to give the desired salt.
The compounds of the present invention can be prepared by processes analogous to those established in the art. Therefore, compounds of Formula I and II wherein R
1
-R
5
are as defined above, can be prepared by coupling a reagent of Formula A with a reagent of Formula B in an alcoholic solvent such as ethanol at temperatures in the range of 25-100° C., preferably at from 50-80° C., followed by dehydrogenation of the intermediate imidazoline, as shown in the scheme below. This dehydrogenation reaction can be accomplished by heating the imidazoline with a catalyst like platinum, palladium or nickel in an inert solvent and under a stream of an inert gas. Preferred dehydrogenation conditions include using palladium on carbon as catayst in refluxing toluene under an atmosphere of nitrogen.
Reagents of Formula A can be prepared from the corresponding phenyl acetonitrile compound by treatment with ethanol in the presence of an appropriate acid such as hydrochloric acid in an inert solvent such as ether at temperatures in the range of 0° C. to 30° C., preferably 0° C. to 25° C. Reagents B are commercially available, and can be prepared using well established procedures known to one skilled in the art.
The phenyl acetonitrile precursors to Reagent A compounds are commercially available, and can be prepared from reagents of Formula C, wherein X is a leaving group such as a halogen or tosyl group, by treatment with sodium cyanide in a polar solvent at temperatures in the range of 50 to 100° C. Preferred conditions are ethanol/water (6:1) at temperatures in the range of 75-100° C.
Reagents of Formula C are commercially available, and can be synthesized by established techniques, for example by treating the alcohol with halogenating reagents such as CBr
4
and triphenylphosphine (X=Br) or thionyl chloride (X=Cl) in inert solvents such as methylene chloride and benzene.
The above alcohol precursor to reagents of Formula C are also commercially available, and can be prepared by reduction of the corresponding aldehyde using metal hydride reducing reagents in inert solvents such as ethanol, ether and tetrahydrofuran, at temperatures in the range of 0-70° C. Preferred conditions for reduction of the aldehyde are sodium borohydride in ethanol at temperatures in the range of 30-60° C.
Most of the above aldehydes are commercially available, however, they also can be prepared from the corresponding amines by displacement of the diazonium salt, prepared by reaction of the amine with sodium nitrite in the presence of an acid such as hydrochloric acid, with paraformaldehyde.
In an embodiment of the invention, the compound is provided in labeled form, such as radiolabeled form, e.g. labeled by incorporation within its structure
3
H or
14
C or by conjugation to
125
I. In another aspect of the invention, the compounds in labeled form can be used to identify 5-HT
1D
-like receptor ligands by techniques common in the art. This can be achieved by incubating the receptor in the presence of a ligand candidate and then incubating the resulting preparation with an equimolar amount of radiolabele
Bacon & Thomas
Owens Amelia
Virginia Commonwealth University
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