Naphtho-imidazo pyridine derivatives useful in treating...

Details Naphtho-imidazo pyridine derivatives useful in treating... Naphtho-imidazo pyridine derivatives useful in treating...

1998-10-05

2001-03-13

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S242000, C514S245000, C514S255050, C514S256000, C514S269000, C514S272000, C514S274000, C514S275000, C544S182000, C544S198000, C544S209000, C544S212000, C544S238000, C544S301000, C544S312000, C544S316000, C544S317000, C544S319000, C544S321000, C544S323000, C544S329000, C544S332000, C544S336000, C544S407000, C544S408000, C544S409000, C546S070000

Reexamination Certificate

active

06200984

ABSTRACT:

BACKGROUND OF THE INVENTION
The gamma-aminobutyric acid-A receptor (GABA-A receptor) is the most abundant inhibitory receptor in the brain of mammals. It is comprised of a heteropolymeric structure that forms a chloride ion channel, and bears multiple recognition sites for the binding of modulatory molecules. The binding of GABA to its specific recognition site on the GABA-A receptor opens the ion channel and allows chloride ions to flow into the nerve cell. This action hyperpolarizes the cell membrane of that neuron and thereby makes the cell less reactive to excitatory stimuli. The chloride ion current may also be regulated by various drugs that serve as positive or negative modulators of the GABA-A receptor (Smith and Olsen, Trends Pharm. Sci., 1995, 16, 162; Stephenson, Biochem. J., 1995, 310,1). The so-called benzodiazepine (BZD) receptor is a site for such allosteric modulators on the GABA-A receptor. This site mediates two opposing effects, one that amplifies the action of GABA (“positive” efficacy) and the other that reduces the action of GABA (“negative” efficacy). Agents facilitating GABA-receptor/chloride ion-channel functions via the BZD site are referred to as agonists, while agents reducing such function are referred to as inverse agonists. Antagonists at this site block the effects of agonists or inverse agonists by competitively inhibiting their binding. It is thus possible to have a series of compounds in which members equally bind to the BZD site but have equal and opposite regulatory effects on the GABA-A receptor/chloride ion channel. Also, within the series a continuum of activity is possible (Takada, S. et al. J. Med. Chem. 1988, 31, 1738). Thus BZD receptor ligands can induce a wide spectrum of pharmacological effects ranging from muscle relaxant, hypnotic, sedative, anxiolytic, and anticonvulsant activities, produced by full or partial agonists (“positive”), to the proconvulsant, anti-inebriant, and anxiogenic activities, produced by inverse agonists (“negative”). (A further understanding of this area can be gleaned from: Mohler, H. Arzneim.-Forsch./Drug Res, 1992, 42 (2a), 211; Haefely, W. et al., Advances in Drug Research, Academic Press, vol. 14,1985, pp. 165-322; Skolnick, P. et al., GABA and Benzodiazepine Receptors, Squires, R., Ed., 1987, pp. 99-102 and references cited therein.)
The naphtho-imidazo derivatives are a class of compounds which bind to the BZD receptor with high affinity. Most of the drugs in use are agonist-type ligands for the receptor. Such compounds are generally useful for their anticonvulsant, anxiolytic, sedative and muscle relaxant effects. Antagonists of the BZD binding site are useful for the treatment of benzodiazepine drug overdoses and inverse agonists are useful in managing alcoholism.
The present invention relates to novel compositions of matter, their use and their method of preparation. Compounds having some structural similarity to those of the present invention are described in U.S. Pat. No. 5,639,760 which is assigned to the assignee of the present invention.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of the following formula I:
wherein Ar, R and R
1
are as hereinafter defined. The compounds of formula I are useful in treating central nervous system disorders. The compounds are ligands for the BZD binding site on GABA-A receptors and are thus useful as muscle relaxants, hypnotics/sedatives including sleep-aids, anxiolytics, anticonvulsants/antiepileptics and antidotes for drug overdose, particularly benzodiazepine overdoses.
DETAILED DESCRIPTION OF THE INVENTION
More particularly, the present invention is directed to compounds of the following formula I
wherein R
1
is
X is selected from one or more of the group consisting of hydrogen, alkyl (C
1
-C
8
), branched alkyl (C
3
-C
8
), halo, perfluoro(lower alkyl), hydroxy, lower alkoxy, di(lower alkyl) amino, lower alkoxycarbonyl and lower alkylthio; there may be up to six independent substituents on the phenyl ring; X is preferably selected from any of lower alkoxy, hydrogen, halogen and lower alkyl;
R is selected from any of hydrogen, lower alkyl (C
1
-C
6
), aralkyl (C
6
-C
10
), substituted aralkyl (C
6
-C
10
) (where the phenyl substituents are alkyl (C
1
-C
8
), branched alkyl (C
3
-C
8
), halo, perfluoro(lower alkyl), hydroxy, lower alkoxy, di(lower alkyl) amino, lower alkoxycarbonyl or lower alkylthio), phenyl, substituted phenyl (where the substituents are alkyl (C
1
-C
8
), branched alkyl (C
3
-C
8
), halo, perfluoro(lower alkyl), hydroxy, lower alkoxy, di(lower alkyl) amino, lower alkoxycarbonyl or lower alkylthio),
(CH
2
)
n
OR
4
where
n=1-4,
R
4
is hydrogen, alkyl (C
1
-C
12
), cycloalkyl (C
3
-C
10
), alkoxy (C
1
-C
8
), phenyl and substituted phenyl, (where the substituents are alkyl (C
1
-C
8
), branched alkyl (C
3
-C
8
), halo, perfluoro(lower alkyl), hydroxy, lower alkoxy, di(lower alkyl) amino, mono(lower alkyl)amino, lower alkoxycarbonyl or lower alkylthio, (CH
2
)
n
NR
2
R
3
, where
n=1-4,
R
2
and R
3
together or independently are hydrogen, alkyl (C
1
-C
12
), perfluoro(lower alkyl), cycloalkyl (C
3
-C
10
), alkoxy (C
1
-C
8
), phenyl and substituted phenyl, where the substituents are alkyl (C
1
-C
8
), branched alkyl (C
3
-C
8
), halo, perfluoro(lower alkyl), hydroxy, lower alkoxy, di(lower alkyl) amino, mono(lower alkyl)amino, lower alkoxycarbonyl and lower alkylthio);
Ar is selected from any of phenyl and substituted phenyl, (where the phenyl substituents are alkyl (C
1
-C
8
), branched alkyl (C
3
-C
8
), halo, perfluoro(lower alkyl), hydroxy, lower alkoxy, di(lower alkyl) amino, mono(lower alkyl)amino, lower alkoxycarbonyl and lower alkylthio); a heterocycle where the heterocycle is selected from any of pyridine, thiazole, thiophene, furan, indole, pyridazine, pyrimidine, indoline, imidazole, triazine, pyrazine, isoxazole, thiadiazole, triazole and; a substituted heterocycle where the substituents are selected from one or more of halo, perfluoro(lower alkyl), nitro, lower alkylthio, lower alkoxy, lower alkyl, di(lower alkyl) amino, carboxy, lower alkoxycarbonyl,.
As used herein, unless otherwise noted, alkyl and alkoxy whether used alone or as part of a substituent group include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl, neopentyl, hexyl, 1-methylpentyl, and 3-methylpentyl. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. Halo includes chloro, bromo, fluoro and iodo. Unless otherwise noted, “lower” when used with alkyl and alkoxy means a carbon chain composition of 1-8 carbon atoms. Of course, if the alkyl or alkoxy substituent is branched there must be at least 3 carbons. The term “aralkyl” means a radical containing a lower alkyl group substituted with an aryl radical; the term “aryl” indicates aromatic hydrocarbon groups such as phenyl or napthyl. With reference to substituents, the term independently means that when more than one of such substituents is possible, such substituents may be the same or different from each other.
The definition of formula I as shown in the specification and as used in the claims includes possible isomers, such as tautotmers and rotomers. Also included in the invention are the pharmaceutically acceptable salts, solvates and hydrates thereof.
Examples of particularly preferred compounds of formula I include:
3-oxo-1,2,3,5-tetrahydronaphtho[2′,3′:4,5]imidazo[1,2-a]pyridine-4-carboxylic acid (2-fluorophenyl)amide (Va, Ar=2-FPh)
3-oxo-1,2,3,5-tetrahydronaphtho[2′,3′:4,5]imidazo[1,2-a]pyridine-4-carboxylic acid (2,6-difluorophenyl)amide (Vb, Ar=2,6-diFPh)
5-ethyl-3-oxo-1,2,3,5-tetrahydronaphtho[2′,3′:4,5]imidazo[1,2-a]pyridine-4-carboxylic acid (2-fluorophenyl)amide (VIa, Ar=2-FPh, R=Et)
5-(2-methoxyethyl)-3-oxo-1,2,3,5-tetrahydrona

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