Diazabicyclooctane derivatives and therapeutic uses thereof

Details Diazabicyclooctane derivatives and therapeutic uses thereof Diazabicyclooctane derivatives and therapeutic uses thereof

2001-08-01

2003-03-11

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S253040, C540S582000, C540S583000, C540S584000, C544S362000

Reexamination Certificate

active

06531468

ABSTRACT:

The present invention is directed to diazabicyclooctane derivatives and pharmaceutically acceptable salts thereof, to pharmaceutical compositions thereof, and to the use thereof to block selectively serotonin reuptake in the central nervous system of a mammal. The present invention is also directed to the use of the diazabicyclooctane derivatives of the invention in a method for the treatment of various diseases, disorders and conditions of the central nervous system. Further, the present invention is directed to processes for the preparation of diazabicyclooctane derivatives and intermediates useful therein.
Serotonin (5-hydroxytryptamine, “5-HT”) is a monoamine neurotransmitter active in the central nervous systems of mammals, including humans. The cell bodies of serotoninergic cells are located in the brain stem, and the axons project therefrom into a variety of other areas, e.g., the amygdala, hippocampus, hypothalamus, nucleus accumbens and the striatum. Serotonin-producing cells store the neurotransmitter in intracellular vesicles, where it is either converted with monoamine oxidase (“MAO” EC 1.4.3.4) into 5-hydroxyindoleacetic acid (“5-HIAA”) or released into synapses. In the synapses, serotonin is either resorbed into the presynaptic neurons and stored within intracellular vesicles of the presynaptic neurons or remains available for interaction with serotonin receptors, e.g., the 5-HT
2A
receptor, in post-synaptic membranes.
Altered functioning of this serotonin-based neurotransmission system has been implicated (see, e.g.,
Lancet,
2: 717-719 (1989)) in a variety of central nervous system related disorders, both psychiatric and non-psychiatric. These disorders include, without limitation, schizophrenia, psychosis, depression, aggression, sleep disorders, anxiety disorders, migraines, compulsive disorders, bipolar disorders, vision disorders, emesis, feeding disorders, learning disorders, sexual behavior disorders, phobias and substance abuse disorders. Compounds that either block serotonin reuptake into presynaptic neurons or that antagonize its interaction with post-synaptic membrane receptors have a wide variety of potential applications in the treatment of mammals, including humans, afflicted with central nervous system related disorders. Such compounds act to restore some semblance of normal neurotransmitter functioning. Moreover, compounds which accomplish these objectives selectively can be used with a lower risk of attendant and unwanted side effects, e.g., sexual dysfunction, etc.
French Patent Application No. 2,531,709 A1 relates to pyrimidinyl diazabicyclo[3.2.1]octane derivatives with anxiolytic, hypnotic and sedative activity and discusses the synthesis of benzyl, phenyl and tolyl derivatives of diazabicyclo[3.2.1]octane. Occelli et al.,
Farmaco Ed. Sci,
32(4), pp. 237-47 (1977) discusses the anti-Parkinson activity of 3,8-diazabicyclo[3.2.1]octanes. Fontanella et al.,
Farmaco Ed. Sci,
27(1), pp. 68-78 (1972) has noted the pharmacological activity of 3,8-diazabicyclo[3.2.1]octane-2,4-diones. Ghelardini et al. have discussed the antiamnesic activity of a diazabicyclo[3.2.1]octane nicotinic agonist, DBO-83, in mice in
Drug Dev. Res.,
45(2), pp. 45-51 (1998).
WO 99/11647 discusses the preparation of fused thiophene compounds as anti-psychotics. WO 96/13503 relates to certain tricyclic substituted diazabicyclo[3.2.1]octane derivatives useful as dopamine receptor ligands, and particularly as atypical anti-psychotics. U.S. Pat. No. 3,905,979 relates to a variety of diazabicyclooctane based diethylcarbamazine derivatives useful as bronchodilators and antifilarial agents and their synthetic preparation from diethyl meso-&agr;,&agr;′-dibromoadipate. German Patent No. 63-1595893 shows a series of 3,8-diazabicyclo[3.2.1]octane derivatives useful as analgesics. Czech patent application No. CS 70-5352 relates to the neuroleptic activity of 3,8-diazabicyclo[3.2.1]octane enamine derivatives of the dibenzo[b,f]thiepin series. Czech patent application No. 70-5354 relates to neuroleptic piperazine enamines derived from tricyclic skeletons. Jilek et al.,
Czech. Chem. Commun.,
36(12), 4074 (1971) discussed the neurotropic and psychotropic activity of 3,8-diazabicyclo[3.2.1]octyl derivatives of dibenzo[b,f]thiepin. The synthesis and pharmacological properties of phenothiazine and 10,11-dihydrodibenzocycloheptene derivatives of 3,8-diazabicyclo[3.2.1]octanes are discussed in Cignarella et al.,
J. Med. Chem.,
12(5), 836-9 (1969). The synthesis of disubstituted 3,8-diazabicyclo[3.2.1]octane derivatives and the use of these compounds as local anesthetics and spasmolytics are discussed in U.S. Pat. No. 3,328,396. WO 93/25527 relates to piperidine, tetrahydropyridine and piperazine derivatives as nervous system agents.
Japanese Kokai No. 63-098662 relates to the use of substituted 3,8-diazabicyclo[3:2:1]octane derivatives as photographic photosensitive materials. U.S. Pat. Nos. 4,018,895, 4,194,009, 4,314,081 and 5,026,707 discuss potent inhibitors of the uptake of various physiologically active monoamines, including serotonin, norepinephrine and dopamine. Certain 8-methyl-3-aryl-8-azabicyclo[3.2.1]-2-enes have been reported to possess useful monoamine neurotransmitter reuptake inhibition activity in International Patent publication No. WO 97/13770. The monoamine uptake inhibition activity of tropane derivatives: 8-azabicyclo[3.2.1]-2-enes and 8-azabicyclo[3.2.1]-2-anes has been discussed in European Application Nos. EP 0 969 005, EP 0 859 777, EP 0 944 626, EP 0 929 319, and EP 0 604354; U.S. Pat. Nos. 5,922,732 and 5,980,860; and International Patent publication Nos. WO 92/22554, WO 94/04146.
European Application No. 0 952 154 discusses diazabicyclo[2.2.1]heptane derivatives as 5HT1 agonists or antagonist. International Patent publication No. WO 98/50030 discusses diazabicyclo[2.2.1]heptane derivatives as inhibitors of protein isoprenyl transferases. International Patent publication No. WO 97/40049 discusses diazabicyclo[2.2.1]heptane derivatives as inhibitors of acetylcholinesterases useful for treatment of dementia and Alzheimer's disease. U.S. Pat. No. 5,478,939 discusses (R,R)- and (S,S)-2,5-diazabicyclo[2.2.1]heptane derivatives as muscarinic agonists. European Patent Application No. 0 324 543 discusses bridged diazabicyclo[2.2.1]heptane derivatives as antiarrhythmic agents. International Patent publication No. WO 97/26258 discusses angiogenesis inhibiting pyridazinamines containing bridged diazabicyclo[2.2.2]octane derivatives. Japanese Kokai No. 09-020758 discusses piperazinylbutyronitrile derivatives containing a bridged diazabicyclo[2.2.2]octane structure element as muscarinic antagonists.
U.S. Pat. No. 5,382,584 and European Patent Application No. 0 582 164 discuss adenosine re-uptake inhibiting diphenyl oxazoles, thiazoles and imidazoles derivatives containing a bridged diazabicyclo[2.2.2]octane structure element. U.S. Pat. Nos. 3,951,980 and 3,947,445; and
J. Med. Chem.,
17(5), pp. 481-7 (1974) discuss carbamazine derivatives useful as bronchodilators and antifilarial agents containing diazabicyclooctane and diazabicycloheptane substructures.
J. Org. Chem.,
36(22), pp. 3361-5 (1971) reports on the synthesis of 2,5-diphenyl-2,5-diazabicyclo[2.2.2]-octane.
However, none of these documents teach or suggest either the serotonin, dopamine and norepinephrine reuptake inhibitory activity of diazabicyclo[3.2.1], and diazabicyclo[2.2.2} compounds of the present invention or the therapeutic uses of the present invention.
SUMMARY OF THE INVENTION
The present invention provides compounds of formula (I):
and pharmaceutically acceptable salts thereof, wherein the group
R
1
and R
2
are selected independently from H, (C
1
-C
6
)alkyl, (C
1
-C
6
)fluoroalkyl, halogen (e.g., F, Cl

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