Fused isoquinolines as dopamine receptor ligands

Details Fused isoquinolines as dopamine receptor ligands Fused isoquinolines as dopamine receptor ligands

1999-08-13

2001-02-27

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S284000

Reexamination Certificate

active

06194423

ABSTRACT:

FIELD OF THE INVENTION
This invention is directed to novel ligands for dopamine receptors. More particularly, the present invention is directed to optionally substituted tetrahydro-1H-naph[1,2,3-de]isoquinoline compounds and their use in pharmaceutical for mulations for treatment of dopamine-related dysfunction of the central and peripheral nervous system.
BACKGROUND AND SUMMARY OF THE INVENTION
Dopamine, a neurotransmitter in the central nervous system, has been implicated in numerous neurological disorders. For example it has been hypothesized that excess stimulation of dopamine receptor subtypes may be linked to schizophrenia. Additionally, it is generally recognized that either excessive or insufficient functional dopaminergic activity in the central and/or peripheral nervous system may cause hypertension, narcolepsy, and other behavioral, neurological, physiological, and movement disorders including Parkinson's disease, a chronic, progressive disease characterized by an inability to control the voluntary motor system.
Dopamine receptors have traditionally been classified into one of two families (D
1
and D
2
) based on pharmacological and functional evidence. D
1
receptors preferentially recognize the phenyltetrahydrobenzazepines and lead to stimulation of the enzyme adenylate cyclase, whereas D
2
receptors recognize the butyrophenones and benzamides and are coupled negatively (or not at all) to adenylate cyclase. It is now known that several subtypes of dopamine receptors exist and at least five genes code for subtypes of dopamine receptors: D
1
, D
2
, D
3
, D
4
and D
5
. The traditional classification, however, remains useful, with the D
1
-like class comprising the D
1
(D
1A
) and the D
5
(D
1B
) receptors, whereas the D
2
-like class consists of the D
2
, D
3
and D
4
receptors.
Central nervous system drugs exhibiting affinity for the dopamine receptors are generally classified not only by their receptor selectivity, but further by their agonist (receptor stimulating) or antagonist (receptor blocking) activity. While the physiological activities associated with the interaction of dopamine with the various receptor subtypes are not fully understood, it is known that ligands exhibiting selectivity for a particular receptor subtype will produce more or less predicable neuropharmaceutical results. The availability of selective dopamine receptor antagonist and agonist compounds will enable the design of experiments to enhance understanding of the manifold functional roles of D
1
receptors and lead to new treatments for various central and peripheral nervous system disorders.
Initially, studies of dopamine receptors were focused on the D
2
family, however the critical role of the dopamine D
1
receptor in nervous system function has recently become apparent. Early work on selective D
1
receptor ligands primarily focused on molecules from a single chemical class, the phenyltetrahydrobenzazepines, such as the antagonist SCH23390 (1):
Several of the phenyltetrahydrobenzazepines were found to be D
1
receptor agonists; however, the agonists derived from this class [including for example SKF38393 (+)-2] generally lacked full intrinsic efficacy. Even SKF 82958, purported to be a full agonist, recently has been shown not to have full intrinsic efficacy in preparations with decreased receptor reserve. The differentiation between agonists of full and partial efficacy is important to the medical research community due to the difference in the effect these compounds have on complex central nervous system mediated events. For example, dihydrexidine and the full agonist, A-77636, have exceptional anti-parkinsonian effects in the MPTP-treated monkey model, whereas partial agonists are without significant activity. More recent data suggest that full and partial agonists also differ in their effects on other complex neural functions.
Accordingly, researchers have directed their efforts to design ligands that are full agonists, having full intrinsic efficacy. One such compound is dihydrexidine (3), a hexahydrobenzo[a]phenanthridine of the formula:
The structure of dihydrexidine (3) is unique from other D
1
agonists because the accessory ring system is tethered, making the molecule relatively rigid. Molecular modeling studies of dihydrexidine (3) have shown that the compound as a limited number of low energy conformations, in all of which the aromatic rings are held in a relatively coplanar arrangement. The recent elucidation of the configuration of the active enantiomer of dihydrexidine (3) was consistent with predictions from this model.
Unlike other high affinity, high intrinsic activity D
1
agonists like 3-substituted aminomethylisochromans, dihydrexidine (3) provided a semi-rigid template for developing a dopamine ligand model. The essential features of this model include the presence of a transoid &bgr;-phenyldopamine moiety, an eguatorially oriented electron lone pair on the basic nitrogen atom, and near coplanarity of the pendant phenyl ring with the catechol ring. The dihydrexidine-based model has a transoid &bgr;-phenyldopamine moiety, whereas the dopaminergic phenyltetrahydrobenzazepines have a cisoid &bgr;-phenyldopamine conformation. The dihydrexidine-based model has served as the basis for the design of additional D
1
receptor agonists. The design and synthesis of D
1
receptor agonists having high intrinsic activity is important to the medical research community due to the potential use of full agonists to treat complex central nervous system mediated events and also conditions in which peripheral dopamine receptors are involved. For example, the compositions of the present invention have potential use as agents for lowering blood pressure.
One embodiment of the present invention is a novel class of dopamine receptor agonists of the general formula:
and pharmaceutically acceptable salts thereof, and pharmaceutical formulations of such compounds. The present compounds are useful for treating patients having a dopamine-related dysfunction of the central nervous system, and also conditions in which peripheral dopamine receptors are involved, as evidenced by an apparent neurological, psychological, physiological, or behavioral disorder.


REFERENCES:
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patent: 5420134 (1995-05-01), Nichols et al.
patent: 5959110 (1999-09-01), Nichols et al.
patent: WO 92/04356 (1992-03-01), None
Sami, et al., “Amino-substituted 2-[2′-(dimethylamino)ethyl]-1,2-dihydro-3H-debenz[de,h] isoquinoline-1,3-diones. Synthesis, Antitumor Activity, and Quantitative Structure-Activity Relationship,” Mar. 17, 1995,J. Med. Chem.,vol. 38, No. 6, pp. 983-993.
Brewster, et al., “trans-10,11-Dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine: A Highly Potent Selective Dopamine D1Full Agonist,” 1990,J. Med. Chem., vol. 33, No. 6, pp. 1756-1764.
Riggs, et al., “Specific Dopamine D-1 and DA1Properties of 4-(Mono- and -dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline and Its Tetrahydrothieno[2,3-c ]pyridine Analogues,” 1987,J. Med. Chem., vol. 30, No. 8, pp. 1454-1458.
Sami, et al., “2-substituted 1,2-dihydro-3H-dibenz [de,h] isoquinoline-1,3-diones. A New Class of Antitumor Agent.” Mar. 19, 1993,J. Med. Chem., vol. 36, No. 6, pp. 765-770.
Sami, et al., “6- and 7-Substituted 2-[2′-(Dimethylamino)ethyl]-1,2-dihydro-3H-dibenz [de,h] isoquinoline-1,3-diones: Synthesis, Nucleophilic Displacements, Antitumor Activity, and Quantitative Structure-Activity Relationships.” Apr. 12, 1996,J. Med. Chem., vol. 39, No. 8, pp. 1609-1618.
Ghosh et al, J. Med. Chem., vol. 39 pp. 549-555 (1996).
Nichols et al “Development of Potentially Selective Dopamine Agonists”, Experimental Methods p. 29. (Jun. 1990) NIH Grant paper.

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