Pyridine substituted isoquinoline derivatives

Details Pyridine substituted isoquinoline derivatives Pyridine substituted isoquinoline derivatives

2002-10-29

2004-12-14

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S144000

Reexamination Certificate

active

06831087

ABSTRACT:

BACKGROUND
The present invention relates to compounds of formula:
Compounds of the present invention are NMDA(N-methyl-D-aspartate)-receptor subtype selective blockers.
Under pathological conditions of acute and chronic forms of neurodegeneration overactivation of NMDA receptors is a key event for triggering neuronal cell death. NMDA receptors are composed of members from two subunit families, namely NR-1 (8 different splice variants) and NR-2 (A to D) originating from different genes. Members from the two subunit families show a distinct distribution in different brain areas. Heteromeric combinations of NR-1 members with different NR-2 subunits result in NMDA receptors displaying different pharmaceutical properties. Possible therapeutic indications for NMDA NR-2B receptor subtype specific blockers include acute forms of neurodegeneration caused, e.g., by stroke and brain trauma, and chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis), neurodegeneration associated with bacterial or viral infections, and, in addition, depression and chronic and acute pain.
SUMMARY
A compound of formulae:
wherein
R
1
and R
2
are independently selected from the group consisting of hydrogen, lower alkyl, —(CH
2
)
n
—OH, —(CH
2
)
n
—N(R
6
)
2
, —NR
6
C(O)C(O)O-lower alkyl, —NR
6
—(CH
2
)
n
—OH, —NR
6
C(O)-lower alkyl, —NH-benzyl and NR
6
C(O)—(CH
2
)
n
—OH;
R
6
is independently hydrogen or lower alkyl;
R′ is hydrogen or lower alkyl;
R
3
is hydrogen or amino;
R
4
is hydrogen or lower alkyl;
R
5
is hydrogen or halogen; or
R
1
and R′ together with the carbon atoms to which they are attached form the group —(CH
2
)
4
—; or
R
2
and R
3
together with the carbon atoms to which they are attached form the group —N(R
6
)—CH
2
—O—CH
2
—; and
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable acid addition salt thereof.
The compounds of formula IA and IB and their salts are distinguished by valuable therapeutic properties. Compounds of the present invention are NMDA(N-methyl-D-aspartate)-receptor subtype selective blockers, which have a key function in modulating neuronal activity and plasticity. Accordingly, compounds of the invention are useful in mediating processes underlying development of CNS as well as learning and memory formation.
The present invention relates to compounds of formula IA, IB, combinations thereof and pharmaceutically acceptable acid addition salts thereof, and the preparation of the compounds of formula IA, IB and salts thereof. The present invention also relates to pharmacuetical compositions containing a compound of formula IA, IB, combinations thereof or a pharmaceutically acceptable acid addition salt thereof and the preparation of such pharmaceutical compositions. The invention also relates to a method of treatment of diseases responsive to modulation of NMDA(N-methyl-D-aspartate)-receptors by subtype selective blockers, comprising administering a therapeutically effective amount of the compounds of formula IA, IB, combinations thereof or their pharmaceutically acceptable salts to a patient in need of such treatment.


REFERENCES:
patent: 1088818 (2001-04-01), None
patent: 1090917 (2001-04-01), None
patent: WO 97/23458 (1997-07-01), None
Chatani , Journal of the American Chemical Society, vol. 122, No. 51, pp. 12882-12883, 2000.*
E. Saxena et al.,Indian J. Chem, vol. 19 B, pp. 873-878(1980).
N. Chatani et al.,J. Am. Chem. Soc., vol. 123, pp. 10935-10941(2001).
Davies & Shipton,J. Chem. Soc. Perkins Trans. 1, pp. 501-507(1991).
S. Zimmerman et al.,J. Am. Chem. Soc., vol. 113, p. 183-196(1991).

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