Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-02
2002-03-12
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S426000, C549S491000, C549S346000, C514S459000, C514S471000, C514S675000
Reexamination Certificate
active
06355674
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to novel substituted aminotetralins useful as 5-HT
1D
agonists.
Over the last several years it has become apparent that serotonin (5-hydroxytryptamine; 5-HT) is associated directly or indirectly with a number of physiological phenomena, including appetite, memory, thermo-regulation, sleep, sexual behavior, anxiety, depression, and hallucinogenic behavior [Glennon, R. A.,
J. Med. Chem.
30, 1 (1987)].
5-HT receptors have been identified in the central nervous system (CNS; brain and spinal cord) and in peripheral tissues including the gastrointestinal tract, lung, heart, blood vessels, and various other smooth muscle tissues.
It has been recognized that there are multiples types of 5-HT receptors. These receptors have been classificed as 5-HT
1
, 5-HT
2
and 5-HT
3
receptors, with the former being further divided into the sub-classes 5-HT
1A
, 5-HT
1B
, 5-HT
1C
, 5-HT
1D
, 5-HT
1E
, and 5-HT
1F
.
Within the 5-HT
1
receptor class, several subtypes have been distinguished on the basis of their pharmacological binding profiles, second messenger coupling and physiological roles. One such subtype, the 5-HT
1D
receptor, was originally defined as a particular type of [
3
H]5-HT binding site in the bovine caudate (Heuring and Peroutka,
J. Neurosci.,
7:894 (1987)).
Few ligands have selectivity for 5-HT
1D
receptors. Sumatriptan possesses limited 5-HT
1D
selectivity. GR 127935 has also been identified as a patent and selective 5-HT
1D
receptor antagonist. Hayer, et al.,
Pharmacological Reviews,
Vol. 46, No. 2, pp. 157-203 (1994).
Molecular cloning has demonstrated that pharmacologically defined
5
-HT
1D
receptors are encloded by two separate but closely related genes, designated 5-HT
1D&agr;
and 5-HT
1D&bgr;
, which are members of the GPRC superfamily. These receptors display highly conserved transmembrane homology (75%) and similar binding properties and second messenger coupling (inhibition of adenylate cyclase). Leonhardt, S., et al.,
J. Neurochem,
53:465-471 (1989).
The 5-HT
1D&agr;
receptor is a species homolog of the 5-HT
1D
receptor of bovine calif caudate and guinea-pig brain. Hartig, et al., supra.
The 5-HT
1B
and 5-HT
1D&bgr;
receptors have recently been shown to be species homologues of the same receptor subtype. They display similarities in their pharmacology, second messenger coupling, and anatomical distribution. The 5-HT
1B
subtype appears to be confined to rat, mouse, and opossum whereas 5-HT
1D&bgr;
sites have been demonstrated in human, pig, guinea pig and calf. Adham, N., et al.,
Mol. Pharmacol.,
41:1-7 (1992).
The rat 5-HT
1B
receptor differs from its human counterpart at only 4% of its transmembrane amino acids, but its pharmacological binding properties are dramatically different from those of the human
5
-HT
1DB
receptor. Hartig, et al.,
Trends Pharmacol. Sci.,
13:152-159 (1992).
We have now discovered a further class of compounds which have selective 5-HT
1D&agr;
agonist activity useful in treatment of dementia, Parkinson's Disease, appetite modulation, anxiety, migraine, sexual dysfunction, irritative bladder symptoms of benign prostatic hyperplasia, urge incontinence and excessive bladder activity caused by bacterial cystitis, interstitial cystitis, radiation/chemotherapy-induced cystitis, outlet obstruction, neurogenic bladder, spinal cord injury, stroke, and nocturnal enurisis.
It is desirable to develop new compounds and treatments for these 5-HT
1D&agr;
mediated diseases.
This invention provides a compound of formula I
wherein:
R
1
and R
2
are each individually hydrogen or —(C
1
-C
6
)alkyl;
R
3
is —(C
2
-C
8
)alkenyl, —(CH
2
)
q
(C
3
-C
8
)cycloalkyl —(CH
2
)
n
O(CH
2
)
p
R
5
,
or
substituted with one substituent selected from the group consisting of —(C
1
-C
6
)alkyl and —(C
3
-C
8
)cycloalkyl;
where
A—B is >C═CH— or >CR
4
CH
2
—;
D is —CH
2
— or oxygen;
R
4
is hydrogen or —OH;
R
5′
is —(C
3
-C
8
)cycloalkyl, or phenyl substituted with one substituent selected from the group consisting of halo, —(C
1
-C
6
)alkyl and (C
1
-C
6
)alkoxy;
m is an integer from 1 to 5 both inclusive;
n is an integer from 0 to 4 both inclusive;
p is an integer from 1 to 7 both inclusive; and
q is an integer from 0 to 4 both inclusive;
or a pharmaceutically acceptable salt or optical isomer thereof;
provided that when D is oxygen, >A—B is not >C═CH—; and when R
4
is —OH, D is oxygen.
This invention also provides a pharmaceutical formulation comprising a compound of formula I in association with one or more pharmaceutically acceptable diluents, carriers and excipients.
This invention further provides a method of activating the 5-HT
1D&agr;
receptor comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula II
wherein:
R
1
and R
2
are each individually hydrogen or —(C
1
-C
6
)alkyl;
R
3′
is —(C
1
-C
8
)alkyl, —(CH
2
)
q
(C
3
-C
8
)cycloalkyl, —(C
2
-C
8
)alkenyl, —(C
1
-C
8
)alkan-1-ol-1-yl, —(CH
2
)
n
O(CH
2
)
p
R
5′
,
or
substituted with one substituent selected from the group consisting of —(C
1
-C
6
)alkyl and —(C
3
-C
8
)cycloalkyl;
where
A—B is >C═CH— or >CR
4
CH
2
—;
D is —CH
2
— or oxygen;
R
4
is hydrogen or —OH;
R
5′
is —(C
1
-C
6
)alkyl, —(C
3
-C
8
)cycloalkyl, —(C
1
-C
6
)alkoxy, phenyl or phenyl substituted with one substituent. selected from the group consisting of halo, —(C
1
-C
6
)alkyl and (C
1
-C
6
)alkoxy;
m is an integer from 1 to 5 both inclusive;
n is an integer from 0 to 4 both inclusive;
p is an integer from 1 to 7 both inclusive; and
q is an integer from 0 to 4 both inclusive;
or a pharmaceutically acceptable salt or optical isomer thereof;
provided that when D is oxygen, >A—B is not >C═CH—.
This invention also provides a method of alleviating the pathological effects of 5-HT
1D&agr;
receptor-activated diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula II.
A still further aspect of the invention is a method of treating a mammal suffering from or susceptible to any condition activated by the 5HT
1D&agr;
receptor of the type represented by dementia, Parkinson's disease, anxiety, migraine, appetite modulation, sexual dysfunction, irritative bladder symptoms of benign prostatic hyperplasia, urge incontinence and excessive bladder activity caused by bacterial cystitis, interstitial cystitis, radiation/chemotherapy-induced cystitis, outlet obstruction, neurogenic bladder, spinal cord injury, stroke and nocturnal enurisis which comprises administering to said mammal a therapeutically-effective amount of a compound of formula (II).
Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.
Definitions
As used herein, the term, “(C
1
-C
8
)alkyl” by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl and the like. The term “(C
1
-C
8
)alkyl” encompasses “(C
1
-C
6
)alkyl”.
The term “halo” means chloro, fluoro, bromo or iodo.
The term “(C
1
-C
6
)alkoxy” denotes a straight or branched alkyl chain having one to six carbon atoms attached to the remainder of the molecule by an oxygen atom. Typical (C
1
-C
6
) alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentoxy, isopentoxy, neopentoxy and the like.
The term “(C
3
-C
8
) cycloalkyl” referes to a hydrocarbon ring having the stated number of carbon atoms. Typical (C
3
-C
8
) cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
The term, “(C
2
-C
8
)alkenyl,” as used herein, means a straight chain or branched monovalent hydrocarbon group attached to the tet
Schaus John M
Walker Clint D
Xu Yao-Chang
Berch Mark L.
Eli Lilly and Company
Habte Kahsay
Joyner Charles T.
Lentz Nelson L.
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