Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-16
2004-11-02
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S456000, C514S430000, C549S023000, C549S362000, C549S396000, C549S406000, C549S407000
Reexamination Certificate
active
06812225
ABSTRACT:
FIELD OF THE INVENTION
Background of the Invention
Serotonin (5-HT) has been implicated in many psychiatric disorders including but not limited to depression, generalized anxiety, eating disorders, dementia, panic disorder, and sleep disorders. Furthermore serotonin has been implicated in gastrointestinal disorders, cardiovascular regulation, motor disorders, endocrine disorders, vasospasm and sexual dysfunction. Serotonin receptors have been subdivided into at least 14 subtypes, see Barnes and Sharp, Neuropharmacology, 1999, 38, 1083-1152, incorporated herein by reference. These various subtypes are responsible for serotonin's action in many pathophysicogical conditions. The 5-HT
1
family of receptors has high affinity for serotonin and consists of five related receptors. This family includes the 5-HT
1B
and 5-HT
1D
receptor subtypes. Compounds that interact with the 5-HT
1
family are known to have therapeutic potential in the above mentioned disorders and diseases. In particular, compounds that are 5HT
1B
and 5HT
1D
antagonist have been known to be antidepressant and anxiolytic agents. Compounds that are 5HT
1B
and 5HT
1D
agonists have been used in the treatment of migraine.
SUMMARY OF THE INVENTION
Provided herein is a compound having the formula (I):
wherein
R
1
is, at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, thiomethoxy, —NHA, —NA
2
, —NHC(═O)A, aminocarbonyl, —C(═O)NHA, —C(═O)NA
2
, halogen, hydroxy, —OA, cyano or aryl;
A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl;
R
2
is represented by (i), (ii), (iii), or (iv) below:
R
3
is independently at each position represented by —H, optionally substituted C
1-6
alkyl, optionally substituted C
2-6
alkenyl, optionally substituted C
2-6
alkynyl, optionally substituted C
3-6
cycloalkyl or AOH;
n is 2, 3 or 4;
P is a heterocyclic ring;
R
4
is —H or optionally substituted C
1-4
alkyl;
R
5
is —H, ═O, —OR
4
, —NR
4
2
═NR
4
, —SR
4
or ═S;
R
6
is —H or methyl;
X is O, N, NH or S;
Y is —C(═O)NH—, —C(═O)NA—, —C(═O)N(A)—, —NHC(═O)—, —C(═S)NH—, —CH
2
NH—, —C(═O)CH
2
—, —CH
2
C(═O)—, —C(═O)-piperazine-, —NAC(═O)—, —C(═S)N(A)—, CH
2
NA, NACH
2
or a 5-membered heterocyclic;
R
7
is a monocyclic or bicyclic aromatic ring or a heterocycle optionally substituted by one or more substituents selected from R
8
-R
9
and R
10
; wherein R
7
is connected to Y either by a single bond as tether, or by a ring fusion comprising a bond and two ring atoms shared by both rings;
R
8
is —CH
2
—, —C(═O)—, —SO
2
—, —SO
2
NH—, —C(═O)NH—, —O—, —S—, —S(═O)— a single bond as tether from R
7
to R
9
, or a five-membered heterocyclic connected to R
7
by either a single bond or by a ring fusion comprising a bond and two ring atoms shared by both rings, R
9
is optionally substituted heterocycle, optionally substituted aryl, optionally substituted piperazinyl-R11, optionally substituted morpholinyl-R11 or optionally substituted, C(═O)A;
R
10
is optionally substituted alkyl, optionally substituted cycloalkyl, hydroxy, aryl, cyano, halogen, —C(═O)NH
2
, methylthio, —NHA, —NA
2
, —NHC(═O)A, —C(═O)NHA, —C(═O)NA
2
, or —OA;
R
11
is —H, alkyl, AOH, —SO
2
A, —SO
2
NH
2
, —SO
2
NHA, —SO
2
NA
2
, —SO
2
NHAR
9
, —C(═O)R
9
, -alkylR
9
, C(═O)A, C(═O)NH
2
, C(═O)NHA, C(═O)NA
2
or C(═O)OA; or a pharmaceutically acceptable salt of said compound.
{overscore (------)} represents a bond which may be either a single bond or a double bond, with the proviso that multiple double bonds are separated from one another by at least one single bond.
In another aspect of the invention, R
5
and X are both O and thus provides a compound represented by the formula (II):
wherein
R
1
is, at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, thiomethoxy, —NHA, —NA
2
, —NHC(═O)A, aminocarbonyl, —C(═O)NHA, —C(═O)NA
2
, halogen, hydroxy, —OA, cyano or aryl;
A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl;
R
2
is represented by (i), (ii), (iii), or (iv) below:
R
3
is independently at each position represented by —H optionally substituted C
1-6
alkyl, optionally substituted C
2-6
alkenyl, optionally substituted C
2-6
alkynyl, optionally substituted C
3-6
cycloalkyl or AOH;
n is 2, 3 or 4;
P is a heterocyclic ring;
R
6
is —H or methyl;
Y is —C(═O)NH—, —C(═O)NA—, —C(═O)N(A)—, —NHC(═O)—, —C(═S)NH—, —CH
2
NH—, —C(═O)—, —C(═O)CH
2
—, —CH
2
C(═O)—, —C(═O)-piperazine-, —[NAC(═O)—, —C(═S)N(A)—, —CH
2
NA—, —NACH
2
— or a 5-membered heterocyclic.
R
7
is a monocyclic or bicyclic aromatic ring or a heterocycle optionally substituted by one or more substituents selected from R
8
-R
9
and R
10
; wherein R
7
is connected to Y either by a single bond or by a ring fusion;
R
8
is —CH
2
—, —C(═O)—, —SO
2
—, —SO
2
NH—, —C(═O)NH—, —O—, —S—, —S(═O)—, a single bond as tether from R
7
to R
9
, a five membered heterocyclic connected to R
7
by either a single bond or by a ring fusion;
R
9
is optionally substituted heterocycle, optionally substituted aryl, optionally substituted piperazinyl-R11, optionally substituted morpholinyl-R11 or optionally substituted thiomorpholinyl or —C(═O)A;
R
10
is optionally substituted alkyl, optionally substituted cycloalkyl, hydroxy, aryl, cyano, halogen, —C(═O)NH
2
—, methylthio, —NHA, —NA
2
, —NHC(═O)A, —C(═O)NHA, —C(═O)NA
2
or OA;
R
11
is —H, alkyl, —AOH, —SO
2
A, —SO
2
NH
2
, —SO
2
NHA, —SO
2
NA
2
, —SO
2
NHAR
9
, —C(═O)R
9
, -alkylR
9
, C(═O)A, C(═O)NH
2
, C(═O)NHA, C(═O)NA
2
or —C(═O)OA; or a pharmaceutically acceptable salt of said compound.
In another aspect of the invention, R
5
is H and X is O and thus is provided a compound represented by the formula (III):
wherein
R
1
is, at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, thiomethoxy, —NHA, —NA
2
, —NHC(═O)A, aminocarbonyl, —C(═O)NHA, —C(═O)NA
2
, halogen, hydroxy, —OA, cyano or aryl;
A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl;
R
2
is represented by (i), (ii), (iii), or (iv) below:
R
3
is —H ,optionally substituted C
1-6
alkyl, optionally substituted C
2-6
alkenyl, optionally substituted C
2-6
alkynyl, optionally substituted C
3-6
cycloalkyl or AOH;
n is 2, 3 or 4;
P is a heterocyclic ring;
R
6
is —H or methyl;
Y is —C(═O)NH—, —C(═O)NA—, —C(═O)N(A)—, —NHC(═O), —C(═S)NH—, —CH
2
NH—, —C(═O)—, —C(═O)CH
2
—, —CH
2
C(═O)—, —C(═O)-piperazine-, —NAC(═O)—, —C(═S)N(A)—, CH
2
NA, NACH
2
or a 5-membered heterocyclic.
R
7
is a monocyclic or bicyclic aromatic ring or a heterocycle optionally substituted by one or more substituents selected from R
8
-R
9
and R
10
; wherein R
7
is connected to Y either by a single bond or by a ring fusion;
R
8
is —CH
2
—, —C(═O)—, —SO
2
—, —SO
2
NH—, —C(═O)NH—, —O—, —S—, —S(═O)—, a single bond as tether from R
7
to R
9
, 5-membered heterocycle connected to R
7
by either a single bond or by a ring fusion;
R
9
is optionally substituted heterocycle, optionally substituted aryl, optionally substituted piperazinyl-R11, optionally substituted morpholinyl-R11 or optionally substituted or C(═O)A;
R
10
is optionally substituted alkyl, optionally substituted cycloalkyl, hydroxy, aryl, cyano, halogen, —C(═O)NH
2
—, methylthio, —NHA, —NA
2
, —NHC(═O)A, C(═O)NHA, C(═O)NA
2
or OA;
R
11
is —H, alkyl, AOH, —SO
2
A, —SO
2
NH
2
, —SO
2
NHA, —SO
2
NA
2
, —SO
2
NHAR
9
, —C(═O)R
9
, -alky
Chapdelaine Marc
Davenport Timothy
Haeberlein Markus
Horchler Carey
McCauley John P.
AstraZeneca AB
Gilbert George A.
Patel Sudhaker B.
Raymond Richard L.
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