Title: Pyridyl sulfone derivatives
Abstract: The invention provides compounds of the formula ##STR1##and methods of using those compounds for treating a disease or condition in a mammal wherein a 5-HT receptor, such as a 5-HT.sub.6 receptor, is implicated and modulation of a 5-HT function is desired, wherein A, G and W.sub.1 -W.sub.3 are defined as herein.
Patent Number: 6,855,709 Issued on 02/15/2005 to Tenbrink, et al.
| Inventors:
|
Tenbrink; Ruth E. (Kalamazoo, MI);
Kortum; Steven W. (Kalamazoo, MI)
|
| Assignee:
|
Pharmacia & Upjohn Company (Kalamazoo, MI)
|
| Appl. No.:
|
371391 |
| Filed:
|
February 20, 2003 |
| Current U.S. Class: |
514/218; 514/253.01; 540/575; 544/360 |
| Intern'l Class: |
C07D 243//08; C07D 401//00; A61K 031//55; A61K 031//49.5; A61P 025//22 |
| Field of Search: |
514/218,253.01
540/575
544/360
|
References Cited [Referenced By]
U.S. Patent Documents
| 5770613 | Jun., 1998 | Gaeta et al. | 514/332.
|
| Foreign Patent Documents |
| 0 156 433 | Oct., 1985 | EP.
| |
| 0 815 861 | Jan., 1998 | EP.
| |
| 61-280474 | Nov., 1986 | JP.
| |
| 11-72377 | Jul., 1989 | JP.
| |
| 10182636 | Jul., 1998 | JP | .
|
| 98-24782 | Aug., 1998 | WO.
| |
| WO 99 37623 | Jul., 1999 | WO.
| |
| WO 02/40456 | May., 2002 | WO.
| |
Other References
Gavezzoti (Acc. Chem. Res. 1994, 27, 309-314).
|
Primary Examiner: Kifle; Bruck
Attorney, Agent or Firm: Hosley; Mary J.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of U.S. provisional application Ser.
No. 60/359,174, filed Feb. 22, 2002, under 35 USC 119(e)(i), which is
incorporated herein by reference.
Claims
What is claimed is:
1. A compound of formula I:
##STR12##
wherein
W.sub.1 -W.sub.3 are --C(R) or N with the proviso that no more than one of
W.sub.1 -W.sub.3 are nitrogen, and further provided that when W.sub.2 is N
that W.sub.3 is not --C(CN);
A is a phenyl or naphthyl ring, a five or six-membered heteroaryl ring, a
eight to ten-membered fused heteroaryl ring, the five or six membered
monocyclic heteroaryl ring and the eight or ten membered fused heteroaryl
ring system each optionally containing up to three heteroatoms (O, N, S);
or a nine membered fused heteroaryl ring system containing one to three
heteroatoms (O, N, S); each of the five- or six-membered monocyclic
heteroaryl ring and the eight- to ten-membered ring systems being
optionally substituted with 1-4 of R;
Each R is independently selected from H, halo, alkyl, cycloalkyl,
substituted alkyl, --OH, alkoxy, substituted alkoxy, --SH, --S-alkyl,
--S-substituted alkyl, --CN, --NO.sub.2, --NR.sub.1 R.sub.2, --NR.sub.1
SO.sub.2 -alkyl, --NR.sub.1 SO.sub.2 -aryl, --COOR.sub.3, --CONR.sub.1
R.sub.2, --SO.sub.2 NR.sub.1 R.sub.2, --SO.sub.2 -alkyl, het, substituted
het, aryl and substituted aryl;
G is
##STR13##
Each R.sub.1 and R.sub.2 is independently H, alkyl, cycloalkyl, substituted
alkyl, aryl, het, substituted aryl, and substituted het, or R.sub.1 and
R.sub.2 when taken together form a five, six, or seven-membered ring which
optionally contains a heteroatom selected from N, O, or S;
Each R.sub.3 is independently H, alkyl, cycloalkyl, or substituted alkyl;
Each R.sub.7 is independently H or alkyl, or oxo provided that R.sub.8 is
absent when the oxo moiety is bound to the same carbon;
Each R.sub.8 is independently H or alkyl;
Each R.sub.9 and R.sub.10 is independently H, alkyl, or substituted alkyl;
wherein
cycloalkyl is a cyclic alkyl moiety have between 3 and 7 carbon atoms;
substituted alkyl is an alkyl moiety including 1-4 substituents selected
from halo, cycloalkyl, cycloalkenyl, heterocycloalkyl, het, aryl,
--OQ.sub.10, --SQ.sub.10, --S(O).sub.2 Q.sub.10, --S(O)Q.sub.10,
--OS(O).sub.2 Q.sub.10, --C(.dbd.NQ.sub.10)Q.sub.10, SC(O)Q.sub.10,
--NQ.sub.10 Q.sub.10, --C(O)Q.sub.10, --C(S)Q.sub.10, --C(O)OQ.sub.10,
--OC(O)Q.sub.10, --C(O)NQ.sub.10 Q.sub.10, --C(O)C(Q.sub.16).sub.2
OC(O)Q.sub.10, .dbd.CN, .dbd.O, .dbd.S, --NQ.sub.10 C(O)Q.sub.10,
NQ.sub.10 C(O)NQ.sub.10 Q.sub.10, --S(O).sub.2 NQ.sub.10 Q.sub.10,
--NQ.sub.10 S(O).sub.2 Q.sub.10, --NQ.sub.10 S(O)Q.sub.10, and --NO;
substituted alkoxy is an alkoxy moiety including 1-3 substituents
--OQ.sub.10, --SQ.sub.10, --S(O).sub.2 Q.sub.10, --S(O)Q.sub.10,
--OS(O).sub.2 Q.sub.10, --C(.dbd.NQ.sub.10)Q.sub.10, --SC(O)Q.sub.10,
--NQ.sub.10 Q.sub.10, --C(O)Q.sub.10, --C(S)Q.sub.10, --C(O)OQ.sub.10,
--OC(O)Q.sub.10, --C(O)NQ.sub.10 Q.sub.10, --C(O)C(Q.sub.16).sub.2
OC(O)Q.sub.10, --CN, .dbd.O, .dbd.S, --NQ.sub.10 C(O)Q.sub.10, --NQ.sub.10
C(O)NQ.sub.10 Q.sub.10, --S(O).sub.2 NQ.sub.10 Q.sub.10, --NQ.sub.10
S(O).sub.2 Q.sub.10, --NQ.sub.10 S(O)Q.sub.10, --NO.sub.2, alkyl,
substituted alkyl, halo, cycloalkyl, heterocycloalkyl, het, aryl, and
cycloalkenyl;
het is a C-linked five-(5) membered heteroaryl ring having 1-4 heteroatoms
selected from the group consisting of oxygen, sulfur, and nitrogen; a
C-linked six (6) membered heteroaryl ring having 1-3 nitrogen atoms; a
eight (8) membered bicyclic heteroaryl ring system having 1-3 heteroatoms
selected from the group consisting of oxygen, sulfur, and nitrogen; and a
ten (10) membered bicyclic heteroaryl ring system having 1-3 heteroatoms
selected from the group consisting of oxygen, sulfur, and nitrogen;
substituted het is a het moiety having 1-3 substituents selected from
--OQ.sub.10, --SQ.sub.10, --S(O).sub.2 Q.sub.10, --S(O)Q.sub.10,
--OS(O).sub.2 Q.sub.10, --C(.dbd.NQ.sub.10)Q.sub.10, --SC(O)Q.sub.10,
--NQ.sub.10 Q.sub.10, --C(O)Q.sub.10, --C(S)Q.sub.10, --C(O)OQ.sub.10,
--OC(O)Q.sub.10, --C(O)NQ.sub.10 Q.sub.10, --C(O)C(Q.sub.16).sub.2
OC(O)Q.sub.10, --CN, --NQ.sub.10 C(O)Q.sub.10, --NQ.sub.10 C(O)NQ.sub.10
Q.sub.10, --S(O).sub.2 NQ.sub.10 Q.sub.10, --NQ.sub.10 S(O).sub.2
Q.sub.10, NQ.sub.10 S(O)Q.sub.10, --NO.sub.2, alkyl, substituted alkyl,
halo, cycloalkyl, cycloalkenyl, heterocycloalkyl, het, and aryl;
wherein heterocycloalkyl is a cyclic alkyl moiety having between 5 and 7
ring atoms, including 1-4 heteroatoms in the ring selected from the group
consisting of oxygen, sulfur and nitrogen;
wherein Q.sub.10, Q.sub.11, Q.sub.14, Q.sub.15, and Q.sub.16 are as defined
in the specification;
n is 0-1; and
any racemic, optically active, tautomeric, stereoisomeric form, mixtures or
pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein
each R is independently selected from H, F, Cl, Br, I, C.sub.1 -C.sub.6
alkyl, C.sub.3 -C.sub.7 Cycloalkyl, C.sub.1 -C.sub.3 alkyl-C.sub.3
-C.sub.7 -cycloalkyl, CF.sub.3, OH, O--(C.sub.1 -C.sub.6 -alkyl),
O--C.sub.2 -C.sub.6 -alkyl-OH, O--C.sub.2 -C.sub.6 --NR.sub.1 R.sub.2,
OCF.sub.3, SH, S--(C.sub.1 -C.sub.6 -alkyl) CN, NO.sub.2, NR.sub.1
R.sub.2, NHSO.sub.2 --C.sub.1 -C.sub.4 -alkyl, COOR.sub.3, CONR.sub.1
R.sub.2, SO.sub.2 NR.sub.1 R.sub.2, SO.sub.2 --C.sub.1 -C.sub.4 -alkyl,
and aryl optionally substituted with 1 to 3 of H, F, Cl, Br, I, C.sub.1
-C.sub.6 -alkyl, C.sub.1 -C.sub.6 -cycloalkyl, OH, O--(C.sub.1 -C.sub.6
-alkyl), CN, NR.sub.4 R.sub.5, CONR.sub.4 R.sub.5, and SO.sub.2 NR.sub.4
R.sub.5 ;
each R.sub.1 and R.sub.2 is independently selected from H, C.sub.1 -C.sub.4
-alkyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.1 -C.sub.3 -alkyl-C.sub.3
-C.sub.7 -cycloalkyl, and (CH.sub.2).sub.0-4 -aryl, or R.sub.1 and R.sub.2
when taken together form a five, six, or seven-membered ring which
optionally contains a heteroatom selected from N, O, or S;
each R.sub.3 is independently selected from H, C.sub.1 -C.sub.4 -alkyl,
C.sub.3 -C.sub.7 -cycloalkyl, and C.sub.1 -C.sub.3 -alkyl-C.sub.3 -C.sub.7
-cycloalkyl;
each R.sub.4 and R.sub.5 is independently H, C.sub.1 -C.sub.4 -alkyl,
C.sub.3 -C.sub.7 -cycloalkyl, C.sub.1 -C.sub.3 -alkyl-C.sub.3 -C.sub.7
-cycloalkyl, or R.sub.4 and R.sub.5 when taken together form a five, six,
or seven-membered ring which optionally contains a heteroatom selected
from N, O, or S;
each R.sub.7 is H, C.sub.1 -C.sub.4 -alkyl, or oxo;
each R.sub.8 is H or C.sub.1 -C.sub.4 -alkyl; and
each R.sub.9 and R.sub.10 is independently selected from H, C.sub.1
-C.sub.6 -alkyl, and C.sub.2 -C.sub.4 -alkyl-OH.
3. A compound of claim 1, wherein A is phenyl.
4. A compound of claim 2, wherein A is phenyl.
5. A compound of claim 1, wherein G is
##STR14##
6. A compound of claim 2, wherein G is
##STR15##
7. A compound of claim 6, phenyl 5-(1-piperazinyl)-2-pyridinyl sulfone or a
pharmaceutically acceptable salt thereof.
8. A compound of claim 6, 5-(1,4-diazepan-1-yl)-2-pyridinyl phenyl sulfone
or 5-(1,4-diazepan-1-yl)-2-pyridinyl phenyl sulfone methane sulfonic acid
salt.
9. A compound of claim 1, wherein the compound includes an isotopic label.
10. A compound of claim 9, wherein the compound includes at least one atom
selected from Carbon-11, Nitrogen-13, Oxygen-15 and Fluorine-18.
11. A compound of Formula II, wherein the compound includes an isotopic
label.
12. A compound of claim 11, wherein the compound includes at least an atom
selected from Carbon-11, Nitrogen-13, Oxygen-15 and Fluorine-18.
13. A pharmaceutical composition comprising a therapeutically effective
amount of a compound of formula I:
##STR16##
wherein
W.sub.1 -W.sub.3 are --C(R) or N with the proviso that no more than one of
W.sub.1 -W.sub.3 are nitrogen, and further provided that when W.sub.2 is N
that W.sub.3 is not --C(CN);
A is a phenyl or naphthyl ring, a five or six-membered heteroaryl ring, a
eight to ten-membered fused heteroaryl ring, the five or six membered
monocyclic heteroaryl ring and the eight or ten membered fused heteroaryl
ring system each optionally containing up to three heteroatoms (O, N, S);
or a nine membered fused heteroaryl ring system containing one to three
heteroatoms (O, N, S); each of the five- or six-membered monocyclic
heteroaryl ring and the eight- to ten-membered ring systems being
optionally substituted with 1-4 of R;
Each R is independently selected from H, halo, alkyl, cycloalkyl,
substituted alkyl, --OH, alkoxy, substituted alkoxy, --SH, --S-alkyl,
--S-substituted alkyl, --CN, --NO.sub.2, --NR.sub.1 R.sub.2, --NR.sub.1
SO.sub.2 -alkyl, --NR.sub.1 SO.sub.2 -aryl, --COOR.sub.3, --CONR.sub.1
R.sub.2, --SO.sub.2 NR.sub.1 R.sub.2, --SO.sub.2 --alkyl, het, substituted
het, aryl and substituted aryl;
G is
##STR17##
Each R.sub.1 and R.sub.2 is independently H, alkyl, cycloalkyl, substituted
alkyl, aryl, het, substituted aryl, and substituted het, or R.sub.1 and
R.sub.2 when taken together form a five, six, or seven-membered ring which
optionally contains a heteroatom selected from N, O, or S;
Each R.sub.3 is independently H, alkyl, cycloalkyl, or substituted alkyl;
Each R.sub.7 is independently H or alkyl, or oxo provided that R.sub.8 is
absent when the oxo moiety is bound to the same carbon;
Each R.sub.8 is independently H or alkyl;
Each R.sub.9 and R.sub.10 is independently H, alkyl, or substituted alkyl;
wherein
cycloalkyl is a cyclic alkyl moiety have between 3 and 7 carbon atoms;
substituted alkyl is an alkyl moiety including 1-4 substituents selected
from halo, cycloalkyl, cycloalkenyl, heterocycloalkyl, het, aryl,
--OQ.sub.10, --SQ.sub.10, --S(O).sub.2 Q.sub.10, --S(O)Q.sub.10,
--OS(O).sub.2 Q.sub.10, --C(.dbd.NQ.sub.10)Q.sub.10, SC(O)Q.sub.10,
--NQ.sub.10 Q.sub.10, --C(O)Q.sub.10, --C(S)Q.sub.10, --C(O)OQ.sub.10,
--OC(O)Q.sub.10, --C(O)NQ.sub.10 Q.sub.10, --C(O)C(Q.sub.16).sub.2
OC(O)Q.sub.10, --CN, .dbd.O, .dbd.S, --NQ.sub.10 C(O)Q.sub.10, --NQ.sub.10
C(O)NQ.sub.10 Q.sub.10, --S(O).sub.2 NQ.sub.10 Q.sub.10, --NQ.sub.10
S(O).sub.2 Q.sub.10, --NQ.sub.10 S(O)Q.sub.10, and --NO;
substituted alkoxy is an alkoxy moiety including 1-3 substituents
--OQ.sub.10, --SQ.sub.10, --S(O).sub.2 Q.sub.10, --S(O) Q.sub.10,
--OS(O).sub.2 Q.sub.10, --C(.dbd.NQ.sub.10)Q.sub.10, --SC(O)Q.sub.10,
--NQ.sub.10 Q.sub.10, --C(O)Q.sub.10, --C(S)Q.sub.10, --C(O)OQ.sub.10,
--OC(O)Q.sub.10, --C(O)NQ.sub.10 Q.sub.10, --C(O)C(Q.sub.16).sub.2
OC(O)Q.sub.10, --CN, .dbd.O, .dbd.S, --NQ.sub.10 C(O)Q.sub.10, --NQ.sub.10
C(O)NQ.sub.10 Q.sub.10, --S(O).sub.2 NQ.sub.10 Q.sub.10, --NQ.sub.10
S(O).sub.2 Q.sub.10, --NQ.sub.10 S(O)Q.sub.10, --NO.sub.2, alkyl,
substituted alkyl, halo, cycloalkyl, heterocycloalkyl, het, aryl, and
cycloalkenyl;
het is a C-linked five-(5) membered heteroaryl ring having 1-4 heteroatoms
selected from the group consisting of oxygen, sulfur, and nitrogen; a
C-linked six (6) membered heteroaryl ring having a 1-3 nitrogen atoms; a
eight (8) membered bicyclic heteroaryl ring system having 1-3 heteroatoms
selected from the group consisting of oxygen, sulfur, and nitrogen; and a
ten (10) membered bicyclic heteroaryl ring system having 1-3 heteroatoms
selected from the group consisting of oxygen, sulfur, and nitrogen;
substituted het is a het moiety having 1-3 substituents selected from
--OQ.sub.10, --SQ.sub.10, --S(O).sub.2 Q.sub.10, --S(O)Q.sub.10,
--OS(O).sub.2 Q.sub.10, --C(.dbd.NQ.sub.10)Q.sub.10, --SC(O)Q.sub.10,
--NQ.sub.10 Q.sub.10, --C(O)Q.sub.10, --C(S)Q.sub.10, --C(O)OQ.sub.10,
--OC(O)Q.sub.10, --C(O)NQ.sub.10 Q.sub.10, --C(O)C(Q.sub.16).sub.2
OC(O)Q.sub.10, --CN, --NQ.sub.10 C(O)Q.sub.10, --NQ.sub.10 C(O)NQ.sub.10
Q.sub.10, --S(O).sub.2 NQ.sub.10 Q.sub.10, --NQ.sub.10 S(O).sub.2
Q.sub.10, --NQ.sub.10 S(O)Q.sub.10, --NO.sub.2, alkyl, substituted alkyl,
halo, cycloalkyl, cycloalkenyl heterocycloalkyl, het, and aryl;
wherein heterocycloalkyl is a cyclic alkyl moiety having between 5 and 7
ring atoms, including 1-4 heteroatoms in the ring selected from the group
consisting of oxygen, sulfur and nitrogen;
wherein Q.sub.10, Q.sub.11, Q.sub.14, Q.sub.15, and Q.sub.16 are as defined
in the specification;
n is 0-1;
any racemic, optically active, tautomeric, stereoisomeric form, mixtures or
pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier.
14. The pharmaceutical composition of claim 13, wherein
each R is independently selected from H, F, Cl, Br, I, C.sub.1 -C.sub.6
alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.3 alkyl-C.sub.3
-C.sub.7 -cycloalkyl, CF.sub.3, OH, O--(C.sub.1 -C.sub.6 -alkyl),
O--C.sub.2 -C.sub.6 -alkyl-OH, O--C.sub.2 -C.sub.6 --NR.sub.1 R.sub.2,
OCF.sub.3, SH, S--(C.sub.1 -C.sub.6 -alkyl) CN, NO.sub.2, NR.sub.1
R.sub.2, NHSO.sub.2 --C.sub.2 -C.sub.4 -alkyl, COOR.sub.3, CONR.sub.3
R.sub.2, SO.sub.2 NR.sub.1 R.sub.2, SO.sub.2 --C.sub.1 -C.sub.4 -alkyl,
and aryl optionally substituted with 1 to 3 of H, F, Cl, Br, I, C.sub.1
-C.sub.6 -alkyl, C.sub.1 -C.sub.6 -cycloalkyl, OH, O--(C.sub.1 -C.sub.6
-alkyl), CN, NR.sub.4 R.sub.5, CONR.sub.4 R.sub.5, and SO.sub.2 NR.sub.4
R.sub.5 ;
each R.sub.1 and R.sub.2 is independently selected from H, C.sub.1 -C.sub.4
-alkyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.1 -C.sub.3 -alkyl-C.sub.3
-C.sub.7 -cycloalkyl, and (CH.sub.2).sub.0-4 -aryl, or R.sub.1 and R.sub.2
when taken together form a five, six, or seven-membered ring which
optionally contains a heteroatom selected from N, O, or S;
each R.sub.3 is independently selected from H, C.sub.1 -C.sub.4 -alkyl,
C.sub.3 -C.sub.7 -cycloalkyl, and C.sub.2 -C.sub.3 -alkyl-C.sub.3 -C.sub.7
-cycloalkyl;
each R.sub.4 and R.sub.5 is independently H, C.sub.1 -C.sub.4 -alkyl,
C.sub.3 -C.sub.7 -cycloalkyl, C.sub.1 -C.sub.3 -alkyl-C.sub.3 -C.sub.7
-cycloalkyl, or R.sub.4 and R.sub.5 when taken together form a five, six,
or seven-membered ring which optionally contains a heteroatom selected
from N, O, or S;
each R.sub.7 is H, C.sub.1 -C.sub.4 -alkyl, or oxo;
each R.sub.9 is H or C.sub.1 -C.sub.4 -alkyl;
each R.sub.9 and R.sub.10 is independently selected from H, C.sub.1
-C.sub.6 -alkyl, and C.sub.2 -C.sub.4 -alkyl-OH; and
a pharmaceutically acceptable carrier.
15. The pharmaceutical composition of claim 13, wherein A is phenyl.
16. The pharmaceutical composition of claim 14, wherein A is phenyl.
17. The pharmaceutical composition of claim 13, wherein G is
##STR18##
18. A pharmaceutical composition of claim 14, wherein G is
##STR19##
19. A pharmaceutical composition of claim 18, wherein the compound is
phenyl 5-(1-piperazinyl)-2-pyridinyl sulfone or a pharmaceutically
acceptable salt thereof.
20. A pharmaceutical composition of claim 18, wherein the compound is
5-(1,4-diazepan-1-yl)-2-pyridinyl phenyl sulfone or
5-(1,4-diazepan-1-yl)-2-pyridinyl phenyl sulfone methanesulfonic acid
salt.
21. A method for treating a disease or condition in a mammal selected from
the group consisting of anxiety, depression or schizophrenia, the method
comprising administering to the mammal a therapeutically effective amount
of a compound of formula I as defined in claim 1.
22. A method according to claim 21, wherein the compound administered is
5-(1-piperazyl)-2-pyridinyl sulfone or a pharmaceutically acceptable salt
thereof.
23. A method according to claim 21, wherein the compound administered is
5-(1,4-diazepan-1-yl)-2-pyridinyl phenyl sulfone or
5-(1,4-diazepan-1-yl)-2-pyridinyl phenyl sulfone methane sulfonic acid
salt.
24. A compound of claim 7, wherein the compound includes an isotopic label.
25. A compound of claim 8, wherein the compound includes an isotopic label.
Description
FIELD OF THE INVENTION
The present invention relates to novel pyridylsulfone derivatives, and more
specifically, relates to pyridylsulfone compounds of formulae I and II
described herein below. These compounds are 5-HT receptor ligands and are
useful for treating diseases wherein modulation of 5-HT activity is
desired.
BACKGROUND OF THE INVENTION
Serotonin has been implicated in a number of diseases and conditions that
originate in the central nervous system. These include diseases and
conditions related to sleeping, eating, perceiving pain, controlling body
temperature, controlling blood pressure, depression, anxiety,
schizophrenia, and other bodily states. Serotonin also plays an important
role in peripheral systems, such as the gastrointestinal system, where it
has been found to mediate a variety of contractile, secretory, and
electrophysiologic effects.
As a result of the broad distribution of serotonin within the body, there
is a tremendous interest in drugs that affect serotonergic systems. In
particular, agonists, partial agonists and antagonists are of interest for
the treatment of a wide range of disorders, including anxiety, depression,
hypertension, migraine, obesity, compulsive disorders, schizophrenia,
autism, neurodegenerative disorders (e.g. Alzheimer's disease,
Parkinsonism, and Huntington's chorea), and chemotherapy-induced vomiting.
The major classes of serotonin receptors (5-HT.sub.1-7) contain fourteen to
eighteen separate receptors that have been formally classified. See
Glennon, et al., Neuroscience and Behavioral Reviews, 1990, 14, 35; and D.
Hoyer, et al. Pharmacol. Rev. 1994, 46, 157-203.
There is currently a need for pharmaceutical agents that are useful to
treat diseases and conditions that are associated with 5-HT receptors. In
particular, there is a need for agents that can selectively bind to
individual receptor sub-types (e.g. receptor-specific agonists or
antagonists); such agents would be useful as pharmaceutical agents, or
would be useful to facilitate the study of the 5-HT receptor family, or to
aid in the identification of other compounds that selectively bind to the
specific 5-HT receptors.
For example, The 5-HT.sub.6 receptor was identified in 1993 (Monsma et al.
Mol. Pharmacol. 1993, 43, 320-327 and Ruat, M. et al. Biochem. Biophys.
Res. Com. 1993, 193, 269-276). Several antidepressants and atypical
antipsychotics bind to the 5-HT.sub.6 receptor with high affinity and this
binding may be a factor in their profile of activities (Roth et al. J.
Pharm. Exp. Therapeut. 1994, 268, 1403-1410; Sleight et al. Exp. Opin.
Ther. Patents 1998, 8, 1217-1224; Bourson et al. Brit. J. Pharm. 1998,
125, 1562-1566; Boess et al. Mol. Pharmacol. 1998, 54, 577-583; Sleight et
al. Brit. J. Pharmacol. 1998, 124, 556-562). In addition, the 5-HT.sub.6
receptor has been linked to generalized stress and anxiety states
(Yoshioka et al. Life Sciences 1998, 17/18, 1473-1477). Together these
studies and observations suggest that compounds that antagonize the
5-HT.sub.6 receptor will be useful in treating disorders of the central
nervous system.
INFORMATION DISCLOSURE
U.S. Pat. No. 5,770,613 discloses pyridines useful for the treatment of
cancer and for contraceptive use.
JP 61-280474 discloses alkyl, alkenyl and aryl sulfonyl pyridine used as
intermediates for drugs; agrochemicals, surfactants, etc.
EP 0 156 433 discloses pyridazinamines useful as anti-viral agents.
JP 11-72377 discloses monocyanopyrazines which are useful for agrochemicals
and pharmaceuticals.
WO 98/24782 discloses pyrimidine compounds useful for the prophylaxis and
treatment of TNF-alpha, IL-1beta, IL-6 and/or IL-8 mediated diseases and
other diseases such as pain and diabetes.
SUMMARY OF THE INVENTION
In one aspect, the invention features compounds of formula I:
##STR2##
wherein
W.sub.1 -W.sub.3 are --C(R) or N with the proviso that no more than one of
W.sub.1 -W.sub.3 are nitrogen, and further provided that when W.sub.2 is N
that W.sub.3 is not --C(CN);
A is a five- or six-membered monocyclic aromatic ring; a eight- or
ten-membered fused aromatic ring system, the five- or six-membered
monocyclic aromatic ring and the eight- or ten-membered fused aromatic
ring system each optionally containing up to three heteroatoms (O, N, S);
or a nine-membered fused aromatic ring system containing one to three
heteroatoms (O, N, S), each of the five- or six-membered monocyclic
aromatic ring and the eight- to ten-membered fused aromatic ring systems
being optionally substituted with 1-4 of R;
Each R is independently selected from H, halo, alkyl, cycloalkyl,
substituted alkyl, --OH, alkoxy, substituted alkoxy, --SH, --S-alkyl,
--S-substituted alkyl, --CN, --NO.sub.2, --NR.sub.1 R.sub.2, --NR.sub.1
SO.sub.2 -alkyl, --NR.sub.1 SO.sub.2 -aryl, --COOR.sub.3, --CONR.sub.1
R.sub.2, --SO.sub.2 NR.sub.1 R.sub.2, --SO.sub.2 -alkyl, het, substituted
het, aryl and substituted aryl;
G is
##STR3##
Each R.sub.1 and R.sub.2 is independently H, alkyl, cycloalkyl, substituted
alkyl, aryl, het, substituted aryl, and substituted het, or R.sub.1 and
R.sub.2 when taken together, along with the atom to which they are bound,
form a five, six, or seven-membered ring which contains 1-3 heteroatoms
selected from N, O, or S;
Each R.sub.3 is independently H, alkyl, cycloalkyl, or substituted alkyl;
Each R.sub.7 is independently H, or alkyl, or oxo provided that R.sub.8 is
absent when the oxo moiety is bound to the same carbon;
Each R.sub.8 is independently H or alkyl;
Each R.sub.9 and R.sub.10 is independently H, alkyl, or substituted alkyl;
and
n is 0-1.
Generally, compounds of the present invention are 5-HT ligands. In
particular, they can selectively bind to the 5-HT.sub.6 receptor (e.g.
receptor-specific agonists or antagonists). Thus, they are useful for
treating diseases wherein modulation of 5-HT activity, specifically
5-HT.sub.6 activity, is desired. Therefore, the compounds of this
invention are useful for the treatment of diseases or disorders of the
central nervous system. More specifically, for the treatment of psychosis,
paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform
disorders, anxiety, migraine headache, drug addiction, convulsive
disorders, personality disorders, post-traumatic stress syndrome,
alcoholism, panic attacks, obsessive-compulsive disorders, and sleep
disorders. The compounds of this invention are also useful to treat
psychotic, affective, vegetative, and psychomotor symptoms of
schizophrenia and the extrapyramidal motor side effects of other
antipsychotic drugs. This last action will allow higher doses of
antipsychotics to be used and thus greater antipsychotic efficacy to be
obtained as a result of a reduction in side effects. The compounds of this
invention are also useful in the modulation of eating behavior and thus
are useful in treating excess weight and associated morbidity and
mortality.
The present invention further provides a method for treating diseases or
disorders of the central nervous system comprising administering a
therapeutically effective amount of a compound of formula I or II, or a
pharmaceutically acceptable salt thereof to the mammal. The term treating
includes prophylactic treatment. In particular, compounds of formula I or
II are useful in treating depression, schizophrenia, schizophreniform
disorder, and schizoaffective disorder. In some embodiments compounds of
formula I or II may have activity against other diseases or disorders
including, but are not limited to, the following: obesity, delusional
disorder, a stress related disease (e.g. general anxiety disorder), panic
disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress
syndrome, immune system depression, a stress induced problem with the
urinary, gastrointestinal or cardiovascular system (e.g., stress
incontinence), neurodegenerative disorders, autism, chemotherapy-induced
vomiting, hypertension, migraine headaches, cluster headaches, sexual
dysfunction in a mammal (e.g. a human), addictive disorder and withdrawal
syndrome, an adjustment disorder, an age-associated learning and mental
disorder, anorexia nervosa, apathy, an attention-deficit disorder due to
general medical conditions, attention-deficit hyperactivity disorder,
behavioral disturbance (including agitation in conditions associated with
diminished cognition (e.g., dementia, mental retardation or delirium)),
bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conduct
disorder, cyclothymic disorder, dysthymic disorder, fibromyalgia and other
somatoform disorders, generalized anxiety disorder, an inhalation
disorder, an intoxication disorder, movement disorder, (e.g., Huntington's
disease or Tardive Dyskinesia), oppositional defiant disorder, peripheral
neuropathy, post-traumatic stress disorder, premenstrual dysphoric
disorder, a psychotic disorder (brief and long duration disorders,
psychotic disorder due to medical condition, psychotic disorder NOS), mood
disorder (major depressive or bipolar disorder with psychotic features)
seasonal affective disorder, a sleep disorder, a specific developmental
disorder, agitation disorder, selective serotonin reuptake inhibition
(SSRI) "poop out" syndrome or a Tic disorder (e.g., Tourette's syndrome).
The present invention further provides a method for treating anxiety,
depression or stress related disorders comprising administering a
therapeutically effective amount of a compound of formula I or II, or a
pharmaceutically acceptable salt thereof to the mammal.
The present invention further provides the use of a compound of formula I
or II or a pharmaceutically acceptable salt thereof to prepare a
medicament for treating or preventing diseases or disorders of the central
nervous system.
In another aspect, the invention provides a pharmaceutical composition
comprising a therapeutically effective amount of a compound of formula I
or II, or a pharmaceutically acceptable salt thereof. The composition may
also include a pharmaceutically acceptable carrier.
The present invention further provides a method for treating a disease or
condition in a mammal wherein a 5-HT receptor is implicated and modulation
of a 5-HT function is desired comprising administering to the mammal a
therapeutically effective amount of a compound of formulae I or II, or a
pharmaceutically acceptable salt thereof.
The present invention further provides a method for treating a disease or
condition in a mammal wherein a 5-HT.sub.6 receptor is implicated and
modulation of a 5-HT.sub.6 function is desired comprising administering to
the mammal a therapeutically effective amount of a compound of formula I,
described above, or formula II or a pharmaceutically acceptable salt
thereof. Wherein formula II is:
##STR4##
wherein
W.sub.1 -W.sub.3 are --C(R) or N with the proviso that no more than one of
W.sub.1 -W.sub.3 are nitrogen;
A is a five- or six-membered monocyclic aromatic ring; a eight- or
ten-membered fused aromatic ring system, the five- or six-membered
monocyclic aromatic ring and the eight- or ten-membered fused aromatic
ring system each optionally containing up to three heteroatoms (O, N, S);
or a nine-membered fused aromatic ring system containing one to three
heteroatoms (O, N, S), each of the five- or six-membered monocyclic
aromatic ring and the eight- to ten-membered fused aromatic ring systems
being optionally substituted with 1-4 of R;
Each R is independently selected from H, halo, alkyl, cycloalkyl,
substituted alkyl, --OH, alkoxy, substituted alkoxy, --SH, --S-alkyl,
--S-substituted alkyl, --CN, --NO.sub.2, --NR.sub.1 R.sub.2, --NR.sub.1
SO.sub.2 -alkyl, --NR.sub.1 SO.sub.2 -aryl, --COOR.sub.3, --CONR.sub.1
R.sub.2, --SO.sub.2 NR.sub.1 R.sub.2, --SO.sub.2 -alkyl, het, substituted
het, aryl and substituted aryl;
G is
##STR5##
Each R.sub.1 and R.sub.2 is independently H, alkyl, cycloalkyl, substituted
alkyl, aryl, het, substituted aryl, and substituted het, or R.sub.1 and
R.sub.2 when taken together, along with the atom to which they are bound,
form a five, six, or seven-membered ring which contains 1-3 heteroatoms
selected from N, O, or S;
Each R.sub.3 is independently H, alkyl, cycloalkyl, or substituted alkyl;
Each R.sub.7 is independently H or alkyl, or oxo provided that R.sub.8 is
absent when the oxo moiety is bound to the same carbon
Each R.sub.8 is independently H or alkyl;
Each R.sub.9 and R.sub.10 is independently H, alkyl, or substituted alkyl;
and
n is 0-1.
Embodiments of the invention may include one or more of the following
features. Each R is independently selected from H, F, Cl, Br, I, C.sub.1
-C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.3
alkyl-C.sub.3 -C.sub.7 -cycloalkyl, CF.sub.3, OH, O--(C.sub.1 -C.sub.6
-alkyl), O--C.sub.2 -C.sub.6 -alkyl-OH, O--C.sub.2 -C.sub.6 -NR.sub.1
R.sub.2, OCF.sub.3, SH, S--(C.sub.1 -C.sub.6 -alkyl) CN, NO.sub.2,
NR.sub.1 R.sub.2, NHSO.sub.2 --C.sub.1 -C.sub.4 -alkyl, COOR.sub.3,
CONR.sub.1 R.sub.2, SO.sub.2 NR.sub.1 R.sub.2, SO.sub.2 --C.sub.1 -C.sub.4
-alkyl, and aryl optionally substituted with 1 to 3 of H, F, Cl, Br, I,
C.sub.1 -C.sub.6 -alkyl or -cycloalkyl, OH, O--(C.sub.1 -C.sub.6 -alkyl),
CN, NR.sub.4 R.sub.5, CONR.sub.4 R.sub.5, and SO.sub.2 NR.sub.4 R.sub.5.
Each R.sub.1 and R.sub.2 is independently selected from H, C.sub.1
-C.sub.4 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.1 -C.sub.3
-alkyl-C.sub.3 -C.sub.7 -cycloalkyl, --(CH.sub.2).sub.0-4 -aryl, or
R.sub.1 and R.sub.2 when taken together form a five, six, or
seven-membered ring which optionally contains a heteroatom selected from
N, O, or S. Each R.sub.3 is independently selected from H, C.sub.1
-C.sub.4 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, and C.sub.1 -C.sub.3
-alkyl-C.sub.3 -C.sub.7 -cycloalkyl. Each R.sub.4 and R.sub.5 is
independently H, C.sub.1 -C.sub.4 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl,
C.sub.1 -C.sub.3 -alkyl-C.sub.3 -C.sub.7 -cycloalkyl, or R.sub.4 and
R.sub.5 when taken together form a five, six, or seven-membered ring which
optionally contains a heteroatom selected from N, O, or S. Each R.sub.7 is
H, C.sub.1 -C.sub.4 -alkyl, or oxo. Each R.sub.8 is H or C.sub.1 -C.sub.4
-alkyl. Each R.sub.9 and R.sub.10 is independently selected from H,
C.sub.1 -C.sub.6 -alkyl, and C.sub.2 -C.sub.4 -alkyl-OH. R.sub.7 -R.sub.9
are each H. A is phenyl. The compound is phenyl
5-(1-piperazinyl)-2-pyridinyl sulfone; or
5-(1,4-Diazepan-1-yl)-2-pyridinyl phenyl sulfone; or pharmaceutically
acceptable salt thereof. G is
##STR6##
The compounds of formulae I and II also can include isotopic labels. For
example the compounds may contain an isotopic label such as at least one
atom selected from Carbon-11, Nitrogen-13, Oxygen-15, and Fluorine-18.
Isotopically labeled compounds may be used in positron emission
tomography, nuclear magnetic resonance imaging and single photon emission
tomography.
The present invention further provides isotopically labeled compounds of
formulae I or II.
The present invention further provides a method of performing positron
emission tomography comprising incorporating an isotopically labeled
compound of formulae I or II or a pharmaceutically acceptable salt thereof
into tissue of a mammal and detecting the compound incorporated into said
tissue.
The present invention further provides a method of performing nuclear
magnetic resonance imaging comprising incorporating an isotopically
labeled compound of formulae I or II or a pharmaceutically acceptable salt
thereof into tissue of a mammal and detecting the compound incorporated in
said tissue.
The present invention further provides a method of performing single photon
emission computed tomography comprising incorporating an isotopically
labeled compound of formulae I or II or a pharmaceutically acceptable salt
thereof into tissue of a mammal and detecting the compound incorporated
into said tissue.
The invention may also provide novel intermediates and processes for
preparing the compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are generally named according to the
IUPAC or CAS nomenclature system. Abbreviations which are well known to
one of ordinary skill in the art may be used (e.g. "Ph" for phenyl, "Me"
for methyl, "Et" for ethyl, "h" for hour or hours, "rt" for room
temperature, e.g., 18-25.degree. C., and etc.).
The following definitions are used, unless otherwise described.
The carbon atom content of various hydrocarbon-containing moieties can be
indicated by a prefix designating the minimum and maximum number of carbon
atoms in the moiety, i.e., the prefix C.sub.i-j indicates a moiety of the
integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example,
C.sub.1-7 alkyl refers to alkyl of one to seven carbon atoms, inclusive.
The term "halo" refers to a halogen atom selected from Cl, Br, I, and F.
The term "alkyl" refers to both straight- and branched-chain moieties.
Unless otherwise specifically stated alkyl moieties include between 1 and
10 carbon atoms.
The term "alkenyl" refers to both straight- and branched-chain moieties
containing at least one --C.dbd.C--. Unless otherwise specifically stated
alkenyl moieties include between 1 and 10 carbon atoms.
The term "alkynyl" refers to both straight- and branched-chain moieties
containing at least one --C.ident.C--. Unless otherwise specifically
stated alkynyl moieties include between 1 and 10 carbon atoms.
The term "alkoxy" refers to --O-alkyl groups.
The term "cycloalkyl" refers to a cyclic alkyl moiety. Unless otherwise
specifically stated cycloalkyl moieties will include between 3 and 7
carbon atoms.
The term "cycloalkenyl" refers to a cyclic alkenyl moiety. Unless otherwise
specifically stated cycloalkenyl moieties will include between 3 and 7
carbon atoms and at least one --C.dbd.C-- group within the cyclic ring.
The term "amino" refers to --NH.sub.2.
The term "heterocycloalkyl" refers to a cyclic alkyl moiety including 1-4
heteroatoms in the ring. The heteroatoms are selected from the group
consisting of oxygen, sulfur, and nitrogen. Unless otherwise specifically
stated heterocycloalkyl moieties include between 5 and 7 ring atoms.
The term "aryl" refers to phenyl and naphthyl.
The term "het" is a C-linked five-(5) membered heteroaryl ring having 1-4
heteroatoms selected from the group consisting of oxygen, sulfur, and
nitrogen; a C-linked six (6) membered heteroaryl ring having 1-3 nitrogen
atoms; a eight (8) membered bicyclic heteroaryl ring system having 1-3
heteroatoms selected from the group consisting of oxygen, sulfur, and
nitrogen; and a ten (10) membered bicyclic heteroaryl ring system having
1-3 heteroatoms selected from the group consisting of oxygen, sulfur, and
nitrogen.
Examples of "het" include, but are not limited to, pyridinyl, thiophenyl,
furanyl, pyrazolyl, pyrimidinyl, pyridyl, pyridazinyl, imidazolyl,
isoxazolyl, pyrazolyl, oxazolyl, oxathiazolyl, oxadiazolyl, thiazolyl,
isothiazolyl, thienyl, pyrrolyl, isopyrrolyl, oxathiazolyl-1-oxide,
thiadiazoyl, triazolyl, tetrazolyl, thiazolinyl, thiazoledionyl,
thiatriazolyl, dithiazolonyl, indoyl, indolinyl, benzofuranyl,
benzothiophenyl, benzisoxazolyl, benzimidazoyl, benzoxazolyl, quinolinyl,
isoquinolinyl, and quinovalinyl.
The term "substituted alkyl" refers to an alkyl moiety including 1-4
substituents selected from halo, cycloalkyl, cycloalkenyl,
heterocycloalkyl, het, aryl, --OQ.sub.10, --SQ.sub.10, --S(O).sub.2
Q.sub.10, --S(O)Q.sub.10, --OS(O).sub.2 Q.sub.10,
--C(.dbd.NQ.sub.10)Q.sub.10, --SC(O)Q.sub.10, --NQ.sub.10 Q.sub.10,
--C(O)Q.sub.10, --C(S)Q.sub.10, --C(O)OQ.sub.10, --OC(O)Q.sub.10,
--C(O)NQ.sub.10 Q.sub.10, --C(O)C(Q.sub.16).sub.2 OC(O)Q.sub.10, --CN,
.dbd.O, .dbd.S, --NQ.sub.10 C(O)Q.sub.10, --NQ.sub.10 C(O)NQ.sub.10
Q.sub.10, --S(O).sub.2 NQ.sub.10 Q.sub.10, --NQ.sub.10 S(O).sub.2
Q.sub.10, --NQ.sub.10 S(O)Q.sub.10, and --NO.sub.2. Each of the
cycloalkyl, heterocycloalkyl, het, aryl, and cycloalkenyl may be
optionally substituted with 1-4 substituents independently selected from
halo and Q.sub.15.
The term "substituted aryl" refers to an aryl moiety having 1-3
substituents selected from --OQ.sub.10, --SQ.sub.10, --S(O).sub.2
Q.sub.10, --S(O)Q.sub.10, --OS(O).sub.2 Q.sub.10, --C
(.dbd.NQ.sub.10)Q.sub.10, --SC(O)Q.sub.10, --NQ.sub.10 Q.sub.10,
--C(O)Q.sub.10, --C(S)Q.sub.10, --C(O)OQ.sub.10, --OC(O)Q.sub.10,
--C(O)NQ.sub.10 Q.sub.10, --C(O)C(Q.sub.16).sub.2 OC(O)Q.sub.10, --CN,
--NQ.sub.10 C(O)Q.sub.10, --NQ.sub.10 C(O)NQ.sub.10 Q.sub.10, --S(O).sub.2
NQ.sub.10 Q.sub.10, --NQ.sub.10 S(O).sub.2 Q.sub.10, --NQ.sub.10
S(O)Q.sub.10, --NO.sub.2, alkyl, substituted alkyl, halo, cycloalkyl,
cycloalkenyl, heterocycloalkyl, het, and aryl. The cycloalkyl,
cycloalkenyl, heterocycloalkyl, het, and aryl may be optionally
substituted with 1-3 substituents selected from halo and Q.sub.15.
The term "substituted het" refers to a het moiety having 1-3 substituents
selected from --OQ.sub.10, --SQ.sub.10, --S(O).sub.2 Q.sub.10,
--S(O)Q.sub.10, --OS(O).sub.2 Q.sub.10, --C(.dbd.NQ.sub.10)Q.sub.10,
--SC(O)Q.sub.10, --NQ.sub.10 Q.sub.10, --C(O)Q.sub.10, --C(S)Q.sub.10,
--C(O)OQ.sub.10, --OC(O)Q.sub.10, --C(O)NQ.sub.10 Q.sub.10,
--C(O)C(Q.sub.16).sub.2 OC(O)Q.sub.10, --CN, --NQ.sub.10 C(O)Q.sub.10,
--NQ.sub.10 C(O)NQ.sub.10 Q.sub.10, --S(O).sub.2 NQ.sub.10 Q.sub.10,
--NQ.sub.10 S(O).sub.2 Q.sub.10, --NQ.sub.10 S(O)Q.sub.10, --NO.sub.2,
alkyl, substituted alkyl, halo, cycloalkyl, cycloalkenyl,
heterocycloalkyl, het, and aryl. The cycloalkyl, cycloalkenyl,
heterocycloalkyl, het, and aryl may be optionally substituted with 1-3
substituents selected from halo and Q.sub.15.
The term "substituted alkenyl" refers to a alkenyl moiety including 1-3
substituents --OQ.sub.10, --SQ.sub.10, --S(O).sub.2 Q.sub.10,
--S(O)Q.sub.10, --OS(O).sub.2 Q.sub.10, --C(.dbd.NQ.sub.10)Q.sub.10,
--SC(O)Q.sub.10, --NQ.sub.10 Q.sub.10, --C(O)Q.sub.10, --C(S)Q.sub.10,
--C(O)OQ.sub.10, --OC(O)Q.sub.10, --C(O)NQ.sub.10 Q.sub.10,
--C(O)C(Q.sub.16).sub.2 OC(O)Q.sub.10, --CN, .dbd.O, .dbd.S, --NQ.sub.10
C(O)Q.sub.10, --NQ.sub.10 C(O)NQ.sub.10 Q.sub.10, --S(O).sub.2 NQ.sub.10
Q.sub.10, --NQ.sub.10 S(O).sub.2 Q.sub.10, --NQ.sub.10 S(O)Q.sub.10,
--NO.sub.2, alkyl, substituted alkyl, halo, cycloalkyl, cycloalkenyl,
heterocycloalkyl, het, and aryl. The cycloalkyl, cycloalkenyl,
heterocycloalkyl, het, and aryl may be optionally substituted with 1-3
substituents selected from halo and Q.sub.15.
The term "substituted alkoxy" refers to an alkoxy moiety including 1-3
substituents --OQ.sub.10, --SQ.sub.10, --S(O).sub.2 Q.sub.10,
--S(O)Q.sub.10, --OS(O).sub.2 Q.sub.10, --C(.dbd.NQ.sub.10)Q.sub.10,
--SC(O)Q.sub.10, --NQ.sub.10 Q.sub.10, --C(O)Q.sub.10, --C(S)Q.sub.10,
--C(O)OQ.sub.10, --OC(O)Q.sub.10, --C(O)NQ.sub.10 Q.sub.10,
--C(O)C(Q.sub.16).sub.2 OC(O)Q.sub.10, --CN, .dbd.O, .dbd.S, --NQ.sub.10
C(O)Q.sub.10, --NQ.sub.10 C(O)NQ.sub.10 Q.sub.10, --S(O).sub.2 NQ.sub.10
Q.sub.10, --NQ.sub.10 S(O).sub.2 Q.sub.10, --NQ.sub.10 S(O)Q.sub.10,
--NO.sub.2, alkyl, substituted alkyl, halo, cycloalkyl, heterocycloalkyl,
het, aryl, and cycloalkenyl. The cycloalkyl, heterocycloalkyl, het, aryl,
and cycloalkenyl may be optionally substituted with 1-3 substituents
selected from halo and Q.sub.15.
The term "substituted cycloalkenyl" refers to a cycloalkenyl moiety
including 1-3 substituents --OQ.sub.10, --SQ.sub.10, --S(O).sub.2
Q.sub.10, --S(O)Q.sub.10, --OS(O).sub.2 Q.sub.10,
--C(.dbd.NQ.sub.10)Q.sub.10, --SC(O)Q.sub.10, --NQ.sub.10 Q.sub.10,
--C(O)Q.sub.10, --C(S)Q.sub.10, --C(O)OQ.sub.10, --OC(O)Q.sub.10,
--C(O)NQ.sub.10 Q.sub.10, --C(O)C(Q.sub.16).sub.2 OC(O)Q.sub.10, --CN,
.dbd.O, .dbd.S, --NQ.sub.10 C(O)Q.sub.10, --NQ.sub.10 C(O)NQ.sub.10
Q.sub.10, --S(O).sub.2 NQ.sub.10 Q.sub.10, --NQ.sub.10 S(O).sub.2
Q.sub.10, --NQ.sub.10 S(O)Q.sub.10, --NO.sub.2, alkyl, substituted alkyl,
halo, cycloalkyl, cycloalkenyl, heterocycloalkyl, het, and aryl. The
cycloalkyl, cycloalkenyl, heterocycloalkyl, het, and aryl may be
optionally substituted with 1-3 substituents selected from halo and
Q.sub.15.
Each Q.sub.10 is independently selected from --H, alkyl, cycloalkyl,
heterocycloalkyl, het, cycloalkenyl, and aryl. The het, heterocycloalkyl,
cycloalkyl, cycloalkenyl, and aryl may be optionally substituted with 1-3
substituents selected from halo and Q.sub.13.
Each Q.sub.11 is independently selected from --H, halo, alkyl, aryl, and
cycloalkyl. The alkyl and cycloalkyl may be optionally substituted with
1-3 substituents independently selected from halo, --NO.sub.2, --CN,
.dbd.S, .dbd.O, and Q.sub.14. The aryl may be optionally substituted with
1-3 substituents independently selected from halo, --NO.sub.2, --CN, and
Q.sub.14.
Each Q.sub.13 is independently selected from Q.sub.11, --OQ.sub.11,
--SQ.sub.11, --S(O).sub.2 Q.sub.11, --S(O)Q.sub.11, --OS(O).sub.2
Q.sub.11, --C(.dbd.NQ.sub.11)Q.sub.11, --SC(O)Q.sub.11, --NQ.sub.11
Q.sub.11, --C(O)Q.sub.11, --C(S)Q.sub.11, --C(O)OQ.sub.11,
--OC(O)Q.sub.11, --C(O)NQ.sub.11 Q.sub.11, --C(O)C(Q.sub.16).sub.2
OC(O)Q.sub.10, --CN, .dbd.O, .dbd.S, --NQ.sub.11 C(O)Q.sub.11, --NQ.sub.11
C(O)NQ.sub.11 Q.sub.11, --S(O).sub.2 NQ.sub.11 Q.sub.11, --NQ.sub.11
S(O).sub.2 Q.sub.11, --NQ.sub.11 S(O)Q.sub.11, and --NO.sub.2, provided
that Q.sub.13 is not .dbd.O or .dbd.S when Q.sub.10 is aryl or het.
Each Q.sub.14 is --H or a substituent selected from alkyl, cycloalkyl,
cycloalkenyl, phenyl, or naphthyl, each optionally substituted with 1-4
substituents independently selected from --F, --Cl, --Br, --I,
--OQ.sub.16, --SQ.sub.16, --S(O).sub.2 Q.sub.16, --S(O)Q.sub.16,
--OS(O).sub.2 Q.sub.16, --NQ.sub.16 Q.sub.16, --C(O)Q.sub.16,
--C(S)Q.sub.16, --C(O)OQ.sub.16, --NO.sub.2, --C(O)NQ.sub.16 Q.sub.16,
--CN, --NQ.sub.16 C(O)Q.sub.16, --NQ.sub.16 C(O)NQ.sub.16 Q.sub.16,
--S(O).sub.2 NQ.sub.16 Q.sub.16, and --NQ.sub.16 S(O).sub.2 Q.sub.16. The
alkyl, cycloalkyl, and cycloalkenyl may be further substituted with .dbd.O
or .dbd.S.
Each Q.sub.15 is alkyl, cycloalkyl, cycloalkenyl, phenyl, or naphthyl, each
optionally substituted with 1-4 substituents independently selected from
--F, --Cl, --Br, --I, --OQ.sub.16, --SQ.sub.16, --S(O).sub.2 Q.sub.16,
--S(O)Q.sub.16, --OS(O).sub.2 Q.sub.16, --C(.dbd.NQ.sub.16)Q.sub.16,
--SC(O)Q.sub.16, --NQ.sub.16 Q.sub.16, --C(O)Q.sub.16, --C(S)Q.sub.16,
--C(O)OQ.sub.16, --OC(O)Q.sub.16, --C(O)NQ.sub.16 Q.sub.16,
--C(O)C(Q.sub.16).sub.2 OC(O)Q.sub.16, --CN, --NQ.sub.16 C(O)Q.sub.16,
--NQ.sub.16 C(O)NQ.sub.16 Q.sub.16, --S(O).sub.2 NQ.sub.16 Q.sub.16,
--NQ.sub.16 S(O).sub.2 Q.sub.16, --NQ.sub.16 S(O)Q.sub.16, and --NO.sub.2.
The alkyl, cycloalkyl, and cycloalkenyl may be further substituted with
.dbd.O or .dbd.S.
Each Q.sub.16 is independently selected from --H, alkyl, and cycloalkyl.
The alkyl and cycloalkyl may be optionally substituted with 1-3 halos.
Mammal denotes human and animals.
It is to be understood that the present invention encompasses any racemic,
optically-active, polymorphic, tautomeric, or stereoisomeric form, or
mixture thereof, of a compound of the invention, which possesses the
useful properties described herein.
In cases where compounds are sufficiently basic or acidic to form stable
nontoxic acid or base salts, administration of the compounds as
pharmaceutically acceptable salts may be appropriate. Examples of
pharmaceutically acceptable salts which are within the scope of the
present invention include organic acid addition salts formed with acids
which form a physiological acceptable anion and inorganic salts. Examples
of pharmaceutically acceptable salts include, but are not limited to, the
following acids acetic, aspartic, benzenesulfonic, benzoic, bicarbonic,
bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic,
chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic,
fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic,
hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic,
hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic, malonic,
mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic, muconic,
napsylic, nitric, oxalic, p-nitromethane-sulfonic, pamoic, pantothenic,
phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, phthalic,
polygalactouronic, propionic, salicylic, stearic, succinic, sulfamic,
sulfanilic, sulfonic, sulfuric, tannic, tartaric, teoclic and
toluenesulfonic.
Pharmaceutically acceptable salts may be obtained using standard procedures
well known in the art, or example by reacting a sufficiently basic
compound such as an amine with a suitable acid affording a physiologically
acceptable anion. Alkali metal (for example, sodium, potassium or lithium)
or alkaline earth metal (for example calcium) salts of carboxylic acids
can also be made.
The compounds of this invention may be prepared by the route depicted in
Chart A. Commercially available heteroaryl (2) may be used directly or
prepared from commercially available hydroxyheteroaryls (1) by treatment
with trifluoroacetic anhydride in the presence of base and solvents such
as dichloromethane or THF to form heteroaryl (2) as a triflate;
alternatively, anilinoheteroaryls 1 may be treated with sodium nitrite and
aqueous HCl or HBr to give heteroaryl (2). Heteroaryl (2) is then heated
at temperatures ranging from 100-200.degree. C. with thioaryl (3) in the
absence of solvent or with solvents such as DMF, N-methyl-pyrrolidinone,
dimethylacetamide, THF, dioxane, acetonitrile, ethyl acetate,
dimethoxyethane, ethylene gycol, and ethanol to give arylsulfide (4).
Arylsulfide (4) is oxidized to give arylsulfone (5) using oxidants such as
hydrogen peroxide in acetic acid or m-chloroperoxybenzoic acid in
dichloromethane or other methods such as are taught in March, "Advanced
Organic Chemistry: Reactions, Mechanisms, and Structure," McGraw-Hill Book
Co., Editions 2-4.
Arylsulfone (5) is then treated with heterocyclic amines (6 or 7) in
solvents such as DMF, N-methylpyrrolidinone, dimethylacetamide, THF,
dioxane, acetonitrile, ethyl acetate, dimethoxyethane, ethylene gycol, and
ethanol with bases such as potassium carbonate, sodium carbonate, cesium
carbonate, lithium carbonate, triethylamine, diisopropylethylamine,
pyridine or other solvents and bases well known to those versed in the
art, at temperatures ranging from 70 to 170.degree. C., to give
aminosulfone (8 or 9). Alternatively, arylsulfone (5) and heteocyclic
amine (6 or 7) may be reacted in the presence of a catalyst, base,
solvent, and temperature as discussed in reviews by Buchwald (Acc. Chem.
Res. 1998, 31, 805) and Hartwig (Ang. Chem. Int. Ed. Engl. 1998, 37, 2046)
to give 8 or 9.
##STR7##
In some embodiments, the compounds are isotopically-labeled compounds.
Isotopically-labeled compounds are identical to those recited in Formulae
I and II, but for the fact that one or more atoms are replaced by an atom
having an atomic mass or mass number different from the atomic mass or
mass number usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of hydrogen,
carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine,
such as .sup.3 H, .sup.11 C, .sup.14 C, .sup.13 N, .sup.15 O, .sup.18 F,
.sup.99m Tc, .sup.123 I, and .sup.125 I. Compounds of the present
invention and pharmaceutically acceptable salts and prodrugs of said
compounds that contain the aforementioned isotopes and/or other isotopes
of other atoms are within the scope of the invention. Isotopically-labeled
compounds of the present invention are useful in drug and/or substrate
tissue distribution and target occupancy assays. For example, isotopically
labeled compounds are particularly useful in SPECT (single photon emission
computed tomography) and in PET (positron emission tomography).
Single-photon emission computed tomography (SPECT), acquires information on
the concentration of isotopically labeled compounds introduced to a
mammal's body. SPECT dates from the early 1960's, when the idea of
emission traverse section tomography was introduced by D. E. Kuhl and R.
Q. Edwards prior to either PET, x-ray CT, or MRI. In general, SPECT
requires isotopes that decay by electron capture and/or gamma emission.
Example of viable SPECT isotopes include, but are not limited to,
123-iodine (.sup.123 I) and 99m-technetium (.sup.99m Tc). Subjects are
injected with a radioactively labeled agent, typically at tracer doses.
The nuclear decay resulting in the emission of a single gamma ray which
passes through the tissue and is measured externally with a SPECT camera.
The uptake of radioactivity reconstructed by computers as a tomogram shows
tissue distribution in cross-sectional images.
Positron emission tomography (PET) is a technique for measuring the
concentrations of positron-emitting isotopes within the tissues. Like
SPECT, these measurements are, typically, made using PET cameras outside
of the living subjects. PET can be broken down into several steps
including, but not limited to, synthesizing a compound to include a
positron-emitting isotope; administering the isotopically labeled compound
to a mammal; and imaging the distribution of the positron activity as a
function of time by emission tomography. PET is described, for example, by
Alavi et al. in Positron Emission Tomography. published by Alan R. Liss,
Inc. in 1985.
Positron-emitting isotopes used in PET include, but are not limited to,
Carbon-11, Nitrogen-13, Oxygen-15, and Fluorine-18. In general,
positron-emitting isotopes should have short half-lives to help minimize
the long term radiation exposure that a patient receives from high dosages
required during PET imaging.
In certain instances, PET imaging can be used to measure the binding
kinetics of compounds of this invention with 5-HT.sub.6 serotonin
receptors. For example, administering an isotopically labeled compound of
the invention that penetrates into the body and binds to a 5-HT.sub.6
serotonin receptor creates a baseline PET signal which can be monitored
while administering a second, different, non-isotopically labeled
compound. The baseline PET signal will decrease as the non-isotopically
labeled compound competes for the binding to the 5-HT.sub.6 serotonin
receptor.
In general, compounds of formula I that are useful in performing PET or
SPECT are those which penetrate the blood-brain barrier, exhibit high
selectivity and modest affinity to 5-HT.sub.6 serotonin receptors, and are
eventually metabolized. Compounds that are non-selective or those that
exhibit excessive or small affinity for 5-HT.sub.6 serotonin receptors
are, generally, not useful in studying brain receptor binding kinetics
with respect to 5-HT.sub.6 serotonin receptors. Compounds that are not
metabolized may harm the patient.
In other embodiments, nuclear magnetic resonance spectroscopy (MRS) imaging
can be used to detect the overall concentration of a compound or fragment
thereof containing nuclei with a specific spin. In general, the isotopes
useful in NMR imaging include, but are not limited to, hydrogen-1,
carbon-13, phosphorus-31, and fluorine-19. For instance, compounds
containing .sup.19 F are useful in conducting NMR imaging.
Further, substitution with heavier isotopes such as deuterium, i.e., .sup.2
H, can afford certain therapeutic advantages resulting from greater
metabolic stability, for example increased in vivo half-life or reduced
dosage requirements and, hence, maybe preferred in some circumstances.
Isotopically labeled compounds of Formula I of this invention can
generally be prepared by carrying out the synthetic procedures described
above by substituting an isotopically labeled reagent for a
non-isotopically labeled reagent.
Compounds of the present invention can conveniently be administered in a
pharmaceutical composition containing the compound in combination with a
suitable excipient. Such pharmaceutical compositions can be prepared by
methods and contain excipients which are well known in the art. A
generally recognized compendium of such methods and ingredients is
Remington's Pharmaceutical Sciences by E. W. Martin (Mark Publ. Co., 15th
Ed., 1975). The compounds and compositions of the present invention can be
administered parenterally (for example, by intravenous, intraperitoneal or
intramuscular injection), topically, orally, or rectally.
For oral therapeutic administration, the active compound may be combined
with one or more excipients and used in the form of ingestible tablets,
buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,
and the like. Such compositions and preparations should contain at least
0.1% of active compound. The percentage of the compositions and
preparations may, of course, be varied and may conveniently be between
about 2 to about 60% of the weight of a given unit dosage form. The amount
of active compound in such therapeutically useful compositions is such
that an effective dosage level will be obtained.
The tablets, troches, pills, capsules, and the like may also contain the
following: binders such as gum tragacanth, acacia, corn starch or gelatin;
excipients such as dicalcium phosphate; a disintegrating agent such as
corn starch, potato starch, alginic acid and the like; a lubricant such as
magnesium stearate; and a sweetening agent such as sucrose, fructose,
lactose or aspartame or a flavoring agent such as peppermint, oil of
wintergreen, or cherry flavoring. The above listing is merely
representative and one skilled in the art could envision other binders,
excipients, sweetening agents and the like. When the unit dosage form is a
capsule, it may contain, in addition to materials of the above type, a
liquid carrier, such as a vegetable oil or a polyethylene glycol. Various
other materials may be present as coatings or to otherwise modify the
physical form of the solid unit dosage form. For instance, tablets, pills,
or capsules may be coated with gelatin, wax, shellac or sugar and the
like. A syrup or elixir may contain the active compound, sucrose or
fructose as a sweetening agent, methyl and propylparabens as
preservatives, a dye and flavoring such as cherry or orange flavor. Of
course, any material used in preparing any unit dosage form should be
pharmaceutically acceptable and substantially non-toxic in the amounts
employed. In addition, the active compound may be incorporated into
sustained-release preparations and devices including, but not limited to,
those relying on osmotic pressures to obtain a desired release profile
(e.g., the OROS drug delivery devices as designed and developed by Alza
Corporation).
The compounds or compositions can also be administered intravenously or
intraperitoneally by infusion or injection. Solutions of the active
compound or its salts can be prepared in water, optionally mixed with a
nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid
polyethylene glycols, triacetin, and mixtures thereof and in oils. Under
ordinary conditions of storage and use, these preparations contain a
preservative to prevent the growth of microorganisms.
Pharmaceutical dosage forms suitable for injection or infusion can include
sterile aqueous solutions or dispersions or sterile powders comprising the
active ingredient which are adapted for the extemporaneous preparation of
sterile injectable or infusible solutions or dispersions, optionally
encapsulated in liposomes. In all cases, the ultimate dosage form should
be sterile, fluid and stable under the conditions of manufacture and
storage. The liquid carrier or vehicle can be a solvent or liquid
dispersion medium comprising, for example, water, ethanol, a polyol (for
example, glycerol, propylene glycol, liquid polyethylene glycols, and the
like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures
thereof. The proper fluidity can be maintained, for example, by the
formation of liposomes, by the maintenance of the required particle size
in the case of dispersions or by the use of surfactants. The prevention of
the
