U.S. patent application number 10/777252 was filed with the patent office on 2004-08-19 for arylsulphonyl substituted-tetrahydro-and hexahydro-carbazoles.
This patent application is currently assigned to Pharmacia & Upjohn Company. Invention is credited to Fu, Jian-Min.
Application Number | 20040162332 10/777252 |
Document ID | / |
Family ID | 26986113 |
Filed Date | 2004-08-19 |
United States Patent
Application |
20040162332 |
Kind Code |
A1 |
Fu, Jian-Min |
August 19, 2004 |
Arylsulphonyl substituted-tetrahydro-and hexahydro-carbazoles
Abstract
The invention provides compounds of formula I for use in
treating conditions in which 5-HT.sub.6 receptors are involved such
as in anxiety, depression, schizophrenia, Alzheimer's disease,
stress-related disease, panic, a phobia, obsessive compulsive
disorder, obesity, post-traumatic stress syndrome, epilepsy, and
other CNS disorders. 1
Inventors: |
Fu, Jian-Min; (Kalamazoo,
MI) |
Correspondence
Address: |
FLYNN, THIEL, BOUTELL & TANIS, P.C.
2026 RAMBLING ROAD
KALAMAZOO
MI
49008-1699
US
|
Assignee: |
Pharmacia & Upjohn
Company
|
Family ID: |
26986113 |
Appl. No.: |
10/777252 |
Filed: |
February 12, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10777252 |
Feb 12, 2004 |
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10268627 |
Oct 8, 2002 |
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6727274 |
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60327876 |
Oct 9, 2001 |
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60327875 |
Oct 9, 2001 |
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Current U.S.
Class: |
514/411 ;
548/444 |
Current CPC
Class: |
A61P 25/08 20180101;
A61P 43/00 20180101; A61P 25/22 20180101; A61P 25/28 20180101; A61P
3/04 20180101; A61P 25/24 20180101; A61P 25/18 20180101; C07D
209/88 20130101 |
Class at
Publication: |
514/411 ;
548/444 |
International
Class: |
A61K 031/403; C07D
209/82 |
Claims
What is claimed:
1. A compound of formula I 22wherein ---[b] is a single or double
bond; Each X, Y, and Z is independently selected from H, --OH,
--O-alkyl, and --O-substituted alkyl; R.sub.1 is selected from H,
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and
aryl; R.sub.2 is selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and aryl; R.sub.3 is selected
from H, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, and -A-E-R.sub.8; A is selected from alkyl and
substituted alkyl; E is selected from --N(R.sub.10) C(O)--,
--C(O)N(R.sub.10)--, --N(R.sub.10) C(S)--, --C(S)N(R.sub.10)--,
--S(O)N(R.sub.10)--, --N(R.sub.10) S(O)--,
--S(O).sub.2N(R.sub.10)--, and --N(R.sub.10)S(O).sub.2--; Each
R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is independently selected
from H, halogen, aryl, --CN, --NO.sub.2, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, --OR.sub.9, --NH.sub.2,
--C(O)NH.sub.2, --C(S)NH.sub.2, and --S(O).sub.naryl, provided that
one of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is --S(O).sub.naryl,
and that at least one of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is
H; n is 0, 1, or 2; Each R.sub.8, R.sub.9, and R.sub.10 is
independently selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and aryl; Each R.sub.11 is
independently selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, heterocycloalkyl, phenyl,
naphthyl, and heteroaromatic, provided that any of the alkyl,
cycloalkyl, phenyl, naphthyl, or heteroaromatic is optionally
substituted with up to 3 substituents independently selected from
halogen, alkyl, --CF.sub.3, --OR.sub.12, --SR.sub.12, --CN,
--NO.sub.2, --N.sub.3, --N(R.sub.12).sub.2,
--C(O)N(R.sub.12).sub.2, and --C(S)N(R.sub.12).sub.2; Each R.sub.12
is independently selected from H, alkyl, and cycloalkyl, provided
that any of the alkyl or cycloalkyl is optionally substituted with
up to 2 substituents independently selected from halogen,
--CF.sub.3, --NO.sub.2, --NH.sub.2, --N.sub.3, --CN, --OH,
--O-lower alkyl, and --O-lower substituted alkyl; and
pharmaceutically acceptable salts thereof.
2. A compound of claim 1 having the Formula Ib 23wherein Each X, Y,
and Z is independently selected from H, --OH, --O-alkyl, and
--O-substituted alkyl; R.sub.1 is selected from H, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, and aryl;
R.sub.2 is selected from H, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, and aryl; R.sub.3 is selected from H,
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and
-A-E-R.sub.8; A is selected from alkyl and substituted alkyl; E is
selected from --N(R.sub.10)C(O)--, --C(O)N(R.sub.10)--,
--N(R.sub.10)C(S)--, --C(S)N(R.sub.10)--, --S(O)N(R.sub.10)--,
--N(R.sub.10)S(O)--, --S(O).sub.2N(R.sub.10)--, and
--N(R.sub.10)S(O).sub.2--; Each R.sub.4, R.sub.5, R.sub.6, and
R.sub.7 is independently selected from H, halogen, aryl, --CN,
--NO.sub.2, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, --OR.sub.9, --NH.sub.2, --C(O)NH.sub.2, --C(S)NH.sub.2,
and --S(O).sub.naryl, provided that one of R.sub.4, R.sub.5,
R.sub.6, and R.sub.7 is --S(O).sub.naryl, and that at least one of
R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is H; n is 0, 1, or 2; Each
R.sub.8, R.sub.9, and R.sub.10 is independently selected from H,
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and
aryl; Each R.sub.11 is independently selected from H, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl,
heterocycloalkyl, phenyl, naphthyl, and heteroaromatic, provided
that any of the alkyl, cycloalkyl, phenyl, naphthyl, or
heteroaromatic is optionally substituted with up to 3 substituents
independently selected from halogen, alkyl, --CF.sub.3,
--OR.sub.12, --SR.sub.12, --CN, --NO.sub.2, --N.sub.3,
--N(R.sub.12).sub.2, --C(O)N(R.sub.12).sub.2, and
--C(S)N(R.sub.12).sub.2; Each R.sub.12 is independently selected
from H, alkyl, and cycloalkyl, provided that any of the alkyl or
cycloalkyl is optionally substituted with up to 2 substituents
independently selected from halogen, --CF.sub.3, --NO.sub.2,
--NH.sub.2, --N.sub.3, --CN, --OH, --O-lower alkyl, and --O-lower
substituted alkyl; and pharmaceutically acceptable salts
thereof.
3. The compound of claim 2, wherein one of R.sub.1 and R.sub.2 is
H, and the other is H, alkyl, or substituted alkyl.
4. The compound of claim 3, wherein R.sub.5 is arylS(O).sub.n--,
and wherein R.sub.4, R.sub.6, and R.sub.7 are H.
5. The compound of claim 4, wherein n is 2.
6. The compound of claim 5, wherein R.sub.3 is H or alkyl.
7. The compound of claim 6, wherein the compound is
(rac)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
(3S)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
(3R)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
(3S)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
(3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
(3R)-N,9-dimethyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ami-
ne; or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7, wherein the stereochemistry at the C-3
position is R.
9. The compound of claim 8, wherein the compound is
(3R)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
(3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
(3R)-N,9-dimethyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ami-
ne; or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound according to
claim 2.
11. A method for treating a disease or condition in a mammal in
need thereof, wherein the 5-HT.sub.6 receptor is implicated,
comprising administering to the mammal a therapeutically effective
amount of compound according to claim 2.
12. The method according to claim 11, wherein the disease or
condition is anxiety, depression, schizophrenia, Alzheimer's
disease, stress-related disease, panic, a phobia, obsessive
compulsive disorder, obesity, post-traumatic stress syndrome, or
epilepsy.
13. The method according to claim 11, wherein said compound is
administered rectally, topically, orally, sublingually, or
parenterally.
14. The method according to claim 11, wherein said compound is
administered from about 0.001 to about 100 mg/kg of body weight of
said mammal per day.
15. The method according to claim 11, wherein said compound is
administered from about 0.1 to about 50 mg/kg of body weight of
said mammal per day.
16. The compound of claim 2, wherein the compound includes at least
one atom selected from Carbon-11, Nitrogen-13, Oxygen-15, and
Fluorine-18.
17. A method of performing positron emission tomography comprising:
incorporating an isotopically labeled compound into tissue of a
mammal, wherein the isotopically labeled compound is selected from
a compound of Formula Ib as defined in claim 1.
18. The method according to claim 17, wherein the compound is
selected from
6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
(3S)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
(3R)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
(3S)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
(3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
or
(3R)-N,9-dimethyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3--
amine.
19. A compound of claim 1 having the Formula Ia 24wherein Each X,
Y, and Z is independently selected from H, --OH, --O-alkyl, and
--O-substituted alkyl; R.sub.1 is selected from H, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, and aryl;
R.sub.2 is selected from H, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, and aryl; R.sub.3 is selected from H,
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and
-A-E-R.sub.8; A is selected from alkyl and substituted alkyl; E is
selected from --N(R.sub.10)C(O)--, --C(O)N(R.sub.10)--,
--N(R.sub.10)C(S)--, --C(S)N(R.sub.10)--, --S(O)N(R.sub.10)--,
--N(R.sub.10)S(O)--, --S(O).sub.2N(R.sub.10)--, and
--N(R.sub.10)S(O).sub.2--; Each R.sub.4, R.sub.5, R.sub.6, and
R.sub.7 is independently selected from H, halogen, aryl, --CN,
--NO.sub.2, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, --OR.sub.9, --NH.sub.2, --C(O)NH.sub.2, --C(S)NH.sub.2,
and --S(O).sub.naryl, provided that one of R.sub.4, R.sub.5,
R.sub.6, and R.sub.7 is --S(O).sub.naryl, and that at least one of
R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is H; n is 0, 1, or 2; Each
R.sub.8, R.sub.9, and R.sub.10 is independently selected from H,
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and
aryl; Each R.sub.11 is independently selected from H, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl,
heterocycloalkyl, phenyl, naphthyl, and heteroaromatic, provided
that any of the alkyl, cycloalkyl, phenyl, naphthyl, or
heteroaromatic is optionally substituted with up to 3 substituents
independently selected from halogen, alkyl, --CF.sub.3,
--OR.sub.12, --SR.sub.12, --CN, --NO.sub.2, --N.sub.3,
--N(R.sub.12).sub.2, --C(O)N(R.sub.12).sub.2, and
--C(S)N(R.sub.12).sub.2; Each R.sub.12 is independently selected
from H, alkyl, and cycloalkyl, provided that any of the alkyl or
cycloalkyl is optionally substituted with up to 2 substituents
independently selected from halogen, --CF.sub.3, --NO.sub.2,
--NH.sub.2, --N.sub.3, --CN, --OH, --O-lower alkyl, and --O-lower
substituted alkyl; and pharmaceutically acceptable salts
thereof.
20. The compound of claim 19, wherein one of R.sub.1 and R.sub.2 is
H, and the other is H, alkyl, or substituted alkyl.
21. The compound of claim 20, wherein R.sub.5 is arylS(O).sub.n--,
and wherein R.sub.4, R.sub.6, and R.sub.7 are H.
22. The compound of claim 21, wherein n is 2.
23. The compound of claim 22, wherein R.sub.3 is H or alkyl.
24. The compound of claim 23, wherein the compound is
(3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-am-
ine;
(3S)-9-methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol--
3-amine;
(3R)-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-ami-
ne;
(3S)-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-amine;
(rac)-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol;
(3S)-N,9-dimethyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol--
3-amine; (3R)-N,
9-dimethyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H--
carbazol-3-amine; and pharmaceutically acceptable salts
thereof.
25. The compound of claim 23, wherein the stereochemistry at the
C-3 position is R.
26. The compound of claim 25, wherein the compound is
(3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-am-
ine; or a pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition comprising a compound according to
claim 19.
28. A method for treating a disease or condition in a mammal in
need thereof, wherein the 5-HT.sub.6 receptor is implicated,
comprising administering to the mammal a therapeutically effective
amount of compound according to claim 19.
29. The method according to claim 28, wherein the disease or
condition is anxiety, depression, schizophrenia, Alzheimer's
disease, stress-related disease, panic, a phobia, obsessive
compulsive disorder, obesity, post-traumatic stress syndrome, or
epilepsy.
30. The method according to claim 28, wherein said compound is
administered rectally, topically, orally, sublingually, or
parenterally.
31. The method according to claim 28, wherein said compound is
administered from about 0.001 to about 100 mg/kg of body weight of
said mammal per day.
32. The method according to claim 28, wherein said compound is
administered from about 0.1 to about 50 mg/kg of body weight of
said mammal per day.
33. The compound of claim 19, wherein the compound includes at
least one atom selected from Carbon-11, Nitrogen-13, Oxygen-15, and
Fluorine-18.
34. A method of performing positron emission tomography comprising:
incorporating an isotopically labeled compound into tissue of a
mammal, wherein the isotopically labeled compound is selected from
claim 19.
35. The method according to claim 34, wherein the compound is
(3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-am-
ine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
application Serial No. 60/327,876 and U.S. provisional application
Serial No. 60/327,875, both filed on 9 Oct. 2001, under 35 USC
119(e) (i), which are incorporated herein by reference in their
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to substituted 6-arylsulphonyl
tetrahydro- and hexahydro-carbazoles which are serotonin receptor,
5-HT.sub.6, ligands and are useful for treating anxiety,
depression, schizophrenia, Alzheimer's disease, stress-related
disease, panic, a phobia, obsessive compulsive disorder, obesity,
post-traumatic stress syndrome, epilepsy, and other central nervous
system (CNS) disorders in humans and animals.
BACKGROUND
[0003] Serotonin has been implicated in a number of diseases,
disorders, and conditions that originate in the CNS. 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 electrophysiological
effects.
[0004] Because of the broad distribution of serotonin within the
body, a heightened interest exists for drugs that affect
serotonergic systems. In particular, agonists, partial agonists,
and antagonists of serotonergic systems are of interest for the
treatment of a wide range of disorders.
[0005] The major classes of serotonin receptors (5-HT.sub.1-7)
contain several 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.
[0006] 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.
[0007] 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 a typical 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, such as anxiety,
depression, schizophrenia, stress-related disease, panic, a phobia,
obsessive compulsive disorder, obesity, post-traumatic stress
syndrome, and epilepsy. In general, compounds of formula I, e.g.,
tetrahydro carbazole compounds including an arylsulphonyl
substituent, exhibit selective inhibition of 5-HT.sub.6 serotonin
receptors relative to the inhibition of other 5-HT serotonin
receptors.
[0008] General anxiety disorder (GAD) occurs when a person worries
about things such as family, health, or work when there is no
reason to worry and is unable not to worry. About 3 to 4% of the
U.S. population has GAD during the course of a year. GAD most often
strikes people in childhood or adolescence, but can begin in
adulthood, too. It affects women more often than men. Currently,
treatment involves cognitive-behavioral therapy, relaxation
techniques, and biofeedback to control muscle tension and
medications such as benzodiazepines, imipramine, and buspirone.
These drugs are effective but all have side-effect liabilities.
Therefore, there is a need of a pharmaceutical agent to address the
symptoms with fewer side effects.
[0009] Depression is a mood disorder of varying lengths of normally
several months to more than two years and of varying degrees of
feelings involving sadness, despair, and discouragement. The
heterocyclic antidepressants (HCA's) are currently the largest
class of antidepressants, but monoamine oxidase inhibitors (MAOI's)
are used in particular types of depression. Common side effects
from HCA's are sedation and weight gain. In elderly patients with
organic brain disease, the side effects from HCA's can also include
seizures and behavioral symptoms. The main side effects from using
MAOI's occur from dietary and drug interactions. Therefore, agents
with fewer side effects would be useful.
[0010] Schizophrenia is a disease having multiple aspects.
Currently available drugs are generally aimed at controlling the
positive aspects of schizophrenia, such as delusions. One drug,
Clozapine, is aimed at a broader spectrum of symptoms associated
with schizophrenia. This drug has many side effects and is thus not
suitable for many patients. Thus, there is a need for a drug to
treat the cognitive and attention deficits associated with
schizophrenia. Similarly, there is a need for a drug to treat the
cognitive and attention deficits associated with schizoaffective
disorders, or similar symptoms found in the relatives of
schizophrenic patients.
[0011] Post-traumatic stress disorder (PTSD) is a form of anxiety
triggered by memories of a traumatic event that directly affected
the patient or that the patient may have witnessed. The disorder
commonly affects survivors of traumatic events including sexual
assault, physical assault, war, torture, natural disasters, an
automobile accident, an airplane crash, a hostage situation, or a
death camp. The affliction also can affect rescue workers at an
airplane crash or a mass shooting, someone who witnessed a tragic
accident or someone who has unexpectedly lost a loved one.
Treatment for PTSD includes cognitive-behavioral therapy, group
psychotherapy, and medications such as Clonazepam, Lorazepam and
selective serotonin-reuptake inhibitors such as Fluoxetine,
Sertraline, Paroxetine, Citalopram and Fluvoxamine. These
medications help control anxiety as well as depression. Various
forms of exposure therapy (such as systemic desensitization and
imaginal flooding) have all been used with PTSD patients. Exposure
treatment for PTSD involves repeated reliving of the trauma, under
controlled conditions, with the aim of facilitating the processing
of the trauma. Therefore, there is a need for better pharmaceutical
agents to treat Post traumatic stress disorder.
[0012] Stress may increase the release of epinephrine from the
adrenal medulla and norepinephrine from adrenergic neurons
activated by central nervous system (CNS) stimulation. High levels
of circulating epinephrine mediate alpha-adrenergic effects
including increases in heart rate and cardiac output. Epinephrine
may also be taken up by beta.sub.2 receptors on the presynaptic
neuronal membrane and may enhance release of norepinephrine from
storage granules. Transient epinephrine surges resulting from
stress may produce considerably more prolonged vasoconstriction.
Stress-induced activation of the sympathetic nervous system may
lead to hypertension. Stress also can cause stress gastritis and
affect the efficacy of medical treatment in some ulcer patients.
There is a need for pharmaceutical agents to treat stress-related
diseases.
[0013] Panic disorders, phobias, and obsessive compulsive behavior
are forms of neurosis. They are all related to excessive anxiety.
All humans experience fear and anxiety in response to an external
threat, or a difficult situation. However, the neuroses noted
above, are abnormal responses to ordinary situations. The causes of
such neurotic disorders are not fully known.
[0014] Anxiety can arise suddenly, as in panic, or gradually over
many minutes, hours, or even days. Anxiety may last for variable
periods of time ranging from less than a minute to years. Brief
panic attacks are common. However, most persons recover without
treatment, and panic disorder is much less common.
[0015] Phobias are similar to panic attacks in that they involve
anxiety. However, in the various phobias the anxiety is not the
free-floating anxiety of panic disorder, but instead focuses on
specific situations or stimuli. Persons who have a phobia often
realize that their anxiety is excessive, but nonetheless, they tend
to avoid the situations or stimuli that disturb them. If they must
be exposed to such situations or stimuli they endure them with
great distress. Some relatively commonly observed phobias include
agoraphobia, that is, the fear of being trapped in closed places,
fear of snakes, fear of heights, fear of the dark, fear of
strangers, fear of storms, fear of water, heights, and fear of
flying.
[0016] Persons suffering from an obsessive-compulsive disorder feel
compelled to perform repetitive, purposeful, rituals to control
their obsessions. For example, a person with an obsessive fear of
contamination might compensate with excessive hand washing.
[0017] These panic and anxiety disorders may be treated with
behavior therapy and antidepressants and benzodiazepines. Obsessive
compulsive disorders may be treated with behavior therapy and
various drugs such as serotonin reuptake inhibitors (SRIs),
selective serotonin reuptake inhibitors (SSRIs--eg, fluoxetine,
fluvoxamine, paroxetine, sertraline), and clomipramine (a tricyclic
antidepressant) Augmentation with haloperidol, or a typical
antipsychotics may be effective. However, these drugs, especially
the benzodiazepines and the antipsychotics, have potentially
serious side effects. Therefore, there is a need for a
pharmaceutical agent to treat these conditions.
[0018] Epilepsy is a recurrent, paroxysmal disorder of cerebral
function characterized by sudden, brief attacks of altered
consciousness, motor activity, sensory phenomena, or inappropriate
behavior caused by excessive discharge of cerebral neurons.
Treatment aims primarily to control seizures. A causative disorder
may need to be treated as well. No single drug controls all types
of seizures, and different drugs are required for different
patients. Patients rarely require several drugs. Commonly used
drugs include phenyloin, carbamazepine, or valproate gabapentin,
lamotrigine, and topiramate. Therefore, there is a need for a
pharmaceutical agent to treat epilepsy.
[0019] Traditionally, obesity has been defined as a body weight of
>30% above ideal or desirable weight on standard height-weight
tables. Currently, obesity is usually defined in terms of the body
mass index (BMI)--weight (in kilograms) divided by the square of
the height (in meters). The general cause of obesity is
simple--expending less energy than is consumed. However, how people
regulate body weight, primarily body fat, is still elusive and not
fully understood. Typically, the determinants of obesity are
divided into three categories: genetic, environmental, and
regulatory. Recent genetic discoveries have helped explain how
genes may determine obesity and how they may influence the
regulation of body weight. Scientific studies estimate that
genetics may account for about 33% of the variation in body weight.
The remaining variation may be caused by environmental and
regulatory factors. Environmental factors include socioeconomic
status, large food intake, and sedentary lifestyle. Regulatory
factors include pregnancy, endocrine, and psychological influences.
Despite the analysis of obesity in terms of these three factors,
the final common pathway to caloric balance lies in behavior
mediated by the CNS. Recent attempts at pharmacotherapy of obesity
has lead to widespread valvular heart disease in patients who
received fenfluramine alone or in combination with phentermine
(often referred to as fen-phen). Therefore, there is a need for a
pharmaceutical agent to treat obesity.
[0020] General CNS disease to be treated by the compounds of the
present invention include cognitive disorders such as mild
cognitive impairment, Alzheimer's disease (AD), and attention
deficit disorder with or without hyperactivity. Alzheimer's disease
(AD) is a complex disease related with age that slowly progresses
to loss of memory and language skills, with the related problems of
having difficulties in learning and making decisions and judgments.
Approximately 4 million Americans are reported to be suffering from
AD. Currently available drugs, tacrine, donepezil and rivostigmine,
are used to only retard the progression of the disease. The
above-mentioned drugs are to enhance the cholinergic transmission.
However, these drugs have serious side effects. There is a need for
a drug to treat AD more effectively and have fewer side effects.
Meneses, A., Drug News Perspect., 2001, 14, 396-400.
[0021] In U.S. Pat. Nos. 4,172,834, 1,2,3,4-tetrahydrocarbazoles
are described as antihistaminic agents. U.S. Pat. No. 5,827,871
discloses 1,2,3,4-tetrahydrocarbazoles that are described as being
useful as 5-HT.sub.1 like agonist.
SUMMARY OF THE INVENTION
[0022] In general, the invention features compounds of Formula I
2
[0023] wherein
[0024] ---[b] is a single or double bond;
[0025] Each X, Y, and Z is independently selected from H, --OH,
--O-alkyl, and --O-substituted alkyl;
[0026] R.sub.1 is selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and aryl;
[0027] R.sub.2 is selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and aryl;
[0028] R.sub.3 is selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and -A-E-R.sub.8;
[0029] A is selected from alkyl and substituted alkyl;
[0030] E is selected from --N(R.sub.10)C(O)--, --C(O)N(R.sub.10)--,
--N(R.sub.10)C(S)--, --C(S)N(R.sub.10)--, --S(O)N(R.sub.10)--,
--N(R.sub.10)S(O)--, --S(O).sub.2N(R.sub.10)--, and
--N(R.sub.10)S(O).sub.2--;
[0031] Each R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is independently
selected from H, halogen, aryl, --CN, --NO.sub.2, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, --OR.sub.9,
--NH.sub.2, --C(O)NH.sub.2, --C(S)NH.sub.2, and --S(O).sub.naryl,
provided that one of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is
--S(O).sub.naryl, and that at least one of R.sub.4, R.sub.5,
R.sub.6, and R.sub.7 is H;
[0032] n is 0, 1, or 2;
[0033] Each R.sub.8, R.sub.9, and R.sub.10 is independently
selected from H, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, and aryl;
[0034] Each R.sub.11 is independently selected from H, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl,
heterocycloalkyl, phenyl, naphthyl, and heteroaromatic, provided
that any of the alkyl, cycloalkyl, phenyl, naphthyl, or
heteroaromatic is optionally substituted with up to 3 substituents
independently selected from halogen, alkyl, --CF.sub.3,
--OR.sub.12, --SR.sub.12, --CN, --NO.sub.2, --N.sub.3,
--N(R.sub.12).sub.2, --C(O)N(R.sub.12).sub.2, and
--C(S)N(R.sub.12).sub.2- ;
[0035] Each R.sub.12 is independently selected from H, alkyl, and
cycloalkyl, provided that any of the alkyl or cycloalkyl is
optionally substituted with up to 2 substituents independently
selected from halogen, --CF.sub.3, --NO.sub.2, --NH.sub.2,
--N.sub.3, --CN, --OH, --O-lower alkyl, and --O-lower substituted
alkyl; and pharmaceutically acceptable salts thereof.
[0036] Embodiments of the invention may include one or more or
combination of the following.
[0037] Advantageously, the compounds of Formula I interact with
serotonin receptors. Unexpectedly, the compounds of this invention
selectively interact with the 5-HT.sub.6 serotonin receptor
relative to other 5-HT serotonin receptors. Due to the selective
interaction with 5-HT.sub.6, the compounds of Formula I are useful
to treat anxiety, depression, schizophrenia, Alzheimer's disease,
stress-related disease, including irritable bowel syndrome, panic,
a phobia, obsessive compulsive disorder, obesity, post-traumatic
stress syndrome, epilepsy, and other CNS disorders.
[0038] Surprisingly, the 3R isomer of the tetrahydro carbazoles of
formula I exhibit higher selectivity towards the 5-HT.sub.6
serotonin receptor relative to the 3S isomer. One embodiment of the
present invention is the group of compounds of Formula I having the
3R stereochemistry. Another embodiment of the present invention is
the use of the compounds of Formula I in the treatment of anxiety,
depression, schizophrenia, Alzheimer's disease, stress-related
disease, panic, a phobia, obsessive compulsive disorder, obesity,
post-traumatic stress syndrome, epilepsy, and other CNS
disorders.
[0039] Another aspect of the present invention is the group of
compounds of Formula Ia where the bond represented by --- and
referenced by [b] is a single bond: 3
[0040] wherein
[0041] Each X, Y, and Z is independently selected from H, --OH,
--O-alkyl, and --O-substituted alkyl;
[0042] R.sub.1 is selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and aryl;
[0043] R.sub.2 is selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and aryl;
[0044] R.sub.3 is selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and -A-E-R.sub.8;
[0045] A is selected from alkyl and substituted alkyl;
[0046] E is selected from --N(R.sub.10)C(O)--, --C(O)N(R.sub.10)--,
--N(R.sub.10)C(S)--, --C(S)N(R.sub.10)--, --S(O)N(R.sub.10)--,
--N(R.sub.10)S(O)--, --S(O).sub.2N(R.sub.10)-, and
--N(R.sub.10)S(O).sub.2--;
[0047] Each R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is independently
selected from H, halogen, aryl, --CN, --NO.sub.2, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, --OR.sub.9,
--NH.sub.2, --C(O)NH.sub.2, --C(S)NH.sub.2, and --S(O).sub.naryl,
provided that one of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is
--S(O).sub.naryl, and that at least one of R.sub.4, R.sub.5,
R.sub.6, and R.sub.7 is H;
[0048] n is 0, 1, or 2;
[0049] Each R.sub.8, R.sub.9, and R.sub.10 is independently
selected from H, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, and aryl;
[0050] Each R.sub.11 is independently selected from H, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl,
heterocycloalkyl, phenyl, naphthyl, and heteroaromatic, provided
that any of the alkyl, cycloalkyl, phenyl, naphthyl, or
heteroaromatic is optionally substituted with up to 3 substituents
independently selected from halogen, alkyl, --CF.sub.3,
--OR.sub.12, --SR.sub.12, --CN, --NO.sub.2, --N.sub.3,
--N(R.sub.12).sub.2, --C(O)N(R.sub.12).sub.2, and
--C(S)N(R.sub.12).sub.2- ;
[0051] Each R.sub.12 is independently selected from H, alkyl, and
cycloalkyl, provided that any of the alkyl or cycloalkyl is
optionally substituted with up to 2 substituents independently
selected from halogen, --CF.sub.3, --NO.sub.2, --NH.sub.2,
--N.sub.3, --CN, --OH, --O-lower alkyl, and --O-lower substituted
alkyl; and pharmaceutically acceptable salts thereof.
[0052] Another aspect of the present invention is the group of
compounds of Formula Ib where the bond represented by --- and
referenced by [b] is a double bond: 4
[0053] wherein
[0054] Each X, Y, and Z is independently selected from H, --OH,
--O-alkyl, and --O-substituted alkyl;
[0055] R.sub.1 is selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and aryl;
[0056] R.sub.2 is selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and aryl;
[0057] R.sub.3 is selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and -A-E-R.sub.8;
[0058] A is selected from alkyl and substituted alkyl;
[0059] E is selected from --N(R.sub.10)C(O)--, --C(O)N(R.sub.10)--,
--N(R.sub.10)C(S)--C(S)N(R.sub.10)--, --S(O)N(R.sub.10)--,
--N(R.sub.10) S(O)--, --S(O).sub.2N(R.sub.10)--, and
--N(R.sub.10)S(O).sub.2--;
[0060] Each R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is independently
selected from H, halogen, aryl, --CN, --NO.sub.2, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, --OR.sub.9,
--NH.sub.2, --C(O)NH.sub.2, --C(S)NH.sub.2, and --S(O).sub.naryl,
provided that one of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is
--S(O).sub.naryl, and that at least one of R.sub.4, R.sub.5,
R.sub.6, and R.sub.7 is H;
[0061] n is 0, 1, or 2;
[0062] Each R.sub.8, R.sub.9, and R.sub.10 is independently
selected from H, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, and aryl;
[0063] Each R.sub.11 is independently selected from H, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl,
heterocycloalkyl, phenyl, naphthyl, and heteroaromatic, provided
that any of the alkyl, cycloalkyl, phenyl, naphthyl, or
heteroaromatic is optionally substituted with up to 3 substituents
independently selected from halogen, alkyl, --CF.sub.3,
--OR.sub.12, --SR.sub.12, --CN, --NO.sub.2, --N.sub.3,
--N(R.sub.12).sub.2, --C(O)N(R.sub.12).sub.2, and
--C(S)N(R.sub.12).sub.2- ;
[0064] Each R.sub.12 is independently selected from H, alkyl, and
cycloalkyl, provided that any of the alkyl or cycloalkyl is
optionally substituted with up to 2 substituents independently
selected from halogen, --CF.sub.3, --NO.sub.2, --NH.sub.2,
--N.sub.3, --CN, --OH, --O-lower alkyl, and --O-lower substituted
alkyl; and pharmaceutically acceptable salts thereof.
[0065] Another aspect of the present invention is the group of
compounds of Formulas I, Ia and Ib where X, Y, and Z are
independently any one of the following: H, --OH, --O-alkyl, and
--O-substituted alkyl. Another aspect of the present invention is
the group of compounds of Formulas I, Ia and Ib where X, Y, and Z
are all H. Another aspect of the present invention is the group of
compounds of Formulas I, Ia and Ib where any two of X, Y, or Z are
H and the other is independently selected from H, --OH, --O-alkyl,
and --O-substituted alkyl.
[0066] Another aspect of the present invention is the group of
compounds of Formulas I, Ia and Ib where one of R.sub.1 and R.sub.2
is H and the other is selected from any of the following: H, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, and aryl.
Another aspect of the present invention is the group of compounds
of Formulas I, Ia and Ib where both R.sub.1 and R.sub.2 are H.
Another aspect of the present invention is the group of compounds
of Formulas I, Ia and Ib where one of R.sub.1 and R.sub.2 is H and
the other is alkyl. Another aspect of the present invention is the
group of compounds of Formulas I, Ia and Ib where one of R.sub.1
and R.sub.2 is H and the other is lower alkyl, substituted lower
alkyl, or cycloalkyl. Another aspect of the present invention is
the group of compounds of Formulas I, Ia and Ib where one of
R.sub.1 and R.sub.2 is H and the other is methyl. Another aspect of
the present invention is the group of compounds of Formulas I, Ia
and Ib where one of R.sub.1 and R.sub.2 is H and the other is
aryl.
[0067] Another aspect of the present invention is the group of
compounds of Formulas I, Ia and Ib where R.sub.3 is any one of the
following: H, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, and -A-E-R.sub.8. Another aspect of the present
invention is the group of compounds of Formulas I, Ia and Ib where
A is either alkyl or substituted alkyl. Another aspect of the
present invention is the group of compounds of Formulas I, Ia and
Ib where E is any one of the following: --N(R.sub.10)C(O)--,
--C(O)N(R.sub.10)--, --N(R.sub.10) C(S)--, --C(S)N(R.sub.10)--,
--S(O)N(R.sub.10)--, --N(R.sub.10)S(O)--,
--S(O).sub.2N(R.sub.10)--, and --N(R.sub.10)S(O).sub.2--.
[0068] Another aspect of the present invention is the group of
compounds of Formulas I, Ia and Ib where R.sub.3 is H. Another
aspect of the present invention is the group of compounds where
R.sub.3 is alkyl, including lower alkyl. Another aspect of the
present invention is the group of compounds where R.sub.3 is
methyl.
[0069] Another aspect of the present invention is the group of
compounds of Formulas I, Ia and Ib where at least one of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 is --S(O).sub.naryl, where at least
one of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is H, and the others
are independently any one of the following: H, halogen, aryl, --CN,
--NO.sub.2, alkyl, substituted alkyl, --OR.sub.9, --NH.sub.2,
--C(O)NH.sub.2, --C(S)NH.sub.2, and --S(O).sub.naryl. Another
aspect of the present invention is the group of compounds of
Formulas I, Ia and Ib where n has any of the following values: 0,
1, or 2.
[0070] Another aspect of the present invention is the group of
compounds of Formulas I, Ia and Ib where each R.sub.8, R.sub.9, and
R.sub.10 is independently any one of the following: H, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, and aryl.
Another aspect of the present invention is the group of compounds
of Formulas I, Ia and Ib where each R.sub.8, R.sub.9, and R.sub.10
are H.
[0071] Another aspect of the present invention is the group of
compounds of Formulas I, Ia and Ib where each R.sub.11 is
independently any one of the following: H, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl,
phenyl, naphthyl, and heteroaromatic, provided that any of the
alkyl, cycloalkyl, phenyl, naphthyl, or heteroaromatic is
optionally substituted with up to 3 substituents independently
selected from halogen, alkyl, --CF.sub.3, --OR.sub.12, --SR.sub.12,
--CN, --NO.sub.2, --N.sub.3, --N(R.sub.12).sub.2,
--C(O)N(R.sub.12).sub.2, and --C(S)N(R.sub.12).sub.2;
[0072] Another aspect of the present invention is the group of
compounds of Formulas I, Ia and Ib where each R.sub.12 is any one
of the following: H, alkyl, and cycloalkyl, provided that any of
the alkyl or cycloalkyl is optionally substituted with up to 2
substituents independently selected from halogen, --CF.sub.3,
--NO.sub.2, --NH.sub.2, --N.sub.3, --CN, --OH, --O-lower alkyl, and
--O-lower substituted alkyl;
[0073] One of ordinary skill in the art will recognize that where
alkyl or substituted alkyl is allowed, lower alkyl or lower
substituted alkyl, respectively, is also allowed.
[0074] Embodiments of the invention wherein the compound has the
Formula Ib as the free base or as a pharmaceutically acceptable
salt thereof:
[0075]
6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
[0076]
(3S)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
[0077]
(3R)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;
[0078]
(3S)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3--
amine;
[0079]
(3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3--
amine;
[0080]
(3R)-N,9-dimethyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-
-3-amine; or
[0081]
(3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazo-
l-3-amine.
[0082] Embodiments of the invention wherein the compound has the
Formula Ia as the free base or as a pharmaceutically acceptable
salt thereof;
[0083]
(3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazo-
l-3-amine;
[0084]
(3S)-9-methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazo-
l-3-amine;
[0085]
(3R)-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-amine-
;
[0086]
(3S)-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-amine-
;
[0087] 6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol;
[0088]
(3S)-N,9-dimethyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-car-
bazol-3-amine;
[0089]
(3R)-N,9-dimethyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-car-
bazol-3-amine;
[0090] and pharmaceutically acceptable salts thereof.
[0091] Further aspects and embodiments of the invention may become
apparent to those skilled in the art from a review of the following
detailed description, taken in conjunction with the examples and
the appended claims. While the invention is susceptible of
embodiments in various forms, described hereafter are specific
embodiments of the invention with the understanding that the
present disclosure is intended as illustrative, and is not intended
to limit the invention to the specific embodiments described
herein.
DETAILED DESCRIPTION OF THE INVENTION
[0092] In general, the invention features compounds of Formula I:
5
[0093] wherein
[0094] ---[b] is a single or double bond;
[0095] Each X, Y, and Z is independently selected from H, --OH,
--O-alkyl, and --O-substituted alkyl;
[0096] R.sub.1 is selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and aryl;
[0097] R.sub.2 is selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and aryl;
[0098] R.sub.3 is selected from H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and -A-E-R.sub.8;
[0099] A is selected from alkyl and substituted alkyl;
[0100] E is selected from --N(R.sub.10)C(O)--, --C(O)N(R.sub.10)--,
--N(R.sub.10)C(S)--, --C(S)N(R.sub.10)--, --S(O)N(R.sub.10)--,
--N(R.sub.10) S(O)--, --S(O).sub.2N(R.sub.10)--, and
--N(R.sub.10)S(O).sub.2--;
[0101] Each R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is independently
selected from H, halogen, aryl, --CN, --NO.sub.2, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, --OR.sub.9,
--NH.sub.2, --C(O)NH.sub.2, --C(S)NH.sub.2, and --S(O).sub.naryl,
provided that one of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 is
--S(O).sub.naryl, and that at least one of R.sub.4, R.sub.5,
R.sub.6, and R.sub.7 is H;
[0102] n is 0, 1, or 2;
[0103] Each R.sub.8, R.sub.9, and R.sub.10 is independently
selected from H, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, and aryl;
[0104] Aryl is phenyl, naphthyl, hetereoaromatic, substituted
phenyl, substituted naphthyl, or substituted heteroaromatic;
[0105] Heteroaromatic is a 5-, 6-, 9-, or 10-member heteroaromatic
mono- or bicyclic ring system containing 1-3 hetero atoms selected
from N, O, and S;
[0106] Substituted phenyl is phenyl having 1-3 substituents
independently selected from halogen, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, --OR.sub.11, --SR.sub.11, --CN,
--NO.sub.2, --N.sub.3, --N(R.sub.11).sub.2,
--C(O)N(R.sub.11).sub.2, --C(S)N(R.sub.11).sub.2, tetrazole,
triazole, amidine, guanidine, thioguanidine, cyanoguanidine,
phenyl, naphthyl, and heteroaromatic, provided that any of the
phenyl, naphthyl, or heteroaromatic is optionally substituted with
up to 3 substituents independently selected from halogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, --OR.sub.12,
--SR.sub.12, --CN, --NO.sub.2, --N.sub.3, --N(R.sub.11).sub.2,
--C(O)N(R.sub.11).sub.2- , and --C(S)N(R.sub.11).sub.2;
[0107] Substituted naphthyl is naphthyl having 1-6 substituents
independently selected from halogen, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, --OR.sub.11, --SR.sub.11, --CN,
--NO.sub.2, --N.sub.3, --N(R.sub.11).sub.2,
--C(O)N(R.sub.11).sub.2, --C(S)N(R.sub.11).sub.2, tetrazole,
triazole, amidine, guanidine, thioguanidine, cyanoguanidine,
phenyl, naphthyl, and heteroaromatic, provided that any of the
phenyl, naphthyl, or heteroaromatic is optionally substituted with
up to 3 substituents independently selected from halogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, --OR.sub.12,
--SR.sub.12, --CN, --NO.sub.2, --N.sub.3, --N(R.sub.11).sub.2,
--C(O)N(R.sub.11).sub.2, and --C(S)N(R.sub.11).sub.2- ;
[0108] Substituted heteroaromatic is the heteroaromatic ring having
1-3 substituents independently selected from halogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, --OR.sub.11,
--SR.sub.11, --CN, --NO.sub.2, --N.sub.3, --N(R.sub.11).sub.2,
--C(O)N(R.sub.11).sub.2- , --C(S)N(R.sub.11).sub.2, tetrazole,
triazole, amidine, guanidine, thioguanidine, cyanoguanidine,
phenyl, naphthyl, and heteroaromatic, provided that any of the
phenyl, naphthyl, or heteroaromatic is optionally substituted with
1-3 substituents independently selected from halogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, --OR.sub.12,
--SR.sub.12, --CN, --NO.sub.2, --N.sub.3, --N(R.sub.11).sub.2,
--C(O)N(R.sub.11).sub.2, and --C(S)N(R.sub.11).sub.2- ;
[0109] Alkyl is both straight- and branched-chain moieties having
from 1-9 carbon atoms;
[0110] Substituted alkyl is the alkyl moiety having at least one
substituent having 0-(2n+1) substituents independently selected
from --F, --Cl, --Br, and --I, where n is the maximum number of
carbon atoms in the moiety and further having 0-1 substituent
selected from --CF.sub.3, --OR.sub.11, --SR.sub.11, --N(R.sub.11)
2, --C(O)R.sub.11, --C(O)N(R.sub.11) 2, --CN,
--NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2,
--NR.sub.11S(O).sub.2R.sub.11, --NO.sub.2, phenyl, naphthyl, or
heteroaromatic, provided that any of the phenyl, naphthyl, or
heteroaromatic is optionally substituted with up to 3 substituents
independently selected from halogen, alkyl, --CF.sub.3,
--OR.sub.12, --SR.sub.12, CN, NO.sub.2, --N.sub.3,
--N(R.sub.11).sub.2, --C(O)N(R.sub.11).sub.2, and
--C(S)N(R.sub.11).sub.2;
[0111] Cycloalkyl is a cyclic alkyl moiety having from 3-8 carbon
atoms;
[0112] Substituted cycloalkyl is the cycloalkyl moiety having at
least one substituent having up to 4 substituents independently
selected from --F, --Cl, --Br, and --I, and further having up to 1
substituent selected from --CF.sub.3, --CN, --NO.sub.2,
--OR.sub.11, --SR.sub.11, --N(R.sub.11).sub.2, --C(O)R.sub.11,
--C(O)N(R.sub.11).sub.2, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2N(R.sub.11).sub.2, --NR.sub.11S(O).sub.2R.sub.11,
phenyl, naphthyl, and heteroaromatic, provided that any of the
phenyl, naphthyl, or heteroaromatic is optionally substituted with
1-3 substituents independently selected from halogen, alkyl,
--CF.sub.3, --OR.sub.12, --SR.sub.12, CN, NO.sub.2, --N.sub.3,
--N(R.sub.11).sub.2, --C(O)N(R.sub.11).sub.2, and
--C(S)N(R.sub.11).sub.2;
[0113] Heterocycloalkyl is a cyclic ring moiety having from 4-7
atoms with 1-2 atoms within the ring selected from N, O, and S;
[0114] Each R.sub.11 is independently selected from H, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl,
heterocycloalkyl, phenyl, naphthyl, and heteroaromatic, provided
that any of the alkyl, cycloalkyl, phenyl, naphthyl, or
heteroaromatic is optionally substituted with up to 3 substituents
independently selected from halogen, alkyl, --CF.sub.3,
--OR.sub.12, --SR.sub.12, --CN, --NO.sub.2, --N.sub.3,
--N(R.sub.12).sub.2, --C(O)N(R.sub.12).sub.2, and
--C(S)N(R.sub.12).sub.2- ;
[0115] Each R.sub.12 is independently selected from H, alkyl, and
cycloalkyl, provided that any of the alkyl or cycloalkyl is
optionally substituted with up to 2 substituents independently
selected from halogen, --CF.sub.3, --NO.sub.2, --NH.sub.2,
--N.sub.3, --CN, --OH, --O-lower alkyl, and --O-lower substituted
alkyl;
[0116] Lower alkyl is both straight- and branched-chain moieties
having from 1-4 carbon atoms;
[0117] Lower substituted alkyl is the lower alkyl moiety having at
least one substituent optionally having up to (2n+1) substituents
independently selected from --F, --Cl, --Br, and --I, where n is
the maximum number of carbon atoms in the moiety and optionally
further having up to 1 substituent independently selected from
--CF.sub.3, --NO.sub.2, --NH.sub.2, --CN, --OH, --O-lower alkyl,
wherein the lower alkyl of --O-lower alkyl is optionally
substituted with 1 substituent selected from --CF.sub.3,
--NO.sub.2, --NH.sub.2, --CN, --OH;
[0118] and pharmaceutically acceptable salts thereof.
[0119] The compounds of Formulas I, Ia and Ib are used to treat
anxiety, depression, or other CNS diseases. The arylsulphonyl
carbazoles (I, Ia and Ib) are administered orally, sublingually,
transdermally or parenterally to provide a dosage of about 0.1 to
about 50 mg/kg/day. It is preferred that the dosage range be from
about 0.1 to about 10 mg/kg/day. The arylsulphonyl carbazoles (I)
can be administered in divided doses either two, three or four
times daily. For parenteral administration, a saline solution,
dextrose solution, or water may be used as a suitable carrier.
Formulations for parenteral administration may be in the form of
aqueous or non-aqueous isotonic sterile injection solutions or
suspensions. These solutions and suspensions may be prepared from
sterile powders or granules having one or more of the carriers or
diluents mentioned for use in the formulations for oral
administration. The compounds may be dissolved in water,
polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, and/or various buffers. Other adjuvants and modes of
administration are well and widely known in the pharmaceutical art.
It is preferred that the arylsulphonyl carbazoles (I, Ia and Ib) be
administered orally.
[0120] The exact dosage and frequency of administration depends on
the particular arylsulfonyl carbazole(s) used, the particular
disease being treated, the severity of the disease being treated,
the age, weight, general physical condition of the particular
patient, other medication the individual may be taking as is well
known to those skilled in the art and can be more accurately
determined by measuring the blood level or concentration of the
arylsulphonyl carbazole (I, Ia and Ib) in the patient's blood
and/or the patient's response to the particular condition being
treated.
[0121] The arylsulphonyl carbazole (I, Ia and Ib) compounds of the
present invention may be incorporated into pharmaceutical
compositions for treating different CNS diseases, such as anxiety
or depression. The pharmaceutical compositions may include one or
more arylsulphonyl carbazole (I, Ia and Ib) compounds. The
compositions also may contain well known carriers and excipients in
addition to a therapeutically effective amount of compounds of
Formulas I, Ia and Ib. The term "carrier" material or "excipient"
herein means any substance, not itself a therapeutic agent, used as
a carrier and/or diluent and/or adjuvant, or vehicle for delivery
of a therapeutic agent to a subject or added to a pharmaceutical
composition to improve its handling or storage properties or to
permit or facilitate formation of a dose unit of the composition
into a discrete article such as a capsule or tablet suitable for
oral administration. Excipients can include, by way of illustration
and not limitation, diluents, disintegrants, binding agents,
adhesives, wetting agents, polymers, lubricants, glidants,
substances added to mask or counteract a disagreeable taste or
odor, flavors, dyes, fragrances, and substances added to improve
appearance of the composition. Acceptable excipients include
lactose, sucrose, starch powder, cellulose esters of alkanoic
acids, cellulose alkyl esters, talc, stearic acid, magnesium
stearate, magnesium oxide, sodium and calcium salts of phosphoric
and sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinyl-pyrrolidone, and/or polyvinyl alcohol, and then tableted
or encapsulated for convenient administration. Such capsules or
tablets may contain a controlled-release formulation as may be
provided in a dispersion of active compound in hydroxypropyl-methyl
cellulose, or other methods known to those skilled in the art. For
oral administration, the pharmaceutical composition may be in the
form of, for example, a tablet, capsule, suspension or liquid. If
desired, other active ingredients may be included in the
composition.
[0122] In addition to the oral dosing, noted above, the
compositions of the present invention may be administered by any
suitable route, in the form of a pharmaceutical composition adapted
to such a route, and in a dose effective for the treatment
intended. The compositions may, for example, be administered
parenterally, e.g., intravascularly, intraperitoneally,
subcutaneously, or intramuscularly. For parenteral administration,
saline solution, dextrose solution, or water may be used as a
suitable carrier. Formulations for parenteral administration may be
in the form of aqueous or non-aqueous isotonic sterile injection
solutions or suspensions. These solutions and suspensions may be
prepared from sterile powders or granules having one or more of the
carriers or diluents mentioned for use in the formulations for oral
administration. The compounds may be dissolved in water,
polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, and/or various buffers. Other adjuvants and modes of
administration are well and widely known in the pharmaceutical
art.
DEFINITIONS
[0123] Alkyl is both straight- and branched-chain moieties having
from 1-9 carbon atoms. For example, C.sub.1-9 alkyl includes
methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl,
pentyl, 3-pentyl, hexyl, and isomeric forms thereof.
[0124] Examples of heteroaromatic groups include, but are not
limited to, thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl,
pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl,
benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl,
benzimidazolyl, indolyl, benzoxazolyl, pyrazolyl, triazolyl,
tetrazolyl, isoxazolyl, oxazolyl, pyrrolyl, isoquinolinyl,
cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pydridazinyl,
triazinyl, isoindolyl, purinyl, oxadiazolyl, benzothiophenyl,
benzothiazolyl, quinazolinyl, quinoxalinyl, naphthridinyl, and
furopyridinyl.
[0125] Examples of heterocycloalkyl groups include, but are not
limited to, tetrahydrofurano, tetrahydropyrano, morpholino,
pyrrolidino, piperidino, piperazine, and 6
[0126] where m is 0, 1, or 2.
[0127] All temperatures are in degrees Centigrade.
[0128] HPLC refers to high pressure liquid chromatography.
[0129] DMSO refers to dimethylsulfoxide.
[0130] DMF refers to dimethylformamide.
[0131] Saline refers to an aqueous saturated sodium chloride
solution.
[0132] Chromatography (column and flash chromatography) refers to
purification/separation of compounds expressed as (support,
eluent). It is understood that the appropriate fractions are pooled
and concentrated to give the desired compound(s).
[0133] Generally, the following numbering system is used with the
compounds of the present invention: 7
[0134] IR refers to infrared spectroscopy.
[0135] NMR refers to nuclear (proton) magnetic resonance
spectroscopy, chemical shifts are reported in ppm (6) downfield
from tetramethylsilane.
[0136] HRMS refers to high resolution mass spectrometry. FAB refers
to fast atom bombardment.
[0137] Pharmaceutically acceptable refers to those properties
and/or substances which are acceptable to the patient from a
pharmacological/toxicological point of view and to the
manufacturing pharmaceutical chemist from a physical/chemical point
of view regarding composition, formulation, stability, patient
acceptance and bioavailability.
[0138] When solvent pairs are used, the ratios of solvents used are
volume/volume (v/v).
[0139] When the solubility of a solid in a solvent is used the
ratio of the solid to the solvent is weight/volume (wt/v).
[0140] Compounds of the present invention may be in the form of
pharmaceutically acceptable salts. The term "pharmaceutically
acceptable salts" refers to salts prepared from pharmaceutically
acceptable non-toxic bases including inorganic bases and organic
bases, and salts prepared from inorganic acids, and organic acids.
Salts derived from inorganic bases include aluminum, ammonium,
calcium, ferric, ferrous, lithium, magnesium, potassium, sodium,
zinc, and the like. Salts derived from pharmaceutically acceptable
organic non-toxic bases include salts of primary, secondary, and
tertiary amines, substituted amines including naturally occurring
substituted amines, cyclic amines, such as arginine, betaine,
caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, and the like. Salts derived from
inorganic acids include salts of hydrochloric acid, hydrobromic
acid, hydroiodic acid, sulfuric acid, phosphoric acid, phosphorous
acid and the like. Salts derived from pharmaceutically acceptable
organic non-toxic acids include salts of C.sub.1-6 alkyl carboxylic
acids, di-carboxylic acids, and tri-carboxylic acids such as acetic
acid, propionic acid, fumaric acid, succinic acid, tartaric acid,
maleic acid, adipic acid, and citric acid, and aryl and alkyl
sulfonic acids such as toluene sulfonic acids and the like.
[0141] By the term "effective amount" of a compound as provided
herein is meant a nontoxic but sufficient amount of the compound(s)
to provide the desired effect. As pointed out below, the exact
amount required will vary from subject to subject, depending on the
species, age, and general condition of the subject, the severity of
the disease that is being treated, the particular compound(s) used,
the mode of administration, and the like. Thus, it is not possible
to specify an exact "effective amount." However, an appropriate
effective amount may be determined by one of ordinary skill in the
art using only routine experimentation.
Preparation of Arylsulphonyl Substituted Carbazoles
[0142] Compounds of Formulas I, Ia and Ib of the present invention
may be prepared using the following reaction schemes:
[0143] Arylsulphonylphenylhydrazines can be prepared by the
reactions outlined in Scheme 1. 8
[0144] The appropriately substituted thiols (1) are either known to
those skilled in the art or can be readily prepared from known
starting materials by means well known to those skilled in the art.
Thiol (1) can be coupled with the appropriately substituted
nitrobenzene, e.g., 4-chloro-1-nitrobenzene (2), by known means to
produce the thioether (3). Only one arylsulphonyl group, e.g.,
R.sub.5 in Formula I, and one R group, e.g., one of R.sub.4,
R.sub.6, and R.sub.7, are shown. For simplicity, the other R groups
are not shown. Typically if R.sub.4, R.sub.6, and R.sub.7 are
substituents other than --H, those moieties should be part of the
substituted nitrobenzene (2) so that they become incorporated into
the unsubstituted arylsulfone (10) when it is formed. In general,
adding phenyl substitutents (other than --H) to the unsubstituted
arylsulfone (10) once it is formed is difficult. The substitution
pattern at the C-5, C-6, C-7, and C-8 positions of the carbazoles
of Formulas I, Ia and Ib can be produced by varying the
substitution pattern on the substituted nitrobenzene.
[0145] Oxidizing the thioether (3) with oxone followed by
hydrogenation with rhodium on carbon (5%), all of which is known to
those skilled in the art, produce the amine (5). The amine (5) can
be diazotized by (sodium) nitrite and (hydrochloric) acid followed
by reduction with tin chloride to give the corresponding hydrazine
(6).
[0146] Scheme 2 illustrates a schematic synthesis for preparing
compound (9). Reaction of 4-aminocyclohexanol (7) with
N-carbethoxyphthalimide produces the phthalimide compound (8),
which when oxidized with an oxidant such as pyridinium
chlorochromate (PCC) provides ketone (9). 9
[0147] Compounds of formula I can be prepared by the reactions
outlined in Scheme 3 (where
R.sub.1.dbd.R.sub.2.dbd.R.sub.3.dbd.R.sub.4.dbd.R.sub.6.d-
bd.R.sub.7.dbd.H) Fisher indole synthesis using hydrazine (6) and
cyclohexanone (9) generates indole (10). The phthalimide group can
be removed by reaction with hydrazine to produce the free amine
(11). For convenience of resolution on a chiral column, the amino
group can be protected to form the Boc protected compound (12),
which, in turn, can be subjected to HPLC. After separation,
individually treating the two enantiomers (13) and (14) with acid,
such as hydrochloric acid, provides the hydrochloride salt of
amines (15) and (16), respectively. 10
[0148] Compounds of Formulas I, Ia and Ib can also be prepared by
the reactions outlined in Scheme 4. The R.sub.3 group such as an
alkyl can be introduced on the indole nitrogen by treating compound
(10) with sodium hydride and electrophiles to produce compound
(17). After deprotection with hydrazine, resolving the free amine
(18) on a chiral column generates the two enantiomers (19) and
(20), which can also be protected with a protecting group such as
Boc. The R.sub.1 group can be introduced by reacting 21 (or 22)
with a base such as sodium hydride and quenched with an
electrophile. After removing the protecting group (Boc) under
acidic conditions, such as with hydrochloric acid, reductive
amination with an aldehyde in the presence of a reducing agent such
as sodium cyanoborohydride (see for example Lane, C. F., "Sodium
Cyanoborohydride--A Highly Selective Reducing Agent for Organic
Functional Groups", Synthesis, 1975, 135) provides the tertiary
amines 27 and 28, respectively. 1112
[0149] Compounds of Formula Ia where ---[b] is a single bond which
can be prepared by the reactions outlined in Scheme 5. The resolved
amino compounds 19 (or 20) can be treated with a reducing reagent
such as sodium cyanoborohydride in an acid media such as
trifluoroacetic acid or acetic acid to lead to the formation of the
indoline compounds 29 (or 30). 13
[0150] The invention also includes isotopically-labeled compounds,
which are identical to those recited in Formulas I, Ia and Ib 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.3H, .sup.11C, .sup.14C, .sup.13N,
.sup.15O, .sup.18F, .sup.99m Tc, .sup.123I, and .sup.125I.
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).
[0151] 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.123I)
and 99m-technetium (.sup.99mTc). 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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.
[0157] Further, substitution with heavier isotopes such as
deuterium, i.e., .sup.2H, 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.
EXAMPLES
[0158] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, practice the
present invention to its fullest extent. The following detailed
examples describe how to prepare the various compounds and/or
perform the various processes of the invention and are to be
construed as merely illustrative, and not limitations of the
preceding disclosure in any way whatsoever. Those skilled in the
art will promptly recognize appropriate variations from the
procedures both as to reactants and as to reaction conditions and
techniques.
[0159] Preparation 1:
2-(4-Oxocyclohexyl)-1H-isoindole-1,3(2H)-dione: 14
[0160] Step 1: A solution of 4-aminocyclohexanol hydrochloride
(2.52 g, 16.6 mmol) in water (20.0 mL) was treated with
N-carbethoxyphthalimide (3.82 g, 17.4 mmol) and Na.sub.2CO.sub.3
(3.77 g, 35.6 mmol). The reaction was stirred at room temperature
for 15.6 hours. The reaction was cooled to 0.degree. C. and
quenched with 10% HCl, filtered, and washed with water to give a
white solid. The solid was dissolved in ethyl acetate washed with
water, brine, dried over MgSO.sub.4 and concentrated in vacuo to
give 3.10 g (76%) of 2-(4-hydroxycyclohexyl)-1H-isoindole-1,3-
(2H)-dione as a colorless solid: mp 176.9-177.0.degree. C.; .sup.1H
NMR (400 MHz, Acetone-d.sub.6) .delta. 7.82 4.09, 3.74, 3.62, 2.28,
2.04, 1.76, 1.39; .sup.13C NMR (100 MHz, acetone-d.sub.6) .delta.
168.7, 135.1, 133.0, 123.6, 69.5, 50.8, 35.7, 28.3; IR (mull) 3389,
3318, 2953, 2930, 2876, 2861, 1767, 1703, 1463, 1393, 1377, 1088,
1075, 1061, 720 cm.sup.-1; HRMS (FAB) calcd for
C.sub.14H.sub.16NO.sub.3: 246.1130, found 246.1128; Anal. Calcd for
C.sub.14H.sub.15NO.sub.3: C, 68.56; H, 6.16; N, 5.71. Found: C,
68.39; H, 6.21; N, 5.70.
[0161] Step 2: A solution of
2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-- dione (3.10 g, 12.6
mmol) in CH.sub.2Cl.sub.2 (25.0 mL) was added to a slurry of PCC
(4.10 g, 19.0 mmol) in CH.sub.2Cl.sub.2 (15.0 mL) and stirred at
room temperature for 3.5 hours. The reaction was diluted with
Et.sub.2O (60.0 mL), decanted and the residue swirled with
Et.sub.2O (2.times.40.0 mL). The combined ether layers were
filtered through florisil and concentrated in vacuo to dryness, and
the residue was recrystallized from ethyl acetate/hexane to give
2.01 g (65%) of 2-(4-oxocyclohexyl)-1H-isoindole-1,3(2H)-dione as
colorless needles: mp 140.3-142.1.degree. C.; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.84, 7.74, 4.64, 2.72, 2.54, 2.09; .sup.13C
NMR (100 MHz, CDCl.sub.3) .delta. 208.9, 168.1, 134.1, 131.9,
123.3, 48.4, 39.9, 28.6; IR (mull) 3062, 3031, 2958, 2949, 2919,
2885, 1775, 1762, 1721, 1708, 1611, 1465, 1436, 1419, 1393, 1379,
719 cm.sup.-1; HRMS (FAB) calcd for C.sub.14H.sub.14NO.sub.3:
244.0974, found 244.0976; Anal. Calcd for C.sub.14H.sub.14NO.sub.3:
C, 69.12; H, 5.39; N, 5.76. Found: C, 68.87; H, 5.47; N, 5.73.
Example 1
[0162] 6-(Phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine
hydrochloride (racemic): 15
[0163] Step 1: A solution of
2-(4-oxocyclohexyl)-1H-isoindole-1,3[2H]-dion- e (3.99 g, 16.4
mmol) and 1-[4-(phenylsulfonyl)phenyl]hydrazine (3.69 g, 14.9 mmol)
in formic acid (45.0 mL) was heated to reflux for 15.4 hours then
cooled to room temperature, diluted with ethyl acetate, filtered
and concentrated in vacuo to give 2.678 g (39%) of
(rac)-2-[6-(phenylsulfonyl-
)-2,3,4,9-tertrahydro-1H-carbazol-3-yl]-1H-isoindole-1,3[2H]-dione
as colorless solid. The filtrate was concentrated in vacuo and
subjected to column chromatography (EtOAc/hexane, 1:1 and 1%
triethylamine) to give an additional 0.57 g (8%) of the title
compound: mp>275.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.50, 8.00, 7.90, 7.55, 7.47, 4.49, 3.31, 2.95, 2.68,
2.12; .sup.13C NMR (100 MHz, DMSO-d.sub.6) .delta. 167.8, 142.8,
138.3, 136.9, 134.4, 132.7, 131.4, 130.4, 129.3, 126.7, 126.4,
122.9, 119.3, 117.8, 111.5, 108.3, 47.3, 26.0, 24.1, 22.3; IR
(drift) 2482, 1989, 1710, 1392, 1374, 1342, 1305, 1154, 1109, 1092,
760, 739, 716, 684, 629 cm.sup.-1; HRMS (FAB) calcd for
C.sub.26H.sub.20N.sub.2O.sub.4S+H 457.1222, found 457.1239; Anal.
Calcd for C.sub.26H.sub.20N.sub.2O.sub.4S: C, 68.40; H, 4.42; N,
6.14; S, 7.02. Found: C, 68.38; H, 4.47; N, 6.13.
[0164] Step 2: To a solution of
(rac)-2-[6-(phenylsulfonyl)-2,3,4,9-tertra-
hydro-1H-carbazol-3-yl]-1H-isoindole-1,3[2H]-dione (3.23 g, 7.1
mmol) in methanol (70.0 mL) was added hydrazine hydrate (6.6 mL,
136 mmol). After stirring at room temperature for 2.3 hours the
reaction was concentrated in vacuo to dryness. The residue was
stirred with CH.sub.2Cl.sub.2 for 0.7 hours. The undissolved solid
was removed by filtration, and the filtrate was washed with water,
brine, and concentrated in vacuo to give 1.59 g (69%) of colorless
solid. The colorless solid (0.26 g, 0.80 mmol) was treated with a
4.0 N HCl in dioxane (10.0 mL) and stirred at room temperature for
6.5 hours. After the reaction mixture was concentrated in vacuo,
methanol was added, and the solution was concentrated in vacuo and
recrystallized from CH.sub.3OH/ethyl acetate to give 0.063 g (22%)
of 6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine
hydrochloride (racemic) as a light yellow solid: mp 205-211.degree.
C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.60, 8.40, 8.03,
7.93, 7.57, 7.47, 3.53, 3.13, 2.86, 2.79, 2.20, 1.97; .sup.13C NMR
(100 MHz, DMSO-d.sub.6) .delta. 142.8, 138.2, 136.6, 132.8, 130.5,
129.4, 126.7, 126.2, 119.4, 117.7, 111.6, 106.4, 46.5, 26.3, 25.2,
20.3; IR (drift) 3445, 3404, 3228, 3146, 2947, 2932, 2906, 2842,
1298, 1153, 1143, 1130, 1093, 732, 688 cm.sup.-1; HRMS (FAB) calcd
for C.sub.18H.sub.18N.sub.2O.sub.2S+H: 327.1167, found 327.1166;
Anal. Calcd for C.sub.18H.sub.18N.sub.2O.sub.2S- .HCl.1.2H.sub.2O:
C, 56.23; H, 5.61; N, 7.29. Found: C, 56.32; H, 5.71; N, 7.39.
Example 2
[0165]
(3S)-6-(Phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine
hydrochloride and
(3R)-6-(Phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol- -3-amine
hydrochloride: 16
[0166] Step 1: Di-tert-butyl dicarbonate (1.09 g, 4.98 mmol) was
added to a solution of
(rac)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-- amine
(1.29 mg, 3.96 mmol) in CH.sub.2Cl.sub.2 (30.0 mL). The reaction
was stirred at room temperature for 2.2 hours then washed with
water, saturated NaHCO.sub.3, brine, dried over MgSO.sub.4 and
concentrated in vacuo to a brown oil. The oil was subjected to
column chromatography (50% ethyl acetate/hexane) to give 1.39 g
(82%) of (rac) tert-butyl
6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-ylcarbamate as
a colorless solid. The racemic mixture was separated into the two
enantiomers on HPLC by using a chiral column: 0.46.times.25 cm
chiralpak AD, eluted with 20% isopropanol/hexane at 0.5 mL/min,
detector set at 280 nM.
[0167] Fraction 1 (the first-eluting fraction, 0.62 g, 37%): mp
133.8-137.8.degree. C. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.39, 8.06, 7.93, 7.62, 7.46, 7.32, 4.72, 4.05, 3.06, 2.80, 2.58,
2.09, 1.92, 1.47; .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 155.5,
143.0, 138.4, 135.8, 132.5, 131.6, 129.1, 127.4, 127.2, 120.5,
118.8, 111.2, 109.3, 79.5, 46.3, 28.5, 28.47, 27.9, 20.9; IR
(drift) 3275, 1678, 1510, 1478, 1368, 1337, 1314, 1291, 1263, 1157,
1133, 1091, 727, 687, 640 cm.sup.-1; Anal. Calcd for
C.sub.23H.sub.26N.sub.2O.sub.4S: C, 64.77; H, 6.14; N, 6.57. Found:
C, 64.53; H, 6.24; N, 6.57.
[0168] Fraction 2 (0.55 g, 33%): mp 135.7-139.4.degree. C.; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.39, 8.06, 7.92, 7.62, 7.45,
7.32, 4.72, 4.05, 3.06, 2.80, 2.56, 2.09, 1.92, 1.47; .sup.13C NMR
(100 MHz, CDCl.sub.3) .delta. 155.5, 143.0, 138.4, 135.8, 132.5,
131.6, 129.1, 127.4, 127.2, 120.5, 118.8, 111.1, 109.3, 79.5, 46.3,
28.5, 28.4, 27.9, 20.9; IR (drift) 3275, 1678, 1510, 1478, 1368,
1314, 1291, 1263, 1245, 1156, 1133, 1091, 727, 687, 640 cm.sup.-1;
Anal. Calcd for C.sub.23H.sub.26N.sub.2O.sub.4S: C, 64.77; H, 6.14;
N, 6.57. Found: C, 64.56; H, 6.23; N, 6.55.
[0169] The stereochemistry of Fractions 1 and 2 were not
identified.
[0170] Step 2: Fraction 1 from Step 1 above (0.59 g, 1.38 mmol) was
dissolved in 4.0 N HCl in dioxane (5.0 mL) and stirred at room
temperature for 15.6 hours. After the reaction mixture was
concentrated in vacuo, methanol was added and the solution was
concentrated in vacuo and recrystallized from CH.sub.3OH/ethyl
acetate to give 0.39 g (78%) of one isomer of Example 2 as a
colorless solid: mp 216-218.degree. C.; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.60, 8.37, 8.03, 7.92, 7.57, 7.47, 3.57,
3.13, 2.86, 2.78, 2.20, 1.96; .sup.13C NMR (100 MHz, DMSO-d.sub.6)
.delta. 142.8, 138.2, 136.6, 132.8, 130.5, 129.4, 126.7, 126.2,
119.4, 117.7, 111.6, 106.4, 46.5, 26.3, 25.2, 20.3; IR (drift)
3334, 3218, 3158, 3054, 3002, 2924, 2903, 2850, 1476, 1299, 1151,
1131, 1092, 731, 613 cm.sup.-1; HRMS (FAB) calcd for
C.sub.18H.sub.18N.sub.2O.s- ub.2S+H: 327.1167, found 327.1167;
Anal. Calcd for C.sub.18H.sub.18N.sub.2-
O.sub.2S.HCl.0.5EtOAc.0.75H.sub.2O: C, 57.14; H, 5.87; N, 6.66.
Found: C, 57.19; H, 6.00; N, 6.73.
[0171] Following the general procedure of Step 2, starting with
Fraction 2 from Step 1 above, making non-critical variations, the
other isomer of Example 2 was obtained as a colorless solid (79%):
mp 224-227.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.60, 8.37, 8.04, 7.92, 7.57, 7.47, 3.57, 3.13, 2.86, 2.79, 2.20,
1.96; .sup.13C NMR (100 MHz, DMSO-d.sub.6) .delta. 142.8, 138.2,
136.6, 132.8, 130.5, 129.4, 126.7, 126.2, 119.4, 117.7, 111.6,
106.4, 46.5, 26.3, 25.2, 20.3; IR (drift) 3218, 3156, 3053, 3003,
2924, 2907, 2853, 1477, 1299, 1152, 1131, 1093, 731, 688, 613
cm.sup.-1; HRMS (FAB) calcd for C.sub.18H.sub.18N.sub.2O.su-
b.2S+H: 327.1167, found 327.1175; Anal. Calcd for
C.sub.18H.sub.18N.sub.2O- .sub.2S.HCl.0.35
EtOAc.0.35H.sub.2O.0.40CH.sub.3OH: C, 57.61; H, 5.88; N, 6.79.
Found: C, 57.59; H, 6.06; N, 6.78.
Example 3(a)
[0172]
(3R)-9-Methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3--
amine: 17
Example 3(b)
[0173]
(3S)-9-Methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3--
amine: 18
[0174] Step 1: A solution of
(rac)-2-[6-(phenylsulfonyl)-2,3,4,9-tertrahyd-
ro-1H-carbazol-3-yl]-1H-isoindole-1,3[2H]-dione (2.93 g, 6.4 mmol)
in DMF (10.0 mL) was added to a 0.degree. C. suspension of 60%
sodium hydride (0.51 g, 12.7 mmol) in DMF (3.0 mL) and stirred for
0.4 hours. Methyl iodide (1.50 g, 10.6 mmol) was added, and the
reaction was stirred at room temperature for 3.67 hours. The
reaction was quenched with water and extracted with
CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2 extracts were washed with
water, brine, and the dried over MgSO.sub.4 and concentrated in
vacuo to give 1.74 g (58%) of
(rac)-2-[9-methyl-6-(phenylsulfonyl)-2,3-
,4,9-tertrahydro-1H-carbazol-3-yl]-1H-isoindole-1,3[2H]-dione as a
colorless solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.06,
7.97-7.88, 7.66-7.55, 4.49, 3.70, 3.38-3.33, 3.05-3.01, 2.88-2.86,
2.75-2.70, 2.21; .sup.13C NMR (100 MHz, DMSO-d.sub.6) .delta.
168.1, 143.2, 139.1, 138.5, 134.6, 132.9, 131.8, 130.9, 129.5,
127.0, 126.0, 123.1, 119.4, 118.2, 110.3, 108.4, 47.4, 26.2, 24.3,
21.5; IR (drift) 1710 (s), 1391, 1373, 1303, 1151, 1113, 1089, 814,
743, 719, 692, 644, 638, 618, 611 cm.sup.-1; HRMS (FAB) calcd for
C.sub.27H.sub.22N.sub.2O.su- b.4S+H: 471.1378, found: 471.1383;
Anal. Calcd for C.sub.27H.sub.22N.sub.2- O.sub.4S: C, 68.92; H,
4.71; N, 5.95. Found: C, 68.50; H, 4.82; N, 5.88.
[0175] Step 2: To a solution of (rac)
2-[9-methyl-6-(phenylsulfonyl)-2,3,4-
,9-tertrahydro-1H-carbazol-3-yl]-1H-isoindole-1,3[2H]-dione (1.70
g, 3.6 mmol) in methanol (100 mL) was added hydrazine hydrate (1.6
mL, 33 mmol). After stirring at room temperature for 4.75 hours,
the reaction was concentrated in vacuo. The residue was dissolved
in CH.sub.2Cl.sub.2 and concentrated in vacuo to give 0.77 g (63%)
of (rac)
9-methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine
as a yellow oil, which was separated into enantiomers on HPLC by
using a chiral column: 0.46.times.25 cm chiralpack AD, eluted with
0.05% diethylamine/ethanol at 0.5 mL/min, dector set at 280 nM.
[0176] Example 3(a): Fraction 1: (First-eluting fraction, 86 mg,
7%); mp 189.3-193.2.degree. C.; [.alpha.].sub.D=+29.degree. (C
1.04, DMSO) .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.04,
7.94-7.92, 7.63-7.54, 3.64, 3.39-3.06, 2.91-2.79, 2.66-2.60, 2.14,
1.88; .sup.13C NMR (100 MHz, DMSO-d.sub.6) .delta. 142.7, 138.6,
138.1, 132.8, 130.5, 129.4, 126.7, 125.7, 119.2, 117.7, 110.1,
107.1, 46.5, 29.3, 27.9, 26.8, 19.4; IR (drift) 3225, 3217, 3156,
3054, 2998, 2931, 1611, 1482, 1377, 1312, 1304, 1151, 1091, 729,
624 cm.sup.-1; HRMS (FAB) calcd for
C.sub.19H.sub.20N.sub.2O.sub.2S+H: 341.1324, found: 341.1323; Anal.
Calcd for C.sub.19H.sub.20N.sub.2O.sub.2S.2H.sub.2O: C, 60.62; H,
6.43; N, 7.44. Found: C, 60.36; H, 5.95; N, 7.51.
[0177] Example 3(b): Fraction 2: (114 mg, 9%);
[.alpha.].sub.D=-30.degree. (C 1.02, DMSO) .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.04, 7.94-7.92, 7.63-7.54, 3.64, 3.39-3.06,
2.91-2.79, 2.66-2.60, 2.14, 1.88; .sup.13C NMR (100 MHz,
DMSO-d.sub.6) .delta. 142.7, 138.6, 138.1, 132.8, 130.5, 129.4,
126.7, 125.7, 119.2, 117.8, 110.1, 106.9, 46.5, 29.3, 27.6, 26.5,
19.4; IR (drift) 3055, 3015, 2999, 2931, 2849, 1613, 1481, 1377,
1304, 1150, 1092, 730, 690, 624, 609 cm.sup.-1; HRMS (FAB) calcd
for C.sub.19H.sub.20N.sub.2O.sub.2S+H: 341.1324, found: 341.1335;
Anal. Calcd for C.sub.19H.sub.20N.sub.2O.sub.2S.2H.sub.2O: C,
60.62; H, 6.43; N, 7.44. Found: C, 60.06; H, 5.94; N, 7.51.
[0178] The identification of Example 3(b) was based on the x-ray
crystallography of its (S)-mandelic acid derivative:
[0179]
(2'S)-2'-hydroxy-N-[(3S)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tetrah-
ydro-1H-carbazol-3-yl]-2-phenylethanamide: 19
[0180] To a solution of
(3S)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydr-
o-1H-carbazol-3-amine (0.500 g, 1.47 mmol), (S)-Mandelic acid
(0.224 g, 1.47 mmol), 1-hydorxytriazole (0.199 g, 1.47 mmol) and
triethylamine (0.21 mL, 0.147 mmol) in dichloromethane (15.0 mL)
was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (0.282 g, 1.47 mmol) at 0.degree. C. The resulted
mixture was stirred at room temperature for over night. Water (20.0
mL) and dichloromethane (15.0 mL) were added and separated. The
aqueous layer was extracted with dichloromethane (2.times.20.0 mL).
The combined organic solutions was dried (MgSO.sub.4) and filtered.
The filtrated was concentrated in vacuo to dryness and the residue
was subjected to column chromatography (EtOAc) to give 0.544 g
(78%) of colorless solid as the title compound: mp 138-140.degree.
C. (EtOAc/hex); [.alpha.].sub.D=+78.degree. (c 0.78, CHCl.sub.3);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.02 (d, J=1.7 Hz, 1H),
7.93-7.90 (m, 2H), 7.68-7.66 (dd, J=8.6, 1.7 Hz, 1H), 7.48-7.31 (m,
10H), 7.25 (d, J=8.6 Hz, 1H), 6.49 (d, J=8.0 Hz, 1H), 5.05 (s, 1H),
4.28 (br, 1H), 3.57 (s, 3H), 3.02 (dd, J=15.3, 5.1 Hz, 1H), 2.72
(t, J=6.1 Hz, 2H), 2.52 (dd, J=15.3, 7.6 Hz, 1H), 2.08 (m, 1H),
1.94 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 171.9,
143.1, 139.5, 139.2, 137.2, 132.5, 131.2, 129.1, 128.8, 128.6,
127.2, 126.7, 126.6, 120.1, 118.8, 109.2, 108.2, 74.2, 45.2, 29.5,
28.0, 27.4, 19.9; IR (diffuse reflectance) 3406, 3396, 3268, 1663,
1644, 1638, 1619, 1525, 1522, 1449, 1304, 1288, 1151, 1088, 1061
cm.sup.-1; HRMS (FAB) calcd for C.sub.27H.sub.26N.sub.2O.sub.4S+H
475.1691, found 475.1703; Anal. Calcd for
C.sub.27H.sub.26N.sub.2O.sub.4S.0.25H.sub.2O: C, 67.69; H, 5.57; N,
5.85. Found: C, 67.70; H, 5.64; N, 5.82.
Example 4
[0181]
(3R)-N,9-Dimethyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-
-3-amine hydrochloride: 20
[0182] Step 1: Following the general procedure of EXAMPLE 2(a)
(step 1) and making non-critical variations, tert-butyl
(3R)-9-methyl-6-(phenylsul-
fonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamate was prepared as
a brown solid (74%): mp 155-160.degree. C.; [.alpha.].sub.D=-340 (c
1.01, chloroform); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.11,
7.95-7.92, 7.68, 7.50-7.42, 7.30, 4.65, 4.08, 3.63, 3.09,
2.82-2.79, 2.64, 2.13, 2.02-1.96, 1.46; .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta. 155.4, 143.2, 139.2, 137.3, 132.4, 131.3,
129.0, 127.2, 126.8, 120.2, 118.9, 109.2, 108.5, 79.5, 46.0, 29.5,
28.5, 28.4, 28.0, 19.8; IR (diffuse reflectance) 1701, 1519, 1482,
1367, 1300, 1289, 1181, 1173, 1163, 1151, 731, 687, 626, 613, 607
cm.sup.-1; HRMS (FAB) calcd for C.sub.24H.sub.28N.sub.2O.su- b.4S+H
441.1848, found 441.1873; Anal. Calcd for
C.sub.24H.sub.28N.sub.2O.- sub.4S: C, 65.43; H, 6.41; N, 6.36.
Found: C, 65.35; H, 6.38; N, 6.38.
[0183] Step 2: A solution of tert-butyl
(3R)-9-methyl-6-(phenylsulfonyl)-2-
,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamate (1.74 g, 3.95 mmol) in
DMF (13.0 mL) was added to a 0.degree. C. suspension of 60% sodium
hydride (0.38 g, 9.62 mmol) in DMF (3.0 mL) and stirred at room
temperature for 1.1 hours. Methyl iodide (0.30 mL, 4.81 mmol) was
added, and the reaction was stirred at room temperature for 2.0
hours. The reaction was cooled to 0.degree. C., quenched with water
and filtered. The filtrate was concentrated in vacuo, combined with
the previously filtered solid and partitioned between ethyl acetate
and water. The organic layer was washed with brine, dried over
MgSO.sub.4 and concentrated in vacuo to dryness, the residue was
recrystallized from EtOAc/hexane to give 1.36 g (76%) of tert-butyl
methyl[(3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H--
carbazol-3-yl]carbamate as a colorless solid: mp
181.4-183.2.degree. C.; [.alpha.].sub.D =+1030 (c 1.02, DMSO);
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.06, 7.93-7.91,
7.62-7.53, 4.22, 3.64, 2.96-2.92, 2.84-2.79, 1.99-1.94, 1.42;
.sup.13C NMR (100 MHz, DMSO-d.sub.6) .delta. 155.6, 142.8, 138.7,
138.0, 132.7, 130.5, 129.3, 126.7, 125.9, 119.1, 118.0, 110.0,
108.6, 78.5, 29.3, 28.5, 28.0, 26.4, 23.5, 21.2; IR (diffuse
reflectance) 1684, 1481, 1448, 1398, 1378, 1364, 1357, 1304, 1184,
1149 (s), 1103, 732, 690, 622, 612 cm.sup.-1; HRMS (FAB) calcd for
C.sub.25H.sub.30N.sub.2O.sub.4S+H 455.2004, found 455.2027; Anal.
Calcd for C.sub.25H.sub.30N.sub.2O.sub.4S: C, 66.05; H, 6.65; N,
6.16. Found: C, 65.99; H, 6.66; N, 6.19.
[0184] Step 3: Following the general procedure of EXAMPLE 2 (step
2) and making non-critical variations,
(3R)-N,9-dimethyl-6-(phenylsulfonyl)-2,3,-
4,9-tetrahydro-1H-carbazol-3-amine hydrochloride was prepared as a
colorless solid (47%): mp>275.degree. C.; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.25, 8.11, 7.91, 7.62-7.57, 3.65, 3.42,
3.28, 2.93, 2.81, 2.66, 2.35, 1.99; .sup.13C NMR (100 MHz,
DMSO-d.sub.6) .delta. 142.7, 138.7, 138.0, 132.8, 130.6, 129.4,
126.7, 125.6, 119.4, 117.9, 110.2, 106.2, 54.0, 29.8, 29.4, 24.8,
23.1, 19.4; IR (diffuse reflectance) 2959, 2938, 2931, 2792, 2768,
2748, 2708, 2459, 1478, 1306, 1300, 1151, 1099, 732, 624 cm.sup.-1;
HRMS (FAB) calcd for C.sub.20H.sub.22N.sub.2O.sub.2S+H 355.1480,
found 355.1485; Anal. Calcd for C.sub.20H.sub.22N.sub.2O.sub.2S: C,
61.45; H, 5.93; N, 7.17. Found: C, 61.16; H, 5.93; N, 7.12.
Example 5
[0185]
(3R)-9-Methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazo-
l-3-amine: 21
[0186] Step 1: A freshly prepared solution of sodium
cyanoborohydride (0.91 g, 14.48 mmol) in CH.sub.3OH (3.0 mL) was
added dropwise to a 0.degree. C. solution of
(3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tetrahy-
dro-1H-carbazol-3-amine (1.02 g, 2.99 mmol) in TFA (7.5 mL), then
stirred at room temperature for 3 hours. The reaction was diluted
with H.sub.2O (40 mL) cooled to 0.degree. C. and made basic by the
addition of 50% NaOH. The reaction mixture was extracted with
EtOAc, washed with brine, dried over MgSO.sub.4 and concentrated in
vacuo to give a colorless foam which was recrystallized from
CH.sub.3OH/EtOAc to give 0.19 g (19%) of
(3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-am-
ine as a colorless as a mixture of cis and trans isomers: mp
217.0-219.3.degree. C.; MS m/z 343.2 (M.sup.++H).
5-HT.sub.6 Receport Binding Assay
[0187] Growth of Cells and Membrane Preparation
[0188] Hela cells containing the cloned human 5-HT.sub.6 receptor
were acquired from Dr. David R. Sibley's laboratory in National
Institute of Health (see Sibley, D. R., J. Neurochemistry, 66,
47-56, 1996). Cells were grown in high glucose Dulbecco's modified
Eagle's medium, supplemented with L-glutamine, 0.5% sodium
pyruvate, 0.3% penicillin-streptomycin, 0.025% G-418 and 5% Gibco
fetal bovine serum and then were harvested, when confluent, in cold
phosphate buffered saline.
[0189] Harvested intact cells were washed once in cold
phosphate-buffered saline. The cells were pelleted and resuspended
in 100 ml of cold 50 mM Tris, 5 mM EDTA and 5 mM EGTA, pH 7.4.
Homogenization was with a Vir Tishear generator, 4 cycles for 30
seconds each at setting 50. The homogenized cells were centrifuged
at 700 RPM (1000.times.g) for 10 minutes and the supernatant was
removed. The pellet was resuspended in 100 ml of the above buffer
and rehomogenized for 2 cycles. The rehomogenized cells were then
centrifuged at 700 RPM (1000.times.g) for 10 minutes and the
supernatant was removed. The combined supernatant (200 ml) was
centrifuged at 23,000 RPM (80,000.times.g) for 1 hour in a Beckman
Rotor (42.1 Ti). The membrane pellet was resuspended in 50-8- ml of
assay buffer containing HEPES 20 mM, MgCl2 10 mM, NaCl 150 mM, EDTA
1 mM, pH 7.4 and stored frozen in aliqouts at -70.degree. C.
[0190] 5-HT.sub.6 Receptor Binding Assay
[0191] The radioligand binding assay used [.sup.3H]-lysergic acid
diethylamide (LSD). The assay was carried out in Wallac 96-well
sample plates by the addition of 11 .mu.l of the test sample at the
appropriate dilution (the assay employed 11 serial concentrations
of samples run in duplicate), 11 .mu.l of radioligand, and 178
.mu.l of a washed mixture of WGA-coated SPA beads and membranes in
binding buffer. The plates were shaken for about 5 minutes and then
incubated at room temperature for 1 hour. The plates were then
loaded into counting cassettes and counted in a Wallac MicroBeta
Trilux scintillation counter.
[0192] Binding Constant (Ki) Determination
[0193] Eleven serial dilutions of test compounds were distributed
to assay plates using the PE/Cetus Pro/Pette pipetter. These
dilutions were, followed by radioligand and the bead-membrane
mixture prepared as described above. The specifically bound cpm
obtained were fit to a one-site binding model using GraphPad Prism
ver. 3.0. Estimated IC.sub.50 values were converted to Ki values
using the Cheng-Prusoff equation (Cheng, Y. C. et al., Biochem.
Pharmacol., 22, 3099-108, 1973). The Examples have Ki values from
about 2.9 nM to about 58 nM.
* * * * *