U.S. patent application number 11/071726 was filed with the patent office on 2005-08-04 for new indole derivatives with 5-ht6 receptor affinity.
Invention is credited to Beard, Colin Charles, Clark, Robin Douglas, Fisher, Lawrence Emerson, Harris, Ralph New III, Putman, David George, Repke, David Bruce.
Application Number | 20050171118 11/071726 |
Document ID | / |
Family ID | 26969776 |
Filed Date | 2005-08-04 |
United States Patent
Application |
20050171118 |
Kind Code |
A1 |
Beard, Colin Charles ; et
al. |
August 4, 2005 |
New indole derivatives with 5-HT6 receptor affinity
Abstract
This invention relates to compounds which have generally 5-HT6
receptor affinity and which are represented by Formula I: 1 wherein
one of R.sup.5, R.sup.6 or R.sup.7 is a group of general Formula B,
wherein W is a --CH-- group or a nitrogen atom, and the other
substituents are as defined herein; or individual isomers, racemic
or non-racemic mixtures of isomers, or pharmaceutically acceptable
salts or solvates thereof. The invention further relates to
pharmaceutical compositions containing such compounds, methods for
their use as therapeutic agents, and methods of preparation
thereof.
Inventors: |
Beard, Colin Charles; (Palo
Alto, CA) ; Clark, Robin Douglas; (Lawai, HI)
; Fisher, Lawrence Emerson; (Mountain View, CA) ;
Harris, Ralph New III; (Redwood City, CA) ; Putman,
David George; (Saratoga, CA) ; Repke, David
Bruce; (Milpitas, CA) |
Correspondence
Address: |
ROCHE PALO ALTO LLC
PATENT LAW DEPT. M/S A2-250
3431 HILLVIEW AVENUE
PALO ALTO
CA
94304
US
|
Family ID: |
26969776 |
Appl. No.: |
11/071726 |
Filed: |
March 3, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11071726 |
Mar 3, 2005 |
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10876863 |
Jun 25, 2004 |
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10876863 |
Jun 25, 2004 |
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10164660 |
Jun 6, 2002 |
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6787535 |
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60296705 |
Jun 7, 2001 |
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60340212 |
Dec 13, 2001 |
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Current U.S.
Class: |
514/254.09 ;
514/323; 544/373; 546/200 |
Current CPC
Class: |
C07D 209/30 20130101;
A61P 1/04 20180101; A61P 25/34 20180101; A61P 25/18 20180101; A61P
43/00 20180101; A61P 25/32 20180101; A61P 25/14 20180101; A61P
25/20 20180101; C07D 401/12 20130101; A61P 25/28 20180101; A61P
25/36 20180101; A61P 25/24 20180101; A61P 25/08 20180101; A61P
21/04 20180101; A61K 31/405 20130101; A61P 25/16 20180101; C07D
401/04 20130101; A61P 3/04 20180101; A61P 25/06 20180101; A61P
25/00 20180101 |
Class at
Publication: |
514/254.09 ;
514/323; 546/200; 544/373 |
International
Class: |
A61K 031/496; A61K
031/454; C07D 043/02 |
Claims
1-63. (canceled)
64. A compound of Formula I: 52wherein: R.sup.1 is
--S(O).sub.0-2-A, --C(O)-A, or --(CH.sub.2).sub.0-1-A, wherein A is
selected from aryl and heteroaryl, said heteroaryl being a
monovalent aromatic carbocyclic radical having one or two rings
incorporating one, two, or three heteroatoms chosen from nitrogen,
oxygen, or sulfur, and said aryl and heteroaryl are each
independently in each occurrence optionally substituted with one or
more groups selected from hydroxy, cyano, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, thio-C.sub.1-6-alkyl, halo, halo-C.sub.1-6-alkyl,
hydroxy-C.sub.1-6-alkyl, nitro, C.sub.1-6-alkoxycarbonyl,
C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkylsulfonyl,
halo-C.sub.1-6-alkylsulfonyl, amino, C.sub.1-6-alkylamino,
di-C.sub.1-6-alkylamino, C.sub.1-6-alkylaminocarbon- yl,
C.sub.1-6-alkylcarbonylamino, C.sub.1-6-alkylaminosulfonyl, and
C.sub.1-6-alkylsulfonylamino; R.sup.2 is selected from hydrogen,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, and C.sub.1-6-alkylthio; R.sup.3
is selected from hydrogen and C.sub.1-6-alkyl; R.sup.4 is selected
from hydrogen, halogen, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6alkylthio, halo-C.sub.1-6-alkyl, cyano, and
C.sub.1-6-alkylcarbonyl; and one of R.sup.5, R.sup.6 or R.sup.7 is
a group of general Formula B, wherein W is a --CH-- group, and
R.sup.8, R.sup.9 and R.sup.10 are each independently selected from
hydrogen, C.sub.1-10-alkyl and benzyl; 53and the others are each
independently of each other selected from hydrogen, halogen,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6alkylthio, haloalkyl,
cyano, and C.sub.1-6-alkylcarbonyl; or individual isomers, racemic
or non racemic mixtures of isomers, prodrugs, or pharmaceutically
acceptable salts or solvates thereof.
65. The compound of claim 64, wherein R.sup.1 is --SO.sub.2-A.
66. The compound of claim 65, wherein A is an aryl group.
67. The compound of claim 65, wherein A is phenyl optionally
substituted with one or more groups selected from hydroxy, cyano,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, thio-C.sub.1-6-alkyl, halo,
halo-C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl, nitro,
C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkylcarbonyl,
C.sub.1-6-alkylsulfonyl, halo-C.sub.1-6-alkylsul- fonyl, amino,
C.sub.1-6-alkylamino, di-C.sub.1-6-alkylamino,
C.sub.1-6-alkylaminocarbonyl, C.sub.1-6-alkylcarbonylamino,
C.sub.1-6-alkylaminosulfonyl, and C.sub.1-6-alkylsulfonylamino.
68. The compound of claim 64, wherein R.sup.1 is --S-A.
69. The compound of claim 64, wherein A is an aryl group.
70. The compound of claim 64, wherein A is phenyl optionally
substituted with one or more groups selected from hydroxy, cyano,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, thio-C.sub.1-6-alkyl, halo,
halo-C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl, nitro,
C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkylcarbonyl,
C.sub.1-6-alkylsulfonyl, halo-C.sub.1-6-alkylsul- fonyl, amino,
C.sub.1-6-alkylamino, di-C.sub.1-6-alkylamino,
C.sub.1-6-alkylaminocarbonyl, C.sub.1-6-alkylcarbonylamino,
C.sub.1-6-alkylaminosulfonyl, and C.sub.1-6-alkylsulfonylamino.
71. A compound of Formula I comprising: 54wherein: R.sup.1 is
--SO.sub.0-2-A, --C(O)-A, or --(CH.sub.2).sub.0-1-A, wherein A is
aryl or heteroaryl, said heteroaryl being a monovalent aromatic
carbocyclic radical having one or two rings incorporating one, two,
or three heteroatoms chosen from nitrogen, oxygen, or sulfur; said
aryl and heteroaryl are each independently in each occurrence
optionally substituted with one or more groups selected from
hydroxy, cyano, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
thio-C.sub.1-6-alkyl, halo, halo-C.sub.1-6-alkyl,
hydroxy-C.sub.1-6-alkyl, nitro, C.sub.1-6-alkoxycarbonyl,
C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkylsulfonyl,
halo-C.sub.1-6-alkylsulfonyl, amino, C.sub.1-6-alkylamino,
di-C.sub.1-6-alkylamino, C.sub.1-6-alkylaminocarbon- yl,
C.sub.1-6-alkylcarbonylamino, C.sub.1-6-alkylaminosulfonyl, and
C.sub.1-6-alkylsulfonylamino; R.sup.2 is selected from hydrogen,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, and C.sub.1-6-alkylthio; R.sup.3
is selected from hydrogen and C.sub.1-6-alkyl; R.sup.7 is a group
of general Formula B, wherein W is a --CH-- group, and R.sup.8,
R.sup.9 and R.sup.10 are each independently selected from hydrogen
and C.sub.1-C.sub.10-alkyl; 55and R.sup.4, R.sup.5 and R.sup.6 are
each independently of each other selected from hydrogen, halogen,
C.sub.1-6-alkyl, C.sub.1-6alkylthio, halo-C.sub.1-6-alkyl, cyano,
and C.sub.1-6-alkylcarbonyl; or individual isomers, racemic or non
racemic mixtures of isomers, prodrugs, or pharmaceutically
acceptable salts or solvates thereof.
72. The compound of claim 71, wherein R.sup.1 is --SO.sub.2-A.
73. The compound of claim 72, wherein A is aryl, optionally
substituted with one or more groups selected from hydroxy, cyano,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, thio-C.sub.1-6-alkyl, halo,
halo-C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl, nitro,
C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkylcarbonyl,
C.sub.1-6-alkylsulfonyl, halo-C.sub.1-6-alkylsul- fonyl, amino,
C.sub.1-6-alkylamino, di-C.sub.1-6-alkylamino,
C.sub.1-6-alkylaminocarbonyl, C.sub.1-6-alkylcarbonylamino,
C.sub.1-6-alkylaminosulfonyl, and C.sub.1-6-alkylsulfonylamino.
74. The compound of claim 72, wherein A is phenyl optionally
substituted with one or more groups selected from hydroxy, cyano,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, thio-C.sub.1-6-alkyl, halo,
halo-C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl, nitro,
C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkylcarbonyl,
C.sub.1-6-alkylsulfonyl, halo-C.sub.1-6-alkylsul- fonyl, amino,
C.sub.1-6-alkylamino, di-C.sub.1-6-alkylamino,
C.sub.1-6-alkylaminocarbonyl, C.sub.1-6-alkylcarbonylamino,
C.sub.1-6-alkylaminosulfonyl, and C.sub.1-6-alkylsulfonylamino.
75. The compound of claim 72, wherein A is heteroaryl, said
heteroaryl being a monovalent aromatic carbocyclic radical having
one or two rings incorporating one, two, or three heteroatoms
chosen from nitrogen, oxygen, or sulfur, said heteroaryl optionally
substituted with one or more groups selected from hydroxy, cyano,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, thio-C.sub.1-6-alkyl, halo,
halo-C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl, nitro,
C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkylcarbonyl,
C.sub.1-6-alkylsulfonyl, halo-C.sub.1-6-alkylsul- fonyl, amino,
C.sub.1-6-alkylamino, di-C.sub.1-6-alkylamino,
C.sub.1-6-alkylaminocarbonyl, C.sub.1-6-alkylcarbonylamino,
C.sub.1-6-alkylaminosulfonyl, and C.sub.1-6-alkylsulfonylamino.
76. The compound of claim 72, wherein A is pyridinyl or
benzothiazolyl, said pyridinyl or benzothiazolyl being each
independently of each other optionally substituted with one or more
groups selected from hydroxy, cyano, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, thio-C.sub.1-6-alkyl, halo, halo-C.sub.1-6-alkyl,
hydroxy-C.sub.1-6-alkyl, nitro, C.sub.1-6-alkoxycarbonyl,
C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkylsulfonyl,
halo-C.sub.1-6-alkylsulfonyl, amino, C.sub.1-6-alkylamino,
di-C.sub.1-6-alkylamino, di-C.sub.1-6-alkylaminocar- bonyl,
C.sub.1-6-alkylcarbonylamino, C.sub.1-6-alkylaminosulfonyl, and
C.sub.1-6-alkylsulfonylamino.
77. The compound of claim 71, wherein R.sup.1 is --S-A.
78. The compound of claim 77, wherein A is aryl, optionally
substituted with one or more groups selected from hydroxy, cyano,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, thio-C.sub.1-6-alkyl, halo,
halo-C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl, nitro,
C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkylcarbonyl,
C.sub.1-6-alkylsulfonyl, halo-C.sub.1-6-alkylsul- fonyl, amino,
C.sub.1-6-alkylamino, di-C.sub.1-6-alkylamino,
C.sub.1-6-alkylaminocarbonyl, C.sub.1-6-alkylcarbonylamino,
C.sub.1-6-alkylaminosulfonyl, and C.sub.1-6-alkylsulfonylamino.
79. The compound of claim 77, wherein A is phenyl optionally
substituted with one or more optionally substituted with one or
more groups selected from hydroxy, cyano, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, thio-C.sub.1-6-alkyl, halo, halo-C.sub.1-6-alkyl,
hydroxy-C.sub.1-6-alkyl- , nitro, C.sub.1-6-alkoxycarbonyl,
C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkylsulfonyl,
halo-C.sub.1-6-alkylsulfonyl, amino, C.sub.1-6-alkylamino,
di-C.sub.1-6-alkylamino, C.sub.1-6-alkylaminocarbon- yl,
C.sub.1-6-alkylcarbonylamino, C.sub.1-6-alkylaminosulfonyl, and
C.sub.1-6-alkylsulfonylamino.
80. A compound of Formula I comprising: 56wherein: R.sup.1 is
--S(O).sub.0-2-A, --C(O)-A, or --(CH.sub.2).sub.0-1-A, wherein A is
aryl or heteroaryl, said heteroaryl being a monovalent aromatic
carbocyclic radical having one or two rings incorporating one, two,
or three heteroatoms chosen from nitrogen, oxygen, or sulfur; and
said aryl and heteroaryl are each independently of each other in
each occurrence optionally substituted with one or more groups
selected from hydroxy, cyano, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
thio-C.sub.1-6-alkyl, halo, halo-C.sub.1-6-alkyl,
hydroxy-C.sub.1-6-alkyl, nitro, C.sub.1-6-alkoxycarbonyl,
C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkylsulfonyl,
halo-C.sub.1-6-alkylsulfonyl, amino, C.sub.1-6-alkylamino,
di-C.sub.1-6-alkylamino, C.sub.1-6-alkylaminocarbon- yl,
C.sub.1-6-alkylcarbonylamino, C.sub.1-6-alkylaminosulfonyl, and
C.sub.1-6-alkylsulfonylamino; R.sup.2 is selected from hydrogen,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, and C.sub.1-6-alkylthio; R.sup.3
is selected from hydrogen and C.sub.1-6-alkyl; R.sup.5 is a group
of general formula B, wherein W is a --CH-- group, and R.sup.8,
R.sup.9 and R.sup.10 are each independently selected from hydrogen
and C.sub.1-10-alkyl; 57and R.sup.4, R.sup.6 and R.sup.7 are each
independently of each other selected from hydrogen, halogen,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6alkylthio,
haloC.sub.1-6-alkyl, cyano, and C.sub.1-6-alkylcarbonyl; or
individual isomers, racemic or non racemic mixtures of isomers,
prodrugs, or pharmaceutically acceptable salts or solvates
thereof.
81. The compound of claim 80, wherein R.sup.1 is --SO.sub.2-A.
82. The compound of claim 81, wherein A is aryl.
83. The compound of claim 81, wherein A is phenyl optionally
substituted with one or more optionally substituted with one or
more groups selected from hydroxy, cyano, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, thio-C.sub.1-6-alkyl, halo, halo-C.sub.1-6-alkyl,
hydroxy-C.sub.1-6-alkyl- , nitro, C.sub.1-6-alkoxycarbonyl,
C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkylsulfonyl,
halo-C.sub.1-6-alkylsulfonyl, amino, C.sub.1-6-alkylamino,
di-C.sub.1-6-alkylamino, C.sub.1-6-alkylaminocarbon- yl,
C.sub.1-6-alkylcarbonylamino, C.sub.1-6-alkylaminosulfonyl, and
C.sub.1-6-alkylsulfonylamino.
84. The compound of claim 80, wherein R.sup.1 is --S-A.
85. The compound of claim 84, wherein A is aryl, optionally
substituted with one or more groups selected from hydroxy, cyano,
C.sub.1-6-alkyl, C.sub.1-6alkoxy, thio-C.sub.1-6-alkyl, halo,
halo-C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl, nitro,
C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkylcarbonyl,
C.sub.1-6-alkylsulfonyl, halo-C.sub.1-6-alkylsul- fonyl, amino,
C.sub.1-6-alkylamino, di-C.sub.1-6-alkylamino,
C.sub.1-6-alkylaminocarbonyl, C.sub.1-6-alkylcarbonylamino,
C.sub.1-6-alkylaminosulfonyl, and C.sub.1-6-alkylsulfonylamino.
86. The compound of claim 84, wherein A is phenyl optionally
substituted with one or more groups selected from hydroxy, cyano,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, thio-C.sub.1-6-alkyl, halo,
halo-C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl, nitro,
C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkylcarbonyl,
C.sub.1-6-alkylsulfonyl, halo-C.sub.1-6-alkylsul- fonyl, amino,
C.sub.1-6-alkylamino, di-C.sub.1-6-alkylamino,
C.sub.1-6-alkylaminocarbonyl, C.sub.1-6-alkylcarbonylamino,
C.sub.1-6-alkylaminosulfonyl, and C.sub.1-6-alkylsulfonylamino.
87. The compound of claim 82, wherein R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 are hydrogen.
88. The compound of claim 87, wherein A is phenyl optionally
substituted with one or more groups selected from hydroxy, cyano,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, thio-C.sub.1-6-alkyl, halo,
halo-C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl, nitro,
C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkylcarbonyl,
C.sub.1-6-alkylsulfonyl, halo-C.sub.1-6-alkylsul- fonyl, amino,
C.sub.1-6-alkylamino, di-C.sub.1-6-alkylamino,
C.sub.1-6-alkylaminocarbonyl, C.sub.1-6-alkylcarbonylamino,
C.sub.1-6-alkylaminosulfonyl, and C.sub.1-6-alkylsulfonylamino.
89. A pharmaceutical composition comprising a therapeutically
effective amount of at least one compound of claim 64 in admixture
with at least one pharmaceutically acceptable carrier.
90. A method of treating a subject that has a disease state
selected from schizophrenia, depression, memory disorders,
attention deficit disorder, and Alzheimer's disease, wherein said
method comprises administering to said subject a therapeutically
effective amount of the compound of claim 64.
91. A method for treating a subject that has a disorder of the
gastrointestinal tract, said method comprising administering to
said subject a therapeutically effective amount of the compound of
claim 64.
92. A process for preparing a compound as claimed in claim 64, said
process comprising i) reacting a compound having a general Formula
4 58wherein P is a protecting group and W, R.sup.2, R.sup.4,
R.sup.9 and R.sup.10 are as recited in claim 34, with a compound of
general formula (A-S).sub.2, wherein A is aryl or heteroaryl'ii)
optionally alkylating the nitrogen of the indole group, iii)
removing the protecting group P; to provide a compound of Formula
I, 59wherein R is hydrogen, and A, W, R.sup.2, R.sup.3, R.sup.4,
R.sup.9, and R.sup.10 are as recited in claim 34, and iv)
optionally alkylating to provide a compound of the general Formula
I, wherein R.sup.8 is C.sub.1-10-alkyl, and A, W, R.sup.2, R.sup.3,
R.sup.4, R.sup.9, and R.sup.10 are as recited in claim 64.
93. A process for preparing a compound as claimed in claim 64 which
comprises i) reacting a compound having a general Formula 4
60wherein P is a protecting group and W, R.sup.2, R.sup.4, R.sup.9
and R.sup.10 are as recited in claim 64; with a compound of general
formula (A-S).sub.2, wherein A is aryl or heteroaryl, to provide an
adduct 4a 61ii) oxidizing the sulfur atom of 4a; iii) optionally
alkylating the nitrogen of the indole group of oxidized 4a; iv)
removing of the protecting group P; to provide a compound of
Formula I, 62wherein R.sup.8 is hydrogen, and W, A, R.sup.2,
R.sup.3, R.sup.4, R.sup.9, and R.sup.10 are as recited in claim 34,
and v) optionally alkylating to provide a compound of the general
Formula I, wherein R.sup.8 is C.sub.1-10-alkyl, and W, A, R.sup.2,
R.sup.3, R.sup.4, R.sup.9, and R.sup.10 are as recited in claim 34.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] Pursuant to 35 U.S.C. .sctn.119(e), this application claims
priority to the filing dates of the U.S. Provisional Patent
Application Ser. No. 60/296,705, filed Jun. 7, 2001, and Ser. No.
60/340,212, filed Dec. 13, 2001, which are incorporated herein by
reference in their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to new indole derivatives with 5-HT6
receptor affinity, and associated pharmaceutical compositions,
methods for use as therapeutic agents, and methods of preparation
thereof.
BACKGROUND OF THE INVENTION
[0003] The actions of the neurotransmitter 5-hydroxytryptamine
(5-HT) as a major modulatory neurotransmitter in the brain, are
mediated through a number of receptor families termed 5-HT1, 5-HT2,
5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. Based on a high level of
5-HT6 receptor mRNA in the brain, it has been stated that the 5-HT6
receptor may play a role in the pathology and treatment of central
nervous system disorders. In particular, 5-HT6 selective ligands
have been identified as potentially useful in the treatment of
certain CNS disorders such as Parkinson's disease, Huntington's
disease, anxiety, depression, manic depression, psychoses,
epilepsy, obsessive compulsive disorders, migraine, Alzheimer's
disease (enhancement of cognitive memory), sleep disorders, feeding
disorders such as anorexia and bulimia, panic attacks, attention
deficit hyperactivity disorder (ADHD), attention deficit disorder
(ADD), withdrawal from drug abuse such as cocaine, ethanol,
nicotine and benzodiazepines, schizophrenia, and also disorders
associated with spinal trauma and/or head injury such as
hydrocephalus. Such compounds are also expected to be of use in the
treatment of certain gastrointestinal (GI) disorders such as
functional bowel disorder. (See for ex. B. L. Roth et al., J.
Pharmacol. Exp. Ther., 1994, 268, pages 1403-14120, D. R. Sibley et
al., Mol. Pharmacol., 1993, 43, 320-327, A. J. Sleight et al.,
Neurotransmission, 1995, 11, 1-5, and A. J. Sleight et al.
Serotonin ID Research Alert, 1997, 2 (3), 115-8). Furthermore, the
effect of 5-HT6 antagonist and 5-HT6 antisense aligonucleotides to
reduce food intake in rats has been reported (Br J Pharmac. 1999
Suppl 126, page 66 and J Psychopharmacol Suppl A64 1997, page
255).
SUMMARY OF THE INVENTION
[0004] This invention relates to compounds comprising Formula I:
2
[0005] wherein:
[0006] R.sup.1 is --S(O).sub.0-2-A, --C(O)-A, or
--(CH.sub.2).sub.0-1-A, wherein A is aryl or heteroaryl, and said
aryl or heteroaryl are each independently in each occurrence
optionally substituted with one or more groups selected from
hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo,
haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, alkylcarbonyl,
alkylsulfonyl, haloalkylsulfonyl, amino, alkylamino, dialkylamino,
alkylaminocarbonyl, alkylcarbonylamino, alkylaminosulfonyl, and
alkylsulfonylamino;
[0007] R.sup.2 is selected from hydrogen, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, and C.sub.1-6-alkylthio;
[0008] R.sup.3 is selected from hydrogen and C.sub.1-6-alkyl;
[0009] R.sup.4 is selected from hydrogen, halogen, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, C.sub.1-6-alkylthio, haloalkyl, cyano, and
alkylcarbonyl; and
[0010] one of R.sup.5, R.sup.6 or R.sup.7 is a group of general
Formula B, wherein W is a --CH-- group or a nitrogen atom, and
R.sup.8, R.sup.9 and R.sup.10 are each independently selected from
hydrogen, C.sub.1-10-alkyl and benzyl, or R.sup.8 and R.sup.9
together may form a C.sub.3-C.sub.4 alkylene; 3
[0011] and the others are each independently in each occurrence
selected from hydrogen, halogen, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6alkylthio, haloalkyl, cyano, and alkylcarbonyl;
[0012] or individual isomers, racemic or non racemic mixtures of
isomers, prodrugs, or pharmaceutically acceptable salts or solvates
thereof.
[0013] In another aspect, the invention relates to pharmaceutical
compositions containing a therapeutically effective amount of at
least one compound of Formula I, or individual isomers, racemic or
non-racemic mixtures of isomers, or pharmaceutically acceptable
salts or solvates thereof, in admixture with at least one suitable
carrier.
[0014] In another aspect, this invention relates to a method of
treatment of a disease in a mammal treatable by administration of a
compound of Formula I having a selective affinity for the 5-HT6
receptor, in particular a method of treatment in a subject having a
disease state comprising Alzheimer's disease, central nervous
disorders, such as for example, psychoses, schizophrenia, manic
depressions, neurological disorders, Parkinson's disease,
amyotrophic lateral sclerosis and Huntington's disease. In another
aspect, this invention relates to a method of treatment in a
subject having a gastrointestinal disease comprising irritable
bowel syndrome (IBS).
[0015] In another aspect, the invention relates to a process which
comprises:
[0016] i) reacting a compound having a general Formula 4 4
[0017] wherein P is a protecting group and R.sup.2, R.sup.4,
R.sup.9, and R.sup.10 are as defined herein, with a compound of
general formula (A-S).sub.2, wherein A is aryl or heteroaryl, to
provide an adduct 4a 5
[0018] ii) oxidation of the sulfur atom of 4a;
[0019] iii) optional alkylation of the nitrogen of the indole group
of oxidized 4a; and
[0020] iv) removal of the protecting group P;
[0021] to provide a compound of the general Formula I, 6
[0022] wherein R.sup.8 is hydrogen, and A, R.sup.2, R.sup.3,
R.sup.4, R.sup.9, and R.sup.10 are as defined in the summary of the
invention, and
[0023] v) optional alkylation of the nitrogen of the piperazine or
piperidine group; to provide a compound of the general Formula I,
wherein R.sup.8 is C.sub.1-10-alkyl, and A, R.sup.2, R.sup.3, is
R.sup.4, R.sup.9, and R.sup.10 are as defined in the Summary of the
Invention.
[0024] In another embodiment, the invention further relates to a
process which comprises:
[0025] i) reacting a compound having a general Formula 4 7
[0026] wherein P is a protecting group and R.sup.2, R.sup.4,
R.sup.9 and R.sup.10 are as defined herein, with a compound of
general formula (A-S).sub.2, wherein A is aryl or heteroaryl,
[0027] ii) optional alkylation of the nitrogen of the indole
group,
[0028] iii) removing the protecting group P;
[0029] to provide a compound of the general Formula I, 8
[0030] wherein R.sup.8 is hydrogen, and A, R.sup.2, R.sup.3,
R.sup.4, R.sup.9, and R.sup.10 are as defined in the summary of the
invention, and
[0031] iv) optional alkylation of the nitrogen of the piperazine or
piperidine group to provide a compound of the general Formula I,
wherein R.sup.8 is C.sub.1-10-alkyl, and A, R.sup.2, R.sup.3,
R.sup.4, R.sup.9, and R.sup.10 are as defined in the Summary of the
Invention.
[0032] In another embodiment, the invention further relates to a
process which comprises:
[0033] i) reacting a 1-halo-2-nitrobenzene with a
halomethanesulfonyl benzene to provide a
1-benzenesulfonylmethyl-2-nitrobenzene;
[0034] ii) amination of the 1-benzenesulfonylmethyl-2-nitrobenzene
with a 1-alkylpiperazine to provide a piperazinylated
nitrobenzene;
[0035] iii) reduction of the nitro group of the piperazinylated
nitrobenzene, and
[0036] iv) addition of an orthoformate, followed by cyclization to
yield a compound of Formula 18a, 9
[0037] wherein R.sup.6 is C.sub.1-10-alkyl and A, R.sup.9, and
R.sup.10 are as defined in the summary of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0038] Definitions
[0039] Unless otherwise stated, the following terms used in this
Application, including the specification and claims, have the
definitions given below. It must be noted that, as used in the
specification and the appended claims, the singular forms "a",
"an," and "the" include plural referents unless the context clearly
dictates otherwise.
[0040] "Alkyl" means a monovalent linear or branched saturated
hydrocarbon radical, consisting solely of carbon and hydrogen
atoms, having from one to twelve carbon atoms inclusive, unless
otherwise indicated. Examples of alkyl radicals include, but are
not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,
sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the
like. "Alkyl" also means a cyclic or a combination of linear or
branched, and cyclic saturated hydrocarbon radical consisting
solely of carbon and hydrogen atoms, having from one to twelve
carbon atoms inclusive, unless otherwise indicated. Examples of
such alkyl radicals include but are not limited to, cyclopropyl,
cyclopropylmethyl, cyclohexyl, cyclopropylethyl and the like.
[0041] "Lower alkyl" means a monovalent linear or branched
saturated hydrocarbon radical, consisting solely of carbon and
hydrogen atoms, having from one to six carbon atoms inclusive,
unless otherwise indicated. Examples of lower alkyl radicals
include, but are not limited to, methyl, ethyl, propyl, isopropyl,
sec-butyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, and the
like.
[0042] "Alkylene" means a divalent linear or branched saturated
hydrocarbon radical, consisting solely of carbon and hydrogen
atoms, having from one to six carbons inclusive, unless otherwise
indicated. Examples of alkylene radicals include, but are not
limited to, methylene, ethylene, propylene, 2-methyl-propylene,
butylene, 2-ethylbutylene, and the like.
[0043] "Alkoxy" means a radical --O--R, wherein R is a lower alkyl
radical as defined herein. Examples of alkoxy radicals include, but
are not limited to, methoxy, ethoxy, isopropoxy, and the like.
[0044] "Alkylthio" or "alkylsulfanyl" means a radical --SR, wherein
R is a lower alkyl radical as defined herein. Examples of alkylthio
radicals include, but are not limited to, methylthio, butylthio,
and the like.
[0045] "Alkylsulfonyl" means a radical --SO.sub.2R, wherein R is a
lower alkyl radical as defined herein. Examples of alkylsulfonyl
radicals include, but are not limited to, methylsulfonyl,
ethylsulfonyl, and the like.
[0046] "Aryl" means a monovalent cyclic aromatic hydrocarbon
radical consisting of one or more fused rings in which at least one
ring is aromatic in nature, which can optionally be substituted
with hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo,
haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino,
dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl,
sulfonylamino, and/or trifluoromethyl, unless otherwise indicated.
Examples of aryl radicals include, but are not limited to, phenyl,
naphthyl, biphenyl, indanyl, anthraquinolyl, and the like. Examples
of substituted aryl radicals is include but are not limited to
fluorophenyl, chlorophenyl, dichlorophenyl, trifluoromethylphenyl,
tolyl, and the like.
[0047] "Heteroaryl" means a monovalent aromatic carbocyclic radical
having one or more rings incorporating one, two, or three
heteroatoms within the ring (chosen from nitrogen, oxygen, or
sulfur) which can optionally be substituted with hydroxy, cyano,
lower alkyl, lower alkoxy, thioalkyl, halo, haloalkyl,
hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino,
dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl,
sulfonylamino and/or trifluoromethyl, unless otherwise indicated.
Examples of heteroaryl radicals include, but are not limited to,
imidazolyl, oxazolyl, thiazolyl, pyrazinyl, thiophenyl, furanyl,
pyranyl, pyridinyl, quinolinyl, isoquinolinyl, benzofuryl,
benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl,
benzothiazolyl, benzopyranyl, indazolyl, indolyl, isoindolyl,
naphtyridinyl, and the like.
[0048] "Leaving group" means the group with the meaning
conventionally associated with it in synthetic organic chemistry,
i.e., an atom or group displaceable under alkylating conditions.
Examples of leaving groups include, but are not limited to,
halogen, alkyl- or arylsulfonyloxy, such as methanesulfonyloxy,
ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and
thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy,
isopropyloxy, acyloxy, and the like.
[0049] "Amino-protecting group" means the protecting group that
refers to those organic groups intended to protect the nitrogen
atom against undesirable reactions during synthetic procedures and
includes, but is not limited to, benzyl (Bnz), benzyloxycarbonyl
(carbobenzyloxy, Cbz), p-methoxybenzyloxycarbonyl,
p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (Boc),
trifluoroacetyl, and the like. It is preferred to use either Boc or
Cbz as the amino-protecting group because of the relative ease of
removal, for example by acids in the case of Boc, e.g.,
trifluoroacetic acid or hydrochloric acid in ethyl acetate; or by
catalytic hydrogenation in the case of Cbz.
[0050] "Optional" or "optionally" means that the subsequently
described event or circumstance may but need not occur, and that
the description includes instances where the event or circumstance
occurs and instances in which it does not. For example, "optional
bond" means that the bond may or may not be present, and that the
description includes single, double, or triple bonds.
[0051] "Protective group" or "protecting group" means the group
which selectively blocks one reactive site in a multifunctional
compound such that a chemical reaction can be carried out
selectively at another unprotected reactive site in the meaning
conventionally associated with it in synthetic chemistry. Certain
processes of this invention rely upon the protective groups to
block reactive oxygen atoms present in the reactants. Acceptable
protective groups for alcoholic or phenolic hydroxyl groups, which
may be removed successively and selectively includes groups
protected as acetates, haloalkyl carbonates, benzyl ethers,
alkylsilyl ethers, heterocyclyl ethers, and methyl or alkyl ethers,
and the like. Protective or blocking groups for carboxyl groups are
similar to those described for hydroxyl groups, preferably
tert-butyl, benzyl or methyl esters.
[0052] "Inert organic solvent" or "inert solvent" means the solvent
is inert under the conditions of the reaction being described in
conjunction therewith, including for example, benzene, toluene,
acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform,
methylene chloride or dichloromethane, dichloroethane, diethyl
ether, ethyl acetate, acetone, methyl ethyl ketone, methanol,
ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine,
and the like. Unless specified to the contrary, the solvents used
in the reactions of the present invention are inert solvents.
[0053] "Pharmaceutically acceptable" means that which is useful in
preparing a pharmaceutical composition that is generally safe,
non-toxic, and neither biologically nor otherwise undesirable and
includes that which is acceptable for veterinary as well as human
pharmaceutical use.
[0054] "Pharmaceutically acceptable salts" of a compound means
salts that are pharmaceutically acceptable, as defined herein, and
that possess the desired pharmacological activity of the parent
compound. Such salts include:
[0055] (1) acid addition salts formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or formed with organic acids such as
acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic
acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic
acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphtoic
acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic
acid, malonic acid, mandelic acid, methanesulfonic acid, muconic
acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid,
succinic acid, tartaric acid, p-toluenesulfonic acid,
trimethylacetic acid, trifluoroacetic acid, and the like; or
[0056] (2) salts formed when an acidic proton present in the parent
compound either is replaced by a metal ion, e.g., an alkali metal
ion, an alkaline earth ion, or an aluminum ion; or coordinates with
an organic or inorganic base. Acceptable organic bases include
diethanolamine, ethanolamine, N-methylglucamine, triethanolamine,
tromethamine, and the like. Acceptable inorganic bases include
aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium
carbonate and sodium hydroxide.
[0057] The preferred pharmaceutically acceptable salts are the
salts formed from acetic acid, trifluoroacetic acid, hydrochloric
acid, sulphuric acid, methanesulfonic acid, maleic acid, phosphoric
acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc,
and magnesium.
[0058] It should be understood that all references to
pharmaceutically acceptable salts include solvent addition forms
(solvates) or crystal forms (polymorphs) as defined herein, of the
same acid addition salt.
[0059] "Solvates" means solvent addition forms that contain either
stoichiometric or non stoichiometric amounts of solvent. Some
compounds have a tendency to trap a fixed molar ratio of solvent
molecules in the crystalline solid state, thus forming a solvate.
If the solvent is water the solvate formed is a hydrate, when the
solvent is alcohol, the solvate formed is an alcoholate. Hydrates
are formed by the combination of one or more molecules of water
with one of the substances in which the water retains its molecular
state as H.sub.2O, such combination being able to form one or more
hydrate.
[0060] "Prodrug" or "pro-drug" means a pharmacologically inactive
form of a compound which must be metabolized in vivo, e.g., by
biological fluids or enzymes, by a subject after administration
into a pharmacologically active form of the compound in order to
produce the desired pharmacological effect. Prodrugs of a compound
of Formula I are prepared by modifying one or more functional
group(s) present in the compound of Formula I in such a way that
the modification(s) may be cleaved in vivo to release the parent
compound. Prodrugs include compounds of Formula I wherein a
hydroxy, amino, sulfhydryl, carboxy or carbonyl group in a compound
of Formula I is bonded to any group that may be cleaved in vivo to
regenerate the free hydroxyl, amino, sulfhydryl, carboxy or
carbonyl group respectively. Examples of prodrugs include, but are
not limited to, esters (e.g. acetate, dialkylaminoacetates,
formates, phosphates, sulfates and benzoate derivatives) and
carbamates of hydroxy functional groups (e.g.
N,N-dimethylcarbonyl), esters of carboxyl functional groups (e.g.
ethyl esters, morpholinoethanol esters), N-acyl derivatives (e.g.
N-acetyl), N-Mannich bases, Schiff bases and enaminones of amino
functional groups, oximes, acetals, ketals, and enol esters of
ketones and aldehyde functional groups in compounds of Formula I,
and the like.
[0061] The prodrug can be metabolized before absorption, during
absorption, after absorption, or at a specific site. Although
metabolism occurs for many compounds primarily in the liver, almost
all other tissues and organs, especially the lung, are able to
carry out varying degrees of metabolism. Prodrug forms of compounds
may be utilized, for example, to improve bioavailability, improve
subject acceptability such as by masking or reducing unpleasant
characteristics such as bitter taste or gastrointestinal
irritability, alter solubility such as for intravenous use, provide
for prolonged or sustained release or delivery, improve ease of
formulation, or provide site-specific delivery of the compound.
Reference to a compound herein includes prodrug forms of a
compound. Prodrugs are described in The Organic Chemistry of Drug
Design and Drug Action, by Richard B. Silverman, Academic Press,
San Diego, 1992. Chapter 8: "Prodrugs and Drug delivery Systems"
pp. 352-401; Design of Prodrugs, edited by H. Bundgaard, Elsevier
Science, Amsterdam, 1985; Design of Biopharmaceutical Properties
through Prodrugs and Analogs, Ed. by E. B. Roche, American
Pharmaceutical Association, Washington, 1977; and Drug Delivery
Systems, ed. by R. L. Juliano, Oxford Univ. Press, Oxford,
1980.
[0062] "Subject" means mammals and non-mammals. Mammals means any
member of the Mammalia class including, but not limited to, humans;
non-human primates such as chimpanzees and other apes and monkey
species; farm animals such as cattle, horses, sheep, goats, and
swine; domestic animals such as rabbits, dogs, and cats; laboratory
animals including rodents, such as rats, mice, and guinea pigs; and
the like. Examples of non-mammals include, but are not limited to,
birds, and the like. The term "subject" does not denote a
particular age or sex.
[0063] "Therapeutically effective amount" means an amount of a
compound that, when administered to a subject for treating a
disease state, is sufficient to effect such treatment for the
disease state. The "therapeutically effective amount" will vary
depending on the compound, disease state being treated, the
severity or the disease treated, the age and relative health of the
subject, the route and form of administration, the judgement of the
attending medical or veterinary practitioner, and other
factors.
[0064] "Disease state" means any disease, condition, symptom, or
indication.
[0065] Throughout the application the following abbreviations are
used with the following meaning:
1 Alk Alkyl group Boc N-tert-butoxycarbonyl m-CPBA
m-Chloroperbenzoic acid DTB Di-tert-butyldicarbonate DMF
N,N-Dimethylformamide DMFDMA N,N-dimethylformamide dimethyl acetal
DMSO Dimethylsulfoxide L Leaving group Oxone .TM. Potassium
peroxymonosulfate P Protective group TFA Trifluoroacetic acid THF
Tetrahydrofuran
[0066] Nomenclature
[0067] In general, the nomenclature used in this Application is
based on AUTONOM.TM. v.4.0, a Beilstein Institute computerized
system for the generation of IUPAC systematic nomenclature.
However, because a strict adherence to these recommendations would
result in the names changing substantially when only a single
substituent is changed, compounds have been named in a manner that
maintains consistency of nomenclature for the basic structure of
the molecule.
[0068] For example, a compound of Formula I wherein R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are hydrogen, R.sup.1 is
phenylsulfonyl, and R.sup.7 is piperazinyl is named
3-benzenesulfonyl-7-piperazin-1-yl-1H-ind- ole.
[0069] Preferred Compounds
[0070] While the broadest definition of this invention is set forth
in the Summary of the Invention certain compounds of Formula I, or
individual isomers, racemic or non-racemic mixtures of isomers, or
pharmaceutically acceptable salts or solvates thereof, are
preferred:
[0071] R.sup.1 is --S(O).sub.0-2-A, wherein A is aryl or
heteroaryl. Other preferred compounds are those wherein R.sup.1 is
preferably --S(O).sub.0-2-A, wherein A is phenyl optionally
substituted with one or more substituents selected from
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halogen and haloalkyl. Other
preferred compounds are those wherein R.sup.1 is preferably
--S(O).sub.2-A, wherein A is phenyl optionally substituted with one
or more substituents selected from C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, halogen and haloalkyl. Other preferred compounds
are those wherein R.sup.1 is preferably --S-A, wherein A is phenyl
optionally substituted with one or more substituents selected from
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halogen and haloalkyl.
[0072] In another preferred embodiment R.sup.1 is preferably
--S(O).sub.0-2-A, wherein A is heteroaryl, more preferably
R.sup.1--S(O).sub.2-A, wherein A is pyridinyl or
benzothiazolyl.
[0073] R.sup.2 and R.sup.3 are preferably hydrogen or
C.sub.1-6-alkyl.
[0074] R.sup.4 is preferably hydrogen.
[0075] R.sup.8 is preferably hydrogen or C.sub.1-10-alkyl, and
R.sup.9 and R.sup.10 are preferably hydrogen.
[0076] In a preferred embodiment R.sup.7 is a piperazinyl group of
general Formula B, wherein W is a nitrogen atom, and R.sup.5 and
R.sup.6 are hydrogen.
[0077] In another preferred embodiment R.sup.5 is a piperazinyl
group of general Formula B, wherein W is a nitrogen atom, and
R.sup.5 and R.sup.6 are hydrogen.
[0078] Exemplary particularly preferred compounds, or individual
isomers, racemic or non-racemic mixtures of isomers, or
pharmaceutically acceptable salts or solvates thereof,
comprise:
[0079] 3-benzenesulfonyl-7-piperazin-1-yl-1H-indole;
[0080] 3-benzenesulfonyl-1-methyl-7-piperazin-1-yl-1H-indole;
[0081] 3-benzenesulfonyl-2-methyl-7-piperazin-1-yl-1H-indole;
[0082]
3-(4-chlorobenzenesulfonyl)-2-methyl-7-piperazin-1-yl-1H-indole;
[0083]
3-(4-methoxybenzenesulfonyl)-2-methyl-7-piperazin-1-yl-1H-indole;
[0084] 3-benzenesulfonyl-5-piperazin-1-yl-1H-indole;
[0085] 7-piperazin-1-yl-3-(pyridine-4-sulfonyl)-1H-indole;
[0086] 7-piperazin-1-yl-3-(pyridine-2-sulfonyl)-1H-indole;
[0087]
1-methyl-7-piperazin-1-yl-3-(pyridine-2-sulfonyl)-1H-indole;
[0088] 3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)-1H-indole;
[0089] 3-benzenesulfonyl-1-methyl-5-piperazin-1-yl-1H-indole;
[0090]
3-(3,4-dichloro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole;
[0091] 2-(7-piperazin-1-yl-1H-indole-3-sulfonyl)-benzothiazole;
[0092]
3-(4-fluoro-benzenesulfonyl)-2-methyl-7-piperazin-1-yl-1H-indole;
[0093] 3-(4-fluoro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole;
[0094] 3-benzenesulfonyl-7-piperidin-4-yl-1H-indole;
[0095] 7-piperazin-1-yl-3-(toluene-4-sulfonyl)-1H-indole;
[0096]
3-(3,5-dichloro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole;
[0097] 3-(3-chloro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole;
[0098] 3-(2-chloro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole;
[0099]
7-piperazin-1-yl-3-(2-trifluoromethyl-benzenesulfonyl)-1H-indole;
[0100]
1-methyl-7-piperazin-1-yl-3-(2-trifluoromethyl-benzenesulfonyl)-1H--
indole;
[0101]
3-(4-fluoro-benzenesulfonyl)-1-methyl-7-piperazin-1-yl-1H-indole;
[0102]
1-methyl-7-piperazin-1-yl-3-(pyridine-2-sulfonyl)-1H-indole;
[0103]
1-methyl-7-piperazin-1-yl-3-(3-trifluoromethyl-benzenesulfonyl)-1H--
indole;
[0104]
3-(2-chloro-benzenesulfonyl)-1-methyl-7-piperazin-1-yl-1H-indole;
[0105]
3-(3-chloro-benzenesulfonyl)-1-methyl-7-piperazin-1-yl-1H-indole;
[0106]
3-benzenesulfonyl-1-methyl-7-(4-methyl-piperazin-1-yl)-1H-indole;
[0107]
3-(2,3-dichloro-phenylsulfanyl)-5-piperazin-1-yl-1H-indole;
[0108]
3-(2,3-dichloro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole;
[0109]
3-(2,3-dichloro-benzenesulfonyl)-1-methyl-5-piperazin-1-yl-1H-indol-
e;
[0110]
1-methyl-5-piperazin-1-yl-3-(3-trifluoromethyl-benzenesulfonyl)-1H--
indole;
[0111]
5-piperazin-1-yl-3-(4-trifluoromethyl-benzenesulfonyl)-1H-indole;
[0112] 3-(4-chloro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole;
[0113]
3-(3,5-dichloro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole;
[0114]
3-(3,5-dichloro-benzenesulfonyl)-1-methyl-5-piperazin-1-yl-1H-indol-
e;
[0115] 3-phenylsulfanyl-5-piperazin-1-yl-1H-indole;
[0116] 3-(2-chloro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole;
[0117] 3-(4-fluoro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole;
[0118]
3-(4-fluoro-benzenesulfonyl)-1-methyl-5-piperazin-1-yl-1H-indole;
[0119]
3-(2-chloro-benzenesulfonyl)-1-methyl-5-piperazin-1-yl-1H-indole;
[0120]
3-(3,4-dichloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-ind-
ole;
[0121]
3-(2-chloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-indole;
[0122]
3-(3-chloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-indole;
[0123]
3-(2,4-dichloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-ind-
ole;
[0124]
3-(3,5-dichloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-ind-
ole;
[0125]
7-(4-methyl-piperazin-1-yl)-3-(2-trifluoromethyl-benzenesulfonyl)-1-
H-indole; and
[0126] 3-phenylsulfanyl-7-piperazin-1-yl-1H-indole.
General Synthetic Reaction Schemes
[0127] Compounds of the present invention may be made by the
methods depicted in the illustrative synthetic reaction schemes
shown and described below.
[0128] The starting materials and reagents used in preparing these
compounds generally are either available from commercial suppliers,
such as Aldrich Chemical Co., or are prepared by methods known to
those skilled in the art following procedures set forth in
references such as Fieser and Fieser's Reagents for Organic
Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's
Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989,
Volumes 1-5 and Supplementals; and Organic Reactions, Wiley &
Sons: New York, 1991, Volumes 1-40. The following synthetic
reaction schemes are merely illustrative of some methods by which
the compounds of the present invention may be synthesized, and
various modifications to these synthetic reaction schemes may be
made and will be suggested to one skilled in the art having
referred to the disclosure contained in this Application.
[0129] The starting materials and the intermediates of the
synthetic reaction schemes may be isolated and purified if desired
using conventional techniques, including but not limited to
filtration, distillation, crystallization, chromatography, and the
like. Such materials may be characterized using conventional means,
including physical constants and spectral data.
[0130] Unless specified to the contrary, the reactions described
herein preferably take place at atmospheric pressure over a
temperature range from about -780.degree. C. to about 150.degree.
C., more preferably from about 0.degree. C. to about 125.degree.
C., and most preferably and conveniently at about room (or ambient)
temperature, e.g., about 20.degree. C. 10
[0131] Ortho-nitrotoluenes substituted with a protected piperazinyl
group on the phenyl ring can be converted to 2-unsubstituted
indoles (4a, R.sup.2 and R.sup.3.dbd.H, P is a protecting group)
via the Leimgruber-Batcho synthesis as described in Organic
Synthesis Collective Volume 7, page 34 and in Heterocycles, 22, 195
(1984). The ortho-nitrotoluene (2) is condensed with
N,N-dimethylformamide dimethyl or diethyl acetal,
tert-butoxy-bis(dimethylamino)methane, and the like in a suitable
solvent such as DMF, optionally in the presence of an added amine
such as pyrrolidine to afford the dialkylaminonitrostyrene (3).
Reduction of the nitrostyrene to the indole (4a, R.sup.2 and
R.sup.3.dbd.H) can be affected by a variety of methods such as
catalytic hydrogenation, transfer hydrogenation, or by chemical
reducing agents such as titanium trichloride, iron or zinc
metal.
[0132] 1-Protected 4-piperazinyl nitrotoluene precursors for the
Batcho-Leimgruber indole synthesis can be prepared by nucleophilic
displacement of a nitrobenzene with a leaving group such as a halo
or trifluoromethanesulfonyloxy with a suitably 1-protected
piperazine of general formula a, wherein P is a protecting group,
as described in Synthesis, 1145 (1990) for displacement of
2-trifluoromethanesulfonyloxy nitrobenzene with 1-benzylpiperazine.
Other suitable protecting groups include N-tert-butoxycarbonyl
(Boc), carbobenzyloxy (Cbz), carbethoxy, acetyl, benzoyl, and
formyl groups.
[0133] Alternatively, piperazine can be used in the displacement as
described in J. Med. Chem., 42, 4794 (1999) for the preparation of
1-(2-nitrophenyl)piperazine and the resulting nitrophenyl
piperazine can be protected by conventional methods such as by
treatment with di-tert-butyldicarbonate to afford the Boc
derivative. 11
[0134] Piperazinylindoles or piperidinylindoles can also be
prepared by the Bartoli indole synthesis which is described in
Tetrahedron Letters, 30, 2129 (1989). A suitably protected
2-piperazinyl or 2-piperidinyl nitrobenzene is treated with a vinyl
Grignard reagent in THF to afford the indole (4b) in a single step.
2-Alkyl substituted indoles, which are not available via the
Leimgruber-Batcho synthesis, can be prepared by this route.
[0135] Piperazinylindoles can also be prepared from the
corresponding aminoindole by reaction of the amino group with
bis-chloroethylamine or a suitably protected derivative thereof as
is well known in the art. For example, preparation of
7-(1-piperazinyl)indole by treatment of 7-aminoindole with
bis-chloroethylamine is described in WO 94/15919.
[0136] Piperazinylindoles can also be prepared from
ortho-nitrophenylacetonitriles as described for the preparation of
7-(4-carbethoxypiperazin-1-yl)indole in UK Patent Application GB
2097790.
[0137] Piperazinylindoles can also be prepared from the
corresponding bromoindole by Palladium-catalyzed coupling with a
suitably protected piperazine, such as Boc-piperazine (Buchwald
reaction).
[0138] Piperdinylindoles can be prepared by conversion of a
suitably protected haloindole to the lithio derivative, followed by
condensation with a suitably protected 4-piperidone, and subsequent
dehydration and reduction of the olefin. 12
[0139] 3-Aryl- or 3-heteroaryl sulfanyl indoles of general Formula
(5), wherein P is a protecting group and W is --CH-- or N, are
prepared by reaction of the indole sodium salt with an aryl or a
heteroaryl disulfide as described in Synthesis 480 (1988). Aryl or
heteroaryl disulfides are commercially available or can be easily
prepared by oxidation of the corresponding aryl or heteroaryl thiol
by means well known to those skilled in the art.
[0140] Removal of the protecting group (P) from the piperazine or
piperidine of general Formula (5) under standard conditions can
afford compounds of Formula (12).
[0141] Oxidation of the aryl or heteroaryl sulfanyl group to the
aryl or heteroaryl sulfonyl group can be accomplished with a
suitable oxidizing agent such as potassium peroxymonosulfate
(Oxone.TM.), 3-chloroperoxybenzoic acid, peracetic acid, hydrogen
peroxide, ozone and the like. It will be appreciated that with some
of these oxidizing agents oxidation of the piperazinyl nitrogen may
also occur to give the N-oxide. In these cases, reduction of the
N-oxide back to the parent piperazine of general Formula (6) can be
effected with a suitable reducing agent such as hydrogen (catalytic
hydrogenation), triphenylphosphine and the like.
[0142] Removal of the protecting group (P) from the piperazine or
piperidine of general Formula (6) is accomplished under standard
conditions, e.g., cleavage of the Boc group by treatment with a
strong acid such as trifluoroacetic in a suitable solvent such as
dichloromethane or hydrochloric acid in a suitable solvent such as
water, ethanol or ethyl acetate, to afford compounds of general
Formula (7).
[0143] 1-Substituted derivatives of general Formula (8), wherein
Alk is an alkyl group, are prepared by alkylation of the sodium
salt of the parent indole of general Formula (6) with a suitable
alkylating agent such as an alkyl halide or sulfonate in a suitable
solvent such as tetrahydrofuran or DMF, to afford compounds of
general Formula (9).
[0144] Coupling of compounds of general Formula (7) or (9) with a
carboxyaldehyde under reductive amination conditions can afford
compounds (10) or (11) respectively, wherein R.sup.8 is
C.sub.1-10-alkyl group. 13
[0145] Nitrobenzenes of formula 14 can be prepared from
nitrobenzenes of formula 13, with a halomethane derivative such as
halomethanesulfonyl benzene, halomethanesulfinyl benzene or
halomethanesulfanyl benzene in the presence of a strong base such
as potassium tert-butoxide, sodium hydroxyde, lithium hydroxyde, or
sodiummethoxide, in a suitable solvent such as THF. Nucleophilic
displacement of the nitrobenzene of formula 14 with a leaving group
L, such as a halo group, with a 1-alkylpiperazine can afford a
nitrobenzene compound of formula 15. Reduction of the nitro group
by a variety of methods well known in the art, such as catalytic
hydrogenation, preferably in the presence of Pearlman's catalyst
(Palladium hydroxyde) in a suitable solvent such as THF can afford
an amine of formula 16. Addition of an ortho ester of general
formula R.sup.2C(OR).sub.3 wherein R is an alkyl group and R.sup.2
is hydrogen or alkyl, in the presence of an acid such
p-toluenesulfonic acid, followed by cyclization can afford an
indole of formula 18, wherein R.sup.2 is hydrogen or alkyl.
General Utility
[0146] The compounds of the invention have selective 5-HT6 receptor
affinity and as such are expected to be useful in the treatment of
certain CNS disorders such as Parkinson's disease, Huntington's
disease, anxiety, depression, manic depression, psychosis,
epilepsy, obsessive compulsive disorders, migraine, Alzheimer's
disease (enhancement of cognitive memory), sleep disorders, feeding
disorders such as anorexia and bulimia, panic attacks, attention
deficit hyperactivity disorder (ADHD), attention deficit disorder
(ADD), withdrawal from drug abuse such as cocaine, ethanol,
nicotine and benzodiazepines, schizophrenia, and also disorders
associated with spinal trauma and/or head injury such as
hydrocephalus. Such compounds are also expected to be of use in the
treatment of certain GI (gastrointestinal) disorders such
functional bowel disorder or irritable bowel syndrome (IBS) as well
as obesity.
Testing
[0147] The pharmacology of the compounds of this invention was
determined by art recognised procedures. The in vitro techniques
for determining the affinities of test compounds at the 5-HT6
receptor in radioligand binding and functional assays are described
in Example 15.
Administration and Pharmaceutical Composition
[0148] The present invention includes pharmaceutical compositions
comprising at least one compound of the present invention, or an
individual isomer, racemic or non-racemic mixture of isomers or a
pharmaceutically acceptable salt or solvate thereof, together with
at least one pharmaceutically acceptable carrier, and optionally
other therapeutic and/or prophylactic ingredients.
[0149] In general, the compounds of the present invention will be
administered in a therapeutically effective amount by any of the
accepted modes of administration for agents that serve similar
utilities. Suitable dosage ranges are typically 1-500 mg daily,
preferably 1-100 mg daily, and most preferably 1-30 mg daily,
depending upon numerous factors such as the severity of the disease
to be treated, the age and relative health of the subject, the
potency of the compound used, the route and form of administration,
the indication towards which the administration is directed, and
the preferences and experience of the medical practitioner
involved. One of ordinary skill in the art of treating such
diseases will be able, without undue experimentation and in
reliance upon personal knowledge and the disclosure of this
Application, to ascertain a therapeutically effective amount of the
compounds of the present invention for a given disease.
[0150] In general, compounds of the present invention will be
administered as pharmaceutical formulations including those
suitable for oral (including buccal and sub-lingual), rectal,
nasal, topical, pulmonary, vaginal, or parenteral (including
intramuscular, intraarterial, intrathecal, subcutaneous and
intravenous) administration or in a form suitable for
administration by inhalation or insufflation. The preferred manner
of administration is generally oral using a convenient daily dosage
regimen which can be adjusted according to the degree of
affliction.
[0151] A compound or compounds of the present invention, together
with one or more conventional adjuvants, carriers, or diluents, may
be placed into the form of pharmaceutical compositions and unit
dosages. The pharmaceutical compositions and unit dosage forms may
be comprised of conventional ingredients in conventional
proportions, with or without additional active compounds or
principles, and the unit dosage forms may contain any suitable
effective amount of the active ingredient commensurate with the
intended daily dosage range to be employed. The pharmaceutical
compositions may be employed as solids, such as tablets or filled
capsules, semisolids, powders, sustained release formulations, or
liquids such as solutions, suspensions, emulsions, elixirs, or
filled capsules for oral use; or in the form of suppositories for
rectal or vaginal administration; or in the form of sterile
injectable solutions for parenteral use. Formulations containing
about one (1) milligram of active ingredient or, more broadly,
about 0.01 to about one hundred (100) milligrams, per tablet, are
accordingly suitable representative unit dosage forms.
[0152] The compounds of the present invention may be formulated in
a wide variety of oral administration dosage forms. The
pharmaceutical compositions and dosage forms may comprise a
compound or compounds of the present invention or pharmaceutically
acceptable salts thereof as the active component. The
pharmaceutically acceptable carriers may be either solid or liquid.
Solid form preparations include powders, tablets, pills, capsules,
cachets, suppositories, and dispersible granules. A solid carrier
may be one or more substances which may also act as diluents,
flavouring agents, solubilizers, lubricants, suspending agents,
binders, preservatives, tablet disintegrating agents, or an
encapsulating material. In powders, the carrier generally is a
finely divided solid which is a mixture with the finely divided
active component. In tablets, the active component generally is
mixed with the carrier having the necessary binding capacity in
suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from about one (1) to
about seventy (70) percent of the active compound. Suitable
carriers include but are not limited to magnesium carbonate,
magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,
gelatine, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the
like. The term "preparation" is intended to include the formulation
of the active compound with encapsulating material as carrier,
providing a capsule in which the active component, with or without
carriers, is surrounded by a carrier, which is in association with
it. Similarly, cachets and lozenges are included. Tablets, powders,
capsules, pills, cachets, and lozenges may be as solid forms
suitable for oral administration.
[0153] Other forms suitable for oral administration include liquid
form preparations including emulsions, syrups, elixirs, aqueous
solutions, aqueous suspensions, or solid form preparations which
are intended to be converted shortly before use to liquid form
preparations. Emulsions may be prepared in solutions, for example,
in aqueous propylene glycol solutions or may contain emulsifying
agents, for example, such as lecithin, sorbitan monooleate, or
acacia. Aqueous solutions can be prepared by dissolving the active
component in water and adding suitable colorants, flavours,
stabilising, and thickening agents. Aqueous suspensions can be
prepared by dispersing the finely divided active component in water
with viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, and other well
known suspending agents. Solid form preparations include solutions,
suspensions, and emulsions, and may contain, in addition to the
active component, colorants, flavours, stabilisers, buffers,
artificial and natural sweeteners, dispersants, thickeners,
solubilizing agents, and the like.
[0154] The compounds of the present invention may be formulated for
parenteral administration (e.g., by injection, for example bolus
injection or continuous infusion) and may be presented in unit dose
form in ampoules, pre-filled syringes, small volume infusion or in
multi-dose containers with an added preservative. The compositions
may take such forms as suspensions, solutions, or emulsions in oily
or aqueous vehicles, for example solutions in aqueous polyethylene
glycol. Examples of oily or nonaqueous carriers, diluents, solvents
or vehicles include propylene glycol, polyethylene glycol,
vegetable oils (e.g., olive oil), and injectable organic esters
(e.g., ethyl oleate), and may contain formulatory agents such as
preserving, wetting, emulsifying or suspending, stabilising and/or
dispersing agents. Alternatively, the active ingredient may be in
powder form, obtained by aseptic isolation of sterile solid or by
lyophilisation from solution for constitution before use with a
suitable vehicle, e.g., sterile, pyrogen-free water.
[0155] The compounds of the present invention may be formulated for
topical administration to the epidermis as ointments, creams or
lotions, or as a transdermal patch. Ointments and creams may, for
example, be formulated with an aqueous or oily base with the
addition of suitable thickening and/or gelling agents. Lotions may
be formulated with an aqueous or oily base and will in general also
containing one or more emulsifying agents, stabilising agents,
dispersing agents, suspending agents, thickening agents, or
colouring agents. Formulations suitable for topical administration
in the mouth include lozenges comprising active agents in a
flavoured base, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert base such as gelatine
and glycerine or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0156] The compounds of the present invention may be formulated for
administration as suppositories. A low melting wax, such as a
mixture of fatty acid glycerides or cocoa butter is first melted
and the active component is dispersed homogeneously, for example,
by stirring. The molten homogeneous mixture is then poured into
convenient sized molds, allowed to cool, and to solidify.
[0157] The compounds of the present invention may be formulated for
vaginal administration. Pessaries, tampons, creams, gels, pastes,
foams or sprays containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0158] The compounds of the present invention may be formulated for
nasal administration. The solutions or suspensions are applied
directly to the nasal cavity by conventional means, for example,
with a dropper, pipette or spray. The formulations may be provided
in a single or multidose form. In the latter case of a dropper or
pipette, this may be achieved by the patient administering an
appropriate, predetermined volume of the solution or suspension. In
the case of a spray, this may be achieved for example by means of a
metering atomising spray pump.
[0159] The compounds of the present invention may be formulated for
aerosol administration, particularly to the respiratory tract and
including intranasal administration. The compound will generally
have a small particle size for example of the order of five (5)
microns or less. Such a particle size may be obtained by means
known in the art, for example by micronization. The active
ingredient is provided in a pressurized pack with a suitable
propellant such as a chlorofluorocarbon (CFC), for example,
dichlorodifluoromethane, trichlorofluoromethane, or
dichlorotetrafluoroethane, or carbon dioxide or other suitable gas.
The aerosol may conveniently also contain a surfactant such as
lecithin. The dose of drug may be controlled by a metered valve.
Alternatively the active ingredients may be provided in a form of a
dry powder, for example a powder mix of the compound in a suitable
powder base such as lactose, starch, starch derivatives such as
hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The
powder carrier will form a gel in the nasal cavity. The powder
composition may be presented in unit dose form for example in
capsules or cartridges of e.g., gelatine or blister packs from
which the powder may be administered by means of an inhaler.
[0160] When desired, formulations can be prepared with enteric
coatings adapted for sustained or controlled release administration
of the active ingredient. For example, the compounds of the present
invention can be formulated in transdermal or subcutaneous drug
delivery devices. These delivery systems are advantageous when
sustained release of the compound is necessary and when patient
compliance with a treatment regimen is crucial. Compounds in
transdermal delivery systems are frequently attached to an
skin-adhesive solid support. The compound of interest can also be
combined with a penetration enhancer, e.g., Azone
(1-dodecylazacycloheptan-2-one). Sustained release delivery systems
are inserted subcutaneously into the subdermal layer by surgery or
injection. The subdermal implants encapsulate the compound in a
lipid soluble membrane, e.g., silicone rubber, or a biodegradable
polymer, e.g., polylactic acid.
[0161] The pharmaceutical preparations are preferably in unit
dosage forms. In such form, the preparation is subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packeted
tablets, capsules, and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or
it can be the appropriate number of any of these in packaged
form.
[0162] Other suitable pharmaceutical carriers and their
formulations are described in Remington: The Science and Practice
of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company,
19.sup.th edition, Easton, Pa. Representative pharmaceutical
formulations containing a compound of the present invention are
described in Examples 8-14.
EXAMPLES
[0163] The following preparations and examples are given to enable
those skilled in the art to more clearly understand and to practice
the present invention. They should not be considered as limiting
the scope of the invention, but merely as being illustrative and
representative thereof.
Preparation 1
4-(1H-Indol-7-yl)-piperazine-1-carboxylic Acid tert-butyl Ester
[0164] 14
[0165] Step 1:
Trifluoromethanesulfonic Acid 3-methyl-2-nitrophenyl Ester
[0166] 15
[0167] A solution of 3-methyl-2-nitrophenol (15.3 g, 100 mmol) in
200 mL of dichloromethane and 42 mL of triethylamine was cooled to
-30.degree. C. and trifluoromethanesulfonic anhydride (21 mL, 125
mmol) was slowly added. After 15 min the mixture was washed with
saturated aqueous sodium bicarbonate and brine, dried, and
evaporated to a dark oil. Silica gel chromatography (10% ethyl
acetate-hexane) afforded 26.7 g of trifluoromethanesulfonic acid
3-methyl-2-nitrophenyl ester as a colorless oil.
[0168] Step 2:
4-(3-Methyl-2-nitrophenyl)-piperazine-1-carboxylic Acid tert-butyl
Ester
[0169] 16
[0170] Trifluoromethanesulfonic acid 3-methyl-2-nitrophenyl ester
(26.7 g, 93.6 mmol), 1-tert-butoxycarbonyl piperazine (17 g, 91.3
mmol) and triethylamine (14 mL, 100 mmol) in 250 mL of acetonitrile
was heated under reflux for 25 h. The mixture was concentrated in
vacuo, diluted with water and extracted with ether. The ether was
washed with aqueous ammonium hydroxide and brine, dried, and
evaporated. Purification by silica gel chromatography (10% ethyl
acetate-hexane) afforded 11 g of
4-(3-methyl-2-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl
ester as a golden solid, m.p. 101-102.degree. C.
[0171] Step 3:
4-(1H-Indol-7-yl)-piperazine-1-carboxylic Acid tert-butyl Ester
[0172] 17
[0173] A solution of
4-(3-methyl-2-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl
ester (10 g, 31 mmol), N,N-dimethylformamide dimethyl acetal (13.2
mL, 100 mmol) and pyrrolidine (4 mL, 50 mmol) in 45 mL of DMF was
heated under reflux for 20 h. The mixture was concentrated in vacuo
and the residue was partitioned between ethyl acetate and water.
The ethyl acetate was dried and evaporated. The residue was
hydrogenated in 200 mL of THF containing 2.5 g of 10% Pd-C at 50
psi for 6 h. The mixture was filtered, concentrated in vacuo, and
partitioned between ethyl acetate and aqueous HCl. The ethyl
acetate was washed with brine, dried and evaporated. Silica gel
chromatography (10% ethyl acetate-hexane) afforded 2.5 g of
4-(1H-Indol-7-yl)-piperazine-1-carboxyl- ic acid tert-butyl ester
(19) as a white solid, m.p. 150-151.degree. C.
Preparation 2
4-(1H-indol-5-yl)-piperazine-1-carboxylic Acid tert-butyl Ester
[0174] 18
[0175] Step 1:
4-(3-Methyl-4-nitrophenyl)-piperazine-1-carboxylic Acid tert-butyl
Ester
[0176] 19
[0177] A mixture of 5-fluoro-2-nitrotoluene (2 mL, 16.4 mmol),
1-tert-butoxycarbonyl piperazine (3.35 g, 18 mmol) and potassium
carbonate (2.76 g, 20 mmol) in 7 mL of DMSO was stirred and heated
at 100.degree. C. for 2 h. Water (40 mL) and hexane (30 mL) were
added and the bright yellow precipitate was collected, washed with
water and hexane, and dried in vacuo to afford 4.9 g of
4-(3-methyl-4-nitrophenyl)-- piperazine-1-carboxylic acid
tert-butyl ester, m.p. 145-146.degree. C.
[0178] Step 2
4-(1H-Indol-5-yl)-piperazine-1-carboxylic Acid tert-butyl Ester
[0179] 20
[0180] A solution of
4-(3-methyl-4-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl
ester (4.3 g, 13.5 mmol), N,N-dimethylformamide dimethyl acetal
(2.12 mL, 16 mmol) and pyrrolidine (1.3 mL, 16 mmol) in 15 mL of
DMF was heated at 110.degree. C. for 3 h. Additional
N,N-dimethylformamide dimethyl acetal (0.7 mL, 5 mmol) and
pyrrolidine (0.42 mL, 5 mmol) were added and heating at 110.degree.
C. was continued for 15 h. The mixture was concentrated in vacuo,
taken into 50 mL of ethanol, and slowly added to a hot (just below
boiling) solution of 50 mL of ethanol containing 2 mL of water and
1 g of 10% Pd-C and ammonium formate (4.4 g, 70 mmol). After the
addition was complete the mixture was heated under reflux for 10
min. The mixture was filtered, concentrated in vacuo, and
partitioned between ether and aqueous sodium carbonate. The ether
was washed with water and brine, dried (magnesium sulfate) and
evaporated. Silica gel chromatography (20% ethyl acetate-hexane)
afforded 3 g of 4-(1H-indol-5-yl)-piperazine-1-carboxylic acid
tert-butyl ester (20) as a thick oil.
Alternative Route for the Preparation of
4-(1H-Indol-5-yl)-piperazine-1-ca- rboxylic Acid, tert-butyl Ester
(20)
[0181] 21
[0182] A mixture of 5-bromo-1-triisopropylsilanyl-1H-indole (9 g,
25.5 mmol), 1-tert-butoxycarbonyl piperazine (5 g, 27 mmol),
palladium acetate (0.3 g, 1.3 mmol), tri-tert-butyl phosphine
(0.263 g, 1.3 mmol) and sodium tert-butoxide (3.65 g, 38 mmol) in
75 mL xylene was heated at 1100 for 2 h. The reaction mixture was
diluted with 200 mL 50% ethyl ether/hexane and the mixture was
filtered through a pad of silica gel. Enough 10% ethyl
acetate/hexane was used to elute 4-(1-triisopropylsilany-
l-1H-indol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester
(11.7 g) which was recovered as a light brown heavy syrup by
concentrating the eluate under reduced pressure.
[0183] To a solution of
4-(1-triisopropylsilanyl-1H-indol-5-yl)-piperazine- -1-carboxylic
acid tert-butyl ester (11.7 g, 25 mmol) in 150 mL THF was added 26
mL 1.0 M tetrabutylammonium fluoride in THF. After 2 h at room
temperature, the solution was concentrated under reduced pressure
and the residue was partitioned between 100 mL ethyl ether and 20
mL saturated sodium bicarbonate. The organic phase was washed with
20 mL water, 10 mL saturated sodium chloride, dried (magnesium
sulfate) and concentrated under reduced pressure. The residue was
subjected to column chromatography over silica gel eluting with 20%
ethyl acetate/hexane affording 7 g
4-(1H-indol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester
(20).
Preparation 3
4-(2-Methyl-1H-indol-7-yl)-piperazine-1-carboxylic Acid tert-butyl
Ester
[0184] 22
[0185] Isopropenyl magnesium bromide (234 mL of a 0.5 M solution in
THF, 117 mmol) was slowly added to a -40.degree. C. solution of
4-(4-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester (12
g, 39 mmol) in 200 mL of THF and the resulting mixture was stirred
at -40.degree. C. for 20 min. Saturated aqueous ammonium chloride
was added and the mixture was extracted with ethyl acetate. The
extract was washed with water and brine, dried (sodium sulfate) and
evaporated. Silica gel chromatography (20% ethyl acetate-hexane)
afforded 4.8 g of
4-(2-methyl-1H-indol-7-yl)-piperazine-1-carboxylic acid tert-butyl
ester (21) as an oil, mass spec, M.sup.+315.
Preparation 4
4-(1H-Indol-7-yl)-piperidine-1-carboxylic Acid tert-butyl Ester
[0186] 23
[0187] Step 1:
4-Hydroxy-4-(1H-indol-7-yl)-piperidine-1-carboxylic Acid tert-butyl
Ester
[0188] 24
[0189] To a solution of 7-bromoindole (400 mg, 2.04 mmol) in THF
(20 mL) under an argon atmosphere and cooled to -78.degree. C. was
added n-butyllithium (3.1 mL, 2.0M, 6.1 mmol) dropwise. The
reaction was stirred at -78.degree. C. for 15 minutes then warmed
to 5.degree. C. and maintained for 30 minutes. The reaction was
cooled back to -78.degree. C. and 4-oxo-piperidine-1-carboxylic
acid tert-butyl ester (813 mg, 4.08 mmol) was added dropwise in THF
(5 mL). The reaction was allowed to come to room temperature and
stirred for 1 h. The reaction was quenched with water (15 mL) and
extracted with EtOAc (3.times.20 mL). The combined acetate layers
were washed with brine, dried over MgSO.sub.4 and filtered. The
filtrate was concentrated in vacuo and chromatographed on silica
eluting with 20% acetone in hexanes to afford
4-hydroxy-4-(1H-indol-7-yl)-piperidine-1-carboxylic acid tert-butyl
ester as a white foam (520 mg).
[0190] Step 2:
4-(1H-Indol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic Acid
tert-butyl Ester
[0191] 25
[0192] To a solution of
4-hydroxy-4-(1H-indol-7-yl)-piperidine-1-carboxyli- c acid
tert-butyl ester (117 mg, 0.37 mmol) in pyridine (5 mL) was added
POCl.sub.3 (70 .mu.L, 0.74 mmol) in a single portion. The reaction
was stirred for 24 h, quenched with the slow addition of water (10
mL) and extracted with EtOAc (3.times.10 mL). The combined acetate
layers were washed with brine, dried (MgSO.sub.4) and concentrated
to afford 4-(1H-indol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester as a light yellow oil (100 mg).
[0193] Step 3:
4-(1H-Indol-7-yl)-piperidine-1-carboxylic acid tert-butyl ester
[0194] 26
[0195] To a solution of
4-(1H-indol-7-yl)-3,6-dihydro-2H-pyridine-1-carbox- ylic acid
tert-butyl ester (100 mg) in EtOH (20 mL) was added 10% Pd/C (20
mg). The reaction was placed on a Parr shaker at 55 psi H.sub.2 for
24 h. The reaction was filtered through Celite.TM. and concentrated
to afford 4-(1H-indol-7-yl)-piperidine-1-carboxylic acid tert-butyl
ester (22) as a clear oil (78 mg).
Example 1
3-Benzenesulfonyl-7-piperazin-1-yl-1H-indole
[0196] 27
[0197] Step 1:
4-(3-Phenylsulfanyl-1H-indol-7-yl)-piperazine-1-carboxylic acid
tert-butyl ester
[0198] 28
[0199] Sodium hydride (0.4 g of 60% dispersion in mineral oil, 10
mmol) was added to an ice-cooled solution of
4-(1H-Indol-7-yl)-piperazine-1-car- boxylic acid tert-butyl ester
(19) prepared as described in Preparation 1 (2.3 g, 7.6 mmol) in 20
mL DMF and the resulting mixture was stirred for 10 min. Phenyl
disulfide (1.85 g, 8.5 mmol) was added and the solution was stirred
at room temperature for 16 h. Water was added and the mixture was
extracted with ethyl acetate. The extract was washed with brine,
dried and evaporated to afford 2.9 g of
4-(3-phenylsulfanyl-1H-indol-7-yl- )-piperazine-1-carboxylic acid
tert-butyl ester) as a white solid, m.p. 165-166.degree. C.
[0200] Step 2:
4-(3-Benzenesulfonyl-1H-indol-7-yl)-piperazine-1-carboxylic Acid
tert-butyl Ester
[0201] 29
[0202] Oxone.TM. (9.2 g, 15 mmol) in 40 mL of water was added to a
stirred solution of
4-(3-phenylsulfanyl-1H-indol-7-yl)-piperazine-1-carboxylic acid
tert-butyl ester (2.9 g) in 50 mL of methanol and 10 mL of THF. The
mixture was stirred for 2 h, diluted with water, and extracted with
ethyl acetate. The ethyl acetate was dried (sodium sulfate) and
evaporated to afford a solid residue of the sulfone N-oxide. This
was dissolved in 50 mL of methanol and hydrogenated at atmospheric
pressure over 0.3 g of 10% Pd-C for 12 h. Dichloromethane was added
and the mixture was filtered and evaporated. Trituration of the
residue with ether afforded 2.2 g of
4-(3-benzenesulfonyl-1H-indol-7-yl)-piperazine-1-carboxylic acid
tert-butyl ester as a white solid, m.p. 168-169.degree. C.
[0203] Step 3:
3-Benzenesulfonyl-7-piperazin-1-yl-1H-indole Hydrochloride
[0204] 30
[0205] 4-(3-Benzenesulfonyl-1H-indol-7-yl)-piperazine-1-carboxylic
acid tert-butyl ester (1 g, 2.2 mmol) was dissolved in 5 mL of
dichloromethane and 6 mL of trifluoroacetic acid was added. After
10 min the mixture was concentrated in vacuo, taken into water, and
washed with ether. The aqueous layer was basified with ammonium
hydroxide, extracted with dichloromethane, and the extract was
dried (sodium sulfate) and evaporated to afford the crude free
base. The hydrochloride salt was crystallized from ethanol to
afford 550 mg of 3-benzenesulfonyl-7-piperaz- in-1-yl-1H-indole
hydrochloride (101), m.p. 278-280.degree. C.
[0206] Similarly replacing in Step 1 phenyl disulfide with the
appropriate substituted phenyl disulfides, the following compounds
were prepared:
[0207] 7-piperazin-1-yl-3-(toluene-4-sulfonyl)-1H-indole (102),
m.p. 285-287.degree. C.;
[0208] 3-(3,4-dichloro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole
(103), m.p. 290.degree. C.;
[0209] 3-(4-fluoro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole
(104), m.p. 247-249.degree. C.;
[0210] 3-(3,5-dichloro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole
(105), m.p. 290.degree. C.;
[0211] 3-(2,4-dichloro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole
(106), m.p. 300.degree. C.;
[0212] 3-(3-chloro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole
(107), m.p. 295.degree. C.;
[0213] 3-(2-chloro-benzenesulfonyl)-7-piperazin-1-yl-1H-indole
(108), m.p. 280-282.degree. C.;
[0214]
7-piperazin-1-yl-3-(2-trifluoromethyl-benzenesulfonyl)-1H-indole
(109), m.p. 186-187.degree. C.;
[0215] 3-(3-chloro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole
(110), m.p. 192-197.degree. C.; and
[0216] 3-(3,4-dichloro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole
(111), m.p. >300.degree. C.
[0217] Similarly replacing in Step 1 phenyldisulfide with the
appropriate heteroaryl disulfides the following compounds were
prepared:
[0218] 7-piperazin-1-yl-3-(pyridine-4-sulfonyl)-1H-indole (112),
m.p. 207-208.degree. C.;
[0219] 7-piperazin-1-yl-3-(pyridine-2-sulfonyl)-1H-indole (113),
m.p. 198-199.degree. C.;
[0220] 2-(7-piperazin-1-yl-1H-indole-3-sulfonyl)-benzothiazole
(114), m.p. 295.degree. C.; and
[0221] 6-piperazin-1-yl-3-(pyridine-2-sulfonyl)-1H-indole (115)
m.p. 246.7-247.2.degree. C.
Example 2
3-Benzenesulfonyl-5-piperazin-1-yl-1H-indole
[0222] 31
[0223] Step 1:
4-(3-Phenylsulfanyl-1H-indol-5-yl)-piperazine-1-carboxylic Acid
tert-butyl Ester
[0224] 32
[0225] Sodium hydride (0.29 g, 12 mmol) was added to an ice-cooled
solution of 4-(1H-Indol-5-yl)-piperazine-1-carboxylic acid
tert-butyl ester (20) prepared as described in Preparation 2 (3 g,
10 mmol) in 30 mL DMF and the resulting mixture was stirred for 10
min. Phenyl disulfide (2.6 g, 12 mmol) was added and the solution
was stirred at room temperature for 16 h. Water was added and the
mixture was extracted with ethyl ether. The extract was washed with
brine, dried and evaporated to afford 3.83 g of
4-(3-phenylsulfanyl-1H-indol-5-yl)-piperazine-1-carboxyl- ic acid
tert-butyl ester) as a tan crystalline solid, m.p. 174.degree.
C.
[0226] Step 2:
4-(3-Benzenesulfonyl-1H-indol-5-yl)-piperazine-1-carboxylic Acid
tert-butyl Ester
[0227] 33
[0228] A solution of
4-(3-phenylsulfanyl-1H-indol-5-yl)-piperazine-1-carbo- xylic acid
tert-butyl ester (2.57 g, 6.28 mmol) in dichloromethane (50 mL) was
cooled in ice and treated with 70% m-chloroperbenzoic acid (4.5 g).
The cooling bath was removed and stirring at room temperature
continued for 3 h. The mixture was then concentrated to dryness,
the residue treated with ethyl ether (50 mL), stirred well for 10
min, filtered, the filter cake washed well with ethyl ether and
air-dried to give the sulfone N-oxide m-chlorobenzoic acid salt as
a beige solid. This was dissolved in 45 mL of DMF, treated with
0.24 g of Pearlmann's catalyst, and hydrogenated at atmospheric
pressure for 4 h. The mixture was then filtered free of catalyst,
the filtrate concentrated to dryness, the residue taken up in 450
mL ethyl acetate-chloroform (4:1), washed with 1.5 M sodium
carbonate and then water, dried, filtered, and partially
concentrated to -50 mL. After the mixture was diluted with 75 mL of
ethyl ether, the solid was filtered, washed with ethyl ether and
dried affording 2.4 g of
4-(3-benzenesulfonyl-1H-indol-5-yl)-piperazine-1-carbo- xylic acid
tert-butyl ester as a pinkish-beige solid, m.p. 238-41.degree. C.
(dec.).
Step 3
3-Benzenesulfonyl-5-piperazin-1-yl-1H-indole Hydrochloride
[0229] 34
[0230] 4-(3-Benzenesulfonyl-1H-indol-5-yl)-piperazine-1-carboxylic
acid tert-butyl ester (0.5 g, 1.13 mmol) was dissolved in 5 mL of
ethanol and 3 mL of conc. hydrochloric acid were added. The mixture
was heated to a gentle boil for 2-3 min, cooled to room
temperature, basified with ammonium hydroxide, and diluted with 20
mL of water. After the mixture was allowed to stand overnight, the
solid was filtered, washed with water and dried to give 0.37 g of
3-benzenesulfonyl-5-piperazin-1-yl-1H-indole (201) as a tan
crystalline solid, m.p. 254-264.degree. C. (dec).
[0231] Similarly, following the procedure described above, but
replacing phenyl disulfide with the appropriate substituted phenyl
disulfides, the following compounds were prepared:
[0232] 3-(2,3-dichloro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole
(202), m.p. >300.degree. C.;
[0233]
5-piperazin-1-yl-3-(4-trifluoromethyl-benzenesulfonyl)-1H-indole
(203), m.p. 274.9-280.9.degree. C.;
[0234] 3-(4-chloro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole
(204), m.p. 282-286.4.degree. C.;
[0235] 3-(3,5-dichloro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole
(205), m.p. >300.degree. C.;
[0236] 3-(2-chloro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole
(206), m.p. >300.degree. C.;
[0237] 3-(4-fluoro-benzenesulfonyl)-5-piperazin-1-yl-1H-indole
(207), m.p. 289-291.degree. C.; and
[0238] 3-(3-Chloro-benzenesulfonyl)-7-piperidin-4-yl-1H-indole
(208), m.p. 272.3-272.9.degree. C.
Example 3
3-Benzenesulfonyl-7-piperidin-4-yl-1H-indole
[0239] 35
[0240] Step 1
4-(3-Phenylsulfanyl-1H-indol-7-yl)-piperidine-1-carboxylic Acid
tert-butyl Ester
[0241] 36
[0242] To a solution of 4-(1H-indol-7-yl)-piperidine-1-carboxylic
acid tert-butyl ester (22) prepared as described herein in
Preparation 4 (220 mg, 0.73 mmol) in DMF (15 mL) was added NaH
(95%, 25 mg, 0.95 mmol) in a single portion. The reaction was
stirred at room temperature for 30 minutes and phenyldisulfide (185
mg, 0.88 mmol) was added. The reaction was stirred at room
temperature for 24 h and poured into water (50 mL). The aqueous
layer was extracted with EtOAc (3.times.20 mL) and the combined
organic layers were washed with brine, dried (MgSO.sub.4) and
concentrated in-vacuo. Flash chromatography eluting with 20%
acetone in hexanes afforded
4-(3-phenylsulfanyl-1H-indol-7-yl)-piperidine-1-carboxyl- ic acid
tert-butyl ester as a tan solid (200 mg).
[0243] Step 2:
4-(3-Benzenesulfonyl-1H-indol-7-yl)-piperidine-1-carboxylic Acid
tert-butyl Ester
[0244] 37
[0245] To an ice cold solution of
4-(3-phenylsulfanyl-1H-indol-7-yl)-piper- idine-1-carboxylic acid
tert-butyl ester (190 mg, 0.48 mmol) in methylene chloride (20 mL)
under a nitrogen atmosphere was added m-chloroperbenzoic acid (166
mg, 0.96 mmol) portionwise. The reaction, complete after 2 h at
0.degree. C., was diluted with methylene chloride (30 mL) and
washed with water (15 ml). The organic phase was washed with 5% KOH
(15 mL) and concentrated to afford
4-(3-benzenesulfonyl-1H-indol-7-yl)-piperidine-1-c- arboxylic acid
tert-butyl ester (156 mg).
[0246] Step 3
3-Benzenesulfonyl-7-piperidin-4-yl-1H-indole
[0247] 38
[0248] To a solution of
4-(3-benzenesulfonyl-1H-indol-7-yl)-piperidine-1-c- arboxylic acid
tert-butyl ester (200 mg, 0.45 mmol) in methylene chloride (20 mL)
under a nitrogen atmosphere was added TFA (5 mL). After 30 minutes
the reaction was concentrated in vacuo and partitioned between 10%
aq. KOH (30 mL) and EtOAc (30 mL). The acetate layer was dried
(MgSO.sub.4) and concentrated to afford the product as a light
brown oil. Trituration with ether afforded
3-benzenesulfonyl-7-piperidin-4-yl-1H-ind- ole (301) as a tan solid
(113 mg) m.p. 186-189.5.degree. C.
Example 4
3-Benzenesulfonyl-1-methyl-7-piperazin-1-yl-1H-indole
[0249] 39
[0250] Step 1
4-(3-Benzenesulfonyl-1-methyl-1H-indol-7-yl)-piperazine-1-carboxylic
Acid tert-butyl Ester
[0251] 40
[0252] Sodium hydride (0.12 g of 60% dispersion in mineral oil, 3
mmol) was added to a solution of
4-(3-benzenesulfonyl-1H-indol-7-yl)-piperazine- -1-carboxylic acid
tert-butyl ester (1 g, 2.3 mmol) in 20 mL of DMF with ice cooling.
After stirring 15 min at room temperature the mixture was treated
with methyl iodide (0.17 mL, 3 mmol). Water was added and the
mixture was extracted with ethyl acetate. The extract was washed
with water and brine, dried (sodium sulfate) and evaporated. Silica
gel chromatography (20% ethyl acetate-hexane) afforded 0.9 g of
4-(3-benzenesulfonyl-1-methyl-1H-indol-7-yl)-piperazine-1-carboxylic
acid tert-butyl ester as a foam, mass spec. M.sup.+ 455.
[0253] Step 2
3-Benzenesulfonyl-1-methyl-7-piperazin-1-yl-1H-indole
[0254] 41
[0255] Deprotection of
4-(3-benzenesulfonyl-1-methyl-1H-indol-7-yl)-pipera-
zine-1-carboxylic acid tert-butyl ester as described in step 3
Example 1 afforded the free base of
3-benzenesulfonyl-1-methyl-7-piperazin-1-yl-1H-- indole
hydrochloride (401) as a white solid, m.p. 249-250.degree. C. The
hydrochloride salt had m.p. 293-295.degree. C.
[0256] Similarly following the procedure described above but
replacing
4-(3-benzenesulfonyl-1H-indol-7-yl)-piperazine-1-carboxylic acid
tert-butyl ester in Step 1 with the appropriate indole derivatives
the following compounds were prepared:
[0257] 1-methyl-7-piperazin-1-yl-3-(pyridine-2-sulfonyl)-1H-indole
(402), m.p. 297-298.degree. C.;
[0258] 3-benzenesulfonyl-1-methyl-5-piperazin-1-yl-1H-indole (403),
m.p. 239-240.degree. C. (dec);
[0259]
1-methyl-7-piperazin-1-yl-3-(2-trifluoromethyl-benzenesulfonyl)-1H--
indole (404), m.p. 295.degree. C.;
[0260]
3-(4-fluoro-benzenesulfonyl)-1-methyl-7-piperazin-1-yl-1H-indole
(405), m.p. 300.degree. C.;
[0261]
1-methyl-7-piperazin-1-yl-3-(3-trifluoromethyl-benzenesulfonyl)-1H--
indole (406), m.p. 279-280.degree. C.;
[0262]
3-(2-chloro-benzenesulfonyl)-1-methyl-7-piperazin-1-yl-1H-indole
(407), m.p. 295-297.degree. C.;
[0263]
3-(3-chloro-benzenesulfonyl)-1-methyl-7-piperazin-1-yl-1H-indole
(408), m.p. 300.degree. C.;
[0264]
3-(2,3-dichloro-benzenesulfonyl)-1-methyl-5-piperazin-1-yl-1H-indol-
e (409), m.p. 198-203.degree. C.;
[0265]
1-methyl-5-piperazin-1-yl-3-(3-trifluoromethyl-benzenesulfonyl)-1H--
indole (410), m.p. 235-240.degree. C.;
[0266]
3-(3,5-dichloro-benzenesulfonyl)-1-methyl-5-piperazin-1-yl-1H-indol-
e (411), m.p. 282-284.5.degree. C.
[0267] 1-methyl-7-piperazin-1-yl-3-(pyridine-2-sulfonyl)-1H-indole
(412), m.p. 297-298.degree. C.;
[0268]
3-(4-fluoro-benzenesulfonyl)-1-methyl-5-piperazin-1-yl-1H-indole
(413), m.p. 195-207.degree. C.;
[0269]
3-(2-chloro-benzenesulfonyl)-1-methyl-5-piperazin-1-yl-1H-indole
(414), m.p. 249.6-253.degree. C.;
[0270]
3-(3-chloro-benzenesulfonyl)-1-methyl-5-piperazin-1-yl-1H-indole
(415), m.p. 185.5-188.5.degree. C.; and
[0271] 1-methyl-5-piperazin-1-yl-3-(pyridine-2-sulfonyl)-1H-indole
(416), m.p. 256.8-257.5.degree. C.
[0272] Similarly following the procedure described above but
replacing in Step 1 methyl iodide with isopropyl iodide the
following compound was prepared:
[0273] 3-benzenesulfonyl-1-isopropyl-5-piperazin-1-yl-1H-indole
(417) M+H=384.
Example 5
3-Benzenesulfonyl-7-(4-methyl-piperazin-1-yl)-1H-indole
[0274] 42
[0275] A solution of 3-benzenesulfonyl-7-piperazin-1-yl-1H-indole
(101) (500 mg, 1.46 mmol) and 1 mL of 37% aqueous formaldehyde in
25 mL of ethanol was hydrogenated at atmospheric pressure in the
presence of 250 mg of 10% Pd-C for 30 min. The mixture was
filtered, diluted with water and extracted with ethyl acetate. The
ethyl acetate was washed with water and brine, dried, and
evaporated to yield the crude free base of
3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)-1H-indole.
[0276] The hydrochloride salt was crystallized from ethanol-ether
to afford 290 mg of (501), m.p. 160-162.degree. C.
[0277] Similarly following the procedure described above but
replacing 3-benzenesulfonyl-7-piperazin-1-yl-1H-indole with the
appropriate indoles, the following compounds were prepared:
[0278]
3-benzenesulfonyl-1-methyl-7-(4-methyl-piperazin-1-yl)-1H-indole
(502), m.p. 260-262.degree. C.;
[0279]
3-(3,4-dichloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-ind-
ole (503), m.p. 196-203.degree. C.;
[0280]
3-(2-chloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-indole
(504), m.p. 168.5-175.9.degree. C.;
[0281]
3-(3-chloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-indole
(505), m.p. 163-171.degree. C.;
[0282]
3-(2,4-dichloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-ind-
ole (506), m.p. 199-203.degree. C.;
[0283]
3-(3,5-dichloro-benzenesulfonyl)-7-(4-methyl-piperazin-1-yl)-1H-ind-
ole (507), m.p. 237.1-241.5.degree. C.;
[0284]
7-(4-methyl-piperazin-1-yl)-3-(2-trifluoromethyl-benzenesulfonyl)-1-
H-indole (508), m.p. 237.1-241.5.degree. C.;
[0285] 3-benzenesulfonyl-5-(4-methyl-piperazin-1-yl)-1H-indole
(509) M+H=356; and
[0286]
3-(4-fluoro-benzenesulfonyl)-7-(1-methyl-piperidin-4-yl)-1H-indole
(510), m.p. 178-182.degree. C.
[0287] Similarly following the procedure described above but
replacing formaldehyde with the appropriate aldehydes, the
following compounds were prepared:
[0288] 3-benzenesulfonyl-7-(4-cyclopropylmethyl-piperazin-1-yl)-1
Hindole (511), m.p. 280-282.degree. C.;
[0289] 3-benzenesulfonyl-7-(4-propyl-piperazin-1-yl)-1H-indole
(512), m.p. 290-295.degree. C., and
[0290] 3-benzenesulfonyl-7-(4-ethyl-piperazin-1-yl)-1H-indole
(513), m.p. 274-275.degree. C.
Alterative Preparation of
3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)-1H- -indole (501)
[0291] Step 1:
1-Benzenesulfonylmethyl-3-chloro-2-nitrobenzene
[0292] 43
[0293] 100 g 1-Chloro-2-nitro-benzene (0.52 mole) were dissolved in
450 mL THF containing 86 g chloromethanesulfonyl-benzene (0.52
mole). They were charged into a 12% (1 M) solution of potassieum
tert-butoxide (KotBu) in THF (1.1 kg, 2.2 eq) which was chilled to
-48.degree. C. and mechanically stirred. The rate of addition was
controlled such that the internal temperature of the THF/KOtBu
solution did not exceed -40.degree. C. Following the addition, the
mixture (deep purple) was stirred for another 3 hours at
-45.degree. C. to -40.degree. C. until TLC analysis, 4:1
hexanes:ethylacetate showed all starting material had been
consumed. The mixture was quenched with 200 mL acetic acid and
warmed from this quench to -15.degree. C. This was then slowly
quenched with a total 2.4 L water. The mixture stirred for an
additional 18 hours, and was filtered and washed with 1.5 L water
in 500 mL aliquots. The cake was washed with hexanes and
vacuum-oven dried at 45-50.degree. C. under nitrogen purge to yield
136 g. of 1-benzenesulfonylmethyl-3-chloro-2-nitro-benzene, mp
141-142.degree. C.
[0294] Step 2:
1-(3-Benzenesulfonylmethyl-2-nitro-phenyl)-4-methyl-piperazine
[0295] 44
[0296] 10 g of 1-benzenesulfonylmethyl-3-chloro-2-nitro-benzene
were slurried in 25 mL N-methylpiperazine under nitrogen and
stirred. The mixture was heated to 80.degree. C. (oil bath
temperature) for a period of 14 hours. The reaction was quenched at
80.degree. C. with 125 mL water, and the thick slurry was filtered,
washed with 100 mL water and 100 mL hexanes, and vacuum dried at
45.degree. C. under nitrogen purge for 4 hours, to yield 11.7 g of
1-(3-benzenesulfonylmethyl-2-nitro-phenyl- )-4-methyl-piperazine mp
180-182.degree. C.
[0297] Step 3:
2-Benzenesulfonylmethyl-6-(4-methyl-piperazin-1-yl)-phenylamine
[0298] 45
[0299] A solution of
1-(3-benzenesulfonylmethyl-2-nitro-phenyl)-4-methyl-p- iperazine
(25 g) in tetrahydrofuran (500 mL) prepared by heating to
45.degree. C. was added to a pre-hydrogenated suspension of
Pearlman's catalyst (20% Pd(OH).sub.2/C, 0.5 g) in tetrahydrofuran
(20 mL). Stirring is continued under a hydrogen atmosphere at
45.degree. C. until the reaction is complete (ca. 29 hours). After
cooling, the catalyst is filtered off on Solkafloc.TM. (10 g) and
washed with tetrahydrofuran (50 mL). The filtrate is concentrated
under vacuum to give 24.9 g of
2-benzenesulfonylmethyl-6-(4-methyl-piperazin-1-yl)-phenylamine as
a foam.
[0300] Step 4:
3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)-1H-indole
[0301] 46
[0302] To a solution of 2.3 g of
2-benzenesulfonylmethyl-6-(4-methyl-piper- azin-1-yl)-phenylamine
in 20 mL trimethyl orthoformate was added p-toluenesulfonic acid
(120 mg). The mixture was heated under reflux in a nitrogen
atmosphere for 2 hours. The mixture was cooled to 60.degree. C. and
one flake of KOH was added. The mixture was reheated to reflux for
1.5 hours. The heating oil bath was turned off and the mixture
stirred overnight under nitrogen. The mixture was treated with 50
mL saturated ammonium chloride solution and 100 mL EtOAc. The
purple organic layer was separated from the clear aqueous solution,
and washed with water (45 mL) and evaporated to a foam. This foam
was dissolved in 80 mL 200 proof EtOH. After dissolution, the
freebase crystallized. This mixture was heated under reflux to
redissolve the solid, and after removal of the heating, 5 mL of a
saturated solution of HCl in ethanol was added to this mixture. The
mixture was cooled with stirring to room temperature and seeded to
ensue immediate crystallization. The mixture was concentrated to
ca. 40 mL and filtered. This collected solid was washed with ca. 3
mL EtOH and vacuum oven dried at 50.degree. C. to give 1.9 g
3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)-1H-indole (501) mp
160-162.degree. C.
Example 6
3-Benzenesulfonyl-2-methyl-7-piperazin-1-yl-1H-indole
[0303] 47
[0304] Step 1:
4-(2-Methyl-3-phenylsulfanyl-1H-indol-7-yl)-piperazine-1-carboxylic
Acid tert-butyl Ester
[0305] 48
[0306] Sodium hydride (0.08 g of 60% dispersion in mineral oil, 1.9
mmol) was added to an ice-cooled solution of
4-(2-methyl-1H-Indol-7-yl)-piperaz- ine-1-carboxylic acid
tert-butyl ester (21) prepared as described in Preparation 3 (0.4
g, 1.3 mmol) in 5 mL DMF and the resulting mixture was stirred for
10 min. Phenyl disulfide (0.3 g, 1.4 mmol) was added and the
solution was stirred at room temperature for 4 h. Water was added
and the mixture was extracted with ethyl acetate. The extract was
washed with brine, dried and evaporated to afford 0.5 g of
4-(2-methyl-3-phenylsulfan-
yl-1H-indol-7-yl)-piperazine-1-carboxylic acid tert-butyl ester) as
an oil, M.sup.+=409.
[0307] Step 2:
4-(3-Benzenesulfonyl-2-methyl-1H-indol-7-yl)-piperazine-1-carboxylic
Acid tert-butyl Ester
[0308] 49
[0309] Oxone.TM. (1.5 g, 2.4 mmol) in 20 mL of water was added to a
stirred solution of
4-(2-methyl-3-phenylsulfanyl-1H-indol-7-yl)-piperazin-
e-1-carboxylic acid tert-butyl ester (0.5 g, 1.2 mmol) in 25 mL of
methanol. The mixture was stirred for 2 h, diluted with water, and
extracted with ethyl acetate. The ethyl acetate was dried (sodium
sulfate) and evaporated to afford a solid residue of the sulfone
N-oxide. This was dissolved in 50 mL of methanol and hydrogenated
at atmospheric pressure over 0.3 g of 10% Pd-C for 12 h.
Dichloromethane was added and the mixture was filtered and
evaporated. Trituration of the residue with ether afforded 0.25 g
of 4-(3-benzenesulfonyl-2-methyl-1H-indol-7-yl)-pip-
erazine-1-carboxylic acid tert-butyl ester as a white solid, m.p.
168-169.degree. C.
[0310] Step 3:
3-Benzenesulfonyl-2-methyl-7-piperazin-1-yl-1H-indole
Hydrochloride
[0311] 50
[0312]
4-(3-Benzenesulfonyl-2-methyl-1H-indol-7-yl)-piperazine-1-carboxyli-
c acid tert-butyl ester (0.25 g) was dissolved in 2 mL of
dichloromethane and 2 mL of trifluoroacetic acid was added. After
10 min the mixture was concentrated in vacuo, taken into water, and
washed with ether. The aqueous layer was basified with ammonium
hydroxide, extracted with dichloromethane, and the extract was
dried (sodium sulfate) and evaporated to afford the crude free base
which was crystallized from dichloromethane-ether to afford 35 mg
of 3-benzenesulfonyl-2-methyl-7-pip- erazin-1-yl-1H-indole (601),
m.p. 188-190.degree. C.
[0313] Similarly following the procedure described above but
replacing phenyl disulfide in Step 1 with the appropriate
substituted phenyl disulfides, the following compounds were
prepared:
[0314]
3-(4-chlorobenzenesulfonyl)-2-methyl-7-piperazin-1-yl-1H-indole
(602), m.p. 118-120.degree. C.;
[0315]
3-(4-fluorobenzenesulfonyl)-2-methyl-7-piperazin-1-yl-1H-indole
(603), m.p. 232-236.degree. C.; and
[0316]
3-(4-methoxybenzenesulfonyl)-2-methyl-7-piperazin-1-yl-1H-indole
(604), m.p. 182-184.degree. C.
Example 7
3-Phenylsulfanyl-7-piperazin-1-yl-1H-indole
[0317] 51
[0318] Trifluoroacetic acid (5 mL) was added to a solution of
4-(3-phenylsulfanyl-1H-indol-7-yl)piperazine-1-carboxylic acid
tert-butyl ester (700 mg, 1.7 mmol), prepared as described in
Example 1 Step 1, in 4 mL of dichloromethane. After 15 min the
solution was diluted with water, basified with ammonium hydroxide,
and extracted with dichloromethane. The dichloromethane was washed
with brine and evaporated to afford
3-phenylsulfanyl-7-piperazin-1-yl-1H-indole (701) as a solid. The
hydrochloride salt crystallized from ethanol-HCl to afford 500 mg
of white solid, m.p. 300.degree. C. Similarly replacing
4-(3-phenylsulfanyl-1H-indol-7-yl)piperazine-1-carboxylic acid
tert-butyl ester with the appropriate sulfanyl derivatives,
prepared as described in other examples herein, the following
compounds were prepared:
[0319] 3-(2,3-dichloro-phenylsulfanyl)-5-piperazin-1-yl-1H-indole
(702), mp 255.1-255.5.degree. C.;
3-phenylsulfanyl-5-piperazin-1-yl-1H-indole (703), mp. 246-247,
and
[0320] 3-(2,6-dichloro-phenylsulfanyl)-5-piperazin-1-yl-1H-indole
(704) M+H=378.
Example 8
Composition for Oral Administration
[0321]
2 Ingredient % wt./wt. Active ingredient 20.0% Lactose 79.5%
Magnesium stearate 0.5%
[0322] The ingredients are mixed and dispensed into capsules
containing about 100 mg each; one capsule would approximate a total
daily dosage.
Example 9
Composition for Oral Administration
[0323]
3 Ingredient % wt./wt. Active ingredient 20.0% Magnesium stearate
0.5% Crosscarmellose sodium 2.0% Lactose 76.5% PVP
(polyvinylpyrrolidine) 1.0%
[0324] The ingredients are combined and granulated using a solvent
such as methanol. The formulation is then dried and formed into
tablets (containing about 20 mg of active compound) with an
appropriate tablet machine.
Example 10
Composition for Oral Administration
[0325]
4 Ingredient Amount Active compound 1.0 g Fumaric acid 0.5 g Sodium
chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 g
Granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K
(Vanderbilt Co.) 1.0 g Flavoring 0.035 ml Colorings 0.5 mg
Distilled water q.s. to 100 ml
[0326] The ingredients are mixed to form a suspension for oral
administration.
Example 11
Parenteral Formulation (IV)
[0327]
5 Ingredient % wt./wt. Active ingredient 0.25 g Sodium Chloride qs
to make isotonic Water for injection to 100 ml
[0328] The active ingredient is dissolved in a portion of the water
for injection. A sufficient quantity of sodium chloride is then
added with stirring to make the solution isotonic. The solution is
made up to weight with the remainder of the water for injection,
filtered through a 0.2 micron membrane filter and packaged under
sterile conditions.
Example 12
Suppository Formulation
[0329]
6 Ingredient % wt./wt. Active ingredient 1.0% Polyethylene glycol
1000 74.5% Polyethylene glycol 4000 24.5%
[0330] The ingredients are melted together and mixed on a steam
bath, and poured into molds containing 2.5 g total weight.
Example 13
Topical Formulation
[0331]
7 Ingredients grams Active compound 0.2-2 Span 60 2 Tween 60 2
Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05
BHA (butylated hydroxy anisole) 0.01 Water q.s. 100
[0332] All of the ingredients, except water, are combined and
heated to about 60.degree. C. with stirring. A sufficient quantity
of water at about 60.degree. C. is then added with vigorous
stirring to emulsify the ingredients, and water then added q.s.
about 100 g.
Example 14
[0333] Nasal Spray Formulations
[0334] Several aqueous suspensions containing from about 0.025-0.5
percent active compound are prepared as nasal spray formulations.
The formulations optionally contain inactive ingredients such as,
for example, microcrystalline cellulose, sodium
carboxymethylcellulose, dextrose, and the like. Hydrochloric acid
may be added to adjust pH. The nasal spray formulations may be
delivered via a nasal spray metered pump typically delivering about
50-100 microliters of formulation per actuation. A typical dosing
schedule is 2-4 sprays every 4-12 hours.
Example 15
Radioligand Binding Studies
[0335] The binding activity of compounds of this invention in vitro
was determined as follows.
[0336] Duplicate determinations of ligand affinity are made by
competing for binding of [3H]LSD in cell membranes derived from
HEK293 cells stably expressing recombinant human 5-HT6
receptor.
[0337] All determinations are made in assay buffer containing 50 mM
Tris-HCl, 10 mM MgSO4, 0.5 mM EDTA, 1 mM ascorbic acid, pH 7.4 at
37.degree. C., in a 250 microliter reaction volume. Assay tubes
containing [3H] LSD (5 nM), competing ligand, and membrane are
incubated in a shaking water bath for 60 min. at 37.degree. C.,
filtered onto Packard GF-B plates (pre-soaked with 0.3% PEI) using
a Packard 96 well cell harvester and washed 3 times in ice cold 50
mM Tris-HCl. Bound [3H] LSD is determined as radioactive counts per
minute using Packard TopCount.
[0338] Displacement of [3H]LSD from the binding sites was
quantified by fitting concentration-binding data to a 4-parameter
logistic equation: 1 binding = basal + ( Bmax - basal 1 + 10 - Hill
( lo g [ ligand ] - logIC 50 )
[0339] where Hill is the Hill slope, [ligand] is the concentration
of competing radioligand and IC50 is the concentration of
radioligand producing half-maximal specific binding of radioligand.
The specific binding window is the difference between the Bmax and
the basal parameters.
[0340] Proceeding as in Example 15, compounds of Formula I were
tested and found to be selective 5-HT6 antagonists.
[0341] While the present invention has been described with
reference to the specific embodiments thereof, it should be
understood by those skilled in the art that various changes may be
made and equivalents may be substituted without departing from the
true spirit and scope of the invention. In addition, many
modifications may be made to adapt a particular situation,
material, composition of matter, process, process step or steps, to
the objective spirit and scope of the present invention. All such
modifications are intended to be within the scope of the claims
appended hereto.
* * * * *