2,3,4,5-Tetrahydro-1H-[1,4]diazepino[1,7-a&rs...

Details 2,3,4,5-Tetrahydro-1H-[1,4]diazepino[1,7-a&rs... 2,3,4,5-Tetrahydro-1H-[1,4]diazepino[1,7-a&rs...

2001-03-08

2004-05-11

Coleman, Brenda (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C514S220000

Reexamination Certificate

active

06734301

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention provides novel diazepinoindole compounds of Formula I. These compounds are 5-HT ligands and are useful for treating diseases wherein modulation of 5-HT activity is desired.
2. Technology Description
Serotonin has been implicated in a number of diseases and conditions that originate in the central nervous system. These include diseases and conditions related to sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, schizophrenia, and other bodily states. Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contractile, secretory, and electrophysiologic effects.
As a result of the broad distribution of serotonin within the body, there is a tremendous interest in drugs that affect serotonergic systems. In particular, agonists, partial agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g. Alzheimer's disease, Parkinsonism, and Huntington's chorea), and chemotherapy-induced vomiting.
The major classes of serotonin receptors (5-HT
1-7
) contain fourteen to eighteen separate receptor subtypes that have been formally classified. See Glennon, et al.,
Neuroscience and Behavioral Reviews
, 1990, 14, 35; and D. Hoyer, et al.
Pharmacol. Rev
. 1994, 46, 157-203.
For example, the 5-HT
2
family of receptors is comprised of 5-HT
2A
, 5-HT
2B
, and 5-HT
2C
subtypes, which have been grouped together on the basis of primary structure, secondary messenger system, and operational profile. All three subtypes are G-protein coupled, activate phospholipase C as a principal transduction mechanism, and contain a seven-transmembrane domain structure. There are distinct differences in the distribution of the three 5-HT
2
subtypes. The 5-HT
2B
and 5-HT
2A
receptors are widely distributed in the periphery, while the 5-HT
2C
receptor has been found only in the central nervous system, being highly expressed in many regions of the human brain. See G. Baxter, et al.
Trends in Pharmacol. Sci
. 1995, 16, 105-110.
Subtype 5-HT
2A
has been associated with effects including vasoconstriction, platelet aggregation, and bronchoconstriction, while subtype 5-HT
2C
has been associated with diseases that include depression, anxiety, obsessive compulsive disorder, panic disorders, phobias, psychiatric syndromes, and obesity. Very little is known about the pharmocologic role of the 5-HT
2B
receptor. See F. Jenck, et al.,
Exp. Opin. Invest. Drugs
, 1998, 7, 1587-1599; M. Bos, et al.,
J. Med. Chem
., 1997, 40, 2762-2769; J. R. Martin, et al.,
The Journal of Pharmacology and Experimental Therapeutics
, 1998, 286, 913-924; S. M. Bromidge, et al.,
J. Med. Chem
., 1998, 41, 1598-1612; G. A. Kennett,
Drugs
, 1998, 1, 4, 456-470; and A. Dekeyne, et al.,
Neuropharmacology
, 1999, 38, 415-423.
The following references possibly suggest molecules containing both indole groups and cyclic rings wherein the indolyl nitrogen atom and an additional nitrogen atom form a part of the cyclic ring: SU 460724 and U.S. Pat. No. 4,673,674. However, the molecules described in the above-described references contain additional substituents that the inventors of the instant invention have discovered are not required, and potentially not desired. U.S. Pat. No. 4,210,590 suggests the reduction of indole compounds to indoline compounds to yield compounds having biological and/or pharmacological properties. U.S. Pat. Nos. 3,689,503 and 3,867,374 disclose 2,3,4,5-tetrahydro-1H-[1,4]-diazepino [1,2-a]indole compounds and their use in treating central nervous system diseases or disorders.
Despite the above teachings, there is currently a need for pharmaceutical agents that are useful in treating diseases and conditions that are associated with 5-HT receptors.
BRIEF SUMMARY OF THE INVENTION
In accordance with the present invention novel compounds which demonstrate useful biological activity, and particularly activity as 5-HT receptor ligands are provided. More specifically, the compounds are unsubstituted or substituted 2,3,4,5-tetrahydro-1H-[1,4]-diazepino[1,7-a]indoles.
A first embodiment of the present invention provides compounds of formula I:
A compound of formula I:
where a is a single bond or double bond, and where
R1a, R1b, R2a and R2b are each independently
(a) H, Cl, Br, I, F, CN, CF
3
, OCF
3
, OR5, CONR5R6, COR5, CO2R5, Y(CH
2
)
m
XR5 or YC(O)(CH
2
)
m
XR5, where m=0-3, Y═CH
2
, S, O, or NR6, X═CH
2
, S, O, NR6;
(b) (CH2)
p
Ar where p=0-3 and Ar is aryl or heteroaryl optionally substituted with one or more of the following: H, halogen, CN, NO
2
, OR7, CF
3
, OCF
3
, SR7, SO
2
R7, SO
2
NR7R8, NR7R8, CONR7R8, NR7COR8, NR7CONR8R9, CO
2
R7, COR7, COR7, or R7; or
(c) linear or branched C
1
-C
8
alkyl, linear or branched C
2
-C
8
alkenyl, linear or branched C
2
-C
8
alkynyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkenyl, or C
3
-C
8
cycloalkynyl; wherein any of these groups may be optionally substituted with one or more of the following: halogen, CN, NO
2
, COR7, OR7, NR7R8, SR7, CO2R7, CONR7R8 or NR7COR8; and where
R3 is
(a) H, Cl, Br, I, F, CN, CF
3
, OCF
3
, alkyl, Ar, OR5, SR5, CHO, CONR5R6, COR5, CO2R5, (Y)
o
(CH2)
n
XR5, C(O)C(O)XR5, (Y)
o
(CH
2
)
n
C(O)XR5, C(O)(CH2)
n
XR5, (Y)
o
(CH2)
n
N(R6)C(O)R5, (Y)
o
(CH2)
n
N(R6)S(O)
2
R5, (Y)
o
(CH2)
n
N(R6)C(O)OR5, (Y)
o
(CH2)
n
N(R6)C(O)NR5R6 where o=0 or 1, n=0-3, X═CH
2
, S, O, or NR6 and Y═CH
2
, S, O or NR6, where Ar is aryl or heteroaryl optionally substituted with one or more of the following: H, halogen, CN, NO
2
, OR7, CF
3
, OCF
3
, SR7, SO
2
R7, SO
2
NR7R8, NR7R8, CONR7R8, NR7COR8, NR7CONR8R9, CO
2
R7, COR7, or R7; or
(b) linear or branched C
1
-C
8
alkyl, linear or branched C
2
-C
8
alkenyl, linear or branched C
2
-C
8
alkynyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkenyl, or C
3
-C
8
cycloalkynyl; wherein any of these groups may be optionally substituted with one or more of the following: halogen, CN, NO
2
, COR10, OR10, NR10R8, SR10, CO2R10, CONR10R8 or NR10COR8; and where
R4, R5 and R6 are each independently
(a) H, linear or branched C
1
-C
8
alkyl, linear or branched C
2
-C
8
alkenyl, linear or branched C
2
-C
8
alkynyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkenyl, or C
3
-C
8
cycloalkynyl; wherein any of these groups other than H may be optionally substituted with one or more of the following: halogen, CN, NO
2
, COR10, OR10, NR10R11, SR10, CO2R10, CONR10R11 or NR10COR11; or where R5 and R6 are linked to form a 3 to 8 member ring; or
(b) (CH
2
)
p
Ar where p=0-3 and Ar is aryl or heteroaryl optionally substituted with one or more of the following: H, halogen, CN, NO
2
, OR7, CF
3
, OCF
3
, SR7, SO
2
R7, SO
2
NR7R8, NR7R8, CONR7R8, NR7COR8, NR7CONR8R9, CO
2
R7, COR7, or R7; and where
R7, R8, and R9 are each independently
(a) H, linear or branched C
1
-C
8
alkyl, linear or branched C
2
-C
8
alkenyl, linear or branched C
2
-C
8
alkynyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkenyl, or C
3
-C
8
cycloalkynyl groups, wherein any of these groups other than H may be optionally substituted with halogen, CN, NO
2
, COR10, OR10, NR10R11, SR10, CO2R10, CONR10R11, NR10COR11, NR10CONR11R12, or where R7, R8, or R9 are linked to form a ring; or
(b) (CH2)
p
Ar where p=0-3 and Ar is aryl or heteroaryl optionally substituted with one or more of the following: H, halogen, CN, NO
2
, OR10, CF
3
, OCF
3
, SR10, SO
2
R10, SO
2
NR10R11, NR10R11, CONR10R11, NR10COR11, NR10CONR11R12, CO
2
R10, COR10, or R10; and where
R10, R11 and R12 are each independently H, linear or branched C
1
-C
8
alkyl, linear or branched C
2
-C
8
alkenyl, linear or branched C
2
-C
8
alkynyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkenyl, or C
3
-C
8
cycloalkynyl;
or a stereoisomer or pharmaceu

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