U.S. patent application number 10/264018 was filed with the patent office on 2003-04-24 for tricyclic inhibitors of poly(adp-ribose) polymerases.
Invention is credited to Canan-Koch, Stacie S., Thoresen, Lars Henrik, Tikhe, Jayashree, Webber, Stephen Evan.
Application Number | 20030078254 10/264018 |
Document ID | / |
Family ID | 22361361 |
Filed Date | 2003-04-24 |
United States Patent
Application |
20030078254 |
Kind Code |
A1 |
Webber, Stephen Evan ; et
al. |
April 24, 2003 |
Tricyclic inhibitors of poly(ADP-ribose) polymerases
Abstract
Compounds of the formula below are poly(ADP-ribosyl)transferase
(PARP) inhibitors, and are useful as therapeutics in treatment of
cancers and the amelioration of the effects of stroke, head trauma,
and neurodegenerative disease. 1 As cancer therapeutics, the
compounds of the invention may be used, e.g., in combination with
cytotoxic agents and/or radiation.
Inventors: |
Webber, Stephen Evan; (San
Diego, CA) ; Canan-Koch, Stacie S.; (La Jolla,
CA) ; Tikhe, Jayashree; (San Diego, CA) ;
Thoresen, Lars Henrik; (College Station, TX) |
Correspondence
Address: |
Agouron Pharmaceuticals, Inc.
10777 Science Center Road
San Diego
CA
92121
US
|
Family ID: |
22361361 |
Appl. No.: |
10/264018 |
Filed: |
October 2, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10264018 |
Oct 2, 2002 |
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09479896 |
Jan 10, 2000 |
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6495541 |
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60115431 |
Jan 11, 1999 |
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Current U.S.
Class: |
514/212.06 ;
514/292; 540/520; 546/84 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
25/28 20180101; A61P 9/10 20180101; A61K 31/4375 20130101; A61P
35/00 20180101; A61K 31/277 20130101; A61P 43/00 20180101; A61P
3/10 20180101; C07D 471/06 20130101; C07D 487/06 20130101; A61P
25/00 20180101; A61P 29/00 20180101; A61P 3/00 20180101 |
Class at
Publication: |
514/212.06 ;
514/292; 540/520; 546/84 |
International
Class: |
A61K 031/55; A61K
031/4745; C07D 491/04; C07D 471/04 |
Claims
What is claimed is:
1. A compound selected from the group consisting of: 125or a
pharmaceutically acceptable salt, prodrug, active metabolite, or
solvate thereof.
2. A compound, pharmaceutically acceptable salt, prodrug, active
metabolite, or solvate according to claim 1, having a
PARP-inhibiting activity corresponding to a K.sub.1 of 100 .mu.M or
less in a PARP enzyme inhibition assay.
3. A compound, pharmaceutically acceptable salt, prodrug, active
metabolite, or solvate according to claim 1, having a cytotoxicity
potentiation activity corresponding to a PF.sub.50 of at least 1 in
a cytotoxicity potentiation assay.
4. A pharmaceutical composition comprising: (a) an effective amount
of a PARP-inhibiting agent that is: (i) a compound selected from
the group consisting of: 126(ii) a pharmaceutically acceptable
salt, prodrug, active metabolite, or solvate thereof; and (b) a
pharmaceutically acceptable carrier for said PARP-inhibiting
agent.
5. A method of inhibiting PARP activity of an enzyme, comprising
contacting the enzyme with an effective amount of a compound,
pharmaceutically acceptable salt, prodrug, active metabolite, or
solvate according to claim 1.
6. A method according to claim 5, wherein the enzyme is
poly(ADP-ribose) polymerase or tankyrase.
7. A method of inhibiting PARP enzyme activity in mammalian tissue
by administering to a mammal a therapeutically effective amount of
a compound, pharmaceutically acceptable salt, prodrug, active
metabolite, or solvate according to claim 1.
8. A method of inhibiting PARP activity of an enzyme, comprising
contacting the enzyme with an effective amount of a compound of the
formula: 127wherein: R.sup.1 is: H; halogen; cyano; an optionally
substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, or heteroaryl group; or --C(O)--R.sup.10, where R.sup.10 is:
H; an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl group; or OR.sup.100 or
NR.sup.100R.sup.110, where R.sup.100 and R.sup.110 are each
independently H or an optionally substituted alkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group
R.sup.2 is H or alkyl; R.sup.3 is H or alkyl; R.sup.4 is H, halogen
or alkyl; X is O or S; Y is
(CR.sup.5R.sup.6)(CR.sup.7R.sup.8).sub.n or N.dbd.C(R.sup.5),
where: n is 0 or 1; R.sup.5 and R.sup.6 are each independently H or
an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl group; and R.sup.7 and
R.sup.8 are each independently H or an optionally substituted
alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl group; or a pharmaceutically acceptable salt, prodrug,
active metabolite, or solvate of the compound.
9. A compound of the formula: 128wherein: R.sup.1 is: H; halogen;
cyano; an optionally substituted alkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or
--C(O)--R.sup.10, where R.sup.10 is: H; an optionally substituted
alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl group; 2665 or OR.sup.100 or NR.sup.100R.sup.110, where
R.sup.100 and R.sup.110 are each independently H or an optionally
substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, or heteroaryl group R.sup.2 is H or alkyl; R.sup.3 is H or
alkyl; R.sup.4 is H, halogen or alkyl; X is O or S; Y is
(CR.sup.5R.sup.6)(CR.sup.7R.sup.8).sub.n or N.dbd.C(R.sup.5),
where: n is 0 or 1; R.sup.5 and R.sup.6 are each independently H or
an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl group; and R.sup.7 and
R.sup.8 are each independently H or an optionally substituted
alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl group; where when R.sup.1, R.sup.4, R.sup.5, R.sup.6,
and R.sup.7 are each H, R.sup.8 is not unsubstituted phenyl; or a
pharmaceutically acceptable salt, prodrug, active metabolite, or
solvate of the compound.
10. A compound of the formula: 129wherein: p is 1 or 2; R.sup.11 is
H or alkyl; R.sup.12 is halogen or an optionally substituted aryl,
alkyl, alkenyl, alkynyl or acyl group --C(O)--R.sup.10 where
R.sup.10 is: H; an optionally substituted alkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or
OR.sup.100 or NR.sup.100R.sup.110, where R.sup.100 and R.sup.110
are each independently H or an optionally substituted alkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl
group R.sup.13 is H or alkyl; and R.sup.14 is H or halogen; or a
pharmaceutically acceptable salt, prodrug, active metabolite, or
solvate of the compound.
11. A compound of the formula 130wherein: R.sup.15 is H, halogen,
or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,
or heteroaryl group unsubstituted or substituted with one or more
substituents selected from halogen, hydroxy, nitro, amino, and
alkyl and aryl groups unsubstituted or substituted with one or more
substituents selected from halogen, hydroxy, nitro, and amino;
R.sup.16 is H; halogen; cyano; or an alkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group
unsubstituted or substituted with one or more substituents selected
from halogen, hydroxy, nitro, amino, and alkyl and aryl groups
unsubstituted or substituted with one or more substituents selected
from halogen, hydroxy, nitro, and amino; R.sup.17 is H or alkyl;
and R.sup.18 is H, halogen, or alkyl; where R.sup.15, R.sup.16,
R.sup.17 and R.sup.18 are not all H.
12. A compound selected from the group consisting of 131or a
pharmaceutically acceptable salt, prodrug, active metabolite or
solvate thereof.
13. A compound, pharmaceutically acceptable salt, prodrug, active
metabolite, or solvate according to claim 9, having a
PARP-inhibiting activity corresponding to a K.sub.i of 100 .mu.M or
less in a PARP enzyme inhibition assay.
14. A compound, pharmaceutically acceptable salt, prodrug, active
metabolite, or solvate according to claim 9, having a cytotoxicity
potentiation activity corresponding to a PF.sub.50 of at least 1 in
a cytotoxicity potentiation assay.
15. A pharmaceutical composition comprising: (a) an effective
amount of a PARP-inhibiting agent that is a compound according to
claim 9; or a pharmaceutically acceptable salt, prodrug, active
metabolite, or solvate thereof; and (b) a pharmaceutically
acceptable carrier for said PARP-inhibiting agent.
16. A method of inhibiting PARP activity of an enzyme, comprising
contacting the enzyme with an effective amount of a compound,
pharmaceutically acceptable salt, prodrug, active metabolite, or
solvate according to claim 9.
17. A method according to claim 16, wherein the enzyme is
poly(ADP-ribose) polymerase or tankyrase.
18. A method of inhibiting PARP enzyme activity in mammalian tissue
by administering to a mammal a therapeutically effective amount of
a compound, pharmaceutically acceptable salt, prodrug, active
metabolite, or solvate according to claim 9.
19. A method of inhibiting PARP activity of an enzyme, comprising
contacting the enzyme with an effective amount of a compound,
pharmaceutically acceptable salt, prodrug, active metabolite, or
solvate according to claim 12.
Description
[0001] This application claims priority from Provisional
Application No. 60/115,431 filed Jan. 11, 1999, which is
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The invention pertains to compounds that inhibit
poly(ADP-ribose) polymerases, thereby retarding the repair of
damage to DNA strands, and to methods of preparing such compounds.
The invention also relates the use of such compounds in
pharmaceutical compositions and therapeutic treatments useful for
potentiation of anti-cancer therapies and inhibition of
neurotoxicity consequent to stroke, head trauma, and
neurodegenerative diseases.
BACKGROUND OF THE INVENTION
[0003] Poly(ADP-ribose) polymerases (PARPs), nuclear enzymes found
in almost all eukaryotic cells, catalyze the transfer of ADP-ribose
units from nicotinamide adenine dinucleotide (NAD.sup.+) to nuclear
acceptor proteins, and are responsible for the formation of
protein-bound linear and branched homo-ADP-ribose polymers.
Activation of PARP and resultant formation of poly(ADP-ribose) can
be induced by DNA strand breaks after exposure to chemotherapy,
ionizing radiation, oxygen free radicals, or nitric oxide (NO).
[0004] Because this cellular ADP-ribose transfer process is
associated with the repair of DNA strand breakage in response to
DNA damage caused by radiotherapy or chemotherapy, it can
contribute to the resistance that often develops to various types
of cancer therapies. Consequently, inhibition of PARP may retard
intracellular DNA repair and enhance the antitumor effects of
cancer therapy. Indeed, in vitro and in vivo data show that many
PARP inhibitors potentiate the effects of ionizing radiation or
cytotoxic drugs such as DNA methylating agents. Therefore,
inhibitors of the PARP enzyme are useful as cancer
chemotherapeutics.
[0005] In addition, it has been shown that inhibition of PARP
promotes resistance to brain injury after stroke (Endres et al.,
"Ischemic Brain Injury is Mediated by the Activation of
Poly(ADP-Ribose)Polymerase," J. Cerebral Blood Flow Metab.
17:1143-1151 (1997); Zhang, "PARP Inhibition Results in Substantial
Neuroprotection in Cerebral Ischemia," Cambridge Healthtech
Institute's Conference on Acute Neuronal Injury: New Therapeutic
Opportunities, Sep. 18-24, 1998, Las Vegas, Nev.). The activation
of PARP by DNA damage is believed to play a role in the cell death
consequent to stroke, head trauma, and neurodegenerative diseases.
DNA is damaged by excessive amounts of NO produced when the NO
synthase enzyme is activated as a result of a series of events
initiated by the release of the neurotransmitter glutamate from
depolarized nerve terminals (Cosi et al., "Poly(ADP-Ribose)
Polymerase Revisited: A New Role for an Old Enzyme: PARP
Involvement in Neurodegeneration and PARP Inhibitors as Possible
Neuroprotective Agents," Ann. N.Y. Acad. Sci., 366-379). Cell death
is believed to occur as a result of energy depletion as NAD.sup.+
is consumed by the enzyme-catalyzed PARP reaction. Therefore,
inhibitors of the PARP enzyme are useful inhibitors of
neurotoxicity consequent to stroke, head trauma, and
neurodegenerative diseases.
[0006] Further, inhibition of PARP should be a useful approach for
treatment of conditions or diseases associated with cellular
senescence, such as skin aging, through the role of PARP in the
signaling of DNA damage. See, e.g., U.S. Pat. No. 5,589,483, which
describes a method to extend the lifespan and proliferative
capacity of cells comprising administering a therapeutically
effective amount of a PARP inhibitor to the cells under conditions
such that PARP activity is inhibited. Hence, inhibitors of the PARP
enzyme are useful therapeutics for skin aging.
[0007] In yet a further application, PARP inhibition is being
explored at the clinical level to prevent development of
insulin-dependent diabetes mellitus in susceptible individuals
(Saldeen et al., "Nicotinamide-induced apoptosis in insulin
producing cells in associated with cleavage of poly(ADP-ribose)
polymerase," Mol. Cellular Endocrinol. (1998), 139:99-107). PARP
inhibitors should therefore be useful as diabetes-prevention
therapeutics.
[0008] PARP inhibition is also an approach for treating
inflammatory conditions such as arthritis (Szabo et al.,
"Protective effect of an inhibitor of poly(ADP-ribose) synthetase
in collagen-induced arthritis," Portland Press Proc. (1998),
15:280-281; Szabo, "Role of Poly(ADP-ribose) Synthetase in
Inflammation," Eur. J. Biochem. (1998), 350(1):1-19; Szabo et al.,
"Protection Against Peroxynitrite-induced Fibroblast Injury and
Arthritis Development by Inhibition of Poly(ADP-ribose)
Synthetase," Proc. Natl. Acad. Sci. USA (1998), 95(7):3867-72).
PARP inhibitors are therefore useful as therapeutics for
inflammatory conditions.
[0009] Inhibition of PARP has usefulness for protection against
myocardial ischemia and reperfusion injury (Zingarelli et al.,
"Protection against myocardial ischemia and reperfusion injury by
3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase,"
Cardiovascular Research (1997), 36:205-215). Therefore, PARP
inhibitors are useful in therapy of cardiovascular diseases.
[0010] The PARP family of enzymes is extensive. It has recently
been shown that tankyrases, which bind to the telomeric protein
TRF-1, a negative regulator of telomere length maintenance, have a
catalytic domain that is strikingly homologous to PARP and have
been shown to have PARP activity in vitro. It has been proposed
that telomere function in human cells is regulated by
poly(ADP-ribosyl)ation. PARP inhibitors have utility as tools to
study this function. Further, as a consequence of regulation of
telomerase activity by tankyrase, PARP inhibitors should have
utility as agents for regulation of cell life-span, e.g., for use
in cancer therapy to shorten the life-span of immortal tumor cells,
or as anti-aging therapeutics, since telomere length is believed to
be associated with cell senescence.
[0011] Competitive inhibitors of PARP are known. For example,
Banasik et al. ("Specific Inhibitors of Poly(ADP-Ribose) Synthetase
and Mono(ADP-Ribosyl)transferase," J. Biol. Chem. (1992) 267:
1569-1575) examined the PARP-inhibiting activity of 132 compounds,
the most potent of which were 4-amino-1,8-naphthalimide,
6(5H)-phenanthridone, 2-nitro-6(5H)-phenanthridone, and
1,5-dihydroxyisoquinoline. Griffin et al. reported the
PARP-inhibiting activity for a series of benzamide compounds (U.S.
Pat. No. 5,756,510; see also "Novel Potent Inhibitors of the DNA
Repair Enzyme poly (ADP-ribose)polymerase (PARP)," Anti-Cancer Drug
Design (1995), 10:507-514) and quinalozinone compounds
(International Publication No. WO 98/33802). Suto et al. reported
PARP inhibition by a series of dihydroisoquinoline compounds
("Dihydroisoquinolines: The Design and Synthesis of a New Series of
Potent Inhibitors of Poly(ADP-ribose) Polymerase," Anti-Cancer Drug
Design (1991), 7:107-117). Griffin et al. have reported other PARP
inhibitors of the quinazoline class ("Resistance-Modifying Agents.
5. Synthesis and Biological Properties of Quinazoline Inhibitors of
the DNA Repair Enzyme Poly(ADP-ribose) Polymerase (PARP)," J. Med.
Chem., ASAP Article 10.1021/jm980273t S0022-2623(98)00273-8; Web
Release Date: Dec. 1, 1998).
[0012] Nonetheless, there is still a need for small-molecule
compounds that are potent PARP inhibitors, especially those that
have physical and chemical properties desirable for pharmaceutical
applications.
SUMMARY OF THE INVENTION
[0013] The present invention is directed to compounds that function
as potent poly(ADP-ribosyl)transferase (PARP) inhibitors and are
useful as therapeutics, especially in treatment of cancers and the
amelioration of the effects of stroke, head trauma, and
neurodegenerative disease. As cancer therapeutics, the compounds of
the invention may be used in combination with DNA-damaging
cytotoxic agents, for example, topotecan, irinotecan, or
temozolomide, and/or radiation.
[0014] In particular, the present invention is directed to
compounds of the general formula (I): 2
[0015] wherein:
[0016] R.sup.1 is:
[0017] H;
[0018] halogen;
[0019] cyano;
[0020] an optionally substituted alkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group (e.g.,
unsubstituted or substituted with one or more substituents selected
from halogen, hydroxy, nitro, and amino, alkoxy, alkyl, and aryl
groups unsubstituted or substituted with one or more substituents
selected from halogen, hydroxy, nitro, carboxy, and optionally
substituted amino and ether groups (such as O-aryl)); or
[0021] --C(O)--R.sup.10, where R.sup.10 is: H; an optionally
substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, or heteroaryl group (e.g., unsubstituted or substituted with
one or more substituents selected from halogen, hydroxy, nitro,
amino, and alkyl and aryl groups unsubstituted or substituted with
one or more substituents selected from halo, hydroxy, nitro, and
amino); or OR.sup.100 or NR.sup.100R.sup.110, where R.sup.100 and
R.sup.110 are each independently H or an optionally substituted
alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl group (e.g., unsubstituted or substituted with one or
more substituents selected from alkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups
unsubstituted or substituted with one or more substituents selected
from halogen, hydroxy, nitro, amino, and alkyl and aryl groups
unsubstituted or substituted with one or more substituents selected
from halogen, hydroxy, nitro, and optionally substituted amino
groups);
[0022] R.sup.2is H or alkyl;
[0023] R.sup.3 is H or alkyl;
[0024] R.sup.4 is H, halogen or alkyl;
[0025] X is O or S;
[0026] Y is (CR.sup.5R.sup.6)(CR.sup.7R.sup.8).sub.n or
N.dbd.C(R.sup.5), where:
[0027] n is 0 or 1;
[0028] R.sup.5 and R.sup.6 are each independently H or an
optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl group (e.g., unsubstituted or
substituted with one or more substituents selected from halogen,
hydroxy, nitro, amino, and lower alkyl, lower alkoxy, or aryl
groups unsubstituted or substituted with one or more substituents
selected from halogen, hydroxy, nitro, and amino); and
[0029] R.sup.7 and R.sup.8 are each independently H or an
optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl group (e.g., unsubstituted or
substituted with one or more substituents selected from halogen,
hydroxy, nitro, amino, and lower alkyl, lower alkoxy, and aryl
groups unsubstituted or substituted with one or more substituents
selected from halogen, hydroxy, nitro, and amino);
[0030] where when R.sup.1, R.sup.4, R.sup.5, R.sup.6, and R.sup.7
are each H, R.sup.8 is not unsubstituted phenyl.
[0031] The invention is also directed to pharmaceutically
acceptable salts, prodrugs, active metabolites, and solvates of
such compounds. Preferred compounds of the formula (I) include
those where R.sup.2 and R.sup.3 are each independently selected
from H and methyl.
[0032] In a preferred embodiment, the inventive compounds include
those of generic formula (II): 3
[0033] wherein:
[0034] p is 1 or 2;
[0035] R.sup.11 is H or alkyl;
[0036] R.sup.12 is halogen or an optionally substituted aryl,
alkyl, alkenyl, alkynyl or acyl group --C(O)--R.sup.10 as defined
above;
[0037] R.sup.13 is H or alkyl; and
[0038] R.sup.14 is H or halogen;
[0039] as well as pharmaceutically acceptable salts, prodrugs,
active metabolites, and solvates of such compounds.
[0040] In preferred compounds of the formula (II), R.sup.11 and
R.sup.13 are each independently selected from H and methyl. More
preferably, the invention is directed to compounds of formula (II)
where R.sup.11 and R.sup.13 are each H, and R.sup.12 is optionally
substituted aryl, and to pharmaceutically acceptable salts,
prodrugs, active metabolites, and solvates of such compounds. In
another preferred embodiment of compounds of formula (II), R.sup.11
and R.sup.13 are each H, and R.sup.12 is halogen or optionally
substituted aryl.
[0041] In another preferred embodiment, the inventive compounds
include those of generic formula (III) below, as well as
pharmaceutically acceptable salts, prodrugs, active metabolites,
and solvates thereof: 4
[0042] wherein:
[0043] R.sup.15 is H, halogen, or an alkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group
unsubstituted or substituted with one or more substituents selected
from halogen, hydroxy, nitro, amino, and alkyl and aryl groups
unsubstituted or substituted with one or more substituents selected
from halogen, hydroxy, nitro, and amino;
[0044] R.sup.16 is H; halogen; cyano; or an alkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group
unsubstituted or substituted with one or, more substituents
selected from halogen, hydroxy, nitro, amino, and alkyl and aryl
groups unsubstituted or substituted with one or more substituents
selected from halogen, hydroxy, nitro, and amino;
[0045] R.sup.17 is H or alkyl; and
[0046] R.sup.18 is H, halogen, or alkyl;
[0047] where R.sup.15, R.sup.16, R.sup.17 and R.sup.18 are not all
H.
[0048] In preferred compounds of the formula (III), R.sup.15 is
substituted phenyl or (CH.sub.2).sub.q aryl, where q is 1 or 2.
[0049] In other preferred compounds of the formula (III), R.sup.16
is subsituted or unsubstituted aryl.
[0050] The present invention is also directed to a method of
inhibiting PARP enzyme activity, comprising contacting the enzyme
with an effective amount of a compound of formula (I), (II), or
(III), or a pharmaceutically acceptable salt, prodrug, active
metabolite, or solvate thereof. The compounds of the invention are
potent PARP inhibitors and preferably have a PARP-inhibiting
activity corresponding to a K.sub.i of 100 .mu.M or less in the
PARP enzyme inhibition assay.
[0051] The present invention is further directed to a method of
potentiating the cytotoxicity of a cytotoxic drug or ionizing
radiation, comprising contacting cells with an effective amount of
a compound of formula (I), (II), or (III), or a pharmaceutically
acceptable salt, prodrug, active metabolite, or solvate thereof, in
combination with a cytotoxic drug or ionizing radiation. The
compounds of the invention preferably have a cytotoxicity
potentiation activity corresponding to a PF.sub.50 of at least 1 in
the cytotoxicity potentiation assay.
[0052] The present invention is also directed to pharmaceutical
compositions comprising an effective PARP-inhibiting amount of a
compound of formula (I), (II), or (III), or a pharmaceutically
acceptable salt, prodrug, active metabolite, or solvate thereof,
together with a pharmaceutically acceptable carrier therefor.
[0053] The invention also provides therapeutic interventions
appropriate in disease or injury states where PARP activity is
deleterious to a patient, the therapeutic methods comprising
inhibiting PARP enzyme activity in the relevant tissue of the
patient by administering a compound of formula (I), (II), or (III),
or a pharmaceutically acceptable salt, prodrug, active metabolite,
or solvate thereof. In one such therapeutic intervention method
provided by the present invention, the effectiveness of a cytotoxic
drug or radiotherapy administered to a mammal in the course of
therapeutic treatment is improved by administering to the patient,
e.g., a mammal in need of treatment, an effective PARP-inhibiting
amount of a compound of formula (I), (II), or (III), or a
pharmaceutically acceptable salt, prodrug, active metabolite, or
solvate thereof, in conjunction with the administration of the
cytotoxic drug or radiotherapy.
[0054] Another therapeutic intervention method provided by the
present invention is for delaying the onset of cell senescence
associated with skin aging in a human, comprising administering to
fibroblast cells in the human an effective PARP-inhibiting amount
of a compound of formula (I), (II), or (III), or a pharmaceutically
acceptable salt, prodrug, active metabolite, or solvate
thereof.
[0055] Yet another therapeutic intervention method provided by the
present invention is a method for reducing the neurotoxicity
consequent to stroke, head trauma, and neurodegenerative diseases
in a mammal by administering an effective amount of a compound of
formula (I), (II), or (III), or a pharmaceutically acceptable salt,
prodrug, active metabolite, or solvate thereof, to the mammal.
[0056] The compounds of the present invention provide a therapeutic
approach to treatment of inflammatory conditions, comprising
administering an effective amount of a compound of formula (I),
(II), or (III), or a pharmaceutically acceptable salt, prodrug,
active metabolite, or solvate thereof, to a patient in need of
treatment.
[0057] Yet a further therapeutic intervention method provided by
the present invention is a cardiovascular therapeutic method for
protecting against myocardial ischemia and reperfusion injury in a
mammal, comprising administering to the mammal an effective amount
of a compound of formula (I), (II), or (III), or a pharmaceutically
acceptable salt, prodrug, active metabolite, or solvate
thereof.
[0058] The present invention is further directed to methods of
synthesizing the tricyclic compounds of formula (I), wherein a
4-carboalkoxy indole (IV) is converted to an intermediate
3-substituted-4-carboalkoxy indole, thereby incorporating the
intended ring carbon atoms, terminally substituted with one
nitrogen atom, usually in the form of a nitro group. Additional
functional groups, such as formyl or acyl, may be incorporated at
the 3-position in this step. The nitro group is reduced to an amine
and cyclized upon the 4-carboalkoxy group in an amide-forming
reaction to yield the tricyclic heterocycle. The synthetic methods
may further comprise derivatization at N-1 and C-2. The 3-formyl or
3-acyl intermediates can be converted to nitrogen-containing
intermediates or to tricyclic indoles with N--N bonds, such as the
compounds of formula (III). 5
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
[0059] PARP-Inhibiting Agents:
[0060] In accordance with a convention used in the art, the symbol
6
[0061] is used in structural formulas herein to depict the bond
that is the point of attachment of the moiety or substituent to the
core or backbone structure. In accordance with another convention,
in some structural formulae herein the carbon atoms and their bound
hydrogen atoms are not explicitly depicted, e.g., 7
[0062] represents a methyl group, 8
[0063] represents an ethyl group, 9
[0064] represents a cyclopentyl group, etc.
[0065] As used herein, the term "alkyl" means a branched- or
straight-chained (linear) paraffinic hydrocarbon group (saturated
aliphatic group) having from 1 to 10 carbon atoms in its chain,
which may be generally represented by the formula
C.sub.kH.sub.2k+1, where k is an integer of from 1 to 10. Examples
of alkyl groups include methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, t-butyl, pentyl, n-pentyl, isopentyl, neopentyl,
and hexyl, and the simple aliphatic isomers thereof. A "lower
alkyl" is intended to mean an alkyl group having from 1 to 4 carbon
atoms in its chain.
[0066] The term "alkenyl" means a branched- or straight-chained
olefinic hydrocarbon group (unsaturated aliphatic group having one
or more double bonds) containing 2 to 10 carbons in its chain.
Exemplary alkenyls include ethenyl, 1-propenyl, 2-propenyl,
1-butenyl, 2-butenyl, isobutenyl, and the various isomeric
pentenyls and hexenyls (including both cis and trans isomers).
[0067] The term "alkynyl" means a branched or straight-chained
hydrocarbon group having one or more carbon-carbon triple bonds,
and having from 2 to 10 carbon atoms in its chain. Exemplary
alkynyls include ethynyl, propynyl, 1-butynyl, 2-butynyl, and
1-methyl-2-butynyl.
[0068] The term "carbocycle" refers to a saturated, partially
saturated, unsaturated, or aromatic, monocyclic or fused or
non-fused polycyclic, ring structure having only carbon ring atoms
(no heteroatoms, i.e., non-carbon ring atoms). Exemplary
carbocycles include cycloalkyl, aryl, and cycloalkyl-aryl
groups.
[0069] The term "heterocycle" refers to a saturated, partially
saturated, unsaturated, or aromatic, monocyclic or fused or
non-fused polycyclic, ring structure having one or more heteroatoms
selected from N, O, and S. Exemplary heterocycles include
heterocycloalkyl, heteroaryl, and heterocycloalkyl-heteroaryl
groups.
[0070] A "cycloalkyl group" is intended to mean a non-aromatic
monovalent, monocyclic or fused polycyclic, ring structure having a
total of from 3 to 18 carbon ring atoms (but no heteroatoms).
Exemplary cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, phenanthrenyl,
and like groups.
[0071] A "heterocycloalkyl group" is intended to mean a
non-aromatic monovalent, monocyclic or fused polycyclic, ring
structure having a total of from 3 to 18 ring atoms, including 1 to
5 heteroatoms selected from nitrogen, oxygen, and sulfur.
Illustrative examples of heterocycloalkyl groups include
pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl,
morpholinyl, thiomorpholinyl, aziridinyl, and like groups.
[0072] The term "aryl" means an aromatic monocyclic or fused
polycyclic ring structure having a total of from 4 to 18,
preferably 6 to 18, ring carbon atoms (no heteroatoms). Exemplary
aryl groups include phenyl, naphthyl, anthracenyl, and the
like.
[0073] A "heteroaryl group" is intended to mean an aromatic
monovalent, monocyclic or fused polycyclic, ring structure having
from 4 to 18, preferably 5 to 18, ring atoms, including from 1 to 5
heteroatoms selected from nitrogen, oxygen, and sulfur.
Illustrative examples of heteroaryl groups include pyrrolyl,
thienyl, oxazolyl, pyrazolyl, thiazolyl, furyl, pyridinyl,
pyrazinyl, triazolyl, tetrazolyl, indolyl, quinolinyl,
quinoxalinyl, and the like.
[0074] The term "optionally substituted" is intended to indicate
that the specified group is unsubstituted or substituted by one or
more suitable substituents, unless the optional substituents are
expressly specified, in which case the term indicates that the
group is unsubstituted or substituted with the specified
substituents. Unless indicated otherwise (e.g., by indicating that
a specified group is unsubstituted), the various groups defined
above may be generally unsubstituted or substituted (i.e., they are
optionally substituted) with one or more suitable substituents.
[0075] The term "substituent" or "suitable substituent" is intended
to mean any substituent for a group that may be recognized or
readily selected by the artisan, such as through routine testing,
as being pharmaceutically suitable. Illustrative examples of
suitable substituents include hydroxy, halogen (F, Cl, I, or Br),
oxo, alkyl, acyl, sulfonyl, mercapto, nitro, alkylthio, alkoxy,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy, amino
(primary, secondary, or tertiary), carbamoyl, aryloxy,
heteroaryloxy, arylthio, heteroarylthio, and the like (e.g., as
illustrated by the exemplary compounds described herein). Suitable
substituents are seen from the exemplary compounds that follow.
[0076] Preferred optional substituents for alkyl and aryl groups in
the compounds of the invention include halogens and aryl groups.
Especially preferred for substituted alkyl groups are
perfluoro-substituted alkyls. Especially preferred optional
substituents for aryl moieties include halogen, lower alkyl, --OH,
--NO.sub.2, --CN, --CO.sub.2H, O-lower alkyl, aryl, --O-aryl,
aryl-lower alkyl, --CO.sub.2CH.sub.3, --CONH.sub.2,
--OCH.sub.2CONH.sub.2, --NH.sub.2, --SO.sub.2NH.sub.2,
--OCHF.sub.2, --CF.sub.3, --OCF.sub.3, and the like. Aryl moieties
may also be optionally substituted by two substituents forming a
bridge, for example --O--(CH.sub.2).sub.z--O--, where z is an
integer of 1, 2, or 3.
[0077] A "prodrug" is intended to mean a compound that is converted
under physiological conditions or by solvolysis, or metabolically,
to a specified compound that is pharmaceutically active.
[0078] An "active metabolite" is intended to mean a
pharmacologically active product produced through metabolism in the
body of a specified compound.
[0079] A "solvate" is intended to mean a pharmaceutically
acceptable solvate form of a specified compound that retains the
biological effectiveness of such compound. Examples of solvates
include compounds of the invention in combination with water,
isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,
or ethanolamine.
[0080] A "pharmaceutically acceptable salt" is intended to mean a
salt that retains the biological effectiveness of the free-acid or
base form of the specified compound and that is pharmaceutically
suitable. Examples of pharmaceutically acceptable salts include
sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,
phosphates, monohydrogenphosphates, dihydrogenphosphates,
metaphosphates, pyrophosphates, chlorides, bromides, iodides,
acetates, propionates, decanoates, caprylates, acrylates, formates,
isobutyrates, caproates, heptanoates, propiolates, oxalates,
malonates, succinates, suberates, sebacates, fumarates, maleates,
butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,
methylbenzoates, dinitrobenzoates, hydroxybenzoates,
methoxybenzoates, phthalates, sulfonates, xylenesulfonates,
phenylacetates, phenylpropionates, phenylbutyrates, citrates,
lactates, .gamma.-hydroxybutyrates, glycollates, tartrates,
methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,
naphthalene-2-sulfonates, and mandelates.
[0081] If an inventive compound is a base, a desired salt may be
prepared by any suitable method known in the art, including
treatment of the free base with: an inorganic acid, such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or with an organic acid, such as
acetic acid, maleic acid, succinic acid, mandelic acid, fumaric
acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,
salicylic acid, pyranosidyl acid such as glucuronic acid or
galacturonic acid; alpha-hydroxy acid such as citric acid or
tartaric acid; amino acid such as aspartic acid or glutamic acid;
aromatic acid such as benzoic acid or cinnamic acid; sulfonic acid
such as p-toluenesulfonic acid or ethanesulfonic acid; or the
like.
[0082] If an inventive compound is an acid, a desired salt may be
prepared by any suitable method known in the art, including
treatment of the free acid with an inorganic or organic base, such
as an amine (primary, secondary, or tertiary), an alkali metal or
alkaline earth metal hydroxide, or the like. Illustrative examples
of suitable salts include: organic salts derived from amino acids
such as glycine and arginine; ammonia; primary, secondary, and
tertiary amines; and cyclic amines, such as piperidine, morpholine,
and piperazine; as well as inorganic salts derived from sodium,
calcium, potassium, magnesium, manganese, iron, copper, zinc,
aluminum, and lithium.
[0083] In the case of compounds, salts, or solvates that are
solids, it is understood by those skilled in the art that the
inventive compounds, salts, and solvates may exist in different
crystalline or polymorph forms, all of which are intended to be
within the scope of the present invention and specified
formulas.
[0084] In some cases, the inventive compounds will have chiral
centers. When chiral centers are present, the inventive compounds
may exist as single stereoisomers, racemates, and/or mixtures of
enantiomers and/or diastereomers. All such single stereoisomers,
racemates, and mixtures thereof are intended to be within the broad
scope of the generic structural formulae (unless otherwise
indicated). Preferably, however, the inventive compounds are used
in essentially optically pure form (as generally understood by
those skilled in the art, an optically pure compound is one that is
enantiomerically pure). Preferably, the compounds of the invention
are at least 90% of the desired single isomer (80% enantiomeric
excess), more preferably at least 95% (90% e.e.), even more
preferably at least 97.5% (95% e.e.), and most preferably at least
99% (98% e.e.).
[0085] In some cases, compounds can occur in tautomeric forms. In
such cases, it is intended that both tautomers are encompassed by
the structural formulae.
[0086] The present invention is directed to the following
PARP-inhibiting agents: compounds of the formula 10
[0087] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, X, and Y are as
defined above; and pharmaceutically acceptable salts, prodrugs,
active metabolites, and solvates thereof. In preferred embodiments,
the PARP-inhibiting agents are compounds of the formula (I) where
R.sup.2 and R.sup.3 are each independently H or methyl, and
pharmaceutically acceptable salts, prodrugs, active metabolites,
and solvates thereof.
[0088] More preferably, the agents are compounds of formula (II) or
(III): 11
[0089] wherein the variables are as defined above, or
pharmaceutically acceptable salts, prodrugs, active metabolites, or
solvates thereof. In preferred embodiments for formula (II) and
(III), R.sup.11, R.sup.13, and R.sup.17 are each independently H or
methyl.
[0090] In a preferred embodiment, the inventive agents are
compounds of formula (II) and pharmaceutically acceptable salts,
prodrugs, active metabolites and solvates, where R.sup.11 and
R.sup.13 are each H, and R.sup.12 is an optionally substituted aryl
group. In another preferred embodiment, the inventive agents are
compounds of formula (III) and pharmaceutically acceptable salts,
prodrugs, active metabolites and solvates, where R.sup.17 is H or
methyl and R.sup.15 is optionally substituted aryl or alkyl.
[0091] In other preferred embodiments, R.sup.16 is substituted or
unsubstituted aryl and R.sup.15 is hydrogen.
[0092] In other preferred embodiments, R.sup.16 is H, and R.sup.15
is substituted or unsubstituted aryl or alkyl.
[0093] Preferred compounds of the invention include: 12
[0094] Pharmaceutical Methods and Compositions:
[0095] The invention is also directed to a method of inhibiting
PARP enzyme activity, comprising contacting the enzyme with an
effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt, prodrug, active metabolite, or
solvate thereof. For example, PARP activity may be inhibited in
mammalian tissue by administering a compound of formula (I) or a
pharmaceutically acceptable salt, prodrug, active metabolite, or
solvate thereof. In addition to the compounds specified above, the
following known compounds have been found to be useful for
inhibiting PARP enzyme activity: 13
[0096] "Treating" or "treatment" is intended to mean mitigating or
alleviating an injury or a disease condition in a mammal, such as a
human, that is mediated by the inhibition of PARP activity, such as
by potentiation of anti-cancer therapies or inhibition of
neurotoxicity consequent to stroke, head trauma, and
neurodegenerative diseases. Types of treatment include: (a) as a
prophylactic use in a mammal, particularly when the mammal is found
to be predisposed to having the disease condition but not yet
diagnosed as having it; (b) inhibition of the disease condition;
and/or (c) alleviation, in whole or in part, of the disease
condition.
[0097] One treatment method involves improving the effectiveness of
a cytotoxic drug or radiotherapy administered to a mammal in the
course of therapeutic treatment, comprising administering to the
mammal an effective amount of an agent (compound, pharmaceutically
acceptable salt, prodrug, active metabolite, or solvate) in
conjunction with administration of the cytotoxic drug (e.g.,
topotecan or irinotecan) or radiotherapy. The PARP-inhibiting
agents may also be advantageously used in a method for reducing
neurotoxicity consequent to stroke, head trauma, and
neurodegenerative diseases in a mammal by administering a
therapeutically effective amount of an inventive agent to the
mammal. The PARP-inhibiting agents of the invention may also be
used in a method for delaying the onset of cell senescence
associated with skin aging in a human, comprising administering to
fibroblast cells in the human an effective PARP-inhibiting amount
of an agent. Further, the agents may also be used in a method for
helping prevent the development of insulin-dependent diabetes
mellitus in a susceptible individual, comprising administering a
therapeutically effective amount of an agent. Additionally, the
agents may also be employed in a method for treating an
inflammatory condition in a mammal, comprising administering a
therapeutically effective amount of an agent to the mammal.
Moreover, the agents may also be used in a method for treating
cardiovascular disease in a mammal, comprising administering to the
mammal a therapeutically effective amount of a PARP-inhibiting
agent. As knowledge regarding the therapeutic roles of PARP
inhibitors progresses in the art, other utilities of the
PARP-inhibiting agents of the invention will become apparent.
[0098] The activity of the inventive compounds as inhibitors of
PARP activity may be measured by any of the suitable methods known
or available in the art, including by in vivo and in vitro assays.
An example of a suitable assay for activity measurements is the
PARP enzyme inhibition assay described herein.
[0099] Administration of the compounds of the formula (I) and their
pharmaceutically acceptable prodrugs, salts, active metabolites,
and solvates may be performed according to any of the accepted
modes of administration available in the art. Illustrative examples
of suitable modes of administration include oral, nasal,
parenteral, topical, transdermal, and rectal delivery. Oral and
intravenous delivery are preferred.
[0100] An inventive compound of formula (I) or a pharmaceutically
acceptable salt, prodrug, active metabolite, or solvate thereof may
be administered as a pharmaceutical composition in any
pharmaceutical form recognizable to the skilled artisan as being
suitable. Suitable pharmaceutical forms include solid, semisolid,
liquid, or lyophilized formulations, such as tablets, powders,
capsules, suppositories, suspensions, liposomes, and aerosols.
Pharmaceutical compositions of the invention may also include
suitable excipients, diluents, vehicles, and carriers, as well as
other pharmaceutically active agents (including other
PARP-inhibiting agents), depending upon the intended use.
[0101] Acceptable methods of preparing suitable pharmaceutical
forms of the pharmaceutical compositions are known or may be
routinely determined by those skilled in the art. For example,
pharmaceutical preparations may be prepared following conventional
techniques of the pharmaceutical chemist involving steps such as
mixing, granulating, and compressing when necessary for tablet
forms, or mixing, filling, and dissolving the ingredients as
appropriate to give the desired products for oral, parenteral,
topical, intravaginal, intranasal, intrabronchial, intraocular,
intraaural, and/or rectal administration.
[0102] Solid or liquid pharmaceutically acceptable carriers,
diluents, vehicles, or excipients may be employed in the
pharmaceutical compositions. Illustrative solid carriers include
starch, lactose, calcium sulphate dihydrate, terra alba, sucrose,
talc, gelatin, pectin, acacia, magnesium stearate, and stearic
acid. Illustrative liquid carriers include syrup, peanut oil, olive
oil, saline solution, and water. The carrier or diluent may include
a suitable prolonged-release material, such as glyceryl
monostearate or glyceryl distearate, alone or with a wax. When a
liquid carrier is used, the preparation may be in the form of a
syrup, elixir, emulsion, soft gelatin capsule, sterile injectable
liquid (e.g., solution), or a nonaqueous or aqueous liquid
suspension.
[0103] A dose of the pharmaceutical composition contains at least a
therapeutically effective amount of a PARP-inhibiting agent (i.e.,
a compound of formula (I), (II), or (III), or a pharmaceutically
acceptable salt, prodrug, active metabolite, or solvate thereof),
and preferably contains one or more pharmaceutical dosage units.
The selected dose may be administered to a mammal, for example, a
human patient, in need of treatment of a condition mediated by
inhibition of PARP activity, by any known or suitable method of
administering the dose, including: topically, for example, as an
ointment or cream; orally; rectally, for example, as a suppository;
parenterally by injection; or continuously by intravaginal,
intranasal, intrabronchial, intraaural, or intraocular infusion. A
"therapeutically effective amount" is intended to mean the amount
of an agent that, when administered to a mammal in need thereof, is
sufficient to effect treatment for injury or disease condition
mediated by inhibition of PARP activity, such as for potentiation
of anti-cancer therapies and inhibition of neurotoxicity consequent
to stroke, head trauma, and neurodegenerative diseases. The amount
of a given compound of the invention that will be therapeutically
effective will vary depending upon factors such as the particular
compound, the disease condition and the severity thereof, the
identity of the mammal in need thereof, which amount may be
routinely determined by artisans.
[0104] It will be appreciated that the actual dosages of the
PARP-inhibiting agents used in the pharmaceutical compositions of
this invention will be selected according to the particular complex
being used, the particular composition formulated, the mode of
administration and the particular site, and the host and condition
being treated. Optimal dosages for a given set of conditions can be
ascertained by those skilled in the art using conventional
dosage-deterrnination tests. For oral administration, e.g., a dose
that may be employed is from about 0.001 to about 1000 mg/kg body
weight, with courses of treatment repeated at appropriate
intervals.
[0105] Synthetic Processes:
[0106] The present invention is further directed to methods of
synthesizing the PARP-inhibiting agents by processes such as those
set forth below for exemplary compounds of the invention. In the
following examples, the structures of the compounds were confirmed
by one or more of the following: proton magnetic resonance
spectroscopy, infrared spectroscopy, elemental microanalysis, mass
spectrometry, thin layer chromatography, high performance liquid
chromatography, and melting point.
[0107] Proton magnetic resonance (.sup.1H NMR) spectra were
determined using a 300 megahertz Tech-Mag, Bruker Avance 300DPX, or
Bruker Avance 500 DRX spectrometer operating at a field strength of
300 or 500 megahertz (MHz). Chemical shifts are reported in parts
per million (ppm, .delta.) downfield from an internal
tetramethylsilane standard. Alternatively, .sup.1H NMR spectra were
referenced to residual protic solvent signals as follows:
CHCl.sub.3=7.26 ppm; DMSO=2.49 ppm; C.sub.6HD.sub.5=7.15 ppm. Peak
multiplicities are designated as follows: s=singlet; d=doublet;
dd=doublet of doublets; t=triplet; q=quartet; br=broad resonance;
and m=multiplet. Coupling constants are given in Hertz (Hz).
Infrared absorption (IR) spectra were obtained using a Perkin-Elmer
1600 series or a Midac Corporation FTIR spectrometer. Elemental
microanalyses were performed by Atlantic Microlab Inc. (Norcross,
Ga.) or Galbraith Laboratories (Nashville, Tenn.), and gave results
for the elements stated within .+-.0.4% of the theoretical values.
Flash column chromatography was performed using Silica gel 60
(Merck Art 9385). Analytical thin layer chromatography (TLC) was
performed using precoated sheets of Silica 60 F.sub.254 (Merck Art
5719). Melting points (mp) were determined on a MelTemp apparatus
and are uncorrected. All reactions were performed in septum-sealed
flasks under a slight positive pressure of argon, unless otherwise
noted. All commercial solvents were reagent-grade or better and
used as supplied.
[0108] The following abbreviations may be used herein: Et.sub.2O
(diethyl ether); DMF (N,N-dimethylformamide); DMSO
(dimethylsulfoxide); MeOH (methanol); EtOH (ethanol); EtOAc (ethyl
acetate); THF (tetrahydrofuran); Ac (acetyl); Me (methyl); Et
(ethyl); and Ph (phenyl).
[0109] The general reaction protocols described below may be used
to prepare the compounds of the invention. 14
[0110] In Scheme 1, 798 4-carbomethoxyindole A is formylated or
acylated under various Vilsmeier or Friedel-Crafts conditions to
yield B, where R.sup.23 is CHO or COR.sup.24. 4-Carbomethoxyindole
A serves as substrate for a 1,4-addition reaction to yield the
nitroethyl intermediate B, where R.sup.23 is
CHR.sup.25CH.sub.2NO.sub.2. Intermediate B, where R.sup.23 is CHO,
is transformed to the corresponding oxime (R.sup.27 is CH.dbd.NOH)
or nitroalkene (R.sup.27 is CH.dbd.CHNO.sub.2) C, which is then
catalytically reduced to the aminoalkyl derivative D. Nitroethyl
intermediate B is transformed directly to D (when R.sup.23 is
CHR.sup.25CH.sub.2NO.sub.2) by reduction in some cases. Compound D
spontaneously cyclizes to tricyclic lactams E (n=2) and EE.
Exposure of intermediate D to basic conditions also leads to
tricyclic lactams E and EE. Compound E is optionally N-alkylated to
form N-alkylated E or halogenated to yield F. Intermediate F can be
transformed via a metal-catalyzed reaction (typically with
palladium as catalyst) into a number of different substituted
tricyclic lactams G, where R.sup.29 is aryl, alkyl, alkenyl or
alkynyl. G is optionally further modified at R.sup.22, R.sup.29 and
R.sup.30.
[0111] Acyl-substituted compounds of formula J (e.g., compound 42)
can be made by reaction with CO and the corresponding alcohol with
Pd/C catalyst. The esters J may be further converted to other acyl
derivatives by hydrolysis to the free acid, followed by activation
to --C(O)--Lv, where Lv is a leaving group, by standard methods
(e.g., March, Advanced Organic Chemistry: Reactions, Mechanisms,
and Structure, 4th edition, August 1992, John Wiley & Sons, New
York, ISBN 0471601802), and, for example, conversion to amides or
other acyl derivatives by reactions generally known in the art.
Alternatively, the esters J can be directly converted to amides by
standard aminolysis reactions, e.g., by reaction with primary or
secondary amines such as dimethylamine or pyrrolidine. 15
[0112] R.sup.20=CO.sub.2CH.sub.3
[0113] R.sup.21, R.sup.22=H
[0114] R.sup.23=COR.sup.24, (R.sup.24=H, aryl, (CH).sub.qaryl), q=1
or 2 R.sup.32=H, aryl, (CH.sub.2).sub.qaryl)
[0115] R.sup.29=optionally substituted aryl, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl, or H.
[0116] In Scheme 2, intermediate BB, where R.sup.23 is CHO,
(CO)aryl, or CO(CH.sub.2).sub.qaryl where q is 1 or 2, is
transformed to tricyclic acyl hydrazone H by reaction with
hydrazine. 16
[0117] In Scheme 3, the M, where Lv includes, for example, I, Br,
or triflate, is coupled with a substituted alkyne T using palladium
and copper catalysts (See e.g. Sonogashira, K., Tohda, Y.,
Hagihara, N. Tetrahedron Lett. 1975, 50, 4467-4470, incorporated
herein by reference). The intermediate N can be cyclized with
palladium catalyst (See e.g. Arcadi, A., Cacchu, S., Marinellito,
F. Tetrahedron Lett. 1989, 30, 2581-2584, incorporated herein by
reference) to give P which is further modified as described in
Scheme 1 to the intermediate BB.
EXAMPLES
[0118] The invention is further described by reference to the
following specific examples. Unless otherwise indicated, all
percentages and parts are by weight, and all temperatures are in
degrees Celsius.
Example A
3,4-Dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-one (1)
[0119] Compound 1 was prepared as described below according to the
procedure of Demerson et al., J. Med Chem. (1974), 17:1140,
starting from methyl indole-4-carboxylate. 17
[0120] (a) Methyl Indole-4-carboxylate:
[0121] A solution of methyl 2-methyl-3-nitrobenzoate (9.85 g, 50.5
mmol) and dimethylformamide dimethyl acetal (20.1 mL, 151 mmol) in
DMF (53 mL) was heated at 130.degree. C. for 8 hours (h). The
solution was concentrated on a high-vacuum rotovap to give the
benzoate enamine as a viscous dark-red oil, 12.2 g (97% yield).
.sup.1H NMR (DMSO-d.sub.6) .delta.2.83 (s, 6H), 3.85 (s, 3H), 5.42
(d, 1H, J=13.6 Hz), 6.41 (d, 1H, J=13.6 Hz), 7.25 (t, 1H, J=7.9
Hz), 7.76 (d, 1H, J=7.9 Hz), 7.88 (d, 1H, J=7.9 Hz).
[0122] A solution of the benzoate enamine (12.2 g, 48.4 mmol) in
toluene (200 mL) was treated with 10% palladium-on-carbon (2.7 g),
and the mixture was hydrogenated under 50 p.s.i. of hydrogen at
room temperature for 1.5 h. The mixture was filtered through a pad
of Celite, and the pad was rinsed with EtOAc. The crude product was
purified by flash chromatography (3:1 hexanes:EtOAc) to yield
methyl indole-4-carboxylate as a yellow solid, 6.89 g (81%). mp
68-70.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta.3.95 (s, 3H),
7.02 (s, 1H), 7.25 (t, 1H, J=7.6 Hz), 7.60 (s, 1H), 7.75 (d, 1H,
J=7.6 Hz), 7.80 (d, 1H, J=7.6 Hz), 11.54 (bs, 1H).
[0123] (b) Intermediate J--Methyl 3-formylindole-4-carboxylate:
[0124] A solution of methyl indole-4-carboxylate (250 mg, 1.43
mmol) in dichloroethane (2 mL) was treated with a solution of
POCl.sub.3-DMF (1.5 equivalent (eq)) at room temperature (rt). The
orange solution was heated at 50.degree. C. for 1 hour. The
reaction solution was poured into ice-cold aqueous (aq.) NaOAc (1 g
in 2 mL), the aqueous solution was adjusted to pH=8 with 1M NaOH,
and extracted with EtOAc (10 mL.times.3). The organic solution was
washed with water and brine, dried (Na.sub.2SO.sub.4), filtered,
and concentrated to give methyl 3-formyl-indole-4-carboxylate as an
oil, 271 mg (93%). .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.68
(s, 3H), 7.16 (t, 1H, J=7.8 Hz), 7.40 (dd, 1H, J=7.8, 0.8 Hz), 7.56
(d, 1H, J=7.8, 0.8 Hz), 8.16 (d, 1H, J=3.2 Hz), 10.00 (s, 1H),
12.30 (br s, 1H).
[0125] (c) Intermediate K--Methyl
3-formylindole-4-carboxylate-oxime:
[0126] A mixture of J (2.5 g, 12.3 mmol), N-hydroxylamine
hydrochloride (4.27 g, 61.4 mmol), NaOAc (5.04 g, 61.4 mmol),
H.sub.2O (25 mL), and MeOH (25 mL) was stirred for 1 h at
.about.50.degree. C. At this time the mixture was cooled to room
temperature and concentrated under vacuum to remove the MeOH. Fifty
mL of H.sub.2O was added, and the solid was filtered and washed
with additional H.sub.2O. The pure white solid was dried under
vacuum at 40.degree. C. (2.57 g, 95%). .sup.1H NMR (DMSO-d.sub.6)
.delta.3.88 (s, 3H), 7.23 (t, 1H, J=7.7 Hz), 7.59 (dd, 1H, J=7.4,
1.1 Hz), 7.70 (dd, 1H, J=8.1, 1.1 Hz), 8.01 (s, 1H), 8.52 (d, 1H,
J=3.0 Hz), 11.13 (s, 1H), 11.97 (bs, 1H).
[0127] (d) Intermediate L--Methyl 3-aminomethylindole-4-carboxylate
Hydrochloride:
[0128] Dry HCl gas was added to a solution of oxime intermediate K
(2.4 g, 11 mmol) in 130 mL MeOH. Under an argon atmosphere, 0.2 g
of 10% Pd/C was added. Using a three-way valve, the system was
evacuated under vacuum. Hydrogen gas was introduced via a balloon,
and the reaction mixture was vigorously stirred for 4 h. At this
time the balloon was removed, and argon was reintroduced. The
mixture was filtered and concentrated to give a solid which became
violet in color. The solids were washed with Et.sub.2O, protected
from air and light, and placed under vacuum at room temperature.
The violet solid (2.5 g, 96%) was used without further
purification. .sup.1H NMR (DMSO-d.sub.6) .delta.3.89 (s, 3H), 4.31
(m, 2H), 7.23 (t, 1H, J=7.7 Hz), 7.68 (d, 1H, J=2.6 Hz), 7.74 (dd,
1H, J=8.1, 1.1 Hz), 7.78 (dd, 1H, J=7.2, 1.1 Hz), 8.05 (bs, 3H),
11.92 (bs, 1H).
[0129] (e) Compound
1--3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-one:
[0130] A solution of intermediate L (2.4 g, 10.0 mmol) in 24 mL
absolute EtOH was added to a methanolic solution of NaOMe (0.45 g
Na, 24 mL anhydrous MeOH). After stirring at room temperature for
1.5 h, the mixture was concentrated under vacuum to give a residue.
With stirring, ice-cold H.sub.2O (75 mL) was added to the residue,
and the solids were filtered and washed with cold H.sub.2O (50 mL).
Drying in a vacuum oven at 40.degree. C. afforded 1.51 g (87%) of
analytically pure 1 as a tan solid. .sup.1H NMR (DMSO-d.sub.6)
.delta.4.78 (s, 2H), 7.14 (t, 1H, J=7.7 Hz), 7.18 (s, 1H), 7.30 (d,
1H, J=7.0 Hz), 7.44 (d, 1H, J=8.1 Hz), 7.59 (s, 1H), 11.13 (bs,
1H); HRMS (M+H), 173.0718; Anal. (C.sub.10H.sub.8N.sub.2O.0.2
H.sub.2O) C, H, N.
Example B
2-Bromo-3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-one (2)
[0131] 18
[0132] A suspension of Compound 1 (0.086 g, 0.5 mmol) in 40 mL
CH.sub.2Cl.sub.2 was treated with 90% pyridinium tribromide (0.267
g, 0.75 mmol) at 0.degree. C. The reaction mixture was stirred at
0.degree. C. for 30 minutes (min.). The solvent was removed in
vacuo, and ice-water was added to the residue. The resulting
suspension was stirred vigorously at 0.degree. C. for 30 min. and
then filtered, to give 0.068 g (54%) of a brown solid, which was
used in the next step without further purification. IR (KBr) 3172,
1655, 1606, 1441, 1367, 1292, 755 cm.sup.-1; .sup.1H NMR
(DMSO-d.sub.6) .delta.4.61 (s, 2H), 7.17 (t, 1H, J=6.0 Hz), 7.32
(d, 1H, J=6.0 Hz), 7.39 (d, 1H, J=6.0 Hz), 7.71 (s, 1H), 11.92 (s,
1H); LRMS (M+H) 251/253.
Example C
Phenyl-3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-one (3)
[0133] 19
[0134] To a suspension of 2 (0.1065 g, 0.424 mmol) in 20 mL
toluene/10 mL EtOH was added phenylboronic acid (0.08 g, 0.636
mmol), Na.sub.2CO.sub.3 (0.113 g, 1.06 mmol) dissolved in a minimum
amount of water, LiCl (0.054 g, 1.27 mmol), and
tetrakis(triphenylphosphine)palladium(0) (24.5 mg, 21.0 .mu.mol).
The reaction mixture was refluxed for 16 h. The solvent was removed
in vacuo, and the residue was taken up in EtOAc and washed with
saturated aqueous NaHCO.sub.3, H.sub.2O, and brine. The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated to give a
yellow solid, which was purified by flash column chromatography
eluting with a gradient of 20% of EtOAc in hexanes to give 0.098 g
of a mixture of 3 as a yellow solid. mp 215-218.degree. C. (dec);
.sup.1H NMR (DMSO-d.sub.6) .delta.5.04 (s, 2H), 7.17 (t, 1H, J=7.5
Hz), 7.34 (d, 1H, J=6.6 Hz), 7.35 (d, 1H, J=7.4 Hz), 7.50 (m, 4H),
7.66 (d, 1H, J=7.7 Hz), 7.84 (s, 1H), 11.64 (s, 1H); HRMS (M+H)
249.1023.
Example D
Compounds 4 and 5
[0135] 20 21
[0136] To a suspension of Compound 2 in 30 mL toluene/15 mL EtOH
was added 4-formylbenzeneboronic acid (0.457 g, 3.05 mmol),
Na.sub.2CO.sub.3 (0.538 g, 5.08 mmol) dissolved in a minimum amount
of water, LiCl (0.258 g, 6.09 mmol), and
tetrakis(triphenylphosphine)palladium(0) (0.117 g, 0.102 mmol). The
reaction mixture was refluxed for 48 h. The solvent was removed in
vacuo, and the residue was taken up in EtOAc and washed with
saturated aqueous NaHCO.sub.3, H.sub.2O, and brine. The organic
layer was dried over MgSO.sub.4 and concentrated to give a yellow
solid, which was purified by flash column chromatography eluting
with a gradient of 60-80% of EtOAc in CHCl.sub.3 to give 0.370 g of
a mixture of 4 and 5. Acetal 5 was converted to the aldehyde 4
using 5 mL MeOH/3 mL H.sub.2O and a catalytic amount of conc.
H.sub.2SO.sub.4.
[0137] 4: IR (KBr) 1694, 1653, 1601, 1261, 821, 746 cm.sup.-1;
.sup.1H NMR (DMSO-d.sub.6) .delta.5.09 (s, 2H), 7.26 (t, 1H, J=6.0
Hz), 7.36 (d, 1H, J=6.0 Hz), 7.50 (d, 1H, J=6.0 Hz), 7.85 (d, 2H,
J=9.0 Hz), 7.91 (s, 1H), 8.02 (d, 2H, J=9.0 Hz), 10.01 (s, 1H),
11.86 (s, 1H); LRMS (M+H) 277.
[0138] 5: .sup.1H NMR (DMSO-d.sub.6) .delta.1.15 (t, 6H, J=6.0 Hz),
3.70 (q, 4H, J=6.0 Hz), 5.03 (s, 2H), 5.51 (s, 1H), 7.20 (t, 1H,
J=6.0 Hz), 7.33 (d, 1H, J=6.0 Hz), 7.46 (d, 1H, J=6.0 Hz), 7.51 (d,
2H, J=9.0 Hz), 7.65 (d, 2H, J=9.0 Hz), 7.82 (s, 1H), 11.65 (s,
1H).
Example E
Compound 6
[0139] 22
[0140] To a solution of 2M (CH.sub.3).sub.2NH in MeOH (0.81 mL,
1.61 mmol) was added 5N HCl-MeOH (0.11 mL, 0.536 mmol), followed by
a suspension of the aldehyde 4 (0.074 g, 0.268 mmol) in 3 mL MeOH
and NaBH.sub.3CN (0.017 g, 0.268 mmol). The resulting suspension
was stirred for 72 h at room temperature. Concentrated HCl was
added until the pH was less than 2, and the MeOH was removed in
vacuo. The residue was taken up in H.sub.2O and extracted with
EtOAc. The aqueous solution was brought to about pH 9 with solid
KOH and extracted with EtOAc. The organic layer was dried over
MgSO.sub.4 and concentrated to give a yellow solid, which was
purified by flash silica gel chromatography eluting with a gradient
of 3% MeOH in CHCl.sub.3 to 10% MeOH/NH.sub.3 in CHCl.sub.3, to
give 0.023 g of an orange solid. .sup.1H NMR (DMSO-d.sub.6)
.delta.2.17 (s, 6H), 3.44 (s, 2H), 5.04 (s, 2H), 7.19 (t, 1H, J=6.0
Hz), 7.33 (d, 1H, J=6.0 Hz), 7.42 (d, 1H, J=6.0 Hz), 7.48 (d, 2H,
J=9.0 Hz), 7.63 (d, 2H, J=9.0 Hz), 7.81 (s, 1H), 11.62 (s, 1H);
LRMS (M+H) 306; Anal. (C.sub.19H.sub.19N.sub.3O. 0.75 H.sub.2O) C,
H, N.
Example F
Compounds 7 and 7a
[0141] 23
[0142] Sixty percent sodium hydride (0.267 g, 6.67 mmol) was added
to a solution of 1 (0.50 g, 2.9 mmol) in 7 mL DMF at 0.degree. C.
The reaction mixture was stirred at 0.degree. C. for 30 min., and
then iodomethane (0.18 mL, 2.9 mmol) was added at 0.degree. C. The
reaction mixture was allowed to warm to room temperature and
stirred for 1.5 h. The solvent was removed in vacuo, and the
residue was taken in EtOAc and washed with H.sub.2O and brine. The
organic layer was dried over MgSO.sub.4 and concentrated to give a
brown solid, which was purified by flash silica gel chromatography
eluting with a gradient of 0-1% of MeOH in CHCl.sub.3 to give 0.270
g (50%) of 7 and 0.104 g (18%) of 7a, both as pale yellow
solids.
[0143] 7: IR(KBr) 3205, 1658, 1610, 1475, 1302, 1280, 817
cm.sup.-1; .sup.1H NMR (DMSO-d.sub.6) .delta.3.80 (s, 3H), 4.76 (s,
2H), 7.15 (s, 1H), 7.18 (t, 1H, J=6.0 Hz), 7.31 (d, J=6.0 Hz), 7.51
(d, 1H, J=6.0 Hz), 7.62 (s, 1H); LRMS (M+H) 187.
[0144] 7a: IR(KBr) 1666, 1618, 1425, 1300, 1272, 1189, 742
cm.sup.-1; .sup.1H NMR (DMSO-d.sub.6) .delta.3.05 (s, 3H), 3.81 (s,
3H), 4.89 (s, 2H), 7.17-7.22 (m, 2H), 7.35 (d, 1H, J=6.0 Hz), 7.51
(d, 1H, J=6.0 Hz); LRMS (M+H) 201.
Example G
Compound 9
[0145] 24
[0146] Compound 9 was prepared from bromide 8 using a procedure
similar to that described above for preparing Compound 4. IR (KBr)
1699, 1662, 1601, 1466, 1292, 1226 cm.sup.-1; .sup.1H NMR
(DMSO-d.sub.6) .delta.3.82 (s, 3H), 4.88 (s, 2H), 7.30 (t, 1H,
J=6.0 Hz), 7.39 (d, 1H, J=6.0 Hz), 7.65 (d, 1H, J=6.0 Hz), 7.78 (s,
1H), 7.82 (d, 2H, J=9.0 Hz), 8.05 (d, 2H, J=9.0 Hz), 10.08 (s, 1H);
HRMS (M+H) 291.1130.
Example H
3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one (10)
[0147] 25
[0148] Compound 10 was prepared according to a process generally
described by Clark et. al (J. Med. Chem. (1990), 33:633-641) and
Somei et. al (Chem. Pharm. Bull. (1988), 36:1162-1168). 26
[0149] Compound M was first prepared as follows. A solution of
methyl indole-4-carboxylate (3.28 g, 18.7 mmol) and
nitroethylacetate (2.99 g, 22.5 mmol) in xylenes (23 mL) was
treated with 4-t-butylcatechol (22 mg) and heated at reflux for 3.5
h. The solution was allowed to cool to room temperature and the
solvent removed under reduced pressure. The residue was purified by
flash chromatography (3:1 hexanes:EtOAc), to give a pale-yellow
solid, 4.13 g (89%). mp 101-102.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta.3.54 (t, 2H, J=7.0 Hz), 3.93 (s, 3H), 4.79
(t, 2H, J=7.0 Hz), 7.23 (m, 2H), 7.43 (s, 1H), 7.66 (m, 2H), 11.49
(bs, 1H); HRMS (M+H) Calcd for C.sub.12H.sub.12N.sub.2O.sub.4+H:
249.0875, Found: 249.0870.
[0150] Intermediate M (1.12 g, 4.53 mmol) was dissolved in MeOH (70
mL) by gently heating. Aqueous 2M HCl (70 mL) was added. With
vigorous stirring, 7.0 g of zinc dust was added portionwise, and
the resulting mixture was heated at reflux for 30 min. The hot
reaction mixture was filtered; the filtrate was treated with
aqueous 2M NaOH (85 mL), and the resulting mixture was filtered
through a paper-lined Buchner funnel. The filter cake was rinsed
with MeOH. The MeOH was removed under reduced pressure, and the
aqueous mixture was extracted with EtOAc (2.times.100 mL). The
organic solution was washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The crude product
was crystallized with CH.sub.2Cl.sub.2/MeOH to give the tricycle as
a yellow solid, 611 mg (73%). mp 234-236.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta.2.55 (m, 2H), 2.98 (m, 2H), 7.22 (t, 1H,
J=7.7 Hz), 7.31 (s, 1H), 7.58 (d, 1H, J=7.7 Hz), 7.70 (d, 1H, J=7.7
Hz), 8.04 (bt, 1H), 11.17 (bs, 1H); Anal.
(C.sub.11H.sub.10N.sub.2O) C, H, N.
Example I
2-Bromo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one (11)
[0151] 27
[0152] Compound 10 (264 mg, 1.42 mmol) in CH.sub.2Cl.sub.2 (30 mL)
and THF (30 mL) was treated with pyridinium tribromide (0.534 g,
1.67 mmol) at 0.degree. C. The orange solution was stirred for 10
min., and then allowed to warm to ambient temperature and stirred
for an additional hour. Water (30 mL) was added, and the organic
solvents were removed in vacuo. The aqueous solution was adjusted
to pH=8-9 with 1M NaOH and extracted with CH.sub.2Cl.sub.2
(3.times.30 mL). The organic solution was washed with water and
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated. The
crude product was recrystallized (CH.sub.2Cl.sub.2/MeOH) to yield
the tricyclic bromide as a yellow solid, 305 mg (81%). mp
204-206.degree. C. (dec); .sup.1H NMR (DMSO-d.sub.6) .delta.2.85
(m, 2H), 3.45 (m, 2H), 7.25 (t, 1H, J=7.8 Hz), 7.52 (d, 1H, J=7.8
Hz), 7.72 (d, 1H, J=7.8 Hz), 8.14 (bt, 1H), 12.05 (bs, 1H); HRMS
(M+H) Calcd for C.sub.11H.sub.9BrN.sub.2O+H: 264.9976, Found:
264.9984.
Example J
2-Phenyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one
(12)
[0153] 28
[0154] Tricyclic bromide 11 (0.2 g, 0.75 mmol) in toluene (20 mL)
and EtOH (10 mL) was treated with solid Na.sub.2CO.sub.3 (0.199 g,
1.88 mmol), LiCl (0.095 g, 2.25 mmol), phenylboronic acid (0.138 g,
1.13 mmol), and water (0.50 mL). The solution was degassed and
tetrakis(triphenylphosphin- e)palladium(0) (43 mg, 5 mol %) was
added. The solution was heated at reflux for 5 h, and then cooled
to ambient temperature and diluted with water (20 mL). The aqueous
layer was adjusted to pH=7-8 with saturated aqueous K.sub.2CO.sub.3
and extracted with EtOAc (20 mL.times.3). The organic solution was
washed with water and brine, and dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The crude product was recrystallized
(CH.sub.2Cl.sub.2/MeOH/hexanes) to yield the 2-phenyltricycle as a
pale-yellow solid, 183 mg (93%). mp 249-255.degree. C. (dec);
.sup.1H NMR (CDCl.sub.3/CD.sub.4OD) .delta.3.14 (m, 2H), 3.53 (m,
2H), 7.23 (t, 1H, J=7.7 Hz), 7.33 (m, 1H), 7.44 (m, 2H), 7.55 (m,
3H), 7.83 (d, 1H, J=7.7 Hz); HRMS (M+H) Calcd for
C.sub.17H.sub.14N.sub.2- O+H: 263.1184, Found: 263.1189; Anal.
(C.sub.17H.sub.14N.sub.2O.0.8 H.sub.2O) C, H, N.
Example K
2-(4-Methoxyphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one
(13)
[0155] 29
[0156] Tricyclic bromide 11 (48 mg, 0.18 mmol) in toluene (5 mL)
and EtOH (2.5 mL) was treated with solid Na.sub.2CO.sub.3 (48 mg,
0.45 mmol), LiCl (23 mg, 0.54 mmol), p-methoxyphenylboronic acid
(41 mg, 0.27 mmol), and water (0.25 mL). The solution was degassed,
and tetrakis(triphenylphosphi- ne)palladium(0) (10 mg, 5 mol %) was
added. The solution was heated at reflux for 13 h, and then cooled
to ambient temperature and diluted with water (10 mL). The aqueous
layer was adjusted to pH=7-8 with saturated aqueous K.sub.2CO.sub.3
and extracted with EtOAc (10 mL.times.3). The organic solution was
washed with water and brine, dried (Na.sub.2SO.sub.4), filtered,
and concentrated. The crude product was recrystallized (MeOH/THF)
to yield the 2-(p-methoxyphenyl)tricycle as a white solid, 47.4 mg
(89%). mp 143-148.degree. C. (dec); .sup.1H NMR (DMSO-d.sub.6)
.delta.3.08 (m, 2H), 3.38 (m, 2H), 3.87 (s, 3H), 7.14 (d of ABq,
2H, J=8.6 Hz), 7.22 (t, 1H, J=7.5 Hz), 7.57 (d, 1H, J=7.5 Hz), 7.64
(d of ABq, 2H, J=8.6 Hz), 7.70 (d, 1H, J=7.5 Hz,), 8.11 (bt, 1H),
11.52 (bs, 1H); HRMS (M+H) Calcd for
C.sub.18H.sub.16N.sub.2O.sub.2+H: 293.1290, Found: 293.1301; Anal.
(C.sub.18H.sub.16N.sub.2O.sub.2) C, H, N.
Example L
2-(3-Nitrophenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one
(14)
[0157] 30
[0158] Tricyclic bromide 11 (27 mg, 0.10 mmol) in 1,4-dioxane (1.0
mL) was treated with solid K.sub.2CO.sub.3 (41 mg, 0.30 mmol),
m-nitrophenylboronic acid (34 mg, 0.20 mmol), and water (0.25 mL).
The solution was degassed and
tetrakis(triphenylphosphine)palladium(0) (12 mg, 10 mol %) was
added. The solution was heated at 100.degree. C. for 1 h, then
cooled to ambient temperature and diluted with water (2 mL). The
aqueous layer was adjusted to pH=7-8 with saturated aqueous
K.sub.2CO.sub.3 and extracted with EtOAc (5 mL.times.3). The
organic solution was washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The crude product
was purified by flash chromatography (3-5% MeOH in CHCl.sub.3) to
yield 14 as a yellow solid, 26.3 mg (87%). mp 268-270.degree. C.
(dec.); .sup.1H NMR (DMSO-d.sub.6) .delta.3.16 (m, 2H), 3.45 (m,
2H), 7.33 (m, 1H), 7.65 (m, 1H), 7.76 (m, 1H), 7.78 (m, 1H), 8.30
(m, 1H), 8.53 (bs, 1H), 8.16 (m, 2H), 11.93 (bs, 1H); HRMS (M+Na)
Calcd for C.sub.17H.sub.13N.sub.3O.sub.3+Na: 330.0855, Found:
330.0847; Anal. (C.sub.17H.sub.13N.sub.3O.sub.3.H.sub.2O) C, H,
N.
Example M
2-(3-Hydroxymethylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-o-
ne (16)
[0159] 31
[0160] In a manner similar to that described above for Compound 12,
the tricyclic bromide (381 mg, 1.44 mmol) and
3-formylbenzeneboronic acid (345 mg, 2.16 mmol) were coupled to
yield 2-(3-formylphenyl)-3,4,5,6-tetr-
ahydro-1H-azepino[5,4,3-cd]indol-6-one 15, 346 mg (83%), as a tan
solid. .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.2.86 (m, 2H),
3.16 (m, 2H), 7.01 (t, 1H, J=7.8 Hz), 7.34 (d, 1H, J=7.3 Hz), 7.50
(m, 2H), 7.73 (m, 2H), 7.85 (br t, 1H), 7.94 (s, 1H), 9.88 (s, 1H),
11.50 (br s, 1H).
[0161] Compound 16 was isolated as a by-product from the reductive
amination of 15 with dimethylamine and sodium cyanoborohydride, and
recrystallized (CH.sub.2Cl.sub.2/hexanes), to give a pale-yellow
solid. mp 258-259.degree. C. (dec); .sup.1H NMR (DMSO-d.sub.6)
.delta.3.11 (m, 2H), 3.43 (m, 2H), 4.64 (d, 2H, J=5.5 Hz), 5.36 (t,
1H, J=5.5 Hz), 7.26 (t, 1H, J=7.6 Hz), 7.41 (m, 1H), 7.56 (m, 3H),
7.66 (m, 1H), 7.73 (d, 1H, J=7.6 Hz), 8.14 (m, 1H), 11.64 (bs, 1H);
Anal. (C.sub.18H.sub.18N.sub.2O.- sub.2.0.25 H.sub.2O) C, H, N.
Example N
2-(Phenylethynyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one
(17)
[0162] 32
[0163] Tricyclic bromide 11 (58.6 mg, 0.22 mmol) in DMF (1 mL) was
degassed and treated with tributyl(phenylethynyl)tin (95.2 mg, 0.24
mmol) and tetrakis(triphenylphosphine) palladium(0) (13 mg, 2 mol
%). One crystal of 2,6-di-t-butyl-4-methyl phenol was added, and
the solution was heated at 60.degree. C. for 10 h. Starting
material was still present, so the solution was heated at
100.degree. C. for an additional 2 h. The reaction mixture was
cooled to ambient temperature and diluted with water (2 mL) and
extracted with EtOAc (5 mL.times.3). The organic solution was
washed with water and brine, dried (Na.sub.2SO.sub.4), filtered,
and concentrated. The crude product was purified by radial
chromatography (2 mm SiO.sub.2; 3% MeOH in CH.sub.2Cl.sub.2) to
yield 17 as a white solid (34.8 mg, 55%). mp 255-256.degree. C.
(dec); .sup.1H NMR (DMSO-d.sub.6) .delta.11.86 (s, 1H), 8.17 (m,
1H), 7.75 (d, 1H, J=7.6 Hz), 7.63 (m, 3H), 7.51 (m, 3H), 7.33 (t,
1H, J=7.6 Hz), 3.50 (m, 2H), 3.09 (m, 2H); HRMS (FAB, M+H) Calcd
for C.sub.19H.sub.14N.sub.2O+H: 287.1184, Found: 287.1192; Anal.
(C.sub.19H.sub.14N.sub.2O.0.6 H.sub.2O ) C, H, N.
Example O
1-Methyl-2-phenyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one
(18)
[0164] 33
[0165] A solution of compound 12 (51.3 mg, 0.20 mmol) in THF (1 mL)
and 0.1 mL 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(DMPU) was cooled with an ice/water bath and treated dropwise with
a suspension of NaH (0.45 mmol) in THF (0.5 mL). The yellow mixture
was allowed to stir at 0.degree. C. for 10 min., and was treated
dropwise with a 1M solution of iodomethane in THF (0.22 mL, 0.22
mmol). The mixture was allowed to warm to ambient temperature and
stirred for 30 min. The reaction was quenched at 0.degree. C. with
saturated aqueous NH.sub.4Cl, and extracted with EtOAc (5
mL.times.3). The organic solution was washed with water and brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated. The crude
product was purified by radial chromatography (2 mm SiO.sub.2; 1-5%
MeOH in CH.sub.2Cl.sub.2) to yield 18 as a white solid, 44.9 mg
(81%). mp 254-256.degree. C. (dec.); .sup.1H NMR (DMSO-d.sub.6)
.delta.2.88 (m, 2H), 3.40 (m, 2H), 3.74 (s, 3H), 7.34 (t, 1H, J=7.7
Hz), 7.56 (m, 5H), 7.73 (d, 1H, J=7.7 Hz), 7.80 (d, 1H, J=7.7 Hz),
8.15 (bt, 1H); Anal. (C.sub.18H.sub.16N.sub.2O.0.75 H.sub.2O) C, H,
N.
[0166] Compound 18a,
1,5-dimethyl-2-phenyl-3,4,5,6-tetrahydro-1H-azepino[5-
,4,3-cd]indol-6-one, was isolated as a minor product. mp
175-177.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta.2.91 (m, 2H),
3.19 (s, 3H), 3.65 (m, 2H), 3.75 (s, 3H), 7.34 (t, 2H, J=7.8 Hz),
7.58 (m, 5H), 7.72 (d, 1H, J=7.8 Hz), 7.79 (d, 1H, J=7.8 Hz); Anal.
C.sub.19H.sub.18N.sub.2O.0.5 H.sub.2O) C, H, N.
Example P
1-N-Methyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one
(19)
[0167] 34
[0168] A solution of methyl indole-4-carboxylate (402 mg, 2.30
mmol) in DMF (5 mL) was cooled with an ice/water bath and treated
with NaH (100 mg, 2.5 mmol, 60% in mineral oil). The resulting
yellow solution was allowed to stir at 0.degree. C. for 30 min.,
then a solution of Mel (482 mg, 212 .mu.L, 3.4 mmol) in DMF (3.5
mL) was added dropwise. The solution was allowed to warm to ambient
temperature. The reaction was quenched at 0.degree. C. with
saturated aqueous NH.sub.4Cl and extracted with EtOAc (10
mL.times.3). The organic solution was washed with water and brine,
dried (Na.sub.2SO.sub.4), filtered, and concentrated to give methyl
(N-methyl)-indole-4-carboxylate as a yellow oil, 430 mg (99%). The
N-methyl carboxy indole was converted into the
N-methyl-[5,6,7]-tricyclic indole in a manner similar to that
described for Compound (10) to give
1-N-methyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one as a
shiny white solid, 256 mg (54%, after recrystallization
(CH.sub.2Cl.sub.2/MeOH/- hexanes)). mp 194-195.degree. C.; .sup.1H
NMR (300 MHz, d.sub.6-DMSO) .delta.2.96 (m, 2H), 3.43 (m, 2H), 3.82
(s, 3H), 7.29 (m, 2H), 7.64 (d, 1H, J=7.7 Hz), 7.72 (d, 1H, J=7.7
Hz), 8.09 (br t, 1H); HRMS (FAB, MH+) Calcd for
C.sub.12H.sub.13N.sub.2O: 201.1028, Found: 201.1020; Anal.
(C.sub.12H.sub.12N.sub.2O.0.2 H.sub.2O) C, H, N.
Example Q
(rac)-3-Phenyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one
(20)
[0169] 35
[0170] In a manner similar to that described for the preparation of
methyl 3-(nitroethyl)-indole-4-carboxylate D above, methyl
indole-4-carboxylate (85 mg, 0.49 mmol) and nitrostyrene (80 mg,
0.54 mmol) were heated at 160.degree. C. in a sealed tube for 12 h.
The product was isolated by silica gel chromatography as a brown
oil, 132 mg (83%). The intermediate nitro alkane was
reduced/cyclized as described to give
(rac)-3-phenyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one
as a white solid, 51.4 mg (48%, after chromatography and
recrystallization). mp 201-203.degree. C.; .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.3.73 (m, 2H), 4.42 (m, 1H), 7.28 (br m, 8H),
7.64 (d, 1H, J=7.9 Hz), 7.77 (d, 1H, J=7.9 Hz), 11.32 (br s, 1H);
HRMS (FAB, MH+) Calcd for C.sub.17H.sub.15N.sub.2O: 263.1184,
Found: 263.1180; Anal. (C.sub.17H.sub.14N.sub.2O.0.25 H.sub.2O) C,
H, N.
Example R
2-(4-Fluorophenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one
(23)
[0171] 36
[0172] In a manner similar to that described for Compound 12, the
tricyclic bromide (100 mg, 0.54 mmol) and 4-fluorobenzeneboronic
acid (79 mg, 0.57 mmol) were coupled to yield
2-(4-fluorophenyl)-3,4,5,6-tetrahydr-
o-1H-azepino[5,4,3-cd]indol-6-one, 107 mg (99%), as a pale-yellow
solid. .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.04 (m, 2H),
3.38 (m, 2H), 7.22 (app t, 1H, J=7.7 Hz), 7.39 (m, 2H), 7.56 (dd,
1H, J=8.0, 0.9 Hz), 7.64 (m, 3H), 8.05 (br t, 1H), 11.57 (br s,
1H); HRMS (FAB, MH+) Calcd for C.sub.17H.sub.14FN.sub.2O: 281.1090,
Found: 281.1093; Anal. (C.sub.17H.sub.13FN.sub.2O.0.6 H.sub.2O ) C,
H, N.
Example S
8-Bromo-2-phenyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one
(26)
[0173] 37
[0174] A solution of Compound 12
(2-phenyl-3,4,5,6-tetrahydro-1H-azepino[5- ,4,3-cd]indol-6-one) (22
mg, 0.08 mmol) in CH.sub.2Cl.sub.2 (1 mL) and THF (1 mL) was
treated with pyridinium tribromide (29 mg, 0.09 mmol). The solution
was stirred for 3 hours at room temperature and then diluted with
water (2 mL), and the aqueous layer was adjusted to pH=9-10 with 1M
NaOH. The mixture was extracted with CH.sub.2Cl.sub.2 (3.times.5
mL). The organic solution was washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The crude product
was purified by radial chromatography (1 mm silica gel; 1% MeOH in
CHCl.sub.3) to give the 8-bromo compound, 12.8 mg (47%), as a
pale-yellow solid. .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.06
(m, 2H), 3.39 (m, 2H), 7.43 (app t, 1H, J=7.4 Hz), 7.55 (app t, 2H,
J=7.6 Hz), 7.66 (app d, 2H, J=7.6 Hz), 7.70 (app d, 1H, J=1.5 Hz),
7.75 (app d, 1H, J=1.5 Hz), 8.24 (br t, 1H), 11.77 (br s, 1H); HRMS
(FAB, MH+) Calcd for C.sub.17H.sub.14BrN.sub.2O: 341.0289, Found:
341.0294.
Example T
2-(4-(N,N-Dimethylamino)methylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3--
cd]indol-6-one (21)
[0175] 38
[0176] In a manner similar to that described above for Compound 12,
the tricyclic bromide (168 mg, 0.63 mmol) and
4-formylbenzeneboronic acid (142 mg, 0.95 mmol) were coupled to
yield 2-(4-formylphenyl)-3,4,5,6-tetr-
ahydro-1H-azepino[5,4,3-cd]indol-6-one, 141 mg (77%), as a yellow
solid. mp 238-240.degree. C. (dec.); .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.3.12 (m, 2H), 3.42 (m, 2H), 7.28 (t, 1H, J=7.6
Hz), 7.59 (d, 1H, J=7.6 Hz), 7.62 (d, 1H, J=7.6 Hz), 7.88 (d of
ABq, 2H, J=7.7 Hz), 8.05 (d of ABq, 2H, J=7.7 Hz), 8.11 (br t, 1H),
10.07 (s, 1H), 11.75 (br s, 1H); HRMS (FAB, MH+) Calcd for
C.sub.18H.sub.15N.sub.2O.sub.2: 291.1134, Found: 291.1132.
[0177] The aldehyde (310 mg, 1.07 mmol) in MeOH (40 mL) was treated
with dimethyl amine (2M solution in MeOH, 6.41 mmol). The solution
was cooled with an ice/water bath and treated dropwise with a
solution of sodium cyanoborohydride (74 mg, 1.18 mmol) and zinc
chloride (80 mg, 0.59 mmol) in MeOH (10 mL). The resulting solution
was adjusted to pH=6-7 with 2M methanolic HCl. After stirring for
30 min., the reaction was quenched with conc. HCl (0.2 mL) and the
methanol was removed by evaporation. The residue was diluted with
water (30 mL). The solution adjusted to pH=10-11 with KOH (s) and
extracted with CH.sub.2Cl.sub.2 (30 mL.times.3). The organic
solution was washed with water and brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The crude product was crystallized
(CH.sub.2Cl.sub.2/MeOH/hexanes) to give
2-(4-(N,N-dimethylamino)methylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-
-cd]indol-6-one, 245 mg (72%), as an off-white solid. mp
226-229.degree. C. (dec.); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.2.18 (s, 6H), 3.06 (m, 2H), 3.40 (m, 2H), 3.44 (s, 2H), 7.21
(t, 1H, J=7.7 Hz), 7.43 (d of ABq, 2H, J=7.9 Hz), 7.56 (d, 1H,
J=7.7 Hz), 7.61 (d of ABq, 2H, J=7.9 Hz), 7.69 (d, 1H, J=7.7 Hz),
8.05 (br t, 1H), 11.53 (br s, 1H); HRMS (FAB, MH+) Calcd for
C.sub.20H.sub.22N.sub.3O: 320.1763; Found: 320.1753; Anal.
(C.sub.20H.sub.21N.sub.3O.0.55 H.sub.2O) C, H, N.
Example U
2-(3-(N,N-Dimethylamino)methylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3--
cd]indol-6-one (22)
[0178] 39
[0179] The aldehyde compound 15 (346 mg, 1.19 mmol) in MeOH (40 mL)
was treated with dimethyl amine (2M solution in MeOH, 7.16 mmol).
The solution was cooled with an ice/water bath and treated dropwise
with a solution of sodium cyanoborohydride (82 mg, 1.31 mmol) and
zinc chloride (89 mg, 0.66 mmol) in MeOH (10 mL). The resulting
solution was adjusted to pH=6-7 with 2M methanolic HCl. After
stirring for 30 min., the reaction was quenched with conc. HCl (0.2
mL) and the methanol was removed by evaporation. The residue was
diluted with water (30 mL). The solution was adjusted to pH=10-11
with KOH (s) and extracted with CH.sub.2Cl.sub.2 (30 mL.times.3).
The organic solution was washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The crude product
was crystallized (CH.sub.2Cl.sub.2/MeOH/hexanes) to give
2-(3-(N,N-dimethylamino)methylphenyl)-3,4,5,6-tetrahydro-1H-azepino[-
5,4,3-cd]indol-6-one, 332 mg (87%), as shiny yellow crystals. mp
222-225.degree. C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.2.20
(s, 6H), 3.06 (m, 2H), 3.40 (m, 2H), 3.50 (s, 2H), 7.21 (t, 1H,
J=7.7 Hz), 7.41 (br d, 1H, J=7.4 Hz), 7.50 (m, 4H), 7.69 (d, 1H,
J=7.1 Hz), 8.05 (brt, 1H), 11.56 (br s, 1H); HRMS (FAB, MH+) Calcd
for C.sub.20H.sub.22N.sub.3O: 320.1763, Found: 320.1753; Anal.
(C.sub.20H.sub.21N.sub.3O.0.25 H.sub.2O) C, H, N.
Example V
Compound 25
[0180] 40
[0181] To a solution of 2M (CH.sub.3).sub.2NH in MeOH (0.6 mL, 1.13
mmol) was added 5N HCl-MeOH (0.08 mL, 0.380 mmol) followed by a
suspension of the aldehyde (0.055 g, 0.188 mmol) in 3 mL MeOH and
NaBH.sub.3CN (0.012 g, 0.188 mmol). The resulting suspension was
stirred for 24 h at room temperature. Concentrated HCl was added
until the pH was less than 2, and the MeOH was removed in vacuo.
The residue was taken up in H.sub.2O and extracted with EtOAc. The
aqueous solution was brought to about pH 9 with solid (s) KOH and
extracted with EtOAc. The organic layer was dried over MgSO.sub.4
and concentrated to give a yellow solid, which was purified by
flash silica gel chromatography eluting with a gradient of
CHCl.sub.3 to 10% MeOH/NH.sub.3 in CHCl.sub.3 to give 0.024 g of a
yellow solid. .sup.1H NMR (DMSO-d.sub.6) 2.18 (s, 6H), 3.45 (s,
2H), 5.03 (s, 2H), 7.20-7.30 (m, 2H), 7.35 (d, 1H, J=6 Hz),
7.40-7.58 (m, 3H), 7.60 (s, 1H), 7.79 (s br, 1H), 11.68 (s br, 1H);
HRMS 306.1626.
Example W
1,5-Dihydro-[1,2]diazepino[4,5,6-cd]-indol-6-one (27)
[0182] 41
[0183] A solution of the intermediate J (3-formyl carboxy indole
(246 mg, 1.21 mmol)) in MeOH (10 mL) and AcOH (0.1 mL) was treated
with hydrazine hydrate (176 mg, 3.5 mmol) and the solution was
heated at reflux for 30 min. The solution was cooled in an
ice/water bath and the precipitated solid was collected by
filtration to give 1,5-dihydro-[1,2]diazepino[4,5,-
6-cd]-indol-6-one, 168 mg (75%), as a bright-yellow solid. mp
335-336.degree. C. (dec.); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.7.11 (t, 1H, J=7.8 Hz), 7.44 (m, 3H), 7.56 (d, 1H, J=2.7
Hz), 10.09 (s, 1H), 11.74 (br s, 1H); Anal.
(C.sub.10H.sub.7N.sub.3O) C, H, N.
Example X
1,5-Dihydro-3-phenyl-[1,2]diazepino[4,5,6-cd]-indol-6-one (28)
[0184] 42
[0185] A solution of methyl indole-4-carboxylate (40 mg, 0.23 mmol)
in dichloroethane (2 mL) was treated with benzoyl chloride (0.69
mmol) at room temperature. The orange solution was cooled with an
ice/water bath and treated with aluminum chloride (0.69 mmol). The
dark-orange solution was warmed to room temperature over 1 hour,
then poured into ice-cold aqueous 2M HCl. The aqueous solution was
adjusted to pH=9-10 with KOH (s), and extracted with
CH.sub.2Cl.sub.2 (10 mL.times.3). The organic solution was washed
with water and brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The crude product was purified by radial
chromatography (1 mm silica gel; 3% MeOH in CHCl.sub.3) to give
methyl 3-phenacyl-indole-4-carboxylate as an oil, 63 mg (99%). A
solution of the 3-phenacyl carboxy indole (60 mg, 0.25 mmol) in
MeOH (5 mL) and conc. HCl (0.1 mL) was treated with hydrazine
hydrate (36 mg, 0.73 mmol) and the solution was heated at reflux
for 3 h. The reaction was quenched with ice/water, and the aqueous
layer was adjusted to pH=10-11 with KOH (s) and extracted with
CH.sub.2Cl.sub.2 (30 mL.times.3). The organic solution was washed
with water and brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The crude product was crystallized
(CH.sub.2Cl.sub.2/hexane- s) to give
1,5-dihydro-3-phenyl-[1,2]diazepino[4,5,6-cd]-indol-6-one, 33 mg
(51%), as a bright-yellow solid. mp 177-179.degree. C.; .sup.1H NMR
(300 MHz, d.sub.6-DMSO) .delta.7.22 (m, 2H), 7.47 (m, 3H), 7.58 (m,
4H), 10.45 (s, 1H), 11.92 (br s, 1H); Anal.
(C.sub.10H.sub.7N.sub.3O.0.75 H.sub.2O) C, H, N.
Example Y
1,5-Dihydro-3-phenethyl-[1,2]diazepino[4,5,6-cd]-indol-6-one
(29)
[0186] 43
[0187] A solution of methyl indole-4-carboxylate (250 mg, 1.43
mmol) in dichloroethane (3 mL) was treated with 3-phenylpropionyl
chloride (361 mg, 2.14 mmol) at room temperature. The orange
solution was cooled to 0.degree. C. and treated with aluminum
chloride (572 mg, 4.29 mmol). The reaction mixture was stirred at
room temperature for 2 h, then poured into ice-cold 1M aqueous HCl.
The aqueous solution was adjusted to pH=8 with 1M NaOH, and
extracted with CH.sub.2Cl.sub.2 (10 mL.times.3). The organic
solution was washed with water and brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated to give methyl
3-(3-phenylpropionyl)-indole-4-carboxylate as a pale-yellow solid,
395 mg (90%). A solution of the 3-(3-phenylpropionyl)-4-carboxy
indole (95.5 mg, 0.31 mmol) in MeOH (3 mL) and HCl (0.1 mL) was
treated with hydrazine hydrate (47 mg, 0.93 mmol) and the solution
was heated at reflux for 8 h. The solution was cooled in an
ice/water bath and the precipitated solid was collected by
filtration to give 1,5-dihydro-3-phenethyl-[1,2]diazepin-
o[4,5,6-cd]-indol-6-one, 60.2 mg (71%). The crude product was
purified by radial chromatography (2 mm SiO.sub.2, 5:1
hexanes:EtOAc) to give a yellow solid. mp 182-183.5.degree. C.;
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.2.80 (m, 2H), 2.84 (m,
2H), 7.22 (m, 2H), 7.31 (m, 4H), 7.54 (m, 2H), 7.81 (s, 1H), 10.19
(s, 1H), 11.92 (br s, 1H); Anal. (C.sub.10H.sub.7N.sub.3O.0.1
H.sub.2O) C, H, N.
Example Z
2-(3-Trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-o-
ne (30)
[0188] 44
[0189] In a manner similar to that described for Compound 12, the
tricyclic bromide (300 mg, 1.13 mmol) and
3-trifluoromethylphenylboronic acid (322 mg, 1.70 mmol) were
coupled to yield 2-(3-trifluoromethyl-pheny-
l)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 300 mg (80%),
as a pale-yellow solid. mp 212.5-213.5.degree. C.; .sup.1H NMR (300
MHz, d.sub.6-DMSO) .delta.3.08 (m, 2H), 3.40 (m, 2H), 7.27 (app t,
1H, J=7.8 Hz), 7.60 (d, 1H, J=7.8 Hz), 7.71 (d, 1H, J=7.5 Hz), 7.77
(m, 2H), 7.96 (m, 2H), 8.13 (br, t, 1H), 11.78 (br s, 1H); MS (FAB,
MH+) 331; Anal. (C.sub.18H.sub.13F.sub.3N.sub.2O.0.5 H.sub.2O) C,
H, N.
Example AA
2-(4-Trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-o-
ne (31)
[0190] 45
[0191] In a manner analogous to the method described above for
Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and
4-trifluoromethylphenyl- boronic acid (322 mg, 1.70 mmol) were
coupled to yield
2-(4-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6--
one, 261 mg (70%), as an off-white solid. mp 208-209.degree. C.;
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.09 (m, 2H), 3.40 (m,
2H), 7.27 (app t, 1H, J=7.8 Hz), 7.60 (dd, 1H, J=8.1, 0.9 Hz), 7.71
(dd, 1H, J=7.5, 0.6 Hz), 7.88 (m, 4H), 8.13 (br t, 1H), 11.77 (br
s, 1H); MS (FAB, MH+) 331; Anal.
(C.sub.18H.sub.13F.sub.3N.sub.2O.1.0 H.sub.2O) C, H, N.
Example BB
2-Benzofuran-2-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
(32)
[0192] 46
[0193] In a like manner to the example described above for Compound
12, the tricyclic bromide (300 mg, 1.13 mmol) and
benzo[b]furan-2-boronic acid (202 mg, 1.24 mmol) were coupled to
yield 2-benzofuran-2-yl-1,3,4,5--
tetrahydro-azepino[5,4,3-cd]indol-6-one, 262 mg (77%), as a yellow
solid. mp 207.degree. C. (dec.); .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.3.23 (m, 2H), 3.50 (m, 2H), 7.31 (m, 4H), 7.61
(dd, 1H, J=8.1, 0.9 Hz), 7.70 (m, 3H), 8.14 (br t, 1H), 11.97 (br
s, 1H); MS (FAB, MH+) 303; Anal.
(C.sub.19H.sub.14N.sub.2O.sub.2.1.8 H.sub.2O) C, H, N.
Example CC
2-(3,5-bis-Trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]ind-
ol-6-one (33)
[0194] 47
[0195] In a manner similar to that described for preparation of
Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and
3,5-bis-trifluoromethyl- phenylboronic acid (202 mg, 1.24 mmol)
were coupled to yield
2-(3,5-bis-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]in-
dol-6-one, 70 mg (16%), as a pale-yellow solid. mp 230.degree. C.
(dec.); .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.11 (m, 2H),
3.42 (m, 2H), 7.31 (app t, 1H, J=7.8 Hz), 7.64 (d, 1H, J=8.1 Hz),
7.73 (d, 1H, J=7.5 Hz), 8.13 (br s, 1H), 8.16 (br t, 1H), 8.28 (br
s, 2H), 11.95 (br s, 1H); MS (FAB, MH+) 399; Anal.
(C.sub.19H.sub.12F.sub.6N.sub.2O.0.2 hexanes) C, H, N.
Example DD
2-(4-Bromophenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
(34)
[0196] 48
[0197] In a manner similar to that described for Compound 12,
2-iodo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (85 mg, 0.28
mmol; see Example NN below) and 4-bromophenylboronic acid (62 mg,
0.31 mmol) were coupled to yield
2-(4-bromophenyl)-1,3,5-tetrahydro-azepino[5,4,3-cd- ]indol-6-one,
19 mg (20%), as a white solid. mp 160.degree. C. (dec.); .sup.1H
NMR (300 MHz, d.sub.6-DMSO) .delta.3.04 (m, 2H), 3.39 (m, 2H), 7.23
(app t, 1H, J=7.5 Hz), 7.56 (dd, 1H, J=8.1, 0.9 Hz), 7.60 (d, 2H,
J=8.7 Hz), 7.69 (dd, 1H, J=7.5, 0.6 Hz), 7.73 (d, 2H, J=8.4 Hz),
8.09 (br t, 1H), 11.64 (br s, 1H); MS (FAB, MH+) 341/343; Anal.
(C.sub.17H.sub.13BrN.sub.2O.0.6 H.sub.2O) C, H, N.
Example EE
2-(3-Chloro-4-fluoro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-o-
ne (35)
[0198] 49
[0199] In a manner similar to that described for Compound 12, the
tricyclic bromide (300 mg, 1.13 mmol) and
3-chloro-4-fluorophenylboronic acid (217 mg, 1.24 mmol) were
coupled to yield 2-(3-chloro,
4-fluoro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one,
217 mg (61%), as a pale-yellow solid. mp 234-235.degree. C.;
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.04 (m, 2H), 3.39 (m,
2H), 7.24 (app t, 1H, J=7.8 Hz), 7.57 (dd, 1H, J=8.1, 0.9 Hz), 7.61
(m, 2H), 7.69 (dd, 1H, J=7.5, 0.9 Hz), 7.85 (dd, 1H, J=7.2, 2.1
Hz), 8.10 (br t, 1H), 11.68 (br s, 1H); HRMS (FAB, MH+) Calcd for
C.sub.17H.sub.13ClFN.sub.2O: 315.0700, Found: 315.0704; Anal.
(C.sub.17H.sub.12ClFN.sub.2O.1.0 H.sub.2O.0.5 MeOH) C, H, N.
Example FF
2-(4-tert-Butyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
(36)
[0200] 50
[0201] In a like manner as described for Compound 12, the tricyclic
bromide (300 mg, 1.13 mmol) and 4-tert-butylphenylboronic acid (302
mg, 1.70 mmol) were coupled to yield
2-(4-tert-butyl-phenyl)-1,3,4,5-tetrahyd-
ro-azepino[5,4,3-cd]indol-6-one, 150 mg (42%), as a white solid. mp
243-244.degree. C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.1.33
(s, 9H), 3.05 (m, 2H), 3.38 (m, 2H), 7.20 (app t, 1H, J=7.8 Hz),
7.57 (m, 5H), 7.67 (dd, 1H, J=7.2, 0.6 Hz), 8.07 (br t, 1H), 11.51
(br s, 1H); HRMS (FAB, MH+) Calcd for C.sub.21H.sub.23N.sub.2O:
319.1810, Found: 319.1813; Anal. (C.sub.21H.sub.22N.sub.2O.0.3
H.sub.2O) C, H, N.
Example GG
2-Phenyl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indole-6-thione
(24)
[0202] 51
[0203] Compound 12 (48.6 mg, 0.18 mmol) in toluene (2 mL) was
treated with Lawesson's reagent (75 mg, 0.18 mmol) at room
temperature. The solution was heated at reflux for 2 h, then
allowed to cool to room temperature and diluted with water. The
mixture was extracted with EtOAc (3.times.5 mL). The organic
solution was washed with water and brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The crude product was crystallized
(CH.sub.2Cl.sub.2/hexanes) to give the thioamide 34.4 mg (68%) as a
yellow solid. mp 223-226.degree. C. (dec.); .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.3.10 (m, 2H), 3.50 (m, 2H), 7.23 (app t, 1H,
J=7.8 Hz), 7.57 (m, 1H), 7.61 (m, 3H), 7.69 (m, 2H), 8.19 (d, 1H,
J=7.6 Hz), 10.56 (br t, 1H), 11.68 (br s, 1H); HRMS (FAB, MH.sup.+)
Calcd for C.sub.17H.sub.15N.sub.2S: 279.0956, Found: 279.0952;
Anal. (C.sub.17H.sub.14N.sub.2S.0.25 H.sub.2O) C, H, N, S.
Example HH
2-Phenethyl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
(37)
[0204] 52
[0205]
2-Phenylethynyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one
(Compound 17) (37 mg, 0.13 mmol) and platinum oxide (1.5 mg, 0.05
mmol) were suspended in 2 mL MeOH under an argon atmosphere. The
flask was flushed with hydrogen gas and the resulting mixture
stirred at 24.degree. C. under 1 atmosphere of hydrogen for 20 h.
The catalyst was filtered off and the resulting solution
concentrated, leaving a pale-yellow crystalline solid. Purification
by radial chromatography (5% MeOH in CHCl.sub.3) followed by
recrystallization (MeOH/CHCl.sub.3/hexanes) yielded
2-phenethyl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 14 mg
(37%), as a pale-yellow solid. mp 207-208.degree. C.; .sup.1H NMR
(300 MHz, d.sub.6-DMSO) .delta.2.60 (m, 2H), 2.95 (m, 4H), 3.26 (m,
2H), 7.17 (m, 6H), 7.46 (dd, 1H, J=7.8, 0.6 Hz), 7.61 (dd, 1H,
J=7.5, 0.6 Hz), 7.90 (br t, 1H), 11.16 (br s, 1H); MS (FAB, MH+)
291; Anal. (C.sub.19H.sub.18N.sub.2O) C, H, N.
Example II
2-(2-Chlorophenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
(38)
[0206] 53
[0207] In a manner similar to that described for Compound 12, the
tricyclic bromide (210 mg, 0.79 mmol) and 2-chlorophenylboronic
acid (136 mg, 0.87 mmol) were coupled to yield
2-(2-chlorophenyl)-1,3,4,5-tetrahydr-
o-azepino[5,4,3-cd]indol-6-one, 78 mg (33%), as a shiny white
solid. mp 275.degree. C. (dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.2.76 (m, 2H), 3.38 (m, 2H), 7.23 (app t, 1H, J=7.8 Hz), 7.56
(m, 5H), 7.71 (dd, 1H, J=7.5, 0.9 Hz), 8.07 (br t, 1H), 11.53 (br
s, 1H); MS (FAB, MH+) 297; Anal. (C.sub.17H.sub.13N.sub.2OCl.0.15
H.sub.2O) C, H, N.
Example JJ
2-(2,4-Difluoro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
(39)
[0208] 54
[0209] In a manner similar to that described for Compound 12, the
tricyclic bromide (200 mg, 0.75 mmol) and 2,4-difluorophenylboronic
acid (131 mg, 0.83 mmol) were coupled to yield
2-(2,4-difluoro-phenyl)-1,3,4,5-
-tetrahydro-azepino[5,4,3-cd]indol-6-one, 156 mg (69%), as a
pale-yellow solid. mp 196-197.degree. C.; .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.2.84 (m, 2H), 3.37 (m, 2H), 7.25 (app t, 1H,
J=7.7 Hz), 7.27 (m, 1H), 7.47 (m, 1H), 7.57 (dd, 1H, J=8.1, 0.9
Hz), 7.64 (m, 1H), 7.70 (dd, 1H, J=7.5, 0.9 Hz), 8.08 (br t, 1H),
11.58 (br s, 1H); MS (FAB, MH+) 299; Anal.
(C.sub.17H.sub.12N.sub.2OF.sub.2.0.3 H.sub.2O.0.37 CHCl.sub.3) C,
H, N.
Example KK
2-(3-Chlorophenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
(40)
[0210] 55
[0211] In a manner similar to that described for Compound 12, the
tricyclic bromide (200 mg, 0.75 mmol) and 3-chlorophenylboronic
acid (130 mg, 0.83 mmol) were coupled to yield
2-(3-chlorophenyl)-1,3,4,5-tetrahydr-
o-azepino[5,4,3-cd]indol-6-one, 151 mg (67%), as a shiny
pale-yellow solid. mp 147-149.degree. C.; .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.3.06 (m, 2H), 3.39 (m, 2H), 7.24 (app t, 1H,
J=7.8 Hz), 7.46 (m, 1H), 7.58 (m, 4H), 7.70 (m, 2H), 7.64 (m, 1H),
8.11 (br t, 1H), 11.68 (br s, 1H); MS (FAB, MH+) 297; Anal.
(C.sub.17H.sub.13N.sub.2OCl.0.9 H.sub.2O) C, H, N.
Example LL
2-Naphthalen-1-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
(41)
[0212] 56
[0213] In a manner similar to that described for Compound 12, the
tricyclic bromide (300 mg, 1.13 mmol) and 1-naphthaleneboronic acid
(214 mg, 1.24 mmol) were coupled to yield
2-naphthalen-1-yl-1,3,4,5-tetrahydro-
-azepino[5,4,3-cd]indol-6-one, 70 mg (20%), as an off-white solid.
mp 305.degree. C. (dec.); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.2.70 (m, 2H), 3.38 (m, 2H), 7.25 (app t, 1H, J=7.5 Hz), 7.61
(m, 5H), 7.75 (dd, 1H, J=7.5, 0.9 Hz), 7.82 (m, 1H), 8.06 (m, 3H),
11.67 (br s, 1H); MS (FAB, MH+) 313; Anal.
(C.sub.21H.sub.16N.sub.2O.0.2 H.sub.2O) C, H, N.
Example MM
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid methyl ester (42)
[0214] 57
[0215] 2-Iodo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (85
mg, 0.28 mmol; prepared as described below), palladium
tetrakis(triphenylphosphine- ) (19 mg, 0.02 mmol), and
triethylamine (52 mg, 0.51 mmol) were combined in toluene:methanol
(8:2 (v/v), 2 mL). Carbon monoxide gas was bubbled through the
mixture for 10 min. The reaction was then heated at 85.degree. C.
in a sealed tube for 16 h. The solvent was evaporated and the
orange solid purified by radial chromatography (chloroform to 5%
methanol in chloroform). The white solid was recrystallized
(chloroform/methanol/hexanes) to yield
6-oxo-3,4,5,6-tetrahydro-1H-azepin- o[5,4,3-cd]indole-2-carboxylic
acid methyl ester, 39 mg (100%), as an off-white solid. mp
266-267.degree. C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.25
(m, 2H), 3.43 (m, 2H), 3.89 (s, 3H), 7.38 (app t, 1H, J=7.8 Hz),
7.61 (dd, 1H, J=8.1, 0.9 Hz), 7.74 (dd, 1H, J=7.5, 0.9 Hz), 8.17
(br t, 1H), 11.93 (br s, 1H); MS (FAB, MH+) 245; Anal.
(C.sub.13H.sub.12N.sub.2O.sub.3) C, H, N.
Example NN
Preparation of
2-Iodo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (43)
[0216] 58
[0217] 1,3,4,5-Tetrahydro-azepino[5,4,3-cd]indol-6-one (620 mg,
3.35 mmol) was suspended in 80 mL THF/CH.sub.2Cl.sub.2 (1:1), and
then cooled in an ice bath. Bis(trifluoroacetoxy)-iodo]benzene
(1.73 g, 4.02 mmol) and iodine (850 mg, 3.35 mmol) were added and
the reaction stirred at 0.degree. C. for 25 min. The ice bath was
removed and the reaction allowed to stir for another 30 min. as it
warmed to room temperature. The reaction was quenched by addition
of aqueous sodium bisulfite. The layers were separated, and the
organic layer was dried over MgSO.sub.4, filtered, and concentrated
in vacuo leaving a yellow solid. The crude solid was purified by
flash chromatography (5% MeOH/CHCl.sub.3) to yield
1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 308 mg (30%), as a
pale-yellow solid: .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.2.79
(m, 2H), 3.40 (m, 2H), 7.14 (app t, 1H, J=7.8 Hz), 7.46 (dd, 1H,
J=7.8, 0.6 Hz), 7.64 (dd, 1H, J=7.5, 0.9 Hz), 8.06 (br t, 1H),
11.80 (br s, 1H); MS (FAB, MH+) 313.
[0218] By following methods analogous to those described in the
above examples, the following compounds were also prepared: 59
Example OO
2-(4-(N-Methylamino)methylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]i-
ndol-6-one
[0219] 60
[0220] The p-aldehyde (150 mg, 0.52 mmol) prepared as described for
compound 21 in MeOH (20 mL) was treated, as described, with methyl
amine (8.03 M solution in EtOH, 3.10 mmol) and a solution of sodium
cyanoborohydride (0.57 mmol) and zinc chloride (0.28 mmol) in MeOH
(2 mL) to give, after recrystallization (isopropyl
alcohol/hexanes),
2-(4-(N-methylamino)methylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]-
indol-6-one, 108 mg (68%) as a yellow solid: m.p. 208-210.degree.
C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.2.34 (s, 3H), 3.05
(m, 2H), 3.39 (m, 2H), 3.77 (s, 2H), 7.20 (t, J=7.7 Hz, 1H), 7.54
(m, 3H), 7.61 (d of ABq, J=8.4 Hz, 2H), 7.67 (d, J=7.6 Hz, 1H),
8.07 (br t, 1H), 11.55 (br s, 1H). HRMS (FAB, MH+) Calcd for
C.sub.19H.sub.20N.sub.3O: 306.1606. Found: 306.1601. Anal.
(C.sub.19H.sub.19N.sub.3O.0.4 H.sub.2O) C, H, N.
Example PP
2-(3-(N-Methylamino)methylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]i-
ndol-6-one
[0221] 61
[0222] In a manner similar to that described for Compound 22, the
aldehyde 15 (200 mg, 0.69 mmol) in MeOH (20 mL) was treated with
methyl amine (2.0 M solution in THF, 4.20 mmol) and a solution of
sodium cyanoborohydride (0.76 mmol) and zinc chloride (0.38 mmol)
in MeOH (1.4 mL) to give, after recrystallization
(CH.sub.2Cl.sub.2/MeOH/hexanes),
2-(3-(N-methylamino)methylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]-
indol-6-one, 103 mg (49%) as pale yellow powder: m.p.
190-192.degree. C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.2.37
(s, 3H), 3.07 (m, 2H), 3.40 (m, 2H), 3.82 (s, 2H), 7.22 (t, J=7.7
Hz, 1H), 7.39 (br d, 1H), 7.49 (m, 1H), 7.56 (m, 2H), 7.68 (m, 2H),
8.09 (br t, 1H), 11.61 (br s, 1H). HRMS (FAB, MH+) Calcd for
C.sub.19H.sub.20N.sub.3O: 306.1606. Found: 306.1601. Anal.
(C.sub.19H.sub.19N.sub.3O.0.6 H.sub.2O) C, H, N.
Example QQ
1,5-Dihydro-3-methyl-[1,2]diazepino[4,5,6-cd]-indol-6-one
[0223] 62
[0224] In a manner similar to that described for compound 28, a
solution of methyl indole-4-carboxylate (427 mg, 2.44 mmol) in
dichloroethane (7 mL) was treated with acetyl chloride (0.5 mL) and
aluminum chloride (130 mg). The intermediate ketone (198 mg, 0.92
mmol) in MeOH (5 mL) and conc. HCl (0.05 mL) was treated, as
described, with hydrazine hydrate (0.1 mL). The product
precipitated, was collected by filtration and rinsed with ice-cold
MeOH to give 1,5-dihydro-3-methyl-[1,2]diazepino[4,5,6-cd]-indol-
-6-one, 168 mg (92%) as a bright yellow solid: m.p. 335-336.degree.
C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.2.17 (s, 3H), 7.19
(t, J=7.8 Hz, 1H), 7.54 (m, 2H), 7.67 (d, J=2.8 Hz, 1H), 10.12 (s,
1H), 11.90 (br s, 1H). HRMS (FAB, MH+) Calcd for
C.sub.11H.sub.10N.sub.3O: 200.0824. Found: 200.0827. Anal.
(C.sub.11H.sub.9N.sub.3O) C, H, N.
Example RR
2-(3-Aminophenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one
[0225] 63
[0226] In a manner similar to that described for Compound 12, the
tricyclic bromide (428 mg, 1.61 mmol) and 3-aminobenzeneboronic
acid monohydrate (300 mg, 1.94 mmol) were coupled to yield
2-(3-aminophenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one,
110 mg (25%) as an off-white solid: .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.3.03 (m, 2H), 3.39 (m, 2H), 5.24 (s, 2H), 6.59
(br d, 1H), 6.78 (d, J=7.7 Hz, 6.84 (m, 2H), 7.18 (m, 2H), 7.52 (d,
J=7.9 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 8.04 (br t, 1H), 11.41 (br
s, 1H). URMS (FAB, MH+) Calcd for C.sub.17H.sub.16N.sub.3O:
278.1293. Found: 278.1297. Anal. (C.sub.17H.sub.15N.sub.3O.1.1
H.sub.2O) C, H, N.
Example SS
2-(3-(3-Piperidin-1-ylmethylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd-
]indol-6-one
[0227] 64
[0228] In a manner similar to that described for Compound 22, the
aldehyde 15 (109 mg, 0.38 mmol) in MeOH (10 mL) was treated with
piperidine (0.19 mL, 1.9 mmol) and a solution of sodium
cyanoborohydride (0.57 mmol) and zinc chloride (0.28 mmol) in MeOH
(1.1 mL) to give, after recrystallization
(CH.sub.2Cl.sub.2/hexanes), 2-(3-(3-piperidin-1-ylmethy-
lphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one, 94.1
mg (69%) as pale yellow powder: m.p. 235-237.degree. C.; .sup.1H
NMR (300 MHz, d.sub.6-DMSO) .delta.1.41 (m, 2H), 1.52 (m, 4H), 2.37
(m, 4H), 3.06 (m, 2H), 3.39 (m, 2H), 3.52 (s, 2H), 7.21 (t, J=7.7
Hz, 1H), 7.31 (m, 1H), 7.54 (m, 4H), 7.69 (m, 1H), 8.08 (br t, 1H),
11.58 (br s, 1H). Anal. (C.sub.23H.sub.25N.sub.3O.0.65 H.sub.2O) C,
H, N.
Example TT
N-[3-(6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-phenyl]-ace-
tamide
[0229] 65
[0230] In a manner similar to that described for Compound 12, the
tricyclic bromide (300 mg, 1.13 mmol) and 3-acetamidophenylboronic
acid (304 mg, 1.70 mmol) were coupled to yield
N-[3-(6-Oxo-3,4,5,6-tetrahydro--
1H-azepino[5,4,3-cd]indol-2-yl)-phenyl]-acetamide, 10 mg (3%) as a
clear solid: m.p. 300.5-302.0.degree. C.; .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.2.09 (s, 3H), 3.05 (m, 2H), 3.36 (m, 2H), 7.21
(app t, J=7.8 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.44 (t, J=7.8 Hz,
1H), 7.57 (m, 2H), 7.68 (d, J=7.5 Hz, 1H), 7.92 (br s, 1H), 8.08
(br t, 1H), 10.10 (br s, 1H), 11.56 (brs, 1H). MS (FAB, MH+) 320.
Anal. (C.sub.19H.sub.17N.sub.3O.sub.2- ) C, H, N.
Example UU
2-[3-(4-Fluoro-phenoxy)-phenyl]-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol--
6-one
[0231] 66
[0232] In a manner similar to that described for Compound 12, the
tricyclic bromide (200 mg, 0.75 mmol) and
3-(4-fluoro-phenoxy)-phenylboro- nic acid (213 mg, 0.83 mmol) were
coupled to yield 2-[3-(4-fluoro-phenoxy)-
-phenyl]-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 170 mg
(60%) as a yellow crystalline solid: m.p. 240-241.degree. C.;
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.01 (m, 2H), 3.38 (m,
2H), 6.99 (m, 2H), 7.21 (m, 6H), 7.42 (m, 1H), 7.54 (m, 2H), 7.68
(m, 1H), 8.09 (br t, 1H), 11.60 (br s, 1H). MS (FAB, MH+) 373.
Anal. (C.sub.23H.sub.17N.sub.2O.sub.2 F.0.5 H.sub.2O) C, H, N.
Example VV
2-Biphenyl-4-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
[0233] 67
[0234] In a manner similar to that described for Compound 12, the
tricyclic bromide (150 mg, 0.57 mmol) and 2-Biphenyl-4-boronic acid
(123 mg, 0.62 mmol) were coupled to yield
2-Biphenyl-4-yl-1,3,4,5-tetrahydro-a- zepino[5,4,3-cd]indol-6-one,
87 mg (45%) as a pale yellow solid: m.p. 277-279.degree. C. (dec);
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.11 (m, 2H), 3.41 (m,
2H), 7.23 (app t, J=7.8 Hz, 1H), 7.40 (m, 1H), 7.51 (app t, J=7.2
Hz, 2H), 7.58 (d, J=8.1 Hz, 1H), 7.77 (m, 7H), 8.10 (br t, 1H),
11.64 (br s, 1H). MS (FAB, MH+) 339 Anal.
(C.sub.23H.sub.18N.sub.2O.- 1.15 H.sub.2O) C, H, N.
Example WW
2-(4-Chloro-3-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]-
indol-6-one
[0235] 68
[0236] In a manner similar to that described for Compound 12, the
tricyclic bromide (100 mg, 0.38 mmol) and
4-chloro-3-trifluoromethyl-phen- ylboronic acid (150 mg, 0.45 mmol)
were coupled to yield
2-(4-chloro-3-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd-
]indol-6-one, 121 mg (88%) as a pale yellow solid: m.p.
118.5-119.degree. C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.3.06 (m, 2H), 3.41 (m, 2H), 7.27 (app t, J=7.8 Hz, 1H), 7.60
(dd, J=7.8, 0.9 Hz, 1H), 7.73 (dd, J=7.2, 0.9 Hz, 1H), 7.89 (m,
2H), 8.08 (d, J=1.5 Hz, 1H), 8.14 (br t, 1H), 11.82 (br s, 1H). MS
(FAB, MH+) 365. Anal. (C.sub.18H.sub.12ClF.sub.- 3N.sub.2O.0.45
H.sub.2O.0.2 CHCl.sub.3) C, H, N.
Example XX
2-Naphthalen-2-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
[0237] 69
[0238] In a manner similar to that described for Compound 12, the
tricyclic bromide (300 mg, 1.13 mmol) and 2-naphthaleneboronic acid
(214 mg, 1.24 mmol) were coupled to yield
2-Naphthalen-2-yl-1,3,4,5-tetrahydro-
-azepino[5,4,3-cd]indol-6-one, 130 mg (37%) as a pale yellow solid:
m.p. 261-262.degree. C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.3.18 (m, 2H), 3.42 (m, 2H), 7.24 (app t, J=7.5 Hz, 1H), 7.58
(m, 3H), 7.72 (dd J=7.5, 0.9 Hz, 1H), 7.84 (dd J=8.4, 1.5 Hz, 1H),
8.07 (m, 5H), 11.74 (br s, 1H). MS (FAB, MH+) 313. Anal.
(C.sub.21H.sub.16N.sub.2O.0.9 H.sub.2O) C, H, N.
Example YY
2-[4-(2-Diethylamino-ethyl)-phenyl]-3,4,5,6-tetrahydro-azepino[5,4,3-cd]in-
dol-6-one
[0239] 70
[0240] (As described in Tet. Lett. 1997 p. 3841)
[2-(4-Bromo-phenyl)-ethyl- ]-diethyl-amine (256 mg, 1.00 mmol),
diboron pinacol ester (279 mg, 1.10 mmol),
1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (24 mg, 0.03
mmol), and potassium acetate (294 mg, 3.00 mmol) were combined in a
schlenk tube. The vessel was evacuated then refilled with argon
thrice. Degassed DMF (6 mL) was added and the mixture stirred at
80.degree. C. under an argon atmosphere for 2 h.
2-Bromo--3,4,5,6-tetrahydro-azepino[5,- 4,3-cd]indol-6-one (239 mg,
0.90 mmol), a second portion of
1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (24 mg, 0.03
mmol), and sodium carbonate (2.5 mL of a 2.0 M aqueous solution,
5.00 mmol) were then added and the reaction stirred under an argon
atmosphere at 80.degree. C. for another 17 h. The reaction mixture
was then poured into 25 mL water then extracted with 25%
IPA/CHCl.sub.3 (3.times.20 mL). The combined organic extracts were
dried (MgSO.sub.4) and concentrated in vacou leaving a brown oil.
The crude product was passed through a short silica plug with 25%
MeOH/CHCl.sub.3 then purified by radial chromatography eluting with
20% MeOH/CHCl.sub.3. Crystallization from MeOH/CHCl.sub.3/hexanes
yielded 2-[4-(2-diethylamino-ethyl)-phenyl]-3,4,5-
,6-tetrahydro-azepino[5,4,3-cd]indol-6-one, 69 mg (19%) as a white
solid: m.p. 224-224.5.degree. C. (dec); .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.0.98 (t, J=6.9 Hz, 6H), 2.53 (q, J=7.2 Hz,
4H), 2.69 (m, 4H), 3.04 (m, 2H), 3.37 (m, 2H), 7.19 (t, J=7.8 Hz,
1H), 7.36 (d, J=8.1 Hz, 2H), 7.55 (m, 3H), 7.88 (dd, J=7.5, 0.9 Hz,
1H), 8.06 (br t, 1H), 11.51 (br s, 1H). MS (FAB, MH+): 362. Anal.
(C.sub.23H.sub.27N.sub.3O) C, H, N.
Example ZZ
2-[3-(2-Hydroxy-ethyl)-phenyl]-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-
-one
[0241] 71
[0242] In a manner similar to that described for Example YY,
3-bromophenethyl alcohol (201 mg, 1.00 mmol), diboron pinacol ester
(279 mg, 1.10 mmol), 1,1'-bis(diphenylphosphino)ferrocene
dichloropalladium (24 mg, 0.03 mmol), and potassium acetate (294
mg, 3.00 mmol),
2-bromo-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (239 mg,
0.90 mmol), a second portion of
1,1'-bis(diphenylphosphino)ferrocenedichloropa- lladium (24 mg,
0.03 mmol), and sodium carbonate (2.5 mL of a 2.0 M aqueous
solution, 5.00 mmol) were reacted to yield
2-[3-(2-hydroxy-ethyl)-phenyl]-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol--
6-one, 135 mg (44%) as an off-white solid: m.p. 187.5-188.5.degree.
C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.2.82 (t, J=6.9 Hz,
2H), 3.12 (m, 2H), 3.39 (m, 2H), 3.69 (Abq, J=7.2, 5.1 Hz, 2H),
4.71 (t, J=5.1 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.25 (d, J=7.2 Hz,
1H), 7.49 (m, 4H), 7.68 (dd, J=7.5, 0.9 Hz, 1H), 8.08 (br t, 1H),
11.55 (br s, 1H). MS (FAB, MH+): 307. Anal.
(C.sub.19H.sub.18N.sub.2O.sub.2.0.1 H.sub.2O) C, H, N.
Example AAA
3-[2-(6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-phenyl]-pro-
pionic acid methyl ester
[0243] 72
[0244] In a manner similar to that described for Example YY,
3-(2-bromo-phenyl)-propionic acid methyl ester (243 mg, 1.00 mmol),
diboron pinacol ester (279 mg, 1.10 mmol), 1,1'-bis(diphenyl
phosphino)ferrocene dichloropalladium (24 mg, 0.03 mmol), and
potassium acetate (294 mg, 3.00 mmol),
2-Bromo-3,4,5,6-tetrahydro-azepino[5,4,3-cd]- indol-6-one (239 mg,
0.90 mmol), a second portion of
1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (24 mg, 0.03
mmol), and sodium carbonate (2.5 mL of a 2.0 M aqueous solution,
5.00 mmol) were reacted to yield
3-[2-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4-
,3-cd]indol-2-yl)-phenyl]-propionic acid methyl ester, 92 mg (29%)
as a beige solid: m.p. 201-201.5.degree. C.; .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.2.43 (t, J=7.5 Hz, 2H), 2.68 (m, 2H), 2.86 (t,
J=8.1 Hz, 2H) 3.38 (m, 2H), 3.47 (s, 3H), 7.20 (t, J=7.8 Hz, 1H),
7.37 (m, 4H), 7.52 (dd, J=7.8, 0.6 Hz, 1H), 7.70 (dd, J=7.5, 0.6
Hz, 1H), 8.04 (br t, 1H), 11.41 (br s, 1H). MS (FAB, MH+): 349.
Anal. (C.sub.21H.sub.20N.sub.2- O.sub.3.0.3 CHCl.sub.3) C, H,
N.
Example BBB
2-[2-(3-Hydroxy-propyl)-phenyl]-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol--
6-one
[0245] 73
[0246] In a manner similar to that described for Example YY,
3-(2-bromo-phenyl)-propan-1-ol (215 mg, 1.00 mmol), diboron pinacol
ester (279 mg, 1.10 mmol), 1,1'-bis(diphenyl phosphino) ferrocene
dichloropalladium (24 mg, 0.03 mmol), and potassium acetate (294
mg, 3.00 mmol),
2-Bromo-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (239 mg,
0.90 mmol), a second portion of
1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (24 mg, 0.03
mmol), and sodium carbonate (2.5 mL of a 2.0 M aqueous solution,
5.00 mmol) were reacted to yield
2-[2-(3-hydroxy-propyl)-phenyl]-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-
-6-one, 127 mg (44%) as a beige solid: m.p. 233.5-234.5.degree. C.;
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.1.53 (m, 2H), 2.61 (t,
J=7.8 Hz, 2H), 2.69 (m, 2H), 3.23 (ABq, J=6.6, 5.1 Hz, 2H), 3.37
(m, 2H), 4.39 (t, J=5.1 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 7.35 (m,
4H), 7.51 (dd, J=7.8, 0.9 Hz, 1H), 7.70 (dd, J=7.5, 0.9 Hz, 1H),
8.03 (br t, 1H), 11.39 (br s, 1H). MS (FAB, MH+): 321. Anal.
(C.sub.20H.sub.20N.sub.2O.sub.2.0.1 CH.sub.2Cl.sub.2) C, H, N.
Example CCC
2-(4-Hydroxy-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
[0247] 74
[0248] In a manner similar to that described for Compound YY,
4-iodophenol (220 mg, 1.00 mmol), diboron pinacol ester (279 mg,
1.10 mmol), 1,1'-bis(diphenyl phosphino)ferrocenedichloro palladium
(24 mg, 0.03 mmol), and potassium acetate (294 mg, 3.00 mmol),
2-bromo-3,4,5,6-tetrahy- dro-azepino[5,4,3-cd]indol-6-one (239 mg,
0.90 mmol), a second portion of
1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (24 mg, 0.03
mmol), and sodium carbonate (2.5 mL of a 2.0 M aqueous solution,
5.00 mmol) were reacted to yield
2-(4-hydroxy-phenyl)-1,3,4,5-tetrahydro-azepi-
no[5,4,3-cd]indol-6-one, 39 mg (15%) as a beige solid: m.p.
300.degree. C. (dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.3.00 (m, 2H), 3.37 (m, 2H), 6.92 (d, J=8.7 Hz, 2H), 7.16 (t,
J=7.8 Hz, 1H), 7.49 (m, 3H), 7.65 (dd, J=7.5, 0.9 Hz, 1H), 8.04 (br
t, 1H), 9.73 (br s, 1H), 11.40 (br s, 1H). MS (electrospray, MH+):
279. Anal. (C.sub.17H.sub.14N.sub.2O.sub.2) C, H, N.
Example DDD
2-(2-Hydroxy-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
[0249] 75
[0250] In a manner similar to that described for Example YY,
2-iodophenol (220 mg, 1.00 mmol), diboron pinacol ester (279 mg,
1.10 mmol), 1,1'-bis(diphenyl phosphino)ferrocenedichloro palladium
(24 mg, 0.03 mmol), and potassium acetate (294 mg, 3.00 mmol),
2-bromo-3,4,5,6-tetrahy- dro-azepino[5,4,3-cd]indol-6-one (239 mg,
0.90 mmol), a second portion of
1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (24 mg, 0.03
mmol), and sodium carbonate (2.5 mL of a 2.0 M aqueous solution,
5.00 mmol) were reacted to yield
2-(2-hydroxy-phenyl)-1,3,4,5-tetrahydro-azepi-
no[5,4,3-cd]indol-6-one, 40 mg (15%) as a white solid: m.p.
305.degree. C. (dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.2.86 (m, 2H), 3.46 (m, 2H), 6.92 (t, J=7.5 Hz, 1H), 7.00 (d,
J=7.8 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 7.24 (m, 1H), 7.34 (dd,
J=7.5, 1.2 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H),
8.00 (br t, 1H), 9.84 (br s, 1H), 11.20 (br s, 1H). MS (FAB, MH+):
279. Anal. (C.sub.17H.sub.14N.sub.2O.sub.2.0.44 CHCl.sub.3) C, H,
N.
Example EEE
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carbonitrile
[0251] 76
[0252] Following a procedure from JOC 1998, p. 8224,
2-iodo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (100 mg,
0.32 mmol), sodium cyanide (31 mg, 0.64 mmol), palladium
tetrakis(triphenylphosphine) (19 mg, 0.05 mmol), and copper(I)
iodide were combined in a schlenk tube. The vessel was evacuated
and refilled with argon gas three times. Degassed propionitrile (2
mL) was added, and the reaction was stirred at 80.degree. C. under
an argon atmosphere for 15 h. The reaction mixture was partitioned
between water and 25% iPrOH/CHCl.sub.3. The layers were separated
and the aqueous layer extracted thrice with 25% iPrOH/CHCl.sub.3.
The combined organic layers were dried (MgSO.sub.4) and
concentrated in vacuo. The yellow solid was recrystallized from
CH.sub.2Cl.sub.2/MeOH/hexanes to yield
6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carbonitrile,
38 mg (56%) as a pale yellow solid: m.p. 315.degree. C. (dec);
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.04 (m, 2H), 3.47 (m,
2H), 7.46 (t, J=7.5 Hz, 1H), 7.64 (dd, J=8.1, 0.9 Hz, 1H), 7.81
(dd, J=7.2, 0.9 Hz, 1H), 8.24 (br t, 1H), 12.44 (br s, 1H). MS
(electrospray, [M+Na]+): 234. Anal. (C.sub.12H.sub.9N.sub.3O) C, H,
N.
Example FFF
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid octyl ester
[0253] 77
[0254] Following a procedure similar to that described for Example
MM (Compound 42),
2-iodo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (330 mg,
1.06 mmol), triethylamine (342 mg, 3.38 mmol), and palladium
tetrakis(triphenylphosphine) (61 mg, 0.05 mmol) were reacted in 20
mL 1:1 n-octanol:DMF in a sealed tube under a carbon monoxide
atmosphere to yield
6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid octyl ester, 250 mg (58%), as a white solid: m.p.
170-171.degree. C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.0.85
(t, J=7.2 Hz, 3H), 1.27 (m, 8H), 1.42 (m, 2H), 1.73 (m, 2H), 3.25
(m, 2H), 3.42 (m, 2H), 4.30 (t, J=6.6 Hz, 3H), 7.38 (app t, J=7.5
Hz, 1H), 7.62 (dd, J=8.1, 0.9 Hz, 1H), 7.74 (dd, J=7.5, 0.9 Hz,
1H), 8.17 (br t, 1H), 11.86 (br s, 1H). MS (FAB, MH+) 343. Anal.
(C.sub.20H.sub.26N.sub.2O.sub.3) C, H, N.
Example GGG
2-(4-Chloro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
[0255] 78
[0256] In a manner similar to that described for Compound 12, the
tricyclic bromide (300 mg, 1.13 mmol) and 4-chlorophenylboronic
acid (195 mg, 1.24 mmol) were coupled to yield
2-(4-chloro-phenyl)-1,3,4,5-tetrahyd-
ro-azepino[5,4,3-cd]indol-6-one, 223 mg (66%) as an off-white
solid: m.p. 250-252.degree. C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.3.04 (m, 2H), 3.39 (m, 2H), 7.23 (app t, J=7.5 Hz, 1H), 7.58
(m, 3H), 7.68 (m, 3H), 8.10 (br t, 1H), 11.66 (br s, 1H). MS (FAB,
MH+) 297. Anal. (C.sub.17H.sub.13ClN.sub.2O.0.8 H.sub.2O) C, H,
N.
Example HHH
2-Pyridin-3-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
[0257] 79
[0258] In a manner similar to that described for Compound 12, the
tricyclic bromide (300 mg, 1.13 mmol) and 3-pyridylboronic acid
(153 mg, 1.24 mmol) were coupled to yield
2-pyridin-3-yl-1,3,4,5-tetrahydro-azepin- o[5,4,3-cd]indol-6-one,
75 mg (25%) as a light brown solid: m.p. 260.5-262.0.degree. C.;
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.07 (m, 2H), 3.40 (m,
2H), 7.25 (app t, J=7.8 Hz, 1H), 7.57 (m, 2H), 7.71 (dd, J=7.5, 0.9
Hz, 1H), 8.05 (m, 1H), 8.12 (br t, 1H), 8.59 (m, 1H), 8.88 (m, 1H),
11.75 (br s, 1H). MS (FAB, MH+) 264. Anal.
(C.sub.16H.sub.13N.sub.3O.0.2 H.sub.2O) C, H, N.
Example III
2-(2-Methoxy-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
[0259] 80
[0260] In a manner similar to that described for Compound 12, the
tricyclic bromide (300 mg, 1.13 mmol) and 2-methoxyphenylboronic
acid (189 mg, 1.24 mmol) were coupled to yield
2-(2-methoxy-phenyl)-1,3,4,5-te-
trahydro-azepino[5,4,3-cd]indol-6-one, 177 mg (53%) as a brown
solid: m.p. 254-255.degree. C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.2.81 (m, 2H), 3.36 (m, 2H), 3.83 (s, 3H), 7.08 (app t, J=7.5
Hz, 1H), 7.17 (m, 2H), 7.43 (m, 2H), 7.54 (dd, J=7.8, 0.6 Hz, 1H),
7.67 (dd, J=7.5, 0.6 Hz, 1H), 8.03 (br t, 1H), 11.27 (br s, 1H). MS
(FAB, MH+) 293. Anal. (C.sub.18H.sub.16N.sub.2O.sub.2.0.3 H.sub.2O)
C, H, N.
Example JJJ
2-Pyridin-4-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
[0261] 81
[0262] In a manner similar to that described for Compound 12, the
tricyclic bromide (300 mg, 1.13 mmol) and 4-pyridylboronic acid
(153 mg, 1.24 mmol) were coupled to yield
2-pyridin-4-yl-1,3,4,5-tetrahydro-azepin- o[5,4,3-cd]indol-6-one,
45 mg (15%) as a beige solid: m.p. 250.degree. C. (dec); .sup.1H
NMR (300 MHz, d.sub.6-DMSO) .delta.3.13 (m, 2H), 3.41 (m, 2H), 7.29
(app t, J=7.8 Hz, 1H), 7.63 (m, 3H), 7.72 (dd, J=7.2, 0.9 Hz, 1H),
8.14 (br t, 1H), 8.69 (d, J=6.0 Hz, 2H), 11.82 (br s, 1H). MS (FAB,
MH+) 364. Anal. (C.sub.16H.sub.13N.sub.3O) C, H, N.
Example KKK
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid sodium salt
[0263] 82
[0264] In an attempt to form the piperazine amide,
6-oxo-3,4,5,6-tetrahydr- o-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid methyl ester (100 mg, 0.41 mmol) was dissolved in 1 mL
piperazine. The yellow solution was stirred under argon at
110.degree. C. for 18 h. The reaction mixture was partitioned
between saturated NaHCO.sub.3 and 25% iPrOH/CHCl.sub.3. The layers
were separated and the aqueous layer extracted once with 25%
iPrOH/CHCl.sub.3. The combined organic layers were dried
(MgSO.sub.4) and concentrated in vacuo leaving ca. 3 mg of yellow
solid. After standing overnight at room temperature, a pale yellow
solid crystallized from the aqueous layer 80 mg (78%). The compound
was identified as the sodium salt of
6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid: m.p. 310.degree. C. (dec); .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.3.20 (m, 2H), 3.41 (m, 2H), 7.11 (app t, J=7.8
Hz, 1H), 7.50 (dd, J=8.1, 0.9 Hz, 1H), 7.60 (dd, J=7.5, 0.9 Hz,
1H), 7.96 (br t, 1H), 11.00 (br s, 1H). MS (electrospray,
[M-Na].sup.-) 229. Anal. (C.sub.12H.sub.9N.sub.2O.sub.3Na.0.5
H.sub.2O) C, H, N.
Example LLL
2-(2-Methylsulfanyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-on-
e
[0265] 83
[0266] In a manner similar to that described for Compound 12, the
tricyclic bromide (530 mg, 2.00 mmol) and 2-thioanisole boronic
acid (370 mg, 2.20 mmol) were coupled to yield
2-(2-methylsulfanyl-phenyl)-1,3,4,5--
tetrahydro-azepino[5,4,3-cd]indol-6-one, 264 mg (43%) as an
off-white solid: m.p. 271-272.degree. C.; .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.2.39 (s, 3H), 2.73 (m, 2H), 3.37 (m, 2H), 7.23
(m, 2H), 7.37 (m, 2H), 7.49 (m, 2H), 7.70 (d, J=7.2 Hz, 1H), 8.05
(br t, 1H), 11.41 (br s, 1H). MS (FAB, MH+) 309. Anal.
(C.sub.18H.sub.16N.sub.2OS) C, H, N.
Example MMM
2-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-1,3,4,5-tetrahydro-azepino[5,4,3-cd-
]indol-6-one
[0267] 84
[0268] In a manner similar to that described for
2-[4-(2-diethylamino-ethy-
l)-phenyl]-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (Example
YY), the tricyclic bromide (198 mg, 0.75 mmol) and
1-[2-(4-bromo-phenyl)-ethyl- ]-pyrrolidine were coupled to yield
2-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-
-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 160 mg (59%) as a
beige solid: m.p. 228-229.degree. C. (dec); .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.1.69 (m, 4H), 2.51 (m, 4H), 2.67 (m, 2H), 2.81
(m, 2H), 3.05 (m, 2H), 3.39 (m, 2H), 7.20 (t, J=7.8 Hz, 1H), 7.39
(d, J=8.1 Hz, 2H), 7.56 (m, 3H), 7.68 (d, J=7.5 Hz, 1H), 8.08 (br
t, 1H), 11.31 (br s, 1H). MS (FAB, MH+): 360. Anal.
(C.sub.23H.sub.25N.sub.3O) C, H, N.
Example NNN
N-[4-Fluoro-2-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-ph-
enyl]-acetamide
[0269] 85
[0270] In a manner similar to that described for
2-[4-(2-diethylamino-ethy-
l)-phenyl]-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (Example
YY), the tricyclic bromide (300 mg, 1.13 mmol) and
N-(2-bromo-4-fluoro-phenyl)- -acetamide (276 mg, 1.19 mmol) were
coupled to yield
N-[4-fluoro-2-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-p-
henyl]-acetamide, 83 mg (22%) as a beige solid: m.p.
260-261.degree. C. (dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.1.97 (s, 3H), 2.66 (m, 2H), 3.33 (m, 2H), 7.25 (m, 3H), 7.56
(dd, J=7.5, 0.6 Hz, 1H), 7.70 (dd, J=7.2, 0.6 Hz, 1H), 7.76 (m,
1H), 8.04 (br t, 1H), 11.50 (br s, 1H). MS (FAB, MH+): 338. Anal.
(C.sub.16H.sub.19FN.sub.3O.sub.2.0.16 H.sub.2O) C, H, N.
Example OOO
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
Acid Methylamide
[0271] 86
[0272]
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid methyl ester (50 mg, 0.20 mmol) was suspended in 1 mL of a 33%
solution of methylamine in methanol. The suspension was stirred at
room temperature for 21 h. Another 2 mL 33% methylamine in methanol
was added and the resulting solution stirred another 8 h at room
temperature then 15 h at 30.degree. C. The reaction mixture was
concentrated in vacuo leaving a yellow solid which was crystallized
from DMF/MeOH/CHCl.sub.3 to yield
6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid methylamide, 36 mg (72%) as a yellow solid: m.p.
321-322.degree. C. (dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.2.81 (s, 3H), 3.15 (m, 2H), 3.40 (m, 2H), 7.32 (app t, J=7.8
Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.95 (br
q, 1H), 8.09 (br t, 1H), 11.46 (br s, 1H). MS (electrospray,
[M+Na].sup.+) 266. Anal. (C.sub.13H.sub.13N.sub.3O- .sub.2.0.4
H.sub.2O) C, H, N.
Example PPP
2-(4-Dimethylaminomethyl-3-fluoro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-
-cd]indol-6-one
[0273] 87
[0274]
2-Fluoro-4-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl-
)-benzaldehyde (72 mg, 0.23 mmol. Prepared via the standard
two-step, one-pot suzuki coupling of the tricyclic bromide and
4-bromo-2-fluoro-benzaldehyde as described for Example YY) was
dissolved in 2 mL 2.0 M dimethylamine in methanol. The orange
solution was stirred at room temperature 10 min. The reaction was
then cooled to 0.degree. C. and a solution containing zinc chloride
(17 mg, 0.13 mmol) and sodium cyanoborohydride (16 mg, 0.26 mmol)
in 1 mL methanol, was added dropwise. The pH was adjusted to ca. 3
with concentrated HCl. The reaction was stirred for one hour as the
temperature gradually warmed to room temperature. The reaction was
partitioned between CHCl.sub.3 and water. The pH of the aqueous
layer was adjusted to ca. 13 with solid KOH. The layers were
separated, and the aqueous layer extracted with 25%
iPrOH/CHCl.sub.3. The combined organic layers were dried
(MgSO.sub.4) then concentrated in vacuo. Radial chromatography
(eluting with 5% MeOH/CHCl.sub.3) then crystallization from
CH.sub.2Cl.sub.2/hexanes yielded
2-(4-dimethylaminomethyl-3-fluoro-phenyl)-1,3,4,5-tetrahydro-azep-
ino[5,4,3-cd]indol-6-one, 60 mg (76%) as a yellow solid.: m.p.
221.5-222.5.degree. C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.2.19 (s, 6H), 3.08 (m, 2H), 3.39 (m, 2H), 3.50 (s, 2H), 7.23
(app t, J=7.8 Hz, 1H), 7.50 (m, 4H), 7.69 (d, J=7.5 Hz, 1H) 8.10
(brt, 1H), 11.62 (br s, 1H). MS (FAB, MH+) 338. Anal.
(C.sub.20H.sub.20FN.sub.3O) C, H, N.
Example QQQ
2-(3-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4-
,3-cd]indol-6-one
[0275] 88
[0276] In a manner similar to that described for as described for
Example YY, the tricyclic bromide (1.00 g, 3.77 mmol) and
1-(4-bromo-2-fluoro-ben- zyl)-pyrrolidine (1.07 g, 4.19 mmol) were
coupled to yield
2-(3-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,-
4,3-cd]indol-6-one, 150 mg (11%) as a beige solid: m.p.
139-140.degree. C. (dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.1.71 (m, 4H), 2.50 (m, 4H, obscured by solvent), 3.07 (m,
2H), 3.40 (m, 2H), 3.68 (s, 2H), 7.23 (t, J=7.8 Hz, 1H), 7.45 (m,
2H), 7.55 (m, 2H), 7.70 (dd, J=7.5, 0.6 Hz, 1H), 8.07 (br t, 1H),
11.59 (br s, 1H). MS (electrospray, MH+) 364. Anal.
(C.sub.22H.sub.22FN.sub.3O.0.55 H.sub.2O) C, H, N.
Example RRR
2-Biphenyl-3-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
[0277] 89
[0278] In a manner similar to that described for Compound 12, the
tricyclic bromide (300 mg, 1.13 mmol) and biphenyl-3-boronic acid
(213 mg, 0.83 mmol) were coupled to yield
2-biphenyl-3-yl-1,3,4,5-tetrahydro-a- zepino[5,4,3-cd]indol-6-one,
116 mg (30%) as an off-white crystalline solid: m.p.
160-163.degree. C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.13
(m, 2H), 3.42 (m, 2H), 7.24 (app t, J=7.8 Hz, 1H), 7.42 (m, 1H),
7.61 (m, 7H), 7.79 (m, 2H), 7.94 (b s, 1H), 8.10 (brt, 1H), 11.67
(br s, 1H). MS (FAB, MH+) 339. Anal. (C.sub.23H.sub.18N.sub.2O) C,
H, N.
Example SSS
2-(5-Chloro-2-methoxy-phenyl)-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6--
one
[0279] 90
[0280] In a manner similar to that described for Compound 12, the
tricyclic bromide (129 mg, 0.49 mmol) and
5-chloro-2-methoxy-phenylboroni- c acid (100 mg, 0.54 mmol) were
coupled to yield 2-(5-chloro-2-methoxy-phe-
nyl)-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one, 100 mg (63%)
as an off-white solid: m.p. 160-162.degree. C.; .sup.1H NMR (300
MHz, d.sub.6-DMSO) .delta.2.81 (m, 2H), 3.34 (m, 2H), 3.84 (s, 3H),
7.20 (m, 2H), 7.46 (m, 2H), 7.55 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.5
Hz, 1H), 8.05 (br t, 1H), 11.37 (br s, 1H). MS (FAB, MH+): 327.
Anal. (C.sub.18H.sub.15ClN.sub.2O.sub.2) C, H, N, Cl.
Example TTT
1,3,4,5,1',3',4',5'-Octahydro-[2,2']bi[azepino[5,4,3-cd]indolyl]-6,6'-dion-
e
[0281] 91
[0282] The title compound was isolated as a by-product of the
coupling of the tricyclic bromide (642 mg, 2.42 mmol) under the
conditions described for Example YY, 27 mg (6%) isolated as a
yellow solid: m.p. <400.degree. C. (dec); .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.2.97 (m, 4H), 3.39 (m, 4H), 7.26 (t, J=7.8 Hz,
2H), 7.59 (dd, J=8.1, 0.9 Hz, 2H), 7.72 (dd, J=7.5, 0.9 Hz, 2H),
8.12 (br t, 2H), 11.50 (br s, 2H). MS (electrospray, MH+): 372.
Anal. (C.sub.22H.sub.18N.sub.4O.sub.2.0.25 H.sub.2O) C, H, N.
Example UUU
2-(3-Amino-phenylethynyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
[0283] 92
[0284] In a manner similar to that described for Example N,
Compound 17, 3-ethynyl-analine (129 mg, 1.10 mmol) was coupled to
2-iodo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (312 mmol,
1.00 mmol) to yield
2-(3-amino-phenylethynyl)-1,3,4,5-tetrahydro-azepino[5,4,3-
-cd]indol-6-one, 250 mg (83%) as a pale yellow solid: m.p.
261-262.degree. C. (dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.3.00 (m, 2H), 3.45 (m, 2H), 5.31 (br s, 2H), 6.63 (m, 1H),
6.71 (m, 1H), 6.76 (m, 1H), 7.08 (app t, J=7.8 Hz, 1H), (app t,
J=7.8 Hz, 1H), 7.48 (dd, J=8.1, 0.9 Hz, 1H), 7.70 (dd, J=7.5, 0.6
Hz, 1H), 8.09 (br t, 1H), 11.75 (br s, 1H). MS (electrospray, MH+)
302. Anal. (C.sub.19H.sub.15N.sub.3O.0.15 H.sub.2O) C, H, N.
Example VVV
2-(1H-Indol-5-yl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
[0285] 93
[0286] In a manner similar to that described for Compound 12, the
tricyclic bromide (530 mg, 2.00 mmol) and indole-5-boronic acid
(354 mg, 2.20 mmol) were coupled to yield
2-(1H-indol-5-yl)-1,3,4,5-tetrahydro-aze-
pino[5,4,3-cd]indol-6-one, 396 mg (66%) as a beige solid: m.p.
315-317.degree. C. (dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.3.10 (m, 2H), 3.41 (m, 2H), 6.54 (m, 1H), 7.17 (t, J=7.8 Hz,
1H), 7.42 (m, 2H), 7.55 (m, 2H), 7.68 (d, J=7.5 Hz, 1H), 7.83 (br
s, 1H), 8.05 (br t, 1H), 11.26 (br s, 1H), 11.48 (br s, 1H). MS
(electrospray, MH+) 302. Anal. (C.sub.19H.sub.15N.sub.3O.0.25
H.sub.2O) C, H, N.
Example WWW
4-(6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzoic
acid
[0287] 94
[0288] In a manner similar to that described for Compound 12, the
tricyclic bromide (530 mg, 2.00 mmol) and 4-carboxyphenylboronic
acid (365 mg, 2.20 mmol) were coupled to yield
4-(6-oxo-3,4,5,6-tetrahydro-1H--
azepino[5,4,3-cd]indol-2-yl)-benzoic acid, 340 mg (56%) as a pale
yellow solid: m.p. 345.5-346.5.degree. C. (dec); .sup.1H NMR (300
MHz, d.sub.6-DMSO) .delta.3.10 (m, 2H), 3.40 (m, 2H), 7.25 (t,
J=7.8 Hz, 1H), 7.59 (dd, J=8.1, 0.9 Hz, 1H), 7.70 (dd, J=7.5, 0.6
Hz, 1H), 7.78 (m, 2H), 8.10 (m, 3H), 11.73 (br s, 1H), 13.00 (br s,
1H). MS (electrospray, MH+) 307. Anal.
(C.sub.18H.sub.14N.sub.2O.sub.3.0.9 H.sub.2O) C, H, N.
Example XXX
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid
[0289] 95
[0290]
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid octyl ester (Example FFF) (350 mg, 1.02 mmol) and lithium
hydroxide (122 mg, 5.11 mmol) were dissolved in 10 mL 2:1
methanol:water and stirred at room temperature for 24 h. The
reaction mixture was diluted with water then washed twice with
dichloromethane. The aqueous solution was acidified to ca. pH 2
with conc. HCl. The white precipitate was collected by filtration,
washed with water, and dried in vacuo to yield
6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid, 235 mg (99%) as a white solid: m.p. 298-299.degree. C. (dec);
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.17 (m, 2H), 3.41 (m,
2H), 7.35 (t, J=7.8 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.73 (d, J=7.5
Hz, 1H), 8.14 (brt, 1H), 11.77 (br s, 1H), 13.14 (br s, 1H). MS
(electrospray, MH+): 231. Anal. (C.sub.12H.sub.10N.sub.2O.sub.3.1.0
H.sub.2O) C, H, N.
Example YYY
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid (4-fluoro-phenyl)-amide
[0291] 96
[0292]
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid (100 mg, 0.43 mmol), 4-fluoroaniline (48 mg, 0.43 mmol), and
diisoprophylethylamine (168 mg, 1.30 mmol) were dissolved in 5 mL
dry DMF. HATU (173 mg, 0.46 mmol) was added and the resulting
mixture stirred at room temperature under argon for 3 d. The
reaction mixture was partitioned between water and 25%
iPrOH/CHCl.sub.3. The layers were separated, and the aqueous layer
extracted thrice with 25% iPrOH/CHCl.sub.3. The combined organic
layers were dried (MgSO.sub.4) and concentrated in vacuo leaving an
off-white solid which was recrystallized from chloroform/methanol
to yield 6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4-
,3-cd]indole-2-carboxylic acid (4-fluoro-phenyl)-amide, 70 mg (50%)
as a pale yellow solid: m.p. 330-332.degree. C. (dec); .sup.1H NMR
(300 MHz, d.sub.6-DMSO) .delta.3.28 (m, 2H), 3.42 (m, 2H), 7.22 (m,
2H), 7.35 (app t, J=7.8 Hz, 1H), 7.65 (dd, J=7.8, 0.6 Hz, 1H), 7.77
(m, 3H), 8.16 (br t, 1H), 10.08 (br s, 1H), 11.81 (br s, 1H). MS
(electrospray, MH+) 324. Anal. (C.sub.18H.sub.14FN.sub.3O.sub.2.0.4
H.sub.2O) C, H, N.
Example ZZZ
(4-Chloro-phenyl)-1,5-dihydro-[1,2]diazepino[4,5,6-cd]indol-6-one
[0293] 97
[0294] 2-Iodo-3-nitro-benzoic acid methyl ester:
2-iodo-3-nitro-benzoic acid (61 g, 208 mmol, prepared as described
in Org. Syn. Coll. Vol. 1, 56-58, and 125-127), sulfuric acid (40.8
g, 416 mmol), and trimethyl orthoformate (88.4 g, 833 mmol) were
dissolved in 500 mL dry MeOH. The reaction was refluxed under argon
for 20 h. The reaction mixture was concentrated to 100 mL then
partitioned between saturated NaHCO.sub.3(aq) and CH.sub.2Cl.sub.2.
The layers were separated and the aqueous layer extrated three
times with CH.sub.2Cl.sub.2. The combined organic layers were dried
(MgSO.sub.4) and concentrated in vacuo. The yellow solid was
crystallized from CH.sub.2Cl.sub.2/hexanes yielding
2-iodo-3-nitro-benzoic acid methyl ester, 57.8 g (90%) as a yellow
solid: m.p. 64.0-64.5.degree. C.; 1H NMR (300 MHz, CDCl.sub.3)
.delta.3.99 (s, 3H), 7.54 (app t, J=7.8 Hz, 1H), 7.70 (dd, J=8.1,
1.8 Hz, 1H), 7.77 (dd, J=7.8, 1.8 Hz, 1H).
[0295] 3-Amino-2-iodo-benzoic acid methyl ester:
2-Iodo-3-nitro-benzoic acid methyl ester (1.00 g, 3.26 mmol) was
dissolved in 15 mL MeOH. Tin (II) chloride (2.78 g, 14.66 mmol) and
water (0.35 g, 19.54 mmol) were added and the yellow solution
stirred at room temperature for 20 h. Celite was added to the
solution followed by 10 mL 3 M NaOH. The suspension was diluted
with MeOH and the precipitate filtered off. The filter cake was
washed with three portions boiling CH.sub.2Cl.sub.2. The layers
were separated and the aqueous layers extracted once with
CH.sub.2Cl.sub.2. The combined organic layers were dried
(MgSO.sub.4) and concentrated in vacuo to yield
2-iodo-3-nitro-benzoic acid methyl ester, 0.89 g (99%), as a clear
oil. .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.81 (s, 3H), 5.52
(br s, 2H), 6.72 (dd, J=7.5, 1.2 Hz, 1H), 6.87 (dd, J=7.5, 1.2 Hz,
1H), 6.87 (dd, J=7.8, 1.2 Hz, 1H), 7.12 (app t, J=7.5 Hz, 1H). MS
(electrospray, MH+) 278.
[0296] 3-Amino-2-(4-chloro-phenylethynyl)-benzoic acid methyl
ester: 2-iodo-3-nitro-benzoic acid methyl ester (0.79 g, 2.84
mmol), 1-chloro-4-ethynylbenzene (0.41 g, 2.99 mmol), palladium
tetrakis(triphenylphosphine) (0.16 g, 0.14 mmol), copper (I) iodide
(0.03 g, 0.14 mmol), and triethylamine (1.44 g, 14.19 mmol) were
dissolved in 15 mL toluene. Argon was bubbled through the resulting
solution for 15 min. The reaction was stirred under argon at
80.degree. C. for 2 h and 20 min. The reaction mixture was then
washed once with water, dried (MgSO.sub.4), and concentrated in
vacuo. The orange oil was purified by flash chromatography eluting
with 50 to 100% CHCl.sub.3/hexanes to yield
3-amino-2-(4-chloro-phenylethynyl)-benzoic acid methyl ester, 0.76
g (94%) as a yellow oil. .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.3.84 (s,3H), 5.84 (br s, 2H), 6.97 (dd, J=8.1, 1.3 Hz, 1H),
7.05 (dd, J=7.5, 1.2 Hz, 1H), 7.17 (app t, J=7.5 Hz, 1H), 7.49 (d,
J=8.7 Hz, 2H), 7.63 (d, J=8.7 Hz, 2H). MS (electrospray, MH+)
286.
[0297] 2-(4-Chloro-phenyl)-1H-indole-4-carboxylic acid methyl
ester: 3-amino-2-(4-chloro-phenylethynyl)-benzoic acid methyl ester
(0.73 g, 2.54 mmol) and palladium (II) chloride (23 mg, 0.13 mmol)
were combined in 10 mL acetonitrile. The yellow solution was
stirreed under argon at 75.degree. C. for 17 h. The solvent was
removed in vacuo leaving an orange solid which was purified by
flash chromatography eluting with 50 to 100% CH--Cl.sub.3/hecanes.
2-(4-chloro-henyl)-1H-indole-4-carboxylic acid methyl ester; 0.53 g
(72%) was isolated as an off-white solid: m.p. 150.0-151.5.degree.
C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.93 (s, 3H), 7.23
(app t, J=7.8 Hz, 1H), 7.41 (d, J=1.8 Hz, 1H), 7.57 (d, J=8.7 Hz,
2H), 7.68 (d, J=7.8 Hz, 1H), 7.75 (dd, J=7.5, 0.9 Hz, 1H), 7.95 (d,
J=8.7 Hz, 2H), 11.99 (br s, 1H). HRMS (MALDI, MH+) Calcd for
C.sub.16H.sub.12ClNO.sub.2: 286.0635. Found: 286.0631.
[0298] 2-(4-Chloro-phenyl)-3-formyl-1H-indole-4-carboxylic acid
methyl ester: Phosphorous oxychloride (0.42 g, 2.71 mmol) was added
to DMF (0.99 g, 13.57 mmol) at 0.degree. C. The resulting colorless
solution was added dropwise to a solution of
2-(4-chloro-phenyl)-1H-indole-4-carboxylic acid methyl ester (0.52
g, 1.81 mmol) in 10 mL dry CH.sub.2Cl.sub.2 at 0.degree. C. The
reaction was stirred at 0.degree. C. for 10 min then quenched by
addition of 5 mL 2 M NaOAc(aq). The layers were separated and the
aqueous layer extracted once with CH.sub.2Cl.sub.2. The combined
organic layers were dried (MgSO.sub.4) then concentrated in vacuo
leaving anorange oil which crystallized on standing. The crystals
were rinsed with CH.sub.2Cl.sub.2 then dried in vacuo to yield
2-(4-chloro-phenyl)-3-formyl-1H-indole-4-carboxylic acid methyl
ester, 231 mg (41%) as an off-white solid: m.p. 221-222.degree. C.;
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.93 (s, 3H), 7.49 (app
t, J=7.5 Hz, 1H), 7.71 (m, 4H), 7.94 (d, J=7.8 Hz, 2H), 9.71 (s,
1H), 13.67 (br s, 1H). MS (electrospray, [M-H]) 312.
[0299]
(4-Chloro-phenyl)-1,5-dihydro-[1,2]diazepino[4,5,6-cd]indol-6-one:
2-(4-chloro-phenyl)-3-formyl-1H-indole-4-carboxylic acid methyl
ester (100 mg, 0.32 mmol) was dissolved in 5 mL MeOH. Hydrazine (30
mg, 0.92 mmol) was added causing the immediate precipitate. Acetic
acid (13 mg, 0.22 mmol) was added and the yellow suspension
refluxed for 1.5 h. The yellow solid was collected by filtration,
rinsed once with MeOH, then dried in vacuo to give
(40chloro-phenyl)-1,5-dihydro-[1,2]diazepino[4,5,6-
-cd]indol-6-one, 55 mg (59%) as a bright yellow solid: m.p.
324.0-324.5.degree. C. (dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.7.23 (app t, J=7.8 Hz, 1H), 7.49 (s, 1H), 7.55 (m, 2H), 7.65
(d, J=8.7 Hz, 2H), 7.71 (d, J=Hz, 2H), 10.36 (s, 1H), 12.32 (br s,
1H). HRMS (MALDI, MH+) Calcd for C.sub.16H.sub.10ClN.sub.3O:
296.0591. Found: 296.0586. Anal. (C.sub.16H.sub.10ClN.sub.3O 0.5
H.sub.2O) C, H, N.
Example AAAA
2-(4-Fluoro-phenyl)-1,5-dihydro-[1,2]diazepino[4,5,6-cd]indol-6-one
[0300] 98
[0301] In a manner similar to that described for Example ZZZ,
2-(4-fluoro-phenyl)-3-formyl-1H-indole-4-carboxylic acid methyl
ester (145 mg, 0.49 mmol) was condensed with hydrazine (45 mg, 1.41
mmol) to give
2-(4-fluoro-phenyl)-1,5-dihydro-[1,2]diazepino[4,5,6-cd]indol-6-one,
120 mg (88%) as a bright yellow solid: m.p. 340-341.degree. C.
(dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.7.22 (app t,
J=7.8 Hz 1H), 7.43 (m, 3H), 7.54 (m, 2H), 7.73 (m, 2H), 10.33 (s,
1H), 12.23 (br s, 1H). MS (electrospray, MH+) 280. Anal.
(C.sub.16H.sub.10FN.sub.3O) C, H, N.
Example BBBB
2-Thiophen-2-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
[0302] 99
[0303] In a manner similar to that described for Compound 12, the
tricyclic bromide (300 mg, 1.13 mmol) and thiophene-2-boronic acid
(159 mg, 1.24 mmol) were coupled to yield
2-thiophen-2-yl-1,3,4,5-tetrahydro-a- zepino[5,4,3-cd]indol-6-one,
171 mg (56%) as a beige solid: m.p. 220.5-222.5.degree. C.; .sup.1H
NMR (300 MHz d.sub.6-DMSO) .delta.3.08 (m, 2H), 3.48 (m, 2H), 7.23
(m, 2H), 7.52 (m, 2H), 7.69 (m, 2H), 8.05 (br t, 1H), 11.60 (br s,
1H). MS (electrospray, MH+) 269. Anal. (C.sub.15H.sub.12N.sub.2)S
0.8 H.sub.2O) C, H, N.
Example CCCC
2-Thiophen-3-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
[0304] 100
[0305] In a manner similar to that described for Compound 12, the
tricyclic bromide (300 mg, 1.13 mmol) and thiophene-3-boronic acid
(159 mg, 1.24 mmol) were coupled to yield
2-thiophen-3-yl-1,3,4,5-tetrahydro-a- zepino[5,4,3-cd]indol-6-one,
249 mg (82%) as a beige solid: m.p. 255-256.degree. C.; .sup.1H NMR
(300 MHz, d.sub.6-DMSO) .delta.3.08 (m, 2H), 3.43 (m, 2H), 7.19 (t,
J=7.8 Hz, 1H), 7.54 (m, 2H), 7.67 (dd, J=7.5, 0.9 Hz, 1H), 7.74 (m,
1H), 7.78 (m, 1H), 8.03 (br t, 1H), 11.49 (br s, 1H). MS
(electrospray, MH+) 269. Anal. (C.sub.15H.sub.12N.sub.2OS 0.35
H.sub.2O) C, H, N, S.
Example DDDD
2-(1H-Pyrrol-2-yl)-1,3,4,5-etatrhydro-azepino[5,4,3-cd]indol-6-one
[0306] 101
[0307] In a manner similar to that described for Compound 12, the
tricyclic bromide (300 mg, 1.13 mmol) and
1-)t-butoxycarbonyl)pyrrole-2-b- oronic acid (263 mg, 1.24 mmol)
were coupled with concomitant removal of the BOC group to yield
2-(1H-pyrrol-2-yl)-1,3,4,5-tetrahydro-azepino[5,4,-
3-cd]indol-6-one, 81 mg (28% as a greenish grey solid: m.p.
>400.degree. C. (dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.3.02 (m, 2H), 3.42 (m, 2H), 6.22 (m, 1H), 6.44 (m, 1H), 6.97
(m, 1H), 7.14 (t, J=7.5 Hz, 1H), 7.49 (dd, J=8.1, 0.9 Hz, 1H), 7.64
(dd, J=7.5, 0.6 Hz, 1H), 7.98 (br t, 1H), 11.01 (br s, 1H), 11.13
(br s, 1H). MS (electrospray, MH+) 252. Anal.
(C.sub.15H.sub.13N.sub.3O.0.4 H.sub.2O) C, H, N.
Example EEEE
2-(4-Methylsulfanyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-on-
e
[0308] 102
[0309] In a manner similar to that described for Compound 12, the
tricyclic bormide (1.00 g, 3.77 mmol) and 4-thioanisole boronic
acid (0.70 g, 4.15 mmol) were coupled to tield
2-(4-methylsulfanyl-phenyl)-1,3-
,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 416 mg (36%) as a
beige solid: m.p. 250-251.degree. C.; .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.2.54 (s, 3H), 3.03 (m, 2H), 3.39 (m, 2H), 7.20
(t, J=7.8 Hz, 1H), 7.41 (d, J=7.5, 0.9 Hz, 1H), 8.04 (br t, 1H),
11.52 (br s, 1H). MS (electrospray, MH+) 309. Anal.
(C.sub.18H.sub.16N.sub.2OS 0.6 H.sub.2O) C, H, N.
Example FFFF
2-(4-Methanesulfanyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-o-
ne
[0310] 103
[0311]
2-(4-methylsulfanyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]ind-
ol-6-one (100 mg, 0.32 mmol) was dissolved in 10 mL 1:1
MeOH:CH.sub.2Cl.sub.2. The solution was cooled to 0.degree. C. and
oxone (259 mg, 0.42 mmol) was added dropwise as a solution in 1.5
mL H.sub.2O). The bright yellow reaction mixture was stirred at
0.degree. C. for 15 min. Saturated Na.sub.2S.sub.2O.sub.5(aq) (4
mL) was added. The layers were separated and the aqueous layer
extracted twice with 25% iPrPH/CHCl.sub.3. The combined organic
layers were dried (MgSO.sub.4), concentrated in vacuo, and the two
products (2-(4-methanesulfinyl-phenyl)-
-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and
2-(4-methanesulfonyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6--
one) separated by radial chromatography eluting with 5%
MeOH/CHCl.sub.3. Each was then crystallized from
CH.sub.2Cl.sub.2/MeOH.
2-(4-Methanesulfinyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6--
one, 39 mg (37%), was isolated as a white solid: m.p.
316-317.degree. C. (dec); .sup.1H NMR (300 MHz, d.sup.6-DMSO)
.delta.2.81 (s, 3H), 3.09 (m, 2H), 3.40 (m, 2H), 7.25 (t, J=7.8 Hz,
1H), 7.59 (dd, J=8.1, 0.9 Hz, 1H), 7.71 (dd, J=7.5, 0.9 Hz, 1H),
7.84 (m, 4H), 8.08 (br t, 1H), 11.68 (br s, 1H). MS (electrospray,
MH+) 325. Anal. (C.sub.18H.sub.16N.sub.2O.sub.2S) C, H, N, S.
Example GGGG
2-(4-Methanesulfonyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-o-
ne
[0312] 104
[0313]
2-(4-methanesulfonyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]in-
dol-6-one, 20 mg (18%) was isolated in the chromatography described
above as a white solid: m.p. 308-309.degree. C. (dec); .sup.1H NMR
(300 MHz, d.sub.6-DMSO) .delta.3.10 (m, 2H), 3.28 (s, 3H), 3.41 (m,
2H), 7.28 (t, J=7.8 Hz, 1H), 7.61 (dd, J=8.1, 0.6 Hz, 1H), 7.72
(dd, J=7.5, 0.6 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 8.06 (d, J=8.4 Hz,
2H), 8.11 (br t, 1H), 11.77 (br s, 1H). MS (electrospray, MH+) 341.
Anal. (C.sub.18H.sub.16N.sub.2O.sub.3S) C, H, N, S.
Example HHHH
2-Bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one
[0314] 105
[0315] The title compound was prepared in a manner similar to that
used for 2-bromo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one,
starting from 5-fluoro-2-methylbenzoic acid.
2-Bromo-8-fluoro-1,3,4,5-tetrahydro-a- zepino[5,4,3-cd]indol-6-one
was isolated as an orange solid: m.p. 203-204.degree. C. (dec);
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.2.79 (m, 2H), 3.41 (m,
2H), 7.29 (dd, J=8.7, 1.2 Hz, 1H), 7.74 (dd, J=10.8, 1.5 Hz, 1H),
8.23 (br t, 1H), 12.12 (br s, 1H). MS (electrospray, [M+Na].sup.+)
305/307.
8-Fluoro-2-(3-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-c-
d]indol-6-one
[0316] 106
[0317]
3-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl-
)-benzaldehyde (247 mg, 0.80 mmol; prepared in a manner similar to
that described for compound 12 from
2-bromo-8-fluoro-1,3,4,5-tetrahydro-azepin- o[5,4,3-cd]indol-6-one
and 3-formylphenylboronic acid) was reacted with methylamine (4.91
mmol) as described for Compound PPP to yield
8-fluoro-2-(3-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3--
cd]indol-6-one, 193 mg (74%) as an off-white solid: m.p.
270-272.degree. C. (dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.2.34 (s, 3H), 3.05 (m, 2H), 3.39 (m, 2H), 3.78 (s, 2H), 7.42
(m, 5H), 7.61 (br s, 1H), 8.26 (br t, 1H), 11.70 (br s, 1H). HRMS
(MALDI, MH+) Calcd for C.sub.19H.sub.18N.sub.3OF: 324.1512. Found:
324.1498. Anal. (C.sub.19H.sub.18N.sub.3OF 1.5 H.sub.2O 0.35
CHCl.sub.3) C, H, N.
Example IIII
8-Fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-c-
d]indol-6-one
[0318] 107
[0319]
4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl-
)-benzaldehyde (100 mg, 0.32 mmol; prepared in a manner similar to
that described for compound 12 for
2-bromo-8-fluoro-1,3,4,5-tetrahydro-azepino- [5,4,3-cd]indol-6-one
and 4-formylphenylboronic acid) was reacted with methylamine (1.62
mmol) as described for Compound PPP to yield
8-fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3--
cd]indol-6-one, 32 mg (31%) as a yellow solid: m.p.
1543-155.degree. C.; .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.2.28 (s, 3H), 3.04 (m, 2H), 3.40 (m, 2H), 3.69 (s, 2H), 7.32
(dd, J=9.0, 2.4 Hz, 1H), 7.44 (m, 3H), 7.57 (d, J=8.1 Hz, 2H), 8.25
(br t, 1H), 11.67 (br s, 1H). HRMS (MALDI MH+) Calcd for
C.sub.19H.sub.18N.sub.3OF: 324,1512. Found: 325.1524. Anal.
(C.sub.19H.sub.18N.sub.3OF 0.3 H.sub.2O) C, H, N.
Example JJJJ
8-Fluoro-2-(4-pyrrolidin-1-ylmethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4-
,3-cd]indol-6-one
[0320] 108
[0321] In a manner similar to that described for Compound PPP,
4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)
benzaldehyde (100 mg, 0.32 mmol; prepared in a manner similar to
that described for compound 12 from
2-bromo-8-fluoro-1,3,4,5-tetrahydro-azepin- o[5,4,3-cd]indol-6-one
and 4-formylphenylboronic acid) was reacted with pyrrolidine (115
mg, 1.62 mmol) to yield 8-fluoro-2-(4-pyrrolidin-1-ylmet-
hyl-phenyl)-1,3,4,5-tetrahydro-azepinop5,4,3-cd]indol-6-one, 16 mg
(14%) as a yellow solid: m.p. 264-265.degree. C. (dec), .sup.1H NMR
(300 MHz, d.sub.6-DMSO) .delta.1.72 (m, 4H), 2.49 (m, 4H), 3.04 (m,
2H), 3.39 (m, 2H), 3.64 (br s, 2H), 7.31 (dd, J=9.3, 2.4 Hz, 1H),
7.43 (m, 3H), 7.58 (d, J=8.1 Hz, 2H), 8.25 (br t, 1H), 11.66 (br s,
1H). HRMS (MALDI MH+) Calcd for C.sub.22H.sub.22N.sub.3OF:
362.1825. Found: 364.1810. Anal. (C.sub.22H.sub.22N.sub.3OF 0.5
H.sub.2O) C, H, N.
Example KKKK
6-Oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid phenylamide
[0322] 109
[0323] In a manner similar to that described for Compound YYY,
6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid (60 mg, 0.26 mmol) was coupled with aniline (27 mg, 0.29 mmol)
to yield
6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid phenylamide as a white solid: m.p. 320-322.degree. C. (dec);
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.28 (m, 2H), 3.42 (m,
2H), 7.11 (app t, J=7.5 Hz, 1H), 7.37 (m, 3H), 7.64 (d, J=8.1 Hz,
1H), 7.74 (m, 3H), 8.15 (br t, 1H), 9.98 (br s, 1H), 11.78 (br s,
1H). MS (electrospray, MH+) 306. Anal.
(C.sub.18H.sub.15N.sub.3O.sub.2 0.25 H.sub.2O) C, H, N.
Example LLLL
6-Oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid (4-chloro-phenyl)-amide
[0324] 110
[0325] In a manner similar to that described for Compound YYY,
6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid (60 mg, 0.26 mmol) was coupled with 4-chloroaniline (37 mg,
0.29 mmol) to yield
6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid (4-chloro-phenyl)-amide as a white solid: .sup.1H NMR (300
MHz, d.sub.6-DMSO) .delta.3.26 (m, 2H), 3.42 (m, 2H), 7.36 (app t,
J=7.8 Hz, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.1 Hz, 1H), 7.76
(m, 3H), 8.16 (br t, 1H), 10.12 (br s, 1H), 11.79 (br s, 1H). MS
(electrospray, MH+) 340. Anal. (C.sub.18H.sub.14ClN.sub.3O.sub.2)
C, H, N.
Example MMMM
6-Oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid naphthalen-2-ylamide
[0326] 111
[0327] In a manner similar to that described for Compound YYY,
6-oxo-3,4,5,6-tetrahydro-1H-zepino[5,4,3-cd]indole-2-carboxylic
acid (60 mg, 0.26 mmol) was coupled with 2-naphthylamine (41 mg,
0.29 mmol) to yield
6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid naphthalen-2-ylamide as a white solid: .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.3.33 (m, 2H), 3.45 (m, 2H), 7.38 (app t, J=7.8
Hz, 1H), 7.47 (m, 2H), 7.68 (d, J=8.1 Hz, 1H), 7.78 (m, 2H), 7.91
(m, 3H), 8.19 (br t, 1H), 8.43 (br s, 1H), 10.21 (br s, 1H), 11.84
(br s, 1H). MS (electrospray, MH+.sub.--356. Anal.
(C.sub.22H.sub.17N.sub.3O.sub.2 0.7 H.sub.2O) C, H, N.
Example NNNN
6-Oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid naphthalen-1-ylamide
[0328] 112
[0329] In a manner similar to that described for Compound YYY,
6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid (60 mg, 0.26 mmol) was coupled with 1-naphthylamine (41 mg,
0.29 mmol) to yield
6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid naphthalen-1-ylamide as a white solid: m.p. 330-332.degree. C.
(dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.33 (m, 2H),
3.48 (m, 2H), 7.38 (app t, J=7.8 Hz, 1H), 7.57 (m, 3H), 7.68 (d,
J=7.8 Hz, 1H), 7.77 (m, 2H), 7.87 (d, J=7.8 Hz, 1H), 7.99 (m, 1H),
8.13 (m, 2H), 10.06 (br s, 1H), 11.87 (br s, 1H). MS (electrospray,
MH+) 356. Anal. (C.sub.22H.sub.17N.sub.3O.sub.2 0.5 H.sub.2O) C, H,
N.
Example OOOO
6-Oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid prop-2-ynylamide
[0330] 113
[0331] In a manner similar to that described for Compound YYY,
6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid (60 mg, 0.26 mmol) was coupled with propargylamine (16 mg,
0.29 mmol) to yield
6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid prop-2-ynylamide as a white solid: m.p. 191-192.degree. C.;
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.19 (m, 3H), 3.39 (m,
2H), 4,10 (m, 2H), 7.32 (app t, J=7.8 Hz, 1H), 7.59 (d, J=8.1 Hz,
1H), 7.72 (d, J=7.2 Hz, 1H), 8.12 (br t, 1H), 8.43 (br t, 1H),
11.60 (br s, 1H). MS (electrospray, MH+) 268. Anal.
(C.sub.15H.sub.13N.sub.3O.sub.2 2H.sub.2O) C, H, N.
Example PPPP
6-Oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid isopropyl-amide
[0332] 114
[0333] In a manner similar to that described for Compound YYY,
6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid (60 mg, 0.26 mmol) was coupled with isopropylamine (17 mg,
0.29 mmol) to yield
6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid isopropylamide as a white solid: m.p. 261-262.degree. C.
(dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.1.20 (d, J=6.6
Hz, 1H) 3.22 (m, 2H), 3.38 (m, 2H), 4.90 (m, 1H), 7.32 (app t,
J=7.8 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.81
(d, J=7.5 Hz, 1H), 8.10 (br t, 1H), 11.53 (br s, 1H). MS
(electrospray, MH+) 272. Anal. (C.sub.15H.sub.17N.sub.3O.sub.2
0.2H.sub.2O) C, H, N.
Example QQQQ
6-Oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid cyclopropylamide
[0334] 115
[0335] In a manner similar to that described for Compound YYY,
6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid (60 mg, 0.26 mmol) was coupled with cyclopropylamine (17 mg,
0.29 mmol) to yield
6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic
acid cyclopropyleamide as a white solid: m.p. 249-251.degree. C.;
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.0.56 (m, 2H), 0.75 (m,
2H), 2.95 (m, 2H), 3.37 (m, 2H), 3.61 (m, 1H), 7.30 (app t, J=7.5
Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 8.09 (m,
2H), 11.48 (br s, 1H). MS (electrospray, MH+270. Anal.
(C.sub.15H.sub.15N.sub.3O.sub.2 1H.sub.2O) C, H, N.
Example RRRR
(rac)-3-(4-Methoxyphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-o-
ne
[0336] 116
[0337] In a manner similar to that described for the preparation of
Example Q, methyl indole-4-carboxylate and p-methoxy nitrostyrene
were condensed and the resulting nitro alkane was reduced/cyclized
to give, after recrystallization (CH.sub.2Cl.sub.2/MeOH/hexanes),
(rac)-3-(4-methoxyphenyl)-3,4,5,6-tetrahydro-1H-axepino[5,4,3-cd]indol-6--
one, 16.9 mb (50%) as a white solid: m.p. 221-223.degree. C.;
.sup.1H NMR (300 MHz, d.sub.4-MeOH) .delta.3.57 (br m, 5H), 5.15
(br s, 1H) 6.62 (m, 2H), 6.86 (m, 2H), 7.08 (app t, J=7.8 Hz, 1H),
7.11 (s, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H). Anal.
(C.sub.19H.sub.16N.sub.2O.su- b.2 0.25 H.sub.2O) C, H, N.
Example SSSS
2-(3-Morpholin-4-ylmethylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]in-
dol-6-one
[0338] 117
[0339] In a manner similar to that described for Compound 22, the
aldehyde 15 (29 mg, 0.1 mmol) in MeOH (1 mL) was treated with
morpholine (0.04 mL, 0.5 mmol) and a solution of sodium
cyanoborohydride (0.15 mmol) and zinc chloride (0.08 mmol) in MeOH
(1 mL) to give, after radial chromatography (5% MeOH in
CHCl.sub.3), 2-(3-morpholin-4-ylmethylphenyl)-3,4,5,6-tetrahy-
dro-1H-azepinop5,4,3-cd]indol-6-one, 35 mg (99%) as sticky white
solid: .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.2.37 (m, 4H),
3.02 (m, 2H), 3.35 (m, 2H), 3.51 (m, 6H), 7.17 (app t, J=7.7 Hz,
1H), 7.30 (br d, 1H), 7.52 (m, 4H), 7.64 (d, J=7.5 Hz, 1H), 8.03
(br t, 1H), 11.53 (br s, 1H). HRMS (FAB, MH+) Calcd for
C.sub.22H.sub.24N.sub.3O.sub.2: 362.1869. Found: 362.1866.
Compound TTTT
2-(3-Pyrrolidin-1-ylmethylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]i-
ndol-6-one
[0340] 118
[0341] In a manner similar to that described for Compound 22, the
aldehyde 15 (200 mg, 0.69 mmol) in MeOH (10 mL) was treated with
pyrrolidine (0.34 mL, 4.14 mmol) and a solution of sodium
cyanoborohydride (0.76 mmol) and zinc chloride (0.38 mmol) in MeOH
(1.4 mL) to give, after crystallization (CH2C12/MeOH/hexanes),
2-(3-pyrrolidin-1-ylmethylphenyl)-3,4,5,6-tetrahyd-
ro-1H-azepino[5,4,3-cd]indol-6-one, 139 mg (58%) as pale yellow
solid: m.p. 219-223.degree. C. (dec); .sup.1H NMR (300 MHz,
d.sup.6-DMSO) .delta.1.73 (m, 4H), 2.49 (m, 4H), 3.06 (m, 2H), 3.40
(m, 2H), 3.69 (s, 2H), 7.22 (t, J=7.7 Hz, 1H), 7.34 (br d, 1H),
7.53 (m, 4H), 7.68 (dd, J=7.7, 0.8 Hz, 1H), 8.08 (brt, 1H), 11.59
(brs, 1H). HRMS (FAB, MH+) Calcd for C.sub.22H.sub.24N.sub.3O:
346,1919. Found: 346.1910. Anal. (C.sub.23H.sub.25N.sub.3O.0.6
H.sub.2O) C, H, N.
Example UUUU
2-(4-Pyrrolidin-1-ylmethylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]i-
ndol-6-one
[0342] 119
[0343] In a manner similar that described for Compound 22, the
para-aldehyde (150 mg, 0.52 mmol) in MeOH (10 mL) was treated with
pyrrolidine (0.26 mL, 3.10 mmol) and a solution of sodium
cyanoborohydride (0.57 mmol) and zinc chloride (0.28 mmol) in MeOH
(1.1 mL) to give, after crystallization
(CH.sub.2Cl.sub.2/MeOH/hexanes),
2-(4-pyrrolidin-1-ylmethylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]-
indol-6-one, 141 mg (79%) as pale yellow solid: m.p.
221-225.degree. C. (dec); .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.1.71 (m, 4H), 2.46 (m, 4H), 3.06 (m, 2H), 3.41 (m, 2H), 3.41
(m, 2H), 3.63 (s, 2H), 7.21 (t, J=7.8 Hz, 2H), 7.45 (d of Abq,
J=8.2 Hz, 2H), 7.55 (dd, J=7.9, 0.9 Hz, 1H), 7.59 (d of Abq, J=8.2
Hz, 2H), 7.68 (br d, 1H), 8.07 (br t, 1H), 11.54 (br s, 1H). HRMS
(FAB, MH+) Calcd for C.sub.22H.sub.24N.sub.3O: 346.1919. Found:
346.1911. Anal. (C.sub.23H.sub.25N.sub.3O 0.5 H.sub.2O) C, H,
N.
Example VVVV
2-(4-Morpholin-4-ylmethylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]in-
dol-6-one
[0344] 120
[0345] In a manner similar to that described for Compound 22, the
para-aldehyde (264 mg, 0.91 mmol) in MeOH (10 mL) was treated with
morpholine (0.40 mL, 4.55 mmol) and a solution of sodium
cyanoborohydride (1.36 mmol) and zinc chloride (0.68 mmol) in MeOH
(2.0 mL) to give, after recrystallization
(CH.sub.2Cl.sub.2/MeOH/hexanes) and radial chromatography,
2-(4-morpholin-4-ylmethylphenyl)-3,4,5,6-tetrahydro-1H-az-
epino[5,4,3-cd]indol-6-one, 44.8 mg (14%) as solid: .sup.1H NMR
(300 MHz, d.sub.6-DMSO) .delta.2.39 (m, 4H), 3.06 (m, 2H), 3.41 (m,
2H), 3.53 (s, 2H), 3.59 (m, 4H), 7.21 (br t, 1H), 7.46 (d of Abq,
J=8.0 Hz, 2H), 7.55 (br d, 1H), 7.62 (d of Abq, J=8.0 Hz, 2H), 7.68
(br d, 1H, 8.07 (br t, 1H), 11.55 (br s, 1H). HRMS (FAB, MH+) Calcd
for C.sub.22H.sub.24N.sub.3O- .sub.2: 362.1869. Found:
362.1861.
Example WWWW
2-(4-Hydroxymethylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-o-
ne
[0346] 121
[0347] The title compound was isolated as a reduction by-product
from the reductive amination of the para-paldehyde with morpholine
and sodium cyanoborohydride, and recrystallized
(CH.sub.2Cl.sub.2/MeOH/hexanes) to give
2-(4-hydroxymethylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]ind-
ol-6-one, 64 mg (24%) as a white solid: .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta.3.05 (m, 2H), 3.39 (m, 2H), 4.57 (d, J=5.6 Hz,
2H), 5.27 (t, J=5.6 Hz, --OH), 7.21 (br t, 1H), 7.47 (d of Abq,
J=7.9 Hz, 2H), 7.55 (br d, 1H), 7.62 (d of Abq, J=7/9 Hz, 2H), 7.68
(br d, 1H), 8.07 (br t, 1H), 11.55 (s, 1H). Anal.
(C.sub.18H.sub.16N.sub.2O.sub.2 0.9 H.sub.2O) C, H, N.
Example XXXX
2-(4-(N,N-Dimethylamino)methylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3--
cd]indol-6-one, N-oxide
[0348] 122
[0349] A solution of Compound 21 (58 mg) in acetone (7.0 mL) was
treated with 30% aqueous hydrogen peroxide (0.6 mL) at room
temperature and the yellow solution was allowed to stir for three
days. The acetone was removed in vacuo and the residue was taken-up
in isopropyl alcohol. A solid was precipitated with the addition of
an equal volume of cold hexanes and collected by a quick
filtration. Precautions were taken to prevent the solid from
absorbing moisture from the atmosphere. The solid was
recrystallized (isopropanol/acetone/CH.sub.2Cl.sub.2/hexanes) to
give
2-(4-(N,N-dimethylamino)methylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-
-ced]indol-6-one, N-oxide, 37 mg (60%) as a pale yellow solid:
.sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.3.22 (s, 6H), 3.56 (br
m, 4H), 4.63 (s, 2H), 7.40 (br t, 1H), 7.76 (br d, 1H), 7.87 (m,
5H), 8.29 (br t, 1H), 12.00 (br s, 1H). HRMS (FAB, MH.sup.+--H2O)
Calcd for C.sub.20H.sub.20N.sub.3O: 318.1606. Found: 318.1606.
Anal. (C.sub.20H.sub.21N.sub.3O.sub.23.5 H.sub.2O) C, H, N.
Example YYYY
1,5-Dihydro-3-(4-trifluoromethylphenyl-[1,2]diazepino[4,5,6-cd]-indol-6-on-
e
[0350] 123
[0351] In a manner similar to that described for Compound 28, a
solution of methyl indole-4-carboxylate (250 mg, 1.43 mmol) in
dichloroethane (3 mL) was treated with p-trifluoromethylbenzoyl
chloride (445 mg, 2.14 mmol) and aluminum chloride (572 mg). The
intermediate ketone (95 mg, 0.27 mmol) in MeOH (3 mL) and conc. HCl
(0.05 mL) was treated, as described, with hydrazine hydrate (0.1
mL). The reaction was quenched at 0oC with w M NaOAc and the
aqueous layer was adjusted to pH=8 with 1 M NaOH. The product was
isolated by extraction with CH.sub.2Cl.sub.2, and recrystallized
(CH.sub.2Cl.sub.2/hexanes) to give 1,5-dihydro-3-(4-triflu-
oromethylphenyl-[1,2]diazepino[4,5,6-cd]indol-6-one, 30 mg (34%) as
a yellow solid: .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.7.24
(app br t, 1H), 7.29 (d, J=2.8 Hz, 2H), 7.60 (m, 2H), 7.82 (m, 4H),
10.57 (s, 1H), 12.01 (s, 1H). HRMS (FAB, Mna.sup.+) Calcd for
C.sub.11H.sub.10N.sub.3Ona- : 352.0674. Found: 352.0668.
Example ZZZZ
1,5-Dihydro-3-pentafluoroethyl-[1,2]diazepino[4,5,6-cd]-indol-6-one
[0352] 124
[0353] In a manner similar to that described for Compound 28, a
solution of methyl indole-4-carboxylate (351 mg, 2.01 mmol) in
dichloroethane (7 mL) was treated with pentafluoropropionyl
chloride (2.51 mmol) and aluminum chloride (575 mg). The
intermediate ketone (50 mg, 0.16 mmol) in MeOH (2 mL) and conc. HCl
(0.02 mL) was treated, as described, with hydrazine hydrate (0.1
mL). The reaction was quenched at 0.degree. C. with 1 M NaOAc and
the aqueous layer was adjusted to pH=8 with 1 M NaOH. The product
was isolated by extraction with CH.sub.2Cl.sub.2, and
recrystallized (CH.sub.2Cl.sub.2/MeOH/hexanes) to give
1,5-dihydro-3-pentafluoroethyl-[1,2]diazepino[4,5,6-cd]-indol-6-one,
15 mg (28%) as a yellow solid: .sup.1H NMR (300 MHz, d.sub.6-DMSO)
.delta.7.16 (app br t, 1H), 7.54 (m, 2H), 7.65 (m, 1H), 10.87 (s,
1H), 12.15 (s, 1H). HRMS (FAB, Mna.sup.+) Calcd for
C.sub.11H.sub.10N.sub.3Ona- : 352.0674. Found: 352.0668.
[0354] PARP Enzyme Inhibition Assay:
[0355] The PARP enzyme-inhibiting activities of the compounds of
the invention were assayed as described by Simonin et al. (J. Biol
Chem. (1993), 268:8529-8535) and Marsischky et al. (J. Biol. Chem.
(1995), 270:3247-3254) with minor modifications as follows. Samples
(50 .mu.L) containing 20 nM purified PARP protein, 10 .mu.g/mL
DNAse I-activated calf thymus DNA (sigma), 500 .mu.M NAD.sup.+, 0.5
.mu.Ci [.sup.32P]NAD.sup.+, 2% DMSO, and various concentrations of
test compounds were incubated in sample buffer (50 mM Tris pH 8.0,
10 mM MgCl.sub.2, 1 mM tris(carboxyethyl)phosphine HCl) at
25.degree. C. for 5 minutes. Under these conditions, the reaction
rate was linear for times up to 10 minutes. The reaction was
stopped by the addition of an equal volume of ice-cold 40%
trichloroacetic acid to the samples, which were then incubated on
ice for 15 minutes. The samples were then transferred to a Bio-Dot
microfiltration apparatus (BioRad), filtered through Whatman GF/C
glass-fiber filter paper, washed 3 times with 150 .mu.L of wash
buffer (5% trichloroacetic acid, 1% inorganic pyrophosphate), and
dried. [.sup.32P]ADP-Ribose incorporation into the acid-insoluble
material was quantitated using a Phosphorlmager (Molecular
Dynamics) and ImageQuant software. Inhibition constants (K.sub.l)
were calculated by non-linear regression analyses using the
velocity equation for competitive inhibition (Segel, Enzyme
Kinetics: Behavior and Analysis of Rapid Equilibrium and
Steady-State Enzyme Systems, John Wiley & Sons, Inc., New York
(1975), 100-125). In the case of tight-binding inhibitors, 5 nM
enzyme was used and the reaction was incubated at 25.degree. C. for
25 minutes. K.sub.l values for tight-binding inhibitors were
calculated using the equation described by Sculley et al. (Biochim.
Biophys. Acta (1986), 874:44-53).
[0356] Cytotoxicity Potentiation Assay:
[0357] A549 cells (ATCC, Rockville, Md.) were seeded into 96-well
cell culture plates (Falcon brand, Fisher Scientific, Pittsburgh,
Pa.) 16 to 24 hours before experimental manipulation. Cells were
then treated with a test compound (or a combination of test
compounds where indicated) for either 3 days or 5 days, at a
concentration of 0.4 .mu.m. At the end of treatments, relative cell
number was determined either by MTT assay or SRB assay. For the MTT
assay, 0.2 .mu.g/.mu.l of MTT
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,
Sigma Chemical Co., St. Louis, Mo.) was added to each well of a
plate, and the plate was incubated in a cell-culture incubator for
4 hours. Metabolized MTT in each well was solubilized in 150 .mu.l
of DMSO (Sigma Chemical Co.) with shaking and quantified with a
Wallac 1420 Victor plate reader (EG&G Wallac, Gaithersburg,
Md.) at 540 nm. For the SRB assay, cells were fixed with 10%
trichloroacetic acid (Sigma Chemical Co) for an hour at 4.degree.
C. After extensively washing, fixed cells were stained for 30
minutes with 0.4% sulforhodamine B (SRB, Sigma Chemical Co.) in 1%
acetic acid (Sigma Chemical Co). Unbound SRB was washed away with
1% acetic acid. Then the cultures were air-dried, and bound dye was
solubilized with 10 mM unbuffered Tris base (Sigma Chemical Co)
with shaking. The bound dye was measured photometrically with the
Wallac Victor plate reader at 515 nm. The ratio of the OD (optical
density) value of a compound-treated culture to the OD value of a
mock-treated culture, expressed in percentage, was used to quantify
the cytotoxicity of a compound. The concentration at which a
compound causes 50% cytotoxicity is referred to as IC.sub.50. To
quantify the potentiation of the cytotoxicity of topotecan or
temozolomide by test compounds, a dimensionless parameter PF.sub.50
is used and is defined as the ratio of the IC.sub.50 of topotecan
or temozolomide alone to the IC.sub.50 of topotecan or temozolomide
in combination with a test compound. For the compounds of the
invention, PF.sub.50 values were determined by testing with
topotecan.
[0358] Inhibition constants (K.sub.i values) and cytotoxicity
potentiation parameters (PF.sub.50 values) as determined for
exemplary compounds of the invention are presented in Table 1
below. If there are two K.sub.l values for a single compound, it
means that the compound K.sub.l was tested twice.
1TABLE 1 PARP Enzyme Inhibition and Cytotoxicity Potentiation
Inhibition Constant Cytotoxicity Potentiation Compound No. K.sub.i
(nM) PF.sub.50 69 1.1 3 2.8 N.D. 6 0.7, 1 2.2 10 38 N.D. 12 4.2 1.8
13 6.2, 4.5 N.D. 14 1.4 N.D. 16 5.0 1.9 17 6.5 N.D. 18
>>1,000 N.D. 19 62 N.D. 20 45 N.D. 21 5.0 2.4 22 7.2 2.3 23
4.8, 3.1 2.3 24 57 N.D. 25 4.0 N.D. 26 22, 18 N.D. 27 3.4 1.3 28 4,
3.8 1 29 8 1 30 6.3 2.4 31 5 N.D. 32 11.3 N.D. 33 230 N.D. 34 3.9
N.D. 35 3.8, 5.8 N.D. 36 29 N.D. 37 24 N.D. 38 8.4 N.D. 39 4.8 N.D.
40 5.2 N.D. 41 5.1 N.D. 42 5.1 N.D. 11 7.3 N.D. 43 2.6 N.D. OO 4.1
2.4 PP 5.3 2.3 QQ 5.5, 4.5 N.D. RR 6.9 N.D. SS 14 N.D. TT 12.2, 4.2
N.D. UU 10 1.8 VV 10 2.0 WW 4.4 N.D. XX 4.6 N.D. YY 15.1 N.D. ZZ
9.7 N.D. AAA 11.4 N.D. BBB 20 N.D. CCC 7.3 N.D. DDD 23 N.D. EEE
10.6 N.D. FFF 125 N.D. GGG 4.1 1.9 HHH 6.6 N.D. III 40 N.D. JJJ 5.3
N.D. KKK 222 N.D. LLL 32 N.D. MMM 9.4 2.3 NNN 172 N.D. OOO 14 N.D.
PPP 9.4 2.1 QQQ 10.2 2.3 RRR 23 N.D. SSS 66 N.D. TTT 26 N.D. UUU
11.4 N.D. VVV 9.1 N.D. WWW 263 N.D. XXX 370 N.D. YYY 6.3 1.5 ZZZ
0.7 N.D. AAAA 1.1 N.D. BBBB 4.8 N.D. CCCC 4.8 N.D. DDDD 7.7 N.D.
EEEE 2.9 N.D. FFFF 4.7 N.D. GGGG 6.2 N.D. HHHH 2.2 1.9 IIII 1.4 2.6
JJJJ 4.4 2.4 KKKK 9.6 N.D. LLLL 8.6 N.D. MMMM 16 N.D. NNNN 10 N.D.
OOOO 13 N.D. PPPP 32 N.D. QQQQ 21 N.D. RRRR 61 N.D. SSSS 19 N.D.
TTTT 7.4 1.6 UUUU 5.6 2.0 VVVV 13.2 2.1 WWWW 5.7 N.D. XXXX 18 1.7
YYYY 9 N.D. ZZZZ 40 N.D. Note: N.D. = not determined.
[0359] While the invention has been described by reference to
preferred embodiments and specific examples, those skilled in the
art will recognize that various changes and modifications can be
made without departing from the spirit and scope of the invention.
Thus, the invention should be understood as not being limited by
the foregoing detailed description, but as being defined by the
appended claims and their equivalents.
* * * * *