U.S. patent application number 12/014566 was filed with the patent office on 2008-05-15 for azacyclosteroid histamine-3 receptor ligands.
Invention is credited to Youssef L. Bennani, Marlon D. Cowart, Minghua Sun, Chen Zhao.
Application Number | 20080113982 12/014566 |
Document ID | / |
Family ID | 35061356 |
Filed Date | 2008-05-15 |
United States Patent
Application |
20080113982 |
Kind Code |
A1 |
Zhao; Chen ; et al. |
May 15, 2008 |
AZACYCLOSTEROID HISTAMINE-3 RECEPTOR LIGANDS
Abstract
Azacyclosteroid histamine-3 receptor ligands, pharmaceutical
compositions comprising such compounds, and methods for using such
compounds and compositions are described herein.
Inventors: |
Zhao; Chen; (Libertyville,
IL) ; Sun; Minghua; (Libertyville, IL) ;
Cowart; Marlon D.; (Round Lake Beach, IL) ; Bennani;
Youssef L.; (Shaker Heights, OH) |
Correspondence
Address: |
PAUL D. YASGER;ABBOTT LABORATORIES
100 ABBOTT PARK ROAD
DEPT. 377/AP6A
ABBOTT PARK
IL
60064-6008
US
|
Family ID: |
35061356 |
Appl. No.: |
12/014566 |
Filed: |
January 15, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11096382 |
Apr 1, 2005 |
7345034 |
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12014566 |
Jan 15, 2008 |
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60560151 |
Apr 7, 2004 |
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Current U.S.
Class: |
514/232.8 ;
514/365; 514/410 |
Current CPC
Class: |
C07J 71/00 20130101;
A61P 25/28 20180101; A61P 9/00 20180101; A61P 3/08 20180101 |
Class at
Publication: |
514/232.8 ;
514/410; 514/365 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/403 20060101 A61K031/403; A61K 31/427
20060101 A61K031/427; A61P 3/08 20060101 A61P003/08; A61P 25/28
20060101 A61P025/28; A61P 9/00 20060101 A61P009/00 |
Claims
1. A method of treating a condition modulated by the histamine-3
receptors in a mammal comprising administering an effective amount
of a compound of the formula: ##STR222## or a pharmaceutically
acceptable salt, ester, amide, or prodrug thereof, wherein R.sub.1
is selected from the group consisting of hydrogen, acetyl, alkyl,
fluoroalkyl, and cycloalkyl; R.sub.2 and R.sub.3 are each
independently selected from the group consisting of hydrogen and
alkyl, or R.sub.2 and R.sub.3 taken together form a 3- to
6-membered ring; Ring A of the formula: ##STR223## is selected from
the following: ##STR224## wherein: the dotted line represents an
optional bond; R.sub.4 and R.sub.5 are each independently selected
from the group consisting of hydrogen and fluorine, provided that
R.sub.5 is present only when the bond represented by the dotted
line is absent; R.sub.6 is selected from the group consisting of
hydrogen, alkyl, and fluorine; one of R.sub.7 and R.sub.8 is
hydrogen; and the other of R.sub.7 and R.sub.8 is selected from the
group consisting of: a) NR.sub.18R.sub.19; b) OR.sub.20, SR.sub.20,
O(C.dbd.O)OR.sub.20, O(C.dbd.O)N(R.sub.20)(R.sub.21),
O(C.dbd.O)C(R.sub.23)(R.sub.24)(R.sub.24b), or
O(C.dbd.O)CH(NR.sub.28R.sub.29)R.sub.25; and c)
NR.sub.22(C.dbd.O)R.sub.25, NR.sub.22(C.dbd.O)NR.sub.26R.sub.27,
NR.sub.22(C.dbd.O)CH(NR.sub.28R.sub.29)R.sub.30,
N(R.sub.22)(C.dbd.O)OR.sub.20, or
NR.sub.22(C.dbd.O)C(OR.sub.23)R.sub.3OR.sub.30b; and d)
NR.sub.22SO.sub.2R.sub.31 or
NR.sub.22SO.sub.2N(R.sub.22)(R.sub.23); or R.sub.7 and R.sub.8
taken together with the carbon atom to which each is attached forms
a group of the formula --C.dbd.C(R.sub.a)(R.sub.b), wherein R.sub.a
and R.sub.b are each independently selected from the group
consisting of hydrogen, alkyl, and cycloalkyl; R.sub.9 and R.sub.10
are each independently selected from the group consisting of
hydrogen, halogen, alkyl, and cyano; R.sub.11 and R.sub.12 are each
independently selected from the group consisting of hydrogen,
heteroaryl, heterocycle, aryl, arylalkyl, aryloxy, arylcarbonyl,
arylcarbonyloxy, arylalkoxy, alkylsulfonyl, arylsulfonyl, and
trifluoromethylsulfonyl; or one of R.sub.10 and R.sub.11 or
R.sub.11 and R.sub.12 taken together with the atoms to which each
is attached form a 5- to 6-membered aromatic or heteroaromatic
ring; R.sub.13 is selected from the group consisting of alkyl,
cycloalkyl, aryl, and heteroaryl; R.sub.15 and R.sub.16 taken
together with the atom to which each is attached forms a 5- to
6-membered ring optionally substituted with an alkylamino group;
R.sub.17 is selected from the group consisting of hydrogen, alkyl,
and fluoro; R.sub.18 is hydrogen or C.sub.1-C.sub.6 alkyl and
R.sub.19g is selected from the group consisting of aryl and
heteroaryl, or R.sub.18 and R.sub.19g at each occurrence is taken
together form a 3- to 8-membered heterocycle; R.sub.20 and R.sub.21
at each occurrence are each independently selected from the group
consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, cyanoalkyl,
hydroxyalkyl, haloalkyl, aryl, aryloxy, arylalkyl, arylsulfonyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, and
heterocyclealkyl; R.sub.22 at each occurrence is selected from the
group consisting of hydrogen and alkyl; R.sub.23 at each occurrence
is selected from the group consisting of hydrogen, alkyl, and
alkylcarbonyl; R.sub.24 and R.sub.24b are each independently
selected from the group consisting of hydrogen, alkyl, aryl,
arylalkyl, and cycloalkyl; R.sub.25 at each occurrence is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, alkoxyalkyl, hydroxyalkyl, aryl, arylalkyl, cycloalkyl,
cycloalkylalkyl, cyanoalkyl, haloalkyl, heteroaryl,
heteroarylalkyl, heteroarylcarbonyl, heterocycle, and
heterocyclealkyl; R.sub.26 and R.sub.27 at each occurrence are each
independently selected from the group consisting of alkyl,
alkylcarbonyl, alkoxycarbonyl, cycloalkyl, aryl, heteroaryl, and
heterocycle, or R.sub.26 and R.sub.27 taken together with the
nitrogen atom to which each is attached forms an aromatic or
non-aromatic 5- to 6-membered ring, wherein 0, 1, or 2 carbon atoms
in the ring is substituted with a heteroatom selected from O, S, or
NR.sub.23; R.sub.28 and R.sub.29 at each occurrence are each
independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkyl, aryl, heteroaryl,
and heterocycle, or R.sub.28 and R.sub.29 taken together with the
nitrogen atom to which each is attached forms an aromatic or
non-aromatic 5- to 6-membered ring, wherein 0, 1, or 2 carbon atoms
in the ring is substituted with a heteroatom selected from O, S, or
NR.sub.23; R.sub.30 at each occurrence is independently selected
from the group consisting of hydrogen, alkyl, alkoxyalkyl,
hydroxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,
cyanoalkyl, haloalkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, and heterocyclealkyl; R.sub.30b is
selected from the group consisting of hydrogen and alkyl, or when
R.sub.30 is alkyl and R.sub.30b is alkyl, the alkyl groups can be
bonded together to form a C.sub.3-C.sub.4 cycloalkyl group; and
R.sub.31 is selected from the group consisting of alkyl,
cycloalkyl, aryl, heterocycle, and heteroaryl.
2. The method according to claim 1, wherein the condition is
related to a function in a mammal selected from the group
consisting of memory and cognition processes, neurological
processes, cardiovascular function, and regulation of blood
sugar.
3. The method according to claim 1, wherein the condition is
related to memory and cognition processes.
4. The method according to claim 1, wherein the condition is
selected from the group consisting of acute myocardial infarction,
Alzheimer's disease, asthma, attention-deficit hyperactivity
disorder, bipolar disorder, cognitive enhancement, cognitive
deficits in psychiatric disorders, deficits of memory, deficits of
learning, dementia, cutaneous carcinoma, drug abuse, diabetes, type
II diabetes, depression, epilepsy, gastrointestinal disorders,
inflammation, insulin resistance syndrome, jet lag, medullary
thyroid carcinoma, melanoma, Meniere's disease, metabolic syndrome,
mild cognitive impairment, migraine, mood and attention alteration,
motion sickness, narcolepsy, neurogenic inflammation, obesity,
obsessive compulsive disorder, pain, Parkinson's disease,
polycystic ovary syndrome, schizophrenia, seizures, septic shock,
sleep disorders, Syndrome X, Tourette's syndrome, vertigo, and
wakefulness.
Description
[0001] This application is a divisional application of U.S. patent
application Ser. No. 11/096,382, filed Apr. 1, 2005, which claims
priority from 60/560,151, filed Apr. 7, 2004, which is herein
incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field
[0003] The invention relates to azacyclosteroid compounds,
compositions comprising such compounds, and methods of treating
conditions and disorders using such compounds and compositions.
[0004] 2. Description of Related Technology
[0005] Histamine is a well-known modulator of neuronal activity. At
least four types of histamine receptors have been reported in the
literature, typically referred to as histamine-1, histamine-2,
histamine-3, and histamine-4. The class of histamine receptor known
as histamine-3 receptors is believed to play a role in
neurotransmission in the central nervous system.
[0006] The histamine-3 (H.sub.3) receptor was first characterized
pharmacologically on histaminergic nerve terminals (Nature,
302:832-837 (1983)), where it regulates the release of
neurotransmitters in both the central nervous system and peripheral
organs, particularly the lungs, cardiovascular system and
gastrointestinal tract. H.sub.3 receptors are thought to be
disposed presynaptically on histaminergic nerve endings, and also
on neurons possessing other activity, such as adrenergic,
cholinergic, serotoninergic, and dopaminergic activity. The
existence of H.sub.3 receptors has been confirmed by the
development of selective H.sub.3 receptor agonists and antagonists
((Nature, 327:117-123 (1987); Leurs and Timmerman, ed. "The History
of H.sub.3 Receptor: a Target for New Drugs," Elsevier (1998)).
[0007] The activity at the H.sub.3 receptors can be modified or
regulated by the administration of H.sub.3 receptor ligands. The
ligands can exhibit antagonist, agonist, partial agonist, or
inverse agonist properties. For example, H.sub.3 receptors have
been linked to conditions and disorders related to memory and
cognition processes, neurological processes, cardiovascular
function, and regulation of blood sugar, among other systemic
activities. Although various classes of compounds demonstrating
H.sub.3 receptor-modulating activity exist, it would be beneficial
to provide additional compounds demonstrating activity at the
H.sub.3 receptors that can be incorporated into pharmaceutical
compositions useful for therapeutic methods.
SUMMARY OF THE INVENTION
[0008] The invention is directed to azacyclosteroid compounds,
compositions comprising the compounds, and methods of using such
compounds and compositions. The compounds of the invention have the
formula: ##STR1## or a pharmaceutically acceptable salt, ester,
amide, or prodrug thereof, wherein
[0009] R.sub.1 is selected from the group consisting of hydrogen,
acetyl, alkyl, fluoroalkyl, and cycloalkyl;
[0010] R.sub.2 and R.sub.3 are each independently selected from the
group consisting of hydrogen and alkyl or R.sub.2 and R.sub.3 taken
together form a 3- to 6-membered ring;
[0011] Ring A of the formula: ##STR2## is selected from the
following: ##STR3## wherein:
[0012] the dotted line represents an optional bond;
[0013] R.sub.4 and R.sub.5 are each independently selected from the
group consisting of hydrogen and fluorine, provided that R.sub.5 is
present only when the bond represented by the dotted line is
absent;
[0014] R.sub.6 is selected from the group consisting of hydrogen,
alkyl, and fluorine;
[0015] one of R.sub.7 and R.sub.8 is hydrogen; and the other of
R.sub.7 and R.sub.8 is selected from the group consisting of:
[0016] a) NR.sub.18R.sub.19; [0017] b) OR.sub.20, SR.sub.20,
O(C.dbd.O)OR.sub.20, O(C.dbd.O)N(R.sub.20)(R.sub.21),
O(C.dbd.O)C(R.sub.23)(R.sub.24)(R.sub.24b), or
O(C.dbd.O)CH(NR.sub.28R.sub.29)R.sub.25; and [0018] c)
NR.sub.22(C.dbd.O)R.sub.25, NR.sub.22(C.dbd.O)NR.sub.26R.sub.27,
NR.sub.22(C.dbd.O)CH(NR.sub.28R.sub.29)R.sub.30,
N(R.sub.22)(C.dbd.O)OR.sub.20, or
NR.sub.22(C.dbd.O)C(OR.sub.23)R.sub.30R.sub.30b; and [0019] d)
NR.sub.22SO.sub.2R.sub.31 or
NR.sub.22SO.sub.2N(R.sub.22)(R.sub.23): or R.sub.7 and R.sub.8
taken together with the carbon atom to which each is attached forms
a group of the formula --C.dbd.C(R.sub.a)(R.sub.b), wherein R.sub.a
and R.sub.b are each independently selected from the group
consisting of hydrogen, alkyl, and cycloalkyl;
[0020] R.sub.9 and R.sub.10 are each independently selected from
the group consisting of hydrogen, halogen, alkyl, and cyano;
[0021] R.sub.11 and R.sub.12 are each independently selected from
the group consisting of hydrogen, heteroaryl, heterocycle, aryl,
arylalkyl, aryloxy, arylcarbonyl, arylcarbonyloxy, arylalkoxy,
alkylsulfonyl, arylsulfonyl, and trifluoromethylsulfonyl; or one of
R.sub.10 and R.sub.11 or R.sub.11 and R.sub.12 taken together with
the atoms to which each is attached form a 5- to 6-membered
aromatic or heteroaromatic ring;
[0022] R.sub.13 is selected from the group consisting of alkyl,
cycloalkyl, aryl, and heteroaryl;
[0023] R.sub.18 is hydrogen or C.sub.1-C.sub.6 alkyl and R.sub.19
is selected from the group consisting of aryl and heteroaryl, or
R.sub.18 and R.sub.1g at each occurrence is taken together form a
3- to 8-membered heterocycle;
[0024] R.sub.20 and R.sub.21 at each occurrence are each
independently selected from the group consisting of hydrogen,
alkyl, cycloalkyl, alkoxyalkyl, cyanoalkyl, hydroxyalkyl,
haloalkyl, aryl, aryloxy, arylalkyl, arylsulfonyl, heteroaryl,
heteroarylalkyl, heteroarylcarbonyl, heterocycle, and
heterocyclealkyl, provided that when R.sub.7 or R.sub.8 is
OR.sub.20. R.sub.20 is not hydrogen or methyl;
[0025] R.sub.22 at each occurrence is selected from the group
consisting of hydrogen and alkyl;
[0026] R.sub.23 at each occurrence is selected from the group
consisting of hydrogen, alkyl, and alkylcarbonyl;
[0027] R.sub.24 and R.sub.24b are each independently selected from
the group consisting of hydrogen, alkyl, aryl, arylalkyl, and
cycloalkyl, provided that only one of R.sub.24 and R.sub.24b can be
hydrogen;
[0028] R.sub.25 at each occurrence is independently selected from
the group consisting of C.sub.2-C.sub.6 alkyl, alkoxyalkyl,
hydroxyalkyl, a phenyl ring substituted with 1, 2 or 3 substituents
selected from the group consisting of halogen, cyano, alkyl, and
alkoxy, naphthyl, arylalkyl, cycloalkyl, cycloalkylalkyl,
cyanoalkyl, haloalkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, and heterocyclealkyl;
[0029] R.sub.26 and R.sub.27 are each independently selected from
the group consisting of alkyl, alkylcarbonyl, alkoxycarbonyl,
cycloalkyl, aryl, heteroaryl, and heterocycle, provided that
R.sub.26 and R.sub.27 are not both alkyl, or R.sub.26 and R.sub.27
taken together with the nitrogen atom to which each is attached
forms an aromatic or non-aromatic 5- to 6-membered ring, wherein 0,
1, or 2 carbon atoms in the ring is substituted with a heteroatom
selected from O, S, or NR.sub.23;
[0030] R.sub.28 and R.sub.29 at each occurrence are each
independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkyl, aryl, heteroaryl,
and heterocycle, or R.sub.28 and R.sub.29 taken together with the
nitrogen atom to which each is attached forms an aromatic or
non-aromatic 5- to 6-membered ring, wherein 0, 1, or 2 carbon atoms
in the ring is substituted with a heteroatom selected from O, S, or
NR.sub.23;
[0031] R.sub.30 at each occurrence is independently selected from
the group consisting of hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl,
aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl,
haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heterocycle, and heterocyclealkyl;
[0032] R.sub.30b is selected from the group consisting of hydrogen
and alkyl, or when R.sub.30 is alkyl and R.sub.30b is alkyl, the
alkyl groups can be bonded together to form a C.sub.3-C.sub.4
cycloalkyl group; and
[0033] R.sub.31 is selected from the group consisting of alkyl,
cycloalkyl, aryl, heterocycle, and heteroaryl.
[0034] The invention also relates to a method of treating a
condition modulated by the histamine-3 receptors in a mammal
comprising administering an effective amount of a compound of the
formula: ##STR4## or a pharmaceutically acceptable salt, ester,
amide, or prodrug thereof, wherein
[0035] R.sub.1 is selected from the group consisting of hydrogen,
acetyl, alkyl, fluoroalkyl, and cycloalkyl;
[0036] R.sub.2 and R.sub.3 are each independently selected from the
group consisting of hydrogen and alkyl, or R.sub.2 and R.sub.3
taken together form a 3- to 6-membered ring,
[0037] Ring A of the formula: ##STR5## is selected from the
following: ##STR6## wherein:
[0038] the dotted line represents an optional bond;
[0039] R.sub.4 and R.sub.5 are each independently selected from the
group consisting of hydrogen and fluorine, provided that R.sub.5 is
present only when the bond represented by the dotted line is
absent;
[0040] R.sub.6 is selected from the group consisting of hydrogen,
alkyl, and fluorine;
[0041] one of R.sub.7 and R.sub.8 is hydrogen; and the other of
R.sub.7 and R.sub.8 is selected from the group consisting of:
[0042] a) NR.sub.18R.sub.19; [0043] b) OR.sub.20, SR.sub.20,
O(C.dbd.O)OR.sub.20, O(C.dbd.O)N(R.sub.20)(R.sub.21),
O(C.dbd.O)C(R.sub.23)(R.sub.24)(R.sub.24b), or
O(C.dbd.O)CH(NR.sub.28R.sub.29)R.sub.25; and [0044] c)
NR.sub.22(C.dbd.O)R.sub.25, NR.sub.22(C.dbd.O)NR.sub.26R.sub.27,
NR.sub.22(C.dbd.O)CH(NR.sub.28R.sub.29)R.sub.30,
N(R.sub.22)(C.dbd.O)OR.sub.20, or
NR.sub.22(C.dbd.O)C(OR.sub.23)R.sub.3OR.sub.30b; and [0045] d)
NR.sub.22SO.sub.2R.sub.31 or
NR.sub.22SO.sub.2N(R.sub.22)(R.sub.23); or R.sub.7 and R.sub.8
taken together with the carbon atom to which each is attached forms
a group of the formula --C.dbd.C(R.sub.a)(R.sub.b), wherein R.sub.a
and R.sub.b are each independently selected from the group
consisting of hydrogen, alkyl, and cycloalkyl;
[0046] R.sub.9 and R.sub.10 are each independently selected from
the group consisting of hydrogen, halogen, alkyl, and cyano;
[0047] R.sub.11 and R.sub.12 are each independently selected from
the group consisting of hydrogen, heteroaryl, heterocycle, aryl,
arylalkyl, aryloxy, arylcarbonyl, arylcarbonyloxy, arylalkoxy,
alkylsulfonyl, arylsulfonyl, and trifluoromethylsulfonyl; or one of
R.sub.10 and R.sub.11 or R.sub.11 and R.sub.12 taken together with
the atoms to which each is attached form a 5- to 6-membered
aromatic or heteroaromatic ring;
[0048] R.sub.13 is selected from the group consisting of alkyl,
cycloalkyl, aryl, and heteroaryl;
[0049] R.sub.15 and R.sub.16 taken together with the atom to which
each is attached forms a 5- to 6-membered ring optionally
substituted with an alkylamino group;
[0050] R.sub.17 is selected from the group consisting of hydrogen,
alkyl, and fluoro;
[0051] R.sub.18 is hydrogen or C.sub.1-C.sub.6 alkyl and R.sub.19
is selected from the group consisting of aryl and heteroaryl, or
R.sub.18 and R.sub.19 at each occurrence is taken together form a
3- to 8-membered heterocycle;
[0052] R.sub.20 and R.sub.21 at each occurrence are each
independently selected from the group consisting of hydrogen,
alkyl, cycloalkyl, alkoxyalkyl, cyanoalkyl, hydroxyalkyl,
haloalkyl, aryl, aryloxy, arylalkyl, arylsulfonyl, heteroaryl,
heteroarylalkyl, heteroarylcarbonyl, heterocycle, and
heterocyclealkyl;
[0053] R.sub.22 at each occurrence is selected from the group
consisting of hydrogen and alkyl;
[0054] R.sub.23 at each occurrence is selected from the group
consisting of hydrogen, alkyl, and alkylcarbonyl;
[0055] R.sub.24 and R.sub.24b are each independently selected from
the group consisting of hydrogen, alkyl, aryl, arylalkyl, and
cycloalkyl;
[0056] R.sub.25 at each occurrence is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, alkoxyalkyl,
hydroxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,
cyanoalkyl, haloalkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, and heterocyclealkyl;
[0057] R.sub.26 and R.sub.27 are each independently selected from
the group consisting of alkyl, alkylcarbonyl, alkoxycarbonyl,
cycloalkyl, aryl, heteroaryl, and heterocycle, or R.sub.26 and
R.sub.27 taken together with the nitrogen atom to which each is
attached forms an aromatic or non-aromatic 5- to 6-membered ring,
wherein 0, 1, or 2 carbon atoms in the ring is substituted with a
heteroatom selected from O, S, or NR.sub.23;
[0058] R.sub.28 and R.sub.29 at each occurrence are each
independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkyl, aryl, heteroaryl,
and heterocycle, or R.sub.28 and R.sub.29 taken together with the
nitrogen atom to which each is attached forms an aromatic or
non-aromatic 5- to 6-membered ring, wherein 0, 1, or 2 carbon atoms
in the ring is substituted with a heteroatom selected from O, S, or
NR.sub.23;
[0059] R.sub.30 at each occurrence is independently selected from
the group consisting of hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl,
aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl,
haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heterocycle, and heterocyclealkyl;
[0060] R.sub.30b is selected from the group consisting of hydrogen
and alkyl, or when R.sub.30 is alkyl and R.sub.30b is alkyl, the
alkyl groups can be bonded together to form a C.sub.3-C.sub.4
cycloalkyl group; and
[0061] R.sub.31 is selected from the group consisting of alkyl,
cycloalkyl, aryl, heterocycle, and heteroaryl.
[0062] Another aspect of the invention relates to pharmaceutical
compositions comprising compounds of the invention. Such
compositions can be administered in accordance with a method of the
invention, typically as part of a therapeutic regimen for treatment
or prevention of conditions and disorders related to H.sub.3
receptor activity.
[0063] Yet another aspect of the invention relates to a method of
selectively modulating H.sub.3 receptor activity. The method is
useful for treating and/or preventing conditions and disorders
related to H.sub.3 receptor modulation in mammals. More
particularly, the method is useful for conditions and disorders
related to memory and cognition processes, neurological processes,
cardiovascular function, and body weight.
[0064] The compounds, compositions comprising the compounds, and
methods for treating or preventing conditions and disorders by
administering the compounds are further described herein.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
[0065] Certain terms as used in the specification are intended to
refer to the following definitions, as detailed below.
[0066] The term "acyl" as used herein, means an alkyl group, as
defined herein, appended to the parent molecular moiety through a
carbonyl group, as defined herein. Representative examples of acyl
include, but are not limited to, acetyl, 1-oxopropyl,
2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
[0067] The term "acyloxy" as used herein, means an acyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of acyloxy include, but are
not limited to, acetyloxy, propionyloxy, and isobutyryloxy.
[0068] The term "alkenyl" as used herein, means a straight or
branched chain hydrocarbon containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond formed by the
removal of two hydrogens. Representative examples of alkenyl
include, but are not limited to, ethenyl, 2-propenyl,
2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,
2-methyl-1-heptenyl, and 3-decenyl.
[0069] The term "alkoxy" as used herein, means an alkyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of alkoxy include, but are not
limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy, and hexyloxy.
[0070] The term "alkoxyalkoxy" as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through another alkoxy group, as defined herein. Representative
examples of alkoxyalkoxy include, but are not limited to,
tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and
methoxymethoxy.
[0071] The term "alkoxyalkyl" as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of alkoxyalkyl include, but are not limited to, tert-butoxymethyl,
2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
[0072] The term "alkoxycarbonyl" as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkoxycarbonyl include, but are not limited to,
methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
[0073] The term "alkoxyimino" as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through an imino group, as defined herein. Representative examples
of alkoxyimino include, but are not limited to, ethoxy(imino)methyl
and methoxy(imino)methyl.
[0074] The term "alkoxysulfonyl" as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of alkoxysulfonyl include, but are not limited to,
methoxysulfonyl, ethoxysulfonyl, and propoxysulfonyl.
[0075] The term "alkyl" as used herein, means a straight or
branched chain hydrocarbon containing from 1 to 10 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
and n-decyl.
[0076] The term "alkylcarbonyl" as used herein, means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkylcarbonyl include, but are not limited to,
methylcarbonyl and ethylcarbonyl.
[0077] The term "alkylsulfonyl" as used herein, means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of alkylsulfonyl include, but are not limited to,
methylsulfonyl and ethylsulfonyl.
[0078] The term "alkynyl" as used herein, means a straight or
branched chain hydrocarbon group containing from 2 to 10 carbon
atoms and containing at least one carbon-carbon triple bond.
Representative examples of alkynyl include, but are not limited, to
acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and
1-butynyl.
[0079] The term "amido" as used herein, means an amino, alkylamino,
or dialkylamino group appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of amido include, but are not limited to, aminocarbonyl,
methylaminocarbonyl, dimethylaminocarbonyl, and
ethylmethylaminocarbonyl.
[0080] The term "amino" as used herein, means a --NH.sub.2
group.
[0081] The term "aryl" as used herein, means a monocyclic or
bicyclic aromatic ring system. Representative examples of aryl
include, but are not limited to, phenyl and naphthyl.
[0082] The aryl groups of this invention are substituted with 0, 1,
2, 3, 4, or 5 substituents independently selected from acyl,
acyloxy, alkanoyl, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylsulfonyl,
alkynyl, amido, carbonyl, carboxy, cyano, formyl, haloalkoxy,
haloalkyl, halo, hydroxy, hydroxyalkyl, hydroxyimino, mercapto,
nitro, thioalkoxy, --NR.sub.AR.sub.B, and
(NR.sub.AR.sub.B)sulfonyl.
[0083] The term "arylalkyl" as used herein, means at least one aryl
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of arylalkyl include phenylmethyl, naphthylethyl, and the like.
[0084] The term "aryloxy" as used herein, means an aryl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom, as defined herein. Representative examples of aryloxy
include, but are not limited to, phenoxy and naphthoxy.
[0085] The term "arylalkoxy" as used herein, means an aryl group,
as defined herein, appended to the parent molecular moiety through
an alkoxy group, as defined herein. Representative examples of
arylalkoxy include, but are not limited to, phenylmethoxy,
2-phenylethoxy, 2-naphthylethoxy, and naphthylmethoxy.
[0086] The term "arylsulfonyl" as used herein, means an aryl group,
as defined herein, appended to the parent molecular moiety through
a sulfonyl group, as defined herein. Representative examples of
arylsulfonyl include, but are not limited to, phenylsulfonyl and
naphthylsulfonyl.
[0087] The term "carbonyl" as used herein, means a --C(O)--
group.
[0088] The term "carboxy" as used herein, means a --CO.sub.2H
group, which may be protected as an ester group
--CO.sub.2-alkyl.
[0089] The term "cyano" as used herein, means a --CN group.
[0090] The term "cyanoalkyl" as used herein, means at least one
cyano group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of cyanoalkyl include, but are not limited to,
cyanomethyl.
[0091] The term "cycloalkyl" as used herein, means a saturated
cyclic hydrocarbon group containing from 3 to 8 carbons. Examples
of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl.
[0092] The cycloalkyl groups of the invention are substituted with
0, 1, 2, 3, or 4 substituents selected from acyl, acyloxy, alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,
alkyl, alkynyl, amido, carboxy, cyano, ethylenedioxy, formyl,
haloalkoxy, haloalkyl, halo, hydroxy, hydroxyalkyl, methylenedioxy,
thioalkoxy, and --NR.sub.AR.sub.B.
[0093] The term "cycloalkylalkyl" as used herein, means a
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of cycloalkylalkyl include, but are not
limited to, cyclopropylmethyl, 2-cyclobutylethyl,
cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptyl butyl.
[0094] The term "ethylenedioxy" as used herein, means a
--O(CH.sub.2).sub.2O-- group wherein the oxygen atoms of the
ethylenedioxy group are attached to the parent molecular moiety
through one carbon atom forming a five-membered ring or the oxygen
atoms of the ethylenedioxy group are attached to the parent
molecular moiety through two adjacent carbon atoms forming a
six-membered ring.
[0095] The term "fluoro" as used herein means --F.
[0096] The term "fluoroalkyl" as used herein, means at least one
fluoro group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of fluoroalkyl include, but are not limited to,
fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl,
and 2,2,2-trifluoroethyl.
[0097] The term "formyl" as used herein, means a --C(O)H group.
[0098] The term "halo" or "halogen" as used herein, means --Cl,
--Br, --I or --F.
[0099] The term "haloalkoxy" as used herein, means at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkoxy group, as defined herein. Representative examples
of haloalkoxy include, but are not limited to, chloromethoxy,
2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
[0100] The term "haloalkyl" as used herein, means at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of haloalkyl include, but are not limited to, chloromethyl,
2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and
2-chloro-3-fluoropentyl.
[0101] The term "heteroaryl," as used herein, refers to an aromatic
five- or six-membered ring wherein 1, 2, 3, or 4 heteroatoms are
independently selected from nitrogen, oxygen, or sulfur. Heteroaryl
also refers to fused aromatic nine- and ten-membered bicyclic rings
containing 1, 2, 3, or 4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or a tautomer thereof. Examples of
such rings include, but are not limited to, a ring wherein one
carbon is replaced with an O or S atom; one, two, or three N atoms
arranged in a suitable manner to provide an aromatic ring, or a
ring wherein two carbon atoms in the ring are replaced with one O
or S atom and one N atom. The heteroaryl groups are connected to
the parent molecular moiety through a carbon or nitrogen atom.
Representative examples of heteroaryl include, but are not limited
to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridazinonyl,
pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl,
thiazolyl, thienyl, triazinyl, triazolyl, indolyl, benzothiazolyl,
benzofuranyl, isoquinolinyl, and quinolinyl.
[0102] The heteroaryl groups of the invention are substituted with
0, 1, 2, 3, or 4 substituents independently selected from acyl,
acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylsulfonyl,
alkynyl, amido, carboxy, cyano, formyl, haloalkoxy, haloalkyl,
halo, hydroxy, hydroxyalkyl, mercapto, nitro, thioalkoxy,
--NR.sub.AR.sub.B, and (NR.sub.AR.sub.B)sulfonyl.
[0103] The term "heteroarylalkyl" as used herein, means at least
one heteroaryl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of heteroarylalkyl include thienylmethyl,
triazinylethyl, triazolylethyl, indolylmethyl, and the like.
[0104] The term "heterocycle," as used herein, refers to a three-,
four-, five-, six-, seven-, or eight-membered ring containing one,
two, or three heteroatoms independently selected from the group
consisting of nitrogen, oxygen, and sulfur. Rings containing at
least four members can be saturated or unsaturated. For example,
the four- and five-membered ring has zero or one double bond. The
six-membered ring has zero, one, or two double bonds. The seven-
and eight-membered rings have zero, one, two, or three double
bonds. The heterocycle groups of the invention can be attached to
the parent molecular moiety through a carbon atom or a nitrogen
atom. Representative examples of nitrogen-containing heterocycles
include, but are not limited to, azepanyl, azetidinyl, aziridinyl,
azocanyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl,
pyrrolinyl, and thiomorpholinyl. Representative examples of
non-nitrogen containing heterocycles include, but are not limited
to, tetrahydrofuranyl and tetrahydropyranyl.
[0105] The heterocycles of the invention are substituted with 0, 1,
2, 3, or 4 substituents independently selected from acyl, acyloxy,
alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxyimino, alkoxysulfonyl, alkyl, alkylsulfonyl, alkynyl, amido,
arylalkyl, arylalkoxycarbonyl, carboxy, cyano, formyl, haloalkoxy,
haloalkyl, halo, hydroxy, hydroxyalkyl, mercapto, nitro, oxo,
thioalkoxy, --NR.sub.AR.sub.B, and (NR.sub.AR.sub.B)sulfonyl.
[0106] The term "heterocyclealkyl" as used herein, means at least
one heteroaryl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of heterocyclealkyl include
morpholinylmethyl, piperazinylmethyl, piperidinylethyl,
pyrrolidinylethyl, and pyrrolinylethyl.
[0107] The term "hydroxy" as used herein means an --OH group.
[0108] The term "hydroxyalkyl" as used herein, means at least one
hydroxy group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of hydroxyalkyl include, but are not limited to,
hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.
[0109] The term "hydroxy-protecting group" means a substituent
which protects hydroxyl groups against undesirable reactions during
synthetic procedures. Examples of hydroxy-protecting groups
include, but are not limited to, methoxymethyl, benzyloxymethyl,
2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl,
triphenylmethyl, 2,2,2-trichloroethyl, t-butyl, trimethylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, methylene acetal,
acetonide benzylidene acetal, cyclic ortho esters,
methoxymethylene, cyclic carbonates, and cyclic boronates.
Hydroxy-protecting groups are appended onto hydroxy groups by
reaction of the compound that contains the hydroxy group with a
base, such as triethylamine, and a reagent selected from an alkyl
halide, alkyl triflate, trialkylsilyl halide, trialkylsilyl
triflate, aryldialkylsilyltriflate, or an alkylchloroformate,
CH.sub.2I.sub.2, or a dihaloboronate ester, for example with
methyliodide, benzyl iodide, triethylsilyltriflate, acetyl
chloride, benzylchloride, or dimethylcarbonate. A protecting group
also may be appended onto a hydroxy group by reaction of the
compound that contains the hydroxy group with acid and an alkyl
acetal.
[0110] The term "mercapto" as used herein, means a --SH group.
[0111] The term "methylenedioxy" as used herein, means a
--OCH.sub.2O-- group wherein the oxygen atoms of the methylenedioxy
are attached to the parent molecular moiety through two adjacent
carbon atoms.
[0112] The term "--NR.sub.AR.sub.B" as used herein, means two
groups, R.sub.A and R.sub.B, which are appended to the parent
molecular moiety through a nitrogen atom. R.sub.A and R.sub.B are
independently selected from hydrogen, alkyl, acyl and formyl.
Representative examples of --NR.sub.AR.sub.B include, but are not
limited to, amino, methylamino, acetylamino, and
acetylmethylamino.
[0113] The term "(NR.sub.AR.sub.B)sulfonyl" as used herein, means a
--NR.sub.AR.sub.B group, as defined herein, appended to the parent
molecular moiety through a sulfonyl group, as defined herein.
Representative examples of (NR.sub.AR.sub.B)sulfonyl include, but
are not limited to, aminosulfonyl, (methylamino)sulfonyl,
(dimethylamino)sulfonyl and (ethylmethylamino)sulfonyl.
[0114] The term "nitro" as used herein means a --N(O).sub.2--
group.
[0115] The term "oxo" as used herein means a --O-- group.
[0116] The term "sulfonyl" as used herein means a --S(O).sub.2--
group.
[0117] The term "thioalkoxy" as used herein means an alkyl group,
as defined herein, appended to the parent molecular moiety through
a sulfur atom. Representative examples of thioalkoxy include, but
are not limited to, methylthio, ethylthio, and propylthio.
[0118] As used herein, the term "antagonist" encompasses and
describes compounds that prevent receptor activation by an H.sub.3
receptor agonist alone, such as histamine, and also encompasses
compounds known as "inverse agonists". Inverse agonists are
compounds that not only prevent receptor activation by an H.sub.3
receptor agonist, such as histamine, but inhibit intrinsic receptor
activity.
Compounds of the Invention
[0119] Compounds of the invention can have the general formula (I)
as previously described.
[0120] More particularly, the invention can comprise compounds of
formula (II), having the formula: ##STR7## wherein:
[0121] the dotted line represents an optional bond;
[0122] R.sub.1 is selected from the group consisting of hydrogen,
acetyl, alkyl, fluoroalkyl, and cycloalkyl;
[0123] R.sub.2 and R.sub.3 are each independently selected from the
group consisting of hydrogen and alkyl, or R.sub.2 and R.sub.3
taken together form a 3- to 6-membered ring;
[0124] R.sub.4 and R.sub.5 are each independently selected from the
group consisting of hydrogen and fluorine, provided that R.sub.5 is
present only when the bond represented by the dotted line is
absent;
[0125] R.sub.6 is selected from the group consisting of hydrogen,
alkyl, and fluorine;
[0126] one of R.sub.7 and R.sub.8 is hydrogen; and the other of
R.sub.7 and R.sub.8 is selected from the group consisting of:
[0127] a) NR.sub.18R.sub.19; [0128] b) OR.sub.20, SR.sub.20,
O(C.dbd.O)OR.sub.20, O(C.dbd.O)N(R.sub.20)(R.sub.21),
O(C.dbd.O)C(R.sub.23)(R.sub.24)(R.sub.24b), or
O(C.dbd.O)CH(NR.sub.28R.sub.29)R.sub.25; and [0129] c)
NR.sub.22(C.dbd.O)R.sub.25, NR.sub.22(C.dbd.O)NR.sub.26R.sub.27,
NR.sub.22(C.dbd.O)CH(NR.sub.28R.sub.29)R.sub.30,
N(R.sub.22)(C.dbd.O)OR.sub.20, or
NR.sub.22(C.dbd.O)C(OR.sub.23)R.sub.3OR.sub.30b; and [0130] d)
NR.sub.22SO.sub.2R.sub.31 or
NR.sub.22SO.sub.2N(R.sub.22)(R.sub.23); or R.sub.7 and R.sub.8
taken together with the carbon atom to which each is attached forms
a group of the formula --C.dbd.C(R.sub.a)(R.sub.b), wherein R.sub.a
and R.sub.b are each independently selected from the group
consisting of hydrogen, alkyl, and cycloalkyl;
[0131] R.sub.18 is hydrogen or C.sub.1-C.sub.6 alkyl and R.sub.19
is selected from the group consisting of aryl and heteroaryl, or
R.sub.18 and R.sub.19 at each occurrence is taken together form a
3- to 8-membered heterocycle;
[0132] R.sub.20 and R.sub.21 at each occurrence are each
independently selected from the group consisting of hydrogen,
alkyl, cycloalkyl, alkoxyalkyl, cyanoalkyl, hydroxyalkyl,
haloalkyl, aryl, aryloxy, arylalkyl, arylsulfonyl, heteroaryl,
heteroarylalkyl, heteroarylcarbonyl, heterocycle, and
heterocyclealkyl, provided that when R.sub.7 or R.sub.8 is
OR.sub.20, R.sub.20 is not hydrogen or methyl;
[0133] R.sub.22 at each occurrence is selected from the group
consisting of hydrogen and alkyl;
[0134] R.sub.23 at each occurrence is selected from the group
consisting of hydrogen, alkyl, and alkylcarbonyl;
[0135] R.sub.24 and R.sub.24b are each independently selected from
the group consisting of hydrogen, alkyl, aryl, arylalkyl, and
cycloalkyl, provided that only one of R.sub.24 and R.sub.24b can be
hydrogen;
[0136] R.sub.25 at each occurrence is independently selected from
the group consisting of C.sub.2-C.sub.6 alkyl, alkoxyalkyl,
hydroxyalkyl, a phenyl ring substituted with 1, 2 or 3 substituents
selected from the group consisting of halogen, cyano, alkyl, and
alkoxy, naphthyl, arylalkyl, cycloalkyl, cycloalkylalkyl,
cyanoalkyl, haloalkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, and heterocyclealkyl;
[0137] R.sub.26 and R.sub.27 are each independently selected from
the group consisting of alkyl, alkylcarbonyl, alkoxycarbonyl,
cycloalkyl, aryl, heteroaryl, and heterocycle, provided that
R.sub.26 and R.sub.27 are not both alkyl, or R.sub.26 and R.sub.27
taken together with the nitrogen atom to which each is attached
forms an aromatic or non-aromatic 5- to 6-membered ring, wherein 0,
1, or 2 carbon atoms in the ring is substituted with a heteroatom
selected from O, S, or NR.sub.23;
[0138] R.sub.28 and R.sub.29 at each occurrence are each
independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkyl, aryl, heteroaryl,
and heterocycle, or R.sub.28 and R.sub.29 taken together with the
nitrogen atom to which each is attached forms an aromatic or
non-aromatic 5- to 6-membered ring, wherein 0, 1, or 2 carbon atoms
in the ring is substituted with a heteroatom selected from O, S, or
NR.sub.23;
[0139] R.sub.30 at each occurrence is independently selected from
the group consisting of hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl,
aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl,
haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heterocycle, and heterocyclealkyl;
[0140] R.sub.30b is selected from the group consisting of hydrogen
and alkyl, or when R.sub.30 is alkyl and R.sub.30b is alkyl, the
alkyl groups can be bonded together to form a C.sub.3-C.sub.4
cycloalkyl group; and
[0141] R.sub.31 is selected from the group consisting of alkyl,
cycloalkyl, aryl, heterocycle, and heteroaryl, also are
specifically contemplated. Such compounds are preferred for the
method of the invention.
[0142] Preferred compounds of formula (IA), (1B) and (II) are those
wherein one of R.sub.7 and R.sub.8 is hydrogen; and the other of
R.sub.7 and R.sub.8 is selected from the group consisting of
NR.sub.22(C.dbd.O)R.sub.25,
NR.sub.22(C.dbd.O)CH(NR.sub.28R.sub.29)R.sub.30, and
NR.sub.22(C.dbd.O)C(OR.sub.23)R.sub.3OR.sub.30b.
[0143] The preferred group for R.sub.7 or R.sub.8 in compounds of
formula (IA), (1B), or (II) is
NR.sub.22(C.dbd.O)CH(NR.sub.28R.sub.29)R.sub.30, wherein R.sub.22
is alkyl, R.sub.28 and R.sub.29 are each hydrogen, and R.sub.30 is
selected from the group consisting of alkyl and aryl, particularly
phenyl. Particularly, the compounds wherein R.sub.22 is methyl are
preferred.
[0144] Specific examples of compounds contemplated as part of the
invention, include, but are not limited to, those named and shown
in the Examples, not including the Reference Examples.
[0145] Compounds of the invention may exist as stereoisomers
wherein, asymmetric or chiral centers are present. These
stereoisomers are "R" or "S" depending on the configuration of
substituents around the chiral carbon atom. The terms "R" and "S"
used herein are configurations as defined in IUPAC 1974
Recommendations for Section E, Fundamental Stereochemistry, Pure
Appl. Chem., 1976, 45: 13-30. The invention contemplates various
stereoisomers and mixtures thereof and are specifically included
within the scope of this invention. Stereoisomers include
enantiomers and diastereomers, and mixtures of enantiomers or
diastereomers. Individual stereoisomers of compounds of the
invention may be prepared synthetically from commercially available
starting materials containing asymmetric or chiral centers or by
preparation of racemic mixtures followed by resolution well-known
to those of ordinary skill in the art. These methods of resolution
are exemplified by (1) attachment of a mixture of enantiomers to a
chiral auxiliary, separation of the resulting mixture of
diastereomers by recrystallization or chromatography and optional
liberation of the optically pure product from the auxiliary as
described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's
Textbook of Practical Organic Chemistry", 5th edition (1989),
Longman Scientific & Technical, Essex CM20 2JE, England, or (2)
direct separation of the mixture of optical enantiomers on chiral
chromatographic columns or (3) fractional recrystallization
methods.
Methods for Preparing Compounds of the Invention
[0146] The compounds of the invention can be better understood in
connection with the following synthetic schemes and methods. Such
description illustrates a means by which the compounds can be
prepared.
[0147] As used in the descriptions of the schemes and the examples,
certain abbreviations are intended to have the following meanings:
Ac for acetyl; BINAP for
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; Boc (or BOC) for
butyloxycarbonyl; Bu for butyl; DCM for dichloromethane; DMF for
N,N-dimethylformamide; DMSO for dimethylsulfoxide; EDC for
1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide; EDTA for
ethylenediaminetetraacetic acid; Et for ethyl, EtOH for ethanol;
EtOAc for ethyl acetate; HOBt for hydroxybenzotriazole; HPLC for
high pressure liquid chromatography; Me for methyl; MeOH for
methanol; Ms for methanesulfonyl; OAc for acetate; Pb/Cd for lead
on cadmium; Pd/C for palladium on carbon; Ph for phenyl; PNP for
paranitrophenol; tBu for tert-butyl; TEA for triethylamine; TFA for
trifluoroacetic acid; THF for tetrahydrofuran; Tf for
trifluoromethanesulfonyl; and Troc for
2,2,2-trichloroethylcarbonyl.
[0148] The compounds of this invention can be prepared by a variety
of synthetic procedures. Representative procedures are shown in,
but are not limited to, Schemes 1-5. ##STR8##
[0149] Compounds of formula 1E, 2, 5C and 6 can be prepared as
described in Scheme 1. A compound of formula 1 is prepared
according to the procedure described in Kopach, M. E.; Fray, A. H.
& Meyers A. I., J. Am. Chem. Soc. 1996, 118, 9876. Compound 1
can be hydrogenated under hydrogenation conditions well-known to
those with skill in the art, for example hydrogen gas in the
presence of a palladium catalyst. The two products 1A-a and 1A-b
can be separated by column chromatography. A compound of formula
1A-a is treated with paraformaldehyde and sodium cyanoborohydride
to provide a compound of formula 1B. Compound 1B is demethylated
with tetrabutylammonium iodide and trichloroborane to afford a
compound of formula 1C. Compound 1C is treated with
trifluoromethane sulfonic anhydride in an amine to afford a
compound of formula 1D, which is coupled with R-boronic acid,
wherein R is 4-CHC.sub.6H.sub.4-- or 3-AcC.sub.6H.sub.4-- in the
presence of tetrakis(triphenylphosphine)palladium catalyst to give
compounds of formula 1E and 2, respectively. A compound of formula
1A-b is treated with acetic anhydride and triethyl amine to provide
a compound of formula 5A. A compound of formula 5A is demethylated
with aluminum chloride to afford a compound of formula 5B. Compound
5B is treated with R--Cl, wherein R is Ph-CH.sub.2-- or Ph-CO-- to
give compounds of formula 5C and 6, respectively. ##STR9##
##STR10##
[0150] Compounds of formulas 61, 62, and 63 are prepared as
described above in Scheme 2. A compound of formula 7B are treated
with BOC-N-methyl-D-valine in the presence of
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and
1-hydroxybenzotriazole to provide a compound of formula 61.
Compound 61 is deprotected with trifluoroacetic acid to provide a
compound of formula 62. Compound 62 undergoes addition by treatment
with acetyl chloride to provide a compound of formula 63.
##STR11##
[0151] Compounds of formula 91 and 92 are prepared as described in
Scheme 3. A compound of formula 7B are reacted with
L-2-acetoxy-3-phenyl-propionic acid, which can be prepared from
L-3-phenyllactic acid in a suspension with acetyl chloride and
pyridine in a suitable solvent, for example dichloromethane, to
afford a compound of formula 91. Compound 91 is hydrolyzed under
basic conditions using potassium carbonate and methanol to provide
a compound of formula 92. ##STR12##
[0152] A compound of formula 126 is prepared as shown in Scheme 4.
A compound of formula 7B is reacted with 2-methoxy caproic acid in
the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride and 1-hydroxybenzotriazole to afford a compound of
formula 126. ##STR13##
[0153] Compounds of formulas 161 and 162 are prepared as described
in Scheme 6. A compound of formula 130A, which is prepared
according to procedures described in Hora and Cerny; Collect.
Czech. Chem. Commun. 26, 2217 (1961) and Labler et al. Collect.
Czech. Chem. Commun. 28; 2015 (1963), are reacted with
4-nitrophenylchloroformate in the presence of N-methylmorpholine to
provide compounds of formula 161. A compound of formula 161 is
treated with N-methylfurylamine to provide a compound of formula
162.
[0154] The processes for making compounds described herein can be
used in conjunction with the individual Examples to provide a
variety of compounds within the scope of the claimed compounds and
compounds useful for the claimed methods. In particular, suitable
starting materials can be substituted in the Schemes and Examples
described to provide compounds not specifically described in the
Schemes and/or Examples without undue experimentation.
[0155] The compounds and intermediates of the invention may be
isolated and purified by methods well-known to those skilled in the
art of organic synthesis. Examples of conventional methods for
isolating and purifying compounds can include, but are not limited
to, chromatography on solid supports such as silica gel, alumina,
or silica derivatized with alkylsilane groups, by recrystallization
at high or low temperature with an optional pretreatment with
activated carbon, thin-layer chromatography, distillation at
various pressures, sublimation under vacuum, and trituration, as
described for instance in "Vogel's Textbook of Practical Organic
Chemistry", 5th edition (1989), by Furniss, Hannaford, Smith, and
Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE,
England.
[0156] The compounds of the invention have at least one basic
nitrogen whereby the compound can be treated with an acid to form a
desired salt. For example, a compound may be reacted with an acid
at or above room temperature to provide the desired salt, which is
deposited, and collected by filtration after cooling. Examples of
acids suitable for the reaction include, but are not limited to
tartaric acid, lactic acid, succinic acid, as well as mandelic,
atrolactic, methanesulfonic, ethanesulfonic, toluenesulfonic,
naphthalenesulfonic, carbonic, fumaric, gluconic, acetic,
propionic, salicylic, hydrochloric, hydrobromic, phosphoric,
sulfuric, citric, or hydroxybutyric acid, camphorsulfonic, malic,
phenylacetic, aspartic, glutamic, and the like.
Compositions of the Invention
[0157] The invention also provides pharmaceutical compositions
comprising a therapeutically effective amount of a compound of
formula (I) in combination with a pharmaceutically acceptable
carrier. The compositions comprise compounds of the invention
formulated together with one or more non-toxic pharmaceutically
acceptable carriers. The pharmaceutical compositions can be
formulated for oral administration in solid or liquid form, for
parenteral injection or for rectal administration.
[0158] The term "pharmaceutically acceptable carrier," as used
herein, means a non-toxic, inert solid, semi-solid or liquid
filler, diluent, encapsulating material or formulation auxiliary of
any type. Some examples of materials which can serve as
pharmaceutically acceptable carriers are sugars such as lactose,
glucose and sucrose; starches such as corn starch and potato
starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc, cocoa butter and suppository
waxes; oils such as peanut oil, cottonseed oil, safflower oil,
sesame oil, olive oil, corn oil and soybean oil; glycols; such a
propylene glycol; esters such as ethyl oleate and ethyl laurate;
agar; buffering agents such as magnesium hydroxide and aluminum
hydroxide; alginic acid; pyrogen-free water, isotonic saline;
Ringer's solution; ethyl alcohol, and phosphate buffer solutions,
as well as other non-toxic compatible lubricants such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of one
skilled in the art of formulations.
[0159] The pharmaceutical compositions of this invention can be
administered to humans and other mammals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments or drops), bucally or as an
oral or nasal spray. The term "parenterally," as used herein,
refers to modes of administration, including intravenous,
intramuscular, intraperitoneal, intrasternal, subcutaneous,
intraarticular injection and infusion.
[0160] Pharmaceutical compositions for parenteral injection
comprise pharmaceutically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions and sterile
powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and nonaqueous carriers,
diluents, solvents or vehicles include water, ethanol, polyols
(propylene glycol, polyethylene glycol, glycerol, and the like, and
suitable mixtures thereof), vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate, or suitable
mixtures thereof. Suitable fluidity of the composition may be
maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0161] These compositions may also contain adjuvants such as
preservative agents, wetting agents, emulsifying agents, and
dispersing agents. Prevention of the action of microorganisms may
be ensured by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, and the
like. It may also be desirable to include isotonic agents, for
example, sugars, sodium chloride and the like. Prolonged absorption
of the injectable pharmaceutical form may be brought about by the
use of agents delaying absorption, for example, aluminum
monostearate and gelatin.
[0162] In some cases, in order to prolong the effect of a drug, it
is often desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This may be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug can depend upon its rate of dissolution, which, in turn, may
depend upon crystal size and crystalline form. Alternatively, a
parenterally administered drug form can be administered by
dissolving or suspending the drug in an oil vehicle.
[0163] Suspensions, in addition to the active compounds, may
contain suspending agents, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, tragacanth, and mixtures thereof.
[0164] If desired, and for more effective distribution, the
compounds of the invention can be incorporated into slow-release or
targeted-delivery systems such as polymer matrices, liposomes, and
microspheres. They may be sterilized, for example, by filtration
through a bacteria-retaining filter or by incorporation of
sterilizing agents in the form of sterile solid compositions, which
may be dissolved in sterile water or some other sterile injectable
medium immediately before use.
[0165] Injectable depot forms are made by forming microencapsulated
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides) Depot
injectable formulations also are prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0166] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0167] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic,
parenterally acceptable diluent or solvent such as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, U.S.P. and isotonic
sodium chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil can be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
are used in the preparation of injectables.
[0168] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
one or more compounds of the invention is mixed with at least one
inert pharmaceutically acceptable carrier such as sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as
starches, lactose, sucrose, glucose, mannitol, and salicylic acid;
b) binders such as carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as
glycerol; d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate; e) solution retarding agents such
as paraffin; f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as cetyl alcohol and glycerol
monostearate; h) absorbents such as kaolin and bentonite clay; and
i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents.
[0169] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using lactose or
milk sugar as well as high molecular weight polyethylene
glycols.
[0170] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract in a delayed manner. Examples
of materials useful for delaying release of the active agent can
include polymeric substances and waxes.
[0171] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating carriers
such as cocoa butter, polyethylene glycol or a suppository wax
which are solid at ambient temperature but liquid at body
temperature and therefore melt in the rectum or vaginal cavity and
release the active compound.
[0172] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof.
[0173] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0174] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches. A
desired compound of the invention is admixed under sterile
conditions with a pharmaceutically acceptable carrier and any
needed preservatives or buffers as may be required. Ophthalmic
formulation, eardrops, eye ointments, powders and solutions are
also contemplated as being within the scope of this invention.
[0175] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, animal and
vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites,
silicic acid, talc and zinc oxide, or mixtures thereof.
[0176] Powders and sprays can contain, in addition to the compounds
of this invention, lactose, talc, silicic acid, aluminum hydroxide,
calcium silicates and polyamide powder, or mixtures of these
substances. Sprays can additionally contain customary propellants
such as chlorofluorohydrocarbons.
[0177] Compounds of the invention may also be administered in the
form of liposomes. As is known in the art, liposomes are generally
derived from phospholipids or other lipid substances. Liposomes are
formed by mono- or multi-lamellar hydrated liquid crystals that are
dispersed in an aqueous medium. Any non-toxic, physiologically
acceptable and metabolizable lipid capable of forming liposomes may
be used. The present compositions in liposome form may contain, in
addition to the compounds of the invention, stabilizers,
preservatives, and the like. The preferred lipids are the natural
and synthetic phospholipids and phosphatidylcholines (lecithins)
used separately or together.
[0178] Methods to form liposomes are known in the art. See, for
example, Prescott, Ed., Methods in Cell Biology, Volume XIV,
Academic Press, New York, N.Y., (1976), p 33 et seq.
[0179] Dosage forms for topical administration of a compound of
this invention include powders, sprays, ointments and inhalants.
The active compound is mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants which can be required. Opthalmic
formulations, eye ointments, powders and solutions are also
contemplated as being within the scope of this invention. Aqueous
liquid compositions of the invention also are particularly
useful.
[0180] The compounds of the invention can be used in the form of
pharmaceutically acceptable salts, esters, or amides derived from
inorganic or organic acids. The term "pharmaceutically acceptable
salts, esters and amides," as used herein, refer to carboxylate
salts, amino acid addition salts, zwitterions, esters and amides of
compounds of formula (I) which are, within the scope of sound
medical judgment, suitable for use in contact with the tissues of
humans and lower animals without undue toxicity, irritation,
allergic response, and the like, are commensurate with a reasonable
benefit/risk ratio, and are effective for their intended use.
[0181] The term "pharmaceutically acceptable salt" refers to those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well-known in the art.
The salts can be prepared in situ during the final isolation and
purification of the compounds of the invention or separately by
reacting a free base function with a suitable organic acid.
[0182] Representative acid addition salts include, but are not
limited to acetate, adipate, alginate, citrate, aspartate,
benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate,
maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,
oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate,
picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
phosphate, glutamate, bicarbonate, p-toluenesulfonate and
undecanoate.
[0183] Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides such as methyl,
ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl
sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates;
long chain halides such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides; arylalkyl halides such as benzyl
and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0184] Examples of acids which can be employed to form
pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric
acid and phosphoric acid and such organic acids as oxalic acid,
maleic acid, succinic acid, and citric acid.
[0185] Basic addition salts can be prepared in situ during the
final isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically acceptable metal cation or with ammonia or an
organic primary, secondary or tertiary amine. Pharmaceutically
acceptable salts include, but are not limited to, cations based on
alkali metals or alkaline earth metals such as lithium, sodium,
potassium, calcium, magnesium, and aluminum salts, and the like,
and nontoxic quaternary ammonia and amine cations including
ammonium, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, diethylamine,
ethylamine and the such as. Other representative organic amines
useful for the formation of base addition salts include
ethylenediamine, ethanolamine, diethanolamine, piperidine, and
piperazine.
[0186] The term "pharmaceutically acceptable ester," as used
herein, refers to esters of compounds of the invention which
hydrolyze in vivo and include those that break down readily in the
human body to leave the parent compound or a salt thereof. Examples
of pharmaceutically acceptable, non-toxic esters of the invention
include C.sub.1-to-C.sub.6 alkyl esters and C.sub.5-to-C.sub.7
cycloalkyl esters, although C.sub.1-to-C.sub.4 alkyl esters are
preferred. Esters of the compounds of formula (I) may be prepared
according to conventional methods. Pharmaceutically acceptable
esters can be appended onto hydroxy groups by reaction of the
compound that contains the hydroxy group with acid and an
alkylcarboxylic acid such as acetic acid, or with acid and an
arylcarboxylic acid such as benzoic acid. In the case of compounds
containing carboxylic acid groups, the pharmaceutically acceptable
esters are prepared from compounds containing the carboxylic acid
groups by reaction of the compound with base such as triethylamine
and an alkyl halide, alkyl triflate, for example with methyliodide,
benzyl iodide, cyclopentyl iodide. They also may be prepared by
reaction of the compound with an acid such as hydrochloric acid and
an alkylcarboxylic acid such as acetic acid, or with acid and an
arylcarboxylic acid such as benzoic acid.
[0187] The term "pharmaceutically acceptable amide," as used
herein, refers to non-toxic amides of the invention derived from
ammonia, primary C.sub.1-to-C.sub.6 alkyl amines and secondary
C.sub.1-to-C.sub.6 dialkyl amines. In the case of secondary amines,
the amine may also be in the form of a 5- or 6-membered heterocycle
containing one nitrogen atom. Amides derived from ammonia,
C.sub.1-to-C.sub.3 alkyl primary amides and C.sub.1-to-C.sub.2
dialkyl secondary amides are preferred. Amides of the compounds of
formula (I) may be prepared according to conventional methods.
Pharmaceutically acceptable amides are prepared from compounds
containing primary or secondary amine groups by reaction of the
compound that contains the amino group with an alkyl anhydride,
aryl anhydride, acyl halide, or aryl halide. In the case of
compounds containing carboxylic acid groups, the pharmaceutically
acceptable esters are prepared from compounds containing the
carboxylic acid groups by reaction of the compound with base such
as triethylamine, a dehydrating agent such as dicyclohexyl
carbodiimide or carbonyl diimidazole, and an alkyl amine,
dialkylamine, for example with methylamine, diethylamine,
piperidine. They also may be prepared by reaction of the compound
with an acid such as sulfuric acid and an alkylcarboxylic acid such
as acetic acid, or with acid and an arylcarboxylic acid such as
benzoic acid under dehydrating conditions as with molecular sieves
added.
[0188] The composition can contain a compound of the invention in
the form of a pharmaceutically acceptable prodrug.
[0189] The term "pharmaceutically acceptable prodrug" or "prodrug,"
as used herein, represents those prodrugs of the compounds of the
invention which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use. Prodrugs of the invention may be
rapidly transformed in vivo to a parent compound of formula (I),
for example, by hydrolysis in blood. A thorough discussion is
provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery
Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B.
Roche, ed., Bioreversible Carriers in Drug Design, American
Pharmaceutical Association and Pergamon Press (1987), hereby
incorporated by reference.
[0190] The invention contemplates pharmaceutically active compounds
either chemically synthesized or formed by in vivo
biotransformation to compounds of formula (I).
Methods of the Invention
[0191] Compounds and compositions of formulas (IA), (IB), and (II)
as described for the invention are useful for modulating the
effects of histamine-3 receptors. In particular, the compounds and
compositions of the invention can be used for treating and
preventing disorders modulated by the histamine-3 receptors.
Typically, such disorders can be ameliorated by selectively
modulating the histamine-3 receptors in a mammal, preferably by
administering a compound or composition of the invention, either
alone or in combination with another active agent as part of a
therapeutic regimen.
[0192] The compounds of the invention, including but not limited to
those specified in the examples, possess an affinity for the
histamine-3 receptors. As histamine-3 receptor ligands, the
compounds of the invention may be useful for the treatment and
prevention of diseases or conditions such as acute myocardial
infarction, Alzheimer's disease, asthma, attention-deficit
hyperactivity disorder, bipolar disorder, cognitive enhancement,
cognitive deficits in psychiatric disorders, deficits of memory,
deficits of learning, dementia, cutaneous carcinoma, drug abuse,
diabetes, type II diabetes, depression, epilepsy, gastrointestinal
disorders, inflammation, insulin resistance syndrome, jet lag,
medullary thyroid carcinoma, melanoma, Meniere's disease, metabolic
syndrome, mild cognitive impairment, migraine, mood and attention
alteration, motion sickness, narcolepsy, neurogenic inflammation,
obesity, obsessive compulsive disorder, pain, Parkinson's disease,
polycystic ovary syndrome, schizophrenia, seizures, septic shock,
sleep disorders, Syndrome X, Tourette's syndrome, vertigo, and
wakefulness.
[0193] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
septic shock and cardiovascular disorders, in particular, acute
myocardial infarction may be demonstrated by Imamura et al., Circ.
Res., 78:475-481 (1996), Imamura et. al., Circ. Res. 78:863-869
(1996); R. Levi and N. C. E. Smith, "Histamine H.sub.3-receptors: A
new frontier in myocardial ischemia", J. Pharm. Exp. Ther.,
292:825-830 (2000); and Hatta, E., K. Yasuda and R. Levi,
"Activation of histamine H.sub.3 receptors inhibits
carrier-mediated norepinephrine release in a human model of
protracted myocardial ischemia", J. Pharm. Exp. Ther., 283:494-500
(1997).
[0194] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat sleep
disorders, in particular, narcolepsy may be demonstrated by Lin et
al., Brain Res., 523:325-330 (1990); Monti, et al.,
Neuropsychopharmacology 15:31-35 (1996); Sakai, et al., Life Sci.,
48:2397-2404 (1991); Mazurkiewicz-Kwilecki and Nsonwah, Can. J.
Physiol. Pharmacol., 67:75-78 (1989); Wada, et al., Trends in
Neuroscience 14:415 (1991); and Monti, et al., Eur. J. Pharmacol.
205:283 (1991).
[0195] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
cognition and memory process disorders may be demonstrated by
Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol.,
67:75-78 (1989); P. Panula, et al., Neuroscience, 82:993-997
(1997); Haas, et al., Behav. Brain Res., 66:41-44 (1995); De
Almeida and Izquierdo, Arch. Int. Pharmacodyn., 283:193-198 (1986);
Kamei et al., Psychopharmacology, 102:312-318 (1990); Kamei and
Sakata, Jpn. J. Pharmacol., 57:437-482 (1991); Schwartz et al.,
Psychopharmacology, The fourth Generation of Progress. Bloom and
Kupfer (eds). Raven Press, New York, (1995) 397; and Wada, et al.,
Trends in Neurosci., 14:415 (1991).
[0196] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
attention-deficit hyperactivity disorder (ADHD) may be demonstrated
by Shaywitz et al., Psychopharmacology, 82:73-77 (1984); Dumery and
Blozovski. Exp. Brain Res., 67:61-69 (1987); Tedford et al., J.
Pharmacol. Exp. Ther., 275:598-604 (1995); Tedford et al., Soc.
Neurosci. Abstr., 22:22 (1996); and Fox, et al., Behav. Brain Res.,
131:151-161 (2002).
[0197] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
seizures, in particular, epilepsy may be demonstrated by Yokoyama,
et al., Eur. J. Pharmacol., 234:129 (1993); Yokoyama and linuma,
CNS Drugs 5:321 (1996); Onodera et al., Prog. Neurobiol., 42:685
(1994); R. Leurs, R. C. Volling a and H. Timmerman, "The medicinal
chemistry and therapeutic potential of ligands of the histamine
H.sub.3 receptor", Progress in Drug Research 45:107-165, (1995);
Leurs and Timmerman, Prog. Drug Res., 39:127 (1992); The Histamine
H.sub.3 Receptor, Leurs and Timmerman (eds), Elsevier Science,
Amsterdam, The Netherlands (1998); H. Yokoyama and K. Iinuma,
"Histamine and Seizures: Implications for the treatment of
epilepsy", CNS Drugs, 5(5):321-330 (1995); and K. Hurukami, H.
Yokoyama, K. Onodera, K. Iinuma and T. Watanabe, "AQ-0145, A newly
developed histamine H.sub.3 antagonist, decreased seizure
susceptibility of electrically induced convulsions in mice", Meth.
Find. Exp. Clin. Pharmacol., 17(C):70-73 (1995).
[0198] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
motion sickness, Alzheimer's disease, and Parkinson's disease may
be demonstrated by Onodera, et al., Prog. Neurobiol., 42:685
(1994); Leurs and Timmerman, Prog. Drug Res., 39:127 (1992); and
The Histamine H.sub.3 Receptor, Leurs and Timmerman (eds), Elsevier
Science, Amsterdam, The Netherlands (1998).
[0199] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
narcolepsy, schizophrenia, depression, and dementia may be
demonstrated by R. Leurs, R. C. Volling a and H. Timmerman, "The
medicinal chemistry and therapeutic potential of ligands of the
histamine H.sub.3 receptor", Progress in Drug Research 45:107-165
(1995); The Histamine H.sub.3 Receptor, Leurs and Timmerman (eds),
Elsevier Science, Amsterdam, The Netherlands (1998); and
Perez-Garcia C, et. al., and Psychopharmacology (Berlin)
142(2):215-20 (February, 1999).
[0200] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
wakefulness, cognitive enhancement, mood and attention alteration,
vertigo and motion sickness, and treatment of cognitive deficits in
psychiatric disorders may be demonstrated by Schwartz, Physiol.
Review 71:1-51 (1991).
[0201] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat mild
cognitive impairment, deficits of memory, deficits of learning and
dementia may be demonstrated by C. E. Tedford, in "The Histamine
H.sub.3 Receptor: a target for new drugs", the Pharmacochemistry
Library, vol. 30 (1998) edited by R. Leurs and H. Timmerman,
Elsevier (New York). p. 269 and references also contained
therein.
[0202] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
obesity may be demonstrated by Leurs, et al., Trends in Pharm.
Sci., 19:177-183 (1998); E. Itoh, M. Fujimiay, and A. Inui,
"Thioperamide, A histamine H.sub.3 receptor antagonist, powerfully
suppresses peptide YY-induced food intake in rats," Biol. Psych.,
45(4):475-481 (1999); S. I. Yates, et al., "Effects of a novel
histamine H.sub.3 receptor antagonist, GT-2394, on food intake and
weight gain in Sprague-Dawley rats," Abstracts, Society for
Neuroscience, 102. 10:219 (November, 2000); and C. Bjenning, et
al., "Peripherally administered ciproxifan elevates hypothalamic
histamine levels and potently reduces food intake in the Sprague
Dawley rat," Abstracts, International Sendai Histamine Symposium,
Sendai, Japan, #P39 (November, 2000).
[0203] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
inflammation and pain may be demonstrated by Phillips, et al.,
Annual Reports in Medicinal Chemistry 33:31-40 (1998).
[0204] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
migraine may be demonstrated by R. Leurs, R. C. Volling a and H.
Timmerman, "The medicinal chemistry and therapeutic potential of
ligands of the histamine H.sub.3 receptor," Progress in Drug
Research 45:107-165 (1995); Matsubara, et al., Eur. J. Pharmacol.,
224:145 (1992); and Rouleau, et al., J. Pharmacol. Exp. Ther.,
281:1085 (1997).
[0205] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
cancer, in particular, melanoma, cutaneous carcinoma and medullary
thyroid carcinoma may be demonstrated by Polish Med. Sci. Mon.,
4(5):747 (1998); Adam Szelag, "Role of histamine H.sub.3-receptors
in the proliferation of neoplastic cells in vitro," Med. Sci.
Monit., 4(5):747-755 (1998); and C. H. Fitzsimons, et al.,
"Histamine receptors signalling in epidermal tumor cell lines with
H-ras gene alterations," Inflammation Res., 47 (Suppl 1):S50-S51
(1998).
[0206] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
vestibular dysfunctions, in particular, Meniere's disease may be
demonstrated by R. Leurs, R. C. Volling a and H. Timmerman, "The
medicinal chemistry and therapeutic potential of ligands of the
histamine H.sub.3 receptor," Progress in Drug Research 45:107-165
(1995).
[0207] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to treat
asthma may be demonstrated by A. Delaunois A., et al., "Modulation
of acetylcholine, capsaicin and substance P effects by histamine
H.sub.3 receptors in isolated perfused rabbit lungs," European
Journal of Pharmacology 277(2-3):243-250 (1995), and Dimitriadou,
et al., "Functional relationship between mast cells and C-sensitive
nerve fibres evidenced by histamine H.sub.3-receptor modulation in
rat lung and spleen," Clinical Science 87(2):151-163 (1994).
[0208] The ability of the compounds of the invention, including,
but not limited to, those specified in the examples, to allergic
rhinitis may be demonstrated by McLeod, et al., Progress in Resp.
Research 31:133 (2001).
[0209] Compounds of the invention are particularly useful for
treating and preventing a condition or disorder affecting the
memory or cognition.
[0210] Actual dosage levels of active ingredients in the
pharmaceutical compositions of this invention can be varied so as
to obtain an amount of the active compound(s) which is effective to
achieve the desired therapeutic response for a particular patient,
compositions and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated and
the condition and prior medical history of the patient being
treated. However, it is within the skill of the art to start doses
of the compound at levels lower than required to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved.
[0211] When used in the above or other treatments, a
therapeutically effective amount of one of the compounds of the
invention can be employed in pure form or, where such forms exist,
in pharmaceutically acceptable salt, ester, amide or prodrug form.
Alternatively, the compound can be administered as a pharmaceutical
composition containing the compound of interest in combination with
one or more pharmaceutically acceptable carriers. The phrase
"therapeutically effective amount" of the compound of the invention
means a sufficient amount of the compound to treat disorders, at a
reasonable benefit/risk ratio applicable to any medical treatment.
It will be understood, however, that the total daily usage of the
compounds and compositions of the invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
patient will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; activity
of the specific compound employed; the specific composition
employed; the age, body weight, general health, sex and diet of the
patient; the time of administration, route of administration, and
rate of excretion of the specific compound employed; the duration
of the treatment; drugs used in combination or coincidental with
the specific compound employed; and like factors well known in the
medical arts. For example, it is well within the skill of the art
to start doses of the compound at levels lower than required to
achieve the desired therapeutic effect and to gradually increase
the dosage until the desired effect is achieved.
[0212] The total daily dose of the compounds of this invention
administered to a human or lower animal may range from about 0.003
to about 30 mg/kg/day. For purposes of oral administration, more
preferable doses can be in the range of from about 0.1 to about 15
mg/kg/day. If desired, the effective daily dose can be divided into
multiple doses for purposes of administration; consequently, single
dose compositions may contain such amounts or submultiples thereof
to make up the daily dose.
[0213] The compounds and processes of the invention will be better
understood by reference to the following examples and reference
examples, which are intended as an illustration of and not a
limitation upon the scope of the invention.
EXAMPLES
Example 1
[0214] ##STR14##
1A.
2-Methoxy-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[1,7a-c]py-
rrole (1A-a and 1A-b)
[0215]
8-Benzyl-2-methoxy-6a,7,8,9,10,11-hexahydro-6H-benzo[4,5]indeno[1,-
7a-c]pyrrole (prepared according to the procedure of Kopach, M. E.;
Fray, A. H. and Meyers A. I., J. Am. Chem. Soc. 1996, 118,
9876)(1.0 g, 3.0 mmol) and 10% Pd/C (200 mg) were stirred in
ethanol (30 mL) under hydrogen for 2 h. The reaction mixture was
filtered and concentrated in vacuo to provide 617.8 mg (84.2%) of
the title compounds 1A-a and 1A-b as a 3:1 mixture.
[0216] MS: (M+H).sup.+=244.
[0217] The mixture was separated by column chromatography on silica
gel using 5% methanol and 0.5% ammonium hydroxide in
dichloromethane provided pure 1A-a and 1A-b.
[0218] 1A-a: .sup.1H NMR (CDCl.sub.3): .delta. 7.08 (d, 1H, J=14.0
Hz), 6.73 (dd, 1H, J=14.0, 4.5 Hz), 6.62 (d, J=4.5 Hz), 3.77 (s,
3H), 3.01 (dd, 1H, J=18.0, 12 Hz), 2.89 (d, 1H, J=18 Hz), 2.74 (dd,
1H, J=19, 5.5 Hz), 2.6-2.83 (m, 2H), 2.60 (d, 1H, J=19 Hz),
2.13-2.21 (m, 2H), 1.79-1.98 (m, 4H), 1.50-1.68 (m, 2H), 1.33 (m,
1H).
[0219] MS: (M+H).sup.+=244.
[0220] 1A-b: .sup.1H NMR (CDCl.sub.3): .delta. 6.98 (dd, 1H, J=8.7,
1.2 Hz), 6.66 (s, 1H), 6.64 (d, 1H, J=3.0 Hz), 3.76 (s, 3H), 3.16
(dd, 1H, J=11.5, 6.0 Hz), 3.00 (dd, 1H, J=19, 9.0 Hz), 2.92 (dd,
1H, J=18, 9.0 Hz), 2.89 (m, 1H), 2.84 (dd, 1H, J=11.0, 2.0 Hz),
2.55 (d, 1H, J=12.0 Hz), 2.45 (d, J=12.0 Hz), 2.24 (m, 1H), 2.13
(m, 2H), 2.04 (ddd, 1H, J=12.7, 8.2, 2.5 Hz), 1.91 (m, 1H), 1.58
(m, 1H), 1.56 (m, 1H).
[0221] MS: (M+H).sup.+=244. ##STR15##
1B.
2-Methoxy-8-methyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[-
1,7a-c]pyrrole
[0222]
2-Methoxy-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[1,7a--
c]pyrrole (Example 1A, compound 1A-a) (220.0 mg, 0.90 mmol) and
paraformaldehyde (810 mg, 2.7 mmol) were stirred in methanol (10
mL) at rt for 30 min. NaBH.sub.3CN was added and stirring was
continued for 30 min. The mixture was quenched with 1N NaOH (10
mL), extracted with CH.sub.2Cl.sub.2 (20 mL.times.4). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated in vacuo, providing 230.1 mg (98.9%) of the title
compound 1B as a white solid.
[0223] .sup.1H NMR (CDCl.sub.3): .delta. 7.08 (d, 1H, J=8.4 Hz),
6.72 (dd, 1H, J=10.5, 2.1 Hz). 6.62 (s, 1H), 3.77 (s, 3H), 2.92 (m,
1H), 2.73 (m, 1H), 2.64 (m, 2H), 2.44 (m, 1H), 2.34 (s, 3H), 2.15
(m, 2H), 2.04 (m, 1H), 1.95 (m, 1H), 1.79 (m, 1H), 1.68 (m, 1H),
1.55 (m, 3H).
[0224] MS: (M+H).sup.+=258. ##STR16##
1C.
8-Methyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[1,7a-c]pyr-
rol-2-ol
[0225]
2-Methoxy-8-methyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]ind-
eno[1,7a-c]pyrrole (Example 1B) (190.0 mg, 0.74 mmol) and
tetrabutylammonium iodide (300 mg, 0.81 mmol) were dissolved in
CH.sub.2Cl.sub.2 (20 mL) and cooled to -78.degree. C. BCl.sub.3
(1.85 mL, 1M in CH.sub.2Cl.sub.2) was added dropwise. The mixture
was stirred at 0.degree. C. for 5 hrs. It was then quenched with
aq. satd. NaHCO.sub.3, extracted with CH.sub.2Cl.sub.2 (15
mL.times.4). The combined organic layers were dried over sodium
sulfate, filtered and concentrated in vacuo. The residue was
purified by column chromatography on silica gel using 5% methanol
in dichloromethane, providing 57.1 mg (31.8%) of the title compound
1C.
[0226] .sup.1H NMR (DMSO-d.sub.6): .delta. 9.10 (s, 1H), 6.96 (d,
1H, J=18.5 Hz), 6.57 (dd, 1H, J=14, 3.5 Hz), 6.48 (s, 3H),
1.29-3.50 (m, 14H).
[0227] MS: (M+H).sup.+=244. ##STR17##
1D. Trifluoro-methanesulfonic acid
8-methyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[1,7a-c]pyrrol-
-2-yl ester
[0228]
8-Methyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[1,7a-c-
]pyrrol-2-ol (Example 1C) (54.0 mg, 0.22 mmol) and triethylamine
(42 .mu.L, 0.30 mmol) were dissolved in CH.sub.2Cl.sub.2 (10 mL)
and cooled to -78.degree. C. Trifluoromethane sulfonic anhydride
(42 .mu.L, 0.24 mmol) was added dropwise. The mixture was stirred
at 0.degree. C. for 1 hr. It was then quenched with water (2 mL),
extracted with CH.sub.2Cl.sub.2 (10 mL.times.3). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel using 10% methanol in dichloromethane,
providing (70.0 mg (85.0%) of the title compound 1D.
[0229] MS: (M+H).sup.+=376. ##STR18##
1E.
4-(8-Methyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[1,7a-c]-
pyrrol-2-yl)-benzonitrile
[0230] Trifluoro-methanesulfonic acid
8-methyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[1,7a-c]pyrrol-
-2-yl ester (Example 1D) (23.0 mg, 0.061 mmol) and
4-cyanophenylboronic acid (18 mg, 0.122 mmol) were dissolved in
toluene (2 mL) and ethanol (0.5 mL). 0.15 mL of 1M Na.sub.2CO.sub.3
solution was added. Nitrogen was bubbled through the reaction
mixture for 10 min. Tetrakis(triphenylphosphine)palladium (7.1 mg,
0.006 mmol) was then added. The mixture was stirred at 90.degree.
C. for 20 h. The reaction mixture was quenched with water (2 mL),
extracted with CH.sub.2Cl.sub.2 (5 mL.times.4). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel twice using 10% methanol in
dichloromethane and 0.5% ammonium hydroxide and 5% methanol in
dichloromethane, providing 6.2 mg (30.8%) of the title compound
1E.
[0231] .sup.1H NMR (CDCl.sub.3): .delta. 7.68 (q, 4H), 7.37 (dd,
1H), 7.29-7.31 (m, 2H), 3.33-1.25 (m, 17H).
[0232] MS: (M+H).sup.+=329.
Example 2
[0233] ##STR19##
1-[3-(8-Methyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[1,7a-c]p-
yrrol-2-yl)-phenyl]-ethanone
[0234] Using the procedure of Example 1E, but replacing
4-cyanophenylboronic acid with 3-acetylphenylboronic acid,
provided, after silica gel chromatography using 5% methanol in
dichloromethane, 3.9 mg (14.1%) of the title compound as a yellow
oil.
[0235] 1H NMR (CDCl.sub.3): .delta. 1.53-3.05 (m, 14H) 2.34 (s, 3H)
2.65 (s, 3H) 7.00 (m, 1H) 7.34 (d, J=1.50 Hz, 1H) 7.40 (dd, J=8.48,
1.50 Hz, 1H) 7.51 (t, J=7.80 Hz, 1H) 7.77 (d, J=8.48 Hz, 1H) 7.91
(d, J=7.80 Hz, 1H) 8.16 (m, 1H)
[0236] MS: (M+H).sup.+=346.
Example 3
[0237] ##STR20##
1-[3-(8-Methyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[1,7a-c]p-
yrrol-2-yl)-phenyl]-ethanone oxime
[0238]
1-[3-(8-Methyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[-
1,7a-c]pyrrol-2-yl)-phenyl]-ethanone (Example 2) (10.0 mg, 0.028
mmol), hydroxylamine hydrochloride (2.9 mg, 0.042 mmol), and
pyridine (226 .mu.L, 0.28 mmol) were heated in ethanol (1 mL) at
80.degree. C. for 3 h. The mixture was quenched with water (1 mL),
extracted with CH.sub.2Cl.sub.2 (2 mL.times.4). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel using 5% methanol in dichloromethane,
providing 1.9 mg (18.3%) of the title compound.
[0239] .sup.1H NMR (CDCl.sub.3): .delta. 7.83 (s, 1H), 7.58 (m,
2H), 7.44-7.36 (m, 2H), 7.32 (s, 1H), 7.23 (m, 1H), 3.02 (m, 1H),
2.74 (s, 3H), 2.32 (s, 3H) 2.82-1.48 (m, 13H).
[0240] MS: (M+H).sup.+=361.
Example 4
[0241] ##STR21##
4A.
2-Methoxy-8-methyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[-
1,7a-c]pyrrole
[0242] Using the procedure of Example 1B but replacing the
resultant compound of Example 1A (Compound 1A-a) with the resultant
compound of Example 1A (Compound 1A-b), provided, after silica gel
chromatography using 5% methanol and 0.5% ammonium hydroxide in
dichloromethane, 102.0 mg (88.5%) of the title compound as a white
solid.
[0243] .sup.1H NMR (CDCl.sub.3): .delta. 7.00 (d, 1H, J=9.15 Hz,
1H), 6.67 (s, 1H). 6.66 (d, J=6.44 Hz, 1H), 3.77 (s, 3H), 2.95 (m,
2H), 2.72 (m, 2H), 2.44 (m, 1H), 2.22 (s, 3H), 2.07-1.55 (m,
9H).
[0244] MS: (M+H).sup.+=258. ##STR22##
4B.
8-Methyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[1,7a-c]pyr-
rol-2-ol
[0245] Using the procedure of Example 1C, but replacing the
resultant compound of Example 1B with the resultant compound of
Example 4A, provided, after silica gel chromatography using 5%
methanol and 0.5% ammonium hydroxide in dichloromethane, 26.0 mg
(27.5%) of the title compound as a colorless oil.
[0246] .sup.1H NMR (DMSO-d.sub.6): .delta. 9.10 (s, 1H), 6.96 (d,
1H, J=18.5 Hz), 6.57 (dd, 1H, J=14, 3.5 Hz), 6.48 (s, 3H).
1.29-3.50 (m, 14H).
[0247] MS: (M+H).sup.+=244. ##STR23##
4C. Trifluoro-methanesulfonic acid
8-methyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[1,7a-c]pyrrol-
-2-yl ester
[0248] Using the procedure of Example 1D, but replacing the
resultant compound of Example 1C with the resultant compound of
Example 4B, provided, after silica gel chromatography using 10%
methanol in dichloromethane, 50.2 mg (100%) of the title compound
as a colorless oil.
[0249] MS: (M+H).sup.+=376. ##STR24##
4D.
1-[3-(8-Methyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[1,7a-
-c]pyrrol-2-yl)-phenyl]-ethanone
[0250] Using the procedure of Example 1E, but replacing
4-cyanophenylboronic acid with 3-acetylphenylboronic acid and
replacing the resultant compound of Example 1D with the resultant
compound of Example 4C, provided, after silica gel chromatography
using 5% methanol in dichloromethane, 5.3 mg (15.3%) of the title
compound as a yellow oil.
[0251] 1H NMR (CDCl.sub.3): .delta. 2.47 (s, 3H) 2.65 (s, 3H)
0.85-3.14 (m, 14H) 7.00 (m, 2H) 7.13 (m, 1H) 7.48 (m, 1H) 7.98 (m,
1H) 8.14 (m, 1H) 8.53 (m, 1H)
[0252] MS: (M+H).sup.+=346.
Example 5
[0253] ##STR25##
5A.
1-(2-Methoxy-5,6,6a,7,10,11-hexahydro-4-bH-benzo[4,5]indeno[1,7a-c]pyr-
rol-8-yl)-ethanone
[0254]
2-Methoxy-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[1,7a--
c]pyrrole (Example 1A, compound 1A-b) (50.0 mg, 0.21 mmol) and
triethylamine (86 .mu.L, 0.61 mmol) were dissolved in
CH.sub.2Cl.sub.2 (2 mL). Acetic anhydride (24 .mu.L, 0.25 mmol) was
added dropwise. The mixture was stirred at rt for 2 hr. It was then
quenched with water (2 mL), and extracted with CH.sub.2Cl.sub.2 (5
mL.times.3). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel using 5% methanol
in dichloromethane, providing 59.1 mg (100%) of the title
compound.
[0255] .sup.1H NMR (CDCl.sub.3): .delta. 1.59 (s, 3H) 3.68 (d,
J=12.21 Hz, 14H) 3.77 (m, 3H) 6.68 (m, 2H) 6.99 (m, 1H)
[0256] MS: (M+H).sup.+=286 ##STR26##
5B.
1-(2-Hydroxy-5,6,6a,7,10,11-hexahydro-4-bH-benzo[4,5]indeno[1,7a-c]pyr-
rol-8-yl)-ethanone
[0257]
1-(2-Methoxy-5,6,6a,7,10,11-hexahydro-4-bH-benzo[4,5]indeno[1,7a-c-
]pyrrol-8-yl)-ethanone (Example 5A) (55.0 mg, 0.19 mmol) was
dissolved in ethanethiol (4 mL). Aluminum chloride powder (128 mg,
0.96 mmol) was added. The mixture was stirred at 0.degree. C. for 1
h, quenched with NaHCO.sub.3 (satd.aq., 4 mL), and extracted with
CH.sub.2Cl.sub.2 (5 mL.times.3). The combined organic layers were
dried over sodium sulfate, filtered and concentrated in vacuo. The
residue was purified by column chromatography on silica gel using
5% methanol in dichloromethane, providing 46.2 mg (88.3%) of the
title compound.
[0258] MS: (M+H).sup.+=272 ##STR27##
5C. Benzoic acid
8-acetyl-5,6,6a,7,8,9,10,11-octahydro-4-bH-benzo[4,5]indeno[1,7a-c]pyrrol-
-2-yl ester
[0259]
1-(2-Hydroxy-5,6,6a,7,10,11-hexahydro-4-bH-benzo[4,5]indeno[1,7a-c-
]pyrrol-8-yl)-ethanone (Example 5B) (10.0 mg, 0.037 mmol) and
triethylamine (15.4 .mu.L, 0.11 mmol) were dissolved in
CH.sub.2Cl.sub.2 (2 mL). Benzoyl chloride (5.1 .mu.L, 0.044 mmol)
was added dropwise. The mixture was stirred at rt for 12 hr,
quenched with water (2 mL), and extracted with CH.sub.2Cl.sub.2 (5
mL.times.3). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel using 5% methanol
in dichloromethane, providing 11.1 mg (80.4%) of the title
compound.
[0260] .sup.1H NMR (CDCl.sub.3): .delta. 1.58 (s, 3H) 1.72-3.43 (m,
13H) 3.73 (m, 1H) 6.97 (m, 2H) 7.14 (m, 1H) 7.52 (m, 2H) 7.63 (m,
1H) 8.19 (m, 2H)
[0261] MS: (M+H).sup.+=376
Example 6
[0262] ##STR28##
1-(2-Benzyloxy-5,6,6a,7,10,11-hexahydro-4-bH-benzo[4,5]indeno[1,7a-c]pyrro-
l-8-yl)-ethanone
[0263]
1-(2-Hydroxy-5,6,6a,7,10,11-hexahydro-4-bH-benzo[4,5]indeno[1,7a-c-
]pyrrol-8-yl)-ethanone (Example 5B) (10.0 mg, 0.037 mmol) and
potassium carbonate (25 mg, 0.18 mmol) were dissolved in DMF (0.5
mL). Benzyl chloride (10.2 .mu.L, 0.088 mmol) and sodium iodide (5
mg) were added. The mixture was stirred at rt for 24 hr, quenched
with water (2 mL), and extracted with CH.sub.2Cl.sub.2 (5
mL.times.3). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel using 5% methanol
in dichloromethane, providing 5.5 mg (41.3%) of the title
compound.
[0264] 1H NMR (CDCl.sub.3): .delta. 1.57 (s, 3H) 1.68-2.07 (m, 3H)
2.31 (m, 2H) 2.69 (dd, J=7.80, 6.44 Hz, 1H) 2.96 (m, 3H) 3.24 (m,
1H) 3.46 (m, 1H) 3.70 (m, 1H) 5.03 (d, J=4.75 Hz, 2H) 6.74 (m, 2H)
6.99 (m, 1H) 7.36 (m, 5H)
[0265] MS: (M+H).sup.+=362.
Reference Example 7
[0266] ##STR29##
7A.
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-h-
exadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic
acid 2,2,2-trichloro-ethyl ester
[0267] 2,2,2-Trichloroethylchloroformate (5.94 g, 28 mmol) was
added dropwise to a stirred solution of conessine (10 g, 28 mmol)
in 200 mL benzene. Very thick gel resulted. The mixture was heated
at reflux for 4 h (oil bath temperature 90.degree. C.), then cooled
down to room temperature, quenched with water, the pH adjusted with
25 mL saturated sodium bicarbonate, and extracted with
dichloromethane 3.times.. Organic layers were dried over
Na.sub.2SO.sub.4, filtered, and evaporated to give crude product,
which was purified by flash chromatography to give desired product
(8.8 g, 61% yield).
[0268] .sup.1H NMR (CDCl.sub.3): .delta. 5.35 (m, 1H), 4.74 (m,
2H), 3.90 (m, 1H), 3.75 (m, 2H), 3.34 (m, 1H), 2.92 (s, 3H), 2.80
(d, 3H), 1.52 (s, 3H), 0.95 (s, 3H), 2.60-1.10 (m, 20H).
[0269] MS (DCI): (M+H).sup.+=517/519 ##STR30##
7B.
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-h-
exadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amine
[0270] 10% Pb/Cd couple* (1.2 g, 9 mmol Cd) was added to a rapidly
stirred mixture of Troc-conessine (Reference Example 7A) (800 mg,
1.54 mmol), THF (6 mL) and aq. 1N NH.sub.4OAc (6 mL). The mixture
was stirred for 5 h, then another portion of 10% Pb/Cd couple (1.0
g) was added, and stirred overnight. The solid was filtered, the
filtrate was diluted with water, the pH adjusted with saturated
sodium bicarbonate, and then extracted with dichloromethane
3.times.. The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered, and evaporated to give crude product,
which was purified by flash chromatography using 0.5% ammonium
hydroxide and 5% methanol in dichloromethane to give the desired
product (397 mg, 75% yield).
* Preparation of 10% Pb/Cd Couple:
[0271] Yellow lead oxide (PbO, 108 mg, 0.49 mmol) was dissolved in
5 mL 50% aq. AcOH, and the solution was slowly added to a
vigorously stirred suspension of Cd dust (100 mesh, 546 mg, 4.9
mmol) in deionized water (10 mL). The Cd darkened as Pb deposited
on its surface, and formed clumps that were gently broken up with a
glass rod. The dark, non-pyrophoric Pb/Cd couple was filtered,
washed with water, then acetone, vacuum dried, crushed and stored
in a closed vessel. This gives the 10% Pb/Cd couple (4.9 mmol Cd in
654 mg couple).
[0272] .sup.1H NMR (CDCl.sub.3): .delta. 5.35 (m, 1H), 3.0 (d, 1H),
2.45 (s, 3H), 2.22 (s, 3H), 1.05 (d, 3H), 0.93 (s, 3H), 2.40-1.00
(m, 23H).
[0273] MS (DCI): (M+H).sup.+=343 ##STR31##
7C.
N-Methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11a,11b,12,13--
hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-acetamide
[0274] A mixture of compound 7B (15 mg, 0.044 mmol), acetyl
chloride (2.8 .mu.L, 1.1 eq), triethylamine (15 .mu.L, 3.0 eq) and
dichloromethane (1 mL) was stirred at room temperature for 2 h. The
clear solution was directly loaded on silica gel column and eluted
with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to
give the desired product (10.5 mg, 78% yield)
[0275] .sup.1H NMR (CDCl.sub.3): .delta. 0.93 (m, 3H) 1.08 (m, 3H)
1.31 (m, 4H) 1.57 (m, 3H) 1.68 (m, 3H) 1.87 (m, 7H) 2.10 (m, 3H)
2.23 (m, 3H) 2.37 (m, 1H) 2.52 (m, 1H) 2.80 (m, 3H) 2.87 (m, 3H)
3.35 (m, 1H) 3.73 (m, 1H) 5.36 (m, 1H)
[0276] MS: (M+H).sup.+=385
Reference Example 8
[0277] ##STR32##
N-Methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-h-
exadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-benzamide
[0278] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting benzoyl
chloride for acetyl chloride. MS: (M+H).sup.+=447
Example 9
[0279] ##STR33##
2,2-N-Trimethyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,-
12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-propionami-
de
[0280] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting
trimethylacetyl chloride for acetyl chloride. .sup.1H NMR
(CDCl.sub.3): .delta. 0.93 (m, 3H) 1.08 (m, 3H) 1.26 (s, 9H) 1.31
(m, 4H) 1.57 (m, 3H) 1.68 (m, 3H) 1.87 (m, 6H) 2.10 (m, 3H) 2.23
(m, 3H) 2.37 (m, 1H) 2.52 (m, 1H) 2.86 (s, 3H) 3.35 (m, 1H) 3.73
(m, 1H) 4.02 (m, 1H) 5.36 (m, 1H); MS: (M+H).sup.+=427.
Example 10
[0281] ##STR34##
Furan-2-carboxylic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0282] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting 2-furoyl
chloride for acetyl chloride. MS: (M+H).sup.+=437.
Example 11
[0283] ##STR35##
4-Fluoro-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11-
b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-benzamid-
e
[0284] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting
4-fluorobenzoyl chloride for acetyl chloride. MS:
(M+H).sup.+=465.
Example 12
[0285] ##STR36##
Thiophene-2-carboxylic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0286] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting 2-thiophene
carbonyl chloride for acetyl chloride. .sup.1H NMR (CDCl.sub.3):
.delta. 0.96 (s, 3H) 1.23 (m, 4H) 1.50 (d, J=6.44 Hz, 3H) 1.79 (m,
7H) 2.13 (m, 8H) 2.58 (m, 2H) 2.83 (d, J=4.07 Hz, 3H) 3.07 (s, 3H)
3.32 (m, 1H) 3.88 (m, 1H), 4.20 (m, 1H) 5.37 (d, J=5.09 Hz, 1H)
7.04 (m, 1H) 7.31 (m, 1H) 7.44 (d, J=5.09 Hz, 1H); MS:
(M+H).sup.+=453.
Example 13
[0287] ##STR37##
Isoxazole-5-carboxylic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0288] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting
isoxazole-5-carbonyl chloride for acetyl chloride. MS:
(M+H).sup.+=438.
Example 14
[0289] ##STR38##
N-Methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-h-
exadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-isonicotinamide
[0290] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting
isonicotinoyl chloride hydrochloride for acetyl chloride and using
5 equivalents of triethylamine. .sup.1H NMR (CDCl.sub.3): .delta.
0.91 (s, 3H) 0.96 (s, 3H) 1.00-2.75 (m, 21H) 2.80 (m, 3H) 3.03 (s,
3H) 3.27 (m, 1H) 3.71 (m, 1H) 4.47 (m, 1H) 5.30 (m, 1H) 7.39 (d,
J=4.07 Hz, 2H) 8.71 (d, J=4.07 Hz, 2H); MS: (M+H).sup.+=448
Example 15
[0291] ##STR39##
N-Methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-h-
exadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-nicotinamide
[0292] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting nicotinoyl
chloride hydrochloride for acetyl chloride and using 5 equivalents
of triethylamine. MS: (M+H).sup.+=448.
Example 16
[0293] ##STR40##
3-Chloro-4-fluoro-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,-
11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-
-benzamide
[0294] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting
3-chloro-4-fluorobenzoyl chloride for acetyl chloride. .sup.1H NMR
(CDCl.sub.3): .delta. 0.92 (s, 3H) 1.18 (m, 6H) 1.49 (s, 3H) 1.82
(m, 7H) 2.15 (m, 7H) 2.53 (m, 2H) 2.79 (m, 3H) 2.92 (m, 3H) 3.36
(m, 1H) 3.73 (m, 1H) 5.37 (m, 1H) 7.15 (m, 2H) 7.45 (m, 1H); MS:
(M+H).sup.+=499.
Example 17
[0295] ##STR41##
2-(4-Methoxy-phenyl)-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,-
10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9--
yl)-acetamide
[0296] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting
4-methoxyphenylacetyl chloride for acetyl chloride. MS:
(M+H).sup.+=491.
Example 18
[0297] ##STR42##
2,3,4-Trifluoro-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11-
,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-b-
enzamide
[0298] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting
2,3,4-trifluorobenzoyl chloride for acetyl chloride. MS:
(M+H).sup.+=491.
Example 19
[0299] ##STR43##
4-Cyano-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b-
,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-benzamide
[0300] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting
4-cyanobenzoyl chloride for acetyl chloride. .sup.1H NMR
(CDCl.sub.3): .delta. 0.95 (s, 6H) 1.00-2.65 (m, 22H) 2.79 (d,
J=4.41 Hz, 6H) 3.02 (m, 1H) 3.72 (m, 1H) 5.33 (m, 1H) 7.46 (m, 2H)
7.70 (d, J=8.14 Hz, 2H); MS: (M+H).sup.+=472.
Example 20
[0301] ##STR44##
N-Methyl-2-thiophen-2-yl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11-
,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-a-
cetamide
[0302] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting
2-thiopheneacetyl chloride for acetyl chloride. .sup.1H NMR
(CDCl.sub.3): .delta. 0.93 (s, 3H) 1.04 (d, 3H) 1.05-2.15 (m, 18H)
2.20 (s, 3H) 2.38 (m, 2H) 2.50 (m, 1H) 2.90 (d, 3H) 3.01 (m, 1H)
3.66 (m, 1H) 3.90 (d, 2H) 4.42 (m, 1H) 5.34 (m, 1H) 6.87 (m, 1H)
6.95 (m, 1H) 7.18 (m, 1H); MS: (M+H).sup.+=467.
Example 21
[0303] ##STR45##
3-Chloro-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11-
b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-benzamid-
e
[0304] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting
3-chlorobenzoyl chloride for acetyl chloride. .sup.1H NMR
(CDCl.sub.3): .delta. 0.93 (s, 3H) 1.00-2.65 (m, 23H) 2.80 (d,
J=4.75 Hz, 6H) 3.00 (m, 2H) 3.35 (m, 1H) 3.72 (m, 1H) 5.30 (m, 1H)
7.28 (m, 1H) 7.36 (m, 3H); MS: (M+H).sup.+=481.
Example 22
[0305] ##STR46##
3-Methoxy-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,1-
1b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-benzami-
de
[0306] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting m-anisoyl
chloride for acetyl chloride.
[0307] MS: (M+H)=477.
Example 23
[0308] ##STR47##
4-Methoxy-N-methyl-N-(2,3,11a-trimethyl-2.3.3a,4,5,5a,5b,6,8,9,10,11,11a,1-
1b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-benzami-
de
[0309] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting p-anisoyl
chloride for acetyl chloride. MS: (M+H).sup.+=477.
Example 24
[0310] ##STR48##
4,N-Dimethyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,-
13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-benzamide
[0311] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting p-toluoyl
chloride for acetyl chloride. .sup.1H NMR (CDCl.sub.3): .delta.
0.93 (s, 3H) 1.00-2.30 (m, 21H) 2.37 (s, 3H) 2.54 (m, 2H) 2.79 (s,
3H) 2.80 (s, 3H) 2.95 (m, 2H) 3.31 (m, 1H) 3.72 (m, 1H) 5.30 (m,
1H) 7.18 (d, J=7.80 Hz, 2H) 7.27 (d, J=7.80 Hz, 2H); MS:
(M+H).sup.+=461.
Example 25
[0312] ##STR49##
4-Chloro-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11-
b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-benzamid-
e
[0313] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting
4-chlorobenzoyl chloride for acetyl chloride. .sup.1H NMR
(CDCl.sub.3): .delta. 0.93 (s, 3H) 1.00-2.60 (m, 23H) 2.79 (s, 3H)
2.80 (s, 3H) 2.96 (m, 2H) 3.30 (m, 1H) 3.73 (m, 1H) 5.30 (m, 1H)
7.36 (m, 4H); MS: (M+H).sup.+=482.
Example 26
[0314] ##STR50##
3-Cyano-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b-
,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-benzamide
[0315] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting
3-cyanobenzoyl chloride for acetyl chloride. .sup.1H NMR
(CDCl.sub.3): .delta. 0.95 (s, 6H) 1.00-2.60 (m, 20H) 2.84 (s, 3H)
3.02 (s, 3H) 3.49 (m, 3H) 4.46 (m, 1H) 5.41 (m, 1H) 7.53 (t, J=7.97
Hz, 1H) 7.68 (m, 3H); MS: (M+H).sup.+=471.
Example 27
[0316] ##STR51##
4-Bromo-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b-
,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-benzamide
[0317] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting
4-bromobenzoyl chloride for acetyl chloride. .sup.1H NMR
(CDCl.sub.3): .delta. 0.93 (s, 3H) 1.00-2.60 (m, 23H) 2.79 (s, 3H)
2.99 (s, 3H) 3.35 (m, 2H) 3.72 (m, 1H) 4.44 (m, 1H) 5.30 (m, 1H)
7.23 (d, J=8.48 Hz, 2H) 7.53 (d, J=8.48 Hz, 2H); MS:
(M+H).sup.+=527.
Example 28
[0318] ##STR52##
3,N-Dimethyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,-
13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-butyramide
[0319] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting isovaleryl
chloride for acetyl chloride. .sup.1H NMR (CDCl.sub.3): .delta.
0.98 (m, 12H) 1.00-2.60 (m, 23H) 2.84 (s, 3H) 2.87 (s, 3H) 3.04 (m,
2H) 3.58 (m, 1H) 4.43 (m, 1H) 5.38 (m, 1H), MS:
(M+H).sup.+=427.
Example 29
[0320] ##STR53##
Cyclopropanecarboxylic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0321] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting cyclopropane
carbonyl chloride for acetyl chloride. .sup.1H NMR (CDCl.sub.3):
.delta. 0.75 (m, 4H) 0.96 (s, 3H) 0.98 (s, 3H) 1.00-2.60 (m, 23H)
2.87 (s, 3H) 3.04 (s, 3H) 3.94 (m, 1H) 4.40 (m, 1H) 5.38 (m, 1H);
MS: (M+H).sup.+=411.
Example 30
[0322] ##STR54##
2-Methoxy-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,1-
1b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-acetami-
de
[0323] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting
methoxyacetyl chloride for acetyl chloride. .sup.1H NMR
(CDCl.sub.3): .delta. 0.95 (s, 3H) 1.00-2.60 (m, 28H) 2.87 (s, 3H)
3.01 (m, 1H) 3.43 (s, 3H) 4.09 (m, 2H) 4.38 (m, 1H) 5.36 (m, 1H);
MS: (M+H).sup.+=415.
Example 31
[0324] ##STR55##
N-Methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-h-
exadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-propionamide
[0325] The title compound was prepared according to the procedures
described in Reference Example 7C, except substituting propionyl
chloride for acetyl chloride. .sup.1H NMR (CDCl.sub.3): .delta.
0.95 (d, J=3.73 Hz, 3H) 1.03 (m, 2H) 1.14 (t, J=7.46 Hz, 3H)
1.20-2.60 (m, 28H) 2.85 (d, J=3.39 Hz, 3H) 3.54 (m, 1H) 4.41 (m,
1H) 5.38 (m, 1H); MS: (M+H).sup.+=399.
Example 32
[0326] ##STR56##
2-Isopropyl-4-methyl-thiazole-5-carboxylic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0327] A mixture of compound 7B (15 mg, 0.044 mmol),
2-isopropyl-4-methyl-thiazole-5-carboxylic acid (9.0 mg, 0.048
mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (13 mg, 0.066 mmol), 1-hydroxybenzotriazole (9.0 mg,
0.066 mmol) and dichloromethane (1 mL) was stirred at room
temperature overnight. The solvent was evaporated under reduced
pressure and the residue was dissolved in minimum amount of
dichloromethane and purified on silica gel column, which was eluted
with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to
give the desired product (13 mg, 59% yield). .sup.1H NMR
(CDCl.sub.3): .delta. 0.96 (s, 3H) 1.00-1.35 (m, 6H) 1.38 (d,
J=6.78 Hz, 6H) 1.55-2.35 (m, 21H) 2.39 (s, 3H) 2.59 (m, 2H) 2.95
(s, 3H) 3.26 (m, 2H) 5.37 (m, 1H); MS: (M+H).sup.+=510.
Example 33
[0328] ##STR57##
2-sec-Butyl-4-methyl-thiazole-5-carboxylic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0329] The title compound was prepared according to the procedures
described in Example 32, except substituting
2-sec-butyl-4-methyl-thiazole-5-carboxylic acid for
2-isopropyl-4-methyl-thiazole-5-carboxylic acid. .sup.1H NMR
(CDCl.sub.3): .delta. 0.95 (m, 9H) 1.16 (m, 9H) 1.39 (d, J=6.78 Hz,
3H) 1.60-2.60 (m, 21H) 3.08 (m, 6H) 5.40 (m, 1H); MS:
(M+H).sup.+=524.
Example 34
[0330] ##STR58##
2-Methyl-5-phenyl-furan-3-carboxylic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0331] The title compound was prepared according to the procedures
described in Example 32, except substituting
2-methyl-5-phenyl-furan-3-carboxylic acid for
2-isopropyl-4-methyl-thiazole-5-carboxylic acid. .sup.1H NMR
(CDCl.sub.3): .delta. 0.97 (s, 3H) 1.00-2.65 (m, 26H) 2.44 (s, 3H)
2.67 (m, 1H) 2.98 (s, 3H) 3.22 (m, 1H) 3.79 (m, 1H) 4.45 (m, 1H)
5.37 (m, 1H) 7.37 (m, 3H) 7.62 (m, 3H); MS: (M+H).sup.+=527.
Example 35
[0332] ##STR59##
N-Methyl-2-phenyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11-
b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-acetamid-
e
[0333] The title compound was prepared according to the procedures
described in Example 32, except substituting phenylacetic acid for
2-isopropyl-4-methyl-thiazole-5-carboxylic acid. MS:
(M+H).sup.+=461.
Example 36
[0334] ##STR60##
N-Methyl-2-thiophen-3-yl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11-
,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-a-
cetamide
[0335] The title compound was prepared according to the procedures
described in Example 32, except substituting 3-thiopheneacetic acid
for 2-isopropyl-4-methyl-thiazole-5-carboxylic acid. .sup.1H NMR
(CDCl.sub.3): .delta. 0.92 (s, 3H) 0.94 (s, 3H) 1.00-2.60 (m, 19H)
2.85 (d, J=4.07 Hz, 3H) 3.05 (m, 1H) 3.25 (m, 1H) 3.59 (m, 2H) 3.72
(d, J=9.49 Hz, 3H) 4.44 (m, 1H) 5.28 (m, 2H) 5.35 (m, 1H) 7.01 (d,
J=4.75 Hz, 1H) 7.06 (s, 1H) 7.28 (m, 1H); MS: (M+H).sup.+=467.
Example 37
[0336] ##STR61##
N-Methyl-4-thiophen-2-yl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11-
,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-b-
utyramide
[0337] The title compound was prepared according to the procedures
described in Example 32, except substituting 4-(2-thienyl)butyric
acid for 2-isopropyl-4-methyl-thiazole-5-carboxylic acid. .sup.1H
NMR (CDCl.sub.3): .delta. 0.94 (s, 3H) 1.00-2.60 (m, 29H) 2.81 (s,
3H) 2.84 (s, 3H) 2.91 (t, J=7.29 Hz, 2H) 3.44 (m, 1H) 4.38 (m, 1H)
5.35 (m, 1H) 6.80 (d, J=3.39 Hz, 1H) 6.92 (m, 1H) 7.11 (d, J=5.09
Hz, 1H); MS: (M+H).sup.+=495.
Example 38
[0338] ##STR62##
2-(3-Fluoro-phenyl)-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,1-
0,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-y-
l)-acetamide
[0339] The title compound was prepared according to the procedures
described in Example 32, except substituting 3-fluorophenylacetic
acid for 2-isopropyl-4-methyl-thiazole-5-carboxylic acid. .sup.1H
NMR (CDCl.sub.3): .delta. 7.25 (m, 1H), 6.95 (m, 3H), 5.30 (m, 1H),
4.40 (m, 1H), 3.68 (d, 3H), 2.80 (s, 3H), 0.90 d, 3H), 2.70-1.00
(m, 28H); MS: (M+H).sup.+=479.
Example 39
[0340] ##STR63##
N-Methyl-2-oxo-2-thiophen-2-yl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9-
,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-
-yl)-acetamide
[0341] The title compound was prepared according to the procedures
described in Example 32, except substituting 2-thiopheneglyoxylic
acid for 2-isopropyl-4-methyl-thiazole-5-carboxylic acid. .sup.1H
NMR (CDCl.sub.3): .delta. 7.79 (m, 2H), 7.20 (m, 1H), 5.35 (m, 1H),
4.40 (m, 1H), 3.02 (s, 3H), 2.90 (s, 3H), 0.93 (d, 3H), 2.60-1.00
(m, 26H); MS: (M+H).sup.+=481.
Example 40
[0342] ##STR64##
2-Indol-1-yl-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11-
a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-acet-
amide
[0343] The title compound was prepared according to the procedures
described in Example 32, except substituting indoleacetic acid for
2-isopropyl-4-methyl-thiazole-5-carboxylic acid. .sup.1H NMR
(CDCl.sub.3): .delta. 0.90 (s, 3H) 0.93 (s, 3H) 1.00-2.50 (m, 24H)
2.86 (d, J=2.03 Hz, 3H) 3.00 (m, 1H) 3.52 (m, 1H) 4.36 (m, 1H) 4.91
(d, J=10.17 Hz, 2H) 5.30 (m, 1H) 6.56 (s, 1H) 7.11 (m, 2H) 7.22 (m,
2H) 7.61 (m, 1H), MS: (M+H).sup.+=500.
Example 41
[0344] ##STR65##
2-Benzo[b]thiophen-3-yl-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8-
,9,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-
-9-yl)-acetamide
[0345] The title compound was prepared according to the procedures
described in Example 32, except substituting
benzo[b]thiophene-3-acetic acid for
2-isopropyl-4-methyl-thiazole-5-carboxylic acid. .sup.1H NMR
(CDCl.sub.3): .delta. 0.88 (s, 3H) 0.94 (s, 3H) 1.00-2.50 (m, 22H)
2.87 (d, J=4.41 Hz, 6H) 3.64 (m, 1H) 3.92 (d, J=12.54 Hz, 2H) 4.49
(m, 1H) 5.30 (m, 1H) 7.22 (m, 1H) 7.38 (m, 2H) 7.85 (m, 2H); MS:
(M+H).sup.+=517.
Example 42
[0346] ##STR66##
N-Methyl-2-(3-methyl-benzo[b]thiophen-2-yl)-N-(2,3,11a-trimethyl-2,3,3a,4,-
5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]-
phenanthren-9-yl)-acetamide
[0347] The title compound was prepared according to the procedures
described in Example 32, except substituting
3-methylbenzo[b]thiopheneacetic acid for
2-isopropyl-4-methyl-thiazole-5-carboxylic acid. .sup.1H NMR
(CDCl.sub.3): .delta. 0.92 (d, J=8.14 Hz, 3H) 1.00-2.50 (m, 25H)
2.36 (d, J=6.44 Hz, 3H) 2.86 (s, 3H) 2.93 (s, 3H) 3.65 (m, 1H) 3.94
(m, 2H) 4.37 (m, 1H) 5.30 (m, 1H) 7.32 (m, 2H) 7.62 (m, 1H) 7.74
(m, 1H); MS: (M+H).sup.+=531.
Example 43
[0348] ##STR67##
2-Furan-2-yl-N-methyl-2-oxo-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10-
,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl-
)-acetamide
[0349] The title compound was prepared according to the procedures
described in Example 32, except substituting 2-oxo-2-furanacetic
acid for 2-isopropyl-4-methyl-thiazole-5-carboxylic acid. .sup.1H
NMR (CDCl.sub.3): .delta. 0.95 (d, J=11.87 Hz, 3H) 1.00-2.60 (m,
26H) 2.91 (s, 3H) 3.00 (s, 3H) 4.38 (m, 1H) 5.30 (m, 1H) 6.60 (dd,
J=3.73, 1.70 Hz, 1H) 7.33 (t, J=3.39 Hz, 1H) 7.71 (s, 1H); MS:
(M+H).sup.+=465.
Example 44
[0350] ##STR68##
N-Methyl-3-thiophen-2-yl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11-
,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-p-
ropionamide
[0351] The title compound was prepared according to the procedures
described in Example 32, except substituting 3-(2-thienyl)propanoic
acid for 2-isopropyl-4-methyl-thiazole-5-carboxylic acid. .sup.1H
NMR (CDCl.sub.3): .delta. 0.94 (s, 3H) 1.00-2.60 (m, 25H) 2.66 (m,
2H) 2.83 (s, 3H) 2.86 (s, 3H) 3.20 (m, 2H) 3.53 (m, 1H) 4.40 (m,
1H) 5.34 (m, 1H) 6.83 (d, J=3.39 Hz, 1H) 6.92 (m, 1H) 7.12 (d,
J=5.42 Hz, 1H), MS: (M+H).sup.+=481.
Example 45
[0352] ##STR69##
3-Furan-2-yl-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11-
a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-prop-
ionamide
[0353] The title compound was prepared according to the procedures
described in Example 32, except substituting (2-furyl)propanoic
acid for 2-isopropyl-4-methyl-thiazole-5-carboxylic acid. .sup.1H
NMR (CDCl.sub.3): .delta. 0.95 (s, 3H) 1.00-2.55 (m, 25H) 2.64 (m,
2H) 2.83 (s, 3H) 2.86 (s, 3H) 3.00 (m, 2H) 3.54 (m, 1H) 4.40 (m,
1H) 5.35 (m, 1H) 6.03 (t, J=2.88 Hz, 1H) 6.28 (dd, J=3.22, 1.86 Hz,
1H) 7.30 (s, 1H); MS: (M+H).sup.+=465.
Example 46
[0354] ##STR70##
2-(3-Chloro-phenyl)-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,1-
0,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-y-
l)-acetamide
[0355] The title compound was prepared according to the procedures
described in Example 32, except substituting 3-chlorophenylacetic
acid for 2-isopropyl-4-methyl-thiazole-5-carboxylic acid. MS:
(M+H).sup.+=495/497.
Example 47
[0356] ##STR71##
2-(4-Chloro-phenyl)-N-methyl-N-(2,3,1a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10-
,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl-
)-acetamide
[0357] The title compound was prepared according to the procedures
described in Example 32, except substituting 4-chlorophenylacetic
acid for 2-isopropyl-4-methyl-thiazole-5-carboxylic acid. MS:
(M+H).sup.+=495/497.
Example 48
[0358] ##STR72##
2-(2-Fluoro-phenyl)-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,1-
0,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-y-
l)-acetamide
[0359] The title compound was prepared according to the procedures
described in Example 32, except substituting 2-fluorophenylacetic
acid for 2-isopropyl-4-methyl-thiazole-5-carboxylic acid. MS:
(M+H).sup.+=479.
Example 49
[0360] ##STR73##
2-(4-Fluoro-phenyl)-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,1-
0,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-y-
l)-acetamide
[0361] The title compound was prepared according to the procedures
described in Example 32, except substituting 4-fluorophenylacetic
acid for 2-isopropyl-4-methyl-thiazole-5-carboxylic acid. MS:
(M+H).sup.+=479.
Example 50
[0362] ##STR74##
N-Methyl-2-o-tolyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,1-
1b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-acetami-
de
[0363] The title compound was prepared according to the procedures
described in Example 32, except substituting o-tolylacetic acid for
2-isopropyl-4-methyl-thiazole-5-carboxylic acid. MS:
(M+H).sup.+=475.
Example 51
[0364] ##STR75##
Ethanesulfonic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0365] A mixture of compound 7B (15 mg, 0.044 mmol), ethanesulfonyl
chloride (5 .mu.L, 1.5 eq), triethylamine (15 .mu.L, 3.0 eq) and
dichloromethane (1 mL) was stirred at room temperature overnight.
The clear solution was directly loaded on silica gel column and
eluted with 0.5% ammonium hydroxide and 5% methanol in
dichloromethane to give the desired product (12.5 mg, 82%
yield)
[0366] .sup.1H NMR (CDCl.sub.3): .delta. 5.35 (m, 1H), 3.37 (m,
1H), 2.95 (q, 2H), 2.85 (s, 3H), 2.80 (d, 3H), 1.35 (t, 3H), 0.90
(s, 3H), 2.60-1.00 (m, 20H).
[0367] MS (DCI): (M+H).sup.+=435, (M+NH.sub.4).sup.+=452
Example 52
[0368] ##STR76##
N-Methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-h-
exadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-benzenesulfonamid-
e
[0369] The title compound was prepared according to the procedures
described in Example 51, except substituting benzenesulfonyl
chloride for ethanesulfonyl chloride. .sup.1H NMR (CDCl.sub.3):
.delta. 0.85 (s, 3H) 0.95 (m, 1H) 1.03 (d, 3H) 1.10-1.45 (m, 9H)
1.50-1.90 (m, 9H) 2.03 (m, 1H) 2.18 (s, 3H) 2.34 (m, 2H) 2.78 (s,
3H) 2.95 (m, 1H) 3.76 (m, 1H) 5.22 (m, 1H) 7.48 (m, 2H) 7.57 (m,
1H) 7.81 (m, 2H), MS: (M+H).sup.+=483, (M+NH.sub.4).sup.+=500.
Example 53
[0370] ##STR77##
4-Cyano-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b-
,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-benzenesu-
lfonamide
[0371] The title compound was prepared according to the procedures
described in Example 51, except substituting 4-cyanobenzenesulfonyl
chloride for ethanesulfonyl chloride. .sup.1H NMR (CDCl.sub.3):
.delta. 0.88 (s, 3H) 1.00-2.40 (m, 28H) 2.81 (s, 3H) 2.99 (m, 1H)
3.75 (m, 1H) 5.25 (m, 1H) 7.80 (m, 2H) 7.93 (m, 2H); MS:
(M+H).sup.+=508.
Example 54
[0372] ##STR78##
Thiophene-2-sulfonic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0373] The title compound was prepared according to the procedures
described in Example 51, except substituting thiophene-2-sulfonyl
chloride for ethanesulfonyl chloride. .sup.1H NMR (CDCl.sub.3):
.delta. 0.88 (s, 3H) 1.00-2.40 (m, 29H) 2.82 (s, 3H) 3.77 (m, 1H)
5.24 (m, 1H) 7.09 (m, 1H) 7.55 (m, 2H); MS: (M+H).sup.+=489.
Example 55
[0374] ##STR79##
4-Fluoro-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11-
b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-benzenes-
ulfonamide
[0375] The title compound was prepared according to the procedures
described in Example 51, except substituting
4-fluorobenzenesulfonyl chloride for ethanesulfonyl chloride.
.sup.1H NMR (CDCl.sub.3): .delta. 0.88 (s, 3H) 1.00-2.40 (m, 28H)
2.80 (s, 3H) 2.99 (m, 1H) 3.73 (m, 1H) 5.23 (m, 1H) 7.50 (m, 2H)
7.61 (m, 2H); MS: (M+H).sup.+=501.
Example 56
[0376] ##STR80##
1,1-Dimethyl-3-methyl-3-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11-
a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-sulf-
amide
[0377] The title compound was prepared according to the procedures
described in Example 51, except substituting dimethylsulfomoyl
chloride for ethanesulfonyl chloride. .sup.1H NMR (CDCl.sub.3):
.delta. 0.93 (s, 3H) 1.00-2.50 (m, 25H) 2.77 (m, 12H) 2.98 (m, 1H)
3.56 (m, 1H) 5.38 (m, 1H); MS: (M+H).sup.+=450.
Example 57
[0378] ##STR81##
Pyrrolidine-1-carboxylic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0379] A mixture of compound 7B (10.7 mg, 0.031 mmol),
1-pyrrolidinecarbonyl chloride (13 .mu.L, 3.0 eq), triethylamine
(26 .mu.L, 6.0 eq) and dichloromethane (1 mL) was stirred at room
temperature overnight. The clear solution was directly loaded on
silica gel column and eluted with 0.5% ammonium hydroxide and 5%
methanol in dichloromethane to give the desired product (12 mg, 87%
yield).
[0380] .sup.1H NMR (CDCl.sub.3): .delta. 5.30 (m, 1H), 3.65 (m,
2H), 3.30 (m, 4H), 2.70 (s, 3H), 0.90 (s, 3H), 2.85-1.00 (m,
32H).
[0381] MS: (M+H).sup.+=440
Example 58
[0382] ##STR82##
1,1-Diisopropyl-3-methyl-3-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11-
,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-u-
rea
[0383] The title compound was prepared according to the procedures
described in Example 57, except substituting diisopropylcarbamyl
chloride for 1-pyrrolidinecarbonyl chloride. .sup.1H NMR
(CDCl.sub.3): .delta. 0.91 (s, 3H) 0.98 (m, 2H) 1.26 (d, 12H)
1.30-2.60 (m, 22 H) 2.64 (s, 3H) 2.80 (d, J=4.75 Hz, 3H) 3.37 (m,
2H) 3.55 (m, 2H) 3.72 (m, 1H) 5.33 (m, 1H); MS:
(M+H).sup.+=470.
Example 59
[0384] ##STR83##
Morpholine-4-carboxylic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0385] The title compound was prepared according to the procedures
described in Example 57, except substituting 4-morpholinecarbonyl
chloride for 1-pyrrolidinecarbonyl chloride. .sup.1H NMR
(CDCl.sub.3): .delta. 0.95 (s, 3H) 1.00-2.50 (m, 28H) 2.77 (s, 3H)
2.97 (m, 1H) 3.20 (m, 4H) 3.55 (m, 1H) 3.69 (m, 4H) 5.36 (m, 1H);
MS: (M+H).sup.+=456.
Example 60
[0386] ##STR84##
1,1,3-Trimethyl-3-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,-
12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-urea
[0387] The title compound was prepared according to the procedures
described in Example 57, except substituting dimethylcarbamyl
chloride for 1-pyrrolidinecarbonyl chloride. .sup.1H NMR
(CDCl.sub.3): .delta. 0.95 (s, 3H) 1.00-2.50 (m, 28H) 2.72 (s, 3H)
2.78 (s, 6H) 2.98 (m, 1H) 3.47 (m, 1H) 5.35 (m, 1H); MS:
(M+H).sup.+=414.
Example 61
[0388] ##STR85##
Methyl-{2-methyl-1-[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11-
,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-c-
arbamoyl]-propyl}-carbamic acid tert-butyl ester
[0389] A mixture of compound 7B (240 mg, 0.702 mmol),
Boc-N-methyl-D-valine (176 mg, 0.762 mmol),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (208
mg, 1.085 mmol), 1-hydroxybenzotriazole (146 mg, 1.085 mmol),
dichloromethane (5 mL) and THF (2.5 mL) was stirred at room
temperature overnight. The solvent was evaporated under reduced
pressure and the residue was dissolved in minimum amount of
dichloromethane and purified on silica gel column, which was eluted
with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to
give the desired product (282 mg, 72% yield).
[0390] .sup.1H NMR (CDCl.sub.3): .delta. 0.89 (m, 12H) 1.00-1.40
(m, 11H) 1.46 (m, 9H) 1.50-2.60 (m, 12H) 2.74 (d 3H) 2.85 (d, 3H)
2.94 (d, 3H) 3.91 (m, 1H) 4.34 (m, 1H) 4.65 (m, 1H) 5.38 (m,
1H).
[0391] MS: (M+H).sup.+=556.
Example 62
[0392] ##STR86##
3,N-Dimethyl-2-methylamino-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,-
11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-
-butyramide
[0393] Compound 61 (250 mg, 0.45 mmol) was stirred with a mixture
of trifluoroacetic acid and dichloromethane (5 mL/5 mL) for 3
hours. Solvent was removed under reduced pressure, and the residue
was triturated with dichloromethane 3.times.. The residue was then
dissolved in ethyl acetate, stirred with sodium bicarbonate powder
for 5 min and filtered. The filtrate was concentrated and purified
on silica gel column, which was eluted with 0.5% ammonium hydroxide
and 5% methanol in dichloromethane to give the desired product (202
mg, 98% yield).
[0394] .sup.1H NMR (CDCl.sub.3): .delta. 0.95 (m, 12H) 1.00-2.20
(m, 19H) 2.25 (s, 3H) 2.29 (s, 3H) 2.40-2.80 (m, 3H) 2.91 (d, 3H)
3.05 (m, 3H) 3.65 (m, 1H) 4.48 (m, 1H) 5.38 (m, 1H).
[0395] MS: (M+H).sup.+=456.
Example 63
[0396] ##STR87##
2-(Acetyl-methyl-amino)-3,N-dimethyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b-
,6,8,9,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenant-
hren-9-yl)-butyramide
[0397] Compound 62 (11 mg, 0.024 mmol) was dissolved in 1 mL
dichloromethane. Then triethylamine (20 .mu.L, 6 eq) was added,
followed by acetyl chloride (5.2 .mu.L, 3 eq). The mixture was
stirred at room temperature overnight. The crude mixture was
purified on silica gel column which was eluted with 0.3% ammonium
hydroxide and 3% methanol in dichloromethane to give the desired
product (6 mg, 50% yield).
[0398] MS: (M+H).sup.+=498.
Example 64
[0399] ##STR88##
2-Amino-N-methyl-3-phenyl-N-(2,3,3a,11a-tetramethyl-2,3,3a,4,5,5a,5b,6,8,9-
,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-
-yl)-propionamide
[0400] The title compound was prepared according to the procedures
described in Example 61, except substituting Boc-D-phenylalanine
for Boc-N-Methyl-D-Valine and removing the BOC group as described
in Example 62. MS: (M+H).sup.+=490.
Example 65
[0401] ##STR89##
2-Amino-N-methyl-3-thiazol-4-yl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,-
9,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren--
9-yl)-propionamide
[0402] The title compound was prepared according to the procedures
described in Example 61, except substituting
Boc-D-4-thiazolylalanine for Boc-N-methyl-D-valine and removing the
BOC group as described in Example 62. MS: (M+H).sup.+=497.
Example 66
[0403] ##STR90##
2-Amino-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b-
,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-propionam-
ide
[0404] The title compound was prepared according to the procedures
described in Example 61, except substituting Boc-D-alanine for
Boc-N-methyl-D-valine and removing the BOC group as described in
Example 62. MS: (M+H).sup.+=414.
Example 67
[0405] ##STR91##
2-Amino-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b-
,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-butyramid-
e
[0406] The title compound was prepared according to the procedures
described in Example 61, except substituting Boc-D-ethylglycine for
Boc-N-methyl-D-valine and removing the BOC group as described in
Example 62. MS: (M+H).sup.+=428.
Example 68
[0407] ##STR92##
2-Amino-3-cyano-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11-
,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-p-
ropionamide
[0408] The title compound was prepared according to the procedures
described in Example 61, except substituting
Boc-.beta.-cyano-D-alanine for Boc-N-methyl-D-valine and removing
the BOC group as described in Example 62. MS: (M+H).sup.+=439.
Example 69
[0409] ##STR93##
2-Amino-N-methyl-3-thiophen-2-yl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8-
,9,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-
-9-yl)-propionamide
[0410] The title compound was prepared according to the procedures
described in Example 61, except substituting
Boc-.beta.-(2-thienyl)-D-alanine for Boc-N-methyl-D-valine and
removing the BOC group as described in Example 62. MS:
(M+H).sup.+=496.
Example 70
[0411] ##STR94##
4-Methyl-2-methylamino-pentanoic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]Phenanthren-9-yl)-amide
[0412] The title compound was prepared according to the procedures
described in Example 61, except substituting Boc-N-methyl-D-leucine
for Boc-N-methyl-D-valine and removing the BOC group as described
in Example 62. .sup.1H NMR (CDCl.sub.3): .delta. 0.95 (m, 6H)
1.00-2.90 (m, 38H) 2.96 (s, 3H) 3.37 (m, 1H) 3.90 (m, 1H) 4.25 (m,
1H) 5.39 (m, 1H); MS: (M+H).sup.+=470.
Example 71
[0413] ##STR95##
2-Amino-3-methyl-pentanoic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0414] The title compound was prepared according to the procedures
described in Example 61, except substituting Boc-D-isoleucine for
Boc-N-methyl-D-valine and removing the BOC group as described in
Example 62. .sup.1H NMR (CDCl.sub.3): .delta. 0.80-2.85 (m, 38H)
2.86 (s, 3H) 2.91 (s, 3H) 2.99 (m, 1H) 3.46 (m, 1H) 3.58 (m, 1H)
4.42 (m, 1H) 5.37 (m, 1H); MS: (M+H).sup.+=456.
Example 72
[0415] ##STR96##
2-Amino-3,N-dimethyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a-
,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-butyr-
amide
[0416] The title compound was prepared according to the procedures
described in Example 61, except substituting Boc-D-valine for
Boc-N-methyl-D-valine and removing the BOC group as described in
Example 62. MS: (M+H).sup.+=442.
Example 73
[0417] ##STR97##
2-Amino-3-methyl-pentanoic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0418] The title compound was prepared according to the procedures
described in Example 61, except substituting Boc-L-isoleucine for
Boc-N-methyl-D-valine and removing the BOC group as described in
Example 62. MS: (M+H).sup.+=456.
Example 74
[0419] ##STR98##
2-Amino-4-methyl-pentanoic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0420] The title compound was prepared according to the procedures
described in Example 61, except substituting Boc-L-leucine for
Boc-N-methyl-D-valine and removing the BOC group as described in
Example 62. MS: (M+H).sup.+=456.
Example 75
[0421] ##STR99##
2-Acetylamino-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,1-
1a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-but-
yramide
[0422] The title compound was prepared according to the procedures
described in Example 61, except substituting Boc-D-2-ethyl-glycine
for Boc-N-methyl-D-valine, and further treating according to the
procedures described in Example 62 and 63. MS: (M+H).sup.+=470.
Example 76
[0423] ##STR100##
2-Acetylamino-3-methyl-pentanoic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0424] The title compound was prepared according to the procedures
described in Example 61, except substituting Boc-D-isoleucine for
Boc-N-methyl-D-valine, and further treating according to the
procedures described in Example 62 and 63. MS: (M+H).sup.+=470.
.sup.1H NMR (CDCl.sub.3): .delta. 0.85-2.85 (m, 32H) 2.00 (d, 3H)
2.38 (m, 6H) 2.86 (s, 3H) 3.00 (s, 3H) 4.35 (m, 1H) 4.83 (m, 1H)
5.36 (m, 1H) 6.17 (m, 1H); MS: (M+H).sup.+=498.
Example 77
[0425] ##STR101##
2-Acetylamino-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,1-
1a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-pro-
pionamide
[0426] A mixture of compound 7B (15 mg, 0.044 mmol),
N-acetyl-D-alanine (7 mg, 0.053 mmol),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (13
mg, 0.068 mmol), 1-hydroxybenzotriazole (9 mg, 0.068 mmol),
dichloromethane (1 mL) and THF (0.5 mL) was stirred at room
temperature overnight. The solvent was evaporated under reduced
pressure and the residue was dissolved in minimum amount of
dichloromethane and purified on silica gel column which was eluted
with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to
give the desired product (13 mg, 65% yield).
[0427] .sup.1H NMR (CDCl.sub.3): .delta. 0.90-1.95 (m, 27H) 2.00
(s, 3H) 2.05-2.75 (m, 6H) 2.87 (s, 3H) 2.93 (s, 3H) 4.32 (m, 1H)
4.83 (m, 1H) 5.37 (m, 1H)
[0428] MS: (M+H).sup.+=456
Example 78
[0429] ##STR102##
2-Acetylamino-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,1-
1a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-pro-
pionamide
[0430] The title compound was prepared according to the procedures
described in Example 77, except substituting N-acetyl-L-alanine for
N-acetyl-D-alanine. .sup.1H NMR (CDCl.sub.3): .delta. 0.95 (m, 3H)
1.00-2.80 (m, 28H) 2.00 (s, 3H) 2.87 (s, 3H) 2.93 (s, 3H) 3.62 (m,
1H) 4.32 (m, 1H) 4.85 (m, 1H) 5.37 (m, 1H) 6.68 (m, 1H); MS:
(M+H).sup.+=456.
Example 79
[0431] ##STR103##
2-Acetylamino-N-methyl-3-phenyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,-
9,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren--
9-yl)-propionamide
[0432] The title compound was prepared according to the procedures
described in Example 77, except substituting
N-acetyl-D-phenylalanine for N-acetyl-D-alanine. .sup.1H NMR
(CDCl.sub.3): .delta. 0.89 (m, 3H) 1.04 (d, 3H) 1.05-1.50 (m, 7H)
1.50-1.90 (m, 9H) 1.97 (s, 3H) 2.07 (m, 2H) 2.20 (s, 3H) 2.34 (m,
2H) 2.49 (s, 3H) 2.78 (d, 2H) 2.98 (m, 2H) 3.39 (m, 1H) 4.27 (m,
1H) 5.15 (m, 1H) 5.37 (m, 1H) 6.41 (m, 1H) 7.22 (m, 5H). MS:
(M+H).sup.+=532.
Example 80
[0433] ##STR104##
2-Acetylamino-4-methyl-pentanoic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1.6a-a]phenanthren-9-yl)-amide
[0434] The title compound was prepared according to the procedures
described in Example 77, except substituting N-acetyl-L-leucine for
N-acetyl-D-alanine. .sup.1H NMR (CDCl.sub.3): .delta. 6.30 (m, 1H),
5.40 (m, 1H), 5.00 (m, 1H), 4.30 (m, 1H), 3.60 (m, 1H), 2.95 (s,
3H), 2.83 (s, 3H), 2.60-0.80 (m, 40H); MS: (M+H).sup.+=498.
Example 81
[0435] ##STR105##
2-Acetylamino-3,N-dimethyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,-
11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-
-butyramide
[0436] The title compound was prepared according to the procedures
described in Example 77, except substituting N-acetyl-D-valine for
N-acetyl-D-alanine. MS: (M+H).sup.+=484.
Example 82
[0437] ##STR106##
2-Acetylamino-3,N-dimethyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,-
11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-
-butyramide
[0438] The title compound was prepared according to the procedures
described in Example 77, except substituting N-acetyl-L-valine for
N-acetyl-D-alanine. MS: (M+H).sup.+=484.
Example 83
[0439] ##STR107##
2-Acetylamino-N-methyl-3-phenyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,-
9,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren--
9-yl)-propionamide
[0440] The title compound was prepared according to the procedures
described in Example 77, except substituting
N-acetyl-L-phenylalanine for N-acetyl-D-alanine. .sup.1H NMR
(CDCl.sub.3): .delta. 0.88 (m, 3H) 0.95-2.50 (m, 26H) 1.98 (s, 3H)
2.48 (s, 3H) 2.78 (s, 3 H) 2.97 (m, 2H) 4.27 (m, 1H) 5.15 (m, 1H)
5.30 (m, 1H) 6.39 (m, 1H) 7.20 (m, 5H); MS: (M+H).sup.+=532.
Example 84
[0441] ##STR108##
2-Acetylamino-N-methyl-3-thiophen-2-yl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,-
5b,6,8,9,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phena-
nthren-9-yl)-propionamide
[0442] The title compound was prepared according to the procedures
described in Example 77, except substituting
(S)-N-acetyl-2-(thien-2-yl)-alanine for N-acetyl-D-alanine. .sup.1H
NMR (CDCl.sub.3): .delta. 0.93 (m, 3H) 1.04 (d, 3H) 1.05-1.50 (m,
7H) 1.50-1.90 (m, 9H) 1.97 (s, 3H) 2.07 (m, 2H) 2.20 (s, 3H) 2.34
(m, 2H) 2.49 (s, 3H) 2.78 (d, 2H) 2.98 (m, 2H) 3.39 (m, 1H) 4.27
(m, 1H) 5.15 (m, 1H) 5.37 (m, 1H) 6.41 (m, 1H) 7.22 (m, 5H); MS:
(M+H).sup.+=538.
Example 85
[0443] ##STR109##
2-Acetylamino-4-methyl-pentanoic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0444] The title compound was prepared according to the procedures
described in Example 77, except substituting N-acetyl-D-leucine for
N-acetyl-D-alanine. .sup.1H NMR (CDCl.sub.3): .delta. 0.88-2.60 (m,
37H) 2.03 (s, 3H) 2.86 (s, 3H) 2.95 (s, 3H) 3.62 (m, 1H) 4.30 (m,
1H) 4.98 (m, 1H) 5.40 (m, 1H) 6.30 (m, 1H); MS:
(M+H).sup.+=498.
Example 86
[0445] ##STR110##
4-[Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-he-
xadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amino]-benzonitril-
e
[0446] Compound 7B (20 mg, 0.058 mmol), 4-bromobenzonitrile (16 mg,
0.088 mmol), tris(dibenzylideneacetone)dipallidium (2.1 mg, 0.0023
mmol), racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP)
(2.2 mg, 0.0035 mmol), cesium carbonate (29 mg, 0.088 mmol) and
toluene (1 mL) were mixed and heated at 100.degree. C. overnight.
The reaction mixture was cooled, quenched with water, and extracted
with dichloromethane 3.times.. Combined organic layer was dried
over sodium sulfate, filtered and concentrated to give the crude
product, which was then purified on silica gel column which was
eluted with 0.3% ammonium hydroxide and 3% methanol in
dichloromethane to give the desired product (12 mg, 46% yield).
[0447] .sup.1H NMR (CDCl.sub.3): .delta. 0.85-2.80 (m, 32H) 2.88
(s, 3H) 3.63 (m, 1H) 5.39 (m, 1H) 6.69 (d, J=8.80 Hz, 2H) 7.44 (d,
J=8.80 Hz, 2H)
[0448] MS: (M+H).sup.+=444
Example 87
[0449] ##STR111##
3-[Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-he-
xadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amino]-benzonitril-
e
[0450] The title compound was prepared according to the procedures
described in Example 86, except substituting 3-bromobenzonitrile
for 4-bromobenzonitrile. .sup.1H NMR (CDCl.sub.3): .delta. 0.99 (s,
3H) 1.05-2.50 (m, 28H) 2.83 (s, 3H) 3.00 (m, 1H) 3.55 (m, 1H) 5.38
(m, 1H) 6.92 (m, 2H) 7.25 (m, 2H)
[0451] MS: (M+H).sup.+=444
Example 88
[0452] ##STR112##
Methyl-thiazol-2-yl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11-
b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amine
[0453] The title compound was prepared according to the procedures
described in Example 86, except substituting 2-bromothiazole for
4-bromobenzonitrile. .sup.1H NMR (CDCl.sub.3): .delta. 0.99 (s, 3H)
1.03-2.55 (m, 29H) 3.00 (s, 3H) 3.85 (m, 1H) 5.40 (m, 1H) 6.46 (d,
J=3.39 Hz, 1H) 7.17 (d, J=3.39 Hz, 1H); MS: (M+H).sup.+=426.
Example 89
[0454] ##STR113##
1-{3-[Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-
-hexa
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amino]-phenyl}-
-ethanone
[0455] The title compound was prepared according to the procedures
described in Example 86, except substituting 2-bromoacetophenone
for 4-bromobenzonitrile. .sup.1H NMR (CDCl.sub.3): .delta. 0.97 (s,
3H) 1.04-2.60 (m, 28H) 2.83 (s, 3H) 2.87 (s, 3H) 2.00 (m, 1H) 3.15
(m, 1H) 5.40 (m, 1H) 7.30 (m, 3H) 8.13 (s, 1H); MS:
(M+H).sup.+=461.
Example 90
[0456] ##STR114##
1-{4-[Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-
-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amino]-phenyl}--
ethanone
[0457] The title compound was prepared according to the procedures
described in Example 86, except substituting 4-bromoacetophenone
for 4-bromobenzonitrile. MS (M+H).sup.+=461.
Example 91
[0458] ##STR115##
Acetic acid
1-[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-h-
exadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamoyl]-2-phen-
yl-ethyl ester
[0459] L-3-Phenyllactic acid (0.2 g, 1.2 mmol) was suspended in 3
mL of dichloromethane. Pyridine (0.234 mL, 2.89 mmol) was added and
the suspension became a clear solution. Acetyl chloride (0.103 mL,
1.4 mmol) was added dropwise at room temperature, the clear
solution became cloudy. The mixture was stirred at room temperature
for 4 hours, then quenched with 10% aqueous citric acid, extracted
with dichloromethane 3.times.. The combined organic layers were
dried over sodium sulfate, filtered, and the filtrate was
concentrated to give the crude L-2-acetoxy-3-phenyl-propionic acid,
which was used in the next step without purification.
[0460] A mixture of compound 7B (40 mg, 0.117 mmol),
L-2-acetoxy-3-phenyl-propionic acid (37 mg, 0.175 mmol),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (45
mg, 0.235 mmol), 1-hydroxybenzotriazole (32 mg, 0.235 mmol) and
dichloromethane (1.5 mL) was stirred at room temperature overnight.
The solvent was evaporated under reduced pressure and the residue
was dissolved in minimum amount of dichloromethane and purified on
silica gel column which was eluted with 0.3% ammonium hydroxide and
3% methanol in dichloromethane to give the desired product (50 mg,
81% yield).
[0461] .sup.1H NMR (CDCl.sub.3): .delta. 0.89 (d, 3H) 0.95-1.90 (m,
18H) 2.08 (s, 3H) 2.18 (m, 3H) 2.38 (m, 2H) 2.64 (s, 3H) 2.79 (s,
3H) 2.97 (m, 1H) 3.10 (m, 2H) 3.37 (m, 1H) 4.32 (m, 1H) 5.35 (m,
2H) 5.52 (m, 1H) 7.27 (m, 5H)
[0462] MS: (M+H).sup.+=533
Example 92
[0463] ##STR116##
2-Hydroxy-N-methyl-3-phenyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10-
,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl-
)-propionamide
[0464] Potassium carbonate (51 mg, 0.37 mmol) in 0.5 mL water was
added to Compound 91 (36 mg, 0.073 mmol) in 1 mL methanol. The
mixture was stirred at room temperature for 4 hours, then quenched
with 1 mL water and extracted with dichloromethane to give the
crude product which was purified on silica gel column and eluted
with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to
give the desired product (25 mg, 76% yield).
[0465] .sup.1H NMR (CDCl.sub.3): .delta. 0.93 (s, 3H) 1.00-2.60 (m,
25H) 2.66 (s, 3H) 2.89 (m, 4H) 3.36 (m, 1H) 3.76 (m, 1H) 4.32 (m,
1H) 4.57 (m, 2H) 5.38 (m, 1H) 7.25 (m, 5H)
[0466] MS: (M+H).sup.+=491
Example 93
[0467] ##STR117##
Acetic acid
1-[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-h-
exadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamoyl]-2-phen-
yl-ethyl ester
[0468] The title compound was prepared according to the procedures
described in Example 91, except substituting D-3-phenyllactic acid
for L-3-phenyllactic acid. .sup.1H NMR (CDCl.sub.3): .delta. 0.90
(d, J=5.09 Hz, 3H) 1.00-2.40 (m, 25H) 2.64 (s, 3H) 2.80 (s, 3H)
3.10 (m, 4H) 3.56 (m, 1H) 4.32 (m, 1H) 5.19 (m, 1H) 5.36 (m, 1H)
5.46 (m, 1H) 7.26 (m, 5H)
[0469] MS: (M+H).sup.+=533
Example 94
[0470] ##STR118##
2-Hydroxy-N-methyl-3-phenyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10-
,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl-
)-propionamide
[0471] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 93 for
compound 91. .sup.1H NMR (CDCl.sub.3): .delta. 0.95 (d, J=4.75 Hz,
3H) 1.03 (m, 3H) 1.14-2.50 (m, 22H) 2.66 (s, 3H) 2.92 (m, 5H) 3.41
(m, 1H) 3.79 (dd, J=8.14, 2.71 Hz, 1H) 4.31 (m, 1H) 4.54 (m, 1H)
5.37 (m, 1H) 7.26 (m, 5H)
[0472] MS: (M+H).sup.+=491
Example 95
[0473] ##STR119##
Acetic acid
3-methyl-1-[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11-
b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamoy-
l]-butyl ester
[0474] The title compound was prepared according to the procedures
described in Example 91, except substituting 2-hydroxyisocaproic
acid for L-3-phenyllactic acid. MS: (M+H).sup.+=499
Example 96
[0475] ##STR120##
2-Hydroxy-4-methyl-pentanoic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0476] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 95 for
compound 91. MS: (M+H).sup.+=457
Example 97
[0477] ##STR121##
[0478] Acetic acid
2-methyl-1-[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11-
b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamoy-
l]-propyl ester
[0479] The title compound was prepared according to the procedures
described in Example 91, except substituting
2-hydroxy-3-methylbutyric acid for L-3-phenyllactic acid. .sup.1H
NMR (CDCl.sub.3): .delta. 0.95-2.75 (m, 34H) 2.12 (s, 3H) 2.86 (s,
3H) 3.00 (s, 3H) 3.71 (m, 1H) 4.39 (m, 1H) 4.97 (m, 1H) 5.08 (m,
1H) 5.36 (m, 1H)
[0480] MS: (M+H).sup.+=485
Example 98
[0481] ##STR122##
2-Hydroxy-3,N-dimethyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,1-
1a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-but-
yramide
[0482] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 97 for
compound 91. MS: (M+H).sup.+=443
Example 99
[0483] ##STR123##
Acetic acid
1-methyl-1-[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11-
b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamoy-
l]-propyl ester
[0484] The title compound was prepared according to the procedures
described in Example 91, except substituting
2-hydroxy-2-methylbutyric acid for L-3-phenyllactic acid. MS:
(M+H).sup.+=485
Example 100
[0485] ##STR124##
2-Hydroxy-2,N-dimethyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,1-
1a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-but-
yramide
[0486] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 99 for
compound 91. .sup.1H NMR (CDCl.sub.3): .delta. 0.96 (m, 3H)
1.05-2.60 (m, 33H) 2.84 (s, 3H) 2.87 (s, 3H) 2.98 (m, 1H) 3.50 (m,
1H) 4.42 (m, 1H) 5.37 (m, 1H)
[0487] MS: (M+H).sup.+=443
Example 101
[0488] ##STR125##
Acetic acid
1-[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-h-
exadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamoyl]-cyclop-
ropyl ester
[0489] The title compound was prepared according to the procedures
described in Example 91, except substituting
1-hydroxy-1-cyclopropanecarboxylic acid for L-3-phenyllactic acid.
MS: (M+H).sup.+=469
Example 102
[0490] ##STR126##
1-Hydroxy-cyclopropanecarboxylic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0491] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 101 for
compound 91. .sup.1H NMR (CDCl.sub.3): .delta. 0.78-2.60 (m, 31H)
2.87 (s, 3H) 2.91 (s, 3H) 3.01 (m, 1H) 3.72 (m, 1H) 4.21 (m, 1H)
4.35 (m, 1H) 5.38 (m, 1H)
[0492] MS: (M+H).sup.+=427
Example 103
[0493] ##STR127##
Acetic acid
1-[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-h-
exadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamoyl]-pentyl
ester
[0494] The title compound was prepared according to the procedures
described in Example 91, except substituting 2-hydroxycaproic acid
for L-3-phenyllactic acid. .sup.1H NMR (CDCl.sub.3): .delta.
0.91-2.60 (m, 37H) 2.12 (s, 3H) 2.86 (s, 3H) 2.95 (s, 3H) 3.58 (m,
1H) 4.35 (m, 1H) 5.24 (m, 1H) 5.36 (m, 1H)
[0495] MS: (M+H).sup.+=499
Example 104
[0496] ##STR128##
2-Hydroxy-hexanoic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0497] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 103 for
compound 91. .sup.1H NMR (CDCl.sub.3): .delta. 0.88-2.60 (m, 37H)
2.85 (s, 3H) 2.90 (s, 3H) 2.99 (m, 1H) 3.35 (m, 1H) 3.83 (m, 1H)
4.33 (m, 1H) 5.38 (m, 1H)
[0498] MS: (M+H).sup.+=457
Example 105
[0499] ##STR129##
Acetic acid
[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hex-
adecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamoyl]-phenyl-m-
ethyl ester
[0500] The title compound was prepared according to the procedures
described in Example 91, except substituting DL-mandelic acid for
L-3-phenyllactic acid. MS: (M+H).sup.+=519
Example 106
[0501] ##STR130##
2-Hydroxy-N-methyl-2-phenyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10-
,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl-
)-acetamide
[0502] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 105 for
compound 91. MS: (M+H).sup.+=477
Example 107
[0503] ##STR131##
Acetic acid
2,2,2-trifluoro-1-[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11-
,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-c-
arbamoyl]-ethyl ester
[0504] The title compound was prepared according to the procedures
described in Example 91, except substituting
3,3,3-trifluoro-2-hydroxypropanoic acid for L-3-phenyllactic acid.
MS: (M+H).sup.+=511, (M+NH.sup.4).sup.+=528
Example 108
[0505] ##STR132##
3,3,3-Trifluoro-2-hydroxy-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6-
,8,9,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthr-
en-9-yl)-propionamide
[0506] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 107 for
compound 91. .sup.1H NMR (CDCl.sub.3): .delta. 0.97 (s, 3H)
1.05-2.60 (m, 26H) 2.95 (s, 3H) 2.99 (s, 3H) 3.42 (m, 1H) 4.43 (m,
1H) 4.76 (m, 1H) 5.40 (m, 1H)
[0507] MS: (M+H).sup.+=469, (M+NH.sup.4).sup.+=486
Example 109
[0508] ##STR133##
Acetic acid
(4-fluoro-phenyl)-[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11-
,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-c-
arbamoyl]-methyl ester
[0509] The title compound was prepared according to the procedures
described in Example 91, except substituting 4-fluoromandelic acid
for L-3-phenyllactic acid. .sup.1H NMR (CDCl.sub.3): .delta. 0.92
(m, 3H) 1.00-2.60 (m, 23H) 2.16 (s, 3H) 2.79 (s, 3H) 2.85 (s, 3H)
3.00 (m, 1H) 3.52 (m, 1H) 4.32 (m, 1H) 4.90 (m, 1H) 5.38 (m, 1H)
6.18 (m, 1H) 7.08 (m, 2H) 7.43 (m, 2H)
[0510] MS: (M+H).sup.+=537
Example 110
[0511] ##STR134##
2-(4-Fluoro-phenyl)-2-hydroxy-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,-
5b,6,8,9,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phena-
nthren-9-yl)-acetamide
[0512] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 109 for
compound 91. .sup.1H NMR (CDCl.sub.3): .delta. 0.86 (s, 3H)
1.00-2.50 (m, 25H) 2.62 (s, 3H) 2.91 (s, 3H) 3.30 (m, 1H) 4.82 (m,
1H) 4.97 (m, 1H) 5.15 (m, 1H) 5.38 (m, 1H) 7.04 (m, 2H) 7.28 (m,
2H)
[0513] MS: (M+H).sup.+=495
Example 111
[0514] ##STR135##
Acetic acid
(4-methoxy-phenyl)-[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,1-
1,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)--
carbamoyl]-methyl ester
[0515] The title compound was prepared according to the procedures
described in Example 91, except substituting 4-methoxymandelic acid
for L-3-phenyllactic acid. .sup.1H NMR (CDCl.sub.3): .delta. 0.89
(d, J=9.83 Hz, 3H) 1.00-2.60 (m, 24H) 2.15 (s, 3H) 2.76 (s, 3H)
2.85 (s, 3H) 2.96 (m, 1H) 3.55 (m, 1H) 3.82 (s, 3H) 4.39 (m, 1H)
5.40 (m, 1H) 6.14 (m, 1H) 6.90 (m, 2H) 7.36 (m, 2H)
[0516] MS: (M+H).sup.+=549
Example 112
[0517] ##STR136##
2-Hydroxy-2-(4-methoxy-phenyl)-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a-
,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phen-
anthren-9-yl)-acetamide
[0518] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 111 for
compound 91. .sup.1H NMR (CDCl.sub.3): .delta. 0.85 (s, 3H) 0.92
(s, 3H) 1.04-2.60 (m, 21H) 2.62 (s, 3H) 2.90 (s, 3H) 2.97 (m, 1H)
3.42 (m, 1H) 3.81 (s, 3H) 4.77 (m, 1H) 4.92 (m, 1H) 5.13 (m, 1H)
5.38 (m, 1H) 6.88 (m, 2H) 7.23 (m, 2H)
[0519] MS: (M+H).sup.+=507
Example 113
[0520] ##STR137##
Acetic acid
(3,4-difluoro-phenyl)-[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,1-
0,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-y-
l)-carbamoyl]-methyl ester
[0521] The title compound was prepared according to the procedures
described in Example 91, except substituting 3,3-difluoromandelic
acid for L-3-phenyllactic acid. .sup.1H NMR (CDCl.sub.3): .delta.
0.91 (d, J=6.10 Hz, 3H) 1.00-2.60 (m, 28H) 2.16 (s, 3H) 2.85 (m,
3H) 2.98 (m, 1H) 4.34 (m, 1H) 5.38 (m, 1H) 6.14 (m, 1H) 7.18 (m,
2H) 7.34 (m, 1H)
[0522] MS: (M+H).sup.+=555
Example 114
[0523] ##STR138##
2-(3,4-Difluoro-phenyl)-2-hydroxy-N-methyl-N-(2,3,11a-trimethyl-2,3,3a,4,5-
,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]p-
henanthren-9-yl)-acetamide
[0524] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 113 for
compound 91. .sup.1H NMR (CDCl.sub.3): .delta. 0.87 (s, 3H) 0.93
(s, 3H) 1.05-2.55 (m, 20H) 2.65 (s, 3H) 2.91 (s, 3H) 2.98 (m, 1H)
3.33 (m, 1H) 4.38 (m, 1H) 4.82 (m, 1H) 4.98 (m, 1H) 5.13 (m, 1H)
5.39 (m, 1H) 7.14 (m, 3H)
[0525] MS: (M+H).sup.+=513
Example 115
[0526] ##STR139##
Acetic acid
[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hex-
adecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamoyl]-phenyl-m-
ethyl ester
[0527] The title compound was prepared according to the procedures
described in Example 91, except substituting (S)-(+)-mandelic acid
for L-3-phenyllactic acid. .sup.1H NMR (CDCl.sub.3): .delta.
0.88-2.50 (m, 29H) 2.78 (s, 3H) 2.85 (s, 3H) 2.95 (t, J=9.05 Hz,
2H) 3.56 (m, 1H) 4.37 (m, 1H) 5.38 (m, 1H) 6.20 (m, 1H) 7.41 (m,
5H)
[0528] MS: (M+H).sup.+=519
Example 116
[0529] ##STR140##
2-Hydroxy-N-methyl-2-phenyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10-
,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl-
)-acetamide
[0530] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 115 for
compound 91. .sup.1H NMR (CDCl.sub.3): .delta. 0.85 (s, 3H) 1.03
(d, J=6.44 Hz, 3H) 1.05-2.50 (m, 19H) 2.62 (s, 3H) 2.90 (s, 3H)
2.95 (m, 2H) 3.42 (m, 1H) 4.41 (m, 1H) 4.75 (m, 1H) 4.96 (m, 1H)
5.18 (m, 1H) 5.40 (m, 1H) 7.32 (m, 5H)
[0531] MS: (M+H).sup.+=477
Example 117
[0532] ##STR141##
Acetic acid
[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hex-
adecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamoyl]-phenyl-m-
ethyl ester
[0533] The title compound was prepared according to the procedures
described in Example 91, except substituting (R)-(-)-mandelic acid
for L-3-phenyllactic acid. .sup.1H NMR (CDCl.sub.3): .delta. 0.88
(d, J=11.19 Hz, 3H) 1.00-2.60 (m, 24H) 2.17 (s, 3H) 2.78 (s, 3H)
2.85 (s, 3H) 3.26 (m, 1H) 3.62 (m, 1H) 4.37 (m, 1H) 5.37 (m, 1H)
6.16 (d, J=4.07 Hz, 1H) 7.41 (m, 5H)
[0534] MS: (M+H).sup.+=519
Example 118
[0535] ##STR142##
2-Hydroxy-N-methyl-2-phenyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10-
,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl-
)-acetamide
[0536] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 117 for
compound 91. .sup.1H NMR (CDCl.sub.3): .delta. 0.85 (s, 3H) 1.03
(d, J=6.24 Hz, 3H) 1.10-2.50 (m, 16H) 2.19 (s, 3H) 2.62 (s, 3H)
2.90 (s, 3H) 2.95 (m, 2H) 3.42 (m, 1H) 4.41 (m, 1H) 4.74 (m, 1H)
4.98 (m, 1H) 5.19 (m, 1H) 5.39 (m, 1H) 7.32 (m, 5H)
[0537] MS: (M+H).sup.+=477
Example 119
[0538] ##STR143##
Acetic acid
3-methyl-1-[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11-
b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamoy-
l]-butyl ester
[0539] The title compound was prepared according to the procedures
described in Example 91, except substituting
(S)-(-)-2-hydroxyisocaproic acid for L-3-phenyllactic acid. .sup.1H
NMR (CDCl.sub.3): .delta. 0.90-2.60 (m, 33H) 2.11 (s, 3H) 2.41 (m,
3H) 2.85 (s, 3H) 2.93 (s, 3H) 2.94 (m, 1H) 3.53 (m, 1H) 4.34 (m,
1H) 5.33 (m, 2H)
[0540] MS: (M+H).sup.+=499
Example 120
[0541] ##STR144##
2-Hydroxy-4-methyl-pentanoic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0542] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 119 for
compound 91. .sup.1H NMR (CDCl.sub.3): .delta. 0.92-2.60 (m, 38H)
2.84 (s, 3H) 2.90 (s, 3H) 2.95 (m, 1H) 3.75 (m, 1H) 4.34 (m, 1H)
5.38 (m, 1H)
[0543] MS: (M+H).sup.+=457
Example 121
[0544] ##STR145##
Acetic acid
3-methyl-1-[methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11-
b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamoy-
l]-butyl ester
[0545] The title compound was prepared according to the procedures
described in Example 91, except substituting
(R)-(+)-2-hydroxyisocaproic acid for L-3-phenyllactic acid. .sup.1H
NMR (CDCl.sub.3): .delta. 0.92-2.65 (m, 33H) 2.11 (s, 3H) 2.42 (m,
3H) 2.85 (s, 3H) 2.94 (s, 3H) 3.02 (m, 1H) 3.60 (m, 1H) 4.34 (m,
1H) 5.31 (m, 2H)
[0546] MS: (M+H).sup.+=499
Example 122
[0547] ##STR146##
2-Hydroxy-4-methyl-pentanoic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0548] The title compound was prepared according to the procedures
described in Example 92, except substituting compound 121 for
compound 91. .sup.1H NMR (CDCl.sub.3): .delta. 0.94-2.60 (m, 38H)
2.84 (s, 3H) 2.89 (s, 3H) 2.95 (m, 1H) 3.75 (m, 1H) 4.34 (m, 1H)
5.40 (m, 1H)
[0549] MS: (M+H).sup.+=457
Example 123
[0550] ##STR147##
2-Methoxy-N-methyl-2-phenyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10-
,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl-
)-acetamide
[0551] A mixture of compound 7B (30 mg, 0.088 mmol),
R-(-)-.alpha.-methoxyphenylacetic acid (22 mg, 0.132 mmol),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (34
mg, 0.177 mmol), 1-hydroxybenzotriazole (24 mg, 0.177 mmol) and
dichloromethane (1 mL) was stirred at room temperature overnight.
The solvent was evaporated under reduced pressure and the residue
was dissolved in minimum amount of dichloromethane and purified on
silica gel column which was eluted with 0.3% ammonium hydroxide and
3% methanol in dichloromethane to give the desired product (40 mg,
93% yield).
[0552] .sup.1H NMR (CDCl.sub.3): .delta. 0.86 (s, 3H) 0.91 (s, 3H)
1.06-2.50 (m, 20H) 2.74 (s, 3H) 2.84 (s, 3H) 3.04 (m, 1H) 3.45 (s,
3H) 3.78 (m, 1H) 4.41 (m, 1H) 5.02 (d, J=13.22 Hz, 2H) 5.37 (m, 1H)
7.36 (m, 5H)
[0553] MS: (M+H).sup.+=491
Example 124
[0554] ##STR148##
2-Methoxy-N-methyl-2-phenyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10-
,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl-
)-acetamide
[0555] The title compound was prepared according to the procedures
described in Example 123, except substituting 2-methoxyphenylacetic
acid for R-(-)-.alpha.-methoxyphenylacetic acid. .sup.1H NMR
(CDCl.sub.3): .delta. 0.86 (s, 3H) 0.91 (s, 3H) 1.00-2.40 (m, 20H)
2.74 (s, 3H) 2.84 (s, 3H) 2.96 (m, 1H) 3.74 (m, 3H) 3.78 (m, 1H)
4.40 (m, 1H) 5.02 (d, J=11.87 Hz, 2H) 5.37 (m, 1H) 7.36 (m, 5H);
MS: (M+H).sup.+=491.
Example 125
[0556] ##STR149##
2-Methoxy-N-methyl-2-phenyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10-
,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl-
)-acetamide
[0557] The title compound was prepared according to the procedures
described in Example 123, except substituting
(S)-(+)-.alpha.-methoxyphenylacetic acid for
R-(-)-.alpha.-methoxyphenylacetic acid. .sup.1H NMR (CDCl.sub.3):
.delta. 0.86 (s, 3H) 0.91 (s, 3H) 1.06-2.50 (m, 20H) 2.74 (s, 3H)
2.84 (s, 3H) 3.01 (m, 1H) 3.46 (s, 3H) 3.76 (m, 1H) 4.39 (m, 1H)
5.02 (d, J=11.87 Hz, 2H) 5.37 (m, 1H) 7.36 (m, 5H); MS:
(M+H).sup.+=491.
Example 126
[0558] ##STR150##
2-Methoxy-hexanoic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0559] 2-Hydroxy caproic acid (152 mg, 1.15 mmol) was dissolved in
3 mL anhydrous THF. Sodium hydride (95%, 61 mg, 2.41 mmol) was
added and the mixture was stirred at room temperature for 40 min.
Iodomethane (0.7 mL) was added and the mixture was stirred at room
temperature overnight. It was quenched with water, stirred for 4
hours to hydrolyze the methyl ester, and then adjusted to pH 4 with
10% citric acid. The mixture was extracted with 5% methanol in
dichloromethane, organic layer dried over sodium sulfate, filtered,
and the filtrate was concentrated to give the crude 2-methoxy
caproic acid which was used in next step without further
purification.
[0560] A mixture of compound 7B (30 mg, 0.088 mmol), 2-methoxy
caproic acid (20 mg, 0.137 mmol),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (34
mg, 0.177 mmol), 1-hydroxybenzotriazole (24 mg, 0.177 mmol) and
dichloromethane (1 mL) was stirred at room temperature overnight.
The solvent was evaporated under reduced pressure and the residue
was dissolved in minimum amount of dichloromethane and purified on
silica gel column, which was eluted with 0.3% ammonium hydroxide
and 3% methanol in dichloromethane to give the desired product (38
mg, 92% yield).
[0561] .sup.1H NMR (CDCl.sub.3): .delta. 0.88-2.75 (m, 37H) 2.87
(s, 3H) 2.98 (s, 3H) 3.31 (s, 3H) 3.99 (m, 2H) 4.40 (m, 1H) 5.37
(m, 1H)
[0562] MS: (M+H).sup.+=471
Example 127
[0563] ##STR151##
2-Methoxy-4-methyl-pentanoic acid
methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexa-
decahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-amide
[0564] The title compound was prepared according to procedures
described in Example 126, except substituting 2-hydroxyisocaproic
acid for 2-hydroxy caproic acid. .sup.1H NMR (CDCl.sub.3): .delta.
0.91-2.60 (m, 37H) 2.86 (s, 3H) 2.97 (s, 3H) 3.32 (d, J=5.43 Hz,
3H) 3.91 (m, 1H) 4.06 (dd, J=9.32, 4.24 Hz, 1H) 4.40 (m, 1H) 5.37
(m, 1H); MS: (M+H).sup.+=471.
Example 128
[0565] ##STR152##
2-Methoxy-N-methyl-3-phenyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10-
,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl-
)-propionamide
[0566] The title compound was prepared according to procedures
described in Example 126, except substituting L-3-phenyllactic acid
for 2-hydroxy caproic acid. .sup.1H NMR (CDCl.sub.3): .delta. 0.93
(m, 3H) 1.04 (d, J=6.24 Hz, 3H) 1.10-2.60 (m, 18H) 2.72 (s, 3H)
2.83 (s, 3H) 3.02 (m, 6H) 3.31 (d, J=3.43 Hz, 3H) 3.61 (m, 1H) 4.29
(m, 1H) 4.40 (m, 1H) 5.35 (m, 1H) 7.24 (m, 5H); MS:
(M+H).sup.+=505.
Example 129
[0567] ##STR153##
2-Methoxy-3,N-dimethyl-N-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,1-
1a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-but-
yramide
[0568] The title compound was prepared according to procedures
described in Example 126, except substituting
2-hydroxy-3-methylbutyric acid for 2-hydroxy caproic acid. .sup.1H
NMR (CDCl.sub.3): .delta. 0.89-2.65 (m, 35H) 2.88 (s, 3H) 3.00 (s,
3H) 3.32 (s, 3H) 3.64 (m, 1H) 4.01 (m, 1H) 4.42 (m, 1H) 5.36 (m,
1H); MS: (M+H).sup.+=457.
Example 130
[0569] ##STR154##
130A.
2,3,11a-Trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadec-
ahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-ol
[0570] The title compound was prepared according to the procedure
of Hora and Cerny; Collect. Czech. Chem. Commun. 26,1961, 2217 and
Labler et al.; and Collect. Czech. Chem. Commun., 28, 1963, 2015.
.sup.1H NMR (CDCl.sub.3): .delta. 0.95 (s, 3H) 1.00-1.50 (m, 12H)
1.50-2.00 (m, 10H) 2.07 (m, 1H) 2.26 (m, 5H) 2.45 (m, 1H) 3.05 (m,
1H) 3.52 (m, 1H) 5.34 (m, 1H); MS: (M+H).sup.+=330. ##STR155##
130B.
2,3,11a-Trimethyl-1,2,3,3a,4,5,5a,5b,6,8,10,11,11a,11b,12,13-hexadec-
ahydro-2-aza-pentaleno[1,6a-a]phenanthren-9-one
[0571] A mixture of Compound 130A (200 mg, 0.607 mmol) Dess-Martin
periodinane (386 mg, 0.91 mmol) and dichloromethane (10 mL) was
stirred at room temperature for 4.5 hours. The reaction was
quenched with 10% sodium thiosulfate and extracted with
dichloromethane. Organic layer was dried over sodium sulfate,
filtered, and the filtrate was concentrated under reduced pressure
to give the crude product, which was purified on silica gel column
eluted with 0.3% ammonium hydroxide and 3% methanol in
dichloromethane to give the desired product (156 mg, 83%
yield).
[0572] .sup.1H NMR (CDCl.sub.3): .delta. 1.13 (s, 3H) 1.20-2.80 (m,
23H) 2.73 (s, 3H) 3.26 (m, 2H) 3.88 (m, 1H) 5.35 (m, 1H)
[0573] MS: (M+H).sup.+=328 ##STR156##
130C.
9-Ethylidene-2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,-
12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthrene
[0574] Potassium t-butoxide (1.0M in THF, 0.3 mL, 0.30 mmol) was
added dropwise to a stirred solution of ethyl triphenylphosphonium
bromide (156 mg, 0.42 mmol) in 2 mL anhydrous toluene. A bright
orange suspension resulted and was stirred at room temperature for
5 hours. Compound 130B (25 mg, 0.076 mmol) in 1 mL THF was added to
the above suspension and stirred overnight. The reaction was
quenched with saturated ammonium chloride and extracted with
dichloromethane to give the crude product, which was purified on
silica gel column eluted with 0.3% ammonium hydroxide and 3%
methanol in dichloromethane to give the desired product (12 mg, 46%
yield).
[0575] .sup.1H NMR (CDCl.sub.3): (0.80-2.60 (m, 34H) 2.98 (m, 1H)
5.23 (m, 1H) 5.71 (m, 1H)
[0576] MS: (M+H).sup.+=340
Example 131
[0577] ##STR157##
9-Isopropylidene-2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12-
,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthrene
[0578] The title compound was prepared according to procedures
described in Example 130C. except substituting
isopropyltriphenylphosphonium iodide for ethyl triphenylphosphonium
bromide; MS: (M+H).sup.+=354.
Reference Example 132
[0579] ##STR158##
9-Methoxy-2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hex-
adecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthrene
[0580] Compound 130A (30 mg, 0.091 mmol) was dissolved in 1.5 mL
anhydrous DMF. Sodium hydride (60% dispersion in mineral oil, 6 mg,
0.137 mmol) was added and the mixture was stirred at room
temperature for 1 hour before iodomethane (39 mg, 0.274 mmol) was
added. The reaction mixture and stirred overnight, quenched with
water and extracted with dichloromethane to give the crude product,
which was purified on silica gel column eluted with 0.3% ammonium
hydroxide and 5% methanol in dichloromethane to give the desired
product (12 mg, 38% yield).
[0581] .sup.1H NMR (CDCl.sub.3): .delta. 0.95 (s, 3H) 1.01-2.25 (m,
263H) 2.38 (m, 2H) 3.05 (m, 2H) 3.36 (s, 3H) 5.37 (m, 1H)
[0582] MS: (M+H).sup.+=344
Example 133
[0583] ##STR159##
9-Benzyloxy-2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-h-
exadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthrene
[0584] The title compound was prepared according to procedures
described in Reference Example 132, except substituting benzyl
bromide for iodomethane. .sup.1H NMR (CDCl.sub.3): .delta. ppm 0.96
(s, 3H) 1.04 (d, 3H) 1.06-2.00 (m, 18H) 2.08 (m, 1H) 2.20 (s, 3H)
2.36 (m, 3H) 2.99 (m, 1H) 3.28 (m, 1H) 4.55 (s, 2H) 5.36 (m, 1H)
7.25 (m, 2H) 7.34 (m, 3H), MS: (M+H).sup.+=420.
Example 134
[0585] ##STR160##
Acetic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0586] Compound 130A (15 mg, 0.045 mmol) was dissolved in 1 mL
anhydrous dichloromethane. Triethylamine (32 .mu.L, 0.228 mmol) was
added followed by acetyl chloride (6.5 .mu.L, 0.09 mmol). The
mixture was stirred at room temperature overnight. The crude
product was purified on silica gel column eluted with 0.3% ammonium
hydroxide and 3% methanol in dichloromethane to give the desired
product (23 mg, 68% yield).
[0587] .sup.1H NMR (CDCl.sub.3): .delta. 0.96 (s, 3H) 1.03-1.90 (m,
23H) 2.04 (s, 3H) 2.20-2.35 (m, 5H) 2.98 (m, 1H) 4.59 (m, 1H) 5.39
m, 1H)
[0588] MS: (M+H).sup.+=372
Example 135
[0589] ##STR161##
Benzoic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0590] The title compound was prepared according to procedures
described in Example 134, except substituting benzoyl chloride for
acetyl chloride. MS: (M+H).sup.+=434.
Example 136
[0591] ##STR162##
Thiophen-2-yl-acetic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0592] The title compound was prepared according to procedures
described in Example 134, except substituting 2-thiopheneacetyl
chloride for acetyl chloride. .sup.1H NMR (CDCl.sub.3): .delta.
0.90 (s, 3H) 0.96 (d, J=3.73 Hz, 3H) 1.00-2.40 (m, 27H) 3.00 (m,
1H) 4.66 (m, 1H) 5.37 (m, 1H) 6.94 (m, 2H) 7.21 (m, 1H); MS:
(M+H).sup.+=454.
Example 137
[0593] ##STR163##
4-Cyano-benzoic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0594] The title compound was prepared according to procedures
described in Example 134, except substituting 4-cyanobenzoyl
chloride for acetyl chloride. .sup.1H NMR (CDCl.sub.3): .delta.
1.01 (s, 3H) 1.04-2.30 (m, 25H) 2.47 (d, 3H) 3.00 (m, 1H) 4.87 (m,
1H) 5.44 (m, 1H) 7.74 (m, 2H) 8.14 (m, 2H); MS:
(M+H).sup.+=459.
Example 138
[0595] ##STR164##
3-Methyl-butyric acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0596] The title compound was prepared according to procedures
described in Example 134, except substituting isovaleryl chloride
for acetyl chloride. .sup.1H NMR (CDCl.sub.3): .delta. 0.95 (d, 9H)
1.00-2.35 (m, 31H) 3.00 (m, 1H) 4.62 (m, 1H) 5.39 (m, 1H); MS:
(M+H).sup.+=414.
Example 139
[0597] ##STR165##
Furan-2-carboxylic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0598] The title compound was prepared according to procedures
described in Example 134, except substituting 2-furoyl chloride for
acetyl chloride. .sup.1H NMR (CDCl.sub.3): .delta. 1.00 (s, 3H)
1.05-2.35 (m, 25H) 2.45 (d, J=7.46 Hz, 3H) 3.00 (m, 1H) 4.84 (m,
1H) 5.42 (m, 1H) 6.50 (dd, J=3.39, 1.70 Hz, 1H) 7.17 (d, J=4.41 Hz,
1H) 7.57 (s, 1H); MS: (M+H).sup.+=424.
Example 140
[0599] ##STR166##
Cyclopropanecarboxylic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0600] The title compound was prepared according to procedures
described in Example 134, except substituting cyclopropanecarbonyl
chloride for acetyl chloride. .sup.1H NMR (CDCl.sub.3): .delta.
0.82-2.38 (m, 36H) 3.01 (m, 1H) 4.61 (m, 1H) 5.38 (m, 1H); MS:
(M+H).sup.+=398.
Example 141
[0601] ##STR167##
Methoxy-acetic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0602] The title compound was prepared according to procedures
described in Example 134, except substituting methoxyacetyl
chloride for acetyl chloride. .sup.1H NMR (CDCl.sub.3): .delta.
0.96 (s, 3H) 1.00-2.30 (m, 25H) 2.35 (d, J=7.46 Hz, 3H) 3.01 (m,
1H) 3.45 (s, 3H) 4.01 (s, 2H) 4.71 (m, 1H) 5.40 (m, 1H); MS:
(M+H).sup.+=402.
Example 142
[0603] ##STR168##
Isobutyric acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0604] The title compound was prepared according to procedures
described in Example 134, except substituting isobutyryl chloride
for acetyl chloride. .sup.1H NMR (CDCl.sub.3): .delta. 0.97 (s, 3H)
1.15 (d, J=7.12 Hz, 6H) 1.00-2.30 (m, 26H) 2.32 (s, 3H) 3.01 (m,
1H) 4.63 (m, 1H) 5.37 (m, 1H); MS: (M+H).sup.+=400.
Example 143
[0605] ##STR169##
Cyclobutanecarboxylic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0606] The title compound was prepared according to procedures
described in Example 134, except substituting cyclobutanecarbonyl
chloride for acetyl chloride. .sup.1H NMR (CDCl.sub.3): .delta.
0.96 (s, 3H) 1.00-2.35 (m, 35H) 3.10 (m, 1H) 4.61 (m, 1H) 5.38 (m,
1H);
[0607] MS: (M+H).sup.+=412.
Example 144
[0608] ##STR170##
Propionic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0609] The title compound was prepared according to procedures
described in Example 134, except substituting propionyl chloride
for acetyl chloride. .sup.1H NMR (CDCl.sub.3): .delta. 0.96 (s, 3H)
1.08-2.38 (m, 33H) 3.59 (m, 1H) 4.61 (m, 1H) 5.38 (m, 1H); MS:
(M+H).sup.+=386.
Example 145
[0610] ##STR171##
Phenyl-acetic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0611] The title compound was prepared according to procedures
described in Example 134, except substituting phenylacetyl chloride
for acetyl chloride. MS: (M+H).sup.+=448.
Example 146
[0612] ##STR172##
Benzenesulfonic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0613] The title compound was prepared according to procedures
described in Example 134, except substituting benzenesulfonyl
chloride for acetyl chloride. .sup.1H NMR (CDCl.sub.3): .delta.
0.92 (m, 3H) 1.05-2.50 (m, 28H) 2.94 (m, 1H) 4.37 (m, 1H) 5.31 (m,
1H) 7.54 (m, 2H) 7.63 (m, 1H) 7.92 (m, 2H); MS:
(M+H).sup.+=470.
Example 147
[0614] ##STR173##
4-Cyano-benzenesulfonic acid 2,3,11a-trimethyl-2,3,3a
4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydro-1H-2-aza-pentaleno[1,6a-
-a]phenanthren-9-yl ester
[0615] The title compound was prepared according to procedures
described in Example 134, except substituting
4-cyanobenzenesulfonyl chloride for acetyl chloride. .sup.1H NMR
(CDCl.sub.3): .delta. 0.92 (m, 3H) 1.05-2.50 (m, 28H) 2.94 (m, 1H)
4.37 (m, 1H) 5.38 (m, 1H) 7.85 (m, 2H) 8.02 (m, 2H); MS:
(M+H).sup.+=495.
Example 148
[0616] ##STR174##
(4-Fluoro-phenyl)-acetic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0617] A mixture of compound 130A (20 mg, 0.06 mmol),
4-fluorophenylacetic acid (14 mg, 0.09 mmol),
1,3-dicyclohexylcarbodiimide (25 mg, 0.12 mmol), 4-(dimethylamino)
pyridine (2 mg, 0.016 mmol) and THF (1 mL) was stirred at room
temperature overnight. The crude reaction mixture was loaded
directly onto silica gel column and eluted with 0.2% ammonium
hydroxide and 2% methanol in dichloromethane to give the pure
desired product (25 mg, 87% yield).
[0618] .sup.1H NMR (CDCl.sub.3): .delta. 0.96 (s, 3H) 1.08-2.38 (m,
27H) 3.01 (s, 2H) 3.45 (m, 1H) 4.00 (m, 1H), 4.60 (m, 1H) 5.37 (m,
1H) 7.01 (m, 2H) 7.23 (m, 2H)
[0619] MS: (M+H).sup.+=466
Example 149
[0620] ##STR175##
2-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-butyric acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0621] The title compound was prepared according to procedures
described in Example 148, except substituting Boc-N-methyl-D-valine
for 4-fluorophenylacetic acid. MS: (M+H).sup.+=543.
Example 150
[0622] ##STR176##
3-Methyl-2-methylamino-butyric
acid-2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadec-
ahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0623] Compound 149 (10 mg, 0.018 mmol) was stirred with 1:1
mixture of TFA and dichloromethane (1 mL) for 2 h. Solvent was
evaporated under reduced pressure, and the residue was triturated
with ethyl acetate twice and dried on high vacuum to give the
desired product.
[0624] MS: (M+H).sup.+=443
Example 151
[0625] ##STR177##
Tetrahydro-furan-2-carboxylic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0626] The title compound was prepared according to procedures
described in Example 148, except substituting tetrahydro-2-furoic
acid for 4-fluorophenylacetic acid. .sup.1H NMR (CDCl.sub.3):
.delta. 0.96 (s, 3H) 1.00-2.60 (m, 30H) 3.01 (s, 3H) 3.95 (m, 2H)
4.42 (m, 1H) 4.67 (m, 1H) 5.38 (m, 1H); MS: (M+H).sup.+=427.
Example 152
[0627] ##STR178##
Furan-2-yl-oxo-acetic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0628] The title compound was prepared according to procedures
described in Example 148, except substituting 2-oxo-2-furanylacetic
acid for 4-fluorophenylacetic acid. .sup.1H NMR (CDCl.sub.3):
.delta. 1.00 (s, 3H) 1.05-2.60 (m, 26H) 3.02 (s, 3H) 4.87 (m, 1H)
5.43 (m, 1H) 6.62 (dd, J=3.73, 1.70 Hz, 1H) 7.69 (d, J=3.05 Hz, 1H)
7.75 (s, 1H); MS: (M+H).sup.+=452.
Example 153
[0629] ##STR179##
2-Acetoxy-3-phenyl-propionic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0630] The title compound was prepared according to procedures
described in Example 148, except substituting
L-2-acetoxy-3-phenylpropionic acid for 4-fluorophenylacetic acid
and the corresponding carboxylic acid was prepared according to the
procedure used in Example 91. .sup.1H NMR (CDCl.sub.3): .delta.
0.96 (s, 3H) 1.08-2.40 (m, 29H) 2.09 (s, 3H) 3.11 (m, 2H) 4.62 (m,
1H) 5.15 (dd, J=8.14, 5.09 Hz, 1H) 5.36 (m, 1H) 7.29 (m, 5H); MS:
(M+H).sup.+=520, (M+NH.sub.4).sup.+=537.
Example 154
[0631] ##STR180##
2-Acetoxy-4-methyl-pentanoic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0632] The title compound was prepared according to procedures
described in Example 148, except substituting 2-acetoxyisocaproic
acid for 4-fluorophenylacetic acid and the corresponding carboxylic
acid was prepared according to the procedure used in Example 91.
.sup.1H NMR (CDCl.sub.3): .delta. 0.95 (m, 9H) 1.00-2.00 (m, 28H)
2.13 (s, 3H) 2.33 (m, 3H) 2.78 (m, 1H) 4.64 (m, 1H) 4.96 (m, 1H)
5.38 (m, 1H); MS: (M+H).sup.+=486.
Example 155
[0633] ##STR181##
2-Acetoxy-3-methyl-butyric acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0634] The title compound was prepared according to procedures
described in Example 148, except substituting
2-acetoxy-3-methylbutyric acid for 4-fluorophenylacetic acid and
the corresponding carboxylic acid was prepared according to the
procedure used in Example 91. .sup.1H NMR (CDCl.sub.3): .delta.
0.99 (m, 12H) 1.10-2.05 (m, 22H) 2.14 (s, 3H) 2.26 (m, 5H) 4.68 (m,
1H) 4.78 (d, J=4.75 Hz, 1H) 5.39 (m, 1H); MS: (M+H).sup.+=472.
Example 156
[0635] ##STR182##
2-Acetoxy-2-methyl-butyric acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0636] The title compound was prepared according to procedures
described in Example 148, except substituting
2-hydroxy-2-methylbutyric acid for 4-fluorophenylacetic acid and
the corresponding carboxylic acid was prepared according to the
procedure used in Example 91. .sup.1H NMR (CDCl.sub.3): .delta.
0.92 (m, 9H) 1.10-1.95 (m, 26H) 2.03 (d, 3H) 2.31 (m, 3H) 2.52 (m,
2H) 4.62 (m, 1H) 5.38 (m, 1H); MS: (M+H).sup.+=472.
Example 157
[0637] ##STR183##
1-Acetoxy-cyclopropanecarboxylic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0638] The title compound was prepared according to procedures
described in Example 148, except substituting
1-acetoxy-1-cyclopropanecarboxylic acid for 4-fluorophenylacetic
acid and the corresponding carboxylic acid was prepared according
to the procedure used in Example 91. .sup.1H NMR (CDCl.sub.3):
.delta. 0.93 (s, 3H) 1.15-1.90 (m, 27H) 2.10 (s, 3H) 2.15-2.90 (m,
6H) 4.61 (m, 1H) 5.37 (m, 1H); MS: (M+H).sup.+=456.
Example 158
[0639] ##STR184##
2-Acetoxy-2-ethyl-butyric acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0640] The title compound was prepared according to procedures
described in Example 148, except substituting
2-ethyl-2-acetoxybutyric acid for 4-fluorophenylacetic acid and the
corresponding carboxylic acid was prepared according to the
procedure used in Example 91. .sup.1H NMR (CDCl.sub.3): .delta.
0.85 (t, J=7.46 Hz, 6H) 0.96 (s, 3H) 1.00-2.00 (m, 27H) 2.07 (s,
3H) 2.10-2.35 (m, 6H) 4.65 (m, 1H) 5.38 (m, 1H); MS:
(M+H).sup.+=486.
Example 159
[0641] ##STR185##
2-Acetoxy-hexanoic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0642] The title compound was prepared according to procedures
described in Example 148, except substituting 2-acetoxycaproic acid
for 4-fluorophenylacetic acid and the corresponding carboxylic acid
was prepared according to the procedure used in Example 91. .sup.1H
NMR (CDCl.sub.3): .delta. 0.93 (m, 9H) 1.00-2.00 (m, 26H) 2.13 (s,
3H) 2.34 (m, 6H) 4.66 (m, 1H) 4.93 (t, J=6.44 Hz, 1H) 5.39 (m, 1H);
MS: (M+H).sup.+=503.
Example 160
[0643] ##STR186##
Methoxy-phenyl-acetic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0644] The title compound was prepared according to procedures
described in Example 148, except substituting 2-methoxyphenylacetic
acid for 4-fluorophenylacetic acid. .sup.1H NMR (CDCl.sub.3):
.delta. 0.93 (s, 3H) 1.00-2.30 (m, 27H) 2.33 (d, J=7.80 Hz, 3H)
3.41 (s, 3H) 4.68 (m, 1H) 5.35 (m, 1H) 7.36 (m, 3H) 7.44 (m, 2H);
MS: (M+H).sup.+=478, (M+NH.sub.4).sup.+=495.
Example 161
[0645] ##STR187##
Carbonic acid 4-nitro-phenyl ester
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0646] Compound 130A (250 mg, 0.76 mmol) was dissolved in 10 mL
dichloromethane and cooled to 0.degree. C.
4-Nitrophenylchloroformate (170 mg, 0.84 mmol) was added followed
by N-methylmorpholine (125 .mu.L, 1.14 mmol). The mixture was
stirred overnight while warmed up slowly to room temperature. TLC
indicated that the reaction was not completed.
4-Nitrophenylchloroformate (309 mg, 1.52 mmol) and
N-methylmorpholine (250 .mu.L, 2.28 mmol) were added and stirred at
room temperature for 3 hours. Reaction was complete. It was loaded
on silica gel column and eluted with 0.5% ammonium hydroxide and 5%
methanol in dichloromethane to give the paranitrophenol-carbonate
(PNP-carbonate, 260 mg, 69% yield).
[0647] .sup.1H NMR (CDCl.sub.3): .delta. 0.98 (s, 3H) 1.05-2.60 (m,
26H) 2.79 (m, 2H) 3.69 (m, 1H) 4.60 (m, 1H) 5.45 (m, 1H) 7.39 (m,
2H) 8.28 (m, 2H)
[0648] MS: (M+H).sup.+=495
Example 162
[0649] ##STR188##
Furan-2-ylmethyl-methyl-carbamic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0650] Compound 161 (25 mg, 0.051 mmol), N-methylfurylamine (7
.mu.L, 0.061 mmol), dichloromethane (0.5 mL) and THF (1 mL) were
mixed and stirred at room temperature overnight. The crude reaction
mixture was purified on silica gel column, which was eluted with
0.3% ammonium hydroxide and 3% methanol in dichloromethane to give
the desired product (21 mg, 87% yield).
[0651] MS: (M+H).sup.+=467
Example 163
[0652] ##STR189##
Methyl-propyl-carbamic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0653] The title compound was prepared according to procedures
described in Example 162, except substituting methylpropylamine for
N-methylfurylamine. MS: (M+H).sup.+=429.
Example 164
[0654] ##STR190##
Benzyl-methyl-carbamic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0655] The title compound was prepared according to procedures
described in Example 162, except substituting N-benzylmethylamine
for N-methylfurylamine. .sup.1H NMR (CDCl.sub.3): .delta. 0.96 (s,
3H) 1.04-2.42 (m, 27H) 2.87 (m, 4H) 2.95 (m, 1H) 4.46 (s, 2H) 4.57
(m, 1H) 5.40 (m, 1H) 7.29 (m, 5H); MS: (M+H).sup.+=477,
(M+NH.sup.4).sup.+=494.
Example 165
[0656] ##STR191##
Methyl-(6-methyl-pyridin-2-ylmethyl)-carbamic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0657] The title compound was prepared according to procedures
described in Example 162, except substituting
6-methyl-2-picolyl-methylamine for N-methylfurylamine. .sup.1H NMR
(CDCl.sub.3): .delta. 0.91 (s, 3H) 0.98 (s, 3H) 1.15-2.45 (m, 26H)
2.54 (s, 3H) 2.97 (m, 4H) 4.56 (m, 2H) 5.38 (m, 1H) 7.03 (m, 2H)
7.55 (m, 1H); MS: (M+H).sup.+=492.
Example 166
[0658] ##STR192##
Methyl-(tetrahydro-furan-2-ylmethyl)-carbamic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0659] The title compound was prepared according to procedures
described in Example 162, except substituting
N-methyltetrahydrofurfurylamine for N-methylfurylamine. .sup.1H NMR
(CDCl.sub.3): .delta. 0.96 (s, 3H) 1.03-2.40 (m, 3H) 2.97 (s, 3H)
3.10-3.60 (m, 2H) 3.79 (m, 2H) 4.05 (m, 1H) 4.51 (m, 1H) 5.38 (m,
1H); MS: (M+H).sup.+=471.
Example 167
[0660] ##STR193##
(2-Fluoro-ethyl)-carbamic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0661] The title compound was prepared according to procedures
described in Example 162, except substituting
2-fluoroethylaminehydrochloride for N-methylfurylamine. .sup.1H NMR
(CDCl.sub.3): .delta. 0.96 (s, 3H) 1.00-1.95 (m, 38H) 2.05-2.40 (m,
8H) 3.43 (m, 1H) 3.53 (m, 1H) 4.41 (t, J=4.75 Hz, 2H) 4.50 (m, 1H)
4.57 (t, J=4.75 Hz, 2H) 4.93 (m, 1H) 5.39 (m, 1H); MS:
(M+H).sup.+=419, (M+NH.sup.4).sup.+=436.
Example 168
[0662] ##STR194##
Furan-2-ylmethyl-carbamic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0663] The title compound was prepared according to procedures
described in Example 162, except substituting furfurylamine for
N-methylfurylamine. .sup.1H NMR (CDCl.sub.3): .delta. 0.95 (s, 3H)
1.00-2.40 (m, 28H) 3.02 (m, 1H) 4.34 (d, J=5.43 Hz, 2H) 4.52 (m,
1H) 4.90 (m, 1H) 5.39 (m, 1H) 6.22 (d, J=2.71 Hz, 1H) 6.31 (dd,
J=3.22, 1.86 Hz, 1H) 7.35 (s, 1H); MS: (M+H).sup.+=453.
Example 169
[0664] ##STR195##
(2-Cyano-ethyl)-(tetrahydro-furan-2-ylmethyl)-carbamic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0665] The title compound was prepared according to procedures
described in Example 162, except substituting
3-[(tetrahydrofuran-2-ylmethyl)amino]propane nitrile for
N-methylfurylamine. .sup.1H NMR (CDCl.sub.3): .delta. 0.95 (s, 3H)
1.00-2.40 (m, 34H) 2.71 (m, 2H) 3.60 (m, 2H) 3.73 (m, 2H) 3.85 (m,
1H) 4.01 (m, 1H) 4.54 (m, 1H) 5.38 (m, 1H); MS:
(M+H).sup.+=510.
Example 170
[0666] ##STR196##
[0667] Benzyl-carbamic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0668] The title compound was prepared according to procedures
described in Example 162, except substituting benzylamine for
N-methylfurylamine. MS: (M+H).sup.+=451.
Example 171
[0669] ##STR197##
Propyl-carbamic acid
2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexadecahydr-
o-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl ester
[0670] The title compound was prepared according to procedures
described in Example 162, except substituting propylamine for
N-methylfurylamine. MS: (M+H).sup.+=403.
Reference Example 172
[0671] ##STR198##
172A.
Dimethyl-(2,3,11a-trimethyl-octadecahydro-2-aza-pentaleno[1,6a-a]phe-
nanthren-9-yl)-amine
[0672] Conessine (50 mg, 0.14 mmol) was dissolved in 3 mL ethyl
acetate and 10% Pd/C (20 mg) was added under inert atmosphere. The
reaction mixture was hydrogenated under a hydrogen balloon for 24
hours. Reaction was not complete by TLC. The reaction mixture was
filtered through diatomaceous earth, washed with ethyl acetate, and
the filtrate was concentrated to give the crude product which was
purified by silica gel column eluted with 0.3% ammonium hydroxide
and 3% methanol in dichloromethane to give the desired product (15
mg, 30% yield).
[0673] .sup.1H NMR (CDCl.sub.3): .delta. 0.74 (s, 3H) 0.95-2.00 (m,
29H) 2.32 (s, 3H) 2.43 (s, 6H) 3.12 (m, 1H)
[0674] MS: (M+H).sup.+=359 ##STR199##
172B.
Methyl-(2,3,11a-trimethyl-octadecahydro-2-aza-pentaleno[1,6a-a]phena-
nthren-9-yl)-amine
[0675] The title compound was prepared using the procedures
described in Example 7A and 7B, except substituting Compound 172A
for connessine. .sup.1H NMR (CDCl.sub.3): .delta. 0.75 (s, 3H)
0.90-2.00 (m, 25H) 2.29 (m, 3H) 2.51 (s, 3H) 2.62 (m, 1H) 2.93 (s,
3H) 3.09 (m, 1H) 4.13 (m, 1H); (M+H).sup.+=345. ##STR200##
172C.
N-Methyl-N-(2,3,11a-trimethyl-octadecahydro-2-aza-pentaleno[1,6a-a]p-
henanthren-9-yl)-benzamide
[0676] The title compound was prepared according to procedures
described in Example 7C, except substituting Compound 172B for
Compound 7B and benzoyl chloride for acetyl chloride. .sup.1H NMR
(CDCl.sub.3): .delta. 0.75 (s, 3H) 0.85-2.00 (m, 26H) 2.21 (m, 3H)
2.80 (s, 3H) 2.98 (s, 3H) 3.46 (m, 1H) 7.39 (m, 5H);
(M+H).sup.+=449.
Example 173
[0677] ##STR201##
N-Methyl-2-thiophen-2-yl-N-(2,3,11a-trimethyl-octadecahydro-2-aza-pentalen-
o[1,6a-a]phenanthren-9-yl)-acetamide
[0678] The title compound was prepared according to procedures
described in Example 7C, except substituting Compound 172B for
Compound 7B and 2-thiopheneacetyl chloride for acetyl chloride.
.sup.1H NMR (CDCl.sub.3): .delta. 0.74 (s, 3H) 0.95-2.40 (m, 27H)
2.83 (s, 3H) 2.88 (s, 3H) 3.01 (m, 1H) 3.69 (m, 1H) 3.90 (d,
J=11.53 Hz, 2H) 4.49 (m, 1H) 6.92 (m, 2H) 7.19 (m, 1H);
(M+H).sup.+=469.
Example 174
[0679] ##STR202##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
benzyl ester
[0680] Compound 7B (20 mg, 0.058 mmol) and triethylamine (9.1
.mu.L, 0.064 mmol) were dissolved in dichloromethane (1 mL). Benzyl
chloroformate was added to it. The mixture was stirred at room
temperature for 2 hours. The crude reaction mixture was purified on
silica gel column using 0.5% ammonium hydroxide and 5% methanol in
dichloromethane to give the desired product (18.4 mg, 66.2%
yield).
[0681] .sup.1H NMR (CDCl.sub.3): .delta. ppm 0.94 (s, 3H) 0.98-1.90
(m, 21H) 2.02 (m, 2H) 2.21 (s, 3H) 2.43 (m, 2H) 2.84 (s, 3H) 2.98
(m, 1H) 3.89 (m, 1H) 5.14 (s, 2H) 5.35 (d, J=5.09 Hz, 1H) 7.32 (m,
5H); MS: (M+H).sup.+=477.
Example 175
[0682] ##STR203##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
methyl ester
[0683] The title compound was prepared according to procedures
described in Example 174, except substituting methyl chloroformate
for benzyl chloroformate. MS: (M+H).sup.+=401.
Example 176
[0684] ##STR204##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
2,2-dimethyl-propyl ester
[0685] The title compound was prepared according to procedures
described in Example 174, except substituting neopentyl
chloroformate for benzyl chloroformate. .sup.1H NMR (CDCl.sub.3):
.delta. 0.95 (s, 3H) 0.96 (s, 9H) 0.98-1.70 (m, 17H) 1.78 (td, 2H)
1.90 (m, 2H) 2.05 (td, 2H) 2.26 (s, 3H) 2.43 (td, 2H) 2.83 (s, 3H)
3.04 (m, 1H) 3.77 (s, 2H) 3.92 (m, 1H) 5.35 (d, J=5.09 Hz, 1H); MS:
(M+H).sup.+=457.
Example 177
[0686] ##STR205##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
isobutyl ester
[0687] The title compound was prepared according to procedures
described in Example 174, except substituting isobutyl
chloroformate for benzyl chloroformate. .sup.1H NMR (CDCl.sub.3):
.delta. 0.94 (d, J=6.78 Hz, 6H) 0.95 (s, 3H) 1.01-2.10 (m, 24H)
2.24 (s, 3H) 2.42 (m, 2H) 2.82 (s, 3H) 3.01 (m, 1H) 3.86 (d, J=6.44
Hz, 2H) 3.94 (m, 1H) 5.35 (d, J=5.10 Hz, 1H); MS:
(M+H).sup.+=443.
Example 178
[0688] ##STR206##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
ethyl ester
[0689] The title compound was prepared according to procedures
described in Example 174, except substituting ethyl chloroformate
for benzyl chloroformate. .sup.1H NMR (CDCl.sub.3): .delta. 0.95
(s, 3H) 1.26 (t, J=7.12 Hz, 3H) 0.97-1.91 (m, 21H) 2.02 (m, 2H)
2.19 (s, 3H) 2.41 (td, 2H) 2.81 (s, 3H) 3.00 (m, 1H) 3.86 (m, 1H)
4.13 (q, J=7.12 Hz, 2H) 5.36 (d, J=5.09 Hz, 1H); MS:
(M+H).sup.+=415.
Example 179
[0690] ##STR207##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
tert-butyl ester
[0691] The title compound was prepared according to procedures
described in Example 174, except substituting tert-butyl
chloroformate for benzyl chloroformate. .sup.1H NMR (CDCl.sub.3):
.delta. 0.94 (s, 3H) 1.04 (d, J=6.10 Hz, 3H) 1.46 (s, 9H) 1.54 (s,
3H) 1.10-1.89 (m, 15H) 2.02 (m, 2H) 2.21 (s, 3H) 2.36 (m, 2H) 2.76
(s, 3H) 2.99 (d, J=10.51 Hz, 1H) 3.83 (m, 1H) 5.35 (d, J=5.42 Hz,
1H); MS: (M+H).sup.+=443.
Example 180
[0692] ##STR208##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
isopropyl ester
[0693] The title compound was prepared according to procedures
described in Example 174, except substituting isopropyl
chloroformate for benzyl chloroformate. .sup.1H NMR (CDCl.sub.3):
.delta. 0.95 (s, 3H) 1.24 (d, J=6.44 Hz, 6H) 1.79 (m, 23H) 2.22 (s,
3H) 2.41 (m, 2H) 2.80 (s, 3H) 2.99 (m, 1H) 3.88 (m, 1H) 4.92 (m,
1H) 5.35 (d, J=3.00 Hz, 1H), MS: (M+H).sup.+=429.
Example 181
[0694] ##STR209##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
cyclopentyl ester
[0695] The title compound was prepared according to procedures
described in Example 174, except substituting cyclopentyl
chloroformate for benzyl chloroformate. .sup.1H NMR (CDCl.sub.3):
.delta. 0.94 (s, 3H) 1.54 (m, 29H) 2.00 (m, 2H) 2.22 (s, 3H) 2.41
(m, 2H) 2.79 (s, 3H) 3.00 (m, 1H) 3.81 (m, 1H) 5.11 (m, 1H) 5.35
(d, J=5.42 Hz, 1H); MS: (M+H).sup.+=455.
Example 182
[0696] ##STR210##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
furan-3-ylmethyl ester
[0697] Compound 7B (10 mg, 0.029 mmol), carbonic acid
furan-3-ylmethyl ester 4-nitro-phenyl ester (2.4 mg, 0.032 mmol)
and triethylamine (12.0 .mu.L, 0.087 mmol) were dissolved in THF (1
mL) and stirred at room temperature overnight. The crude reaction
mixture was purified on silica gel column using 0.5% ammonium
hydroxide and 5% methanol in dichloromethane to give the desired
product (10.1 mg, 74.2% yield).
[0698] .sup.1H NMR (CDCl.sub.3): .delta. 0.94 (s, 3H) 1.04-2.04 (m,
23H) 2.24 (s, 3H) 2.42 (m, 2H) 2.81 (s, 3H) 3.03 (m, 1H) 3.85 (m,
1H) 4.99 (s, 2H) 5.35 (d, J=5.09 Hz, 1H) 6.43 (s, 1H) 7.39 (t,
J=1.70 Hz, 1H) 7.46 (s, 1H); MS: (M+H).sup.+=467.
Example 183
[0699] ##STR211##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
5-methoxy-tetrahydro-furan-3-yl ester
[0700] The title compound was prepared according to procedures
described in Example 182, except substituting carbonic acid
5-methoxy-tetrahydro-furan-3-yl ester 4-nitro-phenyl ester for
carbonic acid furan-3-ylmethyl ester 4-nitro-phenyl ester. .sup.1H
NMR (CDCl.sub.3): .delta. 0.95 (m, 3H) 0.99-2.04 (m, 25H) 2.22 (s,
3H) 2.40 (t, J=11.53 Hz, 2H) 2.78 (s, 3H) 2.98 (d, J=2.71 Hz, 1H)
3.35 (s, 3H) 3.69 (m, 1H) 3.93 (d, J=10.17 Hz, 1H) 4.03 (dd,
J=10.50, 4.50 Hz, 1H) 5.17 (dd, J=4.92, 2.88 Hz, 1H) 5.28 (m, 1H)
5.35 (d, J=5.00 Hz, 1H); MS: (M+H).sup.+=487.
Example 184
[0701] ##STR212##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
thiazol-5-yl methyl ester
[0702] The title compound was prepared according to procedures
described in Example 182, except substituting carbonic acid
4-nitro-phenyl ester thiazol-5-ylmethyl ester for carbonic acid
furan-3-ylmethyl ester 4-nitro-phenyl ester. .sup.1H NMR
(CDCl.sub.3): .delta. 0.94 (s, 3H) 1.05-2.11 (m, 23H) 2.22 (s, 3H)
2.40 (m, 2H) 2.82 (d, 3H) 2.99 (m, 1H) 3.83 (m, 1H) 5.33 (s, 2H)
5.35 (m, 1H) 7.87 (s, 1H) 8.80 (s, 1H); MS: (M+H).sup.+=484.
Example 185
[0703] ##STR213##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
hexahydro-furo[2,3-b]furan-3-yl ester
[0704] The title compound was prepared according to procedures
described in Example 182, except substituting carbonic acid
hexahydro-furo[2,3-b]furan-3-yl ester 4-nitro-phenyl ester for
carbonic acid furan-3-ylmethyl ester 4-nitro-phenyl ester. .sup.1H
NMR (CDCl.sub.3): .delta. 0.95 (s, 3H) 0.99-2.04 (m, 25H) 2.21 (s,
3H) 2.43 (m, 2H) 2.83 (d, 3H) 2.99 (d, J=9.83 Hz, 1H) 3.05 (m, 1H)
3.73 (m, 1H) 3.81 (dd, J=9.49, 6.44 Hz, 1H) 3.90 (m, 1H) 3.98 (m,
1H) 4.08 (m, 1H) 5.19 (d, J=7.80 Hz, 1H) 5.37 (d, J=4.75 Hz, 1H)
5.73 (d, J=5.43 Hz, 1H); MS: (M+H).sup.+=499.
Example 186
[0705] ##STR214##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
tetrahydro-furan-3-yl ester
[0706] The title compound was prepared according to procedures
described in Example 182, except substituting carbonic acid
4-nitro-phenyl ester tetrahydro-furan-3-yl ester for carbonic acid
furan-3-ylmethyl ester 4-nitro-phenyl ester. .sup.1H NMR
(CDCl.sub.3): .delta. 0.96 (m, 3H) 1.01-2.22 (m, 28H) 2.41 (m, 2H)
2.80 (s, 3H) 2.99 (m, 1H) 3.70 (m, 1H) 3.87 (m, 4H) 5.27 (m, 1H)
5.36 (d, J=4.75 Hz, 1H); MS: (M+H).sup.+=457.
Example 187
[0707] ##STR215##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
Pyridin-2-yl ester
[0708] The title compound was prepared according to procedures
described in Example 182, except substituting carbonic acid
dipyridin-2-yl ester for carbonic acid furan-3-ylmethyl ester
4-nitro-phenyl ester. .sup.1H NMR (CDCl.sub.3): .delta. 0.97 (s,
3H) 1.02-2.34 (m, 26H) 2.53 (m, 2H) 2.95 (s, 3H) 3.03 (m, 1H) 4.02
(m, 1H) 5.39 (s, 1H) 7.11 (m, 1H) 7.17 (dd, J=7.12, 5.42 Hz, 1H)
7.75 (m, 1H) 8.38 (dd, J=5.09, 1.70 Hz, 1H); MS:
(M+H).sup.+=464.
Example 188
[0709] ##STR216##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
3,5-dimethyl-isoxazol-4-ylmethyl ester
[0710] The title compound was prepared according to procedures
described in Example 182, except substituting carbonic acid
3,5-dimethyl-isoxazol-4-ylmethyl ester 4-nitro-phenyl ester for
carbonic acid furan-3-ylmethyl ester 4-nitro-phenyl ester. .sup.1H
NMR (CDCl.sub.3): .delta. 0.93 (s, 3H) 1.00-2.13 (m, 23H) 2.21 (s,
3H) 2.28 (s, 3H) 2.37 (m, 2H) 2.42 (s, 3H) 2.77 (s, 3H) 2.99 (m,
1H) 3.81 (m, 1H) 4.89 (s, 2H) 5.35 (m, 1H); MS:
(M+H).sup.+=496.
Example 189
[0711] ##STR217##
189A.
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-
-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic
acid chloride
[0712] Compound 7B (125 mg, 0.36 mmol) was dissolved in
dichloromethane (5 mL) and cooled to 0.degree. C. Triethylamine
(150 .mu.L, 1.1 mmol) and phosgene (20% in toluene, 0.23 mL, 0.44
mmol) were added to it. The mixture was stirred at 0.degree. C. for
3 hours. The reaction mixture was quenched with water, extracted
with dichloromethane. The combined extracts were dried over
Na.sub.2SO.sub.4, filtered and concentrated to give crude desired
product (144.6 mg, 97.8%), which was used in next step without
further purification.
[0713] MS: (M+H).sup.+=477. ##STR218##
189B.
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-
-hexadecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic
acid 3-hydroxy-propyl ester
[0714] Compound 189A (30 mg, 0.074 mmol) and 1,3-propanediol (54
.mu.L, 0.061 mmol), were dissolved in pyridine (1 mL). The mixture
was stirred at room temperature for 5 days. Stripped of pyridine,
the crude reaction mixture was purified on silica gel column using
0.5% ammonium hydroxide and 5% methanol in dichloromethane to give
the desired product (7.3 mg, 22.8% yield).
[0715] .sup.1H NMR (CDCl.sub.3): .delta. 0.96 (m, 3H) 1.04-2.11 (m,
25H) 2.22 (s, 3H) 2.42 (m, 2H) 2.56 (br s, 1H) 2.81 (m, 3H) 3.00
(m, 1H) 3.65 (m, 2H) 3.87 (m, 1H) 4.28 (t, J=5.76 Hz, 2H) 5.36 (m,
1H). MS: (M+H).sup.+=445.
Example 190
[0716] ##STR219##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
[1,3]dioxolan-4-ylmethyl ester
[0717] The title compound was prepared according to procedures
described in Example 189B, except substituting glycerol formal for
1,3-propanediol. MS: (M+H).sup.+=473.
Example 191
[0718] ##STR220##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
oxiranyl methyl ester
[0719] The title compound was prepared according to procedures
described in Example 189B, except substituting glycidol for
1,3-propanediol. .sup.1H NMR (CDCl.sub.3): .delta. 0.95 (m, 3H)
1.13-2.25 (m, 26H) 2.43 (m, 2H) 2.64 (dd, J=4.92, 2.54 Hz, 1H) 2.84
(m, 3H) 3.03 (m, 1H) 3.24 (m, 1H) 3.68 (m, 1H) 3.90 (m, 2H) 4.45
(d, J=9.0 Hz, 1H) 5.36 (d, J=5.09 Hz, 1H); MS: (M+H).sup.+=443.
Example 192
[0720] ##STR221##
Methyl-(2,3,11a-trimethyl-2,3,3a,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13-hexad-
ecahydro-1H-2-aza-pentaleno[1,6a-a]phenanthren-9-yl)-carbamic acid
2-hydroxy-ethyl ester
[0721] The title compound was prepared according to procedures
described in Example 189B, except substituting ethylene glycol for
1,3-propanediol. .sup.1H NMR (CDCl.sub.3): .delta. 0.95 (s, 3H)
1.03-2.12 (m, 23H) 2.21 (s, 3H) 2.41 (m, 2H) 2.73 (br s, 1H) 2.84
(s, 3H) 2.97 (m, 1H) 3.83 (d, J=4.75 Hz, 2H) 3.94 (m, 1H) 4.26 (m,
2H) 5.36 (d, J=6.00 Hz, 1H);
[0722] MS: (M+H).sup.+=431.
Example 193
Determination of Biological Activity
[0723] To determine the effectiveness of representative compounds
of this invention as histamine-3 receptor ligands (H.sub.3 receptor
ligands), the following tests were conducted according to methods
previously described (European Journal of Pharmacology, 188:219-227
(1990); Journal of Pharmacology and Experimental Therapeutics,
275:598-604 (1995); Journal of Pharmacology and Experimental
Therapeutics, 276:1009-1015 (1996); and Biochemical Pharmacology,
22:3099-3108 (1973)).
[0724] Briefly, male Sprague-Dawley rat brain cortices were
homogenized (1 g tissue/10 mL buffer) in 50 mM Tris-HCl/5 mM EDTA
containing protease inhibitor cocktail (Calbiochem) using a
polytron set at 20,500 rpm. Homogenates were centrifuged for 20
minutes at 40000.times.g. The supernatant was decanted, and pellets
were weighed. The pellet was resuspended by polytron homogenization
in 40 mL 50 mM Tris-HCl/5 mM EDTA with protease inhibitors and
centrifuged for 20 minutes at 40,000.times.g. The membrane pellet
was resuspended in 6.25 volumes (per gram wet weight of pellet) of
50 mM Tris-HCl/5 mM EDTA with protease inhibitors and aliquots
flash frozen in liquid N.sub.2 and stored at -70.degree. C. until
used in assays. Rat cortical membranes (12 mg wet weight/tube) were
incubated with (3H)-N-.alpha.-methylhistamine (.about.0.6 nM) with
or without H.sub.3 receptor antagonists in a total incubation
volume of 0.5 mL of 50 mM Tris-HCl/5 mM EDTA (pH 7.7). Test
compounds were dissolved in DMSO to provide a 20 mM solution,
serially diluted and then added to the incubation mixtures prior to
initiating the incubation assay by addition of the membranes.
Thioperamide (3 .mu.M) was used to determine nonspecific binding.
Binding incubations were conducted for 30 minutes at 25.degree. C.
and terminated by addition of 2 mL of ice cold 50 mM Tris-HCl (pH
7.7) and filtration through 0.3% polyethylenimine-soaked Unifilter
plates (Packard). These filters were washed 4 additional times with
2 mL of ice-cold 50 mM Tris-HCl and dried for 1 hour. Radioactivity
was determined using liquid scintillation counting techniques.
Results were analyzed by Hill transformation and K.sub.i values
were determined using the Cheng-Prusoff equation.
[0725] Representative compounds of the invention bound to
histamine-3 receptors with binding affinities from about 810 nM to
about 0.12 nM. Preferred compounds of the invention bound to
histamine-3 receptors with binding affinities from about 100 nM to
about 0.12 nM. More preferred compounds of the invention bound to
histamine-3 receptors with binding affinities from about 20 nM to
about 0.12 nM.
[0726] Compounds of the invention are histamine-3 receptor ligands
that modulate function of the histamine-3 receptor by altering the
activity of the receptor. These compounds may be inverse agonists
that inhibit the basal activity of the receptor or they may be
antagonists that completely block the action of receptor-activating
agonists. These compounds may also be partial agonists that
partially block or partially activate the histamine-3 receptor or
they may be agonists that activate the receptor.
[0727] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will
be apparent to those skilled in the art. Such changes and
modifications, including without limitation those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations and/or methods of use of the invention, may
be made without departing from the spirit and scope thereof.
* * * * *