U.S. patent application number 15/001336 was filed with the patent office on 2016-05-19 for substituted cyclopenta[4,5]oxazolo[3,2-a]pyrido[1,2-d]pyrazines as hiv integrase inhibitors.
This patent application is currently assigned to Shionogi & Co., Ltd.. The applicant listed for this patent is Shionogi & Co., Ltd., ViiV Healthcare Company. Invention is credited to Brian Alvin Johns, Takashi Kawasuji, Teruhiko Taishi, Yoshiyuki Taoda.
Application Number | 20160137666 15/001336 |
Document ID | / |
Family ID | 37215098 |
Filed Date | 2016-05-19 |
United States Patent
Application |
20160137666 |
Kind Code |
A1 |
Johns; Brian Alvin ; et
al. |
May 19, 2016 |
SUBSTITUTED CYCLOPENTA[4,5]OXAZOLO[3,2-a]PYRIDO[1,2-d]PYRAZINES AS
HIV INTEGRASE INHIBITORS
Abstract
The present invention is to provide a novel compound (I) shown
below, having the anti-virus activity, particularly the HIV
integrase inhibitory activity, and a drug containing the same,
particularly an anti-HIV drug, as well as a process and an
intermediate thereof. ##STR00001## (wherein Z.sup.1 is NR.sup.4;
R.sup.1 is hydrogen or lower alkyl; X is a single bond, a hetero
atom group selected from O, S, SO, SO.sub.2 and NH, or lower
alkylene or lower alkenylene in which the hetero atom group may
intervene; R.sup.2 is optionally substituted aryl; R.sup.3 is
hydrogen, a halogen, hydroxy, optionally substituted lower alkyl
etc; and R.sup.4 and Z.sup.2 part taken together forms a ring, to
form a polycyclic compound, including e.g., a tricyclic or
tetracyclic compound.
Inventors: |
Johns; Brian Alvin;
(Research Triangle Park, NC) ; Kawasuji; Takashi;
(Osaka, JP) ; Taishi; Teruhiko; (Osaka, JP)
; Taoda; Yoshiyuki; (Osaka, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Shionogi & Co., Ltd.
ViiV Healthcare Company |
Osaka
Wilmington |
|
JP
DE |
|
|
Assignee: |
Shionogi & Co., Ltd.
Osaka
DE
ViiV Healthcare Company
Wilmington
|
Family ID: |
37215098 |
Appl. No.: |
15/001336 |
Filed: |
January 20, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14700679 |
Apr 30, 2015 |
9273065 |
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15001336 |
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14211364 |
Mar 14, 2014 |
9051337 |
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14700679 |
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13763174 |
Feb 8, 2013 |
8778943 |
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14211364 |
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13352686 |
Jan 18, 2012 |
8410103 |
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13763174 |
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11919386 |
Jul 28, 2009 |
8129385 |
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PCT/US2006/016604 |
Apr 28, 2006 |
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13352686 |
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Current U.S.
Class: |
514/250 ;
544/343 |
Current CPC
Class: |
C07D 498/20 20130101;
C07D 498/22 20130101; A61K 31/519 20130101; A61K 45/06 20130101;
A61P 37/02 20180101; A61P 43/00 20180101; A61P 31/12 20180101; C07D
471/14 20130101; A61P 31/18 20180101; A61K 31/551 20130101; A61K
9/0053 20130101; A61K 9/20 20130101; A61P 31/00 20180101; A61K
31/5365 20130101; A61K 31/4985 20130101; C07D 471/22 20130101; C07D
498/04 20130101; C07D 498/14 20130101; C07D 471/04 20130101 |
International
Class: |
C07D 498/14 20060101
C07D498/14 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 28, 2005 |
JP |
2005-131161 |
Oct 27, 2005 |
JP |
2005-312076 |
Claims
1-56. (canceled)
57. A compound of the formula: ##STR00209## wherein: the
stereochemistry of an asymmetric carbon represented by * shows R-
or S-configuration, or a mixture thereof; R.sup.14 and R.sup.X are
independently hydrogen or lower alkyl which is optionally
substituted with 1 to 4 substituents selected from the group
consisting of hydroxy, carboxy, halogen, halo lower alkyl, halo
lower alkoxy, lower alkyl, lower alkenyl, lower alkynyl,
cycloalkyl, cycloalkenyl, lower alkoxy, lower alkenyloxy, lower
alkoxycarbonyl, nitro, nitroso, amino, alkylamino, acylamino,
aralkylamino, aryl, aralkyl, cyano, isocyano, isocyanate,
thiocyanate, isothiocyanate, mercapto, alkylthio, alkylsulfonyl,
alkylsulfonylamino, carbamoyl, alkylcarbamoyl, sulfamoyl, acyl,
formyloxy, haloformyl, oxal, thioformyl, thiocarboxy,
dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino,
hydrazino, azido, ureido, guanidino, phthalimide, oxo, phosphoric
acid, lower alkyl which is substituted with phosphoric acid and may
be intervened with a heteroatom, aryl substituted with phosphoric
acid, aralkyl substituted with phosphoric acid, and hydroxy lower
alkyl; R.sup.3 is hydrogen, halogen, hydroxy, optionally
substituted lower alkyl, optionally substituted cycloalkyl,
optionally substituted lower alkenyl, optionally substituted lower
alkoxy, optionally substituted lower alkenyloxy, optionally
substituted aryl, optionally substituted aryloxy, optionally
substituted heterocyclyl, optionally substituted heterocyclyloxy or
optionally substituted amino, wherein the optional substituents are
1 to 4 substituents selected from the group consisting of hydroxy,
carboxy, halogen, halo lower alkyl, halo lower alkoxy, lower alkyl,
lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, lower
alkoxy, lower alkenyloxy, lower alkoxycarbonyl, nitro, nitroso,
amino, alkylamino, acylamino, aralkylamino, aryl, aralkyl, cyano,
isocyano, isocyanate, thiocyanate, isothiocyanate, mercapto,
alkylthio, alkylsulfonyl, alkylsulfonylamino, carbamoyl,
alkylcarbamoyl, sulfamoyl, acyl, formyloxy, haloformyl, oxal,
thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino,
sulfo, sulfoamino, hydrazino, azido, ureido, guanidino,
phthalimide, oxo, phosphoric acid, lower alkyl which is substituted
with phosphoric acid and may be intervened with a heteroatom, aryl
substituted with phosphoric acid, aralkyl substituted with
phosphoric acid, and hydroxy lower alkyl; R.sup.1 is hydrogen or
lower alkyl; R is halogen; m is 0, 1, 2 or 3; or a pharmaceutically
acceptable salt thereof.
58. The compound according to claim 57, or a pharmaceutically
acceptable salt thereof, wherein R.sup.X and R.sup.14 are
independently hydrogen.
59. The compound according to claim 57, or a pharmaceutically
acceptable salt thereof, wherein R.sup.3 is hydrogen.
60. The compound according to claim 57, or a pharmaceutically
acceptable salt thereof, wherein m is 1 or 2.
61. The compound according to claim 57, or a pharmaceutically
acceptable salt thereof, wherein R.sup.X is hydrogen; R.sup.14 is
hydrogen; and R.sup.3 is hydrogen.
62. A pharmaceutical composition comprising the compound, or
pharmaceutically acceptable salt thereof, according to claim 57,
and a pharmaceutically acceptable carrier or diluent.
Description
TECHNICAL FIELD
[0001] The present invention relates to novel compounds possessing
an antiviral activity, in detail polycyclic carbamoylpyridone
derivatives possessing an inhibitory activity against HIV integrase
and a pharmaceutical composition containing the same, especially an
anti-HIV agent.
BACKGROUND ART
[0002] Among viruses, human immunodeficiency virus (HIV), a kind of
retrovirus, is known to cause acquired immunodeficiency syndrome
(AIDS). The therapeutic agent for AIDS is mainly selected from a
group of reverse transcriptase inhibitors (e.g., AZT, 3TC) and
protease inhibitors (e.g., Indinavir), but they are proved to be
accompanied by side effects such as nephropathy and the emergence
of resistant viruses. Thus, the development of anti-HIV agents
having the other mechanism of action has been desired.
[0003] On the other hand, a combination therapy is reported to be
efficient in treatment for AIDS because of the frequent emergence
of the resistant mutant. Reverse transcriptase inhibitors and
protease inhibitors are clinically used as an anti-HIV agent,
however agents having the same mechanism of action often exhibit
cross-resistance or only an additional activity. Therefore,
anti-HIV agents having the other mechanism of action are
desired.
[0004] Under the circumstances above, an HIV integrase inhibitor
has been focused on as an anti-HIV agent having a novel mechanism
of action (Ref: Patent Documents 1 and 2). As an anti-HIV agent
having such a mechanism of action, known are carbamoyl-substituted
hydroxypyrimidinone derivative (Ref: Patent Documents 3 and 4) and
carbamoyl-substituted hydroxypyrrolidine derivative (Ref: Patent
Document 5). Further, a patent application concerning
carbamoyl-substituted hydroxypyridone derivative has been filed
(Ref: Patent Document 6, Example 8).
[0005] Other known carbamoylpyridone derivatives include
5-alkoxypyridine-3-carboxamide derivatives and
.gamma.-pyrone-3-carboxamide derivatives, which are a plant growth
inhibitor or herbicide (Ref: Patent Documents 7-9).
[0006] Other HIV integrase inhibitors include N-containing
condensed cyclic compounds (Ref: Patent Document 10). [0007]
[Patent Document 1]WO03/0166275 [0008] [Patent Document
2]WO2004/024693 [0009] [Patent Document 3]WO03/035076 [0010]
[Patent Document 4]WO03/035076 [0011] [Patent Document
5]WO2004/004657 [0012] [Patent Document 6] JP Patent Application
2003-32772 [0013] [Patent Document 7] JP Patent Publication
1990-108668 [0014] [Patent Document 8] JP Patent Publication
1990-108683 [0015] [Patent Document 9] JP Patent Publication
1990-96506 [0016] [Patent Document 10] WO2005/016927
DISCLOSURE OF INVENTION
Problem to be Solved by the Invention
[0017] The development of a novel integrase inhibitor has been
desired.
Means to Solve the Problem
[0018] The present inventors have intensively studied to find that
a novel polycyclic carbamoylpyridone derivative possesses a potent
HIV integrase inhibitory activity.
[0019] Moreover, the present inventors have discovered that a
compound of the present invention and a pharmaceutical composition
containing the same are useful as an antiviral agent, an
antiretroviral agent, an anti-HIV agent, an anti-HTLV-1 (Human T
cell leukemia virus type 1) agent, an anti-FIV (Feline
immunodeficiency virus) agent or an anti-SIV (Simian
immunodeficiency virus) agent, especially an anti-HIV agent or
anti-AIDS agent, to accomplish the present invention shown
below.
(1) A compound of the formula:
##STR00002##
(wherein, [0020] Z.sup.1 is NR.sup.4; [0021] R.sup.4 is hydrogen,
optionally substituted lower alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkyl lower alkyl,
optionally substituted lower alkenyl, optionally substituted lower
alkoxy, optionally substituted aryl, optionally substituted aryl
lower alkyl, optionally substituted aryloxy, optionally substituted
heterocyclic group, optionally substituted heterocycle lower alkyl,
optionally substituted heterocyclooxy, hydroxy, optionally
substituted amino, optionally substituted phosphoric acid residue,
aryl substituted with optionally substituted phosphoric acid
residue, aralkyl substituted with optionally substituted phosphoric
acid residue, hydroxy substituted with optionally substituted
phosphoric acid residue, amino substituted with optionally
substituted phosphoric acid residue or lower alkyl substituted with
optionally substituted phosphoric acid residue (the lower alkyl may
be intervened by a heteroatom group selected from CO, O, S, SO,
SO.sub.2, NR.sup.a (R.sup.a is hydrogen or lower alkyl), --N.dbd.
and .dbd.N--)), O or CH.sub.2; [0022] Z.sup.2 is optionally
substituted lower alkylene or optionally substituted lower
alkenylene, each may be intervened by a heteroatom group selected
from O, S, SO, SO.sub.2, NR.sup.5 (R.sup.5 is hydrogen, optionally
substituted lower alkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkyl lower alkyl, optionally
substituted lower alkenyl, optionally substituted lower alkoxy,
optionally substituted aryl, optionally substituted aryl lower
alkyl, optionally substituted aryloxy, optionally substituted
heterocyclic group, optionally substituted heterocycle lower alkyl,
optionally substituted heterocyclooxy, hydroxy or optionally
substituted amino, optionally substituted phosphoric acid residue,
aryl substituted with optionally substituted phosphoric acid
residue, aralkyl substituted with optionally substituted phosphoric
acid residue, hydroxy substituted with optionally substituted
phosphoric acid residue, amino substituted with optionally
substituted phosphoric acid residue or lower alkyl substituted with
optionally substituted phosphoric acid residue (the lower alkyl may
be intervened by a heteroatom group selected from CO, O, S, SO,
SO.sub.2, NR.sup.5 (R.sup.5 is selected independently from the same
substituent group as R.sup.4), --N.dbd. and .dbd.N--)), --N.dbd. or
.dbd.N-- [0023] R.sup.1 is hydrogen or lower alkyl; [0024] X is a
single bond, a heteroatom group selected from O, S, SO, SO.sub.2
and NH, or lower alkylene or lower alkenylene each may be
intervened by the heteroatom; [0025] R.sup.2 is optionally
substituted aryl; [0026] R.sup.3 is hydrogen, halogen, hydroxy,
optionally substituted lower alkyl, optionally substituted
cycloalkyl, optionally substituted lower alkenyl, optionally
substituted lower alkoxy, optionally substituted lower alkenyloxy,
optionally substituted aryl, optionally substituted aryloxy,
optionally substituted heterocyclic group, optionally substituted
heterocyclooxy or optionally substituted amino; [0027] R.sup.4 and
Z.sup.2 part taken together forms a ring, where the compound (I) is
represented by the following formula (I-1), or (I-11):
##STR00003##
[0027] (wherein, [0028] A ring is optionally substituted
heterocycle; [0029] R.sup.14 and R.sup.X are independently
hydrogen, optionally substituted lower alkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkyl lower
alkyl, optionally substituted lower alkenyl, optionally substituted
lower alkoxy, optionally substituted lower alkenyloxy, optionally
substituted aryl, optionally substituted aryl lower alkyl,
optionally substituted aryloxy, optionally substituted heterocyclic
group, optionally substituted heterocycle lower alkyl, optionally
substituted heterocyclooxy, optionally substituted phosphoric acid
residue, aryl substituted with optionally substituted phosphoric
acid residue, aralkyl substituted with optionally substituted
phosphoric acid residue, hydroxy substituted with optionally
substituted phosphoric acid residue, amino substituted with
optionally substituted phosphoric acid residue or lower alkyl
substituted with optionally substituted phosphoric acid residue
(the lower alkyl may be intervened by a heteroatom group selected
from O, S, SO, SO.sub.2, NR.sup.5 (R.sup.5 is selected
independently from the same substituent group as R.sup.4), --N.dbd.
and .dbd.N--), hydroxy, optionally substituted amino, optionally
substituted lower alkyl carbonyl, optionally substituted
cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl
carbonyl, optionally substituted lower alkoxy carbonyl, optionally
substituted arylcarbonyl, optionally substituted aryl lower alkyl
carbonyl, optionally substituted aryloxycarbonyl, optionally
substituted heterocyclocarbonyl, optionally substituted heterocycle
lower alkyl carbonyl, optionally substituted heterocyclooxy
carbonyl or optionally substituted aminocarbonyl; [0030] a broken
line represents the presence or absence of a bond, provided that
when the broken line represents the presence of a bond, R.sup.X is
not present; [0031] R.sup.1 is hydrogen or lower alkyl; [0032] X is
a single bond, a heteroatom group selected from O, S, SO, SO.sub.2
and NH, or lower alkylene or lower alkenylene each may be
intervened by the heteroatom group; [0033] R.sup.2 is optionally
substituted aryl; [0034] R.sup.3 is hydrogen, halogen, hydroxy,
optionally substituted lower alkyl, optionally substituted
cycloalkyl, optionally substituted lower alkenyl, optionally
substituted lower alkoxy, optionally substituted lower alkenyloxy,
optionally substituted aryl, optionally substituted aryloxy,
optionally substituted heterocyclic group, optionally substituted
heterocyclooxy or optionally substituted amino)
##STR00004##
[0034] (wherein, [0035] D ring is optionally substituted
heterocycle; [0036] R.sup.1 is hydrogen or lower alkyl; [0037] X is
a single bond, a heteroatom group selected from O, S, SO, SO.sub.2
and NH, or lower alkylene or lower alkenylene each may be
intervened by the heteroatom group; [0038] R.sup.2 is optionally
substituted aryl; [0039] R.sup.3 is hydrogen, halogen, hydroxy,
optionally substituted lower alkyl, optionally substituted
cycloalkyl, optionally substituted lower alkenyl, optionally
substituted lower alkoxy, optionally substituted lower alkenyloxy,
optionally substituted aryl, optionally substituted aryloxy,
optionally substituted heterocyclic group, optionally substituted
heterocyclooxy or optionally substituted amino)), its
pharmaceutically acceptable salt, or solvate thereof. (2) A
compound according to the above (1), pharmaceutically acceptable
salt, or solvate thereof, wherein R.sup.1 is hydrogen. (3) A
compound according to the above (1), pharmaceutically acceptable
salt, or solvate thereof, wherein X is lower alkylene; R.sup.2 is
phenyl or phenyl substituted with at least halogen. (4) A compound
according to the above (1), pharmaceutically acceptable salt, or
solvate thereof, wherein R.sup.3 is hydrogen, halogen, hydroxy,
lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or
optionally substituted amino. (5) A compound according to the above
(1), pharmaceutically acceptable salt, or solvate thereof, wherein
R.sup.3 is hydrogen. (6) A compound according to the above (1),
pharmaceutically acceptable salt, or solvate thereof, wherein
R.sup.1 is hydrogen or lower alkyl; X is lower alkylene; R.sup.2 is
phenyl or phenyl substituted with at least halogen; R.sup.3 is
hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower
alkoxy, lower alkenyloxy or optionally substituted amino. (7) A
compound of the formula:
##STR00005##
[0039] (wherein, [0040] A ring is optionally substituted
heterocycle; [0041] R.sup.14 and R.sup.X are independently
hydrogen, optionally substituted lower alkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkyl lower
alkyl, optionally substituted lower alkenyl, optionally substituted
lower alkoxy, optionally substituted lower alkenyloxy, optionally
substituted aryl, optionally substituted aryl lower alkyl,
optionally substituted aryloxy, optionally substituted heterocyclic
group, optionally substituted heterocycle lower alkyl, optionally
substituted heterocyclooxy, optionally substituted phosphoric acid
residue, aryl substituted with optionally substituted phosphoric
acid residue, aralkyl substituted with optionally substituted
phosphoric acid residue, hydroxy substituted with optionally
substituted phosphoric acid residue, amino substituted with
optionally substituted phosphoric acid residue or lower alkyl
substituted with optionally substituted phosphoric acid residue
(the lower alkyl may be intervened by a heteroatom group selected
from O, S, SO, SO.sub.2, NR.sup.5 (R.sup.5 is selected
independently from the same substituent group as R.sup.4), --N.dbd.
and .dbd.N--), hydroxy, optionally substituted amino, optionally
substituted lower alkyl carbonyl, optionally substituted
cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl
carbonyl, optionally substituted lower alkoxy carbonyl, optionally
substituted arylcarbonyl, optionally substituted aryl lower alkyl
carbonyl, optionally substituted aryloxycarbonyl, optionally
substituted heterocyclocarbonyl, optionally substituted heterocycle
lower alkyl carbonyl, optionally substituted heterocyclooxy
carbonyl or optionally substituted aminocarbonyl; [0042] a broken
line represents the presence or absence of a bond, provided that
when the broken line represents the presence of a bond, R.sup.X is
not present; [0043] R.sup.1 is hydrogen or lower alkyl; [0044] X is
a single bond, a heteroatom group selected from O, S, SO, SO.sub.2
and NH, or lower alkylene or lower alkenylene each may be
intervened by the heteroatom group; [0045] R.sup.2 is optionally
substituted aryl; [0046] R.sup.3 is hydrogen, halogen, hydroxy,
optionally substituted lower alkyl, optionally substituted
cycloalkyl, optionally substituted lower alkenyl, optionally
substituted lower alkoxy, optionally substituted lower alkenyloxy,
optionally substituted aryl, optionally substituted aryloxy,
optionally substituted heterocyclic group, optionally substituted
heterocyclooxy or optionally substituted amino), its
pharmaceutically acceptable salt, or solvate thereof (8) A compound
according to the above (7), pharmaceutically acceptable salt, or
solvate thereof, wherein R.sup.1 is hydrogen or lower alkyl; X is
lower alkylene; R.sup.2 is phenyl or phenyl substituted with at
least halogen; R.sup.3 is hydrogen, halogen, hydroxy, lower alkyl,
lower alkenyl, lower alkoxy, lower alkenyloxy or optionally
substituted amino. (9) A compound according to the above (7),
pharmaceutically acceptable salt, or solvate thereof, wherein a
broken line represents the absence of a bond, (10) A compound
according to the above (7), pharmaceutically acceptable salt, or
solvate thereof, wherein R.sup.X is hydrogen; R.sup.14 is hydrogen
or optionally substituted lower alkyl, (11) A compound according to
the above (7), pharmaceutically acceptable salt, or solvate
thereof, wherein A ring is an optionally substituted and optionally
condensed 5- to 7-membered heterocycle containing 1 to 2 hetero
atom(s). (12) A compound of the formula:
##STR00006##
[0046] (wherein, [0047] A ring is an optionally substituted and
optionally condensed 5- to 7-membered heterocycle containing 1 to 2
hetero atom(s); [0048] the stereochemistry of an asymmetric carbon
represented by * shows R- or S-configuration, or a mixture thereof;
[0049] R.sup.14 and R.sup.X are independently hydrogen, optionally
substituted lower alkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkyl lower alkyl, optionally
substituted lower alkenyl, optionally substituted lower alkoxy,
optionally substituted lower alkenyloxy, optionally substituted
aryl, optionally substituted aryl lower alkyl, optionally
substituted aryloxy, optionally substituted heterocyclic group,
optionally substituted heterocycle lower alkyl, optionally
substituted heterocyclooxy, optionally substituted phosphoric acid
residue, aryl substituted with optionally substituted phosphoric
acid residue, aralkyl substituted with optionally substituted
phosphoric acid residue, hydroxy substituted with optionally
substituted phosphoric acid residue, amino substituted with
optionally substituted phosphoric acid residue or lower alkyl
substituted with optionally substituted phosphoric acid residue
(the lower alkyl may be intervened by a heteroatom group selected
from O, S, SO, SO.sub.2, NR.sup.5 (R.sup.5 is selected
independently from the same substituent group as R.sup.4), -N.dbd.
and .dbd.N--), hydroxy, optionally substituted amino, optionally
substituted lower alkyl carbonyl, optionally substituted
cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl
carbonyl, optionally substituted lower alkoxy carbonyl, optionally
substituted arylcarbonyl, optionally substituted aryl lower alkyl
carbonyl, optionally substituted aryloxycarbonyl, optionally
substituted heterocyclocarbonyl, optionally substituted heterocycle
lower alkyl carbonyl, optionally substituted heterocyclooxy
carbonyl or optionally substituted aminocarbonyl; [0050] R.sup.8 is
hydrogen, halogen, hydroxy, optionally substituted lower alkyl,
optionally substituted cycloalkyl, optionally substituted lower
alkenyl, optionally substituted lower alkoxy, optionally
substituted lower alkenyloxy, optionally substituted aryl,
optionally substituted aryloxy, optionally substituted heterocyclic
group, optionally substituted heterocyclooxy or optionally
substituted amino), its pharmaceutically acceptable salt, or [0051]
R.sup.1 is hydrogen or lower alkyl; [0052] R is independently
selected from halogen and Substituent group S1;
[0053] Substituent group S1: optionally substituted phosphoric acid
residue, aryl substituted with optionally substituted phosphoric
acid residue, aralkyl substituted with optionally substituted
phosphoric acid residue, hydroxy substituted with optionally
substituted phosphoric acid residue, amino substituted with
optionally substituted phosphoric acid residue, or lower alkyl
substituted with optionally substituted phosphoric acid residue
(wherein the lower alkyl may be intervened with a heteroatom
group(s) selected from CO, O, O, S, SO, SO.sub.2, NR.sup.a (R.sup.a
is hydrogen or lower alkyl), --N.dbd. and .dbd.N--), lower alkoxy
lower alkyl, amino lower alkyl optionally substituted with mono- or
di-lower alkyl, halogenated lower alkyl, lower alkoxy, carbamoyl
optionally substituted with mono- or di-lower alkyl, optionally
substituted lower alkyl sulfonyl amino, halogenated lower alkoxy,
hydroxy lower alkyl) [0054] m is an integer of 0 to 3, its
pharmaceutically acceptable salt, or solvate thereof. (13) A
compound according to the above (12), pharmaceutically acceptable
salt, or solvate thereof, wherein R.sup.X and are independently
hydrogen or optionally substituted lower. (14) A compound according
to the above (12), pharmaceutically acceptable salt, or solvate
thereof, wherein R.sup.X and R.sup.14 are hydrogens. (15) A
compound according to the above (12), pharmaceutically acceptable
salt, or solvate thereof, wherein R.sup.3 is hydrogen. (16) A
compound according to the above (12), pharmaceutically acceptable
salt, or solvate thereof, wherein m is 0, or 1 to 3 and at least
one of R is halogen. (17) A compound according to the above (7) or
(12), pharmaceutically acceptable salt, or solvate thereof, wherein
A ring is any one of the following:
##STR00007##
[0054] (wherein, R.sup.20 to R.sup.40 are each independently a
group selected from Substituent group S2, or any two groups of
R.sup.20 to R.sup.40, which bonds to the same carbon atom, taken
together with the carbon atom, may form an optionally substituted
carbocycle or optionally substituted heterocycle, or each
combination of (R.sup.50 and R.sup.22), (R.sup.23 and R.sup.24),
(R.sup.25 and R.sup.26), (R.sup.27 and R.sup.29), (R.sup.30 and
R.sup.31), (R.sup.32 and R.sup.34), (R.sup.35 and R.sup.36),
(R.sup.37 and R.sup.38), and (R.sup.39 and R.sup.40), taken
together with the neighboring atom, may form an optionally
substituted carbocycle or optionally substituted heterocycle.
[0055] Substituent group S2: hydrogen, optionally substituted lower
alkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkyl lower alkyl, optionally substituted lower alkenyl,
optionally substituted lower alkoxy, optionally substituted lower
alkenyloxy, optionally substituted aryl, optionally substituted
aryl lower alkyl, optionally substituted aryloxy, optionally
substituted heterocycle, optionally substituted heterocycle lower
alkyl, optionally substituted heterocyclooxy, hydroxy, optionally
substituted amino, optionally substituted lower alkylcarbonyl,
optionally substituted cycloalkylcarbonyl, optionally substituted
cycloalkyl lower alkylcarbonyl, optionally substituted lower
alkoxycarbonyl, optionally substituted arylcarbonyl, optionally
substituted aryl lower alkylcarbonyl, optionally substituted aryl
oxycarbonyl, optionally substituted heterocyclocarbonyl, optionally
substituted heterocycle lower alkylcarbonyl, optionally substituted
heterocyclooxycarbonyl, optionally substituted aminocarbonyl,
optionally substituted phosphoric acid, residue, aryl substituted
with optionally substituted phosphoric acid residue, aralkyl
substituted with optionally substituted phosphoric acid residue,
hydroxy substituted with optionally substituted phosphoric acid
residue, amino substituted with optionally substituted phosphoric
acid residue, or lower alkyl substituted with optionally
substituted phosphoric acid residue (the lower alkyl may be
intervened with a heteroatom group(s) selected from CO, O, S, SO,
SO.sub.2, NR.sup.5 (R.sup.5 is independently selected from the same
Substituent group as R.sup.4), --N.dbd. and .dbd.N--) [0056] the
stereochemistry of an asymmetric carbon represented by * shows R-
or S-configuration, or a mixture thereof) (18) A compound according
to the above (17), pharmaceutically acceptable salt, or solvate
thereof, wherein R.sup.20 to R.sup.40 are each independently
hydrogen or substituted lower alkyl, or any two groups of R.sup.20
to R.sup.40, which bonds to the same carbon atom, taken together
with the carbon atom, may form an optionally substituted 3- to
7-membered carbocycle or optionally substituted 3- to 7-membered
heterocycle, or each combination of (R.sup.20 and R.sup.22),
(R.sup.23 and R.sup.24), (R.sup.25 and R.sup.26), (R.sup.27 and
R.sup.29), (R.sup.30 and R.sup.31), (R.sup.32 and R.sup.34),
(R.sup.35 and R.sup.36), (R.sup.37 and R.sup.38), and (R.sup.39 and
R.sup.40), taken together with the neighboring atom, may form an
optionally substituted 5- to 7-membered carbocycle or optionally
substituted 5- to 7-membered heterocycle. (19) A compound according
to the above (17), pharmaceutically acceptable salt, or solvate
thereof, wherein A ring is a ring represented by (A-1); one of
R.sup.20 to R.sup.25 is optionally substituted lower alkyl and the
others are hydrogens. (20) A compound according to the above (17),
pharmaceutically acceptable salt, or solvate thereof, wherein A
ring is a ring represented by (A-1); one of (R.sup.20 and
R.sup.22), (R.sup.20 and R.sup.24), and (R.sup.25 and R.sup.26),
taken together with the neighboring atom, may form an optionally
substituted 5- to 7-membered carbocycle or optionally substituted
5- to 7-membered heterocycle. (21) A compound according to the
above (17), pharmaceutically acceptable salt, or solvate thereof,
wherein A ring is a ring represented by (A-1); Z.dbd.NR.sup.26, and
R.sup.25 and R.sup.26 taken together with the neighboring atom may
form an optionally substituted 5- to 7-membered heterocycle. (22) A
compound according to the above (17), pharmaceutically acceptable
salt, or solvate thereof, wherein A ring is a ring represented by
(A-2); one of R.sup.27 to R.sup.30 is optionally substituted lower
alkyl and the others are hydrogens. (23) A compound according to
the above (17), pharmaceutically acceptable salt, or solvate
thereof, wherein A ring is a ring represented by (A-2); one of
(R.sup.27 and R.sup.29) and (R.sup.30 and R.sup.31), taken together
with the neighboring atom, may form an optionally substituted 5- to
7-membered carbocycle or optionally substituted 5- to 7-membered
heterocycle. (24) A compound according to the above (17),
pharmaceutically acceptable salt, or solvate thereof, wherein A
ring is a ring represented by (A-2); Z.dbd.NR.sup.31, and R.sup.30
and R.sup.31 taken together with the neighboring atom may form an
optionally substituted 5- to 7-membered heterocycle. (25) A
compound according to the above (17), pharmaceutically acceptable
salt, or solvate thereof, wherein A ring is a ring represented by
(A-3); one of R.sup.32 to R.sup.39 is optionally substituted lower
alkyl and the others are hydrogens. (26) A compound according to
the above (17), pharmaceutically acceptable salt, or solvate
thereof, wherein A ring is a ring represented by (A-3); one of
(R.sup.32 and R.sup.34), (R.sup.35 and R.sup.36), (R.sup.37 and
R.sup.38), and (R.sup.39 and R.sup.40), taken together with the
neighboring atom, may form an optionally substituted 5- to
7-membered carbocycle or optionally substituted 5- to 7-membered
heterocycle. (27) A compound according to the above (17),
pharmaceutically acceptable salt, or solvate thereof, wherein A
ring is a ring represented by (A-3); Z.dbd.NR.sup.40, and R.sup.39
and R.sup.40 taken together with the neighboring atom may form an
optionally substituted 5- to 7-membered heterocycle. (28) A
compound according to the above (12), pharmaceutically acceptable
salt, or solvate thereof, wherein R.sup.X is hydrogen; R.sup.14 is
hydrogen or optionally substituted lower; R.sup.3 is hydrogen; m is
1 to 3 and at least one of Rs is halogen; A ring is a ring
described in claim 17. (29) A compound according to the above (12),
pharmaceutically acceptable salt, or solvate thereof, wherein
R.sup.X is hydrogen; R.sup.14 is hydrogen; R.sup.3 is hydrogen; m
is 0, or 1 to 3 and at least one of Rs is halogen; A ring is a ring
described in claim 17; R.sup.20 to R.sup.40 are each independently
hydrogen or substituted lower alkyl, or any two groups of R.sup.20
to R.sup.40, which bonds to the same carbon atom, taken together
with the carbon atom, may form an optionally substituted 3- to
7-membered carbocycle or optionally substituted 3- to 7-membered
heterocycle, or each combination of (R.sup.20 and R.sup.22),
(R.sup.23 and R.sup.24), (R.sup.25 and R.sup.26), (R.sup.27 and
R.sup.29), (R.sup.30 and R.sup.31), (R.sup.32 and R.sup.34),
(R.sup.35 and R.sup.36), (R.sup.37 and R.sup.38), and (R.sup.39 and
R.sup.40), taken together with the neighboring carbon atom, may
form an optionally substituted 5- to 7-membered carbocycle or
optionally substituted 5- to 7-membered heterocycle. (30) A
compound of the formula:
##STR00008##
[0056] (wherein, [0057] D ring is optionally substituted
heterocycle; [0058] R.sup.1 is hydrogen or lower alkyl; [0059] X is
a single bond, a heteroatom group selected from O, S, SO, SO.sub.2
and NH, or lower alkylene or lower alkenylene each may be
intervened by the heteroatom group; [0060] R.sup.2 is optionally
substituted aryl; [0061] R.sup.3 is hydrogen, halogen, hydroxy,
optionally substituted lower alkyl, optionally substituted
cycloalkyl, optionally substituted lower alkenyl, optionally
substituted lower alkoxy, optionally substituted lower alkenyloxy,
optionally substituted aryl, optionally substituted aryloxy,
optionally substituted heterocyclic group, optionally substituted
heterocyclooxy or optionally substituted amino), pharmaceutically
acceptable salt, or solvate thereof (31) A compound selected from
the group consisting of: [0062]
(3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,-
3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxami-
de; [0063]
(4aR,13aS)--N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-diox-
o-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo-
[1,2-d]pyrazine-8-carboxamide; [0064]
(3aS,13aS)--N-[(2,4-Difluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4-
,5,7,9,13,13a-decahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrim-
idine-10-carboxamide; [0065]
(4aS,13aR)--N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5-
,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyr-
azine-8-carboxamide; [0066]
(4aS,13aR)--N-[(4-Fluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,1-
1,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazin-
e-8-carboxamide; [0067]
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylme-
thyl)-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-c-
arboxamide; [0068]
(3aS,13aS)--N-[(4-Fluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7-
,9,13,13a-decahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidin-
e-10-carboxamide; [0069]
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(1S)-1-methylpropy-
l]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyraz-
ine-8-carboxamide; [0070]
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,-
3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxami-
de; [0071]
(3S,11aR)--N-[(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-di-
oxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-car-
boxamide; [0072]
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-3-(1,1-dimethylethyl)-6-hydroxy-
-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-
e-8-carboxamide; [0073]
(3S,11aR)-3-(1,1-Dimethylethyl)-N-[(4-fluorophenyl)methyl]-6-hydroxy-5,7--
dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-c-
arboxamide; [0074] (3S,11aR)--N-[(2)
4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-phenyl-2,3,5,7,11,11a-hexa-
hydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide; [0075]
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(hydroxymethyl)-5,7-
-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8--
carboxamide; [0076]
(2S,3R)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2-ph-
enyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-ca-
rboxamide; [0077]
(3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylme-
thyl)-2,3,5,7,11,11a-hexhydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-ca-
rboxamide; [0078]
(3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(2-methylpropyl)-5,-
7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-
-carboxamide; [0079]
(5aR,14aR)--N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,4-
,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1',2':3,4]imidazo[1,2-d]py-
razine-9-carboxamide; [0080]
(2S,3S)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(methyloxy)methyl]-5-
,7-dioxo-2-phenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]-
pyrazine-8-carboxamide; [0081]
(3S,11aR)-3-(Cyclohexylmethyl)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5-
,7-dioxo-2,3,6,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine--
8-carboxamide; [0082]
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1-methylethyl)-5,7-
-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8--
carboxamide; [0083]
(5aR,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-5a,6a,7-
,11,13,14a-hexahydro-5H-indeno[1',2':4,5][1,3]oxazolo[3,2-a]pyrido[1,2-d]p-
yrazine-10-carboxamide; [0084]
(2S,3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3-diph-
enyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-ca-
rboxamide; [0085]
(2S,3R,11aR)--N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3-diph-
enyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-ca-
rboxamide; [0086]
(3S,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1-methylethyl)-5,7-
-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8--
carboxamide; [0087]
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[2-(methylthio)ethy-
l]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyraz-
ine-8-carboxamide; [0088]
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[2-(methylsulfonyl)-
ethyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]p-
yrazine-8-carboxamide; [0089]
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1H-indol-3-ylmethy-
l)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyraz-
ine-8-carboxamide; [0090]
(4R,12aR)--N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropy-
l)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]p-
yrimidine-9-carboxamide; [0091]
(4R,12R)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-
-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyr-
imidine-9-carboxamide; [0092]
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylp-
ropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-
-a]pyrimidine-9-carboxamide; [0093]
(4S,12aS)-1-(Cyclopropylmethyl)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy--
4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1-
,2-a]pyrimidine-9-carboxamide; [0094]
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-1-(2-furanylmethyl)-7-hydroxy-4-
-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,-
2-a]pyrimidine-9-carboxamide; [0095]
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1--
(1,3-thiazol-2-ylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyra-
zino[1,2-a]pyrimidine-9-carboxamido; [0096]
(4aR,6aR,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3-
,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]pyrazino[1,2-a][3,1]b-
enzoxazine-10-carboxamide; [0097]
(4aR,6aR,14aS)--N-[(4-Fluorophenyl)methyl]-12-hydroxy-11,18-dioxo-1,3,4,4-
a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]pyrazino[1,2a]-[3,1]benzo-
xazine-10-carboxamide [0098]
(3S,4aR,6aR,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo--
3-phenyl-1,3,11,13,14a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]pyra-
zino[1,2-a][3,1]benzoxazine-10-carboxamide; [0099]
(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-(2-methylprop-
yl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':4,5]-
pyrazino[1,2-a]quinazoline-10-carboxamide; [0100]
(6aR,7aS,11aS)--N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,-
7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1,2-a]benzimi-
dazole-3-carboxamide; [0101]
(6aS,7aS,11aS)--N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,-
7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1,2-a]benzimi-
dazole-3-carboxamide; [0102]
(5aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,4-
,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1',2':3,4]imidazo[1,2-d]py-
razine-9-carboxamide; [0103]
(4aR,14aR)--N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8,10-dioxo-2,3,4,4a,-
5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1',2':4,5]pyrazino[1,2-a]-
pyrimidine-11-carboxamide; [0104]
(4R,12aR)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylb-
utyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2--
a]pyrimidine-9-carboxamide; [0105]
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methyle-
thyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2--
a]pyrimidine-9-carboxamide; [0106]
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylb-
utyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2--
a]pyrimidine-9-carboxamide; [0107]
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1--
(3-pyridinylmethyl)-1,2,8,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[-
1,2-a]pyrimidine-9-carboxamide; [0108]
(4S,12aS)-1-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-
-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyr-
imidine-9-carboxamide; [0109]
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-[2-(methyl-
oxy)ethyl]-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino-
[1,2-a]pyrimidine-9-carboxamide; [0110]
(3aS,5aS,13aS)--N-[(2,4-Difluorophenyl)methyl]-hydroxy-5-(2-methylpropyl)-
-10,12-dioxo-2,3,3a,4,5,5a,6,10,12,13a-decahydro-1H-cyclopenta(e)pyrido[1'-
,2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide; [0111]
(3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-3-ethyl-6-hydroxy'5,7-dioxo-2,3-
,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamid-
e; [0112]
(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(-
4-morpholinyl)ethyl]-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydro-
pyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide; [0113]
(3aR,5aR,13aS)--N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2-
,3,3a,4,5a,6,10,12,13a-decahydrocyclopenta[d]pyrido[1',2':4,5]pyrazino[2,1-
-b][1,3]oxazine-9-carboxamide; [0114]
(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-methyl-11,13--
dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':4,5]pyrazino[1-
,2-a]quinazoline-10-carboxamide; [0115]
(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(methyloxy-
)ethyl]-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':-
4,5]pyrazino[1,2-a]quinazoline-10-carboxamide; [0116]
(4aS,6aS,14aS)-6-[2-(Acetylamino)ethyl]-N-[(2,4-difluorophenyl)methyl]-12-
-hydroxy-1,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':-
4,5]pyrazino[1,2-a]quinazoline-10-carboxamide; [0117]
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3-
,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamid-
e; [0118]
(3S,11aR)-3-Butyl-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-d-
ioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-ca-
rboxamide; [0119]
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(4-hydroxyphenyl)m-
ethyl]dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazi-
ne-8-carboxamide [0120]
(4S,12aS)-1-Cyclobutyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl--
6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyri-
midine-9-carboxamide; [0121]
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1--
(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,-
5]pyrazino[1,2-a]pyrimidine-9-carboxamide; [0122]
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropy-
l)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]p-
yrimidine-9-carboxamide; [0123]
(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-(2-hydroxyeth-
yl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':4,5]-
pyrazino[1,2-a]quinazoline-10-carboxamide; [0124]
(4aS,6aS,14aS)-6-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]-12-hydroxy-11-
,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2'4,6]pyrazin-
o[1,2-a]quinazoline-10-carboxamide; [0125]
(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-6-[-
2-(1-pyrrolidinyl)ethyl]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1-
',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide; [0126]
(4aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8,10-dioxo-2,3,4,4a,-
5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1',2':4,5]pyrazino[1,2-a]-
pyrimidine-11-carboxamide; [0127]
(4S,12aS)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-[2-(methyloxy)-
ethyl]-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-
-a]pyrimidine-9-carboxamide; [0128]
(4S,12aS)-1-Cyclobutyl-N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8--
dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidi-
ne-9-carboxamide; [0129]
(4S,12aS)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropy-
l)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]p-
yrimidine-9-carboxamide; [0130]
(4S,12aS)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo-1,-
2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-car-
boxamide; [0131]
(4S,12aS)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tet-
rahydro-2H-thiopyran-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino-
[1,2-a]pyrimidine-9-carboxamide; [0132]
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-diox-
o-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-
-carboxamide; [0133]
(4S,12aS)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl-
)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]py-
rimidine-9-carboxamide; [0134]
(4S,12aS)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6-
,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrim-
idine-9-carboxamide; enantiomers thereof; diastereomers thereof;
mixtures of enantiomers thereof; mixtures of diastereomers thereof;
mixtures of enantiomers and diastereomers thereof; and
pharmaceutically acceptable salts thereof. (32) A compound selected
from the group consisting of: [0135]
(4aS,13aR)--N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2-
,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,-
2-d]pyrazine-8-carboxamide; [0136]
(4aS,13aR)--N-[(4-Fluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,1-
1,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazin-
e-8-carboxamide; [0137]
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(1S)-1-methylpropy-
l]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyraz-
ine-8-carboxamide; [0138]
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,-
3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxami-
de; [0139]
(3S,11aR)--N-[(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-di-
oxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-car-
boxamide; [0140]
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylp-
ropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1
',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide; [0141]
(4S,12aS)-1-(Cyclopropylmethyl)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy--
4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1-
,2-a]pyrimidine-9-carboxamide; [0142]
(4aR,6aR,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3-
,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]pyrazino[1,2-a][3,1]b-
enzoxazine-10-carboxamide; [0143]
(4aR,6aR,14aS)--N-[(4-Fluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3,4,4-
a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]pyrazino[1,2-a][3,1]benzo-
xazine-10-carboxamide [0144]
4S,9aR)-5-Hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a-
,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;
[0145]
4R,9aS)-5-Hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a-
,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;
[0146]
2R,9aS)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a-
,8a-diaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide;
enantiomers thereof; diastereomers thereof; mixtures of enantiomers
thereof; mixtures of diastereomers thereof; mixtures of enantiomers
and diastereomers thereof; and pharmaceutically acceptable salts
thereof. (33) A compound according to the above (31) or (32)
wherein the pharmaceutically acceptable salt is a sodium salt. (34)
A pharmaceutical composition comprising a compound according to any
one of the above (1) to (33), or a pharmaceutically acceptable
salt, or solvate thereof. (35) A pharmaceutical composition
according to the above (34), which is an anti-HIV agent. (36) A
process for the preparation of a compound of formula (I-20a)
##STR00009##
[0146] wherein R.sup.e is one or two halogen; R.sup.z is
C.sub.1-8alkyl, C.sub.6-14arylC.sub.1-8alkyl, C.sub.6-14aryl, or
alkoxy; and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; comprising
condensing a compound of the formula
##STR00010##
wherein R.sup.e is one or two halogen; R.sup.50 is C.sub.1-8alkyl;
and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; with a compound of the
formula
##STR00011##
wherein R.sup.x is C.sub.1-8alkyl, C.sub.6-14arylC.sub.1-8alkyl,
C.sub.6-14aryl, or alkoxy; to form a compound of formula (I-20a).
(37) A process for the preparation of a compound of formula
(I-20b)
##STR00012##
wherein R.sup.e is one or two halogen; R.sup.x is C.sub.1-8alkyl,
C.sub.6-14arylC.sub.1-8alkyl, C.sub.6-14aryl, or alkoxy; and
P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; comprising condensing a
compound of the formula
##STR00013##
wherein R.sup.e is one or two halogen; R.sup.60 is C.sub.1-8alkyl;
and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; with a compound of the
formula
##STR00014##
wherein R.sup.x is C.sub.1-8alkyl, C.sub.6-14arylC.sub.1-8alkyl,
C.sub.6-14aryl, or alkoxy; to form a compound of formula (I-20b).
(38) A process for the preparation of a compound of formula
(I-21a)
##STR00015##
wherein R.sup.e is one or two halogen; and P.sup.1 is
C.sub.6-14arylC.sub.1-8alkyl; comprising condensing a compound of
the formula
##STR00016##
wherein R.sup.e is one or two halogen; R.sup.50 is C.sub.1-8alkyl;
and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; with a compound of the
formula
##STR00017##
to form a compound of formula (I-21a). (39) A process for the
preparation of a compound of formula (I-21b)
##STR00018##
wherein R.sup.e is one or two halogen; and P.sup.1 is
C.sub.6-14arylC.sub.1-8alkyl; comprising condensing a compound of
the formula
##STR00019##
wherein R.sup.e is one or two halogen; R.sup.50 is C.sub.1-8alkyl;
and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; with a compound of the
formula
##STR00020##
to form a compound of formula (I-21b). (40) A process for the
preparation of a compound of formula (I-22a)
##STR00021##
wherein R.sup.e is one or two halogen; and P.sup.1 is
C.sub.6-14arylC.sub.1-8alkyl; comprising condensing a compound of
the formula
##STR00022##
wherein R.sup.e is one or two halogen; R.sup.50 C.sub.1-8alkyl; and
P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; with a compound of the
formula
##STR00023##
to form a compound of formula (I-22a), (41) A process for the
preparation of a compound of formula (I-22b)
##STR00024##
wherein R.sup.e is one or two halogen; and P.sup.1 is
C.sub.6-14arylC.sub.1-8alkyl; comprising condensing a compound of
the formula
##STR00025##
wherein R.sup.e is one or two halogen; R.sup.50 is C.sub.1-8alkyl;
and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; with a compound of the
formula
##STR00026##
to form a compound of formula (I-22b). (42) A process for the
preparation of a compound of formula (I-23a)
##STR00027##
wherein R.sup.e is one or two halogen; and P.sup.1 is
C.sub.6-14arylC.sub.1-8alkyl; comprising condensing a compound of
the formula
##STR00028##
wherein R.sup.e is one or two halogen; R.sup.50 is C.sub.1-8alkyl;
and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; with a compound of the
formula
##STR00029##
to form a compound of formula (I-23a). (43) A process for the
preparation of a compound of formula (I-23b)
##STR00030##
wherein R.sup.e is one or two halogen; and P.sup.1 is
C.sub.6-14arylC.sub.1-8alkyl; comprising condensing a compound of
the formula
##STR00031##
wherein R.sup.e is one or two halogen; R.sup.50 is C.sub.1-8alkyl;
with a compound of the formula
##STR00032##
to form a compound of formula (I-23b). (44) A process for the
preparation of a compound of formula (I-24a)
##STR00033##
wherein R.sup.e is one or two halogen; R.sup.z is C.sub.1-8alkyl;
R.sup.z1 is hydrogen, C.sub.3-6cycloalkyl, heterocycle, or
C.sub.1-8alkyl optionally substituted with hydroxy,
C.sub.3-6cycloalkyl, alkoxy, heterocycle, heteroaryl,
C.sub.6-14aryl, or amino, wherein said amino may be optionally
substituted with --C(O)C.sub.1-8alkyl or C.sub.1-8alkyl; and
P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; comprising condensing a
compound of the formula
##STR00034##
wherein R.sup.e is one or two halogen; and R.sup.50 is
C.sub.1-8alkyl; and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; with a
compound of the formula
##STR00035##
wherein R.sup.z is C.sub.1-8alkyl; R.sup.z1 is hydrogen,
C.sub.3-6cycloalkyl, heterocycle, or C.sub.1-8alkyl optionally
substituted with hydroxy, C.sub.3-6cycloalkyl, alkoxy, heterocycle,
heteroaryl, C.sub.6-14aryl, or amino, wherein said amino may be
optionally substituted with --C(O)C.sub.1-8alkyl or C.sub.1-8alkyl;
to form a compound of the formula (I-24a). (45) A process for the
preparation of a compound of formula (I-24b)
##STR00036##
wherein R.sup.e is one or two halogen; R.sup.z is C.sub.1-8alkyl;
R.sup.z1 is hydrogen, C.sub.3-6cycloalkyl, heterocycle, or
C.sub.1-8alkyl optionally substituted with hydroxy,
C.sub.3-6cycloalkyl, alkoxy, heterocycle, heteroaryl,
C.sub.6-14aryl, or amino, wherein said amino may be optionally
substituted with --C(O)C.sub.1-8alkyl or C.sub.1-8alkyl; and
P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; comprising condensing a
compound of the formula
##STR00037##
wherein R.sup.e is one or two halogen; R.sup.50 is C.sub.1-8alkyl;
and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; with a compound of the
formula
##STR00038##
wherein R.sup.z is C.sub.1-8alkyl; and R.sup.z1 is hydrogen,
C.sub.3-6cycloalkyl, heterocycle, or C.sub.1-8alkyl optionally
substituted with hydroxy, C.sub.3-6cycloalkyl, alkoxy, heterocycle,
heteroaryl, C.sub.6-14aryl, or amino, wherein said amino may be
optionally substituted with C(O)C.sub.1-8alkyl or C.sub.1-8alkyl;
to form a compound of the formula (I-24b). (46) A process for the
preparation of a racemic compound of formula (I-25)
##STR00039##
wherein R.sup.e is one or two halogen; R.sup.z1 is hydrogen,
C.sub.3-6cycloalkyl, heterocycle, or C.sub.1-8alkyl optionally
substituted with hydroxy, C.sub.3-6cycloalkyl, alkoxy, heterocycle,
heteroaryl, C.sub.6-14aryl, or amino, wherein said amino may be
optionally substituted with --C(O)C.sub.1-8alkyl or C.sub.1-8alkyl;
and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; comprising condensing
a compound of the formula
##STR00040##
wherein R.sup.e is one or two halogen; and R.sup.50 is
C.sub.1-8alkyl; and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; with a
racemic compound of the formula
##STR00041##
wherein R.sup.z1 is hydrogen, C.sub.3-6cycloalkyl, heterocycle, or
C.sub.1-8alkyl optionally substituted with hydroxy,
C.sub.3-6cycloalkyl, alkoxy, heterocycle, heteroaryl,
C.sub.6-14aryl, or amino, wherein said amino may be optionally
substituted with --C(O)C.sub.1-8alkyl or C.sub.1-8alkyl; to form a
racemic compound of the formula (I-25). (47) A process for the
preparation of a racemic compound of formula (I-26)
##STR00042##
wherein R.sup.e is one or two halogen; R.sup.z1 is hydrogen,
C.sub.3-6cycloalkyl, heterocycle, or C.sub.1-8alkyl optionally
substituted with hydroxy, C.sub.3-6cycloalkyl, alkoxy, heterocycle,
heteroaryl, C.sub.6-14aryl, or amino, wherein said amino may be
optionally substituted with --C(O)C.sub.1-8alkyl or C.sub.1-8alkyl;
and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; comprising condensing
a compound of the formula
##STR00043##
wherein R.sup.e is one or two halogen; R.sup.50 is C.sub.1-8alkyl;
and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; with a racemic
compound of the formula
##STR00044##
wherein R.sup.z1 is hydrogen, C.sub.3-6cycloalkyl, heterocycle, or
C.sub.1-8alkyl optionally substituted with hydroxy,
C.sub.3-6cycloalkyl, alkoxy, heterocycle, heteroaryl,
C.sub.6-14aryl, or amino, wherein said amino may be optionally
substituted with --C(O)C.sub.1-8alkyl or C.sub.1-8alkyl; to form a
racemic compound of formula (I-26). (48) A process for the
preparation of a racemic compound of formula (I-27)
##STR00045##
wherein R.sup.e is halogen; and P.sup.1 is C.sub.6-14
arylC.sub.1-8alkyl; comprising condensing a compound of the
formula
##STR00046##
wherein R.sup.e is one or two halogen; R.sup.50 is C.sub.1-8alkyl;
and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl; with a racemic
compound of the formula
##STR00047##
to form a racemic compound of formula (I-27). (49). A compound of
formula (I-20a) described in above (36), formula (I-20b) described
in above (37), formula (I-21a) described in above (38), formula
(I-21b) described in above (39), formula (I-22a) described in above
(40), formula (I-22b) described in above (41), formula (I-23a)
described in above (42), formula (I-23 h) described in above (43),
formula (I-24a) described in above (44), formula (I-24b) described
in above (45), formula (I-25) described in above (46), formula
(I-26) described in above (47), or formula (I-27) described in
above (48), or a pharmaceutically acceptable salt thereof. (50) A
compound of formula (I-20a) described in above (36), formula
(I-20b) described in above (37), formula (I-21a) described in above
(38), formula (I-21b) described in above (39), formula (I-22a)
described in above (40), formula (I-22b) described in above (41),
formula (I-23a) described in above (42), formula (I-23b) described
in above (43), formula (I-24a) described in above (44), formula
(I-24b) described in above (45), formula (I-25) described in above
(46), formula (I-26) described in above (47), or formula (I-27)
described in above (48), or a pharmaceutically acceptable salt
thereof, wherein each P.sup.1 is hydrogen.
[0147] The present invention further provides a pharmaceutical
composition containing any of the compounds shown above, a
pharmaceutically acceptable salt or a solvate thereof, especially
an anti-HIV agent.
Effect of the Invention
[0148] The present invention compounds possess an integrase
inhibitory activity and/or a cell-growth inhibitory activity
against virus, especially HIV. Accordingly, they are useful for the
prevention or treatment of various diseases mediated by integrase
or virus infection diseases (e.g., AIDS). The present invention
further provides a process for preparing a diastereomer, a mixture
thereof, or racemate.
PREFERRED EMBODIMENT OF THE INVENTION
[0149] The terms used herein are explained below, Each term, alone
or in combination with another term, means as follows.
[0150] "Lower alkylene" means a straight or branched C1 to C6
alkylene such as methylene, ethylene, trimethylene, n-propylene,
tetramethylene, ethylethylene, pentamethylene, or hexamethylene,
preferably C1 to C4 straight alkylene such as methylene, ethylene,
trimethylene, and tetramethylene, more preferably methylene or
ethylene.
[0151] "Lower alkenylene" means a straight or branched C2 to C6
alkenylene, which consists of the above "Lower alkylene" having one
or more double bonds, such as vinylene, propylene, or butenylene,
preferably a straight C2 to C3 alkenylene such as vinylene or
propylene.
[0152] "Lower alkyl" means a straight or branched C1 to C10 alkyl
such as methyl, ethyl, n-propyl, t-butyl, isobutyl, sec-butyl,
n-pentyl, and n-hexyl, and preferred is C1 to C3 alkyl, more
preferred is methyl, ethyl or n-propyl, n-pentyl, isopentyl,
neopentyl, tert-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl,
n-nonyl, and n-desyl, preferably C1 to C6 lower alkyl, more
preferably C1 to C4 lower alkyl such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
isopentyl, neopentyl, tert-pentyl, n-hexyl, and isohexyl.
[0153] When lower alkyl is intervened with "--N.dbd." ".dbd.N--",
the lower alkyl may have a double bond to form
CH.sub.2--N.dbd.CH.sub.2, --CH.dbd.N--CH.sub.3 etc.
[0154] "Alkenyl" means a straight or branched C2 to C8 alkenyl,
which consists of the above "alkyl" having one or more double
bonds, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,
3-butenyl, 1,3-butadienyl, and 3-methyl-2-butenyl, preferably C2 to
C6 alkenyl, and more preferably C2 to C4 alkenyl.
[0155] "Lower alkenyloxy" means oxy attached to the above lower
alkenyl, such as vinyloxy, 1-propenyloxy, 2-propenyloxy,
1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 1,3-butadienyloxy, and
3-methyl-2-butenyloxy.
[0156] "Cycloalkyl" means C3 to C8 cyclic saturated hydrocarbon,
such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopentyl, and cyclooctyl, preferably C3 to C6 cycloalkyl.
[0157] "Cycloalkyl lower alkyl" means lower alkyl substituted with
the above cycloalkyl, such as cyclopropylmethyl, cyclopropylethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and
cyclohexylethyl, and preferably C8 to C6 cycloalkyl lower
alkyl.
[0158] "Aryl" means monocyclic aromatic hydrocarbon (e.g., phenyl)
and polycyclic hydrocarbon (e.g., 1-naphthyl, 2-naphthyl,
1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl,
3-phenanthryl, 4-phenanthryl, 9-phenanthryl), preferably phenyl or
naphthyl (e.g., 1-napthyl, 2-naphthyl).
[0159] "Aralkyl" or "aryl lower alkyl" means the above lower alkyl
substituted with 1 to 3 of the above aryl, such as benzyl,
diphenylmethyl, triphenylmethyl, phenethyl, 1-napthylmethyl,
2-napthylmethyl, preferably benzyl.
[0160] "Aryloxy" means oxy attached to the above aryl, such as
1-naphthyloxy, 2-naphthyloxy, 1-anthryloxy, 2-anthryloxy,
9-anthryloxy, 1-phenanthryloxy, 2-phenanthryloxy, 3-phenanthryloxy,
4-phenanthryloxy, and 9-phenanthryloxy, preferably phenyloxy or
naphthyloxy (e.g., 1-napthyloxy, 2-naphthyloxy).
[0161] "Heterocyclic group" means "heteroring" or "heteroaryl".
[0162] "Heteroring" means a non-aromatic ring which has at least
one of N, O and/or S in the ring and may be bonded at any
substitutable position, preferably 5- to 7-membered ring, such as
1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrrolidinyl, 2-pyrrolidinyl,
3-pyrrolidinyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,
1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,
1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl,
3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl,
3-piperidyl, 4-piperidyl, 1-piperadinyl, 2-piperadinyl,
2-morpholinyl, 3-morpholinyl, morpholino, and tetrahydropyranyl.
The non-aromatic ring is a saturated or unsaturated ring.
[0163] "Heteroaryl" means monocyclic aromatic hetero-type ring or
condensed aromatic hetero-type ring.
[0164] "Monocyclic aromatic hetero-type ring" means a 5- to
8-membered aromatic ring, which contains 1 to 4 of O, S, P and/or N
and may be bonded at any substitutable position.
[0165] "Condensed aromatic hetero-type ring" means a group wherein
an aromatic ring containing 1 to 4 of O, S, P and/or N is condensed
with 1 to 4 of 5- to 8-membered aromatic ring(s) or the other 5- to
8-membered aromatic heteroring(s).
[0166] Examples of "heteroaryl" include furyl (e.g., 2-furyl,
3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g.,
1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g.,
1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g.,
1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g.,
1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-4-yl),
tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl),
oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl
(e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (e.g.,
2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl
(e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridil
(e.g., 2-pyridil, 3-pyridil, pyridazinyl 3-pyridazinyl,
4-pyridazinyl))pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl), furazanyl (e.g., 3-furazanyl), pyrazinyl (e.g.,
2-pyrazinyl), oxadiazolyl (e.g., 1,3,4-oxadiazole-2-yl), benzofuryl
(e.g., 2-benzo[b]furyl, 8-benzo[b]furyl, 4-benzo[b]furyl,
5-benzo[b]furyl, 6-benzo[b]furyl, 7-benzo[b]furyl),
benzothienyl(e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl,
4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl,
7-benzo[b]thienyl), benzoimidazolyl (e.g., 1-benzoimidazolyl,
2-benzoimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl),
dibenzofuryl, benzooxazolyl, quinoxalinyl (e.g., 2-quinoxalinyl,
5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (e.g., 3-cinnolinyl,
4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl,
quinazolinyl (e.g., 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl,
6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinolyl(e.g.,
2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl,
7-quinolyl, 8-quinolyl), phthalazinyl (e.g., 1-phthalazinyl,
5-phthalazinyl, 6-phthalazinyl), isoquinolyl (e.g., 1-isoquinolyl,
3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7
isoquinolyl, 8-isoquinolyl), purinyl, pteridinyl (e.g.,
2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl),
carbazolyl, phenanthridinyl, acridinyl (e.g., 1-acridinyl,
2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), indolyl (e.g.,
1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl,
7-indolyl), isoindolyl, phenadinyl (e.g., 1-phenandinyl,
2-phenadinyl) or phenothiadinyl (e.g., 1-phenothiadinyl,
2-phenothiadinyl, phenothiadinyl, 4-phenothiadinyl).
[0167] "Heterocycle" means a cycle which can be lead to the above
heterocyclic group.
[0168] "Heterocyclic group lower alkyl" or "Heterocycle lower
alkyl" means lower alkyl substituted with the above heterocyclic
group.
[0169] "Heterocyclic group oxy" or "Heterocycle oxy" means an oxy
attached to the above heterocyclic group.
[0170] "Heterocyclic group carbonyl" or "Heterocyclocarbonyl" means
a carbonyl attached to the above heterocyclic group
[0171] "Lower alkoxy" or "alkoxy" means an oxy attached to the
above lower alkyl, such as methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, isobutoxy, tert-butoxy.
[0172] "Lower alkylcarbonyl", "cycloalkylcarbonyl", "cycloalkyl
lower alkylcarbonyl", "lower alkoxycarbonyl", "arylcarbonyl", "aryl
lower alkylcarbonyl", "aryloxycarbonyl", "heterocyclocarbonyl",
"heterocycle lower alkylcarbonyl", and "heterocycle oxycarbonyl",
each means a carbonyl attached to the above "lower alkyl",
"cycloalkyl", "cycloalkyl lower alkyl", "lower alkoxy", "aryl",
"aryl lower alkyl", "aryloxy", "heterocycle", "heterocycle lower
alkyl", and "heterocyclooxy", respectively.
[0173] When a substituent(s) is/are present on "optionally
substituted lower alkyl", "optionally substituted cycloalkyl",
"optionally substituted cycloalkyl lower alkyl", "optionally
substituted lower alkenyl", "optionally substituted lower alkoxy",
"optionally substituted aryl", "optionally substituted aryl lower
alkyl", "optionally substituted aryloxy", "optionally substituted
aryloxy lower alkyl", "optionally substituted heterocycle,
"optionally substituted heterocyclic group", "optionally
substituted heterocycle lower alkyl", "optionally substituted
heterocyclooxy", "optionally substituted lower alkenyloxy",
"optionally substituted lower alkylcarbonyl", "optionally
substituted cycloalkylcarbonyl", "optionally substituted cycloalkyl
lower alkylcarbonyl", "optionally substituted lower
alkoxycarbonyl", "optionally substituted arylcarbonyl", "optionally
substituted aryl lower alkylcarbonyl", "optionally substituted
aryloxycarbonyl", "optionally substituted heterocyclocarbonyl",
"optionally substituted heterocycle lower alkylcarbonyl",
"optionally substituted heterocyclooxycarbonyl", "optionally
substituted lower alkylene", "optionally substituted lower
alkenylene", "optionally substituted phosphoric acid residue",
"optionally substituted carbocycle" or "optionally substituted
heterocycle", each may be substituted with the same or different, 1
to 4 group(s) selected from Substituent group B at any
position.
[0174] Examples of Substituent group B include hydroxy, carboxy,
halogen (F, Cl, Br, I), halo lower alkyl (e.g., CF.sub.3,
CH.sub.2CF.sub.3, CH.sub.2CCl.sub.3), halo lower alkoxy (e.g.,
OCF.sub.3, OCH.sub.2CF.sub.3, OCH.sub.2CCl.sub.3), lower alkyl
(e.g., methyl, ethyl, isopropyl, tert-butyl), lower alkenyl (e.g.,
vinyl), lower alkynyl ethynyl), cycloalkyl (e.g., cyclopropyl),
cycloalkenyl cyclopropenyl), lower alkoxy (e.g., methoxy, ethoxy,
propoxy, butoxy), lower alkenyloxy vinyloxy, allyloxy), lower
alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,
tert-butoxycarbonyl), nitro, nitroso, optionally substituted amino
(e.g., alkylamino methylamino, ethylamino, dimethylamino),
acylamino (e.g., acetylamino, benzoylamino), aralkylamino
benzylamino, tritylamino), hydroxyamino), azido, aryl (e.g.,
phenyl), aralkyl benzyl), cyano, isocyano, isocyanate, thiocyanate,
isothiocyanate, mercapto, alkylthio methylthio), alkylsulfonyl
(e.g., methanesulfonyl, ethanesulfonyl), optionally substituted
alkylsulfonyl amino (e.g., methanesulfonylamino,
ethanesulfonylamino, N-methylsulfonyl-N'-methylamino), optionally
substituted carbamoyl (e.g., alkylcarbamoylmethylcarbamoyl,
ethylcarbamoyl, dimethylcarbamoyl)), sulfamoyl, acyl formyl,
acetyl), formyloxy, haloformyl, oxal, thioformyl, thiocarboxy,
dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino,
hydrazino, azido, ureido, amizino, quanidino, phthalimide, oxo,
phosphoric acid residue, lower alkyl which is substituted with a
phosphoric acid residue and may be intervened with a heteroatom
group(s), aryl substituted with a phosphoric acid residue, aralkyl
substituted with a phosphoric acid residue, hydroxyl lower alkyl,
preferably hydroxy, carboxy, halogen (F, Cl, Br, I), halo lower
alkyl (e.g., CF.sub.3, CH.sub.2CF.sub.3, CH.sub.2CCl.sub.3), halo
lower alkoxy (e.g., OCF.sub.3, OCH.sub.2CF.sub.3,
OCH.sub.2CCl.sub.3), lower alkyl (e.g., methyl, ethyl, isopropyl,
tert-butyl), lower alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy),
optionally substituted amino (e.g., alkylamino methylamino,
ethylamino, dimethylamino), oxo, or phosphoric acid residue.
[0175] Examples of a substituent of "optionally substituted amino"
or "optionally substituted carbamoyl" include mono- or di-lower
alkyl, lower alkylcarbonyl, lower alkylsulfonyl, optionally
substituted lower alkyl (e.g., methyl, ethyl, isopropyl, benzyl,
carbamoylalkyl (e.g., carbamoylmethyl), mono- or di-lower
alkylcarbamoyl lower alkyl (e.g., dimethylcarbamoylmethyl),
hydroxyl lower alkyl, heterocycle lower alkyl (e.g.,
morpholinoethyl, tetrahydropyranylethyl), alkoxycarbonyl lower
alkyl (e.g., ethoxycarbonylmethyl, ethoxycarbonylethyl), mono- or
di-lower alkylamino lower alkyl (e.g., dimethylaminoethyl)), lower
alkoxy lower alkyl (e.g., methoxyethyl, ethoxymethyl, ethoxyethyl,
isopropoxyethyl), acyl formyl, optionally substituted lower
alkylcarbonyl (e.g., acetyl, propionyl, butylyl, isobutynyl,
valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl,
methoxymethylcarbonyl, 2,2,2-trifluoroethylcarbonyl,
ethoxycarbonylmethylcarbonyl), lower alkoxy lower alkylcarbonyl
methoxyethylcarbonyl), lower alkylcarbamoyl lower alkylcarbonyl
methylcarbamoylehtylcarbonyl), alkoxycarbonylacetyl), optionally
substituted arylcarbonyl benzoyl, toloyl), optionally substituted
aralkyl (e.g., benzyl, 4-fluorobenzyl), hydroxy, optionally
substituted lower alkylsulfonyl methane sulfonyl, ethanesulfonyl,
isopropylsulfonyl, 2,2,2-trifluoroethanesulfonyl, benzylsulfonyl,
methoxyethylsulfonyl), lower alkyl, or arylsulfonyl optionally
substituted with halogen (e.g., benzenesulfonyl, toluenesulfonyl,
4-fluorobenzenesulfonyl, fluorobenzenesulfonyl), cycloalkyl
cyclopropyl), aryl optionally substituted with lower alkyl (e.g.,
phenyl, trithyl), lower alkyl aminosulfonyl (e.g.,
methylaminosulfonyl, dimethylaminosulfonyl), lower
alkylaminocarbonyl dimethylaminocarbonyl), lower alkoxycarbonyl
ethoxycarbonyl), cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,
cyclohexylcarbonyl), optionally substituted sulfamoyl,
methylsulfamoyl, dimethylsulfamoyl), lower alkylcarbonylamino
(e.g., methylcarbonylamino), heterocycle (e.g., morpholino,
tetrahydropyranyl), optionally substituted amino (e.g., mono- or
di-alkylamino dimethylamino), formylamino).
[0176] As to amino of "optionally substituted amino", "optionally
substituted carbamoyl", or "optionally substituted
carbamoylcarbonyl", two substituents on the amino together with the
neighboring N atom may form an N-containing heterocycle which
optionally contains S and/or O in the ring (preferably 5- to
7-membered ring or saturated ring) and is optionally substituted
with oxo or hydroxy. The optional S atom in the ring may be
substituted with oxo. The N-containing heterocycle is preferably a
5- or 6-membered ring such as piperadinyl, piperidino, morpholino,
pyrrolidino, 2-oxopiperidino, 2-oxopyrrolidino,
4-hydroxymorpholine.
[0177] "Phosphoric acid residue" means a group shown of the
formula: --PO(OH).sub.2. "Optionally substituted phosphoric acid
residue" means a phosphoric acid residue wherein the OH part and/or
a hydrogen of the OH is optionally substituted with a phosphoric
acid residue, preferably shown by the formula:
##STR00048##
(wherein, R.sup.A and R.sup.B each is independently OR.sup.C or
NR.sup.DR.sup.E (wherein R.sup.C, R.sup.D and R.sup.E are each
independently hydrogen, optionally substituted lower alkyl,
optionally substituted cycloalkyl, optionally substituted aryl,
optionally substituted heterocyclic group, or R.sup.D and R.sup.E
taken together with the neighboring N atom may form an optionally
substituted heterocycle (preferably 5- to 6-membered ring)) or
R.sup.A and RD taken together with the neighboring P atom may form
an optionally substituted heterocycle (preferably 5- to 6-membered
ring)).
[0178] Preferably, R.sup.A and R.sup.B are both OR.sup.C, or one of
them is OR.sup.C and the other is NR.sup.DR.sup.E. R.sup.C, R.sup.D
and R.sup.E each is preferably, independently, lower alkyl (e.g.,
methyl, ethyl).
[0179] The optionally substituted heterocycle formed by R.sup.A and
R.sup.B taken together with the neighboring P atom may be the
following structure:
##STR00049##
(wherein, the broken line means a part of the ring)
[0180] Hydroxy substituted with optionally substituted phosphoric
acid residue is preferably hydroxy substituted with a phosphoric
acid residue substituted with di lower alkyls, and more preferably
a group of the formula:
##STR00050##
[0181] Amino substituted with optionally substituted phosphoric
acid residue is preferably amino substituted with a phosphoric acid
residue substituted with di lower alkyls, and more preferably a
group of the formula:
##STR00051##
More Preferable Embodiments
[0182] R.sup.1 is hydrogen or lower alkyl, preferably hydrogen.
[0183] X is a single bond, a heteroatom group selected from O, S,
SO, SO.sub.2 and NH (hereafter also referred to as "M"), or lower
alkylene or lower alkenylene each may be intervened by the
heteroatom. The term of "intervened by" means the following
cases:
1) The heteroatom group is present between carbon atoms which
constitutes the alkylene or alkenylene. 2) The heteroatom group is
attached to the N atom of the carbamoyl group neighboring to X. 3)
The heteroatom group is attached to R.sup.2 neighboring to X.
[0184] The heteroatom group (M) may be the same or different, and
one or more atoms. Examples of that lower alkylene is intervened by
a heteroatom group include -M-CH.sub.2--, --CH.sub.2-M-CH.sub.2,
--CH.sub.2-M-, and --CH.sub.2-M-M-CH.sub.2--.
[0185] X is preferably a spacer consisting 1 to 3 joined atoms. X
is more preferably lower alkylene or lower alkenylene each may be
intervened by a heteroatom group, or O. X is most preferably C1 to
C3 alkylene, C2 to C3 alkenylene, or O. Especially preferred is
methylene or O.
[0186] R.sup.2, is optionally substituted aryl, preferably phenyl.
A substituent on the aryl is the same or different, 1 to 3,
preferably 1 to 2 substituent(s), including preferably halogen,
hydroxy, amino, lower alkylamino, cyano, carboxy, formyl, oxo,
lower alkyl, lower alkoxy, lower alkylthio, carbamoyl, and lower
alkylcarbamoyl, and Substituent group S1: optionally substituted
phosphoric acid residue, aryl substituted with optionally
substituted phosphoric acid residue, aralkyl substituted with
optionally substituted phosphoric acid residue, hydroxyl
substituted with optionally substituted phosphoric acid residue,
amino substituted with optionally substituted phosphoric acid
residue, lower alkyl substituted with optionally substituted
phosphoric acid residue (said lower alkyl may be intervened with a
hetero atom group(s) selected from O, S, SO, SO.sub.2, NR.sup.5
(R.sup.5 is independently selected from the same substituent group
for R.sup.4), --N.dbd. and .dbd.N--), lower alkoxy lower alkyl,
amino lower alkyl optionally substituted with mono- or di-lower
alkyl, halogenated lower alkyl, lower alkoxy, carbamoyl optionally
substituted with mono- or di-lower alkyl, optionally substituted
lower alkylsulfonylamino, halogenated lower alkoxy, hydroxyl lower
alkyl), more preferably halogen, hydroxy, amino, cyano, lower
alkyl, lower alkoxy or Substituent group S1, and most preferred is
halogen (e.g., F) and/or a group selected from Substituent group
S1, A substituent on the aryl is preferably at the 4-position,
R.sup.2 is more preferably phenyl or phenyl substituted with at
least halogen, and most preferably 4-halogenophenyl (e.g.,
4-F-phenyl). In another embodiment, R.sup.2 is preferably phenyl
optionally substituted with 1 to 3 R(s) mentioned below.
[0187] In all compounds of the present invention, the structure of
"--X--R.sup.2" is preferably shown by the formula below:
##STR00052##
[0188] R each is independently a group selected from halogen and
Substituent group S1.
[0189] Substituent group S1: optionally substituted phosphoric acid
residue, aryl substituted with optionally substituted phosphoric
acid residue, aralkyl substituted with optionally substituted
phosphoric acid residue, hydroxyl substituted with optionally
substituted phosphoric acid residue, amino substituted with
optionally substituted phosphoric acid residue, lower alkyl
substituted with optionally substituted phosphoric acid residue
(said lower alkyl may be intervened by a heteroatom group(s)
selected from CO, O, S, SO, SO.sub.2, NR.sup.a (R.sup.a is hydrogen
or lower alkyl), --N.dbd. and .dbd.N--), lower alkoxy lower alkyl,
optionally substituted amino lower alkyl (the substituent: mono- or
di-lower alkyl, lower alkylcarbonyl, or lower alkylsulfonyl),
halogenated lower alkyl, lower alkoxy, optionally substituted
carbamoyl (the substituent; mono- or di-lower alkyl, lower
alkylcarbonyl, or lower alkylsulfonyl), optionally substituted
lower alkylsulfonylamino, halogenated lower alkoxy, and hydroxyl
lower alkyl.
[0190] m is an integer of 0 to 3, preferably 0 or 1 to 2, when m is
1, R is preferably halogen. When m is 2, R is more preferably the
same or different group selected from halogen, lower alkyl, lower
alkoxy, lower alkoxylower alkyl, halogenated lower alkyl,
halogenated lower alkoxy, lower alkylsulfonylamino, carbamoyl, and
lower alkylcarbamoyl. More preferably, R is two halogens, or
halogen and another group. R preferably locates at the 4-position
and optional another position of the benzene ring.
[0191] R.sup.3 can be a various substituent which does not bring a
negative effect to the pharmacological activity, including
hydrogen, halogen, hydroxy, optionally substituted lower alkyl,
optionally substituted cycloalkyl, optionally substituted lower
alkenyl, optionally substituted lower alkoxy, optionally
substituted lower alkenyloxy, optionally substituted aryl,
optionally substituted aryloxy, optionally substituted heterocyclic
group, optionally substituted heterocyclooxy, and optionally
substituted amino. Examples of substituent of "optionally
substituted" include halogen, hydroxy, amino, lower alkylamino,
cyano, carboxy, formyl, oxo, lower alkyl, lower alkoxy, lower
alkylthio, carbamoyl, lower alkylcarbamoyl, aryl, heterocyclic
group, lower alkylcarbonyl, lower alkylcarbonyloxy, lower
alkoxycarbonyl, halogenated lower alkyl, halogenated lower alkoxy,
and preferably halogen, hydroxy, amino, lower alkylamino, lower
alkyl, and lower alkoxy. R.sup.3 is more preferably hydrogen,
halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower
alkenyloxy or optionally substituted amino, and most preferably
hydrogen or lower alkyl (e.g., methyl), esp. hydrogen.
[0192] Z.sup.2 shows C, CH, optionally substituted lower alkylene,
lower alkenylene etc., and Z.sup.2 and R.sup.4 of Z.sup.1 taken
together form a ring, whereby compound (I) shows a tricyclic
compound (I-1) or (I-11) shown below, or its derivative,
tetracyclic compound.
##STR00053##
[0193] A ring is optionally substituted heterocycle containing at
least an N atom. The heterocycle is a 5- to 7-membered ring which
contains preferably 1 to 3, more preferably 2 to 3 atoms of 0, S
and/or N. The heterocycle is preferably selected from the above
heterocycle. The arc optionally contains 1 to 2 heteroatom(s) at
any possible position. One of preferable embodiments of A ring is
an optionally substituted ring shown below.
##STR00054## ##STR00055##
(Z is CH.sub.2, O, S, SO, SO.sub.2 or NR.sup.19) [0194] A ring is
preferably a ring of (a), (b), or (c). [0195] Z is preferably O or
NR.sup.19.
[0196] When Z is NR.sup.19, examples of R.sup.19 include 1)
hydrogen, 2) optionally substituted lower alkyl (the substituent is
e.g., amino optionally substituted with mono- or di-lower alkyl;
cycloalkyl; hydroxy; optionally substituted heterocyclic group
(preferably 5- to 7-membered ring, e.g., furyl, thienyl, thiazolyl,
pyridil, morpholino, imidazole; examples of the substituent include
lower alkyl, halogen); optionally substituted heterocyclocarbonyl
(the heterocycle is preferably 5- to 7-membered ring, e.g.,
morpholinocarbonyl); optionally substituted phenyl (the substituent
is e.g., lower alkyl, amino, lower alkylamino, hydroxy, halogen,
halogenated lower alkyl, lower alkoxy, halogenated lower alkoxy,
lower alkylthio, lower alkylsulfonyl), acetylamino, carbamoyl,
carbamoyl substituted with mono- or di-lower alkyl, lower
alkylsulfonylamino, lower alkoxy, carbonyl, halogen, thiol, lower
alkylthio), 3) lower alkenyl, 4) acyl (e.g., lower alkylcarbonyl),
s) lower alkylsulfonyl, R.sup.19 may be selected from Substituent
group S2 shown below.
[0197] The other substituent on A ring may be selected from
R.sup.15 to R.sup.18 or Substituent group S2, preferably lower
alkyl. Substituents on A ring may form a condensed ring or a spiro
ring as mentioned below, whereby compound (I) includes a
tetracyclic compound.
[0198] A ring is more preferably any of the following rings:
##STR00056##
(wherein, R.sup.20 to R.sup.40 are each independently a group
selected from Substituent group S2, or any two groups of R.sup.20
to R.sup.40, which bonds to the same carbon atom, taken together
with the carbon atom, may form a spiro ring, i.e., an optionally
substituted carbocycle or optionally substituted heterocycle, or
each combination of (R.sup.20 and R.sup.22), (R.sup.23 and
R.sup.24), (R.sup.25 and R.sup.26), (R.sup.27 and R.sup.29),
(R.sup.30 and R.sup.31), (R.sup.32 and R.sup.34), (R.sup.35 and
R.sup.36), (R.sup.37 and R.sup.38), and (R.sup.39 and R.sup.40),
taken together with the neighboring atom, may form an optionally
substituted carbocycle or optionally substituted heterocycle.
[0199] Substitution group S2: hydrogen, optionally substituted
lower alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkyl lower alkyl, optionally substituted lower
alkenyl, optionally substituted lower alkoxy, optionally
substituted lower alkenyloxy, optionally substituted aryl,
optionally substituted aryl lower alkyl, optionally substituted
aryloxy, optionally substituted heterocycle, optionally substituted
heterocycle lower alkyl, optionally substituted heterocyclooxy,
hydroxy, optionally substituted amino, optionally substituted lower
alkylcarbonyl, optionally substituted cycloalkylcarbonyl,
optionally substituted cycloalkyl lower alkylcarbonyl, optionally
substituted lower alkoxycarbonyl, optionally substituted
arylcarbonyl, optionally substituted aryl lower alkylcarbonyl,
optionally substituted aryl oxycarbonyl, optionally substituted
heterocyclocarbonyl, optionally substituted heterocycle lower
alkylcarbonyl, optionally substituted heterocyclooxycarbonyl,
optionally substituted aminocarbonyl, optionally substituted
phosphoric acid residue, aryl substituted with optionally
substituted phosphoric acid residue, aralkyl substituted with
optionally substituted phosphoric acid residue, hydroxy substituted
with optionally substituted phosphoric acid residue, amino
substituted with optionally substituted phosphoric acid residue, or
lower alkyl substituted with optionally substituted phosphoric acid
residue (the lower alkyl may be intervened with a heteroatom
group(s) selected from CO, O, S, SO, SO.sub.2, NR.sup.5 (R.sup.5 is
independently selected from the same substitution group as
R.sup.4), --N.dbd. and .dbd.N--)
[0200] The stereochemistry of an asymmetric carbon represented by *
shows the R- or S-configuration, or a mixture thereof)
[0201] In one embodiment, R.sup.20 to R.sup.40 each is preferably
hydrogen, optionally substituted lower alkyl (examples of the
substituent: OH, lower alkoxy, cycloalkyl, lower alkylthio, lower
alkylsulfonyl, heterocyclic group, aryl, optionally substituted
amino (examples of the substituent: lower alkyl, acyl)),
cycloalkyl, optionally substituted aryl (examples of the
substituent: OH, lower alkyl), and optionally substituted
heterocyclic group.
[0202] In one embodiment, R.sup.20 to R.sup.25, R.sup.27 to
R.sup.30, and R.sup.32 to R.sup.99, each is preferably hydrogen,
C1-C8 alkyl, C6-C14 aryl C1-C8 alkyl, C6-C14 aryl, or alkoxy.
[0203] In one embodiment, R.sup.26, R.sup.31, and R.sup.40, each is
preferably hydrogen, C3-6 cycloalkyl, heterocycle, or C1-8 alkyl
optionally substituted with hydroxy, C3-6 cycloalkyl, alkoxy,
heterocycle, heteroaryl, C6-14 aryl, or amino, wherein said amino
may be optionally substituted with --C(O)C1-8 alkyl or C1-8
alkyl.
[0204] More Preferred embodiments are shown below for example
[0205] I) When A ring is A-1, preferred is that 1) Z is NR.sup.26
and R.sup.26 and R.sup.24 taken together form heterocycle, and the
others are hydrogens; 2) Z is O or NR.sup.26, (R.sup.20 and
R.sup.22) or (R.sup.23 and R.sup.24) taken together form cycloalkyl
which is substituted with phenyl, the others are hydrogens or
optionally substituted lower alkyl.
[0206] II) When A ring is A-2, preferred is that 1) Z is O,
R.sup.27 or R.sup.28 is lower alkyl, and the others are hydrogens;
2) Z is NR.sup.31 and R.sup.30 and R.sup.31 taken together form
heterocycle and the others are hydrogens, or R.sup.27 and R.sup.29
taken together form cycloalkyl and the others are hydrogens; 3) Z
is O, R.sup.27 and R.sup.29 taken together form cycloalkyl which
may be condensed with phenyl, and the others are hydrogens
[0207] R.sup.14 and R.sup.x are each independently hydrogen,
optionally substituted lower alkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkyl lower alkyl,
optionally substituted lower alkenyl, optionally substituted lower
alkoxy, optionally substituted lower alkenyloxy, optionally
substituted aryl, optionally substituted aryl lower alkyl,
optionally substituted aryloxy, optionally substituted heterocyclic
group, optionally substituted heterocycle lower alkyl, optionally
substituted heterocyclooxy, hydroxy, optionally substituted amino,
optionally substituted lower alkylcarbonyl, optionally substituted
cycloalkylcarbonyl, optionally substituted cycloalkyl lower
alkylcarbonyl, optionally substituted lower alkoxycarbonyl,
optionally substituted arylcarbonyl, optionally substituted aryl
lower alkylcarbonyl, optionally substituted aryloxycarbonyl,
optionally substituted heterocyclocarbonyl, optionally substituted
heterocycle lower alkylcarbonyl, optionally substituted
heterocyclooxycarbonyl, optionally substituted aminocarbonyl,
optionally substituted phosphoric acid residue, aryl substituted
with optionally substituted phosphoric acid residue, aralkyl
substituted with optionally substituted phosphoric acid residue,
hydroxy optionally substituted with optionally substituted
phosphoric acid residue, amino substituted with optionally
substituted phosphoric acid residue, or lower alkyl substituted
with optionally substituted phosphoric acid residue (the lower
alkyl may be intervened with a heteroatom group(s) selected from O,
S, SO, SO.sub.2, NR.sup.a (R.sup.a is hydrogen or lower alkyl),
--N.dbd. and .dbd.N--).
[0208] R.sup.14 and R.sup.x are each independently, preferably,
hydrogen, hydroxyl, optionally, substituted lower alkyl (the
substituent is preferably, e.g., amino, lower alkyl amino, hydroxy,
lower alkoxy). R.sup.14 and R.sup.x are preferably hydrogens.
[0209] A broken line in the compound (I-1) represents the presence
or absence of a bond, provided that when the broken line represents
the presence of a bond, R.sup.X is not present.
[0210] The compound (I) includes the following compounds,
##STR00057##
(wherein each symbol is as defined above)
##STR00058##
[0211] F ring means the same heterocycle as A ring, preferably 5-
to 7-membered ring, and the substituents on F ring are the same as
those for A ring. The other symbols are as defined above.
##STR00059##
(wherein each symbol is as defined above; Z is O or NR.sup.19;
R.sup.15 to R.sup.19 are each independently hydrogen or a group
selected from the above Substituent group S2, or each combination
of (R.sup.15 and R.sup.16, (R.sup.17 and R.sup.18), (R.sup.16 and
R.sup.18), and (R.sup.18 and R.sup.19) taken together with the
neighboring atom(s), may form an optionally substituted carbocycle
(preferably 5- to 6-membered ring) or an optionally substituted
heterocyle (preferably 5- to 6-membered ring); or each combination
of (R.sup.15 and R.sup.16) and (R.sup.17 and R.sup.18) taken
together may form oxo)
[0212] Compound (I-3) is preferably as follows.
(1) R.sup.1 is hydrogen; R.sup.3 is hydrogen; in is 1 or 2;
R.sup.14 is hydrogen. (2) m is 1 or 2, R is each independently
halogen, halogenated lower alkyl, lower alkoxy, halogenated lower
alkoxy, lower alkoxy lower alkyl, hydroxy lower alkyl, optionally
substituted amino lower alkyl (the substituent is mono- or di-lower
alkyl, lower alkylcarbonyl, or lower alkylsulfonyl), optionally
substituted carbamoyl (the substituent is mono- or di-lower alkyl,
lower alkylcarbonyl, or lower alkylsulfonyl), phosphoric acid
residue, aryl substituted with optionally substituted phosphoric
acid residue, aralkyl substituted with optionally substituted
phosphoric acid residue or sulfonylamino optionally substituted
with lower alkyl; R.sup.1 is hydrogen; R.sup.3 is hydrogen;
R.sup.14 is hydrogen, hydroxyl or lower alkyl optionally
substituted with mono- or di-lower alkylamino; Z is O or NR.sup.19
(R.sup.19) is hydrogen or lower alkyl, lower alkoxy lower alkyl,
optionally substituted phosphoric acid residue, aryl substituted
with optionally substituted phosphoric acid residue, aralkyl
substituted with optionally substituted phosphoric acid residue,
hydroxy substituted with optionally substituted phosphoric acid
residue, amino substituted with optionally substituted phosphoric
acid residue, or lower alkyl substituted with optionally
substituted phosphoric acid residue). (3) R is each independently,
--F, --CF.sub.3, --OMe, --OCF.sub.3, --CH.sub.2OMe, --CH.sub.2OH,
--CH.sub.2N(Me).sub.2, --CONHMe, --CON(Me).sub.2,
--CH.sub.2PO(OEt).sub.2, --PO(OEt).sub.2, --NHSO.sub.2Me, or
--NMeSO.sub.2Me; R.sup.1 is hydrogen; R.sup.3 is hydrogen; in is 1
or 2; R.sup.14 is hydrogen, hydroxyl or --CH.sub.2N(Me).sub.2; Z is
O or NR.sup.19 (R.sup.19 is hydrogen or --CH(Me).sub.2,
--(CH.sub.2).sub.2OMe, --(OH.sub.2).sub.2PO(OEt).sub.2). (4)
R.sup.15 and R.sup.16 are hydrogens; R.sup.17 and R.sup.18 are
hydrogens or taken together with the neighboring atom form a 3- to
7-membered carbocycle; and/or Z is O or NH. This case preferably
also satisfy the above (2) or (3).
##STR00060##
[0213] D ring means the same heterocycle as A ring, preferably 5-
to 7-membered ring, and the substituents on D ring are the same as
those for A ring. The other symbols are as defined above.
[0214] The structure of compound (I) has at least the following
characteristics.
(1) The main structure, condensed heterocycle, is substituted with
oxo (.dbd.O), hydroxyl (OH) and oxo. (2) A substituted carbamoyl
group (--CONR.sup.1XR.sup.2) is attached to the position
neighboring to the oxo group on the condensed heterocycle.
[0215] The above structure contributes to a remarkably potent
integrase inhibitory activity and/or cell-growth inhibitory
activity against virus including HIV. In contrast, the structures
of the other parts such as Z.sup.1, Z.sup.2, and R.sup.3 each may
be of variety, being optionally substituted or optionally
condensed, and its condensed ring is also optionally
substituted.
[0216] The present invention provides a pharmaceutically acceptable
salt or a solvate of compound (I). All theoretically possible
tautomer, geometrical isomer, optically active compound, and
racemate thereof are within the scope of the invention.
[0217] Pharmaceutically acceptable salts of a compound of the
present invention include, as basic salts, for example, alkali
metal salts such as sodium or potassium salts; alkaline-earth metal
salts such as calcium or magnesium salts; ammonium salts; aliphatic
amine salts such as trimethylamine, triethylamine,
dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine or
procaine salts; aralkyl amine salts such as
N,N-dibenzylethylenediamine salts; heterocyclic aromatic amine
salts such as pyridin salts, picoline salts, quinoline salts or
isoquinoline salts; quaternary ammonium salts such as
tetramethylammonium salts, tetraethylammonium salts,
benzyltrimethylammonium salts, benzyltriethylammonium salts,
benzyltributylammonium salts, methyltrioctylammonium salts or
tetrabutylammonium salts; and basic amino acid salts such as
arginine salts or lysine salts. Acid salts include, for example,
mineral acid salts such as hydrochloride, sulfates salts, nitrate
salts, phosphates salts, carbonates salts, hydrogencarbonates or
perchlorate; organic acid salts such as acetates, propionates,
lactates, maleates, fumarates, tartaric acid salts, malates,
citrates salts, ascorbates, formic acid; sulfonates such as
methanesulfonates, isethionates, benzenesulfonates, or
p-toluenesulfonates; and acidic amino acid salts such as aspartates
or glutamates.
[0218] Solvates of a compound of the present invention include
alcholates and hydrates.
[0219] A general process for producing the present compound will be
exemplified below.
(Method of Preparing Raw Material)
##STR00061##
[0220] (wherein L.sup.1 is a leaving group (e.g.: halogen); P.sup.1
and P.sup.2 are a hydroxy protecting group; P.sup.3 is a carboxy
protecting group (e.g.: lower alkyl); R.sup.a and R.sup.b are
hydrogen or a substituent on an amino group)
[0221] Examples of a hydroxy protecting group (P.sup.1, P.sup.2)
include acyl (e.g.: acetyl, pivaloyl, benzoyl), aralkyl (e.g.:
benzyl), lower alkyl (e.g.: methyl), alkoxyalkyl (e.g.:
methoxymethyl, methoxyethyl), lower alkylsulfonyl (e.g.: methane
sulfonyl), arylsulfonyl (e.g.: benzenesulfonyl, toluenesulfonyl),
alkoxycarbonyl methoxycarbonyl) and the like.
[0222] As a carboxy protecting group (P.sup.3), lower alkyl (e.g.;
methyl, ethyl), and aralkyl benzyl) are exemplified.
(First Step)
[0223] The present step is a reaction for condensing a compound
(II) and a compound (III) to synthesize a compound (IV). The
reaction may be performed according to the condition for a reaction
of amidating carboxylic acid which is generally performed. A
compound (II) may be reacted as it is, or may be reacted after
converted into corresponding acid chloride or active ester.
Preferably, the reaction is performed in a suitable solvent in the
presence of a condensing agent.
[0224] As a condensing agent, dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the
like may be used. If necessary, a reagent such as
1-hydroxybenzotriazole and N-hydroxysuccinimide, or a base such as
triethylamine, N-methylmorpholine, and pyridine may be added.
[0225] A reaction temperature is 0 to 150.degree. C., preferably
room temperature to 70.degree. C.
[0226] As a reaction solvent, a non-protonic solvent can be broadly
used, and tetrahydrofuran (THF), 1,4-dioxane, dimethylformamide
(DMF), methylene chloride, chloroform and the like are
preferable.
[0227] A reaction time is a few minutes to a few tens hours,
preferably 9 to 17 hours.
(Second Step)
[0228] The present step is a reaction for introducing a protected
hydroxy group (OP.sup.1) into a compound (IV) to produce a compound
(V). The reaction may be performed according to the condition for
an alkoxylating-reaction which is generally performed.
[0229] For example, a compound (V) in which P.sup.1 is methyl can
be synthesized by reacting a compound (IV) with metal alkoxide
(e.g.: sodium methoxide).
[0230] A reaction temperature is 0 to 200.degree. C., preferably 80
to 120.degree. C.
[0231] As a reaction solvent, alcohol, dimethylformamide (DMF), and
dimethyl sulfoxide (DMSO) are exemplified.
[0232] A reaction time is a few minutes to a few tens hours,
preferably 5 to 10 hours.
(Third Step)
[0233] The present step is a reaction for protecting a hydroxy
group of a compound (V) to produce a compound (VI). The reaction
may be performed according to the condition for a reaction of
protecting a hydroxy group which is generally performed. For
example, by using diisopropyl azodicarboxylate or diethyl
azodicarboxylate together with an alcohol and various phosphines, a
compound (VI) in which P.sup.2 is alkyl can be synthesized.
[0234] A reaction temperature is 0 to 100.degree. C., preferably
0.degree. C. to room temperature.
[0235] As a reaction solvent, THF, toluene, dichloromethane and the
like are exemplified.
[0236] A reaction time is a few minutes to a few tens hours,
preferably 1 to 3 hours.
(Fourth Step)
[0237] The present step is a reaction of oxidizing a nitrogen atom
of a compound (VI) to produce a compound (VII). The reaction may be
performed according to the condition for an oxidation reaction
using an oxidizing agent which is generally performed.
[0238] A reaction temperature is 0 to 100.degree. C., preferably
under ice cooling to room temperature.
[0239] As a reaction solvent, chloroform, methylene chloride,
acetic acid and the like are exemplified.
[0240] Examples of an oxidizing agent include metachloroperbenzoic
acid, hydrogen peroxide and the like.
[0241] A reaction time is a few minutes to a few tens hours,
preferably 1 to 5 hours.
(Fifth Step)
[0242] The present step is a reaction for hydroxylating a methyl
group of a compound (VII). Preferably, after acetoxylation by a
reaction with acetic anhydride (reaction temperature: 0 to
150.degree. C., preferably 120 to 140.degree. C.), this may be
hydrolyzed (e.g.: treatment with a base (e.g.: alkali metal
hydroxide)).
[0243] A reaction time is a few minutes to a few tens hours,
preferably 0.5 to 2 hours for acetoxylation, and 0.5 to 1 hour for
hydrolysis.
(Sixth Step)
[0244] The present step is a reaction for oxidizing a hydroxy group
of a compound (VIII) to synthesize a compound (IX).
[0245] A reaction temperature is 0 to 150.degree. C., preferably
room temperature to 70.degree. C.
[0246] As a reaction solvent, chloroform and the like are
exemplified.
[0247] As an oxidizing agent, dimethyl sulfoxide and the like are
exemplified.
[0248] A reaction time is a few minutes to a few tens hours,
preferably 0.1 to 1 hour.
(Seventh Step)
[0249] The present step is a reaction for oxidizing a formyl group
of a compound (IX) to synthesize a compound (X).
[0250] A reaction temperature is 0 to 150.degree. C., preferably
under ice-cooling to room temperature.
[0251] As a reaction solvent, an alcohol and the like are
exemplified.
[0252] As an oxidizing agent, potassium hydroxide and iodine are
exemplified.
[0253] A reaction time is a few minutes to a few tens hours,
preferably 0.5 to 3 hours.
(Eighth Step)
[0254] The present step is a reaction for deprotecting an OP.sup.2
part of a compound (X) to synthesize a compound (XI). The reaction
may be performed according to the condition for a reaction of
deprotecting a hydroxy protecting group which is generally
performed.
[0255] A reaction temperature is 0 to 150.degree. C., preferably
under ice-cooling to room temperature.
[0256] As a reaction solvent, acetonitrile, methylene chloride, THF
and the like are exemplified.
[0257] A reaction time is a few minutes to a few tens hours,
preferably 1 to 3 hours.
(Ninth Step)
[0258] The present step is a reaction for deprotecting an OP' part
of a compound (XI) to synthesize a compound (I-A). The reaction may
be treated preferably with a Lewis acid (e.g.: aluminum
chloride).
[0259] A reaction temperature is 0 to 150.degree. C., preferably 10
to 50.degree. C.
[0260] As a reaction solvent, methylene chloride, THF and the like
are exemplified.
[0261] A reaction time is a few minutes to a few tens hours,
preferably 1 to 3 hours.
(Tenth Step)
[0262] The present step is a reaction for deprotecting an ester
part (COOPS) of a compound (X) to synthesize carboxylic acid (XII).
Preferably, hydrolysis with an alkali (e.g.: NaOH) may be
performed.
[0263] A reaction temperature is 0 to 150.degree. C., preferably 10
to 50.degree. C.
[0264] As a reaction solvent, methanol, water and the like are
exemplified.
[0265] A reaction time is a few minutes to a few tens hours,
preferably a few minutes to 2 hours.
[0266] Carboxylic acid (XII) can be converted into various
derivatives (e.g.; amide).
(Eleventh Step)
[0267] The present step is a reaction for reacting a compound (XII)
with various amines to synthesize a compound (XIII). The reaction
may be performed according to the condition for a reaction of
amidating carboxylic acid which is generally performed and, for
example, the reaction may be performed as in the first step.
[0268] A reaction temperature is 0 to 150.degree. C., preferably
room temperature to 70.degree. C.
[0269] As a reaction solvent, a non-protonic solvent can be broadly
used, and tetrahydrofuran (THF), 1,4-dioxane, dimethylformamide
(DMF), methylene chloride, chloroform and the like are
preferable.
[0270] A reaction time is a few minutes to a few tens hours,
preferably a few minutes to 3 hours.
[0271] An amide part of the resulting compound (XIII) may be
further chemically modified (e.g.: N-alkylation).
(Twelfth Step)
[0272] The present step is a reaction for deprotecting OP.sup.1 and
OP.sup.2 parts of a compound (XIII) to synthesize a compound (I-B).
The reaction may be performed according to the condition for a
reaction of deprotecting a hydroxy protecting group which is
generally performed.
[0273] For example, when pyridine hydrochloride is used, a reaction
temperature is 0 to 200.degree. C., preferably 150 to 180
degree.
[0274] A reaction time is a few minutes to a few tens hours,
preferably 1 to 5 minutes.
(Thirteenth Step)
[0275] The present step is a reaction for deprotecting an ester
part (COOP.sup.3) of a compound (XI) to synthesize carboxylic acid
(XIV). Preferably, hydrolysis with an alkali (e.g.: lithium
hydroxide) may be performed.
[0276] A reaction temperature is 0 to 150.degree. C., preferably 10
to 50.degree. C.
[0277] As a reaction solvent, methanol, water and the like are
exemplified.
[0278] A reaction time is a few minutes to a few tens hours,
preferably a few minutes to 3 hours.
(Fourteenth Step)
[0279] The present step is a reaction for deprotecting an OP.sup.1
part of a compound (XIV) to synthesize a compound (I-C). The
reaction may be treated preferably with a Lewis acid (e.g.: boron
tribromide).
[0280] A reaction temperature is 0 to 150.degree. C., preferably
under ice-cooling to room temperature.
[0281] As a reaction solvent, dichloromethane and the like are
exemplified.
[0282] A reaction time is a few minutes to a few tens hours,
preferably a few minutes to 5 hours.
[0283] The monocyclic carbamoylpyridone derivative obtained above
is derived into a bicyclic compound by the following method.
(Process 1)
##STR00062##
[0284] (wherein R.sup.1, X, R.sup.2, P.sup.1, P.sup.3 and R.sup.4
are as define above, and L.sup.2 is a leaving group such as halogen
etc.)
(Fifteenth Step)
[0285] The present step is a reaction for reacting the compound
(XI) or a compound (XI') which is a tautomer thereof with an allyl
compound to synthesize a compound (XV). A compound (XI') can be
synthesized, for example, according to the method of Example
A-1.
[0286] The reaction is performed preferably in the presence of a
base (e.g.: cesium carbonate).
[0287] A reaction temperature is 0 to 100.degree. C., preferably 10
to 40.degree. C.
[0288] As a reaction solvent, dimethylformamide and the like are
exemplified.
[0289] A reaction time is a few minutes to a few tens hours,
preferably 1 to 10 hours.
(Sixteenth Step)
[0290] The present step is a reaction for oxidizing a compound (XV)
to synthesize a compound (XVI). As an oxidizing agent, osmium
tetraoxide and alkali metal osmium tetraoxide (e.g.:
K.sub.2OsO.sub.4) are exemplified.
[0291] A reaction temperature is 0 to 100.degree. C., preferably 10
to 40.degree. C.
[0292] As a reaction solvent, 1,4-dioxane, tetrahydrofuran and the
like are exemplified.
[0293] A reaction time is a few minutes to a few tens hours,
preferably 1 to 5 hours.
(Seventeenth Step)
[0294] The present step is a reaction for reacting a compound (XVI)
with amine (XVII) to perform dehydration condensation to synthesize
a compound (XVIII).
[0295] A reaction temperature is 0 to 200.degree. C., preferably
140 to 180.degree. C.
[0296] As a reaction solvent, methylene chloride, acetonitrile and
the like are exemplified.
[0297] A reaction time is a few minutes to a few tens hours,
preferably 0.5 to 1.5 hours.
(Eighteenth Step)
[0298] The present step is a reaction for deprotecting a compound
(XVIII) preferably with an acid to synthesize a compound (XIX), and
may be performed according to the condition for a conventional
reaction of deprotecting a protected hydroxy group.
[0299] A reaction temperature is 0 to 200.degree. C.
[0300] As an acid, pyridine hydrochloride, trifluoroacetic acid and
the like are exemplified.
[0301] As a reaction solvent, the acid and trimethylsilyl iodide
are exemplified.
[0302] A reaction time is a few minutes to a few tens hours,
preferably 15 minutes to 1 hour.
(Nineteenth Step)
[0303] The present step is a reaction for reducing a compound
(XVIII) to synthesize a compound (XX).
[0304] As a reducing agent, H.sub.2/Pd.C and the like are
exemplified.
[0305] A reaction temperature is 0 to 100.degree. C., preferably 10
to 30.degree. C.
[0306] As a reaction solvent, dimethylformamide, methanol,
tetrahydrofuran and the like are exemplified.
[0307] A reaction time is a few minutes to a few tens hours,
preferably 5 to 20 hours.
(Process 2)
[0308] The intermediate (XVIII) may be also synthesized by a method
shown below.
##STR00063##
(Twentieth Step)
[0309] The present step is a reaction for reacting a compound (XIV)
with a compound (XXI) to synthesize a compound (XXII). The present
reaction may be performed according to the condition for a
conventional amidation reaction.
[0310] A reaction temperature is 0 to 100.degree. C., preferably 0
to 50.degree. C.
[0311] As a reaction solvent, dimethylformamide, methylene
chloride, tetrahydrofuran and the like are exemplified.
[0312] A reaction time is a few minutes to a few tens hours,
preferably 1 to 10 hours.
(Twenty-First Step)
[0313] The present step is a reaction for reacting a compound
(XXII) with an acid to perform deprotection and intramolecular ring
closure, to synthesize a compound (XXIII). The present reaction may
be performed according to the condition for a conventional reaction
of deprotecting acetal.
[0314] A reaction temperature is 0 to 100.degree. C., preferably
room temperature to 80.degree. C.
[0315] As a reaction solvent, dioxane, tetrahydrofuran and the like
are exemplified.
[0316] A reaction time is a few minutes to a few tens hours,
preferably 0.5 to 1 hour.
[0317] As an acid, hydrochloric acid, and paratoluenesulfonic acid
are exemplified.
(Twenty-Second Step)
[0318] The present step is a reaction for dehydrating a compound
(XXIII) to synthesize a compound (XXIV). The present reaction may
be performed according to the condition for a conventional
dehydration reaction.
[0319] A reaction temperature is 0 to 100.degree. C., preferably
room temperature to 80.degree. C.
[0320] As a reaction solvent, acetonitrile, methylene chloride and
the like are exemplified.
[0321] A reaction time is a few minutes to a few tens hours,
preferably 1 to 5 hours.
(Process 3)
##STR00064##
[0322] (Twenty-Third Step)
[0323] The present step is a reaction for reacting a compound (XVI)
with amine (XXIV) to perform dehydration condensation to synthesize
a compound (XXV) according to the seventeenth step or a method of
synthesizing a compound 17-1, Preferably, as a reaction catalyst,
an acid (e.g.: acetic acid) is added, and a microwave reaction
apparatus is used.
[0324] A reaction temperature is 0 to 200.degree. C., preferably
140 to 180.degree. C.
[0325] As a reaction solvent, methylene chloride, acetonitrile and
the like are exemplified.
[0326] A reaction time is a few minutes to a few tens hours,
preferably 0.5 to 1.5 hours.
(Twenty-Fourth Step)
[0327] The present step is a reaction for deprotecting a compound
(XXV) preferably with an acid to synthesize a compound (XXVI)
according to the eighteenth step, and may be performed according to
the condition for a conventional reaction of deprotecting a
protected hydroxy group.
[0328] A reaction temperature is 0 to 200.degree. C.
[0329] As an acid, pyridine hydrochloride, trifluoroacetic acid and
the like are exemplified.
[0330] As a reaction solvent, the aforementioned acid and
trimethylsilyl iodide are exemplified.
[0331] A reaction time is a few minutes to a few tens hours,
preferably 15 minutes to 1 hour.
(Process 4)
##STR00065##
[0332] (Twenty-Fifth Step)
[0333] The present step is a reaction for reacting a compound (XIV)
with a compound (XXIV) to synthesize a compound (XXVII) according
to the twentieth step. The present reaction may be performed
according to the condition for a conventional amidation
reaction.
[0334] A reaction temperature is 0 to 100.degree. C., preferably 0
to 50.degree. C.
[0335] As a reaction solvent, dimethylformamide, methylene
chloride, tetrahydrofuran and the like are exemplified.
[0336] A reaction time is a few minutes to a few tens hours,
preferably 1 to 10 hours.
(Twenty-Sixth Step)
[0337] The present step is a reaction for reacting a compound
(XXVII) or a tautomer thereof with an allyl compound to synthesize
a compound (XXVIII) according to the fifteenth step.
[0338] A reaction is performed preferably in the presence of a base
(e.g.: cesium carbonate).
[0339] A reaction temperature is 0 to 100.degree. C., preferably 10
to 40.degree. C.
[0340] As a reaction solvent, dimethylformamide and the like are
exemplified.
[0341] A reaction time is a few minutes to a few tens hours,
preferably 1 to 10 hours.
(Twenty-Seventh Step)
[0342] The present step is a reaction for oxidizing a compound
(XXVIII) to synthesize a compound (XXIX) according to the sixteenth
step.
[0343] As an oxidizing agent, osmium tetraoxide and alkali metal
osmium tetraoxide (e.g.: K.sub.2OsO.sub.4) are exemplified.
[0344] A reaction temperature is 0 to 100.degree. C., preferably 10
to 40.degree. C.
[0345] As a reaction solvent 1,4-dioxane, tetrahydrofuran and the
like are exemplified.
[0346] A reaction time is a few minutes to a few tens hours,
preferably 1 to 5 hours.
(Twenty-Eighth Step)
[0347] The present step is a reaction for dehydration-condensing a
compound (XXIX) to synthesize a compound (XXX) according to the
seventeenth step or a method of synthesizing a compound 17-1.
Preferably, as a reaction catalyst, an acid (e.g.: acetic acid) is
added, and a microwave reaction' apparatus is used.
[0348] A reaction temperature is 0 to 200.degree. C., preferably
140 to 180.degree. C.
[0349] As a reaction solvent, methylene chloride, acetonitrile and
the like are exemplified.
[0350] A reaction time is a few minutes to a few tens hours,
preferably 0.5 to 1.5 hours.
(Twenty-Ninth Step)
[0351] The present step is a reaction for deprotecting a compound
(XXX) preferably with an acid to synthesize a compound (XXXI)
according to the eighteenth step, and may be performed according to
the condition for a conventional reaction of deprotecting a
protected hydroxy group.
[0352] A reaction temperature is 0 to 200.degree. C.
[0353] As an acid, pyridine hydrochloride, trifluoroacetic acid and
the like are exemplified.
[0354] As a reaction solvent, the aforementioned acid and
trimethylsilyl iodide are exemplified.
[0355] A reaction time is a few minutes to a few tens hours,
preferably 15 minutes to 1 hour.
(Process 5)
[0356] A compound (I-3) in which Z is NR.sup.19 can be synthesized
according to the following reaction scheme, according to Process
4,
##STR00066##
(Process 10)
##STR00067##
[0357] (wherein respective symbols are as defined above)
Forty-Ninth Step
[0358] A compound (XIV-16) is obtained by reacting a compound (XIV)
with an amine reagent, according to the thirty-fifth step.
(Fiftieth Step)
[0359] A compound (XIV-17) is obtained by subjecting a compound
(XIV-16) to a general acetal deprotecting reaction according to the
forty-fourth step.
[0360] (Fifty-First Step)
[0361] A compound (XIV-18) is obtained CD ring formation) by
deprotecting a P.sup.1 part of a compound (XIV-14) according to the
thirty-eighth step.
[0362] The present invention further provides various intermediates
(I-P) shown below and a process for preparing the same, as well as
a process for preparing the above mentioned compound (I) comprising
the deprotection of the intermediate.
(Intermediates)
##STR00068##
[0363] (P.sup.1 is a hydroxyl-protecting group; the other symbols
are as defined above)
[0364] Preferred compounds are shown below. Each P.sup.1 is a
hydroxyl-protecting group, such as C.sub.6-14aryl-C.sub.1-8alkyl
(e.g., benzyl (.dbd.Bn)),
##STR00069##
[0365] Preferably, wherein R.sup.e is one or two halogen; R.sup.z
is C.sub.1-8alkyl, C.sub.6-14arylC.sub.1-8alkyl, C.sub.6-14aryl, or
alkoxy; and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl;
##STR00070##
[0366] Preferably, wherein R.sup.e is one or two halogen; R.sup.z
is C.sub.1-8alkyl, C.sub.6-14arylC.sub.1-8alkyl, C.sub.6-14aryl, or
alkoxy; and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl;
##STR00071##
[0367] Preferably, wherein R.sup.e is one or two halogen; and
P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl;
##STR00072##
[0368] Preferably, wherein R.sup.e is one or two halogen; and
P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl;
##STR00073##
[0369] Preferably, wherein R.sup.e is one or two halogen; and
P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl;
##STR00074##
[0370] Preferably, wherein R.sup.e is one or two halogen; and
P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl;
##STR00075##
[0371] Preferably, wherein R.sup.e is one or two halogen; and
P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl;
##STR00076##
[0372] Preferably, wherein R.sup.e is one or two halogen; and
P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl;
##STR00077##
[0373] Preferably, wherein R.sup.e is one or two halogen; R.sup.z
is C.sub.1-8alkyl; R.sup.z1 is hydrogen, C.sub.3-6cycloalkyl,
heterocycle, or C.sub.1-8alkyl optionally substituted with hydroxy,
C.sub.3-6cycloalkyl, alkoxy, heterocycle, heteroaryl,
C.sub.6-14aryl, or amino, wherein said amino may be optionally
substituted with --C(O)C.sub.1-8alkyl or C.sub.1-8alkyl;
##STR00078##
[0374] Preferably, wherein R.sup.e is one or two halogen; R.sup.z
is C.sub.1-8alkyl; R.sup.z1 is hydrogen, C.sub.3-6cycloalkyl,
heterocycle, or C.sub.1-8alkyl optionally substituted with hydroxy,
C.sub.3-6cycloalkyl, alkoxy, heterocycle, heteroaryl,
C.sub.6-14aryl, or amino, wherein said amino may be optionally
substituted with --C(O)C.sub.1-8alkyl or C.sub.1-8alkyl; and
P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl;
##STR00079##
[0375] Preferably, wherein R.sup.e is one or two halogen; R.sup.z1
is hydrogen, C.sub.3-6cycloalkyl, heterocycle, or C.sub.1-8alkyl
optionally substituted with hydroxy, C.sub.3-6cycloalkyl, alkoxy,
heterocycle, heteroaryl, C.sub.6-14aryl, or amino, wherein said
amino may be optionally substituted with --C(O)C.sub.1-8alkyl or
C.sub.1-8alkyl; and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl;
##STR00080##
[0376] Preferably, wherein R.sup.e is one or two halogen; R.sup.z1
is hydrogen, C.sub.3-6cycloalkyl, heterocycle, or C.sub.1-8alkyl
optionally substituted with hydroxy, C.sub.3-6cycloalkyl, alkoxy,
heterocycle, heteroaryl, C.sub.6-14aryl, or amino, wherein said
amino may be optionally substituted with --C(O)C.sub.1-8alkyl or
C.sub.1-8alkyl; and P.sup.1 is C.sub.6-14arylC.sub.1-8alkyl;
##STR00081##
[0377] Preferably, wherein R.sup.e is halogen; and P.sup.1 is
C.sub.6-14arylC.sub.1-8alkyl;
[0378] The above intermediates, compound (I-20a), (I-20b), (I-21a),
(I-21b), (I-22a), (I-22b), (I-23a), (I-23b), (I-24a), (I-24b),
(I-25), (I-26), or (I-27), can be prepared by condensing a compound
of the formula:
##STR00082##
wherein R.sup.e is one or two halogen; and R.sup.50 is
C.sub.1-8alkyl; with each amine shown below, respectively:
##STR00083##
wherein R.sup.z is C.sub.1-8alkyl, C.sub.6-14arylC.sub.1-8alkyl,
C.sub.6-14aryl, or alkoxy;
##STR00084##
wherein R.sup.z is C.sub.1-8alkyl, C.sub.6-14arylC.sub.1-8alkyl,
C.sub.6-14aryl, or alkoxy;
##STR00085##
wherein R.sup.z is C.sub.1-8alkyl; R.sup.z1 is hydrogen,
C.sub.3-6cycloalkyl, heterocycle, or C.sub.1-8alkyl optionally
substituted with hydroxy, C.sub.3-6cycloalkyl, alkoxy, heterocycle,
heteroaryl, C.sub.6-14aryl, or amino, wherein said amino may be
optionally substituted with --C(O)C.sub.1-8alkyl or
C.sub.1-8alkyl;
##STR00086##
wherein R.sup.z is C.sub.1-8alkyl; R.sup.z1 is hydrogen,
C.sub.3-6cycloalkyl, heterocycle, or C.sub.1-8alkyl optionally
substituted with hydroxy, C.sub.3-6cycloalkyl, alkoxy, heterocycle,
heteroaryl, C.sub.6-14aryl, or amino, wherein said amino may be
optionally substituted with --C(O)C.sub.1-8alkyl or
C.sub.1-8alkyl;
##STR00087##
wherein R.sup.z1 is hydrogen, C.sub.3-6cycloalkyl, heterocycle, or
C.sub.1-8alkyl optionally substituted with hydroxy,
C.sub.3-6cycloalkyl, alkoxy, heterocycle, heteroaryl,
C.sub.6-14aryl, or amino, wherein said amino may be optionally
substituted with --C(O)C.sub.1-8alkyl or
##STR00088##
wherein R.sup.z1 is hydrogen, C.sub.3-6cycloalkyl, heterocycle, or
C.sub.1-8alkyl optionally substituted with hydroxy,
C.sub.3-6cycloalkyl, alkoxy, heterocycle, heteroaryl,
C.sub.6-14aryl, or amino, wherein said amino may be optionally
substituted with --C(O)C.sub.1-8alkyl or C.sub.1-8alkyl;
##STR00089##
[0379] The condition for the above condensation is illustrated
below for example.
[0380] Examples of the solvent include halocarbons such as
dichloromethane, dichloroethane, and acetic acid.
[0381] The reaction temperature is preferably, 0 to 200.degree. C.,
more preferably, 50 to 170.degree. C.
[0382] The reaction time is usually several minutes to several
hours.
[0383] The above intermediates, compound (I-20a), (I-20b), (I-21a),
(I-21b), (I-22a), (I-22b), (I-23a), (I-23b), (I-24a), (I-24b),
(I-26), or (I-27), can be deprotected to give each corresponding
deprotected compound wherein P.sup.1 is hydrogen, or its
pharmaceutically acceptable salt, which are encompassed within the
scope of compound (I) of the present invention.
[0384] In addition, the present compound obtained above may be
further chemically modified to synthesize another compound. In
addition, when there is a reactive functional group (e.g.: OH,
COOH, NH.sub.2) on a side chain part etc. in the above reaction,
the group may be protected before the reaction and may be
deprotected after the reaction, if desired.
[0385] The present compound is useful, for example, as a drug such
as an anti-virus drug. The present compound has the remarkable
inhibitory action on integrase of a virus. Therefore, the present
compound can be expected to have the preventive or therapeutic
effect for various diseases derived from a virus which produces at
least integrase, and is grown at infection in an animal cell, and
is useful as an integrase inhibiting agent for retrovirus (e.g.
HIV-1, HIV-2, HTLV-1, SIV, FIV etc.), and is useful as an anti-HIV
drug etc.
[0386] In addition, the present compound may be used in joint use
therapy by combining an anti-HIV drug having the different action
mechanism such as a reverse trascriptase inhibitor and/or a
protease inhibiting agent, Particularly, currently, an integrase
inhibitor is not marketed, and it is useful to use in joint use
therapy by combining the present compound with a reverse
transcriptase inhibitor and/or a protease inhibitor.
[0387] Further, the above use includes not only use as a medical
mixture for anti-HIV, but also use as a joint use agent for
increasing the anti-HIV activity of other anti-HIV drug such as
cocktail therapy.
[0388] In addition, the present compound can be used in order to
prevent infection with a retrovirus vector from spreading into a
tissue other than an objective tissue, upon use of a retrovirus
vector based on HIV or MLV in the field of gene therapy.
Particularly, when a cell is infected with a vector in vitro, and
the cell is returned into a body, if the present compound is
administered in advance, extra infection can be prevented in a
body.
[0389] The present compound can be administered orally or
parenterally. In the case of oral administration, the present
compound can be also used as a conventional preparation, for
example, as any dosage form of a solid agent such as tablets,
powders, granules, capsules and the like; an aqueous agent; an oily
suspension; or a liquid agent such as syrup and elixir. In the case
of parenteral administration, the present compound can be used as
an aqueous or oily suspension injectable, or a nasal drop, Upon
preparation of it, conventional excipients, binders, lubricants,
aqueous solvents, oily solvents, emulsifiers, suspending agents,
preservatives, stabilizers and the like may be arbitrarily used. As
an anti-HIV-drug, particularly, an oral agent is preferable. A
preparation of the present invention is prepared by combining (e.g.
mixing) a therapeutically effective amount of the present compound
with a pharmaceutically acceptable carrier or diluent.
[0390] A dose of the present invention is different depending on an
administration method, an age, a weight and condition of a patient,
and a kind of a disease and, usually, in the case of oral
administration, about 0.05 mg to 3000 mg, preferably about 0.1 mg
to 1000 mg may be administered per adult a day, if necessary, by
dividing the close. In addition, in the case of parenteral
administration, about 0.01 mg to 1000 mg, preferably about 0.06 mg
to 600 mg is administered per adult a day.
[0391] Examples are shown below.
Example A-1
9-Hydroxy-2-(2-methoxy-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrid[1,2-a]pyrazin-
e-7-carboxylic acid 4-fluoro-benzylamide
Example B-1
9-Hydroxy-2-(2-methoxy-ethyl)-dioxo-1,3,4,8-tetrahydro-2H-pyrid[1,2-a]pyra-
zine-7-carboxylic acid 4-fluoro-benzylamide
##STR00090## ##STR00091##
[0393] 1) Mantol 1 (189 g, 1.5 mol) was dissolved in
dimethylformamide (1890 ml), and benzyl bromide (1.84 ml, 1.5 mol)
was added. After the solution was stirred at 80.degree. C. for 15
minutes, potassium carbonate (228 g, 1.65 mol) was added, and the
mixture was stirred for 1 hour. After the reaction solution was
cooled to room temperature, an inorganic salt was filtered, and the
filtrate was distilled off under reduced pressure. To the again
precipitated inorganic salt was added tetrahydrofuran (1000 ml),
this was filtered, and the filtrate was distilled off under reduced
pressure to obtain the crude product (329 g, >100%) of
3-benzyloxy-2-methyl-pyran-4-one 2 as a brown oil. NMR (CDCl.sub.3)
.delta.: 2.09 (3H, s), 5.15 (2H, s), 6.36 (1H, d, J=5.6 Hz),
7.29-7.41 (5H, m), 7.60 (1H, d, J=5.6 Hz).
[0394] 2) The compound 2 (162.2 g, 750 mmol) was dissolved in
ethanol (487 ml), and aqueous ammonia (28%, 974 ml) and a 6N
aqueous sodium hydroxide solution (150 ml, 900 mmol) were added.
After the reaction solution was stirred at 90.degree. C. for 1
hour, this was cooled to under ice cooling, and ammonium chloride
(58 g, 1080 mmol) was added. To the reaction solution was added
chloroform, this was extracted, and the organic layer was washed
with an aqueous saturated sodium bicarbonate solution, and dried
with anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, isopropyl alcohol and diethyl ether were added to
the residue, and precipitated crystals were filtered to obtain
3-benzyloxy-2-methyl-1H-pyridine-4-one 3 (69.1 g, 43%) as a pale
yellow crystal.
[0395] NMR (DMSO-d.sub.6) .delta.: 2.05 (3H, s), 5.04 (2H, s), 6.14
(1H, d, J=7.0 Hz), 7.31-7.42 (5H, m), 7.46 (1H, d, J=7.2 Hz), 11.29
(1H, brs).
[0396] 3) The above compound 3 (129 g, 599 mmol) was suspended in
acetonitrile (1300 ml), and N-bromosuccinic acid imide (117 g, 659
mmol) was added, followed by stirring at room temperature for 90
minutes, Precipitated crystals were filtered, and washed with
acetonitrile and diethyl ether to obtain
3-benzyloxy-5-bromo-2-methyl-pyridine-4-ol 4 (154 g, 88%) as a
colorless crystal.
[0397] NMR (DMSO-d.sub.6) .delta.: 2.06 (3H, s), 5.04 (2H, s),
7.32-7.4.2 (5H, m), 8.03 (1H, d, J=5.5 Hz), 11.82 (1H, brs).
[0398] 4) To a solution of the compound 4 (88 g, 300 mmol),
palladium acetate (13.4 g, 60 mmol) and
1,3-bis(diphenylphosphino)propane (30.8 g, 516 mmol) in
dimethylformamide (660 ml) were added methanol (264 ml) and
triethylamine (210 ml, 1.5 mol) at room temperature. The interior
of a reaction vessel was replaced with carbon monoxide, and the
material was stirred at room temperature for 30 minutes, and
stirred at 80 degree for 18 hours. A vessel to which ethyl acetate
(1500 ml), an aqueous saturated ammonium chloride solution (1500
ml) and water (1500 ml) had been added was stirred under
ice-cooling, and the reaction solution was added thereto.
Precipitates were filtered, and washed with water (300 ml), ethyl
acetate (300 ml) and diethyl ether (300 ml) to obtain
5-benzyloxy-4-hydroxy-6-methyl-nicotinic acid methyl ester 5 (44.9
g, 55%) as a colorless crystal.
[0399] NMR (DMSO-d.sub.6) .delta.: 2.06 (3H, s), 3.72 (3H, s), 5.02
(2H, s), 7.33-7.42 (5H, m), 8.07 (1H, s).
[0400] 5) After a solution of the compound 5 (19.1 g, 70 mmol) in
acetic anhydride (134 ml) was stirred at 130.degree. C. for 40
minutes, the solvent was distilled off under reduced pressure to
obtain 4-acetoxy-5-benzyloxy-6-methyl-nicotinic acid methyl ester 6
(19.9 g, 90%) as a flesh colored crystal.
[0401] NMR (CDCl.sub.3) .delta.: 2.29 (3H, s), 2.52 (3H, s), 3.89
(3H, s), 4.98 (2H, s), 7.36-7.41 (5H, m), 8.85 (1H, s).
[0402] 6) To a solution of the compound 6 (46.2 g, 147 mmol) in
chloroform (370 ml) was added metachloroperbenzoic acid (65%) (42.8
g, 161 mmol) in portions under ice-cooling, and this was stirred at
room temperature for 90 minutes. To the reaction solution was added
a 10% aqueous potassium carbonate solution, and this was stirred
for 10 minutes, followed by extraction with chloroform. The organic
layer was washed with successively with a 10% aqueous potassium
carbonate solution, an aqueous saturated ammonium chloride
solution, and an aqueous saturated sodium chloride solution, and
dried with anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure, and the residue was washed with diisopropyl
ether to obtain 4-acetoxy-5-benzyloxy-6-methyl-1-oxy-nicotinic acid
methyl ester 7 (42.6 g, 87%) as a colorless crystal.
[0403] NMR (CDCl.sub.3) .delta.: 2.30 (3H, s), 2.41 (3H, s), 3.90
(3H, s), 5.02 (2H, s), 7.37-7.39 (5H, m), 8.70 (1H, s).
[0404] 7) To acetic anhydride (500 ml) which had been heated to
stir at 130.degree. C. was added the compound 7 (42.6 g, 129 mmol)
over 2 minutes, and this was stirred for 20 minutes. The solvent
was distilled off under reduced pressure to obtain
4-acetoxy-6-acetoxymethyl-5-benzyloxy-nicotinic acid methyl ester 8
(49.6 g, >100%) as a black oil.
[0405] NMR (CDCl.sub.3) .delta.: 2.10 (3H, s), 2.28 (3H, s), 3.91
(3H, s), 5.07 (2H, s), 5.20 (2H, s), 7.35-7.41 (5H, m), 8.94 (1H,
s).
[0406] 8) To a solution of the compound 8 (46.8 g, 1.25 mmol) in
methanol (140 ml) was added a 2N aqueous sodium hydroxide solution
(376 ml) under ice-cooling, and this was stirred at 50.degree. C.
for 40 minutes. To the reaction solution were added diethyl ether
and 2N hydrochloric acid under ice-cooling, and precipitated
crystals were filtered. Resulting crystals were washed with water
and diethyl ether to obtain
5-benzyloxy-4-hydroxy-6-hydroxymethyl-nicotinic acid 9 (23.3 g,
68%) as a colorless crystal.
[0407] NMR (DMSO-d.sub.6) .delta.: 4.49 (2H, s), 5.19 (2H, s), 5.85
(1H, brs), 7.14-7.20 (2H, m), 7.33-7.43 (7H, m), 8.30 (1H, s),
10.73 (1H, t, J=5.8 Hz), 11.96 (1H, brs).
[0408] 9) To a solution of the compound 9 (131 g, 475 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (219 g,
1140 mmol) and 1-hydroxybenzotrizole (128 g, 950 mmol) in
dimethylformamide (1300 ml) was added 4-fluorobenzylamine (109 ml,
950 mmol), and this was stirred at 80.degree. C. for 1.5 hours.
After the reaction solution was cooled to room temperature,
hydrochloric acid was added, followed by extraction with ethyl
acetate. The extract was washed with a 5% aqueous potassium
carbonate solution, an aqueous saturated ammonium chloride
solution, and an aqueous saturated sodium chloride solution, and
dried with, anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure to obtain a mixture (175 g) of 10 and 11,
the resulting mixture was dissolved in acetic acid (1050 ml) and
water (1050 ml), and zinc (31.1 g, 475 mmol) was added, followed by
heating to reflux for 1 hour. After the reaction solution was
cooled to room temperature, a 10% aqueous potassium carbonate
solution was added, followed by extraction with ethyl acetate. The
extract was washed with an aqueous saturated ammonium chloride
solution, and an aqueous saturated sodium chloride solution, and
dried with anhydrous sodium sulfate. After the solvent was
distilled off under reduced pressure, this was washed with diethyl
ether to obtain
5-benzyloxy-N-(4-fluoro-benzyl)-4-hydroxy-6-hydroxymethyl-nicot-
inic acid amide 10 (107 g, 59%) as a colorless crystal.
[0409] NMR (DMSO-d.sub.6) .delta.: 4.45 (2H, d, J=4.3 Hz), 4.52
(2H, d, J=5.8 Hz), 5.09 (2H, s), 6.01 (1H, brs), 7.36-7.43 (5H, m),
8.31 (1H, s), 12.63 (1H, brs).
[0410] 10) After manganese dioxide (49 g) was added to a suspension
of the compound 10 (9.8 g, 25.6 mmol) in chloroform (490 ml), the
mixture was stirred at room temperature for 1 hour. After the
reaction solution was stirred at 60.degree. C. for 20 minutes,
Celite filtration was performed, and this was washed with
chloroform heated at 50.degree. C. The filtrate was distilled off
under reduced pressure to obtain
5-benzyloxy-N-(4-fluoro-benzyl)-6-formyl-4-hydroxy-nicotinic acid
amide 12 (8.2 g, 84%) as a pale yellow crystal.
[0411] NMR (DMSO-d.sub.6) .delta.: 4.53 (2H, d, J=5.8 Hz), 5.38
(2H, s), 7.15-7.21 (2H, m), 7.35-7.46 (7H, m), 8.33 (1H, s), 0.90
(1H, s), 10.35 (1H, t, 5.8 Hz), 12.49 (1H, brs).
[0412] 11) To an aqueous solution (105 ml) of sodium chlorite (7.13
g, 78.8 mmol), and sulfamic acid (7.65 g, 78.8 mmol) was added a
solution of the compound 12 (15.0 g, 39.4 mmol) in tetrahydrofuran
(630 ml) under ice-cooling, and the mixture was stirred at room
temperature for 1 hour. After water (2500 ml) was added to the
reaction solution, precipitated crystals were filtered. Washing
with diethyl ether afforded
3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-hydroxy-pyridine-2-carboxylic
acid 13 (14.0 g, 90%) as a colorless crystal.
[0413] NMR (DMSO-d.sub.6) .delta.: 4.52 (2H, d, J=5.8 Hz), 5.13
(2H, s), 7.14-7.19 (2H, m), 7.31-7.40 (5H, m), 7.47-7.49 (2H, m),
8.31 (1H, d, J=4.5 Hz), 10.44 (1H, t, J=5.9 Hz), 12.47 (1H,
brs).
[0414] 12) A solution of the compound 13 (198 mg, 0.500 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115
mg, 0.600 mmol) and 1-hydroxybenzotriazole (81 mg, 0.600 mmol) in
dimethylformamide (3 ml) was stirred at room temperature for 1.5
hours. Then, methanol (3 ml) and triethylamine (153 ul, 1.10 mmol)
were added, and the mixture was heated to reflux for 1.5 hours. The
reaction solution was diluted with ethyl acetate, washed with an
aqueous saturated sodium bicarbonate solution, a 10% aqueous citric
acid solution, and an aqueous saturated sodium chloride solution,
and dried with anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the residue was washed with diethyl
ether to obtain
[0415]
3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-hydroxy-pyridine-2-carbo-
xylic acid methyl ester 14 (141 mg, 69%) as a colorless
crystal.
[0416] NMR (DMSO-d.sub.6) .delta.: 3.85 (3H, s), 4.52 (2H, d, J=6.0
Hz), 5.15 (2H, s), 7.13-7.21 (2H, m), 7.81-7.47 (7H, m), 8.33 (1H,
s), 10.41 (1H, t, J=6.0 Hz), 12.59 (1H, brs).
[0417] 13) After 3-bromopropene (2.15 ml, 24.8 mmol) was added to a
solution of the compound 14 (6.79 g, 16.5 mmol), and cesium
carbonate (8.09 g, 24.8 mmol) in dimethylformamide (54 ml), the
mixture was stirred at room temperature for 4.5 hours. To the
reaction solution was added an aqueous ammonium chloride solution,
and this was extracted with ethyl acetate, washed with water and an
aqueous saturated sodium chloride solution, and dried with
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the residue was washed with diethyl ether to
obtain
1-allyl-3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-oxo-1,4-dihydro-pyridi-
ne-2-carboxy lie acid methyl ester 15 (6.15 g, 83%) as a colorless
crystal.
[0418] NMR (CDCl.sub.3) .delta.: 3.76 (3H, s), 4.54 (2H, d, J=6.0
Hz), 4.60 (2H, d, J=6.0 Hz), 5.20-5.37 (2H, m), 5.25 (2H, s),
5.80-5.93 (1H, m), 6.98-7.04 (2H, m), 7.31-7.35 (7H, m), 8.45 (1H,
s), 10.41 (1H, m).
[0419] 14) To a solution of the compound 15 (7.6 g, 16.9 mmol) in
1,4-dioxane (228 ml) was added an aqueous solution (38 ml) of
potassium osmate dihydrate (372 mg, 1.01 mmol), and sodium
metaperiodate (14.5 g, 67.6 mmol) was further added, followed by
stirring at room temperature for 2 hours. The reaction solution was
added to a vessel to which ethyl acetate (300 ml) and water (300
ml) had been added, while stirring. The organic layer was washed
with water, a 5% aqueous sodium hydrogen sulfite solution and an
aqueous saturated sodium chloride solution, and dried with
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the residue was washed with diethyl ether to
obtain
[0420]
3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-oxo-1-(2-oxo-ethyl)-1,4--
dihydro-pyridine-2-carboxylic acid methyl ester 16 (5.39 g, 71%) as
a colorless crystal.
[0421] NMR (CDCl.sub.3) .delta.: 3.74 (3H, s), 4.60 (2H, d, J=5.9
Hz), 4.87 (2H, s), 5.27 (2H, s), 6.98-7.04 (2H, m), 7.30-7.40 (7H,
m), 8.39 (1H, s), 9.58 (1H, s), 10.38 (1H, s).
[0422] 15) To a solution of the compound 16 (400 mg, 0.884 mmol) in
methylene chloride (12 ml) were added 2-methoxyethylamine (77
.mu.l, 0.884 mmol) and acetic acid (18 ul), and the mixture was
stirred at room temperature for 5 minutes. Thereafter, the reaction
was performed at 140.degree. C. for 30 minutes in a microwave
reaction apparatus. The solvent was distilled off under reduced
pressure, the residue was subjected to silica gel column
chromatography, and fractions eluting with toluene-acetone were
concentrated under reduced pressure to obtain
[0423]
9-benzyloxy-2-(2-methy-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a-
]pyrazine-7-carboxylic acid 4-fluoro-benzylamide 17-1 (226 mg, 54%)
as a yellow solid.
[0424] NMR (CDCl.sub.3) .delta.: 3.35 (3H, s), 3.65 (2H, t, J=5.1
Hz), 3.97 (2H, t, J=4.5 Hz), 4.63 (2H, d, J=5.7 Hz), 5.28 (2H, s),
6.56 (2H, m), 7.01 (2H, t, J=8.7 Hz), 7.38-7.30 (5H, m), 7.65 (2H,
d, J=6.6 Hz), 10.63 (1H, s).
[0425] 16) To the compound 17-1 (14.0 mg, 0.293 mmol) was added
trifluoroacetic acid (1.4 ml) under ice-cooling, and the mixture
was stirred at 0.degree. C. for 5 minutes and, then, at room
temperature for 1.5 hours. The solvent was distilled off under
reduced pressure, and this was diluted with chloroform, and added
to ice water. This was washed with an aqueous, saturated sodium
bicarbonate solution, a 10% aqueous citric acid solution and water,
and dried with anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the residue was recrystallized with
methylene chloride-ethanol to obtain Example A-1 (89 mg, 79%) as a
yellow crystal.
[0426] melting point: 223-224.degree. C.
[0427] NMR (DMSO-d.sub.6) .delta.: 3.25 (3H, s), 3.58 (2H, t, J=5.4
Hz), 3.92 (2H, t, J=5.1 Hz), 4.53 (2H, d, J=5.7 Hz), 6.87 (1H, d,
6.3 Hz), 7.14 (2H, t, J=9.0 Hz), 7.33-7.38 (2H, m), 7.47 (1H, d,
J=6.0 Hz), 8.77 (1H, s), 10.56 (1H, t, J=6.0 Hz), 12.00 (1H,
brs).
[0428] 17) The compound 17-1 (157 mg, 0.329 mmol) was dissolved in
dimethylformamide (18 ml) and methanol (1 ml), 10% palladium-carbon
powder (31 mg) was added, and the mixture was stirred at room
temperature for 20 hours under the hydrogen atmosphere. The
reaction solution was filtered with Celite, and the filtrate was
concentrated under reduced pressure. The residue was dissolved in
chloroform, this was filtered with Celite again, and the filtrate
was concentrated under reduced pressure. The residue was
recrystallized with methylene chloride-methanol to obtain Example
B1 (66 mg, 52%) as a brown crystal.
[0429] melting point: 197-199.degree. C.
[0430] NMR (DMSO-d.sub.6) .delta.: 3.27 (3H, s), 3.55 (2H, t, J=5.1
Hz), 3.68 (2H, t, J=5.1 Hz), 3.79 (2H, s), 4.36 (2H, s), 4.51 (2H,
d, J=5.7 Hz), 7.15 (2H, t, J=8.7 Hz), 7.32-7.37 (2H, m), 8.38 (1H,
s), 10.46 (1H, t, J=5.4 Hz), 12.41 (1H, s).
Example C-1
##STR00092##
[0432] 1) A compound 33 was synthesized using
1-aminomethylcyclopentanol hydroxyethylamine according to the
method of synthesizing a compound 1.7-1.
[0433] 1H-NMR (CDCl.sub.3) .delta.: 1.30-1.80 (10H, m), 3.47 (1H,
d, J=11.4 Hz), 3.61 (1H, d, J=11.4 Hz), 3.80-3.95 (1H, m), 4.30
(1H, dd, J=14.7, 3.0 Hz), 4.60 (2H, d, J=5.7 Hz), 5.17-5.23 (2H,
m), 5.39 (1H, d, J=9.9 Hz), 6.95-7.1.0 (2H, m), 7.20-7.40 (5H, m),
7.58 (2H, d, J=7.2 Hz), 8.41 (1H, s), 10.40 (1H, s).
[0434] 2) A compound 33.2 was synthesized using hydroxyethylamine
according to the similar method.
Compound 33-2
5-Benzyloxy-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1-oxa-3a,8a-diaza-cyclopenta[-
b]naphthalene-7-carboxylic acid 4-fluorobenzylamide
[0435] 1H-NMR (DMSO-d.sub.6) .delta.: 3.48-3.58 (1H, m), 3.73-3.86
(1H, m), 3.97-4.10 (2H, m), 4.20-4.30 (1H, m), 4.46-4.60 (2H, m),
4.85 (1H, dd, J=12.3, 3.5 Hz), 5.40 (1H, d, J=10.2 Hz), 5.18 (1H,
d, J=10.2 Hz), 5.28 (1H, dd, J=10.2, 3.2 Hz), 7.10-7.20 (2H, m),
7.23-7.40 (5H, m), 7.50-7.73 (2H, m), 8.60 (1H, s), 10.22 (1H,
m).
[0436] 3) Example C-1 was synthesized using a compound 83,
according to the method of synthesizing Example A-1.
[0437] Melting point: >300.degree. C.
[0438] 1H-NMR (DMSO-d.sub.6) .delta.: 1.10-1.60 (10H, 3.25 (1H, d,
J=11.4 Hz), 3.37 (1H, J=11.4 Hz), 3.76 (1H, t, J=10.5 Hz), 4.30
(2H, d, J=5.8 Hz), 4.66 (1H, dd, J=12.2, 3.8 Hz), 5.22 (1H, dd,
J=3.8, 10.4 Hz), 6.90-6.96 (2H, m), 7.10-7.15 (2H, m), 8.25 (1H,
s), 10.10 (1H, brs), 11.32 (1H, brs).
[0439] The following compounds were synthesized using the similar
method.
Example C-2
5-Hydroxy-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1-oxa-3a,8a-diaza-cyclopenta[b]-
naphthalene-7-carboxylic acid 4-fluorobenzylamide
[0440] Melting point: 272.274.degree. C.
[0441] 1H-NMR (DMSO-d.sub.6) .delta.: 3.59-3.67 (1H, m), 3.72-3.81
(1H, m), 3.98-4.10 (2H, m), 4.27-4.35 (1H, m), 4.52 (2H, d, J=7.2
Hz), 4.92 (1H, dd, J=12.3, 12.3 Hz), 5.27 (1H, dd, J=3.6, 9.9 Hz),
7.11-7.20 (2H, m), 7.30-7.40 (2H, m), 8.49 (1H, s), 1.0.32 (1H, t,
J=5.6 Hz), 11.53 (1H, s).
Example C-3
5-Hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diazaanthracen-
e-7-carboxylic acid 4-fluorobenzylamide
[0442] melting point: 259.degree. C.
[0443] 1H-NMR (DMSO-d.sub.6) .delta.: 1.60-1.67 (1H, m), 1.72-1.85
(1H, m), 3.25 (1H, td, J=12.8, 3.5 Hz), 3.86-3.93 (1H, m), 4.06
(1H, dd, J=11.4, 4.2 Hz), 4.44-4.57 (5H, m), 5.28 (1H, t, J=3.8
Hz), 7.13-7.18 (2H, m), 7.33-7.37 (2H, m), 8.51 (1H, s), 10.36 (1H,
t, J=6.0 Hz), 12.47 (1H, s).
Example C-4
5-Hydroxy-1-isopropyl-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1H-1,3a,8a-triaza-c-
yclopenta[b]naphthalene-7-carboxylic acid 4-fluoro-benzylamide
[0444] melting point: 232-234.degree. C.
[0445] 1H-NMR (DMSO-d.sub.6) .delta.: 1.03 (3H, d, 6.6 Hz), 1.14
(3H, d, 6.6 Hz), 2.79-3.66 (5H, m), 3.82 (1H, t, 10.8 Hz), 4.51
(3H, m), 4.90 (1H, m), 7.15 (2H, t, 9.0 Hz), 7.34 (2H, m), 8.45
(1H, s), 10.39 (1H, t, 5.4 Hz), 11.60 (1H, s).
Example C-5
5-Hydroxy-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1H-1,3a,8a-triaza-cyclopenta[b]-
naphthalene-7-carboxylic acid 4-fluoro-benzylamide
[0446] melting point: 256-258.degree. C.
[0447] 1H-NMR (DMSO-d.sub.6) .delta.: 3.00-3.55 (5H, m), 3.96 (1H,
t, 11.4 Hz), 4.52 (2H, d, 11.7 Hz), 4.76 (2H, m), 7.16 (2H, t, 8.7
Hz), 7.35 (2H, m), 8.48 (1H, s), 10.42 (1H, t, 5.4 Hz), 11.91 (1H,
s).
Example C-6
5-Hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-
-7-carboxylic acid 4-fluoro-benzylamide
[0448] melting point: 255.degree. C.
[0449] NMR (DMSO-d.sub.6) .delta.: 1.60 (1H, s), 2.75-3.16 (4H, m),
4.52 (2H, d, 6.0 Hz), 4.13-4.68 (4H, m), 7.16 (2H, 9.0 Hz, t), 7.34
(2H, m), 10.42 (1H, s), 10.44 (1H, 6.0 Hz, t), 12.81 (1H, s).
Example C-7
1-(2-Diethylamino-ethyl)-5-hydroxy-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1H-1,3-
a,8a-triaza-cyclopenta[b]naphthalene-7-carboxylic acid
4-fluoro-benzylamide
[0450] melting point: 186.187.degree. C.
[0451] NMR (DMSO-d.sub.6) .delta.: 0.97 (6H, t, 7.2 Hz), 2.42-2.91
(10H, m), 3.44-3.87 (5H, m), 4.23 (1H, m), 4.51 (2H, d, 5.7 Hz),
5.00 (1H, m), 7.16 (2H, t, 9.0 Hz), 7.33-7.37 (2H, m), 8.43 (1H,
s), 10.39 (1H, t, 5.7 Hz), 11.81 (1H, s).
Example C-8
1-Hydroxy-2,11-dioxo-2,5,5a,7,8,9,10,11-octahydro-6-oxa-4a,10a-diaza-cyclo-
hepta[b]naphthalene-3-carboxylic acid 4-fluoro-benzylamide
[0452] melting point: 242-244.degree. C.
[0453] NMR (DMSO-d.sub.6) .delta.: 1.40-2.00 (4H, m), 3.20-3.30
(1H, m), 3.66-3.77 (2H, m), 4.14-4.23 (1H, m), 4.38-4.41 (1H, m),
4.52 (2H, d, 6.3 Hz), 4.58-4.63 (1H, m), 5.34 (1H, brs), 7.15 (2H,
t, 9.0 Hz), 7.33-7.37 (2H, m), 8.50 (1H, s), 10.39 (1H, brs), 12.14
(1H, s).
Example C-9
5-Hydroxy-1-(2-hydroxy-ethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,-
8a-triaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide
[0454] NMR (DMSO-d.sub.6) .delta.: 1.58-1.80 (1H, m) 2.70-3.60 (7H,
m), 4.40-4.54 (6H, m), 4.77-4.82 (1H, m), 7.15 (2H, t, 9.0 Hz),
7.33-7.38 (2H, m), 8.52 (1H, s), 10.43 (1H, brs), 12.57 (1H,
s).
Example C-10
1-Hydroxy-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-triaza-cyclo-
hepta[b]naphthalene-3-carboxylic acid 4-fluoro-benzylamide
[0455] melting point: 256.degree. C.
[0456] NMR (DMSO-d.sub.6) .delta.: 1.47-1.77 (4H, m), 2.69-2.81
(2H, m), 3.34-3.41 (1H, m), 4.08-4.12 (1H, m), 4.26-4.40 (2H, m),
4.52 (2H, d, J=6.0 Hz), 7.15 (2H, t, 8.8 Hz), 7.33-7.36 (2H, m),
8.43 (1H, s), 10.46 (1H, t, J=6.0 Hz), 12.68 (1H, s).
Example C-11
5-Hydroxy-1-(2-methoxy-ethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,-
8a-triaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide
[0457] melting point: 147.degree. C.
[0458] NMR (DMSO-d.sub.6) .delta.: 1.56-1.74 (2H, m), 2.53-2.58
(1H, m), 2.66-3.10 (4H, m), 3.18 (3H, s), 3.41-3.39 (2H, m),
4.37-4.52 (5H, m), 4.73-4.80 (1H, m), 7.15 (2H, t, 8.8 Hz),
7.33-7.37 (2H, m), 8.56 (1H, s), 10.40 (1H, t, J=6.0 Hz), 12.62
(1H, s).
Example C-12
5-Hydroxy-1-(2-isopropoxy-ethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,-
4a,8a-triaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide
[0459] melting point: 151.degree. C.
[0460] NMR (DMSO-d.sub.6) .delta.: 1.02 (6H, dd, J=4.0, 6.0 Hz),
1.56-1.67 (2H, m), 2.53-2.58 (1H, m), 2.74-3.04 (4H, m), 3.18 (3H,
s), 3.41-3.52 (3H, m), 4.41-4.59 (5H, m), 4.79-4.83 (1H, m), 7.15
(2H, t, 8.8 Hz), 7.34-7.36 (2H, m), 8.58 (1H, s), 10.40 (1H, t,
J=6.0 Hz), 12.56 (1H, s).
Example C-13
5-Hydroxy-3,3-dimethyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-oxa-4a,8a-dia-
za-anthracene-7-carboxylic acid 4-fluoro-benzylamide
[0461] melting point: 275-277.degree. C.
[0462] NMR (DMSO-d.sub.6) .delta.: 2.97 (3H, s), 3.01 (3H, s),
3.00-3.18 (3H, m), 4.45-4.56 (5H, m), 5.16 (1H, s), 7.15 (2H, t,
J=9 Hz), 7.35 (2H, dd, J=5.4 Hz, 8.7 Hz), 8.51 (1H, s), 10.36 (1H,
t, J=5.7 Hz), 12.4 (1H, s).
Example C-14
1-Cyclohexyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-tria-
za-anthracene-7-carboxylic acid-4-fluoro-benzylamide
[0463] melting point: 275.277.degree. C.
[0464] NMR (DMSO-d.sub.6) .delta.: 1.22-1.70 (2H, m), 2.50-3.02
(3H, m), 4.45 (4H, m), 4.52 (2H, s), 4.78 (1H, d, J=13.2 Hz), 7.16
(2H, t, J=8.7 Hz), 7.35 (2H, dd, J=5.7 Hz, 8.4. Hz), 8.62 (1H, s),
10.52 (1H, s), 12.55 (1H, s).
Example C-15
5-Hydroxy-1-isopropyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaz-
a-anthracene-7-carboxylic acid-4-fluoro-benzylamide
[0465] melting point: 220.degree. C.
[0466] NMR (DMSO-d.sub.6) .delta.: 0.94 (6H, d, J=9.6 Hz),
1.53-1.67 (2H, m), 2.92-3.30 (3H, m), 4.32-4.40 (4H, m), 4.52 (2H,
d, J=5.7 Hz), 4.89 (1H, d, J=14.1 Hz), 7.16 (2H, t, J=9.0 Hz), 7.35
(2H, dd, J=6.3 Hz, 9.0 Hz), 8.61 (1H, s), 10.46 (1H, s), 12.55 (1H,
s).
Example C-16
5-Hydroxy-3,3-dimethyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-tria-
za-anthracene-7-carboxylic acid 4-fluoro-benzylamide
[0467] melting point: 280.degree. C.
[0468] NMR (DMSO-d.sub.6) .delta.: 0.87 (3H, s), 0.93 (3H, s),
2.59-3.15 (6H, m), 4.09-4.57 (6H, 7.14 (2H, d, J=9.0 Hz), 7.34 (2H,
dd, J=5.4 Hz, 8.4 Hz), 8.42 (1H, s), 10.46 (1H, s), 12.77 (1H,
s).
Example C-17
5-Hydroxy-1-(2-morpholin-4-yl-2-oxo-ethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-oc-
tahydro-1,4a,8a-triaza-anthracene-7-carboxylic acid
4-fluorobenzylamide
[0469] melting point: 140.degree. C.
[0470] NMR (DMSO-d.sub.6) .delta.: 1.60 (2H, m), 2.91-3.62 (13H,
m), 4.41 (2H, m), 4.51 (2H, d, J=4.8 Hz), 4.80 (2H, m), 7.15 (2H,
t, J=8.7 Hz), 7.34 (2H, m), 8.44 (1H, s), 10.43 (1H, s), 12.54 (1H,
s).
Example C-18
1-(3-Acetylamino-propyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro--
1,4a,8a-triaza-anthracene-7-carboxylic acid
4-fluoro-benzylamide
[0471] melting point: 177-178.degree. C.
[0472] NMR (DMSO-d.sub.6) .delta.: 1.74 (3H, s), 1.49-2.98 (9H, m),
3.60 (1H, s), 4.25-4.65 (7H, m), 7.14 (2H, t, J=8.4 Hz), 7.34 (2H,
m), 7.71 (1H, s), 8.26 (1H, s), 10.60 (1H, s).
Example C-19
1-Dimethycarbamoylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro--
1, 4a,8a-triaza-anthracene-7-carboxylic acid
4-fluoro-benzylamide
[0473] melting point: 190.degree. C.
[0474] NMR (DMSO-d.sub.6) .delta.: 1.60 (2H, m), 2.76 (3H, s), 2.83
(3H, s), 2.90-3.59 (5H, s), 4.40 (2H, m), 4.51 (2H, d, 5.7 Hz),
4.80 (1H, d, d=14.4 Hz), 4.98 (1H, s), 7.16 (2H, t, 7.34 (2H, m),
8.54 (1H, s), 10.42 (1H, s).
Example C-20
5-Hydroxy-1-(3-methanesulfonylamino-propyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-o-
ctahydro-1,4a,8a-triaza-anthracene-7-carboxylic acid
4-fluoro-benzylamide
[0475] melting point: 176.degree. C.
[0476] NMR (DMSO-d.sub.6) .delta.: 1.54-1.75 (4H, m), 2.80 (3H, s),
2.30-3.04 (8H, m), 4.45 (2H, m), 4.52 (2H, d, J=5.6 Hz), 4.75 (1H,
d, J=13.2 Hz), 6.91 (1H, t, J=5.6 Hz), 7.16 (2H, t, J=8.8 Hz), 7.36
(2H, m), 8.61 (1H, S), 10.41 (1H, t, J=5.6 Hz), 12.58 (1H, s).
Example C-21
5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-
anthracene-7-carboxylic acid 4-fluorobenzylamide
[0477] NMR (CDCl.sub.3) .delta.: 1.27 (3H, d, J=6.0 Hz), 1.55-1.78
(2H, m), 3.11 (1H, td, J=12.9, 3.7 Hz), 3.89-4.00 (1H, m), 4.16
(1H, dd, J=13.8, 3.9 Hz), 4.34 (1H, dd, J=13.8, 3.9 Hz), 4.60 (2H,
d, J=6.0 Hz), 4.71 (1H, ddd, J=13.5, 4.8, 1.8 Hz), 5.08 (1H, t,
J=3.9 Hz), 6.96-7.04 (2H, m), 7.26-7.35 (2H, m), 8.82 (1H, s),
10.41 (1H, br s), 12.41 (1H, br s).
Example F-1
5-Hydroxy-1-isobutyl-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1H-1,3a,8a-triazacyc-
lopenta[b]naphthalene-7-carboxylic acid-4-fluorobenzylamide
##STR00093##
[0479] 1) According to the method of synthesizing a compound 17-1,
the crude purified product (503 mg) of a compound 48 was obtained
at a yield of 82% from a compound 16 (600 mg).
[0480] 2) To a solution of a compound 48 (1.00 mg, 0.22 mmol),
isobutylaldehyde (39 .mu.l, 0.482 mmol) and acetic acid (25 .mu.l,
0.432 mmol) in dichloromethane (4 ml) was added sodium
triacetoxyborohydride (92 mg, 0.432 mmol) under ice-cooling, and
the mixture was stirred at room temperature for 2 hours. Further,
isobutylaldehyde (200) and sodium triacetoxyborohydride (46 mg)
were added, and the mixture was stirred for 30 minutes. To the
reaction solution was added water, this was extracted with
chloroform, and the organic layer was washed with an aqueous
saturated sodium bicarbonate solution. After dying, the solvent was
distilled off under reduced pressure, and this was purified by
silica gel column chromatography. A compound 49 (87 mg) was
obtained as a colorless crystal at a yield of 78%.
[0481] 1H-NMR (CDCl.sub.3) .delta.: 0.96 (3H, d, J=6.6 Hz), 0.97
(3H, d, J=6.3 Hz), 1.72-1.86 (1H, m), 2.25-2.41 (2H, m), 2.47-2.58
(1H, m), 3.39-3.46 (1H, m), 3.69-3.76 (2H, m), 3.85-3.93 (1H, m),
4.06 (1H, dd, J=9.9, 2.7 Hz), 4.16-4.22 (1H, m), 4.57 (1H, dd,
J=15.3, 5.1 Hz), 4.64 (1H, dd, J=14.7, 5.1 Hz), 5.20 (1H, d, J=9.9.
Hz), 5.38 (1H, d, J=9.9 Hz), 6.96-7.05 (2H, m), 7.28-7.36 (5H, m),
7.58-7.62 (2H, m), 8.4.0 (1H, s), 10.44 (1H, br s).
[0482] 3) According to the method of a step 17) of Example B-1, a
compound F-1 (43 mg) was obtained at a yield of 64% from a compound
49 (81 mg).
[0483] 1H-NMR (DMSO-d.sub.6) .delta.: 0.90 (3H, d, J=6.4 Hz), 0.91
(3H, d, J=6.0 Hz), 1.75-1.84 (1H, m), 2.24-2.39 (1H, m), 2.39-2.54
(2H, m), 3.36-3.43 (1H, m), 3.52-3.60 (1H, m), 3.67-3.73 (1H, m),
3.81-3.88 (1H, m), 4.19-4.23 (1H, m), 4.52 (2H, d, J=6.0 Hz),
4.94-4.99 (1H, m), 7.12-7.20 (2H, m), 7.32-7.38 (2H, m), 8.45 (1H,
s), 10.37 (1H, t, J=2.0 Hz), 11.74 (1H, s).
[0484] According to the same manner as that of Example F-1, the
following Example compounds F-2 to F-63 were synthesized.
Example F-2
5-Hydroxy-1-isobutyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-
anthracene-7-carboxylic acid 4-fluorobenzylamide
[0485] melting point: 14.6-14.8.degree. C.
[0486] 1H-NMR (DMSO-d.sub.6) .delta.: 0.63 (3H, d, J=6.6 Hz), 0.79
(3H, d, J=6.6 Hz), 1.56-1.66 (2H, m), 1.67-1.75 (1H, m), 1.94-1.99
(1H, m), 2.41-2.54 (2H, m), 2.96-3.06 (2H, m), 4.41-4.59 (5H, m),
4.76-4.81 (1H, m), 7.14-7.21 (2H, m), 7.33-7.38 (2H, m), 8.61 (1H,
s), 10.40 (1H, d, J=5.8 Hz), 12.56 (1H, s).
Example F-3
1-Cyclopropylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,-
8a-triaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide
[0487] melting point: 182.184.degree. C.
[0488] NMR (DMSO-d.sub.6) .delta.: 0.06 (2H, m), 0.43 (2H, d, 8.4
Hz), 0.80 (1H, m), 1.66 (2H, m), 2.28-3.30 (4H, m), 4.40-4.50 (4H,
m), 4.52 (2H, d, 6.0 Hz), 4.78 (2H, m), 7.15 (2H, t, 8.7 Hz), 7.34
(2H, m), 8.55 (1H, s), 10.47 (1H, s), 12.55 (1H, s).
Example F-4
1-Cyclopentylmethyl-5-hydroxy-6,1-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8-
a-triaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide
[0489] melting point: 184-185.degree. C.
[0490] NMR (DMSO-d.sub.6) .delta.: 0.88-2.10 (1H, m), 2.60 (2H, m),
2.95-3.28 (2H, m), 4.38-4.53 (6H, m), 4.82 (1H, m), 7.15 (2H, L,
9.0 Hz), 7.34 (2H, m), 8.57 (1H, s), 10.42 (1H, s), 12.45 (1H,
s).
Example F-5
5-Hydroxy-1-(4-methylsulfanylbenzyl)-6,10-dioxo-1,2,3,4,9,9a,10-octahydro--
1,4a,8a-triazaanthracene-7-carboxylic acid 4-fluorobenzylamide
[0491] (DMSO-d.sub.6) .delta.: 1.51-1.56 (1H, m), 1.69-1.74 (1H,
m), 2.42 (3H, s), 2.55-2.62 (1H, m), 2.80-2.84 (1H, m), 3.00-3.08
(1H, m), 3.32-3.36 (1H, m), 3.93 (1H, d, J=13.6 Hz), 4.45-4.53 (4H,
m), 4.58 (1H, s), 4.83 (1H, d, J=1.5.2 Hz), 7.11-7.19 (6H,
7.33-7.40 (2H, m), 8.34 (1H, s), 10.38 (1H, t, J=6.0 Hz), 12.58
(1H, s).
Example F-6
1-(5-Chloro-1,3-dimethyl-1H-pyrazol-4-ylmethyl)-5-hydroxy-6,10-dioxo-1,2,3-
,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylic acid
4-fluorobenzylamide
[0492] (DMSO-d.sub.6) .delta.: 1.56-1.59 (2H, m), 1.88 (3H, s),
2.37-2.45 (11H, m), 2.76-2.80 (1H, m), 3.00-3.06 (2H, m), 3.64 (3H,
s), 3.87 (1H, d, J=13.2 Hz), 4.40-4.55 (5H, m), 4.97 (1H, d, J=14.4
Hz), 7.13-7.19 (2H, m), 7.33-7.38 (2H, m), 8.56 (1H, s), 10.39 (1H,
t, J=6.0 Hz), 12.46 (1H, s).
Example F-7
5-Hydroxy-1-(3-methoxybenzyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,-
8a-triazaanthracene-7-carboxylic acid 4-fluorobenzylamide
[0493] (DMSO-d.sub.6) .delta.: 1.52-1.57 (1H, m), 1.70-1.80 (1H,
m), 2.60-2.68 (1H, m), 2.84-2.90 (1H, m), 3.01-3.09 (1H, m), 3.36
(1H, d, J=14.0 Hz), 3.61 (3H, s), 3.91 (1H, d, J=14.0 Hz),
4.45-4.52 (4H, m), 4.58 (1H, s), 4.76 (1H, d, J=14.8 Hz), 6.68-6.73
(2H, m), 6.77 (1H, d, J=7.6 Hz), 7.13-7.19 (3H, m), 7.33-7.38 (2H,
m), 8.17 (1H, s), 10.38 (1H, t, J=6.0 Hz), 12.57 (1H, s).
Example F-8
5-Hydroxy-1-(4-methanesulfonylbenzoyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahy-
dro-1,4a,8a-triazaanthracene-7-carboxylic acid
4-fluorobenzylamide
[0494] (DMSO-d.sub.6) .delta.: 1.54-1.58 (1H, m), 1.74-1.80 (1H,
m), 2.67-1.74 (1H, m), 2.83-2.87 (1H, m), 3.05-3.12 (1H, m), 3.18
(3H, s), 3.52 (1H, d, J=14.8 Hz), 4.09 (1H, d, J=14.8 Hz),
4.46-4.52 (4H, m), 4.67 (1H, s), 4.73 (1H, d, J=14.8 Hz),
7.12-7.1.8 (2H, m), 7.32-7.36 (2H, m), 7.46 (2H, m), 7.80 (2H, d,
J=8.0 Hz), 8.17 (1H, s), 10.37 (1H, t, J=5.8 Hz), 12.59 (1H,
s).
Example F-9
5-Hydroxy-1-(6-methoxypyridin-3-ylmethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-oct-
ahydro-1,4a,8a-triazaanthracene-7-carboxylic acid
4-fluorobenzylamide
[0495] (DMSO-d.sub.6) .delta.: 1.51-1.56 (1H, m), 1.71-1.77 (1H,
m), 2.58-2.66 (1H, m), 2.80-2.86 (1H, m), 3.01-3.09 (1H, m), 3.38
(1H, d, J=13.6 Hz) 3.78 (3H, s), 3.87 (1H, d, J=13.6 Hz), 4.45-4.52
(4H, m), 4.60 (1H, s), 4.82 (1H, d, J=13.6 Hz), 6.71 (1H, d, J=8.6
Hz), 7.12-7.19 (2H, m), 7.33-7.38 (2H, m), 7.49 (1H, d, J=8.6 Hz),
7.98 (1H, s), 8.30 (1H, s), 10.37 (1H, t, J=6.0 Hz), 12.58 (1H,
s).
Example F-10
5-Hydroxy-1-isobutyl-3,3-dimethyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1-
,4a,8a-triazaanthracene-7-carboxylic acid 4-fluorobenzylamide
[0496] (DMSO-d.sub.6) .delta.: 0.64 (3H, d, J=6.4 Hz), 0.82 (3H, d,
J=6.8 Hz), 0.90 (3H, s), 0.91 (8H, s), 1.59-1.67 (1H, m), 1.92-1.97
(1H, m), 2.11-2.15 (1H, m), 2.51-2.57 (1H, m), 2.67 (1H, d, J=12.0
Hz), 2.77 (1H, d, J=12.8 Hz), 4.13 (1H, s), 4.21 (1H, d, J=12.8
Hz), 4.47-4.59 (3H, s), 4.80 (1H, dd, J=14.4, 2.8 Hz), 7.14-7.19
(2H, m), 7.34-7.38 (2H, m), 8.66 (1H, s), 10.41 (1H, t, J=6.0 Hz),
12.44 (1H, s).
Example F-11
5-Hydroxy-1,3,3-trimethyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-t-
riazaanthracene-7-carboxylic acid 4-fluorobenzylamide
[0497] (DMSO-d.sub.6) .delta.: 0.89 (6H, s), 2.14-2.18 (1H, m),
2.24 (3H, s), 2.54-2.58 (1H, m), 2.74-2.78 (1H, s), 3.88 (1H, s),
4.21 (1H, d, J=13.2 Hz), 4.45-4.53 (3H, m), 4.72-4.76 (1H, m),
7.13-7.19 (2H, m), 7.33-7.38 (2H, m), 8.64 (1H, s), 10.40 (1H, t,
J=6.0 Hz), 12.46 (1H, s).
Example F-12
4-[7-(4-Fluorobenzylcarbamoyl)-5-hydroxy-6,10-dioxy-3,4,6,9,9a,10-hexahydr-
o-2H-1,4a,8a-triazaanthracene-1-yl]butanoic acid ethyl ester
[0498] (CDCl.sub.3) .delta.: 1.23 (3H, t, J=7.1 Hz), 1.70-1.79 (1H,
m), 1.86-2.00 (1H, m), 2.17-2.34 (2H, m), 2.46-2.57 (1H, m),
2.61-2.77 (2H, m), 2.85-2.92 (1H, m), 3.13-3.18 (1H, m), 4.13 (2H,
J=7.1 Hz), 4.27-4.34 (2H, m), 4.57-4.63 (3H, m), 4.66-4.73 (1H, m),
6.95-7.03 (2H, m), 7.29-7.36 (2H, m), 8.36 (1H, s), 10.48 (1H, t,
J=4.8 Hz), 12.50 (1H, s).
Example F-13
1-(3-Dimethylcarbamoylpropyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octah-
ydro-1,4a,8a-triazaanthracene-7-carboxylic acid
4-fluorobenzylamide
[0499] (CDCl.sub.3) .delta.: 1.62-1.82 (3H, m), 1.83-2.00 (1H, m),
2.10-2.35 (2H, m), 2.57-2.65 (2H, m), 2.75-2.95 (2H, m), 2.92 (3H,
s), 2.96 (3H, s), 3.07-3.14 (1H, m), 4.23-4.30 (2H, m), 4.60 (2H,
d, J=6.0 Hz), 4.68 (1H, dd, J=13.2, 4.5 Hz), 5.12 (1H, d, J=12.6
Hz), 6.95-7.02 (2H, m), 7.28-7.35 (2H, m), 8.42 (1H, s), 1054 (1H,
t, J=5.4 Hz), 12.51 (1H, s).
Example F-14
5-Hydroxy-1-(4-morpholin-4-yl-4-oxobutyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-oct-
ahydro-1,4a,8a-triazaanthracene-7-carboxylic acid
4-fluorobenzylamide
[0500] (CDCl.sub.3) .delta.: 1.61-1.83 (3H, m), 1.84-2.00 (1H, m),
2.12-2.23 (1H, m), 2.25-2.36 (1H, m), 2.56-2.64 (2H, m), 2.75-2.95
(2H, m), 3.09-3.15 (1H, m), 3.37 (2H, t, 3.61-3.66 (6H, m),
4.26-4.32 (2H, m), 4.59 (2H, d, J=5.7 Hz), 4.68 (1H, dd, J=13.2,
4.5 Hz), 4.95-5.01 (1H, m), 6.95-7.03 (2H, m), 7.28-7.35 (2H, m),
8.40 (1H, s), 10.52 (1H, t, J=5.7 Hz), 12.51 (1H, s).
Example F-15
5-Hydroxy-1-methyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaan-
thracene-7-carboxylic acid 4-fluorobenzylamide
[0501] melting point: 252-253.degree. C.
[0502] (DMSO-d.sub.6) .delta.: 1.56-1.75 (2H, m), 2.22 (3H, s),
2.50-2.55 (1H, m), 2.90-3.10 (2H, m), 4.17 (1H, brs), 4.39-4.42
(2H, m), 4.52 (2H, d, J=6.0 Hz), 4.74-4.78 (1H, m), 7.13-7.17 (2H,
m), 7.33-7.37 (2H, m), 8.61 (1H, s), 10.40 (1H, t, J=6.0 Hz), 12.54
(1H, s).
Example F-16
5-Hydroxy-6,10-dioxo-1-thiophen-3-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4-
a,8a-triazaanthracene-7-carboxylic acid 4-fluorobenzylamide
[0503] melting point: 242-24.3.degree. C.
[0504] (DMSO-d.sub.6) .delta.: 1.52'1.73 (2H, m), 2.69-2.62 (1H,
m), 2.87-3.03 (2H, m), 3.52 (1H, d, J=13.6 Hz), 3.90 (1H, d, J=14.4
Hz), 4.40-4.56 (5H, m), 4.83-4.90 (3H, m), 6.92 (1H, d, J=5.2 Hz),
7.13-7.17 (2H, m), 7.28-7.37 (3H, m), 7.42-7.44 (1H, m), 8.46 (1H,
s), 10.39 (1H, t, J=6.0 Hz), 12.58 (1H, s).
Example F-17
5-Hydroxy-6,10-dioxo-1-thiazol-2-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a-
,8a-triazaanthracene-7-carboxylic acid 4-fluorobenzylamide
[0505] melting point: 214-215.degree. C.
[0506] (DMSO-d.sub.6) .delta.: 1.54-1.72 (2H, m), 2.75-2.81 (1H,
m), 2.95-3.07 (2H, m), 3.80 (1H, d, J=16.0 Hz), 4.37 (1H, d, J=16.4
Hz), 4.44-4.51 (4H, m), 4.69 (1H, brs), 4.89-4.93 (1H, 7.13-7.17
(2H, m), 7.32-7.35 (2H, m), 7.55 (1H, d, J=3.2 Hz), 7.69 (1H, d,
J=3.2 Hz), 8.37 (1H, s), 10.36 (1H, t, J=6.0 Hz), 12.50 (1H,
s).
Example F-18
5-Hydroxy-(3-methylsulfanyl-propyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-
-1,4a,8a-triazaanthracene-7-carboxylic acid 4-fluorobenzylamide
[0507] melting point: 162-164.degree. C.
[0508] (DMSO-d.sub.6) .delta.: 1.50-1.82 (4H, m), 2.27 (3H, s),
2.32-2.44 (3H, m), 2.60-2.82 (2H, m), 3.00-3.14 (2H, m), 4.37-4.59
(5H, m), 4.75-4.79 (1H, m), 7.13-7.17 (2H, m), 7.33-7.35 (2H, m),
8.60 (1H, s), 10.40 (1H, t, J=6.0 Hz), 12.57 (1H, s).
Example F-19
5-Hydroxy-6,10-dioxo-1-pyridin-4-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a-
,8a-triazaanthracene-7-carboxylic acid 4-fluorobenzylamide
[0509] melting point: 180-183.degree. C.
[0510] (DMSO-d.sub.6) .delta.: 1.52-1.76 (2H, m), 2.62-2.80 (2H,
m), 3.01-3.07 (1H, m), 3.42 (1H, d, J=1.5.2 Hz), 4.05 (1H, d,
J=15.2 Hz), 4.49-4.50 (4H, m), 4.64 (1H, brs), 4.78-4.81 (1H, m),
7.12-7.21 (1H, m), 7.32-7.36 (2H, m), 8.33 (1H, s), 8.42 (2H, d,
10.39 (1H, t, J=6.0 Hz), 12.55 (1H, s).
Example F-20
1-Cyclohexylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8-
a-triazaanthracene-7-carboxylic acid 4-fluorobenzylamide
[0511] melting point: 201-202.degree. C.
[0512] (DMSO-d.sub.6) .delta.: 0.56-0.59 (1H, m), 0.87-0.84 (1H,
m), 1.02-1.13 (3H, m), 1.23-1.29 (1H, m), 1.49-1.70 (6H, m),
1.92-1.97 (1H, m), 2.52-2.55 (1H, m), 2.96-3.03 (2H, m), 4.40-4.43
(3H, m), 4.52 (2H, d, J=6.0 Hz), 4.73-4.77 (1H, m), 7.12-7.16 (2H,
m), 7.32-7.36 (2H, m), 8.59 (1H, s), 10.40 (1H, t, J=5.2 Hz), 12.58
(1H, s).
Example F-21
5-Hydroxy-6,10-dioxo-1-pyridin-2-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a-
,8a-triazaanthracen-7-carboxylic acid 4-fluorobenzylamide
[0513] melting point: 216-219.degree. C.
[0514] (DMSO-d.sub.6) .delta.: 1.52-1.76 (2H, m), 2.66-2.80 (1H,
m), 2.90-3.07 (2H, m), 3.67 (1H, d, J=15.2 Hz), 4.01 (1H, d, J=13.2
Hz), 4.37-4.97 (4H, m), 4.62 (1H, brs), 4.85-4.88 (1H, m),
7.07-7.25 (4H, m), 7.33-7.36 (2H, m), 7.64-7.68 (1H, m), 8.26 (1H,
s), 8.45 (1H, s), 10.36 (1H, t, J=6.0 Hz), 12.57 (1H, s).
Example F-22
1-(2-Ethyl-butyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-
-triazaanthracen-7-carboxylic acid 4-fluorobenzylamide
[0515] melting point: 137-140.degree. C.
[0516] (DMSO-d.sub.6) .delta.: 0.62 (3H, t, J=7.2 Hz), 0.77 (3H, t,
J=7.2 Hz), 0.99-1.30 (5H, m), 1.57-1.71 (2H, m), 1.97-2.02 (1H, m),
2.44-2.58 (2H, m), 3.02-3.32 (2H, m), 4.34-4.57 (5H, m), 4.78-4.82
(1H, m), 7.13-7.17 (2H, m), 7.32-7.36 (2H, m), 8.60 (1H, s), 10.39
(1H, t, J=5.2 Hz), 12.54 (1H, s).
Example F-23
5-Hydroxy-1-(2-morpholin-4-ylethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-
-1,4a,8a-triazaanthracen-7-carboxylic acid 4-fluorobenzylamide
[0517] melting point: 254-256.degree. C.
[0518] (DMSO-d.sub.6) .delta.: 1.55-1.68 (2H, m), 2.28-2.39 (8H,
m), 2.59-2.65 (1H, m), 2.82-3.09 (3H, m), 3.33-3.58 (5H, m),
4.34-4.50 (3H, m), 4.52 (2H, d, J=6.2 Hz), 4.79-4.84 (11-1,
7.12-7.17 (2H, m), 7.32-7.36 (2H, m), 8.52 (1H, s), 10.45 (1H, t,
J=5.2 Hz), 12.55 (1H, s).
Example F-24
1-Hydroxy-6-methyl-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-tri-
aza-cyclohepta[b]naphthalene-3-carboxylic acid
4-fluorobenzylamide
[0519] melting point: 255.degree. C.
[0520] (DMSO-d.sub.6) .delta.: 1.48-1.55 (1H, m), 1.67-1.80 (3H,
m), 2.29 (3H, s), 2.75-2.80 (2H, 3.23-3.31 (1H, m), 4.07-4.09 (1H,
m), 4.36-4.40 (1H, m), 4.45-4.59 (3H, m), 4.68-4.69 (1H, m),
7.13-7.17 (2H, m), 7.30-7.37 (2H, m), 8.50 (1H, s), 10.42 (1H, t,
12.42 (1H, s).
Example F-25
1-Hydroxy-6-isobutyl-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-t-
riaza-cyclohepta[b]naphthalene-3-carboxylic acid
4-fluorobenzylamide
[0521] melting point: 221-223.degree. C.
[0522] DMSO-d.sub.6) .delta.: 0.81 (3H, d, J=6.8 Hz), 0.84 (3H, d,
J=6.4 Hz), 1.45-1.78 (5H, m), 2.36-2.54 (2H, m), 2.27-2.93 (2H, m),
3.17-3.23 (1H, m), 4.03-4.06 (1H, m), 4.32-4.56 (4H, m), 4.82-4.85
(1H, m), 7.13-7.17 (2H, m), 7.30-7.37 (2H, m), 8.48 (1H, s), 10.42
(1H, t, J=6.0 Hz), 12.53 (1H, s).
Example F-26
6-Cyclopropylmethyl-1-hydroxy-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4-
a,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylic acid
4-fluorobenzylamide
[0523] melting point: 21.3.degree. C.
[0524] DMSO-d.sub.6) .delta.: 0.15-0.26 (2H, m), 0.46-0.48 (2H, m),
0.86-1.06 (1H, m), 1.45-1.75 (4H, m), 2.45-2.65 (1H, m), 2.68-2.83
(1H, m), 2.91-2.98 (2H, m), 3.17-3.26 (1H, m), 4.08-4.14 (1H,
4.43-4.45 (2H, m), 4.54 (2H, d, J=5.6 Hz), 4.89-4.91 (1H, m),
7.15-7.19 (2H, m), 7.35-7.39 (2H, m), 8.50 (1H, s), 10.47 (1H, t,
12.52 (1H, s).
Example F-27
1-Furan-2-ylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8-
a-triaza-anthracene-7-carboxylic acid 4-fluorobenzylamide
[0525] melting point: 193-197.degree. C.
[0526] DMSO-d.sub.6) .delta.: 1.67 (2H, m), 2.61 (3H, s), 2.93 (2H,
m), 3.75 (1H, d, J=14.8 Hz), 3.84 (1H, d, J=14.8 Hz), 4.34-4.47
(3H, m), 4.52 (2H, d, J=6.0 Hz), 4.96 (1H, d, J=14.8 Hz), 6.36 (2H,
s), 7.16 (2H, t, J=8.8 Hz), 7.35 (2H, m), 7.59 (1H, s), 8.97 (1H,
s), 10.4.3 (1H, s), 12.51 (1H, s).
Example F-26
1-(4-Dimethylamino-benzyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydr-
o-1,4a,8a-triaza-anthracene-7-carboxylic acid
4-fluorobenzylamide
[0527] melting point: 221-223.degree. C.
[0528] DMSO-d.sub.6) .delta.: 1.55-1.99 (2H, m), 2.87 (6H, s),
2.87-3.06 (4H, m), 3.80 (1H, d, J=14.0 Hz), 4.50 (5H, m), 4.83 (1H,
d, J=14.0 Hz), 6.58 (2H, d, 6.98 (2H, d, J=8.8 Hz), 7.15 (2H, t,
7.35 (2H, m), 8.31 (1H, s), 10.39 (1H, s), 12.58 (1H, s).
Example F-29
5-Hydroxy-6,10-dioxo-1-(4-trifluoromethyl-benzyl)-1,2,3,4,6,9,9a,10-octahy-
dro-1,4a,8a-triaza-anthracene-7-carboxylic acid
4-fluorobenzylamide
[0529] melting point: 273-277.degree. C.
[0530] DMSO-d.sub.6) .delta.: 1.52-1.70 (2H, m), 2.63-3.04 (3H, m),
3.50 (1H, d, 4.10 (1H, d, J=14.8 Hz), 4.54 (5H, m), 4.79 (1H, d,
J=14.8 Hz), 7.14 (2H, t, J=8.8 Hz), 7.33 (2H, m), 7.55 (2H, d,
J=6.8 Hz), 7.61 (2H, d, J=8.0 Hz), 8.22 (1H, s), 10.40 (1H, s),
12.56 (1H, s).
Example F-30
5-Hydroxy-6,10-dioxo-1-pyridin-3-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a-
,8a-triaza-anthracene-7-carboxylic acid 4-fluorobenzylamide
[0531] melting point: 210-212.degree. C.
[0532] DMSO-d.sub.6) .delta.: 1.51-1.76 (2H, m), 2.63 (1H, t,
J=12.8 Hz), 2.80 (1H, d, J=12.0 Hz), 3.07 (1H, t, J=12.8 Hz), 3.44
(1H, d, J=13.2 Hz), 4.00 (1H, d, 14.0 Hz), 4.4.7 (4H, m), 4.62 (1H,
s), 4.84 (1H, d, J=14.0 Hz), 7.16 (2H, t, J=8.8 Hz), 7.33 (2H, m),
7.58 (1H, d, J=7.6 Hz), 8.30 (1H, s), 8.45 (2H, s), 10.41 (1H, s),
12.57 (1H, s).
Example F-31
1-(2-Chloro-6-fluoro-benzyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahy-
dro-1,4a,8a-triaza-anthracene-7-carboxylic acid
4-fluorobenzylamide
[0533] melting point: 213-215.degree. C.
[0534] DMSO-d.sub.6) .delta.: 1.58 (2H, 2H), 2.55-8.09 (3H, m),
3.45 (1H, d, J=12.4 Hz), 4.16 (1H, d, J=12.4 Hz), 4.40-4.58 (4H,
m), 5.12 (1H, d, J=14.41 Hz), 7.15-7.38 (7H, m), 8.66 (1H, s),
10.41 (1H, t, J=6.4 Hz), 12.46 (1H, s):
Example F-32
5-Hydroxy-1-(4-methoxy-benzyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a-
,8a-triaza-anthracene-7-carboxylic acid 4-fluorobenzylamide
[0535] melting point: 191-193.degree. C.
[0536] NMR (DMSO-d.sub.6) .delta.: 1.50-1.77 (2H, m), 2.58-3.06
(3H, m), 3.68 (3H, s), 3.88 (1H, d, J=13.6 Hz), 4.41-4.55 (4H, m),
4.80 (2H, d, J=14.4 Hz), 6.80 (2H, d, J=8.8 Hz), 7.09 (2H, d, J=8.4
Hz), 7.15 (2H, t, J=8.8 Hz), 7.35 (2H, m), 8.28 (1H, s), 10.48 (1H,
s), 12.58 (1H, s).
Example F-33
1-(3,5-Bis-trifluoromethyl-benzyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10--
octahydro-1,4a,8a-octahydro-1,4a,8a-triaza-anthracene-7-carboxylic
acid 4-fluorobenzylamide
[0537] melting point: 275-277.degree. C.
[0538] NMR (DMSO-d.sub.6) .delta.: 1.58-1.88 (2H, m), 2.51-3.14
(3H, m), 3.33-4.10 (3H, m), 4.51 (2H, m), 4.73 (1H, m), 7.15 (2H,
m), 7.34 (2H, m), 7.82-7.93 (4H, m), 10.31 (1H, s), 12.57 (1H,
s).
Example F-34
1-(4-Diethylamino-benzyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-
-1,4a,8a-triaza-anthracene-7-carboxylic acid
4-fluorobenzylamide
[0539] melting point: 182.degree. C.
[0540] NMR (DMSO-d.sub.6) .delta.: 1.04 (6H, t, J=6.8 Hz),
1.50-1.69 (2H, m), 2.55-3.05 (3H, m), 3.26 (4H, q, J=7.2 Hz), 3.80
(1H, d, J=13.6 Hz), 4.44-4.57 (4H, m), 4.91 (1H, d, J=12.4 Hz),
6.52 (2H, d, J=8.8 Hz), 6.94 (2H, d, J=8.4 Hz), 7.15 (2H, t, J=8.4
Hz), 7.35 (2H, m), 8.46 (1H, s), 10.41 (1H, s), 12.60 (1H, s).
Example F-35
5-Hydroxy-1-((E)-2-methyl-but-2-enyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahyd-
ro-1,4a,8a-triaza-anthracene-7-carboxylic acid
4-fluorobenzylamide
[0541] melting point: 175-177.degree. C.
[0542] NMR (DMSO-d.sub.6) .delta.: 1.35 (3H, s), 1.51 (3H, d, J=6.0
Hz), 1.52-1.69 (3H, m), 2.60-3.15 (3H, m), 4.31-4.52 (5H, m),
4.67-4.76 (1H, m), 5.30-5.40 (1H, m), 7.15 (2H, t, J=8.4 Hz),
7.28-43 (2H, m), 8.46 (1H, s), 10.39 (1H, brs), 12.60 (1H, s).
Example F-36
1-(3-Dimethylamino-2-methyl-propyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,
10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylic acid
4-fluoro-benzylamide
[0543] NMR (DMSO-d.sub.6) .delta.: 0.63-0.68 (2H, m), 1.57-1.82
(3H, m), 2.11-2.49 (10H, m), 2.98-3.11 (2H, m), 4.41-4.54 (5H, m),
4.73-4.80 (1H, m), 7.14-7.18 (2H, m), 7.31-7.38 (2H, m), 8.58 (1H,
s), 10.40 (1H, s), 12.57 (1H, s).
Example F-37
1-(3,3-Dimethyl-butyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,-
4a,8a-triaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide
[0544] melting point: 175-177.degree. C.
[0545] NMR (DMSO-d.sub.6) .delta.: 1.19-1.36 (2H, m), 1.57-1.70
(2H, m), 2.23-2.30 (1H, m), 2.51-2.69 (2H, m), 2.97-3.04 (2H, m),
4.42-4.54 (5H, m), 4.78 (1H, d, J=14.0 Hz), 7.13-7.17 (2H, m),
7.33-7.36 (2H, m), 8.63 (1H, s), 10.39 (1H, t, J=6.0 Hz), 12.56
(1H, s).
Example F-38
1-Ethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-an-
thracene-7-carboxylic acid 4-fluoro-benzylamide
[0546] melting point: 221.degree. C.
[0547] NMR (DMSO-d.sub.6) .delta.: 0.94 (3H, t, J=6.8 Hz),
1.56-1.71 (2H, m), 2.45-2.50 (1H, m), 2.59-2.76 (2H, m), 2.96-3.03
(2H, m), 4.40-4.44 (3H, m), 4.52 (2H, d, J=6.0 Hz), 4.77-4.82 (1H,
m), 7.14-7.18 (2H, m), 7.34-7.38 (2H, m), 8.62 (1H, s), 10.41 (1H,
t, J=6.0 Hz), 12.59 (1H, s).
Example F-39
5-Hydroxy-6,10-dioxo-1-(2-oxo-propyl)-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a--
triaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide
[0548] melting point: 244-246.degree. C.
[0549] NMR (DMSO-d.sub.6) .delta.: 1.54-1.61 (1H, m), 1.67-1.76
(1H, m), 2.22 (3H, s), 2.50-2.56 (1H, m), 2.91-3.02 (2H, m), 4.18
(1H, s), 4.38-4.15 (2H, m), 4.52 (2H, d, J=6.0 Hz), 4.76 (1H, d,
J=14.4 Hz), 7.13-7.18 (2H, m), 7.34-7.37 (2H, m), 8.61 (1H, s),
1.0.40 (1H, t, J=6.0 Hz), 12.54 (1H, s).
Example F-40
5-Hydroxy-6,10-dioxo-1-(4,4,4-trifluoro-butyl)-1,2,3,4,6,9,9a,10-octahydro-
-1,4a,8a-triaza-anthracene-7-carboxylic acid
4-fluoro-benzylamide
[0550] melting point: 220.degree. C.
[0551] NMR (DMSO-d.sub.6) .delta.: 1.53-1.62 (2H, m), 1.67-1.75
(1H, m), 2.07-2.18 (2H, m), 2.40-2.47 (1H, m), 2.64-2.78 (2H, m),
2.96-3.04 (2H, m), 4.42-4.49 (2H, m), 4.53 (2H, d, J=5.2 Hz), 4.74
(1H, d, J=12.8 Hz), 7.13-7.17 (2H, m), 7.33-7.37 (2H, m), 8.61 (1H,
s), 10.40 (1H, t, J=6.0 Hz), 12.57 (1H, s).
Example F-4.1
5-Hydroxy-1-(3-methyl-butyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8-
a-triaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide
[0552] melting point: 151.degree. C.
[0553] NMR (DMSO-d.sub.6) .delta.: 0.78 (6H, dd, J=7.6, 16.2 Hz),
1.21-1.28 (2H, m), 1.41-1.48 (1H, m), m), 2.22-2.31 (1H, m),
2.51-2.59 (1H, m), 2.66-2.73 (1H, m), 2.96-3.05 (2H, m), 4.41-4.55
(5H, m), 4.80 (1H, d, J=13.2 Hz), 7.13-7.18 (2H, m), 7.33-7.37 (2H,
m), 8.64 (1H, s), 10.40 (1H, t, J=6.0 Hz), 12.57 (1H, s).
Example F-42
5-Hydroxy-1-isobutyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-
-anthracene-7-carboxylic acid 3-chloro-2-fluoro-benzylamide
[0554] melting point: 180-182.degree. C.
[0555] NMR (DMSO-d.sub.6) .delta.: 0.62 (3H, d, J=6.0 Hz), 0.78
(3H, d, J=6.4 Hz), 1.55-1.69 (3H, m), 1.93-1.99 (1H, m), 2.97-3.08
(2H, m), 4.39-4.46 (3H, m), 4.59-4.64 (2H, m), 4.75-4.81 (1H, m),
7.16-7.23 (1H, m), 7.27-7.34 (1H, m), 7.47-7.53 (1H, m), 8.59 (1H,
s), 10.44 (1H, s), 12.57 (1H, s).
Example F-43
1-Cyclopropylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,-
8a-triaza-anthracene-7-carboxylic acid
3-chloro-2-fluoro-benzylamide
[0556] melting point: 189-192.degree. C.
[0557] NMR (DMSO-d.sub.6) .delta.: 0.00-0.10 (2H, m), 0.35-0.41
(2H, m), 0.70-0.77 (1H, m), 1.57-1.69 (2H, m), 2.52-2.65 (1H, m),
2.67-2.85 (1H, m), 2.91-2.99 (1H, m), 4.30-4.41 (2H, m), 4.48-4.52
(2H, m), 4.71-4.80 (1H, m), 7.06-7.10 (1H, m), 7.18-7.22 (1H, m),
7.36-7.40 (1H, m), 8.62 (1H, s), 10.30 (1H, s), 12.26 (1H, s).
Example F-44
1-Furan-2-ylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8-
a-triaza-anthracene-7-carboxylic acid
3-chloro-2-fluoro-benzylamide
[0558] melting point: 190.192.degree. C.
[0559] NMR (DMSO-d.sub.6) .delta.: 1.56-1.68 (2H, m), 2.54-2.63
(1H, m), 2.89-2.99 (2H, 3.80 (2H, dd, J=18.4, 33.2 Hz), 4.37-4.51
(3H, m), 4.62 (2H, d, J=6.0 Hz), 4.97 (1H, d, J=15.2 Hz), 6.39 (2H,
s), 7.18-7.22 (1H, m), 7.31-7.34 (1H, m), 7.48-7.51 (1H, m), 7.58
(1H, s), 8.64 (1H, s), 10.45 (1H, t, J=6.0 Hz), 12.55 (1H, s).
Example F-45
5-Hydroxy-6,10-dioxo-1-thiazol-2-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a-
,8a-triaza-anthracene-7-carboxylic acid
3-chloro-2-fluoro-benzylamide
[0560] melting point: 217-219.degree. C.
[0561] NMR (DMSO-d.sub.6) .delta.: 1.59-1.74 (2H, m), 2.76-2.83
(1H, m), 2.97-3.08 (2H, m), 3.90 (1H, d, J=16.0 Hz), 4.36 (1H, d,
J=16.0 Hz), 4.46-4.69 (5H, m), 4.89 (1H, d, J=14.8 Hz), 7.18-7.22
(1H, 7.28-7.31 (1H, m), 7.47-7.53 (1H, m), 7.54 (1H, d, J=3.2 Hz),
7.68 (1H, d, J=3.2 Hz), 8.34 (1H, s), 10.40 (1H, d, 12.52 (1H,
s).
Example F-46
5-Hydroxy-6,10-dioxo-1-pyridin-2-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a-
,8a-triaza-anthracene-7-carboxylic acid
3-chloro-2-fluoro-benzylamide
[0562] melting point: 190-193.degree. C.
[0563] NMR (DMSO-d.sub.6) .delta.: 1.54-1.61 (1H, m), 1.69-1.75
(1H, m), 2.66-2.74 (1H, m), 2.91-3.08 (2H, m), 3.68 (1H, d, J=14.4
Hz), 4.02 (1H, d, J=14.8 Hz), 4.40-4.67 (5H, m), 4.85 (1H, d,
J=12.4 Hz), 7.16-7.35 (3H, m), 7.46-7.52 (1H, m), 7.61-7.69 (1H,
m), 8.20 (1H, s), 8.43-8.47 (1H, m), 10.41 (1H, d, J=6.0 Hz), 12.58
(1H, s).
Example F-47
5-Hydroxy-1-isobutyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-
-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
[0564] melting point: 194.degree. C.
[0565] NMR (DMSO-d.sub.6) .delta.: 0.62 (3H, d, J=6.4 Hz), 0.78
(3H, d, J=6.4 Hz), 1.55-1.69 (3H, m), 1.93-1.99 (1H, m), 2.97-3.08
(2H, m), 4.39-4.46 (3H, m), 4.50-4.59 (2H, m), 4.77 (1H, d, J=14.4
Hz), 7.03-7.09 (1H, m), 7.20-7.28 (1H, m), 7.36-7.43 (1H, m), 8.59
(1H, s), 10.39 (1H, s), 12.56 (1H, s).
Example F-48
1-Cyclopropylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,-
8a-triaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
[0566] melting point: 169-171.degree. C.
[0567] NMR (DMSO-d.sub.6) .delta.: 0.00-0.10 (2H, m), 0.42-0.44
(2H, m), 0.77-0.81 (1H, m), 1.59-1.74 (2H, m), 2.27-2.32 (1H, m),
2.62-2.72 (1H, m), 3.05-3.12 (1H, m), 4.30-4.58 (5H, 4.69 (1H, d,
J=14.8 Hz), 7.03-7.11 (1H, m), 7.22-7.26 (1H, m), 7.37-7.40 (1H,
m), 8.62 (1H, s), 10.40 (1H, t, J=6.0 Hz), 12.57 (1H, s).
Example F-49
1-Furan-2-ylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8-
a-triaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
[0568] melting point: 186-188.degree. C.
[0569] NMR (DMSO-d.sub.6) .delta.: 1.55-1.68 (2H, m), 2.55-2.64
(1H, m), 2.88-2.99 (2H, m), 3.80 (2H, dd, J=15.6, 34.8 Hz),
4.36-4.56 (5H, m), 4.97 (1H, d, J=16.0 Hz), 6.39 (2H, s), 7.05-7.08
(1H, m), 7.21-7.26 (1H, m), 7.37-7.44 (1H, m), 7.58 (1H, s), 8.64
(1H, s), 10.38 (1H, t, J=5.6 Hz), 12.53 (1H, s).
Example F-50
5-Hydroxy-6,10-dioxo-1-thiazol-2-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a-
,8a-triaza-anthracene-7-carboxylic acid
2,4-difluoro-benzylamide
[0570] melting point: 168-170.degree. C.
[0571] NMR (DMSO-d.sub.6) .delta.: 1.59-1.74 (2H, m), 2.76-2.83
(1H, m), 2.97-3.08 (2H, m), 3.89 (1H, d, J=16.4 Hz), 4.36 (1H, d,
J=1.6.0 Hz), 4.44-4.55 (4H, m), 4.69 (1H, s), 4.89 (1H, d, J=14.8
Hz), 7.03-7.09 (1H, m), 7.20-7.27 (1H, m), 7.34-7.41 (1H, m), 7.54
(1H, d, J=3.2 Hz), 7.68 (1H, d, J=3.2 Hz), 8.34 (1H, s), 10.35 (1H,
d, J=6.0 Hz), 12.50 (1H, s).
Example F-51
5-Hydroxy-6,10-dioxo-1-pyridin-2-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a-
,8a-triaza-anthracene-7-carboxylic acid
2,4-difluoro-benzylamide
[0572] melting point: 200-203.degree. C.
[0573] NMR (DMSO-d.sub.6) .delta.: 1.54-1.61 (1H, m), 1.69-1.78
(1H, m), 2.71-2.79 (1H, m), 2.91-3.09 (2H, m), 3.72 (1H, d, J=14.4
Hz), 4.07 (1H, d, J=14.4 Hz), 4.44-4.54 (4H, m), 4.70 (1H, s), 4.82
(1H, d, J=14.4 Hz), 7.04-7.10 (1H, m), 7.21-7.42 (4H, m), 7.74-7.80
(1H, m), 8.17 (1H, s), 8.47-8.49 (1H, m), 10.35 (1H, d, 3=6.0 Hz),
12.57 (1H, s).
Example F-52
1-Hydroxy-6-methyl-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-tri-
aza-cyclohepta[b]naphthalene-3-carboxylic acid 3-chloro-2-fluoro-
benzylamide
[0574] melting point: 230-231.degree. C.
[0575] NMR (DMSO-d.sub.6) .delta.: 1.47-1.53 (1H, m), 1.62-1.78
(3H, m), 2.29 (3H, s), 2.77-2.81 (2H, m), 4.05-4.10 (1H, m),
4.35-4.40 (1H, m), 4.54-4.64 (3H, m), 4.70 (1H, s), 7.18-7.22 (1H,
m), 7.30-7.34 (1H, m), 7.47-7.52 (1H, m), 8.49 (1H, s), 10.47 (1H,
d, J=6.0 Hz), 12.44 (1H, s).
Example F-53
1-Hydroxy-6-isobutyl-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-t-
riaza-cyclohepta[b]naphthalene-3-carboxylic acid
3-chloro-2-fluoro-benzylamide
[0576] melting point: 215-216.degree. C.
[0577] NMR (DMSO-d.sub.6) .delta.: 0.83 (6H, dd, J=6.8, 13.6 Hz),
1.45-1.80 (5H, m), 2.36-2.41 (1H, m), 2.77-2.93 (2H, m), 3.17-3.24
(1H, m), 4.02-4.09 (1H, m), 4.32-4.40 (2H, m), 4.61 (2H, d, J=5.6
Hz), 4.82-4.84 (1H, m), 7.18-7.22 (1H, m), 7.30-7.33 (1H, m),
7.48-7.51 (1H, m), 8.47 (1H, s), 10.48 (1H, t, J=6.0 Hz), 12.55
(1H, s).
Example F-5
6-Cyclopropylmethyl-1-hydroxy-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4-
a,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylic acid
3-chloro-2-fluoro-benzylamide
[0578] melting point: 212.degree. C.
[0579] NMR (DMSO-d.sub.6) .delta.: 0.00-0.10 (2H, m), 0.40-45 (2H,
m), 0.80-0.87 (1H, m), 1.45-1.77 (3H, m), 2.64-2.69 (1H, m),
2.85-2.95 (2H, m), 3.13-3.20 (1H, m), 4.03-4.09 (1H, m), 4.36-4.40
(2H, m), 4.59 (2H, d, J=5.6 Hz), 4.8-4.86 (1H, m), 7.16-7.20 (1H,
m), 7.28-7.32 (1H, m), 7.46-7.50 (1H, m), 8.45 (1H, s), 10.46 (1H,
t, J=6.0 Hz), 12.50 (1H, s).
Example F-55
6-Furan-2-ylmethyl-1-hydroxy-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a-
,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylic acid
3-chloro-2-fluoro-benzylamide
[0580] Melting point: 189-190.degree. C.
[0581] NMR (DMSO-d.sub.6) .delta.: 1.48-1.63 (3H, m), 1.70-1.77
(1H, m), 2.79-2.83 (2H, m), 3.90 (2H, dd, J=14.8, 39.6 Hz),
4.05-4.11 (1H, m), 4.40-4.51 (2H, m), 4.61 (2H, d, J=5.6 Hz),
4.89-4.91 (1H, m), 6.30-6.33 (1H, m), 6.38-6.40 (1H, m), 7.18-7.22
(1H, m), 7.30-7.34 (1H, m), 7.48-7.53 (1H, m), 7.57 (1H, s), 8.45
(1H, s), 10.45 (1H, t, J=6.0 Hz), 12.44 (1H, s).
Example F-56
1-Hydroxy-6-methyl-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-tri-
aza-cyclohepta[b]naphthalene-3-carboxylic acid
2,4-difluoro-benzylamide
[0582] melting point: 241.degree. C.
[0583] NMR (DMSO-d.sub.6) .delta.: 1.47-1.53 (1H, m), 1.62-1.78
(3H, m), 2.29 (3H, s), 2.77-2.81 (2H, m), 4.05-4.10 (1H, m),
4.35-4.40 (1H, m), 4.53-4.61 (3H, m), 4.69 (1H, s), 7.03-7.08 (1H,
7.20-7.27 (1H, m), 7.37-7.43 (1H, m), 8.49 (1H, s), 10.42 (1H, d,
J=6.0 Hz), 12.43 (1H, s).
Example F-57
1-Hydroxy-6-isobutyl-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-t-
riaza-cyclohepta[b]naphthalene-3-carboxylic acid
2,4-difluoro-benzylamide
[0584] melting point: 203.degree. C.
[0585] NMR (DMSO-d.sub.6) .delta.: 0.82 (6H, dd, J=6.4, 1.32 Hz),
1.45-1.80 (5H, m), 2.36-2.42 (1H, m), 2.77-2.93 (2H, m), 3.15-3.23
(1H, 4.02-4.08 (1H, m), 4.32-4.41 (2H, m), 4.54 (2H, d, 4.82-4.84
(1H, m), 7.02-7.09 (1H, 7.20-7.27 (1H, m), 7.36-7.43 (1H, m), 8.47
(1H, s), 10.41 (1H, t, 12.54 (1H, s).
Example F-58
6-Cyclopropylmethyl-1-hydroxy-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4-
a,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylic acid
2,4-difluoro-benzylamide
[0586] melting point: 182-183.degree. C.
[0587] NMR (DMSO-d.sub.6) .delta.: 0.00-0.10 (2H, m), 0.40-45 (2H,
m), 0.80-0.87 (1H, m), 1.43-1.77 (3H, m), 2.60-2.69 (1H, m),
2.85-2.95 (2H, m), 3.11-3.19 (1H, m), 4.00-4.06 (1H, 4.36-4.40 (2H,
m), 4.51 (2H, d, J=5.6 Hz), 4.83-4.87 (1H, m), 7.00-7.07 (1H, m),
7.16-7.23 (1H, m), 7.34-7.38 (1H, m), 8.44 (1H, s), 10.39 (1H, t,
J=6.0 Hz), 12.47 (1H, s).
Example F-59
6-Furan-2-ylmethyl-1-hydroxy-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a-
,6,10a-triaza-cyclohepta[b]napthalene-3-carboxylic acid
2,4-difluoro-benzylamide
[0588] melting point: 171-173.degree. C.
[0589] NMR (DMSO-d.sub.6) .delta.: 1.47-1.64 (3H, m), 1.70-1.77
(1H, 2.79-2.83 (2H, 3.90 (2H, dd, J=15.6, 39.6 Hz), 4.05-4.11 (1H,
m), 4.41-4.57 (4H, m), 4.90-4.92 (1H, m), 6.30-6.33 (1H, m),
6.38-6.40 (1H, m), 7.03-7.09 (1H, m), 7.20-7.27 (1H, m), 7.37-7.45
(1H, m), 7.57 (1H, s), 8.44 (3H, s), 10.41 (1H, t, J=6.0 Hz), 12.43
(1H, s).
Example F-60
5-Hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthrace-
ne-7-carboxylic acid 3-chloro-2-fluoro-benzylamide
[0590] melting point: 276.degree. C.
[0591] NMR (DMSO-d.sub.6) .delta.: 1.60-1.68 (1H, m), 1.77-1.84
(1H, m), 3.85-3.93 (1H, m), 4.03-4.07 (1H, m), 4.43-4.62 (5H, m),
5.28 (1H, s), 7.17-7.22 (1H, an), 7.29-7.34 (1H, m), 7.47-7.52 (3H,
m), 8.49 (1H, s), 10.41 (1H, d, J=6.0 Hz), 12.48 (1H, s).
Example F-61
5-Hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthrace-
ne-7-carboxylic acid 2,4-difluoro-benzylamide
[0592] melting point: 258.degree. C.
[0593] NMR (DMSO-d.sub.6) .delta.: 1.60-1.69 (1H, 1.77-1.85 (1H,
m), 3.86-3.92 (1H, 4.04-4.08 (1H, m), 4.43-4.55 (5H, m), 5.28 (1H,
s), 7.03-7.09 (1H, m), 7.21-7.27 (1H, m), 7.36-7.43 (1H, m), 8.50
(1H, s), 10.35 (1H, d, J=6.0 Hz), 12.47 (1H, s).
Example F-62
5-Hydroxy-1-(2-methoxy-ethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,-
8a-triaza-anthracene-7-carboxylic acid
3-chloro-2-fluoro-benzylamide
[0594] melting point: 193.degree. C.
[0595] NMR (DMSO-d.sub.6) .delta.: 1.53-1.73 (2H, m), 2.51-2.58
(1H, m), 2.71-2.78 (1H, m), 2.81-2.87 (1H, m), 2.95-3.08 (2H, m),
3.1.7 (3H, s), 4.40-4.52 (3H, m), 4.62 (1H, d, J=5.6 Hz), 4.78 (1H,
d, J=14.4 Hz), 7.18-7.22 (1H, m), 7.30-7.34 (1H, m), 7.47-7.52 (1H,
m), 8.55 (1H, s), 10.45 (1H, d, J=6.0 Hz), 1.2.59 (1H, s).
Example F-63
5-Hydroxy-1-(2-methoxy-ethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,-
8a-triaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
[0596] melting point: 166-168.degree. C.
[0597] NMR (DMSO-d.sub.6) .delta.: 1.55-1.72 (2H, m), 2.51-2.58
(1H, m), 2.70-2.77 (1H, m), 2.80-2.87 (1H, m), 2.97-3.07 (2H, m),
3.18 (3H, s), 4.39-4.52 (3H, m), 4.54 (1H, d, 4.78 (1H, d, J=13.6
Hz), 7.03-7.09 (1H, m), 7.20-7.27 (1H, m), 7.37-7.4.3 (1H, m), 8.55
(1H, s), 10.40 (1H, d, J=6.0 Hz), 12.58 (1H, s).
Example F-64
5-Hydroxy-1-(1H-imidazol-4-ylmethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydr-
o-1,4a,8a-triazaanthracene-7-carboxylic acid
4-fluorobenzylamide
[0598] (DMSO-d.sub.6) .delta.: 1.55-1.59 (1H, m), 1.64-1.70 (1H,
m), 2.58-2.66 (1H, m), 2.87-2.95 (2H, m), 3.67 (1H, d, J=15.2 Hz),
3.73 (1H, d, J=15.2 Hz), 4.34 (1H, s), 4.38-4.43 (1H, m), 4.47-4.54
(3H, m), 5.05 (1H, d, J=14.0 Hz), 7.00 (1H, s), 7.13-7.3.9 (2H, m),
7.33-7.38 (1H, m), 7.59 (1H, s), 8.55 (1H, s), 10.41 (1H, t, J=5.6
Hz), 11.95 (1H, br s), 12.59 (1H, s).
Example H-1
1-Acetyl-5-hydroxy-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1-H-1,3a,8a-triaza-cyc-
lopenta[b]naphthalene-7-carboxylic acid 4-fluorobenzylamide
##STR00094##
[0600] 1) To a solution of a compound 48 (120 mg, 0.26 mmol) in
methylene chloride (1.2 ml) were added triethylamine (43 .mu.l,
0.31 mmol), acetic anhydride (29 .mu.l, 0.31 mmol), and
4-dimethylaminopyridine (cat.) at room temperature, and the mixture
was stirred for 30 minutes. Further, triethylamine (18 .mu.l, 0.13
mmol) and acetic anhydride (12 .mu.l, 0.13 mmol) were added, and
the mixture was stirred for 4 hours, 2N hydrochloric acid was
added, this was extracted with chloroform, and the organic layer
was washed with water, dried with sodium sulfate, and concentrated
under reduced pressure. Diisopropyl ether was added to crystallize
the material, which was filtered to obtain 53 (112 mg) as a pale
orange crystal at a yield of 86%.
[0601] 2) An Example compound H-1 (71 mg) was obtained at a yield
of 82% from a compound 53 (106 mg), according to the method of
Example B-1 17).
[0602] melting point: 290.degree. C.
[0603] NMR (DMSO-d.sub.6) .delta.: 2.08 (3H, s), 3.44-4.21 (5H, m),
4.51 (2H, d, 5.7 Hz), 4.93 (1H, m), 5.46-5.62 (1H, m), 7.15 (2H, t,
9.0 Hz), 7.34 (2H, m), 8.49 (1H, s), 10.40 (1H, t, 5.7 Hz), 11.48
(1H, s).
[0604] An Example compound H-2 was synthesized according to the
same manner as that of Example H-1.
Example H-2
1-Acetyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-a-
nthracene-7-carboxylic acid 4-fluoro-benzylamide
[0605] melting point: 290.degree. C.
[0606] NMR (DMSO-d.sub.6) .delta.: 1.95 (2H, m), 2.14 (3H, s), 2.85
(2H, m), 4.45 (4H, m), 4.51 (2H, d, 5.7 Hz), 5.99 (1H, s), 7.15
(2H, t, 9.0 Hz), 7.34 (2H, m), 8.37 (1H, s), 10.46 (1H, s), 12.28
(1H, s).
Example I-1
5-Hydroxy-1-methanesulfonyl-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1H-1,3a,8a-tr-
iaza-cyclopenta[b]naphthalene-7-carboxylic acid
4-fluoro-benzylamide
##STR00095##
[0608] 1) To a solution of a compound 48 (140 mg, 0.30 mmol) in
pyridine (1.4 ml) were added methanesulfonyl chloride (28 .mu.l,
0.36 mmol), and 4-dimethylaminopyridine (cat.) at room temperature,
and the mixture was stirred for 3 hours. After 2N hydrochloric acid
was added, this was extracted with ethyl acetate, and the organic
layer was washed with water, dried with sodium sulfate, and
concentrated under reduced pressure. Diisopropylether was added to
crystallize the material, which was filtered to obtain 54 (127 mg)
as a pale orange crystal at a yield of 78%.
[0609] 2) According to the method of Example B-1 17), an Example
compound I-1 (21 mg) was obtained at a yield of 21% from a compound
54 (123 mg).
[0610] melting point: 260.degree. C.
[0611] NMR (DMSO-d.sub.6) .delta.: 3.16 (3H, s), 3.30-4.15 (5H, m),
4.45 (2H, d, 5.7 Hz), 4.27 (2H, 5.36 (1H, m), 7.1.4 (2H, t, 8.7
Hz), 7.33 (2H, m), 8.22 (1H, s), 10.53 (1H, s).
[0612] According to the same manner as that of Example I-1, an
Example compound 1-2 was synthesized.
Example I-2
5-Hydroxy-1-methanesulfonyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-
-triaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide
[0613] melting point: 257.259.degree. C.
[0614] NMR (DMSO-d.sub.6) .delta.: 1.80-1.96 (2H, m), 3.02-3.58
(2H, m), 3.16 (3H, s), 4.76 (2H, m), 5.56 (1H, s), 7.16 (2H, t, 9.0
Hz), 7.35 (2H, m), 8.36 (1H, s), 10.39 (1H, s).
Example L-1
5,9-Dihydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-1H-2-oxa-4a,8a-diaza-anth-
racene-7-carboxylic acid 4-fluoro-benzylamide
##STR00096##
[0616] 1) According to the method of synthesizing a compound 66, a
compound 62 (278 mg, 57%) was obtained from a compound 13 (357
mg).
[0617] 2) According to the method of synthesizing a compound 57, a
compound 63 (202 mg, 79%) was obtained from a compound 62 (278
mg).
[0618] 3) To a solution of a compound 63 (200 mg, 0.403 mmol) in
chloroform (2 ml) were added dimethyl sulfoxide (286 .mu.l, 4.03
mmol), and triethylamine (337 .mu.l, 2.42 mmol), the mixture was
stirred for 10 minutes under ice-cooling, a sulfur
trioxide-pyridine complex (321 mg, 2.02 mmol) was added, and the
mixture was stirred at room temperature for 2 hours. To the
reaction solution was added water (3 ml), and chloroform was
distilled off under reduced pressure, followed by extraction with
ethyl acetate. The organic layer was washed with water, dried with
anhydrous sodium sulfate, and the solvent was distilled off under
reduced pressure. The crystalline residue was washed with ethyl
acetate to obtain a compound 64 (60 mg) at a yield of 30%.
[0619] 4) Using a compound 64, and according to the method of
synthesizing Example A-1, an Example compound L-1 was
synthesized.
[0620] NMR (DMSO-d.sub.6) .delta.: 2.98-3.10 (1H, m), 3.38-3.60
(2H, m), 3.80-4.20 (5H, 4.40-4.55 (2H, m), 5.48 (1H, brs), 5.85
(1H, s), 7.15 (2H, t, J=8.4 Hz), 7.33-7.37 (2H, m), 8.45 (1H, s),
8.60 (1H, s), 10.27-10.42 (1H, m), 12.61 (1H, brs).
Example M-1
1-Hydroxy-2,10-dioxo-2,4b,5,6,7,8,9,10-octahydro-4a,9a-diaza-benzo[a]azule-
ne-3-carboxylic acid 4-fluoro-benzylamide
##STR00097##
[0622] 1) According to the method of synthesizing a compound 21, a
compound 65 (207 mg) was obtained at a yield of 24. % from a
compound 13 (250 mg).
[0623] 2) According to the method of synthesizing a compound 64, a
compound 66 (313 mg, 67%) was obtained from a compound 65 (470
mg).
[0624] 3) After trifluoroacetic acid (10 ml) was added to a
compound 66 (100 mg, 0.020 mmol), the mixture was stirred at
75.degree. C. for 4 hours. The solvent was distilled off under
reduced pressure, and, this was diluted with chloroform, and added
to ice water. This was washed with an aqueous saturated sodium
bicarbonate solution, a 10% aqueous citric acid solution, and
water, and dried with anhydrous sodium sulfate, and the solvent was
distilled off under reduced pressure. The residue was subjected to
silica gel column chromatography, and fractions eluted with
chloroform-methanol were concentrated under reduced pressure, and
recrystallized with ethyl acetate-diisopropyl ether to obtain an
Example compound M-1 (23 mg, 16%).
[0625] melting point 281-283.degree. C.
[0626] NMR (DMSO-d.sub.6) .delta.: 1.43-1.52 (2H, m), 1.62-1.83
(3H, m), 2.04-2.18 (1H, m), 2.23-2.35 (1H, m), 4.08-4.16 (1H, m),
4.48-4.53 (2H, m), 5.58-5.61 (1H, m), 7.11-7.20 (2H, m), 7.30-7.38
(2H, m), 8.29 (1H, s), 10.30-10.36 (1H, m), 12.78 (1H, brs).
Example X-1
(R)-6-Hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1-
,2-d]pyrazine-8-carboxylic acid 4-fluoro-benzylamide
##STR00098##
[0628] 1) Selenium dioxide (666 mg, 6.0 mmol) was added to the
solution of compound 2 (216 mg, 1.0 mmol) in bromobenzene (2 ml).
Then the mixture was heated up to 1.60.degree. C., and stirred for
16 h. After celite filtration the solvent was evaporate. The
precipitate was purified by silicagel column chromatography, and
fractions eluting With n-hexan/EtOAc were concentrated under
reduced pressure to obtain compound 100 (164 mg, 71%) as a yellow
oil.
[0629] 1H-NMR (CDCl.sub.3) .delta.: 5.52 (1H, s), 6.50 (1H, d,
J=6.0 Hz), 7.36 (5H, m), 7.74 (1H, d, J=6.3 Hz), 9.88 (1H, s).
[0630] 2) Sulfamic acid (1.50 g, 15.4 mmol) and NaClO.sub.2 (1.05
g, 11.6 mmol) was added to the solution of compound 100 (2.54 g,
11.0 mmol) in acetone (20 ml) and water (30 ml). Then the mixture
was stirred for 3 h. The solvent was evaporated under reduced
pressure to obtain compound 101 (2.18 mg, 80%) as a white
solid.
[0631] 1H-NMR (DMSO-d.sub.6) .delta.: 5.11 (2H, s), 6.55 (1H, d,
J=5.4 Hz), 7.32-7.46 (5H, m), 8.21 (1H, d, J=5.7 Hz).
[0632] 3) (R)-2-N--BOC-aminomethyl pyrrolidine (391 mg, 1.95 mmol)
was added to the solution of compound 101 (400 mg, 1.62 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (373
mg, 1.95 mmol), and 1-hydroxybenzotriazole (219 mg, 1.62 mmol) in
THF (6 ml). After stirring for 16 h NaHCO.sub.3 aqueous solution
was added to the mixture. The mixture was extracted with EtOAc,
which was washed with N11401 aqueous solution and brine. The
organic phase was dried over MgSO.sub.4. After a filtration the
solvent was removed under reduced pressure to obtain compound 102
(694 mg, 100%) as a white solid.
[0633] 1H-NMR (CDCl.sub.3) .delta.: 1.46 (9H, s), 1.56-2.14 (4H,
m), 3.29 (4H, m), 4.18 (1H, m), 5.24 (1H, s), 5.27 (1H, s), 6.46
(1H, d, J=5.7 Hz), 7.35 (5H, m), 7.69 (1H, d, J=5.7 Hz).
[0634] 4) The solution of compound 102 (694 mg, 1.95 mmol) in
HCl/EtOAc (4 mol/l, 8 ml) was stirred for 30 min. The solvent was
removed under reduced pressure, diluted with EtOH (16 ml) then. A
saturated NaHCO.sub.3 aqueous solution was added to the solution to
control pH at 9. The mixture was stirred at 50.degree. C. for 2 h,
then diluted with water. The mixture was extracted with CHCl.sub.3,
washed with brine, and dried over MgSO.sub.4. The solvent was
removed under reduced pressure to obtain compound 103 (413 mg-68%)
as a yellow solid.
[0635] 1H-NMR (CDCl.sub.3) .delta.: 1.54-2.22 (4H, m), 3.60 (2H,
m), 3.80 (1H, t, J=12.0 Hz), 4.18 (1H, d, J=12.0 Hz), 5.15 (1H, d,
3=9.9 Hz), 5.35 (1H, d, J=9.9 Hz), 6.71 (1H, d, J=5.4 Hz), 7.33
(3H, m), 7.50 (1H, d, J=5.1 Hz), 7.63 (2H, d, J=7.2 Hz).
[0636] 5) NaOAc (118 mg, 1.44 mmol) and bromine (0.234 ml, 2.62
mmol) were added to the solution of compound 103 (408 mg, 1.31
mmol) in acetic acid (8 ml), stirred for 30 min then. An aqueous
solution of NaOH (2M) was added to the mixture, and extracted with
CH.sub.2Cl.sub.2, washed with brine, and dried over
Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to
give compound 104 (390 mg, 77%) as a white solid.
[0637] 1H-NMR (CDCl.sub.3) .delta.: 1.55-2.19 (4H, m), 3.55-4.02
(5H, m), 5.12 (1H, d, J=9.6 Hz), 5.35 (1H, d, J=9.9 Hz), 7.29-7.38
(3H, m), 7.61 (1H, s), 7.67 (2H, d, J=6.6 Hz).
[0638] 6) Tetrakis triphenylphosphine paradium (0) (77 mg, 0.067
mmol) and N,N-diisopropylethylamine (0.29 ml, 1.67 mmol) were added
to the solution of compound 104 (1.30 mg, 0.334 mmol) in DMSO (2.6
ml). The mixture was stirred under CO atmosphere for 2 h at
80.degree. C. The reaction mixture was diluted with a saturated
NH.sub.4Cl aqueous solution, extracted with EtOAc then. And the
organic phase was washed with brine, and dried over
Na.sub.2SO.sub.4. The precipitate was purified by silicagel column
chromatography, and fractions eluting with MeOH/EtOAc were
concentrated under reduced pressure to obtain compound 105 (115 mg,
75%) as a white oil.
[0639] 1H-NMR (CDCl.sub.3) .delta.: 1.56-2.33 (4H, m), 3.66 (2H,
m), 3.90 (2H, m), 4.19 (1H, s), 4.66 (2H, m), 5.20 (1H, d, J=9.9
Hz), 5.37 (1H, d, J=9.9 Hz), 7.00 (2H, t, J=8.7 Hz), 7.33 (5H, m),
7.61 (2H, m), 8.39 (1H, m), 10.50 (1H, s).
[0640] 7) A mixture of compound 105 (111 mg, 0.241 mmol) and
paradium-carbon (10%, 22 mg) in THF (8 ml) and MeOH (2 ml) was
stirred under hydrogen atmosphere for 3 h. After celite filtration
the solvent was removed under reduced pressure to give the example
X-1 (57 mg, 64%) as a white solid.
[0641] Melting point: 274.degree. C.
[0642] 1H-NMR (DMSO-dB) .delta.: 1.56-2.25 (4H, m), 3.48-3.65 (2H,
m), 4.01 (2H, m), 4.51 (2H, d, J=5.7 Hz), 4.71 (1H, d, J=9.9 Hz),
7.14 (2H, t, J=9.0 Hz), 7.33 (2H, dd, J=5.7, 8.7 Hz), 8.41 (1H, s),
10.44 (1H, t, J=6.0 Hz), 12.18 (1H, 8).
[0643] The following compounds were synthesized using the similar
method.
Example X-2
(R)-6-Hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1-
,2-d]pyrazine-8-carboxylic acid 2,4-difluoro-benzylamide
[0644] Melting point: 300.degree. C.
[0645] 1H-NMR (DMSO-d.sub.6) .delta.: 1.03-2.20 (4H, m), 3.39-3.66
(2H, m), 4.02 (2H, m), 4.54 (2H, d, J=6.0 Hz), 4.71 (1H, d, J=9.9
Hz), 7.06 (1H, m), 7.23 (1H, m), 7.38 (1H, m), 8.41 (1H, s), 10.43
(1H, t, J=6.0 Hz), 12.19 (1H, s).
Example X-3
(R)-6-Hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1-
,2-d]pyrazine-8-carboxylic acid 3-chloro-2-fluoro-benzylamide
[0646] Melting point: 304.degree. C.
[0647] 1H-NMR (DMSO-d.sub.6) .delta.: 3.44-3.66 (2H, m), 4.01 (2H,
m), 4.61 (2H, d, J=5.4 Hz), 4.70 (1H, d, J=9.0 Hz), 7.20 (1H, m),
7.31 (1H, m), 7.49 (1H, m), 8.41 (1H, s), 10.49 (1H, t, J=5.7 Hz),
12.20 (1H, s).
Example X-4
1-Hydroxy-2,9-dioxo-2,5,6,7,8,9,10,10a-octahydro-4a,8a-diaza-anthracene-3--
carboxylic acid 4-fluoro-benzylamide
[0648] Melting point: 259.degree. C.
[0649] 1H-NMR (DMSO-d.sub.6) .delta.: 1.33-1.79 (6H, m), 2.51 (1H,
m), 3.88 (1H, m), 4.12 (1H, dd, J=9.3, 14.1 Hz), 4.38 (1H, d,
J=12.9 Hz), 4.53 (3H, m), 7.16 (2H, t, J=9.0 Hz), 7.34 (2H, dd,
J=5.7, 8.7 Hz), 8.39 (1H, s), 10.44 (1H, t, J=6.3 Hz), 12.84 (1H,
s).
[0650] According to the same manner as that of Example C-21, the
following Example compounds Y-1 to Y-18 were synthesized.
Example Y-1
(3S,9aS)-5-Hydroxy-3-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a-
,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
Example Y-9
(3R,9aR)-5-Hydroxy-3-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a-
,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
[0651] 1H-NMR (CDCl.sub.3) .delta.: 0.90 (3H, d, J=6.9 Hz),
2.00-2.10 (1H, m), 2.70 (1H, dd, J=11.6, 13.4 Hz), 3.41 (1H, dd,
J=11.2, 12.9 Hz), 4.05-6.45 (2H, m), 4.30-4.38 (1H, dd, J=4.0, 14.1
Hz), 4.63 (2H, d, J=5.9 Hz), 6.65-475 (1H, m), 4.98 (1H, t, J=3.7
Hz), 6.80-6.84 (2H, m), 7.32-7.40 (1H, m), 8.31 (1H, s), 10.38 (1H,
brs), 12.37 (1H, s).
Example Y-2
(4S,9aR)-5-Hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a-
,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
Example Y-3
(4R,9aS)-5-Hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a-
,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
[0652] 1H-NMR (CDCl.sub.3) .delta.: 1.42 (3H, d, J=7.0 Hz), 1.56
(1H, dd, J=2.0, 14.0 Hz), 2.19-2.30 (1H, 4.02 (1H, d, J=2.2 Hz),
4.05 (1H, t, J=2.3 Hz), 4.12 (1H, dd, J=6.0, 13.6 Hz), 4.27 (1H,
dd, J=4.2, 13.4 Hz), 4.64 (2H, d, J=5.9 Hz), 4.95-5.05 (1H, m),
5.26 (2H, d, J=4.1, 5.8 Hz), 6.75-6.85 (2H, m), 7.30-7.40 (1H, m),
8.30 (1H, s), 10.38 (1H, brs), 12.45 (1H, s).
Example Y-4
(2R,9aR)-5-Hydroxy-2-methoxymethyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-
-oxa-4a,8a-diaza-anthracene-7-carboxylic acid
2,4-difluoro-benzylamide
Example Y-8
(2S,9aS)-5-Hydroxy-2-methoxymethyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-
-oxa-4a,8a-diaza-anthracene-7-carboxylic acid
2,4-difluoro-benzylamide
[0653] 1H-NMR (CDCl.sub.3) .delta.: 1.60-1.80 (2H, m), 3.09-3.21
(1H, m), 3.37 (3H, s), 3.35-3.50 (2H, m), 4.00-4.11 (1H, m), 4.24
(1H, d, J=13.1 Hz), 4.36 (1H, d, J=10.1 Hz), 4.64 (1H, d, J=5.9
Hz), 4.70-4.80 (1H, m), 5.12 (1H, s), 6.75-6.85 (2H, m), 7.30-7.40
(1H, m), 8.30 (1H, s), 10.38 (1H, brs), 12.33 (1H, brs).
Example Y-5
(5aR,6aS,10aR)-1-Hydroxy-2,12-dioxo-2,5,5a,7,8,9,10,10a,11,12-decahydro-6a-
H-6-oxa-4a,11a-diaza-naphthacene-3-carboxylic acid
2,4-difluoro-benzylamide[racemate]
[0654] 1H-NMR (DMSO-d.sub.6) .delta.: 1.00-1.85 (9H, m), 2.90 (1H,
t, J=4.2 Hz), 4.36 (1H, dd, J=4.2, 12.9 Hz), 4.44-4.57 (4H, m),
5.32 (1H, t, J=3.9 Hz), 7.03-7.09 (1H, m), 7.20-7.27 (1H, m),
7.35-7.43 (1H, m), 8.49 (1H, s), 10.34 (1H, brs).
Example Y-6
(2S,9aR)-2-Ethyl-5-hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,-
8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
Example Y-7
(2R,9aS)-2-Ethyl-5-hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,-
8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
[0655] 1H-NMR (DMSO-d.sub.6) .delta.: 0.87 (3H, d, 1.40-1.51 (3H,
m), 1.75 (1H, d, J=10.8 Hz), 3.22 (1H, t, J=10.2 Hz), 3.73-3.78
(1H, m), 4.41-4.57 (4H, m), 5.29 (1H, s), 7.03-7.07 (1H, m),
7.21-7.26 (1H, m), 7.37-7.42 (1H, 8.50 (1H, s), 10.34 (1H, brs),
12.48 (1H, s).
Example Y-10
(2S,9aS)-5-Hydroxy-6,10-dioxo-2-phenyl-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a-
,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
[0656] 1H-NMR (CDCl.sub.3) .delta.: 1.70-1.82 (1H, m), 1.98 (1H, d,
J=9.6 Hz), 3.49 (1H, t, J=9.6 Hz), 4.54-4.68 (5H, m), 4.98 (1H, d,
J=8.7 Hz), 5.51 (1H, s), 7.04-7.08 (1H, m), 7.21-7.42 (7H, m), 8.50
(1H, s), 10.38 (1H, s), 12.45 (1H, s).
Example Y-11
(2S,9aS)-5-Hydroxy-2-isopropyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-
-4a,8a-diaza-anthracene-7-carboxylic acid
2,4-difluoro-benzylamide
Example Y-12
(2H,9aR)-5-Hydroxy-2-isopropyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-
-4a,8a-diaza-anthracene-7-carboxylic acid
2,4-difluoro-benzylamide
[0657] 1H-NMR (DMSO-d.sub.6) .delta.: 0.86 (6H, dd, J=4.8, 13.5
Hz), 1.41-1.49 (1H, m), 1.57-1.69 (1H, m), 1.72-1.78 (1H, m), 3.20
(1H, t, J=8.4 Hz), 3.52-3.59 (1H, m), 4.41-4.46 (5H, m), 5.29 (1H,
s), 7.01-7.08 (1H, m), 7.21-7.26 (1H, m), 7.37-7.43 (1H, m), 8.50
(1H, s), 10.35 (1H, brs), 12.48 (1H, s).
Example Y-1.3
(3S,9aS)-5-Hydroxy-3-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-oxa-4a,8-
a-diaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide
Example Y-14
(3R,9aR)-5-Hydroxy-3-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a-
,8a-diaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide
[0658] 1H-NMR (DMSO-d.sub.6) .delta.: 0.81 (3H, d, J=6.6 Hz),
1.84-1.93 (1H, m), 2.86 (1H, t, J=1.2.5 Hz), 3.48 (1H, t, J=11.1
Hz), 3.97-4.03 (1H, m), 4.41-4.60 (3H, m), 4.52 (2H, d, 5.20 (1H,
t, J=3.8 Hz), 7.12-7.20 (2H, m), 7.3-2.7.38 (2H, m), 8.52 (1H, s),
10.36 (1H, t, J=5.9 Hz), 12.45 (1H, s).
Example Y-15
(2R,9aS)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a-
,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
Example Y-16
(2S,9aR)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a-
,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
[0659] 1H-NMR (DMSO-d.sub.6) .delta.: 1.14 (3H, d, J=6.0 Hz), 1.38
(1H, m), 175 (1H, d, J=13.8 Hz), 3.18-3.29 (1H, 3.95-4.06 (1H, m),
4.42-4.58 (3H, m), 4.54 (2H, d, J=5.7 Hz), 5.30 (1H, t, J=3.9 Hz),
7.03-7.10 (1H, m), 7.20-7.29 (1H, m), 7.35-7.44 (1H, m), 8.50 (1H,
s), 10.35 (1H, t, J=5.7 Hz), 12.48 (1H, s).
Example Y-17
(2S,9aR)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-3-oxa-4a-
,8a-diaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide
Example Y-18
(2R,9aS)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a-
,8a-diaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide
[0660] 1H-NMR (DMSO-d.sub.6) .delta.: 1.15 (3H, d, J=6.0 Hz),
1.35-1.50 (1H, m), 1.75 (1H, d, J=12.9 Hz), 3.23 (1H, td, J=13.0,
2.8 Hz), 3.95-4.03 (1H, m), 4.41-4.59 (8H, 4.52 (2H, d, J=6.0 Hz),
5.30 (1H, t, J=3.9 Hz), 7.12-7.19 (2H, m), 7.32-7.38 (2H, m), 8.52
(1H, s), 10.36 (1H, t, J=6.0 Hz), 12.48 (1H, s).
[0661] Corresponding amino-alcohol derivatives used in syntheses of
Y-1 to Y-18 were prepared as optically pure version using methods
similar to those described in the following reports.
[0662] 3-Amino-2-methyl-propan-1-ol, and 4-Amino-butan-2-ol were
prepared according to the method of Russell A. Barrow (J. Am, Chem.
Soc. 1995, 117, 2479-2490).
[0663] 3-Amino-butan-1-ol were prepared according to the method of
P. Besse (Tetrahedron Asymmetry 10 (1999) 2213-2224).
[0664] 1-Amino-pentan-3-ol, 1-Amino-4-methyl-pentan-3-ol,
4-Amino-1-methoxy-butan-2-ol, and 3-Amino-1-phenyl-propan-1-ol were
prepared according to the method described in the following
literatures, U.S. Pat. Appl. Publ., 2004133029, 8 Jul. 2004, PCT
Int. Appl., 2002012173, 14 Feb. 2002.
[0665] All examples below consist of >95% ee and >6:1
diastereomeric purity unless indicated otherwise. The compounds
shown in table ZZ consist of mixtures of diastereoniers at the
depicted stereocenter in ratios of 1:1 to >10:1. Stereocenters
that were formed during the process' below have been assigned using
NMR techniques well know in the art (1D and 2D method) and/or using
vibrational circular dichroism techniques, Stereochemical
assignment determinations were performed on representative examples
and closely related compounds were assigned by analogy in some
cases. The schemes below are meant to be general guidance to how
examples were synthesized. It will be possible that one skilled in
the art may rearrange the order of steps or change substituents to
apply the method described below and in the examples to construct
compounds of the general formula. Additional methods known to those
skilled in the art or commonly present in the literature may also
be applied to perform similar transformations and arriving at the
same compounds of the general formula or amino alcohol and diamino
precursors.
##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103##
##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108##
##STR00109## ##STR00110## ##STR00111## ##STR00112##
Example Z-1
(3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3-
,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamid-
e sodium salt
##STR00113##
[0667] a)
(3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[-
(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d-
]pyrazine-8-carboxamide. To a solution of 16a (409 mg, 0.87 mmol)
in dichloroethane (20 mL) was added (2R)-2-amino-1-propanol (0.14
mL, 1.74 mmol) and 10 drops of glacial acetic acid. The resultant
solution was heated at reflux for 2 h. Upon cooling, Celite was
added to the mixture and the solvents removed in vacuo and the
material was purified via silica gel chromatography (2%
CH.sub.3OH/CH.sub.2Cl.sub.2 gradient elution) to give
(3R,11aS)--N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylme-
thyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-
-8-carboxamide (396 mg, 92%) as a glass. .sup.1H NMR (CDCl.sub.3)
.delta. 10.38 (m, 1H), 8.42 (s, 1H), 7.54-7.53 (m, 2H), 7.37-7.24
(m, 4H), 6.83-6.76 (m, 2H), 5.40 (d, J=10.0 Hz, 1H), 5.22 (d,
J=10.0 Hz, 1H), 5.16 (dd, J=9.6, 6.0 Hz, 1H), 4.62 (m, 2H), 4.41
(m, 1H), 4.33-4.30 (m, 2H), 3.84 (dd, J=12.0, 10.0 Hz, 1H), 3.63
(dd, J=3.4, 7.2 Hz, 1H), 1.37 (d, J=6.0 Hz, 3H); ES.sup.+ MS: 496
(M+1).
[0668] b)
(3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-
-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8--
carboxamide sodium salt. To a solution of
(3R,11aS)--N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylme-
thyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-
-8-carboxamide (396 mg, 0.80 mmol) in methanol (30 mL) was added
10% Pd/C (25 mg). Hydrogen was bubbled through the reaction mixture
via a balloon for 2 h. The resultant mixture was filtered through
Celite with methanol and dichloromethane. The filtrate was
concentrated 112 vacuo to give
(3R,11aS)--N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,-
3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxami-
de as a pink tinted white solid (278 mg, 86%). .sup.1H NMR
(CDCl.sub.3) .delta. 11.47 (m, 1H), 10.29 (m, 1H), 8.32 (s, 1H),
7.36 (m, 1H), 6.82 (m, 2H), 5.31 (dd, J=9.6, 3.6 Hz, 1H), 4.65 (m,
2H), 4.47-4.38 (m, 3H), 3.93 (dd, J=12.0, 10.0 Hz, 1H), 3.75 (m,
1H), 1.49 (d, J=5.6 Hz, 3H); ES.sup.+ MS: 406 (M+1). The above
material (278 mg, 0.66 mmol) was taken up in ethanol (10 mL) and
treated with 1 N sodium hydroxide (aq) (0.66 mL, 0.66 mmol). The
resulting suspension was stirred at room temperature for 30 min,
Ether was added and the liquids were collected to provide the
sodium salt of the title compound as a white powder (291 mg, 99%).
.sup.1H NMR (DMSO-d.sub.6) .delta. 10.68 (m, 1H), 7.90 (s, 1H),
7.35 (m, 1H), 7.20 (m, 1H), 7.01 (m, 1H), 5.20 (m, 1H), 4.58 (m,
1H), 4.49 (m, 2H), 4.22 (m, 2H), 3.74 (dd, J=11.2, 10.4 Hz, 1H),
3.58 (m, 1H), 1.25 (d, J=4.4 Hz, 3H).
Example Z-2
(4aR,13aS)--N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,-
9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyra-
zine-8-carboxamide
##STR00114##
[0670] a)
(4aR,13aS)--N-[(2,4-Difluorophenyl)methyl]-9,11-dioxo-10-[(pheny-
lmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':-
3,4]imidazo[1,2-d]pyrazine-8-carboxamide. A solution of 16a (24 mg,
0.05 mmol), [(2S)-2-pyrrolidinylmethyl]amine (0.1 mL) and 2 drops
of glacial acetic acid were heated under microwave conditions at
140.degree. C. for 10 min. Upon cooling, Celite was added to the
mixture and the solvents removed in vacuo and the material was
purified via silica gel chromatography (2%
CH.sub.3OH/CH.sub.2Cl.sub.2 gradient elution) to give
(4aR,13aS)--N-[(2,4-difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)o-
xy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imida-
zo[1,2-d]pyrazine-8-carboxamide (19 mg, 71%) as a white solid.
.sup.1H NMR (CDCl.sub.3) .delta. 10.41 (m, 1H), 8.38 (s, 1H), 7.56
(m, 2H), 7.38-7.24 (m, 4H), 6.80 (m, 2H), 5.38 (d, J=9.6 Hz, 1H),
5.10 (d, J=10.0 Hz, 1H), 4.62 (m, 2H), 4.40 (m, 1H), 4.25 (dd,
J=12.0, 6.8 Hz, 1H), 4.10 (d, J=12.8 Hz, 1H), 3.83 (m, 1H), 3.71
(m, 1H), 3.14-3.04 (m, 2H), 2.78 (m, 1H), 2.11-1.58 (m, 4H);
ES.sup.+ MS: 521 (M+1).
[0671] b)
(4aR,130.6)--N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-diox-
o-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo-
[1,2-d]pyrazine-8-carboxamide. To a solution of
(4aR,13aS)--N-[(2,4-difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)o-
xy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imida-
zo[1,2-d]pyrazine-8-carboxamide (19 mg, 0.04 mmol) in methanol (8
mid) was added 10% Pd/C (10 rug). Hydrogen was bubbled through the
reaction mixture via a balloon for 2 h. The resultant mixture was
filtered through Celite with methanol and dichloromethane. The
filtrate was concentrated in vacuo to give the title compound (6
mg, 38%) as a white solid. .sup.1H NMR (CDCl.sub.3) .delta. 11.78
(m, 1H), 10.36 (m, 1H), 8.31 (s, 1H), 7.33 (m, 1H), 6.78 (m, 2H),
4.62 (m, 2H), 4.50 (m, 1H), 4.27-4.19 (m, 2H), 3.87-3.77 (m, 2H),
3.16-3.08 (m, 2H), 2.33 (m, 1H), 2.11-1.65 (m, 4H); ES.sup.+ MS:
481 (M+1).
Example Z-3
(3aS,13aS)--N-[(2,4-Difluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,-
5,7,9,13,13a-decahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimi-
dine-10-carboxamide
##STR00115##
[0673] a) N--BOC-(2S)-2-(Hydroxymethyl)-1-pyrrolidine. To a
solution of N--BOC-L-proline (4.17 g, 19.4 mmol) in THF (40 mL) at
0.degree. C. was added BH.sub.3-THF (21.4 mL, 1M in THF, 21.4 mmol)
dropwise. The bath was removed and the resultant Solution stirred
at room temperature for 2 h. Methanol was added to quench the
mixture and the solvents were removed in vacuo. The residue was
taken up in ethyl acetate and washed with sodium bicarbonate and
brine. The aqueous layers were extracted twice with ethyl acetate.
The combined organics were dried over Na.sub.2SO.sub.4, filtered
and concentrated to give
N--BOC-(2S)-2-(hydroxymethyl)-1-pyrrolidine (3.82 g, 98%) as a
clear oil. This material was used without further purification.
.sup.1H NMR (CDCl.sub.3) .delta. 3.94 (m, 1H), 3.62 (dd, J=11.2,
3.2 Hz, 1H), 3.56 (ad, J=10.8, 7.2 Hz, 1H), 3.44 (m, 1H), 3.29 (m,
1H), 2.62 (br, 1H), 1.98 (m, 1H), 1.85-1.72 (m, 2H), 1.58 (m,
1H).
[0674] b)
N--BOC-(2S)-2-({[(4-Methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolid-
ine. To a cold (0.degree. C.) solution of
N--BOC-(2S)-2-(hydroxymethyl)-1-pyrrolidine (350 mg, 1.74 mmol) in
dichloromethane (20 mL) was added triethylamine (0.29 mL, 2.08
mmol), and toluenesulfonyl chloride (398 mg, 2.08 mmol).
N,N-dimethylaminopyridine (70 mg) was added and the resultant
solution was allowed to warm to rt as the bath warmed and stirred
for 4 h. Water was added and the layers separated. The aqueous
layer was washed with sodium bicarbonate and then with brine. The
combined organics were dried over Na.sub.2SO.sub.4, filtered and
concentrated followed by flash chromatography purification to give
--N--BOC-(2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyrroli-
dine (460 mg, 75%) as a clear oil. .sup.1H NMR exists as rotomers
(CDCl.sub.3) .delta. 7.77 (d, 2H), 7.33 (m, 2H), 4.08 (m, 1H),
3.97-3.88 (m, 1H), 3.35-3.25 (m, 2H), 2.43 (s, 3H), 1.95-1.79 (m,
4H), 1.40 and 1.35 (s, 9H rotameric BOC t-butyl).
[0675] c) N--BOC-(2S)-2-Cyano-1-pyrrolidine. A mixture of
--N--BOC-(2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidine
(460 mg, 1.29 mmol) and KCN (256 mg, 3.88 mmol) were heated at
90.degree. C. in DMSO (10 mL) for 6.5 h. The mixture was cooled to
room temperature and EtOAc and water were added. The organics were
washed with water twice and then with brine. The aqueous layers
were extracted with EtOAc and the combined organics dried over
Na.sub.2SO.sub.4, filtered and concentrated followed by flash
chromatography purification to give
N--BOC-(2S)-2-cyano-1-pyrrolidine (179 mg, 66%) as an oil. .sup.1H
NMR exists as rotomers (CDCl.sub.3) .delta. 3.99 (m, 1H), 3.43-3.37
(m, 2H), 2.83-2.51 (m, 2H), 2.17-1.83 (m, 4H), 1.46 and 1.44 (s, 9H
rotameric BOC t-butyl).
[0676] d) N--BOC-(2S)-2-(2-Aminoethyl)-1-pyrrolidine. A solution of
N--BOC-(2S)-2-cyano-1-pyrrolidine (179 mg, 0.85 mmol) in ethanol
saturated with anhydrous ammonia was treated with Raney-Ni (1 mL of
50% aq. Suspension) and 50 psi of H.sub.2 overnight. The mixture
was filtered through Celite and the filtrate was concentrated in
vacuo. The residue was purified by flash chromatography (10%
CH.sub.3OH/CH.sub.2Cl.sub.2 with 1% NH.sub.4OH gradient elution)
through a short plug of silica gel to give
--N--BOC-(2S)-2-(2-aminoethyl)-1-pyrrolidine (90 mg, 50%) as a
clear oil. .sup.1H NMR exists as rotomers (CDCl.sub.3) .delta.
3.88-3.77 (m, 1H), 3.33-3.24 (m, 2H), 2.66 (m, 2H), 1.89-1.54 (m,
6H), 1.40 (s, 9H).
[0677] e) {2-[(2S)-2-Pyrrolidinyl]ethyl}amine. A solution of
--N--BOC-(2S)-2-(2-aminoethyl)-1-pyrrolidine (90 mg, 0.42 mmol) in
THF mL) was treated with 4 N HCl (aq) mL) and stirred at room
temperature for 3 h. The mixture was concentrated in vacuo to give
the title compound as its HCl salt. A portion of this material (40
mg) was dissolved in methanol and treated with solid supported
carbonate resin (MP-Carbonate, Argonaut Technologies) to freebase
the amines. After 30 minutes, the solution was filtered through a
fritted tube and the solvents removed carefully in vacuo to give
{2-[(2S)-2-pyrrolidinyl]ethyl}amine (30 mg) as its free base.
.sup.1H NMR (CDCl.sub.3) .delta. 3.06 (m, 1H), 2.94 (m, 1H), 2.83
(m, 1H), 2.79-2.69 (m, 2H), 1.90-1.56 (m, 6H).
[0678] f)
(3aS,13aS)--N-[(2,4-Difluorophenyl)methyl]-7,9-dioxo-8-[(phenylm-
ethyl)oxy]-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1',2':4,5]pyrazino[1,2--
a]pyrrolo[1,2-c]pyrimidine-10-carboxamide. A solution of 16a (30
mg, 0.06 mmol), {2-[(2S)-2-pyrrolidinyl]ethyl}amine (30 mg, 0.26
mmol) and 2 drops of glacial acetic acid were heated under
microwave conditions at 140.degree. C. for 10 min. Upon cooling,
Celite was added to the mixture and the solvents removed in vacuo
and the material was purified via silica gel chromatography (2%
CH.sub.3OH/CH.sub.2Cl.sub.2 gradient elution) to give
(3aS,13S)--N-[(2,4-Difluorophenyl)methyl]-7,9-dioxo-8-[(phenylmethyl)oxy]-
-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrrolo[-
1,2-c]pyrimidine-10-carboxamide. (25 mg, 74%) as a film. .sup.1H
NMR (CDCl.sub.3) .delta. 10.44 (m, 1H), 8.32 (s, 1H), 7.59 (m, 2H),
7.38-7.24 (m, 4H), 6.80 (m, 2H), 5.28-5.22 (m, 2H), 4.67 (dd,
J=13.6, 2.8 Hz, 1H), 4.62 (m, 2H), 4.26 (m, 1H), 4.11-4.03 (m, 2H),
2.91 (m, 1H), 2.81 (m, 1H), 2.37 (m, 1H), 2.24 (m, 1H), 1.92 (m,
1H), 1.82-1.76 (m, 3H), 1.52-1.38 (m, 2H); ES.sup.+ MS: 535
(M+1).
[0679] g)
(3aS,13aS)--N-[(2,4-Difluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1-
,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrrolo[1,-
2-a]pyrimidine-10-carboxamide. To a solution of
(3aS,13aS)--N-[(2,4-difluorophenyl)methyl]-7,9-dioxo-8-[(phenylmethyl)oxy-
]-1,2,3,3a,4,
5,7,9,13,13a-decahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrim-
idine-10-carb oxamide (25 mg, 0.05 mmol) in methanol (8 mL) was
added 10% Pd/C (10 mg). Hydrogen was bubbled through the reaction
mixture via a balloon for 18 h. The resultant mixture was filtered
through. Celite with methanol and dichloromethane. The filtrate was
concentrated in vacuo to give the title compound (14 mg, 67%) as a
white solid. .sup.1H NMR (CDCl.sub.3) .delta. 12.53 (br, 1H), 10.44
(s, 1H), 8.29 (s, 1H), 7.34 (m, 1H), 6.78 (m, 2H), 4.71-4.58 (m,
3H), 4.29-4.14 (m, 3H), 2.99 (m, 1H), 2.88 (m, 1H), 2.44 (m, 1H),
2.30 (m, 1H), 1.97-1.88 (m, 6H); ES.sup.+ MS: 445 (M+1).
Example Z-4
(4aS,13aR)--N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,-
9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyra-
zine-8-carboxamide sodium salt
##STR00116##
[0681] a) [(2R)-2-Pyrrolidinylmethyl]amine. To a solution of
N--BOC-(2R)-2-(aminomethyl)-1-pyrrolidine (1.37 g, 6.85 mmol) in
THF (20 mL) was added 4 N HCl (aq) (8 mL). The resultant solution
was stirred at room temperature overnight. The solvents were
removed in vacuo and the residue was treated with MP-carbonate
resin in methanol and dichloromethane. After 1 h, the resin was
removed via filtration through a fritted tube and the volatiles
were removed carefully in vacuo to produce the free based amine
(760 mg crude >100%) as a oil. This material was used without
further purification. .sup.1H NMR (CDCl.sub.3) .delta. 3.13 (m,
1H), 2.92 (m, 1H), 2.82-2.62 (m, 5H), 1.88-1.80 (m, 4H).
[0682] b)
(4aS,13aR)--N-[(2,4-Difluorophenyl)methyl]-9,11-dioxo-10-[(pheny-
lmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':-
3,4]imidazo[1,2-d]pyrazine-8-carboxamide. In a similar manner as
described in example Z-2 from 16a (435 mg, 0.93 mmol) and
[(2R)-2-pyrrolidinylmethyl]amine (200 nag, 2.0 mmol) in
1,2-dichloroethane (20 mL) and 15 drops of glacial acetic acid was
obtained
(4aS,13R)--N-[(2,4-difluorophenyl)methyl]-9,11-dioxo-10-[(phenyl-
methyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-Pyrido[1,2-a]pyrrolo[1',2':3-
,4]imidazo[1,2-d]pyrazine-8-carboxamide (321 mg, 67%) as a white
solid. 1H NMR (CDCl.sub.3) .delta. 10.41 (m, 1H), 8.35 (s, 1H),
7.56 (m, 2H), 7.55-7.24 (m, 4H), 6.80 (m, 2H), 5.35 (d, J=10.0 Hz,
3H), 5.13 (d, J=10.0 Hz, 1H), 4.60 (m, 2H), 4.38 (dd, J=10.4, 3.2
Hz, 1H), 4.21 (dd, J=12.0, 6.8 Hz, 1H), 4.04 (dd, J=12.4, 2.8 Hz,
1H), 3.77 (apparent t, J=11.6 Hz, 1H), 3.68 (m, 1H), 3.11-3.00 (m,
2H), 2.75 (m, 1H), 2.08-1.84 (m, 8H), 1.65 (m, 1H); ES.sup.+ MS:
521 (M+1).
[0683] c)
(4aS,13aR)--N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-
-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[-
1,2-d]pyrazine-8-carboxamide. In a similar manner as described in
example Z-2 from
(4aS,13aR)--N-[(2,4-difluorophenyl)methyl]-9,11-dioxo-10-[(pheny-
lmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':-
3,4]imidazo[1,2-d]pyrazine-8-carboxamide (518 mg, 0.99 mmol) and
1.0% Pd/C (35 mg) in methanol (40 mL) was obtained
(4aS,13aR)--N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5-
,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyr-
azine-8-carboxamide (430 mg, 99%) as a white solid. .sup.1H NMR
(CDCl.sub.3) .delta. 11.73 (m, 1H), 10.36 (m, 1H), 8.32 (s, 1H),
7.35 (m, 1H), 6.79 (m, 2H), 4.64 (m, 2H), 4.54 (dd, J=10.8, 4.0 Hz,
1H), 4.28-4.19 (m, 2H), 3.90-3.79 (m, 2H), 3.18-3.10 (m, 2H), 2.84
(m, 1H), 2.14-1.92 (m, 3H), 1.72 (m, 1H).
[0684] d)
(4aS,13aR)--N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-
-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[-
1,2-d]pyrazine-8-carboxamide sodium salt. In a similar manner as
described in example Z-1 from
(4aS,13aR)--N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5-
,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyr-
azine-8-carboxamide (430 mg, 1.0 mmol) and sodium hydroxide (1.0
mL, 1.0 M aq, 1.0 mmol) in 20 mL of ethanol was formed the
corresponding sodium salt (425 mg, 94%) as a white solid. .sup.1H
NMR (D.sub.2O) .delta. 7.85 (s, 1H), 7.23 (m, 1H), 6.82 (m, 2H),
4.51-4.46 (m, 3H), 4.28 (m, 1H),3.95 (m, 1H), 3.84 (m, 1H), 3.62
(m, 1H), 3.16 (m, 1H), 2.89 (m, 1H), 2.84 (m, 1H), 1.90 (m, 2H),
1.73 (m, 1H), 1.60 (m, 1H). ES.sup.+ MS: 431 (M+1).
Example Z-5
(4aS,13aR)--N-[(4-Fluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11-
,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-
-8-carboxamide
##STR00117##
[0686] The title compound was made in two steps using a similar
process to that described in example Z-2. 16 (60 mg, 0.13 mmol) and
[(2R)-2-pyrrolidinylmethyl]amine (100 mg, 1.0 mmol) were reacted in
dichloromethane (2 mL) with acetic acid to give
(4aS,13aR)--N-[(4-fluorophenyl)methyl]-9,11-dioxo-10-[phenylmethyl)oxy]-2-
,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,-
2-d]pyrazine-8-carboxamide (60 mg, 91%). This material was
hydrogenated in a second step as described in example Z-2 to give
(4aS,13aR)--N-[(4-fluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,1-
1,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazin-
e-8-carboxamide (21 mg, 42%) as a white solid. .sup.1H NMR
(CDCl.sub.3) .delta. 11.72 (m, 1H), 1.37 (m, 1H), 8.33 (s, 1H),
7.29 (m, 2H), 6.97 (m, 2H), 4.57 (m, 2H), 4.52 (m, 1H), 4.24-4.19
(m, 2H), 3.87-3.76 (m, 2H), 3.14-3.07 (m, 2H), 2.82 (m, 1H),
2.11-1.89 (m, 3H), 1.68 (m, 1H); ES.sup.+ MS: 413 (M+1).
Example Z-6
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-8-(phenylmet-
hyl)-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2a]pyrido[1,2-d]pyrazine-8-car-
boxamide
##STR00118##
[0688] The title compound was made in two steps using a similar
process to that described in example Z-2. 16a (37 mg, 0.08 mmol)
and (2S)-2-amino-3-phenyl-1-propanol (35 mg, 0.24 mmol) were
reacted in dichloromethane (2 mL) with acetic acid to give
(3S,11aR)--N-[(2,4-difluorophenyl)methyl]-5,7-dioxo-3-(phenylmethyl)
6-[(phenylmethyloxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,-
2-d]pyrazine-8-carboxamide (4.1 mg, 91%). This material was
hydrogenated in a second step as described in example Z-2 to give
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylme-
thyl)-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-c-
arboxamide. (25 mg, 75%) as a white solid. .sup.1H NMR (CDCl.sub.3)
.delta. 11.47 (br, 1H), 10.28 (m, 1H), 8.35 (m, 1H), 7.37-7.26 (m,
4H), 7.18 (m, 2H), 6.79 (m, 2H), 5.03 (m, 1H), 4.64-4.61 (m, 3H),
4.40 (m, 1H), 4.23 (apparent t, J=7.2 Hz, 1H), 3.96 (dd, J=8.8, 6.4
Hz, 1H), 3.88 (apparent t, J=11.2 Hz, 1H), 3.37 (dd, J=13.6, 3.2
Hz, 1H), 2.99 (dd, J=13.2 8.8 Hz, 1H); ES.sup.+ MS: 482 (M+1).
Example Z-7
(3aS,13aS)--N-[(4-Fluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,7,9,-
13,13a-decahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrrolo[1,2-
c]pyrimidine-10-carboxamide
##STR00119##
[0690] The title compound was made in two steps using a similar
process to that described in example Z-2. 16 (84 mg, 0.13 mmol) and
{2-[(2S)-2-Pyrrolidinyl]ethyl}amine (150 mg, 1.3 mmol) were reacted
in dichloromethane (2 mL) with acetic acid to give
(3aS,13aS)--N-[(4-fluorophenyl)methyl]-7,9-dioxo-8-[(phenylmethyl)oxy]-1,-
2,3,3a,4,5,7,9,13,13a-decahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrrolo[1,2-
-c]pyrimidine-10-carboxamide (86 mg, 90%). This material was
hydrogenated in a second step as described in example Z-2 give
(3aS,13aS)--N-[(4-Fluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7-
,9,13,13a-decahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidin-
e-10-carboxamide. (63 mg, 88%) as a white solid. .sup.1H NMR
(CDCl.sub.3/CD.sub.3OD) .delta. 10.45 (m, 1H), 8.23 (s, 1H), 7.35
(m, 2H), 6.94 (t, J=8.8 Hz, 2H), 4.63 (m, 1H), 4.58-4.48 (m, 2H),
4.33 (dd, J=13.6, 3.6 Hz, 1H), 4.21 (m, 1H), 4.11 (m, 1H), 2.98 (m,
1H), 2.85 (td, J=13.2, 3.2 Hz, 1H), 2.41 (m, 1H), 2.29 (m, 1H),
1.92 (m, 1H), 1.83-1.75 (m, 3H), 1.54-1.35 (m, 2H); ES.sup.+ MS:
427 (M+1).
Example Z-8
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(1S)-1-methylpropyl-
]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazi-
ne-8-carboxamide sodium salt
##STR00120##
[0692] The title compound was made in two steps using a similar
process to that described in example Z-1. 16a (417 mg, 0.89 mmol)
and L-isoleucinol (259 mg, 2.21 mmol) were reacted in
1,2-dichloroethane (40 mL) with acetic acid to give
(3S,11aR)--N-[(2,4-difluorophenyl)methyl]-3-[(1S)-1-methylpropyl]-5,7-dio-
xo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido-
[1,2-d]pyrazine-8-carboxamide (426 mg, 90%). This material was
hydrogenated in a second step as described in example Z-1 to give
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(1S)-1-methylpropy-
l]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-H]pyrido[1,2-d]pyraz-
ine-8-carboxamide (376 mg, 99%) as a coarse white solid. .sup.1H
NMR (CDCl.sub.3) .delta. 11.43 (br, 1H), 10.27 (br, 1H), 8.32 (s,
1H, 7.33 (m, 1H), 6.79 (m, 2H), 5.26 J=9.6, 4.0 Hz, 1H), 4.62 (m,
2H), 4.42-4.35 (m, 2H), 4.19 (dd, J=8.8, 7.2 Hz, 1H), 4.01 (dd,
J=8.8, 5.6 Hz, 1H), 3.86 (dd, J=12.0, 10.0 Hz, 1H), 2.27 (m, 1H),
1.40 (m, 1H), 1.15 (m, 1H), 0.97 (t, J=7.2 hz, 3H), 0.91 (d, J=6.8
Hz, 3H); ES.sup.+ MS: 448 (M+1). This material (360 mg, 0.81 mmol)
was treated with sodium hydroxide (0.81 mL, 1.0 M, 0.81 mmol) in
ethanol (15 mL) as described in example Z-1 to provide its
corresponding sodium salt (384 mg, 99%) as a white solid. .sup.1H
NMR (DMSO-d.sub.6) .delta. 10.82 (m, 1H), 7.80 (m, 1H), 7.33 (m,
1H), 7.18 (m, 1H), 7.00 (m, 1H), 5.14 (m, 1H), 4.47 (d, J=5.6 Hz,
2H), 4.31 (m, 1H), 4.18 (m, 1H), 3.96 (m, 1H), 3.84 (m, 1H), 3.71
(m, 1H), 3.40 (m, 1H), 1.88 (m, 1H), 1.36 (m, 1H), 1.04 (m, 1H),
0.85 (t, J=7.2 Hz, 3H), 0.80 (d, J=6.8 Hz, 3H); ES.sup.+ MS: 448
(M+1).
Example Z-9
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3-
,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamid-
e sodium salt
##STR00121##
[0694] The title compound was made in two steps using a similar
process to that described in example Z-1. 16a (510 mg, 1.08 mmol)
and (2S)-2-amino-1-propanol (0.17 mL, 2.17 mmol) were reacted in
1,2-dichloroethane (20 mL) with acetic acid to give
(3S,11aR)--N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylme-
thyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-
-8-carboxamide (500 mg, 93%). This material was hydrogenated in a
second step as described in example Z-1 to give
3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3-
,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamid-
e (386 mg, 94%) as a tinted white solid. .sup.1H NMR (CDCl.sub.3)
.delta. 11.46 (m, 1H), 10.28 (m, 1H), 8.32 (s, 1H), 7.35 (m, 1H),
6.80 (m, 2H), 5.30 (dd, J=10.0, 4.0 Hz, 1H), 4.63 (m, 2H),
4.48-4.37 (m, 3H), 3.91 J=12.0, 10.0 Hz, 1H), 8.73 (m, 1H), 1.48
(d, J=6.0 Hz, 3H); ES.sup.+ MS: 406 (M+1). This material (385 mg,
0.95 mmol) was treated with sodium hydroxide (0.95 mL, 1.0 M, 0.95
mmol) in ethanol (15 mL) as described in example Z-1 to provide its
corresponding sodium salt (381 mg, 94%) as a white solid. .sup.1H
NMR (DMSO-d.sub.6) .delta. 10.66 (m, 1H), 7.93 (s, 1H), 7.33 (m,
1H), 7.20 (m, 1H), 7.01 (m, 1H), 5.19 (m, 1H), 4.59 (m, 1H), 4.48
(m, 2H), 4.22 (m, 2H), 3.75 (m, 1H), 3.57 (m, 1H), 1.24 (d, J=5.6
Hz, 3H).
Example Z-10
(3S,11aS)--N-[(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7-
,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
##STR00122##
[0696] The title compound was made in two steps using a similar
process to that described in example Z-2. 16 (100 mg, 0.22 mmol)
and (2S)-2-amino-1-propanol (0.10 mL, 1.28 mmol) were reacted in
dichloromethane (2 mL) with acetic acid to give
(3S,11aR)--N-[(4-fluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl-
)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-c-
arboxamide (100 mg, 95%). This material was hydrogenated in a
second step as described in example Z-2 to give
(3S,11aR)--N-[(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,-
7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
(80 mg, 99%) as a white solid. .sup.1H NMR (CDCl.sub.3) .delta.
11.43 (br, 1H), 10.28 (br, 1H), 8.35 (s, 1H), 7.28 (m, 2H), 6.97
(m, 2H), 5.29 (m, 1H), 4.55-4.38 (m, 5H), 3.89 (apparent t, J=10.8
Hz, 1H), 3.70 (m, 1H), 1.45 (d, J=5.6 Hz, 3H); ES.sup.+ MS: 386
(M+1).
Example Z-11
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-3-(1,1-dimethylethyl)-6-hydroxy--
5,5-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-
-8-carboxamide
##STR00123##
[0698] The title compound was made in two steps using a similar
process to that described in example Z-2. 16a (41 mg, 0.09 mmol)
and freebased L-tert-leucinol (59 mg, 0.50 mmol) were reacted in
dichloromethane (2 mL) with acetic acid to give
(3S,11aR)--N-[(2,4-difluorophenyl)methyl]-3-(1,1-dimethylethyl)-5,7-dioxo-
-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1-
,2-d]pyrazine-8-carboxamide (40 mg, 86%). This material was
hydrogenated in a second step as described in example Z-2 to give
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-3-(1,1-dimethylethyl)-6-hydroxy-
-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-
e-8-carboxamide (33 mg, 99%) as a tinted white solid. .sup.1H NMR
(CDCl.sub.3) .delta. 10.29 (s, 1H), 8.37 (s, 1H), 7.34 (m, 1N),
6.79 (m, 2H), 5.43 (m, 1H), 4.62 (m, 2H), 4.36 (m, 2H), 4.21 (m,
1H), 3.99 (1H), 3.81 (m, 1H), 1.03 (S, 9H); ES.sup.+ MS: 448
(M+1).
Example Z-12
(3S,11aR)-3-(1,1-Dimethylethyl)-N-[(4-fluorophenyl)methyl]-6-hydroxy-5,7-d-
ioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-ca-
rboxamide
##STR00124##
[0700] The title compound was made in two steps using a similar
process to that described in example Z-2, 16 (41 mg, 0.09 mmol) and
freebased L-tert-leucinol (59 mg, 0.50 mmol) were reacted in
dichloromethane (2 mL) with acetic acid to give
(3S,11aR)-3-(1,1-Dimethylethyl)-N-[(4-fluorophenyl)methyl]-5,7-dioxo-6-[(-
phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]-
pyrazine-8-carboxamide (40 mg, 85%). This material was hydrogenated
in a second step as described in example Z-2 to give
(3S,11aR)-3-(1,1-Dimethylethyl)-N-[(4-fluorophenyl)methyl]-6-hydroxy-5,7--
dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-c-
arboxamide (32 mg, 97%) as a tinted white solid. .sup.1H NMR
(CDCl.sub.3) .delta. 11.15 (br, 1H), 1.0.32 (s, 1H), 8.38 (s, 1H),
7.29 (m, 2H), 6.98 (m, 2H), 5.43 (m, 1H), 4.58 (m, 2H), 4.36 (m,
2H), 4.21 (m, 1H), 3.99 (1H), 3.79 (m, 1H), 1.02 (s, 9H); ES.sup.+
MS: 4.30 (M+1).
Example Z-13
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-phenyl-2,3-
,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamid-
e
##STR00125##
[0702] The title compound was made in two steps using a similar
process to that described in example Z-2. 16a (33 mg, 0.07 mmol)
and L-phenylglycinol (19 mg, 0.14 mmol) were reacted in
dichloromethane (2 mL) with acetic acid to give
(3S,11aR)--N-[(4-fluorophenyl)methyl]-5,7-dioxo-3-phenyl-6-[(phenylmethyl-
)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-c-
arboxamide (37 mg, 95%). This material was hydrogenated in a second
step as described in example Z-2 to give
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-phenyl-2,-
3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxami-
de (33 mg, 99%) as a tinted white solid. .sup.1H NMR (CDCl.sub.3)
.delta. 11.23 (br, 1H), 10.27 (s, 1H), 8.39 (s, 1H), 7.43-7.32 (m,
6H), 6.80 (m, 2H), 5.58 (d, J=6.8 Hz, 1H), 5.37 (apparent t, J=6.8
Hz, 1H), 4.67-4.62 (m, 3H), 4.54 (d, J=10.4 Hz, 1H), 4.11 (m, 1H),
4.01 (m, 1H); ES.sup.+ MS: 468 (M+1).
Example Z-14
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(hydroxymethyl)-5,7--
dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-c-
arboxamide
##STR00126##
[0704] The title compound was made in two steps using a similar
process to that described in example Z-2. 16a (50 mg, 0.10 mmol)
and (2R)-2-amino-3-[(phenylmethyl)oxy]-1-propanol (0.1 mL) were
reacted in dichloromethane (2 mL) with acetic acid to give
(3S,11aR)--N-[(2,4-difluorophenyl)methyl]-5,7-dioxo-6-[(phenylmethyl)oxy]-
-3-{[(phenylmethyl)oxy]methyl}-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]-
pyrido[1,2-d]pyrazine-8-carboxamide (61 mg, 99%). This material was
hydrogenated in a second step as described in example Z-2 to give
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(hydroxymethyl)-5,7-
-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8--
carboxamide (37 mg, 87%) as a tinted white solid. .sup.1H NMR
(CDCl.sub.3/CD.sub.3OD) .delta. 8.23 (s, 1H), 7.32 (m, 1H), 6.79
(m, 2H), 5.31 (d, J=7.6 Hz, 1H), 4.56 (s, 2H), 4.42-4.36 (m, 3H),
4.17-4.11 (m, 2H), 3.85 (m, 1H), 3.62 (d, J=11.2 Hz, 1H).
Example Z-15
(2S,3R)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2-phe-
nyl-2,3,5,7,11,11a-hexahydro[1,3]oxazole[3,2-a]pyrido[1,2-d]pyrazine-8-car-
boxamide
##STR00127##
[0706] The title compound was made in two steps using a similar
process to that described in example Z-2. 16a (25 mg, 0.05 mmol)
and (1S,2R)-(+)-norephedrine (0.1 mL) were reacted in
dichloromethane (2 mL) with acetic acid to give
(2S,3R)--N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-2-phenyl-6-[(p-
henylmethyl)oxy]-2,3,6,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]p-
yrazine-8-carboxamide (30 mg, 99%). This material was hydrogenated
in a second step as described in example Z-2 to give
(2S,3R)--N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2-ph-
enyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-c]pyrazine-8-ca-
rboxamide (25 mg, 91%) as a white solid. This material is a single
diastereomer (>6:1 diastereomeric ratio but unconfirmed relative
stereochemistry at the aminal center). .sup.1H NMR
(CDCl.sub.3/CD.sub.3OD) .delta. 10.28 (m, 1H), 8.38 (s, 1H),
7.10-7.30 (m, 6H), 6.78 (m, 2H), 5.70 (d, J=7.6 Hz, 1H), 5.36 (d,
J=5.2 Hz, 1H), 4.82 (m, 1H), 4.61 (m, 2H), 4.47 (d, J=10.4 Hz, 1H),
4.00 (apparent t, J=10.4 Hz, 1H), 0.94 (d, J=6.4 Hz, 3H); ES.sup.+
MS: 482 (M+1).
Example Z-16
(3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylmet-
hyl)-2,3,5,7,11,11a-hexahydro[1,3]oxazolo-[3,2-a]pyrido[1,2-d]pyrazine-8-c-
arboxamide
##STR00128##
[0708] The title compound was made in two steps using a similar
process to that described in example Z-2. 16a (34 sag, 0.07 mmol)
and (2R)-2-amino-3-phenyl-1-propanol (D-phenylalaninol) (50 mg,
0.33 mmol) were reacted in dichloromethane (2 mL) with acetic acid
to give
(3R,11aS)--N-[(2,4-difluorophenyl)methyl]-5,7-dioxo-3-(phenylmethyl)-6-[(-
phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]-
pyrazine-8-carboxamide (29 mg, 70%). This material was hydrogenated
in a second step as described in example Z-2 to give
(3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylme-
thyl)-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-c-
arboxamide (24 mg, 98%) as a white solid. .sup.1H NMR (CDCl.sub.3)
.delta. 11.46 (br, 1H), 10.27 (m, 1H), 8.33 (m, 1H), 7.32-7.16 (m,
6H), 6.78 (m, 2H), 5.02 (m, 1H), 4.61 (m, 3H), 4.39 (m, 1H), 4.22
(m, 1H), 3.95 (m, 1H), 3.87 (m, 1H), 3.36 (m, 1H), 2.97 (dd, J=13.2
8.8 Hz, 1H); ES.sup.+ MS: 482 (M+1).
Example Z-17
(3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(2-methylpropyl)-5,7-
-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8--
carboxamide
##STR00129##
[0710] The title compound was made in two steps using a similar
process to that described in example Z-2. 16a (32 mg, 0.07 mmol)
and (2R)-2-amino-4-methyl-1-pentanol (0.1 mL) were reacted in
dichloromethane (2 mL) with acetic acid to give
(3R,11aS)--N-[(2,4-difluorophenyl)methyl]-3-(2-methylpropyl)-5,7-dioxo-6--
[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2--
d]pyrazine-8-carboxamide (43 mg, 99%). This material was
hydrogenated in a second step as described in example Z-2 to give
(3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(2-methylpropyl)-5,-
7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-
-carboxamide (32 mg, 90%) as a white solid. .sup.1H NMR
(CDCl.sub.3) .delta. 11.47 (br, 1H), 10.29 (m, 1H), 8.35 (s, 1H),
7.39 (m, 1H), 6.80 (m, 2H), 5.31 (m, 1H), 4.62 (m, 2H), 4.44 (m,
2H), 4.37 (m, 1H), 3.88 (m, 1H), 3.84 (dd, J=8.0, 5.6 Hz, 1H), 2.04
(m, 1H), 1.62 (m, 1H), 1.41 (m, 1H), 1.00 (d, 5.6 Hz, 3H), 0.99 (d,
J=6.0 Hz, 3H); ES.sup.+ MS: 448 (M+1).
Example Z-18
(5aR,14aR)--N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,4,-
5a,6,10,12,11,14a-decahydropyrido[1,2-a]pyrido[1,2':3,4]imidazo[1,2-d]pyra-
zine-9-carboxamide
##STR00130##
[0712] a)
1,1-Dimethylethyl(2R)-2-(aminocarbonyl)-1-piperidinecarboxylate. To
a cold (0.degree. C.) solution of
(2R)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-piperidinecarboxylic
acid (1.0 g, 4.36 mmol) in THF (20 mL) was added triethylamine
(0.60 mL, 4.36 mmol) followed by slow addition of methyl
chloroformate (0.34 mL, 4.36 mmol). After a few minutes a
suspension had formed. To this mixture was added concentrated
NH.sub.4OH (1.5 mL) and the solution was allowed to warm to rt as
the bath warmed and stirred for a total of 4 h. The mixture was
concentrated in vacuo and the residue was taken up in EtOAc. The
organic layer was washed with citric acid, bicard and then brine,
dried over Na.sub.2SO.sub.4. Filtration and concentration gave
1,1-dimethylethyl(2R)-2-(aminocarbonyl)-1-piperidinecarboxylate
(1.0 g, 99%). .sup.1H NMR (CDCl.sub.3) .delta. 6.03 (br, 1H), 5.45
(br, 1H), 4.77 (br, 1H), 4.06 (br, 1H), 2.82 (m, 1H), 2.29 (m, 1H),
1.67-1.43 (m, 13H).
[0713] b) 1, 1-Dimethylethyl(2R)-2-cyano-1-piperidinecarboxylate.
To a cold (0.degree. C.) solution of
1,1-dimethylethyl(2R)-2-(aminocarbonyl)-1-piperidinecarboxylate
(269 mg, 1.17 mmol) in THF (10 mL) was added triethylamine (0.33
mL, 2.34 mmol) and then trifluoroacetic anhydride (0.17 mL, 1.17
mmol). The mixture was stirred at 0.degree. C. for 1 h and
concentrated in vacuo. The residue was taken up in EtOAc and washed
successively with sodium bicarbonate, 0.5 N HCl and brine. The
organics were dried over Na.sub.2SO.sub.4, filtered and
concentrated to give
1,1-dimethylethyl(2R)-2-cyano-1-piperidinecarboxylate (255 mg, 99%)
as a crystalline solid upon standing. .sup.1H NMR (CDCl.sub.3)
.delta. 5.23 (br, 1H), 4.05 (br, 1H), 2.93 (br, 1H), 1.93-1.39 (m,
6H), 1.46 (s, 9H).
[0714] c)
1,1-Dimethylethyl(2R)-2-(aminomethyl)-1-piperidinecarboxylate. An
ammonia saturated ethanol solution of
1,1-dimethylethyl(2R)-2-cyano-1-piperidinecarboxylate (255 mg, 1.19
mmol) was reduced with Raney-Ni in a similar manner to that
described in example Z-3 to give after filtration through a short
plug of silica,
1,1-dimethylethyl(2R)-2-(aminomethyl)-1-piperidinecarboxylate (236
mg, 91%), as an oil. .sup.1H NMR (CDCl.sub.3/CD.sub.3OD) .delta.
4.15 (br, 1H), 3.97 (m, 1H), 2.96 (m, 1H), 2.75-2.69 (m, 2H),
2.23-2.08 (m, 3H), 1.59-1.55 (m, 3H), 1.43 (s, 9H).
[0715] d) [(2R)-2-Piperidinylmethyl]amine his HCl salt. A solution
of 1,1-dimethylethyl(2R)-2-(aminomethyl)-1-piperidinecarboxylate
(236 mg, 1.08 mmol) in THF (10 mL) was treated with 4 N HCl (3 mL)
as described in example Z-3 to give the his HCl salt of
[(2R)-2-Piperidinylmethyl]amine. .sup.1H NMR (DMSO-d.sub.6) .delta.
9.67 (br, 1H), 9.48 (br, 1H), 8.48 (br, 2H), 3.70 (br, 2H), 3.20
(m, 1H), 3.04 (m, 1H), 2.86 (m, 1H), 1.89-1.41 (m, 6H).
[0716] e)
(5aR,14aR)--N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-diox-
o-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1',2':3,4]imidazo-
[1,2-d]pyrazine-9-carboxamide. The title compound was made in two
steps using a similar process to that described in example Z-2. 16a
(50 mg, 0.11 mmol) and [(2R)-2-Piperidinylmethyl]amine (150 mg,
1.31 mmol) (free based using carbonate resin as described in
example Z-3) were reacted in dichloromethane (2 mL) with acetic
acid to give
(5aR,14aR)--N-[(2,4-difluorophenyl)methyl]-10,12-dioxo-11-[(phenylmethyl)-
oxy]-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-A]pyrido[1',2':3,4]imid-
azo[1,2-d]pyrazine-9-carboxamide (50 mg, 88%). This material was
hydrogenated in a second step as described in example Z-2 to give
(5aR,14aR)--N-[(2,4-difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,4-
,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1',2':3,4]imidazo[1,2-d]py-
razine-9-carboxamide (11 mg, 44%) as a white solid. .sup.1H NMR
(CD.sub.3OD/CDCl.sub.3) .delta. 10.46 (m, 1H), 8.32 (s, 1H), 7.31
(m, 1H), 6.80 (m, 2H), 4.64-4.52 (m, 3H), 4.14 (dd, J=10, 4, 2.8
Hz, 1H), 3.91-3.82 (m, 2H), 3.19 (apparent, t, J=10.8 Hz, 1H), 3.08
(d, J=10.4 Hz, 1H), 2.50 (m, 1H), 2.27 (m, 1H), 1.99-1.30 m, 6H);
ES.sup.+ MS: 445 (M+1).
Example Z-19
(2S,3S)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(methyloxy)methyl]-5,-
7-dioxo-2-phenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]p-
yrazine-8-carboxamide
##STR00131##
[0718] The title compound was made in two steps using a similar
process to that described in example Z-2. 16a (36 mg, 0.07 mmol)
and (2R)-2-amino-4-methyl-1-pentanol (0.1 mL) were reacted in
dichloromethane (2 mL) with acetic acid to give
(2S,3S)--N-[(2,4-difluorophenyl)methyl]-3-[(methyloxy)methyl]-5,7-dioxo-2-
-phenyl-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2a]py-
rido[1,2-d]pyrazine-8-carboxamide. This material was hydrogenated
in a second step as described in example Z-2 to give
(2S,3S)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(methyloxy)methyl]-5-
,7-dioxo-2-phenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]-
pyrazine-8-carboxamide (25 mg, 64% for 2 steps) as a white solid.
This material is a single diastereomer (>6:1 diastereomeric
ratio but unconfirmed relative stereochemistry at the aminal
center). .sup.1H NMR (CDCl.sub.3) .delta. 11.48 (hr, 1H), 10.30 (m,
1H), 8.39 (s, 1H), 7.39-7.24 (m, 6H), 6.78 (m, 2H), 5.46 (dd,
J=10.0, 3.6 Hz, 1H), 5.33 (d, J=7.2 Hz, 1H), 4.63 (m, 2H), 4.54
(dd, J=12, 4, 4.0 Hz, 1H), 4.19 (m, 1H), 4.12 (dd, J=10.4, 3.2 Hz,
1H), 4.06 (m, 1H), 3.55 (dd, J=10.4, 1.6 Hz, 1H), 3.4.0 (s, 3H);
ES.sup.+ MS: 512 (M+1).
Example Z-20
(3S,11aR)-3-(Cyclohexylmethyl)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,-
7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-
-carboxamide
##STR00132##
[0720] The title compound was made in two steps using a similar
process to that described in example Z-2. 16a (36 mg, 0.08 mmol)
and (2S)-2-amino-3-cyclohexyl-1-propanol (30 mg, 0.19 mmol) were
reacted in dichloromethane (2 mL) with acetic acid to give
(3S,11aR)-3-(cyclohexylmethyl)-N-[(2,4-difluorophenyl)methyl]-5,7-dioxo-6-
-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-
-d]pyrazine-8-carboxamide (27 mg, 61%). This material was
hydrogenated in a second step as described in example Z-2 to give
(3S,11aR)-3-(cyclohexylmethyl)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5-
,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine--
8-carboxamide (25 mg, 99%) as a white solid. .sup.1H NMR
(CDCl.sub.3) .delta. 11.48 (br, 1H), 10.28 (s, 1H), 8.33 (s, 1H),
7.33 (m, 1H), 6.78 (m, 2H), 5.29 (m, 1H), 4.61 (m, 2H), 4.47-4.33
(m, 3H), 3.87-3.81 (m, 2H), 2.05 (m, 1H), 0.1.75-1.64 (m, 6H), 1.39
(m, 1H), 1.25-1.14 (m, 3H), 1.02-0.97 (m, 2H); ES.sup.+ MS: 488
(M+1).
Example Z-21
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1-methylethyl)-5,7--
dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-
d]pyrazine-8-carboxamide
##STR00133##
[0722] The title compound was made in two steps using a similar
process to that described in example Z-1. 16a (42 mg, 0.09 mmol)
and (2,3)-2-amino-3-methyl-1-butanol (0.1 mL) were reacted in
1,2-dichloroethane (8 mL) with acetic acid to give
(3S,11aR)--N-[(2,4-difluorophenyl)methyl]-3-(1-methylethyl)-5,7-dioxo-6-[-
(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d-
]pyrazine-8-carboxamide (40 mg, 86%). This material was
hydrogenated in a second step as described in example Z-1 to give
(3S,11aR)--N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-(1-methylethyl)-5,7-
-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-c]pyrido[1,2-d]pyrazine-8--
carboxamide (34 mg, 99%) as a white solid. .sup.1H NMR (CDCl.sub.3)
.delta. 10.29 (br, 1H), 8.36 (s, 1H), 7.33 (m, 1H), 6.79 (m, 2H),
5.29 (d, J=6.4 Hz, 1H), 4.61 (m, 2H), 4.44 (d, J=9.6 Hz, 1H), 4.34
(m, 1H), 4.17 (m, 1H), 4.02 (dd, J=8.4, 5.2 Hz, 1H), 3.86 (m, 1H),
2.37 (m, 1H), 0.97 (m, 6H); ES.sup.+ MS: 434 (M+1).
Example Z-22
(5aR,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-5a,6a
7,11,13,14a-hexahydro-5H-indeno[1',2':4,5][1,3]oxazolo[3,2-a]pyrido[1,2-d-
]pyrazine-10-carboxamide
##STR00134##
[0724] The title compound was made in two steps using a similar
process to that described in example Z-1. 16a (42 mg, 0.09 mmol)
and (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (100 mg, 0.67 mmol)
were reacted in 1,2-dichloroethane (5 mL) with acetic acid to give
(5aR,14aS)--N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)-
oxy]-5a,6a,7,11,13,14a-hexahydro-5H-indeno[1',2':4,5][1,3]oxazolo[3,2-a]py-
rido[1,2-d]pyrazine-10-carboxamide (55 mg, 99%). This material was
hydrogenated in a second step as described in example Z-1 to give
(5 aR,14aS)
[(2,4-difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-5a,6a,7,11,1-
3,14a-hexahydro-5H-indeno[1',2':4,5][1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazi-
ne-10-carboxamide (45 mg, 97%) as a white solid. .sup.1H NMR
(CDCl.sub.3) .delta. 10.28 (m, 1H), 8.33 (s, 1H), 7.69 (d, J=7.2
Hz, 1H), 7.34-7.19 (m, 4H), 6.78 (m, 2H), 5.96 (d, J=6.0 Hz, 1H),
5.32 (m, 1H), 5.22 (m, 1H), 4.60 (m, 2H), 4.45 (d, J=9.2 Hz, 1H),
3.96 (apparent t, J=10.8 Hz, 1H), 3.40 (dd, J=18.0, 6.8 Hz, 1H),
3.24 (d, J=17.6 Hz, 1H); ES.sup.+ MS: 480 (M+1).
Example Z-23 & Z-24
(2S,3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3-diphe-
nyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-car-
boxamide &
(2S,3R,11aR)--N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-diox-
o-2,3-diphenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyr-
azine-8-carboxamide
##STR00135##
[0726] The title compounds were made in two steps using a similar
process to that described in example Z-1, 16a (40 mg, 0.09 mmol)
and (1S,2R)-2-amino-1,2-diphenylethanol (50 mg, 0.23 mmol) were
reacted in 1,2-dichloroethane (5 mL) with acetic acid to give
(2S,3R,11aS)--N-[(2,4-difluorophenyl)methyl]-5,7-dioxo-2,3-diphenyl-6-[(p-
henylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]p-
yrazine-8-carboxamide (34 mg, 63%) and
(2S,3R,11aS)--N-[(2,4-difluorophenyl)methyl]-5,7-dioxo-2,3-diphenyl-6-[(p-
henylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[8,2-a]pyrido[1,2-d]p-
yrazine-8-carboxamide (13 mg, 24%). These materials were
hydrogenated in a second step as described in example Z-1 to give
(2S,3R,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3-diph-
enyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-ca-
rboxamide (example Z-23, 29 mg, 99%) as a white solid and
(2S,3R,11aR)--N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3-diph-
enyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-ca-
rboxamide (example Z-24, 10 mg, 89%) as a white solid respectively.
For example Z-23: .sup.1H NMR (DMSO-d.sub.6) .delta. 10.29 (t,
J=5.6 Hz, 1H), 8.55 (s, 1H), 7.38 (m, 1H), 7.22 (m, 1H), 7.11-6.95
(m, 11H), 6.16 (dd, J=10.4, 3.6 Hz, 1H), 5.71 (m, 2H), 4.90 (m,
1H), 4.54 (m, 2H), 4.38 (t, J=11.2 Hz, 1H); ES.sup.+ MS: 544 (M+1).
For example Z-24: .sup.1H NMR (CDCl.sub.3) .delta. 11.64 (br, 1H),
10.30 (s, 1H), 8.45 (s, 1H), 7.34 (m, 1H), 7.01-6.90 (m, 10H), 6.80
(m, 2H), 5.56 (m, 2H), 5.42 (d, J=6.4 Hz, 1H), 4.73 (m, 1H), 4.63
(m, 2H), 4.49 (m, 1H); ES.sup.+ MS: 544 (M+1).
Example Z-25
(3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1-methylethyl)-5,7--
dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-c-
arboxamide
##STR00136##
[0728] The title compound was made in two steps using a similar
process to that described in example Z-1, 16a (40 mg, 0.09 mmol)
and (2R)-2-amino-3-methyl-1-butanol (0.1 mL) were reacted in
1,2-dichloroethane (8 mL) with acetic acid to give
(3R,11aS)--N-[(2,4-difluorophenyl)methyl]-3-(1-methylethyl)-5,7-dioxo-6-[-
(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d-
]pyrazine 8-carboxamide (41 mg, 92%). This material was
hydrogenated in a second step as described in example Z-1 to give
(3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1-methylethyl)-5,7-
-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8--
carboxamide (32 mg, 94%) as a white solid. .sup.1H NMR (CDCl.sub.3)
.delta. 11.42 (br, 1H), 10.27 (br, 1H), 8.34 (s, 1H), 7.31 (m, 1H),
6.78 (m, 2H), 5.28 (d, J=6.0 Hz, 1H), 4.60 (m, 2H), 4.42 (m, 1H),
4.33 (m, 1H), 4.16 (m, 1H), 4.01 (dd, J=8.8, 5.2 Hz, 1H), 3.85 (m,
1H), 2.37 (m, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.95 (d, J=6.4 Hz, 3H);
ES.sup.+ MS: 434 (M+1).
Example Z-26
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[2-(methylthio)ethyl-
]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazi-
ne-8-carboxamide
##STR00137##
[0730] The title compound was made in two steps using a similar
process to that described in example Z-1. 16a (43 mg, 0.09 mmol)
and (2S)-2-amino-4-(methylthio)-1-butanol (0.1 mL) were reacted in
1,2-dichloroethane (5 mL) with acetic acid to give
(3S,11aR)--N-[(2,4-difluorophenyl)methyl]-3-[2-(methylthio)ethyl]-5,7-dio-
xo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido-
[1,2-d]pyrazine-8-carboxamide (41 mg, 81%). This material (20 mg,
0.04 mmol) was treated with trifluoroacetic acid (1 mL) in
dichloromethane (3 mL) at 0.degree. C. to rt over 6 h. The mixture
was concentrated in vacuo and subjected to reverse phase
preparative HPLC purification to provide
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[2-(methylthio)ethy-
l]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-a]pyraz-
ine-8-carboxamide (12 mg, 72%) as a white solid. .sup.1H NMR
(CDCl.sub.3) .delta. 11.35 (br, 1H), 10.25 (s, 1H), 8.34 (s, 1H),
7.33 (m, 1H), 6.79 (m, 2H), 5.32 (m, 1H), 4.62-4.53 (m, 3H),
4.43-4.39 (m, 2H), 3.91-3.87 (m, 2H), 2.63-2.53 (m, 2H), 2.39 (m,
1H), 2.12 (s, 3H), 1.89 (m, 1H); ES.sup.+ MS: 466 (M+1).
Example Z-27
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[2-(methylsulfonyl)e-
thyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]py-
razine-8-carboxamide
##STR00138##
[0732] To a solution of
(3S,11aR)--N-[(2,4-difluorophenyl)methyl]-3-[1,2-(methylthio)ethyl]-5,7-d-
ioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyri-
do[1,2-d]pyrazine-8-carboxamide (20 mg, 0.04 mmol) in
dichloromethane (5 mL) at 0.degree. C. was added m-CPBA (20 mg,
70%, 0.082 mmol). The resultant solution was allowed to warm as the
bath warmed and stirred a total of 3 h. The reaction was quenched
by the addition of Na.sub.2S.sub.2O.sub.3 (aq) and sodium
bicarbonate. The layers were separated and the organic layer washed
with brine. The aqueous layer was extracted with dichloromethane
and the combined organics dried over Na.sub.2SO.sub.4. Filtration
and concentration provided
(3S,11aR)--N-[(2,4-difluorophenyl)methyl]-3-[2-(methylsulfonyl)ethyl]-5,7-
-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]py-
rido[1,2-d]pyrazine-8-carboxamide (26 mg, 99%) as a white solid.
This material was hydrogenated in a second step as described in
example Z-1 to give
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[2-(methylsulf-
onyl)ethyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,-
2-d]pyrazine-8-carboxamide (22 mg, 99%) as a white solid. .sup.1H
NMR (CDCl.sub.3) .delta. 11.00 (br, 1H), 10.16 (s, 1H), 8.83 (s,
1H), 7.36 (m, 1H), 6.81 (m, 2H), 5.42 (m, 1H), 4.62 (m, 3H), 4.41
(m, 2H), 3.93 (m, 2H), 3.31 (m, 2H), 2.98 (s, 3H), 2.40 (m, 1H),
2.28 (m, 1H); ES.sup.+ MS: 498 (M+1).
Example Z-28
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-hydroxy-3-(1H-indol-3-ylmethyl)--
5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[8,2-a]pyrido[1,2-d]pyrazine-
-8-carboxamide
##STR00139##
[0734] The title compound was made in two steps using a similar
process to that described in example Z-1. 16a (4.3 mg, 0.09 mmol)
and (2S)-2-amino-3-(1H-indol-3-yl)-1-propanol (100 mg, 0.52 mmol)
were reacted in 1,2-dichloroethane (5 mL) with acetic acid to give
(3S,11aR)--N-[(2,4-difluorophenyl)methyl]-3-(1H-indol-3-ylmethyl)-5,7-dio-
xo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido-
[1,2-d]pyrazine-8-carboxamide (36 mg, 64%). This material was
hydrogenated in a second step as described in example Z-1 to give
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1H-indol-3-ylmethy-
l)-5,7-dioxo-2,3,5, 7,
11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
(29 mg, 95%) as a white solid. .sup.1H NMR (CDCl.sub.3/CD.sub.3OD)
.delta. 10.34 (m, 1H), 8.98 (br, 1H), 8.24 (s, 1H), 7.58 (d, J=8.0
Hz, 1H), 7.32 (m, 2H), 7.15-7.01 (m, 3H), 6.78 (m, 2H), 4.94 (d,
J=6.8 Hz, 1H), 4.71 (d, J=5.6 Hz, 1H), 4.59 (m, 2H), 4.35 (d,
J=10.4 Hz, 1H), 4.22 (m, 1H), 3.99 (m, 1H), 3.81 (m, 1H), 3.40 (dd,
J=13.6, 11.6 Hz, 1H), 3.18 (dd, J=14.0, 8.4. Hz, 0.1H); ES.sup.+
MS: 521 (M+1).
Example Z-29
(4R,12aR)--N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl-
)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]py-
rimidine-9-carboxamide
##STR00140##
[0736] a) (2R)-2-({[(1,1-Dimethylethyl)oxy]carbonyl}amino)propyl
methanesulfonate. To a stirred solution of
1,1-dimethylethyl[(1R)-2-hydroxy-1-methylethyl]carbamate (5.00 g,
28.5 mmol) and triethylamine (5.92 mL, 42.9 mmol) in
CH.sub.2Cl.sub.2 (30 mL) cooled to 0.degree. C. and under a
nitrogen atmosphere was added dropwise a solution of
methanesulfonyl chloride (2.43 mL, 31.5 mmol) in CH.sub.2Cl.sub.2
(25 mL), Stirring was continued for 20 minutes at 0.degree. C.,
after which time the reaction was judged complete by TLC analysis
(1:1-hexanes/EtOAc). The solution was poured into water and the
layers were separated. The organic phase was washed with 0.1 N HCl
and then with 5% NaHCO.sub.3, dried over Na.sub.2SO.sub.4, filtered
and concentrated to give
(2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl
methanesulfonate (7.08 g, 98%) as a white solid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 1.23 (d, J=6.8 Hz, 3H), 1.44 (s, 9H), 3.03
(s, 3H), 3.97 (m, 1H), 4.15 (dd, J=4.2, 9.8 Hz, 1H), 4.21 (m, 1H),
4.61 (br s, 1H).
[0737] b) 1,1-Dimethylethyl[(1R)-2-cyano-1-methylethyl]carbamate.
To a stirred solution of
(2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl
methanesulfonate (7.08 g, 27.9 mmol) in DMSO (50 mL) was added NaCN
(3.78 g, 84.0 mmol). The solution was stirred at 70.degree. C. for
2 hours, over which time the formation of a precipitate was
observed, After cooling at room temperature, water was added and
the mixture was extracted with Et.sub.2O. The ethereal layers were
washed with a brine solution, dried over Na.sub.2SO.sub.4, filtered
and concentrated to give
1,1-dimethylethyl[(1R)-2-cyano-1-methylethyl]carbamate (3.81 g,
73%) as a pale yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 1.30 (d, J=6.8 Hz, 314), 1.42 (s, 9H), 2.51 (dd, J=3.8,
16.6 Hz, 1H), 2.73 (m, 1H), 3.93 (m, 1H), 4.63 (br s, 1H).
[0738] c) 1,1-Dimethylethyl[(1R)-3-amino-1-methylpropyl]carbamate.
A solution of
1,1-dimethylethyl[(1R)-2-cyano-1-methylethyl]carbamate (1.30 g, 7.1
mmol) in ethanol saturated with anhydrous ammonia was treated with
Raney-Ni (1.5 mL of 50% aq. Suspension) and 55 psi of H.sub.2
overnight. The mixture was filtered through Celite and the filtrate
was concentrated in vacuo. The residue was purified by flash
chromatography (80:19:1 CH.sub.2CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH
(37%) gradient elution) through a short plug of silica gel to give
1,1-dimethylethyl[(1R)-3-amino-1-methylpropyl]carbamate (1.37 g,
100%) as a clear oil that solidified. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.14 (d, J=6.8 Hz, 3H), 1.4.3-1.62 (m, 13H),
2.76 (m, 2H), 3.77 (m, 1H), 4.57 (m, 1H).
[0739] d)
1,1-Dimethylethyl{(1R)-1-methyl-3-[(2-methylpropyl)amino]propyl}-
carbamate. 1,1-dimethylethyl[(1R)-3-amino-1-methylpropyl]carbamate
(0.320 g, 1.70 mmol), isobutyraldehyde (150 .mu.L, 1.62 mmol), and
sodium triacetoxyborohydride (0.512 g, 2.42 mmol) were stirred in
anhydrous dichloroethane (10 mL) at ambient temperature overnight.
The reaction was quenched by the addition of saturated NaHCO.sub.3
and then extracted with dichloromethane. The combined extracts were
washed with water, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by flash chromatography
(80:19:1 CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (37%) gradient elution)
through a short plug of silica gel to afford
1,1-dimethylethyl{(1R)-1-methyl-3-[(2-methylpropyl)amino]propyl}carbamate
(0.158 g, 40%) as a clear oil. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 0.90 (d, J=6.4 Hz, 6H), 1.13 (d, J=6.4 Hz, 3H), 1.42-1.51
(m, 1H), 1.67-1.75 (m, 2H), 2.33-2.42 (m, 2H), 2.58-2.72 (m, 2H),
3.72 (m, 1H), 5.20 (m, 1H).
[0740] e) [(3R)-3-Aminobutyl]-(2-methylpropyl)amine. An ice cold
solution of
1,1-dimethylethyl{(1R)-1-methyl-3-[(2-methylpropyl)amino]propyl}carbam-
ate (0.158 g, 0.65 mmol) in THF (8 mL) was treated with 4 N HCl
(aq) (2 mL) and then stirred at room temperature for 2 h. The
mixture was concentrated in vacuo to give
[(3R)-3-aminobutyl](2-methylpropyl)amine dihydrochloride. The HCl
salt was then dissolved in dichloromethane and a minimal amount of
methanol and treated with solid supported carbonate resin
(MP-Carbonate, Argonaut Technologies). After 30 minutes, the
solution was filtered through a fritted tube and the solvents
removed carefully in vacuo to give
[(3R)-3-aminobutyl](2-methylpropyl)amine (65 mg). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 0.88 (d, J=6.0 Hz, 6H), 1.06 (d, J=5.6 Hz,
3H), 1.23-1.53 (m, 5H), 1.71-1.74 (m, 1H), 2.39 (m, 2H), 2.65 (m,
2H), 2.97 (m, 1H).
[0741] f)
(4R,12aR)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-me-
thylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazin-
o[1,2-a]pyrimidine-9-carboxamide. The title compound was made in
two steps using a similar process to that described in example Z-2,
16 (40 mg, 0.09 mmol) and [(3R)-3-aminobutyl](2-methylpropyl)amine
(65 mg, 0.45 mmol) were reacted in dichloromethane (2 mL) with
acetic acid to give
(4R,12aR)--N-[(4-fluorophenyl)methyl]-4-methyl-1-(2-methylpropyl)-6,8-dio-
xo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyra-
zino[1,2-a]pyrimidine-9-carboxamide (29 mg, 60%). This material was
hydrogenated in a second step as described in example Z-2 to give
(4R,12aR)--N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropy-
l)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]p-
yrimidine-9-carboxamide (18 mg, 76%) as a tan solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 0.77 (d, J=6.4 Hz, 3H), 0.84 (d,
J=6.4 Hz, 3H), 1.32 (d, J=7.2 Hz), 1.45-1.49 (m, 1H), 1.57-1.67 (m,
1H), 2.03-2.12 (m, 2H), 2.21-2.27 (m, 1H), 2.73-2.79 (m, 1H),
2.87-2.92 (m, 1H), 4.16-4.24 (m, 2H), 4.45 (s, 1H), 4.54-4.64 (m,
2H), 4.96-4.99 (m, 1H), 6.96-7.00 (m, 2H), 7.29-7.32 (m, 2H), 8.27
(s, 1H), 10.46 (s, 1H), 12.56 (s, 1H); ES.sup.+ MS: 456 (M+1).
Example Z-30
(4R,12aR)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-
-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyr-
imidine-9-carboxamide
##STR00141##
[0743] a) [(3R)-3-Aminobutyl](1-methylethyl)amine. The free diamine
was prepared in a similar manner as described in example Z-29.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.04 (d, J=6.4 Hz, 6H),
1.06 (d, J=6.4 Hz, 3H), 1.41-1.58 (m, 5H), 2.62-2.66 (m, 2H),
2.74-2.80 (m, 1H), 2.92-3.00 (m, 1H).
[0744] b)
(4R,12aR)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-me-
thylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino-
[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two
steps using a similar process to that described in example Z-2. 16
(40 mg, 0.088 mmol) and [(3R)-3-aminobutyl](1-methylethyl)amine (78
mg, 0.60 mmol) were reacted in dichloromethane (2 with acetic acid
to give
(4R,12aR)--N-[(4-fluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-diox-
o-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyraz-
ino[1,2-a]pyrimidine-9-carboxamide (26 mg, 56%). This material was
hydrogenated in a second step as described in example Z-2 to give
(4R,12aR)--N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl-
)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]py-
rimidine-9-carboxamide (21 mg, 90%) as an off-white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 1.01 (d, J=5.6 Hz, 3H), 1.06 (d,
J=6.0 Hz, 3H), 1.31 (d, J=6.8 Hz, 3H), 1.57 (m, 1H), 1.98 (m, 1H),
2.70-2.82 (m, 2H), 3.16 (m, 1H), 4.15-4.19 (m, 1H), 430 (m, 1H),
4.48 (s, 1H), 4.54-4.59 (m, 2H), 0.97 (m, 1H), 6.98 (m, 2H),
7.29-7.32 (m, 2H), 8.27 (s, 1H), 10.49 (s, 1H), 12.52 (s, 1H).
Example Z-31
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpr-
opyl)-6,8-dioxo-1,2,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]-
pyrimidine-9-carboxamide
##STR00142##
[0746] a) 1,1-Dimethylethyl[(1S)-2-cyano-1-methylethyl]carbamate.
The nitrile was prepared in two steps using a modified procedure as
described in example Z-29. To a stirred solution of
(2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl
methanesulfonate (8.40 g, 33.2 mmol) in DMSO (50 mL) and KCN (6.51
g, 100.0 mmol) cooled to 0.degree. C. was added 18-crown-6 (9.05 g,
34.3 mmol). The solution was allowed to warm to room temperature
and then heated to 70.degree. C. for 1 hour. After cooling at room
temperature, water was added and the mixture was extracted with
Et.sub.2O. The ethereal layers were washed with a brine solution,
dried over Na.sub.2SO.sub.4, filtered and concentrated to give
1,1-dimethylethyl[(1S)-2-cyano-1-methylethyl]carbamate (5.37 g,
88%) as a pale yellow solid. .sup.1H NMR (400 MHz, cDCl.sub.3)
.delta. 1.32 (d, J=6.8 Hz, 3H), 1.44 (s, 9H), 2.52 (dd, J=4.0, 16.4
Hz, 1H), 2.74 (m, 1H), 3.95 (m, 1H), 4.65 (br s, 1H)
[0747] b) [(3S)-3-Aminobutyl](2-methylpropyl)amine dihydrochloride
was prepared in a similar manner as described in example Z-29.
.sup.1H NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta. 0.99 (m,
61-1), 1.34 (m, 3H), 2.13-2.27 (m, 3H), 2.76 (m, 2H), 3.07 (m, 2H),
3.47 (m, 1H), 8.22 (m, 1H), 8.83 (m, <1H).
[0748] c)
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(-
2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyr-
azino[1,2-a]pyrimidine-9-carboxamide. The title compound was made
in two steps using a similar process to that described in example
Z-2. 16a (80 mg, 0.17 mmol) and free based
[(3S)-3-aminobutyl](2-methylpropyl)amine (107 mg, 0.74 mmol) were
reacted in dichloromethane (2 with acetic acid to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(2-methylpro-
pyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1'-
,2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (76 mg, 76%) as a
film. This material was hydrogenated in a second step as described
in example Z-2 to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylp-
ropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-
-a]pyrimidine-9-carboxamide (39 mg, 80%) as an off-white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.76 (d, J=6.4 Hz, 3H),
0.84 (d, J=6.4 Hz, 3H), 1.32 (d, J=7.2 Hz, 3H), 1.45-1.50 (m, 1H),
1.60-1.69 (m, 1H), 2.03-2.12 (m, 2H), 2.21-2.27 (m, 1H), 2.73-2.79
(m, 1H), 2.87-2.93 (m, 1H), 4.16-4.25 (m, 2H), 4.45 (s, 1H),
4.57-4.68 (m, 2H), 4.96-5.01 (m, 1H), 6.75-6.82 (m, 2H), 7.32-7.38
(m, 1H), 8.26 (s, 1H), 10.45 (s, 1H), 12.56 (s, 1H); ES.sup.+ MS:
475 (M+1).
Example Z-32
(4S,12aS)-1-(Cyclopropylmethyl)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-
-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,-
2-a]pyrimidine-9-carboxamide
##STR00143##
[0750] a)
1,1-Dimethylethyl{(1S)-3-[(cyclopropylmethyl)amino]-1-methylprop-
yl}carbamate. The protected diamine was prepared using a modified
procedure as described in example Z-29.
1,1-dimethylethyl[(1S)-3-amino-1-methylpropyl]carbamate (0.293 g,
1.56 mmol), cyclopropane carboxaldehyde (96 .mu.L, 1.30 mmol), and
sodium triacetoxyborohydride (0.439 g, 2.07 mmol) were stirred in a
1:1 mixture of anhydrous dichloroethane and tetrahydrofuran (10 mL)
at ambient temperature overnight. The reaction was quenched by the
addition of saturated NaHCO.sub.3 and then extracted with EtOAc.
The combined extracts were washed with saturated NaHCO.sub.3, then
a solution of brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by flash chromatography
(80:19:1 CH.sub.2Cl.sub.2MeOH/NH.sub.4OH (37%) gradient elution)
through a short plug of silica gel to afford
1,1-dimethylethyl{(1S)-3-[(cyclopropylmethyl)amino]-1-methylpropyl}carbam-
ate (76 mg, 26%) as a clear oil. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 0.09-0.13 (m, 2H), 0.44-0.49 (m, 2H), 0.92-0.95 (m, 1H),
1.14 (d, J==6.4 Hz, 3H), 1.43-1.70 (m, 12H), 2.38-2.50 (m, 2H),
2.62-2.73 (m, 2H), 3.74 (m, 1H), 4.88 (m, 1H).
[0751] b) [(3S)-3-Aminobutyl](cyclopropylmethyl)amine
dihydrochloride was prepared in a similar manner as described in
example Z-29. .sup.1H NMR (4.00 MHz, CDCl.sub.3/CD.sub.3OD) .delta.
0.40 (m, 2H), 0.64 (m, 2H), 1.15 (m, 1H), 1.34 (m, 3H), 2.12-2.25
(m, 2H), 2.82 (m, 2H), 3.08 (m, 2H) 3.47 (m, 1H), 8.25 (br,
<1H), 9.04 (br, <1H).
[0752] c)
(4S,12aS)-1-(Cyclopropylmethyl)-N-[(2,4-difluorophenyl)methyl]-7-
-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]p-
yrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made
in two steps using a similar process to that described in example
Z-2. 16a (50 mg, 0.106 mmol) and free based
[(3S)-3-aminobutyl](cyclopropylmethyl)amine (44 mg, 0.31 mmol) were
reacted in dichloromethane (2 mL) with acetic acid to give
(4S,12aS)-1-(cyclopropylmethyl)-N-[(2,4-difluorophenyl)methyl]-4-methyl-6-
,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,-
5]pyrazino[1,2-a]pyrimidine-9-carboxamide (50 mg, 83%) as a film.
This material was hydrogenated in a second step as described in
example Z-2 to give
(4S,12aS)-1-(cyclopropylmethyl)-N-[(2,4-difluorophenyl)methyl]-7-hyd-
roxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyraz-
ino[1,2-a]pyrimidine-9-carboxamide (23 mg, 56%) as an off-white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.11 (m, 2H),
0.56-0.59 (m, 2H), 0.77 (m, 1H), 1.34 (d, J=7.2 Hz, 3H), 1.46-1.50
(m, 1H) 2.04-2.13 (m, 1H), 2.30-2.34 (m, 1H), 2.46-2.51 (m, 1H),
2.90-2.96 (m, 1H), 3.16-3.19 (m, 1H), 4.21-4.30 (m, 2H), 4.51 (s,
1H), 4.58-4.67 (m, 2H), 5.00-5.05 (m, 1H), 6.76-6.82 (m, 2H),
7.31-7.37 (m, 1H), 8.28 (s, 1H), 10.46 (s, 1H), 12.55 (br, 1H);
ES.sup.+ MS: 473 (M+1).
Example Z-33
(4S,12aR)--N-[(2,4-Difluorophenyl)methyl]-1-(2-furanylmethyl)-7-hydroxy-4--
methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-
-a]pyrimidine-9-carboxamide
##STR00144##
[0754] a) [(3S)-3-Aminobutyl](2-furanylmethyl)amine dihydrochloride
was prepared in a similar manner as described in example Z-32.
.sup.1H NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta. 1.27 (d, J=6.4
Hz, 3H), 1.96-2.05 (m, 1H), 2.14-2.19 (m, 1H), 3.00-3.04 (m, 2H),
3.38-3.39 (m, 1H), 4.11-4.18 (m, 2H), 6.34 (m, 1H), 6.59 (m, 1H),
7.40 (m, 1H), 8.18 (br, <1H), 9.41 (br, <1H).
[0755] b)
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-1-(2-furanylmethyl)-7--
hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]py-
razino[1,2-a]pyrimidine-9-carboxamide. The title compound was made
in two steps using a similar process to that described in example
Z-2. 16a (36 mg, 0.076 mmol) and free based
[(3S)-3-aminobutyl](2-furanylmethyl)amine (70 mg, 0.42 mmol) were
reacted in dichloromethane (2 mL) with acetic acid to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-1-(2-furanylmethyl)-4-methyl-6,-
8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5-
]pyrazino[1,2-a]pyrimidine-9-carboxamide (32 mg, 70%) as a film.
This material was hydrogenated in a second step as described in
example Z-2 to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-1-(2-furanylmethyl)-7-hydr-
oxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazi-
no[1,2-a]pyrimidine-9-carboxamide (20 mg, 76%), as an off-white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.24 (d, J=6.8 Hz,
3H), 1.45-1.49 (m, 1H), 2.04-2.13 (m, 1H), 2.77-2.82 (m, 1H),
2.94-3.01 (m, 1H), 3.65 (d, J=15.6 Hz, 1H), 3.89 (d, J=16.0 Hz,
1H), 4.27-4.31 (m, 1H), 4.39-4.41 (m, 1H), 4.49-4.53 (m, 1H),
4.58-4.66 (m, 1H), 4.98-5.03 (m, 1H), 6.24 (m, 1H), 6.36 (m, 1H),
6.75-6.82 (m, 2H), 7.31-7.39 (m, 1H), 7.40 (m, 1H), 8.26 (s, 1H),
10.47 (m, 1H), 12.50 (br, 114); ES.sup.+ MS: 499 (M+1).
Example Z-34
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(-
1,3-thiazol-2-ylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyraz-
ino[1,2-a]pyrimidine-9-carboxamide
##STR00145##
[0757] a) [(3S)-3-Aminobutyl](1,3-thiazol-2-ylmethyl)amine
dihydrochloride was prepared in a similar manner as described in
example Z-32. .sup.1H NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta.
1.28 (d, J=6.4 Hz, 3H), 2.05 (m, 1H), 2.17 (m, 1H), 3.20 (m, 2H),
3.39 (m, 1H), 4.51-4.58 (m, 2H), 7.52 (d, 1H), 7.82 (d, 1H).
[0758] b)
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-
-dioxo-1-(1,3-thiazol-2-ylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2'-
:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound
was made in two steps using a similar process to that described in
example Z-2. 16a (35 mg, 0.074 mmol) and free based
[(3S)-3-aminobutyl](1,3-thiazol-2-ylmethyl)amine were reacted in
dichloromethane (2 mL) with acetic acid to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylme-
thyl)oxy]-1-(1,3-thiazol-2-ylmethyl)-1,2,8,4,6,8,12,12a-octahydropyrido[1'-
,2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (36 mg, 80%) as a
film. This material was debenzylated in a second step to in a
manner similar to Z-26 to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1--
(1,3-thiazol-2-ylmethyl)
1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9--
carboxamide (18 mg, 60%) as an off-white solid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 1.30 (d, J=7.2 Hz, 3H), 1.49-1.53 (m, 1H),
2.12-2.18 (m, 1H), 2.93-2.96 (an, 1H), 3.07-3.13 (m, 1H), 3.99-4.03
(m, 1H), 4.13-4.17 (m, 1H), 4.24-4.27 (m, 1H), 4.57-4.61 (m, 3H),
5.03-5.06 (m, 1H), 6.75-6.82 (m, 2H), 7.26 (m, 1H), 7.31-7.37 (m,
2H), 7.76 (m, 1H), 7.94 (m, 1H), 10.40 (m, 1H), 12.48 (m, 1H);
ES.sup.+ MS: 516 (M+1).
Example Z-35
racemic-(4aR,6aR,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-di-
oxo-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]pyrazino[1,2-a-
][3,1]benzoxazine-10-carboxamide
##STR00146##
[0760] a)
racemic-(4aR,6aR,14aS)--N-[(2,4-Difluorophenyl)methyl]-11,13-dio-
xo-12-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1'-
,2':4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide.
racemic-cis-2-Hydroxymethyl-1-cyclohexylamine hydrochloride (24 mg,
0.186 mmol) was dissolved in a dichloromethane solution containing
a small amount of methanol (to dissolve) and excess MP-Carbonate
(Argonaut Technologies) was added, the mixture was stirred for 30
minutes, and the MP-Carbonate was removed by filtration. The free
amine solution was transferred to a microwave vessel containing 16a
(29 mg, 0.0617 mmol), One drop of glacial acetic acid was added and
the solution was heated for 10 minutes at 140.degree. C. The
resultant solution was absorbed on celite and the material was
purified by silica gel chromatography (0-12%
methanol/dichloromethane gradient elution) to yield the desired
product as a white solid (18 mg, 53%). .sup.1H NMR (CDCl.sub.3)
.delta. 10.40 (m, 1H), 8.35 (s, 1H), 7.60 (m, 2H), 7.34-7.26 (m,
4H), 6.80 (m, 2H), 5.35-5.23 (m, 2H), 5.13 (m, 1H), 4.77 (m, 1H),
4.70 (m, 2H), 4.22 (dd, J=13.2, 3.2 Hz, 1H), 4.07 (dd, J=13.2, 6.4,
1H), 3.96 (m, 1H), 3.76 (dd, J=11.2, 4.4, 1H), 2.22 (m, 1H), 1.84
(m, 1H), 1.74-1.40 (m, 6H), 1.17 (m, 1H); ES.sup.+ MS: 550
(M+1).
[0761] b)
racemic-(4a,6aR,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-
-11,13-dioxo-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]pyraz-
ino[3,1]benzoxazine-10-carboxamide
racemic-(4aR,6aR,14aS)--N-[(2,4-Difluorophenyl)methyl]-11,13-dioxo-12-[(p-
henylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]p-
yrazino[1,2-a][3,1]benzoxazine-10-carboxamide (13 mg, 0.0236 mmol)
was dissolved in tetrahydrofuran and 10 w.t. % Pd/C (13 mg) was
added. Hydrogen was passed through the solution several times and
the mixture was stirred at 1 atm hydrogen for 18 hours until the
reaction was determined complete by TLC (5%
methanol/dichloromethane). The mixture was filtered through Celiac,
eluting with methanol/chloroform and the filtrate was concentrated
under reduced pressure and purified by HPLC to yield the title
compound (7.3 mg, 73%) .sup.1H NMR (CDCl.sub.3) .delta. 12.45 (m,
1H), 10.38 (s, 1H), 8.30 (s, 1H), 7.32 (m, 1H), 6.83-6.76 (m, 2H),
5.23 (m, 1H), 4.75 (m, 1H), 4.63 (m, 2H), 4.26 (m, 1H), 4.12-4.01
(m, 2H), 3.83 (m, 1H), 2.30 (m, 1H), 1.91 (m, 1H), 1.80 (m, 1H),
1.67-1.40 (m, 5H), 1.20 (m, 1H); ES.sup.+ MS: 460 (M+1).
Example Z-36
Racemic-(4aR,6aR,14aS)--N-[(4-Fluorophenyl)methyl]-12-hydroxy-11,13-dioxo--
1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]pyrazino[1,2-a][3,-
1]benzoxazine-10-carboxamide
##STR00147##
[0763] a)
racemic-(4aR,6aR,14aS)--N-[(4-Fluorophenyl)methyl]-11,13-dioxo-1-
2-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':-
4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide. In a manner
similar to that described in example Z-35, from
racemic-cis-2-Hydroxymethyl-1-cyclohexylamine hydrochloride (50 mg,
0.303 mmol) and 16 (45 mg, 0.0995 mmol) was prepared
racemic-(4aR,6aR,14aS)--N-[(4-fluorophenyl)methyl]-11,13-dioxo-12-[(pheny-
lmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]pyraz-
ino[1,2-a][3,1]benzoxazine-10-carboxamide (4.8 mg, 91%) as a white
solid. .sup.3H NMR (CDCl.sub.3) .delta. 10.42 (m, 1H), 8.37 (s,
1H), 7.59 (m, 2H), 7.88-7.24 (m, 5H), 6.98 (m, 2H), 5.26-5.18 (m,
2H), 5.07 (m, 1H), 4.74 (m, 1H), 4.62-4.51 (m, 2H), 4.20 (dd,
J=18.6, 4 Hz, 1H), 4.04 (m, 1H), 3.91 (m, 1H), 3.71 (dd, J=11.3,
4.8 Hz, 1H), 2.18 (m, 1H), 1.82 (m, 1H), 1.73-1.63 (m, 2H),
1.62-1.56 (m, 2H), 1.48 (1H), 1.38 (m, 1H), 1.14 (m, 1H); MS: 532
(M+1).
[0764] b)
racemic-(4aR,6aR,14aS)--N-[(4-Fluorophenyl)methyl]-12-hydroxy-11-
,13-dioxo-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]pyrazino-
[1,2-a][3,1]benzoxazine-10-carboxamide. In a manner similar to that
described in example Z-37, from
racemic-(4aR,6aR,14aS)--N-[(4-fluorophenyl)methyl]-11,13-dioxo-12-[(pheny-
lmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]pyraz-
ino[1,2-a][3,1]benzoxazine-10-carboxamide (37 mg, 0.0696 mmol) and
10 w.t. % Pd/C (3 mg) was prepared the title compound (18 mg, 58%)
as a white solid after purification by HPLC. .sup.1H NMR
(CDCl.sub.3) .delta. 12.47 (s, 1H), 10.39 (m, 1H), 8.32 (s, 1H),
7.30 (m, 2H), 6.98 (m, 2H), 5.22 (m, 1H), 4.74 (m, 1H), 4.58 (m,
2H), 4.28 (dd, J=13.2, 4 Hz, 1H), 4.12-3.98 (m, 2H), 3.81 (dd,
J=11.6, 4.8 Hz, 1H), 2.29 (m, 1H), 1.91-1.19 (m, 8H); ES.sup.+ MS:
442 (M+1).
Example Z-37
racemic-(3S,4aR,6aR,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-
-dioxo-3-phenyl-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]py-
razino[1,2-a]-[3,1]benzoxazine-10-carboxamide
##STR00148##
[0766] a)
racemic-(3S,4aR,6aR,14aS)--N-[(2,4-Difluorophenyl)methyl]-11,13--
dioxo-3-phenyl-12-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro--
2H-pyrido[1',2':4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide.
In a manner similar to that described in example Z-35, from
racemic-[(1R,2S,5S)-2-amino-5-phenylcyclohexyl]methanol
hydrochloride (32 mg, 0.160 mmol) and 16a (30 mg, 0.064 mmol) was
prepared
racemic-(3S,4aR,6aR,14aS)--N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-3-p-
henyl-12-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido-
[1',2':4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide (35 mg,
88%) as a white solid. .sup.1H NMR (CDCl.sub.3) .delta. 10.41 (m,
1H), 8.38 (s, 1H), 7.66 (m, 2H), 7.40-7.26 (m, 6H), 6.81 (m, 3H),
5.32-5.25 (m, 2H), 5.17 (m, 1H), 4.89 (m, 1H), 4.66-4.62 (m, 2H),
4.26 (dd, J=13.6, 4 Hz, 1H), 4.13-4.04 (m, 2H), 3.85 (dd, J=11.2,
4.4 Hz, 1H), 2.56 (m, 1H), 2.37 (m, 1H), 2.03-1.64 (m, 6H);
ES.sup.+ MS: 626 (M+1).
[0767] b)
racemic-(3S,4aR,6aR,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hyd-
roxy-11,13-dioxo-3-phenyl-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1'-
,2':4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide
racemic-(3S,4aR,6aR,14aS)--N-[(2,4-Difluorophenyl)methyl]-11,13-dioxo-3-p-
henyl-12-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido-
[1',2':4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide (27 mg,
0.0432 mmol) was suspended in methanol, 10 w.t. % Pd/C (3 mg) was
added and hydrogen was bubbled through the system several times
until the reaction was determined complete by TLC (5%
methanol/dichloromethane). The suspension was filtered through
Celite eluting with methanol/chloroform and the filtrate was
concentrated under reduced pressure and purified by HPLC to give
the title compound (13 mg, 57%) as a white solid. .sup.1H NMR
(CDCl.sub.3) .delta. 12.40 (br s, 1H), 10.37 (m, 1H), 8.32 (s, 1H),
7.37-7.28 (m, 3H), 7.24-7.15 (m, 4H), 6.79 (m, 2H), 5.78 (br s,
1H), 4.85 (m, 1H), 4.62 (m, 2H), 4.29 (m, 1H), 4.16-4.09 (m, 2H),
3.92 (dd, J=11.6, 4.8 Hz, 1H), 2.58 (m, 1H), 2.46 (m, 1H),
2.07-1.64 (m, 7H); ES.sup.+ MS: 536 (M+1).
Example Z-38
Sodium
racemic-(4aS,6aS,14aS)-10-({[(2,4-difluorophenyl)methyl]amino}carbo-
nyl)-6-(2-methylpropyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahy-
dropyrido[1',2':4,5]pyrazino[1,2-a]quinazolin-12-olate
##STR00149##
[0769] a)
racemic-1,1-Dimethylethyl[(1S,2R)-2-(hydroxymethyl)cyclohexyl]ca-
rbamate. racemic-[(1R,2S,5S)-2-Amino-5-phenylcyclohexyl]methanol
hydrochloride (800 mg, 4.82 mmol) was dissolved in MeOH (40 mL) and
bis(1,1-dimethylethyl) Bicarbonate (1.16 g, 5.30 mmol) and
triethylamine (4 mL, 28.92 mmol) were added and the mixture was
stirred 18 hours at ambient temperature. The solvents were removed
under reduced pressure, ethyl acetate and aqueous saturated sodium
bicarbonate were added and the product was extracted with ethyl
acetate. The combined organics were dried over sodium sulfate and
the solvents were removed under reduced pressure. Purification by
silica gel chromatography (9:1-hexane:ethyl acetate to ethyl
acetate gradient elution) gave 1,1-dimethylethyl
racemic-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]carbamate (934 mg,
85%) as a white solid. .sup.1H NMR (CDCl.sub.3) .delta. 4.87 (m,
1H), 4.03-3.95 (m, 2H), 3.26 (m, 1H), 3.15 (m, 1H), 1.73-1.48 (m,
5H), 1.38 (s, 9H), 1.27-1.15 (m, 3H), 0.887 (m, 1H).
[0770] b)
racemic-1,1-Dimethylethyl[(1S,2R)-2-Formylcyclohexyl]carbamate. To
a solution of dimethylsulfoxide (0.2 mL, 2.88 mmol) in
dichloromethane (3 mL) at -78.degree. C. was added oxalyl chloride
(0.72 mL, 1.44 mmol) dropwise. The mixture was stirred minutes and
racemic-1,1-dimethylethyl[(1S,2R)-2-(hydroxymethyl)cyclohexyl]carbamate
(220 mg, 0.961 mmol) in dichlormethane was added dropwise and
stirred 10 minutes, Triethylamine (0.53 mL, 3.84 mmol) was added
slowly and the reaction was stirred at -78.degree. C. for one hour
and allowed to warm to ambient temperature. Water was added and
product was extracted with dichloromethane. The combined organics
were washed with brine and dried over sodium sulfate. Removal of
solvents under reduced pressure afforded
racemic-1,1-dimethylethyl[(1S,2R)-2-formylcyclohexyl]carbamate (223
mg, quantitative) as a yellow oil, .sup.1H NMR (CDCl.sub.3) .delta.
9.61 (s, 1H), 5.19 (m, 1H), 3.88 (m, 1H), 2.61 (m, 1H), 1.85 (m,
1H), 1.63-1.49 (m, 4H), 1.37-1.16 (m, 12H).
[0771] c)
racemic-1,1-dimethylethyl((1S,2S)-2-{[(2-Methylpropyl)amino]meth-
yl}cyclohexyl)carbamate.
racemic-1,1-Dimethylethyl[(1S,2R)-2-formylcyclohexyl]carbamate (223
mg, 0.982 mmol) was dissolved in dichloroethane and
2-methylpropyl)amine (0.15 mL, 1.47 mmol) and sodium
triacetoxyborohydride (290 mg, 1.37 mmol) were added and the
reaction was stirred at ambient temperature for 18 hours, Aqueous
sodium bicarbonate was added and the product was extracted with
dichloromethane. The combined extracts were dried over sodium
sulfate and the solvents were removed under reduced pressure.
Purification by silica gel chromatography (dichloromethane to 1%
ammonium hydroxide 19% methanol 80% dichloromethane gradient
elution) afforded
racemic-1,1-dimethylethyl((1S,2S)-2-{[(2-methylpropyl)amino]methyl}cycloh-
exyl)carbamate (112 mg, 40%) as a clear colorless oil. .sup.1H NMR
(CDCl.sub.3) .delta. 6.06 (br s, 1H), 3.76 (br s, 1H), 2.63 (m,
1H), 2.43-2.37 (m, 2H), 2.25 (m, 1H), 1.81 (m, 1H), 1.71-1.59 (m,
3H), 1.44-1.32 (m, 14H), 1.27-1.19 (m, 2H), 0.866 (m, 6H).
[0772] d)
racemic-(1S,2S)-2-{[(2-Methylpropyl)amino]methyl}cyclohexanamine
hydrochloride.
[0773] In a manner similar to that describe in example Z-3, step e,
from
racemic-1,1-dimethylethyl((1S,2S)-2-{[(2-methylpropyl)amino]methyl}cycloh-
exyl)carbamate (112 mg, 0.394 mmol) was prepared
(1S,2S)-2-([(2-methylpropyl)amino]methylcyclohexanamine
hydrochloride (180 mg, >100%) as a white solid. .sup.1H NMR
(methanol-d.sub.4/CDCl.sub.3) .delta. 8.68-8.28 (m, 1H), 3.62 (br
s, 1H), 3.26 (m, 1H), 2.83-2.78 (m, 3H), 2.54 (br s, 1H), 2.12 (m,
1H), 1.82-1.66 (m, 3H), 1.53-1.39 (m, 5H), 0.96 (m, 6H), 0.766 (m,
1H).
[0774] e)
racemic-(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-6-(2-meth-
ylpropyl)-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-
-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide.
In a manner similar to that described in Z-35, from
racemic-(1S,2S)-2-{[(2-methylpropyl)amino]methyl}cyclohexanamine
hydrochloride (130 mg, 0.508 mmol) and 16a (55 mg, 0.117 mmol) was
prepared
racemic-(4aS,6aS,14aS)--N-[(2,4-difluorophenyl)methyl]-6-(2-meth-
ylpropyl)-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-
-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide
(44 mg, 62%) with a 12:1 d.r. .sup.1H NMR (CDCl.sub.3) .delta.
10.46 (m, 1H), 8.33 (s, 1H), 7.59 (m, 2H), 7.37-7.24 (m, 4H), 6.79
(m, 2H), 5.30-5.23 (m, 2H), 4.75-4.56 (m, 3H), 4.23-4.09 (m, 3H),
2.69-2.66 (m, 2H), 2.21-1.98 (m, 3H), 1.80 (m, 1H), 1.71-1.33 (m,
6H), 1.26-1.19 (m, 2H), 0.810 (m, 3H), 0.720 (m, 3H); ES.sup.+ MS:
605 (M+1).
[0775] f)
racemic-(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydrox-
y-6-(2-methylpropyl)-11,13-dioxo-1,2,3,4,4a,5,6,
6a,7,11,13,14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10--
carboxamide. In a manner similar to that described in example Z-37,
from
racemic-(4aS,6aS,14aS)--N-[(2,4-difluorophenyl)methyl]-6-(2-methylpropyl)-
-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahy-
dropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (39
mg, 0.064 mmol) and 10 w.t. % Pd/C (7 mg) was prepared
racemic-(4aS,6aS,14aS)--N-[(2,4-difluorophenyl)methyl]-12-hydroxy-6-(2-me-
thylpropyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1'-
,2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (36 mg, >100%)
as a tan solid. .sup.1H NMR (CDCl.sub.3) .delta. 12.60 (br s, 1H),
10.43 (br s, 1H), 8.25 (s, 1H), 7.35 (m, 1H), 6.78 (an, 2H), 4.77
(m, 1H), 4.63 (m, 2H), 4.49 (br s, 1H), 4.30-4.13 (m, 2H),
3.63-3.40 (m, 2H), 2.88-2.71 (m, 2H), 2.32-2.21 (m, 2H), 2.05 (m,
1H), 1.88-1.11 (m, 7H), 0.830 (m, 3H), 0.760 (m, 3H); AP.sup.+ MS:
515 (M+1).
[0776] g) Sodium
racemic-(4aS,6aS,14aS)-10-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-6-
-(2-methylpropyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyr-
ido[1',2':4,5]pyrazino[1,2-a]quinazolin-12-olate. In a manner
similar to that described in example Z-1, from
racemic-(4aS,6aS,14aS)--N-[(2,4-difluorophenyl)methyl]-12-hydroxy-6-(2-me-
thylpropyl)dioxo-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyri-
do[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (37 mg,
0.071 mmol) and 1 N sodium hydroxide (0.07 mL) the title compound
was prepared as a yellow solid (26 mg, 68%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 10.73 (m, 1H), 7.94 (s, 1H), 7.32 (m, 1H),
7.19 (m, 1H), 7.00 (m, 1H), 4.59-4.41 (m, 3H), 4.28 (m, 2H), 4.14
(br s, 1H), 2.63-2.60 (m, 2H), 1.98-1.61 (m, 5H), 1.48-1.36 (m,
4H), 0.997 (m, 3H), 0.760 (m, 3H), 0.660 (m, 2H); AP.sup.+ MS: 515
(M+1 of free acid).
Example Z-39
(6aR,7aS,11aS)--N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,7-
,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1,2-a]benzimid-
azole-3-carboxamide
& Example Z-40
[0777]
(6aS,7aS,11aS)--N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dio-
xo-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1,2-a-
]benzimidazole-3-carboxamide
##STR00150##
[0778] a)
(6aR,7aS,11aS)--N-[(2,4-Difluorophenyl)methyl]-2,13-dioxo-1-[(ph-
enylmethyl)oxy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]p-
yrazino[1,2-a]benzimidazole-3-carboxamide and
(6aS,7aS,11aS)--N-[(2,4-difluorophenyl)methyl]-2,13-dioxo-1-[(phenylmethy-
l)oxy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1-
,2-a]benzimidazole-3-carboxamide. In a manner similar to that
described in example Z-2, from [(1S,2S)-2-aminocyclohexyl]amine
(122 mg, 1.07 mmol) and 16a (200 mg, 0.426 mmol) was prepared
(6aS,7aS,11aS)--N-[(2,4-difluorophenyl)methyl]-2,13-dioxo-1-[(phenylmethy-
l)oxy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1-
,2-a]benzimidazole-3-carboxamide (58 mg) and
(6aS,7aS,11aS)--N-[(2,4-difluorophenyl)methyl]-2,13-dioxo-1-[(phenylmethy-
l)oxy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1-
,2-a]benzimidazole)-3-carboxamide (10.6 mg) after separation of the
diastereomers using silica gel chromatography (0-12%
methanol/dichloromethane).
(6aR,7aS,11aS)--N-[(2,4-difluorophenyl)methyl]-2,13-dioxo-1-[(phenylmethy-
l)oxy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1-
,2-a]benzimidazole-3-carboxamide (major): .sup.1H NMR (CDCl.sub.3)
.delta. 10.40 (m, 1H), 8.33 (s, 1H), 7.57 (m, 2H), 7.40-7.25 (m,
4H), 6.81 (m, 2H), 5.32 (d, J=10 Hz, 0.1H), 5.13 (d, J=10 Hz, 1H),
4.64-4.58 (m, 3H), 4.21 (dd, J=12.4, 3.2 Hz, 1H), 3.79 (m, 1H),
3.04 (m, 1H), 2.73 (m, 1H), 2.53 (m, 1H), 2.01-1.79 (m, 4H),
1.36-1.24 (m, 4H); ES.sup.+ MS: 535 (M+1).
(6aS,7aS,11aS)--N-[(2,4-difluorophenyl)methyl]-2,13-dioxo-1-[(phen-
ylmethyl)oxy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]pyr-
azino[1,2-a]benzimidazole-3-carboxamide (minor diastereomer):
.sup.1H NMR (CDCl.sub.3) .delta. 10.33 (m, 1H), 8.28 (s, 1H), 7.61
(m, 2H), 7.39-7.28 (m, 3H), 6.79 (m, 2H), 5.29 (d, J=9.6 Hz, 1H),
5.05 (d, J=9.6 Hz, 1H), 4.84 (m, 1H), 4.60 (m, 2H), 3.90-3.84 (m,
2H), 3.07 (m, 1H), 2.75 (m, 1H), 2.49 (m, 1H), 2.07 (m, 1H),
1.90-1.51 (m, 4H), 1.33-1.19 (m, 4H); MS data matches that of its
diastereomer.
[0779] b) (For example Z-39),
(6aR,7aS,11aS)--N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,-
7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1,2-a]benzimi-
dazole-3-carboxamide. In a manner similar to that described in
example Z-37, from the minor diastereomer prepared in step a
(6aR,7aS,11aS)--N-[(2,4-difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-1-[(p-
henylmethyl)oxy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]-
pyrazino[1,2-a]benzimidazole-3-carboxamide (7 mg, 0.0131 mmol) and
10 w.t. % Pd/C (catalytic amount) was prepared
(6aR,7aS,11aS)--N-[(2,4-difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,-
7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1,2-a]benzimi-
dazole-3-carboxamide (2.8 mg, 48%) after purification by HPLC.
.sup.1H NMR (CDCl.sub.3) .delta. 12.15 (br s, 1H), 10.42 (br s,
1H), 8.31 (s, 1H), 7.36 (m, 1H), 6.80 (m, 2H), 5.01 (m, 1H), 4.63
(m, 2H), 4.16 (m, 1H), 3.96 (m, 1H), 3.06-2.93 (m, 2H), 2.61 (m,
1H), 2.18 (m, 1H), 1.93 (m, 1H), 1.60-1.13 (m, 4H), 0.893-0.840 (m,
2H); ES.sup.+ MS: 44.5 (M+1).
[0780] c) (For example Z-40).
(6aS,7aS,11aS)--N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,-
7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1,2-a]benzimi-
dazole-3-carboxamide. In a manner similar to that described in
example Z-37, from the major diastereomer (30 mg, 0.0561 mmol)
prepared in step a and 10 w.t. % Pd/C (catalytic amount),
(6aS,7aS,11aS)--N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,-
7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1,2-a]benzimi-
dazole-3-carboxamide was prepared as a white solid (15 mg, 60%)
after purification by HPLC. .sup.1H NMR
(methanol-d.sub.4/CDCl.sub.3) .delta. 10.41 (m, 1H), 8.25 (s, 1H),
7.30 (m, 1H), 6.77 (m, 2H), 4.77 (m, 1H), 0.57 (m, 2H), 4.45 (m,
1H), 3.91 (m, 1H), 3.12 (m, 1H), 2.67 (m, 1H), 2.12 (m, 1H),
1.87-1.84 (m, 2H), 1.47-1.33 (m, 4H); ES.sup.+ MS: 44.5 (M+1).
Example Z-41
(5aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,4,-
5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1',2':3,4]imidazo[1,2-d]pyr-
azine-9-carboxamide
##STR00151##
[0782] a)
(5aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-10,12-dioxo-11-[(phen-
ylmethyl)oxy]-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1',2'-
:3,4]imidazo[1,2-d]pyrazine-9-carboxamide. In a manner similar to
that described in example Z-18, from 16a (50 mg, 0.108 mmol) and
[(2S)-2-piperidinylmethyl]amine hydrochloride (50 mg, 0.289 mmol,
made in a similar manner as described in example Z-18) was prepared
(5aS,14aS)--N-[(2,4-difluorophenyl)methyl]-10,12-dioxo-11-[(phenylmethyl)-
oxy]-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1',2':3,4]imid-
azo[1,2-d]pyrazine-9-carboxamide (40 mg, 78%). .sup.1H NMR
(CDCl.sub.3) .delta. 10.43 (m, 1H), 8.38 (s, 1H), 7.59 (m, 2H),
7.59-7.25 (m, 4H), 0.81 (m, 2H), 5.38 (d, J=10 Hz, 1H), 5.19 (d,
J=10 Hz, 1H), 4.65-4.82 (m, 2H), 4.20 (dd, J=12, 2.8 Hz, 1H), 4.00
(dd, J=12.4, 2.8 Hz, 1H), 3.85 (m, 1H), 3.74 (m, 1H), 3.27 (m, 1H),
2.99 (m, 1H), 2.43 (m, 1H), 2.24 (m, 1H), 1.94-1.87 (m, 2H),
1.77-1.58 (m, 2H), 1.39-1.24 (m, 2H); ES.sup.+ MS: 535 (M+1).
[0783] b)
(5aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-diox-
o-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1',2':3,4]imidazo-
[1,2-d]pyrazine-9-carboxamide. In a manner similar to that
described in example Z-37, from
(5aS,14aS)--N-[(2,4-difluorophenyl)methyl]-10,12-dioxo-11-[(phenylmethyl)-
oxy]-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1',2':3,4]imid-
azo[1,2-d]pyrazine-9-carboxamide (18 mg, 0.0337 mmol) and 1.0 w.t.
% Pd/C (catalytic amount) was prepared the title compound as a
white solid (13 mg, 87%) after purification by HPLC. .sup.1H NMR
(CDCl.sub.3) .delta. 11.71 (br s, 1H), 10.36 (br s, 1H), 8.31 (s,
1H), 7.34 (m, 1H), 6.78 (m, 2H), 4.64-4.57 (m, 2H), 4.28 (m, 1H),
4.12 (m, 1H), 3.92-3.89 (m, 2H), 3.22 (m, 1H), 3.04 (m, 1H), 2.49
(m, 3H), 2.28 (m, 1H), 1.97-1.89 (m, 2H), 1.78 (m, 1H), 1.66-1.60
(m, 2H), 1.43-1.36 (m, 2H); ES.sup.+ MS: 445 (M+1).
Example Z-42
(4aR,14aR)--N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8,10-dioxo-2,3,4a,5,6-
,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1',2':4,5]pyrazino[1,2-a]pyr-
imidine-11-carboxamide
##STR00152##
[0785] a)
Phenylmethyl(2R)-2-(hydroxymethyl)-1-piperidinecarboxylate. In a
manner similar to that described in example Z-3a, from
(2R)-1-{[(phenylmethyl)oxy]carbonyl}-2-piperidinecarboxylic acid
(4.93 g, 18.75 mmol) was prepared
phenylmethyl(2R)-2-(hydroxymethyl)-1-piperidinecarboxylate (2.24 g,
48%) as an oil that solidified upon standing to a white solid.
.sup.1H NMR (CDCl.sub.3) .delta. 7.36-7.26 (m, 5H), 5.18-5.10 (m,
2H), 4.37 (m, 1H), 4.03 (m, 1H), 3.84 (m, 1H), 3.63 (m, 1H), 2.96
(br s, 1H), 1.71-1.42 (m, 6H).
[0786] b) Phenylmethyl(2R)-2 (cyanomethyl)-1-piperidinecarboxylate.
In a manner similar to that described in example Z-3b, from
phenylmethyl(2R)-2-(hydroxymethyl)-1-piperidinecarboxylate (1.09 g,
4.38 mmol) was prepared
phenylmethyl(2R)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-piperidineca-
rboxylate (1.05 g, 59% impure with uncharacterized byproduct) as a
clear colorless oil after purification using silica gel
chromatography (10-100% ethyl acetatehexanes). It is necessary to
use this material in the next step as soon as possible or yields
deteriorate dramatically, in a manner similar to that described in
example Z-3c, from
phenylmethyl(2R)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-piperidineca-
rboxylate (1.05 g, 2.61 mmol) and sodium cyanide (383 mg, 7.82
mmol) was prepared
phenylmethyl(2R)-2-(cyanomethyl)-1-piperidinecarboxylate (171 mg,
25%) as a yellow oil. .sup.1H NMR (CDCl.sub.3) .delta. 7.35-7.29
(m, 5H), 5.13 (s, 2H), 4.65 (m, 1H), 4.10 (m, 1H), 2.96 (m, 1H),
2.60 (m, 2H), 1.82-1.67 (m, 4H), 1.54-1.39 (m, 2H).
[0787] d)
Phenylmethyl(2R)-2-(2-aminoethyl)-1-piperidinecarboxylate. In a
manner similar to that described in example Z-3d, from
phenylmethyl(2R)-2-(cyanomethyl)-1-piperidinecarboxylate (171 mg,
0.663 mmol) was prepared
phenylmethyl(2R)-2-(2-aminoethyl)-1-piperidinecarboxylate (119 mg,
68%) as a clear colorless residue. .sup.1H NMR (CDCl.sub.3) .delta.
7.32-7.25 (m, 5H), 5.08 (m, 2H), 4.39 (br s, 1H), 4.01 (br s, 1H),
2.78 (m, 1H), 2.60-2.56 (m, 2H), 1.95-1.86 (m, 3H), 1.63-1.35 (m,
6H).
[0788] e) {2-[(2R)-2-Piperidinyl]ethyl}amine.
Phenylmethyl(2R)-2-(2-aminoethyl)-1-piperidinecarboxylate (119 mg,
0.454 mmol) was dissolved in methanol and 10 w.t. % Pd/C (120 mg)
was added. Hydrogen was bubbled through the solution for 15 minutes
and the reaction was stirred under 1 atm hydrogen for 18 hours
until determined complete by TLC (1% ammonium hydroxide 19%
methanol 80% dichloromethane). The suspension was filtered through
Celite eluting with methanol and the filtrate was carefully
concentrated under reduce pressure to yield a clear colorless
liquid (58 mg, quantitative). .sup.1H NMR (CDCl.sub.3) .delta. 2.99
(m, 1H), 2.71-2.66 (m, 2H), 2.57-2.48 (m, 2H), 1.72 (m, 1H),
1.61-1.52 (m, 2H), 1.48-1.42 (m, 2H), 1.35-1.25 (m, 2H), 1.05 (m,
1H).
[0789] f)
(4aR,14aR)--N-[(2,4-Difluorophenyl)methyl]-8,10-dioxo-9-[(phenyl-
methyl)oxy]-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1',2-
':4,5]pyrazino[1,2-a]pyrimidine-11-carboxamide. In a manner similar
to that described in example Z-35, from 16a (50 mg, 0.106 mmol) and
{2-[(2R)-2-piperidinyl]ethyl}amine (58 mg, 0.454-mmol) was prepared
(4aR,14aR)--N-[(2,4-difluorophenyl)methyl]-8,10-dioxo-9-[(phenylmethyl)ox-
y]-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-d]pyrido[1',2':4,5]pyr-
azino[1,2-a]pyrimidine-11-carboxamide (47 mg, 81%). .sup.1H NMR
(CDCl.sub.3) .delta. 10.50 (br s, 1H), 8.33 (s, 1H), 7.60 (s, 2H),
7.38-7.24 (m, 4H), 6.80 (m, 2H), 5.29-5.22 (m, 2H), 4.66-4.56 (m,
3H), 4.30 (m, 1H), 4.19 (m, 1H), 3.78 (br s, 1H), 2.86-2.80 (m,
2H), 2.18 (br s, 1H), 1.94 (m, 1H), 1.68-1.36 (m, 6H), 1.23 (br s,
2H); ES.sup.+ MS: 54.9 (M+1).
[0790] g)
(4aR,14aR)--N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8,10-dioxo--
2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1',2':4,5]pyrazi-
no[1,2-a]pyrimidine-11-carboxamide. In a manner similar to that
described in example Z-37, from
(4aR,14aR)--N-[(2,4-difluorophenyl)methyl]-8,10-dioxo-9-[(phenylmethyl)ox-
y]-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1',2':4,5]pyr-
azino[1,2-a]pyrimidine-11-carboxamide (47 mg, 0.0857 mmol) and a
catalytic amount of 10 w.t. % Pd/C was prepared the title compound
as a white solid (19 mg, 54%) after purification by HPLC. .sup.1H
NMR (CDCl.sub.3) .delta. 10.49 (m, 1H), 8.29 (s, 1H), 7.34 (m, 1H),
6.79 (m, 2H), 4.67-4.56 (m, 3H), 4.41 (m, 1H), 4.20 (m, 1H), 3.93
(s, 1H), 2.94-2.87 (m, 2H), 2.28 (br s, 1H), 2.01 (m, 1H),
1.68-1.54 (m, 4H), 1.44 (m, 1H), 1.29-1.23 (m, 3H), 0.850 (m, 1H);
ES.sup.+ MS: 459 (M+1).
Example Z-43
(4R,12aR)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbu-
tyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a-
]pyrimidine-9-carboxamide
##STR00153##
[0792] a) [(3R)-3-Aminobutyl](3-methylbutyl)amine dihydrochloride
was prepared in a similar manner as described in example Z-32.
.sup.1H NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta. 0.87 (d, J=5.2
Hz, 6H), 1.32 (m, 3H), 1.61 (m, 3H), 2.10-2.20 (m, 2H), 2.90-3.04
(m, 4H), 3.45 (m, 1H), 8.23 (br, <1H), 8.96 (br, <1H).
[0793] b)
(4R,12aR)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(-
3-methylbutyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyra-
zino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in
two steps using a similar process to that described in example Z-2.
16a (40 mg, 0.085 mmol) and free
[(3R)-3-aminobutyl](3-methylbutyl)amine (46 mg, 0.35 mmol) were
reacted in dichloromethane (2 mL) with acetic acid to give
(4R,12aR)--N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(3-methylbutyl)-
-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':-
4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (44 mg, 90%) as a film.
This material was hydrogenated in a second step as described in
example Z-2 to give
(4R,12aR)--N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-me-
thylbutyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino-
[1,2-a]pyrimidine-9-carboxamide (11 mg, 30%) as an off-white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (d, J=6.8 Hz, 3H),
0.86 (d, J=6.8 Hz, 3H), 1.24-1.36 (m, 5H), 1.47-1.53 (m, 2H),
2.02-2.11 (m, 1H), 2.36-2.43 (m, 1H), 2.54-2.61 (m, 1H), 2.77-2.92
(m, 2H), 4.16-4.26 (m, 2H), 4.44 (m, 1H), 4.62-4.64 (m, 2H),
4.95-5.02 (m, 1H), 6.75-6.81 (m, 2H), 7.31-7.37 (m, 1H), 8.27 (s,
1H), 10.43 (m, 1H), 12.54 (s, 1H); ES.sup.+ MS: 489 (M+1).
Example Z-44
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylet-
hyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a-
]pyrimidine-9-carboxamide
##STR00154##
[0795] a) [(3S)-8-Aminobutyl](1-methylethyl)amine dihydrochloride
was prepared in a similar manner as described in example Z-29.
.sup.1H NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta. 1.20-1.25 (m,
9H), 1.93-2.02 (m, 2.92 (m, 2H), 3.20-3.29 (m, 2H), 8.04 (br,
<1H), 8.64 (br, <1H).
[0796] b)
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(-
1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyra-
zino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in
two steps using a similar process to that described in example Z-2.
16a (60 mg, 0.13 mmol) and free based
[(3S)-3-aminobutyl](1-methylethyl)amine (55 mg, 0.42 mmol) were
reacted in dichloromethane (2 mL) with acetic acid to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-
-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':-
4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (40 mg, 57%) as a film.
This material was hydrogenated in a second step as described in
example Z-2 to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-me-
thylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino-
[1,2-a]pyrimidine-9-carboxamide (17 mg, 50%) as an off-white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.02 (d, J=6.4 Hz, 3H),
1.07 (d, J=6.4 Hz, 3H), 1.33 (d, J=7.2 Hz, 3H), 1.55-1.58 (m, 1H),
1.94-2.03 (m, 1H), 2.70-2.77 (m, 1H), 2.81-2.86 (m, 1H), 3.11-3.18
(m, 1H), 4.17 (dd, J=3.0, 13.8 Hz, 1.11), 4.32 (dd, J=3.2, 14.0 Hz,
1H), 4.48 (m, 1H), 4.59-4.69 (m, 2H), 4.97-5.00 (m, 1H), 6.77-6.83
(m, 2H), 7.33-7.39 (m, 1H), 8.28 (s, 1H), 10.50 (m, 1H), 12.55 (s,
1H); ES.sup.+ MS: 461 (M+1).
Example Z-45
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbu-
tyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a-
]pyrimidine-9-carboxamide
##STR00155##
[0798] a) [(3S)-3-Aminobutyl](3-methylbutyl)amine dihydrochloride
was prepared in a similar manner as described in example Z-32.
.sup.1H NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta. 0.86 (d, J=5.6
Hz, 6H), 1.27 (d, J=6.0 Hz, 3H), 1.58 (m, 3H), 2.03-2.14 (m, 2H),
2.87-2.09 (m, 4H), 3.38 (m, 1H), 8.1.5 (br, <1H), 8.87 (br,
<1H).
[0799] b)
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(-
3-methylbutyl)-6,8-dioxo-1,2,8,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyra-
zino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in
two steps using a similar process to that described in example Z-2.
16a (0.100 g, 0.21 mmol) and free based
[(3S)-3-aminobutyl](3-methylbutyl)amine (0.104 g, 0.66 mmol) were
reacted in dichloromethane (2 mL) with acetic acid to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(3-methylbutyl)-6,8--
dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]p-
yrazino[1,2-a]pyrimidine-9-carboxamide (88 mg, 72%) as a film. This
material was hydrogenated in a second step as described in example
Z-2 to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-me-
thylbutyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino-
[1,2-a]pyrimidine-9-carboxamide (55 mg, 74%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 0.84 (d, J=6.4 Hz, 3H), 0.85 (d, J=6.4 Hz, 3H),
1.24-1.37 (m, 5H), 1.45-1.53 (m, 2H), 2.02-2.11 (m, 1H), 2.37-2.44
(m, 1H), 2.56-2.63 (m, 1H), 2.80-2.92 (m, 2H), 4.22-4.29 (m, 2H),
4.45 (s, 1H), 4.62-4.63 (m, 2H), 4.97-5.00 (m, 1H), 6.75-6.82 (m,
2H), 7.31-7.37 (m, 1H), 8.37 (s, 1H), 10.48 (m, 1H), 12.53 (br,
1H); ES.sup.+ MS: 489 (M+1).
Example Z-46
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(-
3-pyridinylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1-
,2-a]pyrimidine-9-carboxamide
##STR00156##
[0801] a)
1,1-Dimethylethyl{(1S)-1-methyl-3-[(3-pyridinylmethyl)amino]prop-
yl}carbamate. The protected diamine was prepared using a modified
procedure as described in example Z-32. A solution of
1,1-dimethylethyl[(1S)-3-amino-1-methylpropyl]carbamate (0.296 g,
1.6 mmol) and 3-pyridinecarboxaldehyde (120 .mu.L, 1.3 mmol) in a
1:1 mixture of anhydrous dichloroethane and tetrahydrofuran (10 mL)
was treated with acetic acid (374 .mu.L, 6.6 mmol) and stirred for
80 minutes. Sodium triacetoxyborohydride (0.444 g, 2.1 mmol) was
added and the solution was stirred for 2 hours. The resultant was
subjected to a workup and purification procedure as described in
example Z-32 to give
1,1-dimethylethyl{(1S)-1-methyl-3-[(3-pyridinylmethyl)amino]propyl}carbam-
ate (0.245 g, 66%) as a clear oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.12 (d, J=6.4 Hz, 3H), 1.42 (s, 9H), 1.46-1.54
(m, 1H), 1.68 (m, 1H), 2.61-2.75 (m, 2H), 3.73-3.80 (m, 3H), 4.86
(m, 1H), 7.22-7.24 (m, 1H), 7.68 (d, J==8.0 Hz, 1H), 8.48 (m, 1H),
8.53 (m, 1H).
[0802] b) [(3S)-3-Aminobutyl](3-pyridinylmethyl)amine
dihydrochloride was prepared in a similar manner as described in
example Z-29.
[0803] c)
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-
-dioxo-1-(3-pyridinylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]-
pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was
made in two steps using a similar process to that described in
example Z-2. 16a (60 mg, 0.13 mmol) and free based
[(3S)-3-aminobutyl](3-pyridinylmethyl)amine (83 mg, 0.47 mmol) were
reacted in dichloromethane (2 with acetic acid to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylme-
thyl)oxy]-1-(3-pyridinylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4-
,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (72 mg, 95%) as a film.
This material was hydrogenated in a second step as described in
example Z-2 to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dio-
xo-1-(3-pyridinylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyra-
zino[1,2-a]pyrimidine-9-carboxamide (34 mg, 56%) as an off-white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.37 (d, J=6.8 Hz,
3H), 1.43-1.47 (m, 1H), 2.12 (m, 1H), 2.60-2.92 (m, 2H), 3.53 (d,
J=14.0 Hz, 1H), 3.82 (d, J=14.4 Hz, 1H), 4.23-4.31 (m, 2H),
4.55-4.64 (m, 3H), 5.06-5.11 (m, 1H), 6.75-6.82 (m, 2H), 7.20-7.28
(m, 1H), 7.31-7.36 (m, 1H), 7.50 (m, 1H), 7.92 (s, 1H), 8.48 (s,
1H), 10.39 (m, 1H), 12.5 (br, 1H); ES.sup.+ MS: 510 (M+1).
Example Z-47
(4S,12aS)-1-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl--
6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyri-
midine-9-carboxamide
##STR00157##
[0805] a) 1,1-Dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate. To
a stirred solution of
1,1-dimethylethyl[(1S)-2-cyano-1-methylethyl]carbamate (0.656 g,
3.56 mmol) in anhydrous ether cooled to -40.degree. C. was added
dropwise a 1.0 M solution of diisobutylaluminum hydride in hexanes
(14.2 mL, 14.2 mmol) over 20 minutes. Stirring was continued at
this temperature for an additional 20 minutes. The yellow solution
was quenched with Rochelle's salt and the resultant stirred at room
temperature for 1 hour. The solids were filtered off through celite
and rinsed with EtOAc. The organics were washed with brine,
concentrated, and flash chromatographed (10-100% EtOAc/hexanes) to
give 1,1-dimethyethyl[(1S)-1-methyl-3-oxopropyl]carbamate (0.193 g,
30%) as a clear oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.22
(d, J=6.8 Hz, 3H), 1.41 (s, 9H), 2.58-2.65 (m, 2H), 4.08-4.13 (m,
1H), 4.63 (m, 1H), 9.74-9.75 (m, 1H).
[0806] b)
1,1-Dimethylethyl[(1S)-3-(cyclopropylamino)-1-methylpropyl]carba-
mate. The protected diamine was prepared using a modified procedure
as described in example Z-32. A solution of
1,1-dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate (0.178 g,
0.95 mmol) and cyclopropylamine (197 .mu.L, 2.85 mmol) in anhydrous
dichloroethane (10 mL) was treated with acetic acid (272 .mu.L, 4.8
mmol) and stirred for 30 minutes, Sodium triacetoxyborohydride
(0.444 g, 2.1 mmol) was added and the solution was stirred for 20
hours. The resultant was subjected to a workup and purification
procedure as described in example Z-32 to give
1,1-dimethylethyl[(1S)-3-(cyclopropylamino)-1-methylpropyl]carbamate
(0.186 g, 63%) as a clear oil. .sup.1H NMR (4.00 MHz, CDCl.sub.3)
.delta. 0.32-0.42 (m, 4H), 1.12 (d, J=6.8 Hz, 3H), 1.39-1.51 (m,
10H), 1.58-1.92 (m, 2H), 2.05-2.10 (m, 1H), 2.67-2.80 (m, 2H),
3.71, (m, 1H), 4.78 (m, 1H).
[0807] c) [(3S)-3-Aminobutyl]cyclopropylamine dihydrochloride was
prepared in a similar manner as described in example Z-29. .sup.1H
NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta. 0.70-0.75 (m, 2H),
0.90-0.94 (m, 2H), 1.18 (d, =6.8 Hz, 3H), 1.84-1.94 (m, 1H),
1.97-2.05 (m, 1H), 2.49-2.54 (m, 1H), 2.99-3.04 (m, 2H), 3.23-3.28
(m, 1H).
[0808] d)
(4S,12aS)-1-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-
-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[-
2-a]pyrimidine-9-carboxamide. The title compound was made in two
steps using a similar process to that described in example Z-2. 16a
(80 mg, 0.17 mmol) and free based
[(3S)-3-aminobutyl]cyclopropylamine (75 mg, 0.59 mmol) were reacted
in dichloromethane (2 mL) with acetic acid to give
(4S,12aS)-1-cyclopropyl-N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8--
dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]p-
yrazino[1,2-a]pyrimidine-9-carboxamide (74 mg, 80%) as a film. This
material was hydrogenated in a second step as described in example
Z-2 to give
(4S,12aS)-1-cyclopropyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-m-
ethyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2--
a]pyrimidine-9-carboxamide (32 mg, 52%) as an off-white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.37-0.54 (m, 3H),
0.64-0.70 (m, 1H), 1.35 (d, J=7.2 Hz, 3H), 1.45-1.49 (m, 1H),
1.76-1.80 (m, 1H), 2.03-2.12 (m, 1H), 2.80-2.93 (m, 1H), 2.99-3.04
(m, 1H), 4.30 (dd, J=4.0, 13.6 Hz, 1H), 4.49-4.67 (m, 4H),
5.00-5.07 (m, 1H), 6.75-6.82 (m, 2H), 7.32-7.36 (m, 1H), 8.28 (s,
10.49 (m, 1H), 12.53 (s, 1H); ES.sup.+ MS: 459 (M+1).
Example Z-48
(4S,12aS)--N-[(2,4-Difluoropbenyl)methyl]-7-hydroxy-4-methyl-1-[2-(methylo-
xy)ethyl]-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[-
1,2-a]pyrimidine-9-carboxamide
##STR00158##
[0810] a) [(3S)-3-Aminobutyl][2-(methyloxy)ethyl]amine
dihydrochloride. The protected diamine,
1,1-dimethylethyl((1S)-1-methyl-3-{[2-(methyloxy)ethyl]amino}propyl)carba-
mate was prepared in a similar manner as described in example Z-47,
Subsequently, [(3S)-3-aminobutyl][2-(methyloxy)ethyl]amine
dihydrochloride was prepared in a similar manner as described in
example Z-29. .sup.1H NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta.
1.21 (d, J=5.6 Hz, 3H), 1.93 (m, 1H), 2.04 (m, 1H), 2.98-3.05 (m,
4H), 3.22 (m, 2H), 3.26-3.31 (m, 4H), 8.06 (br, <1H), 8.81 (br,
<1H).
[0811] b)
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-[-
2-(methyloxy)ethyl]-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5-
]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was
made in two steps using a similar process to that described in
example Z-2. 16a (60 mg, 0.13 mmol) and free based
[(3S)-3-aminobutyl][2-(methyloxy)ethyl]amine (53 mg, 0.37 mmol)
were reacted in dichloromethane (2 mL) with acetic acid to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-4-methyl-1-[2-(methyloxy)ethyl]-
-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':-
4,5]pyrazino[1,2-a]pyrimidin-9-carboxamide (47 mg, 63%) as a film.
This material was hydrogenated in a second step as described in
example to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-[2-(m-
ethyloxy)ethyl]-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyr-
azino[1,2-a]pyrimidine-9-carboxamido (38 mg, 97%) as an off-white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.34 (d, J=7.2 Hz,
3H), 1.49 (m, 1H), 2.03-2.12 (m, 1H), 2.67-2.70 (m, 1H), 2.81-2.92
(m, 2H), 3.06-3.15 (m, 1H), 3.30-3.37 (m, 4H), 3.58-3.63 (m, 1H),
4.20 (dd, J=3.4, 14.2 Hz, 1H), 4.50-4.59 (m, 1H), 4.62-4.65 (m,
3H), 5.00-5.03 (m, 1H), 6.75-6.81 (m, 2H), 7.31-7.37 (m, 1H), 8.27
(s, 1H), 10.46 (s, 1H), 12.54 (s, 1H); ES.sup.+ MS: 477 (M+1).
Example Z-49
racemic-(3aS,5aS,13aS)--N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-5-(2-met-
hylpropyl)-10,12-dioxo-2,3,3a,4,5,5a,6,10,12,13a-decahydro-1H-cyclopenta[e-
]pyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide
##STR00159##
[0813] a)
racemic-(1S,2S)-2-{[(2-Methylpropyl)amino]methyl}cyclopentanamin- e
hydrochloride.
[0814] In a manner to example Z-18a-c, from
racemic-(1R,2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclopentaneca-
rboxylic acid (255 mg, 1.11 mmol) was prepared
racemic-1,1-dimethylethyl[(1S,2S)-2-(aminomethyl)cyclopentyl]carbamate
(153 mg, 64% over 3 steps) as a white green residue. Reductive
amination with isobutyraldehyde followed by deprotection as
described in Z-38 steps c and d respectively, gave
racemic-(1S,2S)-2-{[(2-methylpropyl)amino]methyl}cyclopentanamine
hydrochloride (105 mg, 39% over 5 steps from amino acid). .sup.1H
NMR (methanol-d.sub.4/CDCl.sub.3) 8.90 (br s, <1H), 8.64 (br s,
<1H), 8.28 (m, 1H), 3.97 (br s, 1H), 3.37 (m, 1H), 2.83-2.69 (m,
3H), 2.18-1.69 (m, 7H), 0.996 (m, 6H).
[0815] b)
racemic-(3aS,5aS,13aS)--N-[(2,4-Difluorophenyl)methyl]-11-hydrox-
y-5-(2-methylpropyl)-10,12-dioxo-2,3,3a,4,5,5a,6,10,12,13a-decahydro-1H-cy-
clopenta[e]pyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.
In a manner similar to that described in example Z-35, from
racemic-(1S,2S)-2-{[(2-methylpropyl)amino]methyl}cyclopentanamine
hydrochloride 105 mg, 0.434 mmol) and 16a (56 mg, 0.119 mmol) was
prepared
racemic-(3aS,5aS,13aS)--N-[(2,4-difluorophenyl)methyl]-5-(2-meth-
ylpropyl)-10,12-dioxo-11-[(phenylmethyl)oxy]-2,3,3a,4,5,5a,6,10,12,13a-dec-
ahydro-1H-cyclopenta[e]pyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carbox-
amide (52 mg, 74%). This material was deprotected in a second step
similar to the procedure described in example Z-37. Thus, from
racemic-(3aS,5aS,13aS)--N-[(2,4-difluorophenyl)methyl]-5-(2-methylpropyl)-
-10,12-dioxo-11-[(phenylmethyl)oxy]-2,
3,3a,4,5,5a,6,10,12,13a-decahydro-1H-cyclopenta[e]pyrido[1',2':4,5]pyrazi-
no[1,2-a]pyrimidine-9-carboxamide (48 mg, 0.081 mmol) and 10% Pd/C
(catalytic amount), the title compound was prepared as a white
solid after purification by HPLC (30 mg, 75%). .sup.1H NMR
(CDCl.sub.3) 12.59 (s, 1H), 10.42 (s, 1H), 828 (s, 1H), 7.34 (m,
1H), 6.79 (m, 2H), 4.83 (s, 1H), 4.63-4.58 (m, 3H), 4.29 (m, 1H),
4.14 (m, 1H), 2.91 (m, 1H), 2.46-2.32 (m, 3H), 2.15-2.09 (m, 2H),
1.85-1.61 (m, 5H), 1.39 (m, 1H), 0.88 (m, 6H); ES.sup.+ MS: 501
(M+1).
Example Z-50
(3R,11aS)--N-[(2,4-difluorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3,-
5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2d]pyrazine-8-carboxamide
##STR00160##
[0817] The title compound was made in two steps using a similar
process to that described in example Z-2. 16a (40 mg, 0.09 mmol)
and (2R)-2-amino-1-butanol (0.02 mL, 0.21 mmol) were reacted in
dichloromethane (2 mL) with acetic acid to give
(3R,11aS)--N-[(2,4-difluorophenyl)methyl]-3-ethyl-5,7-dioxo-6-[(phenylmet-
hyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine--
8-carboxamide (40 mg, 93%). This material was hydrogenated in a
second step as described in example Z-2 to give
(3R,11aS)--N-[(2,4-Difluorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3-
,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamid-
e (30 mg, 91%) as a white solid. .sup.1H NMR (CDCl.sub.3) .delta.
11.49 (br, 1H), 10.28 (m, 1H), 8.35 (s, 1H), 7.34 (m, 1H), 6.79 (m,
2), 5.30 (m, 1H), 4.62 (m, 2H), 4.45-4.32 (m, 3H), 3.93-3.86 (m,
2H), 2.11 (m, 1H), 1.65 (m, 7H), 0.98 (t, J=7.6 Hz, 3H); ES.sup.+
MS: 420 (M+1).
Example Z-51
racemic-(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(4--
morpholinyl)ethyl]-11,13-dioxo-1,2,4,4a,5,6,6a,7,11,13,14a-
dodecahydropyrido-[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide
##STR00161##
[0819] a)
racemic-1,1-Dimethylethyl[(1S,2R)-2-formylcyclohexyl]carbamate. An
alternative procedure from the one given in example Z-38b follows:
To a solution of Dess-Martin Periodane (564 mg, 1.33 mmol) in
dichloromethane was added
racemic-1,1-dimethylethyl[(1S,2R)-2-(hydroxymethyl)cyclohexyl]carbamate
(305 mg, 1.33 mmol, see example Z-38a) dropwise as a solution in
dichloromethane. The reaction was stirred 1 hour at ambient
temperature until judged complete by TLC (1:1 hexanes:ethyl acetate
KMnO.sub.4 stain). The reaction was quenched with aqueous sodium
bicarbonate and sodium thiosulfate solutions, extracted with
dichloromethane, and the combined organics were dried over sodium
sulfate. Silica gel chromatography (0-50% ethyl acetate/hexanes
gradient elution) gave
racemic-1,1-dimethylethyl[(1S,2R)-2-formylcyclohexyl]carbamate
(280, 93%), See example Z-38b for NMR data.
[0820] b)
racemic-{[(1S,2S)-2-Aminocyclohexyl]methyl}[2-(4-morpholinyl)eth-
yl]amine hydrochloride. In a manner similar to that described in
example Z-38c-d from
racemic-1,1-dimethylethyl[(1S,2R)-2-formylcyclohexyl]carbamate (78
mg, 0.344 mmol, prepared using the procedure from example Z-38b)
and [2-(4-morpholinyl)ethyl]amine (67 mg, 0.515 mmol) was prepared
racemic-{[(1S,2S)-2-aminocyclohexyl]methyl}[2-(4-morpholinyl)ethyl]amine
hydrochloride (95 mg, 78% over 2 steps) as a white solid. .sup.1H
NMR (methanol-d.sub.4/CDCl.sub.3) 8.18 (br s, 1H), 3.84-3.493 (m,
11H), 3.19-3.119 (m, 5H), 2.42 (m, 1H), 2.11 (br s, 2H), 1.87-1.17
(m, 10H).
[0821] c)
racemic-4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-
-6-[2-(4-morpholinyl)ethyl]-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dode-
cahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide.
In a manner similar to that described in example Z-35, from
racemic-{[(1S,2S)-2-aminocyclohexyl]methyl}[2-(4-morpholinyl)ethyl]amine
hydrochloride (95 mg, 0.272 mmol) and 16a (45 mg, 0.0957 mmol) was
prepared
racemic-(4aS,6aS,14aS)--N-[(2,4-difluorophenyl)methyl]-6-[2-(4-m-
orpholinyl)ethyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,1-
1,13,14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxa-
mide (27 mg, 43%). This material was deprotected in a second step
similar to the procedure described in example Z-37. From
racemic-(4aS,6aS,14aS)--N-[(2,4-difluorophenyl)methyl]-6-[2-(4-morpholiny-
l)ethyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a--
dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide
(27 mg, 0.0408 mmol) and 10% Pd/C (1 mg) the title compound was
prepared as a white solid after purification HPLC. .sup.1H NMR
(CDCl.sub.3) 12.30 (br s, <1H), 10.41 (br s, 1H), 8.29 (s, 1H),
7.34 (m, 2H), 6.78 (m, 2H), 4.76 (m, 1H), 4.62-4.54 (m, 3H), 4.29
(m, 2H), 3.65 (m, 4H), 3.01 (m, 1H), 2.76 (m, 2H), 2.58-2.42 (m,
7H), 2.21 (m, 1H), 1.89-1.23 (m, 8H); ES.sup.+ MS: 572 (M+1).
Example Z-52
racemic-(3aR,5aR,13aS)--N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-di-
oxo-1,2,3,4,5a,6,10,12,13a-decahydrocyclopenta[d]pyrido[1',2':4,5]pyrazino-
[2,1-b][1,3]oxazino-9-carboxamide
##STR00162##
[0823] a)
racemic-1,1-Dimethylethyl[(1S,2R)-2-(hydroxymethyl)cyclopentyl]c-
arbamate.
racemic-(1R,2S)-2-({[(1,1-Dimethylethyl)oxy]carbonyl}amino)cyclo-
pentanecarboxylic acid (22 mg, 0.096 mmol) was dissolved in
tetrahydrofuran and placed in an ice-water bath. Triethylamine was
added, followed by the slow addition of methyl chloroformate. The
reaction was stirred ten minutes in the icebath and sodium
borohydride was added. Methanol was then added slowly and stirring
was continued for two hours while the ice-bath expired, 1 M
Potassium hydrogen sulfate was added, the reaction was partially
concentrated, and product was extracted with dichloromethane. The
combined organics were washed with sodium bicarbonate, brine, and
dried over sodium sulfate. Removal of solvents under reduced
pressure afforded
racemic-1,1-dimethylethyl[(1S,2R)-2-(hydroxymethyl)cyclopentyl]carbamate
(25 mg, >100%). .sup.1H NMR (CDCl.sub.3) 4.50 (br s, 1H), 4.06
(m, 1H), 3.54 (m, 1H), 3.37 (m, 1H), 2.09 (m, 1H), 1.96 (m, 1H),
1.64 (m, 3H), 1.52 (m, 1H), 1.43 (s, 9H), 1.11 (m, 2H).
[0824] b) racemic-[(1R,2S)-2-Aminocyclopentyl]methanol
hydrochloride. In a manner similar to that described in example,
from
racemic-1,1-dimethylethyl[(1S,2R)-2-(hydroxymethyl)cyclopentyl]carbamate
and 4 N HCl was prepared
racemic-[(1R,2S)-2-aminocyclopentyl]methanol hydrochloride (20 mg,
quantitative). .sup.1H NMR (methanol-d.sub.4-CDCl.sub.3) 7.76 (br
s, <1H), 3.73 (m, 1H), 3.61-3.28 (m, 3H), 2.27 (br s, 1H), 2.01
(m, 2.01 (m, 1H), 1.74-1.70 (m, 2H), 1.56-1.42 (m, 2H), 1.16 (br s,
1H), 1.05 (br s, 1H).
[0825] c)
racemic-(3aR,13aS)--N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10-
,12-dioxo-1,2,3,3a,4,5a,6,10,12,13a-decahydrocyclopenta[d]pyrido[1',2':4,5-
]pyrazino[2,1-b][1,3]oxazine-9-carboxamide. In a manner similar to
that described in example Z-35, from
racemic-[(1R,2S)-2-aminocyclopentyl]methanol hydrochloride (20 mg,
0.132 mmol) and 16a (24 mg, 0.051 mmol) was prepared
racemic-(3aR,13aS)--N-[(2,4-difluorophenyl)methyl]-10,12-dioxo-11-[(pheny-
lmethyl)oxy]-1,2,3,3a,4,5a,6,10,12,13a-decahydrocyclopenta[d]pyrido[1',2':-
4,5]pyrazino[2,1]-b][1,3]-oxazine-9-carboxamide (7 mg, 26%) as a
white solid. This material was deprotected in a second step similar
to the procedure described in example Z-37. Thus, from
racemic-(3aR,13aS)--N-[(2,4-difluorophenyl)methyl]-10,12-dioxo-11-[(pheny-
lmethyl)oxy]1,2,3,3a,4,5a,6,10,12,13a-decahydrocyclopenta[d]pyrido[1',2':4-
,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (7 mg, 0.012 mmol) and
10% Pd/C (1 mg),
racemic-(3aR,13aS)--N-[(2,4-difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-
-1,2,3,3a,4,5a,6,10,12,13a-decahydrocyclopenta[d]pyrido[1',2':4,5]pyrazino-
[2,1-b][1,3]oxazine-9-carboxamide (4 mg, 72%) white solid. .sup.1H
NMR (CDCl.sub.3) 12.20 (br s, 1H), 10.37 (br s, 1H), 8.31 (s, 1H),
7.35 (m, 1H), 6.80 (m, 2H), 5.16 (m, 1H), 4.77 (m, 1H), 4.64 (m,
2H), 4.28 (m, 1H), 4.09 (m, 1H), 3.97 (m, 1H), 3.45 (m, 1H),
2.49-2.20 (m, 2H), 1.89-1.58 (m, 4H), 0.936-0.840 (m, 1H); ES.sup.+
MS: 446 (M+1).
Example Z-53
racemic-(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-methyl-
-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':4,5]pyr-
azino[1,2-a]quinazoline-10-carboxamide
##STR00163##
[0827] a) racemic-{[(1S,2S)-2-Aminocyclohexyl]methyl}methylamine
hydrochloride. In a manner similar to that described in example
Z-38c-d from
racemic-1,1-dimethylethyl[(1S,2R)-2-formylcyclohexyl]carbamate
(0.410 mmol) and methyl amine (0.5 mL, of a 2 M tetrahydrofuran
solution) was prepared
racemic-{[(1S,2S)-2-aminocyclohexyl]methyl}methylamine
hydrochloride in two steps as a white solid (46 mg, 63% 2 steps).
.sup.1H NMR (methanol-d.sub.4/CDCl.sub.3) 9.05 (br s, <1H), 8.72
(br s, <1H), 8.24 (br s, 1H), 3.34 (m, 1H), 3.29 (m, 1H), 2.85
(br, s, 1H), 2.66 (br s, 4H), 2.38 (br s, 1H), 2.07-1.83 (m, 2H),
1.67-1.14 (m, 6H).
[0828] b)
racemic-(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydrox-
y-6-methyl-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',-
2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide. In a manner
similar to that, described in example Z-35, from
racemic-{[(1S,2S)-2-aminocyclohexyl]methyl)}methylamine
hydrochloride (46 mg, 0.215 mmol) and 16a (35 mg, 0.0744 mmol) was
prepared
racemic-(4aS,6aS,14aS)--N-[(2,4-difluorophenyl)methyl]-6-methyl-11,13-dio-
xo-12-[(phenylmethyl)oxy]1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1-
',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (17 mg, 41%) as
a white solid. This material was deprotected in s second step
similar to the procedure described in example Z-37. Thus, from
racemic-(4aS,6aS,14aS)--N-[(2,4-difluorophenyl)methyl]-6-methyl-11,13-dio-
xo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[-
1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (17 mg, 0.0302
mmol) and 10% Pd/C (1 mg) was prepared the title compound as a
white solid (9 mg, 64%). .sup.1H NMR (CDCl.sub.3) 10.44 (m, 1H),
8.29 (s, 1H), 7.34 (m, 1H), 6.79 (m, 2H), 4.78 (m, 1H), 4.62 (br s,
2H), 4.29 (br s, 2H), 3.41 (s, 1H), 2.92 (m, 1H), 2.66 (m, 1H),
2.35-2.25 (m, 4H), 1.90-1.74 (m, 2H), 1.67-1.24 (m, 6H); ES.sup.+
MS: 473 (M+1).
Example Z-54
racemic-(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(me-
thyloxy)ethyl]11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[-
1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide
##STR00164##
[0830] a)
racemic-{[(1S,2S)-2-Aminocyclohexyl]methyl}[2-(methyloxy)ethyl]a-
mine hydrochloride.
[0831] In a manner similar to that described in example Z-38c-d
from racemic-1,1-dimethylethyl[(1S,2R)-2-formylcyclohexyl]carbamate
(93 mg, 0.410 mmol) and [2-(methyloxy)ethyl]amine (0.05 mL, 0.615
mmol) was prepared in two steps
racemic-{[(1S,2S)-2-aminocyclohexyl]methyl)}[2-(methyloxy)ethyl]amine
hydrochloride (63 mg, 60% 2 steps) as a white solid. .sup.1H NMR
(methanol-d.sub.4/CDCl.sub.3) 9.02 (br s, <1H), 8.78 (br s,
<1H), 8.29 (br s, 1H), 3.69 (br s, 2H), 3.46 (s, 3H), 3.36-3.18
(m, 4H), 2.97 (br s, 1H), 2.46 (br s, 1H), 1.86-1.40 (m, 8H).
[0832] b)
racemic-4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-
-6-[2-(methyloxy)ethyl]-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahy-
dropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide. In a
manner similar to that described in example Z-35, from
racemic-{[(1S,2S)-2-aminocyclohexyl]methyl}[2-(methyloxy)ethyl]amine
hydrochloride (63 mg, 0.244 mmol) and 16a (40 mg, 0.0851 mmol) was
prepared
racemic-(4aS,6aS,14aS)--N-[(2,4-difluorophenyl)methyl]-6-(methyl-
oxy)ethyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,18,14-
a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide
(44 mg, 81%) as a white solid. This material was deprotected in a
second step similar to the procedure described in example Z-37.
Thus, from
racemic-(4aS,6aS,14aS)--N-[(2,4-difluorophenyl)methyl]-6-[2-(methyloxy)et-
hyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dode-
cahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide
(44 mg, 0.0726 mmol) and 10% Pd/C (1 mg) the title compound was
prepared as a white solid (37 mg, quantitative). .sup.1H NMR
(CDCl.sub.3) 12.60 (br s, 1H), 10.47 (m, 1H), 8.28 (a, 1H), 7.34
(m, 1H), 6.79 (m, 2H), 4.81 (m, 1H), 4.64 (m, 3H), 4.51 (m, 1H),
4.26 (m, 1H), 3.63 (m, 1H), 3.31 (s, 3H), 3.10 (m, 1H), 2.86 (m,
1H), 2.67 (2m, 2H), 2.21 (m, 1H), 1.01-1.78 (m, 2H), 1.67-1.52 (m,
4H), 1.46-1.24 (m, 3H); ES.sup.+ MS: 517 (M+1).
Example Z-55
[0833] racemic-(4aS,6aS
14aS)-6-[2-(Acetylamino)ethyl]-N-[(2,4-difluorophenyl)methyl]-12-hydroxy--
11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':4,5]pyra-
zino[1,2-a]quinazoline-10-carboxamide
##STR00165##
[0834] a)
racemic-N-[2-({[(1S,2S)-2-Aminocyclohexyl]methyl}amino)ethyl]ace-
tamide hydrochloride. In a manner similar to that described in
example Z-38c-d from
racemic-1,1-dimethylethyl[(1S,2R)-2-formylcyclohexyl]carbamate (93
mg, 0.41 mmol) and N-(2-aminoethyl)acetamide (63 mg, 0.615 mmol),
racemic-N-[2-({[(1S,2S)-2-aminocyclohexyl]methyl}amino)ethyl]acetamide
hydrochloride was prepared in two steps as a white solid (82 mg),
71% 2 steps), .sup.1H NMR (methanol-d.sub.4/CDCl.sub.3) 8.86 (br s,
1H), 8.20 (br s, 1H), 3.62-3.51 (m, 3H), 3.40-3.28 (m, 4H),
3.22-2.93 (m, 3H), 2.47 (m, 1H), 2.08-2.06 (m, 4H), 1.83-1.75 (m,
2H), 1.56-1.44 (m, 3H), 1.23 (m, 1H).
[0835] b)
racemic-4aS,6aS,14aS)-6-[2-(Acetylamino)ethyl]-N-[(2,4-difluorop-
henyl)methyl]-12-hydroxy-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecah-
ydropyrido[1',2':4,5]-pyrazino[1,2-a]quinazoline-10-carboxamide. In
a manner similar to that described in example Z-35, from
racemic-N-[2-({[(1S,2S)-2-aminocyclohexyl]methyl}amino)ethyl]acetamide
hydrochloride (82 mg, 0.349 mmol) and 16a (50 mg, 0.106 mmol) was
prepared the title compound (24 mg, 36%). This material was
deprotected in a second step similar to the procedure described in
example Z-37. Thus, from
racemic-(4aS,6aS,14aS)-6-[2-(acetylamino)ethyl]-N-[(2,4-difluorophenyl)me-
thyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dod-
ecahydropyrido[1',2'3,5]pyrazino[1,2-a]quinazoline-10-carboxamide
(24 mg, 0.0379 mmol) and 10% Pd/C (1 mg) was prepared the title
compound as a white solid after purification by HPLC. .sup.1H NMR
(CDCl.sub.3) 12.59 (s, 1H), 10.44 (s, 1H), 8.35 (s, 1H), 7.32 (m,
1H), 6.79 (m, 2H), 5.86 (s, 1H), 4.78 (m, 1H), 4.61-4.50 (m, 3H),
4.30 (m, 1H), 3.35 (m, 1H), 3.18 (m, 1H), 2.96 (m, 1H), 2.76 (m,
2H), 2.48 (m, 1H), 2.19 (m, 1H), 1.89-1.23 (m, 12H); ES.sup.+ MS:
544 (M+1).
Example Z-56
(3S,11aR)--N-[(2,4-Difluorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3,-
5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
##STR00166##
[0837] The title compound was made in two steps using a similar
process to that described in example Z-2. 16a (40 mg, 0.09 mmol)
and (2S)-2-amino-1-butanol (0.1 mL) were reacted in dichloromethane
(2 mL) with acetic acid to give
(3S,11aR)--N-[(2,4-difluorophenyl)methyl]-3-ethyl-5,7-dioxo-6-[(phenylmet-
hyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine--
8-carboxamide (39 mg, 90%). This material was hydrogenated in a
second step as described in example Z-2 to give
(3S,11aR)--N-[(2,4-difluorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3-
,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamid-
e (27 mg, 99%) as a tinted white solid. .sup.1H NMR (CDCl.sub.3)
.delta. 11.47 (br, 1H), 10.26 (m, 1H), 8.35 (a, 1H), 7.32 (m, 1H),
6.77 (m, 2), 5.29 (m, 1H), 4.60 (m, 2H), 4.47-4.32 (m, 3H),
3.93-3.85 (m, 2H), 2.08 (m, 1H), 1.68 (m, 7H), 0.95 (t, J=7.6 Hz,
3H); ES.sup.+ MS: 420 (M+1).
Example Z-57
(3S,11aR)-3-Butyl-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5-
,7,11,11a-hexahydro[1,3]oxazolo[3,2a]pyrido[1,2-d]pyrazine-8-
carboxamide
##STR00167##
[0839] The title compound was made in two steps using a similar
process to that described in example Z-2. 16a (40 mg, 0.09 mmol)
and (2S)-2-amino-1-hexanol (100 mg) were reacted in dichloromethane
mL) with acetic acid to give
(3S,11aR)-3-butyl-N-[(2,4-difluorophenyl)methyl]-5,7-dioxo-6-[(phenylmeth-
yl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-
-carboxamide (43 mg, 94%). This material was hydrogenated in a
second step as described in example Z-2 to give
(3S,11aR)-3-butyl-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,-
5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
(33 mg, 92%) as a tinted white solid. .sup.1H NMR (CDCl.sub.3)
.delta. 11.48 (br, 1H), 10.27 (br, 1H), 8.36 (br, 1H), 7.31 (m,
1H), 6.77 (m, 2), 5.28 (m, 1H), 4.59-4.36 (m, 5H), 3.83 (m, 2H),
2.08 (m, 1H), 1.58 (m, 1H), 1.39-1.23 (m, 4H), 0.90 (t, J=6.8 Hz,
3H); ES.sup.+ MS: 448 (M+1).
Example Z-58
(3S,11aS)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy
3-[(4-hydroxyphenyl)methyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazol-
o[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
##STR00168##
[0841] The title compound was made in two steps using a similar
process to that described in example Z-2. 16a (40 mg, 0.09 mmol)
and 4-[(2S)-2-amino-3-hydroxypropyl]phenol (43 mg, 0.21 mmol) were
reacted in dichloromethane (2 mL) with acetic acid to give
(3S,11aR)--N-[(2,4-difluorophenyl)methyl][(4-hydroxyphenyl)methyl]-5,7-di-
oxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrid-
o[1,2-d]pyrazine-8-carboxamide (10 mg, 20%). This material was
hydrogenated in a second step as described in example Z-2 and
purified via preparative HPLC to give
(3S,11aR)--N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-[(4-hydroxyphenyl)m-
ethyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]p-
yrazine-8-carboxamide (7 mg, 63%) as a white solid. .sup.1H NMR
(CD.sub.3OD) .delta. 10.43 (m, 1H), 8.34 (s, 1H), 7.33 (m, 1H),
7.00 (d, J=8.4 Hz, 2H), 6.82 (m, 2H), 6.71 (d, J=8.4 Hz, 2H), 5.05
(m, 1H), 4.67-4.57 (m, 1H), 4.21 (ad, J=8.8, 7.2 Hz, 1H), 3.94 (dd,
J=8.8, 6.4 Hz, 1H), 3.21 (dd, J=13.2, 3.2 Hz, 1H), 2.90 (dd,
J=13.6, 8.8 Hz, 1H); ES.sup.+ MS: 498 (M+1).
Example Z-59
(4S,12aS)-1-Cyclobutyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6-
,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-
a]pyrimidine-9-carboxamide
##STR00169##
[0843] a) [(3S)-3-Aminobutyl]cyclobutylamino dihydrochloride was
prepared in a similar manner as described in example Z-47. .sup.1H
NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta. 1.23 (d, J=6.4 Hz,
3H), 1.69-2.26 (m, 8H), 2.83 (m, 2H), 3.31-3.33 (m, 1H), 3.55 (m,
1H), 8.08 (br, <1H), 9.07 (br, <1H).
[0844] b)
(4S,12aS)-1-Cyclobutyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy--
4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1-
,2-a]pyrimidine-9-carboxamide. The title compound was made in two
steps using a similar process to that described in example Z-2. 16a
(80 mg, 0.17 mmol) and free based
[(3S)-3-aminobutyl]cyclobutylamine (96 mg, 0.68 mmol) were reacted
in dichloromethane (2 mL) with acetic acid to give
(4S,12aS)-1-cyclobutyl-N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo--
7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazin-
o[1,2-a]pyrimidine-9-carboxamide (68 mg, 70%) as a film. This
material was hydrogenated in a second step as described in example
Z-2 to give
(4S,12aS)-1-cyclobutyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl--
6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyri-
midine-9-carboxamide (57 mg, 100%) as an off-white solid. .sup.1H
NMR (4.00 MHz, CDCl.sub.3) .delta. 1.31 (d, J=6.8 Hz, 3H),
1.46-1.70 (m, 4H), 1.91-2.12 (m, 4H), 2.52 (m, 1H), 2.90-2.93 (m,
1H), 3.06 (m, 1H), 4.16-4.29 (m, 3H), 4.57-4.66 (m, 2H), 4.09-5.05
(m, 1H), 6.75-6.82 (m, 2H), 7.32-7.38 (m, 1H), 8.20 (s, 1H), 10.44
(s, 1H), 12.51 (s, 1H); ES.sup.+ MS: 473 (M+1).
Example Z-60
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(-
tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5-
]pyrazino[1,2-a]pyridine-9-carboxamide
##STR00170##
[0846] a) [(3S)-3-Aminobutyl]tetrahydro-2H-thiopyran-4-ylamine
dihydrochloride was prepared in a similar manner as described in
example Z-47. .sup.1H NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta.
1.21 (d, J 6.4 Hz, 3H), 1.65-1.75 (m, 2H), 1.90-2.10 (m, 2H), 2.35
(m, 2H), 2.56-2.61 (m, 4H), 2.92-2.98 (m, 3H), 3.27-3.31 (m, 1H),
8.05 (br, <1H), 8.90 (br, <1H).
[0847] b)
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-
-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido-
[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title
compound was made in two steps using a similar process to that
described in example Z-2. 16a (80 mg, 0.17 mmol) and free based
[(3S)-3-aminobutyl]tetrahydro-2H-thiopyran-4-ylamine (108 mg, 0.58
mmol) were reacted in dichloromethane (2 with acetic acid to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-7--
[(phenylmethyl)oxy]-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-oc-
tahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (56
mg, 54%) as a film. This material was debenzylated in a second step
to in a manner similar to Z-26 to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1--
(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,-
5]pyrazino[1,2-a]pyrimidine-9-carboxamide (56 mg, >100%) as an
off-white solid. .sup.1H NMR (400 MHz, CDCl3) .delta. 1.30 (d,
J=6.8 Hz, 3H), 1.54-1.58 (m, 1H), 1.72-1.82 (m, 3H), 1.97-2.11 (m,
2H), 2.60-2.76 (5H), 2.86 (m, 2H), 4.17-4.30 (m, 2H), 4.62-4.66 (m,
3H), 4.92-4.96 (m, 1H), 6.75-6.82 (m, 2H), 7.32-7.38 (m, 8.31 (s,
1H), 10.46 (s, 1H), 12.48 (s, 1H); ES.sup.+ MS: 519 (M+1).
Example Z-61
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl-
)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]py-
rimidine-9-carboxamide
##STR00171##
[0849] a) [(3S)-3-Amino-5-methylhexyl](2-methylpropyl)amine
dihydrochloride was prepared in a similar manner as described in
example Z-32. .sup.1H NMR (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta.
0.87 (d, J=6.4 Hz, 6H), 0.97 (d, J=6.8 Hz, 6H), 1.34-1.41 (m, 1H),
1.45-1.52 (m, 1H), 1.58-1.66 (m, 1H), 2.01-2.13 (m, 2H), 2.72-2.73
(m, 2H), 3.03-3.06 (m, 2H), 3.29 (m, 2H), 8.07 (br, <1H), 8.71
(br, <1H).
[0850] b)
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-bis(2-me-
thylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazin-
o[1,2-R]pyrimidine-9-carboxamide. The title compound was made in
two steps using a similar process to that described in example Z-2.
16a (80 mg, 0.17 mmol) and free based
[(3S)-3-amino-5-methylhexyl](2-methylpropyl)amine (117 nag, 0.63
mmol) were reacted in dichloromethane (2 mL) with acetic acid to
give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-1,4-bis(2-methylpropyl)-6,8-dio-
xo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyra-
zino[1,2-a]pyrimidine-9-carboxamide (68 mg, 66%) as a film. This
material was hydrogenated in a second step as described in example
Z-2 to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropy-
l)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]p-
yrimidine-9-carboxamide (56 mg, 97%) as an off-white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 0.74 (d, J=6.4 Hz, 3H), 0.84 (d,
J=6.4 Hz, 3H), 0.97-1.00 (m, 6H), 1.37-1.83 (m, 2.03-2.12 (m, 2H),
2.21-2.28 (m, 1H), 2.77 (m, 1H), 2.90-2.93 (m, 1H), 4.19-4.40 (m,
3H), 4.59-4.70 (m, 2H), 4.96-4.97 (m, 1H), 6.77-6.83 (m, 2H),
7.33-7.39 (m, 1H), 8.28 (s, 1H), 10.47 (s, 1H), 12.59 (br, 1H);
ES.sup.+ MS: 517 (M+1).
Example Z-62
racemic-(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-(2-hyd-
roxyethyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',-
2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide
##STR00172##
[0852] a)
racemic-2-({[(1S,2S)-2-Aminocyclohexyl]methyl}amino)ethanol
hydrochloride. In a manner similar to that described in example
Z-55a, from
racemic-1,1-dimethylethyl[(1S,2R)-2-formylcyclohexyl]carbamate (112
mg, 0.497 mmol) and 2-aminoethanol (0.04 mLm 0.746 mmol) was
prepared
racemic-2-({[(1S,2S)-2-aminocyclohexyl]methyl}amino)ethanol bis
hydrochloride in two steps (102 mg, 84% over 2 steps). .sup.1H NMR
(methanol-d.sub.4/CDCl.sub.3) 8.81-8.40 (m, <2H), 8.16 (br s,
1H), 4.02-3.93 (m, 2H), 3.80 (br s, 2H), 3.53 (m, 1H), 3.36-2.93
(m, 6H), 2.41 (br s, 1H), 2.05 (m, 1H), 1.75-1.41 (m, 4H).
[0853] b)
racemic-(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydrox-
y-6-(2-hydroxyethyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydro-
pyrido[1',2':4,5]-pyrazino[1,2-a]quinazoline-10-carboxamide. In a
manner similar to that described in example Z-35, from 16a (45 mg,
0.0957 mmol) and
racemic-2-({[(1S,2S)-2-aminocyclohexyl]methyl}amino)ethanol
hydrochloride (102 mg, 0.418 mmol) was prepared
racemic-(4aS,6aS,14aS)--N-[(2,4-difluorophenyl)methyl]-6-(2-hydroxyethyl)-
-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahy-
dropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (7
mg, 12%) as a white solid after silica gel chromatography (1-12%
methanol/dichloromethane gradient elution). This material was
deprotected in a second step similar to the procedure described in
example Z-37. Thus, from
racemic-(4aS,6aS,14aS)--N-[(2,4-difluorophenyl)methyl]-6-(2-hydroxyethyl)-
-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahy-
dropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (7
mg, 0.0118 mmol) the title compound was prepared after purification
by HPLC (3 mg, 50%). .sup.1H NMR (CDCl.sub.3) 12.57 (br s, 1H),
10.45 (m, 1H), 8.20 (s, 1H), 7.34 (m, 1H), 6.78 (m, 2H), 4.80 (m,
1H), 4.71 (a, 1H), 4.62 (m, 2H), 4.44 (m, 1H), 4.33 (m, 1H), 3.75
(m, 1H), 3.62-3.20 (m, 3H), 3.13 (m, 1H), 2.74-2.71 (m, 2H), 2.24
(m, 1H), 1.90-137 (m, 12H), 1.27-1.23 (m, 3H) 1.12 (m, 1H);
ES.sup.+ MS: 503 (M+1).
[0854] Example Z-63
racemic-(4aS,6aS,14aS)-6-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]-12-hyd-
roxy-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':4,5-
]pyrazino[1,2-a]quinazoline-10-carboxamide
##STR00173##
[0856] a)
racemic-(1S,2S)-2[(Cyclopropylamino)methyl]cyclohexanamine
hydrochloride. In a manner similar to that described in example
Z-55a, from
racemic-1,1-dimethylethyl[(1S,2R)-2-formylcyclohexyl]carbamate (112
mg, 0.497 mmol) and cyclopropylamine (0.05 mL, 0.746 mmol) was
prepared
racemic-(1S,2S)-2-[(cyclopropylamino)methyl]cyclohexanamine bis
hydrochloride salt in two steps (102 mg, 86% over 2 steps). This
material was used without further purification. .sup.1H NMR
(nethanol-d.sub.4/CDCl.sub.3) 8.31 (br s, 1H), 3.75 (br s, 1H),
3.54 (m, 1H), 2.96 (m, 1H), 2.71 (m, 1H), 2.27 (m, 1H), 1.94 (m,
1H), 1.76-1.15 (m, 8H), 0.88-0.78 (m, 3H).
[0857] b)
racemic-(4aS,6aS,14aS)-6-Cyclopropyl-N-[(2,4-difluorophenyl)meth-
yl]-12-hydroxy-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido-
[1',2':4,5]pyrazino[1,2a]quinazoline-10-carboxamide. In a manner
similar to that described in example Z-35, from 16a (45 mg, 0.0957
mmol) and
racemic-(1S,2S)-2-[(cyclopropylamino)methyl]cyclohexanamine
hydrochloride (102 mg, 0.425 mmol) was prepared
racemic-(4aS,6aS,14aS)-6-cyclopropyl-N-[(2,4-difluorophenyl)methyl]-11,13-
-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyr-
ido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide as a white
solid after silica gel chromatography (1-12%
methanol/dichloromethane gradient elution). This material was
deprotected in a second step similar to the procedure described in
example Z-37. Thus, from
racemic-(4aS,6aS,14aS)-6-cyclopropyl-N-[(2,4-difluorophenyl)methyl]-11,13-
-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyr-
ido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (56 mg,
0.0949 mmol) the title compound was prepared as a white solid (41
mg, 81%). .sup.1H NMR (CDCl.sub.3) 12.10 (br s, <1H), 10.45 (m,
1H), 8.27 (s, 1H), 7.33 (m, 1H), 6.88 (m, 2H), 477 (m, 1H),
4.61-4.49 (m, 4H), 4.33 (m, 1H), 2.94 (m, 1H), 2.79 (m, 1H), 2.17
(m, 1H), 1.86-0.86 (m, 10H), 0.658 (m, 1H), 0.499-0.32 (m, 2H);
ES.sup.+ MS: 499 (M+1).
Example Z-64
[0858]
racemic-(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-1-
1,13-dioxo-6-[2'(1-pyrrolidinyl)ethyl]-1,2,3,4,4a,5,6,6a,7,7,11,13,14a-dod-
ecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide
formic acid salt
##STR00174##
[0859] a)
racemic-(1S,2S)-2-({[2-(1-Pyrrolidinyl)ethyl]amino}methyl)cycloh-
exanamine hydrochloride. In a manner similar to that described in
example Z-55a, from
racemic-1,1-dimethylethyl[(1S,2R)-2-formylcyclohexyl]carbamate
(1.12 mg, 0.497 mmol) and 2-(1-pyrrolidinyl)ethanamine (0.09 mL,
0.746 mmol) was prepared
racemic-(1S,2S)-2-({[2-(1-pyrrolidinyl)ethyl]amino}methyl)cycloh-
exanamine (88 mg, 60% 2 steps) as the bis hydrochloride salt in two
steps as a white solid. .sup.1H NMR (methanol-d.sub.4/CDCl.sub.3)
9.68 (br s, <1H), 9.24 (br s, <1H), 8.25 (br s, 1H),
3.75-3.04 (m, 11H), 2.87 (br s, 1H), 2.06-1.20 (m, 12H).
[0860] b)
racemic-(4aS,6aS,14aS)--N-[(2,4-Difluorophenyl)methyl-12-hydroxy-
-11,13-dioxo-6-[2-(1-pyrrolidinyl)ethyl]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dod-
ecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide
formic acid salt.
[0861] In a manner similar to that described in example Z-35, from
16a (30 mg, 0.0638 mmol) and
racemic-(1S,2S)-2-({[2-(1-pyrrolidinyl)ethyl]amino}methyl)cyclohexanamine
hydrochloride (88 mg, 0.296 mmol) was prepared
racemic-(4aS,6aS,14aS)--N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12-[(p-
henylmethyl)oxy]-6-(2-(1-pyrrolidinyl)ethyl]-1,2,3,4,4a,5,6,6a,7,11,13,14a-
-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide
as a white solid (31 mg, 76%) after silica gel chromatography
(1-12% methanol/dichloromethane gradient elution). This material
was deprotected in a second step similar to the procedure described
in example Thus, from
racemic-(4aS,6aS,14aS)--N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12-[(p-
henylmethyl)oxy]-6-[2-(1-pyrrolidinyl)ethyl]-1,2,3,4,4a,5,6,6a,7,11,13,14a-
-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-carboxamide
(31 mg, 0.048 mmol) the title compound was prepared as a yellow
solid after purification by HPLC (18 mg, 66%). .sup.1H NMR
(CDCl.sub.3) 10.39 (br s, 1H), 8.56 (br s, 1H), 8.39 (br s, 1H),
7.34 (m, 1H), 6.78 (m, 2H), 4.76-4.40 (m, 6H), 3.26-2.89 (m, 7H),
2.73 (m, 1H), 2.15 (an, 1H), 2.02-1.18 (m, 14H); ES.sup.+ MS: 556
(M+1).
Example Z-65
4aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8,10-dioxo-2,3,4,4a,5,-
6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1',2':4,5]pyrazino[1,2-a]py-
rimidine-11-carboxamide
##STR00175##
[0863] a) {2-[(2S)-2-Piperidinyl]ethyl}amine. This compound was
prepared in a similar manner as its enantiomer described in example
Z-42a.
[0864] b)
(4aS,14aS)--N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8,10-dioxo--
2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1',2':4,5]pyrazi-
no[1,2-a]pyrimidine-11-carboxamide. In a manner similar to that
described in example Z-35, from {2-[(2S)-2-piperidinyl]ethyl}amine
(28 mg, 0.218 mmol) and 16a (30 mg, 0.0638 mmol) was prepared
(4aS,14aS)--N-[(2,4-difluorophenyl)methyl]-8,10-dioxo-9-[(phenylmethyl)ox-
y]-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1',2':4,5]pyr-
azino[1,2-a]pyrimidine-11-carboxamide (29 mg, 82%). This material
was deprotected in a second step similar to that described in
example Z-37 to give the title compound as a white solid (26 mg,
quantitative). .sup.1H NMR (CDCl.sub.3) .delta. 12.44 (br s, 1H),
10.48 (s, 1H), 8.26 (s, 1H), 7.36 (m, 1H), 6.80 (m, 2H), 4.68-4.57
(m, 2H), 0.38 (m, 1H), 4.20 (m, 1H), 3.93 (s, 1H), 3.63-3.39 (m,
2H), 2.91 (m, 2H), 2.29 (br s, 1H), 2.02 (m, 1H), 1.69-1.45 (m,
4H), 1.30-1.24 (m, 2H), 1.12 (br s, 1H); ES.sup.+ MS: 459
(M+1).
Example Z-66
(4S,12aS)--N-1-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-[2-(methyloxy-
)ethyl]-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido-9-carboxamide
##STR00176##
[0866] a) [(3S)-3-Aminobutyl][2-(methyloxy)ethyl]amine bis
hydrochloride. In a manner similar to that described in example
Z-47, from 1,1-dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate
(76 mg, 0.406 mmol) and 2-(methyloxy)ethyl]amine (0.05 mL, 0.609
mmol) was prepared [(3S)-3-aminobutyl][(2-(methyloxy)ethyl]amine as
the his hydrochloride salt in two steps (19 mg, quantitative).
.sup.1H NMR (methanol-d.sub.4/CDCl.sub.3) .delta. 9.02 (<1H),
8.24 (<1H), 3.68 (br s, 2H), 3.49 (br s, 1H), 3.34 (br s, 4H),
3.15 (br s, 4H), 2.26-2.11 (m, 2H), 1.35 (br s, 3H).
[0867] b)
(4S,12aS)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-[2-(m-
ethyloxy)ethyl]-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyr-
azino[1,2-a]pyrimidine-9-carboxamide. In a manner similar to that
described in example Z-35, from 16 (15 mg, 0.034 mmol) and
[(3S)-3-Aminobutyl][2-(methyloxy)ethyl]amine bis hydrochloride (19
mg, 0.087 mmol),
(4S,12aS)--N-[(4-fluorophenyl)methyl]-4-methyl-1-[2-(methyloxy)ethyl]-6,8-
-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]-
pyrazino[1,2-a]pyrimidine-9-carboxamide was prepared as a white
solid after silica gel chromatography (1-12%
methanol/dichloromethane). This material was deprotected in a
second step similar to that described in example Z-37 to give the
title compound as a yellow solid (9 mg, 60%, 2 steps). .sup.1H NMR
(CDCl.sub.3) .delta. 12.56 (s, 1H), 10.51 (m, 1H), 8.29 (s, 1H),
7.82 (m, 2H), 6.98 (m, 2H), 5.03 (m, 1H), 4.65-4.59 (m, 2H), 4.53
(m, 1H), 4.21 (m, 1H), 3.61-3.40 (m, 2H), 3.34-3.13 (m, 3H), 3.08
(m, 1H), 2.94-2.84 (m, 2H), 2.68 (m, 1H), 2.07 (m, 1H), 1.50 (m,
1H), 1.35 (d, J=7.2 Hz, 3H), 1.14 (m, 1H); ES.sup.+ MS: 459
(M+1).
Example Z-67
(4S,12aS)-1-Cyclobutyl-N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-d-
ioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]-pyrazino[1,2-a]pyrimidi-
ne-9-carboxamide
##STR00177##
[0869] a) [(3S)-3-Aminobutyl]cyclobutylamine bis-hydrochloride. In
a manner similar to that described in example Z-47, from
1,1-dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate (76 mg, 0.406
mmol) and cyclobutylamine (0.05 mL, 0.609 mmol) was prepared
[(3S)-3-Aminobutyl]cyclobutylamine bis-hydrochloride in two steps
(23 mg, 27%). .sup.1H NMR (methanol-d.sub.4/CDCl.sub.3) .delta.
8.86 (s, <1H), 7.97 (s, <1H), 3.46 (m, 1H), 3.21 (m, 1H),
2.74 (m, 2H), 2.14-2.08 (m, 4H), 1.94-1.62 (m, 5H), 1.13 (d, J=6
Hz, 1H).
[0870] b)
(4S,12aS)-1-Cyclobutyl-N-[(4-fluorophenyl)methyl]-7-hydroxy-4-me-
thyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a-
]pyrimidine-9-carboxamide. In a similar manner to that described in
example Z-35a, from 16 (18 mg, 0.39 mmol) and
[(3S)-3-Aminobutyl]cyclobutylamine bis-hydrochloride (23 mg, 0.107
mmol),
(4S,12aS)-1-cyclobutyl-N-[(4-fluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(-
phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,-
2-a]pyrimidine-9-carboxamide was prepared as a white solid. This
material was deprotected in a second step similar to that described
in example Z-37 to give the title compound as a white solid after
purification by HPLC (4.5 mg, 25% 2 steps), .sup.1H NMR
(CDCl.sub.3) .delta. 12.54 (s, 1H), 10.48 (s, 1H), 8.20 (s, 1H),
7.31 (m, 2H), 6.98 (m, 2H), 5.02 (m, 1H), 4.61-4.57 (m, 2H),
4.26-4.14 (m, 3H), 3.05 (m, 1H), 2.90 (m, 1H), 2.49 (m, 1H), 2.12
(m, 1H), 2.05-1.87 (m, 3H), 1.84-1.61 (m, 3H), 1.46 (m, 1H), 1.32
(m, 3H); ES.sup.+ MS: 455 (M+1).
Example Z-68
(4S,12aS)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl-
)-6,8-dioxo-2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyri-
midine-9-carboxamide
##STR00178##
[0872] a) [(3S)-3-Aminobutyl](2-methylpropyl)amine
bis-hydrochloride. In a manner similar to that described in example
Z-47, this compound was prepared from
1,1-dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate (76 mg, 0.406
mmol) and (2-methylpropyl)amine (0.06 mL, 0.609 mmol) in two steps
as the bis-hydrochloride salt (22 mg, 25%). .sup.1H NMR
(methanol-d.sub.4/CDCl.sub.3) .delta. 3.25 (br s, 1H), 2.91 (br s,
2H), 2.64 (m, 2H), 2.02-1.93 (m, 3H), 1.17 (m, 3H), 0.88 (m,
6H).
[0873] b)
(4S,12aS)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-me-
thylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido
1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. In a similar
manner to that described in example Z-35, from 16 (16 mg, 0.035
mmol) and [(3S)-3-Aminobutyl](2-methylpropyl)amine
bis-hydrochloride (20 mg, 0.0925 mmol),
(4S,12aS)--N-[(4-fluorophenyl)methyl]methyl-1-(2-methylpropyl)
6,8-dioxo-7-[(phenylmethyl)oxy]1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4-
,5]pyrazino[1,2-a]pyrimidine carboxamide was prepared as a white
solid. This material was deprotected in a second step similar to
that described in example Z-37 to give the title compound as a tan
solid (13 mg, 68% 2 steps). .sup.1H NMR (CDCl.sub.3) .delta. 12.57
(s, 1H), 10.46 (s, 1H), 8.27 (s, 1H), 7.32 (m, 2H), 6.99 (m, 2H),
4.98 (m, 1H), 4.63-4.54 (m, 2H), 4.45 (m, 1H),4.26-4.16 (m, 2H),
2.91 (m, 1H), 2.77 (m, 1H), 2.24 (m, 1H), 2.14-2.03 (m, 2H), 1.63
(m, 1H), 1.48 (m, 1H), 1.33 (m, 3H), 1.09 (m, 1H), 0.850 (m, 3H),
0.789 (m, 3H); ES.sup.+ MS: 457 (M+1).
Example Z-69
(4S,12aS)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo-1,2-
,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carb-
oxamide
##STR00179##
[0875] a) [3S)-3-Aminobutyl]methylamine bis-hydrochloride. In a
manner similar to that described in example Z-47, this compound was
prepared from 1,1-dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate
(76 mg, 0.409 mmol) and excess methylamine (2 M in tetrahydrofuran)
in two steps as the his hydrochloride salt (17% 2 seeps). .sup.1H
NMR (methanol-d.sub.4/CDCl.sub.3) .delta. 3.16 (m, 1H), 3.08 (s,
2H), 2.83 (m, 2H), 2.45 (s, 3H), 1.88 (m, 1H), 1.75 (m, 1H), 1.09
(m, 3H).
[0876] b),
(4S,12aS)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,-
8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimi-
dine-9-carboxamide. In a similar manner to that described in
example Z-35, from 16 (18 mg, 0.0398 mmol) and
[(3S)-3-aminobutyl]methylamine bis-hydrochloride (19 mg, 0.109
mmol,
(4S,12aS)--N-[(4-fluorophenyl)methyl]-1,4-dimethyl-6,8-dioxo-7-[(phenylme-
thyl)oxy]-1,2,8,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyri-
midine-9-carboxamido was prepared as a white solid. This material
was deprotected in a second step similar to that described in
example Z-37 to give the title compound as a tan solid (7 mg, 4.4%
2 steps). .sup.1H NMR (CDCl.sub.3) .delta. 12.53 (s, 1H), 10.47 (s,
1H), 8.29 (a, 1H), 7.32 (m, 2H), 6.99 (m, 2H), 5.04 (1H), 4.60 (m,
2H), 4.23 (s, 3H), 2.83-2.80 (m, 2H), 2.82 (s, 3H), 2.13 (m, 1H),
1.48 (m, 1H), 1.34 (m, 3H); ES.sup.+ MS: 4.15 (M+1).
Example Z-70
(4S,12aS)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetr-
ahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyr-
azino[1,2-a]pyrimidine-9-carboxamide
##STR00180##
[0878] The title compound was made in two steps using a similar
process to that described in example Z-2, 16 (25 mg, 0.055 mmol)
and free based [(3S)-3-aminobutyl]tetrahydro-2H-thiopyran-4-ylamine
(48 mg, 0.26 mmol) were reacted in dichloromethane (2 mL) with
acetic acid to give
(4S,12aS)--N-[(4-fluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylmethyl-
)oxy]-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[-
1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (16 mg, 49%) as a
film. This material was debenzylated in a second step in a manner
similar to Z-26 to give
(4S,12aS)--N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tet-
rahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]py-
razino[1,2-a]pyrimidine-9-carboxamide (8 mg, 59%) as an off-white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.30 (d, J 7.2 Hz,
3H), 1.53-1.58 (m, 1H), 1.72-2.10 (m, 5H), 2.56-2.76 (m, 5H),
2.84-2.87 (m, 2H), 4.18 (dd, J=2.8, 14.0 Hz, 1H), 4.26 (dd, J=3, 4,
14.2 Hz, 1H), 4.92-4.97 (m, 1H), 6.96-7.00 (m, 2H), 7.29-7.36 (m,
2H), 8.31 (s, 1H), 10.48 (m, 1H), 12.48 (br, 1H); ES.sup.+ MS: 501
(M+1).
Example Z-71
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo-
-1,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2a]-pyrimidine-9-ca-
rboxamide
##STR00181##
[0880] a) [(3S)-3-Aminobutyl)methylamine dihydrochloride was
prepared in a similar manner as described in example Z-47. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 1.18 (d, J=6.8 Hz, 3H), 1.82-1.91
(m, 1H), 1.94-2.03 (m, 1H), 2.53 (s, 3H), 2.89-2.93 (m, 2H),
3.22-3.30 (m, 1H), 8.02 (br, <1H), 8.81 (br, <1H).
[0881] b)
(4S,12aS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-
-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyr-
imidine-9-carboxamide. The title compound was made in two steps
using a similar process to that described in example Z-2. 16a (40
mg, 0.085 mmol) and free based [(3S)-3-aminobutyl]methylamine (24
mg, 0.23 mmol) were reacted in dichloromethane (2 mL) with acetic
acid to give
(4S,12aS)--N-[(2,4-difluorophenyl)methyl]-1,4-dimethyl-6,8-dioxo-7-[(phen-
ylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]-
pyrimidine-9-carboxamide (39 mg, 89%) as a film. This material was
hydrogenated in a second step as described in example Z-2 to give
(4,5,12aS)--N-[(2,4-difluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dio-
xo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine--
9-carboxamide (32 mg, 97%) as an off-white solid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 1.33 (d, J=6.4 Hz 3H), 1.46-1.50 (m, 1H),
2.12-2.14 (m, 1H), 2.32 (s, 3H), 2.83 (m, 2H), 4.24 (m, 3H), 4.62
(m, 2H), 5.02 (m, 1H), 6.77-6.79 (m, 2H), 7.33 (m, 1H), 8.30 (s,
1H), 10.43 (s, 1H), 12.50 (br, 1H); ES.sup.+ MS: 4.33 (M+1).
Example Z-72
(4S,12aS)--N'-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl-
)-6,8-dioxo-1,2,8,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]py-
rimidine-9-carboxamide
##STR00182##
[0883] The title compound was made in two steps using a similar
process to that described in example Z-2, 16 (27 mg, 0.060 mmol)
and free based [(3S)-3-aminobutyl](1-methylethyl)amine (67 mg, 0.51
mmol) were reacted in dichloromethane (2 mL) with acetic acid to
give
(4S,12aS)--N-[(4-fluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-diox-
o-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyraz-
ino[1,2-a]pyrimidine-9-carboxamide (18 mg, 56%) as a film. This
material was hydrogenated in a second step as described in example
Z-2 to give
(4S,12aS)--N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl-
)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]py-
rimidine-9-carboxamide (15 mg, >100%) as an off-white solid.
.sup.1H NMR (400 MHz, CDCl3) .delta. 1.02 (d, J=, 6.4 Hz, 3H), 1.07
(d, J=6.4 Hz, 3H), 1.32 (d, J=6.8 Hz, 3H), 1.54-1.58 (m, 1H),
1.94-2.03 (m, 1H), 2.71-2.76 (m, 1H), 2.82-2.88 (m, 1H), 3.13-3.16
(m, 1H), 4.16-4.19 (m, 1H), 4.30-4.33 (m, 1H), 4.48 (m, 1H),
4.55-4.65 (m, 2H), 4.97-5.00 (m, 1H), 6.97-7.01 (m, 2H), 7.30-7.34
(m, 2H), 8.28 (s, 1H), 10.51 (m, 1H), 12.55 (s, 1H); ES.sup.+ MS:
443 (M+1).
Example Z-73
(4S,12aS)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,-
8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimi-
dine-9-carboxamide
##STR00183##
[0885] The title compound was made in two steps using a similar
process to that described in example Z-2. 16 (25 mg, 0.055 mmol)
and free based [(3S)-3-amino-5-methylhexyl](2-methylpropyl)amine
(21 mg, 0.11 mmol) were reacted in dichloromethane (2 mL) with
acetic acid to give
(4S,12aS)--N-[(4-fluorophenyl)methyl]-1,4-bis(2-methylpropyl)-6,8-dioxo-7-
-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino-
[1,2-a]pyrimidine-9-carboxamide (8 mg, 25%) as a film. This
material was hydrogenated in a second step as described in example
Z-2 to give
(4S,12aS)--N-[(4-fluorophenyl)methyl]-7-hydroxy-1,4-bis(2'-methylpropyl)--
6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyri-
midine-9-carboxamide (5 mg, 78%) as an off-white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 0.74 (d, J=6.4 Hz, 3H), 0.84 (d,
J=6.4 Hz, 3H), 0.97-1.00 (m, 6H), 1.37-1.66 (m, 5H), 1.75-1.82 (m,
2.05-2.09 (m, 2H), 2.21-2.26 (m, 1H), 2.72-2.70 (m, 1H), 2.87-2.93
(m, 1H), 4.16-4.26 (m, 2H), 4.38 (m, 1H), 4.55-4.66 (m, 2H),
4.93-4.99 (m, 1H), 6.97-7.02 (m, 2H) 7.31-7.34 (m, 2H), 8.27 (s,
1H), 10.49 (m, 1H), 12.61 (s, 1H); ES.sup.+ MS: 499 (M+1).
Example ZZ-1 to ZZ-24
[0886] Examples in table below were isolated as a mixture of
diastereomers ranging from 1:1 to >10:1 ratios of stereoisomers
at the center indicated as undefined. Characterization data
reported herein consists of observed mass spectral signals for
molecular ions (M+1) of the compounds using electrospray ionization
methods in the positive mode using LC/MS techniques well known in
the field. Reported retention times refer to observed UV peaks
confirmed by NMR methods for the examples below using the following
gradient on a phenomenex C18 reverse phase HPLC column (150
mm.times.4.6 mm 5 micron). Solvent A=water w/0.1% formic acid,
solvent B=acetonitrile w/0.1% formic acid. Gradient=10% B for 1
min, gradient from 10% to 90% B from 1 to 9 min, ramping to 100% B
at 9.01 min and holding at 100% B for 2 min. In several cases the
diastereomers were not separable by the standard HPLC conditions
reported above and thus reported as a single retention time.
TABLE-US-00001 TABLE A Example Observed LC/MS or No. Structure HPLC
data ZZ-1 ##STR00184## ES.sup.+ MS: 419 (M + 1) ZZ-2 ##STR00185##
ES.sup.+ MS: 406 (M + 1) ZZ-3 ##STR00186## ES.sup.+ MS: 509 (M + 1)
ZZ-4 ##STR00187## ES.sup.+ MS: 429 (M + 1) ZZ-5 ##STR00188##
ES.sup.+ MS: 415 (M + 1) ZZ-6 ##STR00189## ES.sup.+ MS: 491 (M + 1)
ZZ-7 ##STR00190## ES.sup.+MS: 509 (M + 1) ZZ-8 ##STR00191##
ES.sup.+ MS: 443 (M + 1) ZZ-9 ##STR00192## ES.sup.+ MS: 461 (M + 1)
ZZ-10 ##STR00193## ES.sup.+ MS: 501 (M + 1) ZZ-11 ##STR00194##
ES.sup.+ MS: 475 (M + 1) ZZ-12 ##STR00195## ES.sup.+ MS: 489 (M +
1) ZZ-13 ##STR00196## ES.sup.+ MS: 460 (M + 1) ZZ-14 ##STR00197##
ES.sup.+ MS: 442 (M + 1) ZZ-15 ##STR00198## ES.sup.+ MS: 489 (M +
1) ZZ-16 ##STR00199## 8.174 & 8.295 min. ZZ-17 ##STR00200##
ES.sup.+ MS: 461 (M + 1) ZZ-18 ##STR00201## ES.sup.+ MS: 447 (M +
1) ZZ-19 ##STR00202## ES.sup.+MS: 446 (M + 1) ZZ-20 ##STR00203##
ES.sup.+ MS: 432 (M + 1) ZZ-21 ##STR00204## 7.368 min. ZZ-22
##STR00205## 7.150 min. ZZ-23 ##STR00206## ES.sup.+ MS: 447 (M + 1)
ZZ-24 ##STR00207## ES.sup.+ MS: 447 (M + 1)
[0887] The present invention further includes the following
compounds.
##STR00208##
TABLE-US-00002 TABLE B No (R)m R.sup.a 1 4-F --CH.sub.3 2 4-F
--CH(CH.sub.3).sub.2 3 4-F --CH.sub.2CH.sub.2OCH.sub.3 4 2,4-F
--CH.sub.3 5 2,4-F --CH(CH.sub.3).sub.2 6 2,4-F
--CH.sub.2CH.sub.2OCH.sub.3 7 2-F,3-Cl --CH.sub.3 8 2-F,3-Cl
--CH(CH.sub.3).sub.2 9 2-F,3-Cl --CH.sub.2CH.sub.2OCH.sub.3
Experimental Example 1
[0888] The HIV integrase inhibitory activity was investigated based
on the following assay method.
(1) Preparation of DNA Solution
[0889] By the same method as that described in Experimental Example
1 of WO 2004/024693, a substrate DNA solution (2 pmol/.mu.l) and a
target DNA solution (5 pmol/.mu.l) were prepared. After each target
DNA solution was once boiled, a temperature was slowly lowered to
anneal complementary chains, which was used. Each sequence of a
substrate DNA and a target DNA is as described in the same
Experimental Example.
(2) Measurement of Inhibition Rate (IC.sub.50 Value)
[0890] Streptavidin (manufactured by Vector Laboratories) was
dissolved in a 0.1M carbonate buffer solution (composition: 90 mM
Na.sub.2CO.sub.2, 10 mM NaHCO.sub.3) to a concentration of 40
.mu.g/ml. Each 50 .mu.l of this solution was added to a well of an
immunoplate (manufactured by NUNC), this is allowed to stand at
4.degree. C. overnight to adsorb. Then, each well was washed with a
phosphate buffer (composition: 13.7 mM NaCl, 0.27 mM KCl, 0.43 mM
Na.sub.2HPO.sub.4, 0.14 mM KH.sub.2PO.sub.4) two times, and 300
.mu.l of a phosphate buffer containing 1% skim milk to block it for
30 minutes. Further, each well was washed with a phosphate buffer
two times, 50 .mu.l of a substrate DNA solution (2 pmol/.mu.l) was
added to adsorb at room temperature for 30 minutes while shaking,
and this was washed with a phosphate buffer two times and, then,
distilled water once.
[0891] Then, to each well prepared as described above were added 12
.mu.l of a buffer (composition: 150 mM MOPS (pH7.2), 75 mM
MnCl.sub.2, 50 mM 2-mercaptoethanol, 25% glycerol, 500 .mu.g/ml
bovine serum albumin-fraction V), and 51 .mu.l of a reaction
solution prepared from 39 .mu.l of distilled water. Then, 9 .mu.l
of an integrase solution (30 pmol) was added, and the mixture was
mixed well. To a well as a negative control (NC) was added 9 .mu.l
of a diluting solution (composition: 20 mM MOPS (pH7.2), 400 mM
potassium glutamate, 1 mM EDTA, 0.1% NP-40, 20% glycerol, 1 mM DTT,
4 M urea), and this was mixed well using a plate mixer.
[0892] After the plate was incubated at 30.degree. C. for 60
minutes, the reaction solution was discarded, followed by washing
with 250 .mu.l of a washing buffer (composition: 150 mM MOPS
(pH7.2), 50 mM 2-mercaptoethanol, 25% glycerol, 500 .mu.g/ml bovine
serum albumin-fraction V) three times.
[0893] Then, to each well were added 12 .mu.l of a buffer
(composition: 150 mM MOPS (pH7.2), 75 mM MgCl.sub.2, 50 mM
2-mercaptoethanol, 25% glycerol, 500 .mu.g/ml bovine serum
albumin-fraction V), and 53 .mu.l of a reaction solution prepared
from 41 .mu.l of distilled water. Further, 6 .mu.l of a solution of
a test compound in DMSO was added to each well, and 6 .mu.l of DMSO
was added to a well as a positive control (PC), followed by mixing
well using a plate mixer. After the plate was incubated at
30.degree. C. for 30 minutes, 1 .mu.l of a target DNA (5
pmol/.mu.l) was added, and this was mixed well using a plate
mixer.
[0894] After each plate was incubated at 30.degree. C. for 10
minutes, the reaction solution was discarded, followed by washing
with a phosphate buffer two times. Then, an anti-digoxigenin
antibody labeled with alkaline phosphatase (sheep Fab fragment:
manufactured by Boehringer) was diluted 2000-fold with an antibody
diluting solution, 100 .mu.l of the diluent was added to bind at
30.degree. C. for 1 hour, and this was washed successively with a
phosphate buffer containing 0.05% Tween 20 two times, and a
phosphate buffer once. Then, 150 .mu.l of an alkaline phosphatase
coloring buffer (composition: 10 mM paranitrophenyl phosphate
(manufactured by Vector Laboratories), 5 mM MgCl.sub.2, 100 nM
NaCl, 100 mM Tris-HCl (pH 9.5)) was added to react at 30.degree. C.
for 2 hours, 50 .mu.l of a 1N NaOH solution was added to stop the
reaction, an absorbance (OD405 nm) of each well was measured, and
an inhibition rate (IC.sub.50) was obtained according to the
following calculation equation.
Inhibition rate (%)=100[1-{(Cabs.-NCabs.)/(PCabs.-NCabs.)}] [0895]
C abs.: absorbance of well of compound [0896] NC abs.: absorbance
of NC [0897] PC abs.: absorbance of PC
[0898] Results are shown below.
TABLE-US-00003 TABLE 1 Integrase inhibitory activity Example No.
(IC50, ng/ml) C-2 3.3 F-2 3.8 H-2 3.2
[0899] The present compound showed the strong integrase inhibitory
activity against HIV.
Experimental Example 2
[0900] A derivative of 293T cells expressing an attachment factor
to improve adherence to plastic were used for the assay. A VSV-g
pseudotyped HIV vector that expresses luciferase (herein referred
to as PHIV) was produced by transfection of cells with the
pGJ3-Luci vector plasmid (Jarmy, G. et al., J. Medical Virology,
64: 223-231, 2001) and pVSV-g (Clontech). Cells were mixed with the
PHIV vector and then mixed with serially diluted compounds. After
incubation at 37.degree. C. and 5% CO.sub.2 for two days, the
plates were read by using Steady Glo luciferase assay reagent
(Promega) as recommended by the manufacturer. To assess non-HIV
specific inhibition, a similar assay was performed, except that
cell/PHIV vector mixture was replaced by cells which had been
previously transduced and constitutively expressed luciferase.
TABLE-US-00004 TABLE 2 PHIV IC.sub.50 * = <10 nM, Example ** =
10-100 nM, number *** >100 nM Z-1 * Z-2 * Z-3 * Z-4 * Z-5 * Z-6
* Z-7 * Z-8 ** Z-9 * Z-10 * Z-11 * Z-12 * Z-13 ** Z-14 ** Z-15 *
Z-16 * Z-17 --* Z-18 * Z-19 * Z-20 ** Z-21 * Z-22 * Z-23 * Z-24 *
Z-25 * Z-26 * Z-27 *** Z-28 * Z-29 * Z-30 * Z-31 * Z-32 * Z-33 *
Z-34 * Z-35 * Z-36 * Z-37 * Z-38 ** Z-39 * Z-40 * Z-41 * Z-42 *
Z-43 * Z-44 * Z-45 * Z-46 * Z-47 * Z-48 * Z-49 * Z-50 * Z-51 * Z-52
* Z-53 * Z-54 * Z-55 ** Z-59 * Z-60 *
Formulation Example
[0901] A term "active ingredient" means the present compound, a
tautomer thereof, a pharmaceutically acceptable thereof, or a
solvate thereof.
Formulation Example 1
[0902] A hard gelatin capsule is prepared using the following
ingredients:
TABLE-US-00005 dose (mg/capsule) Active ingredient 250 Starch
(dried) 200 Magnesium stearate 10 Total 460 mg
Formulation Example 2
[0903] A tablet is prepared using the following ingredients:
TABLE-US-00006 dose (mg/tablet) Active ingredient 250 Cellulose
(microcrystalline) 400 Silicon dioxide (fumed) 10 Stearic acid 5
Total 665 mg
[0904] Ingredients are mixed, and compressed to obtain tablets,
each weighing 665 mg.
* * * * *