U.S. patent application number 14/142313 was filed with the patent office on 2014-08-07 for substituted spiropyrido[1,2-a]pyrazine derivative and pharmaceutical use of same as hiv integrase inhibitor.
This patent application is currently assigned to JAPAN TOBACCO INC.. The applicant listed for this patent is JAPAN TOBACCO INC.. Invention is credited to Hirotaka ISOSHIMA, Seiji KAWASHITA, Susumu MIYAZAKI, Noboru NAGAHASHI, Kengo OSHITA, Masakazu TERASHITA.
Application Number | 20140221380 14/142313 |
Document ID | / |
Family ID | 51021350 |
Filed Date | 2014-08-07 |
United States Patent
Application |
20140221380 |
Kind Code |
A1 |
MIYAZAKI; Susumu ; et
al. |
August 7, 2014 |
SUBSTITUTED SPIROPYRIDO[1,2-a]PYRAZINE DERIVATIVE AND
PHARMACEUTICAL USE OF SAME AS HIV INTEGRASE INHIBITOR
Abstract
[Summary] [Problem] Provided is a substituted
spiropyrido[1,2-a]pyrazine derivative or a pharmaceutically
acceptable salt thereof, which is useful as an anti-HIV agent.
[Solving Means] The present invention relates to a compound
represented by the following formula [I] or [II] or a
pharmaceutically acceptable salt thereof: ##STR00001## wherein each
symbol is as defined in the specification.
Inventors: |
MIYAZAKI; Susumu; (Osaka,
JP) ; ISOSHIMA; Hirotaka; (Osaka, JP) ;
OSHITA; Kengo; (Osaka, JP) ; KAWASHITA; Seiji;
(Osaka, JP) ; NAGAHASHI; Noboru; (Osaka, JP)
; TERASHITA; Masakazu; (Osaka, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
JAPAN TOBACCO INC. |
TOKYO |
|
JP |
|
|
Assignee: |
JAPAN TOBACCO INC.
TOKYO
JP
|
Family ID: |
51021350 |
Appl. No.: |
14/142313 |
Filed: |
December 27, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61746457 |
Dec 27, 2012 |
|
|
|
Current U.S.
Class: |
514/250 ;
544/231 |
Current CPC
Class: |
C07D 471/10 20130101;
A61P 43/00 20180101; C07D 471/04 20130101; A61P 31/18 20180101;
C07D 487/10 20130101; A61K 45/06 20130101; A61K 31/499
20130101 |
Class at
Publication: |
514/250 ;
544/231 |
International
Class: |
C07D 471/04 20060101
C07D471/04; A61K 45/06 20060101 A61K045/06; A61K 31/499 20060101
A61K031/499 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 27, 2012 |
JP |
2012284827 |
Claims
1. A compound represented by the following formula [I] or [II], or
a pharmaceutically acceptable salt thereof: ##STR00354## wherein
R.sup.1 is halogen atom, R.sup.2 is hydrogen atom, halogen atom or
trifluoromethyl group, each R.sup.3 is the same or different and is
(1) halogen atom, (2) C.sub.1-6 alkoxy group, or (3)
2-oxopyrrolidinyl group, R.sup.4 is C.sub.1-6alkyl group or
cyclopropyl group, R.sup.5 is (1) hydroxy group, (2) C.sub.1-6
alkoxy group, (3) benzyloxy group, (4) C.sub.1-6alkoxy C.sub.2-6
alkyleneoxy group, (5) carboxy group, (6) --CO--NR.sup.6aR.sup.6b
wherein R.sup.6a and R.sup.6b are the same or different and each is
(i) hydrogen atom, or (ii) C.sub.1-6 alkyl group, (7)
--NR.sup.7aCOR.sup.7b wherein R.sup.7a and R.sup.7b are the same or
different and each is (i) hydrogen atom, or (ii) C.sub.1-6 alkyl
group, (8) methanesulfonyl group, or (9) methanesulfonyloxy group,
p is an integer of 0 to 3, q is 0 or 1, and r is 0 or 1.
2. The compound according to claim 1, wherein q is 1 or a
pharmaceutically acceptable salt thereof.
3. The compound according to claim 1, wherein q is 0 or a
pharmaceutically acceptable salt thereof.
4. The compound according to claim 1, wherein p is 0 or 1, or a
pharmaceutically acceptable salt thereof.
5. The compound according to claim 1, wherein r is 1, or a
pharmaceutically acceptable salt thereof.
6. The compound according to claim 1, wherein r is 0, or a
pharmaceutically acceptable salt thereof.
7. The compound according to claim 1, wherein R.sup.2 is halogen
atom, or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1, wherein R.sup.4 is C.sub.1-6
alkyl group, or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1, wherein R.sup.5 is (1)
hydroxy group, (2) C.sub.1-6 alkoxy group, (3) benzyloxy group, (4)
C.sub.1-6 alkoxy C.sub.2-6alkyleneoxy group, (5) carboxy group, or
(6) --CO--NR.sup.6aR.sup.6b wherein R.sup.6a and R.sup.6b are the
same or different and each is (i) hydrogen atom, or (ii)
C.sub.1-6alkyl group, or a pharmaceutically acceptable salt
thereof.
10. The compound according to claim 9, wherein R.sup.5 is (1)
hydroxy group, (2) C.sub.1-6 alkoxy group, or (3)
--CO--NR.sup.6aR.sup.6b wherein R.sup.6a and R.sup.6b are the same
or different and each is (i) hydrogen atom, or (ii) C.sub.1-6 alkyl
group, or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising the compound according
to claim 1 or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
12. An anti-HIV agent comprising the compound according to claim 1
or a pharmaceutically acceptable salt thereof, as an active
ingredient.
13. An HIV integrase inhibitor comprising the compound according to
claim 1 or a pharmaceutically acceptable salt thereof, as an active
ingredient.
14. An anti-HIV agent comprising the compound according to claim 1
or a pharmaceutically acceptable salt thereof, in combination with
one or more other kinds of anti-HIV active substances.
15. (canceled)
16. (canceled)
17. A method for the prophylaxis or treatment of an HIV infection
in a mammal, comprising administering an effective amount of the
compound according to claim 1 or a pharmaceutically acceptable salt
thereof, to the mammal.
18. The method according to claim 17, further comprising
administering an effective amount of one or more other kinds of
anti-HIV active substances to the mammal.
19. A method for inhibiting HIV integrase in a mammal, comprising
administering an effective amount of the compound according to
claim 1 or a pharmaceutically acceptable salt thereof, to the
mammal.
Description
TECHNICAL FIELD
[0001] The present invention relates to a substituted
spiropyrido[1,2-a]pyrazine derivative useful as an anti-HIV agent
and a pharmaceutically acceptable salt thereof. In addition, the
present invention relates to a pharmaceutical composition
comprising the derivative or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier; an anti-HIV
agent, an HIV integrase inhibitor and the like, comprising the
derivative or a pharmaceutically acceptable salt thereof as an
active ingredient; an anti-HIV agent comprising a combination of
the derivative or a pharmaceutically acceptable salt thereof, and
one or more kinds of other anti-HIV active substances; and the
like.
BACKGROUND ART
[0002] HIV (Human Immunodeficiency Virus (type 1)) belonging to
retrovirus is a causative virus of AIDS (Acquired Immunodeficiency
Syndrome).
[0003] HIV targets CD4 positive cell groups such as helper T cell,
macrophage and dendritic cell and destroys these immunocompetent
cells to cause immunodeficiency.
[0004] Accordingly, a medicament that eradicates HIV in a living
organism or suppresses its growth is effective for the prophylaxis
or treatment of AIDS.
[0005] HIV possesses a bimolecular RNA gene in a shell, which is
covered with an envelope protein. The RNA codes for several enzymes
(protease, reverse transcriptase, integrase) characteristic of the
virus and the like. Translated reverse transcriptase and integrase
are present in the shell, and protease is present inside and
outside the shell.
[0006] HIV contacts and invades a host cell, causes uncoating, and
releases a complex of RNA and integrase and the like into the
cytoplasm. From the RNA, DNA is transcribed by reverse
transcriptase, and a full length double stranded DNA is produced.
The DNA moves into the nucleus of the host cell and is incorporated
by integrase into the DNA of the host cell. The incorporated DNA is
converted to an mRNA by polymerase of the host cell, from which
mRNA various proteins necessary for forming a virus are synthesized
by HIV protease and the like, and a virus particle is finally
formed, which then undergoes budding and its release.
[0007] These virus specific enzymes are considered to be essential
for the growth of HIV. These enzymes are drawing attention as the
target of the development of antiviral agents, and several anti-HIV
agents have been already developed.
[0008] For example, zidovudine, didanosine, lamivudine and the like
have been already on the market as reverse transcriptase
inhibitors, and indinavir, nelfinavir and the like as protease
inhibitors.
[0009] In addition, a multiple drug combination therapy using these
medicaments in combination (to be also referred to as HAART (highly
active antiretroviral therapy)) is also used. For example, 3 agent
combination therapy using two agents from reverse transcriptase
inhibitors (zidovudine and lamivudine, or tenofovir and
emtricitabine), and a non-nucleoside reverse transcriptase
inhibitor (efavirenz), or a protease inhibitor (lopinavir,
fosamprenavir or atazanavir) in combination with ritonavir, and the
like is used in clinical practice, and such cART is becoming the
mainstream of the AIDS treatment.
[0010] However, some of these medicaments are known to cause side
effects such as liver function failure, central nervous disorders
(e.g., vertigo), and the like. In addition, acquisition of
resistance to a medicament causes a problem. Even worse, emergence
of an HIV that shows multiple drug resistance in a cART has been
known.
[0011] Under the circumstances, a further development of a novel
medicament, particularly a development of an anti-HIV agent based
on a new mechanism, has been desired, wherein a development of an
anti-HIV agent having an integrase inhibitory activity is expected,
because the integrase that is a feature of retrovirus is an
essential enzyme for the growth of HIV.
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0012] From the findings obtained from pharmacological studies and
clinical results heretofore, an anti-HIV agent is effective for the
prophylaxis or treatment of AIDS, and particularly a compound
having an integrase inhibitory activity can be an effective
anti-HIV agent.
[0013] Therefore, the present invention aims at provision of a
compound having an anti-HIV activity, particularly a compound
having an integrase inhibitory activity.
Means of Solving the Problems
[0014] The present inventors have conducted intensive studies in an
attempt to find a compound having an anti-HIV action, particularly
a compound having the integrase inhibitory action, and completed
the present invention.
[0015] More specifically, the present invention provides the
following.
[1] A compound represented by the following formula [I] or [II] or
a pharmaceutically acceptable salt thereof:
##STR00002##
wherein R.sup.1 is halogen atom, R.sup.2 is hydrogen atom, halogen
atom or trifluoromethyl group, each R.sup.3 is the same or
different and is
[0016] (1) halogen atom,
[0017] (2) C.sub.1-6 alkoxy group, or
[0018] (3) 2-oxopyrrolidinyl group,
R.sup.4 is C.sub.1-6 alkyl group or cyclopropyl group,
R.sup.5 is
[0019] (1) hydroxy group,
[0020] (2) C.sub.1-6 alkoxy group,
[0021] (3) benzyloxy group,
[0022] (4) C.sub.1-6 alkoxy C.sub.2-6 alkyleneoxy group,
[0023] (5) carboxy group,
[0024] (6) --CO--NR.sup.6aR.sup.6b [0025] wherein R.sup.6a and
R.sup.6b are the same or different and each is [0026] (i) hydrogen
atom, or [0027] (ii) C.sub.1-6 alkyl group,
[0028] (7) --NR.sup.7aCOR.sup.7b [0029] wherein R.sup.7a and
R.sup.7b are the same or different and each is [0030] (i) hydrogen
atom, or [0031] (ii) C.sub.1-6 alkyl group,
[0032] (8) methanesulfonyl group, or
[0033] (9) methanesulfonyloxy group,
p is an integer of 0 to 3, q is 0 or 1, and r is 0 or 1. [2] The
compound of the above-mentioned [1], wherein q is 1 or a
pharmaceutically acceptable salt thereof. [3] The compound of the
above-mentioned [1], wherein q is 0 or a pharmaceutically
acceptable salt thereof. [4] The compound of the above-mentioned
[1], wherein p is 0 or 1, or a pharmaceutically acceptable salt
thereof. [5] The compound of any one of the above-mentioned [1] to
[4], wherein r is 1, or a pharmaceutically acceptable salt thereof.
[6] The compound of any one of the above-mentioned [1] to [4],
wherein r is 0, or a pharmaceutically acceptable salt thereof. [7]
The compound of any one of the above-mentioned [1] to [4], wherein
R.sup.2 is halogen atom, or a pharmaceutically acceptable salt
thereof. [8] The compound of any one of the above-mentioned [1] to
[4], wherein R.sup.4 is C.sub.1-6 alkyl group, or a
pharmaceutically acceptable salt thereof. [9] The compound of any
one of the above-mentioned [1] to [4], wherein R.sup.5 is
[0034] (1) hydroxy group,
[0035] (2) C.sub.1-6 alkoxy group,
[0036] (3) benzyloxy group,
[0037] (4) C.sub.1-6 alkoxy C.sub.2-6 alkyleneoxy group,
[0038] (5) carboxy group, or
[0039] (6) --CO--NR.sup.6aR.sup.6b [0040] wherein R.sup.6a and
R.sup.6b are the same or different and each is [0041] (i) hydrogen
atom, or [0042] (ii) C.sub.1-6 alkyl group, or a pharmaceutically
acceptable salt thereof.
[0043] [10] The compound of the above-mentioned [9], wherein
R.sup.5 is
[0044] (1) hydroxy group,
[0045] (2) C.sub.1-6 alkoxy group, or
[0046] (3) --CO--NR.sup.6aR.sup.6b [0047] wherein R.sup.6a and
R.sup.6b are the same or different and each is [0048] (i) hydrogen
atom, or [0049] (ii) C.sub.1-6 alkyl group, or a pharmaceutically
acceptable salt thereof. [11] A pharmaceutical composition
comprising the compound of any one of the above-mentioned [1] to
[10] or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier. [12] An anti-HIV agent
comprising the compound of any one of the above-mentioned [1] to
[10] or a pharmaceutically acceptable salt thereof, as an active
ingredient. [13] An HIV integrase inhibitor comprising the compound
of any one of the above-mentioned [1] to [10] or a pharmaceutically
acceptable salt thereof, as an active ingredient. [14] An anti-HIV
agent comprising the compound of any one of the above-mentioned [1]
to [10] or a pharmaceutically acceptable salt thereof, in
combination with one or more other kinds of anti-HIV active
substances. [15] Use of the compound of any one of the
above-mentioned [1] to [10] or a pharmaceutically acceptable salt
thereof, for the production of an anti-HIV agent. [16] Use of the
compound of any one of the above-mentioned [1] to [10] or a
pharmaceutically acceptable salt thereof, for the production of an
HIV integrase inhibitor. [17] A method for the prophylaxis or
treatment of an HIV infection in a mammal, comprising administering
an effective amount of the compound of any one of the
above-mentioned [1] to [10] or a pharmaceutically acceptable salt
thereof, to the mammal. [18] The method of the above-mentioned
[17], further comprising administering an effective amount of one
or more other kinds of anti-HIV active substances to the mammal.
[19] A method for inhibiting HIV integrase in a mammal, comprising
administering an effective amount of the compound of any one of the
above-mentioned [1] to [10] or a pharmaceutically acceptable salt
thereof, to the mammal.
Effect of the Invention
[0050] The compound of the present invention can be medicaments
effective for the prophylaxis or treatment of HIV infections or
AIDS, as anti-HIV agents, having an HIV integrase inhibitory
activity. In addition, by a combined use with other anti-HIV
agent(s) such as protease inhibitor, reverse transcriptase
inhibitor and the like, they can be more effective anti-HIV agents.
Furthermore, having high inhibitory activity specific for
integrase, they can be medicaments safe for human body with a fewer
side effects.
DESCRIPTION OF EMBODIMENTS
[0051] The definitions of respective substituents and terms in
respective moieties used in the present specification are as
follows.
[0052] The "halogen atom" is fluorine atom, chlorine atom, bromine
atom or iodine atom. It is preferably fluorine atom or chlorine
atom.
[0053] The "C.sub.1-6 alkyl group" is a straight chain or branched
chain alkyl group having 1 to 6 carbon atoms, preferably a straight
chain or branched chain alkyl group having 1 to 4 carbon atoms.
Specific examples include methyl group, ethyl group, propyl group,
isopropyl group, butyl group, isobutyl group, sec-butyl group,
tert-butyl group, pentyl group, isopentyl group, 1,1-dimethylpropyl
group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group,
1-ethylpropyl group, hexyl group and the like, and methyl group,
ethyl group, propyl group, isopropyl group, butyl group, isobutyl
group, sec-butyl group or tert-butyl group is preferable.
[0054] The "C.sub.1-6 alkoxy group" is a straight chain or branched
chain alkoxy group having 1 to 6 carbon atoms, preferably a
straight chain or branched chain alkoxy group having 1 to 4 carbon
atoms. Specific examples include methoxy group, ethoxy group,
propoxy group, isopropoxy group, butoxy group, isobutyloxy group,
tert-butyloxy group, pentyloxy group, hexyloxy group and the like,
more preferably, methoxy group, ethoxy group, propoxy group,
isopropoxy group, butoxy group, isobutyloxy group or tert-butyloxy
group.
[0055] The "C.sub.1-6 alkoxy C.sub.2-6alkyleneoxy group" is
alkoxyalkyleneoxy group wherein the alkoxy moiety is the
above-defined "C.sub.1-6 alkoxy group" and the alkyleneoxy moiety
is a straight chain or branched chain alkyleneoxy group having 2 to
6 carbon atoms. It is preferably alkoxyalkyleneoxy group wherein
the alkoxy moiety is a straight chain or branched chain alkoxy
group having 1 to 4 carbon atoms and the alkyleneoxy moiety is a
straight chain or branched chain alkyleneoxy group having 2 to 4
carbon atoms. For example, methoxyethoxy group, methoxypropoxy
group, methoxybutoxy group, methoxypentyloxy group, methoxyhexyloxy
group, ethoxyethoxy group, ethoxypropoxy group, ethoxybutoxy group,
ethoxypentyloxy group, ethoxyhexyloxy group, propoxyethoxy group,
propoxypropoxy group, propoxybutoxy group, propoxypentyloxy group,
propoxyhexyloxy group, butoxyethoxy group, butoxypropoxy group,
butoxybutoxy group, butoxypentyloxy group, butoxyhexyloxy group,
pentyloxyethoxy group, pentyloxypropoxy group, pentyloxybutoxy
group, pentyloxypentyloxy group, pentyloxyhexyloxy group,
hexyloxyethoxy group, hexyloxypropoxy group, hexyloxybutoxy group,
hexyloxypentyloxy group, hexyloxyhexyloxy group and the like can be
mentioned, with preference given to methoxyethoxy group and
methoxypropoxy group.
[0056] In the compounds represented by the formula [I] or [II],
preferable embodiments are as described below.
##STR00003##
[0057] A preferable embodiment of R.sup.1 is fluorine atom.
[0058] A preferable embodiment of R.sup.2 is hydrogen atom,
chlorine atom or trifluoromethyl group. A more preferable
embodiment of R.sup.2 is hydrogen atom or chlorine atom.
[0059] One of the preferable embodiments of R.sup.3 is the same or
different and is halogen atom or C.sub.1-6 alkoxy group.
[0060] One of the preferable embodiments of R.sup.3 is fluorine
atom, methoxy group, ethoxy group, isopropoxy group or
2-oxopyrrolidinyl group. A more preferable embodiment of R.sup.3 is
fluorine atom, methoxy group, ethoxy group or isopropoxy group.
[0061] A preferable embodiment of p is 0 or 1. A more preferable
embodiment of p is 0.
[0062] In a preferable embodiment of a combination of R.sup.2 and
p, R.sup.2 is halogen atom and p is 0. In a more preferable
embodiment of a combination of R.sup.2 and p, R.sup.2 is chlorine
atom and p is 0.
[0063] In a preferable embodiment of a combination of R.sup.2,
R.sup.3 and p, R.sup.2 is hydrogen atom, R.sup.3 is halogen atom,
and p is 1. More preferably, R.sup.2 is hydrogen atom, R.sup.3 is
fluorine atom, and p is 1.
[0064] A preferable embodiment of R.sup.4 is methyl group, ethyl
group, isopropyl group or cyclopropyl group. A more preferable
embodiment of R.sup.4 is methyl group, ethyl group or isopropyl
group.
[0065] One of the preferable embodiments of R.sup.5 is hydroxy
group, C.sub.1-6 alkoxy group or --CO--NR.sup.6aR.sup.6b. A more
preferable embodiment of R.sup.5 is hydroxy group. A more
preferable embodiment of R.sup.5 is C.sub.1-6 alkoxy group. A more
preferable embodiment of R.sup.5 is --CO--NR.sup.6aR.sup.6b
[0066] One of the preferable embodiments of R.sup.5 is hydroxy
group, methoxy group, ethoxy group, propoxy group, isopropoxy
group, benzyloxy group, 2-methoxyethoxy group, carboxy group,
methylcarbamoyl group, dimethylcarbamoyl group, acetylamino group,
N-acetyl-N-methylamino group, methanesulfonyl group or
methanesulfonyloxy group. A more preferable embodiment of R.sup.5
is hydroxy group. A more preferable embodiment of R.sup.5 is
methoxy group, ethoxy group, propoxy group or isopropoxy group. A
more preferable embodiment of R.sup.5 is methylcarbamoyl group or
dimethylcarbamoyl group.
[0067] A preferable embodiment of a compound represented by the
formula [I] or [II], wherein q is 1, is as described below.
[0068] R.sup.1 is halogen atom,
[0069] R.sup.2 is hydrogen atom or halogen atom,
[0070] R.sup.3 is
[0071] (1) halogen atom, or
[0072] (2) C.sub.1-6 alkoxy group,
[0073] R.sup.4 is C.sub.1-6 alkyl group,
[0074] R.sup.5 is
[0075] (1) hydroxy group,
[0076] (2) C.sub.1-6 alkoxy group,
[0077] (3) benzyloxy group,
[0078] (4) C.sub.1-6 alkoxy C.sub.2-6 alkyleneoxy group,
[0079] (5) --CO--NR.sup.6aR.sup.6b [0080] wherein R.sup.6a and
R.sup.6b are the same or different and each is [0081] (i) hydrogen
atom, or [0082] (ii) C.sub.1-6 alkyl group,
[0083] (6) --NR.sup.7aCOR.sup.7b [0084] wherein R.sup.7a and
R.sup.7b are the same or different and each is [0085] (i) hydrogen
atom, or [0086] (ii) C.sub.1-6 alkyl group, or
[0087] (7) methanesulfonyloxy group, and
[0088] p is 0 or 1.
[0089] A preferable embodiment of R.sup.1 is fluorine atom.
[0090] A preferable embodiment of R.sup.2 is hydrogen atom or
chlorine atom.
[0091] A preferable embodiment of R.sup.3 is fluorine atom or
methoxy group.
[0092] A preferable embodiment of R.sup.4 is methyl group, ethyl
group or isopropyl group.
[0093] One of the preferable embodiments of R.sup.5 is hydroxy
group, C.sub.1-6 alkoxy group or --CO--NR.sup.6aR.sup.6b. A more
preferable embodiment of R.sup.5 is hydroxy group. A more
preferable embodiment of R.sup.5 is C.sub.1-6 alkoxy group. A more
preferable embodiment of R.sup.5 is --CO--NR.sup.6aR.sup.6b
[0094] One of the preferable embodiments of R.sup.5 is hydroxy
group, methoxy group, ethoxy group, propoxy group, isopropoxy
group, benzyloxy group, 2-methoxyethoxy group, methylcarbamoyl
group, dimethylcarbamoyl group, acetylamino group,
N-acetyl-N-methylamino group or methanesulfonyloxy group. A more
preferable embodiment of R.sup.5 is hydroxy group. A more
preferable embodiment of R.sup.5 is methoxy group, ethoxy group,
propoxy group or isopropoxy group. A more preferable embodiment of
R.sup.5 is methylcarbamoyl group or dimethylcarbamoyl group.
[0095] A preferable embodiment of p is 0.
[0096] A preferable embodiment of a compound represented by the
formula [I] or [II], wherein q is 1 and r is 1, is as described
below.
[0097] R.sup.1 is halogen atom,
[0098] R.sup.2 is hydrogen atom or halogen atom,
[0099] R.sup.3 is
[0100] (1) halogen atom, or
[0101] (2) C.sub.1-6 alkoxy group,
[0102] R.sup.4 is C.sub.1-6 alkyl group,
[0103] R.sup.5 is
[0104] (1) hydroxy group,
[0105] (2) C.sub.1-6 alkoxy group, or
[0106] (3) --NR.sup.7aCOR.sup.7b [0107] wherein R.sup.7a and
R.sup.7b are the same or different and each is [0108] (i) hydrogen
atom, or [0109] (ii) C.sub.1-6 alkyl group, and
[0110] p is 0 or 1.
[0111] A preferable embodiment of R.sup.1 is fluorine atom.
[0112] A preferable embodiment of R.sup.2 is hydrogen atom or
chlorine atom.
[0113] A preferable embodiment of R.sup.3 is fluorine atom or
methoxy group.
[0114] A preferable embodiment of R.sup.4 is methyl group, ethyl
group or isopropyl group.
[0115] One of the preferable embodiments of R.sup.5 is hydroxy
group or C.sub.1-6 alkoxy group.
[0116] One of the preferable embodiments of R.sup.5 is hydroxy
group, methoxy group, ethoxy group or acetylamino group. A more
preferable embodiment of R.sup.5 is hydroxy group. A more
preferable embodiment of R.sup.5 is methoxy group or ethoxy
group.
[0117] A preferable embodiment of p is 0.
[0118] A preferable embodiment of a compound represented by the
formula [I] or [II], wherein q is 1 and r is 0, is as described
below.
[0119] R.sup.1 is halogen atom,
[0120] R.sup.2 is hydrogen atom or halogen atom,
[0121] R.sup.3 is halogen atom or C.sub.1-6 alkoxy group,
[0122] R.sup.4 is C.sub.1-6 alkyl group,
[0123] R.sup.5 is
[0124] (1) hydroxy group,
[0125] (2) C.sub.1-6 alkoxy group,
[0126] (3) benzyloxy group,
[0127] (4) C.sub.1-6 alkoxy C.sub.2-6alkyleneoxy group,
[0128] (5) --CO--NR.sup.6aR.sup.6b [0129] wherein R.sup.6a and
R.sup.6b are the same or different and each is [0130] (i) hydrogen
atom, or [0131] (ii) C.sub.1-6 alkyl group,
[0132] (6) --NR.sup.7aCOR.sup.7b [0133] wherein R.sup.7a and
R.sup.7b are the same or different and each is [0134] (i) hydrogen
atom, or [0135] (ii) C.sub.1-6 alkyl group, or
[0136] (7) methanesulfonyloxy group, and
[0137] p is 0 or i.
[0138] A preferable embodiment of R.sup.1 is fluorine atom.
[0139] A preferable embodiment of R.sup.2 is hydrogen atom or
chlorine atom.
[0140] A preferable embodiment of R.sup.3 is fluorine atom or
methoxy group.
[0141] A preferable embodiment of R.sup.4 is methyl group, ethyl
group or isopropyl group.
[0142] One of the preferable embodiments of R.sup.5 is hydroxy
group, C.sub.1-6 alkoxy group or --CO--NR.sup.6aR.sup.6b. A more
preferable embodiment of R.sup.5 is hydroxy group. A more
preferable embodiment of R.sup.5 is C.sub.1-6 alkoxy group. A more
preferable embodiment of R.sup.5 is --CO--NR.sup.6aR.sup.6b
[0143] One of the preferable embodiments of R.sup.5 is hydroxy
group, methoxy group, ethoxy group, propoxy group, isopropoxy
group, benzyloxy group, 2-methoxyethoxy group, methylcarbamoyl
group, dimethylcarbamoyl group, N-acetyl-N-methylamino group or
methanesulfonyloxy group. A more preferable embodiment of R.sup.5
is hydroxy group. A more preferable embodiment of R.sup.5 is
methoxy group, ethoxy group, propoxy group or isopropoxy group. A
more preferable embodiment of R.sup.5 is methylcarbamoyl group or
dimethylcarbamoyl group.
[0144] A preferable embodiment of p is 0.
[0145] A preferable embodiment of a compound represented by the
formula [I] or [II], wherein q is 0, is as described below.
[0146] R.sup.1 is halogen atom,
[0147] R.sup.2 is hydrogen atom, halogen atom or trifluoromethyl
group,
[0148] R.sup.3 is
[0149] (1) halogen atom,
[0150] (2) C.sub.1-6 alkoxy group, or
[0151] (3) 2-oxopyrrolidinyl group,
[0152] R.sup.4 is C.sub.1-6 alkyl group or cyclopropyl group,
[0153] R.sup.5 is
[0154] (1) hydroxy group,
[0155] (2) C.sub.1-6 alkoxy group,
[0156] (3) carboxy group,
[0157] (4) --CO--NR.sup.6aR.sup.6b [0158] wherein R.sup.6a and
R.sup.6b are the same or different and each is [0159] (i) hydrogen
atom, or [0160] (ii) C.sub.1-6 alkyl group, or
[0161] (5) methanesulfonyl group, and
[0162] p is 0 or 1.
[0163] A preferable embodiment of R.sup.1 is fluorine atom.
[0164] A preferable embodiment of R.sup.2 is hydrogen atom,
chlorine atom or trifluoromethyl group. A more preferable
embodiment of R.sup.2 is hydrogen atom. A more preferable
embodiment of R.sup.2 is chlorine atom.
[0165] One of the preferable embodiments of R.sup.3 is halogen atom
or C.sub.1-6 alkoxy group.
[0166] One of the preferable embodiments of R.sup.3 is fluorine
atom, methoxy group, ethoxy group, isopropoxy group or
2-oxopyrrolidinyl group. A more preferable embodiment of R.sup.3 is
fluorine atom. A more preferable embodiment of R.sup.3 is methoxy
group, ethoxy group or isopropoxy group.
[0167] A preferable embodiment of R.sup.4 is methyl group, ethyl
group, isopropyl group or cyclopropyl group. A preferable
embodiment of R.sup.4 is methyl group, ethyl group or isopropyl
group.
[0168] One of the preferable embodiments of R.sup.5 is hydroxy
group, C.sub.1-6 alkoxy group or --CO--NR.sup.6aR.sup.6b. A more
preferable embodiment of R.sup.5 is hydroxy group. A more
preferable embodiment of R.sup.5 is C.sub.1-6 alkoxy group. A more
preferable embodiment of R.sup.5 is --CO--NR.sup.6aR.sup.6b.
[0169] One of the preferable embodiments of R.sup.5 is hydroxy
group, methoxy group, ethoxy group, carboxy group, methylcarbamoyl
group, dimethylcarbamoyl group or methanesulfonyl group. A more
preferable embodiment of R.sup.5 is hydroxy group. A more
preferable embodiment of R.sup.5 is methoxy group or ethoxy group.
A more preferable embodiment of R.sup.5 is methylcarbamoyl group or
dimethylcarbamoyl group.
[0170] A preferable embodiment of p is 0.
[0171] A preferable embodiment of a compound represented by the
formula [I] or [II], wherein q is 0 and r is 1, is as described
below.
[0172] R.sup.1 is halogen atom,
[0173] R.sup.2 is hydrogen atom, halogen atom or trifluoromethyl
group,
[0174] R.sup.3 is
[0175] (1) halogen atom,
[0176] (2) C.sub.1-6 alkoxy group, or
[0177] (3) 2-oxopyrrolidinyl group,
[0178] R.sup.4 is C.sub.6 alkyl group,
[0179] R.sup.5 is
[0180] (1) hydroxy group,
[0181] (2) C.sub.1-6 alkoxy group, or
[0182] (3) methanesulfonyl group, and
[0183] p is 0 or 1.
[0184] A preferable embodiment of R.sup.1 is fluorine atom.
[0185] A preferable embodiment of R.sup.2 is hydrogen atom,
chlorine atom or trifluoromethyl group. A more preferable
embodiment of R.sup.2 is hydrogen atom. A more preferable
embodiment of R.sup.2 is chlorine atom.
[0186] One of the preferable embodiments of R.sup.3 is halogen atom
or C.sub.1-6 alkoxy group.
[0187] One of the preferable embodiments of R.sup.3 is fluorine
atom, methoxy group, ethoxy group, isopropoxy group or
2-oxopyrrolidinyl group. A more preferable embodiment of R.sup.3 is
fluorine atom. A more preferable embodiment of R.sup.3 is methoxy
group, ethoxy group or isopropoxy group.
[0188] A preferable embodiment of R.sup.4 is methyl group, ethyl
group or isopropyl group.
[0189] One of the preferable embodiments of R.sup.5 is hydroxy
group or C.sub.1-6 alkoxy group.
[0190] One of the preferable embodiments of R.sup.5 is hydroxy
group, methoxy group, ethoxy group or methanesulfonyl group. A more
preferable embodiment of R.sup.5 is hydroxy group. A more
preferable embodiment of R.sup.5 is methoxy group or ethoxy
group.
[0191] A preferable embodiment of p is 0.
[0192] A preferable embodiment of a compound represented by the
formula [I] or [II], wherein q is 0 and r is 0, is as described
below.
[0193] R.sup.1 is halogen atom,
[0194] R.sup.2 is hydrogen atom or halogen atom,
[0195] R.sup.3 is halogen atom or C.sub.1-6 alkoxy group,
[0196] R.sup.4 is C.sub.1-6 alkyl group or cyclopropyl group,
[0197] R.sup.5 is
[0198] (1) carboxy group, or
[0199] (2) --CO--NR.sup.6aR.sup.6b [0200] wherein R.sup.6a and
R.sup.6b are the same or different and each is [0201] (i) hydrogen
atom, or [0202] (ii) C.sub.1-6 alkyl group, and
[0203] p is 0 or 1.
[0204] A preferable embodiment of R.sup.1 is fluorine atom.
[0205] A preferable embodiment of R.sup.2 is hydrogen atom or
chlorine atom.
[0206] A preferable embodiment of R.sup.3 is fluorine atom.
[0207] A preferable embodiment of R.sup.4 is ethyl group, isopropyl
group or cyclopropyl group. A more preferable embodiment of R.sup.4
is ethyl group or isopropyl group.
[0208] A preferable embodiment of R.sup.5 is carboxy group,
methylcarbamoyl group or dimethylcarbamoyl group.
[0209] One of the preferable embodiments of a compound represented
by the formula [I]
##STR00004##
wherein R.sup.1 is halogen atom, R.sup.2 is hydrogen atom, halogen
atom or trifluoromethyl group,
[0210] each R.sup.3 is the same or different and is
[0211] (1) halogen atom,
[0212] (2) C.sub.1-6 alkoxy group, or
[0213] (3) 2-oxopyrrolidinyl group,
R.sup.4 is C.sub.1-6 alkyl group or cyclopropyl group,
R.sup.5 is
[0214] (1) hydroxy group,
[0215] (2) C.sub.1-6 alkoxy group,
[0216] (3) benzyloxy group,
[0217] (4) C.sub.1-6 alkoxy C.sub.2-6 alkyleneoxy group,
[0218] (5) carboxy group,
[0219] (6) --CO--NR.sup.6aR.sup.6b [0220] wherein R.sup.6a and
R.sup.6b are the same or different and each is [0221] (i) hydrogen
atom, or [0222] (ii) C.sub.1-6 alkyl group,
[0223] (7) --NR.sup.7aCOR.sup.7b [0224] wherein R.sup.7a and
R.sup.7b are the same or different and each is [0225] (i) hydrogen
atom, or [0226] (ii) C.sub.1-6 alkyl group,
[0227] (8) methanesulfonyl group, or
[0228] (9) methanesulfonyloxy group,
p is an integer of 0 to 3, q is 0 or 1, and r is 0 or 1, is a
compound wherein q is 1.
[0229] One of the preferable embodiments of a compound represented
by the formula [I], wherein q is 1, is a compound wherein r is
1.
[0230] A preferable embodiment of a compound represented by the
formula [I], wherein q is 1 and r is 1, is as described below.
[0231] R.sup.1 is halogen atom,
[0232] R.sup.2 is hydrogen atom or halogen atom,
[0233] R.sup.3 is
[0234] (1) halogen atom, or
[0235] (2) C.sub.1-6 alkoxy group,
[0236] R.sup.4 is C.sub.1-6 alkyl group,
[0237] R.sup.5 is
[0238] (1) hydroxy group,
[0239] (2) C.sub.1-6 alkoxy group, or
[0240] (3) --NR.sup.7aCOR.sup.7b [0241] wherein R.sup.7a and
R.sup.7b are the same or different and each is [0242] (i) hydrogen
atom, or [0243] (ii) C.sub.1-6 alkyl group, and
[0244] p is 0 or 1.
[0245] A preferable embodiment of R.sup.1 is fluorine atom.
[0246] A preferable embodiment of R.sup.2 is hydrogen atom or
chlorine atom.
[0247] A preferable embodiment of R.sup.3 is fluorine atom or
methoxy group.
[0248] A preferable embodiment of R.sup.4 is methyl group, ethyl
group or isopropyl group.
[0249] A preferable embodiment of R.sup.5 is hydroxy group, methoxy
group, ethoxy group or acetylamino group.
[0250] One of the preferable embodiments of a compound represented
by the formula [II] wherein q is 1 is a compound wherein r is
0.
[0251] A preferable embodiment of a compound represented by the
formula [I], wherein q is 1 and r is 0, is as described below.
[0252] R.sup.1 is halogen atom,
[0253] R.sup.2 is hydrogen atom or halogen atom,
[0254] R.sup.3 is halogen atom,
[0255] R.sup.4 is C.sub.1-6 alkyl group,
[0256] R.sup.5 is
[0257] (1) hydroxy group,
[0258] (2) C.sub.1-6 alkoxy group,
[0259] (3) benzyloxy group,
[0260] (4) C.sub.1-6 alkoxy C.sub.2-6alkyleneoxy group,
[0261] (5) --CO--NR.sup.6aR.sup.6b [0262] wherein R.sup.6a and
R.sup.6b are the same or different and each is [0263] (i) hydrogen
atom, or [0264] (ii) C.sub.1-6 alkyl group,
[0265] (6) --NR.sup.7aCOR.sup.7b [0266] wherein R.sup.7a and
R.sup.7b are the same or different and each is [0267] (i) hydrogen
atom, or [0268] (ii) C.sub.1-6 alkyl group, or
[0269] (7) methanesulfonyloxy group, and
[0270] p is 0 or 1.
[0271] A preferable embodiment of R.sup.1 is fluorine atom.
[0272] A preferable embodiment of R.sup.2 is hydrogen atom or
chlorine atom.
[0273] A preferable embodiment of R.sup.3 is fluorine atom.
[0274] A preferable embodiment of R.sup.4 is methyl group, ethyl
group or isopropyl group.
[0275] A preferable embodiment of R.sup.5 is hydroxy group, methoxy
group, ethoxy group, propoxy group, isopropoxy group, benzyloxy
group, 2-methoxyethoxy group, methylcarbamoyl group,
dimethylcarbamoyl group, N-acetyl-N-methylamino group or
methanesulfonyloxy group.
[0276] One of the preferable embodiments of a compound represented
by the formula [I] is a compound wherein q is 0.
[0277] One of the preferable embodiments of a compound represented
by the formula [I] wherein q is 0 is a compound wherein r is 1.
[0278] A preferable embodiment of a compound represented by the
formula [I], wherein q is 0 and r is 1, is as described below.
[0279] R.sup.1 is halogen atom,
[0280] R.sup.2 is hydrogen atom, halogen atom or trifluoromethyl
group,
[0281] R.sup.3 is
[0282] (1) halogen atom,
[0283] (2) C.sub.1-6 alkoxy group, or
[0284] (3) 2-oxopyrrolidinyl group,
[0285] R.sup.4 is C.sub.1-6 alkyl group,
[0286] R.sup.5 is
[0287] (1) hydroxy group,
[0288] (2) C.sub.1-6 alkoxy group, or
[0289] (3) methanesulfonyl group, and
[0290] p is 0 or 1.
[0291] A preferable embodiment of R.sup.1 is fluorine atom.
[0292] A preferable embodiment of R.sup.2 is hydrogen atom,
chlorine atom or trifluoromethyl group.
[0293] A preferable embodiment of R.sup.3 is fluorine atom, methoxy
group, ethoxy group, isopropoxy group or 2-oxopyrrolidinyl
group.
[0294] A preferable embodiment of R.sup.4 is methyl group, ethyl
group or isopropyl group.
[0295] A preferable embodiment of R.sup.5 is hydroxy group, methoxy
group, ethoxy group or methanesulfonyl group.
[0296] One of the preferable embodiments of a compound represented
by the formula [I] wherein q is 0 is a compound wherein r is 0.
[0297] A preferable embodiment of a compound represented by the
formula [I], wherein q is 0 and r is 0, is as described below.
[0298] R.sup.1 is halogen atom,
[0299] R.sup.2 is hydrogen atom or halogen atom,
[0300] R.sup.3 is halogen atom,
[0301] R.sup.4 is C.sub.1-6 alkyl group or cyclopropyl group,
[0302] R.sup.5 is
[0303] (1) carboxy group, or
[0304] (2) --CO--NR.sup.6aR.sup.6b [0305] wherein R.sup.6a and
R.sup.6b are the same or different and each is [0306] (i) hydrogen
atom, or [0307] (ii) C.sub.1-6 alkyl group, and
[0308] p is 0 or 1.
[0309] A preferable embodiment of R.sup.1 is fluorine atom.
[0310] A preferable embodiment of R.sup.2 is hydrogen atom or
chlorine atom.
[0311] A preferable embodiment of R.sup.3 is fluorine atom.
[0312] A preferable embodiment of R.sup.4 is ethyl group, isopropyl
group or cyclopropyl group.
[0313] A preferable embodiment of R.sup.5 is carboxy group,
methylcarbamoyl group or dimethylcarbamoyl group.
[0314] One of the preferable embodiments of a compound represented
by the formula [I] is a compound wherein p is 0 or 1.
[0315] One of the preferable embodiments of a compound represented
by the formula [I] wherein p is 0 or 1 is a compound wherein q is
1.
[0316] One of the preferable embodiments of a compound represented
by the formula [I], wherein p is 0 or 1 and q is 1, is a compound
represented by the formula [I-1] or a pharmaceutically acceptable
salt thereof.
##STR00005##
wherein R.sup.10 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and r are as defined
in the formula [I].
[0317] One of the preferable embodiments of a compound represented
by the formula [I-1] is as described below.
[0318] R.sup.1 is halogen atom,
[0319] R.sup.2 is hydrogen atom or halogen atom,
[0320] R.sup.10 is
[0321] (1) hydrogen atom,
[0322] (2) halogen atom, or
[0323] (3) C.sub.6 alkoxy group,
[0324] R.sup.4 is C.sub.6 alkyl group,
[0325] R.sup.5 is
[0326] (1) hydroxy group,
[0327] (2) C.sub.1-6 alkoxy group,
[0328] (3) benzyloxy group,
[0329] (4) C.sub.1-6 alkoxy C.sub.2-6 alkyleneoxy group,
[0330] (5) --CO--NR.sup.6aR.sup.6b [0331] wherein R.sup.6a and
R.sup.6b are the same or different and each is [0332] (i) hydrogen
atom, or [0333] (ii) C.sub.1-6 alkyl group,
[0334] (6) --NR.sup.7aCOR.sup.7b [0335] wherein R.sup.7a and
R.sup.7b are the same or different and each is [0336] (i) hydrogen
atom, or [0337] (ii) C.sub.1-6 alkyl group, or
[0338] (7) methanesulfonyloxy group, and
[0339] r is 0 or 1.
[0340] A preferable embodiment of R.sup.1 is fluorine atom.
[0341] A preferable embodiment of R.sup.2 is hydrogen atom or
chlorine atom.
[0342] A preferable embodiment of R.sup.10 is hydrogen atom,
fluorine atom or methoxy group.
[0343] A preferable embodiment of R.sup.4 is methyl group, ethyl
group or isopropyl group.
[0344] One of the preferable embodiments of R.sup.5 is hydroxy
group, C.sub.1-6 alkoxy group or --CO--NR.sup.6aR.sup.6b. A more
preferable embodiment of R.sup.5 is hydroxy group. A more
preferable embodiment of R.sup.5 is C.sub.1-6alkoxy group. A more
preferable embodiment of R.sup.5 is --CO--NR.sup.6aR.sup.6b.
[0345] One of the preferable embodiments of R.sup.5 is hydroxy
group, methoxy group, ethoxy group, propoxy group, isopropoxy
group, benzyloxy group, 2-methoxyethoxy group, methylcarbamoyl
group, dimethylcarbamoyl group, acetylamino group,
N-acetyl-N-methylamino group or methanesulfonyloxy group.
[0346] A more preferable embodiment of R.sup.5 is hydroxy group. A
more preferable embodiment of R.sup.5 is methoxy group, ethoxy
group, propoxy group or isopropoxy group. A more preferable
embodiment of R.sup.5 is methylcarbamoyl group or dimethylcarbamoyl
group.
[0347] One of the preferable embodiments of a compound represented
by the formula [I-1] is a compound represented by the formula
[I-1a] or a pharmaceutically acceptable salt thereof.
##STR00006##
wherein R.sup.10 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and r are as defined
in the formula [I].
[0348] One of the preferable embodiments of a compound represented
by the formula [I-1] is a compound represented by the formula
[I-1b] or a pharmaceutically acceptable salt thereof.
##STR00007##
wherein R.sup.10 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and r are as defined
in the formula [I].
[0349] A preferable embodiment of R.sup.1, R.sup.2, R.sup.10,
R.sup.4 and R.sup.5 in the formula [I-1a] and [I-1b] is the same as
that of R.sup.1, R.sup.2, R.sup.10, R.sup.4 and R.sup.5 in the
formula [I-1].
[0350] One of the preferable embodiments of a compound represented
by the formula [I] wherein p is 0 or 1 is a compound wherein q is
0.
[0351] A preferable embodiment of a compound represented by the
formula [I] wherein p is 0 or 1 and q is 0 is a compound
represented by the formula [I-3] or a pharmaceutically acceptable
salt thereof.
##STR00008##
wherein R.sup.12 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and r are as defined
in the formula [I].
[0352] One of the preferable embodiments of a compound represented
by the formula [I-3] is as described below.
[0353] R.sup.1 is halogen atom,
[0354] R.sup.2 is hydrogen atom, halogen atom or trifluoromethyl
group,
[0355] R.sup.12 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group,
[0356] R.sup.4 is C.sub.1-6 alkyl group or cyclopropyl group,
[0357] R.sup.5 is
[0358] (1) hydroxy group,
[0359] (2) C.sub.1-6 alkoxy group,
[0360] (3) carboxy group,
[0361] (4) --CO--NR.sup.6aR.sup.6b [0362] wherein R.sup.6a and
R.sup.6b are the same or different and each is [0363] (i) hydrogen
atom, or [0364] (ii) C.sub.1-6 alkyl group, or
[0365] (5) methanesulfonyl group, and
[0366] r is 0 or 1.
[0367] A preferable embodiment of R.sup.1 is fluorine atom.
[0368] A preferable embodiment of R.sup.2 is hydrogen atom,
chlorine atom or trifluoromethyl group. A more preferable
embodiment of R.sup.2 is hydrogen atom. A more preferable
embodiment of R.sup.2 is chlorine atom.
[0369] A preferable embodiment of R.sup.12 is hydrogen atom,
fluorine atom, methoxy group or ethoxy group. A more preferable
embodiment of R.sup.12 is fluorine atom. A more preferable
embodiment of R.sup.12 is methoxy group or ethoxy group.
[0370] A preferable embodiment of R.sup.4 is methyl group, ethyl
group, isopropyl group or cyclopropyl group. A more preferable
embodiment of R.sup.4 is methyl group, ethyl group or isopropyl
group.
[0371] One of the preferable embodiments of R.sup.5 is hydroxy
group, C.sub.1-6 alkoxy group or --CO--NR.sup.6aR.sup.6b. A more
preferable embodiment of R.sup.5 is hydroxy group. A more
preferable embodiment of R.sup.5 is C.sub.1-5 alkoxy group. A more
preferable embodiment of R.sup.5 is --CO--NR.sup.6aR.sup.6b.
[0372] One of the preferable embodiments of R.sup.5 is hydroxy
group, methoxy group, ethoxy group, carboxy group, methylcarbamoyl
group, dimethylcarbamoyl group or methanesulfonyl group. A more
preferable embodiment of R.sup.5 is hydroxy group. A more
preferable embodiment of R.sup.5 is methoxy group or ethoxy group.
A more preferable embodiment of R.sup.5 is methylcarbamoyl group or
dimethylcarbamoyl group.
[0373] One of the preferable embodiments of a compound of the
formula [I-3] is a compound represented by the formula [I-3a] or a
pharmaceutically acceptable salt thereof.
##STR00009##
wherein R.sup.12 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and r are as defined
in the formula [I].
[0374] One of the preferable embodiments of a compound of the
formula [I-3] is a compound represented by the formula [I-3b] or a
pharmaceutically acceptable salt thereof.
##STR00010##
wherein R.sup.12 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and r are as defined
in the formula [I].
[0375] One of the preferable embodiments of a compound of the
formula [I-3] is a compound represented by the formula [I-3c] or a
pharmaceutically acceptable salt thereof.
##STR00011##
wherein R.sup.12 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and r are as defined
in the formula [I].
[0376] One of the preferable embodiments of a compound of the
formula [I-3] is a compound represented by the formula [I-3d] or a
pharmaceutically acceptable salt thereof.
##STR00012##
wherein R.sup.12 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and r are as defined
in the formula [I].
[0377] A preferable embodiment of R.sup.1, R.sup.2, R.sup.12,
R.sup.4 and R.sup.5 in the formula [I-3a], [I-3b], [I-3c] and
[I-3d] is the same as that of R.sup.1, R.sup.2, R.sup.12, R.sup.4
and R.sup.5 in the formula [I-3].
[0378] One of the preferable embodiments of a compound represented
by the formula [I] wherein p is 0 or 1, and q is 0 is a compound
represented by the formula [I-4] or a pharmaceutically acceptable
salt thereof.
##STR00013##
wherein R.sup.13 is hydrogen atom, C.sub.1-6 alkoxy group or
2-oxopyrrolidinyl group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and
r are as defined in the formula [I].
[0379] One of the preferable embodiments of a compound represented
by the formula [I-4] is as described below.
[0380] R.sup.1 is halogen atom,
[0381] R.sup.2 is halogen atom,
[0382] R.sup.13 is hydrogen atom, C.sub.1-6 alkoxy group or
2-oxopyrrolidinyl group,
[0383] R.sup.4 is C.sub.1-6 alkyl group,
[0384] R.sup.5 is C.sub.1-6 alkoxy group, and
[0385] r is 0 or 1.
[0386] A preferable embodiment of R.sup.1 is fluorine atom.
[0387] A preferable embodiment of R.sup.2 is chlorine atom.
[0388] A preferable embodiment of R.sup.13 is hydrogen atom,
methoxy group, ethoxy group, isopropoxy group or 2-oxopyrrolidinyl
group. A more preferable embodiment of R.sup.13 is methoxy group,
ethoxy group or isopropoxy group.
[0389] A preferable embodiment of R.sup.4 is methyl group.
[0390] A preferable embodiment of R.sup.5 is methoxy group.
[0391] One of the preferable embodiments of a compound represented
by the formula [I-4] is a compound represented by the formula
[I-4-a] or a pharmaceutically acceptable salt thereof.
##STR00014##
wherein R.sup.13 is hydrogen atom, C.sub.1-6 alkoxy group or
2-oxopyrrolidinyl group, and R.sup.1, R.sup.2, R.sup.4, R.sup.58
and r are as defined in the formula [I].
[0392] One of the preferable embodiments of a compound represented
by the formula [I-4] is a compound represented by the formula
[I-4b] or a pharmaceutically acceptable salt thereof.
##STR00015##
wherein R.sup.13 is hydrogen atom, C.sub.1-6 alkoxy group or
2-oxopyrrolidinyl group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and
r are as defined in the formula [I].
[0393] One of the preferable embodiments of a compound represented
by the formula [I-4] is a compound represented by the formula
[I-4c] or a pharmaceutically acceptable salt thereof.
##STR00016##
wherein R.sup.13 is hydrogen atom, C.sub.1-6 alkoxy group or
2-oxopyrrolidinyl group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and
r are as defined in the formula [I].
[0394] One of the preferable embodiments of a compound represented
by the formula [I-4] is a compound represented by the formula
[I-4d] or a pharmaceutically acceptable salt thereof.
##STR00017##
wherein R.sup.13 is hydrogen atom, C.sub.1-6 alkoxy group or
2-oxopyrrolidinyl group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and
r are as defined in the formula [I].
[0395] A preferable embodiment of R.sup.1, R.sup.2, R.sup.13,
R.sup.4 and R.sup.5 in the formula [I-4a], [I-4b], [I-4c] and
[I-4-d] is the same as that of R.sup.1, R.sup.2, R.sup.13, R.sup.4
and R.sup.5 in the formula [I-4].
[0396] One of the preferable embodiments of a compound represented
by the formula [II]
##STR00018##
wherein R.sup.1 is halogen atom, R.sup.2 is hydrogen atom, halogen
atom or trifluoromethyl group, each R.sup.3 is the same or
different and is
[0397] (1) halogen atom,
[0398] (2) C.sub.1-6 alkoxy group, or
[0399] (3) 2-oxopyrrolidinyl group,
R.sup.4 is C.sub.1-6 alkyl group or cyclopropyl group,
R.sup.5 is
[0400] (1) hydroxy group,
[0401] (2) C.sub.1-6 alkoxy group,
[0402] (3) benzyloxy group,
[0403] (4) C.sub.1-6 alkoxy C.sub.2-6 alkyleneoxy group,
[0404] (5) carboxy group,
[0405] (6) --CO--NR.sup.6aR.sup.6b [0406] wherein R.sup.6a and
R.sup.6b are the same or different and each is [0407] (i) hydrogen
atom, or [0408] (ii) C.sub.1-6 alkyl group,
[0409] (7) --NR.sup.7aCOR.sup.7b [0410] wherein R.sup.7a and
R.sup.7b are the same or different and each is [0411] (i) hydrogen
atom, or [0412] (ii) C.sub.1-6 alkyl group,
[0413] (8) methanesulfonyl group, or
[0414] (9) methanesulfonyloxy group,
p is an integer of 0 to 3, q is 0 or 1, and r is 0 or 1, is a
compound wherein q is 1.
[0415] One of the preferable embodiments of a compound represented
by the formula [II] wherein q is 1 is a compound wherein r is
1.
[0416] A preferable embodiment of a compound represented by the
formula [II] wherein q is 1 and r is 1 is as described below.
[0417] R.sup.1 is halogen atom,
[0418] R.sup.2 is halogen atom,
[0419] R.sup.4 is C.sub.1-6 alkyl group,
[0420] R.sup.5 is hydroxy group or C.sub.1-6 alkoxy group, and
[0421] p is 0.
[0422] A preferable embodiment of R.sup.1 is fluorine atom.
[0423] A preferable embodiment of R.sup.2 is chlorine atom.
[0424] A preferable embodiment of R.sup.4 is ethyl group.
[0425] A preferable embodiment of R.sup.5 is hydroxy group or
methoxy group.
[0426] One of the preferable embodiments of a compound represented
by the formula [II] wherein q is 1 is a compound wherein r is
0.
[0427] A preferable embodiment of a compound represented by the
formula [II] wherein q is 1 and r is 0 is as described below.
[0428] R.sup.1 is halogen atom,
[0429] R.sup.2 is hydrogen atom or halogen atom,
[0430] R.sup.3 is halogen atom,
[0431] R.sup.4 is C.sub.1-6 alkyl group,
[0432] R.sup.5 is hydroxy group or C.sub.1-6 alkoxy group, and
[0433] p is 0 or i.
[0434] A preferable embodiment of R.sup.1 is fluorine atom.
[0435] A preferable embodiment of R.sup.2 is hydrogen atom or
chlorine atom.
[0436] A preferable embodiment of R.sup.3 is fluorine atom.
[0437] A preferable embodiment of R.sup.4 is methyl group, ethyl
group or isopropyl group.
[0438] A preferable embodiment of R.sup.5 is hydroxy group, methoxy
group or ethoxy group.
[0439] One of the preferable embodiments of a compound represented
by the formula [II] is a compound wherein q is 0.
[0440] One of the preferable embodiments of a compound represented
by the formula [II] wherein q is 0 is a compound wherein r is
1.
[0441] A preferable embodiment of a compound represented by the
formula [II] wherein q is 0 and r is 1 is as described below.
[0442] R.sup.1 is halogen atom,
[0443] R.sup.2 is hydrogen atom or halogen atom,
[0444] R.sup.3 is
[0445] (1) halogen atom, or
[0446] (2) C.sub.1-6 alkoxy group,
[0447] R.sup.4 is C.sub.1-6 alkyl group,
[0448] R.sup.5 is hydroxy group or C.sub.1-6 alkoxy group, and
[0449] p is 0 or 1.
[0450] A preferable embodiment of R.sup.1 is fluorine atom.
[0451] A preferable embodiment of R.sup.2 is hydrogen atom or
chlorine atom.
[0452] A preferable embodiment of R.sup.3 is fluorine atom or
methoxy group.
[0453] A preferable embodiment of R.sup.4 is methyl group, ethyl
group or isopropyl group.
[0454] A preferable embodiment of R.sup.5 is hydroxy group, methoxy
group or ethoxy group.
[0455] One of the preferable embodiments of a compound represented
by the formula [II] is a compound wherein p is 0 or 1.
[0456] One of the preferable embodiments of a compound represented
by the formula [II] wherein p is 0 or 1 is a compound wherein q is
1.
[0457] One of the preferable embodiments of a compound represented
by the formula [II] wherein p is 0 or 1 and q is 1 is a compound
represented by the formula [II-1] or a pharmaceutically acceptable
salt thereof.
##STR00019##
wherein R.sup.14 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and r are as defined
in the formula [II].
[0458] A preferable embodiment of R.sup.14 is hydrogen atom or
halogen atom.
[0459] One of the preferable embodiments of a compound represented
by the formula [II-1] is as described below.
[0460] R.sup.1 is halogen atom,
[0461] R.sup.2 is hydrogen atom or halogen atom,
[0462] R.sup.14 is hydrogen atom or halogen atom,
[0463] R.sup.4 is C.sub.1-6 alkyl group,
[0464] R.sup.5 is hydroxy group or C.sub.1-6 alkoxy group, and
[0465] r is 0 or 1.
[0466] A preferable embodiment of R.sup.1 is fluorine atom.
[0467] A preferable embodiment of R.sup.2 is hydrogen atom or
chlorine atom.
[0468] A preferable embodiment of R.sup.14 is hydrogen atom or
fluorine atom.
[0469] A preferable embodiment of R.sup.4 is methyl group, ethyl
group or isopropyl group.
[0470] One of the preferable embodiments of R.sup.5 is hydroxy
group. One of the preferable embodiments of R.sup.5 is C.sub.1-6
alkoxy group, more preferably methoxy group or ethoxy group.
[0471] One of the preferable embodiments of a compound represented
by the formula [II-1] is a compound represented by the formula
[II-1a] or a pharmaceutically acceptable salt thereof.
##STR00020##
wherein R.sup.14 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and r are as defined
in the formula [II].
[0472] One of the preferable embodiments of a compound represented
by the formula [II-1] is a compound represented by the formula
[II-1b] or a pharmaceutically acceptable salt thereof.
##STR00021##
wherein R.sup.14 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and r are as defined
in the formula [II].
[0473] A preferable embodiment of R.sup.1, R.sup.2, R.sup.14,
R.sup.4 and R.sup.5 in the formula [II-1a] and [II-1b] is the same
as that of R.sup.1, R.sup.2, R.sup.14, R.sup.4 and R.sup.5 in the
formula [II-1].
[0474] One of the preferable embodiments of a compound represented
by the formula [II] is a compound wherein q is 0.
[0475] One of the preferable embodiments of a compound represented
by the formula [II] wherein q is 0 is a compound wherein p is 0 or
1.
[0476] One of the preferable embodiments of a compound of the
formula [II] wherein p is 0 or 1 and q is 0 is a compound
represented by the following formula [II-3] or a pharmaceutically
acceptable salt thereof.
##STR00022##
wherein R.sup.16 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and r are as defined
in the formula [II].
[0477] One of the preferable embodiments of a compound represented
by the formula [II-3] is as described below.
[0478] R.sup.1 is halogen atom,
[0479] R.sup.2 is hydrogen atom or halogen atom,
[0480] R.sup.16 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group,
[0481] R.sup.4 is C.sub.6 alkyl group,
[0482] R.sup.5 is hydroxy group or C.sub.1-6 alkoxy group, and
[0483] r is 0 or 1.
[0484] A preferable embodiment of R.sup.1 is fluorine atom.
[0485] A preferable embodiment of R.sup.2 is hydrogen atom or
chlorine atom. One of the more preferable embodiments of R.sup.2 is
hydrogen atom. One of the more preferable embodiments of R.sup.2 is
chlorine atom.
[0486] A preferable embodiment of R.sup.16 is hydrogen atom,
fluorine atom or methoxy group. One of the more preferable
embodiments of R.sup.16 is fluorine atom. One of the more
preferable embodiments of R.sup.16 is methoxy group.
[0487] A preferable embodiment of R.sup.4 is methyl group, ethyl
group or isopropyl group.
[0488] One of the preferable embodiments of R.sup.5 is hydroxy
group. One of the preferable embodiments of R.sup.5 is C.sub.1-6
alkoxy group, more preferably methoxy group or ethoxy group.
[0489] One of the preferable embodiments of R.sup.5 is hydroxy
group, methoxy group or ethoxy group.
[0490] One of the preferable embodiments of the compound of the
formula [II-3] is a compound represented by the following formula
[II-3a] or a pharmaceutically acceptable salt thereof.
##STR00023##
wherein R.sup.16 is hydrogen atom, halogen atom or C.sub.1-6 alkoxy
group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and r are as defined
in the formula [II].
[0491] One of the preferable embodiments of the compound of the
formula [II-3] is a compound represented by the following formula
[II-3b] or a pharmaceutically acceptable salt thereof.
##STR00024##
wherein R.sup.16 is hydrogen atom, halogen atom or C.sub.6, alkoxy
group, and R.sup.1, R.sup.2, R.sup.4, R.sup.5 and r are as defined
in the formula [II].
[0492] A preferable embodiment of R.sup.1, R.sup.2, R.sup.16,
R.sup.4 and R.sup.5 in the formula [II-3a] and [II-3b] is the same
as that of R.sup.1, R.sup.2, R.sup.16, R.sup.4 and R.sup.5 in the
formula [II-3]
[0493] In the above-mentioned formulae [I-1a], [I-3b], [I-3d],
[I-4b], [I-4-d], [II-1a] and [II-3a], wherein r is 0, the steric
configuration of R.sup.5 is the steric configuration shown in the
following partial structural formula.
##STR00025##
[0494] In the above-mentioned formulae [I-1b], [I-3a], [I-3c],
[I-4a], [I-4c], [II-1b] and [II-3b], wherein r is 0, the steric
configuration of R.sup.5 is the steric configuration shown in the
following partial structural formula.
##STR00026##
[0495] As the "compound represented by the above-mentioned formula
[I], [II], [I-1], [I-1a], [I-1b], [I-3], [I-3a], [I-3b], [I-3c],
[I-3d], [I-4], [I-4a], [I-4b], [I-4c], [I-4-d], [II-1], [II-1a],
[II-1b], [II-3], [II-3a] or [II-3b]" (hereinafter to be also
referred to as the compound of the present invention), a compound
represented by the following formula, or a pharmaceutically
acceptable salt thereof is preferable.
##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031##
##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036##
##STR00037## ##STR00038## ##STR00039##
[0496] A pharmaceutically acceptable salt of the compound of the
present invention may be any salt as long as it forms an atoxic
salt with the compound of the present invention. Examples thereof
include a salt with an inorganic acid, a salt with an organic acid,
a salt with an inorganic base, a salt with an organic base, a salt
with an amino acid and the like.
[0497] Examples of the salt with an inorganic acid include salts
with hydrochloric acid, nitric acid, sulfuric acid, phosphoric
acid, hydrobromic acid and the like.
[0498] Examples of the salt with an organic acid include salts with
oxalic acid, malonic acid, maleic acid, citric acid, fumaric acid,
lactic acid, malic acid, succinic acid, tartaric acid, acetic acid,
trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic
acid, benzenesulfonic acid, p-toluenesulfonic acid and the
like.
[0499] Examples of the salt with an inorganic base include sodium
salt, potassium salt, calcium salt, magnesium salt, ammonium salt
and the like.
[0500] Examples of the salt with an organic base include salts with
methylamine, diethylamine, trimethylamine, triethylamine,
ethanolamine, diethanolamine, triethanolamine, ethylenediamine,
tris(hydroxymethyl)methylamine, dicyclohexylamine,
N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline,
choline, cinchonine, meglumine and the like.
[0501] Examples of the salt with an amino acid include salts with
lysine, arginine, aspartic acid, glutamic acid and the like.
[0502] Such salts can be obtained by reacting the compound of the
present invention with an inorganic base, an organic base, an
inorganic acid, an organic acid or an amino acid according to a
method known per se.
[0503] In the present invention, as the pharmaceutically acceptable
salt of the compound of the present invention, salts with
hydrochloric acid (e.g., monohydrochloride, dihydrochloride), salts
with hydrobromic acid (e.g., monohydrobromide, dihydrobromide) and
sodium salt are preferred embodiments.
[0504] The compound of the present invention or a pharmaceutically
acceptable salt thereof may exist as a solvate.
[0505] The "solvate" is the compound of the present invention or a
pharmaceutically acceptable salt thereof, with which a molecule of
a solvent is coordinated, and also encompasses hydrate (also
referred to as water-containing compound). The solvate is, for
example, a pharmaceutically acceptable solvate, such as a
monohydrate, a hemihydrate, a dihydrate, a monohydrate of sodium
salt, a monomethanolate, a monoethanolate, a monoacetonitrilate, a
2/3 ethanolate of dihydrochloride of the compound of the present
invention and the like.
[0506] A solvate of the compound of the present invention or a
pharmaceutically acceptable salt thereof can be obtained according
to a method known in the art.
[0507] In addition, there can be various isomers of the compound of
the present invention. For example, E form and Z form are present
as geometric isomers, and when an asymmetric carbon atom is
present, enantiomers and diastereomers are present as stereoisomers
based on them. In addition, when axial chirality is present,
stereoisomers based thereon are present. Where necessary, tautomers
can be present. Accordingly, all of such isomers and mixtures
thereof are encompassed in the scope of the present invention.
[0508] When a specific isomeric configuration is not indicated with
regard to the formulae and compounds described in the present
specification, all of possible stereoisomers (S form, R form, cis
form, trans form and the like) and mixtures thereof are
encompassed.
[0509] As the compound of the present invention, one isolated and
purified from various isomers, by-products, metabolites or prodrugs
is preferable, and one having a purity of not less than 90% is
preferable and one having a purity of not less than 95% is more
preferable.
[0510] In addition, the compound of the present invention may be
crystal or amorphous.
[0511] In addition, the compound of the present invention may be
labeled with an isotope (e.g., .sup.3H, .sup.14C, .sup.35S
etc.).
[0512] As the compound of the present invention or a
pharmaceutically acceptable salt thereof, the substantially
purified compound of the present invention or a pharmaceutically
acceptable salt thereof is preferable. More preferred is the
compound of the present invention or a pharmaceutically acceptable
salt thereof which has been purified to a purity of not less than
80%.
[0513] In the present invention, a prodrug of the compound of the
present invention can also be a useful medicament.
[0514] A "prodrug" is a derivative of the compound of the present
invention, which has a chemically or metabolically decomposable
group and which restores to the original compound to show its
inherent efficacy after administration to the body by, for example,
hydrolysis, solvolysis or decomposition under physiological
conditions. It includes a complex and a salt, not involving a
covalent bond.
[0515] The prodrug is utilized, for example, for improving
absorption by oral administration or targeting of a target
site.
[0516] Examples of the site to be modified include highly reactive
functional groups in the compound of the present invention, such as
hydroxy group, carboxyl group, amino group and the like.
[0517] Examples of the hydroxy-modifying group include acetyl
group, propionyl group, isobutyryl group, pivaloyl group, palmitoyl
group, benzoyl group, 4-methylbenzoyl group, dimethylcarbamoyl
group, dimethylaminomethylcarbonyl group, sulfo group, alanyl
group, fumaryl group and the like. In addition, a sodium salt of
3-carboxybenzoyl group, 2-carboxyethylcarbonyl group and the like
can also be used.
[0518] Examples of the carboxy-modifying group include methyl
group, ethyl group, propyl group, isopropyl group, butyl group,
isobutyl group, tert-butyl group, pivaloyloxymethyl group,
carboxymethyl group, dimethylaminomethyl group, 1-(acetyloxy)ethyl
group, 1-(ethoxycarbonyloxy)ethyl group,
1-(isopropoxycarbonyloxy)ethyl group,
1-(cyclohexyloxycarbonyloxy)ethyl group,
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, benzyl group, phenyl
group, o-tolyl group, morpholinoethyl group,
N,N-diethylcarbamoylmethyl group, phthalidyl group and the
like.
[0519] Examples of the amino-modifying group include hexylcarbamoyl
group, 3-methylthio-1-(acetylamino)propylcarbonyl group,
1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group,
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group and the like.
[0520] Examples of the "pharmaceutical composition" include oral
preparations such as tablet, capsule, granule, powder, troche,
syrup, emulsion, suspension and the like, and parenteral agents
such as external preparation, suppository, injection, eye drop,
transnasal agent, pulmonary preparation and the like.
[0521] The pharmaceutical composition of the present invention
(e.g., an anti-HIV composition, a pharmaceutical composition for
HIV integrase inhibitory etc.) is produced by appropriately
admixing a suitable amount of a compound of the present invention
or a salt thereof with at least one kind of a pharmaceutically
acceptable carrier according to a method known in the technical
field of pharmaceutical preparations. The content of the compound
of the present invention or a salt thereof in the pharmaceutical
composition varies depending on the dosage form, the dose and the
like, and the like. It is, for example, 0.1 to 100 wt % of the
whole composition.
[0522] Examples of the "pharmaceutically acceptable carrier"
include various organic or inorganic carrier substances
conventionally used as preparation materials such as excipient,
disintegrant, binder, glidant, lubricant and the like for solid
preparations, and solvent, solubilizing agent, suspending agent,
isotonic agent, buffering agent, soothing agent and the like for
liquid preparations. Where necessary, additives such as
preservative, antioxidant, colorant, sweetening agent and the like
are used.
[0523] Examples of the "excipient" include lactose, sucrose,
D-mannitol, D-solbitol, cornstarch, dextrin, crystalline cellulose,
crystalline cellulose, carmellose, carmellose calcium, sodium
carboxymethyl starch, low-substituted hydroxypropylcellulose, gum
arabic and the like.
[0524] Examples of the "disintegrant" include carmellose,
carmellose calcium, carmellose sodium, sodium carboxymethyl starch,
croscarmellose sodium, crospovidone, low-substituted
hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline
cellulose and the like.
[0525] Examples of the "binder" include hydroxypropylcellulose,
hydroxypropylmethylcellulose, povidone, crystalline cellulose,
sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic
and the like.
[0526] Examples of the "glidant" include light anhydrous silicic
acid, magnesium stearate and the like.
[0527] Examples of the "lubricant" include magnesium stearate,
calcium stearate, talc and the like.
[0528] Examples of the "solvent" include purified water, ethanol,
propylene glycol, macrogol, sesame oil, corn oil, olive oil and the
like.
[0529] Examples of the "solubilizing agent" include propylene
glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine,
sodium carbonate, sodium citrate and the like.
[0530] Examples of the "suspending agent" include benzalkonium
chloride, carmellose, hydroxypropylcellulose, propylene glycol,
povidone, methylcellulose, glycerol monostearate and the like.
[0531] Examples of the "isotonic agent" include glucose,
D-sorbitol, sodium chloride, D-mannitol and the like.
[0532] Examples of the "buffering agent" include sodium hydrogen
phosphate, sodium acetate, sodium carbonate, sodium citrate and the
like.
[0533] Examples of the "soothing agent" include benzyl alcohol and
the like.
[0534] Examples of the "preservative" include ethyl
parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium
dehydroacetate, sorbic acid and the like.
[0535] Examples of the "antioxidant" include sodium sulfite,
ascorbic acid and the like.
[0536] Examples of the "colorant" include food colors (e.g., Food
Color Red No. 2 or 3, Food Color yellow 4 or 5 etc.),
.beta.-carotene and the like.
[0537] Examples of the "sweetening agent" include saccharin sodium,
dipotassium glycyrrhizinate, aspartame and the like.
[0538] The pharmaceutical composition of the present invention can
be administered not only to human but also to mammals other than
human (e.g., mouse, rat, hamster, guinea pig, rabbit, cat, dog,
swine, bovine, horse, sheep, monkey etc.) orally or parenterally
(e.g., topical, rectal, intravenous administration etc.). While the
dose varies depending on the subject of administration, disease,
symptom, dosage form, administration route and the like, for
example, the dose for oral administration to an adult patient (body
weight: about 60 kg) is generally within the scope of about 1 mg to
1 g per day, based on the compound of the present invention as an
active ingredient. The amount can be administered in one to several
portions.
[0539] The compound of the present invention or a pharmaceutically
acceptable salt thereof inhibits HIV integrase, and can be used as
an active ingredient of a therapeutic agent or prophylactic agent
for HIV infection.
[0540] To "inhibit HIV integrase" means to specifically inhibit the
function as HIV integrase to eliminate or attenuate the activity
thereof, for example, to specifically inhibit the function of HIV
integrase under the conditions of the below-mentioned Experimental
Example 1. As the "inhibition of HIV integrase", preferred is
"inhibition of human HIV integrase". As the "HIV integrase
inhibitor", preferred is a "human HIV integrase inhibitor".
[0541] The compound of the present invention or a pharmaceutically
acceptable salt thereof can be used in combination with other
single or plural medicaments (hereinafter to be also referred to as
a concomitant drug) by a conventional method generally employed in
the medicament field (hereinafter to be referred to as combination
use).
[0542] In the combination use, the timing of administration of the
compound of present invention including its pharmaceutically
acceptable salts and the concomitant drug is not limited, and they
may be administered as a combined agent to the subject of
administration, or the two may be administered simultaneously or at
certain time intervals. In addition, they may be used as a
medicament in the form of a kit containing the pharmaceutical
composition of the present invention and a concomitant drug. The
dose of the concomitant drug may be determined according to the
dosage used clinically, and can be appropriately determined
depending on the subject of administration, disease, symptom,
dosage form, administration route, administration time, combination
and the like. The dosing regimen of the concomitant drug is not
particularly limited, and the concomitant drug needs only be
combined with the compound of the present invention or a salt
thereof.
[0543] An anti-HIV agent is generally required to sustain its
effect for a long time, so that can be effective not only for
temporal suppression of viral growth but also prohibition of viral
re-growth. This means that a prolonged administration is necessary
and that a high single dose may be frequently inevitable to sustain
effect for a longer period through the night. Such prolonged and
high dose administration may increase the risk of causing side
effects.
[0544] In view of this, one of the preferable embodiments of the
compound of the present invention is such compound permitting high
absorption by oral administration, and such compound capable of
maintaining blood concentration of the administered compound for an
extended period of time.
[0545] One of other preferable embodiments of the compound of the
present invention is a compound having fine pharmacological
activity (e.g., a compound having strong HIV integrase inhibitory
activity, a compound having high anti-HIV activity), a compound
having fine bioavailability (e.g., a compound having high cellular
membrane permeability, a compound stable to metabolic enzyme, a
compound with low binding ability to protein and the like) and the
like.
[0546] Among the compounds of the present invention, a compound
having high pharmacological activity (concretely, EC.sub.50 of HIV
integrase inhibitory activity is less than 0.1 .mu.M, preferably
less than 0.01 .mu.M) and having high oral absorption, whose blood
concentration is maintained for a long time after administration is
more preferable.
[0547] Using the above-mentioned compound, dose and/or frequency of
administration of the compound of the present invention to human
are/is expected to be decreased. Preferable administration
frequency is not more than twice a day, more preferably, not more
than once a day (e.g., once a day, once in two days, etc.).
[0548] The compound of the present invention can be used for the
improvement of viremia due to HIV and/or maintenance of improved
condition thereof, prophylaxis and treatment of virus infections,
particularly, an HIV infection and/or maintenance of improved
condition thereof.
[0549] As an index of the "treatment", "improvement" or "effect", a
decrease in the virus level or HIV RNA level in the body,
particularly in blood, can be used.
[0550] The "prophylaxis of HIV infection" includes administration
of a medicament to a person with suspected or possible HIV
infection (infection due to transfusion, infection from mother to
child), and the like.
[0551] By the "prophylaxis of AIDS" is meant, for example,
administration of a medicament to an individual who tested HIV
positive but has not yet developed the disease state of AIDS;
administration of a medicament to an individual who shows an
improved disease state of AIDS after treatment but who carries HIV
still to be eradicated and whose relapse of AIDS is worried;
administration of a medicament before infection with HIV out of a
fear of possible infection; and the like.
[0552] Examples of the "other anti-HIV agents" and "other anti-HIV
active substances" to be used for a multiple drug combination
therapy include an anti-HIV antibody or other antibody, an HIV
vaccine or other vaccine, immunostimulants such as interferon,
interferon agonist and the like, a ribozyme against HIV, an HIV
antisense drug, an HIV reverse transcriptase inhibitor, an HIV
protease inhibitor, an HIV integrase inhibitor, an inhibitor of
attachment between a receptor (CD4, CXCR4, CCR5 and the like) of a
host cell recognized by virus and the virus (CCR5 antagonist and
the like), a DNA polymerase inhibitor or DNA synthesis inhibitor, a
medicament acting on HIVp24, an HIV fusion inhibitor, an IL-2
agonist or antagonist, a TNF-.alpha. antagonist, an
.alpha.-glucosidase inhibitor, a purine nucleoside phosphorylase
inhibitor, an apoptosis agonist or inhibitor, a cholinesterase
inhibitor, an immunomodulator and the like.
[0553] Specific examples of the HIV reverse transcriptase inhibitor
include Retrovir(R) (zidovudine), Epivir(R) (lamivudine), Zerit(R)
(sanilvudine), Videx(R) (didanosine), Hivid(R) (zalcitabine),
Ziagen(R) (abacavir sulfate), Viramune(R) (nevirapine), Stocrin(R)
(efavirenz), Rescriptor(R) (delavirdine mesylate), Combivir(R)
(zidovudine+lamivudine), Trizivir(R) (abacavir
sulfate+lamivudine+zidovudine), Coactinon(R) (emivirine),
Phosphonovir(R), Coviracil(R), alovudine
(3'-fluoro-3'-deoxythymidine), Thiovir(R) (thiophosphonoformic
acid), capravirin
(5-[(3,5-dichlorophenyl)thio]-4-isopropyl-1-(4-pyridylmethyl)imidazole-2--
methanol carbamic acid), tenofovir disoproxil fumarate
((R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic
acid bis(isopropoxycarbonyloxymethyl)ester fumarate), DPC-083
((4S)-6-chloro-4-[(1E)-cyclopropylethenyl]-3,4-dihydro-4-trifluoromethyl--
2(1H)-quinazolinone), DPC-961
((4S)-6-chloro-4-(cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1-
H)-quinazolinone), DAPD((-)-.beta.-D-2,6-diaminopurine dioxolane),
Immunocal, MSK-055, MSA-254, MSH-143, NV-01, TMC-120, DPC-817,
GS-7340, TMC-125, SPD-754, D-A4FC, capravirine, UC-781,
emtricitabine, alovudine, Phosphazid, BCH-10618, DPC-083,
Etravirine, BCH-13520, MIV-210, Abacavir sulfate/lamivudine,
GS-7340, GW-5634, GW-695634, TMC-278 and the like, wherein (R)
means a registered trademark and other names of medicaments are
generic names (hereinafter the same).
[0554] Specific examples of the HIV protease inhibitor include
Crixivan(R) (indinavir sulfate ethanolate), saquinavir, Invirase(R)
(saquinavir mesylate), Norvir(R) (ritonavir), Viracept(R)
(nelfinavir mesylate), lopinavir, Prozei(R) (amprenavir),
Kaletra(R) (ritonavir+lopinavir), mozenavir dimesylate
([4R-(4.alpha.,5.alpha.6.beta.)]-1,3-bis[(3-aminophenyl)methyl]-hexahydro-
-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one
dimethanesulfonate), tipranavir
(3'-[(1R)-1-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-phenylethyl-6-propyl-2H-p-
yran-3-yl]propyl]-5-(trifluoromethyl)-2-pyridinesulfonamide),
lasinavir
(N-[5(S)-(tert-butoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-tri-
methoxybenzyl)hexanoyl]-L-valine 2-methoxyethylenamide), KNI-272
((R)--N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N--[(R)-2-N-(isoquinolin-5-ylox-
yacetyl)amino-3-methylthiopropanoyl]amino-4-phenylbutanoyl]-5,5-dimethyl-1-
,3-thiazolidine-4-carboxamide), GW-433908, TMC-126, DPC-681,
buckminsterfullerene, MK-944A (MK944
(N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-[4-(2-ben-
zo[b]furanylmethyl)-2(S)-(tert-butylcarbamoyl)piperazin-1-yl]pentanamide)+-
indinavir sulfate), JE-2147
([2(S)-oxo-4-phenylmethyl-3(S)-[(2-methyl-3-oxy)phenylcarbonylamino]-1-ox-
abutyl]-4-[(2-methylphenyl)methylamino]carbonyl-4(R)-5,5-dimethyl-1,3-thia-
zole), BMS-232632 (dimethyl
(3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenyl-
methyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecaned-
icarboxylate), DMP-850
((4R,5S,6S,7R)-1-(3-amino-1H-indazol-5-ylmethyl)-4,7-dibenzyl-3-butyl-5,6-
-dihydroxyperhydro-1,3-diazepin-2-one), DMP-851, RO-0334649,
Nar-DG-35, R-944, VX-385, TMC-114, Tipranavir, Fosamprenavir
sodium, Fosamprenavir calcium, Darunavir, GW-0385, R-944,
RO-033-4649, AG-1859 and the like.
[0555] The HIV integrase inhibitor is exemplified by S-1360,
L-870810, ISENTRESS(R) (Raltegravir), JTK-303 (Elvitegravir),
S/GSK1 349572 (Doltegravir) and the like, the DNA polymerase
inhibitor or DNA synthesis inhibitor is exemplified by Foscavir(R),
ACH-126443 (L-2',3'-didehydro-dideoxy-5-fluorocytidine), entecavir
((1S,3S,4S)-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]guanine-
), calanolide A
([10R-(10.alpha.,11.beta.,12.alpha.)]-11,12-dihydro-12-hydroxy-6,6,10,11--
tetramethyl-4-propyl-2H,6H,10H-benzo[1,2-b:3,4-b':5,6-b'']tripyran-2-one),
calanolide B, NSC-674447 (1,1'-azobisformamide), Iscador (viscum
alubm extract), Rubitecan and the like, the HIV antisense drug is
exemplified by HGTV-43, GEM-92 and the like, the anti-HIV antibody
or other antibody is exemplified by NM-01, PRO-367, KD-247,
Cytolin(R), TNX-355 (CD4 antibody), AGT-1, PRO-140 (CCR5 antibody),
Anti-CTLA-4MAb and the like, the HIV vaccine or other vaccine is
exemplified by ALVAC(R), AIDSVAX(R), Remune(R), HIV gp41 vaccine,
HIV gp120 vaccine, HIV gp140 vaccine, HIV gp160 vaccine, HIV p17
vaccine, HIV p24 vaccine, HIV p55 vaccine, AlphaVax Vector System,
canarypox gp160 vaccine, AntiTat, MVA-F6 Nef vaccine, HIV rev
vaccine, C4-V3 peptide, p2249f, VIR-201, HGP-30W, TBC-3B,
PARTICLE-3B, Antiferon (interferon-.alpha. vaccine) and the like,
the interferon or interferon agonist is exemplified by
Sumiferon(R), MultiFeron(R), interferon-.tau., Reticulose, human
leukocyte interferon .alpha. and the like, the CCR5 antagonist is
exemplified by SCH-351125 and the like, the medicament acting on
HIV p24 is exemplified by GPG-NH2 (glycyl-prolyl-glycinamide) and
the like, the HIV fusion inhibitor is exemplified by FP-21399
(1,4-bis[3-[(2,4-dichlorophenyl)carbonylamino]-2-oxo-5,8-disodium
sulfonyl]naphthyl-2,5-dimethoxyphenyl-1,4-dihydrazone), T-1249,
Synthetic Polymeric Construction No 3, pentafuside, FP-21399,
PRO-542, Enfuvirtide and the like, the IL-2 agonist or antagonist
is exemplified by interleukin-2, Imunace(R), Proleukin(R),
Multikine(R), Ontak(R) and the like, the TNF-.alpha. antagonist is
exemplified by Thalomid(R) (thalidomide), Remicade(R) (infliximab),
curdlan sulfate and the like, the .alpha.-glucosidase inhibitor is
exemplified by Bucast(R) and the like, the purine nucleoside
phosphorylase inhibitor is exemplified by peldesine
(2-amino-4-oxo-3H,5H-7-[(3-pyridyl)methyl]pyrrolo[3,2-d]pyrimid-
ine) and the like, the apoptosis agonist or inhibitor is
exemplified by Arkin Z(R), Panavir(R), Coenzyme Q10
(2-deca(3-methyl-2-butenylene)-5,6-dimethoxy-3-methyl-p-benzoquinone)
and the like, the cholinesterase inhibitor is exemplified by
Cognex(R) and the like, and the immunomodulator is exemplified by
Immunox(R), Prokine(R), Met-enkephalin
(6-de-L-arginine-7-de-L-arginine-8-de-L-valinamide-adrenorphin),
WF-10 (10-fold dilute tetrachlorodecaoxide solution), Perthon,
PRO-542, SCH-D, UK-427857, AMD-070, AK-602 and the like.
[0556] In addition, Neurotropin(R), Lidakol(R), Ancer 20(R),
Ampligen(R), Anticort(R), Inactivin(R), PRO-2000, Rev M10 gene, HIV
specific cytotoxic T cell (CTL immunotherapy, ACTG protocol 080
therapy, CD4-.zeta. gene therapy), SCA binding protein, RBC-CD4
complex, Motexafin gadolinium, GEM-92, CNI-1493, (.+-.)--FTC,
Ushercell, D2S, BufferGel(R), VivaGel(R), Glyminox vaginal gel,
sodium lauryl sulfate, 2F5, 2F5/2G12, VRX-496, Ad5gag2, BG-777,
IGIV-C, BILR-255 and the like are exemplified.
[0557] The compound of the present invention can be combined with
one or more (e.g., 1 or 2) kinds of other anti-HIV active
substances (to be also referred to as other anti-HIV agents), and
used as an anti-HIV agent and the like for the prophylaxis or
treatment of HIV infection. As the "other anti-HIV agents" and
"other anti-HIV active substances" to be used for a multiple drug
combination therapy with the compound of the present invention,
preferred are an HIV reverse transcriptase inhibitor and an HIV
protease inhibitor. Two or three, or even a greater number of
medicaments can be used in combination, wherein a combination of
medicaments having different action mechanisms is one of the
preferable embodiments. In addition, selection of medicaments free
of side effect duplication is preferable.
[0558] Specific examples of the combination of medicaments include
a combination of a group consisting of efavirenz, tenofovir,
emtricitabine, indinavir, nelfinavir, atazanavir,
ritonavir+indinavir, ritonavir+lopinavir, ritonavir+saquinavir,
didanosine+lamivudine, zidovudine+didanosine, stavudine+didanosine,
zidovudine+lamivudine, stavudine+lamivudine and
tenofovir+emtricitabine, and the compound of the present invention
(Guidelines for the Use of Antiretroviral Agents in HIV-Infected
Adults and Adolescents. Aug. 13, 2001). Particularly preferred is a
combined use of two agents with efavirenz, indinavir, nelfinavir,
tenofovir, emtricitabine, zidovudine or lamivudine, and a combined
use of three agents with zidovudine+lamivudine,
tenofovir+lamivudine, tenofovir+zidovudine, tenofovir+efavirenz,
tenofovir+nelfinavir, tenofovir+indinavir, tenofovir+emtricitabine,
emtricitabine+lamivudine, emtricitabine+zidovudine,
emtricitabine+efavirenz, emtricitabine+nelfinavir,
emtricitabine+indinavir, nelfinavir+lamivudine,
nelfinavir+zidovudine, nelfinavir+efavirenz, nelfinavir+indinavir,
efavirenz+lamivudine, efavirenz+zidovudine,
efavirenz+indinavir.
[0559] In the case of combined administration, the compound of the
present invention can be administered simultaneously with a
medicament to be used in combination (hereinafter concomitant drug)
or administered at certain time intervals. In the case of combined
administration, a pharmaceutical composition comprising the
compound of the present invention and a concomitant drug can be
administered. Alternatively, a pharmaceutical composition
comprising the compound of the present invention and a
pharmaceutical composition comprising a concomitant drug may be
administered separately. The administration route of the compound
of the present invention and that of the concomitant drug may be
the same or different.
[0560] In the case of a combined administration, the compound of
the present invention can be administered once a day or several
times a day in a single dose of 0.01 mg to 1 g, or may be
administered at a smaller dose. The concomitant drug can be
administered at a dose generally used for the prevention or
treatment of an HIV infection, for example, at a single dose of
0.01 mg to 0.3 g. Alternatively, it may be administered in a
smaller dose.
[0561] Now, production methods of the compound of the present
invention are specifically explained. However, the present
invention is not limited to these production methods. For
production of the compound of the present invention, the order of
reactions can be appropriate. The reactions may be performed from a
reasonable step or a reasonable substitution moiety. In addition,
an appropriate substituent conversion (conversion or further
modification of substituent) step may be inserted between
respective steps. When a reactive functional group is present,
protection and deprotection may be appropriately performed.
Furthermore, to promote the progress of reactions, reagents other
than those exemplified below may be used as appropriate. The
starting compounds whose production methods are not described are
commercially available or can be easily prepared by a combination
of known synthesis reactions. The compound obtained in each step
can be purified by conventional methods such as distillation,
recrystallization, column chromatography and the like. In some
cases, the next step may be performed without isolation and
purification.
[0562] In the following Production methods, the "room temperature"
means 1 to 40.degree. C.
[0563] A compound represented by the formula [I] or [II]
##STR00040##
or a pharmaceutically acceptable salt thereof, or a solvate
thereof, can be produced by the following Production method 1 or
Production method 2.
Production Method 1
##STR00041##
[0564] wherein Ra is hydroxy-protecting group such as benzyl group,
or tert-butyl group, trimethylsilyl group, triethylsilyl group,
tert-butyldimethylsilyl group, triisopropylsilyl group,
tert-butyldiphenylsilyl group and the like, and other symbols are
as mentioned above.
Step 1
[0565] A compound of the formula [C] can be produced by reacting a
compound of the formula [B] and a compound of an acid chloride
which can be produced by reacting a compound of the formula [A] and
a chlorinating agent.
[0566] The reaction of a compound of the formula [A] and a
chlorinating agent is performed in the presence of, where
necessary, a catalyst.
[0567] Examples of the solvent include a single or mixed solvent of
hexane, chloroform, methylene chloride, ethyl acetate, toluene,
1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran (THF) and the
like.
[0568] Examples of the chlorinating agent include oxalyl
dichloride, thionyl chloride, phosphorus trichloride and the
like.
[0569] Examples of the catalyst include N,N-dimethylformamide (DMF)
and the like.
[0570] The reaction temperature is preferably under ice-cooling to
room temperature.
[0571] The reaction of the acid chloride and a compound of the
formula [B] is generally performed in the presence of a base.
[0572] Examples of the solvent include a single or mixed solvent of
hexane, chloroform, methylene chloride, ethyl acetate, toluene,
1,2-dimethoxyethane, 1,4-dioxane, THF and the like.
[0573] Examples of the base include triethylamine,
diisopropylethylamine, pyridine and the like.
[0574] The reaction temperature is preferably -78.degree. C. to
room temperature.
Step 2
[0575] A compound of the formula [E-I] or a compound of the formula
[E-II] can be produced by reacting a compound of the formula [C]
and the corresponding compound of the formula [D-I] or the formula
[D-II] in a solvent.
[0576] The reaction of a compound of the formula [C] and the
corresponding compound of the formula [D-I] or the formula [D-II]
is generally performed in the presence of a base. An additive may
be used where necessary.
[0577] Examples of the solvent include a single or mixed solvent of
chloroform, dichloromethane, DMF, N,N-dimethylacetamide (DMA),
dimethyl sulfoxide (DMSO), acetonitrile, 1,2-dimethoxyethane, so
1,4-dioxane, THF, toluene, water and the like.
[0578] Examples of the base include triethylamine,
diisopropylethylamine, diazabicycloundecene, sodium carbonate,
potassium carbonate, sodium hydrogen carbonate and the like.
[0579] Examples of the additive include acetic acid,
p-toluenesulfonic acid, methanesulfonic acid and the like.
[0580] The reaction temperature is preferably from room temperature
to under heating.
Step 3
[0581] A compound of the formula [I] or the formula [II] can be
produced by deprotecting hydroxy-protecting group Ra of a compound
of the formula [E-I] or a compound of the formula [E-II] in a
solvent. For example, when the hydroxy-protecting group is benzyl
group, the deprotection is generally performed under acidic
conditions.
[0582] Examples of the solvent include a single or mixed solvent of
hexane, chloroform, methylene chloride, ethyl acetate, toluene,
methanol, ethanol, 2-propanol, THF, 1,4-dioxane, acetonitrile,
water and the like.
[0583] Examples of the acid include hydrochloric acid, sulfuric
acid, hydrogen bromide, phosphoric acid, acetic acid,
trifluoroacetic acid and the like.
[0584] The reaction temperature is preferably under ice-cooling to
room temperature.
[0585] When a compound of the formula [I], a compound of the
formula [II], a compound of the formula [E-I] or a compound of the
formula [E-II] is a mixture of stereoisomers, the compounds can be
separated into each single compound by silica gel column
chromatography, high performance liquid chromatography (HPLC) and
the like.
Production Method 2
[0586] A compound represented by the formula [I] or [II] or a
pharmaceutically acceptable salt thereof, or a solvate thereof can
be produced from a compound of the formula [E-Ia] or a compound of
the formula [E-IIa], which is a compound of the formula [E-I] or
[E-II] wherein R.sup.5 is hydroxy group in Production method 1,
according to the following method. In this Production method 2,
when the compound obtained from a compound of the formula [E-Ia] or
a compound of the formula [E-IIa] is a mixture of stereoisomers,
the compounds can be separated into each single compound by silica
gel column chromatography, HPLC and the like.
##STR00042##
Production Method 2-1
[0587] A compound of the formula [E-I] or a compound of the formula
[E-II] wherein R.sup.5 is C.sub.1-6 alkoxy group or benzyloxy group
can be produced by reacting a compound of the formula [E-Ia] or a
compound of the formula [E-IIa] with a C.sub.1-6 alkylating agent,
benzyl bromide or benzyl chloride in a solvent. A compound of the
formula [E-Ia] or a compound of the formula [E-IIa] and a C.sub.1-6
alkylating agent are generally reacted in the presence of a base. A
catalyst may be added where necessary.
[0588] Examples of the solvent include a single or mixed solvent of
toluene, methylene chloride, 1,2-dimethoxyethane, 1,4-dioxane, THF,
DMF, DMA, acetonitrile, water and the like.
[0589] As the C.sub.1-6 alkylating agent, C.sub.1-6 alkyl halide
such as iodomethane, iodoethane and the like, or dialkyl sulfate
such as dimethyl sulfate, diethyl sulfate and the like is
preferable.
[0590] Examples of the base include sodium hydride, potassium
tert-butoxide, potassium carbonate, sodium hydroxide and the
like.
[0591] Examples of the catalyst include tetrabutylammonium hydrogen
sulfate salt and the like.
[0592] The reaction temperature is preferably from under
ice-cooling to under heating.
Production Method 2-2
[0593] A compound of the formula [E-I] or a compound of the formula
[E-II] wherein R.sup.5 is C.sub.1-6 alkoxy C.sub.2-6 alkyleneoxy
group can be produced by reacting a compound of the formula [E-Ia]
or a compound of the formula [E-IIa] with C.sub.1-6 alkoxy
C.sub.2-6 alkylating agent in a solvent. A compound of the formula
[E-Ia] or a compound of the formula [E-IIa] and C.sub.1-6 alkoxy
C.sub.2-6 alkylating agent are generally reacted in the presence of
a base. A catalyst may be added where necessary.
[0594] Examples of the solvent include a single or mixed solvent of
toluene, methylene chloride, 1,2-dimethoxyethane, 1,4-dioxane, THF,
DMF, DMA, acetonitrile, water and the like.
[0595] As the C.sub.1-6 alkoxy C.sub.2-6 alkylating agent,
C.sub.1-6 alkoxy C.sub.2-6 alkyl halide such as
1-bromo-2-methoxyethane, 1-bromo-3-methoxypropane and the like is
preferable.
[0596] Examples of the base include sodium hydride, potassium
tert-butoxide, potassium carbonate, sodium hydroxide and the
like.
[0597] Examples of the catalyst include tetrabutylammonium hydrogen
sulfate and the like.
[0598] The reaction temperature is preferably from under
ice-cooling to under heating.
Production Method 2-3
Production Method 2-3-1
[0599] A compound of the formula [E-I] or a compound of the formula
[E-II] wherein r is 0 and R.sup.5 is carboxy group can be produced
by reacting a compound of the formula [E-Ia] or a compound of the
formula [E-IIa] wherein r is 1 with an oxidizing agent, in the
presence of a catalyst where necessary, in a solvent.
[0600] Examples of the solvent include a single or mixed solvent of
acetone, carbon tetrachloride, DMF, DMA, acetonitrile, water and
the like.
[0601] As the oxidizing agent, sodium hypochlorite, sodium
chlorite, potassium permanganate and the like are preferably used
alone or in combination.
[0602] As the catalyst, 2,2,6,6-tetramethylpiperidin-1-oxyl is
preferable.
[0603] The reaction temperature is preferably under ice-cooling to
room temperature.
Production Method 2-3-2
[0604] A compound of the formula [E-I] or a compound of the formula
[E-II] wherein r is 1 and R.sup.5 is carboxy group can be produced
from a compound of the formula [E-Ia] or a compound of the formula
[E-IIa] wherein r is 1, via a compound of the formula [E-I] or a
compound of the formula [E-II] wherein R.sup.5 is
methanesulfonyloxy group, and a cyano intermediate, in a
solvent.
[0605] A compound of the formula [E-I] or a compound of the formula
[E-II] wherein R.sup.5 is methanesulfonyloxy group can be produced
by reacting a compound of the formula [E-Ia] or a compound of the
formula [E-IIa] wherein r is 1 with methanesulfonyl chloride in a
solvent. The reaction of a compound of the formula [E-Ia] or a
compound of the formula [E-IIa] and methanesulfonyl chloride is
generally performed in the presence of a base.
[0606] Examples of the solvent include a single or mixed solvent of
toluene, methylene chloride, chloroform, 1,2-dimethoxyethane,
1,4-dioxane, THF, pyridine and the like.
[0607] Examples of the base include triethylamine,
diisopropylethylamine, pyridine and the like.
[0608] The reaction temperature is preferably under ice-cooling to
room temperature.
[0609] The cyano intermediate can be produced by reacting a
compound of the formula [E-I] or a compound of the formula [E-II]
wherein R.sup.5 is methanesulfonyloxy group with KCN or NaCN in a
solvent.
[0610] Examples of the solvent include a single or mixed solvent of
1,2-dimethoxyethane, 1,4-dioxane, THF, DMF, DMA, DMSO,
acetonitrile, water and the like.
[0611] The reaction temperature is preferably from under
ice-cooling to under heating.
[0612] A compound of the formula [E-I] or a compound of the formula
[E-II] wherein R.sup.5 is carboxy group can be produced by
hydrolyzing a cyano intermediate in a solvent. The cyano
intermediate is generally hydrolyzed in the presence of a base.
[0613] Examples of the solvent include a single or mixed solvent of
1,2-dimethoxyethane, 1,4-dioxane, THF, ethanol, ethylene glycol,
DMF, DMA, DMSO, water and the like.
[0614] Examples of the base include potassium hydroxide, sodium
hydroxide and the like.
[0615] The reaction temperature is preferably under heating.
Production Method 2-4
[0616] A compound of the formula [E-I] or a compound of the formula
[E-II] wherein R.sup.5 is --CO--NR.sup.6aR.sup.6b can be produced
by reacting a compound of the formula [E-I] or a compound of the
formula [E-II] obtained in Production method 2-3-1 or 2-3-2,
wherein R.sup.5 is carboxy group, with HNR.sup.6aR.sup.6b and a
condensing agent in a solvent.
[0617] Examples of the solvent include DMF, DMA, acetonitrile and
the like.
[0618] Examples of the condensing agent include
N,N'-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochloride
and the like.
[0619] The reaction temperature is preferably room temperature.
Production Method 2-5
[0620] A compound of the formula [E-I] or a compound of the formula
[E-II] wherein R.sup.5 is --NR.sup.7aCOR.sup.7b can be produced
from a compound of the formula [E-Ia] or a compound of the formula
[E-IIa], via ketone intermediate 1 or aldehyde intermediate 1 and
amine intermediate 1.
[0621] The ketone intermediate 1 or aldehyde intermediate 1 can be
produced by reacting a compound of the formula [E-Ia] or a compound
of the formula [E-IIa] with an oxidizing agent.
[0622] Examples of the solvent include methylene chloride,
chloroform, acetonitrile and the like.
[0623] Examples of the oxidizing agent include
1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin
reagent), tetrapropylammonium perruthenate, chlorochromic acid,
pyridinium dichromate and the like.
[0624] The reaction temperature is preferably under ice-cooling to
room temperature.
[0625] The amine intermediate 1 can be produced by reacting ketone
intermediate 1 or aldehyde intermediate 1, R.sup.7aNH.sub.2 and a
reducing agent.
[0626] Examples of the solvent include methylene chloride,
chloroform and the like.
[0627] Examples of the reducing agent include sodium
triacetoxyborohydride and the like.
[0628] The reaction temperature is preferably under ice-cooling to
room temperature.
[0629] A compound of the formula [E-I] or a compound of the formula
[E-II] wherein R.sup.5 is --NR.sup.7aCOR.sup.7b can be produced by
reacting amine intermediate 1 with an acylating agent.
[0630] The amine intermediate 1 and the acylating agent are
generally reacted in the presence of a base.
[0631] Examples of the solvent include methylene chloride,
chloroform, 1,2-dimethoxyethane, 1,4-dioxane, THF, pyridine and the
like.
[0632] Examples of the acylating agent include R.sup.bCOCl,
(R.sup.bCO).sub.2O and the like.
[0633] Examples of the base include triethylamine,
diisopropylethylamine, pyridine and the like.
[0634] The reaction temperature is preferably under ice-cooling to
room temperature.
Production Method 2-6
[0635] A compound of the formula [E-I] or a compound of the formula
[E-II] wherein R.sup.5 is methanesulfonyl group can be produced by
reacting a compound of the formula [E-I] or the formula [E-II]
wherein R.sup.5 is methanesulfonyloxy group with sodium
methanesulfinate in a solvent.
[0636] Examples of the solvent include DMF, DMA and the like.
[0637] The reaction temperature is preferably under heating.
[0638] Alternatively, a compound of the formula [E-I] or a compound
of the formula [E-II] wherein R.sup.5 is methanesulfonyl group can
be produced from a compound of the formula [E-Ia] or a compound of
the formula [E-IIa], via halo intermediate 1.
[0639] The halo intermediate 1 can be produced by reacting a
compound of the formula [E-Ia] or a compound of the formula [E-IIa]
with a halogenating agent.
[0640] Examples of the solvent include methylene chloride,
chloroform, carbon tetrachloride and the like.
[0641] Examples of the halogenating agent include thionyl chloride,
phosphorus oxychloride, phosphorus oxybromide, oxalyl dichloride
and the like.
[0642] The reaction temperature is preferably from room temperature
to under heating.
[0643] A compound of the formula [E-I] or a compound of the formula
[E-II] wherein R.sup.5 is methanesulfonyl group can be produced by
reacting halo intermediate 1 with sodium methanesulfinate.
[0644] Examples of the solvent include DMF, DMA and the like.
[0645] The reaction temperature is preferably under heating.
Production Method 3
Production Method of a Compound of the Formula [A] in Production
Method 1
##STR00043##
[0646] wherein Rb is carboxy-protecting group such as methyl group,
ethyl group, benzyl group, tert-butyl group and the like, and other
symbols are as mentioned above.
Step 1
[0647] A compound of the formula [A-2] can be produced by reacting
a compound of the formula [A-1] with a compound of the formula
[A-1-1] in a solvent.
[0648] The reaction of a compound of the formula [A-1] and a
compound of the formula [A-1-1] is generally performed in the
presence of a base.
[0649] Examples of the solvent include DMF, DMA, DMSO, THF, toluene
and the like.
[0650] Examples of the base include sodium hydride, lithium
diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS) and
the like.
[0651] The reaction temperature is preferably -78.degree. C. to
room temperature.
Step 2
[0652] A compound of the formula [A-3] can be produced by reacting
a compound of the formula [A-2] with N,N-dimethylformamide dimethyl
acetal in a solvent.
[0653] Examples of the solvent include DMF, acetonitrile, THF,
chloroform, ethyl acetate, methylene chloride, toluene and the
like.
[0654] The reaction temperature is preferably from room temperature
to under heating.
Step 3
[0655] A compound of the formula [A-4] can be produced by reacting
a compound of the formula [A-3] with ethyl chloroglyoxylate.
[0656] The reaction of a compound of the formula [A-3] and ethyl
chloroglyoxylate is generally performed in the presence of a
base.
[0657] Examples of the solvent include DMF, DMA, DMSO, THF, toluene
and the like.
[0658] Examples of the base include sodium hydride, LDA, LHMDS and
the like. It is preferable to further treat with triethylamine,
diisopropylethylamine and the like after reacting with a
compound.
[0659] The reaction temperature is preferably -78.degree. C. to
room temperature.
Step 4
[0660] A compound of the formula [A] can be produced by
deprotecting the carboxy-protecting group Rb of a compound of the
formula [A-4] in a solvent. The carboxy-protecting group Rb is
deprotected by a known method.
[0661] For example, when the protecting group is tert-butyl group,
the deprotection is performed under acidic conditions.
[0662] Examples of the solvent include a single or mixed solvent of
hexane, chloroform, methylene chloride, ethyl acetate, toluene,
1,2-dimethoxyethane, 1,4-dioxane, THF, methanol, ethanol,
2-propanol, DMSO, DMF, DMA, acetonitrile, water and the like.
[0663] Examples of the acid include p-toluenesulfonic acid,
methanesulfonic acid, boron trifluoride, boron trichloride, boron
tribromide, aluminum trichloride, hydrochloric acid, hydrogen
bromide, phosphoric acid, sulfuric acid, acetic acid, to
trifluoroacetic acid and the like.
[0664] The reaction temperature is preferably from under
ice-cooling to under heating.
Production Method 4
Production Method of a Compound of the Formula [B] in Production
Method 1
[0665] Compound [B] may be a commercially available compound, or
can be produced from a commercially available compound by a known
method.
##STR00044##
wherein Xa is halogen atom, and other symbols are as mentioned
above.
Step 1
[0666] A compound of the formula [B-2] can be produced by reacting
a compound of the formula [B-1] with a halogenating agent.
[0667] Examples of the solvent include hexane, methylene chloride,
chloroform, carbon tetrachloride, concentrated sulfuric acid,
acetic acid and the like.
[0668] Examples of the halogenating agent include
N-iodosuccinimide, N-bromosuccinimide, bromine, iodine and the
like.
[0669] The reaction temperature is preferably from under
ice-cooling to under heating.
Step 2
[0670] A compound of the formula [B-3] can be produced by reacting
a compound of the formula [B-2] with a reducing agent.
[0671] Examples of the solvent include hexane, toluene,
1,2-dimethoxyethane, 1,4-dioxane, THF and the like.
[0672] As the reducing agent, borane-THF complex are
preferable.
[0673] The reaction temperature is preferably from under
ice-cooling to under heating.
[0674] Alternatively, a compound of the formula [B-3] can be
produced by reacting a compound of the formula [B-2] with ethyl
chlorocarbonate and the like to convert the compound into an active
ester, and reacting same with a reducing agent.
[0675] Examples of the solvent include solvents such as
1,2-dimethoxyethane, 1,4-dioxane, THF, water and the like and a
mixed solvent thereof.
[0676] As the reducing agent, sodium borohydride is preferable.
[0677] The reaction temperature is preferably under ice-cooling to
room temperature.
Step 3
[0678] A compound of the formula [B-4] can be produced by reacting
a compound of the formula [B-3] with a compound represented by the
formula R.sup.3--H. Here, H of R.sup.3--H means hydrogen atom
bonded to a hetero atom for R.sup.3.
[0679] The reaction of a compound of the formula [B-3] and the
compound represented by the formula R.sup.3--H is generally
performed in the presence of a base, by adding a catalyst and a
ligand where necessary.
[0680] Examples of the solvent include a single or mixed solvent of
toluene, 1,2-dimethoxyethane, 1,4-dioxane, THF, methanol, ethanol,
2-propanol, DMSO, DMF, DMA, acetonitrile, water and the like.
[0681] Examples of the base include sodium methoxide, potassium
tert-butoxide, potassium carbonate, cesium carbonate, potassium
phosphate and the like.
[0682] Examples of the catalyst include copper(I) iodide,
palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0) and
the like.
[0683] Examples of the ligand include 1,10-phenanthroline,
4,5'-bis(diphenylphosphino)-9,9'-dimethylxanthene and the like.
[0684] The reaction temperature is preferably from under
ice-cooling to under heating.
[0685] When R.sup.3 is C.sub.1-6 alkoxy group, a compound of the
formula [B-4] can also be produced from a compound of the formula
[B-3], via hydroxy intermediate 1.
[0686] The hydroxy intermediate 1 can be produced by reacting a
compound of the formula [B-3] with water.
[0687] The reaction of a compound of the formula [B-3] and water is
generally performed in the presence of a base, by adding a catalyst
and a ligand where necessary.
[0688] Examples of the solvent include a single or mixed solvent of
1,2-dimethoxyethane, 1,4-dioxane, THF, methanol, ethanol,
2-propanol, DMSO, DMF, DMA, acetonitrile, water and the like.
[0689] Examples of the base include potassium hydroxide, sodium
hydroxide and the like.
[0690] As the catalyst, copper(I) iodide is preferable.
[0691] As the ligand, 1,10-phenanthroline is preferable.
[0692] The reaction temperature is preferably from room temperature
to under heating.
[0693] A compound of the formula [B-4] can be produced by reacting
hydroxy intermediate 1 with a C.sub.1-6 alkylating agent.
[0694] The reaction of hydroxy intermediate 1 and a C.sub.1-6
alkylating agent is generally performed in the presence of a
base.
[0695] Examples of the solvent include a single or mixed solvent of
1,2-dimethoxyethane, 1,4-dioxane, THF, DMSO, DMF, DMA, acetonitrile
and the like.
[0696] As the C.sub.1-6 alkylating agent, C.sub.1-6 alkyl halide
such as iodomethane, iodoethane and the like or dialkyl sulfate
such as dimethyl sulfate, diethyl sulfate and the like is
preferable.
[0697] Examples of the base include potassium tert-butoxide,
potassium carbonate, cesium carbonate, sodium hydrogen carbonate,
potassium phosphate and the like.
[0698] The reaction temperature is preferably from under
ice-cooling to under heating.
Step 4
[0699] A compound of the formula [B] can be produced from a
compound of the formula [B-4], via phthalimide intermediate 1.
[0700] The phthalimide intermediate 1 can be produced by reacting a
compound of the formula [B-4], phthalimide, an azo compound and an
additive in a solvent.
[0701] Examples of the solvent include a single or mixed solvent of
THF, methylene chloride, chloroform, DMF, ethyl acetate, toluene
and the like.
[0702] Examples of the azo compound include diisopropyl
azodicarboxylate, diethyl azodicarboxylate,
N,N,N',N'-tetramethylazodicarboxamide,
1,1'-(azodicarbonyl)dipiperidine and the like.
[0703] Examples of the additive include phosphorus reagents such as
triphenylphosphine, diphenyl(2-pyridyl)phosphine,
tributylphosphine, tri-tert-butylphosphine etc., and the like.
[0704] The reaction temperature is preferably under ice-cooling to
room temperature.
[0705] A compound of the formula [B] can be produced by reacting
phthalimide intermediate 1 with hydrazine in a solvent.
[0706] Examples of the solvent include a single or mixed solvent of
methanol, ethanol, toluene and the like.
[0707] The reaction temperature is preferably under heating.
Production Method 5
Production Method of a Compound of the Formula [D-I] in Production
Method 1
##STR00045##
[0708] Production Method 5-1
[0709] A compound of the formula [D-I] wherein q is 1 (hereinafter
to be referred to as a compound of the formula [D-Ia]) can be
produced by the following Production methods 5-1-1 to 5-1-3.
##STR00046##
Production Method 5-1-1
##STR00047##
[0710] wherein Rc is carboxy-protecting group such as methyl group,
ethyl group, benzyl group, tert-butyl group and the like, Rd is
hydroxy-protecting group such as C.sub.1-6 alkyl group, or
C.sub.1-6 alkoxy C.sub.2-6 alkylene group, benzyl group,
tert-butyldimethylsilyl group, triisopropylsilyl group,
tert-butyldiphenylsilyl group and the like, and other symbols are
as mentioned above.
Step 1
[0711] A compound of the formula [D-Ia-01] can be produced by
esterifying commercially available 3-oxocyclobutanecarboxylic acid
D-Ia-s1 by a known method. For example, when Rc is benzyl group, a
compound of the formula [D-Ia-01] can be produced by reacting
3-oxocyclobutanecarboxylic acid with benzyl chloride or benzyl
bromide in a solvent. The reaction of 3-oxocyclobutanecarboxylic
acid and benzyl chloride or benzyl bromide is generally performed
in the presence of a base.
[0712] Examples of the solvent include toluene,
1,2-dimethoxyethane, 1,4-dioxane, THF, DMF, DMA, acetonitrile and
the like.
[0713] Examples of the base include sodium hydride, potassium
carbonate and the like.
[0714] The reaction temperature is preferably room temperature.
Step 2
[0715] A compound of the formula [D-Ia-02] can be produced by
ketalizing compound [D-Ia-01] with ethylene glycol and an additive
in a solvent by a known method.
[0716] Examples of the solvent include toluene,
1,2-dimethoxyethane, 1,4-dioxane, chloroform, methylene chloride
and the like.
[0717] Examples of the additive include pyridinium
p-toluenesulfonate, p-toluenesulfonic acid hydrate, camphorsulfonic
acid and the like.
[0718] The reaction temperature is preferably from room temperature
to under heating.
Step 3
[0719] The compound D-Ia-03 can be produced by reacting a compound
of the formula [D-Ia-02] with a reducing agent in a solvent.
[0720] Examples of the solvent include THF, 1,2-dimethoxyethane,
1,4-dioxane and the like ether solvents.
[0721] As the reducing agent, diisobutylaluminum hydride, lithium
aluminum hydride are preferable.
[0722] The reaction temperature is preferably under ice-cooling to
room temperature.
Step 4
[0723] A compound of the formula [D-Ia-04] can be produced from the
compound D-Ia-03 in the same manner as in Production method 2-1 or
2-2 in a solvent, or by protecting the hydroxy group of the
compound D-Ia-03. The hydroxy group of the compound D-Ia-03 may be
protected by a known method. For example, when Rd is
tert-butyldiphenylsilyl group, a compound of the formula [D-Ia-04]
can be produced by reacting the compound D-Ia-03 with
tert-butyldiphenylsilyl chloride in a solvent.
[0724] The reaction of compound D-Ia-03 and tert-butyldiphenylsilyl
chloride is generally performed in the presence of a base.
[0725] Examples of the solvent include toluene,
1,2-dimethoxyethane, 1,4-dioxane, THF, DMF, DMA, acetonitrile and
the like.
[0726] Examples of the base include triethylamine, imidazole and
the like.
[0727] The reaction temperature is preferably room temperature.
Step 5
[0728] A compound of the formula [D-Ia-05] can be produced by
reacting a compound of the formula [D-Ia-04] with an acid in a
solvent.
[0729] A compound of the formula [D-Ia-04] and acid may be reacted
according to a known method.
[0730] Examples of the solvent include a single or mixed solvent of
chloroform, methylene chloride, toluene, 1,2-dimethoxyethane,
1,4-dioxane, THF, methanol, ethanol, 2-propanol, water and the
like.
[0731] As the acid, 1N or 2N aqueous hydrochloric acid solution is
preferable.
Step 6
[0732] A compound of the formula [D-Ia-06] can be produced by
subjecting a compound of the formula [D-Ia-05], aqueous ammonia,
potassium cyanide and an additive to Strecker reaction in a
solvent.
[0733] Examples of the solvent include a single or mixed solvent of
water, methanol, ethanol, 2-propanol, 1,4-dioxane, THF and the
like.
[0734] Examples of the additive include ammonium chloride and the
like.
[0735] The reaction temperature is preferably under ice-cooling to
room temperature.
##STR00048##
wherein Re and Re' are the same or different and each is
amino-protecting group such as tert-butoxycarbonyl group,
benzyloxycarbonyl group and the like, and other symbols are as
mentioned above.
Step 7
[0736] A compound of the formula [D-Ia-07] can be produced by
protecting the amino group of a compound of the formula
[D-Ia-06].
[0737] The amino group may be protected according to a known
method.
[0738] For example, when Re is tert-butoxycarbonyl group, a
compound of the formula [D-Ia-07] can be produced by reacting a
compound of the formula [D-Ia-06] with di-tert-butyl dicarbonate in
a solvent.
[0739] The reaction of a compound of the formula [D-Ia-06] and
di-tert-butyl dicarbonate is generally performed in the presence of
a base.
[0740] Examples of the solvent include a single or mixed solvent of
chloroform, methylene chloride, ethyl acetate, toluene,
1,2-dimethoxyethane, 1,4-dioxane, THF, DMF, DMA, acetonitrile,
water and the like.
[0741] Examples of the base include sodium hydrogen carbonate,
triethylamine and the like.
[0742] The reaction temperature is preferably room temperature.
Step 8
[0743] A compound of the formula [D-Ia-08] can be produced by
reacting a compound of the formula [D-Ia-07] with a reducing agent
in a solvent.
[0744] Examples of the solvent include methanol, ethanol and the
like.
[0745] As the reducing agent, a complex of sodium borohydride and
cobalt(II) chloride hexahydrate is preferable.
[0746] The reaction temperature is preferably under ice-cooling to
room temperature.
Step 9
[0747] A compound of the formula [D-Ia-09] can be produced by
reacting a compound of the formula [D-Ia-08] and a ketone compound
or an aldehyde compound corresponding to R.sup.4 with a reducing
agent in a solvent.
[0748] Examples of the solvent include DMF, acetonitrile, THF,
chloroform, ethyl acetate, methylene chloride, toluene and the
like.
[0749] The ketone compound corresponding to R.sup.4 is, for
example, acetone when R.sup.4 is isopropyl group, and
cyclopropanone when R.sup.4 is cyclopropyl group.
[0750] The aldehyde compound corresponding to R.sup.4 is, for
example, acetaldehyde when R.sup.4 is methyl group, and
propionaldehyde when R.sup.4 is ethyl group.
[0751] Examples of the reducing agent include sodium borohydride,
sodium triacetoxyborohydride and the like.
[0752] The reaction temperature is preferably under ice-cooling to
room temperature.
Step 10
[0753] A compound of the formula [D-Ia-10] can be produced by
protecting the amino group of a compound of the formula
[D-Ia-09].
[0754] For example, when Re' is tert-butoxycarbonyl group, a
compound of the formula [D-Ia-10] can be produced in the same
manner as in the above-mentioned step 7.
Step 11
[0755] A compound of the formula [D-Ia-11] can be produced by
deprotecting the amino-protecting group of a compound of the
formula [D-Ia-09] or a compound of the formula [D-Ia-10]. The
amino-protecting group may be deprotected by a known method.
[0756] For example, when Re and Re' are tert-butoxycarbonyl groups,
the amino-protecting group is deprotected under acidic
conditions.
[0757] Examples of the solvent include a single or mixed solvent of
hexane, chloroform, methylene chloride, ethyl acetate, toluene,
1,2-dimethoxyethane, 1,4-dioxane, THF, methanol, ethanol,
2-propanol, DMSO, DMF, DMA, acetonitrile, water and the like.
[0758] Examples of the acid include trifluoroacetic acid,
hydrochloric acid, hydrogen bromide and the like.
Step 12
[0759] A compound of the formula [D-Ia-12] can be produced by
deprotecting the hydroxy-protecting group of a compound of the
formula [D-Ia-11]. For example, when Rd is benzyl group, the
hydroxy-protecting group is deprotected under acidic
conditions.
[0760] Examples of the solvent include toluene,
1,2-dimethoxyethane, 1,4-dioxane, THF, DMF, DMA, acetonitrile and
the like.
[0761] Examples of the acid include hydrogen bromide/acetic acid,
hydrogen bromide and the like.
[0762] The reaction temperature is preferably under ice-cooling to
room temperature.
[0763] When Rd is tert-butyldiphenylsilyl group, the
hydroxy-protecting group is deprotected by reacting with a
fluorinating agent such as tetrabutylammonium fluoride and the
like.
[0764] A compound of the formula [D-Ia-06], a compound of the
formula [D-Ia-07], a compound of the formula [D-Ia-08], a compound
of the formula [D-Ia-09], a compound of the formula [D-Ia-10], a
compound of the formula [D-Ia-11] and a compound of the formula
[D-Ia-12] can be each separated into a single compound (cis form or
trans form) by silica gel column chromatography, HPLC and the like.
The separated each compound can be reacted in the same manner as in
the above-mentioned step 7 to step 12.
##STR00049##
Production Method 5-1-2
##STR00050##
[0765] Step 1
[0766] A compound of the formula [D-Ia-21] can be produced by
hydrolyzing a compound of the formula [D-Ia-s2] in a solvent.
[0767] A compound of the formula [D-Ia-s2] is generally hydrolyzed
in the presence of a base.
[0768] Examples of the solvent include solvents such as THF,
methanol, ethanol, water and the like and a mixed solvent
thereof.
[0769] Examples of the base include sodium hydroxide, potassium
hydroxide and the like.
[0770] The reaction temperature is preferably heating under
reflux.
[0771] A compound of the formula [D-Ia-s2] may be commercially
available diethyl 3-benzyloxy-1,1-cyclobutanedicarboxylate, or can
be produced from commercially available diethyl
3-hydroxy-1,1-cyclobutanedicarboxylate in the same manner as in
Production method 5-1-1, step 4.
Step 2
[0772] A compound of the formula [D-Ia-22] can be produced from a
compound of the formula [D-Ia-21] via acid azide intermediate
1.
[0773] The acid azide intermediate 1 can be produced by reacting a
compound of the formula [D-Ia-21] with an azide reagent in a
solvent. The reaction of a compound of the formula [D-Ia-21] and an
azide reagent is generally performed in the presence of a base.
[0774] Examples of the solvent include toluene, tert-butyl alcohol,
1,2-dimethoxyethane, 1,4-dioxane, THF, DMF, acetonitrile and the
like solvent and a mixed solvent thereof.
[0775] Examples of the base include triethylamine, to
diisopropylethylamine and the like.
[0776] Examples of the azide reagent include diphenylphosphoryl
azide (DPPA) and the like.
[0777] The reaction temperature is preferably from room temperature
to under heating.
[0778] Alternatively, the acid azide intermediate 1 can be produced
by converting a compound of the formula [D-Ia-21] to an active
ester by reacting with ethyl chlorocarbonate and the like, and
reacting the active ester with an azide reagent. In this case, the
reaction is generally performed in the presence of a base.
[0779] Examples of the solvent include solvents such as toluene,
tert-butyl alcohol, 1,2-dimethoxyethane, 1,4-dioxane, THF, DMF,
acetonitrile, acetone, water and the like and a mixed solvent
thereof.
[0780] Examples of the azide reagent include sodium azide and the
like.
[0781] The reaction temperature is preferably from room temperature
to under heating.
[0782] A compound of the formula [D-Ia-22] can be produced by
subjecting the acid azide intermediate 1 to Curtius rearrangement
in a solvent to give an isocyanate, and reacting same with
tert-butyl alcohol, benzyl alcohol and the like. The
above-mentioned reaction is generally performed in the presence of
a base.
[0783] Examples of the solvent include solvents such as toluene,
tert-butyl alcohol, 1,2-dimethoxyethane, 1,4-dioxane, THF, DMF,
acetonitrile, acetone and the like and a mixed solvent thereof.
[0784] Examples of the base include triethylamine,
diisopropylethylamine and the like.
[0785] The reaction temperature is preferably from room temperature
to under heating.
Step 3
[0786] A compound of the formula [D-Ia-23] can be produced by
reacting a compound of the formula [D-Ia-22] with a reducing agent
in a solvent.
[0787] Examples of the solvent include THF, 1,4-dioxane and the
like.
[0788] Examples of the reducing agent include lithium aluminum
hydride and the like.
[0789] The reaction temperature is preferably under ice-cooling to
room temperature.
Step 4
[0790] A compound of the formula [D-Ia-24] can be produced from a
compound of the formula [D-Ia-23] via aldehyde intermediate 2.
[0791] The aldehyde intermediate 2 can be produced by reacting a
compound of the formula [D-Ia-23] with an oxidizing agent in a
solvent.
[0792] Examples of the solvent include methylene chloride,
chloroform, acetonitrile and the like.
[0793] Examples of the oxidizing agent include
1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin
reagent), tetrapropylammonium perruthenate, chlorochromic acid,
pyridinium dichromate and the like.
[0794] The reaction temperature is preferably under ice-cooling to
room temperature.
[0795] A compound of the formula [D-Ia-24] can be produced by
reacting aldehyde intermediate 2, R.sup.4NH.sub.2 and a reducing
agent in a solvent.
[0796] Examples of the solvent include methylene chloride,
chloroform and the like.
[0797] Examples of the reducing agent include sodium
triacetoxyborohydride and the like.
[0798] The reaction temperature is preferably under ice-cooling to
room temperature.
Step 5
[0799] A compound of the formula [D-Ia-25] can be produced by
reacting a compound of the formula [D-Ia-24] in the same manner as
in Production method 5-1-1, step 11.
Step 6
[0800] A compound of the formula [D-Ia-26] can be produced by
reacting a compound of the formula [D-Ia-25] in the same manner as
in Production method 5-1-1, step 12.
[0801] A compound of the formula [D-Ia-21], a compound of the
formula [D-Ia-22], a compound of the formula [D-Ia-23], a compound
of the formula [D-Ia-24], a compound of the formula [D-Ia-25] and a
compound of the formula [D-Ia-26] can be each separated into a
single compound (cis form or trans form) by recrystallization,
silica gel column chromatography, HPLC and so the like. The
separated each compound can be reacted in the same manner as in the
above-mentioned step 2 to step 6.
##STR00051## ##STR00052##
Production Method 5-1-3
##STR00053##
[0802] Step 1
[0803] A compound of the formula [D-Ia-31] can be produced by
reacting a compound of the formula [D-Ia-12] or a compound of the
formula [D-Ia-26] in the same manner as in Production method 5-1-1,
step 7.
Step 2
[0804] A compound of the formula [D-Ia-32] can be produced by
reacting a compound of the formula [D-Ia-31] in the same manner as
in Production methods 2-1 to 2-6.
Step 3
[0805] A compound of the formula [D-Ia] can be produced by reacting
a compound of the formula [D-Ia-32] in the same manner as in
Production method 5-1-1, step 11.
[0806] The compounds of the formula [D-Ia-12], the formula
[D-Ia-26], the formula [D-Ia-31], the formula [D-Ia-32] and the
formula [D-Ia] can be each separated into a single compound (cis
form or trans form) by silica gel column chromatography, HPLC and
the like. The separated each compound can be reacted in the same
manner as in the above-mentioned step 1 to step 3.
##STR00054##
wherein each symbol is as mentioned above.
Production Method 5-2
[0807] A compound of the formula [D-I] wherein q is 0 (hereinafter
to be referred to as a compound of the formula [D-Ib]) can be
produced by the following Production methods 5-2-1 to 5-2-9.
Production Method 5-2-1
##STR00055##
[0808] wherein each symbol is as mentioned above.
Step 1
[0809] A compound of the formula [D-Ib-01] can be produced by
reacting a commercially available compound
((R)-(-)-2,2-dimethyl-1,3-dioxolan-4-methanol, Tokyo Chemical
Industry Co., Ltd., specific optical rotation
[.alpha.].sub.D.sup.20 -11.0 to -15.0 deg(neat)) in the same manner
as in Production method 5-1-1, step 4.
Step 2
[0810] A compound of the formula [D-Ib-02] can be produced by
reacting a compound of the formula [D-Ib-01] in the same manner as
in Production method 5-1-1, step 5.
Step 3-6
[0811] A compound of the formula [D-Ib-05] or a compound of the
formula [D-Ib-06] can be produced from a compound of the formula
[D-Ib-02] according to the method described in Synthesis, 1996,
1463. When Re of a compound of the formula [D-Ib-06] is
benzyloxycarbonyl group, benzyl alcohol may be used instead of
tert-butanol.
##STR00056##
wherein each symbol is as mentioned above.
Step 7
[0812] A compound of the formula [D-Ib-07] can be produced by
reacting a compound of the formula [D-Ib-06] with a reducing
agent.
[0813] Examples of the solvent include ether solvents such as
tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and the like.
[0814] As the reducing agent, diisobutylaluminum hydride, lithium
aluminum hydride are preferable.
[0815] The reaction temperature is preferably under ice-cooling to
room temperature.
Step 8
[0816] A compound of the formula [D-Ib-08] can be produced by
reacting a compound of the formula [D-Ib-07] with an oxidizing
agent.
[0817] Examples of the solvent include methylene chloride,
chloroform, acetonitrile and the like.
[0818] Examples of the oxidizing agent include
1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin
reagent), tetrapropylammonium perruthenate, chlorochromic acid,
pyridinium dichromate and the like.
[0819] The reaction temperature is preferably under ice-cooling to
room temperature.
Step 9
[0820] A compound of the formula [D-Ib-09] can be produced by
reacting a compound of the formula [D-Ib-09], R.sup.4NH.sub.2 and a
reducing agent in a solvent.
[0821] Examples of the solvent include methylene chloride,
chloroform and the like.
[0822] Examples of the reducing agent include sodium
triacetoxyborohydride and the like.
[0823] The reaction temperature is preferably under ice-cooling to
room temperature.
Step 10
[0824] A compound of the formula [D-Ib-10] can be produced by
reacting a compound of the formula [D-Ib-09] in the same manner as
in Production method 5-1-1, step 11.
Step 11
[0825] A compound of the formula [D-Ib-11] can be produced by
reacting a compound of the formula [D-Ib-10] in the same manner as
in Production method 5-1-1, step 12.
Production Method 5-2-2
##STR00057##
[0826] wherein each symbol is as mentioned above.
Step 1
[0827] A compound of the formula [D-Ib-21] can be produced by
reacting a compound of the formula [D-Ib-05] with
N,O-dimethylhydroxylamine hydrochloride in the same manner as in
Production method 2-4.
Step 2
[0828] A compound of the formula [D-Ib-22] can be produced by
hydrolyzing a compound of the formula [D-Ib-21].
[0829] A compound of the formula [D-Ib-21] is generally hydrolyzed
in the presence of a base.
[0830] Examples of the solvent include solvents such as THF,
methanol, ethanol, water and the like and a mixed solvent
thereof.
[0831] Examples of the base include sodium hydroxide, potassium
hydroxide and the like.
[0832] The reaction temperature is preferably room temperature.
Step 3
[0833] A compound of the formula [D-Ib-23] can be produced by
reacting a compound of the formula [D-Ib-22] in the same manner as
in Production method 5-2-1, step 6.
Step 4
[0834] A compound of the formula [D-Ib-24] can be produced by
reacting a compound of the formula [D-Ib-23] with a reducing
agent.
[0835] Examples of the solvent include ether solvents such as
tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and the like.
[0836] As the reducing agent, diisobutylaluminum hydride, lithium
aluminum hydride are preferable.
[0837] The reaction temperature is preferably under
ice-cooling.
Step 5
[0838] A compound of the formula [D-Ib-25] can be produced by
reacting a compound of the formula [D-Ib-24], R.sup.4NH.sub.2 and a
reducing agent.
[0839] Examples of the solvent include DMF, acetonitrile, THF,
chloroform, ethyl acetate, methylene chloride, toluene and the
like.
[0840] Examples of the reducing agent include sodium
triacetoxyborohydride and the like.
[0841] The reaction temperature is preferably under ice-cooling to
room temperature.
Step 6
[0842] A compound of the formula [D-Ib-26] can be produced by
reacting a compound of the formula [D-Ib-25] in the same manner as
in Production method 5-1-1, step 11.
Step 7
[0843] A compound of the formula [D-Ib-27] can be produced by
reacting a compound of the formula [D-Ib-26] in the same manner as
in Production method 5-1-1, step 12.
Production Method 5-2-3
[0844] The following compounds can be produced from a commercially
available compound ((S)-(+)-2,2-dimethyl-1,3-dioxolan-4-methanol,
Tokyo Chemical Industry Co., Ltd., specific optical rotation
[.alpha.].sub.D.sup.20 +13.5 to +14.5 deg(neat)) in the same manner
as in Production method 5-2-1.
##STR00058##
wherein each symbol is as mentioned above.
Production Method 5-2-4
[0845] The following compound can be produced from a compound of
the formula [D-Ib-35] obtained in Production method 5-2-3, step 5
in the same manner as in Production method 5-2-2.
##STR00059##
wherein each symbol is as mentioned above.
Production Method 5-2-5
##STR00060##
[0846] wherein TBS means tert-butyldimethylsilyl group, and Bn
means benzyl group.
Step 1
[0847] The compound D-Ib-61 or D-Id-61' can be produced from the
compound D-Ib-s3 that can be synthesized from
1,3:4,5-di-O-benzylidenemannitol (D form), via the compound D-Ib-s4
according to the method described in Tetrahedron: Asymmetry 11
(2000) 1015-1025, respectively.
##STR00061##
wherein Bn is benzyl group, and other symbols are as mentioned
above.
Step 2
[0848] The compound D-Ib-62 can be produced by reacting the
compound D-Ib-61 in the same manner as in Production method 5-1-1,
step 8.
Step 3
[0849] A compound of the formula [D-Ib-63] can be produced by
reacting the compound D-Ib-62 in the same manner as in Production
method 5-1-1, step 9.
Step 4
[0850] A compound of the formula [D-Ib-64] can be produced from a
compound of the formula [D-Ib-63] by deprotecting methoxycarbonyl
group by a known method.
[0851] The methoxycarbonyl group is generally deprotected in the
presence of a base.
[0852] Examples of the solvent include a single or mixed solvent of
1,2-dimethoxyethane, 1,4-dioxane, THF, methanol, ethanol,
2-propanol, water and the like.
[0853] Examples of the base include sodium hydroxide, potassium
hydroxide, sodium methoxide and the like.
[0854] The reaction temperature is preferably from room temperature
to under heating.
Step 5
[0855] A compound of the formula [D-Ib-65] can be produced from a
compound of the formula [D-Ib-64] by deprotecting benzyl group by a
known method.
[0856] The benzyl group is generally deprotected in the presence of
a catalyst under a hydrogen atmosphere.
[0857] Examples of the solvent include a single or mixed solvent of
hexane, chloroform, methylene chloride, ethyl acetate, toluene,
1,2-dimethoxyethane, 1,4-dioxane, THF, methanol, ethanol,
2-propanol, water and the like.
[0858] Examples of the catalyst include palladium/carbon, palladium
hydroxide and the like.
[0859] The reaction temperature is preferably room temperature.
Production Method 5-2-6
[0860] A compound of the formula [D-Ib-65'] can be produced by
reacting the compound D-Ib-61' obtained in Production method 5-2-5,
step 1, in the same manner as in Production method 5-2-5, step 2 to
step 5.
##STR00062##
Production Method 5-2-7
##STR00063##
[0861] wherein TBS means tert-butyldimethylsilyl group, and Bn
means benzyl group.
Step 1
[0862] The compound D-Ib-71 or D-Ib-71' can be produced from the
compound D-Ib-s5 that can be synthesized from
1,3:4,5-di-O-benzylidenemannitol (L form), via the compound D-Ib-s6
in the same manner as in Production method 5-2-5, step 1.
Step 2-5
[0863] A compound of the formula [D-Ib-75] can be produced by
reacting the compound D-Ib-71 obtained step 1 in the same manner as
in Production method 5-2-5, step 2 to step 5.
##STR00064##
wherein Bn means benzyl group, and other symbols are as mentioned
above.
Production Method 5-2-8
[0864] A compound of the formula [D-Ib-75'] can be produced by
reacting the compound D-Ib-71' obtained in Production method 5-2-7,
step 1, in the same manner as in Production method 5-2-5, step 2 to
step 5.
##STR00065##
wherein Bn is benzyl group, and other symbols are as mentioned
above.
Production Method 5-2-9
##STR00066##
[0865] Step 1
[0866] A compound of the formula [D-Ib-91], a compound of the
formula [D-Ib-92], a compound of the formula [D-Ib-93] and a
compound of the formula [D-Ib-94] can be produced by reacting a
compound of the formula [D-Ib-11], a compound of the formula
[D-Ib-27], a compound of the formula [D-Ib-41], a compound of the
formula [D-Ib-57], a compound of the formula [D-Ib-65], a compound
of the formula [D-Ib-65'], a compound of the formula [D-Ib-75] or a
compound of the formula [D-Ib-75'] in the same manner as in
Production method 5-1-1, step 10, Production methods 2-1 to 2-6,
and then Production method 5-1-1, step 11.
Production Method 6
Production Method of a Compound of the Formula [D-II] in Production
Method 1
##STR00067##
[0867] Production Method 6-1
[0868] A compound of the formula [D-II] wherein q is 1 (hereinafter
to be referred to as a compound of the formula [D-IIa]) can be
produced by the following Production methods 6-1-1 to 6-1-3.
##STR00068##
Production Method 6-1-1
##STR00069##
[0869] wherein each symbol is as mentioned above.
Step 1
[0870] A compound of the formula [D-11a-01] can be produced by
reacting a compound of the formula [D-Ia-07] obtained in Production
method 5-1-1, step 7, with R.sup.4--Xb wherein Xb is chlorine atom,
bromine atom or iodine atom in a solvent.
[0871] The reaction of a compound of the formula [D-Ia-07] and
R.sup.4--Xb is generally performed in the presence of a base.
[0872] Examples of the solvent include DMF, acetonitrile, THF,
toluene and the like.
[0873] Examples of the base include sodium hydride, potassium
carbonate and the like.
[0874] The reaction temperature is preferably under ice-cooling to
room temperature.
Step 2
[0875] A compound of the formula [D-IIa-02] can be produced by
reacting a compound of the formula [D-IIa-01] in the same manner as
in Production method 5-1-1, step 8.
Step 3
[0876] A compound of the formula [D-IIa-03] can be produced by
reacting a compound of the formula [D-IIa-02] in the same manner as
in Production method 5-1-1, step 11.
Step 4
[0877] A compound of the formula [D-IIa-04] can be produced by
reacting a compound of the formula [D-IIa-03] in the same manner as
in Production method 5-1-1, step 12.
[0878] A compound of the formula [D-IIa-01], a compound of the
formula [D-IIa-02], a compound of the formula [D-IIa-03] and a
compound of the formula [D-IIa-04] can be each separated into a
single compound (cis form or trans form) by silica gel column
chromatography, HPLC and the like. The separated each compound can
be reacted in the same manner as in the above-mentioned step 1 to
step 4.
##STR00070##
wherein each symbol is as mentioned above.
Production Method 6-1-2
##STR00071##
[0879] wherein each symbol is as mentioned above.
Step 1
[0880] A compound of the formula [D-IIa-21] can be produced by
reacting a compound of the formula [D-Ia-22] obtained in Production
method 5-1-2, step 2 in the same manner as in Production method
6-1-1, step 1.
Step 2
[0881] A compound of the formula [D-IIa-22] can be produced by
reacting a compound of the formula [D-IIa-21] in the same manner as
in Production method 5-1-2, step 3.
Step 3
[0882] A compound of the formula [D-IIa-23] can be produced from
the formula [D-IIa-22] via phthalimide intermediate 1.
[0883] The phthalimide intermediate 1 can be produced by reacting a
compound of the formula [D-IIa-22], phthalimide, an azo compound
and an additive in a solvent.
[0884] Examples of the solvent include a single or mixed solvent of
THF, methylene chloride, chloroform, DMF, ethyl acetate, toluene
and the like.
[0885] Examples of the azo compound include diisopropyl
azodicarboxylate, diethyl azodicarboxylate,
N,N,N',N'-tetramethylazodicarboxamide,
1,1'-(azodicarbonyl)dipiperidine and the like.
[0886] Examples of the additive include phosphorus reagents such as
triphenylphosphine, diphenyl(2-pyridyl)phosphine,
tributylphosphine, tri-tert-butylphosphine, etc., and the like.
[0887] The reaction temperature is preferably room temperature.
[0888] A compound of the formula [D-IIa-23] can be produced by
reacting the phthalimide intermediate 1 with hydrazine in a
solvent.
[0889] Examples of the solvent include methanol, ethanol and the
like.
[0890] The reaction temperature is preferably under heating.
Step 4
[0891] A compound of the formula [D-IIa-24] can be produced by
reacting a compound of the formula [D-IIa-23] in the same manner as
in Production method 5-1-1, step 11.
Step 5
[0892] A compound of the formula [D-IIa-25] can be produced by
reacting a compound of the formula [D-IIa-24] in the same manner as
in Production method 5-1-1, step 12.
[0893] A compound of the formula [D-Ia-22], a compound of the
formula [D-IIa-21], a compound of the formula [D-IIa-22], a
compound of the formula [D-IIa-23], a compound of the formula
[D-IIa-24] and a compound of the formula [D-IIa-25] can be each so
separated into a single compound (cis form or trans form) by
recrystallization, silica gel column chromatography, HPLC and the
like. The separated each compound can be reacted in the same manner
as in the above-mentioned step 1 to step 5.
##STR00072##
wherein each symbol is as mentioned above.
Production Method 6-1-3
##STR00073##
[0894] wherein each symbol is as mentioned above.
Step 1
[0895] A compound of the formula [D-IIa-31] can be produced by
reacting a compound of the formula [D-IIa-04] or a compound of the
formula [D-IIa-25] in the same manner as in Production method
5-1-1, step 7.
Step 2
[0896] A compound of the formula [D-IIa-32] can be produced by
reacting a compound of the formula [D-IIa-31] in the same manner as
in Production methods 2-1 to 2-6.
Step 3
[0897] A compound of the formula [D-IIa] can be produced by
reacting a compound of the formula [D-IIa-32] in the same manner as
in Production method 5-1-1, step 11.
[0898] The compound of a compound of the formula [D-IIa-04], the
formula [D-IIa-25], a compound of the formula [D-IIa-31], a
compound of the formula [D-IIa-32] and a compound of the formula
[D-IIa] can be each separated into a single compound (cis form or
trans form) by silica gel column chromatography, HPLC and the like.
The separated each compound can be reacted in the same manner as in
the above-mentioned step 1 to step 3.
##STR00074##
wherein each symbol is as mentioned above.
Production Method 6-2
[0899] A compound of the formula [D-II] wherein q is 0 (hereinafter
to be referred to as a compound of the formula [D-IIb]) can be
produced by the following Production methods 6-2-1 to 6-2-9.
Production Method 6-2-1
##STR00075##
[0900] wherein each symbol is as mentioned above.
Step 1
[0901] A compound of the formula [D-IIb-01] can be produced by
reacting a compound of the formula [D-Ib-07] obtained in Production
method 5-2-1, step 7, phthalimide, an azo compound, and an additive
in a solvent.
[0902] Examples of the solvent include a single or mixed solvent of
THF, methylene chloride, chloroform, DMF, ethyl acetate, toluene
and the like.
[0903] Examples of the azo compound include diisopropyl
azodicarboxylate, diethyl azodicarboxylate,
N,N,N',N'-tetramethylazodicarboxamide,
1,1'-(azodicarbonyl)dipiperidine and the like.
[0904] Examples of the additive include phosphorus reagents such as
triphenylphosphine, diphenyl(2-pyridyl)phosphine,
tributylphosphine, tri-tert-butylphosphine, etc., and the like.
[0905] The reaction temperature is preferably room temperature.
Step 2
[0906] A compound of the formula [D-IIb-02] can be produced by
reacting a compound of the formula [D-IIb-01] in the same manner as
in Production method 5-1-1, step 11.
Step 3
[0907] A compound of the formula [D-IIb-03] can be produced by
reacting a compound of the formula [D-IIb-02] in the same manner as
in Production method 5-1-1, step 9.
Step 4
[0908] A compound of the formula [D-IIb-04] can be produced by
reacting a compound of the formula [D-IIb-03] with hydrazine in a
solvent.
[0909] Examples of the solvent include methanol, ethanol and the
like.
[0910] The reaction temperature is preferably under heating.
Step 5
[0911] A compound of the formula [D-IIb-05] can be produced by
reacting a compound of the formula [D-IIb-04] in the same manner as
in Production method 5-1-1, step 12.
Production Method 6-2-2
##STR00076##
[0912] wherein each symbol is as mentioned above.
Step 1
[0913] A compound of the formula [D-IIb-11] can be produced from a
compound of the formula [D-Ib-23] obtained in Production method
5-2-2, step 3 in the same manner as in Production method 6-1-1,
step 1.
Step 2
[0914] A compound of the formula [D-IIb-12] can be produced by
reacting a compound of the formula [D-IIb-11] with a reducing
agent.
[0915] Examples of the solvent include ether solvents such as
tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and the like.
[0916] As the reducing agent, diisobutylaluminum hydride, lithium
aluminum hydride are preferable.
[0917] The reaction temperature is preferably under ice-cooling to
room temperature.
Step 3
[0918] A compound of the formula [D-IIb-13] can be produced from a
compound of the formula [D-IIb-12] in the same manner as in
Production method 6-1-2, step 3.
Step 4
[0919] A compound of the formula [D-IIb-14] can be produced from a
compound of the formula [D-IIb-13] in the same manner as in
Production method 5-1-1, step 11.
Step 5
[0920] A compound of the formula [D-IIb-15] can be produced from a
compound of the formula [D-IIb-14] in the same manner as in
Production method 5-1-1, step 12.
Production Method 6-2-3
[0921] The following compounds can be produced from [D-Ib-37] in
Production method 5-2-3, and in the same manner as in Production
method 6-2-1.
##STR00077##
wherein each symbol is as mentioned above.
Production Method 6-2-4
[0922] The following compounds can be produced from [D-Ib-53] in
Production method 5-2-4, and in the same manner as in Production
method 6-2-2.
##STR00078##
wherein each symbol is as mentioned above.
Production Method 6-2-5
##STR00079##
[0923] wherein each symbol is as mentioned above.
Step 1
[0924] A compound of the formula [D-IIb-41] can be produced by
reacting the compound D-Ib-62 obtained in Production method 5-2-5,
step 2 in the same manner as in Production method 5-1-1, step
7.
Step 2
[0925] A compound of the formula [D-IIb-42] can be produced by
reacting a compound of the formula [D-IIb-41] in the same manner as
in Production method 5-2-5, step 4.
Step 3
[0926] A compound of the formula [D-IIb-43] can be produced by
reacting a compound of the formula [D-IIb-42] in the same manner as
in Production method 5-1-1, step 9.
Step 4
[0927] A compound of the formula [D-IIb-44] can be produced by
reacting a compound of the formula [D-IIb-43] in the same manner as
in Production method 5-1-1, step 11.
Step 5
[0928] A compound of the formula [D-IIb-45] can be produced by
reacting a compound of the formula [D-IIb-44] in the same manner as
in Production method 5-2-5, step 5.
Production Method 6-2-6
[0929] The following compounds can be produced from [D-Ib-62'] in
Production method 5-2-6, and in the same manner as in Production
method 6-2-5.
##STR00080##
wherein each symbol is as mentioned above.
Production Method 6-2-7
[0930] The following compounds can be produced from [D-Ib-72] in
Production method 5-2-7, in the same manner as in Production method
6-2-5.
##STR00081##
wherein each symbol is as mentioned above.
Production Method 6-2-8
[0931] The following compounds can be produced from [D-Ib-72'] in
Production method 5-2-8, and in the same manner as in Production
method 6-2-5.
##STR00082##
wherein each symbol is as mentioned above.
Production Method 6-2-9
##STR00083##
[0932] wherein each symbol is as mentioned above.
Step 1
[0933] A compound of the formula [D-IIb-61], a compound of the
formula [D-IIb-62], a compound of the formula [D-IIb-63] and a
compound of the formula [D-IIb-64] can be produced by reacting a
compound of the formula [D-IIb-05], a compound of the formula
[D-IIb-55], a compound of the formula [D-IIb-15], a compound of the
formula [D-IIb-55'], a compound of the formula [D-IIb-25], a
compound of the formula [D-IIb-45'], a compound of the formula
[D-IIb-35] or a compound of the formula [D-IIb-45] in the same
manner as in Production method 5-1-1, step 10, Production methods
2-1 to 2-6, and then Production method 5-1-1, step 11.
EXAMPLES
[0934] Now, the production methods of the compound of the present
invention are specifically explained by referring to Examples,
which are not to be construed as limitative.
[0935] The abbreviations used in the specification mean the
following.
Bn: benzyl group Boc: tert-butoxycarbonyl group Et: ethyl group Me:
methyl group TBS: tert-butyldimethylsilyl group Z:
benzyloxycarbonyl group THF: tetrahydrofuran
DMF: N,N-dimethylformamide
[0936] DMSO: dimethyl sulfoxide DME: 1,2-dimethoxyethane TFA:
trifluoroacetic acid DPPA: diphenylphosphoryl azide HOBt.H.sub.2O:
1-hydroxybenzotriazole hydrate EDC:
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride DIAD:
diisopropyl azodicarboxylate HATU:
O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate Dess-Martin reagent:
1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one DBU:
diazabicycloundecene
[0937] In addition, the following .sup.1H-NMR values were measured
by resolution 400 MHz.
Reference Example 1
Step R1-1
##STR00084##
[0939] Under nitrogen, a solution of 1M lithium
bis(trimethylsilyl)amide-THF/ethylbenzene (100 mL) in THF (100 mL)
was cooled to -70.degree. C. and, under stirring, tert-butyl
acetate (13.5 mL) was added dropwise. After stirring for 15 min,
benzyloxyacetyl chloride (7.52 mL) was added dropwise. After
stirring for 1 hr, 2N aqueous hydrochloric acid solution was added
until the reaction mixture became pH=3 and the mixture was allowed
to warm to room temperature. The mixture was extracted with ethyl
acetate, and the organic layer was washed with 2N aqueous
hydrochloric acid solution and saturated brine, dried over sodium
sulfate and concentrated. The above operation was repeated again,
and the both were combined to give compound R1-1 (40.3 g) as a
crude product.
Step R1-2
##STR00085##
[0941] To a solution of compound R1-1 (38 g) obtained in step R1-1
in toluene (80 mL) was added dimethylformamide dimethyl acetal (38
mL), and the mixture was stirred at 100.degree. C. for 1 hr. The
mixture was allowed to cool, concentrated, and purified by silica
gel column chromatography (ethyl acetate:hexane=1:2 to ethyl
acetate) to give compound R1-2 (11.3 g).
[0942] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.66 (s, 1H), 7.40-7.13
(m, 5H), 4.60 (s, 2H), 4.42 (s, 2H), 3.40-2.65 (m, 6H), 1.45 (s,
9H).
step R1-3
##STR00086##
[0944] Under nitrogen, a solution of 1M lithium
bis(trimethylsilyl)amide-THF/ethylbenzene (42.5 mL) in THF (150 mL)
was cooled to -70.degree. C. and, under stirring, a solution of
compound R1-2 (11.3 g) obtained in step R1-2 in THF (50 mL) was
added dropwise over 3 min. After stirring for 20 min, ethyl
chloroglyoxylate (4.75 mL) was added at once. After stirring for 25
min, saturated aqueous potassium hydrogen sulfate solution and
ethyl acetate were added, and the mixture was allowed to warm to
room temperature. The organic layer was separated and washed with
saturated brine, dried over sodium sulfate, and concentrated.
Toluene was added to the residue, and the mixture was once
concentrated. Toluene (100 mL) and triethylamine (10 mL) were added
and the mixture was stirred at room temperature. One hour later,
the mixture was concentrated and purified by silica gel column
chromatography (ethyl acetate:hexane=1:6 to 1:3) to give compound
R1-3 (6.03 g).
[0945] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.39 (s, 1H), 7.51-7.47
(m, 2H), 7.39-7.30 (m, 3H), 5.32 (s, 2H), 4.34 (q, 2H, J=7.2 Hz),
1.57 (s, 9H), 1.31 (t, 3H, J=7.2 Hz).
Step R1-4
##STR00087##
[0947] To a solution of compound R1-3 (18.7 g) obtained in step
R1-3 in ethyl acetate (20 mL) was added under stirring 4N
hydrochloric acid/ethyl acetate (200 mL), and the mixture was
stirred at room temperature for 1 hr. Hexane (1 L) was added to the
reaction mixture and, after stirring for a while, crystals were
collected by filtration, and dried to give compound R1 (11.1
g).
[0948] .sup.1H-NMR (CDCl.sub.3) .delta.: 13.03 (s, 1H), 8.80 (s,
1H), 7.47-7.43 (m, 2H), 7.41-7.35 (m, 3H), 5.38 (s, 2H), 4.40 (q,
2H, J=7.2 Hz), 1.35 (t, 3H, J=7.2 Hz).
Example 1
Production of
N-(3-chloro-2-fluorobenzyl)-9'-hydroxy-cis-3-methoxy-2'-methyl-1',8'-diox-
o-1',2',3',8'-tetrahydrospiro[cyclobutane-1,4'-pyrido[1,2-a]pyrazine]-7'-c-
arboxamide hydrochloride
Step 1
##STR00088##
[0950] To a mixed solution of commercially available
3-benzyloxycyclobutane-1,1-dicarboxylic acid diethyl ester (5.00 g)
in ethanol-water (42 mL-10.5 mL) was added potassium hydroxide (981
mg, 85%), and the mixture was stirred at 100.degree. C. for 16 hr.
The reaction mixture was concentrated, water was added, and the
mixture was extracted 3 times with diethyl ether to give organic
layer 1-1 and aqueous layer 1-1.
[0951] The organic layer 1-1 was dried over magnesium sulfate, and
concentrated to give a residue 1-1-1 (949 mg).
[0952] To aqueous layer 1-1 was added potassium hydrogen sulfate
(7.67 g), and the mixture was extracted 3 times with ethyl acetate.
The organic layer was washed with saturated brine, dried over
magnesium sulfate, and concentrated. Toluene was added and the
mixture was concentrated to give residue 1-1-2.
[0953] To the residue 1-1-1 (949 mg) were added ethanol (8 mL),
water (2 mL), and potassium hydroxide (194 mg, 85%), and the
mixture was stirred at 100.degree. C. for 3.5 hr, and stood at room
temperature for 3 days. To the reaction mixture was added aqueous
potassium hydrogen sulfate solution, and the mixture was extracted
twice with ethyl acetate. The organic layer was washed with
saturated brine, dried over magnesium sulfate and concentrated to
give a residue 1-1-3.
[0954] The residue 1-1-2 and the residue 1-1-3 were combined and
purified by silica gel column chromatography (hexane:ethyl
acetate=1:2 to ethyl acetate:acetone=3:1) to give compound 1-1
(4.04 g).
[0955] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37-7.14 (m, 5H), 4.44
(s, 2H), 4.27-4.14 (m, 3H), 2.87-2.80 (m, 2H), 2.64-2.57 (m, 2H),
1.31-1.27 (m, 3H).
Step 2
##STR00089##
[0957] To a solution of compound 1-1 (104 mg) obtained in the
above-mentioned step in toluene (1 mL) were added triethylamine
(104 .mu.L) and DPPA (113 .mu.L) at room temperature under an argon
atmosphere, and the mixture was stirred at room temperature for 20
min. tert-Butanol (3 mL) was added, and the mixture was stirred at
110.degree. C. for 4 hr. The reaction mixture was concentrated,
toluene was added, and the mixture was concentrated to give a
residue 1-2-1. Similarly, to a solution of compound 1-1 (3.91 g) in
toluene (40 mL) were added triethylamine (4.00 mL) and DPPA (4.25
mL) at room temperature under an argon atmosphere, and the mixture
was stirred at room temperature for 20 min. tert-Butanol (120 mL)
was added, and the mixture was stirred at 110.degree. C. for 18 hr.
The reaction mixture was concentrated, toluene was added, and the
mixture was concentrated to give a residue 1-2-2.
[0958] The residue 1-2-1 and the residue 1-2-2 were combined and
purified by silica gel column chromatography (hexane:ethyl
acetate=10:1 to 5:1) to give compound 1-2 (4.49 g).
[0959] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.35-7.28 (m, 5H),
5.16-5.08 (br m, 1H), 4.96-4.86 (br m, 1H), 4.45-4.44 (m, 2H),
4.28-4.20 (m, 1H), 4.22-4.16 (m, 2H), 2.94-2.89 (m, 1H), 2.66-2.61
(m, 1H), 2.51-2.43 (br m, 1H), 2.33-2.25 (br m, 1H), 1.43 (s, 9H),
1.29-1.25 (m, 3H).
Step 3
##STR00090##
[0961] To a solution of lithium aluminum hydride (1.00 g) in THF
(30 mL) was added dropwise a solution of compound 1-2 (4.49 g) in
THF (15 mL) under ice-cooling under a nitrogen atmosphere. The
mixture was stirred for 30 min, and at room temperature for 1 hr.
The reaction mixture was ice-cooled, water (1.00 mL) and 10%
aqueous sodium hydroxide solution (1.00 mL) were successively
added, and the mixture was stirred for 3 min. Water (3.01 mL) was
added again, and the mixture was stirred at room temperature for 30
min. The solid was filtered off, and washed with THF. The filtrate
was concentrated, toluene was added and the mixture was
concentrated. The operation of concentration with toluene was
performed twice to give compound 1-3 (4.37 g).
[0962] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.38-7.27 (m, 5.00H),
4.89-4.87 (br m, 0.45H), 4.83-4.80 (br m, 0.55H), 4.42 (s, 0.90H),
4.41 (s, 1.10H), 4.24 (tt, 0.55H, J=7.2, 5.3 Hz), 3.91 (quint,
0.45H, J=7.0 Hz), 3.76-3.75 (m, 1.10H), 3.64-3.61 (m, 0.90H),
2.67-2.62 (m, 0.90H), 2.47-2.42 (m, 1.10H), 2.20-2.14 (m, 1.10H),
2.05-2.00 (m, 0.90H), 1.44 (s, 4.95H), 1.43 (s, 4.05H).
Step 4
##STR00091##
[0964] To a solution of compound 1-3 (198 mg) obtained in the
above-mentioned step in chloroform (3 mL) was added Dess-Martin
reagent (554 mg), and the mixture was stirred at room temperature
for 1 hr. To the reaction mixture was added saturated aqueous
sodium hydrogen carbonate solution, sodium sulfite was added, and
the mixture was extracted twice with ethyl acetate. The organic
layer was washed with saturated brine, dried over magnesium sulfate
and concentrated to give a crude product of compound 1-4. The
obtained crude product of compound 1-4 was directly used in the
next step.
Step 5
##STR00092##
[0966] To a solution of methylamine hydrochloride (285 mg) in
chloroform (4 mL) was added triethylamine (577 .mu.L), and the
mixture was stirred at room temperature for 16 min. A solution of
the crude product of compound 1-4 in chloroform (4 mL) and acetic
acid (212 .mu.L) were successively added, and the mixture was
stirred at room temperature for 15 min. Sodium
triacetoxyborohydride (800 mg) was added, and the mixture was
stirred at room temperature for 3 days. To the reaction mixture was
added saturated aqueous sodium hydrogen carbonate solution, and the
mixture was extracted 3 times with chloroform. The organic layer
was dried over magnesium sulfate and concentrated to give a crude
product of compound 1-5. The obtained crude product of compound 1-5
was directly used in the next step.
Step 6
##STR00093##
[0968] To the crude product of compound 1-5 obtained in the
above-mentioned step was added TFA (2 mL), and the mixture was
stood at room temperature for 20 min. The reaction mixture was
concentrated, chloroform was added and the mixture was concentrated
again to give a crude product of compound 1-6. The obtained crude
product of compound 1-6 was directly used in the next step.
Step 7
##STR00094##
[0970] To a solution of the crude product of compound 1-6 obtained
in the above-mentioned step in THF (3 mL) were added triethylamine
(1 mL) and ethanol (0.5 mL), and a solution of compound P1 (269 mg)
obtained in the below-mentioned Preliminary step 1-1 in THF (2 mL)
was added. After stirring at room temperature for 30 min, the
reaction mixture was concentrated, toluene (15 mL) and DBU (1 mL)
were added, and the mixture was stirred at 80.degree. C. for 1 hr.
To the reaction mixture was added acetic acid (2 mL), and the
mixture was stirred at 100.degree. C. for 1 hr. The reaction
mixture was concentrated, ethyl acetate and 10% aqueous potassium
hydrogen sulfate solution were added, and the mixture was extracted
3 times with ethyl acetate. The organic layer was washed with
saturated brine, dried over magnesium sulfate, and concentrated.
The residue was purified by silica gel column chromatography
(hexane:ethyl acetate=2:1 to 0:1), and then silica gel thin layer
chromatography (ethyl acetate) to give compound 1-7a (126 mg) and
compound 1-7b (115 mg).
Compound 1-7a
[0971] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.54 (t, 1H, J=6.0 Hz),
8.76 (s, 1H), 7.61-7.59 (m, 2H), 7.40-7.27 (m, 10H), 7.06-7.02 (m,
1H), 5.30 (s, 2H), 4.71 (d, 2H, J=6.0 Hz), 4.49 (s, 2H), 3.98
(quint, 1H, J=6.6 Hz), 3.40 (s, 2H), 3.15 (s, 3H), 2.62-2.59 (m,
4H).
Compound 1-7b
[0972] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.57-10.54 (br m, 1H),
8.65 (s, 1H), 7.61-7.58 (m, 2H), 7.40-7.27 (m, 10H), 7.06-7.02 (m,
1H), 5.30 (s, 2H), 4.70 (d, 2H, J=6.2 Hz), 4.48 (s, 2H), 4.39-4.34
(m, 1H), 3.72 (s, 2H), 3.15 (s, 3H), 2.87-2.82 (m, 2H), 2.35-2.30
(m, 2H).
Step 8
##STR00095##
[0974] To compound 1-7a (126 mg) obtained in the above-mentioned
step were added 1,4-dioxane (3 mL) and 48% aqueous hydrogen bromide
solution (4.5 mL), and the mixture was stirred at 80.degree. C. for
3.5 hr. The reaction mixture was concentrated, toluene was added
and the mixture was concentrated. The operation of concentration
with toluene was performed 3 times to give a crude product of
compound 1-8.
Step 9
##STR00096##
[0976] To the crude product of compound 1-8 obtained in the
above-mentioned step were added potassium carbonate (300 mg), DMF
(3 mL), and benzyl bromide (80 .mu.L), and the mixture was stirred
at room temperature for 8 hr. Potassium carbonate (100 mg) and
benzylbromide (30 .mu.L) were added, and the mixture was stirred at
room temperature for 1 hr and stood for 3 days. To the reaction
mixture was added saturated brine, and the mixture was extracted 3
times with ethyl acetate. The organic layer was washed with
saturated brine, dried over magnesium sulfate, concentrated and
purified by silica gel thin layer chromatography
(chloroform:acetone=1:1) to give compound 1-9 (101 mg).
[0977] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.62-10.59 (br m, 1H),
8.80 (s, 1H), 7.62-7.59 (m, 2H), 7.37-7.27 (m, 5H), 7.06-7.02 (m,
1H), 5.30 (s, 2H), 4.71 (d, 2H, J=6.2 Hz), 4.36-4.31 (m, 1H), 3.43
(s, 2H), 3.18 (s, 3H), 2.85 (d, 1H, J=6.5 Hz), 2.74-2.69 (m, 2H),
2.66-2.61 (m, 2H).
Step 10
##STR00097##
[0979] To a mixed solution of compound 1-9 (27 mg) obtained in the
above-mentioned step in toluene-methylene chloride (3 mL-3 mL) were
added tetrabutylammonium hydrogen sulfate (30 mg), dimethyl sulfate
(33 .mu.L) and 50% aqueous sodium hydroxide solution (48 .mu.L),
and the mixture was stirred at room temperature for 20 min.
Dimethyl sulfate (33 .mu.L) and 50% aqueous sodium hydroxide
solution (48 .mu.L) were added 3 times every 30 min, and the
mixture was further stirred at room temperature for 30 min. To the
reaction mixture was added triethylamine (0.5 mL) and the mixture
was stirred for 50 min. 10% Aqueous potassium hydrogen sulfate
solution was added, and the mixture was extracted 3 times with
chloroform. The organic layer was dried over magnesium sulfate,
concentrated, and purified by silica gel thin layer chromatography
(chloroform:acetone=3:2) to give compound 1-10 (24 mg).
[0980] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.54 (t, 1H, J=6.0 Hz),
8.76 (s, 1H), 7.62-7.60 (m, 2H), 7.37-7.27 (m, 5H), 7.06-7.02 (m,
1H), 5.30 (s, 2H), 4.71 (d, 2H, J=6.0 Hz), 3.85 (quint, 1H, J=6.5
Hz), 3.43 (s, 2H), 3.29 (s, 3H), 3.18 (s, 3H), 2.67-2.62 (m, 2H),
2.59-2.54 (m, 2H).
Step 11
##STR00098##
[0982] To compound 1-10 (24 mg) obtained in the above-mentioned
step were successively added 4N hydrochloric acid/dioxane (1 mL)
and TFA (3 mL), and the mixture was stood at room temperature for 2
hr. The reaction mixture was concentrated, ethyl acetate was added
and the mixture was concentrated again. Ethyl acetate (200 L),
hexane (7.5 mL), and 4N hydrochloric acid/ethyl acetate (100 .mu.L)
were added. The mixture was stirred for a while and supernatant
liquid was removed by decantation. Ethyl acetate (400 .mu.L),
hexane (11.5 mL), and 4N hydrochloric acid/ethyl acetate (100
.mu.L) were added again. The mixture was stirred for a while and
supernatant liquid was removed by decantation. The obtained residue
was dried under reduced pressure to give the title compound (8.7
mg).
[0983] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.83 (br s, 1H), 10.43
(t, 1H, J=6.0 Hz), 8.48 (s, 1H), 7.52-7.47 (m, 1H), 7.35-7.31 (m,
1H), 7.22-7.18 (m, 1H), 4.62 (d, 2H, J=6.0 Hz), 3.97 (quint, 1H,
J=6.4 Hz), 3.79 (s, 2H), 3.20 (s, 3H), 3.12 (s, 3H), 2.70-2.65 (m,
2H), 2.42-2.37 (m, 2H).
Preliminary Step 1-1
##STR00099##
[0985] To a solution of compound R1 (504 mg) obtained in Reference
Example 1, step R1-4 in chloroform (6 mL) were added oxalyl
chloride (276 .mu.L) and a catalytic amount of DMF under
ice-cooling, and the mixture was stirred at room temperature for 30
min. The mixture was concentrated, and dissolved in chloroform (6
mL) and a solution of commercially available
3-chloro-2-fluorobenzylamine (215 mg) and triethylamine (441 .mu.L)
in chloroform (8 mL) was added dropwise at an outer temperature of
-50.degree. C. After the completion of the dropwise addition, the
mixture was stirred at room temperature overnight. To the reaction
mixture were added ethyl acetate and 0.5N hydrochloric acid and,
after partitioning, the organic layer was washed with 0.5N aqueous
sodium hydroxide solution and saturated brine. The mixture was
dried, concentrated and purified by silica gel column
chromatography (hexane:ethyl acetate=20:1 to 2:1) to give compound
P1 (581 mg).
[0986] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.62-9.47 (m, 1H), 8.79
(s, 1H), 7.50-7.43 (m, 2H), 7.40-7.24 (m, 5H), 7.06 (t, 1H, J=7.9
Hz), 5.28 (s, 2H), 4.68 (d, 2H, J=6.2 Hz), 4.37 (q, 2H, J=7.2 Hz),
1.33 (t, 3H, J=7.2 Hz).
Example 2
Production of
N-(3-chloro-2-fluorobenzyl)-9'-hydroxy-trans-3-methoxy-2'-methyl-1',8'-di-
oxo-1',2',3',8'-tetrahydrospiro[cyclobutane-1,4'-pyrido[1,2-a]pyrazine]-7'-
-carboxamide hydrochloride
Step 1
##STR00100##
[0988] From compound 1-7b (115 mg) obtained in Example 1, step 7,
and by a method similar to that in Example 1, step 8, a crude
product of compound 2-1 was obtained. The obtained crude product of
compound 2-1 was directly used in the next step.
step 2
##STR00101##
[0989] From a crude product of compound 2-1 obtained in the
above-mentioned step, and by a method similar to that in Example 1,
step 9, compound 2-2 (112 mg) was obtained.
[0990] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.56 (br s, 1H), 8.65 (s,
1H), 7.62-7.59 (m, 2H), 7.37-7.28 (m, 5H), 7.06-7.00 (m, 1H), 5.31
(s, 2H), 4.74-4.70 (m, 3H), 3.79 (s, 2H), 3.20 (s, 3H), 2.95-2.88
(m, 2H), 2.33-2.31 (m, 1H), 2.30-2.28 (m, 1H), 2.17-2.15 (m,
1H).
Step 3
##STR00102##
[0992] From compound 2-2 (24 mg) obtained in the above-mentioned
step, and by a method similar to that in Example 1, step 10,
compound 2-3 (22 mg) was obtained.
[0993] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.56 (t, 1H, J=6.2 Hz),
8.67 (s, 1H), 7.62-7.59 (m, 2H), 7.37-7.28 (m, 5H), 7.06-7.02 (m,
1H), 5.31 (s, 2H), 4.71 (d, 2H, J=6.2 Hz), 4.18-4.13 (m, 1H), 3.71
(s, 2H), 3.30 (s, 3H), 3.19 (s, 3H), 2.86-2.81 (m, 2H), 2.33-2.30
(m, 1H), 2.29-2.27 (m, 1H).
Step 4
##STR00103##
[0995] From compound 2-3 (22 mg) obtained in the above-mentioned
step, and by a method similar to that in Example 1, step 11, the
title compound (15.2 mg) was obtained.
[0996] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.89 (br s, 1H), 10.45
(t, 1H, J=6.1 Hz), 8.48 (s, 1H), 7.52-7.47 (m, 1H), 7.35-7.31 (m,
1H), 7.22-7.18 (m, 1H), 4.62 (d, 2H, J=6.1 Hz), 4.11-4.05 (m, 1H),
3.88 (s, 2H), 3.20 (s, 3H), 3.11 (s, 3H), 2.86-2.81 (m, 2H),
2.35-2.30 (m, 2H).
Example 3
Production of
N-(3-chloro-2-fluorobenzyl)-9'-hydroxy-cis-3-(methoxymethyl)-2'-methyl-1'-
,8'-dioxo-1',2',3',8'-tetrahydrospiro[cyclobutane-1,4'-pyrido[1,2-a]pyrazi-
ne]-7'-carboxamide hydrochloride
Step 1
##STR00104##
[0998] To a solution of commercially available
3-oxocyclobutanecarboxylic acid (14.9 g) in DMF (210 mL) were added
potassium carbonate (27.07 g) and benzyl bromide (18.6 mL), and the
mixture was stirred at room temperature for 2 hr. To the reaction
mixture was added acetic acid (22.4 mL) over 12 min, and the
mixture was stirred at room temperature for 10 min. Water (350 mL)
was added, and the mixture was extracted 3 times with ethyl
acetate. The organic layer was washed 4 times with saturated brine,
dried over magnesium sulfate and concentrated. Toluene was added
and the mixture was concentrated to give a crude product of
compound 3-1. The obtained crude product of compound 3-1 was
directly used in the next step.
Step 2
##STR00105##
[1000] To a solution of a crude product of compound 3-1 obtained in
the above-mentioned step in toluene (400 mL) were added pyridinium
p-toluenesulfonate (4.91 g) and ethylene glycol (8 mL), and the
mixture was stirred under reflux by heating for 2.5 hr. Ethylene
glycol (1.5 mL) was added, and the mixture was stirred under reflux
by heating for 1.5 hr. Ethylene glycol (2.3 mL) was added again,
and the mixture was further stirred under reflux by heating for 2
hr. The reaction mixture was allowed to cool to room temperature,
saturated aqueous sodium hydrogen carbonate solution was added, and
the mixture was extracted twice with ethyl acetate. The organic
layer was washed with saturated brine, dried over magnesium sulfate
and concentrated to give a crude product of compound 3-2. The
obtained crude product of compound 3-2 was directly used in the
next step.
Step 3
##STR00106##
[1002] To a solution of lithium aluminum hydride (5.93 g) in THF
(150 mL) was added dropwise a solution of the crude product of
compound 3-2 obtained in the above-mentioned step in THF (150 mL)
over 15 min under ice-cooling under a nitrogen atmosphere. The
mixture was stirred at room temperature for 40 min, ice-cooled
again, ethyl acetate (36 mL), water (18 mL), 4.0M aqueous sodium
hydroxide solution (18 mL), and water (54 mL) were successively
added, and the mixture was stirred at room temperature for 1 hr.
The reaction mixture was filtered through Celite, and washed with
ethyl acetate and water, and the filtrate was concentrated to give
residue 3-3.
[1003] To the residue 3-3 were added ethyl acetate and water, and
the mixture was extracted 9 times with ethyl acetate. The organic
layer was washed successively with saturated aqueous sodium
hydrogen carbonate solution and saturated brine, dried over sodium
sulfate, and concentrated. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate=100:0 to 1:100) to give
compound 3-3 (15.20 g).
[1004] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.93-3.86 (m, 4H), 3.68
(dd, 2H, J=6.7, 5.5 Hz), 2.47-2.40 (m, 2H), 2.34-2.24 (m, 1H),
2.14-2.07 (m, 2H), 1.41 (t, 1H, J=5.5 Hz).
Step 4
##STR00107##
[1006] To a solution of compound 3-3 (5.00 g) obtained in the
above-mentioned step in DMF (25 mL) were added sodium hydride (60%
dispersion, 2.77 g) and benzyl bromide (6.19 mL) under ice-cooling,
and the mixture was warmed to room temperature and stirred for 2
hr. To the reaction mixture was added under ice-cooling saturated
aqueous ammonium chloride solution, and the mixture was extracted
with ethyl acetate. The organic layer was washed successively with
water and saturated brine, dried over sodium sulfate, and
concentrated. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate=100:0 to 85:15) to give
compound 3-4 (7.23 g).
[1007] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37-7.27 (m, 5H), 4.52
(s, 2H), 3.91-3.84 (m, 4H), 3.50 (d, 2H, J=6.9 Hz), 2.46-2.30 (m,
3H), 2.13-2.07 (m, 2H).
Step 5
##STR00108##
[1009] To a solution of compound 3-4 (7.21 g) obtained in the
above-mentioned step in THF (36 mL) was added 2N hydrochloric acid
(15.4 mL) at room temperature, and the mixture was stirred at room
temperature overnight. The reaction mixture was extracted with
ethyl acetate, and the organic layer was washed successively with
saturated aqueous sodium hydrogen carbonate solution, water and
saturated brine, dried over sodium sulfate, and concentrated to
give compound 3-5 (6.32 g).
[1010] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.38-7.27 (m, 5H), 4.56
(s, 2H), 3.60 (d, 2H, J=6.6 Hz), 3.17-3.08 (m, 2H), 2.92-2.84 (m,
2H), 2.75-2.64 (m, 1H).
Step 6
##STR00109##
[1012] To compound 3-5 (5.09 g) obtained in the above-mentioned
step was added under ice-cooling 7N ammonia/methanol (25 mL), and
the mixture was stirred at the same temperature for 1 hr to give
solution 3-6.
[1013] Ammonium chloride (3.58 g) and potassium cyanide (2.27 g)
were dissolved in 28% aqueous ammonia (50 mL), and the solution 3-6
was added dropwise. The mixture was stirred at room temperature for
3 days, and extracted with chloroform and the organic layer was
washed with saturated brine, dried over sodium sulfate, and
concentrated. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate=100:0 to 20:80) to give
compound 3-6 (major form: 1.89 g, minor form: 861 mg, 63:37
major/minor mixture: 1.68 g).
Major Form
[1014] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37-7.27 (m, 5H), 4.52
(s, 2H), 3.47 (d, 2H, J=5.3 Hz), 2.76-2.70 (m, 2H), 2.68-2.58 (m,
1H), 2.09-2.03 (m, 2H), 1.85 (br s, 2H).
Minor Form
[1015] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37-7.27 (m, 5H), 4.53
(s, 2H), 3.49 (d, 2H, J=6.2 Hz), 2.92-2.81 (m, 1H), 2.48-2.43 (m,
2H), 2.20-2.15 (m, 2H), 1.82 (br s, 2H).
Step 7
##STR00110##
[1017] To a solution of compound 3-6 (1.0 g, 63:37 major/minor
mixture) obtained in the above-mentioned step in 1,4-dioxane (5 mL)
were added saturated aqueous sodium hydrogen carbonate solution (5
mL) and di-tert-butyl dicarbonate (1.21 g), and the mixture was
stirred at room temperature overnight. To the reaction mixture was
added water, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine, dried over sodium
sulfate, and concentrated. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate=100:0 to 60:40) to give
compound 3-7 (1.54 g).
[1018] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37-7.27 (m, 5.00H), 4.87
(br s, 1.00H), 4.53 (s, 0.70H), 4.51 (s, 1.30H), 3.51 (d, 0.70H,
J=6.2 Hz), 3.44 (d, 1.30H, J=3.5 Hz), 2.83-2.73 (m, 2.30H),
2.60-2.54 (m, 0.70H), 2.43-2.38 (m, 0.70H), 2.22-2.17 (m, 1.30H),
1.48 (s, 3.15H), 1.47 (s, 5.85H).
Step 8
##STR00111##
[1020] To a solution of compound 3-7 (300 mg) obtained in the
above-mentioned step in methanol (9 mL) was added cobalt(II)
chloride hexahydrate (226 mg) under ice-cooling. Then, sodium
borohydride (179 mg) was added by small portions, and the mixture
was stirred at the same temperature for 10 min, and at room
temperature overnight. To the reaction mixture were added under
ice-cooling saturated aqueous sodium hydrogen carbonate solution
and chloroform, and the insoluble material was filtered off through
Celite. The filtrate was extracted with chloroform. The organic
layer was washed with saturated brine, dried over sodium sulfate,
and concentrated to give a crude product of compound 3-8 (339 mg).
The obtained crude product of compound 3-8 was directly used in the
next step.
Step 9
##STR00112##
[1022] To a suspension of 1,1'-carbonyldiimidazole (161 mg) in THF
(3 mL) was added formic acid (37.6 .mu.L), and the mixture was
stirred at room temperature for 10 min. A solution of the crude
product of compound 3-8 (339 mg) obtained in the above-mentioned
step in THF (3 mL) was added, and the mixture was stirred at room
temperature for 3 hr. To the reaction mixture was added saturated
aqueous sodium hydrogen carbonate solution, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, dried over sodium sulfate, and concentrated to
give a crude product of compound 3-9 (341 mg). The obtained crude
product of compound 3-8 was directly used in the next step.
Step 10
##STR00113##
[1024] To a solution of a crude product of compound 3-9 (341 mg)
obtained in the above-mentioned step in THF (3 mL) was added
borane-THF complex/THF solution (0.9M, 1.5 mL) under ice-cooling,
and the mixture was stirred at room temperature for 4 hr.
Borane-THF complex/THF solution (0.9M, 1.0 mL) was added under
ice-cooling, and the mixture was stirred at room temperature
overnight. To the reaction mixture was added saturated aqueous
sodium hydrogen carbonate solution, and the mixture was extracted
with chloroform. The organic layer was washed with saturated brine,
dried over sodium sulfate, and concentrated. The residue was
purified by silica gel column chromatography
(chloroform:methanol=100:0 to 80:20) to give compound 3-10 (96
mg).
[1025] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.36-7.27 (m, 5.00H), 5.08
(br s, 1.00H), 4.51 (s, 2.00H), 3.52 (d, 1.30H, J=6.5 Hz), 3.46 (d,
0.70H, J=6.2 Hz), 2.84 (s, 1.30H), 2.80 (s, 0.70H), 2.74-2.72 (br
m, 0.35H), 2.49 (s, 1.95H), 2.43 (s, 1.05H), 2.39-2.31 (m, 1.30H),
2.17 (s, 2.35H), 1.94-1.89 (m, 1.00H), 1.45 (s, 3.15H), 1.43 (s,
5.85H).
Step 11
##STR00114##
[1027] To compound 3-10 (93 mg) obtained in the above-mentioned
step was added TFA (0.9 mL), and the mixture was stirred at room
temperature for 30 min. The reaction mixture was concentrated to
give a crude product of compound 3-11. The obtained crude product
of compound 3-11 was directly used in the next step.
Step 12
##STR00115##
[1029] To a solution of the crude product of compound 3-11 obtained
in the above-mentioned step in THF (1.9 mL) were successively added
under ice-cooling triethylamine (194 .mu.L) and compound P1 (128
mg) obtained in Example 1, Preliminary step 1-1, and the mixture
was stirred at room temperature for 2 hr. The reaction mixture was
concentrated to give residue 3-12.
[1030] To a solution of the residue 3-12 in toluene (1.9 mL) was
added DBU (167 .mu.L), and the mixture was stirred at 80.degree. C.
for 2 hr. Acetic acid (319 .mu.L) was added, and the mixture was
stirred at 110.degree. C. for 2 hr. A saturated aqueous sodium
hydrogen carbonate solution was added, and the mixture was
extracted with ethyl acetate. The organic layer was washed
successively with water and saturated brine, dried over sodium
sulfate, concentrated, and purified by silica gel thin layer
chromatography (ethyl acetate) to give compound 3-12a (88 mg) and
compound 3-12b (50 mg).
Compound 3-12a
[1031] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.56 (t, 1H, J=6.0 Hz),
8.81 (s, 1H), 7.62-7.60 (m, 2H), 7.37-7.27 (m, 10H), 7.06-7.02 (m,
1H), 5.30 (s, 2H), 4.72 (d, 2H, J=6.0 Hz), 4.57 (s, 2H), 3.54 (s,
2H), 3.51 (d, 2H, J=4.9 Hz), 3.18 (s, 3H), 2.59-2.53 (m, 2H),
2.52-2.44 (m, 1H), 2.32-2.27 (m, 2H).
Compound 3-12b
[1032] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.61 (t, 1H, J=6.0 Hz),
8.80 (s, 1H), 7.62-7.59 (m, 2H), 7.41-7.28 (m, 10H), 7.06-7.01 (m,
1H), 5.30 (s, 2H), 4.71 (d, 2H, J=6.0 Hz), 4.56 (s, 2H), 3.60 (s,
2H), 3.55 (d, 2H, J=3.2 Hz), 2.95 (s, 3H), 2.88-2.82 (m, 1H),
2.67-2.61 (m, 2H), 2.41-2.36 (m, 2H).
Step 13
##STR00116##
[1034] To a solution of compound 3-12a (84 mg) obtained in the
above-mentioned step in 1,4-dioxane (1.7 mL) was added 48% aqueous
hydrogen bromide solution (1.7 mL), and the mixture was stirred at
80.degree. C. for 3 hr. The reaction mixture was concentrated,
toluene and 1,4-dioxane were added and the mixture was
concentrated. The operation of concentration with toluene and
1,4-dioxane was performed 3 times to give a crude product of
compound 3-13. The obtained crude product of compound 3-13 was
directly used in the next step.
Step 14
##STR00117##
[1036] To a solution of the crude product of compound 3-13 obtained
in the above-mentioned step in DMF (1.7 ml) were added potassium
carbonate (367 mg) and benzyl bromide (0.79 ml), and the mixture
was stirred at 60.degree. C. for 2 hr. The reaction mixture was
cooled to room temperature, water was added, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over sodium sulfate, concentrated,
and purified by silica gel thin layer chromatography
(chloroform:methanol=95:5) to give compound 3-14 (70 mg).
[1037] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.61 (t, 1H, J=6.0 Hz),
8.84 (s, 1H), 7.63-7.60 (m, 2H), 7.38-7.28 (m, 5H), 7.06-7.01 (m,
1H), 5.30 (s, 2H), 4.71 (d, 2H, J=6.0 Hz), 3.74-3.72 (m, 2H), 3.57
(s, 2H), 3.21 (s, 3H), 2.67-2.62 (m, 2H), 2.49-2.43 (m, 1H),
2.31-2.26 (m, 2H), 2.08 (br s, 1H).
Step 15
##STR00118##
[1039] To a solution of compound 3-14 (25 mg) obtained in the
above-mentioned step in dichloromethane (1.5 ml) were added
tetrabutylammonium hydrogen sulfate (15.7 mg), dimethyl sulfate
(8.8 .mu.L) and 50% aqueous sodium hydroxide solution (50 .mu.L),
and the mixture was stirred at room temperature for 40 min.
Dimethyl sulfate (8.8 .mu.L) was added, and the mixture was stirred
at room temperature for 40 min. Dimethyl sulfate (16.6 .mu.L) and
50% aqueous sodium hydroxide solution (50 .mu.L) were added 4 times
every 30 min, and the mixture was stirred at room temperature for 3
days. To the reaction mixture was added triethylamine (0.3 ml), and
the mixture was stirred at room temperature for 30 min. Water was
added and the mixture was extracted with chloroform. The organic
layer was washed with saturated brine, dried over sodium sulfate,
concentrated, and purified by silica gel thin layer chromatography
(chloroform:methanol=95:5) to give compound 3-15 (22 mg).
[1040] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.58 (t, 1H, J=6.0 Hz),
8.82 (s, 1H), 7.63-7.59 (m, 2H), 7.37-7.27 (m, 5H), 7.06-7.02 (m,
1H), 5.30 (s, 2H), 4.72 (d, 2H, J=6.0 Hz), 3.55 (s, 2H), 3.43 (d,
2H, J=4.6 Hz), 3.41 (s, 3H), 3.19 (s, 3H), 2.61-2.55 (m, 2H),
2.51-2.41 (m, 1H), 2.32-2.26 (m, 2H).
Step 16
##STR00119##
[1042] To compound 3-15 (21 mg) obtained in the above-mentioned
step was added TFA (0.6 ml), and the mixture was stirred at room
temperature for 30 min. The reaction mixture was concentrated,
toluene was added and the mixture was concentrated. The operation
of concentration with toluene was performed 3 times. Ethyl acetate
and 4N hydrochloric acid/ethyl acetate were added and the mixture
was stirred at room temperature for 15 min. The mixture was
concentrated again and crystallized from diethyl ether-hexane to
give the title compound (15.1 mg).
[1043] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.82 (s, 1H), 10.45 (t,
1H, J=6.0 Hz), 8.53 (s, 1H), 7.52-7.47 (m, 1H), 7.35-7.31 (m, 1H),
7.22-7.18 (m, 1H), 4.62 (d, 2H, J=6.0 Hz), 3.90 (s, 2H), 3.39 (d,
2H, J=5.3 Hz), 3.27 (s, 3H), 3.14 (s, 3H), 2.61-2.54 (m, 1H),
2.37-2.25 (m, 4H).
Example 4
Production of
N-(3-chloro-2-fluorobenzyl)-9'-hydroxy-trans-3-(methoxymethyl)-2'-methyl--
1',8'-dioxo-1',2',3',8'-tetrahydrospiro[cyclobutane-1,4'-pyrido[1,2-a]pyra-
zine]-7'-carboxamide hydrochloride
Step 1
##STR00120##
[1045] From compound 3-12b (48 mg) obtained in Example 3, step 12,
and by a method similar to that in Example 3, step 13, a crude
product of compound 4-1 was obtained. The obtained crude product of
compound 4-1 was directly used in the next step.
Step 2
##STR00121##
[1047] From a crude product of compound 4-1 obtained in the
above-mentioned step, and by a method similar to that in Example 3,
step 14, compound 4-2 (34 mg) was obtained.
[1048] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.61 (t, 1H, J=5.7 Hz),
8.83 (s, 1H), 7.63-7.60 (m, 2H), 7.37-7.28 (m, 5H), 7.06-7.02 (m,
1H), 5.31 (s, 2H), 4.72 (d, 2H, J=5.7 Hz), 3.73 (t, 2H, J=3.5 Hz),
3.65 (s, 2H), 3.17 (s, 3H), 2.88-2.80 (br m, 1H), 2.65-2.59 (m,
2H), 2.44-2.38 (m, 2H), 1.66 (t, 1H, J=3.5 Hz).
Step 3
##STR00122##
[1050] From compound 4-2 (20 mg) obtained in the above-mentioned
step, and by a method similar to that in Example 3, step 15,
compound 4-3 was obtained. The total amount of the obtained
compound 4-3 was directly used in the next step.
[1051] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.62 (t, 1H, J=5.8 Hz),
8.81 (s, 1H), 7.62-7.60 (m, 2H), 7.37-7.28 (m, 5H), 7.07-7.02 (m,
1H), 5.30 (s, 2H), 4.71 (d, 2H, J=5.8 Hz), 3.64 (s, 2H), 3.42 (d,
2H, J=3.2 Hz), 3.42 (s, 3H), 3.16 (s, 3H), 2.89-2.78 (m, 1H),
2.64-2.58 (m, 2H), 2.39-2.34 (m, 2H).
Step 4
##STR00123##
[1053] From compound 4-3 obtained in the above-mentioned step, and
by a method similar to that in Example 3, step 16, the title
compound (15.2 mg) was obtained.
[1054] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.95 (br s, 1H), 10.46
(t, 1H, J=6.0 Hz), 8.58 (s, 1H), 7.52-7.48 (m, 1H), 7.36-7.32 (m,
1H), 7.23-7.18 (m, 1H), 4.62 (d, 2H, J=6.0 Hz), 3.82 (s, 2H), 3.42
(d, 2H, J=6.0 Hz), 3.28 (s, 3H), 3.10 (s, 3H), 2.73-2.63 (m, 1H),
2.57-2.51 (m, 2H), 2.25-2.20 (m, 2H).
Example 5
Production of
N-(3-chloro-2-fluorobenzyl)-2'-ethyl-9'-hydroxy-trans-3-methoxy-1',8'-dio-
xo-1',2',4',8'-tetrahydrospiro[cyclobutane-1,3'-pyrido[1,2-a]pyrazine]-7'--
carboxamide hydrochloride
Step 1
##STR00124##
[1056] To a mixed solution of commercially available
3-benzyloxycyclobutane-1,1-dicarboxylic acid diethyl ester (5.00 g)
in ethanol-water (42 mL-10.5 mL) was added potassium hydroxide (981
mg, 85%), and the mixture was stirred at 100.degree. C. for 16 hr.
The reaction mixture was concentrated, water was added, and the
mixture was extracted 3 times with diethyl ether to give an organic
layer 5-1 and an aqueous layer 5-1.
[1057] The organic layer 5-1 was dried over magnesium sulfate, and
concentrated to give residue 5-1-1 (949 mg).
[1058] To the aqueous layer 5-1 was added potassium hydrogen
sulfate (7.67 g), and the mixture was extracted 3 times with ethyl
acetate. The organic layer was washed with saturated brine, dried
over magnesium sulfate, and concentrated, toluene was added and the
mixture was concentrated to give residue 5-1-2.
[1059] To the residue 5-1-1 (949 mg) were added ethanol (8 mL),
water (2 mL), and potassium hydroxide (194 mg, 85%), and the
mixture was stirred at 100.degree. C. for 3.5 hr and stood at room
temperature for 3 days. To the reaction mixture was added aqueous
potassium hydrogen sulfate solution, and the mixture was extracted
twice with ethyl acetate. The organic layer was washed with
saturated brine, dried over magnesium sulfate and concentrated to
give residue 5-1-3.
[1060] The residue 5-1-2 and the residue 5-1-3 were combined and
purified by silica gel column chromatography (hexane:ethyl
acetate=1:2 to ethyl acetate:acetone=3:1) to give compound 5-1
(4.04 g).
[1061] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37-7.14 (m, 5H), 4.44
(s, 2H), 4.27-4.14 (m, 3H), 2.87-2.80 (m, 2H), 2.64-2.57 (m, 2H),
1.31-1.27 (m, 3H).
Step 2
##STR00125##
[1063] To a solution of compound 5-1 (104 mg) obtained in the
above-mentioned step in toluene (1 mL) were added triethylamine
(104 .mu.L) and DPPA (113 .mu.L) at room temperature under an argon
atmosphere, and the mixture was stirred at room temperature for 20
min. tert-Butanol (3 mL) was added, and the mixture was stirred at
110.degree. C. for 4 hr. The reaction mixture was concentrated,
toluene was added, and the mixture was concentrated to give residue
5-2-1. Similarly, to a solution of compound 5-1 (3.91 g) in toluene
(40 mL) were added triethylamine (4.00 mL) and DPPA (4.25 mL) at
room temperature under an argon atmosphere, and the mixture was
stirred at room temperature for 20 min. tert-Butanol (120 mL) was
added, and the mixture was stirred at 110.degree. C. for 18 hr. The
reaction mixture was concentrated, toluene was added, and the
mixture was concentrated to give residue 5-2-2.
[1064] The residue 5-2-1 and the residue 5-2-2 were combined and
purified by silica gel column chromatography (hexane:ethyl
acetate=10:1 to 5:1) to give compound 5-2 (4.49 g).
[1065] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.35-7.28 (m, 5H),
5.16-5.08 (br m, 1H), 4.96-4.86 (br m, 1H), 4.45-4.44 (m, 2H),
4.28-4.20 (m, 1H), 4.22-4.16 (m, 2H), 2.94-2.89 (m, 1H), 2.66-2.61
(m, 1H), 2.51-2.43 (br m, 1H), 2.33-2.25 (br m, 1H), 1.43 (s, 9H),
1.29-1.25 (m, 3H).
Step 3
##STR00126##
[1067] To a solution of lithium aluminum hydride (1.00 g) in THF
(30 mL) was added dropwise a solution of compound 5-2 (4.49 g)
obtained in the above-mentioned step in THF (15 mL) under
ice-cooling under a nitrogen atmosphere. The mixture was stirred
for 30 min, and at room temperature for 1 hr. The reaction mixture
was ice-cooled, water (1.00 mL) and 10% aqueous sodium hydroxide
solution (1.00 mL) were successively added, and the mixture was
stirred for 3 min. Water (3.01 mL) was added again, and the mixture
was stirred at room temperature for 30 min. The solid was filtered
off, and washed with THF. The filtrate was concentrated, toluene
was added, and the mixture was concentrated. The operation of
concentration with toluene was performed twice to give compound 5-3
(4.37 g).
[1068] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.38-7.27 (m, 5.00H),
4.89-4.87 (br m, 0.45H), 4.83-4.80 (br m, 0.55H), 4.42 (s, 0.90H),
4.41 (s, 1.10H), 4.24 (tt, 0.55H, J=7.2, 5.3 Hz), 3.91 (quint,
0.45H, J=7.0 Hz), 3.76-3.75 (m, 1.10H), 3.64-3.61 (m, 0.90H),
2.67-2.62 (m, 0.90H), 2.47-2.42 (m, 1.10H), 2.20-2.14 (m, 1.10H),
2.05-2.00 (m, 0.90H), 1.44 (s, 4.95H), 1.43 (s, 4.05H).
Step 4
##STR00127##
[1070] To a solution of compound 5-3 (682 mg) obtained in the
above-mentioned step, triphenylphosphine (1.76 g) and phthalimide
(992 mg) in toluene (20 mL) was added dropwise DIAD (1.31 mL) at
room temperature, and the mixture was stirred at the same
temperature for 1 hr. Ethanol (2 mL), and hydrazine hydrate (2.5
mL) were added, and the mixture was stirred at 80.degree. C. for 2
hr. The reaction mixture was cooled to room temperature, and the
solid was filtered off and washed with an ethanol-toluene (1:10)
mixed solution. The filtrate was concentrated, toluene was added
and the mixture was concentrated. The operation of concentration
with toluene was performed 3 times to give compound 5-4. The
obtained compound 5-4 was directly used in the next step.
Step 5
##STR00128##
[1072] To compound 5-4 obtained in the above-mentioned step were
added ethyl acetate (15 mL), sodium hydrogen carbonate (3.02 g),
water (15 mL), and benzyl chloroformate (0.75 mL), and the mixture
was stirred at room temperature for 15 hr. To the reaction mixture
was added isopropylamine (1 mL), and the mixture was stirred at
room temperature for 1 hr and extracted 3 times with ethyl acetate.
The organic layer was washed successively with saturated brine, 10%
aqueous potassium hydrogen sulfate solution and saturated brine,
dried over magnesium sulfate and concentrated to give compound 5-5.
The obtained compound 5-5 was directly used in the next step.
Step 6
##STR00129##
[1074] To compound 5-5 obtained in the above-mentioned step was
added 4N hydrochloric acid/ethyl acetate (15 mL), and the mixture
was stirred at room temperature for 20 min. To the reaction mixture
were added hexane (10 mL) and ethyl acetate (5 mL), and the mixture
was extracted 4 times with water. The aqueous layers were combined,
and washed successively with toluene, and hexane-ethyl acetate
(1:2). Under ice-cooling, potassium carbonate (10 g) was added, and
the mixture was extracted 4 times with chloroform. The organic
layer was dried over magnesium sulfate and concentrated to give
compound 5-6 (546 mg).
[1075] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.38-7.27 (m, 10.00H),
5.26-5.09 (m, 3.00H), 4.42 (s, 0.68H), 4.39 (s, 1.32H), 4.26-4.20
(m, 0.66H), 3.88-3.80 (m, 0.34H), 3.28 (d, 1.32H, J=6.2 Hz), 3.16
(d, 0.68H, J=5.5 Hz), 2.57-1.79 (m, 4.00H).
Step 7
##STR00130##
[1077] To a solution of compound 5-6 (252 mg) obtained in the
above-mentioned step in chloroform (8 mL) were added acetaldehyde
(40 .mu.L) and acetic acid (51 .mu.L) under ice-cooling, and the
mixture was stirred at room temperature for 40 min. Sodium
triacetoxyborohydride (200 mg) was added, and the mixture was
stirred at room temperature for 1.5 hr. To the reaction mixture was
added saturated aqueous sodium hydrogen carbonate solution, and the
mixture was extracted 3 times with chloroform. The organic layer
was dried over magnesium sulfate and concentrated to give compound
5-7. The obtained compound 5-7 was directly used in the next
step.
Step 8
##STR00131##
[1079] To compound 5-7 obtained in the above-mentioned step was
added 48% aqueous hydrogen bromide solution (5 mL), and the mixture
was stirred at 80.degree. C. for 4 hr. The reaction mixture was
cooled to room temperature, toluene was added, and the mixture was
extracted 4 times with water. The obtained aqueous layer was washed
with toluene, and concentrated to give residue 5-7.
[1080] To the residue 5-8 was added methanol and the mixture was
concentrated again to give compound 5-8 (250 mg). The obtained
compound 5-8 was directly used in the next step.
Step 9
##STR00132##
[1082] To a solution of compound 5-8 (250 mg) obtained in the
above-mentioned step in THF (10 mL) were added ethanol (3 mL),
methanol (2 mL), triethylamine (3 mL), and compound P1 (347 mg)
obtained in Example 1, Preliminary step 1-1. The mixture was
stirred at room temperature for 20 min, and concentrated, toluene
(30 mL) and DBU (3 mL) were added, and the mixture was stirred at
80.degree. C. for 6 hr. The reaction mixture was cooled to room
temperature, 10% aqueous potassium hydrogen sulfate solution was
added and the mixture was extracted 4 times with chloroform. The
organic layer was washed with saturated brine, dried over magnesium
sulfate, concentrated and purified by silica gel thin layer
chromatography (chloroform:acetone=1:1) to give compound 5-9 (224
mg).
[1083] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.60 (t, 0.68H, J=6.0
Hz), 10.56 (t, 0.32H, J=5.6 Hz), 8.43 (s, 0.68H), 8.34 (s, 0.32H),
7.58-7.54 (m, 2.00H), 7.35-7.28 (m, 5.00H), 7.07-7.02 (m, 1.00H),
5.32 (s, 0.64H), 5.32 (s, 1.36H), 4.71 (d, 2.00H, J=6.0 Hz),
4.56-4.52 (m, 0.68H), 4.40 (s, 1.36H), 4.21-4.18 (m, 0.32H), 3.95
(s, 0.64H), 3.69 (q, 0.64H, J=7.0 Hz), 3.61 (q, 1.36H, J=7.0 Hz),
2.60-2.54 (m, 1.36H), 2.45-2.39 (m, 0.64H), 2.33-2.27 (m, 0.64H),
2.04-2.02 (m, 0.68H), 2.01-1.98 (m, 0.68H), 1.22 (t, 0.96H, J=7.0
Hz), 1.21 (t, 2.04H, J=7.0 Hz).
Step 10
##STR00133##
[1085] To a solution of compound 5-9 (62 mg) obtained in the
above-mentioned step in toluene (1.5 mL) were added
tetrabutylammonium hydrogen sulfate (75 mg), dimethyl sulfate (70
.mu.L) and 50% aqueous sodium hydroxide solution (103 .mu.L), and
the mixture was stirred at room temperature for 5 min. Dimethyl
sulfate (70 .mu.L), and 50% aqueous sodium hydroxide solution (103
.mu.L) were added, and the mixture was stirred at room temperature
for 7 min. Dimethyl sulfate (70 .mu.L), and 50% aqueous sodium
hydroxide solution (103 .mu.L) were added, and the mixture was
stirred at room temperature for 24 min. Dimethyl sulfate (70
.mu.L), and 50% aqueous sodium hydroxide solution (103 .mu.L) were
added, and the mixture was further stirred at room temperature for
20 min. To the reaction mixture was added triethylamine (1 mL) and
the mixture was stirred for 15 min. 10% Aqueous potassium hydrogen
sulfate solution was added and the mixture was extracted 4 times
with chloroform. The organic layer was dried over magnesium
sulfate, concentrated and purified by silica gel thin layer
chromatography (chloroform:acetone=3:1) to give compound 5-10a (36
mg) and compound 5-10b (15 mg).
Compound 5-10a
[1086] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.58 (t, 1H, J=5.8 Hz),
8.40 (s, 1H), 7.59-7.57 (m, 2H), 7.35-7.27 (m, 5H), 7.07-7.02 (m,
1H), 5.32 (s, 2H), 4.72 (d, 2H, J=5.8 Hz), 4.27 (s, 2H), 3.98 (tt,
1H, J=6.9, 1.6 Hz), 3.63 (q, 2H, J=7.0 Hz), 3.24 (s, 3H), 2.52-2.46
(m, 2H), 2.06-2.02 (m, 2H), 1.21 (t, 3H, J=7.0 Hz).
Compound 5-10b
[1087] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.56 (t, 1H, J=5.8 Hz),
8.35 (s, 1H), 7.56-7.53 (m, 2H), 7.35-7.28 (m, 5H), 7.07-7.02 (m,
1H), 5.33 (s, 2H), 4.71 (d, 2H, J=5.8 Hz), 3.96 (s, 2H), 3.69
(quint, 1H, J=6.5 Hz), 3.67 (q, 2H, J=7.1 Hz), 3.25 (s, 3H),
2.40-2.35 (m, 2H), 2.26-2.21 (m, 2H), 1.21 (t, 3H, J=7.1 Hz).
Step 11
##STR00134##
[1089] To compound 5-10a (36 mg) obtained in the above-mentioned
step were successively added TFA (1 mL), and 4N hydrochloric
acid/ethyl acetate (400 .mu.L), and the mixture was stirred at room
temperature for 15 min. The reaction mixture was concentrated,
ethyl acetate was added and the mixture was concentrated to give
residue 5-11.
[1090] To the residue 5-11 were added 4N hydrochloric acid/ethyl
acetate (200 .mu.L), hexane (8 mL), and ethyl acetate (1.5 mL), and
the precipitated solid was collected by filtration to give the
title compound (24 mg).
[1091] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.39 (br s, 1H), 10.47
(t, 1H, J=5.9 Hz), 8.45 (s, 1H), 7.52-7.47 (m, 1H), 7.35-7.31 (m,
1H), 7.22-7.18 (m, 1H), 4.61 (d, 2H, J=5.9 Hz), 4.46 (s, 2H),
4.09-4.04 (m, 1H), 3.65 (q, 2H, J=6.9 Hz), 3.18 (s, 3H), 2.70-2.64
(m, 2H), 2.20-2.16 (m, 2H), 1.17 (t, 3H, J=6.9 Hz).
Example 6
Production of
N-(3-chloro-2-fluorobenzyl)-2'-ethyl-9'-hydroxy-cis-3-methoxy-1',8'-dioxo-
-1',2',4',8'-tetrahydrospiro[cyclobutane-1,3'-pyrido[1,2-a]pyrazine]-7'-ca-
rboxamide hydrochloride
Step 1
##STR00135##
[1093] From compound 5-10b (15 mg) obtained in Example 5, step 10,
and by a method similar to that in Example 5, step 11, the title
compound (8.8 mg) was obtained.
[1094] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 10.46 (t, 1H, J=6.0 Hz),
8.46 (s, 1H), 7.52-7.48 (m, 1H), 7.33 (t, 1H, J=7.4 Hz), 7.20 (t,
1H, J=7.9 Hz), 4.62 (d, 2H, J=6.0 Hz), 4.39 (s, 2H), 3.89 (quint,
1H, J=6.7 Hz), 3.65 (q, 2H, J=7.1 Hz), 3.17 (s, 3H), 2.51-2.48 (m,
2H), 2.30-2.25 (m, 2H), 1.15 (t, 3H, J=7.1 Hz).
Example 7
Production of
N-(3-chloro-2-fluoro-4-methoxybenzyl)-9'-hydroxy-trans-3-(methoxymethyl)--
2'-methyl-1',8'-dioxo-1',2',3',8'-tetrahydrospiro[cyclobutane-1,4'-pyrido[-
1,2-a]pyrazine]-7'-carboxamide hydrochloride
Step 1
##STR00136##
[1096] To compound 3-10 (145 mg) obtained in the same manner as in
Example 3, step 10 was added TFA (3 mL), and the mixture was stood
at room temperature for 15 min. The reaction mixture was
concentrated, toluene was added, and the mixture was concentrated
to give residue 7-1-1.
[1097] To a mixed solution of the residue 7-1-1 in ethanol-acetic
acid (1 mL-1 mL) was added palladium-platinum/carbon (ASCA2,
manufactured by N.E. CHEMCAT Corporation, 145 mg), and the mixture
was stirred overnight under a hydrogen atmosphere (normal pressure)
at room temperature. The reaction mixture was filtered through
Celite, and concentrated, ethanol was added, and the mixture was
concentrated. 4N Hydrochloric acid/dioxane was added, and the
mixture was concentrated to give residue 7-1-2.
[1098] To the residue 7-1-2 was added diisopropyl ether and the
supernatant liquid was removed by decantation. This operation was
performed twice, and the resulting residue was dried under reduced
pressure to give a crude product of compound 7-1. The obtained
crude product of compound 7-1 was directly used in the next
step.
Step 2
##STR00137##
[1100] From the crude product of compound 7-1 obtained in the
above-mentioned step and compound P7 (170 mg) obtained in
below-mentioned Preliminary step 7-9, and in the same manner as in
Example 5, step 9, compound 7-2 (165 mg) was obtained.
Step 3
##STR00138##
[1102] From compound 7-2 (80 mg) obtained in the above-mentioned
step, and in the same manner as in Example 5, step 10, compound
7-3a (23 mg) and 7-3b (51 mg) were obtained.
Step 4
##STR00139##
[1104] From compound 7-3a (23 mg) obtained in the above-mentioned
step, and in the same manner as in Example 1, step 11, the title
compound (19 mg) was obtained.
[1105] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.93 (br s, 1H), 10.39
(t, 1H, J=5.6 Hz), 8.58 (s, 1H), 7.32 (t, 1H, J=8.9 Hz), 6.99 (dd,
1H, J=8.8, 1.2 Hz), 4.54 (d, 2H, J=5.6 Hz), 3.87 (s, 3H), 3.82 (s,
2H), 3.43 (d, 2H, J=6.0 Hz), 3.28 (s, 3H), 3.10 (s, 3H), 2.73-2.63
(m, 1H), 2.57-2.51 (m, 2H), 2.25-2.20 (m, 2H).
Preliminary Step 7-1
##STR00140##
[1107] To a solution of commercially available
3-chloro-2,4-difluorobenzoic acid (10 g) in DMF (30 mL) was added
cesium carbonate (17.8 g), and the mixture was heated to 70.degree.
C. To the reaction mixture was added dropwise 2-iodopropane (5.96
mL), and the mixture was stirred at the same temperature for 3.5
hr. The reaction mixture was ice-cooled, and water (50 mL), ethyl
acetate (200 mL) and hexane (20 mL) were added to partition the
mixture. The organic layer was washed twice with water and with
saturated brine, dried over sodium sulfate and concentrated to give
compound P7-1 (11 g).
[1108] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.86 (ddd, 1H, J=8.9, 7.7,
6.4 Hz), 7.03 (ddd, 1H, J=8.9, 7.7, 1.6 Hz), 5.27 (sep, 1H, J=6.0
Hz), 1.39 (d, 6H, J=6.0 Hz).
Preliminary step 7-2
##STR00141##
[1109] To a solution of compound P7-1 (11 g) obtained in the
above-mentioned step in DMF (22 mL) was added cesium carbonate
(33.6 g), and the mixture was heated to 60.degree. C. A solution of
2-(methylsulfonyl)ethanol (10.9 mL) in DMF (6 mL) was added
dropwise over 20 min, and the mixture was stirred at the same
temperature for 6 hr. The reaction mixture was ice-cooled, 6N
hydrochloric acid (38 mL) and water (60 mL) were successively
added, and the mixture was extracted with ethyl acetate. The
organic layer was washed twice with water, and with saturated
brine, dried over sodium sulfate and concentrated.
[1110] Crystallization from hexane-ethyl acetate (1:3) gave
compound P7-2 (2.3 g).
[1111] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 11.61 (br s, 1H), 7.69
(t, 1H, J=8.7 Hz), 6.90 (dd, 1H, J=8.7, 1.2 Hz), 5.10 (sep, 1H,
J=6.4 Hz), 1.29 (d, 6H, J=6.4 Hz).
Preliminary Step 7-3
##STR00142##
[1113] To a solution of compound P7-2 (690 mg) obtained in the
above-mentioned step in DMF (7 mL) were added potassium carbonate
(820 mg) and iodomethane (280 .mu.L), and the mixture was stirred
at 50.degree. C. for 30 min. The reaction mixture was ice-cooled,
water was added and the mixture was extracted with an ethyl
acetate-hexane mixed solvent. The organic layer was washed with
saturated brine, dried over sodium sulfate and concentrated to give
compound P7-3 (840 mg).
Preliminary Step 7-4
##STR00143##
[1115] To a solution of compound P7-3 (840 mg) obtained in the
above-mentioned step in THF (5 mL) were added methanol (5 mL) and
2N aqueous sodium hydroxide solution (2.3 mL), and the mixture was
stirred at 55.degree. C. for 45 min. The reaction mixture was
concentrated, water (10 mL) and 2N hydrochloric acid (2.5 mL) were
added, and the mixture was stirred at room temperature for a while.
The solid was filtered off, and the filtrate was dried under
reduced pressure to give compound P7-4 (587 mg).
Preliminary Step 7-5
##STR00144##
[1117] To a solution of compound P7-4 (587 mg) obtained in the
above-mentioned step in THF (6 mL) were successively added
triethylamine (520 .mu.L) and isobutyl chloroformate (484 .mu.L)
under ice-cooling, and the mixture was stirred at the same
temperature for 30 min. The reaction mixture was filtered to give
filtrate P7-5.
[1118] To a solution of sodium borohydride (326 mg) in water (1.3
mL) was added dropwise filtrate P7-5 under ice-cooling, and the
mixture was stirred at the same temperature for 1.5 hr. To the
reaction mixture was added saturated aqueous ammonium chloride
solution, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine, dried over sodium
sulfate and concentrated. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate=4:1 to 2:1) to give
compound P7-5 (500 mg).
[1119] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.26 (t, 1H, J=8.5 Hz),
6.73 (dd, 1H, J=8.5, 1.6 Hz), 4.71 (d, 2H, J=6.0 Hz), 3.92 (s, 3H),
1.77 (t, 1H, J=6.0 Hz).
Preliminary Step 7-6
##STR00145##
[1121] To a solution of compound P7-5 (500 mg) obtained in the
above-mentioned step in THF (6 mL) were successively added
triethylamine (550 .mu.L) and methanesulfonyl chloride (305 .mu.L)
under ice-cooling, and the mixture was stirred at room temperature
for 30 min. The mixture was ice-cooled again, lithium bromide (2.2
g) was added and the mixture was stirred at the same temperature
for 30 min. To the reaction mixture was added water under
ice-cooling, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine, dried over sodium
sulfate and concentrated to give compound P7-6 (690 mg). The
obtained compound P7-6 was directly used in the next step.
Preliminary Step 7-7
##STR00146##
[1123] To a solution of compound P7-6 (690 mg) obtained in the
above-mentioned step in DMF (7 mL) were added cesium carbonate
(1.42 g) and di-tert-butyl iminodicarboxylate (867 mg), and the
mixture was stirred at 60.degree. C. for 1 hr. The reaction mixture
was cooled to room temperature, water was added, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
saturated brine, dried over sodium sulfate and concentrated. The
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=8:1 to 6:1) to give compound P7-7 (1.06
g).
[1124] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.13 (t, 1H, J=8.5 Hz),
6.69 (dd, 1H, J=8.5, 1.6 Hz), 4.80 (s, 2H), 3.90 (s, 3H), 1.48-1.46
(m, 18H).
Preliminary Step 7-8
##STR00147##
[1126] To a solution of compound P7-7 (1.06 g) obtained in the
above-mentioned step in chloroform (5 mL) was added TFA (5 mL), and
the mixture was stirred at room temperature for 30 min. The
reaction mixture was concentrated, 4N hydrochloric acid/dioxane (5
mL) was added and the mixture was concentrated again.
Crystallization from diisopropyl ether gave compound P7-8 (515
mg).
Preliminary Step 7-9
##STR00148##
[1128] From compound R1 (870 mg) obtained in Reference Example 1,
step R1-4 and compound P7-8 (515 mg) obtained in the
above-mentioned step, and by a method similar to that in Example 1,
Preliminary step 1-1, compound P7 (700 mg) was obtained.
[1129] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.49 (t, 1H, J=5.8 Hz),
8.78 (s, 1H), 7.48-7.45 (m, 2H), 7.39-7.31 (m, 3H), 7.27 (t, 1H,
J=8.5 Hz), 6.72-6.69 (m, 1H), 5.27 (s, 2H), 4.61 (d, 2H, J=5.8 Hz),
4.36 (q, 2H, J=7.1 Hz), 3.90 (s, 3H), 1.33 (t, 3H, J=7.1 Hz).
Example 8
Production of
N-(3-chloro-2-fluoro-4-methoxybenzyl)-9'-hydroxy-cis-3-(methoxymethyl)-2'-
-methyl-1',8'-dioxo-1',2',3',8'-tetrahydrospiro[cyclobutane-1,4'-pyrido[,
2-a]pyrazine]-7'-carboxamide hydrochloride
Step 1
##STR00149##
[1131] From compound 7-3b (51 mg) obtained in Example 7, step 3,
and in the same manner as in Example 1, step 11, the title compound
(40 mg) was obtained.
[1132] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.81 (br s, 1H), 10.38
(t, 1H, J=6.0 Hz), 8.53 (s, 1H), 7.32 (t, 1H, J=8.5 Hz), 7.02-6.96
(m, 1H), 4.54 (d, 2H, J=6.0 Hz), 3.90 (s, 2H), 3.87 (s, 3H), 3.39
(d, 2H, J=5.2 Hz), 3.28 (s, 3H), 3.14 (s, 3H), 2.64-2.47 (m, 1H),
2.40-2.23 (m, 4H).
Example 9
Production of
(1S,2S)--N-(2,4-difluorobenzyl)-9'-hydroxy-2-(hydroxymethyl)-2'-isopropyl-
-1',8'-dioxo-1',2',3',8'-tetrahydrospiro[cyclopropane-1,4'-pyrido[1,2-a]py-
razine]-7'-carboxamide hydrochloride
Step 1
##STR00150##
[1134] To a solution of
((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (15.4 g) in DMF (850
mL) was added sodium hydride (7 g) under ice-cooling, and the
mixture was stirred at room temperature for 45 min. The mixture was
ice-cooled again, benzyl bromide (16.6 mL) was added, and the
mixture was stirred at room temperature overnight. To the reaction
mixture was added water (150 mL) under ice-cooling, and the solvent
was evaporated under reduced pressure. Water (600 mL) was added,
and the mixture was extracted 3 times with chloroform (200 mL) and
washed with saturated brine. The mixture was dried, and
concentrated to give a crude product of compound 9-1. The obtained
crude product of compound 9-1 was directly used in the next
step.
[1135] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.38-7.26 (m, 5H), 4.60
(d, 1H, J=12.1 Hz), 4.55 (d, 1H, J=12.1 Hz), 4.34-4.27 (m, 1H),
4.06 (dd, 1H, J=8.4, 6.5 Hz), 3.75 (dd, 1H, J=8.4, 6.5 Hz), 3.56
(dd, 1H, J=9.8, 5.8 Hz), 3.48 (dd, 1H, J=9.8, 5.6 Hz), 1.42 (s,
3H), 1.36 (s, 3H).
Step 2
##STR00151##
[1137] To a crude product of compound 9-1 obtained in the
above-mentioned step was added an acetic acid-water (400 mL-100 mL)
mixed solution, and the mixture was stirred at 55.degree. C. for
1.5 hr. The mixture was concentrated and purified by silica gel
column chromatography (hexane:ethyl acetate=1:1 to 1:2) to give
compound 9-2 (15.87 g).
[1138] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.39-7.27 (m, 5H), 4.56
(s, 2H), 3.94-3.86 (m, 1H), 3.76-3.53 (m, 4H), 2.56 (d, 1H, J=5.1
Hz), 2.07-2.02 (m, 1H).
Step 3
##STR00152##
[1140] To a solution of compound 9-2 (13.87 g) obtained in the
above-mentioned step in carbon tetrachloride (76 mL) was added
dropwise a solution of thionyl chloride (6.7 ml) in carbon
tetrachloride (10 mL), and the mixture was heated under reflux for
30 min. Acetonitrile (80 mL), ruthenium(III) chloride n-hydrate (20
mg), sodium periodate (24.4 g) and water (120 mL) were successively
added, and the mixture was stirred at room temperature for 1.5 hr.
Diisopropyl ether (600 mL) was added and, after partitioning, the
organic layer was washed successively with water, saturated aqueous
sodium hydrogen carbonate solution and saturated brine, dried and
purified by silica gel column chromatography (hexane:ethyl
acetate=2:1) to give compound 9-3 (14.9 g).
[1141] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.41-7.29 (m, 5H),
5.08-5.00 (m, 1H), 4.71 (dd, 1H, J=8.8, 6.5 Hz), 4.66-4.57 (m, 3H),
3.83-3.67 (m, 2H).
Step 4
##STR00153##
[1143] To a suspension of sodium hydride (5.1 g) in DME (450 mL)
was added dropwise a solution of diethyl malonate (9.26 mL) in DME
(25 mL), and the mixture was stirred at room temperature for 10
min. A solution of compound 9-3 (14.9 g) obtained in the
above-mentioned step in DME (25 mL) was added, and the mixture was
stirred at overnight. After concentration, water was added, and the
mixture was extracted 3 times with ethyl acetate. The organic layer
was washed successively with saturated aqueous sodium hydrogen
carbonate solution and saturated brine, dried, concentrated and
purified by silica gel column chromatography (hexane:ethyl
acetate=20:1 to 10:1) to give compound 9-4 (16.6 g).
[1144] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37-7.24 (m, 5H), 4.48
(s, 2H), 4.26-4.07 (m, 4H), 3.57-3.46 (m, 2H), 2.30-2.20 (m, 1H),
1.57-1.52 (m, 1H), 1.42 (dd, 1H, J=9.1, 4.7 Hz), 1.31-1.20 (m,
6H).
Step 5
##STR00154##
[1146] To a solution of compound 9-4 (7.59 g) obtained in the
above-mentioned step in ethanol (24 mL) was added a solution of
sodium carbonate (5.8 g) in water (70 mL), and the mixture was
stirred at 60.degree. C. overnight. Ethanol (20 mL) was added, and
the mixture was stirred at 60.degree. C. for 9 hr. After
concentration, water was added, and the mixture was washed twice
with diisopropyl ether. The aqueous layer was acidified with 5%
aqueous potassium hydrogen sulfate solution, and the mixture was
extracted 3 times with ethyl acetate, dried and concentrated to
give compound 9-5 (6.09 g).
[1147] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.38-7.25 (m, 5H), 4.51
(d, 1H, J=12.1 Hz), 4.42 (d, 1H, J=12.1 Hz), 4.28-4.18 (m, 1H),
4.15-4.05 (m, 1H), 3.87 (dd, 1H, J=10.9, 5.8 Hz), 3.50 (dd, 1H,
J=10.7, 9.3 Hz), 2.53-2.42 (m, 1H), 2.08-2.02 (m, 1H), 1.82 (dd,
1H, J=8.4, 4.2 Hz), 1.21 (t, 3H, J=7.2 Hz).
Step 6
##STR00155##
[1149] To a solution of compound 9-5 (6.09 g) obtained in the
above-mentioned step in tert-butanol (100 mL) were successively
added dropwise triethylamine (3.6 mL) and DPPA (5.2 mL), and the
mixture was heated under reflux overnight. After concentration, the
residue was dissolved in ethyl acetate, and the mixture was washed
successively with saturated aqueous sodium hydrogen carbonate
solution and saturated brine. The mixture was dried, concentrated,
and purified by silica gel column chromatography (hexane:ethyl
acetate=10:1 to 5:1) to give compound 9-6 (3.87 g).
[1150] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37-7.24 (m, 5H), 5.18
(br s, 1H), 4.45 (s, 2H), 4.22-4.07 (m, 2H), 3.79 (dd, 1H, J=10.2,
5.8 Hz), 3.53 (t, 1H, J=9.3 Hz), 1.83-1.73 (m, 1H), 1.70-1.58 (m,
1H), 1.46-1.31 (m, 1H), 1.44 (s, 9H), 1.23 (t, 3H, J=7.0 Hz).
Step 7
##STR00156##
[1152] To a suspension of lithium aluminum hydride (70 mg) in THF
(2 mL) was added dropwise under ice-cooling a solution of compound
9-6 (431 mg) obtained in the above-mentioned step in THF (2 mL),
and the mixture was stirred at room temperature for 1 hr. Under
ice-cooling, water (70 .mu.L), 15% aqueous sodium hydroxide
solution (70 .mu.L), and water (210 .mu.L) were successively added
dropwise, the mixture was stirred at room temperature for 30 min,
and the insoluble material was filtered off. The filtrate was
dried, and concentrated to give compound 9-7 (377 mg).
[1153] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.39-7.26 (m, 5H), 5.22
(br s, 1H), 4.54 (dd, 2H, J=18.4, 11.6 Hz), 3.98 (t, 1H, J=11.2
Hz), 3.85 (dd, 1H, J=10.7, 6.0 Hz), 3.46-3.28 (m, 2H), 3.16 (t, 1H,
J=10.5 Hz), 1.43 (s, 9H), 1.28-1.11 (m, 1H), 0.82-0.70 (m, 1H).
Step 8
##STR00157##
[1155] To a solution of oxalyl chloride (120 .mu.L) in chloroform
(3 mL) was added dropwise a solution of DMSO (191 .mu.L) in
chloroform (1 mL) at an inside temperature of -50 to -60.degree.
C., and the mixture was stirred at the same temperature for 2 min.
A solution of compound 9-7 (377 mg) obtained in the above-mentioned
step in chloroform (1 mL) was added dropwise, and the mixture was
stirred at the same temperature for 15 min. Triethylamine (850
.mu.L) was added, and the mixture was further stirred at the same
temperature for 5 min. The mixture was allowed to warm to room
temperature, water was added, and the mixture was extracted with
chloroform. The organic layer was washed with saturated brine,
dried, concentrated, and purified by silica gel column
chromatography (hexane:ethyl acetate=10:1 to 5:1) to give compound
9-8 (293 mg).
[1156] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.44 (s, 1H), 7.35-7.25
(m, 5H), 5.18-5.18 (m, 1H), 4.43 (s, 2H), 3.84-3.72 (m, 1H),
3.51-3.37 (m, 1H), 2.00-1.87 (m, 1H), 1.75-1.63 (m, 1H), 1.45-1.40
(m, 10H).
Step 9
##STR00158##
[1158] To a solution of compound 9-8 (293 mg) obtained in the
above-mentioned step in chloroform (10 mL) were successively added
isopropylamine (106 .mu.L), acetic acid (55 .mu.L) and sodium
triacetoxyborohydride (204 mg) under ice-cooling, and the mixture
was stirred at room temperature overnight. To the reaction mixture
was added saturated aqueous sodium hydrogen carbonate solution and,
after partitioning, the organic layer was washed with saturated
brine, dried, concentrated, and purified by silica gel column
chromatography (chloroform:methanol=10:1) to give compound 9-9 (228
mg).
[1159] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37-7.25 (m, 5H), 5.41
(br s, 1H), 4.56 (d, 1H, J=11.9 Hz), 4.49 (d, 1H, J=11.9 Hz),
3.73-3.61 (m, 1H), 3.35-3.24 (m, 1H), 3.10-2.91 (m, 1H), 2.81-2.70
(m, 1H), 2.61-2.45 (m, 1H), 1.43 (s, 10H), 1.19-1.08 (m, 1H), 0.99
(t, 6H, J=6.3 Hz), 0.77-0.57 (m, 1H).
Step 10
##STR00159##
[1161] To a suspension of palladium-platinum/carbon (ASCA2,
manufactured by N.E. CHEMCAT Corporation, 200 mg) in ethanol (6 mL)
was added a solution of acetic acid (45 .mu.L) and compound 9-9
(228 mg) obtained in the above-mentioned step in ethanol (1 mL),
and the mixture was stirred under a hydrogen atmosphere at room
temperature for 3 hr. The catalyst was filtered off, and the same,
fresh catalyst (200 mg) was added, and the mixture was stirred
under a hydrogen atmosphere at room temperature overnight. The
insoluble material was filtered off, and the filtrate was
concentrated to give a crude product of compound 9-10. The obtained
crude product of compound 9-10 was directly used in the next
step.
[1162] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.24 (br s, 1H), 4.31-4.21
(m, 1H), 3.71-3.62 (m, 1H), 3.26-3.14 (m, 1H), 3.00 (t, 1H, J=12.1
Hz), 2.61 (d, 1H, J=12.8 Hz), 1.69-1.58 (m, 1H), 1.46-1.32 (m, 1H),
1.43 (s, 9H), 1.32 (t, 6H, J=6.7 Hz), 0.88-0.79 (m, 1H).
Step 11
##STR00160##
[1164] To the crude product of compound 9-10 obtained in the
above-mentioned step was added 4N hydrochloric acid/dioxane (10
mL), and the mixture was stirred for 1 hr, and concentrated to give
a crude product of compound 9-11 (125 mg). The obtained crude
product of compound 9-11 was directly used in the next step.
[1165] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 9.41-9.23 (m, 1H),
9.20-9.04 (m, 1H), 3.81 (dd, 1H, J=12.4, 5.5 Hz), 3.52-3.21 (m,
4H), 1.75-1.64 (m, 1H), 1.32-1.26 (m, 6H), 1.24-1.15 (m, 2H).
Step 12
##STR00161##
[1167] To a solution of the crude product (40 mg) of compound 9-11
obtained in the above-mentioned step in THF (1.5 mL) were
successively added ethanol (300 .mu.L), triethylamine (96 .mu.L)
and compound P9 (65 mg) obtained in below-mentioned Preliminary
step 9-1, and the mixture was stirred at room temperature for 1 hr.
DBU (104 .mu.L) was added, and the mixture was further stirred for
1 hr. After concentration, toluene (5 ml), ethanol (500 .mu.L), and
acetic acid (80 .mu.L) were successively added, and the mixture was
stirred at 100.degree. C. for 1 hr. Acetic acid (120 .mu.L) was
added, and the mixture was stirred at 100.degree. C. overnight. To
the reaction mixture was added saturated aqueous sodium hydrogen
carbonate solution, and the mixture was extracted 3 times with
chloroform. The organic layer was washed with saturated brine,
dried, concentrated, and purified by silica gel column
chromatography (ethyl acetate:methanol=100:4) to give compound 9-12
(70 mg).
[1168] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.51 (t, 1H, J=6.0 Hz),
8.34 (s, 1H), 7.62-7.58 (m, 2H), 7.40-7.25 (m, 4H), 6.84-6.75 (m,
2H), 5.32 (d, 1H, J=10.0 Hz), 5.25 (d, 1H, J=10.0 Hz), 4.92-4.82
(m, 1H), 4.61 (d, 2H, J=6.0 Hz), 4.11-4.02 (m, 1H), 3.80-3.70 (m,
1H), 3.59 (d, 1H, J=14.2 Hz), 3.41 (d, 1H, J=14.2 Hz), 2.23-2.13
(m, 1H), 1.90-1.81 (m, 1H), 1.60-1.42 (m, 1H), 1.18-1.13 (m,
6H).
Step 13
##STR00162##
[1170] To compound 9-12 (20 mg) obtained in the above-mentioned
step was added TFA (1.5 mL) and the mixture was stirred for 30 min.
After concentration, the residue was azeotropically distilled 4
times with methanol. The residue was dissolved in methanol (1 mL),
4N hydrochloric acid/ethyl acetate was added, and the mixture was
concentrated. Hexane was added and the supernatant liquid was
removed by decantation. The resulting residue was crystallized from
ethyl acetate-hexane to give the title compound (9 mg).
[1171] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.89-12.73 (m, 1H),
10.38 (t, 1H, J=6.0 Hz), 8.14 (s, 1H), 7.43-7.35 (m, 1H), 7.26-7.19
(m, 1H), 7.10-7.02 (m, 1H), 4.78-4.68 (m, 1H), 4.53 (d, 2H, J=6.0
Hz), 4.42-3.99 (m, 1H), 3.80-3.67 (m, 3H), 3.51 (dd, 1H, J=12.1,
7.7 Hz), 1.94-1.84 (m, 1H), 1.74-1.67 (m, 1H), 1.19 (d, 3H, J=7.0
Hz), 1.17 (d, 3H, J=7.0 Hz), 1.03 (t, 1H, J=7.2 Hz).
Preliminary Step 9-1
##STR00163##
[1173] From compound R1 (12.15 g) obtained in Reference Example 1,
step R1-4, and commercially available 2,4-difluorobenzylamine (3.6
mL) and by a method similar to that in Example 1, Preliminary step
1-1, compound P9 (11.7 g) was obtained.
[1174] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.54-9.45 (m, 1H), 8.79
(s, 1H), 7.48-7.43 (m, 2H), 7.42-7.30 (m, 4H), 6.89-6.79 (m, 2H),
5.27 (s, 2H), 4.62 (d, 2H, J=6.3 Hz), 4.37 (q, 2H, J=7.2 Hz), 1.33
(t, 3H, J=7.2 Hz).
Example 10
Production of
(1S,2S)--N-(2,4-difluorobenzyl)-9'-hydroxy-2'-isopropyl-2-(methoxymethyl)-
-1',8'-dioxo-1',2',3',8'-tetrahydrospiro[cyclopropane-1,4'-pyrido[1,2-a]py-
razine]-7'-carboxamide hydrochloride
Step 1
##STR00164##
[1176] To a solution of compound 9-12 (29 mg) obtained in Example
9, step 12, in toluene (1 mL) were successively added
tetrabutylammonium hydrogen sulfate (2 mg), 50% aqueous sodium
hydroxide solution (17 .mu.L) and dimethyl sulfate (10 .mu.L) under
ice-cooling, and the mixture was stirred at room temperature for 20
min. 50% Aqueous sodium hydroxide solution (8 .mu.L) and dimethyl
sulfate (5 .mu.L) were successively added, and the mixture was
further stirred at room temperature for 20 min. To the reaction
mixture was added saturated aqueous sodium hydrogen carbonate
solution, and the mixture was extracted 3 times with chloroform and
washed with saturated brine, dried, concentrated, and purified by
silica gel thin layer chromatography (ethyl acetate:methanol=100:5)
to give compound 10-1 (23 mg).
[1177] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.51 (t, 1H, J=6.3 Hz),
8.34 (s, 1H), 7.64-7.60 (m, 2H), 7.40-7.24 (m, 4H), 6.85-6.77 (m,
2H), 5.34 (d, 1H, J=9.8 Hz), 5.27 (d, 1H, J=9.8 Hz), 4.92-4.84 (m,
1H), 4.63 (d, 2H, J=5.8 Hz), 3.78 (dd, 1H, J=10.7, 3.7 Hz),
3.58-3.45 (m, 2H), 3.38 (d, 1H, J=14.0 Hz), 3.35 (s, 3H), 2.21-2.11
(m, 1H), 1.58-1.44 (m, 1H), 1.18-1.11 (m, 7H).
Step 2
##STR00165##
[1179] To compound 10-1 (23 mg) obtained in the above-mentioned
step was added TFA (1.5 mL), and the mixture was stirred at room
temperature for 30 min. After concentration, the residue was
azeotropically distilled twice with ethyl acetate, and dissolved in
ethyl acetate (1 mL), and 4N hydrochloric acid/ethyl acetate was
added. After concentration, hexane was added and the supernatant
liquid was removed by decantation. Crystallization from ethyl
acetate-hexane gave the title compound (8 mg).
[1180] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.83 (s, 1H), 10.36 (t,
1H, J=6.0 Hz), 8.10 (s, 1H), 7.43-7.35 (m, 1H), 7.27-7.19 (m, 1H),
7.09-7.02 (m, 1H), 4.77-4.68 (m, 1H), 4.52 (d, 2H, J=6.0 Hz), 3.80
(d, 1H, J=14.2 Hz), 3.66 (d, 1H, J=14.2 Hz), 3.61-3.40 (m, 2H),
3.23 (s, 3H), 1.93-1.84 (m, 2H), 1.17 (dd, 6H, J=6.5, 1.4 Hz),
1.10-1.06 (m, 1H).
Example 11
Production of
(1R,2R)--N-(2,4-difluorobenzyl)-9'-hydroxy-2-(hydroxymethyl)-2'-isopropyl-
-1',8'-dioxo-1',2',3',8'-tetrahydrospiro[cyclopropane-1,4'-pyrido[1,2-a]py-
razine]-7'-carboxamide hydrochloride
Step 1
##STR00166##
[1182] From ((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (15.29
g) and by an operation similar to that in Example 9-1, a crude
product of compound 11-1 was obtained.
[1183] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.38-7.26 (m, 5H), 4.60
(d, 1H, J=12.1 Hz), 4.55 (d, 1H, J=12.1 Hz), 4.34-4.27 (m, 1H),
4.06 (dd, 1H, J=8.4, 6.5 Hz), 3.75 (dd, 1H, J=8.4, 6.5 Hz), 3.56
(dd, 1H, J=9.8, 5.8 Hz), 3.48 (dd, 1H, J=9.8, 5.6 Hz), 1.42 (s,
3H), 1.36 (s, 3H).
Step 2
##STR00167##
[1185] From compound 11-1 obtained in the above-mentioned step and
by a method similar to that in Example 9, step 2, compound 11-2
(21.42 g) was obtained.
[1186] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.39-7.27 (m, 5H), 4.56
(s, 2H), 3.94-3.86 (m, 1H), 3.76-3.53 (m, 4H), 2.56 (d, 1H, J=5.1
Hz), 2.07-2.02 (m, 1H).
Step 3
##STR00168##
[1188] From compound 11-2 (21.42 g) obtained in the above-mentioned
step and by a method similar to that in Example 9, step 3, compound
11-3 (26.2 g) was obtained.
[1189] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.41-7.29 (m, 5H),
5.08-5.00 (m, 1H), 4.71 (dd, 1H, J=8.8, 6.5 Hz), 4.66-4.57 (m, 3H),
3.83-3.67 (m, 2H).
Step 4
##STR00169##
[1191] From compound 11-3 (26.2 g) obtained in the above-mentioned
step and by a method similar to that in Example 9, step 4, compound
11-4 (31.6 g) was obtained.
[1192] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37-7.24 (m, 5H), 4.48
(s, 2H), 4.26-4.07 (m, 4H), 3.57-3.46 (m, 2H), 2.30-2.20 (m, 1H),
1.57-1.52 (m, 1H), 1.42 (dd, 1H, J=9.1, 4.7 Hz), 1.31-1.20 (m,
6H).
Step 5
##STR00170##
[1194] From compound 11-4 (13.09 g) obtained in the above-mentioned
step and by a method similar to that in Example 9, step 5, compound
11-5 (9.01 g) was obtained.
[1195] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.38-7.25 (m, 5H), 4.51
(d, 1H, J=12.1 Hz), 4.42 (d, 1H, J=12.1 Hz), 4.28-4.18 (m, 1H),
4.15-4.05 (m, 1H), 3.87 (dd, 1H, J=10.9, 5.8 Hz), 3.50 (dd, 1H,
J=10.7, 9.3 Hz), 2.53-2.42 (m, 1H), 2.08-2.02 (m, 1H), 1.82 (dd,
1H, J=8.4, 4.2 Hz), 1.21 (t, 3H, J=7.2 Hz).
Step 6
##STR00171##
[1197] From compound 11-5 (9.01 g) obtained in the above-mentioned
step and by a method similar to that in Example 9, step 6, compound
11-6 (8.56 g) was obtained.
[1198] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37-7.24 (m, 5H), 5.18
(br s, 1H), 4.45 (s, 2H), 4.22-4.07 (m, 2H), 3.79 (dd, 1H, J=10.2,
5.8 Hz), 3.53 (t, 1H, J=9.3 Hz), 1.83-1.73 (m, 1H), 1.70-1.58 (m,
1H), 1.46-1.31 (m, 1H), 1.44 (s, 9H), 1.23 (t, 3H, J=7.0 Hz).
Step 7
##STR00172##
[1200] From compound 11-6 (8.56 g) obtained in the above-mentioned
step and by a method similar to that in Example 9, step 7, compound
11-7 was obtained. The obtained compound 11-7 was directly used in
the next step.
[1201] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.39-7.26 (m, 5H), 5.22
(br s, 1H), 4.54 (dd, 2H, J=18.4, 11.6 Hz), 3.98 (t, 1H, J=11.2
Hz), 3.85 (dd, 1H, J=10.7, 6.0 Hz), 3.46-3.28 (m, 2H), 3.16 (t, 1H,
J=10.5 Hz), 1.43 (s, 9H), 1.28-1.11 (m, 1H), 0.82-0.70 (m, 1H).
Step 8
##STR00173##
[1203] From compound 11-7 obtained in the above-mentioned step and
by a method similar to that in Example 1, step 4, a crude product
of compound 11-8 was obtained. The crude product of compound 11-8
was purified by silica gel column chromatography (hexane:ethyl
acetate=3:1) to give compound 11-8 (2.78 g).
[1204] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.44 (s, 1H), 7.35-7.25
(m, 5H), 5.18-5.18 (m, 1H), 4.43 (s, 2H), 3.84-3.72 (m, 1H),
3.51-3.37 (m, 1H), 2.00-1.87 (m, 1H), 1.75-1.63 (m, 1H), 1.45-1.40
(m, 10H).
Step 9
##STR00174##
[1206] From compound 11-8 (950 mg) obtained in the above-mentioned
step and by a method similar to that in Example 9, step 9, compound
11-9 (510 mg) was obtained.
[1207] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37-7.25 (m, 5H), 5.41
(br s, 1H), 4.56 (d, 1H, J=11.9 Hz), 4.49 (d, 1H, J=11.9 Hz),
3.73-3.61 (m, 1H), 3.35-3.24 (m, 1H), 3.10-2.91 (m, 1H), 2.81-2.70
(m, 1H), 2.61-2.45 (m, 1H), 1.43 (s, 10H), 1.19-1.08 (m, 1H), 0.99
(t, 6H, J=6.3 Hz), 0.77-0.57 (m, 1H).
Step 10
##STR00175##
[1209] From compound 11-9 (510 mg) obtained in the above-mentioned
step and by a method similar to that in Example 9, step 10, a crude
product of compound 11-10 was obtained. The obtained crude product
of compound 11-10 was directly used in the next step.
[1210] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.24 (br s, 1H), 4.31-4.21
(m, 1H), 3.71-3.62 (m, 1H), 3.26-3.14 (m, 1H), 3.00 (t, 1H, J=12.1
Hz), 2.61 (d, 1H, J=12.8 Hz), 1.69-1.58 (m, 1H), 1.46-1.32 (m, 1H),
1.43 (s, 9H), 1.32 (t, 6H, J=6.7 Hz), 0.88-0.79 (m, 1H).
Step 11
##STR00176##
[1212] From the crude product of compound 11-10 obtained in the
above-mentioned step and by a method similar to that in Example 9,
step 11, a crude product of compound 11-11 (163 mg) was obtained.
The obtained crude product of compound 11-11 was directly used in
the next step.
[1213] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 9.41-9.23 (m, 1H),
9.20-9.04 (m, 1H), 3.81 (dd, 1H, J=12.4, 5.5 Hz), 3.52-3.21 (m,
4H), 1.75-1.64 (m, 1H), 1.32-1.26 (m, 6H), 1.24-1.15 (m, 2H).
Step 12
##STR00177##
[1215] From the crude product of compound 11-11 obtained in the
above-mentioned step (140 mg) and compound P9 obtained in Example
9, Preliminary step 9-1, and by a method similar to that in Example
9, step 12, compound 11-12 (190 mg) was obtained. .sup.1H-NMR
(CDCl.sub.3) .delta.: 10.51 (t, 1H, J=6.0 Hz), 8.34 (s, 1H),
7.62-7.58 (m, 2H), 7.40-7.25 (m, 4H), 6.84-6.75 (m, 2H), 5.32 (d,
1H, J=10.0 Hz), 5.25 (d, 1H, J=10.0 Hz), 4.92-4.82 (m, 1H), 4.61
(d, 2H, J=6.0 Hz), 4.11-4.02 (m, 1H), 3.80-3.70 (m, 1H), 3.59 (d,
1H, J=14.2 Hz), 3.41 (d, 1H, J=14.2 Hz), 2.23-2.13 (m, 1H),
1.90-1.81 (m, 1H), 1.60-1.42 (m, 1H), 1.18-1.13 (m, 6H).
Step 13
##STR00178##
[1217] From compound 11-12 (15 mg) obtained in the above-mentioned
step and by a method similar to that in Example 9, step 13, the
title compound (7 mg) was obtained.
[1218] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.82 (s, 1H), 10.38 (t,
1H, J=6.0 Hz), 8.14 (s, 1H), 7.44-7.35 (m, 1H), 7.27-7.19 (m, 1H),
7.10-7.02 (m, 1H), 4.98-4.80 (m, 1H), 4.78-4.69 (m, 1H), 4.53 (d,
2H, J=6.0 Hz), 3.86-3.58 (m, 3H), 3.56-3.47 (m, 1H), 1.95-1.83 (m,
1H), 1.72 (dd, 1H, J=10.6, 6.6 Hz), 1.19 (d, 3H, J=6.8 Hz), 1.17
(d, 3H, J=6.8 Hz), 1.03 (t, 1H, J=7.1 Hz).
Example 12
Production of
(1R,2R)--N-(2,4-difluorobenzyl)-9'-hydroxy-2'-isopropyl-2-(methoxymethyl)-
-1',8'-dioxo-1',2',3',8'-tetrahydrospiro[cyclopropane-1,4'-pyrido[1,2-a]py-
razine]-7'-carboxamide hydrochloride
Step 1
##STR00179##
[1220] From compound 11-12 (130 mg) obtained in Example 11, step 12
and by a method similar to that in Example 10, step 1, compound
12-1 (118 mg) was obtained.
[1221] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.51 (t, 1H, J=6.3 Hz),
8.34 (s, 1H), 7.64-7.60 (m, 2H), 7.40-7.24 (m, 4H), 6.85-6.77 (m,
2H), 5.34 (d, 1H, J=9.8 Hz), 5.27 (d, 1H, J=9.8 Hz), 4.92-4.84 (m,
1H), 4.63 (d, 2H, J=5.8 Hz), 3.78 (dd, 1H, J=10.7, 3.7 Hz),
3.58-3.45 (m, 2H), 3.38 (d, 1H, J=14.0 Hz), 3.35 (s, 3H), 2.21-2.11
(m, 1H), 1.58-1.44 (m, 1H), 1.18-1.11 (m, 7H).
Step 2
##STR00180##
[1223] From compound 12-1 (118 mg) obtained in the above-mentioned
step and by a method similar to that in Example 10, step 2, the
title compound (53 mg) was obtained.
[1224] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.96-12.71 (m, 1H),
10.36 (t, 1H, J=6.2 Hz), 8.10 (s, 1H), 7.43-7.35 (m, 1H), 7.27-7.19
(m, 1H), 7.09-7.02 (m, 1H), 4.78-4.68 (m, 1H), 4.52 (d, 2H, J=6.0
Hz), 3.80 (d, 1H, J=14.1 Hz), 3.67 (d, 1H, J=14.1 Hz), 3.61-3.53
(m, 1H), 3.50-3.42 (m, 1H), 3.23 (s, 3H), 1.94-1.84 (m, 2H), 1.17
(dd, 6H, J=6.6, 1.5 Hz), 1.11-1.05 (m, 1H).
Example 13
Production of
(1R,2S)--N-(2,4-difluorobenzyl)-9'-hydroxy-2-(hydroxymethyl)-2'-isopropyl-
-1',8'-dioxo-1',2',3',8'-tetrahydrospiro[cyclopropane-1,4'-pyrido[1,2-a]py-
razine]-7'-carboxamide hydrochloride
Step 1
##STR00181##
[1226] To a solution of compound 9-5 (1.5 g) obtained in the same
manner as in Example 9, step 5, in DMF (10 mL) were added
N,O-dimethylhydroxylamine hydrochloride (1.1 g), triethylamine (1.6
mL), HOBt.H.sub.2O (1.1 g) and EDC (1.55 g) under ice-cooling, and
the mixture was stirred at room temperature for 3 hr. To the
reaction mixture were added under ice-cooling a saturated aqueous
sodium hydrogen carbonate solution and ethyl acetate to allow for
partitioning, and the organic layer was washed with saturated
brine. The mixture was dried, concentrated and purified by silica
gel column chromatography (hexane:ethyl acetate=2:1) to give
compound 13-1 (1.38 g).
[1227] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.36-7.22 (m, 5H), 4.51
(dd, 2H, J=14.1, 11.7 Hz), 4.20-4.05 (m, 2H), 3.72-3.61 (m, 1H),
3.66 (s, 3H), 3.53 (dd, 1H, J=10.5, 8.1 Hz), 3.24 (s, 3H),
2.38-2.20 (m, 1H), 1.60-1.55 (m, 1H), 1.39-1.27 (m, 1H), 1.21 (t,
3H, J=7.3 Hz).
Step 2
##STR00182##
[1229] To a solution of compound 13-1 (1.38 g) obtained in the
above-mentioned step in methanol (14 mL) was added 2N aqueous
sodium hydroxide solution (4.6 mL), and the mixture was stirred for
2 hr. 2N Aqueous sodium hydroxide solution (4.6 mL) was added, and
the mixture was further stirred overnight. The mixture was
neutralized with 2N hydrochloric acid, and extracted with ethyl
acetate. The organic layer was washed with saturated brine, dried,
and concentrated to give residue 13-2 (1 g). The obtained residue
13-2 was directly used in the next step.
Step 3
##STR00183##
[1231] To a solution of residue 13-2 (1 g) obtained in the
above-mentioned step in toluene (10 mL) were added triethylamine
(1.43 mL) and DPPA (1.84 mL), and the mixture was stirred at
90.degree. C. for 40 min. tert-Butanol (15 mL) was added, and the
mixture was stirred at 100.degree. C. overnight. The reaction
mixture was concentrated, and saturated aqueous sodium hydrogen
carbonate solution and ethyl acetate were added to allow for
partitioning. The organic layer was washed with saturated brine,
dried, concentrated, and purified by silica gel column
chromatography (hexane:ethyl acetate=5:1 to 1:1) to give compound
13-3 (350 mg).
[1232] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.39-7.24 (m, 5H),
5.52-5.30 (m, 1H), 4.64-4.52 (m, 1H), 4.52-4.41 (m, 1H), 3.85 (dd,
1H, J=10.9, 5.2 Hz), 3.65 (s, 3H), 3.38 (t, 1H, J=10.1 Hz), 3.17
(s, 3H), 1.96-1.86 (m, 1H), 1.81-1.70 (m, 1H), 1.43 (s, 9H),
1.02-0.85 (m, 1H).
Step 4
##STR00184##
[1234] To a suspension of lithium aluminum hydride (73 mg) in THF
(2 mL) was added dropwise a solution of compound 13-3 (350 mg)
obtained in the above-mentioned step in THF (3 mL) under
ice-cooling, and the mixture was stirred at the same temperature
for 15 min. To the reaction mixture were successively added water
(73 .mu.L), 4N aqueous sodium hydroxide solution (73 .mu.L), and
water (219 .mu.L), and the mixture was stirred for 45 min.
Anhydrous sodium sulfate and ethyl acetate were added, the
insoluble material was filtered off through Celite and the filtrate
was concentrated and purified by silica gel column chromatography
(hexane:ethyl acetate=5:1 to 4:1) to give compound 13-4 (170
mg).
[1235] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.30 (s, 1H), 7.39-7.26
(m, 5H), 5.43-5.10 (m, 1H), 4.59-4.44 (m, 2H), 3.83 (dd, 1H,
J=10.9, 5.6 Hz), 3.38 (t, 1H, J=9.7 Hz), 2.04-1.92 (m, 1H),
1.82-1.68 (m, 1H), 1.45 (s, 9H), 1.31-1.21 (m, 1H).
Step 5
##STR00185##
[1237] To a solution of compound 13-4 (85 mg) obtained in the
above-mentioned step in chloroform (1 mL) were successively added
isopropylamine (31 .mu.L), acetic acid (20 .mu.L) and sodium
triacetoxyborohydride (71 mg) under ice-cooling, and the mixture
was stirred at room temperature for 2 hr 20 min. Under ice-cooling,
isopropylamine (31 .mu.L), acetic acid (20 .mu.L), and sodium
triacetoxyborohydride (71 mg) were added, and the mixture was
further stirred at room temperature for 1 hr. To the reaction
mixture was added saturated aqueous sodium hydrogen carbonate
solution and ethyl acetate to allow for partitioning, and the
organic layer was washed with saturated brine, dried, concentrated,
and purified by silica gel column chromatography
(chloroform:methanol=15:1 to 10:1) to give compound 13-5 (93
mg).
[1238] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.39-7.25 (m, 5H),
5.43-5.24 (m, 1H), 4.56 (d, 1H, J=12.1 Hz), 4.49 (d, 1H, J=12.1
Hz), 3.67 (dd, 1H, J=10.5, 6.0 Hz), 3.43-3.30 (m, 1H), 2.98-2.81
(m, 2H), 2.75-2.27 (m, 1H), 1.43 (s, 9H), 1.36-0.99 (m, 2H), 1.08
(d, 6H, J=6.0 Hz), 0.84-0.70 (m, 1H).
Step 6
##STR00186##
[1240] To compound 13-5 (93 mg) obtained in the above-mentioned
step was added TFA (1 mL), and the mixture was stirred at room
temperature for 1 hr 40 min. After concentration, the residue was
azeotropically distilled 3 times with methanol to give a crude
product of compound 13-6. The obtained crude product of compound
13-6 was directly used in the next step.
Step 7
##STR00187##
[1242] The crude product of compound 13-6 obtained in the
above-mentioned step was dissolved in an acetic acid-ethanol (1
mL-1 mL) mixed solution, palladium-platinum/carbon (ASCA2,
manufactured by N.E. CHEMCAT Corporation, 100 mg) was added, and
the mixture was stirred under a hydrogen atmosphere at room
temperature overnight. The insoluble material was filtered off, and
the filtrate was concentrated and azeotropically distilled 3 times
with methanol. 4N Hydrochloric acid/dioxane was added, and the
mixture was concentrated to give a crude product of compound 13-7
(70 mg). The obtained crude product of compound 13-7 was directly
used in the next step.
[1243] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 9.39-9.04 (m, 1H),
8.92-8.72 (m, 2H), 3.75 (dd, 1H, J=12.1, 4.8 Hz), 3.64-3.56 (m,
1H), 3.38-3.22 (m, 3H), 1.64-1.54 (m, 1H), 1.33-1.21 (m, 7H), 1.03
(t, 1H, J=6.9 Hz).
Step 8
##STR00188##
[1245] To a solution of compound 13-7 (70 mg) obtained in the
above-mentioned step in THF (1 mL) were successively added
chloroform (1 mL), ethanol (500 .mu.L), triethylamine (211 .mu.L)
and compound P9 (111 mg) obtained in Example 9, Preliminary step
9-1, and the mixture was stirred at room temperature for 25 min and
concentrated. Toluene (2.5 mL), ethanol (250 .mu.L), and DBU (250
.mu.L) were added, and the mixture was stirred at 80.degree. C. for
2 hr. Toluene (5 mL) and acetic acid (1.5 mL) were further added,
and the mixture was stirred at 110.degree. C. overnight. To the
reaction mixture were added ethyl acetate and 5% aqueous potassium
hydrogen sulfate solution to allow for partitioning, and the
organic layer was washed successively with saturated aqueous sodium
hydrogen carbonate solution and saturated brine, dried and
concentrated to give residue 13-8.
[1246] The residue 13-8 was dissolved in methanol (3 mL), potassium
carbonate (160 mg) was added, and the mixture was stirred at room
temperature for 20 min. Ethyl acetate and saturated brine were
added to allow for partitioning. The organic layer was dried,
concentrated, and purified by silica gel thin layer chromatography
(ethyl acetate:methanol=15:1) to give compound 13-8 (66 mg).
[1247] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.56 (t, 1H, J=85.8 Hz),
8.29 (s, 1H), 7.59-7.53 (m, 2H), 7.41-7.24 (m, 4H), 6.86-6.76 (m,
2H), 5.35 (d, 1H, J=10.1 Hz), 5.22 (d, 1H, J=10.1 Hz), 4.89-4.76
(m, 1H), 4.61 (d, 2H, J=6.0 Hz), 3.77 (d, 1H, J=13.7 Hz), 3.69 (dd,
1H, J=12.1, 4.8 Hz), 3.09 (dd, 1H, J=12.1, 8.5 Hz), 2.60 (d, 1H,
J=13.7 Hz), 1.94-1.87 (m, 1H), 1.49-1.38 (m, 1H), 1.37-1.29 (m,
1H), 1.15 (d, 3H, J=6.9 Hz), 1.08 (d, 3H, J=6.9 Hz).
Step 9
##STR00189##
[1249] From compound 13-8 (33 mg) obtained in the above-mentioned
step, and by a method similar to that in Example 9, step 13, the
title compound (18 mg) was obtained.
[1250] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.61 (s, 1H),
10.43-10.36 (m, 1H), 8.15 (s, 1H), 7.45-7.35 (m, 1H), 7.27-7.20 (m,
1H), 7.10-7.02 (m, 1H), 4.79-4.69 (m, 1H), 4.57-4.49 (m, 2H), 4.04
(d, 1H, J=13.6 Hz), 3.55-3.48 (m, 1H), 3.18 (d, 1H, J=13.6 Hz),
2.69-2.51 (m, 1H), 1.95-1.90 (m, 1H), 1.44-1.37 (m, 2H), 1.18 (d,
3H, J=6.7 Hz), 1.12 (d, 3H, J=6.7 Hz).
Example 14
Production of
(1R,2S)--N-(2,4-difluorobenzyl)-9'-hydroxy-2'-isopropyl-2-(methoxymethyl)-
-1',8'-dioxo-1',2',3',8'-tetrahydrospiro[cyclopropane-1,4'-pyrido[1,2-a]py-
razine]-7'-carboxamide
Step 1
##STR00190##
[1252] From compound 13-8 (34 mg) obtained in Example 13, step 8,
and by a method similar to that in Example 10, step 1, compound
14-1 was obtained. The obtained compound 14-1 was directly used in
the next step.
[1253] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.56-10.49 (m, 1H), 8.35
(s, 1H), 7.65-7.61 (m, 2H), 7.41-7.25 (m, 4H), 6.87-6.77 (m, 2H),
5.36 (d, 1H, J=9.9 Hz), 5.24 (d, 1H, J=9.9 Hz), 4.94-4.85 (m, 1H),
4.69-4.58 (m, 2H), 3.84 (d, 1H, J=13.6 Hz), 3.51-3.42 (m, 1H), 3.08
(s, 3H), 2.78 (dd, 1H, J=10.9, 8.6 Hz), 2.63 (d, 1H, J=13.6 Hz),
1.94-1.88 (m, 1H), 1.55-1.36 (m, 2H), 1.18 (d, 3H, J=6.7 Hz), 1.10
(d, 3H, J=6.9 Hz).
Step 2
##STR00191##
[1255] To compound 14-1 obtained in the above-mentioned step was
added TFA (1 mL), and the mixture was stirred for 1 hr. After
concentration, the residue was dissolved in ethyl acetate (300
.mu.L), 4N hydrochloric acid/ethyl acetate (100 .mu.L), and hexane
(1 mL) were added, and the mixture was concentrated. Saturated
aqueous sodium hydrogen carbonate solution was added, and the
mixture was extracted twice with chloroform, dried, concentrated
and crystallized from ethyl acetate:hexane to give the title
compound (17 mg).
[1256] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.58 (s, 1H),
10.40-10.30 (m, 1H), 8.18 (s, 1H), 7.47-7.35 (m, 1H), 7.29-7.18 (m,
1H), 7.12-6.99 (m, 1H), 4.80-4.67 (m, 1H), 4.53 (d, 2H, J=5.6 Hz),
4.05 (d, 1H, J=13.7 Hz), 3.45 (d, 1H, J=11.3 Hz), 3.21 (d, 1H,
J=13.7 Hz), 2.92 (s, 3H), 2.61-2.42 (m, 1H), 2.11-1.98 (m, 1H),
1.58-1.44 (m, 2H), 1.16 (d, 3H, J=6.4 Hz), 1.12 (d, 3H, J=6.9
Hz).
Example 15
Production of
(1S,2R)--N-(2,4-difluorobenzyl)-9'-hydroxy-2-(hydroxymethyl)-2'-isopropyl-
-1',8'-dioxo-1',2',3',8'-tetrahydrospiro[cyclopropane-1,4'-pyrido[1,2-a]py-
razine]-7'-carboxamide hydrochloride
Step 1
##STR00192##
[1258] To a suspension of sodium hydride (1.2 g) in DME (50 mL) was
added dropwise under water-cooling a solution of di-tert-butyl
malonate (3.1 mL) in DME (10 mL) and the mixture was stirred at
room temperature for 10 min. A solution of compound 11-3 (3.4 g)
obtained in the same manner as in Example 11, step 3, in DME (30
mL) was added, and the mixture was stirred at an outer temperature
of 85.degree. C. overnight (reaction 1). In reaction 1, DME (30 mL)
was added to the reaction mixture during the overnight stirring
mentioned above and the stirring was continued. In the same manner
as above, separately, to a suspension of sodium hydride (2.86 g) in
DME (120 mL) was added dropwise a solution of di-tert-butyl
malonate (7.7 mL) in DME (45 mL) under water-cooling, and the
mixture was stirred at room temperature for 10 min. A solution of
compound 11-3 (8.37 g) obtained in the same manner as in Example
11, step 3, in DME (40 mL) was added, and the mixture was stirred
at an outer temperature of 85.degree. C. overnight (reaction 2).
The reaction mixture of reaction 1 and that of reaction 2 were
combined (reaction mixture 3). To the reaction mixture 3 was added
water, and the mixture was extracted 3 times with ethyl acetate.
The organic layer was washed successively with saturated aqueous
sodium hydrogen carbonate solution and saturated brine, dried,
concentrated, and purified by silica gel column chromatography
(hexane:ethyl acetate=20:1 to 10:1) to give compound 15-1 (17.37
g).
[1259] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.36-7.25 (m, 5H), 4.53
(d, 1H, J=11.9 Hz), 4.48 (d, 1H, J=11.9 Hz), 3.54 (dd, 1H, J=10.6,
6.8 Hz), 3.41 (dd, 1H, J=10.6, 7.1 Hz), 2.19-2.10 (m, 1H), 1.46 (s,
9H), 1.44 (s, 9H), 1.37 (dd, 1H, J=7.3, 4.6 Hz), 1.27 (dd, 1H,
J=9.0, 4.6 Hz).
Step 2
##STR00193##
[1261] To a solution of compound 15-1 (3.3 g) obtained in the
above-mentioned step in THF (50 ml) were added potassium
tert-butoxide (2.04 g) and water (164 .mu.l) under ice-cooling, and
the mixture was stirred at room temperature overnight. To the
reaction mixture was added water, and the mixture was washed twice
with diisopropyl ether. The aqueous layer was acidified with a 5%
aqueous potassium hydrogen sulfate solution, and extracted 3 times
with ethyl acetate. The organic layer was washed with saturated
brine, dried, and concentrated to give a crude product of compound
15-2 (2.24 g). The obtained crude product of compound 15-2 was
directly used in the next step.
Step 3
##STR00194##
[1263] From the crude product of compound 15-2 obtained in the
above-mentioned step (2.24 g) and by a method similar to that in
Example 13, step 1, compound 15-3 (1.86 g) was obtained.
[1264] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37-7.24 (m, 5H), 4.54
(d, 1H, J=11.8 Hz), 4.50 (d, 1H, J=11.8 Hz), 3.70-3.54 (m, 2H),
3.67 (s, 3H), 3.24 (s, 3H), 2.30-2.14 (m, 1H), 1.53-1.47 (m, 1H),
1.45-1.22 (m, 1H), 1.40 (s, 9H).
Step 4
##STR00195##
[1266] To compound 15-3 (2.29 g) obtained in the above-mentioned
step was added TFA (40 mL), and the mixture was stirred for 30 min.
After concentration, the residue was azeotropically distilled 6
times with toluene to give a crude product of compound 15-4 (1.71
g). The obtained crude product of compound 15-4 was directly used
in the next step.
[1267] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.36-7.12 (m, 5H), 4.54
(d, 1H, J=11.8 Hz), 4.49 (d, 1H, J=11.8 Hz), 3.75 (dd, 1H, J=10.9,
6.2 Hz), 3.68 (s, 3H), 3.57 (dd, 1H, J=10.6, 8.3 Hz), 3.26 (s, 3H),
2.37-2.27 (m, 1H), 1.59 (dd, 1H, J=7.6, 4.9 Hz), 1.45 (dd, 1H,
J=9.2, 4.9 Hz).
Step 5
##STR00196##
[1269] From the crude product of compound 15-4 obtained in the
above-mentioned step (1.71 g) and by a method similar to that in
Example 13, step 3, compound 15-5 (1.5 g) was obtained.
[1270] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.39-7.24 (m, 5H),
5.52-5.30 (m, 1H), 4.64-4.52 (m, 1H), 4.52-4.41 (m, 1H), 3.85 (dd,
1H, J=10.9, 5.2 Hz), 3.65 (s, 3H), 3.38 (t, 1H, J=10.1 Hz), 3.17
(s, 3H), 1.96-1.86 (m, 1H), 1.81-1.70 (m, 1H), 1.43 (s, 9H),
1.02-0.85 (m, 1H).
Step 6
##STR00197##
[1272] From compound 15-5 (1.5 g) obtained in the above-mentioned
step and by a method similar to that in Example 13, step 4, a crude
product of compound 15-6 (1.05 g) was obtained. The obtained crude
product of compound 15-6 was directly used in the next step.
[1273] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.30 (s, 1H), 7.39-7.26
(m, 5H), 5.43-5.10 (m, 1H), 4.59-4.44 (m, 2H), 3.83 (dd, 1H,
J=10.9, 5.6 Hz), 3.38 (t, 1H, J=9.7 Hz), 2.04-1.92 (m, 1H),
1.82-1.68 (m, 1H), 1.45 (s, 9H), 1.31-1.21 (m, 1H).
Step 7
##STR00198##
[1275] From the crude product of compound 15-6 obtained in the
above-mentioned step (510 mg) and by a method similar to that in
Example 13, step 5, compound 15-7 (361 mg) was obtained.
[1276] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.39-7.25 (m, 5H),
5.43-5.24 (m, 1H), 4.56 (d, 1H, J=12.1 Hz), 4.49 (d, 1H, J=12.1
Hz), 3.67 (dd, 1H, J=10.5, 6.0 Hz), 3.43-3.30 (m, 1H), 2.98-2.81
(m, 2H), 2.75-2.27 (m, 1H), 1.43 (s, 9H), 1.36-0.99 (m, 2H), 1.08
(d, 6H, J=6.0 Hz), 0.84-0.70 (m, 1H).
Step 8
##STR00199##
[1278] From compound 15-7 (52 mg) obtained in the above-mentioned
step and by a method similar to that in Example 13, step 6, a crude
product of compound 15-8 was obtained. The obtained crude product
of compound 15-8 was directly used in the next step.
Step 9
##STR00200##
[1280] From the crude product of 15-8 obtained in the
above-mentioned step and by a method similar to that in Example 13,
step 7, a crude product of compound 15-9 (62 mg) was obtained. The
obtained crude product of compound 15-9 was directly used in the
next step.
[1281] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 9.39-9.04 (m, 1H),
8.92-8.72 (m, 2H), 3.75 (dd, 1H, J=12.1, 4.8 Hz), 3.64-3.56 (m,
1H), 3.38-3.22 (m, 3H), 1.64-1.54 (m, 1H), 1.33-1.21 (m, 7H), 1.03
(t, 1H, J=6.9 Hz).
Step 10
##STR00201##
[1283] From the crude product of compound 15-9 obtained in the
above-mentioned step (62 mg) and compound P9 (66 mg) obtained in
Example 9, Preliminary step 9-1, and by a method similar to that in
Example 13, step 8, compound 15-10 (42 mg) was obtained.
[1284] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.56 (t, 1H, J=85.8 Hz),
8.29 (s, 1H), 7.59-7.53 (m, 2H), 7.41-7.24 (m, 4H), 6.86-6.76 (m,
2H), 5.35 (d, 1H, J=10.1 Hz), 5.22 (d, 1H, J=10.1 Hz), 4.89-4.76
(m, 1H), 4.61 (d, 2H, J=6.0 Hz), 3.77 (d, 1H, J=13.7 Hz), 3.69 (dd,
1H, J=12.1, 4.8 Hz), 3.09 (dd, 1H, J=12.1, 8.5 Hz), 2.60 (d, 1H,
J=13.7 Hz), 1.94-1.87 (m, 1H), 1.49-1.38 (m, 1H), 1.37-1.29 (m,
1H), 1.15 (d, 3H, J=6.9 Hz), 1.08 (d, 3H, J=6.9 Hz).
Step 11
##STR00202##
[1286] From compound 15-10 (10 mg) obtained in the above-mentioned
step and by a method similar to that in Example 9, step 13, the
title compound (6 mg) was obtained.
[1287] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.61 (s, 1H),
10.43-10.36 (m, 1H), 8.15 (s, 1H), 7.45-7.35 (m, 1H), 7.27-7.20 (m,
1H), 7.10-7.02 (m, 1H), 4.79-4.69 (m, 1H), 4.57-4.49 (m, 2H), 4.04
(d, 1H, J=13.6 Hz), 3.55-3.48 (m, 1H), 3.18 (d, 1H, J=13.6 Hz),
2.69-2.51 (m, 1H), 1.95-1.90 (m, 1H), 1.44-1.37 (m, 2H), 1.18 (d,
3H, J=6.7 Hz), 1.12 (d, 3H, J=6.7 Hz).
Example 16
Production of
(1S,2R)--N-(2,4-difluorobenzyl)-9'-hydroxy-2'-isopropyl-2-(methoxymethyl)-
-1',8'-dioxo-1',2',3',8'-tetrahydrospiro[cyclopropane-1,4'-pyrido[1,2-a]py-
razine]-7'-carboxamide
Step 1
##STR00203##
[1289] From compound 15-10 (30 mg) obtained in Example 15, step 10,
and by a method similar to that in Example 10, step 1, compound
16-1 (22 mg) was obtained.
[1290] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.56-10.49 (m, 1H), 8.35
(s, 1H), 7.65-7.61 (m, 2H), 7.41-7.25 (m, 4H), 6.87-6.77 (m, 2H),
5.36 (d, 1H, J=9.9 Hz), 5.24 (d, 1H, J=9.9 Hz), 4.94-4.85 (m, 1H),
4.69-4.58 (m, 2H), 3.84 (d, 1H, J=13.6 Hz), 3.51-3.42 (m, 1H), 3.08
(s, 3H), 2.78 (dd, 1H, J=10.9, 8.6 Hz), 2.63 (d, 1H, J=13.6 Hz),
1.94-1.88 (m, 1H), 1.55-1.36 (m, 2H), 1.18 (d, 3H, J=6.7 Hz), 1.10
(d, 3H, J=6.9 Hz).
Step 2
##STR00204##
[1292] From compound 16-1 (22 mg) obtained in the above-mentioned
step and by a method similar to that in Example 14, step 2, the
title compound (9 mg) was obtained.
[1293] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.58 (s, 1H), 10.36 (t,
1H, J=5.8 Hz), 8.18 (s, 1H), 7.45-7.37 (m, 1H), 7.27-7.20 (m, 1H),
7.10-7.03 (m, 1H), 4.78-4.69 (m, 1H), 4.53 (d, 2H, J=5.8 Hz), 4.05
(d, 1H, J=13.6 Hz), 3.45 (dd, 1H, J=11.1, 3.7 Hz), 3.21 (d, 1H,
J=13.6 Hz), 2.92 (s, 3H), 2.61-2.42 (m, 1H), 2.07-2.01 (m, 1H),
1.55-1.45 (m, 2H), 1.16 (d, 3H, J=6.7 Hz), 1.12 (d, 3H, J=6.9
Hz).
Example 17
Production of
(1S,2S)--N-(3-chloro-2-fluorobenzyl)-2'-ethyl-9'-hydroxy-2-(methoxymethyl-
)-1',8'-dioxo-1',2',4',8'-tetrahydrospiro[cyclopropane-1,3'-pyrido[1,2-a]p-
yrazine]-7'-carboxamide
Step 1
##STR00205##
[1295] To a solution of compound 9-7 (800 mg) obtained in the same
manner as in Example 9, step 7, in THF (20 mL) were added
triphenylphosphine (2.8 g), phthalimide (2 g) and DIAD (2.1 mL),
and the mixture was stirred at room temperature overnight. After
concentration, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=5:1 to 2:1) to give compound
17-1. The obtained compound 17-1 was directly used in the next
step.
[1296] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.89-7.79 (m, 2H),
7.78-7.65 (m, 2H), 7.37-7.25 (m, 5H), 4.56 (d, 1H, J=11.7 Hz), 4.52
(d, 1H, J=11.7 Hz), 4.25 (d, 1H, J=14.6 Hz), 3.85-3.71 (m, 1H),
3.67-3.48 (m, 2H), 1.60-1.05 (m, 12H).
Step 2
##STR00206##
[1298] To compound 17-1 obtained in the above-mentioned step was
added TFA (15 mL), and the mixture was stirred at room temperature
for 1 hr. After concentration, saturated aqueous sodium hydrogen
carbonate solution was added, and the mixture was extracted 3 times
with chloroform and washed with saturated brine. The mixture was
dried, concentrated, and purified by silica gel column
chromatography (ethyl acetate to chloroform:methanol=10:1) to give
compound 17-2 (659 mg).
[1299] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.88-7.82 (m, 2H),
7.75-7.69 (m, 2H), 7.35-7.24 (m, 5H), 4.55 (d, 1H, J=12.1 Hz), 4.51
(d, 1H, J=12.1 Hz), 4.14-4.07 (m, 1H), 3.83 (dd, 1H, J=10.7, 6.0
Hz), 3.65 (d, 1H, J=14.4 Hz), 3.39 (dd, 1H, J=10.7, 9.8 Hz),
1.48-1.39 (m, 1H), 0.86-0.80 (m, 1H), 0.72 (dd, 1H, J=6.0, 5.1
Hz).
Step 3
##STR00207##
[1301] To a solution of compound 17-2 (305 mg) obtained in the
above-mentioned step in chloroform (10 mL) were added acetaldehyde
(51 .mu.L) and acetic acid (52 .mu.L) under ice-cooling, and the
mixture was stirred at room temperature for 1 hr. The mixture was
ice-cooled again, sodium triacetoxyborohydride (250 mg) was added,
and the mixture was stirred at room temperature overnight. To the
reaction mixture was added saturated aqueous sodium hydrogen
carbonate solution, and the mixture was extracted with chloroform,
washed with saturated brine, dried, concentrated and purified by
silica gel column chromatography (chloroform:ethyl acetate=10:1 to
ethyl acetate) to give compound 17-3 (127 mg).
[1302] Separately, this step was similarly performed with compound
17-2 (396 mg) to give compound 17-3 (106 mg).
[1303] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.87-7.81 (m, 2H),
7.74-7.68 (m, 2H), 7.36-7.22 (m, 5H), 4.58 (d, 1H, J=11.9 Hz), 4.50
(d, 1H, J=11.9 Hz), 4.30 (dd, 1H, J=14.7, 1.4 Hz), 3.84 (dd, 1H,
J=10.7, 6.0 Hz), 3.49 (d, 1H, J=14.7 Hz), 3.40-3.33 (m, 1H),
3.11-3.01 (m, 1H), 2.77-2.65 (m, 1H), 1.47-1.37 (m, 1H), 1.08 (t,
3H, J=7.2 Hz), 0.86-0.80 (m, 1H), 0.79-0.73 (m, 1H).
Step 4
##STR00208##
[1305] To a solution of compound 17-3 (233 mg) obtained in the
above-mentioned step in ethanol (10 mL) was added hydrazine
monohydrate (124 .mu.L), and the mixture was stirred at 100.degree.
C. for 1 hr. After concentration, toluene (10 mL) was added, the
insoluble material was filtered off and the filtrate was
concentrated. This operation was performed twice to give a crude
product of compound 17-4 (136 mg). The obtained crude product of
compound 17-4 was directly used in the next step.
[1306] .sup.1H-NMR (CDC.sub.3) .delta.: 7.38-7.25 (m, 5H), 4.55 (d,
1H, J=11.9 Hz), 4.48 (d, 1H, J=11.9 Hz), 3.73 (dd, 1H, J=10.6, 5.7
Hz), 3.14 (t, 1H, J=10.6 Hz), 2.95 (d, 1H, J=13.7 Hz), 2.79-2.69
(m, 1H), 2.63-2.53 (m, 1H), 2.49 (d, 1H, J=13.7 Hz), 1.36-1.22 (m,
1H), 1.07 (t, 3H, J=7.1 Hz), 0.83 (dd, 1H, J=9.5, 5.1 Hz), 0.24 (t,
1H, J=5.1 Hz).
Step 5
##STR00209##
[1308] To a suspension of palladium-platinum/carbon (ASCA2,
manufactured by N.E. CHEMCAT Corporation, 200 mg) in acetic acid (4
mL) was added a solution of compound 17-4 (136 mg) obtained in the
above-mentioned step in ethanol (5 mL), and the mixture was stirred
under a hydrogen atmosphere at room temperature overnight. The
insoluble material was filtered off, the filtrate was concentrated,
dissolved in methanol (5 mL), 4N hydrochloric acid/ethyl acetate (5
mL) was added, and the mixture was concentrated again to give a
crude product of compound 17-5 (152 mg). The obtained crude product
of compound 17-5 was directly used in the next step.
Step 6
##STR00210##
[1310] From the crude product of compound 17-5 obtained in the
above-mentioned step (70 mg) and compound P1 (114 mg) obtained in
Example 1, Preliminary step 1-1, and by a method similar to that in
Example 13, step 8, compound 17-6 (100 mg) was obtained.
[1311] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.68-10.60 (m, 1H), 8.29
(s, 1H), 7.60-7.55 (m, 2H), 7.37-7.24 (m, 5H), 7.04 (t, 1H, J=7.9
Hz), 5.42 (d, 1H, J=10.4 Hz), 5.30 (d, 1H, J=10.4 Hz), 4.70 (d, 2H,
J=6.0 Hz), 4.24 (d, 1H, J=12.9 Hz), 4.18-4.09 (m, 1H), 3.82-3.72
(m, 1H), 3.66-3.54 (m, 1H), 3.51-3.38 (m, 1H), 3.37-3.23 (m, 1H),
1.94-1.74 (m, 1H), 1.44-1.21 (m, 2H), 1.17 (t, 3H, J=7.2 Hz), 1.04
(t, 1H, J=6.9 Hz).
Step 7
##STR00211##
[1313] From compound 17-6 (50 mg) obtained in the above-mentioned
step and by a method similar to that in Example 10, step 1,
compound 17-7 (40 mg) was obtained.
[1314] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.60 (t, 1H, J=6.0 Hz),
8.29 (s, 1H), 7.61-7.56 (m, 2H), 7.36-7.25 (m, 5H), 7.07-6.99 (m,
1H), 5.39 (d, 1H, J=10.1 Hz), 5.31 (d, 1H, J=10.1 Hz), 4.79-4.64
(m, 2H), 4.19-4.05 (m, 2H), 3.60-3.44 (m, 2H), 3.41-3.28 (m, 1H),
3.21 (s, 3H), 3.16 (dd, 1H, J=10.6, 7.3 Hz), 1.60-1.45 (m, 1H),
1.30-1.23 (m, 1H), 1.19-1.13 (m, 3H), 0.99 (t, 1H, J=7.1 Hz).
Step 8
##STR00212##
[1316] From compound 17-6 (40 mg) obtained in the above-mentioned
step and by a method similar to that in Example 14, step 2, the
title compound (6 mg) was obtained.
[1317] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 11.97 (s, 1H), 10.49 (t,
1H, J=6.0 Hz), 8.41 (s, 1H), 7.52-7.47 (m, 1H), 7.35-7.29 (m, 1H),
7.20 (t, 1H, J=7.9 Hz), 4.65-4.58 (m, 2H), 4.49 (d, 1H, J=13.6 Hz),
4.41 (d, 1H, J=13.6 Hz), 3.63 (dd, 1H, J=10.9, 6.0 Hz), 3.52-3.40
(m, 1H), 3.39-3.21 (m, 2H), 3.13 (s, 3H), 1.85-1.74 (m, 1H), 1.44
(dd, 1H, J=10.2, 6.7 Hz), 1.08 (t, 3H, J=7.2 Hz), 0.98 (t, 1H,
J=7.2 Hz).
Example 18
Production of
(1R,2R)--N-(3-chloro-2-fluorobenzyl)-2'-ethyl-9'-hydroxy-2-(methoxymethyl-
)-1',8'-dioxo-1',2',4',8'-tetrahydrospiro[cyclopropane-1,3'-pyrido[1,2-a]p-
yrazine]-7'-carboxamide
Step 1
##STR00213##
[1319] To a solution of compound 11-6 (1.09 g) obtained in the same
manner as in Example 11, step 6, in DMF (20 mL) was added sodium
hydride (162 mg) under ice-cooling, and the mixture was stirred at
room temperature for 30 min. Ethyl iodide (39 .mu.L) was added, and
the mixture was stirred at room temperature overnight. To the
reaction mixture was added water, and the mixture was extracted 3
times with ethyl acetate. The organic layer was washed successively
with saturated aqueous sodium hydrogen carbonate solution (twice)
and saturated brine (twice), dried, concentrated, and purified by
silica gel column chromatography (hexane:ethyl acetate=20:1 to
10:1) to give compound 18-1 (399 mg).
[1320] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.37-7.25 (m, 5H),
4.60-4.40 (m, 2H), 4.21-4.03 (m, 2H), 3.93-3.10 (m, 4H), 2.03-1.85
(m, 1H), 1.80-1.01 (m, 17H).
Step 2
##STR00214##
[1322] From compound 18-1 (399 mg) obtained in the above-mentioned
step and by a method similar to that in Example 9, step 7, compound
18-2 (304 mg) was obtained.
[1323] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.39-7.24 (m, 5H), 4.59
(d, 1H, J=12.0 Hz), 4.53 (d, 1H, J=12.0 Hz), 3.99-3.66 (m, 3H),
3.50-3.20 (m, 3H), 1.75-0.65 (m, 6H), 1.45-1.45 (m, 9H).
Step 3
##STR00215##
[1325] From compound 18-2 (304 mg) obtained in the above-mentioned
step and by a method similar to that in Example 17, step 1,
compound 18-3 (243 mg) was obtained.
[1326] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.88-7.76 (m, 2H),
7.75-7.60 (m, 2H), 7.40-7.25 (m, 5H), 4.65-4.50 (m, 2H), 4.37-2.76
(m, 6H), 1.68-0.90 (m, 15H).
Step 4
##STR00216##
[1328] From compound 18-3 (243 mg) obtained in the above-mentioned
step and by a method similar to that in Example 17, step 2, a crude
product of compound 18-4 (219 mg) was obtained. The obtained crude
product of compound 18-4 was directly used in the next step.
[1329] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.87-7.81 (m, 2H),
7.74-7.68 (m, 2H), 7.36-7.22 (m, 5H), 4.58 (d, 1H, J=11.9 Hz), 4.50
(d, 1H, J=11.9 Hz), 4.30 (dd, 1H, J=14.7, 1.4 Hz), 3.84 (dd, 1H,
J=10.7, 6.0 Hz), 3.49 (d, 1H, J=14.7 Hz), 3.40-3.33 (m, 1H),
3.11-3.01 (m, 1H), 2.77-2.65 (m, 1H), 1.47-1.37 (m, 1H), 1.08 (t,
3H, J=7.2 Hz), 0.86-0.80 (m, 1H), 0.79-0.73 (m, 1H).
Step 5
##STR00217##
[1331] From compound 18-4 (219 mg) obtained in the above-mentioned
step and by a method similar to that in Example 17, step 4, a crude
product of compound 18-5 (96 mg) was obtained. The obtained crude
product of compound 18-5 was directly used in the next step.
[1332] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.38-7.25 (m, 5H), 4.55
(d, 1H, J=11.9 Hz), 4.48 (d, 1H, J=11.9 Hz), 3.73 (dd, 1H, J=10.6,
5.7 Hz), 3.14 (t, 1H, J=10.6 Hz), 2.95 (d, 1H, J=13.7 Hz),
2.79-2.69 (m, 1H), 2.63-2.53 (m, 1H), 2.49 (d, 1H, J=13.7 Hz),
1.36-1.22 (m, 1H), 1.07 (t, 3H, J=7.1 Hz), 0.83 (dd, 1H, J=9.5, 5.1
Hz), 0.24 (t, 1H, J=5.1 Hz).
Step 6
##STR00218##
[1334] From compound 18-5 (96 mg) obtained in the above-mentioned
step and by a method similar to that in Example 17, step 5, a crude
product of compound 18-6 (97 mg) was obtained. The obtained crude
product of compound 18-6 was directly used in the next step.
Step 7
##STR00219##
[1336] From compound 18-6 (97 mg) obtained in the above-mentioned
step and compound P1 (120 mg) obtained in Example 1, Preliminary
step 1-1, and by a method similar to that in Example 17, step 6,
compound 18-7 (100 mg) was obtained.
[1337] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.68-10.60 (m, 1H), 8.29
(s, 1H), 7.60-7.55 (m, 2H), 7.37-7.24 (m, 5H), 7.04 (t, 1H, J=7.9
Hz), 5.42 (d, 1H, J=10.4 Hz), 5.30 (d, 1H, J=10.4 Hz), 4.70 (d, 2H,
J=6.0 Hz), 4.24 (d, 1H, J=12.9 Hz), 4.18-4.09 (m, 1H), 3.82-3.72
(m, 1H), 3.66-3.54 (m, 1H), 3.51-3.38 (m, 1H), 3.37-3.23 (m, 1H),
1.94-1.74 (m, 1H), 1.44-1.21 (m, 2H), 1.17 (t, 3H, J=7.2 Hz), 1.04
(t, 1H, J=6.9 Hz).
Step 8
##STR00220##
[1339] From compound 18-7 (65 mg) obtained in the above-mentioned
step and by a method similar to that in Example 10, step 1,
compound 18-8 (44 mg) was obtained.
[1340] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.60 (t, 1H, J=6.0 Hz),
8.29 (s, 1H), 7.61-7.56 (m, 2H), 7.36-7.25 (m, 5H), 7.07-6.99 (m,
1H), 5.39 (d, 1H, J=10.1 Hz), 5.31 (d, 1H, J=10.1 Hz), 4.79-4.64
(m, 2H), 4.19-4.05 (m, 2H), 3.60-3.44 (m, 2H), 3.41-3.28 (m, 1H),
3.21 (s, 3H), 3.16 (dd, 1H, J=10.6, 7.3 Hz), 1.60-1.45 (m, 1H),
1.30-1.23 (m, 1H), 1.19-1.13 (m, 3H), 0.99 (t, 1H, J=7.1 Hz).
Step 9
##STR00221##
[1342] From compound 18-8 (44 mg) obtained in the above-mentioned
step and by a method similar to that in Example 14, step 2, the
title compound (20 mg) was obtained.
[1343] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 11.97 (s, 1H), 10.49 (t,
1H, J=6.0 Hz), 8.41 (s, 1H), 7.52-7.47 (m, 1H), 7.35-7.29 (m, 1H),
7.20 (t, 1H, J=7.9 Hz), 4.65-4.58 (m, 2H), 4.49 (d, 1H, J=13.6 Hz),
4.41 (d, 1H, J=13.6 Hz), 3.63 (dd, 1H, J=10.9, 6.0 Hz), 3.52-3.40
(m, 1H), 3.39-3.21 (m, 2H), 3.13 (s, 3H), 1.85-1.74 (m, 1H), 1.44
(dd, 1H, J=10.2, 6.7 Hz), 1.08 (t, 3H, J=7.2 Hz), 0.98 (t, 1H,
J=7.2 Hz).
Example 19
Production of
(1S,2S)--N.sup.7'-(2,4-difluorobenzyl)-2'-ethyl-9'-hydroxy-N.sup.2,N.sup.-
2-dimethyl-1',8'-dioxo-1',2',3',8'-tetrahydrospiro[cyclopropane-1,4'-pyrid-
o[1,2-a]pyrazine]-2,7'-dicarboxamide hydrochloride
Step 1
##STR00222##
[1345] From compound 9-8 (812 mg) obtained in the same manner as in
Example 9, step 8, and by a method similar to that in Example 9,
step 9, compound 19-1 (808 mg) was obtained.
[1346] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.39-7.26 (m, 5H),
5.87-5.54 (m, 1H), 4.60 (d, 1H, J=11.6 Hz), 4.48 (d, 1H, J=11.6
Hz), 3.82-3.64 (m, 1H), 3.29 (t, 1H, J=10.2 Hz), 3.20-3.01 (m, 1H),
2.77-2.53 (m, 3H), 1.54-1.43 (m, 1H), 1.42 (s, 9H), 1.22-1.07 (m,
1H), 1.04 (t, 3H, J=7.2 Hz), 0.74-0.65 (m, 1H).
Step 2
##STR00223##
[1348] To compound 19-1 (808 mg) obtained in the above-mentioned
step was added TFA (20 mL), and the mixture was stirred for 1 hr,
and concentrated to give a crude product of compound 19-2. The
obtained crude product of compound 19-2 was directly used in the
next step.
[1349] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.81-8.18 (m, 3H),
7.40-7.27 (m, 5H), 4.53 (d, 1H, J=11.7 Hz), 4.47 (d, 1H, J=11.7
Hz), 3.78 (dd, 1H, J=11.0, 5.7 Hz), 3.49 (d, 1H, J=14.6 Hz), 3.32
(dd, 1H, J=11.0, 9.3 Hz), 3.18-3.09 (m, 1H), 3.08-2.94 (m, 2H),
1.80-1.70 (m, 1H), 1.27 (dd, 1H, J=9.9, 6.6 Hz), 1.17 (t, 3H, J=7.1
Hz), 1.11 (t, 1H, J=6.8 Hz).
Step 3
##STR00224##
[1351] From the crude product of compound 19-2 obtained in the
above-mentioned step and by a method similar to that in Example 13,
step 7, a crude product of compound 19-3 (447 mg) was obtained. The
obtained crude product of compound 19-3 was directly used in the
next step.
Step 4
##STR00225##
[1353] From the crude product of compound 19-3 obtained in the
above-mentioned step (290 mg) and compound P9 (503 mg) obtained in
Example 9, Preliminary step 9-1, and by a method similar to that in
Example 9, step 12, compound 19-4 (356 mg) was obtained.
[1354] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.51 (t, 1H, J=5.7 Hz),
8.32 (s, 1H), 7.62-7.57 (m, 2H), 7.40-7.25 (m, 4H), 6.86-6.76 (m,
2H), 5.34-5.24 (m, 2H), 4.62 (d, 2H, J=6.2 Hz), 4.08-4.00 (m, 1H),
3.92-3.81 (m, 1H), 3.76-3.55 (m, 3H), 3.37-3.26 (m, 1H), 2.00-1.90
(m, 2H), 1.72 (dd, 1H, J=10.4, 7.5 Hz), 1.27-1.15 (m, 4H).
Step 5
##STR00226##
[1356] To a solution of compound 19-4 (156 mg) obtained in the
above-mentioned step in chloroform (10 mL) was added Dess-Martin
reagent (180 mg) under ice-cooling, and the mixture was stirred at
room temperature for 1 hr. An aqueous sodium sulfite solution and
saturated aqueous sodium hydrogen carbonate solution were added,
and the mixture was stirred for 1 hr. After partitioning, the
organic layer was washed with saturated brine, and dried. After
concentration, the residue was purified by silica gel column
chromatography (ethyl acetate) to give compound 19-5 (156 mg).
[1357] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.38 (t, 1H, J=6.0 Hz),
9.97 (s, 1H), 8.28 (s, 1H), 7.60-7.56 (m, 2H), 7.42-7.27 (m, 4H),
6.86-6.78 (m, 2H), 5.40 (d, 1H, J=10.2 Hz), 5.23 (d, 1H, J=10.2
Hz), 4.63 (d, 2H, J=6.0 Hz), 3.85 (d, 1H, J=14.1 Hz), 3.80-3.69 (m,
1H), 3.50 (d, 1H, J=14.1 Hz), 3.16-3.05 (m, 1H), 2.57 (t, 1H, J=8.6
Hz), 2.43 (t, 1H, J=8.6 Hz), 2.07 (t, 1H, J=7.6 Hz), 1.11 (t, 3H,
J=7.2 Hz).
Step 6
##STR00227##
[1359] To a solution of compound 19-5 (156 mg) obtained in the
above-mentioned step in acetone (6 mL) were successively added
water (2 mL), sodium dihydrogen phosphate (35 mg), 2-methylpropene
(135 .mu.L) and sodium chlorite (111 mg), and the mixture was
stirred at room temperature for 1 hr. An aqueous sodium sulfite
solution was added, and the mixture was stirred for 30 min and
acidified with 5% aqueous potassium hydrogen sulfate solution. The
precipitated crystals were collected by filtration and dried to
give compound 19-6 (117 mg).
[1360] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 13.02 (br s, 1H), 10.37
(t, 1H, J=5.8 Hz), 8.22 (s, 1H), 7.56-7.52 (m, 2H), 7.46-7.29 (m,
4H), 7.27-7.19 (m, 1H), 7.10-7.03 (m, 1H), 5.16 (d, 1H, J=10.4 Hz),
5.06 (d, 1H, J=10.4 Hz), 4.57-4.52 (m, 2H), 4.10 (d, 1H, J=14.1
Hz), 3.61-3.52 (m, 2H), 3.24-3.15 (m, 1H), 2.56-2.30 (m, 2H),
1.73-1.67 (m, 1H), 1.07 (t, 3H, J=7.2 Hz).
Step 7
##STR00228##
[1362] To a solution of compound 19-6 (50 mg) obtained in the
above-mentioned step in acetonitrile (4 mL) were successively added
dimethylamine hydrochloride (30 mg), diisopropylethylamine (162
.mu.L) and HATU (503 mg), and the mixture was stirred at room
temperature for 1 hr. The mixture was concentrated, diluted with
ethyl acetate, washed successively with saturated aqueous sodium
hydrogen carbonate solution and saturated brine and dried. After
concentration, the residue was purified by silica gel column
chromatography (ethyl acetate:methanol=50:1 to 10:1) to give
compound 19-7 (46 mg).
[1363] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.42 (t, 1H, J=6.0 Hz),
8.31 (s, 1H), 7.58-7.53 (m, 2H), 7.41-7.26 (m, 4H), 6.87-6.77 (m,
2H), 5.40 (d, 1H, J=10.4 Hz), 5.28 (d, 1H, J=10.4 Hz), 4.69-4.57
(m, 2H), 3.82 (d, 1H, J=13.9 Hz), 3.70-3.59 (m, 1H), 3.51 (d, 1H,
J=13.9 Hz), 3.25-3.15 (m, 1H), 3.03 (s, 3H), 2.99 (s, 3H),
2.29-2.18 (m, 2H), 2.07-2.02 (m, 1H), 1.09 (t, 3H, J=7.4 Hz).
Step 8
##STR00229##
[1365] From compound 19-7 (46 mg) obtained in the above-mentioned
step and by a method similar to that in Example 10, step 2, the
title compound (25 mg) was obtained.
[1366] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.59 (s, 1H), 10.33 (t,
1H, J=5.8 Hz), 8.13 (s, 1H), 7.42-7.35 (m, 1H), 7.25-7.18 (m, 1H),
7.08-7.01 (m, 1H), 4.56 (dd, 1H, J=14.8, 6.2 Hz), 4.47 (dd, 1H,
J=14.8, 5.5 Hz), 4.13 (d, 1H, J=13.6 Hz), 3.54-3.43 (m, 1H),
3.36-3.18 (m, 2H), 2.93 (s, 3H), 2.83 (s, 3H), 2.73-2.64 (m, 1H),
2.43-2.35 (m, 1H), 1.71 (t, 1H, J=7.9 Hz), 0.98 (t, 3H, J=7.2
Hz).
Example 20
Production of
N-(2,4-difluorobenzyl)-9'-hydroxy-2'-isopropyl-3-(N-methylacetamido)-1',8-
'-dioxo-1',2',3',8'-tetrahydrospiro[cyclobutane-1,4'-pyrido[1,2-a]pyrazine-
]-7'-carboxamide hydrochloride
Step 1
##STR00230##
[1368] From compound 1-3 (399 mg) obtained in Example 1, step 3,
and in the same manner as in Example 1, step 4, residue 20-1 was
obtained.
[1369] To a solution of the residue 20-1 in chloroform (4 mL) were
successively added isopropylamine (228 .mu.L), acetic acid (228
.mu.L) and triacetoxyborohydride (860 mg), and the mixture was
stirred at room temperature for 7 min. Isopropylamine (110 .mu.L)
was added, and the mixture was stirred at room temperature for 3
hr. To the reaction mixture was added saturated aqueous sodium
hydrogen carbonate solution, and the mixture was extracted 3 times
with chloroform. The organic layer was dried over magnesium sulfate
and concentrated. Toluene was added and the mixture was
concentrated again, and dried under reduced pressure to give a
crude product of compound 20-1. The obtained crude product of
compound 20-1 was directly used in the next step.
Step 2
##STR00231##
[1371] To the crude product of compound 20-1 obtained in the
above-mentioned step was added a 48% aqueous hydrogen bromide
solution (15 mL), and the mixture was stirred at room temperature
for 10 min, and at 80.degree. C. for 17.5 hr. An operation
including adding ethanol to the reaction mixture, concentrating the
mixture, adding ethanol and concentrating the mixture, an operation
including adding toluene and concentrating the mixture, and an
operation including adding ethanol and concentrating the mixture
were performed successively. The mixture was dried under reduced
pressure to give a crude product of compound 20-2. The obtained
crude product of compound 20-2 was directly used in the next
step.
Step 3
##STR00232##
[1373] To a mixed solution of the crude product of compound 20-2
obtained in the above-mentioned step in THF-ethanol (8 mL-4 mL)
were added triethylamine (4 mL) and compound P9 (525 mg) obtained
in Preliminary step 9-1. After stirring at room temperature for 30
min, the mixture was concentrated, dried under reduced pressure,
toluene (30 mL) and DBU (3 mL) were added and the mixture was
stirred at 80.degree. C. for 30 min. To the reaction mixture were
added acetic acid (6 mL) and ethanol (5 mL), and the mixture was
stirred at 100.degree. C. for 50 min and stood at room temperature
overnight. To the reaction mixture were added toluene and a 10%
aqueous potassium hydrogen sulfate solution, and the mixture was
extracted with toluene to give an organic layer 20-3-1 and an
aqueous layer 20-3-1. The aqueous layer 20-3-1 was extracted twice
with chloroform to give an organic layer 20-3-2.
[1374] The organic layer 20-3-1 and the organic layer 20-3-2 were
combined, washed with saturated brine to give an organic layer
20-3-3 and an aqueous layer 20-3-2. The organic layer 20-3-3 was
washed twice with a saturated aqueous sodium hydrogen carbonate
solution to give an organic layer 20-3-4 and an aqueous layer
20-3-3. The aqueous layer 20-3-3 was extracted twice with
chloroform to give an organic layer 20-3-5. The organic layer
20-3-4 and the organic layer 20-3-5 were combined, and the mixture
was dried over magnesium sulfate, concentrated and purified by
silica gel column chromatography (chloroform:acetone=4:1 to 2:3) to
give compound 20-3 (457 mg).
[1375] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.58-10.52 (m, 1.0H),
8.80 (s, 0.5H), 8.66 (s, 0.5H), 7.63-7.60 (m, 2.0H), 7.41-7.27 (m,
4.0H), 6.85-6.79 (m, 2.0H), 5.30 (s, 2.0H), 4.97-4.90 (m, 1.0H),
4.77-4.69 (m, 0.5H), 4.66-4.64 (m, 2.0H), 4.34-4.25 (m, 0.5H), 3.66
(s, 1.0H), 3.28 (s, 1.0H), 2.96-2.85 (m, 1.0H), 2.75-2.69 (m,
1.5H), 2.65-2.59 (m, 1.0H), 2.34-2.28 (m, 1.0H), 2.24-2.22 (m,
0.5H), 1.22 (d, 3.0H, J=6.9 Hz), 1.19 (d, 3.0H, J=6.9 Hz).
Step 4
##STR00233##
[1377] To a solution of compound 20-3 (60 mg) obtained in the
above-mentioned step in chloroform (1.8 mL) was added Dess-Martin
reagent (96 mg), and the mixture was stirred at room temperature
for 40 min. Chloroform (1 mL) and Dess-Martin reagent (47 mg) were
added, and the mixture was stirred at room temperature for 1 hr. To
the reaction mixture were added a saturated aqueous sodium hydrogen
carbonate solution and sodium sulfite, and the mixture was
extracted twice with ethyl acetate. The organic layer was washed
with saturated brine, dried over magnesium sulfate, concentrated
and dried under reduced pressure to give residue 20-4-1.
[1378] To a solution of compound 20-3 (180 mg) obtained in the
above-mentioned step in chloroform (5 mL) was added Dess-Martin
reagent (444 mg), and the mixture was stirred at room temperature
for 1 hr. To the reaction mixture were added a saturated aqueous
sodium hydrogen carbonate solution and sodium sulfite, and the
mixture was extracted twice with ethyl acetate. The organic layer
was washed with saturated brine, dried over magnesium sulfate and
concentrated to give residue 20-4-2.
[1379] The residue 20-4-1 (19 mg was removed from the total amount)
and the residue 20-4-2 were combined and the mixture was dissolved
in chloroform and concentrated. Hexane was added, and the mixture
was concentrated, and dried under reduced pressure to give compound
20-4 (235 mg).
[1380] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.43 (t, 1H, J=6.0 Hz),
8.74 (s, 1H), 7.63-7.60 (m, 2H), 7.40-7.29 (m, 4H), 6.86-6.78 (m,
2H), 5.32 (s, 2H), 4.97 (sep, 1H, J=6.7 Hz), 4.64 (d, 2H, J=6.0
Hz), 3.81-3.75 (m, 2H), 3.54 (s, 2H), 3.32-3.27 (m, 2H), 1.21 (d,
6H, J=6.7 Hz).
Step 5
##STR00234##
[1382] From compound 20-4 (103 mg) obtained in the above-mentioned
step, and by an operation similar to that in Example 1, step 5, a
crude product of compound 20-5 (97 mg) was obtained. The obtained
crude product of compound 20-5 was directly used in the next
step.
Step 6
##STR00235##
[1384] To a solution of compound 20-5 (43 mg) obtained in the
above-mentioned step in deuterated chloroform (600 .mu.L) were
added 4-dimethylaminopyridine (14.3 mg), triethylamine (60 .mu.L)
and acetic anhydride (25 .mu.L), and the mixture was stirred at
room temperature for 1.5 hr. To the reaction mixture was added a
10% aqueous potassium hydrogen sulfate solution, and the mixture
was extracted 3 times with chloroform. The organic layer was washed
with saturated brine, dried over magnesium sulfate, concentrated,
and purified by silica gel thin layer chromatography (ethyl
acetate:methanol=12:1) to give compound 20-6 (36 mg).
Step 7
##STR00236##
[1386] To compound 20-6 (36 mg) obtained in the above-mentioned
step was added TFA (1 mL), and the mixture was stood at room
temperature for 20 min. The reaction mixture was concentrated,
ethyl acetate was added and the mixture was concentrated to give
residue 20-7.
[1387] To the residue 20-7 were successively added ethyl acetate
(400 .mu.L), 4N hydrochloric acid/ethyl acetate (100 .mu.L), and
ethyl acetate (4.5 mL), and the mixture was stirred at room
temperature for 10 min. Ethyl acetate (5 mL) was added and the
mixture was further stirred at room temperature for 10 min. The
precipitated solid was collected by filtration, and dried under
reduced pressure to give the title compound (4.5 mg).
[1388] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 10.43-10.39 (br m, 1H),
8.56-8.53 (m, 1H), 7.46-7.38 (m, 1H), 7.27-7.21 (m, 1H), 7.09-7.04
(m, 1H), 4.81-4.63 (m, 1H), 4.55 (d, 2H, J=5.3 Hz), 3.83-3.76 (m,
2H), 2.98-2.92 (m, 2H), 2.87-2.79 (m, 3H), 2.67-2.60 (m, 1H),
2.50-2.45 (m, 2H), 2.08-1.99 (m, 3H), 1.25-1.19 (m, 6H).
Example 21
Production of
(1R,2R)--N-(3-chloro-2-fluorobenzyl)-9'-hydroxy-2'-isopropyl-2-(methylsul-
fonylmethyl)-1',8'-dioxo-1',2',3',8'-tetrahydrospiro[cyclopropane-1,4'-pyr-
ido[1,2-a]pyrazine]-7'-carboxamide hydrochloride
Step 1
##STR00237##
[1390] From the crude product of compound 11-11 (122 mg) obtained
in the same manner as in Example 11, step 11, and compound P1 (206
mg) obtained in Example 1, Preliminary step 1-1, and in the same
manner as in Example 9, step 12, compound 21-1 (210 mg) was
obtained.
[1391] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.66 (t, 1H, J=6.0 Hz),
8.38 (s, 1H), 7.67-7.54 (m, 2H), 7.45-7.20 (m, 5H), 7.05-6.99 (m,
1H), 5.33 (d, 1H, J=10.1 Hz), 5.25 (d, 1H, J=10.1 Hz), 4.92-4.80
(m, 1H), 4.67 (d, 2H, J=6.0 Hz), 4.10-4.03 (m, 1H), 3.68 (d, 1H,
J=14.1 Hz), 3.67-3.60 (m, 1H), 3.34 (d, 1H, J=14.1 Hz), 2.37-2.25
(m, 1H), 1.51-1.42 (m, 1H), 1.19-1.13 (m, 6H), 1.10-1.03 (m,
1H).
Step 2
##STR00238##
[1393] To a solution of compound 21-1 (71 mg) obtained in the
above-mentioned step in chloroform (3 mL) was added thionyl
chloride (19 .mu.L), and the mixture was stirred at room
temperature overnight. A saturated aqueous sodium hydrogen
carbonate solution was added and, after partitioning, the aqueous
layer was extracted with chloroform. The organic layers were
combined, washed with saturated brine, and dried. After
concentration, the residue was purified by silica gel column
chromatography (ethyl acetate) to give compound 21-2 (69 mg).
[1394] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.49 (t, 1H, J=6.0 Hz),
8.34 (s, 1H), 7.64-7.60 (m, 2H), 7.42 (s, 2H), 7.39-7.26 (m, 3H),
7.06-7.00 (m, 1H), 5.35 (d, 1H, J=9.9 Hz), 5.28 (d, 1H, J=9.9 Hz),
4.96-4.87 (m, 1H), 4.69 (d, 2H, J=6.0 Hz), 3.83 (dd, 1H, J=12.0,
6.2 Hz), 3.60-3.50 (m, 2H), 3.31 (d, 1H, J=14.1 Hz), 2.45-2.35 (m,
1H), 1.78-1.70 (m, 1H), 1.19 (t, 6H, J=6.7 Hz), 1.10 (t, 1H, J=7.2
Hz).
Step 3
##STR00239##
[1396] To a solution of compound 21-2 (69 mg) obtained in the
above-mentioned step in DMF (3 mL) was added sodium
methanesulfinate (44 mg), and the mixture was stirred at 80.degree.
C. for 3 hr. Water was added, and the mixture was extracted 3 times
with ethyl acetate, and the organic layer was washed 4 times with
saturated brine. The mixture was dried, concentrated, and purified
by silica gel column chromatography (ethyl acetate to ethyl
acetate:methanol=20:1), and successively by silica gel thin layer
chromatography (ethyl acetate:acetone=4:1) to give compound 21-3
(18 mg).
[1397] .sup.1H-NMR (CDCl.sub.3) .delta.: 10.49-10.42 (m, 1H), 8.34
(s, 1H), 7.63-7.58 (m, 2H), 7.39-7.13 (m, 5H), 7.07-6.99 (m, 1H),
5.31 (s, 2H), 4.95-4.87 (m, 1H), 4.69 (d, 2H, J=6.0 Hz), 3.52-3.30
(m, 3H), 3.08-2.99 (m, 1H), 3.03 (s, 3H), 2.23-2.13 (m, 1H),
1.99-1.91 (m, 1H), 1.32-1.24 (m, 1H), 1.21-1.16 (m, 6H).
Step 4
##STR00240##
[1399] From compound 21-3 (18 mg) obtained in the above-mentioned
step and by a method similar to that in Example 10, step 2, the
title compound (13 mg) was obtained.
[1400] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.90-12.80 (m, 1H),
10.41 (t, 1H, J=6.0 Hz), 8.13 (s, 1H), 7.51-7.46 (m, 1H), 7.34-7.28
(m, 1H), 7.22-7.16 (m, 1H), 4.79-4.70 (m, 1H), 4.64-4.55 (m, 2H),
3.85 (d, 1H, J=14.3 Hz), 3.73-3.55 (m, 2H), 3.41-3.32 (m, 1H), 3.01
(s, 3H), 2.15-2.08 (m, 1H), 2.01-1.90 (m, 1H), 1.27-1.15 (m, 1H),
1.18 (dd, 6H, J=9.2, 6.9 Hz).
[1401] By a method similar to the above-mentioned Examples 1 to 21,
or using other conventional method as necessary, the compounds of
Examples S1 to S63 and Examples T1 to T50 shown in the following
Tables were produced. The structural formulas and property data of
the compounds of Examples S1 to S63 and Examples T1 to T50 are
shown in the following Tables. The compound obtained in Example S1
is sometimes also referred to as compound S1.
TABLE-US-00001 TABLE 1-1 Example No. structural formula salt
compound name S1 ##STR00241## HCl trans-3-(benzyloxy)-N-(2,4-
difluorobenzyl)-9'-hydroxy- 2'-isopropyl-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine-]
7'-carboxamide hydrochloride S2 ##STR00242## HCl
cis-3-(benzyloxy)-N-(2,4- difluorobenzyl)-9'-hydroxy-
2'-isopropyl-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride S3
##STR00243## HBr N-(2,4-difluorobenzyl)- trans-3,9'-dihydroxy-2'-
isopropyl-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrobromide S4
##STR00244## N-(2,4-difluorobenzyl)-cis-
3,9'-dihydroxy-2'-isopropyl- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide S5 ##STR00245## HCl N-(2,4-difluorobenzyl)-9'-
hydroxy-2'-isopropyl-trans- 3-methoxy-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride
TABLE-US-00002 TABLE 1-2 Example No. structural formula salt
compound name S6 ##STR00246## HCl N-(2,4-difluorobenzyl)-9'-
hydroxy-2'-isopropyl-cis-3- methoxy-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S7 ##STR00247## HCl
N-(2,4-difluorobenzyl)- trans-3-ethoxy-9'-hydroxy-
2'-isopropyl-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride S8
##STR00248## HCl N-(2,4-difluorobenzyl)-9'-
hydroxy-2'-isopropyl-trans- 3-(2-methoxyethoxy)-1',8'-
dioxo-1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride S9
##STR00249## HCl trans-3-(benzyloxy)-N-(2,4-
difluorobenzyl)-9'-hydroxy- 2'-methyl-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S10 ##STR00250## HCl
cis-3-(benzyloxy)-N-(2,4- difluorobenzyl)-9'-hydroxy -
2'-methyl-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride
TABLE-US-00003 TABLE 1-3 Example No. structural formula salt
compound name S11 ##STR00251## HBr N-(2,4-difluorobenzyl)-
trans-3,9'-dihydroxy-2'- methyl-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrobromide S12 ##STR00252## HBr
N-(2,4-difluorobenzyl)-cis- 3,9'-dihydroxy-2'-methyl-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrobromide S13
##STR00253## HCl N-(2,4-difluorobenzyl)-9'-
hydroxy-trans-3-methoxy-2'- methyl-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S14 ##STR00254## HCl
N-(2,4-difluorobenzyl)-9'- hydroxy-cis-3-methoxy-2'-
methyl-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride S15
##STR00255## HCl trans-3-(benzyloxy)-N-(2,4-
difluorobenzyl)-2'-ethyl-9'- hydroxy-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride
TABLE-US-00004 TABLE 1-4 Example No. structural formula salt
compound name S16 ##STR00256## HCl cis-3-(benzyloxy)-N-(2,4-
difluorobenzyl)-2'-ethyl-9'- hydroxy-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S17 ##STR00257## HBr
N-(2,4-difluorobenzyl)-2'- ethyl-trans-3,9'-dihydroxy-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrobromide S18
##STR00258## HBr N-(2,4-difluorobenzyl)-2'-
ethyl-cis-3,9'-dihydroxy- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrobromide S19 ##STR00259## HCl
N-(2,4-difluorobenzyl)-2'- ethyl-9'-hydroxy-trans-3-
methoxy-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride S20
##STR00260## HCl N-(2,4-difluorobenzyl)-2'- ethyl-9'-hydroxy-cis-3-
methoxy-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride
TABLE-US-00005 TABLE 1-5 Example No. structural formula salt
compound name S21 ##STR00261## HCl N-(2,4-difluorobenzyl)-cis-
3-ethoxy-2'-ethyl-9'- hydroxy-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S22 ##STR00262## HBr
N-(2,4-difluorobenzyl)-9'- hydroxy-cis-3- (hydroxymethyl)-2'-
isopropyl-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrobromide S23
##STR00263## HCl N-(2,4-difluorobenzyl)-9'-
hydroxy-2'-isopropyl-cis-3- (methoxymethyl)-1',8'-dioxo-
1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride S24
##STR00264## HBr N-(2,4-difluorobenzyl)-9'- hydroxy-trans-3-
(hydroxymethyl)-2'- isopropyl-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrobromide S25 ##STR00265## HCl
N-(2,4-difluorobenzyl)-9'- hydroxy-2'-isopropyl-trans-
3-(methoxymethyl)-1',8'- dioxo-1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride
TABLE-US-00006 TABLE 1-6 Example No. structural formula salt
compound name S26 ##STR00266## HCl N-(3-chloro-2-fluorobenzyl)-
trans-3,9'-dihydroxy-2'- methyl-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S27 ##STR00267## HCl
N-(3-chloro-2-fluorobenzyl)- cis-3,9'-dihydroxy-2'-
methyl-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride S28
##STR00268## HCl N-(3-chloro-2-fluorobenzyl)-
trans-3-ethoxy-9'-hydroxy- 2'-methyl-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S29 ##STR00269## HCl
N-(3-chloro-2-fluorobenzyl)- cis-3-ethoxy-9'-hydroxy-2'-
methyl-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride S30
##STR00270## HCl N.sup.7'-(2,4-difluorobenzyl)-9'-
hydroxy-2'-isopropyl-N.sup.3- methyl-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
cis-3,7'-dicarboxamide hydrochloride
TABLE-US-00007 TABLE 1-7 Example No. structural formula salt
compound name S31 ##STR00271## HCl
N.sup.7'-(2,4-difluorobenzyl)-9'-
hydroxy-2'-isopropyl-N.sup.3,N.sup.3- dimethyl-1',8'-dioxo-
1',2',3',8' tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- cis-3,7'-dicarboxamide hydrochloride
S32 ##STR00272## HCl N-(2,4-difluorobenzyl)-9'-
hydroxy-trans-3-isopropoxy- 2'-isopropyl-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S33 ##STR00273## HCl
N-(2,4-difluorobenzyl)-9'- hydroxy-cis-3-isopropoxy-2'-
isopropyl-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride S34
##STR00274## HCl 7'-(2,4- difluorobenzylcarbamoyl)-9'-
hydroxy-2'-isopropyl-1',8'- dioxo-1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
trans-3-yl methanesulfonate hydrochloride
TABLE-US-00008 TABLE 1-8 Example No. structural formula salt
compound name S35 ##STR00275## HCl 7'-(2,4-
difluorobenzylcarbamoyl)-9'- hydroxy-2'-isopropyl-1',8'-
dioxo-1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- cis-3-yl methanesulfonate
hydrochloride S36 ##STR00276## N-(3-chloro-2-fluorobenzyl)-
9'-hydroxy-trans-3- (hydroxymethyl)-2'-methyl-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide S37 ##STR00277## HCl
N-(3-chloro-2-fluorobenzyl)- 9'-hydroxy-cis-3-
(hydroxymethyl)-2'-methyl- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S38 ##STR00278## HCl
cis-3-(acetamidomethyl)-N- (2,4-difluorobenzyl)-9'-
hydroxy-2'-isopropyl-1',8'- dioxo-1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride
TABLE-US-00009 TABLE 1-9 Example No. structural formula salt
compound name S39 ##STR00279## HCl N-(3-chloro-2-fluorobenzyl)-
cis-3-(ethoxymethyl)-9'- hydroxy-2'-methyl-1',8'-
dioxo-1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride S40
##STR00280## HCl N-(3-chloro-2-fluorobenzyl)- 9'-hydroxy-trans-3-
isopropoxy-2'-methyl-1',8'- dioxo-1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S41 ##STR00281## HCl
N-(3-chloro-2-fluorobenzyl)- 9'-hydroxy-cis-3-isopropoxy-
2'-methyl-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride S42
##STR00282## HCl N-(3-chloro-2-fluorobenzyl)-
9'-hydroxy-2'-methyl-1',8'- dioxo-trans-3-propoxy- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride
TABLE-US-00010 TABLE 1-10 Example No. structural formula salt
compound name S43 ##STR00283## HCl N-(3-chloro-2-fluorobenzyl)-
9'-hydroxy-2'-methyl-1',8'- dioxo-cis-3-propoxy- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S44 ##STR00284## HCl
N-(3-chloro-2-fluorobenzyl)- 2'-ethyl-9'-hydroxy-trans-3-
(hydroxymethyl)-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S45 ##STR00285## HCl
N-(3-chloro-2-fluorobenzyl)- 2'-ethyl-9'-hydroxy-trans-3-
(methoxymethyl)-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S46 ##STR00286## HCl
N-(3-chloro-2-fluorobenzyl)- 2'-ethyl-9'-hydroxy-cis-3-
(hydroxymethyl)-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S47 ##STR00287## HCl
N-(3-chloro-2-fluorobenzyl)- 2'-ethyl-9'-hydroxy-cis-3-
(methoxymethyl)-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride
TABLE-US-00011 TABLE 1-11 Example No. structural formula salt
compound name S48 ##STR00288## HCl N-(3-chloro-2-fluorobenzyl)-
cis-3-(ethoxymethyl)-2'- ethyl-9'-hydroxy-1',8'- dioxo-1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S49 ##STR00289##
N-(3-chloro-2-fluoro-4- methoxybenzyl)-9'-hydroxy-
trans-3-(hydroxymethyl)-2'- methyl-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclobutane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide S50 ##STR00290## N-(3-chloro-2-fluoro-4-
methoxybenzyl)-9'-hydroxy- cis-3-(hydroxymethyl)-2'-
methyl-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide S51 ##STR00291## HCl
N-(2,4-difluorobenzyl)-cis- 3-ethoxy-9'-hydroxy-2'-
methyl-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclobutane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride
TABLE-US-00012 TABLE 1-12 Example No. structural formula salt
compound name S52 ##STR00292## HCl N-(2,4-difluorobenzyl)-9'-
hydroxy-2'-isopropyl-trans- 3-methoxy-1',8'-dioxo- 1',2',4',8'-
tetrahydrospiro[cyclobutane- 1,3'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S53 ##STR00293## HCl
N-(2,4-difluorobenzyl)-9'- hydroxy-2'-isopropyl-cis-3-
methoxy-1',8'-dioxo- 1',2',4',8'- tetrahydrospiro[cyclobutane-
1,3'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride S54
##STR00294## HCl N-(2,4-difluorobenzyl)- trans-3,9'-dihydroxy-2'-
isopropyl-1',8'-dioxo- 1',2',4',8'- tetrahydrospiro[cyclobutane-
1,3'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride S55
##STR00295## HCl N-(2,4-difluorobenzyl)-cis-
3,9'-dihydroxy-2'-isopropyl- 1',8'-dioxo-1',2',4',8'-
tetrahydrospiro[cyclobutane- 1,3'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S56 ##STR00296## HCl
N-(3-chloro-2-fluorobenzyl)- trans-3-ethoxy-2'-ethyl-9'-
hydroxy-1',8'-dioxo- 1',2',4',8'- tetrahydrospiro[cyclobutane-
1,3'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride
TABLE-US-00013 TABLE 1-13 Example No. structural formula salt
compound name S57 ##STR00297## HCl N-(3-chloro-2-fluorobenzyl)-
cis-3-ethoxy-2'-ethyl-9'- hydroxy-1',8'-dioxo- 1',2',4',8'-
tetrahydrospiro[cyclobutane- 1,3'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S58 ##STR00298## HCl
N-(3-chloro-2-fluorobenzyl)- 2'-ethyl-9'-hydroxy-trans-3-
(hydroxymethyl)-1',8'-dioxo- 1',2',4',8'-
tetrahydrospiro[cyclobutane- 1,3'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S59 ##STR00299## HCl
N-(3-chloro-2-fluorobenzyl)- 2'-ethyl-9'-hydroxy-trans-3-
(methoxymethyl)-1',8'-dioxo- 1',2',4',8'-
tetrahydrospiro[cyclobutane- 1,3'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S60 ##STR00300## HCl
N-(3-chloro-2-fluorobenzyl)- 2'-ethyl-9'-hydroxy-cis-3-
(hydroxymethyl)-1',8'-dioxo- 1',2',4',8'-
tetrahydrospiro[cyclobutane- 1,3'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride
TABLE-US-00014 TABLE 1-14 Example No. structural formula salt
compound name S61 ##STR00301## HCl N-(3-chloro-2-fluorobenzyl)-
2'-ethyl-9'-hydroxy-cis-3- (methoxymethyl)-1',8'-dioxo-
1',2',4',8'- tetrahydrospiro[cyclobutane-
1,3'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride S62
##STR00302## HCl N-(3-chloro-2-fluorobenzyl)-
9'-hydroxy-trans-3-methoxy- 2'-methyl-1',8'-dioxo- 1',2',4,8'-
tetrahydrospiro[cyclobutane- 1,3'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride S63 ##STR00303## HCl
N-(3-chloro-2-fluorobenzyl)- 9'-hydroxy-cis-3-methoxy-2'-
methyl-1',8'-dioxo- 1',2',4',8'- tetrahydrospiro[cyclobutane-
1,3'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride
TABLE-US-00015 TABLE 1-15 Example No. 1H-NMR (DMSO-d6) .delta.
(peak, integ., J) S1 1H-NMR (DMSO-d6) .delta.: 12.89 (s, 1H), 10.40
(t, 1H, J = 6.0 Hz), 8.49 (s, 1H), 7.44-7.21 (m, 7H), 7.09-7.04 (m,
1H), 4.75 (sep, 1H, J = 6.7 Hz), 4.55 (d, 2H, J = 6.0 Hz), 4.45 (s,
2H), 4.32-4.26 (m, 1H), 3.83 (s, 2H), 2.90-2.84 (m, 2H), 2.35-2.31
(m, 2H), 1.15 (d, 6H, J = 6.7 Hz). S2 1H-NMR (DMSO-d6) .delta.:
12.86 (br s, 1H), 10.39 (t, 1H, J = 6.0 Hz), 8.53 (s, 1H),
7.44-7.21 (m, 7H), 7.08- 7.03 (m, 1H), 4.75 (sep, 1H, J = 6.7 Hz),
4.55 (d, 2H, J = 6.0 Hz), 4.46 (s, 2H), 4.22 (quint, 1H, J = 6.3
Hz), 3.68 (s, 2H), 2.64-2.59 (m, 2H), 2.51-2.45 (m, 2H), 1.19 (d,
6H, J = 6.7 Hz). S3 1H-NMR (DMSO-d6) .delta.: 10.40 (t, 1H, J = 5.8
Hz), 8.46 (s, 1H), 7.41 (dt, 1H, J = 6.5, 8.6 Hz), 7.24 (ddd, 1H, J
= 10.5, 9.3, 2.6 Hz), 7.09-7.04 (m, 1H), 4.77 (sep, 1H, J = 6.7
Hz), 4.54 (d, 2H, J = 5.8 Hz), 4.40-4.34 (m, 1H), 3.83 (s, 2H),
2.83-2.78 (m, 2H), 2.21-2.16 (m, 2H), 1.19 (d, 6H, J = 6.7 Hz). S4
1H-NMR (DMSO-d6) .delta.: 10.42 (t, 1H, J = 5.8 Hz), 8.57 (s, 1H),
7.44-7.38 (m, 1H), 7.26-7.21 (m, 1H), 7.09- 7.04 (m, 1H), 5.51 (d,
1H, J = 7.9 Hz), 4.76 (sep, 1H, J = 6.7 Hz), 4.55 (d, 2H, J = 5.8
Hz), 4.26-4.17 (m, 1H), 3.63 (s, 2H), 2.59-2.52 (m, 2H), 2.41-2.35
(m, 2H), 1.19 (d, 6H, J = 6.7 Hz). S5 1H-NMR (DMSO-d6) .delta.:
10.40 (t, 1H, J = 5.9 Hz), 8.48 (s, 1H), 7.44-7.38 (m, 1H), 7.24
(ddd, 1H, J= 10.7, 9.5, 2.8 Hz), 7.09-7.04 (m, 1H), 4.77 (sep, 1H,
J = 6.7 Hz), 4.55 (d, 2H, J = 5.9 Hz), 4.10-4.04 (m, 1H), 3.79 (s,
2H), 3.21 (s, 3H), 2.85-2.80 (m, 2H), 2.28-2.23 (m, 2H), 1.18 (d,
6H, J = 6.7 Hz). S6 1H-NMR (DMSO-d6) .delta.: 12.87 (br s, 1H),
10.38 (t, 1H, J = 5.8 Hz), 8.49 (s, 1H), 7.41 (dt, 1H, J = 6.5, 8.6
Hz), 7.24 (ddd, 1H, J = 10.7, 9.3, 2.6 Hz), 7.09-7.04 (m, 1H), 4.76
(sep, 1H, J = 6.7 Hz), 4.55 (d, 2H, J = 5.8 Hz), 4.03 (quint, 1H, J
= 6.3 Hz), 3.67 (s, 2H), 3.21 (s, 3H), 2.63-2.58 (m, 2H), 2.43-
2.38 (m, 2H), 1.20 (d, 6H, J = 6.7 Hz). S7 1H-NMR (DMSO-d6)
.delta.: 12.90 (br s, 1H), 10.40 (t, 1H, J = 5.9 Hz), 8.48 (s, 1H),
7.44-7.38 (m, 1H), 7.26- 7.21 (m, 1H), 7.09-7.04 (m, 1H), 4.77
(sep, 1H, J = 6.7 Hz), 4.55 (d, 2H, J = 5.9 Hz), 4.18-4.12 (m, 1H),
3.82 (s, 2H), 3.39 (q, 2H, J = 7.1 Hz), 2.86- 2.80 (m, 2H),
2.28-2.23 (m, 2H), 1.18 (d, 6H, J = 6.7 Hz), 1.14 (t, 3H, J = 7.1
Hz). S8 1H-NMR (DMSO-d6) .delta.: 12.89 (br s, 1H), 10.40 (t, 1H, J
= 5.9 Hz), 8.48 (s, 1H), 7.44-7.38 (m, 1H), 7.24 (ddd, 1H, J =
10.5, 9.3, 2.3 Hz), 7.09-7.04 (m, 1H), 4.76 (sep, 1H, J = 6.7 Hz),
4.55 (d, 2H, J = 5.9 Hz), 4.22-4.14 (m, 1H), 3.83 (s, 2H),
3.49-3.46 (m, 4H), 3.27 (s, 3H), 2.86-2.80 (m, 2H), 2.28-2.23 (m,
2H), 1.19 (d, 6H, J = 6.7 Hz). S9 1H-NMR (DMSO-d6) .delta.: 12.87
(br s, 1H), 10.39 (t, 1H, J = 6.0 Hz), 8.48 (s, 1H), 7.44-7.21 (m,
7H), 7.09- 7.04 (m, 1H), 4.55 (d, 2H, J = 6.0 Hz), 4.44 (s, 2H),
4.32-4.26 (m, 1H), 3.92 (s, 2H), 3.10 (s, 3H), 2.89-2.84 (m, 2H),
2.42-2.37 (m, 2H).
TABLE-US-00016 TABLE 1-16 Example No. 1H-NMR (DMSO-d6) .delta.
(peak, integ., J) S10 1H-NMR (DMSO-d6) .delta.: 12.83 (br s, 1H),
10.38 (t, 1H, J = 6.0 Hz), 8.53 (s, 1H), 7.44-7.21 (m, 7H), 7.08-
7.03 (m, 1H), 4.55 (d, 2H, J = 6.0 Hz), 4.45 (s, 2H), 4.16 (quint,
1H, J = 6.5 Hz), 3.79 (s, 2H), 3.11 (s, 3H), 2.72-2.66 (m, 2H),
2.51-2.45 (m, 2H). S11 1H-NMR (DMSO-d6) .delta.: 10.39 (t, 1H, J =
6.0 Hz), 8.46 (s, 1H), 7.44-7.38 (m, 1H), 7.26-7.21 (m, 1H), 7.09-
7.04 (m, 1H), 4.54 (d, 2H, J = 6.0 Hz), 4.40-4.34 (m, 1H), 3.92 (s,
2H), 3.11 (s, 3H), 2.84-2.78 (m, 2H), 2.26-2.21 (m, 2H). S12 1H-NMR
(DMSO-d6) .delta.: 10.41 (t, 1H, J = 6.0 Hz), 8.57 (s, 1H),
7.44-7.38 (m, 1H), 7.26-7.20 (m, 1H), 7.09- 7.04 (m, 1H), 4.55 (d,
2H, J = 6.0 Hz), 4.16 (quint, 1H, J = 6.7 Hz), 3.75 (s, 2H), 3.11
(s, 3H), 2.65- 2.59 (m, 2H), 2.40-2.34 (m, 2H). S13 1H-NMR
(DMSO-d6) .delta.: 13.03-12.71 (m, 1H), 10.39 (t, 1H, J = 6.0 Hz),
8.48 (s, 1H), 7.46-7.37 (m, 1H), 7.27-7.20 (m, 1H), 7.10-7.03 (m,
1H), 4.55 (d, 2H, J = 6.0 Hz), 4.12-4.02 (m, 1H), 3.88 (s, 2H),
3.20 (s, 3H), 3.11 (s, 3H), 2.90-2.79 (m, 2H), 2.37-2.29 (m, 2H).
S14 1H-NMR (DMSO-d6) .delta.: 12.83 (br s, 1H), 10.37 (t, 1H, J =
6.0 Hz), 8.49 (s, 1H), 7.44-7.38 (m, 1H), 7.26- 7.21 (m, 1H),
7.09-7.04 (m, 1H), 4.55 (d, 2H, J = 6.0 Hz), 3.97 (quint, 1H, J =
6.4 Hz), 3.79 (s, 2H), 3.20 (s, 3H), 3.12 (s, 3H), 2.70-2.65 (m,
2H), 2.42- 2.37 (m, 2H). S15 1H-NMR (DMSO-d6) .delta.: 12.85 (s,
1H), 10.39 (t, 1H, J = 6.0 Hz), 8.48 (s, 1H), 7.44-7.21 (m, 7H),
7.09-7.04 (m, 1H), 4.55 (d, 2H, J = 6.0 Hz), 4.45 (s, 2H),
4.32-4.26 (m, 1H), 3.92 (s, 2H), 3.54 (q, 2H, J = 7.1 Hz),
2.90-2.85 (m, 2H), 2.37-2.32 (m, 2H), 1.15 (t, 3H, J = 7.1 Hz). S16
1H-NMR (DMSO-d6) .delta.: 12.82 (s, 1H), 10.38 (t, 1H, J = 6.0 Hz),
8.53 (s, 1H), 7.44-7.21 (m, 7H), 7.09-7.04 (m, 1H), 4.55 (d, 2H, J
= 6.0 Hz), 4.45 (s, 2H), 4.19 (quint, 1H, J = 6.4 Hz), 3.79 (s,
2H), 3.56 (q, 2H, J = 7.1 Hz), 2.67-2.62 (m, 2H), 2.51-2.45 (m,
2H), 1.17 (t, 3H, J = 7.1 Hz). S17 1H-NMR (DMSO-d6) .delta.: 10.39
(t, 1H, J = 6.0 Hz), 8.45 (s, 1H), 7.41 (td, 1H, J = 8.6, 6.6 Hz),
7.24 (ddd, 1H, J = 10.6, 9.5, 2.6 Hz), 7.09-7.04 (m, 1H), 4.54 (d,
2H, J = 6.0 Hz), 4.40-4.34 (m, 1H), 3.93 (s, 2H), 3.55 (q, 2H, J =
7.2 Hz), 2.84-2.79 (m, 2H), 2.23-2.18 (m, 2H), 1.17 (t, 3H, J = 7.2
Hz). S18 1H-NMR (DMSO-d6) .delta.: 10.41 (t, 1H, J = 6.0 Hz), 8.57
(s, 1H), 7.44-7.38 (m, 1H), 7.26-7.21 (m, 1H), 7.09- 7.04 (m, 1H),
4.55 (d, 2H, J = 6.0 Hz), 4.19 (quint, 1H, J = 6.7 Hz), 3.75 (s,
2H), 3.56 (q, 2H, J = 7.1 Hz), 2.61-2.56 (m, 2H), 2.41-2.36 (m,
2H), 1.17 (t, 3H, J = 7.1 Hz).
TABLE-US-00017 TABLE 1-17 Example No. 1H-NMR (DMSO-d6) .delta.
(peak, integ., J) S19 1H-NMR (DMSO-d6) .delta.: 12.85 (s, 1H),
10.39 (t, 1H, J = 6.0 Hz), 8.48 (s, 1H), 7.44-7.38 (m, 1H),
7.26-7.21 (m, 1H), 7.09-7.04 (m, 1H), 4.55 (d, 2H, J = 6.0 Hz),
4.11-4.05 (m, 1H), 3.89 (s, 2H), 3.55 (q, 2H, J = 7.2 Hz), 3.21 (s,
3H), 2.86-2.81 (m, 2H), 2.30- 2.25 (m, 2H), 1.16 (t, 3H, J = 7.2
Hz). S20 1H-NMR (DMSO-d6) .delta.: 10.37 (t, 1H, J = 5.8 Hz), 8.49
(s, 1H), 7.44-7.38 (m, 1H), 7.26-7.21 (m, 1H), 7.09- 7.03 (m, 1H),
4.55 (d, 2H, J = 5.8 Hz), 4.00 (quint, 1H, J = 6.2 Hz), 3.79 (s,
2H), 3.57 (q, 2H, J = 7.1 Hz), 3.20 (s, 3H), 2.67-2.61 (m, 2H),
2.43-2.38 (m, 2H), 1.18 (t, 3H, J = 7.1 Hz). S21 1H-NMR (DMSO-d6)
.delta.: 12.83 (br s, 1H), 10.38 (t, 1H, J = 5.9 Hz), 8.50 (s, 1H),
7.44-7.38 (m, 1H), 7.23 (ddd, 1H, J = 10.4, 9.5, 2.5 Hz), 7.09-7.03
(m, 1H), 4.55 (d, 2H, J = 5.9 Hz), 4.08 (quint, 1H, J = 6.4 Hz),
3.79 (s, 2H), 3.57 (q, 2H, J = 7.2 Hz), 3.41 (q, 2H, J = 7.0 Hz),
2.67-2.61 (m, 2H), 2.42-2.37 (m, 2H), 1.17 (t, 3H, J = 7.2 Hz),
1.13 (t, 3H, J = 7.0 Hz). S22 1H-NMR (DMSO-d6) .delta.: 10.41 (t,
1H, J = 6.0 Hz), 8.54 (s, 1H), 7.45-7.37 (m, 1H), 7.27-7.20 (m,
1H), 7.10- 7.03 (m, 1H), 4.83-4.72 (m, 1H), 4.54 (d, 2H, J = 6.0
Hz), 3.93-3.54 (m, 2H), 3.44 (d, 2H, J = 4.6 Hz), 2.54-2.47 (m,
1H), 2.45-2.33 (m, 2H), 2.19-2.10 (m, 2H), 1.22 (d, 6H, J = 6.9
Hz). S23 1H-NMR (DMSO-d6) .delta.: 12.98-12.72 (m, 1H), 10.41 (t,
1H, J = 6.0 Hz), 8.54 (s, 1H), 7.46-7.38 (m, 1H), 7.28-7.20 (m,
1H), 7.10-7.03 (m, 1H), 4.82-4.73 (m, 1H), 4.55 (d, 2H, J = 6.0
Hz), 3.78 (s, 2H), 3.50- 3.33 (m, 2H), 3.28 (s, 3H), 2.70-2.56 (m,
1H), 2.41- 2.31 (m, 2H), 2.27-2.18 (m, 2H), 1.22 (d, 6H, J = 6.7
Hz). S24 1H-NMR (DMSO-d6) .delta.: 10.45-10.39 (m, 1H), 8.60 (s,
1H), 7.46-7.38 (m, 1H), 7.27-7.20 (m, 1H), 7.10-7.03 (m, 1H),
4.79-4.70 (m, 1H), 4.55 (d, 2H, J = 6.0 Hz), 3.74 (s, 2H),
3.64-3.30 (m, 2H), 2.53-2.45 (m, 3H), 2.25-2.14 (m, 2H), 1.19 (d,
6H, J = 6.7 Hz). S25 1H-NMR (DMSO-d6) .delta.: 13.13-12.80 (m, 1H),
10.42 (t, 1H, J = 6.0 Hz), 8.59 (s, 1H), 7.46-7.38 (m, 1H),
7.27-7.20 (m, 1H), 7.10-7.03 (m, 1H), 4.80-4.70 (m, 1H), 4.55 (d,
2H, J = 6.0 Hz), 3.74 (s, 2H), 3.48- 3.33 (m, 2H), 3.30 (s, 3H),
2.76-2.48 (m, 3H), 2.22- 2.13 (m, 2H), 1.19 (d, 6H, J = 6.9 Hz).
S26 1H-NMR (DMSO-d6) .delta.: 13.06-12.73 (m, 1H), 10.45 (t, 1H, J
= 6.0 Hz), 8.46 (s, 1H), 7.52-7.46 (m, 1H), 7.36-7.30 (m, 1H),
7.23-7.17 (m, 1H), 4.61 (d, 2H, J = 6.0 Hz), 4.41-4.33 (m, 1H),
3.92 (s, 2H), 3.12 (s, 3H), 2.86-2.77 (m, 2H), 2.29-2.20 (m, 2H).
S27 1H-NMR (DMSO-d6) .delta.: 12.92-12.78 (m, 1H), 10.49-10.43 (m,
1H), 8.57 (s, 1H), 7.52-7.46 (m, 1H), 7.36-7.30 (m, 1H), 7.23-7.17
(m, 1H), 4.62 (d, 2H, J = 6.0 Hz), 4.20-4.12 (m, 1H), 3.75 (s, 2H),
3.11 (s, 3H), 2.69-2.56 (m, 2H), 2.41-2.30 (m, 2H).
TABLE-US-00018 TABLE 1-18 Example No. 1H-NMR (DMSO-d6) .delta.
(peak, integ., J) S28 1H-NMR (DMSO-d6) .delta.: 13.14-12.59 (m,
1H), 10.45 (t, 1H, J = 6.0 Hz), 8.47 (s, 1H), 7.52-7.46 (m, 1H),
7.36-7.30 (m, 1H), 7.23-7.17 (m, 1H), 4.62 (d, 2H, J = 6.0 Hz),
4.20-4.12 (m, 1H), 3.90 (s, 2H), 3.39 (q, 2H, J = 6.9 Hz), 3.11 (s,
3H), 2.88-2.79 (m, 2H), 2.37-2.29 (m, 2H), 1.13 (t, 3H, J = 6.9
Hz). S29 1H-NMR (DMSO-d6) .delta.: 12.94-12.70 (m, 1H), 10.43 (t,
1H, J = 6.0 Hz), 8.49 (s, 1H), 7.52-7.47 (m, 1H), 7.35-7.30 (m,
1H), 7.23-7.17 (m, 1H), 4.62-4.62 (m, 2H), 4.09-4.01 (m, 1H), 3.79
(s, 2H), 3.40 (q, 2H, J = 6.9 Hz), 3.12 (s, 3H), 2.72-2.63 (m, 2H),
2.43-2.31 (m, 2H), 1.13 (t, 3H, J = 6.9 Hz). S30 1H-NMR (DMSO-d6)
.delta.: 13.06-12.60 (m, 1H), 10.39 (t, 1H, J = 5.8 Hz), 8.57 (s,
1H), 7.95-7.85 (m, 1H), 7.46-7.38 (m, 1H), 7.28-7.19 (m, 1H),
7.10-7.03 (m, 1H), 4.83-4.73 (m, 1H), 4.55 (d, 2H, J = 5.8 Hz),
3.79 (s, 2H), 3.72-3.03 (m, 1H), 2.72-2.61 (m, 2H), 2.60 (d, 3H, J
= 4.6 Hz), 2.40-2.30 (m, 2H), 1.22 (d, 6H, J = 6.9 Hz). S31 1H-NMR
(DMSO-d6) .delta.: 12.97-12.80 (m, 1H), 10.38 (t, 1H, J = 5.8 Hz),
8.50 (s, 1H), 7.46-7.37 (m, 1H), 7.27-7.19 (m, 1H), 7.10-7.02 (m,
1H), 4.84-4.73 (m, 1H), 4.54 (d, 2H, J = 5.8 Hz), 3.85 (s, 2H),
3.62- 3.49 (m, 1H), 2.93 (s, 3H), 2.84 (s, 3H), 2.76-2.65 (m, 2H),
2.43-2.31 (m, 2H), 1.24 (d, 6H, J = 6.7 Hz). S32 1H-NMR (DMSO-d6)
.delta.: 12.89 (s, 1H), 10.41 (t, 1H, J = 6.0 Hz), 8.48 (s, 1H),
7.45-7.38 (m, 1H), 7.27-7.20 (m, 1H), 7.10-7.03 (m, 1H), 4.80-4.72
(m, 1H), 4.55 (d, 2H, J = 6.0 Hz), 4.28-4.20 (m, 1H), 3.81 (s, 2H),
3.65-3.58 (m, 1H), 2.89-2.80 (m, 2H), 2.28-2.20 (m, 2H), 1.19 (d,
6H, J = 6.9 Hz), 1.10 (d, 6H, J = 6.2 Hz). S33 1H-NMR (DMSO-d6)
.delta.: 12.86 (s, 1H), 10.38 (t, 1H, J = 6.2 Hz), 8.49 (s, 1H),
7.45-7.37 (m, 1H), 7.27-7.20 (m, 1H), 7.09-7.03 (m, 1H), 4.80-4.72
(m, 1H), 4.55 (d, 2H, J = 6.0 Hz), 4.24-4.15 (m, 1H), 3.68 (s, 2H),
3.68-3.58 (m, 1H), 2.68-2.56 (m, 2H), 2.42-2.31 (m, 2H), 1.20 (d,
6H, J = 6.7 Hz), 1.11 (d, 6H, J = 6.2 Hz). S34 1H-NMR (DMSO-d6)
.delta.: 12.93-12.84 (m, 1H), 10.40 (t, 1H, J = 6.0 Hz), 8.49 (s,
1H), 7.46-7.38 (m, 1H), 7.27-7.20 (m, 1H), 7.10-7.03 (m, 1H),
5.28-5.20 (m, 1H), 4.80-4.71 (m, 1H), 4.55 (d, 2H, J = 6.0 Hz),
3.85 (s, 2H), 3.24 (s, 3H), 3.18-3.09 (m, 2H), 2.71- 2.62 (m, 2H),
1.20 (d, 6H, J = 6.9 Hz). S35 1H-NMR (DMSO-d6) .delta.: 12.90-12.79
(m, 1H), 10.37 (t, 1H, J = 6.0 Hz), 8.52 (s, 1H), 7.45-7.38 (m,
1H), 7.27-7.19 (m, 1H), 7.10-7.03 (m, 1H), 5.29-5.20 (m, 1H),
4.79-4.70 (m, 1H), 4.55 (d, 2H, J = 6.0 Hz), 3.75 (s, 2H), 3.24 (s,
3H), 2.96-2.87 (m, 2H), 2.85- 2.76 (m, 2H), 1.21 (d, 6H, J = 6.9
Hz). S36 1H-NMR (CDCl3) .delta.: 12.83-12.68 (m, 1H), 10.57 (s,
1H), 8.77 (s, 1H), 7.33-7.24 (m, 2H), 7.07-6.98 (m, 1H), 4.77-4.67
(m, 2H), 3.79 (s, 2H), 3.73 (br s, 2H), 3.20 (s, 3H), 2.91-2.77 (m,
1H), 2.64-2.52 (m, 2H), 2.50-2.39 (m, 2H).
TABLE-US-00019 TABLE 1-19 Example No. 1H-NMR (DMSO-d6) .delta.
(peak, integ., J) S37 1H-NMR (DMSO-d6) .delta.: 10.46 (t, 1H, J =
6.0 Hz), 8.54 (s, 1H), 7.53-7.46 (m, 1H), 7.36-7.30 (m, 1H), 7.24-
7.17 (m, 1H), 4.61 (d, 2H, J = 6.0 Hz), 3.89 (s, 2H), 3.57 (s, 2H),
3.15 (s, 3H), 2.27-2.13 (m, 2H), 2.53-2.29 (m, 3H). S38 1H-NMR
(DMSO-d6) .delta.: 13.08-12.60 (m, 1H), 10.40 (t, 1H, J = 6.0 Hz),
8.49 (s, 1H), 8.08-7.96 (m, 1H), 7.46-7.37 (m, 1H), 7.27-7.19 (m,
1H), 7.10-7.02 (m, 1H), 4.82-4.71 (m, 1H), 4.55 (d, 2H, J = 6.0
Hz), 3.75 (s, 2H), 3.17 (t, 2H, J = 6.2 Hz), 2.55-2.37 (m, 1H),
2.35-2.14 (m, 4H), 1.83 (s, 3H), 1.21 (d, 6H, J = 6.9 Hz). S39
1H-NMR (DMSO-d6) .delta.: 12.83 (s, 1H), 10.44 (t, 1H, J = 6.0 Hz),
8.57 (s, 1H), 7.53-7.46 (m, 1H), 7.36-7.30 (m, 1H), 7.23-7.17 (m,
1H), 4.61 (d, 2H, J = 6.0 Hz), 3.89 (s, 2H), 3.52-3.40 (m, 4H),
3.14 (s, 3H), 2.71-2.48 (m, 1H), 2.44-2.19 (m, 4H), 1.09 (t, 3H, J
= 6.9 Hz). S40 1H-NMR (DMSO-d6) .delta.: 13.08-12.69 (m, 1H), 10.45
(t, 1H, J = 6.0 Hz), 8.48 (s, 1H), 7.52-7.46 (m, 1H), 7.36-7.31 (m,
1H), 7.23-7.18 (m, 1H), 4.62 (d, 2H, J = 6.0 Hz), 4.28-4.20 (m,
1H), 3.89 (s, 2H), 3.66- 3.55 (m, 1H), 3.11 (s, 3H), 2.90-2.80 (m,
2H), 2.37- 2.28 (m, 2H), 1.09 (d, 6H, J = 6.0 Hz). S41 1H-NMR
(DMSO-d6) .delta.: 12.99-12.65 (m, 1H), 10.43 (t, 1H, J = 6.0 Hz),
8.48 (s, 1H), 7.52-7.46 (m, 1H), 7.35-7.30 (m, 1H), 7.23-7.17 (m,
1H), 4.62 (d, 2H, J = 6.0 Hz), 4.18-4.09 (m, 1H), 3.79 (s, 2H),
3.67- 3.57 (m, 1H), 3.12 (s, 3H), 2.73-2.64 (m, 2H), 2.41- 2.31 (m,
2H), 1.10 (d, 6H, J = 6.0 Hz). S42 1H-NMR (DMSO-d6) .delta.:
12.92-12.83 (m, 1H), 10.45 (t, 1H, J = 6.0 Hz), 8.47 (s, 1H),
7.52-7.46 (m, 1H), 7.36-7.30 (m, 1H), 7.23-7.17 (m, 1H), 4.62 (d,
2H, J = 6.0 Hz), 4.19-4.11 (m, 1H), 3.90 (s, 2H), 3.29 (t, 2H, J =
6.7 Hz), 3.11 (s, 3H), 2.88-2.79 (m, 2H), 2.37-2.28 (m, 2H),
1.58-1.47 (m, 2H), 0.89 (t, 3H, J = 7.4 Hz). S43 1H-NMR (DMSO-d6)
.delta.: 12.83 (s, 1H), 10.43 (t, 1H, J = 6.0 Hz), 8.49 (s, 1H),
7.52-7.46 (m, 1H), 7.36-7.30 (m, 1H), 7.23-7.17 (m, 1H), 4.62 (d,
2H, J = 6.0 Hz), 4.09-4.00 (m, 1H), 3.79 (s, 2H), 3.35-3.27 (m,
2H), 3.12 (s, 3H), 2.73-2.63 (m, 2H), 2.43-2.31 (m, 2H), 1.57-1.46
(m, 2H), 0.86 (t, 3H, J = 7.4 Hz). S44 1H-NMR (DMSO-d6) .delta.:
12.93 (s, 1H), 10.47 (t, 1H, J = 6.0 Hz), 8.59 (s, 1H), 7.53-7.46
(m, 1H), 7.37-7.31 (m, 1H), 7.21 (t, 1H, J = 7.9 Hz), 4.62 (d, 2H,
J = 6.0 Hz), 3.83 (s, 2H), 3.58-3.44 (m, 4H), 2.71-2.44 (m, 3H),
2.26-2.16 (m, 2H), 1.17 (t, 3H, J = 7.2 Hz). S45 1H-NMR (DMSO-d6)
.delta.: 13.09-12.70 (m, 1H), 10.46 (t, 1H, J = 6.0 Hz), 8.58 (s,
1H), 7.52-7.46 (m, 1H), 7.37-7.30 (m, 1H), 7.23-7.17 (m, 1H), 4.62
(d, 2H, J = 6.0 Hz), 3.83 (s, 2H), 3.55 (q, 2H, J = 7.2 Hz), 3.43
(d, 2H, J = 5.8 Hz), 3.29 (s, 3H), 2.76-2.49 (m, 3H), 2.23-2.14 (m,
2H), 1.17 (t, 3H, J = 7.2 Hz).
TABLE-US-00020 TABLE 1-20 Example No. 1H-NMR (DMSO-d6) .delta.
(peak, integ., J) S46 1H-NMR (DMSO-d6) .delta.: 12.84 (s, 1H),
10.46 (t, 1H, J = 6.0 Hz), 8.54 (s, 1H), 7.53-7.46 (m, 1H),
7.36-7.30 (m, 1H), 7.23-7.17 (m, 1H), 4.81 (t, 1H, J = 5.3 Hz),
4.61 (d, 2H, J = 6.0 Hz), 3.89 (s, 2H), 3.59 (q, 2H, J = 7.2 Hz),
3.47-3.40 (m, 2H), 2.60-2.31 (m, 3H), 2.21-2.12 (m, 2H), 1.19 (t,
3H, J = 7.2 Hz). S47 1H-NMR (DMSO-d6) .delta.: 12.81 (br s, 1H),
10.46 (t, 1H, J = 6.0 Hz), 8.53 (s, 1H), 7.53-7.47 (m, 1H), 7.36-
7.30 (m, 1H), 7.23-7.18 (m, 1H), 4.62 (d, 2H, J = 6.0 Hz), 3.89 (s,
2H), 3.59 (q, 2H, J = 7.2 Hz), 3.42-3.35 (m, 2H), 3.27 (s, 3H),
2.69-2.51 (m, 1H), 2.42-2.30 (m, 2H), 2.29-2.19 (m, 2H), 1.19 (t,
3H, J = 7.2 Hz). S48 1H-NMR (DMSO-d6) .delta.: 12.83 (s, 1H), 10.45
(t, 1H, J = 6.0 Hz), 8.54 (s, 1H), 7.52-7.46 (m, 1H), 7.36-7.29 (m,
1H), 7.23-7.16 (m, 1H), 4.61 (d, 2H, J = 6.0 Hz), 3.89 (s, 2H),
3.59 (q, 2H, J = 7.2 Hz), 3.48- 3.36 (m, 4H), 2.70-2.51 (m, 1H),
2.41-2.31 (m, 2H), 2.30-2.20 (m, 2H), 1.19 (t, 3H, J = 7.4 Hz),
1.10 (t, 3H, J = 7.2 Hz). S49 1H-NMR (DMSO-d6) .delta.: 12.93 (s,
1H), 10.43-10.36 (m, 1H), 8.58 (s, 1H), 7.32 (t, 1H, J = 8.5 Hz),
7.02- 6.97 (m, 1H), 4.77 (t, 1H, J = 5.2 Hz), 4.54 (d, 2H, J = 6.0
Hz), 3.87 (s, 3H), 3.82 (s, 2H), 3.47 (t, 2H, J = 5.2 Hz), 3.10 (s,
3H), 2.69-2.40 (m, 3H), 2.28-2.19 (m, 2H). S50 1H-NMR (DMSO-d6)
.delta.: 12.80 (br s, 1H), 10.39 (t, 1H, J = 6.0 Hz), 8.53 (s, 1H),
7.32 (t, 1H, J = 8.5 Hz), 7.01-6.97 (m, 1H), 4.82 (t, 1H, J = 5.2
Hz), 4.53 (d, 2H, J = 6.0 Hz), 3.89 (s, 2H), 3.87 (s, 3H), 3.43 (t,
2H, J = 4.8 Hz), 3.14 (s, 3H), 2.55-2.30 (m, 3H), 2.25-2.15 (m,
2H). S51 1H-NMR (DMSO-d6) .delta.: 12.83 (br s, 1H), 10.38 (t, 1H,
J = 6.0 Hz), 8.49 (s, 1H), 7.45-7.37 (m, 1H), 7.28- 7.19 (m, 1H),
7.10-7.02 (m, 1H), 4.55 (d, 2H, J = 6.0 Hz), 4.10-4.01 (m, 1H),
3.79 (s, 2H), 3.41 (q, 2H, J = 6.9 Hz), 3.12 (s, 3H), 2.72-2.63 (m,
2H), 2.44-2.31 (m, 2H), 1.13 (t, 3H, J = 6.9 Hz). S52 1H-NMR
(DMSO-d6) .delta.: 12.40 (s, 1H), 10.41 (t, 1H, J = 6.0 Hz), 8.43
(s, 1H), 7.44-7.36 (m, 1H), 7.27-7.20 (m, 1H), 7.09-7.03 (m, 1H),
4.54 (d, 2H, J = 6.0 Hz), 4.44 (s, 2H), 4.15-4.01 (m, 2H), 3.18 (s,
3H), 2.76-2.65 (m, 2H), 2.23-2.15 (m, 2H), 1.46 (d, 6H, J = 6.7
Hz). S53 1H-NMR (DMSO-d6) .delta.: 10.41 (t, 1H, J = 6.0 Hz), 8.45
(s, 1H), 7.44-7.36 (m, 1H), 7.27-7.20 (m, 1H), 7.10- 7.02 (m, 1H),
4.54 (d, 2H, J = 6.0 Hz), 4.37 (s, 2H), 4.32-4.14 (m, 1H),
3.91-3.83 (m, 1H), 3.18 (s, 3H), 2.56-2.42 (m, 2H), 2.40-2.30 (m,
2H), 1.43 (d, 6H, J = 6.9 Hz). S54 1H-NMR (DMSO-d6) .delta.:
12.58-12.27 (m, 1H), 10.42 (t, 1H, J = 6.0 Hz), 8.40 (s, 1H),
7.44-7.36 (m, 1H), 7.27-7.20 (m, 1H), 7.10-7.02 (m, 1H), 5.01-3.98
(m, 2H), 4.54 (d, 2H, J = 6.0 Hz), 4.49 (s, 2H), 2.80-2.68 (m, 2H),
2.13-2.04 (m, 2H), 1.45 (d, 6H, J = 6.9 Hz).
TABLE-US-00021 TABLE 1-21 Example No. 1H-NMR (DMSO-d6) .delta.
(peak, integ., J) S55 1H-NMR (DMSO-d6) .delta.: 12.54-12.20 (m,
1H), 10.43 (t, 1H, J = 6.0 Hz), 8.46 (s, 1H), 7.44-7.36 (m, 1H),
7.33-7.18 (m, 1H), 7.10-7.03 (m, 1H), 4.54 (d, 2H, J = 6.0 Hz),
4.43-3.77 (m, 2H), 4.35 (s, 2H), 2.47-2.37 (m, 2H), 2.37-2.28 (m,
2H), 1.44 (d, 6H, J = 6.7 Hz). S56 1H-NMR (DMSO-d6) .delta.: 12.39
(br s, 1H), 10.47 (t, 1H, J = 6.0 Hz), 8.45 (s, 1H), 7.52-7.46 (m,
1H), 7.35- 7.29 (m, 1H), 7.23-7.17 (m, 1H), 4.61 (d, 2H, J = 6.0
Hz), 4.46 (s, 2H), 4.20-4.12 (m, 1H), 3.64 (q, 2H, J = 7.2 Hz),
3.36 (q, 2H, J = 6.9 Hz), 2.72-2.63 (m, 2H), 2.22-2.13 (m, 2H),
1.21-1.12 (m, 6H). S57 1H-NMR (DMSO-d6) .delta.: 12.38-12.24 (m,
1H), 10.46 (t, 1H, J = 5.8 Hz), 8.45 (s, 1H), 7.52-7.47 (m, 1H),
7.35-7.29 (m, 1H), 7.23-7.17 (m, 1H), 4.62 (d, 2H, J = 5.8 Hz),
4.39 (s, 2H), 4.02-3.93 (m, 1H), 3.65 (q, 2H, J = 7.2 Hz),
3.45-3.32 (m, 2H), 2.54-2.46 (m, 2H), 2.34-2.23 (m, 2H), 1.19-1.09
(m, 6H). S58 1H-NMR (DMSO-d6) .delta.: 12.58-12.31 (m, 1H), 10.47
(t, 1H, J = 6.0 Hz), 8.49 (s, 1H), 7.52-7.46 (m, 1H), 7.35-7.29 (m,
1H), 7.23-7.17 (m, 1H), 4.61 (d, 2H, J = 6.0 Hz), 4.42 (s, 2H),
3.72 (q, 2H, J = 7.2 Hz), 3.52-3.47 (m, 2H), 2.59-2.40 (m, 3H),
2.08-1.98 (m, 2H), 1.22 (t, 3H, J = 7.2 Hz). S59 1H-NMR (DMSO-d6)
.delta.: 12.45 (s, 1H), 10.47 (t, 1H, J = 6.0 Hz), 8.53 (s, 1H),
7.53-7.46 (m, 1H), 7.36-7.29 (m, 1H), 7.24-7.16 (m, 1H), 4.62 (d,
2H, J = 6.0 Hz), 4.42 (s, 2H), 3.72 (q, 2H, J = 6.9 Hz), 3.46 (d,
2H, J = 6.9 Hz), 3.28 (s, 3H), 2.74-2.60 (m, 1H), 2.59-2.46 (m,
2H), 2.05-1.96 (m, 2H), 1.22 (t, 3H, J = 6.9 Hz). S60 1H-NMR
(DMSO-d6) .delta.: 12.40 (br s, 1H), 10.48 (t, 1H, J = 6.0 Hz),
8.53 (s, 1H), 7.54-7.46 (m, 1H), 7.36- 7.29 (m, 1H), 7.20 (t, 1H, J
= 7.9 Hz), 4.62 (d, 2H, J = 6.0 Hz), 4.50 (s, 2H), 3.67 (q, 2H, J =
6.9 Hz), 3.46-3.41 (m, 2H), 2.70-2.24 (m, 3H), 2.06-1.96 (m, 2H),
1.16 (t, 3H, J = 6.9 Hz). S61 1H-NMR (DMSO-d6) .delta.: 12.83-11.92
(m, 1H), 10.47 (t, 1H, J = 6.0 Hz), 8.52 (s, 1H), 7.53-7.46 (m,
1H), 7.36-7.29 (m, 1H), 7.23-7.17 (m, 1H), 4.62 (d, 2H, J = 6.0
Hz), 4.50 (s, 2H), 3.66 (q, 2H, J = 7.2 Hz), 3.43-3.35 (m, 2H),
3.27 (s, 3H), 2.61-2.38 (m, 1H), 2.29-2.20 (m, 2H), 2.13-2.03 (m,
2H), 1.15 (t, 3H, J = 7.2 Hz). S62 1H-NMR (DMSO-d6) .delta.: 12.43
(s, 1H), 10.46 (t, 1H, J = 6.0 Hz), 8.46 (s, 1H), 7.52-7.46 (m,
1H), 7.35-7.29 (m, 1H), 7.23-7.16 (m, 1H), 4.61 (d, 2H, J = 6.0
Hz), 4.47 (s, 2H), 4.11-4.01 (m, 1H), 3.18 (s, 3H), 3.14 (s, 3H),
2.79-2.70 (m, 2H), 2.20-2.11 (m, 2H). S63 1H-NMR (DMSO-d6) .delta.:
12.64-12.00 (m, 1H), 10.46 (t, 1H, J = 6.0 Hz), 8.46 (s, 1H),
7.53-7.47 (m, 1H), 7.35-7.29 (m, 1H), 7.23-7.17 (m, 1H), 4.62 (d,
2H, J = 6.0 Hz), 4.41 (s, 2H), 3.91-3.83 (m, 1H), 3.17 (s, 3H),
3.11 (s, 3H), 2.47-2.31 (m, 4H).
TABLE-US-00022 TABLE 2-1 Example No. structural formula salt
compound name T1 ##STR00304## HCl (1S,2S)-N-(2,4-
difluorobenzyl)-2'-ethy1-9'- hydroxy-2-(hydroxymethyl)-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride T2
##STR00305## HCl (1S,2S)-N-(2,4- difluorobenzyl)-2'-ethyl-9'-
hydroxy-2-(methoxymethyl)- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride T3 ##STR00306## HCl (1S,2S)-N-(2,4-
difluorobenzyl)-9'-hydroxy-2- (methoxymethyl)-2'-methyl-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride T4
##STR00307## HCl (1S,2S)-N-(2,4- difluorobenzyl)-9'-hydroxy-2-
(hydroxymethyl)-2'-methyl- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride T5 ##STR00308## HCl
(1R,2R)-N-(3-chloro-2- fluorobenzyl)-9'-hydroxy-2-
(hydroxymethyl)-2'-isopropyl- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride
TABLE-US-00023 TABLE 2-2 Example No. structural formula salt
compound name T6 ##STR00309## HCl (1R,2R)-N-(3-chloro-2-
fluorobenzyl)-9'-hydroxy-2'- isopropyl-2-(methoxymethyl)-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride T7
##STR00310## HCl (1S,2S)-7'-(2,4- difluorobenzylcarbamoyl)-2'-
ethyl-9'-hydroxy-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
2-carboxylic acid hydrochloride T8 ##STR00311## HCl
(1S,2S)-N.sup.7'-(2,4- difluorobenzyl)-2'-ethyl-9'-
hydroxy-N.sup.2-methyl-1',8'- dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
2,7'-dicarboxamide hydrochloride T9 ##STR00312## HCl
(1R,2R)-N-(2,4- difluorobenzyl)-2'-ethyl-9'-
hydroxy-2-(methoxymethyl)- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride T10 ##STR00313## HCl (1R,2R)-N-(2,4-
difluorobenzyl)-2'-ethyl-9'- hydroxy-2-(hydroxymethyl)-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride
TABLE-US-00024 TABLE 2-3 Example No. structural formula salt
compound name T11 ##STR00314## HCl (1S,2S)-N-(3-chloro-2-
fluorobenzyl)-9'-hydroxy-2- (hydroxymethyl)-2'-isopropyl-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride T12
##STR00315## HCl (1S,2S)-N-(3-chloro-2-
fluorobenzyl)-9'-hydroxy-2'- isopropyl-2-(methoxymethyl)-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride T13
##STR00316## HCl (1S,2S)-N.sup.7'-(3-chloro-2-
fluorobenzyl)-9'-hydroxy-2'- isopropyl-N.sup.2,N.sup.2-dimethyl-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 2,7'-dicarboxamide hydrochloride T14
##STR00317## HCl (1R,2R)-N.sup.7'-(3-chloro-2-
fluorobenzyl)-9'-hydroxy-2'- isopropyl-N.sup.2,N.sup.2-dimethyl-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 2,7'-dicarboxamide hydrochloride T15
##STR00318## HCl (1S,2S)-N-(3-chloro-2- fluorobenzyl)-9'-hydroxy-2-
(hydroxymethyl)-2'-methyl- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride
TABLE-US-00025 TABLE 2-4 Example No. structural formula salt
compound name T16 ##STR00319## HCl (1S,2S)-N-(3-chloro-2-
fluorobenzyl)-9'-hydroxy-2- (methoxymethyl)-2'-methyl-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride T17
##STR00320## HCl (1R,2R)-N-(3-chloro-2- fluorobenzyl)-2'-ethyl-9'-
hydroxy-2-(hydroxymethyl)- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride T18 ##STR00321## HCl
(1S,2S)-N-(3-chloro-2- fluorobenzyl)-2'-ethyl-9'-
hydroxy-2-(hydroxymethyl)- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride T19 ##STR00322##
(1S,2S)-N-(3-chloro-2- fluorobenzyl)-2'-ethyl-9'-
hydroxy-2-(methoxymethyl)- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide T20 ##STR00323## HCl (1R,2R)-N-(3-chloro-2-
fluorobenzyl)-2'-ethyl-9'- hydroxy-2-(methoxymethyl)-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride
TABLE-US-00026 TABLE 2-5 Example No. structural formula salt
compound name T21 ##STR00324## (1S,2S)-N-(3-chloro-2-fluoro-
5-methoxybenzyl)-9'-hydroxy- 2-(methoxymethyl)-2'-methyl-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide T22 ##STR00325## HCl
(1S,2S)-N-(3-chloro-2-fluoro- 4-methoxybenzyl)-9'-hydroxy-
2-(methoxymethyl)-2'-methyl- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride T23 ##STR00326## HCl
(1R,2R)-N-(3-chloro-2- fluorobenzyl)-9'-hydroxy-2-
(hydroxymethyl)-2'-methyl- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride T24 ##STR00327## HCl
(1R,2R)-N-(3-chloro-2- fluorobenzyl)-9'-hydroxy-2-
(methoxymethyl)-2'-methyl- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride T25 ##STR00328## HCl
(1S,2S)-N-(3-chloro-5-ethoxy- 2-fluorobenzyl)-9'-hydroxy-2-
(methoxymethyl)-2'-methyl- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride
TABLE-US-00027 TABLE 2-6 Example No. structural formula salt
compound name T26 ##STR00329## HCl (1S,2S)-N-(3-chloro-2-fluoro-
5-isopropoxybenzyl)-9'- hydroxy-2-(methoxymethyl)-2'-
methyl-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride T27
##STR00330## (1S,2S)-2'-ethyl-N-(2-fluoro-
3-(trifluoromethyl)benzyl)- 9'-hydroxy-2-(methoxymethyl)-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide T28 ##STR00331## HCl
(1S,2R)-N-(3-chloro-2- fluorobenzyl)-9'-hydroxy-2-
(hydroxymethyl)-2'-isopropyl- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride T29 ##STR00332## HCl
(1S,2R)-N-(3-chloro-2- fluorobenzyl)-2'-ethyl-9'-
hydroxy-2-(hydroxymethyl)- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carbcxamide hydrochloride T30 ##STR00333##
(1S,2R)-N-(3-chloro-2- fluorobenzyl)-2'-ethyl-9'-
hydroxy-2-(methoxymethyl)- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide
TABLE-US-00028 TABLE 2-7 Example No. structural formula salt
compound name T31 ##STR00334## (1S,2S)-N-(3-chloro-2-fluoro-
4-methoxybenzyl)-2- (ethoxymethyl)-9'-hydroxy-2'-
methyl-1',8'-dioxo- 1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide T32 ##STR00335##
(1S,2S)-N.sup.7'-(3-chloro-2- fluorobenzyl)-2'-cyclopropyl-
9'-hydroxy-N.sup.2,N.sup.2-dimethyl- 1',8'-dioxo-1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
2,7'-dicarboxamide T33 ##STR00336## (1R,2R)-N.sup.7'-(3-Chloro-2-
fluorobenzyl)-2'-cyclopropyl- 9'-hydroxy-N.sup.2,N.sup.2-dimethyl-
1',8'-dioxo-1',2',3',8,- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 2,7'-dicarboxamide T34 ##STR00337##
(1S,2S)-N-(3-chloro-2-fluoro- 5-(2-oxopyrrolidin-1-
yl)benzyl)-9'-hydroxy-2- (methoxymethyl)-2'-methyl-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide T35 ##STR00338## HCl
(1R,2R)-N-(3-chloro-2-fluoro- 4-methoxybenzyl)-2-
(ethoxymethyl)-9'-hydroxy-2'- methyl-1',8'-dioxo- 1',2',3',8'-
tetrahydrospiro[cyclopropane- 1,4'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride
TABLE-US-00029 TABLE 2-8 Example No. structural formula salt
compound name T36 ##STR00339## HCl (1R,2R)-N-(3-chloro-2-fluoro-
4-methoxybenzyl)-9'-hydroxy- 2-(methoxymethyl)-2'-methyl-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride T37
##STR00340## HCl (1S,2S)-N-(3-chloro-4-ethoxy-
2-fluorobenzyl)-9'-hydroxy-2- (methoxymethyl)-2'-methyl-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride T38
##STR00341## HCl (1R,2R)-N-(3-chloro-4-ethoxy-
2-fluorobenzyl)-9'-hydroxy-2- (methoxymethyl)-2'-methyl-
1',8'-dioxo-1',2',3',8'- tetrahydrospiro[cyclopropane-
1,4'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride T39
##STR00342## HCl (1S,2S)-N-(2,4- difluorobenzyl)-2'-ethyl-9'-
hydroxy-2-(hydroxymethyl)- 1',8'-dioxo-1',2',4',8'-
tetrahydrospiro[cyclopropane- 1,3'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride T40 ##STR00343## HCl (1S,2S)-N-(2,4-
difluorobenzyl)-2'-ethyl-9'- hydroxy-2-(methoxymethyl)-
1',8'-dioxo-1',2',4',8'- tetrahydrospiro[cyclopropane-
1,3'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride
TABLE-US-00030 TABLE 2-9 Example No. structural formula salt
compound name T41 ##STR00344## (1S,2S)-N-(2,4-
difluorobenzyl)-9'-hydroxy- 2'-isopropyl-2-
(methoxymethyl)-1',8'-dioxo- 1',2',4',8'-
tetrahydrospiro[cyclopropane- 1,3'-pyrido[1,2-a]pyrazine]-
7'-carboxamide T42 ##STR00345## (1S,2S)-N-(2,4-
difluorobenzyl)-9'-hydroxy-2- (hydroxymethyl)-2'-isopropyl-
1',8'-dioxo-1',2',4',8'- tetrahydrospiro[cyclopropane-
1,3'-pyrido[1,2-a]pyrazine]- 7'-carboxamide T43 ##STR00346##
(1S,2S)-N-(2,4- difluorobenzyl)-2- (ethoxymethyl)-9'-hydroxy-2'-
isopropyl-1',8'-dioxo- 1',2',4',8'- tetrahydrospiro[cyclopropane-
1,3'-pyrido[1,2-a]pyrazine]- 7'-carboxamide T44 ##STR00347## HCl
(1S,2S)-N-(3-chloro-2- fluorobenzyl)-2'-ethyl-9'-
hydroxy-2-(hydroxymethyl)- 1',8'-dioxo-1',2',4',8'-
tetrahydrospiro[cyclopropane- 1,3'-pyrido[1,2-a]pyrazine]-
7'-carboxamide hydrochloride T45 ##STR00348##
(1S,2S)-N-(3-chloro-2- fluorobenzyl)-2- (ethoxymethyl)-2'-ethyl-9'-
hydroxy-1',8'-dioxo- 1',2',4',8'- tetrahydrospiro[cyclopropane-
1,3'-pyrido[1,2-a]pyrazine]- 7'-carboxamide
TABLE-US-00031 TABLE 2-10 Example No. structural formula salt
compound name T46 ##STR00349## HCl (1R,2R)-N-(3-chloro-2-
fluorobenzyl)-2'-ethyl-9'- hydroxy-2-(hydroxymethyl)-
1',8'-dioxo-1',2',4',8'- tetrahydrospiro[cyclopropane-
1,3'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride T47
##STR00350## (1S,2S)-N-(3-chloro-2- fluorobenzyl)-9'-hydroxy-2-
(hydroxymethyl)-2'-isopropyl- 1',8'-dioxo-1',2',4',8'-
tetrahydrospiro[cyclopropane- 1,3'-pyrido[1,2-a]pyrazine]-
7'-carboxamide T48 ##STR00351## HCl (1S,2S)-N-(3-chloro-2-fluoro-
4-methoxybenzyl)-2'-ethyl-9'- hydroxy-2-(hydroxymethyl)-
1',8'-dioxo-1',2',4',8'- tetrahydrospiro[cyclopropane-
1,3'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride T49
##STR00352## (1R,2R)-N-(3-chloro-2- fluorobenzyl)-9'-hydroxy-2-
(hydroxymethyl)-2'-methyl- 1',8'-dioxo-1',2',4',8'-
tetrahydrospiro[cyclopropane- 1,3'-pyrido[1,2-a]pyrazine]-
7'-carboxamide T50 ##STR00353## HCl (1R,2R)-N-(3-chloro-2-
fluorobenzyl)-9'-hydroxy-2- (methoxymethyl)-2'-methyl-
1',8'-dioxo-1',2',4',8'- tetrahydrospiro[cyclopropane-
1,3'-pyrido[1,2-a]pyrazine]- 7'-carboxamide hydrochloride
TABLE-US-00032 TABLE 2-11 Example 1H-NMR (DMSO-d6) No. .delta.
(peak, integ., J) T1 1H-NMR (DMSO-d6) .delta.: 12.86-12.61 (m, 1H),
10.37 (t, 1H, J = 6.0 Hz), 8.14 (s, 1H), 7.43-7.35 (m, 1H),
7.27-7.19 (m, 1H), 7.09-7.02 (m, 1H), 4.52 (d, 2H, J = 6.0 Hz),
3.85 (s, 2H), 3.76 (dd, 1H, J = 12.1, 5.3 Hz), 3.65-3.54 (m, 1H),
3.54-3.42 (m, 2H), 1.96-1.86 (m, 1H), 1.69 (dd, 1H, J = 10.6, 6.6
Hz), 1.30-1.21 (m, 1H), 1.16 (t, 3H, J = 7.3 Hz), 1.07 (t, 1H, J =
7.1 Hz). T2 1H-NMR (DMSO-d6) .delta.: 12.73 (s, 1H), 10.35 (t, 1H,
J = 6.0 Hz), 8.10 (s, 1H), 7.43-7.35 (m, 1H), 7.27-7.19 (m, 1H),
7.09-7.02 (m, 1H), 4.52 (d, 2H, J = 6.0 Hz), 3.96 (d, 1H, J = 13.9
Hz), 3.71 (d, 1H, J = 13.9 Hz), 3.67-3.57 (m, 2H), 3.50-3.38 (m,
2H), 3.24 (s, 3H), 1.95-1.85 (m, 2H), 1.15 (t, 3H, J = 7.3 Hz),
1.14-1.08 (m, 1H). T3 1H-NMR (DMSO-d6) .delta.: 12.67 (s, 1H),
10.35 (t, 1H, J = 5.8 Hz), 8.10 (s, 1H), 7.44-7.35 (m, 1H),
7.26-7.19 (m, 1H), 7.09-7.02 (m, 1H), 4.52 (d, 2H, J = 6.0 Hz),
4.02 (d, 1H, J = 13.9 Hz), 3.67-3.59 (m, 2H), 3.45-3.33 (m, 1H),
3.25 (s, 3H), 3.06 (s, 3H), 1.95-1.81 (m, 2H), 1.20-1.13 (m, 1H).
T4 1H-NMR (DMSO-d6) .delta.: 12.81-12.59 (m, 1H), 10.36 (t, 1H, J =
6.0 Hz), 8.14 (s, 1H), 7.43-7.35 (m, 1H), 7.26-7.19 (m, 1H),
7.09-7.02 (m, 1H), 4.52 (d, 2H, J = 6.0 Hz), 3.91 (d, 1H, J = 14.1
Hz), 3.80-3.73 (m, 2H), 3.40 (dd, 1H, J = 12.0, 8.6 Hz), 3.08 (s,
3H), 1.94-1.82 (m, 1H), 1.74-1.68 (m, 1H), 1.18 (t, 1H, J = 7.2
Hz). T5 1H-NMR (DMSO-d6) .delta.: 12.90-12.74 (m, 1H), 10.43 (t,
1H, J = 5.6 Hz), 8.14 (s, 1H), 7.49 (t, 1H, J = 7.3 Hz), 7.31 (t,
1H, J = 6.9 Hz), 7.19 (t, 1H, J = 8.1 Hz), 4.80-4.68 (m, 1H), 4.59
(d, 2H, J = 6.0 Hz), 3.80-3.68 (m, 3H), 3.57-3.47 (m, 1H),
1.95-1.84 (m, 1H), 1.76-1.66 (m, 1H), 1.31-1.22 (m, 1H), 1.19 (d,
3H, J = 6.9 Hz), 1.17 (d, 3H, J = 6.9 Hz), 1.03 (t, 1H, J = 7.3
Hz). T6 1H-NMR (DMSO-d6) .delta.: 12.89-12.76 (m, 1H), 10.46-10.35
(m, 1H), 8.10 (s, 1H), 7.49 (t, 1H, J = 7.7 Hz), 7.31 (t, 1H, J =
7.3 Hz), 7.19 (t, 1H, J = 7.7 Hz), 4.79-4.68 (m, 1H), 4.59 (d, 2H,
J = 6.0 Hz), 3.80 (d, 1H, J = 14.1 Hz), 3.67 (d, 1H, J = 14.1 Hz),
3.61-3.53 (m, 1H), 3.51-3.42 (m, 1H), 3.23 (s, 3H), 1.95-1.83 (m,
2H), 1.18 (d, 6H, J = 6.9 Hz), 1.11-1.03 (m, 1H). T7 1H-NMR
(DMSO-d6) .delta.: 13.09-12.95 (m, 1H), 12.62-12.57 (m, 1H),
10.34-10.26 (m, 1H), 8.12 (s, 1H), 7.44-7.36 (m, 1H), 7.27-7.19 (m,
1H), 7.09-7.02 (m, 1H), 4.60-4.45 (m, 2H), 4.29-4.19 (m, 1H),
3.71-3.60 (m, 1H), 3.55-3.44 (m, 1H), 3.42-3.30 (m, 1H), 2.69-2.40
(m, 1H), 2.34-2.22 (m, 1H), 1.81-1.65 (m, 1H), 1.12-1.01 (m, 3H).
T8 1H-NMR (DMSO-d6) .delta.: 12.68 (s, 1H), 10.30 (t, 1H, J = 6.0
Hz), 8.32-8.25 (m, 1H), 8.15 (s, 1H), 7.42-7.34 (m, 1H), 7.25-7.18
(m, 1H), 7.08-7.01 (m, 1H), 4.55-4.49 (m, 2H), 4.11 (d, 1H, J =
13.6 Hz), 3.68 (d, 1H, J = 13.6 Hz), 3.56-3.46 (m, 1H), 3.34-3.20
(m, 1H), 2.60 (d, 3H, J = 4.6 Hz), 2.40-2.30 (m, 1H), 2.14 (t, 1H,
J = 8.6 Hz), 1.62 (t, 1H, J = 7.6 Hz), 1.03 (t, 3H, J = 7.2 Hz). T9
1H-NMR (DMSO-d6) .delta.: 12.73 (s, 1H), 10.35 (t, 1H, J = 6.0 Hz),
8.10 (s, 1H), 7.43-7.35 (m, 1H), 7.27-7.19 (m, 1H), 7.09-7.02 (m,
1H), 4.52 (d, 2H, J = 6.0 Hz), 3.97 (d, 1H, J = 14.1 Hz), 3.71 (d,
1H, J = 14.1 Hz), 3.66-3.57 (m, 2H), 3.49-3.35 (m, 2H), 3.24 (s,
3H), 1.96-1.85 (m, 2H), 1.15 (t, 3H, J = 7.3 Hz), 1.14-1.08 (m,
1H).
TABLE-US-00033 TABLE 2-12 Example 1H-NMR (DMSO-d6) No. .delta.
(peak, integ., J) T10 1H-NMR (DMSO-d6) .delta.: 12.82-12.64 (m,
1H), 10.37 (t, 1H, J = 6.0 Hz), 8.14 (s, 1H), 7.43-7.35 (m, 1H),
7.27-7.19 (m, 1H), 7.10-7.02 (m, 1H), 4.52 (d, 2H, J = 6.0 Hz),
3.85 (s, 2H), 3.76 (dd, 1H, J = 11.7, 5.1 Hz), 3.65-3.55 (m, 1H),
3.54-3.42 (m, 2H), 1.96-1.86 (m, 1H), 1.69 (dd, 1H, J = 10.8, 6.8
Hz), 1.29-1.21 (m, 1H), 1.16 (t, 3H, J = 7.3 Hz), 1.07 (t, 1H, J =
7.3 Hz). T11 1H-NMR (DMSO-d6) .delta.: 12.90-12.74 (m, 1H), 10.43
(t, 1H, J = 5.6 Hz), 8.14 (s, 1H), 7.49 (t, 1H, J = 7.3 Hz), 7.31
(t, 1H, J = 6.9 Hz), 7.19 (t, 1H, J = 8.1 Hz), 4.80-4.68 (m, 1H),
4.59 (d, 2H, J = 6.0 Hz), 3.80-3.68 (m, 3H), 3.57-3.47 (m, 1H),
1.95-1.84 (m, 1H), 1.76-1.66 (m, 1H), 1.31-1.22 (m, 1H), 1.19 (d,
3H, J = 6.9 Hz), 1.17 (d, 3H, J = 6.9 Hz), 1.03 (t, 1H, J = 7.3
Hz). T12 1H-NMR (DMSO-d6) .delta.: 12.89-12.76 (m, 1H), 10.46-10.35
(m, 1H), 8.10 (s, 1H), 7.49 (t, 1H, J = 7.7 Hz), 7.31 (t, 1H, J =
7.3 Hz), 7.19 (t, 1H, J = 7.7 Hz), 4.79-4.68 (m, 1H), 4.59 (d, 2H,
J = 6.0 Hz), 3.80 (d, 1H, J = 14.1 Hz), 3.67 (d, 1H, J = 14.1 Hz),
3.61-3.53 (m, 1H), 3.51-3.42 (m, 1H), 3.23 (s, 3H), 1.95-1.83 (m,
2H), 1.18 (d, 6H, J = 6.9 Hz), 1.11-1.03 (m, 1H). T13 1H-NMR
(DMSO-d6) .delta.: 12.84-12.65 (m, 1H), 10.41 (t, 1H, J = 6.0 Hz),
8.15 (s, 1H), 7.51-7.46 (m, 1H), 7.35-7.29 (m, 1H), 7.22-7.16 (m,
1H), 4.71-4.61 (m, 2H), 4.59-4.51 (m, 1H), 3.99 (d, 1H, J = 13.7
Hz), 3.30 (d, 1H, J = 13.7 Hz), 2.94 (s, 3H), 2.81 (s, 3H),
2.73-2.65 (m, 1H), 2.45-2.36 (m, 1H), 1.75 (t, 1H, J = 7.3 Hz),
1.09 (d, 3H, J = 6.9 Hz), 0.95 (d, 3H, J = 6.4 Hz). T14 1H-NMR
(DMSO-d6) .delta.: 12.84-12.65 (m, 1H), 10.41 (t, 1H, J = 6.0 Hz),
8.15 (s, 1H), 7.51-7.46 (m, 1H), 7.35-7.29 (m, 1H), 7.22-7.16 (m,
1H), 4.71-4.61 (m, 2H), 4.59-4.51 (m, 1H), 3.99 (d, 1H, J = 13.7
Hz), 3.30 (d, 1H, J = 13.7 Hz), 2.94 (s, 3H), 2.81 (s, 3H),
2.73-2.65 (m, 1H), 2.45-2.36 (m, 1H), 1.75 (t, 1H, J = 7.3 Hz),
1.09 (d, 3H, J = 6.9 Hz), 0.95 (d, 3H, J = 6.4 Hz). T15 1H-NMR
(DMSO-d6) .delta.: 12.70 (s, 1H), 10.42 (t, 1H, J = 6.0 Hz), 8.14
(s, 1H), 7.52-7.46 (m, 1H), 7.34-7.28 (m, 1H), 7.22-7.16 (m, 1H),
4.94-4.79 (m, 1H), 4.59 (d, 2H, J = 6.0 Hz), 3.91 (d, 1H, J = 13.9
Hz), 3.81-3.72 (m, 2H), 3.44-3.26 (m, 1H), 3.08 (s, 3H), 1.94-1.83
(m, 1H), 1.75-1.68 (m, 1H), 1.12 (t, 1H, J = 6.9 Hz). T16 1H-NMR
(DMSO-d6) .delta.: 12.68 (s, 1H), 10.44-10.38 (m, 1H), 8.10 (s,
1H), 7.52-7.45 (m, 1H), 7.34-7.28 (m, 1H), 7.22-7.16 (m, 1H), 4.59
(d, 2H, J = 6.0 Hz), 4.02 (d, 1H, J = 14.1 Hz), 3.67-3.59 (m, 2H),
3.41-3.31 (m, 1H), 3.25 (s, 3H), 3.06 (s, 3H), 1.95-1.84 (m, 2H),
1.20-1.13 (m, 1H). T17 1H-NMR (DMSO-d6) .delta.: 12.74 (s, 1H),
10.42 (t, 1H, J = 6.0 Hz), 8.14 (s, 1H), 7.52-7.46 (m, 1H),
7.34-7.28 (m, 1H), 7.22-7.16 (m, 1H), 4.90-4.84 (m, 1H), 4.59 (d,
2H, J = 6.0 Hz), 3.85 (s, 2H), 3.79-3.72 (m, 1H), 3.67-3.54 (m,
1H), 3.54-3.41 (m, 2H), 1.97-1.86 (m, 1H), 1.73-1.66 (m, 1H), 1.16
(t, 3H, J = 7.2 Hz), 1.07 (t, 1H, J = 6.9 Hz). T18 1H-NMR (DMSO-d6)
.delta.: 12.74 (s, 1H), 10.42 (t, 1H, J = 6.0 Hz), 8.14 (s, 1H),
7.52-7.46 (m, 1H), 7.34-7.28 (m, 1H), 7.22-7.16 (m, 1H), 4.90-4.84
(m, 1H), 4.59 (d, 2H, J = 6.0 Hz), 3.85 (s, 2H), 3.79-3.72 (m, 1H),
3.67-3.54 (m, 1H), 3.54-3.41 (m, 2H), 1.97-1.86 (m, 1H), 1.73-1.66
(m, 1H), 1.16 (t, 3H, J = 7.2 Hz), 1.07 (t, 1H, J = 6.9 Hz).
TABLE-US-00034 TABLE 2-13 Example 1H-NMR (DMSO-d6) No. .delta.
(peak, integ., J) T19 1H-NMR (DMSO-d6) .delta.: 12.81-12.64 (m,
1H), 10.52-10.30 (m, 1H), 8.21-8.01 (m, 1H), 7.63-6.98 (m, 3H),
4.74-4.46 (m, 2H), 4.12-3.84 (m, 1H), 3.83-3.05 (m, 8H), 2.00-1.79
(m, 2H), 1.49-0.75 (m, 4H). T20 1H-NMR (DMSO-d6) .delta.: 12.74 (s,
1H), 10.41 (t, 1H, J = 6.0 Hz), 8.10 (s, 1H), 7.51-7.46 (m, 1H),
7.34-7.28 (m, 1H), 7.22-7.16 (m, 1H), 4.59 (d, 2H, J = 6.0 Hz),
3.96 (d, 1H, J = 14.1 Hz), 3.71 (d, 1H, J = 14.1 Hz), 3.66-3.57 (m,
2H), 3.49-3.37 (m, 2H), 3.24 (s, 3H), 1.96-1.84 (m, 2H), 1.15 (t,
3H, J = 7.2 Hz), 1.14-1.09 (m, 1H). T21 1H-NMR (DMSO-d6) .delta.:
12.73-12.63 (m, 1H), 10.38 (t, 1H, J = 6.0 Hz), 8.10 (s, 1H), 7.07
(dd, 1H, J = 5.6, 2.8 Hz), 6.85 (dd, 1H, J = 5.6, 3.2 Hz), 4.54 (d,
2H, J = 6.0 Hz), 4.03 (d, 1H, J = 13.7 Hz), 3.73 (s, 3H), 3.68-3.59
(m, 2H), 3.40-3.33 (m, 1H), 3.25 (s, 3H), 3.06 (s, 3H), 1.96-1.83
(m, 2H), 1.19-1.13 (m, 1H). T22 1H-NMR (DMSO-d6) .delta.:
12.79-12.51 (m, 1H), 10.33 (t, 1H, J = 6.0 Hz), 8.10 (s, 1H), 7.30
(t, 1H, J = 8.9 Hz), 6.98 (dd, 1H, J = 8.9, 1.6 Hz), 4.51 (d, 2H, J
= 6.0 Hz), 4.06-3.99 (m, 1H), 3.87 (s, 3H), 3.67-3.59 (m, 2H),
3.40-3.33 (m, 1H), 3.25 (s, 3H), 3.06 (s, 3H), 1.95-1.82 (m, 2H),
1.21-1.14 (m, 1H). T23 1H-NMR (DMSO-d6) .delta.: 12.70 (br s, 1H),
10.42 (t, 1H, J = 6.0 Hz), 8.14 (s, 1H), 7.52-7.45 (m, 1H),
7.35-7.28 (m, 1H), 7.22-7.16 (m, 1H), 4.59 (d, 2H, J = 6.0 Hz),
3.91 (d, 1H, J = 13.9 Hz), 3.81-3.73 (m, 2H), 3.48-3.32 (m, 1H),
3.08 (s, 3H), 1.92-1.82 (m, 1H), 1.76-1.68 (m, 1H), 1.12 (t, 1H, J
= 7.2 Hz). T24 1H-NMR (DMSO-d6) .delta.: 12.68 (br s, 1H), 10.41
(t, 1H, J = 6.0 Hz), 8.10 (s, 1H), 7.52-7.45 (m, 1H), 7.35-7.28 (m,
1H), 7.22-7.16 (m, 1H), 4.59 (d, 2H, J = 6.0 Hz), 4.03 (d, 1H, J =
14.1 Hz), 3.68-3.59 (m, 2H), 3.45-3.32 (m, 1H), 3.25 (s, 3H), 3.06
(s, 3H), 1.95-1.81 (m, 2H), 1.21-1.12 (m, 1H). T25 1H-NMR (DMSO-d6)
.delta.: 12.79-12.58 (m, 1H), 10.38 (t, 1H, J = 6.0 Hz), 8.10 (s,
1H), 7.05 (dd, 1H, J = 5.6, 3.2 Hz), 6.82 (dd, 1H, J = 5.6, 3.2
Hz), 4.54 (d, 2H, J = 6.0 Hz), 4.03 (d, 1H, J = 13.7 Hz), 3.99 (q,
2H, J = 6.9 Hz), 3.68-3.59 (m, 2H), 3.41-3.33 (m, 1H), 3.25 (s,
3H), 3.06 (s, 3H), 1.97-1.82 (m, 2H), 1.28 (t, 3H, J = 6.9 Hz),
1.20-1.13 (m, 1H). T26 1H-NMR (DMSO-d6) .delta.: 12.87-12.54 (m,
1H), 10.38 (t, 1H, J = 6.0 Hz), 8.10 (s, 1H), 7.05 (dd, 1H, J =
5.6, 3.2 Hz), 6.80 (dd, 1H, J = 5.6, 3.2 Hz), 4.60-4.51 (m, 1H),
4.54 (d, 2H, J = 6.0 Hz), 4.03 (d, 1H, J = 14.1 Hz), 3.68-3.59 (m,
2H), 3.40-3.33 (m, 1H), 3.25 (s, 3H), 3.06 (s, 3H), 1.98-1.82 (m,
2H), 1.22 (d, 6H, J = 6.0 Hz), 1.20-1.13 (m, 1H). T27 1H-NMR
(DMSO-d6) .delta.: 12.74 (s, 1H), 10.44 (t, 1H, J = 6.0 Hz), 8.10
(s, 1H), 7.72-7.63 (m, 2H), 7.38 (t, 1H, J = 7.6 Hz), 4.63 (d, 2H,
J = 6.0 Hz), 3.96 (d, 1H, J = 13.9 Hz), 3.71 (d, 1H, J = 13.9 Hz),
3.69-3.57 (m, 2H), 3.50-3.37 (m, 2H), 3.24 (s, 3H), 1.97-1.84 (m,
2H), 1.15 (t, 3H, J = 7.4 Hz), 1.15-1.08 (m, 1H).
TABLE-US-00035 TABLE 2-14 Example 1H-NMR (DMSO-d6) No. .delta.
(peak, integ., J) T28 1H-NMR (DMSO-d6) .delta.: 12.89-12.38 (m,
1H), 10.44 (t, 1H, J = 6.0 Hz), 8.15 (s, 1H), 7.52-7.46 (m, 1H),
7.35-7.29 (m, 1H), 7.23-7.17 (m, 1H), 4.79-4.70 (m, 1H), 4.66-4.54
(m, 2H), 4.04 (d, 1H, J = 13.5 Hz), 3.52 (dd, 1H, J = 11.9, 4.0
Hz), 3.18 (d, 1H, J = 13.5 Hz), 2.69-2.55 (m, 1H), 1.98-1.87 (m,
1H), 1.45-1.35 (m, 2H), 1.18 (d, 3H, J = 6.6 Hz), 1.12 (d, 3H, J =
6.8 Hz), 0.91-0.81 (m, 1H). T29 1H-NMR (DMSO-d6) .delta.:
12.70-12.47 (m, 1H), 10.43 (t, 1H, J = 5.8 Hz), 8.15 (s, 1H),
7.52-7.46 (m, 1H), 7.35-7.29 (m, 1H), 7.23-7.17 (m, 1H), 4.60 (d,
2H, J = 5.8 Hz), 4.27 (d, 1H, J = 13.4 Hz), 3.66-3.55 (m, 1H),
3.54-3.37 (m, 2H), 3.15 (d, 1H, J = 13.4 Hz), 2.69-2.53 (m, 1H),
1.91 (t, 1H, J = 6.9 Hz), 1.60-1.49 (m, 1H), 1.34 (dd, 1H, J = 9.2,
7.9 Hz), 1.14 (t, 3H, J = 7.4 Hz). T30 1H-NMR (DMSO-d6) .delta.:
12.57 (s, 1H), 10.40 (t, 1H, J = 6.0 Hz), 8.18 (s, 1H), 7.52-7.46
(m, 1H), 7.35-7.29 (m, 1H), 7.23-7.17 (m, 1H), 4.60 (d, 2H, J = 6.0
Hz), 4.27 (d, 1H, J = 13.4 Hz), 3.66-3.56 (m, 1H), 3.48-3.38 (m,
2H), 3.17 (d, 1H, J = 13.4 Hz), 2.93 (s, 3H), 2.03 (t, 1H, J = 6.9
Hz), 1.72-1.62 (m, 1H), 1.43 (dd, 1H, J = 9.9, 8.1 Hz), 1.20-1.11
(m, 4H). T31 1H-NMR (DMSO-d6) .delta.: 12.70-12.63 (m, 1H), 10.34
(t, 1H, J = 6.0 Hz), 8.09 (s, 1H), 7.30 (t, 1H, J = 8.9 Hz), 6.98
(d, 1H, J = 8.9 Hz), 4.51 (d, 2H, J = 5.6 Hz), 4.04 (d, 1H, J =
13.7 Hz), 3.87 (s, 3H), 3.73-3.58 (m, 2H), 3.50-3.32 (m, 3H), 3.06
(s, 3H), 2.00-1.79 (m, 2H), 1.20-1.05 (m, 4H). T32 1H-NMR (DMSO-d6)
.delta.: 12.67 (s, 1H), 10.45-10.34 (m, 1H), 8.13 (s, 1H),
7.53-7.44 (m, 1H), 7.37-7.27 (m, 1H), 7.25-7.14 (m, 1H), 4.73-4.48
(m, 2H), 4.14 (d, 1H, J = 13.7 Hz), 3.16 (d, 1H, J = 13.7 Hz), 2.90
(s, 3H), 2.85 (s, 3H), 2.84-2.76 (m, 1H), 2.71-2.61 (m, 1H),
2.49-2.30 (m, 1H), 1.74 (t, 1H, J = 7.3 Hz), 0.97-0.81 (m, 1H),
0.73-0.62 (m, 1H), 0.57-0.45 (m, 2H). T33 1H-NMR (DMSO-d6) .delta.:
12.67 (s, 1H), 10.45-10.34 (m, 1H), 8.13 (s, 1H), 7.53-7.44 (m,
1H), 7.37-7.27 (m, 1H), 7.25-7.14 (m, 1H), 4.73-4.48 (m, 2H), 4.14
(d, 1H, J = 13.7 Hz), 3.16 (d, 1H, J = 13.7 Hz), 2.90 (s, 3H), 2.85
(s, 3H), 2.84-2.76 (m, 1H), 2.71-2.61 (m, 1H), 2.49-2.30 (m, 1H),
1.74 (t, 1H, J = 7.3 Hz), 0.97-0.81 (m, 1H), 0.73-0.62 (m, 1H),
0.57-0.45 (m, 2H). T34 1H-NMR (DMSO-d6) .delta.: 12.70-12.64 (m,
1H), 10.39 (t, 1H, J = 6.0 Hz), 8.09 (s, 1H), 7.84-7.79 (m, 1H),
7.62-7.57 (m, 1H), 4.58 (d, 2H, J = 6.0 Hz), 4.06-3.98 (m, 1H),
3.82-3.74 (m, 2H), 3.67-3.58 (m, 2H), 3.40-3.31 (m, 1H), 3.25 (s,
3H), 3.06 (s, 3H), 2.51-2.45 (m, 2H), 2.09-1.97 (m, 2H), 1.95-1.82
(m, 2H), 1.20-1.13 (m, 1H). T35 1H-NMR (DMSO-d6) .delta.:
12.76-12.58 (m, 1H), 10.34 (t, 1H, J = 6.0 Hz), 8.09 (s, 1H), 7.30
(t, 1H, J = 8.9 Hz), 6.98 (dd, 1H, J = 8.9, 1.6 Hz), 4.51 (d, 2H, J
= 6.0 Hz), 4.04 (d, 1H, J = 13.7 Hz), 3.87 (s, 3H), 3.72-3.59 (m,
2H), 3.50-3.34 (m, 3H), 3.06 (s, 3H), 1.96-1.80 (m, 2H), 1.20-1.13
(m, 1H), 1.10 (t, 3H, J = 6.9 Hz). T36 1H-NMR (DMSO-d6) .delta.:
12.79-12.51 (m, 1H), 10.33 (t, 1H, J = 6.0 Hz), 8.10 (s, 1H), 7.30
(t, 1H, J = 8.9 Hz), 6.98 (dd, 1H, J = 8.9, 1.6 Hz), 4.51 (d, 2H, J
= 6.0 Hz), 4.06-3.99 (m, 1H), 3.87 (s, 3H), 3.67-3.59 (m, 2H),
3.40-3.33 (m, 1H), 3.25 (s, 3H), 3.06 (s, 3H), 1.95-1.82 (m, 2H),
1.21-1.14 (m, 1H).
TABLE-US-00036 TABLE 2-15 Example 1H-NMR (DMSO-d6) No. .delta.
(peak, integ., J) T37 1H-NMR (DMSO-d6) .delta.: 12.72-12.60 (m,
1H), 10.33 (t, 1H, J = 6.0 Hz), 8.10 (s, 1H), 7.27 (t, 1H, J = 8.6
Hz), 6.96 (dd, 1H, J = 8.6, 1.4 Hz), 4.51 (d, 2H, J = 6.0 Hz), 4.13
(q, 2H, J = 6.9 Hz), 4.02 (d, 1H, J = 14.1 Hz), 3.68-3.59 (m, 2H),
3.41-3.32 (m, 1H), 3.25 (s, 3H), 3.06 (s, 3H), 1.95-1.82 (m, 2H),
1.35 (t, 3H, J = 6.9 Hz), 1.20-1.13 (m, 1H). T38 1H-NMR (DMSO-d6)
.delta.: 12.72-12.60 (m, 1H), 10.33 (t, 1H, J = 6.0 Hz), 8.10 (s,
1H), 7.27 (t, 1H, J = 8.6 Hz), 6.96 (dd, 1H, J = 8.6, 1.4 Hz), 4.51
(d, 2H, J = 6.0 Hz), 4.13 (q, 2H, J = 6.9 Hz), 4.02 (d, 1H, J =
14.1 Hz), 3.68-3.59 (m, 2H), 3.41-3.32 (m, 1H), 3.25 (s, 3H), 3.06
(s, 3H), 1.95-1.82 (m, 2H), 1.35 (t, 3H, J = 6.9 Hz), 1.20-1.13 (m,
1H). T39 1H-NMR (DMSO-d6) .delta.: 12.11-11.99 (m, 1H), 10.45 (t,
1H, J = 6.0 Hz), 8.37 (s, 1H), 7.43-7.35 (m, 1H), 7.26-7.19 (m,
1H), 7.08-7.01 (m, 1H), 4.52 (d, 2H, J = 6.0 Hz), 4.43 (s, 2H),
3.72 (dd, 1H, J = 11.8, 5.3 Hz), 3.47-3.19 (m, 3H), 1.76-1.65 (m,
1H), 1.35-1.28 (m, 1H), 1.08 (t, 3H, J = 7.2 Hz), 0.90 (t, 1H, J =
6.9 Hz). T40 1H-NMR (DMSO-d6) .delta.: 11.95 (s, 1H), 10.42 (t, 1H,
J = 6.0 Hz), 8.39 (s, 1H), 7.42-7.34 (m, 1H), 7.26-7.19 (m, 1H),
7.09-7.01 (m, 1H), 4.56-4.50 (m, 2H), 4.47 (d, 1H, J = 13.6 Hz),
4.39 (d, 1H, J = 13.6 Hz), 3.62 (dd, 1H, J = 10.9, 5.8 Hz),
3.49-3.22 (m, 3H), 3.11 (s, 3H), 1.83-1.73 (m, 1H), 1.46-1.39 (m,
1H), 1.06 (t, 3H, J = 6.9 Hz), 0.96 (t, 1H, J = 6.9 Hz). T41 1H-NMR
(DMSO-d6) .delta.: 11.96 (s, 1H), 10.45 (t, 1H, J = 5.6 Hz), 8.39
(s, 1H), 7.44-7.36 (m, 1H), 7.28-7.20 (m, 1H), 7.10-7.02 (m, 1H),
4.61-4.44 (m, 3H), 4.38 (d, 1H, J = 13.7 Hz), 4.22-4.11 (m, 1H),
3.59 (dd, 1H, J = 10.9, 6.0 Hz), 3.27-3.18 (m, 1H), 3.09 (s, 3H),
1.85-1.74 (m, 1H), 1.63-1.56 (m, 1H), 1.31 (d, 3H, J = 6.9 Hz),
1.31 (d, 3H, J = 6.9 Hz), 0.96 (t, 1H, J = 7.3 Hz). T42 1H-NMR
(DMSO-d6) .delta.: 12.13-12.00 (m, 1H), 10.47 (t, 1H, J = 6.0 Hz),
8.36 (s, 1H), 7.45-7.37 (m, 1H), 7.28-7.20 (m, 1H), 7.10-7.02 (m,
1H), 4.54 (d, 2H, J = 6.0 Hz), 4.42 (s, 2H), 4.22-4.12 (m, 1H),
3.69 (dd, 1H, J = 11.7, 5.6 Hz), 3.32 (dd, 1H, J = 11.7, 8.5 Hz),
1.83-1.72 (m, 1H), 1.45 (dd, 1H, J = 10.1, 6.4 Hz), 1.35-1.29 (m,
6H), 1.29-1.20 (m, 1H), 0.92-0.83 (m, 1H). T43 1H-NMR (DMSO-d6)
.delta.: 11.95-11.88 (m, 1H), 10.46 (t, 1H, J = 5.6 Hz), 8.36 (s,
1H), 7.42-7.34 (m, 1H), 7.27-7.20 (m, 1H), 7.09-7.01 (m, 1H),
4.60-4.47 (m, 3H), 4.34 (d, 1H, J = 13.7 Hz), 4.22-4.11 (m, 1H),
3.63 (dd, 1H, J = 10.9, 5.2 Hz), 3.30-3.13 (m, 3H), 1.75-1.59 (m,
2H), 1.31 (t, 6H, J = 6.4 Hz), 0.97 (t, 1H, J = 6.4 Hz), 0.82 (t,
3H, J = 7.3 Hz). T44 1H-NMR (DMSO-d6) .delta.: 12.08 (s, 1H), 10.52
(t, 1H, J = 6.0 Hz), 8.38 (s, 1H), 7.53-7.46 (m, 1H), 7.35-7.29 (m,
1H), 7.23-7.17 (m, 1H), 4.61 (d, 2H, J = 6.0 Hz), 4.44 (s, 2H),
3.74 (dd, 1H, J = 11.8, 5.8 Hz), 3.47-3.26 (m, 3H), 1.78-1.67 (m,
1H), 1.33 (dd, 1H, J = 10.4, 6.5 Hz), 1.09 (t, 3H, J = 7.2 Hz),
0.92 (t, 1H, J = 6.9 Hz). T45 1H-NMR (DMSO-d6) .delta.: 11.97-11.91
(m, 1H), 10.50 (t, 1H, J = 5.6 Hz), 8.39 (s, 1H), 7.52-7.46 (m,
1H), 7.33-7.26 (m, 1H), 7.22-7.16 (m, 1H), 4.64-4.59 (m, 2H), 4.52
(d, 1H, J = 13.7 Hz), 4.38 (d, 1H, J = 13.7 Hz), 3.68 (dd, 1H, J =
10.5, 5.6 Hz), 3.59-3.48 (m, 1H), 3.36-3.19 (m, 4H), 1.76-1.65 (m,
1H), 1.56-1.48 (m, 1H), 1.08 (t, 3H, J = 7.3 Hz), 0.97 (t, 1H, J =
7.3 Hz), 0.86 (t, 3H, J = 7.3 Hz).
TABLE-US-00037 TABLE 2-16 Example 1H-NMR (DMSO-d6) No. .delta.
(peak, integ., J) T46 1H-NMR (DMSO-d6) .delta.: 12.08 (s, 1H),
10.52 (t, 1H, J = 6.0 Hz), 8.38 (s, 1H), 7.53-7.46 (m, 1H),
7.35-7.29 (m, 1H), 7.23-7.17 (m, 1H), 4.61 (d, 2H, J = 6.0 Hz),
4.44 (s, 2H), 3.74 (dd, 1H, J = 11.8, 5.8 Hz), 3.47-3.26 (m, 3H),
1.78-1.67 (m, 1H), 1.33 (dd, 1H, J = 10.4, 6.5 Hz), 1.09 (t, 3H, J
= 7.2 Hz), 0.92 (t, 1H, J = 6.9 Hz). T47 1H-NMR (DMSO-d6) .delta.:
12.13-12.00 (m, 1H), 10.53 (t, 1H, J = 6.0 Hz), 8.36 (s, 1H),
7.53-7.46 (m, 1H), 7.36-7.29 (m, 1H), 7.24-7.17 (m, 1H), 4.68 (t,
1H, J = 4.8 Hz), 4.61 (d, 2H, J = 5.6 Hz), 4.42 (s, 2H), 4.23-4.12
(m, 1H), 3.73-3.65 (m, 1H), 1.84-1.71 (m, 1H), 1.49-1.40 (m, 1H),
1.33 (d, 3H, J = 6.9 Hz), 1.32 (d, 3H, J = 6.9 Hz), 1.29-1.21 (m,
1H), 0.93-0.83 (m, 1H). T48 1H-NMR (DMSO-d6) .delta.: 12.17-11.93
(m, 1H), 10.44 (t, 1H, J = 6.0 Hz), 8.38 (s, 1H), 7.34-7.23 (m,
1H), 7.01-6.95 (m, 1H), 4.53 (d, 2H, J = 6.0 Hz), 4.44 (s, 2H),
3.87 (s, 3H), 3.77-3.70 (m, 1H), 3.46-3.29 (m, 3H), 1.78-1.67 (m,
1H), 1.33 (dd, 1H, J = 10.1, 6.4 Hz), 1.29-1.21 (m, 1H), 1.09 (t,
3H, J = 7.3 Hz), 0.91 (t, 1H, J = 6.9 Hz). T49 1H-NMR (DMSO-d6)
.delta.: 12.22 (br s, 1H), 10.52 (t, 1H, J = 6.0 Hz), 8.39 (s, 1H),
7.53-7.47 (m, 1H), 7.35-7.30 (m, 1H), 7.23-7.17 (m, 1H), 4.70-4.65
(m, 1H), 4.61 (d, 1H, J = 6.0 Hz), 4.51 (d, 1H, J = 13.7 Hz), 4.45
(d, 1H, J = 13.7 Hz), 3.79-3.65 (m, 1H), 3.44-3.28 (m, 1H), 2.89
(s, 3H), 1.83-1.70 (m, 1H), 1.45 (dd, 1H, J = 10.1, 6.6 Hz), 0.86
(t, 1H, J = 7.3 Hz). T50 1H-NMR (DMSO-d6) .delta.: 12.13 (s, 1H),
10.49 (t, 1H, J = 6.2 Hz), 8.41 (s, 1H), 7.52-7.47 (m, 1H),
7.34-7.28 (m, 1H), 7.23-7.17 (m, 1H), 4.65-4.59 (m, 2H), 4.55 (d,
1H, J = 13.6 Hz), 4.42 (d, 1H, J = 13.6 Hz), 3.61 (dd, 1H, J =
10.9, 6.0 Hz), 3.33-3.24 (m, 1H), 3.11 (s, 3H), 2.88 (s, 3H),
1.90-1.79 (m, 1H), 1.55 (dd, 1H, J = 10.2, 6.7 Hz), 0.91 (t, 1H, J
= 6.7 Hz).
Experimental Example 1
Evaluation of Antiviral Activity
[1402] The antiviral activity of the compound of the present
invention was evaluated in an acute infection system of MT-4 cell
with HIV-1 NL4-3 strain.
(i) Obtainment of HIV-1 NL4-3 Strain (Subclone AF324493.2) (Wild
Type)
[1403] A 5.times.10.sup.5 cells/mL 293T cell suspension (2 mL)
prepared using a medium was added to each well of a 6-well plate
(manufactured by Corning Incorporated), and cultured at 37.degree.
C. for 24 hr. medium composition: D-MEM, 10% FBS (fetal bovine
serum).
[1404] Then, using Lipofectamine 2000 (manufactured by Invitrogen),
plasmid pNL4-3 was transfected at 2 .mu.g/well, and cultured at
37.degree. C. for 4 hr. The medium was exchanged with one
containing 100 U/mL penicillin and 100 .mu.g/mL streptomycin and,
after culture for 48 hr, the virus in the culture supernatant was
recovered.
medium composition: D-MEM, 10% FBS, 100 U/mL penicillin, 100
.mu.g/mL streptomycin.
(ii) Measurement of Antiviral (HIV-1) Activity
[1405] The medium (40 .mu.L), a test substance (10 .mu.L) diluted
with the medium, and a 1.times.10.sup.5 cells/mL MT-4 cell
suspension (50 .mu.L) wherein HIV-1 NL4-3 strain was infected with
MOI (infection multiplicity) 0.05 were added to each well of a
96-well black plate (manufactured by Corning Incorporated), and the
mixture was cultured at 37.degree. C. for 5 days.
medium composition: RPMI1640, 10% FBS, 100 U/mL penicillin, 100
.mu.g/mL streptomycin.
[1406] Then, Cell Titer-Glo (manufactured by Promega Corporation,
100 .mu.L) was added to each well, and the mixture was stood at
room temperature for 10 min, and the luminescence intensity was
measured.
[1407] The antiviral activity (EC.sub.50) of the compound of the
present invention was calculated from the inhibition rate according
to the following formula:
inhibition rate(%)=[(Object-Control)/(Mock
control-Control)].times.100
Object: (luminescence intensity of well in the presence of test
compound and in the presence of infected cells)-[(luminescence
intensity of Blank well (in the absence of test compound and in the
absence of cells))] Control: (luminescence intensity of well in the
absence of test compound and in the presence of infected
cells)-(luminescence intensity of Blank well) Mock control:
(luminescence intensity of well in the absence of test compound and
in the presence of uninfected cells)-(luminescence intensity of
Blank well)
[1408] The results are shown in the following Tables.
TABLE-US-00038 TABLE 3 Example No. EC.sub.50 (nM) 1 3.1 2 4.2 3 3.2
4 2.9 5 2.9 6 2 7 5 8 8.1 9 5.6 10 3.6 11 5.8 12 5 13 5.4 14 9.1 15
7.2 16 6.1 17 3.4 18 2.6 19 4.2 20 20 21 48
TABLE-US-00039 TABLE 4-1 Example No. EC.sub.50 (nM) S1 7.7 S2 10 S3
11 S4 4.9 S5 4.4 S6 3.7 S7 3.7 S8 5.3 S9 5.2 S10 6.1 S11 25 S12 23
S13 4.5 S14 3.9 S15 6.9 S16 7.8 S17 20 S18 16 S19 4.8 S20 3.5 S21
3.8
TABLE-US-00040 TABLE 4-2 Example No. EC.sub.50 (nM) S22 5 S23 6.3
S24 16 S25 7 S26 3.4 S27 14 S28 3.6 S29 4.3 S30 170 S31 24 S32 6.6
S33 6.4 S34 5.7 S35 7.3 S36 15 S37 3.8 S38 50 S39 3.5 S40 2.3 S41
3.5 S42 4.3
TABLE-US-00041 TABLE 4-3 Example No. EC.sub.50 (nM) S43 4.7 S44 11
S45 3.9 S46 4.4 S47 3.5 S48 4.3 S49 65 S50 37 S51 2.4 S52 3.5 S53
10 S54 27 S55 33 S56 5.1 S57 4.7 S58 6.8 S59 4 S60 13 S61 5.1 S62
4.6 S63 4
TABLE-US-00042 TABLE 5-1 Example No. EC.sub.50 (nM) T1 18 T2 4.2 T3
4.5 T4 30 T5 4 T6 3.8 T7 15 T8 6.1 T9 5.8 T10 16 T11 6 T12 5.7 T13
3.4 T14 4.8 T15 20 T16 4.2 T17 5.7 T18 10 T19 3.8 T20 3.5
TABLE-US-00043 TABLE 5-2 Example No. EC.sub.50 (nM) T21 6.1 T22 4.9
T23 9.6 T24 3.2 T25 7 T26 15 T27 97 T28 5.2 T29 4.8 T30 4.4 T31 12
T32 3.3 T33 3.3 T34 23 T35 17 T36 10 T37 93 T38 77 T39 2.8 T40
1.9
TABLE-US-00044 TABLE 5-3 Example No. EC.sub.50 (nM) T41 2.2 T42 3.7
T43 5.3 T44 5.1 T45 4.4 T46 3.4 T47 4 T48 18 T49 7.2 T50 3.7
Experimental Example 2
Evaluation of Anti-Integrase Activity
[1409] The following explains evaluation methods of the HIV
integrase inhibitory activity of the compound of the present
invention.
(i) Construction of Recombinant Integrase Gene Expression
System
[1410] A full-length gene sequence (Accession No.: M19921) of HIV-1
pNL4-3 integrase is inserted into restriction enzyme Nde I and Xho
I sites of plasmid pET21a(+) (manufactured by Novagen) to construct
an integrase expression vector pET21a-IN-Wild type.
(ii) Production and Purification of Integrase Protein
[1411] Escherichia coli recombinant BL21(DE3) transformed with
plasmid pET21a-IN-Wild type obtained in (i) is shake cultured at
30.degree. C. in a liquid medium containing ampicillin. When the
culture reached the logarithmic growth phase,
isopropyl-.beta.-D-thiogalactopyranoside is added to promote
expression of integrase gene. The culture is continued for 5 hr to
promote accumulation of the integrase protein. The recombinant E.
coli is collected in pellets by centrifugal separation and
preserved at -80.degree. C.
[1412] This Escherichia coli is suspended in Lysis buffer (50 mM
Tris-HCl (pH 7.6), 10 mM MgCl.sub.2, 5 mM DTT), and disrupted by
repeating treatments of pressurization and depressurization, and
insoluble fraction is collected by centrifugation at 4.degree. C.,
18,000 rpm for 60 min. This is suspended in Lysis buffer containing
a protease inhibitor, 1.25 mM sodium chloride and 10 mM CHAPS are
added, and the mixture is stirred at 4.degree. C. for 30 min.
Water-soluble fraction is collected by centrifugation at 4.degree.
C., 9,000 rpm for 30 min. The obtained fraction is diluted with a
column buffer (50 mM Tris-HCl (pH 7.6), 1 mM DTT, 10% Glycerol, 10
mM CHAPS) to 5-fold, and the mixture is applied to heparin column
(HiPrep 16/10 Heparin FF column: manufactured by GE Healthcare
Bio-Sciences). Using a column buffer containing 1M NaCl, a protein
is eluted with 0-1M NaCl concentration gradient, and an eluted
fraction containing an integrase protein is collected. The obtained
fraction is diluted 5-fold with a column buffer (50 mM Tris-HCl (pH
7.6), 1 mM DTT, 10% Glycerol, 10 mM CHAPS), and the mixture is
applied to cation exchange column (Mono-S column: manufactured by
GE Healthcare Bio-Sciences). Using a column buffer containing 1M
NaCl, a protein is eluted with 0-1M NaCl concentration gradient,
and an eluted fraction containing an integrase protein is
collected. The obtained fractions of the integrase protein are
collected, and preserved at -80.degree. C.
(iii) Preparation of DNA Solution
[1413] The following DNA synthesized by FASMAC is dissolved in TE
buffer (10 mM Tris-hydrochloric acid (pH 8.0), 1 mM EDTA) and mixed
with donor DNA, target DNA, and each complementary strand (+ and -
strands) to 1 .mu.M. The mixture is heated at 95.degree. C. for 5
min, 80.degree. C. for 10 min, 70.degree. C. for 10 min, 60.degree.
C. for 10 min, 50.degree. C. for 10 min and 40.degree. C. for 10
min and kept at 25.degree. C. to give a double stranded DNA, which
is used for the test.
TABLE-US-00045 Donor DNA (+ strand having biotin attached to the 5'
terminus) Donor + strand: (SEQ ID NO: 1) 5'-Biotin-ACC CTT TTA GTC
AGT GTG GAA AAT CTC TAG CA-3' Donor - strand: (SEQ ID NO: 2) 5'-ACT
GCT AGA GAT TTT CCA CAC TGA CTA AAA G-3' Target DNA (+, - strands
both having digoxi- genin attached to the 3' terminus) Target +
strand: (SEQ ID NO: 3) 5'-TGA CCA AGG GCT AAT TCA CT-Dig-3' Target
- strand: (SEQ ID NO: 4) 5'-AGT GAA TTA GCC CTT GGT CA-Dig-3'
(iv) Determination of Enzyme (HIV Integrase) Inhibitory
Activity
[1414] The donor DNA is diluted with TE buffer to 20 nM, of which
50 .mu.L is added to each well of streptavidin-coated black plate
(manufactured by PIAS Corporation) and allowed to adsorb at
37.degree. C. for 20 min. The plate is washed with phosphate buffer
(Dulbecco's PBS, Takara) containing 0.1% Tween 20 and phosphate
buffer. Then, an enzyme reaction mixture (70 .mu.L), a test
substance (10 .mu.L) diluted with the enzyme reaction mixture and
0.75 .mu.M integrase protein (10 .mu.L) are added to each well and
the mixture is reacted at 37.degree. C. for 60 min.
composition of enzyme reaction mixture: 30 mM MOPS
(3-morpholinopropanesulfonic acid), 5 mM magnesium chloride, 3 mM
DTT (dithiothreitol), 0.1 mg/mL BSA (bovine serum albumin), 5%
glycerol, 10% DMSO (dimethyl sulfoxide), 0.01% Tween 20.
[1415] Then, 25 nM target DNA (10 .mu.L) is added, and the mixture
is reacted at 37.degree. C. for 20 min and washed with phosphate
buffer containing 0.1% Tween 20 to stop the reaction.
[1416] Then, 100 mU/mL peroxidase labeled anti-digoxigenin antibody
solution (Roche, 100 .mu.L) is added, and the mixture is reacted at
37.degree. C. for 60 min, followed by washing with phosphate buffer
containing 0.1% Tween 20.
[1417] Then, peroxidase fluorescence substrate solution
(manufactured by PIAS Corporation, 100 .mu.L) is added, and the
mixture is reacted at room temperature for 20 min to 30 min. A
reaction quenching liquid (manufactured by PIAS Corporation, 100
.mu.L) is added to discontinue the reaction, and fluorescence
intensity at excitation wavelength 325 nm/fluorescence wavelength
420 nm is measured.
[1418] The HIV integrase inhibitory activity (IC.sub.50) of the
compound of the present invention is calculated from the inhibition
rate according to the following formula:
inhibition rate(%)=[1-(Object-Blank)/(Control-Blank)].times.100
Object: fluorescence intensity of well in the presence of test
compound Control: fluorescence intensity of well in the absence of
test compound Blank: fluorescence intensity of well in the absence
of test compound and integrase protein
Experimental Example 3
In Vitro Combined Use Test
[1419] The effect of combined use of the compound of the present
invention and existent anti-HIV agents can be determined in the
following manner.
[1420] For example, the effect of combined use of existent
nucleoside reverse transcriptase inhibitors (zidovudine,
lamivudine), non-nucleoside reverse transcriptase inhibitors
(efavirenz, etravirine) or protease inhibitors (atazanavir,
darunavir) and test substance A and the like are evaluated using
MT-2 cells infected with HIV-1 IIIB by CellTiter-Glo.
[1421] Prior to the combined use test, EC.sub.50 and CC.sub.50 of
each medicament alone are measured. 5 concentrates of medicament A
and 7 concentrates of medicament B, determined based on these
results, are combined to evaluate the effect of combined use of two
agents.
[1422] The test results of the test substance and concomitant drug
alone or in combination thereof are analyzed based on the programs
of Prichard and Shipman MacSynergy II. A three-dimensional plot is
drawn from % inhibition at the concentrations of each combined
medicament, the obtained from 3 times of tests, with 95% confidence
limits, and the effect of the combined use is evaluated based on
the numerical values of .mu.M.sup.2% calculated therefrom. The
criteria of evaluation are shown in the following.
TABLE-US-00046 Definition of interaction .mu.M.sup.2 % Strong
synergistic action >100 Slight synergistic action +51 to +100
Additive action +50 to -50 Slight antagonistic action -51 to -100
Strong antagonistic action <-100
[1423] Formulation Example is given below. This example is merely
for the exemplification purpose and does not limit the
invention.
FORMULATION EXAMPLE
TABLE-US-00047 [1424] (a) compound of Example 1 10 g (b) lactose 50
g (c) corn starch 15 g (d) sodium carboxymethylcellulose 44 g (e)
magnesium stearate 1 g
[1425] The entire amounts of (a), (b) and (c) and 30 g of (d) are
kneaded with water, dried in vacuo and granulated. The obtained
granules are mixed with 14 g of (d) and 1 g of (e) and processed
into tablets with a tableting machine to give 1000 tablets each
containing 10 mg of (a).
INDUSTRIAL APPLICABILITY
[1426] The compounds of the present invention show a high
inhibitory activity against HIV integrase.
[1427] Therefore, these compounds can be medicaments effective for,
for example, the prophylaxis or treatment of AIDS, as integrase
inhibitors, antiviral agents, anti-HIV agents and the like, having
an HIV integrase inhibitory activity. In addition, by a combined
use with other anti-HIV agent(s) such as protease inhibitor,
reverse transcriptase inhibitor and the like, they can be more
effective anti-HIV agents. Furthermore, having high inhibitory
activity specific for integrase, they can be medicaments safe for
human body with a fewer side effects.
SEQUENCE LISTING FREE TEXT
[1428] SEQ ID NO: 1: Donor+ chain for HIV integrase activity
measurement SEQ ID NO: 2: Donor- chain for HIV integrase activity
measurement SEQ ID NO: 3: Target+ chain for HIV integrase activity
measurement SEQ ID NO: 4: Target- chain for HIV integrase activity
measurement
Sequence CWU 1
1
4132DNAArtificial SequenceDonor plus strand for activity
determination of HIV integrase 1acccttttag tcagtgtgga aaatctctag ca
32231DNAArtificial SequenceDonor minus strand for activity
determination of HIV integrase 2actgctagag attttccaca ctgactaaaa g
31320DNAArtificial SequenceTarget plus strand for activity
determination of HIV integrase 3tgaccaaggg ctaattcact
20420DNAArtificial SequenceTarget minus strand for activity
determination of HIV integrase 4agtgaattag cccttggtca 20
* * * * *