U.S. patent application number 09/795093 was filed with the patent office on 2001-12-27 for oxygen-containing heterocyclic compounds.
Invention is credited to Manabe, Haruhiko, Masuda, Yoshiaki, Miki, Ichiro, Ohshima, Etsuo, Yanagawa, Koji.
Application Number | 20010056117 09/795093 |
Document ID | / |
Family ID | 26423777 |
Filed Date | 2001-12-27 |
United States Patent
Application |
20010056117 |
Kind Code |
A1 |
Ohshima, Etsuo ; et
al. |
December 27, 2001 |
Oxygen-containing heterocyclic compounds
Abstract
The present invention relates to oxygen-containing heterocyclic
compounds represented by the following formula (I): 1 wherein m
represents an integer of 0 to 4; R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 independently represent a hydrogen atom, substituted or
unsubstituted lower alkyl, etc.; R.sup.5 represents substituted or
unsubstituted lower alkoxy etc.; R.sup.6 represents a hydrogen atom
etc.; and Y represents the following formula (II): 2 wherein
R.sup.9 represents cyano etc., R.sup.10 represents a hydrogen atom
etc., R.sup.1 represents carboxy etc., and R.sup.2 represents a
hydrogen atom etc.; and the like; or pharmaceutically acceptable
salts thereof.
Inventors: |
Ohshima, Etsuo; (Chiba,
JP) ; Yanagawa, Koji; (Shizuoka, JP) ; Manabe,
Haruhiko; (Shizuoka, JP) ; Miki, Ichiro;
(Shizuoka, JP) ; Masuda, Yoshiaki; (Shizuoka,
JP) |
Correspondence
Address: |
FITZPATRICK CELLA HARPER & SCINTO
30 ROCKEFELLER PLAZA
NEW YORK
NY
10112
US
|
Family ID: |
26423777 |
Appl. No.: |
09/795093 |
Filed: |
March 1, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09795093 |
Mar 1, 2001 |
|
|
|
PCT/JP99/04788 |
Sep 3, 1999 |
|
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|
Current U.S.
Class: |
514/452 ;
549/362 |
Current CPC
Class: |
A61P 13/02 20180101;
A61P 9/10 20180101; C07D 319/20 20130101; A61P 11/06 20180101; A61P
37/08 20180101; C07D 405/04 20130101; A61P 13/04 20180101; A61P
13/12 20180101; A61P 25/24 20180101; C07D 317/46 20130101; A61P
17/06 20180101; A61P 31/18 20180101; C07D 407/08 20130101; A61P
29/00 20180101; A61P 3/10 20180101; A61P 43/00 20180101; A61P 37/02
20180101; A61P 25/28 20180101; C07D 407/04 20130101; A61P 9/04
20180101 |
Class at
Publication: |
514/452 ;
549/362 |
International
Class: |
C07D 319/16; A61K
031/357 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 3, 1998 |
JP |
249685/98 |
Mar 26, 1999 |
JP |
82758/99 |
Claims
1. An oxygen-containing heterocyclic compound represented by the
following formula (I): 87wherein m represents an integer of 0 to 4;
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 independently represent a
hydrogen atom, substituted or unsubstituted lower alkyl,
substituted or unsubstituted cycloalkyl, polycycloalkyl,
substituted or unsubstituted lower alkoxycarbonyl, substituted or
unsubstituted lower alkanoyl, substituted or unsubstituted lower
alkanoyloxy, cyano, hydroxy, substituted or unsubstituted lower
alkoxy, substituted or unsubstituted lower alkenyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted aryl, a
substituted or unsubstituted aromatic hetecyclic group, substituted
or unsubstituted aralkyl, or --CONR.sup.7R.sup.8 (wherein R.sup.7
and R.sup.8 independently represent a hydrogen atom, substituted or
unsubstituted lower alkyl, substituted or unsubstituted lower
alkanoyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, a substituted or unsubstituted aromatic
heterocyclic group or substituted or unsubstituted aralkyl, or
R.sup.7 and R.sup.8 are combined to represent a substituted or
unsubstituted heterocyclic group together with the adjacent
nitrogen atom); two groups present on the same carbon atom among
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are combined to represent a
saturated spiro carbon ring together with the said carbon atom; two
groups present on the adjacent carbon atoms among R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are combined to represent a saturated carbon
ring together with the said adjacent two carbon atoms; two groups
present on the adjacent carbon atoms among R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are combined to represent a single bond
(forming a double bond together with the already-existing bond);
R.sup.5 represents hydroxy, or substituted or unsubstituted lower
alkoxy; R.sup.6 represents a hydrogen atom or halogen; Y represents
the following formula (II): 88wherein R.sup.9 represents cyano,
ethynyl or carbamoyl, and R.sup.10 represents a hydrogen atom, or
R.sup.9 and R.sup.10 are combined to represent a single bond
(forming a double bond together with the already-existing bond),
R.sup.11 represents hydroxy, formyl, substituted or unsubstituted
lower alkoxy, substituted or unsubstituted tetrazolyl,
--NR.sup.13R.sup.14 (wherein R.sup.13 and R.sup.14 independently
represent a hydrogen atom, substituted or unsubstituted lower
alkyl, substituted or unsubstituted lower alkanoyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl, a
substituted or unsubstituted aromatic heterocyclic group or
substituted or unsubstituted aralkyl, or R.sup.13 and R.sup.14 are
combined to represent a substituted or unsubstituted heterocyclic
group together with the adjacent nitrogen atom), --COOR.sup.15
(wherein R.sup.15 represents a hydrogen atom, or substituted or
unsubstituted lower alkyl), --CONR.sup.16R.sup.17 (wherein R.sup.16
and R.sup.17 independently represent a hydrogen atom, substituted
or unsubstituted lower alkyl, substituted or unsubstituted lower
alkanoyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, a substituted or unsubstituted aromatic
heterocyclic group, or substituted or unsubstituted aralkyl, or
R.sup.16 and R.sup.17 are combined to represent a substituted or
unsubstituted heterocyclic group together with the adjacent
nitrogen atom), or --CH.sub.2COOR.sup.8 (wherein R.sup.8 represents
a hydrogen atom or substituted or unsubstituted lower alkyl),
R.sup.12 represents a hydrogen atom, or substituted or
unsubstituted lower alkoxy, or R.sup.11 and R.sup.12 are combined
together to represent --OCH.sub.2(CH.sub.2).sub.pO-- (wherein p
represents an integer of 1 to 3), --CR.sup.19R.sup.20O-- (wherein
R.sup.19 and R.sup.20 independently represent a hydrogen atom or
cyano),.dbd.CHOR.sup.21 (wherein R.sup.21 represents substituted or
unsubstituted lower alkyl, substituted or unsubstituted lower
alkenyl, or substituted or unsubstituted aralkyl),
.dbd.CHCOOR.sup.22 (wherein R.sup.22 represents a hydrogen atom, or
substituted or unsubstituted lower alkyl) or .dbd.O; the following
formula (III): 89wherein n represents an integer of 0 to 4, X
represents CH.sub.2, NR.sup.23 (wherein R.sup.23 represents a
hydrogen atom, substituted or unsubstituted lower alkyl,
substituted or unsubstituted lower alkanoyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl, a
substituted or unsubstituted aromatic heterocyclic group, or
substituted or unsubstituted aralkyl) or O; the following formula
(IV): 90wherein Z.sup.1--Z.sup.2--Z.sup.3 represents O--N.dbd.CH,
S--N.dbd.CH, O--CH.dbd.CH, S--CH.dbd.CH, N.dbd.CH--S, N.dbd.CH--O,
C(.dbd.O)--NH--NH, C(.dbd.O)--N.dbd.N,
C(.dbd.O)--CH.sub.2--C(.dbd.O), C(.dbd.O)--NR.sup.a--C(.dbd.O)
(wherein R.sup.a represents a hydrogen atom, substituted or
unsubstituted lower alkyl, or substituted or unsubstituted aralkyl)
or CH.sub.2--NR.sup.b--C (.dbd.O) (wherein R.sup.b represents a
hydrogen atom, substituted or unsubstituted lower alkyl, or
substituted or unsubstituted aryl); 2,1,3-benzothiadiazolyl; or
2,1,3-benzofurazanyl; or a pharmaceutically acceptable salt
thereof.
2. The oxygen-containing heterocyclic compound according to claim
1, wherein Y is the formula (II), or a pharmaceutically acceptable
salt thereof.
3. The oxygen-containing heterocyclic compound according to claim
2, wherein R.sup.9 is cyano, or a pharmaceutically acceptable salt
thereof.
4. The oxygen-containing heterocyclic compound according to any one
of claims 1 to 3, wherein m is 0 to 2, or a pharmaceutically
acceptable salt thereof.
5. The oxygen-containing heterocyclic compound according to any one
of claims 1 to 4, wherein all of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are hydrogen atoms, or one group among R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 is substituted or unsubstituted lower alkyl
while other three groups are hydrogen atoms, or a pharmaceutically
acceptable salt thereof.
6. The oxygen-containing heterocyclic compound according to any one
of claims 1 to 5, wherein R.sup.11 represents carboxy or hydroxy,
or R.sup.11 and R.sup.12 are combined together to represent .dbd.O,
or a pharmaceutically acceptable salt thereof.
7. The oxygen-containing heterocyclic compound according to claim
1, wherein Y is the formula (III), or a pharmaceutically acceptable
salt thereof.
8. The oxygen-containing heterocyclic compound according to claim
7, wherein n is 1, or a pharmaceutically acceptable salt
thereof.
9. The oxygen-containing heterocyclic compound according to claim 7
or 8, wherein X is CH.sub.2, or a pharmaceutically acceptable salt
thereof.
10. A method of inhibiting phosphodiesterase (PDE) IV, which
comprises administering an effective dose of at least one
oxygen-containing heterocyclic compound according to any one of
claims 1 to 9 or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising an effective amount of
at least one oxygen-containing heterocyclic compound according to
any one of claims 1 to 9 or a pharmaceutically acceptable salt
thereof together with a pharmaceutically acceptable carrier or
diluent.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This is a continuation-in-part application of PCT/JP99/04788
filed on Sep. 3, 1999.
BACKGROUND OF THE INVENTION
[0002] Heretofore, it is known that the funct ions of numerous
hormones and neurotransmitters are expressed by an increase in the
concentration of adenosine 3', 5'-cyclic monophosphate (cAMP) or
guanosine 3', 5'-cyclic monophosphate (cGMP), both of which are the
secondary messengers in cells. The cellular concentrations of cAMP
and cGMP are controlled by the generation and decomposition
thereof, and their decomposition is carried out by
phosphodiesterase (PDE). Therefore, when PDE is inhibited, the
concentrations of these secondary cellular messengers increase. up
to the present, 8 kinds of PDE isozymes have been found, and the
isozyme-selective PDE inhibitors are expected to exhibit
pharmaceutical effect based on their physiological significance and
distribution in vivo [TiPS, 11, 150 (1990), ibid., 12, 19 (1991),
and Biochemical & Biophysical Research Communications, 250, 751
(1998)].
[0003] It is known that the activation of inflammatory leukocytes
can be suppressed by increasing the concentration of the cellular
cAMP. The extraordinary activation of leukocytes causes secretion
of inflammatory cytokines such as tumor necrosis factor (TNF), and
expression of the cellular adhesion molecules such as intercellular
adhesion molecules (ICAM), followed by cellular infiltration [J.
Mol. Cell. Cardiol., 12 (Suppl. II), S61 (1989)].
[0004] It is known that the contraction of a respiratory smooth
muscle can be suppressed by increasing the concentration of the
cellular CAMP (T. J. Torphy in Directions for New Anti-Asthma
Drugs, eds S. R. O'Donell and C. G. A. Persson, 1988, 37,
Birkhauser-Verlag). The extraordinary contraction of a respiratory
smooth muscle is a main symptom of bronchial asthma. Infiltration
of inflammatory-leukocytes such as neutrophils is observed in
lesions of organopathy associated withischemia-reperfusionsuc-
hasmyocardial ischemia. Ithas been found that the type IV PDE (PDE
IV) mainly participates in the decomposition of cAMP in these
inflammatory cells and tracheal smooth muscle cells. Therefore, the
inhibitors selective for PDE IV are expected to have therapeutic
and/or preventive effect on inflammatory diseases, respiratory
obstructive diseases, and ischemic diseases.
[0005] The PDE IV inhibitors are expected to prevent the progress
and spread of the inflammatory reaction transmitted by inflammatory
cytokines such as TNF.alpha. and interleukin (IL)-8, because the
PDE IV inhibitors suppress the secretion of these cytokines by
increasing the concentration of cAMP. For example, TNFa is reported
to be a factor of insulin-resistant diabetes because it declines
the phosphorylating mechanism of insulin receptors in muscle and
fat cells [J. Clin. Invest., 94, 1543 (1994)]. Similarly, it is
suggested that the PDE IV inhibitors may be useful for autoimmune
diseases such as rheumatoid arthritis, multiple sclerosis, and
CrohnIs disease because TNFa participates in the onset and progress
of these diseases [Nature Medicine, 1, 211 (1995) and ibid., 1, 244
(1995)].
[0006] Further, participation of TNFa in the fatigued feeling after
dialysis and that of patients suffering from cancer has been also
reported [International Journal of Artificial organs, 21, 83 (1998)
and oncology Nursing Forum, 19, 419 (1992)]. Accordingly, a PDE IV
inhibitor can be expected to be effective for improvement in
fatigue, malaise, and the like.
[0007] It has been reported that a drug which increases cAMP
promotes the healing of wounds [The 68th Annual Meeting of Japan
Pharmacological Society (in Nagoya), Presentation P3-116
(1995)].
[0008] PDE-IV inhibitors exhibit a therapeutic effect to
carcinomatous osteopenia model, sciatic nerve excision model and
ovariectomic model which are animal models for osteoporosis and
their possibility as a therapeutic agent for osteoporosis is
suggested [Jpn. J. Pharmacol., 79, 477 (1999)].
[0009] Relaxation of ureter has been known to promote the excretion
of calculus while a PDE IV inhibitor suppresses the vermicular
movement of ureter, and therefore, there is a suggestion for the
probability that it is effective for the therapy and/or prevention
of urinary calculus [J. Urol., 160, 920 (1998)].
[0010] Japanese Published Unexamined Patent Application Nos.
95/242543 and 95/242655 disclose 1,4-benzodioxane derivatives as a
therapeutic agent for hepatic diseases. WO 92/10494 discloses
1,4-benzodioxane derivatives having an antagonistic action to
serotonin (5HT).sub.3 receptors.
[0011] In U.S. Pat. No. 5,166,367, 1,4-benzodioxane derivatives
having an anti-hallucination action are disclosed.
[0012] In Japanese Published Unexamined Patent Application No.
88/179868, 1,4-benzodioxane derivatives having a vasodilating
action are disclosed.
[0013] AU 521225 discloses 1,4-benzodioxane derivatives as
intermediates for the synthesis of cinnamoylpiperazine.
[0014] WO 98/22455 discloses 1,4-benzodioxane derivatives having
PDE IV inhibitory activity.
SUMMARY OF THE INVENTION
[0015] The present invention relates to oxygen-containing
heterocyclic compounds which have phosphodiesterase (PDE) IV
inhibitory activity and which are useful as a therapeutic agent for
inflammatory allergic diseases such as bronchial asthma, allergic
rhinitis, atopic dermatitis and nephritis; autoimmune diseases such
as chronic obstructive pulmonary disease, rheumatism, multiple
sclerosis, Crohn's disease, psoriasis and systemic lupus
erythematosus; diseases of the central nervous system such as
depression, amnesia and dementia; organopathy associated with
ischemia-reperfusion caused by cardiac failure, shock and
cerebrovascular disease, and the like; insulin-resistant diabetes;
wounds; AIDS; osteoporosis; urinary calculus; urinary incontinence
and the like; and as a recuperative agent for fatigue, malaise and
the like.
DETAILED DESCRIPTION OF THE INVENTION
[0016] Novel and useful PDE IV inhibitors are expected to have a
preventive or therapeutic effect to diseases of a broad range. An
object of the present invention is to provide novel
oxygen-containing heterocyclic compounds having a bronchodilating
or an anti-inflammatory action due to the presence of a PDE
IV-selective inhibiting action so that cAMP concentrations in cells
are increased.
[0017] The present invention relates to oxygen-containing
heterocyclic compounds represented by the following formula (I):
3
[0018] wherein m represents an integer of 0 to 4; R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 independently represent a hydrogen atom,
substituted or unsubstituted lower alkyl, substituted or
unsubstituted cycloalkyl, polycycloalkyl, substituted or
unsubstituted lower alkoxycarbonyl, substituted or Aunsubstituted
lower alkanoyl, substituted or unsubstituted lower alkanoyloxy,
cyano, hydroxy, substituted or unsubstituted lower alkoxy,
substituted or unsubstituted lower alkenyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted aryl, a
substituted or unsubstituted aromatic hetecyclic group, substituted
or unsubstituted aralkyl, or --CONR.sup.7R.sup.8 (wherein R.sup.7
and R.sup.8 independently represent a hydrogen atom, substituted or
unsubstituted lower alkyl, substituted or unsubstituted lower
alkanoyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, a substituted or unsubstituted aromatic
heterocyclic group or substituted or unsubstituted aralkyl, or
R.sup.7 and R.sup.8 are combined to represent a substituted or
unsubstituted heterocyclic group together with the adjacent
nitrogen atom); two groups present on the same carbon atom among
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are combined to represent a
saturated spiro carbon ring together with the said carbon atom; two
groups present on the adjacent carbon atoms among R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are combined to represent a saturated carbon
ring together with the said adjacent two carbon atoms; two groups
present on the adjacent carbon atoms among R.sup.1, R.sup.2,
R.sup.3 and R.sup.4are combined to represent a single bond (forming
a double bond together with the already-existing bond)
[0019] R.sup.5 represents hydroxy, or substituted or unsubstituted
lower alkoxy;
[0020] R.sup.6 represents a hydrogen atom or halogen;
[0021] Y represents the following formula (II): 4
[0022] wherein R.sup.9 represents cyano, ethynyl or carbamoyl, and
R.sup.10 represents a hydrogen atom, or R.sup.9 and R.sup.10 are
combined to represent a single bond (forming a double bond together
with the already-existing bond), R.sup.11 represents hydroxy,
formyl, substituted or unsubstituted lower alkoxy, substituted or
unsubstituted tetrazolyl, --NR.sup.13R.sup.14 (wherein R.sup.13 and
R.sup.14 independently represent a hydrogen atom, substituted or
unsubstituted lower alkyl, substituted or unsubstituted lower
alkanoyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, a substituted or unsubstituted aromatic
heterocyclic group or substituted or unsubstituted aralkyl, or
R.sup.13 and R.sup.14 are combined to represent a substituted or
unsubstituted heterocyclic group together with the adjacent
nitrogen atom), --COOR.sup.15 (wherein R.sup.15 represents a
hydrogen atom, or substituted or unsubstituted lower alkyl),
--CONR.sup.16R.sup.17 (wherein R.sup.16 and R.sup.17 independently
represent a hydrogen atom, substituted or unsubstituted lower
alkyl, substituted or unsubstituted lower alkanoyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl, a
substituted or unsubstituted aromatic heterocyclic group, or
substituted or unsubstituted aralkyl, or R.sup.16 and R.sup.17 are
combined to represent a substituted or unsubstituted heterocyclic
group together with the adjacent nitrogen atom), or
--CH.sub.2COOR.sup.18 (wherein R.sup.8 represents a hydrogen atom
or substituted or unsubstituted lower alkyl), R.sup.12 represents a
hydrogen atom, or substituted or unsubstituted lower alkoxy, or
R.sup.11 and R.sup.12 are combined together to represent
--OCH.sub.2(CH.sub.2).sub.pO-- (wherein p represents an integer of
1 to 3), --CR.sup.19R.sup.20O-- (wherein R.sup.9 and R.sup.20
independently represent a hydrogen atom or cyano),=CHOR.sup.21
(wherein R.sup.21 represents substituted or unsubstituted lower
alkyl, substituted or unsubstituted lower alkenyl, or substituted
or unsubstituted aralkyl), .dbd.CHCOOR.sup.22 (wherein R.sup.22
represents a hydrogen atom, or substituted or unsubstituted lower
alkyl) or=O; the following formula (III): 5
[0023] wherein n represents an integer of 0 to 4, X represents
CH.sub.2, NR.sup.23 (wherein R.sup.23 represents a hydrogen atom,
substituted or unsubstituted lower alkyl, substituted or
unsubstituted lower alkanoyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl, a substituted or
unsubstituted aromatic heterocyclic group, or substituted or
unsubstituted aralkyl) or 0; the following formula (IV): 6
[0024] wherein Z.sup.1--Z.sup.2--Z.sup.3 represents O--N.dbd.CH,
S--N.dbd.CH, O--CH.dbd.CH, S--CH.dbd.CH, N.dbd.CH--S, N.dbd.CH--O,
C(.dbd.O)--NH--NH, C(.dbd.O)--N.dbd.N,
C(.dbd.O)--CH.sub.2--C(.dbd.O), C(.dbd.O)--NR.sup.a--C(.dbd.O)
(wherein R.sup.a represents a hydrogen atom, substituted or
unsubstituted lower alkyl, or substituted or unsubstituted aralkyl)
or CH.sub.2--NR.sup.b--C(.dbd.O) (wherein R.sup.b represents a
hydrogen atom, substituted or unsubstituted lower alkyl, or
substituted or unsubstituted aryl); 2,1,3-benzothiadiazolyl; or
2,1,3-benzofurazanyl; or pharmaceutically acceptable salts
thereof.
[0025] The present invention relates to oxygen-containing
heterocyclic compounds wherein Y in the formula (I) is the formula
(II) or pharmaceutically acceptable salts thereof. Among the above,
oxygen-containing heterocyclic compounds wherein R.sup.9 is cyano
or pharmaceutically acceptable salts thereof are preferred.
[0026] In the present invention, oxygen-containing heterocyclic
compounds wherein m is 0 to 2 in the formula (I) or
pharmaceutically acceptable salts thereof, oxygen-containing
heterocyclic compounds wherein all of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are hydrogen atoms or pharmaceutically acceptable salts
thereof and oxygen-containing heterocyclic compounds wherein one
group among R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is substituted or
unsubstituted lower alkyl while other three groups are hydrogen
atoms or pharmaceutically acceptable salts thereof are preferred
examples as well.
[0027] Further, in the above-mentioned compounds group,
oxygen-containing heterocyclic compounds wherein R.sup.11
represents carboxy or hydroxy, or R.sup.11 and R.sup.12 are
combined together to represent .dbd.O or pharmaceutically
acceptable salts thereof are preferred as well.
[0028] Furthermore, oxygen-containing heterocyclic compounds
wherein Y in the formula (I) is the formula (III) or
pharmaceutically acceptable salts thereof are preferred as well.
Still further, among the above, oxygen-containing heterocyclic
compounds wherein n is 1 or pharmaceutically acceptable salts
thereof and oxygen-containing heterocyclic compounds wherein X is
CH.sub.2 or pharmaceutically acceptable salts thereof are
preferred.
[0029] The present invention further relates to a pharmaceutical
composition comprising an effective amount of at least one
oxygen-containing heterocyclic compound represented by the formula
(I) together with a pharmaceutically acceptable carrier or
diluent.
[0030] The present invention furthermore relates to a method of
inhibiting phosphodiesterase (PDE) IV, which comprises
administering an effective dose of at least one oxygen-containing
heterocyclic compound represented by the formula (I) or a
pharmaceutically acceptable salt thereof.
[0031] Hereinafter, the compounds represented by the formula (I)
are referred to as a compound (I). The same applies to the
compounds of other formula numbers.
[0032] In the definitions of the groups in the formula (I), the
lower alkyl and the lower alkyl moiety of the lower alkoxy, the
lower alkanoyl, the lower alkanoyloxy and the lower alkoxycarbonyl
include straight-chain or branched alkyl groups having 1 to 8
carbon atom(s) such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl;
the cycloalkyl includes cycloalkyl groups having 3 to 10 carbon
atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl; and the
polycycloalkyl includes polycycloalkyl groups having 5 to 12 carbon
atoms such as bicyclo[3.2.1]octyl, bicyclo[ 4.3.2 ]undecyl,
adamantyl and noradamantyl. The lower alkenyl includes
straight-chain or branched alkenyl groups having 2 to 8 carbon
atoms such as vinyl, 1-propenyl, allyl, methacryl, 1-butenyl,
crotyl, pentenyl, isoprenyl, hexenyl, heptenyl and octenyl; and the
cycloalkenyl includes cycloalkenyl groups having 4 to 10 carbon
atoms such as cyclobutenyl, cyclopentenyl, cyclohexenyl,
cycloheptenyl, cyclooctenyl, cyclononenyl and cyclodecenyl. The
aryl includes phenyl and naphthyl for example; and the aralkyl
includes aralkyl groups having 7 to 15 carbon atoms such as benzyl,
phenethyl, benzhydryl and naphthylmethyl. The aromatic heterocyclic
group includes 5- or 6-membered monocyclic aromatic heterocyclic
groups having 1 to 2 oxygen atom(s), 5- or 6-membered monocyclic
aromatic heterocyclic groups having 1 to 2 sulfur atom(s), 5- or
6-membered monocyclic aromatic heterocyclic groups having 1 to 4
nitrogen atom(s), condensed bicyclic aromatic heterocyclic groups
consisting of 5- and 6-membered rings and condensed bicyclic
aromatic heterocyclic groups consisting of 6- and 6-membered rings,
where oxygen, sulfur and nitrogen may be mixedly present therein.
Specific examples thereof include furyl, thienyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, quinolyl, isoquinolyl,
phthalazinyl, quinazolinyl, quinoxalinyl, naphthylidinyl, pyrrolyl,
pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,
indolyl, indazolyl, benzimidazolyl, benzotriazolyl and purinyl.
[0033] The heterocyclic group which is formed together with the
adjacent nitrogen atom includes 5-, 6- or 7-membered monocyclic
heterocyclic groups and condensed heterocyclic groups consisting of
6- and 6-membered rings, such as pyrrolidinyl, piperidino,
piperazinyl, morpholino, thiomorpholino, homopiperidino,
homopiperazinyl, tetrahydropyridyl, tetrahydroquinolyl and
tetrahydroisoquinolyl.
[0034] The saturated spiro carbon ring which is formed by two
groups present on the same carbon atom together with the said
carbon atom and the saturated carbon ring which is formed by two
groups present on the adjacent carbon atoms together with the said
two carbon atoms include those having 3 to 10 carbon atoms such as
cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,
cyclooctane, cyclononane and cyclodecane. Halogen includes
fluorine, chlorine, bromine and iodine atoms.
[0035] The substituents in the substituted lower alkyl, the
substituted lower alkoxy, the substituted lower alkoxycarbonyl, the
substituted lower alkanoyl, the substituted lower alkanoyloxy, the
substituted lower alkenyl, the substituted cycloalkyl and the
substituted cycloalkenyl are the same or different 1 to 3
substituent(s), such as lower alkyl, lower alkenyl, cyano,
cycloalkyl, cycloalkenyl, hydroxy, lower alkoxy, carboxy and
halogen where the lower alkyl, the lower alkenyl, the cycloalkyl,
the cycloalkenyl, the lower alkoxy and the halogen each have the
same meanings as defined above.
[0036] The substituents in the substituted aryl, the substituted
tetrazolyl, the substituted aromatic heterocyclic group, the
substituted heterocyclic group which is formed together with the
adjacent nitrogen atom and the substituted aralkyl are the same or
different 1 to 3 substituent(s), such as substituted or
unsubstituted lower alkyl, hydroxy, lower alkoxy, lower alkanoyl,
lower alkoxycarbonyl, carboxy, carbamoyl, trifluoromethyl, amino,
mono- or di-lower alkyl-substituted amino, cyano, nitro and
halogen. The lower alkyl, the lower alkyl moiety of the lower
alkoxy, the lower alkanoyl, the lower alkoxycarbonyl and the mono-
or di-lower alkyl-substituted amino and the halogen each have the
same meanings as defined above where the substituent(s) in the
substituted lower alkyl has/have the same meaning(s) as defined
above.
[0037] The pharmaceutically acceptable salts of the compound (I)
include pharmaceutically acceptable acid addition salts, metal
salts, ammonium salts, and organic amine addition salts.
[0038] The pharmaceutically acceptable acid addition salts of the
compound (I) include inorganic acid addition salts such as a
hydrochloride, a sulfate, a nitrate, and a phosphate, and organic
acid addition salts such as an acetate, a maleate, a fumarate, and
a citrate; the pharmaceutically acceptable metal salts include
alkali metal salts such as a sodium salt and a potassium salt,
alkaline earth metal salts such as a magnesium isalt and a calcium
salt, an aluminium salt, and a zinc salt; the pharmaceutically
acceptable ammonium salts include ammonium and tetramethylammonium;
and the pharmaceutically acceptable organic amine addition salts
include an addition salt with morpholine or piperidine.
[0039] Processes for preparing the compound (I) are described
below.
[0040] Producing method: The compound (I) can be obtained according
to the following process.
[0041] Process 1 7
[0042] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6have the same meanings as defined above.)
[0043] The starting compound (V) can be obtained by a known method
[Khimiya Geterotsiklicheskikh Soedinenii, 12, 1614 (1982), etc.] or
by a method similar thereto.
[0044] After the formyl group of the compound (V) is directly
converted to the corresponding halogenated methyl derivative or
after the formyl group of the compound (V) is reduced and the
resulting hydroxymethyl derivative is converted to the
corresponding halide or sulfonate derivative, it is reacted with a
metal cyanide whereupon the compound (VI) can be obtained.
[0045] The compound (V) is reacted with one equivalent to a large
excess of trialkylsilyl halide or triarylsilane halide, or with one
equivalent to a large excess of a halogenated salt and one
equivalent to a large excess of trimethylsilyl chloride in an inert
solvent at the temperature between -50.degree. C. and the boiling
point of the used solvent for 5 minutes to 5 hours, followed by
treatment with one equivalent to a large excess of a reducing agent
at the temperature between --50.degree. C. and the boiling point of
the used solvent for 5 minutes to 48 hours, whereupon the
corresponding halide can be obtained.
[0046] Alternatively, the compound (V) is treated with one
equivalent to a large excess of a reducing agent in an inert
solvent at the temperature between -50.degree. C. and the boiling
point of the used solvent for 5 minutes to 48 hours whereby the
corresponding hydroxylmethyl derivative is obtained. The resulting
hydroxylmethyl derivative is reacted with one equivalent to a large
excess of a halogenating agent in an inert solvent at the
temperature between -30.degree. C. and the boiling point of the
used solvent for 5 minutes to 120 hours to give the corresponding
halide.
[0047] Alternatively, the resulting hydroxymethyl derivative is
treated with one equivalent to a large excess of an alkylsulfonyl
chloride or an arylsulfonyl chloride in the presence of one
equivalent to a large excess of a base in an inert solvent at the
temperature between -30.degree. C. and the boiling point of the
used solvent for 5 minutes to 120 hours whereby the corresponding
sulfonate derivative is obtained.
[0048] The resulting halide or sulfonate derivative is treated with
one equivalent to a large excess of a metal cyanide in an insert
solvent at the temperature between -30.degree. C. and the boiling
point of the used solvent for 5 minutes to 120 hours whereupon the
compound (VI) can be obtained.
[0049] Examples of the trialkylsilyl halide or the triarylsilyl
halide are trimethylsilyl chloride, trimethylsilyl bromide,
trimethylsilyl iodide, triethylsilyl chloride, dimethylethylsilyl
chloride and triphenylsilyl chloride.
[0050] Examples of the halogenated salt are lithium bromide, sodium
bromide, potassium bromide, lithium chloride, sodium chloride,
potassium chloride, lithium iodide, sodium iodide and potassium
iodide.
[0051] Examples of the reducing agent are
1,1,3,3-tetramethyldisiloxane, triethylsilane, sodium borohydride,
sodium cyanoborohydride, sodium triacetoxyborohydride and lithium
aluminum hydride.
[0052] Examples of the halogenating agent are hydrochloric acid,
hydrogen bromide, hydrogen iodide, thionyl chloride, phosphorus
oxychloride and phosphorus tribromide.
[0053] Examples of the base are triethylamine,
N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene
(hereinafter, abbreviated as DBU), potassium carbonate and sodium
hydride.
[0054] Examples of the alkylsulfonyl chloride or arylsulfonyl
chloride are methanesulfonyl chloride, p-toluenesulfonyl chloride
and benzenesulfonyl chloride.
[0055] Examples of the metal cyanide are sodium cyanide, potassium
cyanide and copper cyanide.
[0056] Examples of the inert solvent are tetrahydrofuran
(hereinafter, abbreviated as THF), dioxane, 1,2-dimethoxyethane,
diethyl ether, acetonitrile, dimethylformamide (hereinafter,
abbreviated as DMF), dimethyl sulfoxide (hereinafter, abbreviated
as DMSO), methanol, ethanol, propanol, dichloromethane, chloroform,
benzene, toluene, pyridine and ethyl acetate.
[0057] Process 2 8
[0058] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 have the same meanings as defined above and
R.sup.24 stands for the lower alkyl having the same meaning as
defined above.)
[0059] The compound (VIII) can be obtained by the following
method.
[0060] The compound (VI) is treated with the compound (VII) in an
inert solvent in the presence of a catalytic amount to a large
excess amount of a base at the temperature between 0.degree. C. and
the boiling point of the used solvent for 5 minutes to 48 hours
whereby the compound (VIII) can be obtained.
[0061] Examples of the base are benzyltrimethylammonium hydroxide
(Triton B ), sodium hydroxide, potassium hydroxide, sodium hydride,
potassium hydride, sodium methoxide, lithium diisopropylamide
(hereinafter, abbreviated as LDA), pyridine, potassium
tert-butoxide, DBU, triethylamine and diisopropylethylamine.
[0062] Examples of the inert solvent are THF, dioxane, diethyl
ether, methanol, ethanol, 1-propanol, 2-propanol, n-butanol,
tert-butyl alcohol, pyridine, acetonitrile, DMF, DMSO,
1,2-dimethoxyethane, diethylene glycol methyl ether,
dichloromethane, chloroform, benzene and toluene.
[0063] Process 3 9
[0064] The compound (IX) can be obtained by the following method
from the compound (VIII).
[0065] The compound (VIII) is treated in an inert solvent in the
presence of one equivalent to a large excess of a base at the
temperature between 0.degree. C. and the boiling point of the used
solvent for 5 minutes to 48 hours whereupon the compound (IX) can
be obtained.
[0066] Examples of the base are sodium hydride, potassium hydride,
sodium hydroxide, potassium hydroxide, sodium methoxide, sodium
ethoxide, LDA, pyridine, potassium tert-butoxide, DBU,
triethylamine and diisopropylethylamine.
[0067] Examples of the inert solvent are THF, dioxane, pyridine,
diethyl ether, methanol, ethanol, 1-propanol, 2-propanol,
1-butanol, tert-butyl alcohol, acetonitrile, DMF, DMSO,
1,2-dimethoxyethane, diethylene glycol methyl ether,
dichloromethane, chloroform, benzene and toluene.
[0068] Process 4 10
[0069] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.24 have the same meanings as defined
above.)
[0070] The compound (Ia) can be obtained according to the following
reaction step.
[0071] The compound (IX) is treated in an inert solvent in the
presence of one equivalent to a large excess of water at the
temperature between 60.degree. C. and the boiling point of the used
solvent for 5 minutes to 120 hours whereupon the compound (Ia) can
be obtained. If necessary, a catalytic amount to an excess amount
of a salt such as sodium chloride, lithium chloride, sodium iodide,
lithium iodide or sodium cyanide may be added thereto.
[0072] Examples of the inert solvent are dioxane, toluene, DMF,
DMSO, tert-butyl alcohol, acetonitrile, 1,2-dimethoxyethane,
diethylene glycol methyl ether, ethylene glycol, triethylene glycol
and water.
[0073] Process 5 11
[0074] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6have the same meanings as defined above.)
[0075] The compound (X) can be obtained according to the following
reaction step.
[0076] 2-Trimethylsilyl-1,3-dithiane is treated with a base in an
inert solvent at the temperature between -100.degree. C. and
0.degree. C., followed by reaction with the compound (Ia) at the
temperature between -100.degree. C. and 30.degree. C. for 1 minute
to 12 hours whereupon the compound (X) can be obtained.
[0077] Examples of the base are sodium hydride, potassium hydride,
sodium hydroxide, potassium hydroxide, sodium methoxide, butyl
lithium, LDA, lithiumbistrimethylsilylamide, sodium
bistrimethylsilylamide, potassium bistrimethylsilylamide, potassium
tert-butoxide, DBU, triethylamine, diisopropylethylamine and ethyl
magnesium bromide.
[0078] Examples of the inert solvent are THF, dioxane, diethyl
ether, 1,2-dimethoxyethane and diisopropyl ether.
[0079] Process 6 12
[0080] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 have the same meanings as defined above and
R.sup.25 represents the same lower alkyl as defined above.)
[0081] The compound (Ib) can be obtained according to the following
reaction step.
[0082] The compound (X) is treated in a solvent [with regard to the
said solvent, a lower alcohol which will be mentioned later may be
used solely or as a mixed solvent containing the lower alcohol
(dioxane/lower alcohol, THF/lower alcohol, and the like); and the
said lower alcohol also acts as a reagent for esterifying the
carboxyl group which is obtained by the reaction] in the presence
of one equivalent to an excess amount of a divalent mercury salt
and an acid at the temperature between 0.degree. C. and the boiling
point of the used solvent for 5 minutes to 48 hours whereupon the
compound (Ib) can be obtained.
[0083] Examples of the divalent mercury salt are mercury chloride
(HgCl.sub.2) and mercury acetate [Hg(OCOCH.sub.3).sub.2]. Examples
of the acid are perchloric acid, sulfuric acid, hydrochloric acid,
trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid
and boron trifluoride.
[0084] Examples of the solvent are lower alcohols (methanol,
ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-1-propanol,
2-butanol, tert-butyl alcohol, 1-pentanol, 1-hexanol, 1-heptanol,
I-octanol, andthelike), amixed solvent of dioxane/a lower alcohol
(wherein the lower alcohol has the same meaning as defined above)
and a mixed solvent of THF/a lower alcohol (wherein the lower
alcohol has the same meaning as defined above).
[0085] Process 7 13
[0086] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6 and R.sup.25 have the same meanings as defined
above.)
[0087] The compound (Ic) can be obtained according to the following
reaction step.
[0088] The compound (Ib) is treated with an aqueous solution of an
alkali in an inert solvent at the temperature between 0.degree. C.
and the boiling point of the used solvent for 5 minutes to 48 hours
whereupon the compound (Ic) can be obtained.
[0089] Examples of the aqueous solution of an alkali are aqueous
solutions of sodium hydroxide, potassium hydroxide and lithium
hydroxide while examples of the inert solvent are ethanol, dioxane,
methanol, THF, amixedsolventofethanol/THF, amixed solvent of
methanol/THF, and DMSO.
[0090] Process 8 14
[0091] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 have the same meanings as defined above.)
[0092] The compound (Id) can be obtained according to the following
reaction step.
[0093] One equivalent to an excess amount of
methoxymethyl-triphenylphosph- onium chloride is treated with one
equivalent to an excess amount of a base in an inert solvent at the
temperature between -100.degree. C. and the boiling point of the
used solvent, followed by reaction with the compound (Ia) at the
temperature between -100.degree. C. and the boiling point of the
used solvent for 5 minutes to 12 hours whereupon the compound (Id)
can be obtained.
[0094] Examples of the base are sodium hydride, potassium hydride,
sodium hydroxide, potassium hydroxide, sodium methoxide, butyl
lithium, LDA, lithium bistrimethylsilylamide, sodium
bistrimethylsilylamide, potassium bistrimethylsilylamide, potassium
tert-butoxide, DBU, sodium amide and sodium ethoxide.
[0095] Examples of the inert solvent are THF, dioxane, diethyl
ether, 1,2-dimethoxyethane, DMF and diisopropyl ether.
[0096] Process 9 15
[0097] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 have the same meanings as defined above.)
[0098] The compound (Ie) can be obtained according to the following
reaction step.
[0099] The compound (Id) is treated with a catalytic amount to an
excess amount of an acid in the absence of a solvent or in an inert
solvent at the temperature between 0.degree. C. and the boiling
point of the used solvent for 5 minutes to 48 hours whereupon the
compound (Ie) can be obtained.
[0100] Examples of the acid are hydrochloric acid, sulfuric acid,
acetic acid, trifluoroacetic acid, p-toluenesulfonic acid,
methanesulfonic acid, 10-camphorsulfonic acid, boron trifluoride
and aluminum chloride.
[0101] Examples of the inert solvent are THF, acetone,
acetonitrile, methanol, ethanol, dioxane and a mixed solvent of
such an inert solvent with water.
[0102] Process 10 16
[0103] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 have the same meanings as defined above.)
[0104] The compound (If) can be obtained according to the following
reaction step.
[0105] The compound (Ia) is treated with one equivalent to a large
excess of trimethylsulfoxonium iodide or trimethylsulfonium iodide
in the presence of one equivalent to a large excess of a base in an
inert solvent at the temperature between -30.degree. C. and the
boiling point of the used solvent for 5 minutes to 48 hours
whereupon the compound (If) can be obtained.
[0106] Examples of the base are sodium hydride, potassium hydride,
sodium hydroxide, potassium hydroxide, sodium methoxide, butyl
lithium, LDA, lithium bistrimethylsilylamide, sodium
bistrimethylsilylamide, potassium bistrimethylsilylamide, potassium
tert-butoxide, DBU, sodium amide and sodium ethoxide.
[0107] Examples of the inert solvent are THF, dioxane, diethyl
ether, 1,2-dimethoxyethane, DMF and diisopropyl ether.
[0108] Process 11 17
[0109] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6have the same meanings as defined above.)
[0110] The compound (Ie) can be obtained according to the following
reaction step.
[0111] The compound (If) is treated with one equivalent to an
excess amount of an acid in the absence of a solvent or in an inert
solvent at the temperature between 0.degree. C. and the boiling
point of the used solvent for 5 minutes to 48 hours whereupon the
compound (Ie) can be obtained.
[0112] Examples of the acid are hydrochloric acid, sulfuric acid,
hydrogen bromide, magnesium chloride, magnesium bromide, lithium
bromide, trifluoroacetic acid, lithium perchlorate,
p-toluenesulfonic acid, methanesulfonic acid, 10-camphorsulfonic
acid, boron trifluoride, aluminum chloride and silica gel.
[0113] Examples of the inert solvent are THF, acetone,
acetonitrile, methanol, ethanol and dioxane.
[0114] Process 12 18
[0115] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6have the same meanings as defined above.)
[0116] The compound (Ic) can be obtained according to the following
reaction step.
[0117] The compound (Ie) is treated with one equivalent to an
excess amount of an oxidizing agent in an inert solvent at the
temperature between 0.degree. C. and the boiling point of the used
solvent for 5 minutes to 48 hours whereupon the compound (Ic) can
be obtained.
[0118] Examples of the oxidizing agent are sodium chlorite,
potassium permanganate and hydrogen peroxide.
[0119] When sodium chlorite is used as an oxidizing agent, one
equivalent to an excess amount of 2-methyl-2-butene, sulfamic acid,
DMSO, an aqueous solution of hydrogen peroxide, or the like may be
added if necessary, or further, one equivalent to an excess amount
of sodium dihydrogen phophate may be added thereto.
[0120] Examples of the inert solvent are tert-butyl alcohol, acetic
acid, DMSO, acetone and acetonitrile.
[0121] Process 13 19
[0122] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 have the same meanings as defined above.)
[0123] The compound (Ig) can be obtained according to the following
reaction step.
[0124] The compound (Ia) is treated with one equivalent to a ilarge
excess of chloroacetonitrile in the presence of one equivalent to a
large excess of a base in an inert solvent at the temperature
between -10.degree. C. and the boiling point of the used solvent
for 5 minutes to 48 hours whereupon the compound (Ig) can be
obtained. If necessary, a catalytic amount to an excess amount of a
salt such as benzyltriethylammonium chloride,
benzyltriethylammonium bromide, benzyltrimethylammonium chloride,
benzyltrimethylammonium bromide, tetrabutylammonium chloride,
tetrabutylammonium bromide, tetraethylammonium chloride or
triethylmethylammonium bromide may be added thereto.
[0125] Examples of the base are potassium carbonate, sodium
carbonate, sodium hydride, potassium hydride, lithium hydroxide,
sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium
methoxide, butyl lithium, potassium tert-butoxide, DBU and sodium
ethoxide.
[0126] Examples of the inert solvent are methanol, ethanol,
1-propanol, 2-propanol, tert-butyl alcohol, ethyl acetate, toluene,
THF, 1,2-dimethoxyethane, DMF, DMSO and diisopropyl ether.
[0127] Process 14 20
[0128] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 have the same meanings as defined above.)
[0129] The compound (IC) can be obtained according to the following
reaction step.
[0130] The compound (Ig) is treated with one equivalent to an
excess amount of magnesium bromide or lithium bromide in the
absence of a solvent or in an inert solvent in the presence of one
equivalent to an excess amount of water at the temperature between
0.degree. C. and the boiling point of the used solvent for 5
minutes to 48 hours whereupon the compound (Ic) can be
obtained.
[0131] Examples of the inert solvent are THF, DMF, acetone,
acetonitrile, methanol, ethanol, dioxane and a mixed solvent of
DMF/acetonitrile.
[0132] Process 15 21
[0133] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.11 and R.sup.12 each have the same meanings
as defined above and L.sup.1 represents chlorine, bromine or
iodine.)
[0134] The compound (XIII) can be obtained according to the
following reaction step.
[0135] The starting compound (XI) can be obtained according to a
known method (WO 98/22455) or a method similar thereto. A
commercially available compound can be used as the compound
(XII).
[0136] The compound (XI) is treated with one equivalent to an
excess amount of a base in an inert solvent at the temperature
between -100.degree. C. and room temperature for 5 minutes to 10
hours, followed by reaction with one equivalent to an excess amount
of the compound (XII) at the temperature between -100.degree. C.
and room temperature for 5 minutes to 30 hours whereupon the
compound (XIII) can be obtained. If necessary,
tetramethylethylenediamine, cerium chloride, or the like may be
added thereto.
[0137] Examples of the base are lithium, magnesium, methyl lithium,
methyl magnesium bromide, ethyl magnesium bromide and butyl
lithium.
[0138] Examples of the inert solvent are THF, dioxane, diethyl
ether, 1, 2-dimethoxyethane, diethylene glycol dimethyl ether,
benzene, toluene and hexane.
[0139] Process 16 22
[0140] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.11 and R.sup.12 have the same meanings as
defined above.)
[0141] The compound (Ih) can be obtained according to the following
reaction step.
[0142] The compound (XIII) is treated with one equivalent to an
excess amount of an acid in the absence of a solvent or in an inert
solvent at the temperature between 0.degree. C. and the boiling
point of the used solvent for 5 minutes to 48 hours whereupon the
compound (Ih) can be obtained. If necessary, water may be added
thereto.
[0143] Examples of the acid are hydrochloric acid, sulfuric acid,
10-camphorsulfonic acid, acetic acid, formic acid, trifluoroacetic
acid, p-toluenesulfonic acid, methanesulfonic acid, boron
trifluoride and aluminum chloride.
[0144] Examples of the inert solvent are THF, acetone,
acetonitrile, toluene, xylene, methanol, ethanol, 1-propanol,
2-propanol, 1-butanol, 2-butanol, tert-butyl alcohol,
1-pentanol,,I-hexanol, 1-heptanol, 1-octanol and dioxane.
[0145] Process 17 23
[0146] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.11 and R.sup.12 have the same meanings as
defined above.)
[0147] The compound (Ii) can be obtained according to the following
reaction step.
[0148] The compound (XIII) is treated with one equivalent to an
excess amount of a cyanide in the presence of one equivalent to an
excess amount of an acid in an inert solvent at the temperature
between -100.degree. C. and the boiling point of the used solvent
for 5 minutes to 48 hours whereupon the compound (Ii) can be
obtained.
[0149] Examples of the acid are hydrochloric acid, sulfuric acid,
10-camphorsulfonic acid, acetic acid, formic acid, trifluoroacetic
acid, p-toluenesulfonic acid, methanesulfonic acid, titanium
tetrachloride, boron trifluoride and aluminum chloride.
[0150] Examples of the cyanide are trimethylsilyl cyanide, sodium
cyanide and potassium cyanide.
[0151] Examples of the inert solvent are THF, dioxane, diethyl
ether, 1,2-dimethoxyethane, methanol, ethanol, acetonitrile,
dichloromethane, 1, 2-dichloroethane, chloroform and toluene.
[0152] Process 18 24
[0153] (In the formulae, m, p, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 have the same meanings as defined above.)
[0154] The compound (Ia) can be obtained according to the following
reaction step.
[0155] The starting compound (Iia) can be synthesized in such a
manner that a compound (XIII) wherein R.sup.11 and R.sup.12 have a
ketal structure is obtained using a compound (XII) wherein R.sup.11
and R.sup.12 have a ketal structure as a starting material in
Process 15 and a method mentioned in Process 17 is applied using
the compound (XIII) wherein R.sup.11 and R.sup.1 2 have a ketal
structure as a starting material.
[0156] The compound (Iia) is treated with one equivalent to an
excess amount of an acid in the absence of a solvent or in an inert
solvent at the temperature between 0.degree. C. and the boiling
point of the used solvent for 5 minutes to 48 hours whereupon the
compound (Ia) can be obtained.
[0157] Examples of the acid are hydrochloric acid, sulfuric acid,
10-camphorsulfonic acid, acetic acid, formic acid, trifluoroacetic
acid, p-toluenesulfonic acid, methanesulfonic acid, boron
trifluoride and aluminum chloride.
[0158] Examples of the inert solvent are THF, acetone,
acetonitrile, toluene, methanol, ethanol, 1-propanol, 2-propanol,
1-butanol, 2-butanol, tert-butyl alcohol, 1-pentanol, 1-hexanol,
1-heptanol, 1-octanol, dioxane and a mixed solvent of such an
insert solvent with water.
[0159] Process 19 25
[0160] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6have the same meanings as defined above.)
[0161] The compound (Ij) can be obtained according to the following
reaction step.
[0162] The compound (Ia) is treated with one equivalent to an
excess amount of a reducing agent in an inert solvent at the
temperature between -100.degree. C. and the boiling point of the
used solvent for 5 minutes to 48 hours whereupon the compound (Ij)
can be obtained.
[0163] Examples of the reducing agent are
1,1,3,3-tetramethyldisiloxane, triethylsilane, sodium borohydride,
sodium cyanoborohydride, sodium triacetoxyborohydride and lithium
aluminum hydride.
[0164] Examples of the inert solvent are methanol, ethanol,
1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butyl alcohol,
1-pentanol, 1-hexanol, 1-heptanol, 1-octanol and dioxane.
[0165] Process 20 26
[0166] (In the formulae, m, n, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, L.sup.1 and X each have the same meanings as
defined above, and L.sup.2 represents chlorine, bromine, iodine or
a trifluoromethanesulfonate group.)
[0167] The compound (Ik) can be obtained according to the following
reaction step.
[0168] With regard to the compound (XIV), the commercially
available one may be used or it may be obtained according to a
known method [Tetrahedron Lett., 30, 5499 (1992)].
[0169] After the compound (XI) is treated with a base in an inert
solvent at the temperature between -100.degree. C. and room
temperature for 5 minutes to 10 hours, the resulting compound is
treated with a metal halide or a boron compound at the temperature
between -100.degree. C. and the boiling point of the used solvent
for 5 minutes to 30 hours, followed by further reaction with the
compound (XIV) in an inert solvent in the presence of a catalytic
amount to an excess amount of a palladium complex at the
temperature between room temperature and the boiling point of the
used solvent for 5 minutes to 30 hours whereupon the compound (Ik)
can be obtained. Incidentally, in the above reaction which is
carried out in the presence of a catalytic amount to an excess
amount of a palladium complex, a salt such as lithium chloride or
silver oxide may be added, if necessary.
[0170] Examples of the base are lithium, magnesium, methyl lithium,
methyl magnesium bromide, ethyl magnesium bromide and butyl
lithium.
[0171] Examples of the metal halide are halogenated alkyl tin
derivatives such as chlorotributyltin and chlorotrimethyltin and
halogenated zinc derivatives such as zinc chloride, zinc bromide
and zinc iodide while examples of the boron compound are trimethyl
borate, triisopropyl borate, tributyl borate, triethyl borate and
borane.
[0172] Examples of the palladium complex are
tetrakis(triphenylphosphine) palladium,
dichlorobis(triphenylphosphine) palladium,
dichlorobis(acetonitrile) palladium,
[1,1'-bis(diphenylphosphino)ferrocen- e] dichloropalladium and
palladium acetate.
[0173] Examples of the inert solvent used in the reaction with a
metal halide or a boron compound are THF, dioxane, diethyl ether,
1,2-dimethoxyethane, diethyleneglycol dimethyl ether, benzene,
toluene and hexane.
[0174] Examples of the inert solvent used in the reaction in the
presence of a palladium complex are THF, dioxane, diethyl ether,
ethylene glycol, triethylene glycol, 1,2-dimethoxyethane,
diethylene glycol dimethyl ether, methanol, ethanol, 1-butanol,
2-propanol, dichloromethane, chloroform, acetonitrile, benzene,
toluene, dimethylacetamide, DMF and DMSO.
[0175] Process 21 27
[0176] (In the formulae, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, L.sup.1 and Z.sup.1--Z.sup.2--Z.sup.3 each have
the same meanings as defined above, Z.sup.4represents an oxygen
atom or a sulfur atom, and L.sup.3and L.sup.4 represent chlorine,
bromine, iodine or a trifluoromethanesulfoxy group.) The compound
(Im) and the compound (In) can be obtained according to the
following reaction step.
[0177] With regard to the compound (XV) and the compound (XVI), the
commercially available ones may be used or they may be obtained
according to known methods [J. Chem. Soc., Perkin Trans. 1, 1954
(1973); J. Org. Chem., 60(7), 1936 (1995); Tetrahedron Lett.,
30(42), 7719 (1994); Chem. Pharm. Bull., 40(10), 2597 (1992); J.
Heterocyclic Chem., 7, 815 (1970); J. Chem. Soc. Chem. Comm., 1183
(1985); etc.]
[0178] The compound (XI) is treated with a base in an inert solvent
at the temperature between -100.degree. C. and room temperature for
5 minutes to 10 hours, followed by reaction with a metal halide or
a boron compound at the temperature between -100.degree. C. and the
boiling point of the used solvent for 5 minutes to 30 hours. The
resulting compound is treated with the compound (XV) in an inert
solvent in the presence of a catalytic amount to an excess amount
of a palladium complex or a nickel complex at the temperature
between room temperature and the boiling point of the used solvent
for 5 minutes to 30 hours whereby the compound (Im) can be
obtained. Incidentally, when the compound (XVI) is used instead of
the compound (XV) and the same reaction as in the case of the
compound (XV) is carried out, the compound (In) is obtained.
[0179] In the above-mentioned reaction carried out in the presence
of a catalytic amount to an excess amount of a palladium complex or
a nickel complex, a salt such as lithium chloride or silver oxide
may be added thereto, if necessary.
[0180] Examples of the base are lithium, magnesium, methyl lithium,
methyl magnesium bromide, ethyl magnesium bromide and butyl
lithium.
[0181] Examples of the metal halide are halogenated alkyl tin
derivatives such as chlorotributyltin and chlorotrimethyltin and
halogenated zinc derivatives such as zinc chloride, zinc bromide
and zinc iodide while examples of the boron compound are trimethyl
borate, triisopropyl borate, tributyl borate, triethyl borate and
borane.
[0182] Examples of the palladium complex are
tetrakis(triphenylphosphine) palladium,
dichlorobis(triphenylphosphine) palladium,
dichlorobis(acetonitrile) palladium,
[1,1'-bis(diphenylphosphino)ferrocen- e] dichloropalladium and
palladium acetate.
[0183] Examples of the nickel complex are
[1,11-bis(diphenylphosphino)ferr- ocene] dichloronickel and
dichlorobis(triphenylphosphine) nickel.
[0184] Examples of the inert solvent used in the reaction with a
metal halide or a boron compound are THF, dioxane, diethyl ether,
1,2-dimethoxyethane, diethylene glycol dimethyl ether, benzene,
toluene and hexane.
[0185] Examples of the inert solvent used in the reaction in the
presence of a palladium complex or a nickel catalyst are THF,
dioxane, diethyl ether, ethylene glycol, triethylene glycol,
1,2-dimethoxyethane, diethylene glycol dimethyl ether, methanol,
ethanol, 1-butanol, 2-propanol, dichloromethane, chloroform,
acetonitrile, benzene, toluene, dimethylacetamide, DMF and
DMSO.
[0186] The compound (Ima) which is the compound (Im) wherein
Z.sup.1--Z.sup.2--Z.sup.3 is C(.dbd.O)--NH--C(.dbd.O) can also be
obtained in such a way that a reaction similar to that mentioned in
Process 21 is carried out using the compound (XI) and a diethyl
4-halogenated phthalate such as diethyl 4-bromophthalate followed
by hydrolysis and the product obtained thereby is treated with
urea.
[0187] The compound (I) wherein R.sup.9 is carbamoyl can be
obtained using the compound (I) wherein R.sup.9is cyano according
to a known method ["Jikken Kagaku Koza (Handbook of Experimental
Chemistry)", fourth edition, edited by the Chemical Society of
Japan, 22, 151-154 (1992)] or a method similar thereto.
[0188] The compound (I) wherein R.sup.9 is cyano is converted to
the compound wherein the moiety corresponding to R.sup.9 is an
aldehyde according to a known method ["Jikken Kagaku Koza (Handbook
of Experimental Chemistry)", fourth edition, edited by the Chemical
Society of Japan, 21, 89-94 (1992)] or a method similarly thereto,
and then the compound (I) wherein R.sup.9 is ethynyl can be
obtained according to a known method ["Jikken Kagaku Koza (Handbook
of Experimental Chemistry)", fourth edition, edited by the Chemical
Society of Japan, 19, 306-307 (1992)] or a method similar
thereto.
[0189] The intermediates and the desired compounds in each of the
above-mentioned process can be isolated and purified by separation
and purification methods conventionally used in synthetic organic
chemistry such as filtration, extraction, washing, drying,
concentration, recrystallization and various kinds of
chromatography. The intermediates may be subjected to the
subsequent reaction without particular purification.
[0190] When it is desired to obtain a salt of the compound (I), the
compound (I) is dissolved or suspended in a suitable solvent, then
an acid or a base is added thereto, and the resulting salt may be
isolated and purified.
[0191] Further, the compound (I) and pharmaceutically acceptable
salts thereof can also exist in the form of adducts with water or
various solvents, which are also within the scope of the present
invention.
[0192] Specific examples of the compound (I) obtained according to
the present invention are shown in Table 1.
1TABLE 1 28 Compd. No. W R m 1 29 H 1 2 30 H 1 3 31 H 1 4 32 H 1 5
33 H 1 6 34 H 1 7 35 H 1 8 36 H 1 9 37 H 1 10 38 H 1 11 39 H 1 12
40 H 1 13 41 CH.sub.3 0 14 42 CH.sub.3 0 15 43 CH.sub.3 0 16 44 H 1
17 45 H 1 18 46 H 1 19 47 H 1 20 48 H 1 21 49 H 1 22 50 H 1 23 51 H
1 24 52 H 2 25 53 H 2 26 54 H 0 27 55 H 0 56 Compd. No. W R m
R.sup.5 28 57 H 1 OH 29 58 H 1 OH 30 59 H 1 OCHF.sub.2 31 60 H 1
OCHF.sub.2 32 61 H 0 OH 33 62 H 0 OH 34 63 H 0 OCHF.sub.2 35 64 H 0
OCHF.sub.2 36 65 H 2 OH 37 66 H 2 OH 38 67 H 2 OCHF.sub.2 39 68 H 2
OCHF.sub.2 40 69 CH.sub.3 0 OCH.sub.3 41 70 CH.sub.3 0 OCH.sub.3 42
71 --(CH.sub.2).sub.4-- 0 OCH.sub.3 43 72 --(CH.sub.2).sub.4-- 0
OCH.sub.3 44 73 CH.sub.3 0 OH 45 74 CH.sub.3 0 OH 46 75 CH.sub.3 0
OCHF.sub.2 47 76 CH.sub.3 0 OCHF.sub.2 48 77 --(CH.sub.2).sub.4-- 0
OH 49 78 --(CH.sub.2).sub.4-- 0 OH 50 79 --(CH.sub.2).sub.4-- 0
OCHF.sub.2 51 80 --(CH.sub.2).sub.4-- 0 OCHF.sub.2 52 81 CH.sub.3 1
OCH.sub.3 53 82 CH.sub.3 1 OCH.sub.3 54 83 CH.sub.3 1 OH 55 84
CH.sub.3 1 OH 56 85 CH.sub.3 1 OCHF.sub.2 57 86 CH.sub.3 1
OCHF.sub.2
[0193] The pharmacological activities of the representative the
compounds (I) are described in more detail by Test Examples.
[0194] Test Example 1: Inhibition Test on Recombinant Human PDE IV
Enzyme
[0195] Human phosphodiesterase CDNA (HSPDE4A) was isolated from
testicles. Its predicted amino acid sequence is identical with the
sequence (HSPDE4A5) reported by Bolger, G. et al. (Mol. Cell.
Biol., 6558 (1993)) except that 223 amino acids have been deleted
from the N-terminal thereof. This recombinant protein was expressed
by an E. coli expression plasmid and then purified. The PDE
activity was measured in thefollowing 2-step process according to
the method of Kincaid, R. and Manganiello, V. [Method. Enzymol.,
159, 457 (1988)]. The substrateused was[.sup.3H]cAMP (final
concentration: 1 .mu.mol/L), and the reaction was performed in a
standard mixture containing
N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (50 mmol/L, pH
7.2), MgCl.sub.2(1 mmol/L) and soybean trypsin inhibitor (0.1
mg/ml). The reaction was initiated by adding the enzyme thereto,
and the mixture was incubated at 30.degree. C. for 10 to 30
minutes. The reaction was quenched by hydrochloric acid, and the
formed 5'-AMP was completely decomposed with 5'-nucleosidase. This
sample was subjected to chromatography on DEAE-Sephadex A-25, and
the eluted [.sup.3H]adenosine was counted with a scintillation
counter. The test compound was added after dissolved
(concentration: 1.7%) in DMSO.
[0196] In this study, Compound 5 showed enzyme inhibitory activity
of over 87% at a drug concentration of 1 .mu.mol/L.
[0197] Although the compound (I) or pharmaceutically acceptable
salts thereof can also be administered as such, it is usually
desirable to provide them in the form of various pharmaceutical
preparations. Such pharmaceutical preparations may be used for
animals and humans.
[0198] The pharmaceutical preparations according to the present
invention may contain the compound (I) or a pharmaceutically
acceptable salt thereof as an active ingredient, alone or as a
mixture with other therapeutically effective components. Further,
such pharmaceutical preparations are obtained by any means which
are well-known in the technical field of pharmaceutics after mixing
the active ingredient with one or more pharmaceutically acceptable
carriers.
[0199] Examples of the effective ingredient to be mixed therewith
are a serotonin (5HT).sub.3 receptor antagonist, a serotonin
(5HT).sub.4 receptor agonist, a serotonin (5HT).sub.1A receptor
agonist, a dopamine (D).sub.2 receptor antagonist, a histamine
(H).sub.1 receptor antagonist, a muscarine receptor antagonist, a
neurokinin (NK).sub.1 receptor antagonist and an endothelin
(ET).sub.A receptor antagonist.
[0200] It is desired to use the administration route which is the
most effective in therapy such as oral administration and
parenteral administration which includes intrabuccal,
intratracheal, intrarectal, subcutaneous, intramuscular and
intravenous administration.
[0201] The administration form includes sprays, capsules, tablets,
granules, syrups, emulsions, suppositories, injections, ointments
and tapes.
[0202] Liquid preparations such as emulsions and syrups which are
suitable for oral administration can be obtained using water,
sugars such as sucrose, sorbitol and fructose, glycols such as
polyethylene glycol and propylene glycol, oils such as sesame oil,
olive oil and soybean oil, preservatives such as p-hydroxybenzoate
and flavors such as strawberry flavor and peppermint. Capsules,
tablets, powder and granules can be obtained using excipients such
as lactose, glucose, sucrose and mannitol, disintegrators such as
starch and sodium alginate, lubricants such as magnesium stearate
and talc, binders such as polyvinyl alcohol, hydroxypropyl
cellulose and gelatin, surfactants such as fatty acid esters, and
plasticizers such as glycerin.
[0203] Preparations suitable for parenteral administration comprise
a sterilized aqueous agent containing the active compound, which is
preferably isotonic to the blood of a patient. For example, a
solution for injection is prepared using a carrier such as a salt
solution, a glucose solution or a mixture of a saline solution and
a glucose solution. Preparations for intrarectal administration are
prepared using a carrier such as cacao fat, hydrogenated fat and
hydrogenated carboxylic acid, and provided as suppositories. Sprays
are prepared using an active compound itself or an active compound
with a carrier which can disperse the active compound as fine
particles to facilitate absorption without stimulating oral or
respiratory mucosa. Examples of such carriers are lactose and
glycerin. Preparations such as aerosol and dry powder can be used
depending on the properties of the active compound and carriers
used.
[0204] These parenteral preparations may also contain one or more
auxiliary components selected from diluents, flavors,
preservatives, excipients, disintegrators, lubricants, binders,
surfactants, and plasticizers, all of which are mentioned in the
above oral preparations.
[0205] The effective dose and administration schedule of the
compound (I) or a pharmaceutically acceptable salt thereof may vary
depending on the form of administration, the age and body weight of
a patient, and the type or degree of the disease to be treated, but
usually, in the case of oral administration, the compound (I) or a
pharmaceutically acceptable salt thereof is administered in a dose
of 0.01 mg to 1 g/adult/day, preferably 0.05 to 50 mg/adult/day, at
one time or in several parts. In the case of parenteral
administration such as intravenous administration, the compound (I)
or a pharmaceutically acceptable salt thereof is administered in a
dose of 0.001 to 100 mg/adult/day, preferably 0.01 to 10
mg/adult/day, at one time or in several parts. However, these doses
vary depending on the various conditions described above.
[0206] Hereinafter, the mode of the present invention is described
by Examples.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
EXAMPLE 1
[0207] 4-Cyano-4-(8-methoxy-1,4-benzodioxan-5-yl) cyclohexanone
(Compound 1)
[0208] (Step A) Synthesis of
2-(8-methoxy-1,4-benzodioxan-5-yl)acetonitril- e (Compound 1a)
[0209] To a solution of 8-methoxy-1,4-benzodioxane-5-carbaldehyde
(12 g, 62 mmol) in acetonitrile (140 mL) was added lithium bromide
(12 g, 110 mmol), and then trimethylsilyl chloride (12 mL, 95 mmol)
was added dropwise. After 15 minutes, the mixture was ice-cooled,
and 1,1,3,3-tetramethyldisiloxane (19 mL, 110 mmol) was added
dropwise, followed by stirring at room temperature for 2 hours. The
mixture was diluted with dichloromethane, and then was filtered
through Celite. The solvent was evaporated in vacuo to give a pale
yellow oil. To a solution of the obtained crude
5-bromomethyl-8-methoxy-1,4-benzodioxane in DMF(180 mL) was added
sodium cyanide (9.2 g, 190 mmol), followed by stirring at room
temperature for 60 hours. To the mixture was added water under
ice-cooling, and the precipitated solid was collected by filtration
to give Compound 1a (6.8 g, 53%) as an ash-colored solid.
[0210] Melting Point: 121 - 125.degree. C.
[0211] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 3.60 (s, 2H), 3.88
(s, 3H), 4.33 (s, 4H), 6.50 (d, J=8 Hz, 1H), 6.86 (d, J=8 Hz, 1H).
MASS (m/z) 205 (M.sup.+).
[0212] (Step B) Synthesis of dimethyl
4-cyano-4-(8-methoxy-1,4-benzodioxan- -5-yl)pimelate (Compound
1b)
[0213] To a solution of Compound la (6.2 g, 30 mmol) obtained in
Step A in acetonitrile (94 mL) were added a 40% methanolic solution
of Triton B (1.4 mL, 3.0 mmol) and methyl acrylate (27 mL, 300
mmol), followed by refluxing for 5 hours. The mixture was allowed
to cool, and then poured into water, followed by extraction with
ethyl acetate. The organic layer was washed with brine and dried
over sodium sulfate, and the solvent was evaporated in vacuo. The
residue was purified by silica gel column chromatography (eluted
with hexane/ethyl acetate 2/1) to give Compound 1b (6.4 g, 56%) as
a pale yellow oil.
[0214] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 2.05-2.37 (m, 4H),
2.39-2.59 (m, 2H), 2.62-2.82 (m, 2H), 3.60 (s, 6H), 3.87 (s, 3H),
4.20-4.40 (m, 14H), 6.48 (d, J=9 Hz, 1H), 7.01 (d, J=9 Hz, 1H).
MASS (m/z) 377 (M.sup.+).
[0215] (Step C) Synthesis of
4-cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)-2--
methoxycarbonylcyclohexanone (Compound 1c)
[0216] To a solution of Compound 1b (6.4 g, 17 mmol) obtained in
Step B in 1,2-dimethoxyethane (96 mL) was added 60% sodium hydride
(2.0 g, 50 mmol). After refluxing for 3 hours, the mixture was
allowed to cool, poured into ice water, acidified with 6 mol/L
hydrochloric acid and extracted with ethyl acetate. The organic
layer was washed with brine and dried over sodium sulfate, and the
solvent was evaporated. The residue was purified by silica gel
column chromatography (eluted with hexane/ethyl acetate=2/1) to
give Compound 1c (5.0 g, 86%) as a white solid.
[0217] Melting Point: 129 - 132.degree. C.
[0218] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 2.21-2.50 (m, 3H),
2.61-2.89 (m, 2H), 3.11(d, J=15 Hz, 1H), 3.79 (s, 3H), 3.89 (s,
3H), 4.37 (s, 4H), 6.49 (d, J=9 Hz, 1H), 6.84 (d, J=9 Hz, 1H), 12.2
(s, MASS (m/z) 345 (M.sup.+).
[0219] (Step D) Synthesis of Compound 1
[0220] A mixture of Compound 1c (5.0 g, 15 mmol) obtained in Step
C, DMSO(50 mL), water (5 mL), and sodium chloride (5.0 g) was
stirred at 150.degree. C. for 5 hours. The mixture was allowed tto
cool, and added water, followed by extraction with ethyl acetate.
The organic layer was washed with brine and dried over sodium
sulfate, and the solvent was evaporated in vacuo. The residue was
purified by silica gel column chromatography (eluted with
hexane/ethyl acetate=3/1) to give Compound 1 (3.6 g, 86%) as a
white solid.
[0221] Melting Point: 157 - 161.degree. C.
[0222] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 2.21-2.41 (m, 2H),
2.45-2.72 (m, 4H), 2.81-3.00 (m, 2H), 3.89 (s, 3H), 4.37 (s, 4H),
6.51 (d, J=9 Hz, 1H), 6.88 (d, J=9 Hz, 1H). MASS (m/z) 287
(M.sup.+).
EXAMPLE 2
[0223] 4-Cyano-4-(8-methoxy-1,4-benzodioxan-5-yl) cyclohexanone
ethyleneketal (Compound 2)
[0224] (Step A) Synthesis of
4-hydroxy-4-(8-methoxy-1,4-benzodioxan-5-yl)c- yclohexanone
ethyleneketal (Compound 2a)
[0225] To a solution of 5- bromo-8-methoxy-1,4-benzodioxane (10 g,
41 mmol) in THF (65 mL) was added dropwise a 1.59 mol/L solution of
n-butyl lithium in hexane (28 mL, 45 mmol) at -78.degree. C. After
15 minutes, a solution of 1,4-cyclohexadione monoethyleneketal (9.6
g, 61 mmol) in THF (50 mL) was added dropwise. The mixture was
stirred for 1 hour, followed by stirring at room temperature for 20
minutes. Water was added and the mixture was extracted with ethyl
acetate. The extract was washed with brine and dried over sodium
sulfate. The solvent was evaporated, and the residue was purified
by silica gel column chromatography (eluted with hexane/ethyl
acetate =1/1) to give Compound 2a (9.0 g, 68%) as a white
solid.
[0226] Melting Point: 94 - 96.degree. C.
[0227] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.58-1.72 (m, 2H),
1.88-2.28 (m, 6H), 3.57 (s, 1H), 3.86 (s, 3H), 3.90-4.07 (m, 4H),
4.35 (s, 4H), 6.46 (d, J=9 Hz, 1H), 6.82 (d, J=9 Hz, 1H).
[0228] MASS (m/z) 322 (M.sup.+).
[0229] (Step B) Synthesis of Compound 2
[0230] To a solution of Compound 2a (0.49 g, 1.5 mmol) obtained in
Step A in dichloromethane (4.9 mL), trimethylsilyl cyanide (0.26
mL, 1.9 mmol) was added at -78.degree. C., then boron
trifluoride-ethyl ether complex (0.20 mL, 1.6 mmol) was added
dropwise, and the mixture was stirred for 10 minutes, followed by
stirring at room temperature for 10 minutes. A saturated aqueous
solution of sodium bicarbonate was added and the mixture was
extracted with ethyl acetate. The extract was washed with brine and
dried over sodium sulfate, and the solvent was evaporated. The
residue was purified by silica gel column chromatography (eluted
with hexane/ethyl acetate=2/1) to give Compound 2 (0.30 g, 61%)as a
colorless oil.
[0231] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.79-1.95 (m, 2H),
2.06-2.20 (m, 4H), 2.30-2.46 (m, 2H), 3.87 (s, 3H), 3.90-4.07 (m,
4H), 4.36 (s, 4H), 6.48 (d, J=9 Hz, 1H), 6.82 (d, J=9 Hz, 1H). MASS
(m/z) 331 (M.sup.+).
EXAMPLE 3
Compound 1
[0232] To a solution of Compound 2 (0.29 g, 0.87 mmol) obtained in
Example 2 in acetone (2.9 mL), 6 mol/L hydrochloric acid (1.2 mL,
7.2 mmol) was added, and the mixture was refluxed for 3 hours. The
mixture was allowed to cool and poured into a saturated aqueous
solution of sodium bicarbonate, the mixture was extracted with
ethyl acetate, and the extract was washed with brine. The mixture
was dried over sodium sulfate, and the solvent was evaporated to
give Compound 1 (0.23 g, 92%) as a white solid.
EXAMPLE 4.
[0233] Methyl
cis-4-cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)cyclohexanecar-
boxylate (Compound 3) and methyl
trans-4-cyano-4-(8-methoxy-1,4-benzodioxa-
n-5-yl)cyclohexanecarboxylate (Compound 4)
[0234] (Step A) Synthesis of
2-[4-cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)-
cyclohexylidene]-1,3-dithiane (Compound 3a)
[0235] To a solution of 2-trimethylsilyl-1,3-dithiane (5.0 mL, 26
mmol) in THF (50 mL) was added dropwise a 1. 54 mol/L solution of
n-butyl lithium in hexane (17 mL, 26 mmol) under ice-cooling. After
10 minutes, the mixturewas cooled to -78.degree. C., and a solution
of Compound 1 (3.6 g, 13 mmol) obtained in Example 1 in THF (40 ml)
was added dropwise. After 10 minutes, brine was added to the
mixture, followed by addition of water at room temperature. The
mixture was extracted with ethyl acetate, the extract was dried
over sodium sulfate, and the solvent was evaporated. The residue
was purified by silica gel column chromatography (elutedwith
hexane/ethyl acetate=4/1) to give
[0236] Compound 3a (3.9 g, 79%) as a white solid.
[0237] Melting Point: 164 - 166.degree. C.
[0238] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.70-1.92 (m, 2H),
2.05-2.24 (m, 2H), 2.28-2.53 (m, 4H), 2.89 (t, J=6 Hz, 4H),
3.18-3.38 (m, 2H), 3.87 (s, 3H), 4.36 (s, 4H), 6.47 (d, J=9 Hz,
1H), 6.79 (d, J=9 Hz, 1H).
[0239] MASS (m/z) 389 (M.sup.+).
[0240] (Step B) Synthesis of Compound 3 and Compound 4
[0241] To a suspension of Compound 3a (3.9 g, 10 mmol) obtained in
Step A in methanol (120 mL), 70% perchloric acid (1.7 mL, 20 mmol),
and mercury chloride (HgCl.sub.2) (4.3 g, 16 mmol) were added, and
the mixture was stirred for 4 hours. The mixture was diluted with
dichloromethane and was filtered through Celite, the filtrate was
poured into a saturated aqueous solution of sodium bicarbonate, and
the mixture was extracted with dichloromethane. The organic layer
was washed with brine and dried over sodium sulfate and the solvent
was evaporated. The residue was purified by silica gel column
chromatography (eluted with hexane/ethyl acetate=1/1) to give the
crude Compound 3 as a white solid and also to give Compound 4 (0.18
g, 5.5%) as a colorless oil. Compound 3 was further recrystallized
from ethyl acetate to give white crystals (0.57 g, 17%).
Compound 3
[0242] Melting Point: 123 - 124.degree. C.
[0243] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.75-2.22 (m, 6H),
2.27-2.51 (m, 3H), 3.71 (s, 3H), 3.88 (s, 3H), 4.36 (s, 4H), 6.48
(d, J=9 Hz, 1H), 6.84 (d, J=9 Hz, 1H).
[0244] MASS (m/z) 331 (M.sup.+).
Compound 4
[0245] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.92-2.38 (m, 8H),
2.70-2.88 (m, 1H), 3.69 (s, 3H), 3.87 (s, 3H), 4.36 (s, 4H), 6.48
(d, J=9 Hz, 1H), 6.81 (d, J=9 Hz, 1H).
[0246] MASS (m/z) 331 (M+D).
EXAMPLE 5
[0247]
cis-4-Cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)cyclohexanecarboxylic
acid (Compound 5)
[0248] To a solution of Compound 3 (0.55 g, 1.7 mmol) obtained in
Example 4 in methanol (3.3 mL) and THF (3.3 mL) was added dropwise
a 1.3 mol/L aqueous solution of potassium hydroxide (2.6 mL),
followed by stirring at room temperature for 1 hour. The mixture
was poured into water, ethyl acetate was added, and an aqueous
layer was extracted. The aqueous layer was acidified with 1 mol/L
hydrochloric acid, and the precipitated solid was collected by
filtration and re-slurried with ethanol to give of Compound 5 (0.45
g, 86%) as a white solid.
[0249] Melting Point: 228 - 230.degree. C.
[0250] .sup.1H-NMR (DMSO-d.sub.6, .delta., ppm) 1.59-1.90 (m, 4H),
1.94-2.10 (m, 2H), 2.20-2.45 (m, 3H), 3.75 (s, 3H), 4.27 (dd, J=5,
12 Hz, 4H), 6.60 (d, J=9 Hz, 1H), 6.79 (d, J=9 Hz, 1H), 12.2 (br s,
1H).
[0251] MASS (m/z) 317 (M.sup.+).
[0252] Elemental analysis: C.sub.17H.sub.19NO.sub.5
[0253] Found (%) C. : 64.09, H : 6.01, N : 4.51
[0254] Calcd. (%) C. : 64.34, H : 6.03, N : 4.41
EXAMPLE 6
[0255]
1-(8-Methoxy-1,4-benzodioxan-5-yl)-4-methoxymethylenecyclohexane
carbonitrile (Compound 6)
[0256] To a suspension of (methoxymethyl)triphenylphosphonium
chloride (34 g, 99 mmol) in THF (320 mL) was added potassium
tert-butoxide (11 g, 99mmol). The mixturewas stirred at room
temperature for 15 minutes, and a solution of Compound 1 (15 g, 52
mmol) obtained in Example 1 in THF (150 mL) was added dropwise,
followed by stirring at room temperature for 45 minutes. Water was
added to the reaction mixture and the mixture was extracted with
ethyl acetate. The organic layer was washed with brine and dried
over sodium sulfate. The solvent was evaporated in vacuo, and the
residue was purified by silica gel column chromatography (eluted
with hexane/ethyl acetate=3/1) to give Compound 6 (14 g, 82%) as a
white solid.
[0257] Melting Point: 112 - 113.degree. C.
[0258] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.67-1.82 (m, 2H),
2.08-2.60 (m, 5H), 2.82-2.98 (m, 1H), 3.57 (s, 3H), 3.87 (s, 3H),
4.36 (s, 4H), 5.84 (s, 1H), 6.47 (d, J=9 Hz, 1H), 6.80 (d, J=9 Hz,
1H).
[0259] MASS (m/z) 315 (M.sup.+).
EXAMPLE 7
[0260] cis-4-Cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)cyclohexane
carbaldehyde (Compound 7) and
trans-4-cyano-4-(8-methoxy-1,4-benzodioxan-- 5-yl)cyclohexane
carbaldehyde (Compound 8)
[0261] To a solution of Compound 6 (10 g, 32 mmol) obtained in
Example 6 in acetone (100 mL) was added dropwise 6 mol/L
hydrochloric acid (210 mL), and the mixture was stirred at room
temperature for 2 hours, neutralized by adding a 5 mol/L aqueous
solution of sodium hydroxide and extracted with ethyl acetate. The
organic layer was washed with a saturated aqueous solution of
sodium bicarbonate and then with brine. The mixture was dried over
magnesium sulfate, the solvent was evaporated in vacuo, and the
residue was purified by silica gel column chromatography (eluted
with hexane/ethyl acetate=2/1) to give Compound 7 (7.7 g, 80%) and
Compound 8 (1.7 g, 18%) each being as a colorless oil.
Compound 7
[0262] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.80-2.35 (m, 7H),
2.38-2.57 (m, 2H), 3.88 (s, 3H), 4.36 (s, 4H), 6.49 (d, J=9 Hz,
1H), 6.85 (d, J=9 Hz, 1H), 9.68 (s, 1H).
[0263] MASS (m/z) 301 (M.sup.+).
Compound 8
[0264] .sup.1H-NMR (CDCL.sub.3, .delta., ppm) 1.75-1.96 (m, 2H),
2.06-2.37 (m, 6H), 2.56-2.65 (m, 1H), 3.87 (s, 3H), 4.33 (s, 4H),
6.46 (d, J=9 Hz, 1H), 6.78 (d, J=9 Hz, 1H), 9.73 (s, 1H). MASS
(m/z) 301 (M.sup.+).
EXAMPLE 8
[0265]
cis-4-Cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)cyclohexanecarboxylic
acid (Compound 5)
[0266] To a solution of Compound 7 (7.7 g, 26 mmol) obtained in
Example 7, sodium dihydrogen phosphate (3.1 g, 26 mmol) and
2-methyl-2-butene (12 mL, 120 mmol) in tert-butyl alcohol (155 mL)
was added dropwise 46 mL of a aqueous solution of 80% sodium
chlorite (3.2 g, 28 mmol) under ice-cooling, and the mixture was
stirred at room temperature for 1 hour. To the mixture was added
sodium hydrogen sulfite (5.3 g, 51 mmol), followed by stirring for
15 minutes, a 2 mol/L aqueous solution of sodium hydroxide was
added, and the resulting mixture was washed with ethyl acetate. The
mixture was adjusted to pH 3.5 with 6 mol/L hydrochloric acid, and
the precipitated solid was collected by filtration and
recrystallized from ethanol to give Compound 5 (5.5 g, 67%) as
white crystals.
EXAMPLE 9
[0267] cis-4-Cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)cyclohexanol
(Compound 9)
[0268] To a solution of Compound 1 (0.42 g, 1.5 mmol) obtained in
Example 1 in methanol (8.4 mL) was added sodium borohydride (0.11
g, 3.0 mmol) under ice-cooling. The mixture was stirred at room
temperature for 1 hour, sodium borohydride (0.057 g, 1.5 mmol) was
added again under ice-cooling, followed by stirring at room
temperature for 30 minutes, 1 mol/L hydrochloric acid was added
thereto under ice-cooling, and the mixture was extracted with ethyl
acetate. The organic layer was washed with brine and dried over
sodium sulfate, and the solvent was evaporated in vacuo. The
residue was purified by silica gel column chromatography (eluted
with hexane/ethyl acetate=1/2), followed by recrystallization from
ethanol to give Compound 9 (0.20 g, 48%) as white crystals.
[0269] Melting Point: 137 - 138.degree. C.
[0270] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.75-1.99 (m, 4H),
2.01-2.22 (m, 2H), 2.30-2.54 (m, 2H), 3.56-3.79 (m, 1H), 3.87 (s,
3H), 4.38 (s, 4H), 6.48 (d, J=8 Hz, 1H), 6.83 (d, J=8 Hz, 1H).
[0271] MASS (m/z) 289 (M.sup.+).
[0272] Elemental analysis:
C.sub.16H.sub.19NO.sub.4.multidot.0.1H.sub.2O
[0273] Found (%) C. : 66.21, H:6.94, N:4.82
[0274] Calcd. (%) C. : 66.01, H:6.65, N:4.81
EXAMPLE 10
[0275] Ethyl
4-cyano-4-(8-methoxy-1,4-benzodioxan-5-1)yl)cyclohexanylidene-
acetate (Compound 10)
[0276] To a solution of triethyl phosphonoacetate (0.72 mL, 3.6
mmol) in THF (9.4 mL) was added 60% sodium hydride (0.15 g, 3.6
mmol) under ice-cooling. The mixture was stirred at room
temperature for 15 minutes, Compound 1 (0.94 g, 3.3 mmol) obtained
in Example 1 was added under ice-cooling, and the mixture was
stirred at room temperature for 30 minutes. Then, water was added
under ice-cooling, the mixture was extracted with ethyl acetate,
and the organic layer was washed with brine and dried over sodium
sulfate. The solvent was evaporated in vacuo, and the residue was
purified by silica gel-column chromatography (eluted with
hexane/ethyl acetate=2/1) to give Compound 10 (1.4 g, 97%) as a
white solid.
[0277] Melting Point: 110 - 112.degree. C.
[0278] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.28 (t, J=7 Hz, 3H),
1.85-2.10 (m, 2H), 2.31-2.60(m, 4H), 2.67-2.89 (m, 1H), 3.87 (s,
3H), 3.92-4.12 (m, 1H), 4.16 (q, J=7 Hz, 2H), 4.36 (s, 4H), 5.71
(s, 1H), 6.48 (d, J=9 Hz, 1H), 6.81 (d, J=9 Hz, 1H).
[0279] MASS (m/z) 357 (M.sup.+).
EXAMPLE 11
[0280]
4-Cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)cyclohexanylideneacetic
acid (Compound 11)
[0281] To a suspension of Compound 10 (0.31 g, 0.87 mmol) obtained
in Example 10 in ethanol (3.1 mL) and THF (3.1 mL) was added a 2
mol/L aqueous solution of sodium hydroxide (0.65 mL, 1.3 mmol), the
mixture was stirred at 70.degree. C. for 1 hour, and then a 2 mol/L
aqueous solution of sodium hydroxide (0.65 mL, 1.3 mmol) was
further added, followed by stirring at 70.degree. C. for 1 hour. 1
mol/L hydrochloric acid was added dropwise under ice-cooling, and
the mixture was extracted with ethyl acetate. The organic layer was
washed with brine and dried over sodium sulfate, the solvent was
evaporated in vacuo, and the residue was triturated with ethanol to
give Compound 11 (0.23 g, 82%) as a white solid.
[0282] Melting Point: 203 - 204.degree. C.
[0283] .sup.1H-NMR (DMSO-d.sub.6.delta., ppm) 1.75-2.00 (m, 2H),
2.05-2.67 (m, 5), 3.74 (s, 31), 3.80-4.00 (m, 1H), 4.15-4.43 (m,
4H), 5.69 (s, 1H), 6.59 (d, J=9 Hz, 1H), 6.81 (d, J=9 Hz, 1H), 12.1
(br s, 1H).
[0284] MASS (m/z) 329 (M.sup.+).
[0285] Elemental analysis:
C.sub.18H.sub.19NO.sub.5.multidot.H.sub.2O
[0286] Found (%) C.: 65.30, H:6.09, N:4.19
[0287] Calcd. (%) C.: 65.29, H: 5.84, N: 4.23
EXAMPLE 12
[0288]
4-Cyano-4-(2,2-dimethyl-7-methoxy-1,3-benzodioxol-4-yl)cyclohexanon-
e (Compound 12)
[0289] (Step A) Synthesis of
2-.(2,2-dimethyl-7-methoxy-1,3-benzodioxol-4-- yl)acetonitrile
(Compound 12a)
[0290] To a solution of
2,2-dimethyl-7-methoxy-1,3-benzodioxole-4-carbalde- hyde (9.3 g, 45
mmol) obtained by the method mentioned in the Japanese Published
Unexamined Patent Application No. 98/147585 and by a method similar
thereto in acetonitrile (47 mL) was added lithiumbromide (8.9 g, 85
mmol), and then trimethylsilyl chloride (8.5 mL, 67 mmol) was added
dropwise. After 15 minutes, the mixture was ice-cooled, and
1,1,3,3-tetramethyldisiloxane (13 mL, 76 mmol) was added dropwise,
followed by stirring at room temperature for 2 hours. The resulting
mixture was diluted with toluene and filtered through Celite. The
solvent was evaporated in vacuo from the filtrate to give a pale
yellow oil. To a solution of this crude
7-bromomethyl-2,2-dimethyl-4-methoxy-1,3-benzodiox- ole in DMF (73
mL) was added sodium cyanide (5.0 g, 102 mmol), and the mixture was
stirred at room temperature for 18hours. Under ice-cooling, water
was added, and the mixture was extracted with ethyl acetate. The
organic layer was washed with brine and dried over sodium sulfate,
and the solvent was evaporated in vacuo. The residue was purified
by silica gel column chromatography (eluted with hexane/ethyl
acetate=5/1) to give Compound 12a (9.1 g, 92%) as an ash-colored
solid.
[0291] Melting Point: 58 - 59.degree. C.
[0292] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.71 (s, 6H), 3.60
(s, 2H), 3.88 (s, 3H), 6.50 (d, J 9 Hz, 1H), 6.76 (d, J=9 Hz,
1H).
[0293] MASS (m/z) 219 (M.sup.+).
[0294] (Step B) Synthesis of dimethyl
4-cyano-4-(2,2-dimethyl-7-methoxy-1,- 3-benzodioxol-4-yl)pimelate
(Compound 12b)
[0295] To a solution of Compound 12a (9.0 g, 41 mmol) obtained in
Step A in acetonitrile (135 mL) were added a 40% methanolic
solution of Triton B (1.9 mL, 4.1 mmol) and methyl acrylate (37 mL
, 410 mmol), and the mixture was stirred at room temperature for 30
minutes. Water and 1 mol/L hydrochloric acid were added, followed
by extraction with ethyl acetate. The organic layer was washed with
brine and dried over sodium sulfate, and the solvent was evaporated
in vacuo. The residue was purified by silica gel column
chromatography (eluted with hexane/ethyl acetate=5/2) to give
Compound 12b (11 g, 68%) as a pale yellow oil.
[0296] .sup.1H-NMR (CDCl.sub.3,.delta., ppm) 1.69 (s, 6H),
2.05-2.31 (m, 4H), 2.40-2.64 (m, 4H), 3.60 (s, 6H), 3.89 (s, 3H),
6.49 (d, J=9 Hz, 1H), 6.88 (d, J=9 Hz, 1H).
[0297] MASS (m/z) 391 (M.sup.+).
[0298] (Step C) Synthesis of
4-cyano-4-(2,2-dimethyl-7-methoxy-1,3-benzodi-
oxol-4-yl)-2-methoxycarbonylcyclohexanone (Compound 12c)
[0299] To a solution of Compound 12b (11 g, 27 mmol) obtained in
Step B in 1,2-dimethoxyethane (161 mL) was added 60% sodium hydride
(3.3 g, 83 mmol). After refluxing for 3 hours, the mixture was
allowed to cool and poured into ice water, and the mixture was
acidified with 6 mol/L hydrochloric acid and extracted with ethyl
acetate. The organic layer was washed with brine and dried over
sodium sulfate, and the solvent was evaporated. The residue was
purified by silica gel column chromatography (eluted with
hexane/ethyl acetate 3/1) to give Compound 12c (8.4 g, 86%) as a
white solid.
[0300] Melting Point: 146 - 147.degree. C.
[0301] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.71 (s, 3H), 1.73
(s, 3H), 2.12-2.27 (m, 1H), 2.32-2.55 (m, 2H), 2.67-3.00 (m, 3H),
3.78 (s, 3H), 3.89 (s, 3H), 6.51 (d, J=9 Hz, 1H), 6.92 (d, J=9 Hz,
1H), 12.2 (s, 1H).
[0302] MASS (m/z) 359 (M.sup.+).
[0303] (Step D) Synthesis of Compound 12
[0304] A mixture of Compound 12c (8.3 g, 23 mmol) obtained in the
step C, DMSO (83 mL), water (8.3 mL) and sodium chloride (8.3 g)
was stirred at 150.degree. C. for 12 hours. The mixture was allowed
to cool, and water was added, followed by extraction with ethyl
acetate. The organic layer was washed with brine and dried over
sodium sulfate, and the solvent was evaporated. The residue was
purified by silica gel column chromatography (eluted with
hexane/ethyl acetate=3/1) to give Compound 12 (5.6 g, 81%) as a
white solid.
[0305] Melting Point: 153 - 154.degree. C.
[0306] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.72 (s, 6H),
2.35-2.61 (m, 6H), 2.77-2.97 (m, 2H), 3.90 (s, 3H), 6.53 (d, J=9
Hz, 1H), 6.97 (d, J=9 Hz, 1H).
[0307] MASS (mlz) 301 (M.sup.+).
EXAMPLE 13
[0308] Methyl
cis-4-cyano-4-(2,2-dimethyl-7-methoxy-1,3-benzodioxol-4-yl)c-
yclohexanecarboxylate (Compound 13) and
trans-4-cyano-4-(2,2-dimethyl-7-me-
thoxy-1,3-benzodioxol-4-yl)cyclohexanecarboxylate (Compound 14)
[0309] (Step A) Synthesis of
2-[4-cyano-4-(2,2-dimethyl-7-methoxy-1,3-benz-
odioxol-4-yl)cyclohexylidene]-1,3-dithiane (Compound 13a)
[0310] To a solution of 2-trimethylsilyl-1,3-dithiane (0.56 mL, 3.0
mmol) in THF (5.6 mL) was added dropwise a solution of 1.54 mol/L
of n-butyl lithium in hexane (1.9 mL, 3.0 mmol) under ice-cooling.
After 15 minutes, the mixture was cooled to -78.degree. C., and a
solution of Compound 12 (0.42 g, 1.4 mmol) obtained in Example 12
in THF (0.6 mL) was added dropwise. After 20 minutes, brine was
added and then water was added at room temperature. The mixture was
extracted with ethyl acetate, the extract was dried over sodium
sulfate, and the solvent was evaporated. The residue was purified
by silica gel column chromatography (eluted with hexane/ethyl
acetate =6/1) to give Compound 13a (0.53 g, 93%) as a white
solid.
[0311] Melting Point: 194 - 197.degree. C.
[0312] .sup.1H-NMR (CDCl.sub.3,.delta., ppm) 1.72 (s, 6H),
1.86-2.53 (m, 8H), 2.90 (t, J=6 Hz, 4H), 3.17-3.33 (m, 2H), 3.88
(s, 3H), 6.48 (d, J=9 Hz, 1H), 6.86 (d, J=9 Hz, 1H).
[0313] MASS (m/z) 403 (M.sup.+).
[0314] (Step B) Synthesis of Compound 13 and Compound 14
[0315] To a suspension of Compound 13a (3.0 g, 7.4 mmol) obtained
in Step A in methanol (105 mL) were added 70% perchloric acid (1.3
mL, 15 mmol) and mercury chloride (HgCl.sub.2)(3.2 g, 12 mmol), and
the mixture was stirred at 60.degree. C. for 1 hour. The mixture
was diluted with dichloromethane and filtered through Celite, and
the filtrate was poured into a saturated aqueous solution of sodium
bicarbonate, followed by extraction with dichloromethane. The
organic layer was washed with brine and dried over sodium sulfate,
and the solvent was evaporated. The residue was purified by silica
gel column chromatography (eluted with hexane/ethyl acetate=3/1) to
give Compound 13 (1.4 g, 53%) as a white solid and Compound 14
(0.31 g, 12%) as a colorless oil.
Compound 13
[0316] Melting Point: 79 - 80.degree. C.
[0317] .sup.1H-NMR(CDCl, .delta., ppm) 1.72(s, 6H), 1.87-2.27 (m,
8H), 2.30-2.43 (m, 1H), 3.71 (s, 3H), 3.88 (s, 3H), 6.49 (d, J 9
Hz, 1H), 6.92 (d, J=9 Hz, 1H).
[0318] MASS (m/z) 345 (M.sup.+).
Compound 14
[0319] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.71 (s, 6H),
1.90-2.26 (m, 8H), 2.72-2.80 (m, 1H), 3.70 (s, 3H), 3.88 (s, 3H),
6.48 (d, J=9 Hz, 1H), 6.83 (d, J=9 Hz, 1H).
[0320] MASS (m/z) 345 (M.sup.+).
EXAMPLE 14
[0321]
cis-4-Cyano-4-(2,2-dimethyl-7-methoxy-1,3-benzodioxol-4-yl)cyclohex-
anecarboxylic acid (Compound 15)
[0322] To a mixture of Compound 13 (1.7 g, 5.0 mmol) obtained in
Example 13 and methanol (10 mL) was dissolved in THF (5.2 mL). To
the mixture was added dropwise a 1.3 mol/L aqueous solution of
potassium hydroxide (7.7 mL, 10 mmol), followed by stirring at room
temperature for 2 hours. Water was added, the mixture was washed
with ethyl acetate, and the aqueous layer was acidified with 1
mol/L hydrochloric acid. The mixture was extracted with ethyl
acetate, and the extract was washed with brine and dried over
sodium sulfate. The solvent was evaporated, and the residue was
recrystallized from ethanol to give Compound 15 (1.1 g, 64%) as
white crystals.
[0323] Melting Point: 195 - 198.degree. C.
[0324] .sup.1H-NMR (DMSO-d.sub.6, .delta., ppm) 1.50-1.78 (m, 8H),
1.79-2.13 (m, 4H), 2.15-2.37 (m, 3H), 3.79 (s, 3H), 6.64 (d, J=9
Hz, 1H), 6.81 (d, J=9 Hz, 1H), 12.3 (br s, 1H).
[0325] MASS (m/z) 331 (M.sup.+).
[0326] Elemental analysis: C.sub.18H.sub.21NO.sub.5
[0327] Found (%) C. : 65.33, H:6.40, N:4.27
[0328] Calcd. (%) C. : 65.24, H:6.39, N:4.23
EXAMPLE 15.
[0329] 4-(8-Methoxy-1,4-benzodioxan-5-yl)-3-cyclohexenone (Compound
16)
[0330] To the mixture of Compound 2a (1.2 g, 3.6 mmol) obtained in
Step A of Example 2 and p-toluenesulfonic acid monohydrate (1.2 mg,
0.0063 mmol) were added water (70 mL) and toluene (140 mL ),
followed by refluxing for 4 hours. The mixture was allowed to cool,
the mixture was extracted with toluene, and the extract was washed
with a saturated aqueous solution of sodium bicarbonate and then
with brine. The mixture was dried over sodium sulfate, the solvent
was evaporated, and the residue was purified by silica gel column
chromatography (eluted with hexane/ethyl acetate=2/1) to give
Compound 16 (0.88 g, 94%) as a pale yellow solid.
[0331] Melting Point: 56 - 59.degree. C.
[0332] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 2.59 (t, J=7 Hz, 2H),
2.75-2.85 (m, 2H), 2.97-3.10 (m, 2H), 3.88 (s, 3H), 4.25-4.37 (m,
4H), 5.83 (t, J=4 Hz, 1H), 6.48 (d, J=8 Hz, 1H), 6.81 (d, J=8 Hz,
1H).
[0333] MASS (m/z) 260 (M.sup.+).
EXAMPLE 16
[0334] 5-(8-Methoxy-1,4-benzodioxan-5-yl)-1-indanone (Compound
17)
[0335] To a mixture of Compound A (0.30 g, 1.8 mmol) obtained in
Reference Example 1 and commercially available 5-bromo-1-indanone
(0.39 g, 1.8 mmol) was dissolved in DMF (3.0 mL) under a nitrogen
atmosphere and were added sodium carbonate (0.39 g, 3.7 mmol) and
palladium acetate (0.020 g, 0.090mmol). The mixture was stirred at
100.degree. C. for 2 hours, followed by stirring at 110.degree. C.
for 0.9 hour. Ethyl acetate was added to the reaction mixture, and
the solid was filtered off. The resulting solution was washed with
water and with brine and dried over sodium sulfate.
Afterthesolidwas filtered off, the filtrate was concentrated in
vacuo, and the concentrate was purified by silica gel column
chromatography (eluted with hexane/ethyl acetate=3/1) and
recrystallized from acetone to give Compound 17 (0.15 g, 28%) as a
white solid.
[0336] Melting Point: 168.degree. C.
[0337] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 2.70-2.74 (m, 2H),
3.18 (br t, 2H), 3.93 (s, 3H), 4.28-4.32 (m, 2H), 4.36-4.39 (m,
2H), 6.61 (d, J=9 Hz, 1H), 6.90 (d, J=9 Hz, 1H), 7.53 (dd, J=2, 8
Hz, 1H), 7.61 (d, J=2 Hz, 1H), 7.78 (d, J=8 Hz, 1H).
[0338] MASS (m/z) 296 (M.sup.+).
EXAMPLE 17
[0339] 6-(8-Methoxy-1,4-benzodioxan-5-yl)-1-tetralone (Compound
18)
[0340] To a mixture of Compound A (0.37 g, 1.7 mmol) obtained in
Reference Example 1 and 6-trifluoromethanesulfonyl-1-tetralone
(0.51 g, 1.7mmol) [Synthetic Communication,23(21), 2965 (1993)
etc.] was dissolved in DMF (3.7 mL), and then were added sodium
carbonate (0.37 g, 3.5 mmol), and palladium acetate (0.020 g, 0.090
mmol). The mixture was stirred at 100.degree. C. for 1.5 hours,
followed by stirring at 120.degree. C. for 2.3 hours. Ethyl acetate
was added to the reaction mixture, the solid was filtered off, and
the resulting solution was washed with water and with brine and
dried over sodium sulfate. The solid was filtered off, the filtrate
was concentrated in vacuo, and the concentrate was purified by
silica gel column chromatography (eluted with hexane/ethyl
acetate=3/1) and recrystallized from acetone and then from ethanol
to give Compound 18 (0.070 g, 8.0%) as a white solid.
[0341] Melting Point: 156 - 158 OC
[0342] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 2.12-2.21(m, 2H),
2.67(t, J=7 Hz, 2H), 3.01(t, J=6 Hz, 2H), 3.93(s, 3H), 4.28-4.31
(m, 2H), 4.36-4.38 (m, 2H), 6.59 (d, J=9 Hz, 1H), 6.88 (d, J=9 Hz,
1H), 7.39 (d, J=1 Hz, 1H), 7.46 (dd, J=2, 8 Hz, 1H), 8.06 (d, J=8
Hz, 1H).
[0343] MASS (m/z) 310 (M.sup.+).
EXAMPLE 18
[0344] 7-(8-Methoxy-1,4-benzodioxan-5-yl)-1-benzosuberone (Compound
19)
[0345] To a mixture of Compound A (0.37 g, 1.6 mmol) obtained in
Reference Example 1 and 7-bromo-1-benzosuberone (0.38 g, 1.6 mmol)
was dissolved in DMF (3.3 mL) under a nitrogen atmosphere and were
added sodium carbonate (0.33 g, 3.1 mmol) and palladium acetate
(0.020 g, 0.080 mmol). The mixture was stirred at 100.degree. C.
for 6.5 hours, ethyl acetate was added to the reaction mixture, and
the solid was filtered off. The resulting solution was washed with
water and with brine and dried over sodium sulfate. The solid was
filtered off, the filtrate was concentrated in vacuo, and the
concentrate was purified by silica gel column chromatography
(eluted with hexane/ethyl acetate=3/1) and recrystallized from
ethanol and then from acetone to give Compound 19 (0.16 g, 32%) as
a white solid.
[0346] Melting Point: 124 - 126.degree. C.
[0347] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.83-1.94 (m, 4H),
2.74-2.78 (m, 2H), 2.96-3.01 (m, 2H), 3.93 (s, 3H), 4.28-4.31 (m,
2H), 4.36-4.39 (m, 2H), 6.59 (d, J=9 Hz, 1H), 6.89 (d, J=9 Hz, 1H),
7.36 (d, J=2 Hz, 1H), 7.47 (dd, J=2, 8 Hz, 1H), 7.79 (d, J=8 Hz,
1H).
[0348] MASS (m/z) 324 (M.sup.+).
EXAMPLE 19
[0349] Ethyl
2-[4-cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)cyclohexan-1-yl]-
acetate (Compound 20)
[0350] To a solution of Compound 10 (0.55 g, 1.5 mmol) obtained in
Example 10 in ethanol (5.5 mL) and acetone (8.0 m) was added 10%
palladium-carbon (containing 50% of water) (0.11 g), and the
mixture was subjected to a hydrogenation reaction at room
temperature and ordinary pressure for 3 hours. After removal of the
catalyst, the solvent was evaporated in vacuo from the filtrate to
give Compound 20 (0.54 g, 100%) as a mixture of isomers in a pale
yellow oil.
[0351] NMR (CDCl.sub.3, .delta., ppm) 1.18-1.33 (m, 3H), 1.45-1.73
(m, 3H), 1.77-1.97(m, 4H), 2.25-2.42 (m, 4H), 3.87 and 3.88 (each
s, total 3H), 4.04-4.27 (m, 2H), 4.35(s, 4H), 6.48 and 6.49 (each
d, J=9 Hz, total 1H), 6.84 and 6.88 (each d, J=9 Hz, total 1H).
[0352] MASS (m/z) 359 (M.sup.+).
EXAMPLE 20
[0353]
2-[4-Cyano-4-(8-methoxy-1,4-benzodioxan-5-yl)cyclohexan-1-yl]acetic
acid (Compound 21)
[0354] To a solution of Compound 20 (0.41 g, 1.1 mmol) obtained in
Example 19 in ethanol (4.1 mL) was added a 2 mol/L aqueous solution
of sodium hydroxide (1.1 mL), and the mixture was stirred at room
temperature for 1 hour and then stirred at 60.degree. C. for 20
minutes. The mixture was allowed to cool, and water and ethyl
acetate were added to the mixture, followed by separating into an
organic layer and an aqueous layer. The aqueous layer was acidified
with 6 mol/L aqueous hydrochloric acid and extracted with ethyl
acetate, and the extract was washed with brine and dried over
sodium sulfate. The solvent was evaporated in vacuo, toluene was
added to the residue, and the mixture was evaporated in vacuo. To
the residue was added diisopropyl ether, and the precipitated solid
was collected by filtration and recrystallized from ethanol to give
Compound 21 (0.13 g, 36%) as a mixture of isomers in white
crystals.
[0355] Melting Point: 149 - 150.degree. C.
[0356] NMR (DMSO-d.sub.6, .delta., ppm) 1.25-1.57 (m, 2H),
1.63-1.95 (m, 5H), 2.08-2.35 (m, 4H), 3.74 (s, 3H), 4.15-4.42 (m,
4H), 6.59 (d, J-=9 Hz, 1H), 6.81 and 6.86 (each d, J=9 Hz, total
1H), 12.1 (s, 1H).
[0357] MASS (m/z) 359 (M.sup.+).
EXAMPLE 21
[0358] 4-(8-Methoxy-1,4-benzodioxan-5-yl)-1(3H)-isobenzofuranone
(Compound 22)
[0359] To ethyl
4-(8-methoxy-1,4-benzodioxan-5-yl)-2-acetoxymethylbenzoate (0.61 g)
which was obtained by treating Compound A (0.40 g, 1.9 mmol)
obtained in Reference Example 1 and Compound C. (0.57 g, 1.9 mmol)
obtained in Reference Example 3 in the same manner as in Example 17
were added ethanol (6.0 mL) and a 5 mol/L solution of potassium
hydroxide (1.2 mL) and the mixture was stirred at room temperature
for 35 minutes. The mixture was evaporated in vacuo, and water was
added to the residue. To the resulting solution was added 6 mol/L
hydrochloric acid to adjust it to pH 2, and the precipitated solid
was collected by filtration and dried in vacuo to give a white
solid (0.46 g).
[0360] To this solid was added acetic acid(4.2 mL), followed by
stirring at 90.degree. C. To the reaction mixture was added a
saturated aqueous solution of sodium bicarbonate so that acetic
acid was neutralized, and the mixture was extracted with ethyl
acetate. The organic layer was washed with a saturated aqueous
solution of sodium bicarbonate and brine and dried over magnesium
sulfate. The solid was filtered off, the filtrate was concentrated
in vacuo, and the concentrate was purified by silica gel column
chromatography (eluted with hexane/ethyl acetate=3/2) and
recrystallized from ethanol to give Compound 22 (0.33 g, 70%) as a
white solid.
[0361] Melting Point: 158 - 160.degree. C.
[0362] NMR (CDCl.sub.3, .delta., ppm) 3.94 (s, 3H), 4.28-4.32 (m,
2H), 4.37-4.40 (m, 2H), 5.35 (s, 2H), 6.62 (d, J=8.6 Hz, 2H), 6.89
(d, J =8.6 Hz, 2H), 7.62 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.93 (d,
J=8.3 Hz, 1H).
[0363] MASS(m/z) 298(M.sup.+).
[0364] Elemental analysis: C.sub.17H.sub.14O.sub.5
[0365] Found (%) C: 68.55, H: 4.61
[0366] Calcd. (%) C: 68.45, H: 4.73
EXAMPLE 22
[0367] 4-(8-Methoxy-1,4-benzodioxan-5-yl)phthalimide (Compound
23)
[0368] To Compound B (0.12 g, 0.4 mmol) obtained in Reference
Example 2 were added ethylene glycol (0.6 mL) and urea (0.02 g, 0.4
mmol) under argon atmosphere, followed by stirring at 150.degree.
C. for 5.3 hours. To the reaction mixture was added ethanol at room
temperature, and the precipitated solid was collected by filtration
and dried in vacuo to give Compound 23 (0.08 g, 73%) as a yellow
solid.
[0369] Melting Point: 285 - 287.degree. C.
[0370] NMR (CDCl.sub.3, .delta., ppm) 3.94 (s, 3H), 4.29-4.32 (m,
2H), 4.37-4.40 (m, 2H), 6.62 (d, J 8.6 Hz, 1H), 6.91 (d, J=8.6 Hz,
lH), 7.27 (br s, lH), 7.84-7.88 (br t, 2H), 8.04 (s, 1H).
[0371] MASS(m/z) 311(M.sup.+).
[0372] Elemental analysis: C.sub.17H.sub.13NO.sub.5
[0373] Found (%) C: 65.49, H:4.25, N:4.22
[0374] Calcd. (%) C: 65.59, H:4.21, N:4.50
EXAMPLE 23
[0375] Ethyl
cis-4-cyano-4-(3,4-dihydro-9-methoxy-2H-1,5-benzodioxepin-6-y-
l)cyclohexanecarboxylate (Compound 24)
[0376] (Step A) Synthesis of ethyl
4-hydroxy-4-(3,4-dihydro-9-methoxy-2H-1-
,5-benzodioxepin-6-yl)cyclohexanecarboxylate (Compound 24a)
[0377] To a solution of
9-bromo-3,4-dihydro-6-methoxy-2H-1,5-benzodioxepin- e (25.7 g,
99.2mmol) in THF (154mL) was added dropwise a 1.5 mol/L solution of
n-butyl lithium in hexane (69 mL, 104 mmol) at -78.degree. C., and
the mixture was stirred at -78.degree. C. for 10 minutes.
[0378] The reaction mixture was added dropwise to a solution of
ethyl 4-cyclohexanonecarboxylate (20.5 mL, 129 mmol) in THF (385
mL) at -78.degree. C., followed by stirring at -78.degree. C. for 1
hour. The reaction mixture was added to an aqueous solution of
ammonium chloride while adjusting the mixture to pH 7 with 6 mol/L
hydrochloric acid, and water was added. The mixture was extracted
with ethyl acetate, and the extract was washed with water and brine
and dried over magnesium sulfate. The solid was filtered off, the
solvent was evaporated, and the residue was purified by silica gel
column chromatography (eluted with hexane/ethyl
acetate=3/1.fwdarw.2/1) to give Compound 24a (12.9 g, 40%) as a
pale yellow oil (a mixture of isomers).
[0379] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.2-1.3 (m, 3H),
1.7-2.6 (m, 11H), 3.65 and 3.69 (each s, total 1H), 3.83 (s, 3H),
4.1-4.2 (m, 2H), 4.2-4.4 (m, 4H), 6.54 and 6.55 (each d, J=9 Hz,
total 1H), 6.91 and 6.92 (each d, J=9 Hz, total 1H).
[0380] MASS (m/z) 330 [(M+H).sup.+].
[0381] (Step B) Synthesis of Compound 24
[0382] To a solution of Compound 24a (7.36 g, 21.0 mmol) obtained
in Step A in dichloromethane (74 mL) was added trimethylsilyl
cyanide (5.6 mL, 42 mmol) followed by cooling the mixture to
-78.degree. C., and boron trifluoride-ethyl ether complex (2.1 mL,
17 mmol) was added dropwise. The mixture was stirred at -78.degree.
C. for 50 minutes followed by stirring at 0.degree. C. for 30
minutes. To the mixture was added a saturated aqueous solution of
sodium bicarbonate, and the organic layer was washed with water and
brine and dried over magnesium sulfate. The solid was filtered off,
the solvent was evaporated, and the residue was purified by silica
gel column chromatography (eluted with hexane/ethyl
acetate=3/1.fwdarw.30/11) and recrystallized from ethanol to give
Compound 24 (2.04 g, 27%) as a white solid. Melting Point: 117 -
118.degree. C.
[0383] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.30(t, J=7 Hz, 3H),
1.6-2.5 (m, 11H), 3.86 (s, 3H), 4.17 (q, J=7 Hz, 3H), 4.2-4.3 (m,
4H), 6.58 (d, J=9 Hz, 1H), 6.86 (d, J=9 Hz, 1H).
[0384] MASS(m/z) 360[(M+H).sup.+].
EXAMPLE 24
[0385]
cis-4-Cyano-4-(3,4-dihydro-9-methoxy-2H-1,5-benzodioxepin-6-yl)cycl-
ohexanecarboxylic acid (Compound 25)
[0386] To a mixture of Compound 24 (1.53 g, 4.26 mmol) obtained in
Example 23 and ethanol (15 mL) was added dropwise a 2 mol/L aqueous
solution of sodium hydroxide (21 mL) followed by stirring at room
temperature for 4.6 hours. The mixture was cooled to 0.degree. C.
and acidified with 6 mol/L hydrochloric acid, and the precipitated
solid was collected by filtration and re-slurried with ethanol to
give Compound 25 (1.35 g, 96%) as a white solid.
[0387] Melting Point: 274 - 275.degree. C.
[0388] .sup.1H-NMR (DMSO-d.sub.6, .delta., ppm) 1.6-2.4 (m, 11H),
3.75 (s, 3H), 4.0-4.2 (m, 4H), 6.74 (d, J=9 Hz, 1H), 6.93 (d, J 9
Hz, 1H), 12.26(brs, 1H).
[0389] MASS(m/z) 330[(M-H).sup.-]. Elemental analysis:
C.sub.18H.sub.21N.sub.5
[0390] Found (%) C: 65.24, H:6.39, N:4.23
[0391] Calcd. (%) C: 65.41, H:6.33, N:4.24
EXAMPLE 25
[0392] Ethyl
cis-4-cyano-4-(7-methoxy-1,3-benzodioxol-4-yl)cyclohexanecarb-
oxylate (Compound 26)
[0393] (Step A) Synthesis of ethyl
4-hydroxy-4-(7-methoxy-1,3-benzodioxol--
4-yl)cyclohexanecarboxylate (Compound 26a)
[0394] To a solution of 7-bromo-4-methoxy-1,3-benzodioxole (6.17 g,
19.1 mmol) in THF (135 mL) was added dropwise a 1.5 mol/L solution
of n-butyl lithium in hexane (27 mL, 41 mmol) at -78.degree. C.,
followed by stirring at -78.degree. C. for 10 minutes. To a
solution of ethyl 4-cyclohexanonecarboxylate (8.1 mL, 51 mmol) in
THF (135 mL) was added dropwise this reaction mixture at
-78.degree. C., followed by stirring at -78.degree. C. for 30
minutes. To an aqueous solution of ammonium chloride was added to
this reaction mixture. The mixture was adjusted to pH 7 with 6
mol/L hydrochloric acid, and water was added. The mixture was
extracted with ethyl acetate, and the extract was washed with water
and brine and dried over magnesium sulfate. The solid was filtered
off, the solvent was evaporated, and the residue was purified by
silica gel column chromatography (eluted with hexane/ethyl
acetate=5/1.fwdarw.3/1) to give Compound 26a (6.73 g, 54%) as a
pale yellow oil (a mixture of isomers).
[0395] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.2-1.3 (m, 3H),
1.7-2.7 (m, 9H), 3.89 (s, 3H), 4.1-4.2 (m, 2H), 5.97 and 5.97 (each
s, total 1H), 6.50 and 6.51 (each d, J 9 Hz, total 1H), 6.84 and
6.88 (each d, J=9 Hz, total 1H)(A proton of hydroxy is not
found).
[0396] MASS(m/z) 323[(M+H).sup.+].
[0397] (Step B) Synthesis of Compound 26
[0398] To a solution of Compound 26a (6.17 g, 19.1 mmol) obtained
in Step A in dichloromethane (62 mL) was added trimethylsilyl
cyanide(5.1 mL, 38 mmol). To this mixture was added dropwise boron
trifluoride-ethyl ether complex (1.9 mL, 15 mmol) at -78.degree.
C., and the mixture was stirred at -78.degree. C. for 55 minutes
followed by stirring at 0.degree. C. for 25 minutes. A saturated
aqueous sodium bicarbonate was added, and the organic layer was
washed with water and with brine and dried over magnesium sulfate.
The solid was filtered off, the solvent was evaporated from the
filtrate, and the residue was purified by silica gel column
chromatography (eluted with hexane/ethyl acetate=3/1) and
recrystallized from ethanol to give Compound 26 (2.39 g, 38%) as a
white solid.
[0399] Melting Point: 109 - 112.degree. C.
[0400] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.27 (t, J=7 Hz, 3H),
1.9-2.4 (m, 9H), 3.90 (s, 3H), 4.16 (q, J=7 Hz, 2H), 6.01 (s, 2H),
6.53 (d, J=9 Hz, 1H), 6.96 (d, J=9 Hz, 1H),
[0401] MASS(m/z) 331(M.sup.+).
EXAMPLE 26
[0402]
cis-4-Cyano.-4-(7-methoxy-1,3-benzodioxol-4-yl)cyclohexanecarboxyli-
c acid (Compound 27)
[0403] To a mixture of Compound 26 (0.60 g, 1.8 mmol) obtained in
Example 25 and ethanol (12 ml) was added dropwise a 2 mol/L aqueous
solution of sodium hydroxide (3.6 mL) followed by stirring at room
temperature for 1.7 hours. Ethanol was evaporated in vacuo, and the
mixture was cooled to 0.degree. C. and acidified with 6 mol/L
hydrochloric acid. The precipitated solid was collected by
filtration and recrystallized from ethanol to give Compound 27
(0.50 g, 92%) as a white solid.
[0404] Melting Point: 206 - 208.degree. C.
[0405] .sup.1H-NMR (DMSO-d.sub.6, .delta., ppm) 1.6-2.4 (m, 9H),
3.82 (s, 3H), 6.05 (s, 2H), 6.70 (d, J=9 Hz, 1H), 6.87 (d, J=9 Hz,
1H), 12.30(brs, 1H).
[0406] MASS(m/z) 302[(M-H).sup.-].
[0407] Elemental analysis: C.sub.16H.sub.17NO.sub.5
[0408] Found (%) C: 63.36, H:5.65, N:4.62
[0409] Calcd. (%) C: 63.48, H:5.76, N:4.50
EXAMPLE 27
[0410]
cis-4-Cyano-4-(8-hydroxy-1,4-benzodioxan-5-yl)cyclohexanecarboxylic
acid (Compound 28)
[0411] To a suspension of Compound 5 (1.80 g, 5.67 mmol) obtained
in Example 5 in dichloromethane (57 mL) was added dropwise a 1
mol/L solution of boron tribromide in dichloromethane (11.3 mL,
11.3 mmol) at6.degree. C. followed by stirring at room temperature
overnight. The reaction mixture was cooled to 5.degree. C., and
water (57 mL) was added to the mixture. The precipitated solid was
collected by filtration and dried in vacuo to give Compound 28 (916
mg, 53%) as an ash-colored solid.
[0412] Melting Point: 258 - 260.degree. C.
[0413] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.6-2.5 (m, 9H),
4.2-4.3 (m, 4H), 6.40(d, J=9 Hz, 1H), 6.64 (d, J- 9 Hz, 1H), 9.29
(s, 1H), 12.24 (brs, 1H).
[0414] MASS(m/z) 302[(M-H).sup.-].
EXAMPLE 28
[0415] Ethyl
cis-4-cyano-4-(8-hydroxy-1,4-benzodioxan-5-yl)cyclohexanecarb-
oxylate (Compound 29)
[0416] To a suspension of Compound 28 (682 mg, 2.25 mmol) obtained
in Example 27 in ethanol (6.8 mL) was added a 4 mol/L solution of
hydrogen chloride in ethyl acetate (0.5 mL, 2.0 mmol) followed by
stirring at room temperature for 2 days. Water (30 mL) was added to
the mixture, and the precipitated solid was collected by filtration
and dried in vacuo to give Compound 29 (634 mg, 85%) as a white
solid.
[0417] Melting Point: 136.degree. C.
[0418] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.30 (t, J=7 Hz, 3H),
1.7-2.5 (m, 9H), 4.15 (q, J=7 Hz, 2H), 4.3-4.4 (m, 4H), 5.40 (s,
1H), 6.52 (d, J=9 Hz, 1H), 6.78 (d, J=9 Hz, 1H).
EXAMPLE 29
[0419] Ethyl
cis-4-cyano-4-(8-difluoromethoxy-1,4-benzodioxan-5-yl)cyclohe-
xanecarboxylate(Compound 30)
[0420] A mixture of Compound 29 (500 mg, 1.51 mmol) obtained in
Example 28, chlorodifluoromethyl acetate (436 mg, 3.02 mmol),
potassium carbonate (438 mg, 3.17 mmol), and DMF (1.0 mL) was
stirred at 80.degree. C. for 0.4 hour followed by stirring at 900C.
for 3 hours. To the mixture was added DMF (2.0 mL) followed by
stirring at 90.degree. C. for 2.8 hours. There action mixture was
cooled to room temperature, 1 mol/L hydrochloric acid was added
thereto to neutralize it, and ethyl acetate was added thereto for
partition. The organic layer was washed with water twice and with
brine twice and dried over magnesium sulfate. The solid was
filtered off, the solvent was evaporated from the resulting
solution, and the residue was purified by silica gel column
chromatography (eluted with hexane/ethyl acetate=1/1) to give
Compound 30 (97 mg, 79%) as a colorless oil.
[0421] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.28 (t, J=7 Hz, 3H),
1.7-2.6 (m, 9H), 4.15 (q, J=7 Hz, 2H), 4.3-4.4 (m, 4H), 6.55 (t,
J=75 Hz, 1H), 6.76 (d, J=9 Hz, 1H), 6.86 (d, J=9 Hz, 1H).
EXAMPLE 30
[0422]
cis-4-Cyano-4-(8-difluoromethoxy-1,4-benzodioxan-5-yl)cyclohexaneca-
rboxylic acid (Compound 31)
[0423] To a solution of Compound 30 (90 mg, 0.24 mmol) obtained in
Example 29 in ethanol (1.8 mL) was added dropwise a 6 mol/L aqueous
solution of potassium hydroxide (0.36 mL, 2.16 mmol) followed by
stirring at room temperature for 6 hours. To the reaction mixture
was added water, and 6 mol/L hydrochloric acid was added thereto to
adjust the mixture to pH 1. The precipitated solid was collected by
filtration and dried in vacuo to give Compound 31 (73 mg, 88%) as a
white solid.
[0424] Melting Point: 208 - 213.degree. C.
[0425] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 1.8-2.5 (m, 9H),
4.3-4.5 (m, 4H), 6.55 (t, J 74 Hz, 1H), 6.77 (d, J=9 Hz, 1H), 6.87
(d, J=9 Hz, 1H)(A proton of carboxy is not found).
[0426] MASS(m/z) 352[(M-H).sup.-].
[0427] Reference Example 1. 8-Methoxy-1,4-benzodioxane-5-boric acid
(Compound A)
[0428] To a solution of 5-bromo-8-methoxy-1,4-benzodioxane (7.4 g,
30 mmol) in THF (74 mL) was added dropwise a 1.54 mol/L solution of
n-butyl lithium in hexane (23 mL, 35 mmol) at -78.degree. C.,
followed by stirring at -78.degree. C. for 0.5 hour.
[0429] To this reaction mixture was added a solution of trimethyl
borate (4.8 mL, 42 mmol) in THF (15 mL) at -78.degree. C., and the
mixture was stirred for 1.7 hours, followed by stirring for 1.8
hours at room temperature. Hydrochloric acid was added to adjust
the mixture to pH 1, the mixture was extracted with ethyl acetate,
and the extract was washed with water and brine and dried over
magnesium sulfate. The solid was filtered off, and the solvent was
evaporated in vacuo, followed by recrystallization from toluene to
give Compound A (4.35 g, 68%) as a milky white solid.
[0430] Melting Point:>300.degree. C.
[0431] .sup.1H-NMR (CDCl.sub.3, .delta., ppm) 3.91 (s, 3H),
4.34-4.41 (m, 4H), 5.73 (s, 2H), 6.59 (d, J=8 Hz, 1H), 7.37 (d, J=8
Hz, 1H).
[0432] MASS (m/z) 210 (M.sup.+).
[0433] Reference Example 2.
4-(8-Methoxy-1,4-benzodioxan-5-yl)phthalic acid (Compound B)
[0434] To a mixture of diethyl
4-(8-methoxy-1,4-benzodioxan-5-yl)phthalate (0.69 g, 1.8 mmol)
obtained by treating Compound A (0.70 g, 3.3 mmol) obtained in
Reference Example 1 and known diethyl 4-bromophthalate (1.00 g, 3.3
mmol) by the same reaction as in Example 17 were added ethanol (7.0
mL) and a 6 mol/L aqueous solution of potassium hydroxide (1.4 mL),
the mixture was stirred at room temperature for 2 hours, and then
ethanol was evaporated in vacuo. Water was added to the resulting
solution, the mixture was adjusted to pH 2 with 6 mol/L
hydrochloric acid, and the precipitated solid was collected by
filtration and dried in vacuo to give Compound B (0.55 g, 94%) as a
white solid.
[0435] Melting Point: 192 - 196.degree. C.
[0436] NMR (DMSO-d.sub.6, .delta., ppm) 3.79 (s, 3H), 4.26 (s, 4H),
4.37-4.40 (m, 2H), 6.69 (d, J=8.6 Hz, 1H), 6.89 (d, J=8.6 Hz, 1H),
7.63-7.72 (m, 3H), 13.07 (br s, 1H).
[0437] MASS(m/e) 312(M.sup.+-H.sub.2O).
[0438] Reference Example 3. Ethyl 2-acetoxymethyl-4-bromobenzoate
(Compound C)
[0439] (Step A) Ethyl 4-bromo-2-bromomethylbenzoate (Compound
Ca)
[0440] To a mixture of ethyl 4-bromo-2-methylbenzoate (10.0 g, 41
mmol) and .alpha.,.alpha.,.alpha.-trifluorotoluene (300 mL) were
added N-bromosuccinimide (7.54 g, 42 mmol) and
azobisisobutyronitrile (2.0 g, 12 mmol), followed by stirring at
80.degree. C. for 5.5 hours. Water was added to the reaction
mixture for partition, and the organic layer was washed with water
and brine and dried over magnesium sulfate. The solid was filtered
off, the filtrate was concentrated in vacuo, and the concentrate
was purified by silica gel column chromatography (eluted with
hexane/ethyl acetate=20/1), followed by recrystallizationfrom
hexaneto giveCompoundCa(4.07 g,31%) as a white solid.
[0441] Melting Point: 56.0 - 57.0.degree. C.
[0442] NMR (CDCl.sub.3, .delta., ppm) 1.42 (t, J=7.1 Hz, 3H), 4.40
(q, J=7.1 Hz, 2H), 4.89 (s, 2H), 7.50 (dd, J=2.0, 8.4 Hz, 1H), 7.62
(d, J=2.0 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H).
[0443] MASS(m/e) 300(M.sup.+), 300(M.sup.++2), 300(M.sup.++4).
(Step B) Compound C
[0444] To a mixture of Compound Ca (1.0 g, 3.2 mmol) and acetic
acid (10 mL) was addedsodiumacetate (4.0 g, 49 mmol), followed by
stirring at 120.degree. C. for 0.5 hour. A saturated aqueous
solution of sodium bicarbonate was added to the reaction mixture so
that acetic acid was neutralized, and then ethyl acetate was added
for partition. The organic layer was washed with a saturated
aqueous solution of sodium bicarbonate and then with brine and
dried over magnesium sulfate. The solid was filtered off, the
filtrate was concentrated in vacuo, and the concentrate was
purified by silica gel column chromatography (eluted with
hexane/ethyl acetate 25/1) to give Compound C. (0.69 g, 71%) as a
white solid.
[0445] Melting Point: 51.5 - 52.5.degree. C.
[0446] NMR (CDCl.sub.3, .delta., ppm) 1.39 (t, J=7.1 Hz, 3H), 2.17
(s, 3H), 4.36 (q, J=7.1 Hz, 2H), 5.50 (s, 2H), 7.51 (dd, J=2.0, 8.4
Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H).
[0447] MASS(m/e) 300(M.sup.+), 300(M.sup.++2).
Industrial Applicability
[0448] According to the present invention, there can be provided
oxygen-containing heterocyclic compounds which have
phosphodiesterase (PDE) IV inhibitory activity and which are useful
as a therapeutic agent for inflammatory allergic diseases such as
bronchial asthma, allergic rhinitis, atopic dermatitis and
nephritis; autoimmune diseases such as chronic obstructive
pulmonary disease, rheumatism, multiple sclerosis, Crohn's disease,
psoriasis and systemic lupus erythematosus; diseases of the central
nervous system such as depression, amnesia and dementia;
organopathy associated with ischemia-reperfusion caused by cardiac
failure, shock and cerebrovascular disease, and the like;
insulin-resistant diabetes; wounds; AIDS; osteoporosis; urinary
calculus; urinary incontinence and the like; or as a recuperative
agent for fatigue, malaise and the like.
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