U.S. patent application number 10/853829 was filed with the patent office on 2004-11-04 for oxa(thia)zolidine derivatives and anti-inflammatory drugs.
This patent application is currently assigned to Nippon Soda Co. Ltd.. Invention is credited to Ishimitsu, Keiichi, Nishibe, Tadayuki, Takagi, Masae.
Application Number | 20040220244 10/853829 |
Document ID | / |
Family ID | 27342821 |
Filed Date | 2004-11-04 |
United States Patent
Application |
20040220244 |
Kind Code |
A1 |
Takagi, Masae ; et
al. |
November 4, 2004 |
Oxa(thia)zolidine derivatives and anti-inflammatory drugs
Abstract
The present invention provides medicinal compositions
characterized by containing as the active ingredient either a
compound represented by a general formula (1) or a pharmaceutically
acceptable composite thereof, 1 wherein X represents oxygen or
sulfur; R.sub.1 represents hydrogen, C.sub.1-4 alkyl, etc.; R.sub.2
represents, e.g., phenyl optionally substituted by A.sub.1; R.sub.3
represents, e.g., hydrogen, C.sub.1-4 alkyl optionally substituted
by A.sub.2, or a group represented by either one of the following
formulae; 2 R represents oxygen, sulfur, or a group represented by
a formula (N-G)], in particular, inhibitor of phospholipase A(2)
activity; use of the composition; and compound represented by a
general formula (1-1); 3 wherein X, R.sub.1, R.sub.2, R.sub.3 and
G.sub.1 are the same as defined in the description.
Inventors: |
Takagi, Masae; (Kanagawa,
JP) ; Ishimitsu, Keiichi; (Kanagawa, JP) ;
Nishibe, Tadayuki; (Kanagawa, JP) |
Correspondence
Address: |
MASON LAW, PL
17757 US HWY 19 N.
CLEARWATER
FL
33764
US
|
Assignee: |
Nippon Soda Co. Ltd.
|
Family ID: |
27342821 |
Appl. No.: |
10/853829 |
Filed: |
May 26, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10853829 |
May 26, 2004 |
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10240075 |
Sep 25, 2002 |
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6762200 |
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10240075 |
Sep 25, 2002 |
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PCT/JP01/02481 |
Mar 27, 2001 |
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Current U.S.
Class: |
514/365 ;
514/314; 514/374 |
Current CPC
Class: |
A61K 31/496 20130101;
A61P 11/06 20180101; A61K 31/427 20130101; A61K 31/439 20130101;
A61K 31/4439 20130101; A61P 17/06 20180101; A61P 13/12 20180101;
C07D 413/04 20130101; A61P 1/04 20180101; A61K 31/4709 20130101;
C07D 409/12 20130101; C07D 263/16 20130101; C07D 413/10 20130101;
A61P 1/16 20180101; A61P 37/08 20180101; A61P 9/02 20180101; A61P
29/00 20180101; C07D 263/28 20130101; C07D 413/12 20130101; A61K
31/506 20130101; A61K 31/422 20130101; A61P 37/02 20180101; A61P
9/10 20180101; C07D 413/06 20130101; A61P 17/16 20180101; C07D
417/06 20130101; A61P 11/02 20180101; C07D 277/16 20130101; A61K
31/421 20130101; A61P 7/10 20180101; C07D 417/14 20130101; A61P
17/00 20180101; C07D 417/12 20130101; A61P 27/16 20180101; A61K
31/426 20130101; A61P 7/02 20180101; C07D 277/14 20130101; A61P
9/00 20180101; C07D 263/26 20130101; A61P 31/04 20180101; A61K
31/5377 20130101; A61P 43/00 20180101; A61K 31/454 20130101; A61P
19/02 20180101; A61P 11/00 20180101; A61P 25/00 20180101; C07D
277/18 20130101; C07D 417/04 20130101 |
Class at
Publication: |
514/365 ;
514/374; 514/314 |
International
Class: |
A61K 031/427; A61K
031/422 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 28, 2000 |
JP |
2000-88078 |
May 15, 2000 |
JP |
2000-141395 |
Jun 19, 2000 |
JP |
2000-182811 |
Claims
1.-12. (Canceled)
13. A pharmaceutical composition for an anti-inflammatory drug,
and/or an anti-allergic drug, and/or an immune controlling drug,
and/or an analgesic drug, the composition having as an active
ingredient either a compound represented by a formula (1) or a
pharmaceutically acceptable composite thereof; 59wherein X
represents oxygen or sulfur, R.sub.1 represents hydrogen, C.sub.1-4
alkyl or C.sub.1-4 haloalkyl, R.sub.2 represents phenyl optionally
substituted by A.sub.1, naphthyl optionally substituted by A.sub.1,
5 to 6-membered heterocyclic group optionally substituted by
A.sub.1 containing at least one heteroatom selected from a group
consisting of oxygen, sulfur and nitrogen, quinolyl optionally
substituted by A.sub.1, or a group represented by a formula (2);
60wherein Q represents --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--
or --OCH.sub.2O--, R.sub.3 represents hydrogen, C.sub.1-4 alkyl
optionally substituted by A.sub.2, C.sub.1-4 alkoxy optionally
substituted by A.sub.2, C.sub.1-4 alkylcarbonyl optionally
substituted by A.sub.2, C.sub.1-4 alkoxycarbonyl optionally
substituted by A.sub.2, C.sub.2-4 alkenylcarbonyl optionally
substituted by A.sub.2, phenyliminomethyl optionally substituted by
A.sub.3, phenyl optionally substituted by A.sub.3, anilino
optionally substituted by A.sub.3, or a group represented by the
following formulae; 61wherein Y represents oxygen or sulfur,
R.sub.4 represents hydrogen or C.sub.1-4 alkyl, R.sub.5 represents
C.sub.1-6 alkyl optionally substituted by A.sub.2, C.sub.2-6
alkenyl optionally substituted by A.sub.2, C.sub.2-6 alkynyl
optionally substituted by A.sub.2, C.sub.1-6 alkoxy optionally
substituted by A.sub.2, C.sub.2-6 alkenyloxy optionally substituted
by A.sub.2, mono- or di-(C.sub.1-6 alkyl)amino optionally
substituted by A.sub.2, C.sub.3-7 cycloalkyl optionally substituted
by A.sub.4, C.sub.5-7 cycloalkenyl optionally substituted by
A.sub.4, phenyl optionally substituted by A.sub.3, benzoyl
optionally substituted by A.sub.3, anilino optionally substituted
by A.sub.3, C.sub.1-6 alkoxycarbonyl optionally substituted by
A.sub.2, phenylsulfonyl optionally substituted by A.sub.3,
C.sub.1-6 alkoxysulfonyl optionally substituted by A.sub.2, mono-
or di-(C.sub.1-6 alkyl)aminosulfonyl optionally substituted by
A.sub.2, or 5- to 7-membered heterocyclic group optionally
substituted by A.sub.4 containing at least one atom selected from a
group consisting of oxygen, sulfur and nitrogen as a heteroatom,
and n represents 0, 1 or 2, R represents oxygen, sulfur or a group
represented by a formula of N-G, wherein G represents hydrogen,
nitro, cyano, C.sub.1-4 alkyl optionally substituted by A.sub.2,
C.sub.1-4 alkoxy, C.sub.1-4 alkylcarbonyl, phenyl optionally
substituted by A.sub.3, benzoyl optionally substituted by A.sub.3,
anilino optionally substituted by A.sub.3, a group represented by a
formula of NHCOR.sub.6, wherein R.sub.6 represents C.sub.1-4 alkyl
or phenyl optionally substituted by A.sub.3, or a group represented
by the following formula; 62wherein Z represents oxygen or sulfur,
R.sub.7 represents C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl optionally
substituted by A.sub.4, phenyl optionally substituted by A.sub.3,
benzoyl optionally substituted by A.sub.3, or optionally
substituted 5- to 7-membered heterocyclic group, A.sub.1 represents
halogeno, amino, nitro, cyano, C.sub.1-12 alkyl, C.sub.2-6 alkenyl,
C.sub.1-4 haloalkyl, C.sub.3-7 cycloalkyl, phenyl optionally
substituted by halogeno, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl,
pyridyl, thienyl, C.sub.1-4 alkoxy, methylenedioxy, C.sub.1-4
alkylthio, C.sub.1-4 alkylsulfenyl, C.sub.1-4 alkylsulfonyl, mono-
or di-(C.sub.1-4 alkyl)amino, C.sub.1-4 haloalkoxy, benzyl,
phenetyl, phenoxy, phenylthio, C.sub.1-4 alkoxycarbonyl, C.sub.1-4
haloalkoxycarbonyl, C.sub.1-4 alkylcarbonyloxy, carbamoyl, or mono-
or di-(C.sub.1-4 alkyl)carbamoyl, A.sub.2 represents halogeno,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxy C.sub.1-4 alkoxy, amino, mono-
or di-(C.sub.1-4 alkyl)amino, C.sub.1-4 alkylcarbonyloxy, C.sub.1-4
alkoxycarbonyl, halo C.sub.1-4 alkoxycarbonyl, C.sub.1-4
alkylcarbamoyl, di-(C.sub.1-4 alkyl)carbonylamino, morpholino,
phenyl, or pyridyl optionally substituted by halogeno, A.sub.3
represents halogeno, hydroxy, oxo, mercapto, nitro, amino, cyano,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, pyridyl, C.sub.1-4 alkoxy,
C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfenyl, C.sub.1-4
alkylsulfonyl, mono- or di-(C.sub.1-4 alkyl)amino, C.sub.1-4
haloalkoxy, C.sub.1-4 alkylcarbonyl, C.sub.1-4 alkoxycarbonyl,
C.sub.1-4 haloalkoxycarbonyl, carbamoyl, mono- or di-(C.sub.1-4
alkyl)carbamoyl, or C.sub.1-4 alkoxycarbonyl C.sub.1-4 alkylthio,
and A.sub.4 represents halogeno, hydroxy, oxo, C.sub.1-4 alkyl,
halo C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, halo
C.sub.1-4 alkoxy, halo C.sub.1-4 alkylthio, C.sub.1-4 alkoxy
C.sub.1-4 alkoxy, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkoxycarbonyl, or C.sub.1-4 haloalkoxycarbonyl, provided that R is
oxygen or sulfur, R.sub.3 represents a group represented by the
following formula; 63wherein Y, R.sub.4 and R.sub.5 are as defined
above, and R represents not a group represented by a formula of N-G
when X is oxygen.
14. Compounds represented by a formula (1-1); 64wherein R.sub.1
represents hydrogen, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl,
R.sub.2 represents phenyl optionally substituted by A.sub.1,
naphthyl optionally substituted by A.sub.1, 5 to 6-membered
heterocyclic group optionally substituted by A.sub.1 containing at
least one heteroatom selected from a group consisting of oxygen,
sulfur and nitrogen, quinolyl optionally substituted by A.sub.1, or
a group represented by a formula (2); 65wherein Q represents
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4-- or --OCH.sub.2O--,
R.sub.3 represents hydrogen, C.sub.1-4 alkyl optionally substituted
by A.sub.2, C.sub.1-4 alkoxy optionally substituted by A.sub.2,
C.sub.1-4 alkylcarbonyl optionally substituted by A.sub.2,
C.sub.1-4 alkoxycarbonyl optionally substituted by A.sub.2,
C.sub.2-4 alkenylcarbonyl optionally substituted by A.sub.2,
phenyliminomethyl optionally substituted by A.sub.3, phenyl
optionally substituted by A.sub.3, anilino optionally substituted
by A.sub.3, or a group represented by the following formulae;
66wherein Y represents oxygen or sulfur, R.sub.4 represents
hydrogen or C.sub.1-4 alkyl, R.sub.5 represents C.sub.1-6 alkyl
optionally substituted by A.sub.2, C.sub.2-6 alkenyl optionally
substituted by A.sub.2, C.sub.2-6 alkynyl optionally substituted by
A.sub.2, C.sub.1-6 alkoxy optionally substituted by A.sub.2,
C.sub.2-6 alkenyloxy optionally substituted by A.sub.2, mono- or
di-(C.sub.1-6 alkyl)amino optionally substituted by A.sub.2,
C.sub.3-7 cycloalkyl optionally substituted by A.sub.4, C.sub.5-7
cycloalkenyl optionally substituted by A.sub.4, phenyl optionally
substituted by A.sub.3, benzoyl optionally substituted by A.sub.3,
anilino optionally substituted by A.sub.3, C.sub.1-6 alkoxycarbonyl
optionally substituted by A.sub.2, phenylsulfonyl optionally
substituted by A.sub.3, C.sub.1-6 alkoxysulfonyl optionally
substituted by A.sub.2, mono- or di-(C.sub.1-6 alkyl)aminosulfonyl
optionally substituted by A.sub.2, or 5- to 7-membered heterocyclic
group optionally substituted by A.sub.4 containing at least one
atom selected from a group consisting of oxygen, sulfur and
nitrogen as a heteroatom, and n represents 0, 1 or 2, G.sub.1
represents nitro, cyano, C.sub.1-4 alkylcarbonyl, benzoyl
optionally substituted by A.sub.3, NHCOR.sub.6, wherein R.sub.6
represents C.sub.1-4 alkyl or phenyl optionally substituted by
A.sub.3, or a group represented by the following formula; 67wherein
Z represents oxygen or sulfur, R.sub.7 represents C.sub.1-4 alkyl,
C.sub.3-7 cycloalkyl optionally substituted by A.sub.4, phenyl
optionally substituted by A.sub.3, benzoyl optionally substituted
by A.sub.3, or optionally substituted 5- to 7-membered heterocyclic
group, A.sub.1 represents halogeno, amino, nitro, cyano, C.sub.1-12
alkyl, C.sub.2-6 alkenyl, C.sub.1-4 haloalkyl, C.sub.3-7
cycloalkyl, phenyl optionally substituted by halogeno, C.sub.1-4
alkyl or C.sub.1-4 haloalkyl, pyridyl, thienyl, C.sub.1-4 alkoxy,
methylenedioxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfenyl,
C.sub.1-4 alkylsulfonyl, mono- or di-(C.sub.1-4 alkyl)amino,
C.sub.1-4 haloalkoxy, benzyl, phenetyl, phenoxy, phenylthio,
C.sub.1-4 alkoxycarbonyl, C.sub.1-4 haloalkoxycarbonyl, C.sub.1-4
alkylcarbonyloxy, carbamoyl, or mono- or di-(C.sub.1-4
alkyl)carbamoyl, A.sub.2 represents halogeno, C.sub.1-4 alkoxy,
C.sub.1-4 alkoxy C.sub.1-4 alkoxy, amino, mono- or di-(C.sub.1-4
alkyl)amino, C.sub.1-4 alkylcarbonyloxy, C.sub.1-4 alkoxycarbonyl,
halo C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkylcarbamoyl,
di-(C.sub.1-4 alkyl)carbonylamino, morpholino, phenyl, or pyridyl
optionally substituted by halogeno, A.sub.3 represents halogeno,
hydroxy, oxo, mercapto, nitro, amino, cyano, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, pyridyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylthio, C.sub.1-4 alkylsulfenyl, C.sub.1-4 alkylsulfonyl, mono-
or di-(C.sub.1-4 alkyl)amino, C.sub.1-4 haloalkoxy, C.sub.1-4
alkylcarbonyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4
haloalkoxycarbonyl, carbamoyl, mono- or di-(C.sub.1-4
alkyl)carbamoyl, or C.sub.1-4 alkoxycarbonyl C.sub.1-4 alkylthio,
and A.sub.4 represents halogeno, hydroxy, oxo, C.sub.1-4 alkyl,
halo C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, halo
C.sub.1-4 alkoxy, halo C.sub.1-4 alkylthio, C.sub.1-4 alkoxy
C.sub.1-4 alkoxy, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkoxycarbonyl, or C.sub.1-4 haloalkoxycarbonyl, provided that R is
oxygen or sulfur, R.sub.3 represents a group represented by the
following formula; 68wherein Y, R.sub.4 and R.sub.5 are as defined
above.
15. A method to treat inflammatory diseases or disorders, allergic
diseases or auto-immune disease by administering an effective
amount of a pharmaceutical composition, of a compound of formula
(1) and the pharmaceutically acceptable carrier thereof, to a
mammal, 69wherein X represents oxygen or sulfur, R.sub.1 represents
hydrogen, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl, R.sub.2
represents phenyl optionally substituted by A.sub.1, naphthyl
optionally substituted by A.sub.1, 5 to 6-membered heterocyclic
group optionally substituted by A.sub.1 containing at least one
heteroatom selected from a group consisting of oxygen, sulfur and
nitrogen, quinolyl optionally substituted by A.sub.1, or a group
represented by a formula (2); 70wherein Q represents
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4-- or --OCH.sub.2O--,
R.sub.3 represents hydrogen, C.sub.1-4 alkyl optionally substituted
by A.sub.2, C.sub.1-4 alkoxy optionally substituted by A.sub.2,
C.sub.1-4 alkylcarbonyl optionally substituted by A.sub.2,
C.sub.1-4 alkoxycarbonyl optionally substituted by A.sub.2,
C.sub.2-4 alkenylcarbonyl optionally substituted by A.sub.2,
phenyliminomethyl optionally substituted by A.sub.3, phenyl
optionally substituted by A.sub.3, anilino optionally substituted
by A.sub.3, or a group represented by the following formulae;
71wherein Y represents oxygen or sulfur, R.sub.4 represents
hydrogen or C.sub.1-4 alkyl, R.sub.5 represents C.sub.1-6 alkyl
optionally substituted by A.sub.2, C.sub.2-6 alkenyl optionally
substituted by A.sub.2, C.sub.2-6 alkynyl optionally substituted by
A.sub.2, C.sub.1-6 alkoxy optionally substituted by A.sub.2,
C.sub.2-6 alkenyloxy optionally substituted by A.sub.2, mono- or
di-(C.sub.1-6 alkyl)amino optionally substituted by A.sub.2,
C.sub.3-7 cycloalkyl optionally substituted by A.sub.4, C.sub.5-7
cycloalkenyl optionally substituted by A.sub.4, phenyl optionally
substituted by A.sub.3, benzoyl optionally substituted by A.sub.3,
anilino optionally substituted by A.sub.3, C.sub.1-6 alkoxycarbonyl
optionally substituted by A.sub.2, phenylsulfonyl optionally
substituted by A.sub.3, C.sub.1-6 alkoxysulfonyl optionally
substituted by A.sub.2, mono- or di-(C.sub.1-6 alkyl)aminosulfonyl
optionally substituted by A.sub.2, or 5- to 7-membered heterocyclic
group optionally substituted by A.sub.4 containing at least one
atom selected from a group consisting of oxygen, sulfur and
nitrogen as a heteroatom, and n represents 0, 1 or 2, R represents
oxygen, sulfur or a group represented by a formula of N-G, wherein
G represents hydrogen, nitro, cyano, C.sub.1-4 alkyl optionally
substituted by A.sub.2, C.sub.1-4 alkoxy, C.sub.1-4 alkylcarbonyl,
phenyl optionally substituted by A.sub.3, benzoyl optionally
substituted by A.sub.3, anilino optionally substituted by A.sub.3,
a group represented by a formula of NHCOR.sub.6, wherein R.sub.6
represents C.sub.1-4 alkyl or phenyl optionally substituted by
A.sub.3, or a group represented by the following formula; 72wherein
Z represents oxygen or sulfur, R.sub.7 represents C.sub.1-4 alkyl,
C.sub.3-7 cycloalkyl optionally substituted by A.sub.4, phenyl
optionally substituted by A.sub.3, benzoyl optionally substituted
by A.sub.3, or optionally substituted 5- to 7-membered heterocyclic
group, A.sub.1 represents halogeno, amino, nitro, cyano, C.sub.1-12
alkyl, C.sub.2-6 alkenyl, C.sub.1-4 haloalkyl, C.sub.3-7
cycloalkyl, phenyl optionally substituted by halogeno, C.sub.1-4
alkyl or C.sub.1-4 haloalkyl, pyridyl, thienyl, C.sub.1-4 alkoxy,
methylenedioxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfenyl,
C.sub.1-4 alkylsulfonyl, mono- or di-(C.sub.1-4 alkyl)amino,
C.sub.1-4 haloalkoxy, benzyl, phenetyl, phenoxy, phenylthio,
C.sub.1-4 alkoxycarbonyl, C.sub.1-4 haloalkoxycarbonyl, C.sub.1-4
alkylcarbonyloxy, carbamoyl, or mono- or di-(C.sub.1-4
alkyl)carbamoyl, A.sub.2 represents halogeno, C.sub.1-4 alkoxy,
C.sub.1-4 alkoxy C.sub.1-4 alkoxy, amino, mono- or di-(C.sub.1-4
alkyl)amino, C.sub.1-4 alkylcarbonyloxy, C.sub.1-4 alkoxycarbonyl,
halo C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkylcarbamoyl,
di-(C.sub.1-4 alkyl)carbonylamino, morpholino, phenyl, or pyridyl
optionally substituted by halogeno, A.sub.3 represents halogeno,
hydroxy, oxo, mercapto, nitro, amino, cyano, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, pyridyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylthio, C.sub.1-4 alkylsulfenyl, C.sub.1-4 alkylsulfonyl, mono-
or di-(C.sub.1-4 alkyl)amino, C.sub.1-4 haloalkoxy, C.sub.1-4
alkylcarbonyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4
haloalkoxycarbonyl, carbamoyl, mono- or di-(C.sub.1-4
alkyl)carbamoyl, or C.sub.1-4 alkoxycarbonyl C.sub.1-4 alkylthio,
and A.sub.4 represents halogeno, hydroxy, oxo, C.sub.1-4 alkyl,
halo C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, halo
C.sub.1-4 alkoxy, halo C.sub.1-4 alkylthio, C.sub.1-4 alkoxy
C.sub.1-4 alkoxy, C.sub.1-4 alkysulfonyl, C.sub.1-4 alkoxycarbonyl,
or C.sub.1-4 haloalkoxycarbonyl, provided that R is oxygen or
sulfur, R.sub.3 represents a group represented by the following
formula; 73wherein Y, R.sub.4 and R.sub.5 are as defined above, and
R represents not a group represented by a formula of N-G when X is
oxygen.
16. The method according to claim 15, wherein the inflammatory
diseases or the disorders are any of anaphylaxis, allergic
inflammation, asthma, rhinitis, bronchitis, pneumonia, and adult
respiratory distress syndrome, inflammatory intestine disorder,
Crohn's disease, ulcerative colitis, ischemia/reperfusion injuries,
vasculitis, arteriosclerosis, hepatitis, nephritis, nerve
degenerative diseases, arthritis, dermatitis, solar keratosis,
psoriasis, septic shock and fever.
17. The method according to claim 15, wherein the progress of the
sick condition is due to inflammatory disease or disorder that is
accompanied with the enhanced phospholipase A(2) activity.
18. The method according to claim 15, wherein the inflammatory
disease or disorder is mediated by pro-inflammatory lipid
mediators, such as arachidonic acid and the metabolites thereof,
and/or lysophosphatidylcholine, and/or the platelet activating
factor (PAF).
19. The method according to claim 18, wherein the pro-inflammatory
lipid mediators are suppressed by the inhibitor of the
phospholipase A(2) activity.
20. A method for treating a patient in order to reduce inflammatory
and/or allergic conditions and/or sick conditions associated with
auto-immune diseases and disorders, the method comprising
administering to said patient a medicinal composition manufactured
from a compound derivative of the formula (1) 74wherein X
represents oxygen or sulfur, R.sub.1 represents hydrogen, C.sub.1-4
alkyl or C.sub.1-4 haloalkyl, R.sub.2 represents phenyl optionally
substituted by A.sub.1, naphthyl optionally substituted by A.sub.1,
5 to 6-membered heterocyclic group optionally substituted by
A.sub.1 containing at least one heteroatom selected from a group
consisting of oxygen, sulfur and nitrogen, quinolyl optionally
substituted by A.sub.1, or a group represented by a formula (2);
75wherein Q represents --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--
or --OCH.sub.2O--, R.sub.3 represents hydrogen, C.sub.1-4 alkyl
optionally substituted by A.sub.2, C.sub.1-4 alkoxy optionally
substituted by A.sub.2, C.sub.1-4 alkylcarbonyl optionally
substituted by A.sub.2, C.sub.1-4 alkoxycarbonyl optionally
substituted by A.sub.2, C.sub.2-4 alkenylcarbonyl optionally
substituted by A.sub.2, phenyliminomethyl optionally substituted by
A.sub.3, phenyl optionally substituted by A.sub.3, anilino
optionally substituted by A.sub.3, or a group represented by the
following formulae; 76wherein Y represents oxygen or sulfur,
R.sub.4 represents hydrogen or C.sub.1-4 alkyl, R.sub.5 represents
C.sub.1-6 alkyl optionally substituted by A.sub.2, C.sub.2-6
alkenyl optionally substituted by A.sub.2, C.sub.2-6 alkynyl
optionally substituted by A.sub.2, C.sub.1-6 alkoxy optionally
substituted by A.sub.2, C.sub.2-6 alkenyloxy optionally substituted
by A.sub.2, mono- or di-(C.sub.1-6 alkyl)amino optionally
substituted by A.sub.2, C.sub.3-7 cycloalkyl optionally substituted
by A.sub.4, C.sub.5-7 cycloalkenyl optionally substituted by
A.sub.4, phenyl optionally substituted by A.sub.3, benzoyl
optionally substituted by A.sub.3, anilino optionally substituted
by A.sub.3, C.sub.1-6 alkoxycarbonyl optionally substituted by
A.sub.2, phenylsulfonyl optionally substituted by A.sub.3,
C.sub.1-6 alkoxysulfonyl optionally substituted by A.sub.2, mono-
or di-(C.sub.1-6 alkyl)aminosulfonyl optionally substituted by
A.sub.2, or 5- to 7-membered heterocyclic group optionally
substituted by A.sub.4 containing at least one atom selected from a
group consisting of oxygen, sulfur and nitrogen as a heteroatom,
and n represents 0, 1 or 2, R represents oxygen, sulfur or a group
represented by a formula of N-G, wherein G represents hydrogen,
nitro, cyano, C.sub.1-4 alkyl optionally substituted by A.sub.2,
C.sub.1-4 alkoxy, C.sub.1-4 alkylcarbonyl, phenyl optionally
substituted by A.sub.3, benzoyl optionally substituted by A.sub.3,
anilino optionally substituted by A.sub.3, a group represented by a
formula of NHCOR.sub.6, wherein R.sub.6 represents C.sub.1-4 alkyl
or phenyl optionally substituted by A.sub.3, or a group represented
by the following formula; 77wherein Z represents oxygen or sulfur,
R.sub.7 represents C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl optionally
substituted by A.sub.4, phenyl optionally substituted by A.sub.3,
benzoyl optionally substituted by A.sub.3, or optionally
substituted 5- to 7-membered heterocyclic group, A.sub.1 represents
halogeno, amino, nitro, cyano, C.sub.1-12 alkyl, C.sub.2-6 alkenyl,
C.sub.1-4 haloalkyl, C.sub.3-7 cycloalkyl, phenyl optionally
substituted by halogeno, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl,
pyridyl, thienyl, C.sub.1-4 alkoxy, methylenedioxy, C.sub.1-4
alkylthio, C.sub.1-4 alkylsulfenyl, C.sub.1-4 alkylsulfonyl, mono-
or di-(C.sub.1-4 alkyl)amino, C.sub.1-4 haloalkoxy, benzyl,
phenetyl, phenoxy, phenylthio, C.sub.1-4 alkoxycarbonyl, C.sub.1-4
haloalkoxycarbonyl, C.sub.1-4 alkylcarbonyloxy, carbamoyl, or mono-
or di-(C.sub.1-4 alkyl)carbamoyl, A.sub.2 represents halogeno,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxy C.sub.1-4 alkoxy, amino, mono-
or di-(C.sub.1-4 alkyl)amino, C.sub.1-4 alkylcarbonyloxy, C.sub.1-4
alkoxycarbonyl, halo C.sub.1-4 alkoxycarbonyl, C.sub.1-4
alkylcarbamoyl, di-(C.sub.1-4 alkyl)carbonylamino, morpholino,
phenyl, or pyridyl optionally substituted by halogeno, A.sub.3
represents halogeno, hydroxy, oxo, mercapto, nitro, amino, cyano,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, pyridyl, C.sub.1-4 alkoxy,
C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfenyl, C.sub.1-4
alkylsulfonyl, mono- or di-(C.sub.1-4 alkyl)amino, C.sub.1-4
haloalkoxy, C.sub.1-4 alkylcarbonyl, C.sub.1-4 alkoxycarbonyl,
C.sub.1-4 haloalkoxycarbonyl, carbamoyl, mono- or di-(C.sub.1-4
alkyl)carbamoyl, or C.sub.1-4 alkoxycarbonyl C.sub.1-4 alkylthio,
and A.sub.4 represents halogeno, hydroxy, oxo, C.sub.1-4 alkyl,
halo C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, halo
C.sub.1-4 alkoxy, halo C.sub.1-4 alkylthio, C.sub.1-4 alkoxy
C.sub.1-4 alkoxy, C.sub.1-4 alkylsulfonyl C.sub.1-4 alkoxycarbonyl,
or C.sub.1-4 haloalkoxycarbonyl, provided that R is oxygen or
sulfur, R.sub.3 represents a group represented by the following
formula; 78wherein Y, R.sub.4 and R.sub.5 are as defined above, and
R represents not a group represented by a formula of N-G when X is
oxygen.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to inhibitor compositions of
phospholipase A(2) (hereinafter referred to as PLA (2)) activity
characterized by comprising as the active ingredient either an
oxa(thia)zolidine derivative or a pharmaceutically acceptable
composite thereof, a use of said inhibitor compositions in
mammalian which require to relieve sick conditions accompanied by
the enhanced PLA(2) activity, and novel oxa(thia)zolidine
derivatives which are useful as an active ingredient for said
inhibitor compositions.
BACKGROUND OF THE INVENTION
[0002] Inflammation is a series of defensive response process
caused in the tissues, induced by the applied injurious events
(inflammatory stimuli) on any parts of a human body. When the
tissues are damaged by inflammatory stimuli that could be caused by
bacterial infections, immunological responses or physical injuries,
the tissues respond (acute inflammation) to the stimuli, followed
by excluding the stimuli to repair the damages. Alternatively, if
the exclusion is difficult, the damages are progressed to induce
continuously tissue swelling (chronic inflammation). Inflammation
is well known to be associated with several diseases, and various
mediators are known to be associated with each step during the
inflammation process, constituted with activation and interactions
of various cells.
[0003] PLA(2) is a diverse class of enzymes, catalyzing
preferentially the hydrolysis of the sn-2 acyl-ester of
glycerophospholipids, that are major components of cell membranes,
to liberate fatty acids. It is also well known that the PLA(2)s are
responsible for deacylation-reacylation process required for cell
membrane repair and maintenance, and the hydrolyzed products, as
well as the further metabolites, are lipid mediators with strong
diverse physiological activities. The liberated product,
arachidonic acid with some activity as mediator, is further
metabolized in respective inflammation-associated cells to
prostagladins, thromboxanes, lipoxins, leukotrienes, etc., which
induce characteristic physiological responses, respectively
(Irvine, R., Biochemical Journal 204: 3-16 (1982).). The other
product, lysophosphatidylcholine not only plays roles as mediator,
but also is utilized as a precursor of platelet activating factor
(hereinafter referred to as PAF). These lipid mediators play an
essential role to maintain homeostasis of living organisms,
however, when they produced to excessive amounts under sick
conditions associated with inflammation, they could cause adversely
effects. In fact, steroidal anti-inflammatory drugs and various
non-steroidal anti-inflammatory drugs (hereinafter referred to as
NSAID) are known to interfere with the arachidonic acid cascade,
have been widely used in clinical therapy. As PLA(2) is positioned
at the upstream of the arachidonic acid cascade and is believed to
be the rate-limiting step in the generation of these lipid
mediators, this enzyme has been expected to be the promising target
for research and development of novel anti-inflammatory drugs
(Glaser, K. B., Advances in Pharmacology 32: 31-66 (1995).).
[0004] Recently, numerous PLA(2)s have been identified and rapidly
become a large superfamily consisted of more than 15 isozymes are
subdivided into four groups, on the basis of the protein structures
and the characteristics in the enzymatic activities (Dennis, E. A.,
Trends in Biochemical Science, 22: 1-2 (1997), and Balsinde, J. et
al, Annual Review of Pharmacology and Toxicology, 39: 175-189
(1999), etc.). Among them, it is noted that only the particular
isozymes are shown high specificity against
arachidonyl-phospholipids, as well as the enzymatic activity of the
particular isozymes are selectively enhanced in a case of
inflammatory disorder. As the examples for such
inflammation-associated PLA(2)s, type IV-cytosolic PLA(2)
(hereinafter referred to as IV-cPLA(2); molecular weight 85 kDa)
and the subtypes IIA, IID, V and X of secretory PLA(2) (hereinafter
referred to as sPLA(2); molecular weight 14 kDa) may be
exemplified. Among these, IV-cPLA(2) is particularly considered as
the responsible isozyme for producing the lipid mediators in the
inflammatory diseases, which is supported by findings from the
`knockout`(IV-cPLA(2).s- up.-/-)mice (Uozumi, N. et al, Nature 390:
619-622 (1997), and Bonventre, J. V. et al, Nature 390: 622-625
(1997).). Therefore, the enhanced lipid mediators production under
sick conditions could be suppressed by inhibiting IV-cPLA(2)
activity, thereby facilitating remedy and/or prevention of the
inflammatory diseases. Such diseases can be exemplified as
following: anaphylaxis induced by various inflammatory stimuli,
septic shock, fever and pain; respiratory diseases, such as
bronchitis, pneumonia, and adult respiratory distress syndrome;
digestive diseases, such as inflammatory intestine disorder,
Crohn's disease, ulcerative colitis, hepatitis, and nephritis;
cardio-vascular diseases, such as vasculitis and arteriosclerosis;
allergic inflammatory diseases, such as rhinitis, asthma and atopic
syndromes; and auto-immune diseases such as rheumatism;
ischemia/reperfusion injuries, such as cerebral infarction and
myocardial infarction; nerve degenerative diseases, solar
keratosis, psoriasis, and the like.
[0005] However, as no drug has been developed yet, which shows
remedial effects in the clinical therapies by inhibiting the enzyme
activity, it is desired to develop such a new drug that can
specifically and comprehensively control the lipid mediators
production in inflammatory diseases, with excellent therapeutic and
preventive effects.
[0006] In WO97/05135, compounds represented by the following
general formula; 4
[0007] are disclosed as oxa(thia)zolidine derivatives having
activity of inhibiting the PLA (2) activity. However, the compounds
which show to have said inhibitory activity are limited to ones
wherein the second and the fourth positions are substituted by
either oxo or thio. Furthermore, in WO93/10789,
2-imino-4-oxothiazolidine derivative represented by the following
chemical formula is disclosed. 5
[0008] It is described in Jpn. Pat. Appln. KOKAI publication No.
63-41471 that the oxa(thia)zolidine derivatives related to the
present invention have acaricidal activity. However, it is not
known so far that those oxa(thia)zolidine derivatives have PLA(2)
inhibitory activity or anti-inflammatory activity.
DISCLOSURE OF THE INVENTION
[0009] As described above, it is understood that the enhanced
PLA(2) activity plays a major role in the progress of various
inflammatory diseases. Therefore, an object of the present
invention is to provide medicinal compositions which is effective
to remedy the inflammatory sick condition and to cure or prevent
the relevant disease, and novel compounds to be used for the
medicinal composition.
[0010] As a result of the studies by the inventors of the present
invention for aiming at achieving the aforementioned object, it is
found out that the oxa(thia)zolidine derivatives, which had been
known to have acaricidal activity, have been found out also having
inhibitory activity on PLA(2), thereby reaching the present
invention.
[0011] The present invention is constituted with the following
aspects (1) through (12).
[0012] (1) A medicinal composition characterized by containing as
the active ingredient either a compound represented by a general
formula (1) or a pharmaceutically acceptable composite thereof;
6
[0013] wherein X represents oxygen or sulfur,
[0014] R.sub.1 represents hydrogen, C.sub.1-4 alkyl or C.sub.1-4
haloalkyl,
[0015] R.sub.2 represents phenyl optionally substituted by A.sub.1,
naphthyl optionally substituted by A.sub.1, 5 to 6-membered
heterocyclic group optionally substituted by A.sub.1 containing at
least one heteroatom selected from a group consisting of oxygen,
sulfur and nitrogen, quinolyl optionally substituted by A.sub.1, or
a group represented by a formula (2); 7
[0016] wherein Q represents --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4-- or --OCH.sub.2O--,
[0017] R.sub.3 represents hydrogen, C.sub.1-4 alkyl optionally
substituted by A.sub.2, C.sub.1-4 alkoxy optionally substituted by
A.sub.2, C.sub.1-4 alkylcarbonyl optionally substituted by A.sub.2,
C.sub.1-4 alkoxycarbonyl optionally substituted by A.sub.2,
C.sub.2-4 alkenylcarbonyl optionally substituted by A.sub.2,
phenyliminomethyl optionally substituted by A.sub.3, phenyl
optionally substituted by A.sub.3, anilino optionally substituted
by A.sub.3, or a group represented by the following formulae; 8
[0018] wherein Y represents oxygen or sulfur, R.sub.4 represents
hydrogen or C.sub.1-4 alkyl, R.sub.5 represents C.sub.1-6 alkyl
optionally substituted by A.sub.2, C.sub.2-6 alkenyl optionally
substituted by A.sub.2, C.sub.2-6 alkynyl optionally substituted by
A.sub.2, C.sub.1-6 alkoxy optionally substituted by A.sub.2,
C.sub.2-6 alkenyloxy optionally substituted by A.sub.2, mono- or
di-(C.sub.1-6 alkyl)amino optionally substituted by A.sub.2,
C.sub.3-7 cycloalkyl optionally substituted by A.sub.4, C.sub.5-7
cycloalkenyl optionally substituted by A.sub.4, phenyl optionally
substituted by A.sub.3, benzoyl optionally substituted by A.sub.3,
anilino optionally substituted by A.sub.3, C.sub.1-6 alkoxycarbonyl
optionally substituted by A.sub.2, phenylsulfonyl optionally
substituted by A.sub.3, C.sub.1-6 alkoxysulfonyl optionally
substituted by A.sub.2, mono- or di-(C.sub.1-6 alkyl)aminosulfonyl
optionally substituted by A.sub.2, or 5- to 7-membered heterocyclic
group optionally substituted by A.sub.4 containing at least one
atom selected from a group consisting of oxygen, sulfur and
nitrogen as a heteroatom, and n represents 0, 1 or 2,
[0019] R represents oxygen, sulfur or a group represented by a
formula of N-G, wherein G represents hydrogen, nitro, cyano,
C.sub.1-4 alkyl optionally substituted by A.sub.2, C.sub.1-4
alkoxy, C.sub.1-4 alkylcarbonyl, phenyl optionally substituted by
A.sub.3, benzoyl optionally substituted by A.sub.3, anilino
optionally substituted by A.sub.3, a group represented by a formula
of NHCOR.sub.6, wherein R.sub.6 represents C.sub.1-4 alkyl or
phenyl optionally substituted by A.sub.3, or a group represented by
the following formula; 9
[0020] wherein Z represents oxygen or sulfur, R.sub.7 represents
C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl optionally substituted by
A.sub.4, phenyl optionally substituted by A.sub.3, benzoyl
optionally substituted by A.sub.3, or optionally substituted 5- to
6-membered saturated heterocyclic group,
[0021] A.sub.1 represents halogeno, amino, nitro, cyano, C.sub.1-12
alkyl, C.sub.2-6 alkenyl, C.sub.1-4 haloalkyl, C.sub.3-7
cycloalkyl, phenyl optionally substituted by halogeno, C.sub.1-4
alkyl or C.sub.1-4 haloalkyl, pyridyl, thienyl, C.sub.1-4 alkoxy,
methylenedioxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfenyl,
C.sub.1-4 alkylsulfonyl, mono- or di-(C.sub.1-4 alkyl)amino,
C.sub.1-4 haloalkoxy, benzyl, phenethyl, phenoxy, phenylthio,
C.sub.1-4 alkoxycarbonyl, C.sub.1-4 haloalkoxycarbonyl, C.sub.1-4
alkylcarbonyloxy, carbamoyl, or mono- or di-(C.sub.1-4
alkyl)carbamoyl,
[0022] A.sub.2 represents halogeno, C.sub.1-4 alkoxy, C.sub.1-4
alkoxy C.sub.1-4 alkoxy, amino, mono- or di-(C.sub.1-4 alkyl)amino,
C.sub.1-4 alkylcarbonyloxy, C.sub.1-4 alkoxycarbonyl, halo
C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkylcarbamoyl, di-(C.sub.1-4
alkyl)carbonylamino, morpholino, phenyl, or pyridyl optionally
substituted by halogeno,
[0023] A.sub.3 represents halogeno, hydroxy, oxo, mercapto, nitro,
amino, cyano, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, pyridyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfenyl,
C.sub.1-4 alkylsulfonyl, mono- or di-(C.sub.1-4 alkyl)amino,
C.sub.1-4 haloalkoxy, C.sub.1-4 alkylcarbonyl, C.sub.1-4
alkoxycarbonyl, C.sub.1-4 haloalkoxycarbonyl, carbamoyl, mono- or
di-(C.sub.1-4 alkyl)carbamoyl, or C.sub.1-4 alkoxycarbonyl
C.sub.1-4 alkylthio, and
[0024] A.sub.4 represents halogeno, hydroxy, oxo, C.sub.1-4 alkyl,
halo C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, halo
C.sub.1-4 alkoxy, halo C.sub.1-4 alkylthio, C.sub.1-4 alkoxy
C.sub.1-4 alkoxy, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkoxycarbonyl, or C.sub.1-4 haloalkoxycarbonyl,
[0025] provided that R is oxygen or sulfur, R.sub.3 represents a
group represented by the following formula; 10
[0026] wherein Y, R.sub.4 and R.sub.5 are as defined above.
[0027] (2) Compounds represented by a general formula (1-1); 11
[0028] wherein X, R.sub.1, R.sub.2 and R.sub.3 are as defined in
the section (1) described above, G.sub.1 represents nitro, cyano,
C.sub.1-4 alkylcarbonyl, benzoyl optionally substituted by A.sub.3,
NHCOR.sub.6, wherein R.sub.6 represents C.sub.1-4 alkyl or phenyl
optionally substituted by A.sub.3, or a group represented by the
following formula; 12
[0029] wherein Z and R.sub.7 are as defined in the section (1)
described above, and A.sub.3 is as defined in the section (1)
described above.
[0030] (3) An inhibitor of PLA(2) activity comprising as the active
ingredient at least one selected from a group consisting of
heterocyclic compounds represented by the general formula (1) and
the pharmaceutically acceptable composites thereof.
[0031] (4) A use of a composition for a mammalian animals which
requiring remedy for inflammatory diseases or disorders, where the
composition is characterized by containing as the active ingredient
at least one selected from a group consisting of heterocyclic
compounds represented by the general formula (1) and the
pharmaceutically acceptable composites thereof.
[0032] (5) A method to remedy or reduce inflammatory diseases or
disorders, curing and/or preventing taking turn for the worth by
administering a medicinal composition, which is comprising an
effective dose of at least one selected from a group consisting of
compounds represented by the general formula (1) and the
pharmaceutically acceptable composites thereof to a mammalian
requiring treatment.
[0033] (6) The method defined in the section (5) described above;
wherein the inflammatory diseases or the disorders are any of
anaphylaxis, allergic inflammation, asthma, rhinitis, bronchitis,
pneumonia, and adult respiratory distress syndrome, inflammatory
intestine disorder, Crohn's disease, ulcerative colitis,
ischemia/reperfusion injuries, vasculitis, arteriosclerosis,
hepatitis, nephritis, nerve degenerative diseases, arthritis,
dermatitis, solar keratosis, psoriasis, septic shock and fever.
[0034] (7) The method defined in the section (5) described above,
wherein the progress of the sick condition is due to inflammatory
disease or disorder that is accompanied with the enhanced PLA(2)
activity.
[0035] (8) The method defined in the section (5) described above,
wherein the inflammatory disease or disorder is mediated by
pro-inflammatory lipid mediators, such as arachidonic acid and the
metabolites thereof, and/or lysophosphatidylcholines, and/or
PAF.
[0036] (9) The method defined in the section (8) described above,
wherein the pro-inflammatory lipid mediators are suppressed by the
inhibitor of PLA(2) activity.
[0037] (10) A use of a heterocyclic derivative of the general
formula (1) for manufacturing of a medicinal composition, which is
used for reducing inflammatory and/or allergic sick condition
and/or sick condition associated with immunity, and/or for the
remedy of such diseases and disorders.
[0038] (11) A use of a composition as a medicine, where the
composition contains as the active ingredient at least one selected
from a group consisting of heterocyclic derivatives represented by
the general formula (1) and the pharmaceutically acceptable
composites thereof.
[0039] (12) A use of a composition as an anti-inflammatory drug,
anti-allergic drug and/or immune controlling drug, where the
composition contains as the active ingredient at least one selected
from a group consisting of heterocyclic derivatives represented by
the general formula (1) and the pharmaceutically acceptable
composites thereof.
EMBODIMENTS FOR CARRYING OUT THE INVENTION
[0040] In the compounds according to the present invention, which
are represented by the general formula (1),
[0041] X represents oxygen or sulfur,
[0042] R.sub.1 represents hydrogen; C.sub.1-4 alkyl selected from
methyl, ethyl, propyl, isopropyl, butyl, i-butyl, sec-butyl and
t-butyl; or C.sub.1-4 haloalkyl, such as chloromethyl,
fluoromethyl, bromomethyl, dichloromethyl, trichloromethyl,
trifluoromethyl and pentafluoromethyl,
[0043] R.sub.2 represents phenyl optionally substituted by A.sub.1;
naphthyl optionally substituted by A.sub.1; 5- to 6-membered
heterocyclic group containing at least one heteroatom selected from
oxygen, sulfur and nitrogen, such as thienyl, furyl,
tetrahydrothiapyranyl, 2H, 5H, 6H-thiapyranyl, pyranyl,
tetrahydropyranyl, pyridyl, pyrimidyl, imidazolyl, oxazolyl and
thiazolyl, optionally substituted by A.sub.1; quinolyl optionally
substituted by A.sub.1; or a group represented by the following
formula (2); 13
[0044] wherein Q represents a group represented by
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4-- or --OCH.sub.2O--,
[0045] R.sub.3 represents hydrogen; C.sub.1-4 alkyl, such as methyl
and ethyl, optionally substituted by A.sub.2; C.sub.1-4 alkoxy,
such as methoxy, ethoxy and propoxy, optionally substituted by
A.sub.2; C.sub.1-4 alkylcarbonyl, such as acetyl, ethylcarbonyl,
propylcarbonyl and butylcarbonyl, optionally substituted by
A.sub.2; C.sub.1-4 alkoxycarbonyl, such as methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl, optionally
substituted by A.sub.2; C.sub.2-4 alkenylcarbonyl, such as
ethenylcarbonyl and allylcarbonyl, optionally substituted by
A.sub.2; phenyliminomethyl optionally substituted by A.sub.3;
phenyl optionally substituted by A.sub.3; anilino optionally
substituted by A.sub.3; or a group represented by the following
formulae; 14
[0046] wherein Y represent oxygen or sulfur,
[0047] R.sub.4 represents hydrogen, or C.sub.1-4 alkyl such as
methyl and ethyl,
[0048] R.sub.5 represents C.sub.1-6 alkyl, such as methyl and
ethyl, optionally substituted by A.sub.2; C.sub.2-6 alkenyl, such
as ethenyl and allyl, optionally substituted by A.sub.2; C.sub.2-6
alkynyl, such as ethynyl and propynyl, optionally substituted by
A.sub.2; C.sub.1-6 alkoxy, such as methoxy, ethoxy and butoxy,
optionally substituted by A.sub.2; C.sub.2-6 alkenyloxy, such as
ethenyloxy and allyloxy, optionally substituted by A.sub.2; mono-
or di-(C.sub.1-6 alkyl)amino, such as methylamino, dimethylamino
and ethylamino, optionally substituted by A.sub.2; C.sub.3-7
cycloalkyl, such as cyclopropyl, cycloheptyl and cyclohexyl,
optionally substituted by A.sub.4; C.sub.5-7 cycloalkenyl such as
cyclohexenyl optionally substituted by A.sub.4; phenyl optionally
substituted by A.sub.3; benzoyl optionally substituted by A.sub.3;
anilino optionally substituted by A.sub.3; C.sub.1-6
alkoxycarbonyl, such as methoxycarbonyl and ethoxycarbonyl,
optionally substituted by A.sub.2; phenylsulfonyl optionally
substituted by A.sub.3; C.sub.1-6 alkoxysulfonyl such as
methoxysulfonyl optionally substituted by A.sub.2; mono- or
di-(C.sub.1-6 alkyl)aminosulfonyl, such as methylaminosulfonyl,
dimethylaminosulfonyl and diethylaminosulfonyl, optionally
substituted by A.sub.2; or 5- to 7-membered heterocyclic group
containing at least one selected from oxygen, sulfur and nitrogen
as an heteroatom, optionally substituted by A.sub.4, and n
represents 0, 1 or 2, and
[0049] R represents oxygen, sulfur or a group represented by a
formula of N-G, wherein G represents hydrogen, nitro, cyano,
C.sub.1-4 alkyl optionally substituted by A.sub.2, C.sub.1-4
alkoxy, C.sub.1-4 alkylcarbonyl, phenyl optionally substituted by
A.sub.3, benzoyl optionally substituted by A.sub.3, anilino
optionally substituted by A.sub.3, NHCOR.sub.6, wherein R.sub.6
represents C.sub.1-4 alkyl or phenyl optionally substituted by
A.sub.3, or a group represented by the following formula; 15
[0050] wherein Z represents oxygen or sulfur, R.sub.7 represents
C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl optionally substituted by
A.sub.4, phenyl optionally substituted by A.sub.3, benzoyl
optionally substituted by A.sub.3, or optionally substituted 5- to
7-membered heterocyclic group.
[0051] The 5- to 7-membered heterocyclic group in the definition
for the group represented by R.sub.5 and R.sub.7 means a saturated
or unsaturated heterocyclic group constituted by 5 to 7 atoms and
containing at least one heteroatom selected from oxygen, sulfur and
nitrogen. Particularly, the 5- to 7-membered heterocyclic group
includes tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl,
pyrazolidinyl, imidazolidinyl, tetrahydropyranyl,
tetrahydrothiapyranyl, piperidinyl, pyrimidinyl, pyridyl, and the
like, and examples for the substituted "5- to 7-membered
heterocyclic group" includes N-methylpiperidinyl,
2,6-dimethylmorpholino, 3-methyloxathianyl,
6-methoxytetrahydropyranyl, and the like.
[0052] In the definition for the groups represented by A.sub.1,
A.sub.2, A.sub.3 and A.sub.4, the halogeno denotes fluoro, chloro,
bromo, iodo and the like, the C.sub.1-4 alkyl denotes a normal or
branched chain alkyl having 1 to 4 carbon atoms, which specifically
includes methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl,
s-butyl and t-butyl,
[0053] the C.sub.1-12 alkyl denotes pentyl, hexyl, dodecyl and the
like in addition to said C.sub.1-4 alkyls,
[0054] the C.sub.1-4 haloalkyl denotes chloromethyl, bromomethyl,
trifluoromethyl and the like,
[0055] the C.sub.3-7 cycloalkyl means a cyclic saturated
hydrocarbon containing 3 to 7 carbon atoms, which specifically
includes cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the
like,
[0056] the C.sub.1-4 alkoxy denotes methoxy, ethoxy and the like,
and the C.sub.1-4 alkylthio denotes methylthio, ethylthio and the
like,
[0057] the C.sub.1-4 alkoxy C.sub.1-4 alkoxy denotes methoxymethy,
ethoxymethyl, methoxyethyl and the like,
[0058] the alkylsulfenyl denotes methylsulfenyl, ethylsulfenyl and
the like, and the C.sub.1-4 alkylsulfonyl denotes methanesulfonyl,
ethanesulfonyl and the like,
[0059] the mono- or di-(C.sub.1-4 alkyl)amino denotes methylamino,
dimethylamino, ethylamino, methylethylamino and the like,
[0060] the C.sub.1-4 haloalkoxy denotes chloromethoxy,
bromomethoxy, trifluoromethoxy, chloroethoxy, fluoroethoxy and the
like,
[0061] the C.sub.1-4 alkoxycarbonyl denotes methoxycarbonyl,
ethoxycarbonyl and the like, the C.sub.1-4 haloalkoxycarbonyl
denotes chloromethoxycarbonyl, trifluoromethoxycarbonyl and the
like, and C.sub.1-4 alkylcarbonyloxy denotes acetoxy,
ethylcarbonyloxy and the like, and
[0062] the mono- or di-(C.sub.1-4 alkyl)carbamoyl denotes
methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,
propylcarbamoyl, isopropylcarbamoyl and the like,
[0063] provided that R is oxygen or sulfur, R.sub.3 represents a
group represented by the following formula; 16
[0064] wherein Y, R.sub.4 and R.sub.5 are as defined above.
[0065] Among the compounds according to the present invention, the
compounds in which R is a group represented by N-G.sub.1 are novel
compounds which have not been described in the previous references.
Furthermore, among the compounds in which R is either oxygen or
sulfur, most compounds in which R.sub.2 is naphthyl optionally
substituted by A.sub.1, 5- to 6-membered heterocyclic groups
optionally substituted by A.sub.1, quinolyl optionally substituted
by A.sub.1, or a group represented by the formula (2), are novel
compounds.
[0066] "The pharmaceutically acceptable composite" denotes a
composite comprising the compound described above and an atoxic
low-molecular compound those interact with ionic, hydrogen or
coordinate bonds each other, at a particular combining ratio, and
the compound should be liberated after the composite is solubilyzed
in an aqueous solution. Specific examples for the pharmaceutically
acceptable composite include salts with ionic materials such as
hydrochlorides, organic acids, amino acids and the like, and
solvates such as hydrates.
[0067] Now, the process for manufacturing the compounds according
to the present invention is explained below.
[0068] Among the compounds represented by the general formula (1),
the compounds except the novel compounds represented by the general
formula (1-1) and the pharmaceutically acceptable composite thereof
may be prepared according to the preparation process disclosed in
Jpn. Pat. Appln. KOKAI Publication No. 63-41471, etc.
[0069] The compounds represented by the general formula (1-1) may
be prepared according to the following processes.
[0070] Preparation Process 1: The compounds wherein G.sub.1 is
either cyano or nitro, and X is oxygen: 17
[0071] wherein R.sub.1, R.sub.2, R.sub.5 and Z are as defined
above, G.sub.1' is either cyano or nitro, and R.sub.3' represents
the same groups represented by R.sub.3 except groups represented by
a formula of Y'NR.sub.4R.sub.5 wherein Y' represents C.dbd.O or
C.dbd.S, and R.sub.4 and R.sub.5 are as defined above.
[0072] Preparation Process 2: The compounds wherein G.sub.1 is
either cyano or nitro and X is sulfur may be prepared according to
the process described in Jpn. Pat. Appln. KOKAI Publication No.
63-41471. 18
[0073] Preparation process 3: The compounds wherein G.sub.1 and/or
R.sub.3 is Y'NR.sub.4R.sub.5 may be prepared according to the
following reaction scheme. 19
[0074] The reaction of the compound (2) and the compound (3) in the
preparation process 1 may be carried out in an organic solvent for
1 to several hours at the temperature ranging from room temperature
to the boiling point of the used solvent. As the organic solvent
for the above reaction, alcohols, dioxane, THF, DMF and the like
may be used.
[0075] The respective reactions of the compounds (1-2), (1-5),
(1-10) and (1-12) with a halide are carried out in an organic
solvent in the presence of a base for 1 to scores of hours at the
temperature ranging from -20.degree. C. to the boiling point of the
used solvent, and preferably from 0.degree. C. to 50.degree. C. As
the organic solvent for these reactions, DMF, THF, DMSO, alcohols
and the like may be used. As the base for these reactions, sodium
hydride may be used, or any of alkoxides, triethylamine,
1,8-diazabicyclo(5,4,0)undecene-7 (hereinafter referred to as DBU)
and the like may be used as well.
[0076] The respective reactions of the compounds (1-2), (1-5) and
(1-8) with either a cyanate or an isothiocyanate represented by a
formula of R.sub.5NCZ may be carried out in an organic solvent in
the presence of a base for 1 to scores of hours at the temperature
ranging from -20.degree. C. to 60.degree. C., and preferably from
0.degree. C. to room temperature. As the organic solvent for these
reactions, DMF, DMSO, THF, dioxane, benzene, ethyl acetate and the
like may be used. As the base for these reactions, triethylamine,
DBU, Pyridine and the like may be used.
[0077] After each reaction represented above, work-up may be
employed as conventionally to obtain the objective compound.
[0078] The chemical structures of the compounds according to the
present invention were determined by means of MASS, NMR, etc.
[0079] The compounds represented by the general formula (1)
respectively include their structural isomers associated with at
least the fourth and fifth positions of the oxa(thia)zolidine
portion and their optical isomers. In addition, when R.sub.3 in the
compound is hydrogen, the following tautomers may be arisen. 20
[0080] It is to be noted that each of the compounds according to
the present invention is not limited to the specific isomers,
namely compounds may include all possible isomers as well as
possible racemic modifications. Furthermore, depending on
circumstances, the compounds according to the present invention
also may include the prodrugs and the metabolites of the compounds
indicated above.
[0081] Now, the medicinal composition according to the present
invention and the use thereof are explained below.
[0082] The compound represented by the general formula (1) or the
pharmaceutically acceptable composite thereof may be administrated
to humans and animals either directly or together with common
carriers for pharmaceutical formulations. For applying the
composite, the administration route is not limited, and either
route of systemic administration or topical application, i.e.
non-systemic administration, may be selected appropriately upon
necessity. Examples of the drug form for medical treatment include
pharmaceutical formulations for oral administration such as
tablets, capsules, granules, and powders, drinkable solutions,
troches and the like; and parenteral solutions or suspensions for
intravenous injection, intramuscular injection, subcutaneous
injection and the like. In addition, other administration routes,
such as through rectum with suppositories, and through lung
(through nose or inhalation through mouth) with aerosols, powder
inhalants, etc. may be employed for applying the medicinal
composition according to the present invention. As pharmaceutical
formulations suitable for the topical application to penetrate the
active ingredient into the inflammatory regions through skins and
mucosae, solutions, liniments, creams, emulsions, ointments and
pastes, as well as drops suitable for the treatment to eyes, ears
and noses may be exemplified. There is no limit for the amount of
the active ingredient to be applied, and therefore, the dose may be
appropriately selected in a wide range depending upon the
administration routes, the applied compounds, and the treated
patients, namely to humans or animals. In order to exert the
desired medicinal effectiveness, the compound of the present
invention is preferably administrated at a daily dose of 0.01-100
mg per kg body weight, with or without dividing the dose into
several times. For the pharmaceutical formulations, it is
preferable to contain the active ingredient in unit dosage form at
a dose of 0.01 to 1,000 mg.
[0083] The pharmaceutical formulations for oral administration
comprising the compound according to the present invention, such as
tablets, capsules, granules and drinkable solutions, may be
prepared according to any of the conventional methods. More
specifically, the tablets may be prepared by mixing the compound
represented by the general formula (1) or the pharmaceutically
acceptable composite thereof with pharmaceutical fillers, such as
starch, lactose, gelatin, magnesium stearate, talc, gum arabic, and
the like, and forming into tablets. The capsules may be prepared by
mixing the compound represented by the general formula (1) or the
pharmaceutically acceptable composite thereof with an inactive
pharmaceutical filler or diluent, and then charged into capsules
made of hard gelatin, soft capsules, or the like to. The medicated
syrups and elixirs for oral administration may be prepared by
mixing the compound represented by the general formula (1) or the
pharmaceutically acceptable composite thereof with a sweetener such
as sucrose, an antiseptic such as Methylparaben and Propylparaben,
a coloring agent, a flavor, and the like. Further, the parenteral
pharmaceutical formulations of the compound of the present
invention may be prepared according to any of the conventional
processes. For example, a parenteral pharmaceutical formulation may
be prepared by dissolving the compound represented by the general
formula (1) or the pharmaceutically acceptable composite thereof
with a sterilized liquid carrier. As the liquid carrier, water or
saline solution may be preferably used. In order to provide the
solution with a desired transparency, stability and congeniality
for the parenteral use, approximately 0.1 to 1,000 mg of the active
ingredient may be dissolved in either water or an organic solvent,
and further dissolved with polyethylene glycol having a molecular
weight of 200 to 5,000. For the preparation of the solution, it is
preferable that a lubricant, such as polyvinylpyrrolidone,
polyvinyl alcohol, sodium carboxymethyl cellulose, and methyl
cellulose, is incorporated therein. Furthermore, a bactericide such
as benzyl alcohol, phenol and Thimerosal, and a fungicide may be
incorporated into the solution, in addition, an osmotic pressure
conditioner, such as sucrose and sodium chloride, a local
anesthetic, a stabilizer, a buffer agent and the like may be
incorporated into the solution upon necessity. More stable
pharmaceutical formulation for parenteral use may be provided by
removing moisture in the frozen preparation following to the
filling, by means of freeze-drying technique known in the field.
Accordingly, it is also possible to resolve the lyophilized powder
thereof to prepare a pharmaceutical formulation just before the
use.
BEST MODE FOR CARRYING OUT THE INVENTION
[0084] Now, the present invention is further explained with
reference to the examples for the pharmaceutical formulations
comprising the compound according to the present invention.
However, it should be noted that the following examples are only
for the purpose of illustrating the present invention, and that the
present invention is not limited to the following examples.
PHARMACEUTICAL FORMULATION EXAMPLE 1
Tablets
[0085]
1 Compositions Amount (g) Compound of the present invention 5
Lactose (The Pharmacopoeia of Japan) 50 Corn starch (The
Pharmacopoeia of Japan) 25 Crystalline cellulose 25 (The
Pharmacopoeia of Japan) Methyl cellulose (The Pharmacopoeia of
Japan) 1.5 Magnesium stearate 1
[0086] A compound of the present invention, lactose, corn starch
and crystalline cellulose were incorporated thoroughly. The mixture
was formed into the granules with 5% aqueous solution of methyl
cellulose, and the granules were passed through a sieve of 300 mesh
and then dried carefully. The dried granules were incorporated with
magnesium stearate and then prepared into tablets according to the
conventional method to obtain 1,000 tablets.
PHARMACEUTICAL FORMULATION EXAMPLE 2
Capsules
[0087]
2 Compositions Amount (g) Compound of the present invention 10
Lactose (The Pharmacopoeia of Japan) 80 Starch (The Pharmacopoeia
of Japan) 30 Talc (The Pharmacopoeia of Japan) 5 Magnesium stearate
1 (The Pharmacopoeia of Japan)
[0088] The compositions recited above were incorporated and crushed
into fine particulates. The particulates of the mixture were then
stirred thoroughly so as to obtain the homogenous mixture. The
mixture was then charged into capsules made of gelatin for oral
administration use to obtain 1,000 pieces of two-pieces type
gelatin capsules.
PHARMACEUTICAL FORMULATION EXAMPLE 3
Solution for Injection
[0089]
3 Compositions Amount (g) Compound of the present invention 1
Polyethylene glycol 4000 0.3 (The Pharmacopoeia of Japan) Sodium
chloride (The Pharmacopoeia of Japan) 0.9 Polyoxyethylene sorbitan
monooleate 0.4 (The Pharmacopoeia of Japan) Sodium metabisulfite
0.1 (The Pharmacopoeia of Japan) Methylparaben (The Pharmacopoeia
of Japan) 0.18 Propylparaben (The Pharmacopoeia of Japan) 0.02
Distilled water for injection use Appropriate (Final volume) 100
(ml)
[0090] The Parabens, sodium metabisulfite and sodium chloride were
dissolved with approximately half of the final volume of distilled
water for injection use at 80.degree. C. while stirring. Then, the
obtained solution was cooled down to 40.degree. C. The compound of
the present invention, and subsequently polyethylene glycol and
polyoxyethylene sorbitan monooleate were added to the solution and
dissolve therewith. Next, the rest portion of the distilled water
was added into the solution so as to adjust the volume to the final
volume mentioned. The solution was then filtered through an
appropriate filter to sterilize to obtain the pharmaceutical
formulation of aqueous solution suitable for parenteral use.
PHARMACEUTICAL FORMULATION EXAMPLE 4
Ointment
[0091]
4 Compositions Amount (g) Compound of the present invention 0.1
White soft paraffin 10
[0092] The compound of the present invention was incorporated into
the base material so as to be homogeneous therein.
PHARMACEUTICAL FORMULATION EXAMPLE 5
Aerosol
[0093]
5 Compositions Amount (g) Compound of the present invention 0.25
Ethanol 29.75 Propelant 22(Chlorodifluoromethane) 70
[0094] The compound of the present invention was incorporated into
ethanol and then added with 1 part of Propelant 22 to obtain a
mixture. The mixture was then cooled down to -30.degree. C. and
then placed in a charging apparatus. Next, an amount of the mixture
required for a administration was transferred into a stainless
container and was diluted with the rest portion of the Propelant 22
to prepare the solution for aerosol. The stainless container was
then mounted with a valve unit to be ready for the
administration.
PHARMACEUTICAL FORMULATION EXAMPLE 6
Dry Powder for Inhalation
[0095]
6 Compositions Amount (g) Compound of the present invention 5
[0096] Lactose
[0097] The compound of the present invention was mixed with lactose
to obtain a homogeneous mixture. The mixture was then charged into
an inhaler for dry powder.
PHARMACEUTICAL FORMULATION EXAMPLE 7
Suppositories
[0098]
7 Compositions Amount (g) Compound of the present invention 0.225
Saturated fatty acid glyceride 2.000
[0099] The compound of the present invention was passed through No.
60 mesh U.S. sieve and then suspended in saturated fatty acid
glyceride having been melted beforehand with minimum heat. The
mixture was charged into a molding for suppositories with the
indication capacity of 2 g and then cooled.
[0100] Although the compounds represented by the general formula
(1) or the pharmaceutically acceptable composites thereof show to
have strong inhibitory activity on the liberation of arachidonic
acid during inflammatory reaction, they have very weak inhibitory
activity on the enzymatic hydrolysis due to secretary type
IB-PLA(2) of porcine pancreas (hereinafter referred to as
IB-sPLA(2); molecular weight 14 kDa) when using a phospholipid, of
which carbon in the oleic acid substituent at the second position
being labeled with a radioactive isotope, as the substrate. From
this reason, an advanced safety can be expected for the compounds
represented by the general formula (1) and the pharmaceutically
acceptable composites thereof.
[0101] Since a part of the compounds of the present invention also
shows hypolipemic activity by the oral administration, the
compounds may be useful as anti-arteriosclerosis drugs.
[0102] Furthermore, a part of the compounds of the present
invention has herbicidal, insecticidal, acaricidal and/or
fungicidal activities as well, and they can be used as pesticides.
In particular, an excellent performance can be expected, as a drug
provided by the compounds which additionally have inhibitory
activity against fungi that causes infectious diseases to mammalian
animals, such as pneumonia by an opportunistically fungus
infection.
[0103] Among the compounds of the present invention, represented by
the general formula (1), the compounds in which R.sub.3 is
C(.dbd.Y)NHR.sub.5 are particularly excellent in the activity as
the aforementioned drugs, and the compounds in which R.sub.5 is
tetrahydrofuranyl or tetrahydropyranyl are specially useful as said
drugs.
[0104] Now, the present invention is further explained in detail
with reference to the examples described below. However, it should
be noted that the following examples are only for the purpose of
illustrating the present invention, and the present invention is
not limited to the following examples.
EXAMPLE 1
Preparation of
trans-5-(4-chlorophenyl)-4-methyl-2-nitroiminooxazolidine
[0105] 21
[0106] 1.8 g of threo-2-amino-1-(4-chlorophenyl)propanol and 1.7 g
of dimethyl N-nitrodithioiminocarbonate were added into 20 ml of
ethanol, and the mixture was refluxed for two hours. After the
completion of the reaction, the reaction solution was condensed
under reduced pressure, and the oily product obtained was purified
by column chromatography to give 1.8 g of the title compound.
EXAMPLE 2
Preparation of
trans-5-(4-chlorophenyl)-4-methyl-3-(2-chloro-5-pyridylmeth-
yl)-2-nitroiminooxazolidine
[0107] 22
[0108] 1.0 g of
trans-5-(4-chlorophenyl)-4-methyl-2-nitroiminooxazolidine obtained
in Example 1 and 0.2 g of 60% sodium hydride were added into 20 ml
of DMF. 0.7 g of 2-chloro-5-chloromethylpyridine was added
gradually to the mixture with stirring on cooling. Then, the
mixture was further stirred for 6 hours at 70.degree. C., followed
by pouring the reaction mixture into ice water. The solution was
extracted with ethyl acetate, and the organic layer was dried and
then condensed under reduced pressure. The oily product obtained
was purified by column chromatography to give 0.5 g of the title
compound.
EXAMPLE 3
Preparation of
trans-2-cyclohexylcarbamoylimino-3-cyclohexylcarbamoyl-4-me-
thyl-5-(4-methylphenyl)thiazolidine
[0109] 23
[0110] 1.0 g of
trans-2-imino-4-methyl-5-(4-methylphenyl)thiazolidine was dissolved
in 20 ml of benzene. To the solution were added 1.3 g of
cyclohexylisocyanate and one drop of triethylamine, respectively.
The mixture was stirred for an hour at room temperature and
refluxed for further an hour. The reaction solution was condensed
under reduced pressure. The oily product obtained was purified by
column chromatography to give 1.1 g of the title compound.
EXAMPLE 4
Preparation of
trans-5-(4-methylphenyl)-4-methyl-2-cyclohexylcarbamoylimin-
othiazolidine
[0111] 24
[0112] 9.3 g of
trans-2-cyclohexylcarbamoyl-4-methyl-5-(4-methylphenyl)thi-
azolidine was added into a mixture of 70 ml of ethanol and 70 ml of
3N hydrochloric acid, and the mixture was refluxed for 2 hours. The
reaction mixture was neutralized with 5% aqueous solution of sodium
hydroxide and extracted with ethyl acetate. The extract was washed
with water, dried, and condensed under reduced pressure to give an
oily product, which was purified by column chromatography to yield
5.4 g of the title compound.
[0113] The representative compounds usable in the present invention
including the compounds prepared in the Examples described above
are presented in Tables 1 and 2. The abbreviations and the
reference symbols in the tables have the following meanings,
respectively.
[0114] Me: methyl, Et: ethyl, Pr: propyl, Bu: butyl, Pn: pentyl,
Hex: hexyl, Hep: heptyl, Allyl: allyl, Ac: acetyl, Ph: phenyl,
Naph: naphthyl, Bn: benzyl, Bz: benzoyl, THF: tetrahydrofuranyl,
Pyr: pyrrolidinyl, Dxln: 1,3-dioxolanyl, Im: imidazolyl, THP:
tetrahydropyranyl, Py: pyridyl, Pip: piperidyl, Dxn: 1,3-dioxanyl,
Morph: morpholinyl, pymd: pyrimidinyl, n: normal, i: iso, s:
secondary, t: tertiary, c; cyclo.
8TABLE 1 25 Physical Com- Constant pound [ ]:Melting No. X R.sub.1
R.sub.2 R.sub.3 G R.sub.1/R.sub.2 Point .degree. C. 1-1 S Me
4-Me-Ph --CONH-cHex H cis [180-182] 1-2 S Me Ph --CONH-cHex H trans
Oily substance*.sup.1 1-3 S Me 4-Me-Ph --CONH-cHex H trans
[116-118.5] 1-4 S Me 4-Cl-Ph --CONH-cHex H trans [111.5- 112.5] 1-5
S Me 4-Cl-Ph 26 CN trans n.sub.D.sup.25 1.5994 1-6 S Me 4-Cl-Ph
--CONH-cHex CN trans 1-7 S Me 4-Cl-Ph --SO.sub.2NHMe CN trans 1-8 S
Me 4-Cl-Ph 27 CN trans 1-9 S Me 4-Cl-Ph --CONH.sub.2THP CN trans
1-10 O Me 4-Cl-Ph H NO.sub.2 trans [123-126] 1-11 S Me 4-Cl-Ph H
NO.sub.2 trans [161-164] 1-12 O Me 4-Cl-Ph 28 NO.sub.2 trans
n.sub.D.sup.25.5.sup. 1.5989 1-13 S Me 4-Cl-Ph --CONH-cHex NO.sub.2
trans 1-14 O Me 4-Cl-Ph --SO.sub.2NMe.sub.2 NO.sub.2 trans
[160-162] 1-15 S Me 4-Cl-Ph --SO.sub.2NHMe NO.sub.2 trans 1-16 S Me
4-Cl-Ph --SO.sub.2NHPh NO.sub.2 trans 1-17 S Me 4-Cl-Ph 29 NO.sub.2
trans 1-18 S Me 4-Cl-Ph --CONH-2-THP NO.sub.2 trans 1-19 O Me
4-Cl-Ph H Me trans [127- 129] 1-20 O Me 4-Cl-Ph --CONH-cHex Me
trans n.sub.D.sup.21 1.5511 1-21 O Me 4-Me-Ph --CONH-cHex Me trans
n.sub.D.sup.22.5 1.5409 1-22 O Me 4-Me-Ph --CONH-2-THP Me trans
n.sub.D.sup.22 .sup. 1.5392 1-23 S Me 4-Me-Ph --CONH-2-THP Me trans
1-24 O Me 4-Me-Ph --CONHPh Me trans [87-95] 1-25 O Me 4-Me-Ph
--CONH-(4-Cl-Ph) Me trans [106- .sup. 109] 1-26 O Me 4-Me-Ph
--CONH-cHex Me trans [120- .sup. 123] 1-27 O Me 4-Me-Ph --CONH-cHex
Et trans n.sub.D.sup.21 .sup. 1.5386 1-28 O Me 4-Cl-Ph --CONH-cHex
i-Pr trans [69-72] 1-29 O Me 4-Me-Ph --CONH-cHex t-Bu trans [98-
.sup. 100] 1-30 O Me 4-Me-Ph --CONH-(4-Cl-Ph) t-Bu trans [132-
.sup. 133] 1-31 S Me 4-Cl-Ph H t-Bu trans [215-218] 1-32 O Me
4-Me-Ph --CONH-cHex t-Bu trans [107- .sup. 110] 1-33 O Me 4-Me-Ph
--CONH-(4-Cl-Ph) t-Bu trans [137- .sup. 140] 1-34 O Me 4-Me-Ph
--CONH-cHex CH.sub.2CHCl trans n.sub.D.sup.25 .sup. 1.5265 1-35 S
Me 4-Me-Ph H CH.sub.2COOEt trans [184] 1-36 S Me 4-Cl-Ph
--CONH-cHex CH.sub.2COOEt trans 1-37 S Me 4-Me-Ph
.quadrature..quadrature. CH.sub.2COOEt trans 1-38 S Me 4-Cl-Ph H
cHex trans [133-135] 1-39 S Me 4-Cl-Ph H OEt trans [83-86] 1-40 S
Me 4-Cl-Ph COMe OEt trans n.sub.D.sup.23.5 .sup. 1.5719 1-41 S Me
4-Cl-Ph COCH.dbd.CH.sub.2 OEt trans n.sub.D.sup.21.5 .sup. 1.5782
1-42 S Me Ph CH.sub.2CH(Ph)OCOMe COMe trans [154-155] 1-43 S Me Ph
--CONH-cHex COMe trans [156-158] 1-44 S Me Ph --CONH-2-THP COMe
trans 1-45 S Me 4-Cl-Ph 30 COMe trans 1-46 S Me Ph --CONH-cHex
COiPr trans 1-47 S Me Ph --CONH-2-THP COiPr trans 1-48 S Me 4-Me-Ph
--CONH-cHex COCH.sub.2Cl trans [128-130] 1-49 S Me 4-Me-Ph
--CONH-cHex COCH.dbd.CH.sub.2 trans [158-159] 1-50 S Me 4-Me-Ph
--CONH-cHex COOMe trans [172-178] 1-51 S Me 4-Me-Ph --CONH-cHex
COOnBu trans [136-137] 1-52 S Me 4-Me-Ph --CONH-cHex COOPh trans
Oily substance 1-53 S Me 4-Cl-Ph H Ph trans [150- .sup. 151.5] 1-54
S Me Ph H Ph trans [136-137] 1-55 S Me Ph H 2,6-diMe- trans
[152-153] Ph 1-56 S Me Ph H 4-Cl-Ph trans [187-188] 1-57 S Me
4-Cl-Ph H 2-Me-Ph trans [119-124] 1-58 S Me 4-Cl-Ph H 4-Cl-Ph trans
[157-159] 1-59 S Me 4-Cl-Ph H 4-Me-Ph trans [163-165] 1-60 S Me
4-Cl-Ph H 4-CF.sub.3O-Ph trans [119-120] 1-61 S Me 4-Cl-Ph --CONHEt
4-CF.sub.3O-Ph trans n.sub.D.sup.25.5 .sup. 1.5586 1-62 S Me
4-Cl-Ph --CONH-(4-Cl- 4-CF.sub.3O-Ph trans [131-132] Ph) 1-63 S Me
4-Cl-Ph --CONH-(4-NO.sub.2-- 4-CF.sub.3O-Ph trans Ph) 1-64 S Me
4-Cl-Ph --CONH-(4-OMe- 4-CF.sub.3O-Ph trans 1-65 S Me 4-Cl-Ph
--CONH-(4-SO.sub.2Me- 4-CF.sub.3O-Ph trans Ph) 1-66 S Me 4-Cl-Ph
--C.dbd.N-(2-Me-4- 2-Me-4-Cl- trans [55-57] Cl-Ph) Ph 1-67 O Me
4-Me-Ph --CONH-cHex 2-Me-4-Cl- trans [160-162] Ph 1-68 O Me 4-Me-Ph
--CONH-cHex 2-Me-4-Cl- trans n.sub.D.sup.26 1.5865 Ph 1-69 O Me
4-Me-Ph --CONH-cHex Ph trans n.sub.D.sup.25 .sup. 1.5765 1-70 O Me
4-Me-Ph --CONH-(4-Cl- 2-Me-4-Cl- trans [199-201] Ph) Ph 1-71 S Me
4-Cl-Ph --CONH-cHex Ph trans [116.5- .sup. 118] 1-72 S Me 4-Cl-Ph H
--CO-2,6- trans [114-116] diF-Ph 1-73 O Me 4-Me-Ph H --CO-(2-Me-
cis [104-106] 6-Cl-Ph 1-74 S Me 4-Cl-Ph --CONH-cHex CO-Ph trans
1-75 S Me 4-Cl-Ph H NHPh trans [145-146] 1-76 S Me 4-Cl-Ph
--CONH-(4-Cl- NHPh trans [57-59] Ph) 1-77 S Me 4-Cl-Ph --CONHEt
NHPh trans [50-52] 1-78 S Me Ph H NHPh trans [159.5]dec 1-79 S Me
Ph --CONH-cHex NHPh trans 1-80 S Me Ph H NHCOPh cis [199-201] 1-81
S Me Ph --CONH-2-THP NHCOPh trans 1-82 S Me Ph --CONH-cHex NHCOPh
trans 1-83 S Me Ph H NHCOPh trans 1-84 S Me 4-Cl-Ph 4-Cl-Ph
--CONH-cHex trans [134- .sup. 136.5] 1-85 S Me 4-Cl-Ph 4-Me-Ph
--CONH-cHex trans [122.5- .sup. 124.5] 1-86 S Me 4-Cl-Ph H
--CONH-cHex trans n.sub.D.sup.26 1.5547 1-87 S Me 4-Cl-Ph 4-Cl-Ph
--CONH(4- trans [115-117] Cl-Ph) 1-88 S Me 4-Cl-Ph OEt --CONHPh
trans n.sub.D.sup.20.5 .sup. 1.6142 1-89 S Me 4-Cl-Ph 2-Me-4-Cl-Ph
--CONH-cHex trans n.sub.D.sup.19 1.5632 1-90 S Me 4-Cl-Ph 4-Me-Ph
--CONH-cHex trans [70-71] 1-91 S Me 4-Cl-Ph 2,4-diCl-Ph --CONH-cHex
trans n.sub.D.sup.25.5 .sup. 1.5586 1-92 S Me 4-Cl-Ph 2-Me-4-Cl-Ph
--CONH-cHex trans [119-120] 1-93 S Me 4-Cl-Ph 2-Me-4-Cl-Ph
--CONH-Et trans [117-119] 1-94 S Me 4-Cl-Ph 2-Me-4-Cl-Ph --CONH-(4-
trans n.sub.D.sup.25 1.5891 Cl-Ph) 1-95 S Me 4-Cl-Ph 2,4-diMe-Ph
--CONH-(4- trans n.sub.D.sup.25.5 Cl-Ph) .sup. 1.5796 1-96 S Me
4-Cl-Ph Ph --CONH-cHex cis n.sub.D.sup.25.5 .sup. 1.5697 1-97 S Me
4-Cl-Ph 2-Me-4-Cl-Ph --CONH-cHex cis [79-81] 1-98 S Me 4-Cl-Ph
4-Cl-Ph --CONH-cHex cis [132-133] 1-99 S Me 4-Cl-Ph 2,4-diCl-Ph
--CONH-cHex cis [80-82] 1-100 S Me 4-Cl-Ph 2,4-diMe-Ph --CONH-cHex
cis [78-80] 1-101 S Me 4-Cl-Ph Me --CONH-cHex cis n.sub.D.sup.27
1.5658 1-102 S Me 4-Cl-Ph NH-Ph --CONH-cHex trans [70-72] 1-103 S
Me Ph --CONH-cHex 4-CF.sub.3O-Ph trans Oily substance 1-104 S Me Ph
31 --CONH-cHex trans 1-105 S Me 4-Me-Ph --CONH-cHex --CONH-cHex
trans Oily substance*.sup.2 1-106 S Me 4-Me-Ph --CONH-2-THP
--CONH-2- trans THP 1-107 S Me 4-Me-Ph --CONH-(2-Me- --CONH-(2-
trans cHex) Me-cHex) 1-108 S Me 4-Me-Ph H --CONH-Ph trans [152.5-
.sup. 154] 1-109 S Me 4-Me-Ph --COCH.sub.2Cl --CONH-cHex trans
[155-157] 1-110 S Me 4-Me-Ph H --CONH-iPr trans [94-95] 1-111 S Me
4-Me-Ph --CONH-cHex --CONH-cHex trans [83-85] 1-112 S Me 4-Me-Ph H
--CSNH-cHex trans [154-155] 1-113 S Me 4-Cl-Ph H CONHCO-- trans
[220-223] 2,6-diCl- Ph 1-114 S Me 4-Me-Ph H CONHCO-- trans
[216-219] 2,6-diCl- Ph 1-115 S Me 4-Cl-Ph H --CONH-iPr trans [185]
1-116 S Me Ph H --CONHCOPh trans [168-169] 1-117 S Me Ph H
--CONHCOPh 1-118 S Me Ph --CONHCOPh --CONHCOPh trans 1-119 S Me 32
--CONH-cHex --CONH-cHex trans 1-120 S Me
2-N.quadrature..quadrature..- quadrature. --CONH-cHex --CONH-cHex
trans 1-121 S Me 4-Me-Ph --CONH-(3-Ac- -Me trans cHex) 1-122 S Me
4-Me-Ph --CONH-(3-OMe- -Ac trans 2-THP) 1-123 O Me 4-Me-Ph
--CONH-(3-OH- -NO.sub.2 Cis cHex) .sup.1H NMR spectrum
.delta.(CDCl.sub.3): *.sup.1: 0.9 .about. 2.1 (m 13H), 3.45 .about.
3.9 (m 1H), 4.0 .about. 4.35 (m 1H), 4.4 (d 8Hz 1H), 7.25 .about.
7.55 (m 5H) *.sup.2: 1.0 .about. 2.1 (m 23H), 2.2 (m 3H), 3.55
.about. 3.9 (m 2H), 4.0 .about. 4.05 (m 1H), 5.0 .about. 5.05 (d
1H), 5.05 .about. 5.2 (m 1H), 7.1 (m 4H), 9.7 .about. 9.8 (d
1H)
[0115]
9TABLE 2 33 Physical Com- Constant pound [ ]:Melting No. X Y Z
R.sub.1 R.sub.2 R.sub.4 R.sub.5 R.sub.1/R.sub.2 Point .degree. C.
2-1 S O O Me 2-NO.sub.2--Ph H cHex trans n.sub.D.sup.26 1.5739 2-2
S O S Me 4-Cl--Ph Me Me trans n.sub.D.sup.30 1.6183 2-3 S O O Me
4-MeS--Ph H cHex trans n.sub.D.sup.20 1.5936 2-4 S O O Me
4-CHF.sub.2O--Ph H cHex trans [76-79] 2-5 S O O Me 4-AcO--Ph H cHex
trans n.sub.D.sup.23.5 1.5638 2-6 S O O Me 4-Me--Ph Et cHex trans
n.sub.D.sup.23.5 1.5572 2-7 S O O Me 4-Me--Ph n-Pr cHex trans
n.sub.D.sup.20.5 1.5551 2-8 S O O Me 4-Cl--Ph H 4-CF.sub.3O-Ph
trans [136-138] 2-9 S O O Me 4-Cl--Ph H 2-F-4-Cl-6-iPrO--Ph trans
[127-130] 2-10 S O O Me 4-Cl--Ph H O-Allyl trans n.sub.D.sup.21
1.5501 2-11 S O O Me 4-Cl--Ph H OEt trans [72-74] 2-12 S O O Me
4-Cl--Ph H 4-(2-Py)-Ph trans [158-160] 2-13 S O O Me 4-Ph--Ph H
2-THP cis [110-112] 2-14 S O O Me 4-Cl--Ph H 2,6-F.sub.2-Bz trans
[37-40] 2-15 S O O Me 4-Cl--Ph H 2-F-cHex trans [97-98] 2-16 S O O
Me 4-Cl--Ph H 2-F-cHex trans [65-66] Diastereomer of No. 15 2-17 S
O O Me 4-Cl--Ph H 3,4-Br.sub.2-cHex trans [66-67] 2-18 S O O Me
4-Cl--Ph H 2,3-Br.sub.2-cHex trans [168-169] 2-19 S O O Me
4-nBu--Ph H 4-Cl--Ph trans [79-80] 2-20 S O O Me 4-nPn--Ph H
4-Cl--Ph trans [101-102] 2-21 S O O Me 4-Cl--Ph H 4-Py trans
[167-169] 2-22 S O O Me 4-Cl--Ph H NMe.sub.2 trans [91-92] 2-23 S O
O Me 4-Cl-Ph H 34 trans n.sub.D.sup.22.5 1.6090 2-24 S O O Me
4-FCH.sub.2CH.sub.2O-- H cHex trans n.sub.D.sup.26.5 1.5445 Ph 2-25
S O O H 3-Me-4- H 4-Morph -- n.sub.D.sup.28 1.5250
FCH.sub.2CH.sub.2O-- Ph 2-26 S O O Me 4-Cl--Ph H 35 trans
n.sub.D.sup.19.5 1.5219 2-27 S O O Me 4-PhC.sub.2H.sub.2-Ph H 2-THP
trans 2-28 S O O Me 4-Cl--Ph Me cHex trans [126-128] 2-29 S O O Et
4-Cl--Ph H cHex trans [78-79] 2-30 S O O nPr 4-Cl--Ph H cHex trans
[109-110] 2-31 S O O Me 4-EtO--Ph H cHex trans n.sub.D.sup.24
1.5527 2-32 S O O Me 4-iPrO--Ph H cHex trans [73-75] 2-33 S O O Me
4-nPr--Ph H cHex trans n.sub.D.sup.27.5 1.5458 2-34 S S O Me
4-Cl--Ph H 36 trans [151-153] 2-35 S O O Me 4-Cl--Ph H 37 trans
[175-177] 2-36 S O O Me 4-Cl--Ph H --SO.sub.2-(2-Cl-Ph) trans
[152-154] 2-37 S S O Me 4-Cl--Ph H --C.sub.2H.sub.4-4-Morp- h trans
[123-126] 2-38 S O O Me 4-Cl--Ph H Bz trans n.sub.D.sup.22.5 1.5973
2-39 S O O Me 4-Cl--Ph H 2,6-Cl.sub.2-Ph trans [106-107] 2-40 S O O
Me 4-Cl--Ph H 2,6-Me.sub.2-Ph trans [117-119] 2-41 S O O Me
4-CF.sub.3--Ph H 2-THP trans 2-42 S O O Me 4-MeO--Ph H 2-THP trans
2-43 S O O Me 4-CF.sub.3O--Ph H 2-THP trans 2-44 S O O Me 4-Cl--Ph
H 2,3-(CF.sub.3O).sub.2-- trans cHex 2-45 S O O Me 4-CF.sub.3--Ph H
3-MeO-cHex trans 2-46 O O O Me 4-Me--Ph H 4-Cl-Ph trans [142-144]
2-47 .quadrature. .quadrature. .quadrature.
.quadrature..quadrature. 4-Me--Ph .quadrature. 2-MeOCO-cHex trans
2-48 O O O Me 4-Me--Ph H C.sub.2H.sub.4Cl trans [78-80] 2-49 O O O
Me 4-Me--Ph H Bn trans [89-91] 2-50 O O O Me 4-Me--Ph H
--C.sub.2H.sub.4-Ph trans n.sub.D.sup.28 1.5604 2-51 O O O Me
4-Me--Ph Me cHex trans [97-99] 2-52 .quadrature. O O Me 4-Me--Ph H
2-MeSO.sub.2-cHex trans 2-53 O O O Me 4-Me--Ph H 2,6-Cl.sub.2-Bz
trans [147-149] 2-54 O O O Me 4-Me--Ph H CH(Me)COOEt trans
n.sub.D.sup.22.5 1.5208 2-55 O O O Me 4-Me--Ph H SO.sub.2NEt.sub.2
trans n.sub.D.sup.16 1.5340 2-56 O O O Me 4-Me--Ph H SO.sub.2Ome
trans n.sub.D.sup.17 1.5292 2-57 O S O Me 4-Me--Ph H COOMe trans
[89-92] 2-58 O O O Me 4-Me--Ph Ac cHex trans [107-110] 2-59 O O O
Me 4-MeS--Ph H cHex trans [87.5-89] 2-60 O O O Me 4-Me--Ph H
SO.sub.2-(2-Me-Ph) trans [121-123] 2-61 O O O Me 3-CF.sub.3--Ph H
2-THP trans n.sub.D.sup.30.5 1.5012 2-62 O O O Me 3-CF.sub.3--Ph H
2-THP trans [104-106] Diastereomer of No. 61 2-63 O O O Me
4-MeSO--Ph H cHex trans [112.5-116] 2-64 O O O Me 4-MeSO.sub.2---Ph
H cHex trans [172-175] 2-65 O O O CH.sub.2 Ph H cHex trans
n.sub.D.sup.22 1.5519 Cl 2-66 O O O Me 4-N(Me).sub.2--Ph H cHex
trans [130-131.5] 2-67 O O O CH.sub.2 Ph H cHex trans
n.sub.D.sup.17.5 1.5624 Br 2-68 O O O Me 1-Naph H .quadrature.Hex
trans [131-133] 2-69 O O O Me 1-Naph H 4-Cl--Ph trans [154-157]
2-70 O O O Me 2-Naph H cHex trans [99-101] 2-71 O O O Me 2-Naph H
4-Cl--Ph trans [180-182] 2-72 O O O Me 4-Me--Ph H 4-Cl--Ph cis
[130-132] 2-73 O O O Me 4-Me--Ph H 2-Cl--Ph cis [165-167] 2-74 O O
O Me 4-Ph--Ph H 2-Cl--Ph cis [123-125] 2-75 O S O Me 4-Ph--Ph H
cHex cis [158-160] 2-76 O O O H Ph H 4-Cl-Ph -- [168-171] 2-77 O O
O H 4-Ph--Ph H 4-Cl-Ph -- [205-208] 2-78 O O O H 4-Ph--Ph H 2-THP
-- [89-92] 2-79 O O O Me 4-Me--Ph H 2,6-F.sub.2-Bz cis [134-136]
2-80 O O O Me 4-Ph--Ph H 2-THP trans [38-40] 2-81 O O O CH.sub.2 Ph
H cHex trans [94-96] F 2-82 O O O CH.sub.2 4-Ph--Ph H 2-THP trans
[54-57] Cl 2-83 O O O CH.sub.2 4-Ph-Ph H cHex trans n.sub.D.sup.23
1.5680 Cl 2-84 O O O Me 4-tBu-Ph H 2-THP cis [148-1501 2-85 O O O
Me 4-PhO-Ph H 2-THP cis [39-40] 2-86 O O O Me 4-(4-Cl-Ph)- H 2-THP
cis [165-167] Ph 2-87 O S O Me 4-Ph-Ph H 2-THP cis [139-141] 2-88 O
O O Me 4-cHex-Ph H 2-THP trans [176-177] 2-89 O O O Me 4-(4-Cl-Ph)-
H 4-Cl-Ph cis [222-223] Ph 2-90 O O O Me 4-(4-Me-Ph)- H 4-Cl-Ph cis
[219-222] Ph 2-91 O O O Me 4-Ph-Ph H 38 cis [167-168] 2-92 O O O Me
4-nBu-Ph H 4-Cl-Ph cis [168-170] 2-93 O O O Me 4-cHex-Ph H 4-Cl-Ph
trans [136-138] 2-94 O O O Me 4-nPn-Ph H 4-Cl-Ph cis [147-149] 2-95
O O O Me 4-(4-Me- H 2-THP cis [150-153] Ph)-Ph 2-96 O O O Me
3-Ph-Ph H 4-Cl-Ph cis [149-151] 2-97 O O O Me 4-Ph-Ph H 4-Py cis
[186] 2-98 O O O Me 4-Ph-Ph H 4-Morph cis [164-165] 2-99 O O O Me
4-Ph-Ph H NMe.sub.2 trans [135-137] 2-100 O O O Me 3-Ph-Ph H 2-THP
cis [55-58] 2-101 O O O Me 4-nBu-Ph H 2-THP cis [77-80] 2-102 O O O
Me 4-(2-Py)-Ph H 4-Cl-Ph cis [214-216] 2-103 O O O Me 4-Me-Ph H
NMe.sub.2 trans [115-116] 2-104 O O O Me 2,6-Cl.sub.2-Ph H 4-Cl-Ph
trans [146-147] 2-105 O O O Me 4-Ph-Ph H 1-Pip cis [150-151] 2-106
O O O Me 4-(4-Cl-Ph)- H 1-Pip trans [180-182] Ph 2-107 O O O Me
4-(4-Cl-Ph)- H 1-Pip cis [196-198] Ph 2-108 O O O Me 4-Me-Ph H
--NH-Ph trans [129-132] 2-109 O O O Me 4-(4-CF.sub.3-- H 2-THP cis
Ph-Ph 2-110 O O O Me 2,6-diF-Ph H 2,4-diCl-Ph cis [135-137] 2-111 O
O O Me 4-Me-Ph H --CH(--COOEt)- cis n.sub.D.sup.19.5 1.5068
C.sub.2H.sub.4COOEt 2-112 O O O Me 4-Me-Ph H
--C.sub.2H.sub.4NEt.sub.2 cis n.sub.D.sup.20.5 1.5209 2-113 O O O
Me 1-Naph H 2-THP cis [74-80] 2-114 O O O Me 4-Ph-Ph Me 2-THP cis
n.sub.D.sup.18 1.5603 2-115 O O O Me 2-Naph H 2-THP cis Oil 2-116 O
O O Me 4-PhO-Ph H --OEt cis [119-120] 2-117 O O O Me
4-B.quadrature.-Ph H 2-THP cis [103-107] 2-118 O O O Me 4-PhO-Ph H
--C.sub.2H.sub.4OC.sub.2H.sub.4OEt cis n.sub.D.sup.20 1.5330 2-119
O O O Me 4-PhS-Ph H 2-THP cis [108-114] 2-120 O O O Me 4-PhO-Ph H
--CH.sub.2-2-THF cis n.sub.D.sup.20 1.5640 2-121 O O O Me 4-Ph-Ph H
Me cis [118-123] 2-122 O O O Me 2-(1-MeO)- H 2-THP cis [158-162]
Naph 2-123 O O O Me 4-PhO-Ph H 2-Dxn cis n.sub.D.sup.19 1.5507
2-124 O O O Me 2-Naph H 2-Dxn cis n.sub.D.sup.20 1.5605 2-125 O O O
Me 39 H 2-THP cis [60-62] 2-126 O O O Me 2-Naph H SO.sub.2N(Et)-iPr
cis n.sub.D.sup.25 1.5544 2-127 O O O Me 40 H 2-THP cis [52-56]
2-128 O O O Me 4-PhO-Ph H 2-THF cis [103-106] 2-129 O O O Me 2-Naph
H 2-THF cis Oily substance 2-130 O O O H 2-Naph H 2-THP --
[117-120] 2-131 O O O H 2-Naph H 2-THP -- Oily substance 2-132 O O
O Me 2-Naph H --C(.dbd.O)nBu cis [84-87] 2-133 O O O Me 2-Naph H
2-(6-MeO-THP) cis n.sub.D.sup.27 1.5655 2-134 O O O Me 2-Naph H
2-DxIn cis [116-124] 2-135 O O O Me 41 H 2-(6-MeO-THP) cis
n.sub.D.sup.31 1.5462 2-136 O O O Me 42 H 2-THP cis Oily substance
2-137 O O O Me 43 H 2-THP trans 2-138 O O O Me 4-Ph-Ph H 3-MeO-cHex
cis 2-139 O O O Me 4-Ph-Ph H 44 cis 2-140 O O O Me 4-Ph-Ph H
4-MeO-Ph cis 2-141 O O O Me 4-Ph-Ph H 4-NO.sub.2-Ph cis 2-142 O O O
Me 4-Ph-Ph H 4-MeSO.sub.2-Ph cis 2-143 O O O Me 45 H 4-CF.sub.3-Ph
trans n.sub.D.sup.18 1.5506 2-144 O O O Me 46 H 4-Cl-Ph trans
[132-133] 2-145 S O O Me 3-Py H cHex trans [88-90] 2-146 O O O Me
2-Py H 4-Cl-Ph cis n.sub.D.sup.28 1.6070 2-147 O O O Me 47 H
4-Cl-Ph [180-200] 2-148 O O O Me 48 H 4-Cl-Ph n.sub.D.sup.22 1.5815
2-149 O O O Me 49 H 4-Cl-Ph trans [110-111] 2-150 O O O Me 50 H
4-Cl-Ph cis [185-187] 2-151 O O O Me 51 H 2-THP cis [166-169] 2-152
O O O Me 3,4-(MeO).sub.2-- H cHex trans [127-128.5] Ph 2-153 O O O
Me 3,4-OCH.sub.2O-- H 2-THP trans [127-129] Ph 2-154 O O O Me
4-Me-Ph H 52 trans [95-96] 2-155 O O O Me Ph H 2-THP trans
n.sub.D.sup.19.3 1.5395 2-156 O O O Me 3,4-diMe-Ph H 2-THP trans
[88-90] 2-157 O O O Me 4-Me-Ph H 53 trans [109-111] 2-158 O O O Me
4-Cl-Ph H 2-THP trans [75-76] 2-159 O O O Me 4-Me-Ph H 4-THP trans
[95-97] 2-160 O O O Me 4-Me-Ph H 2-Dxn trans [85-104] 2-161 O O O
Me 4-Me-Ph H 54 trans [78-80] 2-162 O O O Me 4-Me-Ph H 55 trans
n.sub.D.sup.20.5 1.5603 2-163 O O O Me 4-F-Ph H cHex trans
[122-123] 2-164 O O O Me 3-CF.sub.3-Ph H c.quadrature.Hex trans
[125-127] 2-165 O O O Me 3-Cl-Ph H cHex trans [105-107] 2-166 O O O
Me 2,4-Cl.sub.2-Ph H cHex trans [80-82] 2-167 O O O Me 4-MeO-Ph H
cHex trans [76-78] 2-168 O O O Me 3,4-Me.sub.2-Ph H cHex trans
[66-68] 2-169 O O O Me 4-Br-Ph H cHex trans [126-128] 2-170 O O O
Me 4-Me-Ph H 2-THP trans [94.5-94.6] 2-171 O O O Me 4-tBu-Ph H cHex
trans [105-107] 2-172 O O O Me 3,4-Cl.sub.2-Ph H cHex trans
[160-162] 2-173 O O O Me 4-CF.sub.3-Ph H cHex trans [152-154] 2-174
O O O Me 3,4-OCH.sub.2O-- H cHex trans [74-76] Ph 2-175 O O O Me
4-iPr-Ph H cHex trans [76-78] 2-176 O O O Me 56 H cHex trans
[45-47] 2-177 O O O Me 4-nC.sub.12H.sub.25-- H cHex trans [50-52]
Ph 2-178 O O O Me 3-Cl-Ph H cHex trans [89-90.5] 2-179 O O S Me
4-Me-Ph H 2-THP trans n.sub.D.sup.20.5 1.5800 2-180 O S O Me Ph H
cHex trans [93-95] 2-181 O O S Me 4-Cl-Ph H cHex trans [89-91]
2-182 O S O Me 3,4-diMe- H cHex trans [90-92] Ph 2-183 O O O Me
4-PhO-Ph H 4-Cl-Ph trans [164-165] 2-184 O O O Me 3-Ph-Ph H cHex
trans [112-115] 2-185 O O O Me 4-Ph-Ph H cHex trans [134-136] 2-186
O O O Me 4-Ph-Ph H 4-Cl-Ph trans [137-139] 2-187 O O O Me 4-Ph-Ph H
4-Cl-Ph cis [216-218] 2-188 O O O Me 3-PhO-Ph H cHex trans [98-101]
2-189 S O O Me 4-Me-Ph H 2-THP trans n.sub.D.sup.27 1.5638 2-190 S
O O Me 4-nC.sub.12H.sub.25-- H cHex trans [46-49] Ph 2-191 S S O Me
4-Me-Ph H cHex trans [94.5-97] 2-192 S O O Me 2-Me-Ph H cHex trans
[116-117.5] 2-193 S O O Me 3,4-Cl.sub.2-Ph H cHex trans [136-138]
2-194 S S O Me 4-Cl-Ph H cHex trans [108-110] 2-195 S O O Me
4-MeO-Ph H cHex trans n.sub.D.sup.30.5 1.5590 2-196 S O O Me
2-Cl-Ph H cHex trans [97-99] 2-197 S O O Me 3-Me-Ph H cHex trans
n.sub.D.sup.30 1.5657 2-198 S O O Me 3,5-Me.sub.2-Ph H cHex trans
[99-102.5] 2-199 S O O Me 4-Et-Ph H cHex trans [85.5-88] 2-200 S O
O Me 4-Cl-Ph H 2-THP trans n.sub.D.sup.29 1.5801 2-201 S O O Me
4-Cl-Ph H 2-THP trans n.sub.D.sup.29 1.5760 2-202 S O O Me
4-CH.sub.2Br- H cHex trans [106-108] Ph 2-203 S O O Me 3-Cl-4-Me- H
cHex trans [120-121] Ph 2-204 S O O Me 2,4-Me.sub.2-Ph H cHex trans
[95-97] 2-205 S O O Me 4-iPr-Ph H cHex trans [120-123] 2-206 S O O
Me 4-Me-Ph H 2-Dxn trans n.sub.D.sup.21 1.5679 2-207 S O O Me
4-Me-Ph H 57 trans [67-68] 2-208 S O O Me 2-Thienil H cHex trans
[133-134] 2-209 S O O Me 3,4-(MeO).sub.2-Ph H cHex trans [117-119]
2-210 S O O Me 4-NO.sub.2-Ph H cHex trans [144-147] 2-211 S O O Me
4-Me-Ph H 2-OH-cHex trans 2-212 S O O Me 4-Me-Ph H 3-OH-cHex trans
2-213 S O O Me 4-Me-Ph H 3-oxo-cHex trans 2-214 S O O Me 4-Me-Ph H
4-OH-cHex trans 2-215 S O O Me 4-Me-Ph H 2-oxo-cHex trans 2-216 S O
O Me 4-Me-Ph H 4-oxo-cHex trans 2-217 S O O Me 4-Me-Ph H
3,4-(OH).sub.2-cHex trans 2-218 S O S Me 3-CF.sub.3-Ph H cHex trans
n.sub.D.sup.21.5 1.5775 2-219 S O O Me 4-Ph-Ph H cHex trans
[145-147] 2-220 O O O Me 4-Me-Ph H 4-Morph trans [124-1251 2-221 O
O O Me Ph H 4-Morph trans [110-111] 2-222 O O O Me 4-Me-Ph H 1-Pip
trans [96-98] 2-223 O O O Me 4-Me-Ph H 1-Pyld trans [81-83] 2-224 O
O O Me 4-Me-Ph H 58 trans [98-100] 2-225 O O O Me 4-Me-Ph H
4-(2,6-diMe- trans [64-65] Morph) 2-226 O O O Me 4-CF.sub.3-Ph H
1-Pip trans [131-132] 2-227 O O O Me 3,4-OCH.sub.2O-- H 1-Pip trans
[90-91] Ph 2-228 O O O Me 3,4-Me.sub..quadrature.- H 4-Morph trans
[116-117] Ph 2-229 S O O Me 4-F-Ph H 4-Morph trans [144-146] 2-230
S O O Me 4-Me-Ph H 4-Morph trans [115-116] 2-231 S O O Me Ph H
4-Morph trans [121-122] 2-232 S O O Me 4-Me-Ph H 1-Pip trans
[107-108] 2-233 S O O Me Ph H 1-Pip trans [123-124] 2-234 S O O Me
4-Cl-Ph H 1-(2,6-diMe-Pip) trans n.sub.D.sup.24 1.5420 2-235 S O O
Me 3-CF.sub.3-Ph H 1-Pip trans [117-118] 2-236 S O O Me 4-MeO-Ph H
4-Morph trans [119-120] 2-237 S O S Me 4-Me-Ph H 4-Morph trans
[101-103] 2-238 S O O Me 4-CN-Ph H 2-THP trans 2-239 S O O Me
4-COOMe- H 2-THP trans Ph 2-240 S O O Me 4- H 2-THP trans
COOCF.sub.3-- Ph 2-241 O O O Me 4-CONH.sub.2-- H 2-THP cis Ph 2-242
O O O Me 4- H 5-Ome-2-THP cis CONHMe Ph 2-243 S O O Me 4-Me-Ph H
6-OXO-2-THP trans Physical Com- Constant Optical pound [ ]:Melting
Rotation No. X Y Z R.sub.1 R.sub.2 R.sub.4 R.sub.5 R.sub.1/R.sub.2
Point .degree. C. (CHCl.sub.3) 2-244 O O O Me 4-Me-Ph H 2-THP trans
[88-91] [.alpha.].sub.D.sup.23 +6.2.degree. (4R, 5R) 2-245 O O O Me
4-Me-Ph H 2-THP trans [121-125] [.alpha.].sub.D.sup.23
+19.2.degree. (4R, 5R) Diastereomer 2-246 S O O Me 4-Cl-Ph H 2-THP
trans n.sub.D.sup.31.5 [.alpha.].sub.D.sup.25 +176.degree. (4R, 5R)
1.5789 2-247 S O O Me 4-Cl-Ph H 2-THP trans [120-122]
[.alpha.].sub.D.sup.25 +199.8.degree. (4R, 5R) Diastereomer
[0116] Industrial Use
PHARMACOLOGICAL TEST EXAMPLE 1
[0117] PLA(2) Activity
[0118] The PLA(2) activity was measured by quantitatively analyzing
the fluorescent product of hydrolysis from
1,2-bis-(4,4-difluoro-5,7-dimethyl-
-4-bora-3a,4a-diaza-s-indecene-3-undecanoyl)-sn-glycero-3-phosphocholine
(hereinafter referred to bis-BODIPY.RTM.FL C.sub.11-PC, Molecular
Probes, Inc., B-7701) using activated U937 cells (human monoblastic
lymphoma cell line) by inflammatory stimulus (Meshulam, T. et al.,
The journal of Biological Chemistry 267 (30): 21465-21470 (1992);
and Solito, E. et al., British Journal of Pharmacology 124:
1675-1683 (1998).). The substrate bis-BODIPY.RTM.FL C.sub.11-PC is
incorporated into cellular membranes, the proximity of the BODIPY
FL fluorophores on adjacent phospholipid acyl chains causes
fluorescence self-quenching. Separation of the fluorophores upon
hydrolytic cleavage of one of the acyl chains by PLA(1) or the
PLA(2) results in increased fluorescence. In the activated U937 by
inflammatory stimulus, it is shown that this substrate should be
cleaved enzymatically by IV-cPLA(2) from the feature of its
behaviors including sensitivity profiles against the
inhibitors.
[0119] The human cell line U937 was purchased from Dai-Nippon
Pharmaceuticals Co., Ltd. The cells were maintained by transferring
every 3-4 days into RPMI 1640 medium (Sigma Chemical Co., R6504)
supplemented with heat-inactivated 10% fetal bovine serum (Fetal
Bovine Serum, Sigma Chemical Co., F 4135) in a 5% CO.sub.2
humidified atmosphere at 37.degree. C. The cells were transferred
into the culture medium described above, containing 1.2% (v/v)
dimethylsulfoxide (hereinafter referred to as DMDO, Nacalai tesque
Co., Ltd., D 134-45), and pre-cultured for 96 to 120 hours so as to
differentiate into the macrophage-like cells to be provided for the
assay. The macrophage-like cells were collected and washed by
centrifugation with the Assay medium (Dulbecco's phosphate buffered
saline (hereinafter referred to as PBS)-2.2 mM glucose-2.5 .mu.m
albumin). Then, Phorbol 12-Myristate 13-Acetate (hereinafter
referred to as TPA, Sigma Chemical Co., P 8139) was added to the
Assay medium to be 1.times.10.sup.-8M as the final concentration.
Then, the macrophage-like cells were further cultured for an hour
to be activated (Rzigalinski, B. A. & Rosenthal, M. D.,
Biochimica et Biophysica Acta 1223: 219-225 (1994); and Gonchar, M.
V. et al., Biochemical and Biophysical Research Communication, 249:
829-832 (1998).).
[0120] For preparing substrate liposome suspension,
bis-BODIPY.RTM.FL C.sub.11-PC was combined with phosphatidylcholine
(Sigma Chemical Co., P 7769) at 1:9 molar ratio in chloroform, and
dried under nitrogen flow. The dried mixture was suspended with the
Assay medium at 100 .mu.g/mL, voltexed and sonicated for an hour on
ice under dark condition.
[0121] The test compound was dissolved with DMSO at 30 mM, and the
solution diluted with either DMSO or the Assay medium before
addition into the reaction mixture. The DMSO concentration in the
reaction mixture was controlled so as to be no more than 0.1%. The
30-fold concentration of test compound solution was put into each
well of MICRPTEST.TM. Tissue Culture Plate, 96 Well (Falcon, 3072)
at a rate of 2.5 .mu.L/well. To the respective well was added 25
.mu.L/well of the activated U937 cell suspension (6.times.10.sup.6
cells/mL), and the cells were pre-cultured for 120 min. at
37.degree. C. in a 5% CO.sub.2 atmosphere incubator. 47.5
.mu.L/well of the substrate liposome suspension with
1.5.times.10.sup.-6M A23187 (Sigma Chemical Co., C 7522) was added
into each well to prepare 75 .mu.L/well of the total reaction
mixture, followed by culture for 30 min. under the same conditions
with shielding against light. 100 .mu.L/well of 0.1% GEDTA (Dojindo
Laboratories Co. Ltd., 348-01311) methanol solution was added into
each well and mixed to stop the reaction. The increased
fluorescence of the hydrolysis product by the enzyme was determined
by measuring the fluorescence emission intensity at 535 nm with
excitation at 485 nm from the top side of each plate at 37.degree.
C., using a Multi Functional Microplate Reader SPECTRA FLUOR PLUS
(TECAN Austria GmbH). The measurements for the same test lot were
carried out under the same sensitivity as the optimum gain
condition for the first microplate measurement. In the test, each
treatment was repeated three times, the reaction mixture plot
without cells was used as the blank, and arachidonyl
trifluoromethyl ketone (hereinafter referred to as AACOCF.sub.3,
Calbiochem-Novabiochem Corp., 100109) was used for the positive
control treatment. PLA(2) activity in each test plot was determined
by subtracting the mean value of the fluorescence emission
intensity in the blank plot from that of each well, respectively.
There was statistically no significant difference between the plots
with and without 0.1% DMSO. In the pre-examination, the
fluorescence emission intensity based on the substrate hydrolysis
was increased linearly with time progression until 90 min. Besides,
hydrolysis as the basic metabolic activity, which was measured as
the enzymatic activity in the subcultured cells neither being
differentiated nor activated, without A23187 treatment condition,
was shown about one seventh of that exerted by the activated cells.
Thus, the difference obtained by subtracting the basic metabolic
activity from each enzymatic activity was determined as the
inflammatory activated PLA(2) activity, and the inhibition rate was
calculated by the inflammatory activated PLA(2) activity per the
mean value of that of the control plots with and without DMSO, for
evaluating the activity of the respective test compounds. The
inhibitory activity measured for the respective compounds of the
present invention are shown in Table 3 below, for example.
10 TABLE 3 Compound No. Concentration (.mu.M) Inhibition (%) 1-1
0.1 97 1-5 0.1 66 1-10 0.1 79 1-11 0.1 88 1-12 0.1 52 1-22 0.1 84
1-25 0.1 100 1-28 0.1 93 1-35 0.1 57 1-49 0.1 91 1-42 0.1 94 1-73
0.1 68 1-77 1 100 1-112 1 72 2-21 1 100 2-22 0.1 100 2-26 0.1 77
2-36 0.1 61 2-37 0.1 63 2-38 1 87 2-48 0.1 77 2-54 0.1 95 2-55 0.1
94 2-56 0.1 92 2-60 0.1 100 2-75 0.1 83 2-78 0.01 100 2-79 0.1 55
2-113 1 72 2-115 0.1 63 2-116 0.1 54 2-117 0.1 82 2-125 0.1 62
2-126 0.1 72 2-127 0.01 54 2-128 1 81 2-130 0.1 68 2-133 1 75 2-135
0.01 64 2-145 0.1 72 2-146 0.1 85 2-151 0.01 64 2-155 0.1 95 2-156
0.1 88 2-157 0.1 96 2-159 0.1 95 2-161 1 65 2-170 0.1 82 2-176 0.1
100 2-180 0.1 100 2-182 0.1 91 2-186 0.1 75 2-187 0.1 74 2-189 0.01
86 2-194 1 78 2-201 1 94 2-244 0.1 78 2-245 0.1 93 2-246 0.01 78
AACOCF.sub.3 3 65
PHARMACOLOGICAL TEST EXAMPLE 2
[0122] Mouse Ear Edema Induced by TPA
[0123] This test was carried out referring to the method of
Carlson, R. P. et al. (Agents and Actions, 17(2): 197-204 (1985).)
and the method of Chang, J. (European Journal of Pharmacology, 142:
197-205 (1987).). More specifically, 5 .mu.g/20 .mu.L of TPA (Sigma
Chemical Co.), dissolved with ethanol, was topically applied to the
anterior and posterior surfaces of the right ear of an ICR-strain
male mouse (6-7 weeks old). 6 hours later, the thickness of each
ear at the particular part was respectively measured three times
using a digimatic micrometer to calculate the mean value. Ear edema
was determined by subtracting the mean thickness of the left ear as
without treatment from that of the right ear as TPA-applied.
Topical application activity was evaluated by applying an acetone
solution of the compound of the present invention or 0.1% Tween
80/acetone solution thereof similarly to the anterior and posterior
surfaces of the right ear 30 min. before and 15 min. after the
TPA-application. As the positive control, an acetone solution of
Dexamathasone-21-acetate (hereinafter referred to as DEX-Ac, Sigma
Chemical Co., D 1881) and an acetone solution of indomethacin were
applied similarly as for the compound of the present invention.
Oral administration activity was evaluated by administrating 0.2%
Tween 80 suspension of the compound of the present invention
forcibly and perorally to the mouse an hour prior to the
TPA-application. As the positive control, 100 mg/kg of
Hydrocortisone (Sigma Chemical Co., H 4001) suspension was applied
to the mouse similarly as for the compound of the present
invention. By the treatment with the compounds of the present
invention, anti-inflammatory activities, for example as shown in
Table 4, were measured for the respective compounds. Furthermore,
it was noted that the mice of both DEX-Ac administration group and
indomethacin administration group showed generally bad symptoms and
reducing their body weight after 24 hours. On the contrary, the
mice in the each group applied with the compounds of the present
invention showed good condition and no significant change in their
body weight.
11 TABLE 4 Ear Edema Inhibition Compound No. Dose (mg/.mu.L/ear
.times. 2) (%) 1-12 0.3 mg/20 .mu.L/ear .times. 2 79 1-22 0.3 mg/20
.mu.L/ear .times. 2 56 1-28 1 mg/20 .mu.L/ear .times. 2 36 1-73 1
mg/40 .mu.L/ear .times. 2 86 1-90 1 mg/20 .mu.L/ear .times. 2 41
1-112 1 mg/40 .mu.L/ear .times. 2 69 2-26 0.3 mg/20 .mu.L/ear
.times. 2 86 2-36 0.3 mg/20 .mu.L/ear .times. 2 41 2-54 0.3 mg/20
.mu.L/ear .times. 2 64 2-55 1 mg/40 .mu.L/ear .times. 2 54 2-60 1
mg/40 .mu.L/ear .times. 2 53 2-125 1 mg/40 .mu.L/ear .times. 2 62
2-127 1 mg/40 .mu.L/ear .times. 2 81 2-128 1 mg/40 .mu.L/ear
.times. 2 49 2-135 0.3 mg/20 .mu.L/ear .times. 2 84 2-146 1 mg/40
.mu.L/ear .times. 2 80 2-156 1 mg/20 .mu.L/ear .times. 2 48 2-170
0.3 mg/20 .mu.L/ear .times. 2 57 2-189 0.3 mg/20 .mu.L/ear .times.
2 84 2-244 1 mg/40 .mu.L/ear .times. 2 48 20246 1 mg/40 .mu.L/ear
.times. 2 74 DEX-Ac 1 mg/20 .mu.L/ear .times. 2 80 DEX-Ac 0.3 mg/20
.mu.L/ear .times. 2 49
PHARMACOLOGICAL TEST EXAMPLE 3
[0124] Mouse Delayed Contact Dermatitis Induced by Picryl
Chloride
[0125] This pharmacological test was carried out referring to the
method of Asherson, G. L. & Ptak, W. (Immunology, 15: 405-416
(1968).) and the method of Jun Hiroi (Folia Pharmacology of Japan,
86: 233-239 (1985).). More specifically, hairs on the abdomen of an
ICR-strain male mouse were removed using an electric clip and an
electric shaver. Then, 0.1 mL of 7% ether solution of picryl
chloride (Tokyo Kasei Kogyo Co., Ltd., C 0307) was applied onto the
abdomen for sensitization. On the sixth day after the
sensitization, 20 .mu.L/ear of 1% olive oil solution of picryl
chloride was topically applied to the anterior and posterior
surfaces of both ears of the mouse to induce contact dermatitis
(first induction). Before and 24 hours after the induction, the
thicknesses of the particular parts on the both ears were measured
three times, respectively, using a digimatic micrometer (Mitsutoyo
Co., Ltd.) to work out the average values. Ear edema of the both
ears was respectively determined by subtracting the average
thickness of the each ear before the induction from that on 24
hours after the induction, so that a grouping was carried out to
separate the appropriate individuals. On the fourth day after the
first induction, the hairs on the abdomen were removed again, and
0.1 mL of 7% ethanol solution of picryl chloride was applied
thereto for additional sensitization. The contact dermatitis for
evaluating activity was induced by re-applying 20 .mu.L/ear of 1%
olive oil solution of picryl chloride to the anterior and posterior
surfaces of both ears (second induction) on the seventh day after
the additional sensitization (on the 18th day after the first
sensitization). The activity of each compound of the present
invention was evaluated as the inhibition on the contact dermatitis
as compared with that of the vehicle applied control. That is, the
thicknesses of the particular portions of the both ears were
measured respectively three times with a digimatic micrometer to
work out the mean values before, 24 hours and 48 hours after the
second induction. Ear swelling was determined by subtracting the
ear thickness before the second induction from that on 24 hours and
48 hours after the second induction, respectively. Topical
application activity was evaluated by applying 25 .mu.L of the
acetone solution of the compound of the present invention similarly
to the anterior and posterior surfaces of the right ear one hour
before and 16 hours after the second induction. As the positive
control, 0.02 mg/20 .mu.L of acetone solution of Dexamethasone
(hereinafter referred to as DEX, Wako Pure Chemical Industries
Ltd., 047-18863) was applied similarly as for the compound of the
present invention. With respect to the inhibitory activity in
topical application tests, the topical activity was determined by
the inhibition of the applied right ear edema, and the
translocation and distribution property was determined by the
activity onto the swelling of non-treated left ear. Oral
administration activity was evaluated by administrating 0.5% methyl
cellulose suspension of the compound of the present invention
forcibly and perorally to the mouse an hour before and 16 hours
after the second induction. As the positive control, 20 mg/kg of
Prednisolone (Sigma Chemical Co., P 6004) suspension was
administrated similarly as for the compounds of the present
invention. With respect to the compounds of the present invention,
the anti-allergic activities as shown in Table 4 were measured.
Furthermore, it was noted that the mice of DEX administrated group
showed generally bad symptoms and reducing their body weight
significantly 48 hours after the second induction. On the contrary,
the mice in the each group applied with the compounds of the
present invention showed good condition and no significant change
in their body weight. As the examples, the body weight changes in
the mice for 48 hours after the second induction when they were
administrated with the compounds shown in Table 5 are shown in
Table 6.
12TABLE 5 Dose Ear swelling after 24 hours Compound (mg/25 .mu.L/
Right (Applied) Left (Not applied) No. ear .times. 2) (Mean .+-.
S.E., mm) (Mean .+-. S.E., mm) Vehicle -- 0.288 .+-. 0.012 0.273
.+-. 0.013 Control 1-43 1.5 0.196 .+-. 0.029 0.201 .+-. 0.008 2-194
1.5 0.223 .+-. 0.010 0.226 .+-. 0.016 2-240 1.5 0.246 .+-. 0.009
0.238 .+-. 0.024 DEX 0.02 0.057 .+-. 0.009 -0.005 .+-. 0.033
[0126]
13TABLE 6 Change in body Body weight weight 48 hours before
induction after induction Compound Dose (mg/ (Mean .+-. S.E.) (Mean
.+-. S.E.) No. ear .times. 2) (g) (g) (%) Vehicle -- 34.54 .+-.
0.66 -0.42 .+-. 0.16 -1.21 .+-. 0.46 Control 1-43 1.5 34.74 .+-.
1.19 -0.0 .+-. 0.23 -0.13 .+-. 0.71 2-194 1.5 35.97 .+-. 1.15 0.10
.+-. 0.21 0.26 .+-. 0.58 2-240 1.5 32.48 .+-. 0.75 -0.18 .+-. 0.04
-0.56 .+-. 0.12 DEX 0.02 32.84 .+-. 0.73 -1.42 .+-. 0.20 -4.30 .+-.
0.59
PHARMACOLOGICAL TEST EXAMPLE 4
[0127] Acetic Acid Writhing
[0128] This test was carried out referring to the method of Inoue,
K., Motonaga, A. & Nishimura, T (Arzneimittel Forshung/Drug
Research, 41 (1): 235-239 (1991)). More specifically, 7.5 mL/kg of
0.9% acetic acid solution was injected intraperitoneally into an
ICR-strain male mouse (5 to 7 weeks old), and the induced writhes
(characteristic behaviors of convulsive contracting the abdomen,
twisting the body and/or extending the legs) were observed. Number
of writhes of each mouse was measured during 10 to 20 min. period
after acetic acid administration. The compound of the present
invention was homogeneously suspended in 2% Tween 80/saline for
injection use, and was injected intraperitoneally 30 min. before
the induction by the acetic acid injection. Alternatively, the
compound of the present invention was homogeneously suspended in 2%
Tween 80/distilled water, and was administrated orally two hours
before the induction by the acetic acid injection. The analgesic
activity of the compounds according to the present invention was
evaluated on the basis of the degree of inhibiting the number
writhes by the administration of the compounds. As the positive
control, indomethacin or aspirin was administrated. The analgesic
activity of the compounds according to the present invention
measured in this test were exemplified in Table 7.
14TABLE 7 Application Dose Number of writhes Compound No. route
(mg/kg) (Mean .+-. S.E.) Vehicle Control i.p. -- 25.2 .+-. 2.2 1-12
i.p. 1 10.0 .+-. 1.1 1-22 i.p. 1 12.7 .+-. 4.1 2-26 i.p. 0.3 9.8
.+-. 1.9 2-135 i.p. 1 0.8 .+-. 0.8 2-189 i.p. 1 0.8 .+-. 0.5
Indomethacin i.p. 10 4.8 .+-. 0.9 Indomethacin i.p. 3 13.8 .+-. 3.0
Aspirin i.p. 30 9.5 .+-. 2.0
[0129] In addition, no remarkable intoxicated symptom was observed
on any mouse in the groups, which was injected intravenously in the
tails even 100 mg/kg of the compounds according to the present
invention.
[0130] As it is understood from the results of the foregoing
pharmacological tests, it is apparent that the compounds according
to the present invention have excellent inhibitory activities on
the PLA(2) activity, being less toxic, having strong
anti-inflammatory activities and/or anti-allergic activities. Thus,
the composites containing the compounds according to the present
invention are useful as therapeutic and/or protective drugs of new
type, since sick conditions accompanied the activated PLA(2)
activity are cured to show excellent effects against such
associated diseases, by the administration of the composites.
* * * * *