U.S. patent number RE37,556 [Application Number 09/245,914] was granted by the patent office on 2002-02-19 for superoxide radical inhibitor.
This patent grant is currently assigned to Otsuka Pharmaceutical Co., Ltd.. Invention is credited to Masatoshi Chihiro, Hajime Komatsu, Michiaki Tominaga, Yoichi Yabuuchi.
United States Patent |
RE37,556 |
Chihiro , et al. |
February 19, 2002 |
**Please see images for:
( Certificate of Correction ) ** |
Superoxide radical inhibitor
Abstract
A superoxide radical inhibitor containing, as an effective
ingredient, an azole derivative represented by the general formula
(1), ##STR1## [wherein R.sup.1 represents a phenyl group which may
have 1-3 lower alkoxy groups as substituent(s) on the phenyl ring,
a phenyl group having a lower alkylenedioxy group, or the like;
R.sup.2 represents a hydrogen atom, a phenyl group, a halogen atom,
a lower alkoxycarbonyl group, a lower alkyl group, an amino-lower
alkyl group which may have a lower alkyl group as a substituent, a
dihydrocarbostyril group, or the like; R.sup.3 represents a group
of the formula, ##STR2## (R.sup.4B represents a hydroxyl group, a
carboxy group, a lower alkenyl group or a lower alkyl group, m
represents 0, 1 or 2); X represents a sulfur atom or an oxygen
atom] or a salt thereof.
Inventors: |
Chihiro; Masatoshi (Naruto,
JP), Komatsu; Hajime (Tokyo, JP), Tominaga;
Michiaki (Itano-Gun, JP), Yabuuchi; Yoichi
(Tokushima, JP) |
Assignee: |
Otsuka Pharmaceutical Co., Ltd.
(Tokyo, JP)
|
Family
ID: |
18311399 |
Appl.
No.: |
09/245,914 |
Filed: |
February 8, 1999 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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916082 |
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Reissue of: |
444728 |
May 19, 1995 |
05643932 |
Jul 1, 1997 |
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Foreign Application Priority Data
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Nov 30, 1990 [JP] |
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2-337727 |
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Current U.S.
Class: |
514/365; 544/366;
514/342; 544/165; 544/35; 544/39; 544/52; 546/135; 546/269.7;
548/169; 548/181; 548/203; 548/204 |
Current CPC
Class: |
A61P
1/16 (20180101); A61P 19/02 (20180101); A61P
37/00 (20180101); C07F 9/6539 (20130101); A61P
3/00 (20180101); A61P 43/00 (20180101); A61P
9/10 (20180101); C07D 417/14 (20130101); C07D
413/04 (20130101); C07D 277/68 (20130101); C07H
15/26 (20130101); A61P 25/28 (20180101); C07D
513/04 (20130101); A61P 9/00 (20180101); C07D
417/04 (20130101); A61P 3/10 (20180101); A61P
13/02 (20180101); A61P 29/00 (20180101); A61P
15/00 (20180101); C07D 277/24 (20130101); C07H
13/04 (20130101); A61P 9/08 (20180101); A61P
13/12 (20180101); A61P 1/00 (20180101) |
Current International
Class: |
C07D
277/24 (20060101); C07D 277/00 (20060101); C07D
277/68 (20060101); C07H 15/26 (20060101); C07F
9/6539 (20060101); C07F 9/00 (20060101); C07H
15/00 (20060101); C07D 513/04 (20060101); C07D
417/00 (20060101); C07D 417/04 (20060101); C07D
513/00 (20060101); C07D 417/14 (20060101); C07D
413/04 (20060101); C07D 413/00 (20060101); C07D
413/04 (); A61K 031/425 () |
Field of
Search: |
;548/181,203,204,169
;514/365,342 ;544/35,39,52,165,366 ;546/135,269.7 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
A-204094 |
|
Nov 1983 |
|
DD |
|
1 962493 |
|
Jun 1970 |
|
DE |
|
A-1670383 |
|
Oct 1970 |
|
DE |
|
A-2023425 |
|
Oct 1970 |
|
DE |
|
2221647 |
|
Nov 1972 |
|
DE |
|
2152367 |
|
Apr 1973 |
|
DE |
|
24 53 083 |
|
May 1975 |
|
DE |
|
27 11 655 |
|
Sep 1978 |
|
DE |
|
A-3002595 |
|
Aug 1980 |
|
DE |
|
A-3601411 |
|
Jul 1987 |
|
DE |
|
39 29 233 |
|
Jul 1991 |
|
DE |
|
A-0018080 |
|
Oct 1980 |
|
EP |
|
0 037 274 |
|
Jul 1981 |
|
EP |
|
A-0159677 |
|
Oct 1985 |
|
EP |
|
0 167 973 |
|
Jan 1986 |
|
EP |
|
0 310 386 |
|
May 1989 |
|
EP |
|
A-0423632 |
|
Apr 1991 |
|
EP |
|
8.018 |
|
Jun 1970 |
|
FR |
|
A-2082164 |
|
Dec 1971 |
|
FR |
|
1226548 |
|
Mar 1971 |
|
GB |
|
A-1381860 |
|
Jan 1975 |
|
GB |
|
A-1574583 |
|
Sep 1980 |
|
GB |
|
A-2133007 |
|
Jul 1984 |
|
GB |
|
39-10130 |
|
Jun 1964 |
|
JP |
|
46-15935 |
|
Apr 1971 |
|
JP |
|
46-24696 |
|
Jul 1971 |
|
JP |
|
46-37822 |
|
Nov 1971 |
|
JP |
|
46-39856 |
|
Nov 1971 |
|
JP |
|
46-41542 |
|
Dec 1971 |
|
JP |
|
46-43776 |
|
Dec 1971 |
|
JP |
|
47 784 |
|
Jan 1972 |
|
JP |
|
A-47-1469 |
|
Jan 1972 |
|
JP |
|
47 7368 |
|
Mar 1972 |
|
JP |
|
48-49757 |
|
Jul 1973 |
|
JP |
|
49-38267 |
|
Oct 1974 |
|
JP |
|
49-38268 |
|
Oct 1974 |
|
JP |
|
49-39262 |
|
Oct 1974 |
|
JP |
|
50-3315 |
|
Feb 1975 |
|
JP |
|
50-30619 |
|
Feb 1975 |
|
JP |
|
50-111067 |
|
Sep 1975 |
|
JP |
|
54 14970 |
|
Feb 1979 |
|
JP |
|
A-54-61936 |
|
May 1979 |
|
JP |
|
54 66674 |
|
May 1979 |
|
JP |
|
A-55-11579 |
|
Jan 1980 |
|
JP |
|
55 111418 |
|
Aug 1980 |
|
JP |
|
55 111478 |
|
Aug 1980 |
|
JP |
|
55 133366 |
|
Oct 1980 |
|
JP |
|
55 149263 |
|
Nov 1980 |
|
JP |
|
56-123544 |
|
Sep 1981 |
|
JP |
|
56 154472 |
|
Nov 1981 |
|
JP |
|
58-120257 |
|
Jul 1983 |
|
JP |
|
58-201771 |
|
Nov 1983 |
|
JP |
|
58-219169 |
|
Dec 1983 |
|
JP |
|
59 25380 |
|
Feb 1984 |
|
JP |
|
59 25381 |
|
Feb 1984 |
|
JP |
|
60-51111 |
|
Mar 1985 |
|
JP |
|
60 58981 |
|
Apr 1985 |
|
JP |
|
60 222481 |
|
Nov 1985 |
|
JP |
|
A-60-230147 |
|
Nov 1985 |
|
JP |
|
61-10557 |
|
Jan 1986 |
|
JP |
|
61 33186 |
|
Feb 1986 |
|
JP |
|
61-40276 |
|
Feb 1986 |
|
JP |
|
61-23790 |
|
Jul 1986 |
|
JP |
|
61 167688 |
|
Jul 1986 |
|
JP |
|
61 200985 |
|
Sep 1986 |
|
JP |
|
A-62-22493 |
|
Jan 1987 |
|
JP |
|
63 60978 |
|
Mar 1988 |
|
JP |
|
1-113367 |
|
May 1988 |
|
JP |
|
63 192755 |
|
Aug 1988 |
|
JP |
|
A-2-171280 |
|
Feb 1990 |
|
JP |
|
A 6715532 |
|
May 1968 |
|
NL |
|
A-6905474 |
|
Oct 1969 |
|
NL |
|
WO 87/06429 |
|
Nov 1987 |
|
WO |
|
Other References
Chemical Abstracts, vol. 76, No. 7, Feb. 14, 1972. .
Chemical Abstracts, vol. 69, No. 19, Nov. 4, 1968. .
Chemical Abstracts, vol. 91, No. 17, Oct. 22, 1979. .
Chemical Abstracts, vol. 101. No. 22, Nov. 26, 1984. .
Chemical Abstracts, vol. 101, No. 25, Dec. 17, 1984. .
March, Advanced Organic Chemistry 4th ed. pp. 70-74, 1992.* .
Khadse Indian J. Chem. Sect B 26B 856 (1987). .
Sawheny, Ind. J. Chem. 15B 727 (1977). .
J. Med. Chem., 1988, vol. 31, pp. 1778-1785 (1984). .
Chemical Abstracts, vol. 101, (1), 101: 7145p. .
Chemical Abstracts, vol. 100, (9), 100: 68214m (1984). .
Chemical Abstracts, vol. 106, (15), 106:116059n (1987). .
Chemical Abstracts, vol. 91, (23), 91: 186442c (1987). .
Chemical Abstracts, vol. 90, (13), 90:103886f (1979. .
Chemical Abstracts, vol. 87, (19), 87:152066Zk (1977). .
Chemical Abstracts, vol. 89, (17), 89: 146824f (1978). .
Chemical Abstracts, vol. 96, (9), 96: 68881a (1982). .
Chemical Abstracts, vol. 86, (23), 86:171308m (1977). .
Chemical Abstracts, vol. 86, (17), 86:121232m (1977). .
Chemical Abstracts, vol. 82, (9), 57594u (1975). .
Chemical Abstracts, vol. 87, (7), 87: 53142a (1977). .
Chemical Abstracts, vol. 87, (13), 87: 96735p (1977). .
Chemical Abstracts, vol. 87, (13), 87: 96736q (1977). .
Chemical Abstracts, vol. 85, (25), 85:192613b (1976). .
Chemical Abstracts, vol. 87, (3), 87:16437e (1977). .
Chemical Abstracts, vol. 87, (9), 87:68218d (1977). .
Chemical Abstracts, vol. 85, (21), 85:159962e (1976). .
Chemical Abstracts, vol. 84, (13), 90050c (1976). .
Chemical Abstracts, vol. 69, (11), 43837v (1968). .
Chemical Abstracts, vol. 60, (3), (29219) (1964). .
Chemical Abstracts, vol. 96, (15), 96:122757e (1982). .
Chemical Abstracts, vol. 96, (15), 96:122675b (1982). .
Chemical Abstracts, vol. 92, (13), 92:110908j (1980). .
Chemical Abstracts, vol. 81, (15), 91408a (1974). .
Chemical Abstracts, vol. 85, (25), 85:192614c (1976). .
Chemical Abstracts, vol. 88, (25), 88:190657q (1978). .
Chemical Abstracts, vol. 94, (3), 94: 15628a (1981). .
Chemical Abstracts, vol. 103, (3), 103: 22508u (1985). .
Chemical Abstracts, vol. 104, (9), 104: 68782c (1986). .
Chemical Abstracts, vol. 73, (15), 77117h (1970). .
Chemical Abstracts, vol. 75, (21), 129708q (1971). .
Chemical Abstracts, vol. 89, (17), 89:197388z (1978). .
Chemical Abstracts, vol. 109, (3), 109:22883m (1988). .
Chemical Abstracts, vol. 66, (22), 96203e (1967). .
Chemical Abstracts, vol. 86, (9), 86:55326 (1977). .
Chemical Abstracts, vol. 96, (3), 96:20015u (1982). .
"Synthesis and Cardiotonic Activity of 5-(2-Substituted
Thiazol-4-YL)-2-Pyridones and Thiazolo[4,5-f]Quinolinones", Fukatsu
et al., Heterocycles, vol. 29, No. 8, pp. 1517-1528, 1989. .
"Heterocycles from 2-bromoacetyl heterocycles", Kempter et al.,
Chemical Abstracts, vol. 70, 11630b, 1969..
|
Primary Examiner: Gerstl; Robert
Attorney, Agent or Firm: Finnegan, Henderson, Farabow,
Garrett & Dunner, L.L.P.
Parent Case Text
This application is a continuation of application Ser. No.
07/916,082 .Iadd.filed Jul. 29, 1992.Iaddend., filed as
PCT/JP91/01659, Nov. 29, 1991, now abandoned.
Claims
We claim:
1. A thiazole derivative of the general formula, ##STR982##
wherein:
R.sup.1 represents a phenyl group which may have .[.,substituents
on the phenyl ring, 1-5 groups selected from the group consisting
of an alkoxy group, a tri-lower alkyl group substituted silyloxy
group, a lower alkyl group, a hydroxyl group, a lower alkenyloxy
group, a lower alkylthio group, a phenyl group which may have a
group selected from the group consisting of a thiazole group
having, as a substituent on the thiazolyl ring, a phenyl group
which may have a lower alkoxy group on the phenyl ring, a carboxyl
group and a hydroxyl group, a lower alkylsulfinyl group, a lower
alkylsulfonyl group, a halogen atom, a nitro group, a group of the
formula. ##STR983##
(wherein A represents a lower alkylene group or a group
##STR984##
l represents 0 or 1; and R.sup.8 and R.sup.9, which may be the same
or different, each represent a hydrogen atom, a lower alkyl group,
a lower alkanoyl group, an amino-lower alkyl group which may have a
lower alkyl group as a substituent, or a piperidinyl-lower alkyl
group; further R.sup.8 and R.sup.9 as well as the adjacent nitrogen
atom being bonded thereto, together with or without another
nitrogen atom or oxygen atom may form a five- to six-membered
saturated or unsaturated heterocyclic group; said five- to
six-membered heterocyclic group may have a lower alkanoyl group or
a lower alkyl group as a substituent), a lower alkanoyl group, a
lower alkanoyloxy group, a lower alkoxycarbonyl group, a cyano
group, a tetrahydropyranyloxy group which may have 1-4
substitutents, selected from the group consisting of a hydroxyl
group, a lower alkoxycarbonyl group, a phenyl-lower alkoxy group, a
hydroxyl group or a lower alkanoyloxy group-substituted lower alkyl
group and a lower alkanoyloxy group, and amidino group, a
hydroxysulfonyloxy group, a lower alkoxycarbonyl-substituted lower
alkoxy group, a carboxy-substituted lower alkoxy group, a mercapto
group, a lower alkoxy-substituted lower alkoxy group, a lower alkyl
group having hydroxyl groups, a lower alkenyl group, an
aminothiocarbonyloxy group which may have a lower alkyl group as a
substituent an aminocarbonylthio group which may have a lower alkyl
group as a substituent, a lower alkanoyl-substituted lower alkyl
group, a carboxy group, a group of the formula, ##STR985##
(wherein R.sup.21 and R.sup.22, which may be the same or different
each represent a hydrogen atom or a lower alkyl group), a
phenyl-lower alkoxycarbonyl group, a lower alkynyl group, a lower
alkoxycarbonyl-substituted lower alkyl group, a carboxy-substituted
lower alkyl group, a lower alkoxycarbonyl-substituted alkenyl
group, a carboxy-substituted lower alkenyl group, a lower
alkyl-sulfonyloxy group, which may have a halogen atom, a lower
alkoxy-substituted lower alkoxycarbonyl group, a lower alkenyl
group having halogen atoms and a phenyl-lower alkoxy group; and a
phenyl group having a lower alkylenedioxy group.]. .Iadd.from 1 to
3 lower alkoxy groups as substituents.Iaddend.;
R.sup.2E represents a hydrogen atom; and
R.sup.3E represents a .[.5 to 15 membered monocyclic, bicyclic or
tricyclic heterocyclic residual group having 1 to 2 hetero atoms
selected from the group consisting of a nitrogen atom, an oxygen
atom and a sulfur atom, and said heterocyclic residual group.].
.Iadd.pyridyl group which .Iaddend.may have 1 to 3 substituents
selected from the group consisting of an .[.oxo group, an.]. alkyl
group, a benzoyl group, a lower alkanoyl group, a .[.hydroxy.].
.Iadd.hydroxy .Iaddend.group, a carboxy group, a lower
alkoxycarbonyl group, a lower alkylthio group, a group of the
formula. ##STR986##
(wherein A is lower alkylene group or a group ##STR987##
and; R.sup.23 and R.sup.24, which may be the same or different,
each represent a hydrogen atom or a lower alkyl group; further
R.sup.23 and R.sup.24 as well as the adjacent nitrogen atom being
bonded thereto, together with or without another nitrogen atom or
oxygen atom may form a five- to six-membered saturated heterocyclic
group; and said five- to six-membered heterocyclic group may have a
lower alkyl group as a substituent), a cyano group, a lower alkyl
group having hydroxy groups, a phenylaminothiocarboyl group and an
amino-lower alkoxycarbonyl group which may have a lower alkyl group
as a substituent .Iadd.or a furyl group which has 1 to 3
substituents selected from the group consisting of an alkyl group,
a benzoyl group, a lower alkanoyl group, a hydroxy group, a carboxy
group, a lower alkoxycarbonyl group, a lower alkylthio group, a
group of the formula:.Iaddend..Iadd. ##STR988##
.Iaddend..Iadd.(wherein A is a lower alkylene group or a
group.Iaddend..Iadd. ##STR989##
.Iaddend..Iadd.and R.sup.23 and R.sup.24, which may be the same or
different, each represent a hydrogen atom or a lower alkyl group;
further R.sup.23 and R.sup.24 as well as the adjacent nitrogen atom
being bonded thereto, together with or without another nitrogen
atom or oxygen atom may form a five- to six-membered saturated
heterocyclic group; and said five- to six-membered heterocyclic
group may have a lower alkyl group as a substituent), a cyano
group, a lower alkyl group having hydroxy groups, a
phenylaminothiocarbonyl group and an amino-lower alkoxycarbonyl
group which may have a lower alkyl group as a substituent,
.Iaddend.or a salt thereof.[.;
provided that R.sup.3E is not a unstubstituted pyrazinyl group;
provided further that R.sup.3 is not a
3-hydroxy-2,5-dioxo-3-pyrrolinyl group;
provided further that when R.sup.3E is a julolidine or
tetrahydroquinoline group, which may have a C.sub.1 -C.sub.6 alkyl
group, then R.sub.1 is not a group of the formula: ##STR990##
(wherein R.sup.CC is a hydroxyl group, mono- or di- C.sub.1
-C.sub.6 alkylated amino group; and each of R.sup.AA and R.sup.BB,
which may be the same or different, is a hydrogen atom a C.sub.1
-C.sub.6 alkoxy group which may be substituted by a carboxyl group,
or a C.sub.1 -C.sub.6 alkyl group which may be substituted by a
carboxyl group); and
provided further that R.sup.3E is not a substituted or
unsubstituted cumarinyl group or a substituted or unsubstituted
5,6-benzocumarinyl group.]. .Iadd.; provided that when R.sup.3E is
a pyridyl group which may have 1 to 3 hydroxy groups as
substituents, then the pyridyl group is not substituted at the
2-position with a hydroxy group..Iaddend..[.
2. The thiazole derivative of claim 1, wherein R.sup.1 phenyl group
which may have from 1-3 substituents selected the group consisting
of an alkoxy group and a hydroxyl group, or a salt
thereof..]..[.
3. The thiazole derivative of claim 2, wherein R.sup.1 i phenyl
group which may have from 1-3 lower alkoxy groups as substituents,
or a salt thereof..]..[.
4. The thiazole deriative of claim 3, wherein the heterocyclic
residual group of R.sup.3E is pyrrolidinyl, piperidinyl,
piperazinyl, morpholin, pyridyl, 1,2,5-6-tetrahydropyridyl,
thienyl, quinolyl, 1-4-dihydroquinolyl, benzothiazolyl, pyr,
pyrimidyl, pyridazylthienyl, pyrrolyl, carbostyryl, 3-4-dih
carbostyryl, 1,2,3,4-tetrahydroquinolyl, indolyl, isoindoly,
indolinyl, benzoimidazolyl, benzooxazolyl, imidazolidnyl,
isoquinolyl, quinazolidinyl, quinoxalinyl, cinnolinyl,
phthalazinyl, carbazolyl, acrydinyl, chromanyl, isoindoliny
isochromanyl, pyrazolyl, imidazolyl, pyrazolidinyl, phenothiazinyl,
benzofuryl, 2,3-dihydrobenzo(b) furyl, benzothienyl, phenoxthiinyl,
phenoxazinyl, 4H-chromenyl, 1H-indazolyl, phenazinyl, xanthenyl,
thianthrenyl, isoindolinyl, imidazolinyl, 2-pyrrolinyl, furyl,
oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, pyranyl,
pyrazolidinyl, 2-pyrazoli quinclidinyl, 1-4-benzoxazinyl,
3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl,
1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl,
1,3-dithiadihydronaphthalenyl, phenanthridinyl,
1,4-dithianaphthalenyl, dibenzo(b,e)azepine or
6,11-dihydro-5H-dibenzo(b,e)azepine, or a salt thereof..]..[.
5. The thiazole derivative of claim 4, wherein the heterocyclic
residual group is a pyridyl group, or a salt thereof..]..[.
6. The thiazole derivative according to claim 1, wherein R.sup.1 is
a phenyl group which may have 1 to 3 lower alkoxy groups as
substituents; R.sup.3E is a pyridyl or furyl heterocyclic residual
group which may have 1 to 3 substituents selected from the group
consisting of an oxo group, an alkyl group, a benzoyl group, a
lower alkanoyl group, a hydroxyl group, a carboxy group, a lower
alkoxycarbonyl group, a lower alkylthio group, a group of the
formula: ##STR991##
(wherein A is the same as defined above; R.sup.23 and R.sup.24
which may be the same or different, each represents a hydrogen atom
or a lower alkyl group; further R.sup.23 and R.sup.24, as well as
the adjacent nitrogen atom being bonded thereto, together with or
without another nitrogen atom or oxygen atom may form a five- to
six-membered saturated heterocyclic group which may have a lower
aklyl group as a substituent), a cyano group, a lower alkyl group
having hydroxyl groups, a phenylaminothiocarbonyl group and an
amino-lower alkoxycarbonyl group which may have a lower alkyl group
as a substituent; or a salt thereof..].
7. The thiazole derivative according to claim .[.6.]. .Iadd.1
.Iaddend.wherein R.sup.3E is a pyridyl .[.or furyl heterocyclic
residual.]. group which may have 1 to 3 substituents selected from
the group consisting of a carboxy group, a .[.hydroxyl.].
.Iadd.hydroxy .Iaddend.group, a lower alkoxycarbonyl group and a
lower alkyl group having .[.hydroxyl.]. .Iadd.hydroxy
.Iaddend.groups; or a salt thereof.
8. The thiazole derivative according to claim 7, wherein R.sup.3E
is a pyridyl group which may have 1 to 3 substituents selected from
the group consisiting of a carboxy group, .[.a hydroxyl group,.].
.Iadd.and .Iaddend.a lower alkoxycarbonyl group .[. and a lower
alkyl group having hydroxyl groups.]. ; or a salt thereof.
9.
2-(3,4-Diethoxyphenyl)-4-(2-carboxy-.sigma.-pyridyl)-thiazole.
10. A superoxide radical inhibitor comprising as the active
ingredient a thiazole derivative or a salt thereof of claim 1 and a
pharmaceutically acceptable carrier.
11. A superoxide radical inhibitor comprising as the active
ingredient 2-(3,4-diethoxyphenyl)-4-(2-carboxy-6-pyridyl) thiazole
and a pharmaceutically acceptable carrier..Iadd.
12. The thiazole derivative according to claim 1, wherein R.sup.3E
is a furyl group which has 1 to 3 substituents selected from the
group consisting of a carboxy group, a hydroxy group, a lower
alkoxycarbonyl group and a lower alkyl group having hydroxy groups;
or a salt thereof..Iaddend.
Description
TECHNICAL FIELD
The present invention relates to a superoxide radical inhibitor
containing an azole derivative as the effective ingredient.
1. Background Art
It is thought that neutrophilic leukocytes show a germicidal
activity to foreign invaders in living bodies by a wondering
reaction, a feeding action, generation of superoxide radical
(O.sub.2.sup.-) and release of lysosomal enzyme and play an
important role in protection of living body. While neutrophilic
leukocytes have the above reaction for living body protection, it
has been made clear that the superoxide radical released by tissues
or neutrophilic leukocytes during ischemia of tissues and
subsequent blood re-perfusion or during acute inflammation at early
stage destroys cells, causing functional disturbances of tissues
[B. R. Lucchesi: Annual Review of Pharmacology and Toxicology, Vol.
26, p. 201 (1986); B. A. Freeman et al.: Laboratory Investigation,
Vol. 47, p. 412 (1982); E. Braunwald, R. A. Kloner: Journal of
Clinical Investigation, Vol. 76, p. 1713 (1985); J. L. Romson et
al.: Circulation, Vol. 67, p. 1016 (1983)].
2. Disclosure of the Invention
Based on the thought that the major cause for the above-mentioned
disturbances in cells, in particular the disturbances after
ischemia and re-perfusion in heart, brain, kidney, lung and
digestive tract lies in the superoxide radical released by
neutrophilic leukocytes, the present invention has an object of
providing a new drug for inhibiting the release of the superoxide
radical.
The present inventors made study for the above object and, as a
result, found that certain azole derivatives show a very strong
inhibitory activity for release of superoxide radical in living
bodies. Further study based on the finding has led to the
completion of the present invention.
Therefore, the present invention relates to a superoxide radical
inhibitor containing, as the effective ingredient, at least one of
the azole derivatives represented by the following general formula
(1).
Azole derivatives represented by the general formula (1),
##STR3##
{wherein R.sup.1 and R.sup.3 which may be the same or different,
each represent a phenyl group which may have 1 to 5 substituents on
the phenyl ring, selected from the group consisting of an alkoxy
group, a tri-lower alkyl group-substituted silyloxy group, a lower
alkyl group, a hydroxyl group, a lower alkenyloxy group, a lower
alkylthio group, a phenyl group which may have a group selected
from the group consisting of a thiazolyl group having, as a
substituent on the thiazolyl ring, a phenyl group which may have a
lower alkoxy group on the phenyl ring, a carboxyl group and a
hydroxyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl
group, a halogen atom, a nitro group, a group of the formula,
##STR4##
{wherein A represents a lower alkylene group or a group of the
formula ##STR5##
l represents 0 or 1; R.sup.8 and R.sup.9, which may be the same or
different, each represent a hydrogen atom, a lower alkyl group, a
lower alkanoyl group, an amino-lower alkyl group which may have a
lower alkyl group as a substituent, or a piperidinyl-lower alkyl
group, further R.sup.8 and R.sup.9 as well as the adjacent nitrogen
atom being bonded thereto, together with or without other nitrogen
atom or oxygen atom may form a five- to six-membered saturated or
unsaturated heterocyclic group; said five- to six-membered
heterocyclic group may have a lower alkanoyl group or a lower alkyl
group as a substituent.], a lower alkanoyl group, a lower
alkanoyloxy group, an alkoxycarbonyl group, a cyano group, a
tetrahydropyranyloxy group which may have 1-4 substituents selected
from the group consisting of a hydroxyl group, a lower
alkoxycarbonyl group, a phenyl-lower alkoxy group, a hydroxyl
group- or lower alkanoyloxy group-substituted lower alkyl group and
a lower alkanoyloxy group, an amidino group, a hydroxysulfonyloxy
group, a lower alkoxycarbonyl-substituted lower alkoxy group, a
carboxy-substituted lower alkoxy group, a mercapto group, a lower
alkoxy-substituted lower alkoxy group, a lower alkyl group having
hydroxyl groups, a lower alkenyl group, an aminothiocarbonyloxy
group which may have a lower alkyl group as a substituent, an
aminocarbonylthio group which may have a lower alkyl group as a
substituent, a lower alkanoyl-substituted lower alkyl group, a
carboxy group, a group of the formula, ##STR6##
(R.sup.21 and R.sup.22 which may be the same or different, each
represent a hydrogen atom or a lower alkyl group.), a phenyl-lower
alkoxycarbonyl group, a cycloalkyl group, a lower alkynyl group, a
lower alkoxycarbonyl-substituted lower alkyl group, a
carboxy-substituted lower alkyl group, a lower
alkoxycarbonyl-substituted lower alkenyl group, a
carboxy-substituted lower alkenyl group, a lower alkylsulfonyloxy
group which may have a halogen atom, a lower alkoxy-substituted
lower alkoxycarbonyl group, a lower alkenyl group having halogen
atoms and a phenyl-lower alkoxy group; a phenyl group having a
lower alkylenedioxy group; a 5- to 15-membered monocyclic, bicyclic
or tricyclic heterocyclic residual group having 1 to 2 hetero atoms
selected from the group consisting of a nitrogen atom, an oxygen
atom and a sulfur atom [said heterocyclic residual group may have 1
to 3 substituents selected from the group consisting of an oxo
group, an alkyl group, a benzoyl group, a lower alkanoyl group, a
hydroxyl group, a carboxy group, a lower alkoxycarbonyl group, a
lower alkylthio group, a group of the formula, ##STR7##
(A is the same as defined above, R.sup.23 and R.sup.24, which may
be the same or different, each represent a hydrogen atom or a lower
alkyl group; further, R.sup.23 and R.sup.24 as well as the adjacent
nitrogen atom being bonded thereto, together with or without other
nitrogen atom or oxygen atom may form a five- to six-membered
saturated heterocyclic group; said five- to six-membered
heterocyclic group may have a lower alkyl group as a substituent.),
a cyano group, a lower alkyl group having hydroxyl groups, a
phenylaminothiocarbonyl group and an amino-lower alkoxycarbonyl
group which may have a lower alkyl group as a substituent.]; a
lower alkyl group; a lower alkoxycarbonyl-lower alkyl group; a
lower alkoxycarbonyl group; a carbamoyl-lower alkyl group; a
2,3-dihydroindenyl group which may have an oxo group or/and a
hydroxyl group as substituent(s); a phenyl-lower alkyl group which
may have a lower alkoxy group as a substituent on the phenyl ring
or may have a hydroxyl group as a substituent on the lower alkyl
group; a benzoyl group which may have a lower alkoxy group as a
substituent on the phenyl ring; a phenyl-lower alkenyl group which
may have a lower alkoxy group as a substituent on the phenyl ring;
a piperazinyl-lower alkyl group which may have a lower alkyl group
on the piperazine ring; or an adamantyl group; R.sup.3 may
represent, besides the above, a hydrogen atom; R.sup.2 represents a
hydrogen atom, a phenyl group, a halogen atom, a lower
alkoxycarbonyl group, a lower alkyl group, an amino-lower alkyl
group (which may have a lower alkyl group as a substituent), or a
dihydrocarbostyril group; R.sup.2 and R.sup.3 may bond to each
other to form a group of the formula, ##STR8##
a group of the formula, ##STR9##
or a group of the formula, ##STR10##
X represents a sulfur atom or an oxygen atom.}, and salts
thereof.
The compounds of the present invention have an activity of
inhibiting the release of superoxide radical from neutrophilic
leukocytes or of removing the superoxide radical. Accordingly, they
have an action of preventing or lowering the in vivo production of
peroxidized lipids. Hence, the compounds are useful as an agent for
preventing and treating various disturbances and diseases caused by
excessive generation of superoxide radical, in vivo accumulation of
peroxidized lipids, or defect of protective organizations therefor.
More specifically, the drugs of the present invention are useful in
a pharmaceutical field as a drug for protecting various tissue
cells from disturbances associated with ischemia and blood
re-perfusion, for example, a remedy for ulcers of the digestive
tract (e.g. stress ulcer), a remedy for ischemic heart disease
(e.g. myocardial infarction, arrhythmia), a remedy for
cerebrovascular diseases (e.g. cerebral hemorrhage, cerebral
infarction, temporal cerebral ischemic attack), and a hepatic and
renal function improver for disturbances caused by transplant,
microcirculation failure, etc., or as an agent for inhibiting
various cell function disturbances believed to be caused by the
superoxide radical abnormally generated by factors other than
ischemia, for example, a remedy for Bechcet disease,
dermatovascular inflammation, ulcerative colitis, malignant
rheumatoid, arthritis, arteriosclerosis, diabetes mellitus,
etc.
It is described in Japanese Patent Publication No. 15935/1971 that
the compounds represented by the following general formula,
##STR11##
(wherein R.sup.1 is a group selected from the group consisting of a
hydrogen atom and a straight-chain or branched-chain lower alkyl
group of 1 to 5 carbon atoms; R.sup.2 is a group selected from the
group consisting of a lower alkyl group having 1 to 5 carbon atoms,
a phenylalkyl group which may be substituted with a lower alkyl or
lower alkoxy group having 1 to 5 carbon atoms, or substituted with
one or more halogen atoms, and a phenyl group; and A is a group
selected from the group consisting of a hydrogen atom, a halogen
atom, a hydroxyl group and a lower alkyl or lower alkoxy group
having 1 to 5 carbon atoms.) have properties which are advantageous
for fibrinolysis, platelet stickiness, ulcers and immunological
treatments and can be used for prevention and treatment of
thrombosis, arteriosclerosis, gastric ulcer and hypersecretion.
Among the compounds of the present invention, the thiazole
derivatives represented by the following general formula (A),
##STR12##
[wherein R.sup.A represents a hydrogen atom or a hydroxyl group;
R.sup.1A and R.sup.2A each represent a methoxy group or an ethoxy
group; R.sup.3A represents a hydrogen atom or a lower alkyl group;
R.sup.A is substituted at the 4- or 6-position in the phenyl ring;
R.sup.1A and R.sup.2A should not be a methoxy group simultaneously]
and their salts contain some compounds which are similar to the
compounds of the above prior art in chemical structure; however,
the compounds of the present invention are not disclosed in said
prior art. Further, the compounds of the present invention, as
shown in the pharmacological tests given later in Table 16, exhibit
very strong inhibitory activities for releasing superoxide radical,
even though as compared with the most similar compounds.
Among the compounds of the present invention, preferable are:
thiazole derivatives represented by the general formula (B),
##STR13##
{wherein R.sup.1B represents a phenyl group which may have 1 to 3
lower alkoxy groups as substituent(s) on the phenyl ring; a phenyl
group having a lower alkylenedioxy group; a pyridyl group which may
have an oxo group; a thienyl group; a carbostyril group; a pyrazyl
group; a pyrrolyl group; a quinolyl group which may have an oxo
group; or a 3,4-dihydrocarbostyril group; R.sup.2B represents a
hydrogen atom; R.sup.3B represents a group of the formula,
##STR14##
[R.sup.4B represents an alkoxy group; a tri-lower alkyl
group-substituted silyloxy group; a lower alkyl group; a hydroxyl
group; a lower alkenyloxy group; a lower alkylthio group; a phenyl
group which may have a group selected from the group consisting of
a thiazolyl group having, as a substituent on the thiazolyl ring, a
phenyl group which may have a lower alkoxy group on the phenyl
ring, a carboxyl group and a hydroxyl group; a lower alkylsulfinyl
group; a lower alkylsulfonyl group; a halogen atom; a nitro group;
a group of the formula, ##STR15##
(wherein A represents a lower alkylene group or a group
##STR16##
l represents 0 or 1; R.sup.8 and R.sup.9, are each the same or
different, and are each a hydrogen atom, a lower alkyl group, a
lower alkanoyl group, an amino-lower alkyl group which may have a
lower alkyl group as a substituent, or a piperidinyl-lower alkyl
group; further R.sup.8 and R.sup.9 well as the adjacent nitrogen
atom being bonded thereto, together with or without other nitrogen
atom or oxygen atom may form a five- to six-membered saturated or
unsaturated heterocyclic group; said five- to six-membered
heterocyclic group may have a lower akanoyl group or a lower alkyl
group as a substituent.); a lower alkanoyl group; a lower
alkanoyloxy group; an alkoxycarbonyl group; a cyano group; a
tetrahydropyranyloxy group which may have 1-4 substituents selected
from the group consisting of a hydroxyl group, a lower
alkoxycarbonyl group, a phenyl-lower alkoxy group, a lower
alkanoyloxy group-substituted lower alkyl group and a lower
alkanoyloxy group; an amidino group; a hydroxysulfonyloxy group; a
lower alkoxycarbonyl-substituted lower alkoxy group; a
carboxy-substituted lower alkoxy group; a mercapto group; a lower
alkoxy-substituted lower alkoxy group; a lower alkyl group having
hydroxyl groups; a lower alkenyl group; an aminothiocarbonyloxy
group which may have a lower alkyl group as a substituent; an
aminocarbonylthio group which may have a lower alkyl group as a
substituent; a lower alkanoyl-substituted lower alkyl group; a
carboxy group; a group of the formula, ##STR17##
(R.sup.21 and R.sup.22 which may be the same or different, each
represent a hydrogen atom or a lower alkyl group.); a phenyl-lower
alkoxycarbonyl group; a cycloalkyl group; a lower alkynyl group; a
lower alkoxycarbonyl-substituted lower alkyl group; a
carboxy-substituted lower alkyl group; a lower
alkoxycarbonyl-substituted lower alkenyl group; a
carboxy-substituted lower alkenyl group; a lower alkylsulfonyloxy
group which may have a halogen atom; a lower alkoxy-substituted
alkoxycarbonyl group; a lower alkenyl group having halogen atoms;
or a phenyl-lower alkoxy group. m represents 0, 1 or 2.]; or, a
phenyl group having 1-3 substituents, on the phenyl ring, selected
from the group consisting of a lower alkanoyloxy group, a
hydroxysulfonyloxy group, a cyano group, an amidino group, a nitro
group, a lower alkylthio group, a lower alkylsulfonyl group, a
tetrahydropyranyloxy group which may have 1 to 4 substituents
selected from the group consisting of a hydroxyl group, a lower
alkoxycarbonyl group, a phenyl-lower alkoxy group, a hydroxyl
group- or lower alkanoyloxy group-substituted lower alkyl group and
a lower alkanoyloxy group, a phenyl group which may have a group
selected from the group consisting of a thiazolyl group which may
have, as a substituent on the thiazolyl ring, a phenyl group which
may have a lower alkoxy group on the phenyl ring, a carboxyl group
and a hydroxyl group, a lower alkyl group having hydroxyl groups,
and a group of the formula, ##STR18##
(R.sup.21 and R.sup.22 are the same as defined above); a phenyl
group having a lower alkylenedioxy group; a lower alkyl group; a
lower alkoxycarbonyl-lower alkyl group; a lower alkoxycarbonyl
group; a carbamoyl-lower alkyl group; a 2,3-dihydroindenyl group
which may have an oxo group or/and a hydroxyl group as
substituent(s); a phenyl-lower alkyl group which may have a lower
alkoxy group as a substituent on the phenyl ring or may have a
hydroxyl ring as a substituent on the lower alkyl group; a benzoyl
group which may have a lower alkoxy group as a substituent on the
phenyl ring; a phenyl-lower alkenyl group which may have a lower
alkoxy group as a substituent on the phenyl ring; a
piperazinyl-lower alkyl group which may have a lower alkyl group as
a substituent on the piperazinyl ring; or an adamantyl group. When
R.sup.4B represents a lower alkoxycarbonyl group-substituted lower
alkyl group or a carboxy-substituted lower alkyl group, then, m
represents 2}, and their salts;
thiazole derivatives represented by the general formula (C),
##STR19##
[wherein R.sup.1C represents a phenyl group which may have 1 to 3
lower alkoxy groups as substituent(s) on the phenyl ring; R.sup.2C
represents a hydrogen atom; R.sup.3C represents a group of the
formula, ##STR20##
(wherein R.sup.4C represents a hydrogen atom, a lower alkyl group,
a phenyl-lower alkyl group or a lower alkoxy-substituted lower
alkyl group; R.sup.5C represents an amino group, a lower alkoxy
group-substituted lower alkyl group, a lower alkyl group, a nitro
group, a lower alkenyl group, a lower alkanoyl group, a lower
alkenyl group having halogen atoms, a phenyl-lower alkoxy group, a
halogen atom or a hydroxyl group-substituted lower alkyl group; n
represents 2)], and their salts;
thiazole derivatives represented by the general formula (D),
##STR21##
[wherein R.sup.1D represents a phenyl group which may have 1 to 3
lower alkoxy groups as substituent(s) on the phenyl ring; R.sup.2D
represents a hydrogen atom; R.sup.3D represents a group of the
formula, ##STR22##
(wherein R.sup.4D represents a hydrogen atom or a lower alkyl
group; R.sup.5D represents an amino group, a lower
alkoxycarbonyl-lower alkoxy group, a nitro group, a lower
alkenyloxy group, a lower alkoxy-substituted lower alkoxy group, a
mercapto group, a lower alkanoyloxy group, an aminocarbonylthio
group which may have a lower alkyl group as a substituent, an
aminothiocarbonyloxy group which may have a lower alkyl group as a
substituent, a carboxy-substituted lower alkoxy group or a lower
alkylsulfoniumoxy group which may have a halogen atom)], and their
salts;
thiazole derivatives represented by the general formula,
##STR23##
{wherein R.sup.1 is the same as defined above; R.sup.2E represents
a hydrogen atom; R.sup.3E represents a 5- to 15-membered
monocyclic, bicyclic or tricyclic heterocyclic residual group
having 1 to 2 hetero atoms selected from the group consisting of a
nitrogen atom, an oxygen atom and a sulfur atom [said heterocyclic
residual group may have 1 to 3 substituents selected from the group
consisting of an oxo group, an alkyl group, a benzoyl group, a
lower alkanoyl group, a hydroxyl group, a carboxy group, a lower
alkoxycarbonyl group, a lower alkylthio group, a group of the
formula, ##STR24##
(A and l are the same as defined above; R.sup.23 and R.sup.24, are
each the same or different, and are each represents a hydrogen atom
or a lower alkyl group; further R.sup.23 and R.sup.24 as well as
the adjacent nitrogen atom being bonded thereto, together with or
without other nitrogen atom or oxygen atom may form a five- to
six-membered saturated heterocyclic group; said five- to
six-membered heterocyclic group may have a lower alkyl group as a
substituent), a cyano group, lower alkyl group having hydroxy
groups, a phenylamino- thiocarbonyl group and an amino-lower
alkoxycarbonyl group which may have a lower alkyl group as a
substituent]}, and their salts; and
thiazole derivatives represented by the general formula (F),
##STR25##
[wherein R.sup.1 is the same as defined above; R.sup.2F represents
a hydrogen atom, R.sup.3F represents a group of the formula,
##STR26##
(wherein A, l and m are the same as defined above; R.sup.8F and
R.sup.9F which may be the same or different, each represent a lower
alkanoyl group, an amino-lower alkyl group which may have a lower
alkyl group as a substituent, or a piperidinyl-lower alkyl group;
further R.sup.8F and R.sup.9F as well as the adjacent nitrogen atom
being bonded thereto, together with or without other nitrogen atom
or oxygen atom may form a five- to six-membered saturated or
unsaturated heterocyclic group; said five- to six-membered
heterocyclic group may have a lower alkanoyl group or a lower alkyl
group as a substituent); R.sup.4F is the same as the
above-mentioned R.sup.4B other than a hydroxyl group)], or their
salts.
BEST MODE FOR CARRYING OUT THE INVENTION
Each group shown in the present specification is specifically as
follows.
The alkoxy group can be exemplified by straight-chain or
branched-chain alkoxy groups having 1 to 18 carbon atoms such as
methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy,
pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy,
undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy,
hexadecyloxy, heptadecyloxy, octadecyloxy and the like.
The lower alkyl group can be exemplified by straight-chain or
branched-chain alkyl groups having 1 to 6 carbon atoms such as
methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl
and the like.
The lower alkylthio group can be exemplified by straight-chain or
branched-chain alkylthio groups having 1 to 6 carbon atoms such as
methylthio, ethylthio, propylthio, isopropylthio, butylthio,
tert-butylthio, pentylthio, hexylthio and the like.
The lower alkylsulfonyl group can be exemplified by straight-chain
or branched-chain alkylsulfonyl groups having 1 to 6 carbon atoms
such as methylsulfonyl, ethylsulfonyl, isopropylsulfonyl,
butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl
and the like.
As the halogen atom, there can be mentioned, for example, a
fluorine atom, a chlorine atom, a bromine atom and an iodine
atom.
As the lower alkanoyl group, there can be mentioned straight-chain
or branched-chain alkanoyl groups having 1 to 6 carbon atoms such
as formyl, acetyl, propionyl, butyryl, isobutyryl, pentamoyl,
tert-butylcarbonyl, hexanoyl and the like.
The lower alkoxycarbonyl group can be exemplified by straight-chain
or branched-chain alkoxycarbonyl groups having 1 to 6 carbon atoms
such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,
pentyloxycarbonyl, hexyloxycarbonyl and the like.
As to the lower alkylenedioxy group, there can be mentioned
straight-chain or branched-chain alkylenedioxy groups having 1 to 3
carbon atoms such as methylenedioxy, ethylenedioxy,
trimethylenedioxy, tetramethylenedioxy and the like.
As to the alkyl group, there can be mentioned, in addition to the
lower alkyl groups mentioned above, straight-chain or
branched-chain alkyl groups having 1 to 18 carbon atoms such as
heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl,
tetradecyl, pentadecyl, hexadecyl, octadecyl and the like.
As to the lower alkoxycarbonyl-lower alkyl group, there can be
mentioned straight-chain or branched-chain alkoxy-carbonylalkyl
groups having 1 to 6 carbon atoms whose alkyl moieties are each a
straight-chain or branched-chain alkyl group having 1 to 6 carbon
atoms, such as methoxycarbonylmethyl, 3-methoxycarbonyl-propyl,
ethoxycarbonylmethyl, 4-ethoxycarbonylbutyl,
6-propoxycarbonylhexyl, 5-isopropoxycarbonylpentyl,
1,1-dimethyl-2-butoxycarbonylethyl,
2-methyl-3-tert-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl,
hexyloxycarbonylmethyl and the like.
As to the carbamoyl-lower alkyl group, there can be mentioned
carbamoylalkyl groups whose alkyl moieties are each a
straight-chain or branched-chain alkyl group having 1 to 6 carbon
atoms, such as carbamoylmethyl, 2-carbamoylethyl, 1-carbamoylethyl,
3-carbamoylpropyl, carbamoylpropyl, 4-carbamoylbutyl,
5-carbamoylpentyl, 6-carbamoylhexyl, 1,1-dimethyl-2-carbamoylethyl,
2-methyl-3-carbamoylpropyl and the like.
The 2,3-dihydroindenyl group which may have an oxo group or/and a
hydroxyl group as substituent(s), can be exemplified by
2,3-dihydroindenyl groups which may each have an oxo group or/and a
hydroxyl group as substituent(s), such as
1-oxo-7-hydroxy-2,3-dihydroindenyl,
1-oxo-6-hydroxy-2,3-dihydroindenyl,
1-oxo-5-hydroxy-2,3-dihydroindenyl,
1-oxo-4-hydroxy-2,3-dihydroindenyl, 1-oxo-2,3-dihydroindenyl,
2-oxo-2,3-dihydroindenyl, 2-oxo-7-hydroxy-2,3-dihydroindenyl and
the like.
The phenyl group which may have, on the phenyl ring, 1 to 5
substituent(s) selected from the group consisting of an alkoxy
group, a tri-lower alkyl group-substituted silyloxy group, a lower
alkyl group, a hydroxyl group, a lower alkenyloxy group, a lower
alkylthio group, a phenyl group, a lower alkylsulfonyl group, a
lower alkylsulfinyl group, a halogen atom, a nitro group, a group
of the formula, ##STR27##
(wherein A, l, R.sup.8 and R.sup.9 are the same as defined above),
a lower alkanoyl group, a lower alkanoyloxy group, a lower
alkoxycarbonyl group, a cyano group, a tetrahydropyranyloxy group
which may have 1 to 4 substituents selected from the group
consisting of a hydroxyl group, a lower alkoxycarbonyl group, a
phenyl-lower alkoxy group, a lower alkanoyloxy group-substituted
lower alkyl group and a lower alkanoyloxy group, an amidino group,
a hydroxysulfonyloxy group, a lower alkoxycarbonyl-substituted
lower alkoxy group, a carboxy-substituted lower alkoxy group, a
mercapto group, a lower alkoxy-substituted lower alkoxy group, a
lower alkyl group having hydroxyl groups, a lower alkenyl group, an
aminothiocarbonyloxy group which may have a lower alkyl group as a
substituent, an aminocarbonylthio group which may have a lower
alkyl group as a substituent, a lower alkanoyl-substituted lower
alkyl group, a carboxy group, a group of the formula, ##STR28##
(R.sup.21 and R.sup.22, are each the same or different, and are
each represents a hydrogen atom or a lower alkyl group), a
phenyl-lower alkoxycarbonyl group, a cycloalkyl group, a lower
alkynyl group, a lower alkoxycarbonyl-substituted lower alkyl
group, a carboxy-substituted lower alkyl group, a lower
alkoxycarbonyl-substituted lower alkenyl group, a
carboxy-substituted lower alkenyl group, a halogen-substituted or
unsubstituted lower alkylsulfonyloxy group which may have a halogen
atom, a lower alkoxy-substituted lower alkoxycarbonyl group, a
lower alkenyl group having halogen atoms and a phenyl-lower alkoxy
group, or the phenyl group having a lower alkylenedioxy group can
be exemplified by, for example, phenyl groups which may each have,
on the phenyl ring, 1 to 5 substituents selected from the group
consisting of a C.sub.1-18 straight-chain or branched-chain alkoxy
group, a silyloxy group substituted with three straight-chain or
branched-chain alkyl groups having 1 to 6 carbon atoms, a C.sub.1-6
straight-chain or branched-chain alkyl group, a hydroxyl group, a
C.sub.2-6 straight-chain or branched-chain alkenyloxy group, a
C.sub.1-6 straight-chain or branched-chain alkylthio group, a
phenyl group, a C.sub.1-6 straight-chain or branched-chain
alkylsulfonyl group, a C.sub.1-6 straight-chain or branched-chain
alkylsulfinyl group, a halogen atom, a nitro group, a group of the
formula, ##STR29##
[wherein A represents a C.sub.1-6 straight-chain or branched-chain
alkylene group or a group of the formula ##STR30##
l represents 0 or 1; R.sup.8 and R.sup.9, are each the same or
different, and are each represents a hydrogen atom, a C.sub.1-6
straight-chain or branched-chain alkyl group, a C.sub.1-6
straight-chain or branched-chain alkanoyl group or a C.sub.1-6
straight-chain or branched-chain alkyl group having an amino group
which may have, as substituent(s), one to two C.sub.1-6
straight-chain or branched-chain alkyl groups, further R.sup.8 and
R.sup.9 as well as the adjacent nitrogen atom being bonded thereto,
together with or without other nitrogen atom or oxygen atom may
form a five- to six-membered saturated or unsaturated heterocyclic
ring. The heterocyclic ring may have a C.sub.1-6 straight-chain or
branched-chain alkanoyl group or a C.sub.1-6 straight-chain or
branched-chain alkyl group as a substituent]; a C.sub.1-6
straight-chain or branched-chain alkanoyl group, a C.sub.1-6
straight-chain or branched-chain alkoxycarbonyl group, a cyano
group, a tetrahydropyranyloxy group which may have, as
substituent(s), 1 to 4 groups selected from the group consisting of
a hydroxyl group, a C.sub.1-6 straight-chain or branched-chain
alkoxycarbonyl group, a phenylalkoxy group whose alkoxy moiety is a
C.sub.1-6 straight-chain or branched-chain phenylalkoxy group, a
C.sub.1-6 straight-chain or branched-chain alkyl group having one
to three hydroxy groups or C.sub.2-6 straight-chain or
branched-chain alkanoyloxy groups, and a C.sub.2-6 straight-chain
or branched-chain alkanoyloxy group, an amidino group, a
hydroxysulfonyloxy group, a C.sub.1-6 straight-chain or
branched-chain alkoxycarbonylalkoxy group whose alkoxy moiety is a
C.sub.1-6 straight-chain or branched-chain alkoxy group, a
carboxyalkoxy group whose alkoxy moiety is a C.sub.1-6
straight-chain or branched-chain alkoxy group, a mercapto group, a
alkoxyalkoxy group whose alkoxy moiety is a C.sub.1-6
straight-chain or branched-chain alkoxy group, a C.sub.1-6
straight-chain or branched-chain alkyl group having 1 to 3 hydroxyl
groups, a C.sub.2-6 straight-chain or branched-alkenyl group, a
thiocarbonyloxy group having an amino group which may have one to
two C.sub.1-6 straight-chain or branched-chain alkyl groups as
substituent(s), a carbonylthio group having an amino group which
may have one to two C.sub.1-6 straight-chain or branched-chain
alkyl groups as substituent(s), a C.sub.1-6 straight-chain or
branched-chain alkyl group having one to three C.sub.1-6
straight-chain or branched-chain alkanoyl group, a carboxy group, a
group of the formula, ##STR31##
(R.sup.21 and R.sup.22, are each the same or different, and are
each represents a hydrogen atom or a C.sub.1-6 straight-chain or
branched-chain alkyl group), a phenylalkoxy group whose alkoxy
moiety is a C.sub.1-6 straight-chain or branched-chain alkoxy
group, a C.sub.2-6 straight-chain or branched-chain alkynyl group,
an alkoxycarbonylalkyl group having a C.sub.1-6 straight-chain or
branched-chain alkoxy moiety and a C.sub.1-6 straight-chain or
branched-chain alkyl moiety, a carboxyalkyl group whose alkyl
moiety is a C.sub.1-6 straight-chain or branched-chain alkyl group,
an alkoxycarbonyl-alkenyl group having a C.sub.1-6 straight-chain
or branched-chain alkoxy moiety and a C.sub.2-6 straight-chain or
branched-chain alkenyl moiety, a carboxyalkenyl group whose alkenyl
moiety is a C.sub.2-6 straight-chain or branched-chain alkenyl
group, a C.sub.1-6 straight-chain or branched-chain
alkylsulfonyloxy group which may have 1 to 3 halogen atoms, an
alkoxyalkoxycarbonyl group whose alkoxy moiety is a C.sub.1-6
straight-chain or branched-chain alkoxy group, a C.sub.2-6
straight-chain or branched-chain alkenyl group having 1 to 3
halogen atoms, and a phenylalkoxy group having a C.sub.1-6
straight-chain or branched-chain alkoxy moiety, or phenyl groups
each having a C.sub.1-4 straight-chain or branched-chain
alkylenedioxy group, such as phenyl, 2-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl,
4-ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl,
4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl,
3-ethoxy-4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-diethoxyphenyl,
3,5-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl,
3,4,5-trimethoxyphenyl, 3,4-dipentyloxyphenyl, 2-methylphenyl,
3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl,
4-ethylphenyl, 3-butylphenyl, 4-isopropylphenyl, 4-pentylphenyl,
4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl,
2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl,
2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,
3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 2,5-dihydroxyphenyl,
2,4-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4,5-trihydroxyphenyl,
2-methylthiophenyl, 3-methylthiophenyl, 4-methylthiophenyl,
2-ethylthiophenyl, 3-ethylthiophenyl, 4-ethylthiophenyl,
4-isopropylthiophenyl, 4-pentylthiophenyl, 4-hexylthiophenyl,
3,4-dimethylthiophenyl, 3,4-diethylthiophenyl,
2,5-dimethylthiophenyl, 2,6-dimethylthiophenyl,
3,4,5-trimethylthiophenyl, 2-phenylphenyl, 3-phenylphenyl,
4-phenylphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl,
4-methylsulfonylphenyl, 2-ethylsulfonylphenyl,
4-isopropylsulfonylphenyl, 4-pentylsulfonylphenyl,
4-hexylsulfonylphenyl, 3,4-dimethylsulfonylphenyl,
3,4-diethylsulfonylphenyl, 2,5-dimethylsulfonylphenyl,
2,6-dimethylsulfonylphenyl, 3,4,5-trimethylsulfonylphenyl,
2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl,
3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl,
4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl,
3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl,
2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl,
3,5-dibromophenyl, 3,4,5-trichlorophenyl,
2,3,4,5,6-pentafluorophenyl, 2-nitrophenyl, 3-nitrophenyl,
4-nitrophenyl, 3,4-dinitrophenyl, 2,5-dinitrophenyl,
2,6-dinitrophenyl, 3,4,5-trinitrophenyl, 2-aminophenyl,
3-aminophenyl, 4-aminophenyl, 2-methylaminophenyl,
3-ethylaminophenyl, 4-propylaminophenyl, 2-isopropylaminophenyl,
3-butylaminophenyl, 4-pentylamino-phenyl, 2-hexylaminophenyl,
4-dimethylaminophenyl, 3-(N-methyl-N-ethylamino)phenyl,
3-dihexylaminophenyl, 2-(N-methyl-N-acetylamino)phenyl,
4-(N-acetylamino)phenyl, 3-(N-acetylamino)phenyl,
4-(N-formylamino)phenyl, 4-(N-isobutyrylamino)phenyl,
2-(N-pentanoylamino)phenyl, 3,4-di(N-acetylamino)phenyl,
3,4-diaminophenyl, 3,4,5-triaminophenyl, 2,6-diaminophenyl,
2,5-diaminophenyl, 2-carbamoylphenyl, 3-carbamoylphenyl,
4-carbamoylphenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl,
2-formylphenyl, 3-propionylphenyl, 4-isobutyrylphenyl,
2-pentanoylphenyl, 3-hexanoylphenyl, 3,4-diacetylphenyl,
2,5-diacetylpheni, 3,4,5-triacetylphenyl, 2-methoxycarbonylphenyl,
2-ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl,
4-ethoxycarbonylphenyl, 3-propoxycarbonylphenyl,
4-butoxycarbonylphenyl, 4-pentyloxycarbonylphenyl,
4-hexyloxycarbonylphenyl, 3,4-diethoxycarbonylphenyl,
2,5-diethoxycarbonylphenyl, 2,6-diethoxycarbonylphenyl,
3,4,5-triethoxycarbonylphenyl, 2-carboxyphenyl, 3-carboxyphenyl,
4-carboxyphenyl, 3,4-dicarboxyphenyl, 2,5-dicarboxyphenyl,
2,6-dicarboxyphenyl, 3,4,5-tricarboxyphenyl,
3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl,
2,3-trimethylenedioxyphenyl, 3,4-tetramethylenedioxyphenyl,
3,5-di-tert-butyl-4-hydroxyphenyl, 3-hydroxy-4-pentyloxyphenyl,
2-hydroxy-5-tert-butylphenyl, 3,5-dichloro-4-aminophenyl,
3-(N-acetylamino)-4-hydroxyphenyl, 3-amino-4-hydroxyphenyl,
3-(N-methyl-N-acetylamino)-4-methoxyphenyl,
3-nitro-4-(N-acetylamino)phenyl, 3-nitro-4-chlorophenyl,
3-chloro-4-methylphenyl, 3-methoxy-4-hydroxyphenyl,
3-hydroxy-4-methoxyphenyl, 3-methoxy-4-hydroxy-5-iodophenyl,
3,4-dimethoxy-5-bromophenyl, 3,5-diiodo-4-hydroxyphenyl,
4-(dimethyl-tert-butylsilyloxy)phenyl,
3-(tri-tert-butylsilyloxy)phenyl, 2-(trimethylsilyloxy)phenyl,
3-amino-4-(dimethyl-tert-butylsilyloxy)phenyl, 4-allyloxyphenyl,
2-vinyloxyphenyl, 3-(2-butenyloxy)phenyl, 2-(3-butenyloxy)phenyl,
3-(1-methylallyloxy)phenyl, 4-(2-pentenyloxy)phenyl,
2-(2-hexenyloxy)phenyl, 3-methyl-4-allyloxyphenyl,
3-methoxy-4-octadecyloxyphenyl, 4-dimethylamidophenyl,
2-methylamidophenyl, 3-ethylamidophenyl, 4-propylamidophenyl,
2-isopropylamidophenyl, 3-butylamidophenyl, 4-pentylamidophenyl,
2-hexylamidophenyl, 3-diethylamidophenyl,
4-(N-methyl-N-propylamido)phenyl, 2-methylsulfinylphenyl,
3-methylsulfinylphenyl, 4-methylsulfinylphenyl,
2-ethylsulfinylphenyl, 3-ethylsulfinylphenyl,
4-ethylsulfinylphenyl, 4-isopropylsulfinylphenyl,
4-pentylsulfinylphenyl, 4-hexylsulfinylphenyl,
3,4-dimethylsulfinylphenyl, 3,4-diethylsulfinylphenyl,
2,5-dimethylsulfinylphenyl, 2,6-dimethylsulfinylphenyl,
3,4,5-trimethylsulfinylphenyl, 3-methoxy-4-methylsulfinylphenyl,
2-acetyloxyphenyl, 3-acetyloxyphenyl, 4-acetyloxyphenyl,
2-formyloxyphenyl, 3-propionyloxyphenyl, 4-isobutyryloxyphenyl,
2-pentanoyloxyphenyl, 3-hexanoyloxyphenyl, 3,4-diacetyloxyphenyl,
2,5-diacetyloxyphenyl, 3,4,5-triacetyloxyphenyl,
3,5-bis(acetylamino)phenyl, 2-amidinophenyl, 4-amidinophenyl,
3-amidinophenyl, 4-(4-methyl-1-piperazinyl)-3-nitriophenyl,
4-hydroxysulfonyloxyphenyl, 3-hydroxysulfonyloxyphenyl,
2-hydroxysulfonyloxyphenyl, 4-hydroxy-3-acetylaminophenyl,
4-(2,3,4,6-tetra-o-acetyl-.beta.-D-glucopyranosyloxy)phenyl,
4-(.beta.-D-glucopyranosyloxy) phenyl,
4-(2,3,4,6-tetra-o-benzyl-.beta.-D-glucopyranosyloxy) phenyl,
3,5-bis(dimethylamino)phenyl, 4-chloro-3-nitrophenyl,
4-(4-methyl-1-piperazinyl)-3-nitrophenyl, 4-cyanophenyl,
3-acetylamino-4-(methyl-1-piperazinyl) phenyl,
3-nitro-4-morpholinophenyl, 4-(1-piperazinyl)-3-nitrophenyl,
4-(1-piperazinyl)-3-nitrophenyl, 4-hydroxy-3-carboxyphenyl,
4-morpholino-3-aminophenyl, 4-hydroxy-3-aminophenyl,
4-hydroxy-3-(2-dimethylaminoethylamino) phenyl,
4-methoxy-3-(4-acetyl-1-piperazinyl)phenyl,
4-methoxy-3-(1-piperazinyl)phenyl,
4-methoxy-3-(4-methyl-1-piperazinyl)phenyl,
4-methoxy-3-(4-ethyl-1-piperazinyl)phenyl, 4-hydroxy-3-aminophenyl,
4-hydroxy-3-[(4-methyl-1-piperazinyl)methyl]phenyl,
4-methoxy-3-[(1-pyrrolidinyl)methyl]phenyl, 3,5-diacetyloxyphenyl,
3-methoxy-5-methoxycarbonylphenyl, 3-methoxy-5-carboxyphenyl,
3-methoxy-5-[(4-methyl-1-piperazinyl) carbonyl]phenyl,
3-methoxy-5-[(1-pyrrolidinyl)-carbonyl]phenyl,
3-methoxy-5-[(4-methyl-1-piperzinyl)methyl]phenyl,
3-amino-4-carboxyphenyl, 3-carbamoyl-4-hydroxyphenyl,
4-hydroxy-3-dimethylamido-phenyl,
3-methoxycarbonyl-4-methoxycarbonylmethoxy-phenyl,
4-allyloxy-3-methoxycarbonylphenyl,
3-carboxy-4-carboxymethoxyphenyl,
4-hydroxy-4-allyl-3-methoxycarbonylphenyl,
3-carboxy-4-allyloxyphenyl, 4-hydroxy-3-carboxy-5-allylphenyl,
4-mercapto-3-carboxyphenyl,
5-nitro-4-hydroxy-3-methoxycarbonylphenyl,
5-nitro-3-methoxycarbonylphenyl,
3-methoxycarbonyl-4-methoxymethoxyphenyl,
3-methoxycarbonyl-5-aminophenyl, 3-carboxy-5-aminophenyl,
5-methoxycarbonyl-3-bromo-2-aminophenyl, 2-cyanophenyl,
4-cyanophenyl, 3-cyanophenyl, 3-methoxycarbonyl-4-hydroxyphenyl,
3-carboxy-4-hydroxy-5-(1,1-dimethyl-2-propenyl)phenyl,
2-hydroxy-3-carboxyphenyl,
3-carboxy-4-hydroxy-5-(2-isopropenyl)phenyl,
3-carboxy-4-hydroxy-5-methylphenyl,
3-methoxycarbonyl-4-methoxyphenyl,
3-methoxycarbonyl-4-hydroxy-5-aminophenyl,
3-carboxy-4-hydroxy-5-propylphenyl,
3-carboxy-4-hydroxy-5-aminophenyl,
3-carboxy-4-hydroxy-5-chlorophenyl, 3-carboxy-6-hydroxyphenyl,
4-ethoxyphenyl, 3,4-dibutoxyphenyl, 3,4-dipropoxyphenyl,
3-methoxy-4-ethoxyphenyl, 3-propoxy-4-methoxyphenyl,
3-ethoxy-4-methoxyphenyl, 3,4-didecyloxyphenyl, 2,4-diethoxyphenyl,
3-ethoxy-4-propoxyphenyl, 3-carboxy-4-hydroxy-5-isobutylphenyl,
3-carboxy-4-acetylaminophenyl,
3-carboxy-4-hydroxy-5-(2-hydroxyethyl)phenyl,
3-carboxy-4-amino-6-hydroxyphenyl,
3-carboxy-4-hydroxy-5-(2,3-dihydroxypropyl)phenyl,
3-carboxy-4-aminophenyl, 3-carboxy-4-acetyloxyphenyl,
3-ethyl-4-hydroxyphenyl, 3-carboxy-5-hydroxyphenyl,
4-carboxy-3,5-dihydroxyphenyl, 3-carboxy-4,6-dihydroxyphenyl,
5-methoxycarbonyl-3-amino-2-hydroxyphenyl,
2-allyloxy-5-methoxycarbonylphenyl, 3-carboxy-6-methoxyphenyl,
3-methoxycarbonyl-6-hydroxyphenyl, 3-carbonyl-6-allyloxyphenyl,
3-carboxy-5-nitro-6-hydroxyphenyl,
3-carboxy-5-allyl-6-hydroxyphenyl, 3-carboxy-6-hydroxyphenyl,
3-carboxy-5-amino-6-hydroxyphenyl,
3-methoxycarbonyl-4-dimethylaminothiocarbonyloxyphenyl,
3-methoxycarbonyl-4-dimethylaminocarbonylthiophenyl,
3-methoxycarbonyl-4-hydroxy-5-(2,3-dihydroxypropyl)phenyl,
3-methoxycarbonyl-4-hydroxy-5-formylmethylphenyl,
3-methoxycarbonyl-4-hydroxy-5-(2-hydroxyethyl)phenyl,
3-ethoxycarbonyl-4-acetylaminophenyl,
3-methoxycarbonyl-5-hydroxyphenyl,
3-methoxycarbonyl-4-acetylamino-6-hydroxyphenyl,
3-methoxycarbonyl-6-methoxyphenyl, 4-propoxy-3-ethoxyphenyl,
3-methoxycarbonyl-5-allyl-6-hydroxyphenyl,
3-methoxycarbonyl-4-(2-butenyloxy)phenyl,
3-methoxycarbonyl-4-hydroxy-5-(1-methyl-2-propenyl)phenyl,
3-methoxycarbonyl-4-(2-isopentenyloxy)phenyl,
3-methoxycarbonyl-4-hydroxy-5-(1,1-dimethyl-2-propenyl)-phenyl,
3-methoxycarbonyl-4-(2-methyl-2-propenyloxy)-phenyl,
3-methoxycarbonyl-4-hydroxy-5-(2-methyl-2-propenyl)phenyl,
5-chloro-4-hydroxy-3-methoxycarbonyl-phenyl,
3-methoxycarbonyl-4-hydroxy-5-methylphenyl,
3,5-dinitro-4-hydroxyphenyl, 4-hydroxy-3-nonyloxycarbonyl-phenyl,
4-hydroxy-3-benzyloxycarbonylphenyl,
4-hydroxy-3-(2-methyl-2-propenyl)-5-benzyloxycarbonyl,
4-hydroxy-3-(2-methyl-2-propenyl)-5-nonyloxycarbonylphenyl,
##STR32##
4-[2-(1-piperidinyl)ethylamino]-3-carboxyphenyl,
4-methoxy-3-carboxyphenyl, 2-methyl-4-hydroxy-5-carboxyphenyl,
3-ethyl-4-hydroxy-3-carboxyphenyl,
3-(4-ethyl-1-piperazinyl)-4-hydroxyphenyl,
4-(2-hydroxy-3-carboxyphenyl)phenyl,
4-[2-(3,4-diethoxyphenyl)-4-thiazolyl]-3-hydroxy-2-carboxyphenyl,
4-hydroxy-3-hydroxymethylphenyl, 4-ethoxy-3-carboxyphenyl,
4-n-butoxy-3-n-butoxycarbonylphenyl, 4-n-butoxy-3-carboxyphenyl,
3-acetylmethyl-4-hydroxy-3-carboxyphenyl,
3-n-butyl-4-hydroxy-3-carboxyphenyl,
3-allyl-4-hydroxy-3-carboxyphenyl,
3-hydroxymethyl-4-hydroxy-3-carboxyphenyl,
3-formyl-4-hydroxy-5-carboxyphenyl,
5-(2-carboxyethyl)-4-hydroxy-3-carboxyphenyl,
5-(2-methoxycarboxyethyl)-4-hydroxy-3-carboxyphenyl,
5-methylaminomethyl-4-hydroxy-3-carboxyphenyl,
5-(2-carboxyvinyl)-4-hydroxy-3-carboxyphenyl,
5-(2-methoxycarboxyvinyl)-4-hydroxy-3-carboxyphenyl,
5-acetyl-4-hydroxy-3-carboxyphenyl,
5-phenyl-4-hydroxy-3-carboxyphenyl,
5-bromo-4-hydroxy-3-carboxyphenyl,
5-cyano-4-hydroxy-3-carboxyphenyl, 4,5-hydroxy-3-carboxy-phenyl,
5-methoxy-4-hydroxy-3-carboxyphenyl,
5-ethylamino-4-hydroxy-3-carboxyphenyl,
5-acetylamino-4-hydroxy-3-carboxyphenyl,
3,5-dicarboxy-4-hydroxyphenyl, 4-methoxy-3-carboxyphenyl,
4-ethoxy-3-carboxyphenyl, 4-n-butyoxy-3-carboxyphenyl,
4-dimethylamino-3-hydroxyphenyl,
4-dimethylamino-3-hydroxymethylphenyl,
4-dimethylamino-3-methoxycarboxyphenyl,
4-trifluoro-methylsulfonyloxy-3-methoxycarbonylphenyl,
3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(1-propenyl)-phenyl,
3-methoxymethoxycarbonyl-4-methoxymethoxy-5-formylphenyl,
3-methoxymethoxycarbonyl-4-methoxymethoxy-5-acetylmethylphenyl,
5-(2-methyl-2-propenyl)-4-methoxymethoxy-3-methoxymethoxycarbonylphenyl
and the like.
The 5- to 15-membered monocyclic, bicyclic or tricyclic
heterocyclic residual group having 1 to 2 hetero atoms selected
from the group consisting of a nitrogen atom, an oxygen atom and a
sulfur atom can be exemplified by pyrrolidinyl, piperidinyl,
pierazinyl, morpholino, pyridyl, 1,2,5,6-tetrahydropyridylthienyl,
quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl,
pyridazylthienyl, pyrrolyl, carbostyril, 3,4-dihydrocarbostyril,
1,2,3,4-tetrahydroquinolyl, indolyl, isoindolyl, indolinyl,
benzoimidazolyl, benzoxazolyl, imidazolidinyl, isoquinolyl,
quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl, carbazolyl,
acrydinyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl,
imidazolyl, pyrazolidinyl, phenothiazinyl, benzofuryl,
2,3-dihydrobenzo[b]furyl, benzothienyl, phenoxthinyl, phenoxazinyl,
4H-chromenyl, 1H-indazolyl, phenazinyl, xanthenyl, thianthrenyl,
isoindolinyl, 2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl,
isooxazolyl, thiazolyl, isothiazolyl, pyranyl, pyrazolidinyl,
2-pyrazolinyl, quinuclidinyl, 1,4-benzoxazinyl,
3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl,
1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl,
1,3-dithia-2,4-dihydronaphthalenyl, phenanthridinyl,
1,4-dithianaphthalenyl, dibenzo[b,e]azepine and
6,11-dihydro-5H-dibenzo[b,e]azepine.
The heterocyclic ring having 1 to 3 groups selected from the group
consisting of an oxo group, an alkyl group, a benzoyl group, a
lower alkanoyl group, a hydroxyl group, a carboxy group, a lower
alkoxycarbonyl group, a lower alkylthio group, a group
##STR33##
(A and 1 are the same as defined above; R.sup.23 and R.sup.24 are
each the same of different, and are each represents a hydrogen atom
or a lower alkyl group; further R.sup.23 and R.sup.24 as well as
the adjacent nitrogen atom being bonded thereto, together with or
without other nitrogen atom or oxygen atom may form a five- to
six-membered saturated heterocyclic group; said five- to
six-membered heterocyclic group may have a lower alkyl group as a
substituent.), a cyano group, a lower alkyl group having hydroxyl
groups, a phenylaminothiocarbonyl group and an amino-lower
alkoxycarbonyl group which may have lower alkyl groups as
substituents, can be exemplified by heterocyclic rings each having
1to 3 groups selected from the group consisting of an oxo group, a
C.sub.1-18 straight-chain or branched-chain alkyl group, a benzoyl
group, a C.sub.1-6 straight-chain or branched-chain alkanoyl group,
a hydroxyl group, a carboxy group, a C.sub.1-6 straight-chain or
branched-chain alkoxycarbonyl group, a C.sub.1-6 straight-chain or
branched-chain alkylthio group, a group of the formula,
##STR34##
(A is the same as defined above; R.sup.23 and R.sup.24, are each
the same or different, and are each represent a hydrogen atom or a
C.sub.1-6 straight-chain or branched-chain alkyl group, further
R.sup.23 and R.sup.24 as well as the adjacent nitrogen atom being
bonded thereto, together with or without other nitrogen atom or
oxygen atom may form a five- to six-membered saturated heterocyclic
ring, said heterocyclic ring may have a C.sub.1-6 straight-chain or
branched-chain alkyl group as a substituent.), a cyano group, a
C.sub.1-6 straight-chain or branched-chain alkyl group having 1 to
3 hydroxyl groups, a phenylaminothiocarbonyl group and a C.sub.1-6
straight-chain or branched-chain alkoxycarbonyl group having an
amino group which may have one to two C.sub.1-6 straight-chain or
branched-chain alkyl groups as substituent(s), such as
dibenzo[b,e]-azepin-3-yl-6-one, 4-oxo-1,4-dihydroquinolyl,
1-oxopyridyl, 2-oxo-pyridyl, 1-methyl-3,4-dihydrocarbostyril,
1-ethylcarbostyril, 1-buytl-3,4-dihydrocarbostyril,
1-hexylcarbostyril, 1-octadecyl-3,4-dihydrocarbostyril,
3-oxo-4-methyl-3,4-dihydro-2H-1,4-benzothiazinyl,
3-oxo-3,4-dihydro-2H-1,4-benzothiazinyl,
1-benzoyl-1,2,3,4-tetrahydroquinolyl,
1-octadecyl-1,2,3,4-tetrahydroquinolyl, 1-benzoylcarbostyril,
4-benzoyl-3,4-dihydro-2H-1,4-benzothiazolyl,
4-methyl-1,2,3,4-tetrahydroquinoxalinyl,
4-benzoyl-1,2,3,4-tetrahydroquinoxalinyl,
1-acetyl-1,2,3,4-etrahydroquinolyl,
1-acetyl-3,4-dihydrocarbostyril, 4-acetyl-3,4-dihydro-2H-1,
4-benzothiazolyl, 4-benzoyl-3,4-dihydro-2H-1,4-benzoxazinyl,
4-acetyl-3,4-dihydro-2H-1,4-benzoxazinyl,
4-acetyl-1,2,3,4-tetrahydroquinoxalinyl,
1-methyl-1,2,3,4-tetrahydroquinolyl,
7-hydroxy-3,4-dihydrocarbostyril, 8-hydroxy-3,4-dihydrocarbostyril,
2-methylthiobenzothiazolyl, 3-oxo-3,4-dihydro-2H-1,4-benzoxazinyl,
1-acetylindolinyl, 2-oxobenzoimidazolyl,
4-methyl-3,4-dihydro-2H-1,4-benzoxazinyl, 10-acetylphenothiazinyl,
2-oxobenzothiazolyl, 2-oxobenzoxazolyl,
2-oxo-3-methyl-benzothiazolyl, 1,3-dimethyl-2-oxobenzoimidazolyl,
6-hydroxy-3,4-dimethylquinolyl, 4-oxopyridyl,
1-propyl-1,2,3,4-tetrahydroquinolyl,
4-pentyl-1,2,3,4-tetrahydroquinoxalinyl,
1-propanoyl-1,2,3,4-tetrahydroquinolyl, 1-butylcarbostyril,
4-pentanoyl-3,4-dihydro-2H-1,4-benzothiazolyl,
4-hexanoyl-3,4-dihydro-2H-1,4-benzoxazinyl,
2-ethylthiobenzoxazolyl, 2-propylthiobenziomidazolyl,
2-butylthiobenzothiazolyl, 6-pentylcarbostyril,
7-hexylthio-3,4-dihydrocarbostyril, 2-carboxypyridyl,
2-carboxypyrrolyl, 2-ethoxycarbonylpyridyl,
2-methoxycarbonylpyrrolyl, 1-methylpyridinum,
1-methyl-1,2,5,6-tetrahydropyridyl, 2-methoxycarbonylfuryl,
2-carboxyfuryl, 2-dimethylaminocarbonylpyridyl, 2-acetylpyrrolyl,
2-hydroxymethylpyridyl, 2-ethoxycarbonyl-4-methylpyridyl,
2-carboxy-4-methylpyridyl,
2-(4-methyl-1-piperazinyl)carboxypyridyl,
2-(2-dimethylaminomethoxycarbonyl)pyridyl,
2-dimethylaminonethylpyridyl, 2-ethoxycarbonylthienyl,
2-methyl-7-carboxybenzofuryl, 2-carboxythienyl,
4-ethoxycarbonylthiazolyl, 4-carboxypyridyl,
2,2-dimethyl-7-carboxy-2,3-dihydrobenzo[b]furyl, 4-carboxypyridyl,
2-methyl-4-carboxylpyridyl, 2,6-dimethyl-3-carbamoylpyidyl,
2-phenylaminothiocarbonylpyridyl, 2-methyl-3-carboxypyridyl,
2,6-dimethyl-3-carboxypyridyl and the like.
As to the lower alkenyloxy group, there can be mentioned C.sub.2-6
straight-chain or branched-chain alkenyloxy groups such as
vinyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy, 1-methylallyloxy,
2-pentenyloxy, 2-hexanyloxy and the like.
The lower alkylsulfonyl group can be exemplified by C.sub.1-6
straight-chain or branched-chain alkylsulfonyl groups such as
methylsulfonyl, ethylsulfinyl, isopropylsulfinyl, butylsulfinyl,
tert-butylsulfinyl, pentylsulfinyl, hexylsulfinyl and the like.
As to the lower alkanoyloxy group, there can be mentioned C.sub.1-6
straight-chain or branched-chain alkanoyloxy groups such as
formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy,
pentanoyloxy, tert-butylcarbonyloxy, hexanoyloxy and the like.
The tri-lower alkyl group-substituted silyloxy group can be
exemplified by silyloxy groups each substituted with three
C.sub.1-6 straight-chain or branched0chain alkyl groups, such as
trimethylsiyloxy, triethylsilyloxy, triisopropylsilyloxy,
tributylsilyloxy, tri-tert-butylsilyloxy, tripentylsilyloxy,
trihexylsilyloxy, dimethyl-tert-butylsilyloxy and the like.
The phenyl-lower alkyl group which may have a lower alkoxy group as
a substituent on the phenyl ring and a hydroxyl group as a
substituent on the lower alkyl group, can be exemplified by
phenylalkyl groups each having a C.sub.1-6 straight-chain or
branched-chain alkyl group moiety, which may each have one to three
C.sub.1-6 straight chain or branched chain alkoxy groups as
substituent(s) on the phenyl ring and a hydroxyl group as a
substituent on the lower alkyl group, such as benzyl,
2-phenylethyl, 1-phenylethyl. 3-phenylpropyl, 4-pehnylbutyl,
1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl,
2-methyl-3-phenylpropyl, 2-methoxybenzyl, 2-(3-methoxyphenyl)ethyl,
1-(4-methoxyphenyl)ethyl, 3-(2-ethoxyphenyl)propyl,
4-(3-ethoxyphenyl)butyl, 1,1-dimethyl-2-(4-isopropoxyphenyl) ethyl,
5-(4-pentyloxyphenyl)pentyl, 6-(4-hexyloxyphenyl) hexyl,
3,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl,
3,4,5-trimethoxybenzyl, 1-phenyl-1-hydroxymethyl,
2-phenyl-1-hydroxyethyl, 1-phenyl-2-hydroxyethyl,
3-phenyl-1-hydroxypropyl, 4-phenyl-4-hydroxybutyl,
5-phenyl-5-hydroxypentyl, 6-phenyl-6-hydroxyhexyl,
2-methyl-3-phenyl-3-hydroxypropyl,
1-(2-methothyphenyl)-1-hydroxymethyl,
2-(3-methoxyphenyl)-1-hydroxyethyl,
3-(2-ethoxyphenyl)-2-hydroxypropyl,
4-(3-ethoxyphenyl)-3-hydroxybutyl,
5-(4-pentyloxyphenyl)-4-hydroxypentyl,
6-(4-hexyloxyphenyl)-5-hydroxyhexyl,
6-(4-hexyloxyphenyl)-1-hydroxhexyl,
1-(3,4-dimethoxyphenyl)-1-hydroxymethyl,
1-(3,4,5-trimethoxyphenyl-1-hydroxymethyl and the like.
The benzoyl group which may have lower alkoxy groups as
substituents on the phenyl ring, can be exemplified by benzoyl
groups which may each have one to three C.sub.1-6 straight-chain or
branched-chain alkoxy groups as substituent(a) on the phenyl ring,
such as benzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl,
4-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoyl,
4-isopropoxybenzoyl, 4-pentyloxybenzoyl, 4-hexyloxybenzoyl,
3,4-dimethoxybenzoyl, 3-ethoxy-4-methoxybenzoyl,
2,3-dimethoxybenzoyl, 3,4-diethoxybenzoyl, 2,5-dimethoxybenzoyl,
2,6-dimethoxybenzoyl, 3,5-dimethoxybenzoyl, 3,4-dipentyloxybenzoyl,
3,4,5-trimethoxybenzoyl and the like.
The phenyl-lower alkenyl group which may have lower alkoxy groups
as substituents on the phenyl group, can be exemplified by
phenylalkenyl groups each having a C.sub.3-6 straight chain or
branched chain alkenyl moiety which may each have one to three
C.sub.1-6 straight chain or branched chain alkoxy groups as
substituents on the phenyl ring, such as cinnamyl, stryyl,
4-phenyl-3-butenyl, 4-phenyl-2-butenyl, 5-phenyl-4-pentenyl,
5-phenyl-3-pentenyl, 5-phenyl-2-pentenyl, 6-phenyl-5-hexenyl,
6-phenyl-4-hexenyl, 6-phenyl-3-hexenyl, 6-phenyl-2-hexenyl,
2-methyl-4-phenyl-3-butenyl, 2-methylcinnamyl, 1-methylcinnamyl,
2-methoxystyryl, 3-methoxycinnamyl, 4-methoxystyryl,
2-ethoxycinnamyl, 3-ethoxystyryl, 4-ethoxystyryl, 2-propoxystyryl,
3-propoxystyryl, 4-propoxycinnamyl, 3-(tert-butoxy)styryl,
4-pentyloxycinnamyl, 3-hexyloxystyryl, 3,4-dimethoxystyryl,
3,5-dimethoxystyryl, 2,6-dimethoxystyryl, 3,4-diethoxystyryl,
3,4-deithoxystyryl, 3,4,5-trimethoxystyryl,
4-ethoxyphenyl-3-butenyl, 4-(3-tertbutoxyphenyl)-2-butenyl,
5-(4-hexyloxyphenyl-4-pentenyl, 6-(3,4-dimethoxyphenyl-5-hextenyl,
6-(3,4,5-triethoxyphenyl)-3-hexenyl and the like.
The amino-lower alkyl group which may have lower alkyl groups as
substituents, can be exemplified by amino group-containing
C.sub.1-6 straight-chain or branched-chain alkyl groups which may
each gave one to two C.sub.1-6 straight-chain or branched-chain
alkyl groups as substituent(s), such as aminomethyl, 2-eminoethyl,
1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl,
6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl,
methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl,
3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl,
6-hexylaminohexyl, dimethylaminomethyl,
(N-ethyl-N-propylamino)methyl, 2-(N-methyl-N-hexylamino)ethyl and
the like.
The five- or six-membered saturated or unsaturated heterocyclic
ring which R.sup.8 and R.sup.9 as well as the adjacent nitrogen
atom bonded thereto may form together with or without other
nitrogen atom or oxygen atom, can be exemplified by piperazinyl,
pyrrolidioyl, morpholinyl, piperidinyl, pyrrolyl, imidazolyl,
pyrazolyl, 2-pyrrolinyl, 2-imidazolinyl, imidazolidinyl,
2-piperazolinyl, pyrazolidinyl, imidazolidinyl, 2-piperazolinyl,
pyrazolidinyl, 1,2,5,6-tetrahydropyridyl, etc.
The above heterocyclic ring substituted with a lower aklanoyl group
or a lower alkyl group can be exemplified by above heterocyclic
rings each substituted with a C.sub.1-6 straight-chain or
branched-chain Alkanoyl group or a C.sub.1-6 straight-chain or
branched-chain alkyl group, such as 4-acetylpiperazinyl,
3-formylpyrrolidinyl, 2-propionylpyrrolidinyl,
4-butyrylpiperidinyl, 3-pentanoylpiperazinyl, 2-hexanoylmorpholino,
4-methylpiperazinyl, 4-ethylpiprazinyl, 3-ethylpyrrolidinyl,
2-propylpyrrolidinyl, 4-butylpiperidinyl, 3-pentylmorpholino,
2-hexylpiprazinyl, 2-acetylpyrrolyl and the like.
The phenyl-lower alkoxy group can be exemplified by phenylalkoxy
groups each having a C.sub.1-6 straight-chain or branched-chain
alkoxy moiety, such as benzoyloxy, 2-phenylethoxy, 1-phenylethoxy,
3-phenylpropoxy, 4-phenylbutoxy, 1,1-dimethyl-2-phenylethoxy,
5-phenylpentyloxy, 6-phenylhexyloxy, 2-methyl-3-phenylpropoxy and
the like.
As to the hydroxyl group- or lower alkanoyloxy group-substituted
lower alkyl group, there can be mentioned C.sub.1-6 straight-chain
or branched-chain alkyl groups each having one to three hydroxyl
groups or one to three C.sub.1-6 straight-chain or branched-chain
alkanoyloxy groups, such as hydroxymethyl, 2-hydroxyethyl,
1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl,
4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl,
5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl,
1-hydroxyiscpropyl, 2-methyl-3-hydroxypropyl, acetyloxymethyl,
2-propionyloxyethyl, 1-butyryloxyethyl, 3-acetyloxypropyl,
2,3-diacetyloxypropyl, 4-isobutyryloxybutyl, 5-pentanoyloxypentyl,
6-tert-butylcarbonyloxyhexyl, 1,1-dimethyl-2-hexanoyloxyethyl,
5,5,4-triacetyloxypentyl, 2-methyl-3-acetyloxypropyl and the
like.
The tetrahydropyranyloxy group which may have, as substituent(s),
one to four groups selected from the group consisting of a hydroxyl
group, a lower alkoxycarbonyl group, a phenyl-lower alkoxy group, a
hydroxyl group- or lower alkanoyloxy group-substituted lower alkyl
group and a lower alkanoyloxy group, can be exemplified by
tetrahydropyranyloxy groups which may each have, as substituent(s),
one to four groups selected from the group consisting of a hydroxyl
group, a C.sub.1-6 straight-chain or branched-chain alkoxycarbonyl
group, a phenylalkoxy group having a C.sub.1-6 straight-chain or
branched-chain alkyl group having one to three hydroxyl groups or
one to three C.sub.1-6 straight-chain or branched-chain alkanoyloxy
groups, and a C.sub.2-6 straight-chain or branched-chain
alkanoyloxy group, such as 2-, 3- or 4-tetrahydropyranyoxy,
3,4,5-trihydroxy-6-methoxycarbonyl-2-tetrahydropyranyloxy,
3,4,5-tribenzyloxy-6-hydroxymethyl-2-tetrahydropyranyloxy,
3,4,5-triacetyloxy-6-acetyloxymethyl-2-tetrahydropyranyloxy,
3,4,5-trihydroxy-6-hydroxymethyl-2-tetrahyfropyranyloxy,
3-hydroxy-2-tetrahydropyranyloxy,
2,4-dihydroxy-3-tetrahydropyranyloxy,
2,3,5-trihydroxy-4-tetrahydropyranyloxy,
3-(2,3-dihydroxypropyl)-2-tetrahydropyranyloxy,
6-(5,5,4-trihdroxypentyl)-2-tetrahydropyranyloxy,
4-ethoxycarbonyl-3-tetrahydropyranyloxy,
4,6-dimethoxycarbonyl-4-tetrahydropyranyloxy,
4,5,6-trimethoxycarbonyl-2-tetrahydropyranyloxy,
2-propoxyxarbonyl-3-tetrahydropyranyloxy,
6-butoxycarbonyl-4-tetrahydrypyranyloxy,
6-pentyloxycarbonyl-2-tetrahydropyranyloxy
4-hexyloxycarbonyl-3-tetrahydropyranyloxy,
3,4,5,6-tetrahydroxy-2-tetrahydropyranyloxy,
6-benzyloxy-2-tetrahydropyranyloxy,
4-(2-phenylethoxy)-3-tetrahydropyranyloxy,
4,6-dibenzyloxy-4-tetrahydropyranyloxy,
4,5,6-tribenzyloxy-2-tetrahydropyranyloxy,
2-(3-phenylpropoxyl-3-tetrahydropyranyloxy,
6-(4-phenylbutoxy)-4-tetrahydropyranyloxy,
6-(5-phenylpentyloxy)-2-tetrahydropyranyloxy,
4-(6-phenylhexyloxy)-3-tetrahydropyranyloxy,
3,4,5-trihydroxy-6-benzyloxy-2-tetrahydropyranyloxy,
6-acetyloxy-2-tetrahydropyranyloxy,
4-propionyloxy-3-tetrahydropyranyloxy,
4,6-diacetyloxy-4-tetrahydropyranyloxy,
4,5,6-triacetyloxy-2-tetrahydropyranyloxy,
2-butyryloxy-3-tetrahydropyranyloxy,
6-pentanoyloxy-3-tetrahydropyranyloxy,
4-hexanoylozy-3-tetrahydropyranyloxy,
3,4,5-trihydroxy-6-acetyloxy-2-tetrahydropyranyloxy,
6-hydroxymethyl-2-tetrahydropyranyloxy,
4-(2-hydroxyethyl-2-tetrahydropyranyloxy,
4,6-dihydroxymethyl-4-tetrahydropyranyloxy,
4,5,6-dihydroxymethyl-2-tetrahydropyranyloxy,
2-(3-hydroxypropyl)-3-tetrahydropyranyloxy,
6-acetyloxyethyl-2-tetrahydropyranyloxy,
4-(2-acetyloxyethyl)-2-tetrahydropyranyloxy,
4,6-diacetyloxymethyl-4-tetrahydropyranyloxy,
4,5,6-triacetyloxymethyl-2-tetrahydropyramyloxy,
2-(3-propionyloxypropyl)-3-3-tetrahydropyranyloxy,
6-(5-hydroxypentyl)-2-tetrahydropyranyloxy,
4-(6-hexanoyloxyhexyl)-3-tetrahydropyranyloxy,
3,4,5-trihydroxymethyl-6-acetyloxymethyltetrahydropyranyloxy and
the like.
The piperazinyl-lower alkyl group which may have lower alkyl groups
as substituents on the piperazine ring, can be exemplified by
piperazinylalkyl groups each having a C.sub.1-6 straight-chain or
branched-chain lower alkyl moiety, which may each have one to three
C.sub.1-6 straight-chain or branched-chain alkyl groups as
substituent(s) on the piperazine ring, such as
(1-peperazinyl)methyl, 2-(1-piperazinyl)ethyl,
1-(1-piperazinyl)ethyl, 3-(1-piperazinyl)propyl, 4-(1-piperazinyl)
butyl, 5-(1-piperazinyl)methyl, 6(1-piperazinyl)hexyl,
1,1-dimethyl-2(1piperazinyl)ethyl, 2-methyl-3-(1-piperazinyl)
propyl, (4-methyl-1-piperazinyl)methyl,
2-(4-ethyl-1-piperazinyl)ethyl, 1-(4-propyl-1-piperazinyl)ethyl,
3-(4-butyl-1-piperazinyl)propyl, 4-(4-pentyl-1-piperazinyl)butyl
5-(4-hexyl-1-piperazinyl)pentyl, 6-(3,4-dimethyl-1-
piperazinyl)hexyl,
1,1-dimethyl-(3,4,5-trimethyl-1-piperazinyl)ethyl and the like.
As to the lower alkoxycarbonyl-substituted lower alkoxy group,
there can be mentioned C.sub.1-6 straight-chain or branched-chain
alkoxycarbonylalkoxy groups each having a C.sub.1-6 straight-chain
or branched-chain alkoxy moiety, such as methoxycarbonylmethoxy,
3-methoxycarbonylpropoxy, ethoxycarbonylmethoxy,
4-ethoxycarbonylbutoxy, 6-propoxycarbonylhexyloxy,
5-isopropoxycarbonylpentyloxy, 1,1-dimethyl-2-butoxycarbonylethoxy,
2-methyl-3-tert-butoxycarbonylpropoxy, 2-pentyoxycarbonylethoxy,
hexyloxycarbonylmethoxy and the like.
As to the carboxy-substituted lower alkoxy group, there can be
mentioned carboxyalkoxy groups each having a C.sub.1-6
straight-chain or branched-chain alkoxy moiety, such as
carboxymethoxy, 2-carboxyethoxy, 1-carboxyethoxyl, 3-carboxypropyl,
4-carboxybotoxy, 5-carboxypentyloxy, 6-carboxyhexyloxy,
1,1-dimethyl-2-carboxyethoxy, 2-methyl-3-carboxypropoxy and the
like.
As to the lower alkoxy-substituted alkoxy group, there can be
mentioned alkoxyalkoxy groups each having a C.sub.1-6
straight-chain or branched-chain alkoxy moiety, such as
methoxymethoxy, 3-methoxypropoxy, ethoxymethoxy, 4-ethoxybutoxy,
6-propoxyhexyloxy, 5-isopropoxypentyloxy,
1,1-dimethyl-2-butoxyethoxy, 2-methyl-3-tert-butoxypropoxy,
2-pentyloxyethoxy, hexyloxymethoxy and the like.
The lower alkyl group having hydroxyl groups can be exemplified by
C.sub.1-6 straight-chain or branched-chain alkyl groups each having
one to three hydroxyl groups, such as hydroxymethyl,
2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl,
2,3-dihydroxypropyl, 4-hydroxyisopropyl,
1,1-dimethyl-2-hydroxyethy, 5,5,4-trihydroxypentyl,
5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl,
2-methyl-3-hydroxypropyl and the like.
The lower alkenyl group can be exemplified by C.sub.1-6
straight-chain or branched-chain alkenyl groups such as vinyl,
allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl
and the like.
The aminothiocarbonyloxy group which may have lower alkyl groups as
substituents, can be exemplified by thiocarbonyloxy groups each
having an amino group which may have one to two C.sub.1-6
straight-chain or branched-chain alkyl groups as substituent(s),
such as thiocarbamoyloxy, methylaminothiocarbonyloxy,
ethylaminothiocarbonyloxy, propylaminothiocarbonyloxy,
isopropylaminothiocarbonyloxy, butylaminothiocarbonyloxy,
pentylaminothiocarbonyloxy, hexylaminothiocarbonyloxy,
dimethylaminothiocarbonyloxy, (N-ethyl-N-propylamino)
thiocarbonyloxy, (N-methyl-N-hexylamino)-thiocarbonyloxy and the
like.
The aminocarbonylthio group which may have lower alkyl groups as
substituents, can be exemplified by carbonylthio groups having an
amino group which may have one to two C.sub.1-6 straight-chain or
branched-chain alkyl groups as substituent(s), such as
aminocarbonylthio, methylaminocarbonylthio, ethylaminocarbonylthio,
propylaminocarbonylthio, 3-isopropylaminocarbonylthio,
butylaminocarbonylthio, pentylaminocarbonylthio,
hexylaminocarbonylthio, dimethylaminocarbonylthio,
(N-ethyl-N-propylamino)carbonylthio,
(N-methyl-N-hexylamino)carbonylthio and the like.
As to the lower alkanoyl-substituted lower alkyl group, there can
ge mentioned C.sub.1-6 straight-chain or branched-chain alkyl
groups each having one to three C.sub.1-6 straight-chain or
branched-chain alkanoyl groups, such as formylmethyl, acetylmethyl,
2-propionylethyl, 1-butyrylethyl, 3-acetylpropyl,
2,3-diacetylpropyl, 4-isobutyrylbutyl, 5-pentanoylpentyl,
6-tert-butylcarbonylhexyl, butylcarbonylhexyl,
1,1-dimethyl-2-hexanoylethyl, 5,5,4-triacetylpentyl,
2-methyl-3-acetylpropyl and the like.
The phenyl group which may have one to three lower alkoxy groups as
substituents on the phenyl ring, can be exemplified by phenyl rings
which may each have one to three C.sub.1-6 straight-chain or
branched-chain alkoxy groups as substituents on the phenyl ring,
such as phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,
2-ethoxyphenyl, 3-ethoxyphenyl, 4-pentyloxyphenyl,
4-isopropoxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl,
2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl,
3-propoxy-4-methoxyphenyl, 3,5-dimethoxyphenyl,
3,4-dipentyloxyphenyl, 3,4,5-trimethoxyphenyl,
3-methoxy-4-ethoxyphenyl and the like.
The pyridyl group which may have an oxo group, can be exemplified
by pyridyl groups which may each have an oxo group, such as
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-oxo-3-pyridyl, 4-oxo-2-pyridyl,
1-oxo-3-pyridyl, 3-oxo-2-pyridyl and the like.
The quinolyl group which may have an oxo group, can be exemplified
by quinolyl groups which may each have an oxo group, such as
2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl,
7-quinolyl, 8-quinolyl, 2-oxo-4-quinolyl, 2-oxo-7-quinolyl,
2-oxo-5-quinolyl, 2-oxo-8-quinolyl, 4-oxo-6-quinolyl and the
like.
The phenyl group having, as substituents on the phenyl ring, one to
three groups selected from the group consisting of a lower
alkanoyloxy group, a nitro group, a lower alkylsulfonyl group and a
tetrahydropyranyloxy group which may have, as substituents, one to
four groups selected from the group consisting of a hydroxyl group,
a lower alkoxycarbonyl group, a phenyl-lower alkoxy group, a lower
alkanoyloxy-substituted lower alkyl group and a lower alkanoyloxy
group, can be exemplified by phenyl groups each having as
substituent(s) on the phenyl ring, one to three groups selected
from the group consisting of a C.sub.1-6 straight-chain or
branched-chain alkanoyloxy group, a hydroxysulfonyloxy group, a
cyano group, an amidino group a nitro group, a C.sub.1-6
straight-chain or branched-chain alkylsulfonyl group and a
tetrahydropyranyloxy group which may have, as substituents, one to
four groups selected from the group consisting of a hydroxyl group,
a C.sub.1-6 straight-chain or branched-chain alkoxycarbonyl group,
a phenylalkoxy group having a C.sub.1-6 straight-chain or
branched-chain alkoxy moiety, a C.sub.1-6 straight-chain or
branched-chain alkyl group having one to three C.sub.2-6
straight-chain or branched-chain alkanoyloxy groups, and a
C.sub.2-6 straight-chain or branched-chain alkanoyloxy group, such
as 2-acetyloxyphenyl, 3-acetyloxyphenyl, 4-acetyloxyphenyl,
2-formyloxyphenyl, 3-propionyloxyphenyl, 4-isobutyryloxyphenyl,
2-pentanoyloxyphenyl, 3-hexanoyloxyphenyl, 3,4-diacetyloxyphenyl,
2,5-diacetyloxyphenyl, 3,4,5-triaceyloxyphenyl,
4-hydroxysulfonyloxyphenyl, 3-hydroxysulfonyloxyphenyl,
2-hydroxysulfonyloxyphenyl, 4-cyanophenyl, 3-cyanophenyl,
2-cyanophenyl, 4-amidinophenyl, 3-amidinophenyl, 2-amidinophenyl,
2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3,4-dinitrophenyl,
2,5-dinitrophenyl, 2,6-dinitrophenyl, 3,4,5-trinitrophenyl,
3,5-dinitro-4-acetyloxyphenyl, 4-methylsulfonylphenyl,
2-methylsulfonylphenyl, 3-methylsulfonylphenyl,
2-ethylsulfonylphenyl, 4-isopropylsulfonylphenyl,
4-pentylsulfonylphenyl, 4-hexysulfonylphenyl,
3,4-dimethylsulfonylphenyl, 3,4-diethylsulfonylphenyl,
2,5-dimethylsulfonylphenyl, 2,6-dimethylsulfonylphenyl,
3,4,5-trimethylsulfonylphenyl,
4-(2,3,4,6-tetra-o-acetyl-.beta.-D-glucopyranosyloxy)phenyl,
4-(.beta.-D glucopyranosyloxy) phenyl,
4-(2,3,4,6-tetra-o-benzyl-.beta.-D-glucopyranosyloxy) phenyl and
the like.
The amino group which may have a lower alkanoyl group, can be
exemplified by amino groups which may each have a C.sub.1-6
straight-chain or branched-chain alkanoyl group, such as amino,
formylamino, acetylamino, propionylamino, butyrylamino,
isobutyrylamino, pentanoylamino, tertbutylcarbonylamino,
pentanaylamino, hexanoylamino and the like.
The phenyl group which may have groups selected from the group
consisting of a thiazolyl group having, as a substituent on the
thiazolyl ring, a phenyl group which may have lower alkoxy groups
on the phenyl ring, a carboxyl group and a hydroxyl group, can be
exemplified by phenyl groups which may each have one to three
groups selected from the group consisting of a thiazolyl group
having as a substituent on the thiazolyl ring, a phenyl group which
may have one to three C.sub.1-6 straight-chain or branched-chain
alkoxy groups on the phenyl ring, a carboxyl group and a hydroxyl
group, such as phenyl, 2-(3,4-diethoxyphenyl)-4-thiazolylphenyl,
[4-(3,4,5-trimethoxyphenyl)-2thiazolyl]phenyl,
[5-(3-propoxyphenyl)-2-thiazolyl]-phenyl,
[2-(2-butoxyphenyl)-4-thiazolyl]phenyl, 2-hydroxy-3-carboxyphenyl,
2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,
3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 2,5-dihydroxyphenyl,
2,4-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4,5-trihydroxyphenyl,
2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl,
3,4-dicarboxyphenyl, 2,5-dicarboxyphenyl, 2,6-dicarboxyphenyl,
3,4,5-tricarboxyphenyl, 3-carboxy-4-hydroxyphenyl,
3-carboxy-6-hydroxyphenyl and the like.
As the piperidinyl-lower alkyl group, there can be mentioned
piperidinylalkyl groups each having a C.sub.1-6 straight-chain or
branched-chain alkyl moiety, such as (1-piperidinyl)methyl,
2-(1-piperidinyl)ethyl, 1-(1-piperidinyl)ethyl,
3-(1-piperidinyl)propyl, 4-(1-piperidinyl) butyl,
5-(2-piperidinyl)pentyl, 6-(3-piperidinyl)hexyl,
1,1-dimethyl-2-(4-piperidinyl)ethyl, 2-methyl-3-(1-piperidinyl)
propyl and the like.
The alkoxycarbonyl group can be exemplified by, in addition to the
above-mentioned lower alkoxycarbonyl groups, C.sub.1-18
straight-chain or branched-chain alkoxycarbonyl groups, such as
heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl,
decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl,
tridecyloxycarbonyl, tetradecyloxycarbonyl, pentadecyloxycarbonyl,
hexadecyloxycarbonyl, heptacecyloxycarbonyl, octadecyloxycarbonyl
and the like.
The amino-lower alkoxycarbonyl group which may have a lower alkyl
group as a substituent, can be exemplified by C.sub.1-6
straight-chain or branched-chain alkoxycarbonyl groups each having
an amino group which may have one to two C.sub.1-6 straight-chain
or branched-chain alkyl groups as substituents, such as
aminomethoxycarbonyl, 2-aminoethoxycarbonyl, 1-aminoethoxycarbonyl,
3-aminopropoxycarbonyl, 4-aminobutoxycarbonyl,
5-aminopentyloxycarbonyl, 6-aminohexloxycarbonyl,
1,1-dimethyl-2-aminoethoxycarbonyl,
2-methyl-3-aminopropoxycarbonyl, methylaminomethoxycarbonyl,
1-ethylaminoethoxycarbonyl, 2-propylaminoethoxycarbonyl,
3-isopropylaminopropoxycarbonyl, 4-butylaminobutoxycarbonyl,
5-pentylaminopentyloxycarbonyl, 6-hexylaminohexyloxycarbonyl,
dimethylaminomethoxycarbonyl, 2-dimethylaminoethoxycarbonyl,
3-dimethylaminopropoxycarbonyl,
(N-ethyl-N-propylamino)-methoxycarbonyl,
2-(N-methyl-N-hexylamino)ethoxycarbonyl and the like.
The phenyl-lower alkoxycarbonyl group-can be exemplified by
phenylalkoxycarbonyl groups each having a C.sub.1-6 straight-chain
or branched-chain alkoxy moiety, such as benzyloxycarbonyl,
2-phenylethoxycarbonyl, 1-phenylethoxycarbonyl,
3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl,
1,1-dimethyl-2-phenylethoxycarbonyl, 5-phenylpentyloxycarbonyl,
6-phenylhexyloxycarbonyl, 2-methyl-3-phenylpropoxycarbonyl and the
like.
The lower alkynyl group there can be mentioned alkynyl groups each
having C.sub.2-6 straight-chain or branched-chain alkynyl moiety,
such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl,
1-methyl-2-propynyl, 2-pentynyl, 2-hexynyl and the like.
As to the carboxy-substituted lower alkyl group, there can be
mentioned carboxyalkyl groups each having a C.sub.1-6
straight-chain or branched-chain alkyl moiety, such as
carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, 3-carboxypropyl,
4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl,
1,1-dimethyl-2-carboxyethyl, 2-methyl-3-carboxypropyl and the
like.
As to the lower alkoxycarbonyl-lower alkenyl group, there can be
mentioned alkoxycarbonylalkenyl groups each having a C.sub.1-6
straight-chain or branched-chain alkoxy moiety and a C.sub.2-6
straight-chain or branched-chain alkenyl moiety, such as
2-methoxycarbonylvinyl, 3-methoxycarbonylallyl,
2-ethoxycarbonylvinyl, 4-ethoxycarbonyl-2-butenyl,
6-propoxycarbonyl-3-hexenyl, 5-isopropoxycarbonyl-1-pentenyl,
1,1-dimethyl-2-butoxycarbonyl-3-propenyl,
2-methyl-3-tertbutoxycarbonyl-1-propenyl, 2-pentyloxycarbonylvinyl,
4-hexyloxycarbonyl-1-butenyl and the like.
As to the carboxy-substituted lower alkenyl group, there can be
mentioned carboxyalkenyl groups each having a C.sub.2-6
straight-chain or branched-chain alkenyl moiety, such as
2-carboxyvinyl, 2-carboxyallyl, 4-carboxy-2-butenyl,
6-carboxy-3-hexenyl, 5-carboxy-1-pentenyl,
1,1-dimethyl-2-carboxy-2-propenyl, 2-methyl-3-carboxy-1-propenyl,
5-carboxy-4-pentenyl, 4-carboxy-1-butenyl and the like.
The five- or six-membered saturated heterocyclic ring which
R.sup.23 and R.sup.24 as well as the adjacent nitrogen atom being
bonded thereto may from together with or without other nitrogen
atom or oxygen atom, can be exemplified by piperazinyl,
pyrrolidinyl, morpholinyl and piperidinyl.
The above heterocyclic ring substituted with a lower alkyl group
can be exemplified by above heterocyclic rings each substituted
with a C.sub.1-6 straight-chain or branched-chain alkyl group. Such
as 4-methylpiperazinyl, 4-ethylpiperazinyl, 3-ethylpyrrolidinyl,
2-propylpyrrolidinyl, 4-butylpiperidinyl, 3-pentylmorpholino,
2-hexylpiperazinyl and the like.
The lower alkylsulfonyloxy group which may have halogen atoms, can
be exemplified by C.sub.1-6 straight-chain or branched-chain
alkylsulfonyloxy groups which may each have one to three halogen
atoms, such as methylsulfonyloxy, ethylsulfonyloxy,
propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy,
tert-butylsulfonyloxy, pentylsulfonyloxy, hexylsulfonyloxy,
chloromethylsulfonyloxy, bromomethylsulfonylosy,
iodomethylsulfonyloxy, triflouromethylsulfonyloxy,
2-fluoroethylsulfonyloxy, 2,2-diflouroethylsulfonyloxy,
2,2,2-trifluoroethylsulfonyloxy, 3-chloropropylsulfonyloxy,
4-chlorobutylsulfonyloxy, 3,4-dichlorobutylsulfonyloxy,
3-flouropentylsulfonyloxy, 2,3,4-trifluoropentylsulfonyloxy,
2,3-dichlorohexylsulfonyloxy, 6,6-dibromohexylsulfonyloxy and the
like.
As the lower alkoxy-substituted lower alkoxycarbonyl group, there
can be mentioned C.sub.1-6 straight-chain or branched-chain
alkoxyalkoxycarbonyl groups each having a C.sub.1-6 straight-chain
or branched-chain alkoxy moiety, such as methoxymethoxycarbonyl,
3-methoxypropoxycarbonyl, ethoxymethoxycarbonyl,
4-ethoxybutoxycarbonyl, 6-propoxyhexyloxycarbonyl,
5-isopropoxypentyloxycarbonyl, 1,1-dimethyl-2-butoxyethoxycarbonyl,
2-methyl-3-tert-butoxypropoxycarbonyl, 2-pentyloxyethoxycarbonyl,
hexyloxymethoxycarbonyl and the like.
The phenyl group which may have one to three lower alkoxy groups as
substituents on the phenyl ring, can be exemplified by phenyl
groups which may each have one to three C.sub.1-6 straight-chain or
branched-chain alkoxy groups as substitutes on the phenyl ring,
such as phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-ethoxyphenyl,
2-ethoxyphenyl, 3-ethoxyphenyl, 4-methoxyphenyl,
4-isopropoxyphenyl, 3-butoxyphenyl, 4-pentyloxyphenyl,
4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3-ethoxy-4-methoxyphenyl,
2,3-dimethoxyphenyl, 3,4-diethoxyphenyo, 3,5-dimethoxyphenyl,
2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3.4.5-trimethoxyphenyl,
3,4-dipentyloxyphenyl and the like.
The pyridyl group which may have an oxo group, can be exemplified
by pyridyl groups which may each have an oxo group, such as
pyridyl, 2-oxopyridyl, 3-oxopyridyl, 4-oxopyridyl and the like.
The quinolyl group which may have an oxo group, can be exemplified
by 2-oxoquinolyl and 4-oxoquinolyl.
The phenyl group having, as substituent(s) on the phenyl ring, one
to three groups selected from the group consisting of a lower
alkanoyloxy group, a hydroxysulfonyloxy group, a cyano group, an
amidino group, a nitro group, a lower alkylsulfonyl group, a
tetrahydropyranyloxy group which may have, as substituent(s), one
to four groups selected from the group consisting of a hydroxyl
group, a lower alkoxycarbonyl group, a phenyl-lower alkoxy group, a
hydroxyl group- or lower alkanoyloxy group-substituted lower alkyl
group and a lower alkanoyloxy group, a phenyl group which may have
groups selected from the group consisting of a thiazolyl group
having, as a substituent on the thiazolyl ring, a phenyl group
which may have lower alkoxy groups on the phenyl ring, a carboxyl
group and a hydroxyl group, a lower alkyl group having hydroxyl
groups, and a group ##STR35##
(wherein R.sup.21 and R.sup.22 are the same as defined above, can
be exemplified by phenyl groups each having, as substituent(s) on
the phenyl ring, one to three groups selected from the group
consisting of a C.sub.1-6 straight-chain or branched-chain
alkanoyloxy group, a hydroxysulfonyloxy group, a cyano group, an
amidino group, a nitro group, a C.sub.1-6 straight-chain or
branched-chain alkylthio group, a tetrahydropyranyloxy group which
may have, as substituents, one to four groups selected from the
group consisting of a hydroxyl group, a C.sub.1-6 straight-chain or
branched-chain alkoxycarbonyl group, a phenylalkoxy group having a
C.sub.1-6 straight-chain or branched-chain alkoxy moiety, a
C.sub.1-6 straight-chain or branched-chain alkyl group having one
to three hydroxyl groups or one to three C.sub.1-6 straight-chain
or branched-chain alkanoyloxy groups and a C.sub.1-6 straight-chain
or branched-chain alkanoyloxy group, a phenyl group which may have
one to three groups selected from the group consisting of a
thiazolyl group having, as a substituent on the thiazolyl ring, a
phenyl group which may have one to three C.sub.1-6 straight-chain
or branched-chain aloxy groups on the phenyl ring, a carboxyl group
and a hydroxyl group, a C.sub.1-6 straight-chain or branched-chain
alkyl group having one to three hydroxyl groups, and a group
##STR36##
(wherein R.sup.21 and R.sup.22, which may be th same or different,
each represent a hydrogen atom or a C.sub.1-6 straight-chain or
branched-chain alkyl group, such as 2-methylthiophenyl,
3-methylthiophenyl, 4-methylthiophenyl, 2-ethylthiophenyl,
3-ethylthiophenyl, 4-ethylthiophenyl, 4-isopropylthiophenyl,
4-pentylthiophenyl, 4-hexylthiophenyl, 3,4-dimethylthiophenyl,
3,4-diethylthiophenyl, 2-acetyloxyphenyl, 3-acetyloxyphenyl,
4-acetyloxyphenyl, 2-formyloxyphenyl, 3-propionyloxyphenyl,
4-isobutyryloxyphenyl, 2-pentanoyloxyphenyl, 3-hexanoyloxyphenyl,
3,4-diacetyloxyphenyl, 3,5-diacetyloxyphenyl,
2,5-diacetyloxyphenyl, 3,4,5-triacetyloxyphenyl-dimethylthiophenyl,
2,6-dimethylthiophenyl, 3,4,5-trimethylthiophenyl, 3-phenylphenyl,
4-phenylphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl,
4-methylsulfonylphenyl, 2-ethylsulfonylphenyl,
4-isopropylsulfonylphenyl, 4-pentylsulfonylphenyl,
4-hexylsulfonylphenyl, 3,4-dimethylsulfonylphenyl,
2,5-dimethylsulfonylphenyl, 2,6-dimethylsulfonylphenyl,
3,4,5-trimethylsulfonylphenyl, 2-amidinophenyl, 4-amidinophenyl,
3-amidinophenyl, 3-nitrophenyl, 4-hydroxysulfonyloxyphenyl,
3-hydroxysulfonyloxyphenyl, 2-hydroxysulfonyloxyphenyl,
4-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)phenyl,
4-(.beta.-D-glucopyranosyloxy) phenyl,
4-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy) phenyl,
3,5-bis(dimethylamino)phenyl, 2,nitrophenyl, 4-nitrophenyl,
3,4-dinitrophenyl, 3,4,5-trinitrophenyl, 3,5-dinitrophenyl,
2-cyanophenyl, 4-cyanophenyl, 3-cyanophenyl,
3-(2,3-dihydroxypropyl)phenyl, 3-(2-hydroxyethyl)phenyl,
4-(2-hydroxy-3-carboxyphenyl) phenyl,
4-[2-(3,4-diethoxyphenyl-4-thiazolyl]phenyl, 3-hydroxymethylphenyl,
##STR37##
and the like.
As to the lower alkoxy-substituted lower alkyl group, there can be
mentioned alkoxyalkyl groups each having a C.sub.1-6 straight-chain
or branched-chain alkoxy moiety and a 1-6 straight-chain or
branched-chain alkyl moiety, such as methoxymethyl,
3-methoxypropyl, ethoxymethyl, 4-ethoxybutyl, 6-propoxyhexyl,
5-isopropoxypentyl, 1,1-dimethyl-2-butoxyethyl,
2-methyl-3-tert-butoxypropyl, 2-pentyloxyethyl, hexyloxymethyl and
the like.
The lower alkenyl group having halogen atoms can be exemplified by
C.sub.2-6 straight-chain or branched-chain alkenyl groups each
having one to three halogen atoms, such as 2,2-dibromovinyl,
2-chlorovinyl, 1-fluorovinyl, 3-iodoallyl, 4,4-dichloro-2-butenyl,
4,4,3-tribromo-3-butenyl, 3-chloro-1-methylallyl,
5-bromo-2-pentenyl, 5,6-difluoro-2-hexenyl and the like.
As the phenyl-lower alkyl group, there can be mentioned phenylalkyl
groups each having a C.sub.1-6 straight-chain or branched-chain
alkyl moiety, such as benzyl 2-phenylethyl, 1-phenylpentyl,
3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl,
1,1-dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl and the
like.
The compound of general formula (I) according to the present
invention can be produced by, for example, the processes shown
below. ##STR38##
(wherein X, R.sup.1, R.sup.2, and R.sup.3 are the same as defined
above, Y represents a halogen atom).
The reaction between the compound (2) and the compound (3) can be
conducted by heating in an appropriate solvent. The solvent can be
exemplified by alcohols such as methanol, ethanol, propanol,
butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve
and the like; aromatic hydrocarbons such as benzene, toluene,
xylene, o-dichlorobenzene and the like; ethers such as diethyl
ether, tetrahydrofuran, dioxane, diglyme, monoglyme and the like;
halogenated hydrocarbons such as dichloromethane, chloroform,
carbon tetrachloride and the like; polar solvents such as
dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric
triamide, acetonitrile and the like; and mixed solvents thereof.
The reaction is conducted ordinarily at room temperature to
150.degree. C., preferably at about room temperature to 100.degree.
C. and is completed in about 1-15 hours.
The proper amount of the compound (3) used is at least 1mole,
preferably about 1 to 1.5 moles per 1 mole of the compound (2).
##STR39##
wherein r.sup.1, R.sup.2, R.sup.3 and Y are the same as defined
above).
The reaction between the compound (2) and the compound (3) can be
conducted in an appropriate solvent in the presence of a basic
compound. The solvent can be exemplified by lower alcohols such as
methanol, ethanol, propanol and the like; ethers such as diethyl
ether, tetrahydrofuran, dioxane, ethylene glycol monomethyl ether
and the like; halogenated hydrocarbons such as dichloromethane,
chloroform, carbon tetrachloride and the like; aromatic
hydrocarbons such as benzene, toluene, xylene and the like; asters
such as methyl acetate, ethyl acetate and the like; ketones such as
acetone, methyl ethyl ketone and the like; polar solvents such as
acetonitrile, dimethylformamide, dimethyl sulfoxide,
hexamethylphosphoric triamide and the like; and mixed solvents
thereof. The basic compound can be exemplified by inorganic bases
such as sodium hydroxide, potassium hydroxide, sodium carbonate,
potassium carbonate, sodium hydrogencarbonate, potassium
hydrogencarbonate, sodium hydride and the like; alkali metals such
as metallic sodium, metallic potassium and the like; alkali metal
alcoholates such as sodium methylate, sodium ethylate and the like;
and organic bases such as triethylamine, pyridine,
N,N-dimethylaniline, N-methylmorpholine, 4-methylaminopyridine,
bicyclo[4,3,0]nonene-5 (DBN), 1,8-diazabicyclo[5,4,0]-undecene-7
(DBU), 1-4-diazabicyclo[2,2,2]octane (DABCO) and the like.
The proper amount of the compound (4) used is at least 1 mole,
preferably about 1 to 1.5 moles per 1 mole of the compound (2).
The reaction is conducted ordinarily at room temperature to
200.degree. C., preferably at room temperature to about 150.degree.
C. and is completed in about 1-5 hours.
The reaction for converting the compound (5) into the compound (1a)
can be conducted in an appropriate solvent in the presence of an
ammonia water or an ammonium salt such as ammonium acetate,
ammonium chloride, ammonium sulfate or the like. The solvent can be
any of the solvents usable in the reaction between the compound (2)
and the compound (4); besides them, there can also be mentioned
alkanoic acids (e.g. acetic acid), etc. The proper amount of the
ammonia water or ammonium salt used is at least 1 mole, preferably
1 to 5 moles per 1 mole of the compound (5). The reaction is
conducted ordinarily at room temperature to 200.degree. C.,
preferably at about room temperature to 150.degree. C. and is
completed in about 1-5 hours. ##STR40##
(wherein R.sup.1, R.sup.2 and R.sup.3 are the same as defined
above).
The reaction between the compound (6) and the compound (4) can be
achieved by subjecting them to an ordinary amide bonding formation
reaction.
In this case, as to the carboxylic acid (4), an activated compound
thereof may be used. The conditions used in the amide bonding
formation reaction can be those used in ordinary amide bonding
formation reactions. For example, there can be used (a) a mixed
acid anhydride method, i.e. a method which comprises reacting a
carboxylic acid (4) with an alkylhalocarboxylic acid to obtain a
mixed acid anhydride and reacting the anhydride with a compound
(6); (b) an active ester or active amide method, i.e. a method
which comprises converting a carboxylic acid (4) into an active
ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester,
1-hydroxybenzotriazole ester or the like, or into an active amide
with benzoxazolin-2-thion and then reacting the active ester or
active amide with a compound (6); (c) a carbodiimide method, i.e. a
method which comprises subjecting a carboxylic acid (4) and a
compound (6) to dehydration in the presence of a dehydrating agent
such as dicyclohexylcarbodiimide, carbonyldiimidazole or the like;
(d) a carboxylic acid halide method, i.e. a method which comprises
converting a carboxylic acid (4) into a halide and reacting the
halide with a compound (6); and (e) other methods such as a method
which comprises reacting a carboxylic acid (4) with a dehydrating
agent such as acetic anhydride or the like to convert into a
carboxylic acid anhydride and reacting the anhydride with a
compound (4) or a method which comprises converting a carboxylic
acid (4) into an ester and reacting the ester with a compound (6)
at a high temperature at a high pressure. There can also be used a
method which comprises activating a carboxylic acid (4) with a
phosphorus compound such as triphenylphosphine, diethyl
chlorophosphate or the like and reacting the reaction product with
a compound (6).
As to the alkylhalocarboxylic acid used in the mixed acid anhydride
method, there can be mentioned, for example, methyl chloroformate,
methyl bromoformate, ethyl chloroformate, ethylbromoformate and
isobutyl chloroformate. The mixed acid anhydride can be obtained by
an ordinary Schotten-Baumann reaction and ordinarily, without being
subjected to an isolation procedure, is reacted with a compound
(6), whereby a compound (7) can be produced. The Schotten-Baumann
reaction is ordinarily conducted in the presence of a basic
compound. The basic compound is those conventionally used in the
Schotten-Baumann reaction; and there can be mentioned organic bases
such as triethylamine, trimethylamine, pyridine, dimethylaniline,
N-methyl-morpholine, 4-dimethylaminopyridine, DBN, DBU, DABCO and
the like, and inorganic bases such as potassium carbonate, sodium
carbonate, potassium hydrogen-carbonate, sodium hydrogencarbonate
and the like. The reaction is conducted at about -20.degree. C. to
100.degree. C., preferably 0.degree.-50.degree. C. The reaction
time is about 5 minutes to 10 hours, preferably 5 minutes to 2
hours. The reaction between the thus obtained mixed acid anhydride
and the compound (6) is conducted at about -20.degree. C. to
150.degree. C., preferably 10.degree.-50.degree. C. for about 5
minutes to 10 hours, preferably about 5 minutes to 5 hours. The
mixed acid anhydride method needs no solvent, but is generally
conducted in a solvent. The solvent can be any of those
conventionally used in the mixed acid anhydride method, and there
can be specifically mentioned, for example, halogenated
hydrocarbons such as methylene chloride, chloroform, dichloroethane
and the like, aromatic hydrocarbons such as benzene, toluene,
xylene and the like, ethers such as diethyl ether, diisopropyl
ether, tetrahydrofuran, dimethoxyethane and the like, esters such
as methyl acetate, ethyl acetate and the like, and aprotic polar
solvents such as dimethylformamide, dimethyl sulfoxide,
hexamethylphosphoric triamide and the like. In the above method,
the amounts of the carboxylic acid (4), the alkylhalocarboxylic
acid and the compound (6) used are ordinarily at least equimolar,
but preferably the alkylhalocarboxylic acid and the compound (6)
are used each in an amount of 1-2 moles per 1 mole of the
carboxylic acid (4).
The active ester or active amide method (b), when a case of using,
for example, benzoxazolin-2-thionamide is mentioned, is conducted
by carrying out a reaction at 0.degree.-150.degree. C., preferably
10.degree.-100.degree. C. for 0.5-75 hours in an appropriate
solvent not affecting the reaction, for example, the same solvent
as used in the above mixed acid anhydride method, or
1-methyl-2-pyrrolidone. The amounts of the compound (6) and
benzoxazolin-2-thionamide used are such that the latter is used in
an amount of at least 1 mole, preferably 1-2 moles per 1 mole of
the former. In a case using an N-hydroxysuccinimide ester, the
reaction proceeds advantageously by using an appropriate base, for
example, the same base as used in the carboxylic acid halide method
to be described later.
The carboxylic acid halide method (c) is conducted by reacting a
carboxylic acid (4) with a halogenating agent to convert into a
carboxylic acid halide and, after or without isolating and
purifying the halide, reacting the halide with a compound (6). The
reaction between the carboxylic acid halide and the compound (6) is
conducted in an appropriate solvent in the presence or absence of a
dehydrohalogenating agent. As to the dehydrohalogenating agent,
there is ordinarily used a basic compound, and there can be
mentioned the basic compounds used in the above Schotten-Baumann
reaction, sodium hydroxide, potassium hydroxide, sodium hydride,
potassium hydride, alkali metal alcholates (e.g. sodium methylate,
sodium ethylate), etc. Incidentally, it is possible to use the
compound (6) in an excessive amount to utilize the compound (6)
also as a dehydrohalogenating agent. As the solvent, there can be
mentioned, for example, water, alcohols (e.g. methanol, ethanol,
propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl
cellosolve), pyridine, acetone, acetonitrile and mixed solvents
thereof, in addition to the same solvents as used in the above
Schotten-Baumann reaction. The proportions of the compound (6) and
the carboxylic acid halide used are not particularly restricted and
can be selected from a wide range, but the latter is used in an
amount of ordinarily at least 1 mole, preferably 1-5 moles per 1
mole of the former. The reaction is conducted ordinarily at about
-30.degree. C. to 180.degree. C., preferably at about
0.degree.-150.degree. C. and is complete generally in 5 minutes to
30 hours. The carboxylic acid halide used is produced by reacting a
carboxylic acid (4) with a halogenating agent in the presence or
absence of a solvent. The solvent, can be any as long as it gives
no influence on the reaction, and includes aromatic hydrocarbons
such as benzene, toluene, xylene and the like, halogenated
hydrocarbons such as chloroform, methylene chloride, carbon
tetrachloride and the like, ethers such as dioxane,
tetra-hydrofuran, diethyl ether and the like, dimethylformamide,
dimethyl sulfoxide, etc. As the halogenating agent, there can be
used ordinary halogenating agents capable of converting the
hydroxyl group of carboxylic group into a halogen, and there can be
mentioned, for example, thionyl chloride, oxalyl chloride,
phosphorus oxychloride, phosphorus oxybromide, phosphorus
pentachloride and phosphorus pentabromide. The proportions of the
carboxylic acid (4) and the halogenating agent used are not
particularly restricted and can be selected appropriately; however,
when the reaction is conducted in a solventless state, the latter
is used ordinarily in a large excess relative to the former and,
when the reaction is conducted in a solvent, the latter is used in
an amount of ordinarily at least about 1 mole, preferably 2-4 moles
per 1 mole of the former. The reaction temperature and time are not
particularly restricted, either, but the reaction is conducted
ordinarily at about room temperature to 100.degree. C., preferably
at 50.degree.-80.degree. C. for about 30 minutes to 6 hours.
The method which comprises activating a carboxylic acid (4) with a
phosphorus compound such as triphenylphosphine, diethyl
chlorophosphate, diethyl cyanophosphate or the like and then
reacting the resulting product with a compound (6), is conducted in
an appropriate solvent. The solvent can be any as long as it gives
no influence on the reaction, and specifically includes halogenated
hydrocarbons such as dichloromethane, chloroform, dichloroethane
and the like, aromatic hydrocarbons such as benzene, toluene,
xylene and the like, ethers such as diethyl ether, tetrahydrofuran,
dimethoxyethane and the like, esters such as methyl acetate, ethyl
acetate and the like, aprotic polar solvents such as
dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric
triamide and the like, and so forth. In the reaction, the compound
(6) per se acts as a basic compound, and accordingly the reaction
proceeds advantageously by using it in an amount larger than the
stoichiometric amount; however, there may be used, as necessary,
other basic compound, for example, an organic base (e.g.
triethylamine, trimethylamine, pyridine, dimethylaminopyridine,
DBN, DBU, DABCO) or an inorganic base (e.g. potassium carbonate,
sodium carbonate, potassium hydrogencarbonate, sodium
hydrogencarbonate). The reaction is conducted at about
0.degree.-150.degree. C., preferably at about 0.degree.-100.degree.
C. and is complete in about 1-30 hours. The proportions of the
phosphorus compound and carboxylic acid (4) used relative to the
compound (6) are each ordinarily at least about 1 mole, preferably
1-3 moles per I mole of the compound (6).
The reaction for converting the compound (7) into the compound (1b)
can be conducted in a solventless state or in an appropriate
solvent in the presence of a sulfurizing agent such as
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide
(Lawesson's Reagent), phosphorus pentasulfide or the like. The
solvent can be any of those used in the reaction between the
compound (2) and the compound (4) in the above Reaction
scheme-2.
The proper amount of the sulfurizing agent used is ordinarily 0.5-2
moles, preferably 0.5-1.5 moles per 1 mole of the compound (7).
The reaction is conducted ordinarily at 50.degree.-300.degree. C.,
preferably at about 50.degree. C. to 250.degree. C. and is
completed in about 1-7 hours.
The compound (2) as a starting material can be produced by, for
example, the method of the following Reaction scheme-4 or -5.
##STR41##
(wherein R.sup.2, R.sup.3 and Y are the same as defined above).
The halogenation reaction for the compound (8) can be conducted in
an appropriate solvent in the presence of a halogenating agent. The
halogenating agent can be exemplified by halogen molecules (e.g.
bromine molecules, chlorine molecules), iodine chloride, sulfuryl
chloride, copper compounds (e.g. cuprous bromide) and N-halogenated
succinimides (e.g. N-bromo-succinimide, N-chlorosuccinimide). The
solvent can be exemplified by halogenated hydrocarbons (e.g.
dichloromethane, dichloroethane, chloroform, carbon tetrachloride),
fatty acids (e.g. acetic acid, propionic acid) and carbon
disulfide.
The proper amount of the halogenating agent used is ordinarily 1-10
moles, preferably 1-5 moles per 1 mole of the compound (8).
The reaction is conducted ordinarily at 0.degree. C. to the boiling
point of the solvent used, preferably at about 0.degree. C. to
100.degree. C. and is completed ordinarily in about 5 minutes to 20
hours. ##STR42##
(wherein R.sup.2 and Y are the same as defined above; Y.sub.1
represents a halogen atoms; R.sup.3 represents the above-mentioned
R.sup.3 other than a hydrogen atom, a lower alkyl group, a lower
alkoxycarbonyl-lower alkyl group, a lower alkoxycarbonyl group, a
carbamoyl-lower alkyl group, a phenyl-lower alkyl group which may
have a lower alkoxy group as a substituent on the phenyl ring and
hydroxyl groups as substituents on the lower alkyl group, a benzoyl
group which may have a lower alkoxy group as a substituent on the
phenyl ring, a phenyl-lower alkenyl group which may have a lower
alkoxy group as a substituent on the phenyl ring, and an adamantyl
group).
The reaction between the compound (9) and the compound (10) or the
compound (11) is generally called as Friedel-Crafts reaction and
can be conducted in an appropriate solvent in the presence of a
Lewis acid. The Lewis acid can be any one of Lewis acids generally
used in said reaction, and can be exemplified by aluminum chloride,
zinc chloride, iron chloride, tin chloride, boron tribromide, boron
trifuloride and concentrated sulfuric acid. The solvent can be
exemplified by carbon disulfide, aromatic hydrocarbons (e.g.
nitrobenzene, chlorobenzene) and halogenated hydrocarbons (e.g.
dichloromethane, dichloroethane, carbon tetrachloride,
tetrachloroethane). The proper amount of the compound (10) or the
compound (11) used is at least 1 mole, preferably 1-5 moles per 1
mole of the compound (9). The proper amount of the Lewis acid used
is ordinarily 2-6 moles per 1 mole of the compound (9).
The reaction is conducted ordinarily at 0.degree.-120.degree. C.,
preferably at about 0.degree.-70.degree. C. and is completed in
about 0.5-24 hours.
The compound (3) as a starting material can be produced by, for
example, the method of the following Reaction scheme-6 or -7.
##STR43##
(R.sup.1 is the same as defined above; R.sup.4 represents a lower
alkyl group).
The reaction between the compound (12) and the compound (13) can be
conducted in an appropriate solvent in the presence of an acid.
The solvent can be any of those used in the reaction between the
compound (2) and the compound (4) in the reaction scheme 2.
The acid can be exemplified by mineral acids such as hydrochloric
acid, hydrobromic acid, sulfuric acid and the like.
The amount of the compound (13) used is ordinarily 1-5 moles,
preferably 1-3 moles per 1 mole of the compound (12).
The reaction is conducted ordinarily at room temperature to
200.degree. C., preferably at about room temperature to 150.degree.
C. and is complete in about 1-15 hours. ##STR44##
(wherein R.sup.1 is the same as defined above).
The reaction for converting the compound (14) into the compound
(3b) can be conducted in an appropriate solvent in the presence of
a.degree. sulfurizing agent.
The solvent can be any of those used in the reaction between the
compound (2) and the compound (4) in the reaction scheme 2.
The sulfurizing agent can be exemplified by phosphorus pentasulfide
and Lawesson's Reagent.
The proper amount of the sulfurizing agent used is ordinarily 1-10
moles, preferably 1-2 moles per 1 mole of the compound (14).
The reaction is conducted ordinarily at room temperature to
150.degree. C., preferably at about room temperature to 100.degree.
C. and is complete in about 10 minutes to 5 hours.
When in general formula (1), R.sup.1 and R.sup.3 is a 5- to
15-membered monocyclic, bicyclic or tricyclic heterocyclic residual
group having at least one tertiary nitrogen atom, the compound (1)
can be converted, by oxidation, into a corresponding compound where
the at least one nitrogen atom of said heterocyclic residual group
is converted into an oxide form (N.fwdarw.0). Also, when in general
formula (1), R.sup.1 or R.sup.3 is a phenyl group having at least
one lower alkylthio group, the phenyl group can be converted, by
the oxidation under the same conditions, into a phenyl group having
at least one lower alkylsulfinyl group or at least one lower
alkylsulfonyl group.
When the compound (1) has both of the above two groups (the 5- to
15-membered monocyclic, bicyclic or tricyclic heterocyclic residual
group having at least one tertiary nitrogen atom and the phenyl
group having at least one lower alkylthio group), then it is
possible that the two groups be oxidized simultaneously under the
above oxidation conditions. The oxidation product can be easily
separated.
These oxidation reactions can be conducted in an appropriate
solvent in the presence of an oxidizing agent. The solvent can be
exemplified by water, organic acids (e.g. formic acid, acetic acid,
trifluoroacetic acid), alcohols (e.g. methanol, ethanol),
halogenated hydrocarbons e.g. chloroform, dichloromethane) and
mixed solvents thereof. As to the oxidizing agent, there can be
mentioned, for example, peracids (e.g. performio acid, peracetic
acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic
acid, o-carbonylperbenzoic acid), hydrogen peroxide, sodium
metaperiodate, bichromic acid, bichromates (e.g. sodium bichromate,
potassium bichromate), permanganic acid and permanganates (e.g.
potassium permanganate, sodium permanganate).
The proper amount of the oxidizing agent used is ordinarily at
least 1 mole, preferably 1-2 moles per 1 mole of the starting
material. The reaction is conducted ordinarily at
0.degree.-40.degree. C. preferably at about 0.degree. C. to room
temperature and is completed in about 1-15 hours.
When in general formula (1), R.sup.1 or R.sup.3 is a 5- to
15-membered monocyclic, bicyclic or tricyclic heterocyclic residual
group having at least one N-oxide group, the heterocyclic residual
group can be converted into a 5- to 15-membered monocyclic,
bicyclic or tricyclic heterocyclic residual group having at least
one oxo group, by a reaction in a high-boiling solvent (e.g.
tetralin, diphenyl ether, diethylene glycol dimethyl ether or
acetic anhydride), ordinarily at 100.degree.-250.degree. C.,
preferably at about 100.degree.-200.degree. C. for about 1-10
hours.
When in general formula (1), R.sup.1 or R.sup.3 is a 5- to
15-membered monocyclic, bicyclic or tricyclic heterocyclic residual
group having at least one oxo group adjacent to the nitrogen atom
of the heterocyclic ring, the compound (1) can be converted, by
reduction, into a corresponding compound where said at least one
oxo group is converted into a methylene group.
The reduction can be conducted by, for example, catalytic
hydrogenation in an appropriate solvent in the presence of a
catalyst. As to the solvent, there can be mentioned, for example,
water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol),
hydrocarbons (e.g. hexane, cyclohexane), ethers (e.g. diethylene
glycol dimethyl ether, dioxane, tetrahydrofuran, diethyl ether),
esters (e.g. ethyl acetate, methyl acetate), aprotic polar solvents
(e.g. dimethylformamide) and mixed solvents thereof. As to the
catalyst, there can be used, for example, palladium, palladium
black, palladium-carbon, platinum, platinum oxide, copper chromite
and Raney nickel. The proper amount of the catalyst used is
generally about 0.02-1 time the weight of the starting material.
Desirably, the reaction temperature is ordinarily about -20.degree.
C. to 100.degree. C., preferably about 0.degree.-70.degree. C. and
the hydrogen pressure is ordinarily 1-10 atm. The reaction is
complete generally in about 0.5-20 hours. The reduction may be
conducted by catalytic hydrogenation, but can be conducted
preferably by a method using a hydride reducing agent. As the
hydride reducing agent, there can be mentioned, for example,
lithium aluminum hydride, sodium boron hydride and diborane. The
amount of the hydride reducing agent used is ordinarily at least 1
mole, preferably 1-15 moles per 1 mole of the starting compound.
The reduction reaction is conducted ordinarily at about -60.degree.
C. to 150.degree. C. preferably -30.degree. C. to 100.degree. C.
for about 10 minutes to 10 hours, ordinarily using an appropriate
solvent, for example, water, a lower alcohol (e.g. methanol,
ethanol, isopropanol), an ether (e.g. tetrahydrofuran, diethyl
ether, diisopropyl ether, diglyme) or a mixture thereof. The use of
an anhydrous solvent such as diethyl ether, diisopropyl ether,
tetrahydrofuran, diglyme or the like is preferred when the reducing
agent used is lithium aluminum hydride or diborane.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one lower alkoxy group or at least one lower
alkoxy-substituted lower alkoxy group, the phenyl group can be
converted into a phenyl group having at least one hydroxyl group,
by a dealkylation reaction or a dealkoxy-alkylation reaction.
The dealkylation reaction is conducted by treating the compound (1)
in the presence of a catalytic reduction catalyst (e.g.
palladium-carbon, palladium black) at about 0.degree.-100.degree.
C. at a hydrogen pressure of 1-10 atm. for about 0.5-3 hours in an
appropriate solvent, for example, water, a lower alcohol (e.g.
methanol, ethanol, isopropanol), an ether (e.g. dioxane,
tetrahydrofuran), acetic acid or a mixed solvent thereof, or by
heat-treating the compound (1) at 30.degree.-150.degree. C.,
preferably 50.degree.-120.degree. C. in a mixture of an acid (e.g.
hydrobromic acid, hydrochloric acid) with a solvent (e.g. water,
methanol, ethanol, isopropanol), whereby a compound (1) having a
hydroxyl group as R.sup.1 or R.sup.3 can be derived. A compound (1)
having a hydroxyl group as R.sup.1 or R.sup.3 can also be obtained
by hydrolysis. This hydrolysis is conducted in an appropriate
solvent in the presence of an acid or a basic compound. As to the
solvent, there can be mentioned, for example, water, lower alcohols
(e.g. methanol, ethanol, isopropanol), ethers (e.g. dioxane,
tetrahydrofuran), halogenated hydrocarbons (e.g. dichloromethane,
chloroform, carbon tetrachloride), polar solvents (e.g.
acetonitrile), fatty acids (e.g. acetic acid) and mixed solvents
thereof. As to the acid, there can be mentioned, for example,
mineral acids (e.g. hydrochloric acid, hydrobromic acid), organic
acids (e.g. trifluoroacetic acid). Lewis acids (e.g. boron
trifluoride, boron tribromide, aluminum chloride), iodides (e.g.
sodium iodide, potassium iodide) and mixtures between said Lewis
acid and said iodide. As to the basic compound, there can be
mentioned, for example, metal hydroxides such as sodium hydroxide,
potassium hydroxide, calcium hydroxide and the like. The reaction
proceeds favorably ordinarily at room temperature to 200.degree.
C., preferably at room temperature to 150.degree. C. and is
completed generally in about 0.5-50 hours.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one hydroxyl group, the phenyl group can be
converted into a phenyl group having at least one lower alkoxy
group or at least one lower alkoxy-substituted lower alkoxy group,
by an alkylation reaction. The alkylation reaction can be
conducted, for example, by reacting the compound (1) with an
alkylating agent such as a dialkyl sulfate (e.g. dimethyl sulfate),
diazomethane or a compound represented by the general formula,
(wherein R.sup.5 is a lower alkyl group or a lower
alkoxy-substituted lower alkyl group and Y represents a halogen
atom) in an appropriate solvent in the presence of a basic
compound. The solvent can be exemplified by alcohols such as
methanol, ethanol, propanol and the like; ethers such as diethyl
ether, tetrahydrofuran, dioxane, ethylene glycol monomethyl ether
and the like; aromatic hydrocarbons such as benzene, toluene,
xylene and the like; esters such as methyl acetate, ethyl acetate
and the like; ketones such as acetone, methyl ethyl ketone and the
like; polar solvents such as acetonitrile, dimethylformamide,
dimethyl sulfoxide, hexamethylphosphoric triamide and the like; and
mixed solvents thereof. The basic compound can be exemplified by
inorganic bases such as sodium hydroxide, potassium hydroxide,
sodium carbonate, potassium carbonate, sodium hydrogencarbonate,
potassium hydrogencarbonate, sodium hydride and the like; alkali
metals such as metallic sodium, metallic potassium and the like;
alkali metal alcoholates such as sodium ethylate, sodium ethylate
and the like; and organic bases such as triethylamine, pyridine,
N,N-dimethylaniline, N-methylmorpholine, 4-methylaminopyridine,
DBN, DBU, DABCO and the like.
The proper amount of the alkylating agent used is at least 1 mole,
preferably 1-5 moles per 1 mole of the starting compound.
The reaction is conducted ordinarily at 0.degree.-150.degree. C.,
preferably at about room temperature to 100.degree. C. and is
completed in about 0.5-20 hours.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one group selected from an alkoxycarbonyl group, a
lower alkoxy-substituted lower alkoxycarbonyl group, a lower
alkoxycarbonyl-substituted alkenyl group and a lower
alkoxycarbonyl-lower alkyl group, or is a 5- to 15-membered
monocyclic, bicyclic or tricyclic heterocyclic residual group
having 1-2 nitrogen, oxygen or sulfur atoms, having at least one
lower alkoxycarbonyl group, the R.sup.1 or R.sup.3 can be
converted, by hydrolysis, into a phenyl group having at least one
group selected from a carboxy group, a carboxy-substituted lower
alkenyl group and a carboxy-substituted lower alkyl group, or into
a 5- to, 15-membered monocyclic, bicyclic or tricyclic heterocyclic
residual group having 1-2 nitrogen, oxygen or sulfur atoms, having
at least one carboxy group.
The hydrolysis reaction can be conducted under any conditions
ordinarily employed in hydrolysis. It is specifically conducted in
the presence of a basic compound (e.g. sodium carbonate, potassium
carbonate, sodium hydroxide, potassium hydroxide or barium
hydroxide), a mineral acid (e.g. sulfuric acid, hydrochloric acid
or nitric acid), an organic acid (e.g. acetic acid or aromatic
sulfonic acid) or the like in a solvent such as water, alcohol
(e.g. methanol, ethanol or isopropanol), ketone (e.g. acetone or
methyl ethyl ketone), ether (e.g. dioxane or ethylene glycol
dimethyl ether), acetic acid or the like, or in a mixed solvent
thereof. The reaction proceeds ordinarily at room temperature to
200.degree. C., preferably at about from room temperature to
180.degree. C. and is completed generally in about 10 minutes to 30
hours.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one amino group which may have a lower alkyl group
or a lower alkanoyl group, a phenyl group having, as a substituent
on the phenyl ring, a group of the formula ##STR45##
wherein R.sup.8 and R.sup.9, together with the nitrogen atom being
bonded thereto, form a 5- to 6-membered saturated heterocyclic ring
having a secondary nitrogen atom, or a 5- to 15-membered
monocyclic, bicyclic or tricyclic heterocyclic residual group
having at least one secondary nitrogen atom, then the R.sup.1 or
R.sup.3 can be converted, by an alkylation reaction, into a phenyl
group which has at least one amino group having 1-2 lower alkyl
groups or having a lower alkyl group and a lower alkanoyl group, a
phenyl group having, as a substituent on the phenyl ring, a group
of the formula ##STR46##
wherein R.sup.8 and R.sup.9, together with the nitrogen atom being
bonded thereto, form a 5- to 6-membered saturated heterocyclic ring
having a nitrogen atom to which a lower alkyl group is bonded, or a
5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic
residual group having at least one nitrogen atom having a lower
alkyl group as a substituent thereon. When the compound (1) has
both of the above two groups (the phenyl group having at least one
amino group, the 5- to 15-membered monocyclic, bicyclic or
tricyclic heterocyclic residual group having at least one secondary
nitrogen atom, or the amino-lower alkyl group), it is possible that
the two groups be alkylated simultaneously, and the alkylation
product can be separated easily.
The alkylation reaction is conducted by reacting the compound (1)
with a compound represented by the general formula
(wherein R.sup.5 and Y are the same as defined above) in an
appropriate inert solvent in the presence of a dehydrohalogenating
agent.
The inert solvent can be exemplified by halogenated hydrocarbons
such as dichloromethane, chloroform and the like; ethers such as
tetrahydrofuran, diethyl ether and the like; aromatic hydrocarbons
such as benzene, toluene, xylene and the like; esters such as
methyl acetate, ethyl acetate and the like; and polar solvents such
as dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric
triamide, acetonitrile, acetone, acetic acid, pyridine, water and
the like. As the dehydrohalogenating agent, there can be mentioned,
for example, organic bases such as triethylamine, trimethylamine,
pyridine, dimethylaniline, N-methyl-morpholine,
4-dimethylaminopyridine, 4-(1-pyrrolidinyl)-pyridine,
1,5-diazabicyclo[4,3,0]nonene-5 (DBN),
1,8-diazabicyclo[5,4,0]undecene-7 (DBU),
1,4-diazabicyclo-[2,2,2]octane (DABCO), sodium acetate and the
like, as well as inorganic bases such as sodium hydride, potassium
carbonate, sodium carbonate, potassium hydrogencarbonate, sodium
hydrogencarbonate, potassium hydroxide, sodium hydroxide and the
like. The proper amount of the compound (15) used is ordinarily at
least 1 mole, preferably 1-3 moles per 1 mole of the starting
material. The reaction is conducted ordinarily at about -20.degree.
C. to 150.degree. C., preferably at 0.degree.-100.degree. C. and is
completed in about 5 minutes to 15 hours.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one amino group which may have a lower alkyl group,
a phenyl group having at least one hydroxyl group, a 5- to
15-membered monocyclic, bicyclic or tricyclic heterocyclic residual
group having at least one secondary nitrogen atom, a phenyl group
having, as a substituent on the phenyl ring, a group of the formula
##STR47##
wherein R.sup.8 and R.sup.9, together with the nitrogen atom being
bonded thereto, form a 5- to 6-membered saturated heterocyclic ring
having a secondary nitrogen atom, or a phenyl group having at least
one tetrahydropyranyloxy group having, as a substituent, at least
one group selected from a hydroxyl group and a hydroxyl
group-substituted lower alkyl group, the R.sup.1 or R.sup.3 can be
converted, by a lower alkanoylation reaction, into a phenyl group
having at least one amino group which has a lower alkanoyl group or
has a lower alkanoyl group and a lower alkyl group, a phenyl group
having at least one alkanoyloxy group, a 5- to 15-membered
monocyclic, bicyclic or tricyclic heterocyclic residual group
having at least one nitrogen atom having a lower alkanoyl group as
a substituent thereon, a phenyl group having, as a substituent on
the phenyl ring, a group of the formula ##STR48##
wherein R.sup.8 and R.sup.9 together with the nitrogen atom being
bonded thereto, form a 5- to 6-membered saturated heterocyclic ring
having a nitrogen atom to which a lower alkanoyl group is bonded,
or a phenyl group having at least one tetrahydropyranyloxy group
having, as a substituent, at least one group selected from a lower
alkanoyloxy group and a lower alkanoyloxy group-substituted lower
alkyl group. In the above reaction, when the compound (1) has the
above three groups (the phenyl group having at least one amino
group which may have a lower alkyl group, the phenyl group having
at least one hydroxyl group and the 5- to 15-membered monocyclic,
bicyclic or tricyclic heterocyclic residual group having at least
one secondary nitrogen atom), it is possible that all of the three
groups be alkanoylated simultaneously, and the alkanoylation
product can be separated easily.
The alkanoylation reaction is conducted by reacting the compound
(1) with an alkanoylating agent, for example, a compound
represented by the general formula,
or
(wherein R.sup.6 represents a lower alkanoyl group and Y is the
same as above) in a solventless state or in an appropriate solvent
in the presence or absence, preferably the presence of a basic
compound. As to the appropriate solvent, there can be used, for
example, the above-mentioned aromatic hydrocarbons, lower alcohols
(e.g. methanol, ethanol, propanol), DMF, DMSO, halogenated
hydrocarbons (e.g. chloroform, methylene chloride), acetone and
pyridine. The basic compound can be exemplified by tertiary amines
(e.g. triethylamine, pyridine), sodium hydroxide, potassium
hydroxide and sodium hydride. The proper amount of the lower
alkanoylation agent used is at least 1 mole, preferably 1-10 moles
per 1 mole of the starting material. The reaction is conducted
ordinarily at room temperature to 200.degree. C., preferably at
room temperature to 150.degree. C. and is completed in about 0.5-15
hours.
When in the compound (1), R.sup.1 or R.sup.3 is a 5- to 15-membered
monocyclic, bicyclic or tricyclic heterocyclic residual group
having at least one secondary nitrogen atom, the R.sup.1 or R.sup.3
can be converted into a 5- to 15-membered monocyclic, bicyclic or
tricyclic heterocyclic residual group having at least one nitrogen
atom having a benzoyl group as a substituent thereon, by reacting
the compound (1) with a compound represented by the general
formula,
(wherein R.sup.7 represents a benzoyl group and Y represents a
halogen atom).
The reaction can be conducted under the same conditions as employed
in the above alkylation reaction.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one carboxy group or a 5- to 15-membered
monocyclic, bicyclic or tricyclic heterocyclic residual group
having 1-2 hetero atoms selected from a nitrogen atom, an oxygen
atom and a sulfur atom, having at least one carboxy group, the
R.sup.1 or R.sup.3 can be converted, by an esterification reaction,
into a phenyl group having at least one alkoxycarbonyl group or at
least one phenyl-lower alkoxycarbonyl group, or a 5- to 15-membered
monocyclic, bicyclic or tricyclic residual group having 1-2 hetero
atoms selected from a nitrogen atom, an oxygen atom and a sulfur
atom, having at least one lower alkoxycarbonyl group.
The esterification reaction can be conducted by reacting the
compound (1) with an alcohol such as methyl alcohol, ethyl alcohol,
isopropyl alcohol, benzyl alcohol or the like, in the presence of a
mineral acid (e.g. hydrochloric acid, sulfuric acid) and a
halogenating agent (e.g. thionyl chloride, phosphorus oxychloride,
phosphorus pentachloride, phosphorus trichloride) ordinarily at
0.degree.-150.degree. C., preferably at 50.degree.-100.degree. C.
for about 1-10 hours.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having a hydroxyl group and an amino group, the hydroxyl group and
the amino group being adjacent to each other, the compound (1) can
be converted into a compound (1) where R.sup.1 or R.sup.3 is
benzoxazol-2-one, by reacting the former compound (i) with phosgene
in an appropriate solvent in the presence of a basic compound. The
basic compound and the solvent can each be any of those used in the
reaction between the compound (2) and the compound (4) in the
Reaction scheme-2.
The reaction is conducted ordinarily at 0.degree.-100.degree. C.,
preferably at about 0.degree.-70.degree. C. and is complete in
about 1-5 hours.
A compound (1) where R.sup.1 or R.sup.3 is a phenyl group having at
least one amide group which may have a lower alkyl group as a
substituent, can be obtained by reacting a compound (1) where
R.sup.1 or R.sup.3 is a phenyl group which may have at least one
carboxy group, with an amine which may have a lower alkyl group as
a substituent, under the same conditions as employed in the amide
bonding formation reaction in the reaction scheme 3.
A compound (1) where R.sup.1 or R.sup.3 is a benzoyl group which
may have a lower alkoxy group as a substituent on the phenyl ring,
when reduced by the same reduction using a hydride reducing agent
as employed for the compound where R.sup.1 or R.sup.3 is a 5- to
15-membered monocyclic, bicyclic or tricyclic heterocyclic residual
group having at least one oxo group adjacent to the nitrogen atom
of the heterocyclic ring, can be converted into a compound (1)
where R.sup.1 or R.sup.3 is a phenyl-lower alkyl group which may
have a lower alkoxy group as a substituent on the phenyl ring and
which has a hydroxyl group as a substituent on the lower alkyl
group.
A compound (1) where R.sup.1 or R.sup.3 is a benzyl group which may
have a lower alkoxy group as a substituent on the phenyl ring, when
oxidized under the same conditions as employed for the compound
where R.sup.1 or R.sup.3 is a 5- to 15-membered monocyclic,
bicyclic or tricyclic heterocyclic residual group having at least
one tertiary nitrogen atom, except that the reaction temperature is
changed to ordinarily room temperature to 200.degree. C.,
preferably room temperature to 150.degree. C., can be converted
into a compound (1) where R.sup.1 or R.sup.3 is a benzoyl group
which may have a lower alkoxy group as a substituent on the phenyl
ring. ##STR49##
[wherein R.sup.1, R.sup.2, R.sup.8, R.sup.9 and X are the same as
defined above; R.sup.10 represents an alkoxy group, a tri-lower
alkyl group-substituted silyloxy group, a lower alkyl group, a
hydroxyl group, a lower alkenyloxy group, a lower alkylthio group,
a phenyl group which may have a group selected from the group
consisting of a thiazolyl group which may have, as a substituent on
the thiazolyl group, a phenyl group which may have a lower alkoxy
group on the phenyl ring, a carboxy group and a hydroxyl group, a
lower alkylsulfinyl group, a lower alkylsulfonyl group, a halogen
atom, a nitro group, a group of the formula, ##STR50##
(wherein A, l, R.sup.8 and R.sup.9 are the same as above), a lower
alkanoyl group, a lower alkanoyloxy group, an alkoxycarbonyl group,
a cyano group, a tetrahydropyranyloxy group which may have 1-4
substituents selected from the group consisting of a hydroxyl
group, a lower alkoxycarbonyl group, a phenyl-lower alkoxy group, a
hydroxyl group- or lower alkanoyloxy group-substituted lower alkyl
group and a lower alkanoyloxy group, an amidino group, a
hydroxysulfonyloxy group, a lower alkoxycarbonyl-substituted lower
alkoxy group, a carboxy-substituted lower alkoxy group, a mercapto
group, a lower alkoxy-substituted lower alkoxy group, a lower alkyl
group having hydroxyl groups, a lower alkenyl group, an
aminothiocarbonyloxy group which may have a lower alkyl group as a
substituent, an aminocarbonylthio group which may have a lower
alkyl group as a substituent, a lower alkanoyl-substituted lower
alkyl group, a carboxy group, an amino-lower alkoxycarbonyl group
which may have a lower alkyl group as a substituent, a group of the
formula, ##STR51##
(R.sup.21 and R.sup.22, which may be the same or different, each
represent a hydrogen atom or a lower alkyl group), a phenyl-lower
alkoxycarbonyl group, a cycloalkyl group, a lower alkynyl group, a
lower alkoxycarbonyl-substituted lower alkyl group, a
carboxy-substituted alkyl group, a lower alkoxycarbonyl-substituted
lower alkenyl group, a carboxy-substituted lower alkenyl group, an
amino-lower alkoxy group which may have a lower alkyl group as a
substituent, an amino-lower alkoxy-substituted lower alkyl group
which may have a lower alkyl group as a substituent, an amino-lower
alkoxycarbonyl-substituted lower alkyl group which may have a lower
alkyl group as a substituent, a lower alkylsulfonyloxy group which
may have a halogen atom, or a lower alkoxy-substituted lower
alkoxycarbonyl group) m and m' are each represent 0 or an integer
of 1-3.]
The reaction between the compound (1c) and the compound (19) can be
conducted by, for example,
1 a method (Mannich reaction) wherein ,the compound (1c) is reacted
with ##STR52##
(R.sup.8 and R.sup.9 are the same as defined above) and
formaldehyde, or
2 a method wherein the compound (1c) is reacted with a compound
(20), ##STR53##
The method 1 is conducted by reacting the compound (1c), the
compound (19) and formaldehyde in an appropriate solvent in the
presence or absence of an acid. The solvent can be any of those
ordinarily used in the Mannich reaction, and can be exemplified by
water, alcohols (e.g. methanol, ethanol, isopropanol), alkanoic
acids (e.g. acetic acid, propionic acid), acid anhydrides (e.g.
acetic anhydride), plar solvents (e.g. acetone, dimethylformamide)
and mixed solvents thereof. The acid can be exemplified by mineral
acids (e.g. hydrochloric acid, hydrobromic acid) and organic acids
(e.g. acetic acid). As the formaldehyde, there are ordinarily used
an aqueous solution containing 20-40% by weight of formaldehyde, a
formaldehyde trimer, a formaldehyde polymer (paraformaldehyde),
etc. The proper amount of the compound (19) used is ordinarily at
least 1 mole, preferably 1-5 moles per 1 mole of the compound (1c).
The proper amount of formaldehyde used is at least 1 mole per 1
mole of the compound (1c) and ordinarily a large excess relative to
the compound (1c). The reaction proceeds ordinarily at
0.degree.-200.degree. C., preferably at about room temperature to
150.degree. C. and is completed in about 0.5-10 hours.
The method 2 is conducted by carrying out the reaction in the
presence of an acid in an appropriate solvent or without solvent.
The acid can be exemplifed by mineral acids (e.g. hydrochloric
acid, hydrobromic acid, sulfuric acid) and organic acids (e.g.
acetic acid, acetic anhydride), preferably acetic anhydride. The
solvent can be any of those used in the method 1. The proper amount
of the compound (20) used is ordinarily at least 1 mole, preferably
1-5 moles per 1 mole of the compound (1c). The reaction is
conducted ordinarily at 0.degree.-150.degree. C., preferably at
about room temperature to 100.degree. C. and is completely in about
0.5-5 hours.
In said reaction, when R.sup.1 represents a group of the formula,
##STR54##
there may also be formed, in some cases, a reaction product between
the group of R' in compound (1c) with compound (19) or the compound
(20), and such product, can easily be separated from the reaction
mixture. ##STR55##
(wherein R.sup.2, R.sup.3, R.sup.8, R.sup.9, R.sup.10, m, m' and X
are the same as defined above).
The reaction for converting the compound (1c') into a compound
(1d') can be conducted under the same conditions as employed in the
reaction for convering the compound (1c) into a compound (1d) in
the Reaction scheme-8.
In said reaction, when R.sup.3 represents a group of the formula,
##STR56##
there may also be formed, in some cases, a reaction product of the
group of R.sup.3 in compound (1c') with compound (19) or the
compound (20), and such product, can easily be separated from the
reaction mixture. ##STR57##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.9, R.sup.10, and X are
the same as defined above; n represents 0 or an integer of
1-4).
The reaction between the compound (1e) and the compound (19) and
the reaction between the compound (1e') and the compound (19) can
be conducted under the same conditions as employed in the reaction
between the compound (6) and the compound (4) in the Reaction
scheme-3. ##STR58##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.8, R.sup.9, R.sub.10, n
and X are the same as defined above).
The reaction for converting the compound (1f) into a compound (1g)
and the reaction for converting the compound (1f') into a compound
(1g') can be conducted under the same conditions as employed in the
above-mentioned reduction reaction for the compound (1) where
R.sup.1 or R.sup.3 is a 5- to 15- membered monocyclic, bicyclic or
tricyclic heterocyclic residual group having at least one oxo group
adjacent to the nitrogen atom of the heterocyclic ring.
##STR59##
(wherein R.sup.1, R.sup.2, R.sup.8, R.sup.9, R.sup.10, X and n are
the same as defined above; Y.sup..alpha. represents a halogen atom
or a lower alkylsulfonyloxy group which may have a halogen
atom).
The reaction between the compound (1h) and the compound (19) and
the reaction between the compound (1h') and the compound (19) are
conducted in an appropriate inert solvent in the presence or
absence of a basic compound. The inert solvent can be exemplified
by halogenated hydrocarbons such as dichloromethane, chloroform and
the like; ethers such as tetrahydrofuran, diethyl ether and the
like; aromatic hydrocarbons such as benzene, toluene, xylene and
the like; esters such as methyl acetate, ethyl acetate and the
like; and polar solvents such as dimethylformamide, dimethyl
sulfoxide, hexamethylphosphoric triamide, acetonitrile, acetone,
acetic acid, pyridine, water and the like. As to the basic
compound, there can be mentioned, for example, organic bases such
as triethylamine, trimethylamine, pyridine, dimethylaniline,
N-methylmorpholine, 4-dimethylaminopyridine,
4-(1-pyrrolidinyl)pyridine, 1,5-diazabicyclo[4,3,0]nonene-5 (DBN),
1,8-diazabicyclo-[5,4,0]undecene-7 (DBU),
1,4-diazabicyclo[2,2,2]octane (DABCO), sodium acetate and the like;
and inorganic bases such as sodium hydride, potassium carbonate,
sodium carbonate, potassium hydrogencarbonate, sodium
hydrogencarbonate, potassium hydroxide, sodium hydroxide and the
like. The proper amount of the compound (19) used is ordinarily at
least 1 mole, preferably 1-3 moles per 1 mole of the compound (1b)
or the compound (1h'). The reaction is conducted ordinarily at
about -20.degree. C. to 180.degree. C., preferably at
0.degree.-150.degree. C. and is completed in about 5 minutes to 15
hours. The reaction proceeds favorably when a catalyst such as
copper powder or the like is added. ##STR60##
(wherein R.sup.1 and X are the same as defined above; R.sup.10a and
R.sup.11 each represent a lower alkoxycarbonyl group).
The reaction between the compound (ij) and the compound (21) is
conducted in an appropriate solvent in a sealed tube. The solvent
can be any of those used in the reaction between the compound (2)
and the compound (3) in the Reaction Scheme-1. The proper amount of
the compound (21) used is at least 1 mole per 1 mole of the
compound (1j) and is ordinarily a large excess relative to the
compound (1j). The reaction is conducted ordinarily at
50.degree.-200.degree. C., preferably at about
50.degree.-150.degree. C. and is completed in about 10-50 hours.
##STR61##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.8, R.sup.9, R.sup.10, X,
n and Y are the same as defined above; A' represents a lower
alkylene group).
The reaction between the compound (1l) and the compound (19) and
the reaction between the compound (1l') and the compound (19) are
conducted in an appropriate inert solvent in the presence of a
dehydro-halogenating agent. The inert solvent can be exemplified by
halogenated hydrocarbons such as dichloromethane, chloroform and
the like; ethers such as tetrahydrofuran, diethyl ether and the
like; aromatic hydrocarbons such as benzene, toluene, xylene and
the like; esters such as methyl acetate, ethyl acetate and the
like; polar solvents such as dimethylformamide, dimethyl sulfoxide,
hexamethylphosphoric triamide, acetonitrile, acetone, acetic acid,
pyridine, water and the like; and mixed solvents thereof. As to the
dehydrohalogenating agent, there can be mentioned, for example,
organic bases such as triethylamine, trimethylamine, pyridine,
dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine,
4-(1-pyrrolidinyl)-pyridine, 1,5-diazabicyclo[4,3,0]nonene-5 (DBN),
1,8-diazabicyclo[5,4,0]undecene-7 (DBU),
1,4-diazabicyclo-[2,2,2]octane (DABCO), sodium acetate and the
like; and inorganic bases such as sodium hydride, potassium
carbonate, sodium carbonate, potassium hydrogencarbonate, sodium
hydrogencarbonate, potassium hydroxide, sodium hydroxide and the
like. The proper amount of the compound (19) used is ordinarily at
least 1 mole, preferably 1-3 moles per 1 mole of the compound (1l)
or the compound (1l'). The reaction is conducted ordinarily at
about -20.degree. C. to 150.degree. C., preferably at
0.degree.-100.degree. C. and is completed in about 5 minutes to 20
hours. ##STR62##
(wherein R.sup.1, R.sup.2, X and Y are the same as defined above;
R.sup.12 represents a phenyl group which may have a lower alkoxy
group as a substituent on the phenyl ring).
The reaction between the compound (1n) and the compound (22) and
the reaction between the compound (1n') and the compound (22) can
be conducted in an appropriate solvent generally at -70.degree. C.
to room temperature, preferably at about -30.degree. C. to room
temperature for 1-6 hours. The solvent can be exemplified by ethers
such as diethyl ether, dioxane, tetrahydrofuran and the like;
aromatic hydrocarbons such as benzene, toluene and the like; and
saturated hydrocarbons such as hexane, heptane, pentane,
cyclohexane and the like. The proper amount of the compound (22)
used is at least 1 mole, preferably 1-2 moles per 1 mole of the
compound (1n) or the compound (1n'). The reaction for converting
the compound (1o) into a compound (1p) and the reaction for
converting the compound (1o') into a compound (1p') are conducted
in an appropriate solvent in the presence of an oxidizing agent.
The oxidizing agent can be exemplified by DDQ, pyridinium chromates
(e.g. pyridinium chlorochromate, pyridinium dichlorochromate),
dimethyl sulfoxide-oxalyl chloride, bichromic acid, bichromates
(e.g. sodium bichromate, potassium bichromate), permanganic acid,
and permanganates (e.g. potassium permanganate, sodium
permanganate). The solvent can be exemplified by water; organic
acids such as formic acid, acetic acid, trifluoroacetic acid and
the like; alcohols such as methanol, ethanol and the like;
halogenated hydrocarbons such as chloroform, dichloromethane and
the like; ethers such as tetrahydrofuran, diethyl ether, dioxane
and the like; dimethyl sulfoxide; dimethylformamide; and mixed
solvents thereof. Desirably, the oxidizing agent is ordinarily used
in a large excess relative to the starting material. The reaction
is conducted ordinarily at about 0.degree.-150.degree., preferably
at about 0.degree.-200.degree. C. and is completed in about 1-7
hours. ##STR63##
(wherein R.sup.1, R.sup.2, R.sup.3 and X are the same as defined
above; R.sup.13, R.sup.14 and R.sup.15 are each represents a phenyl
group or a lower alkyl group; R.sup.16 represents a phenyl-lower
alkyl group which may have a lower alkyl group as a substituent on
the phenyl ring).
The reaction between the compound (1n) and the compound (23) and
the reaction between the compound (1n') and the compound (23) are
each a so-called Witting reaction. The reaction is conducted in a
solvent in the presence of a basic compound. The basic compound can
be exemplified by inorganic bases such as metallic sodium, metallic
potassium, sodium hydride, sodium amide, sodium hydroxide,
potassium hydroxide, sodium carbonate, potassium carbonate, sodium
hydrogencarbonate and the like; metal alcoholates such as potassium
ter-butoxide, sodium methylate, sodium ethylate and the like;
lithium salts such as methyllithium, n-butyllithium, phenyllithium
and the like; and organic bases such as pyridine, piperidine,
quinoline, triethylamine, N,N-dimethylaniline and the like. The
solvent can be any as long as it gives no adverse effect to the
reaction, and there can be mentioned, for example, ethers (e.g.
diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme),
aromatic hydrocarbons (e.g. benzene, toluene, xylene), aliphatic
hydrocarbons (e.g. n-hexane, pentane, heptane, cyclohexane), amines
(e.g. pyridine, N,N-dimethylaniline) and aprotic polar solvents
(e.g. dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric
triamide). The proper amount of the compound (23) used is
ordinarily at least about 1 mole, preferably about 1-5 moles per 1
mole of the compound (1n) or the compound (1n'). The proper
reaction temperature is ordinarily about -70.degree. C. to
150.degree. C., preferably about -50.degree. C. to 120.degree. C.
The reaction is complete generally in about 0.5-15 hours.
##STR64##
(wherein A', Y, R.sup.1, R.sup.2 and X are the same as defined
above; Y' represents a halogen atom; R.sup.17 represents a
piperazinyl group which may have a lower alkyl group as a
substituent on the piperazine ring).
The reaction between the compound (24) and the compound (3) can be
conducted under the same conditions as employed for the reaction
between the compound (2) and the compound (3) in the above Reaction
scheme-1. The reaction between the compound (25) and the compound
(26) can be conducted under the same conditions as employed for the
reaction between the compound (1#') and the compound (19) in the
above Reaction scheme-14. ##STR65##
(wherein R.sup.1, R.sup.3 and X are the same as defined above;
R.sup.19 and R.sup.20 are each the same or different, and are each
represents a hydrogen atom or a lower alkyl group).
The reaction between the compound (1s) and the compound (30) can be
conducted by, for example, 1 a method wherein the compound (1s) is
reacted with ##STR66##
(R.sup.19 and R.sup.20 are the same as defined above) and
formaldehyde (i.e., Mannich reaction), or 2 a method wherein the
compound (1s) is reacted with ##STR67##
(R.sup.19 and R.sup.2o are the same are defined above).
The method (1) is conducted by reacting the compound (1s), the
compound (30) and formaldehyde in an appropriate solvent in the
presence or absence of an acid. The solvent can be any of those
ordinarily used in the Mannich reaction, and can be exemplified by
water, alcohols (e.g. methanol, ethanol, isopropanol), alkanoic
acids (e.g. acetic acid, propionic acid), acid anhydrides (e.g.
acetic anhydride), polar solvents (e.g. acetone, dimethylformamide)
and mixed solvents thereof. The acid can be examplified by mineral
acids (e.g. hydrochloric acid, hydrobromic acid) and organic acids
(e.g. acetic acid). As the formaldehyde, there are ordinarily used
an aqueous solution containing 20-40% by weight of formaldehyde, a
formaldehyde de trimer, a formaldehyde polymer (paraformaldehyde),
etc., The proper amount of the compound (30) used is ordinarily at
least 1 mole, preferably 1-5 moles per 1 mole of the compound (1s).
The proper amount of formaldehyde used is at least 1 mole per 1
mole of the compound (1s) and ordinarily a large excess amount
relative to the compound (1s). The reaction proceeds ordinarily at
0.degree.-200.degree. C., preferably at about room temperature to
150.degree. C. and is complete in about 0.5-10 hours.
The method 2 is conducted by carrying out the reaction in the
presence of an acid in an appropriate solvent or without solvent.
The acid can be exemplified by mineral acids (e.g. hydrochloric
acid, hydrobromic acid, sulfuric acid) and organic acids (e.g.
acetic acid, acetic anhydride). Acetic anhydride is preferred. The
solvent can be any of those used in the method 1. The proper amount
of the compound (31) used is ordinarily at least 1 mole, preferably
1-5 moles per 1 mole of the compound (1s). The reaction is
conducted ordinarily at 0.degree.-150.degree. C., preferably at
about room temperature to 100.degree. C. and is complete in about
0.5-5 hours.
When in general formula (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one nitro group as a substituent on the phenyl
ring, then R.sup.1 or R.sup.3 can be converted, by reduction, into
a phenyl group having at least one amino group as a substituent on
the phenyl ring. The reduction reaction can be conducted under the
same conditions as employed in the above-mentioned catalytic
reduction reaction for the oxo group adjacent to the nitrogen atom
of the heterocyclic ring. The reduction reaction can also be
conducted by using a reducing agent such as mentioned below. As to
the reducing agent, there can be mentioned, for example, a mixture
of iron, zinc, tin or stannous chloride with an acid (e.g. acetic
acid, hydrochloric acid, sulfuric acid), or a mixture of iron,
ferrous sulfate, zinc or tin with an alkali metal hydroxide (e.g.
sodium hydroxide), a sulfide (ammonium sulfide), ammonia water, or
an ammonium salt (e.g. ammonium chloride). The inert solvent can be
exemplified by water, acetic acid, methanol, ethanol and dioxane.
The conditions of the reduction reaction can be suitably selected
depending upon the type of the reducing agent used. For example,
when the reducing agent is a mixture of stannous chloride with
hydrochloric acid, the reaction can be advantageously conducted at
about 0.degree. C. to room temperature for about 0.5-10 hours. The
amount of the reducing agent used is at least 1 mole, ordinarily
1-10 moles per 1 mole of the starting material.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one hydroxyl group as a substituent on the phenyl
ring, then R.sup.1 or R.sup.3 can be converted, by reaction with a
tetrahydrofuran derivative (27), having at least one hydroxyl group
as substituent(s), into a phenyl group having at least one
substituted- or unsubstituted-tetrahydropyranyloxy group as the
substituent on the phenyl ring. The reaction can be conducted in an
appropriate solvent (e.g. tetrahydrofuran, diethyl ether, dioxane)
in the presence of a phosphorus compound (e.g. triphenylphosphine)
and an azo compound (e.g. diethyl azocarboxylate) ordinarily at
0.degree.-100.degree. C., preferably at about 0.degree.-70.degree.
C. for about 1-20 hours. The compound (27) is desirably used in an
amount of at least 1 mole, preferably 1-2 moles per 1 mole of the
starting material.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having, as substituent(s) on the phenyl ring, at least one
tetrahydropyranyloxy group having at least one lower alkanoyloxy
group, then R.sup.1 or R.sup.3 can be converted, by hydrolysis,
into a phenyl group having, as substituent(s) on the phenyl ring,
at least one tetrahydropyranyloxy group having at least one
hydroxyl group. The hydrolysis reaction can be conducted in an
appropriate solvent in the presence of a basic compound. The basic
compound can be exemplified by sodium carbonate, potassium
carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide
and alkali metal alcoholates (e.g. sodium methylate, sodium
ethylate). The solvent can be exemplified by water; alcohols such
as methanol, ethanol, isopropanol and the like; ethers such as
tetrahydrofuran, dioxane, dimethoxyethane and the like; halogenated
hydrocarbons such as chloroform, dichloromethane, carbon
tetrachloride and the like; dimethylformamide, dimethyl sulfoxide,
hexamethylphosphoric triamide and mixed solvents thereof. The above
reaction proceeds ordinarily at about 0.degree.-200.degree. C.,
preferably at about room temperature to 150.degree. C. and is
complete generally in about 0.5-15 hours.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one hydroxyl group as a substituent on the phenyl
ring, then R.sup.1 or R.sup.3 can be converted, by reaction with a
compound of the formula (28),
(Y is the same as defined above), into a phenyl group having at
least one hydroxysulfonyloxy group as a substituent on the phenyl
ring. The reaction can be conducted under the same conditions as
employed in the reaction between the compound (11) and the compound
(19) in the Reaction scheme-14. Preferably, the amount of the
compound (28) used is ordinarily in a large excess amount relative
to the starting material.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one hydroxyl as a substituent on the phenyl ring,
then R.sup.1 or R.sup.3, can be converted, by reaction with a
compound of the formula (29),
(R.sup.18 represents a lower alkoxycarbonyl-substituted lower alkyl
group, a lower alkenyl group or a thiocarbamoyl group which may
have a lower alkyl group as a substituent; and Y is the same as
defined above) or with a compound of the formula (30),
(R.sup.25 represents a lower alkyl group which may have halogen
atoms), into a phenyl group having, on the phenyl ring, at least
one substituent selected from a group of the formula, -OR.sup.18
(R.sup.18 is the same as defined above) and a group of the formula,
R.sup.25 SO.sub.2 --(R.sup.25 is the same as defined above). The
reaction can be conducted under the same conditions as employed in
the reaction of the compound (1l) with the compound (19) in the
Reaction scheme-14.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one lower alkenyloxy group as a substituent on the
phenyl ring, then R.sup.1 or R.sup.3 can be converted, by the
Claisen rearrangement, into a phenyl group having, on the phenyl
ring, at least two substituents selected from a hydroxyl group and
a lower alkenyl group. The reaction can be conducted by heating in
an appropriate solvent. The solvent can be exemplified by one
having high-boiling point such as dimethylformamide,
tetrahydronaphthalene, o-dichlorobenzene, N,N-dimethylaniline,
N,N-diethylaniline and diphenyl ether. The reaction is conducted
ordinarily at 100.degree.-250.degree. C., preferably at
150.degree.-250.degree. C. and is completed in about 1-30
hours.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having, as substituent(s) on the phenyl ring, a thiocarbamoyloxy
group which may have a lower alkyl group, then R.sup.1 or R.sup.3
can be converted, by heating, into a phenyl group having, as
substituent(s on the phenyl ring, at least one aminocarbonylthio
group which may have a lower alkyl group as a substituent. The
reaction is conducted in the absence of a solvent ordinarily at
100.degree.-250.degree. C., preferably at 150.degree.-250.degree.
C. and is completed in about 1-10 hours.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having, as substituent(s) on the phenyl ring, at least one
aminocarbonylthio group which may have a lower alkyl group, then
R.sup.1 or R.sup.3 can be converted into a phenyl group having at
least one mercapto group as a substituent on the phenyl ring, by
hydrolysis under the same conditions as employed in the hydrolysis
reaction for the compound (1) where R.sup.1 or R.sup.3 is a phenyl
group having at least one lower alkoxycarbonyl group.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one nitro group, as substituent(s) on the phenyl
ring, then R.sup.1 or R.sup.3 can be converted, by reduction, into
a phenyl group having at least one amino group, as substituent(s)
on the phenyl ring.
The reduction reaction is conducted by, for example, 1 reduction in
an appropriate solvent using a catalytic reduction catalyst or 2
reduction, in an appropriate inert solvent using, as a reducing
agent, for example, a mixture between a metal or a metal salt and
an acid, or between a metal or a metal salt and an alkali metal
hydroxide, ammonium sulfide or the like.
In the case 1 using a reduction catalyst, the solvent includes, for
example, water; acetic acid; alcohols such as methanol, ethanol,
isopropanol and the like; halogenated hydrocarbons such as
dichloromethane, chloroform, dichloroethane and the like;
hydrocarbons such as hexane, cyclohexane and the like; ethers such
as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol
dimethyl ether and the like; esters such as ethyl acetate, methyl
acetate and the like; aprotic polar solvents such as
N,N-dimethylformamide and the like; and mixed solvents thereof. The
catalytic reduction catalyst includes, for example, palladium,
palladium black, palladium-carbon, platinum, platinum oxide, copper
chromite and Raney nickel. The proper amount of the catalyst used
is generally about 0.02-1 time the weight of the starting material.
Desirably, the reaction temperature is ordinarily about -20.degree.
C. to 150.degree. C., preferably about 0.degree.-100.degree. C. and
the reaction pressure is ordinarily 1-10 atom. The reaction is
completed generally in about 0.5-10 hours. An acid such as
hydrochloric acid or the like may be added in the reaction.
In the case 2, there is used, as a reducing agent, a mixture of
iron, zinc, tin or stannous chloride with a mineral acid such as
hydrochloric acid, sulfuric acid or the like, or a mixture of iron,
ferrous sulfate, zinc or tin with an alkali metal hydroxide (e.g.
sodium hydride), a sulfide (e.g. ammonium sulfide), ammonia water
or an ammonium salt (e.g. ammonium chloride). The inert solvent can
be exemplified by water, acetic acid, methanol, ethanol and
dioxane. The conditions for the reduction reaction can be suitably
selected depending upon the type of the reducing agent used. For
example, when the reducing agent is a mixture of stannous chloride
with hydrochloric acid, the reaction can be conducted
advantageously about 0.degree. C. to room temperature for about
0.5-70 hours. The amount of the reducing agent is at least 1 mole,
ordinarily 1-5 moles per 1 mole of the starting material.
When in the compound 91), R.sup.1 or R.sup.3 is a phenyl group
having at least one lower alkenyl group as a substituent on the
phenyl ring, then R.sup.1 or R.sup.3 can be converted, by
oxidation, into a phenyl group having, as substituent(s) on the
phenyl ring, at least one lower alkyl group having two hydroxyl
groups.
The reaction can be conducted by reacting the compound (1) with an
oxidizing agent in the presence of a co-oxidizing agent in an
appropriate solvent.
As to the solvent used in the reaction with an oxidizing agent,
there can be mentioned, for example, ethers such as dioxane,
tetrahydrofuran, diethyl ether and the like; aromatic hydrocarbons,
such as benzene, toluene, xylene and the like; halogenated
hydrocarbons such as dichloromethane, dichloroethane, chloroform,
carbon tetrachloride and the like; esters such as ethyl acetate and
the like; water; alcohols such as methanol, ethanol, isopropanol,
tert-butanol and the like; and mixed solvents thereof. The
co-oxidizing agent can be exemplified by organic amine N-oxides
such as pyridine N-oxide, N-ethyldiisopropylamine N-oxide,
4-methylmorpholine N-oxide, trimethylamine N-oxide, triethylamine
N-oxide and the like. The oxidizing agent can be exemplified by
osmium tertoxide. The proper amount of the oxidizing agent used is
ordinarily 1 mole, preferably 1-5 moles per 1 mole of the starting
compound. The reaction is conducted at -20.degree. C. to
150.degree. C., preferably at room temperature to 100.degree. C.
and is complete generally in about 1-15 hours.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one lower alkenyl group as substituent(s) on the
phenyl ring, then R.sup.1 or R.sup.3 can be converted, by
oxidation, into a phenyl group having, as substituent(s) on the
phenyl ring, at least one lower alkanoyl group-substituted lower
alkyl group or at least one lower alkanoyl group. The reaction can
be conducted in an appropriate solvent in the presence of an
oxidizing agent. As to the solvent, there can be mentioned, for
example, ethers such as dioxane, tetrahydrofuran, diethyl ether and
the like; aromatic hydrocarbons such as benzene, toluene, xylene
end the like; halogenated hydrocarbons such as dichloromethane,
dichloroethane, chloroform, carbon tetrachloride and the like;
esters such as ethyl acetate and the like; water; alcohols such as
methanol, ethanol, isopropanol, tert-butanol and the like; and
mixed solvents thereof. The oxidizing agent can be exemplified by
ozone and osmium tetroxide-sodium metaperiodate. The reaction is
conducted at 20.degree.-150.degree. C., preferably at about
00.degree.-100.degree. C. and is complete generally in about 1-20
hours.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one formyl group-substituted lower alkyl group as
substituent(s) on the phenyl, then R.sup.1 or R.sup.3 can be
converted, by reduction, into a phenyl group having at least one
lower alkyl group having hydroxyl groups, as substituent(s) on the
phenyl ring. The reduction can be conducted under the same
conditions as employed in the reduction reaction using a hydride
reducing agent, for the compound (1) where R.sup.1 or R.sup.3 is a
5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic
residual group having at least one oxo group adjacent to the
nitrogen atom of the heterocyclic ring.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one nitrile group or at least one carbamoyl group
as substituent(s) on the phenyl ring, or a 5- to 15-membered
monocyclic, bicyclic or tricyclic heterocyclic residual group
having 1-2 hetero atoms selected from a nitrogen atom, an oxygen
atom and a sulfur atom, having at least one nitrile group or at
least one carbamoyl group as substituent(s), then R.sup.1 or
R.sup.3 can be converted, by hydrolysis, into a phenyl group having
at least one carboxy group as substituent(s) on the phenyl ring, or
a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic
residual group having 1-2 hetero atoms selected from a nitrogen
atom, an oxygen atom and a sulfur atom, having at least one
carboxyl group as substituent(s). The hydrolysis reaction can be
conducted under the same conditions as employed in the hydrolysis
reaction for the compound 91) where R.sup.1 or R.sup.3 is a phenyl
group having at least one alkoxycarbonyl group.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having, as substituent(s) on the phenyl ring, at least one group of
the formula, ##STR68##
(A and l are the same as above; R.sup.8a represents a lower
alkanoyl group; R.sup.9a represents a hydrogen atom, a lower alkyl
group, a lower alkanoyl group, an amino-lower alkyl group which may
have a lower alkyl group as a substituent, or a piperidinyl-lower
alkyl group), then R.sup.1 or R.sup.3 can be converted, by
hydrolysis, into a phenyl group having, as substituent(s) on the
phenyl ring, at least one group of the formula,
(A, l and R.sup.9a are the same as defined above). The hydrolysis
reaction can be conducted under the same conditions as employed in
the hydrolysis reaction for the compound (1) where R.sup.1 or
R.sup.3 is a phenyl group having at least one lower alkoxycarbonyl
group.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one lower alkenyl group as substituent(s) on the
phenyl ring, then R.sup.1 or R.sup.3 can be converted, by
reduction, into a phenyl group having at least one lower alkyl
group as substituent(s) on the phenyl ring.
The reduction can be conducted under the same conditions as
employed in the reduction reaction by catalytic hydrogenation for
the compound (1) where R.sup.1 or R.sup.3 is a 5- to 15-membered
monocyclic, bicyclic or tricyclic heterocylic residual group having
at least one oxy group adjacent to the nitrogen atom of mthe
heterocyclic ring.
When in the compound 91), R.sup.1 or R.sup.3 is a phenyl group
having at least one hydroxyl group as substituent(s) on the phenyl
ring, then R.sup.1 or R.sup.3 can be converted, by carboxylation,
into a phenyl group having at least one hydroxyl group and at least
one carboxyl group on the phenyl ring.
The carboxylation reaction can be conducted by reacting the
compound (1) with carbon dioxide in the presence of an alkali metal
carbonate such as potassium hydrogencarbonate, potassium carbonate
or the like in an appropriate solvent or in the absence of a
solvent. The solvent can be exemplified by ehters such as dioxane,
tetrahydrofuran, diethyl ether and the like; ketones such as methyl
ethyl ketone, acetone and the like; water; pyridine; and glycerine.
The reaction is conducted ordinarily under 1 to 10 atmospheric
pressure at 100.degree.-250.degree. C., preferably at about
100.degree.-200.degree. C. and is complete in about 1-20 hours.
When in the compound (1), R.sup.1 or R.sup.3 is a substituted or
unsubstituted phenyl group, then R.sup.1 or R.sup.3 can be
converted, by nitration, into a phenyl group having at least one
nitro group on the phenyl ring. The nitration reaction is conducted
under the same conditions as ordinarily employed in the nitration
for aromatic compounds, for example, by using a nitrating agent in
the absence of or presence of an appropriate inert solvent. The
inert solvent can be exemplified by acetic acid, acetic anhydride
and concentrated sulfuric acid, concentrated nitric acid, mixed
acid (a mixture of sulfuric acid, fuming sulfuric acid, phosphoric
acid or acetic anhydride with nitric acid) and a mixture of
sulfuric acid-alkali metal nitrate (e.g. potassium nitrate, sodium
nitrate). The proper amount of the nitrating agent used is at least
1 mole per 1 mole of the starting compound and is ordinarily a
large excess relative to the starting compound. The reaction is
advantageously conducted at about 0.degree. C. to room temperature
for 1-4 hours.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one carboxyl group as substituent(s) on the phenyl
ring, then R.sup.1 or R.sup.3 can be converted, by reaction with a
compound of the general formula (32),
(R.sup.32 represents an alkyl group, a phenyl-lower alkyl group or
a lower alkoxy-substituted lower alkyl group), into a phenyl group
having at least one group --COOR.sup.32 (R.sup.32 is the same as
defined above) as substituent(s) on the phenyl ring. The reaction
can be conducted under the same conditions as employed in the
reaction between the compound (11) and the compound (19) in the
Reaction scheme-14.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one lower alkenyl group having halogen atoms, as
substituent(s) on the phenyl ring, then R.sup.1 or R.sup.3 can be
converted into a phenyl group having at least one lower alkynyl
group as substituent(s) on the phenyl ring, by a reaction in an
appropriate solvent in the presence of a basic compound.
The solvent can be exemplified by ethers such as diethyl ether,
dioxane, tetrahydrofuran, monoglyme, diglyme and the like; aromatic
hydrocarbons such as benzene, toluene, xylene and the like; and
aliphatic hydrocarbons such as n-hexane, heptane, cyclohexane and
the like. The basic compound can be exemplified by alkyl- or
aryl-lithium and lithium amides such as methyllithium,
n-butyllithium phenyllithium lithium diisopropylamide and the
like.
The reaction temperature is -80.degree. C. to 100.degree. C.,
preferably at about -80.degree. C. to 70.degree. C. The reaction is
completed in about 0.5-15 hours.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one formyl group as substituent(s) on the phenyl
ring, then R.sup.1 or R.sup.3 can be converted into a phenyl group
having at least one cyano group as substituent(s) on the phenyl
ring, by a reaction with hydroxylamino-O-sulfonic acid in an
appropriate solvent. The solvent can be the same as used in the
reaction between the compound (1l) and the compound (19) in the
Reaction scheme-14. The reaction is conducted ordinarily at
0.degree.-100.degree. C. preferably at about 0.degree.-70.degree.
C. and is complete in about 1-10 hours. The proper amount of
hydroxylamine-O-sulfonic acid used is at least 1 mole, preferably
about 1-2 moles per 1 mole of the starting material.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one halogen atom as substituent(s) on the phenyl
ring, then R.sup.1 or R.sup.3 can be converted, by halogenation,
into a phenyl group having at least one hydroxyl group as
substituent(s) on the phenyl ring.
The reaction can be conducted by a reaction with a lower
alkylsiloxane such as hexamethyldisolxane or the like in an
appropriate solvent in the presence of a basic compound.
The solvent can be exemplified by ethers such as diethyl ether,
dioxane, tetrahydrofuran, monoglyme, diglyme and the like; aromatic
hydrocarbons such as benzene, toluene, xylene and the like; and
aliphatic hydrocarbons such as n-hexane, heptane, cyclohexane and
the like. The basic compound can be exemplified by alkyl- or
aryl-lithium and lithium amides such as methyllithium,
n-butyllithium, phenyllithium, lithium diisopropylamide and the
like. The reaction temperature is -80.degree. C. to 100.degree. C.,
preferably about -80.degree. C. to 70.degree. C., and the reaction
is complete in about 0.5-15 hours. The proper amount of the lower
alkylsiloxane used is at least 1 mole, preferably about 1-2 moles
per 1 mole of the starting material.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one formyl group as substituent(s) on the phenyl
ring, then R.sup.1 or R.sup.3 can be converted, by oxidation, into
a phenyl group having at least one carboxy group on the phenyl
ring.
The reaction can be conducted in an appropriate solvent in the
presence of an oxidizing agent. The solvent can be exemplified by
water; alcohols such as methanol, ethanol, isopropanol and the
like; ketones such as acetone, methyl ethyl ketone and the like;
carboxylic acids such as acetic acid, propionic acid and the like;
esters such as ethyl acetate and the like; aromatic hydrocarbons
such as benzene, chlorobenzene, toluene, xylene and the like;
hexamethylphosphoric triamide; dimethylformamide; dimethyl
sulfoxide; pyridine; and mixed solvents thereof. As the oxidizing
agent, there can be mentioned, for example, per acids (e.g.
performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic
acid, m-chloroperbenzoic acid, o-carbonylperbenzoic acid), hydrogen
peroxide, sodium metaperiodate, bichromic acid, bichromates (e.g.
sodium bichromate, potassium bichromate), permanganic acid,
permanganates (e.g. potassium permanganate, sodium permanganate),
lead salts (e.g. lead tetraacetate) and silver oxide. The proper
amount of the oxidizing agent used is ordinarily at least 1 mole,
preferably 1-2 moles per 1 mole of the starting material.
The reaction is conducted ordinarily at -10.degree. C. to
100.degree. C., preferably at about 0.degree.-50.degree. C. and is
complete in about 30 minutes to 24 hours.
When in the compound (1), R.sup.1 or R.sup.3 is a phenyl group
having at least one hydroxyl group as substituent(s) on the phenyl
ring, the R.sup.1 or R.sup.3 can be converted into a phenyl group
having at least one tri-lower alkyl group substituted silyloxy
group as substituent(s) on the phenyl ring, by a reaction with a
tri-lower alkyl-halogensilane.
The reaction can be conducted in an appropriate solvent in the
presence of a basic compound. The solvent can be any of those used
in the reaction between the compound (1l) and the compound (19) in
the Reaction scheme 14.
The basic compound can be exemplified by organic bases such as
imidazole and the like. The reaction is conducted ordinarily at
-20.degree. C. to 150.degree. C., preferably at
0.degree.-100.degree. C. and is complete in about 5 minutes to 10
hours.
The proper amount of the tri-lower alkyl-halogenosilane used is at
least 1 mole, preferably 1-3 moles per 1 mole of the starting
material. ##STR69##
(wherein R.sup.1, R.sup.2 and X are the same as above. R.sup.26
represents a lower alkyl group.)
The reduction of the compound (1u) is preferably conducted by a
reduction using a hydride reducing agent. As the hydride reducing
agent, there can be mentioned, for example, lithium aluminum
hydride, sodium boron hydride and diborane. The amount of the
reducing agent used is ordinarily at least 1 mole, preferably 1-15
moles per 1 mole of the starting compound. The reduction reaction
is conducted ordinarily at about -60.degree. C. to 150.degree. C.,
preferably at -30.degree. C. to 100.degree. C. for about 1-20 hours
ordinarily in an appropriate solvent such as water, lower alcohol
(e.g. methanol, ethanol, isopropanol), ether (e.g. tetrahydrofuran,
diethyl ether, diisopropyl ether, diglyme), or mixed solvent
thereof. When lithium aluminum hydride or diborane is used as the
reducing agent, there is preferably used an anhydrous solvent such
as diethyl ether, diisopropyl ether, tetrahydrofuran, diglyme or
the like. ##STR70##
{wherein R.sup.1, R.sup.2, R.sup.3 and X are the same as defined
above. R.sup.27 represents a group of the formula, ##STR71##
(R.sup.10 and n are the same as defined above; R.sup.29 represents
a formyl group or an alkoxycarbonyl group.) or a group of the
formula, ##STR72##
[the group of ##STR73##
represents a 5- to 15-membered monocyclic bicyclic or tricyclic
heterocyclic residual group having 1-2 hetero atoms selected from a
nitrogen atom, an oxygen atom and a sulfur atom; R.sup.20 may have
1-3 substituents selected from the group consisting of an oxo
group, an alkyl group, a benzoyl group, a lower alkanoyl group, a
hydroxyl group, a carboxy group, a lower alkoxycarbonyl group, a
lower alkylthio group, a group of the formula, ##STR74##
(A is the same as above, R.sup.23 and R.sup.24, which may be the
same or different, each represent a hydrogen atom or a lower alkyl
group; R.sup.23 and R.sup.24 as well as the nitrogen atom being
bonded thereto, together with or without other nitrogen atom or
oxygen atom, may form a 5- to 6-membered saturated heterocyclic
ring. The heterocyclic ring may have a lower alkyl group as a
substituent.); a cyano group, a lower alkyl group having hydroxyl
groups, a phenylaminothiocarbonyl group and an amino-lower
alkoxycarbonyl group which may have a lower alkyl group as a
substituent. R.sup.31 represents a formyl group or a lower
alkoxycarbonyl group. p represents 0 or an integer of 1 or 2.]
R.sup.28 represents a group of the formula, ##STR75##
(R.sup.10 and n are the same as defined above) or a group of the
formula, ##STR76##
(the group of ##STR77##
R.sup.30 and p are the same as defined above).}
The reduction of the compound (1x) or the compound (1z) can be
conducted under the same conditions as employed in the reduction
conducted using a hydride reducing agent for the compound (1) where
R.sup.1 or R.sup.3 is a 5- to 15-membered monocyclic, bicyclic or
tricyclic heterocyclic residual group having at least one oxo group
adjacent to the nitrogen atom of the heterocyclic ring.
##STR78##
[wherein R.sup.1, R.sup.2, R.sup.3, X, R.sup.30, p and
##STR79##
are the same as defined above; R.sup.31 represents a group of the
formula, ##STR80##
(R.sup.23 and R.sup.24 are the same as defined above) or an
amino-lower alkoxy group which may have a lower alkyl group as a
substituent.]
The reaction between the compound (1D) and the compound (31) can be
conducted under the same conditions as employed in the reaction
between the compound (6) and the compound (4) in the Reaction
scheme 3. ##STR81##
(wherein R.sup.1, R.sup.2, X, R.sup.30, p, R.sup.23, R.sup.24 and
RA are the same as defined above.)
The reduction of the compound (1F) or (1H) can be conducted under
the same conditions as employed in the reduction reaction for the
compound (1) where R.sup.1 or R.sup.3 is a 5- to 15-membered
monocyclic, bicyclic or tricyclic heterocyclic residual group
having at least one oxo group adjacent to the nitrogen atom of the
heterocyclic ring. ##STR82##
[wherein R.sup.1, R.sup.2, X, p and R.sup.30 are the same as above.
R.sup.32 R.sup.33 and R.sup.34 each represent a hydrogen atom or a
lower alkyl group. The bond between the 2- and 3-positions in the
compound (1K) or (1M) represents a single bond or a double
bond.]
The reaction for converting the compound (1J) or (1L) into a
compound (1K) or (1M), respectively, can be conducted in an
appropriate solvent in the presence of a catalyst. The solvent can
be any of those used in the reaction between the compound (2) and
the compound (3) in the reaction scheme 1. The catalyst can be
exemplified by metal compounds such as Pd(OAc).sub.2
+Cu(OAc).sub.2.multidot.H.sub.2 O and the like, and halides such as
KI+I.sub.2 and the like. The proper amount of the catalyst used is
ordinarily 0.1-1 mole per 1 mole of the compound (1J) or (1L). When
a halide is used, it is used ordinarily in an amount of 0.005-3
moles per 1 mole of the compound (1J) or (1L). The reaction is
conducted ordinarily at room temperature to 250.degree. C.,
preferably at room temperature to 200.degree. C. and is complete
ordinarily in about 5-40 hours. When a metal compound is used as
the catalyst, the reaction is preferably conducted in an oxygen
atmosphere. When R.sup.32 represents a lower alkyl group, the bond
between the 2- and 3-positions of the compound (1K) represents a
single bond. ##STR83##
wherein R.sup.1, R.sup.2, R.sup.3, X and Y are the same as above;
R.sup.35 and R.sup.36 each represent the above-mentioned
R.sup.30).
The reaction between the compound (1W) and the compound (32) and
the reaction between the compound (1P) and the compound (32) can be
conducted under the same conditions as employed in the reaction
between the compound (2) and the compound (3) in the Reaction
scheme 1. ##STR84##
[wherein R.sup.1, R.sup.2, R.sup.3, X, R.sup.8 and R.sup.9 are the
same as defined above; R.sup.37 represents a group of the formula,
##STR85##
(R.sup.10 and n are the same as defined above) or a group of the
formula, ##STR86##
(RA, R.sup.30 and p are the same as defined above); R.sup.38
represents a group of the formula, ##STR87##
(R.sup.10, R.sup.8, R.sup.9 and n are the same as defined above) or
a group of the formula, ##STR88##
(R.sup.30, R.sup.23, R.sup.24, RA and p are the same as defined
above)].
In the above reaction, when the R.sup.37 of the compound (1R) or
(1T) represents a group of the formula, ##STR89##
the compound (1R) or (1T) reacts with the compound (19); when the
R.sup.37 represents a group of the formula, ##STR90##
the compound (1R) or (1T) reacts with the compound (33).
The reaction between the compound (1R) or (1T) and the compound
(19) or (33) is conducted in the absence of a solvent or in an
appropriate solvent in the presence of a reducing agent. The
solvent can be exemplified by water; alcohols such as methanol,
ethanol, isopropanol and the like; acetic acid; ethers such as
dioxane, tetrahydrofuran, diethyl ether, diglyme and the like; and
aromatic hydrocarbons such as benzene, toluene, xylene and the
like. The reduction method can be exemplified by a method using
formic acid or a hydride reducing agent such as sodium boron
hydride, sodium cyanoborohydride, lithium aluminum hydride or the
like, and a catalytic reduction method using a catalytic reduction
catalyst such as palladium black, palladium-carbon, platinum oxide,
platinum black, Raney nickel or the like. When formic acid is used
as the reducing agent, the appropriate reaction temperature is
ordinarily room temperature to 200.degree. C., preferably about
50.degree.-150.degree. C., and the reaction is complete in about
1-10 hours. The proper amount of formic acid used is a large excess
relative to the compound (1R) or (1T). When a hydride reducing
agent is used, the appropriate reaction temperature is ordinarily
-30.degree. C. to 100.degree. C., preferably about
0.degree.-70.degree. C., and the reaction is complete in about 30
minutes to 20 hours. The proper amount of the reducing agent is
ordinarily 1-20 moles, preferably 1-15 moles per 1 mole of the
compound (1R) or (1T). In particular, when lithium aluminum hydride
is used as the reducing agent, it is preferable to use, as a
solvent, an ether such as dioxane, tetrahydrofuran, diethyl ether,
diglyme or the like, or an aromatic hydrocarbon such as benzene,
toluene, xylene or the like. When a catalytic reduction catalyst is
used, the reaction is conducted in a hydrogen atmosphere of
ordinarily normal pressure to 20 atm., preferably normal pressure
to 10 atm. ordinarily at -30.degree. C. to 100.degree. C.
preferably at 0.degree.-60.degree. C. The proper amount of the
catalyst used is ordinarily 0.1-40% by weight, preferably 1-20% by
weight based on the compound (1R) or (1T). The proper amount of the
compound (19) or (33) used is ordinarily 1 mole per 1 mole of the
compound (1R) or (1T), preferably equimolar to a large excess
relative to the compound (1R) or (1T). ##STR91##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.10, n and X are the same
as above; R.sup.39 represents a lower alkanoyl group; R.sup.40
represents a lower alkenyl group, a lower
alkoxycarbonyl-substituted lower alkenyl group, a
carboxy-substituted lower alkenyl group or a lower alkenyl group
having halogen atoms; R.sup.41 represents a lower alkyl group, a
lower alkoxycarbonyl-substituted lower alkyl group or a
carboxy-substituted lower alkyl group).
The reaction for converting the compound (1V) or (1Y) into a
compound (1W) or (1Z), respectively, is conducted in an appropriate
solvent in the presence of a Witting reagent and a basic
compound.
As the Witting reagent, there can be mentioned, for example,
phosphorus compounds represented by the general formula (A).
(wherein R.sup.42 represents a phenyl group, and R.sup.35
represents a lower alkyl group which may have a lower
alkoxycarbonyl group, a carboxyl group or a halogen atom as a
substituent; Y is the same as above), and phosphorus compounds
represented by general formula (B), ##STR92##
(wherein R.sup.44 represents a lower alkoxy group; and R.sup.45
represents a lower alkyl group). The basic compound can be
exemplified by inorganic bases such as metallic sodium, metallic
potassium, sodium hydride, sodium amide, sodium hydroxide,
potassium hydroxide, sodium carbonate, potassium carbonate, sodium
hydrogencarbonate and the like; metal alcoholates such as sodium
methylate, sodium ethylate, potassium tert-butoxide and the like;
alkyl- or aryllithiums and lithium amides such as methyllithium,
n-butyllithium, phenyllithium, lithium diisopropylamide and the
like; and organic bases such as pyridine, piperidine, quinoline,
triethylamine, N,N-dimethylaniline and the like. The solvent can be
any as long as it gives no adverse effect on the reaction, and
there can be mentioned, for example, ethers such as diethyl ether,
dioxane, tetrahydrofuran, monoglyme, digyme and the like; aromatic
hydrocarbons such as benzene, toluene, xylene and the like;
aliphatic hydrocarbons such as n-hexane, heptane, cyclohexane and
the like; aprotic polar solvents such as pyridine,
N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric
triamide and the like; and alcohols such as methanol, ethanol,
isopropanol and the like. The appropriate reaction temperature is
ordinarily -80.degree. C. to 150.degree. C., preferably about
-80.degree. C. to 120.degree. C., and the reaction is complete
generally in about 0.5-15 hours.
When the R.sup.40 of the compound (1W) or (1Z) is a group other
than a lower alkenyl group which have a halogen atom, the reaction
for converting the compound (1W) or (1Z) into a compound (1X) or
(1aa), respectively, can be conducted under the same conditions as
employed in the reduction reaction by catalytic hydrogenation for
the compound (1) where R.sup.1 or R.sup.3 is a 5- to 15-membered
monocyclic, bicyclic or tricyclic heterocyclic residual group
having at least one oxo group adjacent to the nitrogen atom of the
heterocyclic ring. ##STR93##
(wherein R.sup.1, R.sup.2, R.sup.3, X, ##STR94##
R.sup.30 and p are the same as above.)
The reaction for converting the compound (1bb) and (1cc) into a
compound (1cc) and (1ff), respectively, can be conducted by heating
with aniline and sulfur in the absence of a solvent state.
The reaction is conducted ordinarily at 100.degree.-250.degree. C.,
preferably at about 100.degree.-200.degree. C., and is complete in
about 1-20 hours.
The amounts of aniline and sulfur used are each ordinarily 1-10
moles, preferably 1-2 moles per 1 mole of the compound (1bb) or
(1ee).
The reaction for converting the compound (1cc) and (1ff) into a
compound (1dd) and (1gg), respectively, can be conducted under the
same condition as employed in the above-mentioned hydrolysis
reaction for the compound (1) where R.sup.1 or R.sup.3 is a phenyl
group having at least one alkoxycarbonyl group.
The products thus obtained in each step can be separated and
purified by ordinary means. The separation means can be exemplified
by solvent extraction, dilution, recrystallization, column
chromatography and preparative thin-layer chromatography.
Needless to say, the compounds of the present invention include
stereoisomers and optical isomers.
The oxazole derivatives represented by general formula (1) of the
present invention can be easily converted into acid addition salts
by allowing a pharmaceutically acceptable acid to act on said
derivatives. The acid addition salts are also included in the
present invention. As the acid, there can be mentioned, for
example, inorganic acids such as hydrochloric acid, sulfuric acid,
phosphoric acid, hydrobromic acid and the like, as well as organic
acids such as acetic acid, oxalic acid, succinic acid, maleic acid,
fumaric acid, malic acid, tartaric acid, citric acid, malonic acid,
methanesulfonic acid, benzoic acid and the like.
Of the thiazole or oxazole derivatives represented by general
formula (1) of the present invention, those compounds having acidic
groups can be easily converted into respective salts by allowing a
pharmaceutically acceptable basic compound to act on the compounds.
As the basic compound, there can be mentioned, for example, sodium
hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate
and potassium hydrogencarbonate.
The compounds of the present invention are generally used in the
form of ordinary pharmaceutical preparations. The pharmaceutical
preparations are prepared using diluents or excipients ordinarily
used, such as filler, bulking agent, binder, humectant,
disintegrator, surfactant, lubricant and the like. The
pharmaceutical preparations can be used in various forms depending
upon the purpose of remedy, and typical forms include tablets,
pills, powders, solutions, suspensions, emulsions, granules,
capsules, suppositories, injections (solutions, suspensions, etc.),
ointments, etc. In preparing tablets, various carriers
conventionally known in the art can be used. The carriers can be
exemplified by excipients such as lactose, white sugar, sodium
chloride, grape sugar, urea, starch, calcium carbonate, kaolin,
crystalline cellulose, silicic acid and the like; binders such as
water, ethanol, propanol, simple syrup, grape sugar solution,
starch solution, gelation solution, carboxymethyl cellulose,
shellac, methyl cellulose, potassium phosphate,
polyvinylpyrrolidone and the like; disintegrators such as dry
starch, sodium alginate, powdered agar, powdered laminaran, sodium
hydrogencarbonate, calcium carbonate, polyoxyethylene
sorbitan-fatty acid esters, sodium lauryl sulfate, stearic acid
monoglyceride, starch, lactose and the like; disintegration
inhibitors such as white sugar, stearin, cacao butter, hydrogenated
oil and the like; absorption promoters such as quaternary ammonium
salts, sodium lauryl sulfate and the like; humectants such as
glycerine, starch and the like; adsorbents such as starch, lactose,
kaolin, bentonite, colloidal silicic acid and the like; and
lubricants such as refined talc, stearic acid salts, boric acid
powder, polyethylene glycol and the like. The tablets can be
prepared, as necessary, in the form of ordinary coated tablets,
such as sugar-coated tablets, enteric coated tablets or film-coated
tablets, or in the form of double-layered tablets or multi-layered
tablets. In preparing pills, various carriers conventionally known
in the art can be used. The carriers can be exemplified by
excipients such as grape sugar, lactose, starch, cacao butter,
hardened vegetable oils, kaolin, talc and the like; binders such as
powdered acacia, powdered tragacanth gelatin, ethanol and the like;
and disintegrators such as laminaran, agar and the like. In
preparing suppositories, various carriers conventionally known in
the art can be used. The carriers can be exemplified by a
polyethylene glycol, cacao butter, a higher alcohol, a higher
alcohol ester, gelatin and a semi-synthetic glyceride. In preparing
injections (solutions, emulsions, suspensions), they are sterilized
and preferably isotonic to blood. In preparing these solutions,
emulsions and suspensions, there can be used all of the diluents
conventionally used in the art, such as water, aqueous lactic acid
solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl
alcohol, polyoxyisostearyl alcohol and polyoxyethylene
sorbitan-fatty acid ester. In this case, the injections may contain
sodium chloride, grape sugar or glycerine in an amount sufficient
to make the injections isotonic, and may further contain a
solubilizing agent, a buffer solution, a soothing agent, etc. all
ordinarily used. The pharmaceutical preparations may furthermore
contain, as necessary, a coloring agent, a preservative, a perfume,
a flavoring agent, a sweetening agent and other drugs. In preparing
pastes, creams and gels, there can be used various diluents
conventionally known in the art, such as white petrolatum,
paraffin, glycerine, cellulose derivative, polyethylene glycol,
silicon, bentonite and the like.
The amount of the present compound of general formula (1) or a salt
thereof to be contained in a pharmaceutical preparation is not
particularly restricted and can be appropriately selected in a wide
range, but preferably is ordinarily 1-70% by weight in the
pharmaceutical preparation.
The method for administering the pharmaceutical preparation is not
particularly restricted. The pharmaceutical preparation can be
administered in various methods depending upon the form of
preparation, the age, sex and other conditions of patient, the
degree of disease condition of patient, etc. For example, tablets,
pills, a solution, a suspension, an emulsion, granules or capsules
are administered orally. An injection is intravenously administered
singly or in admixture with an ordinary auxiliary solution of grape
sugar, amino acid or the like, or, as necessary, is singly
administered intramuscularly, intradermally, subcutaneously or
intraperitoneally. Suppositories are administered
intrarectally.
The dose of the pharmaceutical preparation of the present invention
is appropriately selected depending upon the administration method,
the age, sex and other conditions of patient, the degree of disease
condition of patient, etc., but preferably is ordinarily about
0.2-200 mg per kg of body weight per day in terms of the amount of
the active ingredient, i.e. the present compound (1).
Examples
The present invention is hereinafter described with reference to
Reference Examples. Examples, Preparation Examples and
Pharmacological Tests.
Reference Example 1
25 g of 3,4-dimethyoxybenzonitrile and 23 g of thioacetamide were
dissolved in 120 ml of 10% hydrochloric acid-DMF. The solution was
heated at 90.degree. C. for 3 hours. The solution was further
heated at 130.degree. C. for 5 hours to conduct a reaction. The
solvent was removed by distillation. The residue was washed twice
with 100 ml of diethyl ether. Similar washing was conducted with
100 ml of water. The resulting crystals were collected by
filtration and dried. Recrystallization from methanol was conducted
to obtain 18.7 g of 3,4-dimethoxythiobenzamide as light brown
columnar crystals.
M.p.: 170.degree.-175.degree. C. (decomposed NMR (CDC"3) .delta.:
3.94 (3H, s) 3.95 (3H, s) 6.83 (1H, d, J=8.4 Hz), 7.15 (1H, brs),
7.38 (1H, dd, J=2.2 Hz, 8.4 Hz), 7.52 (1H, brs), 7.63 (1H, d, J=2.2
Hz).
Reference Example 2
500 mg of 3,4,5-trimethoxybenzamide was suspended in 15 ml of
benzene. Thereto was added 526 mg of phosphorus pentasulfide. The
mixture was refluxed for 30 minutes with heating. The solvent was
removed by distillation. To the residue were added 5 ml of 10%
sodium hydroxide and 5 ml of water. The mixture was stirred for 30
minutes. The reaction mixture was filtered, and the resulting solid
was washed with small amounts of water and ethanol and dried to
obtain 330 mg of 3,4,5-trimethoxythiobenzamide as a yellow
powder.
M.p.: 182.5.degree.-184.degree. C.
Reference Example 3
4 g of 3',5'-diacetyloxyacetophenone was suspended in 75 ml of
carbon disulfide. Thereto was dropwise added a solution of 0.90 ml
of bromine dissolved in 25 ml of carbon disulfide, at room
temperature in about 1 hour. The system was heated to about
50.degree. C. ocassionally in the course of dropwise addition and,
each time when a reaction started, the system was returned to room
temperature and stirred. After the completion of the dropwise
addition, stirring was conducted at room temperature for 1 hour.
After the completion of the reaction, the solvent was removed by
distillation to obtain 5.53 g of
3',5'-diacetyloxy-2-bromoacetophenone as brown crystals.
M.p.: 61.degree.-62.degree. C.
Reference Example 4
5.47 g of chloroacetyl chloride was dissolved in 20 ml of
dichloromethane. Thereto was added 6.46 g of finely ground aluminum
chloride with ice-cooling. Stirring was conducted for 30 minutes.
Thereto was added 2 g of 3,4-dihydro-2H-1,4-benzothiazin-3(4H)-one.
The mixture was stirred for 4 hours with ice-cooling and then
overnight at room temperature. The reaction mixture was poured into
ice water. The resulting crystals were collected by filtration,
water-washed and dried to obtain 3.03 g of
6-.alpha.-chloroacetyl-3,4-dihydro-2H-1,4-benzothiazin-3-one.
NMR (DNSO-d6) .delta.: 3.55 (2H, s), 5.10 (2H, s), 7.65-7.45 (3H,
m), 10.76 (1H, s).
Reference Example 5
2 g of 3,4-dimethoxybenzoic acid was dissolved in 80 ml of
methanol. Thereto was added 600 mg of sodium methoxide. The mixture
was stirred for 30 minutes. The solvent was removed by
distillation. The residue was dissolved in 50 ml of DMF. Thereto
was added 2.56 g of 6-.alpha.-chloroacetyl-3,4-dihydrocarbostyril.
The mixture was stirred at 140.degree. C. for 2 hours. The solvent
was removed by distillation. Water was added to the residue. The
resulting crystals were collected by filtration and dried to obtain
4.8 g of
6-[2-(3,4-dimethoxybenzoyloxy)acetyl]-3,4-dihydrocarbostyril as a
white powder.
M.p.: 215.degree.-216.degree. C.
Reference Example 6
3 g of 6-.alpha.-aminoacetyl-3,4-dihydrocarbostyril
monohydrochloride was suspended in 60 ml of tetrahydrofuran.
Thereto were added 7 ml of triethylamine and 2.8 g of
3,4-dimethoxybenzoyl chloride. The mixture was stirred at room
temperature. After 3 hours, the resulting crystals were collected
by filtration, methanol-washed and dried to obtain 2.6 g of
6-[2-(3,4-dimethoxybenzoylamino)acetyl]-3,4-dihydrocarbostyril as
white acicular crystals.
M.p.: 246.degree.-247.degree. C.
Reference Examples 7-38
Compounds shown in Table 1 were obtained by using respective
starting materials, in the same procedure as in Reference Example 1
or 2.
TABLE 1 ##STR95## Reference Example R.sup.1 Properties 7 ##STR96##
NMR (DMSO-d.sub.6) .delta.: 8.62-8.67(1H, m) 8.83(1H, d, J=2.6Hz),
9.55(1H, d, J=1.4Hz), 10.02(1H, brs), 10.32(1H, brs) 8 ##STR97##
NMR (DMSO-d.sub.6) .delta.: 7.60(1H, t, J=4.8Hz), 8.89(2H, d,
J=4.8Hz), 9.89(1H, brs), 10.30(1H, brs) 9 ##STR98## Crystal form:
Light brown acicular (recrystallized from ethanol) Mp:
86-87.degree. C. (HCl salt) 10 ##STR99## NMR (DMSO-d.sub.6)
.delta.: 6.12(2H, s), 6.96(1H, d, J=8.2Hz), 7.51(1H, d, J=1.8Hz),
7.59(1H, dd, J=1.8Hz, 8.2Hz), 9.37(1H, brs), 9.73(1H, brs) 11
##STR100## Crystal form: Yellow columnar (recrystallized from ethyl
acetate-n-hexane) Mp: 116-117.degree. C. 12 ##STR101## Crystal
form: Yellow columnar (recrystallized from ethyl acetate) Mp:
130-131.degree. C. 13 ##STR102## NMR (DMSO-d.sub.6) .delta.:
3.80(3H, s), 3.84(3H, s), 6.50-6.63(2H, m), 8.00-8.10(1H, m),
9.14(1H, brs), 9.79(1H, brs) 14 ##STR103## Crystal form: Brown
plate (recrystallized from methanol) Mp: 144-145.degree. C. 15
##STR104## Crystal form: Light brown powder (recrystallized from
ethanol) Mp: 133-134.degree. C. 16 ##STR105## Crystal form: Brown
powder (recrystallized from dimethylformamide- ethanol) Mp:
243-246.degree. C. 17 ##STR106## Crystal form: Yellow scaly
(recrystallized from dimethylformamide- water) 18 ##STR107## NMR
(DMSO-d.sub.6) .delta.: 12.90(1H, brs), 11.66(1H, brs), 9.81(1H,
brs), 9.39(1H, d, J=7Hz), 8.27(1H, d, J=8Hz), 7.9-7.6(2H, m),
7.6-7.4(1H, m) 19 ##STR108## NMR (CDCl.sub.3) .delta.: 7.57(1H, dd,
J=5.1Hz, 1.1Hz), 7.50(1H, dd, J=3.9Hz, 1.1Hz), 7.09(1H, dd,
J=5.0Hz, 3.9Hz), 7.6-6.9(2H, br) 20 ##STR109## NMR (CDCl.sub.3)
.delta.: 8.00(1H, dd, J=3.0Hz, 1.4Hz), 7.51(1H, dd, J=5.1Hz,
1.4=Hz), 7.33(1H, dd, J=5.1Hz, 3.0Hz), 7.9-7.0(2H, br) 21
##STR110## NMR (CDCl.sub.3) .delta.: 10.0-9.3(1H, br), 7.05(1H,
brs), 7.1-6.7(2H, br), 6.65(1H, brs), 6.35-6.25(1H, m) 22
##STR111## NMR (DMSO-d.sub.6) .delta.: 10.38(1H, brs), 10.15(1H,
brs), 8.25-8.0(2H, m), 7.7-7.45(2H, m) 23 ##STR112## NMR
(CDCl.sub.3) .delta.: 7.71(1H, d, J=2.1Hz), 7.6(1H, brs), 7.3(1H,
brs), 7.32(1H, dd, J=8.3Hz, 2.1Hz), 7.27(1H, s), 6.89(1H, d,
J=8.3Hz), 6.22(1H, s), 3.97(3H, s) 24 ##STR113## NMR (CDCl.sub.3)
.delta.: 7.55(1H, dd, J=8.5Hz, 2.3Hz), 7.5(1H, brs), 7.45(1H, d,
J=2.3Hz), 7.15(1H, brs), 6.86(1H, d, J=8.5Hz), 5.73(1H, s),
3.95(3H, s) 25 ##STR114## NMR (CDCl.sub.3) .delta.: 8.0-7.85(2H,
m), 7.55(1H, brs), 7.1(1H, brs), 7.0-6.85(2H, m), 3.86(3H, s) 26
##STR115## NMR (DMSO-d.sub.6) .delta.: 10.22(1H, brs), 9.81(1H,
brs), 8.24(2H, d, J=8.6Hz), 8.01(2H, d, J=8.8Hz) 27 ##STR116## NMR
(DMSO-d.sub.6) .delta.: 9.95(1H, brs), 9.55(1H, brs), 7.95-7.85(2H,
m), 7.55-7.45(2H, m) 28 ##STR117## NMR (DMSO-d.sub.6) .delta.:
10.06(1H, brs), 9.67(1H, brs), 8.15-7.85(4H, m), 4.33(2H, dg,
J=7.2Hz, 4.0Hz), 1.31(3H, t, J=7.2Hz) 29 ##STR118## NMR
(DMSO-d.sub.6) .delta.: 9.62(1H, brs), 9.30(1H, brs), 7.65-7.5(2H,
m), 6.95(1H, d, J=9.1Hz), 4.07(2H, q, J=7Hz), 4.04(2H, q, J=7Hz),
1.33(6H, t, J=7Hz) 30 ##STR119## NMR (DMSO-d.sub.6) .delta.:
10.05(1H, brs), 9.65(1H, brs), 8.02-7.85(4H, m), 2.60(3H, s) 31
##STR120## NMR (DMSO-d.sub.6) .delta.: 9.68(1H, brs), 9.33(1H,
brs), 7.71(1H, d, J=1.7Hz), 7.63(1H, dd, J=7.8Hz, 1.9Hz), 7.15(1H,
d, J=7.9Hz), 2.24(6H, s) 32 ##STR121## NMR (DMSO-d.sub.6) .delta.:
9.88(1H, brs), 9.50(1H, brs), 8.05-7.9(2H, m), 7.3-7.15(2H, m) 33
##STR122## NMR (DMSO-d.sub.6) .delta.: 9.93(1H, brs), 9.54(1H,
brs), 7.93(1H, d, J=1.8Hz), 7.77(1H, dd, J=8.0Hz, 1.9Hz) 7.39(1H,
d, J=8.0Hz), 2.34(3H, s) 34 ##STR123## NMR (DMSO-d.sub.6) .delta.:
10.21(1H, brs), 9.85(1H, brs), 8.69(1H, t, J=2Hz), 8.4-8.2(2H, m),
7.71(1H, t, J=8Hz) 35 ##STR124## NMR (DMSO-d.sub.6) .delta.:
10.09(1H, brs), 9.66(1H, brs), 8.08(1H, d, J=2.2Hz), 7.86(1H, dd,
J=8.6Hz, 2.2Hz), 7.69(1H, d, J=8.6Hz) 36 ##STR125## NMR
(DMSO-d.sub.6) .delta.: 9.76(1H, brs), 9.43(1H, brs), 7.59(1H, dd,
J=6.6Hz, 1.4Hz), 7.49(1H, d, J=1.3Hz), 7.14(1H, d, J=6.6Hz),
3.85(3H, s), 2.41(3H, s) 37 ##STR126## NMR (DMSO-d.sub.6) .delta.:
9.95(1H, brs), 9.56(1H, brs), 7.9-7.7(2H, m), 7.7-7.5(2H, m) 38
##STR127## NMR (DMSO-d.sub.6) .delta.: 9.65(1H, brs), 9.32(1H,
brs), 7.65-7.5(2H, m), 7.45-7.3(1H, m), 7.15-6.9(1H, m),
6.15-5.9(1H, m), 5.5-5.2(2H, m), 4.8-4.55(2H, m), 3.80(3H, s)
Reference Examples 39-60
Compounds shown in Table 3 were obtained by using respective
starting materials, in the same procedure as in Reference Example 3
or 4.
TABLE 2 ##STR128## Reference Example R.sup.2 R.sup.3 Y Properties
39 H ##STR129## Cl Crystal form: White powder (recrystallized from
acetone) Mp: 210-212.degree. C. (decomposed) 40 H ##STR130## Br
Crystal form: White powder (recrystallized from ethyl
acetate-n-hexane) Mp: 85-86.degree. C. 41 H ##STR131## Br NMR
(CDCl.sub.3) .delta.: 4.42(2H, s), 8.93(2H, s) 42 H ##STR132## Br
NMR (DMSO-d.sub.6) .delta.: 12.75(1H, brs), 8.64(1H, d, J=6.8Hz),
8.23(1H, d, J=8.1Hz), 7.8-7.6(2H, m), 7.55-7.4(1H, m), 4.93(2H, s)
43 H ##STR133## Cl NMR (DMSO-d.sub.6) .delta.: 10.76(1H, s),
7.65-7.45(3H, m), 5.10(2H, s), 3.55(2H, s) 44 H ##STR134## Cl NMR
(CDCl.sub.3) .delta.: 2.30(6H, s), 4.65(2H, s), 7.64(2H, s) 45 H
##STR135## Cl NMR (CDCl.sub.3) .delta.: 1.32(9H, s), 1.42(9H, s),
4.75(2H, s), 7.50(1H, d, J=2.4Hz), 7.60(1H, d, J=2.4Hz) 46 H
##STR136## Cl NMR (CDCl.sub.3) .delta.: 2.53(3H, s), 4.66(2H, s),
7.29(1H, d, J=8.8Hz), 7.87(1H, d, J=8.8Hz) 47 H ##STR137## Cl NMR
(CDCl.sub.3) .delta.: 1.33(9H, s), 4.30(1H, s), 4.76(1H, s),
6.91-7.18(1H, m), 7.34-7.48(1H, m), 7.58-7.72(1H, m) 48 H
##STR138## Br NMR (CDCl.sub.3) .delta.: 7.89(1H, d, J=8.6Hz),
7.14(1H, dd, J=8.6Hz, 2.3Hz), 7.05(1H, d, J=2.2Hz), 4.40(2H, s),
2.37(3H, s), 2.32(3H, s) 49 H ##STR139## Cl Crystal form: White
powder Mp: 189-191.degree. C. 50 ##STR140## Br Crystal form: Light
green acicular (recrystallized from methanol) Mp: 151-153.degree.
C. 51 H ##STR141## Cl Crystal form: Colorless acicular Mp:
238-240.degree. C. 52 H ##STR142## Cl NMR (DMSO-d.sub.6) .delta.:
5.14(2H, s), 7.06(1H, d, J=8.2Hz), 7.52(1H, s), 7.70(1H, dd,
J=1.6Hz, 8.2Hz), 10.97(1H, s), 11.12(1H, s) 53 H ##STR143## Br
Crystal form: White powder Mp: 201-210.degree. C. (decomposed) 54 H
##STR144## Cl Crystal form: Colorless plate Mp: 210-215.degree. C.
55 H ##STR145## Cl Crystal form: Light yellow acicular Mp:
179-180.degree. C. 56 H ##STR146## Cl Crystal form: White powder
(recrystallized from methanol-chloroform) Mp: 246.5-247.degree. C.
57 H ##STR147## Cl Crystal form: White powder Mp: 146-148.degree.
C. 58 H ##STR148## Cl NMR (DMSO-d.sub.6) .delta.: 2.43-2.56(2H, m),
2.93-3.03(2H, m), 5.13(2H, s), 7.35(1H, d, J=6.4Hz), 7.43(1H, d,
J=1.4Hz), 7.58(1H, dd, J=1.4Hz, 6.4Hz), 10.28(1H, s) 59 H
##STR149## Br Crystal form: White powder NMR (DMSO-d.sub.6)
.delta.: 4.82(2H, s), 7.18(1H, d, J=8.4Hz), 7.90(1H, dd, J=1.8Hz,
8.4Hz), 8.25(1H, d, J=1.8Hz) 60 H ##STR150## Br Crystal form:
Yellow acicular (recrystallized from ethyl acetate-n-hexane) Mp:
83-84.degree. C.
Reference Example 61
1.5 g of 1,3-dichloroacetone and 2.3 g of
3,4-dimethoxythiobenzamide were suspended in 100 ml of ethanol. The
suspension was heated for 3 hours to complete the reaction. The
solvent was removed by distillation. The residue was purified by
silica gel column chromatography to obtain 1.86 g of
2-(3,4-dimethoxyphenyl)-4-chloromethylthiazole as a colorless
viscous oil.
NMR (CDCl.sub.3) .delta.: 3.94 (3H, s), 3.99 (3H, s), 4.74 (2H, s),
6.90 (1H, d, J=8.3 Hz), 7.24 (1H, s), 7.46 (1H, dd, J=2.1 Hz, 8.3
Hz), 7.53 (1H, d, J=2.1 Hz).
Reference Examples 62-70
Compounds shown in Table 3 where obtained by using respective
starting materials, in the same procedure in Reference Example 1 or
2.
TABLE 3 ##STR151## Reference Example R.sup.1 Properties 62
##STR152## NMR (DMSO-d.sub.6) .delta.: 0.86(6H, brs),
1.10-1.53(28H, m), 1.60-1.8(4H, m), 3.85-4.15(4H, m), 6.94(1H, d,
J=9.2Hz), 7.53-7.65(2H, m), 9.29(1H, brs), 9.61(1H, brs) 63
##STR153## NMR (DMSO-d.sub.6) .delta.: 0.92(6H, t, J=7.2Hz),
1.30-1.55(4H, m), 1.55-1.81(4H, m), 3.99(4H, q, J=6.2Hz), 6.96(1H,
d, J=9.1Hz), 7.50- 7.65(1H, m), 9.30(1H, brs), 9.62(1H, brs) 64
##STR154## NMR (DMSO-d.sub.6) .delta.: 0.97(6H, t, J=7.4Hz),
1.58-1.85(4H, m) 3.95(4H, q, J=6.4Hz), 6.96(1H, d, J=9.1Hz),
7.50-7.62(2H, m), 9.30(1H, brs), 9.62(1H, brs) 65 ##STR155## NMR
(DMSO-d.sub.6) .delta.: 0.96(3H, t, J=7.3Hz), 1.61-1.86(2H, m),
3.97(3H, s), 3.96(2H, t, J=6.6Hz), 6.96(1H, d, J=9.2Hz),
7.50-7.62(2H, m), 9.32(1H, brs), 9.63(1H, brs) 66 ##STR156## NMR
(DMSO-d.sub.6) .delta.: 0.92(3H, t, J=7.2Hz), 1.30-1.55(2H, m),
1.55-1.80(2H, m), 3.78(3H, s), 4.00(2H, t, J=6.5Hz), 6.96(1H, d),
J=9.1Hz), 7.52-7.66(2H, m), 9.31(1H, brs), 9.63(1H, brs) 67
##STR157## NMR (DMSO-d.sub.6) .delta.: 1.33(3H, t, J=6.9Hz),
3.80(3H, s), 4.04(2H, q, J=6.9Hz), 6.96(1H, d, J=8.2Hz),
7.50-7.66(2H, m), 9.31(1H, brs), 9.63(1H, brs) 68 ##STR158## NMR
(DMSO-d.sub.6) .delta.: 0.97(3H, t, J=7.4Hz), 1.63-1.88(2H, m),
3.80(3H, s), 3.94(2H, t, J=6.6Hz), 6.96(1H, d, J=8.3Hz),
7.53-7.67(2H, m), 9.31(1H, brs), 9.63(1H, brs) 69 ##STR159## NMR
(DMSO-d.sub.6) .delta.: 1.33(3H, t, J=7.0Hz), 3.78(3H, s), 4.05(2H,
q, J=7.0Hz), 6.95(1H, d, J=9.1Hz), 7.51-7.66(2H, m), 9.31(1H, brs),
9.64(1H, brs) 70 ##STR160## NMR (DMSO-d.sub.6) .delta.: 3.77(3H,
s), 3.87(3H, s), 7.58(1H, d, J=2.1Hz), 7.75(1H, d, J=2.1Hz), 9.52
(1H, brs), 9.95(1H, brs)
Reference Examples 71-74
Compounds shown in Table 4 were obtained by using respective
starting materials, in the same procedure as in Reference Example 3
or 4.
TABLE 4 ##STR161## Reference Example R.sup.2 R.sup.3 Y Properties
71 ##STR162## Br NMR (CDCl.sub.3) .delta.: 3.91(3H, s), 3.96(3H,
s), 4.49 (2H, s), 7.66-7.75(1H, m), 7.75- 7.86(1H, m), 8.19(1H, t,
J=1.4Hz) 72 ##STR163## Br NMR (DMSO-d.sub.6) .delta.: 4.90(2H, s),
7.10(1H, t, J=6.5Hz), 8.04-8.20(1H, m), 8.45(1H, d, J=1.7Hz) 73 H
##STR164## Cl Light pink powder NMR (DMSO-d.sub.6) .delta.:
2.05(3H, s), 2.84-3.30(4H, m), 3.52-3.67(4H, m), 3.92(3H, s),
5.13(2H, s), 7.12(1H, d, J=8.6Hz), 7.45(1H, d, J=2.0Hz), 7.73(1H,
dd, J=2.0Hz, 8.6Hz) 74 H ##STR165## Br NMR (CDCl.sub.3) .delta.:
4.50(2H, s), 9.07-9.49(3H, m)
Reference Examples 75-77
Compounds shown in Table 5 were obtained by using respective
starting materials, in the same procedure as in Reference Examples
1 or 2.
TABLE 5 ##STR166## Reference Example R.sup.1 Properties 75
##STR167## NMR (CDCl.sub.3) .delta.: 4.00(3H, s), 7.25(1H, d,
J=8.8Hz), 7.15(1H, brs), 7.52(1H, brs), 8.08 (1H, dd, J=2.5Hz,
8.8Hz), 8.46(1H, d, J=2.5Hz), 11.17(1H, s) 76 ##STR168## NMR
(CDCl.sub.3) .delta.: 1.05(3H, t, J=7.5Hz), 1.46(3H, t, J=7.0Hz),
1.79-1.93(2H, m), 4.02(2H, t, J=6.8Hz), 4.13(2H, q, J=7.0Hz), 6.85
(1H, d, J=8.4Hz), 7.16(1H, brs), 7.37 (1H, dd, J=2.3Hz, 8.4Hz),
7.54(1H, brs), 7.60(1H, d, J=2.3Hz) 77 ##STR169## NMR (CDCl.sup.3)
.delta.: 1.43(3H, t, J=7.0Hz), 1.50(3H, t, J=7.0Hz), 4.01-4.23(4H,
m) 6.43(1H, d, J=2.3Hz), 6.53(1H, dd, J=9.0Hz, 2.3Hz), 7.98(1H,
brs), 8.69(1H, d, J=9.0Hz), 9.23(1H, brs)
Reference Examples 78-97
Compounds shown in Table 6 were obtained by using respective
starting materials, in the same procedure as in Reference Example 3
or 4.
TABLE 6 ##STR170## Crystal form Melting point Reference
(recrystallization (.degree. C.) Example R.sup.2 R.sup.3 Y solvent)
(salt form) 78 H ##STR171## Br NMR.sup.1) (-) 79 -- ##STR172## --
NMR.sup.2) (1) 80 -- ##STR173## -- NMR.sup.3) (1) 81 H ##STR174##
-- NMR.sup.4) (-) 82 -- ##STR175## -- NMR.sup.5) (-) 83 --
##STR176## -- NMR.sup.6) (-) 84 H ##STR177## -- NMR.sup.7) (-) 85
-- ##STR178## -- NMR.sup.8) (-) 86 -- ##STR179## -- NMR.sup.9) (-)
87 H ##STR180## Br NMR.sup.10) (-) 88 -- ##STR181## Cl White
powdery crystals (ethyl acetate-n- hexane) 105-107 (-) 89 --
##STR182## -- White powdery crystals (ethyl acetate-n- hexane)
99-100 (-) 90 -- ##STR183## -- White powdery crystals (ethyl
acetate) 109-110 (-) 91 H ##STR184## Cl Colorless prismatic
crystals (ethyl acetate-n- hexane) 126-127 (-) 92 -- ##STR185## Br
Light brown acicular crystals (dichloro-methane- ethanol) 130-131
(-) 93 -- ##STR186## Cl NMR.sup.11) (-) 94 CH.sub.3 ##STR187## Br
White acicular crystals (n-hexane-dichloro- methane) 102-103 (-) 95
H ##STR188## Cl White acicular crystals (ethyl acetate-n- hexane)
121-122 (-) 96 -- ##STR189## -- NMR.sup.12) (-) 97 -- ##STR190## Br
NMR.sup.13) (-)
NMR.sup.1) Compound of Reference Example 78
NMR (CDCl.sub.3) .delta.ppm: 2.65 (3H, s) 4.65 (2H, s) 7.98-8.16
(5H, m)
NMR.sup.2) Compound of Reference Example 79
NMR (CDCl.sub.3) .delta.ppm: 4.06 (3H, s) 4.57 (2H, s) 8.91 (1H, t,
J=1.9 Hz) 8.98 (1H, t, J=1.9 Hz) 9.05 (1H, t, J=1.9 Hz)
NMR.sup.3) Compound of Reference Example 80
NMR (CDCl.sub.3) .delta.ppm: 4.00 (3H, s) 4.42 (2H, s) 7.76 (1H, t,
J=8.0 Hz) 8.11 (1H, dd, J=1.1 Hz, J=8.0 Hz) 8.32 (1H, dd, J=1.1 Hz,
J=8.0 Hz)
NMR.sup.4) Compound of Reference Example 81
NMR (CDCl.sub.3) .delta.ppm: 3.88 (3H, s) 4.52 (2H, s) 5.62 (2H,
brs) 8.40 (1H, d, J=1.8 Hz) 8.42 (1H, d, J=1.8 Hz)
NMR.sup.5) Compound of Reference Example 82
NMR (CDCl.sub.3) .delta.ppm: 4.45 (2H, s) 7.65 (1H, m) 7.67 (1H, m)
8.21 (1H, m) 8.28 (1H, m)
NMR.sup.6) Compound of Reference Example 83
NMR (CDCl.sub.3) .delta.ppm: 2.27 (3H, s) 2.62 (3H, s) 3.94 (3H, s)
4.43 (2H, s) 8.30 (1H, s) 8.48 (1H, s)
NMR.sup.7) Compound of Reference Example 84
NMR (CDCl.sub.3) .delta.ppm: 2.34 (3H, s) 3.94 (3H, s) 4.52 (2H, s)
7.89 (1H, m) 7.97 (1H, m) 8.43 (1H, m)
NMR.sup.8) Compound of Reference Example 85
NMR (CDCl.sub.3) .delta.ppm: 2.39 (3H, s) 3.96 (3H, s) 4.46 (2H, s)
7.21 (1H, d, J=8.6 Hz) 8.29 (1H, dd, J=2.0 Hz, J=8.6 Hz) 8.58 (1H,
d, J=2.0 Hz)
NMR.sup.9) Compound of Reference Example 86
NMR (CDCl.sub.3) .delta.ppm: 3.94 (3H, s) 4.54 (2H, s) 7.09 (1H, d,
J=8.7 Hz) 8.15 (1H, dd, J=2.0 Hz, J=8.7 Hz) 8.49 (1H, d, J=2.0 Hz)
12.11 (1H, s)
NMR.sup.10) Compound of Reference Example 87
NMR (CDCl.sub.3) .delta.ppm: 4.00 (3H, s) 4.64 (2H, s) 8.76 (2H, d,
J=2.2 Hz) 8.85 (1H, d, J=2.2 Hz) 12.50 (1H, brs)
NMR.sup.11) Compound of Reference Example 93
NMR (CDCl.sub.3) .delta.ppm: 1.27 (3H, t, J=7.5 Hz) 2.68 (2H, t,
J=7.5 Hz) 4.67 (3H, s) 5.73 (1H, s) 6.85 (1H, d, J=8.4 Hz) 7.75
(1H, dd, J=2.3 Hz, 8.4 Hz) 7.82 (1H, d, J=2.3 Hz)
NMR.sup.12) Compound of Reference Example 96
NMR (CDCl.sub.3) .delta.ppm: 3.91 (3H, s) 4.48 (2H, s) 7.35 (1H, m)
7.71 (1H, m) 10.48 (1H, brs)
NMR.sup.13) Compound of Reference Example 97
NMR (DMSO-d.sub.6) .delta.ppm: 5.04 (2H, s) 7.56 (1H, brs)
8.10-8.39 (3H, m)
Reference Examples 98-116
Compounds shown in Table 7 were obtained using respective starting
materials, in the same procedure as in Reference Example 3 or
4.
TABLE 7 ##STR191## Crystal form Melting point Reference
(recrystallization (.degree. C.) Example R.sup.2 R.sup.3 Y solvent)
(salt form) 98 H ##STR192## Cl NMR.sup.14) (-) 99 -- ##STR193## --
NMR.sup.15) (-) 100 H ##STR194## Cl Brown solid NMR.sup.16) (-) 101
-- ##STR195## -- NMR.sup.17) (-) 102 -- ##STR196## -- White
acicular crystals NMR.sup.18) (-) 103 H ##STR197## Cl White
acicular crystals (ethanol) 107-108 (-) 104 -- ##STR198## Br
NMR.sup.19) (-) 105 -- ##STR199## -- NMR.sup.20) (-) 106 --
##STR200## -- NMR.sup.21) (-) 107 H ##STR201## Br NMR.sup.22) (-)
108 -- ##STR202## -- NMR.sup.23) (HBr) 109 -- ##STR203## --
NMR.sup.24) (HBr) 110 -- ##STR204## -- NMR.sup.25) (HBr) 111 H
##STR205## Br NMR.sup.26) (-) 112 -- ##STR206## -- NMR.sup.27)
(HBr) 113 -- ##STR207## -- NMR.sup.28) (-) 114 -- ##STR208## --
NMR.sup.29) (HBr) 115 H ##STR209## Br NMR.sup.30) (HBr)
NMR data of the compounds of Reference Examples 98-102, 105-113 and
115-116
NMR.sup.14): Compound of Reference Example 98
.sup.1 H-NMR(CDCl.sub.3) .delta.: 2.59 (3H, s) 4.00 (3H, s) 4.64
(2H, s), 6.90 (1H, s) 8.25 (1H, s), 11.12 (1H, s)
NMR.sup.15): Compound of Reference Example 99
.sup.1 H-NMR(CDCl.sub.3) .delta.: 2.33 (3H, s) 3.96 (3H, s) 4.62
(2H, s), 6.79 (1H, d, J=8.1 Hz), 7.80 (1H, d, J=8.1 Hz), 11.40 (1H,
s)
NMR.sup.16): Compound of Reference Example 100
.sup.1 H-NMR(CDCl.sub.3) .delta.: 1.25 (3H, t, J=7.5 Hz), 2.73 (2H,
q, J=7.5 Hz), 4.00 (3H, s), 4.67 (2H, s), 7.98 (1H, d, J=1.7 Hz),
8.35 (1H, d, J=1.7 Hz), 11.66 (1H, s)
NMR.sup.17): Compound of Reference Example 101
.sup.1 H-NMR(CDCl.sub.3) .delta.: 4.06 (3H, s), 4.68 (2H, s), 4.75
(2H, s), 7.74 (1H, dd, J=2.0 Hz, 6.7 Hz), 8.06 (1H, dd, J=2.0 Hz,
6.7 Hz), 8.19 (1H, d, J=2.3 Hz), 8.55 (1H, d, J=2.3 Hz), 12.04 (1H,
s)
NMR.sup.18): Compound of Reference Example 102
.sup.1 -NMR(CDCl.sub.3) .delta.3.99 (3H, s), 4.75 (2H, s) 7.00 (1H,
t, J=7.8 Hz), 7.56 (1H, d, J=7.8 Hz), 7.99 (1H, dd, J=1.8 Hz, 7.8
Hz), 8.03 (2H, d, J=8.5 Hz), 11.43 (1H, s), 7.74 (2H, d, J=8.5
Hz)
NMR.sup.19): Compound of Reference Example 104
.sup.1 H-NMR(CDCl.sub.3) .delta.: 3.92 (3H, s), 4.28 (2H, s), 6.90
(1H, dd, J=2.1 Hz, 3.3 Hz), 6.95 (1H, dd, J=2.1 Hz, 3.3 Hz), 9.90
(1H, brs)
NMR.sup.20): Compound of Reference Example 105
.sup.1 H-NMR(CDCl.sub.3) .delta.: 3.95 (3H, s), 4.42 (2H, s), 7.26
.delta.(1H, d, J=3.7 Hz), 7.34 (1H, d, J=3.7 Hz)
NMR 21): Compound of Reference Example 106
.sup.1 H-NMR(CDCl.sub.3) .delta.: 1.47 (3H, t, J=7.1 Hz), 2.61 (3H,
s), 4.46 (2H, q, J=7.1 Hz), 5.00 (2H, s), 8.21 (2H, m)
NMR 22): Compound of Reference Example 107
.sup.1 H-NMR(CDCl.sub.3) .delta.: 1.40 (3H, t, J=7.1 Hz), 4.36 (2H,
s) 4.38 (2H, q, J=7.1 Hz,), 7.74 (1H, d. J=4.0 Hz), 7.78 (1H, d,
J=4.0 Hz)
NMR.sup.23): Compound of Reference Example 108
.sup.1 H-NMR(CDCl.sub.3) .delta.: 4.10 (3H, s), 4.92 (2H, s),
9.41-10.01 (3H, m)
NMR.sup.24): Compound of Reference Example 109
.sup.1 H-NMR(DMSO-d.sub.6) .delta.: 5.05 (2H, s), 8.20 (1H, dd,
J=1.6 Hz, 5.0 Hz), 8.42 (1H, dd, J=0.9 Hz, 1.6 Hz) 9.01 (1H, dd,
J=0.9 Hz, 5.0 Hz)
NMR.sup.25): Compound of Reference Example 110
.sup.1 H-NMR(DMSO-d.sub.6) .delta.: 2.73 (3H, s), 5.03 (2H, s),
8.17 (1H, brs), 8.26 (1H, brs), 8.44 (1H, d, J=2.1 Hz), 8.54 (1H,
d, J=2.1 Hz)
NMR.sup.26): Compound of Reference Example 111
.sup.1 H-NMR(CDCl.sub.3) .delta.: 4.01 (3H, s), 4.88 (2H, s), 8.15
(1H, dd, J=0.7 Hz, 8.1 Hz), 8.45 (1H, dd, J=2.1 Hz, 8.1 Hz), 9.13
(1H, m)
NMR.sup.27): Compound of Reference Example 112
.sup.1 H-NMR(CDCl.sub.3) .delta.: 1.45 (3H, t, J=7.1 Hz), 4.52 (2H,
q, J=7.1 Hz), 4.78 (2H, s), 8.49 (1H, d, J=8.1 Hz) 8.96 (1H, dd,
J=1.9 Hz, 8.1 Hz), 9.55 (1H, d, J=1.9 Hz)
NMR.sup.28): Compound of Reference Example 113
.sup.1 H-NMR(DMSO-d.sub.6) .delta.: 2.77 (3H, s), 5.08 (2H, s),
8.11 (1H, d, J=5.7 Hz), 8.25 (1H, s), 8.96 (1H, d, J=5.7 Hz)
NMR.sup.29): Compound of Reference Example 114
.sup.1 H-NMR(CDCl.sub.3) .delta.:4.11 (3H, s), 4.76 (2H, s), 7.60
(1H, dd, J=4.8 Hz, 7.9 Hz), 8.12 (1H, dd, J=1.5 Hz, 7.9 Hz), 8.96
(1H, dd, J=1.5 Hz, 4.8 Hz)
NMR.sup.30): Compound of Reference Example 115
.sup.1 H-NMR(DMSO-d.sub.6) .delta.: 2.82 (3H, s), 2.87 (3H, s),
5.20 (2H, s), 8.09 (1H, brs), 8.42 (1H, brs), 9.01 (1H, s)
Example 1
In 20 ml of ethanol were suspended 367 mg of
3',4'-dihydroxy-2-chloroacetophenone and 430 mg of
3,4-dimethoxythiobenzamide. The suspension was refluxed for 3 hours
with heating. After cooling, the resulting crystals were collected
by filtration, ethanol-washed and dried. The dried material was
recrystallized from ethinol to obtain 160 mg of
2-(3,4-dimethoxyphenyl)-4-(3,4-dihydroxyphenyl) thiazole
hydrochloride as yellow acicular crystals.
M.p.: 146.degree.-148.degree. C.
Examples 2-136
Compounds shown in Tables 8 and 9 were obtained by using respective
starting materials, in the same procedure as in Example 1.
TABLE 8 ##STR210## Compound of Example 2 ##STR211## ##STR212##
Crystal form: yellow prismatic (recrystallized from methanol) Mp:
182-183.degree. C. (decomposed, 1/4FeCl.sub.2 salt) Compound of
Example 3 ##STR213## ##STR214## Crystal form: light brown powdery
(recrystallized from dimethylformamide) Mp: 300.degree. C. or above
Compound of Example 4 ##STR215## ##STR216## Crystal form: colorless
acicular (recrystallized from diethyl ether-n-hexane) Mp:
59-60.degree. C. Compound of Example 5 ##STR217## ##STR218##
Crystal form: light yellow prismatic (recrystallized from ethanol)
Mp: 172-173.degree. C. Compound of Example 6 ##STR219## ##STR220##
Crystal form: light brown acicular (recrystallized from ethanol)
Mp: 88-89.degree. C. (HCl salt) Compound of Example 7 ##STR221##
##STR222## Crystal form: brown powdery (recrystallized from ethanol
acetate) Mp: 140-141.degree. C. Compound of Example 8 ##STR223##
##STR224## Crystal form: light brown plate (recrystallized from
ethanol) Mp: 129-130.degree. C. Compound of Example 9 ##STR225##
##STR226## Crystal form: colorless acicular (recrystallized from
methanol- ethyl acetate) Mp: 188-189.degree. C. Compound of Example
10 ##STR227## ##STR228## Crystal form: light brown acicular
(recrystallized from ethyl acetate) Mp: 129-130.degree. C. Compound
of Example 11 ##STR229## ##STR230## Crystal form: light green
columnar (recrystallized from methanol) Mp: 135-136.degree. C.
Compound of Example 12 ##STR231## ##STR232## Crystal form:
colorless acicular (recrystallized from diethyl ether-n-hexane) Mp:
57.5-58.5.degree. C. Compound of Example 13 ##STR233## ##STR234##
Crystal form: white acicular (recrystallized from diethyl
ether-n-hexane) Mp: 91.5-92.degree. C. Compound of Example 14
##STR235## ##STR236## Crystal form: light brown plate
(recrystallized from methanol) Mp: 206-207.degree. C. (decomposed)
Compound of Example 15 ##STR237## ##STR238## Crystal form: orange
powdery (recrystallized from ethanol-water) Mp: 209-210.degree. C.
(decomposed, HCl salt) Compound of Example 16 ##STR239## ##STR240##
Crystal form: colorless acicular (recrystallized from diethyl
ether-n-hexane) Mp: 83-84.degree. C. Compound of Example 17
##STR241## ##STR242## Crystal form: colorless acicular
(recrystallized from diethyl ether-n-hexane) Mp: 76-78.degree. C.)
Compound of Example 18 ##STR243## ##STR244## Crystal form: brown
powdery (recrystallized from dimethylformamide-water) Mp:
300.degree. C. or above Compound of Example 19 ##STR245##
##STR246## Crystal form: yellow powdery (recrystallized from
dioxane-water) Mp: 280-281.degree. C. Compound of Example 20
##STR247## ##STR248## Crystal form: yellow powdery (recrystallized
from dimethylformamide-water) Mp: 262-263.degree. C. Compound of
Example 21 ##STR249## ##STR250## Crystal form: light yellow powdery
(recrystallized from ethyl acetate) Mp: 180-181.degree. C.
(decomposed) Compound of Example 22 ##STR251## ##STR252## Crystal
form: yellow prismatic (recrystallized from ethanol) Mp:
124-126.degree. C. (HCl salt) Compound of Example 23 ##STR253##
##STR254## Crystal form: yellow acicular (recrystallized from ethyl
acetate- diethyl ether) Mp: 128-129.degree. C. (HCl--1/2H.sub.2 O
salt) Compound of Example 24 ##STR255## ##STR256## Crystal form:
light brown powdery (recrystallized from dimethylformamide-water)
Mp: 187-188.degree. C. Compound of Example 25 ##STR257## ##STR258##
Crystal form: yellow powdery (recrystallized from ethanol) Mp:
248-249.degree. C. (HCl salt) Compound of Example 26 ##STR259##
##STR260## Crystal form: white acicular (recrystallized from
ethanol) Mp: 205-206.degree. C. Compound of Example 27 ##STR261##
##STR262## Crystal form: light brown powdery (recrystallized from
ethanol) Mp: 156-158.degree. C. (HCl salt) Compound of Example 28
##STR263## ##STR264## Crystal form: light brown acicular
(recrystallized from dimethylformamide) Mp: 282-284.degree. C.
(decomposed) Compound of Example 29 ##STR265## ##STR266## Crystal
form: colorless acicular (recrystallized from dimethylformamide)
Mp: 199-200.degree. C. Compound of Example 30 ##STR267## ##STR268##
Crystal form: colorless prismatic (recrystallized from ethyl
acetate) Mp: 163-163.5.degree. C. Compound of Example 31 ##STR269##
##STR270## Crystal form: light yellow plate (recrystallized from
n-hexane) Mp: 98-99.degree. C. Compound of Example 32 ##STR271##
##STR272## Crystal form: light yellow powdery (recrystallized from
dimethylformamide) Mp: 249-250.degree. C. Compound of Example 33
##STR273## ##STR274## Crystal form: white acicular (recrystallized
from ethanol) Mp: 149-150.degree. C. Compound of Example 34
##STR275## ##STR276## Crystal form: white acicular (recrystallized
from methanol) Mp: 160-161.degree. C. Compound of Example 35
##STR277## ##STR278## Crystal form: light yellow powdery
(recrystallized from dimethylformamide-water) Mp: 143.5-144.degree.
C. Compound of Example 36 ##STR279## ##STR280## Crystal form: white
powdery (recrystallized from ethanol) Mp: 94-95.degree. C. Compound
of Example 37 ##STR281## ##STR282## Crystal form: light brown
acicular (recrystallized from ethanol) Mp: 151-152.degree. C.
Compound of Example 38 ##STR283## ##STR284## Crystal form: white
acicular (recrystallized from petroleum ether) Mp: 67-68.degree. C.
Compound of Example 39 ##STR285## ##STR286## Crystal form: white
acicular (recrystallized from methanol) Mp: 122-123.degree. C.
Compound of Example 40 ##STR287## ##STR288## Crystal form: light
yellow powdery (recrystallized from ethanol) Mp:
152.5-153.5.degree. C. Compound of Example 41 ##STR289## ##STR290##
Crystal form: light yellow prismatic (recrystallized from ethanol-
water) Mp: 83-84.degree. C. Compound of Example 42 ##STR291##
##STR292## Crystal form: yellow powdery (recrystallized from
ethanol) Mp: 69-70.degree. C. Compound of Example 43 ##STR293##
##STR294## Crystal form: colorless acicular (recrystallized from
ethyl acetate) Mp: 174.5-175.5.degree. C. Compound of Example 44
##STR295## ##STR296## Crystal form: colorless acicular
(recrystallized from ethanol) Mp: 147.5-148.5.degree. C. Compound
of Example 45 ##STR297## ##STR298## Crystal form: light yellow
acicular (recrystallized from methanol) Mp: 151-152.degree. C.
Compound of Example 46 ##STR299## ##STR300## Crystal form:
colorless plate (recrystallized from diethyl ether- petroleum
ether) Mp: 150-152.degree. C. Compound of Example 47 ##STR301##
##STR302##
Crystal form: white powdery (recrystallized from ethyl
acetate-n-hexane) Mp: 126-127.degree. C. Compound of Example 48
##STR303## ##STR304## Crystal form: yellow powdery (recrystallized
from ethanol-diethyl ether) Mp: 124-126.degree. C. (HCl salt)
Compound of Example 49 ##STR305## ##STR306## Crystal form: white
powdery (recrystallized from dimethylformamide) Mp: 263-265.degree.
C. Compound of Example 50 ##STR307## ##STR308## Crystal form:
colorless prismatic (recrystallized from dimethylformamide-water)
Mp: 249-250.degree. C. (decomposed) Compound of Example 51
##STR309## ##STR310## Crystal form: light brown prismatic
(recrystallized from dimethylformamide) Mp: 225-226.degree. C.
Compound of Example 52 ##STR311## ##STR312## Crystal form: light
brown acicular (recrystallized from dimethylformamide) Mp:
250-251.degree. C. Compound of Example 53 ##STR313## ##STR314##
Crystal form: white powdery (recrystallized from dimethylformamide)
Mp: 145-146.degree. C. Compound of Example 54 ##STR315## ##STR316##
Crystal form: light brown acicular (recrystallized from
dimethylformamide-methanol) Mp: 182-283.degree. C. Compound of
Example 55 ##STR317## ##STR318## Crystal form: light brown
prismatic (recrystallized from dimethylformamide-methanol) Mp:
184-185.degree. C. Compound of Example 56 ##STR319## ##STR320##
Crystal form: white prismatic (recrystallized from dioxane) Mp:
223-234.degree. C. Compound of Example 57 ##STR321## ##STR322##
Crystal form: light brown granular (recrystallized ethanol) Mp:
178-179.degree. Compound of Example 58 ##STR323## ##STR324##
Crystal form: light brown powdery (recrystallized from ethanol-
water) Mp: 159-161.degree. C. (HCl salt) Compound of Example 59
##STR325## ##STR326## Crystal form: white powdery (recrystallized
from dimethylformamide) Mp: 300.degree. or above Compound of
Example 60 ##STR327## ##STR328## Crystal form: light brown powdery
(recrystallized from dimethylformamide) Mp: 215-216.degree. C.
Compound of Example 61 ##STR329## ##STR330## Crystal form:
colorless acicular (recrystallized from acetonitrile) Mp:
156-157.degree. C. Compound of Example 62 ##STR331## ##STR332##
Crystal form: light yellow powdery (recrystallized from ethanol)
Mp: 128-130.degree. C. (HCl salt) Compound of Example 63 ##STR333##
##STR334## Crystal form: colorless acicular (recrystallized from
ethyl acetate) Mp: 155-156.degree. C. Compound of Example 64
##STR335## ##STR336## Crystal form: light yellow acicular
(recrystallized from dimethylformamide-water) Mp: 206-208.degree.
C. Compound of Example 65 ##STR337## ##STR338## Crystal form: light
brown acicular (recrystallized from dimethylformamide) Mp:
168-169.degree. C. Compound of Example 66 ##STR339## ##STR340##
Crystal form: white powdery (recrystallized from ethanol) Mp:
191-192.degree. C. Compound of Example 67 ##STR341## ##STR342##
Crystal form: white powdery (recrystallized from
dimethylformamide-methanol) Mp: 226-227.degree. C. Compound of
Example 68 ##STR343## ##STR344## Crystal form: light brown acicular
(recrystallized from dimethylformamide-water) Mp: 227-228.degree.
C. Compound of Example 69 ##STR345## ##STR346## Crystal form: white
powdery (recrystallized from methanol) Mp: 271-272.degree. C.
Compound of Example 70 ##STR347## ##STR348## Crystal form: yellow
powdery (recrystallized from methanol) Mp: 165-167.degree. C.
(decomposed, 2HCl salt) Compound of Example 71 ##STR349##
##STR350## Crystal form: white powdery (recrystallized from diethyl
ether- petroleum ether) Mp: 114-115.degree. C. Compound of Example
72 ##STR351## ##STR352## Crystal form: white powdery
(recrystallized from ethanol-n-hexane) Mp: 229-230.degree. C.
Compound of Example 73 ##STR353## ##STR354## Crystal form: Orange
plate (recrystallized from ethanol) Mp: 192-192.5.degree. C.
Compound of Example 74 ##STR355## ##STR356## Crystal form: light
yellow prismatic (recrystallized from ethanol-n-hexane) Mp:
196-197.degree. C. Compound of Example 75 ##STR357## ##STR358##
Crystal form: light brown powdery (recrystallized from
dimethylformamide) Mp: 203-204.degree. C. Compound of Example 76
##STR359## ##STR360## Crystal form: white powdery (recrystallized
from diethyl ether) Mp: 111-112.degree. C. Compound of Example 77
##STR361## ##STR362## Crystal form: yellow acicular (recrystallized
from acetonitrile) Mp: 219-220.5.degree. C. Compound of Example 78
##STR363## ##STR364## Crystal form: light brown powdery
(recrystallized from acetonitrile) Mp: 172.5-173.5.degree. C.
Compound of Example 79 ##STR365## ##STR366## Crystal form: light
yellow powdery (recrystallized from ethanol-n-hexane) Mp:
203-204.degree. C. Compound of Example 80 ##STR367## ##STR368##
Crystal form: yellow acicular (recrystallized from ethanol) Mp:
177-178.degree. C. Compound of Example 81 ##STR369## ##STR370##
Crystal form: light yellow powdery (recrystallized from
acetonitrile) Mp: 224-225.degree. C. Compound of Example 82
##STR371## ##STR372## Crystal form: white acicular (recrystallized
from ethanol-water) Mp: 125-126.degree. C. Compound of Example 83
##STR373## ##STR374## Crystal form: yellow prismatic
(recrystallized from ethyl acetate-n-hexane) Mp: 147-148.degree. C.
Compound of Example 84 ##STR375## ##STR376## Crystal form: light
yellow powdery (recrystallized from isopropanol) Mp:
202-204.degree. C. (HBr salt) Compound of Example 85 ##STR377##
##STR378## Crystal form: brown plate (recrystallized from ethyl
acetate) Mp: 131-132.degree. C. Compound of Example 86 ##STR379##
##STR380## Crystal form: colorless acicular (recrystallized from
ethanol) Mp: 147-149.degree. Compound of Example 87 ##STR381##
R.sup.3 = --CH.sub.3 Crystal form: white powdery (recrystallized
from ethanol-water) Mp: 147-148.degree. C. (HCl salt) Compound of
Example 88 ##STR382## R.sup.3 = --CH.sub.2 CO.sub.2 C.sub.2 H.sub.5
Crystal form: white prismatic (recrystallized from ethanol) Mp:
119-120.degree. C. (HCl salt) Compound of Example 89 ##STR383##
R.sup.3 = --CH.sub.2 CONH.sub.2 Crystal form: white prismatic
(recrystallized from ethanol) Mp: 198-200.degree. C. (decomposed,
HCl salt) Compound of Example 90 ##STR384## ##STR385## Crystal
form: white powdery (recrystallized from ethanol-water) Mp:
118-119.degree. C. Compound of Example 91 ##STR386## ##STR387##
Crystal form: yellow columnar (recrystallized from ethanol) Mp:
176-177.degree. C. Compound of Example 92 ##STR388## ##STR389##
Crystal form: light brown acicular (recrystallized from
ethanol)
Mp: 184-185.degree. C. Compound of Example 93 ##STR390## ##STR391##
Crystal form: yellow powdery (recrystallized from ethanol) Mp:
255-258.degree. C. (decomposed, HBr salt) Compound of Example 94
##STR392## ##STR393## Crystal form: light brown acicular
(recrystallized from DMF) Mp: 235-236.degree. C. Compound of
Example 95 ##STR394## ##STR395## Crystal form: light brown powdery
(recrystallized from dimethylformamide) Mp: 236-237.degree. C.
Compound of Example 96 ##STR396## R.sup.3 = H Crystal form: white
powdery (recrystallized from methanol) Mp: 235-236.degree. C.
Compound of Example 97 ##STR397## ##STR398## Crystal form:
colorless prismatic (recrystallized from ethyl acetate) Mp:
198-199.degree. C. Compound of Example 98 ##STR399## Crystal form:
light brown prismatic (recrystallized from ethanol- diethyl ether)
Mp: 148-149.degree. C. (HCl salt) Compound of Example 99 ##STR400##
Crystal form: yellow acicular (recrystallized from ethanol) Mp:
226-228.degree. C. (HBr salt) Compound of Example 100 ##STR401##
##STR402## Crystal form: dark green acicular (recrystallized from
ethanol) Mp: 154-155.degree. C. (HBr salt) Compound of Example 101
##STR403## ##STR404## Crystal form: light brown acicular
(recrystallized from ethanol) Mp: 128-129.degree. C. Compound of
Example 102 ##STR405## ##STR406## Crystal form: white acicular
(recrystallized from ethanol) Mp: 170-171.degree. C. Compound of
Example 103 ##STR407## ##STR408## Crystal form: yellow acicular
(recrystallized from chloroform- ethanol) Mp: 149-150.degree. C.
Compound of Example 104 ##STR409## ##STR410## Crystal form: light
violet plate (recrystallized from ethanol) Mp: 167-169.degree. C.
(decomposed) Compound of Example 105 ##STR411## ##STR412## Crystal
form: red powdery (recrystallized from ethanol) Mp: 184-186.degree.
C. (decomposed) Compound of Example 106 ##STR413## ##STR414##
Crystal form: brown acicular (recrystallized from ethanol) Mp:
221-224.degree. C. Compound of Example 107 ##STR415## ##STR416##
NMR (DMSO-D.sub.6) .delta.: 10.5(2H, brs), 8.18(1H, d, J=1.7Hz),
8.09(1H, s), 7.96(1H, dd, J=8.5Hz, 1.7Hz), 7.71(1H, d, J=8.5Hz),
7.5-7.65(2H, m), 7.09(1H, d, J=8.4Hz), 3.86(3H, s), 3.83(3H, s)
Compound of Example 108 ##STR417## ##STR418## Crystal form:
colorless prismatic (recrystallized from ethanol) Mp:
216-217.degree. C. Compound of Example 109 ##STR419## ##STR420##
Crystal form: light yellow prismatic (recrystallized from
dimethylformamide) Mp: 263-264.degree. C. Compound of Example 110
##STR421## ##STR422## Crystal form: orange acicular (recrystallized
from dimethylformamide) Mp: 300.degree. C. or above Compound of
Example 111 ##STR423## ##STR424## Crystal form: light yellow plate
(recrystallized from dimethylformamide) Mp: 231-232.degree. C.
Compound of Example 112 ##STR425## ##STR426## Crystal form: light
brown powdery (recrystallized from dioxane) Mp: 272.5-273.5.degree.
C. Compound of Example 113 ##STR427## ##STR428## Crystal form:
light yellow prismatic (recrystallized from dioxane) Mp:
242-243.degree. C. Compound of Example 114 ##STR429## ##STR430##
Crystal form: light yellow acicular (recrystallized from dioxane)
Mp: 236-237.degree. C. Compound of Example 115 ##STR431##
##STR432## Crystal form: light brown prismatic (recrystallized from
dimethylformamide) Mp: 255-256.degree. C. Compound of Example 116
##STR433## ##STR434## Crystal form: light yellow columnar
(recrystallized from diethylformamide) Mp: 264-265.degree. C.
Compound of Example 117 ##STR435## ##STR436## Crystal form: light
yellow powdery (recrystallized from dimethylformamide) Mp:
300.degree. C. or above Compound of Example 118 ##STR437##
##STR438## Crystal form: light yellow acicular (recrystallized from
dimethylformamide) Mp: 264-265.degree. C. Compound of Example 119
##STR439## ##STR440## Crystal form: colorless acicular
(recrystallized from acetonitrile) Mp: 209-210.degree. C. Compound
of Example 120 ##STR441## ##STR442## Crystal form: light yellow
powdery (recrystallized from dimethylformamide) Mp: 300.degree. C.
or above Compound of Example 121 ##STR443## ##STR444## Crystal
form: white powdery (recrystallized from dimethylformamide-water)
Mp: 284-286.degree. C. Compound of Example 122 ##STR445##
##STR446## Crystal form: colorless acicular (recrystallized from
dioxane- water) Mp: 252-253.degree. C. Compound of Example 123
##STR447## ##STR448## Crystal form: light green powdery
(recrystallization from ethanol- water) Mp: 256-258.degree. C. (HCl
salt) Compound of Example 124 ##STR449## ##STR450## Crystal form:
colorless acicular (recrystallized from dioxane) Mp:
191-192.degree. C. Compound of Example 125 ##STR451## ##STR452##
Crystal form: colorless prismatic (recrystallized from dioxane-
water) Mp: 178-179.degree. C. Compound of Example 126 ##STR453##
##STR454## Crystal form: white powdery (recrystallized from
dimethylformamide) Mp: 185-186.degree. C. (HCl salt) Compound of
Example 127 ##STR455## ##STR456## Crystal form: light brown
acicular (recrystallized from chloroform-ethanol) Mp:
249-251.degree. C. Compound of Example 128 ##STR457## ##STR458##
Crystal form: Light brown prisms (recrystallized from ethyl
acetate) Mp: 188-189.degree. C. Compound of Example 129 ##STR459##
##STR460## Crystal form: Brown granules (recrystallized from
ethanol) Mp. 231-231.degree. C. Compound of Example 130 ##STR461##
##STR462## Crystal form: white powdery (recrystallized from
dimethylformamide) Mp: 300.degree. C. or above Compound of Example
131 ##STR463## ##STR464## Crystal form: white powdery
(recrystallized from ethanol) Mp: 127-128.degree. C. Compound of
Example 132 ##STR465## ##STR466## Crystal form: colorless columnar
(recrystallized from petroleum ether-diethyl ether) Mp:
141-142.degree. C. Compound of Example 133 ##STR467## ##STR468##
Crystal form: light yellow powdery (recrystallized from ethanol)
Mp: 157-167.degree. C. (decomposed, HCl salt)
NMR(CDCl.sub.3).delta.: 3.80(3H, s), 3.87(3H, s), 7.06(1H, d,
J=8.5Hz), 7.56(1H, dd, J=2.1Hz, 8.5Hz), 7.65-7.82(2H, m), 8.31(1H,
t, J=6.7Hz), 8.46(1H, d, J=7.9Hz), 8.65-8.82(2H, m) Compound of
Example 134 ##STR469## ##STR470## Crystal form: light yellow
powdery (recrystallized from methanol) Mp: 270-271.degree. C.
(decomposed, 1/2FeCl.sub.2 salt) Compound of Example 135 ##STR471##
##STR472## Crystal form: yellow powdery (recrystallized from
dimethylformamide-water) Mp: 182-183.degree. C.
TABLE 9 ##STR473## Compound of Example 136 ##STR474## ##STR475##
Crystal form: light brown powdery (recrystallized from ethanol) Mp:
191-192.degree. C.
EXAMPLE 137
In 25 ml of acetic acid was dissolved 2 g of
6-[2-(3,4-dimethoxybenzoyloxy)acetyl]-3,4-dihydro-carbostyril.
Thereto was added 2 g of ammonium acetate. The mixture was stirred
at 130.degree. C. for 3 hours with heating. The solvent was removed
by distillation, The residue was dissolved in ethanol. The solution
was treated with active carbon, and then recrystallization was
conducted to obtain 120 mg of
2-(3,4-dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl) oxazole as
light brown acicular crystals.
M.p.: 191.degree.-192.degree. C.
EXAMPLE 138
There were mixed, each in a powdery state, 500 mg of
6-[2-(3,4-dimethoxybenzoylamino)acetyl]-3,4-dihydrocarbostyril and
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide
(Lawesson's reagent), The mixture was stirred at 200.degree. C.
with heating. After 3 hours, the reaction was completed. The
residue was subjected to silica gel column chromatography
(dichloromethane:methanol=49:1 by v/v), A solid obtained from the
eluate was recrystallized from ethanol to obtain 98 mg of
2-(3,4-dimethoxyphenyl)-5-(3,4-dihydrocarbostyril-6-yl) thiazole as
a white powder.
M.p. 235.degree.236.degree. C.
The compounds of Examples 1-95 and 97-135 were obtained by using
respective starting materials, in the same procedure as in Example
138.
EXAMPLE 139
In 50 ml of dichloromethane was dissolved 1 g of
2-(pyridin-3-yl)-4-phenylthiazole. Thereto was added 900 mg of
m-chloroperbenzoic acid at room temperature. The mixture was
stirred at the same temperature for 2 hours. The reaction mixture
was washed with an aqueous sodium hydrogencarbonate solution and
dried The solvent was removed by distillation. The residue was
recrystallized from ethyl acetate to obtain 306 mg of
3-(4-phenylthiazol-2-yl) pyridine-N-oxide as a brown powder.
M.p.: 140.degree.-141.degree. C.
EXAMPLE 140
In 25 ml of acetic anhydride was dissolved 2.8 g of
3-(4-phenylthiazol-2-yl)pyridine-N-oxide. The solution was refluxed
for 6 hours with heating. The solvent was removed by distillation.
The residue was treated with ammonia water and extracted with
dichloromethane. The extract was water-washed, dried and subjected
to solvent removal by distillation. The residue was mixed with a
small amount of dichloromethane. The resulting crystals were
collected by filtration and recrystallized from methanol to obtain
60 mg of 2-(2-oxopyridin-3-yl)4-phenylthiazole as light brown plate
crystals.
M.p.: 206.degree.-207.degree. C. (decomposed)
EXAMPLE 141
In 50 ml of tetrahydrofuran was suspended 103 mg of lithium
aluminum hydride. Thereto was added, in small portions, 1 g of
2-(3,4-dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole.
The mixture was stirred at 90.degree. C. for 3 hours with heating.
0.3 ml of water was added under ice-cooling, and the mixture was
stirred and then filtered. The residue was extracted with
dichloromethane. The extract was water-washed, dried and subjected
to solvent removal by distillation. The residue was treated with
active carbon and then converted into a hydrochloride with
methanolhydrochloric acid. The hydrochloride was recrystallized
from ethanol to obtain 465 mg of
2-(3,4-dimethoxyphenyl)-4-(1,2,3,4-tetrahydroquinolin-6-yl)
thiazole hydrochloride as a light brown powder.
M.p.: 156.degree.-158.degree. C.
EXAMPLE 142
In 4 ml of acetic acid and 2 ml of hydrobromic acid was suspended
500 mg of
2-(3,4-dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole.
The suspension was refluxed for 6 hours with heating. After
cooling, the resulting crystals were collected by filtration, dried
and recrystallized from ethanol to obtain 67 mg of
2-(3,4-dihydroxyphenyl)-4-(3,4-(dihydrocarbostyreil-6-yl)thiazole
as a yellow powder.
M.p.: 255.degree.-258.degree. C. (decomposed)
EXAMPLE 143
In 20 ml of DMF was dissolved 0.57 g of
2-(3,4-dimethoxyphenl)-4-(3,4-dihydro-2H-1,4-benzothiazin-3
(4H)-one-6-yl)thiazole, 0.065 g of 60% sodium hydride was added
under ice-cooling. The mixture was stirred for 30 minutes. 0.18 ml
of methyl iodide was added, and the mixture was stirred at
0.degree. C. to room temperature overnight. The solution was
concentrated and mixed with water. The resulting crystals were
collected by filtration, water-washed as dried. The crystals were
recrystallized from DMF-water to obtain 0.32 g of
2-(3,4-dimethoxyphenyl)-4-(4-methyl-2H-1,4-benzothiazin-3(4H)-one-6-yl)thi
azole as a light yellow powder.
M.p.: 143.5.degree.-144.degree. C.
The compounds of Examples 11, 29, 36, 42, 48, 61, 62, 71, 75, 78,
102 and 123 were obtained by using respective starting materials,
in the same procedure as in Example 143.
EXAMPLE 144
In 10 ml of pyridine was dissolved 1 g of
2-(3,4-dimethoxyphenyl)-4-(1,2,3,4-tetrahydroquinolin-6-yl)
thiazole. Thereto was added 0.44 g of benzoyl chloride at 0.degree.
C., and the mixture was stirred for 5 hours. The solution was
concentrated and mixed with ethanol and water in this order. The
resulting crystals were collected by filtration and recrystallized
from ethanol to obtain 0.7 g of
2-(3,4-dimethoxyphenyl)-4-(1-benzoyl-1,2,3,4-tetrahydroquinolin-6-yl)thiaz
ole as a light yellow powder.
M.p.: 152.5.degree.-153.5.degree. C.
EXAMPLE 145
In 20 ml of tetrahydrofuran was dissolved 300 mg of
2-(3,4-dimethoxyphenyl)-4-(3-amino-4-hydroxyphenyl) thiazole.
Thereto was added 0.46 ml of, triethylamine at room temperature.
The mixture was stiffed at the same temperature for 30 minutes. 100
mg of phosgene was blown thereinto, and the resulting mixture was
stirred for 2 hours. The solvent was distilled off. The residue was
washed with diethyl ether, followed by filtration to collect
crystals. The crystals were recrystallized from methanol to obtain
50 mg of 2-(3,4-dimethoxyphenyl)-4-(benzoxazol- 2-on-5-yl) thiazole
as a white powder.
M.p.: 271.degree.-272.degree. C.
EXAMPLE 146
In 10 ml of aceticanhydride and 10 ml of pyridine was dissolved 1 g
of
2-(3,4-dimethoxyphenyl)-4-(1,2,3,4-tetrahydroquinolin-6-yl)thiazole.
The solution was stirred at room temperature overnight. The
reaction mixture was concentrated. The concentrate was mixed with
water. The resulting crystals were collected by filtration,
water-washed and dried. Recrystallization from ethanol was
conducted to obtain 0.31 g of
2-(3,4-dimethoxyphenyl)-4-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)thiazo
le as colorless acicular crystals.
M.p.: 147.5.degree.148.5.degree. C.
The compounds of Examples 57, 63, 66, 76, 77 and 81 were obtained
by using respective starting materials, in the same procedure as in
Example 146.
EXAMPLE 147
2.05 g of
2-(4-ethoxycarbonylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole
was suspended in 20 ml of a 10% aqueous potassium hydroxide
solution and 50 ml of ethanol. The suspension was refluxed for 5
hours. Ethanol was removed by distillation. After cooling, the
residue was mixed with hydrochloric acid to make it acidic (pH 1).
The resulting crystals were collected by filtration and
recrystallized from dimethylformamide to obtain 0.70 g of
2-(4-carboxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole as a
light yellow powder.
M.p.: 300.degree. C. or above EXAMPLE 148
In 20 ml of oxalyl chloride was suspended 0.62 g of
2-(4-carboxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl) thiazole. The
suspension was refluxed for 1 hour with heating. Oxalyl chloride
was distilled off. The residue was suspended in acetone under
ice-cooling. Thereto was added ammonia water, The mixture was
returned to room temperature and stirred overnight, The mixture was
mixed with water. The resulting crystals were collected by
filtration, water-washed, dried and recrystallized from
dimethylformamide to obtain 0.29 g of
2-(4-carbamoylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole as a
light yellow powder.
M.p.: 300.degree. C. or above.
EXAMPLE 149
In 150 ml of chloroform-ethanol was suspended 3.40 g of
2-(3-methoxy-4-methylthiophenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole.
Thereto was added, in small portions, 1.97 g of
methachloroperbenzoic acid (80%) under ice-cooling. The mixture was
stirred for 1 hour. Then the mixture was returned to room
temperature and stirred overnight, Thereto was added an aqueous
sodium carbonate solution. The mixture was extracted with
chloroform three times. The combined extract was washed with a
saturated aqueous sodium chloride solution and dried over magnesium
sulfate. The solvent was distilled off and the resulting crystals
were recrystallized from dimethylformamide to obtain 0.50 g of
2-(3-methoxy-4-methylsulfinylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazo
le as light yellow acicular crystals.
M.p.: 264.degree.-265.degree. C.
The compound of Example 45 was obtained by using the starting
material, in the same procedure as in Example 149.
EXAMPLE 150
In 100 ml of chloroform-ethanol was suspended 2.9 g of
2-(3-methoxy-4-methylsulfinylphenyl)- 4-
(3,4-dihydrocarbostyril-6-yl)thiazole. Under ice-cooling, 1.72 g of
m-chloroperbenzoic acid (80%) was added in small portions and the
mixture was stiffed for 1 hour. Then, the mixture was returned to
room temperature and stirred overnight. The resulting crystals were
collected by filtration, washed with ethanol and diethyl ether, and
dried. Recrystallization from dimethylformamide-water to obtain
0.50 g of 2-(3-methoxy-4-methylsulfonylphenyl)-4-(3,4-
dihydrocarbostyril-6-yl)thiazole as a white powder.
M.p.: 284.degree.-286.degree. C.
EXAMPLE 151
In 6 ml of chloroform was dissolved 100 mg of
2-(3,4-dimethoxybenzoyl)-4-(3,4-dihydroxycarbostyril-6-yl)
thiazole. Thereto was added sodium boron hydride at room
temperature. and the mixture was stirred for 1 hour at the same
temperature. The solvent was distilled off. The residue was
extracted with chloroform. The extract was water-washed, dried and
then subjected to solvent removal by distillation. The residue was
purified by silica get column chromatography (eluent:
chloroform/methanoi=99/1) and then recrystallized from ethyl
acetate to obtain 52 mg of
2-[1-(3,4-dimethoxyphenyl)-1-hydroxymethyl]-4-(3,4-dihydroxycarbostyril-6-
yl)thiazole as light brown prismatic crystals.
M.p.: 188.degree.-189.degree. C.
EXAMPLE 152
In 50 ml of acetic add was suspended 2 g of
2-(3,4-dimebthoxybenzyl)-3,4-dihydroxycarbostyril-6-yl)thiazole.
Thereto was added 1.2 g of CrO.sub.3. The mixture was stirred at
70.degree.-80.degree. C. for 3 hours. Then, 2 g of activated
magnesium silicate [Florisil (trade name) manufactured by Wako Pure
Chemical Industry; Ltd.] was added, and the mixture was stirred at
room temperature for 1 hour. After the completion of a reaction,
the solvent was removed by distillation, and the residue was
suspended in a chloroform-methanol (4:1) mixture The suspension was
filtered The filtrate was subjected to solvent removal by
distillation. The residue was purified by silica gel column
chromatography (eluent: chloroforin/methanol=199/1) and then
recrystallized from chloroform-ethanol to obtain 300 mg of
2-(3,4-dimethoxybenzoyl)-4-(3,4-dihydroxycarbostyril-6-yl) thiazole
as light brown acicular crystals.
M.p.: 249.degree.-251.degree. C.
EXAMPLES 154-234
Compounds shown in the following Table 10 were obtained by using
respective starting materials, in the same procedure as in Examples
1 and 138.
TABLE 10 ##STR476## Compound of Example 154 ##STR477## ##STR478##
Crystal form: yellow powdery (recrystallized from dioxane) Mp:
196.5-197.degree. C. Form: free Compound of Example 155 ##STR479##
##STR480## Crystal form: light brown acicular (recrystallized from
methanol) Mp: 133-135.degree. C. Form: free Compound of Example 156
##STR481## ##STR482## Crystal form: light yellow powdery
(recrystallized from ethanol-water) Mp: 198-200.degree. C. Form: 2
HCl salt Compound of Example 157 ##STR483## ##STR484## Crystal
form: colorless acicular (recrystallized from dioxane) Mp:
185-186.degree. C. Form: free Compound of Example 158 ##STR485##
##STR486## Crystal form: white powdery (recrystallized from
ethanol) Mp: 121-123.degree. C. Form: free Compound of Example 159
##STR487## ##STR488## Crystal form: white powdery (recrystallized
from dioxane-water) Mp: 255-256.degree. C. Form: free Compound of
Example 160 ##STR489## ##STR490## Crystal form: white powdery
(recrystallized from dioxane) Mp: 164-165.degree. C. Form: free
Compound of Example 161 ##STR491## ##STR492## Crystal form:
colorless acicular (recrystallized from dioxane) Mp:
203-204.degree. C. Form: free Compound of Example 162 ##STR493##
##STR494## Crystal form: colorless acicular (recrystallized from
ethanol) Mp: 125.5-126.5.degree. C. Form: free Compound of Example
163 ##STR495## ##STR496## Crystal form: colorless acicular
(recrystallized from ethanol) Mp: 170-171.degree. C. Form: free
Compound of Example 164 ##STR497## ##STR498## Crystal form: white
powdery (recrystallized from dioxane) Mp: 203-204.degree. C. Form:
free Compound of Example 165 ##STR499## ##STR500## Crystal form:
colorless acicular (recrystallized from dioxane) Mp:
179-181.degree. C. Form: free Compound of Example 166 ##STR501##
##STR502## Crystal form: light yellow prismatic (recrystallized
from dioxane) Mp: 250-251.degree. C. Form: free Compound of Example
167 ##STR503## ##STR504## Crystal form: white acicular
(recrystallized from dioxane-water) Mp: 188-189.degree. C. Form:
free Compound of Example 168 ##STR505## ##STR506## Crystal form:
light yellow acicular (recrystallized from dioxane-water) Mp:
189-190.degree. C. Form: free Compound of Example 169 ##STR507##
##STR508## Crystal form: light brown prismatic (recrystallized from
ethyl acetate) Mp: 171-172.degree. C. Form: free Compound of
Example 170 ##STR509## ##STR510## Crystal form: colorless acicular
(recrystallized from ethanol) Mp: 125-126.degree. C. Form: free
Compound of Example 171 ##STR511## ##STR512## Crystal form:
colorless acicular (recrystallized from ethanol) Mp:
195-197.degree. C. Form: free Compound of Example 172 ##STR513##
##STR514## Crystal form: light yellow powdery (recrystallized from
ethanol-water) Mp: 96-97.degree. C. Form: HCl salt Compound of
Example 173 ##STR515## ##STR516## Crystal form: light brown powdery
(recrystallized from ethanol) Mp: 138-139.degree. C. Form:
dihydrochloride Compound of Example 174 ##STR517## ##STR518##
Crystal form: light yellow powdery Mp: 248-249.degree. C. Form:
free Compound of Example 175 ##STR519## ##STR520## Crystal form:
light yellow plate (recrystallized from ethanol) Mp:
195-196.degree. C. Form: free Compound of Example 176 ##STR521##
##STR522## Crystal form: white powdery (recrystallized from ethyl
acetate) Mp: 180-181.degree. C. Form: free Compound of Example 177
##STR523## ##STR524## Crystal form: light yellow prismatic
(recrystallized from dioxane) Mp: 254-255.degree. C. Form: free
Compound of Example 178 ##STR525## ##STR526## Crystal form: brown
powdery (recrystallized from ethanol-diethyl ether) Mp:
164-165.degree. C. Form: dihydrochloride Compound of Example 179
##STR527## ##STR528## Crystal form: light yellow acicular
(recrystallized from ethanol) Mp: 138-139.degree. C. Form: free
Compound of Example 180 ##STR529## ##STR530## Crystal form: yellow
acicular (recrystallized from ethanol) Mp: 117-118.degree. C. Form:
dihydrochloride Compound of Example 181 ##STR531## ##STR532##
Crystal form: colorless acicular (recrystallized from ethanol) Mp:
168-170.degree. C. Form: trihydrochloride Compound of Example 182
##STR533## ##STR534## Crystal form: white prismatic (recrystallized
from toluene) Mp: 175-176.degree. C. Form: free Compound of Example
183 ##STR535## ##STR536## Crystal form: white powdery
(recrystallized from ethyl acetate-n-hexane) Mp: 180-181.degree. C.
Form: free Compound of Example 184 ##STR537## ##STR538## Crystal
form: white acicular (recrystallized from ethanol) Mp:
138-140.degree. C. Form: free Compound of Example 185 ##STR539##
##STR540## Crystal form: yellow powdery recrystallized from
ethanol-water) Mp: 175-176.degree. C. Form: free Compound of
Example 186 ##STR541## ##STR542## Crystal form: light yellow
acicular (recrystallized from ethanol-diethyl ether) Mp:
138-140.degree. C. Form: hydrochloride Compound of Example 187
##STR543## ##STR544## Crystal form: orange acicular (recrystallized
from ethyl acetate-n-hexane) Mp: 119-120.degree. C. Form: free
Compound of Example 188 ##STR545## ##STR546## Crystal form: brown
prismatic (recrystallized from ethanol) Mp: 202-203.degree. C.
Form: hydrochloride Compound of Example 189 ##STR547## ##STR548##
Crystal form: yellow acicular (recrystallized from dioxane-water)
Mp: 142-143.degree. C. Form: free Compound of Example 190
##STR549## ##STR550## Crystal form: white acicular (recrystallized
from ethanol) Mp: 194-195.degree. C. Form: free Compound of Example
191 ##STR551## ##STR552## Crystal form: colorless acicular
(recrystallized from ethanol-water) Mp: 173-175.degree. C. Form:
hydrochloride Compound of Example 192 ##STR553## ##STR554## Crystal
form: light yellow acicular (recrystallized from ethanol) Mp:
98-99.degree. C. Form: free Compound of Example 193 ##STR555##
##STR556## Crystal form: colorless acicular (recrystallized from
ethanol) Mp: 95-96.degree. C. Form: free Compound of Example 194
##STR557## ##STR558## Crystal form: yellow acicular (recrystallized
from dioxane-water) Mp: 145-146.5.degree. C. Form: free Compound of
Example 195 ##STR559## ##STR560## Crystal form: colorless acicular
(recrystallized
from ethanol) Mp: 114-114.5.degree. C. Form: free Compound of
Example 196 ##STR561## ##STR562## Crystal form: yellow powdery
(recrystallized from ethanol) Mp: 158-180.degree. C. (decomposed)
Form: dihydrochloride NMR(DMSO-d.sub.6).delta.: 1.28-1.5(6H, m),
4.02-4.25(4H, m), 7.10(1H, d, J= 8.3Hz), 7.19(1H, d, J=8.5Hz),
7.46-7.63(2H, m), 7.83-7.97(2H, m), 8.12(1H, d, J=2Hz) Compound of
Example 197 ##STR563## ##STR564## Crystal form: light green powdery
(recrystallized from ethanol-water) Mp: 230.degree. C. (decomposed)
Form: hydrochloride Compound of Example 198 ##STR565## ##STR566##
Crystal form: colorless acicular (recrystallized from ethanol) Mp:
244.degree. C. (decomposed) Form: hydrochloride Compound of Example
199 ##STR567## ##STR568## Crystal form: colorless acicular
(recrystallized from ethanol) Mp: 111-112.degree. C. Form: free
Compound of Example 200 ##STR569## ##STR570## Crystal form:
colorless column (recrystallized from dioxane) Mp: 228-229.degree.
C. Form: free Compound of Example 201 ##STR571## ##STR572## Crystal
form: white powdery (recrystallized from ethanol-water) Mp:
186-188.degree. C. Form: dihydrochloride Compound of Example 202
##STR573## ##STR574## Crystal form: yellow acicular (recrystallized
from methanol-ethyl acetate) Mp: 170-171.degree. C. Form: free
Compound of Example 203 ##STR575## ##STR576## Crystal form: white
powdery (recrystallized from ethyl acetate-n-hexane) Mp:
112-113.degree. C. Form: free Compound of Example 204 ##STR577##
##STR578## Crystal form: white powdery (recrystallized from
ethanol) Mp: 150-154.degree. C. (decomposed) Form: dihydrochloride
Compound of Example 205 ##STR579## ##STR580## Crystal form: white
powdery (recrystallized from methanol-ethyl acetate) Mp:
206-208.degree. C. Form: trihydrochloride Compound of Example 206
##STR581## ##STR582## Crystal form: white powdery (recrystallized
from ethanol) Mp: 155-158.degree. C. (decomposed) Form:
trihydrochloride Compound of Example 207 ##STR583## ##STR584##
Crystal form: white powdery (recrystallized from ethanol) Mp:
241-242.degree. C. Form: trihydrochloride Compound of Example 208
##STR585## ##STR586## Crystal form: yellow powdery (recrystallized
from ethanol) Mp: 156-162.degree. C. Form: dihydrochloride Compound
of Example 209 ##STR587## ##STR588## NMR(DMSO-d.sub.6).delta.:
2.83(3H, brs), 3.28-3.82(8H, m), 3.85(3H, s), 3.91(3H, s), 7.11(2H,
d, J=8.4Hz), 7.52-7.68 (2H, m), 7.87(1H, s), 7.98(1H, dd, J=2.0Hz,
8.5Hz), 8.30(1H, d, J=2.0Hz) Crystal form: yellow powdery
(recrystallized from ethanol) Mp: 178-190.degree. C. Form:
trihydrochloride Compound of Example 210 ##STR589## ##STR590##
Crystal form: white powdery (recrystallized from ethanol) Mp:
188-192.degree. C. (decomosed) Form: dihydrochloride Compound of
Example 211 ##STR591## ##STR592## Crystal form: yellow acicular
(recrystallized from ethyl acetate-ethanol) Mp: 166-170.degree. C.
Form: trihydrochloride Compound of Example 212 ##STR593##
##STR594## Crystal form: yellow powdery (recrystallized from
ethanol) Mp: 167-171.degree. C. Form: dihydrochloride Compound of
Example 213 ##STR595## ##STR596## Crystal form: white acicular
(recrystallized from ethanol) Mp: 137-138.degree. C. Form: free
Compound of Example 214 ##STR597## ##STR598## Crystal form:
colorless prismatic (recrystallized from ethyl acetate) Mp:
121-122.degree. C. Form: free Compound of Example 215 ##STR599##
##STR600## Crystal form: colorless acicular (recrystallized from
ethanol) Mp: 176-177.degree. C. Form: free Compound of Example 216
##STR601## ##STR602## Crystal form: white powdery (recrystallized
from ethyl acetate) Mp: 185-186.degree. C. Form: hydrochloride
Compound of Example 217 ##STR603## ##STR604## Crystal form: white
granular (recrystallized from diisopropyl ether) Mp:
113-114.degree. C. Form: free Compound of Example 218 ##STR605##
##STR606## Crystal form: white powdery (recrystallized from ethyl
acetate) Mp: 212-214.degree. C. Form: dihydrochloride Compound of
Example 219 ##STR607## ##STR608## Crystal form: white plate
(recrystallized from ethanol) Mp: 126-128.degree. C. Form: free
Compound of Example 220 ##STR609## ##STR610## Crystal form: light
yellow acicular (recrystallized from ethanol) Mp: 97-98.degree. C.
Form: free Compound of Example 221 ##STR611## ##STR612## Crystal
form: white acicular (recrystallized from ethanol) Mp:
161-164.degree. C. Form: hydrochloride Compound of Example 222
##STR613## R.sup.2 = -- CO.sub.2 C.sub.2 H.sub.5, R.sup.3 =
--CO.sub.2 C.sub.2 H.sub.5, Crystal form: white powdery
(recrystallized from ethyl acetate) Mp: 212-214.degree. C. Form:
dihydrochloride Compound of Example 223 ##STR614## ##STR615##
Crystal form: yellow powdery (recrystallized from
dimethylformamide) Mp: 270-279.degree. C. (decomposed) Form: free
NMR(DMSO-D.sub.6).delta.: 1.39(3H, t, J=6.8Hz), 1.40(3H, t,
J=6.8Hz), 4.00-4.3(4H, m), 7.13(1H, d, J=8.4Hz), 7.16(1H, d,
J=2.0Hz), 7.68(1H, dd, J=2.0Hz, 8.4Hz), 11.97(2H, brs) Compound of
Example 224 ##STR616## ##STR617## Crystal form: light brown powdery
(recrystallized from ethanol) Mp: 188-210.degree. C. (decomposed)
Form: dihydrochloride NMR(DMSO-d.sub.6).delta.: 2.82(3H, s),
3.25-3.78(8H, m), 3.85(3H, s), 3.88 (3H, s), 4.49(2H, brs),
7.09(1H, d, J=8.6Hz), 7.44-7.60(2H, m), 7.92(1H, s) Compound of
Example 225 ##STR618## ##STR619## Crystal form: yellow powdery
(recrystallized from acetone) Mp: 114-115.degree. C. Form:
hydrochloride Compound of Example 226 ##STR620## ##STR621## Crystal
form: light brown powdery (recrystallized from diethyl ether) Mp:
122-123.degree. C. Form: free Compound of Example 227 ##STR622##
##STR623## Crystal form: white powdery (recrystallized from ethyl
acetate-n-hexane) Mp: 128-129.degree. C. Form: free Compound of
Example 228 ##STR624## ##STR625## Crystal form: dark yellow powdery
(recrystallized from dimethylformamide-water) Mp: 285-290.degree.
C. (decomposed) Form: free Compound of Example 229 ##STR626##
##STR627## Crystal form: colorless prismatic (recrystallized from
ethyl) Mp: 130-131.degree. C. Form: free Compound of Example 230
##STR628## ##STR629## Crystal form: light brown powdery
(recrystallized from dimethylformamide-ethanol) Mp: 256-257.degree.
C. Form: free Compound of Example 231 ##STR630## ##STR631## Crystal
form: light yellow powdery Mp: 94-95.degree. C. Form: free Compound
of Example 232 ##STR632## ##STR633## Compound of Example 233
##STR634## ##STR635## Crystal form: colorless prismatic
(recrystallized from methylene chloride-ethanol) Mp:
195-196.degree. C. Form: free Compound of Example 234 ##STR636##
##STR637##
EXAMPLE 235
5.9 g of 4-(3,5dinitrophenyl)-2-(3,4-dimethoxyphenyl) triazole and
a solution of 2,4 g. of stannous chloride dihydrate dissolved in 90
ml of concentrated hydrochloric acid were stirred at room
temperature for 2 hours. After cooling, the resulting crystals were
collected by filtration and recrystallized from ethanol-water to
obtain 3.73 g of
4-(3,5-diaminophenyl)-2-(3,4-dimethoxyphenyl)thiazole
dihydrochloride.
M.p.: 198.degree.-200.degree. C.
Light yellow powder
The compounds of Examples 55, 91, 104, 181, 191, 196, 197, 198, 208
and 232 were obtained using respective starting materials, in the
same procedure as in Example 235.
EXAMPLE 236
In 45 ml of tetrahydrofuran were dissolved 1.5 g of
4-(4-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole, 1.4 g of
2,3,4,6-tetra-O-acetyl-.beta.-(3,4-diethoxyphenyl)thiazole, 1.4 g
triphenylphosphine. Thereto was added, in small portions at
0.degree. C. a solution of 0.9 g of diethyl azodicarboxylate
dissolved in 5 ml of tetrahydrofuran. The mixture was stirred at
room temperature for 14 hours. The solvent was removed by
distillation. The residue was purified by silica gel column
chromatography (elutant: dichloromethane) and recrystallized from
ethyl acetate-n-hexane to obtain 1.52 g of 4-[4-(2.
3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)phenyl]-2-(3,4-diethoxyphe
nyl)-thiazole.
M.p.: 180.degree.-181.degree. C.
White powder
The compounds of Examples 171 and 184 were obtained using
respective starting materials, in the same procedure as in Example
236.
EXAMPLE 237
In 6 ml of a methanol-dichloromethane (2:1) mixed solvent was
suspended 0.15 g of
4-[4-(2,3,4,6-tetra-O-acetyl-.beta.-D-glucopyranosyloxy)phenyl]-2-(3,4-die
thoxyphenyl)thiazole. Thereto was added a catalytic amount of
sodium methylate. The mixture was stirred at room temperature for 2
hours. The solvent was removed by distillation. The residue was
recrystallized from methanol to obtain 71 mg of
4-[4-(.beta.-D-glucopyranosyloxy)-phenyl]-2-(3,4-diethoxyphenyl)thiazole.
M.p.: 138.degree.-140.degree. C.
White acicular crystals
EXAMPLE 238
2 ml of chlorosulfonic acid was dropwise added to 40 ml of pyridine
at room temperature. The mixture was stirred at 50.degree. C. for
12 hours. Thereto was added 0.33 g of
4-(4-hydroxyphenyl-2-(3,4-dimethoxyphenyl)thiazole. The mixture was
stirred at 50.degree. C. for 6 hours and then at room temperature
overnight. The reaction mixture was concentrated to dryness under
reduced pressure. The residue was mixed with water and the
resulting crystals were collected by filtration. The resulting
4-(4-hydroxysulfonyloxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole
pyridinium salt was suspended in 3 ml of methanol. Thereto was
added 5 ml of a 0.1N aqueous potassium hydroxide solution. The
mixture was stirred at room temperature overnight, The reaction
mixture was concentrated. The residue was dissolved in water. The
solution was treated with 0.5 g of an ion exchange resin (Dowex
50Wx8), The filtrate was concentrated to obtain 0.04 g of
4-(4-hydroxysulfonyloxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole.
M.p.: 248.degree.-249.degree. C.
Light yellow powder
EXAMPLE 239
In 25 ml of ethanol were suspended 0.5 g of
4-(4-hydroxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole, 1 g of
paraformaldehyde and 0.5 g of N-methylpiperazine. The suspension
was refluxed for 8 hours with heating. The reaction mixture was
subjected to distillation under reduced pressure to remove the
solvent. The residue was purified by silica get column
chromatography (eluent: dichloromethane/methanol=49/1 by v/v) and
dissolved in 10 ml of ethanol. Thereto was added 0.5 ml of ethanol
saturated with hydrogen chloride gas, and the mixture was allowed
to stand. The resulting crystals were collected by filtration,
dried and recrystallized from ethanol to obtain 0.2 g of
4-[4-hydroxy-3-(4-methyl-1-piperazinylmethyl)phenyl]-2-(3,4-dimethoxypheny
l)thiazole trihydrochloride.
M.p.: 178.degree.-190.degree. C.
Yellow powder
NMR (DMSO-d.sub.6) .delta.:
2.83-3.82 (3H, brs), 3.28-3.82 (8H, m), 3.85 (3H, s).391 (3H, s)
7.11 (2H, d, J=8.4 Hz), 7.52-7.68 (2H, m), 7.87 (1H, s) 7.98 (1H,
dd, J=2.0 Hz, 8.5 Hz), 8.30 (1H, d, J=2.0 Hz).
EXAMPLE 240
20 ml of a dimethylformamide solution containing 1.5 g of
4-(3-methoxy-5-carboxyphenyl)-2-(3,4-diethoxyphenyl) thiazole, 0.4
g of N-methylpiperazine and 0.7 g of diethyl cyanophosphonate was
stirred with ice-cooling. Thereto was added 0.6 ml of
triethylamine. The mixture was stirred at room temperature for 14
hours. The solvent was destroyed off. The residue was mixed with 80
ml of dichloromethane and 30 ml of water. Phase separation was
conducted and the dichloromethane layer was washed with 20 ml of a
saturated aqueous sodium hydrogencarbonate solution was 20 ml of a
saturated aqueous sodium chloride solution, and dried. The solvent
was removed by distillation. The residue was purified by silica gel
column chromatography (eluent: dichloromethane/methanol=200/3 by
v/v) and then dissolved in ethyl acetate. To the solution was added
hydrochloric acid-ethanol. The resulting crystals were collected by
filtration, dried and recrystallized from ethyl acetate to obtain
1.2 g of
4-[3-methoxy-5-(4-methyl-1-piperzinylcarbonyl)phenyl]-2-(3,4-diethoxypheny
l)thiazole hydrochloride.
White powder
M.p.: 185.degree.-186.degree. C.
The compounds of Examples 120, 217 and 233 were obtained by using
respective starting materials, in the same procedure as in Example
240.
EXAMPLE 241
In 20, of tetrahydrofuran was dissolved 0.4 g of
4-[3-methoxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl-2-(3,4-diethoxypheny
l)thiazole. Thereto was added 32 mg of lithium aluminum hydride in
small portions. The mixture was stirred at 0.degree. C. for 30
minutes and at room temperature for 2 hours. Then, there were added
0.05 ml of a 10% aqueous sodium hydroxide solution and 0.1 ml of
water. The mixture was stirred at room temperature for 20 minutes.
The reaction mixture was filtered. The filtrate was concentrated.
The residue was purified by silica gel column chromatography
(eluent: dichloromethane/methanol=99/1 by v/v) and dissolved in
ethyl acetate. Thereto was added hydrochloric acid-ethanol. The
resulting crystals were collected by filtration, dried and
recrystallized from ethyl acetate to obtain 40 mg of
4-[3-methoxy-5-(4-methyl-1piperazinylmethyl)-phenyl]-2-(3,4-diethoxyphenyl
)thiazole dihydrochloride.
White powder
M.p.: 212.degree.-214.degree. C.
The compound of Example 209 was obtained by using starting
materials, in the same procedure as in Example 241.
EXAMPLE 242
A solution of 1 g of
4-(4-chloro-3-nitrophenyl)-2-(3,4-diethoxyphenyl)thiazole and 636
mg of morpholine dissolved in 20 ml of dimethylformamide and 20 ml
of dimethyl sulfoxide was refluxed at 150.degree. C. for 2-3.5
hours with heating. The reaction mixture was subjected to vacuum
distillation. The residue was added to ice water, and an aqueous
sodium hydrogencarbonate solution was added. The solution was
extracted with dichloromethane three times. The combined extract
was washed with an aqueous sodium chloride solution and dried over
magnesium sulfate. The solvent was removed by distillation. The
residue was purified by silica gel column chromatography and
recrystallized from ethyl acetate-n-hexane to obtain 1.03 g of
4-(4-morpholino-3-nitrophenyl)-2-(-3,4-diethoxyphenyl)
thiazole.
Orange acicular crystals
M.p.: 119.degree.-120.degree. C.
The compounds of Examples 173, 180, 188 and 189 were obtained by
using respective starting materials, in the same procedure as in
Example 242.
EXAMPLE 243
In 4 ml of ethanol was suspended 1 g of
4,5-diethoxycarbonyl-2-(3,4-diethoxyphenyl)thiazole. Thereto was
added 2 ml of hydrazine hydrate. The mixture was sealed in a tube
and heated at 130.degree. C. for 48 hours. After cooling, the
resulting crystals were collected by filtration, washed with
ethanol, dried and recrystallized from dimethylformamide to obtain
220 mg of
2-(3,4-diethoxyphenyl)5.6-dihydrothiazolo[4,5-d]pyridazine-4,7-dione.
M.p.: 270.degree.-279.degree. C. (decomposed)
Yellow powder
NMR (DMSO-d.sub.6) .delta.:
1.39 (3H, t, J=6.8 Hz), 1.40 (3H, t, J=6.8 Hz), 4.00-4.35 (4H, m),
7.13 (1H, d, J=8.4 Hz), 7.61 (1H, d, J=2.0 Hz), 7.68 (1H, dd, J=2.0
Hz, 8.4 Hz), 11.97 (2H, hrs).
EXAMPLE 244
In 10 ml of dimethylformamide were dissolved 860 mg of
2-(3,4-dimethoxyphenyl)-4-chloromethylthiazole and 320 mg of
N-methylpiperazine. Thereto was added 130 mg of sodium hydride. The
mixture was stirred at room temperature for 14 hours. The solvent
was removed by distillation. The residue was extracted with
chloroform. The extract was water-washed, dried and subjected to
distillation to remove the solvent, The residue was dissolved in
ethanol. To the solution was added ethanol saturated with hydrogen
chloride gas, and the mixture was allowed to stand. The resulting
crystals were collected by filtration washed with a small amount of
ethanol, dried and recrystallized from ethanol to obtain 820 mg of
2-(3,4-dimethoxyphenyl)-4-(4-methylpiperazinylmethyl)thiazole.
M.p.: 188.degree.210.degree. C. (decomposed)
Light brown powder
The compounds of Examples 209, 212 and 218 were obtained by using
respective starting materials, in the same procedure as in Example
244.
EXAMPLE 245
60 ml of a tetrahydrofuran solution of a Grignard reagent prepared
from 2.4 g of 1-bromo-3,4-dimethoxybenzene was stirred with
ice-cooling. Thereto was added 20 ml of a tetrahydrofuran solution
of 3 g of 2-(3,4-diethoxyphenyl)-4-formylthiazole. The mixture was
stirred at the same temperature for 1 hour and at room temperature
for 3 hours. 10 ml of a saturated aqueous ammonium chloride
solution was added. The solvent was removed by distillation. The
residue was extracted with 100 ml of chloroform. The extract was
washed with 20 ml of water and 20 ml of a saturated aqueous sodium
chloride solution, and dried. The solvent was removed by
distillation. The residue was purified by silica gel column
chromatography (elutant: dichloromethane/acetone=99/1 by v/v) and
recrystallized from diethyl ether to obtain 2.2 g of
2-(3,4-diethoxyphenyl)4-[1-hydroxy-1-(3,
4-dimethoxyphenyl)methlyl]thiazole.
M.p.: 122.degree.-123.degree. C.
Light brown powder
The compound of Example 128 was obtained by using starting
materials, in the same procedure as in Example 245.
EXAMPLE 246
In 20 ml of chloroform was dissolved, 150 mg of
2-(3,4-diethoxyphenyl)-4-[1-hydroxy-1-(3,4-dimethoxyphenyl)
methyl]thiazole. 1 g of manganese dioxide was added. The mixture
was refluxed for 2 hours with heating. The reaction mixture was
filtered. The filtrate was concentrated. The residue was
recrystallized from ethyl acetate-n-hexane to obtain 98 mg
2-(3,4-diethoxyphenyl)-4-(3,4-diethoxybenzoyl)thiazole.
M.p.: 128.degree.-129.degree. C.
White powder
The compound of Example 127 was obtained by using starting
materials, in the same procedure as in Example 246.
EXAMPLE 247
4.2 ml of n-butyllithium was dropwise added in small portions to a
suspension of 2.6 g of benzyltriphenylphosphonium chloride in 10 ml
of tetrahydrofuran, with stirring at -50.degree. C. The mixture was
heated to room temperature and, after cooling again to -50.degree.
C., was mixed with 12 ml of a tetrahydrofuran solution of 2 g of
2-(3,4-diethoxyphenyl)-4-formylthiazole. The mixture was stirred at
the same temperature for 30 minutes and at room temperature for 14
hours. 10 ml of water and 40 ml of ethyl acetate were added to
conduct extraction and phase separation. The solvent layer was
dried and subjected to distillation to remove the solvent. The
residue was purified by silica gel column chromatography to obtain
2 g of 2-(3,4-diethoxyphenyl)-4-styrylthiazole as a 1:1 mixture of
cis form and trans form.
M.p.: 94.degree.-95.degree. C.
Light yellow powder
The compounds of Examples 129 and 135 were obtained by using
respective starting materials, in the same procedure as in Example
247.
EXAMPLE 248
The compounds of Examples 155, 169, 175, 182, 190, 196, 201, 208,
209, 210, 211, 219, 220, 228 and 233 were obtained by using
respective starting materials, in the same procedure as in Example
142.
EXAMPLE 249
The compounds of Examples 172, 178, 180, 181, 186, 201, 206, 207,
209, 210, 211, 216 and 234 were obtained by using respective
starting materials, in the same procedure as in Example 143.
EXAMPLE 250
The compound of Example 226 was obtained by using starting
materials, in the same procedure as in Example 151.
EXAMPLE 251
The compound of Example 227 was obtained by using starting
materials, in the same procedure as in Example 152.
EXAMPLE 252
The compounds of Examples 159, 175, 186, 202 and 203 were obtained
by using respective starting materials, in the same procedure as in
Example 146.
EXAMPLES 253-351
The compounds shown in the following Table 11 were obtained by
using respective starting materials, in the same procedures as in
Examples 1 and 138.
TABLE 11 ##STR638## Compound of Example 253 ##STR639## ##STR640##
Crystal form: white powdery (recrystallized from
methanol-chloroform M.p.: 219.3-220.3.degree. C. Form: free
Compound of Example 254 ##STR641## ##STR642## Crystal form: white
acicular (recrystallized from ethanol) M.p.: 137-138.degree. C.
Form: free Compound of Example 255 ##STR643## ##STR644## Crystal
form: colorless acicular (recrystallized from diisopropyl ether)
M.p.: 96-97.degree. C. Form: free Compound of Example 256
##STR645## ##STR646## Crystal form: white powder (recrystallized
from diisopropyl ether) M.p.: 86-87.degree. C. Form: free Compound
of Example 257 ##STR647## ##STR648## Crystal form: light brown
granular (recrystallized from diisopropyl ether) M.p.:
199-200.degree. C. Form: free Compound of Example 258 ##STR649##
##STR650## Crystal form: colorless prismatic (recrystallized from
dichloromethane-ethanol) M.p.: 195-196.degree. C. Form: free
Compound of Example 259 ##STR651## ##STR652## Crystal form: white
powdery (recrystallized from diethyl ether-n-hexane) M.p.:
131-131.8.degree. C. Form: free Compound of Example 260 ##STR653##
##STR654## Crystal form: colorless prismatic (recrystallized from
diisopropyl ether) M.p.: 118-119.degree. C. Form: free Compound of
Example 261 ##STR655## ##STR656## Crystal form: white acicular
(recrystallized from ethyl acetate) M.p.: 159-160.degree. C. Form:
free Compound of Example 262 ##STR657## ##STR658## Crystal form:
white acicular (recrystallized from ethanol) M.p.: 156-157.degree.
C. Form: free Compound of Example 263 ##STR659## ##STR660## Crystal
form: light brown powdery (recrystallized from dioxane-ethanol)
M.p.: 283-285.degree. C. Form: free Compound of Example 264
##STR661## ##STR662## Crystal form: yellow acicular (recrystallized
from dichloromethane-ethanol) M.p.: 194-195.degree. C. Form: free
Compound of Example 265 ##STR663## ##STR664## Crystal form: yellow
powdery (recrystallized from ethanol-chloroform) M.p.:
150.4-152.degree. C. Form: free Compound of Example 266 ##STR665##
##STR666## Crystal form: white acicular (recrystallized from
ethanol) M.p.: 82-83.degree. C. Form: free Compound of Example 267
##STR667## ##STR668## Crystal form: white acicular (recrystallized
from ethyl acetate) M.p.: 134-135.degree. C. Form: free Compound of
Example 268 ##STR669## ##STR670## Crystal form: white acicular
(recrystallized from methanol) M.p.: 139.8-141.degree. C. Form:
free Compound of Example 269 ##STR671## ##STR672## Crystal form:
brown powdery (recrystallized from methanol) M.p.: 247-248.degree.
C. Form: free Compound of Example 270 ##STR673## ##STR674## Crystal
form: white powdery (recrystallized from diethyl ether-n-hexane)
M.p.: 95.8-94.4.degree. C. Form: free Compound of Example 271
##STR675## ##STR676## Crystal form: white powdery (recrystallized
from methanol-chloroform) M.p.: 248-258.degree. C. Form:
dihydrochloride Compound of Example 272 ##STR677## ##STR678##
Crystal form: light yellow acicular (recrystallized from methanol)
M.p.: 116.6-118.2.degree. C. Form: free Compound of Example 273
##STR679## ##STR680## Crystal form: white acicular (recrystallized
from ethanol) M.p.: 128.6-129.2.degree. C. Form: free Compound of
Example 274 ##STR681## ##STR682## Crystal form: white prismatic
(recrystallized from ethanol) M.p.: 128.2-129.degree. C. Form: free
Compound of Example 275 ##STR683## ##STR684## Crystal form: light
brown granular (recrystallized from ethyl acetate-n-hexane) M.p.:
164-165.degree. C. Form: free Compound of Example 276 ##STR685##
##STR686## Crystal form: white acicular (recrystallized from ethyl
acetate) M.p.: 197-198.degree. C. Form: free Compound of Example
277 ##STR687## ##STR688## Crystal form: white acicular
(recrystallized from ethyl acetate-n-hexane) M.p.: 184-185.degree.
C. Form: free Compound of Example 278 ##STR689## ##STR690## Crystal
form: white acicular (recrystallized from ethyl acetate) M.p.:
211-212.degree. C. Form: free Compound of Example 279 ##STR691##
##STR692## Crystal form: white prismatic (recrystallized from
toluene-diethyl ether) M.p.: 100.6-101.4.degree. C. Form: free
Compound of Example 280 ##STR693## ##STR694## Crystal form: light
brown powdery (recrystallized from ethanol-chloroform) M.p.:
138.6-140.6.degree. C. Form: free Compound of Example 281
##STR695## ##STR696## Crystal form: light pink acicular
(recrystallized from ethanol) M.p.: 192-192.8.degree. C. Form: free
Compound of Example 282 ##STR697## ##STR698## Crystal form: white
powdery (recrystallized from ethanol) M.p.: 208.6-211.6.degree. C.
Form: free Compound of Example 283 ##STR699## ##STR700## Crystal
form: white acicular (recrystallized from methanol) M.p.:
135-136.degree. C. Form: free Compound of Example 284 ##STR701##
##STR702## Crystal form: white powdery (recrystallized from
ethanol) M.p.: 179-180.degree. C. Form: free Compound of Example
285 ##STR703## ##STR704## Crystal form: white powdery
(recrystallized from ethanol) M.p.: 215-216.degree. C. Form: free
Compound of Example 286 ##STR705## ##STR706## Crystal form: light
green acicular (recrystallized from methanol) M.p.: 194-196.degree.
C. Form: free Compound of Example 287 ##STR707## ##STR708## Crystal
form: white powdery (recrystallized from dioxane) M.p.:
272-273.degree. C. Form: free Compound of Example 288 ##STR709##
##STR710## Crystal form: white powdery (recrystallized from
ethanol) M.p.: 140.2-141.6.degree. C. Form: free Compound of
Example 289 ##STR711## ##STR712## Crystal form: white powdery
(recrystallized from ethanol) M.p.: 177.6-178.8.degree. C. Form:
free Compound of Example 290 ##STR713## ##STR714## Crystal form:
white acicular (recrystallized from ethanol) M.p.:
201.5-203.4.degree. C. Form: free Compound of Example 291
##STR715## ##STR716## Crystal form: white powdery (recrystallized
from ethanol) M.p.: 120.2-121.6.degree. C. Form: free Compound of
Example 292 ##STR717## ##STR718## Crystal form: gray acicular
(recrystallized from ethanol) M.p.: 224.5-226.5.degree. C. Form:
free Compound of Example 293 ##STR719## ##STR720## Crystal form:
white powdery (recrystallized from ethanol) 176-176.6.degree. C.
Form: free Compound of Example 294 ##STR721## ##STR722##
Crystal form: white powdery (recrystallized from ethanol) M.p.:
168.4-168.6.degree. C. Form: free Compound of Example 295
##STR723## ##STR724## Crystal form: white acicular (recrystallized
from methanol) M.p.: 180-181.degree. C. Form: free Compound of
Example 296 ##STR725## ##STR726## Crystal form: white powdery
(recrystallized from ethyl acetate) M.p.: 271-273.degree. C. Form:
free Compound of Example 297 ##STR727## ##STR728## Crystal form:
light yellow powdery (recrystallized from ethyl acetate) M.p.:
170-171.degree. C. Form: free Compound of Example 298 ##STR729##
##STR730## Crystal form: dark yellow powdery (recrystallized from
ethanol-ethyl acetate) M.p.: 239-243.degree. C. (decomposed) Form:
free Compound of Example 299 ##STR731## ##STR732## Crystal form:
white acicular (recrystallized from ethyl acetate) M.p.:
199-200.degree. C. Form: free Compound of Example 300 ##STR733##
##STR734## Crystal form: yellow acicular (recrystallized from ethyl
acetate) M.p.: 228-229.degree. C. Form: free Compound of Example
301 ##STR735## ##STR736## Crystal form: white acicular
(recrystallized from ethyl acetate) M.p.: 178-179.degree. C.
(decomposed) Form: free Compound of Example 302 ##STR737##
##STR738## Crystal form: yellow acicular (recrystallized from ethyl
acetate-n-hexane) M.p.: 138-140.degree. C. Form: free Compound of
Example 303 ##STR739## ##STR740## Crystal form: light yellow
powdery (recrystallized from ethanol) M.p.: 203.2-203.8.degree. C.
Form: free Compound of Example 304 ##STR741## ##STR742## Crystal
form: white acicular (recrystallized from ethyl acetate) M.p.:
252-253.degree. C. Form: free Compound of Example 305 ##STR743##
##STR744## Form: free NMR: 54) Compound of Example 306 ##STR745##
##STR746## Crystal form: light brown plate (recrystallized from
ethyl acetate) M.p.: 233-234.degree. C. Form: free Compound of
Example 307 ##STR747## ##STR748## Crystal form: light brown powdery
(recrystallized from ethanol) M.p.: 185.8-187.degree. C. Form: free
Compound of Example 308 ##STR749## ##STR750## Crystal form: yellow
powdery (recrystallized from ethanol-n-hexane-water) M.p.:
239-240.4.degree. C. Form: free Compound of Example 309 ##STR751##
##STR752## Form: free NMR: 55) Compound of Example 310 ##STR753##
##STR754## Crystal form: light yellow acicular (recrystallized from
methanol) M.p.: 132.8-134.degree. C. Form: free Compound of Example
311 ##STR755## ##STR756## Crystal form: white acicular
(recrystallized from ethyl acetate) M.p.: 92.8-94.degree. C. Form:
free Compound of Example 312 ##STR757## ##STR758## Crystal form:
white powdery (recrystallized from ethyl acetate) M.p.:
237.4-238.5.degree. C. Form: free Compound of Example 313
##STR759## ##STR760## Crystal form: white acicular (recrystallized
from ethanol) M.p.: 151.8-152.5.degree. C. Form: free Compound of
Example 314 ##STR761## ##STR762## Crystal form: white powdery
(recrystallized from ethanol) M.P.: 194-195.2.degree. C. Form: free
Compound of Example 315 ##STR763## ##STR764## Crystal form: light
brown powdery (recrystallized from acetic acid) M.p.:
252.8-253.8.degree. C. Form: free Compound of Example 316
##STR765## ##STR766## Crystal form: white powdery (recrystallized
from ethanol) M.p.: 251.6-252.degree. C. Form: free Compound of
Example 317 ##STR767## ##STR768## Crystal form: yellow powdery
(recrystallized from ethanol) M.p.: 230-234.5.degree. C. Form: free
Compound of Example 318 ##STR769## ##STR770## Crystal form: white
powdery (recrystallized from dioxane) M.p.: 270-271.degree. C.
Form: free Compound of Example 319 ##STR771## ##STR772## Crystal
form: yellow powdery (recrystallized from acetone) M.p.:
163-168.degree. C. Form: dihydrochloride Compound of Example 320
##STR773## ##STR774## Crystal form: gray powdery (recrystallized
from ethanol) M.p.: 264-266.degree. C. Form: hydrochloride Compound
of Example 321 ##STR775## ##STR776## Crystal form: white powdery
(recrystallized from methanol) M.p.: 170-171.degree. C. Form: free
Compound of Example 322 ##STR777## ##STR778## Form: free NMR: 31)
Compound of Example 323 ##STR779## ##STR780## Crystal form: yellow
powdery (recrystallized from ethanol) M.p.: 108-109.degree. C.
Form: free Compound of Example 324 ##STR781## ##STR782## Form: free
NMR: 32) Compound of Example 325 ##STR783## ##STR784## Form: free
NMR: 33) Compound of Example 326 ##STR785## ##STR786## Crystal
form: light brown acicular (recrystallized from diethyl ether)
M.p.: 113-114.degree. C. Form: free Compound of Example 327
##STR787## ##STR788## Form: free NMR: 34) Compound of Example 328
##STR789## ##STR790## Crystal form: white acicular (recrystallized
from dichloromethane-ethanol) M.p.: 139-140.degree. C. Form: free
Compound of Example 329 ##STR791## ##STR792## Form: hydrochloride
NMR: 35) Compound of Example 330 ##STR793## ##STR794## Form: free
NMR: 36) Compound of Example 331 ##STR795## ##STR796## Form: free
NMR: 37) Compound of Example 332 ##STR797## ##STR798## Form: free
NMR: 38) Compound of Example 333 ##STR799## ##STR800## Form: free
NMR: 39) Compound of Example 334 ##STR801## ##STR802## Form: free
NMR: 40) Compound of Example 335 ##STR803## ##STR804## Form: free
NMR: 41) Compound of Example 336 ##STR805## ##STR806## Form: free
NMR: 42) Compound of Example 337 ##STR807## ##STR808## Form: free
NMR: 43) Compound of Example 338 ##STR809## ##STR810## Form: free
NMR: 44)
Compound of Example 339 ##STR811## ##STR812## Form: free NMR: 45)
Compound of Example 340 ##STR813## ##STR814## Form: free NMR: 46)
Compound of Example 341 ##STR815## ##STR816## Form: free NMR: 47)
Compound of Example 342 ##STR817## ##STR818## Form: free NMR: 48)
Compound of Example 343 ##STR819## ##STR820## Crystal form: white
acicular (recrystallized from ethanol) M.p.: 103-104.degree. C.
Form: free Compound of Example 344 ##STR821## ##STR822## Crystal
form: colorless amorphous Form: free NMR: 50) Compound of Example
345 ##STR823## ##STR824## Form: free NMR: 50) Compound of Example
346 ##STR825## ##STR826## Form: free NMR: 51) Compound of Example
347 ##STR827## ##STR828## Form: free NMR: 52) Compound of Example
348 ##STR829## ##STR830## Crystal form: white powdery
(recrystallized from ethanol) M.p.: 85-86.degree. C. Form: free
Compound of Example 349 ##STR831## ##STR832## Crystal form: white
powdery (recrystallized from ethanol) M.p.: 178-179.degree. C.
Compound of Example 350 ##STR833## ##STR834## Crystal form: light
brown plate (recrystallized from ethanol) M.p.: 149-150.degree. C.
Form: free Compound of Example 351 ##STR835## ##STR836## Form: free
NMR: 53)
NMR data of the compounds of Examples 305, 309, 322 324, 325, 327,
329-342, 344-347 and 351
NMR: 31) Compound of Example 322:
NMR (CDCl.sub.3) .delta.:
1.49 (3H, t, J=5.6 Hz), 1.52 (3H, t, J=5.6 Hz), 3.08 (3H, s 3.43
(3H, s), 3,49 (3H, s) 3.67 (3H, s), 4.10-4.30 (4H, m), 6.92 (1H, d
J=6.7 Hz), 7.11 (1H, d, J=6.7 Hz), 7.47 (1H, s), 7.52 (1H, dd,
J=1.7 Hz, 6.7 Hz), 7.61 (1H, d, J=1.7 Hz), 8.20 (1H, dd, J=1.8 Hz)
6.4 Hz), 8.56 (1H, d, J=1.8 Hz)
NMR: 32) Compound of Example 324:
NMR (CDCl.sub.3) .delta.:
1.50 (3H, t, J=6.9 Hz), 1.52 (3H, t, J=6.9 Hz), 2.25-2.40 (1H, m),
2.59 (1 H, d, J=5.3 Hz), 2.86-3.14 (2H, m), 3.45-3.80 (2H, m), 4.01
(3H, s), 4.01 (1H, brs), 4.10-4.30 (4H, m), 6.93 (1H, d, J=8.3 Hz),
7.32 (1H, s), 7.54 (1H, dd, J=2.1 Hz, 8.3 Hz), 7.59 (1H, d, J=2.1
Hz), 8.02 (1H, d, J=2.2 Hz), 8.34 (1H, d, J=2.2 Hz), 11.40 (1H,
s)
NMR: 33) Compound of Example 325:
NMR (CDCl.sub.3) .delta.: 1.50 (3H, t, J=7.0 Hz), 1.52 (3H, t,
J=7.0 Hz), 3.82 (2H, d, J=1.8 Hz), 4.01 (3H, s) 4.10-4.30 (4H, m),
6.92 (1H, d, J=8.4 Hz), 7.33 (1H, s) 7.54 (1H, dd, J=2.1 Hz), 8.4
Hz), 7.59 (1H, d, J=2.1 Hz), 8.02 (1H, d, J=2.2 Hz), 8.39 (1H, d,
J=2.2 Hz), 9.81 (1H, t, J=1.8 Hz), 11.20 (1H, s)
NMR: 34) Compound of Example 327:
NMR (CDCl.sub.3) .delta.: 1.40-1.60 (9H, m), 2.26 (3H, s) 4.16 (2H,
q, J=7.0 Hz), 4.23 (2H, q, J=7.0 Hz), 4.44 (2H, q, J=7.1 Hz), 6.93
(1H, d, J=8.4 Hz), 7.40 (1H, s), 7.54 (1H, dd, J=2.1 Hz), 8.4 Hz),
7.64 (1H, d, J=2.1 Hz), 8.14 (1H, dd, J=2.2 Hz, 8.8 Hz), 8.66 (1H,
d, J=2.2 Hz), 8.80 (1H, d, J=8.8 Hz), 11.20 (1H, s)
NMR: 35) Compound of Example 329:
NMR (DMSO-d.sub.6) .delta.: 3.97 (3H, s) 6.82 (1H, d, J=8.2 Hz),
7.16 (1H, d, J=8.9 Hz), 7.32 (1H, dd, J=2.1 Hz, 8.2 Hz), 7.47 (1H,
d, J=2.1 Hz), 7.80 (1H, s), 8.11 (1H, dd, J=2.4 Hz, 8.9 Hz), 8.38
(1H, d, J=2.4 Hz), 10.85 (1H, brs)
NMR: 36) Compound of Example 330:
NMR (CDCl.sub.3) .delta.: 1.35-1.60 (6H, m), 3.94 (3H, s),
4.10-4.30 (4H, m), 5.73 (1H, s), 6.90 (1H, d, J=8.3 Hz), 7.03 (1H,
d, J=8.8 Hz), 7.30 (1H, s) 7.48-7.65 (2H, m), 8.13 (1H, dd, J=2.3
Hz, 8.8 Hz), 8.41 (1H, d, J=2.3 Hz)
NMR: 37) Compound of Example 331:
NMR (CDCl.sub.3) .delta.: 1.46 (6H, t, J=7.0 Hz), 3.92 (3H, s),
4.07-4.21 (4H, m), 6.90 (1H, d, J=8.4 Hz), 7.15 (1H, brs),
7.27-7.49 (2H, m), 7.57 (1H, d, J=2.1 Hz), 7.74 (1H, m), 8.16 (1H,
s)
NMR: 38) Compound of Example 332:
NMR (CDCl.sub.3) .delta.: 1.50 (3H, t, J=6.9 Hz), 1.51 (3H, t,
J=6.9 Hz), 3.93 (3H, s) 4.11-4.24 (4H, m), 6.95 (1H, d, J=8.2 Hz),
7.44-7.49 (3H, m), 8.34 (1H, s) 8.40 (1H, s) 11.19 (1H, s)
NMR: 39) Compound of Example 333:
NMR: (CDCl.sub.3) .delta.: 1.49 (3H, t, J=7.0 Hz), 1.51 (3H, t,
J=7.0 Hz), 3.93 (3H, s) 4.02 (3H, s) 4.10-4.29 (4H, m), 6.95 (1H,
d, J=8.3 Hz), 7.05 (1H, d, J=8.7 Hz), 7.55 (1 H, dd, J=2.0 Hz, 8.3
Hz), 7.64 (1H, d. J=2.0 Hz), 7.86 (1H, s) 8.00 (1H, dd, J=2.3 Hz,
8.7 Hz), 9.05 (1H, d, J=2.3 Hz)
NMR: 40) Compound of Example 334:
NMR (CDCl.sub.3) .delta.: 1.00 (3H, t, J=7.32 Hz), 1.01 (3H, t,
J=7.3 Hz), 1.51-1.58 (4H, m), 1.81-1.90 (4H, m), 4.01 (3H, s),
4.03-4.17 (4H, m), 6.95 (1H, d. J=8.3 Hz), 7.09 (1H, d, J=8.7 Hz),
7.33 (1H, s), 7.52 (1H, dd, J=2.1 Hz, 8.3 Hz), 7.60 (1H, d, J=2.1
Hz), 8.06 (1H, dd, J=2.3 Hz, 8.7 Hz), 8.44 (1H, d, J=2.3 Hz)
NMR: 41) Compound of Example 335:
NMR (CDCl.sub.3) .delta.: 1.07 (3H, t, J=7.4Hz), 1.09 (3H t, J=7.4
Hz), 1.83-1.96 (4H, m), 4.00-4.13 (4H, m), 4.01 (3H, s) 6.95 (1H,
d, J=8.4 Hz), 7.09 (1H, d, J=8.8 Hz), 7.32 (1H, s), 7.52 (1H, dd,
J=2.2 Hz), 8.4 Hz), 7.60 (1H, d, J=2.2 Hz), 8.08 (1H, dd, J=2.2
Hz), 8.8 Hz), 8.45 (1H, d, J=2.2 Hz), 10.86 (1H, s)
NMR: 42) Compound of Example 336:
NMR (CDCl.sub.3) .delta.: 1.54 (3H, t, J=7.0 Hz), 3.94 (3H, s),
4.01 (3H, s) 4.26 (2H, q, J=7.0 Hz), 6.95 (1H, d, J=8.4 Hz), 7.09
(1H, d, J=8.6 Hz), 7.32 (1H, s) 7.54 (1H, dd, J=2.0 Hz, 8.4 Hz),
7.60 (1H, d, J=2.0 Hz), 8.09 (1H, dd, J=2.2 Hz), 8.6 Hz), 8.45 (1H,
d, J=2.2 Hz), 10.86 (1H, s)
NMR: 43) Compound of Example 337:
NMR (CDCl.sub.3) .delta.: 0.88 (6H, t, J=6.4Hz), 1.27 (28H, brs),
1.40-1.63 (4H, m), 1.78-1.91 (4H, m), 3.99 (3H, s), 4.01-4.15 (4H,
m), 6.93 (1H, d, J=8.4 Hz), 7.08 (1H, d, J=8.6 Hz), 7.30 (1H, s),
7.51 (1H, dd, J=2.2 Hz, 8.4 Hz), 7.59 (1H, d. J=2.2 Hz), 8.07 (1H,
dd, J=2.2 Hz), 8.6 Hz), 8.43 (1H, d, J=2.2 Hz), 10.86 (1H, s)
NMR 44) Compound of Example 338:
NMR (CDCl.sub.3) .delta.: 1.45 (3H, t, J=7.0 Hz), 1.62 (3H, t,
J=7.0 Hz), 4.01 (3H, s) 4.09 (2H, q, J=7.0 Hz), 4.22 (2H, q, J=7.0
Hz), 6.55 (1H, d, J=2.4 Hz), 6.61 (1H, dd, J=2.4 Hz), 8.8 Hz), 7.08
(1H, d, J=8.8 Hz), 7.37 (1H, s) 8.10 (1H, dd, J=2.4 Hz), 8.8 Hz),
8.46 (1H, d, J=8.8 Hz), 8.49 (1H, d, J=2.4 Hz), 10.84 (1H, s)
NMR: 45) Compound of Example 339:
NMR (CDCl.sub.3) 67: 1.07 (3H, t, J=7.5 Hz), 1.50 (3H, t, J=6.8
Hz), 1.80-2.10 (2H, m), 4.00 (3H, s) 4.12-4.47 (4H, m), 6.95 (1H,
d, J=8.4 Hz), 7.09 (1H, d, J=8.6 Hz), 7.31-7.49 (1H, m), 7.50-7.77
(2H, m), 8.13-8.27 (1H, m), 8.45 (1H, s) 10.86 (1H, s)
NMR: 46) Compound of Example 340:
NMR (CDCl.sub.3) .delta.: 1.07 (3H, t, J=7.4 Hz), 1.52 (3H, t,
J=7.0 Hz), 1.85-1.96 (2H, m), 4.04 (2H, t, J=6.7 Hz), 4.25 (2H, q,
J=7.0 Hz), 6.95 (1H, d, J=8.3 Hz), 7.49-7.63 (5H, ,m), 8.16-8.20
(1H, m), 8.34 (1H, s)
NMR: 47) Compound of Example 341:
NMR (CDCl.sub.3) .delta.: 1.05 (3H, t, .1=7.1 Hz, 1.43 (3H, t,
J=7.0 Hz), 1.46 (3H, t, J=7.0 Hz), 4.02-4.22 (6H, m), 6.87 (1H, d,
J=8.4 Hz), 7.34-7.49 (3H, m), 7.58-7.62 (2H, m), 7.63-7.74 (1H,
m)
NMR 48) Compound of Example 342:
NMR (CDCl.sub.3) .delta.: 1.50 (3H, t, J=7.0 Hz), 1.52 (3H, t,
J=7.0 Hz), 3,54 (2H, d, J=6.6 Hz), 3.92 (3H, s) 4.12-4.26 (4H, m),
5.09-5.18 (2H, m), 6.09-6.12 (1H, m), 6.96 (1H, d, J=8.3 Hz), 7.45
(1H, d, J=2.0 Hz), 7.49 (1H, dd, J=2.0 Hz, 8.3 Hz), 7.54 (1H, s)
7.84 (1H, d, J=2.2 Hz), 8.28 (1H, d, J=2.2 Hz), 12.84 (1H, s)
NMR: 49) Compound of Example 344:
NMR (CDCl.sub.3) .delta.: 142 (3H, d, J=7.0 Hz), 150 (3H, t, J=7.0
Hz), 1.52 (3H, t, J=7.0 Hz), 4.00 (3H, s) 4.10-433 (4H, m),
5.07-5.23 (2H, m), 6.03-6.25 (1H, m), 6.93 (1H, d, J=8.3 Hz), 7.31
(1H, s) 7.50-7.66 (2H, m), 7.94 (1H, d, J=2.2 Hz), 8.33 (1H, d,
J=2.3 Hz), 11.26 (1H, s)
NMR: 50) Compound of Example 345:
NMR (CDCl.sub.3) .delta.: 1.49 (3H, t, J=7.0 Hz), 1.51 (3H, t,
J=7.0 Hz), 1.78 (6H, d, J=6.7 Hz), 3.93 (3H, s) 4.10-4.30 (4H, m),
4.68 (2H, d, J=6.3 Hz), 5.42-5.62 (1H, m), 6.92 (1H, d, J=8.4 Hz;),
7.04 (1H, d, J=8.8 Hz), 7.34 (1H, s) 7.52 (1H, dd, J=2.1 Hz, 8.3
Hz), 7.61 (1H, d, J=2.0 Hz), 8.10 (1H, dd, J=2.4 Hz), 8.7 Hz), 8.36
(1H, d, J=2.3 Hz)
NMR 51) Compound of Example 346:
NMR (CDCl.sub.3) 67: 1.49 (3H, t, J=7.0 Hz), 1.49 (3H, t, J=7.0
Hz), 3.98 (3H, s) 4.05-4.30 (4H, m), 5.01 (1H,dd, J=1.2 Hz, 5.8
Hz), 5.08 (1H, s) 6.23-6.43 (1H, in), 6.92 (1H, d, J=8.4 Hz), 7.30
(1H, s) 7.54 (1H, dd, J=2.1 Hz), 8.3 Hz), 7.61 (1H, d, J=2.0 Hz),
8.10 (1H, d, J=2.2 Hz), 8.34 (1H, d, J=2.2 Hz), 11.60 (1H, s)
NMR 52) Compound of Example 347:
NMR (CDCl.sub.3) .delta.: 1.49 (3H, t, J=6.9 Hz), 1.51 (3H, t,
J=6.9 Hz), 1.87 (3H, s) 3.94 (3H, s) 4.10-4.30 (4H, m), 4.56 (2H,
s) 5.03 (1H, hrs), 5.22 (1H, hrs), 6.91 (1H, d, J=8.4 Hz), 7.02
(1H, d, J=8.8 Hz), 7.34 (1H, s), 7.52 (1H, dd, J=2.1 Hz), 8.4 Hz),
7.61 (1H, d, J=2.1 Hz), 8.10 (1H, dd, J=2.4 Hz), 8.8 Hz), 8.39 (1H,
d, J=2.4 Hz),
NMR: 53) Compound of Example 351:
NMR (CDCl.sub.3) .delta.: 1.53 (3H, t J=7.0 Hz), 3.92 (3H, s) 3.95
(3H, s) 4.21 (2H, q, J=7.0 Hz), 6.95 (1H, d, J=8.4 Hz), 7.05 (1H,
d. J=8.6 Hz), 7.45 (1H, d, J=2.1 Hz), 7.52 (1H, dd, J=2.1 Hz), 8.4
Hz), 7.64 (1H, s) 7.95 (1H, dd, J=2.1 Hz), 8.6 Hz), 8.39 (1H, d,
J=2.1 Hz), 12.66 (1H, s)
NMR: 54) Compound of Example 305:
NMR (DMSO-d.sub.6) .delta.: 1.38 (3H, J=7.0 Hz), 1.40 (3H, t J=6.9
Hz), 4.07-4.27 (4H, m), 6.81 (2H, s) 7.08 (3H, q, J=8.3 Hz),
7.48-7.58 (2H, m), 8.04 (1H, s) 14.77 (2H, s)
NMR: 55) Compound of Example 309:
NMR (CDCl.sub.3) 67: 1.50 (3H, t, J=7.0 Hz), 1.51 (3H, t, J=7.0
Hz), 4.10-4.33 (4H, m), 6.44 (1H, dd, J=2.5 Hz 8.5 Hz), 6.52 (1H,
d, J=2.5 Hz), 6.93 (1H, d, J=9.0 Hz), 7.29 (1H, s), 7.42-7.57 (3H,
m)
Example 352
In 10 ml of dimethylformamide were suspended 1 g of 2-
(3,4-diethoxyphenyl) 4-(4-hydroxy-3 methoxycarbonylphenyl)thiazole
and 0.35 g of potassium carbonate. The suspension was stirred at
room temperature for 30 minutes. Thereto was added 0.46 g of methyl
bromoacetate. The mixture was stirred at the same temperature for 4
hours. The solvent was removed by distillation. The residue was
extracted with 40 ml of dichloromethane. The extract was washed
with 10 ml of water and 10 ml of a saturated aqueous sodium
chloride solution, dried over magnesium sulfate. and subjected to
distillation to remove the solvent, The residue was recrystallized
from diisopropyl ether to obtain 1.1 g of
2-(3,4-diethoxyphenyl)-4-(4-methoxycarbonylmethoxy-3-methoxycarbonylphenyl
) thiazole.
Colorless acicular crystals
AW 96.degree.97.degree. C.
In the same procedure as in Example 352 were obtained the compounds
of Examples 1, 6, 23, 26-81, 92, 94-96, 101-108, 112, 115, 118,
121, 124, 125-128, 130-133, 135, 136, 154-165, 167-227, 229-234,
253-273, 275-307, 309-316, 318-328 and 330-351, by using respective
starting materials.
Example 353
A solution of 1 g of
2-(3,4-diethoxyphenyl)-4-(4-allyloxy-3-methoxycarbonylphenyl)thiazole
in 25 ml of o-dichlorobenzene was refluxed for 15 hours with
heating. After the completion of a reaction, the solvent was
removed by distillation. The residue was recrystallized from
diisopropyl ether to obtain 1 g of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-allylphenyl)thiazo
le.
Colorless prismatic crystals
M.p.: 118.degree.-119.degree. C.
In the same procedure as in Example 353 were obtained the compounds
of Examples 262, 275, 277, 316, 342, 344, 346 and 348, by using
respective starting materials.
Example 354
4.9 g of
2-(3,4-diethoxyphenyl)-4-(4-dimethylaminothiocarbonyloxy-3-methoxycarbonyl
phenyl)thiazole was stirred with heating, at 170.degree. C. for 5
hours. The product was purified by silica gel column chromatography
(eluent: dichloromethane) and recrystallized from ethanol to obtain
2.83 g of
2-(3,4-diethoxyphenyl)-4-(4-dimethylaminocarbonylthio-3-methoxycarbonylphe
nyl)thiazole.
Yellow powder
M.p.: 108.degree.-109.degree. C.
Example 355
1 ml of 10% potassium hydroxide was added to a solution of 250 mg
of
2-(3,4-diethoxyphenyl-4-(4-dimethylaminocarbonylthio-3-methoxycarbonylphen
yl)thiazole in 5 ml of ethanol. The mixture was refluxed for 8
hours with heating. The solvent was removed by distillation. The
residue was extracted with 40 ml of hot ethyl acetate. The extract
was made acidic with 10% hydrochloric acid, washed with 5 ml of
water and 10 ml of a saturated aqueous sodium chloride solution,
and dried. The solvent was removed by distillation. The residue was
recrystallized from dioxane-ethanol to obtain 130 mg of
2-(3,4-diethoxyphenyl)-4-(4-mercapto-2-carboxyphenyl)-thiazole.
Light brown powder
M.p.: 283.degree.-285.degree. C.
Example 356
To a solution of 1 g of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-4-allylphenyl)thiazo
le in 20 ml of methanol and 20 ml of tetrahydrofuran were added 0.5
ml of osmium tetroxide (a 4% aqueous solution) and 1.22 g
of4-methylmorpholine N-oxide. The mixture was stirred at room
temperature for 4 hours. The solvent was removed by distillation.
The residue was mixed with 50 ml of dichloromethane and 25 ml of
water for phase separation. The organic layer was washed with 25 ml
of a saturated aqueous sodium chloride solution and dried. The
solvent was removed by distillation. The residue was purified by
silica gel column chromatography (eluent:
dichloromethane/methanol=199/1) to obtain 860 mg of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-(2,3-dihydroxyprop
yl)phenyl]thiazole.
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.50 (3H, t, J=6.9Hz), 1.52 (3H,
t, J=6.9Hz), 2.25-2.40 (1H, m), 2.59 (1H, d, J=5.3Hz), 2.86-3.14
(2H, m), 3.45-3.80 (2H, m), 4.01 (3H, s), 4.01 (1H, brs), 4.10-4.30
(4H, m), 6.93 (1H, d, J=8.3Hz), 7.32 (1H, s), 7.54 (1H, dd,
J=2.1Hz, 8.3Hz), 7.59 (1H, d, J=2.1Hz), 8.02 (1H, d, J=2.2Hz), 8.34
(1H, d, J=2.2Hz), 11.40 (1H, s)
Example 357
To a solution of 2 g of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl)-4-hydroxy-5-allylphenyl)thiaz
ole in 100 ml of tetrahydrofuran and 15 ml of water were added 2.5
ml of osmium tetroxide (a 4% aqueous solution) and 3.9 g of sodium
metaperiodate. The mixture was stirred at room temperature for 14
hours. After the completion of a reaction, the solvent was removed
by distillation. The residue was mixed with 60 ml of
dichloromethane and 30 ml of water for extraction and phase
separation. The organic layer was dried and subjected to
distillation to remove the solvent. The residue was purified by
silica gel column chromatography (eluent: dichloromethane) to
obtain 1.33 g of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-formylmethylphenyl
)thiazole.
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.50 (3H, t, J=7.0Hz), 1.52 (3H,
t, J=7.0Hz), 3.82 (2H, d, J=1.8Hz), 4.01 (3H, s), 4.10-4.30 (4H,
m), 6.92 (1H, d, J=8.4Hz), 7.33 (1H, s), 7.54 (1H, dd, J=2.1Hz,
8.4Hz), 7.59 (1H, d, J=2.1Hz), 8.02 (1H, d, J=2.2Hz), 8.39 (1H, d,
J=2.2Hz), 9.81 (1H, t, J=1.8Hz), 11.20 (1H, s)
Example 358
111 mg of sodium boron hydride was added to a solution of 1.3 g of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-formylmethylphenyl
)thiazole in 30 ml of methanol, with stirring under ice-cooling.
The mixture was stirred at the same temperature for 30 minutes.
After the completion of a reaction, the solvent was removed by
distillation. The residue was purified by silica gel column
chromatography (eluent: dichloromethane/n-hexane=4/1) and
recrystallized from diethyl ether to obtain 570 mg of
2-(3,4-diethoxyphenyl)-4-[3-methoxycarbonyl-4-hydroxy-5-(2-hydroxyethyl)ph
enyl]-thiazole.
Light brown acicular crystals
M.p.: 113.degree.-114.degree. C.
Example 359
A solution of 1 g of potassium
3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-6-acetylaminobenzoate in 50
ml of water and 10 ml of 30% potassium hydroxide was refluxed for 8
hours with heating. After the completion of a reaction, the solvent
was removed by distillation. The residue was made weakly acidic
with 10% hydrochloric acid and extracted with 80 ml of ethyl
acetate. The extract was washed with 20 ml of a saturated aqueous
sodium chloride solution, dried and subjected to distillation to
remove the solvent. The residue was recrystallized from ethyl
acetate to obtain 168 mg of
2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-aminophenyl)thiazole.
Yellow acicular crystals
M.p.: 228.degree.-229.degree. C.
The compound of Example 298 was obtained by using starting
materials, in the same procedure as in Example 359.
Example 360
2 g of potassium carbonate was added to a solution of 1.5 g of
2-(3,4-diethoxyphenyl)-4-(2,4-dihydroxyphenyl)thiazole in 40 ml of
acetone. Thereto was added 40 g of dry ice under cooling at
-78.degree. C. The mixture was sealed in a tube and stirred at
150.degree. C. for 18 hours. The solvent was distilled off. The
residue was made weakly acidic with 100 ml of ethyl acetate and 10%
hydrochloric acid, and extraction and phase separation was
conducted. The organic layer was washed with 30 ml of a saturated
aqueous sodium chloride solution and dried. The solvent was
distilled off. The residue was mixed with 40 ml of dichloromethane.
The insoluble was collected by filtration, washed with a small
amount of dichloromethane, dried and recrystallized from ethyl
acetate to obtain 241 mg of
2-(3,4-diethoxyphenyl)-4-(3-carboxy-4,6-dihydroxyphenyl)thiazole.
Light brown plate crystals
M.p.: 233.degree.-234.degree. C.
In the same procedure as in Example 360 were obtained the compounds
of Examples 190, 262, 275, 276, 277, 278, 282, 284-286, 288-293,
295, 297, 299, 304, 305 and 308 by using respective starting
materials.
Example 361
A suspension of 1 g of
2-(3,4-diethoxyphenyl)-4-(3-ethyl-4-hydroxyphenyl)thiazole, 1 g of
paraformaldehyde and 1.1 g of dimethylamine hydrochloride in 20 ml
of ethanol was stirred at 100.degree. C. for 4 hours with heating.
The solvent was distilled off. The residue was mixed with 20 ml of
water and 30 ml of ethyl acetate for extraction and phase
separation. The ethyl acetate layer was extracted with 10%
hydrochloric acid (20 ml.times.3). The combined aqueous layer was
made basic with 10% sodium hydroxide and extracted with
dichloromethane. The extract was washed with 20 ml of a saturated
aqueous sodium chloride solution, dried and subjected to
distillation to remove the solvent. The residue was purified by
silica gel column chromatography (eluent:
dichloromethane/methanol=49/1). The product was dissolved in
acetone, mixed with hydrochloric acid-methanol and heated. The
resulting crystals were collected by filtration, dried and
recrystallized from acetone to obtain 117 mg of
2-(3,4-diethoxyphenyl)-4-(3-ethyl-4-hydroxyphenyl)-5-dimethylaminomethylth
iazole dihydrochloride.
Yellow powder
M.p.: 163.degree.-168.degree. C.
Example 362
A solution of 16 g of
2-(3,4-diethoxyphenyl)-4-(3-cyanophenyl)thiazole in 120 ml of
ethanol and 90 ml of a 40% aqueous sodium hydroxide solution was
refluxed for 15 hours with heating. The reaction mixture was mixed
with water, made acidic with concentrated hydrochloric acid and
extracted with ethyl acetate (200 ml.times.3). The extract was
washed with water (10 ml.times.3) and subjected to distillation to
remove the solvent. The residue was recrystallized from ethanol to
obtain 7 g of
2-(3,4-diethoxyphenyl)-4-(3-carboxyphenyl)thiazole.
Light pink acicular crystals
M.p.: 192.degree.-192.8.degree. C.
Example 363
A catalytic amount of 5% Pd-C was added to a solution of 250 mg of
2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-allylphenyl)thiazole
in 10 ml of methanol. The mixture was stirred in a hydrogen
atmosphere at room temperature for 6 hours. After the completion of
a reaction, the reaction mixture was filtered. The filtrate was
concentrated. The residue was recrystallized from ethanol to obtain
193 mg of
2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-propylphenyl)thiazole.
White powder
M.p.: 179.degree.-180.degree. C.
The compounds of Examples 295, 302 and 319 were obtained in the
same procedure as in Example 363 by using respective starting
materials.
Example 364
A solution of 1 g of
2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxyphenyl)thiazole in 5
ml of acetic anhydride was stirred at 100.degree. C. for 4 hours
with heating. The solvent was distilled off. The residue was
dissolved in 50 ml of ethyl acetate. To the solution was added 10
ml of a saturated sodium hydrogencarbonate solution, and phase
separation was conducted. The ethyl acetate layer was made acidic
with 10% hydrochloric acid, washed with 10 ml of a saturated
aqueous sodium chloride solution, dried and subjected to
distillation to remove the solvent. The residue was recrystallized
from ethyl acetate to obtain 145 mg of
2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-acetyloxyphenyl)thiazole.
White acicular crystals
M.p.: 178.degree.-179.degree. C.
Example 365
1.2 g of ethyl iodide and 1.5 g of potassium carbonate were added
to a solution of 1.2 g of
2-(3-methoxycarbonyl-4-hydroxyphenyl)-4-(3,4-dihydroxyphenyl)thiazole
in 20 ml of dimethylformamide. The mixture was stirred at room
temperature for 14 hours. The solvent was removed by distillation.
The residue was mixed with 40 ml of chloroform and 40 ml of water.
The mixture was made acidic with 10% hydrochloric acid and phase
separation was conducted. The organic layer was washed with 20 ml
of a saturated aqueous sodium chloride solution, dried and
subjected to distillation to remove the solvent. The residue was
purified by silica gel column chromatography (eluent:
dichloromethane/n-hexane=3/1) to obtain 400 mg of
2-(3-methoxycarbonyl-4-hydroxyphenyl)-4-(3,4-diethoxyphenyl)thiazole.
NMR (CDCl.sub.3) .delta.:
1.35-1.60 (6H, m), 3.94 (3H, s), 4.10-4.30 (4H, m), 5.73 (1H, s),
6.90 (1H, d, J=8.3Hz), 7.03 (1H, d, J=8.8Hz), 7.30 (1H, s),
7.48-7.65 (2H, m), 8.13 (1H, dd, J=2.3Hz, 8.8Hz), 8.41 (1H, d,
J=2.3Hz)
In the same procedure as in Example 365 were obtained the compounds
of Examples 1, 6, 23, 26-81, 92, 94-96, 101-108, 112, 115, 118,
121, 124, 125-128, 130-133, 135, 136, 154-165, 167-227, 229-234,
253-273, 275-307, 309-316, 318-328 and 330-351, by using respective
starting materials.
Example 366
In the same procedure as in Example 147 were obtained the compounds
of Examples 253, 257, 259, 261-263, 267, 269, 271, 275-278, 281,
282, 284-296, 297-301, 303-306, 308, 312, 314-318 and 320, by using
respective starting materials.
Example 367
The compound of Example 258 was obtained in the same procedure as
in Example 148, by using starting materials.
Example 368
In the same procedure as in Example 235 were obtained the compounds
of Examples 268, 271, 272, 283, 285, 298, 300, 310 and 320, by
using respective starting materials.
Examples 367-374
The compounds shown in Table 12 were obtained in the same
procedures as ih Example 1 and Example 138, by using respective
starting materials.
TABLE 12 ##STR837## Compound of Example 367 ##STR838## ##STR839##
Crystal form: light brown acicular (recrystallized from ethyl
acetate-n-hexane) M.p.: 92-93.degree. C. Compound of Example 368
##STR840## ##STR841## Crystal form: white acicular (recrystallized
from ethanol) M.p.: 256.8-257.0.degree. C. Form: free Compound of
Example 369 ##STR842## ##STR843## Crystal form: white powdery
(recrystallized from ethyl acetate-ethanol) M.p.:
236.6-238.0.degree. C. Form: free Compound of Example 370
##STR844## ##STR845## Crystal form: light yellow acicular
(recrystallized from ethanol) M.p.: 197.8-199.3.degree. C. Form:
free Compound of Example 371 ##STR846## ##STR847## Crystal form:
white powdery (recrystallized from ethanol) M.p.: 182-184.degree.
C. Form: free Compound of Example 372 ##STR848## ##STR849## Crystal
form: yellow powdery (recrystallized from acetone-diethyl ether)
M.p.: 111-114.degree. C. Form: trihydrochloride 1/2 hydrate
Compound of Example 373 ##STR850## ##STR851## Form: free NMR: 56)
Compound of Example 374 ##STR852## ##STR853## Form: free NMR:
57)
56) NMR (DMSO-d.sub.6) .delta.:
1.37 (3H, t, J=6.9Hz), 1.39 (3H, t, J=6.9Hz), 3.82 (3H, s), 4.13
(4H, m), 7.09 (1H, d, J=8.4Hz), 7.30 (1H, m), 7.48 (1H, dd,
J=2.0Hz, 8.4Hz), 7.58 (2H, m), 7.71 (1H, s), 12.10 (1H, brs)
57) NMR (CDCl.sub.3) .delta.:
1.41-1.54 (9H, m), 4.07-4.26 (6H, m), 6.92 (1H, d, J=8.4Hz), 7.49
(1H, dd, J=2.0Hz, 8.4Hz), 7.63 (1H, d, J=2.0Hz), 7.86-8.05 (2H, m),
8.20 (1H, s), 8.44 (1H, dd, J-1.0Hz, 7.7Hz).
Example 375
The compounds of Examples 368-371 were obtained in the same
procedure as in Example 147, by using respective starting
materials.
Example 376
The compound of Example 368 was obtained in the same procedure as
in Example 363, by using starting materials.
Example 377
The compounds of Examples 367-374 were obtained in the same
procedure as in Example 365, by using respective starting
materials.
The compounds of Examples 378-452, shown in Table 13 were obtained
in the same procedures as in Example 1 and Example 138, by using
respective starting materials.
TABLE 13 ##STR854## Exam- Crystal form ple (recrystallization M.p.
(.degree. C.) No. R.sup.1 R.sup.2 R.sup.3 solvent) (salt form) 378
##STR855## H ##STR856## Yellow powder (diethyl ether) 93-94 (2 HCl)
379 -- H ##STR857## Yellow powder (acetone) 119-122 (3 HCl) 380
##STR858## H ##STR859## Light yellow powder (ethanol) 203-205.6 381
##STR860## H ##STR861## Light yellow powder (ethyl acetate)
188.4-190.4 (decomposed) (-) 382 -- H ##STR862## White powder
(ethanol) 67-68 (-) 383 -- H ##STR863## White powder (ethanol)
108-109 (-) 384 -- H ##STR864## White powder (diethyl ether) 99-100
(-) 385 -- H ##STR865## White acicular (diethyl ether-n- hexane)
94-95 (-) 386 -- H ##STR866## White powder (diethyl ether) 69-71.4
(-) 387 -- H ##STR867## Dark yellow acicular (acetone) 213-214 (I)
388 -- H ##STR868## Light brown powder (diethyl ether) 81.2-83.6
(-) 389 -- H ##STR869## White powder (ethanol-diethyl ether)
212-214 (HCl) 390 -- H ##STR870## White powder (ethanol)
126.8-128.8 (-) 391 -- H ##STR871## White powder (ethyl acetate)
206.8-208.6 (-) 392 -- H ##STR872## White acicular (n-hexane-ethyl
acetate-dichloro- methane) 163.2-164.1 (-) 393 -- H ##STR873##
White acicular (methanol) 123-124 (-) 394 -- H ##STR874## White
acicular (ethyl acetate) 144-145 (-) 395 -- H ##STR875## Light
brown prismatic (ethyl acetate) 171-172 (-) 396 -- H ##STR876##
White powder (ethyl acetate) 216-217 (-) 397 -- H ##STR877## White
powder (ethyl acetate-n- hexane) 109-113 (-) 398 -- H ##STR878##
Yellow powder (ethanol) 181.8-182.4 (decomposed) (-) 399 -- H
##STR879## White acicular (ethyl acetate) 180.8-182.2 (-) 400 -- H
##STR880## Yellow amorphous 242.5 (decomposed) 4 HCl) 401 -- H
##STR881## White acicular (diethyl ether-n- hexane) 216-217 (-) 402
-- H ##STR882## Yellow powder (diethyl ether- ethanol) 195
(decomposed) (2 HCl) 403 ##STR883## H ##STR884## Gray powder
(acetic acid- water) 184-186 (decomposed) (HBr) 404 ##STR885## H
##STR886## Yellow acicular (ethanol) 104.8-108.8 (-) 405 -- H
##STR887## White acicular (ethyl acetate) 217-219 (-) 406 -- H
##STR888## Light yellow powder (ethanol) 189.8-191 (-) 407 -- H
##STR889## White acicular (ethanol) 138.2-139 (-) 408 -- H
##STR890## White acicular (ethanol) 222-223 (-) 409 -- H ##STR891##
White acicular (ethyl acetate- ethanol) 240-242 (-) 410 -- H
##STR892## Light yellow acicular (ethyl acetate) 222-223 411 -- H
##STR893## White powder (ethyl acetate) 215-216 (-) 412 -- H
##STR894## White acicular (ethyl acetate) 158-159 (-) 413 -- H
##STR895## White acicular (ethyl acetate) 140-141 (-) 414 -- H
##STR896## White powder (ethanol) 234.6-239.4 (HCl) 415 -- H
##STR897## White powder (n-hexane) 75-76.5 416 -- H ##STR898##
White acicular (ethyl acetate) 126.5-128 (-) 417 -- H ##STR899##
White powder (ethyl acetate-n- hexane) NMR.sup.58) (-) 418 -- H
##STR900## White acicular (ethyl acetate) 159-161 (-) 419 -- H
##STR901## White acicular (ethyl acetate) 106-107 (-) 420 -- H
##STR902## White powder (ethyl acetate) 236.2-237.3 (-) 421 -- H
##STR903## 422 -- H ##STR904## White powder (ethyl acetate) 212-213
(-) 423 -- H ##STR905## NMR.sup.59) 424 -- H ##STR906## Yellow
powder (ethyl acetate) 210-212 (-) 425 -- H ##STR907## NMR.sup.60)
(-) 426 -- H ##STR908## Light brown granular (dimethylform- amide)
271-273 (-) 427 -- H ##STR909## Yellow powder (ethyl acetate)
260-261 (-) 428 -- H ##STR910## 429 -- H ##STR911## 430 -- H
##STR912## Yellow powder (ethanol) 202-203 431 -- H ##STR913##
Yellow powder (methanol) 254-255 (-) 432 -- H ##STR914## 433 -- H
##STR915## 434 -- H ##STR916## White acicular (ethyl acetate)
243-246 (-) 435 -- H ##STR917## Yellow acicular (ethanol) 243-244
436 -- H ##STR918## Light orange prismatic (ethyl acetate)
230.4-231.4 (-) 437 -- H ##STR919## Dark yellow prismatic (ethyl
acetate- diethyl ether-n- hexane) 11 164.6-165.5 (-) 438 -- H
##STR920## Light brown powder (ethyl acetate) 153.8-155.4 (-) 439
-- H ##STR921## White powder (ethyl acetate) 178-178.6 (-) 440 -- H
##STR922## Light yellow powder (ethanol-diethyl ether) 220.8-223.4
441 -- H ##STR923## Brown powder (ethanol) 174.4-175.6 (-) 442 -- H
##STR924## White acicular (methanol-diethyl ether) 102.5-103.5 (-)
443 -- H ##STR925## White powder (ethanol) 112-113 (-) 444 -- H
##STR926## Colorless oily NMR.sup.61) 445 -- H ##STR927## Light
brown acicular (ethanol) 93-94 (-) 446 -- H ##STR928## Light brown
prismatic (methanol- dichloromethane) 144-145 NMR.sup.62) (-) 447
-- H ##STR929## Brown oily NMR.sup.63) (-) 448 -- H ##STR930##
Colorless oily NMR.sup.64) 449 -- H ##STR931## White solid
NMR.sup.65) 450 -- H ##STR932## White acicular (ethanol) 113-114
(-) 451 -- H ##STR933## Yellow acicular (ethyl acetate) 202-203 (-)
452 -- H ##STR934## NMR.sup.66)
Example 453
94 mg of sodium boron hydride was added, at 0.degree. C., to a
solution of 540 mg of
4-[2-(3,4-diethoxyphenyl)-4-thiazole]-1-methylpyridinium iodide in
60 ml of methanol. The mixture was stirred at room temperature for
15 hours. After the completion of a reaction, the reaction mixture
was concentrated. The residue was mixed with 100 ml of ethyl
acetate and washed with 50 ml of water. The ethyl acetate layer was
dried over sodium sulfate and concentrated. The residue was
recrystallized from diethyl ether to obtain 300 mg of
2-(3,4-diethoxyphenyl)-4-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)thiazole
.
Light brown powder
M.p.: 81.2.degree.-83.6.degree. C.
Example 454
200 mg of lithium aluminum hydride was added, at 0.degree. C., to a
solution of 1.92 g of
2-(3,4-diethoxyphenyl)-4-(2-ethoxycarbonyl-6-pyridyl)thiazole in
150 ml of tetrahydrofuran. The mixture was stirred in an argon
atmosphere for 2 hours. The reaction mixture was mixed with 1 ml of
a saturated sodium sulfate solution. The resulting mixture was
stirred at 0.degree. C. for 30 minutes and filtered through Celite.
The filtrate was concentrated. The residue was purified by silica
gel column chromatography and recrystallized from ethyl
acetate-n-hexane to obtain 360 mg of
2-(3,4-diethoxyphenyl)-4-(2-hydroxymethyl-6-pyridyl)thiazole.
White acicular
M.p.: 109.degree.-113.degree. C.
The compounds of Examples 412, 423 and 442 were obtained in the
same procedure as in Example 454, by using respective starting
materials.
Example 455
1.13 ml of triethylamine was dropwise added, at room temperature,
to a solution of 1 g of
2-(3,4-diethoxyphenyl)-4-(2-carboxy-6-pyridyl)thiazole, 245 mg of
dimethylamine hydrochloride and 515 mg of diethyl cyanophosphate in
15 ml of dimethylformamide. The mixture was stirred at the same
temperature for 3 hours. The reaction mixture was mixed with 20 ml
of water. The resulting mixture was extracted with 50 ml of
dichloromethane three times. The dichloromethane layer was dried
over sodium sulfate and concentrated. The residue was
recrystallized from n-hexane-ethyl acetate-dichloromethane to
obtain 800 mg of
2-(3,4-diethoxyphenyl)-4-(2-dimethylaminocarbonyl-6-pyrdyl)thiazole.
White acicular
M.p.: 163.2.degree.-164.1.degree. C.
The compounds of Examples 379, 400 and 401 were obtained in the
same procedure as in Example 455, using respective starting
materials.
Example 456
730 Milligrams of
2-(3,4-diethoxyphenyl)-4-(2-dimethylaminocarbonyl-6-pyridyl)thiazole
was dissolved in 15 ml of tetrahydrofuran at room temperature, then
this solution was dropwise added to a suspension of 70 mg of
lithium aluminum hydride in 10 ml of diethyl ether, in an argon
atmosphere so as to refluxing the reaction mixture. After the
completion of the dropwise addition, refluxing was continued for a
further 1 hour and 30 minutes. The reaction mixture was mixed with
50 ml of water. The resulting mixture was extracted with three
50-ml portions of dichloromethane. The, dichloromethane layer was
concentrated. The residue was purified by silica gel thin-layer
chromatography. The resulting ethanol solution was mixed with
concentrated hydrochloric acid to obtain a hydrochloride. The
hydrochloride was recrystallized from a diethyl ether-ethanol mixed
solvent to obtain 60 mg of
2-(3,4-diethoxyphenyl)-4-(2-dimethylaminomethyl-6-pyridyl)-thiazole
dihydrochloride as a yellow powder.
M.p.: 195.degree. C. (decomposed)
Example 457
8.5 g of trifluoromethanesulfonic acid anhydride was added to a
solution of 10 g of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxyphenyl)-thiazole
dissolved in 100 ml of dichloromethane. Thereto was dropwise added
6 ml of triethylamine with stirring under ice-cooling. The reaction
mixture was stirred at room temperature for 2 hours. Thereto was
added 40 ml of water for phase separation. The organic layer was
dried and subjected to distillation to remove the solvent. The
residue was recrystallized from ethanol to obtain 12.7 g of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-trifluoromethanesulfonyloxyp
henyl) thiazole as a white powder.
M.p.: 112.degree.-113.degree. C.
Example 458
In 5 ml of dimethylformamide was dissolved 600 mg of
2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-methoxymethoxyphenyl)thiazole.
Thereto was added 56 mg of sodium hydride and 290 mg of
1-bromononane. The mixture was stirred at room temperature for 14
hours. The solvent was removed by distillation. To the residue were
added 80 ml of dichloromethane and 30 ml of a 10% aqueous sodium
hydroxide solution, and phase separation was conducted. The
dichloromethane portion was washed with 20 ml of a saturated
aqueous sodium chloride solution, dried and subjected to
distillation to remove the solvent. The residue was subjected to
silica gel column chromatography. There was obtained, from the
dichloromethane layer, 340 mg of
2-(3,4-diethoxyphenyl)-4-(3-nonyloxycarbonyl-4-methoxymethoxyphenyl)thiazo
le as a colorless oily substance.
Properties: NMR.sup.61)
In the same procedure as in Example 458 were obtained the compounds
of Examples 283-385, 390, 398, 404, 407, 415, 443, 444, 445,
447-450 and 452, by using respective starting materials.
Example 459
In a mixed solvent consisting of 2 ml of dimethylformamide and 0.2
ml of water were dissolved 200 mg of
2-(3,4-diethoxyphenyl)-4-chloromethylthiazole, 73 mg of
2-acetylpyrrole, 200 mg of sodium iodide and 200 mg of sodium
hydroxide. The solution was stirred at 80.degree. C. for 4 hours.
The reaction mixture was subjected to distillation to remove the
solvent. To the residue were added 30 ml of dichloromethane and 20
ml of water, and phase separation was conducted. The organic layer
was washed with 15 ml of a saturated aqueous sodium chloride
solution, dried and subjected to distillation to remove the
solvent. The residue was recrystallized from methanol to obtain 60
mg of 2-(3,4-diethoxyphenyl)-4-(2-acetyl-1-pyrrolyl)methylthiazole
as white acicular crystals.
M.p.: 123.degree.-124.degree. C.
Example 460
In 5 ml of dimethyl sulfoxide were dissolved 1 g of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-trifluoromethylsulfonyloxyph
enyl)thiazole and 0.73 g of 1-(2-aminoethyl)piperidine. The mixture
was stirred at 80.degree. C. for 5 hours. To the reaction mixture
were added 40 ml of ethyl acetate and 20 ml of water, and phase
separation was conducted. The organic layer was washed with 15 ml
of a saturated aqueous sodium chloride solution, dried and
subjected to distillation to remove the solvent. The residue was
purified by silica gel column chromatography (eluant:
dichloromethane/methanol=49/1 by v/v) and dissolved in diethyl
ether. The solution was mixed with hydrochloric acid-methanol to
obtain a hydrochloride. The hydrochloride was recrystallized from
diethyl ether to obtain 330 mg of
2-(3,4-diethoxyphenyl)-4-{3-methoxycarbonyl-4-[2-(1-piperidinyl)ethylamino
]phenyl}thiazole dihydrochloride as a yellow powder.
M.p.: 93.degree.-94.degree. C.
The compounds of Examples 389, 403, 433, 434 and 442 were obtained
in the same procedure as in Example 460, by using respective
starting materials.
Example 461
In 20 ml of ethanol was dissolved 340 mg of
2-(3,4-diethoxyphenyl)-4-(3-nonyloxycarbonyl-4-methoxymethoxyphenyl)thiazo
le. Thereto was added 2 ml of 10% hydrochloric acid, and the
mixture was refluxed for 20 minutes. The solvent was removed by
distillation. To the residue were added 40 ml of dichloromethane
and 20 ml of water, and phase separation was conducted. The organic
layer was washed with 15 ml of a saturated aqueous sodium chloride
solution, dried and subjected to distillation to remove the
solvent. The residue was recrystallized from ethanol to obtain 245
mg of
2-(3,4-diethoxyphenyl)-4-(3-nonyloxycarbonyl-4-hydroxyphenyl)thiazole
as a white powder.
M.p.: 67.degree.-68.degree. C.
In the same procedure as in Example 461 were obtained the compounds
of Examples 379, 380, 382-385, 395, 396, 411, 412, 417, 421-435,
445 and 451 by using respective starting materials.
Example 462
In a mixed solvent consisting of 50 ml of methanol and 5 ml of
water were suspended 1 g of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-allylphenyl)thiazo
le, 50 mg of palladium acetate [Pd(OAc).sub.2 ] and 230 mg of
copper acetate [Cu(OAc)2.H.sub.2 O]. The suspension was stirred in
an oxygen atmosphere at 50.degree. C. for 6 hours. 50 mg of
palladium acetate was further added. After 10 hours, 50 mg of
palladium acetate was furthermore added. After 14 hours, when no
solid starting materials in the reaction mixture were visible, the
reaction mixture was filtered. The litrate was concentrated. The
residue was purified by silica gel column chromatography (eluent:
dichloromethane/hexane=1/1 by v/v) and recrystallized from
methanol-dichloromethane to obtain 230 mg of 2-(3,4- 1
diethoxyphenyl)-4-(2-methyl-7-methoxycarbonyl-5-benzofuryl)thiazole.
Light brown prismatic
M.p.: 144.degree.-145.degree. C.
NMR.sup.62)
Example 463
In 20 ml of methanol was dissolved 1 g of
2-(3,4-diethoxyphenyl)-4-[3-methoxymethoxymethoxycarbonyl-4-methoxymethoxy
-5-(2-methyl-2-propenyl)phenyl]thiazole. Into the solution being
stirred under ice-cooling was blown ozone. After 1 hour, 0.5 ml of
methyl sulfide was added. The mixture was stirred at the same
temperature for 30 minutes. The solvent was removed from the
reaction mixture by distillation. To the residue were added 50 ml
of dichloromethane and 25 ml of water. The organic layer was
separated, washed with 15 ml of a saturated aqueous sodium chloride
solution, dried and subjected to distillation to remove the
solvent. The residue was purified by silica gel column
chromatography (eluent: dichloromethane/n-hexane=2/3 by v/v) to
obtain 500 mg of
2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-acet
ylmethylphenyl)thiazole as a colorless oily substance.
Properties: NMR.sup.64)
The compound of Example 450 was obtained in the same procedure as
in Example 463, by using starting materials.
Example 464
In 15 ml of ethanol was dissolved 220 mg of
2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-acet
ylmethylphenyl)thiazole. Thereto was added 1 ml of 10% hydrochloric
acid, and the mixture was refluxed for 2 hours with heating. The
solvent was removed by distillation. To the residue were added 20
ml of ethyl acetate and 10 ml of water, and phase separation was
conducted. The organic layer was washed with 10 ml of a saturated
aqueous sodium chloride solution, dried and subjected to
distillation to remove the solvent. The residue was purified by
silica gel column chromatography (eluent: chloroform/methanol=99/1
by v/v) and recrystallized from an n-hexane-ethyl acetate mixed
solvent to obtain
2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-acetylmethyl)thiazole
was a white powder.
In the same procedure as in Example 467 were obtained the compounds
of Examples 379-385, 389, 391, 394-396, 399, 403, 411-414, 416-418,
421-435, 445 and 451 by using respective starting materials.
Example 465
In 40 ml of o-dichlorobenzene was dissolved, with heating, 2 g of
2-(3,4-diethoxyphenyl)-4-[3-carboxy-4-hydroxy-5-(2-methyl-2-propenyl)pheny
l]-thiazole. Thereto were added about 10 mg of iodine and 1.5 g of
potassium iodide (ground in-a mortar), and the mixture was refluxed
for 14 hours with heating. The reaction mixture was mixed with 30
ml of water and phase separation was conducted. The organic layer
was mixed with 30 ml of ethyl acetate. The mixture was washed with
20 ml of a saturated aqueous sodium chloride solution, dried and
subjected to distillation to remove the solvent. The residue was
purified by silica gel column chromatography (eluent:
dichloromethane) and recrystallized from diisopropyl ether to
obtain 1 g of
2-(3,4-diethoxyphenyl)-4-(2,2-dimethyl-7-carboxy-2,3-dihydrobenzofuran-5-y
l)thiazole as white powdery crystals.
M.p.: 106.degree.-107.degree. C.
Example 466
In a mixed solvent consisting of 100 ml of tetrahydrofuran and 40
ml of water was dissolved 3.7 g of
2-(3,4-diethoxyphenyl)-4-[3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(1-p
ropenyl)phenyl]thiazole. To the solution were added 100 mg of
osmium tetroxide (OsO.sub.4) and 5.6 g of sodium periodate
(NaIO.sub.4) and the mixture was stirred at room temperature for 14
hours. The reaction mixture was filtered. The filtrate was
concentrated to a 1/3 volume. To the concentrate was added 100 ml
of ethyl acetate, and phase separation was conducted. The organic
layer was washed with 40 ml of a saturated aqueous sodium chloride
solution, dried and subjected to distillation to remove the
solvent. The residue was purified by silica gel column
chromatography (eluant: dichloromethane) to obtain 600 mg of
2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonYl-4-methoxymethoxy-5-form
ylphenyl)thiazole (compound A) and 1.28 g of
2-(3,4-diethoxyphenyl)-4-[3-methoxymethoxy-carbonyl-4-methoxymethoxy-5-(1,
2-dihydroxypropyl)-phenyl]thiazole (compound B). The
2-(3,4-diethoxy-phenyl)-4-[3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(1,
2-dihydroxypropyl)phenyl]thiazole (compound B) was dissolved in 40
ml in methanol. To the solution were added 5 g of sodium periodate
(NaIO.sub.4) and 10 ml of water, and the mixture was stirred at
room temperature for 14 hours. The solvent was removed from the
reaction mixture by distillation. The residue was mixed with 80 ml
of ethyl acetate and 40 ml of water, and phase separation was
conducted. The organic layer was washed with 20 ml of a saturated
aqueous sodium chloride solution, dried and subjected to
distillation to remove the solvent. The residue was combined with
600 mg of the above-obtained
2-(3,4-diethoxyphenyl)-4-(3-methoxy-methoxycarbonyl-4-methoxymethoxy-5-for
mylphenyl)thiazole (compound A). The mixture was recrystallized
from ethanol to obtain 1.6 g of
2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxy-methoxy-5-for
myl-phenyl)thiazole as white acicular crystals.
TABLE 14 ##STR935## Exam- Crystal form ple (recrystallization M.p.
(.degree. C.) No. R.sup.1 R.sup.2 R.sup.3 solvent) (salt form) 467
##STR936## H ##STR937## Yellow oily NMR.sup.67) (-) 468 -- H
##STR938## Reddish brown acicular (ethyl acetate) 122-124 (-) 469
-- H ##STR939## Light yellow acicular (ethyl acetate-n- hexane)
166-167 (-) 470 -- H ##STR940## White acicular (ethyl acetate)
NMR.sup.68) (-) 471 -- H ##STR941## Light brown solid NMR.sup.69)
(-) 472 ##STR942## H ##STR943## White acicular (ethyl acetate-n-
hexane) 167-168 (-) 473 ##STR944## H ##STR945## White powder
(ethanol) 175-176 (-) 474 -- H ##STR946## Light yellow acicular
(ethyl acetate-n- hexane) 106-107 (-) 475 -- H ##STR947## Light
yellow acicular (diisopropyl ether) 89-90 (-) 476 -- H ##STR948##
White acicular (diethyl ether) 103-105 (-) 477 -- H ##STR949##
White acicular (diethyl ether) 107-108 (-) 478 -- H ##STR950##
Colorless oily NMR.sup.70) (-) 479 -- H ##STR951## Colorless oily
NMR.sup.71) (-) 480 -- H ##STR952## Colorless oily NMR.sup.72) (-)
481 -- H ##STR953## Yellow granular (dichloromethane- ether)
179-181 (-) 482 -- H ##STR954## Colorless oily NMR.sup.73) (-) 483
-- H ##STR955## Yellow solid NMR.sup.74) (-) 484 -- H ##STR956##
Yellow powder (ethanol) 94-96 (-) 485 -- H ##STR957## Colorless
oily NMR.sup.75) 486 -- H ##STR958## NMR.sup.76) 487 -- H
##STR959## White acicular (diisopropyl ether) 92-93 (-) 488 -- H
##STR960## White acicular (ethanol) 125.8-127.8 489 -- H ##STR961##
Yellow acicular (ethanol) 226.5-229 (-) 490 -- H ##STR962## White
acicular (ethanol) 152-154 (-) 491 -- H ##STR963## Yellow powder
(ethanol) 172.4-175.6 (HBr) 492 -- H ##STR964## Yellow powder
(ethanol) 237.2-238 (-) 493 -- H ##STR965## NMR.sup.77) (-) 494 --
H ##STR966## Gray powder (ethanol- dimethylformamide) 272-277 495
-- H ##STR967## Yellow powder (ethanol) 215-215.8 (-) 496 -- H
##STR968## Yellow powder (ethanol) 204-205.4 (HBr) 497 -- H
##STR969## Colorless oily NMR.sup.78) 498 -- H ##STR970## White
prismatic (ethyl acetate-n- hexane) 101.3-103 (-) 499 -- H
##STR971## White powder (acetone) 107-110 (-) 500 -- H ##STR972##
Yellow oily NMR.sup.79) 501 -- H ##STR973## 502 -- H ##STR974## 503
-- H ##STR975## 504 -- H ##STR976## White acicular (ethyl acetate)
197-198 (-) 505 -- H ##STR977## 506 -- H ##STR978## 507 -- H
##STR979## NMR.sup.80) (-) 508 -- H ##STR980## NMR.sup.81) (-) 509
-- H ##STR981## NMR.sup.82) (HBr)
M.p.: 113.degree.-114.degree. C.
The compound of Example 416 was obtained in the same procedure as
in Example 466 by using starting materials.
The compounds of Examples 467-509, shown in Table 14 were obtained
in the same procedures as in Example 1 and Example 138, by using
respective starting materials.
Example 510
In 30 ml of methanol was dissolved 500 mg of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxy-methoxy-5-formylphen
yl)thiazole. Thereto was added 3 ml of a 30% methylamine solution.
The mixture was stirred at room temperature for 14 hours and at
70.degree. C. for 1 hour. Thereto was added 530 ml of sodium boron
hydride with stirring under ice-cooling. The mixture was stirred at
room temperature for 3 hours. The solvent was removed from the
reaction mixture by distillation. The residue was mixed with 40 ml
of ethyl acetate and 20 ml of water, and phase separation was
conducted. The organic layer was washed with 10 ml of a saturated
aqueous sodium chloride solution, dried and subjected to
distillation to remove the solvent. The residue was subjected to
silica gel chromatography (eluent: dichloromethane/methanol=49/1 by
v/v). From the eluate was obtained 150 mg of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxymethoxy-5-methylamino
methyl-phenyl)thiazole.
Colorless oily
Properties: NMR.sup.73)
The compound of Example 402 was obtained in the same procedure as
in Example 510, using starting materials.
Example 511
In 20 ml of methanol was suspended 300 mg of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-formylphenyl)thiaz
ole with stirring. Threto was added 26.5 mg of sodium boron hydride
at 0.degree. C. The mixture was stirred at room temperature for 1
hour. 26.5 mg of sodium boron hydride was further added, and the
resulting mixture was stirred at the same temperature for 1 hour.
The solvent was removed from the reaction mixture by distillation.
To the residue were added 30 ml of dichloromethane and 15 ml of
water, and phase separation was conducted. The organic layer was
washed with 10 ml of a saturated aqueous sodium chloride solution,
dried and subjected to distillation to remove the solvent to obtain
300 mg of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-hydroxymethylpheny
l)-thiazole.
Yellow solid
Properties: NMR.sup.74)
The compounds of Examples 397, 412, 423, 445 and 498 were obtained
in the same procedure as in Example 511, by using respective
starting materials.
Example 512
500 mg of
2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-form
ylphenyl)-thiazole was added to 20 ml of a solution of a newly
prepared Wittig reagent (triethyl phosphonacetate: 270 mg, sodium
hydride: 48 mg) in tetrahydrofuran. The mixture was stirred at room
temperature for 4 hours. The solvent was removed from the reaction
mixture by distillation. To the residue were added 20 ml of ethyl
acetate and 15 ml of water, and phase separations was conducted.
The organic layer was washed with 10 ml of a saturated aqueous
sodium chloride solution, dried and subjected to distillation to
remove the solvent. The residue was recrystallized from ethanol to
obtain 380 mg of
2-(3,4-diethoxyphenyl)-4-[3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(2-e
thoxycarbonylvinyl)phenyl]thiazole.
Yellow Powder
M.p.: 94.degree.-96.degree. C.
The compounds of Examples 478, 485, 486, 501 and 501 were obtained
in the same procedures as in Example 512, by using respective
starting materials.
Example 513
535 mg of methyltriphenylphosphonium bromide was suspended in 10 ml
of tetrahydrofuran with stirring. Thereto was added 190 mg of
potassium tert-butoxide at -5.degree. C., and the mixture was
stirred at the same temperature for 1 hour. Thereto was added 500
mg of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxymethoxy-5-formylpheny
l) thiazole. The mixture was stirred at the same temperature for 2
hours and at room temperature for 1 hours. To the reaction mixture
was added 30 ml of ethyl acetate and 20 ml of water, and phase
separation was conducted. The organic layer was washed with 20 ml
of a saturated aqueous sodium chloride solution, dried and
subjected to distillation to remove the solvent. The residue was
purified by silica gel column chromatography (eluent:
dichloromethane/n-hexane=2/1 by v/v) to obtain 240 mg of
2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-hydroxy-5-vinylphenyl
)thiazole (A) and 120 mg of
2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-viny
lphenyl)-thiazole (B).
NMR data of compound (A):
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.49 (3H, t, J=7.0 Hz), 1.51
(3H, t, J=7.0 Hz), 3.58 (3H, s), 3.95 (3H, s), 4.15 (2H, q, J=7.0
Hz), 4.22 (2H, q, J=7.0 Hz), 5.08 (2H, s), 5.43 (1H, dd, J=1.1,
11.11 Hz), 5.89 (1H, dd, J=17.7 Hz), 6.92 (1H, d, J=8.4 Hz), 7.17
(1H, dd, J=11.1, 17.7 Hz), 7.43 (1H, s), 7.54 (1H, dd, J=2.1, 8.4
Hz), 7.61 (1H, d, J=2.1 Hz), 8.29 (2H, d, J=1.3 Hz).
NMR data of compound (B):
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.49 (3H, t, J=7.0 Hz), 1.51
(3H, t, J=7.0 Hz), 3.58 (3H, s), 3.59 (3H, s) 4.15 (2H, q, J=7.0
Hz), 4.22 (2H, q, J=7.0 Hz), 5.10 (2H, s), 5.43 (1H, dd, J=1.1,
11.1 Hz), 5.51 (2H, s), 5.89 (1H, dd, J=1.1, 17.1 Hz), 6.92 (1H, d,
J=8.4 Hz), 7.18 (1H, dd, J=11.1, 17.7 Hz), 7.43 (1H, s), 7.54 (1H,
dd, J=2.1, 8.4 Hz), 7.61 (1H, d, J=2.1 Hz), 8.29 (2H, d, J=1.3
Hz).
Example 514
In 10 ml of ethanol was dissolved 350 mg of
2-(3,4-diethoxyphenyl)-4-[3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(2-e
thoxycarbonylvinyl)phenyl] thiazole. Thereto was added 0.2 ml of
10% hydrochloric acid. The mixture was stirred at 60.degree. C. for
1 hours with heating. Thereto was added 1 ml of 10% sodium
hydroxide. The mixture was refluxed for 4 hours with heating. The
solvent was removed from the reaction mixture by distillation. The
residue was mixed with 15 ml of water. The mixture was made weakly
acidic with 10% hydrochloric acid and extracted with 40 ml of hot
ethyl acetate. The organic layer was washed with 15 ml of a
saturated aqueous sodium chloride solution, dried and subject to
distillation to remove the solvent. The residue was recrystallized
from ethyl acetate to obtain 170 mg of
2-(3,4-diethoxyphenyl)-4-[3-carboxy-4-hydroxy-5-(2-carboxyvinyl)phenyl]
thiazole.
Yellow powder
M.p.: 260.degree.-261.degree. C.
Example 515
In 20 ml of methanol was dissolved 150 mg of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxymethoxy-5-methylamino
methylphenyl)thiazole. Thereto was added 0.2 ml of 10% hydrochloric
acid. The mixture was stirred at 60.degree. C. for 30 minutes. 2 ml
of 10% sodium hydroxide was added, and the mixture was refluxed for
1 hour with heating. The reaction mixture was made neutral with 10%
hydrochloric acid and the solvent was removed by distillation. The
residue was mixed with ethanol. The insoluble was collected by
filtration, washed with water, dried and recrystallized from
dimethylformamide to obtain 35 mg of
2-(3,4-diethoxyphenyl-4-(3-carboxy-4-hydroxy-5-methylaminomethylphenyl)thi
azole.
Light brown granular
M.p.: 271.degree.-273.degree. C.
Example 516
A mixture of 500 mg of
2-(3,4-diethoxyphenyl)-4-(4-cyano-pyridyl)thiazole, 20 ml of
ethanol and 17 ml of a 4% aqueous sodium hydroxide solution was
refluxed for 16 hours with heating. The reaction mixture was
allowed to stand. Then, 200 ml of water was added thereto. The
mixture was extracted with 80 ml of dichromethane two times. The
aqueous layer was made acidic (pH=about 3) with concentrated
hydrochloric acid and extracted with 150 ml of ethyl acetate three
times. The ethyl acetate layer was dried over anhydrous sodium
sulfate and concentrated. The residue was recrystallized from ethyl
acetate to obtain 290 mg of 2(3,
4-diethoxyphenyl)-4-(4-carboxy-2-pyridyl)thiazole.
White acicular crystals
M.p.: 236.2.degree.-237.2.degree. C.
Example 517
5.23 g of imidazole and 4.85 g of tertbutyldimethylchlorosilane
were added, in this order, to a suspension of 4.02 g of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxyphenyl)thiazole
in 60 ml of dimethylformamide at room temperature. The mixture was
stirred at the same temperature for 4 hours. To the reaction
mixture were added 100 ml of ice water and 200 ml of ethyl acetate.
The organic layer was separated, washed with 100 ml of water and 50
ml of a saturated aqueous sodium chloride solution in this order,
dried over anhydrous magnesium sulfate and subjected to
distillation to remove the solvent. The residue was purified by
silica gel column chromatography (eluent: n-hexane/ethyl
acetate=10/1) to obtain 5.14 g of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-tertbutyldimethylsilyloxyphe
nly)thiazole.
Colorless oily substance
Properties
Example 518
548 mg of lithium aluminum hydride was added to a solution of 5.43
g of
2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-tert-butyldimethylsilyloxyph
enyl)-thiazole in 100 ml of tetrahydrofuran, with ice-cooling. The
mixture was stirred at the same temperature for 7 hours. To the
reaction mixture were added 1.1 ml of water and 3 g of sodium
sulfate. The resulting mixture was filtered through Celite. The
filtrate was subjected to distillation to remove the solvent. To
the residue were added 200 ml of ethyl acetate and 50 ml of water.
The mixture was neutralized with 5N hydrochloric acid. The
insoluble was removed by filtration. The filtrate was subjected to
phas separation. The organic layer was washed with 50 ml of water,
dried over anhydrous magnesium sulfate and subjected to
distillation to remove the solvent. The residue was purified by
silica gel column chromatography (eluent: n-hexane/ethyl
acetate=10/1 by v/v) and recrystallized from ethyl acetate-n-hexane
to obtain 1.23 g of
2-(3,4-diethoxyphenyl)-4-(3-hydroxymethyl-4-tert-butyldimethylsilyloxyphen
yl)thiazole.
White prismatic crystals
M.p.: 101.3.degree.-103.degree. C.
The compounds of Examples 397, 412, 423, 445 and 483 were obtained
in the same procedure as in example 518, by using respective
starting materials.
Example 519
The following compound was obtained in the same procedures as in
Examples 1 and 138, by using starting materials.
2-(3,4-Diethoxoyphenyl)-4-[3-carboxy-4-hydroxy-5-(1-isobutenyl)phenyl]thia
zole
Properties: 1H-NMR (DMSO-d.sub.6) .delta.: 1.38 (3H, t, J=6.9 Hz),
1.40 (3H, t, J=6.9 Hz), 1.86 (3H, s), 1.95 (3H, s), 4.12 (2B, q,
J=6.9 Hz), 4.15 (2B, q, J=6.9 Hz), 6.33 (1H, brs), 7.09 (1H, d,
J=8.7 Hz), 7.48-7.62 (2H, m), 7.93 (1H, s), 7.95 (1H, d, J=2.1 Hz),
8.31 (1H, d, J=2.1 Hz).
Example 520
The following compounds were obtained in the same procedures as in
Examples 1 and 138, by using respective starting materials.
4[-(3,4-Diethoxyphenyl)-4-thiazolyl]-pyridinium-1-oxide
Properties: 1H-NMR (DMSO-d.sub.6) .delta.: 1.35 (3H, t, J=6.9 Hz),
1.37 (3H, t, J=6.9 Hz), 4.07 (4H, m), 7.07 (1H, d, J=8.3 Hz), 7.52
(1H, dd, J=2.0 Hz, 8.3 Hz), 7.58 (1H, d, J=2.0 Hz), 8.03 (2H, d,
J=7.2 Hz), 8.29 (2H, d, J=7.2 Hz), 8.33 (1H, s).
2-(3,4-Diethoxyphenyl)-4-(2-cyano-4-pyridinium) thiazole
Properties: .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.36 (3H, t, J=6.9
Hz), 1.38 (3H, t, J=6.9 Hz), 4.08-4.23 (4H, m), 7.08 (1H, d, J=8.3
Hz), 7.55-7.61 (2H, m), 8.32 (1H, dd, J=1.3 Hz, 5.2 Hz), 8.64 (2H,
s), 8.84 (1H, d, J=5.2 Hz).
NMR data of the compounds of Examples 417, 423, 425, 444, 446-449,
452, 467, 470, 471, 478-480, 482, 483, 485, 486, 493, 497, 500 and
507-509 (NMR.sup.58) -NMR.sup.82))
NMR.sup.58) : Compound of Example 417
.sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.38 (3H, t, J=7.0 Hz), 1.40
(3H, t, J=7.0 Hz), 2.22 (3H, s), 3.87 (2H, s), 4.08 (2H, q, J=7.0
Hz), 4.16 (2H, q, J=7.0 Hz), 7.10 (1H, d J=8.2 Hz), 7.48-7.60 (2H,
m), 7.99 (1H, s), 8.08 (1H, d, J=2.3 Hz), 8.38 (1H, d, J=2.3
Hz).
NMR.sup.59) : Compound of Example 423
.sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.38 (3H, t, J=6.9 Hz), 1.40
(3H, t, J=6.9 Hz), 4.11 (2H, q, J=6.9 Hz), 4.15 (2H, q, J=6.9 Hz),
4.60 (2H, s), 7.08 (1H, d, J=8.9 Hz), 7.45-7.63 (2H, m), 7.77 (1H,
s), 8.06 (1H, d, J=2.2 Hz), 8.34 (1H, d, J=2.2 Hz).
NMR.sup.60) : Compound of Example 425
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.48 (3H, t, J=7.0 Hz), 1.50
(3H, t, J=7.0 Hz), 2.78 (2H, t, J=6.7 Hz), 3.09 (2H, t, J=6.7 Hz),
4.07-4.30 (4H, m), 6.91 (1H, d, J=8.3 Hz), 7.52 (1H, d, J=8.3 Hz),
7.60 (1H, brs), 8.02 (1H, brs), 8.38 (1H, brs).
NMR.sup.61) : Compound of Example 444
.sup.1 -NMR (CDCl.sub.3) .delta.: 0.08-1.00 (3H, m), 1.00-1.67
(18H, m), 1.67-1.95 (2H, m), 3.54 (3H, s), 4.16 (2H, q, J=7.0 Hz),
4.23 (2H, q, J=7.0 Hz), 4.35 (2H, t, J=6.6 Hz), 5.30 (2H, S), 6.92
(1H, d, 7.27 (1H, d, J=8.7 Hz), 7.36 (1H, s), 7.53 dd, J=2.0 Hz,
8.4 Hz), 7.62 (1H, d, J=2.0 Hz), 8.08 (1H, dd, J=2.3 Hz, 8.7 Hz),
8.35 (1H, J=2.3 Hz).
NMR.sup.62) : Compound of Example 446
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.50 (3H, t, J=7.0 Hz), 1.52
(3H, t, J=7.0 Hz), 2.55 (3H, d, J=0.9 Hz), 4.04 (3H, s), 4.16 q,
J=7.0 Hz), 4.23 (2H, q, J=7.0 Hz), 6.50 (1H, d, J=1.0 Hz), 6.93
(1H, d, J=8.4 Hz), 7.45 (1H, s), 7.55 (1H, dd, J=2.1 Hz, 8.4 Hz),
7.64 (1H, d, J=2.1 Hz) 8.34 (1H, d, J=1.8 Hz), 8.42 (1H, d, J=1.8
Hz).
NMR.sup.63): Compound of Example 447
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.49 (3H, t, J=7.0 Hz), 1.51
(3H, t, J=7.0 Hz), 1.78 (3H, s), 3.54 (2H, s), 3.59 (3H, s), 4.16
(2H, q, J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 4.71 (1H, brs), 4.90
(1H, brs), 5.09 (2H, s), 5.51 (2H, s), 6.92 (1H, d, J=8.4 Hz), 7.40
(1H, s), 7.53 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.61 (1H, d, J=2.1 Hz),
7.98 (1H, d, J=2.4 Hz), 8.34 (1H, d, J=2.4 Hz).
NMR.sup.64) : Compound of Example 448
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.49 (3H, t, J=7.0 Hz), 1.51
(3H, t, J=7.0 Hz), 2.24 (3H, s), 3.56 (3H, s), 3.59 (3H, s), 3.95
(2H, S), 4.16 (2H, q, J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 5.09 (2H,
S), 5.50 (2H, S), 6.92 (1H, d, J=8.4 Hz), 7.42 (1H, S), 7.52 (1H,
dd, J=2.1 Hz, 8.4 Hz) 7.60 (1H, d, J=2.1 Hz), 8.01 (1H, d, J=2.3
Hz), 8.39 (1H, d, J=2.3 Hz).
NMR.sup.65) : Compound of Example 449
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.50 (3H, t, J=7.0 Hz), 1.51
(3H, t, J=7.0 Hz), 1.97 (3H, dd, J=1.6 Hz, 6.6 Hz), 3.58 (3H, s),
3.59 (3H, s), 4.16 (2H, q, J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 5.09
(2H, s), 5.50 (2H; s), 6.38 (1H, dd, J=15.9 Hz, 6.6 Hz), 6.83 (1H,
d, J=15.9 Hz), 6.93 (1H, d, J=8.4 Hz), 7.42 (1H, s), 7.55 (1H, dd,
J=2.1 Hz, 8.4 Hz), 7.61 (1H, d, J=2.1 Hz), 8.23 (1H, d, J=2.2 Hz),
8.27 (1H, d, J=2.2 Hz).
NMR.sup.66) : Compound of Example 450
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.16 (1.5H, d, J=6.3 Hz), 1.22
(1.5H, d, J=6.3 Hz), 1.43-1.57 (6H, m), 3.59 (3H, s), 3.62 (3H, s),
4.05-4.36 (4H, m), 5.07-5.28 (2H, m), 5.30 (2H, s), 5.50 (2H, s),
6.93 (1H, d, J=8.4 Hz), 7.45 (1H, s), 7.54 (1H, dd, J=2.1 Hz, 8.4
Hz), 7.61 (1H, d, J=2.1 Bz), 8.21 (0.5H, d, J=2.3 Hz), 8.32 (0.5H,
d, J=2.3 Hz), 8.48 (1H, m),
NMR.sup.67) : Compound of Example 467
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.49 (3H, t, J=7.0 Hz), 1.50
(3H, t, J=7.0 Hz), 3.49 (3H, s), 4.17 (2H, q, J=7.0 Hz), 4.19 q,
J=7.0 Hz), 5.28 (2H, s), 5.40 (2H, s), 6.91 (1H, d, J=8.4 Hz),
7.22-7.70 (9H, m), 8.08 (1H, dd, J=2.4 Hz, 8.7 Hz), 8.40 (1H, d,
J=2.4 Hz).
NMR.sup.68) : Compound of Example 470
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.44-1.67 (12H, m), 4.04 (3H,
s), 4.10-4.33 (8H, m), 6.92 (2H, d, J=8.4 Hz), 7.37 (1H, s), 7.46
(1H, s), 7.52-7.63 (3H, m), 7.66 (1H, d, J=2.0 Hz), 7.75 (2H, d,
J=8.4 Hz), 8.08 (2H, d, J=8.4 Hz), 8.20 (1H, d, J=2.2 Hz), 8.46
(1H, d, J=2.2 Hz), 11.43 (1H, s).
NMR.sup.69) : Compound of Example 471
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.50 (3H, t, J=7.0 Hz), 1.53
(3H, t, J=7.0 Hz), 2.42 (3H, s), 3.96 (3H, s), 4.17 (2H, q, J=7.0
Hz), 4.23 (2H, q, J=7.0 Hz), 6.94 (1H, d, J=8.4 Hz), 7.54 (1H, dd,
J=2.1 Hz, 8.4 Hz), 7.59 (1H, s), 7.60 (1H, d, J=2.1 Hz), 8.76 (1H,
d, J=2.3 Hz), 8.80 (1H, d, J=2.3 Hz).
NMR.sup.70) : Compound of Example 478
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.49 (3H, t, J=7.0 Hz), 1.51
(3H, t, J=7.0 Hz), 3.59 (3H, s), 3.59 (2H, d, J=6.3 Hz), 3.94 s),
4.16 (2H, q, J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 5.08 (2H, S),
5.07-5.17 (1H, m), 5.17-5.27 (1H, m), 5.96-6.16 (1H, m), 6.92 (1H,
d, J=8.4 Hz), 7.40 (1H, s), 7.54 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.60
(1H, d, J=2.1 Hz), 7.98 (1H, d, J=2.4 Hz), 8.27 (1H, d, J=2.4
Hz).
NMR.sup.71) : Compound of Example 479
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.48 (3H, t, J=7.0 Hz), 1.51
(3H, t, J=7.0 Hz), 3.55 (3H, s), 3.89 (2H, d, J=1.7 Hz), 3.94 (3H,
s), 4.15 (2H, q, J=7.0 Hz), 4.21 (2H, q, J=7.0 Hz), 5.09 (2H, s),
6.91 (1H, d, J=8.4 Hz), 7.43 (1H, s), 7.52 (1H, dd, J=2.1 Hz, 8.4
Hz), 7.59 (1H, d, J=2.1 Hz), 8.04 (1H, d, J=2.3 Hz), 8.36 (1H, d,
J=2.3 Hz), 9.79 (1H, t, J=1.7 Hz).
NMR.sup.72) : Compound of Example 480
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.50 (3H, t, J=7.0 Hz), 1.52
(3H, t, J=7.0 Hz), 3.60 (3H, s), 3.98 (3H, s), 4.16 (2H, q, J=7.0
Hz), 4.23 (2H, q, J=7.0 Hz), 5.22 (2H, s), 6.92 (1H, d, J=8.4 Hz),
7.50 (1H, s), 7.54 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.60 (1H, d, J=2.1
Hz), 8.57 (1H, d, J=2.5 Hz), 8.73 (1H, d, J=2.5 Hz), 10.50 (1H,
s).
NMR.sup.73) : Compound of Example 482
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.49 (1H, t, J=7.0 Hz), 1.51
(3H, t, J=7.0 Hz), 2.50 (3H, s), 3.60 (3H, s), 3.92 (2H, s), 3.94
(3H, s), 4.15 (2H, q, J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 5.12 (2H,
s), 6.92 (1H, d, J=8.4 Hz), 7.44 (1H, s), 7.54 (1H, dd, J=2.1 Hz,
8.4 Hz), 7.60 (1H, d, J=2.1 Hz), 8.13 (1H, d, J=2.4 Hz), 8.37 (1H,
d, J=2.4 Hz).
NMR.sup.74) : Compound of Example 483
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.50 (3H, t, J=7.0 Hz), 1.52
(3H, t, J=7.0 Hz), 2.41 (1H, t, J=6.6 Hz), 4.01 (3H, s), 4.16 (2H,
q, J=7.0 Hz), 4.23 (2H, q, J=7.0 Hz), 4.82 (2H, d, J=6.6 Hz), 6.93
(1H, d, J=8.4 Hz), 7.34 (1H, s), 7.55 (1H, dd, J=2.0 Hz, 8.4 Hz),
7.60 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=2.3 Hz), 8.40 (1H, d, J=2.3
Hz), 11.38 (1H, s).
NMR.sup.75) : Compound of Example 485
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.49 (3H, t, J=7.0 Hz), 1.51
(3H, t, J=7.0 Hz), 3.58 (3H, s), 3.95 (3H, s), 4.15 (2H, q, J=7.0
Hz), 4.22 (2H, q, J=7.0 Hz), 5.08 (2H, s), 5.43 (1H, dd, J=1.1 Hz,
11.1 Hz), 5.89 (1H, dd, J=1.1 Hz, 17.7 Hz), 6.92 (1H, d, J=8.4 Hz),
7.17 (1H, dd, J=11.1 Hz, 17.1 Hz), 7.43 (1H, s), 7.54 (1H, dd,
J=2.1 Hz, 8.4 Hz), 7.61 (1H, d, J=2.1 Hz), 8.27 (2H, d, J=1.3
Hz).
NMR.sup.76) : Compound of Example 486
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.49 (3H, t, J=7.0 Hz), 1.51
(3H, t, J=7.0 Hz), 3.58 (3H, s), 3.59 (3H, s), 4.15 (2H, q, J=7.0
Hz), 4.22 (2H, q, J=7.0 Hz), 5.10 (2H, s), 5.43 (1H, dd, J=1.1 Hz),
11.1 Hz), 5.51 (2H, s), 5.89 (1H, dd, J=1.1 Hz, 17.7 Hz), 6.92 (1H,
d, J=8.4 Hz), 7.18 (1H, dd, J=11.1 Hz, 17.7 Hz), 7.43 (1H, s), 7.54
(1H, dd, J=2.1 Hz, 8.4 Hz), 7.6 (1H, d, J=2.1 Hz), 8.29 (2H, d,
J=1.3 Hz).
NMR.sup.77) : Compound of Example 493
.sup.1 H-NMR (DMSO-d6) .delta.: 1.35 (3H, t, J=6.9 Hz), 1.37 (3H,
t, J=6.9 Hz), 2.72 (3H, s), 4.11 (4H, m), 7.09 (1H, d, J=9.0 Hz),
7.57 (1H, dd, J=2.2 Hz, 9.0 Hz), 7.60 (1H, d, J=2.2 Hz), 7.89 (1H,
brs), 8.22 brs), 8.44 (1H, s), 8.70 (1H, d, J=2.0 Hz), 9.27 (1H, d,
J=2.0 Hz).
NMR.sup.78) : Compound of Example 497
.sup.1 H-NMR (CDCl.sub.3) .delta.: 0.24 (6H, s), 1.03 (9H, s), 1.49
(3H, t, J=7.0 Hz), 1.51 (3H, t, J=7.0 Hz), 3.91 (3H, s), 4.15 (2H,
q, J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 6.91 (1H, d, J=8.3 Hz), 6.95
(1H, d, J=8.5 Hz), 7.34 (1H, s), 7.51 (1H, dd, J=2.0 Hz, 8.3 Hz),
7.62 (1H, d, J=2.0 Hz), 8.03 (1H, dd, J=2.4 Hz, 8.5 Hz), 8.34 (1H,
d, J=2.4 Hz).
NMR.sup.79) : Compound of Example 500
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.49 (3H, t, J=7.0 Hz), 1.51
(3H, t, J=7.0 Hz), 2.91 (6H, S), 3.94 (3H, S), 4.15 (2H, q, J=7.0
Hz), 4.22 (2H, q, J=7.0 Hz), 6.91 (1H, d, J=8.4 Hz), 6.99 (1H, d,
J=8.8 Hz), 7.28 (1H, s), 7.52 (1H, dd, J=2.0 Hz, 8.4 Hz), 7.62 (1H,
d, J=2.0 Hz), 7.97 (1H, dd, J=2.2 Ez, 8.8 Hz), 8.25 (1H, d, J=2.2
Hz).
NMR.sup.88) : Compound of Example 507
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.49 (3H, t, J=7.0 Hz), 1.51
(3H, t, J=6.9 Hz), 2.63 (3H, s), 4.10-4.27 (4H, m), 6.89 (1H, d,
J=8.4 Hz), 7.48 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.59-7.64 (3H, m), 7.74
(1H, s), 8.53 (1H, d, J=5.2 Hz).
NMR.sup.81) : Compound of Example 508
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.45 (3H, t, J=7.0 Hz), 1.49
(3H, t, J=7.0 Hz), 4.09 (2H, q, J=7.0 Hz), 4.17 (2H, q, J=7.0 Hz),
6.89 (1H, d, J=8.4 Hz), 7.25-7.32 (1H, m), 7.42-7.46 (2H, m), 7.49
(1H, dd, J=2.2 Hz, 8.4 Hz), 7.61 (1H, d, J=2.2 Hz), 7.81 (1H, s),
8.08-8.15 (3H, m), 8.57 (1H, dd, J=0.6 Hz, 5.0 Hz), 9.20 (1H, dd,
J=0.6 Hz, 1.5 Hz), 12.11 (1H, brs).
NMR.sup.82) : Compound of Example 509
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.47 (3H, t, J=7.0 Hz), 1.50
(3H, t, J=7.0 Hz), 3.81 (3H, s), 4.10-4.24 (4H, m), 6.93 (1H, d,
J=8.4 Hz), 7.46-7.55 (3H, m), 8.00 (1H, dd, J=1.6 Hz, 7.8 Hz), 8.21
(1H, s), 8.74-8.76 (1H, m).
Example 521
The following compounds were obtained in the same procedures as in
Examples 1 and 147, by using respective starting materials.
5-Ethoxycarbonyl-2-(.alpha.-bromoacetyl)pyrazine and
3,4-diethoxythiobenzamide were subjected to the same reaction as in
Example 1 and then to the same hydrolysis as in Example 147 to
obtain 2-(3,4-diethoxyphenyl)-4-)5-carboxy-2-pyrazyl)thiazole.
4-Ethoxycarbonyl-2-(.alpha.-bromoacetyl)pyrimidine and
3,4-diethoxythiobenzamide were subjected to the same reaction as in
Example 1 and then to the same hydrolysis as in Example 147 to
obtain
2-(3,4-diethoxyphenyl)-4-)4-carboxy-2-pyrimidyl)thiazole.
5-Ethoxycarbonyl-2-(.alpha.-bromoacetyl)pyrimidine and
3,4-diethoxythiobenzamide were subjected to the same reaction as in
Example 1 and then to the same hydrolysis as in Example 147 to
obtain
2-(3,4-diethoxyphenyl)-4-(5-carboxy-2-pyrimidyl)thiazole.
6-Ethoxycarbonyl-2-(.alpha.-bromoacetyl)pyrazine and
3,4-diethoxythiobenzamide were subjected to the same reaction as in
Example 1 and then to the same hydrolysis as in Example 147 to
obtain 2-(3,4-diethoxyphenyl)-4-(6-carboxy-2-pyrazyl)thiazole.
4-Ethoxycarbonyl-2-(.alpha.-bromoacetyl)pyrrole and
3,4-diethoxythiobenzamide were subjected to the same reaction as in
Example 1 and then to the same hydrolysis as in Example 147 to
obtain 2-(3,4-diethoxyphenyl)-4-(4-carboxy-2-pyrrolyl)thiazole.
4-Ethoxycarbonyl-2-(60-bromoacetyl)furan and
3,4-diethoxythiobenzamide were subjected to the same reaction as in
Example 1 and then to the same hydrolysis as in Example 147 to
obtain
2-(3,4-diethoxythiophenyl)-4-(4-carboxy-2-furyl)thiazole.
5-Ethoxycarbonyl-3-(.alpha.-bromoacetyl)furan and
3,4-diethoxythiobenzamide were subjected to the same reaction as in
Example 1 and then to the same hydrolysis as in Example 147 to
obtain 2-(3,4-diethoxyphenyl)-4-(5-carboxy-3-furyl)thiazole.
4-Ethoxycarbonyl-2-(60-bromoacetyl)thiophene and
3,4-diethoxythiobenzamide were subjected to the same reaction as in
Example 1 and then to the same hydrolysis as in Example 147 to
obtain 2-(3,4-diethoxyphenyl)-4-(4-carboxy-3-thienyl)thiazole.
5-Ethoxycarbonyl-3-(.alpha.-bromoacetyl)thiophene and
3,4-diethoxythiobenzamide were subjected to the same reaction as in
Example 1 and then to the same hydrolysis as in Example 147 to
obtain 2-(3,4-diethoxyphenyl)-4-(5-carboxy-3-thienyl)thiazole.
5-Ethoxycarbonyl-2-(.alpha.-bromoacetyl)thiazole and
3,4-diethoxythiobenzamide were subjected to the same reaction as in
Example 1 and then to the same hydrolysis as in Example 147 to
obtain
2-(3,4-diethoxyphenyl)-4-(5-carboxy-2-thiazolyl)thiazole.
Preparation Example 1
2-(3,4-Dimethoxyphenyl)-4-(3,4- 5 mg
dihydroxycarbostyril-6-yl)thiazole Starch 132 mg Magnesium stearate
18 mg Lactose 45 mg Total 200 mg
Tablets each containing the above components in the above amounts
were produced according to an ordinary method.
Preparation Example 2
2-(3,4-Dimethoxyphenyl)-4-(2-oxo- 500 mg benzoxazol-5-yl)thiazole
Polyethylene glycol (m.w.: 4000) 0.3 g Sodium chloride 0.9 g
Polyoxyethylene sorbitan monoleate 0.4 g Sodium metabisulfite 0.1 g
Methylparaben 0.18 g Proypylparaben 0.02 g Distilled water for
injection 100 ml
The above parabens, sodium metabisulfite and sodium chloride were
dissolved in the above distilled water with stirring at 80.degree.
C. The solution was cooled to 40.degree. C. Therein were dissolved
the present compound, the polyethylene glycol and the
polyoxyethylene sorbitan monoleate in this order. To the solution
was added the distilled water for injection to obtain a desired
final volume. The resulting solution was filtered through an
appropriate filter paper and sterilized. 1 ml of the thus prepared
solution was filled into each ampul to prepare an injection.
PHARMACOLOGICAL TESTS
The pharmacological tests for present compounds were conducted
according to the following methods.
(1) Activity for inhibiting the generation of superoxide radical
(O.sub.2.sup.-) in human neutrophilic leukocytes
Human neutrophilic leukocytes were prepared in accordance with the
method of M. Market et al. (Methods in Enzymology, vol. 105; pp.
358-365, 1984). That is, a whole blood obtained from a healthy
adult and treated by anticoagulation method was subjected to a
dextranhypotonic treatment to obtain leukocyte cells. The leukocyte
cells were then subjected to a density gradient ultracentrifugation
by Ficoll-Paque to obtain a neutrophilic leukocyte fraction.
O.sub.2.sup.- generation was examined by the ferricytochrome C
method in accordance with the method of B. N. Cronstein et al.
[Journal of Experimental Medicine, vol. 158, pp. 1160-1177 (1983)].
That is, 1.times.10.sup.-6 cell of neutrophilic leukocytes were
stimulated with 3.times.10.sup.-7 M of
N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) at 37.degree.
C. in the presence of 1.3 mg/ml of ferricytochrome C and 5 .mu.g/ml
of cytochalasin B in a Hepes-buffered Hank's solution (pH 7.4); the
amount of ferrocytochrome C formed by 4 minutes of reduction was
determined by measuring an absorbance at a wavelength of 550 nm
using a spectrophotometer; an absorbance in the presence of 25.1
.mu.g/ml of superoxide dismutase (SOD) was also measured; the
difference of the two absorbances was taken as the amount of
superoxide radical (O.sub.2.sup.-) generated. Each test compound
was dissolved in dimethyl sulfoxide (DMSO); the solution was added
to neutrophilic leukocytes before the addition of FMLP; then, the
neutrophilic leukocytes were pre-incubated at 37.degree. C. By
using the amount of superoxide radical (O.sub.2.sup.-) generated
when the test compound solution was added and the amount of
superoxide radical (O.sub.2.sup.-) generated when only the solvent
(DMSO) was added, a ratio of inhibition (%) was calculated, and the
activity for inhibiting superoxide radical (O.sub.2.sup.-)
generation was expressed as 50% inhibitory concentration
(IC.sub.50).
TEST COMPOUNDS
1. 2-(3-Pyridyl)-4-phenylthiazole-1/4 ferous chloride salt
2. 2-(3,4-Dimethoxyphenyl)-4-phenylthiazole
3. 2,4-Di(3-pyridyl)thiazole
4. 2-(3-pyridyl)-4-methyl-5-ethoxycarbonylthiazole
hydrochloride
5.
2-(2,4-Dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole
6. 2-(2-Pyridon-3-yl)-4-phenylthiazole
7.
2-(3,4-Dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole
8. 2-(3,4-Dimethoxyphenyl)-4-(3,4-dihydroxyphenyl)-thiazole
hydrochloride
9. 2-(4-Pyridyl)-4-(3,4-dihydroxyphenyl)thiazole hydrochloride
10. 2-(3-Thienyl)-4-(3,4-dihydroxyphenyl)thiazole
11. 2-(2-Thfenyl)-4-(3,4-dihyroxyphenyl)thiazole
12.
2-(4-Oxo-1,4-dihydroquinolin-3-yl)-4-(3,4-dihydroxyphenyl)thiazole
13. 2-(Pyrazin-2-yl)-4-(3,4-dihydroxyphenyl)thiazole
14. 2-(3,4-Dihydroxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole
hydrobromide
15. 2-(Carbostyril-3-yl)-4-(3,4-dihydroxyphenyl)-thiazole
16. 2-(Pyrrol-2-yl)-4-(3,4-dihydroxyphenyl)thiazole
17.
2-(3,4-Dimethoxyphenyl)-4-(4-methyl-2H-1,4-benzothiazin-3(4H)-on-6-yl)thia
zole
18.
2-(3,4-Dimethoxyphenyl)-4-(3-hydroxy-4-pentyloxyphenyl)-thiazole
19. 2-(3,4-Dimethoxyphenyl)-4-(4-methylsulfonylphenyl)thiazole
20. 2-Phenyl-4-)3,4-dihydroxyphenyl)thiazole hydrochloride
21. 2-(3,4,5-Trimethoxyphenyl)-4-(3,4-dihydroxyphenyl)-thiazole
hydrochloride
22.
2-(3,4-Methylenedioxyphenyl)-4-(3,4-dihydroxyphenyl)-thiazole
23. 2-(3,4-Dimethoxyphenyl)-4-(carbostyril-6-yl)-thiazole
24.
2-(3,4-Dimethoxyphenyl)-4-(7-hydroxy-3,4-dihyrocarbostyril-6-yl)thiazole
25. 2-(3,4-Dimethoxyphenyl)-4-(2-oxyindol-5-yl)thiazole
26.
2-(3,4-Dihydrocarbostyril-6-yl)-4-(3,4-dihydroxyphenyl)-thiazole
hydrochloride
27.
1-(3,4-Dimethoxyphenyt)-4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)thiazo
le
28.
2-(3,4)-Dimethoxyphenyl)-4-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)thiazole
hydrochloride
29. 2-(3,4-Dimethoxyphenyl)-4-(2-oxobenzimidazole-5-yl)thiazole
30.
2-(3,4-Dimethoxyphenyl)-4-(3-oxo-4-methyl-3,4-dihydro-2H-2,4-benzoxazin-6-
yl)thiazole
31.
2-(3,4-Dimethoxyphenyl)-4-(10-acetylphenothiazin-2-yl)thiazole
32. 2,4-Di(3,4-dimethoxyphenyl)thiazole
33.
2-(3,4-Dimethoxyphenyl)-4-(3-acetylamino-4-hydroxyphenyl)-thiazole
34.
2-(3,4-Dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-7-yl)thiazole
35. 2-(3,4-Dimethoxyphenyl)-4-(2-oxobenzothiazole-6-yl)thiazole
36. 2-(3,4-Dimethoxyphenyl)-4-(2-oxobenzoxazol-5-yl)thiazole
37. 2-(3,4-Dimethoxyphenyl)-4-(3-amino-4-hydroxyphenyl)thiazole
dihydrochloride
38.
2-(3,4-Dimethoxyphenyl)-4-(1-methyl-3,4-dihydrocarbo-styril-7-yl)thiazole
39. 2-(3,4-Dimethoxyphenyl)-4-(3,5-dihydroxyphenyl)-thiazole
40. 2-(3,4-Dimethoxyphenyl)-4-(2,5-dihydroxyphenyl)-thiazole
41. 2-(3,4-Dimethoxyphenyl)-4-(2,6-dihydroxyphenyl)-thiazole
42.
2-(3,4-Dimethoxyphenyl)-4-(2-oxo-3-methylbenzothiazol-6-yl)thiazole
43.
2-(3,4-Dimethoxyphenyl)-4-(3-nitro-4-acetylaminophenyl)thiazole
44.
2-(3,4-Dimethoxyphenyl)-4-(1,3-dimethyl-2-oxobenzimidazol-5-yl)thiazole
45. 2-(3,4-Dimethoxyphenyl)-4-(2,4-dihydroxyphenyl)-thiazole
46. 2-(3,4-Dimethoxyphenyl)-4-(3-nitro-4-chlorophenyl)-thiazole
47.
2-(3,4-Dimethoxyphenyl)-5-(3,4-dihydrocarbostyril-6-yl)thiazole
48. 2-(3,4-Dimethoxyphenyl)-4-(3,4-diacetylaminophenyl)thiazole
49.
2-(3,4-Dimethoxyphenyl)-4-(2-oxo-3-methylbenzoxazol-5-yl)thiazole
50. 2-(3,4-Dimethoxyphenyl)-4-(3-nitrophenyl)thiazole
51.
2-(3,4-Dimethoxyphenyl)-4-(3,5-diamino-4-hydroxyphenyl)thiazole
52.
2-(3,4-Dimethoxyphenyl)-4-(3,5-dinitro-4-hydroxyphenyl)thiazole
53.
2-(3-Methoxy-4-methylthiophenyl)-4-(3,4-dihydrocarbo-styril-6-yl)thiazole
54.
2-(3-Methoxy-4-methylsulfinylphenyl)-4-(3,4-dihydrocarbo-styril-6-yl)thiaz
ole
55. 2-(3,4-Dimethoxyphenyl)-4-(2-oxobenzoxazol-6-yl)thiazole
56. 2-(3-Pyridyl)-4-(4-fluorophenyl)thiazole-1/3 FeCl.sub.2
salt
57.
2-(3,4-Dimethoxyphenyl)-4-(2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-6-yl)th
iazole
58.
2-(3,4-Dimethoxybenzoyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole
59.
2-(3,4-Diethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole
60. 2-(3,4-Dimethoxyphenyl)-4-(2-pyridyl)thiazole hydrochloride
61. 4-(3,5-Dihydroxyphenyl)-2-(3,4-diethoxyphenyl)-thiazole
62.
4-(3-Carboxy-4-hydroxyphenyl)-2-(3,4-diethoxy-phenyl)thiazole
63.
4-(4-Hydroxysulfonyloxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole
64. 4-(4-Hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole
65.
4-(3-Acetylamino-4-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole
66. 4-(4-Hydroxy-3-aminophenyl)-2-(3,4-diethoxyphenyl)thiazole
dihydrochloride
67. 4-(4-Cyanophenyl)-2-(3,4-diethoxyphenyl)thiazole
68.
4-(3,4-Dihydrocarbostyril-6-yl)-2-(4-methoxy-3-propoxy-phenyl)thiazole
69. 4-(4-Amidinophenyl)-2-(3,4-diethoxyphenyl)thiazole
hydrochloride
70. 4-(2,4,6-Trihydroxyphenyl)-2-(3,4-dimethoxyphenyl) thiazole
71. 4-(3,5-Diaminophenyl)-2-(3,4-dimethoxyphenyl) thiazole
dihydrochloride
72. 4-(4-Aminophenyl)-2-(3,4-diethoxyphenyl)thiazole
hydrochloride
73.
4-[1-Hydroxy-1-(3,4-dimethoxyphenyl)methyl]-2-(3,4-diethoxyphenyl)thiazole
74.
4-[4-Methoxy-3-(4-ethyl-1-piperazinyl)phenyl]-2-(3,4-dihydroxyphenyl)thiaz
ole trihydrochloride
75. 4-(4-Chlorophenyl)-2-(3,4-diethoxyphenyl)thiazole
76. 4-(3,4-Diacetyloxyphenyl)-2-(3-pyridyl)thiazole
77. Methyl
4-[2-(3,4-dimethoxyphenyl)thiazole-4-yl]phenyl-.beta.-D-glucopyranosidouro
nate
78.
2-(3,4-Diethoxyphenyl)-4-[4-(2,3,4,6-tetra-0-acetyl-.beta.-D-glucopyranosy
loxy)phenyl]thiazole
79. 4-(3,5-Diacetyloxyphenyl)-2-(3,4-diethoxyphenyl) thiazole
80.
4-(4-Hydroxy-3-methoxycarbonylphenyl)-2-(3,4-diethoxyphenyl)thiazole
81.
4-(4-Methoxycarbonylmethoxy-3-methoxycarbonylphenyl)-2-(3,4-diethoxyphenyl
)thiazole
82.
4-(4-Hydroxy-3-carbamoylphenyl)-2-(3,4-diethoxyphenyl)thiazole
83.
4-(3-Carboxy-4-hydroxy-5-allylphenyl)-2-(3,4-diethoxyphenyl)thiazole
84.
4-{3-Carboxy-4-hydroxy-5-(2-methyl-2-propenyl)-phenyl}-2-(3,4-diethoxyphen
yl)thiazole
85.
4-(3-Carboxy-4-hydroxy-5-methylphenyl)-2-(3,4-diethoxyphenyl)thiazole
86.
4-(3-Methoxycarbonyl-4-hydroxyphenyl)-2-(3-methoxy-4-ethoxyphenyl)thiazole
87. 4-(3-Carboxyphenyl)-2-(3,4-diethoxyphenyl)thiazole
88.
4-(3-Carboxy-4-hydroxyphenyl)-2-(3-methoxy-4-ethoxyphenyl)thiazole
89.
4-(3-Amino-4-hydroxy-5-methoxycarbonylphenyl)-2-(3,4-diethoxyphenyl)thiazo
le
90.
4-(3-Carboxy-4-hydroxy-5-propylphenyl)-2-(3,4-diethoxyphenyl(thiazole
91.
4-(3-Carboxy-6-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole
92.
4-(3-Carboxy-4-hydroxyphenyl)-2-(3-ethoxy-4-methoxyphenyl)thiazole
93.
4-(3-Carboxy-4-hydroxy-5-isobutylphenyl)-2-(3,4-diethoxyphenyl)thiazole
94.
3-{3-Carboxy-4-hydroxy-5-(2-hydroxyethyl)phenyl}-2-(3,4-diethoxyphenyl)thi
azole
95.
4-(3-Carboxy-4-amino-6-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole
96. 4-(3-Carboxy-4-aminophenyl)-2-(3,4-diethoxyphenyl)-thiazole
97.
4-(3-Carboxy-4-acetyloxyphenyl)-2-(3,4-diethoxyphenyl)-2-(3,4-diethoxyphen
yl)thiazole
98. 4-(3-Ethyl-4-hydroxyphenyl)-2-(3,4-Diethoxyphenyl)thiazole
99.
4-(3-Carboxy-4-hydroxyphenyl)-2-(3,4-diethoxyphenyl)-5-methylthiazole
100.
4-(3-Carboxy-4,6-dihydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole
101.
4-(3-Methoxycarbonyl-5-nitro-6-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazo
le
102.
4-(3-Methoxycarbonyl-5-amino-6-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazo
le
103.
4-(3-Carboxy-5-allyl-6-hydroxyphenyl)-2-(3,4-diethoxy-phenyl)thiazole
104.
4-(3-Carboxy-6-hydroxyphenyl)-2-(3-ethoxy-4-methoxy-phenyl)thiazole
105. 4-(3-Carboxy-4-hydroxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole
(a compound mentioned in Example 3 of Japanese Patent Publication
No. 15935/1971)
106. 4-(3-Carboxy-4-hydroxyphenyl)-2-phenylthiazole (a compound
mentioned in Example 2 of Japanese Patent Publication No.
15935/1971)
107. 4-(3-Carboxy-4-methoxyphenyl)-2-phenylthiazole (a compound
mentioned in Example 4 of Japanese Patent Publication No.
15935/1971)
108. 4-(3-Carboxy-4-methoxyphenyl)-2-benzylthiazole (a compound
mentioned in Example 9 of Japanese Patent Publication No.
15936/1971)
109. 4-(3-Carboxyphenyl)-2-(4-chlorophenyl)thiazole (a compound
included in Japanese Patent Publication No. 15935/1971)
110. 4-(3-Carboxy-5-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole
(a compound included in Japanese Patent Publication No.
15935/1971)
111. 4-(3-Carboxy-4-hydroxyphenyl)-2-(3,4-dibutoxyphenyl)thiazole
(a compound included in Japanese Patent Publication No.
15953/1971)
112. 4-(3-Carboxy-6-methoxyphenyl)-2-(3,4-diethoxyphenyl)thiazole
(a compound included in Japanese Patent Publication No.
15953/1971)
113.
4-(2-Hydroxy-3-amino-5-carboxyphenyl)-2-(3,4-diethoxy-phenyl)thiazole
hydrochloride
114.
4-(2-Hydroxy-3-propyl-5-carboxyphenyl)-2-(3,4-diethoxy-phenyl)thiazole
115. 4-(6-Carboxy-2-pyridyl)-2-(3,4-diethoxyphenyl)-thiazole
116. 2-(3,4-Diethoxyphenyl)-4-phenylthiazole
117.
2-(3,4-Diethoxyphenyl)-4-{3-methoxycarbonyl-4-[2-(1-piperidinyl)ethylamino
]phenyl}thiazole dihydrochloride
118.
2-(3,4-Diethoxyphenyl)-4-[4-hydroxy-3-(2-dimethylaminoethoxycarbonyl)pheny
l]thiazole trihydrochloride
119. 2-(3,4-Diethoxyphenyl)-4-(2-carboxy-5-pyrrolyl)-thiazole
120.
2-(3,4-Diethoxyphenyl)-4-(4-hydroxy-3-n-nonyloxy-carbonylphenyl)thiazole
121.
2-(3,4-Diethoxyphenyl)-4-(2-methoxycarbonyl-5-furyl)thiazole
122. 2-(3,4-Diethoxyphenyl)-4-(2-carboxy-5-furyl)-thiazole
123.
2-(3,4-Diethoxyphenyl)-4-(2-dimethylaminocarbonyl-6-pyridyl)thiazole
124.
2-(3,4-Diethoxyphenyl)-4-(2-acetyl-1-pyrrolyl)-methylthiazole
125.
2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-methoxyphenyl(thiazole
126.
2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-ethylphenyl)thiazole
127.
2-(3,4-Diethoxyphenyl)-4-(2-hydroxymethyl-6-pyrrolidyl)thiazole
128. 2-(3,4-Diethoxyphenyl)-4-[2-(4-methyl-1-piperazinyl)
carbonyl)-6-pyridyl]thiazole
129. 2-(3,4-Diethoxyphenyl)-4-(2-carboxy-5-thienyl)-thiazole
130.
2-(3,4-Diethoxyphenyl)-4-(2-methyl-7-carboxy-5-benzofuryl)thiazole
131.
2-(3,4-Diethoxyphenyl)-4-(4-ethoxycarbonyl-2-thiazolyl)thiazole
132. 2-(3,4-Diethoxyphenyl)-4-(4-carboxy-2-thiazolyl)-thiazole
133.
2-(3,4-Diethoxyphenyl)-4-(4-hydroxy-3-hydroxymethylphenyl)thiazole
134.
2-(3,4-Diethoxyphenyl)-4-(4-ethoxy-3-carboxyphenyl)thiazole
135. 2-(3,4-Diethoxyphenyl)-4-(3-carboxy-5-pyridyl)-thiazole
hydrochloride
136.
2-(3,4-Diethoxyphenyl)-4-(3-n-butoxycarbonyl-4-n-butoxyphenyl)thiazole
137.
2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-n-butoxyphenyl)thiazole
138.
2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-n-propoxyphenyl)thiazole
139.
2-(3,4-Diethoxyphenyl)-4-(2,2-dimethyl-7-carboxy-2,3-dihydrobenzofuran-5-y
l)thiazole
140.
2-(3,4-Diethoxyphenyl)-4-[3-carboxy-4-hydroxy-5-(1-propenyl)phenyl]thiazol
e
141.
2-(3,4-Diethoxyphenyl)-4-(2-methyl-3-carboxy-5-pyridyl)thiazole
142.
2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-formylphenyl)thiazole
143. 2-(3,4-Diethoxyphenyl)-4-(3-carboxy-6-pyridyl)-thiazole
144. 2-(3,4-Diethoxyphenyl)-4-(2-carboxy-5-pyridyl)-thiazole
145.
2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-bromophenyl)thiazole
146.
2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-dimethylaminophenyl)thiazole
147.
2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-vinylphenyl)thiazole
The results are shown in Table 15. In Table are shown the results
of the comparative test between present compounds (test compounds
Nos. 62, 87, 88, 91, 92 and 104) and prior art compounds.
TABLE 15 Test compound IC.sub.50 (No.) (.mu.M) 1 1 2 0.08 3 1 4 0.5
5 0.3 6 0.7 7 0.3 8 0.05 9 0.5 10 0.4 11 0.3 12 1 13 0.4 14 1 15
0.3 16 0.5 17 0.3 18 1 19 0.5 20 0.4 21 0.5 22 0.3 23 0.4 24 0.3 25
1 26 0.8 27 1 28 1 29 0.07 30 0.05 31 0.1 32 0.08 33 0.04 34 1 35
0.05 36 0.03 37 0.07 38 0.5 39 0.01 40 0.03 41 0.2 42 0.08 43 0.4
44 0.04 45 0.3 46 1 47 1 48 1 49 0.07 50 0.4 51 0.03 52 0.2 53 0.4
54 0.8 55 0.07 56 1 57 0.3 58 1.0 59 0.08 60 0.05 61 0.003 62 0.01
63 0.03 64 0.04 65 0.06 66 0.06 67 0.07 68 0.08 69 0.1 70 0.2 71
0.2 72 0.2 73 0.2 74 0.3 75 0.6 76 0.6 77 0.8 78 1 79 0.0013 80
0.01 81 0.026 82 0.06 83 0.04 84 0.02 85 0.08 86 0.033 87 0.0048 88
0.1 89 0.007 90 0.008 91 0.023 82 0.02 93 0.012 94 0.18 95 0.0087
96 0.023 97 0.1 98 0.083 99 0.72 100 0.048 101 0.01 102 0.069 103
0.094 104 0.034 113 0.025 114 0.1 115 0.08 116 0.37 117 0.46 118
0.56 119 0.024 120 0.49 121 0.038 122 0.019 123 0.38 124 0.12 125
0.19 126 0.014 127 0.02 128 0.58 129 0.082 130 0.24 131 0.19 132
0.05 133 0.0092 134 0.13 135 0.035 136 0.13 137 0.11 138 0.14 139
0.1 140 0.0047 141 0.094 142 0.12 143 0.27 144 0.035 145 0.11 146
0.11 147 0.01
TABLE 16 Test compound IC.sub.50 (No.) (.mu.M) Present compound 62
0.01 87 0.0048 88 0.1 91 0.023 92 0.02 104 0.034 Prior art compound
105 1.0 106 NE 107 NE 108 NE 109 NE 110 0.66 111 8.3 112 8.7 NE:
Abbreviation of "not effective"
(2) Activity for inhibiting the generation of ventricular
arrhythmia in rat heart when the coronary artery was closed and
then blood was reperfused
There were used male rats of Spaque Dawley (SD) strain (7-10 week
old, body weight: 250-350 g). Each test compound was administered
at a dose of 33 .mu.l/kg in a form dissolved in a physiological
saline solution. Each rat was anesthesized with pentobarbital and
thoracotomized under artificial respiration; the descending branch
before left coronary artery was ligated with a piece of silk string
for 10 minutes; then, the blood was reperfused and observation was
made for 10 minutes. The incidence of ventricular arrhythmia was
examined using a standard four-legs secondary induced cardiograph.
A test compound was intravenously administered at a dose of 1 mg/kg
5 minutes before the ligature of the coronary artery.
The results on the test compound-administered group and the
physiological saline solution-administered group as a control are
shown in Table 17.
TABLE 17 Duration of Test ventricular fibrillation when compound
blood reperfused (sec) Motality (%) No. 37 16.6 20 Control group
89.9 60 (physiological saline solution)
(3) Activity for inhibiting the renal disturbances appearing when
kidney was in ischemia and then blood was reperfused
In this test were used male rats of SD strain (body weight: about
250 g) which had been fasted for 18 hours. Each test compound was
administered at a dose of 1 ml/kg of body weight, in a 20% or 40%
solution dissolved in DMF. The right kidney of each rat was
enucleated; the artery blood circulation in the left kidney was
shut down for 60 minutes; then, the blood was reperfused. Each test
compound was intravenously administered at a dose of 3 mg/kg 15
minutes before reperfusion, and blood drawing was made from each
rat 24 hours and 4 hours after reperfusion to measure blood plasma
creatinine (mg/100 ml) using a cratinine test kit manufactured by
Wako Pure Chemical Industries, Ltd. and calculate "Mean.+-.S.E."
therefrom.
The results are shown in Table 18.
TABLE 18 Test compound 24 hours 48 hours Control (20% DMF) 3.64
.+-. 0.44 3.37 .+-. 0.77 No. 8 2.21 .+-. 0.19 2.04 .+-. 0.40
Control (40% DMF) 3.30 .+-. 0.38 3.37 .+-. 0.72 No. 33 2.63 .+-.
0.47 1.76 .+-. 0.18
1 (4) Activity for inhibiting the heart muscle necrosis in rat
caused by clogging of the coronary artery and subsequent blood
reperfusion
Male rats of SD strain (7-10 week old, 250-350 g) were used in this
test. The activity of creatine phosphokinase (CPK) in tissue was
used as an indication of heart muscle necrosis.
A test compound was dissolved in a small amount of 1N aqueous NaOH
solution, then diluted with a physiological saline solution, and
administered at a dose of 1 ml/kg of body weight. Each rat was
anesthetized with pentobarbital and thoracotomized under artifical
respiration; the descending branch before left coronary artery was
ligated with a piece of silk string for 12 minutes; then, the blood
was reperfused. Thereafter, the thoracotomized chest was closed and
the rat was waken from anesthesia. 2 hours after reperfusion, the
heart was enucleated under anesthesia; only the ischemic area was
homogenized; and the activity of CPK contained therein was
measured. The test compound was intravenously administered at a
dose of 6 mg/kg 5 mintues before ligature of the coronary
artery.
The results on the NaOH/physiological saline solution-administered
group as a control and the compound-administered group are shown in
Table 19.
TABLE 19 Activity of creatine phosphokinase in tissue (U/mg of
protein) n Mean .+-. S.E. Control group 14.86 .+-. 0.89 Test
compound No. 62 19.53 .+-. 1.56* *: p < 0.05 2-way ANOVA
ANALYSIS (comparison with control group) n: Number of tests
The reduction in CPK activity in tissue was inhibited
significantly. Hence, it is considered that the present compound
inhibited the disturbances of cell functions in heart caused by
ischemia and subsequent reperfusion.
* * * * *