U.S. patent application number 09/800988 was filed with the patent office on 2002-01-17 for tricyclic compounds, their production and use.
Invention is credited to Ohkawa, Shigenori, Setoh, Masaki, Terashita, Zen-ichi.
Application Number | 20020006944 09/800988 |
Document ID | / |
Family ID | 17243906 |
Filed Date | 2002-01-17 |
United States Patent
Application |
20020006944 |
Kind Code |
A1 |
Ohkawa, Shigenori ; et
al. |
January 17, 2002 |
Tricyclic compounds, their production and use
Abstract
A compound of the formula: 1 wherein R.sup.1 is H or a
substituent; m is 1-3; Ar is an aromatic group which may be
substituted; X is a bond or a divalent straight-chain group having
1-6 atoms which may be substituted; Y is --S--, --O--, or
--N(R.sup.2)-- (R.sup.2 is H or a substituent group), Z is --N.dbd.
or --C(R.sup.3).dbd. (R.sup.3 is H or a hydrocarbon group), ring A
is a benzene ring; ring B is a 5- to 7-membered ring which may be
substituted, or a salt thereof is useful for eliciting a
prostaglandin I.sub.2 receptor agonistic effect.
Inventors: |
Ohkawa, Shigenori; (Osaka,
JP) ; Setoh, Masaki; (Osaka, JP) ; Terashita,
Zen-ichi; (Osaka, JP) |
Correspondence
Address: |
TAKEDA PHARMACEUTICALS NORTH AMERICA, INC
INTELLECTUAL PROPERTY DEPARTMENT
475 HALF DAY ROAD
SUITE 500
LINCOLNSHIRE
IL
60069
US
|
Family ID: |
17243906 |
Appl. No.: |
09/800988 |
Filed: |
March 7, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09800988 |
Mar 7, 2001 |
|
|
|
09254446 |
Mar 9, 1999 |
|
|
|
6248766 |
|
|
|
|
09254446 |
Mar 9, 1999 |
|
|
|
PCT/JP97/03384 |
Sep 24, 1997 |
|
|
|
Current U.S.
Class: |
514/375 ;
514/394; 514/411; 514/443; 514/468; 548/150; 548/217; 548/302.1;
548/427; 549/43; 549/458 |
Current CPC
Class: |
C07D 277/60 20130101;
C07D 513/04 20130101; C07D 277/84 20130101 |
Class at
Publication: |
514/375 ;
514/394; 514/468; 514/443; 514/411; 548/217; 548/150; 548/302.1;
548/427; 549/43; 549/458 |
International
Class: |
C07D 333/74; C07D 37/92;
C07D 277/84 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 25, 1996 |
JP |
8-252912 |
Claims
1. A compound of the formula: 122wherein R.sup.1 represents
hydrogen or a substituent group; m represents an integer of 1 to 3;
Ar represents an aromatic group which may be substituted; X
represents a bond or a divalent straight-chain group which have 1
to 6 atoms and may be substituted; Y represents --S--, --O-- or
--N(R.sup.2)-- wherein R.sup.2 represents hydrogen or a substituent
group; Z represents --N.dbd. or --C(R.sup.3).dbd. wherein R.sup.3
represents hydrogen or a hydrocarbon group; ring A represents a
benzene ring which may be substituted by a substituent in addition
to a group of the formula: --O(CH.sub.2).sub.mCOR.sup.1 wherein the
respective symbols have the same meanings as defined above; and
ring B represents a 5- to 7-membered ring which may be substituted,
or a salt thereof.
2. A compound according to claim 1 wherein R.sup.1 is (i) hydrogen,
(ii) a hydroxy which may be substituted by a C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.6-14 aryl or C.sub.7-16 aralkyl group, each of which may be
substituted by 1 to 5 substituents selected from the group
consisting of halogen, C.sub.1-6 alkyl which may be halogenated,
C.sub.2-6 alkenyl which may be halogenated, C.sub.2-6 alkynyl which
may be halogenated, C.sub.3-6 cycloalkyl which may be halogenated,
C.sub.6-10 aryl, C.sub.7-11 aralkyl, C.sub.1-6 alkoxy which may be
halogenated, C.sub.6-10 aryloxy, C.sub.1-6 alkyl-carbonyl,
C.sub.6-10 aryl-carbonyl, C.sub.7-11 aralkyl-carbonyl, C.sub.1-6
alkyl-carbonyloxy, C.sub.6-10 aryl-carbonyloxy, carboxy, C.sub.1-6
alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl,
di-C.sub.1-6 alkyl-carbamoyl, amidino, imino, amino, mono-C.sub.1-6
alkylamino, di-C.sub.1-6 alkylamino, 3- to 6-membered cyclic amino,
C.sub.1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo,
sulfino, phosphono, sulfamoyl, mono-C.sub.1-6 alkylsulfamoyl,
di-C.sub.1-6 alkylsulfamoyl, C.sub.1-6 alkylthio which may be
halogenated, C.sub.6-10 arylthio, C.sub.1-6 alkylsulfinyl,
C.sub.6-10 arylsulfinyl, C.sub.1-6 alkylsulfonyl and C.sub.6-10
arylsulfonyl, or (iii) an amino which may be substituted by 1 or 2
substituents selected form the group consisting of C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.6-14 aryl and C.sub.7-16 aralkyl group, each of which may be
substituted by 1 to 5 substituents selected from the group
consisting of halogen, C.sub.1-6 alkyl which may be halogenated,
C.sub.2-6 alkenyl which may be halogenated, C.sub.2-6 alkynyl which
may be halogenated, C.sub.3-6 cycloalkyl which may be halogenated,
C.sub.6-10 aryl, C.sub.7-11 aralkyl, C.sub.1-6 alkoxy which may be
halogenated, C.sub.6-10 aryloxy, C.sub.1-6 alkyl-carbonyl,
C.sub.6-10 aryl-carbonyl, C.sub.7-11 aralkyl-carbonyl, C.sub.1-6
alkyl-carbonyloxy, C.sub.6-10 aryl-carbonyloxy, carboxy, C.sub.1-6
alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl,
di-C.sub.1-6 alkyl-carbamoyl, amidino, imino, amino, mono-C.sub.1-6
alkylamino, di-C.sub.1-6 alkylamino, 3- to 6-membered cyclic amino,
C.sub.1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo,
sulfino, phosphono, sulfamoyl, mono-C.sub.1-6 alkylsulfamoyl,
di-C.sub.1-6 alkylsulfamoyl, C.sub.1-6 alkylthio which may be
halogenated, C.sub.6-10 arylthio, C.sub.1-6 alkylsulfinyl,
C.sub.6-10 arylsulfinyl, C.sub.1-6 alkylsulfonyl and C.sub.6-10
arylsulfonyl; m is an integer of 1 to 3; Ar is a (i) C.sub.6-14
aryl or (ii) 5- to 10-membered aromatic heterocyclic group
containing 1 to 4 hetero atoms selected from among nitrogen, sulfur
and oxygen as a ring member other than carbon, each of which may be
substituted by 1 to 5 substituents selected from the group
consisting of halogen, C.sub.1-3 alkylenedioxy, nitro, cyano,
C.sub.1-6 alkyl which may be halogenated, C.sub.3-6 cycloalkyl,
C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio
which may be halogenated, hydroxy, amino, mono-C.sub.1-6
alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkyl-carbonyl,
carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6
alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10
aryl-carbamoyl, sulfo, C.sub.1-6 alkylsulfonyl, C.sub.6-10 aryl and
C.sub.6-10 aryloxy; X is (i) a bond or (ii) a divalent group of the
formula: --Xa--Xb-- wherein Xa is a bond, S, SO, SO.sub.2, O or
NR.sup.4, wherein R.sup.4 is hydrogen, C.sub.1-6 alkyl, C.sub.3-6
cycloalkyl, C.sub.6-14 aryl, C.sub.7-11 aralkyl, formyl, C.sub.1-6
alkyl-carbonyl or C.sub.6-10 aryl-carbonyl; and Xb is (a) a bond or
(b) C.sub.1-5 alkylene, C.sub.2-5 alkenylene, C.sub.2-5 alkynylene
or a group of the
formula:(CH.sub.2).sub.p--Xc--(CH.sub.2).sub.q--wherein Xc is S,
SO, SO.sub.2, O or NR.sup.4a, wherein R.sup.4a is hydrogen,
C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-14 aryl, C.sub.7-11
aralkyl, formyl, C.sub.1-6 alkyl-carbonyl or C.sub.6-10
aryl-carbonyl; p and q are independently an integer of 0 to 4 and
p+q is an integer of 0 to 4, each of which group may be substituted
by 1 to 5 substituents selected from the group consisting of (1)
halogen, (2) nitro, (3) cyano, (4) C.sub.1-6 alkyl which may be
halogenated, (5) C.sub.3-6 cycloalkyl, (6) C.sub.7-11 aralkyl, (7)
C.sub.1-6 alkoxy which may be halogenated, (8) C.sub.1-6 alkylthio
which may be halogenated, (9) hydroxy, (10) amino, (11)
mono-C.sub.1-6 alkylamino, (12) di-C.sub.1-6 alkylamino, (13)
C.sub.6-10 aryloxy, (14) C.sub.1-6 alkyl-carbonyl, (15) C.sub.6-10
aryl-carbonyl, (16) oxo and (17) a (17-i) C.sub.6-14 aryl or
(17-ii) 5- to 10-membered aromatic heterocyclic group containing 1
to 4 hetero atoms selected from among nitrogen, sulfur and oxygen
as a ring member other than carbon, each of which may be
substituted by 1 to 5 substituents selected from the group
consisting of halogen, C.sub.1-3 alkylenedioxy, nitro, cyano,
C.sub.1-6 alkyl which may be halogenated, C.sub.3-6 cycloalkyl,
C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio
which may be halogenated, hydroxy, amino, mono-C.sub.1-6
alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkyl-carbonyl,
carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6
alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10
aryl-carbamoyl, sulfo, C.sub.1-6 alkylsulfonyl, C.sub.6-10 aryl and
C.sub.6-10 aryloxy; R.sup.2 is (i) hydrogen, (ii) C.sub.1-6 alkyl,
(iii) C.sub.2-6 alkenyl, (iv) C.sub.2-6 alkynyl, (v) C.sub.3-6
cycloalkyl, (vi) C.sub.6-14 aryl, (vii) C.sub.7-16 aralkyl, (viii)
formyl, (ix) C.sub.1-6 alkyl-carbonyl, (x) C.sub.6-10
aryl-carbonyl, (xi) C.sub.7-11 aralkyl-carbonyl, (xii) C.sub.1-6
alkylsulfonyl, (xiii) C.sub.6-10 arylsulfonyl which may be
substituted by 1 to 3 substituents selected from the group
consisting of C.sub.1-6 alkyl, C.sub.1-6 alkoxy and nitro or (xiv)
C.sub.7-11 aralkylsulfonyl; R.sup.3 is hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.6-14 aryl or C.sub.7-16 aralkyl; ring A is a benzene ring
which may be substituted by 1 to 3 substituents selected from the
group consisting of halogen, C.sub.1-3 alkylenedioxy, nitro, cyano,
C.sub.1-6 alkyl which may be halogenated, C.sub.3-6 cycloalkyl,
C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio
which may be halogenated, hydroxy, amino, mono-C.sub.1-6
alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkyl-carbonyl,
carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6
alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10
aryl-carbamoyl, sulfo, C.sub.1-6 alkylsulfonyl, C.sub.6-10 aryl and
C.sub.6-10 aryloxy, in addition to a group of the formula:
--O(CH.sub.2).sub.mCOR.sup.1; and ring B is a 5- to 7-membered ring
of the formula: 123wherein Ba is --CH.sub.2--,
--(CH.sub.2).sub.2--; --(CH.sub.2).sub.3--, --CH.dbd.CH--, --O--,
--O--CH.sub.2--, --CH.sub.2--O--, --O--CH.sub.2--CH.sub.2--,
--CH.sub.2--O--CH.sub.2--, --S(O).sub.r--, --S(O).sub.r--CH.sub.2--
or --S(O).sub.r--(CH.sub.2).sub.- 2-- wherein r is an integer of 0
to 2, which ring may be substituted by 1 to 3 substituents selected
from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.6-14 aryl and
C.sub.7-16 aralkyl.
3. A compound according to claim 1 wherein the group of the
formula: --COR.sup.1 is carboxy which may be esterified or
amidated.
4. A compound according to claim 1 wherein R.sup.1 is hydroxy which
may be substituted.
5. A compound according to claim 1 wherein R.sup.1 is hydroxy.
6. A compound according to claim 1 wherein m is 1.
7. A compound according to claim 1 wherein Ar is a C.sub.6-14 aryl
which may be substituted by 1 to 3 substituents selected from the
group consisting of halogen, C.sub.1-3 alkylenedioxy, nitro, cyano,
C.sub.1-6 alkyl which may be halogenated, C.sub.3-6 cycloalkyl,
C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio
which may be halogenated, hydroxy, amino, mono-C.sub.1-6
alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkyl-carbonyl,
carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6
alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10
aryl-carbamoyl, sulfo, C.sub.1-6 alkylsulfonyl, C.sub.6-10 aryl and
C.sub.6-10 aryloxy.
8. A compound according to claim 1 wherein Ar is phenyl which may
be halogenated.
9. A compound according to claim 1 wherein X is a divalent group of
the formula: --Xa.sup.1--Xb.sup.1-- wherein Xa.sup.1 is S, SO or
SO.sub.2; and Xb.sup.1 is C.sub.1-5 alkylene which may be
substituted by a C.sub.6-14 aryl which may be substituted by 1 to 3
substituents selected from the group consisting of halogen,
C.sub.1-3 alkylenedioxy, nitro, cyano, C.sub.1-6 alkyl which may be
halogenated, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy which may be
halogenated, C.sub.1-6 alkylthio which may be halogenated, hydroxy,
amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino,
C.sub.1-6 alkyl-carbonyl, carboxy, C.sub.1-6 alkoxy-carbonyl,
carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6
alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, sulfo, C.sub.1-6
alkylsulfonyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy.
10. A compound according to claim 9 wherein Xa.sup.1 is S.
11. A compound according to claim 9 wherein Xb.sup.1 is C.sub.1-3
alkylene which may be substituted by a phenyl which may be
halogenated.
12. A compound according to claim 1 wherein Y is --S--.
13. A compound according to claim 1 wherein Z is --N.dbd..
14. A compound according to claim 1 wherein ring B is a ring of the
formula: 124wherein Ba.sup.1 is --CH.sub.2--, --(CH.sub.2).sub.2--,
--O--CH.sub.2-- or --O--.
15. A compound according to claim 1 which is a compound of the
formula: 125wherein the respective symbols have the same meanings
as defined in claim 1.
16. A compound according to claim 15 wherein R.sup.1 is hydroxy; m
is 1; Ar is phenyl which may be halogenated; X is a divalent group
of the formula: --Xa.sup.2--Xb.sup.2-- wherein Xa.sup.2 is S, SO or
SO.sub.2; and Xb.sup.2 is C.sub.1-3 alkylene which may be
substituted by a phenyl which may be halogenated; and ring B is a
ring of the formula: 126wherein Ba.sup.2 is --CH.sub.2--,
--(CH.sub.2).sub.2--, --O--CH.sub.2-- or --O--.
17. A compound according to claim 1 wherein R.sup.1 is hydroxy
which may be substituted by a C.sub.1-6 alkyl; m is an integer of 1
to 3; Ar is C.sub.6-14 aryl which may be substituted by 1 to 3
substituents selected from the group consisting of halogen, nitro,
cyano, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy
and C.sub.6-10 aryl; X is (i) a bond or (ii) a divalent group of
the formula: --Xa.sup.3--Xb.sup.3-- wherein Xa.sup.3 is a bond, S,
SO, SO.sub.2, O or NH; and Xb.sup.3 is a C.sub.1-5 alkylene or
C.sub.2-5 alkenylene group which may be substituted by a phenyl
which may be halogenated; Y is --S--; Z is --N.dbd.; ring A is a
benzene ring which may be substituted by 1 to 3 C.sub.1-6 alkyl, in
addition to a group of the formula: --O(CH.sub.2).sub.mCOR.sup.1;
and ring B is a ring of the formula: 127wherein Ba.sup.3 is
--CH.sub.2--, --(CH.sub.2).sub.2--, --O--CH.sub.2-- or --O--.
18. A compound according to claim 1 which is
[(2-diphenylmethylthio-4,5-di-
hydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-(2,2-diphenylethyl)th-
io-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-diphenylmethyl)sulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]ace-
tic acid,
[(2-bis(3-fluorophenyl)methylsulfonyl-4,5-dihydronaphto[1,2-d]th-
iazol-6-yl)oxy]acetic acid,
[(2-bis(2-fluorophenyl)methylsulfonyl-4,5-dihy-
dronaphto[1,2-d]thiazol-6-yl)oxy]acetic acid, or a salt
thereof.
19. A compound according to claim 1 which is
[(2-diphenylmethylthio-4,5-di-
hydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-(2,2-diphenylethyl)th-
io-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic acid,
[(2-diphenylmethyl)sulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]ace-
tic acid,
[(2-bis(3-fluorophenyl)methylsulfonyl-4,5-dihydronaphto[1,2-d]th-
iazol-6-yl)oxy]acetic acid,
[(2-bis(2-fluorophenyl)methylsulfonyl-4,5-dihy-
dronaphto[1,2-d]thiazol-6-yl)oxy]acetic acid, or a pharmaceutically
acceptable metal salt.
20. A process for producing a compound of claim 1 which comprises
i) reacting a compound of the formula: 128wherein Hal represents
halogen; the other symbols have the same meanings as defined in
claim 1, or a salt thereof with a compound of the formula:
129wherein the respective symbols have the same meanings as defined
in claim 1, or a salt thereof, optionally followed by hydrolysis or
oxidation of the resultant compound; or ii) subjecting a compound
of the formula: 130wherein X' represents SH, OH or NH.sub.2; the
other symbols have the same meanings as defined in claim 1, or a
tautomer thereof, or a salt thereof, to alkylation, optionally
followed by hydrolysis or oxidation of the resultant compound.
21. A compound of the formula: 131wherein R.sup.1 represents
hydrogen or a substituent group; m represents an integer of 1 to 3;
X' represents SH, OH or NH.sub.2; Y represents --S--, --O-- or
--N(R.sup.2)-- wherein R.sup.2 represents hydrogen or a substituent
group; Z represents --N.dbd. or --C(R.sup.3).dbd. wherein R.sup.3
represents hydrogen or a hydrocarbon group; ring A represents a
benzene ring which may be substituted by a substituent in addition
to a group of the formula: --O(CH.sub.2).sub.mCOR.sup.1 wherein the
respective symbols have the same meanings as defined above; and
ring B represents a 5- to 7-membered ring which may be substituted,
or a tautomer thereof, or a salt thereof.
22. A pharmaceutical composition which comprises a compound of
claim 1, if necessary together with a pharmaceutically acceptable
carrier.
23. A composition according to claim 22 which is for eliciting a
prostaglandin I.sub.2 receptor agonistic effect.
24. A composition according to claim 22 which is for inhibiting a
platelet aggregation.
25. A composition according to claim 22 which is for the
prophylaxis or treatment of transient ischemic attack, diabetic
neuropathy, peripheral vascular diseases or ulcer.
26. A method for eliciting a prostaglandin I.sub.2 receptor
agonistic effect in a mammal in need thereof which comprises
administering to such mammal an effective amount of a compound of
claim 1 with a pharmaceutically acceptable excipient, carrier or
diluent.
27. Use of a compound of claim 1 for manufacturing a pharmaceutical
composition for eliciting a prostaglandin I.sub.2 receptor
agonistic effect.
Description
TECHNICAL FIELD
[0001] The present invention relates to tricyclic compounds having
very satisfactory prostaglandin I.sub.2 receptor agonistic
activity, their production, intermediates and use.
BACKGROUND ART
[0002] It is known that prostaglandin I.sub.2 (PGI.sub.2) is a
substance which is biosynthesized from arachidonic acid through
prostaglandin H.sub.2 (PGH.sub.2) and has potent platelet
aggregation inhibitory activity, vasodilative activity, lipid
deposition inhibitory activity, and leukocyte activation inhibitory
activity. As such, PGI.sub.2 is considered to be effective in the
treatment of peripheral vascular diseases (e.g. peripheral
embolism, vibration syndrome, Raynaud's disease, etc.), systemic
lupus erythematosus, post-PTCA (percutaneous transluminal coronary
angioplasty) arterial reobliteration/restenosis, atherosclerosis,
thrombosis, diabetic neuropathy, hypertension, ischemic diseases
(e.g. cerebral infarction, myocardial infarction, etc.), transient
ischemic attack, and glomerulonephritis.
[0003] Meanwhile, WO 96/20925, for instance, reports a
non-prostanoid PGI.sub.2 receptor agonist compound of the formula:
2
[0004] wherein R.sup.1 represents --X--(CH.sub.2).sub.nCOOR.sup.3
wherein X represents --O--, --S-- or --CH.sub.2--; R.sup.3
typically represents hydrogen or C.sub.1-5 lower alkyl; n
represents 1-3; R.sup.2 typically represents
--CR.sup.4.dbd.CR.sup.5--O-- or --CR.sup.5.dbd.CR.sup.4--O--
wherein R.sup.4 represents --(CH.sub.2).sub.m--Y--R.sup.8 wherein m
represents 1-4; Y typically represents --O-- or --CH.sub.2--;
R.sup.8 typically represents phenyl; R.sup.5 typically represents
hydrogen or C.sub.1-5 lower alkyl.
[0005] JP-A-62-252780 discloses an antiulcer tricyclic compound of
the formula: 3
[0006] wherein X and Y independently represent hydrogen, halogen,
lower alkyl or lower alkoxy; n represents 0-4; R.sub.1 represents
hydrogen, lower alkyl, unsubstituted or substituted phenyl; R.sub.2
typically represents lower alkyl, unsubstituted or substituted
phenyl, heterocyclic group or cyclic amino; R.sub.3 represents
hydrogen, lower alkyl, or acyl; R.sub.2 and R.sub.3 optionally
taken together represent cyclic amino.
[0007] PGI.sub.2 is by no means chemically and biologically stable
enough for use as a medicine. Moreover, it is not clear-cut in the
desired action or actions versus other actions, thus unavoidably
inducing adverse drug reactions.
[0008] Meanwhile, no information is available on the relation of
those known tricyclic compounds to the affinity for PGI.sub.2
receptors. Under the circumstances, there is a keen demand for
creation of a compound structurally removed from PGI.sub.2 and yet
having a high affinity for PGI.sub.2 receptors and acting as a
PGI.sub.2 receptor agonist with improved chemical stability and
stability against metabolism and greater clinical efficacy than
PGI.sub.2, thus being very satisfactory for use as a medicine.
[0009] The inventors of the present invention explored for
compounds having PGI.sub.2 receptor agonistic activity and
succeeded in the creation of a compound of the formula: 4
[0010] wherein R.sup.1 represents hydrogen or a substituent
group;
[0011] m represents an integer of 1 to 3;
[0012] Ar represents an aromatic group which may be
substituted;
[0013] X represents a bond or a divalent straight-chain group which
have 1 to 6 atoms and may be substituted;
[0014] Y represents --S--, --O-- or --N(R.sup.2)-- wherein R.sup.2
represents hydrogen or a substituent group;
[0015] Z represents --N.dbd. or --C(R.sup.3)-- wherein R.sup.3
represents hydrogen or a hydrocarbon group;
[0016] ring A represents a benzene ring which may be substituted by
a substituent in addition to a group of the formula:
--O(CH.sub.2).sub.mCOR.sup.1 wherein the respective symbols have
the same meanings as defined above; and
[0017] ring B represents a 5- to 7-membered ring which may be
substituted, or a salt thereof,
[0018] which compound is structurally characterized in that the
benzene ring (ring A) of the tricyclic skeletal system of the
formula: 5
[0019] wherein the respective symbols have the meanings defined
above, has a substituent group of the formula
--O(CH.sub.2).sub.mCOR.sup.1 wherein the respective symbols have
the meanings defined above.
[0020] The inventors further discovered that because of the above
unique chemical structure, the above compound or a salt thereof
[hereinafter sometimes referred to briefly as compound (I)], is an
excellent PGI.sub.2 receptor agonist having a high affinity for
PGI.sub.2 receptors, high chemical stability, and high stability
against metabolism and, thus, being fully satisfactory as a
medicine. The present invention is predicated on the above
findings.
DISCLOSURE OF INVENTION
[0021] The present invention to:
[0022] (1) compound (I);
[0023] (2) a compound of the above (1) wherein R.sup.1 is (i)
hydrogen,
[0024] (ii) a hydroxy which may be substituted by a C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.6-14 aryl or C.sub.7-16 aralkyl group, each of which may be
substituted by 1 to 5 substituents selected from the group
consisting of halogen, C.sub.1-6 alkyl which may be halogenated,
C.sub.2-6 alkenyl which may be halogenated, C.sub.2-6 alkynyl which
may be halogenated, C.sub.3-6 cycloalkyl which may be halogenated,
C.sub.6-10 aryl, C.sub.7-11 aralkyl, C.sub.1-6 alkoxy which may be
halogenated, C.sub.6-10 aryloxy, C.sub.1-6 alkyl-carbonyl,
C.sub.6-10 aryl-carbonyl, C.sub.7-11 aralkyl-carbonyl, C.sub.1-6
alkyl-carbonyloxy, C.sub.6-10 aryl-carbonyloxy, carboxy, C.sub.1-6
alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl,
di-C.sub.1-6 alkyl-carbamoyl, amidino, imino, amino, mono-C.sub.1-6
alkylamino, di-C.sub.1-6 alkylamino, 3- to 6-membered cyclic amino,
C.sub.1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo,
sulfino, phosphono, sulfamoyl, mono-C.sub.1-6 alkylsulfamoyl,
di-C.sub.1-6 alkylsulfamoyl, C.sub.1-6 alkylthio which may be
halogenated, C.sub.6-10 arylthio, C.sub.1-6 alkylsulfinyl,
C.sub.6-10 arylsulfinyl, C.sub.1-6 alkylsulfonyl and C.sub.6-10
arylsulfonyl, or
[0025] (iii) an amino which may be substituted by 1 or 2
substituents selected form the group consisting of C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.6-14 aryl and C.sub.7-16 aralkyl group, each of which may be
substituted by 1 to 5 substituents selected from the group
consisting of halogen, C.sub.1-6 alkyl which may be halogenated,
C.sub.2-6 alkenyl which may be halogenated, C.sub.2-6 alkynyl which
may be halogenated, C.sub.3-6 cycloalkyl which may be halogenated,
C.sub.6-10 aryl, C.sub.7-11 aralkyl, C.sub.1-6 alkoxy which may be
halogenated, C.sub.6-10 aryloxy, C.sub.1-6 alkyl-carbonyl,
C.sub.6-10 aryl-carbonyl, C.sub.7-11 aralkyl-carbonyl, C.sub.1-6
alkyl-carbonyloxy, C.sub.6-10 aryl-carbonyloxy, carboxy, C.sub.1-6
alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl,
di-C.sub.1-6 alkyl-carbamoyl, amidino, imino, amino, mono-C.sub.1-6
alkylamino, di-C.sub.1-6 alkylamino, 3- to 6-membered cyclic amino,
C.sub.1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo,
sulfino, phosphono, sulfamoyl, mono-C.sub.1-6 alkylsulfamoyl,
di-C.sub.1-6 alkylsulfamoyl, C.sub.1-6 alkylthio which may be
halogenated, C.sub.6-10 arylthio, C.sub.1-6 alkylsulfinyl,
C.sub.6-10 arylsulfinyl, C.sub.1-6 alkylsulfonyl and C.sub.6-10
arylsulfonyl;
[0026] m is an integer of 1 to 3;
[0027] Ar is a (i) C.sub.6-14 aryl or (ii) 5- to 10-membered
aromatic heterocyclic group containing 1 to 4 hetero atoms selected
from among nitrogen, sulfur and oxygen as a ring member other than
carbon, each of which may be substituted by 1 to 5 substituents
selected from the group consisting of halogen, C.sub.1-3
alkylenedioxy, nitro, cyano, C.sub.1-6 alkyl which may be
halogenated, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy which may be
halogenated, C.sub.1-6 alkylthio which may be halogenated, hydroxy,
amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino,
C.sub.1-6 alkyl-carbonyl, carboxy, C.sub.1-6 alkoxy-carbonyl,
carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6
alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, sulfo, C.sub.1-6
alkylsulfonyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy;
[0028] X is (i) a bond or
[0029] (ii) a divalent group of the formula: --Xa--Xb-- wherein Xa
is a bond, S, SO, SO.sub.2, or NR.sup.4, wherein R.sup.4 is
hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-11 aralkyl, formyl, C.sub.1-6 alkyl-carbonyl or C.sub.6-10
aryl-carbonyl; and
[0030] Xb is (a) a bond or (b) C.sub.1-5 alkylene, C.sub.2-5
alkenylene, C.sub.2-5 alkynylene or a group of the formula:
(CH.sub.2).sub.p--Xc--(CH.sub.2).sub.q--
[0031] wherein Xc is S, SO, SO.sub.2, O or NR.sup.4a,
[0032] wherein R.sup.4a is hydrogen, C.sub.1-6 alkyl, C.sub.3-6
cycloalkyl, C.sub.6-14 aryl, C.sub.7-11 aralkyl, formyl, C.sub.1-6
alkyl-carbonyl or C.sub.6-10 aryl-carbonyl; p and q are
independently an integer of 0 to 4 and p+q is an integer of 0 to 4,
each of which group may be substituted by 1 to 5 substituents
selected from the group consisting of (1) halogen, (2) nitro, (3)
cyano, (4) C.sub.1-6 alkyl which may be halogenated, (5) C.sub.3-6
cycloalkyl, (6) C.sub.7-11 aralkyl, (7) C.sub.1-6 alkoxy which may
be halogenated, (8) C.sub.1-6 alkylthio which may be halogenated,
(9) hydroxy, (10) amino, (11) mono-C.sub.1-6 alkylamino, (12)
di-C.sub.1-6 alkylamino, (13) C.sub.6-10 aryloxy, (14) C.sub.1-6
alkyl-carbonyl, (15) C.sub.6-10 aryl-carbonyl, (16) oxo and (17) a
(17-i) C.sub.6-14 aryl or (17-ii) 5- to 10-membered aromatic
heterocyclic group containing 1 to 4 hetero atoms selected from
among nitrogen, sulfur and oxygen as a ring member other than
carbon, each of which may be substituted by 1 to 5 substituents
selected from the group consisting of halogen, C.sub.1-3
alkylenedioxy, nitro, cyano, C.sub.1-6 alkyl which may be
halogenated, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy which may be
halogenated, C.sub.1-6 alkylthio which may be halogenated, hydroxy,
amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino,
C.sub.1-6 alkyl-carbonyl, carboxy, C.sub.1-6 alkoxy-carbonyl,
carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6
alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, sulfo, C.sub.1-6
alkylsulfonyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy;
[0033] R.sup.2 is (i) hydrogen, (ii) C.sub.1-6 alkyl, (iii)
C.sub.2-6 alkenyl, (iv) C.sub.2-6 alkynyl, (v) C.sub.3-6
cycloalkyl, (vi) C.sub.6-14 aryl, (vii) C.sub.7-16 aralkyl, (viii)
formyl, (ix) C.sub.1-6 alkyl-carbonyl, (x) C.sub.6-10
aryl-carbonyl, (xi) C.sub.7-11 aralkyl-carbonyl, (xii) C.sub.1-6
alkylsulfonyl, (xiii) C.sub.6-10 arylsulfonyl which may be
substituted by 1 to 3 substituents selected from the group
consisting of C.sub.1-6 alkyl, C.sub.1-6 alkoxy and nitro or (xiv)
C.sub.7-11 aralkylsulfonyl;
[0034] R.sup.3 is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.6-14 aryl or
C.sub.7-16 aralkyl;
[0035] ring A is a benzene ring which may be substituted by 1 to 3
substituents selected from the group consisting of halogen,
C.sub.1-3 alkylenedioxy, nitro, cyano, C.sub.1-6 alkyl which may be
halogenated, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy which may be
halogenated, C.sub.1-6 alkylthio which may be halogenated, hydroxy,
amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino,
C.sub.1-6 alkyl-carbonyl, carboxy, C.sub.1-6 alkoxy-carbonyl,
carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6
alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, sulfo, C.sub.1-6
alkylsulfonyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy, in addition
to a group of the formula: --O(CH.sub.2).sub.mCOR.sup.1; and
[0036] ring B is a 5- to 7-membered ring of the formula: 6
[0037] wherein Ba is --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --CH.dbd.CH--, --O--, --O--CH.sub.2--,
--CH.sub.2--O--, --O--CH.sub.2--CH.sub.2--,
--CH.sub.2--O--CH.sub.2--, --S(O).sub.r--, S(O).sub.r--CH.sub.2--,
or --S(O).sub.r--(CH.sub.2).sub.2- -- wherein r is an integer of 0
to 2,
[0038] which ring may be substituted by 1 to 3 substituents
selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.6-14 aryl
and C.sub.7-16 aralkyl;
[0039] (3) a compound of the above (1) wherein the group of the
formula: --COR.sup.1 is carboxy which may be esterified or
amidated;
[0040] (4) a compound of the above (1) wherein R.sup.1 is hydroxy
which may be substituted;
[0041] (5) a compound of the above (1) wherein R.sup.1 is
hydroxy;
[0042] (6) a compound of the above (1) wherein m is 1;
[0043] (7) a compound of the above (1) wherein Ar is a C.sub.6-14
aryl which may be substituted by 1 to 3 substituents selected from
the group consisting of halogen, C.sub.1-3 alkylenedioxy, nitro,
cyano, C.sub.1-6 alkyl which may be halogenated, C.sub.3-6
cycloalkyl, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6
alkylthio which may be halogenated, hydroxy, amino, mono-C.sub.1-6
alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkyl-carbonyl,
carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6
alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10
aryl-carbamoyl, sulfo, C.sub.1-6 alkylsulfonyl, C.sub.6-10 aryl and
C.sub.6-10 aryloxy;
[0044] (8) a compound of the above (1) wherein Ar is phenyl which
may be halogenated;
[0045] (9) a compound of the above (1) wherein X is a divalent
group of the formula: --Xa.sup.1--Xb.sup.1-- wherein Xa.sup.1 is S,
SO or SO.sub.2; and Xb.sup.1 is C.sub.1-5 alkylene which may be
substituted by a C.sub.6-14 aryl which may be substituted by 1 to 3
substituents selected from the group consisting of halogen,
C.sub.1-3 alkylenedioxy, nitro, cyano, C.sub.1-6 alkyl which may be
halogenated, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy which may be
halogenated, C.sub.1-6 alkylthio which may be halogenated, hydroxy,
amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino,
C.sub.1-6 alkyl-carbonyl, carboxy, C.sub.1-6 alkoxy-carbonyl,
carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6
alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, sulfo, C.sub.1-6
alkylsulfonyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy;
[0046] (10) a compound of the above (9) wherein Xa.sup.1 is S;
[0047] (11) a compound of the above (9) wherein Xb.sup.1 is a
C.sub.1-3 alkylene which may be substituted by a phenyl which may
be halogenated;
[0048] (12) a compound of the above (1) wherein Y is --S--;
[0049] (13) a compound of the above (1) wherein Z is --N.dbd.;
[0050] (14) a compound of the above (1) wherein ring B is a ring of
the formula: 7
[0051] wherein Ba.sup.1 is --CH.sub.2--, --(CH.sub.2).sub.2--,
--O--CH.sub.2-- or --O--;
[0052] (15) a compound of the above (1) which is a compound of the
formula: 8
[0053] wherein the respective symbols have the same meanings as
defined above;
[0054] (16) a compound of the above (15) wherein R.sup.1 is
hydroxy;
[0055] m is 1;
[0056] Ar is phenyl which may be halogenated;
[0057] X is a divalent group of the formula: --Xa.sup.2--Xb.sup.2--
wherein Xa.sup.2 is S, SO or SO.sub.2; and Xb.sup.2 is a C.sub.1-3
alkylene which may be substituted by a phenyl which may be
halogenated; and
[0058] ring B is a ring of the formula: 9
[0059] wherein Ba.sup.2 is --CH.sub.2--, --(CH.sub.2).sub.2--,
--O--CH.sub.2-- or --O--;
[0060] (17) a compound of the above, (1) wherein
[0061] R.sup.1 is hydroxy which may be substituted by a C.sub.1-6
alkyl;
[0062] m is an integer of 1 to 3;
[0063] Ar is C.sub.6-14 aryl which may be substituted by 1 to 3
substituents selected from the group consisting of halogen, nitro,
cyano, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy
and C.sub.6-10 aryl;
[0064] X is (i) a bond or
[0065] (ii) a divalent group of the formula: --Xa.sup.3--Xb.sup.3--
wherein Xa.sup.3 is a bond, S, SO, SO.sub.2, O or NH; and
[0066] Xb.sup.3 is a C.sub.1-5 alkylene or C.sub.2-5 alkenylene
group which may be substituted by a phenyl which may be
halogenated;
[0067] Y is --S--;
[0068] Z is --N.dbd.;
[0069] ring A is a benzene ring which may be substituted by 1 to
3
[0070] C.sub.1-6 alkyl, in addition to a group of the formula:
--O(CH.sub.2).sub.mCOR.sup.1; and
[0071] ring B is a ring of the formula: 10
[0072] wherein Ba.sup.3 is --CH.sub.2--, --(CH.sub.2).sub.2--,
--O--CH.sub.2-- or --O--;
[0073] (18) a compound of the above (1) which is
[0074]
[(2-diphenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]ac-
etic acid,
[0075]
[(2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)o-
xy]acetic acid,
[0076]
[(2-diphenylmethyl)sulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)o-
xy]acetic acid,
[0077]
[(2-bis(3-fluorophenyl)methylsulfonyl-4,5-dihydronaphto[1,2-d]thiaz-
ol-6-yl)oxy]acetic acid,
[0078]
[(2-bis(2-fluorophenyl)methylsulfonyl-4,5-dihydronaphto[1,2-d]thiaz-
ol-6-yl)oxy]acetic acid, or a salt thereof;
[0079] (19) a compound of the above (1) which is
[0080]
[(2-diphenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]ac-
etic acid,
[0081]
[(2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)o-
xy]acetic acid,
[0082]
[(2-diphenylmethyl)sulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)o-
xy]acetic acid,
[0083]
[(2-bis(3-fluorophenyl)methylsulfonyl-4,5-dihydronaphto[1,2-d]thiaz-
ol-6-yl)oxy]acetic acid,
[0084]
[(2-bis(2-fluorophenyl)methylsulfonyl-4,5-dihydronaphto[1,2-d]thiaz-
ol-6-yl)oxy]acetic acid, or a pharmaceutically acceptable metal
salt;
[0085] (20) a process for producing a compound of the above (1)
which comprises
[0086] i) reacting a compound of the formula: 11
[0087] wherein Hal represents halogen; the other symbols have the
same meanings as defined above, or a salt thereof with a compound
of the formula: 12
[0088] wherein the respective symbols have the same meanings as
defined above, or a salt thereof, optionally followed by hydrolysis
or oxidation of the resultant compound; or
[0089] ii) subjecting a compound of the formula: 13
[0090] wherein X' represents SH, OH or NH.sub.2; the other symbols
have the same meanings as defined above, or a tautomer thereof, or
a salt thereof, to alkylation, optionally followed by hydrolysis or
oxidation of the resultant compound;
[0091] (21) a compound of the formula: 14
[0092] wherein X' represents SH, OH, or NH.sub.2; the other symbols
have the same meanings as defined above or a tautomer thereof, or a
salt thereof;
[0093] (22) a pharmaceutical composition which comprises a compound
of the above (1), if necessary together with a pharmaceutically
acceptable carrier;
[0094] (23) a composition of the above (22) which is for eliciting
a prostaglandin I.sub.2 receptor agonistic effect;
[0095] (24) a composition of the above (22) which is for inhibiting
a platelet aggregation;
[0096] (25) a composition of the above (22) which is for the
prophylaxis or treatment of transient ischemic attack, diabetic
neuropathy, peripheral vascular diseases or ulcer;
[0097] (26) a method for eliciting a prostaglandin I.sub.2 receptor
agonistic effect in a mammal in need thereof which comprises
administering to such mammal an effective amount of a compound of
the above (1) with a pharmaceutically acceptable excipient, carrier
or diluent; and
[0098] (27) use of a compound of the above (1) for manufacturing a
pharmaceutical composition for eliciting a prostaglandin I.sub.2
receptor agonistic effect.
[0099] Referring to the above formula, the "substituent group"
represented by R.sup.1 includes, for example, a hydroxy which may
be substituted and an amino which may be substituted.
[0100] The "substituent" for the "hydroxy which may be substituted"
and for the "amino which may be substituted" includes, for example,
hydrocarbon groups which may be substituted. The "amino which may
be substituted" may have 1 or 2 substituent groups.
[0101] The "hydrocarbon group" of the "hydrocarbon group which may
be substituted" means a monovalent group available upon elimination
of one hydrogen atom from a hydrocarbon compound and includes both
acyclic and cyclic hydrocarbon groups (e.g. alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, aralkyl, etc.). Preferred are acyclic
and cyclic hydrocarbon groups containing 1 to 16 carbon atoms, such
as the following.
[0102] a) C.sub.1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.),
[0103] b) C.sub.2-6 alkenyl (e.g. vinyl, allyl, isopropenyl,
butenyl, etc.),
[0104] c) C.sub.2-6 alkynyl (e.g. ethynyl, propargyl, butynyl,
1-hexynyl, etc.),
[0105] d) C.sub.3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, etc.),
[0106] e) C.sub.6-14 aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl,
2-anthryl, etc.),
[0107] f) C.sub.7-16 aralkyl (e.g. benzyl, phenethyl,
diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,
2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl,
etc.), preferably benzyl.
[0108] Among the above hydrocarbon groups, C.sub.1-6 alkyl,
C.sub.6-14 aryl, and C.sub.7-16 aralkyl are preferred.
[0109] The "substituent" for the "hydrocarbon group which may be
substituted" includes, for example, halogen (e.g. fluorine,
chlorine, bromine, iodine, etc.), C.sub.1-6 alkyl which may be
halogenated, C.sub.2-6 alkenyl which may be halogenated, C.sub.2-6
alkynyl which may be halogenated, C.sub.3-6 cycloalkyl which may be
halogenated, C.sub.6-10 aryl (e.g. phenyl, naphthyl, etc.),
C.sub.7-11 aralkyl (e.g. benzyl, .alpha.-methylbenzyl, phenethyl,
etc.), C.sub.1-6 alkoxy which may be halogenated, C.sub.6-10
aryloxy (e.g. phenoxy etc.), C.sub.1-6 alkyl-carbonyl (e.g. acetyl,
propionyl, butyryl, isobutyryl, etc.), C.sub.6-10 aryl-carbonyl
(e.g. benzoyl, naphthoyl, etc.), C.sub.7-11 aralkyl-carbonyl (e.g.
benzylcarbonyl, phenethylcarbonyl, etc.), C.sub.1-6
alkyl-carbonyloxy (e.g. acetyloxy, propionyloxy, butyryloxy,
isobutyryloxy, etc.), C.sub.6-10 aryl-carbonyloxy (e.g. benzoyloxy,
naphthoyloxy, etc.), carboxy, C.sub.1-6 alkoxy-carbonyl (e.g.
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
tert-butoxycarbonyl, etc.), carbamoyl, mono-C.sub.1-6
alkyl-carbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.),
di-C.sub.1-6 alkyl-carbamoyl (e.g. dimethylcarbamoyl,
diethylcarbamoyl, etc.), amidino, imino, amino, mono-C.sub.1-6
alkylamino (e.g. methylamino, ethylamino, propylamino,
isopropylamino, butylamino, etc.), di-C.sub.1-6 alkylamino (e.g.
dimethylamino, diethylamino, ethylmethylamino, dipropylamino,
diisopropylamino, dibutylamino, etc.), 3- to 6-membered cyclic
amino which may contain 1 to 3 hetero atoms selected from among
oxygen, sulfur and nitrogen as ring members in addition to carbon
and one nitrogen atom (e.g. aziridinyl, azetidinyl, pyrrolidinyl,
pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl,
piperidino, morpholino, thiomorpholino, dihydropyridyl, pyridyl,
N-methylpiperazinyl, N-ethylpiperazinyl, etc.), C.sub.1-3
alkylenedioxy (e.g. methylenedioxy, ethylenedioxy, etc.), hydroxy,
nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl,
mono-C.sub.1-6 alkylsulfamoyl (e.g. methylsulfamoyl,
ethylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl,
butylsulfamoyl, etc.), di-C.sub.1-6 alkylsulfamoyl (e.g.
diethylsulfamoyl, diethylsulfamoyl, dipropylsulfamoyl,
dibutylsulfamoyl, etc.), C.sub.1-6 alkylthio which may be
halogenated, C.sub.6-10 arylthio (e.g. phenylthio, naphthylthio,
etc.), C.sub.1-6 alkylsulfinyl (e.g. methylsulfinyl, ethylsulfinyl,
propylsulfinyl, butylsulfinyl, etc.), C.sub.6-10 arylsulfinyl (e.g.
phenylsulfinyl, naphthylsulfinyl, etc.), C.sub.1-6 alkylsulfonyl
(e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl,
etc.), and C.sub.6-10 arylsulfonyl (e.g. phenylsulfonyl,
naphthylsulfonyl, etc.).
[0110] The above-mentioned "C.sub.1-6 alkyl which may be
halogenated" includes, for example, C.sub.1-6 alkyl (e.g. methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, hexyl, etc.) optionally having 1 to 5, preferably 1 to 3,
halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.).
Specifically, mention may be made of methyl, chloromethyl,
difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl,
3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc.
[0111] The "C.sub.1-6 alkenyl which may be halogenated" includes,
for example, C.sub.2-6 alkenyl (e.g. vinyl, propenyl, isopropenyl,
2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, etc.) optionally having
1 to 5, preferably 1 to 3, halogen atoms (e.g. fluorine, chlorine,
bromine, iodine, etc.).
[0112] The "C.sub.2-6 alkynyl which may be halogenated" includes,
for example, C.sub.2-6 alkynyl (e.g. 2-butyn-1-yl, 4-pentyn-1-yl,
5-hexyn-1-yl, etc.) optionally having 1 to 5, preferably 1 to 3,
halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.).
[0113] The "C.sub.3-6 cycloalkyl which may be halogenated"
includes, for example, C.sub.3-6 cycloalkyl (e.g. cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, etc.) optionally having 1 to
5, preferably 1 to 3, halogen atoms (e.g. fluorine, chlorine,
bromine, iodine, etc.). Specifically, mention may be made of
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl,
4-chlorocyclohexyl, etc.
[0114] The "C.sub.1-6 alkoxy which may be halogenated" includes,
for example, C.sub.1-6 alkoxy optionally having 1 to 5, preferably
1 to 3, halogen atoms (e.g. fluorine, chlorine, bromine, iodine,
etc.). Specifically, mention may be made of methoxy,
difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,
propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy,
sec-butoxy, pentyloxy, hexyloxy, etc.
[0115] The "C.sub.1-6 alkylthio which may be halogenated" includes,
for example, C.sub.1-6 alkylthio (e.g. methylthio, ethylthio,
propylthio, isopropylthio, butylthio, sec-butylthio,
tert-butylthio, etc.) optionally having 1 to 5, preferably 1 to 3,
halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.).
Specifically, mention may be made of methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,
isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio,
hexylthio, etc.
[0116] The above-mentioned "hydrocarbon group" may have 1 to 5,
preferably 1 to 3, substituents selected from the group consisting
of the above-mentioned substituents in its substitutable position
or positions and when 2 or more substitutions are involved, the
substituents may be the same group or different groups.
[0117] The formula: --COR.sup.1 preferably represents carboxy which
may be esterified or amidated.
[0118] R.sup.1 preferably represents hydroxy which may be
substituted. More preferred is hydroxy.
[0119] Preferably, m is 1.
[0120] The "aromatic group" of the "aromatic group which may be
substituted" as mentioned for Ar includes, for example, aromatic
hydrocarbon groups and aromatic heterocyclic (heteroaromatic)
groups.
[0121] The "aromatic hydrocarbon group" mentioned above includes,
for example, monocyclic or fused polycyclic aromatic hydrocarbon
groups having 6 to 14 carbon atoms. Specifically, C.sub.6-14 aryl
such as phenyl, 1-naphthyl, 2-naphthyl, anthryl, etc. can be
mentioned. Preferred is phenyl, 1-naphthyl or 2-naphthyl.
Particularly preferred is phenyl.
[0122] The "aromatic heterocyclic group" mentioned above includes,
for example, 5- to 10-membered monocyclic or its fused
heteroaromatic groups containing one or more, for example 1 to 4,
hetero atoms selected from among nitrogen, sulfur and oxygen as a
ring member other than carbon. Specifically, it includes monovalent
groups available upon elimination of any one hydrogen atom each
from 5- or 6-membered monocyclic heteroaromatic rings or fused ring
systems consisting of any such heteroaromatic ring and 1 or 2
(preferably 1) aromatic rings (e.g. benzene ring, pyridine ring,
etc.), such as thiophene, furan, pyrrole, imidazole, pyrazole,
pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole,
triazine, 1,2,3-oxadiazole, 1,2,3-triazole, 1,2,4-triazole,
1,3,4-thiadiazole, etc. Preferred examples of the "aromatic
heterocyclic group" include 5- to 10-membered heteroaromatic groups
such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl,
4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl,
4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl,
2-benzothiazolyl, 2-benzothienyl, benzofuranyl, 2-thienyl,
3-thienyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-pyridothiazolyl,
etc. More preferred are 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-quinolyl, 3-quinolyl, 4-quinolyl, etc. Those heteroaromatic
groups may be in the N-oxide form, where applicable.
[0123] The "substituent" for the "aromatic group which may be
substituted" as mentioned for Ar includes, for example, halogen
(e.g. fluorine, chlorine, bromine, iodine, etc.), C.sub.1-3
alkylenedioxy (e.g. methylenedioxy, ethylenedioxy, etc.), nitro,
cyano, C.sub.1-6 alkyl which may be halogenated, C.sub.3-6
cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
etc.), C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6
alkylthio which may be halogenated, hydroxy, amino, mono-C.sub.1-6
alkylamino (e.g. methylamino, ethylamino, propylamino,
isopropylamino, butylamino, etc.), di-C.sub.1-6 alkylamino (e.g.
dimethylamino, diethylamino, ethylmethylamino, dipropylamino,
dibutylamino, etc.), C.sub.1-6 alkyl-carbonyl (e.g. acetyl,
propionyl, etc.), carboxy, C.sub.1-6 alkoxy-carbonyl (e.g.
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,
etc.), carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl (e.g.
methylcarbamoyl, ethylcarbamoyl, etc.), di-C.sub.1-6
alkyl-carbamoyl (e.g. dimethylcarbamoyl, diethylcarbamoyl, etc.),
C.sub.6-10 aryl-carbamoyl (e.g. phenylcarbamoyl, naphthylcarbamoyl,
etc.), sulfa, C.sub.1-6 alkylsulfonyl (e.g. methylsulfonyl,
ethylsulfonyl, etc.), C.sub.6-10 aryl (e.g. phenyl, naphthyl,
etc.), and C.sub.6-10 aryloxy (e.g. phenyloxy, naphthyloxy, etc.).
When the substituent is C.sub.1-3 alkylenedioxy, it preferably
forms a ring in combination with the two adjacent carbon atoms.
[0124] The above-mentioned "C.sub.1-6 alkyl which may be
halogenated", "C.sub.1-6 alkoxy which may be halogenated", and
"C.sub.1-6 alkylthio which may be halogenated" may be the same
groups as those respectively mentioned above in the definition of
"the substituent" for the "hydrocarbon group which may be
substituted".
[0125] The "aromatic group" of the "aromatic group which may be
substituted" may have 1 to 5, preferably 1 to 3, substituents as
selected from among the above-mentioned substituents in its
substitutable position or positions of the aromatic ring and where
two or more substitutions are involved, the substituents group may
be the same group or different groups.
[0126] Preferably, Ar is C.sub.6-14 aryl which may be substituted,
etc. More preferably, Ar is phenyl which may be halogenated.
[0127] The "divalent straight-chain group which have 1 to 6 atoms
and may be substituted" as mentioned for X includes, for example,
divalent groups of the formula: --Xa--Xb-- wherein Xa represents a
bond, S, SO, SO.sub.2, O, or NR.sup.4; Xb represents a bond or a
divalent aliphatic hydrocarbon group having 1 to 5 atoms
(preferably 1 to 4 atoms) which may be substituted and may contain
oxygen, nitrogen, or sulfur. In the above formula, R.sup.4
represents hydrogen, C.sub.1-6 alkyl (e.g. methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, pentyl, hexyl, etc.), C.sub.3-6
cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, etc.),
C.sub.6-14 aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, etc.),
C.sub.7-11 aralkyl (e.g. benzyl, phenethyl, etc.), formyl,
C.sub.1-6 alkyl-carbonyl (e.g. acetyl, propionyl, butyryl,
isobutyryl, etc.), or C.sub.6-10 aryl-carbonyl (e.g. benzoyl,
naphthoyl, etc.), for instance.
[0128] Xa is preferably a bond, S, SO, SO.sub.2, O, or NH. More
preferred is S, SO, SO.sub.2, O, or NH. Particularly preferred is
S, SO or SO.sub.2. Most preferably, Xa is S.
[0129] The "divalent aliphatic hydrocarbon group having 1 to 5
atoms which may contain sulfur, oxygen, or nitrogen" of the
"divalent aliphatic hydrocarbon group having 1 to 5 atoms which may
be substituted and may contain sulfur, oxygen, or nitrogen" as
mentioned for Xb means a divalent aliphatic hydrocarbon group
having 1 to 5 atoms which is available upon elimination of two
hydrogen atoms from a saturated or an unsaturated aliphatic
hydrocarbon and optionally containing 1 or 2 (preferably 1) sulfur,
oxygen, or nitrogen atom between carbon atoms or in its terminal
position. Specifically, the examples include
[0130] (i) C.sub.1-5 alkylene (e.g. --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
--(CH.sub.2).sub.5--, etc.)
[0131] (ii) C.sub.2-5 alkenylene (e.g. --CH.dbd.CH--,
--CH.sub.2--CH.dbd.CH--, --CH.sub.2--CH.dbd.CH--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.dbd.CH--,
--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.su- b.2--, etc.)
[0132] (iii) C.sub.2-5 alkynylene (e.g. --C.ident.C--,
--CH.sub.2--C.ident.C--, --CH.sub.2--C.ident.C--CH.sub.2--,
etc.)
[0133] (iv) groups of the formula:
--(CH.sub.2).sub.p--Xc--(CH.sub.2).sub.- q-- wherein Xc represents
S, SO, SO.sub.2, O, or NR .sup.4a; p and q independently represent
an integer of 0 to 4 and p+q is an integer of 0 to 4. R.sup.4a- in
this formula includes the same groups as those mentioned for
R.sup.4.
[0134] The above-mentioned "divalent aliphatic hydrocarbon group
having 1 to 5 atoms which may contain sulfur, oxygen, or nitrogen"
is preferably C.sub.1-5 alkylene or C.sub.2-5 alkenylene.
Particularly preferred is methylene.
[0135] The "substituent" for the "divalent straight-chain group
which have 1 to 6 atoms and may be substituted" or for the
"divalent aliphatic hydrocarbon group having 1 to 5 atoms which may
be substituted and may contain sulfur, oxygen, or nitrogen"
includes, for example, halogen (e.g. fluorine, chlorine, bromine,
iodine, etc.), nitro, cyano, C.sub.1-6 alkyl which may be
halogenated, C.sub.3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, etc.), C.sub.7-11 aralkyl (e.g. benzyl,
phenethyl, etc.), C.sub.1-6 alkoxy which may be halogenated,
C.sub.1-6 alkylthio which may be halogenated, hydroxy, amino,
mono-C.sub.1-6 alkylamino (e.g. methylamino, ethylamino,
propylamino, isopropylamino, butylamino, etc.), di-C.sub.1-6
alkylamino (e.g. dimethylamino, diethylamino, ethylmethylamino,
dipropylamino, dibutylamino, etc.), C.sub.6-10 aryloxy (e.g.
phenyloxy, naphthyloxy, etc.), C.sub.1-6 alkyl-carbonyl (e.g.
acetyl, propionyl, butyryl, isobutyryl, etc.), C.sub.6-10
aryl-carbonyl (e.g. benzoyl, naphthoyl, etc.), oxo, and aromatic
groups which may be substituted.
[0136] The above-mentioned "C.sub.1-6 alkyl which may be
halogenated", "C.sub.1-6 alkoxy which may be halogenated", and
"C.sub.1-6 alkylthio which may be halogenated" include those
specific groups as respectively mentioned as the substituent for
the "hydrocarbon group which may be substituted".
[0137] The above-mentioned "aromatic group which may be
substituted" includes the same groups as those mentioned for the
"aromatic group which may be substituted" for Ar.
[0138] Among those substituents, halogen, hydroxy, and an aromatic
group which may be substituted are preferred. Particularly
preferred is C.sub.6-14 aryl.
[0139] Those substituents may occur in 1 to 5, preferably 1 to 3,
substitutable positions and where two or more substitutions are
involved, the substituents may be the same group or different
groups.
[0140] Xb is preferably (i) a bond, (ii) C.sub.1-5 alkylene which
may be substituted by 1 to 3 substituents selected from the group
consisting of halogen, hydroxy and an aromatic group which may be
substituted, or (iii) C.sub.2-5 alkenylene which may be substituted
by 1 to 3 substituents selected from the group consisting of
halogen, hydroxy and an aromatic group which may be substituted.
Preferred examples of the above "aromatic group which may be
substituted" are C.sub.6-14 aryl or 5- to 10-membered aromatic
heterocyclic group each containing 1 to 4 hetero atoms selected
from among nitrogen, sulfur, and oxygen as ring members in addition
to carbon, each of which may be substituted by 1 to 3 substituents
selected from the group consisting of halogen, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy and hydroxy.
[0141] It is also preferable that this "aromatic group which may be
substituted" be present on the carbon atom in the terminal position
where Ar is attached.
[0142] More preferably, Xb is (i) a bond or (ii) a C.sub.1-5
alkylene which may be substituted by an aromatic group (preferably
C.sub.6-14 aryl) which may be substituted. Particulary preferred is
a C.sub.1-5 alkylene which may be substituted by a C.sub.6-14 aryl
which may be substituted. Most preferred is a C.sub.1-3 alkylene
which may be substituted by a phenyl which may be halogenated.
[0143] X is preferably a divalent group of the formula:
--Xa.sup.1--Xb.sup.1--
[0144] wherein Xa.sup.1 is S, SO or SO.sub.2; and Xb.sup.1 is
C.sub.1-5 alkylene which may be substituted by a C.sub.6-14 aryl
which may be substituted by 1 to 3 substituents selected from the
group consisting of halogen, C.sub.1-3 alkylenedioxy, nitro, cyano,
C.sub.1-6 alkyl which may be halogenated, C.sub.3-6 cycloalkyl,
C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio
which may be halogenated, hydroxy, amino, mono-C.sub.1-6
alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkyl-carbonyl,
carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6
alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10
aryl-carbamoyl, sulfo, C.sub.1-6 alkylsulfonyl, C.sub.6-10 aryl and
C.sub.6-10 aryloxy. Xa.sup.1 is preferably S. Xb.sup.1 is
preferably C.sub.1-3 alkylene which may be substituted by a phenyl
which may be halogenated.
[0145] R.sup.2 in --N(R.sup.2)-- for Y represents hydrogen or a
substituent group and this "substituent group" may for example be a
hydrocarbon group or an acyl.
[0146] The above-mentioned "hydrocarbon group" includes the same
hydrocarbon group as the "hydrocarbon group" of the "hydrocarbon
group which may be substituted".
[0147] The above-mentioned "acyl" may for example be an acyl
derived from a carboxylic acid or a sulfonic acid. Preferred
examples are formyl, C.sub.1-6 alkyl-carbonyl (e.g. acetyl,
propionyl, butyryl, isobutyryl, etc.), C.sub.6-10 aryl-carbonyl
(e.g. benzoyl, naphthoyl, etc.), C.sub.7-11 aralkyl-carbonyl (e.g.
benzylcarbonyl, phenethylcarbonyl, naphthylmethylcarbonyl, etc.),
C.sub.1-6 alkylsulfonyl (e.g. mesyl, ethylsulfonyl, propylsulfonyl,
etc.), C.sub.6-10 arylsulfonyl which may be substituted, and
C.sub.7-11 aralkylsulfonyl (e.g. benzylsulfonyl, phenethylsulfonyl,
naphthylmethylsulfonyl, etc.).
[0148] The "C.sub.6-10 arylsulfonyl" of the above-mentioned
"C.sub.6-10 arylsulfonyl which may be substituted" includes, for
example, phenylsulfonyl and naphthylsulfonyl. The "substituent" for
this "C.sub.6-10 arylsulfonyl which may be substituted" includes,
for example, C.sub.1-6 alkyl (e.g. methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, pentyl, hexyl, etc.), C.sub.1-6 alkoxy
(e.g. methoxy, ethoxy, propoxy, butoxy, etc.), and nitro. The
"C.sub.6-10 arylsulfonyl" of the "C.sub.6-10 arylsulfonyl which may
be substituted" may have 1 to 3 substituents selected from among
the substituents mentioned above and where two or more substituents
are present, they may be the same group or different groups.
Specific examples are tosyl and m-nitrobenzenesulfonyl.
[0149] R.sup.2 is preferably hydrogen.
[0150] Y is preferably --S--, --O--, or --NH--. More preferred is
--S--.
[0151] R.sup.3 in --C(R.sup.3).dbd. for Z represents hydrogen or a
hydrocarbon group. The "hydrocarbon group" includes the same
hydrocarbon group as the "hydrocarbon group" of the "hydrocarbon
group which may be substituted".
[0152] R.sup.3 is preferably hydrogen.
[0153] Z is preferably --N.dbd..
[0154] The "substituent" for the "benzene ring which may be
substituted by a substituent, in addition to a group of the
formula: --O(CH.sub.2).sub.mCOR.sup.1 (wherein the respective
symbols have the same meanings as defined above)" as mentioned for
ring A may number 1 to 3 and includes the same groups as the
substituents mentioned for the "aromatic group which may be
substituted" for Ar. Where two or more substitutions are involved,
the substituents may be the same group or different groups.
[0155] The "5- to 7-membered ring" of the "5- to 7-membered ring
which may be substituted" as mentioned for ring B is a 5- to
7-membered carbocyclic ring or a 5- to 7-membered heterocyclic ring
which may contain 1 to 3 hetero atoms selected from among oxygen,
sulfur, and nitrogen (preferably one hetero atom selected from the
group consisting of oxygen and sulfur) as ring members in addition
to carbon. Among preferred examples of the "5- to 7-membered ring"
are 5- to 7-membered rings of the formula: 15
[0156] wherein Ba represents --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --CH.dbd.CH--, --O--, --O--CH.sub.2--,
--CH.sub.2--O--, --O--CH.sub.2--CH.sub.2--,
--CH.sub.2--O--CH.sub.2--, --S(O).sub.r--,
--S(O).sub.r--CH.sub.2--, or --S(O).sub.r--(CH.sub.2).sub- .2--
wherein r represents an integer of 0 to 2.
[0157] Preferably, Ba is --CH.sub.2--, --(CH.sub.2).sub.2--,
--O--CH.sub.2-- or --O--.
[0158] The "substituent" for the above-mentioned "5 to 7-membered
ring" may for example be a hydrocarbon group. This "hydrocarbon
group" includes the same hydrocarbon group as mentioned for the
"hydrocarbon group" of the "hydrocarbon group which may be
substituted".
[0159] This "5- to 7-membered ring" may have 1 to 3 substituents
selected from among the above-mentioned substituents in
substitutable positions and where two or more substitutions are
involved, the substituents may be the same group or different
groups.
[0160] Among the compounds of formula (I), preferred is the
compound of the following formula or a salt thereof. 16
[0161] wherein the respective symbols have the same meanings as
defined above. More preferred is the compound, inclusive of its
salt, wherein R.sup.1 is hydroxy; m is 1;
[0162] Ar is phenyl which may be halogenated;
[0163] X is a divalent group of the formula: --Xa.sup.2--Xb.sup.2--
wherein Xa.sup.2 is S, SO or SO.sub.2; and Xb.sup.2 is C.sub.1-3
alkylene which may be substituted by a phenyl which may be
halogenated; and
[0164] ring B is a ring of the formula: 17
[0165] wherein Ba.sup.2 is --CH.sub.2--, --(CH.sub.2).sub.2--,
--O--CH.sub.2-- or --O--.
[0166] In compound (I), the preferred is a compound wherein R.sup.1
is hydroxy which may be substituted by a C.sub.1-6 alkyl;
[0167] m is an integer an 1 to 3;
[0168] Ar is C.sub.6-14 aryl which may be substituted by 1 to 3
substituents selected from the group consisting of halogen, nitro,
cyano, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy
and C.sub.6-10 aryl;
[0169] X is (i) a bond or
[0170] (ii) a divalent group of the formula: --Xa.sup.3--Xb.sup.3--
wherein Xa.sup.3 is a bond, S. SO, SO.sub.2, O or NH; and
[0171] Xb.sup.3 is a C.sub.1-5 alkylene or C.sub.2-5 alkenylene
group which may be substituted by a phenyl which may be
halogenated;
[0172] Y is --S--;
[0173] Z is --N.dbd.;
[0174] ring A is a benzene ring which may be substituted by 1 to 3
C.sub.1-6 alkyl, in addition to a group of the formula:
--O(CH.sub.2).sub.mCOR.sup.1; and
[0175] ring B is a ring of the formula: 18
[0176] wherein Ba.sup.3 is --CH.sub.2--, --(CH.sub.2).sub.2--,
--O--CH.sub.2-- or --O--.
[0177] The preferred species of compound (I) of the invention
include:
[0178]
[(2-diphenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]ac-
etic acid,
[0179]
[(2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)o-
xy]acetic acid,
[0180]
[(2-diphenylmethyl)sulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)o-
xy]acetic acid,
[0181]
[(2-bis(3-fluorophenyl)methylsulfonyl-4,5-dihydronaphto[1,2-d]thiaz-
ol-6-yl)oxy]acetic acid,
[0182]
[(2-bis(2-fluorophenyl)methylsulfonyl-4,5-dihydronaphto[1,2-d]thiaz-
ol-6-yl)oxy]acetic acid, and a salt thereof. As the salt, a
pharmaceutically acceptable metal salt is preferred.
[0183] Depending on the kinds of substituents it possesses,
compound (I) gives rise to stereoisomers. Such stereoisomers and
mixtures thereof also fall within the scope of the invention.
[0184] The salt of compound (I) according to the present invention
typically includes various pharmacologically acceptable salts.
Examples of the salt include salts with inorganic bases, ammonium
salts, salts with organic bases, salts with inorganic acids, salts
with organic acids, and salts with basic or acidic amino acids. The
preferred salt with an inorganic base includes, for example, alkali
metal salts such as sodium salt, potassium salt, etc., alkaline
earth metal salts such as calcium salt, magnesium salt, etc., and
aluminum salt. The preferred salt with an organic base includes,
for example, salts with trimethylamine, triethylamine, pyridine,
picoline, 2,6-lutidine, ethanolamine, diethanolamine,
triethanolamine, cyclohexylamine, dicyclohexylamine,
N,N'-dibenzylethylenediamine, etc. The preferred salt with an
inorganic acid includes, for example, salts with hydrochloric acid,
hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
The preferred salt with an organic acid includes, for example,
salts with formic acid, acetic acid, trifluoroacetic acid, phthalic
acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric
acid, succinic acid, malic acid, methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, etc. The preferred
salt with a basic amino acid includes, for example, salts with
arginine, lysine, ornithine, etc. The preferred salt with an acidic
amino acid includes, for example, salts with aspartic acid,
glutamic acid, etc.
[0185] Particularly preferred are pharmaceutically acceptable
salts. For example, when the compound (I) contains a basic
functional group, the preferred salt includes, for example, salts
with such inorganic acids as hydrochloric acid, hydrobromic acid,
nitric acid, sulfuric acid, phosphoric acid, etc. and salts with
such organic acids as acetic acid, phthalic acid, fumaric acid,
oxalic acid, tartaric acid, maleic acid, citric acid, succinic
acid, methanesulfonic acid, p-toluenesulfonic acid, etc. When an
acidic functional group is present, for example, alkali metal salts
such as sodium salt and potassium salt, etc., alkaline earth metal
salts such as calcium salt and magnesium salt, and ammonium salts
are preferred.
[0186] The process for producing the compound (I) of the invention
is now described.
[0187] Compound (I) of the invention can be produced by the per se
known processes or by any processes analogous thereto, for example
in accordance with the following reaction schemes (Reaction scheme
1 and Reaction scheme 2). The symbols used for the respective
compounds in those schemes have the same meanings as defined above.
Compounds (II) to (XIV) in the reaction schemes include their
salts. The salts may for example be of the same kind as the salt of
compound (I). 19
[0188] Compound (II) wherein R.sup.a represents a hydrocarbon
group; the other symbols have the same meanings as defined above,
can be produced by the per se known method, for example the process
described in Berichte deutschen chemischen Gesellschaft 58B, 1947
(1925), or by any process analogous thereto.
[0189] The "hydrocarbon group" mentioned for R.sup.a includes the
same hydrocarbon group as those mentioned for the "hydrocarbon
group".
[0190] Compound (VI) wherein R.sup.b represents a hydrocarbon
group, can be produced by the per se known method, for example the
process described in Journal of the Chemical Society, 1434 (1951),
or by any process analogous thereto.
[0191] The "hydrocarbon group" mentioned for R.sup.b includes the
same hydrocarbon group as those mentioned above for the
"hydrocarbon group".
[0192] Compound (VII) can be produced by the per se known method,
for example the process described in Organic Syntheses, 27, 73
(1947), or by any process analogous thereto.
[0193] Compound (IX) may be purchased from a commercial source if
it is available on the market or can be produced by the per se
known method, for example the process described in Shin Jikken
Kagaku Koza (New Series in Experimental Chemistry) 14, III,
1628-1644 (1978).
[0194] Compound (III) can be produced by hydrolyzing compound (II)
using an acid catalyst. The acid catalyst includes, for example,
mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric
acid, etc., silicon compounds such as trimethylsilyl iodide
(Me.sub.3SiI), trimethylsilyl chloride (Me.sub.3SiCl), etc., and
Lewis acids such as aluminum chloride, boron tribromide, etc. If
necessary, an additive as ethanedithiol or sodium iodide may be
used in combination with a Lewis acid. The amount of the acid
catalyst, taking a mineral acid as an example, is generally about 1
to 100 moles, preferably about 10 to 50 moles, per mole of compound
(II), and when a silicon compound or a Lewis acid is used, is
generally about 1 to 20 moles, preferably about 1 to 5 moles, per
mole of compound (II). The amount of the additive used in
combination with a Lewis acid is generally about 0.1 to 20 moles,
preferably about 1 to 10 moles, per mole of compound (II).
[0195] This reaction can be advantageously carried out in the
absence of a solvent or in the presence of a solvent indifferent to
the reaction (hereinafter referred to as an inert solvent). There
is no particular limitation on the inert solvent that can be used
unless the progress of the reaction is interferred with. When a
mineral acid is used, for instance, the solvent is preferably water
or mixtures of water with organic solvents, for example, alcohols
such as methanol, ethanol, propanol, etc., saturated hydrocarbons
such as cyclohexane, hexane, etc., aromatic hydrocarbons such as
benzene, toluene, xylene, etc., ethers such as tetrahydrofuran,
dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether,
etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide,
hexamethylphosphoric triamide, etc., sulfoxides such as dimethyl
sulfoxide etc., and halogenated hydrocarbons such as
dichloromethane, chloroform, carbon tetrachloride,
1,2-dichloroethane, etc.
[0196] When a silicon compound or a Lewis acid is used, the solvent
is preferably saturated hydrocarbons such as cyclohexane, hexane,
etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc.,
ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane,
diethyl ether, diisopropyl ether, etc., amides such as
N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric
triamide, etc., sulfoxides such as dimethyl sulfoxide etc.,
halogenated hydrocarbons such as dichloromethane, chloroform,
carbon tetrachloride, 1,2-dichloroethane, etc., and mixtures of
these solvents.
[0197] The reaction time is generally 30 minutes to 24 hours,
preferably 30 minutes to 6 hours. The reaction temperature is
generally -78.degree. C. to 200.degree. C., preferably -20.degree.
C. to 150.degree. C.
[0198] The reaction product can be used, either as the reaction
mixture as such or in a partially purified form, in the next
reaction. However, the product compound can be isolated from the
reaction mixture in the routine manner and expediently purified by
the conventional purification procedure (e.g. recrystallization,
distillation, chromatography, etc.).
[0199] Compound (IV) can be produced by reacting compound (III)
with a compound of the formula: L--(CH.sub.2).sub.mCOR.sup.1
wherein L represents a leaving group; R.sup.1 is as defined above,
and a salt thereof.
[0200] The "leaving group" for L includes, for example, halogen
(e.g. fluorine, chlorine, bromine, iodine, etc.), C.sub.1-6
alkylsulfonyloxy (e.g. methanesulfonyloxy, ethanesulfonyloxy,
etc.), and C.sub.6-10 arylsulfonyloxy which may be substituted. The
"C.sub.6-10 arylsulfonyloxy which may be substituted" includes, for
example, C.sub.6-10 arylsulfonyloxy (e.g. phenylsulfonyloxy,
naphthylsulfonyloxy, etc.) which may be substituted by 1 to 3
substituents selected from the group consisting of C.sub.1-6 alkyl,
C.sub.1-6 alkoxy and nitro. Specifically, it includes
m-nitrobenzenesulfonyloxy and p-toluenesulfonyloxy, among
others.
[0201] The base includes, for example, inorganic bases, e.g. alkali
metal hydroxides such as sodium hydroxide, potassium hydroxide,
etc., alkali metal alkoxides such as sodium methoxide, sodium
ethoxide, potassium tert-butoxide, etc., alkali metal hydrides such
as sodium hydride, potassium hydride, etc., metal amides such as
sodium amide, lithium diisopropylamide, lithium
hexamethyldisilazide, etc., and basic salts such as potassium
hydrogen carbonate, sodium carbonate, potassium carbonate, sodium
acetate, etc. The amount of the base is generally about 0.5 to 5
moles, preferably about 1 to 3 moles, per mole of compound
(III).
[0202] The proportion of the compound of the formula:
L--(CH.sub.2).sub.mCOR' wherein the respective symbols have same
meanings as defined above, is about 0.8 to 2 moles, preferably
about 1 to 1.5 moles, per mole of compound (III).
[0203] This reaction can be carried out with advantage in an inert
solvent. Among such solvents are alcohols such as methanol,
ethanol, propanol, etc., saturated hydrocarbons such as
cyclohexane, hexane, etc., aromatic hydrocarbons such as benzene,
toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane,
1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., amides
such as N,N-dimethylformamide, N,N-dimethylacetamide,
hexamethylphosphoric triamide, etc., sulfoxides such as dimethyl
sulfoxide etc., halogenated hydrocarbons such as dichloromethane,
chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., ketones
such as acetone, methyl ethyl ketone, etc., water, and mixtures of
these solvents.
[0204] The reaction time is generally 10 minutes to 8 hours,
preferably 30 minutes to 3 hours. The reaction temperature is
generally 0.degree. C. to 120.degree. C., preferably 25.degree. C.
to 100.degree. C.
[0205] The reaction product can be directly used, either as the
reaction mixture as such or in a partially purified form, in the
next reaction. If desired, however, the product compound can be
isolated from the reaction mixture in the routine manner and
expediently purified by the conventional purification procedure
(e.g. recrystallization, distillation, chromatography, etc.).
[0206] Where R.sup.1 in compound (IV) is hydroxy, the compound can
be obtained by esterification or ester-exchange reaction in the per
se known method using an acid as a catalyst, if desired.
[0207] For example, the compound (IV) wherein R.sup.1 is hydroxy
may be reacted with the corresponding alcohol or ester using an
acid as a catalyst. The corresponding alcohol mentioned above
includes a compound of the formula: R.sup.1a--OH wherein R.sup.1a
represents the "substituent" of the "hydroxy group which may be
substituted" for above R.sup.1. The corresponding ester includes a
compound of the formula: R--COOR.sup.1b wherein R represents a
hydrocarbon group; and R.sup.1b has same meanings as mentioned for
R.sup.1a.
[0208] The "hydrocarbon group" mentioned for R includes the same
hydrocarbon group as those mentioned for the "hydrocarbon
group".
[0209] The amount of the corresponding alcohol or ester to be used
is about 10 to 1,000 moles per mole of compound (IV).
[0210] While the above alcohol or ester is generally expected to
serve as the solvent as well, other solvents, for example saturated
hydrocarbons such as cyclohexane, hexane, etc., aromatic
hydrocarbons such as benzene, toluene, xylene, etc., ethers such as
tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether,
diisopropyl ether, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, hexamethylphosphoric triamide, etc.,
sulfoxides such as dimethyl sulfoxide etc., halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride, 1,2-dichloroethane, etc., and mixtures of these
solvents can be optionally employed.
[0211] The acid catalyst mentioned above includes, for example,
mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric
acid, etc., sulfonic acids such as p-toluenesulfonic acid,
methanesulfonic acid, etc., and Lewis acids such as boron
trifluoride ether complexes. The amount of the acid catalyst to be
used is about 0.01 to 2 moles, preferably about 0.1 to 1 mole, per
mole of compound (IV).
[0212] The reaction time is generally 15 minutes to 24 hours,
preferably 30 minutes to 6 hours. The reaction temperature is
generally -10.degree. C. to 150.degree. C., preferably 50.degree.
C. to 120.degree. C.
[0213] The compound (IV) wherein R.sup.1 is hydroxy may be reacted
with a halogenating agent (e.g. thionyl chloride, phosphorus
oxychloride, etc.) to give the acid halide (chloride) which can
then be reacted with the corresponding alcohol. The corresponding
alcohol includes a compound of the formula: R.sup.1a--OH wherein
R.sup.1a has same meanings as mentioned above. The proportion of
the halogenating agent is generally about 1 to 50 moles, preferably
about 1 to 10 moles, per mole of compound (IV). The proportion of
the corresponding alcohol is generally about 1 to 5 moles,
preferably about 1 to 2 moles, per mole of compound (IV).
[0214] This reaction can be carried out with advantage in the
absence of a solvent or in the presence of an inert solvent. There
is no particular limitation on the kind of inert solvent unless the
progress of the reaction is interferred with. The inert solvent
includes, for example, esters such as methyl acetate, ethyl
acetate, amyl acetate, etc., saturated hydrocarbons such as
cyclohexane, hexane, etc., aromatic hydrocarbons such as benzene,
toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane,
1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., amides
such as N,N-dimethylformamide, N,N-dimethylacetamide,
hexamethylphosphoric triamide, etc., sulfoxides such as dimethyl
sulfoxide etc., halogenated hydrocarbons such as dichloromethane,
chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., and
mixtures of these solvents.
[0215] The reaction time is generally 30 minutes to 6 hours,
preferably 30 minutes to 2 hours. The reaction temperature is
generally -10.degree. C. to 150.degree. C., preferably 0.degree. C.
to 100.degree. C.
[0216] The reaction product can be directly used, either as the
reaction mixture as such or in a partially purified form, in the
next reaction. If desired, however, the product compound can be
isolated from the reaction mixture in the routine manner and
expediently purified by the conventional purification procedure
(e.g. recrystallization, distillation, chromatography, etc.).
[0217] Compound (V) can be produced by reacting compound (IV) with
a copper (II) halide (e.g. copper (II) bromide). The proportion of
the copper halide is generally about 1 to 3 moles, preferably about
1.5 to 2 moles, per mole of compound (V).
[0218] This reaction can be carried out with advantage in an inert
solvent. There is no particular limitation on the kind of inert
solvent unless the progress of the reaction is interferred with.
The inert solvent includes, for example, esters such as methyl
acetate, ethyl acetate, amyl acetate, etc., saturated hydrocarbons
such as cyclohexane, hexane, etc., aromatic hydrocarbons such as
benzene, toluene, xylene, etc., ethers such as tetrahydrofuran,
dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether,
etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide,
hexamethylphosphoric triamide, etc., sulfoxides such as dimethyl
sulfoxide etc., halogenated hydrocarbons such as dichloromethane,
chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., and
mixtures of these solvents.
[0219] The reaction time varies with the species of reagent and
solvent used but is generally 1 to 24 hours, preferably 1 to 14
hours. The reaction temperature is generally 0.degree. C. to
150.degree. C., preferably 20.degree. C. to 100.degree. C.
[0220] If desired, compound (V) can also be produced by reacting
compound (IV) with a halogen (e.g. bromine, etc.) or a halogenating
reagent (e.g. pyridinum hydrobromide perbromide, etc.) optionally
in the presence of a base. The proportion of the halogen or the
halogenating reagent per mole of compound (IV) is about 1 to 2
moles and preferably about 1 to 1.1 moles. The base that can be
used for this purpose includes, for example, inorganic bases, e.g.
alkali metal hydroxides such as sodium hydroxide, potassium
hydroxide, etc. and ammonia, organic bases such as triethylamine,
pyridine, etc., and basic salts such as potassium hydrogen
carbonate, sodium carbonate, potassium carbonate, sodium acetate,
etc. The proportion of the base per mole of compound (V) is
generally about 0.1 to 5 moles and preferably about 1 to 2
moles.
[0221] This reaction can be advantageously carried out in an inert
solvent. The solvent is not so critical in kind unless the progress
of the reaction is interferred with. The inert solvent includes,
for example, alcohols such as methanol, ethanol, propanol, etc.,
saturated hydrocarbons such as cyclohexane, hexane, etc., organic
acids such as formic acid, acetic acid, etc., ethers such as
tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether,
diisopropyl ether, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, carbon tetrachloride,
1,2-dichloroethane, etc., and mixtures of these solvents.
[0222] The reaction time is generally 5 minutes to 5 hours,
preferably 10 minutes to 1 hour. The reaction temperature is
generally -10.degree. C. to 100.degree. C., preferably 0.degree. C.
to 60.degree. C.
[0223] The reaction product can be directly used, either as the
reaction mixture as such or in a partially purified form, in the
next reaction. If desired, however, the product compound can be
isolated from the reaction mixture in the routine manner and
expediently purified by the conventional purification procedure
(e.g. recrystallization, distillation, chromatography, etc.).
[0224] Compound (VIII) can be produced by reacting compound (V)
with compound (II) or compound (VII) optionally in the presence of
a base or an acid. The amount of compound (VI) or compound (VII)
per mole of compound (V) is generally about 1 to 1.5 moles and
preferably about 1 to 1.2 moles. The base that can be used includes
inorganic bases such as alkali metal hydroxides, e.g. sodium
hydroxide, potassium hydroxide, etc., ammonia, etc., organic bases
such as triethylamine, pyridine, etc., and basic salts such as
potassium hydrogen carbonate, sodium carbonate, potassium
carbonate, sodium acetate, etc. The acid that can be used includes
carboxylic acids such as acetic acid, trifluoroacetic acid,
propionic acid, etc. The amount of the base or the acid is
generally about 0.1 to 5 moles, preferably about 1 to 2 moles, per
mole of compound (V).
[0225] This reaction can be conducted with advantage in an inert
solvent. The solvent is not so critical in kind unless the progress
of the reaction is interferred with. The preferred inert solvent
includes, for example, alcohols such as methanol, ethanol,
propanol, etc., ketones such as acetone, methyl ethyl ketone, etc.,
nitriles such as acetonitrile etc., amides such as
N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric
triamide, etc., carboxylic acid such as acetic acid, etc., water,
and mixtures of these solvents.
[0226] The reaction time varies with the species of reactants and
solvent used but is generally 30 minutes to 24 hours, preferably 30
minutes to 14 hours. The reaction temperature is generally
0.degree. C. to 150.degree. C. and preferably 30.degree. C. to
100.degree. C.
[0227] The reaction product can be directly used, either as the
reaction mixture as such or in a partially purified form, in the
next reaction. If desired, however, the product compound can be
isolated from the reaction mixture in the routine manner and
expediently purified by the conventional purification procedure
(e.g. recrystallization, distillation, chromatography, etc.).
[0228] Compound (I) can be produced by reacting compound (V) with
compound (IX) optionally in the presence of an acid or a base. The
proportion of compound (IX) per mole of compound (V) is generally
about 0.8 to 3 moles and preferably 1 to 1.3 moles. The acid that
can be used includes, for example, mineral acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, etc. The base
that can be used includes, for example, inorganic bases such as
alkali metal hydroxides, e.g. sodium hydroxide, potassium
hydroxide, etc., ammonia, etc., organic bases such as
triethylamine, pyridine, etc., and basic salts such as potassium
hydrogen carbonate, sodium carbonate, potassium carbonate, sodium
acetate, etc. The amount of the acid or base is about 1 to 1.5
moles, preferably about 1 to 1.3 moles, per mole of compound
(V).
[0229] This reaction is conducted with advantage in an inert
solvent. The inert solvent that can be used includes, for example,
amides such as N,N-dimethylformamide, N,N-dimethylacetamide,
hexamethylphosphoric triamide, etc., nitriles such as acetonitrile
etc., ketones such as acetone, methyl ethyl ketone, etc., alcohols
such as methanol, ethanol, propanol, etc., ethers such as
tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether,
diisopropyl ether, etc., halogenated hydrocarbons such as
dichloromethane, chloroform, carbon tetrachloride,
1,2-dichloroethane, etc., trifluoroacetic anhydride, water, and
mixtures of these solvents.
[0230] The reaction time is generally 30 minutes to 48 hours,
preferably 1 to 24 hours. The reaction temperature is generally
0.degree. C. to 150.degree. C., preferably 25.degree. C. to
100.degree. C.
[0231] Alternatively, compound (I) can be produced by subjecting
the X' moiety of compound (VIII) to alkylation optionally in the
presence of a base. Compound (VIII) may be its tautomer. The
tautomer may be a compound of the formula: 20
[0232] wherein X" represents S, O, or NH; the other symbols have
the same meanings as defined above.
[0233] The alkylation can be carried out in the per se known
method. The alkylating agent may for example be a compound of the
formula: Ar--Xb--L wherein the respective symbols have the same
meanings as defined above. The proportion of the alkylating agent
is generally about 0.8 to 5 moles, preferably 1 to 2 moles, per
mole of compound (VIII).
[0234] The base that can be used includes, for example, inorganic
bases such as alkali metal hydroxides, e.g. sodium hydroxide,
potassium hydroxide, etc., organic bases such as triethylamine,
pyridine, etc., alkali metal alkoxides such as sodium methoxide,
sodium ethoxide, potassium tert-butoxide, etc., alkali metal
hydrides such as sodium hydride, potassium hydride, etc., metal
amides such as sodium amide, lithium diisopropylamide, lithium
hexamethyldisilazide, etc., and basic salts such as potassium
hydrogen carbonate, sodium carbonate, potassium carbonate, sodium
acetate, etc. The proportion of the base is about 1 to 5 moles,
preferably about 1 to 1.3 moles, per mole of compound (VIII).
[0235] This reaction can be carried out with advantage in an inert
solvent. The solvent is not so critical in kind unless the progress
of She reaction is interferred with. The preferred inert solvent
includes, for example, amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, hexamethylphosphoric triamide, etc.,
nitrites such as acetonitrile etc., ketones such as acetone, methyl
ethyl ketone, etc., ethers such as tetrahydrofuran, dioxane,
1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., and
mixtures of these solvents.
[0236] The reaction time is generally 30 minutes to 12 hours,
preferably 1 to 12 hours. The reaction temperature is generally
0.degree. C. to 150.degree. C., preferably 0.degree. C. to
80.degree. C.
[0237] The product compound (I) may be subjected to hydrolysis of
its ester bond. This hydrolysis can be carried out in the per se
known method and the catalyst that can be used includes, for
example, mineral acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, etc., inorganic bases such as sodium hydroxide,
potassium hydroxide, etc., and basic salts such as sodium
carbonate, potassium carbonate, etc.
[0238] This reaction can be carried out with advantage in an inert
solvent. The solvent is not particularly critical in kind unless
the progress of the reaction is interferred with. The preferred
inert solvent includes, for example, alcohols such as methanol,
ethanol, propanol, etc., ethers such as tetrahydrofuran, dioxane,
1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., acetic
acid, water, and mixtures of these solvents.
[0239] The reaction time is generally 10 minutes to 6 hours,
preferably 30 minutes to 2 hours. The reaction temperature is
generally 0.degree. C. to 100.degree. C., preferably 10.degree. C.
to 100.degree. C. 21
[0240] Compound (X) wherein R.sup.c represents a hydrocarbon group;
the other symbols have the same meanings as defined above, can be
produced by the per se known production processes, for example the
processes described in Journal of Medicinal Chemistry, 22, 204
(1979), European Journal of Medicinal Chemistry, 23, 31 (1988), and
Journal of Heterocyclic Chemistry, 29, 1245 (1992), or by any
process analogous thereto.
[0241] The "hydrocarbon group" for R.sup.c includes the same group
as the "hydrocarbon group" defined above.
[0242] Compound (XI) may be purchased from a commercial source if
it is available on the market or can be produced by the per se
known method, for example the process described in Shin Jikken
Kagaku Koza (New Series in Experimental Chemistry) 14, II,
1104-1120 (1977).
[0243] Compound (XII) can be produced by reacting compound (X) with
compound (XI) optionally in the presence of a base. Compound (XI)
is used in a proportion of generally about 1 to 5 moles, preferably
about 1 to 1.2 moles, per mole of compound (X). The base that can
be used includes, for example, inorganic bases such as alkali metal
hydroxides, e.g. sodium hydroxide, potassium hydroxide, etc.,
ammonia, etc., organic bases such as triethylamine, pyridine, etc.,
and basic salts such as potassium hydrogen carbonate, sodium
carbonate, potassium carbonate, sodium acetate, etc. The proportion
of the base is generally about 0.1 to 5 moles, preferably about 1
to 2 moles, per mole of compound (X).
[0244] This reaction can be carried out with advantage in the
absence of a solvent or in the presence of an inert solvent. There
is no particular limitation on the kind of inert solvent that can
be used unless the progress of the reaction is interferred with.
The inert solvent includes, for example, a variety of organic
solvents, viz. alcohols such as methanol, ethanol, propanol, etc.,
saturated hydrocarbons such as cyclohexane, hexane, etc., aromatic
hydrocarbons such as benzene, toluene, xylene, etc., ethers such as
tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether,
diisopropyl ether, etc., amides such as N,N-dimethylformamide,
N,N-dimethylacetamide, hexamethylphosphoric triamide, etc.,
sulfoxides such as dimethyl sulfoxide etc., halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride, 1,2-dichloroethane, etc., water, and mixtures of
these solvents.
[0245] The reaction time varies with the species of reagents and
solvent used but is generally 30 minutes to 24 hours, preferably 2
to 14 hours. The reaction temperature is generally 0.degree. C. to
150.degree. C., preferably 30.degree. C. to 100.degree. C.
[0246] The product can be directly used, either as the reaction
mixture as such or in a partially purified form, in the next
reaction. If desired, however, the product compound can be isolated
from the reaction mixture in the routine manner and expediently
purified by the conventional purification procedure (e.g.
recrystallization, distillation, chromatography, etc.).
[0247] Compound (XIII) can be produced from compound (XII) by the
same procedure as described for the production of compound (III)
from compound (II).
[0248] Compound (XIV) can be produced from compound (XIII) by the
same procedure as described for the production of compound (IV)
from compound (III).
[0249] Compound (I) can be produced by reacting compound (XIV) with
ammonium acetate. The proportion of ammonium acetate is generally
about 5 to 100 moles, preferably about 10 to 30 moles, per mole of
compound (XIV).
[0250] This reaction can be conducted with advantage in the absence
of a solvent or in the presence of an inert solvent. The solvent is
not critical in kind unless the progress of the reaction is
interferred with. The preferred inert solvent includes water or
mixtures of water with organic solvents, e.g. organic acids such as
acetic acid, propionic acid, etc., alcohols such as methanol,
ethanol, propanol, etc., saturated hydrocarbons such as
cyclohexane, hexane, etc., aromatic hydrocarbons such as benzene,
toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane,
1,2-dimethoxyethane, diethyl ether, diisopropyl ether, etc., amides
such as N,N-dimethylformamide, N,N-dimethylacetamide,
hexamethylphosphoric triamide, etc., sulfoxides such as dimethyl
sulfoxide etc., and halogenated hydrocarbons such as
dichloromethane, chloroform, carbon tetrachloride,
1,2-dichloroethane, etc.
[0251] The reaction time varies with the species of reactant and
solvent used but is generally 30 minutes to 24 hours, preferably 2
to 14 hours. The reaction temperature is generally 25.degree. C. to
180.degree. C., preferably 80.degree. C. to 150.degree. C.
[0252] When the starting compounds for the above reactions have
amino, carboxyl, and/or hydroxy groups, such functional groups may
have been protected in advance with those protective groups which
are generally used in peptide chemistry and the objective compounds
can be obtained by removing such protective groups after the
respective reactions.
[0253] The amino-protective group includes, for example, formyl as
well as C.sub.1-6 alkyl-carbonyl (e.g. acetyl, propionyl, etc.),
phenylcarbonyl, C.sub.1-6 alkoxy-carbonyl (e.g. methoxycarbonyl,
ethoxycarbonyl, etc.), phenyloxycarbonyl, C.sub.7-11
aralkyloxy-carbonyl (e.g. benzyloxycarbonyl etc.), trityl, and
phthaloyl, each of which may be substituted. The substituent
includes halogen (e.g. fluorine, chlorine, bromine, iodine, etc.),
C.sub.1-6 alkyl-carbonyl (e.g. acetyl, propionyl, valeryl, etc.),
nitro, etc. and the number of substituents may range from 1 to
3.
[0254] The carboxyl-protective group includes, for example,
C.sub.1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl,
tert-butyl, etc.), phenyl, trityl, and silyl, each of which may be
substituted. The substituent includes halogen (e.g. fluorine,
chlorine, bromine, iodine, etc.), formyl, C.sub.1-6 alkyl-carbonyl
(e.g. acetyl, propionyl, butylcarbonyl, etc.), nitro, C.sub.1-6
alkyl (e.g. methyl, ethyl, tert-butyl, etc.), and C.sub.6-10 aryl
(e.g. phenyl, naphthyl, etc.) and the number of substituents may
range from 1 to 3.
[0255] The hydroxy-protecting group includes, for example,
C.sub.1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl,
tert-butyl, etc.), phenyl, C.sub.7-11 aralkyl (e.g. benzyl etc.),
formyl, C.sub.1-6 alkyl-carbonyl (e.g. acetyl, propionyl, etc.),
phenyloxycarbonyl, C.sub.7-11 aralkyloxy-carbonyl (e.g.
benzyloxycarbonyl etc.), tetrahydropyranyl, tetrahydrofuranyl, and
silyl, each of which may be substituted. The substituent includes
halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), C.sub.1-6
alkyl (e.g. methyl, ethyl, tert-butyl, etc.), C.sub.7-11 aralkyl
(e.g. benzyl etc.), C.sub.6-10 aryl (e.g. phenyl, naphthyl, etc.),
nitro, etc. and the number of substituents may range from 1 to
4.
[0256] Such protective groups can be removed by the per se known
deprotection methods or any methods analogous thereto. For example,
the treatment with an acid, a base, ultraviolet radiation,
hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate;
tetrabutylammonium fluoride, or palladium acetate and reduction can
be mentioned by way of example.
[0257] In any of the foregoing processes, the desired compound (I)
can be synthesized by carrying out any of the known deprotection,
acylation, amidation, alkylation, hydrogenation, oxidation,
reduction, carbon chain elongation reaction, and substituent
exchange reaction or two or more of such reactions in combination
as necessary. Those reactions can be typically carried out by the
procedures described inter alia in Shin Jikken Kagaku Koza (New
Experimental Chemistry Series 14, Vol. 15, 1977 (Maruzen Publishing
Co.).
[0258] When the objective compound obtainable by the above reaction
or reactions is a free compound, it can be converted to a salt in
the routine manner. When the product compound is a salt, it can be
converted to the free compound or a different salt by the known
procedure. The compound (I) thus produced can be isolated and
purified from the reaction mixture by the known procedures such as
redistribution, concentration, solvent extraction, fractional
distillation, crystallization, recrystallization, and
chromatography.
[0259] When compound (I) exists as configuration isomers,
diastreomers, or conformers, the respective isomers can be
optionally isolated by the above-mentioned fractionation and
purification procedures. When compound (I) is a racemic compound,
it can be resolved into the (S)- and (R)-forms by the conventional
optical resolution techniques.
[0260] Compound (I) may be a hydrate or an anhydrate.
[0261] The compound of the formula: 22
[0262] wherein X' represents SH, OH or NH.sub.2; the other symbols
have the same meanings as defined above, or a tautomer thereof, or
a salt thereof as obtained in the above reaction processes is novel
compound and can be used as a starting material for the production
of the compound of the present invention.
[0263] Among others, the preferred compound include:
[0264] Ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetat-
e,
[0265] Ethyl
[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate,
[0266] Ethyl
[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)-oxy]acetat- e,
tautomers thereof and salts thereof.
[0267] Compound (I) of the invention has a high affinity for the
PGI.sub.2 receptors with a low toxic potential and a minimal risk
of adverse drug reaction and, as such, is of value as a
medicine.
[0268] Compound (I) of the invention acts as a PGI.sub.2 agonist in
mammals (e.g. mouse, rat, hamster, rabbit, cat, dog, bovine, sheep,
monkey, and human) and has platelet aggregation inhibitory,
vasodilative, bronchodilative, lipid deposition inhibitory,
leukocyte activation inhibitory, and other activities. Thus,
compound (I) is useful for the pharmaceutical composition for the
prophylaxis and/or treatment of transient ischemic attack (TIA),
diabetic neuropathy, peripheral vascular diseases (e.g. peripheral
embolism, vibration syndrome, Raynaud's disease, etc.), systemic
lupus erythematosus, post-PTCA reobliteration/restenosis,
atherosclerosis, thrombosis (e.g. acute phase of cerebral
thrombosis, etc.), diabetic gangrene, hypertension, pulmonary
hypertension, ischemic diseases (e.g. cerebral infarction,
myocardial infarction, etc.), angina pectoris (e.g. stable angina,
unstable angia, etc.), glomerulonephritis, diabetic nephropathy,
allergy, bronchial asthma, ulcer, decubitus, coronary restenosis
after coronary intervention such as atherectomy and stent
implantation, thrombocytopenia during dialysis, etc.
[0269] Compound (I) of the invention is a compound of low toxicity
and can be safely administered either as it is or in the form of a
pharmaceutical composition comprising compound (I) and a
pharmacologically acceptable carrier or vehicle, for example in
such dosage forms as tablets (including dragees and film-coated
tablets), powders, granules, capsules (including soft capsules),
solutions, injections, suppositories, sustained release tablets or
capsules, transdermal drug delivery systems, etc., whether orally
or non-orally (e.g. topically, rectally, or intravenously). The
content of compound (I) in the pharmaceutical composition of the
invention is about 0.01 to 100 weight % based on the total weight
of the composition. The dosage is dependent on the background
factors, administration route, diagnosis, etc. but when the
composition is to be administered orally to an adult human as a
pharmaceutical composition for the prophylaxis and/or treatment of
transient ischemic attack, about 0.1 to 50 mg/kg body weight,
preferably about 0.2 to 30 mg/kg b. wt., more preferably about 0.5
to 10 mg/kg b. wt. as compound (I) can be administered once or in a
few divided doses daily.
[0270] Compound (I) can be used with other active ingredients such
as hypolipidemic (e.g. Pravastatin, etc.), angiotensin II
antagonist (e.g. Candesartan Cilexetil, Losartan, etc.), carcium
blocker (e.g. Amlodipine, Manidipine, etc.), insulin sensibility
activator (e.g. Triglitazone, Pioglitazone, etc.), etc. Compound
(I) and said other active ingredient can be formulated into one
pharmaceutical composition such as tablets (including dragees and
film-coated tablets), powders, granules, capsules (including soft
capsules), solutions, injections, suppositories, sustained release
tablets or capsules, according to per se known methods. They may be
separately formulated into different preparations, which may be
administered to one and the same subject either simultaneously or
at different times.
[0271] The pharmacologically acceptable carrier or vehicle which
can be used in the manufacture of various dosage forms according to
the invention includes those organic and inorganic substances which
are conventionally used in pharmaceutical manufacture, such as the
excipient, lubricant, binder, and disintegrator for solid dosage
forms and the solvent, solubilizer, suspending agent, isotonizing
agent, buffer, and local anesthetic for liquid dosage forms. Where
necessary, the routine additives such as the antiseptic,
antioxidant, coloring agent, sweetener, adsorbent, wetting agent,
etc. can be included in the formulation.
[0272] The excipient mentioned above includes, for example,
lactose, sucrose, D-mannitol, starch, corn starch, crystalline
cellulose, and light silicic anhydride.
[0273] The lubricant includes, for example, magnesium stearate,
calcium stearate, talc, and colloidal silica.
[0274] The binder includes, for example, crystalline cellulose,
sucrose, D-mannitol, dextrin, hydroxypropylcellulose,
hydroxypropylmethylcellulose- , polyvinylpyrrolidone, starch,
gelatin, methylcellulose, and carboxymethylcellulose sodium.
[0275] The disintegrator includes, for example, starch,
carboxymethylcellulose, carboxymethylcellulose calcium,
croscarmellose sodium, carboxymethylstarch sodium, and
L-hydroxypropylcellulose.
[0276] The solvent includes, for example, water for injection,
alcohol, propylene glycol, macrogols, sesame oil, corn oil, and
olive oil.
[0277] The solubilizer includes, for example, polyethylene glycol,
propylene glycol, D-mannitol, benzyl benzoate, ethanol,
trisaminomethane, cholesterol, triethanolamine, sodium carbonate,
and sodium citrate.
[0278] The suspending agent includes, for example, surfactants such
as stearyltriethanolamine, sodium lauryl sulfate,
laurylaminopropionic acid, lecithin, benzalkonium chloride,
benzethonium chloride, glyceryl monostearate, etc. and hydrophilic
macromolecular substances such as polyvinyl alcohol,
polyvinylpyrrolidone, carboxymethylcellulose sodium,
methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and
hydroxypropylcellulose.
[0279] The isotonizing agent includes, for example, glucose,
D-sorbitol, sodium chloride, glycerol, and D-mannitol.
[0280] The buffer includes, for example, buffer solutions such as,
phosphate, acetate, carbonate and citrate.
[0281] The local anesthetic includes, for example, benzyl
alcohol.
[0282] The antiseptic includes, for example, p-hydroxybenzoic
esters, chlorobutanol, benzyl alcohol, phenethyl alcohol,
dehydroacetic acid, and sorbic acid.
[0283] The antioxidant includes, for example, salts of sulfurous
acid, ascorbic acid, and .alpha.-tocopherol.
BEST MODE FOR CARRYING OUT OF THE INVENTION
[0284] The following reference examples, examples, formulation
example, and experimental examples are intended to describe the
present invention in further detail, it being to be understood,
however, that these examples are merely illustrative and not
defining the scope of the invention and that many changes and
modifications may be made by one skilled in the art without
departing from the spirit of the invention.
[0285] The term "room temperature" as used in the following
reference examples and examples generally means a temperature
within the range of about 10.degree. C. to about 35.degree. C. The
symbol % stands for weight percent unless otherwise indicated.
[0286] The various abbreviations used in the text have the
following meanings.
[0287] s: singlet
[0288] d: doublet
[0289] t: triplet
[0290] q: quartet
[0291] dd: double doublet
[0292] dt: double triplet
[0293] m: multiplet
[0294] br: broad
[0295] J: coupling constant
[0296] Hz: Hertz
[0297] Ph: phenyl
[0298] Me: methyl
[0299] Et: ethyl
[0300] CDCl.sub.3: deuterated chloroform
[0301] DMSO-d.sub.6: deuterated dimethyl sulfoxide
[0302] .sup.1H-NMR: proton nuclear magnetic resonance spectrum
EXAMPLES
Reference Example 1
Ethyl [(5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]acetate
[0303] To a solution of 3,4-dihydro-5-hydroxy-1(2H)-naphthalenone
(8.20 g, 50.6 mmol) in N,N-dimethylformamide (80 mL) was added
sodium hydride (60% dispersion in liquid paraffin, 2.22 g, 55.6
mmol) at 0.degree. C. and the mixture was stirred at that
temperature for 10 minutes. Then, ethyl bromoacetate (9.29 g, 55.6
mmol) was added and the mixture was further stirred at room
temperature for 30 minutes. This reaction mixture was poured in
water (80 mL) and extracted with 2 portions of ethyl acetate. The
organic layers were pooled, washed with water, dried over anhydrous
magnesium sulfate (MgSO.sub.4), and filtered, and the filtrate was
concentrated under reduced pressure. The residue was crystallized
from hexane-diisopropyl ether to provide 8.40 g of the title
compound. Yield 67%. m.p. 58-60.degree. C.
[0304] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t, J=7.2 Hz),
2.04-2.23 (2H, m), 2.60-2.71 (2H, m), 3.00 (2H, t, J=6.2 Hz), 4.28
(2H, q, J=7.2 Hz), 4.67 (2H, s), 6.91 (1H, dd, J=8.4, 1.2 Hz),
7.20-7.32 (1H, m), 7.70 (1H, dd, J=8.2, 1.2 Hz).
Reference Example 2
Ethyl [(2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]acetate
[0305] Using 2,3-dihydro-4-hydroxy-1H-inden-1-one, the procedure of
Reference Example 1 was otherwise repeated to synthesize the title
compound. Yield 70%. m.p. 91-93.degree. C. (hexane-diisopropyl
ether)
[0306] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.2 Hz),
2.66-2.74 (2H, m), 3.10-3.18 (2H, m), 4.28 (2H, q, J=7.2 Hz), 4.73
(2H, s), 6.92 (1H, dd, J=7.6, 1.0 Hz), 7.26-7.44 (2H, m).
Reference Example 3
Ethyl [(5,6,7,8-tetrahydro-5-oxo-2-naphthalenyl)oxy]acetate
[0307] Using 3,4-dihydro-6-hydroxy-1(2H)-naphthalene, the procedure
of Reference Example 1 was otherwise repeated to synthesize the
title compound. Yield 89%. m.p. 39-41.degree. C.
(hexane-diisopropyl ether)
[0308] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.4 Hz),
2.03-2.21 (2H, m), 2.57-2.66 (2H, m), 2.87-2.96 (2H, m), 4.29 (2H,
q, J=7.4 Hz), 4.68 (2H, s), 6.73 (1H, d, J=2.4 Hz), 6.82 (1H, dd,
J=8.8, 2.6 Hz), 8.02 (1H, dd, J=8.8, 2.6 Hz).
Reference Example 4
Ethyl [(2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]acetate
[0309] Using 2,3-dihydro-5-hydroxy-1H-inden-1-one, the procedure of
Reference Example 1 was otherwise repeated to synthesize the title
compound. Yield 65%. m.p. 59-61.degree. C. (hexane-ethyl
acetate)
[0310] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.0 Hz),
2.62-2.73 (2H, m), 3.05-3.15 (2H, m), 4.29 (2H, q, J=7.0 Hz), 4.71
(2H, s), 6.86-6.97 (2H, m), 7.71 (1H, d, J=8.4 Hz).
Reference Example 5
Ethyl 4-[(2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]butyrate
[0311] Using 2,3-dihydro-4-hydroxy-1H-inden-1-one and ethyl 4-bromo
butyrate, the procedure of Reference Example 1 was otherwise
repeated to synthesize the title compound. Yield 66%. Oil.
[0312] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.27 (3H, t, J=7.0 Hz),
2.07-2.16 (2H, m), 2.55 (2H, t, J=7.2 Hz), 2.64-2.75 (2H, m),
2.99-3.10 (2H, m), 4.05-4.22 (4H, m), 7.06 (1H, dd, J=6.4, 2.4 Hz),
7.27-7.41 (2H, m).
Reference Example 6
Ethyl
[(2,3-dihydro-5,7-dimethyl-1-oxo-1H-inden-4-yl)oxy]acetate
[0313] Using 2,3-dihydro-4-hydroxy-5,7-dimethyl-1H-inden-1-one, the
procedure of Reference Example 1 was otherwise repeated to
synthesize the title compound. Yield 77%. m.p. 75-77.degree. C.
(hexane-diisopropyl ether)
[0314] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33 (3H, t, J=7.2 Hz),
2.36 (3H, s), 2.55 (3H, s), 2.60-2.71 (2H, m), 3.04-3.13 (2H, m),
4.30 (2H, q, J=7.2 Hz), 4.54 (2H, s), 6.94 (1H, s).
Reference Example 7
Ethyl
[(2,3-dihydro-6,7-dimethyl-1-oxo-1H-inden-4-yl)oxy]acetate
[0315] Using 2,3-dihydro-4-hydroxy-6,7-dimethyl-1H-inden-1-one, the
procedure of Reference Example 1 was otherwise repeated to
synthesize the title compound. Yield 77%. m.p. 100-101.degree. C.
(hexane-diisopropyl ether)
[0316] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.0 Hz),
2.28 (3H, s), 2.51 (3H, s), 2.61-2.69 (2H, m), 2.98-3.05 (2H, m),
4.28 (2H, q, J=7.0 Hz), 4.68 (2H, s), 6.73 (1H, s).
Reference Example 8
Ethyl [(2,3-dihydro-4-oxo-4H-1-benzopyran-8-yl)oxy]acetate
[0317] Using 2,3-dihydro-8-hydroxy-4H-1-benzopyran-4-one, the
procedure of Reference Example 1 was otherwise repeated to
synthesize the title compound. Yield 84%. m.p. 56-66.degree. C.
(ethyl acetate-hexane)
[0318] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t, J=7.2 Hz),
2.84 (2H, t, J=6.4 Hz), 4.28 (2H, q, J=7.2 Hz), 4.65 (2H, t, J=6.4
Hz), 4.71 (2H, s), 6.93 (1H, t, J=7.6 Hz), 7.01 (1H, dd, J=7.6, 1.8
Hz), 7.57 (1H, dd, J=7.6, 1.8 Hz).
Reference Example 9
Ethyl 3-[(2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]propionate
[0319] To a solution of 2,3-dihydro-4-hydroxy-1H-inden-1-one (18.0
g, 121 mmol) in 30% aqueous potassium hydroxide solution (60 mL)
was added 3-chloropropionic acid (18 g, 166 mmol) at room
temperature and the mixture was refluxed for 1 hour. After cooling,
1N-hydrochloric acid was added and the precipitate (10.0 g)
comprised of unreacted 2,3-dihydro-4-hydroxy-1H-inden-1-one was
separated by filtration. The filtrate was extracted with 2 portions
of ethyl acetate and the pooled extract was washed with water,
dried over MgSO.sub.4, and filtered. The filtrate was concentrated
under reduced pressure to provide crude crystals (6.20 g) of
3-[(2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]propionic acid. This
crystal crop was dissolved in ethanol (40 mL) followed by addition
of concentrated sulfuric acid (1.0 mL) at room temperature and the
mixture was refluxed for 1 hour. After cooling, the reaction
mixture was extracted with 2 portions of ethyl acetate and the
pooled organic solution was washed with saturated aqueous sodium
hydrogen carbonate solution, dried over MgSO.sub.4, and filtered.
The filtrate was concentrated under reduced pressure and the
residue was crystallized from hexane-diisopropyl ether to provide
6.50 g of the title compound. Yield 22%. m.p. 90-92.degree. C.
[0320] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (3H, t, J=7.0 Hz),
2.63-2.76 (2H, m), 2.85 (2H, t, J=6.2 Hz), 2.96-3.08 (2H, m), 4.20
(2H, q, J=7.0 Hz), 4.35 (2H, t, J=6.2 Hz), 7.06 (1H, dd, J=6.6, 2.6
Hz), 7.22-7.40 (2H, m).
Reference Example 10
Ethyl
3-[(5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]propionate
[0321] Using 3,4-dihydro-5-hydroxy-1(2H)-naphthalene, the procedure
of Reference Example 9 was otherwise repeated to synthesize the
title compound. Yield 11%. m.p. 57-59.degree. C. (hexane)
[0322] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (3H, t, J=7.0 Hz),
2.02-2.19 (2H, m), 2.57-2.66 (2H, m), 2.77-2.90 (4H, m), 4.18-4.33
(4H, m), 7.04 (1H, d, J=8.0 Hz), 7.26 (1H, t, J=8.0 Hz), 7.66 (1H,
d, J=8.0 Hz).
Reference Example 11
Ethyl
[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]acetate
[0323] To a boiled suspension of copper (II) bromide (10 g, 45.1
mmol) in ethyl acetate (50 mL) was added a solution of ethyl
[(5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]acetate (7.0 g, 28.2
mmol) in ethyl acetate (30 mL) and the mixture was refluxed for 6
hours. The copper (I) bromide was filtered off and the filtrate was
washed with saturated aqueous sodium hydrogen carbonate solution,
dried over MgSO.sub.4, and filtered. The filtrate was concentrated
under reduced pressure and the residue was crystallized from
hexane-ethyl acetate to provide 7.5 g of the title compound. Yield
81%. m.p. 74-75.degree. C.
[0324] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.0 Hz),
2.44-2.54 (2H, m), 3.08-3.17 (2H, m), 4.23 (2H, q, J=7.0 Hz),
4.62-4.75 (3H, m), 6.94 (1H, d, J=8.0 Hz), 7.29 (1H, t, J=8.0 Hz),
7.75 (1H, d, J=8.0 Hz).
Reference Example 12
Ethyl [(2-bromo-2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]acetate
[0325] Using ethyl [(2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]acetate,
the procedure of Reference Example 11 was otherwise repeated to
synthesize the title compound. Yield 77%. m.p. 60-63.degree. C.
(hexane-diisopropyl ether)
[0326] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.2 Hz),
3.41 (1H, dd, J=18.6, 3.0 Hz), 3.84 (1H, dd, J=18.6, 7.4 Hz), 4.28
(2H, q, J=7.2 Hz), 4.65 (1H, dd, J=7.4, 3.0 Hz), 4.73 (2H, s), 6.99
(1H, d, J=7.6 Hz), 7.33-7.51 (2H, m).
Reference Example 13
Ethyl
[(6-bromo-5,6,7,8-tetrahydro-5-oxo-2-naphthalenyl)oxy]acetate
[0327] Using ethyl
[(5,6,7,8-tetrahydro-5-oxo-2-naphthalenyl)oxy]acetate, the
procedure of Reference Example 11 was otherwise repeated to
synthesize the title compound. Yield 73%. Oil.
[0328] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.2 Hz),
2.35-2.62 (2H, m), 2.72-2.95 (1H, m), 3.20-3.41 (1H, m), 4.29 (2H,
q, J=7.2 Hz), 4.62-4.75 (3H, m), 6.74 (1H, d, J=2.4 Hz), 6.87 (1H,
dd, J=8.8, 2.6 Hz), 7.75 (1H, d, J=8.8 Hz).
Reference Example 14
Ethyl [(2-bromo-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]acetate
[0329] Using ethyl [(2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]acetate,
the procedure of Reference Example 11 was otherwise repeated to
synthesize the title compound. Yield 93%. Oil.
[0330] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.32 (3H, t, J=7.0 Hz),
3.38 (1H, dd, J=18.4, 3.2 Hz), 3.79 (1H, dd, J=18.4, 7.6 Hz), 4.30
(2H, q, J=7.0 Hz), 4.65 (1H, dd, J=7.6, 3.2 Hz), 4.73 (2H, s), 6.85
(1H, d, J=2.0 Hz), 6.98 (1H, dd, J=8.6, 2.0 Hz), 7.80 (1H, d, J=8.6
Hz).
Reference Example 15
Ethyl 4-[(2-bromo-2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]butyrate
[0331] Using ethyl
4-[(2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]butyrate, the procedure of
Reference Example 11 was otherwise repeated to synthesize the title
compound. Yield 90%. Oil.
[0332] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.27 (3H, t, J=7.0 Hz),
2.11-2.24 (2H, m), 2.49-2.61 (2H, m), 3.31 (1H, dd, J=18.4, 3.0
Hz), 3.75 (1H, dd, J=18.4, 7.2 Hz), 4.05-4.23 (4H, m), 4.64 (1H,
dd, J=7.2, 3.0 Hz), 7.09 (1H, dd, J=7.2, 2.0 Hz), 7.31-7.45 (2H,
m).
Reference Example 16
Ethyl
3-[(2-bromo-2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]propionate
[0333] Using ethyl
3-[(2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]propionate, the procedure
of Reference Example 11 was otherwise repeated to synthesize the
title compound. Yield 78%. Oil.
[0334] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t, J=7.0 Hz),
2.85 (2H, t, J=6.2 Hz), 3.35 (1H, dd, J=18.6, 3.0 Hz), 3.78 (1H,
dd, J=18.6, 7.4 Hz), 4.20 (2H, q, J=7.0 Hz), 4.35 (2H, t, J=6.2
Hz), 4.66 (1H, dd, J=7.4, 3.0 Hz), 7.11 (1H, dd, J=6.6, 2.6 Hz),
7.25-7.43 (2H, m).
Reference Example 17
Ethyl
3-[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]propionate
[0335] Using ethyl
3-[(5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]propion- ate, the
procedure of Reference Example 11 was otherwise repeated to
synthesize the title compound. Yield 80%. Oil.
[0336] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (3H, t, J=7.0 Hz),
2.41-2.51 (2H, m), 2.84 (2H, t, J=6.2 Hz), 2.99 (2H, t, J=6.2 Hz),
4.21 (2H, q, J=7.0 Hz), 4.31 (2H, t, J=6.2 Hz), 4.70 (1H, t, J=4.4
Hz), 7.09 (1H, d, J=8.0 Hz), 7.31 (1H, t, J=8.0 Hz), 7.72 (1H, d,
J=8.0 Hz).
Reference Example 18
Ethyl
[(2-bromo-2,3-dihydro-5,7-dimethyl-1-oxo-1H-inden-4-yl)oxy]acetate
[0337] Using ethyl
[(2,3-dihydro-5,7-dimethyl-1-oxo-1H-inden-4-yl)oxy]acet- ate, the
procedure of Reference Example 11 was otherwise repeated to
synthesize the title compound. Yield 87%. m.p. 71-73.degree. C.
(hexane-ethyl acetate)
[0338] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33 (3H, t, J=7.0 Hz),
2.38 (3H, s), 2.56 (3H, s), 3.38 (1H, dd, J=18.6, 3.2 Hz), 3.83
(1H, dd, J=18.6, 7.4 Hz), 4.29 (2H, q, J=7.2 Hz), 4.51 (2H, s),
4.61 (1H, dd, J=7.4, 3.2 Hz), 7.02 (1H, s).
Reference Example 19
Ethyl
[(2-bromo-2,3-dihydro-6,7-dimethyl-1-oxo-1H-inden-4-yl)oxy]acetate
[0339] Using ethyl
[(2,3-dihydro-6,7-dimethyl-1-oxo-1H-inden-4-yl)oxy]acet- ate, the
procedure of Reference Example 11 was otherwise repeated to
synthesize the title compound. Yield 90%. m.p. 71-73.degree. C.
(hexane-ethyl acetate)
[0340] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.0 Hz),
2.30 (3H, s), 2.52 (3H, s), 3.30 (1H, dd, J=18.6, 3.0 Hz), 3.73
(1H, dd, J=18.6, 7.6 Hz), 4.28 (2H, q, J=7.2 Hz), 4.61 (1H, dd,
J=7.6, 3.0 Hz), 4.68 (2H, s), 6.79 (1H, s).
Reference Example 20
Ethyl
[(3-bromo-2,3-dihydro-4-oxo-4H-1-benzopyran-8-yl)oxy]acetate
[0341] Using ethyl
[(2,3-dihydro-4-oxo-4H-1-benzopyran-8-yl)oxy]acetate, the procedure
of Reference Example 11 was otherwise repeated to synthesize the
title compound. Yield 77%. m.p. 92.0-93.0.degree. C. (ethyl
acetate-hexane)
[0342] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.2 Hz),
4.29 (2H, q, J=7.2 Hz), 4.64-4.82 (5H, m), 6.97-7.09 (2H, m), 7.62
(1H, dd, J=7.4, 2.0 Hz).
Reference Example 21
Ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate
[0343] A mixture of ethyl
[(2-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthaleny- l)oxy]acetate
(2.63 g, 8.04 mmol), ammonium dithiocarbamate (1.06 g, 9.60 mmol),
and ethanol (30 mL) was refluxed for 14 hours. After cooling, the
solid precipitate was recovered by filtration to provide 1.96 g of
the title compound. Amorphous solid. Yield 76%.
[0344] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.24 (3H, t, J=7.2 Hz),
2.63-2.79 (2H, m), 2.95-3.09 (2H, m), 4.18 (2H, q, J=7.2 Hz), 4.79
(2H, s), 6.88 (1H, d, J=8.0 Hz), 7.20 (1H, t, J=8.0 Hz), 7.40 (1H,
d, J=8.0 Hz), 13.6 (1H, br s).
Reference Example 22
Ethyl [(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate
[0345] Using ethyl
[(2-bromo-2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]acetate, the
procedure of Reference Example 21 was otherwise repeated to
synthesize the title compound. Yield 70%. Amorphous solid.
[0346] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.22 (3H, t, J=7.2 Hz),
3.68 (2H, s), 4.28 (2H, q, J=7.2 Hz), 4.88 (2H, s), 6.84 (1H, dd,
J=8.0, 1.0 Hz), 7.20-7.40 (2H, m), 14.1 (1H, br s).
Reference Example 23
Ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-7-yl)oxy]acetate
[0347] Using ethyl
[(6-bromo-5,6,7,8-tetrahydro-5-oxo-2-naphthalenyl)oxy]a- cetate,
the procedure of Reference Example 21 was otherwise repeated to
synthesize the title compound. Yield 52%. Amorphous solid.
[0348] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.24 (3H, t J=7.0 Hz),
2.63-2.78 (2H, m), 2.87-3.05 (2H, m), 4.19 (2H, q, J=7.0 Hz), 4.79
(2H, s), 6.84-6.92 (2H, m), 7.66 (1H, d, J=8.4 Hz), 13.6 (1H, br
s).
Reference Example 24
Ethyl
3-[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]propionate
[0349] Using ethyl
3-[(2-bromo-2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]propion- ate, the
procedure of Reference Example 21 was otherwise repeated to
synthesize the title compound. Yield 45%. Amorphous solid.
[0350] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.21 (3H, t, J=7.0 Hz),
2.72-2.85 (2H, m), 3.57 (2H, s), 4.12 (2H, q, J=7.0 Hz), 4.28-4.36
(2H, m), 6.80-7.40 (3H, m), 1H not confirmed.
Reference Example 25
Ethyl [(2-mercapto-8H-indeno[1,2-d]thiazol-6-yl)oxy]acetate
[0351] Using ethyl
[(2-bromo-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]acetate, the
procedure of Reference Example 21 was otherwise repeated to
synthesize the title compound. Yield 80%. Amorphous solid.
[0352] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.24 (3H, t, J=7.0 Hz),
3.71 (2H, s), 4.19 (2H, q, J=7.0 Hz), 4.79 (2H, s), 6.88-6.96 (1H,
m), 7.18 (1H, br s), 7.42-7.51 (1H, m), 14.3 (1H, br s).
Reference Example 26
Ethyl
[(2-mercapto-4,6-dimethyl-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate
[0353] Using ethyl
[(2-bromo-2,3-dihydro-5,7-dimethyl-1-oxo-1H-inden-4-yl)-
oxy]acetate, the procedure of Reference Example 21 was otherwise
repeated to synthesize the title compound. Yield 34%. Amorphous
solid.
[0354] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.24 (3H, t, J=7.0 Hz),
2.26 (3H, s), 2.48 (3H, s), 3.76 (2H, s), 4.18 (2H, q, J=7.0 Hz),
4.66 (2H, s), 6.95 (1H, s), 13.6 (1H, br s).
Reference Example 27
Ethyl
[(2-mercapto-4,5-dimethyl-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate
[0355] Using ethyl
[(2-bromo-2,3-dihydro-6,7-dimethyl-1-oxo-1H-inden-4-yl)-
oxy]acetate, the procedure of Reference Example 21 was otherwise
repeated to synthesize the title compound. Yield 64%. Amorphous
solid.
[0356] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.22 (3H, t, J=7.0 Hz),
2.25 (3H, s), 2.37 (3H, s), 3.55 (2H, s), 4.17 (2H, q, J=7.0 Hz),
4.82 (2H, s), 6.69 (1H, s), 13.5 (1H, br s).
Reference Example 28
Ethyl
[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]acetate
[0357] Using ethyl
[(3-bromo-2,3-dihydro-4-oxo-4H-1-benzopyran-8-yl)oxy]ac- etate, the
procedure of Reference Example 21 was otherwise repeated to
synthesize the title compound. Yield 49%. Amorphous solid.
[0358] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (3H, t, J=7.2 Hz),
4.27 (2H, q, J=7.2 Hz), 4.69 (2H, s), 5.22 (2H, s), 6.81 (1H, dd,
J=8.2, 1.6 Hz), 7.20 (1H, t, J=8.2 Hz), 7.32 (1H, dd, J=8.2, 1.6
Hz), 13.4 (1H, br s).
Reference Example 29
Ethyl 4-[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]butyrate
[0359] Using ethyl
4-[(2-bromo-2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]butyrat- e, the
procedure of Reference Example 21 was otherwise repeated to
synthesize the title compound. Yield 68%. Amorphous solid.
[0360] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.27 (3H, t, J=7.2 Hz),
2.09-2.25 (2H, m), 2.56 (2H, t, J=7.2 Hz), 3.61 (2H, s), 4.13 (2H,
t, J=6.0 Hz), 4.17 (2H, q, J=7.2 Hz), 6.80 (1H, d, J=8.2 Hz), 7.14
(1H, d, J=7.2 Hz), 7.25-7.35 (1H, m), 13.6 (1H, br s).
Reference Example 30
Ethyl
3-[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]propionate
[0361] Using ethyl
3-[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy-
]propionate, the procedure of Reference Example 21 was otherwise
repeated to synthesize the title compound. Yield 59%. Amorphous
solid.
[0362] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20 (3H, t, J=7.0 Hz),
2.61-2.93 (6H, m), 4.11 (2H, q, J=7.0 Hz), 4.23 (2H, t, J=6.0 Hz),
6.98 (1H, d, J=8.0 Hz), 7.23 (1H, t, J=8.0 Hz), 7.39 (1H, d, J=8.0
Hz), 13.6 (1H, br s).
Reference Example 31
Ethyl
[(4,5-dihydro-2-hydroxynaphtho[1,2-d]thiazol-6-yl)oxy]acetate
[0363] A mixture of ethyl
[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthaleny- l)oxy]acetate
(3.00 g, 9.17 mmol), ethyl xanthamide (0.96 g, 9.17 mmol), and
ethanol (30 mL) was refluxed for 6 hours. The solvent was then
distilled off under reduced pressure and the residue was diluted
with ethyl acetate and water. After phase separation, the aqueous
layer was extracted with ethyl acetate. The organic layers were
combined, washed with water, dried over MgSO.sub.4, and filtered.
The filtrate was concentrated under reduced pressure and the
residue was subjected to silica gel column chromatography
(hexane-ethyl acetate=1:3) to provide 1.40 g of the title compound.
Yield 50%. m.p. 74-75.degree. C. (ethyl acetate-hexane)
[0364] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.23 (3H, t, J=7.0 Hz),
2.55-2.70 (2H, m), 2.92-3.04 (2H, m), 4.18 (2H, q, J=7.0 Hz), 4.79
(2H, s), 6.82 (1H, dd, J=8.0, 1.4 Hz), 7.08-7.22 (2H, m), 11.7 (1H,
s).
Reference Example 32
2-Methoxy-3,5-dimethylbenzaldehyde
[0365] To a solution of 1-methoxy-2,4-dimethylbenzene (8.00 g, 58.7
mmol) and 1,1-dichloromethyl methyl ether (7.40 g, 64.7 mmol) in
methylene chloride (30 mL) was added titanium tetrachloride (20.0
g, 105 mmol) at 0.degree. C. and the mixture was stirred at that
temperature for 20 minutes. This reaction mixture was poured into
iced water and the organic layer was taken, washed with saturated
aqueous sodium hydrogen carbonate solution, dried over MgSO.sub.4,
and filtered. The filtrate was concentrated under reduced pressure
to-provide 9.40 g of the title compound. Yield 98%. Oil.
[0366] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.306 (3H, s), 2.312 (3H,
s), 3.85 (3H, s), 7.25-7.27 (1H, m), 7.48 (1H, d, J=1.8 Hz), 10.3
(1H, s).
Reference Example 33
(E)-3-(2-methoxy-3,5-dimethylphenyl)propenoic acid
[0367] A solution of 2-methoxy-3,5-dimethylbenzaldehyde (9.40 g,
57.2 mmol), malonic acid (8.90 g, 85.8 mmol), and pyrrolidine (730
mg, 8.58 mmol) in pyridine (80 mL) was refluxed for 14 hours. This
reaction mixture was poured in iced water and extracted with ethyl
acetate. The extract was washed with 2N-hydrochloric acid, dried
over MgSO.sub.4, and filtered. The filtrate was concentrated under
reduced pressure to provide 9.60 g of the title compound. Yield
81%. m.p. 178-180.degree. C.
[0368] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.28 (3H, s), 2.30 (3H,
s), 3.74 (3H, s), 6.49 (1H, d, J=16.0 Hz), 7.07 (1H, s), 7.25 (1H,
s), 8.07 (1H, d, J=16.0 Hz), 9.2-12 (1H, br).
Reference Example 34
3-(2-Methoxy-3,5-dimethylphenyl)propionic acid
[0369] In acetic acid (80 mL) were suspended
(E)-3-(2-methoxy-3,5-dimethyl- phenyl)propenoic acid (9.60 g, 46.5
mmol) and 10% palladium-on-carbon (hydrous) (0.60 g) and the
suspension was stirred in a hydrogen atmosphere at 60.degree. C.
for 14 hours. The catalyst was then filtered off and the filtrate
was concentrated under reduced pressure. The residue was
crystallized from ethanol to provide 8.90 g of the title compound.
Yield 91%. m.p. 74-75.degree. C.
[0370] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.26 (6H, s), 2.61-2.75
(2H, m), 2.87-2.98 (2H, m), 3.72 (3H, s), 6.84 (1H, s), 6.87 (1H,
s), 1H not confirmed.
Reference Example 35
2,3-Dihydro-4-methoxy-5,7-dimethyl-1H-inden-1-one
[0371] A solution of 3-(2-methoxy-3,5-dimethylphenyl)propionic acid
(8.80 g, 42.2 mmol) in thionyl chloride (80 mL) was refluxed for
1.5 hours. After cooling, the reaction mixture was concentrated
under reduced pressure and the residue was dissolved in
1,2-dichloroethane (100 mL). To this solution was added anhydrous
aluminum chloride (5.80 g, 43.5 mmol) gradually at 0.degree. C. and
the mixture was stirred at room temperature for 1.0 hour. After
completion of the reaction, the reaction mixture was poured in iced
water and extracted with 1,2-dichloroethane. The organic layer was
washed serially with 1N-hydrochloric acid, saturated aqueous sodium
hydrogen carbonate solution, and water, dried over MgSO.sub.4, and
filtered. The filtrate was concentrated under reduced pressure to
provide 6.90 g of the title compound. Yield 86%. Oil.
[0372] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.32 (3H, s), 2.35 (3H,
s), 2.60-2.80 (2H, m), 3.00-3.15 (2H, m), 3.82 (3H, 5), 6.92 (1H,
s).
Reference Example 36
2,3-Dihydro-4-methoxy-6,7-dimethyl-1H-inden-1-one
[0373] Using 1-methoxy-3,4-dimethylbenzene, the procedure of
Reference Examples 32-35 was otherwise repeated to synthesize the
title compound. Yield 33%. m.p. 127-128.degree. C. (ethyl
acetate-hexane)
[0374] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.31 (3H, s), 2.51 (3H,
s), 2.58-2.67 (2H, m), 2.85-2.95 (2H, m), 3.87 (3H, s), 6.84 (1H,
s).
Reference Example 37
2,3-Dihydro-8-hydroxy-4H-1-benzopyran-4-one
[0375] 2,3-Dihydro-8-methoxy-4H-1-benzopyran-4-one (7.59 g, 42.4
mmol) was dissolved in xylene (80 mL) followed by addition of
anhydrous aluminum chloride (11.4 g, 85.5 mmol), and the mixture
was stirred at 100.degree. C. for 2 hours. After cooling, the
reaction mixture was poured into iced water and extracted with
ethyl acetate. The organic layer was washed with 1N-hydrochloric
acid and saturated aqueous sodium chloride solution, dried over
MgSO.sub.4, and filtered. The filtrate was concentrated under
reduced pressure and the residue was crystallized from
methanol-ethyl acetate-diethyl ether to provide 3.94 g of the title
compound. Yield 56%. m.p. 93-96.degree. C.
[0376] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.86 (2H, t, J=6.4 Hz),
4.63 (2H, t, J=6.4 Hz), 5.72 (1H, s), 6.93 (1H, t, J=8.0 Hz), 7.14
(1H, dd, J=7.8, 1.6 Hz), 7.44 (1H, dd, J=7.8, 1.6 Hz).
Reference Example 38
2,3-Dihydro-4-hydroxy-5,7-dimethyl-1H-inden-1-one
[0377] Using 2,3-dihydro-4-methoxy-5,7-dimethyl-1H-inden-1-one, the
procedure of Reference Example 37 was otherwise repeated to
synthesize the title compound. Yield 78%. m.p. 152-154.degree. C.
(ethyl acetate)
[0378] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.21 (3H, s), 2.40 (3H,
s), 2.46-2.61 (2H, m), 2.83-2.96 (2H, m), 6.87 (1H, s), 8.81 (1H,
s).
Reference Example 39
2,3-Dihydro-4-hydroxy-6,7-dimethyl-1H-inden-1-one
[0379] Using 2,3-dihydro-4-methoxy-6,7-dimethyl-1H-inden-1-one, the
procedure of Reference Example 37 was otherwise repeated to
synthesize the title compound. Yield 92%. m.p. 171-173.degree. C.
(ethyl acetate)
[0380] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.18 (3H, s), 2.39 (3H,
s), 2.50-2.61 (2H, m), 2.76-2.85 (2H, m), 6.83 (1H, s), 9.41 (1H,
s).
Reference Example 40
3,3-Diphenylpropyl methanesulfonate
[0381] To a mixed solution of 3,3-diphenyl-1-propanol (24.0 g, 113
mmol) and methanesulfonyl chloride (13.7 g, 120 mmol) in
tetrahydrofuran (200 mL) was added triethylamine (17.0 mL, 120
mmol) gradually at 0.degree. C. and the mixture was stirred at room
temperature for 10 minutes. This reaction mixture was diluted with
water (200 mL) and extracted with 2 portions of ethyl acetate. The
combined organic solution was washed with saturated aqueous sodium
chloride solution, dried over MgSO.sub.4, and filtered. The
filtrate was concentrated under reduced pressure and the residue
was crystallized from diisopropyl ether to provide 25.8 g of the
title compound. Yield 79%. m.p. 83-85.degree. C.
[0382] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.50 (2H, dt, J=8.0, 6.4
Hz), 2.90 (3H, s), 4.08-4.21 (3H, m), 7.13-7.41 (10H, m).
Reference Example 41
2,2-Diphenylethyl methanesulfonate
[0383] Using 2,2-diphenyl-1-ethanol, the procedure of Reference
Example 40 was otherwise repeated to synthesize the title compound.
Yield 69%. m.p. 101-102.degree. C. (ethyl acetate-hexane)
[0384] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.73 (3H, s), 4.43 (1H, t,
J=7.4 Hz), 4.72 (2H, d, J=7.4 Hz), 7.13-7.43 (10H, m).
Reference Example 42
4,4-Diphenylbutyl methanesulfonate
[0385] Using 4,4-diphenyl-1-butanol, the procedure of Reference
Example 40 was otherwise repeated to synthesize the title compound.
Yield 68%. m.p. 85-88.degree. C. (ethyl acetate-hexane)
[0386] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62-1.81 (2H, m),
2.10-2.23 (2H, m), 2.95 (3H, s), 3.90 (1H, t, J=8.0 Hz), 4.22 (2H,
t, J=6.4 Hz), 7.13-7.34 (10H, m).
Reference Example 43
3,3-Diphenylpropyl iodide
[0387] To a solution of sodium iodide (2.80 g, 18.9 mmol) in
acetone (20 mL) was added a solution of 3,3-diphenylpropyl
methanesulfonate (5.00 g, 17.2 mmol) in acetone (10 mL) at
0.degree. C. and the mixture was refluxed for 3 hours. After
cooling, the solvent was distilled off under reduced pressure and
the residue was diluted with water (30 mL) and extracted with 2
portions of ethyl acetate. The pooled extract was washed with
saturated aqueous sodium chloride solution, dried over MgSO.sub.4,
and filtered. The filtrate was concentrated under reduced pressure
and the residue was crystallized from methanol to provide 4.70 g of
the title compound. Yield 85%. m.p. 51-55.degree. C.
[0388] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.54 (2H, q, J=7.2 Hz),
3.09 (2H, t, J=7.0 Hz), 4.11 (1H, t, J=7.6 Hz), 7.15-7.40 (10H,
m).
Reference Example 44
2,2-Diphenylethyl iodide
[0389] Using 2,2-diphenylethyl methanesulfonate, the procedure of
Reference Example 43 was otherwise repeated to synthesize the title
compound. Yield 58%. m.p. 76-78.degree. C. (methanol)
[0390] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.74 (2H, d, J=8.2 Hz),
4.34 (1H, t, J=8.2 Hz), 7.18-7.37 (10H, m).
Reference Example 45
4,4-Diphenylbutyl iodide
[0391] Using 4,4-diphenylbutyl methanesulfonate, the procedure of
Reference Example 43 was otherwise repeated to synthesize the title
compound. Yield 67%. Oil.
[0392] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.70-1.86 (2H, m),
2.08-2.25 (2H, m), 3.18 (2H, t, J=6.8 Hz), 3.91 (1H, t, J=7.6 Hz),
7.11-7.36 (10H, m).
Reference Example 46
N-(3,3-diphenylpropyl)thiourea
[0393] A solution of 3,3-diphenylpropylamine (4.00 g, 18.9 mmol)
and ammonium thiocyanate (1.60 g, 20.8 mmol) in bromobenzene (30
mL) was refluxed for 1 hour. After cooling, the solid precipitate
was recovered, rinsed with diethyl ether, water, and ethanol, and
dried to provide 3.00 g (yield 59%) of the title compound.
Amorphous solid.
[0394] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.16-2.35 (2H, m),
3.10-3.40 (2H, br), 3.98 (1H, t, J=7.4 Hz), 6.89 (1H, br s),
7.05-7.43 (10H, m), 7.63 (1H, br s), 1H not confirmed.
Reference Example 47
N-(2,2-diphenylethyl)thiourea
[0395] Using 2,2-diphenylethylamine, the procedure of Reference
Example 46 was otherwise repeated to synthesize the title compound.
Yield 59%. m.p. 205-207.degree. C.
[0396] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.96-4.11 (2H, m), 3.98
(1H, t, J=7.6 Hz), 6.96 (1H, br s), 7.11-7.50 (11H, m), 1H not
confirmed.
Reference Example 48
N-(diphenylmethyl)thiourea
[0397] Using diphenylmethylamine, the procedure of Reference
Example 46 was otherwise repeated to synthesize the title compound.
Yield 59%. Amorphous solid.
[0398] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 6.50-6.72 (1H, m),
7.00-7.52 (12H, m), 8.54 (1H, d, J=8.8 Hz).
Reference Example 49
(2-Naphthyl)phenylmethyl bromide
[0399] To a solution of benzoylnaphthalene (5.00 g, 21.5 mmol) in
methanol (30 mL) was added sodium borohydride (400 mg, 10.8 mmol)
with ice-cooling and the mixture was stirred at room temperature
for 30 minutes. This reaction mixture was diluted with water and
extracted with ethyl acetate. The organic layer was washed with
water, dried over MgSO.sub.4, and filtered and the filtrate was
concentrated under reduced pressure to provide 4.80 g of
(2-naphthyl)phenylmethanol. To a solution of this compound (4.80 g,
20.5 mmol) in diisopropyl ether (30 mL) was added phosphorus
tribromide (3.70 g, 13.7 mmol) with ice-cooling and the mixture was
stirred at room temperature for 1 hour. This reaction mixture was
diluted with water and extracted with diisopropyl ether. The
organic layer was washed with water and saturated aqueous sodium
hydrogen carbonate solution, dried over MgSO.sub.4, and filtered.
The filtrate was concentrated under reduced pressure and the solid
residue was recrystallized from diisopropyl ether-hexane to provide
4.10 g of the title compound. Yield 64%. m.p. 89-90.degree. C.
[0400] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.45 (1H, s), 7.22-7.61
(8H, m), 7.71-7.86 (4H, m).
Reference Example 50
4-Phenylbenzyl bromide
[0401] To a solution of 4-phenylbenzyl alcohol (1.00 g, 5.43 mmol)
in a mixture of diisopropyl ether (10 mL) and chloroform (20 mL)
was added phosphorus tribromide (0.98 g, 3.62 mmol) with
ice-cooling and the mixture was stirred at room temperature for 1
hour. This reaction mixture was diluted with water and extracted
with diisopropyl ether. The organic layer was washed with water and
saturated aqueous sodium hydrogen carbonate solution, dried over
MgSO.sub.4, and filtered. The filtrate was concentrated under
reduced pressure and the residue was recrystallized from
ethanol-hexane to provide 1.00 g of the title compound. Yield 75%.
m.p. 86-88.degree. C.
[0402] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.55 (2H, s), 7.32-7.67
(9H, m)
Reference Example 51
(4-Methylphenyl)(phenyl)methyl bromide
[0403] Using (4-methylphenyl)(phenyl)methanol, the procedure of
Reference Example 50 was otherwise repeated to synthesize the title
compound. Yield 99%. Oil.
[0404] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.33 (3H, s), 6.28 (1H,
s), 7.14 (2H, d, J=8.0 Hz), 7.25-7.49 (7H, m).
Reference Example 52
(4-Chlorophenyl)(phenyl)methyl bromide
[0405] Using (4-chlorophenyl)(phenyl)methanol, the procedure of
Reference Example 50 was otherwise repeated to synthesize the title
compound. Quantitative. Oil.
[0406] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.24 (1H, s), 7.25-7.45
(9H, m).
Reference Example 53
Bis(4-chlorophenyl)methyl bromide
[0407] Using bis(4-chlorophenyl)methanol, the procedure of
Reference Example 50 was otherwise repeated to synthesize the title
compound. Yield 96%. Oil.
[0408] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.20 (1H, s), 7.26-7.39
(8H, m).
Reference Example 54
1,2-Diphenylethyl bromide
[0409] Using benzyl phenyl ketone, the procedure of Reference
Example 49 was otherwise repeated to synthesize the title compound.
Yield 57%. Oil.
[0410] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.39-3.62 (2H, s), 5.13
(1H, t, J=7.6 Hz), 7.06-7.55 (10H, m).
Reference Example 55
(4-Methoxyphenyl)(phenyl)methyl bromide
[0411] Using 4-methoxyphenyl phenyl ketone, the procedure of
Reference Example 49 was otherwise repeated to synthesize the title
compound. Yield 98%. Oil.
[0412] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80 (3H, s), 6.31 (1H,
s), 6.84-6.90 (2H, m), 7.24-7.40 (5H, m), 7.45-7.50 (2H, m).
Reference Example 56
Bis(4-fluorophenyl)methyl bromide
[0413] Using bis(4-fluorophenyl) ketone, the procedure of Reference
Example 49 was otherwise repeated to synthesize the title compound.
Yield 59%. Oil.
[0414] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.26 (1H, s), 6.98-7.09
(4H, m), 7.37-7.44 (4H, m).
Reference Example 57
(4-Nitrophenyl)(phenyl)methyl bromide
[0415] Using 4-nitrophenyl phenyl ketone, the procedure of
Reference Example 49 was otherwise repeated to synthesize the title
compound. Quantitative. Oil.
[0416] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.25 (1H, s), 7.27-7.38
(5H, m), 7.58 (2H, d, J=8.4 Hz), 8.19 (2H, d, J=8.4 Hz).
Reference Example 58
(4-Fluorophenyl)(phenyl)methyl bromide
[0417] Using 4-fluorophenyl phenyl ketone, the procedure of
Reference Example 49 was otherwise repeated to synthesize the title
compound. Yield 84%. Oil.
[0418] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.27 (1H, s), 6.97-7.05
(2H, m), 7.01-7.46 (7H, m).
Reference Example 59
(Phenyl)(4-trifluoromethylphenyl)methyl bromide
[0419] Using phenyl 4-trifluoromethylphenyl ketone, the procedure
of Reference Example 49 was otherwise repeated to synthesize the
title compound. Yield 64%. Oil.
[0420] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.28 (1H, s), 7.30-7.46
(5H, m), 7.59 (4H, s).
Reference Example 60
(4-Cyanophenyl)(phenyl)methyl bromide
[0421] 4-Cyanophenyl phenyl ketone, the procedure of Reference
Example 49 was otherwise repeated to synthesize the title compound.
Yield 90%. Oil.
[0422] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.24 (1H, s), 7.30-7.44
(5H, m), 7.53-7.66 (4H, m).
Reference Example 61
(3-Chlorophenyl)(phenyl)methyl bromide
[0423] Using 3-chlorophenyl phenyl ketone, the procedure of
Reference Example 49 was otherwise repeated to synthesize the title
compound. Yield 62%. Oil.
[0424] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.03 (1H, s), 7.24-7.45
(9H, m).
Reference Example 62
(2-Chlorophenyl)(phenyl)methyl bromide
[0425] Using 2-chlorophenyl phenyl ketone, the procedure of
Reference Example 49 was otherwise repeated to synthesize the title
compound. Yield 71%. Oil.
[0426] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.71 (1H, s), 7.19-7.70
(9H, m).
Reference Example 63
(3-Methylphenyl)(phenyl)methyl bromide
[0427] Using 3-methylphenyl phenyl ketone, the procedure of
Reference Example 49 was otherwise repeated to synthesize the title
compound. Yield 94%. Oil.
[0428] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.34 (3H, s), 6.25 (1H,
s), 7.08 (1H, d,J=6.2 Hz), 7.17-7.37 (6H, m), 7.44-7.48 (2H,
m).
Reference Example 64
(2-Methylphenyl)(phenyl)methyl bromide
[0429] Using 2-methylphenyl phenyl ketone, the procedure of
Reference Example 49 was otherwise repeated to synthesize the title
compound. Quantitative. Oil.
[0430] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.36 (3H, s), 6.49 (1H,
s), 7.14-7.56 (9H, m).
Reference Example 65
(Phenyl)(3-trifluoromethylphenyl)methyl bromide
[0431] Using phenyl 3-trifluoromethylphenyl ketone, the procedure
of Reference Example 49 was otherwise repeated to synthesize the
title compound. Quantitative. Oil.
[0432] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.49 (1H, s), 7.20-7.49
(9H, m).
Reference Example 66
(2-Fluorophenyl)(phenyl)methyl bromide
[0433] Using 2-fluorophenyl phenyl ketone, the procedure of
Reference Example 49 was otherwise repeated to synthesize the title
compound. Yield 98%. Oil.
[0434] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.65 (1H, s), 7.10-7.66
(9H, m).
Reference Example 67
3,4-Dihydro-7-hydroxy-1(2H)-naphthalenone
[0435] Using 3,4-dihydro-7-methoxy-1(2H)-naphthalenone, the
procedure of Reference Example 37 was otherwise repeated to
synthesize the title compound. Yield 89%. m.p. 170-173.degree. C.
(ethyl acetate)
[0436] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.89-2.11 (2H, m),
2.44-2.63 (2H, m), 2.77-2.86 (2H, m), 6.96 (1H, dd, J=8.0, 3.0 Hz),
7.14 (1H, d, J=8.0 Hz), 7.26 (1H, d, J=3.0 Hz), 9.53 (1H, s).
Reference Example 68
Ethyl [(5,6,7,8-tetrahydro-5-oxo-3-naphthalenyl)oxy]acetate
[0437] To a solution of 3,4-dihydro-7-hydroxy-1(2H)-naphthalenone
(15.3 g, 94.3 mmol) in N,N-dimethylformamide (150 mL) were serially
added ethyl bromoacetate (16.5 g, 99.0 mmol) and potassium
carbonate (13.7 g, 99.0 mmol) and the mixture was stirred at
60.degree. C. for 6 hours. This reaction mixture was diluted with
water and extracted with ethyl acetate. The organic layer was
washed with water and saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate (MgSO.sub.4), filtered, and
concentrated under reduced pressure. The residue was crystallized
from hexane-ethyl acetate to provide 19.5 g of the title compound.
Yield 83%. m.p. 84-86.degree. C.
[0438] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t, J=7.2 Hz),
2.01-2.17 (2H, m), 2.54-2.67 (2H, m), 2.85-2.94 (2H, m), 4.26 (2H,
q, J=7.2 Hz), 4.65 (2H, s), 7.08-7.22 (2H, m), 7.45 (1H, d, J=2.6
Hz).
Reference Example 69
Ethyl
[(6-bromo-5,6,7,8-tetrahydro-5-oxo-3-naphthalenyl)oxy]acetate
[0439] Using ethyl
[(5,6,7,8-tetrahydro-5-oxo-3-naphthalenyl)oxy]acetate, the
procedure of Reference Example 11 was otherwise repeated to
synthesize the title compound. Yield 85%. m.p. 91-93.degree. C.
(hexane-ethanol)
[0440] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.2 Hz),
2.35-2.62 (2H, m), 2.86 (1H, dt, J=17.2, 4.4 Hz), 3.15-3.33 (1H,
m), 4.28 (2H, q, J=7.2 Hz), 4.67 (2H, s), 4.72 (1H, t, J=4.4 Hz),
7.15-7.28 (2H, m), 7.49 (1H, d, J=2.2 Hz).
Reference Example 70
Ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]acetate
[0441] Using ethyl
[(6-bromo-5,6,7,8-tetrahydro-5-oxo-3-naphthalenyl)oxy]a- cetate,
the procedure of Reference Example 21 was otherwise repeated to
synthesize the title compound. Yield 72%. Amorphous solid.
[0442] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.24 (3H, t, J=7.0 Hz),
2.66-3.00 (4H, m), 4.19 (2H, q, J=7.0 Hz), 4.76 (2H, s), 6.80 (1H,
dd, J=8.0, 2.6 Hz), 7.17 (1H, d, J=8.4 Hz), 7.40 (1H, d, J=2.6 Hz),
13.5 (1H, br s).
Reference Example 71
Phenylthioacetamide
[0443] A solution of phenylacetonitrile (10.0 g, 85.4 mmol) and
diethyl dithiophosphate (17.5 g, 93.9.mmol) in 4N-HCl/ethyl acetate
(400 mL) was stirred at room temperature for 16 hours. This
reaction mixture was washed with water and saturated aqueous sodium
hydrogen carbonate solution, dried-over MgSO.sub.4, filtered, and
concentrated under reduced pressure. The residue was crystallized
from ethanol to provide 7.1 g of the title compound. Yield 55%.
m.p. 98-100.degree. C.
[0444] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.08 (2H, s), 6.50-7.10
(1H, br), 7.22-7.45 (5H, m), 7.90-8.40 (1H, br).
Reference Example 72
Diphenylthioacetamide
[0445] Using diphenylacetonitrile, the procedure of Reference
Example 71 was otherwise repeated to synthesize the title compound.
Yield 67%. m.p. 152-155.degree. C. (ethanol)
[0446] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.62 (1H, s), 6.60-7.10
(1H, br), 7.15-7.43 (10H, m), 7.83-8.30 (1H, br).
Reference Example 73
Diphenylthiopropionamide
[0447] A solution of 3,3-diphenylpropionic acid (15.0 g, 66.3 mmol)
in thionyl chloride (15 mL) was refluxed for 1 hour. After cooling,
the reaction mixture was concentrated under reduced pressure. The
residue was added to 25% aqueous ammonia (30 mL) gradually at
0.degree. C. and the mixture was stirred at room temperature for 30
minutes. This reaction mixture was extracted with 2 portions of
ethyl acetate and the pooled organic layer was washed with
saturated aqueous sodium chloride solution, dried over MgSO.sub.4,
filtered, and concentrated under reduced pressure to provide 13.0 g
of diphenylpropionamide. To a solution of this compound (5.00 g,
22.2 mmol) in tetrahydrofuran (80 mL) was added phosphorus
pentasulfide (6.30 g, 28.3 mmol), and the mixture was refluxed for
2 hours. After cooling, the reaction mixture was diluted with water
and extracted with 2 portions of ethyl acetate. The pooled organic
layer was washed with saturated aqueous sodium chloride solution,
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure. The residue was crystallized from ethanol to provide 1.5
g of the title compound. Yield 24%. m.p. 150-152.degree. C.
[0448] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.38 (2H, d, J=7.8 Hz),
4.67 (1H, t, J=7.8 Hz), 6.40-6.7 (1H, br), 7.18-7.47 (11H, m).
Reference Example 74
Bis(3-fluorophenyl)methylbromide
[0449] To a solution of 1-bromo-3-fluorobenzene (10.0 g, 57.1 mmol)
in tetrahydrofuran (100 mL) was added n-BuLi (1.6M, 35.7 mL, 62.8
mmol) at -78.degree. C. and the mixture was stirred at that
temperature for 20 minutes. To the mixture was added
3-fluorobenzaldehyde (7.80 g, 62.8 mmol) and the resulting mixture
was stirred at room temperature for 30 minutes. To this mixture was
added water and the product was extracted with ethyl acetate. The
extract was washed with water, dried over MgSO.sub.4, and filtered.
The filtrate was concentrated under reduced pressure to provide
10.1 g of bis(3-fluorophenyl)methanol. To a solution of this
compound (6.60 g, 30.0 mmol) in diisopropylether (50 mL) was added
phosphorus tribromide (5.41 g, 20.0 mmol) with ice-cooling and the
mixture was stirred at that temperature for 1 hour. This reaction
mixture was diluted with water and extracted with diisopropylether.
The organic layer was washed with water and saturated with aqueous
sodium hydrogen carbonate solution, dried over MgSO.sub.4, and
filtered. The filtrate was concentrated under reduced pressure to
provide 5.61 g of the title compound. Yield 53%. Oil.
[0450] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.26 (1H, s), 6.98-7.09
(4H, m), 7.37-7.44 (4H, m).
Reference Example 75
Bis(2-fluorophenyl)methylbromide
[0451] Using 1-bromo-2-fluorobenzene and 2-fluorobenzaldehyde, the
procedure of Reference Example 74 was otherwise repeated to
synthesize the title compound. Yield 65%. Oil.
[0452] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.77 (1H, s), 6.96-7.36
(6H, m), 7.50-7.60 (2H, m).
Reference Example 76
Methyl [2,3-bis(ethoxycarbonylmethoxy)]benzoate
[0453] To a solution of 2,3-dihydroxybenzoic acid (33.0 g, 214
mmol) in methanol (200 mL) was added sulfuric acid (5.0 mL) and the
mixture was refluxed for 14 hours. The solvent was then distilled
off under reduced pressure. To that residue was added water, and
the mixture was extracted with ethyl acetate. The organic layer was
washed with water, dried over MgSO.sub.4, and filtered. The
filtrate was concentrated under reduced pressure to provide 35.0 g
of methyl 2,3-dihydroxybenzoate. A mixture of this compound (35.0
g, 208 mmol), ethyl bromoacetate (70.0 g, 420 mmol), and potassium
carbonate (58.0 g, 420 mmol) in acetone (400 mL) was stirred for 14
hours, and filtered. The filtrate was concentrated under reduced
pressure to provide 58.0 g of the title compound. Yield 80%.
Oil.
[0454] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18-1.45 (6H, m), 3.90
(3H, s), 4.14-4.38 (4H, m), 4.69 (2H, s), 4.78 (2H, s), 6.97-7.14
(2H, m), 7.40 (1H, dd, J=7.6, 1.8 Hz).
Reference Example 77
[2,3-Bis(carboxymethoxy)]benzoic acid
[0455] To a solution of methyl
[2,3-bis(ethoxycarbonylmethoxy)]benzoate (58.0 g, 170 mmol) in
methanol (100 mL) at 60.degree. C. was added 3N-aqueous sodium
hydroxide solution over 30 minutes, and the reaction mixture was
refluxed for 2 hours. The solvent was then distilled off under
reduced pressure. To that residue was added 4N-hydrochloric acid.
The crystal was collected with filtration, and dried to provide
31.3 g of the title compound. Yield 68%. m. p. 195-197.degree.
C.
[0456] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.67 (2H, s), 4.75 (2H,
s), 7.00-7.27 (3H, m), 3H not confirmed.
Reference Example 78
Ethyl [(3-oxo-2,3-dihydrobenzofuran-7-yl)oxy]acetate
[0457] A mixture of [2,3-bis(carboxymethoxy)]benzoic acid (10.0 g,
37.0 mmol), sodium acetate (4.55 g, 55.5 mmol), and acetic acid
(7.0 mL) in acetic anhydride (50 mL) was refluxed for 4 hours. The
solvent was then distilled off under reduced pressure. To that
residue was added water, and the mixture was extracted with ethyl
acetate twice. The organic layer was washed with water, dried over
MgSO.sub.4, and filtered. The filtrate was concentrated under
reduced pressure to provide 6.10 g of
[(3-acetoxybenzofuran-7-yl)oxy]acetate. To a solution of this
compound (5.80 g, 23.2 mmol) in ethanol (20 mL) was added sulfuric
acid (1.0 mL) and refluxed for 30 minutes. The solvent was then
distilled off under reduced pressure. To that residue was added
water, and the mixture was extracted with ethyl acetate. The
organic layer was washed with water, dried over MgSO.sub.4, and
filtered. The filtrate was concentrated under reduced pressure, and
the residue was purified by silica gel column chromatography (ethyl
acetate-hexane 1:8) to provide 3.0 g of the title compound. Yield
36%. m. p. 89-90.degree. C. (ethyl acetate-hexane)
[0458] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t, J=6.8 Hz),
4.28 (2H, q, J=6.8 Hz), 4.69 (2H, s) , 4.79 (2H, s), 6.98-7.13 (2H,
m), 7.32 (1H, dd, J=7.4, 1.2 Hz).
Reference Examle 79
(3-Fluorophenyl)(phenyl)methylbromide
[0459] Using 3-fluorophenyl phenyl ketone, the procedure of
Reference Example 49 was otherwise repeated to synthesize the title
compound. Yield 73%. Oil.
[0460] .sup.1H-NMR(CDCl.sub.3) .delta.: 6.23 (1H, s), 6.90-7.02
(1H, m), 7.10-7.49 (8H, m).
Example 1
[[2-(2,2-Diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acet-
ic acid
[0461] To a solution of ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazo- l-6-yl)oxy]acetate
(1.80 g, 5.60 mmol) in N,N-dimethylformamide (15 mL) was added
2,2-diphenylethyl methanesulfonate (1.80 g, 6.20 mmol) followed by
addition of potassium carbonate (857 mg, 6.20 mmol) and the mixture
was stirred at 60.degree. C. for 2 hours. This reaction mixture was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with water and saturated aqueous sodium chloride
solution, dried over MgSO.sub.4, and filtered. The filtrate was
concentrated under reduced pressure to provide 2.70 g of ethyl
[[2-(2,2-diphenylethyl)thio-4-
,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetate. To a solution of
this compound (0.70 g, 1.44 mmol) in a mixture of tetrahydrofuran
(8 mL) and methanol (2 ml) was added 1N-aqueous sodium hydroxide
solution (1.5 mL) dropwise and the mixture was stirred at room
temperature for 5 minutes. The solvent was then distilled off under
reduced pressure. To the residue was added 1N-hydrochloric acid,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with water and saturated aqueous sodium chloride
solution, dried over MgSO.sub.4, and filtered. The filtrate was
concentrated under reduced pressure and the residue was
recrystallized from ethyl acetate-hexane to provide 0.43 g of the
title compound. Yield 61%. m.p. 223-225.degree. C.
[0462] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.90-3.15 (4H, m), 3.84
(2H, d, J=8.0 Hz), 4.48 (1H, t, J=8.0 Hz), 4.71 (2H, s), 6.83 (1H,
d, J=8.0 Hz), 7.13-7.49 (12H, m), 1H not confirmed.
Example 2
[(2-Benzylthio-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetic acid
[0463] Using ethyl
[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and benzyl
bromide, the procedure of Example 1 was otherwise repeated to
synthesize the title compound. Yield 21%. m.p. 166-169.degree. C.
(diethyl ether-ethanol)
[0464] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.78 (2H, 5), 4.43 (2H,
S), 4.79 (2H, s), 6.70 (1H, d, J=7.8 Hz), 7.24-7.50 (7H, m),
7.8-8.2 (1H, br).
Example 3
[(2-Benzylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic
acid
[0465] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and benzyl bromide, the procedure of Example 1 was otherwise
repeated to synthesize the title compound. Yield 44%. m.p.
180-182.degree. C. (ethanol)
[0466] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.86-3.02 (2H, m),
3.04-3.20 (2H, m), 4.45 (2H, s), 4.73 (2H, s), 6.73 (1H, d, J=8.4
Hz), 6.95 (1H, br s), 7.19-7.42 (6H, m), 7.66 (1H, d, J=7.4
Hz).
Example 4
[(2-(3-Phenyl-2-propenyl)thio-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetic
acid
[0467] Using ethyl
[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and
3-bromo-1-phenyl-1-propene, the procedure of Example 1 was
otherwise repeated to synthesize the title compound. Yield 50%.
m.p. 172-174.degree. C. (ethanol)
[0468] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.83 (2H, s), 4.11 (2H,
d, J=7.6 Hz), 4.79 (2H, s), 6.32-6.51 (1H, m), 6.69 (1H, d, J=15.8
Hz), 6.84 (1H, dd, J=7.0, 2.2 Hz), 7.18-7.45 (7H, m), 1H
not-confirmed.
Example 5
[(2-(3-Phenyl-2-propenyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]ac-
etic acid
[0469] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and 3-bromo-1-phenyl-1-propene, the procedure of Example 1 was
otherwise repeated to synthesize the title compound. Yield 56%.
m.p. 171-172.degree. C. (ethanol)
[0470] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.90-3.20 (4H, m), 4.03
(2H, d, J=6.8 Hz), 4.40-5.10 (3H, m), 6.25-6.44 (1H, m), 6.62 (1H,
d, J=15.4 Hz), 6.73 (1H, d, J=8.0 Hz), 7.18-7.43 (6H, m), 7.67 (1H,
d, J=7.8 Hz).
Example 6
[(2-(3,3-Diphenylpropyl)thio-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetic
acid
[0471] Using ethyl
[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and
3,3-diphenylpropyl iodide, the procedure of Example 1 was otherwise
repeated to synthesize the title compound. Yield 34%. m.p.
100-103.degree. C. (ethanol)
[0472] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.44-3.03 (2H, m),
3.10-3.22 (2H, m), 3.81 (2H, s), 4.17 (1H, t, J=80 Hz), 4.60-5.40
(1H, br), 4.78 (2H, s), 6.71 (1H, d, J=8.0 Hz), 7.10-7.52 (12H,
m).
Example 7
[(2-(3,3-Diphenylpropyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]ace-
tic acid
[0473] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and 3,3-diphenylpropyl iodide, the procedure of Example 1 was
otherwise repeated to synthesize the title compound. Yield 34%.
m.p. 128-130.degree. C. (ethanol)
[0474] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.45-2.63 (2H, m),
2.88-3.02 (2H, m), 3.07-3.21 (4H, m), 4.16 (1H, t, J=7.8 Hz), 4.72
(2H, s), 5.00-5.75 (1H, br), 6.72 (1H, d, J=8.0 Hz), 7.12-7.40
(11H, m), 7.59 (1H, d, J=7.8 Hz).
Example 8
[[2-(2,2-Diphenylethyl)thio-8H-indeno[1,2-d]thiazol-7-yl]oxy]acetic
acid
[0475] Using ethyl
[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and
2,2-diphenylethyl methanesulfonate, the procedure of Example 1 was
otherwise repeated to synthesize the title compound. Yield 37%.
m.p. 207-210.degree. C. (methanol)
[0476] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.84 (2H, s), 4.03 (2H,
d, J=8.0 Hz), 4.46 (1H, t, J=8.0 Hz), 4.81 (2H, s), 6.84 (1H, d,
J=7.4 Hz), 7.16-7.45 (12H, m), 1H not confirmed.
Example 9
[[2-(4,4-Diphenylbutyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acet-
ic acid
[0477] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and 4,4-diphenylbutyl iodide, the procedure of Example 1 was
otherwise repeated to synthesize the title compound. Yield 43%.
m.p. 136-138.degree. C. (ethyl acetate-hexane)
[0478] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.70-1.88 (2H, m),
2.11-2.21 (2H, m), 2.90-3.02 (2H, m), 3.07-3.29 (4H, m), 3.88-4.50
(2H, m), 4.74 (2H, s), 6.73 (1H, d, J=7.4 Hz), 7.10-7.32 (11H, m),
7.60 (1H, t, J=7.0 Hz).
Example 10
[[2-(3,3-Diphenylpropyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-7-yl]oxy]ace-
tic acid
[0479] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-7-yl)oxy]- acetate
and 3,3-diphenylpropyl iodide, the procedure of Example 1 was
otherwise repeated to synthesize the title compound. Yield 54%.
m.p. 138-140.degree. C. (ethyl acetate-hexane)
[0480] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.45-2.62 (2H, m),
2.86-3.22 (6H, m), 4.16 (1H, t, J=7.8 Hz), 4.70 (2H, s), 5.60-6.50
(1H, br), 6.75-6.86 (2H, m), 7.16-7.38 (10H, m), 7.75-7.85 (1H,
m).
Example 11
[[2-(3,3-Diphenylpropyl)thio-4H-[1]benzopyrano[4,3-d]thiazol-6-yl]oxy]acet-
ic acid
[0481] Using ethyl
[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]a- cetate and
3,3-diphenylpropyl iodide, the procedure of Example 1 was otherwise
repeated to synthesize the title compound. Yield 45%. m.p.
112-114.degree. C. (ethyl acetate-diisopropyl ether)
[0482] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.50-2.61 (2H, m), 3.18
(2H, t, J=7.8 Hz), 3.30-4.40 (1H, br), 4.15 (1H, t, J=7.8 Hz), 4.72
(2H, s), 5.47 (2H, s), 6.86 (1H, d, J=8.0 Hz), 6.98 (1H, t, J=8.0
Hz), 7.15-7.30 (10H, m), 7.49 (1H, d, J=8.0 Hz).
Example 12
[[2-(2,2-Diphenylethyl)thio-4H-[1]benzopyrano[4,3-d]thiazol-6-yl]oxy]aceti-
c acid
[0483] Using ethyl
[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]a- cetate and
2,2-diphenylethyl iodide, the procedure of Example 1 was otherwise
repeated to synthesize the title compound. Yield 41%. m.p.
182-184.degree. C. (methanol-ethyl acetate)
[0484] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.00 (2H, d, J=8.0 Hz),
4.46 (1H, t, J=8.0 Hz), 4.68 (2H, s), 5.44 (2H, s), 6.84-6.99 (2H,
m), 7.12-7.40 (11H, m), 12.00-13.00 (1H, br).
Example 13
[(2-Diphenylmethylthio-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]acetic
acid
[0485] Using ethyl
[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]a- cetate and
bromodiphenylmethane, the procedure of Example 1 was otherwise
repeated to synthesize the title compound. Yield 17%. m.p.
129-131.degree. C. (ethyl acetate-hexane)
[0486] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.60-2.80 (1H, br), 4.68
(2H, s), 5.39 (2H, s), 6.07 (1H, s), 6.84 (1H, d, J=7.8 Hz), 6.96
(1H, t, J=7.8 Hz), 7.26-7.49 (11H, m).
Example 14
[[2-(4-Phenylbenzylthio)-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetic
acid
[0487] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and 4-phenylbenzyl bromide, the procedure of Example 1 was
otherwise repeated to synthesize the title compound. Yield 68%.
m.p. 198-200.degree. C. (ethyl acetate-hexane)
[0488] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.90-3.04 (2H, m),
3.11-3.22 (2H, m), 3.40-4.30 (1H, br), 4.50 (2H, s), 4.74 (2H, s),
6.74 (1H, d, J=8.2 Hz), 7.21-7.62 (10H, m), 7.69 (1H, d, J=7.6
Hz).
Example 15
[[2-(2-Naphthyl)phenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy-
]acetic acid
[0489] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (2-naphthyl)phenylmethyl bromide, the procedure of Example 1
was otherwise repeated to synthesize the title compound. Yield 44%.
m.p. 118-121.degree. C. (ethyl acetate-hexane)
[0490] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.70-2.89 (2H, m),
2.99-3.08 (2H, m), 4.4-4.9 (3H, m), 6.22 (1H, s), 6.69 (1H, d,
J=8.0 Hz), 7.24-7.62 (10H, m), 7.76-7.83 (3H, m), 7.91 (1H, s).
Example 16
[[(2-Diphenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-7-yl)oxy]acetic
acid
[0491] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-7-yl)oxy]- acetate
and diphenylmethane bromide, the procedure of Example 1 was
otherwise repeated to synthesize the title compound. Yield 50%.
m.p. 193-195.degree. C. (ethyl acetate)
[0492] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.75-2.98 (4H, m), 4.70
(2H, s), 6.01 (1H, s), 6.00-6.60 (1H, br), 6.74-6.82 (2H, m),
7.20-7.55 (10H, m), 7.80 (1H, d, J=8.8 Hz).
Example 17
[[2-(2-Naphthyl)phenylmethylthio-4H-[1]benzopyrano[4,3-d]thiazol-6-yl]oxy]-
acetic acid
[0493] Using ethyl
[(2-mercapto-4H-[1]benzopyrano(4,3-d]thiazol-6-yl)oxy]a- cetate and
(2-naphthyl)phenylmethyl bromide, the procedure of Example 1 was
otherwise repeated to synthesize the title compound. Yield 45%.
Amorphous solid.
[0494] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.40-3.80 (1H, br), 4.69
(2H, s), 5.36 (2H, s), 6.24 (1H, s), 6.84 (1H, d, J=7.8 Hz), 6.96
(1H, d, J=7.8 Hz), 7.20-7.63 (9H, m), 7.80-7.84 (3H, m), 7.93 (1H,
s).
Example 18
[[2-(4,4-Diphenylbutyl)thio-8H-indeno[1,2-d]thiazol-7-yl]oxy]acetic
acid
[0495] Using ethyl
[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and
4,4-diphenylbutyl iodide, the procedure of Example 1 was otherwise
repeated to synthesize the title compound. Yield 44%. m.p.
110-112.degree. C. (ethyl acetate-hexane)
[0496] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.60-1.85 (2H, m),
2.10-2.31 (2H, m), 3.15-3.30 (2H, m), 3.72-3.96 (3H, m), 4.78 (2H,
s), 6.69 (1H, d, J=8.0 Hz), 7.07-7.37 (11H, m), 7.43 (1H, d, J=7.6
Hz), 8.10-8.56 (1H, m).
Example 19
4-[[2-(2,2-Diphenylethyl)thio-8H-indeno[1,2-d]thiazol-7-yl]oxy]butyric
acid
[0497] Using ethyl
4-[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]butyrat- e and
2,2-diphenylethyl methanesulfonate, the procedure of Example 1 was
otherwise repeated to synthesize the title compound. Yield 35%.
m.p. 137-138.degree. C. (ethyl acetate-hexane)
[0498] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.58-2.01 (1H, br),
2.12-2.25 (2H, m), 2.63 (2H, t, J=7.2 Hz), 3.73 (2H, s), 3.95 (2H,
d, J=8.0 Hz), 4.15 (2H, d, J=6.0 Hz), 4.47 (1H, t, J=8.0 Hz), 6.79
(1H, d, J=6.6 Hz), 7.18-7.43 (12H, m).
Example 20
4-[[2-(3,3-Diphenylpropyl)thio-8H-indeno[1,2-d]thiazol-7-yl]oxy]butyric
acid
[0499] Using
4-[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl]oxy]butyrate and
3,3-diphenylpropyl iodide, the procedure of Example 1 was otherwise
repeated to synthesize the title compound. Yield 27%. m.p.
86-88.degree. C. (ethyl acetate-hexane)
[0500] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.12-2.25 (2H, m),
2.47-2.71 (4H, m), 3.08-3.22 (2H, m), 3.72 (2H, s), 4.09-4.25 (3H,
m), 6.78 (1H, dd, J=7.8, 1.0 Hz), 7.12-7.43 (13H, m).
Example 21
[(2-Diphenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic
acid
[0501] To a solution of ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazo- l-6-yl)oxy]acetate
(1.10 g, 3.42 mmol) in N,N-dimethylformamide (20 mL) were added
diphenylmethane bromide (0.93 g, 3.76 mmol) and potassium carbonate
(0.52 g, 3.76 mmol), and the mixture was stirred at 60.degree. C.
for 3 hours. This reaction mixture was diluted with ethyl acetate
and water and, after phase separation, the aqueous layer was
extracted with ethyl acetate. The pooled organic solution was
washed with water, dried over MgSO.sub.4, and filtered. The
filtrate was concentrated under reduced pressure and the residue
was dissolved in acetic acid (20 mL). To this solution was added
concentrated sulfuric acid (10 ml), and the mixture was refluxed
for 1 hour. After cooling, the reaction mixture was diluted with
water and extracted with 2 portions of ethyl acetate. The pooled
extract was washed with water, dried over MgSO.sub.4, and filtered.
The filtrate was concentrated under reduced pressure and the
residue was crystallized from hexane-ethyl acetate to provide 0.58
g of the title compound. Yield 37%. m.p. 176-179.degree. C.
[0502] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.80-3.08 (4H, m), 4.70
(2H, s), 6.18 (1H, s), 6.82 (1H, d, J=8.4 Hz), 7.15-7.63 (12H, m),
1H not confirmed.
Example 22
3-[[2-(2,2-Diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]pr-
opionic acid
[0503] Using ethyl
3-[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)ox-
y]propionate and 2,2-diphenylethyl iodide, the procedure of Example
21 was otherwise repeated to synthesize the title compound. Yield
29%. m.p. 123-125.degree. C. (ethyl acetate-hexane)
[0504] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.78-3.12 (6H, m), 3.93
(2H, d, J=8.0 Hz), 4.29 (1H, t, J=6.2 Hz), 4.50 (1H, t, J=8.0 Hz),
4.80-6.60 (1H, br), 6.82 (1H, d, J=8.0 Hz), 7.13-7.38 (12H, m),
7.60 (1H, d, J=7.2 Hz).
Example 23
3-[[2-(3,3-Diphenylpropyl)thio-8H-indeno[1,2-d]thiazol-7-yl]oxy]propionic
acid
[0505] Using ethyl
3-[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]propion- ate and
3,3-diphenylpropyl iodide, the procedure of Example 21 was
otherwise repeated to synthesize the title compound. Yield 49%.
m.p. 113-114.degree. C. (ethyl acetate-diethyl ether)
[0506] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.42-2.61 (2H, m),
2.82-2.98 (2H, m), 3.09-3.21 (2H, m), 3.70 (2H, s), 4.17 (1H, t,
J=8.0 Hz), 4.33-4.43 (2H, m), 6.81 (1H, d, J=7.6 Hz), 7.15-7.44
(13H, m).
Example 24
[[2-(3,3-Diphenylpropyl)thio-8H-indeno[1,2-d]thiazol-6-yl]oxy]acetic
acid
[0507] Using ethyl
[(2-mercapto-8H-indeno[1,2-d]thiazol-6-yl)oxy]acetate and
3,3-diphenylpropyl iodide, the procedure of Example 21 was
otherwise repeated to synthesize the title compound. Yield 42%.
m.p. 135-137.degree. C. (ethyl acetate-diethyl ether)
[0508] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.45-2.58 (2H, m),
3.07-3.19 (2H, m), 3.74 (2H, s), 3.80-4.43 (2H, m), 4.72 (2H, s),
6.87-6.95 (1H, m), 7.08-7.33 (11H, m), 7.64 (1H, d, J=8.4 Hz).
Example 25
[[2-(3,3-Diphenylpropyl)thio-4,6-dimethyl-8H-indeno[1,2-d]thiazol-7-yl]oxy-
]acetic acid
[0509] Using ethyl
[(2-mercapto-4,6-dimethyl-8H-indeno[1,2-d]thiazol-7-yl)-
oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example
21 was otherwise repeated to synthesize the title compound. Yield
55%. m.p. 156-158.degree. C. (ethyl acetate-hexane)
[0510] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.33 (3H, s), 2.50-2.68
(5H, m), 3.11-3.20 (2H, m), 3.3-4.0 (3H, m), 4.18 (1H, t, J=8.0
Hz), 4.62 (2H, s), 6.99 (1H, s), 7.13-7.42 (10H, m).
Example 26
[[2-(3,3-Diphenylpropyl)thio-4,5-dimethyl-8H-indeno[1,2-d]thiazol-7-yl]oxy-
]acetic acid
[0511] Using ethyl
[(2-mercapto-4,5-dimethyl-8H-indeno[1,2-d]thiazol-7-yl)-
oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example
21 was otherwise repeated to synthesize the title compound. Yield
53%. m.p. 142-144.degree. C. (ethyl acetate-hexane)
[0512] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.33 (3H, s), 2.50-2.72
(5H, m), 3.10-3.21 (2H, m), 3.73 (2H, m), 4.18 (1H, t, J=8.0 Hz),
4.76 (2H, s), 6.53 (1H, s), 6.7-7.7 (11H, m).
Example 27
[(2-Diphenylmethylthio-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetic
acid
[0513] Using ethyl
[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and
diphenylmethane bromide, the procedure of Example 21 was otherwise
repeated to synthesize the title compound. Yield 61%. m.p.
224-225.degree. C. (chloroform-diethyl ether)
[0514] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.76 (2H, s), 4.78 (2H,
s), 6.17 (1H, s), 6.78-6.85 (1H, m), 7.10-7.42 (8H, m), 7.50 (4H,
d, J=7.0 Hz), 1H not confirmed.
Example 28
3-[(2-Diphenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]propion-
ic acid
[0515] Using ethyl
3-[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)ox-
y]propionate and diphenylmethane bromide, the procedure of Example
21 was otherwise repeated to synthesize the title compound. Yield
39%. m.p. 156-158.degree. C. (ethyl acetate-hexane)
[0516] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.75-3.00 (6H, m), 4.27
(2H, t, J=6.2 Hz), 6.05 (1H, t, J=8.0 Hz), 6.80 (1H, d, J=8.4 Hz),
7.16-7.57 (13H, m).
Example 29
[[2-(2,2-Diphenylethyl)sulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]-
acetic acid
[0517] To a solution of ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazo- l-6-yl)oxy]acetate
(1.80 g, 5.60 mmol) in N,N-dimethylformamide (15 mL) was added
2,2-diphenylethyl methanesulfonate (1.80 g, 6.20 mmol) followed by
addition of potassium carbonate (857 mg, 6.20 mmol), and the
mixture was stirred at 60.degree. C. for 2 hours. This reaction
mixture was diluted with water and extracted with ethyl acetate.
The organic layer was washed with water and saturated aqueous
sodium chloride solution, dried over MgSO.sub.4, and filtered. The
filtrate was concentrated under reduced pressure to provide 2.70 g
of ethyl[[2-(2,2-diphenylethyl)thio-4,-
5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetate. To a solution of
this compound (2.00 g, 3.99 mmol) in ethanol (8 mL)-water (2 mL)
was added sodium periodate (4.30 g, 19.9 mmol) and the mixture was
refluxed for 14 hours. This reaction mixture was diluted with ethyl
acetate and water and, after phase separation, the aqueous layer
was extracted with ethyl acetate. The pooled organic solution was
washed with water, dried over MgSO.sub.4, and filtered and the
filtrate was concentrated under reduced pressure. To a solution of
the above concentration residue in tetrahydrofuran (16 mL)-methanol
(4 mL) was added 1N-aqueous sodium hydroxide solution (2 mL)
dropwise, and the mixture was stirred at room temperature for 10
minutes. The solvent was then distilled off under reduced pressure.
To the residue was added 1N-hydrochloric acid, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and saturated aqueous sodium chloride solution, dried over
MgSO.sub.4, and filtered and the filtrate was concentrated under
reduced pressure. The residue was recrystallized from ethyl
acetate-hexane to provide 0.72 g of the title compound. Yield 41%.
m.p. 168-170.degree. C.
[0518] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.88-3.02 (2H, m),
3.05-3.20 (2H, m), 3.20-3.80 (1H, br), 4.30 (2H, d, J=7.4 Hz),
4.65-4.80 (3H, m), 6.80 (1H, d, J=8.6 Hz), 7.00-7.32 (11H, m), 7.64
(1H, d, J=7.2 Hz).
Example 30
[[2-(3-Phenyl-2-propenyl)sulfonyl-8H-indeno[1,2-d]thiazol-7-yl]oxy]acetic
acid
[0519] Using ethyl
[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and
3-bromo-1-phenyl-1-propene, the procedure of Example 29 was
otherwise repeated to synthesize the title compound. Yield 8%. m.p.
212-214.degree. C. (ethyl acetate-hexane)
[0520] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.30-3.65 (1H, br), 3.95
(2H, s), 4.34 (2H, d, J=7.4 Hz), 4.81 (2H, s), 6.10-6.24 (1H, m),
6.56 (1H, d, J=16.2 Hz), 6.79 (1H, d, J=8.0 Hz), 7.23-7.31 (5H, m),
7.41 (1H, t, J=8.0 Hz), 7.58 (1H, d, J=7.6 Hz).
Example 31
[[2-(3-Phenyl-2-propenyl)sulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]ox-
y]acetic acid
[0521] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and 3-bromo-1-phenyl-1-propene, the procedure of Example 29 was
otherwise repeated to synthesize the title compound. Yield 43%.
m.p. 210-214.degree. C. (ethanol)
[0522] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.95-3.50 (5H, m), 4.53
(2H, d, J=7.6 Hz), 4.74 (2H, s), 6.10-6.33 (1H, m), 6.69 (1H, d,
J=16.0 Hz), 6.92 (1H, d, J=8.0 Hz), 7.15-7.60 (7H, m).
Example 32
[[2-(3,3-Diphenylpropyl)sulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy-
]acetic acid
[0523] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and 3,3-diphenylpropyl iodide, the procedure of Example 29 was
otherwise repeated to synthesize the title compound. Yield 22%.
m.p. 175-176.degree. C. (ethanol)
[0524] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.52-3.30 (7H, m),
3.35-3.50 (2H, m), 4.03 (1H, t, J=8.0 Hz), 4.74 (2H, s), 6.79 (1H,
d, J=8.4 Hz), 7.10-7.34 (11H, m), 7.65 (1H, d, J=7.4 Hz).
Example 33
[[2-(4,4-Diphenylbutyl)sulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]-
acetic acid
[0525] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and 4,4-diphenylbutyl iodide, the procedure of Example 29 was
otherwise repeated to synthesize the title compound. Yield 35%.
m.p. 180-181.degree. C. (ethyl acetate-hexane)
[0526] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.73-1.92 (2H, m),
2.10-2.25 (2H, m), 3.04-3.25 (4H, m), 3.38-3.52 (2H, m), 3.87 (1H,
t, J=8.0 Hz), 3.90-4.06 (1H, br), 4.76 (2H, s), 6.79 (1H, d, J=8.0
Hz), 7.06-7.34 (11H, m), 7.64 (1H, d, J=7.4 Hz).
Example 34
[[2-(3,3-Diphenylpropyl)sulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-7-yl]oxy-
]acetic acid
[0527] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-7-yl)oxy]- acetate
and 3,3-diphenylpropyl iodide, the procedure of Example 29 was
otherwise repeated to synthesize the title compound. Yield 27%.
m.p. 175-177.degree. C. (ethyl acetate-hexane)
[0528] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.50-2.71 (2H, m),
3.00-3.21 (4H, m), 3.33-3.50 (2H, m), 4.02,(1H, t, J=7.8 Hz), 4.74
(2H, s), 5.20-6.50 (1H, br), 6.80-6.92 (2H, m), 7.12-7.34 (10H, m),
7.82-7.91 (1H, m).
Example 35
[[2-(3,3-Diphenylpropyl)sulfonyl-4H-[1]benzopyrano[4,3-d]thiazol-6-yl]oxy]-
acetic acid
[0529] Using ethyl
[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]a- cetate and
3,3-diphenylpropyl iodide, the procedure of Example 29 was
otherwise repeated to synthesize the title compound. Yield 37%.
Amorphous solid.
[0530] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.53-2.65 (2H, m),
3.39-3.47 (2H, m), 4.03 (1H, t, J=8.0 Hz), 4.74 (2H, s), 5.56 (2H,
s), 5.30-6.00 (1H, br), 6.88-6.92 (1H, m), 7.02 (1H, t, J=8.2 Hz),
7.15-7.31 (10H, m), 7.51-7.56 (1H, m).
Example 36
[[2-(3,3-Diphenylpropyl)sulfonyl-8H-indeno[1,2-d]thiazol-7-yl]oxy]acetic
acid
[0531] To a solution of ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazo- l-6-yl)oxy]acetate
(4.00 g, 12.4 mmol) in N,N-dimethylformamide (30 mL) was added
3,3-diphenylpropyl methanesulfonate (3.96 g, 13.6 mmol) followed by
addition of potassium carbonate (1.90 g, 13.6 mmol), and the
mixture was stirred at 60.degree. C. for 2 hours. This reaction
mixture was diluted with water and extracted with ethyl acetate.
The organic layer was washed with water and saturated aqueous
sodium chloride solution, dried over MgSO.sub.4, and filtered. The
filtrate was concentrated under reduced pressure to provide 3.81 g
of ethyl
[[2-(3,3-diphenylpropyl)thio-8H-indeno[1,2-d]thiazol-7-yl]oxy]acetate.
To a solution of this compound (1.10 g, 2.19 mmol) in ethanol (30
mL)-water (3 mL) was added sodium periodate (4.68 g, 21.9 mmol) and
the mixture was refluxed for 14 hours. This reaction mixture was
diluted with ethyl acetate and water and, after phase separation,
the aqueous layer was extracted with ethyl acetate. The organic
layers were pooled, washed with water, dried over MgSO.sub.4, and
filtered. The filtrate was concentrated under reduced pressure and
the residue was dissolved in acetic acid (10 mL). To this solution
was added concentrated sulfuric acid (5 mL) and the mixture was
refluxed for 1 hour. After cooling, the reaction mixture was
diluted with water and extracted with 2 portions of ethyl acetate,
and the combined extract was washed with water, dried over
MgSO.sub.4, and filtered. The filtrate was concentrated under
reduced pressure and the residue was crystallized from hexane-ethyl
acetate to provide 350 mg of the title compound. Yield 17%. m.p.
131-133.degree. C.
[0532] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.52-2.66 (2H, m),
3.37-3.46 (2H, m), 3.60-4.20 (4H, m), 4.83 (2H, s), 6.80 (1H, d,
J=8.0 Hz), 7.10-7.32 (10H, m), 7.36-7.46 (1H, m), 7.50 (1H, t,
J=7.2 Hz).
Example 37
[[2-(4,4-Diphenylbutyl)sulfonyl-8H-indeno[1,2-d]thiazol-7-yl]oxy]acetic
acid
[0533] Using ethyl
[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and
4,4-diphenylbutyl iodide, the procedure of Example 36 was otherwise
repeated to synthesize the title compound. Yield 37%. m.p.
97-101.degree. C. (ethyl acetate-hexane)
[0534] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.70-1.90 (2H, m),
2.08-2.27 (2H, m), 3.37-3.56 (2H, m), 3.85 (1H, t, J=8.0 Hz), 3.93
(2H, s), 4.82 (2H, s), 6.75-7.31 (12H, m), 7.39 (1H, t, J=8.0 Hz),
7.53 (1H, d, J=7.4 Hz).
Example 38
3-[[2-(3,3-Diphenylpropyl)sulfonyl-8H-indeno[1,2-d]thiazol-7-yl]oxy]propio-
nic acid
[0535] Using ethyl
3-[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]propion- ate and
3,3-diphenylpropyl iodide, the procedure of Example 36 was
otherwise repeated to synthesize the title compound. Yield 10%.
m.p. 215-218.degree. C. (ethyl acetate)
[0536] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.40-2.58 (2H, m),
2.70-2.81 (2H, m), 3.30-3.50 (2H, m), 3.95 (2H, s), 4.00-4.18 (1H,
m), 4.30-4.42 (2H, m), 7.02-7.50 (14H, m).
Example 39
[[2-(3,3-Diphenylpropyl)sulfonyl-8H-indeno[1,2-d]thiazol-6-yl]oxy]acetic
acid
[0537] Using ethyl
[(2-mercapto-8H-indeno[1,2-d]thiazol-6-yl)oxy]acetate and
3,3-diphenylpropyl iodide, the procedure of Example 36 was
otherwise repeated to synthesize the title compound. Yield 10%.
m.p. 172-174.degree. C. (ethyl acetate)
[0538] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.45-2.70 (2H, m),
3.30-3.48 (2H, m), 3.6-4.4 (4H, m), 4.76 (2H, s), 6.94-7.32 (12H,
m), 7.76 (1H, d, J=8.4 Hz).
Example 40
[[2-(3,3-Diphenylpropyl)oxy-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acet-
ic acid
[0539] A mixture of ethyl
[(2-hydroxy-4,5-dihydronaphtho[1,2-d]thiazol-6-y- l)oxy]acetate
(1.40 g, 4.58 mmol), sodium hydride (60% dispersion in liquid
paraffin, 200 mg, 5.00 mmol), 3,3-diphenylpropyl iodide (1.60 g,
5.04 mmol), and N,N-dimethylformamide (30 ml) was stirred at
70.degree. C. for 2 hours. This reaction mixture was poured into
water (50 mL) and extracted with 2 portions of ethyl acetate. The
pooled organic solution was washed with water, dried over
MgSO.sub.4, and filtered and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane-ethyl acetate=8:1) to provide 810 mg of
ethyl [[2-(3,3-diphenylpropyl)oxy-4,5-dihydronaphtho-
[1,2-d]thiazol-6-yl]oxy]acetate. To a solution of this compound
(700 mg, 1.40 mmol) in a mixture of tetrahydrofuran (8 mL) and
methanol (2 mL) was added 1N-aqueous sodium hydroxide solution (1.4
mL) dropwise and the mixture was stirred at room temperature for 5
minutes. To this reaction mixture was added 1N-hydrochloric acid,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with water and saturated aqueous sodium chloride
solution, dried over MgSO.sub.4, and filtered. The filtrate was
concentrated under reduced pressure and the residue was
recrystallized from ethyl acetate-hexane to provide 500 mg of the
title compound. Yield 24%. m.p. 165-166.degree. C.
[0540] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.5-2.64 (2H, m),
2.79-2.90 (2H, m), 3.04-3.16 (4H, m), 4.15-4.26 (1H, m), 4.38 (1H,
t, J=6.6 Hz), 4.70 (2H, s), 5.20-6.40 (1H, br), 6.67 (1H, d, J=7.8
Hz), 7.12-7.36 (11H, m), 7.42 (1H, d, J=7.6 Hz).
Example 41
[[2-(3,3-Diphenylpropyl)amino-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]ac-
etic acid
[0541] To a mixture of ethyl
[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthal- enyl)oxy]acetate
(1.20 g, 3.67 mmol), N-(3,3-diphenylpropyl)thiourea (1.10 g, 4.04
mmol), and acetonitrile (30 mL) was added triethylamine (0.56 mL,
4.04 mmol), and the mixture was refluxed for 2 hours. After
cooling, the reaction mixture was diluted with water and extracted
with ethyl acetate. The organic layer was washed with
1N-hydrochloric acid, saturated aqueous sodium chloride solution,
and water, dried over MgSO.sub.4, and filtered. The filtrate was
concentrated under reduced pressure and the residue was purified by
silica gel column chromatography (hexane-ethyl acetate=5:1) to
provide 700 mg of ethyl
[[2-(3,3-diphenylpropyl)amino-4,5-dihydronapht-
ho[1,2-d]thiazol-6-yl]oxy]acetate. To a solution of this compound
in acetic acid (10 mL) was added concentrated hydrochloric acid (5
mL) and the mixture was refluxed for 1 hour. After cooling, the
reaction mixture was diluted with water and extracted with 2
portions of ethyl acetate. The pooled organic layer was washed with
water, dried over MgSO.sub.4, and filtered and the filtrate was
concentrated under reduced pressure. The residue was crystallized
from hexane-ethyl acetate to provide 500 mg of the title compound.
Yield 17%. m.p. 240-243.degree. C.
[0542] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.26-2.50 (2H, m),
2.66-2.85 (2H, m), 2.90-3.08 (2H, m), 3.10-3.30 (2H, m), 4.05-4.17
(1H, m), 4.67 (2H, s), 6.72 (1H, d, J=8.0 Hz), 7.08-7.44 (13H, m),
7.55-7.67 (1H, m).
Example 42
[(2-Diphenylmethylamino-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetic
acid
[0543] To a mixture of ethyl
[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthal- enyl)oxy]acetate
(1.10 g, 3.36 mmol), N-(diphenylmethyl)thiourea (900 mg, 3.70
mmol), and ethanol (15 mL) was added triethylamine (0.51 mL, 3.70
mmol), and the mixture was refluxed for 6 hours. After cooling, the
reaction mixture was diluted with water and extracted with ethyl
acetate. The organic layer was washed with 1N-hydrochloric acid,
saturated aqueous sodium chloride solution, and water, dried over
MgSO.sub.4, and filtered. The filtrate was concentrated under
reduced pressure. To a solution of this concentration residue (0.79
g, 1.70 mmol) in tetrahydrofuran (16 mL)-methanol (4 mL) was added
1N-aqueous sodium hydroxide solution (2.0 mL) dropwise and the
mixture was stirred at room temperature for 10 minutes. The solvent
was then distilled off under reduced pressure and the residue was
recrystallized from acetic acid-water to provide 0.49 g of the
title compound. Yield 33%. m.p. 250-252.degree. C.
[0544] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.62-2.82 (2H, m),
2.85-3.01 (2H, m), 4.66 (2H, s), 6.10 (1H, d, J=8.4 Hz), 6.72 (1H,
d, J=8.0 Hz), 7.11-7.45 (13H, m), 8.48 (1H, d, J=8.4 Hz).
Example 43
[[2-(2,2-Diphenylethyl)amino-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]ace-
tic acid hydrochloride
[0545] To a mixture of ethyl
[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthal- enyl)oxy]acetate
(1.20 g, 3.67 mmol), N-(2,2-diphenylethyl)thiourea (1.00 g, 4.03
mmol), and ethanol (20 mL) was added triethylamine (0.56 mL, 4.04
mmol), and the mixture was refluxed for 4 hours. After cooling, the
reaction mixture was diluted with water and extracted with ethyl
acetate. The organic layer was washed with 1N-hydrochloric acid,
saturated aqueous sodium chloride solution, and water, dried over
MgSO.sub.4, and filtered. The filtrate was concentrated under
reduced pressure and the residue was purified by silica gel column
chromatography (hexane-ethyl acetate=5:1) to provide 1.10 g of
ethyl [[2-(3,3-diphenylpropyl)amino-4,5-dihydronapht-
ho[1,2-d]thiazol-6-yl]oxy]acetate. To a solution of this compound
in acetic acid (20 mL) was added concentrated hydrochloric acid (10
mL), and the mixture was refluxed for 1 hour. After cooling, the
reaction mixture was treated with water for crystallization to
provide 1.00 g of the title compound. Yield 61%. m.p.
136-140.degree. C. (acetic acid-water)
[0546] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.70-2.81 (2H, m),
2.96-3.10 (2H, m), 4.10-4.28 (2H, m), 4.40-4.50 (1H, m), 4.72 (2H,
s), 5.0-5.8 (2H, br), 6.88 (1H, d, J=8.2 Hz), 7.15-7.52 (12H, m),
9.0-9.7 (1H, br).
Example 44
[[2-(2,2-Diphenylethyl)amino-8H-indeno[1,2-d]thiazol-7-yl]oxy]acetic
acid hydrochloride
[0547] Using ethyl
[(2-bromo-2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]acetate and
N-(2,2-diphenylethyl)thiourea, the procedure of Example 43 was
otherwise repeated to synthesize the title compound. Yield 21%.
m.p. 206-210.degree. C. (decomp.) (acetic acid-water)
[0548] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.75-3.00 (6H, m), 4.27
(2H, t, J=6.2 Hz), 6.05 (1H, t, J=8.0 Hz), 6.80 (1H, d, J=8.4 Hz),
7.16-7.57 (13H, m).
Example 45
[[2-(3,3-Diphenylpropyl)amino-8H-indeno[1,2-d]thiazol-7-yl]oxy]acetic
acid hydrochloride
[0549] Using ethyl
[(2-bromo-2,3-dihydro-1-oxo-1H-inden-4-yl)oxy]acetate and
N-(3,3-diphenylpropyl)thiourea, the procedure of Example 43 was
otherwise repeated to synthesize the title compound. Yield 53%.
m.p. 242-245.degree. C. (decomp.) (ethyl acetate)
[0550] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.33-2.58 (2H, m),
3.28-3.42 (2H, m), 3.69 (2H, s), 4.20 (1H, t, J=8.0 Hz), 4.79 (2H,
s), 5.00-5.80 (2H, br), 6.82 (1H, d, J=8.0 Hz), 7.10-7.43 (12H, m),
9.50-10.0 (1H, br).
Example 46
[(2-(1,2-Diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acet-
ic acid
[0551] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and 1-bromo-1,2-diphenylethane, the procedure of Example 1 was
otherwise repeated to synthesize the title compound. Yield 41%.
m.p. 201-204.degree. C. (ethyl acetate)
[0552] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.75-3.11 (4H, m),
3.24-3.52 (2H, m), 4.71 (2H, s), 5.04 (1H, dd, J=6.8, 8.6 Hz), 6.84
(1H, d, J=8.4 Hz), 7.07-7.51 (12H, m), 1H not confirmed.
Example 47
[(2-Phenylamino-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic
acid hydrochloride
[0553] Using ethyl
[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]a- cetate and
1-phenyl-2-thiourea, the procedure of Example 43 was otherwise
repeated to synthesize the title compound. Yield 47%. m.p.
289-292.degree. C. (decomp.) (acetic acid-water)
[0554] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.81-3.13 (4H, m), 4.71
(2H, s), 6.00-8.00 (1H, br), 6.80 (1H, d, J=7.8 Hz), 6.96 (1H, t,
J=8.4 Hz), 7.17-7.43 (4H, m), 7.72 (2H, d, J=7.8 Hz), 10.28 (1H, br
s).
Example 48
Ethyl
[(2-diphenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]ace-
tate
[0555] To a solution of ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazo- l-6-yl)oxy]acetate
(4.00 g, 12.4 mmol) in N,N-dimethylformamide (30 mL) were serially
added bromodiphenylmethane (3.38 g, 13.7 mmol) and potassium
carbonate (1.90 g, 13.7 mmol), and the mixture was stirred at
60.degree. C. for 2 hours. This reaction mixture was diluted with
water and extracted with ethyl acetate. The organic layer was
washed with water and saturated aqueous sodium chloride solution,
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure. The residue was recrystallized from ethyl acetate to
provide 4.50 g of the title compound Yield 74%. m.p.
124-126.degree. C.
[0556] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t, J=7.0 Hz),
2.81-2.93 (2H, m), 3.03-3.14 (2H, m), 4.27 (2H, q, J=7.0 Hz), 4.64
(2H, s), 6.06 (1H, s), 6.67 (1H, d, J=7.6 Hz), 7.15-7.51 (11H, m),
7.58 (1H, d, J=7.4 Hz).
Example 49
Ethyl
[(2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)ox-
y]acetate
[0557] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and 2,2-diphenylethyl iodide, the procedure of Example 48 was
otherwise repeated to synthesize the title compound. Yield 68%.
m.p. 92-93.degree. C. (ethanol)
[0558] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.0 Hz),
2.91-3.00 (2H, m), 3.10-3.21 (2H, m), 3.94 (2H, d, J=7.8 Hz), 4.29
(2H, q, J=7.0 Hz), 4.51 (1H, t, J=7.8 Hz), 4.67 (2H, s), 6.70 (1H,
d, J=8.2 Hz), 7.18-7.41 (11H, m), 7.64 (1H, d, J=6.8 Hz).
Example 50
Ethyl
[(2-diphenylmethylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy-
]acetate
[0559] To a solution of ethyl
[(2-diphenylmethylthio-4,5-dihydronaphtho[1,-
2-d]thiazol-6-yl)oxy]acetate (1.50 g, 3.08 mmol) in chloroform (30
mL) was added m-chloroperbenzoic acid (55%, 1.70 g, 6.77 mmol) at
0.degree. C. and the mixture was stirred at room temperature for 2
hours. This reaction mixture was washed with saturated aqueous
sodium hydrogen carbonate solution and water, dried over
MgSO.sub.4, filtered, and concentrated under reduced pressure. The
residue was crystallized from ethyl acetate-hexane to provide 1.25
g of the title compound. Yield 78%. m.p. 184-187.degree. C.
[0560] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.0 Hz),
2.91-3.18 (4H, m), 4.28 (2H, q, J=7.0 Hz), 4.67 (2H, s), 5.94 (1H,
s), 6.76 (1H, d, J=8.0 Hz), 7.25-7.41 (7H, m), 7.52-7.74 (5H,
m).
Example 51
[(2-Diphenylmethylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]aceti-
c acid
[0561] To a solution of ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazo- l-6-yl)oxy]acetate
(4.00 g, 12.4 mmol) in N,N-dimethylformamide (30 mL) were serially
added bromodiphenylmethane (3.38 g, 13.7 mmol) and potassium
carbonate (1.90 g, 13.7 mmol) and the mixture was stirred at
60.degree. C. for 2 hours. This reaction mixture was diluted with
water and extracted with ethyl acetate. The organic layer was
washed with water and saturated aqueous sodium chloride solution,
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure to provide ethyl
[(2-diphenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate
(2.70 g). This compound (1.40 g, 2.87 mmol) was dissolved in
dichloromethane (30 mL) followed by addition of m-chloroperbenzoic
acid (55%, 2.00 g, 6.32 mmol) at 0.degree. C., and the mixture was
stirred at room temperature for 2 hours. This reaction mixture was
washed with saturated sodium hydrogen carbonate solution and water,
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure to provide ethyl
[(2-diphenylmethylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)ox-
y]acetate (1.10 g). To a solution of this compound (1.10 g, 2.12
mmol) in tetrahydrofuran (10 mL)-methanol (5 mL) was added
1N-aqueous sodium hydroxide (3.0 mL) dropwise and the mixture was
stirred at room temperature for 15 minutes. To this reaction
mixture was added 1N-hydrochloric acid followed by extraction with
ethyl acetate. The organic layer was washed with water and
saturated aqueous sodium chloride solution, dried over MgSO.sub.4,
filtered, and concentrated under reduced pressure. The residue was
crystallized from ethyl acetate to provide 550 mg of the title
compound. Yield 39%. m.p. 219-221.degree. C.
[0562] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.90-3.18 (4H, m), 4.74
(2H, s), 6.33 (1H, s), 6.92 (1H, d, J=8.4 Hz), 7.21-7.75 (12H, m),
1H not confirmed.
Example 52
[(2-Benzyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic
acid
[0563] A solution of ethyl
[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalen- yl)oxy]acetate
(2.16 g, 6.61 mmol) and phenylthioacetamide (1.00 g, 6.61 mmol) in
a mixture of ethanol (25 mL) and N,N-dimethylformamide (5 mL) was
stirred at 60.degree. C. for 14 hours and, then, refluxed for 2
hours. After cooling, the reaction mixture was diluted with water
and extracted with ethyl acetate. The organic layer was washed with
water and saturated aqueous sodium chloride solution, dried over
MgSO.sub.4, filtered, and concentrated under reduced pressure. The
residue was subjected to silica gel column chromatography
(hexane-ethyl acetate=1:5) to provide ethyl
[(2-benzyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]ace- tate (540
mg). To a solution of this compound (0.54 g, 1.42 mmol) in a
mixture of tetrahydrofuran (16 mL) and methanol (4 mL) was added
1N-hydrochloric acid followed by extraction with ethyl acetate. The
organic layer was washed with water and saturated aqueous sodium
chloride solution, dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure. The residue was recrystallized
from ethyl acetate-hexane to provide 320 mg of the title compound.
Yield 14%. m.p. 146-149.degree. C.
[0564] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.84-2.96 (2H, m),
3.05-3.17 (2H, m), 4.36 (2H, s), 4.71 (2H, s), 6.71 (1H, d, J=7.6
Hz), 6.90-7.42 (7H, m), 7.61 (1H, d, J=7.4 Hz).
Example 53
[(2-Diphenylmethyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic
acid
[0565] Using ethyl
[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]a- cetate and
diphenylthioacetamide, the procedure of Example 52 was otherwise
repeated to synthesize the title compound. Yield 31%. Amorphous
solid.
[0566] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.87-3.18 (4H, m), 4.66
(2H, s), 5.93 (1H, s), 6.68 (1H, d, J=7.4 Hz), 7.10-7.45 (12H, m),
7.59 (1H, d, J=7.2 Hz).
Example 54
[(2-Phenyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic
acid
[0567] Using ethyl
[6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]ac- etate and
thiobenzamide, the procedure of Example 52 was otherwise repeated
to synthesize the title compound. Yield 27%. Amorphous solid.
[0568] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.09 (4H, s), 4.73 (2H,
s), 6.85 (1H, d, J=8.2 Hz), 7.26 (1H, t, J=8.2 Hz), 7.46-7.62 (4H,
m), 7.92-8.00 (2H, m), 1H not confirmed.
Example 55
[(2-(2,2-Diphenylethyl)-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetic
acid
[0569] Using ethyl
[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]a- cetate and
3,3-diphenylthiopropionamide, the procedure of Example 52 was
otherwise repeated to synthesize the title compound. Yield 19%.
Amorphous solid.
[0570] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.78-3.11 (4H, m), 3.80
(2H, d, J=7.8 Hz), 4.56 (1H, t, J=7.8 Hz), 4.69 (2H, s), 6.79 (1H,
d, J=7.6 Hz), 6.98-7.56 (12H, m), 12.6-13.5 (1H, br).
Example 56
[(2-(2,4-Dinitrophenyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acet-
ic acid
[0571] To a solution of ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazo- l-6-yl)oxy]acetate
(1.30 g, 4.04 mmol) in N,N-dimethylformamide (20 mL) was added
sodium hydride (60% dispersion in liquid paraffin, 178 mg, 4.45
mmol) at 0.degree. C., and the mixture was stirred at room
temperature for 10 minutes. To this mixture was added
1-chloro-2,4-dinitrobenzene (900 mg, 4.45 mmol) and the mixture was
stirred at room temperature for 30 minutes. This reaction mixture
was poured into water (30 mL) and extracted with 2 portions of
ethyl acetate. The pooled organic layer was washed with water,
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure to provide ethyl [(2-(2,4-dinitrophenyl)thio-4,5-d-
ihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.17 g). To a
solution of this compound (1.17 g, 2.40 mmol) in a mixture of
tetrahydrofuran (16 mL) and methanol (4 mL) was added 1N-aqueous
sodium hydroxide (3.0 mL) dropwise and the mixture was stirred at
room temperature for 20 minutes. After the solvent was distilled
off under reduced pressure, 1N-hydrochloric acid was added to the
residue and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and saturated aqueous sodium
chloride solution, dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure. The residue was recrystallized
from ethyl acetate to provide 0.91 g of the title compound. Yield
49%. m.p. 223-226.degree. C.
[0572] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.02-3.30 (4H, m), 4.75
(2H, s), 6.91 (1H, d, J=8.4 Hz), 7.26 (1H, t, J=8.2 Hz), 7.39(1H,
d, J=9.0 Hz), 7.51 (1H, d, J=7.6 Hz), 8.43 (1H, dd, J=9.0, 2.4 Hz),
8.96 (1H, d, J=2.4 Hz), 1H not confirmed.
Example 57
[(2-Diphenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]acetic
acid
[0573] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]- acetate
and bromodiphenylmethane, the procedure of Example 1 was otherwise
repeated to synthesize the title compound. Yield 90%. m.p.
141-143.degree. C. (ethyl acetate-hexane)
[0574] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.72-3.03 (4H, m),
4.40-4.89 (3H, m), 6.02 (1H, s), 6.80 (1H, dd, J=8.2, 2.6 Hz), 7.09
(1H, d, J=8.6 Hz), 7.19-7.57 (11H, m).
Example 58
[(2-(2,2-Diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]acet-
ic acid
[0575] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]- acetate
and 2,2-diphenylethyl iodide, the procedure of Example 21 was
otherwise repeated to synthesize the title compound. Yield 69%.
m.p. 165-167.degree. C. (ethyl acetate)
[0576] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.95 (4H, s), 3.99 (2H,
d, J=7.6 Hz), 4.50 (1H, t, J=8.0 Hz), 4.68 (2H, s), 6.78 (1H, dd,
J=8.2, 2.8 Hz), 7.15-7.45 (12H, m), 1H not confirmed.
Example 59
[(2-Diphenylmethylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]aceti-
c acid
[0577] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]- acetate
and bromodiphenylmethane, the procedure of Example 51 was otherwise
repeated to synthesize the title compound. Yield 35%. m.p.
169-170.degree. C. (ethyl acetate)
[0578] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.81-3.08 (4H, m), 4.80
(2H, s), 5.98 (1H, s), 6.00-6.45 (1H, br), 6.88 (1H, dd, J=8.4, 2.6
Hz), 7.15 (1H, d, J=8.4 Hz), 7.20-7.72 (11H, m).
Example 60
[(2-(2,2-Diphenylethyl)sulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]-
acetic acid
[0579] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]- acetate
and 2,2-diphenylethyl iodide, the procedure of Example 51 was
otherwise repeated to synthesize the title compound. Yield 39%.
m.p. 183-185.degree. C. (ethyl acetate)
[0580] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.82-3.10 (4H, s), 4.31
(2H, d, J=7.4 Hz), 4.72 (1H, t, J=7.4 Hz), 4.77 (2H, s), 6.87 (1H,
dd, J=8.4, 2.4 Hz), 6.99-7.21 (11H, m), 7.47 (1H, d, J=2.4 Hz),
7.30-8.40 (1H, br).
Example 61
Ethyl
[(2-(2,2-diphenylethylsulfinyl)-4,5-dihydronaphtho[1,2-d]thiazol-6-y-
l)oxy]acetate
[0581] To a solution of ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazo- l-6-yl)oxy]acetate
(1.05 g, 3.27 mmol) in N,N-dimethylformamide (15 mL) were serially
added 2,2-diphenylethyl iodide (1.11 g, 3.60 mmol) and potassium
carbonate (500 mg, 3.60 mmol) and the mixture was stirred at
60.degree. C. for 2 hours. This reaction mixture was diluted with
water and extracted with ethyl acetate. The organic layer was
washed with water and saturated aqueous sodium chloride solution,
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure to provide ethyl
[[2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]ace-
tate (1.11 g). To a solution of this compound (1.00 g, 1.99 mmol)
in ethanol (45 mL)-water (5 mL) was added sodium periodate (0.51 g,
2.39 mmol) and the mixture was refluxed for 3 hours. To this
reaction mixture were added ethyl acetate and water, and the
resulting two layers were separated. The aqueous layer was
extracted with ethyl acetate and the pooled organic layer was
washed with water, dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane-ethyl acetate=1:8) and
recrystallized from ethyl acetate to provide 0.64 g of the title
compound. Yield 42%. m.p. 127-129.degree. C.
[0582] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.0 Hz),
2.97-3.24 (4H, m), 3.72-3.98 (2H, m), 4.28 (2H, q, J=7.0 Hz), 4.67
(2H, s), 4.77 (1H, dd, J=9.6, 6.6 Hz), 6.73 (1H, d, J=8.4 Hz),
7.08-7.42 (11H, m), 7.59 (1H, d, J=7.6 Hz).
Example 62
[(2-(2,2-Diphenylethylsulfinyl)-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]-
acetic acid
[0583] To a solution of ethyl
[(2-(2,2-diphenylethylsulfinyl)-4,5-dihydron-
aphtho[1,2-d]thiazol-6-yl)oxy]acetate (0.50 g, 0.965 mmol) in a
mixture of tetrahydrofuran (16 mL) and methanol (4 mL) was added
1N-aqueous sodium hydroxide (2 mL) dropwise, and the mixture was
stirred at room temperature for 20 minutes. After the solvent was
distilled off under reduced pressure, 1N-hydrochloric acid was
added to the residue and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and saturated
aqueous sodium chloride solution, dried over MgSO.sub.4, filtered,
and concentrated under reduced pressure to provide 0.36 g of the
title compound as amorphous solid. Yield 76%.
[0584] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.95-3.23 (4H, m),
3.78-4.00 (2H, m), 4.1-4.9 (4H, m), 6.76 (1H, d, J=8.6 Hz),
7.10-7.42 (11H, m), 7.60 (1H, d, J=7.4 Hz).
Example 63
[(2-(2-Naphthyl)(phenyl)methylthio-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)ox-
y]acetic acid
[0585] To a suspension of ethyl
[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiaz- ol-6-yl)oxy]acetate
(1.00 g, 3.09 mmol) in acetonitrile (10 mL) were serially added a
solution of (2-naphthyl)phenylmethyl bromide (1.13 g, 4.02 mmol) in
N,N-dimethylformamide (5 mL) and a solution of triethylamine (344
mg, 3.40 mmol) in acetonitrile (5 mL) dropwise, and the mixture was
stirred at room temperature for 1 hour. After the solvent was
distilled off, the residue was diluted with water and extracted
with ethyl acetate. The organic layer was washed with water, dried
over MgSO.sub.4, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(hexane-ethyl acetate=4:1) and the resulting solid was
recrystallized from hexane-ethyl acetate to provide ethyl
[(2-(2-naphthylphenyl)(phenyl)methylthio-4H-[1]b-
enzopyrano[4,3-d]thiazol-6-yl)oxy]acetate (779 mg). To a solution
of this compound (400 mg, 0.74 mmol) in a mixture of
tetrahydrofuran (9 mL) and methanol (3 mL) was added 1N-aqueous
sodium hydroxide (1 mL) dropwise and the mixture was stirred at
room temperature for 1 hour. This reaction mixture was adjusted to
pH 5 with 0.1N-hydrochloric acid and extracted with ethyl acetate.
The organic layer was washed with water and saturated aqueous
sodium chloride solution, dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure to provide 363 mg of the title
compound. Yield 96%. Amorphous solid.
[0586] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.40-3.80 (1H, br), 4.69
(2H, s), 5.36 (2H, s), 6.24 (1H, s), 6.84 (1H, d, J=7.8 Hz), 6.96
(1H, t, J=7.8 Hz), 7.20-7.63 (9H, m), 7.80-7.84 (3H, m), 7.93 (1H,
s).
Example 64
[(2-(4-Methylphenyl)(phenyl)methylthio-4H-[1]benzopyrano[4,3-d]thiazol-6-y-
l)oxy]acetic acid
[0587] Using ethyl
[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]a- cetate and
(4-methylphenyl)(phenyl)methyl bromide, the procedure of Example 63
was otherwise repeated to synthesize the title compound. Yield 4%.
Amorphous solid.
[0588] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.32 (3H, s), 2.60-3.80
(1H, br), 4.70 (2H, s), 5.39 (2H, s), 6.03 (1H, s), 6.81-6.86 (1H,
m), 6.96 (1H, t, J=8.2 Hz), 7.12-7.53 (10H, m).
Example 65
[(2-(4-Chlorophenyl)(phenyl)methylthio-4H-[1]benzopyrano[4,3-d]thiazol-6-y-
l)oxy]acetic acid
[0589] Using ethyl
[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]a- cetate and
(4-chlorophenyl)(phenyl)methyl bromide, the procedure of Example 63
was otherwise repeated to synthesize the title compound. Yield 49%.
Amorphous solid.
[0590] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.75 (2H, s), 5.40 (2H,
s), 6.06 (1H, s), 6.77-6.82 (1H, m), 6.94 (1H, t, J=7.6 Hz),
7.27-7.47 (10H, m), 1H not confirmed.
Example 66
[(2-(4-Methylphenyl)(phenyl)methylthio-4,5-dihydronaphtho[1,2-d]thiazol-6--
yl)oxy]acetic acid
[0591] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (4-methylphenyl)(phenyl)methyl bromide, the procedure of
Example 63 was otherwise repeated to synthesize the title compound.
Yield 98%. Amorphous solid.
[0592] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.31 (3H, s), 2.82-2.91
(2H, m), 3.03-3.11 (2H, m), 4.71 (2H, s), 4.60-5.00 (1H, br), 6.01
(1H, s), 6.70 (1H, d, J=8.8 Hz), 7.11-7.61 (11H, m).
Example 67
[(2-(4-Chlorophenyl)(phenyl)methylthio-4,5-dihydronaphtho[1,2-d]thiazol-6--
yl)oxy]acetic acid
[0593] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (4-chlorophenyl)(phenyl)methyl bromide, the procedure of
Example 63 was otherwise repeated to synthesize the title compound.
Yield 78%. Amorphous solid.
[0594] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.84-2.93 (2H, m),
3.06-3.14 (2H, m), 4.71 (2H, s), 6.04 (1H, s), 6.68 (1H, d, J=8.4
Hz), 7.17-7.57 (11H, m), 1H not confirmed.
Example 68
[(2-(4-Fluorophenyl)(phenyl)methylthio-4,5-dihydronaphtho[1,2-d]thiazol-6--
yl)oxy]acetic acid
[0595] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (4-fluorophenyl)(phenyl)methyl bromide, the procedure of
Example 63 was otherwise repeated to synthesize the title compound.
Yield 79%. Amorphous solid.
[0596] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.84-2.93 (2H, m),
3.04-3.12 (2H, m) 3.80-4.80 (1H, br), 4.72 (2H, s), 6.05 (1H, s),
6.72 (1H, d, J=8.4 Hz), 6.96-7.04 (2H, m), 7.19-7.49 (8H, m), 7.58
(1H, d, J=6.8 Hz).
Example 69
[(2-Bis(4-fluorophenyl)methylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)ox-
y]acetic acid
[0597] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and bis(4-fluorophenyl)methyl bromide, the procedure of Example 63
was otherwise repeated to synthesize the title compound. Yield 77%.
Amorphous solid.
[0598] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.95-3.20 (4H, m), 4.76
(2H, s), 5.94 (1H, s), 6.80 (1H, d, J=7.6 Hz), 7.00-7.09 (4H, m),
7.32 (1H, t, J=7.8 Hz), 7.55-7.62 (4H, m) 7.69-7.73 (1H, m), 1H not
confirmed.
Example 70
[(2-Bis(4-chlorophenyl)methylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)ox-
y]acetic acid
[0599] Using ethyl
[(2-mercapto-4,5-dihydronaphtho-[1,2-d]thiazol-6-yl)oxy- ]acetate
and bis(4-chlorophenyl)methyl bromide, the procedure of Example 63
was otherwise repeated to synthesize the title compound. Yield 77%.
Amorphous solid.
[0600] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.86-2.94 (2H, m),
3.07-3.14 (2H, m), 4.75 (2H, s), 6.04 (1H, s), 6.69 (1H, d, J=8.2
Hz), 7.18-7.41 (9H, m), 7.54 (1H, d, J=7.4 Hz), 1H not
confirmed.
Example 71
[(2-(4-Methoxyphenyl)(phenyl)methylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-
-yl)oxy]acetic acid
[0601] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (4-methoxyphenyl)(phenyl)methyl bromide, the procedure of
Example 63 was otherwise repeated to synthesize the title compound.
Yield 87%. Amorphous solid.
[0602] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.82-2.91 (2H, m),
3.02-3.10 (2H, m), 3.78 (3H, s), 4.20-4.80 (1H, br), 4.71 (2H, s),
6.00 (1H, s), 6.70 (1H, d, J=8.4 Hz), 6.82-6.88 (2H, m), 7.18-7.61
(9H, m).
Example 72
[(2-Phenyl)(4-trifluoromethylphenyl)methylthio-4,5-dihydronaphtho[1,2-d]th-
iazol-6-yl)oxy]acetic acid
[0603] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (phenyl)(4-trifluoromethylphenyl)methyl bromide, the procedure
of Example 63 was otherwise repeated to synthesize the title
compound. Yield 71%. Amorphous solid.
[0604] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.85-2.93 (2H, m),
3.07-3.14 (2H, m), 4.00-5.00 (1H, br), 4.67 (2H, s), 6.14 (1H, s),
6.48 (1H, d, J=8.4 Hz), 7.18-7.65 (1H, m).
Example 73
[(2-(4-Cyanophenyl)(phenyl)methylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-y-
l)oxy]acetic acid
[0605] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (4-cyanophenyl)(phenyl)methyl bromide, the procedure of Example
63 was otherwise repeated to synthesize the title compound. Yield
68%. Amorphous solid.
[0606] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.60-3.40 (1H, br),
2.87-2.94 (2H, m), 3.05-3.13 (2H, m), 4.72 (2H, s), 6.14 (1H, s),
6.72 (1H, d, J=8.0 Hz), 7.19-7.43 (7H, m), 7.53 (1H, d, J=7.2 Hz),
7.61 (3H, s).
Example 74
[(2-(3-Chlorophenyl)(phenyl)methylthio-4,5-dihydronaphtho[1,2-d]thiazol-6--
yl)oxy]acetic acid
[0607] Using ethyl
[2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]a- cetate and
(3-chlorophenyl)(phenyl)methyl bromide, the procedure of Example 63
was otherwise repeated to synthesize the title compound. Yield 64%.
Amorphous solid.
[0608] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.85-2.93 (2H, m),
3.04-3.13 (2H, m), 4.20-5.00 (1H, br), 4.72 (2H, s), 6.03 (1H, s),
6.71 (1H, d, J=7.6 Hz), 7.19-7.60 (11H, m).
Example 75
[(2-(2-Chlorophenyl)(phenyl)methylthio-4,5-dihydronaphtho[1,2-d]thiazol-6--
yl)oxy]acetic acid
[0609] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (2-chlorophenyl)(phenyl)methyl bromide, the procedure of
Example 63 was otherwise repeated to synthesize the title compound.
Yield 63%. Amorphous solid.
[0610] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.82-2.91 (2H, m),
3.02-3.10 (2H, m), 4.20-4.80 (1H, br), 4.71 (2H, s), 6.00 (1H, s),
6.70 (1H, d, J=8.4 Hz), 6.82-6.88 (2H, m), 7.18-7.61 (9H, m).
Example 76
[(2-(3-Methylphenyl)(phenyl)methylthio-4,5-dihydronaphtho[1,2-d]thiazol-6--
yl)oxy]acetic acid
[0611] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (3-methylphenyl)(phenyl)methyl bromide, the procedure of
Example 63 was otherwise repeated to synthesize the title compound.
Yield 72%. Amorphous solid.
[0612] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.32 (3H, s), 2.84-2.92
(2H, m), 3.05-3.13 (2H, m), 4.20-5.00 (1H, br), 4.66 (2H, s), 6.01
(1H, s), 6.68 (1H, d, J=7.2 Hz), 7.06 (1H, d, J=7.2 Hz), 7.17-7.36
(7H, m), 7.46-7.51 (2H, m), 7.58 (1H, d, J=7.8 Hz).
Example 77
[(2-(2-Methylphenyl)(phenyl)methylthio-4,5-dihydronaphtho[1,2-d]thiazol-6--
yl)oxy]acetic acid
[0613] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (2-methylphenyl)(phenyl)methyl bromide, the procedure of
Example 63 was otherwise repeated to synthesize the title compound.
Yield 61%. Amorphous solid.
[0614] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.43 (3H, s), 2.84-2.92
(2H, m), 3.06-3.14 (2H, m), 4.00-4.80 (1H, br), 4.74 (2H, s), 6.29
(1H, s), 6.67 (1H, d, J=8.2 Hz), 7.18-7.65 (11H, m).
Example 78
Ethyl
[(2-(4-nitrophenyl)(phenyl)methylthio-4,5-dihydronaphtho[1,2-d]thiaz-
ol-6-yl)oxy]acetate
[0615] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (4-nitrophenyl)(phenyl)methyl bromide, the procedure of Example
48 was otherwise repeated to synthesize the title compound. Yield
61%. m.p. 128-129.degree. C. (tetrahydrofuran-diethyl ether)
[0616] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t, J=7.2 Hz),
2.85-2.94 (2H, m), 3.07-3.14 (2H, m), 4.27 (2H, q, J=7.2 Hz), 4.65
(2H, s), 6.20 (1H, s), 6.69 (1H, d, J=8.0 Hz), 7.18-7.52 (7H, m),
7.66-7.72 (2H, m), 8.15-8.20 (2H, m).
Example 79
[(2-(Phenyl)(3-trifluoromethylphenyl)methylthio-4,5-dihydronaphtho[1,2-d]t-
hiazol-6-yl)oxy]acetic acid
[0617] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (phenyl)(3-trifluoromethylphenyl)methyl bromide, the procedure
of Example 63 was otherwise repeated to synthesize the title
compound. Yield 59%. Amorphous solid.
[0618] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.83-2.92 (2H, m),
3.07-3.17 (2H, m), 3.80-4.90 (1H, br), 4.62 (2H, s), 6.01 (1H, s),
6.74 (1H, d, J=8.0 Hz), 7.05-7.59 (11H, m).
Example 80
[(2-(2-Fluorophenyl)(phenyl)methylthio-4,5-dihydronaphtho[1,2-d]thiazol-6--
yl)oxy]acetic acid
[0619] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (2-fluorophenyl)(phenyl)methyl bromide, the procedure of
Example 63 was otherwise repeated to synthesize the title compound.
Yield 62%. Amorphous solid.
[0620] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.84-2.92 (2H, m),
3.06-3.14 (2H, m), 4.62 (2H, s), 6.37 (1H, s), 6.72 (1H, d, J=8.4
Hz), 6.99-7.56 (10H, m), 7.69 (1H, t, J=7.5 Hz), 6.80-7.80 (1H,
br).
Example 81
[(2-(4-Methylphenyl)(phenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazo-
l-6-yl)oxy]acetic acid
[0621] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (4-methylphenyl)(phenyl)methyl bromide, the procedure of
Example 51 was otherwise repeated to synthesize the title compound.
Yield 30%. Amorphous solid.
[0622] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.31 (3H, s), 2.94-3.03
(2H, m), 3.09-3.17 (2H, m), 3.20-4.20 (1H, br), 4.75 (2H, s), 5.92
(1H, s), 6.79 (1H, d, J=7.4 Hz), 7.15 (2H, d, J=8.0 Hz), 7.29-7.35
(4H, m), 7.51 (2H, d, J=8.0 Hz), 7.58-7.63 (2H, m), 7.73 (1H, d,
J=7.4 Hz).
Example 82
[(2-(Diphenylmethylsulfonyl)-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]acet-
ic acid
[0623] Using ethyl
[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]a- cetate and
bromodiphenylmethane, the procedure of Example 51 was otherwise
repeated to synthesize the title compound. Yield 55%. m.p.
168.degree. C. (decomp.)
[0624] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.00-2.90 (1H, br), 4.73
(2H, s), 5.45 (2H, s), 5.94 (1H, s), 6.91-6.95 (1H, m), 7.06 (1H,
t, J=7.6 Hz), 7.28-7.38 (6H, m), 7.60-7.66 (5H, m).
Example 83
[(2-(4-Chlorophenyl)(phenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazo-
l-6-yl)oxy]acetic acid
[0625] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (4-chlorophenyl)(phenyl)methyl bromide, the procedure of
Example 51 was otherwise repeated to synthesize the title compound.
Yield 55%. m.p. 180-181.degree. C. (ethyl acetate-hexane)
[0626] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.01-3.13 (4H, m),
3.20-4.40 (1H, br), 4.76 (2H, s), 5.93 (1H, s), 6.79 (1H, d, J=8.0
Hz), 7.29-7.35 (6H, m), 7.55-7.73 (5H, m).
Example 84
[(2-(4-Fluorophenyl)(phenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazo-
l-6-yl)oxy]acetic acid
[0627] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (4-fluorophenyl)(phenyl)methyl bromide, the procedure of
Example 51 was otherwise repeated to synthesize the title compound.
Yield 38%. m.p. 210-211.degree. C. (tetrahydrofuran-diethyl
ether)
[0628] .sup.1H-NMR (CDCl.sub.3+DMSO-d.sub.6) .delta.: 2.95-3.04
(2H, m), 3.11-3.20 (2H, m), 4.66 (2H, s), 5.94 (1H, s), 6.81 (1H,
d, J=8.2 Hz), 7.04-7.08 (2H, m), 7.26-7.36 (4H, m), 7.57-7.69 (5H,
m), 1H not confirmed.
Example 85
[(2-Bis(4-fluorophenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-y-
l)oxy]acetic acid
[0629] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and bis(4-fluorophenyl)methyl bromide, the procedure of Example 51
was otherwise repeated to synthesize the title compound. Yield 38%.
m.p. 186-188.degree. C. (ethyl acetate-hexane)
[0630] .sup.1H-NMR (CDCl.sub.3+DMSO-d.sub.6) .delta.: 3.06 (4H, s),
3.20-4.40 (1H, br), 4.72 (2H, s), 6.42 (1H, s), 6.90 (1H, d, J=8.4
Hz), 7.14-7.33 (5H, m), 7.49 (1H, d, J=7.6 Hz), 7.66-7.73 (4H,
m).
Example 86
[(2-Bis(4-chlorophenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-y-
l)oxy]acetic acid
[0631] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and bis(4-chlorophenyl)methyl bromide, the procedure of Example 51
was otherwise repeated to synthesize the title compound. Yield 55%.
m.p. 197-199.degree. C. (ethyl acetate-hexane)
[0632] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.03-3.14 (4H, m),
3.40-4.20 (1H, br), 4.76 (2H, s), 5.91 (1H, s), 6.80 (1H, d, J=7.6
Hz), 7.27-7.34 (5H, m), 7.50-7.54 (4H, m), 7.68 (1H, d, J=7.6
Hz).
Example 87
[(2-(Phenyl)(4-trifluoromethylphenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-
-d]thiazol-6-yl)oxy]acetic acid
[0633] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (phenyl)(4-trifluoromethylphenyl)methyl bromide, the procedure
of Example 51 was otherwise repeated to synthesize the title
compound. Yield 55%. m.p. 188-190.degree. C.
(tetrahydrofuran-diethyl ether)
[0634] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.86-2.94 (2H, m),
3.01-3.10 (2H, m), 4.60 (2H, s), 5.91 (1H, s), 6.67 (1H, d, J=8.4
Hz), 7.16-7.26 (4H, m), 7.45-7.59 (5H, m), 7.69 (2H, d, J=8.0 Hz),
1H not confirmed.
Example 88
[(2-(4-Cyanophenyl)(phenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-
-6-yl)oxy]acetic acid
[0635] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (4-cyanophenyl)(phenyl)methyl bromide, the procedure of Example
51 was otherwise repeated to synthesize the title compound. Yield
40%. m.p. 200-201.degree. C. (ethyl acetate-diethyl ether)
[0636] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.82-2.89 (2H, m),
3.03-3.10 (2H, m), 4.09 (2H, s), 6.11 (1H, s), 6.70 (1H, d, J=8.2
Hz), 7.16-7.69 (11H, m), 9.20-9.40 (1H, br).
Example 89
[(2-(3-Chlorophenyl)(phenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazo-
l-6-yl)oxy]acetic acid
[0637] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (3-chlorophenyl)(phenyl)methyl bromide, the procedure of
Example 51 was otherwise repeated to synthesize the title compound.
Yield 45%. m.p. 173-174.degree. C. (ethyl acetate-hexane)
[0638] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.97-3.13 (4H, m),
3.00-3.80 (1H, br), 4.74 (2H, s), 6.48 (1H, s), 6.93 (1H, d, J=7.4
Hz), 7.27-7.49 (7H, m), 7.64-7.73 (4H, m).
Example 90
[(2-(2-Chlorophenyl)(phenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazo-
l-6-yl)oxy]acetic acid
[0639] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (2-chlorophenyl)(phenyl)methyl bromide, the procedure of
Example 51 was otherwise repeated to synthesize the title compound.
Yield 70%. m.p. 197-198.degree. C. (ethyl acetate-hexane)
[0640] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.95-3.05 (4H, m), 4.75
(2H, s), 6.55 (1H, s), 6.93 (1H, d, J=8.0 Hz), 7.30 (1H, t, J=8.0
Hz), 7.39-7.57 (9H, m), 8.24 (1H, d, J=8.0 Hz), 1H not
confirmed.
Example 91
[(2-(3-Methylphenyl)(phenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazo-
l-6-yl)oxy]acetic acid
[0641] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (3-methylphenyl)(phenyl)methyl bromide, the procedure of
Example 51 was otherwise repeated to synthesize the title compound.
Yield 63%. m.p. 185-186.degree. C. (tetrahydrofuran-diethyl
ether)
[0642] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.31 (3H, s), 2.94-3.02
(2H, m), 3.09-3.17 (2H, m), 4.00-5.20 (1H, br), 4.75 (2H, s), 5.91
(1H, s), 6.79 (1H, d, J=8.0 Hz), 7.10-7.44 (8H, m), 7.57-7.62 (2H,
m), 7.34 (1H, d, J=8.0 Hz).
Example 92
[(2-(2-Methylphenyl)(phenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazo-
l-6-yl)oxy]acetic acid
[0643] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (2-methylphenyl)(phenyl)methyl bromide, the procedure of
Example 51 was otherwise repeated to synthesize the title compound.
Yield 49%. m.p. 192-193.degree. C. (tetrahydrofuran-diethyl
ether)
[0644] .sup.1H-NMR (CDCl.sub.3+DMSO-d.sub.6) .delta.: 2.32 (3H, s),
2.94-3.19 (4H, m), 4.20-5.00 (1H, br), 4.65 (2H, s), 6.28 (1H, s),
6.80 (1H, d, J=8.6 Hz), 7.06-7.36 (7H, m), 7.54-7.58 (2H, m), 7.67
(1H, d, J=7.2 Hz), 8.17 (1H, d, J=7.2 Hz).
Example 93
Ethyl
[(2-(4-nitrophenyl)(phenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]t-
hiazol-6-yl)oxy]acetate
[0645] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (4-nitrophenyl)(phenyl)methyl bromide, the procedure of Example
50 was otherwise repeated to synthesize the title compound. Yield
49%. m.p. 146-148.degree. C. (diethyl ether-hexane)
[0646] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (3H, t, J=7.4 Hz),
2.85-3.10 (4H, m), 4.19 (2H, q, J=7.2 Hz), 4.59 (2H, s), 5.97 (1H,
s), 6.67 (1H, d, J=8.4 Hz), 7.17-7.28 (4H, m), 7.44-7.48 (2H, m),
7.57 (1H, d, J=7.8 Hz), 7.76 (2H, d, J=9.0 Hz), 8.11 (2H, d, J=9.0
Hz).
Example 94
[(2-(Phenyl)(3-trifluoromethylphenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-
-d]thiazol-6-yl)oxy]acetic acid
[0647] Using ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (phenyl)(3-trifluoromethylphenyl)methyl bromide, the procedure
of Example 51 was otherwise repeated to synthesize the title
compound. Yield 71%. m.p. 180-182.degree. C.
(tetrahydrofuran-diethyl ether)
[0648] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.87-3.13 (4H, m),
3.00-3.60 (1H, br), 4.76 (2H, s), 6.35 (1H, s), 6.83 (1H, d, J=7.4
Hz), 7.14-7.45 (7H, m), 7.60-7.71 (4H, m).
Example 95
[(2-(2-Fluorophenyl)(phenyl)methylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazo-
l-6-yl)oxy]acetic acid
[0649] Using-ethyl
[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]- acetate
and (2-fluorophenyl)(phenyl)methyl bromide, the procedure of
Example 51 was otherwise repeated to synthesize the title compound.
Yield 71%. m.p. 192-193.degree. C. (tetrahydrofuran-diethyl
ether)
[0650] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.06 (4H, s), 2.80-3.80
(1H, br), 4.72 (2H, s), 6.36 (1H, s), 6.91 (1H, d, J=7.4 Hz),
7.12-7.50 (8H, m), 7.60-7.65 (2H, m), 8.03-8.11 (1H, m).
Example 96
[(2-Bis(3-fluorophenyl)methylthio-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy-
]acetic acid
[0651] Using ethyl
[(2-mercapto-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy]a- cetate and
bis(3-fluorophenyl)methylbromide, the procedure of Example 63 was
otherwise repeated to synthesize the title compound. Yield 47%.
m.p. 155-158.degree. C. (ethyl acetate-hexane)
[0652] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.84-3.14 (4H, m), 4.71
(2H, s), 6.06 (1H, s), 6.71 (1H, d, J=8.0 Hz), 6.90-7.42 (10H, m),
7.56 (1H, d, J=7.8 Hz).
Example 97
[(2-Bis(2-fluorophenyl)methylthio-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy-
]acetic acid
[0653] Using ethyl
[(2-mercapto-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy]a- cetate and
bis(2-fluorophenyl)methylbromide, the procedure of Example 63 was
otherwise repeated to synthesize the title compound. Yield 58%.
m.p. 194-196.degree. C. (ethyl acetate)
[0654] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.84-3.09 (4H, m), 4.70
(2H, s), 6.64 (1H, s), 6.82 (1H, d, J=8.0 Hz), 7.10-7.47 (8H, m),
7.58-7.72 (2H, m), 1H not confirmed.
Example 98
[(2-Bis(3-fluorophenyl)methylsulfonyl-4,5-dihydronaphto[1,2-d]thiazol-6-yl-
)oxy]acetic acid
[0655] Using ethyl
[(2-mercapto-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy]a- cetate and
bis(3-fluorophenyl)methylbromide, the procedure of Example 51 was
otherwise repeated to synthesize the title compound. Yield 28%.
m.p. 213-214.degree. C. (ethyl acetate)
[0656] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.82-3.08 (4H, m), 4.70
(2H, s), 6.64 (1H, s), 6.82 (1H, d, J=8.0 Hz), 7.15-7.47 (8H, m),
7.58-7.76 (2H, m) , 1H not confirmed.
Example 99
[(2-Bis(2-fluorophenyl)methylsulfonyl-4,5-dihydronaphto[1,2-d]thiazol-6-yl-
)oxy]acetic acid
[0657] Using ethyl
[(2-mercapto-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy]a- cetate and
bis(2-fluorophenyl)methylbromide, the procedure of Example 51 was
otherwise repeated to synthesize the title compound. Yield 38%.
m.p. 204-208.degree. C. (ethanol)
[0658] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.95-3.21 (4H, m), 4.74
(2H, s), 6.74-6.82 (2H, m), 7.00 (2H, t, J=9.2 Hz), 7.04-7.39 (5H,
m), 7.66 (1H, d, J=7.6 Hz) , 7.98-9.00 (3H, m).
Example 100
Sodium
[(2-diphenylmethylthio-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy]ace-
tate
[0659] To a solution of
[(2-diphenylmethylthio-4,5-dihydronaphto[1,2-d]thi-
azol-6-yl)oxy]acetic acid (1.00 g, 1.09 mmol) in ethanol (50 mL)
was added 1N-aqueous sodium hydroxide solution (2.2 mL) dropwise
and the mixture was stirred at room temperature for 20 minutes. The
solvent was then distilled off under reduced pressure. The residue
was recrystallized from ethanol/water to provide 0.48 g of the
title compound. Yield 46%. m.p. 223-225.degree. C.
[0660] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.79-3.04 (4H, m), 4.18
(2H, s), 6.16 (1H, s), 6.71 (1H, d, J=7.4 Hz), 7.08-7.42 (8H, m),
7.52-7.62 (4H, m).
Example 101
Sodium
[(2-diphenylmethylsulfonyl-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy-
]acetate
[0661] Using
[(2-diphenylmethylsulfonyl-4,5-dihydronaphto[1,2-d]thiazol-6--
yl)oxy]acetic acid, the procedure of Example 100 was otherwise
repeated to synthesize the title compound. Yield 48%. m.p.
226-228.degree. C. (water)
[0662] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.83-3.11 (4H, m), 4.30
(2H, s), 6.30 (1H, s), 6.83 (1H, d, J=8.4 Hz), 7.11-7.42 (8H, m),
7.58-7.75 (4H, m).
Example 102
Ethyl [(2-phenylamino-benzofuro[3,2-d]thiazol-5-yl)oxy]acetate
[0663] To a solution of ethyl
[(3-oxo-2,3-dihydrobenzofuran-7-yl)oxy]aceta- te (1.00 g, 4.23
mmol) in chloroform (30 mL) was added pyridinium hydrobromide
perbromide (1.35 g, 4.23 mmol) at 0.degree. C. and the mixture was
stirred at room temperature for 30 minutes. The reaction mixture
was poured into water. The organic layer was washed with water,
dried over MgSO.sub.4, and filtered. The filtrate was concentrated
under reduced pressure to provide 1.20 g of ethyl
[(2-bromo-3-oxo-2,3-dihydrobe- nzofuran-7-yl)oxy]acetate. A mixture
of this compound (1.20 g, 3.80 mmol) and 1-phenyl-2-thiourea (580
mg, 3.80 mmol) in acetic acid (20 mL) was refluxed for 3 hours. The
solvent was then distilled off under reduced pressure. To that
residue was added water, and the mixture was extracted with ethyl
acetate. The organic layer was washed with water, dried over
MgSO.sub.4, and filtered. The filtrate was concentrated under
reduced pressure, and the residue was purified by silica gel column
chromatography (ethyl acetate-hexane=1:5) to provide 180 mg of the
title compound. Yield 12%. m.p. 196-198.degree. C. (ethyl
acetate-hexane)
[0664] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t, J=7.0 Hz),
4.29 (2H, q, J=7.0 Hz), 4.87 (2H, s), 6.79 (1H, d, J=7.8 Hz),
7.04-7.45 (8H, m).
Example 103
[(2-(3-Fluorophenyl)(phenyl)methylthio-4,5-dihydronaphto[1,2-d]thiazol-6-y-
l)oxy]acetic acid
[0665] Using ethyl
[(2-mercapto-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy]a- cetate and
(3-fluorophenyl)(phenyl)methylbromide, the procedure of Example 63
was otherwise repeated to synthesize the title compound. Yield 38%.
m.p. 159-161.degree. C. (ethyl acetate)
[0666] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.82-3.08 (4H, m), 4.70
(2H, s), 5.40-6.00 (1H, br), 6.71 (1H, d, J=8.0 Hz), 6.92-7.01 (1H,
m), 7.18-7.50 (10H, m), 7.57 (1H, d, J=7.6 Hz).
Example 104
[(2-(3-Fluorophenyl)(phenyl)methylsulfonyl-4,5-dihydronaphto[1,2-d]thiazol-
-6-yl)oxy]acetic acid
[0667] Using ethyl
[(2-mercapto-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy]a- cetate and
(3-fluorophenyl)(phenyl)methylbromide, the procedure of Example 51
was otherwise repeated to synthesize the title compound. Yield 27%.
m.p. 215-217.degree. C. (ethanol)
[0668] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.90-3.10 (4H, m), 4.74
(2H, s), 6.43 (1H, s), 6.92 (1H, d, J=8.2 Hz), 7.10-7.69 (11H, m),
1H not confirmed.
[0669] The chemical formulas of the compounds obtained in Examples
1 to 104 are shown in Tables 1 to 7.
1TABLE 1 23 Ex. No. A.sup.1 A.sup.2 A.sup.3 A.sup.4 B.sup.1 X Ar 1
H H H OCH.sub.2COOH CH.sub.2CH.sub.2 24 Ph 2 H H H OCH.sub.2COOH
CH.sub.2 S--CH.sub.2 Ph 3 H H H OCH.sub.2COOH CH.sub.2CH.sub.2
S--CH.sub.2 Ph 4 H H H OCH.sub.2COOH CH.sub.2 S--CH.sub.2CH.dbd.CH
(E) Ph 5 H H H OCH.sub.2COOH CH.sub.2CH.sub.2 S--CH.sub.2CH.dbd.CH
(E) Ph 6 H H H OCH.sub.2COOH CH.sub.2 25 Ph 7 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 26 Ph 8 H H H OCH.sub.2COOH CH.sub.2 27 Ph 9 H H H
OCH.sub.2COOH CH.sub.2CH.sub.2 28 Ph 10 H H OCH.sub.2COOH H
CH.sub.2CH.sub.2 29 Ph 11 H H H OCH.sub.2COOH OCH.sub.2 30 Ph 12 H
H H OCH.sub.2COOH OCH.sub.2 31 Ph 13 H H H OCH.sub.2COOH OCH.sub.2
32 Ph 14 H H H OCH.sub.2COOH CH.sub.2CH.sub.2 S--CH.sub.2
4-biphenylyl 15 H H H OCH.sub.2COOH CH.sub.2CH.sub.2 33 2-naphthyl
16 H H OCH.sub.2COOH H CH.sub.2CH.sub.2 34 Ph
[0670]
2TABLE 2 35 Ex. No. A.sup.1 A.sup.2 A.sup.3 A.sup.4 B.sup.1 X Ar 17
H H H OCH.sub.2COOH OCH.sub.2 36 2-naphthyl 18 H H H OCH.sub.2COOH
CH.sub.2 37 Ph 19 H H H OCH.sub.2CH.sub.2CH.sub.2COOH CH.sub.2 38
Ph 20 H H H OCH.sub.2CH.sub.2CH.sub.2COOH CH.sub.2 39 Ph 21 H H H
OCH.sub.2COOH CH.sub.2CH.sub.2 40 Ph 22 H H H OCH.sub.2CH.sub.2COOH
CH.sub.2CH.sub.2 41 Ph 23 H H H OCH.sub.2CH.sub.2COOH CH.sub.2 42
Ph 24 H H OCH.sub.2COOH H CH.sub.2 43 Ph 25 CH.sub.3 H CH.sub.3
OCH.sub.2COOH CH.sub.2 44 Ph 26 CH.sub.3 CH.sub.3 H OCH.sub.2COOH
CH.sub.2 45 Ph 27 H H H OCH.sub.2COOH CH.sub.2 46 Ph 28 H H H
OCH.sub.2CH.sub.2COOH CH.sub.2CH.sub.2 47 Ph 29 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 48 Ph
[0671]
3TABLE 3 49 Ex. No. A.sup.1 A.sup.2 A.sup.3 A.sup.4 B.sup.1 X Ar 30
H H H OCH.sub.2COOH CH.sub.2 SO.sub.2--CH.sub.2CH.dbd.CH (E) Ph 31
H H H OCH.sub.2COOH CH.sub.2CH.sub.2 SO.sub.2--CH.sub.2CH.dbd.CH
(E) Ph 32 H H H OCH.sub.2COOH CH.sub.2CH.sub.2 50 Ph 33 H H H
OCH.sub.2COOH CH.sub.2CH.sub.2 51 Ph 34 H H OCH.sub.2COOH H
CH.sub.2CH.sub.2 52 Ph 35 H H H OCH.sub.2COOH OCH.sub.2 53 Ph 36 H
H H OCH.sub.2COOH CH.sub.2 54 Ph 37 H H H OCH.sub.2COOH CH.sub.2 55
Ph 38 H H H OCH.sub.2CH.sub.2COOH CH.sub.2 56 Ph 39 H H
OCH.sub.2COOH H CH.sub.2 57 Ph 40 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 58 Ph 41 H H H OCH.sub.2COOH CH.sub.2CH.sub.2 59
Ph 42 H H H OCH.sub.2COOH CH.sub.2CH.sub.2 60 Ph 43 H H H
OCH.sub.2COOH CH.sub.2CH.sub.2 61 Ph
[0672]
4TABLE 4 62 Ex. No. A.sup.1 A.sup.2 A.sup.3 A.sup.4 B.sup.1 X Ar 44
H H H OCH.sub.2COOH CH.sub.2 63 Ph 45 H H H OCH.sub.2COOH CH.sub.2
64 Ph 46 H H H OCH.sub.2COOH CH.sub.2CH.sub.2 65 Ph 47 H H H
OCH.sub.2COOH CH.sub.2CH.sub.2 NH Ph 48 H H H OCH.sub.2COOEt
CH.sub.2CH.sub.2 66 Ph 49 H H H OCH.sub.2COOEt CH.sub.2CH.sub.2 67
Ph 50 H H H OCH.sub.2COOEt CH.sub.2CH.sub.2 68 Ph 51 H H H
OCH.sub.2COOH CH.sub.2CH.sub.2 69 Ph 52 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 CH.sub.2 Ph 53 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 70 Ph 54 H H H OCH.sub.2COOH CH.sub.2CH.sub.2 --
Ph 55 H H H OCH.sub.2COOH CH.sub.2CH.sub.2 71 Ph 56 H H H
OCH.sub.2COOH CH.sub.2CH.sub.2 S 2,4-di-NO.sub.2--Ph 57 H
OCH.sub.2COOH H H CH.sub.2CH.sub.2 72 Ph 58 H OCH.sub.2COOH H H
CH.sub.2CH.sub.2 73 Ph 59 H OCH.sub.2COOH H H CH.sub.2CH.sub.2 74
Ph
[0673]
5TABLE 5 75 Ex. No. A.sup.1 A.sup.2 A.sup.3 A.sup.4 B.sup.1 X Ar 60
H OCH.sub.2COOH H H CH.sub.2CH.sub.2 76 Ph 61 H H H OCH.sub.2COOEt
CH.sub.2CH.sub.2 77 Ph 62 H H H OCH.sub.2COOH CH.sub.2CH.sub.2 78
Ph 63 H H H OCH.sub.2COOH OCH.sub.2 79 2-naphthyl 64 H H H
OCH.sub.2COOH OCH.sub.2 80 4-Me--Ph 65 H H H OCH.sub.2COOH
OCH.sub.2 81 4-Cl--Ph 66 H H H OCH.sub.2COOH CH.sub.2CH.sub.2 82
4-Me--Ph 67 H H H OCH.sub.2COOH CH.sub.2CH.sub.2 83 4-Cl--Ph 68 H H
H OCH.sub.2COOH CH.sub.2CH.sub.2 84 4-F--Ph 69 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 85 4-F--Ph 70 H H H OCH.sub.2COOH CH.sub.2CH.sub.2
86 4-Cl--Ph 71 H H H OCH.sub.2COOH CH.sub.2CH.sub.2 87 4-MeO--Ph 72
H H H OCH.sub.2COOH CH.sub.2CH.sub.2 88 4-CF.sub.3--Ph 73 H H H
OCH.sub.2COOH CH.sub.2CH.sub.2 89 4-CN--Ph 74 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 90 3-Cl--Ph
[0674]
6TABLE 6 91 Ex. No. A.sup.1 A.sup.2 A.sup.3 A.sup.4 B.sup.1 X Ar 75
H H H OCH.sub.2COOH CH.sub.2CH.sub.2 92 2-Cl--Ph 76 H H H
OCH.sub.2COOH CH.sub.2CH.sub.2 93 3-Me--Ph 77 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 94 2-Me--Ph 78 H H H OCH.sub.2COOEt
CH.sub.2CH.sub.2 95 4-NO.sub.2--Ph 79 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 96 3-CF.sub.3--Ph 80 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 97 2-F--Ph 81 H H H OCH.sub.2COOH CH.sub.2CH.sub.2
98 4-Me--Ph 82 H H H OCH.sub.2COOH OCH.sub.2 99 Ph 83 H H H
OCH.sub.2COOH CH.sub.2CH.sub.2 100 4-Cl--Ph 84 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 101 4-F--Ph 85 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 102 4-F--Ph 86 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 103 4-Cl--Ph 87 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 104 4-CF.sub.3--Ph 88 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 105 4-CN--Ph 89 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 106 3-Cl--Ph
[0675]
7TABLE 7 107 Ex. No. A.sup.1 A.sup.2 A.sup.3 A.sup.4 B.sup.1 X Ar
90 H H H OCH.sub.2COOH CH.sub.2CH.sub.2 108 2-Cl--Ph 91 H H H
OCH.sub.2COOH CH.sub.2CH.sub.2 109 3-Me--Ph 92 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 110 2-Me--Ph 93 H H H OCH.sub.2COOEt
CH.sub.2CH.sub.2 111 4-NO.sub.2--Ph 94 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 112 3-CF.sub.3--Ph 95 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 113 2-F--Ph 96 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 114 3-F--Ph 97 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 115 2-F--Ph 98 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 116 3-F--Ph 99 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 117 2-F--Ph 100 H H H OCH.sub.2COONa
CH.sub.2CH.sub.2 118 Ph 101 H H H OCH.sub.2COONa CH.sub.2CH.sub.2
119 Ph 102 H H H OCH.sub.2COOEt O NH Ph 103 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 120 3-F--Ph 104 H H H OCH.sub.2COOH
CH.sub.2CH.sub.2 121 3-F--Ph
Formulation Example 1
[0676]
8 (1) Compound of Example 21 3.0 g (2) Lactose 60.0 g (3) Corn
starch 35.0 g (4) Gelatin 3.0 g (5) Magnesium stearate 2.0 g
[0677] Using 30 mL of an aqueous solution of gelatin (10 weight %,
3.0 g as gelatin), a mixture of the compound of Example 21 (3.0 g),
lactose (60.0 g), and corn starch (35.0 g) was granulated through a
1 mm-mesh sieve, dried at 40.degree. C., and resieved. The
resultant granules were mixed with 2.0 g of magnesium stearate and
the mixture was compressed. The core tablets thus obtained were
sugar-coated with an aqueous suspension of sucrose, titanium
dioxide, talc, and gum arabic. The coated tablets were glazed with
beeswax to provide 1000 finished tablets.
Experimental Example 1
PGI.sub.2 Receptor Binding Assay
[0678] MES-NaOH buffer (pH 6.0) (500 .mu.L) containing the membrane
fraction (40 .mu.g) of CHO cells caused to express human PGI.sub.2
receptors, [.sup.3H]Iloprost (20 nM), and a test compound solution
(50 .mu.L) was incubated at 37.degree. C. for 1 hour and then
filtered through a membrane filter to separate the membrane-bound
[.sup.3H]Iloprost from the non-membrane-binding [.sup.3H]Iloprost.
The radioactivity of the membrane-bound [.sup.3H]Iloprost was
determined with a liquid scintillation counter and the binding
inhibition rate in each drug treatment group was determined against
the specific binding of [.sup.3H]Iloprost to the human PGI.sub.2
receptor in the control (solvent) group.
[0679] The test compound was added at the final concentrations of
10.sup.-6 to 10.sup.-11 M and the IC.sub.50 values were calculated
from the inhibition rates at the respective concentrations.
[0680] The results are shown below.
9 Compound of Example IC.sub.50, .mu.M 1 0.024 11 0.081 12 0.061 21
0.002 29 0.021
[0681] It is apparent from the above results that compound (I) has
a high affinity for the PGI.sub.2 receptor.
Experimental Example 2
Platelet Aggregation Inhibition Assay
[0682] The citrated blood from healthy male adult donors was
centrifuged-at 1000.times.g for 5 seconds and 20 minutes to harvest
platelet-rich plasma (PRP) and platelet-poor plasma (PPP),
respectively. Then, PRP was diluted with PPP to a platelet count of
300,000/.mu.L. The degree of platelet aggregation was measured with
a platelet aggregation measuring apparatus.
[0683] In the assay cuvette, 200 .mu.L of PRP was incubated at
37.degree. C. for 2 minutes. Then, 20 .mu.L of a test drug solution
was added and the mixture was further incubated for 2 minutes.
Thereafter, aggregation was induced by adding 20 .mu.l of ADP
solution. The aggregation in the drug treatment group was compared
with the maximum aggregation in the control group to find the
inhibition rate. ADP was used in the minimal concentration
(2.times.10.sup.-6 to 3.times.10.sup.-5 M) inducing maximal
aggregation in each assay.
[0684] The test compound was added at the final concentrations of
10.sup.-3 to 10.sup.-9 M and the IC.sub.50 value was calculated
from the inhibition rates at the respective concentrations.
[0685] The results are shown below.
10 Compound of Example IC.sub.50, .mu.M 1 0.54 21 0.21
[0686] It is clear from the above results that compound (I) has
potent aggregation inhibitory activity against human platelets.
INDUSTRIAL APPLICABILITY
[0687] The compound (I) of the invention has a high affinity for
PGI.sub.2 receptors.
[0688] The compound (I) of the invention acts as a PGI.sub.2
agonist in mammals (e.g. mouse, rat, hamster, rabbit, cat, dog,
bovine, sheep, monkey and human) and has platelet aggregation
inhibitory, vasodilative, bronchodilative, lipid deposition
inhibitory, and leukocyte activation inhibitory activities. Thus,
compound (I) is useful for the pharmaceutical composition for the
prophylaxis and/or treatment of transient ischemic attack (TIA),
diabetic neuropathy, peripheral vascular diseases (e.g. peripheral
embolism, vibration syndrome, Raynaud's disease, etc.), systemic
lupus erythematosus, post-PTCA reobliteration/restenosis,
atherosclerosis, thrombosis (e.g. acute phase of cerebral
thrombosis, etc.), diabetic gangrene, hypertension, pulmonary
hypertension, ischemic diseases (e.g. cerebral infarction,
myocardial infarction, etc.), angina pectoris (e.g. stable angina,
unstable angia, etc.), glomerulonephritis, diabetic nephropathy,
allergy, bronchial asthma, ulcer, decubitus, coronary restenosis
after coronary intervention such as atherectomy and stent
implantation, thrombocytopenia during dialysis, and so on.
* * * * *