U.S. patent application number 09/756701 was filed with the patent office on 2001-07-19 for ether and amide compounds and preparation of thereof as antidiadetics..
Invention is credited to Kuroiwa, Keiko, Tomiyama, Akira, Tomiyama, Hiroshi, Tomiyama, Tsuyoshi.
Application Number | 20010008898 09/756701 |
Document ID | / |
Family ID | 26583525 |
Filed Date | 2001-07-19 |
United States Patent
Application |
20010008898 |
Kind Code |
A1 |
Tomiyama, Tsuyoshi ; et
al. |
July 19, 2001 |
Ether and amide compounds and preparation of thereof as
antidiadetics.
Abstract
Ether and amide derivatives are disclosed, which are represented
by the following formula (I) and its pharmaceutical acceptable
salt, and which are useful for the treatment of diabetes. 1 (with
the provisos that (i) when A is --O--, then n is 2 or 3 (ii) when A
is 2 then n is 1 or 2. R.sub.3 is OH--, CH.sub.3SO.sub.2NH--,
CF.sub.3SO.sub.2NH--, CH.sub.3SO.sub.2NHCH.sub.2--,
CF.sub.3SO.sub.2NHCH.sub.2--, HOOC--, CH.sub.3OOC--, 3
HOOC--CH.sub.2SO.sub.2NH--, CF.sub.3--CH.sub.2SO.sub.2NH--, 4
R.sub.8--NHSO.sub.2--, R.sub.8--NHSO.sub.2--CH.sub.2--,
HOOC--CH.sub.2--O--, HSO.sub.3N.dbd.CH--, or
R.sub.9--SO.sub.2NHCO--; R.sub.4 is H, OH, O-alkyl or
O--CH.sub.2OCH.sub.3; R.sub.5 is H, halogen atom, --CH.sub.2COOH or
OH; R.sub.6 and R.sub.7 are hydrogen, t-butyl or pyrolidyl; R.sub.8
is hydrogen or lower alkyl; R.sub.9 is alkyl or thienyl; R.sub.10
is lower alkyl) or a pharmaceutically acceptable salt.
Inventors: |
Tomiyama, Tsuyoshi;
(Hanishina-gun, JP) ; Tomiyama, Akira;
(Hanishina-gun, JP) ; Tomiyama, Hiroshi;
(Hanishina-gun, JP) ; Kuroiwa, Keiko; (Ueda-shi,
JP) |
Correspondence
Address: |
SHERMAN & SHALLOWAY
413 North Washington Street
Alexandria
VA
22314
US
|
Family ID: |
26583525 |
Appl. No.: |
09/756701 |
Filed: |
January 10, 2001 |
Current U.S.
Class: |
514/338 ;
514/340; 546/272.1; 546/280.4; 546/283.7 |
Current CPC
Class: |
C07D 409/12 20130101;
A61P 3/10 20180101; C07D 413/12 20130101; C07D 213/74 20130101;
C07D 213/30 20130101; C07D 263/32 20130101 |
Class at
Publication: |
514/338 ;
514/340; 546/272.1; 546/283.7; 546/280.4 |
International
Class: |
C07D 405/00; A61K
031/44; A01N 043/40 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 11, 2000 |
JP |
6106/2000 |
Nov 22, 2000 |
JP |
356303/2000 |
Claims
What is claimed is:
1. A compound of the general formula (I),R.sub.1--A--R.sub.2 (I)
50(with the provisos that (i) when A is --O--, then n is 2 or 3
(ii) when A is 51then n is 1 or 2. R.sub.3 is OH--,
CH.sub.3SO.sub.2NH--, CF.sub.3SO.sub.2NH--,
CH.sub.3SO.sub.2NHCH.sub.2--, CF.sub.3SO.sub.2NHCH.sub.2--, HOOC--,
CH.sub.3OOC--, 52HOOC--CH.sub.2SO.sub.2NH--,
CF.sub.3--CH.sub.2SO.sub.2NH--, 53R.sub.8--NHSO.sub.2--,
R.sub.8--NHSO.sub.2--CH.sub.2--, HOOC--CH.sub.2--O--,
HSO.sub.3N.dbd.CH--, or R.sub.9--SO.sub.2NHCO--; R.sub.4 is H, OH,
O-alkyl or O--CH.sub.2OCH.sub.3; R.sub.5 is H, halogen atom,
--CH.sub.2COOH or OH; R.sub.6 and R.sub.7 are hydrogen, t-butyl or
pyrolidyl; R.sub.8 is hydrogen or lower alkyl; R.sub.9 is alkyl or
thienyl; R.sub.10 is lower alkyl) or a pharmaceutically acceptable
salt.
2. A compound of claim 1 wherein 54(in which R.sub.3 and R.sub.4
have the above-mentioned meanings) or a pharmaceutically acceptable
salt.
3. A compound of claim 1 wherein 55or a pharmaceutically acceptable
salt.
4. A compound of claim 1 wherein 56or a pharmaceutically acceptable
salt.
5. A compound of claim 1 wherein 57(with the provisos that (i) when
A is --O-- then n is 2 or 3 (ii) when A is 58then n is 1 or 2.
R.sub.5 is H or OH; R.sub.6and R.sub.7is H or t-butyl; R.sub.10 is
lower alkyl) or a pharmaceutically acceptable salt.
6. A pharmaceutical composition according to claim 1 for use as
antidiabetics.
7. A process for the production of a compound of general formula
(I) wherein A is --O--; 59(R.sub.4 has the above-mentioned
meanings) through a compound of general formula; 60(in which
R.sub.2 and R.sub.4 have the above-mentioned meaning) is reduced to
obtain a compound of general formula; 61(in which R.sub.2 and
R.sub.4 have the above-mentioned meaning) is reacted with
CH.sub.3SO.sub.2Cl or CF.sub.3SO.sub.2Cl to obtain the compound of
the general formula (I).
8. A process for the production of a compound of the general
formula (I) wherein A is --O--; 62through a compound of general
formula; 63(in which R.sub.2 has the above-mentioned meaning) is
reduced to obtain a compound of general formula; 64(in which
R.sub.2 has the above-mentioned meaning) is reacted with
CH.sub.3SO.sub.2Cl or CF.sub.3SO.sub.2Cl to obtain the compound of
general formula (I).
9. A process for the production of a compound of the general
formula (I) wherein A is --O--; R has the above-mentioned meanings;
65through a compound of general formula; 66is reacted with a
compound of general formula;X--R.sub.2 (in which X is Br, tosyl or
mesyl; R.sub.2 has the above-mentioned meanings) to obtain a
compound of general formula; 67and followed by hydrolysis to obtain
the compound of general formula (I).
10. A process for the production of a compound of the general
formula (I) wherein A is --O--; R.sub.2 has the above-mentioned
meanings; 68through a compound of general formula; 69is reacted
with a compound of general formula;HO--R.sub.2 (in which R.sub.2
has the above-mentioned meanings) to obtain a compound of general
formula; 70(in which R.sub.2 has the above-mentioned meanings) and
followed by hydrolysis to obtain the compound of general formula
(I).
11. A process for the production of a compound of general formula
(I) wherein A is --O--; R.sub.2 has the above-mentioned meanings;
71through a compound of general formula; 72(in which R.sub.2 has
the above-mentioned meaning) is reacted with 73to obtain a compound
of general formula; 74(in which R.sub.2 has the above-mentioned
meaning) after debenzylation, is converted to a compound of general
formula; 75(in which R.sub.2 has the above-mentioned meanings) is
reacted with CH.sub.3SO.sub.2Cl or CF.sub.3SO.sub.2Cl to obtain the
compound of general formula (I).
12. A process for the production of a compound of the general
formula (I) wherein A is --O--; R.sub.2 has the above-mentioned
meanings; 76through a compound of general formula; 77is reduced to
obtain a compound of general formula; 78(in which R.sub.2 has the
above-mentioned meanings) then reacted with
EtOOC--CH.sub.2--SO.sub.2Cl to obtain a compound of general
formula; 79(in which R.sub.2 has the above-mentioned meanings) and
followed by hydrolysis to obtain the compound of general formula
(I).
13. A process for the production of a compound of the general
formula (I) wherein A is --O--; R.sub.2 has the above-mentioned
meanings; 80through a compound of general formula; 81(in which
R.sub.2 has the above-mentioned meanings) is reduced to obtain a
compound of general formula; 82(in which R.sub.2 has the
above-mentioned meanings) and then reacted with 83to obtain 84(in
which R.sub.2 has the above-mentioned meaning) and then hydrolyzed
to obtain the compound of general formula (I).
14. A process for the production of a compound of the general
formula (I) wherein A is --O--; R.sub.2 has the above-mentioned
meanings; 85through a compound of general formula; 86(in which
R.sub.2 has the above-mentioned meanings) is reduced to obtain a
compound of general formula; 87(in which R.sub.2 has the
above-mentioned meanings) and then reacted with 88to obtain the
compound of genaral formula (I).
15. A method of manufacturing a compound of the general formula (I)
wherein A is --O--; R.sub.2 has the above-mentioned meanings;
89which comprises reduction of a compound of general formula; 90(in
which R.sub.2 has the above-mentioned meanings) to obtain a
compound of general formula; 91(in which R.sub.2 has the
above-mentioned meanings) and then reacted with methyloxalate to
obtain a compound of general formula; 92(in which R.sub.2 has the
above-mentioned meaning) and subjected to hydrolyzed to obtain the
compound of genaral formula (I).
16. A method for manufacturing a compound of the genaral formula
(I) wherein A is --O--; R.sub.2 has the above-mentioned meanings;
93which comprises a reaction of 94with a compound of general
formula;HO--R.sub.2 (in which R.sub.2 has the above-mentioned
meanings) in the presence of NaH to obtain a compound of general
formula (I).
17. A method for manufacturing a compound of the general formula
(I) wherein A is --O--; R.sub.2 has the above-mentioned meanings;
95which comprises a reaction of a compound of general formula;
96(in which R.sub.2 has the above-mentioned meanings) with thienyl
sulfonamide or methyl sulfonamide in the presence of
1,8-Diazabicyclo [5,4,0]undeca-7-en to obtain the compound of
general formula (I).
18. A method for manufacturing a compound of the general formula
(I) wherein A is --O--; R.sub.2 has the above-mentioned meanings;
97which comprises a reaction of 98with a compound of general
formula;HOOC--R.sub.2 (in which P2 has the above-mentioned
meanings) to obtain the compound of general formula (I).
19. A method for manufacturing a compound of the general formula
(I) wherein A is --O--; R.sub.2 has the above-mentioned meanings;
99which comprises a reaction of a compound of general formula;
100(in which R.sub.2 has the above-mentioned meanings) with
H.sub.2NOSO.sub.3H to obtain the compound of general formula (I).
Description
BACKGROUND OF THE INVENTION
[0001] Field of the Invention
[0002] This invention is regarding to new ether and/or amide
derivatives which are useful for the treatment of diabetes and a
pharmaceutical composition containing these compounds as active
ingredients.
[0003] Current Technology
[0004] Biguanide and sulfonyl urea derivatives have been used as
anti-diabetics so far. But these compounds have some drawbacks. For
instance, biguanide compounds cause diabetic acidosis and sulfonyl
urea compounds often cause hypoglycemia and it is required to be
careful for taking these drugs.
[0005] Recently, thiazolidine-2,4-dion derivatives are reported to
have blood glucose lowering activities.
[0006] For example, Troglitazone (T. Yoshioka et al., J.Med.Chem.
1989,32,421), Pioglitazone (H. Ikeda et al., J.Med.Chem.
1992,35,2617) or Rosiglitazone (B. C. C. Cantello et al.,
J.Med.Chem. 1994,37, 3977) are mentioned as Thiazolidine-2,4-dione
derivatives and Troglitazone is applied for clinical use.
[0007] However, these thiazolidime-2,4-dione compound are reported
to cause of liver toxicity (R. Perfetti et al., Diabetes/Metabolism
Review 1998,14(3),207) and further, side effect to troglitazone
treatment have been reported. They include cardiomegaly and hepatic
malfunction such as increasements of amino transferase (AST),
alanin transferees (ALT), and lactic dehydrogenase (LDH). (R. R.
Henry, Endocrinol.Metab,Clin,North Am. 1997,26,553).
[0008] To alleviate the side effect of thiazolidine-2,4-dione
derivatives, several non-thiazolidine-2,4-diones are reported such
as oxazoline-2,4-diones are reported such as oxazoline-2,4-dione
(R. L. Dow et al., J.Med.Chem. 1991,34,1538),
1-oxo-2,4-diazoline-3,5-dione (S. W. Goldstein et al., J.Med.Chem.
1993,36,2238), .alpha.-amino carboxylic acid (R. A. DeFronzo,
Diabetes, 1988,37,667), and Dicarboxylic acid ester (H. Shinkai et
al., J.Med.Chem.1998,41,1927).
[0009] The Subject of Invention
[0010] The present invention concerns ether and amide compounds
which enhance insulin action and show hypoglycemic activity with
low toxicities and a pharmaceutical composition containing these
compounds as active ingredients.
[0011] A Solution to the Problem
[0012] After elaborated to make an anti-diabetic drug, the
inventors found that new compounds as show general formula (I) had
shown potent anti-diabetic activities and fulfilled this
invention.
[0013] Namely, the invention is the compounds as shown in general
formula (I) and its pharmaceutically acceptable salts and a
composition containing these compounds as active ingredients.
R.sub.1--A--R.sub.2 (I)
[0014] 5
[0015] (with the provisos that (i) when A is --O--, then n is 2 or
3 (ii) when A is 6
[0016] then n is 1 or 2. R.sub.3 is OH--, CH.sub.3SO.sub.2NH--,
CF.sub.3SO.sub.2NH--, CH.sub.3SO.sub.2NHCH.sub.2--,
CF.sub.3SO.sub.2NHCH.sub.2--, HOOC--, CH.sub.3OOC--, 7
[0017] HOOC--CH.sub.2SO.sub.2NH--, CF.sub.3--CH.sub.2SO.sub.2NH--,
8
[0018] R.sub.8--NHSO.sub.2--, R.sub.8--NHSO.sub.2--CH.sub.2--,
HOOC--CH.sub.2--O--, HSO.sub.3N.dbd.CH--, or
R.sub.9--SO.sub.2NHCO--;
[0019] R.sub.4 is H, OH, O-alkyl or O--CH.sub.2OCH.sub.3;
[0020] R.sub.5 is H, halogen atom, --CH.sub.2COOH or OH;
[0021] R.sub.6 and R.sub.7 are hydrogen, t-butyl or pyrolidyl;
[0022] R.sub.8 is hydrogen or lower alkyl;
[0023] R.sub.9 is alkyl or thienyl;
[0024] R.sub.10 is lower alkyl).
[0025] Enforcement of Invention
[0026] 70 compounds are exemplified as follow, but the invention is
not limited to these compounds. Further the preparation of the
compounds 1-70 are exemplified in each experimental sections. 9
[0027] Typical preparations of the compounds of general formula (I)
according to the invention are shown.
[0028] (I) The preparation of a compound of general formula (I) in
which
[0029] A is --O--; R.sub.2 is 10
[0030] (wherein: R.sub.5, R.sub.6, and R.sub.7 have the
above-mentioned meanings; n=2)
[0031] (a) In case of
[0032] R.sub.1 is 11
[0033] in which R.sub.3 is CH.sub.3SO.sub.2NH-- or
CF.sub.3SO.sub.2NH-- and R.sub.4 is H.
[0034] The compounds can be obtained by means of the following
reaction diagram: Asparatic acid .beta.-methyl ester (2).
(J.Arg.Chem.Soc.Japan, 1951-1952,25,129):C.A.47,6065i or R. L.
Prestige et al., J.Org.Chem. 1975,40,3287 as a starting material is
converted to compound (3) by the known method (B. Helvin et al.,
J.Med.Chem. 1992,35,1853) and compound (3) is tosylated or
mesylated to obtain compound (4). The coupling reaction of compound
(4) with nitrophenol to obtain compound (5) and then compound (5)
is reduced with H.sub.2--Pd/C to obtain compound (6) and compound
(6) is subjected to react with several sulfonyl chloride (7) and
sulfonic acid anhydride (8) to obtain the compound of genaral
formula (I). 12
[0035] (b) In case of
[0036] R.sub.1 is 13
[0037] in which R.sub.3 is HOOCCH.sub.2SO.sub.2NH-- and R.sub.4 is
H.
[0038] The compounds can be obtained by mean of the following
reaction diagram:
[0039] The reaction of compound (6) and EtOOC.CH.sub.2SO.sub.2Cl as
a sulfonyl chloride, namely CH.sub.3OOCCH.sub.2SO.sub.2Cl (9), to
obtain the ester (11) and then compound (11) is hydrolyzed to
obtain the compound of genaral formula (I).
[0040] The above mentioned compound (9) is obtained by the
chlorination of sulfoacetic acid (HOOCCH.sub.2SO.sub.3H(10)) with
SOCl.sub.2 and then reacted with alcohol (R. L. Hinman et al.
(J.Am.Chem. Soc. 1959,81,5655), (H. T. Lee et al.,
Bioorg.Med.Chem.Lett. 1998,8,289). 14
[0041] (c) In case of
[0042] R.sub.1 is 15
[0043] in which R.sub.3 is HOOC--CONH-- and R.sub.4 is H.
[0044] The compound can be obtained by means of the following
reaction diagram:
[0045] The reaction of compound (6) and methyloxalate to obtain
compound (12) and compound (12) is hydrolyzed to obtain the
compound of general formula (I). Further compound (12) is
N-alkylated with alkylhalide and ther subjected to hydrolyze to
obtain the compound of general formula (I). 16
[0046] in which R.sub.3 is CH.sub.3SO.sub.2NHCH.sub.2--,
CF.sub.3SO.sub.2 NHCH.sub.2-- and HOOC--CONH--, and R.sub.4 is
H.
[0047] The compound can be obtained by means of the following
reaction diagram:
[0048] Compound (4) is reacted with p-hydroxy benzaldehyde to
obtain compound (13) and compound (13) is subjected to reductive
amination using benzylamine and sodium borohydride to obtain
compound (14).
[0049] After debenzylation of compound (14) in H.sub.2--Pd/C,
compound (15) is obtained. Compound (15) is reacted with sulfonyl
chloride, sulfonic acid anhydride, EtOOC.CH.sub.2SO.sub.2Cl or
methyloxalate as the same manner as in case of compound (6) and
compound (12), then the compound of general formula (I) is
obtained. 17
[0050] (e) In case of
[0051] R.sub.1 is 18
[0052] in which R.sub.3 is HOOC-- or CH.sub.3OOC-- and R.sub.4 is
--OH or --O-alkyl.
[0053] As shown in the following reaction diagram,
[0054] compound (32) and compound (3) is subjected to the MITSUNOBU
reaction to obtain the compound (33) which is the compound of
general formula (I). 19
[0055] Further, compound (33) can be converted to compound (34) and
compound (36) as shown in the following diagram. 20
[0056] (f) In case of
[0057] R.sub.1 is 21
[0058] in which R.sub.3 is NH.sub.2SO.sub.3-- or alkyl-NHSO.sub.2--
and R.sub.4 is --OH.
[0059] As shown in the following reaction diagram,
[0060] according to the literature method (J.Med.Chem.
1997,20,1235), compound (51) and (52) are obtained from resorcin
dimethyl ether (50). 22
[0061] Further, obtained compounds (51) and (52) are reacted with
compound (4) to obtain general formula (I) as follow. 23
[0062] (g) In case of
[0063] R.sub.1 is 24
[0064] in which R.sub.3 is CH.sub.3SO.sub.2NH-- or
CF.sub.3SO.sub.2NH--.
[0065] As shown in the following reaction diagram,
[0066] compound (53) is subjected to the MITSUNOBU reaction to
obtain compound (54) and reduction of compound (54) yields compound
(55). Compound (55) is converted to compound (56) according to the
method of the preparation of compound (42) from compound (39).
25
[0067] (h) In case of
[0068] R.sub.1 is 26
[0069] in which R.sub.3 is --COOH.
[0070] As shown in the following reaction diagram,
[0071] compound (57) is reacted with compound (4) and obtain the
ether compound (58) and the resulting compound (58) is hydrolyzed
to obtain compound (59) which is the compound of general formula
(I). 27
[0072] (i) In case of
[0073] R.sub.1 is 28
[0074] in which R.sub.3 is MeOOCCH.sub.2--, and R.sub.4 is
--O-alkyl.
[0075] As shown in the following reaction diagram,
[0076] compound (61), which is obtained from compound (60), is
reacted with compound (4) to obtain the compound of general formula
(I). 29
[0077] (j) In case of
[0078] R.sub.1 is 30
[0079] in which R.sub.3 is NH.sub.2SO.sub.2CH.sub.2-- or
alkyl-NHSO.sub.2CH.sub.2-- and R.sub.4 is OH or --O-alkyl.
[0080] As shown in the following reaction diagram,
[0081] after reduction of compound (62), the obtained compound (63)
is reacted with Na.sub.2SO.sub.3 to obtain compound (64) according
to the reported method (J.C.S.Chem.Comom., 1989,521). Then compound
(64) is chlorinated with POCl.sub.3 and treated with aqueous
NH.sub.3 to obtain the amide compound (65). After debenzylation of
compound (65), compound (66) is obtained. Compound (66) is reacted
with compound (4) to yield the compound of general formula (I).
31
[0082] (II) The preparation of a compound of general formula (I) in
which
[0083] A is --O--; R.sub.2 is 32
[0084] (wherein: R.sub.5, R.sub.6, and R.sub.7 have the above
mentioned meaning; n=3)
[0085] (a) In case of
[0086] R.sub.1 is 33
[0087] in which R.sub.3 is CH.sub.3SO.sub.2NH-- or
CF.sub.3SO.sub.2NH--, and R.sub.4 is H.
[0088] As shown in the following reaction diagram,
[0089] glutamic acid .gamma.-methyl ester (16) is used in stead of
aspartic acid .beta.-methyl ester (2). Compound (17) is obtained
from compound (16) by the same method as compound (3) is obtained
from compound (2).
[0090] After compound (17) is halogenated, tosylated or mesylated,
obtained compound (18) is coupled with nitrophenol and the
resulting compound (19) is hydrogenated to obtain compound (20).
The obtained compound (20) is reacted with several sulfonyl
chlorides, sulfonic acid anhydrides, EtOOC.H.sub.2SO.sub.2Cl or
methyloxalate to obtain the compound of general formula (I). 34
[0091] (III) The preparation of a compound of general formula (I)
in which
[0092] A is --O--; R.sub.2is 35
[0093] (a) In case of
[0094] R.sub.1 is 36
[0095] in which R.sub.3 is CH.sub.3SO.sub.2NH-- or
CF.sub.3SO.sub.2NH--, and R.sub.4 is H.
[0096] As shown in the following reaction diagram,
[0097] after the reaction of 2-methyl 5-ethylpyridine (21) and
formaldehyde using the reported method (Japanese Patent
Publication, 1981-65870), compound (22) is obtained. After compound
(22) is halogenated, tosylated or mesylated, obtained compound (23)
is coupled with nitrophenol and the resulting compound (24) is
hydrogenated to obtain compound (25), by the same method as
compound (4) is obtained from compound (3).
[0098] The obtained compound (25) is reacted with several
sulfonylchlorides (7), sulfonic acid anhydrides (8),
EtOOC.CH.sub.2SO.sub.2Cl or methyloxalate to obtain the compound of
general formula (I). 37
[0099] (b) In case of
[0100] R.sub.1 is 38
[0101] in which R.sub.3 is CH.sub.3SO.sub.2NH-- or
CF.sub.3SO.sub.2NH--, and R.sub.4 is --OH or --O-alkyl.
[0102] As shown in the following reaction diagram,
[0103] compound (37) is reacted with HO--R.sub.2 to obtain compound
(38) and compound (38) is hydrogenated to compound (39), or
compound (38) is alkylated to compound (40) and reduction of
compound (40) is resulting compound (41) . Then compound (39) or
(41) are reacted with RSO.sub.2Cl and obtain compound (42) or
compound (43). 39
[0104] Compound (37) in the diagram can be obtained from resorcin
as follow. 40
[0105] And compound (42) and (43) can be obtained by using the
reported method of coupling reaction of fluorobenzene and alcholol
(Bioorg.Med.Chem.Lett., 1994,4 (10),1181). Namely, 2--OMOM (methoxy
methyl)-4-fluoro nitrozenzene (45) is reacted with HO--R.sub.2 to
give compound (46) and resulting compound (46) is reduced to obtain
compound (47).
[0106] Compound (47) is reacted with RSO.sub.2Cl to obtain compound
(48) and after deprotection of MOM-group in compound (48), compound
(42) is obtained.
[0107] Instead of compound (45), compound (49) is also converted to
compound (41), and compound (43) is obtained from compound (41) by
the same method as compound (48) is obtained from compound
(46).
[0108] The process is shown in the following reaction diagram.
41
[0109] (IV) The preparation of a compound of general formula (I) in
which
[0110] A is --O--; R.sub.2 is 42
[0111] (a) In case of
[0112] R.sub.1 is 43
[0113] in which R.sub.3 is CH.sub.3SO.sub.2NH-- or
CF.sub.3SO.sub.2NH--, and R.sub.4 is --H.
[0114] As shown in the following reaction diagram,
[0115] compound (28), obtained from 2-chloropyridine (26) or
2-methyl amino pyridine (27), is tosylated or mesylated to obtain
compound (29). Compound (29) is subjected to coupling reaction with
nitro phenol and obtained compound (30) using the same manner to
obtain compound (3). Resulting compound (30) is reduced to obtain
compound (31) and compound (31) is reacted several sulfonyl
chlorides (7), sulfonic acid anhydrides (8),
EtOOC.CH.sub.2SO.sub.2Cl and methyloxalate to obtain the compound
of general formula (I). 44
[0116] (V) The preparation of a compound of general formula (I) in
which
[0117] A is --NH--CO--
[0118] (a) In case of
[0119] R.sub.1 is 45
[0120] in which R.sub.3 is CH.sub.3SO.sub.2NH-- or
CF.sub.3SO.sub.2NH--, and R.sub.4 is --H.
[0121] As shown in the following reaction diagram,
[0122] compound (67), intermediate for compound (3), is obtained
according to the reported method (J.Med.Chem. 1999,35,1853) and
compound (67) is hydrolyzed to obtain compound (68). After
chlorination of compound (68), obtained chloride is reacted with
p-nitroaniline to obtain compound (69). 46
[0123] Then compound (69) is hydrogenated to obtain compound (70)
according to the same method to prepare compound (5). Compound (70)
is reacted several sulfonyl chlorides (7), sulfonic acid anhydrides
(8), EtOOC.CH.sub.2SO.sub.2Cl or methyloxalate to obtain the
compound of general formula (I). 47
[0124] (b) In case of
[0125] R.sub.1 is 48
[0126] in which R.sub.3 is R.sub.9SO.sub.2NHCO-- (R.sub.9=alkyl or
thienyl), and R.sub.4 is H.
[0127] As shown in the following reaction diagram,
[0128] carboxylic acid of compound (71) is reacted with CDI
(Carbonyl Diimidazole) and then subjected to react with sulfamine
of compound (72) in the presence of DBU
(1,8-Diazabicyclo[5,4,0]undeca-7-ene) and obtain the compound of
general formula (I). (Bioorg.Med.Chem. Lett. 1995,1155) 49
[0129] As pharmaceutical acceptable salts of a compound of general
formula (I), sodium salt, potassium salt and inorganic base are
mentioned.
[0130] In case of R.sub.1 contains pyridine base, salts of
inorganic and organic acids are mentioned. As the salt of inorganic
acid, hydrochloride and sulfate are mentioned. As the salt of
organic acid, acetate, succinate and fumalate are mentioned.
[0131] A compound of general formula (I) can be used itself or
formulated to pharmaceutical product such as powder, granule,
tablet and capsule by known pharmaceutical technology.
Pharmacological Experiment
[0132] Hypoglycemic activity in mice
[0133] Test compounds were suspended in 0.5% Methyl cellulose
solution and administered (p.o.) to db/db mice (obtained from Nihon
Clea) at a range of 3-30 mg/kg once a day for four consecutive
days. Troglitazone (300 mg/kg) was also administered for control.
The results is shown in Table 1.
[0134] The compound number corresponds to the experimental
number.
1TABLE 1 Compound No. Dosage (mg/kg) Hypoglycemic activity (%) 1 30
24.6 2 10 49.0 8 10 26.0 9 10 24.0 10 10 32.4 11 10 15.4 18 10 34.7
19 10 12.8 21 10 34.6 24 10 25.7 26 30 15.1 30 30 22.1 31 30 19.0
35 30 28.8 40 30 53.4 42 10 29.6 47 10 25.6 48 30 65.4 50 30 21.9
52 30 10.5 57 3 44.0 58 3 43.4 59 3 18.4 63 3 18.4 67 3 33.1 68 3
21.2 70 30 51.0 Troglitazone 300 34.0
EXAMPLE
[0135] The following Examples are provided only for the purpose of
the preparation of the compound and not restrict the disclosed
invention.
Example 1
[0136] 4-[2-(5-Methyl-2-phenyl-1,3-oxazole-4-yl)ethoxy]benzene
methylsulfonamide
[0137] (a) 5-Methyl-4-tosyloxyethyl-2-phenyl-oxazole
[0138] 22.2 g of 5-Methyl-4-hydroxyethyl-2-phenyl-oxazole was
dissolved in a mixture of pyridine (13 mL) and dichloroethane (6
mL) and toluenesulfonyl chloride was added slowly to the mixture
and stirred at room temperature over night. The reaction mixture
was poured into water and extracted with ethyl acetate (50 mL) .
The organic extract was washed with satd. CuSO.sub.4 solution,
H.sub.2O and satd. NaCl solution. Removal of solvents after drying
over anhydro. Na.sub.2SO.sub.4, followed by column chromatography
(ethyl acetate:n-hexane=1:1) yielded 3.33 g (87.6%) of a white
solid of the objective compound.
[0139] MASS(m/e):371(M+),216,186(BP),156,130,105,77,51
[0140] IR(cm.sup.-1):1359,1173,966,927,834,813,753,666
[0141] .sup.1HNMR(CDCl.sub.3) .delta.: 2.01-2.08 (m, 2H,
--CH.sub.2--), 2.29 (S, 3H, --CH.sub.3), 2.42 (S, 3H, --CH.sub.3),
2.55 (t, 2H, --CH.sub.2--, J=6.83,7.33 Hz), 4.08 (t, 2H,
--CH.sub.2--, J=5.86,6.34 Hz), 7.31 (d, 2H, aromatic, J=7.81 Hz),
7.40-7.43 (m, 3H, aromatic), 7.78 (d, 2H, aromatic, J=8.3 Hz), 7.93
(dd, 2H, aromatic, J=7.33, 7.81 Hz)
[0142] (b) 5-Methyl-4-p-nitrophenoxyethyl-2-phenyl-1,3-oxazole
[0143] 0.21 g of NaH was placed in a 50 mL flask and washed twice
with n-hexane and added 10 mL of dimethylformamide. 0.67 g of
p-nitrophenol was added to the solution at 0.degree. C. and stirred
for 30 min. To this mixture, the compound (1.8 g) obtained from the
above mentioned step (a) in dimethyl formamide (5 mL) was added and
stirred at 80.degree. C. over night. After cooling, the reaction
mixture was poured into water and the product was extracted with
ethyl acetate (80 mL). The ethyl acetate phase was washed with
H.sub.2O, satd. NaCl solution and dried over Na.sub.2SO.sub.4 and
filtered. Evaporation of the filtrate gave a residue, from which
1.24 g (75.6%) of the yellowish objective compound was obtained by
silicagel column chromatography (ethyl acetate:n-hexane=1:3).
m.p.=100-103.degree. C.
[0144] MASS(m/e):338(M+),200,173(BP),130,104,77,51
[0145] IR(cm.sup.-1):1590,1500,1332,1263,1107,840
[0146] .sup.1HNMR(CDCl.sub.3) .delta.: 2.18-2.24 (m, 2H,
--CH.sub.2--), 2.29 (S, 3H, --CH.sub.3), 2.71 (t, 2H, --CH.sub.2--,
J=7.33, 6.83 Hz), 4.09 (t, 2H, --CH.sub.2--, J=6.35, 5.86 Hz), 6.95
(d, 2H, aromatic, J=9.28 Hz), 7.41-7.44 (m, 3H, aromatic), 7.97
(dd, 2H, aromatic, J=7.32, 7.82 Hz), 8.19 (d, 2H, aromatic, J=9.28
Hz)
[0147] (c) 5-Methyl-4-p-aminophenoxyethyl-2-phenyl-1,3-oxazole
[0148] 1.23 g of the compound obtained from the above mentioned
step (b) was dissolved in a solution of 25 mL of
methanol-tetrahydrofuran (1:1) and added 0.25 g of 5% Pd--C. To
this solution was introduced hydrogen-gas for 1 hour. After
filtration of the reaction mixture, the filtrate was evaporated to
give a residue, from which 1.02 g (91.1%) of the objective compound
was obtained by silicagel column chromatography (ethyl
acetate:n-hexane=1:1). m.p.=57-59.degree. C.
[0149] MASS(m/e):308(M+),200(BP),174,104,80,53
[0150] IR(cm.sup.-1):1512,1242,825,711,681
[0151] .sup.1HNMR(CDCl.sub.3) .delta.: 2.08-2.15 (m, 2H,
--CH.sub.2--), 2.28 (S, 3H, --CH.sub.3), 2.68 (t, 2H, --CH.sub.2--,
J=7.33, 7.32 Hz), 3.42 (bs, 2H, --NH.sub.2), 3.90 (t, 2H,
--CH.sub.2--, J=6.35, 5.86 Hz), 6.62-6.66 (m, 2H, aromatic),
6.73-6.76 (m, 2H, aromatic), 7.38-7.45 (m, 2H, aromatic), 7.96-7.99
(m, 2H, aromatic)
[0152] (d) 4-[2-(5-Methyl-2-phenyl-1,3-oxazole4-yl)ethoxy]benzene
methylsulfonamide (compound 1)
[0153] To a mixture of 0.4 g of the compound obtained from the
above mentioned step (c) and 0.28 mL of triethylamine in
dichloroethane (4 mL) and 0.16 mL of mesyl chloride were added and
stirred at 30.degree. C. for 30 minutes. The reaction mixture was
poured into water and extracted with ethyl acetate. The ethyl
acetate phase was washed with satd. NH.sub.4Cl solution, water and
satd. NaCl solution and dried over anhydrous Na.sub.2SO.sub.4 and
filtrated. Evaporation of the filtrate gave a residue, from which
0.34 g (66.7%) of the off-white objective compound was obtained by
silicagel column chromatography (ethyl acetate:n-hexane =1:1).
m.p.=121-123.degree. C.
[0154] MASS(m/e):372(M+),264,186(BP),149,104,79,55
[0155] IR(cm.sup.-1):3238,1506,1320,1281,1245,1212,1143,777
[0156] .sup.1HNMR(CDCl.sub.3) .delta.: 2.38 (S, 3H, --CH.sub.3),
2.93 (S, 3H, --SO.sub.2CH.sub.3), 2.98 (t, 2H, --CH.sub.2--,
J=6.35, 6.84 Hz), 4.23 (t, 2H, --CH.sub.2--, J=6.83, 6.84 Hz), 6.25
(S, 1H, --NH), 6.88 (d, 2H, aromatic, J=8.79 Hz), 7.16 (d, 2H,
aromatic, J=9.27 Hz), 7.39-7.45 (m, 3H, aromatic), 7.97 (dd, 2H,
aromatic, J=1.46, 1.95 Hz)
Example 2
[0157] 4-[2-(5-Methyl-2-phenyl-1,3-oxazole4-yl)ethoxy]benzene
trifluoromethyl sulfonamide (compound 2)
[0158] To a mixture of the compound (0.4 g) obtained from Example 1
step (c) in 4 mL of dichloromethane and 0.27 mL of triethylamine
was added trifluoromethanesulfonic acid anhydride (3.3 mL) and
stirred for 30 minutes at 0.degree. C. To the reaction mixture were
added 2 mL of methanol and 1 mL of 10% NaOH solution and the
mixture was stirred for 10 minutes, followed by addition of water
(20 mL) and extracted with ethyl acetate. The extract was washed
with satd. NH.sub.4Cl, water and satd. NaCl and dried over
anhydrous Na.sub.2SO.sub.4. After filtrating, the extract was
evaporated and the residue was purified by silicagel column
chromatography. Using a eluants (ethyl acetate:n-hexane=1:1), 0.38
g (66.7%) of the objective compound was obtained.
m.p.=97-99.degree. C.
[0159] MASS(m/e):441 (M+),200(BP),173,104,69
[0160] IR(cm.sup.-1): 1455,1248,1215,1116,894,597
[0161] .sup.1HNMR(CDCl.sub.3) .delta.: 2.17-2.23 (m, 2H,
--CH.sub.2--), 2.29 (S, 3H, --CH.sub.3), 2.70 (t, 2H, --CH.sub.2--,
J=6.83, 7.33 Hz), 4.05 (t, 2H, --CH.sub.2--, J=5.86, 6.34 Hz), 6.97
(d, 2H, aromatic, J=8.79 Hz), 7.40-7.44 (m, 3H, aromatic), 7.98
(dd, 2H, aromatic, J=7.32, 8.30 Hz)
Example 3
[0162]
5-Methyl-4-[2-(4-carboxymethylsulfonylamino)phenoxy]ethyl-2-phenyl--
1,3-oxazole (compound 3)
[0163] (a) 5-Methyl-4-[2-(4-ethoxycarbonylmethyl
sulfonylamino)phenoxy]eth- yl-2-phenyl-oxazole
[0164] To a solution of the compound (0.36 g) obtained from the
above mentioned Example 1 step (c) and triethylamine (0.26 mL) in
dichloroethane (8 mL) was slowly added ethoxy carbonyl chloride
(0.27 g) at 0.degree. C. and stirred for 2 hours. The reaction
mixture was poured into water and the product was extracted with
ethyl acetate. The extract was washed with satd. NH.sub.4Cl, water
and satd. NaCl and dried over anhydrous Na.sub.2SO.sub.4 and
filtrated. Evaporation of the filtrate gave a residue, from which
0.32 g (59.1%) of the oily objective compound was obtained by
silicagel column chromatography (ethyl acetate:n-hexane =1:1).
[0165] MASS(m/e):443(M+),186(BP),144,108,84,47
[0166] IR(cm.sup.-1): 1734,1341,1299,1248,1158,753
[0167] .sup.1HNMR(CDCl.sub.3) .delta.: 1.32 (t, 3H, --COOEt,
J=6.84, 7.32 Hz), 2.38 (S, 3H, --CH.sub.3), 2.98 (t, 2H,
--CH.sub.2--, J=6.83, 6.35 Hz), 3.86 (S, 2H, --CH.sub.2--), 4.23
(t, 2H, --CH.sub.2--, J=6.83, 6.35 Hz), 4.28 (q, 2H, --COOEt,
J=7.32, 6.83 Hz), 6.74 (S, 1H, --SO.sub.2NH), 6.88 (d, 2H,
aromatic, J=8.78 Hz), 7.25 (d, 2H, aromatic, J=8.30 Hz), 7.39-7.44
(m, 3H, aromatic), 7.97 (q, 2H, aromatic, J=1.46, 1.96 Hz)
[0168] (b) 5-Methyl-4-[2-(4-carboxymethyl
sulfonylamino)phenoxy]ethyl-2-ph- enyl-1,3-oxazole (compound 3)
[0169] To a solution of the compound (0.3 g) obtained from the
above mentioned step (a) in ethanol (5 mL) was added 10% NaOH (2.5
mL) and the solution was stirred for 1 hour. After removing the
solvent, the residue was dissolved in water and washed with ether.
After acidification with 10% HCl, the water phase was extracted
with ethyl acetate. The ethyl acetate phase was washed with water,
satd. NaCl and dried over anhydrous Na.sub.2SO.sub.4. After
removing the solvent, the residue was recruptallized from ethyl
acetate. 0.2 g (71.4%) of the objective compound was obtained.
m.p.=164-167.degree. C.
[0170] MASS(m/e):371(M+--COOH),294,186(BP),144,104,77
[0171] IR(cm.sup.-1):3274,1713,1512,1338,1281,1245,1158,1107
[0172] .sup.1HNMR (CDCl.sub.3) .delta.:2.42 (S, 3H, --CH.sub.3),
3.06 (t, 2H, --CH.sub.2--, J=6.35 Hz), 3.86 (S, 2H, --CH.sub.2--),
4.24 (t, 2H, --CH.sub.2--, J=6.83, 6.35 Hz), 6.85 (d, 2H, aromatic,
J=9.28 Hz), 7.22 (d, 2H, aromatic, J=8.78 Hz), 7.45-7.47 (m, 3H,
aromatic), 7.95 (q, 2H, aromatic, J=2.44, 3.9 Hz)
Example 4-5
[0173] According to the method described in Example 3, compound 4
(oil), compound 5 (m.p.=273-239.degree. C.), compound 6
(m.p.=143-145.degree. C.) and compound 7 (m.p.=114-116.degree. C.)
were obtained.
Example 8
[0174]
2-[4-(2-(5-Methyl-2-phenyl-1,3-oxazole4-yl)ethoxy)phenyl]amino-2-ox-
o-acetic acid (compound 8)
[0175] (a)
2-[4-(2-(5-Methyl-2-phenyl-1,3-oxazole-4-yl)ethoxy)phenyl]amino-
-2-oxo-acetic acid methyl aster
[0176] A mixture of the compound (0.5 g) obtained from the above
mentioned Example 1 step (c) and methyl oxalate (0.6 g) in methanol
(10 mL) was refluxed over night. After cooling, the solvent was
evaporated and a resulting residue was purified by silicagel column
chromatography. Chloroform was used as a eluant. 0.55 g (84.6%) of
the objective compound was obtained. m.p.=128-132
[0177] MASS(m/e):380(M+),321,186(BP),144,105,59
[0178] .sup.1HNMR(CDCl.sub.3) .delta.: 2.37 (S, 3H, --CH.sub.3),
2.98 (t, 2H, --CH.sub.2--, J=6.84, 6.35 Hz), 3.96 (S, 3H, --COOMe),
4.24 (t, 2H, --CH.sub.2--, J=6.35, 6.83 Hz), 6.90 (d, 2H, aromatic,
J=8.79 Hz), 7.38-7.44 (m, 3H, aromatic), 7.53 (d, 2H, aromatic,
J=8.79 Hz), 7.97 (d, 2H, aromatic, J=5.86 Hz), 8.76 (d, S, 1H,
--NH)
[0179] (b)
2-[4-(2-(5-Methyl-2-phenyl-1,3-oxazole-4-yl)ethoxy)phenyl]amino-
-2-oxo-acetic acid (compound 8)
[0180] A mixture of the compound (0.53 g) obtained from the above
mentioned Example 8 step (a) and 10% NaOH in methanol (15 mL) was
stirred for 1 hour and water (30 mL) was added to the mixture,
followed by acidification (pH 4) with 10% HCl to give a crptalline
product. Recrystallization from ethyl acetate gave the objective
compound (0.42 g, 82.3%). m.p.=196-198.degree. C.
[0181] MASS(m/e):366(M+),322,294,186(BP),144,104,77
[0182] .sup.1HNMR(CDCl.sub.3) .delta.: 2.36 (S, 3H, --CH.sub.3),
2.92 (t, 2H, --CH.sub.2--, J=6.35, 6.83 Hz), 3.32 (bs, 1H, --NH),
4.19 (t, 2H, --CH.sub.2--, J=6.34, 6.84 Hz), 6.93 (d, 2H, aromatic,
J=9.27 Hz), 7.45-7.55 (m, 3H, aromatic), 7.67 (dd, 2H, aromatic,
J=2.44 Hz), 7.91 (dd, 2H, aromatic, J=1.47, 1.95 Hz)
Example 9
[0183]
2-[4-(2-(5-Methyl-2-phenyl-1,3-oxazole-4-yl)ethoxy)benzyl]trifluoro-
methylsulfonamide (compound 9)
[0184] (a)
5-Methyl-4-(2-p-benzylaminophenoxy)-ethyl-2-phenyl-1,3-oxazole
[0185] A mixture of
5-methyl-4-[2-(p-formylphenoxy)]ethyl-2-phenyl-1,3-oxa- zole (0.54
g) and benzylamine (0.21 mL) in methanol (10 mL) was stirred for 10
minutes and NaBH.sub.3CN (0.11 g) was added to the mixture. The
mixture was stirred over night and evaporated and to a resulting
residue was added 10% HCl with stirring, followed by addition of
satd. NaHCO.sub.3 to alkalize. The product was extracted with ethyl
acetate. The ethyl acetate phase was washed with H.sub.2O, satd.
NaCl and dried over anhydrous Na.sub.2SO.sub.4 and filtered.
Evaporation of the filtrate gave a residue, from which 0.43 (61.4%)
of the oily objective product was obtained by silicagel column
chromatography.
[0186] MASS(m/e):398(M+),291,212,186(BP),146,104,77
[0187] IR(cm.sup.-1):3022,2914,1608,1509,1452,1242,738,714
[0188] .sup.1HNMR(CDCl.sub.3) .delta.: 2.37 (S, 3H, --CH.sub.3),
2.98 (t, 2H, --CH.sub.2--, J=6.83, 6.84 Hz), 3.73 (S, 2H,
--CH.sub.2--), 3.78 (S, 2H, --CH.sub.2--), 4.24 (t, 2H,
--CH.sub.2--, J=6.84, 6.83 Hz), 6.86 (d, 2H, aromatic, J=8.79 Hz),
7.21-7.44 (m, 10H, aromatic), 7.97 (q, 2H, aromatic, J=1.46, 1.95
Hz)
[0189] (b)
5-Methyl-4-(2-p-aminophenoxy)ethyl-2-phenyl-1,3-oxazole
[0190] The compound (0.4 g) obtained from the above mentioned
Example 9 step (a) was dissolved in methanol (10 mL) containing a
small amount of HOAc and 5% Pd--C (80 mg). The mixture is
hydrogenated and the reaction mixture was filtered and the filtrate
was evaporated. A resulting residue was purified by silicagel
column chromatography using a eluant (CHCl.sub.3:MeOH=10:1). The
objective compound (0.21 g, 67.7%) was obtained.
m.p.=149-152.degree. C.
[0191] MASS(m/e):308(M+),291,186(BP),144,122,104,77
[0192] IR(cm.sup.-1):3430,2962,1608,1248
[0193] .sup.1HNMR(CDCl.sub.3) .delta.: 3.88 (S, 2H, --CH.sub.2--),
4.23 (t, 2H, --CH.sub.2--, J=6.34, 6.84 Hz), 6.90 (d, 2H, aromatic,
J=8.79 Hz), 7.27 (d, 2H, aromatic, J=8.78 Hz), 7.41-7.46 (m, 3H,
aromatic), 7.96 (d, 2H, aromatic, J=7.81 Hz)
[0194] (c)
2-[4-(2-(5-Methyl-2-phenyl-1,3-oxazole4-yl)ethoxy)benzyl]triflu-
oromethyl sulfonamide (compound 9)
[0195] The compound (0.14 g) obtained from the above mentioned
Example 9 step (b) was reacted with trifluoromethanesulfonamide as
same manner as Example 2 and the objective compound (compound 9)
was obtained (0.55 g, 28%). m.p.=113-115.degree. C.
[0196] MASS(m/e):440(M+),186,144,104(BP),77
[0197] IR(cm.sup.-1):3310,1443,1368,1251,1227,1188,1146
[0198] .sup.1HNMR(CDCl.sub.3) .delta.: 2.38 (S, 3H, --CH.sub.3),
2.98 (t, 2H, --CH.sub.2--, J=6.83, 6.84 Hz), 4.25 (t, 2H,
--CH.sub.2--, J=6.84, 6.34 Hz), 4.37 (d, 2H, --CH.sub.2--, J=4.89
Hz), 5.05 (bs, 1H, --NHSO.sub.2--), 6.90 (d, 2H, aromatic, J=8.79
Hz), 7.22 (d, 2H, aromatic, J=8.79 Hz), 7.41-7.45 (m, 3H,
aromatic), 7.97 (q, 2H, aromatic, J=1.95, 1.96 Hz)
Example 10
[0199] 4-[2-(5-Ethylpyridine-2-yl)ethoxy]benzene
trifluoromethylsulfonamid- e (compound 10)
[0200] (a) 2-[2-(4-Nitrophenoxy)]ethyl-5-ethyl-pyridine
[0201] To a mixture of 2-(5-ethylpyridine) ethanol (10 g) and
4-fluoronitrobenzene (9.3 g) in Dimethylformamide (100 mL) was
added NaOH (3.4 g) and the mixture was stirred at 0.degree. C. for
1 hour. After pouring into ice-water, the product was extracted
with ethyl acetate (150 mL). The ethyl acetate phase was washed
with satd. NaCl and dried over anhydrous Na.sub.2SO.sub.4. After
removing the solvent, the resulting residue was purified by
silicagel column chromatography (EtoAc:n-hexane=1:2.fwdarw.2:1).
Recrystallization from EtoAc n-hexane mixture (1:1) gave the
off-white objective compound. 13.4 g (74.4%), m.p.=45-47.degree.
C.
[0202] MASS(m/e):272(M+), 150,134(BP), 119,93,77
[0203] IR(cm.sup.-1):1593,1518,1491,1341,1260,1008,834
[0204] .sup.1HNMR(CDCl.sub.3) .delta.: 1.25 (t, 3H,
--C.sub.2H.sub.5, J=7.81, 7.32 Hz), 2.64 (q, 2H, --C.sub.2H.sub.5,
J=7.33, 7.32 Hz), 3.27 (t, 2H, --CH.sub.2--, J=6.34, 6.84 Hz), 4.46
(t, 2H, --CH.sub.2--, J=6.34, 6.84 Hz), 7.17 (d, 1H, pyridine,
J=8.31 Hz), 7.47 (dd, 1H, pyridine, J=2.44, 2.45 Hz), 8.18 (dd, 2H,
aromatic, J=6.83, 7.32 Hz), 8.40 (d, 1H, pyridine, J=1.95 Hz)
[0205] (b) 2-[2-(4-Aminophenoxy)]ethyl-5-ethyl-pyridine
[0206] The compound (1.85 g) obtained from the above mentioned
Example 10 step (a) was hydrogenated as same manner as Example 1
step (c) and obtained the oily objective compound (1.62 g,
98.2%).
[0207] MASS(m/e):242(M+), 134(BP), 119,106,83,65
[0208] IR(cm.sup.-1):2950,1509,1233,822
[0209] .sup.1HNMR(CDCl.sub.3) .delta.: 1.24 (t, 3H,
--C.sub.2H.sub.5, J=7.81, 7.33 Hz), 2.62 (q, 2H, --C.sub.2H.sub.5,
J=7.33 Hz), 3.19 (t, 2H, --CH.sub.2--, J=6.35, 6.83 Hz), 3.42 (bs,
2H, --NH.sub.2), 4.26 (t, 2H, --CH.sub.2--, J=6.35, 6.84 Hz),
6.61-6.64 (m, 2H, aromatic), 6.72-6.76 (m, 2H, aromatic), 7.18 (d,
1H, pyridine, J=7.81 Hz), 7.44 (dd, 1H, pyridine, J=1.95, 1.96 Hz),
8.39 (d, 1H, pyridine, J=2.46 Hz)
[0210] (c) 4-[2-(5-Ethylpyridine-2-yl)ethoxy]benzene
trifluoromethylsulfonamide (compound 10)
[0211] The compound (1.2 g) obtained from the above mentioned
Example 10 step (b) was reacted with trifluoromethanesulfonic acid
anhydride by the same procedure described in Example 2 and obtained
0.3 g the objective compound (compound 10). m.p.=76-78.degree.
C.
[0212] MASS(m/e):373(M+-1),134(BP),91,69
[0213] IR(cm.sup.-1):1446,1263,1119,897,603
[0214] .sup.1HNMR(CDCl.sub.3) .delta.: 1.25(t, 3H,
--C.sub.2H.sub.5, J=7.81, 7.33 Hz), 2.63 (q, 2H, --C.sub.2H.sub.5,
J=7.32, 7.82 Hz), 3.25 (t, 2H, --CH.sub.2--, J=6.83, 6.35 Hz), 4.39
(t, 2H, --CH.sub.2--, J=6.35 Hz), 6.96 (dd, 2H, aromatic, J=6.84,
6.83 Hz), 7.18 (d, 1H, pyridine, J=7.81 Hz), 7.28 (d, 2H, aromatic,
J=9.28 Hz), 7.46 (dd, 1H, pyridine, J=7.81 Hz), 8.40 (d, 1H,
pyridine, J=1.96 Hz)
Example 11
[0215] 4-[2-(N-Methyl-N-2-pyridyl)aminoethoxy]benzene
trifluoromethanesulonamide (compound 11)
[0216] (a)
4-[2-(N-Methyl-N-2-pyridyl)aminoethoxy]-1-nitrobenzene-2-pyridy-
l-2-methylamino ethanol (4.0 g) was reacted with 4-fluorobenzene by
the same procedure described in Example 6 step (a) and obtained the
oily objective compound (5.9 g, 82.2%).
[0217] MASS(m/e):273(M+),139,121(BP),94,78,51
[0218] IR(cm.sup.-1):2926,1590,1497,1425,1338,1260
[0219] .sup.1HNMR(CDCl.sub.3) .delta.: 3.14 (S, 3H, --CH.sub.3),
4.03 (t, 2H, --CH.sub.2, J=5.86, 5.37 Hz), 4.30 (t, 2H,
--CH.sub.2--, J=5.86 Hz), 5.52 (d, 1H, pyridine, J=8.79 Hz), 6.59
(t, 1H, pyridine, J=4.88, 6.35 Hz), 6.97 (dd, 2H, aromatic, J=8.79
Hz), 7.45-7.50 (m, 1H, pyridine), 8.15-8.20 (m, 2H, pyridine,
aromatic)
[0220] (b)
4-[2-(N-Methyl-N-2-pyridyl)aminoethoxy]-1-aminobenzene
[0221] The compound (5.85 g) obtained from the above mentioned
Example 11 step (a) was hydrogenated by the same procedure
described in Example 1 step (c) and obtained the objective compound
(2.12 g, 40.7%).
[0222] MASS(m/e):243(M+), 135(BP),121,108,94,78,65
[0223] IR(cm.sup.-1):3334,2914,1596,1557,1503,1425,1233,771
[0224] (c) 4-[2-(N-Methyl-N-2-pyridyl)aminoethoxy]benzene
trifluoromethanesulfonamide (compound 11)
[0225] The compound (0.5 g) obtained from the above mentioned
Example 11 step (b) was reacted with trifluoromethanesulfonamide by
the same procedure described in Example 2 and obtained the
objective product (0.67 g, 87.0%). m.p.=60-62.degree. C.
[0226] MASS(m/e):375(M+),304,170,135,108,78(BP),52
[0227] IR(cm.sup.-1):1593,1503,1452,1218,1125,891,600
[0228] .sup.1HNMR(CDCl.sub.3) .delta.: 3.13 (S, 3H, --CH.sub.3),
4.01 (t, 2H, --CH.sub.2, J=5.86, 5.37 Hz), 4.24 (t, 2H,
--CH.sub.2--, J=5.86, 5.37 Hz), 6.51 (d, 1H, pyridine, J=8.30 Hz),
6.57 (t, 1H, pyridine, J=4.88, 6.84 Hz), 6.97 (d, 2H, aromatic,
J=9.27 Hz), 7.27 (d, 2H, aromatic, J=9.77 Hz), 7.44-7.49 (m, 1H,
pyridine), 8.15 (d, 1H, pyridine, J=3.90 Hz)
Example 12-17
[0229] According to the method described in Example 1, compound 12
(m.p.=106-108.degree. C.), compound 13(m.p.=67-68.degree. C.),
compound 14 (m.p.=56-58.degree. C.), compound 15
(m.p.=128-130.degree. C.), compound 16 (126-127.degree. C.) and
compound 17 (m.p.=128-130.degree. C.) were obtained.
Example 18-20
[0230] According to the method described in Example 2, compound 18
(m.p.=197-198.degree. C.), compound 19 (m.p.=70-71.degree. C.) and
compound 20 (m.p.=170-172.degree. C.) were obtained.
Example 21
[0231] 5-Methyl-4-(3-hydroxy)propyl-2-phenyl-1,3-oxazole, prepared
from glutamic acid instead of asparatic acid, was reacted as a
similar manner described in Experimental 2 and obtained compound 21
(m.p.=113-114.degree. C.).
Example 22-24
[0232] According to the same procedure described in Example 4,
compound 22 (m.p.=128-130.degree. C.) and compound 23
(m.p.=217.degree. C. (decomp.)) were obtained.
Example 25
[0233]
2--Hydroxy-4-[2-(5-methyl-2-phenyl-1,3-oxazole4-yl)ethoxy]benzoic
acid methyl ester (compound 25)
[0234] 0.2 g of methyl 2-4-dihydroxybenzoate and 0.23 g of
diisopropyl azodicarboxylate (DIAD) were dissolved in 2 mL of THF.
To this mixture was slowly added a mixture of 0.29 g of
5-methyl-4-hydroxyethyl-3-phenyl-- 1,3-oxazole and 0.31 g of
Ph.sub.3P in 3 mL of THF and the mixture was subjected to Mitsunobu
reaction. After the reaction mixture was allowed to stand over
night, the solvent was removed. The resulting residue was purified
by silicagel column chromatography (ethyl acetate:benzene=1:5).
After removing the solvent, the residue was recrystallized from
benzene. 0.31 g (73.3%) of the colorless objective compound was
obtained. m.p.=133-134.degree. C.
[0235] MASS(m/e):353(M+),217,185,136,104(BP),77,53
[0236] IR(cm.sup.-1):1677,1617,1440,1320,1251,1188,1134
[0237] .sup.1HNMR(CDCl.sub.3) .delta.: 3.90 (S, 3H, --COOMe), 4.27
(t, 2H, --CH.sub.2, J=6.34, 6.84 Hz), 6.42 (dd, 1H, -aromatic,
J=8.79 Hz), 6.46 (d, 1H, aromatic, J=2.44 Hz), 7.39-7.44 (m, 3H,
aromatic), 7.72 (d, 1H, aromatic, J=9.28 Hz), 7.97 (q, 2H,
aromatic, J=7.33, 8.3 Hz), 10.93 (s, 1H, --OH)
Example 26-28
[0238] According to the procedure described in Example 11, compound
26 (m.p.=211-213.degree. C.), compound27 (m.p.=85-87.degree. C.)
and compound 28 (m.p.=130-132.degree. C.) were obtained.
Example 29-30
[0239]
2--Hydroxy-4-[2-(5-methyl-2-phenyl-1,3-oxazole4-yl)ethoxy]benzoic
acid (compound 29)
[0240] 0.17 g of the compound obtained from Example 20 was
dissolved in 2 mL of MeOH:THF (1:1). To the solution was added 2 mL
of 10% NaOH and the mixture was refluxed for 1 hour. After removal
of the solvent, the residue was washed with ether, followed by
acidification with 10% HCl. The resulting precipitate was filtered.
Recrystallization from ethanol gave the colorless objective
compound (0.13 g, 81.3%). m.p.=192-194.degree. C.
[0241] MASS(m/e):339(M+),295,217,186,104(BP)
[0242] IR(cm.sup.-1):2920,1655,1260,1170
[0243] According to the above mentioned procedure compound 30 was
obtained. (m.p.=246-266.degree. C.).
Example 31-32
[0244]
2-Ethoxy-4-[2-(5-methyl-2-phenyl-1,3-oxazole4-yl)ethoxy]benzoic
acid (compound 31)
[0245] (a)
2-Ethoxy-4-[2-(5-methyl-2-phenyl-1,3-oxazole4-yl)ethoxy]benzoic
acid methyl ester
[0246] To a solution of the compound 25 (0.27 g) in DMF (5 mL) was
added K.sub.2CO.sub.3 (0.16 g) and EtI (0.07 mL) and the mixture
was allowed to stand over night. The reaction mixture was poured
into water and the product was extracted with ethyl acetate (30
mL). The ethyl acetate phase was washed with water, satd. NaCl and
dried over anhydrous Na.sub.2SO.sub.4 and filtrated. Evaporation of
the filtered gave a residue, from which 0.28 g (96.6%) of the
colorless objective compound was obtained by silicagel column
chromatography (ethyl acetate:n-hexane =1:3).
[0247] MASS(m/e):381(M+),217,186,144,104(BP),77,51
[0248] IR(cm.sup.-1):2926,1686,1605,1257,1194
[0249] (b)
2-Ethoxy-4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl)ethoxy]benzoi- c
acid (compound 31)
[0250] The compound obtained from above mentioned Example 31-32
step (a) was hydrolyzed by the procedure in Example 29 and obtained
the objective compound (0.22 g). m.p.=128-130.degree. C.
[0251] MASS(m/e):367(M+),217,186,144,104(BP),77,51
[0252] IR(cm.sup.-1):1686,1605,1572,1281,1263,1239,1191
[0253] .sup.1HNMR(CDCl.sub.3) .delta.: 2.99 (t, 2H, --CH.sub.2--,
J=6.84 Hz), 4.25 (q, 2H, oEt, J=6.84 Hz), 4.33 (t, 2H,
--CH.sub.2--, J=6.34, 6.84 Hz), 6.50 (d, 1H, aromatic, J=2.44 Hz),
6.55 (dd, 1H, aromatic, J=1.95 Hz), 7.41-7.44 (m, 3H, aromatic),
7.96-7.99 (m, 2H, aromatic), 8.10 (d, 1H, aromatic, J=8.79 Hz)
[0254] And compound 25 was reacted with methoxy methylchloride to
obtain compound 32. m.p.=129-130.degree. C.
Example 33-38
[0255] Each compounds of
3-benzyl-4-nitrophenol-2,6-difluoro-4-nitrophenol and
5-methyl-4-hydroxyethyl-2-phenyl-1,3-oxazole were subjected to
Mitsunobu reaction in a similar manner described in Example 25 and
the nitro compounds were obtained, followed by the procedures
described in Example 1 step (c) and step (d) yielded compound 33
(m.p.=155-156.degree. C.), compound35 (m.p.=143-144.degree. C.) and
compound 36 (m.p.=78-80.degree. C.). Further, Mitsunobu reaction of
2,4-dihydroxy-benzene sulfonamide and
5-methyl-4-hydroxy-3-phenyl-1,3-oxa- zole yielded compound 34
(m.p.=231-232.degree. C.). Ethylation of the compound 34 yielded
compound 37 (m.p.=171-173.degree. C.). Methyl
4-hydroxy-2-ethoxyphenoxy acetate was reacted in a similar manner
and the resulting compound was hydrolyzed to obtain compound 38
(m.p.=154-156.degree. C.).
Example 39
[0256] 4-[2-(N-Methyl-N-2-pyridyl)aminoethoxy]-2-hydroxyphenyl
trifluoromethane sulfonamide (compound 39)
[0257] (a) 4-[2-(N-Methyl-2--N-pyridyl)aminoethoxy]-2-hydroxy
nitrobenzene.
[0258] To a mixture of 2-(N-methyl, N-hydroxyethyl)-aminopyridine
(0.35 g) and 4-fluoro-2-methoxy-methyloxy-nitrobenzene in DMF (30
mL) was added NaH (0.12 g) and stirred at room temperature over
night. The reaction mixture was poured into ice-water and extracted
with ethyl acetate. The ethyl acetate extract was washed with satd.
NHCl and dried over anhyd. Na.sub.2SO.sub.4 and filtered. After
removal of solvent, the residue was purified by silicagel column
chromatography (ethyl acetate:n-hexane=1:2). The oily objective
compound (0.44 g, 57.1 %) was obtained.
[0259] MASS(m/e):333(M+),121(BP),78,52
[0260] IR(cm.sup.-1):2926,1596,1500,1425,1341,1287,1152
[0261] (b) 4-[2-(N-Methyl-N-2-pyridyl)aminoethoxy]-2-hydroxyphenyl
trifluoromethanesulfonamide (compound 33)
[0262] The compound obtained from the above mentioned step (a) was
reduced with hydrogen in a similar manner described in Example 1
step (c) and the resulting compound was reacted with
trifluoromethanesulfonic acid anhydride in a similar manner
described in Experimental 1 step (d). After removing of the
protection group (MOM, methoxymethyl), the residue was
recrystallized from the mixture of ethyl acetate and n-hexane to
obtain the colorless objective compound (compound 33).
mp-134-135.degree. C.
[0263] MASS(m/e):391 (M+),135(BP),107,78
[0264] IR(cm-1):1611,1509,1419,1404,1227,1176,1146
[0265] .sup.1HNMR(CDCl.sub.3) .delta.: 3.14 (S, 3H, Me), 3.93 (t,
2H, --CH.sub.2, J=5.37 Hz), 4.11 (2H, --CH.sub.2--, J=5.37 Hz),
6.37-6.43, 6.53-6.59 (m, m, 4H, aromatic, pyridine), 7.27 (d, 1H,
aromatic, J=8.79 Hz), 7.46-7.51 (m, 1H, pyridine), 8.08 (d, 1H,
pyridine, J=4.88 Hz)
Example 40-41
[0266] Compound 40 (m.p.=133-135.degree. C.) and compound
41(m.p.=151-153.degree. C.) were obtain from
4-fluoro-2-ethoxy-nitrobenze- ne by proceeding in a similar manner
described in Experimental 39 step (a).
Example 42-45
[0267] In stead of 2-(N-Methyl, N-hydroxyethyl) aminopyridine in
Example 39 step (a), 5-methyl-4-hydroxy-2-phenyl-1,3-oxazole was
reacted in a similar manner and the resulting compound was reacted
with trifluoromethanesulfonic acid anhydride to obtain compound 43
(m.p.=169-171.degree. C.). The compound obtained from Example 39
step (a) was reacted with trifluoromethanesulfonic acid anhydride
to obtain compound 44 (m.p.=124-125.degree. C.). Further,
2-(N-Methyl, N-hydroxyethyl)-amino pyridine in Example 39 step (a)
was reacted with 4-fluoro-2-methoxy-nitrobenzene and the resulting
product was treated with in a similar manner described in Example 1
step (c) to obtain the oily objective compound 45.
Example 46-47
[0268] N-Butyl-2,4-dihydroxy-benzenesulfonamide and
5-methyl-4-bromoethyl-2-phenyl-1,3-oxazole was reacted in a similar
manner described in Example 1 step (b) to obtain compound 46
(m.p.=137-139.degree. C.). After reacting
2,6-dibromo-4-hydroxy-benzoic acid methyl ester and
5-methyl-4-bromoetyl-2-phenyl-1,3-oxazole, compound 47
(m.p.=163-164.degree. C.) was obtained.
Example 48-54
[0269] After chlorination of the compound of general formula (68),
the resulting compound was reacted with 4-nitroaniline or
corresponding aniline to obtain the compound of general formula
(69), followed by reduction in a similar manner described in
Example 1 and the resulting compounds were treated in a similar
manner described in Example 2. The following objective compounds
were obtained. Compound 53 was hydrolyzed to obtain compound 54.
Compound 48 (m.p.=147-149.degree. C.), compound 49
(m.p.=175-177.degree. C.), compound 50 (m.p=166-168.degree. C.),
compound 51 (m.p.=164-166.degree. C.), compound 52
(m.p.=227-229.degree. C.), compound 53 (oil), compound 54
(175.degree. C., decomp.)
Example 55-56
[0270] After activation of carboxylic acid group in general formula
(71) by the reported method (Bioorg.Med.Chem.Lett., 1995,1155), the
resulting compound was reacted with sulfamines in the presence of
DBU to obtain compound 55 (m.p.=150-152.degree. C.) and compound 56
(m.p.=214-216.degree. C.).
Example 57-59
[0271] In stead of 5-methyl-4-p-aminophenoxy-2-phenyl-1,3-oxazole
in Example 2, 5-methyl-4-p-aminophenoxyethyl-2-p-tolyl-1,3-oxazole,
5-methyl-4-p-aminophenoxyethyl-2-p-chlorophenyl-1,3-oxazole and
5-methyl-4-p-aminophenoxyethyl-2-p-fluorophenyl-1,3-oxazole were
reacted in a similar manner described in Example 2 to obtain the
following compounds. Compound 57 (m.p.=173.5-175.degree. C.),
compound 58 (m.p.=189-190.degree. C.), compound 59
(m.p.=161-163.degree. C.).
Example 60-63
[0272] In stead of 5-methyl-4-p-aminophenoxy-2-phenyl-1,3-oxazole,
5-isopropyl-4-p-aminophenoxy-ethyl-2-p-tolyl-1,3-oxazole,
5-isopropyl-4-p-aminophenoxy-2-phenyl-1,3-oxazole,
5-isopropyl-4-p-aminophenoxyethyl-2-p-fluorophenyl-1,3-oxazole and
5-isopropyl-4-p-aminophenoxy-2-(3,5-di-t-butyl-4-hydroxy)phenyl-1,3-oxazo-
le were reacted in a similar manner described in Example 2 to
obtain the following compounds. Compound 60 (m.p.=190-191.degree.
C.), compound 61 (m.p.=155-156.degree. C.), compound 62
(m.p.=189-190.degree. C.), compound 63 (m.p.=142-144.degree. C.).
Example 64-66
[0273] 5-Isopropyl-4-hydroxyethyl-2-phenyl-1,3-oxazole,
5-isopropyl-4-hydroxyethyl-2-p-phenyl-1,3-oxazole and
5-isopropyl-4-hydroxyethyl-2-p-tolyl-1,3-oxazole were reacted with
4-fluoro-2-ethoxy-nitrobenzene in a similar manner described in
Example 39 to obtain the following compounds. Compound 64
(m.p.=142-144.degree. C.), compound 65 (m.p.=179-181.degree. C.),
Compound 66 (m.p.=122-124.degree. C.)
Example 67-68
[0274] Each of
5-methyl-4-hydroxyethyl-2-(p-ethoxycarbonylmethyloxy)phenyl-
-1,3-oxazole and
5-methyl-4-hydroxyethyl-2-(3,5-di-t-butyl-4-ethoxycarbony-
lmethyloxy)phenyl-1,3 -oxazole were transformed to
5-methyl-4-p-nitropheny- l
-2-(p-ethoxycarbonylmethyloxy)phenyl-1,3-oxazole and
5-methyl-4-p-nitrophenyl-2-(3,5-di-t-butyl-4-ethoxycarbomethyloxy)phenyl--
1,3-oxazole using a similar method described in Example 39. The
resulting compounds were hydrolyzed with 10% NaOH--MeOH to obtain
the following compounds. Compound 67 (m.p.=167-168.degree. C.),
compound 68 (m.p.=196-198.degree. C.)
Example 69
[0275] 5-Methyl-4-p-formylphenyl-2-phenyl-1,3-oxazole (1.0 g) was
dissolved in dichlolomethane (10 mL) and hydroxylamine-o-sulfonic
acid (0.59 g) was added. The mixture was stirred for 30 minutes and
the resulting precipitate was collected, followed by washing with
water, MeOH and dichloromethane. 1.03 g of compound 69 was
obtained. m.p.=165-167.degree. C.
[0276] MASS(m/e):403(M+1),401(M-1)
Example70
[0277] According to a similar procedure, described in Example 2,
5-methyl-4-aminophenoxyethyl-2-(3-t-butyl-4-hydroxy)phenyl-1,3-oxazole
were transformed to compound 70. m.p.=58-60.degree. C.
[0278] Effects of the Invention
[0279] This invention concerns to novel ether and/or amide
derivatives which enhance insulin action and show hypoglycemic
activities with low toxicities and useful for antidiabetics.
* * * * *