Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-10
2002-07-02
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S235000
Reexamination Certificate
active
06414001
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to new ether and/or amide derivatives, which are useful for the treatment of diabetes and a pharmaceutical containing these compounds as active ingredients.
2. Current Technology
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 when taking these drugs.
Recently, thiazolidine-2,4-dione derivatives are reported to have blood glucose lowering activities. 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-2,4dione derivatives and Troglitazone is applied for clinical use. However, these thiazolidine-2,4-dione compounds are reported to cause liver toxicity (R. Perfetti et al., Diabetes/Metabolism Review 1998,14(3),207) and further, side effects to troglitazone treatment have been reported. They include cardiomegaly and hepatic malfunction such as increase of amino trasferase (ATL), and lactic dehydrogenase (LDH) (R. R. Henry, Endocrinol.Metab,Clin,North AM. 1997,26,553).
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 (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), &agr;-amino carboxylic acid (R. A. DeFronzo, Diabetes, 1988,37,677), and Dicarboxylic acid ester (H. Shinkai et al., J.Med.Chem. 1998,41,1927).
THE SUBJECT OF INVENTION
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.
A Solution to the Problem
After extensive research to make an anti-diabetic drug, the inventors found that new compounds, as shown by general formula (I), have potent anti-diabetic activities and fulfilled this invention.
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
1
—A—R
2
(I)
wherein
(with the provisos that (i) when A is —O—, then n is 2 or 3 (ii) when
then
n is 1 or 2. R
3
is OH—, CH
3
SO
2
NH—, CF
3
SO
2
NH—, CH
3
SO
2
NHCH
2
—, CF
3
SO
2
NHCH
2
—, HOOC—, CH
3
OOC—,
HOOC—CH
2
SO
2
NH—, CF
3
—CH
2
SO
2
NH—,
R
8
—NHSO
2
—,
R
8
—NHSO
2
—CH
2
—, HOOC—CH
2
—O—, HSO
3
N═CH—, or R
9
—SO
2
NHCO—;
R
4
is H, OH, O-alkyl or O—CH
2
OCH
3
;
R
5
is H, halogen atom, —CH
2
COOH or OH;
R
6
and R
7
are hydrogen, t-butyl or pyrolidyl;
R
8
is hydrogen or lower alkyl;
R
9
is alkyl or thienyl;
R
10
is lower alkyl)
EXAMPLES OF INVENTION
70 compounds are exemplified as follows, but the invention is not limited to these compounds. Further the preparation of the compounds 1-70 are exemplified in each experimental sections.
Typical preparations of the compounds of general formula (I) according to the invention are shown.
(I) The preparation of a compound of general formula (I) in which
A is —O—;
(wherein: R
5
, R
6
, and R
7
have the above-mentioned meanings; n=2)
(a) In case of
in which R
3
is CH
3
SO
2
NH— or CF
3
SO
2
NH— and R
4
is H.
The compounds can be obtained by means of the following reaction diagram: Asparatic acid &bgr;-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 yields compound (5) and then compound (5) is reduced with H
2
—Pd/C to obtain compound (6) and compound (6) is subjected to reaction with sulfonyl chloride (7) or sulfonic acid anhydride (8) to obtain the compound of general formula (I).
(b) In case of
in which R
3
is HOOCCH
2
SO
2
NH— and R
4
is H.
The compounds can be obtained by mean of the following reaction diagram:
The reaction of compound (6) and EtOOC.CH
2
SO
2
Cl as a sulfonyl chloride, namely CH
3
OOCH
2
SO
3
Cl (9), yields the ester (11) and then compound (11) is hydrolyzed to obtain the compound of general formula (I).
The above mentioned compound (9) is obtained by the chlorination of sulfoacetic acid (HOOCCH
2
SO
3
H(10)) with SOCl
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)
(c) In case of
in which R
3
is HOOC—CONH— and R
4
is H.
The compound can be obtained by means of the following reaction diagram:
The reaction of compound (6) and methyloxalate yields compound (12) and compound (12) is hydrolyzed to obtain the compound of general formula (I). Further compound (12) is N-alkylated with alkylhalide and then subjected to hydrolysis to obtain the compound of general formula (I).
(d) In case of
in which R
3
is CH
3
SO
2
NHCH
2
—, CF
3
SO
2
NHCH
2
—and HOOC—CONH—, and R
4
is H.
The compound can be obtained by means of the following reaction diagram:
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).
After debenzylation of compound (14) in H
2
—Pd/C, compound (15) is obtained. Compound (15) is reacted with sulfonyl chloride, sulfonic acid anhydride, EtOOC.CH
2
SO
2
Cl or methyloxalate as the same manner as in case of compound (6) and compound (12), then the compound of general formula (I) is obtained.
(e) In case of
in which R
3
is HOOC— or CH
3
OOC— and R
4
is —OH or —O-alkyl.
As shown in the following reaction diagram,
compound (32) and compound (3) is subjected to the MITSUNOBU reaction to obtain the compound (33) which is the compound of general formula (I).
Further, compound (33) can be converted to compound (34) and compound (36) as shown in the following diagram.
(f) In case of
in which R
3
is NH
2
SO
3
— or alkyl-NHS
2
— and R
4
is —OH.
As shown in the following reaction diagram,
according to the literature method (J.Med.Chem.1997,20,1235), compound (51) and (52) are obtained from resorcin dimethyl ether (50).
Further, obtained compounds (51) and (52) are reacted with compound (4) to obtain general formula (I) as follows.
(g) In case of
in which R
3
is CH
3
SO
2
NH— or CF
3
SO
2
NH—.
As shown in the following reaction diagram,
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).
(h) In case of
in which R
3
is —COOH.
As shown in the following reaction diagram,
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).
(i) In case of
in which R
3
is MeOOCCH
2
—, and R
4
is —O-alkyl.
As shown in the following reaction diagram,
compound (61), which is obtained from compound (60), is reacted with compound (4) to obtain the compound of general formula (I).
(j) In case of
in which R
3
is NH
2
SO
2
CH
2
— or alkyl-NHS
02
CH
2
— and R
4
is OH or —O-alkyl.
As shown in the following reaction diagram,
after reduction of compound (62), the obtained compound (63) is reacted with Na
2
SO
3
to obtain compound (64) according to the reported method (J.C.S.Chem.Comom.,1989,521). Then compound (64) is chlorinated with POCl
3
and treated with aqueous NH
3
to obtain the amide compound (65). After debenzylation of compound (65), compound (66) is obtained. Compound (66) is reacted with compound (4) to yie
Kuroiwa Keiko
Tomiyama Akira
Tomiyama Hiroshi
Tomiyama Tsuyoshi
Desai Rita
Kotobuki Pharmaceutical Co. Ltd.
Rotman Alan L.
Sherman & Shalloway
LandOfFree
Ether and amide compounds preparation thereof composition... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Ether and amide compounds preparation thereof composition..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Ether and amide compounds preparation thereof composition... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2895882