Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-07
2002-03-05
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S183000, C549S039000, C560S009000, C562S426000
Reexamination Certificate
active
06353011
ABSTRACT:
BACKGROUND OF THE INVENTION
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors. Three subtypes of PPARs have been cloned from the mouse and human: i.e., PPAR&agr;, PPAR&bgr; and PPAR&dgr;. The PPARs are believed to play a role in the regulation of lipid metabolism. They can be activated by high concentration of fatty acids and have been shown to regulate the expression levels of fatty acid binding proteins or enzymes involved in fatty acid oxidation.
It has previously been discovered that a certain class of thiazolidinediones are selective PPAR&ggr; agonists (see, Willson et. al.,
J. Med. Chem.
(1996) 39:665-668). Thiazolidinediones are a class of oral insulin-sensitizing agents that improve glucose utilization without stimulating insulin release. For instance, U.S. Pat. No. 4,287,200, discloses certain thiazolidine derivatives having the ability to lower blood glucose levels. In addition, U.S. Pat. No. 4,572,912, discloses thiazolindinedione derivatives having the ability to lower blood lipid and blood glucose levels. These compounds were shown to have the ability to decrease the levels of blood lipid peroxides, blood triglycerides and blood cholesterol.
Moreover, U.S. Pat. No. 5,338,855, discloses thiazolidine derivatives containing a quinone moiety. These compounds were shown to have the ability to reduce insulin resistance in the peripheral tissues and possess the ability to suppress hepatic gluconeogenesis in the liver.
In addition to being anti-diabetic agents which can lower the concentration of glucose and lipids in the blood, U.S. Pat. No. 5,594,015 discloses thiazolidine derivatives as being effective in the treatment of hyperproliferation of epithelial cell conditions, such as psoriatic activity.
The anti-diabetic effect of the thiazolidinediones and their PPAR&ggr; agonist activity has implicated PPAR&ggr; as the molecular target for the anti-diabetic effects of thiazolidinediones. PPAR&ggr; is predominately expressed in adipose tissue and has been implicated as a master regulator of adipocyte differentiation in pre-adipose cell lines.
In view of the role PPAR&ggr; plays in regulation of lipid and glucose metabolism and the agonistic behavior of thiazolidinediones, there remains a need in the art for new thiazolindinedione derivatives and more effective therapies for diabetes and other ailments. The present invention fulfills these and other needs.
SUMMARY OF THE INVENTION
This invention provides new thiazolindinedione derivatives. As such, in one aspect, the present invention provides compounds of Formula I:
In Formula I, R
1
and R
2
are each independently a functional group including, but not limited to, hydrogen, C(O)—R
6
and C(S)—R
6
. R
6
, in Formula I, is a functional group including, but not limited to, hydrogen, (C
1
-C
12
)alkyl, aryl, arylalkyl, (C
1
-C
12
)carboxyl, (C
1
-C
12
)NHR
7
, (C
1
-C
12
)NR
7
R
8
, OR
7
, NHR
7
, SR
7
, NR
7
R
8
. R
7
, and R
8
, in Formula I, are each independently functional groups including, but not limited to, hydrogen, (C
1
-C
12
)alkyl, aryl and arylalkyl. The bond bisecting the functional group containing two sulfurs, indicates that the bond can be attached at anyone of the 3 carbon atoms between the two sulfur atoms.
In an alternative embodiment, R
1
and R
2
together with the sulfurs to which they are bound join to form a 1,2-dithiolane ring. In this embodiment, the 1,2-dithiolane ring can be substituted at the 3-position or the 4-position.
X, in Formula I, is a functional group including, but not limited to O, NR, C(O)O, OC(O)O and C(O)NR, wherein R is a functional group including, but not limited to, hydrogen and optionally substituted (C
1
-C
6
)alkyl. Y, in Formula I, is a functional group including, but not limited to, O, S and NR
6
, wherein R
6
is a functional group including, but not limited to, hydrogen and optionally substituted (C
1
-C
6
)alkyl. In Formula I, the index “n” is an integer from 2 to 14; the index “m” is an integer from 0 to 14; the index “q” is an integer from 0 to 1; and the index “t” is an integer from 0 to 1, provided when m is 0 then q is 0, or a pharmaceutical acceptable salt or solvate thereof. Suitable salts include, but are not limited to, sodium, potassium and ammonium.
In another embodiment, the present invention provides a compound of Formula II:
In Formula II, R
1
and R
2
are each independently a functional group including, but not limited to, hydrogen, C(O)—R
6
and C(S)—R
6
. R
6,
in Formula II, is a functional group including, but not limited to, hydrogen, (C
1
-C
12
)alkyl, aryl, arylalkyl, (C
1
-C
12
)carboxyl, (C
1
-C
12
)NHR
7
, (C
1
-C
12
)NR
7
R
8
, OR
7
, NHR
7
, SR
7
, NR
7
R
8
. R
7
and R
8
, in Formula II, are each independently a functional group including, but not limited to, hydrogen, (C
1
-C
12
)alkyl, aryl and arylalkyl. The bond bisecting the functional group containing two sulfurs, indicates that the bond can be attached at any of the 3 carbon atoms between the two sulfur atoms.
In an alternative embodiment, R
1
and R
2
together with the sulfurs to which they are bound join to form a 1,2-dithiolane ring. The 1,2dithiolane ring can be substituted at the 3-position or at the 4-position.
X, in Formula II, is functional group including, but not limited to O, NR, C(O)O, OC(O)O and C(O)NR, wherein R is a functional group including, but not limited to, hydrogen, optionally substituted (C
1
-C
6
)alkyl and optionally substituted aryl. Y, in Formula II, is a functional group including, but not limited to, O, S and NR
6
, wherein R
6
is a functional group including, but not limited to, hydrogen and optionally substituted (C
1
-C
6
)alkyl. R
4
, in Formula II, is a functional group including, but not limited to, hydrogen, halogen, optionally substituted (C
1
-C
6
)alkyl and optionally substituted (C
1
-C
6
)alkoxy. R
5
, in Formula II, is a functional group including, but not limited to, hydrogen and optionally substituted (C
1
-C
6
)alkyl. In Formula II, the index “n” is an integer from 2 to 14; the index “m” is an integer from 0 to 14; and the index “q” is an integer from 0 to 1, provided when m is 0 then q is 0, or a pharmaceutical acceptable salt or solvate thereof. Suitable salts include, but are not limited to, sodium, potassium and ammonium.
In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the Formula I wherein R, R
1
, R
2
X, Y, R
3
, R
6
, R
7
, R
8
, n, m, q and t have the same meaning as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical acceptable carrier.
In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the Formula II wherein R, R
1
, R
2
X Y, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, n, m, and q have the same meaning as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical acceptable carrier.
In yet another aspect, the present invention relates to a method of treating a PPAR&ggr; mediated disease or oxidative stress, comprising administering a therapeutically effective amount of a compound of Formulae I, II or mixtures thereof, to an individual suffering from a PPAR&ggr; mediated disease. In other aspects, this invention provides methods for synthesizing the compounds of Formulae I and II.
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patent: 4572912 (1986-02-01), Yoshioka et al.
patent: 4918091 (1990-04-01), Cantello et al.
patent: 5338855 (1994-08-01), Yoshioka et al.
patent: 5594015 (1997-01-01), Kurtz et al.
patent: 5661168 (1997-08-01), Panetta et al.
patent: 5925668 (1999-06-01), Biewenga et al.
patent: 6013663 (2000-01-01), Fujita et al.
patent: 6046228 (2000-04-01), Rice et al.
patent: 6090842 (2000-07-01), Packer et al.
patent: 08-201957 (1996-08-01), None
patent: WO 97/31907 (1997-09-01), None
Schweizer, E., et al., “Reactions of Phosphorus Compounds. XIX. Reactions of 3-(o-Formylphenoxy)propyltriphenylphosphonium Bromide and 3-(p-Formylp
Avery Mitchell A.
Pershadsingh Harrihar A.
Gerstl Robert
Townsend and Townsend / and Crew LLP
University of Mississippi
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