Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-06
2004-01-06
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S375000, C546S203000, C548S217000, C548S253000
Reexamination Certificate
active
06673815
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel substituted acid derivatives which modulate blood glucose levels, triglyceride levels, insulin levels and non-esterified fatty acid (NEFA) levels, and thus are particularly useful in the treatment of diabetes and obesity, and to a method for treating diabetes, especially Type 2 diabetes, as well as hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, atherosclerosis and related diseases employing such substituted acid derivatives alone or in combination with another antidiabetic agent and/or a hypolipidemic agent and/or other therapeutic agents.
DESCRIPTION OF THE INVENTION
In accordance with the present invention, substituted acid derivatives are provided which have the structure I
wherein
m is 0, 1 or 2; n is 0, 1 or 2;
Q is C or N;
A is (CH
2
)
x
where x is 1 to 5; or A is (CH
2
)
x
1
where x
1
is 2 to 5, with an alkenyl bond or an alkynyl bond embedded anywhere in the chain; or A is —(CH
2
)
x
2
—O—(CH
2
)
x
3
— where x
2
is 0 to 5 and x
3
is 0 to 5, provided that at least one of x
2
and x
3
is other than 0;
X
1
is CH or N;
X
2
is CR
a
, NR
b
, O or S;
X
3
is CR
c
or NR
d
;
X
4
is CR
e
, NR
f
, O or S, wherein R
a
, R
c
and R
e
are the same or different and are independently selected from a single bond, H, alkyl, alkoxy, aryl, cycloalkyl, amino or substituted amino, and R
b
, R
d
and R
f
are the same or different and are independently selected from a single bond, H, alkyl, aryl, heteroaryl, cycloalkyl or cycloheteroalkyl, provided that at least one of X
2
, X
3
and X
4
is
E is O, S, NR
g
or CR
h
;
M is NR
i
or CR
j
;
G is O, S, NR
k
or CR
l
, wherein R
g
, R
i
and R
k
are the same of different and are independently selected from a single bond, H, alkyl, aryl, heteroaryl, cycloalkyl or cycloheteroalkyl, and R
h
, R
j
and R
l
are the same or different and are independently selected from a single bond, H, alkyl, alkoxy, aryl, cycloalkyl, amino or substituted amino;
provided that at least one of E, M and G is other than CH or C;
and where E, M and G are each
then A is other than —CH
2
—O—; and where in each of X
1
through X
4
as defined above, C may include CH;
R
1
is H or alkyl;
R
2
is H, alkyl, alkoxy, halogen, amino or substituted amino;
R
2a
, R
2b
and R
2c
may be the same or different and are selected from H, alkyl, alkoxy, halogen, amino or substituted amino;
R
3
is selected from aryloxycarbonyl, alkyloxycarbonyl, alkynyloxycarbonyl, alkenyloxycarbonyl, alkyl(halo)aryloxycarbonyl, alkyloxy(halo)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, alkylsulfonyl, alkenylsulfonyl, heteroaryloxycarbonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, hydroxyalkyl, alkoxy, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, haloalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, aryloxyaryloxycarbonyl, heteroaryloxyarylalkyl, aryloxyarylalkyloxycarbonyl, arylalkenyloxycarbonyl, aryloxyalkyloxycarbonyl, arylalkylsulfonyl, arylthiocarbonyl, arylalkenylsulfonyl, heteroarylsulfonyl, arylsulfonyl, heteroarylalkoxycarbonyl, heteroarylalkyloxyarylalkyl, arylalkenylarylalkyl, heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, or polyhaloalkylaryloxycarbonyl;
Y is CO
2
R
4
(where R
4
is H or alkyl, or a prodrug ester) or Y is a C-linked 1-tetrazole, a phosphinic acid of the structure P(O)(OR
4a
)R
5
(R
5
is alkyl or aryl) or a phosphonic acid of the structure P(O)(OR
4a
)
2
(where R
4a
is H or a prodrug ester);
(CH
2
)
x
, (CH
2
)
x
1
, (CH
2
)
x
2
, (CH
2
)
x
3
, (CH
2
)
m
, and (CH
2
)
n
may be optionally substituted with 1, 2 or 3 substituents;
including all stereoisomers thereof, prodrug esters thereof, and pharmaceutically acceptable salts thereof.
Preferred compounds of formula I of the invention have the structure
More preferred are compounds of formula I of the invention having the structure
Still more preferred are compounds of formula I of the invention having the structures
In the above compounds, it is preferred that R
2a
is H or alkoxy, but more preferably H, (CH
2
)
x
is CH
2
, (CH
2
)
2
, (CH
2
)
3
, or
(CH
2
)
m
is CH
2
, or
(where R
a
is alkyl such as methyl, or alkenyl such as
(CH
2
)
n
is CH
2
, R
1
is lower alkyl, preferably CH
3
, R
2
is H, R
2a
is H, R
4
is H, X
1
is CH, and R
3
is arylalkyloxycarbonyl, aryloxycarbonyl, haloaryloxycarbonyl, alkoxyaryloxycarbonyl, alkylaryloxycarbonyl, aryloxyaryloxycarbonyl, heteroaryloxyarylalkyl, heteroaryloxycarbonyl, arylalkenyloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylalkylsulfonyl, arylalkenylsulfonyl, arylthiocarbonyl, cycloheteroalkylalkyloxycarbonyl, cycloheteroalkyloxycarbonyl, or polyhaloalkylaryloxycarbonyl, wherein the above preferred groups may be optionally substituted, such as
where Z is alkoxy, alkyl or halo.
Preferred examples of the group
More preferred are compounds of formula I of the invention having the structure
Preferred compounds of the invention include the following:
In addition, in accordance with the present invention, a method is provided for treating diabetes, especially Type 2 diabetes, and related diseases such as insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, inflammation, Syndrome X, diabetic complications, dysmetabolic syndrome, atherosclerosis and related diseases wherein a therapeutically effective amount of a compound of structure I is administered to a human patient in need of treatment.
In addition, in accordance with the present invention, a method is provided for treating early malignant lesions (such as ductal carcinoma in situ of the breast and lobular carcinoma in situ of the breast), premalignant lesions (such as fibroadenoma of the breast and prostatic intraepithelial neoplasia (PIN), liposarcomas and various other epithelial tumors (including breast, prostate, colon, ovarian, gastric and lung), irritable bowel syndrome, Crohn's disease, gastric ulceritis, and osteoporosis, and proliferative diseases such as psoriasis, wherein a therapeutically effective amount of a compound of structure I is administered to a human patient in need of treatment.
In addition, in accordance with the present invention, a method is provided for treating diabetes and related diseases as defined above and hereinafter, wherein a therapeutically effective amount of a combination of a compound of structure I and another type antidiabetic agent and/or a hypolipidemic agent, and/or lipid modulating agent and/or other type of therapeutic agent, is administered to a human patient in need of treatment.
In the above method of the invention, the compound of structure I will be employed in a weight ratio to the antidiabetic agent (depending upon its mode of operation) within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 10:1.
DETAILED DESCRIPTION OF THE INVENTION
The conditions, diseases, and maladies collectively referenced to as “Syndrome X” or Dysmetabolic Syndrome (as detailed in Johanson,
J. Clin. Endocrinol. Metab.,
1997, 82, 727-734, and other publications) include hyperglycemia and/or prediabetic insulin resistance syndrome, and is characterized by an initial insulin resistant state generating hyperinsulinemia, dyslipidemia, and impaired glucose tolerance, which can progress to Type II diabetes, characterized by hyperglycemia, which can progress to diabetic complications.
The term “diabetes and related diseases” refers to Type II diabetes, Type I diabetes, impaired glucose tolerance, obesity, hyperglycemia, Syndrome X, dysmetabolic syndrome, diabetic complications and hyperinsulinemia.
The conditions, diseases and maladies collectively referred to as “diabetic complications” include retinopathy, neuropathy and nephropathy, and other known complications of diabetes.
The term “other type(s) of therapeutic agents” as employ
Devasthale Pratik
Jeon Yoon T.
Bristol--Myers Squibb Company
McKane Joseph K.
Rodney Burton
Small Andrea D.
LandOfFree
Substituted acid derivatives useful as antidiabetic and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted acid derivatives useful as antidiabetic and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted acid derivatives useful as antidiabetic and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3202485