Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-19
2001-07-17
Lambkin, Deborah C. (Department: 1613)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C564S440000, C564S441000, C568S031000, C568S306000, C568S424000, C568S496000
Reexamination Certificate
active
06262277
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel benzothiepines, derivatives and analogs thereof, pharmaceutical compositions containing them, and their use in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as is associated with atherosclerosis or hypercholesterolemia, in mammals.
2. Description of Related Art
It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Interfering with the circulation of bile acids within the lumen of the intestinal tract is found to reduce the levels of serum cholesterol in a causal relationship. Epidemiological data has accumulated which indicates such reduction leads to an improvement in the disease state of atherosclerosis. Stedronsky, in “Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties,”
Biochimica et Biophysica Acta,
1210 (1994) 255-287 discusses the biochemistry, physiology and known active agents surrounding bile acids and cholesterol.
Pathophysiologic alterations are shown to be consistent with interruption of the enterohepatic circulation of bile acids in humans by Heubi, J. E., et al. See “Primary Bile Acid Malabsorption: Defective in Vitro Ileal Active Bile Acid Transport”,
Gastroenterology,
1982:83:804-11.
In fact, cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation (Reihnér, E. et al, in “Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients”,
Journal of Lipid Research
, Volume 31, 1990, 2219-2226 and Suckling el al, “Cholesterol Lowering and bile acid excretion in the hamster with cholestyramine treatment”,
Atherosclerosis,
89(1991) 183-190). This results in an increase in liver bile acid synthesis by the liver using cholesterol as well as an upregulation of the liver LDL receptors which enhances clearance of cholesterol and decreases serum LDL cholesterol levels.
In another approach to the reduction of recirculation of bile acids, the ileal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption of the enterohepatic circulation with specific transport inhibitors (Kramer, et al, “Intestinal Bile Acid Absorption”
The Journal of Biological Chemistry
, Vol. 268, No. 24, Issue of August 25, pp. 18035-18046, 1993).
In a series of patent applications, eg Canadian Patent Application Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EP Application Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731, Hoechst Aktiengesellschaft discloses polymers of various naturally occurring constituents of the enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL cholesterol level sufficiently to be effective as pharmaceuticals and, in particular for use as hypocholesterolemic agents.
In vitro bile acid transportinhibition is disclosed to show hypolipidemic activity in The Wellcome Foundation Limited disclosure of the world patent application number WO 93/16055 for “Hypolipidemic Benzothiazepine Compounds”.
Selected benzothiepines are disclosed in world patent application number WO93/321146 for numerous uses including fatty acid metabolism and coronary vascular diseases.
Other selected benzothiepines are known for use as hypolipaemic and hypocholesterolaemic agents, especially for the treatment or prevention of atherosclerosis as disclosed by application Nos. EP 508425, FR 2661676, and WO 92/18462, each of which is limited by an amide bonded to the carbon adjacent the phenyl ring of the fused bicyclo benzothiepine ring.
The above references show continuing efforts to find safe, effective agents for the prophylaxis and treatment of hyperlipidemic diseases and their usefulness as hypocholesterolemic agents.
Additionally selected benzothiepines are disclosed for use in various disease states not within the present invention utility. These are EP 568 898A as abstracted by Derwent Abstract No. 93-351589; WO 89/1477/A as abstracted in Derwent Abstract No. 89-370688; U.S. Pat. No. 3,520,891 abstracted in Derwent 50701R-B; U.S. Pat. Nos. 3,287,370, 3,389,144; 3,694,446 abstracted in Derwent Abstr. No. 65860T-B and WO 92/18462.
The present invention furthers such efforts by providing novel benzothiepines, pharmaceutical compositions, and methods of use therefor.
SUMMARY OF THE INVENTION
Accordingly, among its various apects, the present invention provides compounds of formula (I):
wherein:
q is an integer from 1 to 4;
n is an integer from 0 to 2;
R
1
and R
2
are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl,
wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR
9
, NR
9
R
10
, N
+
R
9
R
10
R
w
A
−
, SR
9
, S
+
R
9
R
10
A
−
, P
+
R
9
R
10
R
11
A
−
, S(O)R
9
, SO
2
R
9
, SO
3
R
9
, CO
2
R
9
, CN, halogen, oxo, and CONR
9
R
10
,
wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR
9
, N
+
R
9
R
10
A—, S, SO, SO
2
, S
+
R
9
R
10
A
−
, P
+
R
9
R
10
A
−
, or phenylene,
wherein R
9
, R
10
, and R
w
are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, amoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammoniumalkyl; or
R
1
and R
2
taken together with the carbon to which they are attached form C
3
-C
10
cycloalkyl;
R
3
and R
4
are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR
9
, NR
9
R
10
, SR
9
, S(O)R
9
, SO
2
R
9
, and SO
3
R
9
, wherein R
9
and R
10
are as defined above; or
R
3
and R
4
together form ═O, ═NOR
11
, ═S, ═NNR
11
R
12
, ═NR
9
, or ═CR
11
R
12
,
wherein R
11
and R
12
are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR
9
, NR
9
R
10
, SR
9
, S(O)R
9
, SO
2
R
9
, SO
3
R
9
, CO
2
R
9
, CN, halogen, oxo, and CONR
9
R
10
, wherein R
9
and R
10
are as defined above, provided that both R
3
and R
4
cannot be OH, NH
2
, and SH, or
R
11
and R
12
together with the nitrogen or carbon atom to which they are attached form a cyclic ring;
R
5
and R
6
are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR
9
, SR
9
, S(O)R
9
, SO
2
R
9
, and SO
3
R
9
,
wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR
13
, NR
13
R
14
, SR
13
, S(O)R
13
, SO
2
R
13
, SO
3
R
13
, NR
13
OR
14
, NR
13
NR
14
R
15
, NO
2
, CO
2
R
13
, CN, OM, SO
2
OM, SO
2
NR
13
R
14
, C(O)NR
13
R
14
, C(O)OM, COR
13
, NR
13
C(O)R
14
, NR
13
C(O)NR
14
R
15
, NR
13
CO
2
R
14
, OC(O)R
13
, OC(O)NR
13
R
14
, NR
13
SOR
14
, NR
13
SO
2
R
14
, NR
13
SONR
14
R
15
, NR
13
Banerjee Shyamal C.
Huang Horng-Chih
Lee Len F.
Li Jinglin J.
Miller Raymond E.
G.D. Searle and Company
Lambkin Deborah C.
Williams Scott A.
LandOfFree
Intermediates and processes for the preparation of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Intermediates and processes for the preparation of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Intermediates and processes for the preparation of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2437156