Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-03-05
2001-01-23
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S307000, C546S114000, C546S144000, C546S146000, C546S150000
Reexamination Certificate
active
06177443
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine derivatives, to methods for their preparation, to compositions comprising the compounds, to the use of these compounds as medicaments and their use in therapy, e.g. to their use for treatment of humain and animal disorders. The invention relates to modulation of the activity of molecules with glucose-6-phosphate recognition units, including glucose-6-phosphatases (G-6-Pases) in in vitro systems, microorganisms, eukaryotic cells, whole animals and human beings, especially in the treatment of diseases related to glucose metabolic pathways.
BACKGROUND OF THE INVENTION
Glucose is the major energy substrate in mammals and regulation of blood glucose levels within a narrow range seems to be of crucial importance to devoid serious physiological complications as seen in diabetes (DeFronzo, Bonadonna, & Ferrannini. 1992). Blood glucose homeostasis is maintained by dietary intake of carbohydrates, the uptake of glucose by peripheral tissues and the brain, and storage or release of glucose from the liver. The liver therefore seems to play a major role in the homeostatic regulation of blood glucose levels, Gluconeogenesis and glycogenolysis are the two metabolic pathways from which glucose can be produced in the liver. These pathways are under tight hormonal control. Insulin resistance and insulin deficiency have a substantial impact on glucose production in the liver (Consoli. 1992; DeFronzo, Bonadonna, & Ferrannini. 1992; Clore, Stillman, Stevens, Blackard, Levy, & Richmond. 1996). Glucose-6-phosphatase (G-6-Pase) catalyses the terminal step in the above mentioned pathways by converting glucose-6-phosphate (G-6-P) to glucose, and is largely situated in the liver, with some expression in the kidney after prolonged fasting. The G-6-Pase is a multicomponent system comprising of the G-6-Pase catalytic enzyme with its active site located at the luminal site of the endoplasmic reticulurn (microsomal fraction), a specific transporter TI which mediates entry of G-6-P into the luminal compartment, and transporter T2 and T3 which mediates export to the cytosol of inorganic phosphate and glucose, respectively (Nordlie, Bode, & Foster. 1993; Sukalski & Norcllie. 1989). It has been shown that the rate of hydrolysis of G-6-P and the hepatic glucose output were increased under diabetic conditions (Lyall, Grant, Scott, & Burchell. 1992; DeFronzo, Bonadonna, & Ferrannini. 1992). The increased activity could mainly be accounted for by increased G-6-Pase catalytic enzyme protein (Argaud, Zhang, Pan, Maitra, Pilkis, 4& Lange. 1996; Burchell & Cain. 1985). This makes G-6-Pase enzyme a potential target in control of excess glucose production seen in diabetes.
BIBLIOGRAPHY
Argaud, D., Zhang, Q., Pan, W., Maitra, S., Pilkis, S. J., & Lange, A. (1996). Regulation of rat liver glucose-6-phosphatase gene expression in different nutritional and hormonal states,.
Diabetes,
45:1563-1571.
Arion, J. M., Lange, A. J., & Walls, H. E. (1980). Microsomal membrane integrity and the interactions of phlorizin with the glucose-6-phosphatase system.
J Biol Chem,
255:10387-10395.
Burchell, A., & Cain, D. I. (1985). Rat hepatic microsomal glucose-6-phosphatase protein levels are increased in streptozotocin-induced diabetes.
Diabetologia,
28: (852). 856 Clore, J. N., Stillman, J. S., Stevens, W., Blackard, W. G., Levy, J., & Richmond, V. A. (1996). Chronic hyperinsulinemia supresses glucose-6-phosphatase mRNA.
Diabetes,
44 (suppl 1):253A
Consoli, A. (1992). Role of liver in pathophysiology of NIDDM.
Diabetes Care,
15:430-441.
DeFronzo, R. A., Bonadonna, R. C., & Ferrannini, E. (1992). Pathogenesis of NIDDM: A Balanced overview.
Diabetes Care,
15:318-368.
Lyall, H., Grant, A., Scott, H. M., & Burchell, A. (1992). Regulation of the hepatic microsomal glucose-6-phosphatase enzyme.
Biochem Soc Trans,
20, 271S (abstract).
Nordlie, R. C., Bode, A. M., & Foster, J. D. (1993). Recent advances in hepatic glucose 6-phosphatase regulation and function.
Proc Soc Exp Biol Med,
203:274-285.
Sukalski, K. A., & Nordlie, R. C. (1989). Glucose-6-phosphatase: Two concepts of membrane function relationship. In A. Meister (Ed.),
Advances in Enzymology and related areas of molecular biology.
(pp. 93-117). New York: John Wiley and Sons.
DESCRIPTION OF THE INVENTION
The present invention relates to compounds of the general formula I:
wherein
A together with the double bond of formula I forms a cyclic system selected from the group consisting of benzene, thiophene, furan, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, indole, pyrazole, imidazole, oxazole, isoxazole or thiazole,
R
1
is C
1-6
-alkyl, or aryl, optionally substituted with one or more substituents,
R
2
is C
1-6
-alkyl, aralkyl, or COR
3
optionally substituted with one or more substituents,
R
3
is C
1-6
-alkyl, aralkyl, or aryl, optionally substituted with one or more substituents,
R
4
and R
5
independently are hydrogen, halogen, perhalomethyl, optionally substituted C
1-6
-alkyl, hydroxy, optionally substituted C
1-6
-alkoxy, nitro, cyano, amino, optionally substituted mono- or di-C
1-6
-alkylamino, acylamino, C
1-6
-alkoxycarbonyl, carboxy or carbamoyl,
n is 0, 1, or 2, and
m is 0, 1,or 2,
or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form.
Within its scope the invention includes all isomers of compounds of formula I, some of which are optically active, and also their mixtures including racemic mixture thereof.
The scope of the invention also includes all tautomeric forms of the compounds of formula I.
The compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, acetic, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, methanesulfonic, ethanesulfonic, picric and the like, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference; pharmaceutically acceptable metal salts, such as lithium, sodium, potassium, or magnesium salts and the like; or—optionally alkylated—ammonium salts; or amine salts of the compounds of this invention, such as the sodium, potassium, C
1-6
-alkylamine, di (C
1-6
-alkyl) amine, tri (C
1-6
-alkyl) amine and the four (4) corresponding omegahydroxy analogues (e.g. methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, triethylamine, tripropylamine, di(hydroxyethyl)amine, and the like; Also intended as pharmaceutically acceptable acid addition salts are the hydrates which the present compounds are able to form. The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
The term “C
1-6
-alkyl” as used herein, alone or in combination, refers to a straight or branched, saturated or unsaturated hydrocarbon chain. The C
1-6
-alkyl residues include aliphatic hydrocarbon residues, unsaturated aliphatic hydrocarbon residues, alicyclic hydrocarbon residues. Examples of the aliphatic hydrocarbon residues include saturated aliphatic hydrocarbon residues having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl, isopentyl, neopentyl, tert.pentyl, n-hexyl, isohexyl. Example of the unsaturated aliphatic hydrocarbon residues include those having 2 to 6 carbon atoms such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
Demuth Helle
Heide Morten
Lundbeck Jane Marie
Madsen Peter
Naerum Lars
Gregg, Esq. Valetta
Nelson Steven T.
Novo Nordisk A S
Seaman D. Margaret
LandOfFree
4,5,6,7-tetrahydro-thieno[3, 2-C]pyridine... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 4,5,6,7-tetrahydro-thieno[3, 2-C]pyridine..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 4,5,6,7-tetrahydro-thieno[3, 2-C]pyridine... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2521590