Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-08-24
2002-09-17
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S425000, C514S866000
Reexamination Certificate
active
06451836
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of 2-alkylpyrrolidines in the treatment of diabetes and pharmaceutical compositions containing these compounds.
BACKGROUND OF THE INVENTION
Diabetes is characterized by an impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patients. Underlying defects lead to a classification of diabetes into two major groups: type 1 diabetes, or insulin demanding diabetes mellitus (IDDM), which arises when patients lack &bgr;-cells producing insulin in their pancreatic glands, and type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), which occurs in patients with an impaired &bgr;-cell function in association with a range of other abnormalities.
Type 1 diabetic patients are currently treated with insulin. The majority of type 2 diabetic patients are treated either with sulfonylureas that stimulate &bgr;-cell function, with &agr;-glucosidase inhibitors which decrease carbohydrate uptake from the intestine in association with meals, or with agents that enhance the tissue sensitivity of the patients towards insulin or with insulin. Among the agents applied to enhance tissue sensitivity towards insulin, metformin is a representative example. Examples of &agr;-glucosidase inhibitors are acarbose and voglibose.
Even though sulfonylureas and &agr;-glucosidase inhibitors are widely used in the treatment of NMDDM, this therapy is, in most instances, not satisfactory: Thus, in a large number of NIDDM patients, sulfonylureas and &agr;-glucosidase inhibitors do not suffice to normalize blood sugar levels and the patients are, therefore, at high risk for acquiring diabetic complications. Also, many patients gradually lose the ability to respond to treatment with sulfonylureas and are gradually forced into insulin treatment. This shift of patients from oral hypoglycaemic agents to insulin therapy is usually ascribed to exhaustion of the &bgr;-cells in NIDDM patients.
In normals as well as in diabetics, the liver produces glucose in order to avoid hypoglycemia. This glucose production is derived either from the release of glucose from glycogen stores or from gluconeogenesis, which is a de novo intracellular synthesis of glucose. In type 2 diabetes, however, the regulation of hepatic glucose output is poorly controlled and is increased, and may be doubled after an overnight fast. Moreover, in these patients there exists a strong correlation between the increased fasting plasma glucose levels and the rate of hepatic glucose production (reviewed in R. A. De Fronzo:
Diabetes
37 (1988), 667-687; A. Consoli:
Diabetes Care
15 (1992), 430-441; and J. E. Gerich:
Horm.Metab.Res.
26 (1992), 18-21). Similarly, if type 1 diabetes is not properly controlled by insulin treatment, hepatic glucose production, particularly from glycogen, will be increased and result in fasting hyperglycemia.
Since existing forms of therapy of diabetes does not lead to sufficient glycaemic control and therefore are unsatisfying, there is a great demand for novel therapeutic approaches. Since the liver in diabetes is known to have an increased glucose production, compounds inhibiting this activity are highly desirable.
Recently, patents on inhibitors of the liver specific enzyme, glucose-6-phosphatase, which is necessary for the release of glucose from the liver, have been filed, for example German Offenlepunisschrift Nos. 4,202,183 and 4,202,184 and Japanese patent application No. 4-58565. All these known compounds are benzene derivatives.
International patent application having publication No. WO 92/16640 relates to di-, tri- and tetrasaccharides that are substrates or inhibitors of glycosyltransferase and glycosidase enzymes. Some specific compounds mentioned therein are 2,3,4,5-tetrahydroxypiperidine, 3,4,5-trihydroxy-6-methylpiperidine and 3,4-dihydroxy-5-methylpiperidine.
International Patent Application No. WO 92/21657 relates to certain &ohgr;-deoxyazapyranoses, e.g. 3,4-dihydroxy-5-methyl-piperidine mentioned in claim
16
thereof. It is stated that these compounds have glucosidase inhibiting properties.
European patent application having publication No. 528,495 A1 relates to a class of azacyclic compounds, i.e. compounds comprising an azacyclic ring system substituted by arylmethyloxy or an arylmethylthio moiety. These compounds may be useful as tachykinin antagonists.
European patent application having publication No. 375,651 A1 relates to 1,4-dideoxy-1,4-imino-L-allitol and derivatives thereof having glycosidase inhibitory activity.
Moreover, scientifically it is well realized that inhibition of glycogen phosphorylase is a suitable target for the treatment of diabetes (Martin et al., 1991; Biochemistry 30: 10101-16; Oikonomakos et al., 1994; Eur. J. Drug Metab. Pharmakokin. 3: 185-92). These groups have used glucose analogs.
European patent application No. 422,307 relates to preparation of N-glycosyl 1,4-dideoxy-1,4-imino-D-arabinitols as &agr;-glycosidase inhibitors. These compounds are said to be useful in the treatment of diabaetes mellitus.
European patent application No. 389,723 relates to the preparation of iminoarabinitol derivatives as &agr;-glucosidase inhibitors.
U.S. Pat. No. 4,973,602 relates to antiviral (2S,3S,4S) pyrrolidines having benzyloxycarbonyl or an optionally substituted alkylphenyl group in the 1-position. In said US patent, (2S,3S,4S)-1-([4-chlorophenyl]methyl-2-hydroxymethyl-3,4-dihydroxypyrrolidine is specifically mentioned.
European patent application No. 367,747 relates to antiviral (2S,3S,4S) pyrrolidines, e.g. (2S,3S,4S)-2-hydroxymethyl-3,4-dihydroxypyrrolidines having methyl, butyl, hexyl, nonyl, propionyl, 2-hydroxyethyl or 5-hydroxypentyl in the 1-position.
European patent application No. 322.395 describes some pyrrolidines and piperidines, which can be used for the treatment of AIDS. Examples of specific compounds mentioned therein are 2-hydroxymethyl-3,4-dihydroxypyrrolidine and the corresponding 1-methyl derivative.
One object of the present invention is to furnish compounds which can be used as medicaments.
A further object of this invention is to furnish compounds which can effectively be used in the treatment of diabetes.
A still further object of this invention is to furnish compounds which can effectively be used as inhibitors of glucose production from the liver.
A further object of this invention is to furnish compounds which can effectively be used as phosphorylase inhibitors.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to compounds of the general formula I stated in the claims below.
Surprisingly, it has been found that the compounds stated in the claims, below, have interesting pharmaco-logical properties. For example, the compounds can be used in the treatment of diabetes. Especially, the compounds are active as inhibitors of glucose production from the liver. Consequently, the compounds can be used for the treatment of the increased plasma glucose levels in diabetics.
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the term alkyl, when used alone or in combination with another moiety, is a straight or branched saturated hydrocarbon chain group which preferably contains not more than 8 carbon atoms, more preferred not more than 4 carbon atoms. Especially preferred alkyl groups are methyl, ethyl, propyl and isopropyl.
The term halogen as used herein refers to chloro, bromo or fluoro, preferably fluoro. Preferably, N-alkylamino is N-methylamino. Preferably, N,N-dialkylamino is N,N-dimethylamino. The term acyl as used herein refers to carbonyl sub-stituted with hydrogen, alkyl or phenyl. Herein, cycloalkyl preferably contains 3-7 carbon atoms, more prefered 3-6 carbon atoms. Alkoxy preferably is methoxy or ethoxy. Alkoxycarbonyl preferably is methoxycarbonyl or ethoxycarbonyl. Aralkyl preferably is benzyl. Trifluoroalkyl preferably is trifluoromethyl or 2,2,2-trifluoroethyl. Alkene preferably contains not more than 8 carbon atoms and preferably is allyl. The term “one or more” substituents preferably is 1
Jakobsen Palle
Kristiansen Marit
Lundgren Karsten
Naerum Lars
Nørskov-Lauritsen Leif
Agris, Esq. Cheryl H.
Green, Esq. Reza
Novo Nordisk A S
Weddington Kevin E.
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