Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-18
2003-11-18
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S193000
Reexamination Certificate
active
06649628
ABSTRACT:
An O-(3-piperidino-2-hydroxy-1-propyl) hydroxymic acid halide derivative, its application in the treatment of insulin resistance, and the pharmaceutical preparation containing this derivative as effective agent.
TECHNICAL FIELD OF THE INVENTION
The invention relates to an O-(3-piperidino-2-hydroxy-1-propyl) hydroxymic acid halide derivative, the pharmaceutical use thereof and the pharmaceutical products containing this derivative as active ingredient. Namely, the invention relates to N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, as well as their acid addition salts. Furthermore, the invention also relates to the use of these compounds in the treatment of insulin resistance and the pharmaceutical products containing these derivatives as active ingredient.
BACKGROUND OF THE INVENTION
O-(3-piperidino-2-hydroxy-1-propyl) hydroxymic acid halide derivatives are already known from European Patent Specification No. 0 417 210 B1. According to this patent specification, these compounds exhibit a selective beta blocking effect and are thus suitable for the treatment of diabetic angiopathy, more specifically, of diabetic retinopathy and nephropathy.
According to PCT Publication WO 98/06400, the O-(3-piperidino-2-hydroxy-1-propyl) hydroxymic acid halide derivatives and other compounds of similar structure are effective in protecting and regenerating vascular endothelial cells, and are thus suitable active agents for the treatment of diseases caused by the dysfunction of the endothelium.
The chaperon-expression increasing effect of several hydroxylamine derivatives. among them of the O-(3-piperidino-2-hydroxy-1-propyl) hydroxymic acid halides, and the use of these, compounds in the treatment of diseases connected with the functioning of the chaperon system are known from WO 97/16439. In this patent application, O-(3-piperidino-2-hydroxy-1-propyl)-3-pyridyl hydroxymic acid chloride N-oxide derivatives (among others) are defined and claimed as new compounds, however, the production procedure is only described for piperidine-N-oxide and for the compound containing N-oxide groups both in the piperidine and pyridine rings. The compound of the present invention is not mentioned in the above application.
Insulin resistance is a pathological condition that blocks the effects of insulin. It is generally associated with diabetes, although its formation is also possible independently. Due to insulin resistance, the body needs higher and higher concentrations of insulin for carbohydrate, lipid and protein metabolism, which leads to an extremely high concentration of insulin. A long-lasting high insulin concentration has been proven to be an independent cardio-cerebro-vascular risk factor.
The reduction of insulin resistance is essential in both types of diabetes: in case of diabetes type 2, it is present as a major ethiological factor, while in case of diabetes type 1, insulin resistance is caused by glucose toxicity as well as excessive amounts of insulin applied exogenously for therapeutical purposes.
Several active agents have been provided for the reduction of insulin resistance. Among these, the most significant ones are the insulin sensitizer products, the best known agent therefrom being troglitazone, a member of the thiazolidine-dione group. (A. R. Saltiel et al., Diabetes 45/12/1996 pp. 1661-1669, and S. Kumar et al., Diabetologia 1996/39/6 pp. 701-709). The main effect of this compound is the reduction of insulin resistance by lowering peripheral insulin concentrations both in basal state and after glucose stimulation. As a result, it improves carbohydrate metabolism as well as corrects a number of pathological deviations arising as the secondary effect of high insulin level, such as hyperlipidaemia and pathological hemostasis. Its ultimate positive effect is the reduction of the cardiovascular risk. A. disadvantage is, however, that it may cause serious, mainly hepatotoxic side effects therefore its application is limited and requires due caution.
SUMMARY OF THE INVENTION
During studies in the area of O-(3-piperidino-2-hydroxy-1-propyl) hydroxymic acid halides, detailed examination of the maleate of O-(3-piperidino-2-hydroxy-1-propyl)-3-pyridyne hydroxymic acid-chloride, known as bimoclomol has been performed and found that its most significant effect is on the pathological consequences of chronic neuropathy: it significantly improves motoric and sensory nerve conduction velocity deficits in diabetes, and also favorably effects pathological deviations resulting from autonomous neuropathy. Furthermore, both in animal experiments and in phase II tests on humans, it reduces pathological diabetic urinary albumin excretion, and in the animal tests it reduces pathological histological and electrophysiological alterations resulting from diabetic retinopathy. However, in the reduction of insulin resistance bimoclomol was not effective.
At present, no medicinal products are available which could reduce insulin resistance and at the same time effectively cure deviations resulting from all three chronic diabetic complications.
In a search for suitable active materials, N-oxide derivatives of bimoclomol were tested for biological acitvity. In a preliminary test the effectiveness of the three N-oxide derivatives of bimoclomol on motor and sensor neuropathy in STZ diabetic Wistar rats were studied. The effectiveness of the three bimoclomol N-oxide derivatives in improving the peripheral motor and sensor nerve conduction velocity deficit caused by streptozotocine-induced diabetes was determined with use of the method described in detail in Experiment 2. The results are summarized in the following table.
Improvement of nerve
conduction velocity (%)
Group
n
motor (MNCV)
sensor (SNCV)
bimoclomol 20 mg/kg
7
72,4
66,9
pyridine N-oxide derivative of
8
66,5
63,4
bimoclomol 5 mg/kg
piperidine N-oxide derivative of
8
34,7*
27,3**
bimoclomol 5 mg/kg
double N-oxide derivative of
8
25,9*
29,1**
bimoclomol 5 mg/kg
*p < 0,05 related to bimoclomol
**p < 0,01 related to bimoclomol
As it appears from the above results, the pyridine N-oxide derivative of bimoclomol is equivalent with bimoclomol while the two other N-oxide derivatives have significantly weaker effect on the motor and sensor neuropathy. Based on this experience, investigations were continued with the pyridine N-oxide derivative of bimoclomol, namely N-[2-hydroxy-3-(1-piperidinyl)-1-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.
Our investigations yielded the unexpected result that N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride reduces peripheral insulin resistance in addition to exhibiting an effect equal to or in some cases greater than that of bimoclomol in the treatment of the above mentioned three main diabetic complications. Due to this characteristic, the compound is suitable for the treatment of chronic diabetic complications, especially of retinopathy, neuropathy and nephropathy, and for the simultaneous reduction of peripheral insulin resistance, but it is also suitable for the treatment of non-diabetic pathological insulin resistance and any pathological conditions related to it.
The favorable biological properties of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride were proven by the following experiments. For these tests, the maleate of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride or the maleate of the suitable optically active compound were used as test compounds. In the description of the experiments, the maleate of the racemic compound is referred to as Compound A, while the maleate of the optically active stereoisomer is always specifically indicated.
EXPERIMENT 1
Effect of Treatment by Compound A and Bimoclomol on Carbohydrate Metabolism in Obese, Insulin Resistant, Hyperinsulinaemic Zucker fa/fa Rats with Impaired Glucose Tolerance, Following a 2-Month Treatment.
Materials and Methods
In the exper
Barabás Mihály
Bíró Katalin
Csákai Zita
Kardos Mihályné
Komáromi András
Biorex Kutato es Fejleszto RT
Chang Ceila
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
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