CN1240351A - Use of comt inhibitors for the manufacture of a medicament for the prevention of diabetic vascular dysfunctions - Google Patents

Abstract

The invention is related to the use of COMT inhibitors in the treatment of diabetic vascular dysfunctions.

Description

The COMT inhibitor is used for purposes aspect the prevention of diabetic vascular dysfunctions medicine in preparation

The present invention relates to purposes, especially nephropathy, retinopathy and the neuropathy of catechol O-methyltransferase (COMT) inhibitor aspect the prevention of diabetic vascular dysfunctions disease.

Worldwide all seeking a kind of therapeutic agent that can prevent 1 type and type 2 diabetes mellitus complication.Chronic exposure to diabetes can make the sickness rate of microangiopathy complication raise, and it is relevant with a considerable amount of sickness rate and mortality rate.For example the imbalance of the microcirculation of foot can cause the shank amputation, and it will cause more severe complications conversely.Under the situation of diabetic nephropathy renal failure, it is actually dead reason.In the adult of youth, diabetes also are to cause the modal reason of renal failure.

The factor that causes diabetic nephropathy is widely studied, but does not make clear fully.According to general notion, the early function effect of diabetes (for example excessively filtering) is a principal element.Excessively filtering increases relevant with increase of glomerule pressure and albumin secretion speed (AER).The AER that increases is considered to the early signal of glomerular injury.

Existing the most frequently used therapeutic agent ACE inhibitor can not the prevent diabetes nephropathy development, and can only delay the development of final renal failure.Disclosed OR 462 (nitecapone), a kind of COMT inhibitor have natriuretic effect (people such as Eklof, U.S.'s nephropathy can will 5 (3), 657,1994, people such as Holtback, U.S.'s nephropathy can will 7 (9), 1633,1996).Yet, before this, do not have document to mention the COMT inhibitor for excessive filtration and albuminuretic effect.

Target of the present invention provides the purposes of COMT inhibitor, especially the purposes of OR 462 (3-(3,4-dihydroxy-5-nitrobenzophenone) methylene-2,4-pentane diketone) aspect prevention of diabetic vascular dysfunctions, for example nephropathy, retinopathy and sacred disease.The compounds of this invention can be used for the treatment of the diabetes of any kind.

Document, for example British patent 2200109, and European patent 237929 and PCT application PCT/FI96/00295 are described suitable COMT inhibitor and preparation method thereof.

When using, salt that these chemical compounds are pharmaceutically acceptable and esters can prepare with known method.The acceptable salt all can be with being active medicine on all physiology.Yet, sodium salt, potassium salt, ammonium salt, calcium salt and magnesium salt and and hydrochloric acid, hydrobromic acid, phosphoric acid and sulphuric acid and organic acid such as oxalic acid, fumaric acid, malonic acid, the salt of formation such as acetic acid and citric acid are preferred.

The effective dose of chemical compound is according to the effectiveness of this COMT-inhibitor, and the order of severity and the route of administration of the disease for the treatment of decide.Oral formulations most preferably.Be used for human effective dose and be generally about 20-2000mg/ days.

The compounds of this invention can combine administration with itself or with one or more other active component and/or suitable medicinal non-reactive additives.The latter comprises solvent, and glue forms agent, emulsifying agent, stabilizing agent, coloring agent, antiseptic, lubricant, antiseize paste, filler and widely used excipient and prescription adjuvant.

Used chemical compound can adopt method conventional in the pharmacy to make dosage form among the present invention.Dosage form can be tablet, capsule, granule, suppository, emulsifying agent, suspending agent or solution.According to route of administration and galenic dosage form, the concentration of reactive compound is between about 1-100% (w/w) in the typical formulation.

Say that for those skilled in the art the adjuvant composition of selecting to be used to fill a prescription is the work of a routine.Obviously, suitable solvent, glue forms agent, disperses to form composition, and coloring agent etc. can conventional method use.

The result

OR 462 is to the influence of renal function

Detect OR 462 3-(3,4-dihydroxy-5-nitrobenzophenone) methylene-2 in diabetes rat, 4-pentane diketone is to the influence of renal function.Tail vein injection streptozotocin (STZ) by rat brings out diabetes.Measure the concentration of glucose in the blood routinely.The hyperglycemia phenomenon of suffering from diabetes rat that participates in experiment must be apparent in view after 12 hours at injection STZ, and maintenance stable (16-25mM glucose) in the overall process of observing.Inject back 48 hours,, then it is given up if give plasma glucose concentration＜16.5mM of the not fasting rat of STZ.

OR 462 sees Table 1 to the influence of glomerular filtration speed (GFR).The clearance technique of the routine that adopts is studied rat as the GFR indicator with inulin.Provided the result of the control rats of age-matched simultaneously.Undressed diabetes rat has excessive filtering feature, does not have this feature yet handle the back through OR 462.The GFR of the diabetes rat of handling through OR 462 and the GFR of control rats are as broad as long.

Table 1 is treated with OR 462 (30mg/kg bw BID) every day

Bring out the influence (3 week) of diabetes rat with streptozotocin to GFR

GFRml/min without OR 462 treat 2.25+/-diabetes rat of 0.26* through the diabetes rat non-diabetic rat 1.59+ of OR 462 treatment 1.28+/-0.26/-every group of 0.12n=in 7-8 * with other two groups obviously different (ANOVA) are arranged

After treating every day, rats with diabetes cause the influence of albumin secretion speed (AER) to see Table 2 to suffering from OR 462.The AER of undressed trouble diabetes rat raises, and after OR 462 was handled, the appearance of diabetic complication delayed to some extent and weakens.The AER of the 50% usefulness OR 462 rat of handling all very low (promptly normal) almost.

Table 2, every day treat with OR 462 (30mg/kg bw BID)

The influence of dialogue protein secretion rates (AER)

AER mg/kg GFR3 week, without OR 462 treatment 6.18+/-1.533 weeks, process OR 462 treatment 1.20+/-1.39*6 week, without OR 462 treatment 10.9+/-2.336 weeks, through OR 462 treatment 2.33+/-2.91** is starkly lower than untreated rat.

Except the result of above-mentioned unanimity, occur in diabetes rat intestinal edema on one's body with observing characteristic further, then do not exist on one's body animal through the OR 462 treatment.

It is shocking that the dosage that obtains the needed OR 462 of desired effects is very low.This fact is illustrated by institute's column data in the table 3.To be dissolved in OR 462 (25ug/ml water=9.7mg/kg/ days) in the drinking water and give the Sprague Dawley rat that suffers from diabetes of bringing out, continuous 10 days with streptozotocin.In the time of the 10th day, measure the filtering rate of glomerule.The 7th day mornings 10 point, blood sample collection.Table 3, (be dissolved in drinking water, 9.7mg/kg) to bringing out by streptozotocin with OR 462

Suffer from that rats with diabetes is treated every day and the influence to GFR (10 days) the rat numbering disposition BW that produces takes in NC in the water yield GFR blood plasma

Ml/min ng/ml84A contrasted 281 140 3.36 in g ml/ days, and--84B contrasts 276 140 2.34, and--84C contrasts 276 140 3.31, and--85A contrasts 272 180 3.55--85B contrasts 256 180 3.87--

m272 m156 m3.29

±4 ±10 ±0.392A NC 273 100 2.38 6492B NC 289 100 2.42 5892C NC 279 100 ND 6593A NC 256 110 2.38 4393B NC 269 110 2.87 2993C NC 265 110 2.44 70

m272 m105 m2.50 m55

± 4 ± 5 ± 0.1 ± 6ND=undetermined m=is average ±=se

OR 462 is to the influence of retinopathy

Tested the ability that OR 462 weakens the biochemical marker relevant with diabetic retinopathy with the pig retina fragment epithelial cell (RPE) cultivated.Handle or handle and the content that is exposed to the Protein kinase C (PKC) under normal (5mM) or high (20mM or 50mM) concentration of glucose is measured through OR 462 in the pair cell without OR 462.Tried under the concentration under (10-40mM), OR 462 has the ability that PKC content increases in the RPE cell that glucose brings out of eliminating.This result shows that OR 462 has the effect of anti-retinopathy.

Claims (9)

1, COMT inhibitor or its pharmaceutically acceptable salt class or esters are used for the purposes of medicine aspect the prevention of diabetic vascular dysfunctions in preparation.

2, the purposes described in the claim 1, wherein said prevention is relevant with microangiopathy.

3, the purposes described in the claim 2, wherein said prevention is relevant with nephropathy and/or retinopathy.

4, the purposes described in the claim 3, wherein said prevention is relevant with the minimizing of urine protein.

5, the purposes described in the claim 1-4, COMT inhibitor wherein is an OR 462.

6, COMT inhibitor or its pharmaceutically acceptable salt class or the esters of the mammal effective dose by needing the prevention of this class, the method for preventing described diabetic vascular dysfunctions.

7, the method described in the claim 6, wherein said prevention is relevant with microangiopathy.

8, the method described in the claim 7, wherein said prevention and nephropathy and or retinopathy relevant.

9, the method described in the claim 6-8, wherein said COMT inhibitor is an OR 462.