CN101270084A

CN101270084A - Novel pitavastatin nitryl ester derivant

Info

Publication number: CN101270084A
Application number: CNA2008101124241A
Authority: CN
Inventors: 姚勇敢
Original assignee: Beijing Rundekang Medical Technology Co Ltd
Current assignee: Beijing Rundekang Medical Technology Co Ltd
Priority date: 2008-05-23
Filing date: 2008-05-23
Publication date: 2008-09-24

Abstract

The present invention provides novel pitavastatin nitro ester derivative that is shown in the formula (I). The derivative comprises acceptable salt, hydrate or solvolyte in the pharmacy. In the formula (I), X stands for O, S and NH; R has a bivalent group defined as follows: (a) alkyl or substitutional alkyl with 1 to 20 carbon atoms that can be freely substituted by one or more than one substitutional group; or amino group with 3 to 7 carbon atoms that can be substituted by one or more than one substitutional group; (b) amino acid residue containing hydroxyl, such as serine and threonine residue; (c) n standing for an integral from 0 to 20 and m standing for an integral from 0 to 20.

Description

A kind of novel pitavastatin nitryl ester derivant

Technical field

The present invention relates to a kind of novel pitavastatin nitryl ester derivant, belong to medical technical field.

Background technology

Blood fat is that people's blood the inside is that some fat are arranged, and these fat mainly are these two kinds of cholesterol, triglyceride level, also have a kind of lipoid that cries in addition, and lipoid comprises that phosphatide, glycolipid also have steroid here, and these are generically and collectively referred to as blood fat.Hyperlipidaemia is that cholesterol, triglyceride level and the low-density lipoprotein white level in the blood plasma that is caused by a variety of causes raises and a kind of disease of a kind of whole body matter metabolic disturbance that high-density lipoprotein (HDL) is low excessively, clinical five types of I, II, III, IV, the V that are divided into, any type matter metabolic disturbance is all returned and is caused certain specific lipoprotein to raise in five types, by judging the rising of which type lipoprotein, just can judge it is the hyperlipidaemia of which kind, modal is II and IV type.

The general performance of hyperlipidemia is not clearly.Most hyperlipidaemias oneself is sensation not, is mostly when having a physical examination, and is found when perhaps doing the other diseases inspection.The main performance that hyperlipidemia occurs is a complication; as can be concurrent a lot of other diseases of hyperlipidemia; the problem of concurrent arteriosclerotic, concurrent heart, the problem of brain blood supply occurs or dysfunction of liver occurs or pancreatitis due to hyperlipidemia that kidney has gone wrong even had, these all may become the symptom of hyperlipidaemia.The somebody has xanthoma on the face, is exactly that lipoma can go out two xanchromatic spots on the eyes eyelid, and this is an xanthoma, and these symptoms all are the symptoms of hyperlipidaemia.

At present, Chang Yong fat-reducing medicament has manyly clinically, concludes and to get up can be divided into substantially five big classes, is respectively Statins, shellfish spy class, nicotinic acid class, cholic acid chelating agent and cholesterol absorption inhibitor.Wherein Statins is a most widely used class fat regulation medicine, mainly contains lovastatin, Simvastatin, Pravastatin, fluvastatin and atorvastatin.The mechanism of stanin fat-reducing effect is thought at present because such rate-limiting enzyme that can suppress the synthetic commitment of cell inner cholesterol is the HMG-CoA reductase enzyme, cause the endocellular liberation cholesterol to reduce, and raise the expression of cell surface ldl receptor by feedback, thereby cell ldl receptor number increased and increased activity, quickened the removing of the residual grain of VLDL (or IDL) and LDL in the blood circulation.Yet any medicine all has its duality, i.e. therapeutic action and untoward reaction.Fat-reducing medicament is no exception equally, and especially fat-reducing medicament generally all needs to take the long period and could obtain good prevention effect, so, more can not ignore its untoward reaction patient.

Summary of the invention

The invention provides the novel pitavastatin nitryl ester derivant shown in the formula (I), comprise its pharmaceutically acceptable pharmaceutical salts or hydrate, solvate:

Formula (I)

Wherein X represents O, S, NH, and R has the divalent group as giving a definition:

G) carbonatoms is alkyl or the substituted alkyl of 1-20, can randomly be replaced by one or more substituting groups, or to represent carbonatoms is the cycloalkyl of 3-7, can randomly be replaced by one or more substituting groups;

H) amino-acid residue of hydroxyl such as Serine, threonine residues;

i)

Wherein n is the integer of 0-20, and m is the integer of 0-20;

Wherein preferred compound has, pitavastatin 4-(nitrooxy) butyl ester (I1); Pitavastatin 4-(nitrooxy methyl) benzyl ester (I2); Pitavastatin 2-(nitrooxy methyl) benzyl ester (I3).

The present invention also comprises the medicinal compositions that contains described compound, and said composition is that main active ingredient and pharmaceutical excipient form with any one compound of the present invention, and said composition can be made various oral preparations as required, preferred tablet, capsule,

Compound of the present invention can be used for preparing the medicine of reducing cholesterol and triglyceride levels.It is diseases related to be mainly used to treat hypercholesterolemia and familial hypercholesterolemia and other and hyperlipidemia.Take 1～2mg after 1 dinner every day.According to age and symptom adjustment dosage.Maximal dose 4mg/ day.Described compound is compared lipid-lowering statins commonly used at present, and not only consumption is little, and is evident in efficacy, and can significantly reduce untoward reaction, suitable prolonged application.In addition by to compound of the present invention discover that further this compounds not only can obviously reduce the blood ester, also have the effect of anti-inflammatory, antithrombotic, protection cardio and vascular function.

Embodiment

The preparation of embodiment 1 pitavastatin 4-(nitrooxy) butyl ester (I1)

8.9g is dissolved among the 60mlDMF with pitavastatin sodium, and the ice-water bath cooling drips 1,4-dibromobutane 6.5g-30mlDMF solution.Be warming up to room temperature reaction 22h after drip finishing.Be evaporated to driedly, add entry and ether, be concentrated into dried behind the organic phase anhydrous sodium sulfate drying.Cross post, sherwood oil: ethyl acetate=3: 1 wash-outs, collect required component, evaporated under reduced pressure obtains pitavastatin 4-bromine butyl ester.

The above-mentioned pitavastatin 4-bromine butyl ester that obtains with the dissolving of 100ml acetonitrile, is added Silver Nitrate 3.4g, lucifuge stirring at room reaction 48h.Filter, filtrate decompression is concentrated into dried, crosses post, sherwood oil: ethyl acetate=1: 2 wash-out, collect required component, and evaporated under reduced pressure obtains pitavastatin 4-(nitrooxy) butyl ester 4.9g.Ultimate analysis C ₂₉H ₃₁FN ₂O ₇Calculated value (, %): C 64.68, and H 5.76, and N 5.20; Measured value (, %): C 64.51, and H 5.82, and N 5.06.

The preparation of embodiment 2 pitavastatin 4-(nitrooxy methyl) benzyl esters (I2)

8.9g is dissolved among the 60mlDMF with pitavastatin sodium, and the ice-water bath cooling drips xylylene dichlorides 7.0g-30mlDMF solution.Be warming up to room temperature reaction 24h after drip finishing.Be evaporated to driedly, add entry and ethyl acetate, be concentrated into dried behind the organic phase anhydrous sodium sulfate drying.Cross post, sherwood oil: ethyl acetate=1: 1 wash-out, collect required component, evaporated under reduced pressure obtains pitavastatin 4-chloromethyl benzyl ester.

The above-mentioned pitavastatin 4-chloromethyl benzyl ester that obtains with the dissolving of 80ml acetonitrile, is added Silver Nitrate 4.0g, lucifuge stirring at room reaction 48h.Filter, filtrate decompression is concentrated into dried, crosses post, sherwood oil: ethyl acetate=1: 1 wash-out, collect required component, and evaporated under reduced pressure obtains pitavastatin 4-(nitrooxy methyl) benzyl ester 3.4g.Ultimate analysis C ₃₃H ₃₁FN ₂O ₇Calculated value (, %): C 67.58, and H 5.29, and N 4.78; Measured value (, %): C 67.73, and H 5.46, and N 4.82.

The preparation of embodiment 3 pitavastatin 2-(nitrooxy methyl) benzyl esters (I3)

8.9g is dissolved among the 60mlDMF with pitavastatin sodium, and the ice-water bath cooling drips adjacent xylylene dichlorides 7.0g-30mlDMF solution.Be warming up to room temperature reaction 24h after drip finishing.Be evaporated to driedly, add entry and ethyl acetate, be concentrated into dried behind the organic phase anhydrous sodium sulfate drying.Cross post, sherwood oil: ethyl acetate=1: 1 wash-out, collect required component, evaporated under reduced pressure obtains pitavastatin 2-chloromethyl benzyl ester.

The above-mentioned pitavastatin 2-chloromethyl benzyl ester that obtains with the dissolving of 80ml acetonitrile, is added Silver Nitrate 3.6g, lucifuge stirring at room reaction 48h.Filter, filtrate decompression is concentrated into dried, crosses post, sherwood oil: ethyl acetate=1: 1 wash-out, collect required component, and evaporated under reduced pressure obtains pitavastatin 2-(nitrooxy methyl) benzyl ester 2.9g.Ultimate analysis C ₃₃H ₃₁FN ₂O ₇Calculated value (, %): C 67.58, and H 5.29, and N 4.78; Measured value (, %): C 67.41, and H 5.48, and N 4.87.

Embodiment 4

Pharmacological evaluation 1: fall the ester effect

1. experimental technique:

1.1 animal grouping and administration: 60 Wistar rats, male, body weight (180 ± 20) g is divided into 7 groups at random at the laboratory endoadaptation after 1 week, 10 every group.That is: the basal feed blank is organized (blank), high lipid food model group (model) (cholesterol 2%, cholate 0.2%, Thyreostat I 0.2%, lard 10%, basal feed 87.6%), lovastatin control group (0.010gkg), I ₁Group, I ₂Group, I ₃Group.Experiment beginning is fed except that the blank group and to be raised the basal feed, and other each groups are all fed and raised high lipid food, begins to irritate stomach (ig) administration, every day 3 times after raising for 1 week feeding.Capacity distilled water such as model group and blank group ig.1.2 sample collecting: after each organizes 4 weeks of administration, extract rat eye behind the last administration 12h and get blood, the centrifugal 10rain of 3500rrain extracts supernatant liquor, measure TC, TG, LDL-c, HDL-c in strict accordance with the test kit process specifications, apo-AI, apo-B, ALT, AST content.

2. liver changes

2.1 liver lipid assay: get each mouse liver same area hepatic tissue 0.2g, add chloroform one methyl alcohol (1: 1) 4mL, 3d is soaked in homogenate, and nylon net filter, evaporate to dryness are with Virahol 5mL dissolving.Press the test kit specification sheets and survey liver TC, TG content.

2.2 liver SOD is measured: other gets under each mouse liver organization 1g ice bath low temperature, adds water and makes 10% homogenate, presses the test kit specification sheets and measures the SOD activity, measures absorbancy wavelength 595nm with Xylene Brilliant Cyanine G protein determination method.Calculation formula:

3 results

3.1 Blood Lipid

The model group Serum TC, TG, LDL-c all have obvious rising, with the blank group than P＜0.05 or P＜0.01, illustrate that model sets up.Compare with model group, lovastatin and each invention compound group all have reduction in various degree.Each invention compound group effect is better than the lovastatin group.The results are shown in Table 1.

Table 1 respectively organize the influence that rat blood serum lipid changes (x ± s, n=10)

3.2 liver function, liver lipid and SOD change: serum alt and AST can react liver function, and ALT and AST organize apparently higher than blank in the high lipid food group rat blood serum, and (P＜0.05 or P＜0.01) illustrates that high lipid food has certain damage to rat liver.And each administration group ALT and AST have obvious reduction.TC in the liver, TG also have obvious reduction, and active each the administration group of SOD has rising trend in the liver cell, the results are shown in Table 2.

Table 2 respectively organize rats'liver function and liver fat influence (x ± s, n=10)

Pharmacological evaluation 2: anti thrombotic action

1. experimental technique: 50 of healthy male Wistar rats, body weight 254 ± 16g is divided into 5 groups (10 every group): (1) control group (distilled water 10ml/kg) at random; (2) lovastatin group (0.2mg/kg); (3) 1 group of Compound I (0.02mg/kg); (4) 2 groups of Compound I (0.02mg/kg); (5) 3 groups of Compound I (0.02mg/kg).Control group is irritated stomach with the distilled water of 10ml/kg the weight of animals, and all the other groups are all used corresponding equal-volume suspendible medicine liquid irrigation stomach, and continuous 7 days, once a day, and 1h after the last administration, rat is anaesthetized with 3% vetanarcol intraperitoneal administration.Belly median incision is cut the abdominal cavity, peels off postcava, with left renal vein below thick line ligation postcava, sews up the abdominal cavity, behind the ligation 4h, put to death rat, open the abdominal cavity, folder stopped pipe chamber, 2cm place below ligation, take out hemostasis section blood vessel, cut tube chamber open, removal of thromboses is placed on the filter paper.Blot blood, take by weighing wet weight of thrombus (mg), then thrombus is at room temperature placed 24h, take by weighing thrombus dry weight (mg) with micro-electronic balance.

2. experimental result:, see Table 3 to the thrombotic influence of rats in vitro

The thrombotic influence of table 3 pair rats in vitro (x ± s, n=10)

Claims

1: the invention provides the novel pitavastatin nitryl ester derivant shown in the formula (I), comprise its pharmaceutically acceptable pharmaceutical salts or hydrate, solvate:

Formula (I)

D) carbonatoms is alkyl or the substituted alkyl of 1-20, can randomly be replaced by one or more substituting groups, or to represent carbonatoms is the cycloalkyl of 3-7, can randomly be replaced by one or more substituting groups;

E) amino-acid residue of hydroxyl such as Serine, threonine residues;

f)

Wherein n is the integer of 0-20, and m is the integer of 0-20.

2: the formula of claim 1 (I) compound is preferably pitavastatin 4-(nitrooxy) butyl ester (I1).

3: the formula of claim 1 (I) compound is preferably pitavastatin 4-(nitrooxy methyl) benzyl ester (I2).

4: the formula of claim 1 (I) compound is preferably pitavastatin 2-(nitrooxy methyl) benzyl ester (I3).

5: the medicinal compositions that contains the 1 described compound of having the right.

6: the described composition of claim 5 can be made into various oral preparations.

7: the described oral preparations preferred tablet of claim 6, capsule.

8: right 1 described compound is used for the purposes on the medicine of reducing cholesterol and triglyceride levels in preparation.