WO2012097697A1 - 阿齐沙坦有机胺盐及其制备方法和用途 - Google Patents

阿齐沙坦有机胺盐及其制备方法和用途 Download PDF

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WO2012097697A1
WO2012097697A1 PCT/CN2012/070219 CN2012070219W WO2012097697A1 WO 2012097697 A1 WO2012097697 A1 WO 2012097697A1 CN 2012070219 W CN2012070219 W CN 2012070219W WO 2012097697 A1 WO2012097697 A1 WO 2012097697A1
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Prior art keywords
azilsartan
organic amine
amine salt
administration
day
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PCT/CN2012/070219
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English (en)
French (fr)
Inventor
潘必高
黄龙彬
杨宝海
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江苏豪森医药集团有限公司
江苏豪森医药研究院有限公司
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Priority to CA2824316A priority Critical patent/CA2824316C/en
Priority to BR112013017982-1A priority patent/BR112013017982A2/pt
Priority to EP12736637.5A priority patent/EP2666773B1/en
Priority to JP2013549704A priority patent/JP5981940B2/ja
Priority to MX2013008197A priority patent/MX340590B/es
Priority to AU2012208863A priority patent/AU2012208863B2/en
Priority to RU2013137223/04A priority patent/RU2600986C2/ru
Priority to US13/979,931 priority patent/US9233954B2/en
Publication of WO2012097697A1 publication Critical patent/WO2012097697A1/zh
Priority to ZA2013/05059A priority patent/ZA201305059B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/40—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention relates to azilsartan organic amine salt and a process for the preparation thereof, and to a pharmaceutical composition comprising a therapeutically effective amount of the compound, and its use for the preparation of an antihypertensive drug. Background technique
  • Hypertension is a common cardiovascular disease.
  • the clinical syndrome characterized by persistent increase in systemic arterial blood pressure often causes lesions of important organs such as heart, brain, and kidney, and has corresponding consequences.
  • China is one of the countries most seriously afflicted by hypertension in the world.
  • the estimated number of high blood pressure among adults has increased from 30 million in I960 to 59 million in 1980, and increased in 1991.
  • one third of adults also have high blood pressure. Finding antihypertensive drugs that are effective and have few adverse reactions is imminent.
  • renin angiotensin system is a group of interacting and mutually regulated hormones or precursors secreted by the kidneys and liver, including renin, angiotensinogen, angiotensin I (Ang 1), angiotensin ⁇ (Ang 11), angiotensin converting enzyme (ACE), angiotensin receptor and the like.
  • Ang II is one of the strongest vasoconstrictors and has numerous biological activities.
  • Azilsartan (a structure such as formula A) is an angiotensin II receptor antagonist drug developed by Takeda Pharmaceutical Co., Ltd., which is an angiotensin II receptor antagonist (artan). )drug.
  • the azsartantan potassium salt was approved by the US FDA, and the trade name was Edabi.
  • the drug is administered orally and can be used alone or in combination with other antihypertensive drugs for the treatment of hypertension and related complications.
  • Azilsartan has a significant effect on lowering blood pressure. Compared with losartan and olmesartan medoxomil, azelazanol has a more effective blood pressure lowering effect. (WHITE W B.
  • Azisartan is a prodrug that is rapidly hydrolyzed to acesartan during gastrointestinal absorption and is effective.
  • Azisartan (English name: Azilsartan, structural formula shown as formula B), chemical name 1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazole) -3-yl) [ ⁇ , ⁇ -biphenyl]-4-yl]methyl]-2-ethoxy-1 ⁇ -benzimidazole-7-carboxylic acid, which selectively blocks vascular tone in vivo Binding of the hormone II to the vascular smooth muscle ATI receptor blocks the contraction of blood vessels of angiotensin, thereby lowering blood pressure.
  • EP19921 10668, US5243054A, US20050187269 disclose a process for preparing azilsartan and its structurally similar compounds;
  • Chinese patent CN100503605C discloses azilsartan medolate potassium salt and its preparation and pharmacodynamic effect;
  • WO2010075347 discloses azilsartan and Medical use and pharmacological activity of azilsartan mesylate potassium salt;
  • CN101381366B discloses azilsartan and its ester potassium salt.
  • follow-up studies have shown that as a direct effect of azilsartan, its molecular structure has a carboxyl group, which is poorly absorbed in the body, affecting the efficacy of the drug, and is not suitable for preparation into a pharmaceutical dosage form.
  • the present invention has found that the salt formation of azilsartan and organic amine can improve its pharmacokinetic characteristics, improve its bioavailability, reduce drug toxicity, and is more suitable for conventional preparation processes.
  • the azilsartan organic amine salt is present in a single molecule form or in a complex form.
  • the complex form is a state of molecular existence as understood by those of ordinary skill in the art, and is generally, but not limited to, a binding state formed by intermolecular interaction forces, such as by hydrogen bonding, ionic, or electric charge.
  • the organic amine is selected from the group consisting of methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, ethanolamine, piperazine, dibenzylethylenediamine, meglumine, tromethamine , tetramethyl quaternary ammonium, tetraethyl quaternary ammonium or choline.
  • the azilsartan organic amine salt has a structure as shown in formula (I) or (II), wherein M is an organic amine, and M is selected from the group consisting of methylamine, dimethylamine, trimethylamine, ethylamine, and Ethylamine, triethylamine, ethanolamine, piperazine, dibenzylethylenediamine, meglumine, tromethamine, tetramethyl quaternary ammonium, tetraethyl quaternary ammonium or choline.
  • M is an organic amine
  • M is selected from the group consisting of methylamine, dimethylamine, trimethylamine, ethylamine, and Ethylamine, triethylamine, ethanolamine, piperazine, dibenzylethylenediamine, meglumine, tromethamine, tetramethyl quaternary ammonium, tetraethyl quaternary ammonium or choline.
  • Another object of the present invention is to provide a process for the preparation of the above compound which comprises separately adding azilsartan acid and an organic amine to an alcoholic organic solvent, and forming a salt at room temperature or under heating, preferably in anhydrous form. The reaction in the environment.
  • a choline alcohol solution is preferably added in the preparation of the corresponding azilsartan choline salt, more preferably a 45% choline methanol solution is added, particularly preferably, the added Azisha
  • the molar ratio of tannic acid to choline is 1:1 ⁇ 2:1.
  • the organic amine is selected from the group consisting of methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, ethanolamine, piperazine, dibenzylethylenediamine, meglumine, tromethamine, tetramethyl
  • the molar ratio of azilsartan acid to organic amine added in the alcoholic organic solvent is 2:1.
  • the alcohol solvent described therein is selected from the group consisting of methanol, ethanol, propanol or isopropanol.
  • Another object of the present invention is to provide a pharmaceutical composition for treating hypertension comprising a therapeutically effective amount of azilsartan organic amine salt as an active ingredient of the present invention and a pharmaceutically acceptable carrier.
  • the present invention provides the use of azilsartan organic amine salt and a pharmaceutical composition containing the same for the preparation of an antihypertensive drug.
  • the drug substance is in a form that is convenient to handle and handle. This is important not only from the viewpoint of obtaining a commercially viable preparation method, but also from the viewpoint of subsequently preparing a pharmaceutical preparation containing the active compound.
  • the chemical stability, solid state stability and "shelf life" of the active ingredients are also very important factors.
  • the drug substance and the composition comprising the same should preferably be capable of being effectively stored for a considerable period of time, while the physicochemical properties of the active ingredient (e.g., its chemical composition, density, wettability, and solubility) do not exhibit significant changes.
  • the effective amount of the active ingredient means an effective non-toxic dose, preferably in the range of 0.001 to 100 mg/kg of total body weight, more preferably 0.001 to 50 mg/kg.
  • oral or parenteral administration is preferred, including topical, rectal, transdermal, injection or continuous infusion.
  • the human oral administration dose preferably comprises from 0.05 to 3500 mg of the active ingredient, preferably from 0.5 to 1000 mg of the active ingredient. It is preferred to use a lower dose oral administration form. However, high dose parenteral administration can also be administered when it is safe and convenient for the patient.
  • the above dosages relate to the preferred amount of active ingredient expressed as free acid.
  • the optimal dose and interval of the individual dose of the active ingredient depends on the nature and extent of the treatment of the disease, the dosage form, the route and the site, the specific patient to be treated, and the best solution can be commonly used. Technical determination. It will also be apparent to those skilled in the art that the optimal course of treatment, i.e., the number of doses of the active ingredient administered per day for a given period of time, can be determined by those skilled in the art using commonly used procedures for determining the course of treatment.
  • the compounds of the present invention can be administered orally or parenterally, and can be formulated into tablets, pills, powders, and granules for various routes of administration.
  • the active ingredient is mixed with at least one inert diluent.
  • Oral formulations may also include, in addition to inert diluents, such as lubricants, glidants, and antioxidants, as is conventional practice. If capsules, tablets, and pills are prepared, a buffer is included in the formulation. Tablets and pills can also be formulated as sustained release formulations.
  • the parenteral administration preparation of the present invention includes a sterile aqueous solution, although a nonaqueous solution of the emulsion can also be used. These dosage forms may also include adjuvants such as preservatives, wetting agents, penetrating agents, buffering agents, emulsifying agents and dispersing agents.
  • the sterilization can be carried out by filtration using a bacteria retaining filter, sterilizing agent is added to the composition, and the composition is irradiated or the composition is heated to be sterilized.
  • the salt of the present invention has a markedly increased solubility in a conventional solvent and is suitable for use in a conventional preparation.
  • the salt of the present invention has a better formulation application value.
  • the salt of the present invention has better bioavailability and a better therapeutic effect.
  • the salt of the present invention is prepared in high yield, high purity, fast, convenient and low cost, wherein the ethanolamine salt and the choline salt have an advantage in the process route, and crystals can be directly precipitated.
  • Figure 1 shows the exposure levels of azilsartan acid after administration of 3.0 mg/kg of the compound of Example II (A) and 3.58 mg/kg of azilsartan (B) in rats;
  • Figure 2 is a graph showing the exposure level of M1 after administration of 3.0 mg/kg of the compound of Example II (A) and 3.58 mg/kg of azilsartan (B) in rats;
  • Figure 3 is a graph showing the exposure level of M2 after administration of 3.0 mg/kg of the compound of Example II (A) and 3.58 mg/kg of azilsartan (B) in rats;
  • Figure 4 is a graph showing the effect of the compound of Example 2 on blood pressure of SHR rats after continuous administration for 2 weeks. detailed description
  • Example 1 Azisartan acid and choline are salted into 1:1
  • Example 1 is comparable in solubility to the compound of Example 2.
  • test sample Take the appropriate amount of the test sample, place it in the above weighing bottle and lay it in the weighing bottle.
  • the thickness of the test sample is about 1mm, and the precision is weighed (m 2 ).
  • Deliquescence absorbs enough water to form a liquid
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • Example 2 The compounds of Example 2 and Example 4 have no hygroscopicity, are suitable for the preparation of pharmaceutical preparations, and are beneficial to the stability of the preparation.
  • Test Example 3 Pharmacokinetic test after SD rat administration
  • Blood pressure implant model TA11PA-C40, Data Sciences International.
  • Alzet micro osmotic pump model Alzet, model 2002, Alzet, USA.
  • Test compound code HS-10149 (Example 2 compound); Batch number: 20110324; Provided by Jiangsu Haosen Pharmaceutical Co., Ltd.; Purity: 99.5%; Physical state: White powder; Storage conditions: Sealed, 4-8 °C , dry, protected from light.
  • Solvent Ceolus; Lot No.: B063; Physical State: White powder; Storage conditions: sealed, room temperature, dry.
  • Angiotensin ⁇ lot number: 041M5062V; purity: ⁇ 93%; storage conditions: -20 ° C, Protected from light
  • HS-10149 suspension Accurately weigh the desired compound, dilute to a concentration of 0.20 mg/ml, 0.06 mg/ml, 0.02 mg/ml with a gradient of 2% Ceolus suspension, stir until dissolved.
  • Animals selected for testing were grouped into 24-hour average blood pressure, with an average of 8 animals per group. Male and female, the number of 8 animals in each group meets the requirements of statistical tests and pharmacodynamic guidelines.
  • the solvent control group was a 2% Ceolus suspension.
  • the healthy animals were selected to implant the implant on the 0th day of the test.
  • the micro-osmotic pump was subcutaneously implanted.
  • the blood pressure-selected animals were selected for the 24-hour blood pressure test.
  • a positive drug or test drug was administered in a single dose at 10 am on the 16th day of the test and blood pressure was monitored 24 hours after the administration. After the end of the experiment, the animals were euthanized by excessive inhalation of carbon dioxide.
  • the DSI remote sensing pressure measuring device automatically records the data every 5 seconds, and uses the software to calculate the average value in hours as the raw data.
  • P ⁇ 0.05 indicating that the administration group was significantly different from the solvent control group; **P ⁇ 0.01, indicating that the administration group had a very significant difference compared with the solvent control group.
  • HS-10149 showed a positive correlation of dose-effect within the range of reagents; 23, 13, and 3 hours before administration, 1 hour after administration. There was no significant difference in mean blood pressure between the groups (P>0.05). Compared with the vehicle control group, the mean blood pressure of the low, medium and high dose groups of HS-10149 at 2, 7, 13, 18, 23 hours after administration was extremely significant. Sexual differences (PO.01); The mean blood pressure of HS-10149 low, medium and high dose groups was significantly lower than that of the vehicle control group 23 hours after administration. Thus, the efficacy of HS-10149 after a single administration can last for about 23 hours.
  • OBJECTIVE This study intends to use the approximate lethal dose method to give the compound of Example II or the potassium salt of azilsartan membrane in the Beagle dog to observe the acute toxicity of the animal, and to study the toxicity of the compound of Example II after administration. And comparing the toxicity of the compound of the second embodiment with the potassium salt of azilsartan ester, and providing reference information for the toxicity evaluation of the compound of the second embodiment.
  • Azilsartan mesylate potassium salt group 3.20g.kg group of animals showed vomiting, salivation, and less movement on the day of administration, activity decreased on the 2nd to 8th day, prone on the 5th to 8th day, and died on the 9th day.
  • 2.13g_kg dose group Vomiting, runny, and decreased activity on the day of animal administration. On the second day after administration, the activity decreased, and on the third day, the activity returned to normal, and no abnormalities were observed after the cage observation. Animals in the 1.42 g_kg dose group showed vomiting and less movement on the day of administration. On the second day after the administration, the activity decreased, and on the third day, the activity returned to normal, and no abnormalities were observed after the cage observation.
  • Example 2 Compound group: 3.20 pm dose group animals showed loose stools, watery stools, and salivation on the day of administration, and continued until the end of observation.
  • the watery stool was observed, the activity was reduced, the stool was visible on the 3rd day, the activity returned to normal, and the fecal trait returned to normal on the 4th day, and no abnormality was observed after the cage observation.
  • the 2.13g1 ⁇ 4 dose group no abnormalities were observed on the day of administration.
  • vomiting was observed activity was reduced, and loose stools were observed on the third day. The activity returned to normal.
  • the fecal traits returned to normal, and no abnormalities were observed after the cage observation. Water samples appeared on the day of administration of the 1.42 kg dose group Feel, move less. Activity decreased on the second day after administration, and activity resumed on the third day. No abnormalities were observed after the cage.
  • the body weight of the animals was lower than that of the pre-drug, and the body weight was decreased on the 7th day after administration, and the body weight recovered on the 14th day after administration of all the surviving animals.
  • the electrophysiogram and hematological parameters were not significantly abnormal on the 2nd and 7th day after administration of the azilsartan mesylate potassium salt group and the second compound group of the second embodiment. All the surviving animals were associated with electrocardiogram and blood on the 14th day after administration. There was no obvious abnormality in the examination of the indicators.
  • Systolic blood pressure and diastolic blood pressure decreased in different degrees on day 2 after administration of the azilsartan mesylate potassium salt group and the second compound group of the second compound.
  • the systolic blood pressure and diastolic blood pressure were not 14 days after administration of all surviving animals. See obvious abnormalities.
  • Azilsartan mesylate potassium salt Dosage dose S ⁇ Og.kg Day 2 and Day 7 after dosing
  • ALT, AST, CK, CRE, UREA, UA increased significantly, and died on the 9th day.
  • the ALT, CRE, UREA and UA values were significantly increased on the 2nd day after administration.
  • ALT, CK, CRE and UA increased significantly, and the 14th day returned to normal. abnormal.
  • the dose of 1.42g1 ⁇ 4 dogs on the 2nd day after administration of ALT, CRE, UA increased significantly, on the 7th day CRE, UA increased significantly, the 14th day returned to normal, no other abnormalities.
  • Example 2 Compound group: The CRE, UREA, and UA values of all dogs were significantly increased on the 2nd day after administration, and the CRE and UA values were significantly increased on the 7th day, and returned to normal on the 14th day; wherein the dose was 3.20 ⁇ ] ⁇ - The ALT increased on the 2nd day after the administration of the dog, and returned to normal on the 7th day. No other abnormalities were observed.
  • the PT values of all the animals in the azilsartan mesylate potassium salt group and the second compound group were significantly lower than those before the drug administration.
  • the dose of the azilsartan meso-potassium salt group was 3.20 g_kg.
  • the Fib value was significantly increased on the 2nd day and the 7th day after the administration of the dog; the dose of 2.13 g_kg was significantly increased on the 2nd day after the administration of the dog.
  • Example 2 Compound group administration dose 3.20 g_kg Fib value was significantly increased on the second day after administration. Others did not see obvious abnormalities.
  • Azilsartan mesylate potassium salt group 3.20 g_kg dose group animals died on the 9th day after administration.
  • the gross anatomy of the animal can be seen in the perianal contamination, bloody excretion; the left lung lobe is black-red (caused by the left lateral posture after death), the right lung lobe has no obvious abnormality; the bottom of the stomach is grayish white.
  • the sacral protrusion, the small intestine from the middle part of the jejunum to the colon intestine is reddish brown, the color gradually deepens as the intestine section goes down, the mucosal surface does not see obvious ulcer, the mucosal surface of the intestine is scattered in the dark red area; the other organs are not obvious abnormal.
  • the anesthesia was dissected on the 15th day.
  • the gross anatomy of the animal showed the fundus, the sputum scattered in the red spot, the mucosal surface was red, and a small amount of chyle-like food was seen in the stomach.
  • the other organs showed no abnormality.
  • the animals in the 1.42g_kg dose group were anesthetized on the 15th day.
  • the gross anatomy of the animals showed that the mucous membranes in the stomach were scattered in the red area. A small amount of chyle-like food was seen in the stomach, and no abnormalities were found in the other organs.
  • Example 2 Compound group: 3.20 g_kg group of animals was anesthetized on the 15th day. The samples of each organ were stained with hematoxylin-eosin (HE) and examined under light microscope. No obvious abnormalities were observed in the gross anatomy of the animals. On the 15th day of the 2.13g_kg dose group, the anesthesia was dissected. The gross anatomy of the animals showed a stomach filling, containing a large amount of granular food. The mucosa of the cardia was red, scattered in red dots, and the other organs were not abnormal. On the 15th day of the 1.42g g dose group, the anesthesia was dissected. The gross anatomy of the animals showed that the stomach was full, containing a large amount of granular food, and the mucosa was red on the mucosa, and the remaining organs were not abnormal.
  • HE hematoxylin-eosin
  • Azilsartan mesylate potassium salt 3.20 g.kg dose group animal anatomical observation record: Each organ sample was stained with hematoxylin-eosin (HE) and examined under light microscope. Diffuse hepatic sinus dilatation and congestion in the liver, partial liver tissue autolysis; spleen red pulp and white pulp lymphocytes decreased significantly, red pulp intramedullary fibrous tissue hyperplasia; diffuse lung tissue moderate congestion and edema; renal tissue congestion, autolysis; Gastric mucosal epithelial necrosis, submucosal edema, fibroblast proliferation, some new capillaries; duodenal, jejunal, ileum, colon, cecum and rectal mucosal epithelial focal necrosis or with hemorrhage.
  • HE hematoxylin-eosin

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Abstract

本发明涉及阿齐沙坦有机胺盐及其制备方法和用途。具体而言，本发明涉及阿齐沙坦有机胺盐、其制备方法，以及含有治疗有效量的该化合物的药物组合物，及其在制备抗高血压药物中的用途。

Description

阿齐沙坦有机胺盐及其制备方法和用途 技术领域
本发明涉及阿齐沙坦有机胺盐及其制备方法， 以及含有治疗有效 量的该化合物的药物组合物， 及其用于制备抗高血压药物中的用途。 背景技术
高血压是常见的心血管疾病， 以体循环动脉血压持续性升高为主 要表现的临床综合征， 常引起心、 脑、 肾等重要器官的病变并出现相 应的后果。 我国是世界上高血压危害最严重的国家之一， 在过去几十 年中， 成年人中估计的高血压人数已经从 I960年的 3000万人增加到 1980年的 5900万人， 到 1991年增至 9400万人， 目前已经超过 2亿， 每年死亡的 300万心血管患者中， 50%都与高血压有关。在美国， 也有 1/3成年人患有高血压。寻找有效且不良反应少的抗高血压药物迫在眉 睫。
常见的抗高血压药按其作用部位分为中枢性降压药、 神经节阻断 药、 交感神经末梢抑制药、 肾上腺素能受体阻断药、 血管舒张药、 利 尿药、 血管紧张素转化酶抑制剂（ACEI)、 血管紧张素受体拮抗剂。 肾 素血管紧张素系统 （RAS ) 是由肾脏和肝脏分泌的一组相互作用又相 互调节的激素或前体，包括肾素、血管紧张素原、血管紧张素 I (Ang 1)、 血管紧张素 Π (Ang 11)、 血管紧张素转化酶 （ACE)、 血管紧张素受体 等。 其中 Ang II为最强的血管收缩剂之一， 具有众多的生物学活性。
阿齐沙坦酯 （结构如式 A) 是日本武田制药公司开发的一种用于 治疗高血压症的血管紧张素 II受体拮抗剂药物， 属于血管紧张素 II受 体拮抗剂（沙坦类）药物。 2011年 2月阿齐沙坦酯钾盐获美国 FDA批 准上市， 商品名为 Edabi。 该药为口服用药， 既可单用， 亦可与其他降 压药联合用于高血压以及相关并发症的治疗。 阿齐沙坦酯对于降低血 压有着较为显著的疗效， 与洛沙坦和奥美沙坦酯相比较， 阿奇沙坦酯 具有更高效的降低血压作用。 （WHITE W B. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and hypertension [J] . Hypertension, 2011， 57( 3):413 - 420. )
阿齐沙坦酯是一种前体药物， 在胃肠道吸收期间被迅速水解为阿 齐沙坦酸， 并发挥药效。 阿齐沙坦 （英文名称： Azilsartan, 结构式如 式 B所示）， 化学名为 1-[[2'-(4,5-二氢 -5-氧代 -1,2,4-噁二唑 -3-基) [Ι,Γ- 联苯基 ]-4-基]甲基] -2-乙氧基 -1Η-苯并咪唑 -7-羧酸， 其在体内通过选择 性阻断血管紧张素 II与血管平滑肌 ATI受体的结合而阻断血管紧张素 Π的收缩血管 从而降低血压。
Figure imgf000003_0001
EP19921 10668 , US5243054A, US20050187269公开了阿齐沙坦及 其结构类似化合物的制备方法；中国专利 CN100503605C公开了阿齐沙 坦酯钾盐及其制备和药效作用； WO2010075347 公开了阿齐沙坦酯及 阿齐沙坦酯钾盐的医药用途及药理活性； CN101381366B公开了阿齐沙 坦及其酯钾盐。 但是， 后续研究表明， 作为直接发挥药效的阿齐沙坦， 其分子结 构中具有羧基， 体内吸收较差， 影响了药物发挥疗效， 不利于被制备 成药用剂型。 为了提高其生物利用度， 可以通过化学修饰的方法将其 制成活性酯， 即阿齐沙坦酯， 其生物利用度有较大改进但仍不理想， 而且修饰使得该药物分子结构复杂化， 增加了合成难度， 提高了生产 成本。 发明内容
本发明通过研究发现， 将阿齐沙坦与有机胺成盐能够很好地改善 其药代动力学特征， 提高其生物利用度， 降低药物毒性， 且更适合于 常规制剂工艺。
本发明的目的在于提供阿齐沙坦有机胺盐， 其中阿齐沙坦和有机 胺的比例为 m: l， m为 2〜10， 优选为 2。
优选地， 所述的阿齐沙坦有机胺盐以单分子形式或者复合物形式 存在。 所谓复合物形式是本领域普通技术人员所理解的一种分子存在 状态， 通常但不限于， 指经分子间的相互作用力而形成的一种结合状 态， 如通过氢键型、 离子型、 电荷转移型及范德华力型的分子间作用 力形成的复合状态， 通过配位键作用而形成的络合状态， 通过共价键 作用而形成的共价结合物。
优选地， 所述有机胺选自甲胺、 二甲胺、 三甲胺、 乙胺、 二乙胺、 三乙胺、 乙醇胺、 哌嗪、 二苄基乙二胺、 葡甲胺、 氨基丁三醇、 四甲 基季铵、 四乙基季铵或胆碱。
优选地， 所述阿齐沙坦有机胺盐， 其结构如式 （I) 或 （II) 所示， 其中 M为有机胺， M选自甲胺、 二甲胺、 三甲胺、 乙胺、 二乙胺、 三 乙胺、 乙醇胺、 哌嗪、 二苄基乙二胺、 葡甲胺、 氨基丁三醇、 四甲基 季铵、 四乙基季铵或胆碱。
Figure imgf000005_0001
Figure imgf000006_0001
(n为大于 1的整数）
(IV)
本发明的另一目的在于提供制备上述化合物的方法， 该方法包括 在醇类有机溶剂中分别加入阿齐沙坦酸和有机胺， 室温或者加热下使 之成盐， 优选该方法是在无水的环境中反应的。
当有机胺选自胆碱时， 在制备相应的阿齐沙坦胆碱盐时优选地加 入胆碱醇溶液， 更优选地是加入 45%胆碱甲醇溶液， 特别优选地， 加 入的阿齐沙坦酸和胆碱的摩尔比为 1: 1~2:1。
当有机胺选自甲胺、 二甲胺、 三甲胺、 乙胺、 二乙胺、 三乙胺、 乙醇胺、 哌嗪、 二苄基乙二胺、 葡甲胺、 氨基丁三醇、 四甲基季铵或 四乙基季铵时， 优选地， 在制备相应的阿齐沙坦有机胺盐时， 在醇类 有机溶剂中所加入的阿齐沙坦酸和有机胺的摩尔比为 2:1。
其中所述的醇类溶剂选自甲醇、 乙醇、 丙醇或异丙醇。
本发明的另一目的在于提供一种用于治疗高血压的药物组合物， 其中含有本发明的作为有效成分的治疗有效量的阿齐沙坦有机胺盐和 药学上可接受的载体。
进一步， 本发明提供阿齐沙坦有机胺盐以及含有它们的药物组合 物在制备抗高血压药物中的用途。
在药物组合物的配制过程中， 重要的是药物物质是一种可方便操 作和处理的形式。 不仅从获得商业上可行的制备方法的角度来说， 而 且从随后制备含该活性化合物的药物制剂的角度来说， 这都是很重要 的。
此外， 在制备药物组合物的过程中， 重要的是患者给药后， 提供 一种可靠的、 可再现的和恒定的药物血浆浓度曲线。
活性成分的化学稳定性、 固态稳定性和 "储存寿命"同样是非常重 要的因素。 该药物物质以及包含它的组合物应该优选能够有效地储存 相当一段时间，而活性成分的物理化学特性 (例如它的化学组成、密度、 弓 I湿性和溶解度)没有表现出显著的变化。
此外， 提供尽可能化学纯形式的药物同样是非常重要的。
本领域熟练技术人员可以理解， 典型地， 如果一种药物可以很容 易地以稳定形式获得， 那么可以提供如下优点： 易于处理、 易于制备 合适的药物制剂以及具有可靠的溶解特征。
活性成分有效量是指有效无毒剂量， 优选 0.001〜100 mg/kg总体 重的范围， 更优选 0.001〜50 mg/kg。 当治疗需要阿齐沙坦有机胺盐治 疗的患者时， 优选口服或非肠胃给药包括局部、 直肠、 经皮、 注射或 持续输液。人类口服给药剂量优选包括 0.05〜3500 mg活性成分，最优 选 0.5〜1000 mg活性成分。 使用较低剂量的口服给药形式为优选。 然 而， 在对患者安全方便时， 也可以施用高剂量非肠胃给药。 上述剂量 涉及优选的以游离酸表示的活性成分的量。
本领域技术人员应当肯定， 活性成分个体剂量的最佳给药数量及 间隔视治疗疾病的性质及程度， 给药剂型、 途径及部位， 治疗的具体 患者而定， 并且该最佳方案可通过常用技术确定。 本领域技术人员也 应当明白， 最佳疗程， 即既定时间内每天给予活性成分的剂量次数可 经本领域技术人员使用常用的确定疗程的试验确定。
本发明的化合物可口服或非肠胃给药， 可制成包括片剂、 丸剂、 粉剂及颗粒剂用于各种给药途径。 在这些固体制剂中， 活性成分至少 与一种惰性稀释剂相混合。 按照常规操作， 口服制剂也可包括除惰性 稀释剂以外的其他物质， 如润滑剂、 助流剂及抗氧化剂。 若制成胶囊、 片剂及丸剂， 制剂中包括缓冲剂。 片剂及丸剂还可制成持续释放剂型。
尽管也可采用乳剂的非水溶液， 本发明的非肠胃给药制剂包括无 菌水溶液。 这些剂型也可包括佐剂， 如防腐剂、 润湿剂、 渗透剂、 缓 冲剂、 乳化剂及分散剂。 其灭菌可采用细菌截留滤器 (bacteria retaining filter)过滤， 向组合物中加入灭菌剂， 照射组合物或加热组合物的方法 灭菌。 本发明的阿齐沙坦有机胺盐与阿齐沙坦及其酯相比， 主要优点如 下：
(1) 本发明的盐在常规的溶剂溶解度明显增加， 适用于常规制剂。
(2) 本发明的盐具有更好的制剂应用价值。
(3) 本发明的盐具有更好的生物利用度， 治疗效果更好。
(4) 本发明的盐毒性更小。
(5) 本发明的盐以高收率、高纯度、快速、方便和低成本进行制备， 其中乙醇胺盐、 胆碱盐在工艺路线中有优势， 可以直接析出晶体。 附图说明
图 1为大鼠给予 3.0mg/kg实施例二化合物 (A)和 3.58mg/kg阿齐沙 坦酯 (B)后， 阿齐沙坦酸的暴露水平；
图 2为大鼠给予 3.0mg/kg实施例二化合物 (A)和 3.58mg/kg阿齐沙 坦酯 (B)后， Ml的暴露水平；
图 3为大鼠给予 3.0mg/kg实施例二化合物 (A)和 3.58mg/kg阿齐沙 坦酯 (B)后， M2的暴露水平；
图 4为实施例二化合物连续给药 2周后，对 SHR大鼠血压的影响。 具体实施方式
实施例一 阿齐沙坦酸和胆碱以 1:1成盐
将阿齐沙坦酸（20.00 g, 0.0439 mol)， 加入甲醇（600.0ml) 中， 加 入 46%胆碱水溶液 （11.80 g, 0.0439 mol) 搅拌溶清， 减压浓缩干， 加 入异丙醚 (100.0 ml)搅拌析晶， 抽滤， 真空干燥， 得白色固体 18 g。
^ NMR (DMSO-d6) δ : 1.32 (t, 3Η, CH3)， 3.30 (s, 9H)， 3.43 (t, 2H, CH2), 3.97 (t, 2H, CH2), 4.29 (q, 2H, CH2)， 5.46 (s, 2H, CH2)， 7.29—7.87 (m, 11H), 11.21 (br， 2H， 丽， OH)。
元素分析 (%)： C， 64.30； H， 6.02； N， 12.49。 实施例二 阿齐沙坦酸和胆碱以 2:1成盐
将阿齐沙坦酸（10.00 g, 0.022 mol), 乙醇 （100.0 ml)加入反应瓶 中， 加热至回流， 加入 45%胆碱甲醇溶液（5.90 g, 0.022 mol), 逐渐溶 清后， 保温反应 3 小时， 冷却至室温， 搅拌析晶， 过滤， 真空干燥得 白色固体 6.80 g。
^ NMR (DMSO-d6) 5: 1.38 (t, 6H, CH3), 3.09 (s, 9H), 3.39 (t, 2H, CH2), 3.82 (t, 2H, CH2), 4.58 (q, 4H, CH2), 5.69 (s, 4H, CH2), 7.05— 7.61 (m, 22H), 11.07 (br， 4H， NH， OH, C02H)。
元素分析 （％)： C， 65.22； H， 5.42； N， 12.23。 实施例三 阿齐沙坦酸和乙醇胺以 1: 1成盐
将阿齐沙坦酸（10.00 g, 0.0219 mol)， 加入甲醇（300.0ml) 中， 加 入乙醇胺（1.34 g, 0.0219 mol)搅拌溶清，减压浓缩干，加入异丙醚 (100 ml)搅拌析晶， 抽滤， 真空干燥， 得白色固体 10.30 g。
^ NMR (DMSO-d6) δ: 1.30 (t, 3Η, CH3)， 3.52 (t, 2H, CH2), 4.27 (t, 2H, CH2), 4.29 (q, 2H, CH2)， 5.52 (s, 2H, CH2)， 7.26—7.89 (m, 11H)， 11.32 (br， 5H， 丽， OH, NH3)。
元素分析 （％)： C， 62.59； H， 5.32； N， 13.54。 实施例四 阿齐沙坦酸和乙醇胺以 2: 1成盐
将阿齐沙坦酸 （10.0g， 0.0219mol)， 加入甲醇 （300.0ml) 中， 加 入乙醇胺 （0.67g， O.OllOmol) , 搅拌溶清。 减压浓缩至干， 加入异丙 醚 （100ml) 搅拌析晶， 抽滤， 真空干燥， 得白色固体 8.93g。
¾ NMR (DMSO-d6) δ: 1.33 (t, 6H, CH3), 3.09 (t, 2H, CH2), 3.60 (t, 2H, CH2), 4.30 (q, 4H, CH2), 5.46 (s, 4H, CH2), 7.28-7.93 (m, 22H), 11.0-13.0 (br, 7H, NH, C02H, OH)。
元素分析 （％)： C， 64.07； H， 4.79； N， 13.12。 实施例五 阿齐沙坦酸和哌嗪以 2:1成盐
将阿齐沙坦酸 （10.0g， 0.0219mol)， 加入甲醇 （300.0ml) 中， 加 入哌嗪 （0.94g， 0.0109mol)， 搅拌溶清。 减压浓缩至干， 加入异丙醚 ( 100ml) 搅拌析晶， 抽滤， 真空干燥， 得白色固体 9.45g。
¾ NMR (DMSO-d6) δ: 1.34 (t, 6Η, CH3), 2.68 (s, 8H, CH2), 4.31 (q, 4H, CH2), 5.47 (s, 4H, CH2), 7.27-7.92 (m, 22H), 11.20 (br, 6H, NH, C02H)。 元素分析 (%)： C， 64.79； H， 5.12； N， 14.15。 试验例一 溶解性试验
Figure imgf000010_0001
试验结论： 实施例一化合物与实施例二化合物溶解性相当。
其中 "1:40"是指室温条件下， lg测试样品溶解于 40ml甲醇中，
"1:80"的含义同理； "1:120"是指室温条件下， lg样品溶解于 120ml 乙醇中， "1:200" 的含义同理。 试验例二 引湿性试验
实验方法：
1、 取干燥的具塞玻璃称量瓶 （外径为 50nm， 高为 15nm) 于前一 天置于温度为 25°C±1°C， 相对湿度为 80%±2%的人工气候箱内， 精 密称重 （1^)。
2、 取供试品适量， 置上述称量瓶中并平铺于称量瓶内， 供试品厚 度约 lmm， 精密称重 （m2)。
3、 将称量瓶敞口， 并与瓶盖同置于上述恒温恒湿条件下 24小时。
4、 盖好称量瓶盖子， 精密称重 （m3)。
计算公式： 增重百分率 = (m3-m2) /(m2-mi)*100%
5、 引湿性增重的界定
潮解： 吸收足量水分形成液体
极具引湿性： 引湿增重不小于 15%
有引湿性： 引湿增重小于 15%但不小于 2%
略有引湿性： 引湿增重小于 2%但不小于 0.2%
无或几乎无引湿性： 引湿增重小于 0.2%。
6、 试验结果； 测试样品 引湿性 结论 （有无引湿性） 实施例一化合物 10.51% 有
实施例二化合物 0.02% 无
实施例三化合物 5.66% 有
实施例四化合物 0.08 无
试验结论： 实施例二与实施例四化合物均无引湿性， 适合于药物 制剂的制备， 且有利于制剂的稳定性。 试验例三 SD大鼠给药后药代试验
将体重为 200-250g的 SD大鼠 12只， 雌雄各半， 按体重随机分成 2组， 每组 6只， 雌雄各半。两组分别单次经口给予等摩尔的实施例二 化合物 （阿齐沙坦胆碱盐， Choline Azilsartan) 3mg/kg或阿齐沙坦酯 (Azilsartan medoxomil, Edarbi的 API) 3.58mg/kg。 给药前和给药后 的 0.5,1.0， 2.0,3.0,4.0,5.0,7.0,10,24和 48h从目艮眶采取 0.5ml的血液进行 血桨中阿齐沙坦酸 Γ ΑΚ-536)， 代谢产物 Ml (阿齐沙坦脱羧产物） 和 M2 (0-去垸基产物） 的含量检测， 研究结果见下表和图 1-3。
表：大鼠给予实施例二化合物或阿芥沙坦酯后的药代参数
Dose 1 max Cmax AUCo-∞ MRT tl/2 (mg/kg) (h) (ng/mL) (h*ng/mL) (h) (h) 实施例二化合物 3 1.0 5949±2002 48527±17029 50203±18650 11.1±3.0 9.65±1.96
TAK-536
阿齐沙坦酯 3.58 2.0 3004.2±656 28595±6224 29097±6289 10.5±1.2 8.44±0.76 实施例二化合物 3 1.3 109±85 490±419 515±419 10.4±7.0 7.15±3.44
Ml
阿齐沙坦酯 3.58 2.5 39.4±28.2 231±116 265±110 15.3±13.8 12.0±12.9 实施例二化合物 3 1.5 10.2±5.5 36.9±24.8 50.9±26.1 4.82±1.44 2.84±0.89
M2
阿齐沙坦酯 3.58 2.0 7.98±2.37 31.3±19.5 56.9±20.4 6.58±1.87 3.77±1.55
* 中位数
* -
实验结果表明， 与给予等摩尔的阿齐沙坦酯相比， 给予实施例二 化合物后血浆中的阿齐沙坦酸 Cmax和 AUC分别提高了 98%和 70%, 而且这种差异存在统计上的显著性。 这说明了阿齐沙坦酯改成胆碱盐 后， 能够较大地提高阿齐沙坦酸的暴露水平。 试验例四 SHR (自发性高血压） 大鼠降压效果试验
25周龄的 SHR雄性大鼠 38只， 根据初始血压随机分成 4组， 除 溶剂对照组为 6只外， 其他每组 8只。 分别连续给予 10mg/kg的实施 例二化合物 （阿齐沙坦胆碱盐， Choline Azilsartan), 实施例四化合物 (阿齐沙坦乙醇胺盐）和对照药 （阿齐沙坦酯钾盐）， 溶剂对照组给予 溶媒。 给药体积为 5ml/kg， 给药周期为 2周。
从图 4可以看出， 连续给药 1周或 2周后， 与溶剂对照组比较， 实施例二化合物、实施例四化合物都能显著地降低 SHR大鼠的血压（p < 0.01 )； 相同剂量下 （10mg/kg)， 实施例二化合物降压效果最佳， 实 施例四化合物次之， 两者均优于对照药的降压效果。 试验例五 对血管紧张素 II诱导的高血压大鼠血压影响
1、 实验仪器及其他材料：
( 1 ) 仪器
DSI遥感测压系统
血压植入子型号： TA11PA-C40， Data Sciences International.
Ponemah Software 5.0， Data Sciences
Figure imgf000013_0001
Alzet微渗透压泵型号： Alzet, model 2002， 美国 Alzet公司。
(2 ) 受试药和试剂
受试化合物代号： HS-10149 (实施例二化合物）； 批号： 20110324; 江苏豪森药业股份有限公司提供； 纯度： 99.5%; 物理状态： 白色粉末; 存储条件： 密封， 4-8°C， 干燥， 避光。
溶媒： Ceolus; 批号： B063; 物理状态： 白色粉末； 存储条件： 密 封， 室温， 干燥。
血管紧张素 Π;批号： 041M5062V; 纯度：≥93%； 保存条件： -20°C， 避光；
供应商： Sigma-Aldrich, Inc.
2、 化合物配制
( 1 ) 血管紧张素 Π
血管紧张素 II的建模剂量是根据文献报道 （Harrison-Bernard LM,
Zhuo J, Kobori H, Ohishi M, Navar LG. Intrarenal AT (l)receptor and ACE binding in ANG Il-induced hypertensive rats. Am J Physiol Renal Physiol. 2002 Jan; 282(l):F19-25； Diz DI, Baer PG, Nasjletti A.Angiotensin Il-induced hypertension in the rat. Effects on the plasma concentration, renal excretion, and tissue release of prostaglandins. J Clin Invest. 1983 Aug; 72(2):466-77. ) 确定的。 精确称取所需血管紧张素 Π， 加无菌生理盐水配制成 14.4mg/mL的浓度， 轻轻混匀至澄清。 -20°C避 光保存。
(2 ) 受试药
HS-10149混悬液： 精确称取所需化合物， 用 2%Ceolus混悬液梯度 稀释成 0.20mg/ml， 0.06mg/ml， 0.02mg/ml三个浓度， 搅拌至溶解均匀，
4°C避光保存， 给药之前预热至室温， 混匀。
3、 实验动物
Sprague-Dawley大鼠 37只（上海斯莱克实验动物有限公司提供）， 雌鼠 17只，雄鼠 20只，动物的合格证号：2007000524884, 2007000525715, 2007000526632.
4、 试验过程
( 1 ) 高血压的诱导及血压植入子的埋植
大鼠适应一周后， 选取符合体重要求的动物（雌性： 230-250g， 雄 性 200-220g ) 。 雄鼠用氯胺酮 （44mg/kg, im. ) 与 2%戊巴比妥钠溶液 (30mg/kg, ip. )进行复合麻醉，雌鼠用 2%戊巴比妥钠溶液 (40mg/kg, ip) 进行麻醉；于试验第 0天进行植入子埋植手术，植入微渗透压泵第 7 天， 连续监测 24 小时血压，以 24 小时平均收缩压达到 140mmHg 为标准筛 选动物， 合格的动物进入试验， 不合格的动物被剔除。
(2 ) 分组
将选入试验的动物按 24 小时平均血压分组， 每组平均 8只动物， 雌雄各半， 每组 8只动物数符合统计学检验的要求及药效学指导原则 的要求。
(3 ) 给药
分组后， 溶剂对照组， 受试药低、 中、 高剂量组分别单次灌胃给 予 2%Ceolus， 0.1mg/kg, 0.3 mg/kg, 1.0mg/kg的 HS-10149。 本试验给药 时间为上午 10点至 10点 30分， 灌胃的体积为 5mL/kg。
实验设计
Figure imgf000015_0001
溶剂对照组为 2%Ceolus的混悬液
(4) 实验流程
选择健康的动物于试验第 0天埋植植入子， 第 8天皮下埋入微渗 透泵， 第 15 天监测 24小时血压挑选血压合格的动物进入试验。 试验第 16天上午 10点单次给予阳性药物或受试药物并监测给药后 24小时血 压。 试验结束后， 用过量吸入二氧化碳的方法将动物安乐死。
5、 数据的处理与分析
DSI遥感测压装置每 5秒自动记录一次数据，利用软件计算出以小 时为时间单位的平均值作为原始数据。 P < 0.05, 表示给药组与溶剂对 照组相比具有显著性差异； **P < 0.01, 表示给药组与溶剂对照组相比 具有极显著性差异。
6、 实验结果
( 1 ) 血管紧张素 II 的升血压作用
埋植装有血管紧张素 II的微渗透泵后的第 6天， 监测动物的 24小时 动态血压， 以 24小时平均收缩压升高到 140mmHg 为造模成功的标准， 血压合格的动物进入试验， 血压不合格的动物被剔除。 本次试验中共 有 5只动物 （4 雄 1 雌）被剔除。 进入试验的所有动物的 24小时平均收 缩压的平均值为 167mmHg。 (2 ) HS-10149 对模型动物的血压的影响
数据表明， 溶剂对动物的血压水平没有影响。 给药后， HS-10149
(0.1mg/kg, 0.3 mg/kg, 1.0 mg/kg) 三个剂量组动物的平均血压 （给药 后 23 小时内的平均值） 与溶剂组比较显著降低 （p<0.01 ) ， 平均下降 百分比分别为 24.7%, 39.3%, 44.9%, HS-10149 在受试剂量范围内显示 出量效的正相关性； 各实验组之间给药前 23,13,3小时， 给药后 1 小时 的平均血压均无组间显著差异（P>0.05 )； 与溶剂对照组比较， 给药后 2 , 7， 13， 18， 23小时的 HS-10149低、 中、 高三个剂量组平均血压有 极显著性差异 （PO.01 ) ； 给药后 23 小时 HS-10149 低、 中、 高剂量 组与溶剂对照组比较， 其平均血压有较大幅度的降。 由此可见， 单次 给药后 HS-10149的药效作用可以持续大约 23小时左右。
给药前 23小时平均 MBP与给药后 23小时平均 MBP的比较
(Mean士 S.E. , N=8 )
Figure imgf000016_0001
注： *P<0.05， **P<0.01 vs.溶剂对照组
给药前后典型时间点的平均血压的比较 （Mean±S.E.， N=8)
Figure imgf000017_0001
注： *P<0.05， **P<0.01 vs.溶剂对照组
7、 结论
本试验结果表明， HS-10149在血管紧张素 II诱导的大鼠高血压模 型中显示出明显的降低血压的作用，在 O.lmg/kg 至 1.0mg/kg 的剂量之 间药效与剂量呈正相关性， 最低起效剂量为 0.1mg/kg， 给药后 23hr， 三 个剂量仍表现出很强的降压作用。 试验例六 Beagle犬急性毒性试验研究
目的： 本试验拟采用近似致死剂量法，通过 Beagle犬灌胃给予实施 例二化合物或阿齐沙坦酯钾盐， 观察动物出现的急性毒性反应， 研究 实施例二化合物给药后的毒性情况， 以及比较实施例二化合物与阿齐 沙坦酯钾盐的毒性大小， 为实施例二化合物毒性评价提供参考信息。
方法： 采用近似致死剂量法进行测定， 共使用 6只 Beagle犬， 实施 例二化合物和阿齐沙坦酯钾盐组各 3只动物。 给药剂量分别为 0.09、 0.13, 0.19, 0.28, 0.42, 0.63 , 0.95, 1.42, 2.13 , 3.20 g-kg '10个齐 I」量 序列， 其中 3.20 g_kg剂量已为最大给药剂量 （相当于临床人拟用剂量 的 1081 倍） 。 同时分别在给药前、 给药后第 2天、第 7天、第 14天采血， 进行相应的血液生化指标测定； 在给药前、 给药后第 7天、 第 14天进行 心电图、 体重、 体温测定。
实验结果
阿齐沙坦酯钾盐组 : 3.20g.kg剂量组动物给药当天出现呕吐、流涎、 少动， 第 2~8天活动减少， 第 5~8天俯卧， 第 9天死亡。 2.13g_kg剂量组 动物给药当天出现呕吐、 流涎、 活动减少。 给药后第 2 天活动减少， 第 3 天活动恢复正常，此后笼旁观察未见异常。 1.42g_kg剂量组动物给 药当天出现呕吐、 少动。 给药后第 2天活动减少， 第 3天活动恢复正常， 此后笼旁观察未见异常。
实施例二化合物组： 3.20g g剂量组动物给药当天出现稀便、水样 便、 流涎， 持续至观察结束。 给药后第 2天可见水样便， 活动减少， 第 3天可见稀便， 活动恢复正常， 第 4天粪便性状恢复正常， 此后笼旁观 察未见异常。 2.13g¼剂量组动物给药当天未见异常， 给药后第 2天呕 吐， 活动减少， 第 3天可见稀便， 活动恢复正常， 第 4天粪便性状恢复 正常，此后笼旁观察未见异常。 1.42 kg剂量组动物给药当天出现水样 便、 少动。 给药后第 2天活动减少， 第 3天活动恢复正常， 此后笼旁观 察未见异常。
阿齐沙坦酯钾盐组和实施例二化合物组所有动物体重与药前相 比， 给药后第 7 天体重降低， 全部存活动物给药后第 14天体重恢复增 长。
阿齐沙坦酯钾盐组和实施例二化合物组所有动物给药后第 7天体 温未见明显异常， 全部存活动物给药后第 14天体温未见明显异常。
阿齐沙坦酯钾盐组和实施例二化合物组所有动物给药后第 2天和 第 7天心电图、 血液学指标检查未见明显异常， 全部存活动物给药后第 14天相关心电图、 血液学指标检查未见明显异常。
阿齐沙坦酯钾盐组和实施例二化合物组 5只动物给药后第 2天收缩 压和舒张压均出现不同程度的降低， 全部存活动物给药后第 14天收缩 压和舒张压未见明显异常。
阿齐沙坦酯钾盐组： 给药剂量 S^Og.kg犬给药后第 2天和第 7天
ALT, AST, CK、 CRE、 UREA, UA明显升高， 第 9天死亡。 给药剂量 2.13g.kg犬给药后第 2天 ALT、 CRE、 UREA, UA值明显升高， 第 7天 ALT, CK、 CRE、 UA明显升高， 第 14天恢复正常， 其他未见明显异常。 给药剂量 1.42g¼犬给药后第 2天 ALT、CRE、UA明显升高，第 7天 CRE、 UA明显升高， 第 14天恢复正常， 其他未见明显异常。
实施例二化合物组： 所有犬给药后第 2天 CRE、 UREA, UA值明 显升高， 第 7天 CRE、 UA值明显升高， 第 14天恢复正常； 其中给药剂 量 3.20^]^-犬给药后第 2天 ALT升高， 第 7天恢复正常， 其他未见明显 异常。
阿齐沙坦酯钾盐组和实施例二化合物组所有动物给药后 PT值与药 前比较明显下降。阿齐沙坦酯钾盐组给药剂量 3.20g_kg犬给药后第 2 天 和第 7天 Fib值明显升高； 给药剂量 2.13g_kg犬给药后第 2天 Fib值明显升 高。 实施例二化合物组给药剂量 3.20g_kg给药后第 2天 Fib值明显升高。 其他未见明显异常。
阿齐沙坦酯钾盐组： 3.20g_kg剂量组动物给药后第 9天死亡。 动物 大体解剖可见肛周污秽， 血性排泄物； 左侧肺叶呈黑红色 （疑为死后 左侧卧位姿态所致） ， 右侧肺叶未见明显异常； 胃底部可见一灰白色 疣状突起， 小肠自空肠中段至结肠肠内容物为红褐色， 随肠道段向下 推移颜色逐渐加深， 粘膜面未见明显溃疡， 肠段粘膜面散在暗红色区 域； 其余脏器未见明显异常。 2.13g_kg剂量组动物第 15日麻醉解剖， 动 物大体解剖可见胃底、 贲门散在红色小点， 粘膜面发红， 胃内可见少 量乳糜样食物，其余脏器未见异常。 1.42g_kg剂量组动物第 15日麻醉解 剖， 动物大体解剖可见胃体部粘膜散在红色区域， 胃内可见少量乳糜 样食物， 其余脏器未见异常。
实施例二化合物组： 3.20g_kg剂量组动物第 15 日麻醉解剖， 对各 器官样品经苏木素 -伊红 （HE) 染色， 光镜下进行检查， 动物大体 解剖未见明显异常。 2.13g_kg剂量组动物第 15 日麻醉解剖， 动物大体 解剖可见胃充盈， 含大量颗粒状食物， 贲门粘膜面发红， 散在红色小 点， 其余脏器未见异常。 1.42g g剂量组动物第 15 日麻醉解剖， 动物 大体解剖可见胃充盈， 含大量颗粒状食物， 贲门散在粘膜面发红， 其 余脏器未见异常。
阿齐沙坦酯钾盐 3.20g.kg剂量组动物解剖观察记录： 对各器官样 品经苏木素 -伊红（HE)染色， 光镜下进行检查。 肝脏出现弥漫性 肝窦扩张淤血， 部分肝组织自溶； 脾红髓和白髓内淋巴细胞明显 减少， 红髓内纤维组织增生； 弥漫性肺组织中度淤血水肿； 肾组 织淤血、 自溶； 胃粘膜上皮坏死， 粘膜下层水肿， 成纤维细胞增 生， 可见一些新生毛细血管； 十二指肠、 空肠、 回肠、 结肠、 盲 肠及直肠粘膜上皮局灶性坏死或伴有淤血出血。
实验结论
在本试验条件下， Beagle犬灌胃给予实施例二化合物或阿齐沙坦 酯钾盐，实施例二化合物近似致死剂量大于 3.20g_kg，阿齐沙坦酯钾盐 近似致死剂量范围为 2.13~3.20g_kg 因此实施例二化合物急性毒性较 阿齐沙坦酯钾盐急性毒性低。

Claims

权利要求书：
1、 一种阿齐沙坦有机胺盐， 其中阿齐沙坦和有机胺的比例为 m:l， m为 2〜10的整数。
2、 根据权利要求 1 所述的阿齐沙坦有机胺盐， 其中所述的阿齐沙 坦和有机胺的比例为 2: 1。
3、 根据权利要求 1或 2所述的阿齐沙坦有机胺盐， 其中所述的阿 齐沙坦有机胺盐以单分子形式或者复合物形式存在。
4、 根据权利要求 3所述的阿齐沙坦有机胺盐， 其中所述的有机胺 选自甲胺、 二甲胺、 三甲胺、 乙胺、 二乙胺、 三乙胺、 乙醇胺、 哌嗪、 二苄基乙二胺、 葡甲胺、 氨基丁三醇、 四甲基季铵、 四乙基季铵或胆 碱。
5、 根据权利要求 4所述的阿齐沙坦有机胺盐， 其结构如式 （I) 或 (Π)所示， 其中 M为有机胺， M选自甲胺、 二甲胺、 三甲胺、 乙胺、 二乙胺、 三乙胺、 乙醇胺、 哌嗪、 二苄基乙二胺、 葡甲胺、 氨基丁三 醇、 四甲基季铵、
Figure imgf000021_0001
(I)
Figure imgf000022_0001
6、 根据权利要求 4所述的阿齐沙坦有机胺盐， 其中所述的阿齐沙 坦有机胺盐具有如式 （ΠΙ) 或 （IV) 所示的结构：
Figure imgf000022_0002
Figure imgf000022_0003
7、 一种制备如权利要求 1〜6任意一项所述的阿齐沙坦有机胺盐 的方法， 该方法包括在醇类有机溶剂中分别加入阿齐沙坦酸和有机胺， 室温或者加热下使之成盐， 优选所述方法是在无水环境下反应的。
8、 一种制备如权利要求 6所述的式 （III) 所示的阿齐沙坦胆碱盐 的方法， 该方法包括在醇类有机溶剂中加入阿齐沙坦酸和胆碱醇溶液， 优选地， 所述胆碱醇溶液为 45%胆碱甲醇溶液， 更优选地， 所述阿齐 沙坦酸和胆碱的摩尔比为 1:1~2: 1。
9、 根据权利要求 7或 8所述的方法， 其中所述醇类有机溶剂选自 甲醇、 乙醇、 丙醇或异丙醇。
10、 一种用于治疗高血压的药物组合物， 该药物组合物含有作为有 效成分的治疗有效量的如权利要求 1〜6任意一项所述的阿齐沙坦有机 胺盐和药学上可接受的载体。
11、 如权利要求 1〜6任意一项所述的阿齐沙坦有机胺盐， 或如权 要求 10所述的药物组合物在制备抗高血压药物中的应用。
PCT/CN2012/070219 2011-01-20 2012-01-11 阿齐沙坦有机胺盐及其制备方法和用途 WO2012097697A1 (zh)

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