WO2019170135A1 - Procédé de préparation d'une composition médicinale - Google Patents

Procédé de préparation d'une composition médicinale Download PDF

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WO2019170135A1
WO2019170135A1 PCT/CN2019/077448 CN2019077448W WO2019170135A1 WO 2019170135 A1 WO2019170135 A1 WO 2019170135A1 CN 2019077448 W CN2019077448 W CN 2019077448W WO 2019170135 A1 WO2019170135 A1 WO 2019170135A1
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amino
group
active component
acid
parts
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PCT/CN2019/077448
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English (en)
Chinese (zh)
Inventor
胡晓婧
钱丽娜
张志超
余峥嵘
陈永凯
冯伟
祁雯雯
王朝东
Original Assignee
武汉朗来科技发展有限公司
武汉启瑞药业有限公司
武汉中有药业有限公司
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Publication of WO2019170135A1 publication Critical patent/WO2019170135A1/fr

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/4164—1,3-Diazoles
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a preparation method of a pharmaceutical composition.
  • Cardiovascular disease also known as circulatory disease, refers to a series of diseases involving the circulatory system.
  • the circulatory system mainly includes the heart and blood vessels (arteries, veins, and microvessels).
  • cardiovascular disease is the number one cause of death worldwide, with more deaths from cardiovascular disease each year than any other cause of death.
  • Common cardiovascular diseases include: hypertension, heart failure, coronary heart disease, heart disease, atherosclerosis, angina pectoris, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmia, housing Tremor, cardiac fibrosis, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae.
  • Cardiovascular diseases generally have similar causes, processes, and treatments. Most cardiovascular diseases can be prevented by addressing risk factors such as tobacco use, unhealthy diet, obesity, high blood pressure, diabetes, and elevated blood lipids.
  • the World Health Organization believes that a combination of drugs, such as cholesterol-lowering statins and blood pressure lowering drugs, as well as aspirin, can significantly reduce the risk of cardiovascular recurrence or death.
  • any combination of cardiovascular disease drugs with different mechanisms of action does not necessarily have a beneficial effect. Therefore, the development of a pharmaceutical composition that can exert a combined therapeutic effect may provide a more effective control effect on cardiovascular diseases.
  • Neutral endopeptidase is a zinc metalloproteinase on the surface of endothelial cells. Inhibition of NEP can increase atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). ), the levels of C-type natriuretic peptide (CNP), bradykinin and adrenomedullin, so NEP inhibitors can play a role in diuresis, vasodilation, improvement of endothelial function, and inhibition of vascular smooth muscle cell proliferation under pathological conditions, thereby Improve vascular hemodynamics, prevent atherosclerosis, and delay the progression of heart failure.
  • NEP atrial natriuretic peptide
  • BNP brain natriuretic peptide
  • CNP C-type natriuretic peptide
  • bradykinin bradykinin
  • adrenomedullin adrenomedullin
  • Angiotensin II (Ang II) is an important regulator of the regulation of humoral homeostasis in the body, involving blood pressure, electrolyte balance, etc.
  • a large number of literatures have confirmed that Ang II is in hypertension, arterial disease, cardiac hypertrophy, heart failure and diabetes.
  • the pathogenesis of kidney disease plays a major role. Because the abnormal increase of Ang II level is directly related to the occurrence and development of hypertension, cardiac hypertrophy, heart failure, etc., blocking the binding of Ang II to its specific receptor can protect the heart and blood vessels, and the blood vessels are tight.
  • Angiotensin Receptor Blockers ARB have been proven in many randomized clinical trials to reduce the risk of cardiovascular mortality and morbidity. ARB drugs have been widely used in hypertension abroad.
  • biphenyl tetrazolium including losartan (losartan), valsartan (valsartan), irbesartan (irbesartan), candesartan cilexetil and azsarartan medoxomil
  • non-biphenyltetrazolium including eprosartan and telmisartan
  • Chinese patent application CN1615134A discloses a pharmaceutical composition comprising valsartan or a pharmaceutically acceptable salt thereof and a NEP inhibitor or a pharmaceutically acceptable salt thereof;
  • Chinese patent application CN105693543A discloses a Sacobitril (AHU 377) comprising a NEP inhibitor. , CAS No. 149709-62-6) salt and medicinal adjuvants and combinations of AT1 receptor antagonists such as losartan, eprosartan, valsartan, irbesartan, etc.
  • Chinese patent application CN105837464A discloses a NEP inhibitor containing sacuron and sodium medicinal excipients and other active ingredients such as losartan, eprosartan, valsartan, irbesartan, etc. or a pharmaceutically acceptable salt thereof Pharmaceutical composition.
  • the above compound is a sultan drug coupled with ligustrazine or a NO donor, and is a prodrug of angiotensin II receptor antagonist azilsartan (TAK-536), which releases hydroxyprosin in vivo or NO, thus effective synergy with azilsartan, enhance antihypertensive effect, has a certain heart rate reduction effect, reduce adverse reactions, and has an ideal protective effect on patients' heart and kidney.
  • TAK-536 angiotensin II receptor antagonist azilsartan
  • the pressure effect has a more obvious and lasting effect of lowering heart rate, and has high safety, and has an ideal protective effect on the heart and kidney function of the patient, and can be used for preventing and/or treating hypertension, chronic heart failure, diabetic nephropathy and the like.
  • the present invention provides a method for preparing a pharmaceutical composition, comprising:
  • the first active component is at least one selected from the group consisting of a neutral endopeptidase inhibitor and a precursor thereof, an active metabolite, a stereoisomer, a pharmaceutically acceptable salt, a prodrug, and a solvate;
  • the second active component is at least one selected from the group consisting of a compound represented by the following formula (I) or a precursor thereof, an active metabolite, a stereoisomer, a pharmaceutically acceptable salt, a prodrug and a solvate:
  • Each a is the same or different and is independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 1 represents a substituted or unsubstituted group: C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CH 2 ) n O(CH 2 ) m , Aryl or heteroaryl, wherein Wherein C b and C c represent an alkyl group each containing b or c carbon atoms; b and c are the same or different and are independently selected from each other, 0, 1, 2 , 3, 4, 5 or 6, wherein (CH 2 n , m in n O (CH 2 ) m is the same or different, independently selected from each other, 1, 2, 3, 4, 5 or 6;
  • R 2 represents hydrogen, halogen, nitro, cyano, or a substituted or unsubstituted group: C 1 -C 8 alkoxy, C 1 -C 8 alkyl, C 1 -C 8 alkylsulfonylamino , arylsulfonylamino, heteroarylsulfonylamino, aminosulfonyl, amino;
  • R 3 represents a group which is absent or substituted or unsubstituted: C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 2 -C 8 alkoxy, C 2 -C 8 alkyne Base, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, Aryl, heteroaryl, wherein Wherein b and c represent the number of carbon atoms of the alkyl chain, independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 4 represents a cyano group, or a substituted or unsubstituted group of an aryl group, an arylsulfonyl group, a heteroaryl group, a C 1 -C 8 alkoxy group, a C 1 -C 8 nitrate ester (-C 1 -C) 8- alkyl-ONO 2 ), C 1 -C 8 alkyl;
  • R 5 represents a cyano group, or a substituted or unsubstituted group: aryl, heteroaryl, C 1 -C 8 alkoxy, C 1 -C 8 nitrate, C 1 -C 8 alkyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, (CH 2 ) n O(CH 2 ) m CH 3 , wherein R 3 , R 4 , a, m, n independently of each other have the definitions as described above;
  • R 6 and R 7 independently represent hydrogen, unsubstituted or substituted C 1 -C 8 alkoxy or C 1 -C 8 alkyl;
  • R 8 and R 9 independently represent hydrogen, unsubstituted or substituted C 1 -C 8 alkoxy, C 1 -C 8 nitrate or C 1 -C 8 alkyl;
  • the first auxiliary material is selected from at least one of a filler, a disintegrant, and a lubricant;
  • the second auxiliary material is selected from at least one of a disintegrant and a lubricant
  • the third adjuvant is selected from at least one of, but not limited to, an auxiliary lipid, a glidant, a sweetener, a flavoring agent, a preservative, an antioxidant, a colorant, and a foaming agent.
  • the neutral endopeptidase inhibitor or the pharmaceutically acceptable salt of the compound of the formula (I) is the same or different and is independently selected from Na, K or an ammonium salt (eg, The addition salt of NH 3 );
  • the neutral endopeptidase inhibitor or the pharmaceutically acceptable prodrug of the compound of formula (I) is the same or different and is independently selected from the group consisting of, but not limited to, methyl ester and ethyl ester. , propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester;
  • the first active component is selected from at least one of the following compounds, pharmaceutically acceptable salts, prodrugs or solvates thereof:
  • the first active component is selected from at least one of the following compounds:
  • the first active component is selected from the group consisting of AHU 377, AHU 377 ethyl ester, AHU 377Na, AHU 377 ammonium salt, AHU 377K, N-(3-carboxy-1-oxopropyl)-(4S)-pair -Phenylphenylmethyl)-4-amino-2R-methylbutyric acid, N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4 -Amino-2R-methylbutyrate, N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutyric acid Potassium or 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2- Amido)amino-4
  • the second active component is a K salt selected from the compound of the formula (I), for example, a compound represented by the following formula (II):
  • the K salt of the compound of formula (I) is selected from the structures shown in the formula:
  • the filler in the first adjuvant is selected from the group consisting of starch, lactose, lactose monohydrate, cellulose lactose, pregelatinized starch, sucrose, mannitol, sorbitol, calcium phosphate, dextrin, micro At least one of crystalline cellulose, calcium hydrogen phosphate, mannitol-starch composite; for example, the filler is selected from at least one of microcrystalline cellulose and mannitol.
  • the disintegrant in the first adjuvant is selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethyl starch, methylcellulose, low-substituted hydroxypropyl At least one of a base cellulose, crospovidone, and chitosan; for example, the disintegrant is selected from at least one of croscarmellose sodium and crospovidone.
  • the lubricant in the first auxiliary material is selected from the group consisting of magnesium stearate, colloidal silica, talc, sodium lauryl sulfate, calcium stearate, and polyethylene glycol 4000. At least one of polyethylene glycol 6000, sodium stearyl fumarate, glyceryl monostearate, hydrogenated vegetable oil; for example, the lubricant is selected from at least magnesium stearate and colloidal silica One.
  • the disintegrant in the second adjuvant is selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethyl starch, methylcellulose, low-substituted hydroxypropyl At least one of a base cellulose, crospovidone, and chitosan; for example, the disintegrant is selected from at least one of croscarmellose sodium and crospovidone.
  • the lubricant in the second auxiliary material is selected from the group consisting of magnesium stearate, colloidal silica, talc, sodium lauryl sulfate, calcium stearate, and polyethylene glycol 4000. At least one of polyethylene glycol 6000, sodium stearyl fumarate, glyceryl monostearate, hydrogenated vegetable oil; for example, the lubricant is selected from at least magnesium stearate and colloidal silica One.
  • suitable excipients can include various commercially available specifications such as granules or micronized excipients.
  • suitable examples include, for example, microcrystalline cellulose having a particle diameter of 10 to 200 ⁇ m, and/or colloidal silica having a surface area of about 200 m 2 /g as long as it can be applied to the production method of the present invention.
  • the excipients suitable for use in the pharmaceutical formulations of the invention may also be in liquid or colloidal form.
  • the first active component is formulated in an amount of 5 to 70 parts by weight, preferably 5 to 40 parts by weight.
  • the second active ingredient is formulated in an amount of from 5 to 70 parts, for example from 5 to 40 parts.
  • the filler is prescribed in the first excipient in an amount of 5 to 90 parts, for example, 30 to 70 parts.
  • the amount of the disintegrant in the first excipient is from 1 to 29 parts, for example from 1.5 to 26 parts, such as from 6 to 15 parts.
  • the lubricant is formulated in the first excipient in an amount of from 0.025 to 7.5 parts, for example from 0.05 to 5 parts, such as from 0.25 to 2.5 parts.
  • the formulation amount of the disintegrant in the second adjuvant is from 0.3 to 17.5 parts, for example, from 0.5 to 8 parts, such as from 2 to 5 parts.
  • the lubricant is formulated in the second excipient in an amount of from 0.025 to 7.5 parts, for example from 0.05 to 5 parts, such as from 0.25 to 2.5 parts.
  • the first active component, the second active component, the filler of the first adjuvant, the disintegrant, and the lubricant may be mixed, and then the first auxiliary material is added.
  • Lubricating oil is mixed;
  • the mixing time of the step (2) is 2-15 minutes, for example 5-10 minutes.
  • the dry granulation of the step (3) is carried out under the following conditions: a roll width of 25 mm, a roll diameter of 200 mm, a roll gap of 2 mm, and a feed rotation speed of 7-70 rpm, preferably 7 rpm, 34 rpm, 50 rpm, 70 rpm.
  • the pinch speed is 3-12 rpm, preferably 3 rpm, 8 rpm, 12 rpm, and the sizing speed is 200-700 rpm, preferably 200 rpm, 550 rpm, 600 rpm, 700 rpm.
  • the mixing time of the step (4) is from 1 to 12 minutes, preferably from 3 to 5 minutes.
  • the second mixture obtained in step (4) comprises a first granule and a second auxiliary attached to the surface of the first granule.
  • the attachment can be achieved by adsorption or adhesion, such as physical adsorption.
  • the method further comprises the step (5) of preparing the second mixture into a preparation, for example, tableting or filling the second mixture;
  • the step of drying in the step (5) may be followed by a drying step, and the drying may be drying under reduced pressure; preferably, the drying temperature is 5 to 60 ° C, for example, 10 to 50 ° C, as 10 ° C, 20 ° C, 25 ° C, 40 ° C, 50 ° C; preferably, the drying time is 0.5-18 hours, for example 1-16 hours.
  • the present invention also provides a pharmaceutical composition prepared by the above production method.
  • the invention also provides a pharmaceutical formulation precursor comprising a mixture of the first particles and a second adjuvant attached to the surface of the first particles.
  • the present invention also provides a pharmaceutical preparation comprising the above-mentioned pharmaceutical preparation precursor formed by a formulation.
  • the formulation of the formulation may be, for example, a tableting or filling capsule step.
  • the drying step can also be carried out after tableting.
  • the invention also provides the use of the pharmaceutical composition for the preparation of a medicament for the prevention and/or treatment of cardiovascular diseases.
  • the cardiovascular disease is selected from the group consisting of: hypertension, heart failure, chronic heart failure, coronary heart disease, rheumatic heart disease, congenital heart disease, left ventricular dysfunction, endothelial dysfunction, diastolic dysfunction, hypertrophy Cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmia, atrial fibrillation, cardiac fibrosis, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina pectoris, primary And secondary pulmonary hypertension, renal vascular hypertension.
  • hypertension hypertension
  • heart failure chronic heart failure
  • coronary heart disease rheumatic heart disease
  • congenital heart disease left ventricular dysfunction
  • endothelial dysfunction diastolic dysfunction
  • hypertrophy Cardiomyopathy diabetic cardiomyopathy, supraventricular and ventricular arrhythmia
  • atrial fibrillation cardiac fibrosis
  • atrial flutter harmful vascular remodeling
  • the invention also provides a method of preventing and/or treating a cardiovascular disease comprising administering the pharmaceutical composition or pharmaceutical formulation precursor to an individual in need thereof.
  • one or more includes one or more than one, including, but not limited to, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • halogen means fluoro, chloro, bromo and iodo.
  • the substituent may be unsubstituted or optionally further substituted by one or more substituents which may be the same or different selected from the above.
  • Alkyl as used singly or as a suffix or prefix in the present invention is intended to include both branched and straight-chain saturated fats having from 1 to 20 carbon atoms (or the specific number if a specific number of carbon atoms are provided) A hydrocarbon group.
  • C 1 -C 8 alkyl means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
  • an alkyl group When an alkyl group is substituted by a substituent, it includes an alkyl group substituted with one or more halogens, for example, an alkyl group substituted with 1, 2, 3, 4, 5, 6 halogens, such as a trifluoromethyl group.
  • alkenyl as used herein, alone or as a suffix or prefix, is intended to include a chain comprising alkenyl or olefins having from 2 to 20 carbon atoms, if specified, the specific number of carbon atoms. And a linear aliphatic hydrocarbon group.
  • C 2-6 alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3 Methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.
  • alkynyl used alone or as a suffix or prefix in the present invention is intended to include alkynyl or alkyne containing from 2 to 20 carbon atoms (or the specific number if a specific number of carbon atoms is provided) Branched and linear aliphatic hydrocarbon groups.
  • alkynyl eg, 1-propynyl, 2-propynyl
  • 3-butynyl pentynyl, hexynyl, and 1-methylpent-2-ynyl.
  • aryl as used herein means an aromatic ring structure composed of 5 to 20 carbon atoms.
  • an aromatic ring structure containing 5, 6, 7 and 8 carbon atoms may be a monocyclic aromatic group such as a phenyl group; a ring structure comprising 8, 9, 10, 11, 12, 13 or 14 carbon atoms It may be polycyclic such as naphthyl.
  • the aromatic ring may be substituted with one or more of the ring positions described above.
  • aryl also includes polycyclic ring systems having two or more rings wherein two or more carbons are shared by two adjacent rings (the ring is a "fused ring"), wherein at least One ring is aromatic and the other ring may be, for example, a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and/or heterocyclic group.
  • polycyclic rings include, but are not limited to, 2,3-dihydro-1,4-benzodioxadiene and 2,3-dihydro-1-benzofuran.
  • cycloalkyl as used herein is intended to include saturated cyclic groups having the indicated number of carbon atoms. These terms may include fused or bridged polycyclic systems.
  • the cycloalkyl group has 3 to 40 carbon atoms in its ring structure. In one embodiment, the cycloalkyl has 3, 4, 5 or 6 carbon atoms in its ring structure.
  • C 3-6 cycloalkyl means a group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • heteroaryl refers to a heteroaromatic heterocycle having at least one ring heteroatom such as sulfur, oxygen or nitrogen.
  • Heteroaryl groups include monocyclic systems and polycyclic systems (eg, having 2, 3 or 4 fused rings).
  • heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, fluorene , pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, 1,2,4 -thiadiazolyl, isothiazolyl, benzothienyl, fluorenyl, oxazolyl, benzimidazolyl, benzoxazolyl, azabenzoxazolyl, imidazothiazolyl, benzo[1] 4] dioxolyl, benzo[1,3]dioxolyl and the
  • a heteroaryl has from 3 to 40 carbon atoms and in other embodiments from 3 to 20 carbon atoms. In some embodiments, a heteroaryl group contains 3 to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, a heteroaryl has 1 to 4, 1 to 3 or 1 to 2 heteroatoms. In some embodiments, a heteroaryl has 1 heteroatom.
  • heterocyclyl refers to a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring containing from 3 to 20 atoms, wherein 1, 2, 3, 4 or 5 Ring atoms are selected from nitrogen, sulfur or oxygen, and unless otherwise indicated, may be attached via carbon or nitrogen, wherein the -CH 2 - group is optionally replaced by -C(O)-; and unless otherwise stated to the contrary
  • the ring nitrogen atom or the ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or a ring nitrogen atom, optionally quaternized; wherein -NH in the ring is optionally acetyl, formyl, methyl Or a methylsulfonyl group; and the ring is optionally substituted with one or more halogens.
  • heterocyclic group when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these hetero atoms are not adjacent to each other.
  • the heterocyclic group is bicyclic or tricyclic, at least one ring may be optionally a heteroaromatic or aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclic group is a monocyclic ring, it must not be aromatic. Examples of heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl.
  • the compounds of the invention may also contain one or more asymmetric centers.
  • Asymmetric carbon atoms may exist in the (R) or (S) configuration, with only one asymmetric center, resulting in a racemic mixture containing multiple asymmetric centers, resulting in a mixture of diastereomers.
  • the substituent may exist in a cis or trans isomer form.
  • the compounds of formula (I) also include all possible stereoisomers thereof, which are single stereoisomers or stereoisomers (for example R-isomers or S-isomers, or E-isomers) The form of any mixture of any ratio of the bulk or Z-isomer).
  • Single stereoisomers (e.g., single enantiomers or single diastereomers) of a compound of the invention can be achieved by any suitable prior art method (e.g., chromatography, particularly, for example, chiral chromatography). Separation.
  • the compounds may also exist in tautomeric forms.
  • the compounds of the invention include all possible tautomers of the compounds of formula (I) which are in the form of a single tautomer or any mixture of said tautomers in any ratio.
  • NEP inhibitors of the invention and the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (such as a carboxyl group) and a basic center ( For example, an amino group, it can also form an internal salt.
  • acid addition salts include, but are not limited to, hydrochloride, hydrofluoride, hydrobromide, hydroiodide, sulfate, pyrosulfate, phosphate, nitrate, methanesulfonate , ethanesulfonate, 2-hydroxyethanesulfonate, besylate, tosylate, sulfamate, 2-naphthalenesulfonate, formate, acetoacetate, pyruvic acid, silicate , cinnamate, benzoate, acetate, glycolate, trifluoroacetate, trimethylacetate, propionate, butyrate, hexanoate, heptanoate, ten Monoacid salt, stearate, ascorbate, camphorate, camphor sulfonate, citrate, fumarate, malate, maleate, hydroxymaleate, oxalate, water Salicylate, succinate, glu
  • the preparation process, formulation and precursor thereof according to the present invention are particularly suitable for preparing a compound represented by the formula (I) or a precursor thereof, an active metabolite, a stereoisomer, or a pharmaceutically acceptable substance having good dissolution or release properties.
  • the acceptable pharmaceutical compositions of the salts, prodrugs and solvates surprisingly improve the problem that it is difficult to obtain a pharmaceutical composition having a satisfactory performance in a conventional process, and the dissolution property of the preparation is remarkably improved, and the drug can be effectively promoted. freed.
  • the invention effectively improves the material flowability problem in the process, for example, by improving the fluidity of the material, thereby ensuring that the difference in tablet weight of the tableting process product is small, and the difference in the weight of the final product can be controlled within ⁇ 5%. Etc.
  • the preparation process can be carried out at room temperature, avoiding the high temperature drying step leading to decomposition of the active ingredient.
  • the preparation process of the invention has the advantages of simple preparation process and easy industrialization and large production.
  • AHU 377K The preparation of AHU 377K is similar to this process, replacing concentrated ammonia with potassium hydroxide.
  • composition consisting of only the products of Examples 1 and 2 (100 mg: 50 mg) (excluding the formulation excipient) (excluding the formulation excipient) had a hygroscopic weight gain of 28.31% at a relative humidity of 92.5% and a temperature of 25 ° C for 5 days.
  • the granules were prepared by a dry granulator.
  • the granulation conditions were: a roll width of 25 mm, a roll diameter of 200 mm, a roll gap of 2 mm, a feed speed of 34 rpm, a pinch speed of 3 rpm, and a granule speed of 550 rpm.
  • the granules were prepared by a dry granulator.
  • the granulation conditions were: roll width 25 mm, roll diameter 200 mm, roll gap 2 mm; feed speed 70 rpm, pressure wheel speed 3 rpm, granule rotation speed 700 rpm, screen aperture 18 mesh.
  • the granules were prepared by a dry granulator.
  • the granulation conditions were: a roll width of 25 mm, a roll diameter of 200 mm, a roll gap of 2 mm, a feed speed of 7 rpm, a pinch speed of 12 rpm, and a sizing speed of 200 rpm.
  • the granules were prepared by a dry granulator.
  • the granulation conditions were: a roll width of 25 mm, a roll diameter of 200 mm, a roll gap of 2 mm, a feed speed of 50 rpm, a pinch speed of 8 rpm, and a sizing speed of 600 rpm.
  • the granules were prepared by a dry granulator.
  • the granulation conditions were: a roll width of 25 mm, a roll diameter of 200 mm, a roll gap of 2 mm, a feed speed of 34 rpm, a pinch speed of 12 rpm, and a sizing speed of 200 rpm.

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Abstract

La présente invention concerne un procédé de préparation d'une composition médicinale, comprenant les étapes consistant à : (1) prendre un premier composant actif, un second composant actif, un premier ingrédient et un second ingrédient ; (2) mélanger le premier composant actif, le second composant actif et le premier ingrédient pour disperser le premier composant actif et le second composant actif dans le premier ingrédient ajouté à ceux-ci et obtenir un premier mélange ; (3) préparer le premier mélange en adoptant une granulation sèche pour obtenir une première particule ; et (4) ajouter le second ingrédient dans la première particule au moyen d'un procédé supplémentaire, et mélanger pour obtenir un second mélange.
PCT/CN2019/077448 2018-03-09 2019-03-08 Procédé de préparation d'une composition médicinale WO2019170135A1 (fr)

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US11786471B2 (en) * 2016-07-11 2023-10-17 Wuhan Ll Science And Technology Development Co. Ltd. Complex disintegrant system for oral solid preparation and oral solid preparation comprising said complex disintegrant system
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CN105693543A (zh) * 2014-12-15 2016-06-22 四川海思科制药有限公司 沙库比曲类衍生物、其药物组合物、制备方法及用途

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