WO2012152209A1 - Rétinamidéthanolate de 4-carboxyphényle, son procédé de préparation et composition pharmaceutique le contenant - Google Patents

Rétinamidéthanolate de 4-carboxyphényle, son procédé de préparation et composition pharmaceutique le contenant Download PDF

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WO2012152209A1
WO2012152209A1 PCT/CN2012/075143 CN2012075143W WO2012152209A1 WO 2012152209 A1 WO2012152209 A1 WO 2012152209A1 CN 2012075143 W CN2012075143 W CN 2012075143W WO 2012152209 A1 WO2012152209 A1 WO 2012152209A1
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type
peak
crystal
cancer
skin
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吴素珍
刘瑞文
同琴
刘海宁
张毅
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北京吉科特科技有限责任公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/02—Monohydroxylic acyclic alcohols
    • C07C31/08—Ethanol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to a class of retinoid drug compounds, 4-carboxyphenyl retinyl alcoholate (4-CPRE), and a process and a pharmaceutical composition thereof, which are chemically prevented and/or treated in cancer, and which are in the skin The application of the disease.
  • 4-CPRE 4-carboxyphenyl retinyl alcoholate
  • retinol is a representative of retinol, it has the biological activity and effect of vitamins (maintaining vision, growth, reproduction and epithelial integrity); its metabolite retinoic acid has a strong mechanism of differentiation of cancer cells to induce differentiation (reversal)
  • Abnormal or cancerous cells make it "corrected” and different from the conventional cytotoxic anticancer drug "poisoning" mechanism, which is an effective drug for the treatment and prevention of precancerous lesions, cancer and skin diseases, but as a chemoprevention of cancer
  • the drug which takes a long time and a large amount of use, has its inherent adverse effects such as hyperophthalmia, which affects the high-risk population of cancer books and the long-term use of certain skin diseases.
  • Phenyl) retinamide) 4_CPR for short, chemical structure
  • the CAS number is 74193-17-2. See European patent EP 0009777 on April 16, 1980 or German patent DE 2843811 on October 07, 1978. It is a candidate new drug researched at home and abroad.
  • 4-CPR as a new drug: (1) its physicochemical properties are unstable and affect the quality control and practicability of the drug: because it belongs to the retinoids, like the alcohol, aldehyde, acid and absolute of retinoid Like most derivatives, they are afraid of light, fear of heat, fear of air and fear of moisture, and are prone to oxides, polymers and cis-trans isomers.
  • the present invention was unexpectedly discovered in the in-depth study of 4-CPR chemistry: 4-CPR reacts with ethanol to form a 4-carboxyphenyl retinyl alcoholate easily by hydrogen bonding (referred to as 4-CPRE or 4-CPR ethanolate)
  • the 4-CPR ethanolate comprises a nitrogen atom or an amide oxygen atom of 4-CPR or a carboxylic acid and a nitrogen atom and an amide oxygen atom respectively, and an alcohol hydroxy group; wherein the hydrogen atom or the amide oxygen atom and the nitrogen are confirmed on the nitrogen;
  • the hydrogen atom and the amide oxygen atom are respectively hydrogenated to the ethyl alcohol hydroxyl group in a hydrogen atomic manner and are 4-CPRE in an equimolar ratio, which belongs to a linear or cyclic positional isomer formed by a heterogeneous intermolecular hydrogen bond;
  • the properties, solubility and stability are better than 4-CPR and its homologues of ethyl carboxylate or
  • 4-CPRE is significantly more stable than 4-CPR and other retinoids: it prevents or reduces the peroxides, cis isomers, polymers, hydrolysates, etc. of the latter two during storage and transportation.
  • the formation of product impurities reduces the medicinal substances from 2 to 5% to 1.5%; the drug content increases from 95 to 98% to 98.5%; the effective period increases from 2 years to 5 years; The effect of improving quality and extending the validity period is remarkable.
  • 4-CPRE is a poorly soluble solid organic drug and has many crystal forms, each crystal form has different stability and solubility, and has never been studied or reported.
  • the present invention also provides different crystalline forms and ultrafine pulverization of these crystalline forms. It has been found that there are five crystal forms of 4-CPRE, and the crystal form of Form IV or Form V of Type II and the nano-fine powder of the two are the preferred solid components of the drug substance, and their stability and solubility are better than Type I. Or a type III crystal form in which the nano-fine powder has a higher solubility, which is advantageous for improving bioavailability and efficacy, and reducing the amount of the drug to be used.
  • the present invention also provides various methods for preparing crystal forms and nano-micronization, and pharmaceutical compositions and corresponding dosage forms thereof for 4-CPRE and methods for their preparation.
  • the invention also provides the use of 4-carboxyphenyl retinyl alcoholate in the preparation of a medicament for treating and preventing diseases, wherein the disease is selected from the group consisting of: 1.
  • Precancerous lesion chemoprevention 1.
  • Epithelial dysplasia (or atypical hyperplasia): (1) Respiratory system: 1) Severe hyperplasia of nasopharyngeal mucosa, 2) Nasal papilloma, 3) Laryngeal papilloma, 4) Vocal cord Hyperplasia of the mucosa, leukoplakia, 5) dysplasia of the bronchial epithelium, 6) bronchial adenoma.
  • Inverted papilloma of the bladder 3). Severe prostatic epithelial sarcoma. 4). Cystic hyperplasia of the breast, 5) intraductal papilloma of the breast and breast fibroadenomas. 6). Severe cervical erosion with dysplasia. 7). Endometrial hyperplasia with dysplasia. (4) Skin mucosa: 1). Skin coloring dry skin disease, 2). Skin keratosis (especially palm keratosis between large and small fish). 3). Mucosal leukoplakia with dysplasia, mostly in the mouth, esophagus, vulva, vagina, cervix, penis. 4).
  • Proliferative scars (especially scars caused by chemical burns). 5). Oral erythema, 6). Submucosal fibrosis, 7) Discoid lupus erythematosus, 8) Lichen planus, etc. (5) Endocrine system: 1). Thyroid adenoma, 2) Thyroid papillary adenoma. 2, mesenchymal tissue-derived lesions: 1). Invasive fibromatosis, 2). Adipoma, 3). Smooth muscle myblastoma (heterotypic or odd-type smooth muscle cell tumor called singular leiomyoma). 3, lymphoid tissue-derived lesions: 1). Angioblastic immune cell lymph node disease, 2) pseudo lymphoma, 3.
  • Bone-derived lesions 1) osteoblastoma, 2) benign chondroblastoma, 3) osteochondroma, 4) chondroma, 5) osteofibrillar, 6) Bone histiocytosis X. 7. Malformation osteitis, 8. Osteoarthritis (bone Paget disease). 5, neuroectodermal-derived lesions: 1). ⁇ , 2). APUD tumors. 6. Precancerous lesions of people at high risk of occupational disease cancer (long-term or high-dose exposure to carcinogens): Personnel engaged in arsenic, asbestos, uranium ore and radioactive pollution.
  • the present invention provides a class of pharmaceutical compounds which are derivatives of retinol, which are named herein: Chinese name: 4-carboxyphenyl retinyl alcoholate (referred to as 4-CPR ethanolate);
  • This class of compounds has the following structure:
  • the present invention also includes an isomer of 4-carboxyphenylretinamidoethanolate having the following structure:
  • the invention also provides a method for preparing 4-CPRE, the method comprising the following steps:
  • 4-CPR was produced by the method of European Patent No. EP 0009777, etc.; and 4-CPR was further reacted with ethanol to obtain 4-CPRE of the present invention.
  • the yellow 4-CPR solid was added to 95% ethanol 0. 005 ⁇ 0. 8M (0. 31 ⁇ 45 ml), the temperature was stirred at _18 ⁇ 80 °C for 30 ⁇ 60 minutes, and the solid changed completely from bright yellow to blood. red. Filtered, washed 3 times with 95% ethanol, protected from light, naturally dried to constant weight, and obtained a red blood powdered final product 4-CPRE. Quality meets medicinal standards.
  • the present invention also provides a linear or cyclic positional isomer of 4-CPRE having three heterogeneous intermolecular hydrogen bonds, corresponding crystals. Morphology and preferred crystal morphology and preparation:
  • the differential crystal DSC spectrum and data [by peak temperature (abbreviated as ⁇ ) and extrapolated starting temperature (referred to as Ti)] identify each crystal form, the specificity is better, clearer, less error; Infrared spectroscopy and data (peak position, peak shape and intensity) to identify the similarities and differences of each crystal form; Third, the powder X-ray diffraction spectrum and data (d value and 1/10 value) to identify the crystal system of each crystal sample and Similarity and dissimilarity of strength; Fourth, crystallographic X-ray diffraction spectrum and data were used to identify its crystalline chemical molecular structure and single crystal or polymorphic form; Fifth, thermogravimetric TG identified alcoholate II The type (peak) is a pseudopolymorph (a non-alcoholic 4-CPR compound) that loses one molecule of ethanol.
  • peak temperature abbreviated as ⁇
  • Ti extrapolated starting temperature
  • Type IV differential thermal DSC spectrum Ti l73. 5 ⁇ 5 ° C, Tpl 84 ⁇ 6 ° C peak (referred to as IV peak) and Ti l l3 ⁇ 3 ° C, Tpl25 ⁇ 5 ° C peak (referred to as II peak, Pseudopolymorphism caused by ethanol as ethanol; peak shape: Tpl25 ⁇ 5 °C peak is round (bulk-shaped) broad peak.
  • the peak of Tpl84 ⁇ 6°C is mostly broad or shoulder (when polymorph). It is collectively referred to as a type IV single crystal type, which is a stable crystal form and is proved to be a single crystal type and can be obtained separately.
  • Type IV powder X-ray diffraction spectrum and data Peak position and d value and 1/10 value
  • the peak position, peak shape, d value and I/IO value of type IV are different from the corresponding comparisons of type V and type III.
  • the hydrogen atom and the amide oxygen atom of the 4-CPR nitrogen atom are hydrogen-bonded to the ethanol hydroxyl group in a molecular ratio to 4-CPRE; the 4-CPRE molecule has a hydrogen bond relationship; in the crystalline state, the molecule is hydrogen bonded and Van der Waals gravitationally maintains its stable arrangement in three-dimensional space. It belongs to the type IV single crystal of the second type of space group 2 peak + IV peak, and should also be a single crystal form.
  • the three-dimensional conformation is that the five double bonds are all-trans, the alicyclic half-chair type is a conformational isomer; the type IV single crystal has a density of 1. 10 ⁇ 1. 20 I cm 3 .
  • the above identification results demonstrate that the type IV crystal form is a cyclic positional isomer formed by heterogeneous intermolecular hydrogen bonds.
  • the preparation method of type IV crystal form is as follows:
  • Low-temperature solvent method Add a saturated solution of 4-CPRE sample dissolved in a non-polar solvent to a small amount of ethanol solution at low temperature (-5 ⁇ - 18 °C), continue to maintain the condition to complete the crystallization, and filter , Wash, dry, protected from light, sealed. A general crystalline sample of type IV is obtained.
  • Solid heating or light conversion method The solid containing V type or III type is irradiated with an infrared lamp and heated at 30 to 50 ° C for 12 to 6 hours, and is transformed into a single crystal form of type IV.
  • the solid containing type III or V is refrigerated at 4 ° C for about 1 to 3 years, it can be separately converted into a type IV single crystal form or an incompletely crystallized poly crystal form. Room temperature crystallisation is somewhere in between.
  • Sample A (prepared by chemical method): In low temperature ( ⁇ -18 ° C), >2000 rpm high-speed stirring or ethanol under ultrasonic vibration of 20 ⁇ 60 Hz, quickly add or spray 4- dissolved by heating non-polar solvent The CPRE sample is saturated (maintained at the temperature of no crystallization), and the conditions are maintained to complete the crystallization, filtration, washing, drying, protection from light, and confined storage. A sample of type IV nano-fine powder (diameter ⁇ 10 ⁇ m) was obtained.
  • Sample B (by mechanical dry pulverization or wet pulverization): Wet pulverization (re-evaporation) of an IV type ordinary solid crystal sample by grinding or ball milling, or adding an insoluble solvent to a poorly soluble sample, to obtain a type IV abrasive powder Or ultrafine powder (diameter ⁇ 1 micron). Description and identification of V-type crystal form:
  • V-type crystal differential thermal DSC spectrum Ti l87 ⁇ 10 ° C, Tpl96 ⁇ 6 ° C peak (referred to as V peak) and Ti l l3 ⁇ 3 ° C, Tpl25 ⁇ 5 ° C peak (referred to as II peak, It is a pseudo-polymorph type due to the ethanol compound, and is collectively referred to as a V-type single crystal type, which is a metastable crystal form, and is also proved to be a single crystal type, and can be obtained separately.
  • Peak shape Tpl25 ⁇ 5°C peak is round (bulk-shaped) broad peak.
  • the Tp l96 ⁇ 6°C peak is mostly a peak or a broad peak or a shoulder.
  • the infrared spectrum comparison is similar to the peak position, peak shape and fingerprint area of the same crystal sample identified by DSC.
  • the infrared data table is as follows:
  • 3645 free primary alcohol 0-H stretching vibration, broad peak
  • 3440, 3400 3300-3050 (intermolecular association alcohol 0 ⁇ _ ⁇ stretching vibration), 2918, 2536, 2366, 1780, 1687, 1665, 1595 , 1560, 1530, 1514, 1490, 1404, 1360, 1320, 1310, 1280, 1257, 1159, 1140, 1126, 1080 (alcohol C- 0 ⁇ telescopic), 1043, 960, 951, 877, 858, 771 , 694, 600, 544, 507.
  • the peak position, peak shape, d value and 1/10 value of the V type are different from the corresponding comparisons of the type IV and type III.
  • the three-dimensional conformation is that the five double bonds are all-trans, the alicyclic half-chair type is a conformational isomer; the V-type single crystal density is 1. 10 ⁇ 1. 20 I cm 3 .
  • the above identification results demonstrate that the V-form crystal form is an 8-molecular crystalline polymer in which a heterogeneous intermolecular hydrogen bond forms a linear positional isomer.
  • the preparation method of the V-type crystal form is as follows:
  • Solvent method Single or mixed solvent of non-polar solvent and ethanol (volume ratio 1: ⁇ 1) Recrystallization: Natural crystallization at room temperature, a general crystalline sample of V type (metastable crystal form) can be obtained.
  • the V-type polymorph has the following characteristics: When a solid containing V-type is gradually changed to type IV under standing, heating or illumination, such as 4 ° C for about 275 days or room temperature for several days, it can be crystallized into V type + IV type. Composite polymorph (low temperature and short time incomplete crystal transformation); final crystallization into type IV crystals over time.
  • the preparation method of the V-type crystal form nano ultrafine powder is as follows:
  • V-type abrasive powder or ultrafine powder can be obtained by pulverizing a V-type ordinary crystal sample or an inert solvent sample by grinding or ball milling.
  • the sample was recrystallized from a single or mixed solvent of a polar solvent with ethanol (volume ratio 1: ⁇ 0.31): such as 1 sample / ethanol (lg: 35 ml) ; 2 sample / acetone / ethanol (lg: 10 ml: 5 ml) ; 3 sample / ethyl acetate / ethanol (lg: 5 ml: 2 ml). It can be more crystalline type III.
  • the type III structure is as follows:
  • 4-CPRE is first recrystallized from a non-polar solvent or a medium-polar solvent (eg petroleum ether, ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, ethyl acetate, dichloromethane, etc.) 4-CPR (no crystalline alcohol) solid, followed by addition of ethanol at room temperature at 0.5-lh for alcoholation reaction: V-type + ⁇ -type, 4-CPRE single crystal metastable crystal form.
  • a non-polar solvent or a medium-polar solvent eg petroleum ether, ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, ethyl acetate, dichloromethane, etc.
  • 4-CPR no crystalline alcohol
  • Form I crystal which is a polymorph of 4-CPR (non-alcoholate) itself, is very unstable.
  • Alcohol-free type I ie, the original compound 4-CPR without crystalline alcohol: Alcohol-free type I placed at room temperature for 3 months has deteriorated and is not medicinal, darkens in color, powder agglomerates, melting point drops, TLC There are many noises and it is very unstable.
  • Solid type III and V type crystals are type IV, the speed is proportional to temperature, and the degree is proportional to time; type IV is the final, most stable, single crystal form prepared or transformed.
  • Type IV sample V type sample > ⁇ type sample > > Alcohol free type I sample
  • 4-CPRE is preferred as Form IV and Form V crystals.
  • the present invention also includes micronizing a compound of the present invention or a crystalline form thereof using a micronization technique to obtain a micronized powder, which is also a content of the present invention, and preferably a nano-sized micronized material.
  • the preparation may be carried out by subjecting various crystal solids of 4-CPRE or a suspension of ethanol and an ethanol-containing solvent to physical grinding, sieving (or filtering and concentrating) to obtain ultrafine powder of 10 to 10000 nm, and avoiding Light, sealed and preserved.
  • the micronized powder is used as a raw material for preparing various pharmaceutical preparations.
  • the micronization technology of the present invention is to process the compound or crystal form of the present invention into ultrafine powder having a particle diameter of 10 to 10000 nm by the existing ultrafine pulverization method.
  • the micronization technology has chemical and mechanical methods. Two. Chemical synthesis can produce micron, submicron or even nanometer powders.
  • the mechanical pulverization method can be divided into dry pulverization and wet pulverization to obtain submicron to nanometer powders.
  • dry pulverization has airflow, high frequency vibration, and rotation.
  • Ball (rod) grinding, hammering and self-grinding; wet pulverization is mainly colloid mill, homogenizer and ultrasonic. Any of the above methods can be used in the present invention.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention or a corresponding crystalline form thereof, or a micronized powder thereof, which is a pharmaceutically active ingredient, optionally containing a pharmaceutically acceptable carrier.
  • composition of the present invention preferably in the form of a unit dose of a pharmaceutical preparation, can be formulated into any pharmaceutically acceptable dosage form, which is selected from the group consisting of: tablets, sugar-coated tablets, film-coated tablets, intestines. Soluble tablets, capsules, hard capsules, soft capsules, oral liquids, buccal agents, granules, granules, pills, powders, ointments, dandruffs, suspensions, solutions, injections, suppositories, ointments , plasters, creams, sprays, drops, patches, films.
  • any pharmaceutically acceptable dosage form which is selected from the group consisting of: tablets, sugar-coated tablets, film-coated tablets, intestines. Soluble tablets, capsules, hard capsules, soft capsules, oral liquids, buccal agents, granules, granules, pills, powders, ointments, dandruffs, suspensions, solutions, injections, s
  • a pharmaceutically acceptable carrier may be added in the preparation of the medicament, and the pharmaceutically acceptable carrier may be: the carrier is selected from the group consisting of: mannitol, sorbitol, sorbic acid or potassium salt, sodium metabisulfite, sodium hydrogen sulfite, thiosulfuric acid Sodium, cysteine hydrochloride, thioglycolic acid, methionine, azone, EDTA disodium, EDTA calcium sodium, monovalent alkali metal carbonate, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid , amino acids, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and its derivatives, Alginate, gelatin, polyvinylpyrrolidone,
  • the pharmaceutical preparation of the present invention determines the usage amount according to the condition of the patient at the time of use.
  • the pharmaceutical composition of the present invention in the preparation of the medicament, the unit dose of the medicament may contain the compound of the present invention 0.1-1000 mg, the balance being a pharmaceutically acceptable carrier. 001-99. 9% ⁇
  • the pharmaceutically acceptable carrier may be 0. 001-99. 9% by weight of the total weight of the preparation.
  • retinoids are generally unstable, especially the original compound 4-CPR without crystalline alcohol, left at room temperature in the dark for 3 months, can not be medicinal, darker, crystallized
  • the bonding and melting point decreased, and the number of impurity points identified by TLC increased. HPLC showed that the number and amount of impurity peaks increased.
  • the new compound 4-CPRE is unique in its properties: it prevents or reduces the formation of by-products such as peroxides, cis isomers, polymers, hydrolysates, etc. of 4-CPR, and has little change in mass at room temperature for 24 months.
  • a new alcoholation reaction is carried out to condense the nitrogen atom of the original compound 4-CPR and the hydroxyl group of the alcohol into a 4-CPRE (crystalline alcoholate) by hydrogen bonding and in an equal molecular ratio. Further, the alcoholation reaction can be carried out in a solid phase at room temperature to prevent side reactions such as oxidation and isomerization of 4-CPR at a high temperature.
  • the superiority of the preferred crystal form and ultrafine pulverization is as follows: Since 4-CPRE is a poorly soluble solid organic drug, its solid has five crystal forms, of which ⁇ type (pseudopolymorphism caused by crystalline ethanol) Tp 125 ⁇ 5° ( : Ti 113 ⁇ 3 °C, the most stable; Type III Tp 152 ⁇ 3 ° C, Ti 150 ⁇ 2 ° C, the least solubility, unstable and easy to convert to type IV; type IV Tp 184 ⁇ 6 ° C, Ti 173 ⁇ 5 ° C, converted from type III and type V, solubility and stability are large; V type Tp 196 ⁇ 6 ° C, Ti 187 ⁇ 10 ° C, solubility is large, but unstable and easy to convert to IV Type IV or V can exist as a single crystal.
  • ⁇ type pseudopolymorphism caused by crystalline ethanol
  • the stability and solubility of the crystal form are larger than the general preparation of polymorphs containing type I or type III (see crystal identification and solubility comparison);
  • the nano-ultrafine powder type IV (including type II) has the highest solubility and stability compared with type III and type V. Therefore, nano-superfine powder containing type II type IV or V and both are selected as medicines.
  • the preferred crystalline form it is advantageous to increase bioavailability and reduce the dosage of the drug.
  • Figure 1 shows the differential thermal DSC spectrum of Form IV:
  • Figure 2 shows the infrared spectrum of type IV crystal form.
  • Figure 3 is a powder of type IV crystal powder X-ray diffraction spectrum
  • Figure 4 shows the differential thermal DSC spectrum of the V-type crystal form:
  • Figure 5 shows the infrared spectrum of the V-type crystal form.
  • Figure 6 is a powder of X-ray crystal form X-ray diffraction spectrum
  • Figure 7 shows the differential thermal DSC spectrum of the type III crystal form:
  • Figure 8 shows the infrared spectrum of type III crystal form.
  • Figure 9 is a powder of type III crystal powder X-ray diffraction spectrum
  • Figure 10 is a perspective view of the molecular structure
  • Figure 11 shows the projection of the unit cell along the c direction.
  • 3645, 3440, 3400, 3300-3050 (alcohol 0-H stretching vibration, associative hydroxyl group), 2918, 2655, 2536, 2366, 1780, 1687 (aryl acid carbonyl), 1665 (amide carbonyl), 1595, 1560, 1530 , 1514, 1490, 1404, 1360, 1320, 1310, 1280, 1257, 1159, 1140 and 1080 (alcohol C-0 stretching vibration), 1126, 1043, 960, 951, 877, 858, 771, 694, 600, 544 , 507.
  • the crystal X-ray diffraction spectrum and data prove that: 1
  • the nitrogen and amide oxygen atoms of the original compound 4-CPR are hydrogen bonded to the ethanol hydroxyl group and are alcoholized to 4-CPRE in an equal molecular ratio; Relationship; In the crystalline state, the molecules maintain their stable arrangement in three-dimensional space by hydrogen bonding and van der Waals attraction, and belong to the V-type sample of the second type space group 2 peak + V peak, which is a single crystal form.
  • 3 three-dimensional conformation is 5 double bonds in all-trans form, alicyclic half-chair type is conformational isomer crystal form; V-type ordinary crystalline sample
  • the density is 1. 10 ⁇ L 20 / cm 3 .
  • Thermogravimetry TG spectra and data Identification of weight loss at the type II peak position 9. 64%, is 4-? 1 ⁇ molecular weight 465. 64 lost one molecule of ethanol molecular weight 46. 07 caused. It is proved that type II is a pseudopolymorphic type caused by crystalline ethanol.
  • Solvent method Quickly add 4-CPRE sample dissolved in ethyl acetate (or ethylene glycol dimethyl ether) at room temperature (_18 ° C), vigorously stirred rapidly, continue to stir the mixture vigorously and rapidly to complete crystallization. , Filter, wash, dry, can obtain type IV crystal, save from light.
  • the identification is as follows:
  • the type IV single crystal type (i) the nitrogen atom and the amide oxygen atom of 4-CPR and the ethanol hydroxyl group are hydrogen-bonded and alcoholized to 4-CPRE in an equal molecular ratio; the hydrogen bond relationship exists between the 4-CPRE molecules; In the crystalline state, the molecules maintain their stable arrangement in three-dimensional space by hydrogen bonding and van der Waals attraction. They belong to the V-type single crystal type of the second type space group (ii) II peak + V peak, which is a single crystal form. Therefore, the type IV single crystal of the II peak + IV peak should also be a single crystal form.
  • the three-dimensional conformation is a total of five double bonds in an all-trans form, and the alicyclic is a half-chair type is a conformational isomer; the type IV single crystal has a density of 1. 10 ⁇ 1. 20 I cm 3 .
  • the data sheet is as follows:
  • Solid heating conversion method Solid infrared lamp containing type III or V is heated and heated at 30-5 CTC for 12 to 6 hours, and crystallized into a single crystal form of type IV, see Figures 2 and 3.
  • 2 refrigeration conversion method When the solid containing type III or V is placed at 4 ° C for about 730 days or 386 days or 275 days, can be crystallized into type IV single crystal form or incompletely crystallized polymorph, as shown 4, 6, 7 Example 4:
  • V-type single crystal type Sample / petroleum ether / dichloromethane / ethanol ratio of 1 : 1 : 3 : 3, recrystallization under heating, to obtain V-type single crystal type.
  • Differential thermal DSC spectrum Til77.6°C Tpl90.4°C peak (V peak) and Till3.7°C, Tpl29.6°C peak (II peak, pseudopolymorph due to ethanolate), It is collectively referred to as a V-type single crystal type, which is a metastable crystal form, and is also proved to be a single crystal type, which can be obtained separately.
  • Peak shape: Tpl29.6°C peak is round (bulk-shaped) broad peak.
  • Tp 190.4 ° C peak is a broad peak. See Figure 6.
  • V-type single crystal type 1 the original compound 4-CPR nitrogen atom and amide oxygen atom and the ethanol hydroxyl group are hydrogen-bonded and alcoholized in the same molecular ratio to 4-CPRE (crystalline alcoholate); 4-CPRE intermolecular There is a hydrogen bond relationship; in the crystalline state, the molecule maintains its stable arrangement in a three-dimensional space by hydrogen bonding and van der Waals attraction, and belongs to the V-type single crystal type of the second type space group 2 II peak + V peak, which is a single crystal form.
  • the three-dimensional conformation is that the five double bonds are all-trans, the alicyclic half-chair type is the conformational isomer form; the V-type single crystal density is 1.10 ⁇ 1.20 I cm 3 .
  • the single crystal type which is a metastable crystal form, has also been shown to be a single crystal type and can be obtained separately.
  • the Tp20L5°C peak is a spike.
  • Solid pulverization method The V-type ordinary crystal sample is pulverized by grinding or ball milling, and sieved to obtain a V-type ultrafine powder.
  • the starch is dried, passed through the No. 7 sieve, and the 4-CPRE powder is thoroughly mixed with the starch, and sieved through the No. 7 sieve twice. Into the appropriate capsule.
  • Aqueous phase 4-CPRE 0.3g; ethanol 3ml; azone ketone L5g; soil temperature -80 4g; sorbic acid 0.2; gallic acid ester 0.2g; vitamin C 0.5; triethanolamine 1.4g; water 60ml; Dissolved.
  • Oil phase cetyl alcohol 8 g; beeswax 2 g; sban-80 3 g; liquid paraffin 10 g; propylene glycol 4 ml; heated at 75 ° C until fully dissolved. The oil phase was added dropwise to the aqueous phase under high-speed stirring and holding, and the emulsion was further emulsified for 0.5 hour, and filled in a light-proof, sealed medicinal package.
  • polyethylene glycol 1000 75%) + polyethylene glycol 4000 (25%) (topical)
  • the auxiliary material water bath is heated and melted, the 4-CPRE micropowder is suspended in the matrix under stirring, and the mixture is quickly poured into the cooled mold (or the mold is placed in a refrigerator to be solidified), formed, and the mold is removed, and after passing the inspection, Tin foil sealed packaging.
  • Cervical epithelial dysplasia treatment topical use of 4-CPRE suppository, 1.5 g / suppository (main drug concentration 0.5%, 7.5 mg / granule), 1 capsule / 1 time / day, vaginal, three months for a course of treatment , a total of two courses of treatment. Twenty-seven patients were treated with the first course of treatment, the effective rate was 8 1.2 8 %, and the effective rate was 88.89%. After the second course of treatment, 26 cases were effective (effective rate 96.3%), of which 24 cases of precancerous lesions disappeared (cure rate 88.9%). From the results, 4-CPRE has reversed the precancerous lesions of the cervix to normal. Precancerous blockade with 4-CPRE does not require special medical equipment and conditions. It is easy to use and can be used for self-use. The patient is easy to accept and has no obvious damage to liver and kidney.
  • Treatment of oral leukoplakia Clinical and pathological types were randomized into two groups. Among them, 113 patients in the 4-CPRE treatment group and 61 patients in the control group. Patients in the treatment group received 4-CPRE capsules, 20 mg each time, 2 to 3 times a day, and used for 4 months as a course of treatment. General medication 2 to 3 courses. The control group used the same shape of placebo in the same method. After 1 to 3 courses of treatment, the total effective rate of the 4-CPRE treatment group was 83.2%, and the spontaneous improvement rate of the placebo control group was 11.5%.
  • 4-CPRE was used to treat dysplasia of the digestive tract mucosa, including 104 patients in the 4-CPRE treatment group. 30 patients in the control group.
  • the treatment group took 20 mg of 4-CPRE capsules, 2 to 3 times a day, orally, and even served for 2 to 4 months.
  • Dele control group took Dele granules, each containing colloidal bismuth subcitrate (CBC) lOOmg, 1 packet each time, 2 ⁇ per day 4 times, even for 2 to 3 months.
  • CBC colloidal bismuth subcitrate
  • the total effective rate is 89.4% (93/104), the effective efficiency is 70.2% (73/104); the total effective rate of the Dele group is 40.0% (12/30), and the efficiency is 16.7% (5 /30).
  • the X 2 test, P ⁇ 0.01 the difference was very significant.
  • Treatment of white lesions of the vulva 172 cases of white lesions of the vulva, including 130 cases in the 4-CPRE treatment group and 42 cases in the control group.
  • the treatment group was treated with 4-CPRE capsules orally, 40 mg each time, 2 times a day, and 3 months for 1 course of treatment.
  • 10 cases were treated with external use of hypocrellin ointment, and the method was applied locally to the affected area. 2 times a day; 32 cases were observed by fluorouracil application.
  • the method was applied to the affected area, one (350 mg) each time, once every 3 days, and 3 months for 1 course.
  • the 4-CPRE medication group recovered in 13 patients (10%), markedly improved and improved in 112 patients (86.15%), and ineffective in 5 patients (3.85%).
  • the control 5-FU group was effective in 22 cases (68.8%).
  • 10 cases were discontinued within 3 to 6 months due to ineffectiveness.
  • Treatment of cervical dysplasia Among 64 patients with dysplasia, 34 were treated with blockade in the outpatient department and 30 were treated with blockade in hospital. The treatment for blocking is: Oral 4-CPRE capsules, 20mg each time, 3 times a day, 3 months for 1 course of treatment. Two groups of controls were used: 1 treatment control, compared with 34 cases of laser occlusion for cervical dysplasia; 2 natural conversion control, compared with the natural history of cervical dysplasia in Jingan County, Jiangxi province (247 cases). Among the 64 patients, 37 cases of cervical dysplasia disappeared, 14 cases of alleviation, the cure rate was 57.8%, and the effective rate was 79.7%.
  • Tips 4-CPRE has a certain effect on reversing cervical dysplasia and promoting epithelial differentiation.
  • the treatment method is 4-CPRE capsule 10mg, taken orally twice a day, and the affected area is coated with 0.5% 4-CPRE ointment, 1 ⁇ 2 times a day, continuous medication for 3 ⁇ 4 months (total amount 3g), 4 cases of lesions disappeared or only residual pigmentation; lesions reduced by 50%, ulcer surface secretions decreased significantly, itching was significantly reduced, verrucous hyperplasia flattened, softened in 8 cases; no change in 4 cases; no worse .
  • One case of pathological diagnosis was Bowen's disease and one patient had a 2cmX lcmX 0. 5cm ulcer (pathological diagnosis of keratosis with mild dysplasia). The condition was quickly controlled, ulcer healing, skin Return to normal, no recurrence for more than 1 year.
  • Treatment of mild atypical hyperplasia of tubular adenoma of colon polyps 1 case of multiple outpatient sputum symptoms per day, colonoscopy for transverse and sigmoid mucosa multiple polyps, the larger 3 biopsy diagnosed as tubular gland Mild dysplasia of the tumor epithelium.
  • Blocking treatment is: Oral 4-CPRE capsules, 50mg each time, 2 times a day, 5 months of treatment. Visual impairment occurred after 1 month (indistinct, blind, dry).
  • the above-mentioned adverse reactions are generally mild and more tolerable. When the medication is reduced or discontinued, the symptoms disappear. In some cases, no similar reactions occur after continued medication. All patients were examined for liver and kidney function before and after medication. After treatment, transient transaminase increased and triacylglycerol increased slightly in 17 cases. However, after 10 cases of 4-CPRE and hepatoprotective drugs were taken, the transaminase decreased to normal.
  • the treatment method is 4-CPRE capsule 10mg, taken orally twice a day, and the affected area is coated with 0.5% 4-CPRE cream, 1 ⁇ 2 times a day, continuous medication for 3 ⁇ 4 months (total dosage 3g),
  • the lesions basically disappeared; the lesions were reduced by 50%, the ulcer surface secretions were significantly reduced, and the itching pain was significantly reduced; no further deterioration was observed.
  • Skin keratosis Skin keratosis, follicular keratosis, ichthyosis, lichen planus, acne vulgaris, red pityriasis, facial pityriasis, skin photodermatitis and aging, psoriasis adjuvant therapy, etc.;

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Abstract

Cette invention concerne un rétinamidéthanolate de 4-carboxyphényle, son procédé de préparation, une composition pharmaceutique le contenant et son utilisation contre les cancers.
PCT/CN2012/075143 2011-05-09 2012-05-07 Rétinamidéthanolate de 4-carboxyphényle, son procédé de préparation et composition pharmaceutique le contenant WO2012152209A1 (fr)

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EP0009777A1 (fr) * 1978-10-07 1980-04-16 BASF Aktiengesellschaft N-(carboxy)phényl amides de l'acide rétinoique et 7,8-déhydro-rétinoique, procédé de préparation et compositions pharmaceutiques les contenant
CN1976692A (zh) * 2004-06-23 2007-06-06 西来昂诊疗公司 用视黄基衍生物治疗眼部疾病的方法和组合物
CN102260186A (zh) * 2011-05-09 2011-11-30 北京吉科特科技有限责任公司 4-羧基苯基视黄酰胺基乙醇合物及其制备方法和药物组合物

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CN101229147B (zh) * 2007-12-24 2010-09-01 复旦大学 N-4-羟苯视黄酰胺在制备抗肝纤维化药物中的用途

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EP0009777A1 (fr) * 1978-10-07 1980-04-16 BASF Aktiengesellschaft N-(carboxy)phényl amides de l'acide rétinoique et 7,8-déhydro-rétinoique, procédé de préparation et compositions pharmaceutiques les contenant
CN1976692A (zh) * 2004-06-23 2007-06-06 西来昂诊疗公司 用视黄基衍生物治疗眼部疾病的方法和组合物
CN102260186A (zh) * 2011-05-09 2011-11-30 北京吉科特科技有限责任公司 4-羧基苯基视黄酰胺基乙醇合物及其制备方法和药物组合物

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