CN107469086A - The application of pth receptor analog and its salt or prodrug in the medicine for preparing treatment and/or prevention PUD D - Google Patents
The application of pth receptor analog and its salt or prodrug in the medicine for preparing treatment and/or prevention PUD D Download PDFInfo
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- CN107469086A CN107469086A CN201710637247.8A CN201710637247A CN107469086A CN 107469086 A CN107469086 A CN 107469086A CN 201710637247 A CN201710637247 A CN 201710637247A CN 107469086 A CN107469086 A CN 107469086A
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- KUYMVWXKHQSIAS-UHFFFAOYSA-N tert-butyl 2-chloroacetate Chemical compound CC(C)(C)OC(=O)CCl KUYMVWXKHQSIAS-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- 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
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of pth receptor analog and its new application of pharmaceutically acceptable salt or prodrug, pth receptor analog and its pharmaceutically acceptable salt or prodrug are used to treat and/or prevent lung disease.Pth receptor analog and its pharmaceutically acceptable salt or prodrug can effectively protect alveolar epithelial cells, adjust the synthesis of alveolar epithelial cells surface protein, storage and distribution, promote alveolar epithelial cells ripe, differentiation and cell integrity, be advantageous to the removing of intrapulmonary hydrops, promote to be damaged mitochondria recovery in alveolar epithelial cells, strengthen mitochondria biogenesis, so as to be advantageous to injured pulmonary tissues reparation, prevent and reverse pulmonary fibrosis, adjust immune response, change cancerization environment, reach preventing and treating PUD D, improve the PFTs such as gas exchanges, reach therapeutic effect.
Description
Technical field
The present invention relates to pth receptor analog and its a kind of new application of pharmaceutically acceptable salt or prodrug, tool
Body is related to a kind of pth receptor analog and its pharmaceutically acceptable salt or prodrug and is preparing treatment and/or prevention lung
Application in the medicine of disease.
Background technology
Microorganism population, indoor and outdoors air pollution including smoking in living environment in air, can be directly resulted in
Tuberculosis Susceptible population lung injury, causes lesion, can cause a variety of diseases such as inflammation, ALI, pulmonary fibrosis, lung cancer
Disease.More attract people's attention, with the development that China's economy is advanced by leaps and bounds, environmental pollution getting worse, particularly current mist
The situation is tense for haze.So severe air ambient certainly will threaten the lungs of the numerous common people, and respiratory tract patient will sharply increase.According to pre-
It is alert, will be the PUD D high-incidence season after 5 to six years, it is contemplated that 20 years will be continued, this will bring great social concern.
At present, the medicine of most for the treatment of PUD D is given by whole body body circulation, by oral or be subcutaneously injected,
But these therapeutic effects are limited, serious side effects significantly (including immunosupress, Subsequent infection, Acute Exacerbation Period disease and a large amount of
Bleeding), also in the presence of slight side effect (including gastrointestinal o complications, such as diarrhoea and nausea), these side effects have had a strong impact on disease
The quality of life of people.Therefore, it is necessary to provide a kind of medicine of new treatment PUD D.
Hormone derivative is a kind of compound for playing the part of important biomolecule role in the conversion of a variety of analytic metabolisms.In describedization
In compound, pth receptor analog such as GC-1 (3,5- dimethyl -4- (4- hydroxyl -3- isopropyl benzyls)-phenoxy group second
Acid) be a kind of emerging medicine, by with Thyroid Hormone Receptors selective binding, played in particular organization and intend thyroid hormone
Effect, is related to the speed for controlling a variety of metabolic processes in vivo.Pth receptor analog is widely used in being related to thyroid gland
The treatment of several lesions of obstacle.However, so far there is not yet relevant pth receptor analog and its can pharmaceutically connect
The salt or prodrug received are used to treat and/or prevent reporting for PUD D.
The content of the invention
To solve the above problems, the invention provides a kind of pth receptor analog and its pharmaceutically acceptable salt
Or the new application of prodrug, i.e. the application in the medicine for preparing treatment and/or prevention PUD D.
First aspect present invention provides pth receptor analog and its salt or prodrug and is preparing treatment and/or prevention
Application in the medicine of PUD D.
Wherein, the PUD D includes ALI, pulmonary fibrosis, tracheitis or lung cancer.
Wherein, the pth receptor analog and its salt or prodrug include GC-1, DIMIT, CGS23425,
CGS26214、TRIAC、L-94901、HY-1、KB-141、KTA-439、QH-2、GC-14、NH-3、HY-4、KB-2115、GC-
24th, at least one of MB-07811, T-0681, DITPA and K5B3495.
Wherein, the administering mode of the medicine includes local administration, digestion canal drug administration or parenteral administration.
Wherein, the administering mode of the medicine includes oral, hypodermic injection or intramuscular injection.
Wherein, the pth receptor analog and its salt or prodrug as single-activity composition or with other pharmaceutically
Acceptable active component forms composition to prepare the medicine.
Wherein, the medicine is used in combination with other active agents, and other described active agents include pirfenidone and Buddhist nun
At least one of Da Nibu.
Wherein, the pth receptor analog and its salt or prodrug form composition with pharmaceutically acceptable carrier
To prepare the medicine.
Wherein, the pth receptor analog and its dosage of salt or prodrug are daily micro- g/kg of body of 1-10000
Weight.
Pth receptor analog and its new application of pharmaceutically acceptable salt or prodrug provided by the invention, first shape
Adrenoceptor analog and its pharmaceutically acceptable salt or prodrug can effectively protect alveolar epithelial cells, adjust on alveolar
The synthesis of endothelial cell surface albumen, storage and distribution, promote ripe alveolar epithelial cells, differentiation and cell integrity, be advantageous to lung
The removing of interior hydrops, promote alveolar epithelial cells in be damaged mitochondria recover, strengthen mitochondria biogenesis, so as to be advantageous to by
Lung tissue reparation is damaged, prevents and reverses pulmonary fibrosis, adjust immune response, change cancerization environment, reaches preventing and treating PUD D, change
The PFTs such as kind gas exchanges, reach therapeutic effect.
Brief description of the drawings
Fig. 1 is mouse hydroxyproline content histogram (A) and gene expression analysis figure (B, C, D) after intraperitoneal injection GC-1；
Fig. 2 is Mason's trichrome stain histochemical analysis figure of mouse lung tissue after intraperitoneal injection GC-1；
Fig. 3 is mouse hydroxyproline content histogram (A) and gene expression analysis figure (B, C, D, E, F) after oral GC-1；
Fig. 4 is Mason's trichrome stain histochemical analysis figure of mouse lung tissue after oral GC-1.
Embodiment
As described below is the preferred embodiment of the present invention, it is noted that for those skilled in the art
For, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications are also considered as
Protection scope of the present invention.
Unless otherwise specified, the implication phase that all technical and scientific term herein use in the invention and generally
Together.Although the narration of some methods and material can be used for description of the invention.
Herein, " one " is used to refer to one or more than one (such as at least one).For example, " a kind of composition " contains
Justice is a kind of composition or more than one composition.
Herein, measured value expression, such as quantity, the duration, and similar refer to include ± 20% or ± 10%
Variable, either more accurate ± 5% or ± 1%, more accurately can reach ± 0.1% in some special values, these changes
Amount is more suitable for the method described by article.
Disease or disorder " mitigation " refer to the order of severity of patient's problem symptom, and frequency of disease development has declined, or
Both have.
" giving jointly " one side be meant that and meanwhile give experimenter's trial drug or saline control (reference group) with
Another medicine is treated together, is to separate administration herein, when giving practical operation jointly, simply in the treatment Chinese medicine
Thing is to be used in combination.The medicine given jointly can be various forms or mixture, such as solid, liquid, gel or solution.
Herein, " combination " or " drug regimen " refers to the mixing of more than one medicines used in the present invention,
Use pharmaceutically acceptable carrier.Drug regimen helps medicine to be easier to reach patient or experimental animal focus.In clause
Description multiple technologies include, it is not limited to, intravenously administrable, oral, aerosol suction, parenteral, eye, nasal cavity, lung's drawn game
Portion is administered.
" disease " refers to that the health status of experimental animal can not maintain stable state herein, so disease does not change herein
Kind, the health status of animal is continuous worsening.
" disorder " refers to that the health status of experimental animal is able to maintain that stable state herein, but if experimental animal is good for
Health state ratio does not have the animal of " disorder " poor.If do not treated, " disorder " not necessarily causes experimental animal to be developed
Into morbid state.
" effective dose " herein, " materia medica effective dose " and " treatment effective dose " refer to non-toxicity but sufficient dosage
Required biological results can be caused.These results include the feature for reducing or mitigating disease, symptom, the reason for disease, or
The good direction of the other biology systems of person is developed.Can be according to the normal model of normal experiment data for individual suitable therapeutic dose
Enclose and draw.
Herein, " fibroid PUD D " either " pulmonary fibrosis " or " lung scar " refers to being characterized as in lung's shape
Into or be developing progressively one group of disease of excessive fibrous connective tissue (fibrosis).The symptom of pulmonary fibrosis mainly has：Breathing office
Promote, particularly firmly when；Long-term dry cough；It is weak and weak；Thoracic cavity is uncomfortable；Also loss of appetite and fast weight mitigate.Lung is fine
Caused by dimensionization is probably Other diseases, majority of case is classified as interstitial lung disease, such as autoimmune disease, virus sense
Dye or the microscopic damage of lung.The generation of pulmonary fibrosis can not have known reason (" idiopathic ").Idiopathic pulmonary fibrosis
Diagnosis be to exclude a series of histology/pathological characteristicses of conventional interstitial pneumonias.
The disease and situation that pulmonary fibrosis can be caused include：Suck environment and professional medium pollution thing (asbestosis, silicosis and
Gas exposes)；Hypersensitivity pneumonitis, majority of case are to contain bacterium, fungi or animal product in suction dust；Smoking；Knot
Form tissue disease such as rheumatic arthritis, systemic loupus erythematosus (SLE)；Medicine causes such as amiodarone, and bleomycin (is put down
Positive mycin), busulfan, methotrexate (MTX), apomorphine and furantoin；And the radiotherapy in thoracic cavity.
" patient " herein, " experimental subjects ", " individual " can mutually convert use, for experimental animal and experimental cell
For and in this way, in vivo and in vitro all.In not having conditional embodiment, patient, experimental subjects and individual refer to
People.
Herein, " pharmaceutically acceptable " refers to a kind of material, such as carrier or diluent, and they are in itself not
The biological activity of medicine is influenceed, and relative is nontoxic, for example the material can inject individual in vivo without causing not
Good biologically or the reaction serious with the medicine generation of its carrying.
Herein, " pharmaceutically acceptable carrier " refers to pharmaceutically acceptable material, group and or carrier, than
Such as liquid, solid packing, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, they
Effect be transport the present invention in active ingredient, make it in the due effect of patient's Giving play to physical strength.In general, transport be from
One organ, either certain part of body reach another part of another organ or body.Each carrier
Must be mutually compatible with each formula components, including the active ingredient in invention, it is not had a negative impact patient.These materials
Material includes in pharmaceutically acceptable carrier：Carbohydrate, such as lactose, dextrose and saccharose；Starch, such as cornstarch and horse
Bell sweet potato starch；Cellulose, and its pharmaceutically acceptable salt or prodrug, such as sodium carboxymethylcellulose, ethyl cellulose and
Cellulose acetate；Powdered tragacanth；Malt；Gelatin；Talcum；Excipient, such as cocoa butter and suppository wax；Oil, such as peanut oil,
Cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil；Glycol, such as propane diols；Polyalcohol, such as glycerine, mountain
Pears alcohol, mannitol and polyethylene glycol；Ester, such as ethyl oleate and ethyl laurate；Agar；Buffer, for example, magnesium hydroxide and
Aluminium hydroxide；Surfactant；Alginic acid；Apirogen water；Isotonic saline solution；Ringer's solution；Ethanol；Phosphate buffer solution；With
And other nontoxic pharmaceutically it is being formulated compatible substances.
Herein, " pharmaceutically acceptable carrier " also includes all surface coatings, antibacterial and antifungal preparation, inhales
Delayed-action activator, and the analog with the activity compatible of compound useful in the present invention are received, these in a physiologically can be by patient institute
Receive.
The reactive compound of supplement can also be mixed in combination of active principles.
" pharmaceutically acceptable carrier " can also further comprise in invention in pharmaceutically acceptable effective salt
Composition.Other compositions also include pharmaceutics on composition composition, described in regulations and use this invention, such as
Remington pharmacy is studied science, and ((Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), is hereby incorporated
As reference.
Herein, word " pharmaceutically acceptable salt " is referred to by the change of pharmaceutically acceptable non-toxic acid preparation
The salt of compound, patient, including inorganic acid, organic acid, solvate, hydrate or clathrate compound can be given.
Herein, " prevention " implication be the experimenter that is not fallen ill after medicine is given be avoided that or postpone with disease or
The related symptom of situation occurs.
Embodiment of the present invention first aspect provides a kind of pth receptor analog and its pharmaceutically acceptable
The application of salt or prodrug in the medicine for preparing treatment and/or prevention PUD D.
In embodiment of the present invention, the PUD D includes ALI, pulmonary fibrosis, tracheitis or lung cancer.
In embodiment of the present invention, pth receptor analog (has pth receptor selectivity and/or tissue choosing
The pth receptor analog of effect is selected, also known as thyroid hormone is intended like agent or thyroid hormone receptor agonists) include
GC-1、DIMIT、CGS23425、CGS26214、TRIAC、L-94901、HY-1、KB-141、KTA-439、QH-2、GC-14、NH-
3rd, at least one of HY-4, KB-2115, GC-24, MB-07811, T-0681, DITPA and K5B3495.The change of moieties
It is as follows to learn equation：
Above-mentioned pth receptor analog can be prepared according to existing conventional method, such as GC-1
(Sobetirome) it is to be synthesized by Thomas S.Scanlan seminars in nineteen ninety-five earliest, synthetic route is as follows.First by
2- cumenes methyl ether carries out para-brominated to it, has obtained bromo-derivative as initiation material.To 3,5- dimethyl -4- bromobenzenes
Phenol is methylated, and aldehyde radical obtains aldehyde.The bromo-derivative and the aldehyde are coupled under n-BuLi cryogenic conditions, obtained
To diaryl benzylalcohol, acid catalysis hydrogenation is carried out to the diaryl benzylalcohol, obtains compound, then demethylation obtains two phenolate
Compound, it carries out the tert-butyl ester and hydrolyzes to obtain final product GC-1 after being reacted with chloroacetic acid tert-butyl ester.
In embodiment of the present invention, the pth receptor analog and its pharmaceutically acceptable salt or prodrug conduct
Single-activity composition forms composition to prepare the medicine with other pharmaceutically acceptable active components.
In embodiment of the present invention, the pth receptor analog and its pharmaceutically acceptable salt or prodrug can be with
Pharmaceutically acceptable carrier forms composition to prepare the medicine.In one embodiment, medicine of the invention composition
Use the dose therapeutically effective including medicine in the present invention and a reasonable carrier pharmaceutically.Carrier can be containing for example
Water, ethanol, polyalcohol (such as glycerine, propane diols and liquid macrogol etc.), the solvent of its suitable mixture and vegetable oil
Or decentralized medium.It can be wrapped up by using such as lecithin, by maintaining required granularity in the case of a dispersion and by making
Appropriate mobility is kept with surfactant.Prevent microorganism effect can by various antiseptics and antifungal agent,
Such as p-hydroxybenzoate, methaform, phenol, ascorbic acid, thimerosal etc. are realized.In many cases it is preferred to combining
Isotonic material, such as sugar, sodium chloride or polyalcohol such as mannitol and sorbierite are included in thing.
In one embodiment, medicine of the invention has directly been packaged in together with materia medica composition, including one contains
The container for the treatment of effective dose medicine, it is used alone or is used in conjunction with another pharmacological agents；The present invention can protect
Illustrate to describe with drug therapy, prevention or the application method for mitigating disease or the symptom of disorder.
Preparation can be suitable for any suitable administering mode known in the art pharmaceutically with conventional excipients
The mixture of suitable organic or inorganic carrier material uses.Materia medica preparation can aseptic process, if desired can with it is auxiliary
Auxiliary agent mixes, such as lubricant, preservative, stabilizer, wetting agent, emulsifying agent, influences the salt of osmotic buffering agent, colouring agent,
Flavor enhancement and/or aromatic substance etc..It can also be used as needed with other active ingredient combinations, such as anodyne.
In embodiment of the present invention, medication combined at least one other medicine in the present invention is for treating and preventing fiber
Property tuberculosis effect is more preferable.Other medicines are probably included in invention, or can such as buy, it is known that can prevent
Or mitigate the medicine of fibroid lung disease symptoms.The medicine is used in combination with other active agents, other described active agents bags
Include pirfenidone (5- methyl isophthalic acids-phenylpyridine -2- ketone or its salt or solvate, pirfenidone) and Nintedanib (3Z) -
3- { [(4- { methyl [(4- methylpiperazine-1-yls) acetyl group] amino } phenyl) amino] (phenyl) methylene } -2- oxos -2,3-
At least one of dihydro -1H- indole -6-carboxylic methyl esters, or its salt or solvate, Nintedanib).
Coordinating effectiveness can be calculated according to following methods, Sigmoid-Emax formula (Holford＆Scheiner,
19981,Clin.Pharmacokinet.6:429-453), Loewe additivitys formula (Loewe＆Muischnek, 1926,
Arch.Exp.Pathol Pharmacol.114:313-326) and median effect formula (Chou＆Talalay, 1984,
Adv.Enzyme Regul.22:27-55) above formulas all can generate corresponding chart according to experimental data, to assess joint
The effect of medication.Each corresponding chart related to formula is respectively concentration-effect curve, isopleth curve and combinatorial index
Curve.
In embodiment of the present invention, the medicine can also carry out therapeutic alliance with other modes, such as medicine of the present invention
Using can be combined with oxygen uptake.
In embodiment of the present invention, the administering mode of the medicine includes local administration, digestion canal drug administration or non-digestive tract
Administration.Local administration refers to direct drug injection in the body part to be influenceed, including：Epidermal administration, inhalation, bowel lavage administration,
Dosing eyes, nasal-cavity administration.Digest canal drug administration, including oral, anum administration.Parenteral administration is included through intra arterial injection, quiet
Arteries and veins injection, intramuscular injection, intracardiac injection, hypodermic injection, intra-bone marrow injection, intracutaneous injection, encephalic implantation or cutaneous penetration.Can
Selection of land, the administering mode of the medicine include oral, injection or Neulized inhalation.Specifically, above medicine, which gives mode, includes mist
Change in suction tracheal strips, intrapulmonary and bronchus.Alternatively, the administering mode of the medicine includes oral, hypodermic injection or muscle
Injection.
Pth receptor analog and its pharmaceutically acceptable salt or prodrug can be directly entered lung by inhalator.
This method is advantageous to pth receptor analog and its pharmaceutically acceptable salt or prodrug is directly entered lung and specific
Damage location or region so that therapeutic effect maximizes and allows the potential side effect of Formulations for systemic administration to minimize.
It is suitable to form and give medicament forms and include such as dispersion, suspension, solution, syrup, particle, pearl, powder,
Pill, for nose or oral liquid spray, for the dry powder of suction or aerosolized agent etc..It is worth noting that it is applied to
The pharmacy mode and composition of the present invention is not limited to certain specific method described herein and composition.
The powder and granular preparation of the pharmaceutical preparation of the present invention can use known method to prepare.Such preparation can be with
Directly give in experimental subjects, be adapted to a certain experimental subjects for such as material.One kind can also be included in each preparation
Or a variety of dispersants or wetting agent, suspending agent and preservative.Formulation ingredients can also include other excipient, such as filler
And sweetener, flavor enhancement or colouring agent.
The preparation that the drug regimen of the present invention can be suitable for pulmonary administration by oral cavity prepares, packaging or sale.Preparation
Method can include dry powder particle, wherein including active constituents of medicine, about 0.5 to 7 nanometers of diameter, be most adapted to about 1 to 6 and receive
Rice.For convenience of use, this composition is dry powder form, and the device that can be used includes dry powder reservoir is administered, wherein can
To distribute container with dispersion powders, or using self-propelled solvent/powder according to explanation propellant flowing, such as including activity
Composition is dissolved or suspended in the low boiling propellant in sealing container.Ideally, the granular mass that this powder includes
In at least 98% diameter be more than 0.5 nanometer, in quantity at least 95% particle diameter be less than 7 nanometers.More preferably, powder includes
Granular mass at least 95% diameter be more than 1 nanometer, in quantity at least 90% particle diameter be less than 6 nanometers.Dry powder composition bag
A kind of solid fine powder diluent, such as sugar are included, it is so convenient to provide in a unit.
Low boiling propellant generally comprises liquid impellers, and boiling point is less than 65 Fahrenheits under atmospheric pressure.Generally, propellant can
The 50-99.9% (mass/mass) of composition is formed, active component can account for the 0.1-20% (mass/mass) of composition.Promote
Agent can further include other composition, such as liquid nonionic or solid anionic surfactant or solid diluent
(being preferably provided with and the granular size of the particle same order comprising active component).
The preparation of pharmaceutical composition of the present invention is dedicated for pulmonary administration, to be provided in the form of the drop of solution or suspension
Active component.Such preparation can prepare, and pack or as containing or contain active component, may be selected sterile water-based or dilute
Release alcoholic solution or suspension is sold, and easily can be applied using any atomization or atomising device.This configuration can enter
One step includes one or more extra compositions, for example but is not limited to flavor enhancement such as saccharin sodium, volatile oil, buffer, table
Face activating agent, or preservative such as methyl hydroxybenzoate.The best mean radius of drop that this method of administration provides about 0.1 to
About 200 nanometer ranges.
Formulation for pulmonary delivery method described herein available for pharmaceutical composition of the present invention can also be used for being administered orally.This
The formulation of invention medicine can be tablet, granule, capsule, pill etc..The preparation method of the medicine can be：Take thyroxine
After receptor analogs mix with auxiliary material, medicine is made in the mode such as repressed, extrusion.Wherein, the selection of auxiliary material can be according to formulation
Specific difference is added.
Formulation for pulmonary delivery method described herein available for pharmaceutical composition of the present invention can also be used for subcutaneously or intramuscularly
Drug administration by injection.The formulation of medicine of the present invention can be injection.The preparation method of the medicine can be：Pth receptor is similar
Thing is added to wiring solution-forming in solvent, and after sterilization, the medicine is made.
Dosage regimen can influence the constituent of effective dose.Present invention treatment preparation can be after premorbid or morbidity
Give experimental subjects.In addition, separated several times dosage and staggeredly dosage can daily or order of administration, or dosage can connect
Continuous infusion, or can inject.Further, treat preparation dosage can according to treat or prevent situation emergency in proportion
Ground increases or decreases.Optimum therapeuticing effect can be provided by adjusting dosage.
To patient, preferably mammal, the medicine that more preferably people is applied in the present invention can use known treatment sequence,
Given and performed with the disease or the dosage of disorder stated in the present invention and treatment time.Dose therapeutically effective needs root in this research
Adjusted according to different factors, including patient disease and disorderly developing stage, the age, sex, body weight；The also work of medicine
Property.For example several separated dosage can be applied daily, or agent can be proportionally reduced according to the emergency for the treatment of
Amount.One of non-limiting example is about micro- g/kg of daily 1-10000 for the medicine effective dosage ranges of the present invention
Body weight.
Researcher will can study correlative factor and medicine is determined in the case of without excessively experiment
Effective dose.The content of active ingredient of the invention in practical application, administration way may be different according to each patient, because
It is different to the threshold value of drug toxicity for reflection of each patient to medicine.
The effective dose treated in the present invention and give the dosage of patient will be according to the age of patient, sex and body weight,
It is adjusted through current medicining condition and advancing of disease situation.Doctor, such as physician or animal doctor, have the ability to make
The prescription power to make decision of active ingredient needed for patient.For example the dosage more relatively low than recommended dose can be used to open for physician or animal doctor
Begin to treat, be then gradually increased the therapeutic effect for having reached expected.
Suitable dosage range can be daily 1 μ g/ kg body weights to 1000 μ g/ kg body weights, or 1 μ in the present invention
G/ kg body weights are to 500 μ g/ kg body weights, either 5 μ g/ kg body weights to 250 μ g/ kg body weights or 10 μ g/ kg body weights
To 50 μ g/ kg body weights.This dosage can once be given, or give several times, can be given 1 to 4 times with one day.When multiple
During administration, each dosage can be the same or different.For example daily 1 μ g dosage can be small with 0.5 μ g intervals 12 at twice
When give.
In some embodiments, dosage of the invention is daily 1 to 10000 μ g/ kg body weights.In some embodiments, this
The medication content of invention is less than 1000 μ g/ kg body weights, or less than 500 μ g/ kg body weights, or less than 200 μ g/ kg body weights,
Or less than 50 μ g/ kg body weights.Likewise, in certain embodiments, the dosage of extra drug is to be less than daily in the present invention
1000 μ g/ kg body weights, or less than 800 μ g/ kg body weights, or less than 600 μ g/ kg body weights, or less than 500 μ g/ kilogram bodies
Weight, or less than 400 μ g/ kg body weights or less than 300 μ g/ kg body weights, or less than 200 μ g/ kg body weights, or less than 100 μ g/
Kg body weight, or less than 50 μ g/ kg body weights, or less than 40 μ g/ kg body weights, or less than 30 μ g/ kg body weights, or less than 25
μ g/ kg body weights, or less than 20 μ g/ kg body weights, or less than 15 μ g/ kg body weights, or less than 10 μ g/ kg body weights, or it is few
In 5 μ g/ kg body weights, or less than 2 μ g/ kg body weights, or one median of any of which.
In one of the embodiments, the frequency that the medicine of this research gives patient is once a day to more than five times.
In another embodiment, this research drug administration frequency can be but be not limited to once a day, often once two days, every three days one
It is secondary, until weekly, once every two weeks.It will be apparent that at present administration multiple combinations frequency be not quite similar, depend on but
The age is not limited to, whether disease and disorder carried out treatment, sex, health status and other factorses.Therefore, the present invention not
It should be understood to be limited to any specific dosage, and give the exact dose and composition of any patient, be by examining
Consider the every other factor of patient and carry out physics and determine to determine later.
It is appreciated that the medicine given daily can with but be not limited to once a day, per once two days, every three days
Once, often once four days, per once five days.Such as every two days frequencies given, 5 μ g are given within one day, can be by Monday
Start to give first 5 μ g, then the μ g of Wednesday 5, the μ g of Friday 5, go on successively.
In the case where patient's states improve, according to the judgement of doctor, medicine of the invention can be continuously given；Or
The dosage for the medicine applied temporarily reduces or temporarily stopped a period of time (such as " drug holiday ").The length of drug holiday can
With from 2 days to 1 year, including 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days,
70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days or 365 days.Medicine
It is 10%-100% that thing vacation middle dosage, which reduces scope, it may include 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
Once symptom improvement occurs in patient, the dosage of maintaining treatment can be given.Alternatively, it is also possible to by dosage or frequency,
Or both all reduce, if the body function of patient all makes moderate progress under disease and race conditio.An implementation wherein
In example, patient needs the intelligence of Chronic Intermittent, because the appearance repeatedly and/or infection of symptom.
Medicine application method can be made into the mode of per unit dose in the present invention.Term " unit dosage form " refers to fitting
In the physically discontinuous unit of the unit dose as patient receiving treatment, wherein each unit contains what is calculated in advance
Active material, it is computed producing the dosage of required therapeutic effect, suitable pharmaceutical carrier can also be combined and used.Unit dose
Mode can once a day, can also be secondary more than a day (such as 1 day once to four times).When giving multidose daily, unit
Dosage can be identical or different every time.
The measure of toxicity and therapeutic effect is to may be selected to carry out, as a result from cytologic experiment and zoopery, including
But it is not limited to, the LD50 lethal dose of experimental population 50% (allow) and the ED50 effective dose of experimental population 50% (allow).
The ratio of toxicity and validity is therapeutic index, is LD50 and ED50 ratio.The number that can be obtained according to cytology and zoology
According to being inferred to the dosage range for human body.The dosage of each medicine be preferably in body circulation close to ED50 and toxicity most
It is small.Dosage can be according to giving mode and changed using approach according to this scope.
The embodiments of the invention provide one kind of pth receptor analog and its pharmaceutically acceptable salt or prodrug
New application, pth receptor analog and its pharmaceutically acceptable salt or prodrug can improve lung tissue THRT (thyroid glands
Hormone) it is horizontal, alveolar epithelial cells can be effectively protected, the synthesis of regulation alveolar epithelial cells surface protein, stores and is distributed,
Promote ripe alveolar epithelial cells, differentiation and cell integrity, be advantageous to the removing of intrapulmonary hydrops, promote in alveolar epithelial cells
Impaired mitochondria recovers, and strengthens mitochondria biogenesis, so as to be advantageous to injured pulmonary tissues reparation, prevents and reverse lung fiber
Change, adjust immune response, change cancerization environment, reach preventing and treating PUD D, improve the PFTs such as gas exchanges, reach treatment effect
Fruit.
Embodiment 1
The preparation of pth receptor analog：
GC-1 is taken, is dissolved in dimethyl sulfoxide (DMSO), then with normal saline dilution, liquid is made, for injection and gavage.Work
Volume is 200 microlitres.
Illustrate specific implementation situation of the present invention below in conjunction with the accompanying drawings.
Fig. 1 is mouse hydroxyproline content histogram (A) and gene expression analysis figure (B, C, D) after intraperitoneal injection GC-1；
Fig. 2 is Mason's trichrome stain histochemical analysis figure of mouse lung tissue after intraperitoneal injection GC-1；
Fig. 1 and Fig. 2 shows therapeutic actions of the intraperitoneal injection GC-1 to mouse pulmonary fibrosis.C57BL/6 mouse are through rich next
Mycin (administered dose 1.5U/kg) induces 10 days, starts to inject pth receptor analog GC-1 after there are fibrotic conditions
(being represented in figure with BLM+GC-1), once a day, dosage are 30 micrograms/kg body weight, and continuous 8 days, lung tissue was gone in the 21st day
Carry out fibrosis indices in hepatic analysis, it can be seen that GC-1 has obvious therapeutic action to mouse pulmonary fibrosis.It is additionally provided with simultaneously in experiment
Saline control group (being represented in figure with salt solution), independent bleomycin control group of giving (are represented, i.e., mouse is through rich next in figure with BLM
After mycin induces 10 days a, injecting normal saline), individually give GC-1 control groups (being represented in figure with GC-1) and experimental group and (scheme
In represented with BLM+GC-1), Figure 1A is the histogram influenceed on hydroxyproline content, as can be seen that GC-1 processing from Figure 1A
Significantly reduce lung tissue hydroxyproline content, Figure 1B, Fig. 1 C and Fig. 1 D are respectively I types and type III collagen and into fiber
Cell-specific proteins gene expression analysis figure, it can be clearly seen that, on gene expression dose GC-1 processing significantly inhibit fibre
The expression of the significant Genotype I of dimensionization and type III collagen and fibroblast-like cell specific GFP.Fig. 2 is lung
Mason's trichrome stain histochemical analysis figure of tissue.From figure 2 it can be seen that compared with Normal group mouse, bleomycin can
Cause the obvious fibrotic processes of mouse lung tissue, fibrosis focus is clear.GC-1 processing can be significantly improved by bleomycin
The fibrosis focus of the lung tissue of induction, institutional framework are obviously improved, and collagen content reduces.
Fig. 3 be oral GC-1 after to mouse hydroxyproline content histogram (A) and gene expression analysis figure (B, C, D, E,
F)；
Fig. 4 is Mason's trichrome stain histochemical analysis figure of lung tissue after oral GC-1.
Fig. 3 and Fig. 4 shows therapeutic actions of the oral GC-1 to mouse pulmonary fibrosis.C57BL/6 mouse are through bleomycin
(administered dose 1.5U/kg) is induced 10 days, starts to take (gavage) pth receptor analog GC- after there are fibrotic conditions
1, once a day, dosage is 5 mg kg of body weight, continuous 8 days, goes lung tissue to carry out fibrosis indices in hepatic analysis in the 21st day, can
See that GC-1 has obvious therapeutic action to mouse pulmonary fibrosis.Fig. 3 A are the histogram influenceed on hydroxyproline content, from figure
In 3A as can be seen that compared with control group, bleomycin causes mouse lung tissue hydroxyproline content to increase, and GC-1 processing is aobvious
Writing reduces lung tissue hydroxyproline content, and Fig. 3 B, 3C, 3D and 3E are respectively fibrosis indices in hepatic Genotype I and type III collagen egg
In vain, and fibroblast-like cell specific albumen and flesh move smooth muscle protein gene expression analysis figure, it can be clearly seen that, in gene
GC-1 processing significantly inhibits markers of fibrosis Genotype I and type III collagen on expression and fibroblast is special
Foreign preteins and flesh move the expression of smooth muscle protein gene.3F is GC-1 target gene Ppargc1a gene expression histograms, GC-
1 processing remarkably promotes the expression of Ppargc1a genes.Fig. 4 is Mason's trichrome stain histochemical analysis figure of lung tissue.From Fig. 4
As can be seen that compared with Normal group mouse, bleomycin can cause the obvious fibrotic processes of mouse lung tissue, fibrosis
Focus is clear.GC-1 processing can significantly improve the fibrosis focus of the lung tissue by bleomycin induction, and institutional framework is obvious
Improve, collagen content reduces.
The embodiment of the present invention has also carried out above-mentioned identical experiment, result of the test table to other pth receptor analogs
Bright, other pth receptor analogs can also play and the same or analogous effects of GC-1.
Present invention display, oral or intraperitoneal injection pth receptor analog can mitigate and/or reverse lung acute injury
With the disease process in fibrosis animal model.These results show that pth receptor analog is given in oral and intramuscular injection
It is possible to treat the PUD D such as ALI and pulmonary fibrosis.As a result show, target and give thyroid gland in impaired lung
Plain receptor analogs and its pharmaceutically acceptable salt or prodrug can effectively mitigate or prevent fibrotic processes completely.
As reported herein, zoological research is included in mouse damage model caused by bleomycin, is sent out in disease
The different time points of exhibition repeatedly give GC-1 and are advantageous to disease cured to injured pulmonary tissues.In prevention is tested, GC-1 is rich next
Administration can effectively suppress pulmonary fibrosis after the 3rd day to the 7th day after mycin induction.In Experiment on therapy, GC-1 lures in bleomycin
Start to be administered within the 10th day after leading, be administered every other day, in sampling detection in the 21st day, have obvious therapeutic action to pulmonary fibrosis.
All results are shown, alveolar epithelial cells can effectively be protected by giving GC-1 (no matter oral or inject), tune
The synthesis of alveolar epithelial cells surface protein, storage and distribution are saved, promotes ripe alveolar epithelial cells, differentiation and cell integrity,
Be advantageous to the removing of intrapulmonary hydrops, promote to be damaged mitochondria recovery in alveolar epithelial cells, strengthen mitochondria biogenesis, so as to
Be advantageous to injured pulmonary tissues reparation, prevent and reverse pulmonary fibrosis, adjust immune response, change cancerization environment, reach preventing and treating lung
Portion's disease, improve the PFTs such as gas exchanges, reach therapeutic effect.In a word, the present invention is ALI and pulmonary fibrosis disease
The new method effectively treated is found in disease treatment.
Embodiment described above only expresses the several embodiments of the present invention, and its description is more specific and detailed, but simultaneously
Therefore the limitation to the scope of the claims of the present invention can not be interpreted as.It should be pointed out that for one of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the guarantor of the present invention
Protect scope.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (9)
1. pth receptor analog and its salt or prodrug answering in the medicine for preparing treatment and/or prevention PUD D
With.
2. application as claimed in claim 1, it is characterised in that the PUD D includes ALI, pulmonary fibrosis, gas
Pipe inflammation or lung cancer.
3. application as claimed in claim 1, it is characterised in that the pth receptor analog and salt or prodrug include
GC-1、DIMIT、CGS23425、CGS26214、TRIAC、L-94901、HY-1、KB-141、KTA-439、QH-2、GC-14、NH-
3rd, at least one of HY-4, KB-2115, GC-24, MB-07811, T-0681, DITPA and K5B3495.
4. application as claimed in claim 1, it is characterised in that the administering mode of the medicine includes local administration, alimentary canal
Administration or parenteral administration.
5. application as claimed in claim 4, it is characterised in that the administering mode of the medicine include it is oral, be subcutaneously injected or
Intramuscular injection.
6. application as claimed in claim 1, it is characterised in that the pth receptor analog and its salt or prodrug conduct
Single-activity composition forms composition to prepare the medicine with other pharmaceutically acceptable active components.
7. application as claimed in claim 1, it is characterised in that the medicine is used in combination with other active agents, it is described its
He includes at least one of pirfenidone and Nintedanib by active agents.
8. application as claimed in claim 1, it is characterised in that the pth receptor analog and its salt or prodrug and medicine
Acceptable carrier forms composition to prepare the medicine on.
9. application as claimed in claim 1, it is characterised in that the pth receptor analog and its use of salt or prodrug
Measure as daily 1-10000 micrograms/kg body weight.
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| WO2019178023A1 (en) * | 2018-03-12 | 2019-09-19 | Yale University | Methods of Treating or Preventing Acute Respiratory Distress Syndrome |
| WO2020117962A1 (en) * | 2018-12-05 | 2020-06-11 | Viking Therapeutics, Inc. | Compositions for the treatment of fibrosis and inflammation |
| US10925885B2 (en) | 2005-05-26 | 2021-02-23 | Metabasis Therapeutics, Inc. | Thyromimetics for the treatment of fatty liver diseases |
| US11202789B2 (en) | 2016-11-21 | 2021-12-21 | Viking Therapeutics, Inc. | Method of treating glycogen storage disease |
| US11660281B2 (en) | 2017-06-29 | 2023-05-30 | Yale University | Compositions and methods of treating or preventing fibrotic lung diseases |
| US11707472B2 (en) | 2017-06-05 | 2023-07-25 | Viking Therapeutics, Inc. | Compositions for the treatment of fibrosis |
| US11787828B2 (en) | 2018-03-22 | 2023-10-17 | Viking Therapeutics, Inc. | Crystalline forms and methods of producing crystalline forms of a compound |
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| US20120315320A1 (en) * | 2011-01-06 | 2012-12-13 | Davis Paul J | Uses of formulations of thyroid hormone analogs and nanoparticulate forms thereof to increase chemosensivity and radiosensitivity in tumor or cancer cells |
| US20170105956A1 (en) * | 2014-06-12 | 2017-04-20 | Yale University | Novel methods of treating or preventing fibrotic lung diseases |
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| US20120315320A1 (en) * | 2011-01-06 | 2012-12-13 | Davis Paul J | Uses of formulations of thyroid hormone analogs and nanoparticulate forms thereof to increase chemosensivity and radiosensitivity in tumor or cancer cells |
| US20170105956A1 (en) * | 2014-06-12 | 2017-04-20 | Yale University | Novel methods of treating or preventing fibrotic lung diseases |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US10925885B2 (en) | 2005-05-26 | 2021-02-23 | Metabasis Therapeutics, Inc. | Thyromimetics for the treatment of fatty liver diseases |
| US11202789B2 (en) | 2016-11-21 | 2021-12-21 | Viking Therapeutics, Inc. | Method of treating glycogen storage disease |
| US11707472B2 (en) | 2017-06-05 | 2023-07-25 | Viking Therapeutics, Inc. | Compositions for the treatment of fibrosis |
| US11660281B2 (en) | 2017-06-29 | 2023-05-30 | Yale University | Compositions and methods of treating or preventing fibrotic lung diseases |
| WO2019178023A1 (en) * | 2018-03-12 | 2019-09-19 | Yale University | Methods of Treating or Preventing Acute Respiratory Distress Syndrome |
| US11787828B2 (en) | 2018-03-22 | 2023-10-17 | Viking Therapeutics, Inc. | Crystalline forms and methods of producing crystalline forms of a compound |
| WO2020117962A1 (en) * | 2018-12-05 | 2020-06-11 | Viking Therapeutics, Inc. | Compositions for the treatment of fibrosis and inflammation |
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Application publication date: 20171215 |
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