CN108623591A - A kind of purposes of piperazine Nino peace compound - Google Patents
A kind of purposes of piperazine Nino peace compound Download PDFInfo
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- CN108623591A CN108623591A CN201711409610.7A CN201711409610A CN108623591A CN 108623591 A CN108623591 A CN 108623591A CN 201711409610 A CN201711409610 A CN 201711409610A CN 108623591 A CN108623591 A CN 108623591A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- 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
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Abstract
A kind of purposes of piperazine Nino peace compound.A kind of piperazine Nino peace compound of present invention offer and its derivative demethyl piperazine Nino peace compound and their tautomer, pharmaceutical composition are as drug, especially as the purposes for preparing the drug for treating and preventing tissue or organ fibrosis.
Description
Technical field
The invention belongs to drug fields, and pacify more particularly to a kind of piperazine Nino（penicinotam）Compound, demethyl piperazine
Nino pacifies compound（quinolactacide）And its tautomer, pharmaceutical composition and its as drug, especially as
Prepare the purposes for the drug for treating and preventing tissue fibrosis.
Background technology
Inflammation is a kind of defense reaction of the body to infection, and under normal physiological conditions, inflammation is beneficial to body.In disease
Under the conditions of reason, inflammation can also cause a series of pathological changes, can cause to damage to body, such as arthritis, septicemia, histoorgan
Fibrosis and atherosclerosis etc..When body is damaged, macrophage can release one as first of immune defence line
Series of cell inflammatory factor, including tumor necrosis factor（Tumor necrosis factor, TNF), interleukins
（Interleukin, IL), prostaglandin 2 (Prostaglandin E2, PGE2) and nitric oxide（Nitric
Oxide, NO) etc., these inflammatory factors have great influence to the repair process of body.Inflammation causes parenchymatous disease cell to be sent out
Raw necrosis organizes the pathologic process of extracellular matrix abnormal increase and over-deposit, less serious case to become fibrosis, and severe one causes group
Structure is knitted to destroy and organ sclerosis occurs.
Organ-tissue fibrosis less serious case is known as fibrosis, and severe one causes institutional framework to destroy and organ sclerosis occurs.Tissue
Fibrosis not only occurs on the organs such as lung, liver, and tissue fibrosis can involve the almost all of organ of human body and system, it be due to
Many reasons（Such as inflammation, immune, poisonous substance, ischemic and hemodynamic responses）Cause parenchymal cell destruction, then leads to reality
The inflammation deformation of cell plastid, necrosis simultaneously activate corresponding macrophage release cytokine profiles and growth factor, these factors
Activate the extracellular matrix of quiescent condition（Extracellular martri, ECM) cell is generated, it is allowed to be converted into flesh into fiber
Cell；Myofibroblast is proliferated, and secrete cytokines, is remake for macrophage by paracrine mode.Flesh is at fiber
Cell can synthesize the ECM ingredients such as a large amount of collagens, while ECM degradations are reduced, to cause organ or tissue's fibrosis.
Since each organ or tissue's function, the difference of form and each organ or tissue mainly form the difference of cell, make
Different Organs or tissue fibrosis in its pathogenesis existing general character, also have individual character；Cell is mainly generated with ECM is
, it is hepatic stellate cells in liver, is mesangial cell in glomerulus, is renal interstitial fibroblast, lung in renal interstitial
It is lung fibroblast in dirty, is cardiac fibroblasts in heart, is Peritoneal Mesothelial Cells in peritonaeum.Therefore, in Different Organs
Or there is also certain differences in the pathogenesis and therapy target of tissue fibrosis.
Piperazine Nino is pacified（penicinotam）Compound and its demethyl piperazine Nino pacify compound（quinolactacide）Point
NotBioorganic & Medicinal Chemistry Letters(2010), 20 (11), 3284-3286 andBiosci. Biotechnol. Biochem(2006), 70 (1), 303-306 have been reported that.
Invention content
The present invention provides Formulas I piperazine Nino and pacifies compound, and Formula II demethyl piperazine Nino pacifies derivative, tautomer formula
The application of IV and formula III and its pharmaceutical composition in preparing anti-fibrosis medicine.It is different more particularly to its tautomer, solid
Structure body, racemic modification, the non-equal amount of mixture of enantiomter, geometric isomer, solvate, pharmaceutically acceptable salt or
The solvate of its salt.
The present invention provides compound of formula I piperazine Nino peace and Formula II compound demethyl piperazine Nino peace and its tautomer formula
IV and formula III：
。
Compound I and II have been disclosed in document
Shao, Chang-Lun; Wang, Chang-Yun; Gu, Yu-Cheng; Wei, Mei-Yan; Pan, Jia-
Hui; Deng, Dong-Sheng; She, Zhi-Gang; Lin, Yong-Cheng. Penicinoline, a new
pyrrolyl 4-quinolinone alkaloid with an unprecedented ring system from an
endophytic fungus Penicillium sp. Bioorganic & Medicinal Chemistry Letters
(2010), 20(11), 3284-3286.
Lin, Yongcheng; Shao, Changlun; Wang, Changyun; Zhou, Shining; Gu,
Yucheng; She, Zhigang. Dehydrated methylation product of quinolinone alkaloid
derivative, its preparation process and application. Faming Zhuanli Shenqing
(2010), CN 101691368 A 20100407.
El-Neketi, Mona; Ebrahim, Weaam; Lin, Wenhan; Gedara, Sahar; Badria,
Farid; Saad, Hassan-Elrady A.; Lai, Daowan; Proksch, Peter. Alkaloids and
Polyketides from Penicillium citrinum, an Endophyte Isolated from the
Moroccan Plant Ceratonia siliqua. Journal of Natural Products (2013), 76(6),
1099-1104.
Gao, Huquan; Zhang, Lianqing; Zhu, Tianjiao; Gu, Qianqun; Li, Dehai.
Unusual pyrrolyl 4-quinolinone alkaloids from the marine-derived fungus
Penicillium sp. ghq208. Chemical & Pharmaceutical Bulletin (2012), 60(11),
1458-1460.
Abe, Masaki; Imai, Tetsuya; Ishii, Naoki; Usui, Makio. Synthesis of
quinolactacide via an acyl migration reaction and dehydrogenation with
manganese dioxide, and its insecticidal activities. Bioscience, Biotechnology, and Biochemistry (2006), 70(1), 303-306.
Abe, Masaki; Imai, Tetsuya; Ishii, Naoki; Usui, Makio; Okuda, Toru; Oki,
Toshikazu. Quinolactacide, a new quinolone insecticide from Penicillium
citrinum Thom F 1539. Bioscience, Biotechnology, and Biochemistry (2005), 69
(6), 1202-1205.
Okuda, Toru; Oki, Shunichi; Abe, Masaki; Imai, Tetsuya; Ishii, Naoki.
Agrochemical insecticide OC45159 manufacture with Penicillium citrinum. Jpn.
Kokai Tokkyo Koho (2005), JP 2005176684 A 20050707.
One aspect of the present invention is related to pharmaceutical composition, including the compound of the present invention or its stereoisomer, geometric isomer, mutually
Tautomeric, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or their prodrug, or appoint
Select pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium or combination thereof.
One aspect of the present invention is related to the method for preventing, handling, treating or mitigate patient tissue or organ fibrosis disease, packet
It includes and patient is administered using the pharmaceutical composition pharmaceutically acceptable effective dose of the compounds of this invention.
One aspect of the present invention is related to the method for preventing, handling, treating or mitigate patient tissue or organ fibrosis disease, packet
It includes and patient is administered using the compounds of this invention pharmaceutically acceptable effective dose.
Another aspect of the present invention is related to the compound of the present invention and is used to prepare for preventing, handling, treat or mitigating patient
The purposes of tissue or the drug of organ fibrosis disease.
Another aspect of the present invention, which is related to being used to prepare using a kind of pharmaceutical composition comprising the compound of the present invention, to be used for
The purposes for preventing, handling, treating or mitigate patient tissue or the drug of organ fibrosis disease.
On the other hand, the present invention relates to a kind of animal is being prevented or is treating using the compounds of this invention or its pharmaceutical composition
Or the method for application of tissue or organ fibrosis disease, the purposes include to use the compound of the present invention or its pharmaceutical composition
Pharmaceutically acceptable effective therapeutic dose of object is administered human body or animal.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its
The content of his aspect will make more specific complete description below.
Definition and general terms
The present invention will be corresponding to the content determining materialization document list in detail, embodiment be all accompanied by structural formula and
The explanation of chemical formula.The present invention, which has, expectedly covers all choices, variant and coordinate, these may be as right
Existing invention field is included in defined in it is required that like that.Those skilled in the art will identify it is many similar or equivalent to
This described method and substance, these can be applied to the practice of the present invention.The present invention is limited to absolutely not method and substance
Description.There are many documents and similar substance to distinguish or contradict with the present patent application including but not limited to term
Definition, the usage of term, the technology of description, or the range that is controlled as the present patent application.
The present invention will apply defined below unless other aspects show.Purpose according to the present invention, chemical element is according to member
Plain periodic table, CAS versions and chemicals handbook, 75,thEd, 1994 define.In addition, organic chemistry General Principle is shown in
“Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito:
1999, and “March's Advanced Organic Chemistry,” by Michael B. Smith and Jerry
March, John. Wiley&Sons, New York:2007, therefore all contents have all merged bibliography.
" solvate " of the present invention refers to that one or more solvent molecules are formed by association with the compound of the present invention
Object.Formed solvate solvent include but is not limited to：Water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second
Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
The present invention includes the application of the compounds of this invention and its pharmaceutically acceptable salt, for producing medical product treatment
The disease of patient tissue or organ fibrosis, including those diseases described in the invention.The present invention includes pharmaceutical composition, should
Pharmaceutical composition include formula compound represented at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant,
Effective therapeutic dose needed for the combination of medium.
The present invention equally includes to treat or mitigate the disease of patient tissue or organ fibrosis, or the side sensitive to this illness
Method, this method include Formulas I, and the therapeutically effective amount of Formula II, formula III, formula IV compound represented treats patient.
Unless otherwise indicated, all stereoisomer of the compound of the present invention, geometric isomer, tautomerism
Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to the model of the present invention
It encloses.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes substance or composition must
Must be suitble to chemistry or toxicology, the mammal with the other components of composition preparation and for treatment is related.
If the compound of the present invention is alkaline, conceivable salt can be by provided in the literature any suitable
Method is prepared, for example, using inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or using organic
Acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, oxyacetic acid and salicylic acid；Pyrans
Saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Amino acid, such as asparatate and paddy
Propylhomoserin；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, ethanesulfonic acid, etc..
The salt of the part of compounds of the present invention can be illustrated with the salt for the particular compound listed as follows, but not limited
The present invention：
。
If the compound of the present invention is acid, conceivable salt can be prepared by suitable method, e.g.,
Use inorganic base or organic base, such as ammonia（Primaquine, parahelium, tertiary ammonia）, alkali metal hydroxide or alkaline earth metal hydroxide, etc.
Deng.Suitable salt includes but is not limited to organic salt obtained from amino acids, such as glycine and arginine, ammonia, and such as primaquine, secondary
Ammonia and tertiary ammonia and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium
Inorganic salts.
" solvate " or " solvate of salt " of the present invention refers to the change of one or more solvent molecules and the present invention
It closes object and is formed by associated matter.The solvent of solvate is formed including but not limited to, water, isopropanol, ethyl alcohol, first
Alcohol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by and forms
The solvate of conjunction object, the solvate or salt is selected from：Monohydrate, dihydrate, trihydrate, a methanol solvate,
Diformazan alcohol adduct, an acetonitrile close object, diacetonitrile closes object, an acetone closes object, two acetone close object, hemifumarate monohydrate, richness
Horse hydrochlorate dihydrate, one ethanolates of fumarate；It is preferred that monohydrate, fumarate dihydrate, one second of fumarate
Alcohol adduct.
The solvate of part of compounds or the solvate of its salt of the present invention can use the specific chemical combination listed as follows
The salt of object illustrates, but does not limit the present invention：
。
The characteristics of pharmaceutical composition of the invention includes Formulas I, Formula II, formula III, the compound of formula IV according to another aspect,
And pharmaceutically acceptable carrier, adjuvant or excipient.The amount of compound can effectively detectably in the composition of the present invention
Treatment or the disease for mitigating patient tissue or organ fibrosis.
There are free forms for the compound of the present invention, or it is suitable, as pharmaceutically acceptable derivates.According to this hair
Bright, pharmaceutically acceptable derivates include but is not limited to pharmaceutically acceptable prodrug, salt, ester, the salt or energy of esters
Other any adducts or derivative being directly or indirectly administered according to the needs of patient, the present invention other aspect described in
Compound, metabolite or his residue.
As described in the invention, the pharmaceutically acceptable composition of the present invention further includes pharmaceutically acceptable load
Body, adjuvant or excipient, these are applied as the present invention, including any solvent, diluent or other liquid excipients, point
Powder or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc.,
It is suitable for distinctive target formulation.As described in following documents：In Remington: The Science and
Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott
Williams&Wilkins, Phil adelphia, and Encyclopedia of Pharmaceutical
Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New
York, the content of comprehensive document herein, show different carriers can be applied to pharmaceutically acceptable composition preparation and it
Well known preparation method.In addition to any conventional carrier medium range incompatible with the compound of the present invention, such as produced
Raw any undesirable biological effect generates in harmful manner with any other component of pharmaceutically acceptable composition
Interaction, their purposes is also the range that is considered of the present invention.
As described in the invention, the pharmaceutically acceptable composition of the present invention further includes pharmaceutically acceptable load
Body, adjuvant or excipient, these are applied as the present invention, including any solvent, diluent or other liquid excipients, point
Powder or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc.,
It is suitable for distinctive target formulation.As described in following documents：In Remington: The Science and
Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott
Williams&Wilkins, Phil adelphia, and Encyclopedia of Pharmaceutical
Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New
York, the content of comprehensive document herein, show different carriers can be applied to pharmaceutically acceptable composition preparation and it
Well known preparation method.In addition to any conventional carrier medium range incompatible with the compound of the present invention, such as produced
Raw any undesirable biological effect generates in harmful manner with any other component of pharmaceutically acceptable composition
Interaction, their purposes is also the range that is considered of the present invention.
The substance that can be used as pharmaceutically acceptable carrier includes but is not limited to ion-exchanger, aluminium, aluminum stearate, ovum
Phosphatide, haemocyanin, such as human albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate are saturated vegetable butter
The partial glyceride mixtures of fat acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination
Sodium, zinc salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymerization
Body, lanolin, sugar, such as lactose, dextrose and saccharose；Starch such as cornstarch and potato starch；The derivative of cellulose and it
Such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Gum powder；Malt；Gelatin；Talcum powder；Auxiliary material such as cocoa bean
Fat and suppository wax；Oil such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil；Glycols chemical combination
Object, such as propylene glycol and polyethylene glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer such as magnesium hydroxide and
Aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge（Family name）Solution；Ethyl alcohol, phosphate buffer solution and other are nontoxic
Suitable lubricant such as Sodium Laurylsulfate and magnesium stearate, colorant, releasing agent, coating agents, sweetener, flavoring agent and perfume (or spice)
Material, preservative and antioxidant.
The pharmaceutical composition of the present invention can be oral medication, drug administration by injection, Aerosol inhalation, local administration, per rectum
Administration, nose administration, buccal administration or are administered vagina administration by implantable medicine box.Can be capsule, tablet, pill, powder
Agent, granula and water suspension or solution.Oral medication can use following form：Tablet, pill, capsule, dispersible powder,
Particle or suspension, syrup and elixir；Or it is administered in a manner of external application：Ointment, gel, drug containing adhesive plaster etc., or with it is sterile can
It injects solution or suspension form carries out parenteral routes.The compounds of this invention also can parenteral or intraperitoneal administration.It also can be
Surfactant is properly mixed（Such as hydroxypropyl cellulose, polyvinylpyrrolidone）Water in prepare these reactive compounds
（As free alkali or pharmaceutically acceptable salt）Solution or suspension.It can also be in glycerine, liquid, polyethylene glycol and its in oil
In mixture in prepare dispersion liquid.Under conventional storage and use condition, containing preservative to prevent micro- life in these preparations
Object is grown.
Medicament forms suitable for injection include：Aseptic aqueous solution or dispersion liquid and aseptic powder（It is noted for extemporaneous preparation of sterile
Penetrate solution or dispersion liquid）.In all cases, these forms must be sterile and must be that fluid is discharged with being easy to syringe
Fluid.It must be stable under conditions of manufacture and storage, and must be able to prevent microorganism（Such as bacterium and fungi）Pollution shadow
It rings.Carrier can be solvent or decentralized medium, wherein containing such as water, alcohol（Such as glycerine, propylene glycol and liquid polyethylene glycol）, they
Properly mix object and vegetable oil.
Compound can be applied with local mode, without being applied with system mode.Such as usually to dilute preparation or continue
The form of delivery formulations will be in compound direct injection to organ.In addition, the pharmaceutical composition containing the compounds of this invention can be with
It uses in targeted drug delivery system, such as is delivered in the liposome being coated with organ specific antibody.The liposome
The organ will be targeted and absorbed by the Organic selection.In addition, the composition containing the compounds of this invention can be with fast quick-release
The form for putting preparation, timed release preparations or IR formulation provides.
Sucking is applied, the compound of the present invention can be aerosol, aerosol or powder type.The compounds of this invention
Pharmaceutical composition can easily be delivered in the form of aerosol spray, the aerosol spray can be mounted in pressure vessel
Or in atomizer, suitable propellant such as dicholorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, carbon dioxide are used
Or other suitable gases.In the case of pressurized aerosol, dosage unit can be determined by valve to deliver metering
Amount.For example, by taking capsule and cylindrantherae as an example, for the gelatin of inhalator or insufflator can be prepared as containing the compound with
The mixture of powders of appropriate powdered substrate such as lactose or starch.
The compounds of this invention can also be prepared as rectal compositions such as enema, Gel in rectal administered, rectal foams agent, straight
Intestines aerosol, suppository, gel suppository（gel suppository）Or enema,retention（retention enema）, wherein containing
Conventional suppository base is such as cocoa butter or other glyceride and synthetic polymer such as polyvinylpyrrolidone, PEG.
In the suppository form of composition, low melt wax be such as, but not limited to fatty glyceride optionally with the mixture of cocoa butter first by
Fusing.
In addition, the compounds of this invention can also be with the drug combination of other treatment fibrosis.It is specifically including but not limited to sieve fluorine
Si Te, pirfenidone, magerut, Losartan, interferon, my method-dornase, cortin, methotrexate, tacrolimus
Deng.
Pharmaceutical composition can be prepared according to the usual manner acceptable carrier of one or more physiology, including
It can help excipient and adjuvant that reactive compound is processed as to pharmaceutical preparations.Selected administration method determines appropriate dose
Type.Technology, carrier and excipient known to any can understand use appropriate according in the prior art.Contain the present invention
The pharmaceutical composition of compound can be prepared according to conventional methods, for example, by conventional mixing, dissolving, pelletize, ingot processed, grind
It is prepared by mill, emulsification, packing, encapsulating or pressing process.
Pharmaceutical composition will include at least one pharmaceutical acceptable carrier, diluent or excipient and free acid, free alkali or can
The compound of the present invention of acceptable salt is as active constituent.In addition, pharmaceutical composition may also include other medicine or pharmacy
Activating agent, carrier, adjuvant, such as preservative, stabilizer, wetting agent or emulsifier, dissolution accelerator, adjust osmotic pressure salt or
Buffer.In addition, pharmaceutical composition also contains other substances for having therapeutic value.
The preparation method of composition containing compound described herein include by compound with it is one or more it is inert can
Pharmaceutical excipient or carrier are prepared as solid, semisolid or liquid form together.Solid composite includes but not limited to powder, piece
Agent, dispersible granule, capsule, cachet and suppository.Liquid composition includes wherein being dissolved with the solution of compound, containing
Emulsion, the solution containing the liposome comprising compound disclosed herein, micelle or nano-particle for having compound.Semisolid group
It includes but not limited to gelling agent, suspension and cream to close object.Composition can be aqueous agent or suspended form, be suitble to
In the solid form or emulsion form that are dissolved or suspended in before use in liquid.These compositions can also contain a small amount of nontoxic
Adjuvant, such as wetting agent or emulsifier, pH buffer etc..
The compound of the present invention is preferably prepared into dosage unit form to mitigate the equal of dosage and dosage by pharmaceutical formulation
Even property.Term " dosage " unit type " obtains suitably treating the physical dispersion unit of required drug referred to herein as patient.However, answering
Understand the daily total usage of the compound of the present invention or composition will by attending physician according to reliable medicine range judge come
It determines.Specific effective dose level will include being controlled depending on many factors for any one special patient or organism
The illness for the treatment of and the seriousness of illness, the activity of particular compound, concrete composition used, the age of patient, weight, health
Situation, gender and eating habit, administration time, the discharge rate of administration route and particular compound used, treatment it is lasting when
Between, medicinal application in drug combination or with specific compound combination and some other factor well-known in the field of pharmacy.
The compounds of this invention can be modified by the functional group of additional suitable to improve selectivity organism characteristic.This
The modification of sample is that this field is known and include to biological lacuna（Such as blood, lymphatic system, central nervous system）Infiltration,
It improves Oral Availability, improve dissolubility so as to which the modification of excretion is metabolized and changed by drug administration by injection, change.It can incite somebody to action
The compounds of this invention is modified by the functional group of additional suitable to improve selectivity organism characteristic.
Compound of the present invention or its pharmaceutical salts or its hydrate can effective for prevention, processing, treat or subtract
Light patient tissue or organ fibrosis disease, especially can effectively treat kidney region fibrosis, glomerulosclerosis, liver fibrosis,
Pulmonary fibrosis, peritoneal fibrosiss, myocardial fibrosis, fibrosis of skin, postoperative intestinal adhesion, benign prostatauxe disease, skeletal muscle
Fibrosis, chorionitis, multiple sclerosis pancreatic fibrosis, hepatic sclerosis, muscle tumor, nerve fibre onch- interstitial fibrosis, sugar
The sick nephrosis of urine, the disease of Alzheimer disease or vascular fibrosis.
Embodiment
Anti- fiber-reactive test
The method of cell experiment
1 cell inoculation
The BHK-21 cells for taking exponential phase of growth, when cell growth fusion 85 95%, the digestion of routine passage method is collected thin
Born of the same parents, cell count, adjustment cell density to 2 × 104A/mL is inoculated in 96 porocyte culture plates, 100μThe holes L/,：37
DEG C, 5% CO2Under the conditions of be incubated.
2 cell administrations
After adherent 24 h of cell inoculation, supernatant is abandoned, changes the culture solution 100 of each compound concentration gradient containing above-mentioned preparationμL/
Hole, 3 multiple holes of each concentration group continue culture 48 hours after dosing.
The measurement of 3 absorbance values
After dosing 48h, 10 are added per holeμ(the 1/10 of nutrient solution volume L）CCK-8 solution, after being incubated 2h in incubator, enzyme mark
The absorbance in each hole is detected at instrument 450nm（A）Value.The cell proliferation inhibition rate of each compound, cell are calculated according to surveyed A values
Proliferation inhibition rate（Inhibition ratio,IR）=（1- experimental groups（Ai）Value/control group（A0）Value）× 100%, data processing is soft
Part calculates separately IC of each compound at 48 hours50Value.
Anti- fiber-reactive data are as follows：
Note：" A " indicates that compound concentration is to indicate that compound concentration is 0.05-5.0 mM, " C " less than 0.05 mM, " B " in table
Expression compound concentration is 5-20 mM, and " D " indicates that compound concentration is 20-100 mM；
The common trait of organ fibrosis is extracellular matrix（ECM）Over-deposit, the reconstruction of organ-tissue structure, many of which are thin
Intracellular cytokine takes part in this process.It is screened by In vitro cell experiment, it is non-that the compound activity in the present invention is better than positive drug pyrrole
Buddhist nun's ketone；And the phototoxic reaction that pirfenidone has, safety higher, in anti-fibrosis side is not present in the compound in the present invention
Face has better potential application foreground.
Claims (8)
1. a kind of piperazine Nino pacifies compound（I）And its derivative demethyl piperazine Nino peace（II）, tautomer（IV）With
（III）, stereoisomer, racemic modification, the non-equal amount of mixture of enantiomter, geometric isomer, solvate, pharmaceutically
The solvate of acceptable salt or its salt is in prevention, processing, treatment or mitigates patient tissue or organ fibrosis disease, special
Sign is that compound has the following structure：
。
2. the solvate of solvate described in claim 1 or salt is selected from：Monohydrate, dihydrate, trihydrate, one
Methanol solvate, diformazan alcohol adduct, an acetonitrile close object, diacetonitrile closes object, an acetone closes object, two acetone close object, hemifumarate one
Hydrate, fumarate dihydrate, one ethanolates of fumarate；It is preferred that monohydrate, fumarate dihydrate, rich horse
One ethanolates of hydrochlorate.
3. pharmaceutically acceptable salt described in claim 1 is selected from：Hydrochloride, sulfate, phosphate, oxalates, maleic acid
Salt, methane sulfonates, succinate, citrate, fumarate, glucuronate salt, formates, acetate, succinate.
4. a kind of pharmaceutical composition, it includes according to a kind of compound of claim 1-3 any one of them or several compounds
Or the non-equal amount of mixture of its tautomer, stereoisomer, racemic modification, enantiomter, geometric isomer, solvation
Any one or a few in the solvate of object, pharmaceutically acceptable salt or its salt is as active ingredient.
5. the pharmaceutical composition described in claim 4, it is characterised in that the pharmaceutical composition also includes that at least one pharmaceutically may be used
Carrier, diluent or the excipient of receiving.
6. the pharmaceutical composition described in claim 5, it is characterised in that the pharmaceutical composition also includes other at least one anti-fibres
Chemical drug object is tieed up, roflumilast, pirfenidone, magerut, Losartan, interferon, my method-chain road are specifically including but not limited to
Enzyme, cortin, methotrexate, tacrolimus etc.；The pharmaceutical composition optimizing injection, freeze drying powder injection, is hanged at oral preparation
Floating agent etc..
7. compound or its tautomer, its stereoisomer, its racemic modification described in any one of claim 1-3,
The non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt
Purposes of the pharmaceutical composition in preparing anti-fibrosis medicine described in any one of solvate or claim 4-6.
8. compound or its tautomer described in claim 1-3, its stereoisomer, its racemic modification, its mapping
The non-equal amount of mixture of isomers, the solvation of its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt
Pharmaceutical composition described in object or claim 4-6 effective for prevention, processing, treatment or can mitigate patient tissue or organ
Fibrotic disease especially can effectively treat kidney region fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrotic
It is change, myocardial fibrosis, fibrosis of skin, postoperative intestinal adhesion, benign prostatauxe disease, skeletal muscle fibre, chorionitis, multiple
Property sclerosis, pancreatic fibrosis, hepatic sclerosis, muscle tumor, nerve fibre onch- interstitial fibrosis, diabetic nephropathy, alzheimer '
The disease of silent disease or vascular fibrosis.
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Cited By (1)
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| CN108823108A (en) * | 2018-07-23 | 2018-11-16 | 山东省农业科学院蔬菜花卉研究所 | The superior strain and production method of industrialized production compound Q uinolactacide |
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| JP2005176684A (en) * | 2003-12-18 | 2005-07-07 | Otsuka Chemical Co Ltd | Oc45159 substance-productive fungus, method for producing the substance, and agricultural/horticultural insecticide |
| CN101035777A (en) * | 2004-10-01 | 2007-09-12 | P.安杰莱蒂分子生物学研究所 | Modulators of hcv replication |
| WO2017007658A1 (en) * | 2015-07-07 | 2017-01-12 | Rigel Pharmaceuticals, Inc. | A combination for immune mediated cancer treatment |
| CN108419435A (en) * | 2015-10-09 | 2018-08-17 | 新加坡科技研究局 | Compound and epigenetics for treating cancer |
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| JP2005176684A (en) * | 2003-12-18 | 2005-07-07 | Otsuka Chemical Co Ltd | Oc45159 substance-productive fungus, method for producing the substance, and agricultural/horticultural insecticide |
| CN101035777A (en) * | 2004-10-01 | 2007-09-12 | P.安杰莱蒂分子生物学研究所 | Modulators of hcv replication |
| WO2017007658A1 (en) * | 2015-07-07 | 2017-01-12 | Rigel Pharmaceuticals, Inc. | A combination for immune mediated cancer treatment |
| CN108419435A (en) * | 2015-10-09 | 2018-08-17 | 新加坡科技研究局 | Compound and epigenetics for treating cancer |
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| CN108823108A (en) * | 2018-07-23 | 2018-11-16 | 山东省农业科学院蔬菜花卉研究所 | The superior strain and production method of industrialized production compound Q uinolactacide |
| CN108823108B (en) * | 2018-07-23 | 2021-06-25 | 山东省农业科学院蔬菜花卉研究所 | High-yield strain for industrially producing compound Quinolacctaside and production method |
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