CN108888618A - Newtype drug and its application for treating psoriasis - Google Patents
Newtype drug and its application for treating psoriasis Download PDFInfo
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- CN108888618A CN108888618A CN201810643396.XA CN201810643396A CN108888618A CN 108888618 A CN108888618 A CN 108888618A CN 201810643396 A CN201810643396 A CN 201810643396A CN 108888618 A CN108888618 A CN 108888618A
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- 201000004681 Psoriasis Diseases 0.000 title claims abstract description 30
- 229940079593 drug Drugs 0.000 title abstract description 9
- 239000003814 drug Substances 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims description 25
- 239000002243 precursor Substances 0.000 claims description 20
- 239000012453 solvate Substances 0.000 claims description 17
- 210000003491 skin Anatomy 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 8
- 210000002615 epidermis Anatomy 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 230000008595 infiltration Effects 0.000 claims description 5
- 238000001764 infiltration Methods 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
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- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229960001631 carbomer Drugs 0.000 claims description 4
- 230000001413 cellular effect Effects 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 3
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 230000002500 effect on skin Effects 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
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- 230000004054 inflammatory process Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
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- 238000011282 treatment Methods 0.000 abstract description 10
- 230000001225 therapeutic effect Effects 0.000 abstract description 6
- 206010033898 parapsoriasis Diseases 0.000 description 21
- 229960002751 imiquimod Drugs 0.000 description 19
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 19
- 239000011159 matrix material Substances 0.000 description 16
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- 239000000126 substance Substances 0.000 description 3
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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- 0 C[C@](*)CCNCN* Chemical compound C[C@](*)CCNCN* 0.000 description 1
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
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- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 101150034459 Parpbp gene Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
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- 230000007815 allergy Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
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- 239000004615 ingredient Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 238000005259 measurement Methods 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
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- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- NYBWUHOMYZZKOR-UHFFFAOYSA-N tes-adt Chemical class C1=C2C(C#C[Si](CC)(CC)CC)=C(C=C3C(SC=C3)=C3)C3=C(C#C[Si](CC)(CC)CC)C2=CC2=C1SC=C2 NYBWUHOMYZZKOR-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to the newtype drug for the treatment of psoriasis and its applications.Disclosing compound of the one kind with structural formula shown in formula (I) for the first time has alleviation or therapeutic effect for psoriasis, and the present invention also provides the pharmaceutical compositions etc. containing it.
Description
Technical field
The invention belongs to biomedicine fields, more particularly it relates to treat the newtype drug of psoriasis and its answer
With.
Background technique
Psoriasis is commonly called as " psoriasis ", is the cutaneous immunisation disease that can not be cured, it is included in by World Health Organization (WHO)
The big chronic disease in the world ten.Chinese psoriasis disease incidence is 0.3~0.5%, and patient about 10,000,000, in rising year by year trend.Psoriasis
By infecting, being immunized, heredity, spirit and the factor interactions such as environment and induce;With chronic, recurrent exerbation and aggravates and alleviate
Alternating is characterized, the systemic diseases such as the diabetes that often occur together, coronary heart disease, hypertension, depression, metabolic syndrome.Psoriasis is in
The morbidity crowd of state with 25~45 years old person between twenty and fifty be it is more, children psoriasis disease incidence also gradually increases in recent years.The disease is not
The physical and mental health of patient is only seriously endangered, and seriously affects the quality of life of patient, is important the grinding in world skin disease field
Study carefully project.
Psoriasis pathology is largely scorching with epidermal keratinocytes (keratinocyte, KC) Hypersegmentation proliferation and corium
Disease cellular infiltration is characterized.For this two big pathological characters, the method for clinical treatment psoriasis includes that drug therapy, physics are controlled
Treatment, Biological therapy and traditional Chinese medical herbal treatment etc..The Chinese drug for import treatment psoriasis every year, it is especially scientific and technological
The cost for the biological antibody class drug that content is high, targeting is strong is huge.However, it has been found that biological agent class drug in this field
The serious side effects characterized by immune dysfunction such as tumour, infection are also easy to produce, such as:Anti- CD11a antibody Efalizumab can
Increase the risk that psoriasis patients suffer from progressive multifocal leukoencephalopathy (PML), is removed by Genentech company in April, 2009
City.
Therefore, in this field, the pathogenesis of psoriasis is further furtherd investigate, then develops that targeting is strong, at a specified future date treats
It imitates, is highly-safe, psoriasis new drug is treated by cheap a new generation and treatment method is imperative.
Summary of the invention
The purpose of the present invention is to provide the newtype drug for the treatment of psoriasis and its applications.
In the first aspect of the present invention, provide compound shown in formula (I) or its isomers, solvate or precursor or it
Pharmaceutically acceptable salt purposes, be used to prepare alleviation or treat psoriasis composition.
Wherein, R1~R9 independently selected from:Hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl group, halogen, hydroxyl.
In a preferred embodiment, in compound shown in formula (I), R1~R9 independently selected from:Hydrogen, C1-C2 alkyl.
In another preference, in compound shown in formula (I), R1~R9 is hydrogen, and the compound is formula (II) change
Close object:
In another preference, the compound is substantially reduced the epidermis area in affected part, or is substantially reduced affected part
Skin thickness.
In another preference, the compound substantially reduces the inflammatory exudation in affected part, substantially reduces dermal inflammation
Cellular infiltration.
In another preference, the composition is pharmaceutical composition.
In another preference, the pharmaceutical composition is exterior-applied formulation.
In another preference, in the pharmaceutical composition, compound shown in formula (I) or its isomers, solvent are closed
Object or precursor or their pharmaceutically acceptable salt are mixed with pharmaceutically acceptable carrier.
In another preference, the pharmaceutically acceptable carrier includes but is not limited to:Glycerol, propylene glycol, card
Wave nurse, triethanolamine.
In another preference, the solvate is hydrate.
Other aspects of the invention are apparent to those skilled in the art due to this disclosure
's.
Detailed description of the invention
The therapeutic effect of Fig. 1, formula (II) compound to mouse parapsoriasis.
A, after being handled with the mouse parapsoriasis that formula (II) compound or carrier matrix induce imiquimod (IMQ)
Phenotype compare;
B, the mouse parapsoriasis that IMQ is induced is handled with formula (II) compound or carrier matrix, mouse ear is thick
The situation of change of degree;
C, the mouse parapsoriasis that IMQ is induced is handled with formula (II) compound or carrier matrix, mouse ear is cut
Piece H&E dyes example;
D, the mouse parapsoriasis that IMQ is induced is handled with formula (II) compound or carrier matrix, mouse ear is cut
The epidermis area statistics of piece H&E dyeing.
The therapeutic effect of Fig. 2, formula (II) compound to machin parapsoriasis.
A, with formula (II) compound or carrier matrix to the machin parapsoriasis that IMQ the is induced phenotype ratio that carries out that treated
Compared with;
B, the machin parapsoriasis that IMQ is induced is handled with formula (II) compound or carrier matrix, skin is clinical
The situation of change of scoring;
C, the machin parapsoriasis that IMQ is induced is handled with formula (II) compound or carrier matrix, skin biopsy
H&E dyes example.
Specific embodiment
The invention firstly discloses one kind for treating the effective newtype drug of psoriasis, with structure shown in formula (I)
Formula, the present invention also provides the pharmaceutical compositions etc. containing it.
Term
The term as used herein " alkyl " refer to linear chain or branched chain saturation, containing 1-4 carbon atom (preferably 1-2 carbon
Atom) aliphatic hydrocarbon group.For example, alkyl includes but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl
Base, tert-butyl.
The term as used herein " alkenyl " includes containing at least one carbon-carbon double bond and 2-4 carbon atom (preferably 2-3
A carbon atom) straight chain and branched hydrocarbyl.
The term as used herein " alkynyl group " includes containing at least one triple carbon-carbon bonds and 2-4 carbon atom (preferably 2-3
A carbon atom) straight chain and branched hydrocarbyl.
The term as used herein " halogen " refers to F, Cl, Br or I.
The term as used herein " isomers " includes:Geometric isomer, enantiomter, diastereoisomer are (as along anti-
Isomers, conformer).
The term as used herein " solvate " indicates to carry the compound of solvent molecule, for example, the solvent closes
Object can be hydrate.
In the present invention, term " containing " indicates that various composition can be applied in mixture or composition of the invention together.
Therefore, term " mainly by ... form " and " consist of " were included in term " containing ".
In the present invention, " pharmaceutically acceptable " ingredient is suitable for people and/or animal and (such as without excessive bad side reaction
Toxicity, stimulation and allergy) there is the substance of reasonable benefit/risk ratio.
In the present invention, " pharmaceutically acceptable carrier " is for by formula (I) compound of the invention, isomers, solvent
Close object, precursor or their pharmaceutically acceptable salt send animal to or the acceptable solvent pharmaceutically or on food of people,
Suspending agent or excipient.Carrier can be liquid or solid.
Compound
Present invention firstly provides a kind of such as structure formula (I) compound represented:
Wherein, R1~R9 independently selected from:Hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl group, halogen, hydroxyl.
The invention also includes the isomers of above-mentioned formula (I) compound, solvate, precursor or they can pharmaceutically connect
The salt received, if they also have with formula (I) compound have the function of it is identical or essentially identical.Described " can pharmaceutically connect
The salt received " refers to that compound and inorganic acid, Organic Acid and Base metal or alkaline-earth metal etc. react the salt generated.These salt include (but
It is not limited to):(1) salt formed with following inorganic acid:Such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid;(2) it is formed with following organic acid
Salt, such as acetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, maleic acid or arginine.Other salt include and alkali metal or alkali
The salt that earth metal (such as sodium, potassium, calcium or magnesium) is formed, in the form of ester, carbamate or other conventional " pro-drugs ".
Compound has one or more asymmetric centers.So these compounds can be used as racemic mixture, individually it is right
Isomers, individual diastereoisomer, non-enantiomer mixture, cis or trans isomers is reflected to exist.
" precursor of compound " refer to after being taken with method appropriate, the precursor of the compound in patient body into
Row metabolism or chemical reaction and be transformed into a kind of compound of structure formula (I) or a compound institute group of chemical structure formula (I)
At salt or solution.
As a kind of preferred embodiment of the invention, the compound has structure shown in formula (II).
The entitled N ω-hydroxy-nor-Arginine of English of formula (II) compound is that a kind of molecular weight is
The small molecule compound of 176.176g/mol, molecular formula C5H12N4O3.It is damaged using formula (II) compound treatment ischemia-reperfusion
1 clinical trial phase (the clinical test identification code of wound:NCT02009527) terminated.The result shows that:Formula (II) compound can pass through
Flow-mediated expansion (flow-mediated dilatation, FMD) is promoted to improve ischemical reperfusion injury, thus to blood vessel
Inner skin cell function shields extremely.But this field is not still about such compound and the correlation of psoriasis
Report.
Those skilled in the art should be understood that after knowing the structure of the compounds of this invention, can by a variety of it is well known that
Method, using well known raw material, to obtain the compound of the present invention, such as chemical synthesis or from biological (such as animal or plant)
The method of middle extraction, these methods are included in the present invention.
The compound of synthesis can by further by column chromatography, high performance liquid chromatography etc. in a manner of be further purified.
Purposes
The present inventor has found that formula of the invention (I) compound has significantly more treatment to make psoriasis under study for action
With.
New discovery based on the present inventor, the present invention provides formula (I) compounds represented or its isomers, solvent to close
The purposes of object, precursor or their pharmaceutically acceptable salt is used to prepare alleviation or treats the drug of psoriasis.
Pharmaceutical composition
The present invention also provides a kind of pharmaceutical compositions, contain:(a) a effective amount of formula (I) compound represented or its is different
Structure body, solvate, precursor or their pharmaceutically acceptable salt;(b) pharmaceutically acceptable carrier or excipient.
In the present invention, the pharmaceutical composition contains changes according to shown in the formula (I) that weight ratio is 0.01-20%
Close object or its isomers, solvate, precursor or their pharmaceutically acceptable salt.Preferably, the pharmaceutical composition
Containing according to weight ratio be 0.03-10% formula (I) compound represented or its isomers, solvate, precursor or they
Pharmaceutically acceptable salt.It should be understood that according to preparing or the needs of storage (such as prepare dilution preparation, children preparation or dense
Contraction agent), the content of compound described in described pharmaceutical composition may also be below or be higher than above-mentioned limited range.
The dosage form of pharmaceutical composition of the present invention can be it is diversified, as long as active constituent can be made effective
The dosage form that ground reaches mammalian organism is all possible.For example it can be selected from:Gelling agent, aerosol, tablet, capsule, powder,
Grain, syrup, solution or suspension.The disease type that compound according to the present invention is treated, the those skilled in the art side of can choose
Just the dosage form applied.
In terms of easily prepared and administration position, preferred pharmaceutical composition is solid-state composition, especially tablet and solid
The capsule of body filling or liquid filling.The compound of the present invention or its pharmaceutical composition, which can also be stored in, to be suitable for injecting or instil
Disinfector in.
When for when treating psoriasis, it to be preferred that pharmaceutical composition is administered in a manner of external application.It is various to be suitable for outside preparation
It can be applied in the present invention with the pharmaceutical carriers of dosage form.As preferred embodiment of the invention, described is pharmaceutically acceptable
Carrier includes:Glycerol, propylene glycol, carbomer and/or triethanolamine.
As a kind of preferred embodiment of the invention, the step of preparing external-use gel composition, is:Take a effective amount of formula
(I) for compound into container, dehydrated alcohol, which is added, dissolves formula (I) compound sufficiently, and suitable quantity of water is added in the carbomer of recipe quantity
In, overnight, sufficiently it is swollen;According to recipe quantity by glycerol, propylene glycol, the carbomer and preservative being swollen, with solvent formula (I)
Compound be mixed and stirred for uniformly, with triethanolamine adjust pH value, make composition pH 5.8.Animal experiment proves, described
After the external-use gel preparation for treating of formula (I) compound, psoriasis affected skin may make obviously to tend to normally, it is scorching in dermis of skin
Disease cell quantity substantially reduces.
Formula (I) compound as active constituent effective administration dosage can with administration mode and disease to be treated it is tight
Weight degree and change.However, usually when the compound of the present invention is daily with about 5-500mg/kg, preferably 10-300mg/kg, more
When the dosage of good ground 20-200mg/kg, more preferably 50-75mg/kg the weight of animals are given, satisfactory effect can be obtained, compared with
It is given daily with 1-3 separated dosage, or is administered with sustained release forms goodly.This dosage is adjusted to provide optimal treatment
Response.For example, dosage separated several times can be given once daily, or dosage is subtracted pari passu by an urgent demand for the treatment of situation
It is few.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.
The therapeutic effect of embodiment 1, formula (II) compound to mouse parapsoriasis
In the present invention, mouse parapsoriasis model is constructed, and handle with formula (II) compound, observe formula (II) chemical combination
Effect of the object to mouse parapsoriasis.
Formula (II) structural formula of compound is as follows:
8 week old male C 57 BL/6 J mouse 10 is taken, is randomly divided into two groups, every group 5.5% per daily 20mg dosage
Imiquimod (IMQ) emulsifiable paste continuously smears mouse right ear dorsal skin 6 days.
Daily 25 μ L of intracutaneous injection, 4 μ g/ μ L formula (II) compound or 25 μ L tri-distilled waters after first day smearing IMQ
(carrier matrix), continuous injection 6 days.With vernier caliper measurement and record mouse ear thickness daily.7th day by mouse CO2
Asphyxia is put to death, and photographs to record simultaneously clip auris dextra tissue, 4% paraformaldehyde is fixed, then H&E dyeing is done after row paraffin section.Slice
With Zeiss microscopic filming system (10 times of object lens × 10 times eyepieces) retention of taking pictures.Photo mesocuticle area is by Adobe
Drag-line tool in Photoshop software obtains pixel value after sketching the contours.
With formula (II) compound or carrier matrix to the mouse parapsoriasis that IMQ the is induced phenotype that carries out that treated compare as
Figure 1A, mouse ear thickness statistical result such as Figure 1B.It can be seen that compared with the control, giving the mouse ear of formula (II) compound processing
Thickness it is significantly lower.Illustrate that formula (II) compound can significantly improve the symptom of psoriasis.
The mouse parapsoriasis that IMQ is induced is handled with formula (II) compound or carrier matrix, mouse ear slice
H&E dyes example such as Fig. 1 C.As seen from the figure, the mouse ear for giving the processing of formula (II) compound is significantly thin, and spinous layer of epidermis
Hyperplasia mitigates, microabscess is formed and reduced, and dermal inflammation cellular infiltration is reduced.
The mouse parapsoriasis that IMQ is induced is handled with formula (II) compound or carrier matrix, mouse ear slice
Epidermis area statistical result such as Fig. 1 D of H&E dyeing gives the epidermis area of the mouse ear slice of formula (II) compound processing
It is significant small, illustrate that formula (II) compound can significantly improve the symptom of psoriasis.
Therefore, there is therapeutic effect to psoriasis using formula (II) compound.
The therapeutic effect of embodiment 2, formula (II) compound to machin parapsoriasis
In the present invention, machin parapsoriasis model is constructed, and handle with formula (II) compound, observation formula (II) is changed
Close effect of the object to mouse parapsoriasis.
3 years old male machin 4 is taken, is randomly divided into two groups, every group 2, scapular region shaves the hair of 2*3cm area on right side
Hair.5%IMQ emulsifiable paste per daily 120mg dosage continuously smears shaving area skin 15 days.Since after first day smearing IMQ
50 μ L of daily intracutaneous injection, 10 μ g/ μ L formula (II) compound or 50 μ L tri-distilled waters (carrier matrix), continuous injection 15 days.Daily
Skin lesion progress is observed, and carries out clinical score by 1 standard of table.
Table 1, lattice clinic overall assessment system (Lattice System Physician ' s Global
Assessment)
It photographs to record within 16th day, and clip skin histology is fixed with 4% paraformaldehyde, then H&E dye is done after row paraffin section
Color.
Carrying out that treated to the machin parapsoriasis that IMQ is induced with formula (II) compound or carrier matrix, phenotype compares
Such as Fig. 2A, it is seen that obvious erythema, the scales of skin that peel off occurs in carrier matrix group skin, and gives the skin of the machin of formula (II) compound processing
Skin is only rubescent to a certain degree, has no patch and the scales of skin that peel off.
The machin parapsoriasis that IMQ is induced is handled with formula (II) compound or carrier matrix, skin clinic is commented
The situation of change such as Fig. 2 B divided, it is seen that the skin clinical score for giving the machin of formula (II) compound processing is significantly low, explanation
Formula (II) compound can significantly improve the symptom of psoriasis.
The machin parapsoriasis that IMQ is induced is handled with formula (II) compound or carrier matrix, skin biopsy H&E
Example such as Fig. 2 C is dyed, shows that the skin epidermis for giving the machin of formula (II) compound processing is thinning, inflammatory exudation mitigates, very
Skin inflammatory cell infiltration is reduced.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. the use of compound shown in formula (I) or its isomers, solvate or precursor or their pharmaceutically acceptable salt
On the way, it is used to prepare alleviation or treats the composition of psoriasis.
Wherein, R1~R9 independently selected from:Hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl group, halogen, hydroxyl.
2. compound or its isomers, solvate or precursor or their pharmacy shown in formula (I) as described in claim 1
The purposes of upper acceptable salt, which is characterized in that R1~R9 independently selected from:Hydrogen, C1-C2 alkyl.
3. compound or its isomers, solvate or precursor or their pharmacy shown in formula (I) as claimed in claim 2
The purposes of upper acceptable salt, which is characterized in that R1~R9 is hydrogen, and the compound is formula (II) compound:
4. compound or its isomers, solvate or precursor or their pharmacy shown in formula (I) as described in claim 1
The purposes of upper acceptable salt, which is characterized in that the compound is substantially reduced the epidermis area in affected part, or is substantially reduced trouble
The skin thickness at place.
5. purposes as described in claim 1, which is characterized in that the compound substantially reduces the inflammatory exudation in affected part, shows
It writes and reduces dermal inflammation cellular infiltration.
6. compound or its isomers, solvate or precursor or their pharmacy shown in formula (I) as described in claim 1
The purposes of upper acceptable salt, which is characterized in that the composition is pharmaceutical composition.
7. compound or its isomers, solvate or precursor or their pharmacy shown in formula (I) as claimed in claim 6
The purposes of upper acceptable salt, which is characterized in that the pharmaceutical composition is exterior-applied formulation.
8. compound or its isomers, solvate or precursor or their pharmacy shown in formula (I) as claimed in claim 7
The purposes of upper acceptable salt, which is characterized in that compound shown in formula (I) or its isomers, molten in the pharmaceutical composition
Object or precursor are closed in agent or their pharmaceutically acceptable salt is mixed with pharmaceutically acceptable carrier.
9. compound or its isomers, solvate or precursor or their pharmacy shown in formula (I) as claimed in claim 8
The purposes of upper acceptable salt, which is characterized in that the pharmaceutically acceptable carrier includes:Glycerol, propylene glycol, carbomer,
Triethanolamine.
10. compound or its isomers, solvate or precursor or their pharmacy shown in formula (I) as described in claim 1
The purposes of upper acceptable salt, which is characterized in that the solvate is hydrate.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101721678A (en) * | 2008-10-22 | 2010-06-09 | 王宏林 | New antipsoriatic medicine |
CN101724004A (en) * | 2008-10-22 | 2010-06-09 | 王宏林 | Antipsoriatic new natural medicine (acetyl-11-keto-beta-boswellic acid) |
CN102670689A (en) * | 2011-03-14 | 2012-09-19 | 苏州博创园生物医药科技有限公司 | Method for preparing spray for curing psoriasis |
CN103191154A (en) * | 2012-01-06 | 2013-07-10 | 上海交通大学医学院 | Application of mesenchymal stem cells in preparation of psoriasis treatment medicines, and extraction method of mesenchymal stem cells |
CN103193853A (en) * | 2012-01-06 | 2013-07-10 | 苏州博创园生物医药科技有限公司 | Compound and composition used for treating psoriasis, and preparation method thereof |
-
2018
- 2018-06-21 CN CN201810643396.XA patent/CN108888618A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101721678A (en) * | 2008-10-22 | 2010-06-09 | 王宏林 | New antipsoriatic medicine |
CN101724004A (en) * | 2008-10-22 | 2010-06-09 | 王宏林 | Antipsoriatic new natural medicine (acetyl-11-keto-beta-boswellic acid) |
CN102670689A (en) * | 2011-03-14 | 2012-09-19 | 苏州博创园生物医药科技有限公司 | Method for preparing spray for curing psoriasis |
CN103191154A (en) * | 2012-01-06 | 2013-07-10 | 上海交通大学医学院 | Application of mesenchymal stem cells in preparation of psoriasis treatment medicines, and extraction method of mesenchymal stem cells |
CN103193853A (en) * | 2012-01-06 | 2013-07-10 | 苏州博创园生物医药科技有限公司 | Compound and composition used for treating psoriasis, and preparation method thereof |
Non-Patent Citations (3)
Title |
---|
FANGZHOU LOU ET AL.: "Excessive Polyamine Generation in Keratinocytes 1 Promotes Self-RNA Endosomal Sensing by Dendritic Cells in Psoriasis", 《BIORXIV》 * |
PRIYANKA DAS ET AL.: "Modulation of the Arginase Pathway in the Context of Microbial Pathogenesis: A Metabolic Enzyme Moonlighting as an Immune Modulator", 《PLOS》 * |
S. ABEYAKIRTHI, ET AL.: "Arginase is overactive in psoriatic skin", 《BRITISH JOURNAL OF DERMATOLOGY》 * |
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