CN109985052A - The new application of triterpene compound - Google Patents
The new application of triterpene compound Download PDFInfo
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- CN109985052A CN109985052A CN201711489391.8A CN201711489391A CN109985052A CN 109985052 A CN109985052 A CN 109985052A CN 201711489391 A CN201711489391 A CN 201711489391A CN 109985052 A CN109985052 A CN 109985052A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
Abstract
The present invention relates to a kind of new applications of triterpene compound.Specifically, the present invention provides the purposes of compound shown in Formulas I or its optical isomer or its racemic modification or its solvate or its pharmaceutically acceptable salt or its prodrug, they be used to prepare pharmaceutical composition or preparation, and described pharmaceutical composition or preparation are for preventing and/or treating eye disease caused by crystalline lens lesion.Present invention firstly discovers that compound shown in Formulas I can prevent and/or treat eye disease caused by crystalline lens lesion, such as the prevention and treatment of cataract, and it is highly-safe, toxic side effect is small and has significant therapeutic effect and development and application prospect.
Description
Technical field
The present invention relates to field of medicaments, in particular it relates to a kind of new application of triterpene compound.
Background technique
The crystalline lens of normal eye is made of numerous orderly aligned crystallins, once these crystallins arrange
Mistake accumulation occurs for mistake, will influence the normal transparency of crystalline lens and index of refraction.Wherein, cataract is a kind of main
The form of expression and world wide in the highest disease of blinding.Therefore, the treatment of lens diseases, especially cataract and
Prevention, it is just very important.Regrettably, at present clinically still to perform the operation and replace artificial lens as essential therapeutic arsenals.
How drug is simply utilized, so that it may which prevention even treatment cataract is always the hot spot of ophthalmology research.Have before
Study group reports the cataract that can treat animal using lanosterol, and the structural formula of lanosterol is shown below:
It is important to note, however, that the lanosterol drug of sustained release only combines high frequency time glass cavity drug administration by injection mode
Meanwhile just there is the therapeutic effect of cataract to dog；Also, there is researcher to also indicate that lanosterol can not restore or to improve caryogram white
The transparency of cataract or glaucoma crystal.
Therefore, this field, which needs to develop one kind, can effectively treat crystalline lens lesion or eye relevant to lens disorder change
The drug of disease.
Summary of the invention
It is an object of the invention to provide one kind can effectively treat crystalline lens lesion or eye relevant to lens disorder change
The drug of portion's disease and its application.
The first aspect of the present invention, provide compound shown in a kind of Formulas I or its optical isomer or its racemic modification,
Or the purposes of its solvate or its pharmaceutically acceptable salt or its prodrug or its prodrug, they be used to prepare drug
Composition or preparation, described pharmaceutical composition or preparation are for preventing and/or treating eye disease caused by crystalline lens lesion；
In formula,
Q is 0,1 or 2；
R1a, R1b, R2a, R2b, R3a and R3b are each independently selected from: hydrogen, substituted or unsubstituted C1-C20 alkyl, take
Generation or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C10 naphthenic base ,-
OH, substituted or unsubstituted C1-C10 alkoxy ,-COOH ,-CHO, substituted or unsubstituted C1-C10 ester group-,-SH, replace or
Unsubstituted C1-C10 alkylthio group ,-A-B,
Or R1a and R1b, R2a and R2b, and/or R3a and R3b composition=O；
Wherein, A is nothing, divalent linking group；And B be H ,-OH ,-SH, C1-C3 alkoxy, C1-C3 alkylthio group ,-CHO ,-
COOH, C1-C4 ester group, C3-C10 naphthenic base, aryl, the 5-6 unit's heteroaryl of C3-C10 or benzyl；
Additional conditions are that at least one in R1a, R2a, R3a, R1b, R2b and R3b is the group containing O or S；
Z is selected from the group: H, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, replace or
It is unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C10 naphthenic base, substituted or unsubstituted aryl, substituted or unsubstituted
5-8 unit's heteroaryl, substituted or unsubstituted-(C1-C6 alkylidene)-aryl, substituted or unsubstituted-(C1-C6 alkylidene)-
5-8 unit's heteroaryl, substituted or unsubstituted C1-C20 alkoxy ,-SH, substituted or unsubstituted C1-C20 alkylthio group, takes-OH
Generation or unsubstituted C1-C10 ester group-, substituted or unsubstituted C1-C10 acyl group, substituted or unsubstituted-O- aryl；
R4 is hydrogen, substituted or unsubstituted C1-C4 alkyl；
R7, R12 and R15 are each independently selected from: nothing, hydrogen, substituted or unsubstituted C1-C4 alkyl；
R13a and R13b is each independently selected from nothing, hydrogen, substituted or unsubstituted C1-C8 alkyl ,-OH, replaces or do not take
The C1-C8 alkoxyl in generation ,-SH, substituted or unsubstituted C1-C8 alkylthio group, halogen, substituted or unsubstituted C1-C3 acyl group, or
R13a and R13b composition=O, and in R13a and R13b at most one be nothing；
R11a and R11b be each independently selected from: nothing, hydrogen, substituted or unsubstituted C1-C6 alkyl ,-OH or R11a and
R11b composition=O, and in R11a and R11b at most one be nothing；
R10a, R10b be each independently selected from: hydrogen ,-OH, substituted or unsubstituted C1-C8 alkoxyl ,-SH, replace or not
Substituted C1-C8 alkylthio group ,-OSO3H, the substituted or unsubstituted C1-C7 alkyl of-OCO- ,-OPO3H ,-COOH ,-(replace or not
Substituted C1-C7 alkylidene)-COOH ,-CHO ,-(substituted or unsubstituted C1-C7 alkylidene)-CHO or R10a and R10b be total
Same composition=O；With
R5, R6, R8, R9a, R9b, R14, R16, R17a and R17b are each independently selected from: hydrogen, OH, substituted or unsubstituted
C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxyl, halogen.
In another preferred example, " substitution " refers to have one or more hydrogen replaced group selected from the group below: halogen
Element ,-OH ,-SH ,-COOH ,-(C1-C7 alkylidene)-COOH ,=O ,-CHO ,-(C1-C7 alkylidene)-CHO, C1-C7 alkyl-
OCO-, C1-C3 alkyl, C3-C6 naphthenic base, NRaRb, wherein it is halogenated that Ra and Rb is each independently H, C1-C6 alkyl, C1-C6
Alkyl, C3-C6 naphthenic base or benzyl.
In another preferred example, in the structural formula, the dotted lineThe sum of represented double bond be 0,1,
2,3 or 4.
In another preferred example, the double bond is between following site: a and b, b and c, c and d, e and f, c and f, f
With g, g and h, h and a, b and i, i and j, a and k, and/or k and l.
In another preferred example, in the structural formula, the valence state of each C meet chemical stabilization structure requirement (i.e. C be four
Valence).
When R5, R6, R7, R8, R12, R14, R15 and/or R16 are connected to double bond containing C, the price of the C is 4 valences.
In another preferred example, the divalent linking group has 1-10 connection units selected from the group below :-
CRaRb-；-C(O)Ra-,-NRa-,-O-,-CO-；Wherein, Ra and Rb is each independently H, C1-C6 alkyl, C1-C6 alkyl halide
Base, C3-C6 naphthenic base or benzyl.
In another preferred example, described R1a, R1b, R2a, R2b, R3a and R3b be each independently selected from: hydrogen ,-OH ,-
CHO ,-COOH ,-SH, substituted or unsubstituted C1-C3 alkyl-OCO-, substituted or unsubstituted C1-C4 alkyl ,-A-B or R1a
With R1b, R2a and R2b, and/or R3a and R3b composition=O；
Wherein, A respectively stands alone as substituted or unsubstituted C1-C4 alkylidene, and B is each independently-OH ,-SH, C1-
C3 alkoxy ,-CHO ,-COOH ,=O.
In another preferred example, the Z is (L1) m-L2=Y, m 0,1,2,3 or 4, each L1 is each independently-
CH2,-CO- ,-O- ,-C (C1-C3 alkyl) H-, C (C1-C3 alkyl) 2- ,-C (C1-C3 alkyl) O- or-NH-, L2 be-CH
=,-C (C1-C3 alkyl)=；
Y is=CH2The substituted or unsubstituted C1-C7 alkyl of ,=CH- ,=C- (substituted or unsubstituted C1-C7 alkyl)2、
The substituted or unsubstituted C2-C7 alkenyl of=CH- or the substituted or unsubstituted C2-C7 alkynyl of=CH-.
In another preferred example, for Y, the substitution indicates one or more hydrogen by group institute selected from the group below
Replace: halogen ,-OH ,-SH ,-COOH ,-(C1-C7 alkylidene)-COOH ,=O ,-CHO ,-(C1-C7 alkylidene)-CHO, C1-C7
Alkyl-OCO-, C1-C3 alkyl, C3-C6 naphthenic base, NRaRb, wherein Ra and Rb is each independently H, C1-C6 alkyl, C1-
C6 halogenated alkyl, C3-C6 naphthenic base or benzyl.
In another preference, Y is the group with hydroxyl or SH substituent group.
In another preference, the R4 is hydrogen, methyl.
In another preferred example, R7, R12 and R15 are each independently selected from: nothing, hydrogen, methyl.
In another preferred example, the R13a and R13b is each independently selected from hydrogen, methyl ,-OH ,-SH ,=O, halogen
Element, and in R13a and R13b at most one be nothing.
In another preferred example, described R10a, R10b are each independently selected from: hydrogen ,-OH ,-SH ,-OSO3H、-OPO3H、-
COOH,-CHO；Or R10 and R11 constitutes carbonyl.
In another preferred example, described R5, R6, R8, R9a, R9b, R14, R16, R17a and R17b be each independently selected from hydrogen,
Methyl.
In another preferred example, at least one in R1a and R1b is the group containing O or S.
In another preferred example, at least one in R2a and R2b is the group containing O or S.
In another preferred example, at least one in R3a and R3b is the group containing O or S.
In another preferred example, the Z is not-CH2C(CH3)3；
In another preferred example, the Z is not-CH2C(CH3)2-OH。
In another preferred example, q is 1 or 2.
In another preferred example, the compound of formula I is -1 compound of Formulas I:
Wherein, q, R1a, R1b, R2a, R2b, R3a, R3b, R4, R7, R10a, R10b, R11a, R11b, R12, R13a,
R13b and R15 are as defined above.
In another preferred example, the compound of formula I is -2 compound of Formulas I:
Wherein, the definition of q, R1a, R1b, R2a, R2b, R3a, R3b, R4, R7, R11a, R11b, R13a, R13b and R15 is such as
On.
In another preferred example, the compound of formula I is selected from the group compound:
Wherein, R1a, R1b, R2a, R2b are as defined above.
In another preferred example, the compound of formula I is selected from the group compound:
Wherein, R1a, R1b, R2a, R2b are as defined above.
In another preferred example, compound shown in the Formulas I is with structure shown in Formulas I -7:
Wherein, R1a, R1b, R2a, R2b are as defined above described in text.
In another preferred example, compound shown in the Formulas I is with structure shown in Formulas I -8:
Wherein, R1a, R1b, R2a, R2b are as defined above described in text.
In another preferred example, the Formulas I compound represented is selected from the group:
In another preferred example, eye disease caused by the crystalline lens lesion is selected from the group: cataract, presbyopia,
The ocular complications that myopia, cortex muddiness, presbyopia nuclear hardening, diabetes cause.
It in another preferred example, include: (a) effectively controlling as the first active constituent in described pharmaceutical composition or preparation
The Formulas I compound represented for the treatment of amount or its optical isomer or its racemic modification or its solvate or its can pharmaceutically connect
The salt received or its prodrug；(b) pharmaceutically acceptable carrier.
Wherein, the content of the first active constituent is 0.001-99wt%, preferable 0.01-70wt%, more preferably 0.05-
40wt%'s, according to the total weight of composition.
In another preferred example, the concentration of first active constituent is preferably 1-500mM or 10~200mM, preferably
15~150mM of ground, more preferably 20~50mM；Most preferably 20~30mM.
In another preferred example, the dosage form of the Pharmaceutical composition or preparation is selected from: injection, takes orally external preparation
Preparation.
In another preferred example, the dosage form of the Pharmaceutical composition or preparation is eye-drops preparations, the eye-drops preparations
For eyedrops, emulsion, gel, ophthalmically acceptable cream, sustained-release micro-spheres, intraocular slow-released plant piece, medicinal slow-release medicine-membrane.
In another preferred example, the Pharmaceutical composition or preparation further include: (c) second active constituent, wherein described
The second active constituent be selected from the group: comprising containing in mushroom in wool lipoid substance, all rust leather hole Zoopagales or Aphyllophorales
Any compound (especially steroidal compounds, terpenoid), the azole compounds, glucocorticoids chemical combination having
Object, antibiotic, or combinations thereof.
In another preferred example, the content of second active constituent is 0.01-20wt%, preferably 5-
15wt%, according to the total weight of composition.
In another preferred example, when " second active constituent " is wool lipoid substance or azole compounds,
Concentration is preferably 10~200mM, preferably 15~150mM, more preferably 20~50mM；Most preferably 20~30mM.
In another preferred example, the wool lipoid substance is selected from: lanosterol,
In another preferred example, the glucocorticoid compound is selected from the group: dexamethasone, hydrocortisone or
A combination thereof.
In another preferred example, the antibiotic is selected from the group: tobramycin, gentamicin sulphate, aureomycin, chlorine are mould
Element, or combinations thereof.
In another preferred example, the azole compounds are selected from econazole, Isoconazole, bifonazole, clotrimazole, A Li
Piperazine azoles, ketoconazole, Fluconazole, phenylimidazole, Miconazole, ciproconazole, Triadimenol, Tebuconazole, propiconazole, or combinations thereof.
In the second aspect of the present invention, a kind of method of the improvement crystalline lens transparency of external non-therapeutic is provided, it
It include: by compound or its optical isomer or its racemic modification or its solvate or its pharmacy shown in crystalline lens and Formulas I
Upper acceptable salt or its prodrug thereof, so as to improve (or raising) crystalline lens transparency, wherein change described in the Formulas I
It is as described above to close object.
In the third aspect of the present invention, eye disease caused by a kind of prevention and/or treatment crystalline lens lesion is provided
Method, comprising steps of giving required object Formulas I compound represented or its optical isomer or its racemic modification or its solvent
Compound or its pharmaceutically acceptable salt or its prodrug, wherein compound shown in the Formulas I is as defined above.
In another preferred example, the object behaviour and non-human mammal.Typically, the non-human mammal
Including (but being not limited to): pet (such as dog, cat), domestic animal (such as ox, sheep, horse, pig), various zoo animals (panda, elephant)
Deng.
In another preferred example, the object further includes other animals in addition to people and non-human mammal, such as the non-food in one's mouth
Newborn animal.
In fifth aspect present invention, provide compound shown in Formulas I or its optical isomer or its racemic modification or its
Solvate or its pharmaceutically acceptable salt or its prodrug or its prodrug.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Detailed description of the invention
Fig. 1 is the form of the upper light source of rat lens after cataract modeling success in 1 group of the embodiment of the present invention.
Fig. 2 is the form of the lower light source of rat lens after cataract modeling success in 1 group of the embodiment of the present invention.
Fig. 3 is the form of the upper light source of rat lens after cataract modeling success in 1 group of comparative example of the present invention.
Fig. 4 is the form of the lower light source of rat lens after cataract modeling success in 1 group of comparative example of the present invention.
Fig. 5 be 1 group of experiment of the embodiment of the present invention after rat lens upper light source form.
Fig. 6 be 1 group of experiment of the embodiment of the present invention after rat lens lower light source form.
Fig. 7 be 1 group of experiment of comparative example of the present invention after rat lens upper light source form.
Fig. 8 be 1 group of experiment of comparative example of the present invention after rat lens lower light source form.
Fig. 9 is the form of the upper light source of rat lens after cataract modeling success in 2 groups of the embodiment of the present invention.
Figure 10 is the form of the lower light source of rat lens after cataract modeling success in 2 groups of the embodiment of the present invention.
Figure 11 is the form of the upper light source of rat lens after cataract modeling success in 2 groups of comparative example of the present invention.
Figure 12 is the form of the lower light source of rat lens after cataract modeling success in 2 groups of comparative example of the present invention.
Figure 13 be 2 groups of experiments of the embodiment of the present invention after rat lens upper light source form.
Figure 14 be 2 groups of experiments of the embodiment of the present invention after rat lens lower light source form.
Figure 15 be 2 groups of experiments of comparative example of the present invention after rat lens upper light source form.
Figure 16 be 2 groups of experiments of comparative example of the present invention after rat lens lower light source form.
Specific embodiment
The present inventor by extensively and in-depth study, having unexpectedly discovered that compound shown in a kind of Formulas I can be with for the first time
Eye disease caused by significant prevention and/or treatment crystalline lens lesion.The present invention is the experimental results showed that compound is shown in Formulas I with letter
Single administration mode is rapidly achieved eye disease effect caused by healing and prevention crystalline lens lesion.It completes on this basis
The present invention.
Term
As used herein, " R1 ", " R1" and " R1" meaning it is identical.The meaning of other similar definition is identical.
As used herein, term " C1-C20 alkyl " or " C1-C10 alkyl " or " C1-C8 alkyl " refer to 1-20 or
The linear or branched alkyl group of 1-10 or 1-8 carbon atom, for example, it is methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, secondary
Butyl, tert-butyl, amyl, hexyl, heptyl, octyl, or similar group.
As used herein, term " C1-C8 alkoxyl " or " C1-C4 alkoxy " refer to 1-8 and 1-4 carbon atom
The alkoxy of linear chain or branched chain, such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, Zhong Ding oxygen
Base, tert-butoxy, amoxy, hexyloxy, oxygroup in heptan, octyloxy, or similar group.
As used herein, term " C1-C8 alkylthio group " " or " C1-C4 alkylthio group " refer to straight chain with 1-8 carbon atom or
The alkylthio group of branch, such as methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, butylthio, isobutylthio, secondary butylthio, tertiary fourth
Sulfenyl, penta sulfenyl, own sulfenyl, sulfenyl in heptan, pungent sulfenyl, or similar group.
As used herein, term " C3-C10 naphthenic base " refers to the naphthenic base with 3-10 carbon atom, such as cyclopropyl, ring
Butyl, methyl-cyclobutyl, cyclopenta, or similar group.
As used herein, term " C1-C8 alkylidene " or " C1-C7 alkylidene " or " C1-C6 alkylidene " refer to having
One carbon atom of the alkyl molecule of the branch or straight chain of 1-8 and 1-7 and 1-6 carbon atom removes 2 hydrogen atoms and is formed
In have the group of-CH2-, such as methylene (- CH2-), or similar group.
As used herein, term " C2-C10 alkenyl " refer to the 2-10 carbon atom with one or more double bonds straight chain or
Branched-chain alkene molecule minuses the alkyl of one and the formation of doubly linked hydrogen atom, such as vinyl (CH2=CH-), (C
(CH3)2=CH-), or similar group.
As used herein, term " C2-C8 alkynyl " refers to the straight chain or branch of the 2-8 carbon atom with one or more three keys
Alkynyl group molecule minuses the alkyl of the hydrogen atom formation of one and three key connections, such as acetenyl (tri- CH- of CH), (H3C-C tri-
CH-), or similar to group.
As used herein, term " C1-C6 halogenated alkyl " refers to linear or branched alkyl group-halogen with 1-6 carbon atom
As a result substituent group, such as-CH2Cl、-CH2CH2Br、CH2CHCH2Cl, or similar group.
As used herein, term " halogen " refers to F, Cl, Br and I.
As used herein, term " aryl " refers to the aryl of substituted or unsubstituted C6-C20, including monocycle or bicyclic or three
The aryl of ring, such as phenyl, naphthalene, anthryl.
As used herein, term " C6-C10 member aryl " refers to the cyclic group with aromatic structure, such as phenyl, naphthalene.
As used herein, term " 5-8 unit's heteroaryl " in 5~8 yuan of monocycles or fused polycycle and ring system have N, O
Or the heteroaryl of S, such as pyrrole radicals, pyridyl group, furyl, or similar group.
As used herein, term "comprising", " comprising ", " containing " are used interchangeably, and include not only closed definition, also wrap
Include semiclosed and open definition.In other words, the term include " by ... constitute ", " substantially by ... constitute ".
Active constituent
Present invention firstly discovers that purposes of the compound in terms of lens disorder in a disguised form closes curing eye diseases shown in Formulas I, described
Compound shown in Formulas I is used to prepare pharmaceutical composition or preparation, and described pharmaceutical composition or preparation are for preventing and/or treating crystalline substance
Eye disease caused by shape body lesion.
As used herein, term " the compounds of this invention ", " compound shown in Formulas I " are used interchangeably, and refer to chemical combination shown in Formulas I
Object or its optical isomer or its racemic modification or its solvate or its pharmaceutically acceptable salt or its prodrug.Ying Li
Solution, the term further include the mixture of said components, in the compound shown in Formulas I, if there is asymmetric carbon atom, then and chiral carbon
Atom can be R configuration, or S configuration, or both mixture.
The structure of compound shown in Formulas I is as described in first aspect present invention.
In another preferred example, in the structural formula, the dotted lineThe sum of represented double bond be 0,1,
2,3 or 4.
In another preferred example, the double bond is between following site: a and b, b and c, c and d, e and f, c and f, f
With g, g and h, h and a, b and i, i and j, a and k, and/or k and l.
In another preferred example, in the structural formula, the valence state of each C meet chemical stabilization structure requirement (i.e. C be four
Valence).
In another preferred example, described R1a, R1b, R2a, R2b, R3a and R3b be each independently selected from: hydrogen ,-OH ,-
CHO ,-COOH ,-SH, substituted or unsubstituted C1-C3 alkyl-OCO-, substituted or unsubstituted C1-C4 alkyl ,-A-B or R1a
With R1b, R2a and R2b, and/or R3a and R3b composition=O；
Wherein, A respectively stands alone as substituted or unsubstituted C1-C4 alkylidene, and B is each independently-OH ,-SH, C1-
C3 alkoxy ,-CHO ,-COOH ,=O.
In another preference, Y is the group with hydroxyl or SH substituent group.
In another preference, the R4 is hydrogen, methyl.
In another preferred example, R7, R12 and R15 are each independently selected from: nothing, hydrogen, methyl.
In another preferred example, the R13a and R13b is each independently selected from hydrogen, methyl ,-OH ,-SH ,=O, halogen
At most one is nothing in plain and R13a and R13b.
In another preferred example, described R10a, R10b are each independently selected from: hydrogen,-OH,-SH, -0SO3H、-OPO3H、-
COOH ,-CHO or R10 and R11 constitute carbonyl.
In another preferred example, described R5, R6, R8, R9a, R9b, R14, R16, R17a and R17b be each independently selected from hydrogen,
Methyl.
In another preferred example, the Z is not-CH2C(CH3)3；
In another preferred example, the Z is not-CH2C(CH3)2-OH。
In another preferred example, the compound of formula I is -1 compound of Formulas I.
In another preferred example, the compound of formula I is -2 compound of Formulas I:
In another preferred example, the compound of formula I is selected from the group compound:
Wherein, R1a, R1b, R2a, R2b are as defined above described in text.
In another preferred example, the compound of formula I is selected from the group compound:
Wherein, R1a, R1b, R2a, R2b are as defined above described in text.
: in another preferred example, compound shown in the Formulas I is with structure shown in Formulas I -7:
Wherein, R1a, R1b, R2a, R2b are as defined above described in text.
In another preferred example, compound shown in the Formulas I is with structure shown in Formulas I -8:
Wherein, R1a, R1b, R2a, R2b are as defined above described in text.
In another preferred example, the Formulas I compound represented is selected from the group:
In the present invention, term " pharmaceutically acceptable salt " refers to that the compounds of this invention and acid or alkali are formed by suitable use
Make the salt of drug.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the compounds of this invention and acid
The salt of formation.The acid for suitably forming salt includes but is not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid etc. are inorganic
Acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid,
Picric acid, methanesulfonic acid, benzene methanesulfonic acid, the organic acids such as benzene sulfonic acid；And the acidic amino acids such as aspartic acid, glutamic acid.It is a kind of excellent
The salt of choosing is the salt that the compounds of this invention and alkali are formed.The acid for suitably forming salt includes but is not limited to: sodium hydroxide, hydroxide
The inorganic bases such as potassium, sodium carbonate, sodium bicarbonate, sodium phosphate, the organic bases such as ammonium hydroxide, triethylamine, diethylamine.
In the present invention, term " prodrug " is also referred to as pro-drug, prodrug, forerunner's drug etc., refers to by organism
Just with the compound of pharmacological action after interior conversion.Pro-drug itself is very low without bioactivity or activity, by internal generation
Become active substance after thanking, the purpose of this process is to increase the bioavilability of drug, reinforces targeting, reduce medicine
The Side effect of object.In the present invention, the prodrug of compound shown in formula A is metabolizable (representative at compound shown in Formulas I
Such as Inonotus obliquus alcohol).
Method system well known to those skilled in the art in the prior art can be used in compound shown in Formulas I of the invention
It is standby, the response parameter of each step is not particularly limited.It is obtained in addition, the compound of the present invention can also be bought by market.
Typically, extracting and developing and the purifying preparation gained from Inonotus obliquus of compound shown in Formulas I of the present invention.
In the present invention, inventor carries out pharmacokinetic to compound shown in different Formulas I, as a result, it has been found that, Formulas I institute
Show in compound structure, when at least one in R1a, R2a, R3b, R1b, R2b and R3b is the group containing O or S, can obviously prolong
The half-life period of compound shown in long Formulas I improves the aggregate concentration in eye, extends the residence time of eye, improves to eye disease
The therapeutic effect of disease.
Purposes
Compound or its optical isomer or its racemic modification or its solvate shown in the above-mentioned Formulas I of the present invention or its
Pharmaceutically acceptable salt or its prodrug or its prodrug are used to prepare pharmaceutical composition or preparation, described pharmaceutical composition or system
Agent is for preventing and/or treating eye disease caused by crystalline lens lesion.
In another preferred example, the eye disease (but being not limited to): cataract, presbyopia, myopia, cortex are mixed
The ocular complications that turbid, presbyopia nuclear hardening, diabetes cause.
In another preferred example, term " cataract " refers to shows to cause muddiness on lenticular surface and/or inside
Or it is opaque, or the disease or illness of crystalline lens swelling are induced, including congenital cataract and acquisition cataract.It is representative
, the cataract is to include but is not limited to: age-related cataract, diabetic cataract, relevant white to operation
Cataract caused by cataract, infection caused by cataract, genetic disease caused by cataract or glaucoma, radioactive ray irradiate or drug draw
The cataract risen.
As used herein, term " presbyopia " refers to that the crystalline lens of eyes loses its visual state flexible, thus difficult
To focus on closer object.
Typically, eye disease caused by the crystalline lens lesion does not include conjunctivitis, because of pathogen (such as bacterium, disease
The microorganisms such as poison) caused by eye infection or inflammation of eye section.
As used herein, term " prevention " refer to before eye disease apply therapeutically effective amount Formulas I shown in compound or its
Optical isomer or its racemic modification or its solvate or its pharmaceutically acceptable salt or its prodrug or its prodrug, from
And the eye disease is prevented, time of origin postpone or still occur, but compare do not apply compound shown in Formulas I or
Its optical isomer or its racemic modification or its solvate or its pharmaceutically acceptable salt or its prodrug or its prodrug
Degree mitigate.As used herein, term " treatment ", refer to application therapeutically effective amount Formulas I shown in compound or its optical siomerism
Body or its racemic modification or its solvate or its pharmaceutically acceptable salt or its prodrug or its prodrug, thus reduce,
Mitigate or slow down eye disease, obstruction and illness progress or development.In another embodiment, " treatment " refers to mitigation, slows down
The process of eye disease, obstruction and illness, or improve one or more S or Ss of eye disease, obstruction and illness.
" prevention " and " treatment " of the present invention include delaying and terminating the progress of disease, or eliminate crystalline lens lesion and draw
The eye disease risen, does not need 100% inhibition, elimination and reverse.In some embodiments, and there is no of the present invention
When compound and composition described in Formulas I or preparation (for example, be not exposed to the compound described in formula I and composition or
In the matched control subject of preparation biology or sample) level observed compares, compound described in Formulas I of the present invention and
Eye disease caused by crystalline lens lesion (such as cataract) is mitigated, prevented, inhibited and/or reversed for example by composition or preparation
At least about 10%, at least about 30%, at least about 50% or at least about 80%.
Pharmaceutical composition or preparation and method of administration
Since the compounds of this invention has eye disease caused by excellent prevention and/or treatment crystalline lens lesion,
The pharmaceutical composition or preparation of active constituent containing the compounds of this invention can be used for preventing and/or treating crystalline lens lesion and cause
Eye disease, such as cataract.It include: the effective treatment of (a) as the first active constituent in described pharmaceutical composition or preparation
The Formulas I compound represented of amount or its optical isomer or its racemic modification or its solvate or its is pharmaceutically acceptable
Salt or its prodrug；(b) pharmaceutically acceptable carrier.
Wherein, the content of the first active constituent is 0.001-99wt%, preferable 0.01-70wt%, more preferably 0.05-
40wt%'s, according to the total weight of composition.
In another preferred example, the Pharmaceutical composition or preparation further include: (c) second active constituent, wherein described
The second active constituent be selected from the group: comprising containing in mushroom in wool lipoid substance, all rust leather hole Zoopagales or Aphyllophorales
Any compound for having, azole compounds, glucocorticoids compound, antibiotic, or combinations thereof.
In another preferred example, the content of second active constituent is 0.01-20wt%, preferably 5-
15wt%, according to the total weight of composition.
In another preferred example, when " second active constituent " is wool lipoid substance, concentration is preferably 10
~200mM, preferably 15~150mM, more preferably 20~50mM；Most preferably 20~30mM.
In another preferred example, the wool lipoid substance is selected from: lanosterol,
In another preferred example, the glucocorticoid compound is selected from the group: dexamethasone, hydrocortisone or
A combination thereof.
In another preferred example, the antibiotic is selected from the group: tobramycin, gentamicin sulphate, aureomycin, chlorine are mould
Element, or combinations thereof.
In another preferred example, the azole compounds are selected from econazole, Isoconazole, bifonazole, clotrimazole, A Li
Piperazine azoles, ketoconazole, Fluconazole, phenylimidazole, Miconazole, ciproconazole, Triadimenol, Tebuconazole, propiconazole, or combinations thereof.
As used herein, term " effective therapeutic dose " refers to and generates function or active and can be by people to people and/or animal
And/or the amount that animal is received.It will be apparent to an ordinarily skilled person in the art that " effective quantity " or " effective dose " can
Combine with the form of pharmaceutical composition, administration route, the auxiliary material of drug used, the severity of disease and with other drugs
Situations such as medication it is different and different.
Term " pharmaceutically acceptable carrier " refers to: one or more biocompatible solids, semisolid, liquid or gel
Filler, they are suitable for human body or animal uses and it is necessary to have enough purity and sufficiently low toxicity." compatibility " refers to
The active constituent of each component and drug in pharmaceutical composition and they between mutually admix, and significantly reduce drug effect.
It should be understood that in the present invention, the carrier is not particularly limited, material commonly used in the art can be selected, or use
Conventional method is made, or is commercially available from market.
Pharmaceutically acceptable carrier partial example has cellulose and its derivates (such as methylcellulose, ethyl cellulose, hydroxyl
Third methylcellulose, sodium carboxymethylcellulose etc.), gelatin, talcum powder, solid lubricant (such as stearic acid, magnesium stearate), sulfuric acid
Calcium, vegetable oil (such as soya-bean oil, sesame oil, peanut oil, olive oil), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite
Deng), emulsifier (such as tween), wetting agent (such as lauryl sodium sulfate), buffer, chelating agent, thickener, pH adjusting agent, thoroughly
Skin promotor, colorant, flavoring agent, stabilizer, antioxidant, preservative, bacteriostatic agent, apirogen water etc..
Other than active pharmaceutical ingredient, liquid dosage form may include the inert diluent routinely used in this field, such as water or
Other solvents, solubilizer and emulsifier, for example, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO,
Dimethylformamide and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these objects
The mixture etc. of matter.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent
In the present invention, the dosage form of pharmaceutical composition includes but is not limited to oral preparation, injection, external preparation.Generation
Table includes but is not limited to: tablet, injection, infusion solution, paste, gelling agent, solution, microballoon, film.
A kind of preferred dosage form is eye-drops preparations.It is representative, the eye-drops preparations be eyedrops, emulsion, gel,
Ophthalmically acceptable cream, sustained-release micro-spheres, intraocular slow-released plant piece, medicinal slow-release medicine-membrane.
The eye-drops preparations includes pharmaceutically acceptable pharmaceutical carrier, representative from including but not limited to: solvent
Or diluent, surfactant, thickener, osmotic pressure regulator, pH adjusting agent, bacteriostatic agent, chelating agent.
Solvent
(such as eye drops, eyedrops) use is solvent in eye-drops preparations or diluent includes aqueous solvent or nonaqueous solvents.
The aqueous solvent includes distilled water, physiological saline, water for injection etc.；Nonaqueous solvents used includes ethyl alcohol, propylene glycol, sweet
Oil, vegetable oil (such as castor oil, corn oil, injection soybean oil).
Surfactant
In eye-drops preparations, surfactant is selected from anionic surfactant, cationic surfactant, nonionic table
Face activating agent, chaotropic type (chaotropic) surfactant or combinations thereof.Wherein nonionic surfactant is selected from: tween,
Sapn, fatty glyceride, polyoxyethylene, Pluronic F68, or combinations thereof.General surfactant
Dosage (or content) be 0-2wt%, more preferably 0.1-1wt%.
Thickener
In eye-drops preparations, thickener can be used for improving object system viscosity, and object system is made to keep uniformly stable suspended state
Or milkiness state increases drug in the residence time of eye, to increase eye for effectively small by adding appropriate thickener
The absorption of ingredient.
In eye-drops preparations, thickener is preferably chitosan, hydroxypropyl methyl cellulose (HPMC), methylcellulose (MC),
With povidone (PVP), gelatin, sodium carboxymethylcellulose (CMC-Na) etc..Generally, the dosage (or content) of thickener be 0~
6wt%, preferably 0.1-5wt%.
Osmotic pressure regulator
Osmotic pressure regulator appropriate is added in ophthalmic preparations, makes the infiltration of the osmotic pressure human body ocular environment of eye-drops preparations
Press it is similar, to reduce stimulation to eye.Representativeness, common osmotic pressure regulator include but is not limited to acetic acid, second
Sour sodium, sodium bicarbonate.In general, the dosage (or content) of osmotic pressure regulator make eye-drops preparations be maintained at one it is isotonic or isotonic
In environment.
PH adjusting agent
PH adjusting agent appropriate is added in ophthalmic preparations, so that the pH value of eye-drops preparations is maintained at a proper range, with people
The pH of body ocular environment is similar, to reduce the stimulation to eye.Representativeness, common pH adjusting agent include but is not limited to
Sodium chloride, potassium chloride, glucose.In general, pH adjusting agent dosage (or content) makes the pH value of eye-drops preparations be maintained at 5-9.
Bacteriostatic agent
In eye-drops preparations, it is suitably added
The growth of bacterium in creme is killed or inhibited, prevents bacteria breed excessive, is detrimental to health.In the present invention,
Bacteriostatic agent is not particularly limited, and can be one of nipalgin alcohol, paraben esters or multiple combinations.It is representative, this
Bacteriostatic agent in invention is selected from the group: methylparaben, ethylparaben, propylben, or combinations thereof.
Chelating agent
In ophthalmic preparations, it is suitably added a certain amount of chelating agent, such as EDTA, the stability of preparation can be increased.In general, chela
The concentration range of mixture is 0~0.05wt%.
Composition or preparation method of application of the present invention is not particularly limited, and representative method of application includes (but simultaneously
It is not limited to): the modes such as local administration, oral, injection.
A kind of preferred method of application is that the composition or preparation are carried out topical ocular administration, including but not limited to
It is representative as eyedrops, intraocular injection, eye is added dropwise after conjunctiva, eyeball, on eye circumference, retina, choroid or eye drops etc.
The modes such as portion's Submucous injection, eye mucous membrane film.
Pharmaceutical preparation should match with administration mode.Medicament of the present invention can also be used together (packet with other synergistic treatment agent
Before including, among or use later).It is the medicament administration by safe and effective amount in required when using pharmaceutical composition or preparation
Object (such as people or non-human mammal), the safe and effective amount typically at least about 10 micrograms/kg body weight, and most of
In the case of no more than about 8 mg/kg weight, preferably the dosage is about 1 mg/kg body of about 10 micrograms/kg body weight-
Weight.Certainly, specific dosage is also contemplated that the factors such as administration route, patient health situation, these are all skilled practitioners technical ability ranges
Within.
The method of the improvement crystalline lens transparency of external non-therapeutic
The present invention provides a kind of methods of the improvement crystalline lens transparency of external non-therapeutic, including by eyeball and Formulas I
Shown compound or its optical isomer or its racemic modification or its solvate or its pharmaceutically acceptable salt or its
Prodrug thereof, to inhibit crystalline lens lesion, wherein compound described in the Formulas I is as described herein.
The method of prevention and/or treatment eye disease
The present invention also provides a kind of prevention and/or the methods for the treatment of eye disease, and the method comprising the steps of, needed for giving
Object apply compound or its optical isomer or its racemic modification or its solvate shown in Formulas I of the present invention or its
Pharmaceutically acceptable salt or its prodrug.
In another preferred example, the object behaviour and non-human mammal.Typically, the non-human mammal
Including (but being not limited to): pet (such as dog, cat), domestic animal (such as ox, sheep, horse, pig), various zoo animals (panda, elephant,
Tiger) etc..
In another preferred example, the object further includes other animals in addition to people and non-human mammal, such as the non-food in one's mouth
Newborn animal.
Main advantages of the present invention include:
(a) present invention firstly discovers that compound shown in Formulas I can prevent and/or treat eye disease, such as cataract
It prevents and treats, and there is significant therapeutic effect.
(b) compound shown in Formulas I of the invention has excellent safety, toxic side effect very little or almost non-toxic secondary work
With.
(c) metabolism of formula Compound I vivo environment is slow, and bioavilability is high, is suitble to the various ways such as oral, part
Administration.
(d) formula Compound I for the treatment to eye disease with good development and application prospects.
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.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Embodiment 1
Inonotus obliquus alcohol eye drop formulation:
Inonotus obliquus alcohol eye drop formulation in 1 embodiment 1 of table
| Component | Content |
| Hydroxypropyl-β-cyclodextrin | 4g |
| Tween-80 | 10mg |
| Inonotus obliquus alcohol | 0.125g |
| EDTA-2Na | 10mg |
| PBS solution | It is settled to 10mL |
Preparation method
10mg Tween-80 and 0.125g Inonotus obliquus alcohol is added sequentially in the PBS solution of 2mL, ultrasound to mixing
Uniformly, component A is made.4g hydroxypropyl-β-cyclodextrin is added in 5mL PBS solution again, component B is made.By component B points four
Secondary addition component A, ultrasound add 10mg EDTA-2Na, PBS solution are added to be settled to 10mL to being uniformly mixed.
Comparative example 1
Lanosterol eye drop formulation:
Lanosterol eye drop formulation in table C1 comparative example C1
| Component | Content |
| Hydroxypropyl-β-cyclodextrin | 4g |
| Tween-80 | 10mg |
| Lanosterol | 0.125g |
| EDTA-2Na | 10mg |
| PBS solution | It is settled to 10mL |
Preparation method
10mg Tween-80 and 0.125g lanosterol is added sequentially in the PBS solution of 2mL, ultrasound is equal to mixing
It is even, component A is made.4g hydroxypropyl-β-cyclodextrin is added in 5mL PBS solution again, component B is made.In four times by component B
Component A is added, ultrasound adds 10mg EDTA-2Na, PBS solution is added to be settled to 10mL to being uniformly mixed.
Embodiment 2
Bolt bacterium acid eye drop formulation:
2 bolt bacterium acid eye drop formulation of table
| Component | Content |
| Hydroxypropyl-β-cyclodextrin | 4g |
| Tween-80 | 10mg |
| Bolt bacterium acid | 0.125g |
| EDTA-2Na | 10mg |
| PBS solution | It is settled to 10mL |
Preparation method
10mg Tween-80 and 0.125g bolt bacterium acid is added sequentially in the PBS solution of 2mL, ultrasound to be uniformly mixed,
Component A is made.4g beta-cyclodextrin is added in 5mL PBS solution again, component B is made.Component A is added in component B in four times,
Ultrasound adds 10mg EDTA-2Na, PBS solution is added to be settled to 10mL to being uniformly mixed.
Comparative example 2
Lanosterol eye drop formulation:
Eye drop formulation in table C2 comparative example C2
| Component | Content |
| Hydroxypropyl-β-cyclodextrin | 4g |
| Tween-80 | 10mg |
| Lanosterol | 0.125g |
| EDTA-2Na | 10mg |
| PBS solution | It is settled to 10mL |
Preparation method
10mg Tween-80 and 0.125g lanosterol is added sequentially in the PBS solution of 2mL, ultrasound is equal to mixing
It is even, component A is made.4g beta-cyclodextrin is added in 5mL PBS solution again, component B is made.By component B addition group in four times
Divide A, ultrasound adds 10mg EDTA-2Na, PBS solution is added to be settled to 10mL to being uniformly mixed.
3 cataract therapy effect expedition of embodiment
In the present embodiment, the two kinds of active components of comparing embodiment 1 and comparative example 1 are to crystalline lens lesion (cataract)
Therapeutic effect.
3.1 cataract modelings
Rat cataract model foundation.10-13 days after giving birth to Wistar rats are selected, male and female are unlimited, made with sodium selenite
Mould, every rat is according to 20 μm of ol/kg weight, in back neck subcutaneous injection.Sodium selenite is prepared with medical saline, is prepared
Room temperature is kept in dark place after 0.22 μm of film filtration sterilization of solution afterwards.I.e. eye, which can be observed, obvious caryogram after rat opens eyes
Cataract.
3.2 cataract therapy effect expeditions
By cataract rat model, 2 groups are divided into according to the right and left eyes of every rat, every group 8 corresponding eyeballs are brilliant
1 group of shape body, respectively example 1 group and comparative example, before experiment starts, two lenticular shapes of group rat eye are observed respectively
State, and take pictures, wherein the form of the lenticular upper light source of rat eye and lower light source is divided after example 1 group cataract modeling success
Not not as depicted in figs. 1 and 2；The shape of rat eye lenticular upper light source and lower light source after 1 group of cataract modeling success of comparative example
State difference is as shown in Figure 3 and Figure 4.Scoring of taking pictures after the crystalline lens taking-up of rat is 5 points
Every rat in example 1 group and 1 group of comparative example or so crystalline lens are separately immersed in Inonotus obliquus alcohol medicament for the eyes
It in water and same concentrations analogue lanosterol eyedrops, observing effect and scores after two weeks, wherein example 1 group is real
The form of the lenticular upper light source of rat eye and lower light source difference is as shown in Figure 5 and Figure 6 after testing；1 group of experiment of comparative example
After the form of the lenticular upper light source of rat eye and lower light source difference it is as shown in Figure 7 and Figure 8；Standards of grading are:
5 points-cataract core is full, the smooth of the edge, completely opaque；
4 points-cataract core center is full, disperse occurs in edge, completely opaque；
3 points-cataract Assessment of Nuclear Volume becomes smaller but unobvious, opaque area density declines；
2 points-cataract core is reduced significantly；
1 point-cataract core disappears, and cortex is transparent, and crystal restores normal.
As a result as follows:
3 embodiment 1 of table and comparative example 1 score to the therapeutic effect of cataract
| Group | Rat A | Rat B | Rat C | Rat D | Rat E | Rat F | Rat G | Rat H |
| Embodiment 1 | 2 | 2 | 3 | 2 | 3 | 3 | 3 | 2 |
| Comparative example 1 | 5 | 4 | 5 | 3 | 5 | 4 | 5 | 4 |
As can be seen from Table 3, relative to analogue lanosterol, using Inonotus obliquus alcohol as the formula I of representative
Compound (has the compound of O or S group in specific position), even if with simple administration mode, it may have excellent treatment
The effect of cataract, can be with rapid recovery, healing and prevention animal cataract.
Embodiment 4
In the present embodiment, the two kinds of active components of comparing embodiment 2 and comparative example 2 are to crystalline lens lesion (cataract)
Therapeutic effect.
4.1 cataract modelings
Rat cataract model foundation.10-13 days after giving birth to Wistar rats are selected, male and female are unlimited, made with sodium selenite
Mould, every rat is according to 20 μm of ol/kg weight, in back neck subcutaneous injection.Sodium selenite is prepared with medical saline, is prepared
Room temperature is kept in dark place after 0.22 μm of film filtration sterilization of solution afterwards.I.e. eye, which can be observed, obvious caryogram after rat opens eyes
Cataract.
4.2 cataract therapy effect expeditions
By cataract rat model, 2 groups are divided into according to the right and left eyes of every rat, every group 8 corresponding eyeballs are brilliant
Shape body, respectively 2 groups of embodiment and 2 groups of comparative example before experiment starts, observe two lenticular shapes of group rat eye respectively
State, and take pictures, wherein the form of the lenticular upper light source of rat eye and lower light source is divided after 2 groups of cataract modeling successes of embodiment
Not not as shown in Figure 9 and Figure 10；The shape of rat eye lenticular upper light source and lower light source after 2 groups of cataract modeling successes of comparative example
State difference is as is illustrated by figs. 11 and 12.Scoring of taking pictures after the crystalline lens taking-up of rat is 5 points
Every rat in 2 groups of embodiment and 2 groups of comparative example or so crystalline lens be separately immersed in bolt bacterium acid eyedrops and
In same concentrations analogue lanosterol eyedrops, the 9th day observing effect simultaneously scores (table three).Crystalline lens continuous dipping three
In week, the form of the lenticular upper light source of rat eye and lower light source is respectively such as Figure 13 and Figure 14 institute after 2 groups of experiments of embodiment
Show；The form of the lenticular upper light source of rat eye and lower light source is respectively such as Figure 15 and Figure 16 institute after 2 groups of experiments of comparative example
Show；
Standards of grading are the same as embodiment 3.
As a result as follows:
4 embodiment 2 of table and comparative example 2 score to the therapeutic effect of cataract
As can be seen from Table 4, relative to analogue lanosterol, using bolt bacterium acid as the formula I chemical combination of representative
Object (has the compound of O or S group in specific position), even if with simple administration mode, it may have in excellent treatment is white
The effect of barrier, can be with rapid recovery, healing and prevention animal cataract.
5 pharmacokinetics of embodiment is investigated
Experimental method and result
10 week old or so SD rat is taken, male and female are unlimited, after intraperitoneal injection yellow Jackets anaesthetize and expand pupil, row eye glass
Glass chamber injects art, and all animal eyes inject identical type drug, and drug injection amount is 5 microlitres, every kind in each glass cavity
Pharmaceutical formulation animal subject quantity is 4, drug metabolic condition in postoperative 10 days detection aqueous humors.
Compared with the drug concentration initial value after rigid injection, lanosterol concentration has dropped 82% ± 14.7%, and birch is brown
Pore fungi determining alcohol has dropped 11% ± 2.3%, and bolt bacterium acid concentration is reduced only by 8% ± 1.5%.
The above results suggest that becoming relevant eye disease for lens disorder, the pure and mild bolt bacterium acid of Inonotus obliquus is all had more
For excellent pharmacokinetics performance.
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. compound shown in a kind of Formulas I or its optical isomer or its racemic modification or its solvate or its pharmaceutically may be used
The purposes of the salt of receiving or its prodrug or its prodrug, which is characterized in that be used to prepare pharmaceutical composition or preparation, the drug
Composition or preparation are for preventing and/or treating eye disease caused by crystalline lens lesion；
In formula,
Q is 0,1 or 2；
R1a, R1b, R2a, R2b, R3a and R3b be each independently selected from: hydrogen, substituted or unsubstituted C1-C20 alkyl, replace or
Unsubstituted C2-C20 alkenyl, substituted or unsubstituted C3-C10 naphthenic base ,-OH, takes substituted or unsubstituted C2-C20 alkynyl
Generation or unsubstituted C1-C10 alkoxy ,-CHO, substituted or unsubstituted C1-C10 ester group-,-SH, replace or do not take-COOH
C1-C10 the alkylthio group ,-A-B in generation,
Or R1a and R1b, R2a and R2b, and/or R3a and R3b composition=O；
Wherein, A is nothing, divalent linking group；And B be H ,-OH ,-SH, C1-C3 alkoxy, C1-C3 alkylthio group ,-CHO ,-
COOH, C1-C4 ester group, C3-C10 naphthenic base, aryl, the 5-6 unit's heteroaryl of C3-C10 or benzyl；
Additional conditions are that at least one in R1a, R2a, R3a, R1b, R2b and R3b is the group containing O or S；
Z is selected from the group: H, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, being replaced or is not taken
The C2-C20 alkynyl in generation, substituted or unsubstituted C3-C10 naphthenic base, substituted or unsubstituted aryl, substituted or unsubstituted 5-
8 unit's heteroaryls, substituted or unsubstituted-(C1-C6 alkylidene)-aryl, substituted or unsubstituted-(C1-C6 alkylidene) -5-8
Unit's heteroaryl ,-OH, substituted or unsubstituted C1-C20 alkoxy ,-SH, substituted or unsubstituted C1-C20 alkylthio group, replace or
Unsubstituted C1-C10 ester group-, substituted or unsubstituted C1-C10 acyl group, substituted or unsubstituted-O- aryl；
R4 is hydrogen, substituted or unsubstituted C1-C4 alkyl；
R7, R12 and R15 are each independently selected from: nothing, hydrogen, substituted or unsubstituted C1-C4 alkyl；
R13a and R13b is each independently selected from nothing, hydrogen, substituted or unsubstituted C1-C8 alkyl ,-OH, substituted or unsubstituted
C1-C8 alkoxyl ,-SH, substituted or unsubstituted C1-C8 alkylthio group, halogen, substituted or unsubstituted C1-C3 acyl group or R13a
With R13b composition=O, and in R13a and R13b at most one be nothing；
R11a and R11b is each independently selected from: nothing, hydrogen, substituted or unsubstituted C1-C6 alkyl ,-OH or R11a and R11b structure
At=O, and in R11a and R11b at most one be nothing；
R10a, R10b are each independently selected from: hydrogen ,-OH, substituted or unsubstituted C1-C8 alkoxyl ,-SH, substituted or unsubstituted
C1-C8 alkylthio group ,-OSO3H, the substituted or unsubstituted C1-C7 alkyl of-OCO- ,-OPO3H ,-COOH ,-it is (substituted or unsubstituted
C1-C7 alkylidene)-COOH ,-CHO ,-(substituted or unsubstituted C1-C7 alkylidene)-CHO or the common structure of R10a and R10b
At=O；With
R5, R6, R8, R9a, R9b, R14, R16, R17a and R17b are each independently selected from: hydrogen, OH, substituted or unsubstituted C1-
C8 alkyl, substituted or unsubstituted C1-C8 alkoxyl, halogen；
" substitution " refers to have one or more hydrogen replaced group selected from the group below: halogen ,-OH ,-SH ,-COOH ,-
(C1-C7 alkylidene)-COOH ,=O ,-CHO ,-(C1-C7 alkylidene)-CHO, C1-C7 alkyl-OCO-, C1-C3 alkyl, C3-C6
Naphthenic base, NRaRb, wherein Ra and Rb be each independently H, C1-C6 alkyl, C1-C6 halogenated alkyl, C3-C6 naphthenic base or
Benzyl.
2. purposes as described in claim 1, which is characterized in that the divalent linking group has 1-10 a selected from the group below
Connection unit :-CRaRb-；-C(O)Ra-,-NRa-,-O-,-CO-；Wherein, Ra and Rb be each independently H, C1-C6 alkyl,
C1-C6 halogenated alkyl, C3-C6 naphthenic base or benzyl.
3. purposes as described in claim 1, which is characterized in that described R1a, R1b, R2a, R2b, R3a and the R3b is respectively independent
Ground is selected from: hydrogen ,-OH ,-CHO ,-COOH ,-SH, substituted or unsubstituted C1-C3 alkyl-OCO-, substituted or unsubstituted C1-C4
Alkyl ,-A-B or R1a and R1b, R2a and R2b, and/or R3a and R3b composition=O；
Wherein, A respectively stands alone as substituted or unsubstituted C1-C4 alkylidene, and B is each independently-OH ,-SH, C1-C3 alkane
Oxygroup ,-CHO ,-COOH ,=O.
4. purposes as described in claim 1, which is characterized in that the Z is (L1) m-L2=Y, m 0,1,2,3 or 4, respectively
L1 is each independently-CH2,-CO- ,-O- ,-C (C1-C3 alkyl) H-, C (C1-C3 alkyl) 2- ,-C (C1-C3 alkyl) O-,
Or-NH-, L2 be-CH=,-C (C1-C3 alkyl)=；
Y is=CH2The substituted or unsubstituted C1-C7 alkyl of ,=CH- ,=C- (substituted or unsubstituted C1-C7 alkyl)2,=CH-
Substituted or unsubstituted C2-C7 alkenyl or the substituted or unsubstituted C2-C7 alkynyl of=CH-.
5. purposes as described in claim 1, which is characterized in that described R5, R6, R8, R9a, R9b, R14, R16, R17a and
R17b is each independently selected from hydrogen, methyl.
6. purposes as described in claim 1, which is characterized in that at least one in R1a and R1b is the group containing O or S；And/or
At least one in R2a and R2b is the group containing O or S；And/or
At least one in R3a and R3b is the group containing O or S.
7. purposes as described in claim 1, which is characterized in that the compound of formula I is -1 compound of Formulas I:
Wherein, q, R1a, R1b, R2a, R2b, R3a, R3b, R4, R7, R10a, R10b, R11a, R11b, R12, R13a, R13b and
The definition of R15 is as described in claim 1；
Alternatively, the compound of formula I is -2 compound of Formulas I:
Wherein, the definition of q, R1a, R1b, R2a, R2b, R3a, R3b, R4, R7, R11a, R11b, R13a, R13b and R15 such as right
It is required that described in 1；
Or the compound of formula I is selected from the group compound:
Wherein, the definition of R1a, R1b, R2a, R2b are as described in claim 1；
Alternatively, the compound of formula I is selected from the group compound:
Wherein, the definition of R1a, R1b, R2a, R2b are as described in claim 1；
Alternatively, compound shown in the Formulas I is with structure shown in Formulas I -7:
Wherein, R1a, R1b, R2a, R2b are as defined above described in text；
Alternatively, compound shown in the Formulas I is with structure shown in Formulas I -8:
Wherein, R1a, R1b, R2a, R2b are as defined above described in text.
8. compound as described in claim 1, which is characterized in that the Formulas I compound represented is selected from the group:
9. purposes as described in claim 1, which is characterized in that eye disease caused by the crystalline lens lesion is selected from down
Group: the ocular complications that cataract, presbyopia, myopia, cortex muddiness, presbyopia nuclear hardening, diabetes cause.
10. a kind of method of eye disease caused by prevention and/or treatment crystalline lens lesion, which is characterized in that comprising steps of giving
Give compound shown in Formulas I described in required object or its optical isomer or its racemic modification or its solvate or its pharmacy
Upper acceptable salt or its prodrug, wherein compound shown in the Formulas I is as defined in claim 1.
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| CN201711489391.8A CN109985052A (en) | 2017-12-29 | 2017-12-29 | The new application of triterpene compound |
| CN201880084560.6A CN111526878A (en) | 2017-12-29 | 2018-12-28 | Pharmaceutical composition containing triterpenes and application thereof |
| US16/959,084 US20200384003A1 (en) | 2017-12-29 | 2018-12-28 | Triterpenoid-containing pharmaceutical composition and use thereof |
| PCT/CN2018/125075 WO2019129249A1 (en) | 2017-12-29 | 2018-12-28 | Triterpenoid-containing pharmaceutical composition and use thereof |
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| CN201711489391.8A CN109985052A (en) | 2017-12-29 | 2017-12-29 | The new application of triterpene compound |
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