CN106336397A - Novel compound for treating ophthalmic diseases - Google Patents
Novel compound for treating ophthalmic diseases Download PDFInfo
- Publication number
- CN106336397A CN106336397A CN201510408017.5A CN201510408017A CN106336397A CN 106336397 A CN106336397 A CN 106336397A CN 201510408017 A CN201510408017 A CN 201510408017A CN 106336397 A CN106336397 A CN 106336397A
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- CN
- China
- Prior art keywords
- alkyl
- compound
- pharmaceutical composition
- edema
- macular
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention relates to a prodrug compound A containing axitinib, its local ophthalmological composition and its preparation method and a purpose of the compound for treating ophthalmic diseases.
Description
Technical field
The present invention relates to containing pazopanib (axitinib) prodrug, its topical ophthalmic pharmaceutical compositions and its preparation method and its being used for treating eye
The purposes of section's disease.
Pazopanib, i.e. n- methyl -2- [[3- [(e) -2- pyridine -2- base vinyl] -1h- indazole -6- base] sulfur
Alkyl] Benzoylamide, be a kind of effective anticancer and anti-angiogenic agent, it has various active, including to include vegfr-1, vegfr-2,
The inhibitory activity of vegfr-3, pdgfr and ckit, such as herbst et al., clin.cancerres.2003,9,16 (supplementary issues 1), make a summary c253
Described.
Technical background
Age related degeneration of macula (amd) is a blind main cause of aging population, and is acknowledged as dryness amd and moist
Amd (expert opin.ther.patents (2010), 20 (1), 103-11).This dryness or nonexudativeage form include retinal pigment epithelium (rpe)
Atrophy change and loose change.This dry form is characterized with macula lutea drusen, described macula lutea drusen be containing dead cell and metabolite
Zone domain, it makes retina deform and ultimately results in acute visual to lose.Have nonexudativeage amd (dry form) patient can enter to transform into moist
Or exudative or neovascular amd, wherein pathologic choroidal neovascularization (cnvm) develops under retina, leak fluid and blood
Liquid, and if keeping not treating, in relatively short time range, finally lead to center blinding plate-like cicatrix (centrally blindingdisciform
scar).Choroidal neovascularization (cnv), that is, neovascularity is from choriocapillary network through bruch film/rpe interface growth to neural retina
In, lead under detachment of retina, retina and intraretinal edema and cicatrization.
It is difficult for leading to the choroid between sclera and retina in addition to via blood.Eyes are by three main anatomy compartments
Anterior chamber, back room and vitreous chamber are constituted, and they have limited physiology each other and interact.Retina is located at the rear portion of vitreous chamber, and
It is protected from external action by sclera, described sclera is white, toughness, the impermeability wall of eyes.Choroidal blood flow is transport agent to arteries and veins
The common method of network film, and need for example oral or intravenous administration medicine.Most drug can not pass through eye drop or the bank in ocular vicinity
(depot) it is delivered to choroid.Some medicines are delivered to retina and are therefore delivered to choroid by being injected into the vitreous chamber of eyes, because
It is special that this requires to injection.Due to pazopanib (axitinib) water solublity not good it is difficult to injection system administration, this patent describes compound and is
Pazopanib (axitinib) prodrug, improves tool water solublity, so as to reach the requirement being injected into vitreous chamber, has higher clinical value.
Content of the invention
The present invention provides compound shown in a kind of chemical structural formula a.
A kind of compound of formula a
r1For hydrogen；
r2For hydrogen, alkyl, the alkyl being optionally substituted by halogen, aromatic radical, alkylene, alkynes base, ester alkyl.
r3For the acyl group of acyl group, carbonic ester, phosphono, r4rsn-co-；
r4For hydrogen, alkyl, alkylcarbonyloxyalkyl, alkoxy carbonyl, alkyl-carbonyl, one-or di-alkyl aminoalkylcarbonyloxinsecticidale；
r5For alkylaminoalkyl group, alkyl-carbonyl, alkylcarbonyloxyalkyl, alkylaminoalkylcarbonyl epoxide alkyl, hydrogen, alkyl, hydroxyalkyl,
Aminoalkyl, alkylcarbonylaminoalkyl, Alkylcarbonylalkyl amino diaminourea, alkoxy carbonyl alkyl aminoalkyl, alkoxycarbonyl amino alkane
Base, optionally substituted phenyl, optionally substituted pyridine -2- base or optionally substituted 5- or 6- unit cycloalkyl, acylaminoalkyl, alkylaminoalkyl group
Acyloxyallcyl, or group (r4, r5) n- can form and appoint the pyrrolidine replacing, ketopyrrolidine or piperidines；
X is pharmaceutically acceptable anion.
It is administered orally administration using gained compound of the present invention in people.Solid dosage formss for oral administration include capsule, piece
Agent, pill, powder and granule.In these solid dosage formss, the compounds of this invention is mixed with least one conventional inert adjuvant, such as starch,
Microcrystalline Cellulose, or following compositions mixing: (a) filler, such as Lactose, starch, Microcrystalline Cellulose, dextrin, calcium hydrogen phosphate, Mannitol；
(b) binding agent, such as starch slurry, cellulose derivative, polyvinyl pyrrolidone；(c) disintegrating agent, such as cross-linked carboxymethyl cellulose sodium, crosslinked carboxylic first
Starch Sodium, dried starch；(d) lubricant, such as Pulvis Talci, Polyethylene Glycol, dodecyl sodium sulfate, magnesium stearate.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, suspension, solution, syrup.In addition to the compounds of this invention,
Liquid dosage form can comprise the conventional inert diluent adopting, such as water and other solvents, solubilizing agent and emulsifying agent in this area.
The compounds of this invention injectable administering mode is in people.In addition to the compounds of this invention, injection type comprises the conventional inertia adopting in this area
Diluent, such as water and other solvents, solubilizing agent.
Specific embodiment
Illustrate the present invention below with reference to embodiment, embodiments of the invention are merely to illustrate technical scheme, and non-limiting
The essence of invention.
The synthesis of formula b: pazopanib 4.0g is added in 10ml dmf, stirring is lower to add 2.0g triethylamine, adds 1.5gboc anhydride,
Reaction 1h, adds 20ml water, filters to obtain compound 1, after drying under reduced pressure, obtain 4.1g.Compound 2 is added in 10ml acetonitrile, adds 1,8g
Chloromethyl butylperoxyisopropyl carbonate, reacts 30h in 80 degree, is concentrated to give grease, column chromatography obtains 3.2g formula b.
Claims (8)
1. a kind of compound of formula a
r1For hydrogen；
r2For hydrogen, alkyl, the alkyl being optionally substituted by halogen, aromatic radical, alkylene, alkynes base, ester alkyl.
r3For the acyl group of acyl group, carbonic ester, phosphono, r4r5n-co-；
r4For hydrogen, alkyl, alkylcarbonyloxyalkyl, alkoxy carbonyl, alkyl-carbonyl, one-or di-alkyl aminoalkylcarbonyl
Epoxide alkyl；
r5For alkylaminoalkyl group, alkyl-carbonyl, alkylcarbonyloxyalkyl, alkylaminoalkylcarbonyl epoxide alkyl, hydrogen, alkane
Base, hydroxyalkyl, aminoalkyl, alkylcarbonylaminoalkyl, Alkylcarbonylalkyl amino diaminourea, alkoxy carbonyl alkyl
Aminoalkyl, alkoxycarbonylamino, optionally substituted phenyl, optionally substituted pyridine -2- base or optionally substituted
5- or 6- unit cycloalkyl, acylaminoalkyl, alkylaminoalkyl group acyloxyallcyl, or group (r4, r5) n- can be formed
Appoint the pyrrolidine replacing, ketopyrrolidine or piperidines；
X is pharmaceutically acceptable anion.
2. its pharmaceutically acceptable salt of compound as shown in claim 1 chemical formula a.
3. a kind of pharmaceutical composition is it is characterised in that to comprise compound described in claim 1 and 2 pharmaceutically acceptable with more than one
Filler, binding agent, disintegrating agent, lubricant.
4. pharmaceutical composition as claimed in claim 3 is it is characterised in that described compositionss can be tablet, capsule, granule, mouth
Take the liquid forms such as liquid or suspension.
5. a kind of pharmaceutical composition is it is characterised in that compound shown in chemical structural formula a described in claim 1 and 2, and a kind of or one
Pharmaceutically acceptable solvent more than kind, as injection.
6. the compound as described in claim 1-2 or 3-5 pharmaceutical composition treatment ocular disease include diabetic macular edema,
The Other diseases of diabetic retinopathy, degeneration of macula, age-related macular degeneration and retina and macula lutea, choroid
New vesselses (cnv), choroidal neovascularization (cnvm), retina shedding, retinal pigment epithelium (rep)
Atrophy change, the loose change of retinal pigment epithelium, retinal vein blocks, chorioretinal vein blocks, macula lutea
Edema, blocked the macular edema causing, retinitis pigmentosa, recessive macular dystrophy, glaucoma, inflammatory by retinal vein
Situation, cataract, obstinate sexual abnormality, keratoconuses, retinopathy of prematurity, the angiogenesis of ocular region, angle
Film is scorching, corneal transplantation or the later corneal vessels of keratoplasty generate, drawn by hypoxia (long adherent lenses are worn)
The retinal vessel rising generates, pterygium conjunctiva, subretinal and intraretinal edema.
7. it is used for treating or prevent the compound according to any one of claim 1-5 or the pharmaceutical composition of eye disease, institute
State eye disease and be selected from dryness amd, moist amd or choroidal neovascularization (cnv).
8. the method being used for treating or preventing eye disease, described eye disease is selected from age related degeneration of macula (amd), choroid
New vesselses (cnv), choroidal neovascularization (cnvm), cystoid macular edema (cme), preretinal membrane (erm)
And macular hole, the related choroidal neovascularization of myopia, blood vessel striped, detachment of retina, diabetic retinopathy,
Diabetic macular edema (dme), the atrophy change of retinal pigment epithelium (rpe), the fertilizer of retinal pigment epithelium (rpe)
Big change, retinal vein occlusion, chorioretinal venous occlusion, macular edema, caused by retinal vein occlusion
Macular edema, retinitis pigmentosa, recessive macular dystrophy, glaucoma, inflammatory condition, cataract, stupid same sexual abnormality, circle
Taper cornea, retinopathy of prematurity, the angiogenesis of ocular region, keratitis, corneal transplantation or keratoplasty with
Corneal vessels afterwards generate, and are generated by the corneal vessels that hypoxia (long adherent lenses are worn) causes, pterygium is tied
Film, subretinal and intraretinal edema, methods described includes: applies according to any one of claim 1-5 institute
The compound stated or pharmaceutical composition, described pharmaceutical composition contains the activating agent of pharmacy effective dose.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510408017.5A CN106336397A (en) | 2015-07-07 | 2015-07-07 | Novel compound for treating ophthalmic diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510408017.5A CN106336397A (en) | 2015-07-07 | 2015-07-07 | Novel compound for treating ophthalmic diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106336397A true CN106336397A (en) | 2017-01-18 |
Family
ID=57826552
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510408017.5A Pending CN106336397A (en) | 2015-07-07 | 2015-07-07 | Novel compound for treating ophthalmic diseases |
Country Status (1)
| Country | Link |
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| CN (1) | CN106336397A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021035360A1 (en) * | 2019-08-30 | 2021-03-04 | Risen (Suzhou) Pharma Tech Co., Ltd. | Prodrugs of the tyrosine kinase inhibitor for treating cancer |
| WO2021037183A1 (en) * | 2019-08-30 | 2021-03-04 | 润佳（苏州）医药科技有限公司 | Prodrug compounds and uses thereof for treatment of cancer |
| CN112442011A (en) * | 2019-08-30 | 2021-03-05 | 润佳（苏州）医药科技有限公司 | Prodrug compound and application thereof in treating cancer |
-
2015
- 2015-07-07 CN CN201510408017.5A patent/CN106336397A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021035360A1 (en) * | 2019-08-30 | 2021-03-04 | Risen (Suzhou) Pharma Tech Co., Ltd. | Prodrugs of the tyrosine kinase inhibitor for treating cancer |
| WO2021037183A1 (en) * | 2019-08-30 | 2021-03-04 | 润佳（苏州）医药科技有限公司 | Prodrug compounds and uses thereof for treatment of cancer |
| CN112442011A (en) * | 2019-08-30 | 2021-03-05 | 润佳（苏州）医药科技有限公司 | Prodrug compound and application thereof in treating cancer |
| CN112442011B (en) * | 2019-08-30 | 2023-11-14 | 润佳（苏州）医药科技有限公司 | Prodrug compound and application thereof in treating cancers |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| DD01 | Delivery of document by public notice |
Addressee: Guo Mingshan Document name: Notification of Passing Preliminary Examination of the Application for Invention |
|
| C06 | Publication | ||
| PB01 | Publication | ||
| DD01 | Delivery of document by public notice |
Addressee: Guo Mingshan Document name: Notification of Publication of the Application for Invention |
|
| DD01 | Delivery of document by public notice | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170118 |
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| WD01 | Invention patent application deemed withdrawn after publication |