CN101965188A - Treatment for ocular-related disorders - Google Patents
Treatment for ocular-related disorders Download PDFInfo
- Publication number
- CN101965188A CN101965188A CN2009801075816A CN200980107581A CN101965188A CN 101965188 A CN101965188 A CN 101965188A CN 2009801075816 A CN2009801075816 A CN 2009801075816A CN 200980107581 A CN200980107581 A CN 200980107581A CN 101965188 A CN101965188 A CN 101965188A
- Authority
- CN
- China
- Prior art keywords
- chemical compound
- treatment
- formula
- patient
- degeneration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Abstract
A treatment for ocular related disorders, such as macular degeneration, and preferably age-related macular degeneration, diabetic retinopathy, and diabetic macular edema is disclosed, using a compound of Formula I.
Description
Technical field
The present invention relates to suffering from or easily suffering from the eye relevant disease, such as the mankind of age-related macular degeneration, diabetic retinopathy and diabetic macular edema and the Therapeutic Method of non-human patients.
Background technology
Protein kinase participates in signal conduction incident, and its control response is in activation, growth and the differentiation of the cell of extracellular medium (mediator) and environmental change.In general, these kinases are divided into several groups: the kinases of preferential phosphorylation serine and/or threonine residues and the kinases [S.K.Hanks and T.Hunter, FASEB.J., 1995,9, pages 576-596] of preferential phosphorylated tyrosine residue.Serine/threonine kinase comprises for example Protein kinase C isoform [A.C.Newton, J.Biol.Chem., 1995,270, pages28495-28498] and cyclin-dependant kinase group such as cdc2[J.Pines, Trends inBiochemical Sciences, 1995,18, pages 195-197].Tyrosine kinase comprises transmembrane growth factor receptor such as EGF-R ELISA [S.Iwashita and M.Kobayashi, CellularSignalling, 1992,4, pages 123-132], and the non-receptor kinase of endochylema such as p56tck, p59fYn, ZAP-70 and csk kinases [C.Chan et.al., Ann.Rev.Immunol., 1994, l2, pages 555-592].
Protein kinase activity is too high to relate to many diseases that caused by the cellular abnormality function.The appearance of this situation can be direct or indirect, for example, because the inefficacy of the kinase whose suitable control mechanism relevant with sudden change, overexpression or the activation of inappropriate enzyme of enzyme; Perhaps because also to participate in the generation of the cytokine of signal transduction in kinases upstream or downstream or somatomedin too much or not enough.Under all these situations, think that selectivity suppresses kinase whose activity and can produce useful effect.
Syk is a kind of 72-kDa cytoplasm protein tyrosine kinase, and it is expressed in various hematopoietic cells, and be in several cascade reactions with antigen receptor and the link coupled fundamental of cell response.Therefore, in the signal conductive process of Syk high-affinity IgE receptor Fc ε R1 in mastocyte, and in T lymphocyte and the antigenic signal conductive process of bone-marrow-derived lymphocyte inner recipient, play a key effect.Be present in mastocyte, T cell and the intracellular signal transduction pathway of B and have common characteristic.The ligand binding domain of receptor lacks intrinsic tyrosine kinase activity.Yet, they with contain transduction subunit based on the activation motif (ITAMs) of immunity receptor tyrosine interact [M.Reth, Nature, 1989,338, pages 383-384].These motifs are present in the β of Fc ε R1 and the γ subunit is interior, the ξ-subunit of TXi Baoshouti (TCR) is interior and the IgG α of B-cell receptor (BCR) and interior [the N.S.van Oers andA.Weiss of IgG β subunit, Seminars in Immunology, 1995,7, pages 227-236].Behind antigen combination and multimerization, the ITAM residue is by the protein tyrosine kinase phosphorylation in the Src family.Syk belongs to a unique class tyrosine kinase, and it contains two placed in-line Src albumen homology 2 (SH2) domains and a C end catalyst structure domain.These SH2 domains combine with high-affinity with ITAMs, and the Syk of this SH2 mediation stimulates the Syk kinase activity and makes Syk be positioned plasma membrane with combining of activated receptor.
Angiogenesis that growth by original vascular system causes or new vessels form, and are vital for fetal development and organ.In rheumatoid arthritis, diabetic retinopathy case and the new vessels of observing unusual increase during the tumor development generate phenomenon (Folkman, Nat.Med., 1995,1,27-31.).Angiogenesis is a kind of multistage process of complexity, and it comprises activation, migration, propagation and the survival of endotheliocyte.Past 20 years extensive studies in the tumor-blood-vessel growth field has been determined some treatment targets, comprise kinases, protease and integrin, thereby caused many new anti-angiogenic agents to comprise the discovery of KDR inhibitor, wherein some is in clinical assessment stage (Jekunen at present, et al.Cancer Treatment Rev.1997,23,263-286.).Angiogenesis inhibitor can be used for malignant tumor appearance or regenerated first line, assists even preventive measure.
The serious visual deprivation and the blind important cause of disease are relevant diseases, and wherein ocular angiogenesis system damage or regulation and control are not enough.An eye relevant disease that comprises new vessels formation symptom has many kinds, comprises for example age-related macular degeneration, diabetic retinopathy and diabetic macular edema.Serious visual deprivation that possible is not is directly to be formed by new vessels to cause, but formed by new vessels amphiblestroid effect caused.Retina is the slim and frahile film that eye receives image.Near foveal region of retina be macula lutea, i.e. the oval area of retinal tissue, vision is the sharpest herein.Amphiblestroid fovea centralis is the part of retina most fragile, promptly is positioned at the concavity at macula lutea center.Retina injury and visual deprivation such as retinal degeneration are contacted directly.Though the commonly encountered diseases of detachment of retina, tears retinal and retinal degeneration is because of being the unusual of various ocular tissues, promptly various ocular tissues angiogenesis out of control, situation is not always like this.The atrophy complication of age-related macular degeneration, non-proliferative diabetic retinopathy and inflammatory ocular injury and angiogenesis are also irrelevant, if but do not treat, then may cause serious visual deprivation.The disease relevant with the atrophy factor with new vessels, such as age-related macular degeneration, diabetic retinopathy and diabetic macular edema because various complication take place special refractory.Referring to Diabetic Retinopathy:A Review; JuneChu and Yusuf Ali; Drug Development Research 69:1-14 (2008); NewDevelopments in Diabetic Retinopathy; Expert Rev.Ophthalmol.2 (6), 947-956 (2007); And Diabetic Retinopathy; Robert Frank; N.Engl.J.Med.350; 1; 48-58 (2004).
The result who has been found that now comprises in one embodiment, the method for a kind of prevention or treatment patient's eye relevant disease, and this method comprises the chemical compound of the formula I that gives the medicinal effective dose of patient, perhaps its pharmaceutical salts or prodrug.The eye abnormal vascular takes place or patient's administration of angiogenesis danger can prevent eye to having, and especially amphiblestroid abnormal vascular takes place.Have that the eye abnormal vascular takes place dangerous or be diagnosed as and suffer from the patient that abnormal vascular takes place, the treatment by The compounds of this invention from the susceptible disease state-transition to the disease resistance state.If do not treat, the characteristics of this class disease are neovascularity intrusion eye structure, in retina.It is the commonly encountered diseases of losing one's sight because of, and relate to about 20 kinds of ocular disease.In age-related macular degeneration, relevant visual problem is to be seen through by choroidal capillary to give birth to and produce fiber vascular tissue hypertrophy in the defective of Bruch's membrane (Bruch ' s membrane) below retinal pigment epithelium and cause.The angiogenesis damage is also relevant with diabetic retinopathy and diabetic macular edema.
Age-related macular degeneration (AMD) is a kind of degenerative disease of macula lutea (central retina).In U.S.'s age was 50 years old or above crowd, this was the cause of disease of modal visual deprivation, and its prevalence increased with the age.AMD is caused by the sclerosis of nourishing amphiblestroid tremulous pulse.Needed oxygen and the nutrition in performance function and growth of responsive retinal tissue has been deprived in this sclerosis.Consequently central vision goes down.
The order of severity of degeneration of macula differs greatly.In the worst case, it can cause completely losing of central vision, thereby can't read or drive.Concerning other people, it may only cause slight vision distortion.Fortunately, degeneration of macula can not cause as blind as a bat, because it does not influence peripheral vision.
AMD is divided into wet type (new vessels type) or dry type (non-new vessels type).The patient of about 10% degeneration of macula suffers from wet type AMD.When new angiogenesis when improving the blood supply of anoxia retinal tissue, this type will take place.Yet new vessels is highly brittle weak and breaks easily, thereby causes the destruction of bleeding with surrounding tissue.Though the AMD case that wet type AMD representative is quite few, it is relevant with 90% the remarkable visual deprivation that this disease causes.
The new vessels generative process that present treatment to AMD concentrates on causing the relevant visual deprivation of wet type AMD impacts.Present goldstandard therapy is directly biological preparation to be injected eye.These biological preparation are listed in table 1.This class is treated expensive, loaded down with trivial details and is subjected to dose limitation.Obviously need a kind of to the effective oral therapy of this disease.
Table 1
In view of the present situation of degeneration of macula therapy, obviously need the more effective and better therapy of toleration.
Diabetic retinopathy is a kind of ocular disease, is divided into two stages.A non-proliferative phase and a proliferative phase that at first takes place is arranged usually.Non-hypertrophy diabetic retinopathy is often because retinal edema, especially diabetic macular edema cause patient's visual deprivation (vision loss), and this can cause vascular leakage.Local and dispersivity macula lutea seepage is caused by microaneurysm, capillary seal and retinal hemorrhage in microvascular abnormality, the retina.Secular vascular leakage finally can cause basement membrane thickened and form soft, hard exudate.Non-hypertrophy diabetic retinopathy also has one to be characterised in that the loss of retina pericyte.The proliferative phase of diabetic retinopathy is characterised in that on retina or optic nerve at retina or disk inner surface or neovascularization and fiber angiogenic growth (spot that promptly relates to neuroglia and fibroid composition forms) vitreous chamber.It is the main cause of the visual deprivation relevant with proliferative diabetic retinopathy that retinal neovascularization forms.
The method of generation of treatment eye abnormal vascular and angiogenesis comprises laser therapy at present, and this method is destroyed some retinal tissues to preserve some visions.Obviously need improved method and medicament and prevent and treat to relate to abnormal vascular generation and deleterious angiogenesis disease, such as the pathologic vessels generation of part tissue of eye.
Consider the universality of a relevant disease, still need a kind of effective method with prevention and treatment eye relevant disease, especially those relevant with the neovascularity complication with atrophy eye relevant diseases are such as age-related macular degeneration, diabetic retinopathy and diabetic macular edema.Therefore, the invention relates to the Compounds and methods for of prevention and treatment and eye relevant disease.Of the present invention this a bit and in the detailed description that provides below of other advantages will become apparent.
Summary of the invention
The present invention relates to use the compounds for treating degeneration of macula of formula I, and the method for age-related macular degeneration more particularly.
Formula I
The present invention relates to the azaindole of the replacement of formula I, have now found that, in animal model, it can suppress degeneration of macula effectively.
Another aspect of the present invention is a treatment wet type age-related macular degeneration (wet AMD).
The chemical compound of formula I can be used as effective oral medication of AMD.In addition, based on the data that the inventor obtains, the inventor predicts the useful agents that the Syk inhibitor can become this disease of treatment substantially.The data of these conclusions are summarized as follows.
Another aspect of the present invention is the method by the compounds for treating diabetic retinopathy of the formula I of the medicinal effective dose of patient that needs treatment.
Another aspect of the present invention is the method by the compounds for treating diabetic macular edema of the formula I of the medicinal effective dose of patient that needs treatment.
Another aspect of the present invention is normally used Syk inhibitor for treating patient's degeneration of macula, diabetic retinopathy or diabetic macular edema.
The specific embodiment
Therefore, in one aspect, the present invention relates to Therapeutic Method and pharmaceutical composition, it comprises the chemical compound of general formula (I):
It also can be described as: 2-[4-(7-ethyl-5H-pyrrolo-[2,3-b] pyrazine-6-yl)-phenyl]-propan-2-ol.The synthetic of this chemical compound is known to those skilled in the art, can find from international monopoly WO2008/033798 application.Can recognize also that from the application this chemical compound is a kind of Syk inhibitor.
In this manual, term " chemical compound of the present invention " and suitable statement, expression comprises the chemical compound of aforesaid general formula (I), and this statement also can comprise its prodrug, pharmaceutical salts and solvate, and for example hydrate is decided on context.Similarly, decide on context, when mentioning intermediate, no matter whether propose claim with regard to itself, all expression comprises their salt and solvate.For the purpose of distinct, when context allows, can enumerate some object lesson in the text sometimes, but these examples are not to be intended to get rid of other examples that context allows only as the example explanation.
Definition
Used as mentioned and run through explanation of the present invention, following term should be understood that to have following implication, except as otherwise noted:
" patient " comprises human and other mammal.
" medicinal ester " is meant the ester of hydrolysis in vivo and is included in the human body and decompose and those esters of remaining parent compound or its salt easily, suitable ester group comprises for example from medicinal aliphatic carboxylic acid, especially deutero-those ester groups of alkyl carboxylic acid, thiazolinyl carboxylic acid, cycloalkyl carboxylic acid and alkyl dicarboxylic aid, wherein each alkyl or thiazolinyl advantageously contain no more than 6 carbon atoms.Representational ester comprises formic acid esters, acetas, propionic ester, butyrate, acrylate, ethyl succinate etc.
" medicinal prodrug " is meant those prodrug of chemical compound of the present invention as used herein, in rational medical judgment scope, present the patient of over-drastic toxicity, stimulation and anaphylactic reaction etc. for those, they are suitable for the purposes that contacts with patient tissue, and have reasonably and be benefited/the risk ratio, and they are being effective aspect the desired use of chemical compound of the present invention.Term " prodrug " is meant such chemical compound, and they promptly transform in vivo, for example by hydrolysis in blood, thereby produces the parent compound with above-mentioned formula.The functional group that can transform rapidly by the metabolism cracking, form in vivo a class can with the group of the carboxyl reaction of chemical compound of the present invention.They include but not limited to following group, the monoesters that forms such as alkanoyl (such as acetyl group, propiono, bytyry etc.), the unsubstituted and aroyl (such as the benzoyl of benzoyl and replacement) that replaces, alkoxy carbonyl (such as ethoxy carbonyl), trialkylsilkl (such as trimethyl silyl and triethylsilyl), with dicarboxylic acids (such as succinyl) etc., play a role so contain the chemical compound such as the prodrug of this class group because but the metabolism cracking group of chemical compound of the present invention is easy to cracking in vivo.But the advantage that contains the chemical compound of metabolism cracking group is, but owing to be somebody's turn to do the existence of metabolism cracking group, has improved the dissolubility and/or the absorption rate of parent compound, so can demonstrate the bioavailability of improvement.Following document provides detailed discussion: Design of Prodrugs, H.Bundgaard, ed., Elsevier (1985); Methods in Enzymology; K.Wjdder et al, Ed., Academic Press,
42, 309-396 (1985); A Textbook of Drug Design and Development, Krogsgaard-Larsen and H.Bandaged, ed., Chapter 5; " Design and Applications of Prodrugs " 113-191 (1991); Advanced Drug Delivery Reviews, H.Bundgard,
8, 1-38, (1992); J.Pharm.Sci.,
77, 285 (1988); Chem.Pharm.Bull., N.Nakeya et al, 32,692 (1984); Pro-drugs as Novel Delivery Systems, T.Higuchi and V.Stella,
14A.C.S.Symposium Series, and Bioreversible Carriers in Drug Design, E.B.Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, incorporate its mode by reference into the application.
" pharmaceutical salts " is meant inorganic acid addition salt and the organic acid addition salt and the base addition salts of avirulent relatively chemical compound of the present invention.This class salt can preparation in position in the process of final separation of this chemical compound and purification.Specifically, acid-addition salts can separate reaction by chemical compound behind the purification that makes free alkali form and suitable organic acid or mineral acid, separates formed salt then and prepares.Representational acid-addition salts comprises hydrobromate; hydrochlorate; sulfate; disulfate; phosphate; nitrate; acetate; oxalates; valerate; oleate; palmitate; stearate; laruate; borate; benzoate; lactate; phosphate; toluene fulfonate; citrate; maleate; fumarate; succinate; tartrate; naphthoate; mesylate; glucoheptose salt; Lactobionate (lactobionate); sulfamate; malonate; Salicylate; propionate; methylene-two-β-Qiang Jinaijiasuan salt; gentisate; isethionate; two toluoyl base tartrates; mesylate; ethyl sulfonate; benzene sulfonate; tosilate; cyclohexyl-n-sulfonate and lauryl sulfonate etc.Referring to, S.M.Berge for example, et al., " Pharmaceutical Salts, ", J.Pharm.Sci., 66,1-19 (1977).Base addition salts also can separate reaction by chemical compound behind the purification that makes sour form and suitable organic base or inorganic base, separates formed salt then and prepares.Base addition salts comprises medicinal metal salt and amine salt.Proper metal salt comprises sodium salt, potassium salt, calcium salt, barium salt, zinc salt, magnesium salt and aluminum salt.Particular certain cancers and potassium salt.Suitable inorganic base addition salts is prepared by metal base, and this metal base comprises sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, Lithium hydrate, magnesium hydroxide, zinc hydroxide etc.Suitable amine base addition salts is by some amine preparation, these amine have enough alkalescence to form stable salt, be preferably incorporated in those amine that often use in the medical chemistry, because they have hypotoxicity and the acceptability that is suitable for medical usage: ammonia, ethylenediamine, the N-methylglucosamine, lysine, arginine, ornithine, choline, N, N '-dibenzyl-ethylenediamin, chloroprocaine, diethanolamine, procaine, the N-benzyl-1-phenylethylamine, diethylamine, piperazine, three (hydroxymethyl)-aminomethane, Tetramethylammonium hydroxide, triethylamine, dibenzyl amine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzyl amine, tetramethyl-ammonium, tetraethyl ammonium, methyl amine, dimethyl amine, Trimethylamine, ethamine, basic amino acid is lysine and arginine for example, and dicyclohexylamine etc.
Embodiment
Below be the specific embodiments relevant with invention described here.
Specific embodiments of the present invention is the compounds for treating degeneration of macula by the formula I of the medicinal effective dose of patient that needs treatment.
Another specific embodiments of the present invention is to treat degeneration of macula by the Syk inhibitor of the medicinal effective dose of patient that needs treatment.
Embodiment preferred of the present invention, wherein degeneration of macula is an age-related macular degeneration, and gives the chemical compound of the formula I of effective dose.
Another embodiment preferred of the present invention, wherein degeneration of macula is an age-related macular degeneration, and gives the Syk inhibitor of effective dose.
Another embodiment of the present invention are the compounds for treating diabetic retinopathys by the formula I of the medicinal effective dose of patient that needs treatment.
Another embodiment of the present invention are the compounds for treating diabetic macular edema by the formula I of the medicinal effective dose of patient that needs treatment.
Chemical compound of the present invention randomly provides with the form of salt.Those pharmaceutical salts are particularly interesting, because they are used for goals of medicine in the administration process of aforesaid compound.Non-pharmaceutical salts is used to the purpose of separating and purifying, the stereoisomeric forms in any ratio that is used to separate chemical compound of the present invention in some cases in manufacture process.Latter event is for especially true for the amine salt of optically active amines preparation.
An aspect of of the present present invention provides a kind of pharmaceutical composition, and it comprises chemical compound and pharmaceutical carrier or the diluent of the formula I of medicinal effective dose.
Another aspect of the present invention provides a kind of pharmaceutical composition, and itself is effectively in a kind of useful therapeutic alliance, because it comprises multiple active component that can be used according to the invention.
In aforesaid any application, the amount of the chemical compound of formula I can be medicinal effective dose or be lower than best effective dose (suboptimal effective amount), or both combinations, as long as the final combination of these compositions can comprise the chemical compound of medicinal effective dose of treatment effectively or prevention patient's degeneration of macula, diabetic retinopathy or diabetic macular edema.
The chemical compound of formula I is usefulness in the body of eye relevant disease such as AMD
Several available wet type AMD models in rodent and rabbit are arranged.In laser induced rat degeneration of macula model, assessed the clinical preceding usefulness of the chemical compound of formula I.In this model, on rat retina, cause damage with the laser focusing light beam.This damage has caused angiogenesis with inflammation and form the speckle with visual deprivation relevant subsequently on retina.With the size that suppresses this type of speckle and the ability of thickness, can be used as treatment wet type AMD patient's potential index with the compounds for treating of formula I.With the retina of 75 microns krypton laser irradiation in rats eyes 0.1 second, each 3-4 point.From the 1st day to the 14th day, to the chemical compound (every day twice, oral) of twice formula I of rat orally give every day of irradiation.Used dosage is counted 3mg/kg by body weight, 10mg/kg and 30mg/kg.Extra treatment group gives the vehicle of oral administration of compound, also is twice of oral administration every day.Adopt the 0.5mg triamcinolone acetonide as positive control, be administered under the ophthalmic tendon.At above-mentioned postradiation the 14th day, to rat perfusion FITC-glucosan (Fluorescein Isothiocyanate glucosan) and take off eyes and assess.Assessment is undertaken by examination of ocular fundus and luciferin angiography.The data of the chemical compound of the formula I in this model show, this chemical compound dosage is for by twice oral 30 of body weight every day and 10mg/kg the time, and plaque thickness significantly reduces.Observed result when these results significantly are better than with positive control triamcinolone acetonide (injection steroid in the vitreum).This result is displayed in Table 2.
| Treatment | Plate suppresses % | Significance |
| Vehicle | 0 | |
| The chemical compound 3mg/kg of formula I | 12 | |
| The chemical compound 10mg/kg of formula I | 36 | p＜0.003 |
| The chemical compound 30rmg/kg of formula I | 33 | p＜0.0006 |
| 0.5mg triamcinolone acetonide | 26 | p＜0.0245 |
Table 2
Another aspect of the present invention described here is that treatment suffers from or easily suffer from the patient's of degeneration of macula method, comprises the Syk inhibitor that gives the medicinal effective dose of patient.Herein " treatment " of indication be understood to include prophylactic treatment with prevent or suppress disease generation and the treatment patient to alleviate or to improve this patient's the state of an illness." effective dose " is intended to describe the dosage of chemical compound of the present invention, it is effective in the determination range in rational biology, be suitable for can not producing side effect such as over-drastic toxicity, stimulation and anaphylactic reaction with other mammiferous cells contacting with human, and in treatment, demonstrate reasonably and be benefited/the risk ratio, therefore produce desired therapeutic effect.
A special aspect of the present invention provides the chemical compound of the present invention with the pharmaceutical compositions administration, although this chemical compound can be individually dosed.The character, dosage and the dosage form that depend on administering mode, " pharmaceutical composition " expression compositions of comprising the chemical compound of formula I and being selected from least a following composition: pharmaceutical carrier, diluent, coating, adjuvant, excipient or carrier, such as antiseptic, filler, disintegrating agent, wetting agent, emulsifying agent, Emulsion stabilizing agent, suspensoid, isotonic agent, sweeting agent, flavoring agent, aromatic, coloring agent, antibacterial, antifungal, other therapeutic agent, lubricant, absorption delays or promoter and dispersant.Pharmaceutical composition can following form exist: tablet, pill, granule, powder, aqueous solution or suspension, injection solution, elixir or syrup.Representational suspensoid comprises ethoxylation isooctadecanol, polyoxyethylene sorbitol ester and sorbitan ester, microcrystalline Cellulose, partially aluminium hydroxide, bentonite, agar and Tragacanth, the perhaps mixture of these materials.The antibacterial of representational prophylaxis of microbial effect and antifungal comprise metagin, methaform, phenol, sorbic acid etc.Representational isotonic agent comprises sugar, sodium chloride etc.The representational absorption delayer that is used for delayed absorption comprises aluminum monostearate and gelatin.The representational adsorption enhancer that is used to increase absorption comprises dimethyl sulfoxide and related analogs.Representational carrier, diluent, solvent, vehicle, solubilizing agent, emulsifying agent and Emulsion stabilizing agent comprise water, chloroform, sucrose, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, tetrahydrofurfuryl alcohol, phenylamino benzoic acid methyl ester, polyhydric alcohol, propylene glycol, 1,3 butylene glycol, glycerol, Polyethylene Glycol, dimethyl formamide,
60,
60, cetostearyl alcohol (cetostearyl alcohol), myristyl alcohol, glyceryl monostearate and Laurel alkyl sodium sulfate, sorbitan fatty acid esters, vegetable oil (such as Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Fructus Maydis oil, olive oil, Oleum Ricini and Oleum sesami) and injectable organic ester such as ethyl oleate etc., the perhaps suitable mixture of these materials.Typical excipients comprises lactose, lactose (milk sugar), sodium citrate, calcium carbonate and dicalcium phosphate.Representational disintegrating agent comprises starch, alginic acid and some complex silicate class.Representational lubricant comprises magnesium stearate, sodium lauryl sulfate, Pulvis Talci, and high molecular weight polyethylene glycol.
The other treatment agent can with chemical compound coupling of the present invention, comprise other anti-agent (anti agent).But therapeutic agent separate administration, administration simultaneously or administration successively with chemical compound coupling of the present invention.The regulation that must observe in the ad hoc fashion of chemical property such as dissolubility, administration of reactive compound and the medication practice is depended in the selection of material in the pharmaceutical composition except the chemical compound of formula I usually.For example, excipient such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agent such as starch, alginic acid and some complex silicate class and combinations such as lubricant such as magnesium stearate, sodium lauryl sulfate and Pulvis Talci can be used for preparing tablet.
Pharmaceutical composition can following form administration: such as tablet, pill, granule, powder, aqueous solution or suspension, injection solution, elixir or syrup.
The reactive compound that " liquid dosage form " expression gives patient's doses is to be in liquid state, for example medicinal Emulsion, solution, suspension, syrup and elixir.Except that reactive compound, liquid dosage form also can contain inert diluent commonly used in this area, such as solvent, solubilizing agent and emulsifying agent etc.
Solid composite also can be used as the filler of soft filled capsules and hard filled capsules, is used as excipient with lactose (lactose or milk sugar) and high molecular weight polyethylene glycol etc.
When using aqueous suspension, they can contain emulsifying agent or promote the reagent of suspendible.
The oil phase of Emulsion pharmaceutical composition can be made of known composition in known manner.Though this oil phase can only comprise emulsifying agent (also being known as emulgent (emulsifying agent)), it comprise ideally at least a emulsifying agent and fat or oil or with fat and both mixture of oil.In a kind of specific embodiment, hydrophilic emulsifying agent is used with the lipophilic emulsifier as stabilizing agent.This emulsifying agent with or do not constitute emulsifing wax with stabilizing agent, then constitute the emulsifying ointment base with oil ﹠ fat, the latter forms the oiliness decentralized photo of cream preparation.
If desired, the water of emulsifiable paste matrix for example can comprise the polyhydric alcohol of 30%w/w at least, the alcohol that promptly has two or more hydroxyls is such as propylene glycol, 1,3 butylene glycol, mannitol, Sorbitol, glycerol and Polyethylene Glycol (comprising PEG 400) and composition thereof.The dosage form of surface administration can comprise the chemical compound that can promote to absorb or promote active component transdermal or other affected area ideally.
Be suitable for the oils of preparation or the selection of fat and be based on the character that to realize ideal.Therefore, but this emulsifiable paste should be preferably a kind of non-greasy, not painted product that reaches flush away, and has suitable denseness to avoid seepage from pipe or other containers.The Arrcostab of straight chain or side chain, monobasic or binary such as myristic acid diisopropyl ester, decyl oleate, isopropyl palmitate, butyl stearate, Palmic acid-2-Octyl Nitrite or the blend that is called as the branched ester of spermaceti stearyl alcohol ethylhexoate (Crodamol CAP) all can use.Depend on required character, these auxiliary agents can use separately or coupling.Replacedly, also can use high-melting-point lipid such as white soft paraffin and/or liquid paraffin or other mineral oil.
In practice, chemical compound/pharmaceutical composition of the present invention can be the appropriate formulation form and give humans and animals, by surperficial administration or the administration of whole body administering mode, comprise in oral, suction, rectum, nasal cavity, oral cavity, Sublingual, vagina, colon, parenteral (comprising in subcutaneous, intramuscular, intravenous, Intradermal, the sheath and epidural), the brain pond and intraperitoneal administration.Will be understood that preferred approach can change according to for example receiver's health.
" pharmaceutical dosage form " is meant the dosage form of chemical compound of the present invention, comprise for example tablet, dragee, powder, elixir, syrup, the liquid preparation that comprises suspension, spray, suction tablet, lozenge, Emulsion, solution, granule, capsule and suppository, and be used for injection liquid preparations, comprise Liposomal formulation.Described technology and preparation are found in Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition usually.
" preparation that is suitable for oral administration " can be made into independently the unit such as every dose of capsule, cachet or tablet that contains the scheduled volume active component; Perhaps powder or granule; Perhaps solution or at liquid, aqueous or non-suspension in liquid, aqueous; Perhaps oil in water emulsion or water in oil emulsion.Active component also can be made into bolus, electuary (electuary) or paste.
Tablet can be suppressed or molded mode prepares, and also can randomly contain one or more auxiliary elements.Compressed tablets can randomly with binding agent, lubricant, inert diluent, antiseptic, surfactant or dispersant, suppress forming by being free-flowing form such as powder or particulate active component in suitable machine.Molded tablet can be by carrying out molded forming to the powdered compounds mixture with the inert liquid diluent moistening in suitable machine.Tablet is coating or indentation randomly, also can be mixed with to make its active component lentamente or controlled release.
The solid composite that is used for rectally comprises the suppository of preparing according to known method, and contains at least a chemical compound of the present invention.
If desired, and in order more effectively to distribute, described chemical compound can be in the system of slow release or targeted delivery microencapsulation or be attached to slow release or the system of targeted delivery, described system is such as biocompatible, biodegradable polymer matrix (for example poly-d, the l-lactide is Acetic acid, hydroxy-, bimol. cyclic ester (poly (d altogether, l-lactideco-glycolide))), liposome and microsphere, and be called technology subcutaneous or intramuscular (depot) and carry out subcutaneous injection or intramuscular injection by a kind of, make described one or more chemical compounds in two weeks or longer time, continue release lentamente.This chemical compound can be sterilized, and for example, filters by sterilizing filter, perhaps biocide is added to the sterile solid pharmaceutical composition, described compositions can be dissolved in before use in sterilized water or other aseptic injection media.
" preparation that is suitable for oral administration " expression is suitable for giving through the oral cavity patient's medicine type.Said preparation can be made into separate unit such as every dose of capsule, cachet or tablet that contains the scheduled volume active component; Perhaps powder or granule; Perhaps solution or at liquid, aqueous or non-suspension in liquid, aqueous; Perhaps oil in water emulsion or water in oil emulsion.Active component also can be made into bolus, electuary or paste.
" preparation that is suitable for parenteral " expression is suitable for the medicine type that parenteral gives the patient.Said preparation is aseptic, and comprise Emulsion, suspension, aqueous and non-aqueous injection solution, can contain suspending agent and thickening agent and antioxidant, buffer agent, antibacterial, and make said preparation and expection receiver's blood etc. ooze and have the solute of the pH value of suitable adjusting.
" preparation that is suitable for the whole body administration " expression is suitable for the medicine type that whole body gives the patient.The preferred drug administration by injection of said preparation comprises through muscle (transmuscular), intravenous, intraperitoneal and subcutaneous injection.For injection, chemical compound of the present invention can be formulated in the liquid solution, especially in the buffer of physical compatibility such as Hunk (Hank ' s) solution or woods Ge Shi (Ringer ' s) solution.In addition, this chemical compound can be mixed with solid form and dissolve again before use or suspendible.Also comprise lyophilized form.The whole body administration also can be by the mode administration of through mucous membrane or percutaneous, perhaps also Orally-administrable of this chemical compound.For through mucous membrane or percutaneous dosing, in preparation, use the penetrating agent that is suitable for penetrating obstacle.This class penetrating agent is well-known in this area, and comprises for example bile salts and fusidinic acid (fusidic acid) derivant that is used for mucosal.In addition, also can use the detergent (detergent) that promotes infiltration.Mucosal can be realized by for example using nasal mist or suppository.For oral administration, this chemical compound is formulated into conventional oral administration form such as capsule, tablet and nourishing agent.
" preparation that is suitable for surperficial administration " expression is suitable for the medicine type that the surface gives the patient.Ointment, ointment (salve), powder, spray and inhalant, gel (water base or alcohol radical), the emulsifiable paste that well-known surface in the said preparation preparation cost field can be used; Perhaps add substrate with the patch form application, make that chemical compound can be via the controlled release of skin barrier.When being mixed with ointment, active component can use with paraffin or water-soluble ointment base.Replacedly, active component can be mixed with emulsifiable paste with the oil-in-water emulsifiable paste matrix.The preparation that is suitable for eye surface administration comprises eye drop, and wherein active component dissolves or is suspended in a kind of appropriate carriers, especially is suitable for the aqueous solvent of this active component.Be suitable for comprising the lozenge that contains active component in the flavoured base at the medicament of oral cavity inner surface administration, this substrate is sucrose and arabic gum or Tragacanth normally; Also be included in the fragrant lozenge that contains active component in the inert base, this inert base such as gelatin and glycerol, perhaps sucrose and arabic gum; Also be included in the collutory that contains active component in the suitable liquid-carrier.
The dosage form of " solid dosage forms " expression chemical compound of the present invention is a solid form, for example capsule, tablet, pill, powder, dragee or granule.In this solid dosage forms, chemical compound of the present invention mixes with at least a inert excipient commonly used (perhaps carrier), such as sodium citrate or dicalcium phosphate or (a) filler or bulking agent, starch for example, lactose, sucrose, glucose, mannitol and silicic acid, (b) binding agent, carboxymethyl cellulose for example, the alginic acid salt, gelatin, polyvinylpyrrolidone, sucrose and arabic gum, (c) wetting agent, glycerol for example, (d) disintegrating agent, agar for example, calcium carbonate, potato starch or tapioca, alginic acid, the silicates of some complexation and sodium carbonate, (e) solution blocker, paraffin for example, (f) absorption enhancer, quaternary ammonium compound for example, (g) wetting agent, for example spermol and glyceryl monostearate, (h) adsorbent, for example Kaolin and bentonite, (i) lubricant, for example Talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, (j) opacifier, (k) buffer agent, and can be in intestinal certain part discharge the medicine of one or more chemical compounds of the present invention in the slow release mode.
The actual dose level of the contained active component of compositions of the present invention can change, so that obtain the effective dose of active component, makes the patient produce ideal therapeutic response to certain specific compositions and medication.Therefore, the dosage level of selecting for any particular patient depends on various factors, comprises type and effectiveness, absorption, metabolism and/or excretory speed and other factors of the cause of disease of treatment persistent period, disease of desired therapeutic effect, route of administration, expection and seriousness, patient's the state of an illness, body weight, sex, diet and age, every kind of active component.
The TDD of the chemical compound of the present invention of patient's single every day or part vic can be that for example, every day, to 100mg/kg, preferably 0.01 to 10mg/kg by per kilogram of body weight about 0.001.For example, adult every day, to 100mg/kg, preferably about 0.01 to 10mg/kg by the inhalation dose normally about 0.01 of per kilogram of body weight; Be about 0.01 to 100mg/kg by the oral dose of per kilogram of body weight every day, and preferably about 0.1 to 70mg/kg; More particularly 0.5 to 10mg/kg; Be about 0.01 to 50mg/kg by the intravenous administration dosage of per kilogram of body weight every day, and preferably 0.01 to 10mg/kg.The percentage ratio of active component can change in the compositions, but it must constitute certain ratio, to obtain suitable dosage.The content of units dosage composition can be the part of dosage every day, forms dosage every day by its some unit dose.Obviously, almost administration simultaneously of some unit dosage forms.In order to obtain desired therapeutic effect, can give a certain dosage as required and continually.Some patient may react rapidly to higher or lower dosage, may find that also very low maintenance dose is enough.For other patient, can carry out 1 to 4 dose long-term treatment every day necessarily according to the physiological requirement of each particular patient.Clearly, for other patient, will be necessary that regulation is no more than potion or two doses every day.
Preparation can be prepared into unit dosage form with well-known any method in the pharmaceutical field.These methods comprise the step that active component is combined with the carrier that constitutes one or more auxiliary elements.Usually, these preparations with liquid-carrier or fine dispersed solids carrier or the two all even combination nearly, then, if be necessary, make product shaping with active component.
Preparation can place in unit dose or the multi-dose container, and for example the phial of Mi Feng ampoule and band plug and can store under lyophilizing (lyophilization) condition, only needs before being about to use for example water for injection of the aseptic aqueous carrier of adding.Instant injection solution and the suspension of preparing can be from aforesaid that class sterilized powder, granule and preparation tablets.
According to document and test described herein, the compound exhibits in the scope of the invention significant pharmacological activity, think that this result of the test is with relevant with pharmacological activity in other mammal the people.
With regard to use the most widely aspect the compound of the present invention, more than Yin Shu list of references has just disclosed its described chemical reaction prevailingly with regard to chemical reaction.Sometimes, for every kind of chemical compound in this disclosed chemical compound scope, above-mentioned chemical reaction may be inapplicable.The chemical compound that this thing happens will be discerned at an easy rate by those skilled in the art.Under all these class situations, perhaps can by well-known to those having ordinary skill in the art revise routinely for example suitable protection of measure disturb group, by use instead alternate conventional reagent, by routine change reaction condition etc. and successfully carry out these reactions; Perhaps other reaction disclosed here or other popular response are applied to the preparation of respective compound of the present invention.In all preparation methoies, all initial feed all are known or can be easily from known initial feed preparations.
Suffer from the patient's of macular degeneration disease scheme selects according to various factors with chemical compound of the present invention and/or combination treatment, comprise patient's age, body weight, sex, diet and the state of an illness, infection seriousness, route of administration, pharmacology aspect consider activity, effect, pharmacokinetics and toxicity profile such as the specific compound that uses, and whether use factor such as drug delivery system.The administration of drug regimen disclosed here should continue one period usually until being accepted, and shows the controlled or elimination of disease.The patient who is received in this disclosed drug regimen treatment can obtain monitoring by regular examination of ocular fundus, to determine the effectiveness of treatment.For the successive analysis of the data that obtain with these methods, make and to make modification to therapeutic scheme during the treatment that the dosage of every kind of component reaches optimum in the combination thereby make, and also helps to determine the persistent period of treatment.Therefore, can reasonably revise therapeutic scheme/drug dosage schedule in the therapeutic process, the dosage of every kind of chemical compound reaches minimum in the feasible combination, and can show gratifying effect together, and it is necessary needing only successfully treating degeneration of macula, diabetic retinopathy or diabetic macular edema, just continues with these chemical compounds of combining form administration.
One aspect of the present invention comprises aforesaid anti-VEGF inhibitor and has the active chemical compound coupling of Syk with treatment or prevention degeneration of macula, because their addition or synergism, wherein one or more these compounds exist with medicinal effective dose, and remaining one or more chemical compound then can be lower than clinical medicinal effective dose and exist or exist with effective dose.At this used term
" summation action " described the synergy of two kinds of (perhaps multiple) medical active agent, and it equals the summation of the individually dosed time effect of every kind of medicine.The synergy that " synergism " is meant two kinds of (perhaps multiple) medical active agent is the summation of effect when individually dosed greater than every kind of medicine.
The present invention also can other particular form implements and does not deviate from its spirit or base attribute.
Claims (11)
- One kind treat the patient the eye relevant disease method, this method comprises the chemical compound of the formula I that gives the medicinal effective dose of patient, perhaps its pharmaceutical salts or prodrug.
Formula I - 2. the process of claim 1 wherein that described eye relevant disease is that ocular neovascular forms.
- 3. the method for claim 2, wherein said eye relevant disease is that the eyes retina new vessels forms.
- 4. the process of claim 1 wherein that described eye relevant disease is selected from following disease: age-related macular degeneration, diabetic retinopathy, and diabetic macular edema.
- 5. the method for claim 4, wherein said ocular disease is an age-related macular degeneration.
- 6. the method for claim 4, wherein said ocular disease is a diabetic retinopathy.
- 7. the method for claim 4, wherein said ocular disease is a diabetic macular edema.
- 8. the process of claim 1 wherein that chemical compound with formula I gives simultaneously the patient with the ranizumab treatment.
- 9. pharmaceutical composition that is used for the treatment of degeneration of macula, diabetic retinopathy or diabetic macular edema, it comprises chemical compound or its pharmaceutical salts or the prodrug of formula I.
Formula I - 10. the chemical compound of formula I is used for the treatment of purposes in the pharmaceutical composition of degeneration of macula, diabetic retinopathy or diabetic macular edema in preparation.Formula I
- 11. a method for the treatment of degeneration of macula, diabetic retinopathy or diabetic macular edema, it comprises: the Syk inhibitors of kinases that needs the medicinal effective dose of patient of treatment.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3507308P | 2008-03-10 | 2008-03-10 | |
| US61/035,073 | 2008-03-10 | ||
| PCT/US2009/036119 WO2009114373A1 (en) | 2008-03-10 | 2009-03-05 | Treatment for ocular-related disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101965188A true CN101965188A (en) | 2011-02-02 |
Family
ID=40583469
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009801075816A Pending CN101965188A (en) | 2008-03-10 | 2009-03-05 | Treatment for ocular-related disorders |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP2285378A1 (en) |
| JP (1) | JP2011513488A (en) |
| KR (1) | KR20110009084A (en) |
| CN (1) | CN101965188A (en) |
| AR (1) | AR070975A1 (en) |
| AU (1) | AU2009223501A1 (en) |
| BR (1) | BRPI0909659A2 (en) |
| CA (1) | CA2717991A1 (en) |
| CL (1) | CL2009000551A1 (en) |
| CO (1) | CO6290691A2 (en) |
| CR (1) | CR11644A (en) |
| DO (1) | DOP2010000266A (en) |
| IL (1) | IL207906A0 (en) |
| MA (1) | MA32211B1 (en) |
| MX (1) | MX2010008308A (en) |
| NI (1) | NI201000131A (en) |
| NZ (1) | NZ587906A (en) |
| RU (1) | RU2010141560A (en) |
| SV (1) | SV2010003658A (en) |
| TW (1) | TW200950784A (en) |
| WO (1) | WO2009114373A1 (en) |
| ZA (1) | ZA201005337B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR074776A1 (en) | 2008-12-18 | 2011-02-09 | Sanofi Aventis | METHOD TO TREAT MACULAR DEGENERATION; MODULATING THE PATIENT'S IMMUNE SYSTEM |
| EP2441755A1 (en) | 2010-09-30 | 2012-04-18 | Almirall, S.A. | Pyridine- and isoquinoline-derivatives as Syk and JAK kinase inhibitors |
| EP2489663A1 (en) | 2011-02-16 | 2012-08-22 | Almirall, S.A. | Compounds as syk kinase inhibitors |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP0203895A3 (en) * | 1999-12-24 | 2004-09-28 | Aventis Pharma Ltd West Mallin | Substituted azaindoles and pharmaceutical compositions containing them and their use |
| EP1259236A4 (en) * | 2000-02-25 | 2004-11-03 | Merck & Co Inc | Tyrosine kinase inhibitors |
| WO2007041358A2 (en) * | 2005-09-30 | 2007-04-12 | Miikana Therapeutics, Inc. | Substituted pyrazole compounds |
| CL2007002617A1 (en) * | 2006-09-11 | 2008-05-16 | Sanofi Aventis | COMPOUNDS DERIVED FROM PIRROLO [2,3-B] PIRAZIN-6-ILO; PHARMACEUTICAL COMPOSITION THAT INCLUDES SUCH COMPOUNDS; AND ITS USE TO TREAT INFLAMMATION OF THE ARTICULATIONS, Rheumatoid Arthritis, TUMORS, LYMPHOMA OF THE CELLS OF THE MANTO. |
-
2009
- 2009-03-05 CA CA2717991A patent/CA2717991A1/en not_active Abandoned
- 2009-03-05 JP JP2010550758A patent/JP2011513488A/en not_active Withdrawn
- 2009-03-05 AU AU2009223501A patent/AU2009223501A1/en not_active Abandoned
- 2009-03-05 CN CN2009801075816A patent/CN101965188A/en active Pending
- 2009-03-05 NZ NZ587906A patent/NZ587906A/en not_active IP Right Cessation
- 2009-03-05 BR BRPI0909659A patent/BRPI0909659A2/en not_active IP Right Cessation
- 2009-03-05 WO PCT/US2009/036119 patent/WO2009114373A1/en active Application Filing
- 2009-03-05 KR KR1020107019973A patent/KR20110009084A/en not_active Application Discontinuation
- 2009-03-05 RU RU2010141560/15A patent/RU2010141560A/en unknown
- 2009-03-05 MX MX2010008308A patent/MX2010008308A/en not_active Application Discontinuation
- 2009-03-05 EP EP09718970A patent/EP2285378A1/en not_active Withdrawn
- 2009-03-09 CL CL2009000551A patent/CL2009000551A1/en unknown
- 2009-03-09 AR ARP090100835A patent/AR070975A1/en not_active Application Discontinuation
- 2009-03-09 TW TW098107567A patent/TW200950784A/en unknown
-
2010
- 2010-07-27 ZA ZA2010/05337A patent/ZA201005337B/en unknown
- 2010-07-29 NI NI201000131A patent/NI201000131A/en unknown
- 2010-08-24 CR CR11644A patent/CR11644A/en not_active Application Discontinuation
- 2010-08-31 IL IL207906A patent/IL207906A0/en unknown
- 2010-09-01 CO CO10108103A patent/CO6290691A2/en not_active Application Discontinuation
- 2010-09-02 DO DO2010000266A patent/DOP2010000266A/en unknown
- 2010-09-07 SV SV2010003658A patent/SV2010003658A/en unknown
- 2010-10-06 MA MA33226A patent/MA32211B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0909659A2 (en) | 2015-09-22 |
| CL2009000551A1 (en) | 2009-08-21 |
| CA2717991A1 (en) | 2009-09-17 |
| MA32211B1 (en) | 2011-04-01 |
| RU2010141560A (en) | 2012-04-20 |
| TW200950784A (en) | 2009-12-16 |
| CR11644A (en) | 2010-11-22 |
| AR070975A1 (en) | 2010-05-19 |
| IL207906A0 (en) | 2010-12-30 |
| ZA201005337B (en) | 2011-04-28 |
| JP2011513488A (en) | 2011-04-28 |
| DOP2010000266A (en) | 2010-09-30 |
| CO6290691A2 (en) | 2011-06-20 |
| EP2285378A1 (en) | 2011-02-23 |
| NI201000131A (en) | 2011-09-29 |
| WO2009114373A1 (en) | 2009-09-17 |
| NZ587906A (en) | 2011-12-22 |
| SV2010003658A (en) | 2011-01-31 |
| MX2010008308A (en) | 2010-08-11 |
| AU2009223501A1 (en) | 2009-09-17 |
| KR20110009084A (en) | 2011-01-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102711756A (en) | Pharmaceutical for preventing or treating disorders accompanied by ocular angiogenesis and/or elevated ocular vascular permeability | |
| CA2564025A1 (en) | A method for the treatment or prevention of cardiac hypertrophy | |
| US10905671B2 (en) | Method of using omega 3 fatty acids to treat diseases which involve damage to the nervous system | |
| JP7089603B2 (en) | Demethylation to treat eye diseases | |
| US7834056B2 (en) | Pharmaceutical composition for gout | |
| CN109381471A (en) | Combination product comprising limonoid and biguanide compound | |
| JP2022511371A (en) | Inhibitor of VAP-1 | |
| CN101965188A (en) | Treatment for ocular-related disorders | |
| EP2151237B1 (en) | Pharmaceutical composition combining a non-steroidal anti-inflammatory agent and an anticonvulsant agent | |
| CN101500567B (en) | Use of a p38 kinase inhibitor for treating psychiatric disorders | |
| JP2021512921A (en) | Methods using ibudilast and a second drug for cancer therapy and dosing regimens | |
| CN101123965A (en) | Methylphenidate derivatives and uses of methylphenidate derivatives | |
| CN103391782A (en) | Medicinal agent for prevention or treatment of diseases associated with intraocular neovascularization and/or intraocular vascular hyperpermeability | |
| HU230459B1 (en) | Pharmaceutical composition based on macrolides for topical application in ophthalmology | |
| CN101522185A (en) | Antidepressant agent | |
| JP2022504184A (en) | Combination therapy for the treatment of melanoma of the grape membrane | |
| JP2020504721A (en) | Method for treating glioblastoma multiforme using ibudilast | |
| WO2017106584A1 (en) | Treatment of central nervous system and mental disorders with agonists of beta-3 adrenoceptor | |
| CA2695822A1 (en) | A combination treatment | |
| JPH10147534A (en) | Tumor newborn blood vessel inhibitor and medicine composition | |
| RU2020126396A (en) | USE OF CARRIMYCIN OR ITS ACTIVE INGREDIENTS | |
| US20110112101A1 (en) | Treatment for ocular-related disorders | |
| KR20220137542A (en) | Composition for treating ophthalmological diseases comprising lobeglitazone as an active ingredient | |
| WO2015165507A1 (en) | Treatment of eye diseases using omega 3 fatty acids and aa/epa blood ratio | |
| WO2023285691A1 (en) | Compositions and methods for preventing and/or treating disease associated with il-23 expression |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1148691 Country of ref document: HK |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20110202 |
|
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1148691 Country of ref document: HK |