HK1148691A - Treatment for ocular-related disorders - Google Patents

Description

Treatment of eye-related disorders

Technical Field

The present invention relates to methods of treating human and non-human patients suffering from or susceptible to eye-related diseases, such as age-related macular degeneration, diabetic retinopathy, and diabetic macular edema.

Background

Protein kinases are involved in signaling events that control the activation, growth, and differentiation of cells in response to changes in the extracellular medium (mediator) and environment. In general, these kinases are divided into several groups: kinases that preferentially phosphorylate serine and/or threonine residues and kinases that preferentially phosphorylate tyrosine residues [ s.k.hanks and t.hunter, faseb.j., 1995, 9, pages 576-. Serine/threonine kinases include, for example, the protein kinase C isoforms [ a.c. newton, j.biol.chem., 1995, 270, pages28495-28498] and cyclin-dependent kinase groups such as cdc2[ j.pines, Trends in biochemical Sciences, 1995, 18, pages 195-197 ]. Tyrosine kinases include transmembrane growth factor receptors such as epidermal growth factor receptor [ S.Iwashhita and M.Kobayashi, CellularSignaling, 1992, 4, pages 123-.

Excessive protein kinase activity is implicated in a number of diseases caused by abnormal functioning of cells. This may occur directly or indirectly, for example, due to failure of appropriate control mechanisms for the kinase associated with mutation, overexpression, or inappropriate enzyme activation of the enzyme; or due to excessive or insufficient production of cytokines or growth factors that are also involved in signal transduction upstream or downstream of the kinase. In all of these cases, it is believed that selective inhibition of kinase activity may produce beneficial effects.

Syk is a 72-kDa cytoplasmic protein tyrosine kinase that is expressed in a variety of hematopoietic cells and is an essential element in several cascades that couple antigen receptors to cellular responses. Thus, Syk plays a key role in the signaling of the high affinity IgE receptor fcepsilonr 1 in mast cells, and in the signaling of receptor antigens in T and B lymphocytes. Signal transduction pathways present in mast cells, T cells and B cells share common features. The ligand binding domain of the receptor lacks intrinsic tyrosine kinase activity. However, they interact with transduction subunits containing immunoreceptor tyrosine-based activation motifs (ITAMs) [ M.Reth, Nature, 1989, 338, pages 383-384 ]. These motifs are present in the beta and gamma subunits of Fc ε R1, the ξ -subunit of the T Cell Receptor (TCR), and the IgG α and IgG β subunits of the B Cell Receptor (BCR) [ N.S. van Oers and dA.Weiss, S.S. semiamines in Immunology, 1995, 7, pages 227-. Following antigen binding and multimerization, ITAM residues are phosphorylated by protein tyrosine kinases in the Src family. Syk belongs to a unique class of tyrosine kinases, which contains two tandem Src protein homology 2(SH2) domains and a C-terminal catalytic domain. These SH2 domains bind with high affinity to ITAMs, and this SH 2-mediated binding of Syk to the activating receptor stimulates Syk kinase activity and localizes Syk to the plasma membrane.

Angiogenesis, or neovascularization, through the growth of the native vasculature is critical to embryonic development and organogenesis. Abnormally increased neovascularization was observed in the case of rheumatoid arthritis, diabetic retinopathy and during tumor development (Folkman, nat. med., 1995, 1, 27-31.). Angiogenesis is a complex multi-stage process that involves activation, migration, proliferation and survival of endothelial cells. Extensive research in the field of tumor angiogenesis over the last 20 years has identified several therapeutic targets, including kinases, proteases and integrins, leading to the discovery of many new anti-angiogenic agents, including KDR inhibitors, some of which are currently in clinical evaluation (Jekunen, et al. cancer Treatment rev.1997, 23, 263-286.). Angiogenesis inhibitors can be used as first-line, adjuvant, or even prophylactic measures against the appearance or regeneration of malignant tumors.

An important cause of severe vision loss and blindness is eye-related diseases in which the ocular vascular system is damaged or under-regulated. There are many types of eye-related diseases that include symptoms of neovascularization, including, for example, age-related macular degeneration, diabetic retinopathy, and diabetic macular edema. It is possible that severe vision loss is not caused directly by neovascularization, but by its effect on the retina. The retina is a delicate membrane of the eye that receives the image. Near the center of the retina is the macula, the oval region of retinal tissue where vision is most acute. The fovea is the weakest part of the retina, the central depression located in the center of the macula. Retinal damage such as retinal degeneration is directly linked to vision loss. While a common cause of retinal detachment, retinal tears, and retinal degeneration is abnormalities in various ocular tissues, i.e., uncontrolled angiogenesis of various ocular tissues, this is not always the case. Atrophic complications of age-related macular degeneration, non-proliferative diabetic retinopathy, and inflammatory eye injury are not associated with angiogenesis, but if left untreated, can result in severe vision loss. Diseases associated with neovascularization and atrophic factors, such as age-related macular degeneration, diabetic retinopathy, and diabetic macular edema are particularly refractory to the development of various complications. See Diabetic Retinopathy: a, Review; JuneChu and Yusuf Ali; drug Development Research 69: 1-14 (2008); new developments in Diabetic Retinopathies; ophthalmol.2(6), 947-956 (2007); and Diabetic Retinopathy; robert Frank; n.engl.j.med.350; 1; 48-58(2004).

The results that have now been found include, in one embodiment, a method of preventing or treating an eye-related disorder in a patient, the method comprising administering to the patient a pharmaceutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof. Administration to a patient at risk for ocular aberrant angiogenesis or angiogenesis prevents aberrant angiogenesis in the eye, particularly in the retina. Patients at risk for or diagnosed with abnormal angiogenesis in the eye have been transitioned from a disease-prone state to a disease-resistant state by treatment with the compounds of the present invention. If left untreated, such diseases are characterized by the invasion of new blood vessels into ocular structures, such as the retina. It is a common cause of blindness and is involved in about 20 ocular diseases. In age-related macular degeneration, the associated visual problems are caused by defects in the choroidal capillaries that penetrate Bruch's membrane, resulting in fibrovascular tissue proliferation beneath the retinal pigment epithelium. Angiogenic damage is also associated with diabetic retinopathy and diabetic macular edema.

Age-related macular degeneration (AMD) is a degenerative disorder of the macula (central retina). In the united states, the population aged 50 years or older, this is the most common cause of vision loss, and its prevalence increases with age. AMD is caused by the hardening of arteries that nourish the retina. This sclerosis deprives the sensitive retinal tissue of the oxygen and nutrients needed for its function and development. The result is diminished central vision.

The severity of macular degeneration varies widely. In the worst case, it can result in a complete loss of central vision, which is not read or driven. It may cause only slight visual distortion for others. Fortunately, macular degeneration does not cause complete blindness because it does not affect peripheral vision.

AMD is classified as either wet (neovascular) or dry (non-neovascular). About 10% of patients with macular degeneration have wet form AMD. This type occurs when new blood vessels are formed to improve the blood supply to hypoxic retinal tissue. However, the new blood vessels are very fragile and easily ruptured, causing bleeding and destruction of surrounding tissues. Although wet AMD represents a relatively few cases of AMD, it is associated with a significant 90% loss of vision caused by the disease.

Current treatments for AMD are focused on influencing the neoangiogenic process leading to the visual loss associated with wet AMD. The current gold standard therapy is to directly inject the biologic into the eye. These biologicals are listed in table 1. Such treatments are expensive, cumbersome and dose-limiting. There is clearly a need for an effective oral therapy for this disease.

TABLE 1

In view of the current state of macular degeneration therapy, there is clearly a need for more effective and more tolerable therapies.

Diabetic retinopathy is an ocular disease and is divided into two stages. There is usually a first occurring non-proliferative stage and a proliferative stage. Nonproliferative diabetic retinopathy often results in vision loss (vision loss) in patients due to retinal edema, particularly diabetic macular edema, which can lead to vascular leakage. Local and diffuse macular leaks are caused by microvascular abnormalities, intraretinal microaneurysms, capillary occlusion, and retinal hemorrhages. Prolonged vascular leakage eventually leads to thickening of the basement membrane and the formation of soft, hard exudates. Non-proliferative diabetic retinopathy is also characterized by periretinal cell loss. The proliferative stage of diabetic retinopathy is characterized by neovascularization and fibrovascular growth (i.e., scarring involving glial and fibrous components) from the retina or optic nerve, on the inner surface of the retina or disc, or in the vitreous cavity. Retinal neovascularization is a major cause of vision loss associated with proliferative diabetic retinopathy.

Current methods of treating abnormal angiogenesis and vasculogenesis of the eye include laser treatment, which destroys some retinal tissue to preserve some vision. There is clearly a need for improved methods and agents for preventing and treating conditions involving abnormal angiogenesis and deleterious angiogenesis, such as pathological angiogenesis of ocular tissues.

In view of the prevalence of eye-related diseases, there remains a need for an effective method for preventing and treating eye-related diseases, especially those associated with atrophy and neovascular complications, such as age-related macular degeneration, diabetic retinopathy, and diabetic macular edema. Accordingly, the present invention relates to compounds and methods for preventing and treating diseases associated with the eye. This and other advantages of the invention will become apparent from the detailed description provided below.

Disclosure of Invention

The present invention relates to methods of treating macular degeneration, and more particularly age-related macular degeneration, using compounds of formula I.

Formula I

The present invention relates to substituted azaindoles of formula I, which have been found to be effective in inhibiting macular degeneration in animal models.

Another aspect of the invention is the treatment of wet form age-related macular degeneration (wet AMD).

The compounds of formula I are useful as effective oral treatments for AMD. Furthermore, based on the data obtained by the present inventors, the present inventors foresee that Syk inhibitors could in principle be useful agents for the treatment of this disease. The data for these conclusions are summarized below.

Another aspect of the invention is a method of treating diabetic retinopathy by administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula I.

Another aspect of the invention is a method of treating diabetic macular edema by administering to a patient in need of treatment a pharmaceutically effective amount of a compound of formula I.

Another aspect of the invention is generally the treatment of macular degeneration, diabetic retinopathy or diabetic macular edema in a patient with a Syk inhibitor.

Detailed Description

Accordingly, in one aspect, the present invention relates to methods of treatment and pharmaceutical compositions comprising compounds of general formula (I):

it may also be referred to as: 2- [4- (7-ethyl-5H-pyrrolo [2, 3-b ] pyrazin-6-yl) -phenyl ] -propan-2-ol. The synthesis of this compound is known to the person skilled in the art and can be found in the international patent application WO 2008/033798. It is also understood from the present application that the present compound is a Syk inhibitor.

In the present description, the term "compound of the invention" and its equivalent expressions are meant to include the compounds of general formula (I) as described above, which expressions may also include prodrugs, pharmaceutically acceptable salts and solvates, e.g. hydrates, thereof, depending on the context. Similarly, where intermediates are mentioned, whether or not claimed as such, reference is made to the inclusion of their salts and solvates, depending on the context. For clarity, certain specific examples are sometimes set forth herein where context permits, but these examples are merely illustrative and are not intended to exclude other examples where context permits.

Definition of

As used above and throughout the description of the present invention, the following terms should be understood to have the following meanings, unless otherwise indicated:

"patient" includes humans and other mammals.

By "pharmaceutically acceptable ester" is meant esters which are hydrolysable in vivo and include those which are readily decomposable in the human body to leave the parent compound or a salt thereof, suitable ester groups including, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, especially alkyl carboxylic acids, alkenyl carboxylic acids, cycloalkyl carboxylic acids and alkyl dicarboxylic acids, each alkyl or alkenyl group advantageously containing no more than 6 carbon atoms. Representative esters include formates, acetates, propionates, butyrates, acrylates, ethylsuccinates, and the like.

As used herein, "pharmaceutically acceptable prodrugs" refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients exhibiting excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for the intended use of the compounds of the present invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo, for example by hydrolysis in blood, to yield the parent compound having the formula described above. Functional groups that can be rapidly converted by metabolic cleavage form a class of groups in vivo that can react with the carboxyl groups of the compounds of the invention. They include, but are not limited to, groups such as alkanoyl (such as acetyl, propionyl, butyryl, and the like), unsubstituted and substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as ethoxy)Carbonyl), trialkylsilyl groups such as trimethylsilyl and triethylsilyl, monoesters with dicarboxylic acids such as succinyl, and the like. Since the metabolically cleavable group of the compounds of the present invention are susceptible to cleavage in vivo, compounds containing such groups, such as prodrugs, function. Compounds containing metabolically cleavable groups have the advantage that they may exhibit improved bioavailability due to the enhanced solubility and/or absorption rate of the parent compound as a result of the presence of the metabolically cleavable group. The following documents provide a thorough discussion: design of produgs, H.Bundgaard, ed., Elsevier (1985); methods in Enzymology; 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，14symposium Series, and Bioreversible Carriers in Drug Design, e.b. roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated by reference herein.

"pharmaceutically acceptable salts" refers to the inorganic and organic acid addition salts and base addition salts of the compounds of the present invention that are relatively non-toxic. Such salts may be prepared in situ during the final isolation and purification of the compound. In particular, acid addition salts may be prepared by separately reacting the purified compound in free base form with a suitable organic or inorganic acid and isolating the salt formed. Representative acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthenate, mesylate, glucoheptanoate, lactobionate, sulfamate, malonate, salicylate, propionate, methylene-bis- β -hydroxynaphthoate, gentisate, isethionate, di-p-toluoyl tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and laurylsulfate, and the like. See, e.g., s.m. berge, et al, "Pharmaceutical Salts," j.pharm. sci., 66, 1-19 (1977). Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt formed. Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminum salts. Sodium and potassium salts are preferred. Suitable inorganic base addition salts are prepared from metal bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, and the like. Suitable amine base addition salts are prepared from certain amines which are sufficiently basic to form stable salts, preferably including those amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use: ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N' -dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, diphenylmethylamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine, dicyclohexylamine, and the like.

Detailed description of the preferred embodiments

The following are specific embodiments related to the invention described herein.

A particular embodiment of the invention is the treatment of macular degeneration by administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula I.

Another embodiment of the invention is the treatment of macular degeneration by administering a pharmaceutically effective amount of a Syk inhibitor to a patient in need of treatment.

A preferred embodiment of the invention, wherein the macular degeneration is age-related macular degeneration, and an effective amount of a compound of formula I is administered.

Another preferred embodiment of the invention, wherein the macular degeneration is age-related macular degeneration and the effective amount of a Syk inhibitor is administered.

Another embodiment of the invention is the treatment of diabetic retinopathy by administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula I.

Another embodiment of the invention is the treatment of diabetic macular edema by administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of formula I.

The compounds of the present invention are optionally provided in the form of salts. Those pharmaceutically acceptable salts are of particular interest because they are useful for medical purposes during the administration of the aforementioned compounds. The pharmaceutically acceptable salts are useful for isolation and purification purposes during manufacture, and in some cases, for isolating stereoisomeric forms of the compounds of the invention. This latter case is particularly true for amine salts prepared from optically active amines.

One aspect of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier or diluent.

Another aspect of the present invention is to provide a pharmaceutical composition which is effective in itself in a beneficial combination therapy, as it comprises a plurality of active ingredients which can be used according to the present invention.

In any of the foregoing applications, the amount of the compound of formula I can be a pharmaceutically effective amount or a less than optimal effective amount (or a combination of both) so long as the resulting combination of ingredients comprises a pharmaceutically effective amount of the compound effective to treat or prevent macular degeneration, diabetic retinopathy or diabetic macular edema in a patient.

In vivo efficacy of compounds of formula I in ocular related diseases such as AMD

There are several wet AMD models available in rodents and rabbits. Preclinical efficacy of the compound of formula I was evaluated in a laser-induced rat macular degeneration model. In this model a focused laser beam is used to cause damage to rat retina. This damage results in angiogenesis and inflammation and subsequent formation of plaques on the retina associated with vision loss. The ability to treat with compounds of formula I to inhibit the size and thickness of such plaques may be a potential indicator of treatment for wet AMD patients. The retina of the rat eye was irradiated with 75 micron krypton laser for 0.1 second, 3-4 spots each. The compound of formula I was administered orally to irradiated rats twice daily (twice daily, orally) from day 1 to day 14. The dosages used were 3mg/kg, 10mg/kg and 30mg/kg by body weight. Additional treatment groups were given oral compound vehicle, again twice daily. 0.5mg triamcinolone acetonide was used as a positive control and administered under the tendon in the eye. On the 14 th day after the above irradiation, rats were perfused with FITC-dextran (fluorescein isothiocyanate dextran) and the eyes were removed for evaluation. Evaluation was performed by fundus examination and fluorescein angiography. The data for the compound of formula I in this model show that the plaque thickness is significantly reduced when the compound is dosed at 30 and 10mg/kg orally twice daily on a body weight basis. These results are significantly better than those observed with the positive control triamcinolone acetonide (intravitreal steroid injection). The results are shown in table 2.

Treatment of	Inhibition of plate%	Significance of
			Media	0
3mg/kg of a Compound of formula I	12
			10mg/kg of a Compound of formula I	36	p＜0.003
Compound of formula I30 rmg/kg	33	p＜0.0006
			0.5mg triamcinolone acetonide	26	p＜0.0245

TABLE 2

Another aspect of the invention described herein is a method of treating a patient suffering from or susceptible to macular degeneration, comprising administering to the patient a pharmaceutically effective amount of a Syk inhibitor. As used herein, "treatment" is understood to include prophylactic treatment to prevent or inhibit the occurrence of the disease and treatment of a patient to alleviate or improve the condition of the patient. An "effective amount" is intended to describe a dosage of a compound of the present invention that is effective within the scope of sound biological judgment, suitable for use in contact with cells of humans and other mammals without undue toxicity, irritation, and allergic response as a side effect, and that exhibits a reasonable benefit/risk ratio during therapy and therefore the intended therapeutic effect.

A particular aspect of the invention provides a compound of the invention for administration in the form of a pharmaceutical composition, although the compound may be administered alone. Depending on the nature, dosage and form of administration, "pharmaceutical composition" means a composition comprising a compound of formula I and at least one of the following ingredients: pharmaceutically acceptable carriers, diluents, coatings, adjuvants, excipients or vehicles such as preservatives, fillers, disintegrants, wetting agents, emulsifiers, emulsion stabilizers, suspensions, isotonic agents, sweeteners, flavoring agents, fragrances, colorants, antibacterial agents, antifungal agents, other therapeutic agents, lubricants, adsorption delaying or promoting agents, and dispersing agents. The pharmaceutical composition may exist in the following form: tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups. Representative suspensions include ethoxylated isostearyl alcohols, polyoxyethylene and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these materials. Representative antibacterial and antifungal agents that prevent the action of microorganisms include parabens, chlorobutanol, phenol, sorbic acid, and the like. Representative isotonic agents include sugars, sodium chloride and the like. Representative adsorption retardants for retarding absorption include aluminum monostearate and gelatin. Representative adsorption promoters for increased absorption include dimethyl sulfoxide and related analogs. Representative carriers, diluents, solvents, vehicles, solubilizers, emulsifiers and emulsion stabilizers include water, chloroform, sucrose, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, tetrahydrofurfuryl alcohol, benzyl benzoate, polyols, propylene glycol, 1, 3-butylene glycol, glycerol, polyethylene glycol, dimethylformamide, mannitol, sorbitol,60，60, cetostearyl alcohol (cetostearyl alcohol), myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate, sorbitan fatty acid esters, vegetable oils (such as cottonseed, groundnut, corn germ, olive, castor and sesame oils) and injectable organic esters such as ethyl oleate and the like, or suitable mixtures of these materials. Representative excipients include lactose, lactose (milk sugar), sodium citrate, calcium carbonate, and dicalcium phosphate. Representative disintegrants include starch, alginic acid and certain complex silicates. Representative lubricants include magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycols.

Other therapeutic agents may be combined with the compounds of the invention, including other anti-agents. Therapeutic agents in combination with the compounds of the present invention may be administered separately, simultaneously or sequentially. The choice of substances in the pharmaceutical compositions, in addition to the compounds of the formula I, generally depends on the chemical properties of the active compounds, such as solubility, the particular mode of administration and the regulations to be observed in practice of medication. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acid and certain complex silicates in combination with lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc may be used to prepare tablets.

The pharmaceutical composition may be administered in the form of: such as tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups.

By "liquid dosage form" is meant that the dose of active compound administered to the patient is in a liquid state, such as pharmaceutical emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as solvents, solubilizers, emulsifiers and the like.

Solid compositions may also be employed as fillers in soft and hard-filled capsules using lactose or milk sugar (PEG) and high molecular weight polyethylene glycols and the like as excipients.

When aqueous suspensions are used, they may contain emulsifying agents or agents which facilitate suspension.

The oily phase of the emulsion pharmaceutical composition may be constituted in a known manner by known ingredients. Although the oil phase may comprise only emulsifiers, also known as emulgents, it desirably comprises a mixture of at least one emulsifier with a fat or oil, or with both a fat and an oil. In a particular embodiment, a hydrophilic emulsifier is used together with a lipophilic emulsifier as a stabilizer. The emulsifier, with or without stabilizers, forms an emulsifying wax, and with oils and fats forms the emulsifying ointment base, which forms the oily dispersed phase of the cream formulation.

If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, 1, 3-butylene glycol, mannitol, sorbitol, glycerol, and polyethylene glycols (including PEG 400), and mixtures thereof. Dosage forms for topical administration may desirably include compounds that promote absorption or that promote penetration of the active ingredient through the skin or other affected area.

The choice of oil or fat suitable for formulation is based on whether the desired properties are achieved. Thus, the cream should preferably be a non-greasy, non-staining and washable product with a suitable consistency to avoid leakage from tubes or other containers. Blends of straight or branched chain, mono-or dibasic alkyl esters such as diisopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or the branched chain ester known as cetyl stearyl alcohol ethyl hexanoate (Crodamol CAP) may be used. These auxiliaries can be used alone or in combination, depending on the desired properties. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils may also be used.

In practice, the compounds/pharmaceutical compositions of the present invention may be administered to humans and animals in suitable formulations, by topical or systemic means, including oral, inhalation, rectal, nasal, buccal, sublingual, vaginal, colonic, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), intracisternal and intraperitoneal administration. It will be appreciated that the preferred route may vary depending on, for example, the physical condition of the recipient.

"pharmaceutical dosage forms" refers to dosage forms of the compounds of the invention, including, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalation tablets, lozenges, emulsions, solutions, granules, capsules and suppositories, as well as liquid preparations for injection, including liposomal preparations. Such techniques and formulations are commonly found in Remington's Pharmaceutical Sciences, Mack Publishing co., Easton, PA, latest edition.

"formulations suitable for oral administration" may be presented as discrete units such as capsules, cachets or tablets containing a predetermined amount of the active ingredient per dose; or a powder or granules; or a solution or a suspension in an aqueous liquid or a non-aqueous liquid; either an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be formulated as a bolus, electuary or paste.

Tablets may be prepared by compression or molding and may optionally contain one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may also be formulated so as to provide slow or controlled release of the active ingredient.

Solid compositions for rectal administration include suppositories formulated according to known methods and containing at least one compound of the invention.

If desired, and for more effective distribution, the compounds may be microencapsulated or attached to a sustained-release or targeted delivery system, such as a biocompatible, biodegradable polymer matrix (e.g., poly (d, l-lactide-co-glycolide)), liposomes and microspheres, and the compound(s) are released slowly over a sustained period of two weeks or more by subcutaneous or intramuscular injection by a technique known as subcutaneous or intramuscular depot (depot). The compounds may be sterilized, for example, by filtration through a sterile filter, or by the addition of sterilizing agents to sterile solid pharmaceutical compositions, which may be dissolved in sterile water or other sterile injectable medium prior to use.

By "a formulation suitable for oral administration" is meant a form of medicament suitable for oral administration to a patient. The formulations may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; or a powder or granules; either as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; either an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be formulated as a bolus, electuary or paste.

By "formulation suitable for parenteral administration" is meant a form of medicament suitable for parenteral administration to a patient. The formulations are sterile and include emulsions, suspensions, aqueous and non-aqueous injection solutions, which may contain suspending and thickening agents, as well as antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient and have an appropriately adjusted pH.

By "formulation suitable for systemic administration" is meant a form of medicament suitable for systemic administration to a patient. The formulation is preferably administered by injection, including intramuscular (transmuscular), intravenous, intraperitoneal and subcutaneous injection. For injection, the compounds of the invention may be formulated in liquid solutions, especially physiologically compatible buffers such as Hank's solution or Ringer's solution. In addition, the compounds may be formulated in solid form and reconstituted or suspended prior to use. Lyophilized forms are also included. Systemic administration may also be by transmucosal or transdermal administration, or the compound may also be administered orally. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid (fusidic acid) derivatives. In addition, detergents (detergents) that promote penetration may also be used. Transmucosal administration can be accomplished through the use of, for example, nasal sprays or suppositories. For oral administration, the compounds are formulated into conventional oral administration forms such as capsules, tablets, and tonics.

By "formulation suitable for topical administration" is meant a form of medicament suitable for topical administration to a patient. The formulations may be formulated as topical ointments, salves (salves), powders, sprays and inhalants, gels (water-based or alcohol-based), creams; or in the form of a patch, such that the compound is controllably released via the skin disorder. When formulated as an ointment, the active ingredient may be employed with a paraffinic or water-soluble ointment base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water cream base. Formulations suitable for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent suitable for the active ingredient. Medicaments suitable for topical administration in the oral cavity include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; also included are pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; mouthwashes containing the active ingredient in a suitable liquid carrier are also included.

By "solid dosage form" is meant that the dosage form of the compounds of the invention is a solid form, such as a capsule, tablet, pill, powder, dragee, or granule. In such solid dosage forms, the compounds of the present invention are mixed with at least one of the usual inert excipients (or carriers), such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, for example, glycerol, (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarding agents, for example, paraffin, (f) absorption promoters, for example, quaternary ammonium compounds, (g) wetting agents, for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, for example, kaolin and bentonite, (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, (j) opacifiers, (k) buffering agents, and drugs that release one or more compounds of the present invention in a sustained manner in a certain part of the intestinal tract.

The actual dosage level of the active ingredient contained in the compositions of the present invention may be varied so as to obtain an effective amount of the active ingredient which will produce the desired therapeutic response by the patient for a particular composition and method of administration. Thus, the dosage level selected for any particular patient will depend upon a variety of factors including the desired therapeutic effect, the route of administration, the desired duration of treatment, the etiology and severity of the disease, the condition, body weight, sex, diet and age of the patient, the type and potency of each active ingredient, the rate of absorption, metabolism and/or excretion and other factors.

The total daily dose of a compound of the present invention administered to a patient in a single or divided daily dose may be, for example, about 0.001 to 100mg/kg, preferably 0.01 to 10mg/kg per kg body weight per day. For example, the daily inhaled dose by an adult human per kg body weight is generally from about 0.01 to 100mg/kg, preferably from about 0.01 to 10 mg/kg; the daily oral dosage is about 0.01 to 100mg/kg, preferably about 0.1 to 70mg/kg, per kg body weight; more particularly 0.5 to 10 mg/kg; the daily dose of intravenous administration is about 0.01 to 50mg/kg, preferably 0.01 to 10mg/kg, per kg of body weight. The percentage of active ingredient in the composition may vary, but it should still constitute a proportion to obtain a suitable dosage. The content of the unit dose composition may be a fraction of the daily dose, of which several unit doses constitute the daily dose. Obviously, several unit dosage forms can be administered almost simultaneously. A certain dose may be given as frequently as necessary to obtain the desired therapeutic effect. Some patients may respond rapidly to higher or lower doses, and may find that a very low maintenance dose is sufficient. For additional patients, long-term treatment with 1 to 4 doses per day may be necessary, as per the physiological requirements of each particular patient. Clearly, for additional patients, it will be necessary to prescribe no more than one or two doses per day.

The formulations may be prepared in unit dosage form by any method well known in the art of pharmacy. These methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, these formulations uniformly and intimately involve the active ingredient in association with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials with stoppers, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Compounds within the scope of the present invention show significant pharmacological activity according to the literature and the assays described herein, which results are believed to be related to pharmacological activity in humans and other mammals.

The above-cited references disclose only the chemical reactions generally, as far as they are most widely used in the preparation of the compounds of the present invention. At times, the above-described chemical reactions may not be applicable for each compound within the scope of the compounds disclosed herein. The compounds in which this occurs will be readily recognized by those skilled in the art. In all such cases, these reactions can alternatively be carried out successfully by customary modifications known to those skilled in the art, for example, suitable protection of interfering groups, by adapting alternative conventional reagents, by routinely changing the reaction conditions, etc.; or other reactions disclosed herein or otherwise conventional may be applied to the preparation of the corresponding compounds of the present invention. In all preparation methods, all starting materials are known or can be readily prepared from known starting materials.

The regimen for treating a patient suffering from a macular degenerative disease with a compound and/or composition of the present invention is selected in accordance with a variety of factors, including the age, weight, sex, diet and condition of the patient, the severity of the infection, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicity profile of the particular compound employed, and whether a drug delivery system is employed. Administration of the pharmaceutical combinations disclosed herein should generally be continued for a period of time until acceptable, indicating that the disease has been controlled or eradicated. Patients receiving the drug combination therapy disclosed herein can be monitored by periodic ocular fundus examination to determine the effectiveness of the therapy. Continuous analysis of the data obtained by these methods allows modification of the treatment regimen during treatment to optimize the amount of each component in the combination and also to help determine the duration of treatment. Thus, the treatment regimen/schedule can be modified appropriately during the course of therapy so that the minimum amount of each compound administered in the combination is achieved while still achieving a satisfactory effect, and so long as is necessary for successful treatment of macular degeneration, diabetic retinopathy or diabetic macular edema, the compounds will continue to be administered in combination.

One aspect of the invention includes the combination of an anti-VEGF inhibitor as described above and a compound having Syk activity for the treatment or prevention of macular degeneration, wherein one or more of such compounds is present in a pharmaceutically effective amount and the remaining compound or compounds may be present in a less than clinically effective amount or in an effective amount due to their additive or synergistic effect. The terms used herein

"additive effect" describes the combined effect of two (or more) pharmaceutically active agents, which is equal to the sum of the effects of each drug when administered alone. By "synergistic" is meant that the combined effect of two (or more) pharmaceutically active agents is greater than the sum of the effects of each agent when administered alone.

The present invention may be embodied in other specific forms without departing from its spirit or essential attributes.

Claims (11)

1. A method of treating an eye-related disorder in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof.

Formula I

2. The method of claim 1, wherein the eye-related disease is ocular neovascularization.

3. The method of claim 2, wherein the ocular-related disorder is ocular retinal neovascularization.

4. The method of claim 1, wherein the eye-related disorder is selected from the group consisting of: age-related macular degeneration, diabetic retinopathy, and diabetic macular edema.

5. The method of claim 4, wherein the ocular disease is age-related macular degeneration.

6. The method of claim 4, wherein the ocular disease is diabetic retinopathy.

7. The method of claim 4, wherein the ocular disease is diabetic macular edema.

8. The method of claim 1, wherein the compound of formula I is administered to a patient who is concurrently treated with ranizumab.

9. A pharmaceutical composition for the treatment of macular degeneration, diabetic retinopathy or diabetic macular edema comprising a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof.

Formula I

10. Use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of macular degeneration, diabetic retinopathy or diabetic macular edema.

Formula I

11. A method of treating macular degeneration, diabetic retinopathy, or diabetic macular edema, comprising: administering to a patient in need thereof a pharmaceutically effective amount of a Syk kinase inhibitor.