JP2009527565A - Hydroxylamines and derivatives that inhibit complement activation - Google Patents

Abstract

Disclosed is a method for inhibiting complement activation to treat a condition mediated by complement and to treat a condition mediated by drusen. The method utilizes a hydroxylamine compound and ester derivatives thereof, and an effective amount is administered to the subject.
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Description

This application is related to US patent application Ser. No. 11/677, filed Feb. 21, 2007, which claimed the benefit of provisional application serial number 60 / 775,478, filed Feb. 22, 2006. No. 462 is claimed in its entirety, the entire disclosure of which is incorporated herein by this reference.

  The present invention relates to the field of immunopharmacology. Specifically, the present invention is characterized by compositions and methods that utilize hydroxylamine and certain ester derivatives to inhibit activation of the complement cascade and treat conditions resulting from complement activation. It is.

  Various patents and other publications are referenced herein. The entire disclosure of each of these patents and publications is incorporated herein by this reference. The entire disclosures of co-owned copending US Publication Nos. 2004/0002461, 2005/0130906, and 2005/0131025 are incorporated herein by this reference.

  The complement system is an important tool among body weapons in immune defense against foreign pathogens. Complement proteins are activated by an enzyme cascade that can be triggered by various signals and travel through one of three major pathways: the classical pathway, the alternative pathway, and the lectin pathway. In these pathways, an anaphylatoxin peptide containing C3a and C5a is generated, and as a result, a C5b-9 membrane attack complex (MAC) is generated, which has a function of lysing cells that have invaded. The anaphylatoxins act on blood vessels and promote inflammation as well as smooth muscle contraction and increased vascular permeability.

  In certain situations, the complement system can produce deleterious effects. For example, if complement is inappropriately activated, in vivo cells may be damaged. Complements, especially when immune complexes are generated, can exacerbate tissue damage in autoimmune diseases such as myasthenia gravis and systemic lupus erythematosus and worsen tissue damage after ischemia. (Liszewski MK et al. (1998) Expert Opin. Investig. Drugs. 7: 323-31). Complement has also been implicated in the promotion or exacerbation of various disease states, including glomerulonephritis, adult respiratory syndrome, and transplant tissue rejection (Glovsky MM et al. (2004) Ann. Allergy Asthma Immunol. 93: 513-22; Colvin RB et al. (2005) Nat Rev Immunol. 5: 807-17). Complement-mediated tissue injury was also observed in biocompatibility conditions such as those seen in patients undergoing dialysis or cardiopulmonary bypass (Mollnes TE (1998) Vox Sang. 74 Suppl 2: 303-307). .

  Complement-mediated tissue injury is mediated directly by the production of said MAC, indirectly anaphylatoxins C3a and C5a. These peptides induce injury by acting on neutrophils and mast cells. Plasma and membrane proteins control complement at the stage of C3 and C5 activation. Plasma protein inhibitors induce factor H and C4 binding proteins, and control membrane proteins on the cell surface include complement receptors 1 (CR1), decay-accelerating factor (DAF), and It includes membrane cofactor protein (MCP). These proteins promote the dissociation of the multi-subunit complex and / or inactivate the complement by proteolysis (catalyzed by factor I), thereby producing C3 and C5 converting enzymes (multi-subunits). Inhibits unit proteases.

  Complement is also involved in the formation of drusen. Druse is the name given to extracellular deposits in the part of the eye between the retinal pigmented epithelium (RPE) and the Bruch's membrane, sometimes in the periphery of the retina (Lewis HB et al. (1986) Ophthalmology). 93: 1098-1111). Druses include a variety of lipids, proteins, polysaccharides, and glycosaminoglycans, and drusen proteins are often oxidatively modified (Crab JW et al. (2002) Proc. Natl. Acad. Sci. USA). 99: 14682-7). Druse deposition occurs mainly in the elderly and is a major factor in the development of age-related macular degeneration (AMD) (Abdelsalam A et al. (1999) Surv. Optalmol. 44: 1-29). .

  Although the exact mechanism leading to the formation and deposition of druse has only been partially characterized, the cellular debris of the RPE serves as an irritant for inflammation and then becomes the nucleation site for drusen accumulation It has been speculated (Johnson LV et al. (2000) Exp. Eye Res. 70: 441-9; and Johnson LV et al. (2001) Exp. Eye. Res. 73: 887-96). ). In support of this hypothesis, a variety of inflammatory mediators including complement components C3a, C5a, and said MAC were observed in drusen (Luibl V et al. (2006) J. Clin. Invest. 116: 378-85). Such a complement was found to coexist with amyloid β protein, which is a complement-activating protein, in vesicles with a partial structure of drusen (Johnson LV et al. (2002) Proc. Natl. Acad. Sci. USA 99: 11830-5). Furthermore, recent studies have demonstrated that C3a or C5a neutralization, or the respective receptor, inhibits angiogenesis of AMD (Nozaki M et al. (2006) Proc. Natl. Acad. Sci. USA 2006 Feb 1; [electronically published before printing]). These findings indicate that complement is involved in the inhibition or progression of drusen formation and deposition. As such, complement is an attractive target for inhibiting drusen deposition.

  To date, there are no clinically feasible inhibitors of complement activation, but there are certain candidate drugs for clinical use. Such candidate drugs include recombinant complement receptor 1, known as soluble complement receptor 1 (sCR1), and humanized monoclonal anti-C5 antibody (5G1.1-scFv). All of these substances have been shown to suppress complement activation in an in vivo animal model (Kalli KR et al. (1994) Springer Semin. Immunopathol. 15: 417-31; and Wang et al. (1996) Proc.Natl.Acad.Sci.USA.93: 8563-8). However, each substance has the disadvantage of being a high molecular weight protein (240 kDa and 26,000 kDa, respectively), which is difficult to manufacture and requires infusion administration. Although it has been proposed that CD59, which inhibits MAC association, could also be a therapeutic, it has shown limited activity in vitro (Song H et al. (2003) J. Clin. Invest. 111: 1875-85). Thus, recent research has focused on developing smaller active drugs that are easily reachable to the patient to whom the drug is administered, that are highly soluble and less toxic.

  Hydroxylamine is preferred over nitrogen oxide as a therapeutic because it is relatively non-toxic. In Mater and Patil's published US patent applications Nos. 2004/0002461, 2005/0130906, and 2005/0131025, hydroxylamines and related compounds, and various ophthalmic conditions involving oxidative injury or inflammation are described. Disclosed for use in therapy. Such compounds have a number of advantageous properties, including strong anti-inflammatory and antioxidant activity, and in some cases ocular permeability. However, it has not been reported so far that hydroxylamine has the effect of suppressing complement activation or treating pathologies through complement or drusen such as AMD.

  The present invention is characterized by a method of inhibiting complement activation in a subject by administering to the subject an effective amount of a hydroxylamine compound or ester derivative thereof that inhibits complement activation. Furthermore, the present invention provides a method for treating a condition mediated by complement activation in a subject, and a method for inhibiting drusen formation in a subject, each of which treats a condition mediated by complement activation and treated with drusen. By administering to the subject a composition having an effective amount of a pharmaceutically acceptable carrier that inhibits formation and a hydroxylamine compound or ester derivative thereof. Examples of ophthalmic conditions that can be treated by the compositions and methods of the present invention include retinopathy and age-related macular degeneration (AMD). Furthermore, it is becoming clear that chronic inflammation, such as that due to complement activation, is a factor in many important diseases associated with aging. Accordingly, other conditions that can be treated with the compositions and methods of the present invention include Alzheimer's disease (AD), Parkinson's disease (PD), ALS, to name a few examples. And age-related diseases such as multiple sclerosis, atherosclerosis, heart disease, skin elastic sclerosis, glomerular basement membrane disease, and numerous amyloidosis. The compositions and methods can be used on any animal, preferably used on mammals, and most preferably used on humans.

  In certain embodiments, the hydroxylamine compound comprises Tempol-H, Tempo-H, and Oxano-H, wherein the hydroxylamine compound derivative has the following Formula I:

Where
R ₁ and R ₂ are independently H or C ₁ -C ₃ alkyl;
R ₃ and R ₄ are independently C ₁ -C ₃ alkyl, or R ₁ and R ₂ are bonded together, R ₃ and R ₄ are bonded together, or R ₁ and R ₄ are bonded together. ₂ are bonded together, R ₃ and R ₄ are bonded together, and each is cycloalkyl,
R ₅ is H, OH, or C ₁ -C ₆ alkyl;
R ₆ is C ₁ -C ₆ alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl,
R ₇ is C ₁ -C ₆ alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl, or R ₆ and R ₇ are bonded together, and R ₅ , R ₆ , and R ₇ are bonded together Thus, a carbocyclic ring having 3 to 7 atoms is formed in the ring, or a heterocyclic ring having 3 to 7 atoms is formed in the ring.

  According to some aspects of the invention, the compositions of the invention are used synergistically with other complement inhibitors, anti-inflammatory agents, or antioxidants.

  Other features and advantages of the present invention will be understood by reference to the drawings, detailed description and examples that follow.

  Throughout this specification and claims, various terms relating to the methods and other aspects of the present invention are used. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms shall be construed to be consistent with the definitions provided herein.

  The following abbreviations may be used in the specification and examples. AMD Age-related macular degeneration, MAC membrane attack complex.

  The terms “treat” or “treatment” refer to symptom relief, remission, disappearance or making a patient more tolerated by an injury, condition, or condition, degeneration or slowing the rate of decline, and the end point of degeneration being less exhausted Success or success in attenuating or improving an injury, medical condition, or condition involving subjective or objective parameters, such as loss of gender, improvement of the subject's physical or mental well-being, or prolonged survival Point to signs. Symptom treatment or amelioration can be based on objective or subjective parameters, including physical examination, neurological examination, and / or psychological results.

  “Effective amount” or “therapeutically effective amount” is used interchangeably herein and, as described herein, is a compound, substance, or composition that is effective to achieve a particular biological result. Refers to the amount. Such results include (but are not limited to) inhibition of complement activation, inhibition of drusen formation, treatment of conditions mediated by complement, and treatment of conditions mediated by drusen. Can do.

  “Pharmaceutically acceptable” refers to the patient in terms of composition, formulation, stability, patient acceptance, and bioavailability from the pharmacological / toxicological point of view, to the manufacturing pharmacist from the physical / chemical point of view. Refers to these properties and / or materials that are acceptable. “Pharmaceutically acceptable carrier” refers to a medium that does not interfere with the effectiveness of the biological activity of the active ingredients and is not toxic to the host to which it is administered.

  “Disease state” refers to a structural and functional deviation from the normal state that constitutes the onset or progression of a disease, condition, or condition, or that characterizes a particular disease or condition.

  “Druze” refers to extracellular deposits that accumulate beneath the basement membrane of the retinal pigmented epithelium (RPE) and the inner collagen layer of Bruch's membrane.

  The present invention provides a method of inhibiting complement activation. Also provided are treatments for conditions mediated by complement activation and conditions mediated by drusen formation and deposition. The method comprises administering a hydroxylamine compound or an ester derivative thereof in an amount effective to treat, inhibit, or blunt complement activation, drusen deposition, or the onset or progression of a condition mediated by complement or drusen. Have

  Further in the present invention, in the manufacture of a medicament for treating or inhibiting a pathology via complement activation or a pathology via drusen formation and deposition, including age-related macular degeneration and diabetic retinopathy, Hydroxylamine compounds, including Tempol-H, Tempo-H, and Oxano-H, and all pharmaceutically acceptable salts, analogs, homologues, conjugates, and derivatives thereof are provided.

A suitable example of a class of hydroxylamine compounds suitable for use in the present invention is TEMPOL-H (TPH, a hydroxylamine reduced form of nitrooxide 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-yloxy. ), TEMPO-H (hydroxylamine reduced form of nitrooxide 2,2,6,6-tetramethylpiperidin-1-yloxy), and OXANO-H (2-ethyl-2,4,4-tetramethyl-oxazolidine- 3-ol, OXANO, reduced form of 2-ethyl-2,4,4-trimethyloxazolidin-3-yloxy). Other hydroxylamine compounds suitable for use in the present invention include (but are not limited to) Hahn et al. (1998, see above; 2000, see above), Samuni et al. (2001, see above); And Paolini et al., US Pat. No. 5,981,548 (disclosing specific N-hydroxypiperidine esters and use as antioxidants in many situations); Gupta et al., US Pat. 404,302 (discloses the use of N-hydroxylamine as a light stabilizer in plastic formulations); Behrens et al., US Pat. No. 4,691,015 (hydroxylamine derived from hindered amines). And the use of specific hydroxylamines to stabilize polyolefins Disclosed in U.S. Pat. Nos. 5,462,946 and 6,605,619 to Mitchell et al. A compound corresponding to hydroxylamine of nitrooxide, that is, compound (1) of the formula R ₃ —N (R ₄ ) (R ₅ ), wherein R ₃ is —OH, and R ₄ and R ₅ are nitrogen metal-dependent hydroxylation of formula _{R 3 -N (R 4) (} R 5); or joined to form a heterocyclic ring, or a compound R ₄ and R ₅ itself has a substituted or unsubstituted ring or heterocyclic group and An amine (2), wherein R ₃ is —OH, R ₄ and R ₅ are bonded to the nitrogen atom to which they are bonded to form a 5- or 6-membered heterocyclic group, The nitrogen atom has one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, or R ₄ and R ₅ are each independently substituted or unsubstituted 5- or 6-membered ring group Or a substituted or unsubstituted 5- or 6-membered heterocyclic group, which is a hydroxylamine having one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; or An oxazolidine compound (3) having the chemical formula,

In the formula, R ₁ is —CH ₃ , and R ₂ is —C ₂ H ₅ , —C ₃ H ₇ , —C ₄ H ₉ , —C ₅ H ₁₁ , —C ₆ H ₁₃ , —CH ₂ CH ( CH ₃ ) ₂ , —CHCH ₃ C ₂ H ₅ , or — (CH ₂ ) ₇ CH ₃ , R ₃ is —OH, or R ₁ and R ₂ are bonded together to form spirocyclopentane, spiro An oxazolidine compound that forms cyclohexane, spirocycloheptane, spirocyclooctane, 5-cholestane or norbornane; and a pharmaceutically acceptable salt of any of the foregoing compounds. As far as is known, the aforementioned compounds have never been used for the treatment and suppression of hepatitis.

  Ester derivatives of hydroxylamine suitable for use in the present invention have compounds of formula I or pharmaceutically acceptable salts thereof, examples of which are reported in detail in US Published Application No. 2004/0002461,

Where
R ₁ and R ₂ are independently H or C ₁ -C ₃ alkyl;
R ₃ and R ₄ are independently C ₁ -C ₃ alkyl, or group R ₁ and R ₂ , group R ₃ and R ₄ , or group R ₁ and R ₂ , group R ₃ and R ₄ together, each cycloalkyl is
R ₅ is H, OH, or C ₁ -C ₆ alkyl;
R ₆ is C ₁ -C ₆ alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl,
R ₇ is C ₁ -C ₆ alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl, or R ₆ and R ₇ are bonded together, and R ₅ , R ₆ , and R ₇ are bonded together. To form a carbocyclic ring having 3 to 7 atoms in the ring or a heterocyclic ring having 3 to 7 atoms in the ring.

  In the methods of the present invention, a composition having a pharmaceutically acceptable carrier or excipient and a hydroxylamine compound having an N-hydroxypiperidine moiety that binds to the moiety with altered solubility is also available, said compound being 25 The solubility in water at 0 ° C is at least about 0.25% by weight and the water / n-octanol partition coefficient at 25 ° C is at least about 5. The composition has an N-hydroxypiperidine moiety that is cleavable from the compound under conditions found in biological tissues, such as those found in the eye. The N-hydroxypiperidine moiety is cleaved by an enzyme. The composition may also be present when the N-hydroxypiperidine moiety is 1-oxy-4-hydroxy-2,2,6,6-tetramethylpiperidyl.

The term C ₁ -C _n alkyl, alkenyl or alkynyl means in the sense of the present invention a hydrocarbyl group having 1 to n carbon atoms therein, where n is 1 to about 20, preferably 1 to It is an integer of about 10, more preferably 1 to about 6, and more preferably 1 to about 3. The term thus includes the various isomers such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and pentyl, hexyl. Similarly, the term includes ethenyl, ethynyl, propenyl, propynyl, and similar branched and unbranched unsaturated hydrocarbon groups of up to n carbon atoms. Where the situation permits, such a group may contain one or more functional groups such as hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, aryloxy, arylamino, benzyloxy, benzylamino, heterocycle, or YCO-Z. Y can be O, N, or S, and Z is an alkyl, cycloalkyl, heterocyclic, or aryl substituent.

  The term carbocycle defines a cyclic structure or ring wherein all atoms forming the ring are carbon. Examples of this are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Cyclopropyl is one preferred class. A heterocycle defines a cyclic structure in which at least one atom of the ring is not carbon. Examples of this broad class include furan, dihydrofuran, tetrahydrofuran, pyran, oxazole, oxazoline, oxazolidine, imidazole, etc., especially those having an oxygen atom in the ring. 5-, 6-, and 7-membered rings having at least one oxygen or nitrogen atom in the ring are suitable heterocycles. Furanyl and tetrahydrofuranyl species and the like are preferred.

Certain embodiments are preferred, wherein each of R ₁ -R ₄ is a C ₁ -C ₃ alkyl lower alkyl. Preferably, these groups are all methyl for convenience of synthesis and because of the effects known for molecules where such substituents are in these positions. However, other substituents can be used.

In certain embodiments, R ₆ is C ₁ -C ₆ alkyl substituted with at least one C ₁ -C ₆ alkoxy or benzyloxy group is employed. Of these, compounds having an ethoxy or benzyloxy substituent are preferred. Each of R ₁ -R ₄ is methyl, R ₅ is H or methyl, R ₆ is methyl substituted with benzyloxy or C ₁ -C ₆ alkoxy, and R ₇ is methyl, or R ₆ and R ₇ form a cyclopropyl group, and R _{1 to} R ₄ are each methyl, R ₅ is methyl, R ₆ is ethoxy or benzyloxymethyl, and R ₇ is methyl Also preferred are compounds. Further preferred compounds are those in which each of R _{1 to} R ₄ is methyl, R ₅ is methyl, R ₆ is hydroxymethyl and R ₇ is methyl.

Other useful compounds are those in which R _{1 to} R ₄ are each methyl, and R ₅ , R ₆ and R ₇ are bonded together to form a furanyl group, or R ₆ and R ₇ are bonded together. To form a tetrahydrofuranyl group. More preferred are compounds wherein R _{1 to} R ₄ are methyl, R ₅ is H, and R ₆ and R ₇ form a cyclopropyl ring. Examples of compounds useful in the method of the present invention include (but are not limited to) 1-oxy-4- (3′-ethoxy-2 ′, 2′-dimethyl) propanecarbonyloxy-2, 2,6-6-tetramethylpiperidine; 1-hydroxy-4- (3′-ethoxy-2 ′, 2′-dimethyl) propanecarbonyloxy-2,2,6,6-tetramethylpiperidine hydrochloride; Oxy-4-cyclopropanecarbonyloxy-2,2,6,6-tetramethylpiperidine; 1-hydroxy-4-cyclopropanecarbonyloxy-2,2,6,6-tetramethylpiperidine hydrochloride; 1-oxy- 4- (3′-benzyloxy-2 ′, 2′-dimethyl) propanecarbonyloxy-2,2,6,6-tetramethylpiperidine; 1-sidroxy-4- (3′-benzyloxy -2 ', 2'-dimethyl) propanecarbonyloxy-2,2,6,6-tetramethylpiperidine hydrochloride; 1-hydroxy-4- (3'-hydroxy-2', 2'-dimethyl) propanecarbonyloxy -2,2,6,6-tetramethylpiperidine hydrochloride; 1-oxy-4- (1-methyl-cyclopropane) carbonyloxy-2,2,6,6-tetramethylpiperidine; 1-hydroxy-4- (1-Methyl-cyclopropane) carbonyloxy-2,2,6,6-tetramethylpiperidine hydrochloride; 1-oxy-4- (2-furan) carbonyloxy-2,2,6,6-tetramethylpiperidine 1-hydroxy-4- (2′-furan) carbonyloxy-2,2,6,6-tetramethylpiperidine hydrochloride; 1-oxy-4- (3′-tetrahydrofura ) Carbonyloxy-2,2,6,6-tetramethylpiperidine; 1-hydroxy-4- (3′-tetrahydrofuran) carbonyloxy-2,2,6,6-tetramethylpiperidine hydrochloride, etc. Includes compounds reported in US 2004/0002461 A1. Especially preferred is 1-hydroxy-4-cyclopropanecarbonyloxy-2,2,6,6-tetramethylpiperidine hydrochloride, referred to herein as Compound 1.

Without sticking to theory, compound 1 (compound of formula 1, wherein R ₁ , R ₂ , R ₃ , and R ₄ are methyl, R ₅ is H, R ₆ and R ₇ Applicants believe that other compounds of Formula I exhibit anti-angiogenic and other therapeutic effects in two ways. First, the ester compound is hydrolyzed in a biological position to form a hydroxylamine component that exhibits therapeutic activity. Secondly, since the esterified compound itself has an antioxidant activity, it is considered to have an inhibitory effect on complement activity, thereby supporting the therapeutic effect of the preparation containing the compound.

  It is known that there are a number of esterases in various body tissues and organs in connection with the first basis for the activity of the compounds of formula I, namely the release of the hydroxylamine component by cleavage. Specific esterases that cleave a series of esters in this study need to be identified in order to practice the present invention.

  The composition follows any method suitable in the art for adjusting a given dosage form and can be adjusted in a variety of dosage forms. Pharmaceutically acceptable carriers can be either solid or liquid. Non-limiting examples of solid formulations include powders, tablets, pills, capsules, medicinal candies, capsules, suppositories, dispersible granules and the like. A solid carrier can include one or more substances which can also act as excipients, flavoring agents, buffering agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, acacia, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyethylene glycol, vegetable oil, agar, low melting wax, coco Including avatars. Non-limiting examples of suitable disintegrants include cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Non-limiting examples of liquid formulations include solutions, suspensions, syrups, slurries, and emulsions. Suitable liquid carriers include, for example, suitable organic or inorganic solvents, preferably in sterile form, such as water, alcohol, saline, saline, buffered saline, dextrose solution, aqueous propylene glycol solution and the like.

  The composition can be formulated as a pharmaceutically acceptable salt and administered to the subject. Non-limiting examples of pharmaceutically acceptable salts include hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate Acid addition salts such as those including benzene sulfonate, p-toluene sulfonate, cyclohexyl sulfamate, and quinate. Such salts can be prepared by established methods known in the art using hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid. , P-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid.

  Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions can also be made by dispersing finely divided active ingredients in water using sticky substances such as natural or synthetic rubbers, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Can do.

  The solid form can be adjusted by any method suitable in the art. For example, a capsule can be prepared by mixing the composition with a suitable excipient and filling the capsule with an appropriate amount of the mixture. Tablets are prepared by direct compression, wet granulation, or dry granulation. These formulations usually include excipients, binders, lubricants, and disintegrants in addition to the compound. Non-limiting examples of excipients include various types of starch, cellulose, crystalline cellulose, microcrystalline cellulose, lactose, fructose, sucrose, mannitol, kaolin, phosphate or calcium sulfate, inorganic salts such as sodium chloride, and Contains powdered sugar. Powdered cellulose derivatives are also useful. Non-limiting examples of tablet binders include starch, gelatin, and sugars such as lactose, fructose, glucose. Natural and synthetic rubbers including acacia, alginate, methylcellulose, polyvinylpyrrolidine and the like can also be used. Polyethylene glycol, ethyl cellulose, and waxes can also be binders.

  A lubricant can be used on the tablets to prevent the tablets and punches from clogging. The lubricant can be selected from solids that slide well, such as talc, magnesium and calcium stearate, stearic acid, and hardened vegetable oils. A tablet disintegrant is a substance that expands when it contains water and disintegrates the tablet to release the compound. Starch such as corn and potato starch, clay, cellulose, algin and gum, methylcellulose, agar, bentonite, wood Contains cellulose, powdered sponge, cation exchange resin, alginic acid, guar gum, citrus pulp, carboxymethylcellulose, and sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with a film-forming protective agent to modify the dissolution characteristics of the tablets. As is well established in the art, the compound can be formulated as a chewable tablet using a large amount of a tasting substance such as mannitol in the formulation.

  In some of the embodiments, the composition can be administered orally. For such administration, the pharmaceutical composition can be in liquid form, such as a solution, syrup, or suspension, or presented as a formulation that is re-dissolved in water or other suitable solvent prior to use. . Such liquid formulations include suspensions (eg, sorbitol syrup, cellulose derivatives or hardened edible fats or oils); emulsifiers (eg, lecithin or acacia); non-aqueous solvents (eg, almond oil, oily esters, or fractional distillation). Vegetable oils); and pharmaceutically acceptable additives such as preservatives (eg methyl or propyl-p-hydroxybenzoate or sorbic acid) and can be prepared in a conventional manner. These preparations can contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like. The composition may be in the form of a powder that is dissolved in a suitable solvent such as sterile water, saline, or alcohol prior to use.

  Compositions for topical administration include, for example, liquid or gel formulations suitable for penetrating through the skin, such as creams, coatings, lotions, ointments or pastes, and administration to the eyes, ears or nose. Including suitable drops.

  In some embodiments, the composition includes creams, drops, application agents, lotions, ointments, and pastes, which are externally applied liquid or semi-solid compositions. Such compositions can be prepared by mixing the powder form alone or as a solution or suspension in an aqueous or non-aqueous liquid using a fatty or non-fatty base. The base may comprise glycerol, various forms of paraffins, complex hydrocarbons such as paraffin, beeswax; rubber glue; mineral or edible oils or fatty acids; or macrogels. Such compositions can further have a suitable surfactant such as a surfactant, and other ingredients such as agar, vegetable gums, suspensions such as cellulose derivatives, and preservatives, antioxidants. .

  The composition can be formulated for use in the eye. Such compositions can be adapted for pharmaceutical use for intraocular injection, as eye drops or for contact lenses, inserts and the like. Intraocular injection includes, but is not limited to, intravitreal, intraretinal, and intrathecal injection. Formulating a compound in sterile water containing the desired diluent, salt, pH, modifier, etc. is well known to those of ordinary skill in the pharmaceutical formulation articulations for making formulations suitable for ocular administration. Injections, eye drops, inserts, contact lenses, gels, and other liquid forms may require slightly different formulations. All such formulations consistent with direct administration to the eye are understood herein.

  In order to minimize possible irritation to the eye, a buffering agent may be used to maintain the pH of any of the ophthalmic compositions of the present invention, such as the ophthalmic formulation, in the range of about 4.0 to 8.0. . In certain embodiments, the pH is maintained at about 3.5 to about 6.0, preferably about 4.0 to about 5.5, with the majority of the hydroxylamine being protonated with the highest water solubility. To be. The buffering agent is a weak acid having a pKa of about 4.0 to about 5.5 and its conjugate base, such as acetic acid / sodium acetate; citric acid / sodium citrate. The hydroxylamine has a pKa of about 6.0. For direct intravitreal or intraocular injection, the formulation should be pH 7.2-7.5, preferably pH 7.3-7.4.

  In particular, the aqueous humor and vitreous humor are present in a highly reducing redox state at a location closest to the lens. Therefore, the ophthalmic preparation of the present invention contains at least one reducing agent or is administered separately from the reducing agent, The amine may be maintained in a reduced form. Suitable reducing agents include N-acetylcysteine, ascorbic acid or salt form, and sodium sulfite or sodium metabisulfite, with ascorbic acid and / or N-acetylcysteine or glutathione being particularly suitable for injection solutions. A combination of N-acetylcysteine and sodium ascorbate can be utilized in various formulations. A metal chelator antioxidant such as EDTA (ethylenediaminetetraacetic acid) or possibly DTPA (diethylenetriaminepentaacetic acid) can be added to keep the hydroxylamine in reduced form.

  The composition can also be formulated for injection into the subject. For injection, the compositions of the invention can be formulated by dissolving in an aqueous solution such as water or alcohol, or a physiologically compatible buffer such as Hank's solution, Ringer's solution, or saline buffer. The solution can contain formulations such as suspending agents, stabilizing agents, and / or dispersing agents. The injectable preparation is prepared as a solid preparation intended to be converted into a liquid preparation suitable for injection immediately before use by dissolving it in a suitable solvent such as sterile water, physiological saline, or alcohol before use. You can also.

  A part of this composition can be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound may be formulated with a suitable polymer or hydrophobic material (eg, as an acceptable emulsion in oil) or ion exchange resin, or as a poorly soluble derivative, eg, a poorly soluble salt. can do. Liposomes and emulsions are well known examples of hydrophilic drug delivery vehicles or carriers.

  The composition can further have one or more additional complement inhibitors. Such inhibitors can be organic or inorganic compounds, biomolecules or fragments, analogs, homologues, complexes or derivatives thereof. Examples include soluble complement receptor 1 (sCR1), anti-C5 antibody, CD59, and compstatin.

  The composition can further comprise one or more antioxidants. Typical reducing agents include mercaptopropionyl glycine, N-acetylcysteine, β-mercaptoethylamine, glutathione, ascorbic acid and its salts, sulfites, or sodium metabisulfite, or the like. In addition, antioxidants can include vitamins E, C, leutein, xanthine, beta-carotene, and minerals such as zinc and selenium.

  Methods and formulations for administering the foregoing compositions are described in Remington's Pharmaceutical Sciences, Mead Publishing Col. , Easton, 20th edition (2003).

  Administration of the composition can be infusion or injection (intravenous, intraarterial, intramuscular, intradermal, subcutaneous, intrathecal, duodenum, intraperitoneal, intraocular, etc.). The composition can also be administered intranasally, vaginally, rectally, orally, topically, or transdermally. Preferably, the composition is administered orally. Administration can be at the discretion of the physician.

  For buccal administration, the composition can be in the form of a tablet, troche or medicinal candy formulated by conventional methods. Formulations for oral or buccal administration can be formulated to release the active compound in a controlled manner. Such formulations can include one or more sustained release agents known in the art, such as glyceryl monostearate, glyceryl distearate, and waxes.

  The composition can be administered topically. Such administration includes topically applying the composition to the epidermis, oral cavity, eyes, ears, and nose. This is in contrast to systemic administration achieved with oral, intravenous, intraperitoneal, and intramuscular administration.

  Various alternative drug delivery systems are also available. Non-limiting examples of such systems include liposomes and emulsions. Certain organic solvents such as dimethyl sulfoxide can also be used. Further, the composition can be delivered by a sustained release formulation, such as a solid polymer semipermeable substrate containing the therapeutic agent. The various sustained release formulations that can be utilized are well known to those skilled in the art. Sustained release capsules release the compound over a period of days, weeks or months, depending on their chemical nature.

  The composition can be delivered topically to the eye as an eye drop or eye wash, or as a topical ointment. In some preferred embodiments, the composition is administered to the eye by regular subconjunctival or intraocular injection. A more preferred method of administration is the eye, preferably the macula and retina, and most preferably the eye where drusen may be deposited, such as proximal to the retina or between the pigment epithelium of the retina and the Bruch's membrane. A method of providing continuous administration to the site of

  The composition may include other ophthalmic dosage forms known to those skilled in the art, such as preformed or in-situ gels or liposomes as reported, for example, in Herrero-Vanrel, US Pat. No. 5,718,922. It can be applied to. To treat other ophthalmic diseases, a method of injecting the drug directly into the vitreous cavity has been reported and microspheres or liposomes have been used to gradually release the drug (Moritera, T. et al. “Microspheres of biogradable polymers”. as a drug-delivery system in the vitreous "Invest. Ophthalmol. Vis. Sci. 1991 32 (6): 1785-90).

  The composition may be applied to the lens of the eye in need of treatment via a contact lens (eg, Lidofilcon B, Bausch & Lomb CW79 or DELTACON (Deltafilcon A)) or other object temporarily placed on the ocular surface, or It can be administered through the lens. For example, in US Pat. No. 6,410,045, the contact lens, which can be delivered to ocular fluid, absorbs a drug at a concentration of 0.05% to 0.25% by weight and contains a high A contact lens type drug delivery device having a molecular hydrogel contact lens is reported.

  In other embodiments, a support such as a collagen corneal shield (eg, BIO-COR absorbable corneal shield, Summit Technology, Watertown, Mass.) May be utilized. By means of a cannula from an osmotic pump (ALZET®, Alza Corp., Palo Alto, Calif.) Or a sustained release capsule (OCCUSENT®) or biodegradable disc (OCULEX®) containing the composition (Trademark), OCUSERT (registered trademark)), and the composition can be administered by injecting into the eyeball. These administration routes have the advantage that the composition can be continuously supplied to the eye. This is considered to be an advantage of locally delivering the hydroxylamine compound to the vitreous humor.

  Several other types of administration systems are available that are particularly suitable for administering pharmaceutical compositions inside the eye. For example, Parel et al., US Pat. No. 6,154,671, discloses an apparatus for moving a drug to the eyeball by iontophoresis. The device utilizes a reservoir layer holding the active substance and includes at least one active surface electrode facing the ocular tissue around the cornea. The storage layer also has a counter electrode that contacts the partially closed eyelid of the patient. Wong et al., US Pat. No. 5,869,079, reports a combination of hydrophilic and hydrophobic components for a biodegradable sustained release intraocular implant. Further, Guo et al., US Pat. No. 6,375,972, Chen et al., US Pat. No. 5,902,598, Wong et al., US Pat. No. 6,331,313, Ogura et al. In U.S. Pat. No. 5,707,643, Weiner et al. U.S. Pat. No. 5,466,233, and Avery et al. U.S. Pat. No. 6,251,090, respectively, compounds of the present invention are described. Disclosed are intraocular implant devices and systems that can be used to deliver pharmaceutical compositions having the same.

  Intraocular implants that deliver drugs to the eye are well known in the art. For example, US Pat. No. 6,726,918 reports a method of treating a condition mediated by ocular inflammation, which includes biodegradable implants with steroidal anti-inflammatory drugs and biodegradable polymers. Delivering the drug to the vitreous in an amount sufficient to reach a concentration corresponding to at least about 0.05 μg / ml dexamethasone within about 48 hours. And maintain a concentration corresponding to at least about 0.03 μg / ml dexamethasone for about 3 weeks. Such an implant is particularly suitable for the method of the invention.

  US Pat. No. 6,713,081 reports an intraocular implant device that delivers therapeutic agents to the eye in a controlled and sustained manner. Dual-mode and single-mode drug delivery devices are shown and reported. Implants suitable for subconjunctival and intravitreal implantation have been reported. The patent also reports on the manufacture and implementation associated with intraocular implant devices.

  US Pat. No. 6,429,194 pre-soaks or stores an object to be inserted into the eye, such as an aqueous ophthalmic formulation that drops into the eye, or a solid device that is inserted into a contact lens, ointment, or conjunctival sac. Reports on aqueous ophthalmic preparations. The ophthalmic preparation includes a mucin component equivalent to that found on the surface of normal human eyes.

  In US Pat. No. 6,251,090, a wide range of beneficial drugs, including drugs or other pharmacological substances, can be introduced into the vitreous cavity over a long period of time with only one initial operation of implanting the device Intravitreal drug delivery devices, methods, and implant devices are reported. The devices and methods minimize the surgical incision required for implantation and avoid invasive surgery or procedures that will be performed or repeated in the future. The additional amount of initial drug can be easily introduced, or the drug can be varied or changed as needed. Further, the device and method can control the dose delivered to the vitreous cavity and the patient can manage the timing of the delivery. The device is designed to filter the drug delivered to the vitreous cavity and not damage or interfere with other parts of the eye during implantation or use.

  US Pat. No. 5,824,072 reports a biocompatible intraocular implant with an active drug that is utilized for therapeutic purposes for introduction into the suprachoroidal space or the avascular field of the eye. The administration of the drug is managed and maintained for a long time while ensuring that there is no significant amount at a significant level other than the administration site.

  US Pat. No. 5,773,019 reports a continuous release drug delivery implant that can be implanted either on the outer surface of the eye or within the eye, among other mentioned sites. The center of the drug is covered with a polymer coating layer that allows the poorly soluble drug to permeate, and the release rate is not limited.

  US Pat. No. 5,773,021 reports a bioadhesive intraocular insert that is placed in the conjunctival sac. The insert is prepared by extruding, thermoforming, or hot compressing a polymeric matrix material to deliver the drug. The polymer substrate comprises a water-soluble biocompatible polymer such as hydroxyalkyl cellulose, maltodextrin, chitosan, modified starch, or polyvinyl alcohol; a water-insoluble biocompatible polymer such as alkyl cellulose. Where applicable, bioadhesive polymers such as polyvinyl carboxylic acid type polymers, or specific bioadhesive polysaccharides or derivatives thereof can be used. The intraocular insert is intended for long term and controlled release of drugs and is characterized in the patent.

  US Pat. Nos. 5,443,505 and 5,766,242 report on implants with active drugs that are introduced into the suprachoroidal space or avascular field of the eye and have microcortises with hydrocortisone in the flats Reports on capsule and plaque placement.

  US Pat. No. 5,378,475 reports a sustained release implant that is inserted into the vitreous of the eye. The implant includes a first impermeable coating, such as ethylene vinyl acetate, that surrounds most but not all of the drug storage layer, and the first coating that does not cover the drug storage layer. A second permeable coating, such as a permeable crosslinked polyvinyl alcohol, placed over the coating provides a location where the drug can diffuse out of the implant.

  US Pat. No. 5,725,493 reports an intraocular implant device that provides a drug to the vitreous cavity over an extended period of time. The drug reservoir layer is attached to the outside of the eye and there is a passage through which the drug can enter the vitreous cavity of the eye.

  US Pat. No. 5,164,188 reports on capsules that are introduced onto the choroid of the eye and reports on the placement of microcapsules with hydrocortisone and plaques in the flat.

  US Pat. No. 4,997,652 reports biodegradable intraocular implants with microcapsules and describes a method for implanting microcapsules with hydrocortisone succinate in the back of the eye.

  US Pat. No. 4,014,335 reports an intraocular drug delivery device placed in the sac between the pleura and the lower eyelid that administers the drug and functions as a reservoir. The intraocular device is characterized in the patent as administering a drug to the eye in a continuous administration in a controlled state over an extended period of time. To accomplish this, the intraocular device has a three-layer laminate of polymeric material that retains the drug in the central storage area of the laminate. The drug diffuses from the storage layer through at least one of the polymer layers of the laminate.

  US Pat. No. 4,300,557 describes a drug-fillable capsule that functions as an intraocular implant. The capsule is inserted into the vitreous region of the eye by incising the eye, inserting the capsule, and closing the incision. The capsule can remain in place for a period of time and can be removed by making a second surgical incision in the eye and retrieving the device. The capsule has an accessory tube that passes through the surface of the eye, extends out of the eye, and is useful for subsequent drug infusion. The device is not fixed while in the vitreous and can move almost freely.

  Zhou et al. Disclose a multi-drug implant with 5-fluorouridine, triamcinolone, and human genetically engineered tissue plasminogen activator for intraocular treatment of proliferative vitreoretinopathy (PVR) ( Zhou, T, et al., 1998, “Development of multiple-drug delivery imperative for intra management of proliferative vitality1 on J. 55”.

  The composition utilized in accordance with the method of the present invention can include one or more hydroxylamine compounds. In some embodiments, two or more hydroxylamines are administered simultaneously. In other embodiments, they are administered sequentially.

  Compositions of the invention that treat a condition mediated by complement or drusen can also be co-administered with other well-known therapeutic agents selected to be particularly useful for the condition being treated. For example, such therapeutic agents can be analgesics, anti-inflammatory drugs, antibiotics, antiviral drugs, anti-cirrhotic drugs, or other known drugs that treat or inhibit such symptoms.

  The administration of these additional compounds can be performed simultaneously with the administration of the hydroxylamine compound, or can be administered before or after administration of the hydroxylamine compound as necessary. Any suitable protocol can be devised in which the various compounds included in the combination therapy are administered within minutes, hours, days, or weeks of each other. Repeated administration in a periodic protocol is also intended to be within the scope of the present invention.

  In order to treat a subject's complement or drusen mediated pathology, a therapeutically effective amount of a composition having a pharmaceutically acceptable carrier and at least one hydroxylamine compound or ester derivative thereof is administered to the subject. A therapeutically effective amount provides clinically significant suppression of localized or systemic inflammation, suppression of drusen deposition, suppression or reduction of the rate of macular exacerbation, and the like. The composition is administered to all animals, particularly mammals such as dogs, cats, rats, mice, rabbits, horses, pigs, cows, sheep, donkeys, and preferably to humans.

  Effective amounts of the composition include, but are not limited to, species, race, size, height, weight, age, general health status of the subject, type of formulation, method of administration, or the complement or It is thought to depend on a number of variables including the severity of the condition via druse, or other related conditions. An appropriate effective amount can be routinely determined by one of ordinary skill in the art using routine optimization methods and judgments supported by the practitioner's skill and information, and other factors apparent to those skilled in the art. Preferably, a therapeutically effective amount of a compound described herein provides a therapeutic benefit without causing significant toxicity to the subject.

  Toxic and therapeutic effects of drugs or compounds are standard using cell cultures or experimental animals, eg, determination of LD50 (dose that causes 50% of the population to die) and ED50 (dose that is therapeutically effective in 50% of the population). It can be determined by various pharmaceutical methods. The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Drugs or compositions that exhibit large therapeutic indices are preferred. The dosage of such drugs or compositions is preferably within a range of circulating blood concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration utilized.

  For compositions used in the methods of the invention, the therapeutically effective dose can be estimated initially from in vitro assays, such as cell culture assays. For example, defining a dose in an animal model and achieving a range of circulating plasma concentrations that includes an IC50 determined in cell culture (ie, the concentration of the composition that achieves half-suppression of osteoclast formation or activation) can do. Such information can be used to more accurately determine useful doses in specific subjects such as humans. The treating physician may terminate, discontinue, or adjust the dosage due to toxicity or organ dysfunction, and if necessary, if the clinical response is not sufficient to improve the clinical response Treatment can also be adjusted.

  In the method of the present invention, the composition has a concentration of hydroxylamine compound in the range of about 0.01% to about 90% dry weight of the composition. The daily dose range is preferably about 0.01 mg / kg to about 100 mg / kg per body weight of the subject. Preferably, the daily dose ranges from about 0.1 mg / kg to about 50 mg / kg of the subject's body weight. More preferably, the daily dose ranges from about 1 mg / kg to about 10 mg / kg of the subject's body weight.

  In preferred embodiments, administering to a subject a composition having a hydroxylamine compound results in a range of about 0.1 μM to about 10 mM in the subject's tissues and fluids, preferably the eye, more preferably the macula or retina. A concentration of the hydroxylamine component can be achieved. In some embodiments, the range is 1 μm to 5 mM, and in other embodiments the range is about 10 μM to 2.5 mM. In still other embodiments, the range is about 50 μM to 1 mM. Most preferably, the range of hydroxylamine concentration is 1-100 μM in the tissue and fluid of the subject, preferably the eye, more preferably the macula or retina. In an embodiment in which a reducing agent is contained in the preparation or a reducing agent is administered separately, the concentration of the reducing agent is 1 μM to 5 mM in the tissues and body fluids to which the composition is administered, particularly in the eye, preferably Is in the range of 10 μM to 2 mM. The component concentrations of the composition are adjusted to suit the route of administration as appropriate by typical pharmacokinetics and dilution calculations to achieve the local concentrations.

  Treatment can be initiated with a sub-optimal amount of the hydroxylamine compound, and then the dose can be increased over the course of treatment until the optimal effect under that condition is achieved. If necessary, the total daily dose can be divided and administered in portions during the day.

  For effective treatment of a condition via complement or drusen, one of skill in the art may also recommend an appropriate dosing schedule and dosage for the subject being treated. It is preferred to administer 1 to 4 times a day as long as necessary. When the composition is formulated as a sustained release formulation, the frequency of administration can be reduced. The dosing schedule can be varied depending on the active drug concentration, which may vary depending on the needs of the subject.

  The present invention is not limited to the embodiments described above, but can be changed and modified within the scope of the appended claims.

Claims (51)

A method of inhibiting complement activation in a subject comprising:
Administering to the subject an effective amount of a hydroxylamine compound or an ester derivative thereof that inhibits complement activation of the subject,
The ester derivative of the hydroxylamine compound has the following chemical formula:

Where
R ₁ and R ₂ are independently H or C ₁ -C ₃ alkyl;
R ₃ and R ₄ are independently C ₁ -C ₃ alkyl, or R ₁ and R ₂ are bonded together, R ₃ and R ₄ are bonded together, or R ₁ and R ₄ are bonded together. ₂ are bonded together, R ₃ and R ₄ are bonded together, and each is cycloalkyl,
R ₅ is H, OH, or C ₁ -C ₆ alkyl;
R ₆ is C ₁ -C ₆ alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl,
R ₇ is C ₁ -C ₆ alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl, or R ₆ and R ₇ are bonded together, and R ₅ , R ₆ and R ₇ are bonded together , Forming a carbocyclic ring having 3 to 7 atoms in the ring, or forming a heterocyclic ring having 3 to 7 atoms in the ring,
Method. The method of claim 1, wherein the hydroxylamine compound has the following structure:

Have The method of claim 1, _{wherein, R 1, R 2, R} 3, and _{R 4} are each independently _C 1 -C ₃ alkyl. The method of claim 1, _{wherein, R 1, R 2, R} 3, and _{R 4} is ethyl. The method of claim 1, _{wherein, R 1, R 2, R} 3, and _{R 4} are methyl. _6. The method of claim 5, wherein R ₅ is H or methyl, R ₆ is methyl substituted with benzyloxy or C ₁ -C ₆ alkoxy, and R ₇ is methyl. _6. The method according to claim 5, wherein R ₅ is H or methyl, and R ₆ and R ₇ are bonded together to form a cyclopropyl group. The method of claim 5, wherein the R _5, and R _6, in which and R ₇ together form a bond to furanyl group. _6. The method according to claim 5, wherein R ₅ is H, and R ₆ and R ₇ are bonded together to form a tetrahydrofuranyl group. _6. The method according to claim 5, wherein R ₅ is H, and R ₆ and R ₇ are bonded together to form a cyclopropyl group.   2. The method of claim 1, wherein the subject is a mammal.   12. The method of claim 11, wherein the mammal is a human.   2. The method according to claim 1, wherein the hydroxylamine compound or an ester derivative thereof suppresses the formation of C3a anaphylatoxin.   2. The method according to claim 1, wherein the hydroxylamine compound or an ester derivative thereof suppresses formation of C5a anaphylatoxin. A method of treating a subject having a condition mediated by complement activation comprising:
Administering to said subject a composition having an effective amount of a pharmaceutically acceptable carrier and at least one hydroxylamine compound or ester derivative thereof to inhibit complement activation of said subject;
The ester derivative of the hydroxylamine compound has the following chemical formula:

Where
R ₁ and R ₂ are independently H or C ₁ -C ₃ alkyl;
R ₃ and R ₄ are independently C ₁ -C ₃ alkyl, or R ₁ and R ₂ are bonded together, R ₃ and R ₄ are bonded together, or R ₁ and R ₂ Are bonded together, R ₃ and R ₄ are bonded together, and each is cycloalkyl,
R ₅ is H, OH, or C ₁ -C ₆ alkyl;
R ₆ is C ₁ -C ₆ alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl,
R ₇ is C ₁ -C ₆ alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl, or R ₆ and R ₇ are bonded together, and R ₅ , R ₆ , and R ₇ are bonded together. A carbocyclic ring having 3 to 7 atoms in the ring or a heterocyclic ring having 3 to 7 atoms in the ring. 16. The method of claim 15, wherein the hydroxylamine compound has the structure

It is what has. The method of claim 15 _{wherein, R 1, R 2, R} 3, and _{R 4} are each independently _C 1 -C ₃ alkyl. In method of claim _{15, R 1, R 2, R} 3, and _{R 4} is ethyl. The method of claim 15 _{wherein, R 1, R 2, R} 3, and _{R 4} are methyl. The method of claim 19 wherein, _{R 5} is H or methyl, _{R 6} is methyl substituted with benzyloxy or _C 1 -C ₆ alkoxy, _{R 7} is methyl. The method according to claim 19, wherein R ₅ is H or methyl, and R ₆ and R ₇ are bonded together to form a cyclopropyl group. The method according to claim 19, wherein R ₅ , R ₆ and R ₇ are bonded together to form a furanyl group. The method of claim 19 wherein, R ₅ is H, and forms a tetrahydrofuranyl group attached R ₆ and R ₇ are both. 20. The method of claim 19, wherein R ₅ is H and R ₆ and R ₇ are joined together to form a cyclopropyl group.   16. The method of claim 15, wherein the subject is a mammal.   26. The method of claim 25, wherein the mammal is a human.   16. The method of claim 15, wherein the composition is administered to the eye of the subject.   28. The method of claim 27, wherein the composition is administered to the macular of the eye.   28. The method of claim 27, wherein the composition is administered to the retina of the eye.   28. The method of claim 27, wherein the composition is administered to achieve a hydroxylamine concentration of about 0.1 [mu] M to about 10 mM in the subject's eye.   28. The method of claim 27, wherein the composition is administered to achieve a hydroxylamine concentration of about 1 [mu] M to about 5 mM in the subject's eye.   28. The method of claim 27, wherein the composition is administered to achieve a hydroxylamine concentration of about 10 [mu] M to about 2.5 mM in the subject's eye.   28. The method of claim 27, wherein the composition is administered to achieve a hydroxylamine concentration of about 50 [mu] M to about 1 mM in the subject's eye.   28. The method of claim 27, wherein the composition is administered to achieve a hydroxylamine concentration of about 1 [mu] M to about 100 [mu] M in the subject's eye.   28. The method of claim 27, wherein the condition is drusen formation.   28. The method of claim 27, wherein the condition is macular degeneration.   40. The method of claim 36, wherein the macular degeneration is age-related macular degeneration.   16. The method according to claim 15, wherein the hydroxylamine compound or an ester derivative thereof suppresses the formation of C3a anaphylatoxin.   16. The method according to claim 15, wherein the hydroxylamine compound or an ester derivative thereof suppresses formation of C5a anaphylatoxin. A method of suppressing drusen formation of a subject, comprising the step of administering a hydroxylamine compound or an ester derivative thereof to the subject in an amount effective to inhibit drusen formation of the subject, and an ester of the hydroxylamine compound The derivative has the following chemical formula:

Where
R ₁ and R ₂ are independently H or C ₁ -C ₃ alkyl;
R ₃ and R ₄ are independently C ₁ -C ₃ alkyl, or R ₁ and R ₂ are bonded together, R ₃ and R ₄ are bonded together, or R ₁ and R ₂ Are bonded together, R ₃ and R ₄ are bonded together, and each is cycloalkyl,
R ₅ is H, OH, or C ₁ -C ₆ alkyl;
R ₆ is C ₁ -C ₆ alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl,
R ₇ is C ₁ -C ₆ alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl, or R ₆ and R ₇ are bonded together, and R ₅ , R ₆ , and R ₇ are bonded together And forming a carbocyclic ring having 3 to 7 atoms in the ring, or forming a heterocyclic ring having 3 to 7 atoms in a ring. 41. The method of claim 40, wherein the hydroxylamine compound has the structure

It is what has. The method of claim 40 _{wherein, R 1, R 2, R} 3, and _{R 4} are each independently _C 1 -C ₃ alkyl. The method of claim 40 _{wherein, R 1, R 2, R} 3, and _{R 4} is ethyl. The method of claim 40 _{wherein, R 1, R 2, R} 3, and _{R 4} are methyl. 45. The method of claim 44, wherein R ₅ is H or methyl, R ₆ is methyl substituted with benzyloxy or C ₁ -C ₆ alkoxy, and R ₇ is methyl. The method of claim 44 wherein, R ₅ is H or methyl, is to form a cyclopropyl group attached R ₆ and R ₇ are both. The method of claim 44, wherein the R _5, and R _6, in which R ₇ together form a bond to furanyl group. The method of claim 44 wherein, R ₅ is H, and forms a tetrahydrofuranyl group attached R ₆ and R ₇ together. 45. The method of claim 44, wherein R ₅ is H and R ₆ and R ₇ are joined together to form a cyclopropyl group.   41. The method of claim 40, wherein the subject is a mammal.   41. The method of claim 40, wherein the mammal is a human.