阅读说明：本技术 异吲哚啉衍生物用于治疗免疫球蛋白E（IgE）介导的疾病的应用 (Use of isoindoline derivatives for the treatment of immunoglobulin E (IgE) -mediated diseases ) 是由 张和胜 曾广怀 付伟 于 2019-04-16 设计创作，主要内容包括：公开了2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲磺酰基乙基]-4-乙酰基氨基异吲哚啉-1,3-二酮、其立体异构体或其药物可接受的盐在治疗免疫球蛋白E(IgE)介导的疾病的方法的应用。(2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is disclosed for use in a method of treating an immunoglobulin E (IgE) -mediated disease.)

1. A method of treating an immunoglobulin e (ige) -mediated disease comprising administering to a subject in need thereof a therapeutically effective amount of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

2. 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, including, but not limited to, (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, or (R) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione.

3. The method of claims 1-2, wherein the subject is a mammal, preferably a human.

4. The method of claims 1-2, wherein the disease is selected from the group consisting of urticaria, asthma-COPD overlap syndrome (ACOS), seasonal allergic rhinitis, drug-induced interstitial pneumonia, bronchopulmonary aspergillosis, leprosy, pemphigus vulgaris, and parasitic infections.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of immunoglobulin e (ige) -mediated diseases.

6. A method of treating an immunoglobulin e (ige) -mediated disease comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

7. The method of claim 6, wherein the disease is selected from urticaria, asthma-COPD overlap syndrome (ACOS), seasonal allergic rhinitis, drug-induced interstitial pneumonia, bronchopulmonary aspergillosis, leprosy, pemphigus vulgaris, and parasitic infections.

Brief description of the drawings

Figure 1 illustrates the model animal induction and administration method of biological example 2 of the present disclosure.

Detailed description of the invention

In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth.

Throughout this specification and the claims which follow, unless the disclosure requires otherwise, the words "comprise" and "comprise" are to be construed in an open, inclusive sense, i.e., "including but not limited to".

Reference throughout this specification to "one embodiment" or "another embodiment" or "an embodiment" or "certain embodiments" means that a particular reference element, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "one embodiment" or "an embodiment" or "another embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

It should be understood that, as used in the specification of the present disclosure and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a pharmaceutical composition comprising "a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof" includes a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or two or more compounds of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Definition of

Accordingly, unless indicated to the contrary, the following terms used in the specification and appended claims have the following meanings:

in the present disclosure, the term "a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof" refers to 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione of the present disclosure, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof.

In the present disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cattle, sheep, horses, and humans. In certain embodiments, the mammal comprises a human.

In the present disclosure, the term "patient" refers to animals (e.g., humans), companion animals (e.g., dogs, cats or horses), and livestock (e.g., cattle, pigs and sheep). In certain embodiments, the patient is a mammal including a male and a female. In certain embodiments, the patient is a human.

In the present disclosure, the term "pharmaceutically acceptable" refers to carriers, diluents, excipients, and/or salts that must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

In the present disclosure, the term "any" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

In the present disclosure, the term "pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier, and the like, which has been recognized by the U.S. food and drug administration as being useful for humans or animals in a variety of forms that do not have side effects on the constituent pharmaceutical compositions.

In the present disclosure, the term "carrier" is defined as a compound that facilitates the introduction of the compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is commonly used as a carrier because it facilitates the introduction of certain organic compounds into cells or tissues of an organism.

In the present disclosure, the term "pharmaceutically acceptable salts" includes "acceptable acid addition salts" and "acceptable base addition salts".

In the present disclosure, the term "acceptable acid addition salts" refers to those salts that retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and are formed using inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, and the like, Mucic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

In the present disclosure, the term "acceptable base addition salts" refers to those salts that retain the biological effectiveness and properties of the free acid, which are biologically or otherwise suitable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, salts of cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benzylamine, phenylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. In certain embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

In the present disclosure, the term "solvent or solvent mixture" refers to any and all solvents. In certain embodiments, the solvent or solvent mixture is an organic solvent and water, including, but not limited to, methanol, ethanol, 2-propanol, N-butanol, isobutanol, acetone, methyl ethyl ketone, ethyl acetate, 1, 4-dioxane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, N-dimethylformamide, cyclohexane, cyclopentane, N-hexane, N-heptane, N-pentane, toluene, o-xylene, p-xylene, dimethyl sulfoxide (DMSO), pyridine, acetic acid, anisole, butyl acetate, cumene, ethyl formate, formic acid, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl isobutyl ketone, 2-methyl-1-propanol, 1-pentanol, propyl acetate, ethylene glycol, and 1-methyl-2-pyrrolidone, and mixtures of any and all two or more such solvents. In certain embodiments, the solvent or solvent mixture is a single solvent and a binary mixture. In certain embodiments, the solvent or solvent mixture is a single solvent of water and an organic solvent and a binary mixture of water and an organic solvent.

In the present disclosure, the term "pharmaceutical composition" refers to a formulation of a compound described in the present disclosure with a vehicle generally accepted in the art for delivery of bioactivating compounds to mammals such as humans. Such media include all pharmaceutically acceptable carriers, diluents or excipients.

In the present disclosure, the term "therapeutically effective amount" refers to an amount of a compound or combination of compounds that ameliorates, reduces, or eliminates a particular disease or condition and symptoms of a particular disease or condition, or avoids or delays the onset of a particular disease or condition or symptoms of a particular disease or condition. The amount of the compound described in this disclosure that constitutes a "therapeutically effective amount" will vary according to the compound, the disease state and its severity, and the age, weight, etc., of the mammal to be treated, but can be determined routinely by those skilled in the art, based on their own knowledge and this disclosure.

As used in this disclosure, "treating" or "treatment" encompasses treating a related disease or condition in a mammal, such as a human, suffering from the related disease or condition and includes:

(i) preventing the occurrence of a disease or condition in a mammal, particularly when the mammal is susceptible to said disease condition but has not been diagnosed as having such a disease condition;

(ii) inhibiting a disease or disease state, i.e., preventing its occurrence; or

(iii) Alleviating the disease or condition, even if the disease or condition regresses or does not progress.

As used in this disclosure, the terms "disease" and "disease state" may be used interchangeably, or may be different, in that a particular disease or disease state may not have a known causative agent (and therefore cannot be explained by etiology), and thus is not recognized as a disease, but rather is considered an undesirable disease state or condition, in which a clinician has identified a more or less specific series of symptoms.

In the present disclosure, the term "physiologically acceptable" refers to a carrier or diluent that does not abrogate the biological activity and properties of the compound.

The compounds described in the present disclosure, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers, and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined as (R) -or (S) -, or (D) -or (L) -, of amino acids, in terms of absolute stereochemistry. The present disclosure is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R) -and (S) -, or (D) -and (L) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC using a chiral column. When a compound described in this disclosure contains an olefinic double bond or other center of geometric asymmetry, unless otherwise indicated, it is meant that the compound includes both E and Z geometric isomers. Likewise, all tautomeric forms are also meant to be included.

In the present disclosure, the term "stereoisomer" refers to a compound consisting of the same atoms bonded by the same bonds, but having different three-dimensional structures that are not interchangeable. The present disclosure encompasses various stereoisomers and mixtures thereof.

Detailed description of the preferred embodiments

The isoindoline derivative refers to 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof includes, but is not limited to, (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, or (R) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione.

In one aspect, the disclosure relates to methods of treating immunoglobulin E (IgE) -mediated diseases, comprising administering to a subject in need thereof a therapeutically effective amount of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or administering a therapeutically effective amount of a pharmaceutical composition comprising 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

In yet another aspect, the present disclosure relates to 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating immunoglobulin e (ige) -mediated diseases.

In yet another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient for treating an immunoglobulin e (ige) -mediated disease.

In one aspect, the disclosure relates to methods of treating immunoglobulin E (IgE) -mediated diseases, comprising administering to a subject in need thereof a therapeutically effective amount of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or administering a therapeutically effective amount of a pharmaceutical composition comprising 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient:

in certain embodiments, a method of treating an immunoglobulin e (ige) -mediated disease, comprising administering to a subject in need thereof 1mg to 10g of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a method of treating an immunoglobulin e (ige) -mediated disease, comprising administering to a subject in need thereof 1mg to 3000mg of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a method of treating an immunoglobulin e (ige) -mediated disease, comprising administering to a subject in need thereof 10mg to 1000mg of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a method of treating an immunoglobulin e (ige) -mediated disease, comprising administering to a subject in need thereof 100mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, or 1000mg of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present disclosure relates to 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating immunoglobulin e (ige) -mediated diseases.

In yet another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient for treating an immunoglobulin e (ige) -mediated disease.

In yet another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient for treating an immunoglobulin e (ige) -mediated immunological or allergic disease.

In yet another aspect, the present disclosure relates to a pharmaceutical composition for treating urticaria, asthma-COPD overlap syndrome (ACOS), seasonal allergic rhinitis, drug-induced interstitial pneumonia, bronchopulmonary aspergillosis, leprosy, pemphigus, and parasitic infections comprising a therapeutically effective amount of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

In yet another aspect, the present disclosure relates to a pharmaceutical composition for treating immunoglobulin e (ige) -mediated urticaria, asthma-COPD overlap syndrome (ACOS), seasonal allergic rhinitis, drug-induced interstitial pneumonia, bronchopulmonary aspergillosis, leprosy, pemphigus and parasitic infections comprising a therapeutically effective amount of a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

Pharmaceutical composition

In certain embodiments, a pharmaceutical composition comprises a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

In certain embodiments, the route of administration of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for administration to a mammal for the treatment of an immunoglobulin e (ige) -mediated disease may be a parenteral route or a non-parenteral route.

In certain embodiments, the route of administration of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for treating an immunoglobulin e (ige) -mediated disease when administered to a mammal may be an oral route.

In certain embodiments, the route of administration of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for treating an immunoglobulin e (ige) -mediated disease when administered to a mammal may be an intrarectal route.

The compounds described in the present disclosure may be obtained in any suitable form such as tablets, capsules, powders, oral solutions, suspensions, rectal gels, rectal foams, rectal enemas, or rectal suppositories and the like. Illustrative examples of the tablet include, but are not limited to, plain tablets, sugar-coated tablets, and film-coated tablets.

Examples of pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been recognized by the U.S. food and drug administration as being useful for humans or animals in a variety of forms of carriers that do not have side effects on the constituent pharmaceutical compositions. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical arts and are described, for example, in Remington's pharmaceutical Sciences, 18th ed., Mack Publishing co., Easton, PA (1990)), the entire contents of which are incorporated herein by reference.

The pharmaceutical compositions of the present disclosure may be administered by any method that achieves their intended purpose. For example, administration can be by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intra-articular, intraspinal, transtracheal, ocular, subcutaneous, intraperitoneal, transdermal, or buccal routes. The route of administration may be parenteral, oral, and intrarectal. The dose administered will depend on the age, health and weight of the recipient, and on the type of concurrent treatment, if any, the frequency of the treatment, and the nature of the effect desired.

Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, dragees (dragees), semi-solid formulations, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tape (tape), eye drops, solutions, syrups, aerosols, suspensions, emulsions, which can be prepared according to methods known in the art.

Particularly suitable for oral administration are tablets (plain tablets), sugar-coated tablets, film-coated tablets, pills, capsules, powders, granules, syrups, juices (juice) or drops, for rectal administration are suppositories, for parenteral administration are solutions, also oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, for topical use are ointments, creams or powders. The products of the present disclosure may also be lyophilized, the resulting lyophilizates being used, for example, for the preparation of injections. The given formulations can be sterilized and/or contain adjuvants (assistant), such as wetting agents, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for varying the osmotic pressure, buffer substances, dyes, flavors, and/or numerous additional active ingredients, for example one or more vitamins.

In certain embodiments, the pharmaceutical compositions of the present disclosure are prepared as tablets, solutions, granules, patches, ointments, capsules, aerosols or suppositories for parenteral, transdermal, mucosal, nasal, buccal, sublingual or oral use.

Preservatives, stabilizers, dyes, sweeteners, flavoring agents, perfumes and the like may be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used.

In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methyl aluminate silicate, synthetic aluminum silicate, calcium carbonate, calcium hydrogen phosphate, calcium hydroxymethylcellulose, etc. can be used as excipients; magnesium stearate, talc, hardened oil, etc. may be used as a smoothing agent; coconut oil, olive oil, sesame oil, peanut oil, soybean can be used as suspension or lubricant; cellulose acetate phthalate, which is a derivative of a saccharide such as cellulose or a sugar, or a methyl acetate-methacrylate copolymer, which is a derivative of polyethylene, may be used as the suspension; and plasticizers such as phthalate esters and the like may be used as the suspending agent.

Suitable routes of administration may include, for example, oral, rectal, transmucosal, parenteral delivery, topical, or enteral administration; parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections. The compounds can also be administered in sustained or controlled release dosage forms including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches and the like, for extended and/or timed, pulsatile administration at a predetermined rate.

The pharmaceutical compositions of the present disclosure may be manufactured in accordance with known procedures, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting operations.

Thus, in accordance with the present disclosure, the pharmaceutical compositions employed may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Suitable formulations depend on the chosen route of administration. Any of the well known techniques, carriers and excipients may be used as is appropriate and understood in the art.

Injections can be prepared in the following conventional forms: as a solution or suspension, a solid dosage form suitable for formulation as a solution or suspension prior to injection, or as an emulsion. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like. In addition, the injectable pharmaceutical composition may contain, if necessary, small amounts of nontoxic auxiliary substances such as wetting agents, pH buffering agents and the like. Physiologically suitable buffers include, but are not limited to, Hank's solution, Ringer's solution, or physiological saline buffer. If desired, absorption enhancing agents (e.g., liposomes) can be used.

For oral administration, the compounds can be readily formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, capsules, liquids, gels, syrups, slurries, suspensions, solutions, powders, and the like, for oral ingestion by a patient to be treated. A pharmaceutical preparation for oral administration can be obtained by: the active compound is mixed with a solid excipient, the mixture obtained is optionally ground and the mixture of granules is processed, if desired after addition of suitable auxiliaries, to obtain tablets or dragee cores. Suitable excipients are in particular fillers such as sugars and the like, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, for example maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, for example cross-linked polyvinylpyrrolidone, agar or alginic acid or an alginate such as sodium alginate. The lozenge cores are suitably coated. For this purpose, concentrated sugar solutions may be used, which may optionally comprise gum arabic, talc, polyvinylpyrrolidone, carbopol gel (carbopol gel), polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings in order to identify or characterize different combinations of active compound doses. For this purpose, concentrated sugar solutions may be used, which may optionally comprise gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.

Pharmaceutical formulations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, such as glycerol or sorbitol, and a plasticizer. Push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

In certain embodiments, a pharmaceutical composition of the present disclosure may comprise 0.1% to 95% of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a pharmaceutical composition of the present disclosure may comprise 1% to 70% of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In any event, the composition or formulation to be administered will contain an amount of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, that is effective to treat the disease/condition in the subject being treated.

Method of administration

At least one compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, can be administered to a patient by any method suitable for systemic and/or topical delivery of the compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Non-limiting examples of methods of administration include (a) administration by oral route, including administration in capsules, tablets, granules, sprays, syrups, or other such forms; (b) by non-oral routes of administration, such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraaural, including administration in aqueous suspensions, oily formulations, and the like, or in drops, sprays, suppositories, salves, ointments, and the like; (c) the administration is carried out by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intravesicular injection, intraspinal injection, intrasternal injection and the like, and comprises the delivery of an infusion pump; (d) local (locally) administration such as injection directly in the kidney region or heart region, for example by depot implantation; and (e) topical (topically) administration; a suitable mode of administration, as recognized by one skilled in the art, is contact of the compounds described in this disclosure with living tissue.

The most suitable route depends on the nature and severity of the disease state being treated. Those skilled in the art are also familiar with determining methods of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage forms, appropriate pharmaceutical excipients, and other items relevant to delivering a compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof to a subject in need thereof.

Pharmaceutical compositions suitable for administration include compositions which contain an effective amount of the active ingredient to achieve its intended effect. The dosage required for a therapeutically effective amount of the pharmaceutical compositions described in this disclosure will depend on the route of administration, the type of animal being treated, including humans, and the physical characteristics of the particular animal under consideration. The dosage may be adjusted to achieve the desired effect, but this will depend on the following factors: body weight, diet, concurrent medication, and other factors recognized by those skilled in the medical arts. More specifically, a therapeutically effective amount refers to an amount of a compound effective to prevent, alleviate or ameliorate symptoms of a disease, or to prolong the lifespan of the subject being treated. The determination of a therapeutically effective amount is well within the practical capabilities of those skilled in the art, particularly in light of the detailed disclosure provided by the present disclosure.

As will be apparent to those skilled in the art, the dosage and specific mode of administration for in vivo administration will vary depending upon the age, weight and type of mammal being treated, the specific compound employed and the specific use of the compounds employed. The determination of effective dosage levels, i.e., the dosage levels necessary to determine the desired effect, can be accomplished by those skilled in the art using conventional pharmacological procedures. Generally, the human clinical application of the product is started at lower dosage levels, with increasing dosage levels until the desired effect is achieved. Alternatively, using established pharmacological methods, acceptable in vitro studies can be used to establish effective dosages and routes of administration for the compositions identified by the methods.

In non-human animal studies, the use of potential products begins at higher dosage levels, with the dosage being reduced until the desired effect is no longer achieved or the adverse side effects disappear. The dosage range may be broader depending on the desired effect and the therapeutic indication. Generally, the dose may be from about 10 μ g/kg body weight to 1000mg/kg body weight, in certain embodiments from about 100 μ g/kg body weight to 300mg/kg body weight. Alternatively, as will be appreciated by those skilled in the art, the dose may be based on and calculated in accordance with the body surface area of the patient.

The exact formulation, route of administration, and dosage of the pharmaceutical compositions described in this disclosure can be selected by the individual physician according to the condition of the patient. Generally, the dosage of the composition administered to a patient may range from about 0.5mg/kg to 1000mg/kg of patient body weight. The dosage may be administered once or twice or more times during one or more days, as desired by the patient. Where human dosages of the compounds are established for at least certain conditions, the present disclosure will employ those same dosages, or established human dosages in the range of about 0.1% to 500%, in certain embodiments in the range of 25% to 250%. In the absence of a defined human dose, as in the case of the newly discovered pharmaceutical compound, a suitable human dose can be inferred from the median value of the median effective or infective dose, or other suitable values from in vitro or in vivo studies, as quantified by toxicity studies and efficacy studies in animals.

It should be noted that due to toxicity and organ dysfunction, the attending physician will know how and when to terminate, interrupt or adjust administration. Conversely, if the clinical response is inadequate (to preclude toxicity), the attending physician will also know to adjust the treatment to higher levels. The size of the dose administered in the treatment of a condition of interest will vary with the severity of the disease state to be treated and the route of administration. The severity of the disease state can be assessed, for example, in part, by standard prognostic assessment methods. In addition, the dose and possibly dose frequency will also vary according to the age, weight, and response of the individual patient. Protocols comparable to those discussed above may be used in veterinary medicine.

While the exact dosage can be determined on a drug-by-drug basis, in most cases, some generalizations can be made about the agent. The daily dosage regimen for an adult patient is, for example, an oral dose of from 0.1mg to 2000mg of each active ingredient, in certain embodiments from 1mg to 2000mg of each active ingredient, for example from 5mg to 1500mg of each active ingredient. In other embodiments, the intravenous, subcutaneous, or intramuscular dose of each active ingredient used is from 0.01mg to 1000mg, in certain embodiments from 0.1mg to 1000mg, for example from 1mg to 800 mg. In the case of administration of pharmaceutically acceptable salts, the dosage can be calculated as the free base. In certain embodiments, the composition is administered from 1 to 4 times daily. Alternatively, the compositions described in this disclosure may be administered by continuous intravenous infusion, in certain embodiments at a dose of up to 2000mg of each active ingredient per day. As will be appreciated by those skilled in the art, in certain instances, it may be necessary to administer a compound described in this disclosure in an amount exceeding or well exceeding the dosage ranges described above in order to effectively and rapidly treat a rapidly developing disease or infection. In certain embodiments, the compound is administered during a continuous treatment period, e.g., one week or several weeks, or several months or several years.

The dosage and dosing intervals may be adjusted individually to provide plasma levels of the active moiety that are sufficient to maintain the modulating effect or Minimum Effective Concentration (MEC). The MEC for each compound was different, but MEC could be assessed from in vitro data. The required dose to achieve MEC depends on the individual characteristics and the route of administration. However, the plasma concentration can be determined using HPLC (high performance liquid chromatography) assays or biological assays.

Dosing intervals can also be determined using MEC values. The compositions should be administered using a treatment regimen that maintains plasma levels above MEC for 10-90% of the time, in certain embodiments 30-90% of the time, and in certain embodiments 50-90% of the time.

In the case of topical administration or selective absorption, the effective local concentration of the drug is independent of plasma concentration.

The amount of the composition to be administered will, of course, depend on the individual to be treated, on the weight of said individual, the severity of the affliction, the mode of administration and the judgment of the prescribing physician.

The potency and toxicity of the compounds described in this disclosure can be assessed using known methods. For example, the toxicology of a particular compound or a subset of such compounds sharing certain chemical moieties may be established by determining the toxicity of a cell line, e.g., a mammalian cell line and in certain embodiments, a human cell line, in vitro. The results of such studies can generally predict toxicity in animals, such as mammals, or more specifically, in humans. Alternatively, toxicity of a particular compound in an animal model such as mouse, rat, rabbit or monkey can be determined using known methods. The potency of a particular compound can be determined using several accepted methods, such as in vitro methods, animal models, or human clinical trials. There are well-established in vitro models for almost every class of disease states, including but not limited to cancer, cardiovascular disease, and various immune dysfunctions. Similarly, acceptable animal models can be used to determine the efficacy of chemical drugs for treating these disease states. When selecting a model to determine efficacy, the skilled person is able to select an appropriate model, dosage and route of administration and treatment regimen under the guidance of the state of the art. Of course, human clinical trials can also be used to determine the efficacy of compounds in humans.

If desired, the compositions can be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The package may for example comprise a metal or plastic foil, such as a blister pack. The packaging or dispensing device may carry instructions for administration. The packaging or dispensing device may also carry a notice associated with the container, the notice being mandated by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, the notice reflecting approval by the agency of the pharmaceutical form for human or veterinary administration. Such notice, for example, may be a label approved by the national food and drug administration or the U.S. food and drug administration for a prescribed drug, or an approved product specification. Compositions comprising a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in a suitable container, in a formulation with a pharmaceutically acceptable carrier, may also be prepared, placed, and labeled for treatment of a specified disease state.

Hereinafter, the present disclosure will be explained in detail by the following examples in order to better understand various aspects of the present application and advantages thereof. It should be understood, however, that the following examples are not limiting and are merely illustrative of certain embodiments of the present application.