Methods and compositions for lipid formulations of heterocyclic-type lipophilic small molecule therapeutics

Abstract

For example, methods and compositions for delivering therapeutic agents useful for neuronal regeneration, neuroprotection and / or slowing disease progression. Treatment of diseases and conditions characterized by neurodegeneration.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 209,841, filed June 11, 2021, and U.S. Provisional Patent Application No. 63 / 340,230, filed May 10, 2022, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION Some embodiments of the present invention generally relate to the field of neurological and neuropsychiatric disorders.More specifically, certain embodiments of the present invention provide methods and compositions for the preparation of heterocyclic rings.In some embodiments, the preparations of the present disclosure can prevent, slow down, and / or reverse neurodegenerative diseases. [Background technology]

[0003] Alzheimer's disease is a brain disorder that gradually destroys nerve cells. More than 4.5 million people in the United States have Alzheimer's disease, most of which occurs in older adults. The risk of developing Alzheimer's disease roughly doubles every 5 years after age 65, reaching 50% by age 85. Patients with Alzheimer's disease lose the ability to learn, remember, judge, make decisions, communicate, and perform daily activities. The direct and indirect costs of caring for patients with Alzheimer's disease have risen to at least $100 billion annually.

[0004] Stroke and Parkinson's disease can also cause loss of nerve cells, leading to behavioral decline. Hearing loss caused by injury, aging and the use of pharmaceutical drugs is caused by loss of cochlear nerve cells.

[0005] Many developmental delay disorders, including Down syndrome and fragile X syndrome, may be caused by insufficient hippocampal neurogenesis. Therapies that promote hippocampal neurogenesis may be effective in improving the behavioral phenotypes of Down syndrome and fragile X syndrome.

[0006] There is a need for pharmaceutical formulations that improve the delivery of active pharmaceutical ingredients (APIs) to target areas. More specifically, there is a need for improved methods and compositions, including formulations, for delivering APIs through the blood-brain barrier. There is also a need for compositions that can improve long-term absorption to promote efficacy and allow for increased dosage and stability. Summary of the Invention

[0007] According to some embodiments, the present invention provides methods and compositions, including formulations useful for delivering APIs across the blood-brain barrier.In some embodiments, the disclosed compositions improve long-term absorption to promote efficacy.In some embodiments, the compositions can allow for increased dosage and stability.

[0008] The methods and compositions disclosed herein are particularly useful for treating neurodegenerative diseases such as Alzheimer's disease and neuropsychiatric conditions such as depression. The methods and compositions may also be suitable for the manufacture of research products as a single composition or a mixture of compositions. The methods and compositions comprising the compounds are also useful for inhibiting neurodegeneration. Thus, in some embodiments, the present invention has been found to be particularly useful for treating diseases and conditions characterized by loss of nerve cells, including, but not limited to, Alzheimer's disease, Parkinson's disease, traumatic brain injury and hearing loss. Disclosed herein are representative formulations, methods for producing the compound products, compositions comprising the compounds, and methods for using the compounds.

[0009] In one aspect, the invention provides compositions comprising compounds useful for treating humans, particularly elderly humans, with or without a neurodegenerative disorder.

[0010] In another aspect, the present invention is further directed to methods and compositions comprising compounds that have utility in treating any disease associated with neuronal cell loss.More specifically, the present invention further provides a method of administering API in lipid formulations administered to subjects, such as elderly subjects.In one embodiment, the method can comprise administering liquid formulations to elderly subjects.Compositions comprising compounds described herein can be safely absorbed in elderly subjects and administered in an amount effective to stimulate neuronal cell regeneration.

[0011] In yet another aspect, the present invention also includes pharmaceutical preparations that contain the compounds disclosed herein.Also disclosed are the route of administration and dosage of the effective amount of pharmaceutical composition that contains the compounds.The compounds of the present invention can be administered as liquid, such as by using oral syringe, or in combination with capsules or hard or soft gel capsules, for effective delivery and disease treatment in subjects that require it, such as the elderly.

[0012] In one aspect, a pharmaceutical composition is disclosed comprising an API in a lipid formulation, wherein the API is a compound according to formula (I) (shown below) or a pharma- ceutical acceptable salt thereof.

[0013] In some embodiments, the compound is the following compound: [ka] or one of its physiologically acceptable salts.

[0014] In some embodiments, the compound is [ka] or a physiologically acceptable salt thereof.

[0015] In some embodiments, the compound is [ka] or a physiologically acceptable salt thereof.

[0016] In some embodiments, the lipid formulation comprises about 85-95.5% vehicle, about 1-8% surfactant, and about 0.5-7% viscosity enhancing agent by weight of the lipid formulation.

[0017] In some embodiments, the vehicle comprises one or more of vegetable oils, triglycerides, monoglycerides, diglycerides, oily fatty acids, isopropyl myristate, oily fatty alcohols, esters of sorbitol and fatty acids, oily sucrose esters, mineral oils, and mixtures thereof.

[0018] In some embodiments, the vehicle is a medium chain triglyceride (MCT).

[0019] In some embodiments, the surfactant is selected from the group consisting of sodium lauryl sulfate, esters of polyoxyethylene sorbitan or polyethylene glycol, dioctyl sodium sulfosuccinate (DOSS), lecithin, stearyl alcohol, cetostearyl alcohol, cholesterol, hydrogenated castor oil and derivatives or fractions thereof, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, hydrogenated polyoxyethylene fatty acid glycerides, Pluronic surfactants, and mixtures thereof.

[0020] In some embodiments, the surfactant is a non-ionic surfactant with an HLB value of 12-14.

[0021] In some embodiments, the surfactant is polyoxyl 35 castor oil.

[0022] In some embodiments, the thickener is selected from the group consisting of waxes, polyacrylates and polyacrylate copolymer resins, cellulose and cellulose derivatives and their salts, polyvinylpyrrolidones, polyvinyl resins, other polymeric materials, inorganic thickeners, and mixtures thereof.

[0023] In some embodiments, the thickening agent is selected from the group consisting of colloidal silica, beeswax, microcrystalline wax, and mixtures thereof.

[0024] In some embodiments, the thickening agent is beeswax.

[0025] In some embodiments, the vehicle is medium chain triglyceride (MCT), the surfactant is polyoxyl 35 castor oil, and the thickener is beeswax.

[0026] According to another aspect, a method for delivering an API to a mammal is disclosed: a pharmaceutical composition disclosed herein contained in a capsule or gel capsule is administered to a mammal.

[0027] According to another aspect, a method is disclosed for treating at least one condition selected from the group consisting of developmental delay, psychiatric disorder, neurodegenerative disease, neurological disorder and aging in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0028] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a pet or livestock animal. In other embodiments, the mammal is a human. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] It is understood that the invention is not limited to the particular methodologies, assays, and the like described herein, as these may vary. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Exemplary methods and compositions are described, however, any methods and compositions similar or equivalent to those described herein can be used in the practice or testing of the present invention.

[0031] I. Definition The term "compound" as used herein refers to all iterations of the structures and formulas disclosed herein, and also includes reference to physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the compounds of the present invention include those derived from suitable bases, such as alkali metals, e.g., sodium, and alkaline earth metals, e.g., magnesium, ammonium, and NX4. + (wherein X is C1-C4 alkyl). Physiologically acceptable salts of hydrogen atoms or amino groups may include, but are not limited to, salts of organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid; inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, and the like. Physiologically acceptable salts of compounds of hydroxy groups may include, but are not limited to, salts of Na + and NX4 + X is independently selected from H or a C1-C4 alkyl group.

[0032] For therapeutic use, the salts of the compounds of the present invention are physiologically acceptable, i.e., the salts are derived from physiologically acceptable acids or bases. However, salts of physiologically unacceptable acids or bases may also be used in the preparation and purification of physiologically acceptable compounds. Thus, all salts are within the scope of the present invention, whether derived from physiologically acceptable acids or bases or not.

[0033] "Alkyl" means a C1-C6 alkyl group containing normal, secondary, tertiary or cyclic carbon atoms. 18 It is a hydrocarbon. "Alkenyl" refers to an alkyl group having at least one site of unsaturation, i.e., carbon-carbon, sp 2 C2-C containing normal, secondary, tertiary or cyclic carbon atoms with double bonds 18 It is a hydrocarbon. Examples include, but are not limited to, ethylene or vinyl (--CH==CH2), allyl (--CH2CH==CH2), cyclopentenyl (--C5H7), and 5-hexenyl (--CH2CH2CH2CH2CH==CH2). "Alkynyl" refers to a C2-C alkyl group containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. 18 A hydrocarbon. Examples include, but are not limited to, acetylene (--C≡--CH) and propargyl (--CHC≡--CH).

[0034] "Aryl" means a monovalent aromatic hydrocarbon radical of 6 to 20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.

[0035] "Heteroaryl" means a monovalent aromatic radical of one or more carbon atoms and one or more atoms selected from N, O, S, or P derived by removing one hydrogen atom from a single atom of a parent aromatic ring system. Heteroaryl groups can be monocyclic (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, and S) having 3-7 ring members or bicyclic (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, and S) having 7-10 ring members. Heteroaryl bicyclic rings have 7-10 ring atoms (6-9 carbon atoms and 1-2 heteroatoms selected from N, O, and S) arranged as a bicyclo[4,5], [5,5], [5,6], or [6,6] system or 9-10 ring atoms (8-9 carbon atoms and 1-2 heteroatoms selected from N and S) arranged as a bicyclo[5,6] or [6,6] system. Heteroaryl groups can be attached to the drug scaffold by a stable covalent bond through carbon, nitrogen, sulfur, phosphorus or other atoms. Heteroaryl groups include pyridyl, dihydropyridyl isomers, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl.

[0036] Substituted substituents such as "substituted alkyl," "substituted aryl," and "substituted heteroaryl" refer to alkyl, aryl, and arylalkyl, respectively, in which one or more hydrogen atoms have each been independently replaced with a substituent. Exemplary substituents include --X, --R, --O, --R- ... - , --OR, --SR, --S - , --NR2, --NR3, ==NR, --CX3, --CN, --OCN, --SCN, --N==C==O, --NCS, --NO, --NO2, ==N2, --N3, NC(==O)R, --C(==O)R, --C(==O)NRR --S(==O)2O -, --S(==O)2OH, --S(==O)2R, --OS(==O)2OR, --S(==O2NR, --S(==O)R, --OP(==O)O2RR, --P(==O)O2RR --P(==O)(O - )2, --P(==O)(OH)2, --C(==O)R, --C(==O)X, --C(S)R, --C(O)OR, --C(O)O - , --C(S)OR, --C(O)SR, --C(S)SR, --C(O)NRR, --C(S)NRR, --C(NR)NRR, where each X is independently a halogen: F, Cl, Br, or I; and each R is independently --H, alkyl, aryl, heterocycle, protecting group, or prodrug moiety. Alkylene, alkenylene, and alkynylene groups may also be similarly substituted.

[0037] "Halogen" includes F, Cl, Br, or -I, and is used interchangeably with the term "halo."

[0038] "Heterocycle" means a saturated, unsaturated or aromatic ring system containing at least one N, O, S or P. Heterocycle thus includes heteroaryl groups. Heterocycle as used herein includes, but is not limited to, the heterocycles described in PAQUETTE, PRINCIPLES OF MODERN HETEROCYCLIC CHEMISTRY (WA Benjamin, New York, 1968), especially chapters 1, 3, 4, 6, 7 and 9; THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS, A SERIES OF MONOGRAPHS (John Wiley & Sons, New York, 1950 to present), especially volumes 13, 14, 16, 19 and 28; KATRITTZKY ET AL., COMPREHENSIVE HETEROCYCLIC CHEMISTRY (Pergamon Press, 1996); and 82 J. AM. CHEM. SOC. 5566 (1960).

[0039] Heterocycles include pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidinyl, and the like. pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthene nyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoley, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthridinyl, These include, but are not limited to, indolyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxyindolyl, benzoxazolinyl, and isatinoyl.

[0040] Carbon-bonded heterocycles include, but are not limited to, those bonded to the 2-, 3-, 4-, 5- or 6-position of pyridine, the 3-, 4-, 5- or 6-position of pyridazine, the 2-, 4-, 5- or 6-position of pyrimidine, the 2-, 3-, 5- or 6-position of pyrazine, the 2-, 3-, 4- or 5-position of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, the 2-, 4- or 5-position of oxazole, the imidazole or thiazole, the 3-, 4- or 5-position of isoxazole, the pyrazole or isothiazole, the 2- or 3-position of aziridine, the 2-, 3- or 4-position of azetidine, the 2-, 3-, 4-, 5-position of quinoline, or the 1-, 3-, 4-, 5-position of isoquinoline. Even more typically, the carbon-linked heterocycle comprises 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.

[0041] Nitrogen-bonded heterocycles include, but are not limited to, those bonded to the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, 2-position of isoindole, or isoindoline, 4-position of morpholine, and 9-position of carbazole, or β-carboline. Even more typically, nitrogen-bonded heterocycles include 1-aziridyl, 1-azetyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl. "Carbocycle" means a saturated, unsaturated, or aromatic ring system having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle. Monocyclic carbocycles have 3 to 6 ring atoms, and even more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, arranged for example as a bicyclo[4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo[5,6] or [6,6] system. Monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and naphthyl. Thus, carbocycles include aryl groups.

[0042] As used herein, the term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image partner, and the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0043] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0044] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have physical properties such as different melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.

[0045] "Enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0046] Stereochemical definitions and conventions used herein generally follow the MCGRAW-HILL DICTIONARY OF CHEMICAL TERMS (SP Parker, Ed., McGraw-Hill Book Company, New York, 1984); and ELIEL, ELIEL, E. AND WILEN, S., STEREOCHEMISTRY OF ORGANIC COMPOUNDS (John Wiley & Sons, Inc., New York, 1994). Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule about its chiral centers. The prefixes d and l, or (+) and (-), are used to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, lacking optical activity.

[0047] The terms "treatment", "treat", "therapy", "therapeutic" and the like are generally used herein to refer to obtaining a desired pharmacological and / or physiological effect. The effect may be preventative, in that a disease or its symptoms are completely or partially prevented, and / or may be therapeutic, in that a disease and / or deleterious effects resulting from the disease are partially or completely stabilised or cured. As used herein, "treatment" encompasses any treatment of a disease in a subject, including: (a) preventing a disease or condition from occurring in a subject who may have the disease or condition but has not yet been diagnosed; (b) suppressing a disease symptom, i.e., arresting its onset, or; (c) relieving a disease symptom, i.e., causing regression of the disease or condition.

[0048] The term "pharmaceutical acceptable carrier" used herein refers to any solvent, dispersion medium, coating, antibacterial and antifungal agent, isotonic agent and absorption delaying agent that are known in the art for pharmaceutical active substances.Unless any conventional medium or agent is incompatible with the compound, its use in the therapeutic composition is contemplated.Auxiliary compounds can also be incorporated into the composition.

[0049] The term "additive" as used herein refers to an additive used to convert an active compound into a form suitable for its intended purpose. In compositions of the present invention suitable for human administration, the term "additive" includes additives described in HANDBOOK OF PHARMACEUTICAL EXCIPIENTS, American Pharmaceutical Association, 2nd Ed. (1994) (incorporated herein in its entirety). The term "additive" is meant to include excipients, binders, disintegrants, lubricants, solvents, suspending agents, dyes, fillers, surfactants, adjuvants, etc. The liquid additive can be selected from a variety of oils including oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, hydrogenated vegetable oil, cottonseed oil, peanut oil, corn oil, germ oil, olive oil or castor oil, etc.

[0050] Suitable additives also include, but are not limited to, excipients such as monosaccharides, lactose, fructose, sucrose, inositol, mannitol or sorbitol, xylitol, trehalose, cellulose preparations and / or calcium phosphate, tricalcium phosphate or calcium hydrogen phosphate, as well as starch paste using modified starch, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, crystalline cellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, aluminum metahydroxide, bentonite, sodium carboxymethylcellulose, croscarmellose sodium, crospovidone and sodium starch glycolate, and / or polyvinylpyrrolidine and mixtures thereof. If necessary, disintegrants such as the above-mentioned starches, and carboxymethyl-starch, crosslinked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, may be added. Auxiliaries include, but are not limited to, silica, stearic acid or its salts, such as magnesium stearate, sodium stearyl fumarate or calcium stearate.

[0051] The term "therapeutically effective amount" refers to an amount of a compound disclosed herein effective to prevent, ameliorate, treat or delay the onset of a disease or condition.

[0052] The pharmaceutical compositions of the invention may be administered to any animal that may experience the beneficial effects of the compounds of the invention, including humans and non-humans, such as primates, pets and farm animals.

[0053] II. Active Pharmaceutical Ingredients (API) According to certain embodiments, the pharmaceutical compositions disclosed herein can be used to administer various APIs. Some APIs are disclosed in U.S. Patent No. 8,999,972, the contents of which are incorporated herein by reference. An example of a particularly useful API is a compound of the formula: [ka] [In the formula, each R1 is independently selected from the group consisting of H, F, C1, Br, R7, and -O-R7, where R7 is a substituted alkyl group having 1 to 6 carbon atoms or an aryl or aralkyl group having 6 to 14 carbon atoms; R2 is selected from O or S; R3 is (CH2) m where m is 1, 2 or 3; R4 is N and (CH n wherein n is equal to 1 or 2, with the proviso that when R4 is nitrogen, m in R3 is not equal to 1; R6 is H; each R8 is independently -X, -R9, -OR9, -SR9, -N(R9)2, -CN, -NO2, -NC(O)R9, -C(O)R9, -C(O)N(R9)2, -S(O)2R9, -S(O)2NR9, -S(O)R9, -C(O)R9, -C(O)OR9, or -C(O)N(R9)2; Each X is independently a halogen; each R9 is independently -H, alkyl, alkenyl, alkynyl, aryl, heterocycle, a protecting group, or a prodrug moiety. The present invention includes compounds represented by the formula:

[0054] More specifically, specific examples of useful compounds include the following: [ka] These include, but are not limited to, the compounds and their physiologically acceptable salts.

[0055] According to one embodiment, NNI-362 comprises the following: [ka] and physiologically acceptable salts thereof may be used. NNI-362 is a pale yellow to yellow solid that is soluble in common organic solvents but insoluble in water / aqueous solutions. NNI-362 begins to melt at 152.4°C.

[0056] According to another embodiment, NNI-351, [ka] and physiologically acceptable salts thereof may be used.

[0057] Finally, the general structure of the compounds of the present invention may encompass all saturated states of the indicated substituents, including all ene, diene, triene and yne derivatives of any substituent. The general structure also includes all structural, regio and stereoisomers that may arise from a particular set of substituents. The general structure also includes all enantiomers, diastereomers and other optical isomers (enantiomers or racemates, or mixtures of stereoisomers).

[0058] III. Pharmaceutical Compositions The present invention also includes pharmaceutical compositions comprising the compounds disclosed herein.The administration route and effective dosage of the pharmaceutical compositions comprising the compounds are also disclosed.The compounds of the present invention can be administered in combination with other medicinal substances in various protocols for the effective treatment of diseases.

[0059] The pharmaceutical compositions of the invention may be administered to any animal that may experience the beneficial effects of the compounds of the invention. Such animals include humans and non-humans, such as pets and farm animals (e.g., working animals / farm animals / sled dogs).

[0060] The pharmaceutical compositions of the invention are administered to a subject by methods known in the art. The dosage administered will depend on the age, health, and weight of the recipient, type of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

[0061] In addition to the compounds disclosed herein, the pharmaceutical composition of the present invention may further comprise at least one suitable auxiliary agent, including but not limited to diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, etc. Pharmaceutically acceptable auxiliary agents are preferred. Examples and methods for preparing such sterile solutions are well known in the art, and can be found, for example but not limited to, in REMINGTON'S PHARMACEUTICAL SCIENCES (Gennaro, Ed., 18th Edition, Mack Publishing Co. (1990)). Pharmaceutically acceptable carriers can be routinely selected to suit the method of administration, the solubility and / or stability of the compound.

[0062] Pharmaceutical additives and additives useful in the present invention also include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., saccharides including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides; derivatized saccharides, such as alditols, aldonic acids, esterified sugars, and the like; and polysaccharides or sugar polymers), which may be present alone or in combination and are included alone or in combination in the range of 1-99.99% by weight or volume. Exemplary protein additives include serum albumins, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid components that may also function in a buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like.

[0063] Carbohydrate additives suitable for use in the present invention include monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides such as raffinose, melezitose, maltodextrin, dextrolan, starch, and the like; and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), myo-inositol, and the like.

[0064] Composition may further comprise pharma- ceutically acceptable carrier or vehicle, such as, but not limited to, oil, medium-chain triglyceride, coloring agent, emulsifier, suspending agent, ethanol, EDTA, citric acid buffer, flavoring agent and water.More specifically, examples of vehicle include, but are not limited to, vegetable oil, such as castor oil, olive oil, soybean oil, sesame oil, cottonseed oil, sweet almond oil or peanut oil; triglyceride, such as, for example, semi-synthetic oil (medium-chain triglyceride (MCT) or long-chain triglyceride); monoglyceride; diglyceride; oily fatty acid; isopropyl myristate; oily fatty alcohol; sorbitol and fatty acid ester, oily sucrose ester, or mineral oil, such as liquid paraffin or petrolatum; and generally, physiologically tolerable oily substances, and their mixtures.

[0065] In one embodiment, the vehicle comprises MCT, a triglyceride oil in which the carbohydrate chains have about 8-12 carbon atoms.

[0066] The composition may also include a pharma- ceutically acceptable thickening agent. Examples of thickening agents include, but are not limited to, waxes (e.g., beeswax, carnauba), polyacrylates and polyacrylate copolymer resins (e.g., Carbopol), cellulose and cellulose derivatives and their salts, polyvinylpyrrolidone, polyvinyl resins, other polymeric materials (e.g., tragacanth gum, arabicum gum, alginates), inorganic thickening agents (e.g., attapulgite, bentonite and silicates). Examples of particularly useful thickening agents include, but are not limited to, colloidal silica, beeswax and microcrystalline wax.

[0067] The composition may further comprise one or more surfactants. Examples of useful surfactants include, but are not limited to, sodium lauryl sulfate, esters of polyoxyethylene sorbitan or polyethylene glycol (e.g. Gelucire), dioctyl sodium sulfosuccinate (DOSS), lecithin, stearyl alcohol, cetostearyl alcohol, cholesterol, hydrogenated castor oil and its derivatives or fractions, various grades of Cremophor or Kolliphor, such as Cremophor EL / Kolliphor EL (macrogol glycerol ricinoleate or polyoxyl 35 castor oil) and Cremophor or Kolliphor RH-40 (macrogol glycerol hydroxystearate or polyoxyl 40 hydrogenated castor oil) hydrogenated polyoxyethylene fatty acid glycerides, and Pluronic surfactants. Kolliphor® EL is a particularly useful surfactant in the present formulation. Kolliphor EL is a non-ionic solubilizer and emulsifier made by reacting castor oil with ethylene oxide. Kolliphor® EL is a polyethylene oxide surfactant that is viscous in nature. The hydrophobic lipophilic balance (HLB) value ranges from 12-14.

[0068] The composition of the present invention may also contain the preservative methylparaben (also known as 4-hydroxybenzoic acid methyl ester; methyl p-hydroxybenzoate; or METHYL CHEMOSEPT), ethylparaben (also known as 4-hydroxybenzoic acid ethyl ester; ethyl p-hydroxybenzoate; or ETHYL PARASEPT), propylparaben (also known as 4-hydroxybenzoic acid propyl ester; propyl p-hydroxybenzoate; NIPASOL; or PROPYL CHEMOSEPT) and / or butylparaben (also known as 4-hydroxybenzoic acid propyl ester; propyl p-hydroxybenzoate; or BUTYL CHEMOSEPT).In some embodiments, the composition contains methylparaben and / or propylparaben.

[0069] Emulsifiers of the present invention include, but are not limited to, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0070] The pharmaceutical composition comprising the compound disclosed herein can also comprise buffer or pH adjusting agent.Typically, buffer is the salt prepared from organic acid or base.Representative buffer comprises organic acid salt such as citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid or phthalic acid salt;Tris, tromethamine hydrochloride or phosphate buffer.

[0071] In addition, the pharmaceutical compositions may include polymeric additives / additives such as polyvinylpyrrolidone, ficoll (a polymeric sugar), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin), polyethylene glycol, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates, e.g., "TWEEN 20" and "TWEEN 80"), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA or EGTA). These and further known pharmaceutical additives and / or additives suitable for use in the present invention are known in the art and are described, for example, in REMINGTON: THE SCIENCE & PRACTICE OF PHARMACY (1999). th ed., Williams & Williams (1995)) and PHYSICIAN'S DESK REFERENCE (52 nd ed., Medical Economics (1998), the disclosures of which are expressly incorporated herein by reference in their entireties.

[0072] The present invention provides stable pharmaceutical compositions comprising at least one compound disclosed herein in a pharma- ceutical acceptable composition, and compositions comprising a storage solution and a preservative, as well as multi-use storage compositions suitable for pharmaceutical or veterinary use. Pharmaceutical compositions according to the present invention may optionally contain at least one known preservative. Preservatives include, but are not limited to, phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof in aqueous diluents. Any suitable concentration or mixture may be used, for example, 0.001-5%, or any range or value thereof, as known in the art. Non-limiting examples include no preservatives, no preservatives, 0.1-2% m-cresol, 0.1-3% benzyl alcohol, 0.001-0.5% thimerosal, 0.001-2.0% pheno, 0.0005-1.0% alkylparabens, and the like.

[0073] Other additives, such as isotonicity agents, buffers, antioxidants, preservative enhancers, may be added to the diluent as desired. Isotonicity agents, such as glycerin, are typically used at known concentrations. A physiologically tolerable buffer is preferably added to improve pH control. The pharmaceutical composition encompasses a wide range of pH, such as from about pH 4 to about pH 10, specifically from about pH 5 to about pH 9, more specifically from about 6.0 to about 8.0. In one embodiment, the formulation of the present invention has a pH of about 6.8 to about 7.8. Suitable buffers include phosphate buffer, sodium phosphate, and phosphate buffered saline (PBS).

[0074] Other additives, such as pharma- ceutically acceptable solubilizers, such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate), TWEEN 40 (polyoxyethylene (20) sorbitan monopalmitate), TWEEN 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymer), and PEG (polyethylene glycol) or non-ionic surfactants, such as polysorbate 20 or 80 or poloxamer 184 or 188, PLURONIC® polyols (polyl), other block copolymers, and chelating agents, such as EDTA and EGTA, may be added to the pharmaceutical composition, if desired, to reduce aggregation. These additives are particularly useful when pumps or plastic containers are used to administer the pharmaceutical composition. The presence of a pharma-ceutically acceptable surfactant mitigates the tendency of the composition to aggregate.

[0075] The composition of the present invention may also contain the preservative methylparaben (also known as 4-hydroxybenzoic acid methyl ester; methyl p-hydroxybenzoate; or METHYL CHEMOSEPT), ethylparaben (also known as 4-hydroxybenzoic acid ethyl ester; ethyl p-hydroxybenzoate; or ETHYL PARASEPT), propylparaben (also known as 4-hydroxybenzoic acid propyl ester; propyl p-hydroxybenzoate; NIPASOL; or PROPYL CHEMOSEPT) and / or butylparaben (also known as 4-hydroxybenzoic acid propyl ester; propyl p-hydroxybenzoate; or BUTYL CHEMOSEPT).In some embodiments, the composition contains methylparaben and / or propylparaben.

[0076] The composition of the present invention can also be administered in the form of liposome. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The composition in liposome form can contain, in addition to the compound of the present invention, stabilizers, preservatives, additives, and the like. The preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art (see Prescott, ed., METH. CELL BIOL. 14:33 (1976)). Liposomes, methods of making and methods of use are described in U.S. Patent Nos. 4,089,8091 (process for making liposomes), 4,233,871 (method for bioactive substances in lipid vesicles), 4,438,052 (method for making mixed micelles), 4,485,054 (large multilamellar vesicles), 4,532,089 (giant size liposomes and methods thereof), 4,897,269 (liposomal drug delivery systems), and 5,820,880 (liposomal formulations), among others.

[0077] During any of the processes for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved by conventional protecting groups, such as those described in PROTECTIVE GROUPS IN ORGANIC CHEMISTRY (1973); and GREENE AND WUTS, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (1991). The protecting groups may be removed at a convenient later stage using methods known in the art.

[0078] The compounds disclosed herein may be solubilized or suspended in a preconcentrate (before dilution with a diluent), may be added to a preconcentrate before dilution, may be added to a diluted preconcentrate, or may be added to a diluent before mixing with a preconcentrate. The compounds may also be co-administered as part of an independent dosage form for therapeutic effect. Optionally, the compounds disclosed herein may be present in a first solubilized amount and a second non-solubilized (suspended) amount.

[0079] The pharmaceutical formulations may also contain suitable pharma- ceutically acceptable carriers, including additives and auxiliaries, which facilitate processing of the active compounds, as described herein, into preparations that can be administered to animals.

[0080] For oral administration in the form of tablet or capsule, the compound may be combined with oral non-toxic pharma- ceutically acceptable inert carriers such as ethanol, glycerol, water, etc. In addition, as desired or necessary, binders, lubricants, disintegrants and coloring agents may also be incorporated into the mixture. Suitable binders include, but are not limited to, starch; gelatin; natural sugars, such as glucose or beta-lactose; corn sweeteners; natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethylcellulose; polyethylene glycol; waxes, etc. Lubricants used in these dosage forms include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0081] For oral administration, the compositions also optionally contain a sweetening agent, including, but not limited to, sucrose, fructose, sodium saccharin, sucralose (SPLENDA®), sorbitol, mannitol, aspartame, sodium cyclamate, and the like, and combinations thereof.

[0082] Aqueous suspensions, emulsions and / or elixirs for oral administration of the present invention may be combined with various sweeteners, flavoring agents, such as, but not limited to, orange or lemon flavor, coloring agents, such as dyes, pigments such as natural colors, in addition to diluents as described herein, such as water, glycerin and various combinations.

[0083] Pharmaceutical compositions of the invention suitable for oral administration may be presented as discrete units such as capsules, dragees, cachets or tablets, each containing a predetermined amount of the compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; as an oil-in-water liquid emulsion or water-in-oil emulsion, and as a bolus. Liquid formulations may be administered using an oral syringe.

[0084] Tablets may be produced by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be produced by compressing in a suitable machine a compound in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets may be produced by molding in a suitable machine a mixture of powdered compound moistened with an inert liquid diluent. Tablets may be optionally coated or scored, and may be formulated to provide delayed or controlled release of the compound therein.

[0085] The composition containing the compound can also be incorporated into a biodegradable polymer that allows sustained release of the compound.Biodegradable polymers and their uses are described in detail in Brem et al., 74 J. NEUROSURG. 441-46 (1991).Suitable examples of sustained release compositions include semipermeable matrices of solid hydrophobic polymers containing the compound of the present invention, which matrices are in the form of shaped articles, such as films or microcapsules. Examples of sustained release agents include polyesters, hydrogels (including poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl L-glutamate, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT® (Tap Pharmaceuticals, Inc., Chicago, Ill.) (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprorelin acetate), and poly-D-(−)-3-hydroxybutyric acid.

[0086] Pharmaceutical compositions suitable for parenteral administration may include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the recipient; aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The compositions may be provided in unit-dose or multi-dose containers, sealed ampoules and vials, and may be stored in a lyophilized state, requiring only the addition of the sterile liquid carrier, water for injection, immediately before use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the type described above.

[0087] For parenteral administration, sterile suspensions and solutions are desired. When intravenous administration is desired, isotonic preparations containing suitable preservatives are generally used. The pharmaceutical composition may be administered parenterally by injection of a pharmaceutical composition containing the compound dissolved in an inert liquid carrier. As used herein, the term "parenteral" includes, but is not limited to, subcutaneous injection, intravenous, intramuscular, intraperitoneal injection, or infusion techniques. Acceptable liquid carriers include vegetable oils, such as, for example, peanut oil, cottonseed oil, sesame oil, and the like, and organic solvents, such as solketal, glycerol formal. The pharmaceutical composition may be prepared by dissolving or suspending the compound in a liquid carrier such that the final formulation contains about 0.005-30% by weight of the compound.

[0088] The compositions of the invention may also include additional therapeutic agents, including but not limited to hydrophilic drugs, hydrophobic drugs, hydrophilic polymers, cytokines, peptidomimetics, peptides, proteins, toxoids, serum, antibodies, vaccines, nucleosides, nucleotides, nucleoside analogs, genetic material and / or combinations thereof.

[0089] Examples of therapeutic agents that may be used in the pharmaceutical compositions of the present invention include other antineoplastic agents, analgesics and anti-inflammatory agents, antianginal agents, anthelmintics, antiarrhythmic agents, antiarthritic agents, antiasthmatic agents, antibacterial agents, antiviral agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptic agents, antiemetic agents, antifungal agents, antigout agents, antihypertensive agents, antimalarial agents, antimigraine agents, antimuscarinic agents, antiparkinsonian agents, antiprotozoal agents, antithyroid agents, thyroid therapeutic agents, antitussives, antianxiety agents, hypnotics, antihypertensive agents, antispasmodics ... These include, but are not limited to, hypnotics, neuroleptics, beta-blockers, cardiac inotropes, corticosteroids, diuretics, gastrointestinal drugs, histamine H receptor antagonists, immunosuppressants, keratolytics, lipid regulating drugs, muscle relaxants, nutritional agents, cytokines, peptidomimetics, peptides, proteins, toxoids, serum, sedatives, sex hormones, sex hormone antagonists or agonists, stimulant antibodies, vaccines, nucleosides, nucleoside analogs and genetic material. Amphiphilic therapeutic and nutritional agents may also be included.

[0090] The additional therapeutic agent may be solubilized or suspended in the preconcentrate (before dilution with diluent), added to the preconcentrate before dilution, added to the diluted preconcentrate, or added to the diluent before mixing with the preconcentrate. The additional therapeutic agent may also be co-administered as part of an independent dosage form for therapeutic effect. Optionally, the additional therapeutic agent may be present in a first solubilized amount and a second non-solubilized (suspended) amount. Such additional therapeutic agent may be any substance having therapeutic or other value when administered to animals, particularly mammals, such as drugs, nutritional agents, and diagnostic agents.

[0091] In addition to the compounds and compositions of the present invention and additional pharma- ceutical active substances, the pharmaceutical formulations may also contain suitable pharma- ceutical acceptable carriers, including additives and auxiliaries, described herein, that facilitate processing of the active compounds into preparations that can be administered to animals.

[0092] Pharmaceutical formulations useful in the present invention may contain an amount of a compound effective to treat the condition, disorder, or disease of the subject being treated.

[0093] The present invention also relates to a kit form useful for administration to a patient in need thereof. The kit may have a carrier means tightly closed and compartmentalized to receive therein two or more container means, the first container means having a therapeutically effective amount of the pharmaceutical composition of the present invention and a carrier, excipient or diluent. Optionally, the kit may have an additional container means containing a therapeutically effective amount of an additional drug.

[0094] The kit includes containers for the separate compositions, such as divided bottles or divided foil packets, and the separate compositions can also be included in a single undivided container. Typically, the kit includes instructions for administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician. The kit of the present invention includes test and screening kits and methods to allow physicians to measure the level of active ingredients in body fluids. The kit of the present invention also includes research grade reagents and kits that can be used and purchased by research institutions.

[0095] In one embodiment, the composition of the present disclosure comprises an API in a base composition. According to some embodiments, the base composition comprises a vehicle, a surfactant and a thickener. The following is a representative formulation of the base composition used herein: [Table 1]

[0096] The vehicle may be present in the base formulation in an amount of about 85% to 98.5% by weight of the base formulation. In some embodiments, the vehicle may be present in the base formulation in an amount of about 88% to 97% by weight, about 90% to 95% by weight, about 92% to 94% by weight, or about 94% to 96% by weight.

[0097] The surfactant may be present in the base formulation in an amount of about 1% to 8% by weight of the base formulation. In some embodiments, the surfactant may be present in the base formulation in an amount of about 2 to 6% by weight, about 3 to 5% by weight, about 2 to 4% by weight, or about 2 to 5% by weight.

[0098] The thickening agent may be present in the base formulation in an amount of about 0.5% to 7% by weight of the base formulation. In some embodiments, the thickening agent may be present in the base formulation in an amount of about 1 to 6% by weight, about 2 to 5% by weight, about 2 to 4% by weight, or about 1 to 3% by weight.

[0099] The API may be added to the base formulation to produce the final formulation. According to one embodiment, the API may be added in an amount of about 5-40% of the base formulation. In some embodiments, the API is present in the composition at about 8% to about 35% by weight, about 10% to about 30% by weight, about 12% to about 25% by weight, about 15% to about 35% by weight, about 20% to about 30% by weight, about 22% to about 28% by weight, about 5% to about 18% by weight, or about 8% to about 15% by weight.

[0100] According to some embodiments, the relative ratios of surfactant (eg, Kolliphor EL) and thickener (eg, beeswax) can be kept relatively constant, while the relative ratios of vehicle and API are varied.

[0101] An exemplary composition according to one embodiment is shown below: [Table 2]

[0102] An exemplary composition according to another embodiment is shown below: [Table 3]

[0103] IV. Route of Administration of the Composition The present invention further relates to the administration of at least one compound disclosed herein by a route including, but not limited to, oral, parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraabdominal, intracapsular, intrachondral, intracavitary, intracerebral, intracelial, intracerebellar, intraventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarenal, intraretinal, intrathecal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, iontophoretic or transdermal means.

[0104] It may be desirable to deliver the compounds disclosed herein to a subject for extended periods of time, from a single administration to a week to a year. Certain medical devices can be used to provide continuous intermittent or on-demand administration to a patient. The device can be a diffusion device, pump, or other device that contains a reservoir of drug and, optionally, a diagnostic or monitoring component to control the delivery of the drug. A variety of sustained release, depot, or implant dosage forms can be used. The dosage form may include pharma- ceutically acceptable non-toxic salts of the compounds disclosed herein that have low solubility in body fluids, (a) acid addition salts with polybasic acids, such as phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene mono- or disulfonic acid, polygalacturonic acid, and the like; (b) salts with polyvalent metal cations, such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, and the like, or with organic cations, such as those formed from N,N'-dibenzyl-ethylenediamine or ethylenediamine; or (c) a combination of (a) and (b), zinc tannate salt. The compounds of the invention or relatively insoluble salts, such as those described herein, may also be formulated as gels suitable for injection, such as aluminum monostearate gels with sesame oil. Salts include, but are not limited to, zinc salts, zinc tannate salts, pamoic acid salts, and the like. Another type of injectable sustained release depot formulation comprises a compound or salt dispersed or encapsulated in a slowly degrading, non-toxic, non-antigenic polymer, such as polylactic acid / polyglycolic acid polymers, including the formulations described in U.S. Pat. No. 3,773,919. Compounds or relatively insoluble salts, such as those described above, can be formulated as cholesterol matrix silastic pellets, particularly for use in animals. Additional sustained release, depot or implant formulations, such as gas or liquid liposomes, are known in the literature. See, for example, U.S. Pat. No. 5,770,222; SUSTAINED AND CONTROLLED RELEASE DRUG DELIVERY SYSTEMS (1978).

[0105] Other examples include providing the compounds disclosed herein administered by a sustained release delivery system comprising a biodegradable composition. The biodegradable composition may be composed of a biodegradable, water-coagulable non-polymeric material and a biocompatible, non-toxic organic solvent that is miscible or dispersible in aqueous media. The delivery system may be embedded at the implant site and allow the solvent to dissipate, disperse or leach from the composition through the resulting microporous matrix into the surrounding tissue fluids.

[0106] The term "implant site" is meant to include a site in or on which the non-polymeric composition is applied. The implantation or implantation site may also include incorporating a pharmaceutical composition comprising at least one compound of the present invention into a solid device. The pharmaceutical composition may be incorporated into a coating on a stent that is implanted into the subject. Also, other solid or biodegradable materials may be used as substrates to which the pharmaceutical composition is applied. The coated material comprising the pharmaceutical composition is then implanted, inserted into, or adjacent to the subject or patient. The term "biodegradable" means that the non-polymeric material and / or matrix of the implant degrades over time by the action of enzymes, simple or enzyme-catalyzed hydrolysis, and / or other similar mechanisms within the human body. "Bioerodible" means that the implant matrix erodes or degrades over time, at least in part, due to contact with substances found in the surrounding tissue fluids, cellular action, and the like. "Bioresorbable" means that the non-polymeric matrix degrades and is absorbed by the human body, cells, tissues, and the like.

[0107] The non-polymeric materials that can be used in the composition are generally biocompatible, substantially insoluble in water and body fluids, biodegradable and / or bioerodible. The non-polymeric materials can be at least partially solubilized in water-soluble organic solvents. The non-polymeric materials can also be solidified or solidified to form a solid implant matrix. The non-polymeric materials are combined with a compatible and suitable organic solvent to form a composition with a desired viscosity ranging from watery to viscous to a spreadable putty or paste.

[0108] Suitable organic solvents are those that are biocompatible, medicamentously acceptable, and at least partially dissolve the non-polymeric material. The organic solvent has a solubility ranging from miscible to dispersible in water. Optionally, a pore former can be included in the composition to generate additional pores in the implant matrix. The pore former can be any organic or inorganic medicamentously acceptable substance that is substantially soluble in water or body fluids and dissipates from the solidified non-polymeric material and / or solid matrix of the implant into the body fluids surrounding the implant site.

[0109] The compounds of the present invention can provide local or systemic biological, physiological or therapeutic effects in the body of an animal. In formulating some pharmaceutical compositions described herein, the compounds are preferably soluble or dispersible in the non-polymeric composition to form a homogeneous mixture and become incorporated into the implant matrix upon implantation. As the solid matrix degrades over time, the compounds can be released from the matrix into adjacent tissue fluids and into associated body tissues or organs adjacent or distant from the implant site, preferably at a controlled rate. The release of the compounds from the matrix can vary depending on the solubility of the compounds in aqueous media, the distribution of the compounds within the matrix, the size, shape, porosity, solubility and biodegradability of the solid matrix. See, for example, U.S. Patent No. 5,888,533. The amounts and concentrations of the components in the composition administered to the patient are generally effective to achieve the intended task.

[0110] In other embodiments, the compounds of the present invention can be administered by a bioactive agent delivery system that includes microparticles suspended in a polymer matrix.The microparticles can be microcapsules, microspheres or nanospheres that are currently known in the art.The microparticles must be gels or can be incorporated intact into polymers that become gels when they enter a biological environment.The microparticles can be biodegradable or non-biodegradable.Many microencapsulation techniques are taught in the art that are used to incorporate bioactive agents into microparticle carriers.See, for example, U.S. Patent Nos. 4,652,441; 5,100,669; 4,438,253; and 5,665,428.

[0111] The preferred polymer matrix is ​​biodegradable, water soluble at low temperatures, and undergoes reversible thermogelation at mammalian physiological body temperature. The polymer matrix can release substances incorporated within the matrix in a controlled manner over time. The polymer is gradually degraded by enzymatic or non-enzymatic hydrolysis in an aqueous or physiological environment. See, for example, U.S. Patent No. 6,287,588.

[0112] V. Manufacturing method Methods for preparing various pharmaceutical compositions containing a certain amount of active ingredient are known to those skilled in the art, or will be apparent in light of this disclosure. The methods for preparing the pharmaceutical compositions may incorporate other suitable pharmaceutical excipients and their formulations as described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishing Company, 19th ed. (1995).

[0113] The method of preparing the pharmaceutical preparation of the present invention is prepared by known methods, including conventional mixing, dissolving or freeze-drying process.Accordingly, liquid pharmaceutical preparation can be obtained by combining active compound with solid additive, optionally grinding the obtained mixture, and processing granular mixture, after adding suitable auxiliary as required or necessary.

[0114] VI. Treatment Method Those skilled in the art will understand that the method of administering a pharmacologic effective amount of the compositions disclosed herein to a patient in need thereof can be determined empirically or by standards currently recognized in the medical field. The drug may be administered to the patient as a pharmaceutical composition in combination with one or more pharmacologic acceptable additives. It is understood that when administered to a human patient, the total daily use of the drug of the composition of the present invention will be determined within the scope of sound medical judgment by the attending physician. The specific therapeutically effective dose level for a particular patient will depend on a variety of factors, such as the type and extent of cellular response to be achieved; the activity of the specific drug or composition used; the specific drugs or compositions used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and excretion rate of the drug; the duration of treatment; drugs used in combination or simultaneously with a particular drug; and similar factors well known in the medical field. It is well within the scope of the art to start the dose of the drug at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0115] Dosages can also be administered in a patient specific manner to provide a predetermined concentration of drug in the blood, as determined by techniques accepted and routine in the art.

[0116] VII. Dose Determination In general, the compounds disclosed herein can be used alone or in combination at appropriate doses determined by routine testing to obtain optimal effectiveness while minimizing potential toxicity.The administration regimen utilizing the compounds of the present invention can be selected according to various factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the specific compound used.A physician or veterinarian with ordinary skill can easily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progression of the condition.

[0117] Optimal precision in achieving drug concentration within the range that provides maximum efficacy with minimal toxicity may require a regimen based on the kinetics of compound availability to one or more target sites.When determining the optimal concentration of treatment regimen, drug distribution, equilibrium and elimination may be considered.The dosage of the compounds disclosed herein may be adjusted when combined to achieve desired effects.On the other hand, the dosage of these various therapeutic agents may be optimized independently and combined to achieve synergistic effects that alleviate disease symptoms more than either drug alone.

[0118] In particular, the toxicity and therapeutic efficacy of the compounds disclosed herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., LD 50 (the dose at which 50% of the population is lethal) and ED 50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 The therapeutic index may be expressed as: The therapeutic index of the compound is preferably large, except when the cytotoxicity of the compound is the desired activity or therapeutic outcome. Compounds that exhibit toxic side effects may be used, but the delivery system may target such compounds to the site of affected tissues to minimize potential damage to non-infected cells, thereby reducing side effects. In general, the compounds of the present invention may be administered in a manner that maximizes efficacy and minimizes toxicity.

[0119] The data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds is preferably administered at an ED 50 The therapeutically effective dose for any compound used in the method of the invention can be estimated initially from cell culture assays. The dose can be determined based on the IC 50The concentration of the test compound that achieves half-maximal inhibition of symptoms can be formulated in animal models to achieve a circulating plasma concentration range that includes (the concentration of the test compound that achieves half-maximal inhibition of symptoms). Such information can be used to accurately determine useful doses in humans. Plasma levels can be measured by high performance liquid chromatography.

[0120] Furthermore, the dosage of the pharmaceutical composition of the present invention can be optimized using a pharmacokinetic / pharmacodynamic modeling system. One or more dosage regimens can be selected, and a pharmacokinetic / pharmacodynamic model can be used to determine the pharmacokinetic / pharmacodynamic profile of one or more dosage regimens. Then, one of the dosage regimens that achieves the desired pharmacokinetic / pharmacodynamic response can be selected based on the specific pharmacokinetic / pharmacodynamic profile. See U.S. Patent No. 6,747,002 (expressly incorporated by reference in its entirety).

[0121] For the disclosed pharmaceutical compositions or combinations of drugs, whether formulated in the same composition or not, methods for determining effective doses for therapeutic and prophylactic purposes are known in the art. For therapeutic purposes, the term "jointly effective amount" as used herein means the amount of each active compound or drug, alone or in combination, that induces the biological or medical response in a tissue system, animal or human that is desired by a researcher, veterinarian, physician or other clinician, including the alleviation of symptoms of the disease or disorder being treated. For prophylactic purposes (i.e., inhibiting the onset or progression of a disorder), the term "jointly effective amount" refers to the amount of each active compound or drug, alone or in combination, that inhibits the onset or progression of a disorder in a subject that is desired by a researcher, veterinarian, physician or other clinician. Thus, the invention further provides combinations of two or more therapeutic agents, where (a) each therapeutic agent is administered in an amount that is therapeutically or prophylactically effective independently; (b) at least one therapeutic agent in the combination is administered in an amount that is sub-therapeutic or sub-prophylactic when administered alone, but is therapeutic or prophylactic when administered in combination with a second or further therapeutic agent according to the invention; or (c) both therapeutic agents are administered in amounts that are sub-therapeutic or sub-prophylactic when administered alone, but are therapeutic or prophylactic when administered together. Combinations of three or more therapeutic agents are possible as well. Methods of combination therapy include co-administration of a single formulation containing all active drugs; essentially simultaneous administration of two or more formulations; and administration of two or more active drugs formulated separately.

[0122] More specifically, the pharmaceutical composition may be administered in a single dose per day, or the total daily dosage may be administered in divided doses two, three or four times per day. Doses may be administered for a week, a month, or for several months, 3, 6, 9 or 12 months, or for intervals known in the art and deemed clinically relevant. Doses may be continued throughout the patient's life or discontinued as clinically deemed necessary. The daily dosage of the composition may vary over a wide range from about 0.0001 to about 1,000 mg per patient per day. More specifically, the range may be from about 0.001 mg to 10 mg per kg of body weight per day, from about 0.1 to 100 mg per kg, from about 1.0 to 50 mg, or from about 1.0 to 20 mg per kg per day for an adult (about 60 kg). Additionally, dosages may be about 0.5-10 mg / kg per day, about 1.0-5.0 mg / kg per day, 5.0-10 mg / kg per day, or an equivalent dose as determined by a practitioner to achieve a clinically relevant serum concentration.

[0123] For injection, it is usually convenient to administer about 0.01 to 30 mg, about 0.1 to 20 mg, or about 0.1 to 10 mg per day to an adult (about 60 kg) via the intravenous route. Intravenous administration may include bolus administration or slow administration. For other animals, doses calculated for 60 kg may be administered similarly.

[0124] As a non-limiting example, human or animal treatment may be provided with a compound of the present invention in a single or regular dose of 0.0001 to about 1,000 mg per patient per day. More specifically, the range may be about 0.001 mg to 10 mg per kg of body weight per day, about 0.1 to 100 mg per day, about 1.0 to 50 mg per day, or about 1.0 to 20 mg per day for an adult (about 60 kg). Also, the dosage may be about 0.5 to 10 mg / kg per day, about 1.0 to 5.0 mg / kg per day, 5.0 to 10 mg / kg per day, or an equivalent dose as determined by a specialist to achieve a clinically relevant serum concentration. According to another embodiment, the compounds disclosed herein may be delivered orally or by other delivery methods at a dose of up to about 250 mg / kg.

[0125] Specifically, the pharmaceutical composition of the present invention can be administered at least once a week for several weeks. In one embodiment, the pharmaceutical composition is administered at least once a week for several weeks to several months. In another embodiment, the pharmaceutical composition is administered once a week for 4 to 8 weeks. In yet another embodiment, the pharmaceutical composition is administered once a week for 4 weeks.

[0126] VIII. METHODS OF USING THE COMPOUNDS OF THE PRESENT ART In another aspect, the present invention further relates to a method that has utility in treating any disease associated with a neurodegenerative disease or condition. More specifically, the present invention further provides a method for preventing, slowing down and / or reversing a neurodegenerative disease in a mammal. In certain embodiments, the method can include administering a composition comprising a compound as described herein to a mammal. The composition comprising a compound as described herein can be administered in an amount effective to prevent, ameliorate, treat or slow down the onset of a disease or condition in a mammal.

[0127] In further embodiments, the method of treating a mammal suffering from a neurodegenerative disease or condition may comprise administering to the mammal an effective amount of a composition comprising a compound as described herein. In other embodiments, the neurodegenerative disease or condition may be ischemic stroke, traumatic brain injury, acute disseminated encephalomyelitis, amyotrophic lateral sclerosis (ALS), retinitis pigmentosa, mild cognitive impairment, Alzheimer's disease, Pick's disease, senile dementia, progressive supranuclear palsy, subcortical dementia, Wilson's disease, multi-infarct disease, arteriosclerotic dementia, AIDS-associated dementia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedreich's ataxia, ataxia-telangiectasia, epilepsy-related brain injury, spinal cord injury, restless legs syndrome, Hansch's syndrome, or other neurodegenerative diseases. The neurodegeneration may be selected from the group consisting of: leukocyte nephropathy, Parkinson's disease, striatonigral degeneration, cerebral vasculitis, mitochondrial encephalomyopathy, neuronal ceroid lipofuscinosis, spinal muscular atrophy, lysosomal storage disorders with central nervous system involvement, leukodystrophy, urea cycle deficiency disorders, hepatic encephalopathy, renal encephalopathy, metabolic encephalopathy, porphyria, bacterial meningitis, viral meningitis, meningoencephalitis, prion disease, poisoning by neurotoxic compounds, Guillain-Barre syndrome, chronic inflammatory neuropathies, polymyositis, dermatomyositis, radiation-induced brain injury. Embodiments include neurodegeneration, including peripheral neuropathy, due to cranial irradiation or therapeutic administration of chemotherapeutic agents.

[0128] In another embodiment, a method for treating a mammal suffering from a neuropsychiatric disease or condition can include administering to the mammal an effective amount of a composition comprising a compound described herein. In other embodiments, the neuropsychiatric disease or condition can be selected from the group consisting of anxiety disorders, childhood disorders, eating disorders, mood disorders, cognitive disorders, personality disorders, psychotic disorders, and substance-related disorders.

[0129] More specifically, the types of psychiatric diseases / disorders / conditions that may be treated using the compounds of the present invention include: anxiety disorders, including but not limited to acute stress disorder, panic disorder, agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, and generalized anxiety disorder; pediatric disorders, including but not limited to attention deficit hyperactivity disorder, Asperger's disorder, autistic disorder, conduct disorder, oppositional defiant disorder, separation anxiety disorder, Tourette's disorder; eating disorders, including but not limited to anorexia nervosa and bulimia nervosa; mood disorders, including but not limited to major depressive disorder, bipolar disorder (manic depression), cyclothymic disorder, and dysthymic disorder; cognitive disorders, including but not limited to delirium, multi-infarct dementia, dementia associated with alcoholism, Alzheimer's dementia, and dementia. personality disorders, including but not limited to paranoid personality disorder, schizotypal personality disorder, schizotypal personality disorder, antisocial personality disorder, borderline personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, and obsessive-compulsive personality disorder; psychotic disorders, including but not limited to schizophrenia, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, and shared psychotic disorder; substance-related disorders, including but not limited to alcoholism, amphetamine dependence, cannabis dependence, cocaine dependence, hallucinogen dependence, inhalant dependence, nicotine dependence, opioid dependence, phencyclidine dependence, and sedative dependence.

[0130] Other objects, features and advantages of the present invention will become apparent from the following specific examples. The specific examples, while illustrating particular embodiments of the present invention, are provided for illustrative purposes only. Thus, the present invention also includes various changes and modifications within the spirit and scope of the present invention that may become apparent to those skilled in the art from this detailed description. The present invention is further illustrated by the following non-limiting examples. EXAMPLES

[0131] Example 1 [Table 4]

[0132] Exemplary formulation F2 was prepared by slowly adding NNI-362 while mixing into a jar containing 100 mL of lipid-based MCT / Kolliphor EL / Beeswax (95 / 3 / 2% w / w), then stirring until all powder was wet. The actual weight of NNI-362 was 11.88-12.12 g, yielding a nominal concentration of 120 mg / ml.

[0133] Example 2 A phase 1A randomized, placebo-controlled, single- and multiple-dose, dose-escalation study was conducted to evaluate the safety, tolerability, and pharmacokinetics of oral NNI-362 in healthy elderly volunteers aged 50-72 years. Subjects fasted prior to dosing. Plasma concentrations of NNI-362 were determined by a validated bioanalytical method using liquid chromatography-tandem mass spectrometry (LC-MS / MS). Stable labeled d5-NNI-362 was used as an internal standard in the assay.

[0134] NNI-362 was formulated in 1% (w / v) methylcellulose in sterile water as an oral suspension administered to cohorts A through E. Cohorts F and G received NNI-362 in an oral suspension in a lipid-based formulation (medium chain triglycerides, Kolliphor EL and beeswax; 95 / 3 / 2%; NNI-362 added to 120 mg / ml).

[0135] Methods for analyzing pharmacokinetic data PK data analysis was performed on the plasma concentrations of NNI-362. Plasma concentration data were evaluated using Phoenix 64® WinNonlin® software (Version 8.3) and noncompartmental analysis was performed.

[0136] The following PK parameters were determined for NNI-362 plasma concentrations in each subject: maximum observed plasma concentration (C max ), C maxObservation time until reaching (T max ), until the last blood draw (AUC last ), and extrapolated to infinity (AUC inf ) area under the plasma concentration-time curve, extrapolated AUC inf Percentage of Extra AUC inf ), terminal elimination half-life (t 1 / 2 ), and the mean residence time to infinity (MRT inf ). End 1 / 2 , AUC inf , MRT inf could not be calculated in some subjects because of limited data or poor fit of the terminal phase of the plasma concentration-time curves (r<0.8). Extrapolation of more than 20% of the AUC may make the values ​​of the terminal parameters unreliable.

[0137] PK result Terminal correlation coefficients were determined using WinNonlin. Significant differences in selected pharmacokinetic parameters between the SAD and MAD dose groups in cohorts F and G were assessed using t tests (two-tailed, paired tests; p<0.05).

[0138] Cohort A received a single oral dose of 10 mg per subject, and plasma samples from these subjects did not contain quantifiable concentrations of NNI-362. Cohort B received a dose of 20 mg; two subjects had one plasma sample each with drug concentrations above the limit of quantification (LLOQ=25 pg / ml). Table 1 shows the number of plasma samples containing NNI concentrations above 25 pg / ml for cohorts C, D, and E. Exposure to NNI-362 was low in these samples, and limited pharmacokinetic data were obtained. max The values ​​ranged from 15.1 pg / ml (subject 5006 MAD, 20 mg) to 69.0 pg / ml (subject 3007 SAD, 60 mg). AUC last and AUC for two subjects inf There were enough data points to calculate the terminal t 1 / 2was calculated for two subjects and was 4.09 hours (subject 3007) and 13.7 hours (subject 4008). inf The values ​​were 9.2 hours and 5.5 hours for 3007 and 4008, respectively.

[0139] Due to the low exposure to NNI-362 observed in cohorts A-E, a lipid-based formulation for oral administration of NNI-362 according to one embodiment of the present invention was evaluated. Table 2 shows the pharmacokinetic parameters for cohorts F and G, SAD and MAD phases. All subjects, except those who received placebo, had at least one sample with plasma concentrations above the LLOQ. The doses tested were 120 mg (cohort F, SAD and MAD) and 240 mg (cohort G, SAD and MAD). Exposure based on AUC values ​​was higher after multiple dosing (MAD) than after a single dose. T in cohorts F and G max The values ​​ranged from 0.5 to 8 hours, showing similar variability across all four treatment regimens as shown in Table 2, and the mean T max The mean C in cohort F and SAD was slightly higher than that in SAD, but the difference was not statistically significant. max The C was 92.4±60.6 pg / ml (99.0±63.9 ng / ml in cohort G, SAD). max The values ​​were higher than those after a single dose, 129 ± 67.3 ng / ml (cohort F, MAD) and 239 ± 230 pg / ml (cohort G, MAD), respectively, suggesting a dose-dependent increase in plasma concentrations, although the increase was not statistically significant. AUC inf The values ​​were 590 ± 184 h·pg / ml (Cohort F, SAD); 1323 ± 681 h·pg / ml (Cohort G, SAD); 2826 ± 1959 h·pg / ml (Cohort G, MAD); and 3426 ± 3298 h·pg / ml (Cohort F, MAD). These results indicate that exposure to NNI-362 increases with repeated dosing. Terminal t 1 / 2The values ​​were 6.24 ± 1.84 hours (Cohort F SAD); 12.2 ± 10.2 hours (Cohort F, MAD); 2.58 ± 0.25 hours (Cohort G, SAD); and 11.7 ± 8.94 hours (Cohort G, MAD). 1 / 2 The values ​​indicate that NNI-362 is not completely cleared within 24 hours, resulting in accumulation of NNI-362 and higher AUC values ​​after daily dosing compared to single doses of NNI-362. inf Values ​​were lowest in Cohort F SAD (9.99 ± 2.55 hours) and higher in the other three groups: 19.2 ± 14.3 hours (Cohort F MAD), 16.7 ± 17.5 hours (Cohort G SAD), and 17.7 ± 13.0 (Cohort G MAD).

[0140] conclusion The change in formulation of NNI-362 increased the plasma concentrations observed in cohorts F and G compared to cohorts A-E. Cohorts D and F both received 120 mg of NNI-362, but in two different formulations. Although there was greater intersubject variability, NNI-362 was quantifiable in plasma samples from all subjects in cohort F who received NNI-362, and at more time points than subjects in cohort D who received NNI-362 in the original formulation. Multiple daily dosing and increased dose in the lipid formulation also increased C max and higher exposure and longer terminal t 1 / 2 and MRT inf tended to bring value. [Table 5] [Table 6]

[0141] Having thus described the present invention, it will be understood by those skilled in the art that the same may be practiced within a broad and equivalent range of conditions, formulations and other parameters without affecting the scope of the present invention or any of its embodiments. All patents and publications cited herein are hereby incorporated by reference in their entirety.

Claims

1. 1. A pharmaceutical composition comprising an API in a lipid formulation, wherein the API is represented by formula (I): 【Chemistry 1】 (I) [In the formula, Each R 1 are independently H, F, C1, Br, R 7 AND -OR 7 R 7 is a substituted alkyl group having 1 to 6 carbon atoms or an aryl or aralkyl group having 6 to 14 carbon atoms; R 2 is selected from O or S; R 3 is (CH 2 ) m where m is 1, 2 or 3; R 4 is N and (CH n ), n is equal to 1 or 2, provided that R 4 is nitrogen, R 3 m is not equal to 1; R 6 is H; Each R 8 are, independently, -X, -R 9 , -OR 9 , -SR 9 , -N(R 9 ) 2 , -CN, -NO 2 , -NC(O)R 9 , -C(O)R 9 , -C(O)N(R 9 ) 2 , -S(O) 2 R 9 , -S(O) 2 NR 9 , -S(O)R 9 , -C(O)R 9 , -C(O)OR 9 or -C(O)N(R 9 ) 2 and Each X is independently a halogen; Each R 9 are independently -H, alkyl, alkenyl, alkynyl, aryl, heterocycle, a protecting group, or a prodrug moiety. or a pharma- ceutically acceptable salt thereof.

2. The compound is the following compound: 【Chemistry 2】 and physiologically acceptable salts thereof.

3. The compound is 【Chemistry 3】 or a physiologically acceptable salt thereof.

4. The compound is 【Chemistry 4】 or a physiologically acceptable salt thereof.

5. 5. The pharmaceutical composition of claim 1, wherein the lipid formulation comprises about 85-95.5% vehicle, about 1-8% surfactant, and about 0.5-7% viscosity enhancer by weight of the lipid formulation.

6. 6. The pharmaceutical composition of claim 5, wherein the vehicle is selected from the group consisting of vegetable oils, triglycerides, monoglycerides, diglycerides, oily fatty acids, isopropyl myristate, oily fatty alcohols, esters of sorbitol and fatty acids, oily sucrose esters, mineral oils, and mixtures thereof.

7. 7. The pharmaceutical composition of claim 6, wherein the vehicle is a medium chain triglyceride (MCT).

8. 6. The pharmaceutical composition of claim 5, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, esters of polyoxyethylene sorbitan or polyethylene glycol, dioctyl sodium sulfosuccinate (DOSS), lecithin, stearyl alcohol, cetostearyl alcohol, cholesterol, hydrogenated castor oil and its derivatives or fractions, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, hydrogenated polyoxyethylene fatty acid glycerides, Pluronic surfactants and mixtures thereof.

9. 9. The pharmaceutical composition according to claim 8, wherein the surfactant is a nonionic surfactant having an HLB value of 12 to 14.

10. 9. The pharmaceutical composition of claim 8, wherein the surfactant is polyoxyl 35 castor oil.

11. 6. The pharmaceutical composition of claim 5, wherein the thickening agent is selected from the group consisting of waxes, polyacrylate and polyacrylate copolymer resins, cellulose and cellulose derivatives and their salts, polyvinylpyrrolidones, polyvinyl resins, other polymeric materials, inorganic thickening agents, and mixtures thereof.

12. 12. The pharmaceutical composition of claim 11, wherein the thickening agent is selected from the group consisting of colloidal silica, beeswax, microcrystalline wax and mixtures thereof.

13. 13. The pharmaceutical composition of claim 12, wherein the thickening agent is beeswax.

14. 6. The pharmaceutical composition of claim 5, wherein the vehicle is medium chain triglyceride (MCT), the surfactant is polyoxyl 35 castor oil, and the thickener is beeswax.

15. 13. The pharmaceutical composition of claim 1 for delivering an API to a mammal, wherein the composition is administered to the mammal as a capsule or gel capsule.

16. 10. The pharmaceutical composition of claim 1 for treating at least one condition selected from the group consisting of developmental delay, psychiatric disorders, neurodegenerative diseases, neurological disorders and aging in a subject in need of such treatment.

17. The pharmaceutical composition of claim 16, wherein the subject is a mammal.

18. 18. The pharmaceutical composition of claim 17, wherein the mammal is a pet or livestock.

19. 18. The pharmaceutical composition of claim 17, wherein the mammal is a human.

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