use of a compound to reduce body fat and adipocytes

专利摘要:
METHODS AND COMPOSITIONS FOR REDUCING BODY FAT AND ADIPOCYTES. The present invention provides methods for reducing body fat in an individual, comprising administering locally (e.g., topically) one or more compounds of formula (I) and/or (V) or of a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer or isotopically enriched derivative thereof, or prodrug thereof, wherein X is -OR1, -SR2 or -NR3R4, and R,1 R,2R ,3 R,4 R,5 R,6 R,7,R7', z, Y, n, y and x are as defined herein.
公开号:BR112014014004B1
申请号:R112014014004-9
申请日:2012-12-19
公开日:2021-07-06
发明作者:Murat V. Kalayoglu；Michael S. Singer
申请人:Topokine Therapeutics, Inc.；
IPC主号:

专利说明:

FIELD OF THE INVENTION
[0001] The present invention relates to methods and compositions to reduce fat and/or adipocytes in the body of an individual. More specifically, body fat can be reduced by administering, locally to a subject, the compound including, but not limited to, tafluprost, as described herein. HISTORY OF THE INVENTION
[0002] Excess body fat is an important cause of human disease, disability and cosmetic discomfort. For many people, excess body fat is also a source of psychosocial stress and reduced self-esteem. Excess body fat can be diffused or concentrated in particular portion(s) of the body. This can involve, for example, unwanted, prominent fat deposits on the abdomen, buttocks, chest, thighs, arms and/or waist. This can also involve, for example, excessive breast tissue in a woman or a man, ie gynecomastia. Such local accumulations of body fat can result from constitutional factors, disease, hormonal status, or as side effects of medication or other substances. Even in the absence of disease, cosmetic considerations apply to individuals who, however, perceive excess fat and wish to have it corrected.
[0004] Numerous medical conditions are considered to be causes of excess body fat. Examples include drug-induced obesity, hypothyroidism, pseudohypoparathyroidism, hypothalamic obesity, polycystic ovarian disease, depression, binge eating, Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome, Down syndrome, Turner syndrome, deficiency of growth hormone, resistance to growth hormone and deficiency or resistance to leptin. Disfiguring excess regional fat deposits, eg excess dorsocervical fat, can be found in conditions such as HIV lipodystrophy, Cushing's Syndrome and pseudo Cushing's Syndrome (ie, characteristic excess body fat syndrome and others findings, due to excessive levels of endogenous or exogenous corticosteroids), other acquired lipodystrophy, familial lipodystrophy, lipoma, lipomatosis and Madelung's Disease.
[0005] Medications known to cause excess body fat include cortisol and analogues, other corticosteroids, megace, sulfonyl ureas, antiretrovirals, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, oral contraceptives, insulin, risperidone, clozapine and thiazolidinediones.
[0006] Changes in hormonal status, including physiological changes such as pregnancy or menopause, can result in excess body fat in an individual. Quitting smoking commonly leads to weight gain and excess body fat. Traumas can favor the accumulation of excess body fat due to immobility or disuse of an extremity. Similar problems can affect an individual who is immobilized, for example, due to an injury. Some tumors, for example lipomas and liposarcomas, are characterized by local collections of fat cells that are receptive to methods used to reduce body fat. Lipomatosis is a condition characterized by the formation of multiple lipomas in the body, eg familial multiple lipomatosis, adiposis dolorosis (Dercum's Disease), pelvic lipomatosis, etc.
[0007] Even in the absence of underlying pathology, an individual may have cosmetic questions about local or diffuse body fat deposits. These can usually be attributed to constitutional or hereditary factors, developmental history, age, gender, diet, alcohol use, or other components or lifestyle. Individuals in such circumstances commonly wish to reduce the amount of fat on the abdomen, chest, breasts, buttocks, hips, thighs, legs, knees, arms, chin, neck and/or part of the face. In some cases, the fat is not in actual excess but has become displaced, such as in age-related orbital fat prolapse or malar fat pad sagging.
[0008] Numerous methods have been developed to reduce or remove excess body fat. It is useful to classify these methods as extractive, metabolic, or adipolitical. Extractive methods, such as lipoplasty (eg, liposuction) or local excision, are methods by which fat is physically removed from areas of interest. Such methods are costly and may involve scarring, post-surgical deformity or regression, discomfort, infection and other adverse reactions.
[0009] Unlike extractive methods, metabolic methods, which include systemic medications, nutritional supplements, apparatus and exercise or other treatment for the body, seek to modify the individual's metabolism (for example, whether caloric consumption or caloric expenditure or both) such that the individual incurs a net loss of fat. One disadvantage is that these methods typically cannot target a particular part of the body. Another disadvantage is the potential concomitant loss of water, carbohydrates, protein, vitamins, minerals and other nutrients. In addition, traditional dietary medications can have unwanted side effects, for example, palpitations, tremor, insomnia and/or irritability in an individual using stimulants as appetite suppressants. Despite their wholesome value, traditional metabolic methods of diet and exercise are not practical for everyone.
[0010] Adipolitical methods aim to cause the degradation of adipocytes and/or their lipid content. For example, fat deposits can be reduced by exposure to cold temperature or to deoxycholate, a solubilizer that lyses cell membranes and results in local death. Disadvantages of these methods can include poor discrimination between adipose and other tissues in the vicinity, barriers to delivery that require hypodermic needles or special equipment, and adverse effects such as necrosis, inflammation, and pain.
[0011] Therefore, there is a demand for new compositions and methods for local administration, for fat reduction in an individual's body. SUMMARY OF THE INVENTION
[0012] The present invention is based on the finding that tafluprost is more effective than bimatoprost for local administration for reducing body fat. Analogs of tafluprost, such as other esters, thioesters, amides and the free acid of tafluprost are also expected to be more effective than bimatoprost for local administration to reduce body fat.
[0013] Therefore, in one aspect, methods are provided for reducing fat in an individual in need thereof, the methods comprising administering, locally to the individual, a compound of formula (I):
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof; in which X is: -ORi, where Ri is selected from the group consisting of hydrogen, a protecting group of hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl substituted, optionally substituted heteroaryl; -SR2, wherein the R2 group consists of hydrogen, a thiol protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; or -NR3R4, wherein R3 and R4 are independently selected from the group consisting of hydrogen, an amino protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl , optionally substituted heteroaryl, or R3 and R4 are joined to form an optionally substituted heterocyclyl ring.
[0014] In certain embodiments, when X is -ORi, a compound of formula (II) will be provided for use in the present invention:
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof. In certain embodiments, Ri is hydrogen. In certain embodiments, Rj is an oxygen protecting group. In certain embodiments, Rx is optionally substituted alkyl. In certain embodiments, R1 is methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, isobutyl or s-butyl. In certain embodiments, R1 is isopropyl <-CH(CH3 )2 .
[0015] In certain embodiments, when X is -SR2, a compound of formula (III) will be provided for use in the present invention:
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof. In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is a thiol protecting group. In certain embodiments, R2 is optionally substituted alkyl. In certain embodiments, R2 is methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, isobutyl or s-butyl. In certain embodiments, R2 is isopropyl (-CH(CH3)2).
[0016] In certain embodiments, when X is -NR3R4, a compound of formula (IV) will be provided for use in the present invention:
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof. In certain embodiments, R3 is hydrogen. In certain embodiments, R3 is a nitrogen protecting group. In certain embodiments, R3 is optionally substituted alkyl. In certain embodiments, R3 is methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, isobutyl or s-butyl. In certain embodiments, R3 is isopropyl (-CH(CH3)2). In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is a nitrogen protecting group. In certain embodiments, R4 is optionally substituted alkyl. In certain embodiments, R3 and R4 are joined to form an optionally substituted heterocyclyl ring.
[0017] In certain embodiments, in which R3 is hydrogen, the compound of formula (II) is the compound:
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer or isotopically enriched derivative thereof, which is also referred to herein as tafluprost free acid.
[0018] In certain embodiments, in which R 1 is isopropyl, the compound of formula (II) is the compound:
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer or isotopically enriched derivative thereof; which is also referred to here as tafluprost.
[0019] In another aspect, a method of applying a compound of the formula (V) is provided, for example, alone or in combination with a compound of the formula (I):
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer or isotopically enriched derivative thereof, or prodrug thereof; wherein R5, R6, R7, R7', Z, X, Y, n, y and x are as defined herein.
[0020] In certain embodiments, any of the above methods further comprise administering one or more additional compounds of formula (I), (II), (III), (IV) and/or (V), or a pharmaceutically salt acceptable, hydrate, solvate, stereoisomer, polymorph, tautomer or isotopically enriched derivative thereof.
[0021] In certain modalities, the individual suffers from or is likely to suffer from obesity, excess fat in the breasts, excess fat in the chin, gynecomastia, drug-induced obesity, hypothyroidism, pseudo-hypoparathyroidism, hypothalamic obesity, polycystic ovarian disease , depression, binge eating, postpartum obesity, obesity associated with smoking cessation, Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome, Down syndrome, Turner syndrome, growth hormone deficiency, resistance to growth hormone, leptin deficiency or resistance, Cushing's Syndrome, pseudo-Cushing's Syndrome, dorsocervical fat hypertrophy/dorsocervical fat hypertrophy ("buffalo hump"), lunar surfaces, HIV lipodystrophy, orbital fat prolapse , age-related drop in abdominal fat, other acquired lipodystrophy, familial lipodystrophy, lipoma, lipomatosis, or Madelung's Disease. In certain modalities, the individual suffers from or is likely to suffer from obesity, gynecomastia, HIV lipodystrophy, lipoma or excess chin fat.
[0022] In certain embodiments, the route of administration is selected from the group consisting of topical, subcutaneous, intradermal and intralesional. In certain modalities, the route of administration is topical. In certain embodiments, the site of administration is selected from the group consisting of the skin, the eyes or a mucous membrane. In certain embodiments, the route of administration is selected from the group consisting of subcutaneous, intradermal and intralesional. In certain embodiments, administration is to a body part selected from the group consisting of the abdomen, chest, breasts, buttocks, hips, thighs, legs, knees, arms, chin, neck and face. In certain embodiments, topical administration is transdermal administration.
[0023] In other aspects, pharmaceutical compositions are provided, for example, for reducing body fat, comprising a therapeutically effective amount of one or more compounds of the formula (I), (II), (III), (IV) and/ or (V), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer or isotopically enriched derivative thereof, and optionally one or more excipients. In certain embodiments, the composition is suitable for topical, subcutaneous, intradermal or intralesional delivery. In certain embodiments, the composition comprises from about 0.01% to about 10% (w/w) or (w/v), inclusive, of the compound of formula (I), (II), (III), ( IV) and/or (V). In certain embodiments, the excipient is Lipoderm®.
[0024] The above aspects and embodiments of the invention can be more fully understood by reference to the following Detailed Description, Examples and Claims. Definitions chemical definitions
[0025] Definitions of functional groups and specific chemical terms are described in more detail below. Chemical elements are identified in accordance with the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described herein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, as described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.
Certain compounds, as described herein, may comprise one or more asymmetric centers, and therefore may exist in various isomeric forms, for example, enantiomers and/or diastereomers. The compounds provided herein may be in the form of a single enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In certain embodiments, compounds as described herein are enantiomerically pure compounds. In certain other embodiments, mixtures of stereoisomers are provided.
In addition, certain compounds as described herein may have one or more double bonds which may exist either as cis or trans, or as an E or Z isomer, unless otherwise indicated. The invention further encompasses the compounds as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers, eg racemic mixtures of E/Z isomers or mixtures enriched in one E/Z isomer.
[0028] The expressions "enantiomerically enriched", "enantiomerically pure" and "non-racemic", as used interchangeably herein, refer to compositions in which the percentage by weight of an enantiomer is greater than the amount of that enantiomer in a control mixture of the racemic composition (eg greater than 1:1 by weight). For example, an enantiomerically enriched preparation of the (S) enantiomer means a compound preparation having more than 50% by weight of the (S) enantiomer relative to the (R) enantiomer, more preferably at least 75% by weight, and, even more preferably, at least 80% by weight. In some embodiments, the enrichment can be much greater than 80% by weight, providing a "substantially enantiomerically enriched", "substantially enantiomerically pure" or "substantially non-racemic" preparation, which refers to composition preparations having at least 85% % by weight of one enantiomer relative to another enantiomer, more preferably at least 90% by weight, and even more preferably at least 95% by weight. In preferred embodiments, the enantiomerically enriched composition has a higher potency with respect to therapeutic utility per unit mass than does the racemic mixture of that composition. Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric synthesis. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972).
[0029] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, "C1-6 alkyl" is intended to encompass C1, C2, C3, C4, C5, Cβ, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5. C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5 and C6-6 alkyl.
[0030] As used herein, alone or as part of another group, "alkyl" refers to a radical of a saturated hydrocarbon group, straight or branched, having from 1 to 20 carbon atoms ("C1-2o-alkyl" ). In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C1-10-alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-6-alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-5-alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-4-alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 -alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2-alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C 1 -alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-6-alkyl"). Examples of C1-6-alkyl groups include methyl (C3), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), t-butyl (C4), s-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5) and n-hexyl ( C6) . Unless otherwise specified, each case of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents. In certain embodiments, the alkyl group is unsubstituted C1-6 alkyl (eg, -CH3 ). In certain embodiments, the alkyl group is a substituted C1-6 alkyl.
[0031] As used herein, the expressions "per- or "alkyl substituted with halogen", as defined herein, refers to an alkyl group having from 1 to 10 carbon atoms, all of which hydrogen atoms are each. independently substituted by halogen, for example, selected from fluorine, bromine, chlorine or iodine ("Ci-10-per-haloalkyl") In some embodiments, the alkyl moiety has 1 to 6 carbon atoms ( "Ci-β-perhaloalkyl". In some embodiments, the alkyl portion has 1 to 5 carbon atoms ("Ci-s-perhaloalkyl"). In some embodiments, the alkyl portion has 1 to 4 carbon atoms ( "C1-4-perhaloalkyl". In some embodiments, the alkyl portion has 1 to 3 carbon atoms ("C1-3-per-haloalkyl"). In some embodiments, the alkyl portion has 1 to 2 carbon atoms ("C1-2" -per-haloalkyl"). In some embodiments, all hydrogen atoms are each replaced by fluorine. In some embodiments, all hydrogen atoms are each replaced by chlorine. Examples of perhaloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CC13, -CFC12, -CF2C1 and the like.
As used herein, the word "alkoxy" refers to an alkyl group, as defined herein, substituted with an oxygen atom, the point of attachment being the oxygen atom. In certain embodiments, the alkyl group has 1 to 6 carbon atoms ("C1-6-alkyloxy"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C1-4-alkyloxy"). Examples of C1-4-alkyloxy groups include methoxy (C1-4), ethoxy (C2), propoxy (C3), isopropoxy (C3), butoxy (C4), t-butoxy (C6) and the like. Examples of C1-4 alkyloxy groups include the aforementioned C1-4 alkyloxy groups, as well as (C5) pentyloxy, (C5) isopentyloxy, (C5) neopentyloxy, (C6) hexyloxy and the like. Unless otherwise specified, each instance of the alkyl portion of the alkyloxy group is independently unsubstituted (an "unsubstituted alkyloxy") or substituted (a "substituted alkyloxy") with one or more substituents. In certain embodiments, the alkyloxy group is a Unsubstituted C1-6 alkyloxy. In certain embodiments, the alkyloxy group is a substituted C1-6 alkyloxy.
As used herein, the word "alkyl-carboxy" refers to a group of the formula -C(=O)ORa, in which Ra is an alkyl group as defined herein. In certain embodiments, the alkyl group of the alkyl carboxy group has 1 to 6 carbon atoms ("C 1-6 alkyl carboxy"). In some embodiments, the alkyl group of the alkyl carboxy group has 1 to 5 carbon atoms ("C 1 5 -alkyl carboxy"). In some embodiments, the alkyl group of the alkyl-carboxy group has 1 to 4 carbon atoms ("C1-4-alkyl-carboxy"). In some embodiments, the alkyl group of the alkyl-carboxy group has 1 to 3 carbon atoms ("C1 -alkyl-carboxy"). In some embodiments, the alkyl group of the alkyl carboxy group has 1 to 2 carbon atoms ("C 1 2 -alkyl carboxy"). Unless otherwise specified, each instance of the alkyl group of the alkyl carboxy group is independently unsubstituted (an "unsubstituted alkyl carboxy") or substituted (a "substituted alkyl carboxy") with one or more substituents. In certain embodiments, the alkyl carboxy group is an unsubstituted C 1-6 alkyl carboxy. In certain embodiments, the alkyl carboxy group is a substituted C 1-6 alkyl carboxy.
[0034] As used herein, alone or as part of another group, the word "alkenyl" refers to a radical of a hydrocarbon group, straight or branched, having from 2 to 20 carbon atoms and one or more doubles. carbon-carbon ("C2-2o-alkenyl") bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C2-10 -alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-6-alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-s-alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-4-alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-3-alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms (*C2-alkenyl). The one or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl) Examples of C2-4-alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4) and the like Examples of C2-β-alkenyl groups include the aforementioned C2-4-alkenyl groups, as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6) and the like. Unless otherwise specified, each case of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2_6-alkenyl. the alkenyl group is a substituted C2_6-alkenyl.
[0035] As used herein, alone or as part of another group, "alkynyl" refers to a radical of a hydrocarbon group, straight or branched, having from 2 to 20 carbon atoms and one or more triple carbon bonds -carbon ("C2-20" alkynyl"). In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C2_10-alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (" C2_6-alkynyl". In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2_5-alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2_4-alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (*C2_3-alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C2-alkynyl"). The one or more carbon-carbon triple bonds may be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4) and the like. Examples of C2_6-alkynyl groups include the aforementioned C2_4-alkynyl groups, as well as pentynyl (C5), hexynyl (C6) and the like. Unless otherwise specified, each case of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2_6-alkynyl. In certain embodiments, the alkynyl group is a substituted C2_6-alkynyl.
[0036] As used herein, a "saturated or unsaturated acyclic hydrocarbon" refers to a straight or branched chain saturated or unsaturated hydrocarbon group radical having 1 to 20 carbon atoms and optionally one or more doubles or triple carbon-carbon bonds. In certain embodiments, the hydrocarbon group is saturated. In some embodiments, the hydrocarbon group is unsaturated, and contains one or more carbon-carbon double or triple bonds. In some embodiments, the hydrocarbon group contains 110 carbon atoms. In certain embodiments, the hydrocarbon group contains 1-5 carbon atoms. In some embodiments, the hydrocarbon group contains 1-4 carbon atoms. In some embodiments, the hydrocarbon group contains 1-3 carbon atoms. In some embodiments, the hydrocarbon group contains 1-2 carbon atoms.
[0037] As used herein, "carbocyclyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 7 ring carbon atoms (*C3_7-carbocyclyl") and zero heteroatoms in the non-aromatic ring system In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6-carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6-carbocyclyl"). Exemplary C3_7-carbocyclyl include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl ( C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like. , the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (eg containing a system of fused, bridged or spiro ring, such as a bicyclic ("bicyclic carbocyclyl") system, and may be saturated or may contain one or more double or triple carbon-carbon bonds. "Carbocyclyl" also includes ring systems, wherein the carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, the point of attachment being on the carbocyclyl ring, and in such cases, the carbon number continues to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with 1, 2, 3, 4 or 5 substituents as described herein. In certain embodiments, the carbocyclyl group is an unsubstituted C3-10-carbocyclyl. In certain embodiments, the carbocyclyl group is a C3-10 substituted carbocyclyl.
In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 7 ring carbon atoms ("C3_7-cycloalkyl]a"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-6-cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("Cs-g-cycloalkyl"). Examples of C5-6-cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3_6-cycloalkyl groups include the aforementioned C5_6-cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3_7-cycloalkyl groups include the aforementioned C3_6-cycloalkyl groups, as well as (C7) cycloheptyl. Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-7-cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-7-cycloalkyl.
[0039] As used herein, alone or as part of another group, "heterocyclyl" refers to a radical of a 3 to 8 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, being that each heteroatom is independently selected from nitrogen, oxygen and sulfur ("3- to 8-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as the valence allows. A heterocyclyl group can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (for example, a fused, bridged, or spiro ring system, such as a bicyclic ("bicyclic heterocyclyl") ring system, and can be saturated or can contain one or more carbon-carbon double or triple bonds. Polycyclic heterocyclyl ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems, wherein the heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, the point of attachment being either the carbocyclyl ring or the heterocyclyl ring, or ring systems, wherein the heterocyclyl ring, as defined above, is fused to one or more groups aryl or heteroaryl, the point of attachment being on the heterocyclyl ring, and in such cases, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system.
[0040] In some embodiments, a heterocyclyl group is a non-aromatic 5-8 membered ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a non-aromatic 5-6 membered ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur (" 5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen and sulfur. Exemplary 3-membered heterocyclyls containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyls containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyls containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyls containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyls containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl, and tiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Unless otherwise specified, each case of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-8 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-8 membered heterocyclyl.
[0041] As used herein, alone or as part of another group, "aryl" refers to a radical of a 4n+2 monocyclic or polycyclic (e.g. bicyclic or tricyclic) 4n+2 aromatic ring system having 6- jo ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-10-aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6-aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C10-aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). "Aryl" also includes ring systems, wherein the aryl ring, as defined above, is fused to one or more cycloalkyl or heterocyclyl groups, the radical or point of attachment being on the aryl ring, and, in such cases, the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents as described herein. In certain embodiments, the aryl group is an unsubstituted C6-io-aryl. In certain embodiments, the aryl group is a substituted C6-10-aryl.
[0042] As used herein, alone or as part of another group, "heteroaryl" refers to a 5-14 membered radical of a 4n+2 monocyclic or polycyclic (eg bicyclic) aromatic ring system having 4- 10 ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as the valence allows. Polycyclic heteroaryl ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems, wherein the heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, the point of attachment being on the heteroaryl ring, and, in such cases, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems, wherein the heteroaryl ring, as defined above, is fused to one or more aryl groups, the point of attachment being on either the aryl ring or the heteroaryl ring, and in in such cases, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups, in which a ring does not contain a heteroatom (for example, indolyl, quinolinyl, carbazolyl and the like), the point of attachment may be either on the ring, i.e., or on the ring bearing a heteroatom (for example, 2 - indolyl) or the ring that does not contain the heteroatom (for example, 5-indolyl). In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen and sulfur ("heteroaryl 5-8 membered"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen and sulfur ("5-6 membered heteroaryl"). In 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen and sulfur Exemplary 5-membered heteroaryls containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryls containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. Exemplary 5-membered heteroaryls containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, thiadiazolyl. Exemplary 5-membered heteroaryls containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryls containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryls containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryls containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryls containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and tiepinyl. Exemplary 5,6-bicyclic heteroaryls include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzthiazolyl, and benzthiazolyl. Exemplary 6,6-bicyclic heteroaryls include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Unless otherwise specified, each case of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-10 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-10 membered heteroaryl.
Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, to which it refers without the suffix "-ene," describe an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl monoradical, respectively, and as defined herein, wherein the monoradical is directly linked to a parent molecule or other group by a bond (e.g., a single or a double bond). Monoradical groups, as defined herein, may also be optionally substituted. Groups referred to by the suffix "-ene", such as alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene groups describe an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl diradical, respectively, and as defined herein, wherein the diradical is between and directly linked to two groups (e.g., between the parent molecule and another group) by two bonds (e.g., single or double bonds). Diradical groups can also be optionally substituted.
Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups, as defined herein, are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl group, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl) . In general, the word "substituted", whether preceded by the word "optionally", or not, means that at least one hydrogen present in a group (for example, a carbon or nitrogen atom) is replaced by a substituent permissible, for example, a substituent which, upon substitution, results in a stable compound, for example a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent will be either the same or different at each position. .
Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups as defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl group, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl) . In general, the word "substituted", whether preceded by the word "optionally", or not, means that at least one hydrogen present in a group (for example, a carbon or nitrogen atom) is replaced by a substituent permissible, for example, a substituent which, upon substitution, results in a stable compound, for example a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group (eg, 1, 2, 3, 4 or 5 positions), and when more than one position in any given structure is substituted, the substituent will be either the same or different at each position. The word "substituted" is contemplated to include substitution with all permissible substituents of organic compounds, any one of the substituents described herein results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and/or any suitable substituent as described herein that satisfy the valences of the heteroatoms and that result in the formation of a stable moiety.
[0046] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -ON(Rbb)2, -N( Rbb)2, -N(0Rcc)Rbb, -SH, -SRaa, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)2, -CO2Raa, -OC(=O) Raa, -OCO2Raa, -C (=0) N (Rbb) 2, -OC (=0) N (Rbb) 2, -NRbbC ( =0) Raa, -NRbbC02Raa, -NRbbC (=0) N (Rbb) 2, -C (=NRbb) Raa, -C (=NRbb) 0Raa, -0C (=NRbb) Raa, -0C (=NRbb) 0Raa, -C (=NRbb) N (Rbb) 2, - 0C (= NRbb) N (Rbb) 2, -NRbbC (=NRbb) N (Rbb) 2' -C (=0) NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -0SO2Raa, -S( =O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3 -C (=S) N (Rbb) 2, -C(=O)SRaa, -C(= S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -SC(=O)ORaa, -OC(=O)SRaa, -SC(=O)Raa, -P(=0) 2Raa, -OP(=O)2Raa, -P(=0) (Raa)2, -0P(=0) (Raa)2, -0P(=0) (0Rcc)2, -P(=0) 2N (Rbb) 2, -0P(=0) 2N(Rbb)2, -P(=0) (NRbb)2, - 0P(=0) (NRbb)2, -NRbbP(=0) (0RCC)2, -NRbbP (=0) (NRbb) 2, -P(RCC)2, -P(RCC)3, -0P(RCC)2, -0P(RCC)3, -B(Raa)2, -B(ORCC )2, -BRaa(0Rcc), Ci-6-alky yl, C2_6-alkenyl, C2-6_alkynyl, C3_7-carbocyclyl, 3-8-membered heterocyclyl, C6_10-aryl and 5-10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl being independently substituted with 0, 1, 2, 3, 4 or 5 Rdd groups; or two hydrogens twinned on a carbon atom are replaced by the group =0, =S, =NN(Rbb)2, =NNRbbC (=0)Raa, =NNRbbC (=0) 0Raa, =NNRbbS (=0) 2Raa, =NRbb OR =NORCC; each case of Raa is independently selected from C1-6-alkyl, C2_6-alkenyl, C2_6-alkynyl, C3_7-carbocyclyl, 3-8-membered heterocyclyl, C6_10-aryl and 5-10-membered heteroaryl, or two Raaa groups are joined together. to form a 3-8 membered heterocyclyl ring or 5-10 membered heteroaryl ring, each of which alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 Rdd groups; each case of Rbb is independently selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa , -SO2Raa, -C (=NRCC) 0Raa, -C (=NRCC)N(RCC) 2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC) 2, -C(=O)SRCC, -C( = S)SRCC, -P(=O)2Raa, -P(=0) (Raa)2, -P (=0) 2N (Rcc) 2, - P(=0) (NRCC)2, CX_ 6-alkyl, C2_6-alkenyl, C2_6-alkynyl, C3_7-carbocyclyl, 3-8 membered heterocyclyl, C6_10-aryl and 5-10 membered heteroaryl, or two Rbb groups are joined to form a 3-8 membered heterocyclyl ring or a 5-10 membered heteroaryl ring, each of which alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3 , 4 or 5 Rdd groups; each case of Rcc is independently selected from hydrogen, C1-6-alkyl, C2-6-alkenyl, C2_6-alkynyl, C3-7-carbocyclyl, 3-8-membered heterocyclyl, C6-10-aryl, and 5-10-membered heteroaryl or two Rcc groups are joined to form a 3-8 membered heterocyclyl ring or a 5-10 membered heteroaryl ring, each of which alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3 , 4 or 5 Rdd groups; each case of Rfki is independently selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N( ORee)Rff, -SH, -SRGG, -SSRee, -C(=O)RGG, -CO2H, -C(=O)ORee, -OC(=O)Ree, -OC(=O)ORGG, —C (=O)N(R££) 2, -OC(=O)N(R££)2, -NR££C (=0) RGG, -NR££CO2RGG, -NRf£C (=0) ) N (R££) 2, -C (=NR££)ORGG, -OC (=NR££) RGG, -OC (=NRff)ORee, -C(=NR££)N(R££ )2, -OC ( =NR£Í) N (R££) 2, -NR££C(=NR££)N(R££)2, -NR££SO2RGG, -SO2N(R££ )2, -SO2Ree, -SO2ORGG, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSI(RGG)3, -C(=S)N(R£)2, -C (=O)SRGG, -C(=S)SRee, -SC( = S)SRee, -P(=O)2RGG, -P(=O) (Ree)2, -0P(=0) (RGG) 2, -OP(=O) (OReG)2, C1-6-alkyl, C2_6-alkenyl, C2_6-alkynyl, C3_7-carbocyclyl, 3-8-membered heterocyclyl, C6_10-aryl and 5-10-membered heteroaryl, being that each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 Rgg groups, or two twin Rdd substituents may be joined to form = 0 or =S; each case of Ree is independently selected from C1-6-alkyl, C2_6-alkenyl, C2-and-alkynyl, C3_7-carbocyclyl, 3-8-membered heterocyclyl, C6-10-aryl, and 5-10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R99 groups; each case of Rf is independently selected from hydrogen, C1-6-alkyl, C2_6-alkenyl, C2_6-alkynyl, C3_7-carbocyclyl, 3-8-membered heterocyclyl, C6_10-aryl, and 5-10-membered heteroaryl, or two Rf groups are joined to form a 3-8 membered heterocyclyl ring or a 5-10 membered heteroaryl ring, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl being independently substituted with 0, 1, 2, 3, 4 or 5 R99 groups; and each case of R" is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OCr-6-alkyl, -ON(Ci-6-alkyl)2, -N(Ci -6-alkyl)2, -N(OCi_6-alkyl) (C1-6-alkyl), -N(OH) (C1-6-alkyl), -NH(OH), -SH, -SCi-6-alkyl, -SS ( C1-6-alkyl), -C(=0)(C1-6-alkyl), -CO2H, -CO2(C1-6-alkyl), -OC(=0)(C1-6-alkyl), -OCO2(C1-6-alkyl) -alkyl), -C(=O)NH2, -C(=0)N(C1 -g-alkyl) 2 , -0C (=0) NH (C3_6-alkyl), -NHC (=0) (C1_6 -alkyl), -N(C1-6-alkyl) C(=0)(C1-6-alkyl), -NHC (=0)N(C1-6-alkyl) 2 , -NHC (=0) NH(C1-6-alkyl) alkyl), -NHC(=0)NH2, -C(=NH)0(C1_6-alkyl), -0C(=NH)(C^β-alkyl), -OC (=NH) OCi-g-alkyl, -C(=NH)N(C1-6-alkyl)2, -C(=NH)NH(C1_6-alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6-alkyl)2 - SO2N(Ci_6-alkyl) 2, -SO2NH(Ci_6-alkyl), —SO2NH2, — SO2Ci-6—alkyl, —SO2OC3_6—alkyl, —OSO2C3_6—alkyl, -SOCi_6-alkyl, -Si(Ci_6-alkyl) 3 , -OSi ( C3_6-alkyl)3 -C (=S)N(Ci_6-alkyl)2, C (=S) NH (Ci-θ-alkyl), C(=S)NH2, -C (=0) S (Ci- 6-alkyl), -C (=S) SC1 -alkyl, -SC (=S) SC1-6 -alkyl, -P (=0) 2(C1-6 -alkyl), -P(=0) (C1-6 - alkyl)2, -OP (=0) (C1-6-alkyl) 2, -OP (=0) (OC1-6-alkyl) 2, C1-6-alkyl, C2_6-alkenyl, C2_6-alkynyl, C3_7-carbocyclyl, heterocyclyl with 3-8 membered, C6_10-aryl and 5-10 membered heteroaryl; or two twin R99 substituents can be joined to form =0 or =S.
[0047] Nitrogen atoms can be substituted or unsubstituted, as the valence allows, and include primary, secondary, tertiary and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -0H, -0Raa, -N(RCC)2, -CN, -C(=O)Raa, -C(=0)N(RCC) 2, -CO2Raa, -SO2Raa, -C (=NRbb) Raa, -C(=NRcc)0Raa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, - SORaa, —C (=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=0)2Raa, -P(=0) (Raa)2, - P(=O)2N(RCC)2, -P(=0) (NRCC)2, C3_6-alkyl, C2_6-alkenyl, C2_6-alkynyl, C3_7-carbocyclyl, 3-8-membered heterocyclyl, C6_10-aryl and 5-10 membered heteroaryl, or two Rcc groups linked to an N atom are joined to form a 3-8 membered heterocyclyl ring or a 5-10 membered heteroaryl ring, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined above.
[0048] As used herein, the words "hydroxyl" or "hydroxy" refer to the -OH group. The expressions "substituted hydroxyl" or "substituted hydroxy", by extension, refer to a hydroxyl group, in which the oxygen atom is replaced with a group other than hydrogen, for example, selected from -ORaa, -ON( Rbb)2, -OC(=O)Raa, -OC(=O)SRaa, -OCO2Raa, -OC (=0) N (Rbb) 2, -OC (=NRbb) Raa, -OC (=NRbb) ORaa , -OC (=NRbb)N (Rbb) 2, -OS(=O)Raa, -OSO2Raa, -OSi(Raa)3, -OP(RCC)2, -OP(RCC)3, -OP(=O )2Raa, -OP(=O) (Raa)2, -OP(=O) (ORCC)2, -OP(=0)2N(Rbb)2 and -OP(=O) (NRbb)2, where Raa, Rbb and Rcc are as defined herein.
[0049] As used herein, the words "thiol" or "thio" refer to the -SH group. The expressions "substituted thiol" or "substituted thio," by extension, refers to a thiol group, in which the sulfur atom is replaced with a group other than hydrogen, and includes groups selected from -SRaa, -S= SRCC, -SC(=S)SRaa, -SC(=O)SRaa, -SC(=O)ORaa and -SC(=O)Raa, where Raa and Rcc are as defined herein.
[0050] As used herein, the word "amino" refers to the -NH2 group.
As used herein, the term "substituted amino" refers to a monosubstituted, disubstituted or trisubstituted amino group as defined herein.
[0052] As used herein, the term "monosubstituted amino" refers to an amino group substituted with a hydrogen and a group other than hydrogen, and includes groups selected from -NH(Rbb), -NHC(=O)Raa , -NHCO2Raa, -NHC (=O)N (Rbb) 2, -NHC (=NRbb) N (Rbb) 2, -NHSO2Raa, -NHP (=0) (ORCC) 2e -NHP (=0) (NRbb) 2, where Raa, Rbb and Rcc are as defined herein, and where Rbb of the group -NH(Rbb) is not hydrogen.
[0053] As used herein, the term "disubstituted amino" refers to an amino group substituted with two groups other than hydrogen, and includes groups selected from -N(Rbb)2, -NRbb C(=O)Raa, -NRbbCO2Raa, -NRbbC (=0) N (Rbb) 2, -NRbbC ( =NRbb) N (Rbb) 2, -NRbbSO2Raa, -NRbbP (=0) (0Rcc) 2e -NRbbP (=0) (NRbb) 2 , where Raa, Rbb and Rcc are as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not replaced with hydrogen.
[0054] As used herein, the word "sulfonyl" refers to a group selected from -S(=O)2OH, -S(=0)2N(Rbb)2, -S(=O)2Raa and - S(=O)2ORaa, where Raa and Rbb are as defined herein.
[0055] As used herein, the word "sulfinyl" refers to -S(=O)OH and -S(=O)Raa, with Raa being as defined herein.
[0056] As used herein, the word "carbonyl" refers to a group, in which the carbon directly attached to the parent molecule is sp2 hybridized, and is replaced with an oxygen, nitrogen or sulfur atom, eg a selected group from ketones (-C(=O)Raa), carboxylic acids (-CO2H), aldehydes (-CHO), esters (-CO2Raa, -C(=O)SRaa, -C(=S)SRaa), amides (-C (=0) N (Rbb) 2, -C (=0) NRbbSO2Raa, -C (=S) N (Rbb) 2) and imines (-C (=NRbb) Raa, -C (=NRbb) 0Raa), -C (=NRbb)N (Rbb) 2), where Raa and Rbb are as defined herein.
[0057] As used herein, the word "silyla" refers to the group -Si(Raa)3, with Raa being as defined herein.
[0058] As used herein, the word "boronyl" refers to boranes, boronic acids, boronic esters, borinic acids and borinic esters, for example, boronyl groups of the formula -B(Raa)2, -B(ORCC)2 and -BRaa(ORcc), where Raa and Rcc are as defined herein.
As used herein, the word "phosphine" refers to the group -P(RCC)3, where Rcc is as defined herein. An exemplary phosphine group is triphenylphosphine.
[0060] As used herein, the words "halo" or "halogen" refer to fluorine (fluoro, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I) •
[0061] As used herein, "nitro" refers to the -NO2 group.
[0062] As used herein, "cyan" refers to the -CN group.
[0063] As used herein, "azido" refers to the -N3 group.
[0064] As used here, "oxo" refers to group =0.
[0065] Nitrogen atoms may be substituted or unsubstituted, as valence allows, and include primary, secondary, tertiary and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC) 2, -CO2Raa, -SO2Raa, -C (=NRbb) Raa, -C (=NRcc)ORaa, -C (=NRCC)N(RCC) 2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, - SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)2Raa, -P(=O) (Raa)2, - P(=O)2N(RCC)2, -P(=O) (NRCC)2, C1-10-alkyl, C1-10-perhaloalkyl, C2_10-alkenyl, C2-10-alkynyl, C3_10-carbocyclyl, 3-14 membered heterocyclyl, C6-14-aryl and 5-14 membered heteroaryl, or two R groups attached to an N atom are joined to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring members, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl being independently substituted with 0, 1, 2, 3, 4 or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined above .
[0066] In certain embodiments, the substituent present on the nitrogen atom is an "amino protecting group". Amino protecting groups include, but are not limited to, groups -OH, -ORaa, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC) 2, -CO2Raa, -SO2Raa, -C (=NRCC) Raa, -C (=NRCC) ORaa, -C(=NRcc)N(Rcc)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C( =S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, C1-10-alkyl (e.g., aralkyl, heteroaralkyl), C2-10-alkenyl, C2-10-alkynyl, Cβ -io-carbocyclyl, 3-14-membered heterocyclyl, C6_14-aryl, and 5-14-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl being independently substituted with 0, 1, 2 , 3, 4 or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined herein. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999.
[0067] For example, amino protecting groups, such as amide groups (eg, -C(=O)Raa), include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoro -acetamide, phenyl-acetamide, 3-phenyl-propanamide, picolinamide, 3-pyridyl-carboxamide, N-benzoyl-phenyl-alanyl derivative, benzamide, p-phenyl-benzamide, o-nitro-phenyl-acetamide, o-nitro -phenoxy-acetamide, aceto-acetamide, (N'-dithiobenzyloxy-carbonyl-amino) acetamide, 3-(p-hydroxy-phenyl)propanamide, 3-(o-nitro-phenyl)propanamide, 2-methyl-2-( o-nitro-phenoxy)propanamide, 2-methyl-2-(o-phenylazo-phenoxy)propanamide, 4-chloro-butanamide, 3-methyl-3-nitro-butanamide, o-nitro-cinamide, N-acetyl derivative -methionine, o-nitro-benzamide and o-(benzoyloxy-methyl)benzamide.
[0068] Amino protecting groups, such as carbamate (e.g., -C(=O)ORaa), include, but not limited to, methyl carbamate, ethyl carbamate, 9-fluorenyl-methyl carbamate (Fmoc) , 9-(2-sulfo)fluorenyl-methyl carbamate, 9-(2,7-dibromo)fluoroenyl-methyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo) carbamate -10,10,10,10-tetrahydrothioxantyl)] methyl (DBD-Tmoc), 4-methoxy-phenacyl carbamate (Phenoc), 2,2,2-trichloro-ethyl carbamate (Troe), 2- -trimethyl-silyl-ethyl (Teoc), 2-phenyl-ethyl carbamate (hZ), 1-(1-adamantyl)-1-methyl-ethyl carbamate (Adpoc), 1,1-dimethyl-2-carbamate halo-ethyl, 1,1-dimethyl-2,2-dibromo-ethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloro-ethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl (Bpoc), 1-(3,5-di-t-butyl-phenyl)-1-methyl-ethyl carbamate (t-Bumeoc), 2-( 2'- and 4'-pyridyl) ethyl (Pyoc), 2-(N,N-dicyclohexyl-carboxamido) ethyl carbamate, t-butyl carbamate (BOC), carbam 1-adamantyl act (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl-allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitro-cinnamyl carbamate (Noc ), 8-quinolyl carbamate, N-hydroxy-piperidinyl carbamate, alkyldithio-carbamate, benzyl carbamate (Cbz), p-methoxy-benzyl carbamate (Moz), p-nitro-benzyl carbamate, p-carbamate bromo-benzyl, p-chloro-benzyl carbamate, 2,4-dichloro-benzyl carbamate, 4-methyl-sulfinyl-benzyl carbamate (Msz), 9-antryl-methyl carbamate, diphenyl-methyl carbamate, carbamate of 2-methyl-thioethyl, 2-methyl-sulfonyl-ethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)] methyl carbamate (Dmoc), carbamate 4-methyl-thiophenyl (Mtpc), 2,4-dimethyl-thiophenyl carbamate (Bmpc), 2-phosphonium-ethyl carbamate (Peoc), 2-triphenyl-phosphonium-isopropyl carbamate (Ppoc), 1, carbamate 1-dimethyl-2-cyano-ethyl, m-chloro-p-acyloxy-benzyl carbamate, m-chloro-p-acyloxy-benzyl carbamate p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3rd carbamate, 5-dimethoxy-benzyl, o-nitro-benzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitro-phenyl) methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxycarbonyl vinyl carbamate, hydroxycarbamate o-(N,N-dimethyl-carboxamido) benzyl, 1,1-dimethyl-3-(N,N-dimethyl-carboxamido) propyl carbamate, 1,1-dimethyl-propynyl carbamate, di(2- pyridyl)methyl, 2-furanyl-methyl carbamate, 2-iodo-ethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-carbamate methyl-cyclobutyl, 1-methyl carbamate 1-cyclohexyl, 1-methyl-1-cyclopropyl-methyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazo-carbamate) phenyl) ethyl, 1-methyl-1-phenyl-ethyl carbamate, 1-methyl-1-(4-pyridyl) ethyl carbamate, phenyl carbamate, p-(phenylazo) benzyl carbamate, 2,4 carbamate, 6-tri-t-butyl-phenyl, 4-(trimethyl-ammonium) benzyl carbamate and 2,4,6-trimethyl-benzyl carbamate.
[0069] Amino protecting groups such as sulfonamide groups (for example, -S(=O)2Raa)/ include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,- trimethyl-4-methoxy-benzenesulfonamide (Mtr), 2,4,6-trimethoxy-benzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxy-benzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4 -methoxy-benzenesulfonamide (Mte), 4-methoxy-benzenesulfonamide (Mbs), 2,4,6-trimethyl-benzenesulfonamide (Mts), 2,6-dimethoxy-4-methyl-benzenesulfonamide (iMds), 2,2,5 ,7,8-pentamethyl-chroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethyl-silyl-ethanesulfonamide (SES), 9-anthracenesulfonamide, 4(4',8'-dimethoxy-naphthyl-methyl) benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoro-methyl-sulfonamide and phenacyl-sulfonamide.
[0070] Other amino protecting groups include, but are not limited to, phenothiazinyl-(10)-carbonyl derivative, N'-p-toluenesulfonyl-amino-carbonyl derivative, N'-phenyl-amino-thiocarbonyl derivative , N-benzoyl-phenyl-alanyl derivative, N-acetyl-methionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3- diphenyl-maleimide, N-2,5-dimethyl-pyrrole, addition product of N-1,1,4,4-tetramethyl-disilyl-azacyclopentane (STABASE), 1,3-dimethyl-1,3, 5-triaza 5-substituted cyclohexan-2-one, 1,3-dibenzyl-1,3,5-triaza 5-substituted cyclohexan-2-one, 3,5-dinitro-4-pyridone 1-substituted, N-methyl-amine, N-allyl-amine, N-[2-(trimethyl-silyl)ethoxy] methyl-amine (SEM), N-3-acetoxy-propyl-amine, N-(1-isopropyl-4- nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzyl-amine, N-di(4-methoxy-phenyl)methyl-amine, N-5-dibenzo-suberyl-amine , N-triphenyl-methyl-amine (Tr), N-[(4-methoxy-phenyl) diphenyl-methyl]-amine (MMTr), N-9-phenyl-fluorenyl -amine (PhF), N-2,7-dichloro-9-fluorenyl-methylene-amine, N-ferrocenyl-methyl-amino (Fem), N-2-picolyl-amino N'-oxide, N-1, 1-dimethyl-thiomethylene-amine, N-benzylidene-amine, Np-methoxy-benzylidene-amine, N-diphenyl-methylene-amine, N-[(2-pyridyl) mesityl] methylene-amine, N-(N', N'-dimethylamino-methylene)amine, N,N'-isopropylidene-diamine, Np-nitro-benzylidene-amine, N-salicylidene-amine, N-5-chloro-salicylidene-amine, N-(5- chloro-2-hydroxy-phenyl)phenyl-methylene-amine, N-cyclohexylidene-amine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)-amine, N-borane derivative, derived from N-diphenyl-borinic acid, N-[henyl(pentacarbonyl-chromium- or tungsten)carbonyl]-amine, N-copper chelate, N-zino chelate, N-nitro-amine, N-nitroso-amine, Amine N-oxide, diphenyl-phosphinamide (Dpp), dimethyl-thiophosphinamide (Mpt), diphenyl-thiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitro-benzenesulfenamide (Nps), 2,4-d initro-benzenesulfenamide, pentachloro-benzenesulfenamide, 2-nitro-4-methoxy-benzenesulfenamide, triphenyl-methyl-sulfenamide and 3-nitro-pyridinesulfenamide (Npys).
[0071] In certain embodiments, the substituent present on the oxygen atom is an "oxygen protecting group". Oxygen protection groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=O)Raa, -C(=O)ORaa, -C(=O)SRaa, -C ( =O)N(Rbb) 2, -C (=NRbb) Raa, -C (=NRbb) ORaa, -C (=NRbb) N (Rbb) 2, -S(=O)Raa, -SO2Ra“, - Si(Raa)3, -P(RCC)2, -P(RCC)3, -P(=O)2Raa, -P(=O) (Raa)2, -P(=O) (ORCC)2, -P(=0) 2N (Rbb) 2 and -P(=0) (NRbb) 2 where Raa, Rbta and Rcc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999.
[0072] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxy-methyl (MOM), methyl-thiomethyl (MTM), t-butyl-thiomethyl, (phenyl-dimethyl-silyl) methoxy-methyl ( SMOM), benzyloxy-methyl (BOM), p-methoxy-benzyloxy-methyl (PMBM), (4-methoxy-phenoxy) methyl (p-AOM), guaiacol-methyl (GUM), t-butoxy-methyl, 4- pentenyloxy-methyl (POM), siloxy-methyl, 2-methoxy-ethoxy-methyl (MEM), 2,2,2-trichloro-ethoxy-methyl, bis(2-chloro-ethoxy)methyl, 2-(trimethyl-silyl ) ethoxy-methyl (SEMOR), tetrahydropyranyl (THP), 3-bromo-tetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxy-cyclohexyl, 4-methoxy-tetrahydropyranyl (MTHP), 4-methoxy- tetrahydrothiopyranyl, 4-methoxy-tetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxy-piperidin-4-yl (CTMP), 1,4- dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8.8-trimethyl-4,7-methane-benzofuran- 2-yl, 1-ethoxy-ethyl, 1-(2-chloro-ethoxy)ethyl, 1-methyl-1-methoxy-ethyl, 1- methyl-1-benzyloxy-ethyl, 1-methyl-1-benzyloxy-2-fluoro-ethyl, 2,2,2-trichloro-ethyl, 2-trimethyl-silyl-ethyl, 2-(phenyl-selenyl)ethyl, t - butyl, allyl, p-chloro-phenyl, p-methoxy-phenyl, 2,4-dinitro-phenyl, benzyl, p-methoxy-benzyl, 3,4-dimethoxy-benzyl, o-nitro-benzyl, p-nitro -benzyl, p-halo-benzyl, 2,6-dichloro-benzyl, p-cyano-benzyl, p-phenyl-benzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenyl -methyl, p,p'-dinitro-benzhydryl, 5-dibenzo-suberyl, triphenyl-methyl, ot-naphthyl-diphenyl-methyl, p-methoxy-phenyl-diphenyl-methyl, di(p-methoxy-phenyl) phenyl -methyl, tri(p-methoxy-phenyl) methyl, 4-(4'-bromo-phenacyloxy-phenyl) diphenyl-methyl, 4,4',4''-tris(4,5-dichloro-phthalimido-phenyl) methyl, 4,4',4''-tris(levulinoyloxy-phenyl) methyl, 4,4',4''-tris(benzoyloxy-phenyl) methyl, 3-(imidazol-1-yl)bis(4', 4''-dimethoxy-phenyl)methyl, 1,1-bis(4-methoxy-phenyl)-1'-pyrenyl-methyl, 9-anthryl, 9-(9-phenyl) xanthenyl, 9-(9-phenyl- 10-oxo) anthryl, 1,3-benzodithiolan-2-yl, S,S-dioxide d and benzisothiazolyl, trimethyl-silyl (TMS), triethyl-silyl (TES), tri-isopropyl-silyl (TIPS), dimethyl-isopropyl-silyl (IPDMS), diethyl-isopropyl-silyl (DEIPS), dimethyl-hexyl-silyl, t-butyl-dimethyl-silyl (TBDMS), t-butyl-diphenyl-silyl (TBDPS), tribenzyl-silyl, tri-p-xylyl-silyl, triphenyl-silyl, diphenyl-methyl-silyl (DPMS), t-butyl - methoxy-phenyl-silyl (TBMPS), formate, benzoyl-formate, acetate, chloro-acetate, dichloro-acetate, trichloro-acetate, trifluoro-acetate, methoxy-acetate, triphenyl-methoxy-acetate, phenoxy-acetate, p- chloro-phenoxy-acetate, 3-phenyl-propionate, 4-oxo-pentanoate (levulinate), 4,4-(ethylene-dithio) pentanoate (levulinoyl-dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxy-crotonate, benzoate , p-phenyl-benzoate, 2,4,6-trimethyl-benzoate (mesitoate), methyl carbonate, 9-fluorenyl-methyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloro-ethyl carbonate (Troe), 2-(trimethylsilyl) ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenyl-phosphonium) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, p-nitro-phenyl carbonate, benzyl carbonate, p-methoxy-benzyl carbonate, 3,4-dimethoxy-benzyl carbonate, o-nitro-benzyl carbonate, p-nitro-benzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodo- benzoate, 4-azido-butyrate, 4-nitro-4-methyl-pentanoate, o-(dibromo-methyl) benzoate, 2-formyl-benzenesulfonate, 2-(methyl-thiomethoxy) ethyl, 4-(methyl-thiomethoxy) butyrate , 2-(methyl-thiomethoxy-methyl) benzoate, 2,6-dichloro-4-methyl-phenoxy-acetate, 2,6-dichloro-4-(1,1,3,3-tetramethyl-butyl)phenoxy-acetate , 2,4-bis(1,1-dimethyl-propyl)phenoxy-acetate, chloro-diphenyl-acetate, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxycarbonyl)benzoate, a-naphthoate, N,N,N',N'-tetramethyl-phosphorus-diamidate, N-phenyl-carbamate, dimethyl-phosphino-thioyl, 2,4-dinitro-phenyl-sulfenate, sulfate, methanesulfonate (mesylate), benzyl sulphonate and tosylate (Ts). For protection of 1,2- or 1,3-diols, protecting groups include methylene acetal, ethylidene acetal, 1-t-butyl-ethylidene ketal, 1-phenyl-ethylidene ketal, (4-methoxy-phenyl) ethylidene acetal , 2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p-methoxy-benzylidene acetal, 2,4-dimethoxy-benzylidene ketal, 3,4- dimethoxy-benzylidene acetal, 2-nitro-benzylidene acetal, methoxy-methylene acetal, ethoxy-methylene acetal, dimethoxy-methylene ortho ester, 1-methoxy-ethylidene ortho ester, 1-ethoxy-ethylidine ortho ester, ortho ester of 1,2-dimethoxy-ethylidene, α-methoxy-benzylidene ortho ester, 1-(N,N-dimethyl-amino) ethylidene derivative, α-(N,N'-dimethyl-amino) benzylidene derivative, ortho ester of 2-oxa-cyclopentylidene, di-t-butyl-silylene group (DTBS), 1,3-(1,1,3,3-tetraisopropyl-disiloxanylidene) derivative (TIPDS), tetra-t-butoxy-derived disiloxane-1,3-diylidene (TBDS), cyclic carbonates, boron cyclic nates, ethyl boronate and phenyl boronate.
In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (referred to as a thiol protecting group). Sulfur protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N (Rbb)2, -C (=NRbb)Raa, -C (=NRbb)ORaa, -C (=NRbb) N (Rbb) 2, -S(=O)Raa, -SO2Raa, -Si(Raa)3 , -P(RCC)2, -P(RCC)3, -P(=O)2Raa, -P(=O) (Raa)2, -P(=O) (ORCC)2, -P (=0 ) 2N (Rbb) 2e -P(=O) (NRbb)2, where Raa, Rbb and Rcc are as defined here. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd edition, John Wiley & Sons, 1999.
These and other exemplary substituents are described in more detail in the Detailed Description, Examples and Claims. It is not intended that the present invention be not limited in any way by the above exemplary listing of substituents.
[0075] As used herein, the word "salt" and the expressions "acceptable salt" or "pharmaceutically acceptable salt" refer to those salts which are, within the scope of legitimate medical judgment, suitable for use in contact with the tissues of beings. humans and lower animals without undue toxicity, irritation, allergic response and the like, and that are measured with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid , oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, diglyconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glycoheptonate salts , glycerophosphate, gluconate, hemisulphate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulphonate, lactobionate, lactate, laurate, laurel sulphate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, , palmitate, pamoate, pectinate, persulfate, 3-phenyl-propionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+ (C1-4 alkyl) salts. 4. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium , calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate .
As used herein, the word "prodrug" means a compound that can hydrolyze, oxidize or otherwise react under biological conditions (eg, enzymatic conditions in vitro or in vivo) to provide a pharmacologically active compound. In certain cases, a prodrug has improved physical and/or delivery properties over the parent compound. Prodrugs are typically designed to enhance pharmacologically, pharmaceutically and/or pharmacokinetically based properties associated with the parent compound. The advantage of a prodrug may lie in its physical properties, such as enhanced water solubility for parenteral administration at physiological pH, compared to the parent compound, or it enhances absorption from the digestive tract, or it may enhance the stability of drug during long-term storage. Other definitions
[0077] "Disease", "disorder" and "condition" are used interchangeably herein.
[0078] As used herein, the word "subject", to which administration is contemplated, includes, but is not limited to, human beings (i.e., a male or female of any age group, e.g., a pediatric individual ( eg child, adolescent) or adult individual (eg young adult, middle-aged adult or senior adult), other primates (eg Cynomolgus monkeys, Rhesus monkeys) and commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats and/or dogs In any aspect and/or embodiment of the invention, the mammal is a human.
[0079] As used herein, the expressions "local administration" or "local administration" or "local effect" means administration/application of the active ingredient, or its active metabolite, directly, or in close proximity to, to a part of the body, tissue or lesion, in which the active substance is intended to exert its action. This can include, for example, topical administration to a part of the skin or injection directly into a tissue or lesion where treatment is needed.
As used herein, and unless otherwise specified, the terms "therapeutically effective amount", "a sufficient amount" or "sufficient amount" of a compound mean the level, amount or concentration of the compound necessary to to treat a disease, disorder or condition, or to reduce or decrease a particular parameter (eg, body fat) in an individual's body, without causing significant adverse or adverse side effects to the body or tissue treated. The term "therapeutically effective amount" can encompass an amount that improves the overall therapy, reduces or prevents symptoms or causes the disease or condition, or enhances the therapeutic efficacy of another therapeutically active agent.
[0081] As used herein, the words "reduce", "reduce", "reduce", "decrease" or "decrease" mean to decrease or decrease the volume, size, mass, apparent volume, density, amount and/or the amount of a substance (eg, body fat, adipose tissue) in an individual's body.
[0082] As used herein, the word "eliminate" means to completely remove any volume, size, mass, bulk, density, amount and/or amount of a substance (e.g., excess body fat, excess adipose tissue) in the body of an individual.
[0083] As used herein, the words "suffer", "suffers" or "suffering from" refer to an individual diagnosed with a particular disease or condition. As used herein, the term "prone to suffer" refers to an individual who has not been diagnosed with a particular disease or condition by a medical practitioner, but who has a predisposition (eg, genetic and/or physiological predisposition) , or exhibiting signs or symptoms of the disease or condition.
[0084] As used herein, and unless otherwise specified, the words "treat", "treating" and "treatment" contemplate an action that occurs while an individual is suffering from the specified disease or condition that reduces the severity disease or condition, or delay or slow the progression of the disease or condition.
[0085] As used herein, unless otherwise specified, the words "prevent", "preventing" and "prevention" contemplate an action that occurs before an individual begins to suffer from the specified disease or condition that inhibits or reduce the severity of the disease or condition. BRIEF DESCRIPTION OF THE DRAWINGS
[0086] Figure 1 depicts representative histological sections of treated skin and subcutaneous fat from each of Groups 1, 2 and 3. Compared to Vehicle (Group 1), tafluprost (Group 3) was associated with adipose thickness and size of reduced adipocytes. Bimatoprost (Group 2) did not exhibit these effects. DETAILED DESCRIPTION OF CERTAIN MODALITIES OF THE INVENTION
[0087] It has been previously described that the amide bimatoprost can be used to reduce body fat by topical or local administration. See, for example, U.S. Patent No. 7,666,912; U.S. Patent Application Publication No. 2010-0234466; Aihara et al., Jpn J Ophthalmol 2011;55:600-604; Aydin et al. , Cutan Ocul Toxicol (2010) 29:212-216; Filippopoulos et al., Ophtal Plast Reconstr Surg (2008) 24:302-307; Nakakura et al. , Optom Vis Sci (2011) 88:1140-1144; Park et al., Jpn J Ophthalmol (2011) 55:22-27; Peplinski et al. , Optom Vis Sci (2004) 81:574-577; Tappeiner et al. Klin Monbl Augenheilkd (2008) 225:443-445; Yarn et al., J Ocul Pharmacol Ther (2009) 25:471-472. Recently, Choi et al. described the in vitro activity of bimatoprost, tafluprost and related compounds to inhibit the differentiation of human preadipocytes in primary cell culture. See Choi et al., J. Ocular Pharm Ther (2012) 28:146-152. In an adipocyte differentiation assay, bimatoprost reduced differentiation to 30% of control, whereas tafluprost reduced it somewhat less, to 40% of control; there was no statistical difference. Likewise, bimatoprost exhibited slightly more inhibition than tafluprost on the expression of the adipogenic genes of peroxisome proliferator-activated receptor gamma (PPARy), CCAAT enhancer-binding protein ot (C/EBPα) and lipoprotein lipase; again, there were no statistical differences. Taken together, the literature teaches bimatoprost as the preferred compound for local administration for the reduction of body fat. The publications further suggested that if tafluprost were to have such activity, at best it would be equivalent to bimatoprost.
[0088] However, it has now been found that tafluprost is more effective than bimatoprost for local administration for reducing body fat. Local administration, as described herein, can be directed to particular affected areas of the individual's body, for example, administration to the dorsocervical fat pad of a patient with HIV lipodystrophy or Cushing's Syndrome, or to the breast of a man with gynecomastia. Without being bound by theory, reducing fat as a function of administering the compounds described herein may include reducing the number of fat cells, reducing the volume of one or more fat cells, reducing the maturation of one or more. more fat cells and/or the dedifferentiation of one or more fat cells. Such effects may be mediated through prostaglandin or prostaglandin-like receptors, and compounds according to the invention may exert their effects, as described herein, by acting as agonists at these receptors.
[0089] Therefore, in one aspect, methods of applying a compound according to formula (I) are provided:
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof; wherein X is: - ORi, wherein Rj is selected from the group consisting of hydrogen, a protecting group of hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl substituted, optionally substituted heteroaryl; - SR2, wherein the R2 group consists of hydrogen, a thiol protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; or - NR3R4, wherein R3 and R4 are independently selected from the group consisting of hydrogen, an amino protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl , optionally substituted heteroaryl, or R3 and R4 are joined to form an optionally substituted heterocyclyl ring; for reduction or complete elimination of body fat in an individual, eg a human being.
[0090] In another aspect, there is provided a method for reducing fat in an individual in need thereof, the method comprising administering, locally to the individual, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof.
Compounds of formula (I) encompass tafluprost (i.e. formula (II), in which R3 is -CH(CH3)2), tafluprost free acid (i.e., formula (II), in which R1 is H ), other alkyl esters of tafluprost of formula (II), thio esters of tafluprost of formula (III) and amides of tafluprost of formula (IV). Compounds of formula (I) are members of the prostaglandin FP receptor agonist class. See, for example, Nakajima et al., Biol Pharm Bulli (2003) 26:1691-1695; Ota et al., Br J Ophthalmol (2007) 91:673-676. Such drugs have traditionally been applied to the eyes to reduce intraocular pressure for the treatment of glaucoma.
[0092] In certain embodiments, when X is -ORi, a compound of formula (II) will be provided:
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof.
[0093] In certain embodiments, when X is -SR2, a compound of formula (III) will be provided:
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof.
[0094] In certain embodiments, when X is -NR3R4, a compound of formula (IV) will be provided:
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof.
[0095] In certain embodiments, Ri is hydrogen.
[0096] In certain embodiments, Rx is an oxygen protecting group.
[0097] In certain embodiments, R1 is optionally substituted alkyl. In certain embodiments, Rx is unsubstituted C1 -C12 -alkyl. In certain embodiments, R1 is unsubstituted C1 -C6 alkyl. In certain embodiments, R1 is methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, isobutyl or s-butyl. In certain embodiments, R1 is isopropyl (-CH(CH3)2).
[0098] In certain embodiments, Rx is optionally substituted alkenyl.
[0099] In certain embodiments, Rx is optionally substituted alkynyl.
[00100] In certain embodiments, Rx is optionally substituted carbocyclyl.
[00101] In certain embodiments, Rx is optionally substituted heterocyclyl.
[00102] In certain embodiments, Rx is optionally substituted aryl.
[00103] In certain embodiments, Rx is optionally substituted heteroaryl.
[00104] In certain embodiments, in which Rx is hydrogen, the compound of formula (II) is the compound:
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer or isotopically enriched derivative thereof, which is also referred to herein as tafluprost free acid.
[00105] In certain embodiments, in which R 1 is isopropyl, the compound of formula (II) is the compound:
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer or isotopically enriched derivative thereof; which is also referred to here as tafluprost.
[00106] In certain embodiments, R2 is hydrogen.
[00107] In certain embodiments, R2 is a thiol protecting group.
[00108] In certain embodiments, R2 is optionally substituted alkyl. In certain embodiments, R2 is unsubstituted C1 -C12 -alkyl. In certain embodiments, R2 is unsubstituted C1-Cβ-alkyl. In certain embodiments, R2 is methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, isobutyl or s-butyl. In certain embodiments, R2 is isopropyl (-CH(CH3)2).
[00109] In certain embodiments, R2 is optionally substituted alkenyl.
[00110] In certain embodiments, R2 is optionally substituted alkynyl.
[00111] In certain embodiments, R2 is optionally substituted carbocyclyl.
[00112] In certain embodiments, R2 is optionally substituted heterocyclyl.
[00113] In certain embodiments, R2 is optionally substituted aryl.
[00114] In certain embodiments, R2 is optionally substituted heteroaryl.
[00115] In certain embodiments, R3 is hydrogen.
[00116] In certain embodiments, R3 is an amino-protecting group.
[00117] In certain embodiments, R3 is optionally substituted alkyl. In certain embodiments, R3 is unsubstituted C1 -C12 -alkyl. In certain embodiments, R3 is unsubstituted C1 -C6 -alkyl. In certain embodiments, R3 is methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, isobutyl or s-butyl. In certain embodiments, R3 is isopropyl (-CH(CH3)2).
[00118] In certain embodiments, R3 is optionally substituted alkenyl.
[00119] In certain embodiments, R3 is optionally substituted alkynyl.
[00120] In certain embodiments, R3 is optionally substituted carbocyclyl.
[00121] In certain embodiments, R3 is optionally substituted heterocyclyl.
[00122] In certain embodiments, R3 is optionally substituted aryl.
[00123] In certain embodiments, R3 is optionally substituted heteroaryl.
[00124] In certain embodiments, R4 is hydrogen.
[00125] In certain embodiments, R4 is an amino-protecting group.
[00126] In certain embodiments, R4 is optionally substituted alkyl. In certain embodiments, R4 is unsubstituted C1 -C12 -alkyl. In certain embodiments, R4 is unsubstituted C1 -C6 -alkyl. In certain embodiments, R4 is methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, isobutyl or s-butyl. In certain embodiments, R4 is isopropyl (-CH(CH3)2).
[00127] In certain embodiments, R4 is optionally substituted alkenyl.
[00128] In certain embodiments, R4 is optionally substituted alkynyl.
[00129] In certain embodiments, R4 is optionally substituted carbocyclyl.
[00130] In certain embodiments, R4 is optionally substituted heterocyclyl.
[00131] In certain embodiments, R4 is optionally substituted aryl.
[00132] In certain embodiments, R4 is optionally substituted heteroaryl.
[00133] In certain embodiments, R3 and R4 are joined to form an optionally substituted heterocyclyl ring.
[00134] In another aspect, a method of applying a compound of the formula (V) is provided, for example, alone or in combination with a compound of the formula (I):
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer or isotopically enriched derivative thereof, or prodrug thereof; in which: X is: - ORi, wherein Ri is selected from the group consisting of hydrogen, a protecting group of hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, aryl optionally substituted, optionally substituted heteroaryl; - SR2, wherein the R2 group consists of hydrogen, a thiol protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; or - NR3R4, wherein R3 and R4 are independently selected from the group consisting of hydrogen, an amino protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl , optionally substituted heteroaryl, or R3 and R4 are joined to form an optionally substituted heterocyclyl ring; Z is =0 or represents two hydrogen atoms; one of R5 and R6 is =0, -OH or a group -O(CO)R8, and the other is -OH or -O(CO)R8, or R5 is =0 and R6 is H, where R8 is a saturated or unsaturated acyclic hydrocarbon group having 1 to about 20 carbon atoms or -(CH2)mR9 where m is 0-10, and R9 is cycloalkyl having three to seven carbon atoms, aryl having six to ten carbon atoms or heteroaryl having four to ten carbon atoms and one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; R7 is hydrogen, halogen, -OH or -0(CO)R10, where R10 is a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms or -(CH2)mRii, where m is 0 -10, and Rn is cycloalkyl having three to seven carbon atoms, aryl having six to ten carbon atoms, or heteroaryl having four to ten carbon atoms and one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; R7' is hydrogen or halogen; Y is selected from the group consisting of alkyl, halogen, nitro, amino, thiol, hydroxy, alkyloxy, alkyl-carboxy and alkyl substituted with halogen, the alkyl radical comprising from one to six carbon atoms; yéOoul, exéOoul, as long as x and y are not both 1; and n is 0 or an integer from 1 to 3, inclusive; for reduction or complete elimination of body fat in an individual, eg a human being.
[00135] In certain embodiments, at least one of R7 and R7' is not hydrogen. In certain embodiments, R7 and R7' are both halogen. In certain embodiments, R7 and R7' are both fluorine. In certain embodiments, at least one of R7 and R7' is halogen. In certain embodiments, at least one of R7 and R7' is fluorine.
[00136] Without being bound by any particular theory, it is understood that one or more of the above compounds may exist as prodrugs. Consequently, and without being bound by theory, the invention contemplates that, for example, free acids, for example, such as tafluprost free acid, may represent the main pharmacologically active species for the purposes of this invention, and that other analogues (by eg esters, amides) can be prodrugs, ie substrates for hydrolases in the body (eg esterases, amidases), which in turn produce the corresponding free acid. Because hydrolases can be present (or absent) to varying degrees in different parts of an animal body, there is an opportunity to choose from the various analogues described herein, depending on the desired route of administration and location, tissue or type of cell to be treated. Based on these contemplated properties, it is further understood that there is an opportunity to enhance the therapeutic index by choosing, from among the various analogues, a particular analogue that is more efficiently metabolized from a less active prodrug within of a location, tissue or cell type to be treated. It is understood that compounds as described herein may be substituted with esters or amides, to make a particular compound a substrate for an esterase or an amidase, respectively. Pharmaceutical Compositions and Formulations
[00137] In certain embodiments, the present invention provides pharmaceutical compositions and formulations for application in any of the methods of the invention, described herein, comprising one or more compounds of formula (I), (II), (III), (IV) and/or (V), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof, (the "active ingredient(s)") and optionally one or more pharmaceutically acceptable excipients. In certain embodiments, the composition is suitable for topical, subcutaneous, intradermal or intralesional delivery.
[00138] Pharmaceutically acceptable excipients include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as appropriate for the particular dosage form desired. General considerations in formulating and/or manufacturing agents for pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980), and in Remington : The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).
The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the active ingredient into association with a vehicle and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product in a single-dose or multiple-dose unit desired.
Pharmaceutical compositions can be prepared, packaged and/or sold as a whole as a single unit dose and/or as a plurality of single unit doses. As used herein, the term "unit dose" is a discrete amount of pharmaceutical composition comprising a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dosage of active ingredient that would be administered to an individual and/or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.
[00141] The relative amounts of the active ingredient, the pharmaceutically acceptable carrier and/or any additional ingredients in a pharmaceutical composition of the invention will vary depending on the identity, size and/or condition of the individual treated and additionally depending on the route by which the composition is administered. By way of example, the composition may comprise between 0.001% and 100% (w/w) or (w/v) of the active ingredient. In certain embodiments, the composition comprises between about 0.01% and about 90%, between about 0.01% and about 80%, between about 0.01% and about 70%, between about 0 .01% and about 60%, between about 0.01% and about 50%, between about 0.01% and about 40%, between about 0.01% and about 30%, between about from 0.01% to about 20%, between about 0.01% and about 10%, between about 0.01% and about 5%, between about 0.01% and about 4% between about 0.01% and about 3%, between about 0.01% and about 2%, between about 0.01% and about 1%, or between about 0.01% and about 0.05% (w/w) or (w/v), inclusive, of the active ingredient. In certain embodiments, the composition comprises between about 0.001% and about 90%, between about 0.001% and about 80%, between about 0.001% and about 70%, between about 0.001% and about 60% , between about 0.001% and about 50%, between about 0.001% and about 40%, between about 0.001% and about 30%, between about 0.001% and about 20%, between about 0.001% and about 10%, between about 0.001% and about 5%, between about 0.001% and about 4%, between about 0.001% and about 3%, between about 0.001% and about 2%, between about 0.001% and about 1% or between about 0.001% and about 0.05% (w/w) or (w/v), inclusive, of the active ingredient. In certain embodiments, the composition comprises between about 0.01% and about 10% (w/w) or (w/v), inclusive, of the active ingredient. In certain embodiments, the composition comprises between about 0.01% and about 1% (w/w) or (w/v), inclusive, of the active ingredient. In certain embodiments, the composition comprises between about 0.001% and about 10% (w/w) or (w/v), inclusive, of the active ingredient. In certain embodiments, the composition comprises between about 0.001% and about 1% (w/w) or (w/v), inclusive, of the active ingredient.
[00142] Pharmaceutically acceptable excipients, used in the manufacture of the pharmaceutical compositions provided, include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, drying agents buffering, lubricating agents and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring and perfuming agents may also be present in the composition.
[00143] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, anhydrous starch, corn starch, powdered sugar, etc. and combinations thereof.
[00144] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), carboxy-methyl-sodium starch (sodium starch glycolate), carboxy- methylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (1500 starch), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium and calcium silicate aluminum (Veegum™), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.
[00145] Exemplary surface active agents and/or emulsifiers include natural lipids/emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, condrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool wax, cholesterol, wax and lecithin), colloidal clays (eg bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (eg stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate and propylene glycol monostearate, poly(vinyl alcohol), carbomers (eg, poly(methylene carboxy), poly(acrylic acid ), acrylic acid polymer and carboxy-vinyl polymer), carrageenan, cellulosic derivatives (eg, sodium carboxy-methyl-cellulose, powdered cellulose, hydroxy-methyl-cellulose, hydroxy-propyl-cellulose, hydroxy-prop yl-methylcellulose, methylcellulose), sorbitan fatty acid esters (eg, poly(oxyethylene sorbitan) monolaurate [Tween™ 20], poly(oxyethylene sorbitan) [Tween™ 60], poly monooleate (oxyethylene sorbitan) [Tween™ 80], sorbitan monopalmitate [Span™ 40], sorbitan monostearate [Span™ 60], sorbitan tristearate [Span™ 65], glyceryl monooleate, sorbitan monooleate [Span ™ 80]), polyoxyethylene esters (eg, polyoxyethylene monostearate [Myrj™ 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, poly(oxymethylene stearate) and Solutol™), sucrose fatty acid esters , poly(ethylene glycol) fatty acid esters (eg Cremophor™), polyoxyethylene ethers (eg polyoxyethylene lauryl ether [Brij™ 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, oleate of triethanolamine, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, laurel sulphur sodium act, Pluronic™ F 68, Poloxamer 188, cetrimonium bromide, cetyl pyridinium chloride, benzalkonium chloride, docusate sodium, Lipoderm®, etc. and/or combinations thereof. In certain embodiments, the excipient is Lipoderm®.
Exemplary binding agents include starch (e.g. corn starch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), gums natural and synthetic (eg, acacia, sodium alginate, Irish moss extract, panwar gum, ghatti gum, isapol husk mucilage, carboxy-methyl-cellulose, methyl-cellulose, ethyl-cellulose, hydroxy-ethyl- cellulose, hydroxy-propyl-cellulose, hydroxy-propyl-methyl-cellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum™) and larch arabdogalactan), alginates, poly(oxide of ethylene), poly(ethylene glycol), inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and/or combinations thereof.
[00147] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcoholic preservatives, acidic preservatives, and other preservatives.
[00148] Exemplary antioxidants include alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxy-anisole, butylated hydroxy-toluene, monothio-glycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite and sodium sulfite.
[00149] Exemplary chelating agents include ethylene diamine tetraacetic acid (EDTA) and salts and hydrates thereof (for example, sodium edetate, disodium edetate, trisodium edetate, disodium calcium edetate, dipotassium edetate and the like) , citric acid and salts and hydrates thereof (eg citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof and tartaric acid and salts and hydrates thereof. Representative antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chloro-butanol, chlor-cresol, chlor-xylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidourea, phenol, phenoxy-ethanol, phenyl-ethyl alcohol, phenyl-mercuric nitrate, propylene glycol and thimerosal.
Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate and sorbic acid.
[00151] Exemplary alcoholic preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chloro-butanol, hydroxybenzoate and phenylethyl alcohol.
[00152] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
[00153] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxy-anisole (BHA), butylated hydroxy-toluene (BHT), ethylene-diamine, sodium lauryl sulfate (SLS), lauryl ether- sodium sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glidant Plus, Phenonip, methyl paraben, Germall™ 115, Germaben™ II, Neolone™, Kathon™, and Euxyl™. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelation agent.
[00154] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-glyconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, calcium acetate potassium, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline , Ringer's solution, ethyl alcohol, etc. and combinations thereof.
[00155] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl berranate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc. and combinations thereof.
[00156] Exemplary oils include almond oils, apricot kernels, avocado, babassu, bergamot, blackcurrant seed, borage, cade (Juniperus oxycedrus), chamomile, canola, cumin, carnauba, castor, cinnamon, cocoa butter, coconut , cod liver, coffee, corn, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, cucurbits, grape seed, hazelnut, mugwort, isopropyl myristate, jojoba, kukui nut, lavender, lavender, lemon, litsea cubeba, walnut macadamia, mallow, mango kernel, limnanto seed, mink, nutmeg, orange, orange glass eye, palm, heart of palm, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary , turmeric, sandalwood, sasquana, savory, sea buckthorn, sesame, shea butter, silicone, soy, sunflower, tea, thistle, tsubaki, vetiver, nut and wheat germ. Exemplary oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyl-dodecanol, oleyl alcohol, silicone oil and combinations thereof .
[00157] Liquid dosage forms, for mucosal or parenteral administration, include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may comprise inert diluents commonly used in the art, such as, for example, water or other solvents (eg, ethyl carbonate, ethyl acetate, benzyl benzoate, dimethylformamide) , sorbitan fatty acid esters, polysorbates, solubilizing agents such as alcohols (eg ethyl alcohol, isopropyl alcohol, tetrahydrofurfuryl alcohol, benzyl alcohol, glycerol and glycols (eg 1,3-butylene glycol, propylene) glycol, poly(ethylene glycols)), oils (eg cottonseed, peanut, corn, germ, olive, castor and sesame oils), Cremophor™, cyclodextrins, polymers) and mixtures thereof . In addition to inert diluents, compositions for mucosal administration may include adjuvants such as wetting, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. In certain embodiments, for parenteral administration, the active ingredient is mixed with solubilizing agents, such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers and combinations thereof.
[00158] Injectable preparations, for example, aqueous or oleaginous, injectable, sterile suspensions, can be formulated according to the known art, using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's Solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.
[00159] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other injectable medium sterile, before use.
[00160] Compositions for rectal or vaginal administration are typically suppositories, which can be prepared by mixing the active ingredient with a suitable non-irritating excipient or vehicle such as cocoa butter, poly(ethylene glycol) or a suppository wax, that they are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
Dosage forms for topical and/or transdermal administration of an active ingredient may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. In general, the active ingredient is added under admixture, under sterile conditions, with a pharmaceutically acceptable carrier and/or any necessary preservatives and/or buffers as may be needed. Additionally, the present invention contemplates the application of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled either by providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer and/or gel matrix.
Devices suitable for application in the delivery of intradermal pharmaceutical compositions described herein include short needle devices such as those described in U.S. Patent Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015.235; 5,141,496 and 5,417,662. Intradermal compositions can be administered by devices that limit the effective penetration length of a needle into the skin, such as those described in PCT Publication WO 99/34850, and the functional equivalents thereof. Jet injection devices are suitable, which deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle that pierces the stratum corneum and produces a jet that reaches the dermis. Jet injection devices are described, for example, in U.S. Patent Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; and in PCT Publications WO 97/37705 and WO 97/13537. Ballistic powder/particle delivery devices, which use compressed gas to accelerate vaccine in powder form through the outer layers of the skin into the dermis, are suitable. Alternatively or additionally, conventional syringes can be used in the classic mantoux method of intradermal administration.
Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations can comprise, for example, from about 1% to about 10% (w/w) of active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may additionally comprise one or more of the additional ingredients described herein.
[00164] A pharmaceutical composition of the invention can be prepared, packaged and/or sold in a formulation suitable for ophthalmic administration. Such formulations may be, for example, in the form of eye drops, including, for example, a 0.1/0.1% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid vehicle . Such drops may further comprise buffering agents, salts and/or one or more other of the additional ingredients described herein. Other ophthalmically administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention.
[00165] Although the descriptions of pharmaceutical compositions provided herein are primarily directed to pharmaceutical compositions that are suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to animals of all the types. The modification of pharmaceutical compositions suitable for administration to humans, in order to make the compositions suitable for administration to various animals, is well known, and the veterinary pharmacologist skilled in the art can design and/or carry out such modification with ordinary experimentation. General considerations in formulating and/or manufacturing pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy21® ed., Lippincott Williams &Wilkins, 2005.
[00166] Pharmaceutical packages and/or kits are further encompassed by the invention. Pharmaceutical supplied packs and/or kits may comprise a supplied composition and a container (e.g., a vial, ampoule, bottle, syringe and/or dispenser pack, or other suitable container). In some embodiments, kits optionally provided may additionally include a second container comprising an aqueous vehicle suitable for diluting or suspending the composition provided for preparation for administration to a subject. In some embodiments, the contents of the supplied formulation container and that of the solvent container combine to form at least one unit dosage form.
The active ingredient can be administered using any amount and any effective local route of administration for the treatment. The exact amount needed will vary from individual to individual depending on the species, the age and general condition of the individual, the severity of the infection, the particular composition, its mode of administration, its mode of activity and the like.
Typically, the active ingredient is formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of accurate medical judgment. The specific therapeutically effective dose level for any particular individual will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific active ingredient employed; the specific composition used; the age, body weight, general health, sex and diet of the individual; administration time, administration route and excretion rate of the specific active ingredient employed; duration of treatment; of drugs used in combination or coincidental with the specific active ingredient employed; and from similar factors well known in the medical arts.
The active ingredient can be administered by any suitable local route, parenteral (eg, subcutaneous, intradermal, intralesional, eg, as in a lipoma), and topical administration (eg, transdermal, transmucosal, ophthalmic). In general, the most appropriate route of administration will depend on a variety of factors, including the nature of the active ingredient (eg, its stability in the part of the body, into which it is administered), the condition of the individual (eg, whether the individual is able to tolerate subcutaneous administration), etc.
[00170] The exact amount of active ingredient required to achieve a therapeutically effective amount will vary from individual to individual depending, for example, on the species, age and general condition of an individual, the severity of the side effects or disorder , the identity of the particular compound(s), the mode of administration, and the like. The desired dosage can be delivered three times a day, twice a day, once a day, every other day, every third day, every week, every two weeks, every three weeks or every four weeks . In certain embodiments, the desired dosage can be delivered using multiple administrations (for example, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or more administrations). As demonstrated in the accompanying Examples, daily administration to the subject may be adequate (but not necessarily preferable) to achieve the desired effect. A daily administration schedule is considered convenient for human use. The active ingredient can be administered by the individual to himself, repeatedly and without special equipment or training, although a medical professional may also administer the active ingredient to the individual.
In certain embodiments, a therapeutically effective amount of the active ingredient, for administration one or more times a day, to an adult human being weighing 70 kg, may comprise from about 0.00001 mg to about 3,000 mg, about 0 about 0.0001 mg to about 3,000 mg, about 0.0001 mg to about 2,000 mg, about 0.0001 mg to about 1,000 mg, about 0.001 mg to about 1,000 mg, about 0.01 mg to about 1000mg, about 0.1mg to about 1000mg, about 1mg to about 1000mg, about 1mg to about 100mg, about 10mg to about 1000mg, about 100 mg to about 1,000 mg, about 0.00001 mg to about 0.0001 mg, about 0.00001 mg to about 0.001 mg, about 0.00001 mg to about 0.01 mg, about 0 about 0.0001 mg to about 0.1 mg, about 0.001 mg to about 1 mg, about 0.0001 mg to about 1 mg, or about 0.0001 mg to about 0.01 mg of the active ingredient per unit dosage form. A therapeutically effective amount can comprise between about 0.001 and about 10.0% (w/v), or between about 0.01 and about 10.0% (w/v), inclusive, of the active ingredient in formulations. liquids or semi-solids. It will be appreciated that dose ranges as described herein provide guidance for administering the pharmaceutical compositions provided to an adult. The amount to be administered to, for example, a child or adolescent can be determined by a medical practitioner or person skilled in the art and may be lower or the same as that administered to an adult.
[00172] It will also be appreciated that the active ingredient may be administered in combination with one or more additional therapeutically active agents ("agents" or "active agents"). The compound or composition can be administered concurrently with, prior to or subsequent to one or more additional agents. In general, the active ingredient and each additional active agent will be administered at a dose and/or schedule determined for the ingredient and agent. It will further be appreciated that the active ingredient and active agent used in such a combination can be administered separately in different compositions. The particular combination and whether employed in a regimen will take into account the compatibility of the active ingredient with the active agent and/or the desired therapeutic effect to be achieved. In general, additional active agents, used in combination, are expected to be used at levels that do not exceed the levels at which they are used individually. In some modalities, the levels used in combination will be lower than those used individually.
[00173] The active ingredient can be administered in combination with active agents, which improve its bioavailability, reduce and/or modify its metabolism, inhibit its excretion and/or modify its distribution within the body. It will also be appreciated that the therapy employed can achieve a desired effect for the same disorder (eg, an active ingredient can be administered in combination with an anti-inflammatory and/or antidepressant agent, etc.), and/or it can achieve effects different (eg, control of adverse side effects).
[00174] Exemplary active agents include, but are not limited to, anticancer agents, antibiotics, antiobesity agents, antiviral agents, anesthetics, anticoagulants, steroidal agents, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, antihistamines, immunosuppressive agents, antineoplastic agents, antigens, vaccines, antibodies, decongestants, sedatives, opioids, pain relief agents, analgesics, antipyretics, hormones, prostaglandins, progestational agents, antiglaucoma agents, ophthalmic agents, anticholinergics, antidepressants, antipsychotics , anticonvulsants/antiepileptics (eg Neurontin™, Lyrica™, valproates (eg Depacon™), and other neurostabilising agents), muscle relaxants, antispasmodics, muscle contracters, channel blockers, miotic agents, antisecretory agents, antithrombotic agents, anticoagulants, anticholinergic s, β-adrenergic blocking agents, diuretics, cardiovascular active agents, vasoactive agents, vasodilator agents, antihypertensive agents, angiogenic agents, cell-extracellular matrix interaction modulators (eg, cell growth inhibitors and antiadhesion molecules), or DNA, RNA inhibitors/intercalators, protein-protein interactions, protein-receptor interactions, etc. Active agents include small organic molecules such as drug compounds (eg, compounds approved by the Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, polypeptides or synthetic proteins, small protein-bound molecules, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, vitamin-free oligonucleotides and cells. Methods for Body Fat Reduction
[00175] In certain embodiments, the present invention provides a method of reducing body fat in an individual, comprising administering, locally to an individual in need thereof, one or more compounds of formula (I), (II), ( III), (IV) and/or (V), or of a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof.
[00176] Fat reduction may include fat reduction as measured by at least one of volume, size, mass, apparent volume, density, amount and/or quantity. The present invention is expected to reduce fat by more than or equal to 75%, by more than or equal to 70%, by more than or equal to 60%, by more than or equal to 50%, in more than or equal to 40%, in more than or equal to 30%, in more than or equal to 25%, in more than or equal to 20%, in more than or equal to 15% , by more than or equal to 10% or by more than or equal to 5%. For example, reducing fat can also include reducing the amount of fat cells (eg, the number of fat cells), reducing the volume of fat cells, reducing the maturation of fat cells and/or the dedifferentiation of a fat cell.
[00177] In certain modalities, body fat is local, for example, concentrated in the abdomen, chest, breasts, buttocks, hips, thighs, legs, knees, arms, chin, neck and/or face.
[00178] In certain modalities, the individual suffers from or is likely to suffer from obesity, excess fat in the breasts, excess fat in the chin, gynecomastia, drug-induced obesity, hypothyroidism, pseudo-hypoparathyroidism, hypothalamic obesity, polycystic ovarian disease , depression, binge eating, postpartum obesity, obesity associated with smoking cessation, Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome, Down syndrome, Turner syndrome, growth hormone deficiency, resistance to growth hormone, leptin deficiency or resistance, Cushing's Syndrome, pseudo-Cushing's Syndrome, dorsocervical fat hypertrophy/dorsocervical fat hypertrophy ("buffalo hump"), lunar surfaces, HIV lipodystrophy, orbital fat prolapse , age-related drop in abdominal fat, other acquired lipodystrophy, familial lipodystrophy, lipoma, lipomatosis, or Madelung's Disease. In certain modalities, the individual suffers from or is likely to suffer from obesity, gynecomastia, HIV lipodystrophy, lipoma or excess chin fat.
[00179] In certain embodiments, the route of administration is selected from the group consisting of topical, subcutaneous, intradermal and intralesional. In certain modalities, the route of administration is topical. In certain embodiments, the site of administration is selected from the group consisting of the skin, the eyes or a mucous membrane. In certain embodiments, the route of administration is selected from the group consisting of subcutaneous, intradermal and intralesional. In certain embodiments, administration is to a body part selected from the group consisting of the abdomen, chest, breasts, buttocks, hips, thighs, legs, knees, arms, chin, neck and face. In certain embodiments, topical administration is transdermal administration.
[00180] In certain modalities, the individual has excess body fat as a side effect of medication (eg, cortisol and analogues, corticosteroids, megace, sulfonyl-ureas, antiretrovirals, antidepressants, monoamine oxidase inhibitors, serotonin reuptake inhibitors selective drugs, oral contraceptives, insulin or a form of insulin, risperidone, clozapine and thiazolidine-diones.
[00181] In certain modalities, the individual has excess body fat due to changes in hormonal status (eg, as a result of physiological changes such as pregnancy or menopause).
[00182] In certain modalities, the individual with excess body fat is suffering from or has recently undergone smoking cessation.
[00183] In certain modalities, the individual has body fat of cosmetic importance, for example, due to age-related orbital fat prolapse or falling malar fat pads.
This aspect of the invention may also be useful as an adjunct to any of several types of surgery, or used in the pre-operative, peri-operative or post-operative period. The invention further contemplates applications preceding abdominal, thoracic, oncologic, endocrine, neurologic, transplant, and dermatologic surgery, whereby surgical exposure can be improved; and preceding or following orthopedic procedures, whereby surgical exposure, as well as postoperative recovery, can be improved. Examples
Throughout the description, in which compositions are described as having, including or comprising specific components, or in which processes are described as having, including or comprising specific process steps, it is contemplated that compositions of the present invention may also consist essentially of, or consist of, the mentioned components, and that the processes of the present invention may also consist essentially of, or consist of, the mentioned processing steps. Furthermore, it must be understood that the order of steps or the order for carrying out certain actions is irrelevant as long as the invention remains operable. Furthermore, two or more steps or actions can be carried out simultaneously.
[00186] In light of the foregoing description, the specific non-limiting examples presented below are for illustrative purposes and are not intended to limit the scope of the invention in any way. Example 1
[00187] A randomized controlled trial was conducted in mice (db-/db-). Six-week-old mice were prospectively randomized into groups and assigned to the following treatment conditions (n = 5 animals per group):

[00188] At the beginning of the study, hairs on the right flank of each animal were clipped and shaved. The animals were kept under identical conditions and fed ad libitum. Animals were weighed daily. Following 21 consecutive days of treatment, skin and adjacent fat samples were obtained from the treated flanks, fixed in formalin and stained with hematoxylin and eosin for histological examination.
[00189] Table II summarizes the change in weight in each group during the 21-day study. While animals treated with vehicle and bimatoprost exhibited weight gain of about 23-24% of baseline weight, animals treated with tafluprost exhibited weight loss corresponding to about 8% of baseline body weight.
p < 0.01 by Tu key
[00190] Figure 1 shows representative histological sections of treated skin and subcutaneous fat from each of Groups 1, 2 and 3. Compared to Vehicle (Group 1), tafluprost (Group 3) was associated with adipose thickness and size of reduced adipocytes. Bimatoprost (Group 2) did not exhibit these effects.
[00191] Therefore, the previous experiment shows that local administration of tafluprost inhibited adipose tissue and adipocytes in a mouse, and that these effects are significantly greater than those seen with local administration of equivalent doses of bimatoprost. Example 2
[00192] The following experiment describes a double-blind, randomized study in human subjects to see whether locally administered tafluprost reduces fat in the dorsocervical fat pad of HIV-seropositive patients on antiretroviral therapy who are suffering from HIV lipodystrophy.
[00193] Eligible subjects (eg, n = 40) with HIV lipodystrophy and abnormal accumulation of fat in the dorsal neck are included in a randomized double-blind study. Subjects are randomized 1:1 to receive either tafluprost, eg, 0.03%, in a suitable transdermal vehicle or vehicle only. The vehicle is, for example, Lipoderm® (PCCA, Houston, Texas). Single-dose syringes (eg, 0.5 mL per syringe) are provided to individuals by a study pharmacist; syringes are not labeled for the presence of tafluprost or vehicle.
[00194] Subjects are instructed to apply, once daily, the contents of a syringe to the affected area at the back of the neck.
[00195] Serial ultrasound (US) and/or computed tomography (CT) scans are conducted at the beginning of the study and then at monthly intervals. Treatment continues for 6 months.
[00196] It is contemplated that, over time, for example, after 3 months of treatment, tafluprost will be associated with further reduction in the depth and/or cross-sectional area of dorsocervical fat, as measured by serial US or US serial CT, when compared to the vehicle alone. Example 3
[00197] The following description exemplifies a clinical application of local administration of tafluprost to reduce local fat deposits of functional and/or cosmetic importance.
[00198] A 56-year-old flight attendant is troubled by prominent fat deposits on her hips and thighs, which interfere with her work and lower her self-esteem. Your doctor recommends diet and exercise. The woman loses 3.18 kg (7 lbs), but there is no observable reduction in fat deposits. It is recommended to a plastic surgeon, but declines from lipoplasty due to potential adverse effects.
[00199] The plastic surgeon prescribes a daily application of a tafluprost ointment to the hips and thighs as a treatment for fat deposits. After a period of time, for example, from a few days to several months, the fatty deposits on the woman's hips and/or thighs are reduced. Example 4
The following description exemplifies a clinical application of local administration of tafluprost to reduce prolapsed periorbital fat.
[00201] A 67-year-old man consults an oculoplastic surgeon and complains of "bags under my eyes". Exams reveal involutional periorbital fat prolapse in both lower eyelids. The oculoplastic surgeon prescribes a daily application of tafluprost ointment once daily to the lower eyelids. After a period of time, for example 2-26 weeks, the orbital fatty deposits under the eyes are reduced. Example 5
[00202] The following experiment describes a randomized, controlled trial on human subjects to test whether tafluprost ointment reduces prolapsed orbital fat.
[00203] Eligible subjects (eg, n = 20) with prolapsed orbital fat in the lower eyelids are included in a randomized double-blind study. Subjects are randomized in a 50:50 manner to receive tafluprost ointment on the right or left lower eyelid; the contralateral eye will receive a placebo ointment. Subjects are instructed to apply a small amount (about 0.1 mL) of the corresponding ointment to the lower eyelid of the eye once a day.
[00204] Serial clinical examinations and photographs, and magnetic resonance imaging (MRI) scans are conducted at regular intervals during the study. Treatment continues for 12 weeks.
[00205] It is contemplated that, over time, for example, after 6 to 12 weeks, tafluprost ointment will be associated with a more subjective and objective reduction in orbital fat filling, thickness and/or volume, when compared to vehicle in isolation. Other Modalities
The foregoing has been a description of certain non-limiting embodiments of the invention. Those skilled in the art will appreciate that various changes and modifications in relation to this description can be made without departing from the spirit and scope of the present invention as defined in the following claims.

权利要求:
Claims (16)
[0001]
1. Use of a compound of formula (II):
[0002]
Use according to claim 1, characterized in that R1 is C1-C4-alkyl.
[0003]
Use according to claim 1, characterized in that R1 is methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl or sec-butyl.
[0004]
4. Use according to claim 1, characterized in that RI is hydrogen.
[0005]
5. Use according to claim 1, characterized in that the compound is of the formula:
[0006]
Use according to claim 1, characterized in that R1 is ethyl.
[0007]
Use according to any one of claims 1 to 6, characterized in that the composition comprises between 0.001% and 1% (w/w) and (w/v), inclusive, of the compound.
[0008]
Use according to any one of claims 1 to 6, characterized in that the composition comprises between 0.01% and 1% (w/w) and (w/v), inclusive, of the compound.
[0009]
Use according to any one of claims 1 to 8, characterized in that the composition is suitable for topical delivery.
[0010]
Use according to any one of claims 1 to 9, characterized in that the composition is a cream, gel, lotion or ointment.
[0011]
Use according to any one of claims 1 to 8, characterized in that the composition is suitable for subcutaneous, intradermal or intralesional delivery.
[0012]
Use according to any one of claims 1 to 11, characterized in that the individual is suffering from obesity.
[0013]
Use according to any one of claims 1 to 11, characterized in that the individual is suffering from HIV lipodystrophy.
[0014]
Use according to any one of claims 1 to 11, characterized in that the individual suffers from excess fat on the chin.
[0015]
Use according to any one of claims 1 to 13, characterized in that the fat is located on the abdomen, chest, breasts, buttocks, hips, thighs, legs, knees, arms, chin, neck and face.
[0016]
Use according to any one of claims 1 to 11, characterized in that the fat is orbital fat.

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法律状态:
2018-03-06| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2019-05-21| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-09-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-05-25| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-06-01| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2021-07-06| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 19/12/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201161577332P| true| 2011-12-19|2011-12-19|

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US61/577,332|2011-12-19|

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US13/548,482|US8426471B1|2011-12-19|2012-07-13|Methods and compositions for reducing body fat and adipocytes|

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US13/548,482|2012-07-13|

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PCT/US2012/070581|WO2013096429A2|2011-12-19|2012-12-19|Methods and compositions for reducing body fat and adipocytes|

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