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  • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
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  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
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  • C07D243/24—Oxygen atoms
  • C07D243/30—Preparation including building-up the benzodiazepine skeleton from compounds already containing hetero rings
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  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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Definitions

• M is -C(O)-, -C(S), or -SO 2 -;
• the present invention encompasses the finding that certain isoprenyl compounds have surprising and desirable characteristics as compared with other compounds and/or N-acetyl-S-farnesyl-L-cysteine ("AFC").
• AFC N-acetyl-S-farnesyl-L-cysteine
• the present disclosure illustrates that certain isoprenyl compounds show surprising inhibition of edema, erythema and dermal neutrophil infiltration, as measured by inhibition of MPO (myeloperoxidase), when compared to AFC.
• alkylene chain is a polymethylene group, i.e., -(CH 2 )D-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 3, or 3 to 4, 4 to 5, 5 to 6.
• a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for a substituted aliphatic group.
• Alkylene refers to a divalent group of formula -R a -Ar a - where R a is an
• Carrier The term “carrier” is used in accordance with its art-understood meaning, to refer to a material that is included in a pharmaceutical composition but does not abrogate the biological activity of pharmaceutically active agent(s) that are also included within the composition. Typically, carriers have very low toxicity to the animal to which such compositions are to be administered. In some embodiments, carriers are inert. In some embodiments, carriers are affirmatively beneficial (e.g., providing pharmaceutical and/or cosmetic benefits). In some embodiments, isoprenyl compounds of Formulae I, I 1 and/or Ia, act as acceptable carriers. In some embodiments, AFC acts as an acceptable carrier.
• the effective amount of a composition and/or formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition.
• a therapeutically effective amount will be administered over a series of individual doses.
• the term "effective amount" when used in a pharmaceutical context means that an agent is present in an amount sufficient to achieve a desired therapeutic effect.
• Finely divided emulsif ⁇ ers include aluminum hydroxide, bentonite, magnesium hydroxide, or magnesium trisylicate.
• Synthetic agents include anionic, cationic or nonionic agents, and include benzalkonium chloride, polyethylene glycol 400 monostearate, sodium lauryl sulfate, or combinations thereof.
• Protective refers to an agent that isolates exposed surface of skin or other membrane from harmful or annoying stimuli.
• exemplary protectives include dusting powders, adsorbents, mechanical protective agents, and plasters.
• Mechanical protectives are generally either collodions or plasters, and include, for example aluminum hydroxide gel, collodium, dimethicone, petrolatum gauze, absorbable gelatin film, absorbable gelatin sponge, zinc gelatin, kaolin, lanolin, anhydrous lanolin, mineral oil, mineral oil emulsion, mineral oil light, olive oil, peanut oil, petrolatum, silicones, hydrocolloids and the like.
• Small Molecule refers to an organic compound either synthesized in the laboratory or found in nature. Typically, a small molecule is characterized in that it contains several carbon-carbon bonds, and has a molecular weight of less than 1500, although this characterization is not intended to be limiting for the purposes of the present invention. Examples of “small molecules” that occur in nature include, but are not limited to, taxol, dynemicin, and rapamycin. Examples of "small molecules” that are synthesized in the laboratory include, but are not limited to, the inventive compounds incorporated herein.
• substituted It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties.
• substituted whether preceded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
• substituted is contemplated to include all permissible substituents of organic compounds.
• Compound A demonstrating that administering Compound A at 0.25%, 0.50% and 1.0% dosage levels results in an inhibition in TNF- ⁇ (Figure 4A panel) and IL- l ⁇ ( Figure 4B panel) levels, as determined using a TPA mouse ear inflammation model.
• the L group is - CH 2 CH(phenyl)C(O)-. In certain embodiments, the L group is -CH(phenyl)CH 2 C(O)-. In certain embodiments, L is a C 3 hydrocarbon chain wherein one methylene unit of L is replaced by -C(O)- and one methylene unit is substituted by -NHC(O)NHCH 2 CH 3 . In certain embodiments, the L group is -CH 2 CH[NHC(O)NHCH 2 CH 3 ]C(O)-.
• L is a C3 hydrocarbon chain wherein one methylene unit of L is replaced by an optionally substituted heteroarylene.
• the heteroarylene is thiophenyl.
• the heteroarylene is furanyl.
• L is -CH[(CH 2 ) 2 C(O)NH 2 ]NH-. In certain embodiments, the L group is -C(O)NHCH[CH(CH 3 )(CH 3 )]-. In certain embodiments, the L group is -C(O)NHCH[CH(CH 3 )(CH 3 )]-. In certain embodiments, L is a C 6 hydrocarbon chain wherein two methylene units of L are replaced by -C(O)- and one methylene unit is replaced by -NH- and one methylene unit is substituted by -NH 2 or
• Enantiomeric and stereoisomeric mixtures may be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing a compound as a chiral salt complex, or crystallizing a compound in a chiral solvent or by enzymatic resolution of a compound, its precursor or its derivative.
• Enantiomers and stereoisomers may also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
• Exemplary such compounds include Compound C (Example 5 and Example 5a), Compound N-2, Compound N-18, Compound N-31 (Example 62), Compound N-34 (Example 41a), Compound N-37, Compound N-40 (Example 32), Compound N-41 (Example 33), Compound N-46 (Example 35), Compound N-47, Compound N-61 (Example 27), Compound N-64 (Example 30), Compound N-65 (Example 31), Compound N-77 (Example 65), Compound N-89, Compound N-93, and Compound N-94.
• compounds of the present invention having stereochemistry as depicted in Formula Ia, are provided such that compounds containing an L group of Formula l/-(iii) and compounds containing an L group of Formula l/-(iv) are present in a 1 :1 molar ratio.
• Exemplary such compounds include Compound N-36; Compound N-78 (Example 66); and Compound N-32 (Example 67).
• stereoisomers of L are present.
• a mixture may contain two stereoisomers present in a ratio of about 20:1, 18:1, 16:1, 14:1, 12:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, or 1 :1.
• R 3 of Formula I or Formula I' having stereochemistry as depicted in Formula Ia or Ib, is of Formula Ir:
• compounds of Formula I and/or Formula I' having stereochemistry as depicted in Formula Ia and/or Ib, are provided such that two chiral centers in R 3 are present as racemates.
• Exemplary such regioisomeric mixtures described herein include: (1)
• provided compounds are considered to be inhibitors of inflammation when they result in an ED50 in an edema assay of at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5-fold lower than that observed with AFC.
• provided compounds are considered to be proinflammatory when they show percent inhibition in an edema assay of at least about (-)IO, (-)20, (-)30, (-)40, (-)50, (-)55, (-)60, (-)65, (-)70, (-)75, (-)80, (-)85, (-)90 or (-)95%, for example when provided at a dose of 0.8 mg/20 ⁇ l.
• provided compounds are considered inhibitors of inflammation when they show a percent inhibition of cytokine release in a LPS-TLR4- induced cytokine release model, as determined using HMEC-I cells, of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95%, for example when provided at a dosage of 0.50%.
• provided compounds are considered inhibitors of inflammation when they show a percent inhibition of cytokine release in a LPS-TLR4- induced cytokine release model, as determined using HMEC-I cells, of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95%, for example when provided at a dosage of 1.00%.
• provided compounds are considered inhibitors of inflammation when they show a percent inhibition of cytokine release in an ATP ⁇ S- purinergic receptor-induced cytokine release model, as determined using HMEC-I cells of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95%, for example when provided at a dosage of 0.25%.
• provided compounds are considered inhibitors of inflammation when they show a percent inhibition of cytokine release in a TNF ⁇ -induced cytokine release model, as determined using HUVEC cells, of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95%, for example when provided at a dosage of 0.50%.
• compositions containing isoprenyl compounds for parenteral administration can include pharmaceutical carriers (e.g., sterile and non-sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of isoprenyl compounds in liquid or solid oil bases).
• pharmaceutical carrier solutions also can contain buffers, diluents and other suitable additives.
• Additional active ingredients include, without limitation, one or more, in any combination, of a protective agent, an emollient, an astringent, an irritant, a keratolytic, a sun screening agent, a sun tanning agent, an antibiotic agent, an antifungal agent, an antiviral agent, an antiprotozoal agent, an anesthetic agent, a steroidal anti-inflammatory agent, a non-steroidal anti-inflammatory agent, an antipruritic agent, an anti-oxidant agent, a chemotherapeutic agent, an anti-histamine agent, a vitamin, a hormone, an anti-dandruff agent, an anti-wrinkle agent, an anti-skin atrophy agent, a sclerosing agent, a cleansing agent, a caustic agent and a hypo-pigmenting agent.
• at least one isoprenyl compound of compositions provided herein is an active ingredient.
• any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets.
• oral liquid preparations such as, for example, suspensions, elixirs and solutions
• carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets.
• an isoprenyl compound, carrier and, optionally, additional active ingredients are formed into a composition in the form of a solution, emulsion or gel suspension, as will be further described herein.
• a basic emulsion in the context of the present invention typically contains two or more components (e.g., two immiscible liquid carriers, an emulsifying agent, and an isoprenyl compound).
• a prenyl compound can be an emulsifying agent.
• emulsions incorporate an aqueous phase into a non-aqueous phase (or vice versa).
• anionic and cationic surfactants of the non-aqueous immiscible system glycerin and olive oil Exemplary emulsifying agents are described herein.
• a provided compound of the present invention is formulated with a poly(ortho ester), which may be an auto-catalyzed poly(ortho ester) with any of a variable percentage of lactic acid in the polymeric backbone, and optionally one or more additional excipients.
• poly (D,L-lactide-co-glycolide) polymer PLGA polymer
• PLGA polymer poly (D,L-lactide-co-glycolide) polymer
• PLGA polymer polymer
• PLGA polymer polymer
• a hydrophilic end group such as PLGA RG502H from Boehringer Ingelheim, Inc. (Ingelheim, Germany).
• Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations also may contain a demulcent, a preservative, and flavoring and coloring agents. Demulcents are protective agents employed primarily to alleviate irritation, particularly mucous membranes or abraded tissues. A number of chemical substances possess demulcent properties. These substances include the alginates, mucilages, gums, dextrins, starches, certain sugars, and polymeric polyhydric glycols.
• compositions comprising a therapeutically or pharmaceutically effective amount of an inventive complex may be formulated for administration in unit dosage forms.
• Oral Administration [00309] Because of their ease of administration, tablets and capsules represent an advantageous oral unit dosage form.
• a composition including provided compound of the invention may be coated by standard aqueous or nonaqueous techniques.
• the amount of active compound, i.e. isoprenyl compounds of the present invention, in such therapeutically useful compositions is such that an effective dosage will be obtained.
• sublingual pharmaceutical compositions may be employed, such as sheets, wafers, tablets or the like.
• An active compound can also be administered intranasally as, for example, by liquid drops or spray.
• a tablet may contain the active ingredient(s) in admixture with non-toxic pharmaceutically acceptable additives and/or excipients which are suitable for the manufacture of tablets.
• additives or excipients may be, for example, fillers, wetting agents, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and noneffervescent disintegrating agents, (e.g., corn starch or alginic acid); binding agents (e.g., starch, gelatin or acacia); and lubricating agents (e.g., magnesium stearate, stearic acid or talc).
• fillers wetting agents, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
• granulating and noneffervescent disintegrating agents e.g., corn starch or alginic acid
• binding agents e.g.,
• compositions of the present invention also may be formulated for oral use as hard gelatin capsules, where a provided compound is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules wherein the active ingredient(s) is (are) mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• an oil medium for example, peanut oil, liquid paraffin, or olive oil.
• Liquid based oral dosage forms like their solid counterparts, usually contain at least 0.1 mg of a provided compound.
• One skilled in the art will be able to properly formulate a liquid formulation containing an appropriate amount of a provided compound per fluidic ounce, depending on the additive or carrier selected.
• the actual quantity of provided compounds of the invention administered to a patient will vary depending on the severity and type of indication, the mode of administration, the particular compound used, the formulation used, and the response desired.
• the provided compounds of the present invention are highly active.
• Direct therapeutic approaches include using antibodies or soluble receptors (i.e., biologies) to directly neutralize the specific cytokine of interest.
• biologic cytokine-derived therapies are expensive to produce, require sustained high blood levels in order to develop significant skin levels, may induce the production of neutralizing antibodies (leading to a diminished response to therapy), and must be administered by injection.
• Topical treatments have largely been ineffective, so market growth has been driven by systemic agents that have serious potential side effects. Corticosteroids remain the cornerstone of current topical treatment, but they are far from ideal. Long-term steroid use brings safety concerns ranging from issues of systemic absorption to cutaneous atrophy and its various clinical presentations.
• Psoriasis can be conceived in simple terms, as a self reinforcing loop, in which deregulated inflammatory activity stimulates the epidermal Stat3c signaling pathway in the epidermis resulting in epidermal hyperplasia.
• the affected keratinocytes secrete cytokines which simulate the immune system, including T-helper cell (THc) infiltration and accumulation.
• cytokines associated with atopic dermatitis include but are not limited to TNF ⁇ , ILl ⁇ , IL-6, IL-8, MCP-I, Gro ⁇ , IL-4, IL-5, IL-10, IL- 13, IL-17 and IFN ⁇ .
• Inflammatory Cytokines and Atopic Dermatitis include but are not limited to TNF ⁇ , ILl ⁇ , IL-6, IL-8, MCP-I, Gro ⁇ , IL-4, IL-5, IL-10, IL- 13, IL-17 and IFN ⁇ .
• the present invention provides methods of treating ameloriating, controlling, or preventing inflammatory skin conditions (e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis).
• inflammatory skin conditions e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis.
• the present invention provides methods of treating, ameliorating, controlling, or preventing inflammatory skin conditions (e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis) comprising administering to a subject in need thereof a dosage form comprising at least about 0.1 mg of a isoprenyl compound of Formulae I, I' and/or in described classes and subclasses thereof, wherein cytokine levels and/or activity (e.g., IL-l ⁇ levels and/or activity) are reduced by more than about 20% (e.g., as determined using a TPA-induced mouse ear inflammatory model).
• inflammatory skin conditions e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis
• cytokine levels and/or activity e.g., IL-l ⁇ levels and/or activity
• the present invention provides methods of treating, ameliorating, controlling, or preventing inflammatory skin conditions (e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis) comprising administering to a subject in need thereof a dosage form comprising at least about 0.1 mg of a isoprenyl compound of Formulae I, I' and/or in described classes and subclasses thereof, wherein cytokine levels and/or activity (e.g., TNF- ⁇ levels and/or activity) are reduced by more than about 20% (e.g., as determined using an LPS-TLR4-induced cytokine release inflammatory model in HMEC-I cell line).
• inflammatory skin conditions e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis
• cytokine levels and/or activity e.g., TNF- ⁇ levels and/or activity
• the present invention provides methods of treating, ameliorating, controlling, or preventing inflammatory skin conditions (e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis) comprising administering to a subject in need thereof a dosage form comprising at least about 0.1 mg of a isoprenyl compound of Formulae I, I' and/or in described classes and subclasses thereof, wherein cytokine levels and/or activity (e.g., IL-l ⁇ levels and/or activity) are reduced by more than about 20% (e.g., as determined using an ATP ⁇ S-purinergic receptor-induced cytokine release inflammatory model in HMEC-I cell line).
• inflammatory skin conditions e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis
• cytokine levels and/or activity e.g., IL-l ⁇ levels and/or activity
• the present invention provides methods of treating, ameliorating, controlling, or preventing inflammatory skin conditions (e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis) comprising administering to a subject in need thereof a dosage form comprising at least about 0.1 mg of a isoprenyl compound of Formulae I, I' and/or in described classes and subclasses thereof, wherein cytokine levels and/or activity (e.g., MCP-I levels and/or activity) are reduced by more than about 20% (e.g., as determined using an ATP ⁇ S-purinergic receptor-induced cytokine release inflammatory model in HMEC-I cell line).
• inflammatory skin conditions e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis
• cytokine levels and/or activity e.g., MCP-I levels and/or activity
• the present invention provides methods of treating, ameliorating, controlling, or preventing inflammatory skin conditions (e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis) comprising administering to a subject in need thereof a dosage form comprising at least about 0.1 mg of a isoprenyl compound of Formulae I, I' and/or in described classes and subclasses thereof, wherein cytokine levels and/or activity (e.g., IL-8/KC levels and/or activity) are reduced by more than about 20% (e.g., as determined using a TPA-induced cytokine release inflammatory model in NHEK cell line).
• inflammatory skin conditions e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis
• cytokine levels and/or activity e.g., IL-8/KC levels and/or activity
• the present invention provides methods of treating, ameliorating, controlling, or preventing inflammatory skin conditions (e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis) comprising administering to a subject in need thereof a dosage form comprising at least about 0.1 mg of a isoprenyl compound of Formulae I, I' and/or in described classes and subclasses thereof, wherein cytokine levels and/or activity (e.g., MCP-I levels and/or activity) are reduced by more than about 20% (e.g., as determined using a TNF ⁇ -induced cytokine release inflammatory model in HUVEC cell line).
• inflammatory skin conditions e.g., rosacea, psoriasis, atopic dermatitis and seborrhic dermatitis
• cytokine levels and/or activity e.g., MCP-I levels and/or activity
• UV ultraviolet
• ROS reactive oxygen species
• Exemplary pharmaceutically active agents whose delivery, whether transdermally or by injection, may cause skin irritation include levadopa, pro-drug forms of levadopa, insulin, estradiol, estrogen, progesterone, progestins, progestogen, testosterone, nicotine, nitroglycerin, cholinesterase inhibitors, stimulants, antidepressants, and analgesics.
• certain agents such as, for example, hair relaxants, which commonly are or contain basic agents (e.g., NaOH), can cause skin irritation (e.g., irritation and/or inflammation of the scalp).
• hair relaxants which commonly are or contain basic agents (e.g., NaOH)
• one or more isoprenyl compounds can be administered together with such a hair relaxant (or other agent) to reduce skin irritation and/or inflammation.

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