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WO2025215303A1 - Sulfonamides, compositions comprenant lesdits sulfonamides, procédés de préparation desdits sulfonamides et lesdits sulfonamides pour une utilisation en tant que médicament et dans une méthode pour le traitement ou la prévention d'une maladie ou d'un état oculaire ou de l'hypertension intracrânienne idiopathique - Google Patents

Sulfonamides, compositions comprenant lesdits sulfonamides, procédés de préparation desdits sulfonamides et lesdits sulfonamides pour une utilisation en tant que médicament et dans une méthode pour le traitement ou la prévention d'une maladie ou d'un état oculaire ou de l'hypertension intracrânienne idiopathique

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Publication number
WO2025215303A1
WO2025215303A1 PCT/FI2025/050182 FI2025050182W WO2025215303A1 WO 2025215303 A1 WO2025215303 A1 WO 2025215303A1 FI 2025050182 W FI2025050182 W FI 2025050182W WO 2025215303 A1 WO2025215303 A1 WO 2025215303A1
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WIPO (PCT)
Prior art keywords
group
compound
independently selected
heterocyclic ring
aromatic
Prior art date
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English (en)
Inventor
Stanislav KALININ
Arto Urtti
Peter Wipf
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Ita-Suomen Yliopisto
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Ita-Suomen Yliopisto
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Publication of WO2025215303A1 publication Critical patent/WO2025215303A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • SULFONAMIDES COMPOSITIONS COMPRISING SAID SULFONAMIDES, METHODS FOR THE PREPARATION OF SAID SULFONAMIDES, AND SAID SULFONAMIDES FOR USE AS MEDICAMENT AND IN A METHOD FOR THE TREATMENT OR PREVENTION OF AN OCULAR DISEASE OR CONDITION, OR IDIOPATHIC INTRACRANIAL HYPERTENSION.
  • the present disclosure relates to sulfonamides and in particular to new derivatives of 4- hydrazineylbenzenesulfonamides and 4-(aminooxy)benzenesulfonamides.
  • compositions comprising said sulfonamides, to said sulfonamides for use as a medicament, to said sulfonamides for use in methods for the treatment or prevention of an ocular disease or condition, or idiopathic intracranial hypertension, in particular for the treatment of glaucoma and macular edema (ME), and to a method for the preparation of said compounds.
  • CAIs Carbonic anhydrase inhibitors
  • COAIs are a class of drugs that inhibit the activity of the enzyme carbonic anhydrase. Carbonic anhydrase plays a role in many physiological processes, including fluid and electrolyte balance, acid-base balance, and cell signaling.
  • C AIs are used to treat a variety of ocular diseases and conditions, including glaucoma, idiopathic intracranial hypertension (IIH), and macular edema (ME).
  • IIH idiopathic intracranial hypertension
  • ME macular edema
  • aqueous humor the fluid that fills the front of the eye
  • IOP intraocular pressure
  • Aqueous humor is constantly produced and drained from the eye to maintain a normal intraocular pressure (IOP). If the drainage of aqueous humor is impaired, IOP can increase, leading to glaucoma.
  • CAIs reduce the production of aqueous humor, thereby lowering IOP. This makes them a valuable treatment for glaucoma.
  • CAIs can be used as monotherapy or in combination with other glaucoma medications. In addition to their use in glaucoma, CAIs are also used to treat IIH and ME.
  • IIH is a condition in which the pressure in the cerebrospinal fluid is elevated. This can cause headaches, vision problems, and other symptoms.
  • CAIs are used to lower the pressure in the cerebrospinal fluid and improve symptoms in patients with IIH.
  • ME is a condition in which fluid accumulates in the retina, the light-sensitive tissue at the back of the eye. This can cause blurred vision, distortion, and other vision problems.
  • CAIs are used to reduce fluid accumulation in the retina and improve vision in patients with ME.
  • CAIs are available in both topical and oral formulations.
  • Topical CAIs are applied directly to the eye in the form of drops or ointments. Oral CAIs are taken by mouth and are more effective at lowering IOP than topical CAIs.
  • Specific uses of CAIs in ocular diseases and conditions include: 1 .
  • Glaucoma CAIs are a first-line treatment for most types of glaucoma. They are particularly effective in patients with chronic open-angle glaucoma, the most common type of glaucoma.
  • CAIs can also be used to treat other types of glaucoma, such as (acute) angle-closure glaucoma, open angle glaucoma, pediatric glaucoma and pseudoexfoliative glaucoma. 2.
  • Idiopathic Intracranial Hypertension CAIs are the mainstay treatment for IIH. They are effective in lowering the pressure in the cerebrospinal fluid and improving symptoms in most patients with IIH. 3 .
  • Macular Edema CAIs are used to treat ME secondary to a variety of causes, including diabetes, retinal vein occlusion, and uveitis.
  • CAIs are effective in reducing fluid accumulation in the retina and improving vision in most patients with ME.
  • CAIs are a valuable class of medications for the treatment of a variety of ocular diseases. They are effective in lowering IOP, reducing fluid accumulation in the retina, and improving symptoms in patients with glaucoma, IIH, and ME.
  • An object of the present invention is to provide compounds useful in treating or preventing an ocular disease or condition, in particular glaucoma and macular edema (ME), or idiopathic intracranial hypertension (IIH).
  • an ocular disease or condition in particular glaucoma and macular edema (ME), or idiopathic intracranial hypertension (IIH).
  • T he invention is based on the realization that the compounds are novel melanin-binding CAI inhibitors that reduce IOP and may be used for the treatment or prevention of glaucoma and related ocular diseases, including IIH, and ME.
  • the inhibitors apply a novel hybrid design, connecting a CAI moiety to a melanin-binding aromatic or heteroaromatic moiety through a hydrazone or oxime linker.
  • the combination of melanin-binding aromatic or heteroaromatic moiety and hydrazone/oxime linker may allow for a tuning of drug action over very wide range in the acidic pH of the cellular melanosomes.
  • a compound of formula (I) formula (I), wherein R 1 and R 2 are each independently selected from the group consisting of H, C 1-8 -alkyl, C 6-10 -aryl, C 1-10 -heteroaryl, and derivatives thereof being substituted with one or more halogen; e ach Z is independently selected from the group consisting of C(R), and N; each R is independently selected from the group consisting of H, halogen, preferably F, Cl, or Br; hydroxy, C1-8-alkoxy, C1-8-alkylthio, C1-8-carboxamide group, C1-8-ester group, C1-8- urea group, C1-8-carbamate group, C1-8-alkyl, C6-10-aryl, C5-10-heteroaryl, and derivatives thereof being substituted with one or more halogen; Y is N(R) or O; X is a 5-10 membered aliphatic, aromatic or heterocyclic ring
  • composition comprising the compound as defined in the present disclosure, or a stereoisomer, the pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • a method for the preparation of a compound as defined in the present disclosure comprises: - providing a compound of formula (X) or a salt thereof: formula (X), and a compound of formula (XI ⁇ ): formula (XI ⁇ ) or a compound of formula (XI ⁇ ⁇ ): formula (XI ⁇ ⁇ ), wherein b oth X ⁇ , together with the carbons they are attached to, together form a 5-10 membered aliphatic, aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’, each dotted line represents an optional bond, and R 1, R2, R3, R, R’, X, Y, and Z are as defined in the present disclosure; and - reacting the compound of formula (X) or a salt thereof with the compound of formula (X), and a compound of formula (
  • “Acyloxy” refers to a group having the structure –OC(O)R-, where R may be, for example, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. “Lower acyloxy” groups contain one to six carbon atoms. “Administration” as used herein is inclusive of administration by another person to the subject or self-administration by the subject.
  • the term "aliphatic” is defined as including alkyl, alkenyl, alkynyl, halogenated alkyl and cycloalkyl groups.
  • a "lower aliphatic” group is a branched or unbranched aliphatic group having from 1 to 10 carbon atoms.
  • Alkanediyl refers to a divalent radical derived from aliphatic, cycloaliphatic, aryl, and alkanearyl hydrocarbons.
  • Alkenyl refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and contains one or more double bonds that may or may not be conjugated. Alkenyl groups may be unsubstituted or substituted. “Lower alkenyl” groups contain one to six carbon atoms.
  • alkoxy refers to a straight, branched or cyclic hydrocarbon configuration and combinations thereof, including from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms (referred to as a “lower alkoxy”), more preferably from 1 to 4 carbon atoms, that include an oxygen atom at the point of attachment.
  • An example of an “alkoxy group” is represented by the formula –OR, where R can be an alkyl group, optionally substituted with an alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, alkoxy or heterocycloalkyl group.
  • alkoxy groups and lower alkoxy and C1-8-alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, cyclopropoxy, cyclohexyloxy, and the like.
  • alkylthio refers to a straight, branched or cyclic hydrocarbon configuration and combinations thereof, including from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms (referred also to as a “lower alkylthio”), more preferably from 1 to 4 carbon atoms, that include a sulphur atom at the point of attachment.
  • alkylthio groups and lower alkylthio and C1-8- alkylthio include, but are not limited to, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, sec-butylthio, tert-butylthio, and the like.
  • Alkoxycarbonyl refers to an alkoxy substituted carbonyl radical, –C(O)OR, wherein R represents an optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl or similar moiety.
  • alkyl refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.
  • a “lower alkyl” group is a saturated branched or unbranched hydrocarbon having from 1 to 8 carbon atoms. Preferred alkyl groups have 1 to 4 carbon atoms.
  • Alkyl groups may be “substituted alkyls” wherein one or more hydrogen atoms are substituted with a substituent such as halogen, cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl.
  • a lower alkyl or (C1-C8)alkyl or C1-8-alkyl can be, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, iso- butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • (C 3 -C 6 )cycloalkyl(C 1 -C 8 )alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2- cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl;
  • (C1-C8)alkoxy can be methoxy,
  • alkynyl refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and unless otherwise mentioned typically contains one to twelve carbon atoms, and contains one or more triple bonds. Alkynyl groups may be unsubstituted or substituted. “Lower alkynyl” groups are those that contain one to six carbon atoms.
  • amine refers to a group of the formula –NRR', where R and R' can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, heterocycloalkyl, or carboxyl group.
  • R and R' can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, heterocycloalkyl, or carboxyl group.
  • R and R' can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, heterocycloalkyl, or carboxyl group.
  • an “alkylamino” or “alkylated amino” refers to –NRR
  • aminoalkyl refers to alkyl groups as defined above where at least one hydrogen atom is replaced with an amino group (e.g, -CH 2 -NH 2 ).
  • Aminocarbonyl alone or in combination, means an amino substituted carbonyl (carbamoyl) radical, wherein the amino radical may optionally be mono- or di-substituted, such as, for example, with alkyl, aryl, acyl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like.
  • an aminocarbonyl may be represented by the formula –C(O)NRR', where R and R' independently can be, for example, a hydrogen, alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group.
  • an “analog” is a molecule that differs in chemical structure from a parent compound, for example a homolog (differing by an increment in the chemical structure or mass, such as a difference in the length of an alkyl chain or the inclusion of one of more isotopes), a molecular fragment, a structure that differs by one or more functional groups, or a change in ionization.
  • An analog is not necessarily synthesized from the parent compound.
  • a derivative is a molecule derived from the base structure.
  • An “animal” refers to living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds. The term mammal includes both human and non- human mammals.
  • the term “subject” includes both human and non-human subjects, including birds and non-human mammals.
  • Illustrative non-human mammals include animal models (such as mice), non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats.
  • the term subject applies regardless of the stage in the organism’s life-cycle.
  • the term subject applies to an organism in utero or in ovo, depending on the organism (that is, whether the organism is a mammal or a bird, such as a domesticated or wild fowl).
  • aralkyl refers to an alkyl group wherein an aryl group is substituted for a hydrogen of the alkyl group.
  • An example of an aralkyl group is a benzyl group.
  • Aryl and “aromatic ring” refer to a monovalent or polyvalent unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which can optionally be unsubstituted or substituted.
  • Examples of “C6-10-aryl” or “6-10 membered aromatic ring” include, but are not limited to, phenyl, indanyl, and naphthyl.
  • heteroaryl and a “heteroaryl group” is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Therefore, it is to be understood that an “aromatic ring comprising 0-5 heteroatoms” may be an aryl or an heteroaryl. It is also to be understood that the terms “heterocyclic ring” as used in the present disclosure may include both aromatic and non-aromatic monovalent and polyvalent radicals derived from heterocyclic compounds and, therefore, may be a heteroaryl (such as, but not limited to, pyridinyl and indolyl) or a heterocyclic ring (such as, but not limited to, imidazolidinyl).
  • heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorous.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.
  • the aryl or heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy, or the aryl or heteroaryl group can be unsubstituted.
  • “Aryloxy” or “heteroaryloxy” refers to a group of the formula –OAr, wherein Ar is an aryl group or a heteroaryl group, respectively.
  • Bicyclic or "bicyclyl” as used herein refers to a ring assembly of two rings where the two rings may be fused together, linked by a single bond or linked by two or more bridging atoms.
  • the rings may be selected from carbocyclyls, and heterocyclyls, or a mixture thereof.
  • Compounds having bicyclic rings include, but are not limited to, spiro compounds, fused/condensed bicyclic compounds, and bridged bicyclic compounds.
  • bicyclic 8-13 membered heterocyclic rings include, but are not limited to, 1H-isoindol-3-ylamine, 1H- isoindole, 1H-2,4,7-triazainden-3-ylamine, 1H-2,4-diazainden-3-ylamine, and 2-quinoxalinyl.
  • bicyclic 8-13 membered heterocyclic ring comprising an unsaturated 5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ring is fused with X
  • examples of bicyclic 8-13 membered heterocyclic ring comprising an unsaturated 5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ring is fused with X include, but are not limited to, 1H-isoindol-3-ylamine, 1H-isoindole, 1H-2,4,7- triazainden-3-ylamine, 1H-2,4-diazainden-3-ylamine.
  • Tricyclic refers to a ring assembly of three rings where the three rings may be fused together, linked by single bonds or linked by two or more bridging atoms.
  • the rings may be selected from carbocyclyls, and heterocyclyls, or a mixture thereof.
  • tricyclic compounds may have spiro atoms, and may share two or more atoms.
  • An example of a tricyclic ring includes, but is not limited to, 2,5,8-triazatricyclo[7.4.0.0 3,7 ]trideca- 1(9),2,4,7,10,12-hexaene.
  • An example of a tricyclic 8-13 membered heterocyclic ring comprising an unsaturated 5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ring is fused with X includes, but is not limited to, 2,5,8- triazatricyclo[7.4.0.0 3,7 ]trideca-1(9),2,4,7,10,12-hexaene.
  • a “carbonylamino” group and a “carboxamide group” may be –N(R)-C(O)-R (wherein each R is independently a substitution group such as, for example, alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group, or H).
  • a suitable carbonylamino group is acetamido.
  • T he term “carboxylate” or “carboxyl” refers to the group -COO- or -COOH.
  • the carboxyl group can form a carboxylic acid.
  • Substituted carboxyl refers to -COOR where R is alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group.
  • a substituted carboxyl group could be a carboxylic acid ester or a salt thereof (e.g., a carboxylate).
  • co-administration or “co-administering” refers to administration of a compound disclosed herein with at least one other therapeutic agent or therapy within the same general time period, and does not require administration at the same exact moment in time (although co-administration is inclusive of administering at the same exact moment in time).
  • co-administration may be on the same day or on different days, or in the same week or in different weeks.
  • the co-administration of two or more agents or therapies is concurrent.
  • a first agent/therapy is administered prior to a second agent/therapy.
  • the appropriate dosage for co- administration can be readily determined by one skilled in the art.
  • the respective agents or therapies are administered at lower dosages than appropriate for their administration alone.
  • co-administration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent and/or lowers the frequency of administering the potentially harmful (e.g., toxic) agent.
  • “Co-administration” or “co-administering” encompass administration of two or more active agents to a subject so that both the active agents and/or their metabolites are present in the subject at the same time.
  • Co- administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active agents are present.
  • T he terms “cycloalkyl” and “aliphatic ring” refer to a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptanyl, and the like.
  • heterocycloalkyl group is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorous.
  • aliphatic ring comprising 0-5 heteroatoms may include both cycloalkyls and heterocycloalkyl groups (heterocyclic rings, heterocycles), and may be a monovalent or polyvalent saturated or partially unsaturated aliphatic ring having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., perhydronaphth-2-yl).
  • esters refers to a carboxyl group-containing moiety having the hydrogen replaced with, for example, a C1-6alkyl group (“carboxylC1-6alkyl” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on.
  • CO2C1-3alkyl groups are preferred, such as for example, methylester (CO2Me), ethylester (CO2Et) and propylester (CO2Pr) and includes reverse esters thereof (e.g. –OCOMe, -OCOEt and –OCOPr).
  • each dotted line represents an optional bond” as used herein and hereafter refers one or more bonds that may or may not be present. It is to be understood that when a dotted line is present then it forms, together with the single bond next to it, a double bond.
  • the compound of formula (III) is equal to a compound of formula (IIIa) or formula (IIIb) when one or more dotted lines are present: formula (IIIa), formula (IIIb), and when a dotted line is not present, the compound of formula (I) is equal to a compound of formula (IIIc): formula (IIIc), wherein R 1 , R 2 , R 7 , R 8 , R, X ⁇ , Y, and Z are as defined in the present disclosure.
  • Halo or “halogen”, as used herein, refers to fluoro, chloro, bromo, and iodo.
  • haloalkyl refers to an alkyl group with one or more hydrogen atoms present on these groups substituted with a halogen (F, Cl, Br, I).
  • haloalkyl groups include without limitation chloromethyl, fluoromethyl, -CH2CF3, trifluoromethyl (-CF3) and trichloromethyl (-CCl3).
  • heterocyclic refers to a closed-ring compound, or radical thereof as a substituent bonded to another group, particularly other organic groups, where at least one atom in the ring structure is other than carbon, and typically is oxygen, sulfur and/or nitrogen.
  • heterocyclic ring refers to both aromatic and non-aromatic monovalent and polyvalent radicals derived from heterocyclic compounds and, therefore, may refer to a heteroaryl group, a non-aromatic heterocycloalkyl group and heterocyclic ring.
  • a “5- 10 membered heterocyclic ring” may have a single ring (e.g., pyridinyl) or multiple condensed rings (e.g., indolyl). It is to be understood that the terms “bi- or tricyclic 8-13 membered heterocyclic ring” refer in the present disclosure to 8-13 membered heterocycles having two (bicyclic) or three (tricyclic) condensed rings, wherein at least one of the condensed rings is a heterocyclic ring, typically two or three of the condensed rings are heterocyclic rings.
  • hydroxyl is represented by the formula –OH.
  • hydroxyalkyl refers to an alkyl group that has at least one hydrogen atom substituted with a hydroxyl group.
  • alkoxyalkyl group is defined as an alkyl group that has at least one hydrogen atom substituted with an alkoxy group described above.
  • Inhibiting refers to inhibiting the full development of a disease or condition. “Inhibiting” also refers to any quantitative or qualitative reduction in biological activity or binding, relative to a control.
  • N-Heterocyclic refers to mono- or bicyclic rings or ring systems that include at least one nitrogen heteroatom. The rings or ring systems generally include 1 to 9 carbon atoms in addition to the heteroatom(s) and may be saturated, unsaturated or aromatic (including pseudoaromatic).
  • Aromatic refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings.
  • Aromatic includes pseudoaromatic ring systems, such as pyrrolyl rings.
  • An example of a group of “two of R 4 , R 5 , and R 6 , together with the carbon they are attached to, form a C3-8-cycloalkyl and the rest of R 4 , R 5 , and R 6 is H” is cyclopropyl, i.e., e.g., R 4 and R 5 , together with the carbon they are attached to, form the cyclopropyl and R 6 is H.
  • R 3 is cyclopropyl.
  • 5-membered monocyclic N-heterocycles include pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls) isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls), and dithiazolyl.
  • 6-membered monocyclic N- heterocycles include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and triazinyl.
  • the heterocycles may be optionally substituted with a broad range of substituents, and preferably with C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C 1-6 alkyl)amino.
  • the N-heterocyclic group may be fused to a carbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl.
  • E xamples of 8-, 9- and 10-membered bicyclic heterocycles include 1H thieno[2,3- c]pyrazolyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, and the like.
  • heterocycles may be optionally substituted, for example with C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C1- 6alkyl)amino.
  • optionally substituted N-heterocyclics includes pyridinium salts and the N-oxide form of suitable ring nitrogens.
  • group R’’, group X and the carbon they are both attached to together form an 8-13 membered polycyclic (bi- or tricyclic) group comprising the unsaturated 5-membered heterocyclic ring, which comprises 1 nitrogen and is fused with the 5-10 membered aliphatic, aromatic or heterocyclic ring comprising the 0- 5 heteroatoms each independently selected from the group consisting of N, O, and S.
  • X is a 5-10 membered aliphatic, aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-5 substituents each independently selected from R’ ” may also include the possible alternatives of (substituted) rings that have the unsaturated 5-membered heterocyclic ring comprising 1 nitrogen fused to said rings, i.e., X. Therefore, X may be considered a monovalent or polyvalent radical.
  • bicyclic 8-13 membered heterocyclic ring comprising an unsaturated 5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ring is fused with X include, but are not limited to, 1H- 2,4-diazainden-1-yl, 1H-2,4,7-triazainden-1-yl, and 1H-isoindol-1-yl.
  • tricyclic 8- 13 membered heterocyclic ring comprising an unsaturated 5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ring is fused with X
  • examples of tricyclic 8- 13 membered heterocyclic ring comprising an unsaturated 5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ring is fused with X include, but are not limited to, 2,5,8-triazatricyclo[7.4.0.0 3,7 ]trideca-1(9),2,5,7,10,12-hexaen-4- yl.
  • subject includes both human and non-human subjects, including birds and non-human mammals, such as non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats.
  • subject applies regardless of the stage in the organism’s life-cycle. Thus, the term subject applies to an organism in utero or in ovo, depending on the organism (that is, whether the organism is a mammal or a bird, such as a domesticated or wild fowl).
  • “Substituted” or “substitution” refers to replacement of a hydrogen atom of a molecule or an R-group with one or more additional R-groups.
  • substitution refers to replacement of a hydrogen atom of a molecule or an R-group with one or more additional R-groups.
  • the term “optionally-substituted” or “optional substituent” as used herein refers to a group which may or may not be further substituted with 1, 2, 3, 4 or more groups, preferably 1, 2 or 3, more preferably 1 or 2 groups.
  • the substituents may be selected, for example, from C1-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-8cycloalkyl, hydroxyl, oxo, C1-6alkoxy, aryloxy, C1-6alkoxyaryl, halo, C1-6alkylhalo (such as CF3 and CHF2), C1-6alkoxyhalo (such as OCF3 and OCHF2), carboxyl, esters, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketones, amides, aminoacyl, substituted amides, disubstituted amides, thiol, alkylthio, thioxo, sulfates, sulfonates, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonylamides, substituted sulf
  • N- heterocycles may also include but are not limited to C1-6alkyl i.e. N-C1-3alkyl, more preferably methyl, particularly N-methyl.
  • a "therapeutically effective amount” refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, a therapeutically effective amount of an agent is an amount sufficient to inhibit or treat the disease or condition without causing a substantial cytotoxic effect in the subject. The therapeutically effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition.
  • treatment includes prophylaxis, or prevention of, as well as lowering the individual's risk of falling ill with the named disease, disorder or condition, or alleviation, amelioration, elimination, or cure of the said disease, disorder or condition once it has been established. Therefore, “treatment” may refer to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop. As used herein, the term “ameliorating,” with reference to a disease or condition, refers to any observable beneficial effect of the treatment.
  • the beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.
  • the phrase “treating a disease” may refer to inhibiting at least partially the development, preferably the full development, of a disease, for example, in a subject who is at risk for a disease.
  • a “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing a pathology or condition, or diminishing the severity of a pathology or condition.
  • “Pharmaceutical compositions” are compositions that include an amount (for example, a unit dosage) of one or more of the disclosed compounds together with one or more non-toxic pharmaceutically acceptable additives, including carriers, diluents, and/or adjuvants, and optionally other biologically active ingredients.
  • Such pharmaceutical compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA (19th Edition).
  • salts or esters refers to salts or esters prepared by conventional means that include salts, e.g., of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like.
  • inorganic and organic acids including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid,
  • “Pharmaceutically acceptable salts” of the presently disclosed compounds also include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tri
  • any chemical compound recited in this specification may alternatively be administered as a pharmaceutically acceptable salt thereof.
  • “Pharmaceutically acceptable salts” are also inclusive of the free acid, base, and zwitterionic forms. Descriptions of suitable pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002). When compounds disclosed herein include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. Such salts are known to those of skill in the art. For additional examples of “pharmacologically acceptable salts,” see Berge et al., J.
  • “Pharmaceutically acceptable esters” includes those derived from compounds described herein that are modified to include a carboxyl group.
  • An in vivo hydrolysable ester is an ester, which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • esters thus include carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl, optionally substituted by, for example, halogen, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy) or amino); sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); or amino acid esters (for example, L-valyl or L-isoleucyl).
  • alkyl for example, methyl, n-propyl, t
  • a “pharmaceutically acceptable ester” also includes inorganic esters such as mono-, di-, or tri- phosphate esters.
  • any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms.
  • Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms.
  • Any aryl moiety present in such esters advantageously comprises a phenyl group, optionally substituted as shown in the definition of carbocyclyl above.
  • esters thus include C1-C22 fatty acid esters, such as acetyl, t-butyl or long chain straight or branched unsaturated or omega-6 monounsaturated fatty acids such as palmoyl, stearoyl and the like.
  • Alternative aryl or heteroaryl esters include benzoyl, pyridylmethyloyl and the like any of which may be substituted, as defined in carbocyclyl above.
  • Additional pharmaceutically acceptable esters include aliphatic L-amino acid esters such as leucyl, isoleucyl and especially valyl.
  • salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g.
  • hydrochloric or hydrobromic acid sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e.
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g.
  • addition salt as used hereinabove also comprises the solvates which the compounds described herein are able to form. Such solvates are for example hydrates, alcoholates and the like.
  • quaternary amine as used herein before defines the quaternary ammonium salts which the compounds are able to form by reaction between a basic nitrogen of a compound and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • an appropriate quaternizing agent such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates.
  • a quaternary amine has a positively charged nitrogen.
  • prodrugs of the disclosed compounds also are contemplated herein.
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into an active compound following administration of the prodrug to a subject.
  • prodrug as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds described herein.
  • Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
  • Prodrugs of a compounds described herein may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound.
  • the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. F or a general discussion of prodrugs involving esters see Svensson and Tunek, Drug Metabolism Reviews 165 (1988) and Bundgaard, Design of Prodrugs, Elsevier (1985).
  • prodrug also is intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when the prodrug is administered to a subject. Since prodrugs often have enhanced properties relative to the active agent pharmaceutical, such as, solubility and bioavailability, the compounds disclosed herein can be delivered in prodrug form. Thus, also contemplated are prodrugs of the presently disclosed compounds, methods of delivering prodrugs and compositions containing such prodrugs. Prodrugs of the disclosed compounds typically are prepared by modifying one or more functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent compound.
  • Prodrugs may include compounds having a phosphonate, hydroxy, thio and/or amino group functionalized with any group that is cleaved in vivo to yield the corresponding amino, hydroxy, thio and/or phosphonate group, respectively.
  • Examples of prodrugs can include, without limitation, compounds having an acylated amino group and/or a phosphonate ester or phosphonate amide group.
  • Protected derivatives of the disclosed compounds also are contemplated. A variety of suitable protecting groups for use with the disclosed compounds are disclosed in Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999. In general, protecting groups are removed under conditions that will not affect the remaining portion of the molecule.
  • One preferred method involves the removal of an ester, such as cleavage of a phosphonate ester using Lewis acidic conditions, such as in TMS-Br mediated ester cleavage to yield the free phosphonate.
  • a second preferred method involves removal of a protecting group, such as removal of a benzyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof.
  • a t-butoxy-based group, including t-butoxy carbonyl protecting groups can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as water, dioxane and/or methylene chloride.
  • a suitable solvent system such as water, dioxane and/or methylene chloride.
  • Another exemplary protecting group, suitable for protecting amino and hydroxy functions amino is trityl.
  • Other conventional protecting groups are known and suitable protecting groups can be selected by those of skill in the art in consultation with Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999. When an amine is deprotected, the resulting salt can readily be neutralized to yield the free amine.
  • the compound when an acid moiety, such as a phosphonic acid moiety is unveiled, the compound may be isolated as the acid compound or as a salt thereof.
  • Particular examples of the presently disclosed compounds may include one or more asymmetric centers; thus the compounds described can exist in different stereoisomeric forms. Accordingly, compounds and compositions may be provided as individual pure enantiomers or as stereoisomeric mixtures, including racemic mixtures.
  • the compounds disclosed herein may be synthesized in or may be purified to be in substantially enantiopure form, such as in a 90% enantiomeric excess, a 95% enantiomeric excess, a 97% enantiomeric excess or even in greater than a 99% enantiomeric excess, such as in enantiopure form.
  • the compounds can be isolated as a single isomer or as mixture of isomers by methods utilizing specific chiral resolving agents like quinine, Chiral HPLC, SFC (super critical fluid chromatography) etc. All tautomers of the compounds are also considered part of the disclosure.
  • the presently disclosed compounds also include all isotopes of atoms present in the compounds, which can include, but are not limited to, deuterium, tritium, 13 C, 18 F, stable and radioisotope, etc.
  • X is a 5-6 membered aliphatic, aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-5 substituents each independently selected from R’.
  • R3 is C(R4)(R5)(R6) or R’’, wherein R’’, together with X and the carbon they are attached to, forms a bicyclic 8-9 membered heterocyclic ring comprising an unsaturated 5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5- membered heterocyclic ring is fused with X and is optionally substituted with N(R7)(R8).
  • X is a 5-6 membered aromatic or heterocyclic ring comprising 0- 2 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aromatic and the heterocyclic ring being optionally substituted with 1-2 substituents each independently selected from R’;
  • R 3 is R’’, wherein R’’, together with X and the carbon they are attached to, forms a bicyclic 8-9 membered heterocyclic ring comprising an unsaturated 5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ring is fused with X and is substituted with N(R 7 )(R 8 ); and e ach R’ and R7, and R8 are as defined in the present disclosure; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound has formula (II): formula (II), wherein R 1 , R 2 , R 4 R 5 , R 6 , R, X, Y, and Z are as defined in the present disclosure; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound has formula (III): formula (III), wherein each dotted line represents an optional bond; R 1, R2, R7, R8, R, Y, and Z are as defined in the present disclosure; and both X ⁇ , together with the carbons they are attached to, together form a 5-10 membered aliphatic, aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’; and R’ is as defined in the present disclosure; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • X is a 5-6 membered aromatic heterocyclic ring comprising 1-3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aromatic heterocyclic ring being optionally substituted with 1-3 substituents each independently selected from R’; and R’ is as defined in the present disclosure; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • X is a 5-6 membered aromatic heterocyclic ring comprising 2-3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aromatic heterocyclic ring being optionally substituted with 1-3 substituents each independently selected from R’; and R’ is as defined in the present disclosure; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • R 4 , R 5 , and R 6 are each independently selected from the group consisting of H, halogen, C1-8-alkyl, C1-8-alkyl-N(R9)(R10), C1-6-alkyl-C1-6-cycloalkyl, C1-6- alkyl-C1-6-heterocyclyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substituted with one or more halogen, or two of R 4 , R 5 , and R 6 , together with the carbon they are attached to, form a C3-8-cycloalkyl and the rest of R 4 , R 5 , and R 6 is H, wherein R 9 and R 10 are each independently selected from the group consisting of H, and C 1-8 -alkyl; R 7 , and R 8 are each independently selected from the group consisting of H, and C 1-8 -alkyl, preferably H, methyl, and ethyl; provided that if Y
  • X is a 6 membered aromatic ring, wherein the aromatic ring being optionally substituted with 1-3 substituents each independently selected from R’; wherein e ach R’ is independently selected from the group consisting of C1-8-alkylthio, C1-8- carboxamide group, C1-8-ester group, C1-8-urea group, C1-8-carbamate group, C6-10-aryl, C5-10- heteroaryl, and derivatives thereof being substituted with one or more halogen; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • R 1 and R 2 are each independently selected from the group consisting of H, C 1-8 -alkyl, C 6-10 -aryl, C 1-10 -heteroaryl, and derivatives thereof being substituted with one or more halogen, wherein the C1-10-heteroaryl comprises 1-4 heteroatoms each independently selected from the group consisting of N, O, and S, preferably R 1 and R 2 are both H. Additionally, or alternatively, R 1 and R 2 are H; zero, one, or two Z are N and the rest of Z are C(R); Y is NH; and R is as defined in the present disclosure; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • R 1 and R 2 are H;
  • X is a 5-6 membered aliphatic, aromatic or heterocyclic ring comprising 0-2 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-5 substituents each independently selected from R’, or b oth X ⁇ , together with the carbons they are attached to, together form a 5-6 membered aliphatic, aromatic or heterocyclic ring comprising 0-2 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’; and R’ is as defined in the present disclosure; and Y is NH; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Y is NH; both Z are CH; both R are H; and a t least one of R4, R5 and R6 is each independently selected from the group consisting of C 2-8 -alkyl, C 6-10 -aryl, C 1-10 -heteroaryl, and derivatives thereof being substituted with one or more halogen, and the rest of R 4 , R 5 and R 6 is each independently selected from the group consisting of H, C1-8-alkyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substituted with one or more halogen; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Y is NH; and R 3 is t-Bu; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • R 1 and R 2 are H; both Z are CH; Y is NH; and R 3 is t-Bu; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • R 1 and R 2 are H; z ero, one, or two Z are N and the rest of Z are C(R); Y is O; and R is as defined in the present disclosure; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • R3 is selected from H, trifluoromethyl, t-butyl, cyclopropyl, and -CH 2 CH 2 N(Me) 2 , or R 3 is methyl, provided that X is a 5-10 membered aliphatic, aromatic or heterocyclic ring comprising 2-3 heteroatoms each independently selected from the group consisting of N, O, and S, preferably 2 N, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-5 substituents each independently selected from R’.
  • R is pyridinyl, 2-furanyl, 2-thiophenyl, phenyl or phenyl substituted with 1-3 substituents each independently selected from R’, Y is NH, both Z are CH, and both R are H, then R 3 is not CH3 or CH2CH3; and R and R’ are as defined in the present disclosure.
  • R4, R5, and R6 are each independently selected from the group consisting of H, halogen, C1-8-alkyl, C1-8-alkyl-N(R9)(R10), C1-6-alkyl-C1-6-cycloalkyl, C1-6- alkyl-C1-6-heterocyclyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substituted with one or more halogen, or two of R 4 , R 5 , and R 6 , together with the carbon they are attached to, form a C3-8-cycloalkyl and the rest of R4, R5, and R6 is H, wherein R9 and R10 are each independently selected from the group consisting of H, and C1-8-alkyl, preferably selected from the group consisting of H, methyl, and ethyl; and R 7 , and R 8 are each independently selected from the group consisting of H, and C 1-8 -alkyl, preferably H, methyl,
  • X is a 6-10 membered aromatic heterocycle comprising 2-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aromatic heterocycle being optionally substituted with 1-3 substituents each independently selected from R’; and R3 is H, C(R4)(R5)(R6), or R’’, wherein R’’, together with X and the carbon they are attached to, forms a bi- or tricyclic 8-13 membered heterocyclic ring comprising an unsaturated 5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ring is fused with X and is substituted with N(R7)(R8); wherein R4, R5, R6, R7, R8, R’, and R’’ are as defined in the present disclosure.
  • R 1 and R 2 are H;
  • X is a 5-6 membered aliphatic, aromatic or heterocyclic ring comprising 0-2 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-5 substituents each independently selected from R’, or both X ⁇ , together with the carbons they are attached to, together form a 5-6 membered aliphatic, aromatic or heterocyclic ring comprising 0-2 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’; and R’ is as defined in the present disclosure; and Y is O; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • R 1 and R 2 are H; both Z are N; Y is NH; X is a 6 membered aromatic heterocyclic ring comprising 1-2 N, preferably a pyrimidyl or a pyridyl, wherein the aromatic heterocyclic ring being optionally substituted with 1-2 substituents each independently selected from R’, preferably optionally substituted with 1-2 substituents each independently selected from Br, F, and methyl.
  • R 1 and R 2 are H; each R is H; b oth Z are N or CH; Y is NH; X is a 6 membered aromatic heterocyclic ring comprising 1-2 N, preferably a pyrimidyl or a pyridyl, wherein the aromatic heterocyclic ring being optionally substituted with 1-2 substituents each independently selected from R’, preferably optionally substituted with 1-2 substituents each independently selected from Br, F, and methyl.
  • R 1 and R 2 are H; R 3 is methyl, CF 3 or cyclopropyl, preferably R 3 is methyl; each R is H, or one R is H and one R is halogen, provided that both Z are CH, preferably the halogen is F or Br, preferably each R is H; both Z are N; Y is NH; and X is selected from: , wherein the bond marked with an asterisk is connected to the carbon that X is attached to, and each R’ is independently selected from the group consisting of H, Br, F and methyl, preferably X is selected from: marked with an asterisk is connected to the carbon that X is attached to, and each R’ is independently selected from the group consisting of H, Br, F and methyl, preferably each R’ is selected from H, Br, F and methyl.
  • R 1 and R 2 are H; both Z are N or CH, or one Z is N and one Z is CH; and Y is NH or O.
  • each R is independently selected from the group consisting of H, halogen, preferably F, Cl, or Br; hydroxy, C1-8-acyl, C1-8-alkoxy, C1-8-alkylthio, C1-8- carboxamide group, C1-8-ester group, C1-8-urea group, C1-8-carbamate group, C1-8-alkyl, C6-10- aryl, C 5-10 -heteroaryl, and derivatives thereof being substituted with one or more halogen.
  • Y is O or selected from the group consisting of NH, N-C1-8-acyl, N-C(O)(N(H)(C1-8-alkyl)), N-C(O)C1-8-alkoxy, N-C1-8-alkyl, N-C6-10-aryl, N-C5-10-heteroaryl, and derivatives thereof being substituted with one or more halogen.
  • R 1 and R 2 are H; both Z are N or CH, or one Z is N and one Z is CH; Y is O or selected from the group consisting of NH, N-C1-8-acyl, N-C1-8-alkyl, N-C6-10- aryl, N-C5-10-heteroaryl, and derivatives thereof being substituted with one or more halogen; and e ach R is H.
  • R 1 and R 2 are H; both Z are N or CH, or one Z is N and one Z is CH; Y is O or selected from the group consisting of NH, N-C1-8-alkyl, N-C6-10-aryl, N-C5- 10-heteroaryl, and derivatives thereof being substituted with one or more halogen; and each R is H.
  • the compound has formula (IV): formula (IV), wherein R 1, R2, R7, R8, R, Y, and Z are as defined in the present disclosure; and each X ⁇ ⁇ is independently selected from the group consisting of C(R’), and N; and R ⁇ is as defined in the present disclosure; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. Additionally, or alternatively, 1-2 of X ⁇ ⁇ is/are N and 2-3 of X ⁇ ⁇ are C(R ⁇ ); and R ⁇ is as defined in the present disclosure; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • 1-2 of X ⁇ ⁇ is/are N and 2-3 of X ⁇ ⁇ are CH; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound is selected from: 4-(2-(2,2-dimethyl-1-(pyridin-3-yl)propylidene)hydrazineyl)benzenesulfonamide; (Z)-4-(2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethylidene)hydrazineyl)benzenesulfonamide; (E)-4- (2-(1-(5-bromopyridin-3-yl)ethylidene)hydrazineyl)benzenesulfonamid; (E)-4-(2-(cyclopropyl(5-fluoropyridin-3-yl)methylene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(1
  • the compound is selected from: 4-(2-(2,2-dimethyl-1-(pyridin-3-yl)propylidene)hydrazineyl)benzenesulfonamide; (Z)-4-(2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethylidene)hydrazineyl)benzenesulfonamide; (E)-4- (2-(1-(5-bromopyridin-3-yl)ethylidene)hydrazineyl)benzenesulfonamid; (E)-4-(2-(cyclopropyl(5-fluoropyridin-3-yl)methylene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(1-(quinoxalin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(pyridin-3-ylmethylene)hydra
  • the compounds of the present disclosure may be in different tautomer forms, i.e., there may be two or more tautomers of the same compound.
  • tautomers of compound A12 may have the following structures: Therefore, even though some of the compounds presented in the present disclosure is presented only with one structure (with one tautomeric form), it is to be understood that the compounds of the present invention also include the other possible tautomeric form(s) of the compounds.
  • the terms ”unsaturated 5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ring is fused with X and is optionally substituted with N(R 7 )(R 8 )” should be understood such that the unsaturated 5-membered heterocyclic ring comprising 1 nitrogen may be unsaturated due to one of the tautomeric forms it may have.
  • a composition comprising the compound, or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, as defined in the present disclosure. Additionally, or alternatively, the composition as defined in the present disclosure comprising one or more compounds as defined in the present disclosure in combination with one or more other active ingredients.
  • the one or more other active ingredients are each independently selected from active ingredients for use in the treatment or prevention of an ocular disease or condition, such as glaucoma, macular edema (ME), and a degenerative retinal disease, such as retinitis pigmentosa and AMD; or idiopathic intracranial hypertension (IIH).
  • an ocular disease or condition such as glaucoma, macular edema (ME), and a degenerative retinal disease, such as retinitis pigmentosa and AMD; or idiopathic intracranial hypertension (IIH).
  • the one or more other active ingredients are each independently selected from latanoprost and timolol.
  • CAIs have been shown to have retinoprotective effects (Graefes Arch Clin Exp Ophthalmol. 2005 Feb;243(2):163-8; Expert Opinion on Therapeutic Patents, 2019; 29:10, 761-767; Int. J. Mol. Sci. 2019, 20(3), 467).
  • the compound, or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, as defined in the present disclosure for use in the method as defined in the present disclosure, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound, or the stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound, or the stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • I n one aspect is disclosed a use of a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, as defined in the present disclosure in a method for the treatment or prevention of an ocular disease or condition, or idiopathic intracranial hypertension (IIH).
  • the ocular disease or condition is selected from glaucoma, macular edema (ME), serous retinal detachment and a degenerative retinal disease.
  • the glaucoma is selected from acute angle-closure glaucoma, angle-closure glaucoma, open angle glaucoma, pediatric glaucoma and pseudoexfoliative glaucoma.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound, or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, as defined in the present disclosure.
  • a method for the preparation of a compound as defined in the present disclosure comprises: - providing a compound of formula (X) or a salt thereof: formula (X), and a compound of formula (XI ⁇ ): formula (XI ⁇ ) or a compound of formula (XI ⁇ ⁇ ): formula (XI ⁇ ⁇ ), wherein b oth X ⁇ , together with the carbons they are attached to, together form a 5-10 membered aliphatic, aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’, each dotted line represents an optional bond, and R 1, R2, R3, R, R’, X, Y, and Z are as defined in the present disclosure; and - reacting the compound of formula (X) or a salt thereof with the compound of formula (X), and a compound of formula (
  • the compound of formula (XI ⁇ ⁇ ) formula (XI ⁇ ⁇ ), wherein b oth X ⁇ , together with the carbons they are attached to, together form a 5-6 membered aliphatic, aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’, and each dotted line represents an optional bond.
  • the compound of formula (XI ⁇ ⁇ ) is prepared by reacting a compound of formula (XIII): formula (XIII), with NH 3 , wherein both X ⁇ are as defined in the present disclosure.
  • Compounds herein are disclosed novel melanin-binding CAI inhibitors that reduce IOP and may be used for the treatment or prevention of glaucoma and related ocular diseases, including IIH, and ME.
  • the inhibitors apply a novel hybrid design, connecting a CAI moiety to a melanin-binding aromatic or heteroaromatic moiety through a hydrazone or oxime linker.
  • melanin-binding aromatic or heteroaromatic moiety may allow for a tuning of drug action over very wide range in the acidic pH of the cellular melanosomes.
  • I llustrative example compounds include compounds A1-A14:
  • compositions and Methods of Use The compounds disclosed herein may be used for treating glaucoma, idiopathic intracranial hypertension (IIH), and macular edema (ME).
  • the methods disclosed herein involve administering to a subject in need of treatment a pharmaceutical composition, for example a composition that includes a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds disclosed herein.
  • the compounds may be administered orally, parenterally (including subcutaneous injections (SC or depo-SC), intravenous (IV), intramuscular (IM or depo-IM), intrasternal injection or infusion techniques), sublingually, intranasally (inhalation), intrathecally, topically, ophthalmically, or rectally.
  • the pharmaceutical composition may be administered in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and/or vehicles.
  • the compounds are preferably formulated into suitable pharmaceutical preparations such as tablets, capsules, or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration.
  • the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art.
  • one or more of the disclosed compounds are mixed or combined with a suitable pharmaceutically acceptable carrier to prepare a pharmaceutical composition.
  • Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to be suitable for the particular mode of administration. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21 st Edition (2005), describes exemplary compositions and formulations suitable for pharmaceutical delivery of the compounds disclosed herein.
  • the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.
  • the resulting mixture may be a solution, suspension, emulsion, or the like.
  • Liposomal suspensions may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. Where the compounds exhibit insufficient solubility, methods for solubilizing may be used. Such methods are known and include, but are not limited to, using cosolvents such as dimethylsulfoxide (DMSO), using surfactants such as Tween®, and dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as salts or prodrugs may also be used in formulating effective pharmaceutical compositions.
  • cosolvents such as dimethylsulfoxide (DMSO)
  • surfactants such as Tween®
  • dissolution in aqueous sodium bicarbonate such as sodium bicarbonate.
  • Derivatives of the compounds, such as salts or prodrugs may also be used in formulating effective pharmaceutical compositions.
  • the disclosed compounds may also be prepared with carriers that protect them against rapid elimination from the body, such as time-release formulations or coatings. Such carriers include controlled release formulations, such as, but not limited to, microencapsulated delivery systems.
  • the disclosed compounds and/or compositions can be enclosed in multiple or single dose containers.
  • the compounds and/or compositions can also be provided in kits, for example, including component parts that can be assembled for use.
  • one or more of the disclosed compounds may be provided in a lyophilized form and a suitable diluent may be provided as separated components for combination prior to use.
  • a kit may include a disclosed compound and a second therapeutic agent (such as an anti-retroviral agent) for co-administration.
  • the compound and second therapeutic agent may be provided as separate component parts.
  • a kit may include a plurality of containers, each container holding one or more unit dose of the compound.
  • the containers are preferably adapted for the desired mode of administration, including, but not limited to tablets, gel capsules, sustained-release capsules, and the like for oral administration; depot products, pre-filled syringes, ampoules, vials, and the like for parenteral administration; and patches, medipads, creams, and the like for topical administration.
  • the subject is human.
  • the subject is a non-human subject selected from the group consisting of birds and non-human mammals, such as non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats.
  • the active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the subject treated.
  • a therapeutically effective concentration may be determined empirically by testing the compounds in known in vitro and in vivo model systems for the treated disorder.
  • a therapeutically effective amount of the compound is an amount that lessens or ameliorates at least one symptom of the disorder for which the compound is administered.
  • the compositions are formulated for single dosage administration.
  • concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the active compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.
  • about 0.1 mg to 1000 mg of a disclosed compound, a mixture of such compounds, or a physiologically acceptable salt or ester thereof, is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form.
  • the amount of active substance in those compositions or preparations is such that a suitable dosage in the range indicated is obtained.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the compositions are formulated in a unit dosage form, each dosage containing from about 1 mg to about 1000 mg (for example, about 2 mg to about 500 mg, about 5 mg to 50 mg, about 10 mg to 100 mg, or about 25 mg to 75 mg) of the one or more compounds.
  • the unit dosage form includes about 0.1 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, or more of the disclosed compound(s).
  • the disclosed compounds or compositions may be administered as a single dose, or may be divided into a number of smaller doses to be administered at intervals of time.
  • the therapeutic compositions can be administered in a single dose delivery, by continuous delivery over an extended time period, in a repeated administration protocol (for example, by a multi-daily, daily, weekly, or monthly repeated administration protocol). It is understood that the precise dosage, timing, and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. In addition, it is understood that for a specific subject, dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only.
  • these compositions When administered orally as a suspension, these compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants. If oral administration is desired, the compound is typically provided in a composition that protects it from the acidic environment of the stomach.
  • the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.
  • the composition may also be formulated in combination with an antacid or other such ingredient.
  • Oral compositions will generally include an inert diluent or an edible carrier and may be compressed into tablets or enclosed in gelatin capsules.
  • the active compound or compounds can be incorporated with excipients and used in the form of tablets, capsules, or troches.
  • Pharmaceutically compatible binding agents and adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches, and the like can contain any of the following ingredients or compounds of a similar nature: a binder such as, but not limited to, gum tragacanth, acacia, corn starch, or gelatin; an excipient such as microcrystalline cellulose, starch, or lactose; a disintegrating agent such as, but not limited to, alginic acid and corn starch; a lubricant such as, but not limited to, magnesium stearate; a gildant, such as, but not limited to, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and a flavoring agent such as peppermint, methyl salicylate, or fruit flavoring.
  • a binder such as, but not limited to, gum tragacanth, acacia, corn starch, or gelatin
  • an excipient such as microcrystalline cellulose, starch, or lactose
  • a disintegrating agent such as, but not limited to, alg
  • the dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
  • dosage unit forms can contain various other materials, which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
  • the compounds can also be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors.
  • the compounds When administered orally, the compounds can be administered in usual dosage forms for oral administration.
  • dosage forms include the usual solid unit dosage forms of tablets and capsules as well as liquid dosage forms such as solutions, suspensions, and elixirs.
  • solid dosage forms When the solid dosage forms are used, it is preferred that they be of the sustained release type so that the compounds need to be administered only once or twice daily.
  • an oral dosage form is administered to the subject 1, 2, 3, 4, or more times daily.
  • the compounds can be administered orally to humans in a dosage range of 1 to 1000 mg/kg body weight in single or divided doses.
  • One illustrative dosage range is 0.1 to 200 mg/kg body weight orally (such as 0.5 to 100 mg/kg body weight orally) in single or divided doses.
  • compositions may be provided in the form of tablets containing about 1 to 1000 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of the active ingredient.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • Injectable solutions or suspensions may also be formulated, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer’s solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable non-toxic, parenterally-acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer’s solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, and the like, or a synthetic fatty vehicle such as ethyl oleate, and the like, polyethylene glycol, glycerine, propylene glycol, or other synthetic solvent; antimicrobial agents such as benzyl alcohol and methyl parabens; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, and phosphates; and agents for the adjustment of tonicity such as sodium chloride and dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil
  • Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass, plastic, or other suitable material. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
  • suitable carriers include physiological saline, phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol, polypropyleneglycol, and mixtures thereof.
  • Liposomal suspensions including tissue-targeted liposomes may also be suitable as pharmaceutically acceptable carriers.
  • the compounds can be administered parenterally, for example, by IV, IM, depo-IM, SC, or depo-SC.
  • a therapeutically effective amount of about 0.1 to about 500 mg/day (such as about 1 mg/day to about 100 mg/day, or about 5 mg/day to about 50 mg/day) may be delivered.
  • the dose may be about 0.1 mg/day to about 100 mg/day, or a monthly dose of from about 3 mg to about 3000 mg.
  • T he compounds can also be administered sublingually. When given sublingually, the compounds should be given one to four times daily in the amounts described above for IM administration. T he compounds can also be administered intranasally. When given by this route, the appropriate dosage forms are a nasal spray or dry powder.
  • the dosage of the compounds for intranasal administration is the amount described above for IM administration.
  • these compositions may be prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents.
  • T he compounds can be administered intrathecally. When given by this route, the appropriate dosage form can be a parenteral dosage form.
  • the dosage of the compounds for intrathecal administration is the amount described above for IM administration. T he compounds can be administered topically.
  • the appropriate dosage form is a cream, ointment, or patch.
  • an illustrative dosage is from about 0.5 mg/day to about 200 mg/day. Because the amount that can be delivered by a patch is limited, two or more patches may be used.
  • T he compounds can be administered rectally by suppository. When administered by suppository, an illustrative therapeutically effective amount may range from about 0.5 mg to about 500 mg.
  • these compositions When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • the assay setup included a final concentration of 70 nM hCA II and 0.5 mM NPA (N8130-10G, Sigma-Aldrich St. Louis, USA) in an assay buffer of 200 ⁇ L (comprising of 1 % dimethyl sulfoxide, 0.5 mM ethylenediaminetetraacetic acid, 20 mM Tris buffer, and 33 mM sodium sulfate, pH 7.4).
  • the optimal concentration of hCA II for the assay was determined by titration; NPA substrate concentration of 0.5 mM was chosen based on observed Km-value for the hCA II esterase activity, 10.4 mM (SEM 1.8 mM). The range of inhibitor concentrations chosen based on apparent IC50-value of AAZ (11.8 nM) and followed 10-fold dilution with 3 concentrations above and below the said value. With the initial estimate of the IC 50 -value, the concentration range was adjusted accordingly, and the assay was performed again with 3-fold dilution. All measurements were performed as triplicates. For the inhibition experiments, hCA II was pre-incubated with potential inhibitors for 10 minutes at 25 °C before initiating the reaction with NPA.
  • Enzymatic activity was determined by tracking the formation of the colored compound, 4-nitrophenol (4-NP), measuring its absorbance at 405 nm at 0.5-minute intervals over a span of 10 minutes at 25°C. To ensure accuracy in determining enzyme activity, ethylenediaminetetraacetic acid was added to the assay buffer to suppress the spontaneous hydrolysis of the substrate. The initial rate of the enzymatic reaction was derived from the slope obtained by plotting the absorbance (405 nm) as a function of time. This rate was subsequently utilized to compute the enzyme activity as a percentage. The degree of inhibition rendered by the compounds was estimated by benchmarking against the enzyme's activity in an inhibitor-free environment, set at 100%.
  • Both the melanin suspensions and the test compound solutions were prepared no more than 4 hours before the start of the incubations.
  • 200 ⁇ L of melanin suspension was mixed with 200 ⁇ L of the test compound solution, prepared in triplicate.
  • Control samples (incubated, non-incubated, and filtered) were also made in triplicate by mixing 200 ⁇ L of the test compound solution with 200 ⁇ L of 100 mM potassium phosphate buffer pH 7.4. Melanin samples and incubation controls were incubated at room temperature with gentle shaking for 24 hours. Post-incubation, samples were centrifuged at 16,000g for 30 min.
  • amitriptyline (Amitriptyline hydrochloride A8404-10G Sigma-Aldrich St Louis, MO, USA) were chosen as control compounds with varying affinities towards melanin.
  • Brimonidine has high binding affinity towards melanin while amitriptyline is an intermediate melanin binder, as reported in Drug Metab. Dispos. 23:7, 708-12, (1995), and J. Pharm. Sci. 104:12;3997-4001 (2015).
  • the analysis was conducted using an Agilent UHPLC-QTOF-MS system (Agilent Technologies 1290 LC, 6540 MS, Agilent Technologies, Santa Clara, CA, USA).
  • the discovered high melanin binders were further profiled via an orthogonal assay, namely microscale thermophoresis against melanin nanoparticles.
  • the protocol was based on the method described in Pharmaceutics, 12:6; 554, (2020).
  • a dilution series with concentrations of 1000 ⁇ M, 200 ⁇ M, 100 ⁇ M, 10 ⁇ M, 1 ⁇ M, 0.1 ⁇ M, 0.01 ⁇ M and 0 ⁇ M were prepared in 1xPBS for the compound analyzed, on a PCR-plate (96 Well semi-skirted PCR plates, #4ti0760, 4titude Ltd, Wotton, Surrey, U.K.).
  • PCR tube strips 8-well PCR Tube strips, Nippon Genetics GmbH, Germany
  • melanin solution pipetted with low-binding pipette tips (Maximum Recovery pipet tips, #T-200C-L-R, Corning Incorporated, Salt Lake City, UT, USA) to prevent aggregation and adsorption.
  • PCR strips containing the samples were left on a shaker (Heidolph Titramax 101, Heidolph Instruments GmbH, Germany) to incubate in room temperature for at least 2 hours before analysis.
  • MST profiling of high melanin binders A3, A6, and A9-A14, and A15-A19, brimonidine, and amitriptyline, and propranolol against melanin nanoparticles MST Kd ( ⁇ M) Kd confidence Affinity to melanin Compound Classification ( ⁇ M) nanoparticles B rimonidine 109 136 High binder +++ Intermediate A mitriptyline 265 149 ++ binder P ropranolol 72 39 High binder +++ Intermediate A 3 340 164 ++ binder A 6 216 325 High binder +++ A9 23 19 High binder +++ A10 45 41 High binder +++ A11 158 65 High binder +++ A12 97 48 High binder +++ A13 147 43 High binder +++ A14 174 91 High binder +++ Intermediate A 15 230 85 ++ binder A 16 18 11 High binder +++ A17 17 16 High binder +++ A18 29 21 High binder +++ A19 538
  • EXAMPLE 1 SYNTHESIS OF POTENTIAL MELANIN BINDING CARBONIC ANHYDRASE INHIBITORS ACCORDING TO THE INVENTION General Synthetic Methods. All reaction solvents were dried prior to use. THF was freshly distilled from a sodium/benzophenone radical anion solution and CH2Cl2, acetonitrile, and toluene were freshly distilled over (CaH 2 ). Et 3 N, DIPEA, and pyridine were distilled (CaH 2 . When necessary, degassed solvents were prepared by freeze-pump-thaw techniques. Unless stated otherwise, all reactions were performed under an atmosphere of N 2 that was passed through a short cartridge (10 ⁇ 2 cm) of drierite®.

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Abstract

Sont divulgués des sulfonamides, des compositions comprenant lesdits sulfonamides, des procédés de préparation desdits sulfonamides, et lesdits sulfonamides destinés à être utilisés en tant que médicament et dans une méthode de traitement ou de prévention d'une maladie ou d'un état oculaire, ou de l'hypertension intracrânienne idiopathique.
PCT/FI2025/050182 2024-04-11 2025-04-11 Sulfonamides, compositions comprenant lesdits sulfonamides, procédés de préparation desdits sulfonamides et lesdits sulfonamides pour une utilisation en tant que médicament et dans une méthode pour le traitement ou la prévention d'une maladie ou d'un état oculaire ou de l'hypertension intracrânienne idiopathique Pending WO2025215303A1 (fr)

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PCT/FI2025/050182 Pending WO2025215303A1 (fr) 2024-04-11 2025-04-11 Sulfonamides, compositions comprenant lesdits sulfonamides, procédés de préparation desdits sulfonamides et lesdits sulfonamides pour une utilisation en tant que médicament et dans une méthode pour le traitement ou la prévention d'une maladie ou d'un état oculaire ou de l'hypertension intracrânienne idiopathique

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008017932A2 (fr) * 2006-08-09 2008-02-14 Pfizer Products Inc. HÉTÉROCYCLES UTILES EN TANT QU'inhibiteurs d'anhydrase carbonique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008017932A2 (fr) * 2006-08-09 2008-02-14 Pfizer Products Inc. HÉTÉROCYCLES UTILES EN TANT QU'inhibiteurs d'anhydrase carbonique

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