WO2021113260A1 - Composés contenant un diester pour le traitement de l'hyperhydrose - Google Patents

Composés contenant un diester pour le traitement de l'hyperhydrose Download PDF

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WO2021113260A1
WO2021113260A1 PCT/US2020/062743 US2020062743W WO2021113260A1 WO 2021113260 A1 WO2021113260 A1 WO 2021113260A1 US 2020062743 W US2020062743 W US 2020062743W WO 2021113260 A1 WO2021113260 A1 WO 2021113260A1
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compound
ring
group
set forth
compounds
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PCT/US2020/062743
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English (en)
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Hans E. J. HOFLAND
Sriram Naganathan
Anthony Adrian Shaw
Harlan REESE
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Dermira, Inc.
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Publication of WO2021113260A1 publication Critical patent/WO2021113260A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present disclosure concerns anticholinergic compounds and compositions as well as methods of making and using the same.
  • Anticholinergics are compounds which block acetylcholine from binding to its receptors on certain nerve cells, glands, and muscle cells. Anticholinergics are therefore useful in treating certain diseases, disorders, and conditions, or ameliorating the symptoms of certain diseases, disorder, and conditions.
  • glycopyrronium One anticholinergic compound that has gained prominence is glycopyrronium.
  • Glycopyrronium is a quaternary ammonium cation of the muscarinic anticholinergic group. Glycopyrronium, typically as a bromide salt, has been used in the treatment of a variety of conditions including diarrhea (US Patent Nos. 6,214,792 and 5,919,760), urinary incontinence (US Patent Nos. 6,204,285 and 6,063,808), and anxiety (US Patent No. 5,525,347). Additionally, US Patent No. 5,976,499 discloses a method for diagnosing cystic fibrosis in a patient by, in part, stimulating sweat production through the injection of a glycopyrronium solution into a patient.
  • Glycopyrronium has also been used for the treatment of hyperhidrosis in US Patent Application Publication No. 2010/0276329; and US Patent Nos. US 8,618,160; and US 9,006,462.
  • Other anticholinergic compounds include compounds referred to as soft anticholinergic esters, such as those set forth in US Patent Application Publication No. US 20070123557.
  • anticholinergic compounds One problem associated with the use of anticholinergic compounds is the systemic toxicity associated with certain of these compounds when these compounds remain active in human plasma for extended periods of time.
  • R 5 is present, said compound is preferably in the form of a pharmaceutically acceptable salt with a pharmaceutically acceptable counterion.
  • a pharmaceutical composition comprising a compound or salt set forth herein and pharmaceutically acceptable excipient.
  • set forth herein is a method of treating hyperhidrosis comprising topically administering a therapeutically effective amount of a pharmaceutically acceptable solution of a compound or salt set forth herein or solvate thereof to the skin of a mammal.
  • set forth herein is a method of treating a subject in need thereof comprising topically administering a therapeutically effective amount of a pharmaceutically acceptable solution of a compound set forth herein or solvate thereof to the skin of a mammal.
  • FIG. 1 shows a flow chart for the M3 induced calcium immobilization assay
  • FIG. 2 shows a plot of percent inhibition as a function of concentration of atropine in the M3 induced calcium immobilization assay (FLIPR) screening in BIOLOGICAL EXAMPLE 1.
  • FIG. 3 shows a plot of percent inhibition as a function of concentration of compound 101 in the M3 induced calcium immobilization assay (FLIPR) screening in BIOLOGICAL EXAMPLE 1.
  • FIG. 4 shows a plot of percent inhibition as a function of concentration of compound 102 in the M3 induced calcium immobilization assay (FLIPR) screening in BIOLOGICAL EXAMPLE 1.
  • FIG. 5 shows a plot of percent inhibition as a function of concentration of compound 103 in the M3 induced calcium immobilization assay (FLIPR) screening in BIOLOGICAL EXAMPLE 1.
  • FIG. 6 shows a plot of percent inhibition as a function of concentration of compound 104 in the M3 induced calcium immobilization assay (FLIPR) screening in BIOLOGICAL EXAMPLE 1.
  • FIG. 7 shows a plot of percent inhibition as a function of concentration of compound 105 in the M3 induced calcium immobilization assay (FLIPR) screening in BIOLOGICAL EXAMPLE 1.
  • FIG. 8 shows a plot of percent inhibition as a function of concentration of compound 106 in the M3 induced calcium immobilization assay (FLIPR) screening in BIOLOGICAL EXAMPLE 1.
  • FIG. 9 shows the results of the human plasma stability assay in Biological
  • aryl refers to a monovalent moiety that is a radical of an aromatic compound wherein the ring atoms are carbon atoms.
  • Aryl is optionally substituted and can be monocyclic or polycyclic, e.g., bicyclic or tricyclic. Aryl is unsubstituted unless specified as substituted.
  • aryl moieties include, but are not limited to those having 6 to 20 ring carbon atoms, i.e., C 6-20 aryl; 6 to 15 ring carbon atoms, i.e., C 6-15 aryl, and 6 to 10 ring carbon atoms, i.e., C 6-10 aryl.
  • Examples of aryl moieties include, but are limited to phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, and pyrenyl.
  • the phrase “ameliorated by an anticholinergic,” refers to the reduction of the number or severity of the symptoms associated with a disease, disorder, or condition, in a subject in need thereof by the administration of an anticholinergic compound to the subject.
  • cycloalkyl refers to a cyclic monovalent and saturated hydrocarbon radical moiety.
  • Cycloalkyl includes, but is not limited to, those having 1-20 carbon atoms, i.e., C 1-20 cycloalkyl; 1-12 carbon atoms, i.e., C 1-12 cycloalkyl; 1-8 carbon atoms, i.e., Ci-8cycloalkyl; 1-6 carbon atoms, i.e., C 1-6 cycloalkyl; and 1-3 carbon atoms, i.e., C 1-3 cycloalkyl.
  • cycloalkyl moieties include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl may be optionally substituted but is unsubstituted unless specified as substituted.
  • C 1-3 alkyl refers to a monovalent and saturated hydrocarbon radical moiety having 1-3 carbon atoms.
  • C 1-3 alkyl is optionally substituted and can be linear or branched.
  • C 1-3 alkyl is unsubstituted unless specified as substituted.
  • Examples of C 1-3 alkyl moieties include, but are not limited to methyl, ethyl, n-propyl, and /-propyl.
  • C 1-3 alkoxyl refers to a monovalent and saturated hydrocarbon radical moiety, having 1-3 carbon atoms, wherein the hydrocarbon includes a single bond to an oxygen atom and wherein the radical is localized on the oxygen atom, e.g., CH 3 CH 2 - O for ethoxy.
  • C 1-3 alkoxyl substituents bond to the compound which they substitute through this oxygen atom of the alkoxy substituent.
  • C 1-3 alkoxyl is optionally substituted and can be linear, branched, or cyclic, i.e., cycloalkoxy.
  • C 1-3 alkoxyl is unsubstituted unless specified as substituted. Examples of alkoxy moieties include, but are not limited to methoxy, ethoxy, n-propoxy, and i- propoxy.
  • carbonyl refers to a substituent , wherein the squiggly line , indicates the point of attachment to the compound substituted by the carbonyl substituent.
  • cyano refers to the to the substituent , wherein the squiggly line , indicates the point of attachment to the compound substituted by the cyano substituent.
  • halo refers to a substituent selected from a halogen, e.g., F, Cl, Br, or I.
  • hydroxyl refers to the substituent , wherein the squiggly line , indicates the point of attachment to the compound substituted by the carbonyl substituent.
  • heteroaryl refers to a monovalent moiety that is a radical of an aromatic compound wherein the ring atoms contain carbon atoms and at least one oxygen, sulfur, nitrogen, or phosphorus atom.
  • heteroaryl moieties include, but are not limited to those having 5 to 20 ring atoms; 5 to 15 ring atoms; and 5 to 10 ring atoms.
  • Heteroaryl is optionally substituted. Heteroaryl is unsubstituted unless specified as substituted or optionally substituted.
  • heterocycloalkyl refers to a cycloalkyl in which one or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. Heterocycloalkyl is optionally substituted. Heterocycloalkyl is unsubstituted unless specified as substituted.
  • heterocycloalkyl moieties include, but are not limited to, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, dithiolanyl, oxanyl, and thianyl.
  • the phrase “five-member ring,” refers to a cyclic monovalent hydrocarbon radical moiety having a total of five atoms in the cyclic moiety.
  • ix-member ring refers to a cyclic monovalent hydrocarbon radical moiety having a total of six atoms in the cyclic moiety.
  • the phrase “five-membered aryl,” refers to aryl, as defined above, having a total of five atoms in the cyclic moiety.
  • the phrase “five-membered cycloalkyl,” refers to cycloalkyl, as defined above, having a total of five atoms in the cyclic moiety.
  • the phrase “five-membered heterocycloalkyl,” refers to heterocycloalkyl, as defined above, having a total of five atoms in the cyclic moiety.
  • the phrase “five-membered heteroaryl,” refers to heteroaryl, as defined above, having a total of five atoms in the cyclic moiety.
  • aryl refers to aryl, as defined above, having a total of six atoms in the cyclic moiety.
  • cycloalkyl refers to cycloalkyl, as defined above, having a total of six atoms in the cyclic moiety.
  • the phrase “six-membered heterocycloalkyl,” refers to heterocycloalkyl, as defined above, having a total of six atoms in the cyclic moiety.
  • the phrase “six-membered heteroaryl,” refers to heteroaryl, as defined above, having a total of six atoms in the cyclic moiety.
  • the phrase “selected from the group consisting of,” includes a single member from the group, more than one member from the group, or a combination of members from the group.
  • Selected from the group consisting of A, B, and C includes, for example, A, only, B, only, or C, only, as well as A and B as well as A and C as well as B and C as well as A, B, and C or any combination of A, B, and C.
  • a pharmaceutically acceptable excipient means an excipient approved for use in humans in pharmaceutical formulations including those excipients not yet approved but for whom approval is pending.
  • a pharmaceutically acceptable polymer means an polymer approved for use in humans in pharmaceutical formulations including those polymers not yet approved but for whom approval is pending.
  • terapéuticaally effective amount refers to an amount
  • “treating” or “treatment” of hyperhidrosis refers, in certain embodiments, to ameliorating hyperhidrosis that exists in a subject.
  • “treating” or “treatment” includes ameliorating at least one physical parameter of hyperhidrosis, such as sweating.
  • “treating” or “treatment” includes modulating the hyperhidrosis.
  • “treating” or “treatment” includes delaying or preventing the onset of hyperhidrosis (e.g., a prophylactic treatment).
  • “treating” or “treatment” includes mitigating the incidence of episodes of hyperhidrosis, by periodic administration of a pharmaceutical composition according to the methods provided herein.
  • composition that includes at least 85 or 90% by weight, in certain embodiments 95%, 98 % , 99% or 100% by weight, of the designated enantiomer of that compound.
  • the compounds are substantially free of enantiomers.
  • the term “isolated” with respect to a composition refers to a composition that includes at least 85, 90%, 95%, 98%, 99% to 100% by weight, of the compound, the remainder comprising other chemical species or enantiomers.
  • Solvate refers to a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
  • Isotopic composition refers to the amount of each isotope present for a given atom
  • naturally occurring isotopic composition refers to the naturally occurring isotopic composition or abundance for a given atom
  • Atoms containing their natural isotopic composition may also be referred to herein as “non-enriched” atoms.
  • the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as “H” or "hydrogen”, the position is understood to have hydrogen at its natural isotopic composition.
  • Isotopic enrichment refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom's natural isotopic abundance. For example, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary.
  • “Isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.
  • ring A is selected from cycloalkyl, aryl, heterocycloalkyl, or heteroaryl. In some embodiments, ring A is optionally bridged to ring B.
  • ring B is selected from cycloalkyl, aryl, heterocycloalkyl, or heteroaryl. In some embodiments, ring B is optionally bridged to ring A.
  • ring A and ring B are each, independently in each instance, optionally substituted with 1-5 substituents selected from C 1-3 alkyl, C 1-3 alkoxyl, carbonyl, cyano, halo, hydroxyl, -NO2, -NO 3 , -SO2, -SO 3 , or -PO4.
  • the 1-5 substituents are not further substituted themselves.
  • R 1 and R 2 are each, independently in each instance, selected from absent, H, C 1-3 alkyl, C 1-3 alkoxyl, carbonyl, cyano, halo, hydroxyl, -NO 2 , -NO 3 , -SO 2 , -SO 3 , or -PO 4 .
  • R 3 and R 4 are each, independently in each instance, selected from absent, H, C 1-3 alkyl, C 1-3 alkoxyl, carbonyl, cyano, halo, hydroxyl, -NO 2 , -NO 3 , -SO 2 , -SO 3 , or -PO 4 . If R 1 is carbonyl, then R 2 is absent. If R 2 is carbonyl, then R 1 is absent.
  • R 3 is carbonyl, then R 4 is absent. If R 4 is carbonyl, then R 3 is absent.
  • R 5 is C 1-3 alkyl or absent.
  • R 6 is C 1-3 alkyl or bonded with R 7 to form a five-membered heterocycloalkyl ring.
  • R 7 is H, C 1-3 alkyl, or bonded with R 6 to form a five-membered heterocycloalkyl ring.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are unsubstituted.
  • Subscript p is 1 or 2.
  • Subscript q is 1, 2, or 3.
  • R 5 is absent, the compound is preferably in the form of a pharmaceutically acceptable salt with a pharmaceutically acceptable counter-ion.
  • the compounds having the structure of Formula (I) are selected from Formula (la) or Formula (lb): or
  • Ring A and Ring B are each, independently in each instance, either a five- or six-membered cycloalkyl, aryl, heterocycloalkyl, and heteroaryl.
  • Ring A is a five-membered cycloalkyl, aryl, heterocycloalkyl, and heteroaryl.
  • Ring A is a six-membered cycloalkyl, aryl, heterocycloalkyl, and heteroaryl.
  • Ring B is a five- membered cycloalkyl, aryl, heterocycloalkyl, and heteroaryl.
  • Ring B is a six-membered cycloalkyl, aryl, heterocycloalkyl, and heteroaryl.
  • Ring A is a five-membered cycloalkyl.
  • Ring A is a five-membered aryl.
  • Ring A is a five-membered heterocycloalkyl.
  • Ring A is a five-membered heteroaryl.
  • Ring A is a six- membered cycloalkyl.
  • Ring A is a six-membered aryl.
  • Ring A is a six-membered heterocycloalkyl.
  • Ring A is a six-membered heteroaryl.
  • Ring B is a five-membered cycloalkyl. In some other embodiments, Ring B is a five-membered aryl. In yet other embodiments, Ring B is a five-membered heterocycloalkyl. In still other embodiments, Ring B is a five-membered heteroaryl. In some embodiments, Ring B is a six-membered cycloalkyl. In some other embodiments, Ring B is a six-membered aryl. In yet other embodiments, Ring B is a six- membered heterocycloalkyl. In still other embodiments, Ring B is a six-membered heteroaryl.
  • the compounds having the structure of Formula (I) are selected from Formula (Ic) or Formula (Id): or
  • n is 0 or 1 such that when n is 0, ring B is a five member ring.
  • Ring A and Ring B are unsubstituted. In some embodiments, including any of the foregoing, Ring A is unsubstituted and Ring B is substituted. In some embodiments, including any of the foregoing, Ring A is substituted and Ring B is unsubstituted.
  • Ring A and Ring B are not bridged.
  • subscript p is 1 or 2. In some embodiments, subscript p is 1. In some other embodiments, subscript p is 2.
  • subscript q is 1 or 2. In some embodiments, subscript q is 1. In some other embodiments, subscript q is 2.
  • the compounds having the structure of Formula (I) are selected from Formula (Ie) or Formula (If): or
  • the compounds having the structure of Formula (I) are selected from Formula (Ig) or Formula (Hi):
  • the compounds having the structure of Formula (I) are selected from Formula (Ii), Formula (Ij), Formula (Ik), Formula (II), Formula (Im) or Formula (In):
  • the compounds having the structure of Formula (I) are selected from Formula (Io), Formula (Ip), Formula (Iq), Formula (Ir), Formula (Is), Formula (It), Formula (Iu), or Formula (Iv):
  • R 1 , R 2 , R 3 , and R 4 are H.
  • p is 1.
  • p is 2.
  • q is 1.
  • q is 2.
  • p is 1 and q is 1.
  • p is 1 and q is 2.
  • p is 2 and q is 1.
  • p is 2 and q is 2.
  • the compounds having the structure of Formula (I) are selected from Formula (Iw), Formula (lx), Formula (Iy), or Formula
  • p is 1. In some embodiments, including any of the foregoing, p is 2. In some embodiments, including any of the foregoing, q is 1. In some embodiments, including any of the foregoing, q is 2. In some embodiments, p is 1 and q is 1. In some embodiments, p is 1 and q is 2. In some embodiments, p is 2 and q is 1. In some embodiments, p is 2 and q is 2.
  • the compounds having the structure of Formula (I) are selected from:
  • the compounds having the structure of Formula (I) are selected from: or
  • compounds provided herein have one or more chiral centers and may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that any racemic, optically-active, diastereomeric, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound provided herein, which possess the useful properties described herein is within the scope of the invention. It being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).
  • Examples of methods to obtain optically active materials include at least the following: i) physical separation of crystals - a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization - a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions - a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis - a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired en
  • the resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations - a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
  • kinetic resolutions this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors - a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography - a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase.
  • the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography - a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents - a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes - a technique whereby a racemate is placed in contact with a thin membrane barrier.
  • the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one enantiomer of the racemate to pass through.
  • compositions of a compound that are substantially free of one or more other stereoisomers of that compound are substantially free of other stereoisomers of that compound.
  • the compounds are substantially free of other enantiomers.
  • the composition includes a compound that is at least 85, 90%, 95%, 98%, 99% to 100% by weight, of the compound, the remainder comprising other chemical species or enantiomers or diastereomers.
  • isotopically enriched forms of the compounds provided herein are isotopically enriched forms of the compounds provided herein.
  • Isotopic enrichment for example, deuteration
  • PK pharmacokinetics
  • PD pharmacodynamics
  • toxicity profiles has been demonstrated previously with some classes of drugs. See, for example, Lijinsky et. al, Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et. al, J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et. al, Mutation Res. 308: 33 (1994); Gordon et. al, Drug Metab. Dispos., 15: 589 (1987); Zello et. al, Metabolism, 43: 487 (1994); Gately et. al, J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. 117: 191 (1999).
  • Isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and/or (6) decrees the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.
  • KIE Kinetic Isotope Effect
  • DKIE Deuterium Kinetic Isotope Effect
  • the magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C-H bond is broken, and the same reaction where deuterium is substituted for hydrogen.
  • the DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen.
  • High DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy. Because deuterium has more mass than hydrogen, it statistically has a much lower probability of undergoing this phenomenon.
  • substitution of tritium (“T”) for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects.
  • substitution of isotopes for other elements including, but not limited to, 13 C or 14 C for carbon, 33 S, 34 S, or 36 S for sulfur, 15 N for nitrogen, and 17 O or 18 O for oxygen, may lead to a similar kinetic isotope effect.
  • Racemates and stereoisomers can be prepared by standard techniques, including synthesis from racemic and chiral starting materials. Certain compounds set forth herein may be prepared by starting with racemic cyclopentyl mandelic acid (CPMA).
  • CPMA racemic cyclopentyl mandelic acid
  • R-CPMA cyclopentyl mandelic acid having an R stereocenter
  • Certain compounds set forth herein may be prepared by starting with cyclopentyl mandelic acid having an S stereocenter (S-CPMA):
  • CPMA is commercially available from a variety of chemical suppliers.
  • a-CPMA can be purchased from Sigma-Aldrich as catalog number 706396.
  • CPMA may be prepared according to the processes set forth in US Patent
  • CPMA may be prepared according to the processes set forth in International
  • Patent Application Publication No. WO 2018/026869 entitled PROCESSES FOR MAKING, AND METHODS OF USING, GL Y COP YRRONIUM COMPOUNDS, which published February 08, 2018, the entire contents of which are herein incorporated by reference in their entirety for all purpose.
  • CPMA can be bonded to an halo-substituted alcohol by reacting CPMA with a coupling agent, carbonyldiimidazole (CDI), in a suitable solvent and an alkyl halide.
  • a coupling agent carbonyldiimidazole (CDI)
  • solvents include toluene, DMF, and 1,1,3,3,-tetramethylguanidine.
  • Non- limiting examples of a halo-substituted alcohol include 2-chloro-ethanol.
  • the product of this reaction can be bonded to an ester which contains a terminal amine group by reacting with a glycine in a suitable solvent.
  • glycine include diethylglycine and dimethylglycine.
  • Non-limiting examples of solvents include toluene, DMF, and 1,1,3,3,- tetramethylguanidine.
  • An example reaction is shown below: in which X is halo and R a and R b are independently in each instance selected from methyl or ethyl.
  • CPMA can also be bonded to a halo-acetate with a protected ester moiety in a suitable solvent.
  • solvents include DMF optionally with NaC03.
  • Non- limiting examples of a halo-acetate with a protected ester moiety include tert-butyl 2- bromoacetate.
  • the protected ester can be deprotected by reaction with a mixture of trifluoroacetic acid:dichloromethane.
  • the product of this reaction can be bonded to an alkyl which contains a terminal amine group by reacting it with an amino alcohol in a suitable solvent with CDI.
  • Non-limiting examples of amino alcohol include 2-(dimethylamino)ethan-l-ol.
  • solvents include toluene. An example reaction is shown below:
  • Additional compounds can be prepared by reacting a diester compound with an amino alcohol in a suitable solvent with CDI.
  • amino alcohol include 2- (dimethylamino)ethan-l-ol.
  • solvents include toluene.
  • diester compound include 2-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)acetic acid.
  • Tosylate salts of certain of these compounds can be prepared by reacting the products of the above reactions with methyl 4-methylbenzenesulfonate in toluene.
  • An example reaction is shown below: in which R a and R b are independently in each instance selected from methyl or ethyl.
  • set forth herein is a method of treating hyperhidrosis comprising topically administering a therapeutically effective amount of a pharmaceutically acceptable solution of a compound set forth herein, or solvate thereof, to the skin of a mammal.
  • set forth herein is a method of treating a subject in need thereof comprising topically administering a therapeutically effective amount of a pharmaceutically acceptable solution of a compound set forth herein, or solvate thereof, to the skin of a mammal.
  • the compound has the structure of Formula (I): wherein, in Formula (I), ring A is selected from cycloalkyl, aryl, heterocycloalkyl, or heteroaryl. In some examples, ring A is optionally bridged to ring B. In Formula (I), ring B is selected from cycloalkyl, aryl, heterocycloalkyl, or heteroaryl. In some examples, ring B is optionally bridged to ring A.
  • ring A and ring B are each, independently in each instance, optionally substituted with 1-5 substituents selected from C 1-3 alkyl, C 1-3 alkoxyl, carbonyl, cyano, halo, hydroxyl, -NO 2 , -NO 3 , -SO 2 , -SO 3 , or -PO 4 .
  • the 1-5 substituents on ring A or ring B are not themselves further substituted.
  • R 1 and R 2 are each, independently in each instance, selected from absent, H, C 1-3 alkyl, C 1-3 alkoxyl, carbonyl, cyano, halo, hydroxyl, -NO 2 , -NO 3 , -SO 2 , -SO 3 , or -PO 4 .
  • R 3 and R 4 are each, independently in each instance, selected from absent, H, C 1-3 alkyl, C 1-3 alkoxyl, carbonyl, cyano, halo, hydroxyl, -NO2, -NO 3 , -SO2, -SO 3 , or -PO4.
  • R 5 is C 1-3 alkyl or absent.
  • R 6 is C 1-3 alkyl or bonded with R 7 to form a five-membered heterocycloalkyl ring.
  • R 7 is H, C 1-3 alkyl, or bonded with R 6 to form a five-membered heterocycloalkyl ring.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are unsubstituted.
  • Subscript p is 1 or 2.
  • Subscript q is 1, 2, or 3.
  • the compound has a structure selected from the group consisting of:
  • the subject in need thereof suffers from a disease or condition which is ameliorated by an anticholinergic.
  • the subject in need thereof suffers from a disease or condition selected from chronic obstructive pulmonary disease (COPD), non-allergic rhinitis, excessive drooling, or a combination thereof.
  • COPD chronic obstructive pulmonary disease
  • COPD non-allergic rhinitis
  • excessive drooling or a combination thereof.
  • the subject in need thereof suffers from a disease of condition selected from chronic obstructive pulmonary disease (COPD), non-allergic rhinitis, excessive drooling, overactive bladder (OAB), urinary incontinence, incontinence resulting from bladder detrusor muscle instability, bladder detrusor muscle instability incontinence, stress incontinence, urge incontinence, overflow incontinence, enuresis, post-prostectomy incontinence, acute diarrhea, severe diarrhea, diarrhea which accompanies chemotherapy, diarrhea which accompanies rapid narcotic detoxification, performance anxiety and social phobia, or a combination thereof.
  • the subject is a mammal. In some of these embodiments, the mammal is a human being.
  • set forth herein is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound set forth herein and a pharmaceutically acceptable excipient.
  • compositions of the compounds set forth herein e.g., the compounds of Formula (I), e.g., compositions comprising a compound described herein, a salt, stereoisomer, polymorph thereof, and a pharmaceutically acceptable carrier, diluent, and/or excipient.
  • Suitable carriers, diluents and excipients include, but are not limited to: buffers for maintenance of proper composition pH (e.g., citrate buffers, succinate buffers, acetate buffers, phosphate buffers, lactate buffers, oxalate buffers and the like), saline, polyols (e.g., trehalose, sucrose, xylitol, sorbitol, and the like), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxolate, and the like), antimicrobials, and antioxidants.
  • the topical is selected from a solid stick formulation, a wax, or a deodorant composition.
  • the compounds set forth herein are provided as pharmaceutically acceptable salts.
  • the pharmaceutically acceptable counter salt may be prepared from inorganic and organic acids. Salts derived from inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydrogen fluoride, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include, but are not limited to, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • the compounds set forth herein are provided as a solution.
  • a solvent system that is useful includes, but is not limited to, an alcohol. Skin safe alcohols such as ethanol, isopropanol, acetone, etc. may be used for certain formulations.
  • a combination of ethanol and water delivers the active ingredient to the skin in a cosmetically acceptable manner and ensures rapid drying of formulations, which is important for treating hyperhidrosis.
  • the compounds set forth herein are provided with a buffering agent.
  • any buffering agent that has a good solubility in the solvent system of the formulations according to the disclosure herein and can maintain a pH of about 3.5 to about 6, may be used.
  • the buffering agent include any known buffering agent that can be compatible with a glycopyrronium compound, such as, citric acid, sodium citrate, tromethamine, phosphate buffers, hydrochloride, etc.
  • the buffering agent may be in the amount of about 0.2 to about 0.5% w/w.
  • anhydrous citric acid is added in the amount of about 0.13 to 0.14% w/w and sodium citrate (dehydrate) is added in the amount of 0.09 to 0.11% w/w.
  • the buffering agent maintains the pH of the formulations at about 3.5 to about 6, or at about 4 to 5, or at 4.5.
  • Citric acid and sodium citrate may also be used as buffering agents to achieve and maintain a satisfactory pH range.
  • the compounds set forth herein are provided with a polymer system.
  • the polymer system used in the disclosure herein may include a hydrophobic polymer (e.g., butyl ester of PVM/MA copolymer) in combination with a hydrophilic polymer (e.g., polyvinyl pyrrolidone, Povidone K-90).
  • Non-limiting examples of the hydrophobic polymer include octylacrylamide octylpropenamide acrylate copolymer, aminoalkyl methacrylate copolymer, ammonio methacrylate copolymer, PVP/VA copolymer, PVA, butylester of PVM/MA copolymer, shellac and alkyl acrylates and copolymers thereof.
  • Non-limiting examples of the hydrophilic polymer include hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone (PVP), carbomer, PVM MA decadiene cross polymer and hydroxypropylguar & copolymers thereof.
  • Butyl ester of PVM MA copolymer not only increases water resistance, but also does not have a high pH and thus is compatible with certain compounds herein and is soluble in an ethanol/water solvent system, while insoluble in water only.
  • Polyvinyl pyrrolidone not only has a desireable rub-resistance, but also is not affected by pH and has a low susceptibility to ions.
  • the formulations of the compounds set forth herein consist of an ethanol/water solution ranging from 40% to 60% ethanol by weight. In some embodiments, this solution is included with wipes and packaged as sealed single use pouches.
  • the present formulations may comprise one or more optional additives such as humectants, colorants, perfumes, etc.
  • each of these optional additives should be both miscible and compatible with a compound set forth herein.
  • Compatible additives are those that do not prevent the use of a compound in the manner described herein.
  • Non-limiting examples of the humectants include propylene glycol, sorbitol, glycerin, etc. When included, propylene glycol maybe used in the amount of 2% w/w to 4% w/w.
  • the methods provided herein may further comprise administration of one or more additional agents, for instance to treat hyperhidrosis.
  • additional agents include any of those described in this disclosure or known in the art for the treatment of hyperhidrosis.
  • the additional agent(s) may be administered in the same pharmaceutical composition as the agent recited in the methods provided herein, or in a different pharmaceutical composition, according to the judgment of those skilled in the art.
  • the pharmaceutical compositions set forth herein include more than one anticholinergic agent.
  • the anticholinergic agents are selected from a compound set forth herein, propantheline, oxybutynin, methantheline, benztropine, and sofpironium bromide (BBI-4000; Brickell Biotech, Inc.).
  • the composition comprises a compound set forth herein.
  • the compound set forth herein is glycopyrronium tosylate.
  • the compound set forth herein is glycopyrronium bromide.
  • the compound is sofpironium bromide.
  • the methods provided herein comprises administering a compound in combination with another agent or procedure.
  • the other agent or procedure is selected from an anticholinergic agent, a metal salt, and a toxin.
  • topical administration of an agent is combined with systemic administration of the same agent, or a different agent.
  • topical administration of a compound set forth herein is combined with systemic administration of the compound.
  • the compounds described herein can be administered alone or together with one or more additional therapeutic agents.
  • the one or more additional therapeutic agents can be administered just prior to, concurrent with, or shortly after the administration of the compounds described herein.
  • the present disclosure also includes pharmaceutical compositions comprising any of the compounds described herein in combination with one or more additional therapeutic agents, and methods of treatment comprising administering such combinations to subjects in need thereof.
  • compositions of the compounds described herein e.g., compositions comprising a compound described herein, a salt, stereoisomer, mixture of stereoisomers, polymorph thereof, and a pharmaceutically acceptable carrier, diluent, and/or excipient.
  • suitable carriers, diluents and excipients include, but are not limited to: buffers for maintenance of proper composition pH (e.g., citrate buffers, succinate buffers, acetate buffers, phosphate buffers, lactate buffers, oxalate buffers and the like), carrier proteins (e.g.
  • polyols e.g., trehalose, sucrose, xylitol, sorbitol, and the like
  • surfactants e.g. , polysorbate 20, polysorbate 80, polyoxolate, and the like
  • antimicrobials and antioxidants.
  • compositions described herein can be formulated as pharmaceutical compositions by formulation with additives such as pharmaceutically acceptable excipients, pharmaceutically acceptable carriers, and pharmaceutically acceptable vehicles.
  • suitable pharmaceutically acceptable excipients, carriers and vehicles include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl- ⁇ -cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof.
  • a pharmaceutical composition can comprise a unit dose formulation, where the unit dose is a dose sufficient to have a therapeutic or suppressive effect or an amount effective to modulate or treat a disease or condition described herein.
  • the unit dose may be sufficient as a single dose to have a therapeutic or suppressive effect or an amount effective to modulate or treat a disease or condition described herein.
  • the unit dose may be a dose administered periodically in a course of treatment or suppression of a disorder, or to modulate or treat a disease or condition described herein.
  • compositions containing the compounds or compositions of the invention may be in any form suitable for the intended method of administration, including, for example, a solution, a suspension, or an emulsion.
  • the compositions set forth herein are suitable for topical application.
  • liquid carriers are typically used in preparing solutions, suspensions, and emulsions.
  • Liquid carriers contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more thereof.
  • the liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like.
  • suitable organic solvents include, for example, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols.
  • Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like.
  • the compounds or compositions of the invention may be administered topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • suitable modes of administration include transdermal or transmucosal, intranasal (e.g., via nasal mucosa), and the like, and directly to a specific or affected site on the subject.
  • Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • the compounds or compositions are mixed with pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for the desired route of administration.
  • the compounds described for use herein can be administered in solid form, in liquid form, in aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, creams, solutions, emulsions, dispersions, and in other suitable forms.
  • the compounds can also be administered as prodrugs, where the prodrug undergoes transformation in the treated subject to a form which is therapeutically effective. Additional methods of administration are known in the art.
  • the pharmaceutical composition is a topical dosage form comprising about 5-5000 mg of a compound set forth herein in an alcohol: water solution and with a pH buffering agent.
  • the compound set forth herein is present at a concentration of about 0.25-20% (w/w).
  • the compound set forth is present at a concentration of about 1, 2, 3, or 4% (w/w). In some embodiments, the compound set forth herein is present at a concentration of about 3% (w/w). In an embodiment, the topical dosage form comprises about 70-105 mg of the compound set forth herein. In an embodiment, the topical dosage form comprises about 70 mg of the compound set forth herein. In an embodiment, the topical dosage form comprises about 105 mg of the compound set forth herein. In an embodiment, the alcoho:water ratio of the topical dosage form is selected over the range of 50:50 to 70:30, preferably over the range of 53:47 to 58:42. In an embodiment, the buffering agent is about 0.2 to 0.5% of the topical dosage form.
  • the buffering agent of the topical dosage form is citric acid/sodium citrate.
  • the pH of the topical dosage form is selected over the range of 4.0 to 5.0. In an embodiment, the pH of the topical dosage form is about 4.5.
  • the pharmaceutical composition comprises about 105 mg threo glycopyrronium tosylate, citric acid, sodium citrate, ethanol, and water at a pH of about 4.5.
  • the pharmaceutical composition comprises a compound set forth herein, about 0.15% by weight anhydrous citric acid, about 0.06% sodium citrate dihydrate by weight, between about 57 to about 59.5% by weight of dehydrated ethanol, and the balance as water.
  • the pharmaceutical composition comprises a compound set forth herein, about 0.15% by weight anhydrous citric acid, about 0.06% sodium citrate dihydrate by weight, between about 57 to about 59.5% by weight of dehydrated ethanol, and the balance as water.
  • the pharmaceutical composition is provided as a wipe or cloth moistened with the pharmaceutical formulation.
  • the wipe or cloth can be about 100% polypropylene.
  • the wipe or cloth can be contained in a pouch, for instance a laminated foil pouch.
  • the compounds and pharmaceutical compositions set forth herein may be used to treat hyperhidrosis such as by using a wipe containing a solution of the compounds or pharmaceutical compositions.
  • US Patent No. US 9,006,462 is incorporated by reference in its entirety for all purposes including its disclosure regarding formulations.
  • the compounds and pharmaceutical compositions set forth herein may also be used to treat hyperhidrosis in patients such as by administering a topical containing a compound or pharmaceutical composition set forth.
  • topical what is meant is a material or formulation comprising or containing a compound, or a pharmaceutical composition set forth herein which may be used to deliver a compound set forth herein, including a pharmaceutically effective amount of a compound set forth herein, to a patient.
  • a topical include, but are not limited to, solutions, ointments, gels, lotions, powders, sprays, creams, cream bases, patches, pastes, washes, dressings, masks, gauzes, bandages, swabs, brushes, or pads.
  • the application of the topical may be controlled by controlling the dose amount or the rate of release.
  • the dose may be controlled by dissolving or dispensing a compound or pharmaceutical composition set forth herein, for example, in the appropriate medium.
  • These and other dose controlling formulations may be used to deliver controlled doses such as specific unit doses, metered doses, or multiple doses from the topical.
  • the topical is an absorbent pad.
  • such an absorbent pad may contain another topical such as a solution.
  • absorbent pads and nonwoven wipes are interchangeable and have the same meaning.
  • an absorbent pad containing a compound or pharmaceutical composition set forth herein in solution may be used to treat hyperhidrosis.
  • an absorbent pad containing a compound or pharmaceutical composition set forth herein in solution may be used to treat any disease, disorder, or condition related to the interaction of acetylcholine and the acetylcholine receptor on nerve cells.
  • pads or wipes containing one or more of a compound or pharmaceutical composition in solution may similarly be used to treat hyperhidrosis in patients.
  • the pharmaceutically acceptable solution of a compound or pharmaceutical composition set forth herein is a topical.
  • Solid dispersions can be prepared in a number of different methods known in the art including lyophilization and spray drying.
  • the solid dispersions herein were all created by lyophilization.
  • solid dispersions may be prepared by combining a solution of a compound set forth herein with a solution of an excipient in one or more solvents where both components are soluble. The solutions may be filtered and are then cooled so that the solutions freeze. After freezing, the solutions are dried, such as in a lyophilizer, so as to form dispersions.
  • the presence of a solid dispersion can be verified by comparing, for example, spectra of the starting materials with the purported dispersion or by observing a glass temperature different than either of the components.
  • a mixture would be evident by a simply linear combination of the peaks of the two starting materials whereas in a dispersion, peak shifts indicate the preparation of a different material, namely, a solid dispersion.
  • a solid dispersion is also evident by the presence of a single glass transition temperature.
  • a solid dispersion comprising a compound set forth herein and excipients including monosaccharides, disaccharides, and pharmaceutically acceptable polymers containing cyclic ether moieties may be formed under suitable conditions such as by lyophilization.
  • such solid dispersions have a glass transition temperature of at least about 25° C, including at least about 40° C, and at least about 60° C.
  • the weight ratio of sucrose to a compound set forth herein is about 9:1.
  • the cyclic ethers are six-membered rings, such as in hypromellose acetate succinate (HPMCAS) and such solid dispersions have a glass transition temperature of at least about 25° C, including at least about 40° C, and at least about 60° C.
  • HPMCAS hypromellose acetate succinate
  • the weight ratio of HPMCAS to a compound set forth herein is about 1:1.
  • a solid dispersion comprising a compound set forth herein and excipients including pharmaceutically acceptable polymers containing polyethylene glycol moieties such as a polyvinyl alcohol-polyethylene glycol graft copolymer, such as Kollicoat® IR, or a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, such as Soluplus®, may be formed under suitable conditions such as by lyophilization.
  • such solid dispersions have a glass transition temperature of at least about 30° C, including at least about 40° C.
  • a solid dispersion comprising a compound set forth herein and excipients including pharmaceutically acceptable polymers containing vinyl pyrrolidone moieties such as polyvinyl pyrrolidone or vinyl pyrrolidone-vinyl acetate copolymer may be formed under suitable conditions such as by lyophilization.
  • such solid dispersions have a glass transition temperature of at least about 25° C, including at least about 35° C, and further including about 60° C.
  • polyvinyl pyrrolidone polymers used herein include PVP K29/32 and PVP K90.
  • Examples of a vinyl pyrrolidone-vinyl acetate copolymer used herein include Kollidon® VA 64.
  • HPMCAS may be used to form a solid dispersion with a compound set forth herein in, for example, a ratio of about 1 to 1 of HPMCAS to glycopyrronium by weight.
  • Sucrose may be used to form a solid dispersion with a compound set forth herein in, for example, a ratio of about 9 to 1 of sucrose to glycopyrronium by weight.
  • a polyvinyl alcohol-polyethylene glycol copolymer may be used to form a solid dispersion with a compound set forth herein, in, for example, ratios of between about 1:1 and 9:1.
  • a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer may be used to form a solid dispersion with a compound set forth herein in, for example, a ratio of about 1 to 1 of the polymer to glycopyrronium by weight.
  • a polyvinyl pyrrolidone polymer may be used to form a solid dispersion with a compound set forth herein in, for example, a ratio of about 1 to 1 of the polymer to glycopyrronium by weight or a ratio of about 8 to 1 by weight.
  • a vinyl pyrrolidone-vinyl acetate copolymer may be used to form a solid dispersion with a compound set forth herein in, for example, a ratio of about 1 to 1 of a compound of the copolymer to glycopyrronium by weight.
  • the disclosure herein provides a compound or composition set forth herein in a topical which is not a solution such as ointment or a cream.
  • a topical is a gel.
  • the topical comprises a compound or composition set forth herein.
  • the topical further comprises buffers and/or may be in an aqueous solution.
  • said buffers may be, for example, citric acid and sodium citrate.
  • the buffered topical may further comprise an alcohol such as ethanol.
  • the disclosure herein provides a pharmaceutically acceptable solution comprising a compound set forth herein or a solvate thereof and one or more pharmaceutically acceptable additives.
  • Such additives may include such co-solvents as ethanol and one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable solution comprising a compound set forth herein or a solvate thereof is aqueous and further comprises one or more buffers.
  • the pharmaceutically acceptable solution is aqueous.
  • buffers include, but are not limited to citric acid and sodium citrate dihydrate.
  • the citric acid includes anhydrous citric acid.
  • the solution may also contain one or more alcohols such as ethanol. Dehydrated ethanol is an alcohol that may be used.
  • the pharmaceutically acceptable aqueous solution comprising a compound set forth herein comprises about 0.15% by weight anhydrous citric acid, about 0.06% sodium citrate dihydrate by weight, between about 57 to about 59.5% by weight of dehydrated ethanol, and between about 1% and about 6% by weight a compound set forth herein.
  • the topical is prepared so as to be film-forming.
  • a binding agent used.
  • binding agents include povidones such as povidone K90.
  • Such film-forming solutions further comprise one or more film-forming agents.
  • film forming agents include butyl esters of a polyvinylmethylether/maleic anhydride acid copolymer.
  • An example of such a film forming agent is the GantrezTM ES-425 butyl ester copolymer
  • the aqueous pharmaceutically acceptable solution is prepared so as to be film-forming.
  • a binding agent used.
  • binding agents include povidones such as povidone K90.
  • film-forming solutions further comprise one or more film-forming agents.
  • film forming agents include butyl esters of a polyvinylmethylether/maleic anhydride acid copolymer.
  • An example of such a film forming agent is the GantrezTM ES-425 butyl ester copolymer.
  • the pharmaceutically acceptable solution is absorbed onto a carrier.
  • a carrier may be a pad such as an absorbent pad or nonwoven wipe suitable for holding such solution when in storage as well as for application of the solution to desired areas of skin.
  • the absorbent pad can be based on cotton fabric or non-cotton fabric.
  • the absorbent pad is based on synthetic nonwoven fabric, such as nonwoven rayon and polypropylene fabric.
  • the absorbent pad is a 75:25 rayon and polypropylene pad.
  • the absorbent pad material comprises polypropylene. In other embodiments, the absorbent pad is substantially all polypropylene and in others, the pad is 100% polypropylene.
  • Such pads maybe nonwoven fabric with the following characteristics: [00145] The pH of a topical such as a solution of a compound set forth herein, absorbed onto a pad is between 3.5 and 5.5 and often between about 4.0 and 5.0, including about 4 to 4.7 and about 4.1 to 4.6. For a compound set forth herein monohydrate topical such as for a pad, the amount of a compound set forth herein monohydrate solution used in a pad is typically between about 2 g and 4 g including about 2.8 g or other pharmaceutically acceptable amounts.
  • a topical such as a solution may contain varying weight percents of a compound set forth herein such as a compound set forth herein monohydrate.
  • the weight percent of a compound set forth herein is between about 1% and about 4%, including between 1.25% and about 4%, including between 2.5% and 3.75% and including each of about 1.25%, 2.5% and about 3.75%.
  • the weight percents of a compound set forth herein may also be expressed in weight percent only. For these weight percents, the weight percents may vary between about 0.6% and about 3.2%, including between about 1.6% and about 2.4% and including each of about 0.6%, 1.6% and about 2.4%.
  • a composition set forth herein in any of the embodiments wherein they are absorbed onto the pads or are contained or comprised within the other topicals may be a compound set forth herein.
  • the topicals such as the absorbent pad containing a pharmaceutically acceptable solution can be applied to the area of the body to be treated.
  • Processes for making aqueous solutions of a compound set forth herein include treating a solid of a compound set forth herein in solution with water so as to dissolve the solid the compound in solution.
  • One may also add one or more buffers and/or alcohol, to the solution.
  • the solution so obtained may then be wetted onto an absorbent pad so that a pharmaceutically acceptable amount of glycopyrronium tosylate has been absorbed onto the pad.
  • the alcohol may be ethanol such as dehydrated ethanol.
  • the buffers may be citric acid and sodium citrate.
  • the compound set forth herein or a solvate thereof to be dissolved is in a crystalline form.
  • the compound set forth herein or a solvate thereof is in an x-ray amorphous form.
  • the pouch is heat-sealed after wetting.
  • a typical pouch material is laminate containing aluminum foil as a layer.
  • a pharmaceutically acceptable aqueous solution of a compound set forth herein may be prepared by dissolving a compound set forth herein in a mixture of water with ethanol.
  • One or more pharmaceutically acceptable excipients can be added either prior to or after the addition of the compound set forth herein or a solvate thereof and the aqueous solvent.
  • the pharmaceutically acceptable solution of a compound set forth herein or a solvate thereof is therapeutically useful.
  • the pharmaceutically acceptable solution can be used for treating hyperhidrosis or reducing sweating in mammals.
  • the pharmaceutically acceptable solution is typically applied from a pad on which the solution is absorbed.
  • the disclosure herein provides a method of treating hyperhidrosis in a mammal by topically administering to the skin of the mammal a therapeutically effective amount of a pharmaceutically acceptable solution of a compound set forth herein or a solvate thereof.
  • the mammal is a human.
  • the pharmaceutically acceptable solution can be applied to one or several areas or even the whole body including, but not limited to, the hands, e.g., palms; axillae; feet, e.g., soles; groin; face, e.g., cheeks and forehead; and trunk, e.g., back and abdomen, or scalp.
  • methods of treating primary axillary hyperhidrosis with a compound set forth herein or a solvate thereof comprising topically administering a therapeutically effective amount of an aqueous compound set forth herein solution to the skin of a mammal in need thereof.
  • such administration may be with an absorbent pad.
  • a compound set forth herein may be administered as racemic mixtures of stereoisomers.
  • the compounds set forth herein may be administered as specific stereoisomers.
  • the compound having the structure of Formula (I) may have stereocenters at any one of positions 1, 2, 3, or 4, as labeled below:
  • position 1 is R.
  • position 1 is S.
  • position 2 is R.
  • position 2 is S.
  • position 3 is R.
  • position 3 is S.
  • position 4 is R.
  • position 4 is S.
  • the compounds administered include a mixture of compounds of Formula 1 have R/S configurations at position 1.
  • the compounds administered include a mixture of compounds of Formula 1 have R/S configurations at position 2.
  • the compounds administered include a mixture of compounds of Formula 1 have R/S configurations at position 3.
  • the compounds administered include a mixture of compounds of Formula 1 have R/S configurations at position 4.
  • the compounds and compositions set forth herein are included with an absorbent pad.
  • the topical is an absorbent pad.
  • such an absorbent pad may contain another topical such as a solution.
  • absorbent pads and nonwoven wipes are interchangeable and have the same meaning.
  • an absorbent pad containing a compound set forth herein in solution may be used to treat hyperhidrosis.
  • pads or wipes containing one or more of compounds set forth herein, or their benzoate, edisylate, oxalate, or hydrogen sulfate salts, in solution may similarly be used to treat hyperhidrosis in patients.
  • the compounds and compositions set forth here are included with an absorbent pad.
  • the absorbent pad has a basis weight of 1.231-1.254 ounces/yard 2 ; a machine direction grab tensile of 15.495-18.862 lbf (pounds-force); a cross direction grab tensile of 14.425-16.190 lbf; and/or a fiber denier of 2.443-2.569 dpf (denier per filament).
  • the compounds and compositions set forth herein are included with a wipe.
  • the wipe is a Jerusalem 6" AP686 69 g/m 2 .
  • the size of the wipe in flat form is about 4"- 6"x3.78"-4".
  • the size is about 6"x4", about 6"x3.78", about 5"x4", about 5"x3.78", about 4"x4", or about 4"x3.78".
  • the wipe is folded,
  • the wipe has three folds along the long side, then in half across the other orientation during insertion into a laminated pouch.
  • the compounds and compositions set forth herein are included in a pouch.
  • the pouch is resistant to leakage.
  • the pouch includes an inner lining of linear low density polyethylene (LLDPE).
  • the pouch includes as a laminate,
  • the pouch size is not limited. In some embodiments, the pouch has dimensions of 2.375"x3.5" ⁇ 0.0625".
  • the compounds and compositions set forth herein are effective over a wide dosage range and is generally administered in a therapeutically effective amount.
  • the administered solutions, which are contacted with a wipe contain from about 0.25 to about 6% w/w and more or from 0.5% to 4% w/w of a compound set forth herein. It will be understood, however, that the amount of the compound set forth herein which is actually administered may be determined by a physician in light of the relevant circumstances, including the condition to be treated, the actual compound to be administered and its relative activity, the area to be administered, the response of the individual patient, the severity of the patient's symptoms, and the like.
  • kits for use in the methods provided herein comprises a pharmaceutical composition comprising a compound described herein.
  • the kit can further comprise instructions, for instance for administration, occlusion, and/or monitoring.
  • the kit can further comprise materials for an assessment, e.g. an HDSS assessment or an ASDD assessment modified as described herein, or both.
  • the kit further comprises packaging.
  • this packaging includes a container suitable for holding a pharmaceutical composition.
  • the container can be made of any suitable material. Suitable materials include, for example, glass, plastic paper, laminates, and the like.
  • the samples were prepared by dissolving a small amount of sample in DMSO-ds containing TMS.
  • the liquid-chromatography mass spectrometry instrument was an Agilent
  • Step one 3 g of racemic cyclopentyl mandelic acid (CPMA; molecular weight of 220.27 g/mol) was reacted with the coupling agent, carbonyldiimidazole (CDI) and 1.0 molar equivalents of 2-chloro-ethanol in toluene at 80°C. The reaction proceeded for twelve hours. The reaction produced 2.8 g of 2-chloroethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate (MW of 282.76 g/mol).
  • CPMA racemic cyclopentyl mandelic acid
  • CDI carbonyldiimidazole
  • Step two 500 mg of 2-chloroethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate was then reacted with 1.0 molar equivalents of diethylglycine and 2.0 molar equivalents 1 , 1 ,3,3,-tetramethylguanidine in dimethyl formamide (DMF) at 70 °C. The reaction proceeded for 16 hours. The reaction produced 180 mg of racemic 2-((diethylglycyl)oxy)ethyl 2- cyclopentyl-2-hydroxy-2-phenylacetate (MW of 377.22 g/mol).
  • LC-MS showed a retention time (RT) of 3.099 minutes (min) when analyzed under the following conditions
  • LC-MS showed a retention time (RT) of 1.881 min when analyzed under the following conditions
  • Step one 10 g of racemic cyclopentyl mandelic acid (CPMA; molecular weight of 220.27 g/mol) was reacted with 1.2 molar equivalents of tert-butyl 2-bromoacetate and 2.0 molar equivalents of NaHCO 3 in DMF:H 2 0 (9:1 v:v) at room temperature. The reaction proceeded for 3 hours. The reaction produced 12g of 2-(tert-butoxy)-2-oxoethyl 2-cyclopentyl-2-hydroxy-2- phenylacetate (MW of 334.41 g/mol; Compound 107).
  • CPMA racemic cyclopentyl mandelic acid
  • Step two 12 g of 2-(tert-butoxy)-2-oxoethyl 2-cyclopentyl-2-hydroxy-2- phenylacetate was reacted in trifluoroacetic acid:dichloromethane (TFA:DCM; 1:2 v:v) at room temperature for 6 hours in order to hydrolyze the t-butoxy functional group.
  • TFA:DCM trifluoroacetic acid:dichloromethane
  • Step three 1 g of 2-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)acetic acid was reacted with 1 molar equivalent of CDI in toluene at room temperature for two hours. Then 1.0 molar equivalents of 2-(dimethylamino)ethan-l-ol was added to the reaction in toluene and the reaction was heated to 80° C. The reaction then proceeded for 12 hours. The reaction produced racemic 2-(2-(dimethylamino)ethoxy)-2-oxoethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate (MW of 349.43 as HC1 salt; Compound 104).
  • LC-MS showed a retention time (RT) of 3.013 minutes (min) when analyzed under the following conditions
  • LC-MS showed a retention time (RT) of 1.798 min when analyzed under the following conditions
  • Step one lg of racemic 2-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)acetic acid (MW of 278.30 g/mol) was reacted with 1.0 equivalent of CDI in toluene at room temperature for 2 hours. Then, 1 equivalent of 2-(diethylamino)ethan-l-ol was added to the reaction solution. This reaction proceeded for 12 hours at 80 ° C.
  • LC-MS showed a retention time (RT) of 3.441 minutes (min) when analyzed under the following conditions Column: X-Bridge C8(50X4.6)mm, 3.5 ⁇ m; Mobile phase: A:0.1% TFA in water; Mobile phase:B:0.1%TFA in ACN; Flow:2.0mL/min.
  • LC-MS showed a retention time (RT) of 1.795 min when analyzed under the following conditions
  • Step one 3 g of racemic cyclopentyl mandelic acid (CPMA; molecular weight of 220.27 g/mol) was reacted with the coupling agent, carbonyldiimidazole (CDI) and 1.0 molar equivalents of 2-chloro-ethanol in toluene at 80°C. The reaction proceeded for twelve hours. The reaction produced of 2-chloroethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate (MW of 282.76 g/mol) at about 62% yield.
  • CPMA racemic cyclopentyl mandelic acid
  • CDI carbonyldiimidazole
  • Step two 500 mg of 2-chloroethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate was then reacted with 1.0 molar equivalents of dimethylglycine and 2.0 molar equivalents 1,1,3,3,-tetramethylguanidine in dimethyl formamide (DMF) at 70 °C. The reaction proceeded for 16 hours. The reaction produced racemic 2-((dimethylglycyl)oxy)ethyl 2-cyclopentyl-2- hydroxy-2-phenylacetate (MW of 349.19 g/mol as HCI salt; HCI has MW of 35.98 g/mol) at about 62% yield.
  • DMF dimethyl formamide
  • LC-MS showed a retention time (RT) of 3.343 minutes (min) when analyzed under the following conditions
  • LC-MS showed a retention time (RT) of 1.813 min when analyzed under the following conditions
  • LC-MS showed a retention time (RT) of 1.920 minutes (min) when analyzed under the following conditions
  • LC-MS showed a retention time (RT) of 3.697 min when analyzed under the following conditions
  • BIOLOGICAL EXAMPLE 1 - POTENCY STUDY This Example studied the Muscarinic acetylcholine receptor M3 affinity of various compounds set forth herein, including cyclopentyl mandelic acid (CPMA). See Table 1 below.
  • CPMA cyclopentyl mandelic acid
  • Compounds were screened for their functional effects in a M3 induced calcium mobilization assay in Human M3 receptor overexpressing cells. The ability of purified antibodies to inhibit the functional response was determined using a calcium flux assay conducted in human M3 receptor overexpressing CHO cells in a 384-well plate format using FLIPR.
  • FIG. 1 A flow chart for the M3 induced calcium immobilization assay (FLIPR) screening is shown in FIG. 1.
  • the CHO cells obtained from Thermo Fisher were cultured and maintained in the recommended media. On the day of the assay, the cells were harvested followed by centrifugation and removal of supernatant and then followed by adding fresh media to re-suspend the cell pellet. The cell density was diluted to 0.4 X 106 cells per ml. The single cell suspension was seeded into the assay plate at an appropriate density (which was optimized for this study) to obtain enough signal to noise ratio. The assay plates were incubated for 30 minutes (mins) at room temperature. Next, the assay plates were placed into a humidified 37°C 5% CO 2 incubator for 18-24 hours. The cell media was then aspirated and replaced with FLIPR Calcium 5 dye followed by an incubation for 0.5-1 hour at 37°C.
  • Test compound dilutions were prepared in the relevant assay buffer before being transferred to the dye-loaded cells and incubated at room temperature for 30 minutes.
  • an EC 80 concentration of agonist e.g., carbachol
  • the screening parameters used for the testing purpose were as follows.
  • the assay format included a 384-well black plates. The assay method was calcium mobilization. The cell lines were CHO cells overexpressing human M3 receptor as supplied by the sponsor. The test concentrations were 10 ⁇ M. The screening format included a 10-point IC50 determination in triplicates.
  • a reference antagonist e.g., atropine
  • Fluorescence was used to detect calcium-5 or calcium-6 using a Molecular Devices FLIPR- TETRA detection instrument.
  • the reference agonist was Carbachol.
  • the reference antagonist was Atropine. The results are shown in FIG. 2. Signal window in FIG. 2was observed to > 70 fold. Z prime > 0.81. Signal window in FIG. 2 was observed to > 50 fold. Z prime > 0.76.
  • the screening concentration was 10 ⁇ M.
  • BIOLOGICAL EXAMPLE 2 PLASMA STABILITY STUDY
  • Procaine (Sigma, Cat No. P9879) was used in this Example.
  • Flumazenil (Sigma, Cat No F6300) was used in this Example.
  • DMSO stock solutions (10mM concentration) were prepared and stored at room temperature.
  • Working stock solution-I of ImM were prepared by diluting lOmM stock solution 1 : 10 v/v with DMSO.
  • Working stock solution-II of 100 ⁇ M were prepared by dilution 1 mM stock solution 1:10 v/v with DMSO.
  • the stability assays were carried out at 37 °C with gentle shaking in a water-bath in a final volume of 400 pL. At different time-points, a sample (50 pL) was taken and the reaction was quenched by adding acetonitrile (300 pL) containing internal standard (Tolbutamide, 250 ng/ml). The sample was mixed for 5 minutes using a table top vortex mixer and centrifuged at 4000 RPM (Eppendorf 5810 R, 3220 g) for 10 minutes. Samples were analyzed by a compound specific discovery grade LC-MS/MS method.
  • test compound was mixed with acetonitrile containing internal standard. To this appropriate volume of blank plasma was added and after mixing the sample it was processed as above for bioanalysis.
  • Chromatographic Conditions included a Triple Quad 4500 LC-MS/MS, with the following settings:
  • composition A) 0.1% Formic acid in Water
  • This Example examined the solubilization capacity of different excipients for a set of compounds.
  • Test formulations were prepared at the concentration required (example 1 mg/mL) [00245] Formulations were agitated for 2 hours at room temperature (23°C). Physical appearance was recorded at the end of incubation. Experiment were done in duplicates, with separate weighing.
  • test formulations were centrifuged at 14000 rpm for 10 min to remove undissolved material. From the supernatant, an aliquot was mixed with an organic solvent such as acetonitrile and resulting solution will be analyzed by HPLC-UV.

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Abstract

La présente invention concerne des composés et des compositions pharmaceutiques utiles en tant que composés anticholinergiques. L'invention concerne également des méthodes de traitement de sujets en ayant besoin, par exemple, des sujets souffrant d'hyperhydrose, par administration des composés et des compositions pharmaceutiques selon l'invention. De plus, l'invention concerne des procédés de production de composés et de compositions pharmaceutiques utiles en tant que composés anticholinergiques.
PCT/US2020/062743 2019-12-02 2020-12-01 Composés contenant un diester pour le traitement de l'hyperhydrose WO2021113260A1 (fr)

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