CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims priority to, and the benefit of, both U.S. Provisional Patent

Application No. 63/046,621, filed June 30, 2020, and U.S. Provisional Patent Application No. 62/942,677, filed December 2, 2019. The entire contents of each provisional is incorporated herein by reference in its entirety for all purposes.

FIELD

[002] The present disclosure concerns anticholinergic compounds and compositions as well as methods of making and using the same.

BACKGROUND

[003] Certain diseases, disorders, and conditions, are related to the interaction between acetylcholine and the acetylcholine receptor. 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.

[004] 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. [005] Other anticholinergic compounds include compounds referred to as soft anticholinergic esters, such as those set forth in US Patent Application Publication No. US 20070123557.

[006] 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.

[007] Set forth herein are solutions to this problem, as well as others, including new anticholinergic compounds, methods of making anticholinergic compounds, and methods of using anticholinergic compounds to treating a variety of diseases, disorders, and conditions.

SUMMARY

[008] In one embodiment, set forth herein is a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I): wherein ring A is selected from cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; and ring A is optionally bridged to ring B; ring B is selected from cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; and 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 ; either X is O and Y is C=O; or X is C=O and Y is O; 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, Ci- 3alkoxyl, carbonyl, cyano, halo, hydroxyl, -NO ₂ , -NO ₃ , -SO ₂ , -SO ₃ , or -PO ₄ ; R ⁵ is C _1-3 alkyl or absent; if R ¹ is carbonyl, then R ² is absent; if R ² is carbonyl, then R ¹ is absent; if R ³ is carbonyl, then R ⁴ is absent; if R ⁴ is carbonyl, then R ³ is absent; R ⁶ is C _1-3 alkyl or bonded with R ⁷ to form a five-membered heterocycloalkyl ring; and R ⁷ is H, C _1-3 alkyl, or bonded with R ⁶ to form a five- membered heterocycloalkyl ring; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are unsubstituted; subscript p is 1 or 2; and subscript q is 1, 2, or 3. If R ⁵ is present, said compound is preferably in the form of a pharmaceutically acceptable salt with a pharmaceutically acceptable counterion. [009] In a second embodiment, set forth herein is a pharmaceutical composition comprising a compound or salt set forth herein and pharmaceutically acceptable excipient.

[0010] In a third embodiment, 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.

[0011] In a fourth embodiment, 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.

BRIEF DESCRIPTIONS OF THE DRAWINGS

[0012] FIG. 1 shows a flow chart for the M3 induced calcium immobilization assay

(FLIPR) screening described in BIOLOGICAL EXAMPLE 1.

[0013] 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.

[0014] 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. [0015] 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.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] FIG. 9 shows the results of the human plasma stability assay in Biological

Example 2.

DETAILED DESCRIPTION

[0021] Set forth herein are a series of new compounds and pharmaceutical compositions useful as anticholinergic compounds. Also set forth herein are methods of treating subjects in need thereof, e.g., subjects suffering from hyperhidrosis, by administering the compounds and pharmaceutical compositions set forth herein.

A. DEFINITIONS

[0022] As used herein, the term “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. Examples of 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.

[0023] As used herein, 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.

[0024] As used herein, the term “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. Examples of 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.

[0025] As used herein, the term “ 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.

[0026] As used herein, the term “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.

[0027] As used herein, the term “carbonyl,” refers to a substituent , wherein the squiggly line , indicates the point of attachment to the compound substituted by the carbonyl substituent. [0028] As used herein, the term “cyano,” refers to the to the substituent , wherein the squiggly line , indicates the point of attachment to the compound substituted by the cyano substituent.

[0029] As used herein, the term “halo,” refers to a substituent selected from a halogen, e.g., F, Cl, Br, or I.

[0030] As used herein, the term “hydroxyl,” refers to the substituent , wherein the squiggly line , indicates the point of attachment to the compound substituted by the carbonyl substituent.

[0031] As used herein, the term “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. Examples of 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.

[0032] As used herein, the term “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. Examples of heterocycloalkyl moieties include, but are not limited to, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, dithiolanyl, oxanyl, and thianyl.

[0033] As used herein, the phrase “five-member ring,” refers to a cyclic monovalent hydrocarbon radical moiety having a total of five atoms in the cyclic moiety.

[0034] As used herein, the phrase “six-member ring,” refers to a cyclic monovalent hydrocarbon radical moiety having a total of six atoms in the cyclic moiety.

[0035] As used herein, the phrase “five-membered aryl,” refers to aryl, as defined above, having a total of five atoms in the cyclic moiety.

[0036] As used herein, the phrase “five-membered cycloalkyl,” refers to cycloalkyl, as defined above, having a total of five atoms in the cyclic moiety. [0037] As used herein, the phrase “five-membered heterocycloalkyl,” refers to heterocycloalkyl, as defined above, having a total of five atoms in the cyclic moiety.

[0038] As used herein, the phrase “five-membered heteroaryl,” refers to heteroaryl, as defined above, having a total of five atoms in the cyclic moiety.

[0039] As used herein, the phrase “six-membered aryl,” refers to aryl, as defined above, having a total of six atoms in the cyclic moiety.

[0040] As used herein, the phrase “six-membered cycloalkyl,” refers to cycloalkyl, as defined above, having a total of six atoms in the cyclic moiety.

[0041] As used herein, the phrase “six-membered heterocycloalkyl,” refers to heterocycloalkyl, as defined above, having a total of six atoms in the cyclic moiety.

[0042] As used herein, the phrase “six-membered heteroaryl,” refers to heteroaryl, as defined above, having a total of six atoms in the cyclic moiety.

[0043] As used herein, 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.

[0044] As used herein, the term “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.

[0045] As used herein, the term “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.

[0046] As used herein, the phrase “therapeutically effective amount,” refers to an amount

(of a compound) that is sufficient to provide a therapeutic benefit to a patient in the treatment or management of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition.

[0047] As used herein, “treating” or “treatment” of hyperhidrosis refers, in certain embodiments, to ameliorating hyperhidrosis that exists in a subject. In some embodiments, “treating” or “treatment” includes ameliorating at least one physical parameter of hyperhidrosis, such as sweating. In some embodiments, “treating” or “treatment” includes modulating the hyperhidrosis. In some embodiments, “treating” or “treatment” includes delaying or preventing the onset of hyperhidrosis (e.g., a prophylactic treatment). In some embodiments, “treating” or “treatment” includes mitigating the incidence of episodes of hyperhidrosis, by periodic administration of a pharmaceutical composition according to the methods provided herein. [0048] The term “substantially free of’ or “substantially in the absence of’ with respect to a composition refers to a 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. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of enantiomers.

[0049] Similarly, 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.

[0050] “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.

[0051] “Isotopic composition” refers to the amount of each isotope present for a given atom, and “natural 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. Unless otherwise designated, 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.

[0052] “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. [0053] “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.

B. COMPOUNDS

[0054] In some embodiments, including any of the foregoing, set forth herein is a compound, or pharmaceutically acceptable salt thereof, having the structure of Formula (I):

[0055] In Formula (I), ring A is selected from cycloalkyl, aryl, heterocycloalkyl, or heteroaryl. In some embodiments, ring A is optionally bridged to ring B. In Formula (I), ring B is selected from cycloalkyl, aryl, heterocycloalkyl, or heteroaryl. In some embodiments, ring B is optionally bridged to ring A. In Formula (I), 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. In certain embodiments, X is O and Y is C=O. In certain other embodiments, X is C=O and Y is O. 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. If 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. In Formula (I), 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. When R ⁵ is absent, the compound is preferably in the form of a pharmaceutically acceptable salt with a pharmaceutically acceptable counter-ion.

[0056] In some embodiments, including any of the foregoing, the compounds having the structure of Formula (I), are selected from Formula (la) or Formula (lb): or

[0057] In some embodiments, including any of the foregoing, Ring A and Ring B are each, independently in each instance, either a five- or six-membered cycloalkyl, aryl, heterocycloalkyl, and heteroaryl. In certain embodiments, Ring A is a five-membered cycloalkyl, aryl, heterocycloalkyl, and heteroaryl. In certain other embodiments, Ring A is a six-membered cycloalkyl, aryl, heterocycloalkyl, and heteroaryl. In certain embodiments, Ring B is a five- membered cycloalkyl, aryl, heterocycloalkyl, and heteroaryl. In certain other embodiments, Ring B is a six-membered cycloalkyl, aryl, heterocycloalkyl, and heteroaryl. In some embodiments, Ring A is a five-membered cycloalkyl. In some other embodiments, Ring A is a five-membered aryl. In yet other embodiments, Ring A is a five-membered heterocycloalkyl. In still other embodiments, Ring A is a five-membered heteroaryl. In some embodiments, Ring A is a six- membered cycloalkyl. In some other embodiments, Ring A is a six-membered aryl. In yet other embodiments, Ring A is a six-membered heterocycloalkyl. In still other embodiments, Ring A is a six-membered heteroaryl. In some embodiments, 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.

[0058] In some embodiments, including any of the foregoing, the compounds having the structure of Formula (I), are selected from Formula (Ic) or Formula (Id): or

In Formula (Ic) or Formula (Id), subscript n is 0 or 1 such that when n is 0, ring B is a five member ring.

[0059] In some embodiments, including any of the foregoing, 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.

[0060] In some embodiments, including any of the foregoing, Ring A and Ring B are not bridged.

[0061] In some embodiments, including any of the foregoing, subscript p is 1 or 2. In some embodiments, subscript p is 1. In some other embodiments, subscript p is 2.

[0062] In some embodiments, including any of the foregoing, subscript q is 1 or 2. In some embodiments, subscript q is 1. In some other embodiments, subscript q is 2.

[0063] In some embodiments, including any of the foregoing, the compounds having the structure of Formula (I), are selected from Formula (Ie) or Formula (If): or

[0064] In some embodiments, including any of the foregoing, the compounds having the structure of Formula (I), are selected from Formula (Ig) or Formula (Hi):

or

[0065] In some embodiments, including any of the foregoing, the compounds having the structure of Formula (I), are selected from Formula (Ii), Formula (Ij), Formula (Ik), Formula (II), Formula (Im) or Formula (In):

or

[0066] In some embodiments, including any of the foregoing, 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):

or

[0067] In some embodiments, including any of the foregoing, R ¹ , R ² , R ³ , and R ⁴ are H. In some embodiments, including any of the foregoing, 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.

[0068] In some embodiments, including any of the foregoing, the compounds having the structure of Formula (I) are selected from Formula (Iw), Formula (lx), Formula (Iy), or Formula

(Iz):

or

[0069] In some embodiments, including any of the foregoing, 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.

[0070] In some embodiments, including any of the foregoing, the compounds having the structure of Formula (I) are selected from:

[0071] In some embodiments, including any of the foregoing, the compounds having the structure of Formula (I) are selected from: or

[0072] It is appreciated that 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).

[0073] Examples of methods to obtain optically active materials are known in the art, and 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 enantiomer; v) chemical asymmetric synthesis - a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomer separations - a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. 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. The desired enantiomer is then released from the diastereomer; viii) 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.

[0074] In some embodiments, provided herein are compositions of a compound that are substantially free of one or more other stereoisomers of that compound. In certain embodiments, the compounds are substantially free of other enantiomers. In some embodiments, 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.

[0075] Also provided herein are isotopically enriched forms of the compounds provided herein. Isotopic enrichment (for example, deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics (“PD”), and 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).

[0076] 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.

[0077] Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect (“KIE”). For example, if a C-H bond is broken during a rate-determining step in a chemical reaction (i.e. the step with the highest transition state energy), substitution of a deuterium for that hydrogen will cause a decrease in the reaction rate and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect (“DKIE”). (See, e.g., Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al, Can. J. Physiol. Pharmacol., vol.

77, pp. 79-88 (1999)).

[0078] 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.

[0079] Tritium (“T”) is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators and radiopharmaceuticals. Tritium is a hydrogen atom that has 2 neutrons in the nucleus and has an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly found as T ₂ O. Tritium decays slowly (half-life = 12.3 years) and emits a low energy beta particle that cannot penetrate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope, yet it must be ingested in large amounts to pose a significant health risk. As compared with deuterium, a lesser amount of tritium must be consumed before it reaches a hazardous level. Substitution of tritium (“T”) for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects. Similarly, 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.

C. PROCESSES FOR MAKING COMPOUNDS

[0080] As described herein, provided herein are all described compounds and all stereoisomeric forms thereof, including racemates, enantiomers, stereoisomers, and all mixtures thereof. 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).

[0081] Certain compounds set forth herein may be prepared by starting with cyclopentyl mandelic acid having an R stereocenter (R-CPMA):

[0082] Certain compounds set forth herein may be prepared by starting with cyclopentyl mandelic acid having an S stereocenter (S-CPMA):

[0083] CPMA is commercially available from a variety of chemical suppliers. For example, a-CPMA can be purchased from Sigma-Aldrich as catalog number 706396.

[0084] CPMA may be prepared according to the processes set forth in US Patent

Application Publication No. 2019-0161443 Al, entitled PROCESSES FOR MAKING, AND METHODS OF USING, GL Y COP YRRONIUM COMPOUNDS, which published May 30, 2019, the entire contents of which are herein incorporated by reference in their entirety for all purpose.

[0085] 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.

[0086] 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. Non- limiting examples of 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. Non-limiting examples of 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.

[0087] CPMA can also be bonded to a halo-acetate with a protected ester moiety in a suitable solvent. Non-limiting examples of 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. Non- limiting examples of solvents include toluene. An example reaction is shown below:

[0088] Additional compounds can be prepared by reacting a diester compound with an amino alcohol in a suitable solvent with CDI. Non-limiting examples of amino alcohol include 2- (dimethylamino)ethan-l-ol. Non-limiting examples of solvents include toluene. Non-limiting examples of a diester compound include 2-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)acetic acid. An example reaction is shown below:

[0089] 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.

D. METHODS FOR USING COMPOUNDS

[0090] In an embodiment, 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. [0091] In another embodiment, 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.

[0092] In some embodiments, including any of the foregoing, 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. In Formula (I), 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. In certain examples, X is O and Y is C=O. In certain other examples, X is C=O and Y is O. 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. In Formula (I), 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. [0093] In some specific embodiments, including any of the foregoing, the compound has a structure selected from the group consisting of:

or

[0094] In some embodiments, including any of the foregoing, the subject in need thereof suffers from a disease or condition which is ameliorated by an anticholinergic.

[0095] In some embodiments, including any of the foregoing, 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.

[0096] In some embodiments, including any of the foregoing, 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. [0097] In some embodiments, including any of the foregoing, the subject is a mammal. In some of these embodiments, the mammal is a human being. a. PHARMACEUTICAL COMPOSITIONS

[0098] In some embodiments, including any of the foregoing, set forth herein is a pharmaceutical composition comprising a compound set forth herein and a pharmaceutically acceptable excipient.

[0099] The present disclosure includes pharmaceutical 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. Examples of 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. [00100] In some embodiments, the topical is selected from a solid stick formulation, a wax, or a deodorant composition.

[00101] In some embodiments, including any of the foregoing, 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.

[00102] In some embodiments, including any of the foregoing, 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. In some embodiments, including any of the foregoing, 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. [00103] In some embodiments, including any of the foregoing, 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. Non-limiting examples of 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.

[00104] When used for the present formulations, the buffering agent may be in the amount of about 0.2 to about 0.5% w/w. In some embodiments, 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.

[00105] In some embodiments, including any of the foregoing, 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.

[00106] In some embodiments, including any of the foregoing, 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.

[00107] In some embodiments, including any of the foregoing, 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.

[00108] In some embodiments, including any of the foregoing, the present formulations may comprise one or more optional additives such as humectants, colorants, perfumes, etc. In practice, 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.

[00109] In some embodiments, the methods provided herein may further comprise administration of one or more additional agents, for instance to treat hyperhidrosis. Illustrative 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.

[00110] In some embodiments, including any of the foregoing, the pharmaceutical compositions set forth herein include more than one anticholinergic agent. In certain embodiments, the anticholinergic agents are selected from a compound set forth herein, propantheline, oxybutynin, methantheline, benztropine, and sofpironium bromide (BBI-4000; Brickell Biotech, Inc.). In some embodiments, the composition comprises a compound set forth herein. In some embodiments, the compound set forth herein is glycopyrronium tosylate. In some embodiments, the compound set forth herein is glycopyrronium bromide. In certain embodiments, the compound is sofpironium bromide.

[00111] In some embodiments, the methods provided herein comprises administering a compound in combination with another agent or procedure. In some aspects, the other agent or procedure is selected from an anticholinergic agent, a metal salt, and a toxin.

[00112] In some embodiments, topical administration of an agent is combined with systemic administration of the same agent, or a different agent. In some aspects, topical administration of a compound set forth herein is combined with systemic administration of the compound. [00113] 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.

[00114] The present disclosure includes pharmaceutical 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. Examples of 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. , human serum albumin), 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.

[00115] The compounds or 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-β-cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof. Other suitable pharmaceutically acceptable excipients are described in “Remington's Pharmaceutical Sciences,” Mack Pub. Co., New Jersey (1991), and “Remington: The Science and Practice of Pharmacy,” Lippincott Williams & Wilkins, Philadelphia, 20th edition (2003) and 21st edition (2005), incorporated herein by reference in its entirety for all purposes.

[00116] 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. Alternatively, 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.

[00117] Pharmaceutical 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. In some examples, the compositions set forth herein are suitable for topical application. In some examples, 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.

[00118] 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. For example, 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. [00119] In certain embodiments, 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. In an embodiment, the compound set forth herein is present at a concentration of about 0.25-20% (w/w). In some embodiments, 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. In an embodiment, the buffering agent of the topical dosage form is citric acid/sodium citrate. In an embodiment, 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. In certain embodiments, the pharmaceutical composition comprises about 105 mg threo glycopyrronium tosylate, citric acid, sodium citrate, ethanol, and water at a pH of about 4.5.

[00120] In certain embodiments, 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.

[00121] In certain embodiments, 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.

[00122] In certain embodiments, 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. b. TOPICALS

[00123] As disclosed in US Patent Application Publication No. 2010/0276329; and US Patent Nos. US 8,618,160; and US 9,006,462, 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. [00124] In some embodiments, including any of the foregoing, 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. By 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. Examples of 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.

[00125] In some embodiments, including any of the foregoing, the topical is an absorbent pad. In such embodiments, such an absorbent pad may contain another topical such as a solution. As used herein, absorbent pads and nonwoven wipes are interchangeable and have the same meaning. In another embodiment, including any of the foregoing, an absorbent pad containing a compound or pharmaceutical composition set forth herein in solution may be used to treat hyperhidrosis. In some other embodiments, including any of the foregoing, 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. Further, pads or wipes containing one or more of a compound or pharmaceutical composition in solution may similarly be used to treat hyperhidrosis in patients. In another embodiment, the pharmaceutically acceptable solution of a compound or pharmaceutical composition set forth herein is a topical.

[00126] 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. For example, 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.

[00127] 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. In some embodiments, 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. In these and other embodiments, the weight ratio of sucrose to a compound set forth herein is about 9:1. In other embodiments, 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. In these and other embodiments, the weight ratio of HPMCAS to a compound set forth herein is about 1:1.

[00128] 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. In some embodiments, such solid dispersions have a glass transition temperature of at least about 30° C, including at least about 40° C. [00129] 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. In some embodiments, 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. Examples of 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.

[00130] 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.

[00131] 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.

[00132] 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.

[00133] 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.

[00134] 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.

[00135] 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.

[00136] In another embodiment, 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. An example of such a cream would be cetomacrogol cream. In another embodiment, the topical is a gel.

[00137] In one embodiment, the topical comprises a compound or composition set forth herein. In some of these embodiments, the topical further comprises buffers and/or may be in an aqueous solution. When buffers are used, said buffers may be, for example, citric acid and sodium citrate. The buffered topical may further comprise an alcohol such as ethanol.

[00138] In another embodiment, 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.

[00139] In another embodiment, the pharmaceutically acceptable solution comprising a compound set forth herein or a solvate thereof is aqueous and further comprises one or more buffers. In many embodiments, the pharmaceutically acceptable solution is aqueous. Examples of 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. In one embodiment of the invention, 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.

[00140] In yet another embodiment, the topical is prepared so as to be film-forming. In such embodiments, a binding agent used. Examples of binding agents include povidones such as povidone K90. Such film-forming solutions further comprise one or more film-forming agents. Examples of film forming agents include butyl esters of a polyvinylmethylether/maleic anhydride acid copolymer. An example of such a film forming agent is the Gantrez™ ES-425 butyl ester copolymer

[00141] In yet another embodiment, the aqueous pharmaceutically acceptable solution is prepared so as to be film-forming. In such embodiments, a binding agent used. Examples of binding agents include povidones such as povidone K90. Such film-forming solutions further comprise one or more film-forming agents. Examples of film forming agents include butyl esters of a polyvinylmethylether/maleic anhydride acid copolymer. An example of such a film forming agent is the Gantrez™ ES-425 butyl ester copolymer.

[00142] In some embodiments, the pharmaceutically acceptable solution is absorbed onto a carrier. For example, such 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.

[00143] According to the present invention, the absorbent pad can be based on cotton fabric or non-cotton fabric. In one embodiment, the absorbent pad is based on synthetic nonwoven fabric, such as nonwoven rayon and polypropylene fabric. In one embodiment, the absorbent pad is a 75:25 rayon and polypropylene pad.

[00144] In some embodiments 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.

[00146] 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. In some embodiments, 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.

[00147] 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. In some embodiments, the compound set forth herein or a solvate thereof to be dissolved is in a crystalline form. In some embodiments, the compound set forth herein or a solvate thereof is in an x-ray amorphous form. In other embodiments, pads containing a pharmaceutically acceptable aqueous solution of a compound set forth herein made by such processes which are provided herein. The wetting may be done while the pad is in a pouch. In many embodiments, the pouch is heat-sealed after wetting. A typical pouch material is laminate containing aluminum foil as a layer.

[00148] In another embodiment, 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.

[00149] The pharmaceutically acceptable solution of a compound set forth herein or a solvate thereof is therapeutically useful. For example, 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. In one embodiment, 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. In one embodiment, 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. In some embodiments, 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. In many embodiments, such administration may be with an absorbent pad. In other embodiments, methods of treating palmar or plantar hyperhidrosis with a compound set forth herein or a solvate thereof are provided. Dosing of a compound set forth herein may be daily. [00150] The compounds set forth herein may be administered as racemic mixtures of stereoisomers. In some embodiments, the compounds set forth herein may be administered as specific stereoisomers. For example, the compound having the structure of Formula (I), may have stereocenters at any one of positions 1, 2, 3, or 4, as labeled below:

[00151] In some embodiments, including any of the foregoing, position 1 is R.

[00152] In some embodiments, including any of the foregoing, position 1 is S.

[00153] In some embodiments, including any of the foregoing, position 2 is R.

[00154] In some embodiments, including any of the foregoing, position 2 is S.

[00155] In some embodiments, including any of the foregoing, position 3 is R.

[00156] In some embodiments, including any of the foregoing, position 3 is S.

[00157] In some embodiments, including any of the foregoing, position 4 is R.

[00158] In some embodiments, including any of the foregoing, position 4 is S.

[00159] In some embodiments, including any of the foregoing, the compounds administered include a mixture of compounds of Formula 1 have R/S configurations at position 1.

[00160] In some embodiments, including any of the foregoing, the compounds administered include a mixture of compounds of Formula 1 have R/S configurations at position 2.

[00161] In some embodiments, including any of the foregoing, the compounds administered include a mixture of compounds of Formula 1 have R/S configurations at position 3. [00162] In some embodiments, including any of the foregoing, the compounds administered include a mixture of compounds of Formula 1 have R/S configurations at position 4.

C. ABSORBENT PAD

[00163] In some embodiments, including any of the foregoing, the compounds and compositions set forth herein are included with an absorbent pad. In one embodiment, the topical is an absorbent pad. In such embodiments, such an absorbent pad may contain another topical such as a solution. As used herein, absorbent pads and nonwoven wipes are interchangeable and have the same meaning. In another embodiment, an absorbent pad containing a compound set forth herein in solution may be used to treat hyperhidrosis. Further, 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.

[00164] In some other embodiments, including any of the foregoing, the compounds and compositions set forth here are included with an absorbent pad. In one embodiment, 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).

D. WIPE

[00165] In some embodiments, including any of the foregoing, the compounds and compositions set forth herein are included with a wipe. In some embodiments, the wipe is a Tudor 6" AP686 69 g/m ² . In some embodiments, the size of the wipe in flat form is about 4"- 6"x3.78"-4". In some embodiments, 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". In some embodiments, the wipe is folded,

1 5"x2"±o 125" or 1.5"xl.875"±0.125". In some embodiments, the wipe has three folds along the long side, then in half across the other orientation during insertion into a laminated pouch. E. POUCH

[00166] In some embodiments, including any of the foregoing, the compounds and compositions set forth herein are included in a pouch. In some embodiments, the pouch is resistant to leakage. In some embodiments, the pouch includes an inner lining of linear low density polyethylene (LLDPE). In some embodiments, the pouch includes as a laminate,

Glenroy: 0.48 mil PET/0.75 mil LDPE/0.285 mil Foil/0.75 mil CRC-1/1.50 mil LLPDEF. The pouch size is not limited. In some embodiments, the pouch has dimensions of 2.375"x3.5"±0.0625".

F. DOSAGES

[00167] In some embodiments, including any of the foregoing, the compounds and compositions set forth herein are effective over a wide dosage range and is generally administered in a therapeutically effective amount. In some embodiments, 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.

G. KITS

[00168] Also provided herein are kits for use in the methods provided herein. In some embodiments, the kit 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.

[00169] In some embodiments, the kit further comprises packaging. In some aspects, 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.

F. EXAMPLES

[00170] The solution NMR spectra were acquired with a Bruker 400 MHz (Model: Neo AV III). Operating mode was Manual and Automation. Probe was BBFO (VTO).

[00171] The samples were prepared by dissolving a small amount of sample in DMSO-ds containing TMS.

[00172] The liquid-chromatography mass spectrometry instrument was an Agilent

Technologies; 1290 Infinity II LC with 6125MSD. Reverse phase. Mobile phase Conditions were as follows:

• 0.1% TFA in milli-Q- water/ Acetonitrile

• lOmM Ammonium acetate in milli-Q- water/ Acetonitrile

• 0.1% Formic acid in milli-Q-water/ Acetonitrile

• lOmM Ammonium bicarbonate in milli-Q- water/ Acetonitrile [00173] The columns used were the following:

• Zorbax Eclipse XDB C18 (50 x 4.6)mm, 3.5 micron

• Zorbax Eclipse C18 (50 x 4.6)mm, 3.5 micron

• BEH C8 (50 x 2.1)mm, 1.7 micron

• Xbridge C8 (50 x 4.6)mm, 3.5 micron

• BEH C18 (50 x 2.1)mm, 1.7 micron

SYNTHESIS EXAMPLE 1

[00174] 2-((diethylglycyl)oxy)ethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate (Compound 106) was synthesized according to a two-step process.

[00175] 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).

[00176] 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).

[00177] LC-MS showed a retention time (RT) of 3.099 minutes (min) when analyzed under the following conditions Column: XBridge C8 (50 X4.6)mm, 3.5μm; Flow Rate: 1.5ml/min; Mobile Phase A : 0.1%FA in water; Mobile Phase B: Acetonitrile (ACN).

[00178] LC-MS showed a retention time (RT) of 1.881 min when analyzed under the following conditions Column: BEH C8 (50x2.1mm)1.7 μm; Mobile phase A: 0.1% TFA in H2OACN (95:5); Mobile phase B: 0.1% TFA in ACN; and Flow Rate: 0.8 ml/min.

[00179] ¹ H NMR (400 MHz, DMSO) δ 10.7 (m, 1H), 7.6 (d; 2H), 7.35 (t; 2H), 7.26 (t, 1H), 5.73 (s, 1H), 4.4(m, 4H), 4.1(s, 2H), 3.4 (m, 4H), 2.9 (m, 1H), 1.6-1.4 (m, 5H), 1.35 (s, 1H), 1.2 (m, 8H).

SYNTHESIS EXAMPLE 2

[00180] 2-(2-(dimethylamino)ethoxy)-2-oxoethyl 2-cyclopentyl-2-hydroxy-2- phenylacetate (Compound 104) was synthesized according to a three-step process.

[00181] 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).

[00182] 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. This produced 8 g of 2-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)acetic acid (MW of 278.30 g/mol; Compound 109).

[00183] 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).

[00184] LC-MS showed a retention time (RT) of 3.013 minutes (min) when analyzed under the following conditions Column: XBridge C8 (50 X4.6)mm, 3.5μm; Flow Rate: 2.0ml/min; Mobile Phase A : 0.1%FA in water; Mobile Phase B: Acetonitrile.

[00185] LC-MS showed a retention time (RT) of 1.798 min when analyzed under the following conditions Column: BEH C8 (50x2. lmm) 1.7 μm; Mobile phase A: 0.1% TFA in H ₂ 0:ACN (95:5); Mobile phase B: 0.1% TFA in ACN; Flow Rate: 0.8 ml/min.

[00186] ¹ H NMR (400 MHz, DMSO) d 10.9 (m, 1H), 7.6 (m; 2H), 7.35 (t; 2H), 7.26 (t,

1H), 5.8 (s, 1H), 4.8 (m, 2H), 4.4(m, 2H), 3.3 (m, 2H), 2.9 (m, 1H), 2.75 (m, 6H), 1.7 - 1.1 (m, 8 H).

SYNTHESIS EXAMPLE 3

[00187] 2-(2-(diethylamino)ethoxy)-2-oxoethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate (Compound 103) was synthesized in a one-step process.

[00188] 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. This produced the title compound as a racemic mixture (MW = 364.21 g/mol as tosylate salt; 171.01 g/mol exact mass of tosylate counter-ion) [00189] The starting reagent, 2-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)acetic acid, can be made according to steps 1 and 2 of SYNTHETIC EXAMPLE 2. [00190] 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, 3.5μm; Mobile phase: A:0.1% TFA in water; Mobile phase:B:0.1%TFA in ACN; Flow:2.0mL/min.

[00191] LC-MS showed a retention time (RT) of 1.795 min when analyzed under the following conditions Column: BEH C8 (50x2.1mm)1.7 μm; Mobile phase A: 0.1% TFA in H ₂ 0:ACN (95:5); Mobile phase B: 0.1% TFA in ACN; Flow Rate: 0.8 ml/min.

[00192] ¹ H NMR (400 MHz, DMSO) δ 7.6 (d; 2H), 7.48 (d, 2H), 7.35 (t; 2H), 7.26 (t, 1H), 7.1 (d, 2H), 5.8 (s, 1H), 4.8(t, 2H), 4.5(s, 2H), 3.6 (m, 2H), 3.15-3.05 (m, 9H), 2.9-2.8 (m, 1H), 1.6-1.4 (m, 5H), 1.3 - 1.1. (m, 2H).

SYNTHESIS EXAMPLE 4

[00193] 2-(2-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)acetoxy)-N,N,N -trimethylethan-

1-aminium tosylate (Compound 101) was prepared according to a one-step reaction, by starting with the product from SYNETHIC EXAMPLE 2.

[00194] The product from SYNETHIC EXAMPLE 2 - 2-(2-(dimethylamino)ethoxy)-2- oxoethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate - was synthesized according to the three-step process in SYNTHETIC EXAMPLE 2.

[00195] Next, 2-(2-(dimethylamino)ethoxy)-2-oxoethyl 2-cyclopentyl-2-hydroxy-2- phenylacetate was reacted with methyl 4-methylbenzenesulfonate in toluene for about 2 h at 25 °C. This produced racemic 2-(2-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)acetoxy)-N,N,N - trimethylethan-l-aminium tosylate (MW of 535.65 g/mol) [also known as: 2-(2-(2-cyclopentyl-

2-hydroxy-2-phenylacetoxy)acetoxy)-N,N,N-trimethylethan-1 -aminium 4- methylbenzenesulfonate]. This reaction is illustrated below: SYNTHESIS EXAMPLE 5

[00196] 2-((dimethylglycyl)oxy)ethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate (Compound 105) was prepared according to a two-step process.

[00197] 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.

[00198] 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.

[00199] LC-MS showed a retention time (RT) of 3.343 minutes (min) when analyzed under the following conditions Column: X-Bridge C8(50X4.6)mm, 3.5μm; Mobile phase: A:0.1% TFA in water; Mobile phase: B: 0.1% TFA in ACN; Flow:2.0mL/min.

[00200] LC-MS showed a retention time (RT) of 1.813 min when analyzed under the following conditions Column: BEH C8 (50x2.1mm)1.7 μm; Mobile phase A: 0.1% TFA in H ₂ 0:ACN (95:5); Mobile phase B: 0.1% TFA in ACN; Flow Rate: 0.8 ml/min..

[00201] ¹ H NMR (400 MHz, DMSO) δ 10.8 (m, 1H), 7.6 (d; 2H), 7.35 (t, 2H), 7.25 (t;

1H), 7.26 (t, 1H), 5.7 (s, 1H), 4.8(m, 4H), 4.15(s, 2H), 2.9-2.8 (m, 7H), 1. 6 - 1.1. (m, 8H).

SYNTHESIS EXAMPLE 6

[00202] 2-(2-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)acetoxy)-N,N-d iethyl-N- methylethan-l-aminium tosylate (Compound 102) was prepared according to a one-step reaction, by starting with the product from SYNETHIC EXAMPLE 3 with diethyl amino replacing dimethyl amino.

[00203] The product from SYNETHIC EXAMPLE 3 - 2-(2-(diethylamino)ethoxy)-2- oxoethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate - was synthesized according to the three-step process in SYNTHETIC EXAMPLE 3.

[00204] Next, 2-(2-(diethylamino)ethoxy)-2-oxoethyl 2-cyclopentyl-2-hydroxy-2- phenylacetate was reacted with methyl 4-methylbenzenesulfonate in toluene for about 2 h at 25 °C. This produced racemic 2-(2-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)acetoxy)-N,N- diethyl-N-methylethan-l-aminium tosylate (MW of 563.26 g/mol) [also known as: 2-(2-(2- cyclopentyl-2-hydroxy-2-phenylacetoxy)acetoxy)-N,N-diethyl-N -methylethan-1-aminium 4- methylbenzenesulfonate]. This reaction is illustrated below:

[00205] LC-MS showed a retention time (RT) of 1.920 minutes (min) when analyzed under the following conditions Column: BEH C8 (50x2.1mm)1.7 μm; Mobile phase A: 0.1% TFA in H ₂ 0:ACN (95:5); Mobile phase B: 0.1% TFA in ACN; Flow Rate: 0.8 ml/min.

[00206] LC-MS showed a retention time (RT) of 3.697 min when analyzed under the following conditions Column: X-Bridge C8(50X4.6)mm,3.5μm; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in ACN; Flow: 2.0mL/min.

[00207] ¹ H NMR (400 MHz, DMSO) δ 7.6 (d; 2H), 7.45 (d, 2H), 7.35 (t; 2H), 7.25 (t, 1H), 7.1 (d, 2H), 5.8 (s, 1H), 4.75 (t, 2H), 4.5(s, 2H), 3.55 (s, 2H), 3.4 - 3.3 (m, 4H), 2.9-2.8 (m, 3H), 2.3 (S, 3H), 1.7 - 1.1. (m, 14H).

BIOLOGICAL EXAMPLE 1 - POTENCY STUDY [00208] This Example studied the Muscarinic acetylcholine receptor M3 affinity of various compounds set forth herein, including cyclopentyl mandelic acid (CPMA). See Table 1 below. [00209] 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.

[00210] A flow chart for the M3 induced calcium immobilization assay (FLIPR) screening is shown in FIG. 1.

[00211] 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.

[00212] 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. For agonist stimulation, an EC ₈₀ concentration of agonist (e.g., carbachol) was used before the signal for calcium mobilization was recorded using FLIPR. The screening parameters used for the testing purpose were as follows.

[00213] Calcium Mobilization Assay-FLIPR: 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 μM. The screening format included a 10-point IC50 determination in triplicates.

[00214] Replicates: Triplicates (n=3); Number of Runs: One (N=1).

[00215] Controls included: positive control/“PC”: cells with buffer + fixed concentration of stimulant M3; negative control/“NC”: cells with buffer alone (no compound, no stimulant). A reference antagonist (e.g., atropine) was used. Fluorescence was used to detect calcium-5 or calcium-6 using a Molecular Devices FLIPR- TETRA detection instrument.

[00216] The reference agonist was Carbachol. [00217] 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.

[00218] The screening concentration was 10 μM.

[00219] The dilution was 10 fold.

[00220] The data was analyzed by Microsoft Excel and/or using GraphPad Prism. Each data point represented mean+7- standard deviation (SD) or SEM of three replicates from a single or different experiments respectively. Any replicate data serving as potential or farthest outlier was removed from the analysis using Grubb's rule.

[00221] IC ₅₀ values were determined. The results are shown in FIGs. 1-7 and summarized in Table 1.

[00222] The results herein show no activity for the metabolite, i.e., CPMA. The IC ₅₀ for CPMA was observed to be greater than 3,000 nM. However, other new compounds herein which were tested demonstrated IC ₅₀ values in the 20-100 nM range. These results are to be contrasted with the sofpironium compound where the “inactive metabolite” is only five fold less active than the active parent.

[00223] These results demonstrated that 2R-SGA has the potential to contribute to the systemic side effect profile observed clinically.

BIOLOGICAL EXAMPLE 2 - PLASMA STABILITY STUDY

[00224] Analysis was done using fit-for-purpose discovery grade LC-MS/MS method. [00225] The objective of this study was to evaluate stability of test compound in plasma at 37°C at different time points up to 120 minutes. This was accomplished by spiking DMSO solution of test compound to a final concentration of 1 μM in plasma and incubate at 37°C up to 120 minutes. At different time-points, aliquots were collected and precipitated with acetonitrile containing an internal standard. After removing precipitated protein by brief centrifugation, supernatant samples were analyzed by LC-MS/MS.

[00226] Human plasma male pooled K2-EDTA (Product Number- HUMANPLK21 805303 from BIOIVT, USA) was used in this Example. [00227] SD rat plasma male pooled K2-EDTA (Product Number -RAT00PLK2MNN from Bioreclamation IVT) was used in this Example.

[00228] Dimethyl Sulfoxide (Sigma, Cat No. 34869) was used in this Example.

[00229] Procaine (Sigma, Cat No. P9879) was used in this Example.

[00230] Flumazenil (Sigma, Cat No F6300) was used in this Example.

[00231] Propantheline Bromide (Sigma Cat No.P8891-5G ) was used in this Example. [00232] Acetonitrile (MERCK, Cat No DE8DF68607) was used in this Example.

[00233] Tolbutamide (FLUKA, Cat No T0891) was used in this Example.

[00234] Stock preparation for test & reference compounds were made. 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 100μM were prepared by dilution 1 mM stock solution 1:10 v/v with DMSO.

[00235] Test compound (4pL of IOOμM DMSO stock solution) were added to 396pL of selected matrix. Final concentration of test compound in the assay was 1 μM and final organic (DMSO) content in the assay was 1%. Assay was performed in duplicates (n=2).

[00236] 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.

[00237] For zero minute controls (100%), 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.

[00238] Reference compounds known to undergo hydrolysis in plasma were included as quality controls.

[00239] Assay matrix, time points and reference compounds employed in the stability assays were as follows:

[00240] Typical analytical conditions varied depending on test compound

[00241] Chromatographic Conditions included a Triple Quad 4500 LC-MS/MS, with the following settings:

Software: Analyst Version 1.6.3

Column: Kinetex Cl 830*4.6 mm, 5m

Column Oven : 40°C

Mode : ESI Positive/Negative

Injection volume: 5 pL

Flow Rate: 800 pL/min

Method: Gradient

Composition: A) 0.1% Formic acid in Water

B) 0.1% Formic acid in acetonitrile

[00242] Stability was calculated using the following formulae:

PCR = Percent parent compound remaining; n= specific time-point

The results of the human plasma stability are shown in FIG. 9.

CHEMISTRY MANUFACTURING AND CONTROLS (CMC) EXAMPLE 1 -

STABILITY IN VEHICLE STUDY

[00243] This Example examined the solubilization capacity of different excipients for a set of compounds.

[00244] 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.

[00246] Aliquots of 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.

[00247] The results are summarized in Table 1.

Table 1 - Biological Example Results

[00248] The embodiments and examples described above are intended to be merely illustrative and non-limiting. Those skilled in the art will recognize or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials and procedures. All such equivalents are considered to be within the scope and are encompassed by the appended claims.