WO2017070235A1

WO2017070235A1 - Antitussive compositions and methods

Info

Publication number: WO2017070235A1
Application number: PCT/US2016/057747
Authority: WO
Inventors: Jing Liang; Peter Dicpinigaitis; Brendan Canning
Original assignee: Attenua, Inc.
Priority date: 2015-10-19
Filing date: 2016-10-19
Publication date: 2017-04-27

Abstract

Disclosed herein are compositions and methods based on agmatine and agmatine derivatives that are useful in the suppression of cough.

Description

ANTITUSSIVE COMPOSITIONS AND METHODS

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims the benefit of priority of United States provisional application Serial No. : 62/243,362, filed on October 19^th, 2015, the contents of which are hereby incorporated by reference.

BACKGROUND OF THE DISCLOSURE

[002] The present disclosure relates to new antitussive compositions, and their methods of use.

[003] Cough is the most common symptom for which patients seek medical advice from primary health care providers. Current antitussive therapies are minimally effective and have side effects that limit their utility. In the United States alone, over 2 billion dollars are spent annually on over the counter cough remedies with questionable efficacy, potential toxicity, and abuse potential, and billions more are spent annually in sick days and doctor's visits. Cough is the primary mechanism of transmission of airborne infections, including all forms of influenza, tuberculosis and Bordetella pertussis, the gram negative bacterium causing whooping cough. As such, cough represents a major public health issue that is poorly treated with currently existing therapies. Currently existing cough medications include dextromethorphan and codeine. However, these medications afford limited efficacy effects in clinical trials with significant side effects and are not suitable for chronic use. People suffering from coughing generally take throat lozenges, cough syrups, and cough drops containing these medications for symptomatic relief. While such medications presently exist, there is room for significant improvement in the efficacy of these treatments. Thus, there is a need for new antitussive compositions that are efficacious.

BRIEF SUMMARY OF THE DISCLOSURE

[004] In certain embodiments of the present disclosure, compounds have structural Formula I:

or a salt, ester, or prodrug thereof, wherein: Ri and R₄ are independently selected from H, alkyl, aryl, carboxy, cycloalkyl, and heteroaryl, and is optionally substituted with 1, 2, or 3 Rs groups, or

Ri and R₄, together with the intervening atoms, form a 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl ring, and is optionally substituted with 1, 2, or 3 R₆ groups;

R₂ and R₃ are independently selected from H, alkoxy, alkyl, aryl, carboxy, cyano, cycloalkyl, cycloalkoxy, halo, heteroaryl, and nitro, and is optionally substituted with 1, 2, or 3 R₆ groups, or

R₂ and R₃, together with the intervening atoms, form a 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl ring, and is optionally substituted with 1, 2, or 3 Re groups;

Rs and R₆ are independently selected from alkoxy, alkyl, amino, cyano, carboxy, halo, nitro, and hydroxy.

[005] Certain compounds disclosed herein possess useful antitussive activity, and may be used in the treatment or prophylaxis of cough. Thus, in broad aspect, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of cough.

[006] In certain embodiments, at least one of Ri, R₂, R₃, and R₄ is not hydrogen.

[007] In certain embodiments, Ri and R₄ are both hydrogen.

[008] In certain embodiments, R₂ and R₃ are both hydrogen.

[009] In certain embodiments, neither of Ri and R₄ is hydrogen.

[010] In certain embodiments, neither of R₂ and R₃ is hydrogen.

[011] In certain embodiments, Ri and R₄ are identical substituents.

[012] In certain embodiments, R₂ and R₃ are identical substituents.

[013] In certain embodiments, Ri and R₄ are independently selected from Ci-₄alkyl, aryl, and

[014] In certain embodiments, R₂ and R₃ are independently selected from Ci-₄alkyl, aryl, and

[015] In certain embodiments, Ri and R₄ are independently selected from C₂-₄alkyl, aryl, and heteroaryl. [016] In certain embodiments, R2 and R3 are independently selected from C2-4alkyl, aryl, and heteroaryl.

[017] In certain embodiments, Ri and R₄, together with the intervening atoms, form a 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl ring, and is optionally substituted with 1, 2, or 3 R₆ groups.

[018] In certain embodiments, R2 and R3, together with the intervening atoms, form a 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl ring, and is optionally substituted with 1, 2, or 3 R₆ groups.

[019] In certain embodiments, R5 and R₆ are independently selected from Ci-₄alkoxy and Ci- ₄alkyl.

BRIEF DESCRIPTION OF THE DRAWINGS

[020] FIG. 1. FIG. l shows the cumulative numbers of coughs in response to citric acid aerosols (0.01-0.3M) in control animals compared with increasing doses of agmatine, administered intraperitoneally. Compared to controls 100 mg/kg and 30 mg/kg agmatine both significantly reduced the cumulative number of coughs evoked by citric acid (p<0.02).

DETAILED DESCRIPTION OF THE DISCLOSURE

Definitions

[021] To facilitate understanding of the disclosure, a number of terms and abbreviations as used herein are defined below as follows:

[022] When introducing elements of the present disclosure or the preferred embodiment s) thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[023] The term "and/or" when used in a list of two or more items, means that any one of the listed items can be employed by itself or in combination with any one or more of the listed items. For example, the expression "A and/or B" is intended to mean either or both of A and B, i.e. A alone, B alone or A and B in combination. The expression "A, B and/or C" is intended to mean A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination or A, B, and C in combination. [024] When ranges of values are disclosed, and the notation "from m ... to n₂" or "between ni ... and n₂" is used, where m and m are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range "from 2 to 6 carbons" is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range "from 1 to 3 μΜ (micromolar)," which is intended to include 1 μΜ, 3 μΜ, and everything in between to any number of significant figures (e.g., 1.255 μΜ, 2.1 μΜ, 2.9999 μΜ, etc.).

[025] The term "about," as used herein, is intended to qualify the numerical values that it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term "about" should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

[026] The term "alkoxy," as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

[027] The term "alkyl," as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, the alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, the alkyl will comprise from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like. The term "alkylene," as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term "alkyl" may include "alkylene" groups.

[028] The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, Ν,Ν-ethylmethylamino and the like. [029] The term "alkylidene," as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

[030] The term "alkylthio," as used herein, alone or in combination, refers to an alkyl thioether (R-S-) radical wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

[031] The term "alkynyl," as used herein, alone or in combination, refers to a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, the alkynyl comprises from 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C: : :C- -C≡C- ). Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-l-yl, butyn-2- yl, pentyn-l-yl, 3-methylbutyn-l-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term "alkynyl" may include "alkynylene" groups.

[032] The terms "amido" and "carbamoyl" as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa. The term "C-amido" as used herein, alone or in combination, refers to a -C(0)N(RR') group with R and R' as defined herein or as defined by the specifically enumerated "R" groups designated. The term "N-amido" as used herein, alone or in combination, refers to a RC(0)N(R')- group, with R and R' as defined herein or as defined by the specifically enumerated "R" groups designated. The term "acylamino" as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CH3C(0) H-).

[033] The term "amino," as used herein, alone or in combination, refers to— NRR', wherein R and R' are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may combine to form heterocycloalkyl, either of which may be optionally substituted. [034] The term "aryl," as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together.

The term "aryl" embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.

[035] The term "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.

[036] The term "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.

[037] The term "arylalkyl" or "aralkyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.

[038] The term "arylalkynyl" or "aralkynyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.

[039] The term "arylalkanoyl" or "aralkanoyl" or "aroyl," as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2- naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

[040] The term aryloxy as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.

[041] The terms "benzo" and "benz," as used herein, alone or in combination, refer to the divalent radical C₆H4= derived from benzene. Examples include benzothiophene and benzimidazole.

[042] The term "biaryl," as used herein, refers to a first aryl group attached to the parent molecular moiety, with the first aryl group substituted with a second aryl group. Examples of biaryl groups include biphenyl, 2-(2-pyridyl)phenyl, and 5-(2-naphthyl)-thien-l-yl.

[043] The term "carbamate," as used herein, alone or in combination, refers to an ester of carbamic acid (- HCOO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.

[044] The term "O-carbamyl" as used herein, alone or in combination, refers to a -OC(0) RR', group-with R and R' as defined herein.

[045] The term "N-carbamyl" as used herein, alone or in combination, refers to a ROC(0) R'- group, with R and R' as defined herein. [046] The term "carbonyl," as used herein, when alone includes formyl [-C(0)H] and in combination is a -C(O)- group.

[047] The term "carboxyl" or "carboxy," as used herein, refers to -C(0)OH or the corresponding "carboxylate" anion, such as is in a carboxylic acid salt. An "O-carboxy" group refers to a RC(0)0- group, where R is as defined herein. A "C-carboxy" group refers to a - C(0)OR groups where R is as defined herein.

[048] The term "cyano," as used herein, alone or in combination, refers to -CN.

[049] The term "cycloalkyl," or, alternatively, "carbocycle," as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. In certain embodiments, the cycloalkyl will comprise from 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-lH-indenyl, adamantyl and the like. "Bicyclic" and "tricyclic" as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multi centered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[l, l, l]pentane, camphor, adamantane, and bicyclo[3,2, l]octane.

[050] The term "ester," as used herein, alone or in combination, refers to a carboxy group bridging two moieties linked at carbon atoms.

[051] The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties linked at carbon atoms.

[052] The term "halo," or "halogen," as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.

[053] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[054] The term "haloalkyl," as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethyl ene

(-CFH-), difluoromethylene (-CF₂ -), chloromethylene (-CHC1-) and the like.

[055] The term "heteroalkyl," as used herein, alone or in combination, refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH2-

[056] The term "heteroaryl," as used herein, alone or in combination, refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom selected from the group consisting of O, S, and N. In certain embodiments, the heteroaryl will comprise from 5 to 7 carbon atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like. [057] The terms "heterocycloalkyl" and, interchangeably, "heterocycle," as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each the heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur In certain embodiments, the hetercycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, the hetercycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, the hetercycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, the hetercycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, the hetercycloalkyl will comprise from 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3- dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited.

[058] The term "hydrazinyl" as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -N-N-.

[059] The term "hydroxy," as used herein, alone or in combination, refers to -OH.

[060] The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.

[061] The term "imino," as used herein, alone or in combination, refers to =N-

[062] The term "iminohydroxy," as used herein, alone or in combination, refers to =N(OH) and =N-0-.

[063] The phrase "in the main chain" refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of any one of the formulas disclosed herein.

[064] The term "isocyanato" refers to a -NCO group. [065] The term "isothiocyanato" refers to a -NCS group.

[066] The phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.

[067] The term "lower," as used herein, alone or in a combination, where not otherwise specifically defined, means containing from 1 to and including 6 carbon atoms.

[068] The term "lower aryl," as used herein, alone or in combination, means phenyl or naphthyl, either of which may be optionally substituted as provided.

[069] The term "lower heteroaryl," as used herein, alone or in combination, means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four the members may be heteroatoms selected from the group consisting of O, S, and N, or 2) bicyclic heteroaryl, wherein each of the fused rings comprises five or six ring members, comprising between them one to four heteroatoms selected from the group consisting of O, S, and N.

[070] The term "lower cycloalkyl," as used herein, alone or in combination, means a monocyclic cycloalkyl having between three and six ring members. Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[071] The term "lower heterocycloalkyl," as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring members, of which between one and four may be heteroatoms selected from the group consisting of O, S, and N. Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls may be unsaturated.

[072] The term "lower amino," as used herein, alone or in combination, refers to— RR', wherein R and R' are independently selected from the group consisting of hydrogen, alkyl, and lower heteroalkyl, any of which may be optionally substituted. Additionally, the R and R' of a lower amino group may combine to form a five- or six-membered heterocycloalkyl, either of which may be optionally substituted.

[073] The term "mercaptyl" as used herein, alone or in combination, refers to an RS- group, where R is as defined herein.

[074] The term "nitro," as used herein, alone or in combination, refers to -NO2.

[075] The terms "oxy" or "oxa," as used herein, alone or in combination, refer to -0-.

[076] The term "oxo," as used herein, alone or in combination, refers to =0. [077] The term "perhaloalkoxy" refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.

[078] The term "perhaloalkyl" as used herein, alone or in combination, refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.

[079] The terms "sulfonate," "sulfonic acid," and "sulfonic," as used herein, alone or in combination, refer the -SO3H group and its anion as the sulfonic acid is used in salt formation.

[080] The term "sulfanyl," as used herein, alone or in combination, refers to -S-.

[081] The term "sulfinyl," as used herein, alone or in combination, refers to

-S(O)-.

[082] The term "sulfonyl," as used herein, alone or in combination, refers to -S(0)₂- [083] The term "N-sulfonamido" refers to a RS(=0)₂ R'- group with R and R' as defined herein.

[084] The term "S-sulfonamido" refers to a -S(=0)₂ RR', group, with R and R' as defined herein.

[085] The terms "thia" and "thio," as used herein, alone or in combination, refer to a -S- group or an ether wherein the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.

[086] The term "thiol," as used herein, alone or in combination, refers to an -SH group.

[087] The term "thiocarbonyl," as used herein, when alone includes thioformyl -C(S)H and in combination is a -C(S)- group.

[088] The term "N-thiocarbamyl" refers to an ROC(S) R'- group, with R and R' as defined herein.

[089] The term "O-thiocarbamyl" refers to a -OC(S) RR', group with R and R'as defined herein.

[090] The term "thiocyanato" refers to a -CNS group.

[091] The term "trihalomethanesulfonamido" refers to a X3CS(0)₂ R- group with X is a halogen and R as defined herein.

[092] The term "trihalomethanesulfonyl" refers to a X₃CS(0)₂- group where X is a halogen.

[093] The term "trihalomethoxy" refers to a X3CO- group where X is a halogen.

[094] The term "tri substituted silyl," as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Examples include trimethysilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.

[095] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

[096] When a group is defined to be "null," what is meant is that the group is absent.

[097] The term "optionally substituted" means the anteceding group may be substituted or unsubstituted. When substituted, the substituents of an "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, alkylamino, arylamino, amido, nitro, thiol, alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, tri substituted silyl, N₃, SH, SCH3, C(0)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethyl enedioxy. An optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH2CF3). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, "optionally substituted with." [098] The term R or the term R', appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether an R group has a number designation or not, every R group, including R, R' and Rn where n = (1, 2, 3, ...n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as -C(0)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen.

[099] Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral carbon atom. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this disclosure.

[0100] Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms. [0101] The term "bond" refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.

[0102] The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0103] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint.

[0104] The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

[0105] As used herein, reference to "treatment" of a patient is intended to include prophylaxis. Treatment may also be preemptive in nature, i.e., it may include prevention of disease. Prevention of a disease may involve complete protection from disease, for example as in the case of prevention of infection with a pathogen, or may involve prevention of disease progression. For example, prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease to a clinically significant or detectable level. Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease.

[0106] The term "patient" is generally synonymous with the term "subject" and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human. [0107] The urge-to-cough (UTC) refers to the sensation of irritation that precedes the motor act of coughing.

[0108] The compounds disclosed herein can exist as therapeutically acceptable salts. The present disclosure includes compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0109] The term "therapeutically acceptable salt," as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, di gluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p- tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0110] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, Ν,Ν-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzyl amine, N,N- dibenzylphenethylamine, 1-ephenamine, and Ν,Ν'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0111] A salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.

Agmatine

[0112] Agmatine, (4-aminobutyl)guanidine, is a naturally occurring substance that is formed from the amino acid arginine. Agmatine is synthesized from arginine by arginine decarboxylase. Agmatine is widely distributed in the body. In the brain, agmatine is stored into vesicles and released on the firing of neurons. Agmatine is localized to nerve terminals in the spinal cord and its release can be evoked by capsaicin. Agmatine interacts with multiple neuronal targets and receptors.

[0113] Agmatine has implicated as having activity in various biochemical pathways, including the modulation of nitric oxide formation, Ca²⁺ channels, including NMDA receptors, K⁺ channels, serotonin reuptake pathways, imidazoline receptors, and baroreceptors.

[0114] Agmatine is biologically active with effects in the brain, kidney, stomach and cardiovascular system. Agmatine has been demonstrated to possess antidepressant, antiretinopathic, neuroprotective, antinociceptive, and antihyperalgesic activity. Agmatine is used safely and extensively as a nutritional supplement, and is marketed as a neurally active therapeutic.

[0115] Agmatine is well tolerated and provides partial pain relief in humans. Agmatine has been further shown to have activity in opiate addiction, memory loss, morphine-induced locomotion sensitization, neural discharge, allodynia, prostate contractility, and locomotor function. Agmatine has been cited as influencing levels of T F-α, nitric oxide, and clonidine.

[0116] Provided is an antitussive composition comprising agmatine and derivatives of atmatine.

[0117] Ligands for Agmatine Receptor/ Channel Targets Prevent Coughing in Animals: Imidazoline/ a.2 Adrenergic Receptor Agonists.

[0118] Ligands for Agmatine Receptor/ Channel Targets Inhibit Coughing In Humans: Imidazoline/ a.2 Adrenergic Receptor Agonists.

[0119] Ligands for Agmatine Receptor/ Channel Targets Inhibit Coughing In Animals and Humans: MDA Receptor/ Channel Blockers.

[0120] Ligands for Agmatine Receptor/ Channel Targets Inhibit Coughing In Animals and Humans: NO Synthase Inhibitors.

[0121] Agmatine inhibits citric acid evoked coughing in awake guinea pigs.

[0122] The agmatine may be present in the form of their pharmaceutically acceptable salts, such as, but not limited to, an acid salt such as acetates, tartrates, chloride, phosphate, sulfates, sulfites, carbonates, bicarbonate and citrates.

Additional Antitussives

[0123] In certain embodiments, the antitussive composition comprises an additional antitussive chosen from ambroxol, apomorphine hydrochloride, beechwood creosote, benzonatate, camphor ethanedi sulfonate, caramiphen edisylate, carbetapentane citrate, chlophendianol hydrochloride, codeine, codeine phosphate, codeine sulfate, dextromethorphan, dextromethorphan hydrobromide, diphenhydramine, diphenhydramine hydrochloride, fentanyl, fentanyl citrate, hydrocodone, hydromorphone hydrochloride, levorphanol tartrate, menthol, methadone hydrochloride, morphine, morphine sulfate, nicotine, noscapine, noscapine hydrochloride, oxycodone hydrochloride, and oxymorphone hydrochloride.

Expectorants

[0124] In certain embodiments, the antitussive composition comprises an expectorant chosen from acetylcysteine, ammonium carbonate, ammonium chloride, antimony potassium tartrate, glycerin, guaifenesin, potassium iodide, sodium citrate, terpin hydrate, tolu balsam. Mucolytics

[0125] In certain embodiments, the antitussive composition comprises a mucolytic chosen from acetylcysteine, ambroxol, bromhexine, carbocisteine, domiodol, dornase alfa, eprazinone, erdosteine, letosteine, mesna, neltenexine, sobrerol, stepronin, and tiopronin.

Nasal Decongestants

[0126] In certain embodiments, the antitussive composition comprises a nasal decongestant chosen from ephedrine, ephedrine hydrochloride, ephedrine sulfate, epinephrine bitartrate, hydroxyamphetamine hydrobromide, mephentermine sulfate, methoxamine hydrochloride, naphazoline hydrochloride, oxymetalozine hydrochloride, phenylpropanolamine hydrochloride, propylhexedrine, psuedoephedrine hydrochloride, tetrahydrozoline hydrochloride, and xylometazoline hydrochloride.

Antihistamines

[0127] In certain embodiments, the antitussive composition comprises an antihistamine chosen from antazoline, azatadine, brompheniramine, brompheniramine mepyramine, carbinoxamine, chlorcyclizine, chlorpheniramine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine, diphenhydramine, doxylamine, doxylamine, hydroxyzine, ketotifen, meclizine, pheniramine, promethazine, trimeprazine, and triprolidine.

Opioid A nalgesics

[0128] In certain embodiments, the antitussive composition comprises an opioid analgesic chosen from codeine, diphenoxylate, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, and propoxyphene.

Non-opioid Analgesics

[0129] In certain embodiments, the antitussive composition comprises a non-opioid analgesic is chosen from acetaminophen, aspirin, ibuprofen and naproxen.

Pharmaceutical Compositions

[0130] While it may be possible for the agmatine of the subject disclosure to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0131] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the subject disclosure or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0132] Antitussive compositions described herein can be administered as follows:

Oral

[0133] The compounds of the present disclosure may be administered orally, including swallowing, so the compound enters the gastrointestinal tract, or is absorbed into the blood stream directly from the mouth, including sublingual or buccal administration.

[0134] Suitable compositions for oral administration include solid formulations such as tablets, pills, cachets, lozenges, gums and hard or soft capsules, which can contain liquids, gels, powders, or granules. [0135] In a tablet or capsule dosage form the amount of drug present may be from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight of the dosage form.

[0136] In addition, tablets or capsules may contain a disintegrant, comprising from about 0.5% to about 35%) by weight, more typically from about 2% to about 25% of the dosage form. Examples of disintegrants include methyl cellulose, sodium or calcium carboxymethyl cellulose, croscarmellose sodium, polyvinylpyrrolidone, hydroxypropyl cellulose, starch and the like.

[0137] Suitable binders, for use in a tablet, include gelatin, polyethylene glycol, sugars, gums, starch, hydroxypropyl cellulose and the like. Suitable diluents, for use in a tablet, include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol and starch.

[0138] Suitable surface active agents and glidants, for use in a tablet or capsule, may be present in amounts from about 0.1% to about 3% by weight, and include polysorbate 80, sodium dodecyl sulfate, talc and silicon dioxide.

[0139] Suitable lubricants, for use in a tablet or capsule, may be present in amounts from about 0.1%) to about 5%) by weight, and include calcium, zinc or magnesium stearate, sodium stearyl fumarate and the like.

[0140] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with a liquid diluent. Dyes or pigments may be added to tablets for identification or to characterize different combinations of active compound doses.

[0141] Liquid formulations can include emulsions, solutions, syrups, elixirs and suspensions, which can be used in soft or hard capsules. Such formulations may include a pharmaceutically acceptable carrier, for example, water, ethanol, polyethylene glycol, cellulose, or an oil. The formulation may also include one or more emulsifying agents and/or suspending agents.

[0142] Compositions for oral administration may be formulated as immediate or modified release, including delayed or sustained release, optionally with enteric coating. Topical

[0143] Compounds of the present disclosure may be administered topically (for example to the skin, mucous membranes, ear, nose, or eye) or transdermally. Formulations for topical administration can include, but are not limited to, lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches and the like. Carriers that are pharmaceutically acceptable for topical administration formulations can include water, alcohol, mineral oil, glycerin, polyethylene glycol and the like. Topical administration can also be performed by, for example, electroporation, iontophoresis, phonophoresis and the like.

[0144] Typically, the active ingredient for topical administration may comprise from 0.001% to 10%) w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10%> w/w; less than 5% w/w; from 2% w/w to 5% w/w; or from 0.1%> to 1%> w/w of the formulation.

[0145] Compositions for topical administration may be formulated as immediate or modified release, including delayed or sustained release.

Rectal, Buccal, and Sublingual

[0146] Suppositories for rectal administration of the compounds of the present disclosure can be prepared by mixing the active agent with a suitable non-irritating excipient such as cocoa butter, synthetic mono-, di-, or triglycerides, fatty acids, or polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature, and which will therefore melt in the rectum and release the drug.

[0147] For buccal or sublingual administration, the compositions may take the form of disintegrating tablets, fast melting strips, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

Inhaled

[0148] For administration by inhalation, compounds may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray or powder. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the disclosure may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

[0149] Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the disclosure may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. Preferred unit dosage formulations are those containing an effective dose, as herein recited, or an appropriate fraction thereof, of the active ingredient. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. In addition, the route of administration may vary depending on the condition and its severity. The above considerations concerning effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3^rd Ed.), American Pharmaceutical Association, Washington, 1999.

Methods of Using the Compounds and/or Pharmaceutical Compositions

[0150] Provided is a method of suppressing cough in subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of the antitussive composition as described herein.

[0151] In certain embodiments, in accordance with the methods described herein, can provide some degree of preventing and/or suppressing cough, ameliorate symptoms of cough, and ameliorate to some degree, of the reoccurance of the cough.

[0152] In certain embodiments, the subject is a human.

[0153] In certain embodiments, the antitussive composition is administered once a day. [0154] In certain embodiments, the antitussive composition is administered twice a day.

[0155] In certain embodiments, the antitussive composition is administered at least three times a day.

[0156] In certain embodiments, the cough is a symptom of one or more conditions chosen from sneezing, rhinorrhea, nasal obstruction, nasal congestion, nasal pruritus, rhinorrhea, allergies, allergic vasomotor rhinitis (hay fever), seasonal allergic vasomotor rhinitis, perennial allergic vasomotor rhinitis, a respiratory disease, a cold, acute bronchitis, chronic bronchitis, asthmatic bronchitis, bronchiectasis, pneumonia, lung tuberculosis, silicosis, silicotuberculosis, pulmonary cancer, upper respiratory inflammation, pharyngitis, laryngitis, nasal catarrh, asthma, bronchial asthma, infantile asthma, pulmonary emphysema, pneumoconiosis, pulmonary fibrosis, pulmonary silicosis, pulmonary suppuration, pleuritis, tonsillitis, cough hives, post-viral cough, gastreoesophageal reflux disease, post-nasal drip, nasal congestion, sinusitis and whooping cough; or the cough results from a procedure chosen from a bronchography and a bronchoscopy.

[0157] In certain embodiments, the cough is acute.

[0158] In certain embodiments, the cough is subacute.

[0159] In certain embodiments, the cough is chronic.

[0160] In certain embodiments, the administering is chosen from intravenous, intraarterial, oral, intramuscular injection, subcutaneous injection, intraperitoneal injection, intrathecal, sublingual, rectal, vaginal, nasal, inhalation, and transdermal.

[0161] In certain embodiments, the administering is transdermal.

[0162] In certain embodiments, the administering is nasal.

Abbreviations

AdO = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous; BAST = bis(2-methoxyethyl)aminosulfur trifluoride; Bu = butyl; BmSnH = tributyltin hydride; CD3OD = deuterated methanol; CDCh = deuterated chloroform; CDI = Ι,Γ-carbonyldiimidazole; DAST = (diethylamino)sulfur trifluoride; dba = dibenzylideneacetone; DBU = l,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIBAL-H = di-iso-butyl aluminium hydride; DIEA = DIPEA = Ν,Ν-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = N,N-dimethyl- formamide; DMSO-de = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; dppf = l, l'-bis(diphenylphosphino)ferrocene; EDC*HC1 = EDCI*HC1 = l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et = ethyl; Et₂0 = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; h = hour; HATU=2-(lH-7-azabenzotriazol-l-yl)-l, 1,3,3- tetramethyl uronium hexafluorophosphate methanaminium; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; i-Pr = isopropyl = 2-propyl; i-PrOH = isopropanol; LAH = lithium aluminium hydride; LDA =lithium diisopropyl amide; LiHMDS = Lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; Mel = methyl iodide; MeOH = methanol; MP- carbonate resin = macroporous tri ethyl ammonium methylpolystyrene carbonate resin; MsCl = mesyl chloride; MTBE = methyl tertiary butyl ether; n-BuLi = n-butyllithium; NaHMDS = sodium bis(trimethylsilyl)amide; NaOEt = sodium ethoxide; NaOMe = sodium methoxide; NaOtBu = sodium t-butoxide; BS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NIS = N- iodosuccinimide; MP = N-Methyl-2-pyrrolidone; Pd(PPh₃)4 = tetrakis(triphenylphosphine)- palladium(O); Pd₂(dba)₃ = tris(dibenzylideneacetone)dipalladium(0); PdCl₂(PPh₃)₂ = bis(triphenylphosphine)palladium(II) dichloride; PG = protecting group; Ph = phenyl; prep-HPLC = preparative high-performance liquid chromatography; PMB = para-methoxybenzyl; PMBCl = para-methoxybenzyl chloride; PMBOH = para-methoxybenzyl alcohol; PyBop = (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate; Pyr = pyridine; RT = room temperature; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; sat. = saturated; ss = saturated solution; tBu = t-Bu = tert-butyl = 1, 1-dimethylethyl; TBAF = tetrabutylammonium fluoride; TBDPS = t-butyldiphenylsilyl; t-BuOH = tert-butanol; T3P = Propylphosphonic Anhydride; TEA = Et₃N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; TIPS = triisopropylsilyl; Tol = toluene; TsCl = tosyl chloride; Trt = trityl = (triphenyl)methyl; Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos = 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

General synthetic methods for preparing compounds

[0163] The following schemes can be used to practice the present disclosure. Scheme I

[0164] Scheme I can be used for synthesis of compounds from monoprotected diamines represented by formula 101. Reaction with S-methylisothiourea forms the guanidine core of product 102. The Boc protecting group is then cleaved under acidic conditions, affording primary amine 103. The product originally formed will be the TFA salt, which can be converted to the free base 104 or transformed under ion exchange conditions to alternative salt forms (not shown).

Scheme II

[0165] Scheme II can be used for the synthesis of compounds from Boc-protected aminoaldehydes and aminoketones represented by formula 201. Reaction with ammonia under reductive amination conditions gives differentially proteced diamine 202. Reaction with S- methylisothiourea forms the guanidine core of product 203. The Boc protecting group is then cleaved under acidic conditions, affording the corresponding primary amine as its TFA salt (not shown). This salt can be converted to the free base 204 or transformed under ion exchange conditions to alternative salt forms (not shown). Scheme III

[0166] Scheme III can be used for the synthesis of compounds from symmetrical diamines, for which Ri and R2 are identical substituents, and R3 and R₄ are identical substituents. This class of compounds is represented by formula 301. The monoprotected compound 302 is obtained by reaction with B0C2O. If desired, undesired diprotected compound (not shown) and unreacted starting material can be removed and recycled. The primary amine 302 is then reacted as above, to form the guanidine core of 303. Synthesis is completed by cleavage of the Boc protecting group under acidic conditions, followed by formation of the free base 304 under alkaline conditions.

Scheme IV

[0167] Scheme IV can be used for the synthesis of symmetrical diamines, for use in Scheme III. A suitable 1,3-diene 401 is reacted with Diels-Alder dienophile shown to give the 1,2,3,6- tetrahydropyridazine 402 as shown (J. Chem. Soc. Perkin I, 1984, 2927-2931). Exhaustive reduction hydrogenates the alkene moiety and cleaves the hydrazine bond to give protected diamine 403. If required, stereoisomers will be separated at this or a later point in the synthesis. The carbamate functionality is removed under basic conditions, followed by monoprotection with the more useful Boc protecting group, affording building block 304.

Scheme V

t

[0168] Scheme V can be used for the synthesis of symmetrical diamines having vicinal diol functionality, for use in Scheme III. As in Scheme IV, a suitable 1,3-diene 501 will afford desired hydrazine 502. The olefin can be cis-hydroxylated by methods known the art, such as with Os0₄, to give the diol 503 shown (J. Chem. Soc. Perkin I, 1984, 2927-2931). Alternatively, stepwise epoxidation / ring opening is expected to give the opposite isomer (not shown). If required, stereoisomers will be separated at this or a later point in the synthesis. Reduction hydrogenates the alkene moiety and cleaves the hydrazine bond to give protected diamine 504. The carbamate functionality is removed under basic conditions, followed by monoprotection with the more useful Boc protecting group, affording building block 505.

Scheme VI

[0169] Scheme VI can be used for the synthesis of symmetrical diamines having a cyclic skeleton. Exocyclic dienes such as 601 will afford desired cyclic hydrazine 602. Exhaustive reduction gives cyclic diamine 603 as shown. Finally, the carbamate functionality is removed under basic conditions, followed by monoprotection with the more useful Boc protecting group, affording building block 604.

Scheme VII

OOEt

[H]

[0170] Scheme VII can be used for the synthesis of symmetrical diamines having an alternate cyclic skeleton. Endocyclic dienes such as 701 will afford desired cyclic hydrazine 702. Exhaustive reduction gives cyclic diamine 703 as shown. Finally, the carbamate functionality is removed under basic conditions, followed by monoprotection with the more useful Boc protecting group, affording building block 704.

[0171] It will be apparent to the persons in the art that the schemes as disclosed above can provide selectivity towards certain stereoisomers. It will also be appreciated that stereoselectivity in any of these syntheses is desirable but not required. The small amounts of stereopure compounds required for evaluation will be readily available by using conventional purification techniques, such as semipreparative HPLC.

[0172] It will be apparent to the persons in the art that many of the compounds envisioned herein can exist as absolute stereoismers. It will be appreciated that many enantiopure starting materials are available for synthetic schemes, including enantiopure arginie. It will also be appreciated that many techniques are available for the resolution of racemic mixtures, and that the basic nature of these compounds lends them particularly well for classical resolution techniques, such as diastereomeric salt formation.

[0173] It will be apparent to persons in the art that chiral compounds have value in either enantiopure isomer, generally designated as R or S, or as a racemic mixture. It is well known in the field that either enantipure or racemic compounds have value in the formulation of pharmaceuticals.

[0174] The following compounds can generally be made using the methods known in the art and described above. It is expected that these compounds when made will have activity in the assays described below.

Table 1.

30 [0175] The following example demonstrates a method for dosing and determining the efficacy of the compounds disclosed herein.

[0176] The compounds disclosed herein may be administered orally at a dose of from 0.1 mg to 1 g/kg per day. The dose range for adult humans is generally from 5 mg to 2 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

[0177] The following example illustrate the present disclosure, but are not meant to limit the scope thereof.

Example 1

Antitussive Effects of Agmatine in Guinea Pigs

Citric Acid Induced Cough

[0178] Animals were placed in a transparent chamber (Buxco Research Systems, Wilmington, NC) with a continuous flow of air and exposed to increasing concentrations of citric acid (0.01 M- 0.3 M) is delivered by an ultrasonic nebulizer generating aerosol particles of 3-6 μιη diameter. Coughs were counted during a 5 minute nebulization period and over the subsequent 5 minutes with the assistance of sound and pressure monitoring from the chamber. Respiratory rate and tidal volume were monitored throughout via a calibrated pressure transducer (Emka Technologies, Falls Church, VA).

Animals

[0179] Male Hartley guinea pigs (200-700 g) were studied and all experiments were first approved by the institutional Animal Care and Use Committee.

Compounds and Materials

[0180] Agmatine and citric acid were obtained from Sigma- Aldrich (St. Louis, MO). All drugs were dissolved in 0.9% saline except citric acid (dissolved in distilled water).

Statistical Analysis

[0181] Data were analyzed using SPSS (version 15, SPSS Inc, Chicago, 111) and graphs produced using Prism (version 4, Graphpad Ltd). A 5% level of significance was used throughout. Comparisons of cumulative cough numbers for treatment groups was therefore compared using non-parametric tests (Kruskal Wallis and Mann- Whitney U tests).

Results

[0182] Compared with vehicle, 100 mg/kg agmatine markedly reduced the number of cumulative coughs evoked by 0.01-0.3 M citric acid (p=0.012) (FIG. 1).

[0183] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this disclosure, and without departing from the spirit and scope thereof, can make various changes and modifications of the disclosure to adapt it to various usages and conditions.

Claims

CLAIMS What is claimed is:

1. A compound of structural Formula I

or a salt, ester, or prodrug thereof, wherein:

Ri and R₄ are independently selected from H, alkyl, aryl, carboxy, cycloalkyl, and heteroaryl, and is optionally substituted with 1, 2, or 3 Rs groups, or

R2 and R3 are independently selected from H, alkoxy, alkyl, aryl, carboxy, cyano, cycloalkyl, cycloalkoxy, halo, heteroaryl, and nitro, and is optionally substituted with 1, 2, or 3 R₆ groups, or

R2 and R3, together with the intervening atoms, form a 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl ring, and is optionally substituted with 1, 2, or 3 R₆ groups;

R5 and R₆ are independently selected from alkoxy, alkyl, amino, cyano, carboxy, halo, nitro, and hydroxy; and

at least one of Ri, R2, R3, and R₄ is not hydrogen.

2. The compound as recited in claim 1, wherein Ri and R₄ are both hydrogen.

3. The compound as recited in claim 1, wherein R2 and R3 are both hydrogen.

4. The compound as recited in claim 1, wherein neither of Ri and R₄ is hydrogen.

5. The compound as recited in claim 1, wherein neither of R2 and R3 is hydrogen.

6. The compound as recited in claim 1, wherein Ri and R₄ are identical substituents.

7. The compound as recited in claim 1, wherein R2 and R3 are identical substituents.

8. The compound as recited in claim 1, wherein Ri and R₄ are independently selected from Ci-₄alkyl, aryl, and heteroaryl.

9. The compound as recited in claim 1, wherein R2 and R3 are independently selected from Ci-₄alkyl, aryl, and heteroaryl.

10. The compound as recited in claim 1, wherein Ri and R₄, together with the intervening atoms, form a 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl ring, and is optionally substituted with 1, 2, or 3 R₆ groups.

11. The compound as recited in claim 10, wherein wherein Ri and R₄, together with the intervening atoms, form a 5-, 6-, or 7-membered cycloalkyl ring, and is optionally substituted with 1 or 2 R₆ groups.

12. The compound as recited in claim 2, wherein R₂ and R₃, together with the intervening atoms, form a 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl ring, and is optionally substituted with 1, 2, or 3 Re groups.

13. The compound as recited in claim 11 , wherein wherein R₂ and R₃, together with the intervening atoms, form a 5-, 6-, or 7-membered cycloalkyl ring, and is optionally substituted with 1 or 2 R₆ groups.

14. A compound as recited in claim 1 for use as a medicament.

15. A compound as recited in claim 1 for use in the manufacture of a medicament for the prevention or treatment of cough.

16. Agmatine for use in the manufacture of a medicament for the prevention or treatment of cough.

17. An antitussive composition comprising a compound as recited in any of claims 1-13.

18. An antitussive composition comprising agmatine.

19. A method of suppressing cough in subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of agmatine or a derivative thereof.

20. The method as recited in claim 19, wherein said agmatine derivative is a compound as recited in any one of claims 1-13.

21. The method as recited in any one of claims 19-20, wherein suppressing cough is inhibited by inhibiting the urge to cough.

22. The method as recited in any one of claims 19-20, wherein the subject is a human.

23. The method as recited in any one of claims 19-20, wherein the antitussive composition is administered once a day.

24. The method as recited in any one of claims 19-20, wherein the antitussive composition is administered twice a day.

25. The method as recited in any one of claims 19-20, wherein the antitussive composition is administered at least three times a day.

26. The method as recited in any one of claims 19-20, wherein the cough is a symptom of one or more conditions chosen from sneezing, rhinorrhea, nasal obstruction, nasal congestion, nasal pruritus, rhinorrhea, allergies, allergic vasomotor rhinitis (hay fever), seasonal allergic vasomotor rhinitis, perennial allergic vasomotor rhinitis, a respiratory disease, a cold, acute bronchitis, chronic bronchitis, asthmatic bronchitis, bronchiectasis, pneumonia, lung tuberculosis, silicosis, silicotuberculosis, pulmonary cancer, upper respiratory inflammation, pharyngitis, laryngitis, nasal catarrh, asthma, bronchial asthma, infantile asthma, pulmonary emphysema, pneumoconiosis, pulmonary fibrosis, pulmonary silicosis, pulmonary suppuration, pleuritis, tonsillitis, cough hives, post-viral cough, gastreoesophageal reflux disease, post-nasal drip, nasal congestion, sinusitis and whooping cough; or the cough results from a procedure chosen from a bronchography and a bronchoscopy.

27. The method as recited in any one of claims 19-20, wherein the cough is acute.

28. The method as recited in any one of claims 19-20, wherein the cough is subacute.

29. The method as recited in any one of claims 19-20, wherein the cough is chronic.

30. The method as recited in any one of claims 19-20, wherein the administering is chosen from intravenous, intraarterial, oral, intramuscular injection, subcutaneous injection, intraperitoneal injection, intrathecal, sublingual, rectal, vaginal, nasal, inhalation, and transdermal.

31. The method as recited in any one of claims 19-20, wherein the administering is transdermal.

32. The method as recited in any one of claims 19-20, wherein said administering is nasal.

33. A composition as recited in any one of claim 17-18, for use in human therapy.

34. A composition as recited in any one of claim 17-18, for use in treating cough.

35. Use of a composition comprising agmantine or a compound as recited in any one of claims 1- 13, for the manufacture of a medicament to treat cough.

36. A method of suppressing or reducing cough by orally comsuming a cough suppressing or reducing amount of agmantine or a compound as recited in any one of claims 1-13 or a pharmaceutically acceptable salt thereof.