Patent Description:
The gastrointestinal (GI) tract is the largest producer of serotonin (<NUM>-hydroxytryptamine (<NUM>-HT)) in the body, and as such it is intimately connected with GI function and physiology. Serotonin produced by enterochromaffin (EC) cells is an important enteric mucosal signaling molecule and has been implicated in a number of gastrointestinal disorders or conditions, including inflammatory bowel disease and irritable bowel syndrome.

Alosetron (LOTRONEX), a <NUM>-HT<NUM> receptor antagonist, became the first agent approved by the US Food and Drug Administration for the treatment of diarrhea-predominant IBS in <NUM>. However, the drug has demonstrated a difficult post-approval side effect profile that has resulted in a temporary market withdrawal. Meanwhile, activation of the serotonin <NUM>-HT2B receptor is linked to cardiac valvulopathy and pulmonary hypertension (<NPL>; <NPL>, <NPL>), and attenuation of <NUM>-HT2B receptor signaling may prevent and/or reverse cardiopulmonary disorders (<NPL>;<NPL>). <CIT> discloses peripherically restricted <NUM>-HT<NUM> receptor antagonists.

There remains a need for agents that can safely modulate serotonin receptors (<NUM>-hydroxytryptamine receptors or <NUM>-HT receptors) for the treatment of gastrointestinal and cardiopulmonary disorders or conditions.

Accordingly, the present disclosure provides for compositions and methods that agonize or antagonize one or more serotonin receptors and which find use in, for example, the treatment of various gastrointestinal or cardiopulmonary disorders or conditions.

Disclosed is a compound, or a pharmaceutical composition comprising a compound, having the structure of Formula I:
<CHM>
where R<NUM> to R<NUM> are hydrogen or independently selected substituents. Suitable substituents are disclosed herein.

In various examples, none of R<NUM>, R<NUM>, and R<NUM> is hydrogen. In some examples, R<NUM>, R<NUM>, and R<NUM> are alkyl, e.g. methyl, or may come together to form a heterocyclic ring and each of R<NUM>, R<NUM>, R<NUM>, and R<NUM> is independently hydrogen, hydroxy, sulfoxy, halo, acyl, acyloxy, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, arylhalo, arylhydroxy, arylcyano, aryltrifluoromethyl, aryltrifluoromethoxy, arylnitro, aryltrifluoromethoxy, arylnitro, and arylether, arylester, arylsulfonyl, arylsulfinyl, arylsulfonamidyl, arylsulfonate, arylsulfoxyl, arylphosphate ester, arylcarbonyl, arylcarboxylate, arylcarbamate, arylamine, arylimide, heteroaryl, heteroarylalkyl, heteroarylhalo, heteroarylhydroxy, heteroarylcyano, heteroaryltrifluoromethyl, aryltrifluoromethoxy, arylnitro, heteroaryltrifluoromethoxy, heteroarylnitro, and heteroarylether, heteroarylester, heteroarylsulfonyl, heteroarylsulfinyl, heteroarylsulfonamidyl, heteroarylsulfonate, heteroarylsulfoxyl, heteroarylphosphate ester, heteroarylcarbonyl, heteroarylcarboxylate, heteroarylcarbamate, heteroarylamine, heteroarylimide, quinidine, morpholine, and any ring structure is optionally substituted with any of the substituents described herein, with the proviso that any two adjacent substituents can come together to form a carbocyclic or heterocyclic ring system.

In various examples, any of R<NUM>, R<NUM>, R<NUM>, and R<NUM> is a hydrocarbon or heterocyclic ring system. In some examples, the hydrocarbon or heterocyclic ring system is independently selected from phenyl, thienyl, furanyl, pyrimidinyl, oxazoyl, thiazolyl, pyridyl, naphthyl, quinolinyl, indolyl, benzothiophenyl, benzofuranyl, pyrrolyl, imidazolyl, pyrazole, triazolyl, isoxazolyl, pyridazinyl, pyzazinyl, pyrimidinyl, oxadiazolyl, benzimidazolyl, and triazinyl, each of which may contain substituents (i.e. is optionally substituted). In some examples, the heterocyclic ring system may contain one or more heteroatoms selected from the group consisting of oxygen, sulfur, nitrogen, and combinations thereof.

In a specific example, only R<NUM> is a hydrocarbon or heterocyclic ring system which is optionally substituted. In a specific example, only R<NUM> is a hydrocarbon or heterocyclic ring system which is optionally substituted, all of R<NUM>, R<NUM>, and R<NUM> are alkyl, and each of R<NUM>, R<NUM>, and R<NUM> is independently hydrogen, hydroxy, sulfoxy, halo, acyloxy, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, acyl, and alkoxy.

The compound or composition does not substantially accumulate in the human brain. In various examples the compound or composition is not rapidly metabolized in the periphery. The nitrogen bearing R<NUM>, R<NUM>, and R<NUM> in the above formulae is positively charged. In various examples, the compound or composition has the structure of Formula I and all of R<NUM>, R<NUM>, and R<NUM> are alkyl groups, including methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, and hexyl, which may be optionally substituted. In various examples, all of R<NUM>, R<NUM>, and R<NUM> are identical alkyl groups. In various examples, two of or three of R<NUM>, R<NUM>, and R<NUM> are different alkyl groups. In some examples, R<NUM>, R<NUM>, and R<NUM> are each methyl.

In various examples, the compound or composition is a modulator of one or more of <NUM>-HT<NUM> receptors (e.g. one or more of <NUM>-HT1A, <NUM>-HT1B, <NUM>-HT1C, <NUM>-HT1D, <NUM>-HT1E, <NUM>-HT1F); <NUM>-HT<NUM> receptors (e.g. one or more of <NUM>-HT2A, <NUM>-HT2B, <NUM>-HT2C); <NUM>-HT<NUM> receptors; <NUM>-HT<NUM> receptors; <NUM>-HT<NUM> receptors (e.g. <NUM>-HT5A); <NUM>-HT<NUM> receptors; and HT<NUM> receptors. In some examples, the modulated <NUM>-HT receptor is present in the GI tract (e.g. one or more of the stomach, small intestine, large intestine and rectum and includes all subsections thereof (e.g. duodenum, jejunum and ileum, colon transversum, colon descendens, colon ascendens, colon sigmoidenum and cecum).

In various examples, the compound or composition is substantially enantiomerically pure. In some embodiments, the composition comprises at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>% of a single enantiomer. In various embodiments, a least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>% of a single enantiomer. In some embodiments, the single enantiomer has functional properties (e.g. serotonin receptor selectivity and/or receptor affinity) that are not found in a corresponding enantiomer.

In one aspect, the present invention relates to an at least <NUM>% enantiomerically pure compound that is a <NUM>-HT receptor modulator having the structure of Formula (I):
<CHM>
or pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each of R<NUM>, R<NUM>, and R<NUM> is independently an unsubstituted alkyl or may come together to form a heterocyclic ring, each of R<NUM>, R<NUM>, and R<NUM> is independently hydrogen, unsubstituted alkyl, aryl, halo, nitro, amino, heteroaryl, cycloalkyl, heterocyclic, or alkoxy, and R<NUM> is a phenyl, furan, or naphthyl ring ,said phenyl, furan, or naphthyl ring substituted with one or more unsubstituted alkyl, alkoxy, or halo substituents; and wherein the compound does not substantially accumulate in the human brain.

In a second aspect the present invention relates to a pharmaceutical composition comprising a therapeutic amount of the compound of the first aspect of the invention, and a pharmaceutically acceptable excipient or carrier. In various embodiments, the pharmaceutical compositions of the invention are formulated for long-action or sustained-release. In some embodiments, the formulation is suitable for oral delivery and/or transmucosal delivery (e.g. a capsule, tablet, patch, or lozenge).

In some aspects, the present invention relates to the compound of the first aspect of the invention, or the pharmaceutical composition of the second aspect of the invention, for treating or preventing a gastrointestinal disorder or condition, optionally selected from inflammatory bowel disease, irritable bowel syndrome, celiac disease, and an enteric infection.

Disclosed is a method for treating or preventing a functional GI disorder comprising administering the composition described herein to a patient in need thereof.

In some aspects, the present invention relates to the compound of the first aspect of the invention, or the pharmaceutical composition of the second aspect of the invention, for treating or preventing a cardiopulmonary disorder, preferably wherein the cardiopulmonary disorder is one or more of cardiac valvulopathy and pulmonary hypertension.

The present invention is based, in part, on the discovery of novel serotonin receptor-modulating compounds that do not substantially accumulate in the brain and therefore are useful in treating diseases or disorders of the periphery, including gastrointestinal or cardiopulmonary disorders or conditions.

Disclosed is a compound, or a pharmaceutical composition, comprising a compound, having the structure of Formula I:
<CHM>
where each of R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, and R<NUM> is hydrogen or a substituent, for example, as defined above.

Any of R<NUM>, R<NUM>, R<NUM>, and R<NUM> may be a hydrocarbon or heterocyclic ring system. The hydrocarbon or heterocyclic ring system may be independently selected from phenyl, thienyl, furanyl, pyrimidinyl, oxazoyl, thiazolyl, pyridyl, naphthyl, quinolinyl, indolyl, benzothiophenyl, benzofuranyl, pyrrolyl, imidazolyl, pyrazole, triazolyl, isoxazolyl, pyridazinyl, pyzazinyl, pyrimidinyl, oxadiazolyl, benzimidazolyl, and triazinyl, each of which may contain substituents (i.e. is optionally substituted). The heterocyclic ring system may contain one or more heteroatoms selected from the group consisting of oxygen, sulfur, nitrogen, and combinations thereof.

In a specific example, only R<NUM> is a hydrocarbon or heterocyclic ring system which is optionally substituted. In a specific example, only R<NUM> is a hydrocarbon or heterocyclic ring system which is optionally substituted, each of R<NUM>, R<NUM>, and R<NUM> is alkyl, and each of R<NUM>, R<NUM>, and R<NUM> is independently hydrogen, hydroxy, sulfoxy, halo, acyloxy, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, acyl, and alkoxy. In these examples, the total number of atoms that comprise R<NUM> may be at least about <NUM>, and not more than about <NUM> atoms, not including hydrogen atoms (e.g. between about <NUM> to about <NUM> non-hydrogen atoms, or between about <NUM> to about <NUM> non-hydrogen atoms, or between about <NUM> to about <NUM> non-hydrogen atoms).

The nitrogen bearing R<NUM>, R<NUM>, and R<NUM> in the above formulae may be positively charged (e.g. a quaternary ammonium). For example, the compound or composition may have the structure of Formula I and all of R<NUM>, R<NUM>, and R<NUM> may be alkyl groups, including methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, and hexyl, which may be optionally substituted. In various examples, all of R<NUM>, R<NUM>, and R<NUM> are identical alkyl groups (e.g., methyl). In various examples, two of or three of R<NUM>, R<NUM>, and R<NUM> are different alkyl groups.

The compounds of Formula I may be referred to herein as "<NUM>-PAT" or "<NUM>-APT" compounds. Such nomenclature is derived from the position of the attachment of R<NUM> to the bicyclic core of Formula I, i.e. the tetrahydronaphthyl (tetralin) moiety bearing substituents R<NUM>-R<NUM> and R<NUM>-R<NUM>.

In some examples, each of R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, and R<NUM> is independently hydrogen, alkyl, aryl, halo, nitro, amino, heteroaryl, cycloalkyl, heterocyclic, or alkoxy. In various embodiments, none of R<NUM>, R<NUM>, and R<NUM> is hydrogen. In some embodiments, all of R<NUM>, R<NUM>, and R<NUM> are alkyl, such as methyl.

In some examples, at least one of R<NUM>, R<NUM>, R<NUM>, and R<NUM> is not hydrogen. In some embodiments, at least one of R<NUM>, R<NUM>, R<NUM>, and R<NUM> is halo. In some embodiments, two of R<NUM>, R<NUM>, R<NUM>, R<NUM>, and R<NUM> are halo. In some embodiments, one of R<NUM>, R<NUM>, R<NUM>, and R<NUM> is halo. In some examples, at least one of R<NUM>, R<NUM>, R<NUM>, and R<NUM> is fluoro. In some embodiments, only R<NUM> is a substituent other than H and it is a hydrocarbon ring that is substituted with a halo, including, for example fluoro or chloro.

In some examples, any one of R<NUM> and R<NUM> or R<NUM> and R<NUM> form a phenyl ring, which is substituted or unsubstituted. In various examples, the phenyl ring is substituted with a halo, optionally selected from fluoro and chloro and optionally at one or more of the ortho, meta, and para positions. In various examples, the phenyl ring is unsubstituted.

In various examples, there is an optionally substituted hydrocarbon or heterocyclic ring system, e.g. a phenyl ring or naphthyl ring connected to the <NUM> position of the bicyclic core of Formula I (the core being the top of the structure, i.e. the tetrahydronaphthyl moiety bearing R<NUM>,-R<NUM> and the amino group bearing R<NUM>, R<NUM> and R<NUM>). In some examples, these phenyl or naphthyl rings are substituted with a halo, optionally selected from fluoro and chloro. In some examples, the halo substitution is in the ortho, meta, or para position of the phenyl or the <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> position of the naphthyl ring (where the attachment position to the compounds's core is at position <NUM> or <NUM> of the naphthyl ring). In some examples, the halo substitution is in the ortho of the phenyl or the <NUM> or <NUM> position of the naphthyl ring (where the attachment position to the compounds's core is at position <NUM> or <NUM> of the naphthyl ring).

The total number of atoms that comprise substituents R<NUM> may be at least about <NUM>, and not more than about <NUM> atoms, not including hydrogen atoms (e.g. between about <NUM> to about <NUM> non-hydrogen atoms, or between about <NUM> to about <NUM> non-hydrogen atoms, or between about <NUM> to about <NUM> non-hydrogen atoms). In some examples, the composition is not a good substrate for one or more forms of P450 at levels administered. For instance, without wishing to be bound by theory, larger numbers of non-hydrogen atoms that comprise substituents R<NUM> may prevent metabolism associated with P450 (such metabolism may be, without wishing to be bound by theory, oxidation-mediated). For example, the composition may not be a substrate for one or more families of P450 (e.g. CYP1, CYP2, CYP3, CYP4, CYP5, CYP7, CYP8, CYP11, CYP17, CYP19, CYP20, CYP21, CYP24, CYP26, CYP27, CYP39, CYP46, and CYP51). The composition may not be a substrate for one or more of CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. In these examples, the compound is suited for avoiding P450-mediated reduction in a pharmacological effect.

The compound or composition may be a derivative any one of the genera or species found in International Patent Publication Nos. <CIT>, <CIT>, <CIT>, and <CIT>, and International Patent Application No. <CIT>. The derivitization may be at the nitrogen attached to position <NUM> of the compound or composition's tetrahydronaphthyl (tetralin) core. For clarity, the tetrahydronaphthyl core is shown below and position <NUM> bears an amino group:
<CHM>
In Formula I herein, this amino group at position <NUM> is denoted as bearing R<NUM>, R<NUM>, and R<NUM>. Accordingly, in various examples, any of the compounds of the above referenced documents bear an amino group at position <NUM> and the amino group bears three of any of the substituents described herein to provide a net positive charge e.g. a quaternary ammonium. For example, any of the compounds in the above referenced documents are derivatized to comprise an amino group at position <NUM> that bears three alkyl substituents (e.g. three methyl substituents).

Further, with reference to <CIT>, the present compounds and compositions include derivatives at the amino group of position <NUM> of formula (I) therein, which is a genus of <NUM>-PAT compounds (see pages <NUM>-<NUM> and FIG. <NUM> of <CIT>). For instance, the amino group of position <NUM> of formula (I) of <CIT>, as well as compounds PAT # <NUM>-<NUM> (e.g. page <NUM> of <NUM>/<NUM>) is, in the present disclosure, an amino group bearing three substituents described herein (e.g. three methyl groups) and therefore a positive charge. Such compounds may agonize <NUM>-HT2c. Such compounds may antagonize <NUM>-HT2a and/or <NUM>-HT2b.

Further still, with reference to <CIT>, the present compounds and compositions include derivatives at position R<NUM> of formula (V) therein, which is a genus of <NUM>-PAT compounds. For instance, R<NUM> of formula (V) of <CIT>, the <NUM>-PAT compounds of Table <NUM> (e.g. page <NUM> of <CIT>) and compounds formed by adding the groups of Table <NUM> e.g. at the <NUM>- or <NUM>- position of the tetrahydronaphthyl core (Table <NUM>, pages <NUM>-<NUM> of <CIT>), is, in the present disclosure, an amino group bearing three substituents described herein (e.g. three methyl groups) and therefore a positive charge. Such compounds may agonize <NUM>-HT2c. Such compounds may antagonize <NUM>-HT2a and/or <NUM>-HT2b.

Further still, with reference to International Patent Application No. <CIT>, the present compounds and compositions include, with reference to Formula (I') therein, instances in which all of R<NUM> to R<NUM> are identical e.g. bearing the substituents described herein (e.g. three methyl groups) and therefore have a positive charge or, with reference to Formula (I) therein, the amino group at position <NUM> bears a further substituent in addition to R<NUM> and R<NUM>, the additional substituent and R<NUM> and R<NUM> being substituents described herein (e.g. three methyl groups) and therefore having a positive charge.

In some embodiments, the compound or composition is
<CHM>.

In some embodiments, the compound or composition is the (+) enantiomer of the above compound.

In some embodiments, the compound or composition is:
<CHM>.

In some embodiments the compound or composition is the (+) enantiomer of the above compound.

In some embodiments, the compound or composition is the (-) enantiomer of the above compound.

The compound or composition may be any one of:
<CHM>
<CHM>
<CHM>
and
<CHM>.

In some embodiments, the compound or composition is the (-) or (+) enantiomer of any of the above compounds.

In various embodiments, the compositions of the present invention comprise at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>% of a single enantiomer. In various embodiments, a least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>% of a single enantiomer.

In some embodiments, the compositions of the present invention comprises less than about <NUM>%, or less than about <NUM>%, or less than about <NUM>%, or less than about <NUM>%, or less than about <NUM>%, or less than about <NUM>%, or less than about <NUM>% of a single enantiomer.

In some embodiments, the present compounds and compositions are substantially in the form of a single enantiomer and essentially free of the corresponding enantiomer.

In some embodiments, a single enantiomer has functional properties (e.g. serotonin receptor selectivity) that are not found in a corresponding enantiomer. For example, in some embodiments, the (+) enantiomer has serotonin-receptor modulating properties that are not found in the corresponding (-) enantiomer (e.g. the (-) enantiomer does not bind or modulate one of more serotonin receptors at physiological levels). By way of further example, in some embodiments, the (-) enantiomer has serotonin-receptor modulating properties that are not found in the corresponding (+) enantiomer (e.g. the (+) enantiomer does not bind or modulate one of more serotonin receptors at physiological levels). Such a stereoselectivity, in some embodiments, also applies to (R)- and (S)- and d- and I-. Accordingly, in some embodiments, the invention does not provide racemates or racemic mixtures. In some embodiments, the present compounds and compositions find use as entiopure drugs.

In various embodiments, the present invention requires separation of a racemate into its components, the pure enantiomers, i.e. chiral resolution. Techniques to achieve substantially enantiomerically pure compounds are known and include, by way of non-limiting example, crystallization, chromatography (e.g. HPLC), and enzymatic resolution. Various techniques for chiral resolution are found in <NPL>. In various embodiments, measurement of the Eudysmic ratio may assist in determining the final properties of the composition. For example, one enantiomer is the eutomer while the other enantiomer is the distomer and comparison of two may involve the quotient of activity or binding measurements (e.g. EC<NUM> or IC<NUM>).

In further embodiments, the present compounds and compositions are entiopure drugs. However, in instances in which corresponding enantiomers provide different but desirable properties (e.g. physiologically relevant modulation at different serotonin receptors), such enantiomers may be combined as a combination composition of known amounts.

In various embodiments, the present compounds or compositions modulate one or more serotonin receptors. For example, one or more of <NUM>-HT<NUM> receptors (e.g. one or more of <NUM>-HT1A, <NUM>-HT1B, <NUM>-HT1C, <NUM>-HT1D, <NUM>-HT1E, <NUM>-HT1F), <NUM>-HT<NUM> receptors (e.g. one or more of <NUM>-HT2A, <NUM>-HT2B, <NUM>-HT2C); <NUM>-HT<NUM> receptors; <NUM>-HT<NUM> receptors; <NUM>-HT<NUM> receptors (e.g. <NUM>-HT5A); <NUM>-HT<NUM> receptors; and <NUM>-HT<NUM> receptors may be modulated. In various embodiments, the present compounds or compositions bind one or more serotonin receptors with a binding affinity (Ki) of less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>. In various embodiments, the present compounds or compositions bind one or more serotonin receptors with a binding affinity (Ki) of about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>.

In various embodiments, the present compounds or compositions may be full agonist, partial agonist, antagonist, inverse agonist, etc. at one or more receptors described herein (e.g. one or more serotonin receptors). In some embodiments, the invention provides for partial agonists at one or more receptors described herein (e.g. one or more serotonin receptors) specifically. In some embodiments, the present compounds or compositions are not full agonists at one or more receptors described herein (e.g. one or more serotonin receptors). In some embodiments, such partial agonism may provide constant, weak level of activity at the receptor, as compared to a full agonist. Further, without wishing to be bound by theory, such partial agonism may prevent adaptive regulatory mechanisms that may develop after repeated exposure to potent full agonists or antagonists. Further, in embodiments relating to serotonin receptor modulation, partial agonism of the present compounds or compositions may reduce or eliminate the risk of serotonin syndrome (e.g., fever, cardiac arrhythmia, seizures, loss of consciousness). For example, some <NUM>-HT<NUM> agonists (e.g. triptans) are known to cause serotonin syndrome. Partial agonism is believed to avoid this deleterious side effect.

In various embodiments, the present compound or composition binds to one or more of the serotonin <NUM>-HT<NUM> and <NUM>-HT1A receptor at physiologically relevant levels. In various embodiments, the present compound or composition is a dual agonist of the serotonin <NUM>-HT<NUM> and <NUM>-HT1A receptors. In various embodiments, the present compound or composition binds to the serotonin <NUM>-HT<NUM> receptor with a binding affinity (Ki) of less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>. In various embodiments, the present compound or composition binds to the serotonin <NUM>-HT<NUM> receptor with a binding affinity (Ki) of about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>. In various embodiments, the present compound or composition binds to the serotonin <NUM>-HT1A receptor with a binding affinity (Ki) of less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>. In various embodiments, the present compound or composition binds to the serotonin <NUM>-HT1A receptor with a binding affinity (Ki) of about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>.

In various embodiments, the present compound or composition does not bind or modulate one or more of the serotonin <NUM>-HT2A and <NUM>-HT2C receptors at physiologically-relevant levels. In various embodiments, the present compound or composition binds one or more of the serotonin <NUM>-HT2A and <NUM>-HT2C receptors with an affinity of greater than about <NUM>, or greater than about <NUM>, or greater than about <NUM>, or greater than about <NUM>, or greater than about <NUM>. In some embodiments, the present compound or composition binds one or more of the serotonin <NUM>-HT2A and <NUM>-HT2C receptors with an affinity of about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>.

Accordingly, in some embodiments, the present compound or composition selectively binds to serotonin <NUM>-HT<NUM> and <NUM>-HT1A receptors over other serotonin receptors. In various embodiments, the present compound or composition binds one or more of the serotonin <NUM>-HT<NUM> and <NUM>-HT1A receptors with at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold higher affinity than one or more of the serotonin <NUM>-HT2A and <NUM>-HT2C receptors. In various embodiments, the present compound or composition binds one or more of the serotonin <NUM>-HT<NUM> and <NUM>-HT1A receptors with about a <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold higher affinity than one or more of the serotonin <NUM>-HT2A and <NUM>-HT2C receptors.

In various embodiments, the present compound or composition binds to one or more of the <NUM>-HT2a, <NUM>-HT2b, and <NUM>-HT2c receptors at physiologically relevant levels. In various embodiments, the present compound or composition binds to the one or more of the <NUM>-HT2a, <NUM>-HT2b, and <NUM>-HT2c receptor with a binding affinity (Ki) of less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>, or less than about <NUM>. In various embodiments, the present compound or composition binds to the one or more of the <NUM>-HT2a, <NUM>-HT2b, and <NUM>-HT2c receptor with a binding affinity (Ki) of about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>. In various embodiments, the present compound or composition selectively binds the serotonin <NUM>-HT2c receptor <NUM>-HT2A relative to <NUM>-HT2a or <NUM>- HT2b.

In some embodiments, the selective binding to certain serotonin receptors over other serotonin receptors (e.g. a preference for <NUM>-HT<NUM> and <NUM>-HT1A receptors) is enantiomer-mediated. That is, in some embodiments, one enantiomer of a compound displays the selectively binding while the other does not. For example, in some embodiments, the present compound or composition binds one or more of the serotonin <NUM>-HT<NUM> and <NUM>-HT1A receptors with an at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold higher affinity than a corresponding enantiomer. In some embodiments, the present compound or composition binds one or more of the serotonin <NUM>-HT<NUM> and <NUM>-HT1A receptors with about <NUM>-fold, or about <NUM>-fold, or about <NUM>-fold, or about <NUM>-fold, or about <NUM>-fold, or about <NUM>-fold, or about <NUM>-fold higher affinity than a corresponding enantiomer.

In various embodiments, the present compound or composition does not bind or modulate one or more of the histamine H1 receptor, dopamine D2, and adrenergic α1A and α1B receptors at physiologically-relevant levels.

In various embodiments, the present compound or composition binds one or more of the histamine H1 receptor, dopamine D2, and adrenergic α1A and α1B receptors with an affinity of greater than greater than about <NUM>, or greater than about <NUM>, or greater than about <NUM>. In various embodiments, the present compound or composition binds one or more of the histamine H1 receptor, dopamine D2, and adrenergic α1A and α1B receptors with an affinity of <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>, or about <NUM>.

Accordingly, in some embodiments, the present compound or composition selectively binds one or more serotonin receptor over one or more of the histamine H1 receptor, dopamine D2, and adrenergic α1A and α1B receptors. In various embodiments, the present compound or composition binds one or more serotonin receptor with at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold, or at least about <NUM>-fold higher affinity than one or more of the histamine H1 receptor, dopamine D2, and adrenergic α1A and α1B receptors. In various embodiments, the present compound or composition binds one or more serotonin receptor with about a <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold, or <NUM>-fold higher affinity than one or more of the histamine H1 receptor, dopamine D2, and adrenergic α1A and α1B receptors.

The present disclosure relates to a compound or pharmaceutical composition of the structure represented by Formula (Ia):
<CHM>
or pharmaceutically acceptable salt thereof, where each of R<NUM> ,R<NUM>, and R<NUM> are defined as above for Formula I and X is independently hydrogen, alkyl, aryl, halo, nitro, amino, heteroaryl, cycloalkyl, heterocyclic, or alkoxy.

In some examples, the compound is the (+) enantiomer. In some examples, the compound is the (-) enantiomer.

In some examples, each of R<NUM> ,R<NUM>, and R<NUM> is independently hydrogen, alkyl, aryl, halo, nitro, amino, heteroaryl, cycloalkyl, heterocyclic, or alkoxy. In some examples, R<NUM> ,R<NUM>, and R<NUM> are identical. In some embodiments, R<NUM> ,R<NUM>, and R<NUM> are methyl.

In some examples, X is a halo. In some examples, Xis fluoro. In some examples, Xis chloro. In some examples, X is bromo. In some examples, Xis iodo. In some examples, Xis in the ortho position. In some examples, Xis in the meta position. In some examples, Xis in the para position.

In some examples, the compound of Formula Ia is enantiomerically pure. In some examples, the compound of Formula Ia is substantially the (+) enantiomer. In some examples, the compound of Formula Ia is substantially devoid of the (+) enantiomer. In some examples, the compound of Formula Ia is substantially the (-) enantiomer. In some examples, the compound of Formula Ia is substantially devoid of the (-) enantiomer.

In some embodiments, the compounds and compositions of the present invention may take the form of a pharmaceutically acceptable salt. A pharmaceutically acceptable acid addition salt is formed from a pharmaceutically acceptable acid, as is well known in the art. Such salts include the pharmaceutically acceptable salts listed in, for example, <NPL>) and <NPL>.

In some embodiments, the compounds and compositions of the present invention can be administered to a subject as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. Such compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration.

Pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a subject. Water, saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any agent described herein, if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents.

The compounds and compositions of the present invention can be present in various formulations. Any compound and composition (and/or additional agents) described herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule (see, e.g., <CIT>). Other examples of suitable pharmaceutical excipients are described in <NPL>).

Where necessary, the compounds and compositions can also include a solubilizing agent. Also, the compounds and compositions can be delivered with a suitable vehicle or delivery device as known in the art. Combination therapies outlined herein can be co-delivered in a single delivery vehicle or delivery device.

The formulations comprising the compounds and compositions of the present invention may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the therapeutic agents into association with a carrier, which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation (e.g., wet or dry granulation, powder blends, etc., followed by tableting using conventional methods known in the art).

Routes of administration include, for example: intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin.

The administering may be effected orally. In some embodiments, the administering is by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa). Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer. In various embodiments, the compounds and compositions of the present invention are formulated to be suitable for oral delivery. In various embodiments, the compounds and compositions of the present invention are formulated to be suitable for transmucosal delivery (see, e.g. <NPL>).

Compositions or compounds for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. In some embodiments, the compounds and compositions of the present invention are in the form of a capsule, tablet, patch, or lozenge. Orally administered compositions can comprise one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically capsule containing a driving compound capable of active driving any compound or composition described herein is also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material such as glycerol monostearate or glycerol stearate can also be useful. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade. Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, etc., and mixtures thereof.

In various embodiments, the compounds and compositions of the present invention, or formulations thereof, do not substantially accumulate in the brain. In various embodiments, the compounds and compositions, or formulations thereof, deliver a physiological amount of present compound or composition to the periphery for at least about <NUM> hours, or at least about <NUM> hours, or at least about <NUM> hours, or at least about <NUM> hours, or at least about <NUM> hours, or at least about <NUM> hours, or at least about <NUM> hours. In various embodiments, the compounds and compositions, or formulations thereof, deliver a physiological amount of present compound or composition to the periphery for about <NUM> hours, or about <NUM> hours, or about <NUM> hours, or about <NUM> hours, or about <NUM> hours, or about <NUM> hours, or about <NUM> hours.

Further, the present compounds or compositions may find use as a combination therapy or co-formulation with one or more additional therapeutic agents. For example, such additional therapeutic agents can include an anti-bacterial agent, which includes, but is not limited to, cephalosporin antibiotics (e.g. cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, and ceftobiprole); fluoroquinolone antibiotics (e.g. cipro, Levaquin, floxin, tequin, avelox, and norflox); tetracycline antibiotics (e.g. tetracycline, minocycline, oxytetracycline, and doxycycline); penicillin antibiotics (e.g. amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, vancomycin, and methicillin); monobactam antibiotics (e.g. aztreonam); and carbapenem antibiotics (e.g. ertapenem, doripenem, imipenem/cilastatin, and meropenem). In some embodiments, the additional therapeutic agent is metronidazole (e.g. FLAGYL), fidaxomicin (e.g. DIFICID), or vancomycin (e.g. VANCOCIN), rifaximin, charcoal-based binders/adsorbents (e.g. DAV132), fecal bacteriotherapy, probiotic therapy (see, e.g., <NPL>). In some embodiments, the additional therapeutic agent is an antidiarrheal agent, which include, but are not limited to, DPP-IV inhibitors, natural opioids, such as tincture of opium, paregoric, and codeine, synthetic opioids, such as diphenoxylate, difenoxin and loperamide, bismuth subsalicylate, lanreotide, vapreotide and octreotide, motiln antagonists, COX2 inhibitors like celecoxib, glutamine, thalidomide and traditional antidiarrheal remedies, such as kaolin, pectin, berberine and muscarinic agents. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent such as steroidal anti-inflammatory agents or non-steroidal anti-inflammatory agents (NSAIDS). Steroids, particularly the adrenal corticosteroids and their synthetic analogues, are well known in the art.

Any compound or composition (and/or additional therapeutic agents) described herein can be administered by controlled-release or sustained-release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>. Such dosage forms can be useful for providing controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the agents described herein. The invention thus provides single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.

Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, stimulation by an appropriate wavelength of light, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.

In another embodiment, polymeric materials can be used (see <NPL>); <NPL>); <NPL>; see also<NPL>; <NPL>; <NPL>).

Administration of any compounds or compositions (and/or additional agents) described herein can, independently, be one to four times daily. Administration can be for the duration of one day or one month, two months, three months, six months, one year, two years, three years, and may even be for the life of the subject. Chronic, long-term administration will be indicated in many cases. The dosage may be administered as a single dose or divided into multiple doses. In general, the desired dosage should be administered at set intervals for a prolonged period, usually at least over several weeks or months, although longer periods of administration of several months or years or more may be needed.

The present compounds and compositions also find use in various therapeutic methods.

The present disclosure relates to method for treating or preventing a gastrointestinal disorder or condition, optionally selected from inflammatory bowel disease, irritable bowel syndrome, celiac disease, and an enteric infection, comprising administering the compound or composition described herein to a patient in need thereof. In some aspects, the present invention relates to the compound of the first aspect of the invention, or the pharmaceutical composition of the second aspect of the invention, for treating or preventing a gastrointestinal disorder or condition, optionally selected from inflammatory bowel disease, irritable bowel syndrome, celiac disease, and an enteric infection.

The present disclosure relates to a method for treating or preventing a functional GI disorder comprising administering the composition described herein to a patient in need thereof.

Illustrative gastrointestinal disorders or conditions include, but are not limited to, hyperproliferative diseases, for example, carcinomas (e.g., colorectal cancer); autoimmune and inflammatory bowel diseases (IBD), for example, Celiac's disease, Crohn's disease, and colitis (e.g., ulcerative colitis); irritable bowel syndrome; infectious diseases of the intestine, for example, C. difficile infection (CDI) and/or a C. difficile-associated disease, pseudomembranous colitis, amebiasis or intestinal tuberculosis; parasitic disorders, colonic polyps; cysts; diverticular disease (e.g., diverticulosis, diverticulitis, and diverticular bleeding); constipation; intestinal obstruction; malabsorption syndromes; rectal diseases; ulceration of the mucosa; intestinal dysbiosis (e.g., intestinal bacteria overgrowth); dyspepsia; gastroesophageal reflux disease; gastroparesis; nausea; vomiting; and diarrhea. Additional diseases, disorders and conditions which are suitable for treatment with the compositions and methods of the invention include those listed in Table <NUM> of <CIT>.

In some examples, the present disclosure provides methods for treating or preventing autoimmune and inflammatory bowel diseases (IBD), for example, Celiac's disease, Crohn's disease, and colitis (e.g., ulcerative colitis), comprising administering an effective amount of a pharmaceutical composition and/or formulation (and/or additional therapeutic agent) described herein to a subject or a patient need thereof.

In some examples, the present disclosure provides methods for treating or preventing irritable bowel syndrome (IBS), comprising administering an effective amount of a pharmaceutical composition and/or formulation (and/or additional therapeutic agent) described herein to a subject or a patient need thereof. In an example, the IBS is IBS with constipation (IBS-C). In an example, the IBS is IBS with diarrhea (IBS-D). In an example, the IBS is mixed IBS (IBS-M).

In some examples, methods of the disclosure are useful for treating constipation, dyspepsia, gastroesophageal reflux disease, gastroparesis, nausea, vomiting, diarrhea, and a diverticular disease (e.g., diverticulosis, diverticulitis, and diverticular bleeding).

The present disclosure relates to method for modulating a serotonin receptor in the GI tract, comprising administering the compound or composition described herein to a patient in need thereof.

The present disclosure relates to a method for treating or preventing a cardiopulmonary disorder comprising administering the composition described herein to a patient in need thereof. In some aspects, the present invention relates to the compound of the first aspect of the invention, or the pharmaceutical composition of the second aspect of the invention, for treating or preventing a cardiopulmonary disorder, preferably wherein the cardiopulmonary disorder is one or more of cardiac valvulopathy and pulmonary hypertension.

Illustrative cardiopulmonary disorders include cardiac valvulopathy and pulmonary hypertension. Cardiopulmonary disorders include right-sided and/or left-sided cardiac fibrosis, inclusive of cardiomyopathy and congestive heart failure. Also included are ventricular tachyarrhythmia, left ventricular (LV) dysfunction, and heart failure, as well as right ventricular failure (RVF) and left ventricular failure (LVF). A further cardiopulmonary disorder is heart valve disease, which includes left heart diseases (e.g. diseases of the aortic valve (e.g. aortic valve stenosis, aortic valve insufficiency, aortic valve incompetence, aortic valve regurgitation) and/or the mitral valve (e.g. mitral valve stenosis, mitral valve insufficiency, mitral valve incompetence, mitral valve regurgitation) and/or right heart diseases (e.g. diseases of the tricuspidvalve (e.g. tricuspid valve stenosis, tricuspid valve insufficiency, tricuspid valve incompetence, tricuspid valve regurgitation) and/or the pulmonary valve (e.g. pulmonary valve stenosis, pulmonary valve insufficiency, pulmonary valve incompetence, pulmonary valve regurgitation). Further, cardiopulmonary disorders are heart valve dysplasia; tetralogy of Fallot, Ebstein's anomaly, cardiomyopathies (including, for example, dilated cardiomyopathy, restrictive cardiomyopathy and hypertrophic cardiomyopathy), elevated heart rate, vasoconstriction, and heart failure.

In various embodiments, e.g. those pertaining to treating or preventing a cardiopulmonary disorder, combination therapy or co-formulation with an additional therapeutic agent may be provided. Illustrative additional therapeutic agents include: anticoagulents (e.g. dalteparin (FRAGMIN), danaparoid (ORGARAN), enoxaparin (LOVENOX), heparin, tinzaparin (INNOHEP), and warfarin (COUMADIN)); Antiplatelet Agents (e.g. aspirin, ticlopidine, clopidogrel, and dipyridamole); ACE Inhibitors (e.g. benazepril (LOTENSIN), captopril (CAPOTEN), enalapril (VASOTEC), fosinopril (MONOPRIL), lisinopril (PRINIVIL, ZESTRIL), moexipril (UNIVASC), perindopril (ACEON), quinapril (ACCUPRIL), ramipril (ALTACE) and, trandolapril (MAVIK)); Angiotensin II Receptor Blockers (or Inhibitors) (e.g. candesartan (ATACAND), eprosartan (TEVETEN), irbesartan (AVAPRO), losartan (COZAAR), telmisartan (MICARDIS) and, valsartan (DIOVAN)); beta-blockers (e.g. acebutolol (SECTRAL), atenolol (TENORMIN), betaxolol (KERLONE), bisoprolol/hydrochlorothiazide (ZIAC), bisoprolol (ZEBETA), carteolol (CARTROL), metoprolol (LOPRESSOR, TOPROL XL), nadolol (CORGARD), propranolol (INDERAL), sotalol (BETAPACE) and, timolol (BLOCADREN)); calcium channel blockers (e.g. amlodipine (NORVASC, LOTREL), bepridil (VASCOR), diltiazem (CARDIZEM, TIAZAC), felodipine (PLENDIL), nifedipine (ADALAT, PROCARDIA), nimodipine (NIMOTOP), nisoldipine (SULAR), and verapamil (CALAN, ISOPTIN, VERELAN); diuretics (e.g. amiloride (MIDAMOR), bumetanide (BUMEX), chlorothiazide (DIURIL), chlorthalidone (HYGROTON), furosemide (LASIX), hydrochlorothiazide (ESIDRIX, HYDRODIURIL), indapamide (LOZOL), and Spironolactone (ALDACTONE); vasodilators (e.g. isosorbide dinitrate (ISORDIL), nesiritide (NATRECOR), hydralazine (APRESOLINE), nitrates and minoxidil); digitalis preparations (e.g. lanoxin); and statins (e.g., atorvastatin, pravastatin, fluvastatin).

The term "acyl" means both substituents of the formula Rx-C(O)- , where Rx is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

The term "alkyl" means both "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. Cycloalkyls can be further substituted, e.g., with the substituents described above. An "alkylaryl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). In some embodiments, the alkyl group may have from <NUM> to <NUM> carbon atoms, e.g. about <NUM> carbon atom, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms. Illustrative alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl.

The terms "alkoxyalkyl," "polyaminoalkyl" and "thioalkoxyalkyl" refer to alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms. Illustrative alkoxy substituents include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy. In some embodiments, the alkoxy is a lower alkoxy (containing one to six carbon atoms). The alkoxy substituent is optionally substituted.

The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. In some embodiments, the "alkenyl" or "alkynyl" group may have from <NUM> to <NUM> carbon atoms, e.g. about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms, or about <NUM> carbon atoms.

Amino or "amine" substituents include those of the formula -N(Rb)<NUM>, where Rb is hydrogen, alkyl, (halo)alkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl heteroarylalkyl, or other substituent described herein. When -N(Rb)<NUM> has two Rb substituents other than hydrogen, they can be combined with the nitrogen atom to form a <NUM>-, <NUM>-, <NUM>- or <NUM>-membered ring. For example, -N(Rb)<NUM> is intended to include, for example, pyrrolidinyl and morpholinyl.

Amide or "amido" substituents include those of the formula -C(O)N(Ry)<NUM> or -NHC(O)Ry, where Ry is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, cycloalkyl, aryl, heteroaryl, or other substituent described herein. The Ry of -N(Ry)<NUM> of the amide may optionally be taken together with the nitrogen to which it is attached to form a <NUM>-, <NUM>-, <NUM>- or <NUM>-membered ring.

The term "aryl" as used herein, refers to the radical of aryl groups, including <NUM>- and <NUM>- membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles," "heteroaryls" or "heteroaromatics. " The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The terms "halogen" and "halo" designate fluoro, chloro, bromo or iodo. Thus, substituents include, without limitation, haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy.

The term "heteroaryl" means an aromatic heterocyclyl typically containing from <NUM> to <NUM> ring atoms. A heteroaryl may be a single ring, or two or more fused rings. Non-limiting examples of five-membered heteroaryls include imidazolyl; furanyl; thiophenyl (or thienyl or thiofuranyl); pyrazolyl; oxazolyl; isoxazolyl; thiazolyl; <NUM>,<NUM>,<NUM>-, <NUM>,<NUM>,<NUM>-, <NUM>,<NUM>,<NUM>-, and <NUM>,<NUM>,<NUM>-oxadiazolyl; and isothiazolyl. Non-limiting examples of six-membered heteroaryls include pyridinyl; pyrazinyl; pyrimidinyl; pyridazinyl; and <NUM>,<NUM>,<NUM>-, <NUM>,<NUM>,<NUM>-, and <NUM>,<NUM>,<NUM>-triazinyl. Non- limiting examples of <NUM>/<NUM>-membered fused ring heteroaryls include benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl. Non-limiting examples of <NUM>/<NUM>-membered fused ring heteroaryls include quinolinyl; isoquinolinyl; and benzoxazinyl (including cinnolinyl and quinazolinyl).

The terms "heterocyclic" or "heterocyclo" or "heterocyclyl" refer to a saturated (e.g., "heterocycloalkyl"), partially unsaturated (e.g., "heterocycloalkenyl" or "heterocycloalkynyl") or completely unsaturated (e.g., "heteroaryl") ring system typically containing from <NUM> to <NUM> ring atoms, where at least one of the ring atoms is a heteroatom (i.e., nitrogen, oxygen or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur. A heterocyclyl group can be linked to the parent molecular moiety via any substitutable carbon or nitrogen atom in the group, provided that a stable molecule results. A heterocyclyl may be, without limitation, a single ring, which typically contains from <NUM> to <NUM> ring atoms, from <NUM> to <NUM> ring atoms, from <NUM> to <NUM> ring atoms, or from <NUM> to <NUM> ring atoms. Non- limiting examples of single-ring heterocyclyls include furanyl, dihydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazoly, pyranyl, dihydropyranyl, pyridinyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazinyl, isoxazinyl, oxazolidinyl, isoxazolidinyl, oxathiazinyl, oxadiazinyl, morpholinyl, azepinyl, oxepinyl, thiepinyl, or diazepinyl. A heterocyclyl may also include, without limitation, two or more rings fused together, such as, for example, anthracene, naphthyridinyl, thiazolpyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, or pyridopyrimidinyl. A heterocyclyl may comprise one or more sulfur atoms as ring members; and in some cases, the sulfur atom(s) is oxidized to SO or SO<NUM>. The nitrogen heteroatom(s) in a heterocyclyl may or may not be quaternized, and may or may not be oxidized to N-oxide.

The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.

The term "optionally substituted" is intended to encompass groups that are unsubstituted or are substituted by other than hydrogen at one or more available positions, typically <NUM>, <NUM>, <NUM>, <NUM> or <NUM> positions, by one or more suitable groups (which may be the same or different). Such optional substituents include, the group substituents described above and for example, hydroxy, halogen, cyano, nitro, C<NUM>-C<NUM>alkyl, C<NUM>-C<NUM> alkenyl, C<NUM>-C<NUM>alkynyl, C<NUM>-C<NUM>alkoxy, C<NUM>-C<NUM>alkyl ether, C<NUM>-C<NUM>alkanone, C<NUM>-C<NUM>alkylthio, amino, mono- or di- (Cl-C<NUM>alkyl)amino, haloC<NUM>-C<NUM>alkyl, haloC<NUM>-C<NUM>alkoxy, C<NUM>-C<NUM>alkanoyl, C<NUM>-C<NUM>alkanoyloxy, C<NUM>-C<NUM>alkoxycarbonyl, -COOH, -CONH<NUM>, mono- or di-(C<NUM>-C<NUM>alkyl)aminocarbonyl, -SO<NUM>NH<NUM>, and/or mono or di(C|-C<NUM>alkyl)sulfonamido, as well as carbocyclic and heterocyclic groups. Optional substitution is also indicated by the phrase "substituted with from <NUM> to X substituents," where X is the maximum number of possible substituents. Certain optionally substituted groups are substituted with from <NUM> to <NUM>, <NUM> or <NUM> independently selected substituents (i.e., are unsubstituted or substituted with up to the recited maximum number of substituents).

"Substituted" means having substituents replacing an atom and includes one or more of halo, acyl, acyloxy, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, alkoxy, alkoxycarbonyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, and trimethylsilanyl, ether, ester, sulfide, disulfide, sulfonyl, sulfinyl, sulfonamidyl, sulfonate, sulfoxyl, phosphate ester, phosphine, borate ester, carbonyl, carboxylate, carbamate, amine, imide, and quinidine. Such substituents can also include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The term "sulfhydryl" or "thiol" means -SH.

The term "treat" or "treatment" means any degree of reduction of symptoms or causation of a disease or medical condition. The term "prevent" or "prevention" means any degree of avoiding the onset or acquisition of a disease or medical condition.

As used herein, "consisting essentially of" allows the inclusion of materials or steps that do not materially affect the basic and novel characteristics of the claim. Any recitation herein of the term "comprising" can be exchanged with "consisting essentially of" or "consisting of".

This invention is further illustrated by the following non-limiting examples.

Synthesis of compounds described herein is shown in Scheme <NUM>, which involves <NUM>-steps. Briefly, <NUM>-Br-tetralone (<NUM>), obtained by reacting <NUM>-tetralone with bromine/AlCl<NUM>, was reduced to give the corresponding alcohol (<NUM>) that was treated with pTSA to obtain the olefin (<NUM>) to obtain the epoxide (<NUM>), that was treated with pTSA to obtain key intermediate <NUM>-Br-<NUM>-tetralone (<NUM>). <NUM>-Br-<NUM>-tetralone can be reacted with a wide variety of commercially-available boronic acid derivatives (<NUM>), these organoboron when used in the Suzuki-Miyaura cross coupling reaction allow synthesis of the compounds described herein. Thus, in Scheme <NUM>, <NUM>-bromo-<NUM>-tetralone (<NUM>) was reacted with Tetrakis triphenylphosphine Pd [<NUM>], the mixture was degassed, and the <NUM>'-F- or <NUM>'-Cl-phenylboronic acid was added. The reaction mixture was stirred at <NUM> for <NUM> and then cooled to room temperature before adding H<NUM>O<NUM> to quench excess boronic acid to obtain the <NUM>-(<NUM>'-F- or <NUM>'-Cl)-phenyl-<NUM>-tetralones (<NUM>). Reductive amination with dimethylamine gave <NUM>-(<NUM>'[o]- F or CI)-phenyl-<NUM>-dimethylaminotetralin racemates (<NUM>), resolved by polysaccharide-based chiral stationary phase (CSP)-HPLC to obtain <NUM> each (2R) and (<NUM>)-o-F-PAT and -o-CI-<NUM>-PAT. Other compounds synthesized herein involve this general process.

In addition, the boronic acid derivatives in Chart <NUM> are available to synthesize the corresponding <NUM>-substituted-PAT analogs, according to Scheme <NUM>. Thus analogs are proposed with multiple substitutions to the <NUM>-phenyl moiety, as listed under Hydrogen and Halogen Binding Moieties in Chart <NUM>. Thus, racemic analogs will be synthesized and separated to yield (+)- and (-)-<NUM> (2R)-<NUM>-PAT analogs and/or (2R) and (<NUM>)-<NUM>-PAT analogs.

Any of the compounds described herein may be derivatized at an amino group at <NUM> position of the tetralin core via the reaction shown below:
<CHM>
<CHM>
Example <NUM>: (+)-<NUM>-FPT is Orally Active And Readily Crosses the Blood-Brain Barrier.

The compound (+)-<NUM>-FPT (<NUM>-(<NUM>'-fluorophenyl)-N,N-dimethyl-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydronaphthalen-<NUM>-amine) falls outside of Formula I as is lacks a positive charge on the nitrogen bearing R<NUM>, R<NUM>, and R<NUM>:
<CHM>.

Adult, male, C57BI/6J mice, approximately six months old, and treatment-naive for at least six weeks prior to testing, were injected subcutaneously with (+)-<NUM>-FPT (<NUM>/kg) and returned to their home cages. At <NUM>, <NUM>, or <NUM> later, mice were euthanized by rapid cervical dislocation and decapitation. Trunk blood was collected in pre-chilled, heparin-coated tubes. Brains were quickly excised and frozen in liquid nitrogen. Plasma was collected from blood after centrifugation for <NUM> at <NUM>,<NUM>. Whole brain samples were wrapped in foil, and brain and plasma samples were labeled and stored at -<NUM> until liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) assays were performed. Frozen brain samples were weighed and homogenized in phosphate buffered saline (PBS), pH <NUM>. After the first analysis, the extra brain homogenate was stored at -<NUM> until they were thawed for a second, more dilute, analysis. Plasma samples were used directly upon arrival. The proteins from each plasma sample and a portion of each brain homogenate were immediately precipitated with <NUM>:<NUM> methanol:acetonitrile (4x starting volume) and internal standard ((-)-MBP<NUM>) followed by centrifugation at <NUM>,<NUM> for <NUM> minutes at <NUM>. The resulting supernatants from each sample were dried under nitrogen. Each sample was reconstituted in methanol, vortexed, sonicated briefly, and centrifuged prior to LC-MS/MS analysis. Calibration curves were constructed from the ratios of the peak areas of <NUM>-FPT versus (-)-MBP in extracted standards made in mouse plasma or homogenized mouse brain.

LC-MS/MS analysis was performed using an Agilent <NUM> series HPLC and a Thermo Finnigan Quantum Ultra triple quad mass spectrometer. The mobile phases used were <NUM>% formic acid in water (A) and <NUM>% formic acid in methanol (B) in a <NUM> minute gradient. Samples of <NUM>µL each were injected onto a Phenomenex Gemini C18 column (<NUM> x <NUM>, <NUM>µ) with a C18 guard column. <NUM>-FPT and its internal standard ((-)-MBP) were ionized in ESI+ and detected in SRM mode. Internal standards were used for quantification of the compound level per g tissue or per µL plasma. Four mice were included per group, but plasma levels from one mouse were not detectable due to low volume of blood collected.

Unlike compounds of the present invention, (+)-<NUM>-FPT readily crosses the blood-brain barrier, as evidenced by detection of µg levels <NUM>, <NUM>, and <NUM> after systemic administration (Table <NUM>). Notably, levels of (+)-<NUM>-FPT were substantially lower in plasma relative to brain tissue as soon as <NUM> post-administration, indicating that (+)-<NUM>-FPT is rapidly cleared in the periphery. Meanwhile, the attenuating effects of (+)-<NUM>-FPT (<NUM>/kg) on the DOI HTR remained significant for up to <NUM> hrs. post-administration; at <NUM> hrs. post-administration, (+)-<NUM>-FPT did not block the DOI HTR.

Adult, male, C57BI/6J mice, approximately six months old, and treatment-naive for at least six weeks prior to testing, are injected sc with any of the compounds described above, bearing a positively charged amino group at the <NUM> position of the tetralin core (the "test compound") at a dose of about <NUM>/kg and returned to their home cages. At <NUM>, <NUM>, or <NUM> later, mice are euthanized by rapid cervical dislocation and decapitation. Trunk blood is collected in pre-chilled, heparin-coated tubes. Brains are quickly excised and frozen in liquid nitrogen. Plasma is collected from blood after centrifugation for <NUM> at <NUM>,<NUM>. Whole brain samples are wrapped in foil, and brain and plasma samples are labeled and stored at -<NUM> until liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) assays are performed.

Frozen brain samples are weighed and homogenized in phosphate buffered saline (PBS), pH <NUM>. After the first analysis, the extra brain homogenate is stored at -<NUM> until they are thawed for a second, more dilute, analysis. Plasma samples are used directly upon arrival. The proteins from each plasma sample and a portion of each brain homogenate are immediately precipitated with <NUM>:<NUM> methanol:acetonitrile (4x starting volume) and internal standard (e.g. (-)-MBP<NUM>) followed by centrifugation at <NUM>,<NUM> for <NUM> minutes at <NUM>. The resulting supernatants from each sample are dried under nitrogen. Each sample is reconstituted in methanol, vortexed, sonicated briefly, and centrifuged prior to LC-MS/MS analysis. Calibration curves are constructed from the ratios of the peak areas of test compound versus internal standard in extracted standards made in mouse plasma or homogenized mouse brain.

LC-MS/MS analysis is performed using an Agilent <NUM> series HPLC and a Thermo Finnigan Quantum Ultra triple quad mass spectrometer. The mobile phases used are <NUM>% formic acid in water (A) and <NUM>% formic acid in methanol (B) in a <NUM> minute gradient. Samples of <NUM>µL each are injected onto a Phenomenex Gemini C18 column (<NUM> x <NUM>, <NUM>µ) with a C18 guard column. The test compound and its internal standard ((-)-MBP) were ionized in ESI+ and detected in SRM mode. Internal standards are used for quantification of the test compound level per g tissue or per µL plasma.

The test compounds are not expected to accumulate in the brain and, rather, are expected to be more prevalent in the plasma.

Table <NUM> shows a group of <NUM>-PAT compounds that were synthesized and tested for their in vitro binding affinity to serotonin <NUM>-HT<NUM> receptors using human embryonic kidney <NUM> (HEK293) cells as described in <NPL>. The compounds are tertiary amines and available to bind <NUM>-HT<NUM> receptors both in the brain and in the periphery. Each of the compounds can be derivatized to a corresponding positively-charged quaternary amine, for example, by the addition of a third alkyl group, R<NUM>, to render it impermeable to the blood-brain barrier and specific for peripheral <NUM>-HT<NUM> receptors.

Claim 1:
An at least <NUM>% enantiomerically pure compound that is a <NUM>-HT receptor modulator having the structure of Formula (I):
<CHM>
or pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
each of R<NUM>, R<NUM>, and R<NUM> is independently an unsubstituted alkyl or may come together to form a heterocyclic ring,
each of R<NUM>, R<NUM>, and R<NUM> is independently hydrogen, unsubstituted alkyl, aryl, halo, nitro, amino, heteroaryl, cycloalkyl, heterocyclic, or alkoxy, and
R<NUM> is a phenyl, furan, or naphthyl ring ,said phenyl, furan, or naphthyl ring substituted with one or more unsubstituted alkyl, alkoxy, or halo substituents; and
wherein the compound does not substantially accumulate in the human brain.